Medical Radiology

Radiation Oncology Philip Rubin

L.W. Brady Louis S. Constine
H.-P. Heilmann
M. Molls Lawrence B. Marks
C. Nieder
Editors

ALERT – Adverse Late

Effects of Cancer Treatment
Volume 1: General Concepts and Specific Precepts

123
Medical Radiology
Radiation Oncology

Series Editors
Luther W. Brady
Hans-Peter Heilmann
Michael Molls
Carsten Nieder

For further volumes:

http://www.springer.com/series/4353
Associate Editors

Zeljko Vujaskovic, Ph.D., Professor of Radiation Oncology, Department of Radiation

Oncology, Duke University Medical Center, Box 3085, Durham, NC, 27710, USA

Kishan J. Pandya, MD, Professor Emeritus, School of Medicine and Dentistry, Uni-
versity of Rochester, 601 Elmwood Ave, Box HH67, Rochester, NY, 14620, USA

Advisory Editors

Yuhchyau Chen, MD, Ph.D., Department Chair and Richard Bell Professor, Director
of Clinical Investigation, Department of Radiation Oncology, Professor in Oncology,
James P. Wilmot Cancer Center, 601 Elmwood Ave, Box 647, Rochester, NY, 14642,
USA

Luis Felipe Fajardo, L-G, MD, Emeritus Professor of Pathology, Stanford University
School of Medicine, 4190 Cherry Oaks Place, Palo Alto, CA, 94306, USA

John Hansen, Ph.D., Professor of Neurobiology and Anatomy, and Associate Dean,
School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA

Managing Editor

Sisi Lisa Chen, Executive Coordinator of the Survivorship Advisory Committee, Edi-
torial Assistant, University of Rochester Medical Center, 601 Elmwood Ave, Box 647,
Rochester, NY, 14642, USA

Co-Managing Editor

Liyi Xie, MD, Department of Radiation Oncology, University of North Carolina,

Chapel Hill, NC, USA; Department of Radiation Oncology, Fudan University of
Shanghai Cancer Center, Shanghai, China

Assistant Managing Editor

Callise Wiley, Editorial Assistant to Dr. Philip Rubin, Oncoideas, Inc

Philip Rubin • Louis S. Constine
Lawrence B. Marks
Editors

ALERT – Adverse Late Effects

of Cancer Treatment
Volume 1: General Concepts and Specific
Precepts

123
Editors
Philip Rubin MD Lawrence B. Marks MD, FASTRO
Professor and Chair Emeritus Dr. Sidney K. Simon Distinguished Professor
Department of Radiation Oncology of Oncology Research, Professor and Chairman
Former Associate Director of the James. Department of Radiation Oncology
P. Wilmot Cancer Center, University University of North Carolina and Lineberger,
of Rochester Medical Center Comprehensive Cancer Center
Rochester, NY Chapel Hill, NC
USA USA

Louis S. Constine MD, FASTRO

The Philip Rubin Professor of Radiation
Oncology and Pediatrics, Vice Chair
Department of Radiation Oncology, James P.
Wilmot Cancer Center
University of Rochester Medical Center
Rochester, NY
USA

ISSN 0942-5373
ISBN 978-3-540-72313-4 ISBN 978-3-540-72314-1 (eBook)
DOI 10.1007/978-3-540-72314-1
Springer Heidelberg New York Dordrecht London

Library of Congress Control Number: 2013930143

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This volume recognizes our patients…
Cancer Survivors who have benefited from the
treatment and lived with its consequences
To save one life is to save the whole world
I dedicate this book to my long-time friend Mayer
Mitchell (Bubba), who recently succumbed to cancer
and the late effects of cancer therapy. Mayer’s life
epitomized the challenges of a cancer survivor. He
had stage IV Hodgkin’s disease, Breast cancer,
Prostate cancer, Urinary Bladder cancer, and Rectal
cancer. Each cured cancer was followed by a
radiation/chemotherapy-associated complication.
Nevertheless, he endured and, with his brother Abe,
built thousands of homes, shopping centers in five
southern states over five decades.
Philip Rubin

I dedicate this book to my many teachers and mentors.

My parents were both teachers in the NYC public
schools and I grew up with a strong sense of respect
for teachers. As I have always been drawn to the
physical sciences, I have particularly fond feelings
towards many instructors in math, chemistry, physics
and engineering. At the completion of my third year of
medical school at the University of Rochester (in New
York), I could not envision practicing in any one of the
core clinical specialties; I missed the quantitative
aspects of the physical sciences. While I was
contemplating a career change to become a math
teacher, my then girl friend (now wife) Caryn, who
was also a medical student at Rochester, said to me,
‘‘I heard a talk today from someone who is a radiation
oncologist, you should go talk to them, I think you
might like that field.’’ Serendipity. And she was right!
My subsequent visit to the radiation oncology
department started my [30 year relationship with Dr.
Rubin. As a student at Rochester, I have fond
memories of shadowing Dr. Rubin on Wednesday
afternoons. As I remember it, he used to see all of the
patients under treatment in his department each week.
So, the patients all had two ‘‘weekly checks’’; one with
their primary treating radiation oncologist, and a
second with Dr. Rubin. He used to take great pride in
explaining the rationale for the radiation treatment,
and always emphasized the need to understand the
risks of the radiation treatment when choosing fields
and doses.
Over the next three decades, Dr. Rubin proved to be a
great mentor, role model, and friend. He has
supported and nurtured my interests in radiation-
induced normal tissue injury; e.g. getting me involved
with his LENT-SOMA initiatives and helping me to
formulate ideas and projects. Helping to write a book
with Dr. Rubin, who has helped our field understand
so much about the effects of radiation, has been and
honor. Thank you Phil. Thanks also to Sandy Cons-
tine- a long-time friend and colleague. Sandy has
made tremendous contributions to better understand
the effects of radiation, particularly in children. Your
dedication to ameliorating pediatric late effects is
inspiring. I am glad that we were able to help Phil
with this book- published approximately 35 years
after Phil’s landmark contribution Clinical Radiation
Pathology (published with George Casarett). This
book proved to be a labor of love for us all.
I am thankful to all who contributed to this book; the
authors, editors, administrative assistants, and our
publisher. Your efforts and expertise are much
appreciated. Thank you to my many excellent teachers
and mentors throughout school, including college
(Cooper Union), medical school (University of
Rochester), internship (Sinai Hospital of Baltimore)
and residency (Mass General). Thanks also to my
many colleagues at UNC and Duke for providing a
fertile and productive environment, and for serving as
teachers and mentors. Special thanks to Drs. Leonard
R. Prosnitz, Edward C. Halperin and Gustavo S.
Montana for their mentorship and guidance.
Thank you to my family for their support: to my
parents (Hyman and Helen Marks), to my wife Caryn-
whose love, caring and encouragement are ongoing
sources of strength, and to our three children (Noah,
Samuel and Benjamin).
Lawrence B. Marks

‘‘For the person fighting cancer, each day is precious

and must be faced with courage. For the physician,
each patient is an inspiration. For the survivor of
cancer, the world is full and each day is a celebra-
tion.’’ I wrote these words many years ago, and
continue to reflect on the many sources of inspiration
that grace my life. I feel tremendous gratitude for my
good fortune to work in a field and live a life that
refreshes my spirit on a daily basis. This book honors
the memory of our patients who did not survive
cancer, but also those who have faced mortality but
found a way to embrace all that life offers. A friend of
mine once said: ‘‘That is the essence of surviving
cancer—making your life a passionate statement
instead of just marking time.’’
I am surrounded by individuals who have helped me
understand the wonder of my life, and afforded me the
opportunity to contribute what I can. Philip Rubin, a
giant in our field, towers above all others in my
professional life. On a snowy night in Rochester 32
years ago he persuaded me to join his faculty by
clearly outlining my future…one in which he would
work with me to fulfill whatever personal destiny I
might have. He defined the trait that I value above all
others, curiosity. He combined that with enthusiasm
and creativity, and a drive to benefit others. I have
strived to emulate this great man. I have been
fortunate to have other mentors who also demon-
strated these qualities, notably John Felstiner who
was my English teacher at Stanford, Leigh Thompson
who was a professor at The Johns Hopkins medical
school, Archie Bleyer during my fellowship in Pedi-
atric Oncology at the University of Washington,
Sarah Donaldson during my residency in radiation
oncology at Stanford, and Edward Halperin and
Larry Marks who have been friends and colleagues
during many of these years. However, I am also
appreciative of the many young physicians, nurses,
social workers, and others who are focused on
improving the lives of cancer patients and enable me
to do my job.
My personal life has been graced by the lady who I
met 42 years ago, and then married 41 years ago.
Sally has a spirit of giving to others that cannot be
extinguished, and on a daily basis rekindles my flame.
The joy that we both receive from our remarkable
children, Alysia and Josh, fills us and affirms the
relevance of our lives. For me, they demonstrate the
gifts that life affords, and foster my dedication to
provide my patients with the opportunity to live their
lives as fully as possible.
Louis S. Constine
Foreword

The publication in 1968 of the book by Rubin and Casarett entitled Clinical Radiation
Pathology, in Volumes I and II, represented a hallmark statement regarding the late
effects related to radiation therapy. Since that time, there has been no significant com-
prehensive publication dealing with early and late effects in normal tissues from all
forms of cancer treatment.
The new text by Rubin and his co-workers comprehensively documents contempo-
rary understanding of the adverse late effects of cancer treatment in a coherent, multi-
disciplinary approach related to the care of cancer survivors. All major organs are
affected by the treatment program, whether it be radiation, chemotherapy, or surgical
treatment, and these impacts must be taken into consideration in any discussion on what
might be the most appropriate treatment in cancer management. Modern cancer
treatment is clearly based on safe intensification of radiation therapy, chemotherapy,
and biologic modifiers. Not only has this resulted in a significant general increase in
survivorship from cancer to 64 % overall, but the survival rate is considerably higher for
selected malignancies, such as 87 % for breast cancer and 80 % for childhood cancers.
Malignancies resistant to therapy have necessitated the utilization of aggressive treat-
ment approaches associated with improvement in survivorship but also with increased
risk of normal tissue complications. Late effects can occur years after the cessation of the
treatment regimen, tending to arise earlier with radiation therapy than with chemo-
therapy. The present text, reflecting more recent publications, offers landmark state-
ments with regard to the potential for such effects, the general concepts and principles
relating to their development, and the dynamic interplay among molecular cytologic and
histopathologic events. There is now much greater awareness that modern cancer
treatment leads to not only physiologic and metabolic abnormalities, but also clinical
manifestations that dictate the need for innovative new aggressive programs of
management.
Without question the present text represents a dramatic step forward from the ori-
ginal Rubin/Casarett text, with more emphasis on the contemporary situations that each
oncologist faces in their practice on a day-to-day basis. The efforts on the part of Rubin
and his colleagues have borne fruit. This new book provides readers with significant
information about late effects and how they might be managed. It is recommended for
inclusion on the shelf of every oncologist and should be at the forefront of practitioners’
minds when considering the various treatment regimens.

Luther W. Brady, MD
Hans-Peter Heilmann, MD
Michael Molls, MD
Carsten Nieder, MD

ix
Preface

Concept of the Biocontinuum

‘‘The past is the beginning of the beginning’’

H. G Wells

In 1968, Casarett and Rubin proposed a paradigm to formally link acute and late effects
as a biophysiopathologic and clinical continuum. Over the past four decades, numerous
laboratory and clinical studies have provided additional insights to refine this paradigm.
The first section of this book reviews the general concepts that frame the initial para-
digm, and a series of paradigm shifts. These introductory chapters provide the foun-
dation to the Organ/Site-specific chapters that form the core of this book.
The introductory section:
• ‘‘Prologue: Surviving Cancer: SEER Statistics’’: Biocontinuum of the radiation-
induced pathophysiology was conceptualized as a course of events beginning with
acute injury, followed by recovery, and then arteriocapillary fibrosis that leads to cell
senescence (Casarett paradigm). These concepts of the waxing and waning clinical
expressions of organ damage were based on observations from the beginning of the
supervoltage era that are translated into greater depth doses and increased organ
injury. The natural history of this organ damage was carefully traced, and mecha-
nisms were postulated. (Rubin paradigm).
• ‘‘Biocontinuum of the Pathophysiology Paradigm’’: The importance of the micro-
vasculature and the vascular endothelial cells as the most radiosensitive cell among the
various elements of the mesenchyme was carefully studied in the laboratory and in
pathologic specimens. For many organs, the late effects appeared to be mediated
through injury of the microcirculation reinforcing Casarett’s observations (Fajardo
Paradigm shift). The importance of the interaction of various organs to both radiation
and chemotherapy during a prolonged course of multimodal treatment is embodied in
the multiorgan domino effect and host effects. (Sutherland and Seimann Paradigm
Shift).
• ‘‘Biophysiopathology of the Microvasculature and Microcirculation’’: A series of in
vivo/in vitro experiments demonstrated a perpetual cytokine cascade following radi-
ation that fortified Casarett’s ‘‘there is latent period histologically’’ after radiation or
other cytotoxic treatment. The release of proinflammatory chemokines and cytokines
(ILI, IL6, and TNF) simultaneously with profibrotic cytokines (TGFb and RDGF)
indicated that the biocontinuum, once initiated, continues over time. The incremental
persistence and interrelationships of these families of cytokines after chemotherapy
and surgical wound healing provides a commonality to explain increased toxicity.
(Finklestein and Williams Paradigm Shift).

xi
xii Preface

• ‘‘Molecular Mechanisms of Radiation Induced Injury’’: An improved understanding

of the biological processes that underlie the evolving clinical events affords the
opportunity to target specific mediators of these processes in order to mitigate (i.e.,
reduce or prevent) subsequent late effects.
• ‘‘Biodetection and Biointervention: Cytokine Pathways as a Rationale for Anti-
cytokine Interventions Post-Radiation’’: Advances in Imaging (e.g., CT, SPECT,
MRI, and MRS) were exploited as a powerful means to objectively characterize
regional organ injury in a variety of tissues (e.g., lung, heart, liver, brain, and parotid).
By relating regional dose to the degree of regional injury, dose–response relationships
for regional injury can be defined. These dose–response relationships are largely
volume independent, and thus might be taken as an objective measure of inherent
radiation sensitivity. For a parallel organ, the sum of regional injuries might be
expected to be related to the degree of global injury (Marks paradigm). The available
data for the lung does suggest such a relationship, albeit weak.
• ‘‘Quantitative/Objective Analyses of RT-Induced Late Normal Tissue Injury Using
Functional Imaging’’: Many systems have evolved for grading the adverse effects of
cancer treatment. In 1995 Rubin, Constine, and colleagues developed the SOMA-
LENT scoring system. This approach systematically and objectively distinguished the
subjective, objective, management-based, and analytical-based components of scoring
treatment-related organ injury. A new common toxicity criteria sponsored by all
cancer disciplines and the NCI evolved into a single uniform system merging acute
and late effects. It applied to all modalities a grading dictionary of common terms to
measure toxicity, i.e., CTC version 3.0. (Rubin and Trotti Paradigm Shift).
• ‘‘Biograding of Normal Tissue TNM Toxicity Taxonomy: Scoring the Adverse Effects
of Cancer Treatment’’: The link between radiation exposure to a particular organ and
the clinical manifestation of injury may be complex. It depends on several obvious
factors such as the inherent sensitivity of the target cells and the volume of the organ
irradiated (e.g., parameters from the DVH). Less obvious, but equally important,
factors include the architecture of the organ (series vs. parallel), the ‘‘size/structure’’ of
the organ’s functional subunits, and the distribution of function within the organ
(homogeneous vs. heterogeneous). Further, some clinical endpoints reflect focal injury
to an organ; while others reflect global organ injury, and some endpoints may be
affected by injury to several organs (i.e., endpoints may not be specific to a particular
organ). Milano, Rubin, and Marks review the impact of these various factors, and
how they interact with each other, on one’s ability to relate DVHs to clinical out-
comes. They also review and compare prior attempts to summarize the relationship
between dose/volume and clinical outcomes. (Byfield and Marks Paradigm Shift)
• ‘‘Understanding and Predicting Radiation-Associated Normal Tissue Injury: A
Global and Historical Perspective’’: A variety of chemotherapeutic agents, and
newer biological agents, may both directly affect target organs, and also influence the
impact of radiation on many organs. This is meticulously explored by Kishan and
Fung.
• ‘‘Biotoxicity of Chemotherapy’’: Patients treated with cytotoxic therapy are at risk for
a multiplicity of long-term side effects. Systematic strategies for post-treatment sur-
veillance are often available for survivors of pediatric cancer, but are largely lacking
for adult survivors. Ng and Hudson review the surveillance strategies that have been
suggested, and make some recommendations where well-accepted follow-up recom-
mendations do not exist.
Preface xiii

• ‘‘BioSurveillance and Longitudinal Lifelong Guidelines’’: Children appear to be at

particular risk for treatment-related late effects. This heightened sensitivity appears to
be related to their relatively rapid cellular kinetics (i.e., more mitotic activity than in
adults). Interorgan variations in sensitivity might be related to variations in the cel-
lular kinetics between the different organs. Organ ‘‘growth’’ might reflect hypertrophy,
proliferation, and/or stromal accumulation. In children, therapies might also reduce
their mitotic potential thereby leading to late effects. (Constine Paradigm Shift). The
concept of aging/senescence is portrayed as the loss of ‘‘mitotic potential’’ over time.
Numerous radiation studies have verified this concept and the loss of cell renewal
capacity after chemotherapy (established by exposing mice to busulfan and uncov-
ering a loss in bone marrow renewal capacity). (Botnik and Hellman Paradigm Shift)
• ‘‘BioPediatric Complexities of Growth and Development’’: Genetic and epigenetic
factors that might influence the sensitivity to cytotoxic therapies are reviewed. This is
an area of increasingly active investigation.
The Organ/Site-specific section
• This section comprises 26 chapters. Each of these is organized in a relatively uniform
manner. Where practical, the site-specific chapters share common figures and tables,
and include the following sections:
• Literature Landmarks and Milestones that have contributed to understanding adverse
acute/late effects. There will be more numerous citations in the bibliography
• Anatomy section illustrations are based on ‘‘Tillman’s Anatomy Atlas’’ (Springer) and
each organ’s macrostructure is described as parallel (often solid) or serial (often
hollow) structures, and provide a basis for defining the anatomic/physiologic func-
tional subunits.
• Histology section defines the normal tissue’s microarchitecture often illustrated uti-
lizing ‘‘Zhang’s Histology Atlas’’ (Springer); the parenchymal cell’s mitotic potential
will be notated with Casarett, Cowdry Schema and Relate to cell’s radiosensitivity to
insult by radiation.
• Physiology section enhances the understanding of the functional subunit and provides
parameters and metrics to assess toxicity.
• Biology section describes the molecular events within the normal tissue’s cells (e.g.,
parenchymal, endothelial, macrophageal/lymphocyte, and interstitial stromal fibro-
blasts), and the associated cytokine cascade induced by therapies.
• Pathophysiology section includes histopathologic illustrations of acute/late effects in
the normal tissue.
• Clinical Syndromes section provides an overview of clinical issues including items such
as means of detection, differential diagnoses, risk factors, comorbidities, and man-
agement. Tables from CTC V3.0 and LENT-SOMA will tabulate symptoms and signs
and the grading of treatment toxicity.
• Imaging section will provide illustrations of acute/late events as seen on diagnostic
images (e.g., CT, SPECT, or MRI).
• Endoscopy and Laboratory tests of function are discussed and correlated with treat-
ment-related injury as well.
• Radiation tolerance sections summarize the dose/volume/outcome data and highlight
typical Dose/Time and Dose/Volume limits commonly used clinically. The predictive
ability of measurements such as Mean Dose, V20, and V40 or equivalents is discussed.
xiv Preface

• Chemotherapy agents are tabulated, along with their associated toxicity, and specific
anatomic/physiologic features. The interactions between Radiation and Chemother-
apy (and surgery where applicable) in causing toxicity are reviewed.
• Mitigators, preventive agents, and Interventions are described.
• Future Directions and Special Topics section addresses unique aspects for the specific
site being addressed with prospects for future clinical investigational studies and
laboratory research.
• Literature Landmarks and Milestones that have contributed to understanding adverse
acute/late effects.
• Bibliography provides a selected list of recommended reading (*).
This book represents the most-recent attempt of the authors to summarize/categorize/
understand LENT (late effects of normal tissues) over the last several decades:
1. Rubin & Casarett: Clinical Radiation Pathology, 1968
2. Rubin & Bartelink et al: LENT SOMA IJROBP, 1995
3. Trotti & Rubin et al: NCI common toxicity criteria, CTC version 3, incorporated
adverse late effects, and subsequent updates
4. QUANTEC, 2010
5. Rubin, Constine, Marks: ALERT, 2013
Dr. Marks is supported by NCI Grant CA69579

Philip Rubin
Louis S. Constine
Lawrence B. Marks
Acknowledgements

The editors are grateful for the tremendous effort of Lisa Chen, our managing editor.
She indeed was the glue that held all the pieces of this effort together. She nurtured the
elements through their gestation and now its birth.
Global Acknowledgement
The editors sought to create a comprehensive book covering a wide array of infor-
mation. As such, we relied heavily on prior works addressing similar topics, including
many works that we helped to create. Portions of this book were adopted, with per-
mission, from the following sources:
Special Issue of the Int J Radiat Oncol Biol and Phys from March 30, 1995 dedicated
to the SOMA (subjective, objective, management, analytic) system to assess Late Effects
of Normal Tissues (LENT). This initiative aimed to better standardize the manner in
which normal tissue effects are quantitatively scored.
Special Issue of the Int J Radiat Oncol Biol and Phys from March 1, 2010 dedicated
to QUANTEC (quantitative Analysis of normal tissue effects in the clinic). This ini-
tiative aimed to summarize the available dose/volume/outcome data for normal tissue
effects.
Rubin and Casarett’s textbook, Radiation Pathology, from 1968. This book offered a
comprehensive summary of the effects of radiation on normal tissues.
Cindy L. Schwartz (Editor), Wendy L. Hobbie (Editor), Louis S. Constine (Editor),
& Kathleen S. Ruccione (Editor). Survivors of Childhood and Adolescent Cancer: A
Multidisciplinary Approach (Pediatric Oncology) 2nd ed. Springer-Verlag Berlin Hei-
delberg New York: 2005.
Luis Fajardo’s textbook, Radiation Pathology, from 2001. Fajardo, L, Berthrong M,
Anderson R (2001). Radiation Pathology. Oxford University Press, New York.
Tillman, B.N., & Elbermani, W, ed. Atlas of Human Anatomy, Clinical Edition. 1st
ed. New York: Mud Puddle Books Inc.; 2007.
Zhang, Shu-Xin. An Atlas of Histology. New York: Springer-Verlag Inc.; 1999.
Updated and Supplemental information
Interested readers are encouraged to view additional information from other sources
including:
Common Terminology Criteria for Adverse Events (CTCAE) from the U.S.
Department Of Health And Human Services (National Institutes of Health and
National Cancer Institute). This report provides a grading system for the common
toxicities. It is updated periodically with the last update, version 4.03, published June 14,
2010. Available at http://evs.nci.nih.gov/ftp1/CTCAE/About.html.

xv
Contents

Prologue: Surviving Cancer: SEER Statistics . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Craig C. Earle, Lois B. Travis, and Louis S. Constine

Biocontinuum of the Pathophysiology Paradigm . . . . . . . . . . . . . . . . . . . . . . . . 9

Philip Rubin, and George Casarett

Biophysiopathology of the Microvasculature and Microcirculation . . . . . . . . . . 27

Philip Rubin, and Luis Fajardo

Molecular Mechanisms of Radiation Induced Injury. . . . . . . . . . . . . . . . . . . . . 41

Isabel L. Jackson, Phil Rubin, Caroline Hadley, and Zeljko Vujaskovic

Biodetection and Biointervention: Cytokine Pathways as a Rationale

for Anti-Cytokine Interventions Post-Radiation . . . . . . . . . . . . . . . . . . . . . . . . 53
Paul R. Graves, Isabel Jackson, Mitchell S. Anscher,
Ross Mikkelsen, and Zeljko Vujaskovic

Quantitative/Objective Analyses of RT-Induced Late Normal Tissue

Injury Using Functional Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Jiho Nam, Mike E. Robbins, and Lawrence B. Marks

Biograding of Normal Tissue TNM Toxicity Taxonomy: Scoring the Adverse

Effects of Cancer Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Andy M. Trotti, and Philip Rubin

Understanding and Predicting Radiation-Associated Normal Tissue Injury:

A Global and Historical Perspective. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Michael T. Milano, Philip Rubin, and Lawrence B. Marks

Biotoxicity of Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

Chunkit Fung, and Kishan J. Pandya

BioSurveillance and Longitudinal Lifelong Guidelines . . . . . . . . . . . . . . . . . . . 153

Andrea K. Ng, and Melissa M. Hudson

BioPediatric Complexities of Growth and Development . . . . . . . . . . . . . . . . . . 171

Arnold C. Paulino, Sughosh Dhakal, and Louis S. Constine

BioGenetic and Host Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

Barry S. Rosenstein

xvii
xviii Contents

Bioengineering of Irradiated Normal Tissues by Bone Marrow Stem Cells . . . . 191

Joel S. Greenberger, and Michael W. Epperly

Radiotherapy-Induced Carcinogenesis and Leukemogenesis: Mechanisms

and Quantitative Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
David J. Brenner, Igor Shuryak, and Rainer K. Sachs

The Bioepidemiology of MultiplePrimary Cancers . . . . . . . . . . . . . . . . . . . . . . 227

Lois B. Travis, and Andrea K. Ng

Radiation-Related Second Primary Cancers: Clinical Perspectives . . . . . . . . . . 241

David C. Hodgson, Andrea Ng, and Lois B. Travis

The Psychosocial and Functional Impact of Radiation Therapy. . . . . . . . . . . . . 257

Jason Q. Purnell, Karen Mustian, Pascal Jean-Pierre, Oxana Palesh,
Luke J. Peppone, Supriya G. Mohile, Tom V. Darling, and Gary R. Morrow

Nursing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
Sheila Judge Santacroce, and Madelyn Rubin

Economic Consequences of Late Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

Andre Konski

Radiological and Nuclear Terrorism: Relevance to the Radiation

Oncology and Biology Communities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
C. Norman Coleman, Nathaniel Hafer, Bert Maidment, Ronald Manning,
Pat Prasanna, and Paul Okunieff
Contributors

Mitchell S. Anscher Department of Radiation Oncology, Virginia Commonwealth

University School of Medicine, Richmond, VA, USA
David J. Brenner Center for Radiological Research, Columbia University Medical
Center, New York, NY, USA
George Casarett Department of Radiation Oncology, University of Rochester School
of Medicine and Dentistry, Rochester, NY, USA
C. Norman Coleman Department of Health and Human Services (HHS), Office of the
Assistant Secretary for Preparedness and Response (ASPR), Washington, USA
Louis S. Constine The Philip Rubin Professor of Radiation Oncology and Pediatrics,
Vice ChairDirector, the Judy DiMarzo Cancer Survivorship Program Department of
Radiation Oncology, University of Rochester Medical Center, Rochester, NY, USA
Tom V. Darling Department of Kinesiology and Physical Education, Valdosta State
University, Valdosta, GA, USA
Sughosh Dhakal Radiation Oncology, Department of Radiation Oncology, University
of Rochester School of Medicine and Dentistry, Rochester, NY, USA
Craig C. Earle Department of Medical Oncology, Dana-Farber Cancer Institute,
Boston, MA, USA
Michael W. Epperly Department of Radiation Oncology, University of Pittsburgh
Cancer Institute, Pittsburgh, PA, USA
Luis Fajardo Stanford Medical School, Palo Alto, CA, USA
Chunkit Fung James P Wilmot Cancer Center, University of Rochester Medical Cen-
ter, Rochester, USA
Paul R. Graves Department of Radiation Oncology, New York Methodist Hospital,
Brooklyn, NY, USA
Joel S. Greenberger Department of Radiation Oncology, University of Pittsburgh
Cancer Institute, Pittsburgh, PA, USA
Caroline Hadley Baylor University School of Medicine, Houston, Texas, USA
Philip Rubin Professor and Chair Emeritus Department of Radiation Oncology,
University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

xix
xx Contributors

Nathaniel Hafer National Institutes of Health (NIH), National Institute of Allergy and
Infectious Diseases (NIAID), Bethesda, USA; The American Association for the
Advancement of Science (AAAS) Science and Technology Policy Fellow, Washington,
USA
David C. Hodgson Department of Radiation Oncology, Princess Margaret Hospital,
University of Toronto, Toronto, ON, Canada
Melissa M. Hudson Cancer Survivorship Division, St. Jude Children’s Research
Hospital, Memphis, TN, USA
Isabel L. Jackson Department of Radiation Oncology, University of Maryland Medical
Center, Greenbaum Cancer Center, Baltimore, MD, USA
Pascal Jean-Pierre Department of Psychology, University of Notre Dame, Notre
Dame, IN, USA
Andre Konski Department of Radiation Oncology, Wayne State University School of
Medicine Barbara Ann Karmanos Cancer Center, Detroit, Michigan, USA
Bert Maidment National Institutes of Health (NIH), National Institute of Allergy and
Infectious Diseases (NIAID), Bethesda, USA
Ronald Manning ASPR, Biomedical Advanced Research and Development Authority
(BARDA), Washington, USA
Lawrence B. Marks Department of Radiation Oncology, Lineberger Cancer Center,
University of North Carolina, Chapel Hill, NC, USA
Ross Mikkelsen Department of Radiation Oncology, Virginia Commonwealth
University School of Medicine, Richmond, VA, USA
Michael T. Milano Department of Radiation Oncology, University of Rochester School
of Medicine and Dentistry, Rochester, NY, USA
Supriya G. Mohile Department of Medical Hematology/Oncology, Rochester, NY,
USA
Gary R. Morrow Departments of Radiation Oncology & Psychiatry, Director
University of Rochester Cancer Center Community Clinical Oncology Program
Research Base, Rochester, NY, USA
Karen Mustian Departments of Radiation Oncology and Community and Preventive
Medicine, University of Rochester Medical Center, Rochester, NY, USA
Jiho Nam Department of Radiation Oncology, University of North Carolina at Chapel
Hill Campus, Chapel Hill, NC, USA; Department of Radiation Oncology, Pusan
National University, Yangsan, South Korea
Andrea K. Ng Department of Radiation Oncology, Harvard Medical School, Brigham
and Women’s Hospital, Dana-Farber Cancer Institute, Boston, MA, USA
Paul Okunieff Department of Radiation Oncology, University of Florida Shands
Cancer Center, Gainesville, USA
Oxana Palesh Department of Psychiatry & Behavioral Sciences, Stanford School of
Medicine, Stanford, CA, USA
Kishan J. Pandya Department of Radiation Oncology, Former Associate Director of
the James. P. Wilmot Cancer Center, University of Rochester Medical Center,
Rochester, NY, USA
Contributors xxi

Arnold C. Paulino Department of Radiation Oncology, The Methodist Hospital,

Houston, TX, USA
Luke J. Peppone Department of Kinesiology and Physical Education, Valdosta State
University, Valdosta, GA, USA
Pat Prasanna Division of Cancer Treatment and Diagnosis (DCTD)/Radiation
Research Program (RRP), National Cancer Institute (NCI), Bethesda, USA
Jason Q. Purnell The Brown School/Institute for Public Health, Washington Univer-
sity in St. Louis, St. Louis, MO, USA
Mike E. Robbins Department of Radiation Oncology, Wake Forest School of Medi-
cine, Brain Tumor Center of Excellence, Winston-Salem, NC, USA
Barry S. Rosenstein Radiation Oncology, Dermatology and Community and Pre-
ventive Medicine, Mount Sinai School of Medicine, NYU School of Medicine, New
York, NY, USA
Madelyn Rubin Yale University School of Nursing, New Haven, CT, USA
Rainer K. Sachs Departments of Mathematics and Physics, University of California,
Berkeley, CA, USA
Sheila Judge Santacroce Yale University School of Nursing, New Haven, CT, USA
Igor Shuryak Center for Radiological Research, Columbia University Medical Center,
New York, NY, USA
Lois B. Travis Department of Radiation Oncology, University of Rochester, James P.
Wilmot Cancer Center, Rochester, NY, USA
Andy M. Trotti H. Lee Moffit Cancer Center Research Institute, Tampa, FL, USA
Zeljko Vujaskovic Department of Radiation Oncology, University of Maryland
Medical Center, Greenbaum Cancer Center, Baltimore, MD, USA
Introduction

Our country formally declared war on cancer four decades ago. While many skirmishes have
been won, the battle rages on. Far too many patients still succumb to cancer. Nevertheless, an
increasing number of patients are successfully treated, and the population of cancer survivors
is increasing. An estimated 13.7 million Americans (almost 4 % of the United States
population) were living with a history of cancer on January 1, 2012. By January 1, 2022 that
number is expected to increase to nearly 18 million (Siegel et al. 2012). Overall,
approximately 65 % of adults will survive their malignancy, and this is much higher for
selected cancers such as breast and the lymphomas.
Living beyond cancer should be cause for celebration. However, cancer survivors are
vulnerable to the late effects of their therapy. They have complicated needs including
physical problems, financial obstacles, and mountains of emotions that must be addressed.
All of these hurdles can compromise the quality of life of cancer survivors and their family.
The modern era of cancer therapy is predicated on the safe intensification of surgery,
radiation, chemotherapy, and biologic adjuvants. Malignancies resistant to therapy have
demanded an aggressive treatment approach that often resides on the edge of normal tissue
tolerance, or even exceeds tolerance to some ‘‘acceptable’’ degree. Clearly, the potential to
ameliorate or prevent such normal tissue damage, or to manage and rehabilitate affected
patients, requires an understanding of tissue tolerance to therapy. Because ‘‘late effects’’ can
manifest months or years after cessation of treatment, therapeutic decisions intended to
obviate such effects can be based only on the probability, not the certainty, that such effects
will develop. In making such decisions, the balance between efficacy and potential for
toxicity should be considered and may be influenced by host-, disease-, and treatment-related
risk factors. The determination of the frequency and pathogenesis of late effects is difficult for
several reasons: (a) patients must survive long enough for damage to develop, (b) the number
of patients both affected and unaffected by therapy must be known, and (c) the latent period
to the manifestation of damage compromises discernment of the responsible component of
multimodality therapy. Further complicating our understanding of organ tolerance to therapy
is that tumor and host factors interact with therapy in the causation of late effects.
This book represents a monumental effort by numerous experts on the adverse
consequences of radiation and chemotherapy. It was inspired by our patients, both those
fortunate enough to have survived, but also those who did not. For our survivors, it is our
responsibility to understand, mitigate, treat, and prevent their ‘‘late effects.’’ However, this
book was also inspired by our mentor, Philip Rubin. With George Casarett (Rubin and
Casarett 1968), he pioneered the field of radiation-associated normal tissue damage. At a time
when many radiation oncologists were satisfied to be effectively combating cancer, Phil
Rubin recognized that the quality of survival after cancer was paramount. He was driven to
teach his colleagues and emerging oncologists the critical need to appreciate normal tissue
toxicity and the pathophysiology by which it evolved. At the University of Rochester, he
successfully obtained a succession of program project grants to study normal tissue toxicity.
It has been his lifelong goal to educate future generations of oncologists about the power and
also the consequences of cancer therapy. His motto was always: ‘‘there is no free lunch.’’

xxiii
xxiv Introduction

Finally, he encouraged numerous protégé to follow in his footsteps. His inspiration to

oncologists, pathologists, and biologists throughout the world has allowed for the safe
treatment of an uncountable number of patients.

Louis S. Constine, MD, FASTRO

Lawrence B. Marks, MD, FASTRO

References

Siegel R, DeSantis C, Virgo K et al (2012) Cancer treatment and survivorship statistics. CA

Cancer J Clin 62:220–231
Rubin P, Casarett G (1968) Clinical radiation pathology, vol 1 and 2. WB Saunders,
Philadelphia
 Prologue: Surviving Cancer: SEER Statistics

Craig C. Earle, Lois B. Travis, and Louis S. Constine

Contents Abstract

1 Introduction.......................................................................... 1 • The number of cancer survivors is increasing rapidly

2 Statistics ................................................................................ 2 because of a combination of demographic forces, public
health success, and improving medical treatments.
3 The Oncology Workforce ................................................... 3
• Projections are that the oncology workforce will be
4 Survivorship Care Planning............................................... 5 unable to meet the demand for cancer care in coming
5 Conclusion ............................................................................ 6 decades.
References...................................................................................... 6
• Survivorship care planning can improve the quality of
care and open up the possibility for survivorship care to
be delivered by an array of health care providers.

1 Introduction

There are numerous definitions of the term cancer survivor.

Doctors have traditionally thought of survivors as those
patients whose cancers have been cured. A commonly used
generic milestone is being cancer-free for 5 years, although
the reality is that oncologists use different time frames for
various cancers and even for similar situations within a
given cancer type. The advocacy community, on the other
hand, has commonly used a more expanded definition to
assert that ‘‘from the time of its discovery and for the bal-
ance of life, an individual diagnosed with cancer is a sur-
vivor’’ (National Coalition of Cancer Survivorship charter),
a definition which includes situations in which the cancer is
C. C. Earle (&) incurable. Family and friends affected by the patient’s
Department of Medical Oncology, Dana-Farber Cancer Institute,
cancer are sometimes also called survivors (considered
Boston, MA, USA
e-mail: [email protected] ‘secondary survivors’ by the National Cancer Institute’s
(NCI) Office of Cancer Survivorship (OCS)). More
L. B. Travis
Division of Cancer Epidemiology and Genetics, recently, in the 2005 report From Cancer Patient to Cancer
National Cancer Institute, National Institutes of Health, Survivor: Lost in Transition (Institute of Medicine 2005),
DHHS, Bethesda, MD 20892, USA the Institute of Medicine (IOM) put forth the pragmatic
L. S. Constine definition of cancer survivors as those patients in the period
Department of Radiation Oncology, James P. Wilmot Cancer after the completion of primary cancer treatment until the
Center, University of Rochester Medical Center, 647Rochester,
time of recurrence or death.
NY 14642, USA

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 1
DOI: 10.1007/978-3-540-72314-1_1,  Springer-Verlag Berlin Heidelberg 2014
2 C. C. Earle et al.

Fig. 1 Estimated number of cancer survivors in the United States

from 1971 to 2004. Based on November 2006 SEER data submission

2 Statistics

Cancer is now the leading cause of mortality for adults in

the United States. It will directly afflict one in three persons,
and most of us are affected by cancer in some way. The NCI
estimated that as of January 1st, 2005 there were 10.8
Fig. 2 Age-specific crude SEER cancer incidence rates. For all
million Americans with a personal history of cancer
cancer sites, all ages, all races, both sexes 2000–2005
(Fig. 1), approximately 3.7 % of the population (http://
dccps.nci.nih.gov/ocs/prevalence). This number has been
steadily increasing such that it may be greater than 12
million in 2008. Worldwide, the number of cancer survivors
was over 25 million in 2002 (Parkin et al. 2005). There are
several reasons for this growth in numbers, but demo-
graphics are likely a major contributor. Cancer is, in gen-
eral, a disease of the elderly (Fig. 2), and the baby-boom
generation is now entering the years during which cancer
incidence rates increase. Consequently, there are more
cancer patients, and as a result more survivors.
Demographics, however, do not alone account for the
increasing number of cancer survivors. Other factors,
including public health successes and medical advances,
have also contributed to the rising numbers. As Fig. 3
demonstrates, between 1993 and 2005 the annual age-
adjusted cancer death rates have fallen by an average of
1.1 % per year. These statistics reflect incidence rates that
have finally plateaued and started to decrease (Fig. 4) due to
factors such as lower smoking rates, combined with the
growing proportion of patients cured of cancer. Figure 5
shows that in 1975, the 5 year relative survival rate for all
cancer patients considered together was about 50 %. By Fig. 3 Age-adjusted U.S. cancer mortality rates. For all cancer sites,
2000, the 5 year relative survival rate had increased to all ages, all races, both sexes 1975–2005. Mortality source: U.S.
about 66 %. Effective screening tests which detect cancer at mortality files, National Center for Health Statistics, CDC. Rates are
earlier stages are responsible for much of this improvement age-adjusted to the 2000 U.S. standard population (19 age groups –
Census P25–1130). Regression lines are calculated using the join point
in survival, but increasingly successful primary and adju- regression program version 3.3, April 2008, National Cancer Institute
vant treatments also contribute to these increases.
The estimated number of cancer survivors by time since the most common primary site (22 %), followed by prostate
initial diagnosis and gender is shown in Fig. 6, with 14 % of (19 %), colorectal (10 %), and gynecological malignancies
all patients having survived for 20 or more years. Breast is (9 %, Fig. 7); these cancers have relatively high incidence
Prologue: Surviving Cancer: SEER Statistics 3

Fig. 4 Age-adjusted SEER cancer incidence rates. For all cancer Fig. 5 5 year relative cancer survival rate by year of diagnosis. For
sites, all ages, all races, both sexes 1975–2005. Incidence source: all cancer sites, all ages, all races, both sexes 1975–2000. Survival
SEER 9 areas (San Francisco, Connecticut, Detroit, Hawaii, Iowa, source: SEER 9 areas (San Francisco, Connecticut, Detroit, Hawaii,
New Mexico, Seattle, Utah, and Atlanta). Rates are age-adjusted to the Iowa, New Mexico, Seattle, Utah, and Atlanta). Survival rates are
2000 U.S. standard population (19 age groups – Census P25–1130). relative rates expressed as percents. The 5 year estimates are
Regression lines are calculated using the join point regression program calculated using monthly intervals
version 3.3, April 2008, National Cancer Institute

rates and depending on stage, are generally curable. Lung

cancer, on the other hand, despite being the most common
cancer overall, accounts for only 3 % of survivors because
of its generally poor outcomes. Conversely, the proportion
of cancer survivors under age 19 is only 1 %, given the
rarity of childhood cancers, although these tumors are
typically accompanied by high cure rates. The estimated
proportion of cancer survivors by current age is shown in
Fig. 8, with 60 % of patients over age 65.

Fig. 6 Estimated number of cancer survivors by time from diagnosis

3 The Oncology Workforce and gender. Estimate for January 1, 2004 based on November 2006
SEER data submission. Invasive/first primary cases only; n = 10.8
As the number of cancer survivors has grown, so has the million survivors
recognition that the care of the patient requires attention to
issues that go well beyond treatment of the cancer itself. following issues: appropriate surveillance for relapse;
The first recommendation in the IOM report was that cancer effects of treatment such as organ damage, mobility, fatigue,
survivorship should be recognized ‘‘as a distinct phase of fertility, and sexual dysfunction; and the possibility of
cancer care.’’ This viewpoint represented a remarkable shift second cancers either due to shared genetic or environ-
in thinking. Previously, patients had been viewed as survi- mental exposures that caused the index tumor or that are
vors of a specific cancer, sometimes with a narrow spectrum related to treatment. Other shared issues relate to the fol-
of lasting effects related only to that cancer and/or its lowing factors: the effect of a cancer history on the ability to
treatment. The IOM articulated a view that there are obtain health, life, or disability insurance, and related con-
important cross-cutting issues with which all cancer survi- cerns of how insurability might affect employability and
vors must contend. These include concerns about the finances; and a host of psychosocial effects including fear,
4 C. C. Earle et al.

Fig. 9 Baseline projected supply of and demand for oncologist visits,

2005–2020. Reprinted with permission. 2008 American Society of
Clinical Oncology. All rights reserved. Erikson C et al.: J Oncol
Fig. 7 Estimated proportion of cancer survivors in the U.S. by site. Practice Vol. 3 (2), 2007:79–86
Based on November 2006 SEER data submission

demographic trends, which were mentioned previously,

predict increasing numbers of cancer patients and survivors
who will require ongoing care and monitoring. These sta-
tistics prompted the American Society of Clinical Oncology
(ASCO) to create in 2005 a Workforce in Oncology Task-
force to study the equilibrium of supply and demand. By
gathering information through professional databases and
surveys on the demographics and career plans of the current
oncology workforce as well as those in training, ASCO was
able to project that demand for cancer care is expected to
rise 48 % between 2005 and 2020, while the supply of
oncologists will grow by only about 14 % (Fig. 9). This is
due to a combination of an aging oncology workforce and a
limited number of oncology fellowship positions. The
Workforce Taskforce concluded that the health care system
Fig. 8 Estimated proportion of cancer survivors by current age. will likely have major shortages in its capacity to meet
Based on November 2006 SEER data submission future demand for oncology services and that no single
action (such as training more oncologists or engaging pri-
altered interpersonal relationships, cosmesis, and cognitive mary care physicians (PCPs) and physician-extenders in
effects (e.g., ‘chemo brain’) stemming from cancer treat- cancer care) will fill the gap between supply and demand.
ment. These domains of concern depend less on the par- Instead, policymakers will need to employ a multifaceted
ticular type of cancer, and more on therapeutic exposures strategy in meeting this challenge.
and individual reactions to them. Moreover, the end of It is important to note that the assumptions in the
primary treatment for cancer has been called a ‘teachable Workforce Taskforce analysis included no change in
moment’(Ganz 2005) in recognition that patients may be current oncology practices. This is a very conservative
more receptive to recommendations to change risk behav- assumption given that oncologists generally have
iors related to diet, exercise, smoking, etc., and messages increasingly more management options and treatments to
about general health maintenance (e.g., immunizations, offer patients with each passing year. Even those cancer
other screenings) around the time of a major health crisis, patients who may not be cured are living longer and
such as a cancer diagnosis. requiring care for extended periods of time. Further, this
This more holistic view of caring for cancer survivors model specifically does not take into account the chang-
promises to provide them great benefit, but raises questions ing standards and trends in survivorship care discussed
about how such care can practically be delivered. The herein.
Prologue: Surviving Cancer: SEER Statistics 5

4 Survivorship Care Planning focus on delivering cancer treatment (American Society of

Clinical Oncology 1996). Consequently, shared-care models
It is important to recognize that there is no single optimal appear to be safe and feasible. These models may be
strategy by which survivorship care can be provided. Fol- particularly attractive for managing breast cancer survivors,
low-up care can be carried out by specialists, generalists, where the evidence is strongest and the manpower concerns
physician assistants, or nurse practitioners, combinations of are greatest (Ganz and Hahn 2008). Still, there are also
these providers in a ‘shared care’ model, or in a specialized workforce issues facing many other physician specialties,
survivorship clinic. The mechanism(s) by which care are including primary care providers, (Bodenheimer 2006) and
delivered, however, are less important than ensuring com- there are currently insufficient allied providers to completely
munication and coordination of care among all involved solve the human resource problem (Erikson et al. 2007).
health personnel. Consequently, creative solutions will be needed to address
The IOM had as its second recommendation that the above issues.
‘patients completing treatment should be provided with a The care summary envisioned by the IOM should include
comprehensive care summary and follow-up plan…(the) the following (adapted from the IOM Report: ‘From Cancer
‘‘Survivorship Care Plan’’. The intent of this recommen- Patient to Cancer Survivor: Lost in Transition, Box 3-16,
dation was to create an actionable document that is specific pp. 152–153, which can be found at www.iom.edu and
to each individual patient so that the patient and all pro- which was adapted from the President’s Cancer Panel
viders would have a guide as to what treatments were (2004):
rendered and what procedures should be performed in the (1) Diagnostic tests performed and results.
future. In this way, communication and coordination could (2) Tumor characteristics (e.g., site(s), stage and grade,
be enhanced. As most elements of survivorship care are not hormone receptor status, marker information).
technically demanding, the specifics of which provider is (3) Dates of treatment initiation and completion.
responsible for the different components of care can be (4) Surgery, chemotherapy, radiotherapy, transplant, hor-
customized to best suit each patient’s situation, depending monal therapy, or gene or other therapies provided,
on resource availability and preferences. including agents used, treatment regimen, total dosage,
High-quality data exist on which these new care models identifying number and title of clinical trials (if any),
are based. For example, randomized trials have shown that indicators of treatment response, and toxicities experi-
primary care providers (PCPs) who have been given a brief enced during treatment.
survivorship care plan with explicit directions for follow-up (5) Psychosocial, nutritional, and other supportive services
can achieve the same outcomes as specialists (Grunfeld et al. provided.
1995a, b, 1996a, 1999a, 2006). In breast cancer, the time to (6) Full contact information on treating institutions and key
diagnosis of recurrence is unchanged when follow up is individual providers.
randomized between PCPs and specialists (Grunfeld et al. (7) Identification of a key point of contact and coordinator
1996a) and there is no excess of serious clinical events such of continuing care.
as pathological fractures or spinal cord compression from an The care plan, on the other hand, would provide rec-
unrecognized recurrence (Grunfeld et al. 2006). In addition, ommendations regarding both cancer and non-cancer care.
physical quality of life and mental health (including anxiety It is not reasonable to expect non-specialist providers to
and depression) do not differ, though satisfaction with care remain up to date on surveillance recommendations and the
actually favors non-specialist providers (Grunfeld et al. potential side effects of new cancer treatments, but they are
1999). Randomized trials that examine the follow-up of well-able to act on specific information for a particular
patients with both breast or colorectal cancer have shown patient and implement a care plan. Recommendations for
that care is delivered at lower cost both to the health care surveillance of cancer are available from several sources.
system (fewer, less expensive tests), as well as to the patient The American Society of Clinical Oncology (ASCO) has
(out of pocket costs related to travel) when delivered by evidence-based surveillance guidelines for breast and
non-specialist providers (Grunfeld et al. 1996a, 1999b; colorectal cancer that can be found at: www.asco.org
Wattchow et al. 2006). Moreover, PCPs are generally will- under the Quality Care & Guidelines tab. Consensus
ing to take on the role of follow-up care (Grunfeld et al. guidelines for surveillance for recurrence of other cancers
1995) and patients may prefer it, (Grunfeld et al. 1996) while after treatment are incorporated into the National Compre-
surveys have shown that most oncologists would like to hensive Cancer Network (NCCN) guidelines, found at:
6 C. C. Earle et al.

www.nccn.org. In Europe, the European Society for breast cancer; smoking cessation after lung cancer) and
Medical Oncology also publishes consensus guidelines at monitoring of adherence to these recommendations.
www.esmo.org/resources/clinicalguidelines. (10) Referrals to specific follow-up care providers (e.g.,
Long-term effects are those that first occur during cancer rehabilitation, fertility, psychology), support groups,
treatment and persist after completion of primary therapy, and/or the patient’s primary care provider.
such as peripheral neuropathy from oxaliplatin. Late effects, (11) A listing of cancer-related resources and information
on the other hand, are those signs/symptoms that were not (e.g., Internet-based sources and telephone listings
apparent during primary treatment, but become evident at for major cancer support organizations).
some later time, such as bone loss and increased risk of hip
fracture from pelvic radiation (Baxter et al. 2005). Unfor-
tunately, there are no comprehensive guidelines for moni- 5 Conclusion
toring or managing long-term and late effects of cancer
therapy for survivors of adult cancer, however, the major The data reviewed in this chapter show that demographic
issues can be extrapolated from the consensus guidelines of trends in both the general population and the oncology
the Children’s Oncology Group, found at www. workforce, combined with the results of our success in the
survivorshipguidelines.org. war against cancer, have now presented us with a major
According to the IOM, the care plan should include: health service delivery challenge for cancer survivors.
(1) The likely course of recovery from acute treatment Multifaceted enhancements to the workforce and many
toxicities, as well as the need for ongoing health coexisting models of care delivery will be needed in the
maintenance or adjuvant therapy. future. Careful survivorship care planning has the potential
(2) A description of recommended cancer screening and to improve the quality of care for cancer survivors, enhance
other periodic testing and examinations, and the patient satisfaction through empowerment, and possibly
schedule on which they should be performed (and who contribute to solutions to the looming concerns with regard
should provide them). to the oncology workforce (Erikson et al. 2007).
(3) Information on possible late and long-term effects of
treatment and symptoms of such effects.
(4) Information on possible signs of recurrence and sec- References
ond tumors.
(5) Information on the possible effects of cancer on mar- American Society of Clinical Oncology (1996): Status of the medical
ital/partner relationship, sexual functioning, work, and oncology workforce. J Clin Oncol 14:2612–2621
parenting, and the potential future need for psycho- Baxter NN, Habermann EB, Tepper JE et al (2005) Risk of pelvic
fractures in older women following pelvic irradiation. JAMA
social support. 294:2587–2593
(6) Information on the potential insurance, employment, Bodenheimer T (2006) Primary care–will it survive? N Engl J Med
and financial consequences of cancer and, as neces- 355:861–864
sary, referral to counseling, legal aid, and financial Erikson C, Salsberg E, Forte G et al (2007) Future supply and demand
for oncologists: challenges to assuring access to oncology services.
assistance. J Oncol Pract 3:79–86
(7) Specific recommendations for healthy behaviors (e.g., Ganz PA (2005) A teachable moment for oncologists: cancer
diet, exercise, healthy weight, sunscreen use, immu- survivors, 10 million strong and growing! J Clin Oncol
nizations, smoking cessation, osteoporosis preven- 23:5458–5460
Ganz PA, Hahn EE (2008) Implementing a survivorship care plan for
tion). When appropriate, recommendations that first- patients with breast cancer. J Clin Oncol 26:759–767
degree relatives be informed about their increased risk Grunfeld E, Yudkin P, Adewuyl-Dalton R, et al (1995a) Follow up in
and the need for cancer screening (e.g., breast cancer, breast cancer: Quality of life unaffected by general practice follow
colorectal cancer, prostate cancer). up. BMJ 311:54
Grunfeld E, Mant D, Vessey MP et al (1995b) Evaluating primary care
(8) As appropriate, information on genetic counseling and follow-up of breast cancer: methods and preliminary results of
testing to identify high-risk individuals who could three studies. Ann Oncol 6(Suppl 2):47–52
benefit from more comprehensive cancer surveillance, Grunfeld E, Mant D, Vessey MP et al (1995c) Specialist and general
chemoprevention, or risk-reducing surgery. practice views on routine follow-up of breast cancer patients in
general practice. Fam Pract 12:60–65
(9) As appropriate, information on known effective che- Grunfeld E, Mant D, Yudkin P et al (1996a) Routine follow up of
moprevention and behavioral strategies for secondary breast cancer in primary care: randomised trial. BMJ
prevention (e.g., tamoxifen in women at high risk for 313:665–669
Prologue: Surviving Cancer: SEER Statistics 7

Grunfeld E, Mant D, Yudkin P et al (1996b) Routine follow-up of of family physician versus specialist care. J Clin Oncol 24:
breast cancer in primary care: randomised trial. BMJ 313:665–669 848–855
Grunfeld E, Fitzpatrick R, Mant D et al (1999a) Comparison of breast Institute of Medicine (2005) From cancer patient to cancer survivor:
cancer patient satisfaction with follow-up in primary care versus lost in transition. National Academies Press, Washington
specialist care: results from a randomized controlled trial. Br J Gen Parkin DM, Bray F, Ferlay J et al (2005) Global cancer statistics, 2002.
Pract 49:705–710 CA Cancer J Clin 55:74–108
Grunfeld E, Gray A, Mant D et al (1999b) Follow-up of breast cancer Wattchow DA, Weller DP, Esterman A et al (2006) General practice
in primary care vs specialist care: results of an economic vs surgical-based follow-up for patients with colon cancer:
evaluation. Br J Cancer 79:1227–1233 randomised controlled trial. Br J Cancer 94:1116–1121
Grunfeld E, Levine MN, Julian JA et al (2006) Randomized trial of
long-term follow-up for early-stage breast cancer: a comparison
 Biocontinuum of the Pathophysiology Paradigm
Biocontinuum of Radiation Pathogenesis of Normal Tissue:
The Past is the Prologue to the Future
Philip Rubin and George Casarett

Contents Abstract
Under the various conditions of radiation therapy, the
1 Introduction: Historical Annotation.................................. 2 period of time from irradiation to the end of life may be
2 Prologue I ............................................................................. 2 characterized by continuous complications of clinical
2.1 Normal Cell and Potential Targets for Radiation ................ 2 significance arising from irradiation of normal organs,
2.2 Cell Types According to Mitotic Frequency........................ 2 alternating with clinical complication with clinically
2.3 Classification of Cells According to Relative
‘‘silent’’ periods of the absence of such clinically
Radiosensitivity ..................................................................... 4
2.4 Normal Tissues and Their Relative Radiosensitivity........... 6 significant complications. However, there is at no time
2.5 Biocontinuum of Histologic Sequence of Events ................ 8 a ‘‘silent’’ histopathologic period, i.e., absence of
2.6 Clinical Expression Events of the Biocontinuum ................ 9 radiation-induced changes in the irradiated organs,
3 Prologue II: Concept of Radiation Tolerance Dose ........ 11 although their degree of rate of progression may vary
3.1 Introduction: Historical Annotation ...................................... 11 considerably. Furthermore, the addition of further stress
3.2 Tolerance Dose Effect........................................................... 11 of insult, e.g., from trauma or infection, to the organs that
3.3 Tolerance Volume Effect ...................................................... 12
3.4 Tolerance of Organs .............................................................. 13 have sustained residual radiation damage (e.g. deterio-
ration of the vasculature) may precipitate clinically
4 Prologue III: The Concept of Pediatric Radiation
significant complications during otherwise clinically
Sensitivity.............................................................................. 16
4.1 Introduction: Historical Annotation ...................................... 16 ‘‘silent’’ periods. The histopathologic sequence of events
4.2 Concept of Mitotic Potential Versus Mitotic Activity......... 16 after a brief radiation exposure is divided into four
4.3 The Fetal Model of Radiosensitivity: Prenatal general phases (see Fig. 5): Casarett Hypothesis. The
Organogenesis........................................................................ 17
Biocontinuum diagram illustrates generally, with respect
4.4 The Pediatric Model of Radiosensitivity: Postnatal Growth
Spurts ..................................................................................... 17 to clinical periods, the waxing and waning (vertically), or
organ damage with time and persistence or progression
of residual damage. The upper lines depict radiation
damage of different degrees. The bottom line indicates
the accumulation of organ damage with time of ‘‘aging’’,
may be additive to radiation damage in effect. The rising
arrows indicate the precipitation of damage from
subclinical or clinical levels to clinically significant or
even lethal levels, as a result of complications such as
trauma or infection or as a result of deterioration of
vasculature and failure of the blood circulation. No
precise values of relationships are intended for the slopes
or shapes of the graph lines: Rubin Paradigm.
In memory of George Casarett.

P. Rubin (&)
G. Casarett

Department of Radiation Oncology, University of Rochester
School of Medicine and Dentistry, 601 Elmwood Ave,
Box 647 Rochester, NY 14642, USA
e-mail: [email protected]

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 9
DOI: 10.1007/978-3-540-72314-1_2,  Springer-Verlag Berlin Heidelberg 2014
10 P. Rubin and G. Casarett

Fig. 1 Potential radiation

biologic targets for translational
research. For each of the
pathways detailed molecular and
cellular knowledge is
continuously becoming available
that explains cellular phenotype
and provides novel therapeutic
targets (Modified from Coleman
CN. Harris JR: Current Scientific
issues related to clinical radiation
oncology. Radiat Res
1998:150:125.)

The potential radiation biologic targets for translational

1 Introduction: Historical Annotation research are illustrated in Fig. 1 and Table 1. For each of
the pathways, detailed molecular and cellular knowledge is
In the 1960s, the ‘‘Manhattan Project’’, code for the ‘‘Atomic continually becoming available to explain different cellular
Bomb’’ was declassified and thereby allowed for access to phenotypes and may provide novel therapeutic targets.
numerous radiation biologic and pathologic research theses. Many of the concepts of the induction of chronic oxidative
George Casarett was the senior biopathologist and in col- stress and the inflammatory process followed by fibrogen-
laboration the two-volume work entitled ‘‘Clinical Radiation esis inherent to radiation-induced pathogenesis have paral-
Pathology’’ was published in 1968. The paradigm we lels in chemotherapy and biologics, which includes a similar
developed was the ‘‘Biocontinuum’’ in which we postulated cytohistologic toxicity. The surgical wound healing has a
that once normal tissues are irradiated a sequence of cellular parallel sequence of inflammation, then fibrosis in its his-
responses continues for a lifetime ranging from acute-suba- tologic appearance.
cute-late, and chronic clinical manifestations over decades.
Recent molecular biology studies of a ‘Perpetual Cytokine
Cascade’ induced immediately after tissues are exposed to
2.2 Cell Types According to Mitotic Frequency
radiation, which confirms his observations, ‘‘there is at no
time a ‘silent’ histopathologic latent period’’ prior to the
In his classification of body cells on the basis of the kinds of
clinical expression of radiation reactions.
individual lives they lead, Cowdry (1950) named four
general classes: vegetative intermitotic, differentiating
intermitotic, reverting postmitotic, and fixed postmitotic
2 Prologue I (Fig. 2a, b). Table 2 outlines the properties of these classes
of cells and gives examples.
2.1 Normal Cell and Potential Targets
for Radiation
2.2.1 Vegetative Intermitotic Cells
A knowledge of the normal cell, its structure, and its These cells divide relatively frequently, have relatively
function is essential to an understanding of the complexities short individual lives between divisions, differentiate little
of radiation cytopathology, which is, in turn, essential to the or not at all during their individual lives between divi-
understanding of radiation biopathology and its clinical sions, show minimal aging changes, and function chiefly
manifestations. Once initiated, these normal tissue respon- as producers of cells to replace themselves and the more
ses result in sequence of acute to chronic late effects. This differentiated cells of relatively short life span which die
‘‘Biocontinuum’’ of longitudinal alterations is expressed or are regularly lost from the body. The division of cells
differently over the patients’ lifetime. Paradoxically, radi- of this type produces daughter cells, some of which dif-
ation can save an individual’s life and may ultimately lead ferentiate and others of which remain vegetative intermi-
to his demise decades later. totic cells.
Biocontinuum of the Pathophysiology Paradigm 11

Table 1 Application of molecular biologic concepts to radiation therapy

Process Potential manipulation Examples of therapya
DNA damage Increase damage in tumor cells Hypoxic-cell sensitizers, thymidine analogues
DNA repair Decrease repair in tumor cells Fluoropyrimidines, hydroxyurea, cisplatin
Signal Inhibit protective signalling cascades in Protein kinase C inhibitors (?) phosphotyrosine kinase inhibitors(?)
transduction tumor cells
Radiation-induced Use gene therapy Tumour necrosis factor linked to radiation responsive promotor(?)
gene expression
Growth factor Administer or increase expression of Interleukin-1, granulocyte colony-stimulating factor granulocyte—
expression protective factors macrophage colony-stimulating factor, basic fibroblast growth factor (?)
Block expression of factors producing Antibodies or antisense RNA against epidermal growth factor, transforming
long-term toxicity growth factor b (?)
Apoptosis Force tumor cells to undergo apoptosis Transfection of wild-type TP53(?)
Cell cycle Synchronize tumor cells in sensitive Antimetabolites (early S phase), paclitaxel phase (M), cyclin inhibitors(G, to
phase of cycle (early S or M phase) S phase)
Prevent G2 arrest in tumor cells Cyclin inhibitors(G2 to M phase)(?)
a
A question mark indicates potential therapy
From Licter As, Lawrence TS; Recent advances in radiation oncology, N Engl J Med 1995; 332:371, permission. Copyright  1995 Massa-
chusetts Medical Society. All rights reserved

Fig. 2 a Cell cycle progression, with the major regulatory kinases followed by cells at the G1/S boundary, whereas the period of greatest
indicated. Once a cell passes the restriction point (R), it is committed resistance is at late S. G gaps; G1 first gap before DNA synthesis;
to progress through S-phase, even in the absence of mitogenic signals G2M Second gap before mitosis; S DNA synthesis phase (Adapted
checkpoints (indicated in G2) have also been identified in G1, S1 and from Sinclair WK: Cyclic X-ray responses in mammalian cells
mitosis. b Patterns of radiosensitivity change through the cell cycle. in vitro. Radiat Res 1968; 33:620, with permission. Copyright  1967
This change is known as the ‘‘age function,’’ and varies widely among OPA (Overseas Publishers Association) N.V.)
different cell types. Cells in mitosis are almost always sensitive,

2.2.2 Differentiating Intermitotic Cells completion of differentiation varies with the type of spe-
These cells also divide relatively frequently; have rela- cialized cell in question. For the sake of simplicity, only
tively short individual lives between divisions and show one row of differentiating intermitotic cells is represented
only slight aging changes. However, they undergo steps in in the diagram. Actually there may be several divisions, as
the process of differentiation between divisions. Each in the production of mature blood cells in bone marrow, or
individual differentiation intermitotic cell becomes there may be omission of this stage in other tissues, as in
increasingly more differentiated between divisions until it thin epidermis.
becomes fully capable of performing its specialized func-
tion, at which time it becomes either a reverting or a fixed 2.2.3 Reverting Postmitotic Cells
postmitotic cell. The number of successive divisions in a Reverting postmitotic cells are highly differentiated, func-
line of differentiating intermitotic cells before the tionally mature cells with relatively long individual lives
12 P. Rubin and G. Casarett

Table 2 Kinds of cell lives

Vegetative intermitotics Differentiating Reverting postmitotics Fixed postmitotics
intermitotics
Life span Begins at mitosis Same. Duration short, Begins at mitosis Begins at mitosis
Ends at mitosis perhaps even shorter Ordinarily ends at death. When Ends at death. Duration still
Duration short demand for more cells is great, longer; for nerve cells very long,
ends at mitosis. Duration longer very short for neutrophilic
leucocytes
Differentiation Least. Constitutes More as steps in Still more. Functionally Most. Functionally mature.
reservoir of cells. Aging acquisition of specific mature. Aging marked Aging greatest, ending in death
minimal functions. Aging
slight
Service As cell producers As cells learning how As cell specialists As cell specialists even after
to work death. Erythrocytes, epidermal
cells, corneal cells, and
ganoblasts
Examples Basal epidermal cells, Spinous cells of Renal epithelial cells, smooth Nerve cells. Neutrophilic
spermatogonia of testicle, epidermis, muscle cells, hepatic epithelial leucocytes
hemocytoblasts of bone spermatocytes, cells.
marrow erythroblasts,
myelocytes.
Principal In stratified epithelia Sometimes farther In liver and adrenals nearest the Almost anywhere needed
locations nearer to arterial away as in spinous arterial bloodstream
bloodstream. layer of epidermis
Malignant Occasional Occasional Rare After youth, never
transformation

which show marked aging changes and may die without

producing daughter cells. These cells do not normally
undergo regular or frequent divisions, but when the demand
for more cells of their kind is great, e.g., after pathologic
destruction, some of them may ‘‘revert’’ for a time to an
intermitotic state, in that they divide exuberantly to replace
cells lost.

2.2.4 Fixed Postmitotic Cells

Fixed postmitotic cells are very highly differentiated,
functionally mature cells which have lost completely their
ability to divide, regardless of functional demand. They
show marked aging changes ending in death. Some cell Fig. 3 Relative cell radiosensitivity. (From Rubin P, Casarett GW:
types of this class, such as neurons, have long lives and die Clinical Radiation Pathology. Philadelphia, W.B. Saunders, 1968, with
permission.)
without replacement, whereas others, such as neutrophilic
leukocytes, are relatively short-lived but are replaced by a
supply of precursors produced by the divisions of vegetative Radiation acts at molecular and cellular levels, and tissue
and differentiating intermitotic cells and sometimes by the effects represent a summation of those effects. Because the
division of reverting postmitotic cells. key target cells for the survival of a complex organ depends
on the organization of all its tissues, cellular damage in one
key cell population may result in death of the whole tissue.
2.3 Classification of Cells According For example, small blood vessels are fairly sensitive to
to Relative Radiosensitivity irradiation, so the effects on a tissue from disruption of its
blood supply may be greater than those from the irradiation
The relative radiosensitivity of cells according to the kinds of the parenchymal cells themselves.
of lives they lead is illustrated in Fig. 3. This classification A relative cell radiosensitivity is illustrated in Fig. 3,
is given in the order of decreasing relative radiosensitivity which is based on the classification schema related to cellular
and is based upon the criterion of cell death. division and differentiation by Cowdry. The uncommitted
Biocontinuum of the Pathophysiology Paradigm 13

Table 3 Classification of cells according to relative radiosensitivity

Tissues Relative Chief mechanisms of hypoplasia
radiosensitivity
Lymphoid, hemopoietic (marrow), spermatogenic High Destruction of vegetative or differentiating tissue cells of
epithelium, ovarian follicular epithelium, intestinal high mitotic frequency
epithelium
Oropharyngeal stratified epithelium, epidermal epithelium, Fairly high Destruction of vegetative or differentiating tissue cells of
hair follicle epithelium, sebaceous gland epithelium, urinary fairly high mitotic frequency
bladder epithelium, esophageal epithelium, optic lens
epithelium, gastric gland epithelium, ureteral epithelium
Ordinary interstitial connective tissue, neurological tissue Medium Damage or destruction of connective tissue cells of
(connective tissue of nervous system), finely vasculature, moderate mitotic frequency and damage to the fine
growing cartilage, or bone tissue vasculature
Mature cartilage or bone tissue, mucous or serous gland Fairly low Hypoplasia secondary to damage to associated fine
epithelium, salivary gland epithelium, sweat gland vasculature and connective tissue elements, with relatively
epithelium, nasopharyngeal simple epithelium, renal less contribution by the direct effects on parenchymal cells,
epithelium, pulmonary epithelium, renal epithelium, hepatic which normally divide infrequently
epithelium, pancreatic epithelium, pituitary epithelium,
thyroid epithelium, adrenal epithelium
Neuronal tissue, muscle tissue Low Hypoplasia secondary to damage to associated fine
vasculature and connective tissue elements, with little
contribution by the direct effects on the parenchymal cells,
which do not normally divide

stem cell is a vegetative intermitotic cell; the committed stem 2.3.2 Class 2: Differentiating Intermitotic Cells
cell is a differentiating intermitotic cell. Reverting postmi- These cells are relatively radiosensitive, but are generally
totic cells have the ability to divide when conditioned or somewhat less sensitive to radiation than vegetative inter-
challenged, such as hepatocytes after liver resection. The mitotic cells. They are also relatively short-lived as indi-
organization of tissues and organs by these cell types deter- viduals and are produced by divisions of vegetative
mines their radiosensitivity, which is based on their most intermitotic cells. They normally divide from time to time
radiosensitive cells. Table 3 reviews cell and tissue for a limited number of divisions, and they differentiate to
radiosensitivity. some degree between divisions. The more differentiated
they become, the less sensitive to radiation they become.
2.3.1 Class 1: Vegetative Intermitotic Cells This class includes cells such as dividing differentiating
These are generally the most radiation sensitive of cells. cells of the hematopoietic series in the intermediate stages
They are short-lived as individual cells, they are primitive, of differentiation in both granulocytic and erythrocytic
and they normally divide regularly to produce daughter series in bone marrow, the more differentiated spermato-
cells, some of which will enter into a process of differenti- gonia (intermediate and Type B), and the spermatocytes in
ation and others of which will not differentiate, but remain the seminiferous epithelium and ovocytes.
vegetative intermitotic cells. This class includes cells such as
free stem cells of the hematopoietic tissues, e.g., hemocy- 2.3.3 Class 3: Multipotential Connective Tissue
toblasts, primitive lymphoblasts, primitive erythroblasts, Cells and Endothelial Cells
and primitive myeloblasts; the dividing of cells deep in the This class of cells is intermediate in position between rel-
intestinal glands (crypts of Lieberkuhn); the primitive Type atively radiosensitive cells in classes 1 and 2 and the rela-
A spermatogonia in the seminiferous epithelium; granulosa tively radioresistant cells in classes 4 and 5. These cells may
cells of developing and mature ovarian follicles; basal ger- divide irregularly or sporadically in time and in response to
minal cells of the epidermis and germinal cells of the gastric a variety of special stimuli, and they are generally capable
glands and of holocrine glands such as the sebaceous glands. of undergoing transitions from one to another morphologic
Large and medium-sized lymphocytes also belong to this and functional form under the influence of various stimuli.
class. Small lymphocytes are also highly radiosensitive, but Their life span as individuals with respect to one form of
they do not divide as small lymphocytes. They have been function may be highly variable, but under normal condi-
observed on occasion to divide after first increasing in size. tions it is on average longer than that of cells in classes 1
Nevertheless, they are exceptional in this class, although and 2. This class includes such cells as endothelial cells,
they are among the most radiosensitive cell types. especially those of the smaller vessels, which distinction
14 P. Rubin and G. Casarett

Fig. 4 a Rapid renewal system

illustrating radiation effects on
both parenchyma and micro
vasculature compartments. VIM
vegetative intermitotic cells; DIM
differentiating intermitotic cells;
FPM fixed postmitotic cells;
HHB histo-hernatic barrier; FIB
increased fibrosis; MC
microcirculation (From Rubin P.
Casarett GW: Clinical Radiation
Pathology. Philadelphia, W.B.
Saunders, 1968, with
permission). b Slow renewal
system illustrating effects on the
vascular compartment, which
leads to a late effect in the
parenchymal cells as the capillary
sclerosis and fibrosis increases.
RPM reverting postmitotic cells
(From Rubin P. Casarett GW:
Clinical Radiation Pathology.
Philadelphia, W.B. Saunders,
1968, with permission.)

would imply the existence of some indirect mechanisms as their daughter cells show a relative rejuvenation, with the
yet unknown, and fibroblasts and mesenchymal cells. disappearance of aging changes.

2.3.4 Class 4: Reverting Postmitotic Cells 2.3.5 Class 5: Fixed Postmitotic Cells
In general this class of cells is relatively radiation resistant. The cells in this class are generally the most radiation
These cells experience relatively long lives as individuals, resistant of cells. They normally do not divide or have lost
do not normally undergo regular or periodic division in the completely the ability to divide under any circumstances and
adult and generally do not divide except under abnormal are highly differentiated morphologically and highly spe-
conditions presenting special stimuli. Under an appropriate cialized in function. Some of them have very long lives and
stimulus, usually involving damage, destruction, or loss of others have relatively short lives, but all undergo progressive
considerable numbers of cells of their kind or of cells which aging changes until death, If not killed prematurely. The
they are capable of producing, they can revert to a condition short-lived fixed postmitotic cells, when lost, are replaced by
in which they divide to produce more cells of their kind or the action of vegetative and/or differentiating intermitotic
they undergo heterotypic transformations to produce cells precursor cells. If the loss of precursor cells is also reverting
of certain other kinds. postmitotic primitive fixed stem cells. This class includes
Some of the cell types of this class are highly specialized cells such as the long-lived neurons and perhaps some muscle
in function, while others are not. Some are epithelial and cells, which are not replaceable, and the short-lived poly-
some are connective tissue elements. This class includes morphonuclear granulocytes, erythrocytes, spermatids,
cells such as the epithelial parenchymal cells and the duct spermatozoa, superficial epithelial cells of the alimentary
cells in the salivary glands, liver, kidney, and pancreas; tract and epithelial cells of the sebaceous glands, all of which
basal and parenchymal cells of merocrine glands such as the are replaceable.
sweat glands and of endocrine glands such as the adrenal,
thyroid, parathyroid, and pituitary glands; cells of intersti-
tial gland tissue of the gonads; cells of corpora lutea; Sertoli 2.4 Normal Tissues and Their Relative
cells; septal cells of the lung; fixed stem cells of various Radiosensitivity
tissues, such as the reticulum cells in hematopoietic tissues
and perhaps some smooth muscle cells. The cells in this The histopathologic manifestations of radiation cellular
class may show considerable aging changes, but on division death are pyknosis and karyolysis, swollen vacuolated cells
Biocontinuum of the Pathophysiology Paradigm 15

with loss of staining capacity, and altered permeability, with 2.4.2 Range and Basis of Radiosensitivity
eventual degeneration and phagocytosis. The events fol- of Tissue Types
lowing exposure to radiation doses are determined, in part, by The mechanisms of relatively direct radiation-induced
the radiosensitivity of the cells in the parenchymal com- hypoplasia and atrophy of rapidly and continually self-
partment as well as related to the radiosensitivity of vascular repopulating tissues, i.e., tissues which contain the fre-
stroma and its turnover rate. A rapid renewal system, illus- quently dividing intermitotic cells, may chiefly include
trated in Fig. 4a, consists of vegetative intermitotic cells, temporary or permanent inhibition of mitosis, normal and
differentiating intermitotic cells, and fixed postmitotic cells precocious maturation and loss of cells without replacement
as found in the skin or the mucous membrane of the ali- for a time, and much mitosis-linked death of cells. Since
mentary tract in the testes. The initial fractional doses of these tissues are self-repopulating from vegetative and/or
irradiation destroy the stem cell compartments (vegetative differentiating intermitotic cells, they are highly radiosen-
intermitotic cells and differentiating intermitotic cells) and sitive during mitosis. These cellular effects require rela-
reduce the production of cells that normally flow into the tively small doses, such tissues being highly radiosensitive.
postmitotic compartment. The lining or mucous membrane In the case of in frequently or slowly repopulating tis-
thins and, as the dose increases, the connective tissue sues, i.e., those in which the only source of repopulation are
becomes edematous. With large doses, the parenchymal the rarely dividing, long-lived reverting postmitotic cells,
compartment may be lifted or sloughed as a result of the the chief and almost the only mechanism of relatively direct
edema. The ability of the tissue to regenerate depends on the radiation-induced hypoplasia and atrophy is interphase
survival of stem cells (vegetative intermitotic cells), which death, which requires large doses. Therefore such tissues are
gradually increase in number, differentiate, and rebuild the relatively radioresistant.
postmitotic compartment. The compartments eventually In the case of tissues which cannot repopulate their
stabilize, but they might be relatively reduced as a result of parenchymal cells, i.e., tissues containing irreplaceable,
increased fibrosis and an increased histo-hematic barrier. If long-lived fixed postmitotic cells, the only mechanism of
large doses have been given, the microcirculation might relatively direct radiation-induced hypoplasia and atrophy is
become occluded at a later time, leading to frank delayed interphase death, and therefore such tissues are extremely
necrosis. With lesser degrees of fibrosis, the parenchymal radioresistant.
compartment might atrophy, and when stressed, as by As the dose is gradually increased in the irradiation of an
infection, might show its limited stem cell reserve capacity or organ, more and more indirect effects at the intertissue level
mitotic potential to respond. are brought to bear on the irradiated tissues, reducing the
The sequence of events differs in a slow renewal system or degree of selectivity that is associated with relatively direct
nonrenewal system (Fig. 4b). The parenchymal compartment effects on the tissue. In the case of the relatively resistant,
consists of reverting postmitotic cells or fixed postmitotic slowly repopulating tissues or nonrepopulating tissues, the
cells. Little or no change occurs in the parenchymal com- hypoplasia and atrophy which may be caused by large doses
partment with the fractional dose schemes used clinically. The is often due in large measure to relatively indirect (intert-
vascular stromal compartment more often determines the issue) mechanisms, prominent among which are effects
course of events, although there are effects that can be mediated through damage reactions of the cellular elements
attributed to a direct effect on parenchymal cells. The late of interstitial connective tissue and the fine vasculature. The
expression of injury of these cells is caused by their slow microvasculature has a relative radiosensitivity which is
renewal, hence the slow expression of injury. intermediate between dividing intermitotic cells on the one
hand and reverting or fixed postmitotic cells. Similarly, in
2.4.1 Concept and Criteria of Radiosensitivity the irradiation of organs or segments of the body, more
of Tissues remote indirect (interorgan or systemic) mechanisms may
As in the case of the cell, the radiosensitivity or radiore- contribute to the total effect on tissues being irradiated.
sistance of tissues, relates to differences in degree of The relative radiosensitivity of a tissue is determined
response to similar doses to differences in doses required to largely by the relative radiosensitivity of its parenchymal
produce similar responses. These terms are relative desig- cells. Therefore, the essential radiosensitivity of the fine
nations and depend upon the criterion or effect used as a vasculature and connective tissue cells is modified by the
basis for classification. The criterion of relative radiosen- radiosensitivity of the different tissue types in which it is
sitivity of tissue types used here is the relatively direct loss embedded. The radiation sensitivity of the fine vasculature
(hypoplasia) of the parenchymal (definitive) cells of the and interstitial connective tissue is generally less than that
tissue, with resulting tissue atrophy. The term ‘‘relatively of tissues containing vegetative and/or differentiating
direct’’ is defined as the result of mechanisms entirely intermitotic parenchymal cells, but is generally greater than
contained within the tissue specified. that of tissues composed only of reverting or fixed
16 P. Rubin and G. Casarett

Table 4 Normal tissues and their relative radiosensitivity

Organs Relative Chief mechanisms of parenchymal hypoplasia
radiosensitivity
Lymphoid organs, bone marrow (and blood), testes, ovaries, High Destruction of parenchymal cells, especially the vegetative
intestines or differentiating intermitotic cells that are precursors of the
mature parenchymal cells
Skin and other organs with epidermoid linings (cornea, oral Fairly high Destruction of vegetative and differentiating intermitotic
cavity, esophagus, rectum, vagina, uterine cervix, urinary cells of stratified epithelium
bladder, ureters, etc.)
Optic lens, stomach Fairly high Destruction of proliferating epithelial cells
Growing cartilage Medium Destruction of proliferating chondroblasts, plus some
damage to the fine vasculature and connective tissue
elements
Fine vasculature Medium Damage to the endothelium, plus some inflammatory
reaction to the destruction of associated, dependent, sensitive
parenchymal cells
Growing bone Medium Destruction of connective tissue cells and chondroblasts or
osteoblasts, plus some damage to the fine vasculature
Mature cartilage or bone, salivary glands, respiratory Fairly low Hypoplasia secondary to damage to the fine vasculature and
organs, kidneys, liver, pancreas, thyroid, adrenal, pituitary connective tissue elements with relatively less contribution
by the direct effects on parenchymal tissues
Muscle, brain, spinal cord Low Hypoplasia secondary to damage to the fine vasculature and
connective tissue elements, with little contribution by the
direct effects on parenchymal tissues

postmitotic parenchymal cells. Consequently, in tissues of on parenchymal tissues mediated through damage to the local
the former type (containing sensitive parenchymal cells), fine vasculature and connective tissue; here, too, the chief
radiation can cause early or acute lesions (hypoplasia, mechanisms of the organ effect are indicated.
atrophy) largely through relatively direct mechanisms at the
tissue level, with relatively little mediation of the effect 2.4.4 Organs According to Relative
through damage to the fine vasculature and interstitial Radiosensitivity
connective tissue. On the other hand, in tissues of the latter The order of relative radiosensitivity is given in terms of
type (containing resistant parenchymal cells), the produc- high, fairly high, medium, fairly low, and low. Tissue or
tion of early or acute lesions requires larger doses and is organ parenchymal hypoplasia secondary to damage to
usually associated with more marked mediation of the effect the vasculature and interstitial connective tissue varies
through damage to the fine vasculature and/or connective according to the progressive nature of the damage to
tissue elements and a relatively lesser contribution to the these supporting tissues. A moderate radiation dose may
lesion from relatively direct mechanisms of tissue effect. result in the development over a long period of time of a
The radiation damage changes in the fine vasculature and degree of parenchymal hypoplasia similar to that which
interstitial connective tissue play a very important role in may be caused by a large dose in a short period of time.
the production of chronic or delayed lesions in tissues of all Therefore the order of relative radiosensitivity of the
kinds. The chronic and delayed radiation lesions are tissues and organs listed in Tables 3 and 4 is based
associated with nutritional and metabolic disturbances of arbitrarily on the maximal degree of hypoplasia observed
the tissues. within two months, a period of time sufficient to observe
most of the relatively direct destructive actions of radia-
2.4.3 Classification of Tissues tion in tissues.
In keeping with the above considerations, various types of
tissues are listed in Table 3 in the order of decreasing
radiosensitivity, on the basis of the relatively direct radiation 2.5 Biocontinuum of Histologic Sequence
effect (hypoplasia) on the tissues specified; the chief mech- of Events
anisms of the tissue effect are indicated. Similarly, in Table 4
are listed various organs in the order of decreasing radio- The development of the cellular and histopathologic effects
sensitivity, on the basis of the relatively direct radiation effect of radiation in various organs, from the subclinical levels to
(parenchymal hypoplasia), which would include effects due the levels of clinical importance in radiotherapy, is also
to inter tissue mechanisms within the organs, such as effects greatly dependent on (1) organ radiosensitivity, (2) dose,
Biocontinuum of the Pathophysiology Paradigm 17

(3) time, and (4) volume of organ. But beyond this, such 2.5.2 Phase II
development is dependent upon additional factors, including This phase is characterized chiefly by processes of recovery
(5) the structural nature of the organ as related to its function, from acute damage, although there may be some evidence
(6) the reserve functional capacity of the organ, and therefore of cell necrosis or tissue hypoplasia still persisting and there
(7) the fraction of the organ irradiated, (8) the relative may be evidence of the beginning of chronic or permanent
functional importance of the organ to the body, and (9) the tissue damage. In the tissues that can repopulate themselves
clinical detectability of the related functional changes. with parenchymal cells to replace those lost, regenerative
The acuteness or chronicity of the histopathologic changes replacement is prominent during this phase. If cell regen-
underlying the first appearance of clinical complications eration is very slow or inadequate owing to marked damage,
depends to a considerable extent on the relative radiosensi- repair by secondary intention (replacement fibrosis) may
tivity of the parenchyma of the organ in relation to the relative become relatively prominent. Subtle evidence of continuing
sensitivity of the fine vasculature and supporting tissue. spotty degeneration of the fine vasculature may persist in
Under a given set of conditions, the first appearance of clin- this phase, as well as evidence of both typical repair of the
ical effects in organs containing parenchymal tissue that is endothelium in some regions and atypical repair of the fine
relatively highly sensitive to the cytocidal action of radiation vasculature in the form of spotty fibroblastic activity and
is more likely to be associated with the histopathologic early fibrosis in and around the walls of these vessels and
development of acute degeneration of the parenchyma, interstitially. These early atypical repair processes represent
whereas in organs containing relatively radioresistant paren- the beginning of increases in arteriolocapillary fibrosis and
chyma the underlying histopathologic change is more likely the histo-hematic connective tissue barrier described earlier.
to involve a predominance of chronic deterioration of the fine The severe damage to the fine vasculature caused by
vasculature and secondary degeneration of the parenchyma. large radiation doses results in poor support for continuing
Consequently, under the various conditions of radiation viability or regeneration of any kind of dependent cell,
therapy, the period of time from irradiation to the end of radiosensitive or radioresistant. Under these conditions this
life may be characterized by continuous complications of recovery phase is usually characterized by marked lesions
clinical significance arising from irradiation of normal in which repair by secondary intention (fibrosis) may be the
organs, by alternation of periods of such clinical compli- most prominent repair process.
cation with clinically ‘‘silent’’ periods of the absence of
such clinically significant complications. However, there is 2.5.3 Phase III
at no time a ‘‘silent’’ histopathologic period, i.e., absence of This phase is an intermediate phase of little or no change in
radiation induced changes in the irradiated organs, although parenchymal cellularity after the irradiated tissue has
their degree or rate of progression may vary considerably. regenerated parenchymal cells to the extent of its capability.
Furthermore, the addition of further stress or insult, The duration of this phase, before the beginning of the later
e.g., from trauma or infection, to organs that have sustained phase of parenchymal tissue hypoplasia or premature invo-
residual radiation damage may precipitate clinically lution or necrosis, varies widely and inversely with the dose.
significant complications during otherwise clinically If the dose is very large, this intermediate phase may be
‘‘silent’’ periods. The histopathologic sequence of events virtually nonexistent, with failure of parenchymal regenera-
after a brief radiation exposure is divided into four general tion and with continued or progressive deterioration of the
phases: Casarett Hypothesis. parenchyma cells and fine vasculature. On the other hand,
after small or moderate doses that permit parenchymal cell
2.5.1 Phase I regeneration to normal or near normal levels of cellularity,
This phase is characterized chiefly by the development of this intermediate phase may be relatively long in duration.
acute damage to cells and tissues that are sufficiently sen- Even under these conditions, however, the degenerative
sitive to the dose administered, although recovery processes changes in fine vasculature and the interstitial fibrosis, once
begin during this phase also. In highly radiosensitive tissues initiated, progress in degree or may be added to other similar
there may be conspicuous inhibition of mitosis and changes that develop with time or increasing age.
destruction of parenchymal cells, leading to hypoplasia and
atrophy of the tissues. Lesser degrees of such changes are 2.5.4 Phase IV
seen in this phase in the more radio-resistant tissues. There This phase is characterized by delayed or late parenchymal
may also be damage to small blood vessels and connective degeneration, either in the form of gradual premature invo-
tissues in this phase, partly as a result of the relatively direct lution of tissues, with hypoplasia, atrophy and replacement
effects of radiation on these structures and partly as a result fibrosis, as in premature aging, or in the form of a more rapid
of the secondary effects of parenchymal cell destruction and breakdown or necrosis of tissues. The possibility that unre-
the resulting inflammatory processes. paired intracellular damage such as chromosomal damage
18 P. Rubin and G. Casarett

Fig. 5 Clinical expression

events of the biocontinuum

may contribute to such delayed effects is not precluded. course of the fractionated radiation treatment, is depicted
However, at the histologic level, both these types of delayed on the graph by the sharp initial rise in the radiation
effects seem to be sequentially secondary to the progressively damage. Although recovery processes are operating
increasing degrees of degeneration of the fine vasculature between radiation exposures, the destructive processes
and increasing density of quantity of fibrous connective tis- predominate during the course of radiotherapy. The
sue. In general, the larger the dose, the earlier and more steepness of the radiation damage curve depends upon the
rapidly these late effects develop. relative radiosensitivity of the organ, the dose, and the
schedule of fractionation. The recovery from acute organ
damage (histopathologic phase II) after the cessation of the
2.6 Clinical Expression Events course of radiotherapy is depicted by the gradual decline
of the Biocontinuum in the radiation damage after the peak of acute damage.
The steepness of the recovery curve is usually greater with
The sequence of clinical events after the initiation of radi- lesser degrees of acute radiation damage and complicating
ation therapy will be considered in terms of four successive factors.
periods of time of arbitrary length, as follows: acute clinical Whether or not the radiation damage of an organ is
period (first 6 months), subacute clinical period (second sufficient to reach levels of clinical significance or to exceed
6 months), chronic clinical period (second through fifth tolerance limits and cause death in the acute clinical periods
years), and late clinical period (after 5 years): Rubin depends upon the relative radiosensitivity of the organ, the
Hypothesis (Fig. 5). dose, the schedule of fractionation, and the occurrence or
The diagram illustrates generally, with respect to these absence of complicating factors. In the case of some organs,
clinical periods, the waxing and waning (vertically) or with certain schedules of radiotherapy, the first part of the
organ damage with time and persistence or progression of acute clinical period or even the whole of this period may
residual damage. The upper lines depict radiation damage be clinically silent, with clinically significant changes
of different degrees. The bottom line indicates the accu- appearing for the first time, if at all, in later clinical periods
mulation of organ damage with time or ‘‘aging,’’ may be as a result of deterioration of the vasculature and the
additive to radiation damage in effect. The rising arrows occurrence of complications.
indicate the precipitation of damage from subclinical or
clinical levels to clinically significant or even lethal levels,
as a result of complications such as trauma or infection or as 2.6.2 Subacute Clinical Period (Second 6 Months)
a result of deterioration of the vasculature and failure of the In the radiation damage graph in Fig. 5, the leveling of the
blood circulation. No precise values or relationships are slope or the plateau of the recovery portions of the curves
intended for the slopes or shapes of the graph lines. above the threshold or ‘‘aging’’ damage levels during the
subacute clinical period depicts the end of recovery from
2.6.1 Acute Clinical Periods (First 6 Months) acute damage (end of histopathologic phase II) or the per-
The accumulation of acute organ damage (histopathologic sistence or early progression of permanent residual damage
phase I) during the first part of this period, i.e., during the (histopathologic phase III).
Biocontinuum of the Pathophysiology Paradigm 19

2.6.3 Chronic Clinical Period (Second Through percentage for the risk of complications.
Fifth Years)
In the radiation damage graphs in Fig. 5, the gradually • The minimal tolerance dose is defined as TD5/5, i.e., the
rising lines depict an increase in degree of chronic organ dose to which a given population of patients is exposed
damage, in terms of the progression of permanent residual under a standard set of treatment conditions resulting in
radiation damage and/or the addition of aging damage no more than a 5 % severe complication rate within
(histopathologic phases III and IV). The clinically signifi- 5 years after treatment.
cant problems arising during this clinical period are usually • The maximal tolerance dose is defined as TD50/5 i.e., the
the result of chronic deterioration of the organ’s vasculature dose to which a given population of patients is exposed
and circulation, an increase in the histo-hematic connective under a standard set of treatment conditions resulting in a
tissue barrier, degeneration of dependent parenchyma, and a 50 % severe complication rate at 5 years after treatment.
reduction in resistance to complicating factors such as
infection, trauma, or functional stress. The ‘‘dose limiting tissues or organs’’ in radiation ther-
apy are based upon our inability to define an optimum
2.6.4 Late Clinical Period (After the Fifth Year) tumor dose (many biological factors are unknown clini-
The histopathologic and clinical developments during this cally) so that the radiation oncologist is often required to
clinical period are essentially similar to those described for the treat to tolerance. These dose limiting tissues have been
chronic clinical period, except for the slower progression of defined into three categories or classes:
permanent residual radiation damage and a greater depen- The concept was based on utilizing standard radiation
dence upon the addition of the damage of aging. Radiation regimes as supervoltage radiation became available,
carcinogenesis can be manifested during this period and is i.e., 60–70 Gy, in 6–7 weeks, 10 Gy a week, 5 days each
usually preceded by some manifestation of chronic radiation week, daily dose of 1.8–2.0 cGy. Normal Tissues/Organs
damage. were divided into 3 classes:

• Class I—Organs in which radiation lesions are fatal or

3 Prologue II: Concept of Radiation result in severe morbidity.
Tolerance Dose – Vital Organs (Table 5).
• Class II—Organs in which radiation lesions result in
3.1 Introduction: Historical Annotation
moderate to mild morbidity and in exceptional circum-
stances a fatality, but generally late effects are compatible
The Tolerance Dose is an important concept first generated
with survival.
in collaboration with radiation oncology colleagues in
– Essential Organs (Table 6).
national cooperative oncology groups. In the decades as
• Class III—Organs in which radiation lesions result in
radiation therapy was separating from radiologic diagnosis
mild, transient, reversible effects or in no morbidity.
(1960–1970), NCI supported radiation research symposia
– Tolerant Organs (Table 7).
during which controversial concepts were addressed. ‘‘The
Biology of dose Limiting Tissues: Time and Dose Rela-
tionships in Radiation Biology as applied to Radiotherapy’’.
Mendlesohn indicated how ‘‘Dose Response Data/Curves’’ 3.3 Tolerance Volume Effect
were generated in the laboratory but clinical prudence
limited the ability to create valid data since clinicians The ‘‘Volume Effect’’ was based on whether the whole
avoided producing severe radiation complications. In organ or partial organ was irradiated based on field size and
response, Rubin (Vice Chairman of RTOG and Chairman of length according to the available literature. The concept of
Late Effects Committee) reviewed the available literature, tolerance volume needs to be defined in the same fashion as
consulted with colleagues (Ted Phillips), and generated the tolerance dose. The volume frequently proves to be more
following definitions 3. critical to complications outcome and also serves as a
clinical guide because it is possible to obliterate or lose a
certain volume of a vital organ with large doses; exceeding
3.2 Tolerance Dose Effect the TD50–100 is akin to surgical resection (stereotactic
radiation surgery). Loss of some volume generally does not
The Tolerance Dose is an attempt to express the minimal affect organ survival because the organ can often compen-
and maximal injurious dose acceptable to the clinician. This sate for volume loss, up to a threshold volume, through
requires the assignment of an arbitrary but useful regeneration or hypertrophy and remain, although impaired,
20 P. Rubin and G. Casarett

Table 5 Tolerance dose effect

Class I organs Injury TD5/5 TD50/5 Whole or partial organ Referencea
(Field size or length)
Bone marrow Aplasia, pancytopenia 250 450 Whole Bond et al.
3,000 4,000 Segmental Rubin et al.
Liver Acute and chronic hepatitis 2,500 4,000 Whole Ingold et al.
1,500 2,000 Whole strip Kraut et al.
Stomach Perforation, ulcer hemorrhage 4,500 5,500 100 cm2 Friedman
Intestine Ulcer, perforation, hemorrhage 4,500 5,500 400 cm2 Friedman
5,000 6,500 100 cm2 Roswit et al.
Palmer
Brain Infraction, necrosis 6,000 7,000 Whole Kramer et al.
7,000 8,000 25 % Lindgren
Spinal Cord Infraction, necrosis 4,500 5,500 10 cm Phillips and Buschke
Wara et al.
Heart Pericarditis and pancarditis 4,500 5,500 60 % Newton
Stewart and Fajardo
Lung Acute and chronic pneumonitis 3,000 3,500 100 cm2 Gish et al.
1,500 2,500 Whole Lokick et al.
Wara et al.
Kidney Acute and chronic nephrosclerosis 1,500 2,000 Whole (strip) Kraut et al., Tefft
2,000 2,500 Whole Kunkler et al.
Fetus Death 200 400 Whole Rugh

Table 6 Tolerance dose effect

Class II organs Injury TD5/5 TD50/5 Whole or partial organ
(Field size or length)
Oral cavity/pharynx Ulceration, mucositis 6,000 7,500 50 cm2
Skin acute and chronic dermatitis 5,500 7,000 100 cm2
Esophagus Esophagitis, ulceration 6,000 7,500 75 cm2
Rectum Ulcer, stricture 6,000 8,000 100 cm2
Salivary glands Xerostomia 5,000 7,000 50 cm2
Urinary bladder Contracture 6,000 8,000 Whole
Ureters Stricture 7,500 10,000 5–10 cm
Testes Sterilization 100 200 Whole
Ovaries Sterilization 200–300 625–1200 whole
Growing cartilage, Growth arrest, 1,000 3,000 Whole
Growing bone (Child) Dwarfting 1,000 3,000 10 cm2
Pure cartilage, Necrosis, 6,000 10,000 Whole
Mature bone (Adult) Fracture, sclerosis 6,000 10,000 10 cm2
Eye retina 5,500 7,000 Whole
Cornea 5,000 6,000 Whole
Lens 500 1,200 Whole or part
Endocrine glands Hypothyroidism 4,500 15,000 Whole
Thyroid Hypoadrenalism [6,000 – Whole
Adrenal Hypopituitarism 4,500 20,000–30,000 Whole
Pituitary
Peripheral nerves Neuritis 6,000 10,000 10 cm
Ear middle Serous otitis 5,000 7,000 Whole
Ear inner vestibular Meniere’s syndrome 6,000 7,000 Whole
Biocontinuum of the Pathophysiology Paradigm 21

Table 7 Tolerance dose effect

Class III organs Injury TD5/5 TD50/5 Whole or partial organ
(field size or length)
Muscle (Child) Atrophy 2,000–3,000 4,000–5,000 Whole
Muscle (Adult) Fibrosis 6,000 8,000 Whole
Lymph nodes and Atrophy 5,000 [7,000 Whole node
Lymphatics Sclerosis
Large arteries/veins Sclerosis [8,000 [10,000 10 cm2
Articular cartilage None [50,000 [500,000 Joint surface (mm2)
Uterus Necrosis, [10,000 [20,000 Whole
Perforation
Vagina Ulcer, fistula 9,000 [10,000 Whole
Breast (Child) No development 1,000 1,500 Whole
Breast (Adult) Atrophy, [5,000 [10,000 Whole
Necrosis

Fig. 6 Volume effect: a The dose–response curve is not an absolute from dose–volume histograms. Inst J Radiat Oncol Biol Phys 1987;
or fixed effect but varies as a function of volume. This important 13:103, with permission from Elsevier Science). b for TD5 and TD50,
concept allows the radiation oncologist to give much larger doses to the dose increases as the volume decreases. Note that the slope
partial volumes. (From Lyman JT, Wolbarst AB: Optimization of changes as more than 50 % of the whole organ is included. Small
radiation therapy. III: a method of assessing complication probabilities increments in dose, that is 10–20 %, can prove to be lethal

within functional tolerance for survival. Different organs total volume (as applied to paired organs) is exceeded and
demonstrate a range of tolerance volume (TV) parameters: threatens survival.
1. TV5–25: 5–25 % of the organ volume irradiated can The time when organ decompensation begins clearly
result in a life-threatening or lethal complication. depends on the compensatory regenerative mechanisms that
2. TV50–90: 50–90 % of the organ volume irradiated can come into play when significant organ volume loss occurs.
result in a life-threatening or lethal complication. The dose–response curve is not an absolute or fixed effect but
There are generally two levels of critical volume for varies as a function of volume. This is an important concept
dose-limiting or vital organs. Only the gastrointestinal because it allows the radiation oncologist to give much larger
tract and the central nervous system (CNS) can have doses to partial volumes. For TD5 and TD50, the dose
disastrous outcomes after small volumes (TV 5–10 %) are increases as the volume decreases. Note that the slope chan-
exposed to doses exceeding TD5–50. However, it is ges as more than 50 % of the whole organ is included and is
important to note that necrotic bowel and, on occasion, steeper. Small increments in dose, that is, 10–20 % of the
CNS necrotic foci can be resected successfully. For the total dose, can be lethal. The dose–volume histogram is being
majority of organs considered dose limiting, such as bone adopted by numerous investigators to predict unfavorable
marrow, lung, kidney, and, in all probability, heart and outcomes as a result of volume loss in a critical structure.
liver, high doses can be tolerated to smaller volumes. Such An important and insightful concept was developed by
organs may decompensate when more than 50 % of the Lyman, in which the dose response curve is not an absolute
22 P. Rubin and G. Casarett

Table 8 Parameters of therapy: tolerance doses (TD5/5–TD50/5) tissue toxicities. Thus, although previously defined radia-
Single dose (Gy) Fractionated tion tolerance doses (TD5 and TD50) remain as valuable
dose (Gy) guides, their applicability has changed. Radiation doses
Lymphoid 2–20 Testes 1–2 customarily deemed to be safe may no longer be so. When
Bone marrow 2–10 Ovary 6–10 combined with another therapy, such doses can lead to
Ovary 2–6 Eye (lens) 6–12
severe late effects with regard to different vital organs.
Factors relevant to defining tolerance doses include those
Testes 2–10 Kidney 20–30
from therapy, the host, and the tumor.
Eye (lens) 2–10 Thyroid 20–40
Mucosa 5–20 Lung 23–28 3.4.2 General Therapy Modifying Factors
Lung 7–10 Skin 30–40 • Dose: There is no absolute or fixed dose that ablates a
GI 5–10 Liver 35–40 normal tissue because the TD5/5 and TD50/5 are dependent
Colorectal 10–20 Bone Marrow 40–50 on dose, time, and volume factors.
Kidney 10–20 Heart 43–50 • Fractionation: The radiation fraction dose, the interval
Heart 18–20 GI 50–55 between fractions, and the overall duration of therapy are
major determinants of both early and late effects. The
Vasculo connective 10–20 Vasculo connective 50–60
tissue tissue time to expression of the effect is related to the cell
Liver 15–20 Spinal cord 50–60
kinetics of different subpopulations within a tissue organ.
With alternate fractionation regimens under investigation,
Skin 15–20 Brain 55–70
the TD5/5 and TD50/5 will shift for different organs. Hyper
Peripheral nerve 15–20 Peripheral nerve 65–77
fractionation, accelerated fractionation, and hypo frac-
Spinal cord 15–20 Mucosa 65–77 tionation have different effects on tolerance doses.
Brain 15–25 Bone and cartilage [70 • Volume: A major factor in determining a tolerance dose is
Bone and cartilage [30 Muscle [70 whether the whole or part of an organ is exposed to
Muscle [70 radiation. With more widespread use of large fields, for
example, total body irradiation (TBI) and hemibody
irradiation (HBI), compared with very defined or small
or fixed effect but varies as a function of organ volume. A 3- fields, for example, intraoperative radiation therapy and
D construct allowed for a method of assessing complication stereotactic radiosurgery, single or brief radiation expo-
probabilities from dose–volume histograms (Fig. 6a) this sures with various dose rates to different volumes, will
concept provided the radiation oncologist with a guide as to create a new set of normal tissue toxicities.
varying the dose depending on volume (Fig. 6b). This • Chemotherapy: Of the various modalities, the addition of
concept applied to organ tolerance doses, arbitrarily chemotherapy and the timing of its delivery relative to
choosing 1/3 and 2/3 organ volumes was then published irradiation have a major impact on organ sensitivity. The
with Enami et al. use of an agent may dramatically affect either the same
cells or different cell subpopulations, leading to lower
threshold doses for organ injury. The widespread use of
3.4 Tolerance of Organs drugs is the most common factor altering the tolerance
dose concepts of normal tissues.
3.4.1 Dose–Time–Volume Factors • Innovations: The new modalities, radiosensitizers and
Dose-limiting organs and tissues in radiation oncology radioprotectors, and immunologic and biologic response
have been defined according to their tolerance doses modifiers, including gene therapy, may each or all alter
(Table 8). The minimal tolerance dose (TD5/5) and the late effects.
maximal tissue tolerance dose (TD50/5) refer to severe to The concept of an optimal radiation dose that provides
life-threatening complications occurring in 5 and 50 % of maximal curability and minimal toxicity is the basis of
patients within 5 years of therapeutic radiation treatment. varying fractionation schedules. Strandqvist lines or isoeffect
However, in this era of multimodality, there are many plots based on varying dose-time regimens suggest that an
factors that affect our concepts of radiosensitivity. The optimal zone can be found, yielding a favorable therapeutic
rapid advances of radiation oncology and the related sci- ratio. Although these lines were originally drawn with par-
ences of radiation biology and radiation physics and allel slopes, it became apparent to many investigators that
accumulating information about interactions with other tumors respond differently to normal tissues, and a diver-
therapeutic modalities (e.g., chemotherapy or biologic gence in isoeffect slopes occurs. The importance of the vol-
response modifiers) impact our understanding of normal ume of normal tissue in the field and dose-time factors needs
Biocontinuum of the Pathophysiology Paradigm 23

Table 9 Parameters of therapy: tolerance dose TD5/5–TD50/5

Target cell Complication end point Dose range (Gy)a
TD5/5–TD50/5
Range: 2–10 Gy
Testes/spermatogonia Sterility 1–2
Lymphoid tissue/lymphocytes Lymphopenia 2–10
Diseased bone marrow Severe leukopenia and thrombocytopenia 3–5
(CLL or multiple myeloma) 6–10
Ovary/oocytes
Range: 10–20 Gy
Lens Cataract 6–12
Bone marrow stem cells Acute aplasia 15–20
Range: 20–30 Gy
Lung-type II cells, vasculo connective tissue Pneumonitis/fibrosis 20–30
Kidney-glomeruli Arterionephrosclerosis 23–28
Range: 30–40 Gy 25–35
Bone marrow Hypoplasia 35–40
Liver-central veins Radiation hepatitis
Range: 40–50 Gy 43–50
Heart (whole) Pericarditis and pancarditis 45–50
Bone marrow microenvironments, sinuses Permanent aplasia
Range: 50–60 Gy 50–55
GI organ Infarction necrosis 50–60
Spinal cord Myelopathy 50–60
Brain Encephalopathy 55–65
Heart (partial) Cardiomyopathy
Range: [60–70 Gy 65–75
Mucosa Ulcer 65–75
Rectum Ulcer 65–75
Bladder Ulcer 65–75
Mature bones Fracture
CCL Chronic lymphocytic leukemia
a
Doses are given as the total fractionated dose to whole or partial organs
From Rubin P: Law and order of radiation sensitivity. Absolutely versus relative. In: Vaeth JM, Meyer JL (eds): Frontiers of Radiation Therapy
and Oncology, 23rd edn, p7. Basel, Karger, 1989, with permission

Fig. 7 a The modification of this figure is the line indicating the the line indicating the TD50/5. In unfavorable circumstances, the
TD5/5 proposed. In favorable circumstances, the radiation therapist radiation therapist is often unwilling to exceed the maximal rate
would not be willing to exceed the numerical rate of complication. since the dose–response curve rises sharply. Modified from Mendel-
Modified from Mendelsohn (9). b The modification of this figure is sohn (9)
24 P. Rubin and G. Casarett

to be stressed when considering tolerance of normal tissue or Chap. 8 (Understanding and Predicting Radiation-Associ-
organs (Rf: Von Essen). In re-examining and revising the ated Normal Tissue Injury: A Global and Historical Per-
tolerance doses for different vital dose-limiting tissues and spective), as well as in the site-specific chapters throughout
organs, the volume factor is even more relevant today in view the book.
of the increasing use of TBI and HBI, in which whole organ
systems are exposed. More time concentrated schedules are
in use, varying from single exposures to short, intense hypo 4 Prologue III: The Concept of Pediatric
fractionation schedules of stereotactic radiosurgery. Another Radiation Sensitivity
modality—intraoperative radiation therapy—has led to the
use of large, single doses to large tissue volumes and has
provided new insights into tolerance doses. 4.1 Introduction: Historical Annotation
At present, the prescribed tolerance dose is, at best, a
calculated estimate of the TD5 and TD50 based on recor- ‘‘Pediatric Radiation Tolerance Doses’’ were graduated as a
ded human and animal data. The complication probability function of age in Children Oncology Cooperative groups
of either 5 (TD5) or 50 % (TD50) assumes uniform irra- for most normal tissues. Discovering the postnatal pediatric
diation of all or part of an organ, conventional fraction- growth curves, radiation tolerance doses were redefined as a
ation schedules (1.8–2.0 Gy per fraction and five fractions function of normal tissues evolution from infant to child to
per week), relatively normal organ function as a baseline, adolescence. Uncovering the seminal research thesis and
no adjuvant drugs or surgical manipulations, and age basis which we published in the 1920s is acknowledged to
ranges that exclude children and the elderly (Table 9). In SCAMMON for the first time (not Tanner or Harris). His
ordering the organ radiosensitivity according to dose remarkable thesis is presented to illustrate the importance of
level, a variety of factors are considered, including the end identifying the original reference; counter to emphasizing
point chosen (late rather than acute effects), the use of the most recent publications to be current. In 1980, a ‘‘new
single or fractionated regimens, and the volume of the hypothesis’’ of relating pediatric normal tissue/organ toler-
organs. Because the literature is not always complete or ance to the classic ‘‘Growth curves of different normal tis-
precise, extrapolation is inevitably involved when using sues/organs’’ was developed with Sandy Constine.
either clinical or experimental animal data. The dose
levels are rounded off rather than recorded precisely to
one or two decimals, as is occasionally reported. Such 4.2 Concept of Mitotic Potential Versus
accuracy can be as misleading as the general estimates of Mitotic Activity
tolerance doses offered.
The child, like the embryo, is a mosaic of numerous tissues
3.4.3 Specific Organ Tolerances: Dose-Limiting and organs which are undergoing continual growth and
Tissues maturation. These tissues and organs have cells that are in
Most organ systems are composed of many cell subpopu- various stages of development: totipotential, multipotential,
lations (20–40 or more), each performing an important and eventually unipotential which are either resting or in
activity. Therefore, organ tolerance is determined by the active proliferation without or with differentiation into
radiosensitivity or relevant stem cell subpopulations that specialized tissues or organs. Just as the fetus in its devel-
may not always be proliferating or dividing; the most opment is continually changing in its tissue and cellular
radiosensitive, vital cell population determines organ tol- kinetics, so in turn is its radiosensitivity with critical points
erance and organ failure. Just as the degree of importance in time of exquisite vulnerability to irradiation for specific
held by an irradiated organ determines the survival of an organs. Similarly, the infant and child consist of an array of
organism, the functional capacity of cells is often distinct tissues and organ that vary in radiosensitivity at different
from their regenerative capacity, permitting organ physiol- times according to their developmental stage.
ogy to be preserved in the face of injury and allowing for The hypothesis advanced for understanding the changing
recovery or repair from the insult. radiosensitivity and radioresistance of pediatric tissues is in
Late Effects of Normal Tissue (LENT) syndromes at comprehending their periods of active proliferation and
each organ site are not random events but are specific differentiation and eventual maturation. Growth of an organ
entities that occur at certain times and are expressed in a varies from infancy, childhood, and puberty and is not
recognizable fashion and often can be ameliorated. A LENT constant. Correction factors applied for radiation dose are
paradigm is presented in diagrammatic form for each organ modified by age but do not recognize that various organs
site (Fig. 7a and b). Additional detailed information indeed develop and mature at different rates (Table 9). No
regarding specific organ tolerances are summarized in one formula can be applied universally to all tissues.
Biocontinuum of the Pathophysiology Paradigm 25

Adjusted doses for age assumes that growth occurs at a

constant rate. The growth rate and maturation of each tissue
or organ is the major determinant of its radiosensitivity. A
model for pediatric radiosensitivity of normal tissues and
organs is developed in an analogous fashion to fetal organ
radiosensitivity.

4.3 The Fetal Model of Radiosensitivity:

Prenatal Organogenesis

The susceptibility of the fetus to radiation and the resultant

dramatic occurrence of congenital abnormalities has been
the subject of intense study. Analogies have been drawn
between experimental studies in mammalian fetal radiobi-
ology and abnormalities observed in human circumstances.
It is possible to extrapolate from these laboratory studies to
man.
The principle events in the development of an embryo
include implantation, placentation, organogenesis, and the
differentiation of the various organs. The sequence of
events tends to be the same in different mammalian spe-
cies with only the timescale differing (11, 16, 36). Both in
Fig. 8 The pediatric model of radiosensitivity: postnatal growth
the experimental model and in clinical experience, mod-
spurts
erate doses of ionizing radiation have been shown to
produce catastrophic effects in the fetus which include
growth retardation, fetal death, or gross congenital mal-
formations (36). In the mouse, a dose of 200 rad will lead
to prenatal deaths in the preimplantation phases, abnor-
malities, or neonatal deaths during the organogenesis (38).
Neural tissues are interestingly the most exquisitely sen-
sitive and most rapidly dividing in early fetal develop-
ment. An exposure of 100–500 rad during the course of
embryogenesis suffices to produce neural malformations,
mainly an overall reduction of brain size as micro-opt-
halmy or micro-cephaly (16). In comparison, 2 weeks after
birth, doses greater than 1,000 rad are necessary to pro-
duce neurologic abnormalities in rats (9, 52). Information
available from Japanese survivors of the A bomb attacks
show an increase in fetal deaths, infant deaths, and neu-
rologic abnormalities (24). Doses lower than 250 rad
delivered between the 4th and 20th weeks of gestation Fig. 9 The pediatric model of radiosensitivity: postnatal growth
may lead to severe abnormalities. spurts

becomes mature and differentiates into a specialized system.

4.4 The Pediatric Model of Radiosensitivity: Some systems have rapid proliferation or cell cycle kinetic
Postnatal Growth Spurts characteristics whereas others behave as slow renewal
systems and only become active again if challenged or
Instead of critical moments, days or weeks for fetal organ stimulated. ‘When does a pediatric tissue or organ become
induction and rapid development, in the child there are similar to an adult tissue or organ?’ is a question that needs
longer periods of months of rapid proliferation when the to be answered. Postnatal development has been studied
entire parenchyma of an organ is in a phase of active much less than prenatal development and information about
mitosis. At some point the collection of tissues or cells variation in growth characteristics is less well known.
26 P. Rubin and G. Casarett

In the child, there are two major periods of rapid rate of effects despite intervals up to months or years between
growth development: the postnatal period and puberty. The time of administration of these modes.
growth of the different organs follows four general patterns (6) Correction factors applied for radiation dose must take
(14, 42–44). The first is a general skeletal pattern which has into account the maturation of each organ irradiated and
the two peak periods aforementioned. The organs of circu- not the child as a unit. The doses recommended for
lation and digestion follow the pattern of the body as a whole several organs appears to be in the same range as for
(postnatal and pubertal activity). The neural type is charac- adults: heart, kidney, lung, liver. Data available in the
terized by a rapid postnatal growth which slows in late current literature suggest two periods of increased
infancy and ceases in adolescence. The respiratory and renal sensitivity: the first years of life and the puberty growth
organs tend to follow this pattern according to their matu- spurt. This latter applies for the genital organs, bone,
ration. The genital type shows little change during early life and muscle.
but rapid development just before the coincident with pub-
erty. This is particularly true of breast tissue and applies to The origin of the ‘‘post-natal pediatric curves’’ (PNPC)
testis and ovarian tissue. The lymphoid type is characterized are most often attributed to Tanner (1962); however, the
by a gradual evolution and involution to the time of puberty. PNPC are referenced to Harris 1927. Obtaining this 100-
The number of different organs will be reviewed regarding year-old book, upon inspection was an assemblage of four
their growth maturation and radiosensitivity for the different research PhD theses, entitled: ‘‘The Measurement of Man’’.
stages of proliferation and differentiation. Organ weight and The most remarkable work was by Scammon: The Mea-
size may be helpful guides, but it is essential to determine surement of The Body in Childhood. It is truly an outstanding
when an organ is through or is entering its phase of rapid research project based on autopsy specimens and radio-
proliferation. It is important to distinguish hyperplasia from graphs involving thousands of children and adolescents,
hypertrophy as to the mechanism of organ growth. To fully some followed longitudinally for two decades (1–20 years).
understand an organ’s radiosensitivity it is necessary first to Two graphs are presented (Figs. 8 and 9).
comprehend its biology.
At birth, all of these structures are growing at a rate of between
The following tenets were offered as guidelines to 5–10 % per month of their attained magnitudes and all undergo
pediatric organ radiosensitivity: a very marked reduction in these relative rates of growth in
infancy and early childhood. But thereafter the trends of this
(1) The stage of organogenesis, during fetal development measure of increment become different. The relative growth of
the body as a whole (general type) as exemplified by body
when an organ is being formed, is the most highly weight, falls to a minimum at about 7 years. This shows a dis-
radiosensitive phase. tinct para puberal rise to about 12 years and a decline there-
(2) Specific phases of tissue proliferation during infancy after. The genital organs (the general type), as exemplified by
and childhood when rapid growth spurts occur deter- the testis show an even more pronounced reduction in relative
growth rate but a tremendous prepubertal rise, which like the
mine the organ’s radiosensitivity. Radiosensitivity of a rise in relative growth of the body as a whole, reaches its peak at
tissue/organ is highest prior to and at the time of onset puberty and declines thereafter. The nervous system (the neural
of proliferative activity in each organ system. type) as represented by the brain, shows no rise in relative rate
(3) Maturation occurs at different ages for each tissue/organ of growth in later childhood or adolescence. On the contrary,
there is a steady but slow decline in this measure from childhood
and its identification allows for recognition when the to maturity. And the lymphoid organs (lymphoid type) as illus-
radiosensitivity in children is similar to adults. trated by the thymus show not only a decline, in relative velocity,
(4) Growth of an organ due to increase in cell size is less but in actual negative velocity (indicating a loss of weight) in the
vulnerable to irradiation than when due to an increase in years following puberty. Thus, measures of rates, as well as the
amounts of growth, illustrate the essential similarities of pre-
cell number, i.e., hypertrophy versus hyperplasia. natal growth at a remarkable diversity of post natal growth of
(5) Radiation therapy and chemotherapy can be additive various parts of the human body.—SCAMMON 1910–1930.
even when safe schedules are given and can lead to late
 Biophysiopathology of the Microvasculature
and Microcirculation
Philip Rubin and Luis Fajardo

Contents Abstract
The microvasculature and microcirculation are the
1 Introduction ........................................................................ 27 largest single organ in the human body. The essential
2 Anatomy .............................................................................. 28 radiosensitivity of the fine vasculature and connective
tissue cells associated with various types of dependent
3 Histology of Microvasculature ......................................... 28
tissue seems to vary much less on the basis of the
4 Physiology of Microcirculation ........................................ 29 relatively direct effects rather, than the relative radio-
5 Pathogenesis........................................................................ 30 sensitivity of various dependent tissue types themselves.
6 Capillaries and Arterioles................................................. 32
The radiation sensitivity of the fine vasculature and
interstitial connective tissue is generally less than that of
7 Histohematic Barrier......................................................... 33
the radiosensitive tissues containing more mitotically
8 Distribution of Radiation Effects on Small Vessels active parenchymal cells. Generally the greater that the
at Early Times After Irradiation is Subtle tissues are composed of sensitive parenchymal cells,
and Inconspicuous.............................................................. 33
radiation can cause early or acute lesions. The tissues
9 Microcirculation................................................................. 34 that contain resistant parenchymal cells, the production
10 Rapid Cell Renewal Kinetics............................................ 35 of early or acute lesions require large doses and is
10.1 Gastrointestinal Mucosal Epithelium .................................. 35 usually associated with more marked mediation of the
11 Slow Renewal Kinetics ...................................................... 36 effect through damage to the fine vasculature and or
connective tissue elements. The radiation damage and
12 Special Topics/Effects ........................................................ 38
12.1 Skin Grafts ........................................................................... 38 subsequent progressive changes in fine vasculature and
12.2 Supralethal ........................................................................... 39 interstitial connective tissue play a very important role in
12.3 Miscalculation High Dose ................................................... 39 the production of chronic delayed lesions in a large
12.4 Arterial Restenosis............................................................... 39
variety of tissues. The discussion of microvasculature
References...................................................................................... 39 injury varies with the cell kinetics of the different tissues
and parenchymal cells that constitute the various organs
and viscera in the body.

1 Introduction

P. Rubin (&) The largest normal tissue structure in the human body is the
Professor and Chair Emeritus, Department of Radiation microvasculature. It is generally estimated that there are
Oncology, University of Rochester School of Medicine 50,000 miles of capillaries with a surface area of approxi-
and Dentistry, 601 Elmwood Ave, Box 647, Rochester,
NY 14642, USA mately 1000 square miles. The ubiquitous distribution and
e-mail: [email protected] presence of the microvasculature is essential for survival of
L. Fajardo all normal tissue/organs; the microcirculation supplies
Stanford Medical School, 3801 Miranda Ave, Palo Alto, CA oxygen and nutrients and removes wastes. The fine
94304, USA

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 27
DOI: 10.1007/978-3-540-72314-1_3,  Springer-Verlag Berlin Heidelberg 2014
28 P. Rubin and L. Fajardo

vasculature is widespread, occurs as a component of most

other organs (including larger vessels), and responds to
irradiation in a more sensitive fashion than large vessels and
is directly, intimately, and critically involved in the radia-
tion responses of tissues dependent upon it for metabolic
support.

2 Anatomy

A metarteriole gives rise to capillaries. The precapillary

sphincters of the arteriole and metarteriole control the entry
of blood into capillaries. The distal segment of the thor-
oughfare channel receives capillaries from the microcircu-
latory bed, but no sphincters are present where the afferent
capillaries enter the thoroughfare channels. Blind-ending
lymphatic vessels are shown in association with the capil-
lary bed. Note the presence of anchoring filaments and the
valve system within the lymphatic capillaries (Fig. 1) (Ross
Fig. 1 Diagram of microvasculature (with permission from Ross
et al. 2003). Most arterioles can dilate 60–100 % from their et al. 2003)
resting diameters and can maintain constriction for a long
time.
tubules. There are certain other small blood channels
resembling capillaries in some respects, but which can be
3 Histology of Microvasculature distinguished from them. Prominent examples are sinu-
soids and the rete mirabile.
• Capillaries: structurally the fundamental vascular units • Sinusoids are special channels between larger vessels.
are simple endothelial tubes connecting terminal arteri- Some of them connect arterioles with venules, as in the
oles or precapillaries and venules. There is usually a semi spleen, adrenal cortex, and bone marrow. Others connect
fluid intercellular cement between the endothelial cells of venule with venule, as in the liver and in the anterior lobe
the capillary, and only a delicate reticular network sur- of the pituitary gland. There are also lymphatic sinusoids
rounds the endothelial tube. Outside their walls may be which interconnect lymphatic vessels, as in the lymph
found fixed macrophages and fibroblasts. The average nodes. Sinusoids are relatively wide, up to 30 microns,
diameter of normal blood capillaries is about 8 microns; and are not uniform in caliber. They are lined by an
thus erythrocytes are permitted to pass in single file. The incomplete layer of scattered fixed microphages that
largest normal capillary has a diameter of about 12 project into the lumen, by flat cells that are apparently
microns. Capillaries form networks which may be flat- potential macrophages and by cells in every transition
tened or spongy and vary in shape, conforming to the between these two forms. These lining cells are separated
character of the region they supply. The closeness of the from the surrounding parenchyma only by a network of
mesh generally varies directly with the intensity of the reticular fibrils.
tissue metabolism in the region supplied. Lymphatic • The rete mirabile is a capillary-like plexus inserted in the
capillaries are somewhat broader than blood capillaries course of an arteriole or venule, with an afferent arteriole
and not as uniform in caliber, showing dilatations and or venule carrying blood to it and efferent arteriole or
constrictions. Their walls are composed of endothelium venule draining it. An example is the renal glomerulus,
alone, embedded in connective tissue. These capillaries and similar structures are the sinusoids of the anterior
form dense networks roughly paralleling networks of pituitary (venule-sinusoid-venule) and of the lymph
blood capillaries, and they are often close neighbors of nodes (lymphatic-sinusoid-lymphatic).
blood capillaries. They are found in nearly all parts of the • Precapillaries are vessels intermediate between capillar-
body. Near surfaces, such as the skin and internal mem- ies and arterioles or venules. They are larger than capil-
branes, they often begin as loops or as blind swollen laries but have incomplete accessory coats as compared
Biophysiopathology of the Microvasculature and Microcirculation 29

with arterioles and venules. Arterial precapillaries are 100 microns) but a relatively thin wall and broad lumen.
less than 40 microns in diameter. The smallest of them The tunica intima consists only of an endothelial layer,
consist of an endothelial tube surrounded by scattered the thin tunica media is almost exclusively smooth
smooth muscle fibers; the largest are, in addition, sur- muscle, and the tunica adventitia is a relatively thick
rounded discontinuously by connective tissue cells and component of the very thin wall. An arterial lumen is
fibers. Venous precapillaries are less than 200 microns in always smaller than that of its companion vein of the
diameter; the smallest consist of endothelium surrounded combined lumens of its companion veins, and the arterial
by scattered connective tissue elements, and the larger wall is thicker, more rigid, and more resistant to collapse.
ones are, in addition, surrounded discontinuously by
smooth muscle fibers. With the smooth muscle in the
precapillaries to act as sphincters, the control of vessel 4 Physiology of Microcirculation
size and blood flow through the capillary beds becomes
possible. The microcirculatory apparatus is of special importance in
• Arterioles: All blood vessels larger than precapillaries any consideration of damage and recovery of organs
exhibit a common generally structural organization. because of its intimate and vital supportive relationship to
However, each specific type of vessel shows character- the metabolism of tissues and tissue components. The fine
istic adaptive variations in which certain features of the blood vessels, and usually the fine lymphatic vessels also,
general plan may be emphasized, minimized, or omitted, enter into the composition of most organs. The one-way
or certain new features may be added. Every typical microcirculatory flow carries nutrients, oxygen, hormones,
blood vessel larger than a precapillary is composed of and blood cells to all parts of the body, and collects meta-
three concentric coats of tunics, namely, the tunica intima bolic wastes from the tissues and transports them to the
or interna, the tunica media, and the tunica adventitia or kidneys or, in the case of carbon dioxide, to the lungs.
externa. The tunica intima consists of an endothelium Capillaries are the most important of all vessels func-
(simple squamous epithelium) bounding the lumen, a tionally, since they are in a close relationship with the
subendothelial coat of delicate fibroelastic tissue and a various tissue elements at the site of cellular metabolism,
fenestrated internal elastic membrane, which is the out- where they deliver nutrients and oxygen and receive wastes,
ermost component of the intima. The tunica media con- their thin walls and slow blood flow favor diffusive inter-
sists primarily of smooth muscle circularly arranged, with changes. Capillary blood flow varies in amount and extent
variable amounts of elastic fibers, or circular elastic with tissue activity, being intermittent in resting or rela-
networks, or concentric elastic tubes in certain large tively inactive tissues and voluminous and extensive in
vessels. The tunica adventitia, the outer coat, usually active tissues. Although capillaries are closed tubes they are
contains a concentration of elastic tissue as an elastic normally semi permeable. Water, gases, salts, and nutrients
layer, and close to the tunica media there may be a def- in simple form are among those substances which pass
inite external elastic membrane. The remainder of this through their walls, but most colloids and all microscopi-
coat consists of moderately compact fibroelastic tissue cally visible particles do not normally pass through. How-
which merges gradually with areolar connective tissue. ever, the degree of permeability of capillary walls varies
Blood vessels most than 1 mm in diameter contain regionally and also with local changes in condition. Leu-
nutrient vessels called vasa vasorum. In arteries these are kocytes occasionally pass through the endothelium under
usually limited to the tunica adventitia, but in veins they normal conditions, and when the endothelium is altered, as
may extend through the tunica media. Lymphatic vessels in inflammatory conditions, the passage of leukocytes may
are also present in the walls of the larger blood vessels. be greatly increased; even erythrocytes may escape from the
The arteries include arterioles, the smallest arteries blood through the altered endothelium. True endothelial
(40–300 microns in diameter), which are predominantly cells are not normally phagocytic, as are the cells lining the
muscular; small to medium-sized arteries, which are sinusoids.
predominantly muscular; and large arteries, which are The muscular arteries can regulate the blood flow to any
predominantly elastic. The transition from muscular to part of the body according to its changing needs by means
elastic composition is usually gradual, and there are of nervous control of the muscular layer of the vessels. The
intermediate mixed types. The size and composition of arterioles, with their relatively thick walls and narrow
arteries are not always typically correlated. The arterioles lumens, are the chief controllers of systemic blood pressure
have relatively thick walls and narrow lumens, the walls and local blood flow. Most of the decline in blood pressure
being thicker relative to the caliber of the lumen than in in the mascular system occurs within the arterioles, so that
any other type of blood vessel. As compared with arte- the delicate capillaries normally receive blood gently in a
rioles, venules have a large diameter (between 200 and slow stream.
30 P. Rubin and L. Fajardo

Endothelial cells normally divide from time to time with laminin), as well as various collagens for the surrounding
moderate frequency to replace those cells that die and are tissue matrix.
lost. They are capable of much more rapid proliferation • Vascular tone regulation: through angiotensin converting
under pathologic conditions, e.g., during recovery from enzyme and endothelin, EC contract smooth muscle
local injuries to the vasculature and during neovascular while nitric oxide relaxes it.
formation in the healing of wounds or lesions. In neovas- • Angiogenesis: this, the formation of microvessels in the
cular formation, the endothelium from capillaries forms fully developed vertebrate, is the most dynamic function
solid sprouts which enter injured and regenerating areas. of the endothelium; it occurs in response to a large
The sprouts become hollow, fibroblasts are at hand, myo- number of agonists and antagonists. It is either physio-
blasts soon differentiate, and accessory coats are formed logic (e.g., in wound healing and cyclical endometrial
around the endothelial tubes as needed. growth) or pathologic (e.g., in neoplasia and many
The aging arteries seem to be a physiologic process that inflammatory disease).
passes gradually into arteriosclerosis. Each type of artery The above, and other endothelial cell functions, are
normally shows a characteristic pattern and schedule of regulated by numerous genes, many of which have been
change with increasing time. characterized. EC vary greatly from tissue to tissue and
from one animal species to another. This heterogeneity is
evident morphologically, functionally, and in response to
5 Pathogenesis injury. Figure 2 outlines diagrammatically the most
important of the functions characteristic of EC (compare
A discussion of the radiation effects on endothelial cells with Fig. 3) (Fig. 2) (Fajardo 1989).
should be preceded by some review of the complex physi- The impact of ionizing radiation on the endothelium has
ology of the endothelium. Aside from those activities been studied in vivo and in vitro, the latter using various EC
common to all cells, certain specialized functions are lines, including human umbilical vein cells (HUVEC),
characteristic of Endothelial cells (EC): bovine aortic cells (BAEC), or capillary EC (e.g.,
• EC are the most radiosensitive among the fixed elements HDMEC). The doses varied between \ 1 Gy and as much
of the mesenchyme. Depending on dose, ionizing radia- as 60 Gy, with various fractionation schemes. For the
tion can produce lethal or sublethal injury to EC. The in vitro studies, the doses were often 5 Gy or less. From a
latter may alter considerably the complex physiology of review of various in vitro experiments (too many to list
the endothelium. Some functions are inhibited or abol- here), it appears that radiation becomes lethal to endothelial
ished: fibronolysis, synthesis of various enzymes and cells when it reaches Do values of the order of
cytokines, attachment of EC to the basal lamina, angio- 100–200 cGy in the clonogenic survival curves (higher
genesis, etc. Other functions are enhanced, including values are required in vivo).
permeability, soluble coagulation, platelet adhesion, and EC may undergo mitotic death or apoptosis, the latter
aggregation. There is also upregulation of adhesion through a pathway that probably involves the formation of
molecules for leukocytes. Endothelial cells are hetero- ceramide.
geneous; accordingly, radiation effects vary in quality and Sublethal doses of radiation affect the morphology and
severity from one site to another, and from one animal various functions of EC.
species to another. Common morphologic changes include hypertrophy of
• Coagulation: EC participate in the soluble coagulation EC associated with reorganization of F-actin filaments, and
system by producing both procoagulants (e.g., tissue detachments from the basement membrane. The in vivo
factor and Factor V) and anticoagulants (e.g., plasmino- changes include vascular constrictions, thromboses, and
gen activators and thrombomodulin.). In addition, EC rupture of microvascular walls with resulting hypoperfu-
regulate the adhesion and aggregation of platelets through sion. Most studies show an increase in permeability for
von Willebrand Factor (vWill F), nitric oxide, etc. various molecules (however, serotonin transport is
• Permeability: transport of certain molecules across the decreased). There is hypercoagulation, and platelet aggre-
EC cytoplasm. gation due to enhanced release of vWill F, causing an
• Inflammation and immune response: EC express multiple increased tendency to thrombosis. In addition, ineffective
antigens, including MHCs I and II, and ABO. Several fibrinolysis results from a decrease in plasminogen activa-
cytokines are produced in EC, such as IL1 and GM-CSF. tors. The eicosanoid metabolism is altered, with early
Depending on activation state, lymphocytes, granulo- decrease and late increase in PGI-2. There is enhanced
cytes, and macrophages adhere to specific EC receptors. chemoattraction for leukocytes and upregulation of adhe-
• Synthesis of stromal components: EC produce their own sion molecules (e.g., ELAM-1). EC show decrease in
basement membrane (mainly collagens IV, V, and endothelial enzyme activity (e.g., angiotensin converting
Biophysiopathology of the Microvasculature and Microcirculation 31

Fig. 2 Physiology of normal endothelial cell a normal endothelial ACE, angiotensin converting enzyme; GM-CSF, granulocyte–mono-
cell attached to its basal lamina (bottom), which is partially denuded cyte colony stimulating factor; LDL, low density lipoproteins; MHC I
on the right. The main functions described here are indicated in bold & II, major histocompatibility complexes; NO, nitric oxide; PGI2,pros-
uppercase letters, with examples in lowercase. ABO, blood antigens; tacyclin (Reproduced , with permission, from (Fajardo 1989))

Fig. 3 Radiation effects of

radiation on endothelial = F3.2
P21 CURED I LENT; general
effects of radiation on endothelial
cells. This is a diagrammatical
summary of the most important ,
lethal, and sublethal effects of
ionizing radiation on endothelial
cells. It combines in vitro and
in vivo data and is based on
multiple sources of information
(Reproduced, with permission,
from (Fajardo 1998))

enzyme, alkaline phosphatase). Radiation inhibits angio- Like other normal cells, EC have some innate protection
genesis: the magnitude of this effect depends in part on the from ionizing radiation. For instance, glutathione and
sequence of angiogenic stimulus versus radiation. Various superoxide dismutase provide some defense of EC from
data suggest that the inhibition of angiogenesis is greater reactive oxygen species (e.g., hydroxyl radical and super-
when the radiation exposure occurs prior to the angiogenic oxide respectively). Nevertheless, it appears that endothelial
stimulus instead of following it. This information may be cells are the most radiosensitive elements in the vessel wall.
important when designing the sequence of radiation therapy They may even be the most sensitive among the fixed cells
versus surgery (the angiogenic stimulus, and depends on the of the mesenchyme. Many of the studies suggest that EC are
timing of radiation with regard to the time interval for more radioresponsive in vitro than in vivo. Sublethal
surgery. endothelial radiation injury not only contributes to the very
32 P. Rubin and L. Fajardo

early, acute effects, but also accounts for many of the more jeopardized by small degrees of change in the endo-
delayed effects, such as stromal fibrinous exudate and thelial lining. The production of similar degrees of initial
ischemia. radiation effect on the endothelium of large vessels with
Several of the above described deleterious effects of their large lumens involves much less immediate pathologic
radiation on the EC can be ameliorated or even abrogated consequence to the vessels themselves.
by pharmacologic modifiers. However, as far as we know, Blood sinusoids, which are lined not by typical endo-
there is no single compound that prevents all of these effects thelial cells but by phagocytes, are also less sensitive to
in the endothelium (Fig. 3) (Fajardo 1998). radiation than are the small blood vessels lined by typical
endothelium. The phagocytic cells are considerably more
radioresistant than the endothelial cells, and the lumens of
6 Capillaries and Arterioles sinusoids are usually considerably larger than those of the
fine vasculature line by endothelium.
There are differences in radiation response between small The radiation effects on capillaries reflect the early
and large vessels. The endothelial tissue of the small blood radiation-induced changes in endothelial cells that include
vessels seems to be moderately sensitive to ionizing radia- degeneration, swelling, and necrosis. The swelling of
tion. Its radiosensitivity seems to be intermediate between endothelial cells may be due partly, or sometimes, to rela-
the highly radiosensitive parenchymal tissues containing tively direct or indirect damage to the endothelial cells
vegetative and differentiating intermitotic cells of high themselves and sometimes to excessive contraction and/or
mitotic frequency and the radioresistant tissues composed shortening of the small vessels containing them. In either
of reverting and fixed postmitotic cells. However, the case this results in the bulging of endothelium into the small
endothelium of large blood vessels does not seem to be lumen, with narrowing or obstruction of the lumen and
quite as responsive to radiation as that of smaller blood impedence of circulation. Necrosis or loss of the endothelial
vessels. This difference in itself suggests either an enhanced cells of the lining, which permits contact between the blood
conditional sensitivity of endothelium of small vessels or an and the severely damage endothelium or subendothelial
influence of indirect mechanisms of alteration at the in- connective tissue, promotes the formation of thrombi which
tertissue level, or perhaps even more remote indirect may occlude small lumens rapidly. With doses of degrees of
mechanisms contributing to the total radiation effect vascular damage not large enough to prevent the active
observed in the fine vasculature after moderate doses of regeneration of endothelial cells, the remaining endothelial
radiation. cells may proliferate in response to injury and may even
The reasons for this difference in radiosensitivity overcompensate, with the result that there are increased
between the endothelium of small vessels and that of large numbers of endothelial cells and consequent narrowing or
vessels are not yet entirely clear. One of the possible rea- occlusion of the small lumens. Even without marked over
sons may be related to the fact that greater degrees of compensatory regeneration of endothelial cells, an apparent
endothelial change are seen in the small vessels of irradiated increase in the number of endothelial cells at places along
organs containing radiosensitive parenchymal cells and the course of vessels may result from the shortening of the
showing greater degrees of inflammatory response involv- length of vessels or from the formation of tortuous bends in
ing the vessels (congestion, edema) than in the small vessels vessels when they are reduced in extension. As a result of
of irradiated organs containing radioresistant parenchymal the radiation damage to the endothelium and/or the vascular
cells and showing lesser degrees of such inflammatory response in the inflammation elicited by damaged paren-
response. This suggests that some of the observed radiation- chymal cells, there may occur hyperemia, blood congestion,
induced changes in the endothelium of the fine vasculature and increased permeability of the endothelium. Blood
may depend on the degree of such inflammatory response, congestion from any cause tends to promote increased
which in turn depends on the degree of destruction of permeability of the endothelium. As a consequence, blood
parenchymal cells, which in turn depends on the relative fluid leaks out of the capillaries into the surrounding con-
radiosensitivity of the parenchymal cells in the organs under nective tissue or through the endothelial lining of the arte-
consideration. rioles and venules into the subendothelial connective tissues
Another possible reason for the difference in observed and tunica media. If the increased permeability of fragility
degree of endothelial effect between large and small vessels of the endothelium is marked, leukocytes and even eryth-
may be related to differences in the size of the vascular rocytes may also pass in excessive numbers through the
lumens. The lumens of fine blood vessels are much more endothelium. In severe damage there may be fissuring of the
easily occluded by various effects of radiation on endothe- walls of the small blood vessels, with the consequent
lium than those of large blood vessels, and the integrity of development of punctate hemorrhages. Increases in peri-
the walls of small blood vessels is thereby likely to be much vascular fluid may exert external pressure on the walls of
Biophysiopathology of the Microvasculature and Microcirculation 33

small blood vessels and may—especially in the case of These vasculoconnective tissue changes are also seen to
vessels with thin, weak walls, such as capillaries and ven- increase in association with a variety of diseases.
ules—compress them and impede blood flow. The advancement of cicatrization of the fine blood ves-
The early changes after irradiation just described (i.e., sels by irradiation involves the gradual replacement of the
swelling or an increase in the number of endothelial cells muscle tissue of the small arteries by fibrous tissue, a tissue
relatively or absolutely, thrombosis, vasoconstriction, and that is less resilient and less resistant to stress. Even during
perivascular compression of small vessels) are all relatively early periods after irradiation, the weakening of the walls of
rapid mechanisms by which blood flow may be impeded or irradiated small arteries is manifest in their greater sus-
vessels occluded. The slower mechanisms of occlusion or ceptibility to necrosis caused by hypertension.
reduction of the fine vasculature and of blood flow involve Radiation-induced advancement of progressive fibrosis
the responses of connective tissue, which are discussed in of the fine vasculature leads eventually to premature nar-
the next section. rowing and obliteration of vascular lumens and usually to a
reduction in the total extent of fine vasculature or a reduc-
tion in its effective function. Although there is some
recovery by way of neovascular regeneration, there is usu-
7 Histohematic Barrier ally a net loss of fine vasculature after irradiation. The
reason for the distinction between the reduction of fine
As a result of perivascular or subendothelial edema (early vasculature and the reduction of its effective function is that
inflammatory phase) caused by radiation damage to small under certain critical conditions of dose in certain organs
blood vessels, there may be increased interstitial colloid in the damage to fine vasculature may be followed not simply
the affected regions. Such regions become sites of fibro- by its partial recovery through regeneration, but by supra
blastic activity and of a subsequent increase in the fibrillar neovascularization. In such instances, however, the stimu-
density and amount of the interstitial connective tissue (later lation for the supravascularization seems to reside in the
sclerotic phase). This process of cicatrization of fibrosis presence of marked interstitial fibrosis, or an increase in the
may then continue slowly and progressively for many years histohematic connective tissue barrier, which reduces
indefinitely, and may result in the gradual thickening of the markedly the functional capacity of the fine vasculature. In
vessel wall, the replacement of the muscular media of small other words, supravascularization in the presence of a
vessels with connective tissue, and the narrowing, occlusion marked increase in the histohematic barrier may be asso-
and obliteration of their lumens. This process of circatri- ciated with reduced function of the fine vasculature (Rubin
zation and scarring may be regarded as a process of sec- et al. 1960). Under other circumstances, fibrillogenesis
ondary repair, i.e., replacement of damaged specialized (fibrous barrier formation) has been shown experimentally
tissue with less specialized tissue. Offhand, such a process to inhibit capillary regeneration (Van den Brenk 1959).
of repair of vessels may seem to go too far, in that the end
results seem much more deleterious than the initial damage.
However, it is possible that, in the absence of sufficient 8 Distribution of Radiation Effects
capacity for primary repair (recovery to the typical normal on Small Vessels at Early Times After
state) the process of secondary repair of vessels may be Irradiation is Subtle and Inconspicuous
inherently self-perpetuating, i.e., causing progressively
further damage as a stimulus to its own continuation. In this Furthermore, these changes are spotty in their distribution
regard, although the initial interstitial edema may disappear, along the course of the vessels, rather than uniform and
edema may recur from time to time as the fibrous connec- continuous. Consequently, in any one histologic tissue
tive tissue becomes denser and increases in amount. section, thorough and competent examination of the fine
These responses of interstitial and vascular connective vessels may reveal relatively few sites of prominent change
tissue are more marked, more permanent, and more pro- even when many of the small vessels may be affected at one
gressive as the radiation dose is increased. All these changes or another point along their course. It is obvious that a focal
are nonspecific (not unique to radiation). The interstitial narrowing or occlusion of an arteriole supplying a capillary
fibrosis and the fibrosis of small blood vessels constitute a network, especially if the occlusion is distal to the last
premature increase in the histohematic connective tissue effective collateral channel of blood supply, may be all that
barrier (the barrier between the blood and the dependent is necessary to disrupt the blood supply to tissues dependent
parenchymal tissue cells) through which diffusions of upon the portion of the capillary bed in question. With
nutrients and gases must take place, and a premature progression of the vascular damage and the cicatrization
advance in the development of arteriolocapillary fibrosis, process with passing time, more and more points along the
both of which are progressive processes in ‘‘normal’’ aging. course of the affected small blood vessels may show
34 P. Rubin and L. Fajardo

degenerative and fibrotic changes, so that more and more A factor of prime importance in the resistance or sus-
sections of small blood vessels per unit area of sectioned ceptibility of irradiation tissues and organs to the develop-
tissue may reveal changes and the changes may become ment of delayed radiation-induced lesions of serious clinical
more obvious. significance is the ability retained by the irradiated fine
Marked changes in dependent tissues can be caused by vasculature to regenerate and remodel under conditions of
the radiation induced changes in fine vasculature and added injury or stress. Additional injury or stress that is
interstitial connective tissue, despite their seeming subtlety either so mild or so localized as to require no extensive
and relative inconspicuousness. The amount of damage to vascular remodeling, may be adequately resisted or
dependent tissues caused by interference with their blood repaired. However, more marked or more diffuse injury or
supply and gas and nutrient exchange with the blood stress, such as might result from diffuse infection and
depends upon the rate and degree of reduction of the blood inflammation (which may require for repair a marked gen-
supply and the increase in the histohematic connective tis- eralized hyperemia and considerable vascular remodeling
sue barrier and upon the rapidity and degree of success with without hindrance of the ability of the vascular endothelium
which these factors are compensated by the establishment, by an increased fibrillar connective tissue barrier) may not
if any, of collateral circulation or neovascular formation. If be adequately resisted or repaired and necrosis may result.
the blood supply is rapidly and completely shut off by Infection or diffuse trauma of irradiated organs in which the
changes such as vascular thrombosis, then the resulting fine vasculature has been reduced and in which regenera-
destruction of dependent tissue may be massive and rapid. tion of the fine vasculature is inhibited by an increase in the
Less complete or slowly progressive obstruction of the histohematic fibrous barrier is often a precipitating factor
blood supply or increase in the histohematic barrier, as in in delayed radionecrosis of such organs. Delayed radio-
the case with slowly progressive arteriolocapillary fibrosis necrosis resulting partly from such complications may
and interstitial fibrosis, causes a more gradual atrophy of occur at any time, depending upon the degree of devitali-
dependent tissues. zation of the supporting tissues, which in turn depends upon
These changes in the fine vasculature and connective dose.
tissue are also of fundamental importance to dependent tis- The consequences of similar degrees of damage to the
sues because of the consequent lowering of their resistance to fine vasculature and increased interstitial fibrous tissue vary
further injury, stress, or functional demands and because of among dependent tissues and organs of different types
the consequent reduction of the regenerative powers of the according to their activities, specialization, degree of
fine vasculature itself as well as the dependent tissues. The dependence on blood supply, reserve of vasculature, degree
rate and type of recovery of radiation-damage tissues depend if collateral circulation, capacity for vascular regeneration,
to a large extent on the local blood circulation and on the and the functional demands placed upon their circulatory
condition of the histohematic barrier. Even in the case of apparatus.
slowly progressive arteriolocapillary and interstitial fibrosis,
the obstructive nature of these changes and the instability and
reduced resiliency and regenerative capacity of the affected 9 Microcirculation
fine vasculature may so compromise the vasculature that the
dependent tissues or organs may succumb to added injury, Relationships between Cell/Tissue Renewal Kinetics and
stress, or functional demands, and undergo acute necrosis ‘‘the microvasculature response is faster and earlier in
long after irradiation. Fibrotic arterioles and telangiectatic normal tissues that renew rapidly and is slower in, as well as
capillaries are easily disrupted under additional stresses. later in, slow renewal tissues’’ (Rubin and Casarett 1968). It
As indicated previously, these changes in the fine vas- is important to understand which normal tissues parenchy-
culature and interstitial connective tissue play a prime role mal cells are considered to have rapid or slow renewal
in the production of chronic or delayed lesions in dependent kinetics as well as the radiation sensitivity as a function of
tissues after irradiation, regardless of the relative radio- cell cycle kinetics.
sensitivity of the dependent parenchymal tissues or cells The epithelial tissues that line mucosal surfaces in the
and their inherent regenerative capacity. For example, large upper aerodigestive passages, gastrointestinal (GI) tract,
blood vessels, considered as organs, may not show the early urinary system, and bone marrow are examples of rapid
radiation changes observable in their fine vasculature (vasa renewal tissues. These tissues tend to have uncommitted or
vasorum), but they may show lesions later as a result of committed stem cell compartments that rapidly proliferate
progressive changes in the vasa vasorum and the added or and differentiate. Slow renewal tissues are characterized by
continued stress placed upon these organs, such as hyper- a parenchymal cell compartment that turns over slowly, but
tension or perhaps even the continuous normal pressure of often has the capacity to respond by reverting to a stem cell
the blood. and regenerating or repopulating the lost parenchymal cells.
Biophysiopathology of the Microvasculature and Microcirculation 35

Examples of tissues that are conditionally proliferative Table 1 ‘‘Turnover times‘‘ of the epithelial cells of the alimentary
include liver after partial resection, bone following fracture, tract of the rata
microcirculation in wound healing, endocrine glands fol- Cell population Turnover time (Days)
lowing increased trophic hormone, and bone marrow (pro- Digestive system
tected areas) following irradiation of a large segment. Many Lip 14.7
adult organs have little or no capacity to restore their Oral cavity
parenchymal cells, that is, proliferation occurs primarily
Buccal mucosa 4.3
early in life and is fixed. Examples of this type of tissue or
Tongue surface
organ are the central nervous system (CNS), heart, kidney,
and muscle, in which lost cells are replaced by fibrosis.3 Superior 4.9
Inferior 7.7
Esophagus
10 Rapid Cell Renewal Kinetics At thyroid gland level 8.8
At cardiac junction 11.6
10.1 Gastrointestinal Mucosal Epithelium Stomach
Cardia 9.1
The rapidly dividing epithelium of the alimentary system
Body
varies throughout; the most rapid cell turnover is the small
intestine, then stomach pylorus, followed by oral cavity and Surface epithelium 2.9
anus, then the esophagus and colon, and stomach cardia Glands 6.4
(Table 1) (Bertalanffy and Lau 1962). Pslorus
From the view of cell kinetics, the time of appearance of Surface epithelium 1.9
mucositis in small intestine, and then oral cavity mucositis, Glands 1.8
followed by esophagus, then stomach, and colorectum is Small intestine
explained. Duodenum 1.6
The rapidly dividing epithelium of the digestive system
Jejunum 1.3
undergoing mitotic linked death triggers an early inflam-
Ileum 1.4
matory response in which the microvascular system of this
organ plays a critical role. The early ICAM expression Large intestine
arrests lymphocytes, macrophages, and neutrophils and Colon 10.0
allows their penetration through the capillary wall inciting Rectum 6.2
the reactive mucositis or dermatitis. In contrast, slowly Anus 4.3
dividing cellular systems, the first tissue to respond is the a
From (Bertalanffy and Lau 1962) published by Academic Press Inc
microcirculation as in the heart or liver where diffuse cap-
illary microthrombosis occurs. The volume effect in parallel
organs may reflect the damage to the percentage of the The epithelium of skin is distinct and separate from the
microvasculature injured and in turn the functional units capillary loops in the papillary layer of the dermis. The fine
lost. small arteriole is vulnerable to large single doses or hypo/
It is important to note that expression of mucositis is large fraction regimens. The volume effect first described by
related to cell kinetics and the lifetime of the mature epi- Patterson, then Van Essen is a micro-circulatory effect since
thelial cell. Thus, gastrointestinal mucositis precedes oro- there is no rationale for skin tolerance to change with vol-
pharyngeal and colorectal mucositis. It is important to note ume. Again, rapid closure induces ulceration and necrosis
that most epithelial-lined tissues are hollow organs and the versus slow closure that leads to obliteration of the capillary
fine vasculature is distinct and separate from the epithelial dermis, shortening of loops, and scarring leading to sinu-
surface. The small arteriole often thickens its muscular wall soidal telangiectaisia and contractures.
and if the closure of its lumen is rapid and sudden, the The rapid renewing epithelium of other hollow organs
tissues as gut undergoes necrosis (hypofractionation, single behave similarly and include the lining of the upper respi-
long dose). Alternatively, if the closure is slow and gradual ratory system and larynx, the lining of the urinary system
(none hyperfractionated) then the altered microcirculation from renal pelvis, ureters, to urinary bladder. A major dif-
leads to a slower fibrogenic response. The damage extends ference between upper respiratory and upper digestive
from mucosa to the fine smooth muscle of the digestive systems is the presence of bone and cartilage which main-
lumen tube wall and leads to strictures rather than ulceration tain respiratory lumen in paranasal sinuses, nasopharynx,
and perforation. larynx, and trachea. Fibrosis does not lead to stenosis of
36 P. Rubin and L. Fajardo

these structures. However, bone and cartilage are vulnerable

to necrosis in these tissues when the vasculature is com-
promised. High dose radiation of the larynx or bronchi can
and do result in chondronecrosis.

11 Slow Renewal Kinetics

The microcirculation alterations in slow renewal kinetic

tissues and organs is the predominant factor in the expres-
sion of late effects. Since the parenchymal cell compartment
is not rapidly proliferating the mitotic linked cell death is a
late event often with no detectable acute phase, that is, only
a late manifestation occurs clinically. This absence of an
acute clinical phase of effect, and then an unexpected late
adverse effect occurring is one of the main concerns of
radiation treatment. The classic illustrations of radiation
injury to the microvasculature is the dominant mechanism
that drives the expression of radiation reaction in these
organs.
• CNS. Brain and Spinal Cord: The central nervous system
is a complex organ; however, permanent damage to
neuronal tissues is largely due to injury of the fine vas-
culature of the spinal cord and brain. The classic Boron
Fig. 4 a Microorganism of a nonregressing irradiated Walker tumor
Neutron capture study in which radiation was delivered shows preservation of ample vasculature in the original zone of viable
solely to the vessel wall because of alpha particles tumor (910). The tumor cells appear to be degenerating at the
released without irradiating the nervous tissue reproduced completion of a 6000 R dose, but the vasculature remains intact
the classic pattern of radiation injury of the central ner- despite the higher doses used in their phase. The lumens are narrowed,
giving the lead-filled capilaries a thinned out appreance, but the
vous system. Although the capillary network (blood– dilatation of the channels in the totally necrotic area suggests patency
brain barrier) is the vulnerable target, the medium-size of vessels but stagnation of flow. b Histologic section shows
cerebral arteries can occlude, analogous to coronary persistence of vessels in zones of fibrosis and giant cells to the left
arteries. Numerous studies in our and other laboratories with some persistence of tumor foci to the right (9100) (From Rubin
and Casarett 1966)
established the cerebral and spinal cord capillary vascu-
litis as the mechanism for necrosis and hemorrhaging
associated with cerebral and spinal cord necrosis. The
neuroendocrine apparatus consists of a rich sinusoidal occurs over time, especially if the whole heart volume
network in the hypothesis and pituitary stalk and gland. was treated. Of interest is the vulnerability of other
The vasculature is the vulnerable structure rather than structures especially the coronary arteries. Radiation of
neuroendocrine cells. The occlusion of the hypophysis- coronary arteries was the first recognized and perhaps the
pituitary sinusoidal network can lead to infarction and largest artery that radiation accelerates atherosclerosis,
necrosis leading to an empty sella syndrome (Fig. 4) i.e., 3 mm lumen to 1 mm in size as it descends on the
(Rubin and Casarett 1966). heart wall. The first such evidence was detected in young
• Heart: The classic illustrations are in the heart, the females with Hodgkin’s Lymphoma who developed
musculoskeletal system, the kidneys, and the nervous coronary thrombosis when they reached adulthood. Sub-
system. The classic cardiac radiation experiments of sequently, its appearance decades later was manifested in
Stewart and Fajardo established the fine microvasculature breast cancer survivors but limited to left rather than right
as the radiation target cell rather than the cardiac myo- side tangential chest irradiation. The mesothelial cell
cytes. In contrast, adriamycin vacuolated the cardiomy- lining the pericardium rather than the heart endothelium
ocyte and spread the capillary bed. A diffuse can be more vulnerable in the sudden appearance of
microthrombosis of the myocardial capillary network pericardial effusion, most often at 5–6 months, i.e.,
resulted in diffuse radiation-induced cariomyopathy over increase in capillary permeability of the visceral layer of
time. Since cardiac hypertrophy compensates initially for pericardium. Another adverse late event is calcification of
reduced ejection fraction but heart failure eventually the chorda tendinae of valves due to obliteration of the
Biophysiopathology of the Microvasculature and Microcirculation 37

Fig. 5 The radiation response in the renal parenchyma. The respon- promotes thromboses, possibly leading to infarct. The tubular epithe-
sive cell types are in the endothelium and epithelium. There is fibrinoid lium presents a variable picture, but there is some degree of interstitial
and hyaline accumulation associated with endothelial swelling in the fibrosis. As the vascular compromise develops, larger vessels may be
afferent arterioles, which may spread beneath the glomerular capillary affected, with focal necrosis and accumulations of foamy histiocytes.
endothelium. the basement membrane thickens. Vascular compromise (With Permissions from (White 1975))

fine capillaries in the chorda tendinae leading to valve sinusoids and become the hepatic portal network draining
stenosis or regurgitation. The valves per se are not radi- the gut. The venous capillary sinuses predominate as
ation vulnerable but obliteration of the fine capillaries and compared to the hepatic artery, arterioles, and capillaries
in turn the fine musculature at the base of the chorda which parallels the biliary duct system and are not sig-
tendinae renders them incompetent due to fibrosis and nificant or intimate to the function of the liver lobule and
calcification of the valve. The calcification is due to a its hepatocytes. Thus, central vein thrombosis and con-
slow necrosing turned sclerosing reaction. gestion leads to a Budd Chiari syndrome as the irradiated
• Kidney: The major focus of change is in the arteriolar- liver decompensates.
glomerular region rather than the tubular epithelium, with • Lung: The major physiologic feature of the respiratory
the cortical rather than the medullary tubules being system is to oxygenate blood. Thus radiation acts on the
involved; this involvement usually follows vascular acinar and alveolar capillary bed in contrast to the
alterations (Fig. 5). In a classic study by Glatstein and bronchial artery which bronches and parallels the
colleagues, radiation-induced lesions were shown to dividing decremental bronchial tree. The endothelial cell
occur as a progressive replacement of capillary walls is an early responding cell and its veno-occlusive pat-
leading to glomerular sclerosis, followed by tubular tern is similar to irradiated liver, i.e., VOD. The con-
atrophy. Larger arteries were not affected, although blood gestion that results leads to an increase in capillary
flow was reduced significantly and was still variable permeability and diopedesis of RBCs (smallest circu-
2–3 months after irradiation. The evidence suggests that a lating cell) as compared to the larger neutrophils and
functional lesion occurs in the glomerular capillaries, later reacting Type II pneumocytes. Radiation pneumo-
preceding tubular depletion. However, both elements are nitis is an alveolitis which accounts for its geometric
affected according to Hoopes and coworkers, who pro- shape similar to radiation beam shapes and high dose
posed that multiple target sites exist for radiation, offer- isodose regions rather than its bronchial or major vas-
ing the best explanation for the observed clinical cular anatomy as in infectious pneumonitis or embolism/
syndromes (Fig. 5) (White 1975). infarction respectively.
• Liver: Whole liver irradiation results in ‘‘veno’’ occlusive • Musculoskeletal: Adult bone is a slow renewal system
disease unlike most organs in which the arteriole occlu- and responds to irradiation in a clinically occult fashion.
sion is the predominant lesion. The reason is in its There is no overt reaction except an initial increase in
embryonic origin from the vitelline veins from the yolk blood flow which is followed as the dose increases and
sac which develops into a network of venous liver over time into a sharp decrease in blood flow. The
38 P. Rubin and L. Fajardo

Table 2 Site of microvascular injury

Organ Site of microvascular injury
Skin Capillaries in papillary layer increase permeability, loss of tufting, telangiectasia, neoformation of capillaries, vascular
occlusions
Skin grafts Inhibit neovascularization, increase permeability new vessels once formed, obliterated vessels in cicatrization of capillaries
Oral Cavity Arteriolar capillary fibrosis, telangiectasia, increase HHB
Esophagus Submucosal thickening of smooth muscle, vascular connective tissue change lead to necrosis
Stomach Coagulation necrosis of epithelium, hyperemia, and dilation capillaries
Small Degenerative change microvasculature, endarterites obliterations of ?p.220
intestine
Large + thickening of smooth muscle media, inflamed cells in adventitia with necrosis
intestine
Rectum Intrinsic versus extrinsic reaction (p.208), oliterative endoarteritis
Salivary Inflammation, locular adiposis, obiterative endoarteritis
glands
Liver Central vein of lobule thrombosis p. 274 obliterated central v. p.314
Kidney Arteriolonephrosclerosis, glomerular tufts of/erent arterioles (p.317) rapid endothelial swelling and proliferation, slower
thickening walls arte./vein hypertension
Bladder Increased HHB, hyalinization of arteriole wall, endarteritis obliterans (p.302/3)
Ureter Stenosis
Testis Vascular sclerosis arteriolar p. 385 replacement fibrosis
Ovary Vascular sclerosis
Breast Fibroatrophy of fat
Lung Capillary permeability, thickening septa fibrosis, displace capillaries
Pl 456 damage to fine vasculature, capillaries, arterioles, venules
With Permissions from (Rubin and Casarett 1966; Fajardo 2001)

sclerosis of the capillary network leads to increase in

bone sclerosis, necrosis, and fracture. If bone is exposed, 12 Special Topics/Effects
(i.e., the mandible in the oral cavity), infection and
osteomyelitis and then osteonecrosis occurs. Pelvis frac- 12.1 Skin Grafts
tures lines in high dose overlap of pelvic field seams, can
be insidious and crippling. Radiation due to overlapping Skin graft experimentation in a porcine model correlated
of fields of the chest wall can lead to sclerosis, necrosis, reactions in skin versus the status of the microcirculation
and non-healing fractures of ribs. beds. That is, the radiation response in the epidermis
• Muscle: The striated musculature can withstand large reflected the age or healing of the capillary bed under full or
doses of fractionated or protracted radiation. Slow loss of split thickness grafts.
supporting vasculature can lead to fibroartrophy but • Immediate radiation within 24–48 h of the graft resulting
skeletal muscle seldom undergoes necrosis. Striated in graft necrosis since this is the time for neovasculari-
muscle has no regenerative capacity but can hypertrophy zation and capillary buds are extremely radiosensitive to
when challenged by exercise such as weight lifting. small doses of radiation.
Irradiated muscle loses its capacity to respond and • Early radiation at 2–3 weeks post grafting resulted in an
hypertrophy. acute severe reaction since the graft is supervascularized
In summary, the relationship of the exact site of injury in for 1–6 months as compared to normal skin.
the microvasculature apparatus varies. The specific char- • Late radiation of well-healed skin graft resulted in delayed
acteristic histopathologic-induced lesions are well docu- response as compared to normal skin due to fibrosis and
mented by Fajardo. The specific site in the microcirculation retraction subcutaneously as compared to normal skin.
of each major organ is tabulated in Table 2 (Rubin and However, if the well healed grafted skin reacted it under-
Casarett 1966; Fajardo 2001). went necrosis due to its more limited microcirculation.
Biophysiopathology of the Microvasculature and Microcirculation 39

12.2 Supralethal and total disruption of the microvasculature. Necrosis fol-

lows requiring resection.
A vigorous acute effect in these tissues is followed by a late
effect and has been appropriately referred to as a conse-
quential effect. Excessive high doses of radiation can lead to 12.4 Arterial Restenosis
superlethal adverse effects. That is, the microcirculation
undergoes an obliterative vasculitis causing severe tumor Following angioplasty and stenting of coronary arteries,
hypoxia while simultaneously necrosing the normal tissue restenosis of the lumen often occurs. Endolumenal catheters
site. In head and neck cancers, Andrews extrapolated with a brachytherapy radiation source was designed to
standard fractionation schedules to total doses of 100 Gy in deliver high doses to the stented site. The concept was
10 weeks. Numerous head and neck cancers persisted while based on the use of irradiation for keloids, due to later
the normal tissue site underwent total necrosis, i.e., thrombosis at stent site resulting in acute coronary throm-
advanced tongue and floor of the mouth, i.e., intrinsic and bosis. This use of radiation for benign conditions was
extrinsic musculature (striated muscle) necrosed due to replaced by drug impregnated stents.
thrombosis of the lingual arteriolar network. Similar pat- Arteriovenous malformations in the brain can be treated
terns of liquidification of necrotic normal tissues occurred with high dose stereotactic radiation surgery if not feasible
with high dose protracted continuous irradiation with cancer surgically. Doses range in the 15–30 Gy, in a single fraction
persistence of head and neck cancers. and endothelial obliteration occurs gradually in 1–3 years.
Levels of 90 % and high have been reported, particularly
for A-V-M nidus is less than 4 cm3.
12.3 Miscalculation High Dose

The lack of an early warning skin reaction of high dose

miscalculation error in this megavoltage era is a challenge References
even for an astute clinician. Experience with medical–legal
mishaps due to errors in calculation of dose are different in Bertalanffy FD, Lau C (1962) Cell renewal. Int Rev Cytol 13:357–366
patterns and time of reaction due to beam quality. Mistakes Fajardo LF (1989) The unique physiology of endothelial cells and
its implications in radiobiology. Front Radiat Ther Oncol
in the kilovoltage era were readily apparent because of 23:96–112
earlier acute reaction or persistence of the severe acute Fajardo LF (1998) The endothelial cell is a unique target of radiation:
reactions into a chronic non-healing late effect, usually of an overview. In: Rubin DB (ed) The radiation biology of the
skin or mucosa. Mistakes in the megavoltage era are endothelium. CRC Press, Boca Raton, pp 1–12
Fajardo L, Berthrong M, Anderson R (2001) Radiation Pathology.
unremarkable clinically in that no acute reaction of skin and Oxford University Press, New York, pp 3–155
even mucosa may occur despite daily, weekly, and total Ross M et al (2003) Histology: a text and atlas with cell and molecular
doses that are twice normal, i.e., 4.0 Gy daily to 20 Gy biology, 4th edn. Lippincott Williams & Wilkins, p 340
weekly and 100–120 Gy to total dose. The overdosed breast Rubin P, Casarett G (1966) Microcirculation of tumors. II. The
supervascularized state of irradiated regressing tumors. Clin Radiol
skin reaction occurs after completion of treatment and then 17:346–355
undergoes liquefaction necrosis followed by complete Rubin P, Casarett GW (1968) Clinical Radiation Pathology. Philadel-
obliteration of mammary glands. Now healing occurs with phia, WB Saunders
eventual and with persistent skin ulceration and underlying Rubin P, Casarett GW, Grise J (1960) The vascular pathophysiology of
an irradiated graft. Amer J Roentgenol 83:1097–1104
rib necrosis. A larynx mucosa reacts as anticipated at weeks Van den Brenk HA (1959) The effect of ionizing radiations on
but the mucositis persists, and then vocal cord cartilage capillary sprouting and vascular remodelling in the regenerating
necrosis results, requiring laryngectomy for survival. With repair blastema observed in the rabbit ear chamber. Am J
superficial or low kilovoltages (200–400kv), of very high Roentgenol Radium Ther Nucl Med 81(5):859–884
White DC (1975) An atlas of radiation histopathology. US Energy
dose overexposures, the skin reaction is immediate. That is, Resarch and Development Administration, Oak Ridge, p 177
blistering response due to increased capillary permeability
 Molecular Mechanisms of Radiation
Induced Injury
Isabel L. Jackson, Phil Rubin, Caroline Hadley, and Zeljko Vujaskovic

Contents Abstract
Radiation-induced normal tissue injury represents a
1 Introduction.......................................................................... 41 major impediment to the successful achievement of the
2 ‘‘Target Cell Theory’’ of Radiation Injury ...................... 42 desired clinical outcome from radiation therapy (RT) for
cancer patients; usually improved local control, reduced
3 Role of Free Radical Species and Redox Signaling
in Radiation Response......................................................... 42 risk for disease reoccurrence, and increased survival.
Complications associated with RT can result in dimin-
4 Biological Sources of ROS/RNS and the Role
ished quality of life and carries the potential for severe
of Oxidative Stress in Radiation-Induced
Tissue Injury ........................................................................ 44 debilitating disease. The development of normal tissue
4.1 Amplification of Existing ROS/RNS.................................... 44 protectors/radiomitigators is dependent on improved
4.2 Factors Affecting ROS/RNS Production understanding of the molecular mechanisms associated
by Theses Sources ................................................................. 44
with the development of acute and long-term RT-
5 The ‘‘Perpetual Cytokine Cascade’’ After Radiation induced tissue toxicity. The following chapter provides
Exposure ............................................................................... 45 a comprehensive review of the current state of knowl-
5.1 Transforming Growth Factor-Beta 1 .................................... 46
edge with respect to those mechanisms underlying
6 Vascular Dysfunction Following Ionizing Radiation ...... 47 radiation-induced normal tissue pathologies. Future
7 Multimodality or Multidisciplinary Treatment ............... 48 scientific endeavors will build upon this groundwork to
8 Conclusion ............................................................................ 48 delve deeper into the mechanistic understanding of
disease onset and progression and develop new agents
References...................................................................................... 48
that can be translated from bench to bedside to reduce
the risk for RT-induced complications.

1 Introduction
In memory of George Casarett
Advancements in cancer treatment have led to an increase in
I. L. Jackson
Z. Vujaskovic the number of cancer survivors, a population that now
Division of Translational Radiation Sciences,
Department of Radiation Oncology, University of Maryland
exceeds 11 million people. For the majority of individuals
School of Medicine, Baltimore, MD 21201, USA diagnosed with cancer, radiation therapy will play an
P. Rubin (&)
important role in their treatment. Over the next several dec-
Department of Radiation Oncology, University of Rochester ades, the number of cancer survivors will continue to grow
School of Medicine and Dentistry, 601 Elmwood Ave, and as a result, so too will the number of patients exhibiting
Box 647Rochester, NY 14642, USA the late effects of radiation damage to healthy tissue.
e-mail: [email protected]; [email protected]
The late effects of radiation exposure range from mild to
C. Hadley severe and may last for several weeks or many years fol-
Baylor University School of Medicine, Houston,
Texas 77030, USA
lowing radiotherapy. Depending on the anatomic location of

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 41
DOI: 10.1007/978-3-540-72314-1_4,  Springer-Verlag Berlin Heidelberg 2014
42 I. L. Jackson et al.

the tumor and treatment field, side effects can include mu- stranded breaks are more easily repaired and rarely cause
cositis, pneumonitis/fibrosis, or erectile dysfunction, among lethal injury to the cell where as double stranded breaks
others. Unfortunately, the relative risk of normal tissue often cause cell death either due to apoptosis or mitotic
complications limits the maximum effective radiation dose catastrophe. The classical, ‘‘target cell theory’’ of radiation-
that can be delivered to optimize tumor cytotoxicity, injury suggested that organ-specific sequelae are a result of
achieve local tumor control, and improve survival. This is a threshold level of cell death within a target cell popula-
of particular relevance for cancer types that continue to be tion. The target cell theory suggested that the so-called
associated with poor five-year cancer-free survival, such as ‘‘latent period’’ between the time of exposure and the
lung cancers. In cancers of the lung, dose escalation or development of symptomatic injury was the direct result of
combined treatment regimens have the potential to increase the proliferation kinetics of a critical cell population
survival but the exquisite radiosensitivity of the lungs puts required for proper tissue function. Based on this, the timing
patients at a greater risk for unacceptable treatment-related and expression of injury could be considered a result of the
complications, such as pneumonitis and/or fibrosis. Further proliferation kinetics of the irradiated tissue (Michalowski
complicating matters is the inability to accurately predict 1986). Thus, organs with a rapidly renewing stem cell
which patients are at greater risk for developing normal compartments (i.e., gastrointestinal tissue) would develop
tissue toxicity. In recent years, a number of clinicians and injury earlier than tissues characterized by well-differenti-
basic science researchers have worked to identify specific ated cell populations (i.e., lung).
predictors of normal tissue toxicity, but to date, no single How cells recognize and respond to injury may influence
biomarker or gene polymorphism has been identified which the tissue response to radiation (McBride et al. 2004)
can be associated with individual risk (Fleckenstein et al. Although only a few cells may be directly targeted by the
2007; Azria et al. 2008; Kelsey et al. 2011; Kong et al. ionizing event, bystander effects on non-irradiated cells
2008). The ability to identify predictive markers or develop have been observed up to 1 mm away by Brenner and
effective protective strategies to prevent, mitigate, and/or colleagues (Belyakov et al. 2005). In the lung, as well as
treat radiation injury is impeded by the fact that the other ‘‘late responding tissues’’, the relevance of the target
mechanisms driving radiation-induced normal tissue toxic- cell theory has been challenged in recent years. Based on
ity remain unclear. Therefore, improving our knowledge of work performed over the past several decades implicating a
the pathophysiological mechanisms associated with normal wide range of dynamic signaling events determining whe-
tissue toxicity could lead to therapeutic interventions that ther a cell lives or dies and communication of the trauma to
spare normal tissue from radiation damage without negating surrounding tissues, it is becoming clear that the tissue
the cytotoxic effect of radiation on tumors. response to radiation is driven by a dynamic tissue response
Before advances can be made in elucidating the mech- that begins at the time of irradiation and continues
anisms underlying radiation injury, a thorough understand- throughout the course of disease progression.
ing of classical radiation biology is imperative. It is
impossible to move forward without knowing where we
have been. Thus, this chapter will focus on radiation
chemistry, the cellular effects of radiation at the molecular 3 Role of Free Radical Species and Redox
level, and cell types involved in facilitating radiation injury, Signaling in Radiation Response
with a particular focus on lung injury.
Ionizing radiation directly damages DNA leading to geno-
mic instability and cell death through apoptosis or mitotic
2 ‘‘Target Cell Theory’’ of Radiation Injury catastrophe (O’Neill and Wardman 2009). Investigators
evaluating radiation effects on DNA have found that high
The initial ionizing event lasts for just milliseconds, yet, the linear energy transfer results in ‘‘clustered DNA lesions’’
damage caused by radiation is propagated for weeks to which are inefficiently repaired and are thus thought to be
years after the initial exposure. How and why this occurs biologically relevant to the acute and delayed effects asso-
has been the basis for a number of research studies over the ciated with radiation exposure (O’Neill and Wardman
past several decades. It appears that the early and late 2009). The ionizing event also results in formation of
effects of radiation injury are driven by a cascade of reactive oxygen species (ROS), however the levels gener-
downstream events at the molecular and cellular level ini- ated by therapeutic doses of radiation are negligible com-
tiated at the time of exposure (Fig. 1). pared to those generated by aerobic metabolism (Ward
At the time of irradiation, the production of hydroxyl 1994). Within hours of the initial ionizing exposure, there is
radical due to radiolytic hydrolysis of water can lead to a robust activation of secondary sources of oxidative stress
single or double stranded breaks within the DNA. Single leading to persistent production of free radical species that
Molecular Mechanisms of Radiation Induced Injury 43

Fig. 1 Simplified schematic diagram of the molecular events underlying development of normal tissue toxicity following radiation exposure
(Bentzen 2006)

can participate in cell signaling. A number of transcription substantial role in the development of radiation injury
factors and pro-inflammatory/pro-fibrogenic molecules, (Epperly et al. 1999a, b, 2002; Gauter-Fleckenstein et al.
such as NFjB, HIF-1a, and TGF-b, are sensitive to changes 2007, 2010; Rabbani et al. 2005, 2007; Vujaskovic et al.
in the redox status of the cell. As the level of free radical 2002; Rosenthal et al. 2011).
production is thought to be beyond the capacity of the cell’s While the exact mechanism through which radiation-
antioxidant defense mechanisms to eliminate them, the induced free radical production affects the activity of signal
imbalance between free radicals and antioxidants leads to transduction pathways and transcription factors within the
chronic upregulation of transcription factors, growth fac- irradiated tissue is not clear, it is well known that many
tors, and cytokines involved in radiation injury (Robbins signaling mechanisms and gene expression pathways are
and Zhao 2004; Benderitter et al. 2007; Zhao et al. 2007). sensitive to changes in intracellular oxidation/reduction
The environment of chronic oxidative stress results in status (Mikkelsen and Wardman 2003) leading to changes
oxidative damage to DNA leading to chromatin remod- in signal transduction, transcription factor activation, and
eling and altered gene expression, chronic protein acti- gene expression (Mikkelsen and Wardman 2003; Reboucas
vation/inactivation, and oxidation/peroxidation of 2010; Zhang and Hogg 2005). It is theorized that the
membrane lipids that can result in changes in cell sig- increase in ROS/RNS production in the early radiation
naling (Mikkelsen and Wardman 2003). The ability of response may result in oxidative modification of macro-
potent superoxide dismutase (SOD)-like compounds and molecules participating in signal transduction pathways,
other antioxidants to mitigate radiation-induced injury is resulting in signaling changes that perpetuate tissue injury
further evidence that redox-regulated signaling plays a over time (Reboucas 2010).
44 I. L. Jackson et al.

4 Biological Sources of ROS/RNS nitric oxide and superoxide anion to form peroxynitrite
and the Role of Oxidative Stress (ONOO-), a potent free radical species that has been
in Radiation-Induced Tissue Injury implicated in proteoglycan degradation and matrix turnover
(Cernanec et al. 2007). Depletion of NO through its rapid
It is hypothesized that the initial ionizing event is followed conversion to ONOO- or superoxide mediated inactivation
by a ROS/RNS mediated signaling cascade through down- of key components of the NO signaling pathway may also
stream activation of metabolic sources of prooxidant pro- contribute to vasoconstriction observed after radiation
duction. This includes mitochondria, nitric oxide synthases, (Ward et al. 1983; Fleckenstein et al. 2007).
and oxidoreductase enzymes, most notably the family of
NADPH oxidases.
Non-phagocytic cells predominantly generate ROS/RNS 4.2 Factors Affecting ROS/RNS Production
through activity of the cell membrane-associated family of by Theses Sources
NADPH oxidases (von Lohneysen et al. 2010). A number of
NADPH oxidase family members exist and have remark- It is well known that TGF-b, a ubiquitous cytokine activated
ably varied activation mechanisms and tissue distribution. by radiation, and angiotensin II exert upstream influence
For example, endothelial cells express Nox1, Nox2 over NADPH oxidase activation. The use of angiotensin
(gp91phox), Nox4, and Nox5 isoforms; whereas vascular converting enzyme (ACE) inhibitors to mitigate radiation
smooth muscle cells express the Nox1, Nox4, and Nox5 pneumonitis/fibrosis and nephropathy has been an active
isoforms (Lassegue and Griendling 2010). NADPH oxi- area of research primarily conducted by Moulder and col-
dase-derived superoxide anion (O.2 –) is involved in vascular leagues (Ghosh et al. 2009). Pre-clinical studies using a rat
maintenance and regulation of vascular smooth muscle tone model have shown that clinical doses of Captopril (34 mg/
under physiological conditions (Bengtsson et al. 2003). kg/day) improve survival and restore vascular reactivity in
However, pathological overproduction of O.2 - by NADPH irradiated lung (Ghosh et al. 2009). The equally protective
oxidases may participate in radiation injury by activating ability of both thiol and non-thiol containing ACE inhibitors
redox-sensitive signaling pathways involved in inflamma- suggests that free radical scavenging is not the primary
tion and fibrosis. Collins-Underwood et al. (2008) found mechanism of action for mitigation of radiation toxicity.
that increased expression of NADPH oxidase subunits Possible mechanisms include inhibition of AngII-mediated
(Nox4, p22phox, and p47phox) following in vitro irradiation activation of NADPH oxidase and/or effects on blood
of rat brain microvascular endothelial cells was associated pressure (Moulder et al. 2002). The role of blood pressure in
with a pro-inflammatory response. In these studies, elevated reducing radiation-induced injury is supported by preclini-
intracellular generation of ROS, activation of the pro- cal studies showing that a diet high in sodium ameliorates
inflammatory transcription factor NFjB, and expression of radiation nephropathy ostensibly through inhibition of ACE
vascular adhesion molecules ICAM-1 and PAI-1 could be activity (Moulder et al. 2002). The reduction in nephropathy
prevented by inhibition of NADPH oxidase (Collins- was only observed when a high sodium diet was initiated
Underwood et al. 2008). before the onset of nephropathy; it was not an effective
Nox4 is especially interesting as recent studies have treatment of existing nephropathy (Zhang and Rabbani
shown TGF-b1 induced cell death to be dependent upon 2012).
Nox4-derived H2O2 (Carnesecchi et al. 2011). Nox4 is a It is of note that the protective role of ACE inhibitors in
unique isoform as it produces H2O2 rather than O.2 - due to preclinical models has, to date, not translated to the clinic.
an extra 23-amino acid sequence in its E-loop (Takac et al. Wang and Anscher performed a retrospective study to
2011). In recent studies by Zhang et al. (2012), Nox4 determine the development and onset of radiation pneu-
expression was colocalized with increased PTEN expres- monitis, determined by the NCI common toxicity criteria
sion, which correlated to a progressive and persistent and CT imaging, in 213 patients treated for lung cancer with
increase in cell death between 24 h and 6 months after thoracic irradiation from 1994 to 1997 (Wang et al. 2000).
whole thorax irradiation. The increase in PTEN expression In this study, the authors found the incidence and onset of
coincided with downregulation of Akt signaling. radiation pneumonitis among patients taking ACE inhibitors
(captopril, benazepril, enalapril, lisinopril, quinapril, or
fosinopril) for hypertension was not significantly different
4.1 Amplification of Existing ROS/RNS than those who were not on ACE inhibitors (Wang et al.
2000). Thus, it remains unclear whether the mitigating
Production of ROS/RNS by NADPH oxidases or dysfunc- effect of ACE inhibitors in preclinical models will translate
tional mitochondria can be amplified by the reaction of to the clinic.
Molecular Mechanisms of Radiation Induced Injury 45

Fig. 2 a Suggested chain of

events beginning with the initial
injury to the primary target cell—
the parenchymal cell—and
culminating in activation of the
interstitial cells (e.g., fibroblasts)
to lay down extracellular matrix.
b Hypothetical pathway
indicating the chain of events
from initial injury to the final late
effect (e.g., fibrosis) (With
permission from Rubin and
Williams 2001)

intercellular communication. In our current paradigm, dur-

5 The ‘‘Perpetual Cytokine Cascade’’ After ing the course of LENT induction, the so-called cytokine
Radiation Exposure cascade can be considered to involve four basic cell com-
ponents in tissues or organs—the parenchymal cell, the
Within the first week following exposure to radiation, there inflammatory cell, the endothelial cell, and the interstitial
is a decrease in inflammatory cells followed by an increase cell. These are illustrated in Fig. 2a, are a few of the pro-
in neutrophils and lymphocyte accumulation that quickly inflammatory and profibrotic cytokines that are thought to
returns to normal. Over time, fluctuations in inflammatory be expressed concurrently (Rubin and Williams 2001).
cell subsets infiltrating the irradiated tissue can be observed. An intercellular conversation is initiated at the moment
The ‘‘perpetual cascade of cytokines’’ in the lungs after of irradiation, when injury to cell components occurs (e.g.,
thoracic irradiation was first proposed by Rubin et al. 1995 membrane, cytoplasmic body, or DNA), which leads to
which demonstrated an absence of a ‘‘latent period’’ at the altered gene expression. This reaction is often in the form of
molecular and cellular level in late responding tissues. an immediate release of cytokine mRNA; in time, this
Our group has helped to pioneer the use of increasingly reaction may provoke a series of downstream events
sophisticated molecular biologic methods to assess and through cell signaling, which is illustrated in Fig. 2b.
analyze late effects in normal tissue (LENT). In so doing, Through signal transduction, the receptor cells are acti-
we have extended the paradigm o the clinical pathologic vated; such activation may result in as little as additional or
course of events following irradiation or chemotherapy sequential cytokine expression or it can lead to proliferation
from target cells per se to include and emphasize the or production of extracellular matrix proteins, depending on
46 I. L. Jackson et al.

the species of receptor cell. In the specific case of the et al. 1997). Targeting inflammatory cell recruitment
receptor cell being a fibroblast, activation of the collagen through inhibition of vascular adhesion molecules, specifi-
gene, which has been seen within 24 h of injury, can persist cally ICAM-1, reduces the number of infiltrating inflam-
for days, weeks, or even months. This extended persistence matory cells and blocks the development of fibrosis in
may continue until the pathologic or clinical expression of irradiated lungs of C57BL/6 mice (Hallahan et al. 2002;
injury is manifested (Rubin and Williams 2001). Hallahan and Virudachalam 1997). Although the impact of
Using a mixture of molecular biologic techniques and systemically blocking ICAM-1 on acute and chronic
in vivo/in vitro assays, a number of in-field effects can be inflammation is significant, there is no improvement in
appreciated. The release of cytokines occurs shortly after respiratory function or survival among non-treated and
irradiation and persists until the pathologic and clinical treated animals exposed to radiation (Hallahan et al. 2002).
expression of late effects, and there is an arbitrary temporal This suggests an underlying cause for radiation pneumoni-
division of cytokine expression: tis/fibrosis, which impacts animal survival, distinct from
• Immediate: first 24 h after injury inflammation alone.
• Early: days to *8 weeks post injury
• Late: 3–6 months post injury.
This scenario can be seen to correlate and give further 5.1 Transforming Growth Factor-Beta 1
credence to the postulated shape of the clinical pathologic
course of events. The potential to use cytokines to alter the TGF-b1 is a multipotent cytokine that activates transcrip-
therapeutic ratio favorably is of great interest to clinicians in tional regulators and signal transducers involved in cellular
the protocol design of new clinical trials. proliferation, immunosuppression, extracellular matrix
The most predominant cytokines involved in inflamma- remodeling and inhibition of matrix degradation, chronic
tion appear to be IL-1a/b, IL-6, TNF-a, and TGF-b (Rubin inflammatory disease, and angiogenesis (Flanders 2004;
et al. 1995; Chiang et al. 1997; Herskind et al. 1998; Rube Lewis et al. 1999). TGF-b is secreted as an inactive poly-
et al. 2004; Brush et al. 2007), however the pattern and peptide by virtually all cells, including fibroblasts, epithelial
timing of cytokine expression appears to vary among cells, macrophages, and others. Free radicals produced
studies (Hill 2005), as well as among animal models. The during radiation can activate TGF-b, which can then bind
variation of cytokine expression in response to radiation the TGF-b type II receptor (Ehrhart et al. 1997) setting off a
between mouse strains may present one possible mechanism phosphorylation cascade that transduces the signal from the
for the observed difference in strain sensitivity and response cell membrane to the nucleus (Flanders 2004; Roberts
to radiation. Likewise, baseline differences in the number 1999). Interestingly, it has recently been shown that the
and types of resident inflammatory cell types among strains Smad2/3 phosphorylation cascade downstream of TGF-b1
as well as genetic differences in leukocyte recruitment may is dependent on Nox4 signaling further suggesting a critical
contribute to the variation in radiation response. For role of redox signaling in propagating fibrosis (Amara et al.
example, fibrosing strains have a higher ratio of active to 2010).
latent TGF-b than non-fibrosing strains (Franko et al. 1997). Franko and colleagues 1997 found differential expression
Epperly et al. (1999) found a time dependent progression in of TGF-b latency associated peptide (LAP) in the lungs of
pathological fibrosis coincided with increased IL-1 mRNA C57LJ and C3HeB/FeJ mice after irradiation (11 and 18 Gy
levels and a biphasic wave of TGF-b expression during the respectively). In the C57L/J mice, a significantly greater
development of fibrotic disease in C57BL/6 J mice (Epperly proportion of macrophages and uninvolved tissue expressed
et al. 1999). However, targeting cytokine production has not TGF-b LAP as compared to lesions with acute/intense
been completely effective in improving survival and respi- inflammation and fibrosis. Cells positive for LAP within the
ratory function, nor has any single circulating cytokine been areas of intense inflammation were predominantly macro-
identified as a potential biomarker for susceptibility to phages and Type II Pneumocytes. This was in contrast to
development of radiation-induced injury. C3HeB/FeJ, a non-fibrosing mouse strain, which showed
Cytokines expressed in irradiated tissue, such as inter- significantly higher levels of latent TGF-b (Franko et al.
leukins, monocyte chemoattractant protein-1, and kerati- 1997). Since TGF-b is secreted as an inactive molecule
nocyte chemoattractant (KC), are consistent with what one bound to the extracellular matrix by its LAP, the results of
would expect based on the inflammatory cell infiltrates Franko suggest Type II pneumocytes and macrophages are
found in the tissue and in circulating plasma. Inflammatory the predominant producers of TGF-b following radiation in
cells accumulate in irradiated tissue due to persistent fibrosing mouse strains (C57L background).
upregulation of vascular adhesion markers (Epperly et al. Studies by Epperly et al. (1999) found decreased early
2002; Son et al. 2006; Muller et al. 2006; Jaal and Dorr onset of TGF-b, IL-1, and TNF-a mRNA levels in irradiated
2005; Ikeda et al. 2000; Olschowka et al. 1997; Gaugler lung following intratracheal administration of a manganese-
Molecular Mechanisms of Radiation Induced Injury 47

SOD plasmid/liposome complex correlated with improved of less than 5 min (Wang et al. 1995; Huang et al. 1998).
median survival time. It is important to note that at the time However, under hypoxia, or in the event of oxidative/ni-
of death, TGF-b levels were not significantly different troxidative modification of protein residues in the oxygen
among groups. Several studies using pharmacologic inhib- dependent domain, the alpha subunit of HIF is stabilized
itors to TGF-b or components of its signal transduction and translocated to the nucleus where it forms a heterodimer
pathway have the ability to significantly reduce radiation with its constitutively expressed HIF-1b subunit. The HIF
fibrosis and improve lung function, indicating that unregu- heterodimer binds to the hypoxia response element (HRE)
lated TGF-b is a mediator of fibroproliferative disease of a wide variety of genes regulating cell proliferation,
(Flanders 2004; Anscher et al. 2008; Biswas et al. 2007; migration, pH, apoptosis, energy metabolism, and most
Nishioka et al. 2004; Xavier et al. 2004). importantly, angiogenesis (Brahimi-Horn et al. 2005).
Vujaskovic et al. showed an increase in expression of the
HIF product vascular endothelial growth factor (VEGF)
6 Vascular Dysfunction Following between the time of radiation exposure and development of
Ionizing Radiation symptomatic disease in a rat model of radiation-induced
lung injury (Fleckenstein et al. 2007). Under physiological
It has long been acknowledged that the vascular endothe- conditions, VEGF levels decline as tissues undergo reoxy-
lium may be an important target of ionizing radiation. genation/reperfusion and immature vessels tend to regress
Indeed, several studies have shown both gastrointestinal while healthy vasculature remains unaffected by the change
toxicity and xerostomia to be influenced by endothelial cell in VEGF (Dorr et al. 2000). The involvement of VEGF in
damage. Ionizing radiation can disrupt the structural vascular pruning is a relatively new concept. Under path-
integrity of the vascular architecture resulting in endothelial ological conditions, VEGF remains elevated resulting in
cell damage, barrier breakdown, leakage, and edema (An- little to no vessel regression, increased stimulation of neo-
scher et al. 2005; Martin et al. 2000; Stone et al. 2004). As a vascularization, and long-term irregularities in perfusion
consequence of the disruption in vascular function, hypoxic (Dorr et al. 2000), which have been observed in radiation
regions can develop in the under-perfused tissue. Indeed, studies. Perfusion imaging of normal tissue after radiation
one of the key pathophysiological consequences of vascular demonstrates vascular dysfunction almost immediately
injury after radiation is the development of tissue hypoxia. coinciding with a transient decrease in perfusion, increased
Tissue hypoxia can recruit inflammatory cells, where they edema, and elevated expression of HIF-1a and TGF-b
are then activated to undergo the respiratory burst. Not only (Ward et al. 1983; Fleckenstein et al. 2007). The vascular
does this increase oxidative stress, but also further con- network renormalizes for a brief period of time, before
tributes to tissue hypoxia as oxygen is required for the progressively deteriorating beginning around the time of the
respiratory burst in phagocytic cells. One of the primary cell initial onset of hypoxia and continuing until the develop-
types recruited by hypoxia is the macrophage. Jackson ment of histological and functional disease (Ward et al.
et al., demonstrated that macrophages incubated under 1983; Fleckenstein et al. 2007). Spatial distribution and
hypoxic conditions exhibit a redox-dependent increase in density patterns of VEGF mRNA following the onset of
TGF-b production and the hypoxia-inducible factor-1 alpha radiation-induced spinal cord injury show that transient
(HIF-1a) product VEGF (Jackson et al. 2007). expression of VEGF at the legion border correlates with a
HIF-1a has observed in lung tissue as early as one day local increase in blood vessel density (Bartholdi et al.
after radiation. The ability of free radical scavenging to 1997).
inhibit stabilization of HIF-1a has implicated ROS/RNS as One of the leading producers of HIF after radiation
a critical activator of HIF transcriptional activity (Po- appears to be macrophages. In addition to being one of the
uyssegur and Mechta-Grigoriou 2006; Li et al. 2007). The primary producers of oxidative stress after radiation, mac-
consequences of HIF stabilization in irradiated healthy tis- rophages are known to be a source of pro-angiogenic
sue likely include greater endothelial dysfunction, enhanced stimuli (HIF-1a) (Lewis et al. 1999). Macrophages are
vascular hyperpermeability, formation of temporary fibrin closely associated with areas of inadequate perfusion and
matrices, and angiogenesis (van Hinsbergh et al. 2001; van low partial oxygen pressure (Lewis et al. 1999), thus, it is
Hinsbergh 2001a, b; Semenza 2000). Vascular leakage and not surprising that macrophage accumulation coincides with
fibrin deposition facilitate the formation of new vessels (van a decrease in perfusion and an increase in tissue hypoxia
Hinsbergh et al. 2001) through establishment of a provi- following irradiation (Fleckenstein et al. 2007).
sional fibrin matrix which provides a stable scaffold for In normal tissue, the number of macrophages signifi-
HIF-1a mediated inflammatory and endothelial cell migra- cantly increases within several days to weeks post-radia-
tion and vessel sprouting (Haroon et al. 1999). Under tion(Fleckenstein et al. 2007). Macrophage accumulation
physiological conditions, HIF has a relatively short half-life within the residual alveolar space and interstitium appears
48 I. L. Jackson et al.

prior to the onset of functional damage and is associated Similar cell-cytokine cascades to radiation mediate and
with a surge in cytokine activity (Vujaskovic et al. 2002; drive the initial inflammatory process to fibrogenesis and
2001). Activated macrophages can secrete pro-angiogenic complete the scarring process (Yarnold et al. 2010).
(HIF) (Kureshi et al. 1994) and fibrogenic growth factors Chemotherapy: can induce endocrine, paracrine, and
(TGF-b) to induce the formation of granulation tissue autocrine cytokine cell signaling utilizing similar pathways
containing myofibroblasts and neovessels (Frangogiannis as radiation. Cells sense signals from both extracellular and
2006). In radiation induced late brain injury, macrophages intracellular environments as well as other cells. Most sig-
were found to be a prominent histological feature in 5 out of nals are initiated by ligands and are sensed by cell mem-
6 tissue biopsies studied by Kureshi and colleagues (1994). brane receptors which stimulate the formation of
Under physiological conditions, macrophages respond to multiprotein complexes. These in turn generate small mol-
injured tissue to facilitate wound healing and return the ecule messengers that control the inflammatory and fibro-
environment to homeostatic levels. However, for reasons genic tissue responses. Although pathways induced are
that remain unclear, in irradiated normal tissue, the healing depicted as linear, nearly all pathways induced are very
response is aberrant and furthers the escalation of injury. interconnected and pleotrophic forming networks that allow
Interestingly, in a recent study, O’Brien et al. (2005) dynamic cellular responses resulting in cell death either in
identified differential apoptosis among alveolar macro- mitosis or apoptosis. Thus, the inflammatory and fibrogenic
phages in C3H/HeJ, which develop an acute pneumonitis, responses parallel those of the other modalities in eradi-
and ‘‘fibrosis prone’’ C57BL/6 J mice, which the authors cating cancers producing adverse acute and LENT.
hypothesized could explain the disparity between inflam- Molecular targeted interventions that can block specific
matory response between these strains. signals/cytokines may be applicable to other modalities
The HIF-1a product, carbonic Anhydrase-9 (CA-9), is (DeVita et al. 2011).
frequently used as molecular marker for imaging of hypoxia
because of its colocalization with HIF-1a in tumor tissue.
CA9 is a chimeric enzyme that catalyzes the hydration of 8 Conclusion
carbon dioxide to bicarbonate ion to maintain an alkaline
intracellular pH (Pouyssegur et al. 2001). Altered expression The development of radiation-induced tissue injury begins
of CA9 in hypoxic regions suggests that these regions may with an ionizing event that results in direct damage to DNA
possess metabolic alterations, although the specific changes but also initiates a cascade of events on the cellular and
involved have not been investigated. Evidence of HIF-1a molecular level that proceeds during a period of clinically
upregulation in hypoxia driven pathologies including radia- occult injury. One of the effects of the propagation of the
tion induced normal tissue injury could support the hypoth- initial insult is a disruption of the balance between oxygen
esis that cellular metabolism is altered following radiation, derived free radicals and antioxidants. This imbalance
especially when combined with the observed mitochondrial results in oxidative damage to DNA, lipids, and proteins
dysfunction and nonoxidative synthesis of ATP. within the affected tissues causing increased apoptosis of
cells as well as altering signaling pathway activity. Changes
in cell signaling can result in increased vascular contrac-
7 Multimodality or Multidisciplinary tility and permeability, angiogenesis, and inflammatory
Treatment monocyte migration and inflammation, all of which con-
tribute to development of acute and latent tissue injury.
All cytotoxic treatment modalities utilized in the treatment Because many of the changes that contribute to radiation-
of cancers share common proinflammatory and profibrotic induced tissue injury are the result of a signaling cascade
pathways. initiated by overproduction of ROS/RNS, it is unlikely that
Surgery: with the initial incision through the final exci- modification or elimination of any one event can alter the
sion of the cancer, a similar cascade of cytokines are overall process of progressive radiation injury. The injury is
induced in tissues and organs traumatized by surgery. After self-perpetuating in nature and is, therefore, more likely to
the acute inflammatory phase, the induction of fibrotic be mitigated by interventions which broadly interfere with
scarring follows, resulting in infiltrates of immune cells the propagation of radiation damage.
(neutrophils, lymphocytes, and macrophages releasing
cytokines that stimulate fibroblasts or progenitor cells that
differentiate into myofibroblasts. Myofibroblasts produce References
collagens and metalloproteinases needed for collagen deg-
radation. The ultimate surgical scar is hypocellular as Amara N, Goven D, Prost F et al (2010) NOX4/NADPH oxidase
myofibroblasts and inflammatory cells undergo apoptosis. expression is increased in pulmonary fibroblasts from patients with
Molecular Mechanisms of Radiation Induced Injury 49

idiopathic pulmonary fibrosis and mediates TGFbeta1-induced Epperly MW, Bray JA, Krager S et al (1999a) Intratracheal injection
fibroblast differentiation into myofibroblasts. Thorax 65(8): of adenovirus containing the human MnSOD transgene protects
733–738 athymic nude mice from irradiation-induced organizing alveolitis.
Anscher MS, Chen L, Rabbani Z et al (2005) Recent progress in Int J Radiat Oncol Biol Phys 43(1):169–181
defining mechanisms and potential targets for prevention of normal Epperly MW, Travis EL, Sikora C et al (1999b) Manganese
tissue injury after radiation therapy. Int J Radiat Oncol Biol Phys [correction of Magnesium] superoxide dismutase (MnSOD) plas-
62(1):255–259 mid/liposome pulmonary radioprotective gene therapy: modulation
Anscher MS, Thrasher B, Zgonjanin L et al (2008) Small molecular of irradiation-induced mRNA for IL-I, TNF-alpha, and TGF-beta
inhibitor of transforming growth factor-beta protects against correlates with delay of organizing alveolitis/fibrosis. Biol Blood
development of radiation-induced lung injury. Int J Radiat Oncol Marrow Transpl 5(4):204–214
Biol Phys 71(3):829–837 Epperly MW, Defilippi S, Sikora C et al (2002) Radioprotection of
Azria D, Ozsahin M, Kramar A et al (2008) Single nucleotide lung and esophagus by overexpression of the human manganese
polymorphisms, apoptosis, and the development of severe late superoxide dismutase transgene. Mil Med 167(2 Suppl):71–73
adverse effects after radiotherapy. Clin Cancer Res 14(19): Flanders KC (2004) Smad3 as a mediator of the fibrotic response. Int J
6284–6288 Exp Pathol 85(2):47–64
Bartholdi D, Rubin BP, Schwab ME (1997) VEGF mRNA induction Fleckenstein K, Gauter-Fleckenstein B, Jackson IL et al (2007a) Using
correlates with changes in the vascular architecture upon spinal biological markers to predict risk of radiation injury. Semin Radiat
cord damage in the rat. Eur J Neurosci 9(12):2549–2560 Oncol 17(2):89–98
Batinic-Haberle I, Reboucas JS, Spasojevic I (2010) Superoxide Fleckenstein K, Zgonjanin L, Chen L et al (2007b) Temporal onset of
dismutase mimics: chemistry, pharmacology, and therapeutic hypoxia and oxidative stress after pulmonary irradiation. Int J
potential. Antioxid Redox Signal 13(6):877–918 Radiat Oncol Biol Phys 68(1):196–204
Belyakov OV, Mitchell SA, Parikh D et al (2005) Biological effects in Frangogiannis NG (2006) Targeting the inflammatory response in
unirradiated human tissue induced by radiation damage up to 1 mm healing myocardial infarcts. Curr Med Chem 13(16):1877–1893
away. Proc Natl Acad Sci U S A 102(40):14203–14208 Franko AJ, Sharplin J, Ghahary A et al (1997) Immunohistochemical
Benderitter M, Isoir M, Buard V et al (2007) Collapse of skin localization of transforming growth factor beta and tumor necrosis
antioxidant status during the subacute period of cutaneous radiation factor alpha in the lungs of fibrosis-prone and ‘‘non-fibrosing’’ mice
syndrome: a case report. Radiat Res 167(1):43–50 during the latent period and early phase after irradiation. Radiat
Bengtsson SH, Gulluyan LM, Dusting GJ et al (2003) Novel isoforms Res 147(2):245–256
of NADPH oxidase in vascular physiology and pathophysiology. Gaugler MH, Squiban C, van der Meeren A et al (1997) Late and
Clin Exp Pharmacol Physiol 30(11):849–854 persistent up-regulation of intercellular adhesion molecule-1
Bentzen SM (2006) Preventing or reducing late side effects of (ICAM-1) expression by ionizing radiation in human endothelial
radiation therapy: radiobiology meets molecular pathology. Nat cells in vitro. Int J Radiat Biol 72(2):201–209
Rev Cancer 6(9):702–713 Gauter-Fleckenstein B, Fleckenstein K, Owzar K et al (2007)
Biswas S, Guix M, Rinehart C et al (2007) Inhibition of TGF-beta with Comparison of two Mn porphyrin-based mimics of superoxide
neutralizing antibodies prevents radiation-induced acceleration of dismutase in pulmonary radioprotection. Free Radic Biol Med
metastatic cancer progression. J Clin Invest 117(5):1305–1313 44(6):982–989
Brahimi-Horn C, Mazure N, Pouyssegur J (2005) Signalling via the Gauter-Fleckenstein B, Fleckenstein K, Owzar K et al (2010) Early
hypoxia-inducible factor-1alpha requires multiple posttranslational and late administration of MnTE-2-PyP5 ? in mitigation and
modifications. Cell Signal 17(1):1–9 treatment of radiation-induced lung damage. Free Radic Biol Med
Brush J, Lipnick SL, Phillips T et al (2007) Molecular mechanisms of 48(8):1034–1043
late normal tissue injury. Semin Radiat Oncol 17(2):121–130 Ghosh SN, Zhang R, Fish BL et al (2009a) Renin-Angiotensin system
Carnesecchi S, Deffert C, Donati Y et al (2011) A key role for NOX4 suppression mitigates experimental radiation pneumonitis. Int J
in epithelial cell death during development of lung fibrosis. Radiat Oncol Biol Phys 75(5):1528–1536
Antioxid Redox Signal 15(3):607–619 Ghosh SN, Wu Q, Mader M et al (2009b) Vascular injury after whole
Cernanec JM, Weinberg JB, Batinic-Haberle I et al (2007) Influence of thoracic x-ray irradiation in the rat. Int J Radiat Oncol Biol Phys
oxygen tension on interleukin 1-induced peroxynitrite formation 74(1):192–199
and matrix turnover in articular cartilage. J Rheumatol Hallahan DE, Virudachalam S (1997) Intercellular adhesion molecule
34(2):401–407 1 knockout abrogates radiation induced pulmonary inflammation.
Chiang CS, Hong JH, Stalder A et al (1997) Delayed molecular Proc Natl Acad Sci U S A 94(12):6432–6437
responses to brain irradiation. Int J Radiat Biol 72(1):45–53 Hallahan DE, Geng L, Shyr Y (2002) Effects of intercellular adhesion
Collins-Underwood JR, Zhao W, Sharpe JG et al (2008) NADPH molecule 1 (ICAM-1) null mutation on radiation-induced pulmon-
oxidase mediates radiation-induced oxidative stress in rat brain ary fibrosis and respiratory insufficiency in mice. J Natl Cancer Inst
microvascular endothelial cells. Free Radic Biol Med 45(6): 94(10):733–741
929–938 Haroon ZA, Lai TS, Hettasch JM et al (1999) Tissue transglutaminase
DeVita VT, Lawrence TS, Rosenburg SA et al (eds) (2011) In: Devita, is expressed as a host response to tumor invasion and inhibits
Hellman, and Rosenberg’s Cancer: principles and practice of tumor growth. Lab Invest 79(12):1679–1686
oncology, vol. 5, 9th edn. Lippincott Williams & Wilkins, Herskind C, Bamberg M, Rodemann HP (1998) The role of cytokines
Philadelphia 5: pp 57–67 in the development of normal-tissue reactions after radiotherapy.
Dorr W, Baumann M, Herrmann T (2000) Radiation-induced lung Strahlenther Onkol 174(Suppl 3):12–15
damage: a challenge for radiation biology, experimental and Hill RP (2005) Radiation effects on the respiratory system. BJR Suppl
clinical radiotherapy. Int J Radiat Biol 76(4):443–446 27:75–81
Ehrhart EJ, Segarini P, Tsang ML et al (1997) Latent transforming Huang LE, Gu J, Schau M et al (1998) Regulation of hypoxia-
growth factor beta1 activation in situ: quantitative and functional inducible factor 1alpha is mediated by an O2-dependent degrada-
evidence after low-dose gamma-irradiation. Faseb J 11(12): tion domain via the ubiquitin-proteasome pathway. Proc Natl Acad
991–1002 Sci U S A 95(14):7987–7992
50 I. L. Jackson et al.

Ikeda Y, Ito M, Matsuu M et al (2000) Expression of ICAM-1 and Rabbani ZN, Batinic-Haberle I, Anscher MS et al (2007) Long-
acute inflammatory cell infiltration in the early phase of radiation term administration of a small molecular weight catalytic
colitis in rats. J Radiat Res (Tokyo) 41(3):279–291 metalloporphyrin antioxidant, AEOL 10150, protects lungs
Jaal J, Dorr W (2005) Early and long-term effects of radiation on from radiation-induced injury. Int J Radiat Oncol Biol Phys
intercellular adhesion molecule 1 (ICAM-1) expression in mouse 67(2):573–580
urinary bladder endothelium. Int J Radiat Biol 81(5):387–395 Robbins ME, Zhao W (2004) Chronic oxidative stress and radiation-
Jackson IL, Chen L, Batinic-Haberle I et al (2007) Superoxide induced late normal tissue injury: a review. Int J Radiat Biol
dismutase mimetic reduces hypoxia-induced O2*-, TGF-beta, and 80(4):251–259
VEGF production by macrophages. Free Radic Res 41(1):8–14 Roberts AB (1999) TGF-beta signaling from receptors to the nucleus.
Kelsey CR, Jackson L, Langdon S et al (2011) A polymorphism within Microbes Infect 1(15):1265–1273
the promoter of the tgfbeta1 gene is associated with radiation Rosenthal RA, Fish B, Hill RP et al (2011) Salen Mn complexes
sensitivity using an objective radiologic endpoint. Int J Radiat mitigate radiation injury in normal tissues. Anticancer Agents Med
Oncol Biol Phys 82(2):e247–e255 Chem 11(4):359–372
Kong FM, Ao X, Wang L et al (2008) The use of blood biomarkers to Rube CE, Wilfert F, Palm J et al (2004) Irradiation induces a biphasic
predict radiation lung toxicity: a potential strategy to individualize expression of pro-inflammatory cytokines in the lung. Strahlenther
thoracic radiation therapy. Cancer Control 15(2):140–150 Onkol 180(7):442–448
Kureshi SA, Hofman FM, Schneider JH et al (1994) Cytokine Rubin P, Williams J (eds) (2001) Clinical oncology: a multidisciplin-
expression in radiation-induced delayed cerebral injury. Neurosur- ary approach for physicians and students, 8th edn. Elsevier,
gery 35(5):822–829; discussion 829–830 Philadelphia, p 899, Figure 34-2ab
Lassegue B, Griendling KK (2010) NADPH oxidases: functions and Rubin P, Johnston CJ, Williams JP et al (1995) A perpetual cascade of
pathologies in the vasculature. Arterioscler Thromb Vasc Biol cytokines postirradiation leads to pulmonary fibrosis. Int J Radiat
30(4):653–661 Oncol Biol Phys 33(1):99–109
Lewis JS, Lee JA, Underwood JC et al (1999) Macrophage responses Semenza GL (2000) Oxygen-regulated transcription factors and their
to hypoxia: relevance to disease mechanisms. J Leukoc Biol role in pulmonary disease. Respir Res 1(3):159–162
66(6):889–900 Son EW, Rhee DK, Pyo S (2006) Gamma-irradiation-induced
Li F, Sonveaux P, Rabbani ZN et al (2007) Regulation of HIF-1alpha intercellular adhesion molecule-1 (ICAM-1) expression is associ-
stability through S-nitrosylation. Mol Cell 26(1):63–74 ated with catalase: activation of Ap-1 and JNK. J Toxicol Environ
Martin M, Delanian S, Sivan V et al (2000) Radiation-induced Health A 69(24):2137–2155
superficial fibrosis and TGF-alpha 1. Cancer Radiother Stone HB, Moulder JE, Coleman CN et al (2004) Models for
4(5):369–384 evaluating agents intended for the prophylaxis, mitigation and
McBride WH, Chiang CS, Olson JL et al (2004) A sense of danger treatment of radiation injuries. Report of an NCI workshop, 3–4
from radiation. Radiat Res 162(1):1–19 Dec, 2003. Radiat Res;162(6):711–728
Michalowski A (1986) The pathogenesis of the late side-effects of Takac I, Schroder K, Zhang L et al (2011) The E-loop is involved in
radiotherapy. Clin Radiol 37(3):203–207 hydrogen peroxide formation by the NADPH oxidase Nox4. J Biol
Mikkelsen RB, Wardman P (2003) Biological chemistry of reactive Chem 286(15):13304–13313
oxygen and nitrogen and radiation-induced signal transduction van Hinsbergh VW (2001a) NO or H(2)O(2) for endothelium-
mechanisms. Oncogene 22(37):5734–5754 dependent vasorelaxation: Tetrahydrobiopterin makes the differ-
Moulder JE, Fish BL, Cohen EP (2002) Dietary sodium modification ence. Arterioscler Thromb Vasc Biol 21(5):719–721
and experimental radiation nephropathy. Int J Radiat Biol van Hinsbergh VW (2001b) The endothelium: vascular control of
78(10):903–911 haemostasis. Eur J Obstet Gynecol Reprod Biol 95(2):198–201
Muller K, Kohn FM, Port M et al (2006) Intercellular adhesion van Hinsbergh VW, Collen A, Koolwijk P (2001) Role of fibrin matrix
molecule-1: a consistent inflammatory marker of the cutaneous in angiogenesis. Ann N Y Acad Sci 936:426–437
radiation reaction both in vitro and in vivo. Br J Dermatol von Lohneysen K, Noack D, Wood MR et al (2010) Structural insights
155(4):670–679 into Nox4 and Nox2: motifs involved in function and cellular
Nishioka A, Ogawa Y, Mima T et al (2004) Histopathologic localization. Mol Cell Biol 30(4):961–975
amelioration of fibroproliferative change in rat irradiated lung Vujaskovic Z, Anscher MS, Feng QF et al (2001) Radiation-induced
using soluble transforming growth factor-beta (TGF-beta) receptor hypoxia may perpetuate late normal tissue injury. Int J Radiat
mediated by adenoviral vector. Int J Radiat Oncol Biol Phys Oncol Biol Phys 50(4):851–855
58(4):1235–1241 Vujaskovic Z, Batinic-Haberle I, Rabbani ZN et al (2002) A small
O’Brien TJ, Letuve S, Haston CK (2005) Radiation-induced strain molecular weight catalytic metalloporphyrin antioxidant with
differences in mouse alveolar inflammatory cell apoptosis. Can J superoxide dismutase (SOD) mimetic properties protects lungs
Physiol Pharmacol 83(1):117–122 from radiation-induced injury. Free Radic Biol Med 33(6):
Olschowka JA, Kyrkanides S, Harvey BK et al (1997) ICAM-1 857–863
induction in the mouse CNS following irradiation. Brain Behav Wang GL, Jiang BH, Rue EA et al (1995) Hypoxia-inducible factor
Immun 11(4):273–285 1 is a basic-helix-loop-helix-PAS heterodimer regulated by
O’Neill P, Wardman P (2009) Radiation chemistry comes before cellular O2 tension. Proc Natl Acad Sci U S A 92(12):
radiation biology. Int J Radiat Biol 85(1):9–25 5510–5514
Pouyssegur J, Mechta-Grigoriou F (2006) Redox regulation of the Wang LW, Fu XL, Clough R et al (2000) Can angiotensin-converting
hypoxia-inducible factor. Biol Chem 387(10–11):1337–1346 enzyme inhibitors protect against symptomatic radiation pneumo-
Pouyssegur J, Franchi A, Pages G (2001) pHi, aerobic glycolysis and nitis? Radiat Res 153(4):405–410
vascular endothelial growth factor in tumour growth. Novartis Ward JF (1994) DNA damage as the cause of ionizing radiation-
Found Symp 240:186–196 (discussion 196–188) induced gene activation. Radiat Res 138( Suppl 1):S85–S88
Rabbani ZN, Anscher MS, Folz RJ et al (2005) Overexpression of Ward WF, Solliday NH, Molteni A et al (1983) Radiation injury in rat
extracellular superoxide dismutase reduces acute radiation induced lung II. Angiotensin-converting enzyme activity. Radiat Res
lung toxicity. BMC Cancer 5:59 96(2):294–300
Molecular Mechanisms of Radiation Induced Injury 51

Xavier S, Piek E, Fujii M et al (2004) Amelioration of radiation- Zhang Y Zhang X, Rabbani ZN et al (2012) Oxidative stress mediates
induced fibrosis: inhibition of transforming growth factor-beta lung injury by inducing apoptosis. Int J Radiat Oncol Biol Phys
signaling by halofuginone. J Biol Chem 279(15):15167–15176 83(2):740–748
Yarnold J, Brotons MC (2010) Pathogenetic mechanisms in radiation Zhao W, Diz DI, Robbins ME (2007) Oxidative damage
fibrosis. Radiother Oncol 97(1):149–161 pathways in relation to normal tissue injury. Br J Radiol
Zhang Y, Hogg N (2005) S-Nitrosothiols: cellular formation and 80(1):S23–31
transport. Free Radic Biol Med 38(7):831–838
 Biodetection and Biointervention: Cytokine
Pathways as a Rationale for Anti-cytokine
Interventions Post-Radiation
Paul R. Graves, Isabel Jackson, Mitchell S. Anscher, Ross Mikkelsen,
and Zeljko Vujaskovic

Contents Abstract
Recent advances in our understanding of the molecular
1 Introduction.......................................................................... 53 events underlying the pathogenesis of radiation-induced
2 Molecular Mechanisms of Radiation Injury .................... 54 normal tissue injury has opened up the possibility of
biologically based interventions to prevent, mitigate, or
3 The Importance of Transforming Growth Factor ß1
in Radiation-Induced Injury .............................................. 54 treat these complications. This work has also stimulated
efforts to develop strategies to stratify patients according
4 Using Plasma TGFß1 Levels to Predict Injury Risk ...... 56
to risk of injury as a means to individualize therapy and
5 The Role of Other Cytokines in Radiation-Induced improve the therapeutic ratio. Since many of the proteins
Injury .................................................................................... 57 involved in the pathogenesis of radiation injury, such as
6 Using Other Markers to Predict Radiation-Induced transforming growth factor ß, can be measured in the
Injury .................................................................................... 58 blood, researchers have begun to attempt to identify
7 Chronic Inflammation as a Mediator of Radiation cytokine profiles that might identify patients at risk for
Injury .................................................................................... 58 normal tissue injury. This chapter summarizes the
8 Candidate Proteins for Predicting Radiation Injury ...... 58 current state of this research and discusses approaches
to mitigate or treat radiation injury that targets one or
9 Strategies and Potential Targets for Intervention........... 59
more of the molecular pathways involved in its
10 Conclusion ............................................................................ 61 pathogenesis.
References...................................................................................... 61

1 Introduction

The tolerance of normal tissue surrounding tumors limits

the maximum therapeutic dose of radiation that can be
delivered to treat most malignancies (Milano et al. 2007).
Many cancers present as large masses that require high
doses of radiation to achieve local control or cure. However,
physicians are forced to limit the total dose and volume
M. S. Anscher (&)  R. Mikkelsen irradiated due to the risk of life threatening or fatal com-
Department of Radiation Oncology, Virginia Commonwealth plications. Consequently, cure rates for some of these
University School of Medicine, 401 College Street, malignancies, such as lung cancers or malignant brain
P.O. Box 980058Richmond, VA 23298-0058, USA tumors, are distressingly low. Recent advances in our
e-mail: [email protected]
understanding of the molecular events underlying the
I. Jackson  Z. Vujaskovic pathogenesis of radiation-induced normal tissue injury has
Department of Radiation Oncology, University of Maryland
Medical Center, Greenbaum Cancer Center, opened up the possibility to use biologically based inter-
22 South Greene Street, Baltimore, MD 21201, USA ventions to prevent, mitigate, or treat these complications.
P. R. Graves Likewise, these advances in knowledge have facilitated
Department of Radiation Oncology, New York Methodist efforts to develop new strategies to stratify patients
Hospital, 506 Sixth Street, Brooklyn, NY 11215, USA

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 53
DOI: 10.1007/978-3-540-72314-1_5, Ó Springer-Verlag Berlin Heidelberg 2014
54 P. R. Graves et al.

according to risk of radiation injury as a means to indi- leading to fibrosis via TGFß1 production and stimulates
vidualize therapy and improve treatment outcome and angiogenesis via vascular endothelial growth factor (VEGF)
overall survival. production. In an attempt to respond to the proliferative
stimulus of VEGF, endothelial cells die due to previously
accumulated radiation damage (Rodemann and Blaese
2 Molecular Mechanisms of Radiation 2007). Hypoxia therefore, continuously perpetuates a non-
Injury healing tissue response leading consequently to chronic
radiation-induced injury (Vujaskovic et al. 2001; Anscher
The biologic response to ionizing radiation begins imme- et al. 2005).
diately after the first exposure with the generation of reac- Many of the molecular mediators of normal tissue injury
tive oxygen/reactive nitrogen species (ROS/RNS) (Riley are proteins, which can be measured both in tissue and in
1994). More recently, researchers have described how these blood. The ability to quantify the expression of these pro-
immediate biochemical events rapidly triggered a series of teins, in the normal and diseased state, has led to attempts to
genetic and molecular phenomena leading to clinically and use them as predictors of risk of normal tissue injury after
histologically recognizable injury (Brach et al. 1991; radiation therapy (Anscher et al. 1993, 1994; Vujaskovic
Kharbanda et al. 1994, 1995, 1996a, b; Hong et al. 1995; et al. 1997; Chen et al. 2001; De Jaeger et al. 2004; Gridley
Rubin et al. 1995; Barcellos-Hoff 1998; Hauer-Jensen et al. et al. 2004; Novakova-Jiresova et al. 2004). Until recently,
1999; Vujaskovic et al. 2001; Hallahan et al. 2002; Brush each protein had to be quantified individually using meth-
et al. 2007). This response to radiation is dynamic and ods such as antibody-based enzyme-linked immunosorbent
involves a number of mediators of inflammation and fibrosis assays (ELISA) or bioluminescence assays, which are
produced by macrophages, epithelial cells, and fibroblasts. laborious and time consuming (Kong et al. 1998). Advances
These events appear to be sustained for months to years in bioassay technology now permit researchers to quantify
beyond the completion of therapy; (Fu et al. 2001) however, multiple proteins simultaneously from the same sample in a
the mechanisms underlying the development of delayed rapid and reproducible manner (Jones et al. 2002). This
radiation injury, until recently, have remained unknown (Li technology will greatly enhance the ability to construct
et al. 2001; Vujaskovic et al. 2001). protein expression profiles for individual patients and
The molecular processes responsible for radiation- determine whether these patterns of protein expression can
induced normal tissue injury have been, perhaps, most improve our ability to predict risk of injury from radiation
extensively studied in the lung (Fig. 1). As previously sta- therapy (Hart et al. 2004). Along these lines, blood and
ted, the initial tissue damage from radiation is generated by tissue banks stocked with samples from patients irradiated
direct action of reactive oxygen species (ROS) on DNA. for various malignancies will become invaluable resources
This interaction causes tissue injury including endothelial for normal tissue injury research.
cell damage with an increase in permeability, edema, and
fibrin accumulation in the extracellular matrix. Endothelial
cell damage plays an important role in this process, and 3 The Importance of Transforming
recent evidence suggests that the capillary endothelial cell Growth Factor ß1 in Radiation-Induced
may be the first cellular element to be damaged by RT Injury
(Paris et al. 2001). This is followed by an inflammatory
response dominated by macrophage activation. Activated The most widely studied potential mediator of radiation-
macrophages are known to be a rich source of proinflam- induced normal tissue injury is Transforming Growth
matory and profibrotic cytokines that contribute to the Factor-ß1 (TGFß1). TGFß1 has multiple functions that are
recruitment and activation of additional cells directly important in the development of excess fibrous tissue, one
involved in wound repair (Wynn 2008). The source of the of the hallmarks of late radiation injury. TGFß1 is a che-
macrophages that contribute to radiation-induced lung moattractant for fibroblasts and also promotes differentia-
injury is an active area of investigation and it is possible tion of immature fibroblasts into myofibroblasts, which
that resident macrophages as wells as macrophages recrui- leads to increased production of collagen and extracellular
ted from circulating monocytes play major roles in this matrix (Rodemann and Bamberg 1995, 2007). TGFß1 also
process. Both vascular changes as well as an increase in decreases production of matrix-specific proteases and
oxygen consumption (due to macrophage activation) con- increases production of protease inhibitors, resulting in
tribute to the development of hypoxia (Fleckenstein et al. decrease collagen degradation, with a net result of increased
2007b). Hypoxia further stimulates production of ROS, fibrous tissue formation (Hakenjos et al. 2000; Martin et al.
proinflammatory, profibrogenic, and proangiogenic cyto- 2000). In addition to being autocrine stimulated, TGFß1
kines (Jackson et al. 2007). This perpetuates tissue damage production is also stimulated by hypoxia, which further
Biodetection and Biointervention 55

Fig. 1 Simplified model of processes involved in the pathogenesis of as an increase in oxygen consumption by activated macrophages,
radiation-induced lung injury. As noted in the diagram, each event has contribute to the development and perpetuation of hypoxia and
the potential to influence several other processes. Exposure to ionizing chronic oxidative stress, leading to the non-healing tissue response of
radiation initiates a cascade of cytokines and growth factors. chronic radiation injury. ACE = angiotensin converting enzyme;
Proinflammatory cytokines promote an influx of macrophages and PA = plasminogen activator; PG = prostaglandins; Ang2 = angio-
inflammatory cells, which are stimulated to produce ROS, proinflam- tensin II; CAIX = carbonic anhydrase IX, HIF = hypoxia inducible
matory and profibrotic cytokines. ROS serve as redox regulators of factor; PDGF = platelet derived growth factor; IGF = insulin-like
transcription factors, which further stimulate induction and activation growth factors; bFGF = basic fibroblast growth factor. [Reproduced
of cytokines and growth factors. In addition, vascular changes, as well with permission from Fleckenstein et al. (2007a)]
56 P. R. Graves et al.

promotes collagen formation (Haroon et al. 2000; Moeller activates macrophages to secrete inflammatory and fibro-
et al. 2004; Jackson et al. 2007). genic cytokines, including TGFß1 itself (Ashcroft 1999;
Recent evidence confirms that TGFß1 is an important Roberts et al. 2001). This auto-induction is important in
contributor to the pathogenesis of radiation-induced normal maintaining levels of TGFß1 in wound healing. Following
tissue injury. Rubin et al. (1992) reported that alveolar radiation, however, this process contributes to overproduc-
macrophages obtained from bronchial lavage specimens tion of collagen and inhibition of epithelial cell prolifera-
from irradiated rabbits demonstrated increased production tion, increased local oxygen consumption by activated
and release of TGFß1 as compared to macrophages from macrophages, and decreased oxygen delivery due to
normal lungs. These authors suggested that the fibroblast microvasculature injury creating a hypoxic environment (Li
proliferation and extracellular matrix production found after et al. 2001). These combined factors perpetuate normal
irradiation are controlled by growth factors that are released tissue injury. In addition, sustained overproduction of
from parenchymal cells following radiation exposure. TGFß1 may contribute not only to chronic fibrosis, but may
Anscher et al. (1990) demonstrated that TGFß1 expression also reduce the effectiveness of cancer therapies (Biswas
increased in a dose-dependent manner in the liver of rats et al. 2007) and contribute to the development of radiation-
following irradiation and that this increase in TGFß1 induced malignancy (see below).
expression correlated with the extent of connective tissue
production. Barcellos-Hoff (1995; Barcellos-Hoff and Dix
1996) has shown that free radicals produced during expo- 4 Using Plasma TGFß1 Levels to Predict
sure to ionizing radiation can directly activate the latent Injury Risk
form of TGFß1 which is sequestered in the extracellular
matrix. It is likely that direct activation of TGFß1 from Plasma TGFß1 levels recently has been used to try and
ionizing radiation contributes to the observed increase in identify patients at risk for the development of normal tissue
TGFß1 levels 24 h post-radiation exposure (Fleckenstein injury after exposure to chemotherapy and/or radiotherapy.
et al. 2007b). Likewise, TGFß1 mRNA has also been shown In patients who develop radiation-induced lung injury, Fu
to be elevated following radiation (Rube et al. 2000, 2004). et al. (2001) found sustained elevations in plasma TGFß1
Thus, radiation therapy can both increase local expression, level for as long as 2 years after treatment. In contrast,
as well as TGFß1 activation, resulting in increased fibrosis patients who did not develop symptomatic lung injury did
in irradiated tissues. As further evidence to support the role not exhibit sustained elevations in circulating plasma
of TGFß1 in radiation injury, mice lacking Smad 3 (part of TGFß1. In another patient study, it was shown that TGFß1
the TGFß1 signal transduction pathway) have been shown blood plasma levels increased during the period of radiation
to be resistant to radiation-induced fibrosis (Flanders et al. treatment and also became significantly higher 4 weeks
2002), suggesting that targeting the TGFß1 pathway might after radiotherapy (Kim et al. 2009). In addition, of several
be a useful strategy to prevent radiation injury. cytokines measured, only TGFß1 levels showed a correla-
Indeed, several studies support the idea that reducing tion with the symptomatic occurrence of radiation pneu-
TGFß1 production may be one strategy to reduce normal monitis (Kim et al. 2009). Recently, it was also shown that
tissue damage from radiation. Anscher and colleagues elevated levels of plasma TGFß1 during radiation therapy
demonstrated that administration of a neutralizing TGFß1 was predictive of radiation-induced lung toxicity in patients
antibody reduced radiation-induced macrophage accumu- with non-small-cell lung cancer (Zhao et al. 2009). In ani-
lation, alveolar wall thickness, and TGFß1 activation in the mal experiments, long-term overexpression and activation
lungs of rats (Anscher et al. 2006). More recently, a follow of TGFß1 have been demonstrated in tissue as well (John-
up study showed that a small molecule inhibitor of TGFß1 ston et al. 1995; Vujaskovic et al. 2002a). Thus, elevations
reduced breathing frequencies, lung fibrosis, inflammatory in plasma TGFß1 months after radiation exposure appear to
response, and TGFß1 activity in irradiated rats (Anscher reflect the presence of significantly dysregulated wound
et al. 2008). healing in the irradiated tissues. In contrast, the absence of
A similar conclusion was obtained by inhibiting integrin sustained elevations of circulating TGFß1 levels appear to
signaling in the lung, an important activator of the TGFß1 reflect a more normal wound healing process. Thus, pro-
pathway (Munger et al. 1999). It was shown that integrin longed elevations of plasma TGFß1 following radiation
alpha(v) beta6-deficient mice were completely protected exposure may be a useful means to identify patients at risk
from radiation-induced fibrosis (Puthawala et al. 2008). for late radiation-induced injury. Other investigators, how-
Local activation of TGFß1 in tissues may also be an ever, have not found plasma TGFß1 to be a reliable iden-
important component in sustaining the process of abnormal tifier of patients at increased risk for normal tissue injury
wound healing long after the exposure to radiation has after cancer therapy (Barthelemy-Brichant et al. 2004; De
ended. For example, active TGFß1 both recruits and Jaeger et al. 2004; Novakova-Jiresova et al. 2004). These
Biodetection and Biointervention 57

Table 1 Summary of the function of candidate proteins for profiling

Protein Function
IL-1ß Inflammation, growth factor expression
IL-5 Proinflammatory
IL-6 Proinflammatory, decrease apoptosis of activated lung fibroblasts
IL-7 Proinflammatory
IL-8 Angiogenesis, leukocyte chemotaxis, and collagen synthesis
IL-10 Anti-inflammatory (decrease TNFa production, decrease upregulation of endothelial cell adhesion molecules)
IL-13 Proinflammatory
MCP-1 Inflammation, chemoattraction of monocytes
MIP-1alpha Antiproliferative
PDGF BB Angiogenesis, recruit smooth muscle cells
VEGF Angiogenesis and increased vascular permeability
EGF Epithelial cell motility, mitogenicity, and differentiation
EGFR Receptor for EGF, initial component of EGF signaling pathway
NFkappaB Pleotrophic gene transcription responses
HIF-1 Transcription factor for genes regulating angiogenesis
TGF-alpha Cell motility and proliferation
FGF 2 Angiogenesis and fibroblast proliferation
MMP-1 Degradation of collagen and extracellular matrix proteins
MMP-2 Matrix remodeling, growth factor release
MMP-3 Matrix remodeling, growth factor release
MMP-13 Matrix remodeling, growth factor release
SMAD 2/3 Signal transduction in the TGFß pathway
IGF-1R Binding of IGF-1 (re-epithelialization and granulation tissue formation)
TNF-alpha Growth factor expression, inflammation, matrix production, and remodeling
TGFß1 Profibrotic, immunosuppression, angiogenesis, and metastasis

discrepancies may be due to a number of factors, including both TGFß1 production and signaling, and protects against
differences in techniques used to measure TGFß1, differ- the development of bleomycin-induced pulmonary fibrosis.
ences in patient populations under study, differences in Fedorocko et al. (2002) showed that radiation exposure
tumor type and burden, and the fact that these studies could increase cytokine production both directly (IL-6,
contain relatively small numbers of patients with treatment- TNF-a) and indirectly (GM-CSF), either by locally acting
related injury, thus the power to detect a difference between paracrine or endocrine effects or as a result of systemic
groups is not large (Anscher and Kong 2005). effects of early proinflammatory mediators such as IL-1 or
TNF-a. There is no doubt that protein production is a
dynamic process, which will change as a result of cancer
5 The Role of Other Cytokines treatment. Hong et al. (2003) have documented temporal
in Radiation-Induced Injury and spatial changes in the expression of proinflammatory
cytokines (TNF-a, IL-1a, and IL-1ß) following thoracic
A growing body of evidence points toward a complex web irradiation in mice. Given the impact that radiation has on
of protein interactions as being important in the pathogen- the expression of these and other proteins in tissue and that
esis of radiation injury (see Table 1 and Fig. 1). For exam- these changes in tissue protein expression might be reflected
ple, Huang et al. (2002) have found that IL-7, a cytokine in changes in plasma protein levels, it is reasonable to
that enhances T cell function and IFN-c production, inhibits postulate that it may be possible to quantify an individual
58 P. R. Graves et al.

patient’s inflammatory status by measuring candidate oxidative stress. Furthermore, in vitro studies lend support
protein levels in the blood. to the authors hypothesis that hypoxia stimulates TGFß1
and VEGF production by macrophages in an SOD-inhibit-
able manner.
6 Using Other Markers to Predict Reactive oxygen species (ROS) functionally regulate
Radiation-Induced Injury transcription factors that also influence expression and
activation of cytokines and growth factors (Sun and Oberley
In addition to TGFß1, several other proteins have been 1996). Furthermore, ROS play an important role in intra-
studied in humans to evaluate their potential as biomarkers cellular signaling, including activation of HIF-1a, NFkB,
for radiation-induced injury. Most of this work has been TGFß1, and a variety of other molecules found to play a
carried out in the lung. Of these, the most promising include role in radiation-induced injury (Schmidt-Ullrich et al.
interleukins (IL) 1a, IL-6, IL-8, IL-10, Krebs von den 2000). Over the past several decades, it has been shown that
Lungen protein (KL-6, which is expressed mainly on type II the free radical scavenging ability of endogenous antioxi-
pneumocytes and bronchiolar epithelial cells), soluble dants, most notably superoxide dismutase (SOD), acts as a
intracellular adhesion molecule (sICAM)-1, and surfactant cell-based protective mechanism. As the role of chronic
proteins A and D (Kohno et al. 1992; Ishii and Kitamura oxidative stress in the development of radiation-induced
1999; Chen et al. 2001; Goto et al. 2001; Sasaki et al. 2001; lung injury has emerged, several investigators have
Takahashi et al. 2001; Gridley et al. 2004; Hara et al. 2004, attempted to restore the critical balance between chronic
2005; Chen et al. 2005; Matsuno et al. 2006). Of these, oxidative stress and antioxidant capacity through exogenous
KL-6 is the most extensively studied, and has most con- delivery of SOD. Several preclinical studies have shown
sistently been correlated with the risk of radiation-induced mimics of SOD or liposomal-based delivery of SOD can
lung injury (Fleckenstein et al. 2007a). As with TGFß1, mitigate injury when given after radiation and may even
more prospective studies with larger patient numbers will treat radiation-induced normal tissue injury once clinical
be required to confirm its value as a predictive marker for symptoms become apparent (Epperly et al. 1999, 2000,
lung injury. 2008; Rabbani et al. 2007; Gauter-Fleckenstein et al. 2008,
2010; Borrelli et al. 2009). Thus, SOD-based therapy may
hold potential therapeutic value in the treatment of radia-
7 Chronic Inflammation as a Mediator tion-induced lung injury.
of Radiation Injury Recent evidence suggests the importance of ROS/RNS
generated by macrophages and tumor cells in the processes
Epidemiologic evidence has also suggested a correlation of initiation and progression of malignancy (Wink et al.
between chronic inflammation and the development of 1998; Fukumura et al. 2006; Ridnour et al. 2006; Hirst and
malignancy at the inflamed site. Recent evidence points to a Robson 2007). Thus, it is likely that many, if not all, of the
prolonged and progressive period of oxidative stress fol- proteins involved in the development of radiation-induced
lowing the initial ionizing event in the development of normal tissue inflammation and fibrosis might also be
radiation-induced lung injury. The underlying mechanism involved in the generation of radiation-induced malignancy.
involves recruitment of inflammatory cells, as well as the In support of this idea, recently it has been shown that the
expression of multiple mediators of inflammation, including SOD mimetic, MnTE-2-PyP (5+), a potent catalytic scav-
cytokines, chemokines, and enzymes. Proinflammatory enger of reactive oxygen species that exhibited the ability to
cytokines, such as the interleukins and tumor necrosis factor reduce radiation-induced lung injury (Gauter-Fleckenstein
a, cause an influx of inflammatory cells and fibroblasts into et al. 2008, 2010), also reduced tumor growth in a mouse
the microenvironment (Johnston et al. 2004; Rube et al. model (Rabbani et al. 2009).
2005). These cells, primarily macrophages (Rubin et al.
1992; Vujaskovic et al. 2000), become stimulated to pro-
duce reactive oxygen species and additional proinflamma- 8 Candidate Proteins for Predicting
tory and profibrotic cytokines (Fleckenstein et al. 2007a) Radiation Injury
(Fig. 1).
It is well established that tissue hypoxia is a potent While many proteins have been implicated in the patho-
stimulator of macrophage proliferation and activation. genesis of radiation-induced injury, few have been evalu-
Fleckenstein et al. (Fleckenstein et al. 2007b) found a bi- ated as possible predictors of predisposition to such injury.
phasic decrease in pulmonary perfusion following hemi- At the present time, not every protein implicated in
thoracic irradiation in rats, which correlated to the devel- inflammation, wound healing, fibrogenesis, or radiation
opment of hypoxia, macrophage infiltration, and increased response can be detected in the blood, owing to the lack of
Biodetection and Biointervention 59

Fig. 2 DNA damage-independent and dependent pathways of endo- production of DNA double-strand breaks and activation of ceramide
thelial cell apoptosis. The primary apoptotic response to ionizing synthase. CAPK ceramide-activated protein kinase, PKC protein
radiation in the endothelial cells is DNA damage independent and is kinase C, TNF tumor necrosis factor, BAX bcl-2 associated protein X,
mediated through radiation-induced activation of acid sphingomyeli- BAD bcl-2 antagonist of cell death, cyt cytochrome, casp caspase,
nase (ASMase) and the generation of ceramide. Ceramide mediates PARP poly(adenosine-50 -diphosphate-ribose) polymerase, RB retino-
the activation of the MAPK8 pathway, the mitochondrial pathway, or blastoma protein [Reproduced with permission from Rodemann and
the death receptor pathway. The second source of ceramide occurs via Blaese (2007)]

availability of reliable antibodies to these proteins. Thus, it fact one exists. The role of each of these candidate proteins,
is not yet possible to screen for alterations in expression of relevant to radiation injury, is summarized in Table 1.
every potential candidate protein. In addition, multiple
proteins and signaling pathways are involved in these pro-
cesses, and reliable antibodies are not available to target 9 Strategies and Potential Targets
every individual protein involved in each pathway. Never- for Intervention
theless, the list of proteins below represent components of
the major mechanisms and pathways currently thought to be There are three primary approaches to intervention in the
involved in the response of cells to radiation (Schmidt- injury process, depending upon the timing of intervention
Ullrich 2003; Tsoutsou and Koukourakis 2006). This relative to radiation exposure, and whether or not injury has
approach is likely to detect a profile of protein expression developed (Moulder and Cohen 2007). These approaches
associated with an increased risk of radiation injury, if in are: protection or prophylaxis, mitigation, and treatment.
60 P. R. Graves et al.

targets to inhibit the development of radiation-induced

injury (Delanian et al. 1994; Hallahan and Virudachalam
1997; Adawi et al. 1998; Epperly et al. 1998; Arango et al.
2001; Kang et al. 2002; Vujaskovic et al. 2002b). Examples
include reducing the level of TNFa expression using an
antisense oligonucleotide strategy which reduced radiation-
induced injury in mice (Zhang et al. 2008). In another
approach, administration of the tyrosine kinase receptor
inhibitor, Gefitinib, significantly reduced fibrosis scores and
collagen levels at 5 months post-irradiation (Wang et al.
2008). The use of agents to scavenge free radicals to reduce
oxidative/nitrosative stress has also been employed. In
addition to the delivery of SOD itself or its mimetics,
additional antioxidants have been examined. Taurine, which
has been shown to exhibit antioxidant properties and inhibit
Fig. 3 The interaction between multiple cells, mediated via cyto- TGFß1 mRNA expression, was shown to reduce lung tissue
kines, in the process of connective tissue remodeling. [Reproduced damage and hydroxyproline levels in mice (Robb et al.
with permission from Rodemann and Blaese (2007)]
2009). Genistein, an isoflavone found in soy with antioxi-
dant and anti-inflammatory properties, reduced micronuclei
Protection refers to treatments given before and/or during formation and macrophage accumulation in mouse lungs
radiation. This is the most common strategy utilized in the after radiation (Para et al. 2009). Continuous administration
clinic today and is illustrated by the use of the free radical of flaxseed to mice over *5 months after radiation reduced
scavenger amifostine in the prevention of injury following lipid oxidation at 3 weeks and lung fibrotic index at
radiation to the head and neck (Brizel et al. 2000). Miti- 4 months post-irradiation (Lee et al. 2009). In human stud-
gation refers to therapies started after radiation exposure, ies, berberine, an alkaloid of herbal origin that exhibits anti-
but before overt injury is expressed, as exemplified by the inflammatory activity and reduces the level of TGFß1, was
use of angiotensin converting enzyme inhibitors to prevent shown to decrease radiation-induced lung injury and
renal injury (Moulder et al. 2003). Treatment refers to improve pulmonary function (Liu et al. 2008). Finally, the
interventions begun after overt injury develops, an example use of cerium oxide nanoparticles, which possess free radical
of which would be the use of vitamin E and pentoxifylline scavenging properties, were found to be effective in reducing
to treat established radiation soft tissue fibrosis (Delanian lung injury (Colon et al. 2009). Given the redundancy and
et al. 2003) or the use of SOD mimics to treat symptomatic crosstalk between these multiple pathways, it is likely that
radiation-induced lung injury in rats (Gauter-Fleckenstein strategies to prevent radiation injury may require agents that
et al. 2010). target multiple pathways simultaneously, or combinations of
As we learn more about the specific molecular pathways multiple agents with more specific targets.
involved in the process of radiation injury (Figs. 1, 2, 3), An example of a class of drugs, which target multiple
more targeted therapies are being studied as approaches to cellular pathways, and might prove beneficial in the struggle
the prevention of radiation injury. Given the importance of to prevent radiation-induced normal tissue injury, are the
the TGFß1 pathway in the pathogenesis of radiation injury, statins. As noted above, vascular damage is an important
several investigators have demonstrated the efficacy of component in the pathogenesis of radiation-induced injury.
blocking TGFß1 in preventing radiation injury in animals Vascular damage is important in the phenotype of RT-
(Flanders et al. 2002; Rabbani et al. 2003; Anscher et al. induced rectal injury, where telangiectatic vessels are often
2006, 2008). These agents, to date, have not been utilized in responsible for the bleeding characteristic of this condition.
humans for this purpose. TGFß1 has also been demonstrated The cholesterol lowering agents HMG coA reductase
to work through Smad-independent pathways (Bierie and inhibitors (statins) have been demonstrated to reduce the
Moses 2006) and targeting one or more of these pathways risk of myocardial infarction, in part, through their vascular
may also prove to be an effective approach to prevention of protective effects, which are not dependent on changes in
radiation-induced injury. For example, one of these alter- serum cholesterol levels. In vitro, statins have been shown
native pathways involves signaling via PI3-kinase and cAbl to protect human endothelial cells from ionizing radiation
(Kharbanda et al. 1996a). The use of imatinib, which targets (Gaugler et al. 2005; Boerma et al. 2006; Nubel et al. 2006).
cAbl, has been shown to reduce the severity of bleomycin- Multiple mechanisms appear to be involved, including
induced lung injury (Daniels et al. 2004). In addition to attenuation of extracellular stress responses (Rikitake et al.
TGFß1, other pathways have been demonstrated to be viable 2001; Morikawa et al. 2002), downregulation of
Biodetection and Biointervention 61

chemokines and chemokine receptors (Waehre et al. 2003), radiotherapy for non-small-cell lung cancer (Int J Radiat Oncol
and by exerting anti-inflammatory and anti-thrombotic Biol Phys 2004;58:1378–1387). Int J Radiat Oncol Biol Phys
61(4):1276–1277
effects (Undas et al. 2002; Perez-Guerrero et al. 2003; Shi Anscher MS, Murase T, Prescott DM et al (1994) Changes in plasma
et al. 2003; Boerma et al. 2006) on these cells. In vivo, TGF beta levels during pulmonary radiotherapy as a predictor of
lovastatin has been shown to reduce radiation-induced the risk of developing radiation pneumonitis. Int J Radiat Oncol
normal tissue damage in mice (Ostrau et al. 2009). Lova- Biol Phys 30(3):671–676
Anscher MS, Peters WP, Reisenbichler H et al (1993) Transforming
statin administration attenuated radiation-induced activation growth factor beta as a predictor of liver and lung fibrosis after
of NFkB, the expression of cell adhesion molecules, and the autologous bone marrow transplantation for advanced breast
proinflammatory and profibrotic marker genes including cancer. N Engl J Med 328(22):1592–1598
TNFa, IL-6, TGFß1, and type I and type III collagens. Anscher MS, Thrasher B, Rabbani Z et al (2006) Antitransforming
growth factor-beta antibody 1D11 ameliorates normal tissue
Lovastatin also reduced radiation-induced thrombocytope- damage caused by high-dose radiation. Int J Radiat Oncol Biol
nia (Ostrau et al. 2009). Phys 65(3):876–881
Anscher MS, Thrasher B, Zgonjanin L et al (2008) Small molecular
inhibitor of transforming growth factor-beta protects against
development of radiation-induced lung injury. Int J Radiat Oncol
10 Conclusion Biol Phys 71(3):829–837
Arango D, Ettarh RR, Holden G et al (2001) BB-10010, an analog of
Radiation-induced normal tissue injury is a frequent clinical macrophage inflammatory protein-1alpha, protects murine small
problem that can result in considerable morbidity and limits intestine against radiation. Dig Dis Sci 46(12):2608–2614
Ashcroft GS (1999) Bidirectional regulation of macrophage function
the dose of radiation that can be used in the treatment of a by TGF-beta. Microbes Infect 1(15):1275–1282
variety of malignancies. Cytokines and their pathways Barcellos-Hoff M (1998) How do tissues respond to damage at the
represent promising targets for predicting responses to cellular level? The role of cytokines in irradiated tissues. Radiat
radiotherapy and also for therapeutic intervention. While Res 150(Suppl):S109–S120
Barcellos-Hoff M, Dix T (1996) Redox-mediated activation of latent
considerable progress has been made in understanding the transforming growth factor-ß1. Mol Endocrinol 10:1077–1083
role of cytokines in radiation-induced tissue injury, more Barcellos-Hoff MH (1995). Redox mechanisms for activation of latent
studies are needed to develop safe and effective means of TGF-b. In: 43rd annual meeting of the Radiation Research Society
preventing and treating radiation injuries. Future studies Barthelemy-Brichant N, Bosquee L, Cataldo D et al (2004) Increased
IL-6 and TGF-beta1 concentrations in bronchoalveolar lavage fluid
will need to focus on determining predictive factors asso- associated with thoracic radiotherapy. Int J Radiat Oncol Biol Phys
ciated with radiation injury and the pathways responsible 58(3):758–767
for perpetuating tissue injury. Much work remains to be Bierie B, Moses HL (2006) Tumour microenvironment: TGFbeta: the
done, however, particularly in the areas of mitigation and molecular Jekyll and Hyde of cancer. Nat Rev Cancer
6(7):506–520
treatment (Vujaskovic et al. 2002b) and additional human Biswas S, Guix M, Rinehart C et al (2007) Inhibition of TGF-beta with
studies will be required to identify the most effective agents neutralizing antibodies prevents radiation-induced acceleration of
and approaches to this complex problem. Successful strat- metastatic cancer progression. J Clin Invest 117(5):1305–1313
egies could be implemented in the clinic and offer improved Boerma M, Burton GR, Wang J et al (2006) Comparative expression
profiling in primary and immortalized endothelial cells: changes
treatment outcomes to the population of patients who are in gene expression in response to hydroxy methylglutaryl-
most likely to develop late effects. coenzyme A reductase inhibition. Blood Coagul Fibrinolysis
17(3):173–180
Borrelli A, Schiattarella A, Mancini R et al (2009) A recombinant
MnSOD is radioprotective for normal cells and radiosensitizing for
References tumor cells. Free Radic Biol Med 46(1):110–116
Brach MA, Hass R, Sherman ML et al (1991) Ionizing radiation
Adawi A, Zhang Y, Baggs R et al (1998) Blockade of CD40-CD40 induces expression and binding activity of the nuclear factor kappa
ligand interactions protects against radiation- induced pulmonary B. J Clin Invest 88(2):691–695
inflammation and fibrosis. Clin Immunol Immunopathol Brizel DM, Wasserman TH, Henke M et al (2000) Phase III
89(3):222–230 randomized trial of amifostine as a radioprotector in head and
Anscher MS, Chen L, Rabbani Z et al (2005) Recent progress in neck cancer. J Clin Oncol 18(19):3339–3345
defining mechanisms and potential targets for prevention of normal Brush J, Lipnick SL, Phillips T et al (2007) Molecular mechanisms of
tissue injury after radiation therapy. Int J Radiat Oncol Biol Phys late normal tissue injury. Semin Radiat Oncol 17(2):121–130
62(1):255–259 Chen Y, Hyrien O, Williams J et al (2005) Interleukin (IL)-1A and IL-
Anscher MS, Crocker IR, Jirtle RL (1990) Transforming growth 6: applications to the predictive diagnostic testing of radiation
factor-beta 1 expression in irradiated liver. Radiat Res pneumonitis. Int J Radiat Oncol Biol Phys 62(1):260–266
122(1):77–85 Chen Y, Rubin P, Williams J et al (2001) Circulating IL-6 as a
Anscher MS, Kong FM (2005) In regard to De Jaeger et al.: predictor of radiation pneumonitis. Int J Radiat Oncol Biol Phys
significance of plasma transforming growth factor-beta levels in 49(3):641–648
62 P. R. Graves et al.

Colon J, Herrera L, Smith J et al (2009) Protection from radiation- Goto K, Kodama T, Sekine I et al (2001) Serum levels of KL-6 are
induced pneumonitis using cerium oxide nanoparticles. Nanomed- useful biomarkers for severe radiation pneumonitis. Lung Cancer
icine 5(2):225–231 34(1):141–148
Daniels CE, Wilkes MC, Edens M et al (2004) Imatinib mesylate Gridley DS, Bonnet RB, Bush DA et al (2004) Time course of serum
inhibits the profibrogenic activity of TGF-beta and prevents cytokines in patients receiving proton or combined photon/proton
bleomycin-mediated lung fibrosis. J Clin Invest 114(9):1308–1316 beam radiation for resectable but medically inoperable non-small-
De Jaeger K, Seppenwoolde Y, Kampinga HH et al (2004) Signifi- cell lung cancer. Int J Radiat Oncol Biol Phys 60(3):759–766
cance of plasma transforming growth factor-beta levels in radio- Hakenjos L, Bamberg M, Rodemann H (2000) TGF-ß1-mediated
therapy for non-small-cell lung cancer. Int J Radiat Oncol Biol alterations of rat lung fibroblast differentiation resulting in the
Phys 58(5):1378–1387 radiation-induced fibrotic phenotype. Int J Radiat Biol
Delanian S, Baillet F, Huart J et al (1994) Successful treatment of 76(4):503–509
radiation-induced fibrosis using liposomal Cu/Zn superoxide Hallahan DE, Geng L, Shyr Y (2002) Effects of intercellular adhesion
dismutase: clinical trial. Radiother Oncol 32(1):12–20 molecule 1 (ICAM-1) null mutation on radiation-induced pulmon-
Delanian S, Porcher R, Balla-Mekias S et al (2003) Randomized, ary fibrosis and respiratory insufficiency in mice. J Natl Cancer Inst
placebo-controlled trial of combined pentoxifylline and tocopherol 94(10):733–741
for regression of superficial radiation-induced fibrosis. J Clin Oncol Hallahan DE, Virudachalam S (1997) Intercellular adhesion molecule
21(13):2545–2550 1 knockout abrogates radiation induced pulmonary inflammation.
Epperly M, Bray J, Kraeger S et al (1998) Prevention of late effects of Proc Natl Acad Sci USA 94(12):6432–6437
irradiation lung damage by manganese superoxide dismutase gene Hara R, Itami J, Komiyama T et al (2004) Serum levels of KL-6 for
therapy. Gene Ther 5(2):196–208 predicting the occurrence of radiation pneumonitis after stereotac-
Epperly MW, Bray JA, Krager S et al (1999) Intratracheal injection of tic radiotherapy for lung tumors. Chest 125(1):340–344
adenovirus containing the human MnSOD transgene protects Haroon ZA, Raleigh JA, Greenberg CS et al (2000) Early wound
athymic nude mice from irradiation-induced organizing alveolitis. healing exhibits cytokine surge without evidence of hypoxia. Ann
Int J Radiat Oncol Biol Phys 43(1):169–181 Surg 231(1):137–147
Epperly MW, Defilippi S, Sikora C et al (2000) Intratracheal injection Hart J, Rabbani Z, Pizzo S et al (2004) Cytokine profiling to predict
of manganese superoxide dismutase (MnSOD) plasmid/liposomes radiation-induced lung injury. Int J Radiat Oncol Biol Phys 60(1
protects normal lung but not orthotopic tumors from irradiation. Suppl):S238
Gene Ther 7(12):1011–1018 Hart JP, Broadwater G, Rabbani Z et al (2005) Cytokine profiling for
Epperly MW, Dixon T, Wang H et al (2008) Modulation of radiation- prediction of symptomatic radiation-induced lung injury. Int J
induced life shortening by systemic intravenous MnSOD-plasmid Radiat Oncol Biol Phys 63(5):1448–1454
liposome gene therapy. Radiat Res 170(4):437–443 Hauer-Jensen M, Kong FM, Fink LM et al (1999) Circulating
Fedorocko P, Egyed A, Vacek A (2002) Irradiation induces increased thrombomodulin during radiation therapy of lung cancer. Radiat
production of haemopoietic and proinflammatory cytokines in the Oncol Investig 7(4):238–242
mouse lung. Int J Radiat Biol 78(4):305–313 Hirst DG, Robson T (2007) Nitrosative stress in cancer therapy. Front
Flanders KC, Sullivan CD, Fujii M et al (2002) Mice lacking Smad3 Biosci 12:3406–3418
are protected against cutaneous injury induced by ionizing Hong JH, Chiang CS, Campbell IL et al (1995) Induction of acute
radiation. Am J Pathol 160(3):1057–1068 phase gene expression by brain irradiation. Int J Radiat Oncol Biol
Fleckenstein K, Gauter-Fleckenstein B, Jackson IL et al (2007a) Using Phys 33(3):619–626
biological markers to predict risk of radiation injury. Semin Radiat Hong JH, Jung SM, Tsao TC et al (2003) Bronchoalveolar lavage and
Oncol 17(2):89–98 interstitial cells have different roles in radiation-induced lung
Fleckenstein K, Zgonjanin L, Chen L et al (2007b) Temporal onset of injury. Int J Radiat Biol 79(3):159–167
hypoxia and oxidative stress after pulmonary irradiation. Int J Huang M, Sharma S, Zhu LX et al (2002) IL-7 inhibits fibroblast TGF-
Radiat Oncol Biol Phys 68(1):196–204 beta production and signaling in pulmonary fibrosis. J Clin Invest
Fu X, Huang H, Bentel G et al (2001) Predicting the risk of 109(7):931–937
symptomatic radiation-induced lung injury using both the physical Ishii Y, Kitamura S (1999) Soluble intercellular adhesion molecule-1
and biologic parameters V(30) and transforming growth factor as an early detection marker for radiation pneumonitis. Eur Respir
beta. Int J Radiat Oncol Biol Phys 50(4):899–908 J 13(4):733–738
Fukumura D, Kashiwagi S, Jain RK (2006) The role of nitric oxide in Jackson IL, Chen L, Batinic-Haberle I et al (2007) Superoxide
tumour progression. Nat Rev Cancer 6(7):521–534 dismutase mimetic reduces hypoxia-induced O2*-, TGF-beta, and
Gaugler MH, Vereycken-Holler V, Squiban C et al (2005) Pravastatin VEGF production by macrophages. Free Radic Res 41(1):8–14
limits endothelial activation after irradiation and decreases the Johnston C, Piedboeuf B, Baggs R et al (1995) Differences in
resulting inflammatory and thrombotic responses. Radiat Res correlation of mRNA gene expression in mice sensitive and
163(5):479–487 resistant to radiation-induced pulmonary fibrosis. Radiat Res
Gauter-Fleckenstein B, Fleckenstein K, Owzar K et al (2008) 142:197–203
Comparison of two Mn porphyrin-based mimics of superoxide Johnston CJ, Williams JP, Elder A et al (2004) Inflammatory cell
dismutase in pulmonary radioprotection. Free Radic Biol Med recruitment following thoracic irradiation. Exp Lung Res
44(6):982–989 30(5):369–382
Gauter-Fleckenstein B, Fleckenstein K, Owzar K et al (2010) Early Jones LP, Zheng HQ, Karron RA et al (2002) Multiplex assay for
and late administration of MnTE-2-PyP(5+) in mitigation and detection of strain-specific antibodies against the two variable
treatment of radiation-induced lung damage. Free Radic Biol Med regions of the G protein of respiratory syncytial virus. Clin Diagn
48:1034–1043 Lab Immunol 9(3):633–638
Biodetection and Biointervention 63

Kang S, Rabbani Z, Folz R et al (2002) Overexpression of Munger J, Huang X, Kawakatsu H et al (1999) The integrin avß6 binds
extracellular superoxide dismutase protects mice from radiation and activates latent TGFß1: a mechanism for regulating pulmonary
induced lung injury. Int J Radiat Oncol Biol Phys 54(2):78 inflammation and fibrosis. Cell 96:319–328
Kharbanda S, Bharti A, Pei D et al (1996a) The stress response to Novakova-Jiresova A, Van Gameren MM, Coppes RP et al (2004)
ionizing radiation involoves c-Abl-dependent phosphorylation of Transforming growth factor-beta plasma dynamics and post-
SHPTP1. Proc Natl Acad Sci USA 93(14):6898–6901 irradiation lung injury in lung cancer patients. Radiother Oncol
Kharbanda S, Ren R, Pandey P et al (1995) Activation of the c-Abl 71(2):183–189
tyrosine kinase in the stress response to DNA-damaging agents. Nubel T, Damrot J, Roos WP et al (2006) Lovastatin protects human
Nature 376(6543):785–788 endothelial cells from killing by ionizing radiation without
Kharbanda S, Saleem A, Datta R et al (1994) Ionizing radiation impairing induction and repair of DNA double-strand breaks. Clin
induces rapid tyrosine phosphorylation of p34cdc2. Cancer Res Cancer Res 12(3 Pt 1):933–939
54(6):1412–1414 Ostrau C, Hulsenbeck J, Herzog M et al (2009) Lovastatin attenuates
Kharbanda S, Saleem A, Yuan ZM et al (1996b) Nuclear signaling ionizing radiation-induced normal tissue damage in vivo. Radiother
induced by ionizing radiation involves colocalization of the Oncol 92:492–499
activated p56/p53lyn tyrosine kinase with p34cdc2. Cancer Res Para AE, Bezjak A, Yeung IW et al (2009) Effects of genistein
56(16):3617–3621 following fractionated lung irradiation in mice. Radiother Oncol
Kim JY, Kim YS, Kim YK et al (2009) The TGF-beta1 dynamics 92:500–510
during radiation therapy and its correlation to symptomatic Paris F, Fuks Z, Kang A et al (2001) Endothelial apoptosis as the
radiation pneumonitis in lung cancer patients. Radiat Oncol 4:59 primary lesion initiating intestinal radiation damage in mice.
Kohno N, Hamada H, Fujioka S et al (1992) Circulating antigen KL-6 Science 293(5528):293–297
and lactate dehydrogenase for monitoring irradiated patients with Perez-Guerrero C, Alvarez de Sotomayor M, Jimenez L et al (2003)
lung cancer. Chest 102(1):117–122 Effects of simvastatin on endothelial function after chronic
Kong F-M, Anscher M, Jirtle R (1998). Tumor marker protocols: inhibition of nitric oxide synthase by L-NAME. J Cardiovasc
plasma transforming growth factor beta, a plasma tumor marker. Pharmacol 42(2):204–210
In: Hannausek M, Walaszek Z (eds) Methods in molecular Puthawala K, Hadjiangelis N, Jacoby SC et al (2008) Inhibition of
medicine. Humana Press, Inc., Totowa, pp 417–430 integrin alpha(v)beta6, an activator of latent transforming growth
Lee JC, Krochak R, Blouin A et al (2009) Dietary flaxseed prevents factor-beta, prevents radiation-induced lung fibrosis. Am J Respir
radiation-induced oxidative lung damage, inflammation and fibro- Crit Care Med 177(1):82–90
sis in a mouse model of thoracic radiation injury. Cancer Biol Ther Rabbani ZN, Anscher MS, Zhang X et al (2003) Soluble TGFb type II
8(1):47–53 receptor gene therapy ameliorates acute radiation-induced pul-
Li Y-Q, Ballinger J, Nordal R et al (2001) Hypoxia in radiation- monary injury in rats. Int J Radiat Biol Oncol Phys (in press)
induced blood-spinal cord barrier breakdown. Cancer Res Rabbani ZN, Batinic-Haberle I, Anscher MS et al (2007) Long-term
61:3348–3354 administration of a small molecular weight catalytic metallopor-
Liu Y, Yu H, Zhang C et al (2008) Protective effects of berberine on phyrin antioxidant, AEOL 10150, protects lungs from radiation-
radiation-induced lung injury via intercellular adhesion molecular- induced injury. Int J Radiat Oncol Biol Phys 67(2):573–580
1 and transforming growth factor-beta-1 in patients with lung Rabbani ZN, Spasojevic I, Zhang X et al (2009) Antiangiogenic action
cancer. Eur J Cancer 44(16):2425–2432 of redox-modulating Mn(III) meso-tetrakis(N-ethylpyridinium-2-
Martin M, Lefaix J-L, Delanian S (2000) TGF-ß1 and radiation yl)porphyrin, MnTE-2-PyP(5+), via suppression of oxidative stress
fibrosis: a master switch and a specific target? Int J Radiat Oncol in a mouse model of breast tumor. Free Radic Biol Med
Biol Phys 47(2):277–290 47(7):992–1004
Matsuno Y, Satoh H, Ishikawa H et al (2006) Simultaneous Ridnour LA, Thomas DD, Donzelli S et al (2006) The biphasic nature
measurements of KL-6 and SP-D in patients undergoing thoracic of nitric oxide responses in tumor biology. Antioxid Redox Signal
radiotherapy. Med Oncol 23(1):75–82 8(7–8):1329–1337
Milano MT, Constine LS, Okunieff P (2007) Normal tissue tolerance Rikitake Y, Kawashima S, Takeshita S et al (2001) Anti-oxidative
dose metrics for radiation therapy of major organs. Semin Radiat properties of fluvastatin, an HMG-CoA reductase inhibitor,
Oncol 17(2):131–140 contribute to prevention of atherosclerosis in cholesterol-fed
Moeller BJ, Cao Y, Vujaskovic Z et al (2004) The relationship rabbits. Atherosclerosis 154(1):87–96
between hypoxia and angiogenesis. Semin Radiat Oncol Riley PA (1994) Free radicals in biology: oxidative stress and the
14(3):215–221 effects of ionizing radiation. Int J Radiat Biol 65(1):27–33
Morikawa S, Takabe W, Mataki C et al (2002) The effect of statins on Robb WB, Condron C, Moriarty M et al (2009) Taurine attenuates
mRNA levels of genes related to inflammation, coagulation, and radiation-induced lung fibrosis in C57/Bl6 fibrosis prone mice. Ir J
vascular constriction in HUVEC. Human umbilical vein endothe- Med Sci 179:99–105
lial cells. J Atheroscler Thromb 9(4):178–183 Roberts AB, Piek E, Bottinger EP et al (2001) Is Smad3 a major player
Moulder JE, Cohen EP (2007) Future strategies for mitigation and in signal transduction pathways leading to fibrogenesis? Chest
treatment of chronic radiation-induced normal tissue injury. Semin 120(1 Suppl):43S–47S
Radiat Oncol 17(2):141–148 Rodemann HP, Bamberg M (1995) Cellular basis of radiation-induced
Moulder JE, Fish BL, Cohen EP (2003) ACE inhibitors and AII fibrosis. Radiother Oncol 35(2):83–90
receptor antagonists in the treatment and prevention of bone Rodemann HP, Blaese MA (2007) Responses of normal cells to
marrow transplant nephropathy. Curr Pharm Des 9(9):737–749 ionizing radiation. Semin Radiat Oncol 17(2):81–88
64 P. R. Graves et al.

Rube CE, Uthe D, Schmid KW et al (2000) Dose-dependent induction Undas A, Brozek J, Musial J (2002) Anti-inflammatory and anti-
of transforming growth factor beta (TGF-beta) in the lung tissue of thrombotic effects of statins in the management of coronary artery
fibrosis-prone mice after thoracic irradiation. Int J Radiat Oncol disease. Clin Lab 48(5–6):287–296
Biol Phys 47(4):1033–1042 Vujaskovic Z, Anscher M, Feng Q-F et al (2001) Radiation-induced
Rube CE, Uthe D, Wilfert F et al (2005) The bronchiolar epithelium as hypoxia may perpetuate late normal tissue injury. Int J Radiat
a prominent source of pro-inflammatory cytokines after lung Oncol Biol Phys 50(4):851–855
irradiation. Int J Radiat Oncol Biol Phys 61(5):1482–1492 Vujaskovic Z, Down JD, van Waarde MA et al (1997) Plasma
Rube CE, Wilfert F, Palm J et al (2004) Irradiation induces a biphasic TGFbeta level in rats after hemithoracic irradiation. Radiother
expression of pro-inflammatory cytokines in the lung. Strahlenther Oncol 44(1):41–43
Onkol 180(7):442–448 Vujaskovic Z, Batinic-Haberle I, Rabbani Z et al (2002a) A small
Rubin P, Finkelstein JN, Shapiro D (1992) Molecular biology molecular weight catalytic metalloporphyrin antioxidant with
mechanisms in the radiation induction of pulmonary injury superoxide dismutase (SOD) mimetic properties protects lungs
syndromes: interrelationship between the alveolar macrophage from radiation-induced injury. Free Radic Biol Med 33(6):857
and the septal fibroblast. Int J Radiat Oncol Biol Phys 24:93–101 Vujaskovic Z, Feng QF, Rabbani ZN et al (2002b) Radioprotection of
Rubin P, Johnston CJ, Williams JP et al (1995) A perpetual cascade of lungs by amifostine is associated with reduction in profibrogenic
cytokines post irradiation leads to pulmonary fibrosis. Int J Radiat cytokine activity. Radiat Res 157(6):656–660
Oncol Biol Phys 33:99–109 Vujaskovic Z, Marks L, Anscher M (2000) The physical parameters
Sasaki R, Soejima T, Matsumoto A et al (2001) Clinical significance and molecular events associated with radiation-induced lung
of serum pulmonary surfactant proteins a and d for the early toxicity. Sem Radiat Oncol 10(4):296–307
detection of radiation pneumonitis. Int J Radiat Oncol Biol Phys Waehre T, Damas JK, Gullestad L et al (2003) Hydroxymethylglutaryl
50(2):301–307 coenzyme a reductase inhibitors down-regulate chemokines and
Schmidt-Ullrich RK (2003) Molecular targets in radiation oncology. chemokine receptors in patients with coronary artery disease. J Am
Oncogene 22(37):5730–5733 Coll Cardiol 41(9):1460–1467
Schmidt-Ullrich RK, Dent P, Grant S et al (2000) Signal transduction Wang C, Abe S, Matsuda K et al (2008) Effects of gefitinib on
and cellular radiation responses. Radiat Res 153(3):245–257 radiation-induced lung injury in mice. J Nippon Med Sch
Shi J, Wang J, Zheng H et al (2003) Statins increase thrombomodulin 75(2):96–105
expression and function in human endothelial cells by a nitric Wink DA, Vodovotz Y, Laval J et al (1998) The multifaceted roles of
oxide-dependent mechanism and counteract tumor necrosis factor nitric oxide in cancer. Carcinogenesis 19(5):711–721
alpha-induced thrombomodulin downregulation. Blood Coagul Wynn TA (2008) Cellular and molecular mechanisms of fibrosis.
Fibrinolysis 14(6):575–585 J Pathol 214(2):199–210
Sun Y, Oberley LW (1996) Redox regulation of transcriptional Zhang M, Qian J, Xing X et al (2008) Inhibition of the tumor necrosis
activators. Free Radic Biol Med 21(3):335–348 factor-alpha pathway is radioprotective for the lung. Clin Cancer
Takahashi H, Imai Y, Fujishima T et al (2001) Diagnostic significance Res 14(6):1868–1876
of surfactant proteins A and D in sera from patients with radiation Zhao L, Wang L, Ji W et al (2009) Elevation of plasma TGF-beta1
pneumonitis. Eur Respir J 17(3):481–487 during radiation therapy predicts radiation-induced lung toxicity in
Tsoutsou PG, Koukourakis MI (2006) Radiation pneumonitis and patients with non-small-cell lung cancer: a combined analysis from
fibrosis: mechanisms underlying its pathogenesis and implications Beijing and Michigan. Int J Radiat Oncol Biol Phys
for future research. Int J Radiat Oncol Biol Phys 66(5):1281–1293 74(5):1385–1390
 Quantitative/Objective Analyses of RT-Induced
Late Normal Tissue Injury Using Functional
Imaging
Jiho Nam, Mike E. Robbins, and Lawrence B. Marks

Contents Abstract
There are several ways to score normal tissue injury.
1 Introduction.......................................................................... 65 Imaging is an attractive tool since it allows for an
2 Lung Injury .......................................................................... 66 objective assessment of normal tissue changes in vivo.
Regional changes in tissue structure/function, detected
3 Heart Injury ......................................................................... 68
3.1 SPECT.................................................................................... 69 by imaging, can be related to the different radiation doses
3.2 MRI ........................................................................................ 70 delivered to different regions. This approach has been
3.3 Cardiac PET........................................................................... 71 used for several organs, and for some, there is a clear
4 Brain Injury ......................................................................... 71 dose–response relationship for changes in normal tissue
4.1 SPECT.................................................................................... 71 (e.g., lung density or perfusion). Further, degree/extent
4.2 PET ........................................................................................ 74 of changes in regional imaging may be associated with
4.3 MRI ........................................................................................ 75
changes in global organ function. Future improvements
5 Liver Injury.......................................................................... 79 in imaging (e.g., more functional versus structural
5.1 CT Perfusion Studies............................................................. 79 assessments) will afford additional opportunities for
5.2 MRI ........................................................................................ 80
5.3 PET ........................................................................................ 81 studies to better understand RT-induced normal tissue
injury.
6 Parotid Gland Injury .......................................................... 81
6.1 SPECT and PET .................................................................... 81
6.2 MRI ........................................................................................ 83
7 Summary............................................................................... 84
1 Introduction
References...................................................................................... 87
The study of radiation therapy (RT)-induced normal tissue
injury is challenging. Radiation dose distributions are
complex, and the clinical endpoints used to describe injury
are often nonspecific and difficult to quantify. Imaging is an
attractive tool to address some of these challenges. The
complex dose distributions afforded by modern therapy
(e.g., multifield conformal therapy or intensity modulated
RT) deposits variable doses to different regions of normal
J. Nam
L. B. Marks (&)
Department of Radiation Oncology, University of North tissues. Imaging allows investigators to assess for different
Carolina at Chapel Hill, Campus Box 7512, Chapel Hill, degrees of changes in different regions of organs, and then
NC 27599, USA relate these regional changes to regional doses. Further,
e-mail: [email protected] imaging is usually easily quantifiable, providing an objec-
J. Nam tive assessment of regional effects.
Department of Radiation Oncology, Pusan National University, There are several ways to score normal tissue injury, and
Yangsan, 626-770, South Korea
imaging should be considered in the context of other types
M. E. Robbins of metrics (Table 1). The incidence of injury is highly
Departments of Radiation Oncology, Brain Tumor Center
of Excellence, Wake Forest School of Medicine, dependent on the type of endpoint selected. For most clin-
Winston-Salem, NC 27157, USA ical situations, the rate of imaging changes is higher than

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 65
DOI: 10.1007/978-3-540-72314-1_6, Ó Springer-Verlag Berlin Heidelberg 2014
66 J. Nam et al.

Table 1 Types of endpoints used to assess normal tissue injury 2 Lung Injury
Objective Subjective
Regional Imaging (e.g., CT-defined Symptoms from local Symptomatic pulmonary injury following RT for cancers in
increases in tissue density, effects (e.g., Pain or and around the thorax is common, occurring in *5–35 %
or reduced perfusion) bleeding from a local of patients. The early phase of RT-induced lung injury
ulceration)
[radiation pneumonitis (RP)] usually presents within
Global Laboratories (e.g., Symptoms of global 6 months of RT, and is commonly characterized by cough
Declines in creatinine function (e.g., Shortness
clearance, pulmonary of breath, fatigue)
and dyspnea (Theuws et al. 1998). Late fibrotic injury
function tests, anemia) usually evolves and becomes clinically manifested
C6 months post-RT, and is characterized by progressive
dyspnea, radiologic findings, and possible mortality (The-
uws et al. 1998; Goethals et al. 2003). For patients treated
for lung cancer, *5–35 % will develop symptomatic lung
injury, and 50–100 % develop radiologic evidence of lung
injury (the majority of which are asymptomatic) (Anscher
et al. 2003; Marks 1994; Graham et al. 1999; Marks et al.
2000; Fan et al. 2001; Fu et al. 2001). Similarly, for patients
treated for breast cancer, 0–34 % may develop symptomatic
lung injury, and 0–63 % of patients may develop radiologic
changes (Dorr et al. 2005; Cazzaniga et al. 1998; Kuhnt
et al. 1998; Rotstein et al. 1990; Schratter-Sehn et al. 1993;
Lind et al. 2006b).
Fig. 1 Relation between RT induced normal tissue effects and Review of radiation-induced lung injury by several
subclinical and/or clinical manifestation investigators using various noninvasive imaging techniques
has been previously described in detail (Evans et al. 2007;
Kocak et al. 2007). In brief, nuclear medicine imaging
the rate of abnormalities in other types of metrics. Thus, provides a sensitive means to assess regional lung function.
imaging might be considered as the most sensitive means to Investigators from the Netherlands Cancer Institute (NKI),
assess injury, and some might say that it is too sensitive Princess Margaret Hospital (PMH), and Duke University
(since most patients with imaging-only defined normal tis- have related changes in regional perfusion/ventilation [via
sue effects are asymptomatic). Indeed, there are many single photon emission computed tomography (SPECT)]
patients who have been made unnecessarily concerned due and/or tissue density [via computed tomography (CT)] to
to abnormal radiologic findings post-RT. A good under- the 3D radiation dose map. There is a clear association
standing of the high frequency of RT-induced imaging between regional dose and changes in regional perfusion/
changes is also needed since these findings can be misin- ventilation/density. Further, there appears to be an associ-
terpreted as recurrent disease (e.g., a patient irradiated for ation, albeit weak, between the integrated response (e.g., the
breast cancer develops nodularity [‘rule out tumor’] in the sum of changes in regional perfusion) and changes in whole
anterior ipsilateral superior lung that is due to apical scar- lung function (Fan et al. 2001a, b; Seppenwoolde et al.
ring from the supraclavicular RT field). 2004).
Changes in imaging are often seen well before the more Recent reports have focused on radiation-induced lung
clinically-meaningful symptoms/signs are manifest. In this injury in the context of stereotactic radiosurgery. In a study
regard, there is some hope that imaging changes might be of 31 patients receiving stereotactic radiosurgery for pri-
early surrogate markers of longer term toxicities. However, mary or metastatic lung lesions, Aoki et al. noted asymp-
the association between acute imaging changes and later tomatic increases in CT density 2–6 months post-RT, and
functional changes is not clear for many organs. Further, later fibrotic reactions at 6–15 months post-RT (Aoki et al.
degree/extent of changes in regional imaging may be 2004). While all 31 patients developed radiographic chan-
associated with changes in global organ function (Fig. 1). ges, no patients developed severe symptoms (e.g., Grade C2
In this chapter we will review the data for several organs or requiring steroids). When follow-up CTs were compared
that relates local dose to local imaging changes, as well as to the dose distribution on the treatment planning CT,
the association between these local imaging changes and investigators observed that the minimal dose for the
more meaningful functional changes. development of CT-defined changes in lung tissue ranged
Quantitative/Objective Analyses of RT-Induced Late Normal Tissue Injury Using Functional Imaging 67

Table 2 Summary of studies reporting RT-induced lung injury: imaging and symptoms
Author, year Number Disease site Radiographic Radiologic endpoint Rate Clinical Rate
of cases follow up endpoint
CT/Radiographs
Mah et al. 54 Lung, Breast, 6 months : Lung density 36/54 RP 10/54
1987 Hodgkin’s disease (67 %) (19 %)
Rotstein et al. 33 Breast 9 months : Lung density 24/33 Cough/ 13/33
1990 (73 %) Dyspnea (39 %)
Polansky et al. 37 Breast 0.7–10 years : Radiopacity 16/37 – 0/37
1980 (43 %) (0 %)
Allavena et al. 75 Hodgkin’s disease 3–10 years : Radiopacity 12/75 – 0/45
1992 (16 %) (0 %)
Marks et al. 184 Lung, Breast, 24 months : Lung density 162/259 Dyspnea 34/175
2000 Lymphoma (63 %) (19 %)
SPECT/Scintigraphies
Allavena et al. 75 Hodgkin’s disease 3–10 years ; Perfusion 29/45 – 0/45
1992 (64 %) (0 %)
Boersma et al. 25 Lymphoma 18 months Dose-dependent reductions in 25/25 RP 4/25
1996 perfusion/ventilation and (100 %) (16 %)
partial recovery
Theuws et al. 110 Breast, Lymphoma 48 months Dose-dependent reductions in 110/110 – –
2000 perfusion/ventilation and (100 %)
partial recovery
Seppenwoolde 106 Lung, Breast, 3 months Dose–effect relation for 25/25 – –
2000 Lymphoma perfusion and CT density (100 %)
Marks et al. 184 Lung, Breast, 24 months ; Perfusion 168/230 Dyspnea 34/175
2000 Lymphoma (81 %) (19 %)
Woel et al. 79 Lung, Lymphoma, *65 months Progressive Dose-dependent 79/79 – –
2002 Breast, Other reductions in regional perfusion (100 %)
thoracic tumors
Ogasawara 9 Lung 7.6 months ; and defective perfusion 9/9 Acute RP/ –
et al. 2002 (100 %) RT fibrosis
Tokatli et al. 20 Breast 1 year ; Lung clearance 10/10 Mild RP 2/20
2005 (100 %) (10 %)
Zhang et al. 123 Lung, Lymphoma, 0.1–12 years Dose-dependent reduction in 123/123 – –
2010 Breast, Other serial perfusion scans (100 %)
thoracic tumors Progress up to *18 months
MRI
Yankelevitz 10 Lung 3.5 years : Signal intensity on T1 and T2 10/10 – –
et al. 1994 weighted images (100 %)
Ogasawara 9 Lung 7.6 months Asymmetric enhancement on 9/9 Acute RP/ –
et al. 2002 dynamic perfusion MR (100 %) RT fibrosis
Muryama et al. 40 Lung, Esophagus None (pre RT : Vascular resistance on – RP 9/40
2004 image) Velocity-encoded cine MR in (23 %)
patients with RP
Ireland et al. 5 Lung 1 and ; 3He-MRI ventilation 3/3 – –
2010 3 months (100 %)
PET
Hicks et al. 73 Lung 38 months : FDG uptake 55/73 – –
2004 (75 %)
Guerrero et al. 36 Esophagus 1.3 months Linear relation between 36/36 – –
2007 radiation dose and normalized (100)
FDG uptake
Hart et al. 2007 101 Esophagus 3–12 weeks Linear relation between – BGrade 2 63/101
radiation dose and normalized CTC (62 %)
FDG uptake symptoms
68 J. Nam et al.

2002). Several studies from Japan suggest MRI can detect

RT-induced lung injury in animal models. In the clinical
setting, Yankelevitz et al. and Ogasawara et al. used MRI to
study perfusion characteristics of RT-induced lung injury
(Table 2) (Ogasawara et al. 2002; Yankelevitz et al. 1994).
In a recent study by Muryama et al., velocity-encoded cine
(VEC) MRI was used to investigate whether pulmonary
arterial flow as a function of time could be used to predict
RP (Muryama et al. 2004). Using hyperpolarized helium-3
MRI technique, Ireland et al. demonstrated the feasibility of
detecting ventilation changes between pre- and post-RT in
the patients with non-small cell lung cancer (Fig. 3).
A recent study from M.D. Anderson noted dose depen-
dent changes in regional FDG-PET activity in 101 patients
assessed 3–12 weeks post-RT for esophageal cancer (Hart
Fig. 2 Patient with synchronous bilateral lung lesions treated with et al. 2007). Further, the severity of these regional inflam-
radiosurgery. Follow-up CTs at 5 months post-RT showed significant matory changes appeared to be significantly correlated to
increased in tissue density. Adapted with permission from Hubbs (2008)
the probability of symptoms.
Data from several studies regarding radiographic chan-
ges in the lung following thoracic RT, seen on SPECT, CT,
MRI, and positron emission tomography (PET), are sum-
marized in Table 2, and comparisons of the imaging char-
acteristics of the several imaging modalities are in Table 3.
Figs. 4, 5, 6 illustrate some of these imaging findings and
correlation to dose.
There have been several attempts to relate the extent/
severity of the imaging abnormalities to changes in global
lung function [e.g., changes in pulmonary function tests
(PFTs) or the development of symptoms]. For example,
investigators at Duke and the Netherland Cancer Institute
related the sum of the regional perfusion changes (i.e., the
integrated response) to changes in PFTs. In general, there
are associations, but these associations are not that strong
(Fig. 7).

3 Heart Injury

RT to the thorax may induce both early and late cardiac

Fig. 3 Coronal lung CT images (left) and corresponding ventilation effects if portions of the heart are included in the radiation
images based on hyperpolarized helium-3 MRI (right). The pre-RT field. Patients with breast cancer and Hodgkin’s disease are
images are on the top a and the three-month post-RT images are on the
particularly at risk for developing late myocardial damage,
bottom c. The RT dose distribution is shown on the coronal CT image
in the middle b. Note the reduced regional ventilation seen on the post- due to their longevity and possibly also due to the frequent
RT image (arrow in c. Reproduced with permission from Ireland et al. use of anthracycline-containing chemotherapy. In general,
(2010) one has to wait at least 10 years post-treatment to see these
effects manifest clinically (Darby et al. 2005). The use of
from 16 to 36 Gy. Figure 2 illustrates the pre- and post-RT radiologic methods may allow for the early detection of
change in CT for a patient treated at Duke with radiosurgery treatment-associated dysfunction. Recent studies have
for synchronous pulmonary lesions. investigated the incidence of cardiac effects on patients
Contrast-enhanced magnetic resonance imaging (MRI) receiving RT for lung and esophageal RT. There are some
may also be used to describe perfusion characteristics of preliminary data available on newer imaging technologies
various phases of RT-induced lung injury (Ogasawara et al. such as cardiac MRI and PET to assess RT-induced cardiac
Quantitative/Objective Analyses of RT-Induced Late Normal Tissue Injury Using Functional Imaging 69

Table 3 Comparisons of various imaging modalities used to evaluate radiation-induced lung injury
CT MR PET SPECT
Imaging Non-contrasted imaging. T1, T2 weighted, 18FDG-PET Perfusion or ventilation scans
techniques dynamic perfusion,
velocity-encoded cine
image
Image Increase in lung density Increased signal Increase FDG Reductions in both perfusion and/or
findings intensity uptake value ventilation
Decrease pulmonary
artery acceleration
time
Reported *60–70 % (Marks et al. 2000; *100 % (Ogasawara *75–100 % (Hart *64–100 % (Marks et al. 2000;
frequency of Rotstein et al. 1990; Allavena et al. 2002; et al. 2007; Seppenwoolde et al. 2004; Ogasawara
abnormal et al. 1992; Mah et al. 1987; Yankelevitz et al. Guerrero et al. et al. 2002; Allavena et al. 1992;
findings (%) Polansky et al. 1980) 1994; Muryama et al. 2007; Hicks 2004) Boersma et al. 1996; Theuws et al.
2004) 2000; Tokatli et al. 2005; Woel et al.
2002; Zhang et al. 2010)
Follow-up Median 24 months Median 7.6 months Median 1.3 months Median 21 months
times (range, 6–120) (range, 0–42) (range, 1–38) (range, 3–120)
assessed
Dose/ Yes NA Yes Yes
Volume
dependency*
Pros Easy, Fast, Simple Sensitive Sensitive, Abundant clinical data, sensitive
Images lung and surrounding Images lung and Maybe useful to
soft tissue surrounding soft tissue discriminate
recurrence from
normal tissue
changes
Cons Limited functional data Expense Expense Low resolution and many artifacts

injury in patients with thoracic cancers. However, the vast defects associated with coronary artery disease may cause
majority of available data regarding the imaging of RT- reductions in ejection fraction.
induced heart injury uses SPECT myocardial perfusion Data from several studies relating radiographic changes
imaging in patients with breast cancer and Hodgkin’s disease. in the heart, as seen on SPECT, in patients treated for breast
cancer and Hodgkin’s disease, and preliminary data from
studies in esophageal and lung cancer, are shown in
3.1 SPECT Table 4. The rates of perfusion defects were plotted in
Fig. 9 according to the follow up duration. Unlike the data
SPECT scans provide a noninvasive assessment of myo- for breast cancer, the results as assessed by SPECT for
cardial perfusion and function (changes in wall motion and esophageal and lung cancer, are limited and somewhat
left ventricular ejection fraction). Scans taken in the early mixed. It may be more difficult to draw conclusions about
years following RT may be able to assess for the subclinical the incidence of RT-induced cardiac injury in this group of
damage. The incidence of perfusion defects appears to be patients as many may have pre-existing heart disease and
related to the volume of left ventricle irradiated and largely associated related risks. Further, additional follow-up may
persist up to 6 years after RT in patient irradiated for breast be needed.
cancer (Fig. 8) (Marks et al. 2003, 2005; Prosnitz et al. There is some concern that the abnormalities detected on
2007). Perfusion defects have been associated with wall SPECT may be due to attenuation artifacts related to RT-
motion abnormalities (Marks et al. 2005; Prosnitz et al. induced scarring of the breast/chest-wall; i.e., RT causes
2007; Yu et al. 2003; Seddon et al. 2002), and possibly pericardial scarring that may lead to an ‘‘artificial’’ defect in
episodes of acute pericarditis (Seddon et al. 2002), but their the anterior myocardium. However, a recent study reported
clinical implications are unclear. Relatively large perfusion that the soft tissue density changes in these patients are
70 J. Nam et al.

Fig. 4 Pre- and post-RT lung CT (a, from Duke) (Ma et al. 2010), metabolic activity. For the CT images, the dose response curves for
SPECT perfusion scans (b, from Duke) (Zhang 2010), and FDG-PET longer post-RT time intervals are shown, without the corresponding
images (c, from M.D. Anderson) (Guerrero et al. 2007). For each image images. Reproduced with permission from Ma et al. (2010), Zhang et al.
pair, the associated isodose lines are shown. On the right side are dose (2010), Hubbs (2008), and Guerrero et al. (2007)
response curves for changes in regional density, perfusion, and

typically modest and thus were unlikely to cause ‘‘artifac-

tual’’ perfusion defects (Lawrence et al. 2010).

3.2 MRI

Nuclear medicine imaging provides both qualitative and

quantitative information about regional and global cardiac
function (Hardenbergh et al. 2001), and has been suggested
to be a sensitive means to assess myocardial injury in
patients with coronary artery disease (Li and Deshpande
2001; Hundley et al. 2003). MRI provides assessments of
Fig. 5 Population dose response curves for RT-induced reductions in myocardial wall thickness and, with delayed hyper-
regional perfusion are shown from Duke and the Netherlands Cancer
Institute. Adapted from Munley (2001) enhancement, allows direct visualization of myocardial
Quantitative/Objective Analyses of RT-Induced Late Normal Tissue Injury Using Functional Imaging 71

3.3 Cardiac PET

There is increased interest in the use of cardiac PET to

provide a map of regional myocardial perfusion. PET has
been suggested as having improved resolution and accuracy
as compared to SPECT, in addition to allowing patients
shorter exam times while similar to SPECT, only having the
capability of imaging the left ventricle (Chua et al. 2006). A
case report noted an increased FDG uptake within cardiac
regions receiving C25 Gy approximately 4 years earlier
(Zophel et al. 2007). The patient was asymptomatic and had
a normal ECG (Fig. 11).

4 Brain Injury

Symptomatic brain injury from radiotherapy is relatively

common and likely underestimated due to limited lifespan
of the majority of treated patients and the subtlety of find-
ings (Armstrong et al. 1993; Meyers and Weitzner 1995;
Weitzner and Meyers 1997; Giovagnoli and Boiardi 1994;
Archibald et al. 1994). Neurocognitive alterations can range
from subtle cognitive dysfunction, such as mild short-term
memory loss 1–6 months after treatment, to global irre-
versible/progressive neuropsychological deficits such as
personality change and an overt decrease in IQ [6 months
post RT (Hoppe-Hirsch et al. 1995; Merchant et al. 2005;
Fig. 6 Data from three centers (a Princess Margaret; b NKI; c Duke) Crossen et al. 1994; Taphoorn and Klein 2004). Different
relating changes in CT density to regional lung doses, data taken from manifestations of RT-induced brain injury varying in their
Mah et al. (1994), Boersma et al. (1994), and Levinson et al. (1998)
time of onset and in their clinical and/or radiologic char-
acteristics (e.g., acute, early delayed, and late delayed
injury/fibrosis, and is more sensitive in assessing subendo- effects) were illustrated in Fig. 12 (Tofilon and Fike
cardial injury. Both MRI and the nuclear medicine tech- 2000). The situation is further complicated by neurotoxic
niques provide information regarding wall motion and effects of the tumor as well as effects of surgery and/or
ejection fraction, but MRI has better spatial resolution and chemotherapy.
thus may be more accurate (Wagner et al. 2005; Cuocolo The changes in normal brain following therapy for brain
et al. 2005; Schaefer et al. 2004). Conversely, quantification tumors is often complex. For example, it can be challenging
of myocardial perfusion is better developed with SPECT to differentiate changes in normal brain tissue post-RT from
than with MRI (Cuocolo et al. 2005; Schaefer et al. 2004). recurrent disease. Nevertheless, several studies suggest that
While SPECT images only the left ventricle, MRI affords imaging is a reasonable way to differentiate these entities
the possibility to assess global cardiac function. (Table 5). In addition, the clinical implications of often-
Cardiac MRI has been applied to the study of RT- subtle radiologic findings can be uncertain, and thus imaging
induced cardiac disease for a small number of patients with may over-estimate the risks of RT. The post-RT imaging
lung cancer. In a preliminary abstract (Lind et al. 2006a), findings, and their association (or lack there of) with clinical
there were no apparent changes in 13 evaluable patients findings, for several modalities are summarized below.
2–6 months post-RT. In patients who were treated with
mediastinal RT for Hodgkin’s disease, cardiac MR per-
formed 20–28 years post-RT noted perfusion deficits in 4.1 SPECT
68 % of patients, and other abnormal findings (e.g.,
decreased ejection fraction, hemodynamic valvular dys- SPECT (single photon emission computed tomography) can
function, etc.) in *50 % patients (Fig. 10) (Machann et al. illustrate changes in blood flow following RT. A Japanese
2011). study by Araki et al. utilized Xenon 133 SPECT to evaluate
72 J. Nam et al.

Fig. 7 Association between the

regional perfusion changes and
the changes in pulmonary
function tests adapted from the
studies from Duke and
Netherland Cancer Institute.
Adapted from Fan et al. (2001)
and Theuws (1998a, b)

Fig. 8 SPECT cardiac perfusion

scan images pre-RT a and
6 months post-RT b Note a new
perfusion defect in the left
ventricle which was partly
included inside the tangential
fields (indicated). As the volume
of the left ventricle irradiated
increases, the fraction of patients
with new perfusion defects
increases c. The irradiated left
ventricle volume was highly
correlated with the irradiated
total cardiac volume
d. Reproduced with permission
from Marks et al. (2005)

changes in mean cerebral blood flow of non-tumor bearing therapy in some patients, compared to normal controls. At
areas in 40 patients as compared with 40 normal volunteers 3 months post-RT, significant reductions in blood flow were
(Araki et al. 1990). Mean blood flow increased during seen in three patients.
Quantitative/Objective Analyses of RT-Induced Late Normal Tissue Injury Using Functional Imaging 73

Table 4 Summary of studies using myocardial perfusion scintigraphy to assess for RT-induced cardiac injury in patients with thoracic
malignancies
*Author, year Years Number Median time to Subgroup Incidence of
affiliation, (reference) of RT of cases radiographic follow-up perfusion defects
(%)
Breast cancer—retrospective
Gyenes et al. 1994 Sweden 1971–1976 37 18.4 Left-sided photons 25 (5/20)
or electrons
19 years Right-sided photons 0 (0/17)
or electrons
Gustavsson et al. 1999 1978–1983 90 13 years Left-sided RT 12 (4/34)
Sweden Right-sided or no 4 (2/56)
RT
Hojris et al. 2000 Denmark 1982–1990 16 7.9 years Left-sided electrons 44 (4/9)
No RT 57 (4/7)
Cowen et al. 1998 France 1987–1993 17 8.4 years Left-sided photons 0 (0/17)
Seddon et al. 2002 United Kingdom 1987–1995 36 6.7 years Left-sided photons 71 (17/24)
8.3 years Right-sided photons 17 (2/12)
Sioka et al. 2011, Greece 1998–2010 131 3.3 years Left-sided photons 54 (15/28)
Right-sided photons 44 (8/18)
No RT 33 (28/85)
Breast cancer—prospective
Gyenes et al. 1996 1993–1994 12 1.1 years Left-sided photons 100 (4/4)
Sweden Left-sided electrons 25 (2/8)
#
Marks et al. 2005 Duke University 1998–2001 114 0.5 year Left-sided photons 27 (21/77)
1 year 29 (16/55)
1.5 years 38 (13/34)
2 years 42 (11/26)
#
Prosnitz et al. 2007 Duke University 1998–2006 44 3 years Left-sided photons 38 (3/8)
4 years 58 (7/12)
5 years 67 (4/6)
6 years 67 (2/3)
Other disease sites
Savage et al. 1990 University of 16 9.3 (2.5–21.5) years Lymphoma 6 (1/16)
Rochester
Gustavsson et al. 1990 Sweden) 26 15 (4–20) years Lymphoma 61 (14/23)
Maunoury et al. 1992 France 1978–1988 31 7 (3–11) years Lymphoma 84 (21/25)
Glanzmann et al. 1998 Switzerland 1964–1992 112* 13.7 (1.9–31.5) years Lymphoma 7 (7/100)
Girinsky et al. 2000 France 49 75 (28–208) months Lymphoma 78 (32/41)
Heidenreich et al. 2007 Stanford 1964–1994 294 6.5 (4.0–8.4) years Lymphoma 12 (32/274)
University
Gayed et al. 2006 MDACC 2005–2006 51 3 months Esophageal cancer 54 (14/26)
No RT 16 (4/25)
Lind et al. 2006a Karlinska Institute – 13 2, 6 months Lung Cancer – –*
Adapted with permission from Prosnitz et al. (2007)
#
Some patients overlap, incidence of new perfusion defects listed
*at least one patient with a new perfusion abnormality. Limited data in available abstract
74 J. Nam et al.

Fig. 9 Scatter plot of the rates of perfusion defects extracted from the
reported studies using myocardial perfusion scintigraphy to assess RT
induced cardiac injury in patients with thoracic malignancies. The
incidence of perfusion defects does not consistently increase over time

Harila-Saari et al. studied 25 patients with acute lym-

phoblastic leukemia (ALL) treated with either intrathecal
(IT) chemotherapy or RT. SPECT perfusion defects were Fig. 10 Magnetic resonance images of the heart in patients treated
noted in 11/25 (44 %); eight of whom received chemo- with the mediastinal irradiation for Hodgkin’s disease [ 20 years
therapy alone and three who received cranial RT (Harila- previously. a and b illustrates hypokinesia (i.e., note that the wall
thickness of indicated area is thinner than other region on end-systolic
Saari et al. 1997). The degree of SPECT abnormality has phase) in short-axis steady-state free precession cine image. c and
not been associated with neuropsychologic changes post- d are stress and rest perfusion images, respectively, illustrating
RT. hypointensities (arrows) noting reduced perfusion. Reproduced with
permission from Machann et al. (2011)

4.2 PET

There are limited data regarding the effects of RT on glu-

cose metabolism in the brain assessed via FDG-PET and
clinical symptoms, and the available data are contradictory.
Kahkonen et al. evaluated 40 long term survivors of ALL
half of whom received methotrexate and cranial RT (Kah-
konen et al. 2000). No major differences were found in
regional glucose metabolism in various defined cortical and
subcortical anatomical areas for irradiated versus nonirra-
diated groups. Pre-RT imaging was not available in these
patients. Munley et al. retrospectively evaluated eight
patients with both pre- and post-RT FDG-PET imaging
(Munley et al. 1999). There were no changes in regional
metabolic activity in areas of brain receiving doses up to
50 Gy. Above 50 Gy, the effects varied, one with PET
activity decreasing in one, and increasing in others, to
varying degrees. Both of these studies were very small.
Mineura et al. reported on seven patients studied with
15 Fig. 11 FDG uptake was increased in the myocardium included in the
O-PET before and after RT for gliomas (Mineura et al.
prior RT fields. Note that the distribution did not correspond to
1988). One month post-RT, there were increases in PET-
coronary artery territories. Microvascular or myocardial effects might
defined regional blood flow in the contralateral gray matter be responsible for the imaging changes. Reproduced with permission
felt to be normal tissue by CT. At longer time points, there from Zöphel et al. (2007)
Quantitative/Objective Analyses of RT-Induced Late Normal Tissue Injury Using Functional Imaging 75

Fig. 12 RT induced brain injury

and the characteristics according
to the onset duration of clinical
manifestation

were significant decreases in blood flow from pretreatment parameters can be easily generated on a voxel-by-voxel
with later studies. Hahn et al. performed a prospective study matrix in the specific brain region of interest (Fig. 14).
in patients undergoing therapeutic brain RT. Patients had Several preclinical and clinical studies were reported to
brain imaging (FDG- and 15O-PET) and neurocognitive address the normal brain changes using DTI. A Prospective
testing planned to be performed pre-RT and at 3 weeks and study from University of Michigan revealed progressive
6 months post-RT. Eleven patients were enrolled, with post-RT changes in the genu and splenium areas of the
seven subjects completing the 3-week, and six subjects corpus callosum (Nagesh et al. 2008b). A total of 25 brain
completing the 6-month follow-up imaging studies. Six tumor patients were evaluated in the study. Initially, in the
subjects also completed follow-up neuropsychological high dose region, dose dependent demyelination was
testing. Three weeks and 6 months post-RT images observed. After 6 months follow-up, diffuse demyelination
revealed reductions in FDG uptake in regions of the brain was also noted in both high dose and lower dose areas.
receiving [40 Gy in comparison to pre-treatment scans A pediatric study showed similar results. Post-treatment
(Hahn et al. 2005). The 15O-PET showed increases (\10 %) survivors of childhood brain tumors were studied to com-
at 3 weeks in relative regional blood flow in brain regions pare DTI changes with neurocognitive function changes.
receiving greater than 30 Gy, but less at the 6-month fol- Decreases in IQ test scores were significantly correlated
low-up studies (Fig. 13). There were significant correlations with changes in DTI indices after age and RT dose
between decreases in FDG uptake and several neurocogni- adjustment (Khong et al. 2006).
tive endpoints associated with problem solving, cognitive RT-induced injury to a certain area (e.g., hippocampus)
flexibility, and global measures of psychopathology. in the brain may cause long-term deficits in the specific
neurocognitive function (e.g., memory loss, learning abil-
ity). From a preliminary study, decreased values of FA
4.3 MRI (Fractional anisotropy) in the para-hippocampal cingulum
1 month after whole brain irradiation were observed. These
MRI is an essential tool for the evaluation of tumor and findings suggest that DTI indices can be used as a bio-
normal tissue characteristics, providing detailed information marker for monitoring patients treated with hippocampal
of either anatomic or pathologic structural changes as well sparing brain RT (Fig. 15) (Nagesh et al. 2008a).
as microstructural events. Various MRI techniques are In general, DTI is suitable for the detection of early
available and widely adapted in cancer diagnosis. It is also changes in the white matter integrity after brain RT.
an attractive tool for the differential diagnosis of post- Association between the DTI indices and the neurocogni-
treatment changes and tumor progression with both graph- tive function changes needs to be studied further with
ical appearances and quantifiable numeric parameters. longer follow up and prospective setting.

4.3.1 Diffusion Tensor Imaging 4.3.2 MR Perfusion Imaging

White matter changes (e.g., demyelination or axonal injury) RT-induced vascular damage may lead to increased perme-
after brain RT were reported in the studies using DTI ability in the brain normal tissues. Perfusion MR imaging can
techniques. Several DTI indices were tested for the analysis detect these early changes by tracing the intravenously
of RT-induced imaging changes relating to clinical mani- injected contrast-enhancing pharmaceuticals. The movement
festation (i.e., neurocognitive dysfunction). These objective of pharmaceuticals can be calculated as a value of a transfer
76 J. Nam et al.

Table 5 Radiographic changes to the brain after irradiation

Author, year affiliation, (reference) Number Radiographic Post-RT radiographic response/outcome
of cases follow-up
SPECT
*Araki et al. 1990 Gifu University, Japan 40 3 months : mean blood flow during RT,
; in blood flow in 3 RT patients post-RT
Harila-Saari et al. 1997 Oulu university 25 Varied Defects in 44 % (11/25) – 8 Chemo Alone, 3 RT Alone
central hospital, Finland) (9–13 months)# Impairment in neuropsychological functioning in 19/22 (86 %)
No significant difference intelligence testing between normal
versus abnormal SPECT
Diffusion weighted (DW)—MRI
Hein et al. 2004, Norris Cotton Cancer 18 1–3 years ADC ratios and means significantly ; for recurrent versus
Center intervals nonrecurrent lesions
Asao et al. 2005, Kumamota University 17 – Marked hypointensity (67 %, [8/12]), in lesions due to RT-
injury versus recurrent tumor
Maximal ADC values significantly ; for recurrent versus
nonrecurrent lesions
Diffusion tensor image (DTI)
Khong et al. 2006 30 1 year– Percent difference in fractional anisotropy (DFA %)
significantly correlated with IQ
Nagesh et al. 2008b, University of 25 6 months Progressive post-RT changes in the genu and splenium of the
Michigan corpus callosum
Dose dependent demyelination initially in the high dose region.
After 6 months follow up, diffuse demyelination in both high
and low dose areas
1
HMRSI
Virta et al. 2000, NIH 9 0.5–10.5 years Widespread chemical changes in white matter after RT
Chong et al. 2001, Singapore general 18 Mean 4.6 years ; NAA in RT-induced temporal lobe changes
hospital (range 3.0–9.6 Cr levels relatively more stable than Cho or NAA levels
years) Cho levels may be increased, normal, or reduced
Zeng et al. 2007 Shandong University, 55 2 months Cho/NAA, Cho/Cr, and ADC ratios and means significantly ; in
(MRS and DW-MRI) intervals regions of RT-injury versus recurrent tumor
(1.5–12 months) MRS with DW MRI correctly classified 96.4 % of subjects as
3–4 months recurrence or RT-Injury (100 % correct for RT-Injury group)
intervals
(12-36 mos)
Plotkin et al. 2004 25 9.7 months I-IMT SPECT significantly :for recurrent disease versus
Germany, (I-IMT SPECT 1HMRS) treatment related changes
SPECT yielded more favorable results in differentiating
recurrent tumor versus post-RT changes
Matulewicz et al. 2006 Maria 100 2 years Oscillations in Cho/NAA and Cho/Cr ratios seen in 8 month
Sklodowska-Curie Memorial Cancer cycles
Center, Poland Maxima in Cho/NAA and Cho/Cr ratios seen 2 months after RT
Sundgren et al. 2009 University of 11 6 months ;NAA/Cr and Cho/Cr ratios at 3 weeks during RT and 1 month
Michigan and 6 months after RT
PET
Hahn et al. 2005, Duke University 11 3 weeks; ; FDG uptake
6 months
* Data extracted from Abstract
# Radiographic follow-up not distinguished between patients with and without RT. Follow-up time measured from end of systemic therapy or RT
Abbreviations: Apparent diffusion coefficient (ADC), N-acetyl-aspartate (NAA), Diffusion-weighted (DW), Creatine (Cr), Choline (Cho)

constant or Ktrans. High Ktrans value means the increased sensitive to the RT dose. Vp value increases with higher RT
vascular permeability (i.e., extravasation of contrast- dose delivered during RT and then decreases after RT.
enhancing materials). Changes in blood plasma volume, Cao et al. reported, using dynamic contrast-enhanced MRI,
expressed as Vp, also provide a useful information. Vp is early vascular changes may be a predictor of delayed changes
Quantitative/Objective Analyses of RT-Induced Late Normal Tissue Injury Using Functional Imaging 77

Fig. 13 Coronal CT image of

brain a and registered with 2-
deoxy-2-[18F]-D-glucose positron
emission tomography image
b with three-dimensional
radiation dose distribution shown
on each image. Lower panel
images represent the volume-
weighted population average
percentage of changes in FDG
uptake (c) and 15O-H2O value
(d), respectively. Reproduced
with permission from Hahn et al.
(2005)

in neurocognitive functions (e.g., verbal learning and total increased metabolic turnover; it is elevated in both tumors
recall). Vascular volumes and blood–brain barrier perme- and inflammatory processes. Creatine is a marker of energy
ability increased during RT and then decreased after RT. Six metabolism with relatively constant concentrations
months after RT, changes in verbal learning scores and recall throughout the brain (Sundgren and Cao 2009), while mI is
scores were significantly correlated with vascular volumes and a glial cell marker and has been used as an indicator of
permeability during RT (Fig. 16) (Cao et al. 2009). myelin breakdown (Pasantes-Morales et al. 2000). Changes
in concentration of these metabolites are associated with
4.3.3 MR Proton Spectroscopy tumor and/or normal brain tissue changes.
MR proton spectroscopy (MRS) provides unique informa- Many clinical studies of MRS focus on differentiating
tion about metabolic status in tissues. Proton MRS is a radiation necrosis and tumor progression. Currently, there
noninvasive technique to, (i) interrogate metabolic distri- are limited numbers of clinical and preclinical studies of
butions in the brain (Gillies and Morse 2005; Hoehn et al. normal brain tissue changes after RT. Herynek et al.
2001), (ii) differentiate radiation necrosis from brain tumor reported decreases in creatine and NAA after Gamma Knife
progression (Chong et al. 2002; Schlemmer et al. 2002), and irradiation to the rat brain (Herynek et al. 2004). Chan et al.
(iii) serve as a indicator of neurotoxicity following experi- using 7T MRS, studied changes in concentrations of cho-
mental (Chan et al. 2009; Herynek et al. 2004) and clinical line, glutamate, lactate, and taurine 1 year after RT to rats’
brain irradiation (Chan et al. 2001; Esteve et al. 1998; Lee brain (Chan et al. 2009). Atwood et al. reported similar
et al. 2004; Sundgren et al. 2009; Virta et al. 2000; Walecki results. They suggested a potential relationship between
et al. 1999). Metabolites detected in brain tissue include RT-induced brain injury and neurocognitive dysfunction
choline-containing compounds, creatine, glutamate, lactate, (Fig. 17) (Atwood et al. 2007).
N-acetylaspartate (NAA), myoinositol (mI), and taurine. Chan et al. reported that MRS was able to detect
The concentration of each of these metabolites can be decreasing NAA/Cr and Cho/Cr ratio in childhood ALL
mapped from 2D or 3D spectroscopic images having a survivors treated with IT chemotherapy and prophylactic
voxel size of 0.7–1 cm3. The metabolite, NAA is predom- cranial irradiation with long-term follow up (up to 19 years)
inantly a neuronal marker, and decreases are associated with (Chan et al. 2001). Similar findings were noted in a recent
neuronal damage and dysfunction secondary to radiation. prospective study performed in University of Michigan.
Choline is associated with cell membrane synthesis and/or MRS from 11 adult patients with low grade glioma or
78 J. Nam et al.

Fig. 14 DTI images of coronal brain slices of a rat. a Fractional coded). c Voxel analysis of the specific region of the brain for
Anisotropy values represent water diffusion characteristics within a comparison of individual areas. Reproduced with permission from
voxel. b FA value can be translated as a direction of flow (color Robbins et al. (2012)

Fig. 15 DTI images of the brain treated with whole brain irradiation. parahippocampal white matter showing greater diffusion characteris-
a MR T1-weighted axial image of the region including parahippo- tics (i.e., perpendicular diffusivity, k\) along with white matter fiber
campal cingulum [right side (green) and left (light blue)]. Each side of tract. d 1 month after RT, increase in k\ (brighter color) represents
temporal lobe white matter was also indicated with yellow (right) and early demyelination in the parahippocampal cingulum. Reproduced
blue (left) colors, respectively. b Baseline pre-RT image of the with permission from Robbins et al. (2012)
parahippocampal cingulum (white). c Pre-RT DTI map of
Quantitative/Objective Analyses of RT-Induced Late Normal Tissue Injury Using Functional Imaging 79

Fig. 16 Vascular volume (Vp)

and blood brain barrier
permeability (K) changes
according to the different RT
dose intervals (a, b). Note that
increase in vascular volume at
high dose region during RT.
Changes in neurocognitive
function test scores (learning
score and recall score) 6 months
after RT appear to be correlated
with changes in DVp and
DK during RT (c–f). Reproduced
with permission from Cao et al.
(2009)

benign brain tumors demonstrated decreases in NAA/Cr and important to assess the impact RT-induced liver injury.
Cho/Cr ratios from 3 weeks to 6 months following RT Radiologic changes are often evident on irradiated livers prior
(Fig. 18) (Sundgren et al. 2009). to, or even in the absence of, clinical symptoms (Lawrence
et al. 1995; Kwek et al. 2006). Such imaging changes have
been reported 6 months to 6 years post-RT (Dawson and Ten
Haken 2005; Lawrence et al. 1995; Cao et al. 2007) (Table 6).
5 Liver Injury

Previous RT techniques limited the utility of radiation to the 5.1 CT Perfusion Studies
liver, due to the liver’s low whole organ tolerance. Data from
studies dating back to the 1960s indicated that with doses to Investigators at the University of Michigan have used CT to
the whole liver up to 30–35 Gy using standard fractionation detect RT-induced liver injury. CTs obtained 2–3 months
resulted in a 5 % risk of radiation-induced liver disease post-RT revealed low attenuation within irradiated areas in
(RILD), while smaller volumes of the liver could tolerate of 74 % of 31 patients studied. Using CT-based perfusion
higher doses (Dawson and Ten Haken 2005; Lawrence et al. imaging, Cao et al. assessed the relationship between local
1995; Ingold et al. 1965; Reed 1966). With the advent of 3D radiation dose and changes in regional portal vein perfusion,
conformal therapy and more recently intensity modulated similar to perfusion imaging studies of the lung and heart
radiation therapy (IMRT), it has become increasingly post-RT from other institutions noted above (Cao et al.
80 J. Nam et al.

Fig. 17 T2-weighted MR
images of rat brain with a
5 9 5 9 5 mm voxel region of
interest to measure the
concentration of specific
metabolites using MRS:
a coronal image and b axial
image. Significant metabolites
changes (c) and reduced
cognitive function (d) after 52
and 54 weeks of whole brain
irradiation, respectively (*, **,
and, *** represent statistically
significant results; p-values are
less than 0.01). Reproduced with
permission from Atwood et al.
(2007)

2007). In ten patients with unresectable primary or meta- irradiated liver tissues show T1-weighted hypointensity and
static hepatic tumors, reductions in regional portal vein T2-weighted hyperintensity, potentially due to increased
perfusion *1.5 and 3 weeks into treatment (i.e., during RT) water content (Yankelevitz et al. 1992; Onaya et al.
were related to changes in perfusion at 1 month post-RT 2001). However, severe hepatic fibrosis can cause hypoin-
(Figs. 19, 20). Conceivably, one may be able to alter ther- tensity on T2-weighted images that have been observed
apy based on normal tissue changes noted early-on during a in irradiated patients with Budd-Chiari syndrome (Mori
proposed course of therapy, thereby individualizing therapy. et al. 2002).
Munden et al. noted new CT liver abnormalities in 40 % Special MR imaging techniques may provide a more
(8/20) of patients *8 (range 5–11) weeks post-IMRT for precise differential diagnosis of radiation-induced hepatic
mesothelioma (Munden et al. 2005). The abnormalities injury. In gadolinium-enhanced dynamic studies, the irra-
were in the liver periphery, corresponding to the regions diated liver parenchyma show early hyperintensity that
receiving [45 Gy. All patients with CT-defined abnormal- become more prominent and persists at the end of the
ities were asymptomatic and had normal liver function tests. dynamic studies (Onaya et al. 2001). Recent study using
For those patients with limited additional follow-up, the Gd-EOB-DTPA (gadolinium ethoxybenzyl diethylenetri-
majority of the abnormalities resolved, however additional aminepentaacetate) in patients treated with interstitial
data with longer follow-up is warranted. brachytherapy to metastatic liver disease show hepatic
injury after small volume single-fraction irradiation
(Fig. 21) (Seidensticker et al. 2011). Superparamagnetic
5.2 MRI iron oxide-enhanced (SPIO) MR imaging may also be a
sensitive modality for early and late radiation-induced liver
MRI also provides a noninvasive method of imaging the injury (Fig. 22) (Mori et al. 2000; 2002; Nohara et al. 1997;
RT-induced liver disease. On conventional MR images, Yoshiokaa et al. 2000).
Quantitative/Objective Analyses of RT-Induced Late Normal Tissue Injury Using Functional Imaging 81

Fig. 18 MR images before (a) and 6 months after RT (b). Radiation NAA/Cho at different time interval were plotted (c). d–f represent the
dose distribution was overlaid (a). VOIs for MRS study were shown relationships between radiation dose/volume and the changes of Cho/
with larger white box (a) and individual VOIs for spectral analysis Cr ratio before and following completion of RT. Reproduced with
with smaller white box (b). Changes in ratios of NAA/Cr, Cho/Cr, and permission from Sundgren et al. (2009)

5.3 PET parotid. Radiologic techniques afford the possibility of

quantitatively assessing dose-dependent changes in regional
A study from M.D. Anderson reported hepatic radiation parotid function (Table 7).
injury using FDG-PET in patients with distal esophageal
cancer treated with chemoradiation. Abnormal FDG uptake
in the irradiated liver was found in 19 % of the patients 6.1 SPECT and PET
(Fig. 23) (Iyer et al. 2007). However, CT images demon-
strated atrophy and density changes of irradiated liver in The ability of the parotid to clear 11C-methionine (a sur-
58 % of the same patients group. Among those patients with rogate for salivary flow) was assessed in 12 patients
increased FDG uptake in the liver, an additional diagnostic 8–54 months (median 21 months) post-IMRT using PET
work-up (i.e., biopsy) was frequently required for excluding imaging (Buus et al. 2004). There was a dose-dependent
metastatic disease. reduction in the clearance rate (Fig. 24), with a threshold
for regional injury at about 16 Gy. A 50 % reduction
(TD50) in function was estimated to be 30 Gy, with marked
inter-patient variation in TD50 (ranged from 7 to 50 Gy).
6 Parotid Gland Injury Similar work has also been done with SPECT, with
abnormalities in SPECT images seen at doses as low as
The parotid glands are often incidentally irradiated during 10–15 Gy (Bussels et al. 2004; Van Acker et al. 2001). In a
therapy for head and neck tumors, and the resultant injury study from Medical University of Lübeck (Germany), sig-
can impact speech, chewing, and swallowing (Hakim et al. nificant alterations in radiotracer uptake in irradiated sali-
2004). There is growing interest in sparing parotid function vary glands of rabbits demonstrated that functional
with IMRT, which usually results in a markedly variable impairment could be assessed by scintigraphy as early as
dose of RT being delivered to the different regions of the 24 h post-irradiation (Hakim et al. 2004).
82 J. Nam et al.

Table 6 Imaging assessment of RT-induced liver disease

Author, year Number Disease RT technique Follow-up Radiologic Clinical
affiliation of cases median dose (range) changes RT-
hepatitis
CT
Yamasaki et al. 1995, 31 Primary or High-dose conformal RT 8–12 weeks 74 % 6%
Michigan metastatic hepatic 59 Gy (48–73 Gy) intervals
tumors
Munden et al. 2005, 20 Mesothelioma – 16 weeks range 40 % 0%
MDACC (3–116)
Cao et al. 2007 10 Primary or 67.5 Gy (48–78 Gy) 1.5, 3 weeks during ;Regional –
Michigan, (perfusion) metastatic hepatic RT; 1 month post- Perfusion
tumors RT
Imada et al. 2010, 43 Hepatocellular Carbon ion RT (48.0–79.5 3, 6, 12 months Changes in –
Chiba University carcinoma GyE) liver
volume
PET/CT
Iyer et al. 2007, 26 Distal esophageal 3D-conformal RT 50.4 Gy 6 weeks post-RT 19 % 0%
MDACC cancer
MRI
Yankelevitz et al. 1992, 10 Hodgkins disease – 2, 4, 6, 12 weeks 30 % 0%
Cornell
Onaya et al. 2001 32 Hepatocellular Proton (50-87 Gy) 22 months 35 %* –
carcinoma range (1–75)
Yoshiokaa et al. 2000, 21 Hepatocellular Proton (40.5–72 Gy) 3–9 weeks – –
University of Tsukaba carcinoma Proton (68.8–72 Gy) 4–65 months
Eccles et al. 2009, 11 Primary or 6-fraction conformal RT 1, 3, 6, 12, every 100 % –
Princess Margaret metastatic hepatic mean 43.9 Gy six months interval
tumors (28.8–54 Gy)
Seidensticker et al. 23 Metastatic hepatic Interstitial brachytherapy 3 days, 6, 12, 100 % 0%
2011, University tumors 24 weeks
Magdeburg
*For post-contrast T1- –weighted images

Fig. 19 CT images of radiation-

induced hepatic venous perfusion
changes. Color-coded maps
represents portal vein perfusion
status of pre-RT (a) and post-RT
(after 46.5 Gy delivered) (b).
Reproduced with permission
from Cao et al. (2007)
Quantitative/Objective Analyses of RT-Induced Late Normal Tissue Injury Using Functional Imaging 83

Fig. 20 Changes in portal venous perfusion according to RT dose correlation between portal venous perfusion and regional RT dose.
received at the different time points (a 15 fractions; b 30 fractions; Reproduced with permission from Cao et al. (2007)
c one month following RT). Scatter plots showed the significant

Fig. 21 Six weeks after

irradiation of liver metastasis
(indicated with white arrow), the
hepatic injury of normal liver
parenchyma (indicated with
black arrow) is prominent in the
region of higher radiation dose on
T1-weight gradient echo with
Gd-EOB-DTPA. Pre-RT (a) and
6 weeks Post-RT (b).
Reproduced with permission
from Seidensticker et al. (2011)

Fig. 22 MR images of a patient

with hepatocellular carcinoma
treated with 72 Gy proton beam
RT. T2-weighted images with
(a) or without (b) contrast
enhancement using
superparamagnetic iron oxide-
enhanced technique show higher
signal intensity in the previously
irradiated area compared to the
surrounding normal liver.
Reproduce with permission from
Yoshioka et al. (2000)

6.2 MRI apparent diffusion coefficients (ADC) has been noted in

patients with RT-induced dysfunction as assessed by scin-
MRI has been used to evaluate salivary gland diseases, due tigraphy (Zhang et al. 2001).
to its excellent soft tissue contrast and the visualization of High resolution MRI was used to evaluate the micro-
characteristic changes resulting from RT (Nomayr et al. structural changes of parotid glands before and after RT
2001; Zhang et al. 2001). A reduction in MRI-defined (Kan et al. 2010). There were significant volume reductions
84 J. Nam et al.

Fig. 23 a and b show CT and

fused PET/CT images,
respectively, from a patient with
distal esophageal carcinoma,
obtained after 6 weeks post-RT.
Note the increased FDG uptake
in the left lobe of the liver on
fused PET/CT image and the
well-demarcated low attenuation
on axial nonenhanced CT image.
c and d represent another patient
with metastatic disease with
similar images obtained
18 months post-RT. Reproduced
with permission from Iyer et al.
(2007)

correlated with the regional radiation dose of the parotid

gland (Fig. 26). Houweling et al. reported similar findings
using 3T MRI with various MR protocols. A parameter ve,
the extra-vascular extra-cellular space per unit volume of
tissue, was significantly increased on post-RT T1-weighted
images (Fig. 27). There was a significant correlation
between the radiation mean dose and the changes in T2-
weighted signal (Houweling et al. 2011). Astreindou et al.
noted abnormalities in the parotid gland ducts on 3D-MR
sialography in patients irradiated for head and neck cancer.
Visibility of the parotid ducts was reduced at 6 weeks post-
RT (Fig. 28); after 6 months, some patients showed the
visibility scores (Astreinidou et al. 2007).
Summary findings from several studies using various
radiologic methods to assess RT-associated changes in the
parotid gland are shown in Table 7.

Fig. 24 Radiation dose response for regional parotid gland injury.

Reductions in regional parotid function are measured in 12 patients,
using dynamic PET to assess 11C-methionine clearance (a surrogate 7 Summary
for salivary flow). Data is obtained 8–54 months (median 21 months)
post-IMRT. Reproduced with permission from Buus et al. (2006) Functional imaging can be used to quantitatively detect RT-
induced normal tissue injury in a variety of organs. The data
in the irradiated parotid gland and the decreased width of and images shown for the lung, heart, brain, liver, and
main duct following RT (Fig. 25). These changes were parotid glands are intended to illustrate the concepts of how
Quantitative/Objective Analyses of RT-Induced Late Normal Tissue Injury Using Functional Imaging 85

Table 7 Radiologic changes in the parotid glands after RT

Author, year Number Radiographic follow-up Type of Radiographic response/outcome
affiliation of cases months post-RT median radiographic study
(reference) (range)
PET
11
Buus et al. 8 6 months (minimum) C-methionine Metabolic clearance of 11C-methionine in the parotid and
2004 PET submandibular glands decreased with increasing RT dose
Denmark
11
#Buus et al. 12 21 months (8–54) C-methionine Dose–response analysis revealed a sigmoid relationship with
2006, PET a threshold dose of 16 Gy, and mean TD50- of 30 Gy.
Denmark
MRI
Astreinidou 9 1.5 and 6 months Magnetic- Comparison of pre- and post-RT images revealed RT-induced
et al. 2007, resonance decreases in visible of the parotid and submandibular ducts, at
Utrecht sialography 1.5 months, but subsequent improvement at 6 months.
Nömayr et al. 52 Within 24 months post- MRI RT-induced volume reduction of parotid
2001, RT
Germany
Zhang et al. 21 1 month MRI and Salivary Mean apparent diffusion coefficient (ADC) of dysfunctional
2001, Japan gland scintigraphy parotids decreased by 23 % on diffusion-weighted imaging
(SGS) post-RT
No significant change of ADCs of functional parotids
Kan et al. 14 *3 weeks High resolution Decreased parotid gland volume and narrowing of main duct.
2010, Japan MR
Houweling 18 6 weeks 3T MRI Decreased parotid gland volume. Change in T2-weighted
et al. 2011 signal (i.e., increased intensity) was correlated with mean
radiation dose.
Scitigraphy/SPECT
Maes et al. 39 1 and 4 months Salivary gland The mean loss of SEF in the spared parotid was 67 % and
2002, Belgium scintigraphy 19 % in 1 and 4 months post-RT, respectively. Normal
excretion function was regained in 75 % of the spared
parotids.
Roesink et al. 96 1.5 and 12 months Salivary gland Reduction in salivary excretion fractions (SEF) from 44.7 %
2004, Utrecht scintigraphy to 18.7 % at 6 weeks and to 32.4 % at 12 months post-RT.
Hsiung et al. 16 1 and 9 months Salivary gland Maximal excretion ratio dropped from 53.5 % to 10.7 %, and
2006, Taiwan scintigraphy 23.3 % 1 and 9 months post-IMRT, respectively.
van Acker 21 1 month Salivary gland Linear correlation between RT-induced changes in SEF on
et al. 2001, scintigraphy plus SGS-SPECT and RT dose
Belgium SPECT
Bussels et al. 16 7 months (6–10) Salivary gland Median reduction in salivary excretion fractions (SEF) of
2004, Belgium scintigraphy plus 100 % (range 17–100 %) observed 7 months post-RT
SPECT
# Includes four of the same patients as the other Buus study

imaging can be used to better understand and study radia- degree of radiologically-defined regional normal tissue
tion-associated-normal tissue injury. There are similar, injury may be related to short/long-term clinically-mean-
though lesser, data for other organs such as the sub- ingful endpoints (e.g., changes in global organ function),
mandibular gland, bone, and kidney that are not discussed. but further study is needed to better quantify this associa-
Imaging appears to be a powerful tool to objectively and tion. Additional work is needed to develop methods and
quantitatively assess regional normal tissue injury. The standards to quantitatively score radiologic injury.
86 J. Nam et al.

Fig. 25 High resolution MR images show the gradual volume reduction of the parotid gland according to the increase of the radiation dose.
Significant narrowing (i.e., decreased signal intensity) of duct was also observed. Reproduced with permission from Kan et al. (2010)

Fig. 26 RT induced parotid volume (a) and main duct (b and c) changes according to the mean radiation dose of the individual parotid gland.
Reproduced with permission from Kan et al. (2010)

Fig. 27 T1-weighted MR
images with the overlaid color-
coded parameter ve, showing
post-RT change in both parotid
glands. Dotted lines are pre-RT
contours of both parotid glands.
Reproduced with permission
from Houweling et al. (2011)
Quantitative/Objective Analyses of RT-Induced Late Normal Tissue Injury Using Functional Imaging 87

Fig. 28 MR sialogram of pre-

RT (a) and 6 weeks post-RT
(b) and superimposed radiation
dose plan (c and d). Arrows
indicates parotid ducts on the
same position receiving the dose
of 16 Gy. Reproduced with
permission from Astreindou et al.
(2007)

Acknowledgments Supported in part by grants NIH R01 CA69579, Archibald YM, Lunn D, Ruttan LA et al (1994) Cognitive functioning
CA112593, CA122318, Department of Defense Grants 17-98-1-8071, in long-term survivors of high-grade glioma. J Neurosurg
BC010663, and a grant from the Lance Armstrong Foundation. Thanks 80:247–253
to the University of North Carolina at Chapel Hill for PLUNC plan- Armstrong C, Mollman J, Corn BW, Alavi J, Grossman M (1993)
ning software. Portions of this document were adapted from Evans ES, Effects of radiation therapy on adult brain behavior: evidence for a
Hahn C, Marks L et al. The role of functional imaging in the diagnosis rebound phenomenon in a phase 1 trial. Neurology 43:1961–1965
and management of late normal tissue injury. Seminars in Radiation Asao C, Korogi Y, Kitajima M et al. (2005) Diffusion-weighted
Oncology 17:72-80, 2007; Hubbs JL, Nam J, Zhou S, et al. Bioi- imaging of radiation-induced brain injury for differentiation from
maging in vivo discern the evolution of the late effects temporally and tumor recurrence. Am J Neuroradiol 26:1455–60
spatially. Cured II—Lent Cancer Survivorship Research and Educa- Astreinidou E, Roesink JM, Raaijmakers CP et al (2007) 3D MR
tion: Late Effects on Normal Tissues (Springer); and Imaging radia- sialography as a tool to investigate radiation-induced xerostomia:
tion-induced normal tissue injury, Mike E. Robbins, Judy K. Brunso- feasibility study. Int J Radiat Oncol Biol Phys 68:1310–1319
Bechtold, Ann M. Peiffer et al. Radiation Research in press. Atwood T, Payne VS, Zhao W et al (2007) Quantitative magnetic
resonance spectroscopy reveals a potential relationship between
radiation-induced changes in rat brain metabolites and cognitive
impairment. Radiat Res 168:574–581
References Boersma LJ, Damen EMF, de Boer RW et al (1994) Dose-effect
relations for local functional and structural changes of the lung
after irradiation for malignant lymphoma. Radiother Oncol
Allavena C, Conroy T, Aletti P, Bey P, Lederlin P (1992) Late 32:201–209
cardiopulmonary toxicity after treatment for Hodgkin’s disease. Br Boersma LJ, Damen EM, de Boer RW et al (1996) Recovery of overall
J Cancer 65:908–912 and local lung function loss 18 months after irradiation for
Anscher MS, Marks LB, Shafman TD et al (2003) Risk of long-term malignant lymphoma. J Clin Oncol 14:1431–1441
complications after TFG-? 1-guided very-high-dose thoracic Bussels B, Maes A, Flamen P et al (2004) Dose-response relationships
radiotherapy. Int J Radiat Oncol Biol Phys 56:988–995 within the parotid gland after radiotherapy for head and neck
Aoki T, Nagata Y, Negoro Y et al (2004) Evaluation of lung injury cancer. Radiother Oncol 73:297–306
after three-dimensional conformal stereotactic radiation therapy for Buus S, Grau C, Munk OL, Bender D, Jensen K, Keiding S (2004)
solitary lung tumors CT appearance. Radiology 230:101–108 11C-methionine PET, a novel method for measuring regional
Araki Y, Imao Y, Hirata T, Ando T, Sakai N, Yamada H (1990) salivary gland function after radiotherapy of head and neck cancer.
Cerebral blood flow of the non-affected brain in patients with Radiother Oncol 73:289–296
malignant brain tumors as studied by SPECT; with special Buus S, Grau C, Munk OL et al (2006) Individual radiation response of
reference to adverse effects of radiochemotherapy. No Shinkei parotid glands investigated by dynamic 11C-methionine PET.
Geka 18:601–608 Radiother Oncol 78:262–269
88 J. Nam et al.

Cao Y, Platt JF, Francis IR et al (2007) The prediction of radiation- Fu XL, Huang H, Bentel G et al (2001) Predicting the risk of
induced liver dysfunction using a local dose and regional venous symptomatic radiation-induced lung injury using both the physical
perfusion model. Med Phys 34:604–612 and biologic parameters V30 and transforming growth factor ? Int J
Cao Y, Tsien CI, Sundgren PC et al (2009) Dynamic contrast- Radiat Oncol Biol Phys 50:899–908
enhanced magnetic resonance imaging as a biomarker for predic- Gayed IW, Liu HH, Yusuf SW et al (2006) The prevalence of
tion of radiation-induced neurocognitive dysfunction. Clin Cancer myocardial ischemia after concurrent chemoradiation therapy as
Res 15:1747–1754 detected by gated myocardial perfusion imaging in patients with
Cazzaniga LF, Bossi A, Cosentino D et al (1998) Radiological findings esophageal cancer. J Nucl Med 47:1756–1762
when very small lung volumes are irradiated in breast and chest Gillies RJ, Morse DL (2005) In vivo magnetic resonance spectroscopy
wall treatment. Radiat Oncol Investig 6:58–62 in cancer. Annu Rev Biomed Eng 7:287–326
Chan YL, Roebuck DJ, Yuen MP et al (2001) Long-term cerebral Giovagnoli AR, Boiardi A (1994) Cognitive impairment and quality of
metabolite changes on proton magnetic resonance spectroscopy in life in long-term survivors of malignant brain tumors. Ital J Neurol
patients cured of acute lymphoblastic leukemia with previous Sci 15:481–488
intrathecal methotrexate and cranial irradiation prophylaxis. Int J Girinsky T, Cordova A, Rey A, Cosset JM, Tertian G, Pierga JY
Radiat Oncol Biol Phys 50:759–763 (2000) Thallium-201 scintigraphy is not predictive of late cardiac
Chan KC, Khong PL, Cheung MM, Wang S, Cai KX, Wu EX (2009) complications in patients with Hodgkin’s disease treated with
MRI of late microstructural and metabolic alterations in radiation- mediastinal radiation. Int J Radiat Oncol Biol Phys 48:1503–1506
induced brain injuries. J Magn Reson Imaging 29:1013–1020 Glanzmann C, Kaufmann P, Jenni R, Hess OM, Huguenin P (1998)
Chong VF, Rumpel H, Fan YF, Mukherji SK (2001) Temporal lobe Cardiac risk after mediastinal irradiation for Hodgkin’s disease.
changes following radiation therapy: imaging and proton MR Radiother Oncol 46:51–62
spectroscopic findings. Eur Radiol 11:317–324 Goethals I, Dierckx R, De Meerleer G et al (2003) The role of nuclear
Chong VF, Khoo JB, Chan LL, Rumpel H (2002) Neurological medicine in the prediction and detection of radiation-associated
changes following radiation therapy for head and neck tumours. normal pulmonary and cardiac damage. J Nucl Med 44:1531–1539
Eur J Radiol 44:120–129 Graham MV, Purdy JA, Emami B et al (1999) Clinical dose-volume
Chua SC, Ganatra RH, Green DJ, Groves AM (2006) Nuclear histogram analysis for pneumonitis after 3D treatment for non-small
cardiology: myocardial perfusion imaging with SPECT and PET. cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 45:323–329
Imaging 18:166–177 Guerrero T, Johnson V, Hart J et al. (2007) Radiation pneumonitis:
Cowen D, Gonzague-Casabianca L, Brenot-Rossi I et al (1998) local dose versus [18f]-fluorodeoxyglucose uptake response in
Thallium-201 perfusion scintigraphy in the evaluation of late irradiated lung. Int J Radiat Oncol *Biol* Phys 68:1030–1035
myocardial damage in left-side breast cancer treated with adjuvant Gustavsson A, Eskilsson J, Landberg T et al (1990) Late cardiac
radiotherapy. Int J Radiat Oncol Biol Phys 41:809–815 effects after mantle radiotherapy in patients with Hodgkin’s
Crossen JR, Garwood D, Glatstein E, Neuwelt EA (1994) Neurobe- disease. Ann Oncol 1:355–363
havioral sequelae of cranial irradiation in adults: a review of Gustavsson A, Bendahl PO, Cwikiel M, Eskilsson J, Thapper KL,
radiation-induced encephalopathy. J Clin Oncol 12:627–642 Pahlm O (1999) No serious late cardiac effects after adjuvant
Cuocolo A, Acampa W, Imbriaco M, De Luca N, Iovino GL, Salvatore radiotherapy following mastectomy in premenopausal women with
M (2005) The many ways to myocardial perfusion imaging. Q J early breast cancer. Int J Radiat Oncol Biol Phys 43:745–754
Nucl Med Mol Imaging 49:4–18 Gyenes G, Fornander T, Carlens P, Rutqvist LE (1994) Morbidity of
Darby SC, McGale P, Taylor CW, Peto R (2005) Long-term mortality ischemic heart disease in early breast cancer 15–20 years after
from heart disease and lung cancer after radiotherapy for early adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 28:1235–1241
breast cancer: prospective cohort study of about 300,000 women in Gyenes G, Fornander T, Carlens P, Glas U, Rutqvist LE (1996)
US SEER cancer registries. Lancet Oncol 6:557–565 Myocardial damage in breast cancer patients treated with adjuvant
Dawson LA, Ten Haken RK (2005) Partial volume tolerance of the radiotherapy: a prospective study. Int J Radiat Oncol Biol Phys
liver to radiation. Semin Radiat Oncol 15:279–283 36:899–905
Dorr W, Bertmann S, Herrmann T (2005) Radiation induced lung Hahn CA, Zhou S, Renee DH et al. (2005) Dose-dependent effects of
reactions in breast cancer therapy: Modulating factors and conse- radiation therapy on cerebral blood flow, metabolism and neuro-
quential effects. Strahlenther Onkol 181:567–573 cognitive dysfunction. Int J Radiat Oncol *Biol* Phys 63:S67
Eccles CL, Haider EA, Haider MA, Fung S, Lockwood G, Dawson LA Hakim SG, Jacobsen H, Hermes D et al (2004) Early immunohisto-
(2009) Change in diffusion weighted MRI during liver cancer chemical and functional markers indicating radiation damage of the
radiotherapy: preliminary observations. Acta Oncol 48:1034–1043 parotid gland. Clin Oral Invest 8:30–35
Esteve F, Rubin C, Grand S, Kolodie H, Le Bas JF (1998) Transient Hardenbergh PH, Munley MT, Bentel GC et al (2001) Cardiac
metabolic changes observed with proton MR spectroscopy in perfusion changes in patients treated for breast cancer with
normal human brain after radiation therapy. Int J Radiat Oncol Biol radiation therapy and doxorubicin: preliminary results. Int J Radiat
Phys 40:279–286 Oncol Biol Phys 49:1023–1028
Evans ES, Hahn CA, Kocak Z, Zhou SM, Marks LB (2007) The role of Harila-Saari AH, Ahonen AK, Vainionpaa LK et al (1997) Brain
functional imaging in the diagnosis and management of late normal perfusion after treatment of childhood acute lymphoblastic leuke-
tissue injury. Semin Radiat Oncol 17:72–80 mia. J Nucl Med 38:82–88
Fan M, Marks LB, Hollis D et al (2001a) Can we predict radiation- Hart JP, Guerrero T, Johnson V et al. (2007) Radiation pneumonitis:
induced changes in pulmonary function based on the sum of correlation of clinical toxicity with pulmonary [18f]-fluorodeoxyglu-
predicted regional dysfunction? J Clin Oncol 19:543–550 cose uptake dose response. Int J Radiat Oncol *Biol* Phys 69:S155
Fan M, Marks LB, Lind P et al (2001b) Relating radiation-induced Heidenreich PA, Schnittger I, Strauss HW et al (2007) Screening for
regional lung injury to changes in pulmonary function tests. Int J coronary artery disease after mediastinal irradiation for hodgkin’s
Radiat Oncol Biol Phys 51:311–317 disease. J Clin Oncol 25:43–49
Fan M, Marks LB, Lind P et al (2001c) Relating radiation-induced Hein PA, Eskey CJ, Dunn JF, Hug EB (2004) Diffusion-weighted
regional lung injury to changes in pulmonary function tests. Int J imaging in the follow-up of treated high-grade gliomas: tumor
Radiat Oncol Biol Phys 51:311–317 recurrence versus radiation injury. Am J Neuroradiol 25:201–209
Quantitative/Objective Analyses of RT-Induced Late Normal Tissue Injury Using Functional Imaging 89

Herynek V, Burian M, Jirak D et al (2004) Metabolite and diffusion Kwek JW, Iyer RB, Dunnington J, Faria S, Silverman PM (2006)
changes in the rat brain after Leksell Gamma Knife irradiation. Spectrum of imaging findings in the abdomen after radiotherapy.
Magn Reson Med 52:397–402 AJR Am J Roentgenol 187:1204–1211
Hicks RJ, Mac Manus MP, Matthews JP (2004) Early FDG-PET Lawrence MV, Roper J, Bateman T et al. (2010) Can density changes
imaging after radical radiotherapy for non-small-cell lung cancer: of surrounding soft tissues cause post-RT cardiopulmonary perfu-
inflammatory changes in normal tissues correlate with tumor sion defects? Int J Radiat Oncol *Biol* Phys 78:S47
response and do not confound therapeutic response evaluation. Int J Lawrence TS, Robertson JM, Anscher MS, Jirtle RL, Ensminger WD,
Radiat Oncol Biol Phys 60:412–418 Fajardo LF (1995) Hepatic toxicity resulting from cancer treat-
Hoehn M, Nicolay K, Franke C, van der Sanden B (2001) Application ment. Int J Radiat Oncol Biol Phys 31:1237–1248
of magnetic resonance to animal models of cerebral ischemia. Lee MC, Pirzkall A, McKnight TR, Nelson SJ (2004) 1H-MRSI of
J Magn Reson Imaging 14:491–509 radiation effects in normal-appearing white matter: dose-depen-
Hojris I, Sand NP, Andersen J, Rehling M, Overgaard M (2000) dence and impact on automated spectral classification. J Magn
Myocardial perfusion imaging in breast cancer patients treated with or Reson Imaging 19:379–388
without post-mastectomy radiotherapy. Radiother Oncol 55:163–172 Levinson B, Marks LB, Munley MT et al (1998) Regional dose
Hoppe-Hirsch E, Brunet L, Laroussinie F et al. (1995) Intellectual response to pulmonary irradiation using a manual method.
outcome in children with malignant tumors of the posterior fossa: Radiother Oncol 48:53–60
influence of the field of irradiation and quality of surgery. Childs Li D, Deshpande V (2001) Magnetic resonance imaging of coronary
Nerv Syst 11:340–345; discussion 5–6 arteries. Top Magn Reson Imaging 12:337–348
Houweling AC, Schakel T, van den Berg CAT et al (2011) MRI to Lind PA, Wennberg B, Gagliardi G et al (2006a) ROC curves and
quantify early radiation-induced changes in the salivary glands. evaluation of radiation-induced pulmonary toxicity in breast
Radiother Oncol: J Eur Soc Ther Radiol Oncol 100:386–389 cancer. Int J Radiat Oncol Biol Phys 64:765–770
Hsiung CY, Ting HM, Huang HY, Lee CH, Huang EY, Hsu HC Lind PA, Larsson T, Lidestahl A, Agren-Cronqvist A, Nygren A,
(2006) Parotid-sparing intensity-modulated radiotherapy (IMRT) Brodin O (2006b) 2497: Heart changes on MRI and SPECT after
for nasopharyngeal carcinoma: preserved parotid function after definitive radiation therapy in patients with lung cancer. Int J
IMRT on quantitative salivary scintigraphy, and comparison with Radiat Oncol *Biol* Phys 66:S487
historical data after conventional radiotherapy. Int J Radiat Oncol Ma J, Zhang J, Zhou S et al (2010) Regional lung density changes after
Biol Phys 66:454–461 radiation therapy for tumors in and around thorax. Int J Radiat
Hubbs JL, Nam J, Hahn CA, Marks LB (2008) Bioimaging in vivo to Oncol Biol Phys 76:116–122
discern the evolution of late effects temporally and spatially. In: Machann W, Beer M, Breunig M et al (2011) Cardiac magnetic
Cured II LENT cancer survivorship research and education. resonance imaging findings in 20-year survivors of mediastinal
Springer, pp 7–23 radiotherapy for Hodgkin’s disease. Int J Radiat Oncol Biol Phys
Hundley WG, Hamilton CA, Rerkpattanapipat P (2003) Magnetic 79:1117–1123
resonance imaging assessment of cardiac function. Curr Cardiol Maes A, Weltens C, Flamen P et al (2002) Preservation of parotid
Rep 5:69–74 function with uncomplicated conformal radiotherapy. Radiother
Imada H, Kato H, Yasuda S et al (2010) Compensatory enlargement of Oncol 63:203–211
the liver after treatment of hepatocellular carcinoma with carbon Mah K, Keane TJ, Van Dyk J, Braban LE, Poon PY, Hao Y (1994)
ion radiotherapy—relation to prognosis and liver function. Radio- Quantitative effect of combined chemotherapy and fractionated
ther Oncol 96:236–242 radiotherapy on the incidence of radiation-induced lung damage: A
Ingold JA, Reed GB, Kaplan HS, Bagshaw MA (1965) Radiation prospective clinical study. Int J Radiat Oncol *Biol* Phys
hepatitis. Am J Roentgenol, Radium Ther Nucl Med 93:200–208 28:563–574
Ireland RH, Din OS, Swinscoe JA et al (2010) Detection of radiation- Mah K, Van Dyk J, Keane T, Poon PY (1987) Acute radiation-induced
induced lung injury in non-small cell lung cancer patients using pulmonary damage: a clinical study on the response to fractionated
hyperpolarized helium-3 magnetic resonance imaging. Radiother radiation therapy. Int J Radiat Oncol Biol Phys 13:179–188
Oncol 97:244–248 Marks LB (1994) The pulmonary effects of thoracic irradiation.
Iyer RB, Balachandran A, Bruzzi JF, Johnson V, Macapinlac HA, Oncology (Williston Park, NY) 8:89–106; discussion 0, 3
Munden RF (2007) PET/CT and hepatic radiation injury in Marks LB, Zhou S, Yu X (2003) The impact of irradiated left
esophageal cancer patients. Cancer Imaging 7:189–194 ventricular volume on the incidence of radiation-induced cardiac
Kahkonen M, Metsahonkala L, Minn H et al (2000) Cerebral glucose perfusion changes. Int J Radiat Oncol Biol Phys 57:S129
metabolism in survivors of childhood acute lymphoblastic leuke- Marks LB, Fan M, Clough R et al (2000) Radiation-induced
mia. Cancer 88:693–700 pulmonary injury: symptomatic versus subclinical endpoints. Int
Kan T, Kodani K, Michimoto K, Fujii S, Ogawa T (2010) Radiation- J Radiat Biol 76:469–475
induced damage to microstructure of parotid gland: evaluation Marks LB, Yu X, Prosnitz RG et al (2005) The incidence and
using high-resolution magnetic resonance imaging. Int J Radiat functional consequences of RT-associated cardiac perfusion
Oncol Biol Phys 77:1030–1038 defects. Int J Radiat Oncol Biol Phys 63:214–223
Khong PL, Leung LH, Fung AS et al (2006) White matter anisotropy Matulewicz L, Sokol M, Michnik A, Wydmanski J (2006) Long-term
in post-treatment childhood cancer survivors: preliminary evidence normal-appearing brain tissue monitoring after irradiation using
of association with neurocognitive function. J Clin Oncol proton magnetic resonance spectroscopy in vivo: statistical anal-
24:884–890 ysis of a large group of patients. Int J Radiat Oncol Biol Phys
Kocak Z SL, Sullivan DC, Marks LB (2007) The role of imaging in the 66:825–832
study of radiation-induced normal tissue injury. In: Rubin P CL, Maunoury C, Pierga JY, Valette H, Tchernia G, Cosset JM, Desgrez A
Marks LB, Okunieff P (eds) Cured I—lent late effects of cancer (1992) Myocardial perfusion damage after mediastinal irradiation
treatment on normal tissue, 1st edn. Springer, New York, pp 37–45 for Hodgkin’s disease: a thallium-201 single photon emission
Kuhnt T, Richter C, Enke H, Dunst J (1998) Acute radiation reaction tomography study. Eur J Nucl Med 19:871–873
and local control in breast cancer patients treated with postmas- Merchant TE, Kiehna EN, Li C, Xiong X, Mulhern RK (2005)
tectomy radiotherapy. Strahlenther Onkol 174:257–261 Radiation dosimetry predicts IQ after conformal radiation therapy
90 J. Nam et al.

in pediatric patients with localized ependymoma. Int J Radiat Reed GB Jr, Cox AJ Jr (1966) The human liver after radiation injury.
Oncol Biol Phys 63:1546–1554 A form of veno-occlusive disease. Am J Pathology 48:597–611
Meyers CA, Weitzner MA (1995) Neurobehavioral functioning and Robbins ME, Brunso-Bechtold JK, Peiffer AM, Tsien CI, Bailey JE,
quality of life in patients treated for cancer of the central nervous Marks LB (2012) Imaging radiation-induced normal tissue injury.
system. Curr Opin Oncol 7:197–200 Radiat Res 177(4):449–466
Mineura K, Suda Y, Yasuda T et al (1988) Early and late stage Roesink JM, Moerland MA, Hoekstra A, Van Rijk PP, Terhaard CH
positron emission tomography (PET) studies on the haemocircu- (2004) Scintigraphic assessment of early and late parotid gland
lation and metabolism of seemingly normal brain tissue in patients function after radiotherapy for head-and-neck cancer: a prospective
with gliomas following radiochemotherapy. Acta Neurochir study of dose-volume response relationships. Int J Radiat Oncol
(Wien) 93:110–115 Biol Phys 58:1451–1460
Mori H, Yoshioka H, Ahmadi T, Saida Y, Ohara K, Itai Y (2000) Early Rotstein S, Lax I, Svane G (1990) Influence of radiation therapy on the
radiation effects on the liver demonstrated on superparamegnetic lung-tissue in breast cancer patients: CT-assessed density changes
iron oxide-enhanced T1-weighted MRI. J Comput Assist Tomogr and associated symptoms. Int J Radiat Oncol Biol Phys
24:648–651 18:173–180
Mori H, Yoshioka H, Mori K et al (2002) Radiation-induced liver Savage DE, Constine LS, Schwartz RG, Rubin P (1990) Radiation
injury showing low intensity on T2-weighted images noted in effects on left ventricular function and myocardial perfusion in
Budd-Chiari syndrome. Radiat Med 20:69–76 long term survivors of Hodgkin’s disease. Int J Radiat Oncol Biol
Munden RF, Erasmus JJ, Smythe WR, Madewell JE, Forster KM, Phys 19:721–727
Stevens CW (2005) Radiation injury to the liver after intensity- Seppenwoolde Y, Muller SH, Theuws JC et al. (2000) Radiation dose-
modulated radiation therapy in patients with mesothelioma: an effect relations and local recovery in perfusion for patients with
unusual CT appearance. AJR Am J Roentgenol 184:1091–1095 non-small-cell lung cancer. Int J Radiat Oncol Biol Phys
Munley MT, Marks LB, Strickland JL et al (1999) The effect of 47:681–690
radiotherapy on brain metabolism using F-18 FDG PET imaging. Schaefer WM, Lipke CSA, Nowak B et al. (2004) Validation of QGS
Int J Radiat Biol 45:330–331 and 4D-MSPECT for quantification of left ventricular volumes and
Munley MT, Marks LB Hardenbergh PH, Bentel G (2001) Functional ejection fraction from gated 18F-FDG PET: comparison with
imaging of normal tissues. Semin Radiat Oncol 11:28–36 cardiac MRI. J Nucl Med 45:74–79
Muryama S, Akamine T, Sakai S et al (2004) Risk factor of radiation Schlemmer HP, Bachert P, Henze M et al (2002) Differentiation of
pneumonitis: assessment with velocity-encoded cine magnetic radiation necrosis from tumor progression using proton magnetic
resonance imaging of pulmonary artery. J Comput Assist Tomogr resonance spectroscopy. Neuroradiology 44:216–222
28:204–208 Schratter-Sehn AU, Schurawitzki H, Zach M, Schratter M (1993)
Nagesh V, Tsien CI, Sundgren PC et al. (2008a) Diffusion tensor High-resolution computed tomography of the lungs in irradiated
imaging as a biomarker for neurotoxicity of radiation. Int J Radiat breast cancer patients. Radiother Oncol 27:198–202
Oncol *Biol* Phys 72:S529 Seddon B, Cook A, Gothard L et al (2002) Detection of defects in
Nagesh V, Tsien CI, Chenevert TL et al (2008b) Radiation-induced myocardial perfusion imaging in patients with early breast cancer
changes in normal-appearing white matter in patients with cerebral treated with radiotherapy. Radiother Oncol 64:53–63
tumors: a diffusion tensor imaging study. Int J Radiat Oncol Biol Seidensticker M, Seidensticker R, Mohnike K et al (2011) Quantitative
Phys 70:1002–1010 in vivo assessment of radiation injury of the liver using Gd-EOB-
Nohara C, Matsumine H, Suzuki K et al (1997) (Neurological CPC- DTPA enhanced MRI: tolerance dose of small liver volumes.
59). A 65-year-old man with a history of gastric cancer who Radiat Oncol 6:40
presented progressive loss of vision, memory loss and conscious- Seppenwoolde Y, De Jaeger K, Boersma LJ, Belderbos JSA, Lebesque
ness disturbance. No to shinkei = Brain and nerve 49:1041–1051 JV (2004) Regional differences in lung radiosensitivity after
Nomayr A, Lell M, Sweeney R, Bautz W, Lukas P (2001) MRI radiotherapy for non-small-cell lung cancer. Int J Radiat Oncol
appearance of radiation-induced changes of normal cervical Biol Phys 60:748–758
tissues. Eur Radiol 11:1807–1817 Sioka C, Exarchopoulos T, Tasiou I et al (2011) Myocardial perfusion
Ogasawara N, Suga K, Karino Y, Matsunaga N (2002) Perfusion imaging with (99 m)Tc-tetrofosmin SPECT in breast cancer
characteristics of radiation-injured lung on Gd-DTPA-enhanced patients that received postoperative radiotherapy: a case-control
dynamic magnetic resonance imaging. Invest Radiol 37:448–457 study. Radiat Oncol 6:151
Onaya H, Itai Y, Ahmadi T et al (2001) Recurrent hepatocellular Sundgren PC, Cao Y (2009) Brain irradiation: effects on normal brain
carcinoma versus radiation-induced hepatic injury: differential parenchyma and radiation injury. Neuroimaging Clin N Am
diagnosis with MR imaging. Magn Reson Imaging 19:41–46 19:657–668
Pasantes-Morales H, Franco R, Torres-Marquez ME, Hernandez- Sundgren PC, Nagesh V, Elias A et al (2009) Metabolic alterations: a
Fonseca K, Ortega A (2000) Amino acid osmolytes in regulatory biomarker for radiation-induced normal brain injury-an MR
volume decrease and isovolumetric regulation in brain cells: spectroscopy study. J Magn Reson Imaging 29:291–297
contribution and mechanisms. Cell Physiol Biochem 10:361–370 Taphoorn MJ, Klein M (2004) Cognitive deficits in adult patients with
Plotkin M, Eisenacher J, Bruhn H et al (2004) 123I-IMT SPECT and brain tumours. Lancet Neurol 3:159–168
1H MR-spectroscopy at 3.0 T in the differential diagnosis of Theuws JCM, Kwa SLS, Wagenaar AC et al (1998a) Dose-effect
recurrent or residual gliomas: a comparative study. J Neuro oncol relations for early local pulmonary injury after irradiation for
70:49–58 malignant lymphoma and breast cancer. Radiother Oncol 48:33–43
Polansky SM, Ravin CE, Prosnitz LR (1980) Pulmonary changes after Theuws JCM, Kwa SLS, Wagenaar AC et al (1998b) Prediction of
primary irradiation for early breast carcinoma. AJR Am J overall pulmonary function loss in relation to the 3-D dose
Roentgenol 134:101–105 distribution for patients with breast cancer and malignant lym-
Prosnitz RG, Hubbs JL, Evans ES et al (2007) Prospective assessment phoma. Radiother Oncol 49:233–243
of radiotherapy-associated cardiac toxicity in breast cancer Theuws JC, Seppenwoolde Y, Kwa SL et al (2000) Changes in local
patients: analysis of data 3 to 6 years after treatment. Cancer pulmonary injury up to 48 months after irradiation for lymphoma
110:1840–1850 and breast cancer. Int J Radiat Oncol Biol Phys 47:1201–1208
Quantitative/Objective Analyses of RT-Induced Late Normal Tissue Injury Using Functional Imaging 91

Tofilon PJ, Fike JR (2000) The radio response of the central nervous Yankelevitz DF, Knapp PH, Henschke CI, Nisce L, Yi Y, Cahill P
system: a dynamic process. Radiat Res 153:357–370 (1992) MR appearance of radiation hepatitis. Clin Imaging
Tokatli F, Kaya M, Kocak Z et al (2005) Sequential pulmonary effects 16:89–92
of radiotherapy detected by functional and radiological end points Yankelevitz DF, Henschke CI, Batata M, Kim YS, Chu F (1994) Lung
in women with breast cancer. Clin Oncol (R Coll Radiol) 17:39–46 cancer: evaluation with MR imaging during and after irradiation.
van Acker F, Flamen P, Lambin P et al (2001) The utility of SPECT in J Thorac Imaging 9:41–46
determining the relationship between radiation dose and salivary Yoshiokaa H, Itai Y, Saida Y, Mori K, Mori H, Okumura T (2000)
gland dysfunction after radiotherapy. Nucl Med Commun Superparamagnetic iron oxide-enhanced MR imaging for early and
22:225–231 late radiation-induced hepatic injuries. Magn Reson Imaging
Virta A, Patronas N, Raman R et al (2000) Spectroscopic imaging of 18:1079–1088
radiation-induced effects in the white matter of glioma patients. Yu X, Prosnitz RR, Zhou S et al (2003) Symptomatic cardiac events
Magn Reson Imaging 18:851–857 following radiation therapy for left-sided breast cancer: Possible
Wagner A, Mahrholdt H, Kim RJ, Judd RM (2005) Use of cardiac association with radiation therapy-induced changes in regional
magnetic resonance to assess viability. Current cardiology reports perfusion. Clinical Breast Cancer 4:193–197
7:59–64 Zeng QS, Li CF, Liu H, Zhen JH, Feng DC (2007) Distinction between
Walecki J, Sokol M, Pieniazek P et al (1999) Role of short TE 1H-MR recurrent glioma and radiation injury using magnetic resonance
spectroscopy in monitoring of post-operation irradiated patients. spectroscopy in combination with diffusion-weighted imaging. Int
Eur J Radiol 30:154–161 J Radiat Oncol Biol Phys 68:151–158
Weitzner MA, Meyers CA (1997) Cognitive functioning and quality of Zhang L, Murata Y, Ishida R, Ohashi I, Yoshimura R, Shibuya H
life in malignant glioma patients: a review of the literature. Psycho (2001) Functional evaluation with intravoxel incoherent motion
Oncol 6:169–177 echo-planar MRI in irradiated salivary glands: a correlative study
Woel RT, Munley MT, Hollis D et al (2002) The time course of with salivary gland scintigraphy. J Magn Reson Imaging
radiation therapy-induced reductions in regional perfusion: a 14:223–229
prospective study with [5 years of follow-up. Int J Radiat Oncol Zhang J, Ma J, Zhou S et al (2010) Radiation-induced reductions in
Biol Phys 52:58–67 regional lung perfusion: 0.1-12 year data from a prospective
Yamasaki SA, Marn CS, Francis IR, Robertson JM, Lawrence TS clinical study. Int J Radiat Oncol Biol Phys 76:425–432
(1995) High-dose localized radiation therapy for treatment of Zophel K, Holzel C, Dawel M, Holscher T, Evers C, Kotzerke J (2007)
hepatic malignant tumors: CT findings and their relation to PET/CT demonstrates increased myocardial FDG uptake following
radiation hepatitis. AJR Am J Roentgenol 165:79–84 irradiation therapy. Eur J Nucl Med Mol Imaging 34:1322–1323
 Biograding of Normal Tissue TNM Toxicity
Taxonomy: Scoring the Adverse Effects
of Cancer Treatment
Taxonomy and Classification are Attempts
to Order the Chaos in Nature
Andy M. Trotti and Philip Rubin

Contents Abstract
Although dramatic improvements in cancer survival
1 Introduction and Overview: Genesis and Evolution....... 93 statistics have occurred over the past 5 decades and are
2 The Biologic Basis For Combining Acute and Late well documented in the literature, the same has not been
Criteria.................................................................................. 94 true for detailing the unwanted incidental adverse effects
3 Standardization, and Statistical Reporting ...................... 95 following multimodal cancer treatment. The dramatic
gains in 5-year survival has been compiled by cancer site
4 Normal Tissue/Organ TNM Taxonomy for Adverse
in a SEER tabulation marking the passing of 50 % level
Effects of Cancer Treatment .............................................. 96
4.1 TNM Language...................................................................... 96 for all cancers at the turn of this century. (American
4.2 General Rules ........................................................................ 96 Cancer Society: Cancer Facts and Figures 1995). At
4.3 New Definitions of TNM Applied to Adverse Effects issue and unresolved is the price for the success and how
of Normal Tissue................................................................... 96
to best measure and grade these adverse toxicity effects
4.4 Assigning the Grade for Progression.................................... 97
4.5 Classification According to Evidence for Certainty which persist and progress over time detracting from the
of Grade ................................................................................. 97 cancer survivor’s quality of life.
5 Summary Toxicity Grade ................................................... 98
5.1 NT NN NM Summary Grade.................................................. 98
5.2 Global Toxicity Score of Multiple Organs........................... 98
5.3 Tame ...................................................................................... 99 1 Introduction and Overview: Genesis
6 Therapeutic Ratio Determination and Evolution
and Decision Making........................................................... 100
References...................................................................................... 100 Although dramatic improvements in cancer survival statis-
tics have occurred over the past 5 decades and are well
documented in the literature, the same has not been true for
detailing the unwanted incidental adverse effects following
multimodal cancer treatment. The dramatic gains in 5-year
survival has been compiled by cancer site in a SEER tabu-
lation marking the passing of 50 % level for all cancers at
the turn of this century. (American Cancer Society: Cancer
Facts and Figures 1995). At issue and unresolved is the price
for the success and how to best measure and grade these
adverse toxicity effects which persist and progress over time
detracting from the cancer survivor’s quality of life.
A. M. Trotti (&) The need for a grading system to assess treatment tox-
H. Lee Moffit Cancer Center Research Institute, icities lagged behind the TNM classification of cancers. It
12902 Magnolia Drive, Tampa, FL 33612, USA was in the 1980’s because of the increasing number of
e-mail: [email protected]
clinical trials sponsored by NCI and EORTC that a con-
P. Rubin solidation of numerous individual approaches by each
Department of Radiation Oncology, University of Rochester
School of Medicine and Dentistry, 601 Elmwood Ave, specialty was initiated. The genesis of acute toxicity scoring
Box 647Rochester, NY 14642, USA versus late effect grading originated in a bipolar fashion.

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 93
DOI: 10.1007/978-3-540-72314-1_7,  Springer-Verlag Berlin Heidelberg 2014
94 A. M. Trotti and P. Rubin

Table 1 The Evolution of Toxicity Grading Systems (1979–1998) correlation of symptoms and sign of toxicity with metrics
System Number Number Modality Phase and interventions are future goals. (Trotti and Rubin 2003).
of criteria of organs The most recent collaboration sponsored by all modali-
WHO (1979) 28 9 Chemo Acute ties has resulted in a more comprehensive CTC v3.0, which
CTC (1983) 18 13 Chemo Acute includes more late effects criteria and is inclusive of all
RTOG/EORTC- 14 13 RT Acute
modalities (Available at: http://ctep.info.nih.gov/
Acute (1984) CTC3/ctc.htm. Accessed 1 April 2003; Trotti et al. 2003).
RTOG/EORTC- 68 17 RT Late However, the merging of late effect and acute effect criteria,
Late (1984) although more comprehensive with 510 criteria, when
LENT/SOMA 140 13 RT Late specifying anatomic sites or other subclassifications, raises
(1995) the number to 900 adverse effect criteria for grading. The
CTC v2.0 152 22 RT Late need for a summary toxicity methodology and a global
(1998) adverse effect score, inclusive of multiple organ systems,
CTCAE v3.0 260 22 Alla Acute has yet to be defined, and is essential for outcomes
(2003) reporting.
370 All All Acute
and late
WHO, World Health Organization; Chemo, chemotherapy; RT, 2 The Biologic Basis For Combining
radiation therapy
a
Limited pediatric and surgical criteria
Acute and Late Criteria

The most prominent feature of CTCAE v3.0 is the merging

The NCI, CTEP recognized the need to uniformly score the of early and late effects criteria into a single uniform doc-
toxic acute and subacute effects of chemotherapy. The ument and the development of criteria applicable to all
Common Toxicity Criteria (CTC), first published in 1983, modalities. The research support for the concept of a
was concerned with the physiologic and functional end- ‘‘biologic continuum’’ is based upon the original paradigm
points, many of which are transitory and reversible (Miller by Rubin and Casarett (Rubin and Casarett 1968) in which
et al. 1981). Then, version (2.0) attempted to incorporate the the clinical radiation pathophysiologic course of events
acute effects of other modalities as radiation and expanded incorporating the dynamic sequence of cellular events and
13–22 organ systems and the number of criteria incre- tissue specific effects began at the moment of radiation
mented from 18 to 260 (Table 1) (Trotti et al. 2000; World exposure. The schema illustrated radiation effects, both the
Health Organization 1992). clinical and subclinical events, in each organ system, but
The radiation oncology profession has traditionally been noted that depending on its cell population and tissue
concerned with reporting late effects of cancer treatment organization would express radiation syndromes differently.
and the RTOG in conjunction with EORTC introduced both The underlying pathophysiologic commonality was the
the ‘‘Acute and Late Radiation Morbidity Scoring Criteria’’ obliteration of the normal tissues’ fine microvasculature,
simultaneously (Cox et al. 1995). A series of NCI sponsored whereas the time to clinical expression, the latent period, is
workshops led to the introduction of more comprehensive related to stem cell depletion in either rapid or slow renewal
system entitled: LENT * Late Effects Normal Tissue and system, i.e., acute versus chronic or early versus late effects.
SOMA criteria, representing subjective Symptoms, Objec- This paradigm was the first formalism linking acute and late
tive findings and MAnagement features. The A referred to effects as both a pathophysiologic and a clinical bio con-
Analytic quantifiable parameters in the laboratory or tinuum. More recently, the molecular biologic events cap-
imaging. With acceptance and joint publications on both tured as a persistent cytokine cascade induced by radiation
sides of the Atlantic, RTOG/EORTC hope to standardize in a murine model has recapitulated the shape of the Rubin
reporting of late effects. (Trotti 2002; Rubin et al. 1995a) and Casarett tissue effect over time curves adding further to
Some of the guiding thoughts to reduce interobserver var- their validity (Rubin et al. 1995b). The arbitrary 90 day rule
iability was to replace the commonly used four grades of dividing early and late is no longer acceptable, since
1 ? mild, 2 ? moderate, 3 ? severe, 4 ? life threatening modalities overlap and are administered concurrently, and
with better descriptors with corresponding terms as occa- adjuvant chemotherapy is repeatedly cycled often for
sional, intermittent, persistent and refractory, respectively, months and years. The use of a complex concurrent or
when referring to the expression of symptoms and signs, hybrid sequential schedules undermines the usefulness of a
i.e., pain. Longitudinal clinical trials emphasizing simplistic temporally defined ‘‘early-late’’ construct.
Biograding of Normal Tissue TNM Toxicity Taxonomy 95

Moreover, there is a growing recognition that surgery

(Fedyk et al. 2001; Mercado et al. 2002) and chemotherapy
(Petak and Houghton 2001) much like radiation lead to
molecular events resulting in a perpetual cytokine, chemo-
kine cascade and surgery induces wound healing responses
that result in a inflammation, fibrogenesis, and neoangio-
genesis leading to epithelial regeneration. This multimodal
molecular cascade leads to and supports the biologic con-
tinuum model (Fig. 1).

3 Standardization, and Statistical

Reporting

Standardization of language requires use of the Interna-

tional Dictionary of Medical Terminology and commonly
used disease codes, i.e., ICD 10 (World Health Organization
1992; International Statistical Classification of Diseases and
Related Health Problems. 10th ed. American Psychiatric
Publishing 1992) need to synchronized with both CTC and
LENT-SOMA diagnoses. Thus, the descriptors of adverse
effects language can become more uniform and will reduce
interinvestigator variability. The introduction of quality of
life scales to represent the patients’ viewpoint is an
important aspect of grading adverse effects. Another
important aspect is the need to integrate CTC and LENT-
SOMA more fully. The LENT-SOMA is based on anatomic Fig. 1 The clinicopathologic course of events following irradiation
can be complicated by the addition of chemotherapy. Similarly,
terms consisting of 15–20 major systems with approxi- chemotherapy can result in parallel set of events. a Classically, when
mately 50–60 subsites and is compatible but not identical radiation therapy precedes chemotherapy, the introduction of the
with the terminology of the TNM system (American Joint second mode can lead to expression of subclinical damage or, when
Committee on Cancer (AJCC) 2002). By contrast, the injury is present, to death. b The same is true if chemotherapy precedes
radiation therapy. Reprinted with permission. (With permissions from
CTCAE v3.0 utilizes more physiologic and functional terms Rubin & Casarett, 1968)
and clinical syndromes. There is as much concurrence and
similarities as differences and a comparison of terms is more recently, direct comparison has been made utilizing
presented in Table 2. The anatomical terminology recon- CTC v3.0 and LENT-SOMA. Furthermore, recent analysis
ciliation of the 3 systems is consistent with the International of a validation perspective clinical trial in variety of ana-
Anatomical Terminology (Terminologic Anatomica) tomic sites by RTOG confirms that LENT-SOMA is a
approved in 1998 by the International Federation of the superior instrument as to capturing late effects. Utilizing a
Association of Anatomists (Table 2). (Federative Commit- technique of linguistic analysis there are 12 recurrent cri-
tee on Anatomical Terminology (FCAT) 1998). teria that apply to grading most of the organ systems. The
There is a large and growing literature assessing both the ‘‘shared’’ word descriptors for each grade which can be
CTC systems and LENT-SOMA. Numerous clinical trials identified in both LENT-SOMA and CTC v3.0 allows for a
have been published often comparing these systems with ‘‘concise grading dictionary’’ of well defined lexicons
other late toxicity grading criteria, particularly in Europe. which captures the essence of both systems. The
The literature is equally divided between concordance and SOMAtization of CTC v3.0 is shown in Table 3, which
discordance in confirmation of their applicability. The provides a more focused selection of criteria and should
majority of reports are retrospective and not prospectively enable users to record toxicities more efficiently and accu-
designed to assess validation, especially for LENT-SOMA. rately. The array of criteria relate to five categories:
Davidson et al. (2002, 2003a, b); Routledge et al. (2003); symptoms, physical findings, interventions to ameliorate,
Hoeller et al. (2003); Fehlauer et al. (2003); Denis et al. quality of life, or activities of daily living. Laboratory
(2003); Anacak et al. (2001); Tawfiq et al. (2000) However, values and imaging studies are working in progress as to
96 A. M. Trotti and P. Rubin

Table 2 Anatomic-physiologic systems: hybrid nomenclature common language for cancer staging, cooperative oncology
Anatomic sites LENT/ Physiologic systems group protocols allowed for multimodal regimen to be
AJCCa TNM SOMAb CTC v3.0c designed and tested in clinical trials. The standardization of
Central nervous (2) Neurology TNM staging nomenclature allows for evaluation and
system assessment of the literature. Therefore, a modification of
(Neuroendocrinec) (3) Endocrine this cancer nomenclature will be applied to normal tissue/
Ophthalmologic sites (6) Ocular/Visual organ toxicity.
Head and neck sites (10) Upper respiratory
Digestive system (6) Gastrointestinal
4.2 General Rules
Major digestive (5) Hepato/Biliary/Pancreas
glands
Philosophically, the TNM cancer classification is based on
Thorax breast (1)
the premise that all malignant tumors progress from an early
Lung (1) Pulmonary
localized stage to a more disseminated later stage. The life
Pleura (1) cycle of all cancers shares in having a locus of origin in a
(Heartc) (1) Cardiac, Arrhythmia normal tissue, which invades locally and advances to lymph
c
(Vascular ) (1) Vascular nodes regionally and/or hematogenously to remote sites. In
Genitourinary sites (7) Renal/Genitourinary a parallel fashion, there is a similar life cycle for normal
Male sexual reproduction tissue reactions to multimodal cancer treatment. The normal
Gynecologic sites (7) Female sexual tissues in which the cancer originated will be the target of
reproduction surgery and radiation as well as targeted chemotherapy. The
Musculoskeletal (2) Musculoskeletal normal tissue structures and sites in the region (lymph
Skin (1) Dermatology, nodes) are at risk and often have reactions to the afore-
Lymphatics mentioned modalities, especially in concurrent regimens.
Lymphoid sites (4) Allergy, Immunology Multiagent chemotherapy combinations are designed to
Bone marrow (1) Blood, Bone marrow
diffuse the toxicity and can elicit systemic responses he-
matologically. Remote sites from the cancer can be affected,
Hemorrhage, bleeding
i.e., heart (Adriamycin), kidney (Cisplatinum), etc.
Infection, coagulation
a
The practice of dividing cancer into ‘‘early versus late’’
AJCC Cancer Staging Manual anatomic terms
b was based on the progression from a localized stage to an
LENT/SOMA applies to the number of normal tissue sites and
subsites that are graded for toxicity and are in parentheses advanced stage. In a parallel fashion adverse effects also
c
NCI CTC v3.0 are the basis for the physiologic terms. There are a progress from ‘‘acute to late’’. Just as cancer is staged
number of unique terms in CTC v3.0 as syndromes, second malig- before treatment, the normal tissues—structure and func-
nancies, growth and development that do not fit into a hybrid ana-
tion—need to be noted for baseline values and the presence
tomic/physiologic systems nomenclature
of co-morbidities.
The proper staging of cancer applies to accurate
correlations with gradations of toxicity and at this time recording of the status of host normal tissues and serves a
should not override the other criteria when assigning grade. number of related objectives, such as:
a. Selection of a corrective therapeutic intervention
b. Estimation of eventual prognosis
4 Normal Tissue/Organ TNM Taxonomy c. Assistance in evaluation of results of the intervention
for Adverse Effects of Cancer Treatment d. Facilitates exchange of data amongst investigators
e. Of special importance to cancer control is establishing
4.1 TNM Language the therapeutic ratio.

There is logic for adopting the TNM nomenclature for

normal tissue/organ adverse effects following cancer treat- 4.3 New Definitions of TNM Applied
ment. The TNM language was introduced to allow for to Adverse Effects of Normal Tissue
consistency in the classification and staging of cancer. The
adoption by the AJCC and the UICC 50 years ago has The conceptual design of the NTNM is similar to tumor
enabled oncologists worldwide to stratify patients, allow for spread into 3 compartments: primary tumor site, regional
multidisciplinary communication, better treatment deci- nodes, and systemic dissemination. The adverse effect of
sions, and more accurate end results reporting. With a cancer treatment can be confined to the anatomic site of
Biograding of Normal Tissue TNM Toxicity Taxonomy 97

Table 3 Somatization of CTCAE v3.0

Mild Moderate grade 2+ Severe grade 3+ Life threatening grade 4+
grade 1+
S Asymptomatic Symptomatic usually Persistent symptoms Refractory symptoms
Minimal symptoms Marked symptoms Intensive symptoms Symptoms unresponsive to
medication
O Transient signs Intermittent signs Symptoms apparent Advanced persistent signs
Functionally intact Function altered Function impaired Function collapsed
M No interventions Non-invasive intervention Interventional radiology Rad life saving surg
Occasional medication Continuous medication Surgical correction Intensive care unit
Occasional non-narcotic Regular non-narcotic Occasional narcotic Parenteral narcotic
A Normal laboratory values Abnormal laboratory Very abnormal lab Pailing lab values
Borderline low, Values, Lab values not Potentially lethal
Correctable Correctable Correctable BM \75 %
BM cellularity \25 % B.M. cellularity [25–50 % BM
decrease cellularity [50 %, \75 %
ADL ADL regular ADL Altered ADL impaired ADL extremely poor
QOL KPS 80–100 KP 60–75 KP 30–50 KP 10–25
Fully ambulatory Symptomatic, in bed \50 % Symptomatic, in 100 % bedridden
day bed [50 %

cancer origin or extend to involve other structures in the Grade 2 +: Symptomatic, moderate findings clinically or
neighboring region or be a generalized or systemic toxic in laboratory, that may alter functional endpoints without
effect. impact on quality of life (QOL) or activities of daily living
NT = The normal Tissue, anatomic structure, organ in (ADL) Medications and interventions can be used and be
which the cancer arose and spreads initially. useful.
NN = Neighboring or surrounding normal tissues or Grade 3 +: Effects are indicative of severity of symptoms
organs, viscera that are not involved by the tumor and in the and signs, which persist over time, and disruption of
regional nodal drainage zone. mobility, working, and numerous functional endpoints.
NM = SysteMic effects that are generalized and include More serious intervention as hospitalization or surgery is
hematologic, hepatic toxicity, weight loss. often indicated.
Progression of the adverse effect can be designated Grade 4 +: Effects are potentially life threatening, cata-
numerically and becomes the operational taxonomy unit. strophic, disabling, and result in loss of limb, bowel, and
organ function.
Some more important principles established in CTC v3.0
4.4 Assigning the Grade for Progression are equally applicable to this proposed NTNNNM taxonomy:
• Acute and late effects merged in one system and applied
The progression of a malignancy over time is designated by with restrictive time applications
the assignment of numbers 1, 2, 3, 4 as subscripts to T and • The system applies equally to all modalities
N, the primary tumor and nodal compartments, respectively. • The duration or chronicity should be determined by serial
In an analogous fashion, the translation of late effects into a longitudinal protocol studies.
scale that allows for progression over time is important. The When multiple normal structures are affected each will
general guidelines are in the construction of criteria. be evaluated separately and be given a summary score.
The operational taxonomic unit (OTU) is the grade When multiple normal structures are involved and then
assigned as applied according to criteria in CTCAE v3.0 or compiled, a global toxicity score is derived.
LENT-SOMA which is 1 ? Mild, 2 ? Moderate,
3 ? Severe, or 4 ? Life threatening and will be determined
by the degree of toxicity at each anatomic site, organ. 4.5 Classification According to Evidence
Grade 1 +: Asymptomatic, signs are minimal and not for Certainty of Grade
interfere with functional endpoints, nor impede mobility.
Most often, management is restrained; interventions and As in cancer classification there are 4 types of classification
medication are not required. depending on the diagnostic procedures and the relationship
98 A. M. Trotti and P. Rubin

to the cancer treatment versus an intervention to manage the Summary Score For Specific
adverse effect. Clearly, the adverse normal tissue effect can Organ Time Course in Longitudinal
be assessed before treatment, during and immediately after Study
multimodal treatment. 3.5
a. Clinical classification is based on physical examination, 3.0

Grade of Toxicity
imaging often with CT or MRI, endoscopy, and routine 2.5
laboratory procedures. Minimal invasive procedures as 2.0
needle aspiration are useful and allowable. Most baseline 1.5
values for vital normal tissues and assessments of acute
1.0
and subacute reactions to multimodal treatment are in
0.5
this category CNTNM.
0.0
b. Pathologic classification requires an invasive procedure 0 0.25 0.5 1 2 3 4 5
and as in cancer staging an adverse chemoradiation Time (years)
effect may require a surgical intervention and resection.
Even surgical handling of vasculocompromised tissues Fig. 2 Summary toxicity grade. The summary toxicity grade for a
may precipitate a necrotizing reaction as in exploring specific effect is a function of the grade of the effect over time. This
can be recorded in 3 different parameters: (1) Maximal toxicity grade,
adherent bowel at laparotomy. Such invasive procedures (2) Average grade over time, (3) Area under the curve (grade x time).
are usually performed after multimodal cancer treatment (with permission from Rubin et al. 2007)
to rule out recurrent cancers, which can masquerade as a
late effect. PET or SPECT, MRI/MRS are valuable for
establishing radiation sequelae as a confirmatory tissue divided into subsites (50–60) multiplies the elements and
diagnosis is critical (Tawfiq et al. 2000; Bragg et al. challenges investigators to offer a Summary Grade for
2002). Biopsies, especially generous ones, may precipi- reporting outcomes. LENT-SOMA has a similar complex
tate severe necrosis and need to be done with caution. and detailed compilation of criteria. This has often been
c. Retreatment classification could apply to salvage can- circumnavigated by utilizing the abbreviated late effects
cer treatment as well as management intervention to scales of the RTOG/EORTC cooperative groups. The
ameliorate the adverse effect. Either sophisticated operational taxonomic unit (OTU) is the number assigned to
imaging as PET/SPECT or MRI/MRS can be of value to the grade of toxicity; however, the adverse late effect can
distinguish recurrence or persistence of cancer versus vary over time. The biocontinuum of acute/late effects has
normal tissue necrosis (Tawfiq et al. 2000; Bragg et al. been confirmed both in the laboratory measuring function in
2002) RNTNM. the clinic with physiologic testing. There are numerous
d. Autopsy classification: If a death is attributed to an possibilities for selecting the OTU or summary grade of a
adverse effect usually life threatening (4 +) and fatal specific organ system as a function of time in a longitudinal
(5 +), autopsy is mandatory to exclude incidental co- protocol (Fig. 2). When radiation is combined with che-
morbidities. According to Fajardo et al. there are no motherapy, the variations in toxicity are illustrated as a
pathognomic microscope features but certain constella- function of time (Fig. 3) (Forestiere et al, 2003).
tion of radiation/chemotherapy stigmata and again ruling
out cancer recurrence is essential (Husband and Reznek
1998) ANTNM.
e. Prefixes and suffixes may be added for certain 5.2 Global Toxicity Score of Multiple Organs
circumstances:
m suffix indicates multiple structures, sites and organs Stage grouping is an important aspect of the staging of
may express the adverse effect, i.e., TN(m)M. cancer and applies directly to adverse effects involving
y prefix indicates evaluation performed during or fol- multiple sites. Because in cancer staging there are 4T’s,
lowing initial multimodal therapy, i.e., ypTNM. 3 N’s, and 2 M’s, there are 24 possible combinations. To
recluster TN into the four Stages I, II, III, and IV would be a
challenge when adverse effects are collated in multiple
5 Summary Toxicity Grade normal tissues.
The global toxicity score would be the compilation of the
5.1 NT NN NM Summary Grade summary grades for each normal tissue assessed. With more
than one structure in each of the defined zones, i.e., NT for
The expansion of CTC v3.0 approaches a thousand site of cancer origin or
descriptors involving 15–20 major organ systems, which if NN for site of neighboring tissue
Biograding of Normal Tissue TNM Toxicity Taxonomy 99

of acute effects reported by a typical patient, on average,

over a defined acute-events interval. T scores from multiple
acute-risk intervals (e.g., induction chemotherapy, radio-
therapy, and early follow-up) can be added to derive an
overall T value (e.g., Tinduction ? Tradiotherapy ? Tacute/recov-
ery interval = Toverall).
3.2 A = mean number of grade 3–4 late events for a
treatment regimen during a defined late-toxicity risk period.
The patient’s A score is the number of high-grade events
reported for that individual during the defined late-risk
Fig. 3 The time course of acute and chronic esophagitis; Group interval. Mean A scores, therefore, represent the number of
1 = standard thoracic RT alone or with induction chemotherapy, late effects reported by a typical patient, on average, over a
Group 2 = standard thoracic RT with concurrent chemotherapy, defined late-events interval. In principle, A scores from one
Group 3 = twice daily RT with concurrent chemotherapy. With or more late-risk intervals (e.g., years 1 ? 2 + 3) can be
permission (Forestiere et al. 2003)
added together to derive an overall A value (e.g., A3-year).
NM for systemic toxicities of system. However, for this preliminary work, we defined the late
The recommendation is to score each summary grade as events interval as beginning with the 4-month follow-up
noted and then add the subscripts. Thus, the global toxicity visit and including all subsequent visits (until death or
is the sum of subscripts and creation of stage grouping censoring) combined into a single late-risk interval).
similar to staging cancers. 3.3 M = risk of death attributed to cancer treatment
Stage I = T1N1M1 or T2N1M0 or T3 N0M0 during a given risk period. M is calculated as the cumulative
Total = 1–3 incidence of death due toxicity, from study entry and up to
Stage II = T2N2M2 OR T3N1M0 OR T1N3M1 30 days after completion of cancer treatment, if the cause of
Total = 4–6 death was attributed to treatment by the investigator.
Stage III = T3N3M3 or T4N2M1 or T2N2 ? 2M1 3.4 E = end results.
Total = 7–9 All established methods for analyzing late-events data
Stage IV = T4N4M4 or T3N2M1 or T2N2 ? 2+3M1 ? 2 suffer from the inherent limitation of having small number of
Total = 10–16, or events. Traditional summary approaches to late events
Stage V Total [ 16. analysis include crude incidence and actuarial methods
Obviously, these recommendations and generalizations where all types of late events are consolidated into overall
will need compilation of data from clinical trials before an rates of high-grade injuries. These methods do not capture
accurate global score can be arrived at. the duration of injuries and, therefore, tend to overestimate
injury rates. An area-under-the-curve (AUC)-type approach
is the only method that can measure average duration of an
5.3 Tame injury, but this method is applicable only to individual injury
terms (e.g., fibrosis, necrosis). TAME methods can simul-
TAME is a new reporting system to summarize toxicity taneously summate multiple terms and have the potential to
burden of cancer treatment advocated by Trotti et al. con- measure duration by summing adverse-event burden over
solidating traditional adverse event data into three risk multiple, smaller (e.g., every 3 months) risk intervals,
domains: T (Toxicity, acute short-term): A (Adverse long- thereby representing time factors in a more realistic manner
term late) and M (Mortality risk generated) and E (End (including duration via capture of onset and resolution)
results). TAME definitions use a new set of terms, defini- compared with traditional actuarial approaches (Fig. 4).
tions, endpoints and calculation algorithms (Trotti et al. Traditional methods for summarizing adverse events
2007). systematically exclude important data, giving an inaccurate
3.1 T = mean number of grade 3–4 acute events for a impression of the toxicity burden in complex multimodality
treatment regimen during a defined period of acute toxicity trials. By contrast, T values use data on all high-grade
risk. Mean raw T values for a given treatment group can be adverse events. T values are proportional to the intensity of
calculated by taking the mean of all T scores generated treatment, showing 500 % increase between treatment
from individual patient data (JPD). An IPD T score is groups in acute toxicity burden in RTOG trials of head and
derived by summing the number of high-grade (3 or 4) neck cancer done during this study interval. TAME reporting
acute events reported on that individual for a defined acute- provides a concise and uniform method to compare relative
risk interval. Mean T scores, therefore, represent the range risk among treatment options (Trotti et al. 2007).
100 A. M. Trotti and P. Rubin

Fig. 4 The acute toxicity

relative risk values (T) and
relative max grade values for 13
head and neck cancer treatment
groups ranked by relative risk
(With permission from Trotti
et al. 2007)

American Joint Committee on Cancer (AJCC) (2002) Cancer staging

6 Therapeutic Ratio Determination manual. 6th ed. Springer
Anacak Y, Yalman D, Ozsaran Z et al (2001) Late radiation effects to
and Decision Making the rectum and bladder in gynecologic cancer patients: the
comparison of LENT/SOMA and RTOG/EORTC late-effects
In summary, a compelling reason for developing a parallel scoring systems. Int J Radiat Oncol Biol Phys 50:1107–1112.
TNM system of staging adverse effects of normal tissue is http://ctep.info.nih.gov/CTC3/ctc.htm. Accessed 1 April 2003
Bragg DG, Rubin P, Hricak H (2002) Oncologic imaging, 2nd edn.
to determine therapeutic ratios. An excellent illustration is WB Saunders Company, Philadelphia, PA
when there is no survival advantage in competitive multi- Cox JD, Stetz J, Pajak TF (1995) Toxicity criteria of the Radiation
modal treatment programs but one has less adverse effects. Therapy Oncology Group (RTOG) and the European Organization
A recent report on advanced laryngeal cancers favored for Research and Treatment of Cancer (EORTC). Int J Radiat
Oncol Biol Phys 31:1341–1346
concurrent administration of cisplatinum and 5-fluorouracil CTCAE v3.0 (2003) Development of a comprehensive grading system
followed by radiotherapy or surgery with primary endpoint for the adverse effects of cancer treatment. Semin Radiat Oncol
being laryngeal preservation as well as local regional con- 13(3):176–181
trol, the latter being the same in other arm (Fajardo et al. Davidson SE, Burns M, Routledge J et al (2002) Short report: a
morbidity scoring system for clinical oncology practice: question-
2001). Ideally, cure without complications is a function of naires produced from the LENT SOMA scoring system. Clin Oncol
cancer stage and the aggressiveness of the treatment. The (R Coll Radiol) 14:68–69
classic figure of therapeutic ratio is a dose–response curve Davidson SE, Burns MP, Routledge JA et al (2003a) The impact of
based on cancer control versus normal tissue injury with radiotherapy for carcinoma of the cervix on sexual function
assessed using the LENT SOMA scales. Radiother Oncol
displacement to the left for cancer control and to the right 68:241–247
for the normal tissue. The reality is the cancer control Davidson SE, Burns MP, Routledge JA et al (2003b) Assessment of
curves are displaced to the right as function of cancer stage morbidity in carcinoma of the cervix: a comparison of the LENT
and cancer treatment becomes more aggressive leading to SOMA scales and the Franco-Italian glossary. Radiother Oncol
69:195–200
more complications, displacing normal tissue effects to the Denis F, Garaud P, Bardet E et al (2003) Late toxicity results of
left. Thus, toxicity of treatment often increases as the cancer the GORTEC 94–01 randomized trial comparing radiotherapy
stage advances and the therapeutic window is often closed. with concomitant radiochemotherapy for advanced-stage oro-
pharynx carcinoma: comparison of LENT/SOMA, RTOG/EO-
RTC, and NCI-CTC scoring systems. Int J Radiat Oncol Biol
Phys 55:93–98
References Fajardo LF, Berthrong M, Anderson RE (2001) Radiation pathology.
Oxford University Press, USA
Federative Committee on Anatomical Terminology (FCAT) (1998)
American Cancer Society (1995) Cancer facts and figures. Atlanta, Terminologia Anatomica: International Anatomical Terminology.
American Cancer Society Stuttgart, Georg Thieme Verlag
Biograding of Normal Tissue TNM Toxicity Taxonomy 101

Fedyk ER, Jones D, Critchley HO et al (2001) Expression of stromal- Rubin P, Constine LS, Marks L, Okunieff P (eds) (2007) Late Effects
derived factor-1 is decreased by IL-1 and TNF and in dermal of Cancer Treatment on Normal Tissues: Cured I, Lent. Springer,
wound healing. J Immunol 166:5749–5754 Berlin Heidelberg, New York
Fehlauer F, Tribius S, Holler U et al (2003) Long-term radiation Rubin P, Johnston CJ, Williams JP et al (1995b) A perpetual cascade
sequelae after breast-conserving therapy in women with early-stage of cytokines postirradiation leads to pulmonary fibrosis. Int J
breast cancer: an observational study using the LENT-SOMA Radiat Oncol Biol Phys 33:99–109
scoring system. Int J Radiat Oncol Biol Phys 55:651–658 Tawfiq N, Lagarde P, Stockle E, et al (2000) Conservative treatment of
Forestiere AA, Goepfert H, Maor M et al (2003) Concurrent extremity soft tissue sarcomas. Functional evaluation using LENT-
chemotherapy and radiotherapy for organ preservation in advanced SOMA scales and Enneking scoring. Cancer Radiother (French)
laryngeal cancer. N Engl J Med 349:2091–2098 4:421–7
Hoeller U, Tribius S, Kuhlmey A et al (2003) Increasing the rate of Trotti A (2002) The evolution and application of toxicity criteria. Sem
late toxicity by changing the score? A comparison of RTOG/ Radiat Oncol 12:1–3
EORTC and LENT/SOMA scores. Int J Radiat Oncol Biol Phys Trotti A, Bentzen MS (2004) The need for adverse effects
55:1013–1018 reporting standards in oncologyclinical trials. J Clinc Oncol
Husband JES, Reznek RH (1998) Imaging in oncology. ISIS Medical 22:19–22
Media, Oxford Trotti A, Rubin P (2003) Introduction. Sem Radiat Oncol 13:175
LENT SOMA scales all for anatomic sites. (1995). Int J Radiat Oncol Trotti A, Byhardt R, Stetz J et al (2000) Common toxicity criteria:
Biol Phys 30;31(5):1049–1091 Version 2.0. an improved reference for grading the acute effects of
Mercado AM, Padgett DA, Sheridan JF et al (2002) Altered kinetics of cancer treatment: impact on radiotherapy. Int J Radiat Oncol Biol
IL-1, Il-1, and KGF-1 gene expression in early wounds of Phys 47:13–47
restrained mice. Brain Behav Immun 16:150–162 Trotti A, Colevas DA, Setser A et al (2003) CTCAE v3.0: Develop-
Miller AB, Hoogstraten B, Staquet M et al (1981) Reporting results of ment of a comprehensive grading system for the adverse effects of
cancer treatment. Cancer 47:207–214 cancer treatment. Semin Radiat Oncol 13:176–181
Movsas B (2003) Quality of life in oncology trials: a clinical guide. Trotti A, Pajak T, Gwede C, Paulus R, Cooper J, Forastiere A, Ridge J,
Semin Radiat Oncol 13:189–202 Watkins-Bruner D, Garden A, Ang K, Curran W (2007) TAME:
Petak I, Houghton JA (2001) Shared pathways: death receptors and development of a new method for summarising adverse events of
cytotoxic drugs in cancer therapy. Pathol Oncol Res 7:95–106 cancer treatment by the Radiation Therapy Oncology Group.
Routledge JA, Burns MP, Swindell R et al (2003) Evaluation of the Lancet Oncol 8(7):613–624. Pubmedid: 17543584
LENT-SOMA scales for the prospective assessment of treatment Werner-Wasik M, Pequignot E, Leeper D, Hauck W, Curran W Jr
morbidity in cervical carcinoma. Int J Radiat Oncol Biol Phys (2000) Predictors of severe esophagitis include use of concurrent
56:502–510 chemotherapy, but not the length of irradiated esophagus: a
Rubin P (2001) Clinical Oncology, 8th edn. WB Saunders, Philadel- multivariate analysis of patients with lung cancer treated with
phia, PA nonoperative therapy. Int J Radiat Oncol Biol Phys 48(3):
Rubin P, Casarett GW (1968) Clinical Radiation Pathology. Saunders, 689–696
Philadelphia, PA World Health Organization Icd 10 (1992) International Statistical
Rubin P, Constine S, Fajardo L et al (1995a) Overview of Late Effects Classification of Diseases and Related Health Problems. 10th ed.
of Normal Tissues (LENT) scoring system. Int J Radiat Oncol Biol American Psychiatric Publishing
Phys 31:1041–1042
 Understanding and Predicting Radiation-
Associated Normal Tissue Injury: A Global
and Historical Perspective
Michael T. Milano, Philip Rubin, and Lawrence B. Marks

Contents Abstract
Radiation injury to normal tissues has been recognized
1 Introduction.......................................................................... 103 for many decades, and is dependent upon a multitude of
2 Factors that Influence the Risk of Radiation-Normal factors, including radiation dose and fractionation and
Tissue Injury ........................................................................ 104 volume of tissue or organ exposed to radiation. Since the
2.1 Inherent Cell Sensitivity, Tissue Architecture, and their 1980s, technologic innovations in imaging, radiation
Interaction .............................................................................. 104
planning and radiation delivery have allowed for more
2.2 Distribution of Function ........................................................ 107
2.3 Different Paths, Different Organs, Same Outcomes ............ 107 accurate quantification of dose delivery to tissues, which
2.4 Other Confounding Factors................................................... 108 in turn has resulted in a burgeoning research effort to
3 The Impact of Endpoint Selection..................................... 108 understand and quantify risks to normal tissues after
radiation. This chapter will broadly discuss factors that
4 Tolerance Dose and Dose/Volume/Outcome
potentially influence the risk of radiation-normal tissue
Considerations...................................................................... 108
4.1 Historical Background........................................................... 108 injury, provide a framework for understanding the
4.2 The Incorporation of 3D Dose/Volume Information differences and similarities between organs in their
into Clinical Guidelines......................................................... 111 response to radiation, and describe additional consider-
4.3 Dose-Volume Histograms and Associated Figures
ations that might be more relevant in the future. It also
of Merit .................................................................................. 113
4.4 Shortcomings of DVHs ......................................................... 117 reviews the major efforts in past 2 decades, namely the
1991 Emami, Lyman et al. review and the recent 2010
5 Major Differences between the QUANTEC
and Emami/Lyman Reviews............................................... 118 QUANTEC reviews, which compiled published data,
summarized this data, and provided recommended organ
6 Challenges for Future Study .............................................. 119
dose/volume constraints.
References...................................................................................... 120

1 Introduction

The potentially toxic effects of radiation therapy on normal

tissues have been recognized for decades. Normal tissues
immediately adjacent to targets are at risk, as are normal
tissues well displaced from the target that are nonetheless in
the path of the treatment beam. Given the penetrating nature
of therapeutic radiation beams, incidental irradiation of
nontarget tissues is an unavoidable physical reality of
M. T. Milano (&)  P. Rubin modern external beam radiation therapy. The radiation
Department of Radiation Oncology, University of Rochester treatment planning process is an attempt to deliver a ther-
School of Medicine and Dentistry, 601 Elmwood Ave,
Box 647 Rochester, 14642, NY, USA apeutic dose to the target tissues while ‘‘redistributing the
e-mail: [email protected] dose’’ to normal tissues, in the hope of minimizing risks.
L. B. Marks The total elimination of risk is not possible. The physician
Department of Radiation Oncology, University of North Carolina, therefore needs to have a firm understanding of the
Chapel Hill, NC, USA

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 103
DOI: 10.1007/978-3-540-72314-1_8, Ó Springer-Verlag Berlin Heidelberg 2014,
104 M. T. Milano et al.

predictors for radiation-induced normal tissue injury. This similarities between organs in their response to radiation,
knowledge helps to guide the decisions as to ‘‘where and and describe additional considerations that might be more
how-much’’ radiation will be delivered to the different relevant in the future.
organs.
The art of radiation treatment planning largely involves
the decisions on how to distribute the ‘‘undesired dose’’ 2 Factors that Influence the Risk
within the surrounding normal tissue. This is largely of Radiation-Normal Tissue Injury
accomplished by selecting desirable beam orientations,
energies, and shapes. Other approaches to minimize dose 2.1 Inherent Cell Sensitivity, Tissue
deposition to the surrounding normal tissues include the use Architecture, and their Interaction
of compensators or segmented fields, modulated radiation
beams (e.g., intensity-modulated radiation therapy— The underlying biological/physiological mechanism for
IMRT), improving targeting accuracy (i.e., image-guided radiation-induced normal tissue injury is not fully under-
radiotherapy [IGRT] and stereotactic body radiotherapy/ stood. Historically, radiation sensitivity was modeled with
stereotactic ablative radiotherapy [SBRT/SABR]) and/or respect to inherent cell sensitivity. For example, Casarett
using proton or other ion therapy. Even using the most postulated radiation sensitivity occurring along a spectrum,
modern radiation planning and delivery approaches, for a with uncommitted stem cells (i.e., skin and intestinal basal
given geometric situation (i.e., tumor surrounding or par- layers, hematopoietic blastic cells) and committed stem
tially surrounding a critical organ), often there is little that cells (intermediate hematopoietic cell) exhibiting relatively
can be done to reduce suprathreshold dose delivery to more radiation sensitivity than microcirculation, connective
critical organs without compromising target coverage. tissue, and stroma cells, reverting mature cells (i.e., liver,
Radiation Oncologists have long understood that the risk kidney, pancreas), and fixed mature cells (i.e., neurons)
for radiation-associated normal tissue injury is dependent (Rubin and Casarett 1968). Similarly, Michalowski also
on a variety of factors, including: postulated a spectrum of sensitivity with hierarchal stems
1. The organ’s inherent sensitivity to radiation (related to cells and functional cells representing opposite ends of the
the cellular sensitivity as well as microscopic/macro- spectrum (Michalowski et al. 1984). These models did not
scopic architecture/anatomy); account for the heterogeneity of cells comprising most
2. The volume of normal tissue irradiated; normal tissues, which generally include parenchymal cells
3. Total radiation dose delivered; with differing functions (i.e., alveolar cells and type II
4. The number of fractions delivered (i.e., dose per pneumocytes; or neurons and glial cells), connective tissue
fraction); cells (i.e., fibroblasts), cells constituting the vascular supply,
5. The time interval during which the entire radiation and hematopoietic cells. Broadly speaking, radiation dam-
course is delivered; age may result from injury to the primary parenchymal cells
6. The dose rate for each fraction of the delivered radiation (e.g., hepatocytes, neurons), injury to the supporting struc-
treatment; tures (e.g., vasculature, myelin) or a combination of
7. Pre-existing medical conditions that may influence mechanisms. Alternative mechanisms may also exist (e.g.,
response (e.g., different levels of reserve). modifications to local immunity). Since all organs have a
There are also relatively rare known genetic factors vascular supply, all organs should be sensitive to vascular-
(specifically DNA repair defects) that predispose patients to mediated radiation-induced normal tissue injury. The vas-
greater risks of radiation toxicity, and perhaps unknown cular endothelial cells within small vessels are often con-
host/genetic factors as well. sidered the primary target for such injury. For many organs,
Most modern studies of radiation-associated normal tis- there is a marked increase in risk of late effects when the
sue injury consider the dose/volume characteristics as the prescribed dose exceeds approximately 60 Gy (with con-
major determinant of risk. Prior to the wide-spread use of ventional fractionation). This observation is consistent with
computer tomography (CT)-based radiation planning, the the hypothesis that a vascular injury might be the cause of
three dimensional (3D) dose distribution and the 3D anat- such ‘‘high dose’’ injury.
omy were not as well understood. The wide-spread adoption Other organs demonstrate clinical dysfunction at far
of CT-planning, and modern radiation treatment planning lower doses (e.g., the lung at approximately 30 Gy, the
software, has facilitated many dose/volume/outcome kidney at approximately 22 Gy, and the liver at approxi-
studies. mately 33 Gy). This increased sensitivity maybe due to an
This chapter will broadly discuss several of the factors inherent increased sensitivity of one or several of its critical
that influence the risk of radiation-normal tissue injury, components (e.g., parenchymal cells or supporting struc-
provide a framework for understanding the differences and tures), or a reflection of its architecture—the manner in
Understanding and Predicting Radiation 105

Fig. 1 A hypothetical idealized organ made up of 100 cells (circles), organ) changes. If there is 1 cell per FSU (left side), then 50 % of the
exposed to a dose of radiation that will kill (black cells) 50 % of the FSU remain functional. If there are 100 cells per FSU (right side), then
cells. For illustrative purposes, it is assumed that a FSU, represented that FSU would remain functional. The middle panes reflect an
by—boxes, becomes dysfunctional (gray filled boxes) if there are intermediate of 10 cells per FSU, resulting in 70 % FSUs remaining
fewer than 5 cells remaining (i.e., if there are C5 cells remaining, then functional (though conceptually this could range from 50–100 %
the FSU can be repopulated to be functional). Note how the number of depending on the distribution of damage to the 100 cells). Cell
FSU’s that are functional after the radiation changes dramatically as repopulation is not depicted in this figure
the number of cells per FSU (and the total number of FSUs within the

which the cells or vasculature within the organ are cells making up a FSU, therefore, has a profound impact
organized. on the organ sensitivity. (Fig. 1). At one extreme, if there
Two key concepts in the realm of tissue architecture is one FSU for the entire (hypothetical) organ, then that
include the functional subunit (FSU), and the manner in organ is relatively insensitive to radiation since one or
which these FSUs are ‘connected to each other’ to yield the just a few surviving cells can repopulate the entire organ.
overall organ function (e.g., parallel vs. series structure). If there are very few cells per FSUs (at the extreme one
1. Functional subunit: The FSU is the minimum unit that cell per FSU), then the organ is much more sensitive to
can function independently of the remaining organ (Hall radiation. The tissue rescue unit concept (Hendry and
and Giaccia 2012; Marks 1996) originally described by Thames 1986) can be used to describe the minimum
Withers and Taylor (Withers and Taylor 1993). Irrepa- number of FSUs needed to maintain tissue/organ
rable damage to one subunit will render only that subunit function.
dysfunctional. However, surrounding subunits will Thus, the observed global sensitivity of an organ will
remain functional (in the absence of direct radiation depend on the inherent sensitivity of the target cells, as well
damage to the surrounding FSUs). Further, any surviving as the number of target cells within a FSU. For example, in
cell (or minimum complement of cells) within a single the kidney, each nephron has a proximal tubule, loop of
FSU may repopulate its FSU, but not repopulate (or Henle, and the distal tubule that are dependent on each
rescue from ‘death’) a surrounding FSU. The number of other. One might consider the FSU to be the entire nephron,
106 M. T. Milano et al.

Fig. 2 Illustrative comparison

of serial versus parallel organs. In
this figure, the hypothetical
example (depicted in Fig. 1) of
10 cells (circles) per functional
unit (square) is shown, after
radiation in which 50 % of cells
are killed (black circles), and
FSUs with five or more cells
remain functional after radiation.
Figure 2a shows an organ in
which FSUs are arranged in
series; the organ’s function is
dependent upon connectivity to
its neighboring FSUs. For organs
with FSUs arranged in series
(a) damage to 1 or more FSUs (3
are damaged in figure) results in
complete compromise of that
component (i.e., loop of bowel,
or region of spinal cord). For
organs in which FSUs are
arranged in parallel (b) damage
to a portion of FSUs (3 shown in
figure) results in partial, or no
apparent, organ compromise.
Repopulation within the FSUs is
not shown

or more likely, the most sensitive subcomponent of the 2. Organizational structure between FSUs: A related con-
nephron (e.g., perhaps the arteriolar-glomerular interface). sideration is the manner in which FSUs are ‘connected to
The relatively few number of cells per FSU might explain each other’ to yield the overall organ function (Fig. 2).
the sensitivity of the kidney to radiation, despite the large Normal organs can be broadly classified as having a
number of nephrons (or FSUs) within the kidney. FSUs are parallel versus series architecture, analogous to electrical
thus an often-useful construct, though it is not widely circuits (Hall and Giaccia 2012; Marks 1996; Withers
applicable to all organs. Even in the kidney, there are some and Taylor 1993). In parallel organs, regions of an organ
inter-tubule dependencies. For example, the nephrons can- can be damaged without necessarily impairing global
not concentrate urine without the concentration gradient organ function, since the other regions retain function.
created by the other nephrons globally. Just as a surgeon can remove regions of the lung, liver,
Understanding and Predicting Radiation 107

or kidney, without demonstrable impact on global organ regards, but serial in others. For example, for the endpoint
function, large regions of these organs can be similarly of stricture, the bowel may be considered a series organ.
irradiated to ‘‘locally-damaging’’ radiation doses. The Conversely, for the endpoint of ulceration/bleeding, the
global response of such ‘‘parallel organs’’ depends lar- organ may be considered parallel. These distinctions are
gely on the volume of organ affected. There is typically imperfect. The different regions of small bowel are rela-
little effect on global function until a ‘‘critical volume’’ tively homogeneous in function, but there are clearly
of the organ is affected, at which point global organ regional differences. The entire digestive apparatus can be
function can become compromised. considered as a heterogeneous series (e.g., esophagus,
Conversely, in ‘‘series’’ organs, dysfunction of one stomach, intestines).
region may render the entire organ dysfunctional. This
might be the case for nerves, esophagus, intestines, or
bronchi. For example, a stricture in one portion of the 2.3 Different Paths, Different Organs,
esophagus or bowel renders the region of esophagus or Same Outcomes
bowel both proximal and distal to that injury essentially
nonfunctioning. The response of such series organs to Different types of injuries can lead to the same clinical
radiation is most dependent on the maximum dose delivered outcome. For example, damage to the alveoli (small FSUs
to that organ (e.g., a focal hotspot in the spinal cord can organized in parallel), or damage to the trachea (a likely
cause major neurologic dysfunction). larger FSU organized in series) can both lead to shortness of
breath. Similarly, adding another level of complexity,
symptoms such as dyspnea can reflect lung injury, as well as
2.2 Distribution of Function heart injury, chest wall fibrosis, anemia, or any combination
of the above. These realizations make the study of radia-
The above discussion is idealized as many organs as typi- tion-associated normal tissue injury even more complex and
cally not uniform. Thus, organs can be considered to have interesting.
homogeneous versus heterogeneous function throughout. In In summary, one could then think of organs as being
homogeneous organs, different regions of the organ are comprised of FSUs, which are arranged in parallel or series.
relatively functionally equivalent. This might be the case The number of cells per FSU (as a theoretical construct)
for healthy lung, liver, and kidney. Nevertheless, even in describes the inherent radiation sensitivity of the organs
these settings, there may be some regional differences in components, and the arrangement of the FSUs (parallel or
functional importance (e.g., a more favorable ventilation/ series) describes how FSU damage from radiation impacts
profusion ratio in the lung bases versus lung apices). In organ function. It should be recognized that the concept of a
other organs, variations in regional function are readily FSU describes a model used to explain differences in radi-
apparent (e.g., heart, brain). In these organs, the risk of ation sensitivity between organs. The notion that the FSU
radiation-associated injury is also related to the spatial represents a separate functional unit, and that remaining
distribution of radiation dose within the organ (e.g., ‘‘is the cells within the FSU can repopulate the FSU in a sense is
hot spot in the brain stem [critical] vs. the anterior tip of the assigning two conflicting characteristics to the FSU cells:
temporal lobe [less important]). It may not be enough to (Rubin and Casarett 1968) independent organ function and
know that 20 % of the organ is receiving [40 Gy; one may (Michalowski et al. 1984) progenitor cell differentiation to
need also to know which 20 % of the organ is irradiated. functional cells. The FSU construct also does not account
A good example of this phenomenon is the brain. In for other important mediators of late effects, including small
patients treated with radiosurgery, there is a nice relation- vessel vascular injury and inflammation. While all organs
ship between the prescribed radiation dose, and the inci- possess similar vascularity, conceivably, differences in
dence of radiographic-defined radiation injury. For this radiation sensitivity between organs could reflect differ-
endpoint, the risks are relatively similar in different regions ences in vascular redundancy or angiogenesis after radia-
of the brain. However, for the endpoint of symptomatic tion. The inflammatory reaction after radiation to some
injury, the location of the effected region is critical (Flick- extent is systemic, and therefore similar for all organs (as
inger et al. 2000). manifested by the release of serum cytokines). However,
Table 1 illustrates the association between the concepts local inflammatory reactions, or inflammation in the setting
of parallel versus series, and heterogeneous versus homo- of specific organ conditions may result in different sus-
geneous function. Note that the distinctions are not always ceptibilities to late effects. Figure 3 depicts the complicated
clear. Some organs may be considered parallel in some multifaceted nature of late effects after radiation.
108 M. T. Milano et al.

Table 1 Association between concepts of parallel versus series and which these different types of endpoints are related to each
heterogeneous versus homogeneous function other is variable and organ-dependent. For example, end-
Homogeneous Heterogeneous points of interest among patients undergoing thoracic radi-
Parallel Liver, Kidney, Lung, Brain, lung with COPD, Heart, ation include shortness of breath (clinical), pulmonary
Alveoli (Gas Spinal cord function tests (analytic), and chest CT (imaging). Patients
Exchange) who have a decline in pulmonary function tests may be
Series Small bowel, Nerve, Optic chiasm and nerves, more likely to complain of shortness of breath compared to
Esophagus Digestive Tract, Lung airways
patients without a decline in pulmonary function tests.
(gas conduction)
However, the presence of a change on radiographs may or
may not be associated with the complaints of shortness of
2.4 Other Confounding Factors breath.
Furthermore, specific clinical endpoints may reflect
The study of radiation-associated normal tissue injury is either a regional injury (e.g., structure of the esophagus), or
also confounded by the increasing use of systemic agents a global dysfunction (e.g., hepatic renal insufficiency). Most
for cancer therapy. Concurrent systemic agents (i.e., che- analytic endpoints are reflective of global organ function
motherapy) with radiation are used for the treatment of (e.g., liver function tests, creatinine, pulmonary function
many malignancies, to augment the effect of radiation. tests). There are some association between the different
Incorporating chemotherapy into predictive models is endpoints and their impact on global function, and their
challenging, as the dosing/schedules of these drugs vary, relationship with each other, and the organ’s structure
and there are often new agents being added into the mix. (parallel vs. series, and heterogeneous vs. homogeneous).
The exact timing of the drugs relative to the radiation For example, imaging typically can detect changes in
treatment delivery likely impacts the degree of interaction. regional structure/anatomy. Again in the lung, there is very
Furthermore, chemotherapy in the absence of radiation can good data that relates regional radiologic changes (in tissue
result in late normal tissue effects (i.e., cardiotoxicity from density [CT] or blood perfusion) to regional radiation dose
anthracyclines). Often patients receive chemotherapy prior (Mah and Van Dyk 1988; Marks et al. 1997; Ma et al. 2009,
to or after radiation, and accounting for the possible inter- 2010; Boersma et al. 1993). However, the degree to which
actions of these different therapies can be complicated. the ‘‘average’’ regional radiographic change relates to the
Likewise, prior surgical interventions can result in late change in global function is far less clear. In several studies,
complications, often resulting from post-surgical scarring the sum of regional injuries (or the average change in
and vascular disruption, as can direct effects from the tumor regional imaging) is only weakly related to changes in
itself, presenting even more confounding variables. global function (Fan et al. 2001a, b; Seppenwoolde et al.
The risk of delayed effects is further compounded by the 2004). Further, the relationship between the sum of regional
possibility of ‘‘consequential late effects,’’ which can injuries and changes in global function will necessarily
develop from healing that occurs after a severe acute radi- relate to the distribution of a function within the organ (i.e.,
ation reaction. For example, in a study from Duke, the is the ‘‘global’’ function impacted equally by each region of
major determinant of late esophageal stricture was the the lung). Figure 4 depicts an example of the interaction
severity of the acute reaction (Ahn et al. 2005). Conse- between the various endpoints after radiation to the lung.
quential late effects have also been described in the rectum
and other organs with a brisk acute reaction (Fig. 3).
4 Tolerance Dose and Dose/Volume/
Outcome Considerations
3 The Impact of Endpoint Selection
4.1 Historical Background
A variety of approaches can be taken to define and score
radiation-associated normal tissue injury, and the approach 4.1.1 Introduction: Historical Perspective,
taken will impact the reported injury rate. Endpoints might Background, and Significance
be broadly categorized as symptomatic/clinical (e.g., The need to precisely measure and quantify the radiation
shortness of breath), imaging-based (e.g., changes on chest dose became evident with its discovery by Roentgen and the
X-ray or CT), or analytic (e.g., reduction of pulmonary Curies. The early pioneers unwittingly exposed themselves
function tests or alterations in serum markers such as BUN to radiation in exploring its possible applications in medi-
and creatinine to assess renal function, liver enzymes, and cine and ultimately realized that radiation resulted in
albumin to assess liver function and TSH and thyroid hor- adverse normal tissue reactions. The initial observation of
mone levels to assess thyroid function). The degree to skin erythema and alterations in blood/bone marrow
Understanding and Predicting Radiation 109

Fig. 3 There are many variables

which impact development of
late effects, as described in the
text

translate in time to neoplasia, which proved fatal. Radiation doses’’ and ‘‘normal tissue tolerance doses’’. Figure 5
claimed the lives of its researchers who became its ‘‘mar- depicts a hypothetical dose–response curves for tumor
tyrs,’’ sacrificing themselves to uncover its potential uses. control and normal tissue complication; ideally the thera-
Through decades of research, the benefits of therapeutic peutic dose is chosen to maximize tumor control while
radiation were realized, and ultimately, the field of Radia- minimizing toxicity risks, as graphically demonstrated by
tion Oncology was born. the ‘‘uncomplicated tumor control’’ curve.
Radiation is a double-edged sword as a treatment The biometric of normal tissue tolerance doses was ini-
modality in that it cures and injures simultaneously. In the tially described by Rubin and Casarett (Rubin and Casarett
early years of therapeutic radiation, with the use of rela- 1968, 1972) and remains a commonly used metric. The
tively low energy radiation, skin toxicity was the primary minimal tolerance doses, with respect to specified toxicity
dose-limiting factor. With the introduction of megavoltage endpoints, were described by the TD5/5 (i.e., the dose which
radiation therapy, the radiocurability of a large variety of results in a 5 % severe complication rate within 5 years)
cancers became possible due to improved capability of and the TD50/5 (i.e., the dose that results in 50 % severe
delivering therapeutic dose to greater depth. Historically, complication rate in 5 years). Radiation oncologists are
radiation therapy fields/doses were selected empirically, often faced with the clinical dilemma whereby the optimum
based largely on experience. Physicians relied on clinical dose for tumor control exceeds the normal tissue dose tol-
intuition to select field sizes/doses. They understood that erance of what are considered vital ‘‘dose limiting normal
these empiric guidelines were imprecise and did not fully tissues’’. With the impetus of defining therapeutic ratios in
reflect the underlying anatomy, physiology, and dosimetry. RTOG protocols, Rubin, Phillips, et al. defined tolerance
doses into three categories: (Rubin and Casarett 1968,
4.1.2 Dose-Limiting Normal Tissues 1972).
With the widespread adoption of megavoltage radiation, Class 1: Organs in which radiation lesions can be fatal or
there arose a need to better understand the tolerance of result in severe morbidity (See Table 5 in Chap. 2 ).
internal organs to radiation. The National Cancer Institute Class 2: Organs in which radiation lesions can result in
(NCI) mandated and sponsored research conferences to moderate to mild morbidity, generally late effects are
explore dose/time relationships to define ‘‘tumor lethal compatible with survival (see Table 6 in Chap. 2).
110 M. T. Milano et al.

Fig. 4 A schematic representing the impact of localized radiation to symptoms, objective declines in pulmonary function) or cytokine
the lung on global subjective and objective pulmonary function. release. A similar construct could also be considered for the heart
Regional lung radiation is associated with reasonably well described where there are also dose-dependent changes in regional myocardial
dose-dependent regional imaging changes. The sum of regional perfusion, and where the presence/severity of these regional perfusion
injuries (perhaps reflected by the regional imaging changes) is weakly defects is perhaps weakly related to changes in regional function (e.g.,
associated with changes in global lung function (e.g., pulmonary regional wall motion) or global function (e.g., ejection fraction)

Class 3: Organs in which radiation lesions result in mild, 2. TV50–90: 50–90 % of the organ volume irradiated above
transient, reversible effects, and in no morbidity (see suprathreshold doses can result in a life-threatening or
Table 7 in Chap. 2). lethal complication.
There are generally two levels of critical volume for
4.1.3 Tolerance Volumes (Rubin et al.) dose-limiting vital organs. The gastrointestinal tract, prox-
The concept of tolerance volume is defined in the same imal tracheal-bronchial airway, and central nervous system
fashion as tolerance dose. The dose to a given volume or (CNS) can have disastrous outcomes after small volumes
organ/tissue frequently proves to be more predictive of (TV 5–10 %) are exposed to doses exceeding TD5–50.
complication risks. It is possible to obliterate or lose a However, it is important to note that necrotic bowel and
certain volume of a vital organ with suprathreshold doses, necrotic CNS foci can occasionally be resected success-
akin to surgical resection (i.e., stereotactic radiation sur- fully. For the majority of organs considered dose-limiting,
gery). Depending on the organ, loss of some volume may such as bone marrow, lung, kidney, heart, and liver, high
not affect organ survival because that organ can compensate doses can be tolerated to relatively small volumes. Such
for volume loss, up to a threshold volume, through regen- organs may decompensate when more than 50 % of the
eration or hypertrophy (i.e., liver) and/or remain, although total volume (as applied to paired organs) is exceeded and
impaired, within functional tolerance for survival (i.e., threaten survival.
kidney or lung). Different organs demonstrate a range of The time when organ decompensation begins clearly
tolerance volume (TV) parameters: depends on the compensatory regenerative mechanisms that
1. TV5–25: 5–25 % of the organ volume irradiated above come into play when significant organ volume loss occurs.
suprathreshold doses can result in a life-threatening or The dose–response curve is not an absolute or fixed effect
lethal complication. but varies as a function of volume (Fig. 6a). This is an
Understanding and Predicting Radiation 111

4.1.6 Emami and QUANTEC: Summary of Normal

Tissue Dose/Volume (Emami, Lyman et al.,
and Marks et al.)
In the late 1980s and early 1990s, 3D planning systems
were providing clinicians with a plethora of information. A
great promise of 3D treatment planning was quantitative
correlates of doses/volumes with clinical outcomes. This
promise was partly delivered; guidelines were needed to
help physicians predict the relative safety of proposed
treatment plans, although only limited data were available.
In 1991, to meet this need, investigators pooled their clin-
ical experience, judgment, and information regarding whole
organ partial organ tolerance doses, and produced the
‘‘Emami and Lyman paper’’ (Emami et al. 1991). This
report was, and remains, a landmark summary of decades—
worth of data for a wide variety of organs, supplemented
Fig. 5 The hypothetical dose–response curves for tumor control and with expert opinion where data were lacking. While this
normal tissue complication are shown, along with the associated curve paper is often criticized, it clearly stated the uncertainties
for ‘Uncomplicated Tumor Control’’, [From Rubin Clinical Oncology and limitations in its recommendations, and it is widely
8th edn. Treatment outcomes. Uncomplicated cures (dashed lines) are admired for addressing a clinical need.
the desired result of treatment. This is illustrated as a function of the
therapeutic ratio, i.e. the greater the separation between the tumor During the decades of the 1990s and 2000s, numerous
control (ablation) curve and the normal tissue complication curve, the studies reported associations between dose/volume param-
greater the number of uncomplicated cures that will result. A, B, and C eters and normal tissue outcomes. Much of this was
represent three different dose levels that if chosen, would lead to three reviewed by Milano et al. in 2007 (Milano et al. 2007,
diffrent outcomes. A would result in few tumor cures but no
complications. C would lead to complicate cure in many cases, but 2008). In 2007, a joint task force of physicists and physi-
virtually all patients would suffer complications. The optimal choice in cians was formed, with the support of ASTRO and AAPM,
this group of dose levels is B, which would result in the greatest to summarize the available data in a format useful to cli-
number of cured patients without complications. (Adapted from nicians and to update/refine the estimates provided by
Mendelsohn 1969 with permission)]
Emami, Lyman. The resulting quantitative analysis of nor-
mal tissue effects in the clinic (QUANTEC) review articles
(published in a special issue of the International Journal of
important concept because it describes why large doses can Radiation Oncology, Biology, and Physics in March, 2010)
be delivered to partial volumes. For TD5 and TD50, the dose summarized the available data. A central goal of QUAN-
increases as the volume decreases. TEC was to update and refine the estimates provided by
Emami, Lyman et al. and summarize published information
4.1.4 Tolerance Dose/Volume/Injury Concept in a clinically useful manner (Marks et al. 2010a, b). A
(Lyman and Wolbarst) summary table from the Quantec effort is shown in Table 3.
An important and insightful concept was developed by A brief summary of historical landmarks described
Lyman, in which the dose response curve is not an absolute above, along with our opinion regarding the key contribu-
or fixed effect but varies as a function of organ volume. A tions and shortcomings of these reviews, are provided in
3D construct allowed for a method of assessing complica- Fig. 8 and Table 4.
tion probabilities from dose volume histograms (Fig. 6a)
this concept provided the radiation oncologist with a guide
as to varying the dose depending on volume (Fig. 6b). This
concept applied to organ tolerance doses, was then pub- 4.2 The Incorporation of 3D Dose/Volume
lished by Emami, Lyman et al. (discussed below). Information into Clinical Guidelines

4.1.5 Tolerance Volume: Focal/Global Injury The study of radiation dose/volume/outcome was revolu-
Marks (1996) related the concepts of focal and global injury tionized with the advent of treatment planning computers
to clinical endpoints. The diagram linking these factors for and imaging software, which enabled appreciation of the 3D
the bladder (as an example) is shown in Fig. 7. For many relationship of the delivered radiation dose relative to the
organs, either, or both, focal and global injury are most underlying anatomy. The introduction of 3D treatment
clinically relevant (Table 2). planning offered the promise of quantitative correlates of
112 M. T. Milano et al.

Fig. 6 Volume effect: (a) The dose response curve is not an absolute Rubin Clinical Oncology 8th edn. This important concept allows the
or fixed effect but varies as a function of volume. (b) For TD5 and radiation oncologist to give much larger doses to partial volumes.
TD50, the dose increases as the volume decreases. Note that the slope (From Lyman and Wolbrast 1987 with permission from Elsiever
changes as more than 50 % of the whole organ is included. Small Science)
increments in dose, that is, 10–20 %, can prove to be lethal. From

Fig. 7 A schematic diagram illustrating the dose-volume relationship are shown in panel b. Global bladder injury appears to occur when the
to complications, using urinary bladder as an example. This is shown total dose to the bladder exceeds 50–55 Gy. A focal bladder injury
in two different ways in panels a and b. In panel a, the approximate occurs when the dose to a portion of the bladder exceeds approx-
overall serious complication rate is shown as a function of the dose imately 70–75 Gy, Marks (1995)
delivered and volume exposed. The corresponding clinical situations

doses/volumes with clinical outcomes. Before the Emami 20 years, the Emami and Lyman report was the basis for 3D
and Lyman paper (Emami et al. 1991) was published in radiation dose/volume prescriptions. The sixteen organ-
1991, systematic dose/volume/outcome data to guide clin- specific QUANTEC papers, published in 2010, exhaus-
ical decisions were limited. The Emami and Lyman paper tively, and systematically reviewed relevant studies of
provided a summary table where the risk of injury was radiation dose-volume affects on normal tissue; Marks et al.
related to the dose/volume received by any organ. While the produced a summary table of these reviews, providing
authors reported the one-third and two-thirds partial organ evidenced-based dose-volume metrics for each of the
tolerance doses, for the most part, the clinical experience reviewed organ sites (Marks et al. 2010b). Major differences
which provided the basis for the these tolerance doses was between the Emami and Lyman paper and QUANTEC
based upon 2D radiation planning and delivery. For close to reviews are discussed below.
Understanding and Predicting Radiation 113

Table 2 Example clinically relevant focal and global endpoints for equal to that critical size, might be a useful parameter to
various organs predict outcomes.
Organ Focal endpoint Global endpoint c. Dmax is the maximum dose delivered to an organ, and is
Brain and cranial Focal weakness, Neurocognitive decline most useful for series organs. Dmax is analogous to Dx
nerves blindness as the volume x decreases toward zero.
Eye Visual field cut Acuity d. Mean dose is the simple arithmetic average of the dose
Lung Bronchial Dyspnea to an organ. For parallel organs where there is a gradual
stricture dose response function for radiation-induced regional
Heart Coronary stenosis Pericarditis, reduced injury, the mean dose might reasonably correlate with
ejection fraction outcomes.
Esophagus Stricture, ulcer e. More complex modeling has also been widely used to
Bladder Bleeding Reduced capacity, urinary extract figures of merit that better reflect the entire DVH,
frequency rather than a single point (e.g., Dmax, Dx, Vx). These
Bowel Stricture, bleeding Malabsorption models will ‘‘sum up’’ the risk associated with each
Kidney Reduced renal clearance component of a DVH, and apply different methods of
Liver Reduced hepatic function summing, depending on the type (or architecture/struc-
ture) of the organ. For example, for a series-structured
organ, the high-dose region of the DVH might be most
weighted more heavily in the ‘‘summing’’ while this is
4.3 Dose-Volume Histograms and Associated less strongly considered in a parallel-structured organ.
Figures of Merit Early work in this area lead to the Lyman, Kutcher
Burman (LKB) model, and more recently the equivalent
3D dose/volume data can be difficult for clinicians to uniform dose (EUD) model, that both reduce a DVH to a
readily digest. Visualizing isodose distributions are chal- single normal tissue complication probability (NTCP).
lenging and comparing competing distributions are almost These models and their relationships are summarized
impossible. Therefore, dose-volume histograms (DVH’s; elsewhere (Marks et al. 2010b).
essentially 2D representations of the 3D data) were The Emami et al. report systematically used the same
embraced as a rapid way to summarize the dose distribution. DVH-based construct across many organs; e.g., the TD 5/5
Note that DVH’s discard information regarding the spatial and TD 50/5 for the uniform irradiation of one-third, two-
character of dose as well as (usually) variations in fraction thirds, and the whole volume of an organ (Emami et al.
size. 1991). This uniform approach enabled the application of
Despite the marked data reduction in going from a 3D ‘‘single unifying models’’ of dose/volume/outcome across
plan to a DVH, DVHs also remain challenging for clinicians organs. For example, the dose/volume/outcome estimates
to consider and compare. Therefore, it has become attrac- from Emami et al. were used by Lyman, Kutcher, Burman
tive to further data reduce, and extract ‘figures of merit’ et al. (Burman et al. 1991; Kutcher et al. 1991; Lyman
from the DVH (Fig. 9). Examples include: 1985) to generate a set of organ-specific model parameters.
a. Vx reflects the volume of tissue (generally a percentage) Such a uniform approach is attractive.
receiving CX Gy. This is probably the most commonly During the past two decades, many clinical dose/vol-
used metric for parallel-type organs such as the lung and ume/outcome reports computed parameters for these
kidney. For these, as discussed above, the portions of the ‘‘unifying models’’ [e.g., Ten Haken et al. (Chapet et al.
organ exposed to a ‘‘regionally-injuring’’ dose of radia- 2005; Ten Haken et al. 1993, 2006)]. However, the
tion will become dysfunctional. Thus, the percent of the majority of published clinical dose/volume/outcome data
organ exposed to that dose is a useful parameter. generated over the past two decades has used alternative
b. Dx reflects the minimum dose to the hottest x % (gen- approaches/models that appeared to be better suited to
erally percentage of total volume) of tissue. This specific organs. Therefore, the dose/volume/outcome data
parameter is not widely used clinically. It might be most available for the QUANTEC review was not of a uniform
useful for parallel-type organs where the percent of an format. Outcomes across organs were correlated with a
organ’s function that can be lost is known (e.g., let’s say diverse array of dose/volume metrics (e.g., threshold vol-
30 %). Then, if the D30 is less than the locally injuring umes [Vx], threshold doses [Dx], mean doses). Therefore,
dose, global organ function should remain. Similarly, for the QUANTEC review included model-based parameters
organs where an injury might be clinically manifest if for just a few organs, and not always in a systematic
there is a hotspot of a particular size, the Dx, where x is fashion.
Table 3 QUANTEC Summary: Approximate Dose/Volume/Outcome Data for Several Organs Following Conventional Fractionation (Unless Otherwise Noted)*
114

Organ Volume segmented Irradiation type (partial Endpoint Dose (Gy), or Rate Notes on dose/volume parameters
organ unless otherwise dose/volume (%)
stated) parameters
Brain Whole organ 3D-CRT Symptomatic necrosis Dmax \60 \3 Data at 72 and 90 Gy, extrapolated from BED models
Whole organ 3D-CRT Symptomatic necrosis Dmax = 72 5
Whole organ 3D-CRT Symptomatic necrosis Dmax = 90 10
Whole organ SRS (single fraction) Symptomatic necrosis V12 \5–10 cc \20 Rapid rise when V12 [ 5–10 cc
Brain Whole organ Whole organ Permanent cranial neuropathy Dmax \54 \5
stem Whole organ 3D-CRT or necrosis D1-10 cck B59 \5
Permanent cranial neuropathy
or necrosis
Whole organ 3D-CRT Permanent cranial neuropathy Dmax \64 \5 Point dose \\1 cc
or necrosis
Whole organ SRS (single fraction) Permanent cranial neuropathy Dmax \12.5 \5 For patients with acoustic tumors
or necrosis
Optic Whole organ 3D-CRT Optic neuropathy Dmax \55 \3 Given the small size, 3D CRT is often whole organàà
nerve/ Whole organ 3D-CRT Optic neuropathy Dmax 55–60 3–7
chiasm Whole organ 3D-CRT Optic neuropathy Dmax [60 [7–20
Whole organ SRS (single fraction) Optic neuropathy Dmax \12 \10
Spinal Partial organ 3D-CRT Myelopathy Dmax = 50 0.2 Including full cord cross-section
cord Partial organ 3D-CRT Myelopathy Dmax = 60 6
Partial organ 3D-CRT Myelopathy Dmax = 69 50
Partial organ SRS (single fraction) Myelopathy Dmax =13 1 Partial cord cross-section irradiated 3 fractions, partial
Partial organ SRS (hypofraction) Myelopathy Dmax = 20 1 cord cross-section irradiated
Cochlea Whole organ 3D-CRT Sensory neural hearing loss Mean dose B45 \30 Mean dose to cochlear, hearing at 4 kHz
Whole organ SRS (single fraction) Sensory neural hearing loss Prescription dose \25 Serviceable hearing
B14
Parotid Bilateral whole 3D-CRT Long term parotid salivary Mean dose \25 \20 For combined parotid glands}
parotid glands function reduced to \25% of
pre-RT level
Unilateral whole 3D-CRT Long term parotid salivary Mean dose \20 \20 For single parotid gland.
parotid gland function reduced to \25% of At least one parotid gland spared to \20 Gy}
pre-RT level
}
Bilateral whole 3D-CRT Long term parotid salivary Mean dose \39 \50 For combined parotid glands (per Fig. 3 in paper)
parotid glands function reduced to \25% of
pre-RT level
Pharynx Pharyngeal Whole organ Symptomatic dysphagia and Mean dose \50 \20 Based on Section B4 in paper
constrictors aspiration
(continued)
M. T. Milano et al.
Table 3 (continued)
Organ Volume segmented Irradiation type (partial Endpoint Dose (Gy), or Rate Notes on dose/volume parameters
organ unless otherwise dose/volume (%)
stated) parameters
Larynx Whole organ 3D-CRT Vocal dysfunction Dmax \66 \20 With chemotherapy, based on single study (see Section
A4.2 in paper)
Whole organ 3D-CRT Aspiration Mean dose \50 \30 With chemotherapy, based on single study (see Fig. 1 in
paper)
Whole organ 3D-CRT Edema Mean dose \44 \20 Without chemotherapy, based on single study in patients
Whole organ 3D-CRT Edema V50 \27% \20 without larynx cancer**
Lung Whole organ 3D-CRT Symptomatic pneumonitis V20 B 30% \20 For combined lung. Gradual dose response
Whole organ 3D-CRT Symptomatic pneumonitis Mean dose =7 5 Excludes purposeful whole lung irradiation
Understanding and Predicting Radiation

3D-CRT Mean dose =13 10

3D-CRT Mean dose = 20 20
3D-CRT Mean dose = 24 30
3D-CRT Mean dose = 27 40
Esophagus Whole organ 3D-CRT Grade C3 acute esophagitis Mean dose \34 5–20 Based on RTOG and several studies
Whole organ 3D-CRT Grade C2 acute esophagitis V35 \50% \30 A variety of alternate threshold doses have been
Whole organ 3D-CRT GradeC2 acute esophagitis V50 \40% \30 implicated.
Whole organ 3D-CRT Grade C2 acute esophagitis V70 \20% \30 Appears to be a dose/volume response
Heart Pericardium 3D-CRT Pericarditis Mean dose \26 \15 Based on single study
Pericardium 3D-CRT Pericarditis V30 \46% \15
Whole organ 3D-CRT Long-term cardiac mortality V25 \10% \1 Overly safe risk estimate based on model predictions
àà
Liver Whole liver - GTV 3D-CRT or Whole organ Classic RILD Classic RILD Mean dose \5 Excluding patients with pre-existing liver disease or
Whole liver - GTV 3D-CRT \30–32 \50 hepatocellular carcinoma, as tolerance doses are lower
Mean dose \42 in these patients
Whole liver - GTV 3D-CRT or Whole organ Classic RILD Mean dose \28 \5 In patients with Child-Pugh A preexisting liver disease
Whole liver - GTV 3D-CRT Classic RILD Mean dose \36 \50 or hepatocellular carcinoma, excluding hepatitis B
reactivation
as an endpoint
Whole liver -GTV SBRT (hypofraction) Classic RILD Mean dose \13 \5 3 fractions, for primary liver cancer
Whole liver - GTV SBRT (hypofraction) Classic RILD Mean dose \18 \5 6 fractions, for primary liver cancer
SBRT (hypofraction) Classic RILD Mean dose \15 \5 3 fractions, for liver metastases
SBRT (hypofraction) Classic RILD Mean dose \20 \5 6 fractions, for liver metastases
[700 cc of normal SBRT (hypofraction) Classic RILD Dmax \15 \5 Critical volume based, in 3–5 fractions
liver
Kidney Bilateral whole Bilateral whole organ or Clinically relevant renal Mean dose \5
kidneyà 3D-CRT dysfunction \15–18 \50
Bilateral whole Bilateral whole organ Clinically relevant renal Mean dose \28
kidneyà dysfunction
Bilateral whole 3D-CRT Clinically relevant renal V12 \55% \5 For combined kidney
kidneyà dysfuntction V20 \32%
V23 \30%
115

V28 \20%
(continued)
Table 3 (continued)
116

Organ Volume segmented Irradiation type (partial Endpoint Dose (Gy), or Rate Notes on dose/volume parameters
organ unless otherwise dose/volume (%)
stated) parameters
Stomach Whole organ Whole organ Ulceration D100k Dmin\45 \7
§
Small Individual small 3D-CRT Grade C 3 acute toxicity V15 \120 cc \10 Volume based on segmentation of the individual loops
bowel bowel loops of bowel, not the entire potential peritoneal space
Entire potential 3D-CRT Grade C 3 acute toxicity§ V45 \195 cc \10 Volume based on the entire potential space within the
space within peritoneal cavity
peritoneal cavity
Rectum Whole organ 3D-CRT Grade C 2 late rectal toxicity V50 \50% \15 Prostate cancer treatment
Whole organ 3D-CRT Grade C 3 late rectal toxicity, V60 \35% \10
Whole organ 3D-CRT Grade C 2 late rectal toxicity V65 \25% \15
Whole organ 3D-CRT Grade C 3 late rectal toxicity, V70 \20% \10
Whole organ 3D-CRT Grade C 2 late rectal toxicity V75 \15% \15
Grade C 3 late rectal toxicity, \10
Grade C 2 late rectal toxicity \15
Grade C 3 late rectal toxicity, \10
Grade C 2 late rectal toxicity \15
Grade C 3 late rectal toxicity, \10
Bladder Whole organ 3D-CRT Grade C 3 late RTOG Dmax \65 \6 Bladder cancer treatment.
Variations in bladder size/shape/
location during RT hamper ability to
generate accurate data
Whole organ 3D-CRT Grade C3 late RTOG V65 B50 % Prostate cancer treatment
V70 B35 % Based on current RTOG 0415
V75 B25 % recommendation
V80 B15 %
Penile Whole organ 3D-CRT Severe erectile dysfunction Mean dose to \35
bulb Whole organ 3D-CRT Severe erectile dysfunction 95% of gland \35
Whole organ 3D-CRT Severe erectile dysfunction \50 \55
D90k \50
D60–70 \70
Abbreviations: 3D-CRT = 3-dimensional conformal radiotherapy, SRS = stereotactic radiosurgery, BED = Biologically effective dose, SBRT = stereotactic body radiotherapy, RILD =
radiation-induced liver disease, RTOG = Radiation Therapy Oncology Group
* All data are estimated from the literature summarized in the QUANTEC reviews unless otherwise noted. Clinically, these data should be applied with caution. Clinicians are strongly advised
to use the individual QUANTEC articles to check the applicability of these limits to the clinical situation at hand. They largely do not reflect modern IMRT. The figures and sections noted in the
far right-hand column refer to the individual QUANTEC papers
All at standard fractionation (i.e., 1.8-2.0 Gy per daily fraction) unless otherwise noted. Vx is the volume of the organ receiving C x Gy. Dmax = Maximum radiation dose
à Non-TBI
§
With combined chemotherapy
k
Dx = minimum dose received by the ‘‘hottest’’ x% (or x cc’s) of the organ.D100 = minimum dose
}
Severe xerostomia is related to additional factors including the doses to the submandibular glands
** Estimated by Dr. Eisbruch
Classic Radiation induced liver disease (RILD) involves anicteric hepatomegaly and ascites, typically occurring between 2 weeks and 3 months after therapy. Classic RILD also involves
elevated alkaline phosphatase (more than twice the upper limit of normal or baseline value)
M. T. Milano et al.

àà
For optic nerve, the cases of neuropathy in the 55 to 60 Gy range received &59 Gy (see optic nerve paper for details). Excludes patients with pituitary tumors where the tolerance may be
reduced
Understanding and Predicting Radiation 117

Table 4 Historical overview of several summaries of dose/volume/outcome information

Report Key contributions Key shortcomings
Rubin, NCI Introduced the concept of TD 5/5 and 50/5 Minimal dose/volume data
contract
Rubin Categorized organs into classes based on sensitivity Minimal dose/volume data
RTOG
Emami, Concise summary addressing most clinically meaningful Dose/volume relationship based on limited data and, thus, much
1991 endpoints in a uniform manner expert opinion
Based on available data and expert opinion
QUANTEC, Driven largely by the available 3D dose/volume/ Since dose/volume/outcome data on all meaningful clinical
2010 outcome data outcomes are not available, the summary is not able to guide all
Systematic review addressing many challenges such as clinical practice
organ delineation and confounding factors such as
chemotherapy

throughout treatment, anatomic changes might make the

DVH inaccurate. Just ‘‘adding up DVHs’’ is often not
possible. For parameters such as mean dose, one can
simply ‘‘add up’’ the mean dose from sequential phases
of therapy (assuming the volume remains constant).
However, for parameters such as V20, one needs to fuse
the 3D dose distributions from sequential phases of
therapy to generate a ‘composite plan’ (and assume
spatial consistency as well). Additional challenges occur
since the fraction size within each region might be var-
iable between the different portions of therapy.
Fig. 8 The derivation of figures of merit from a complex 3D dose
5. There is a tendency to ‘‘over contour’’ critical structures,
distribution that are then tested for correlation with normal tissue often to be ‘‘really sure’’ that fields are shaped to limit
toxicity endpoints. From Marks (2010b) exposure and that set-up irregularities do not result in
excess exposure. The resultant DVHs thus may not
4.4 Shortcomings of DVHs accurately reflect the dose/volume characteristics of the
target tissues.
1. The use of DVHs inherently assumes that all regions of 6. Threshold parameters of a DVH (e.g., V20) can often be
an organ are of equal importance, and that function is manipulated by skilled planners, resulting in a ‘‘kink’’ in
distributed relatively uniformly throughout the organ. the DVH just below the constrained threshold limits
This may not be the case for many organs. (e.g., a high value of V15–18 with a low V20). For
2. Further, even if the organ is of uniform structure example, while the lung V20 is predictive of radiation
throughout, the global structure of the organ may reduce pneumonitis in many studies (Marks et al. 2010c) lung
the utility of DVHs. For example, in tubular structures volumes receiving at or below lower doses (i.e. V10 or
(e.g., bowel), the circumferential and longitudinal nature V13) are also predictive, and thus striving for a specific
of the radiation dose may be pertinent but is not dose metric such as lung V20, and ignoring the overall
considered. dose-volume distribution can lead to errors in judgment
3. Differences in fraction size are typically ignored when regarding toxicity risks.
computing a DVH, though one can apply a mathematical 7. The calculated dose distribution and DVHs are affected
‘‘correction.’’ However, there must be some a priori by the algorithms used to calculate dose (i.e., Monte
assumption that the impact of fraction size is understood Carlo calculation is often considered the ‘gold stan-
in order to apply such a correction. dard’). In the presence of tissue inhomogeneities, there
4. For patients that are treated with sequential groups of will be relatively greater discrepancies in the calculated
beams (i.e., boost treatment), there will be unique DVHs dose distribution and DVHs between different planning
for each portion of therapy. Exactly how to combine algorithms (Vanderstraeten et al. 2006). As a result,
these DVHs is unclear, especially if there have been interpreting the published dose tolerances, and using
anatomic changes between the sequential portions of them as a guide to predict toxicity risks becomes more
therapy. Indeed, even if there is one plan used complicated. Differences between planning systems are
118 M. T. Milano et al.

Fig. 9 Radiation planning software generates dose volume histo- Similarly, the dose metrics such as mean organ dose, or organ dose
grams (DVH) by tallying the ‘point doses’ delivered to each voxel of a receiving 20 Gy or less (V20) does not account for how that dose is
contoured structure, and generating a cumulative histogram. The distributed in the organ. Likewise, computer based models which
cumulative histogram depicts the number of voxels (plotted as volume) extract DVH data do not account for spatial distribution of dose.
receiving a given dose or less. This graphical representation discards Reproduced with permission from Marks. (Marks et al. 2010b)
the anatomical spatial distribution of the dose delivered to the patient.

likely relatively modest compared to some of the other treatment planning for high energy photons.’’(Emami
factors herein discussed. et al. 1991) Conversely, the QUANTEC review was
8. As described in each of the QUANTEC reviews, there focused on organs for which the steering committee
are potential challenges in defining a given organ’s thought that there was meaningful dose/volume/outcome
volume, which then impacts the DVHs and therefore data (see Table 5).
interpretation of the DVH. Challenges include intra- b. The QUANTEC reviews had the benefit of 18 additional
fraction and inter-fraction organ motion, difficulty in years of published data from which they could make
defining anatomical borders of an organ, and differing their dose/volume/outcome estimates.
opinions on how to define extent of an organ. There is c. Emami et al. addressed a wide variety of clinical out-
also variability in the published literature in how a given comes, and thus provides the reader with a set of dose/
organ is defined. For example, total lung is defined as volume parameters for essentially all clinical situations.
lung minus GTV in some studies, and lung minus PTV in Conversely, the QUANTEC review was focused on
others (Marks et al. 2010c). These two lung definitions endpoints where there was dose/volume/outcome data. In
would result in substantially different lung dose metrics, this regard, the Emami/Lyman tables are more complete.
particularly with relatively large PTVs. These discrep- For example, consider the QUANTEC summary for the
ancies further complicate the interpretation and use of small bowel. A volume restriction is provided for the
published dose tolerances. endpoint of acute grade C3 toxicity. No guidance is
provided for late small bowel injury, as the authors did
not believe that there was meaningful dose/volume/out-
5 Major Differences come data for late injury. This is a shortcoming of the
between the QUANTEC QUANTEC review as it is not ‘‘complete.’’ When
and Emami/Lyman Reviews evaluating a proposed 3D treatment plan, one obviously
must consider both acute and late injury.
a. Emami et al. provided information for 26 organs, judged d. Emami et al. presented information in a systematic/
necessary to support protocols for ‘‘three dimensional uniform manner, facilitating inter-organ comparisons
Understanding and Predicting Radiation 119

Table 5 Comparison of the character/content of Emami et. al. and based on 3D dose/volume parameters extracted from the
QUANTEC treatment planning CT. Motion of various organs (e.g.,
Characteristic Emami et. al. QUANTEC rectum, bladder) between the time of planning and treat-
Number of 26 16 ment clearly occur. One might argue that such motion
organs should be ‘‘randomly distributed’’ and that therefore anal-
3D data Minimal More/moderate yses based on these treatment planning-based dose/volume
available (18-year interval) parameters would be valid. However, there might be some
Format of dose/ Uniform TD 5/5, 50/5 Non-uniform systematic errors relating to organ motion. Additionally,
volume limits for 1/3, 2/3, 3/3 there can be motion of various organs during treatment (i.e.,
Endpoints Specific, complete Specific, incomplete cardiac and respiratory-associated motion).
Expert opinion A lot Much less Normal tissue effects are highly dependent on fraction
Impact of Not explicitly Addressed size. For a variety of organs, a lower dose per fraction has
chemotherapy discussed individually for each been associated with the reduction in risk of normal tissue
organ injury. With modern 3D treatment planning techniques, in
particular IMRT; the dose delivered to the regions of an
and model-based parameter estimates. The investigators organ may be highly variable. The consideration of dose/
generated an enlarged table wherein the doses that would volume statistics that do not account for this variation in
be expected to cause a 5 % risk of injury with exposure fraction size is a major potential shortcoming. Most DVH-
1/3, 2/3, 3/3 of an organ expected to cause 5 % risk of based analyses do not ‘‘correct’’ for regional differences in
injury. This approach has definite appeal on many levels. fraction size. There are some notable exceptions however,
It is a uniform format, and forced the investigators to where variations in fraction size are considered (Jin et al.
address each organ in a similar manner. However, this 2010).
paradigm might not be logical for some organs. For The impact of fraction size on late toxicity has typically
example, for some organs, in some situations, a 5 % of been modeled using the linear quadratic model (Hall and
risk of injury is not clinically acceptable, such as the case Giaccia 2012). However, this model appears to be less
with spinal cord irradiation. Similarly, it is challenging accurate at high doses per fraction (Milano et al. 2008).
to consider radiation of 1/3, 2/3, 3/3 of small organs such Furthermore, the linear quadratic model, which is based
as the retina, larynx. The QUANTEC reviews presented upon in vivo measurements of cancer cell survival, does not
dose/volume/outcome data in the diverse manner in necessary apply to normal tissues (Glatstein 2008, 2011).
which they were available in the literature. The The emergence of novel technologies such as SBRT/SABR,
reviewers for each organ were free to select what they IGRT, IMRT and 4-dimensional planning facilitate hypo-
thought were the ‘‘optimal parameters’’ to consider. For fractionated radiation delivery, via more accurate position-
example, in the lung, the threshold doses (e.g., V13, ing and targeting. More accurate positioning allows
V20) as well as the mean dose, were both considered. reduction in PTV margins, coupled with the uniformly rapid
For the penile bulb, the minimum dose received by the dose gradient beyond the target (e.g., with SBRT), generally
hottest 75 or 90 % of the organ was considered. Where results in only a small volume of normal tissue exposed to
this might make the QUANTEC reviews slightly more hypofractionated radiation. However, the impact of hypo-
clinically relevant, it does make inter-organ comparisons fractionated radiation on small volumes of normal tissues is
more challenging. not well characterized (Milano et al. 2008; Benedict et al.
e. One of the benefits of having a uniform dose/volume/out- 2010). Thus further efforts are needed to better understand
come construct, as was done in Emami and Lyman, is that the normal tissue response to hypofractionated radiation.
it readily lends itself to the calculation of parameters for a In the future, models predicting dose/volume injury will
unified normal tissue complication probability (NPCP) likely more consistently consider the underlying physiology
modeling. Such modeling was done with the Emami and and substructures of organs. Differences in regional
Lyman estimates. The QUANTEC reports did not also importance (e.g., different regions of the heart maybe being
systematically include modeling-based information. more important, such as the coronary arteries or the left
ventricle). The commonly used NTCP models are not
necessarily physiologically based. The widely used Lyman-
6 Challenges for Future Study Kutcher, Berman model does not have a biologically
physiologic underpinning.
The study of dose/volume/outcome for normal tissues is Additional work is needed to better understand inter-
somewhat hampered by inter- and intra-fraction motion. patient differences in inherent radiation sensitivity. A variety
Almost all analyses, including the QUANTEC effort were of studies in the pre-clinical setting (bacteria, cell culture in
120 M. T. Milano et al.

animals) noted marked inter-variations in radiation sensitiv- Flickinger JC, Kondziolka D, Lunsford LD et al (2000) Development
ity. Numerous studies have been trying to identify predictors of a model to predict permanent symptomatic postradiosurgery
injury for arteriovenous malformation patients. Arteriovenous
of radiation sensitivity in humans. To date none of these have malformation radiosurgery study group. Int J Radiat Oncol Biol
been widely found to be useful, though more recent studies Phys 46:1143–1148
provide reason to be more optimistic (as discussed in ‘‘ Glatstein E (2008) Hypofractionation, long-term effects, and the alpha/
BioPediatric Complexities of Growth and Development’’ by beta ratio. Int J Radiat Oncol Biol Phys 72:11–12
Glatstein E (2011) The omega on alpha and beta. Int J Radiat Oncol
Rosenstein and coauthors). Biol Phys 81:319–320
Current models do not particularly consider potential Hall EJ, Giaccia AJ (2012) Radiobiology for the radiobiologist, 7th
interactions between organs. For example, the risk of edn. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia
pneumonitis has been particularly related to the dose/vol- Hendry JH, Thames HD (1986) The tissue-rescuing unit. Br J Radiol
59:628–630
ume of the lung. It is certainly possible that there might be Jin JY, Kong FM, Chetty IJ et al (2010) Impact of fraction size on lung
interactions between the lung and the heart for the endpoint radiation toxicity: hypofractionation may be beneficial in dose
of shortness of breath. There are similar interactions that escalation of radiotherapy for lung cancers. Int J Radiat Oncol Biol
may exist for the kidney and liver, retina and brain, and Phys 76:782–788
Kutcher GJ, Burman C, Brewster L et al (1991) Histogram reduction
other organs that ‘‘share a function’’. Further investigation method for calculating complication probabilities for three-dimen-
into organ–organ interaction is warranted. sional treatment planning evaluations. Int J Radiat Oncol Biol Phys
The study of radiation-associated normal tissue injury 21:137–146
has interested investigators for decades. Much progress has Lyman JT (1985) Complication probability as assessed from dose-
volume histograms. Radiat Res. (Supplement) 8:S13–S19
been made over the last 20 years, largely in the ‘physical Lyman JT, Wolbrast AB (1987) Optimization of radiation therapy III:
realm.’ Additional technologies (e.g., gating, image-guided a method of assessing complication probabilities from dose-volume
therapy) will provide some refinements in these physical histograms. Int J Radiat Oncol Biol Phys 13:103
advances. There is a huge need to gain further under- Ma J, Zhang J, Zhou S et al (2009) Association between RT-induced
changes in lung tissue density and global lung function. Int J Radiat
standing of the biological underpinnings of radiation-asso- Oncol Biol Phys 74:781–789
ciated normal tissue. This will hopefully improve our Ma J, Zhang J, Zhou S et al (2010) Regional lung density changes after
abilities to predict, prevent and treat radiation-associated radiation therapy for tumors in and around thorax. Int J Radiat
normal tissue injury. Oncol Biol Phys 76:116–122
Mah K, Van Dyk J (1988) Quantitative measurement of changes in
Acknowledgments Portions of this work are adapted from Milano human lung density following irradiation. Radiother Oncol
et al. (2012) (in Gunderson and Tepper), Marks et al. (2010b) 11:169–179
(QUANTEC review), and Rubin (1978) (Clinical Oncology Book) Marks LB, Carroll PR, Dugan TC, Anscher MS (1995) The response
of the urinary bladder, urethra, and ureter to radiation and
chemotherapy. Int J Radiat Oncol Biol Phys 31:1257–1280
References Marks LB (1996) The impact of organ structure on radiation response.
Int J Radiat Oncol Biol Phys 34:1165–1171
Marks LB, Munley MT, Spencer DP et al (1997) Quantification of
Ahn SJ, Kahn D, Zhou S et al (2005) Dosimetric and clinical radiation-induced regional lung injury with perfusion imaging. Int J
predictors for radiation-induced esophageal injury. Int J Radiat Radiat Oncol Biol Phys 38:399–409
Oncol Biol Phys 61:335–347 Marks LB, Ten Haken RK, Martel MK (2010a) Guest editor’s
Benedict SH, Yenice KM, Followill D et al (2010) Stereotactic body introduction to QUANTEC: a users guide. Int J Radiat Oncol Biol
radiation therapy: the report of AAPM Task Group 101. Med Phys Phys 76:S1–S2
37:4078–4101 Marks LB, Yorke ED, Jackson A et al (2010b) Use of normal tissue
Boersma LJ, Damen EM, de Boer RW et al (1993) A new method to complication probability models in the clinic. Int J Radiat Oncol
determine dose-effect relations for local lung-function changes Biol Phys 76:S10–S19
using correlated SPECT and CT data. Radiother Oncol 29:110–116 Marks LB, Bentzen SM, Deasy JO et al (2010c) Radiation dose
Burman C, Kutcher GJ, Emami B et al (1991) Fitting of normal tissue volume effects in the lung. Int J Radiat Oncol Biol Phys 76:S70–
tolerance data to an analytic function. Int J Radiat Oncol Biol Phys S76
21:123–135 Mendelsohn ML (1969) The biology of dose-limiting tissuses. In:
Chapet O, Kong FM, Lee JS et al (2005) Normal tissue complication Time and dose relationship in radiation biology as applied to
probability modeling for acute esophagitis in patients treated with radiotherapy, Brookhaven National Laboratory [BNL] Report 5023
conformal radiation therapy for non-small cell lung cancer. (C-57), Brookhaven National Laboratory, Upton, p 54
Radiother Oncol J Eur Soc Ther Radiol Oncol 77:176–181 Michalowski A, Wheldon TE, Kirk J (1984) Can cell survival
Emami B, Lyman J, Brown A et al (1991) Tolerance of normal tissue parameters be deduced from non clonogenic assays of radiation
to therapeutic irradiation. Int J Radiat Oncol Biol Phys 21:109–122 damage to normal tissues? Br J Cancer Suppl 6:257–261
Fan M, Marks LB, Hollis D et al (2001a) Can we predict radiation- Milano MT, Constine LS, Okunieff P (2007) Normal tissue tolerance
induced changes in pulmonary function based on the sum of dose metrics for radiation therapy of major organs. Semin Radiat
predicted regional dysfunction? J Clin Oncol 19:543–550 Oncol 17:131–140
Fan M, Marks LB, Lind P et al (2001b) Relating radiation-induced Milano MT, Constine LS, Okunieff P (2008) Normal tissue toxicity
regional lung injury to changes in pulmonary function tests. Int J after small field hypofractionated stereotactic body radiation.
Radiat Oncol Biol Phys 51:311–317 Radiat Oncol 3:36
Understanding and Predicting Radiation 121

Milano MT, Marks LB, Constine LS (2012) Survivorship and late probability model in three-dimensional conformal radiation ther-
effects. In: Gunderson LL, Tepper JE (eds) Clinical radiation apy for primary liver carcinoma: in regards to Xu et al. (Int J Radiat
oncology, 3rd edn. Churchill Livingstone, Philadelphia, PA Oncol Biol Phys 2006;65:189–195). Int J Radiat Oncol Biol Phys
Rubin P (1978) Clinical oncology: a multidisciplinary approach for 66:1272; author reply 1272–1273
physicians and students, 5th edn. American Cancer Society, Inc Ten Haken RK, Martel MK, Kessler ML et al (1993) Use of Veff and
Rubin P, Casarett GW (1968) Clinical radiation pathology. W. B. iso-NTCP in the implementation of dose escalation protocols. Int J
Saunders, Philadelphia Radiat Oncol Biol Phys 27:689–695
Rubin P, Casarett GW (1972) A direction for clinical radiation Vanderstraeten B, Reynaert N, Paelinck L et al (2006) Accuracy of
oncology. In: Vaeth JM (ed) Frontiers of radiation therapy and patient dose calculation for lung IMRT: a comparison of Monte
oncology VI. University Park Press, Baltimore, pp 1–16 Carlo, convolution/superposition, and pencil beam computations.
Seppenwoolde Y, De Jaeger K, Boersma LJ et al (2004) Regional Med Phys 33:3149–3158
differences in lung radiosensitivity after radiotherapy for non- Withers HR, Taylor JM (1993) Critical volume model. Int J Radiat
small-cell lung cancer. Int J Radiat Oncol Biol Phys 60:748–758 Oncol Biol Phys 25:151–152
Ten Haken RK, Lawrence TS, Dawson LA () Prediction of radiation-
induced liver disease by Lyman normal-tissue complication
 Biotoxicity of Chemotherapy

Chunkit Fung and Kishan J. Pandya

Contents Abstract
With successful treatment of many malignancies, long-
1 Introduction.......................................................................... 123 term toxicities began to emerge and are becoming
2 Late Effects of Chemotherapy ........................................... 124 increasingly important in the growing number of cancer
2.1 Cardiotoxicity ........................................................................ 124 survivors. Research has begun to investigate manage-
2.2 Pulmonary Toxicity ............................................................... 130 ment options to mitigate these chemotherapy-related
2.3 Nephrotoxicity ....................................................................... 132
toxicities without compromising the therapeutic out-
2.4 Peripheral Neuropathy........................................................... 134
2.5 Ototoxicity ............................................................................. 137 comes. This chapter will discuss these late adverse
2.6 Reproductive Toxicity ........................................................... 138 effects based on organ system, including cardiotoxicity,
2.7 Cognitive Impairment............................................................ 141 pulmonary toxicity, nephrotoxicity, peripheral neuropa-
2.8 Second Malignant Neoplasms............................................... 144
thy, ototoxicity, reproductive toxicity, cognitive impair-
3 Chemotherapy-Induced Late Effects in the Era ment, and risks of second malignant neoplasms. We will
of Pharmacogenomics.......................................................... 145 review the underlying pathophysiology of each of these
3.1 Genes and Chemotherapy-Related Peripheral
Neuropathy............................................................................. 146 long-term complications and will provide the most up-to-
3.2 Genes and Cisplatin-Induced Ototoxicity............................. 147 date evidence-based prevention, follow-up and monitor-
3.3 Genes and Therapy-Related Myeloid Leukemia.................. 147 ing guidelines. In the latter part of the chapter, we will
3.4 Future Survivorship Research Directions in the Era review the current literatures regarding the molecular
of Pharmacogenomics ........................................................... 147
basis of germline genetic susceptibility to some of the
References...................................................................................... 148 late effects of chemotherapy, including peripheral neu-
ropathy, ototoxicity and therapy-induced myeloid leuke-
mia. This rapidly emerging field within cancer
survivorship does not only provide invaluable insights
and inform the development of therapeutic agents to
target the underlying molecular pathway of these adverse
effects, but it may also allow development of a risk-
classification system that incorporates genetic markers to
predict risks of chemotherapy-related side effects. The
final part of this chapter will attempt to look at future
research directions in the development of genetic
markers as well as therapeutic agents to prevent or treat
late-effects of chemotherapy.

1 Introduction
C. Fung
K. J. Pandya (&) The field of cancer chemotherapy developed from the idea
James P Wilmot Cancer Center,
University of Rochester Medical Center, of chemical warfare. Toxic chemicals were developed for
Rochester, USA the explicit purpose of causing biological damage to the
e-mail: [email protected]

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 123
DOI: 10.1007/978-3-540-72314-1_9, Ó Springer-Verlag Berlin Heidelberg 2014
124 C. Fung and K. J. Pandya

enemy. Sulfur mustards were synthesized in 1854, but their 2 Late Effects of Chemotherapy
vesicant properties were not described until 1887. Medical
attention was focused on these properties on the skin, eyes, 2.1 Cardiotoxicity
and respiratory tract during World War I. Serious systemic
toxicities were recognized later on in the form of Cardiotoxicity is a serious complication of numerous
leucopenia. cytotoxic cancer agents and it frequently manifests many
Autopsies of those exposed to sulfur mustard showed years after chemotherapy (Zuppinger and Suter 2010).
bone marrow aplasia, lymphoid tissue dissolution, and These cardiovascular toxicities may include cardiomyo-
gastrointestinal ulcerations. Biological and chemical effects pathy with or without overt congestive heart failure (CHF),
of nitrogen mustard were studied between the two wars in endothelial dysfunction, and arrhythmias (Carver et al.
secrecy. The marked cytotoxic effects on the lymphoid 2007). Anthracyclines (daunorubicin, doxorubicin, and
tissue led to studies on transplanted lymphosarcoma in epirubicin) are perhaps the most well-known chemother-
mice, quickly leading to clinical trials in patients with apeutics that cause CHF (Zuppinger and Suter 2010; Geiger
lymphoid malignancies in 1942, beginning the era of cancer et al. 2010; Yeh and Bickford 2009). Long-term cardio-
chemotherapy. toxicity has been described in other cytotoxic agents as well
Targeting the metabolic pathways, antifolates produced (Geiger et al. 2010; Yeh and Bickford 2009) such as alky-
the first dramatic, but short lived remissions in acute leu- lating agents (cyclophosphamide, ifosfamide, and cisplatin)
kemias in 1948, and first cure of choriocarcinoma in 1963. and the newer targeted therapies (Zuppinger and Suter
In the ensuing decades, a variety of chemical agents were 2010; Geiger et al. 2010; Yeh and Bickford 2009), includ-
shown to have antitumor effects in animal models, and ing monoclonal antibody-based tyrosine kinase inhibitors
began to be tested in human malignancies. Fluorouracil was (bevacizumab and trastuzumab).
the first rationally designed drug that interfered with syn-
thesis and function of nucleic acid in 1957. Natural prod-
ucts, derived mostly from plants, such as vinca alkaloids 2.1.1 Types of Chemotherapeutic Agents
(e.g., vincristine), taxanes (e.g., paclitaxel), podophyllo-
toxins (e.g., etoposide), camptothecins (e.g., irinotecan), as 2.1.1.1 Anthracyclines
well antibiotics derived from fungi such as doxorubicin Since their introduction in the 1960s, anthracyclines have
along with miscellaneous agents such as the platinum been an integral component of many cytotoxic regimens in
compounds (e.g., cisplatin) are the mainstay of antineo- both the pediatric and adult populations (Smith et al. 2010).
plastic chemotherapy today. Doxorubicin and daunorubicin are produced by the fungus
The field of Medical Oncology emerged as a subspe- S. peucetius, and idarubicin and epirubicin are synthetic
cialty of Internal Medicine in 1972, with a focus on maxi- derivatives. They all share a common structure of a tetra-
mizing the beneficial effects and minimizing the side effects cycline ring with quinine and hydroquinone moieties on
of these agents which were by definition highly biotoxic, adjacent rings that permit them to function as electron-
with a very narrow therapeutic index. A great deal of effort accepting and -donating agents. Mitoxantrone is an an-
has been devoted to containing the acute side effects, such throcenedione with less cardiac toxicity than the anthracy-
as nausea, vomiting and diarrhea, as well as myelosup- clines. Unfortunately, anthracyclines can cause cardiac
pression, and is not the topic of this chapter. With suc- dysfunction and this adverse effect is categorized into acute
cessful treatments of many malignancies, long-term reversible and early- and late-onset chronic progressive
toxicities began to emerge, and efforts began to best miti- cardiotoxicity (Yeh and Bickford 2009; Trachtenberg et al.
gate those effects without compromising the therapeutic 2011; Wouters et al. 2005). Cardiac damage caused by
outcomes. This chapter will outline the late effects of che- anthracyclines can manifest as either subclinical or clinical
motherapy based on organ systems, and will provide pre- cardiotoxicity (van Dalen et al. 2009, 2010). The term
vention, follow-up, and monitoring guidelines. It will also subclinical cardiotoxicity is defined by various cardiac
describe the use of pharmacogenomics for mitigation of abnormalities, such as decreased left ventricular ejection
biotoxicity of these agents, and attempt to look at future fraction (LVEF), as confirmed by diagnostic tests in patients
research directions in the development of genetic markers without symptoms (van Dalen et al. 2009, 2010) while
as well as therapeutic agents to prevent or treat late effects clinical cardiotoxicity describes patients who experience
of chemotherapy. symptoms of cardiac damage due to cardiac dysfunction
Biotoxicity of Chemotherapy 125

(van Dalen et al. 2009, 2010). Common clinical manifes- Table 1 Maximum lifetime cumulative doses of various anthracy-
tations of anthracycline-induced cardiotoxicity may include clines (Zuppinger and Suter 2010)
arrhythmias, electrocardiographic abnormalities, heart fail- Types of Maximum lifetime cumulative doses mg/
ure, or a myocarditis and pericarditis syndrome (Trachten- anthracyclines m2
berg et al. 2011). Daunorubicin 550–800
Doxorubicin 400–550
Incidence Epirubicin 900–1000
Acute reversible anthracycline-induced cardiotoxicity Idarubicin 150–225
occurs in \1 % of childhood cancer patients immediately Mitoxantrone 100–140
after infusion of anthracyclines (Giantris et al. 1998) and is
Adapted from Geiger and colleagues with permission
defined by a transient decrease in myocardial contractility
with improvement after discontinuation of treatment
(Wouters et al. 2005; Giantris et al. 1998). In a study of et al. 2005; Von Hoff et al. 1979; Swain et al. 1997). In
adult patients with lymphoma, Nousiainen et al. (2002) contrast, the incidence of heart failure for patients after
reported that the prevalence of subclinical cardiac damage epirubicin (0.9–3.3 %) or idarubicin (5–18 %) appears to be
is at 36 % during anthracycline therapy, as defined by more less (Yeh and Bickford 2009). Table 1 lists the maximum
than 10 % decline in absolute ejection fraction units to a lifetime cumulative doses for various anthracyclines before
final LVEF of B50 %. Although discontinuation of therapy risk of clinical cardiotoxicity becomes clinically significant.
usually results in marked improvement, some patients Aside from high cumulative dose of anthracyclines, other
nonetheless suffer permanent cardiac damage, especially for risk factors for development of cardiotoxicity include young
those who received higher cumulative doses of anthracy- children, elderly people, females, bolus administration and
clines (Wouters et al. 2005). Furthermore, the risk of higher single doses of anthracyclines, history of radiother-
developing heart failure remains a lifelong threat as more apy, concomitant therapy with agents known to have car-
cancer patients are now living longer due to recent advances diotoxic effects, and pre-existing cardiovascular disorders
in oncologic therapies (Zuppinger and Suter 2010; van (Geiger et al. 2010; Trachtenberg et al. 2011; Von Hoff
Dalen et al. 2009, 2010). Kremer et al. (2001) reported that et al. 1979) (Table 2).
the risk of developing clinical heart failure remains elevated Two recent meta-analyses examined if different dosing
at approximately 5 % even at 15 years after anthracycline schedules and various anthracycline derivates reduce car-
therapy for childhood cancer. diotoxicity. The risk of clinical heart failure is significantly
Early-onset chronic anthracycline-induced cardiotoxicity lower with an infusion duration of 6 h or longer of anth-
is defined by progressive depression of myocardial function racyclines as compared to a shorter duration (relative risk
within the first year after treatment and occurs in 1.6–2.1 % (RR) = 0.27; 95 % confidence interval (CI) 0.09–0.81; 5
(Kremer et al. 2001; Krischer et al. 1997) of children treated studies; 557 patients) (van Dalen et al. 2009). However, the
with anthracyclines. Late-onset chronic progressive same authors (van Dalen et al. 2009) reported no statisti-
anthracycline-induced cardiotoxicity occurs at least 1 year cally significant difference in the occurrence of clinical
after anthracycline therapy with a latency period when no heart failure in patients treated with a doxorubicin peak
cardiac dysfunction is detected and the patients have no dose of \60 mg/m2 versus C60 mg/m2 (RR = 0.65; 95 %
symptoms (Giantris et al. 1998). Kremer et al. (2001) CI 0.23–1.88; 2 studies; 4,146 patients), a liposomal
reported that the cumulative incidence of anthracycline- doxorubicin peak dose of 25 mg/m2 versus 50 mg/m2 (No
induced clinical heart failure in children after a mean fol- patients in either treatment groups developed clinical heart
low-up time of 6.3 years is 2.8 % while Von Hoff et al. failure; 1 study; 48 patients), and an epirubicin peak dose of
(1979) reported an incidence of 1.6 %. In adults with breast 83 mg/m2 versus 110 mg/m2 (RR = 0.97; 95 % CI
cancer, Meinardi et al. (2002) reported that the incidence of 0.06–15.48; 1 study; 1,086 patients). Regarding the risk of
clinical heart failure is 30 % at a median of 37 months after cardiotoxicity with various anthracycline derivatives, only
adjuvant treatment with epirubicin and locoregional radio- liposomal-encapsulated doxorubicin is found to be associ-
therapy. Interestingly, the majority of adult patients who ated with a significantly lower rate of clinical heart failure
developed cardiotoxicity have a chronic dilated cardiomy- when compared to conventional doxorubicin (RR = 0.20;
opathy while the pediatric populations experience mainly a 95 % CI 0.05–0.75; 2 studies; 521 patients) (van Dalen
restrictive cardiomyopathy (Giantris et al. 1998). et al. 2010). No evidence for a significant difference in the
The risk of cardiotoxicity increases with higher cumu- occurrence of clinical heart failure exists between epirubi-
lative dose of anthracycline. Heart failure occurs in 3–5, cin versus doxorubicin of the same dose (RR = 0.36; 95 %
7–26, and 18–48 % of patients with cumulative doxorubicin CI 0.12–1.11; 5 studies; 1,036 patients) (van Dalen et al.
dose of 400, 550, and 700 mg/m2, respectively (Wouters 2010).
126 C. Fung and K. J. Pandya

Table 2 Risk factors predisposing patients to anthracycline-associ- affinity for cardiolipin, which is a phospholipid in the inner
ated cardiotoxicity (Zuppinger and Suter 2010; Carver et al. 2007) cell membrane of cardiac mitochondria that facilitates
Risk factors Increased risk in case of transport of anthracyclines (Trachtenberg et al. 2011;
Age at diagnosis Young (\4 years) and old age Wouters et al. 2005). This affinity leads to increased accu-
([65 years) mulation of anthracyclines inside cardiomyocytes (Trach-
Sex Female tenberg et al. 2011; Wouters et al. 2005).
Rate and schedule of Rapid infusion resulting in high peak Other postulated mechanisms for anthracycline-induced
anthracycline dose cardiotoxicity include transcriptional changes in intracel-
administration lular adenosine triphosphate (ATP) production in cardio-
Individual anthracycline Higher daily dose myocytes (Yeh and Bickford 2009); impaired formation of
dose the myofilament protein known as titin in cardiac sarco-
Cumulative anthracycline Increased cumulative dose meres via calcium-dependent protease activation (Yeh and
dose
Bickford 2009; Trachtenberg et al. 2011); downregulation
Radiation therapy Cumulative dose [30 Gy to the of transcription factors involved in sarcomere synthesis
mediastinum or [5 Gy to the heart
such as GATA4 (Trachtenberg et al. 2011); decrease in
Concomitant therapy Trastuzumab, cyclophosphamide,
cardiac glutathione peroxidase activity (Yeh and Bickford
bleomycin, vincristine, amsacrine,
and mitoxantrone 2009); depletion of cardiac stem cells (Trachtenberg et al.
Pre-existing cardiovascular Hypertension, coronary heart disease,
2011); respiratory defects associated with mitochondrial
disorders valvular disorders, prior cardiotoxic DNA damage (Yeh and Bickford 2009; Trachtenberg et al.
treatment 2011), and impaired mitochondrial creatine kinase activity
Medical comorbidities Diabetes, obesity, renal dysfunction, and function (Trachtenberg et al. 2011). Recently, Lyu et al.
pulmonary disease, endocrinopathies, (2007) hypothesized that cardiotoxicity caused by doxoru-
hypocalcemia and hypomagnesemia, bicin may also be due to disruption of the activity of
sepsis, infection, thyrotoxicosis,
alcohol, and pregnancy topoisomerase II beta.
Others Trisomy 21 and African American
ancestry 2.1.1.2 Alkylating Agents
Adapted from Geiger and colleagues (Zuppinger and Suter 2010) and Drugs that contain reactive alkyl groups capable of forming
Trachtenberg and colleagues (Carver et al. 2007) with permission
covalent bonds with DNA are included in this group. Except
cisplatin, these drugs were developed from nitrogen mus-
Pathophysiology tards, and their clinical use launched the era of cancer
The underlying mechanism of anthracycline-induced car- chemotherapy.
diotoxicity is complex and remains incompletely under-
stood despite decades of research (Trachtenberg et al. Incidence
2011). Loss of myofibrils and cytoplasmic vacuolization Cyclophosphamide. No cardiotoxicity has been reported for
caused by dilatation of the sarcoplasmic reticulum in low doses of cyclophosphamide (Floyd et al. 2005). How-
cardiomyocytes are the most prominent histological fea- ever, acute cardiac toxicity has been described after high-
tures (Wouters et al. 2005). Oxidative stress caused by free dose cyclophosphamide (120–200 mg/kg) (Yeh and Bick-
radical formation is generally accepted as the main mech- ford 2009; Floyd et al. 2005; Senkus and Jassem 2011), as
anism (Zuppinger and Suter 2010; Geiger et al. 2010; Yeh commonly administered in high-dose conditioning regimens
and Bickford 2009; Trachtenberg et al. 2011; Wouters et al. for bone marrow transplantation (Floyd et al. 2005). Clin-
2005). Reduction of the quinine moiety of anthracyclines to ical manifestations may include electrocardiogram changes
semiquinone generates reactive oxygen species that initiates (decreased amplitude of the QRS complex and nonspecific
a cascade of free radical formation (Trachtenberg et al. T wave of ST segment abnormalities), arrhythmias, con-
2011), which causes damage to cells, cell membranes, and duction disorders, and hemorrhagic myopericarditis leading
subcellular apparatuses (Trachtenberg et al. 2011; Wouters to pericardial effusion, tamponade, and death in some cases
et al. 2005). Since cardiomyocytes have high oxidative (Floyd et al. 2005; Senkus and Jassem 2011). While an
metabolism as evidenced by the abundance of cardiac asymptomatic transient decrease in ejection fraction has
mitochondria (Trachtenberg et al. 2011) but with fewer been reported that usually resolves over 3–4 weeks (Floyd
natural antioxidants than other organs (Trachtenberg et al. et al. 2005), up to 28 % of patients may develop acute-onset
2011; Wouters et al. 2005), they are most susceptible to fulminant heart failure after high-dose cyclophosphamide
oxidative stress (Trachtenberg et al. 2011; Wouters et al. (Floyd et al. 2005). Risk of cardiotoxicity is increased with
2005). Furthermore, anthracyclines have a very strong elderly patients, prior anthracycline or mitoxantrone
Biotoxicity of Chemotherapy 127

therapy, and mediastinal radiation (Yeh and Bickford 2009; 2.1.1.3 Monoclonal Antibody-Based Tyrosine
Floyd et al. 2005; Senkus and Jassem 2011). Kinase Inhibitors
Ifosfamide. Arrhythmias, ST-T wave changes, and CHF
associated with left ventricular dysfunction have been Incidence
reported for ifosfamide in a dose response manner, usually Trastuzumab. Trastuzumab, a recombinant DNA-derived
observed at doses greater than 6.25–10 g/m2, and these humanized monoclonal antibody that selectively binds to
toxicities are usually reversible with medical treatment the extracellular domain of the HER2 protein, is perhaps the
(Floyd et al. 2005; Senkus and Jassem 2011). However, best recognized targeted compound associated with a rela-
controversy exists regarding if concomitant administration tively high risk of cardiac complications (Floyd et al. 2005;
of both ifosfamide and anthracyclines increases cardiotox- Senkus and Jassem 2011). Various degrees of left ventric-
icity (Floyd et al. 2005). ular systolic dysfunction, which occasionally leads to CHF,
Cisplatin. Acute cardiotoxicity of cisplatin includes is the most common trastuzumab-related cardiac damage
supraventricular tachycardia, bradycardia, ST-T wave (Senkus and Jassem 2011). Improvement of symptoms
changes, left bundle branch block, acute ischemic events, usually occurs within 6 weeks after discontinuation of
myocardial infarction, and ischemic cardiomyopathy (Floyd trastuzumab and its reinstitution is usually possible with
et al. 2005; Senkus and Jassem 2011). Importantly, risk of resolution of symptoms (Senkus and Jassem 2011).
cardiovascular diseases remains elevated many years after In the first landmark clinical trial that evaluated the effi-
treatment with cisplatin (Senkus and Jassem 2011; Fung and cacy and safety of trastuzumab by Slamon et al. (2001), New
Vaughn 2011). For instance, the risk of cardiovascular York Heart Association class III or IV cardiac dysfunction
disease in long-term testicular cancer survivors who occurred in 27 % of the group given an anthracycline,
received cisplatin-based chemotherapy is approximately cyclophosphamide, and trastuzumab; 8 % of the group given
twofold greater than those treated with orchiectomy alone an anthracycline and cyclophosphamide alone; 13 % of the
(Fung and Vaughn 2011). This increased risk of cardio- group given paclitaxel and trastuzumab; and 1 % of the
vascular disease may be an indirect result of increased group given paclitaxel alone. In more recent studies, how-
incidence of hypertension, hyperlipidemia, and metabolic ever, the reported incidence of cardiac complications
syndrome observed in patients after cisplatin-based che- resulting from trastuzumab was lower with careful moni-
motherapy (Fung and Vaughn 2011). toring of cardiac function and avoidance of concomitant
administration of anthracyclines (Senkus and Jassem 2011).
Pathophysiology The incidence of cardiac dysfunction ranges from 2 to 7 %
The precise mechanism of cyclophosphamide-induced car- when trastuzumab is used as monotherapy and 2–13 % when
diotoxicity is unknown. Cyclophosphamide may cause it is combined with paclitaxel (Yeh and Bickford 2009).
endothelial capillary damage leading to extravasations of More importantly, approximately 1 % of patient will ulti-
toxic metabolites resulting in damage to cardiomyocytes and mately develop symptomatic CHF (Hayes and Picard 2006).
hemorrhagic necrosis of the myocardium (Yeh and Bickford A recent phase II trial by Rayson et al. (2011) examined
2009; Floyd et al. 2005; Senkus and Jassem 2011). Ifosfa- the cardiac safety of adjuvant trastuzumab with liposomal
mide may cause cardiotoxicity through a similar mechanism doxorubicin in women with breast cancer. The incidence of
as cyclophosphamide due to their analogous structures (Yeh cardiac toxicity or inability to administer trastuzumab due
and Bickford 2009). Furthermore, ifosfamide can cause to cardiotoxicity was 18.6 % (n = 11) in the group with
nephrotoxicity that results in delayed elimination of cardio- doxorubicin and cyclophosphamide followed by paclitaxel
toxic metabolites along with disturbances of fluid, acid–base, and trastuzumab compared to 4.2 % (n = 5) in the group
and electrolyte homeostasis (Yeh and Bickford 2009; Floyd that replaced doxorubicin with the liposomal formulation
et al. 2005; Senkus and Jassem 2011). (Rayson et al. 2011). In a group of 30 patients with HER2-
Direct endothelial damage caused by cisplatin, as shown overexpressing metastatic breast cancer, Chia et al. (2006)
by elevations in von Willebrand factor, C-reactive protein, reported that after treatment with liposomal doxorubicin
and soluble intercellular adhesion marker 1, may explain and trastuzumab, no patient experienced symptomatic CHF;
the increased risk of cardiotoxicity (Fung and Vaughn however, three patients experienced an asymptomatic
2011). In addition, hypomagnesemia and hypokalemia absolute decline in LVEF of C15 % and all of them had
resulting from cisplatin-induced nephrotoxicity may in turn previous exposure to anthracyclines.
lead to conduction abnormality and cardiac arrhythmias in Increased cumulative dose of trastuzumab does not
the acute setting (Senkus and Jassem 2011). appear to correlate with risk of cardiotoxicity. Risk factors
128 C. Fung and K. J. Pandya

for trastuzumab-induced cardiomyopathy are age defects in their lining that exposes subendothelial collagen,
[50 years, pre-existing cardiovascular disease and border- which subsequently activates tissue factor and increases the
line LVEF, sequence of chemotherapy administration, risk of thrombotic events (Yeh and Bickford 2009). Fur-
mediastinal radiation and prior treatment with [300 mg/m2 thermore, inhibition of VEGF also leads to decreased con-
cumulative dose of anthracyclines (Yeh and Bickford centrations of nitric oxide and prostacyclin and
2009). overproduction of erythropoietin that result in increased
Bevacizumab. Bevacizumab is a recombinant humanized hematocrit and blood viscosity, all of which may predispose
monoclonal antibody that binds to and inhibits the biologic patients to risks of thromboembolism (Yeh and Bickford
activity of human vascular endothelial growth factor 2009).
(VEGF) (Floyd et al. 2005). Hypertension and thrombo-
embolic events are both well-recognized vascular toxicities 2.1.2 Cardioprotective Interventions
of bevacizumab (Senkus and Jassem 2011). Hypertension Dexrazoxane, which is an EDTA-like chelator of iron
occurs in 22–36 % of patients (Senkus and Jassem 2011) (Geiger et al. 2010), is the most widely investigated agent
and this risk is increased 3 times with low dose and 7.5 for reducing anthracycline-induced heart failure (van Dalen
times with high dose of bevacizumab as shown in a meta- et al. 2011). By removing iron from the anthracycline-iron
analysis of 7 trials (n = 1,850) (Zhu et al. 2007). Incidence complex or by binding to free iron, it prevents the formation
of arterial thromboembolic events is approximately 4–5 % of oxygen radicals, which are thought to be the main
(Senkus and Jassem 2011). When used alone, grade 2–4 left mechanism of anthracycline-induced cardiomyopathy
ventricular dysfunction developed in 2 % of patients (Floyd (Wouters et al. 2005). A recent meta-analysis by van Dalen
et al. 2005). Among patients who received concurrent et al. (2011) reported that dexrazoxane is associated with
anthracyclines, CHF occurred in 14 % of them and in 4 % lower risks of clinical heart failure (RR = 0.29; 95 % CI
of those who had prior exposure to anthracycline only 0.20–0.41; 10 studies; 1,619 patients). Furthermore, no
(Floyd et al. 2005). Risk factors for bevacizumab-induced evidence was found for a difference in response rate or
cardiovascular toxicity are age greater than 65 years and survival between the dexrazoxane and control groups in this
prior arterial thromboembolic events (Floyd et al. 2005). meta-analysis (van Dalen et al. 2011).
Dexrazoxane is currently approved in the United States
Pathophysiology and the European Union (Geiger et al. 2010) and is usually
HER2 protein is critical in the embryonic cardiogenesis and administered after a cumulative dose of 300 mg/m2 or at the
pathogenesis of cardiac hypertrophy (Yeh and Bickford beginning of an anthracycline-based chemotherapy (Geiger
2009; Senkus and Jassem 2011) and it activates transcrip- et al. 2010). The American Society of Clinical Oncology
tion factor AP-1 and nuclear kappa B factor, which are has published detailed guidelines regarding adjunctive use
involved in the pathogenesis of cardiac hypertrophy and of dexrazoxane (Hensley et al. 2009) as summarized in
cellular response to stress respectively (Senkus and Jassem Table 3. Aside from dexrazoxane, seven other agents,
2011). Inhibition of this pathway by trastuzumab leads to including N-acetylcysteine, phenethylamine, coenzyme
abnormal growth, repair, and survival of cardiomyocytes Q10, a combination of vitamins E and C and N-acetylcys-
(Yeh and Bickford 2009) and it may also cause ATP teine, L-carnitine, carvedilol, and amifostine, have been
depletion and contractile dysfunction of cardiomyocytes by studied and demonstrated no cardioprotective effects
disrupting the mitochondrial integrity through dysregulation (Hensley et al. 2009).
of the BCL-X proteins (Yeh and Bickford 2009). Other
proposed mechanisms include drug–drug interaction with 2.1.3 Cardiac Monitoring
anthracyclines; induction of immune-mediated destruction Regular monitoring of heart function is important during
of cardiomyocytes; and an indirect consequence of trast- chemotherapy with anthracyclines and trastuzumab (Yeh
uzumab-related effects outside the heart (Floyd et al. 2005). and Bickford 2009). Echocardiography and multi-gated
The underlying mechanism for development of bev- acquisition (MUGA) scan are the most common non-inva-
acizumab-induced CHF involves hypertension and inhibi- sive procedures performed to evaluate LVEF (Geiger et al.
tion of angiogenesis that causes reduction of myocardial 2010; Yeh and Bickford 2009) in order to monitor and
capillary density, cardiac fibrosis, and global contractile diagnose chemotherapy-induced cardiomyopathy (Yeh and
dysfunction (Senkus and Jassem 2011). Inhibition of angi- Bickford 2009). While echocardiography can identify val-
ogenesis may also explain the increased risk of arterial vular, pericardial disease, and both systolic and diastolic
thromboembolic events with bevacizumab (Yeh and Bick- dysfunction, MUGA scans primary detect decline in left
ford 2009). Since VEGF is responsible for endothelial cell ventricular dysfunction only (Yeh and Bickford 2009).
proliferation and survival, inhibition of VEGF decreases Although endometrial biopsy remains the gold standard for
their capability to generate in response to trauma and causes diagnosis of cardiac dysfunction, its invasive nature has
Biotoxicity of Chemotherapy 129

Table 3 American society of clinical oncology guidelines for use of dexrazoxane in 2008 (Geiger et al. 2010)
Category Recommendation
Breast cancer
Initial use in patients with metastatic breast cancer It is recommended that dexrazoxane not routinely be used for patients with
metastatic breast cancer receiving initial doxorubicin-based chemotherapy
Delayed use in patients with metastatic breast cancer who It is suggested that the use of dexrazoxane be considered for patients with
have received more than 300 mg/m2 of doxorubicin metastatic breast cancer who have received more than 300 mg/m2 of
doxorubicin in the metastatic setting and who may benefit from continued
doxorubicin-containing therapy; treatment of patients who received more than
300 mg/m2 in the adjuvant setting and are now initiating doxorubicin-based
chemotherapy in the metastatic setting should be individualized, with
consideration given to the potential for dexrazoxane to decrease response rates
as well as decreasing the risk of cardiac toxicity; these patients were not
included in the clinical trials of dexrazoxane
Use in patients receiving adjuvant chemotherapy for breast The use of dexrazoxane in the adjuvant setting is not suggested outside of a
cancer clinical trial
Other malignancies
Use in adult patients with other malignancies The use of dexrazoxane can be considered in adult patients who have received
more than 300 mg/m2 of doxorubicin-based therapy; caution should be
exercised in the use of dexrazoxane in setting in which doxorubicin-based
therapy has been shown to improve survival
Use in pediatric malignancies There is insufficient evidence to make a recommendation for the use of
dexrazoxane in the treatment of pediatric malignancies
Other anthracycline doses and schedules
Use in patients receiving other anthracyclines or other On the basis of the available data and extrapolations from the experience with
anthracycline dose schedules doxorubicin plus dexrazoxane, the use of dexrazoxane may be considered for
patients responding to anthracycline-based chemotherapy for advanced breast
cancer and for whom continued epirubicin therapy is clinically indicated; data
for using dexrazoxane with epirubicin for treatment of other cancers are
limited; data are insufficient to make a recommendation regarding the use of
dexrazoxane with other potentially cardiotoxic agents
Use in patients receiving high-dose anthracycline therapy There are no new data addressing the use of dexrazoxane, and there are no
new data regarding the clinical use of high-dose anthracyclines; thus, the panel
has elected to delete this particular guideline statement, since its clinical
relevance appears limited
Use in patients with cardiac risk factors There is insufficient evidence on which to base a recommendation for the use
of dexrazoxane in patients with cardiac risk factors or underlying cardiac
cause
Monitoring therapy
Termination of anthracycline therapy for patients receiving Patients receiving dexrazoxane should continue to undergo cardiac
dexrazoxane monitoring; after cumulative doxorubicin doses of 400 mg/m2, cardiac
monitoring should be frequent; the panel suggests repeating the monitoring
study after 500 mg/m2 and subsequently after every 50 mg/m2 of doxorubicin;
the panel suggests that the termination of dexrazoxane/doxorubicin therapy be
strongly considered in patients who develop a decline in LVEP to below
institutional normal limits or who develop clinical congestive heart failure
Dose of dexrazoxane It is suggested that patients who are being treated with dexrazoxane receive
dexrazoxane at a ratio of 10:1 with the doxorubicin dose, given by slow IV
push or short IV infusion, 15–30 min before doxorubicin or epirubicin
administration; a ratio of 10:1 with the epirubicin dose may be reasonable;
however, it should be noted that the optimal dose ratio has not been
determined
Adapted from Hensley and colleagues (Geiger et al. 2010) with permission

limited its use (Yeh and Bickford 2009). In addition, stress ventricular dysfunction (Carver et al. 2007). Tables 4 and 5
testing and dobutamine stress echocardiogram have also summarize proposed respective guidelines for cardiac sur-
been studied extensively but with mixed reported value in veillance during doxorubicin (Schwartz et al. 1987) and
their utility to enhance the diagnostic sensitivity for left trastuzumab (Keefe 2002) therapies.
130 C. Fung and K. J. Pandya

Table 4 Guidelines for monitoring patients receiving doxorubicin (Yeh and Bickford 2009)
Normal baseline LVEF C50 % Abnormal baseline LVEF \50 %
After cumulative dose of 250–300 mg/m2: second examination of LVEF Baseline LVEF B30 %: doxorubicin therapy should not
be initiated
After cumulative dose of 400 mg/m2 in patients with known cardiac risk factors Baseline LVEF between 30–50 %: LVEF should be
and 450 mg/m2 in absence of risk factors: third examination of LVEF with monitored before each dose of doxorubicin
sequential monitoring of cardiac function before each subsequent dose thereafter
Functional signs of cardiotoxicity and/or absolute decrease in LVEF C10 % Absolute decrease in LVEF C10 % and/or overall LVEF
associated with a decline to a level of overall LVEF B50 %: discontinue B30 %: discontinue doxorubicin therapy
doxorubicin therapy
LVEF left ventricular ejection fraction
Adapted from Schwartz and colleagues (Yeh and Bickford 2009) with permission

Table 5 Proposed guidelines for the management of patients treated with trastuzumab (Smith et al. 2010)
Action
Physical status LVEF Trastuzumab LVEF monitoring Management
a
Asymptomatic ; but normal Continue Repeat in 4 weeks
; [10 points but normal Continue Repeat in 4 weeks Consider b-blockers
; 10–20 points and LVEF Continue Repeat in 2–4 weeks Treat for CHF
[40 % *Improved: monitor
*Not improved: stop
trastuzumab
; [20 points to \40 % or Hold Repeat in 2 weeks Treat for CHF
LVEF \30 % *Improved to [45 %: restart
trastuzumab
*Not improved: stop
trastuzumab
Symptomatica ; \10 points Continue Search for noncardiac pathology
(e.g., anemia)
;[10 points and LVEF[50 % Continue Repeat in 2–4 weeks Treat for CHF
*Stable or improved: continue
trastuzumab
*Worsened: stop trastuzumab
; \30 points Stop Treat for CHF
LVEF left ventricular ejection fraction, CHF congestive heart failure
a
Asymptomatic is defined by changes in heart rate (HR) (increase in HR by 10 beats per minute with baseline HR of\80 bpm or an increase by
20 bpm with baseline HR of C80 bpm) and/or weight (weight increase of C2 kg in 1 week) without symptoms of dyspnea on exertion.
Symptomatic is defined by symptoms of dyspnea on exertion, pulmonary vascular congestion, or edema
Adapted from Keefe and colleagues (Smith et al. 2010) with permission

There is evidence that several biochemical markers, 2.2 Pulmonary Toxicity

including elevations in troponin I (Cardinale et al. 2002,
2004) and B-type natriuretic peptide (BNP) (Nousiainen A wide variety of chemotherapeutic agents has pulmonary
et al. 2002), may indicate early myocardial injury before toxicities (Carver et al. 2007; Limper 2004) as shown in
development of left ventricular dysfunction. Therefore, Table 6. Onset of these adverse effects may be acute or
there has been interest in serial measurements of BNP to insidious (Limper 2004), with some of them causing per-
detect changes in left ventricular function (Carver et al. manent lung damage in long-term cancer survivors (Limper
2007). However, no study has thus far validated this as a 2004; Huang et al. 2011). Clinical manifestations include
routine measurement or screening tool in this population dyspnea, nonproductive cough, and fever, which may
(Carver et al. 2007). develop weeks to years after chemotherapy (Limper 2004).
Biotoxicity of Chemotherapy 131

Table 6 Chemotherapy agents associated with pulmonary toxicity cumulative bleomycin dose \300 mg to 20 % with doses
(Trachtenberg et al. 2011; Wouters et al. 2005) [500 mg (Fung and Vaughn 2011). Aside from cumulative
Class of chemotherapy Agents dose of bleomycin, other risk factors that predispose
Antibiotics Bleomycin patients to bleomycin-induced lung injury include medias-
Mitomycin C tinal radiation, renal dysfunction, increased age, smoking,
Alkylating agents Busulfan
exposure to high-inspired oxygen concentration, and pre-
existing pulmonary comorbidity (Carver et al. 2007; Fung
Cyclophosphamide
and Vaughn 2011; Limper 2004). Concomitant adminis-
Chlorambucil
tration of cyclophosphamide, vincristine, doxorubicin, and
Procarbazine methotrexate with bleomycin has also been reported to
Antimetabolites Methotrexate increase risk of pulmonary fibrosis (Huang et al. 2011).
Cytosine arabinoside
Fludarabine Pathophysiology
Gemcitabine The primary mechanism for BIP is direct endothelial
Antimicrotubules agents Docetaxel damage from bleomycin (Huang et al. 2011; Sleijfer 2001;
Cooper et al. 1988), most likely caused by induction of
Paclitaxel
cytokines and free radicals (Sleijfer 2001). These cytokines
Vinca alkaloids
activate lymphocytes and upregulate adhesion molecules of
Nitrosamines Carmustine the endothelial cells, which facilitates adhesion and influx
Topoisomerase inhibitors Etoposide of inflammatory cells, including macrophages, neutrophils,
and lymphocytes, into the lung interstitium via the endo-
thelium (Sleijfer 2001). Damage of the endothelial cells,
Aside from hilar lymphadenopathy that is commonly along with infiltration of inflammatory cells into the inter-
associated with methotrexate-induced lung injury, there is stitium, subsequently activates fibroblasts to deposit colla-
no characteristic radiographic pattern that is specific for gen, which causes pulmonary fibrosis (Sleijfer 2001).
other chemotherapy agents. Bleomycin and busulfan are the
most relevant in terms of late effects and will be the main
focus of this section. 2.2.1.2 Busulfan

2.2.1 Types of Chemotherapeutic Agents Incidence

Busulfan is an alkylating agent with myelosuppressive
2.2.1.1 Bleomycin properties, and is commonly used in the myeloablative
Bleomycin is an antibiotic mixture of two copper chelating conditioning regimen of bone marrow transplantation for
peptides; fermentation products of Streptococcus verticillus, hematologic malignancies (Limper 2004; Bilgrami et al.
used in the curative treatment of lymphomas and testicular 2001) and idiopathic pneumonia syndrome (IPS) has been
tumors. described in this population (Bilgrami et al. 2001). The
incidence of busulfan pulmonary toxicity is approximately
Incidence 6 %, with a range of 2.5–43 % (Limper 2004). The average
As many as 20 % of patients develop pulmonary disease time from initiation of therapy to onset of pulmonary
after bleomycin (Limper 2004) and the mortality rate from symptoms is approximately 3.5 years, with some patients
bleomycin-induced pulmonary diseases reaches as high as developing symptoms up to 10 years after treatment (Lim-
1 % (Limper 2004). Bronchiolitis obliterans, eosinophilic per 2004). Dyspnea, cough, and fever are common clinical
hypersensitivity, and interstitial pneumonitis are common manifestations and occur in a more insidious nature than
bleomycin-related pulmonary disorders (Yousem et al. with other chemotherapy-related lung disease (Limper
1985). Unexplained nonproductive cough and dyspnea on 2004). While some patients improve after discontinuation of
exertion are frequently first signs of bleomycin-induced busulfan and administration of corticosteroids, many
pneumonitis (BIP) (Comis 1990; Sleijfer 2001) followed by develop progressive lung impairment that may ultimately
onset of fever, tachypnea, cyanosis, and dyspnea with pro- lead to death (Limper 2004). Unlike bleomycin, it is
gressive lung injury (Comis 1990; Sleijfer 2001). uncertain if busulfan-related lung injury occurs in a dose-
There is a linear relationship between the cumulative dependent fashion (Limper 2004). However, concomitant
dose of bleomycin and the incidence of pulmonary toxicity radiation and cytotoxic agents, such as cyclophosphamide,
in animal models (Sleijfer 2001). Studies have shown that thiotepa, and melphalan, appear to increase pulmonary
the incidence of BIP increases from 3 to 5 % with toxicities (Limper 2004; Bilgrami et al. 2001).
132 C. Fung and K. J. Pandya

Pathophysiology regarding role of corticosteroids in management of BIP

The exact mechanism for busulfan-induced lung injury is from prospective randomized trials is lacking, corticoste-
unknown, but cell-mediated immune reactions and release roids (for example, prednisone 60–100 mg/day) are the
of cytokines are thought to be involved (Bilgrami et al. mainstay of treatment currently (Sleijfer 2001). For BIP that
2001). Atypical oval or elongated cells, intra-alveolar rather are refractory to standard-dose corticosteroids, azathioprine
than interstitial fibrosis, and multinucleated giant cell con- (150 mg/day) and high-dose corticosteroids have been used
taining eosinophilic nuclear inclusions are common histo- successfully (Fung and Vaughn 2011; Maher and Daly
logical features with busulfan-induced lung toxicity 1993). Similarly, early treatment with corticosteroids is
(Bilgrami et al. 2001). Furthermore, the number of type I common for busulfan-induced pulmonary toxicities (Bilg-
pneumocytes decreases while type II pneumocytes prolif- rami et al. 2001).
erate, delamellate, and migrate into alveolar sacs (Bilgrami
et al. 2001). Consequently, this may lead to extensive
accumulation of alveolar debris that yields a pattern similar 2.3 Nephrotoxicity
to alveolar proteinosis (Limper 2004).
Nephrotoxicity is an inherent adverse effect of several
2.2.2 Pulmonary Function Monitoring chemotherapeutic agents (Kintzel 2001) as shown in
Historically, pulmonary function test (PFT), which includes Table 7. Mechanism of chemotherapy-induced renal dys-
measurement of lung volumes and oxygen diffusion function usually involves vasculature or tubular damage of
capacity, has been used to monitor for BIP (Fung and the kidneys along with inadequate renal perfusion (Kintzel
Vaughn 2011). Bleomycin was traditionally withheld if the 2001; Skinner 2011). Hypertension, proteinuria, and vary-
diffusion capacity of carbon monoxide (DLCO) fell below ing degrees of renal insufficiency are common clinical
40–60 % of the pretreatment value (Comis 1990). Sleijfer manifestations of chemotherapy-induced nephrotoxicity
et al. (1995) examined the validity of using DLCO to detect (Jones et al. 2008). While these symptoms may be transient,
onset of BIP in testicular cancer patients and showed that chronic renal insufficiency may develop insidiously in a
DLCO declined in both groups of patients receiving bleo- minority of patients (Skinner 2011). Long-term renal dys-
mycin, etoposide, and cisplatin (BEP) and etoposide and function associated with cisplatin and ifosfamide (Fung and
cisplatin (EP). However, the decrease in DLCO of the BEP Vaughn 2011; Jones et al. 2008) have been described and
group became significant only at 12 weeks after completion will be the main focus of this section.
of treatment (P \ 0.01) when compared to the EP group.
Therefore, the authors concluded that a decline in DLCO 2.3.1 Types of Chemotherapeutic Agents
during active treatment should not be used as the basis for
discontinuation of bleomycin therapy. In long-term survi- 2.3.1.1 Cisplatin
vors of Hodgkin’s disease, PFT monitoring has been Cisplatin has broad antineoplastic activity, and plays an
reported in several clinical trials and they showed that early indispensible role in the curative treatment regimens for
decline in PFT is followed by subsequent improvement over testicular cancer. It has activity against ovarian cancer as
time in most patients (Carver et al. 2007). well as cancers of the head and neck, lung, bladder, and
Aside from DLCO, Haugnes et al. (2009) have studied esophagus, and is used as adjuvant therapy in many of these
the validity of using other PFT measures to monitor for cancers.
pulmonary damage in 1,049 long-term testicular survivors
after chemotherapy. They reported a decline in both the Incidence
predicted forced vital capacity (FVC) and forced expiratory Clinical manifestations of cisplatin nephrotoxicity include
volume in one second (FEV1) in this cohort of patients. acute and/or chronic renal insufficiency, hypokalemia, and
However, the onset of the decrease in these parameters is hypomagnesemia, which many cause paresthesia, tremor,
unclear and therefore, routine use of FVC and FEV1 to tetany, and convulsions (Fung and Vaughn 2011; Skinner
monitor for chemotherapy-induced pulmonary damage is 2011). Among long-term testicular cancer survivors treated
not currently recommended during chemotherapy for tes- with cisplatin, approximately 20–30 % of them developed a
ticular cancer patients. long-term deterioration in renal function, with an average
decline of 20–30 % in glomerular filtration rate (GFR)
2.2.3 Management of Chemotherapy-Induced (Fung and Vaughn 2011). A recent study by Skinner et al.
Pulmonary Toxicities (2009) examined the incidence of long-term nephrotoxicity
Withholding bleomycin at the earliest clinical signs or in 27 children who received cisplatin. At 10-year follow-up,
symptoms of pulmonary toxicities is the most effective they reported that there was no recovery of cisplatin-
treatment for BIP (Fung and Vaughn 2011). Although data induced renal toxicity, as measured by GFR and serum
Biotoxicity of Chemotherapy 133

Table 7 Chemotherapy agents associated with nephrotoxicity (van 2.3.1.2 Ifosfamide

Dalen et al. 2010)
Class of chemotherapy Agents Incidence
Antibiotics Mitomycin Ifosfamide has a critical role in the treatment of many solid
Alkylating agents Ifosfamide pediatric malignancies, including bone and soft-tissue sar-
Antimetabolites Azacitidine
coma, Wilm’s tumor, neuroblastoma, and germ cell tumors
(Lawson et al. 2008). Proximal tubular dysfunction and
Gemcitabine
decline in GFR, are the most common clinical manifestation
Methotrexate
of ifosfamide-induced nephrotoxicity (Jones et al. 2008),
Pentostatin causing rise in serum creatinine and blood urea nitrogen
Nitrosamines Carmustine levels, oliguria, and proximal tubular wasting of electro-
Semustine lytes, glucose, and amino acids (Kintzel 2001). Although
Platinum agents Carboplatin most acute renal tubular dysfunction resolves, a minority of
Cisplatin kidney damage is permanent and potentially progressive
Vascular endothelial growth inhibitors Bevacizumab (Jones et al. 2008).
In a study of 16 pediatric osteosarcoma patients after high-
Sorafenib
dose ifosfamide (14 g/m2 per course), 25 % of them expe-
Sunitinib
rienced a reduction in GFR, as defined by C3 times increase
Others Interferon-a in normal serum creatinine level (Berrak et al. 2005). Skinner
Adapted from Kintzel and colleagues (van Dalen et al. 2010) with et al. (2000) also reported that 17–50 % of pediatric sarcoma
permission
patients treated with conventional doses of ifosfamide sub-
sequently developed progressive renal insufficiency. Fur-
magnesium. GFR was \60 ml/min/1.73 m2 in 11 % of thermore, Suarez et al. (1991) reported that among 74
them at both completion and 10 years after chemotherapy. children with malignant mesenchymal tumors who received
Risk factors for development of cisplatin nephrotoxicity ifosfamide, 5 % of them developed persistent renal tubul-
include high cumulative cisplatin dose (C500 mg/m2), opathy that resulted in Fanconi syndrome.
increased rate of infusion, older age, pre-existing renal Risk factors that may predispose patients to ifosfamide-
disease, renal radiation (C15 Gy), and concomitant treat- induced nephrotoxicity include younger age at treatment
ment with other nephrotoxins, such as aminoglycosides, (\5 years at time of treatment), higher cumulative dose
amphotericin, immunosuppressants, and methotrexate (C60 g/m2), renal radiation (C15 Gy), and concurrent
(Fung and Vaughn 2011; Skinner 2011; Jones et al. 2008). administration of other nephrotoxins, including cisplatin,
In adults, renal toxicity is less common with low-dose cis- amphotericin, immunosuppressants, and methotrexate
platin (20 mg/m2/day) than high-dose (40 mg/m2/day) (Skinner 2011; Jones et al. 2008; Skinner et al. 2000). While
(Skinner 2011) while children who received [40 mg/m2/ most published reports of ifosfamide-induced renal damage
day developed significantly more nephrotoxicity than those were in infants and young children, the significance of age
at a lower dose (Skinner 2011). as a risk factor remains unclear (Skinner 2011). Although
several studies suggest that young age is a significant risk
Pathophysiology factor (Skinner 2011), this does not appear to predict long-
Cisplatin exerts direct toxic effects on both the renal tubules term nephrotoxicity at 10 years (Skinner et al. 2010).
and collecting ducts (Fung and Vaughn 2011). Filtration of Instead, Oberlin and colleagues recently reported that older
unbound cisplatin at the glomerulus leads to its uptake into age at treatment is associated with decreased GFR at
the renal tubular cells (Yao et al. 2007) where it is partially 10 years among 183 pediatric patients who received a
metabolized to nephrotoxic molecules, which subsequently median dose of 54 g/m2 of ifosfamide (RR = 1.08; 95 %
cause cell injury (Yao et al. 2007). Cisplatin also has other CI 1.01–1.15). Concurrent cisplatin predisposes patients to
intracellular effects that cause tubular damage and dysfunc- higher risk of renal toxicity (Fung and Vaughn 2011). Lo-
tion which may explain sodium, potassium, and magnesium ebstein et al. (1999) reported that the incidence of nephro-
wasting in patients (Yao et al. 2007). These mechanisms toxicity increased from 33.5 to 41.4 % when cisplatin was
include direct cytotoxicity with reactive oxygen species, included in the chemotherapy of pediatric testicular cancer
activation of mitogen-activated protein kinases, induction of patients after a cumulative ifosfamide dose of 45 mg/m2.
apoptosis, and stimulation of inflammation and fibrinogen-
esis (Yao et al. 2007). Furthermore, cisplatin may also induce Pathophysiology
renal vasculature damage, resulting in decreased blood flow The underlying pathogenesis of ifosfamide-induced neph-
and ischemic insult to the kidneys (Pabla and Dong 2008). rotoxicity is currently poorly understood but direct
134 C. Fung and K. J. Pandya

cytotoxicity by ifosfamide or its metabolites is most likely Table 8 ESCP SIG Cancer Care recommendations on the prevention
implicated (Skinner 2011), which may involve production of of cisplatin nephrotoxicity (van Dalen et al. 2009)
reactive oxygen species that causes disruption in tubular cell Before administration
energy pathways and membrane function (Skinner 2011). 1. Estimate GFR or CrCL using MDRD or Cockcroft-Gault formula,
Chloroacetaldehyde (CAA), a metabolite of ifosfamide, is respectively
thought to be the primary causative agent for ifosfamide- 2. Ensure euvolemia is present
induced renal damage (Skinner 2011). In a renal tubular cell Dosage
culture model, CAA causes an experimental Fanconi syn- Adjust cisplatin dosage according to the patient’s renal function
drome possibly by blocking active transport and increasing Administration
the permeability of tubular cell membranes (Skinner 2011).
Administer the platinum slowly
Hydration
2.3.2 Renal Protective Interventions
Aggressive hydration is the best strategy to reduce the risk 1. Use a saline solution infusion that produces a brisk diuresis
of cisplatin nephrotoxicity (Fung and Vaughn 2011). 2. Urine flow should be maintained at 3–4 1/24 h the preceding day
and for the next 2–3 days
However, evidence for forced diuresis using mannitol or
furosemide is controversial (Launay-Vacher et al. 2008). 3. Do not use diuretics, neither mannitol nor furosemide
While several experimental reports (Cvitkovic et al. 1977; 4. There are no data for patients who already are on diuretics, for
Pera et al. 1979) have suggested that these diuretics another concomitant disease such as hypertension
decreased cisplatin nephrotoxicity in animals, two ran- After administration
domized studies in humans (Al-Sarraf et al. 1982; Santoso 1. When feasible, determine serum creatinine 3–5 days after
et al. 2003) showed no such effect. At the same time, completion of the course
concomitant administration of nephrotoxic agents, such as 2. Monitor magnesium levels routinely and supplement when
necessary
aminoglycosides, non-steroidal anti-inflammatory drugs,
and iodinated contrast media, should be avoided in patients 3. Avoid co-adminstration of nephrotoxic drugs (aminoglycosides,
non-steroidal anti-inflammatory drugs, iodinated contrast media,
receiving cisplatin (Fung and Vaughn 2011). In 2008, the zoledronate, etc.)
European Society of Clinical Pharmacy Special Interest
4. Re-evaluate renal function before the next course
Group on Cancer Care published their recommendations on
CrCL Creatinine clearance, MDRD Modification of Diet in Renal
the prevention of cisplatin nephrotoxicity (Launay-Vacher Disease
et al. 2008) as shown in Table 8. Adapted from Launay-Vacher (van Dalen et al. 2009) and colleagues
The most important measure to reduce the risk of if- with permission
osfamide nephrotoxicity is hydration (Fung and Vaughn
2011). While sodium 2-mercaptoethanesulfonate (Mesna) is
effective in preventing hemorrhagic cystitis (Lawson et al.
2008), its renal protective effects are uncertain (Lawson 2.4 Peripheral Neuropathy
et al. 2008). Electrolyte supplementation for patients with
persistent electrolyte wasting is also critical after ifosfamide Chemotherapy-induced peripheral neuropathy (CIPN) is a
administration (Jones et al. 2008). common, potentially severe side effect that can affect the
quality of life in long-term cancer survivors (Cavaletti and
2.3.3 Surveillance of Nephrotoxicity Marmiroli 2010; Manji 2011). Sensory neuropathies,
Due to risks of long-term nephrotoxicity from chemother- including paresthesias and pain, are the most common
apy, patients should be monitored regularly using a defined symptoms of CIPN (Pachman et al. 2011), and they usually
surveillance protocol (Skinner 2011). According to the begin from the fingers and toes and spread proximally in a
Children’s Oncology Group of the United States (2008), ‘‘glove and stocking’’ distribution (Pachman et al. 2011).
pediatric oncology patients should have medical check-up Onset of CIPN usually begins weeks to months after initial
at least yearly that includes blood pressure monitoring and treatment with complete resolution of symptoms (Cavaletti
urinalysis. At the first long-term follow-up visit (C2 years and Marmiroli 2010; Manji 2011; Pachman et al. 2011).
after completion of chemotherapy), a basic metabolic panel However, in some cases, CIPN is only partially reversible
should be obtained to monitor electrolytes, blood urea and can become permanent (Pachman et al. 2011). Table 9
nitrogen, and creatinine levels. In addition, these patients lists the cytotoxic agents commonly associated with CIPN.
should use over-the-counter non-steroidal anti-inflamma- In this section, we will focus on antimicrotubule agents,
tory drugs with caution. platinum analogs, and proteasome inhibitors.
Biotoxicity of Chemotherapy 135

Table 9 Chemotherapy agents associated with peripheral neuropathy faster (Cavaletti and Marmiroli 2010; Carlson and Ocean
(Giantris et al. 1998) 2011). Examining a dataset of 1,540 patients who received
Class of chemotherapy Agents ixabepilone as a monotherapy or in combination with
Antimicrotubules agents Docetaxel capecitabine, Vahdat et al. (2012) reported pre-existing
Ixabepilone neuropathy as the only risk factor for ixabepilone-associ-
Paclitaxel
ated peripheral neuropathy.
Vinca alkaloids, including vincristine, vinorelbine, and
Vincristine
vinflunine, are all associated with CIPN (Cavaletti and
Platinum agents Carboplatin
Marmiroli 2010; Carlson and Ocean 2011). After discon-
Cisplatin tinuation of vincristine, up to 30 % of patients may continue
Oxaliplatin to experience peripheral neuropathy (Carlson and Ocean
Proteasome inhibitor Bortezomib 2011). Aside from sensory neuropathy, moderate to severe
Others Thalidomide autonomic dysfunction is also common after vincrisitine
Adpated from Cavaletti (Giantris et al. 1998) and colleagues with (Cavaletti and Marmiroli 2010; Carlson and Ocean 2011),
permission with colicky abdominal pain and constipation being its
symptoms (Cavaletti and Marmiroli 2010; Carlson and
2.4.1 Type of Chemotherapeutic Agents Ocean 2011). Furthermore, few cases of paralytic ileus and
megacolon have also been reported (Carlson and Ocean
2.4.1.1 Antimicrotubule Agents 2011). With the newer generation of vinca alkaloids, such
Paclitaxel, ixabepilone, and vincristine are microtubule as vinorelbine and vinflunine, patients usually develop a
inhibitors commonly associated with CIPN (Cavaletti and primarily sensory neuropathy that is reversible after dis-
Marmiroli 2010; Manji 2011). While paclitaxel and ixab- continuation of agents (Carlson and Ocean 2011).
epilone both induce polymerization and stabilization of
tubulin dimers, vincristine prevents tubulin polymerization Pathophysiology
from soluble dimers into microtubules (Cavaletti and Mar- The mechanisms for microtubules inhibitors-induced
miroli 2010). peripheral neuropathy have not been elucidated (Cavaletti
and Marmiroli 2010; Carlson and Ocean 2011). Disruption of
Incidence the active transport of proteins and other compounds within
The incidence of paclitaxel-induced grade 3 and 4 sensory the neuron has been proposed as the main mechanism since
neuropathy ranges from 2 to 32 % depending on the dose intact function of the microtubules is critical for anterograde
and schedule of its administration (Carlson and Ocean and retrograde axonal transport and the survival of neurons
2011), with its clinical manifestations including paresthe- (Carlson and Ocean 2011). There are evidence that taxanes,
sias, numbness, and/or pain in a stocking-glove distribution; such as paclitaxel and docetaxel, target both the axons and
decreased proprioception and vibration; sensory ataxia; gait the soma of the sensory neurons (Cavaletti et al. 1995, 1997;
disturbance; and impaired deep tendon reflexes (Cavaletti Persohn et al. 2005) with dorsal root ganglions as the initial
and Marmiroli 2010; Carlson and Ocean 2011). In some site of injury (Carlson and Ocean 2011; Cavaletti et al. 2000).
patients, myopathy accompanied by muscle weakness in Through signal transduction-mediated pathways, microglial
foot, finger, and ankle extensor muscles also develop activation within the spinal cord and macrophage activation
(Cavaletti and Marmiroli 2010; Carlson and Ocean 2011). within the dorsal root ganglion and peripheral nerves appear
Onset of peripheral neuropathy usually occurs after cumu- to be the key pathways in the pathogenesis of taxane-induced
lative doses of 100–300 mg/m2 of paclitaxel (Carlson and peripheral neuropathy (Cavaletti and Marmiroli 2010). The
Ocean 2011). Dose-dense administration of paclitaxel, pathophysiology for ixabepilone-induced peripheral neu-
albumin-bound paclitaxel, and concomitant administration ropathy is hypothesized to be similar to that of the taxanes
of platinum agents are other risk factors for paclitaxel- due to their similar mechanism of action (Carlson and Ocean
induced CIPN (Manji 2011; Carlson and Ocean 2011). 2011). Unlike ixabepilone and the taxanes, however, vinca
Approximately 1–24 % of patients experienced grade 3 alkaloids induce depolymerization of microtubules (Cava-
and 4 sensory neuropathy after ixabepilone, depending of its letti and Marmiroli 2010). This effect on tubulin dimers
dose and administration schedule (Carlson and Ocean causes alteration in the length, arrangement, and orientation
2011). Onset of CIPN usually occurs after cumulative doses of axonal microtubules (Cavaletti and Marmiroli 2010),
of 40–120 mg/m2 of ixabepilone (Carlson and Ocean 2011). which may explain axonal transport dysfunction and Wal-
Compared to peripheral neuropathy associated with paclit- lerian-like axonal degeneration (Cavaletti and Marmiroli
axel, peripheral neuropathy induced by ixabepilone is very 2010) observed in patients after treatment with vinca
similar in nature but its recovery appears to be considerably alkaloids.
136 C. Fung and K. J. Pandya

2.4.1.2 Platinum Agents Table 10 Comparison of cisplatin- and oxaliplatin-induced neurop-

Platinum compounds form DNA intrastrand adducts and athy (Nousiainen et al. 2002)
interstrand crosslinks that disrupt the structure and function Cisplatin Oxaliplatin
of DNA (Cavaletti and Marmiroli 2010) with peripheral Dose-limiting Peripheral Peripheral neuropathy
neuropathy being a significant side effect of both cisplatin toxicity neuropathy
and oxaliplatin (Fung and Vaughn 2011; Cavaletti and Symptoms Paresthesia Paresthesia, sensory ataxia,
Marmiroli 2010; Manji 2011). and dysesthesia
Location Extremities Extremities, perioral area
Incidence Time-course Delayed Acute and delayed
Approximately 7–31 % of testicular cancer patients under- onset
going cisplatin-based chemotherapy develop acute periph- After treatment Deterioration Usually recovery
eral neuropathy (Bajorin et al. 1993; de Wit et al. 2001; Accompanying Ototoxicity Laryngospasms
Nichols et al. 1998). After a median follow-up of 10 years, toxicities
persistent symptomatic peripheral neuropathy occurred in Precipitating None Exposure to cold
up to 30 % of testicular cancer patients after 3–4 cycles of factors
cisplatin-based chemotherapy (Brydoy et al. 2009; Glen- Adapted from Amtoulach and colleagues (Nousiainen et al. 2002) with
denning et al. 2010). Numbness, tingling, decreased pro- permission
prioception, and impaired vibratory and temperature
sensation are common clinical manifestations of cisplatin- Pathophysiology
induced peripheral neuropathy (Fung and Vaughn 2011; Cisplatin causes damage to the dorsal root ganglion, which
Cavaletti and Marmiroli 2010; Amptoulach and Tsavaris subsequently leads to anterograde axonal degeneration via
2011). Onset of peripheral neuropathy usually occurs after a several mechanisms (Fung and Vaughn 2011). By altering
cumulative cisplatin dose of [300 mg/m2 with 50–90 % of structures of neuronal DNA, it causes changes in the cell-
patients experiencing neuropathy after a cumulative dose of cycle kinetics that promote apoptosis, oxidative stress, and
[500 mg/m2 (Fung and Vaughn 2011; Amptoulach and mitochondrial dysfunction (Cavaletti and Marmiroli 2010;
Tsavaris 2011). Cumulative dose of cisplatin is the most Manji 2011). The mechanisms of action for acute and
significant risk factor for cisplatin-induced neuropathy chronic oxaliplatin-induced peripheral neuropathy are dif-
(Fung and Vaughn 2011; Brydoy et al. 2009; Amptoulach ferent and have not been fully elucidated (Argyriou et al.
and Tsavaris 2011). 2008). Evidence suggests that oxalate, a metabolite of ox-
The incidence of acute oxaliplatin-induced peripheral aliplatin, interferes with the voltage-gated sodium channels
neuropathy ranges from 65 to 85 % depending on the dose that are critical for calcium transport of the neurons in acute
and schedule of its administration (Argyriou et al. 2008), oxaliplatin-induced neuropathy (Cavaletti and Marmiroli
with its clinical symptoms including paresthesias and dys- 2010; Argyriou et al. 2008). On the contrary, chronic oxa-
esthesias in the extremities and perioral region that are liplatin-induced neuropathy results from accumulation of
exacerbated by cold exposure (Amptoulach and Tsavaris oxaliplatin in the cells of dorsal root ganglia due to
2011). In 1–2 % of patients, transient laryngopharyngeal decreased cellular metabolism and axonal transport, which
dysesthesia that manifests as shortness of breath and swal- ultimately lead to direct cytotoxicity to the neurons (Ar-
lowing difficulty may develop (Amptoulach and Tsavaris gyriou et al. 2008). Furthermore, injury to the mitochondria
2011; Argyriou et al. 2008). Although these acute toxicities by oxaliplatin has also been proposed as another potential
are reversible in approximately 80 % of patients and usually mechanism (Argyriou et al. 2008).
resolve completely in about 40 % of patients 6–8 months
after discontinuation of oxaliplatin (Amptoulach and 2.4.1.3 Proteasome Inhibitors
Tsavaris 2011), chronic neuropathy has been reported Peripheral neuropathy is an important dose-limiting toxicity
(Amptoulach and Tsavaris 2011; Argyriou et al. 2008). Its of bortezomib, which is a proteasome inhibitor approved for
incidence is related to various risk factors, including single the treatment of multiple myeloma (Cavaletti and Marmiroli
dose per course, cumulative dose, administration schedule, 2010; Cavaletti and Jakubowiak 2010). More importantly,
and pre-existing peripheral neuropathy (Amptoulach and up to 20 % of patients with multiple myeloma experience
Tsavaris 2011; Argyriou et al. 2008). Table 10 compares baseline sensory peripheral neuropathy from the disease
the clinical characteristics of cisplatin and oxaliplatin- itself, which further renders them susceptible to CIPN
induced neurotoxicity. (Manji 2011).
Biotoxicity of Chemotherapy 137

Incidence There are currently no proven pharmacologic treatments

Approximately 37–44 % of patients developed bortezomib- for CIPN (Cavaletti and Marmiroli 2010; Pachman et al.
induced peripheral neuropathy with painful distal sensory 2011). Although the use of anticonvulsant or antidepressant
symptoms as the hallmark of its clinical manifestation drugs, including carbamazepine, lamotrigine, gabapentin,
(Cavaletti and Marmiroli 2010; Cavaletti and Jakubowiak pregabalin, and venlafaxine, are common (Fung and Vau-
2010). This neuropathic pain can be severe and some ghn 2011; Cavaletti and Marmiroli 2010) and have shown
patients also develop distal sensory loss, reduced deep efficacy in treatment of neuropathy from other causes
tender reflexes, and impaired proprioception (Cavaletti and (Pachman et al. 2011), such as diabetes, their data in CIPN
Marmiroli 2010). Onset of bortezomib-induced peripheral are limited (Fung and Vaughn 2011; Pachman et al. 2011).
neuropathy usually occurs within 3 months of treatment As a result, modification or withdrawal of the insulting
initiation (Cavaletti and Jakubowiak 2010) with its recovery chemotherapeutic agent is usually the only option available
taking as long as 1.7 years in some patients (Cavaletti and for oncologists (Pachman et al. 2011). To assess severity of
Jakubowiak 2010). Furthermore, a minority of patients will CIPN, several instruments (Pachman et al. 2011) are com-
experience persistent neuropathy after its discontinuation monly used and they include the NCI CTCAE, the Euro-
(Cavaletti and Jakubowiak 2010). Cumulative treatment pean Organization for Research and Treatment of Cancer
dose appears as the most significant predictor for this risk Quality of Life CINP-20 questionnaire, the Total Neurop-
(Cavaletti and Jakubowiak 2010). athy Score, the Functional Assessment of Cancer Therapy
(FACT)/Gynecologic Oncology Group-Neurotoxicity
Pathophysiology questionnaire, the FACT-taxane tool, the Oxaliplatin-asso-
The exact pathogenesis of bortezomib-induced neuropathy ciated Neuropathy Questionnaire, Patient Neurotoxicity
remains unknown. However, by targeting dorsal root gan- Questionnaire, and the Peripheral Neuropathy Scale.
glion, bortezomib may interfere with transcription, nuclear
processing and transport, and cytoplasmic translation of
messenger RNAs in these neurons (Cavaletti and Marmiroli 2.5 Ototoxicity
2010), which ultimately leads to extensive damage of both
myelinated and unmyelinated axons (Cavaletti and Mar- Ototoxicity is a serious side effect among long-term cancer
miroli 2010). Other mechanisms, including disruption of the survivors after platinum-based chemotherapy (Fung and
neurotrophin network and dysregulation of the mitochon- Vaughn 2011). This impairment has a particularly signifi-
drial and endoplasmic reticulum-medicated calcium trans- cant impact in the pediatric population since it can affect
port, may also be involved in bortezomib-induced their learning, communication, school performance, social
neuropathy (Cavaletti and Marmiroli 2010). interaction, and overall health-related quality of life (Gre-
wal et al. 2010). Ototoxicity is a dose-limiting adverse
2.4.2 Prevention and Treatment of CIPN effect for both cisplatin and carboplatin (Fung and Vaughn
There are currently no pharmacological agents that are 2011; Grewal et al. 2010) and will be discussed in this
commonly used to prevent CIPN. However, the use of section.
calcium and magnesium (Ca/Mg) infusion has shown
promising results. A recent randomized, placebo-controlled, 2.5.1 Type of Chemotherapeutic Agents
double-blind study by Grothey et al. (2011) investigated its
efficacy in prevention of oxaliplatin-induced neuropathy in 2.5.1.1 Cisplatin
102 patients undergoing adjuvant chemotherapy with 5-
fluorouracil, leucovorin, and oxaliplatin (FOLFOX) for Incidence
colon cancer. Ca/Mg reduced the incidence of chronic, Cisplatin causes high frequency hearing loss (4–8 kHz) and
cumulative C grade 2 sensory neurotoxicity as measured by tinnitus (Fung and Vaughn 2011; Rybak et al. 2009) and
the National Cancer Institute Common Terminology Crite- these symptoms may occur within hours to days after
ria for Adverse Events (NCI CTCAE) (P = 0.038) and by treatment (Rybak et al. 2009). Young age at initial treatment
an oxaliplatin-specific sensory neurotoxicity scale (\5 years), high cumulative dose of cisplatin, impaired
(P = 0.018). On the contrary, a recent meta-analysis by baseline renal and hearing function, and concurrent cochlear
Albers et al. (2011) examined eight purported neuropro- radiation (dose[48 Gy) are the most significant risk factors
tective agents for cisplatin-induced neuropathy, including for ototoxicity (Fung and Vaughn 2011; Grewal et al. 2010;
acetylcysteine, amifostine, Ca/Mg, diethyldithiocarbamate, Rybak et al. 2009). Approximately 7–31 % of patients
glutathione, Org2766, oxcarbazepine, and vitamin E, and undergoing treatment with cisplatin-based chemotherapy
concluded that there is insufficient data to show that any of develop transient tinnitus (Fung and Vaughn 2011). In a
them prevent or limit CIPN due to cisplatin. Pediatric Intergroup Study for children and adolescents with
138 C. Fung and K. J. Pandya

high-risk germ cell tumors (Cushing et al. 2004), 14 % of Pathophysiology

patients developed grade 3–4 hearing loss after high-dose The pathogenesis of carboplatin-induced ototoxicity is not
cisplatin (800 mg/m2) compared to 0 % of those with low- well described in the current literature but it may resemble
dose administration (400 mg/m2). Similarly, Bokemeyer that of cisplatin due to their similar mechanisms of action.
et al. (1998) reported that approximately 20 % of testicular
2.5.2 Prevention and Treatment of Ototoxicity
cancer patients treated with B400 mg/m2 experienced self-
The Food and Drug Administration in the United States has
reported tinnitus and hearing loss chronically as compared
not approved any drugs as protective agents for cisplatin
to 50 % of those treated with[400 mg/m2. In another study
ototoxicity (Rybak et al. 2007). Several agents, including
that compared the risks of ototoxicity in testicular cancer
thiols, adenosine A1 receptor agonists, pifithrin or capase
survivors who underwent dose-intensive chemotherapy
inhibitors, combination of ebselen and allopurinol, sodium
([100 mg/m2 of cisplatin per cycle) to those without che-
butyrate, and salicylates, show potential promise for pre-
motherapy, Brydøy et al. (2009) found that patients in the
vention of cisplatin ototoxicity (Fung and Vaughn 2011)
dose-intensive group had 5.3 and 7.1 times higher risks of
and will require further studies in humans. To reduce the
subjective hearing loss and tinnitus respectively.
risk of ototoxicity, patients undergoing platinum-based
chemotherapy should be encouraged to avoid loud noise
Pathophysiology
and ototoxins, such as gentamicin, tobramycin, or furose-
Cisplatin causes damage to several areas of the cochlea,
mide (Fung and Vaughn 2011). Protective ear defenders or
including the outer hair cells in the basal turn, spiral ganglion
ear plugs should also be considered for those who work or
cells, and stria vascularis (Rybak et al. 2007, 2009). The
live in a noisy environment (Fung and Vaughn 2011).
underlying mechanism appears to involve generation of
Although there are no current effective treatment for cis-
reactive oxygen species that triggers apoptosis in the inner ear
platin ototoxicity, gene therapy with antiapoptotic genes
(Rybak et al. 2007, 2009). Cisplatin has been shown to acti-
and intratympanic application of adenosine agonists both
vate an enzyme known as a NOX-3, leading to an increase in
showed promising results in this regard (Rybak et al. 2007).
superoxide production in both cochlear cell lines and cochlea
Since hearing impairment may adversely impact quality
of rates (Rybak et al. 2007). This superoxide production
of life, socio-emotional development, and academic per-
would subsequently activate a cascade of events resulting in
formance in children (Grewal et al. 2010), all childhood
oxidation of lipids and cell death (Rybak et al. 2007).
cancer survivors after ototoxic chemotherapy should
undergo annual audiological evaluation and physical
2.5.1.2 Carboplatin
examination (Grewal et al. 2010). For children with pro-
gressive hearing loss, speech and language therapy, and
Incidence
other educational support, such as preferential classroom
Although carboplatin is less ototoxic than cisplatin,
sitting and FM amplification system, should be considered
approximately 0–38 % of patients still experience hearing
(Grewal et al. 2010).
impairment after treatment with carboplatin (Musial-Bright
et al. 2011). Musial-Bright et al. (2011) recently examined
the incidence of ototoxicity in 19 medulloblastoma patients 2.6 Reproductive Toxicity
who underwent treatment according to HIT protocols with
carboplatin substitution and had adequate baseline and post- In the United States, 1.4 million people are diagnosed with
treatment audiological data. They reported that 10.5 % of cancer every year with approximately 10 % of them
patients developed hearing loss [20 dB. Younger age at \45 years of age (Jemal et al. 2009). As the number of
diagnosis and higher cumulative carboplatin dose were both young cancer survivors increases due to medical advance-
significant risk factors (P \ 0.05) for hearing loss in this ment, infertility due to chemotherapy, as defined by the
study cohort. Similarly, Qaddoumi et al. (2012) reported inability to conceive after 1 year of intercourse without
that twelve of sixty patients (20 %) with retinoblastoma contraception (Lee et al. 2006), has become an important
who received front-line treatment with systemic carboplatin issue in this population. This section will review effects of
and vincristine developed ototoxicity. Furthermore, ten of various chemotherapy regimens on reproductive health
these patients (17 %) had sustained hearing loss after a including fertility, and describe different fertility preserva-
median follow-up of 6.1 years. Young age at the start of tion options that are available for adolescents and young
chemotherapy was again found to be associated with adults with cancer.
increased incidence of hearing loss. However, in three other
studies (Friedman et al. 2000; Lambert et al. 2008; Smits 2.6.1 Effects of Chemotherapy on Fertility
et al. 2006) that examined carboplatin-induced ototoxicity Cytotoxic damage to the rapidly differentiating spermato-
in patients with retinoblastoma, no ototoxicity was reported. gonia is common during chemotherapy in males (Levine
Biotoxicity of Chemotherapy 139

Table 11 Effects of various chemotherapeutic regimen on sperm production in men (Kremer et al. 2001)
Degree of risk Chemotherapy regimen Common usage
High risk: prolonged azoospermia Protocols containing procarbazine: COPP, MOPP, MVPP, Hodgkin’s lymphoma
after treatment ChIVPP, ChIVPP/EVA, MOPP/ABVD, COPP/ABVD
Alkylating chemotherapy for transplantation conditioning BMT/SCT
(cyclophosphamide, busulfan, melphalan)
Any alkylating agent (e.g., procarbazine, nitrogen mustard, Testicular cancer, BMT/SCT, ALL, NHL,
cyclophosphamide) ? TBI, pelvic radiation, or testicular sarcoma, neuroblastoma, Hodgkin’s
radiation lymphoma
Cyclophosphamide [7.5 g/m2 Sarcoma, NHL, neuroblastoma, ALL
Intermediate risk: prolonged BEP 9 2–4 cycles Testicular cancer
azoospermia not common at Cumulative cisplatin dose \400 mg/m2 Testicular cancer
standard dose
Cumulative carboplatin dose B2 g/m2 Testicular cancer
Low risk: temporary azoospermia Nonalkylating chemotherapy: ABVD, OEPA, NOVP, Hodgkin’s lymphoma, NHL
after treatment CHOP, COP
Very low/no risk: no effects on Interferon alfa Multiple cancers
sperm production
Unknown risk Irinotecan Colon cancer
Bevacizumab Colon, non-small cell lung cancer
Cetuximab Colon, head and neck cancer
Erlotinib Non-small cell lung, pancreatic cancer
Imatinib Chronic myeloid leukemia, GI stromal
tumor
TBI total-body irradiation, BMT bone marrow transplantation, SCT stem-cell transplantation, ALL acute lymphoblastic leukemia, NHL non-
Hodgkin’s lymphoma, COPP cyclophosphamide, vincristine, procarbazine, and prednisone, MOPP mechlorethamine, vincristine, procarbazine,
and prednisone, MVPP mechlorethamine, vinblastine, procarbazine, and prednisone, ChIVPP chlorambucil, vinblastine, procarbazine, and
prednisone, EVA etoposide, vinblastine, and doxorubicin, ABVD doxorubicin, bleomycin, vinblastine, and dacarbazine, BEP bleomycin eto-
poside, and cisplatin, OEPA vincristine, etoposide, prednisolone, and doxorubicin, NOVP mitoxantrone, vincristine, vinblastine, and prednisone,
CHOP cyclophosphamide, doxorubicin, vincristine, and prednisone, COP cyclophosphamide, vincristine, and prednisone
Adapted from Levine and colleagues (Kremer et al. 2001) with permission

et al. 2010). Sperm count usually nadir at 6 months after maturation (Levine et al. 2010). Chemotherapy predisposes
completion of chemotherapy and may remain impaired for women to infertility by reducing this fixed number of pri-
up to 2 years (Levine et al. 2010). For those with quanti- mordial follicles as well as the number of larger maturing
tative or qualitative injury to spermatogenic stem cells, follicles (Levine et al. 2010) with the type, dose, and
infertility may become permanent (Levine et al. 2010). The administration schedule of chemotherapy affecting the
risk of infertility depends on age of patient and the type, extent of injury to these follicles (Knopman et al. 2010).
dose and schedule of cytotoxic treatments (Levine et al. Other risk factors for infertility include older age at treat-
2010), with high dose alkylating agents and cisplatin pre- ment, use of alkylating agents, pelvic irradiation, and cra-
disposing patients to highest risk of prolonged or permanent nial radiation ([35–40 Gy) (Levine et al. 2010). Table 12
infertility (Levine et al. 2010). Several other risk factors describes the effect of various chemotherapy on develop-
(Levine et al. 2010) include radiation to the testes ment of amenorrhea (Levine et al. 2010).
([1.2 Gy), total-body irradiation used as conditioning reg-
imen for stem cell transplant, cranial radiation ([35–40 Gy) 2.6.2 Chemotherapy and Risks of Congenital
that results in deficiency of gonadotropin-releasing hor- Anomalies in Offspring
mone, and baseline azoospermia preceding treatment as Due to the effects of chemotherapy on processes critical for
seen in patients with Hodgkin’s lymphoma and testicular embryogenesis, including DNA replication, cell division, and
cancer. Table 11 describes the effect of various chemo- cellular metabolism, many patients who survived cancer
therapy on sperm production in males (Levine et al. 2010). reported fear of congenital anomalies in their offspring as the
On the contrary, females have a relatively finite number primary reason for not pursuing pregnancy (Knopman et al.
of ovarian primordial follicles and their reproductive 2010). Although this is a valid theoretical concern, several
potential declines when this population of follicles drops studies of the offspring of cancer reported no increased inci-
below a threshold number through normal atresia and dence of congenital or chromosomal anomalies in children
140 C. Fung and K. J. Pandya

Table 12 Effects of various chemotherapeutic regimen on development of amenorrhea (Kremer et al. 2001)
Degree of risk Chemotherapy regimen Common usage
High risk: [80 % of women develop CMF, CEF, or CAF 9 6 cycles in women age 40+ Breast cancer
amenorrhea after treatment Cyclophosphamide 5 g/m2 in women 40+ Multiple cancers
Cyclophosphamide 7.5 g/m2 in female age \20 NHL, neuroblastoma, ALL, sarcoma
Alkylating chemotherapy (e.g., cyclophosphamide, BMT/SCT
busulfan, melphalan) conditioning for
transplantation
Any alkylating agent (e.g., cyclophosphamide, BMT/SCT, ovarian cancer, sarcoma,
ifosfamide, busulfan, CNU, CCNU) ? TBI or neuroblastoma, Hodgkin’s lymphoma
pelvic radiation
Protocols containing procarbazine: MOPP, MVPP, Hodgkin’s lymphoma
COPP, ChIVPP, ChIVPP/EVA, BEACOPP, MOPP/
ABVD, COPP/ABVD
Intermediate risk: approximately CMF, CEF, or CAF 9 6 cycles in women age 30–39 Breast cancer
30–70 % of women develop AC in women age 40+ Breast cancer
amenorrhea after treatment
Low risk: \20 % of women develop AC in women age 30–39 Breast cancer
amenorrhea CMF, CEF, or CAF 9 6 cycles in women age \30 Breast cancer
Nonalkylating chemotherapy: ABVD, CHOP, COP Hodgkin’s lymphoma, NHL
Anthracycline ? cytarabine AML
Multiagent therapies ALL
Very low/no risk: negligible effect on Methotrexate ? fluorouracil Breast cancer
menses Vincristine (used in multiagent therapies) Leukemia, Hodgkin’s lymphoma, NHL,
neuroblastoma, rhabdomyosarcoma, Wilms
tumor, Kaposi’s sarcoma
Radioactive iodine Thyroid cancer
Unknown risk Paclitaxel, docetaxel (taxanes used in AC protocols) Breast cancer
Oxaliplatin Ovarian cancer
Irinotecan Colon cancer
Bevacizumab Colon, non-small cell lung cancer
Cetuximab Colon, head and neck cancer
Trastuzumab Breast cancer
Erlotinib Non-small cell lung, pancreatic cancer
Imatinib Chronic myeloid leukemia, GI stromal tumor
TBI total-body irradiation, CMF cyclophosphamide, methotrexate, and fluorouracil, CEF cyclophosphamide, epirubicin, and fluorouracil, CAF
cyclophosphamide, doxorubicin, and fluorouracil, BMT bone marrow transplantation, SCT stem-cell transplantation, NHL non-Hodgkin’s
lymphoma, AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, BCNU carmustine, CCNU lomustine, MOPP mechlorethamine,
vincristine, procarbazine, and prednisone, MVPP mechlorethamine, vinblastine, procarbazine, and prednisone, COPP cyclophosphamide, vin-
cristine, procarbazine, and prednisone, ChIVPP chlorambucil, vinblastine, procarbazine, and prednisone, EVA etoposide, vinblastine, and
doxorubicin, BEACOPP bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, ABVD doxorubicin,
bleomycin, vinblastine, and dacarbazine, AC doxorubicin and cyclophosphamide, CHOP cyclophosphamide, doxorubicin, vincristine, and
prednisone, COP cyclophosphamide, vincristine, and prednisone
Adapted from Levine and colleagues (Kremer et al. 2001) with permission

(Byrne et al. 1998; Li et al. 1979). Boice et al. (2003) also 2.6.3 Fertility Preservation Options for Cancer
reported that there was no difference in the incidence of genetic Patients Undergoing Chemotherapy
or chromosomal anomalies in 6,000 children of 25,000 survi- For patients undergoing chemotherapy during their repro-
vors of childhood cancer when compared to their sibling ductive years, American Society of Clinical Oncology
controls in an international study. Finally, aside from malig- recommends assessment of their infertility risk as an inte-
nancy arising from an inherited syndrome, there does not gral part of the chemotherapy informed consent process
appear to be an increased risk of childhood cancer in the off- (Lee et al. 2006). Furthermore, oncologists should be pre-
spring of long-term cancer survivors (Knopman et al. 2010). pared to discuss fertility preservation options and refer
Biotoxicity of Chemotherapy 141

Table 13 Fertility preservation options for men (Kremer et al. 2001)

Option
Characteristics Sperm Sperm banking Radiation Testicular tissue Testicular Donor sperm Adoption
banking (alternative shielding of freezing sperm
(Masturbation) collection gonads extraction
methods)
Medical status Standard Experimental Standard Experimental Standard Standard Standard
Definition Sperm Sperm obtained Use of Tissue obtained Use of biopsy Sperm Process
obtained through shielding to through biopsy to obtain donated by a that creates
through testicular reduce the and frozen for individual man for a legal
masturbation extraction or dose of future use sperm from artificial parent–
and then electro- radiation testicular insemination child
frozen ejaculation delivered to tissue or IVF relationship
under sedation the testes
Pubertal status After puberty After puberty Before or Before or after After puberty After puberty After
after puberty puberty puberty
Time Outpatient Outpatient In Outpatient Outpatient Readily Varies
requirement procedure procedure conjunction procedure procedure available for depending
with radiation purchase on type of
treatments adoption
Success rates Generally If sperm is Possible with No available 30–70 % in 50–80 % NA
high; the most obtained, select human success postpubescent
established similar to radiation rates patients
technique for standard sperm fields and
men banking anatomy
Cost Approx. Varies greatly Generally $500–$2,500 for $4,000– $200–$500 $2,500–
$1,500 for 3 based on included in surgery; $300– $16,000 (in per vial (in $35,000
samples; collection the cost of $1,000 for addition to addition to
storage fees method radiation freezing; $500/ costs to IVF) costs for IUI
average $500/ treatments year for storage or IVF)
year
Timing Before Before During Before treatment Before or after After After
treatment treatment treatment treatment treatment treatment
Special Deposits can Can be Expertise May be only Center should Can choose Medical
considerations be made every considered if required; cryopreservation be able to donor based history
24 h male cannot does not option for freeze sperm on wide range often a
ejaculate protect prepubescent found at time of factor
against boys of biopsy characteristics
effects of
chemotherapy
IVF in vitro fertilization, NA not applicable, IUI intrauterine insemination
Adapted from Levine and colleagues (Kremer et al. 2001) with permission

those interested to reproductive specialists (Lee et al. 2006). 2.7 Cognitive Impairment
Sperm and embryo cryopreservation should be considered
standard practice and be widely available for patients at There is growing evidence that a subset of long-term cancer
significant risk of infertility (Lee et al. 2006; Wallace 2011) survivors experience permanent cognitive impairment after
while other available fertility preservation methods should completion of chemotherapy (Fardell et al. 2011; Tannock
be considered experimental and only be conducted in et al. 2004), which is particularly well documented in breast
institutions with the necessary expertise (Lee et al. 2006). cancer survivors after adjuvant chemotherapy (Fardell et al.
Tables 13 and 14 summarize preservation option for men 2011; Tannock et al. 2004). Unfortunately, there is a lack of
and women respectively (Levine et al. 2010). acknowledgment or education about this disabling adverse
142 C. Fung and K. J. Pandya

Table 14 Fertility preservations options for women (Kremer et al. 2001)

Option
Characteristics Embryo freezing Egg freezing Ovarian tissue Radiation Ovarian transplantation
freezing shielding of
gonads
Medical status Standard Experimental Experimental Standard Standard
Definition Harvesting eggs, IVF, and freezing Harvesting and Freezing of Use of Surgical repositioning of
of embryos for later implantation freezing of ovarian tissue shielding to ovaries away from the
unfertilized and reduce scatter radiation field
eggs reimplantation radiation to
after cancer the
treatment reproductive
organs
Pubertal status After puberty After puberty Before or after Before or after Before or after puberty
puberty puberty
Time 10–14 days from menses; 10–14 days Outpatient In conjunction Outpatient procedure
requirement outpatient surgical procedure from menses; surgical with radiation
outpatient procedure treatments
surgical
procedure
Success rates Approximately 40 % per transfer; Approximately Case reports of Only possible Approximately 50 % as a
varies by age and center; 21.6 % per seven live births with selected result of altered blood flow
thousands of babies born embryo radiation and scatter radiation
transfer; 900 fields and
live births anatomy
Cost Approximately $12,000/cycle; Approximately $12,000 for Generally Unknown; may be covered
storage fees and pregnancy costs $12,000/cycle; procedure; included in by insurance
additional storage fees storage fees and cost of
and pregnancy reimplantation radiation
costs additional costs additional
Timing Before or after treatment Before or after Before or after During Before treatment
treatment treatment treatment
Special Need partner or donor sperm May be Not suitable if Expertise Expertise required
considerations attractive to high risk of required; does
single women ovarian not protect
or those metastases; only against effects
opposed to cryopreservation of
embryo option for chemotherapy
creation prepubescent
girls
Option
Characteristics Radical trachelectomy Ovarian Donor embryos Donor eggs Gestational Adoption
suppression surrogacy
Medical status Standard Experimental Standard Standard Standard Standard
Definition Surgical removal of the GnRH analogs Embryos Eggs donated Woman carries Process that
cervix with preservation used to donated by a by a woman a pregnancy creates a legal
of the uterus suppress couple for another parent–child
ovaries woman or relationship
couple
Pubertal status After puberty After puberty After puberty After puberty After puberty After puberty
Time Inpatient surgical In conjunction Varies; is done Varies, is done Varies; time is Varies depending
requirement procedure with in conjunction in conjunction required to on types of
chemotherapy with IVF with IVF find surrogate adoption
and implant
embryos
(continued)
Biotoxicity of Chemotherapy 143

Table 14 (continued)
Option
Success rates No evidence of high Unknown; Unknown; high 40–50 % Similar to IVF; NA
cancer recurrence rates in conflicting than that of approximately
appropriate candidates results frozen embryo 30 %
reported; IVF transfers
larger
randomized
trials in
progress
Cost Generally included in the $500/month $5,000–$7,000 $5,000– $10,000– $2,500–$35,000
cost of cancer treatment (in addition to $15,000 (in $100,000
cost for IVF) addition to
costs for IVF)
Timing During treatment During After treatment After treatment After After treatment
treatment treatment
Special Limited to early-stage Does not Donor embryo Patient can Legal status Medical history
considerations cervical cancer offered at protect from available though choose donor varies by state often a factor
a limited number of radiation IVF clinics or based on
centers effects private agencies various
characteristics
IVF in vitro fertilization, GnRH gonadotroponin-releasing hormone, NA not applicable
Adapted from Levine and colleagues (Kremer et al. 2001) with permission

effect by healthcare providers to cancer survivors (Myers methotrexate, and 5-fluorouracil (Fardell et al. 2011; Vardy
2012). Long-term cognitive impairment in this increasing and Tannock 2007). Furthermore, individual characteristics
population of survivors has significant impact on their also affect this risk (Fardell et al. 2011). The presence of the
interpersonal relationships, their ability to perform at pre- APOE e4 allele (The epsilon4 allele of the apolipoprotein E
vious levels of competence, and their work performance gene which is associated with Alzheimer’s disease),
(Fardell et al. 2011; Myers 2012). This section will discuss impaired baseline cognitive reserve before treatment, and
the incidence, mechanism, treatment, and prevention of this increased age at diagnosis all seem to predispose patients to
poorly understood yet serious side effect. increased likelihood of chemotherapy-induced cognitive
impairment (Fardell et al. 2011). Finally, in an over-
2.7.1 Effects of Chemotherapy on Cognitive whelming majority of studies to date, no association was
Function found between cognitive impairment and psychological
While up to 70 % of patients self-report persistent cognitive well being of patients (Fardell et al. 2011).
difficulties after completion of chemotherapy (Fardell et al.
2011), only 15–50 % of cancer survivors were found to 2.7.2 Mechanism of Chemotherapy-Induced
have mild to moderate cognitive dysfunction using stan- Cognitive Impairment
dardized neuropsychological assessment (Fardell et al. Although the underlying neurobiological mechanisms link-
2011). While two longitudinal studies (Ahles et al. 2010; ing chemotherapy with cognitive impairment is not fully
Schagen et al. 2006) reported that this impairment can elucidated in humans, it has been well studied in animal
persist between 1 and 2 years after completion of chemo- models. In healthy rodents, chemotherapy causes cell death
therapy, two cross-sectional studies (de Ruiter et al. 2011; of central nervous system, increase in oxidative stress and
Kreukels et al. 2006) suggested that this effect might last microglia activity, suppression of hippocampal neurogene-
longer for up to 10 years after chemotherapy. Several sis, and decrease in levels of both neurotrophic factors and
domain of cognitive function may be affected by chemo- hippocampal catecholamines (Fardell et al. 2011).
therapy, including attention/concentration, verbal memory, Recently, neuroimaging has identified several structural
visual memory, and speed of information processing (Far- and functional changes in brain region that are hypothesized
dell et al. 2011; Tannock et al. 2004). to be involved in the cognitive deficits experienced by breast
Although the evidence at this juncture is not conclusive, cancer survivors after chemotherapy. Silverman et al. (2007)
several treatment-related factors may predispose patients to used positron emission tomography scanning to examine
higher risk of long-term cognitive impairment, including metabolic activity of the brain in breast cancer patients who
high-dose chemotherapy, adjuvant hormonal therapy after completed adjuvant chemotherapy 5–10 years ago. During
chemotherapy, and the regimen of cyclophosphamide, performance of a short-term recall task, they identified
144 C. Fung and K. J. Pandya

significant altercation of cerebral blood flow to the frontal malignancies in cancer survivors after chemotherapy and
cortex and cerebellum in chemotherapy-treated patients. In discuss management options for this serious late effect.
particular, cerebral activation of the inferior frontal gyrus of
patients with chemotherapy differed most from those without 2.8.1 Second Malignant Neoplasms After
chemotherapy. Similarly, de Ruiter et al. (2011) used func- Chemotherapy
tional magnetic resonance imaging to compare cognitive
function of those who completed high-dose adjuvant che- 2.8.1.1 Hematological Malignancies
motherapy 10 years ago to those who are chemotherapy Therapy-related myeloid neoplasms represent 10–20 % of
naïve. They reported hyporesponsiveness in both the pre- acute leukemias, myelodysplastic syndrome (MDS), and
frontal cortex and parahippocampal gyrus during executive myelodysplastic/myeloproliferative neoplasms (Czader and
functioning and episodic memory tasks in those with che- Orazi 2009) and numerous cytotoxic agents are implicated
motherapy. Interestingly, by using diffusion tensor imaging, in their development (Table 15). In this section, we will
Abramham et al. (2008) reported that adjuvant chemotherapy focus on alkylating agents and topoisomerase II inhibitors,
for breast cancer affects normal-appearing white matter in the which are known to increase risks of two distinct types of
genu of the corpus callous, which may explain the cognitive acute leukemias (Fung and Vaughn 2011; Czader and Orazi
deficits experienced by patients. 2009; Sill et al. 2011). Leukemia due to alkylating agents
usually has a latency period of 5–10 years after treatment
and is frequently preceded by MDS (Fung and Vaughn
2.7.3 Prevention and Treatment
2011; Czader and Orazi 2009). Loss of part or all of chro-
of Chemotherapy-Induced Cognitive
mosomes 5 or 7 are implicated in the development of this
Impairment
leukemia (Fung and Vaughn 2011; Czader and Orazi 2009).
There are currently no pharmacological interventions
By contrast, acute leukemia after topoisomerase II inhibi-
approved for prevention or treatment of chemotherapy-
tors occurs within 2–3 years after therapy (Fung and Vau-
induced cognitive dysfunction. However, the following
ghn 2011), is not preceded by MDS (Fung and Vaughn
agents may have potential benefits for this indication (Far-
2011; Czader and Orazi 2009), and involves rearrangement
dell et al. 2011; Tannock et al. 2004), including erythro-
of the MLL gene with 11q23 chromosomal translocations or
poietin, methylphenidate, modafinil, donepezil, fluoxetine,
shows recurrent cytogenetic abnormalities such as t(8;21),
and antioxidants. Cognitive rehabilitation programs (Fardell
t(15;17), and inv(16) (Czader and Orazi 2009).
et al. 2011; Tannock et al. 2004) may also be efficacious in
Cumulative doses of cisplatin (alkeylating agent) and
cancer patients with cognitive deficits after chemotherapy.
etoposide (topoisomerase II inhibitor) directly correlate with
These programs usually retrain cancer patients to recover
risks of therapy-related myeloid neoplasms (Kollmannsber-
part of their lost cognitive functions; teach them compen-
ger et al. 1999; Travis et al. 1999, 2000). The cumulative
satory methods of using their residual abilities to develop
incidence of leukemia at 5 years after etoposide increased
alternative methods of performing cognitive tasks, and
from 0.5 % for testicular cancer patients with a cumulative
address their social, emotional, and functional issues related
dose of \2,000 mg/m2 to 2.0 % for those with C2,000 mg/
to their cognitive dysfunction using a holistic approach
m2 (Kollmannsberger et al. 1999). Regarding risk of leuke-
(Fardell et al. 2011). Finally, regular exercises (Fardell et al.
mia after cisplatin, Travis et al. (2000) reported that this risk
2011), which have been shown to decrease inflammation,
has a highly significant relationship with cumulative dose of
increase levels of neurotrophic factors, and promote neu-
cisplatin in testicular cancer patients (P-trend = 0.001).
ronal cell proliferation and survival, may decrease the risk
They estimated that there is a 3.2-fold increased risk of leu-
of cognitive decline after chemotherapy.
kemia after a cumulate dose of [650 mg of cisplatin
although the excess risk is small (a total of 16 excess cases
among 10,000 patients followed up for 15 years). Similarly,
2.8 Second Malignant Neoplasms Travis et al. (1999) reported that a highly significant rela-
tionship exists between leukemia risk and cumulative cis-
Second malignant neoplasms (SMNs) are a potentially life- platin dose in patients with ovarian cancer (P-
threatening late effect of chemotherapy. While both alkyl- trend \ 0.001). After a cumulative dose of 500–1,000 mg,
ating agents and topoisomerase II inhibitors are known they estimated that there is a total of 21 excess leukemia
causes of therapy-related myeloid neoplasms in cancer among 10,000 women followed up for 15 years.
survivors (Fung and Vaughn 2011; Czader and Orazi 2009;
Sill et al. 2011), risks of second solid cancer due to che- 2.8.1.2 Solid Malignancies
motherapy alone are less defined. In this section, we will The risks of second solid cancer due to chemotherapy are
review the risks of both second solid and hematological less defined than those of hematological malignancies but
Biotoxicity of Chemotherapy 145

Table 15 Chemotherapy implicated in the development of therapy- However, risk of solid cancer arising from modern era
related myeloid neoplasms (Krischer et al. 1997) cisplatin-based chemotherapy remains to be elucidated in
Class Agent this population since these epidemiologic studies were
Alkylating agents Bulsulfan conducted before current cisplatin-based chemotherapy
Carboplatin became widely accepted. Furthermore, tobacco use increa-
Carmustine
ses risk of solid cancer to a similar extent as chemotherapy
in testicular cancer patients (RR = 1.8) (van den Belt-
Chlorambucil
Dusebout et al. 2007).
Cisplatin
In a cohort of 5,798 patients with Hodgkin’s lymphoma,
Cyclophosphamide Swerdlow et al. (2011) reported significantly increased lung
Dacarbazine cancer risk for those who received chemotherapy alone
Dihydroxybusulfan (RR = 2.9) and this was observed for both alkylating and
Lomustine non-alkylating regimens, whereas two earlier reports (Kal-
Mechlorethamine dor et al. 1992; Swerdlow et al. 1992) showed association
Melphalan with alkylating chemotherapy only. In particular, significant
associations with lung cancer were identified for three
Mitomycin C
chemotherapy regimens, mechlorethamine, vincristine,
Procarbazine
procarbazine, prednisone (MOPP), mechlorethamine, vin-
Semustine blastine, procarbazine, prednisone (MVPP), and chloram-
Thiotepa bucil, vinblastine, procarbazine, prednisone (ChIVPP), with
Topoisomerase II inhibitors Bimolane each having relative risks of 3.1, 2.9, and 4.3, respectively.
Dactinomycin Furthermore, the authors suggested a dose-response effect
Daunorubicin for cycles of alkylating treatments in relation to lung cancer
Doxorubicin risk in their analyses. In particular, this increased lung
4-Epi-doxorubicin
cancer risk does not appear to be a consequence of con-
founding by smoking (Travis et al. 2002).
Etoposide
Mitoxantrone
2.8.2 Management Considerations for Second
Razoxane Malignant Neoplasms
Teniposide Currently, no consensus exists regarding interventions to
Antimetabolites Fludarabine minimize the risks of SMNs after chemotherapy. In general,
6-Mercaptopurine all cancer survivors should adopt practices that are consis-
Methotrexate tent with a healthy lifestyle, including routine exercise
Antimicrotubule agents Docetaxel
regimen, dietary modification, and smoking cessation (Fung
and Vaughn 2011). Furthermore, adoption of age-appro-
Paclitaxel
priate cancer screening is important (Fung and Vaughn
Vinblastine
2011). There are currently no evidence to suggest that fre-
Vincristine quent cancer screening with blood tests or radiographic
Adapted from Czader and colleagues (Krischer et al. 1997) with studies is beneficial. Buchler et al. (2011) reported that only
permission
27 % of second cancers were found on frequent oncology
follow-up in their recent retrospective study.

were best studied in testicular cancer and Hodgkin’s lym-

phoma patients. Travis et al. (2005) reported that the rela- 3 Chemotherapy-Induced Late Effects
tive risk of second solid tumors was significantly increased in the Era of Pharmacogenomics
after chemotherapy alone (RR = 1.8) in an international
series of more than 40,000 patients. However, data on Genetic polymorphisms are inherited germline DNA
specific chemotherapeutic agents were not available. sequence variations that may cause minor disruption in one
Another study (van den Belt-Dusebout et al. 2007) showed or more biological pathways, and less commonly, complete
that the risk of solid tumors doubled in testicular cancer loss of function when there is a deletion polymorphism.
survivors after cisplatin-based regimens when compared Elucidation of the molecular basis of germline genetic
with surgery alone, confirming findings of two other reports susceptibility to late effects of chemotherapy does not only
(Bokemeyer and Schmoll 1993; Wanderas et al. 1997). provide invaluable insights and inform the development of
146 C. Fung and K. J. Pandya

therapeutic agents to target the underlying molecular path- chemotherapy using taxanes and platinum drugs for ovarian
ways of these adverse effects, but it may also allow devel- cancer respectively. However, this association was not
opment of a risk-classification system that incorporates identified in other studies for patients treated with cisplatin
germline genetic markers to predict risks of chemotherapy- or oxaliplatin (Boige et al. 2010; Chen et al. 2010; Goekkurt
related side effects. In this section, we will review the et al. 2009; Hong et al. 2011; Keam et al. 2008; Khrunin
current literatures regarding this rapidly emerging field et al. 2010; Marsh et al. 2007; Seo et al. 2009; Zarate et al.
within cancer survivorship. 2010; Caponigro et al. 2009; Sissung et al. 2008).
Alanine-glyoxylate aminotransferase (AGXT) converts
glyoxylate to glycolate, which is subsequently metabolized
3.1 Genes and Chemotherapy-Related into oxalate by lactate dehydrogenase (Cavaletti et al.
Peripheral Neuropathy 2011). Gamelin et al. (2007) have examined if germline
genetic variations of AGXT are associated with CIPN in
Associations of CIPN with germline genetic variations of colorectal cancer patients treated with oxaliplatin due to its
several genes have been identified, including GSTP1, critical role in oxalate metabolism. They identified two
GSTM1/GSTM3, ERCC1, AGXT, ABCB1, CYP2C8/ SNPs that predispose patients with more severe CIPN,
CYP3A5, and ITGB3 genes (Cavaletti et al. 2011). GSTP1 rs4426527 (1141A ? G) and rs34116584 (153C ? T).
encodes an enzyme of the glutathione S-transferases family However, this association was not identified by Kanai et al.
that detoxifies chemotherapeutic agents by conjugating (2010) in a cohort of 82 Japanese patients treated with
reactive electrophiles to glutathione (Mannervik et al. oxaliplatin.
1985). A single nucleotide polymorphism (SNP) of GSTP1 ATP-binding cassette proteins subfamily B member 1
that causes substitution of isoleucine for valine (rs1695; (ABCB1) is involved in the transport of various molecules
Ile105Val) diminishes the activity of this enzyme and is across extracellular and intracellular membranes (Cavaletti
associated with increased severity of CIPN in ten of twenty- et al. 2011). In particular, ABCB 1 is known to mediate
three studies examining patients after platinum-based che- efflux of paclitaxel and docetaxel from cancer cells (Cava-
motherapy (Boige et al. 2010; Booton et al. 2006; Chen letti et al. 2011). Sissung et al. (2008) reported that patients
et al. 2010; Cho et al. 2010; Gamelin et al. 2007; Goekkurt with SNP rs2032582 (2677G ? T) had more rapid onset of
et al. 2009; Hong et al. 2011; Inada et al. 2010; Kanai et al. CIPN after receiving docetaxel and thalidomide for prostate
2010; Keam et al. 2008; Khrunin et al. 2010; Kim et al. cancer. However, several other studies failed to detect this
2009; Lecomte et al. 2006; Li et al. 2010; Marsh et al. 2007; association (Marsh et al. 2007; Bergmann et al. 2011;
McLeod et al. 2010; Mir et al. 2009; Oldenburg et al. 2007; Chang et al. 2009; Green et al. 2009; Leskela et al. 2011a;
Pare et al. 2008; Ruzzo et al. 2007; Seo et al. 2009; Sto- Rizzo et al. 2010; Sissung et al. 2006).
ehlmacher et al. 2002; Zarate et al. 2010). The enzymes CYP2C8 and CYP3A5 belong to the cyto-
Both GSTM1 and GSTM3 genes encode the l class of chrome P450 superfamily and are involved in the metabolism
glutathione S-transferases that are critical for detoxification of taxanes through successive hydroxylation reactions
of carcinogens, drugs, and environmental toxin through (Cavaletti et al. 2011). Two studies (Green et al. 2009;
glutathione conjugation of electrophilic compounds (Cava- Leskela et al. 2011a, b) have identified patients heterozygous
letti et al. 2011). Khrunin et al. (2010) reported recently that for the CYP2C8*3 allele (rs11572080) were at increased risk
GSTM1 deletion and the AGG/AGG genotype in GSTM3 of CIPN after chemotherapy regimens that include carbo-
(rs1799735) were both associated with decreased risk of platin and taxanes for various solid tumors. However, this
CIPN after treatment with platinum drugs. However, this result was not confirmed by two other studies; a study that
association was not confirmed in other independent studies examined white European women treated with paclitaxel or
(Boige et al. 2010; Cho et al. 2010; Goekkurt et al. 2009; docetaxel for breast cancer (Rizzo et al. 2010) and a retro-
Kim et al. 2009; Lecomte et al. 2006; Mir et al. 2009; spective analysis that examined ovarian cancer patients
Oldenburg et al. 2007; Ruzzo et al. 2007; Seo et al. 2009; (Bergmann et al. 2011). Regarding association of genetic
Zarate et al. 2010). variation of CYP3A5 gene with CIPN, Green et al. (2009)
Excision repair cross-complementing group 1 (ERCC1), reported that the CYP3A5*3 polymorphism (rs776746) is
which is involved in the nucleotide excision-repair pathway associated with reduced risk of CIPN. However, this asso-
and critical for DNA repair (Cavaletti et al. 2011), has also ciation is not confirmed by a retrospective study of ovarian
been studied for its role in development of CIPN. Two cancer patients as previously mentioned (Bergmann et al.
SNPs of ERCC1, rs11615 (542T ? C) (Inada et al. 2010) 2011). Finally, integrin B3 (ITGB3), which are cell surface
and rs3212986 (809C ? A) (Kim et al. 2009) were repor- proteins involved in cell adhesion and cell surface-mediated
ted to predispose patients to higher risks of CIPN after signaling, may be integral in the development of CIPN
oxaliplatin for colorectal cancer and after combination (Cavaletti et al. 2011). In a cohort of 55 colorectal cancer
Biotoxicity of Chemotherapy 147

patients treated with oxaliplatin, Antonacopoulou et al. Table 16 Summary of major research recommendations: late effects
(2010) reported that patients with SNP rs5918 (196T ? C) of testicular cancer and treatment (Travis et al. 2010)
had increased risk of CIPN. Overall recommendations
Fanconi anemia group D2 protein (FANCD2) is critical
1. Institution of lifelong follow-up of testicular cancer survivors with
for assembly of DNA repair machinery (Sucheston et al. a large cohort setting to ascertain risks of emerging toxicities and the
2011) and variation in its expression has been linked to evolution of known late sequelae
chemotherapy resistance in patients with glioma, ovarian 2. Development of comprehensive risk prediction models that
cancer, and multiple myeloma (Sucheston et al. 2011). include treatment factors and genetic modifiers of late sequelae
Recently, Sucheston et al. (2011) identified associations of 3. Elucidation of the effect(s) of decades-long exposure of low serum
4 SNPs (rs7648104, rs7637888, rs6786638, and rs6442150) level of platinum
of the FANCD2 gene with taxane-induced neurotoxicity in 4. Assessment of the overall burden of medical and psychosocial
breast cancer patients. All these SNPs lie within the intronic morbidity
region of the gene with three of them, including rs7648104, 5. The eventual formulation of evidence-based long-term follow-up
rs7637888, and rs6786638, directly correlating with gene guidelines and interventions
expression levels of FANCD2 (Sucheston et al. 2011). Adapted from Travis and colleagues (Travis et al. 2010) with
permission

3.3 Genes and Therapy-Related Myeloid

3.2 Genes and Cisplatin-Induced Ototoxicity Leukemia

Associations of cisplatin-induced ototoxicity have been Three SNPs were recently reported to be associated with
reported for several genes, including those encoding for therapy-related myeloid leukemia in a genome-wide asso-
glutathione-S-transferases (GSTP1, GSTM1, GSTM3) (Old- ciation study (Knight et al. 2009); rs1394384 of the ACCN1
enburg et al. 2007a, b; Peters et al. 2000), thiopurine S- gene, rs1199098 that is in linkage disequilibrium with the
methyltransferase (TPMT) (Ross et al. 2009), catechol-O- IPMK gene, and rs1381392 that is not in proximity with any
methyltransferase (COMT) (Ross et al. 2009), and megalin. known genes, miRNAs, or regulatory elements but is in a
As mentioned previously, glutathione-S-transferases are genetic region frequently deleted in lung cancer. Func-
important in detoxifying chemotherapeutic agents by con- tionally, ACCN1 encodes an amiloride-sensitive cation
jugating reactive electrophiles to glutathione (Mannervik channel. Genetic expression of ACCN1 is not only observed
et al. 1985). Oldenburg and colleagues reported that patients in bone marrow and hematopoietic cells but is also asso-
with both SNP rs1695 of GSTP1 (Ile105Val) (Oldenburg ciated with risks of both autism and multiple sclerosis
et al. 2007a, b) and homozygous deletion in GSTM1 (Old- (Knight et al. 2009). IPMK encodes a multikinase that
enburg et al. 2007) had decreased risk of developing cis- upregulates the AKT kinase and may also alter Wnt/beta-
platin-induced ototoxicity. Furthermore, GSTM3*B allele catenin signaling (Knight et al. 2009).
was found to be protective of ototoxic effect of cisplatin
(Peters et al. 2000).
TPMT transcribes an enzyme that metabolizes thiopurine 3.4 Future Survivorship Research Directions
drugs (Weinshilboum 2006) while COMT encodes an in the Era of Pharmacogenomics
enzyme that metabolizes catecholamine-containing chemical
via methylation (Weinshilboum 2006). Ross et al. (2009) Currently, there is limited knowledge and understanding
reported that the risk alleles of SNP rs12201199 of TPMT and regarding how germline genetic variation may predispose
rs9332377 of COMT predisposed children who received cancer survivors to chemotherapy-related complications
cisplatin chemotherapy to 17.0 times and 5.5 times higher (Travis et al. 2006). Identification of such genetic markers is
odds of cisplatin-induced hearing impairment respectively. a prerequisite to understanding the molecular basis of the
Megalin appears to play a critical role in hearing as it is late effects and rational development of therapeutic agents.
strongly expressed within the marginal cells of the stria It will also be vital in the development of a risk classifi-
vascularis of the cochlea (Mukherjea and Rybak 2011). In a cation system that will allow appropriate screening and
cohort of 74 patients with osteosarcoma, germ cell tumors, early intervention with the goal of decreasing morbidity and
testicular cancers, hepatoblastoma, teratoma, neuroblasto- mortality due to late effects of curative therapy of many
mas, and brain tumors, who received cisplatin-based che- cancers (Travis et al. 2006). An international meeting
motherapy, the A allele of rs2075252 of the megalin gene is devoted to testicular cancer survivorship that was held in
found to be associated with the development of hearing 2009 at the Wilmot P. Cancer Center in Rochester, New
impairment (Riedemann et al. 2008). York by Travis et al. (2010) has summarized the major
148 C. Fung and K. J. Pandya

research recommendations in this area as shown in Table 16 Brydoy M, Oldenburg J, Klepp O et al (2009) Observational study of
and should be considered for cancer survivorship research prevalence of long-term Raynaud-like phenomena and neurolog-
ical side effects in testicular cancer survivors. J Natl Cancer Inst
in other malignancies. 101:1682–1695
Buchler T, Kubankova P, Boublikova L et al (2011) Detection of
second malignancies during long-term follow-up of testicular
References cancer survivors. Cancer 117:4212–4218
Byrne J, Rasmussen SA, Steinhorn SC et al (1998) Genetic disease in
offspring of long-term survivors of childhood and adolescent
Abraham J, Haut MW, Moran MT, Filburn S, Lemiuex S, Kuwabara H cancer. Am J Hum Genet 62:45–52
(2008) Adjuvant chemotherapy for breast cancer: effects on Caponigro F, Lacombe D, Twelves C et al (2009) An EORTC phase I
cerebral white matter seen in diffusion tensor imaging. Clin Breast study of Bortezomib in combination with oxaliplatin, leucovorin
Cancer 8:88–91 and 5-fluorouracil in patients with advanced colorectal cancer. Eur
Ahles TA, Saykin AJ, McDonald BC et al (2010) Longitudinal J Cancer 45:48–55
assessment of cognitive changes associated with adjuvant treat- Cardinale D, Sandri MT, Martinoni A et al (2002) Myocardial injury
ment for breast cancer: impact of age and cognitive reserve. J Clin revealed by plasma troponin I in breast cancer treated with high-
Oncol 28:4434–4440 dose chemotherapy. Ann Oncol 13:710–715
Albers JW, Chaudhry V, Cavaletti G, Donehower RC (2011) Cardinale D, Sandri MT, Colombo A et al (2004) Prognostic value of
Interventions for preventing neuropathy caused by cisplatin and troponin I in cardiac risk stratification of cancer patients undergo-
related compounds. Cochrane Database Syst Rev 2011:CD005228 ing high-dose chemotherapy. Circulation 109:2749–2754
Al-Sarraf M, Fletcher W, Oishi N et al (1982) Cisplatin hydration with Carlson K, Ocean AJ (2011) Peripheral neuropathy with microtubule-
and without mannitol diuresis in refractory disseminated malignant targeting agents: occurrence and management approach. Clin
melanoma: a southwest oncology group study. Cancer Treat Rep Breast Cancer 11:73–81
66:31–35 Carver JR, Shapiro CL, Ng A et al (2007) American Society of
Amptoulach S, Tsavaris N (2011) Neurotoxicity caused by the Clinical Oncology clinical evidence review on the ongoing care of
treatment with platinum analogues. Chemother Res Pract adult cancer survivors: cardiac and pulmonary late effects. J Clin
2011:843019 Oncol 25:3991–4008
Antonacopoulou AG, Argyriou AA, Scopa CD et al (2010) Integrin Cavaletti G, Jakubowiak AJ (2010) Peripheral neuropathy during
beta-3 L33P: a new insight into the pathogenesis of chronic bortezomib treatment of multiple myeloma: a review of recent
oxaliplatin-induced peripheral neuropathy? Eur J Neurol studies. Leuk Lymphoma 51:1178–1187
17:963–968 Cavaletti G, Marmiroli P (2010) Chemotherapy-induced peripheral
Argyriou AA, Polychronopoulos P, Iconomou G, Chroni E, Kalofonos neurotoxicity. Nat Rev Neurol 6:657–666
HP (2008) A review on oxaliplatin-induced peripheral nerve Cavaletti G, Tredici G, Braga M, Tazzari S (1995) Experimental
damage. Cancer Treat Rev 34:368–377 peripheral neuropathy induced in adult rats by repeated intraperi-
Bajorin DF, Sarosdy MF, Pfister DG et al (1993) Randomized trial of toneal administration of taxol. Exp Neurol 133:64–72
etoposide and cisplatin versus etoposide and carboplatin in patients Cavaletti G, Cavalletti E, Montaguti P, Oggioni N, De Negri O,
with good-risk germ cell tumors: a multiinstitutional study. J Clin Tredici G (1997) Effect on the peripheral nervous system of the
Oncol 11:598–606 short-term intravenous administration of paclitaxel in the rat.
Bergmann TK, Green H, Brasch-Andersen C et al (2011) Retrospec- Neurotoxicology 18:137–145
tive study of the impact of pharmacogenetic variants on paclitaxel Cavaletti G, Cavalletti E, Oggioni N et al (2000) Distribution of
toxicity and survival in patients with ovarian cancer. Eur J Clin paclitaxel within the nervous system of the rat after repeated
Pharmacol 67:693–700 intravenous administration. Neurotoxicology 21:389–393
Berrak SG, Pearson M, Berberoglu S, Ilhan IE, Jaffe N (2005) High- Cavaletti G, Alberti P, Marmiroli P (2011) Chemotherapy-induced
dose ifosfamide in relapsed pediatric osteosarcoma: therapeutic peripheral neurotoxicity in the era of pharmacogenomics. Lancet
effects and renal toxicity. Pediatr Blood Cancer 44:215–219 Oncol 12:1151–1161
Bilgrami SF, Metersky ML, McNally D et al (2001) Idiopathic Chang H, Rha SY, Jeung HC et al (2009) Association of the ABCB1
pneumonia syndrome following myeloablative chemotherapy and gene polymorphisms 2677G[T/A and 3435C[T with clinical
autologous transplantation. Ann Pharmacother 35:196–201 outcomes of paclitaxel monotherapy in metastatic breast cancer
Boice JD Jr, Tawn EJ, Winther JF et al (2003) Genetic effects of patients. Ann Oncol 20:272–277
radiotherapy for childhood cancer. Health Phys 85:65–80 Chen YC, Tzeng CH, Chen PM et al (2010) Influence of GSTP1
Boige V, Mendiboure J, Pignon JP et al (2010) Pharmacogenetic I105 V polymorphism on cumulative neuropathy and outcome of
assessment of toxicity and outcome in patients with metastatic FOLFOX-4 treatment in Asian patients with colorectal carcinoma.
colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: Cancer Sci 101:530–535
FFCD 2000–05. J Clin Oncol 28:2556–2564 Chia S, Clemons M, Martin LA et al (2006) Pegylated liposomal
Bokemeyer C, Schmoll HJ (1993) Secondary neoplasms following doxorubicin and trastuzumab in HER-2 overexpressing metastatic
treatment of malignant germ cell tumors. J Clin Oncol breast cancer: a multicenter phase II trial. J Clin Oncol
11:1703–1709 24:2773–2778
Bokemeyer C, Berger CC, Hartmann JT et al (1998) Analysis of risk Kidney Health after Childhood Cancer. Children’s Oncology Group
factors for cisplatin-induced ototoxicity in patients with testicular (2008) (Accessed at http://www.survivorshipguidelines.org/pdf/
cancer. Br J Cancer 77:1355–1362 KidneyHealth.pdf)
Booton R, Ward T, Heighway J, Ashcroft L, Morris J, Thatcher N Cho HJ, Eom HS, Kim HJ, Kim IS, Lee GW, Kong SY (2010)
(2006) Glutathione-S-transferase P1 isoenzyme polymorphisms, Glutathione-S-transferase genotypes influence the risk of chemo-
platinum-based chemotherapy, and non-small cell lung cancer. therapy-related toxicities and prognosis in Korean patients with
J Thorac Oncol 1:679–683 diffuse large B-cell lymphoma. Cancer Genet Cytogenet 198:40–46
Biotoxicity of Chemotherapy 149

Comis RL (1990) Detecting bleomycin pulmonary toxicity: a contin- Hayes DF, Picard MH (2006) Heart of darkness: the downside of
ued conundrum. J Clin Oncol 8:765–767 trastuzumab. J Clin Oncol 24:4056–4058
Cooper JA Jr, Zitnik RJ, Matthay RA (1988) Mechanisms of drug- Hensley ML, Hagerty KL, Kewalramani T et al (2009) American
induced pulmonary disease. Annu Rev Med 39:395–404 Society of Clinical Oncology 2008 clinical practice guideline
Cushing B, Giller R, Cullen JW et al (2004) Randomized comparison update: use of chemotherapy and radiation therapy protectants.
of combination chemotherapy with etoposide, bleomycin, and J Clin Oncol 27:127–145
either high-dose or standard-dose cisplatin in children and adoles- Hong J, Han SW, Ham HS et al (2011) Phase II study of biweekly S-1
cents with high-risk malignant germ cell tumors: a pediatric and oxaliplatin combination chemotherapy in metastatic colorectal
intergroup study—Pediatric Oncology Group 9049 and Children’s cancer and pharmacogenetic analysis. Cancer Chemother Pharma-
Cancer Group 8882. J Clin Oncol 22:2691–2700 col 67:1323–1331
Cvitkovic E, Spaulding J, Bethune V, Martin J, Whitmore WF (1977) Huang TT, Hudson MM, Stokes DC, Krasin MJ, Spunt SL, Ness KK
Improvement of cis-dichlorodiammineplatinum (NSC 119875): (2011) Pulmonary outcomes in survivors of childhood cancer: a
therapeutic index in an animal model. Cancer 39:1357–1361 systematic review. Chest 140:881–901
Czader M, Orazi A (2009) Therapy-related myeloid neoplasms. Am J Inada M, Sato M, Morita S et al (2010) Associations between
Clin Pathol 132:410–425 oxaliplatin-induced peripheral neuropathy and polymorphisms of
de Ruiter MB, Reneman L, Boogerd W et al (2011) Cerebral the ERCC1 and GSTP1 genes. Int J Clin Pharmacol Ther
hyporesponsiveness and cognitive impairment 10 years after 48:729–734
chemotherapy for breast cancer. Hum Brain Mapp 32:1206–1219 Isla D, Sarries C, Rosell R et al (2004) Single nucleotide polymor-
de Wit R, Roberts JT, Wilkinson PM et al (2001) Equivalence of three or phisms and outcome in docetaxel-cisplatin-treated advanced non-
four cycles of bleomycin, etoposide, and cisplatin chemotherapy and small-cell lung cancer. Ann Oncol 15:1194–1203
of a 3- or 5-day schedule in good-prognosis germ cell cancer: a Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer
randomized study of the European Organization for Research and statistics, 2009. CA Cancer J Clin 59:225–249
Treatment of Cancer Genitourinary Tract Cancer Cooperative Group Jones DP, Spunt SL, Green D, Springate JE (2008) Renal late effects in
and the Medical Research Council. J Clin Oncol 19:1629–1640 patients treated for cancer in childhood: a report from the
Fardell JE, Vardy J, Johnston IN, Winocur G (2011) Chemotherapy Children’s Oncology Group. Pediatr Blood Cancer 51:724–731
and cognitive impairment: treatment options. Clin Pharmacol Ther Kaldor JM, Day NE, Bell J et al (1992) Lung cancer following
90:366–376 Hodgkin’s disease: a case-control study. Int J Cancer 52:677–681
Floyd JD, Nguyen DT, Lobins RL, Bashir Q, Doll DC, Perry MC Kanai M, Yoshioka A, Tanaka S et al (2010) Associations between
(2005) Cardiotoxicity of cancer therapy. J Clin Oncol glutathione S-transferase pi Ile105Val and glyoxylate aminotrans-
23:7685–7696 ferase Pro11Leu and Ile340Met polymorphisms and early-onset
Friedman DL, Himelstein B, Shields CL et al (2000) Chemoreduction oxaliplatin-induced neuropathy. Cancer Epidemiol 34:189–193
and local ophthalmic therapy for intraocular retinoblastoma. J Clin Keam B, Im SA, Han SW et al (2008) Modified FOLFOX-6
Oncol 18:12–17 chemotherapy in advanced gastric cancer: results of phase II study
Fung C, Vaughn DJ (2011) Complications associated with chemo- and comprehensive analysis of polymorphisms as a predictive and
therapy in testicular cancer management. Nat Rev Urol 8:213–222 prognostic marker. BMC Cancer 8:148
Gamelin L, Capitain O, Morel A et al (2007) Predictive factors of Keefe DL (2002) Trastuzumab-associated cardiotoxicity. Cancer
oxaliplatin neurotoxicity: the involvement of the oxalate outcome 95:1592–1600
pathway. Clin Cancer Res 13:6359–6368 Khrunin AV, Moisseev A, Gorbunova V, Limborska S (2010) Genetic
Geiger S, Lange V, Suhl P, Heinemann V, Stemmler HJ (2010) polymorphisms and the efficacy and toxicity of cisplatin-based
Anticancer therapy induced cardiotoxicity: review of the literature. chemotherapy in ovarian cancer patients. Pharmacogenomics J
Anticancer Drugs 21:578–590 10:54–61
Giantris A, Abdurrahman L, Hinkle A, Asselin B, Lipshultz SE (1998) Kim HS, Kim MK, Chung HH et al (2009) Genetic polymorphisms
Anthracycline-induced cardiotoxicity in children and young adults. affecting clinical outcomes in epithelial ovarian cancer patients
Crit Rev Oncol Hematol 27:53–68 treated with taxanes and platinum compounds: a Korean popula-
Glendenning JL, Barbachano Y, Norman AR, Dearnaley DP, Horwich tion-based study. Gynecol Oncol 113:264–269
A, Huddart RA (2010) Long-term neurologic and peripheral Kintzel PE (2001) Anticancer drug-induced kidney disorders. Drug Saf
vascular toxicity after chemotherapy treatment of testicular cancer. 24:19–38
Cancer 116:2322–2331 Knight JA, Skol AD, Shinde A et al (2009) Genome-wide association
Goekkurt E, Al-Batran SE, Hartmann JT et al (2009) Pharmacogenetic study to identify novel loci associated with therapy-related myeloid
analyses of a phase III trial in metastatic gastroesophageal leukemia susceptibility. Blood 113:5575–5582
adenocarcinoma with fluorouracil and leucovorin plus either Knopman JM, Papadopoulos EB, Grifo JA, Fino ME, Noyes N (2010)
oxaliplatin or cisplatin: a study of the arbeitsgemeinschaft inter- Surviving childhood and reproductive-age malignancy: effects on
nistische onkologie. J Clin Oncol 27:2863–2873 fertility and future parenthood. Lancet Oncol 11:490–498
Green H, Soderkvist P, Rosenberg P et al (2009) Pharmacogenetic Kollmannsberger C, Hartmann JT, Kanz L, Bokemeyer C (1999)
studies of Paclitaxel in the treatment of ovarian cancer. Basic Clin Therapy-related malignancies following treatment of germ cell
Pharmacol Toxicol 104:130–137 cancer. Int J Cancer 83:860–863
Grewal S, Merchant T, Reymond R, McInerney M, Hodge C, Shearer Kremer LC, van Dalen EC, Offringa M, Ottenkamp J, Voute PA
P (2010) Auditory late effects of childhood cancer therapy: a report (2001) Anthracycline-induced clinical heart failure in a cohort of
from the Children’s Oncology Group. Pediatrics 125:e938–e950 607 children: long-term follow-up study. J Clin Oncol 19:191–196
Grothey A, Nikcevich DA, Sloan JA et al (2011) Intravenous calcium Kreukels BP, Schagen SB, Ridderinkhof KR et al (2006) Effects of
and magnesium for oxaliplatin-induced sensory neurotoxicity in high-dose and conventional-dose adjuvant chemotherapy on long-
adjuvant colon cancer: NCCTG N04C7. J Clin Oncol 29:421–427 term cognitive sequelae in patients with breast cancer: an
Haugnes HS, Aass N, Fossa SD et al (2009) Pulmonary function in electrophysiologic study. Clin Breast Cancer 7:67–78
long-term survivors of testicular cancer. J Clin Oncol Krischer JP, Epstein S, Cuthbertson DD, Goorin AM, Epstein ML,
27:2779–2786 Lipshultz SE (1997) Clinical cardiotoxicity following
150 C. Fung and K. J. Pandya

anthracycline treatment for childhood cancer: the Pediatric Oncol- Mir O, Alexandre J, Tran A et al (2009) Relationship between GSTP1
ogy Group experience. J Clin Oncol 15:1544–1552 Ile(105)Val polymorphism and docetaxel-induced peripheral neu-
Lambert MP, Shields C, Meadows AT (2008) A retrospective review ropathy: clinical evidence of a role of oxidative stress in taxane
of hearing in children with retinoblastoma treated with carboplatin- toxicity. Ann Oncol 20:736–740
based chemotherapy. Pediatr Blood Cancer 50:223–226 Mukherjea D, Rybak LP (2011) Pharmacogenomics of cisplatin-
Launay-Vacher V, Rey JB, Isnard-Bagnis C, Deray G, Daouphars M induced ototoxicity. Pharmacogenomics 12:1039–1050
(2008) Prevention of cisplatin nephrotoxicity: state of the art and Musial-Bright L, Fengler R, Henze G, Hernaiz Driever P (2011)
recommendations from the European Society of Clinical Pharmacy Carboplatin and ototoxicity: hearing loss rates among survivors of
Special Interest Group on Cancer Care. Cancer Chemother childhood medulloblastoma. Childs Nerv Syst 27:407–413
Pharmacol 61:903–909 Myers JS (2012) Chemotherapy-related cognitive impairment: the
Lawson M, Vasilaras A, De Vries A, Mactaggart P, Nicol D (2008) breast cancer experience. Oncol Nurs Forum 39:E31–E40
Urological implications of cyclophosphamide and ifosfamide. Nichols CR, Catalano PJ, Crawford ED, Vogelzang NJ, Einhorn LH,
Scand J Urol Nephrol 42:309–317 Loehrer PJ (1998) Randomized comparison of cisplatin and
Lecomte T, Landi B, Beaune P, Laurent-Puig P, Loriot MA (2006) etoposide and either bleomycin or ifosfamide in treatment of
Glutathione S-transferase P1 polymorphism (Ile105Val) predicts advanced disseminated germ cell tumors: an Eastern Cooperative
cumulative neuropathy in patients receiving oxaliplatin-based Oncology Group, Southwest Oncology Group, and Cancer and
chemotherapy. Clin Cancer Res 12:3050–3056 Leukemia Group B Study. J Clin Oncol 16:1287–1293
Lee SJ, Schover LR, Partridge AH et al (2006) American Society of Nousiainen T, Jantunen E, Vanninen E, Hartikainen J (2002a) Early
Clinical Oncology recommendations on fertility preservation in decline in left ventricular ejection fraction predicts doxorubicin
cancer patients. J Clin Oncol 24:2917–2931 cardiotoxicity in lymphoma patients. Br J Cancer 86:1697–1700
Leskela S, Jara C, Leandro-Garcia LJ et al (2011a) Polymorphisms in Nousiainen T, Vanninen E, Jantunen E et al (2002b) Natriuretic
cytochromes P450 2C8 and 3A5 are associated with paclitaxel peptides during the development of doxorubicin-induced left
neurotoxicity. Pharmacogenomics J 11:121–129 ventricular diastolic dysfunction. J Intern Med 251:228–234
Leskela S, Leandro-Garcia LJ, Mendiola M et al (2011b) The miR-200 Oldenburg J, Kraggerud SM, Brydoy M, Cvancarova M, Lothe RA,
family controls beta-tubulin III expression and is associated with Fossa SD (2007a) Association between long-term neuro-toxicities
paclitaxel-based treatment response and progression-free survival in testicular cancer survivors and polymorphisms in glutathione-s-
in ovarian cancer patients. Endocr Relat Cancer 18:85–95 transferase-P1 and -M1, a retrospective cross sectional study.
Levine J, Canada A, Stern CJ (2010) Fertility preservation in J Transl Med 5:70
adolescents and young adults with cancer. J Clin Oncol Oldenburg J, Kraggerud SM, Cvancarova M, Lothe RA, Fossa SD
28:4831–4841 (2007b) Cisplatin-induced long-term hearing impairment is asso-
Li FP, Fine W, Jaffe N, Holmes GE, Holmes FF (1979) Offspring of ciated with specific glutathione s-transferase genotypes in testicular
patients treated for cancer in childhood. J Natl Cancer Inst cancer survivors. J Clin Oncol 25:708–714
62:1193–1197 Pabla N, Dong Z (2008) Cisplatin nephrotoxicity: mechanisms and
Li QF, Yao RY, Liu KW, Lv HY, Jiang T, Liang J (2010) Genetic renoprotective strategies. Kidney Int 73:994–1007
polymorphism of GSTP1: prediction of clinical outcome to Pachman DR, Barton DL, Watson JC, Loprinzi CL (2011) Chemo-
oxaliplatin/5-FU-based chemotherapy in advanced gastric cancer. therapy-induced peripheral neuropathy: prevention and treatment.
J Korean Med Sci 25:846–852 Clin Pharmacol Ther 90:377–387
Limper AH (2004) Chemotherapy-induced lung disease. Clin Chest Pare L, Marcuello E, Altes A et al (2008) Pharmacogenetic prediction
Med 25:53–64 of clinical outcome in advanced colorectal cancer patients receiv-
Loebstein R, Atanackovic G, Bishai R et al (1999) Risk factors for ing oxaliplatin/5-fluorouracil as first-line chemotherapy. Br J
long-term outcome of ifosfamide-induced nephrotoxicity in chil- Cancer 99:1050–1055
dren. J Clin Pharmacol 39:454–461 Pera MF Jr, Zook BC, Harder HC (1979) Effects of mannitol or
Lyu YL, Kerrigan JE, Lin CP et al (2007) Topoisomerase IIbeta furosemide diuresis on the nephrotoxicity and physiological
mediated DNA double-strand breaks: implications in doxorubicin disposition of cis-dichlorodiammineplatinum-(II) in rats. Cancer
cardiotoxicity and prevention by dexrazoxane. Cancer Res Res 39:1269–1278
67:8839–8846 Persohn E, Canta A, Schoepfer S et al (2005) Morphological and
Maher J, Daly PA (1993) Severe bleomycin lung toxicity: reversal morphometric analysis of paclitaxel and docetaxel-induced periph-
with high dose corticosteroids. Thorax 48:92–94 eral neuropathy in rats. Eur J Cancer 41:1460–1466
Manji H (2011) Toxic neuropathy. Curr Opin Neurol 24:484–490 Peters U, Preisler-Adams S, Hebeisen A et al (2000) Glutathione S-
Mannervik B, Alin P, Guthenberg C et al (1985) Identification of three transferase genetic polymorphisms and individual sensitivity to the
classes of cytosolic glutathione transferase common to several ototoxic effect of cisplatin. Anticancer Drugs 11:639–643
mammalian species: correlation between structural data and Qaddoumi I, Bass JK, Wu J et al (2012) Carboplatin-associated
enzymatic properties. Proc Natl Acad Sci U S A 82:7202–7206 ototoxicity in children with retinoblastoma. J Clin Oncol 30(10):1034
Marsh S, Paul J, King CR, Gifford G, McLeod HL, Brown R (2007) Rayson D, Suter TM, Jackisch C et al (2011) Cardiac safety of
Pharmacogenetic assessment of toxicity and outcome after plati- adjuvant pegylated liposomal doxorubicin with concurrent trast-
num plus taxane chemotherapy in ovarian cancer: the Scottish uzumab: a randomized phase II trial. Ann Oncol 18(1):48–59
Randomised Trial in Ovarian Cancer. J Clin Oncol 25:4528–4535 Riedemann L, Lanvers C, Deuster D et al (2008) Megalin genetic
McLeod HL, Sargent DJ, Marsh S et al (2010) Pharmacogenetic polymorphisms and individual sensitivity to the ototoxic effect of
predictors of adverse events and response to chemotherapy in cisplatin. Pharmacogenomics J 8:23–28
metastatic colorectal cancer: results from North American Gastro- Rizzo R, Spaggiari F, Indelli M et al (2010) Association of CYP1B1
intestinal Intergroup Trial N9741. J Clin Oncol 28:3227–3233 with hypersensitivity induced by taxane therapy in breast cancer
Meinardi MT, Van Der Graaf WT, Gietema JA et al (2002) Evaluation patients. Breast Cancer Res Treat 124:593–598
of long term cardiotoxicity after epirubicin containing adjuvant Ross CJ, Katzov-Eckert H, Dube MP et al (2009) Genetic variants in
chemotherapy and locoregional radiotherapy for breast cancer TPMT and COMT are associated with hearing loss in children
using various detection techniques. Heart 88:81–82 receiving cisplatin chemotherapy. Nat Genet 41:1345–1349
Biotoxicity of Chemotherapy 151

Ruzzo A, Graziano F, Loupakis F et al (2007) Pharmacogenetic Smith LA, Cornelius VR, Plummer CJ et al (2010) Cardiotoxicity of
profiling in patients with advanced colorectal cancer treated with anthracycline agents for the treatment of cancer: systematic review
first-line FOLFOX-4 chemotherapy. J Clin Oncol 25:1247–1254 and meta-analysis of randomised controlled trials. BMC Cancer
Rybak LP, Whitworth CA, Mukherjea D, Ramkumar V (2007) 10:337
Mechanisms of cisplatin-induced ototoxicity and prevention. Hear Smits C, Swen SJ, Theo Goverts S, Moll AC, Imhof SM, Schouten-
Res 226:157–167 van Meeteren AY (2006) Assessment of hearing in very young
Rybak LP, Mukherjea D, Jajoo S, Ramkumar V (2009) Cisplatin children receiving carboplatin for retinoblastoma. Eur J Cancer
ototoxicity and protection: clinical and experimental studies. 42:492–500
Tohoku J Exp Med 219:177–186 Stoehlmacher J, Park DJ, Zhang W et al (2002) Association between
Santoso JT, Lucci JA 3rd, Coleman RL, Schafer I, Hannigan EV glutathione S-transferase P1, T1, and M1 genetic polymorphism
(2003) Saline, mannitol, and furosemide hydration in acute and survival of patients with metastatic colorectal cancer. J Natl
cisplatin nephrotoxicity: a randomized trial. Cancer Chemother Cancer Inst 94:936–942
Pharmacol 52:13–18 Suarez A, McDowell H, Niaudet P, Comoy E, Flamant F (1991) Long-
Schagen SB, Muller MJ, Boogerd W, Mellenbergh GJ, van Dam FS term follow-up of ifosfamide renal toxicity in children treated for
(2006) Change in cognitive function after chemotherapy: a malignant mesenchymal tumors: an international society of
prospective longitudinal study in breast cancer patients. J Natl pediatric oncology report. J Clin Oncol 9:2177–2182
Cancer Inst 98:1742–1745 Sucheston LE, Zhao H, Yao S et al (2011) Genetic predictors of
Schwartz RG, McKenzie WB, Alexander J et al (1987) Congestive taxane-induced neurotoxicity in a SWOG phase III intergroup
heart failure and left ventricular dysfunction complicating doxo- adjuvant breast cancer treatment trial (S0221). Breast Cancer Res
rubicin therapy. Seven-year experience using serial radionuclide Treat 130:993–1002
angiocardiography. Am J Med 82:1109–1118 Swain SM, Whaley FS, Gerber MC et al (1997) Cardioprotection with
Senkus E, Jassem J (2011) Cardiovascular effects of systemic cancer dexrazoxane for doxorubicin-containing therapy in advanced breast
treatment. Cancer Treat Rev 37:300–311 cancer. J Clin Oncol 15:1318–1332
Seo BG, Kwon HC, Oh SY et al (2009) Comprehensive analysis of Swerdlow AJ, Douglas AJ, Hudson GV, Hudson BV, Bennett MH,
excision repair complementation group 1, glutathione S-transfer- MacLennan KA (1992) Risk of second primary cancers after
ase, thymidylate synthase and uridine diphosphate glucuronosyl Hodgkin’s disease by type of treatment: analysis of 2846 patients
transferase 1A1 polymorphisms predictive for treatment outcome in the British National Lymphoma Investigation. BMJ
in patients with advanced gastric cancer treated with FOLFOX or 304:1137–1143
FOLFIRI. Oncol Rep 22:127–136 Swerdlow AJ, Higgins CD, Smith P et al (2011) Second cancer risk
Sill H, Olipitz W, Zebisch A, Schulz E, Wolfler A (2011) Therapy- after chemotherapy for Hodgkin’s lymphoma: a collaborative
related myeloid neoplasms: pathobiology and clinical characteris- British cohort study. J Clin Oncol 29:4096–4104
tics. Br J Pharmacol 162:792–805 Tannock IF, Ahles TA, Ganz PA, Van Dam FS (2004) Cognitive
Silverman DH, Dy CJ, Castellon SA et al (2007) Altered frontocor- impairment associated with chemotherapy for cancer: report of a
tical, cerebellar, and basal ganglia activity in adjuvant-treated workshop. J Clin Oncol 22:2233–2239
breast cancer survivors 5–10 years after chemotherapy. Breast Trachtenberg BH, Landy DC, Franco VI et al (2011) Anthracycline-
Cancer Res Treat 103:303–311 associated cardiotoxicity in survivors of childhood cancer. Pediatr
Sissung TM, Mross K, Steinberg SM et al (2006) Association of Cardiol 32:342–353
ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy Travis LB, Holowaty EJ, Bergfeldt K et al (1999) Risk of leukemia
and neutropenia. Eur J Cancer 42:2893–2896 after platinum-based chemotherapy for ovarian cancer. N Engl J
Sissung TM, Baum CE, Deeken J et al (2008) ABCB1 genetic Med 340:351–357
variation influences the toxicity and clinical outcome of patients Travis LB, Andersson M, Gospodarowicz M et al (2000) Treatment-
with androgen-independent prostate cancer treated with docetaxel. associated leukemia following testicular cancer. J Natl Cancer Inst
Clin Cancer Res 14:4543–4549 92:1165–1171
Skinner R (2011) Nephrotoxicity—what do we know and what don’t Travis LB, Gospodarowicz M, Curtis RE et al (2002) Lung cancer
we know? J Pediatr Hematol Oncol 33:128–134 following chemotherapy and radiotherapy for Hodgkin’s disease.
Skinner R, Cotterill SJ, Stevens MC (2000) Risk factors for J Natl Cancer Inst 94:182–192
nephrotoxicity after ifosfamide treatment in children: a UKCCSG Travis LB, Fossa SD, Schonfeld SJ et al (2005) Second cancers among
Late Effects Group study. United Kingdom Children’s Cancer 40,576 testicular cancer patients: focus on long-term survivors.
Study Group. Br J Cancer 82:1636–1645 J Natl Cancer Inst 97:1354–1365
Skinner R, Parry A, Price L, Cole M, Craft AW, Pearson AD (2009) Travis LB, Rabkin CS, Brown LM et al (2006) Cancer survivorship—
Persistent nephrotoxicity during 10-year follow-up after cisplatin genetic susceptibility and second primary cancers: research strat-
or carboplatin treatment in childhood: relevance of age and dose as egies and recommendations. J Natl Cancer Inst 98:15–25
risk factors. Eur J Cancer 45:3213–3219 Travis LB, Beard C, Allan JM et al (2010) Testicular cancer
Skinner R, Parry A, Price L, Cole M, Craft AW, Pearson AD (2010) survivorship: research strategies and recommendations. J Natl
Glomerular toxicity persists 10 years after ifosfamide treatment in Cancer Inst 102:1114–1130
childhood and is not predictable by age or dose. Pediatr Blood Vahdat LT, Thomas ES, Roche HH et al (2012) Ixabepilone-associated
Cancer 54:983–989 peripheral neuropathy: data from across the phase II and III clinical
Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemother- trials. Support Care Cancer 20:2661
apy plus a monoclonal antibody against HER2 for metastatic breast van Dalen EC, van der Pal HJ, Caron HN, Kremer LC (2009) Different
cancer that overexpresses HER2. N Engl J Med 344:783–792 dosage schedules for reducing cardiotoxicity in cancer patients
Sleijfer S (2001) Bleomycin-induced pneumonitis. Chest 120:617–624 receiving anthracycline chemotherapy. Cochrane Database Syst
Sleijfer S, van der Mark TW, Schraffordt Koops H, Mulder NH (1995) Rev 2009:CD005008
Decrease in pulmonary function during bleomycin-containing van Dalen EC, Michiels EM, Caron HN, Kremer LC (2010) Different
combination chemotherapy for testicular cancer: not only a anthracycline derivates for reducing cardiotoxicity in cancer
bleomycin effect. Br J Cancer 71:120–123 patients. Cochrane Database Syst Rev 2010:CD005006
152 C. Fung and K. J. Pandya

van Dalen EC, Caron HN, Dickinson HO, Kremer LC (2011) Zarate R, Rodriguez J, Bandres E et al (2010) Oxaliplatin, irinotecan
Cardioprotective interventions for cancer patients receiving anth- and capecitabine as first-line therapy in metastatic colorectal
racyclines. Cochrane Database Syst Rev 2011:CD003917 cancer (mCRC): a dose-finding study and pharmacogenomic
van den Belt-Dusebout AW, de Wit R, Gietema JA et al (2007) analysis. Br J Cancer 102:987–994
Treatment-specific risks of second malignancies and cardiovascular Zhu X, Wu S, Dahut WL, Parikh CR (2007) Risks of proteinuria and
disease in 5-year survivors of testicular cancer. J Clin Oncol hypertension with bevacizumab, an antibody against vascular
25:4370–4378 endothelial growth factor: systematic review and meta-analysis.
Vardy J, Tannock I (2007) Cognitive function after chemotherapy in Am J Kidney Dis 49:186–193
adults with solid tumours. Crit Rev Oncol Hematol 63:183–202 Zuppinger C, Suter TM (2010) Cancer therapy-associated cardiotox-
Von Hoff DD, Layard MW, Basa P et al (1979) Risk factors for icity and signaling in the myocardium. J Cardiovasc Pharmacol
doxorubicin-induced congestive heart failure. Ann Intern Med 56:1 41–146
91:710–717
Wallace WH (2011) Oncofertility and preservation of reproductive
capacity in children and young adults. Cancer 117:2301–2310
Wanderas EH, Fossa SD, Tretli S (1997) Risk of subsequent non-germ General References
cell cancer after treatment of germ cell cancer in 2006 Norwegian
male patients. Eur J Cancer 33:253–262 Band P (2010) The birth of the subspecialty of medical oncology and
Weinshilboum RM (2006) Pharmacogenomics: catechol O-methyl- examples of its early scientific foundations. J Clin Oncol
transferase to thiopurine S-methyltransferase. Cell Mol Neurobiol 28:3653–3658
26:539–561 Goodman and Gilman’s The Pharmacologic Basis of Therapeutics,
Wouters KA, Kremer LC, Miller TL, Herman EH, Lipshultz SE (2005) 12th edition. New York, McGraw-Hill 2012, Brunton LL, Chabner
Protecting against anthracycline-induced myocardial damage: a BA, Knollmann BC, eds. Editors of the online editon: Editor-in-
review of the most promising strategies. Br J Haematol Chief: Brunton LL. Assoc eds: Blumenthal DK, Murri N, Hilal-
131:561–578 Dandan R. Consulting ed: Knollmann BC. Chapter 60, Chabner
Yao X, Panichpisal K, Kurtzman N, Nugent K (2007) Cisplatin BA. General Principles of Cancer Chemotherapy. Chapter 61,
nephrotoxicity: a review. Am J Med Sci 334:115–124 Chabner BA, Bertino J, Cleary J et al. Cytotoxic Agents. Chapter
Yeh ET, Bickford CL (2009) Cardiovascular complications of cancer 62, Chabner BA, Barnes J, Neal J et al. Targeted Therapies:
therapy: incidence, pathogenesis, diagnosis, and management. Tyrosine Kinase Inhibitors, Monoclonal Antibodies, and Cytokines
J Am Coll Cardiol 53:2231–2247 Perry MC (ed) (2008) The chemotherapy source book, 4th edn.
Yousem SA, Lifson JD, Colby TV (1985) Chemotherapy-induced Lippincott, Williams and Wilkins, Philadelphia
eosinophilic pneumonia. Relation to bleomycin. Chest 88:103–106
 BioSurveillance and Longitudinal Lifelong
Guidelines
Andrea K. Ng and Melissa M. Hudson

Contents Abstract

1 Introduction.......................................................................... 154 • Given the increased risk of a wide range of late effects
2 Follow-up Guidelines for Survivors of Pediatric faced by cancer survivors, lifelong follow-up of these
Malignancies......................................................................... 154 patients are essential.
3 Follow-up Guidelines for Survivors of Adult-Onset • Existing guidelines are largely based on the known types
Malignancies......................................................................... 160 of late effects, their temporal trend and modifying risk
factors after specific treatments for various primary
4 Specific Areas for Surveillance/Interventions .................. 161
4.1 Second Malignancy ............................................................... 161 malignancies.
4.2 Cardiovascular Disease ......................................................... 162 • Well-established follow-up guidelines exist for survivors
4.3 Endocrine Function ............................................................... 163 of pediatric malignancies, most of which are based on
4.4 Bone Health ........................................................................... 164
prior treatment exposures.
4.5 Psychosocial Issues................................................................ 164
• Less data are available on the optimal follow-up strate-
5 Conclusions ........................................................................... 164 gies for survivors of adult-onset cancer.
6 Future Directions................................................................. 164 • Additional efforts are needed to prospectively evaluate
References...................................................................................... 165 the feasibility and efficacy of the follow-up recommen-
dations including screening and prevention strategies.
• Need to initiate transition from multidisciplinary oncol-
ogy to medical community care through individualized
survivorship care plan (p 5, paragraph 1).
• Community health care providers are unfamiliar with
health risks associated with cancer survivors and need to
be supplemented by patient education and self advocacy
(p 5, paragraph 2, 3).
• Currently, deficiencies include lack of standard defini-
tions of toxicity, use of variable testing strategies,
inconsistency as to evaluation time in relation to thera-
peutic exposures (p 6, paragraph 1).
• Early identification leads to early intervention for late
onset therapy-related complications (p 6, paragraph 4).
• NCCN guidelines provide follow-up algorithms for
cancer relapse rather than late effects of treatment (p 8,
A. K. Ng (&) paragraph 1).
Radiation Oncology, Dana-Farber/Harvard Cancer Center, • Long-term surveillance guidelines beyond 5 years are
75 Francis St ASB1-L2, Boston, MA 02115, USA
e-mail: [email protected] available for 15 different cancers and again are designed
for detecting cancer recurrence (p 9, paragraph 2).
M. M. Hudson
Cancer Survivorship Division, St. Jude Children’s • Second malignant neoplasms (SMN) have been most
Research Hospital, MS 735, Room S-6014, actively pursued in Hodgkin’s lymphoma survivors
262 Danny Thomas Place, Memphis, TN 38105-3678, USA

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 153
DOI: 10.1007/978-3-540-72314-1_10,  Springer-Verlag Berlin Heidelberg 2014
154 A. K. Ng and M. M. Hudson

(breast cancer and lung cancer ) (p 10, paragraph 3, p 11, as genetic predisposition, health habits, environmental
paragraph 1, p 12). exposures, immune dysfunction, or infectious causes.
• SMN skin cancers are increased in Hodgkin’s lymphoma While ample data exist describing the increased risk of
and TBI/BMT survivors (p 13). various late effects after cancer therapy, especially for
• SMN uterine cancer is increased in breast cancer survivors selected subtypes of cancers which are characterized by
on estrogen therapy by 50 % in high-risk women (p 19). young age at diagnosis, high cure rate and/or a long natural
• Cardiovascular disease complications are seen after history, relatively little information are available on how to
radiation in breast cancer and Hodgkin’s lymphoma cope with the known increased risk. Potential approaches
survivors, with varied guidelines for annual blood pres- include early detection of late effects through surveillance
sure, serum glucose and lipid screening, and utility of and screening, allowing early intervention and treatment, as
baseline stress test/echocardiogram (p 16). well as risk reduction and prevention strategies. Raising the
• Endocrine deficiencies after head and neck radiation awareness of patients and health care providers of the
leads to 30–40 % risk of hypothyroidism (p 18). increased risks of late effects, and education on risk
• Osteopenia can occur due to increased bone turnover in reduction through health habit modification and adherence
treatment-induced ovarian ablation and prostate cancer to screening recommendations are also key to the success of
treated with gonadotrophin-releasing hormone agonists a survivorship program.
(p 18). Currently, concrete guidelines and recommendations for
• Osteonecrosis and bone fracture can occur after radiation the follow-up of long-term cancer survivors are lacking.
doses of 60 Gy and have been shown in survivors of The key exception is with pediatric oncology, a group in
cervix cancer (p 18). which historically significant effort is dedicated to the
• Psychosocial distress issues include fear, anxiety, sui- lifelong care of childhood cancer survivors (Landier et al.
cidal ideation, depression, highlighting importance of 1999; Bhatia et al. 2005; Robison 2005; Hudson 2008). In
implementing routine psychological screening and access addition to careful documentation and reporting of late
to mental health professionals (p 20). effects, well-established guidelines, based on existing evi-
Future Directions dence and/or expert consensus, have been specifically
• Recognize need for adult guidelines in follow-up of developed to provide recommendations on the follow-up of
cancer survivors, especially those treated by radia- long-term childhood cancer survivors (Landier et al. 2004).
tion ± chemotherapy and surgery (p 20). Although follow-up guidelines for survivors of adult-onset
• Need information on feasibility, level of compliance effi- cancer exist, these often focused on detection of cancer
cacy, cost-effectiveness for surveillance strategies (p 20). recurrences, rather than management of late effects. In this
• Optimal types of testing and interventions, their timing chapter, we will review and discuss available follow-up
and frequency needs to be better defined and assessed in guidelines designed to screen for, reduce the risk of, and
prospective cohorts of cancer survivors (p 20). provide intervention for late effects in long-term cancer
• Develop internet contact and resources that may provide survivors.
optimal means to maintain contact for long-term follow-up
of cancer survivors in our highly mobile society (p 20).
2 Follow-up Guidelines for Survivors
of Pediatric Malignancies
1 Introduction
Therapeutic success has made long-term survival a reality
Improvement in cancer screening, advances in cancer for the vast majority of children, adolescents, and young
therapy and supportive care, along with the aging popula- adults diagnosed with cancer. Following contemporary
tion have led to an increasing number of cancer survivors. therapy, over 80 % of children and adolescents will survive
After successful cancer therapy, a substantial proportion of 5 or more years from their cancer diagnosis and most are
patients face a wide range of late effects, including medical effectively cured of the disease (Ries et al. 2007). Investi-
and psychosocial sequelae. According to the American gations of long-term health outcomes in the growing pop-
Society of Clinical Oncology (ASCO), late effects are ulation of childhood cancer survivors have identified
defined as a side effect that occurs more than 5 years after a morbidity predisposed by specific therapeutic exposures, as
diagnosis of cancer because of the related treatments, such well host-, cancer-, and behavioral-related factors influ-
as chemotherapy, radiation therapy, and surgery. It should encing risk of future disease (Oeffinger et al. 2004). These
be noted, however, that survivors are also at risk for other cancer-related sequelae, known as late effects, encompass a
events unrelated to their prior therapy, but that may be due spectrum of health problems that may adversely affect
to shared etiologic risk factors with the initial cancer, such quality of life and predispose to early mortality (Oeffinger
 BioSurveillance and Longitudinal Lifelong Guidelines 155

et al. 2004; Mertens 2007). Moreover, late effects are with the health risks associated with childhood cancer,
commonly experienced by adults surviving childhood can- which includes a heterogeneous group of relatively rare
cer and become more prevalent with increasing time from diseases managed with diverse therapeutic approaches that
cancer diagnosis (Oeffinger et al. 2006; Geenen et al. 2007). have evolved over the years (Landier et al. 2006). Access to
The substantial knowledge about cancer-related effects preventive care may also be hindered by survivors who are
gained through health outcomes research has established a uninformed about their cancer history and its associated
foundation for risk-based survivor care and the currently health risks (Kadan-Lottick et al. 2002).
available health screening guidelines proposed for child- Because most survivors do not have access to late effects
hood cancer survivors (Skinner et al. 2005). Optimal risk- experts in their community to coordinate health care after
based care involves as a systematic plan for lifelong cancer, patient education and self-advocacy have been pro-
screening, surveillance, and prevention that incorporates moted as a means of disseminating awareness about cancer-
risks based on the previous cancer, cancer therapy, genetic related health risks to community providers (Landier et al.
predispositions, lifestyle behaviors, and comorbid health 2006). Resources that provide busy clinicians with accurate
conditions (Oeffinger 2003; Oeffinger et al. 2004). Infor- and succinct information about cancer-related late effects can
mation that is essential to the coordination of risk-based help survivors gain access to appropriate health screening. To
care includes age at cancer diagnosis, cancer histology, address this need, several groups have developed guidelines
organs/tissues involved by cancer, and therapeutic inter- aiming to facilitate and standardize risk-based care of
ventions undertaken such as surgery, chemotherapy childhood cancer survivors (Skinner et al. 2005). Limitations
administration, radiation treatment (fields and doses), in high quality health outcomes investigations posed chal-
hematopoietic cell transplantation, and blood product lenges in efforts to organize an evidence-base to support
transfusion. Knowledge of cumulative dosages or dose specific screening recommendations. Deficiencies encoun-
intensity of chemotherapeutic agents like anthracyclines is tered included the lack of standard definitions of toxicity, use
also important in estimating risk and determining screening of variable testing strategies, and inconsistency in evaluation
frequency. Ideally, this information is outlined in a treat- time in relation to therapeutic exposure, and bias related to
ment summary organized by staff at the pediatric cancer incomplete participation of at-risk cohorts. Since childhood
center. Figure 1 provides an example of a treatment sum- cancer comprises a relatively small proportion of cancer
mary detailing therapeutic exposures and health screening diagnoses, establishing through randomized clinical trials
recommended by the Children’s Oncology Group. that screening of asymptomatic survivors can reduce mor-
It is anticipated that early detection of health problems, bidity and mortality is not feasible. Consequently, studies
institution of preventive or remedial therapy, and modifi- evaluating utility and cost-effectiveness of screening
cation of maladaptive health behaviors will provide aging asymptomatic survivors are unlikely to be undertaken.
childhood cancer survivors with opportunities to maintain Despite the considerable limitations in the evidence
or improve health. Implementation of risk-based care currently available to guide health screening recommenda-
requires a working knowledge about health risks predis- tions for childhood cancer survivors, compelling evidence
posed by treatment for childhood cancer, an expertise that is does exist linking adverse outcomes to specific therapeutic
likely to be available only at a long-term follow-up program exposures. These data prompted the use of a hybrid-model
in a pediatric cancer center (Aziz et al. 2006). An essential for the development of health screening recommendations
service of these multidisciplinary programs is to facilitate to address the medically vulnerable and growing population
the transition from oncology to community care by orga- of childhood cancer survivors. Group methods have varied
nizing an individualized survivorship care plan that includes in the magnitude and scope of the assessment of the evi-
details about therapeutic interventions undertaken for dence-base of adverse outcomes. However, all proposed
childhood cancer and their potential health risks, personal- screening recommendations based on the collective clinical
ized health screening recommendations, and information experience of late effects experts that matched the magni-
about lifestyle factors that modify risks. The survivorship tude of the risk with the intensity of the screening recom-
prescription is extremely important because the survivor’s mendation. A brief description of the guideline
contact with the cancer center becomes less frequent with development methodology and content used by the Chil-
increasing passage of time from diagnosis and therapy dren’s Oncology Group (COG), the Scottish Intercollegiate
(Oeffinger et al. 2004). Guideline Network (SIGN) and the Late Effects Group of
Coordination of risk-based care becomes more chal- the United Kingdom Children’s Cancer Study Group
lenging as survivors age out of pediatric long-term follow- (UKCCSG) is summarized in Table 1.
up programs and return to community providers for both The COG and SIGN Guidelines and UKCCSG Practice
their primary and cancer-related care. Research has dem- Statement represent important educational resources for
onstrated that community providers are largely unfamiliar survivors of childhood cancer and providers who supervise
156 A. K. Ng and M. M. Hudson

SUMMARY OF CANCER TREATMENT

Date Prepared: 06/30/2008

Survivor Name: Date of Birth:

Treatment Center: St. Jude Children’s Research Hospital
Cancer Diagnosis: Acute lymphoblastic leukemia
Date of Diagnosis: 02/18/1972 Age at Diagnosis: 4.9 years Date of Completion of Therapy: 09/18/1974
Cancer Treatment
Radiation Therapy
Date start Date Stop Field Dose (cGy)
03/20/1972 04/05/1972 Cranium 2400
Chemotherapy
Drug Name Dose (units or mg/m2)
L-asparaginase Yes
Daunorubicin Yes – 50 mg/m2
Mercaptopurine Yes
Methotrexate Yes
Prednisone Yes
Vincristine Y es
Cancer Treatment Late Effects Risks Screening Health Behavior Recommendations
Recommendations**
Any cancer history Difficulty with healthcare and Complete physical exam every Have regular screening exams appropriate for cancer treatment
insurance access year exposures
Hypothalamic-pituitary axis Hypothyroidism Body mass index Get regular exercise (> 20-30 3 times weekly).
radiation Metabolic syndrome Free T4, TSH Eat a variety of healthy foods with an emphasis on plant
Hypertension Fasting glucose, insulin and sources and calcium rich foods.
Dyslipidemia lipid profile Limit fat in diet to < 30%.
Overweight/Obesity Maintain a healthy weight.
Hyperinsulinism/Insulin
resistance
Daunorubicin Cardiomyopathy Baseline EKG at 2 or more years Do not smoke.
after completion of therapy Get regular exercise (> 20-30 minutes 3 times weekly).
Echocardiogram every 5 years Eat a variety of healthy foods with an emphasis on plant
sources and calcium rich foods.
Limit fat in diet to < 30%.
Maintain a healthy weight.
Methotrexate/Corticosteroids Osteopenia/Osteoporosis Bone density test Do not smoke.
Get regular weight-bearing exercise (> 20-30 minutes 3 times
weekly).
Eat a variety of healthy foods with an emphasis on plant
sources and calcium rich foods.
Limit your intake of alcohol (< 1 drink/day for women; < 2
drinks/day for men)

**Screening recommendations from the CureSearch Children’s Oncology Group Long-Term Follow-Up Guidelines at http://www.survivorshipguidelines.org.

Fig. 1 After completion of therapy clinical summary for an adult survivor of childhood acute lymphoblastic leukemia detailing therapeutic
exposures and health screening recommended by the Children’s Oncology Group

their care. It is anticipated that increased awareness about about health risks and false-positive screening evaluations.
adverse outcomes after childhood cancer offer the potential In addition, the costs of long-term follow-up care may be
benefits of early identification of and intervention for late prohibitive for some patients. These issues are particularly
onset therapy-related complications. However, survivors relevant since the evidence supporting optimal screening
may also experience potential harms including anxiety methods for most outcomes and the benefits of treating
Table 1 Guidelines for follow-up care after childhood cancer
Organization Search methods Scoring of evidence Content/Features
Children’s Oncology Group Systematic literature review via Scoring by multidisciplinary 136 sections of exposure-based
Long-Term Follow-Up MEDLINE (National Library of panel of late effects experts potential late effects with
Guidelines for Survivors of Medicine, Bethesda, MD) using according to a modified version periodic health screening recommendations, and supporting
Childhood, Adolescent and key search words comprised of the National Comprehensive references.
Young Adult Cancers ‘‘childhood cancer therapy,’’ Cancer Network ‘‘Categories of Delineation of ‘‘At Risk’’ and ‘‘Highest Risk’’ groups
Version 1.0 released March 2003 ‘‘complications,’’ ‘‘late effects’’, Consensus’’ system (high to
Version 2.0 released March 2006 and specific toxicities lower level of evidence)
Available at: References from the Each score reflects expert panel’s Health counseling and further considerations complemented
http://www.survivorshipguidelines.org bibliographies of selected assessment of strength of evidence by patient education materials handouts called ‘‘Health Links’’
articles were used to broaden the from the literature linking specific Adult cancer screening recommendations for standard
search’’ adverse outcomes to specific therapeutic and high-risk groups
Multidisciplinary system-based exposures
(e.g., cardiovascular, Assessment of appropriateness of
neurocognitive, reproductive, screening recommendation based
etc.) task forces monitor the on expert panel’s collective clinical
literature and provide experience
BioSurveillance and Longitudinal Lifelong Guidelines

recommendations for guideline

revision as new information
becomes available
Scottish Intercollegiate Systematic review and critical Rating of methodological quality Detailed analysis of 5 key survivor outcomes:
Guidelines Network appraisal of literature using (low to high risk of bias) (1) growth
Long-Term Follow-Up of SIGN methodology of eligible studies by two (2) puberty and fertility
Survivors of Childhood Cancer— independent reviewers. (3) cardiac abnormalities
SIGN 76: Recommendation for evidence’s (4) thyroid function
A National Clinical Guideline use in guiding management (5) neurodevelopment and psychological health
Release date January 2004 decisions graded (A to D) based on Recommendations for levels of long-term follow-up
Updated March 2005 multidisciplinary team’s collective care based on intensity of treatment received
Available at: http://www.sign.ac.uk/ clinical experience and knowledge
guidelines/fulltext/76. of evidence
Recommendation of ‘‘best practices’’
based on clinical experience of
guideline development group
United Kingdom Children’s Formal literature searches of key Assessment of data from literature Brief summary of exposure-based outcomes by any treatment,
Cancer Study Group topics review complemented by expert chemotherapy, radiation, and surgery
Late Effects Group committee reports and opinions 25 key content sections highlighting potential adverse
Practice Statement: Therapy and clinical experience and practice outcomes, risk factors, screening recommendations, further
Based Long Term Follow Up. of respected authorities management, and supporting references
1st Edition released 1995 Formal critical appraisal undertaken Appendices offering expanded detail about health outcomes
2nd Edition released April 2005 in specific contributions cross-referenced in high risk groups (CNS tumors, transplant recipients),
2nd Edition updated June 2006 to the SIGN 76 Guidelines other general topics (puberty, fertility, immunization),
Available at: and template of treatment summary
http://www.ukccsg.org/public/
followup/PracticeStatement
157
158 A. K. Ng and M. M. Hudson

asymptomatic survivors with subclinical dysfunction have The American College of Radiology Appropriateness
not been established. Prospective and scientifically rigorous Criteria also provide evidence-based guidelines for man-
research is required to identify accurate and cost-effective agement of a selected number of primary cancer sites,
screening modalities and appropriate screening frequency including breast cancer, Hodgkin lymphoma, lung cancer,
and to establish the impact of screening on long-term sur- prostate cancer, and rectal-anal cancer (www.acr.org). The
vivor health outcomes. guidelines were developed by expert panels that consisted
of oncologists as well as other specialists depending on the
disease site. Of these disease sites, a separate topic dedi-
3 Follow-up Guidelines for Survivors cated to follow-up of patients were only available for lung
of Adult-Onset Malignancies cancer and Hodgkin lymphoma. For post-therapy follow-up
for lung cancer, in addition to recommendations regarding
In contrast to follow-up guidelines for survivors of pediatric follow-up for recurrences, discussions were made on the
malignancies, which are based on treatment exposures, role of life-long chest computed tomography (CT) screen-
guidelines for survivors of adult-onset malignancies are ing due to the increased risk of second lung cancer in these
largely based on cancer types, in part because of the wider patients, although the frequency of the screening CT was
range of malignancies and the greater patient and clinical considered controversial. For follow-up after Hodgkin
scenario heterogeneity in the adult population. In addition, lymphoma therapy, more detailed discussions were avail-
follow-up recommendations for the adult-onset cancer sur- able on the follow-up of a number of late effects, including
vivors tend to be less comprehensive and specific, and are hypothyroidism, second malignancy, in particular breast
available only for a restricted number of primary cancer cancer and lung cancer, and cardiovascular complications.
diagnosis. Recommendations were also made regarding areas of
One of the most well-recognized and widely-used patient counseling and education, both for raising patient
guidelines in adult oncology is the National Comprehensive awareness as well as for promoting life style changes.
Cancer Network (NCCN) Clinical Practice Guidelines in Increasingly, information specific to cancer survivors are
Oncology, developed through review of the evidence in available on websites of major cancer centers as well as
conjunction with expert judgment by multidisciplinary cancer organizations including the American Society of
panels from NCCN Member Institutions (2008). For each Clinical Oncology and the American Cancer Society (
disease entity, guidelines for diagnosis and staging, primary www.cancer.net; www.cancer.org). Most of these sites
intervention, adjuvant treatment, surveillance, management describe the key late effects in cancer survivors and provide
of recurrent, or disseminated disease, as well as guidelines additional links to other relevant sites and resources. At MD
for symptom management/supportive care are provided and Anderson Cancer Center, follow-up guidelines, entitled
continually updated. Table 2 summarizes the NCCN fol- ‘‘Long-Term Surveillance Guidelines Beyond 5 Years’’ for
low-up recommendations for each of the cancer sites. The 15 different disease sites were listed (www.mdanderson.org
algorithms for all disease entities included surveillance ). These included acute myelogenous leukemia, bladder
recommendations. However, many were intended solely for cancer, bone cancer, breast cancer, cervical cancer, colo-
detection of relapses rather than for late effects. For several rectal cancer, endometrial, head and neck, kidney, lung,
cancer sites, references were made for the follow-up and/or lymphoma, melanoma, ovarian cancer, prostate cancer, and
management of treatment-related late effects, most notably soft tissue sarcoma. Although most of these guidelines were
for survivors of breast cancer, head and neck cancer and again designed for detection of recurrence, some of the
Hodgkin lymphoma. For some cancer sites, the recom- recommendations were related to the screening for second
mendations were based on anticipated adverse events rela- malignancy, thyroid dysfunction, and bone loss associated
ted to their original cancer diagnosis rather than cancer prior cancer therapy.
therapy exposures. These include survivors of breast can-
cers who were also BRCA-1 and/or -2 carriers, survivors of
patients with hereditary nonpolyposis colorectal cancer 4 Specific Areas for Surveillance/
(HNPCC), survivors of melanoma or non-melanoma skin Interventions
cancers whose first skin malignancy were likely related to
sun exposures, and survivors of lung cancer in whom the There are several well-documented late effects in long-term
first lung malignancy may be related to tobacco use. For cancer survivors, some of which may be life-threatening,
these survivors the NCCN provide recommendations while others may have considerable impact on patients’
regarding more intensive cancer screening, prevention and quality of life, that deserve special attention. Early detection
health habit modifications. at a treatable stage, and increased efforts toward risk
 BioSurveillance and Longitudinal Lifelong Guidelines 159

Table 2 NCCN surveillance guidelines for individual cancer types

Disease site Surveillance guidelines
Acute myeloid leukemia Surveillance for relapse only
Bladder cancer Surveillance for relapse only
Bone cancer Surveillance for relapse
Surveillance/intervention for late effects
Survivorship prescription to schedule follow-up with multidisciplinary team
Extended therapy and surveillance may be necessary to address potential late effects of surgery, radiation and
chemotherapy for long-term survivors
Breast cancer Surveillance for relapse
Surveillance/intervention for late effects
After tamoxifen, annual gynecological examination if uterus present and rapid assessment of any vaginal
spotting
After aromatase inhibitor or ovarian failure, monitoring of bone health
Consider breast MRI in women at high risk of bilateral disease, e.g. BRCA-1 or -2 carriersa
Cardiac monitoring at baseline, 3 , 6 and 9 months after Trastuzumab therapy
Central nervous system Surveillance for relapse only
cancer
Cervical cancer Surveillance for relapse
Surveillance/intervention for late effects
Use of vaginal dilator after radiation therapy in women who wish to remain sexually active
Chronic myelogenous Surveillance for relapse only
leukemia
Colorectal cancer Surveillance for relapse
Surveillance/intervention for late effects
Surveillance post-treatment colonoscopy aimed at identifying and removing metachronous polyps given the
increased risk of developing second cancersa
More frequent (annual) surveillance colonoscopy for patients with HNPCCa
Anal cancer Surveillance for relapse only
Esophageal cancer Surveillance/intervention for relapse
Surveillance for late effects
Some patients may require dilatation of an anastamotic or a chemoradiation-induced stricture
Nutritional counseling may be extremely valuable
Gastric cancer Surveillance for relapse
Surveillance/intervention for late effects
Vitamin B12 levels should be monitored for patients who have had proximal/total gastrectomy
Head and neck cancer Surveillance for relapse
Surveillance/intervention for late effects
TSH q 6–12 months if neck irradiated.
Speech/hearing and swallowing evaluation and rehabilitation as indicated
Smoking cessation counselinga
Dental follow-up
Hepatobiliary cancer Surveillance for relapse only
(continued)
160 A. K. Ng and M. M. Hudson

Table 2 (continued)
Disease site Surveillance guidelines
Hodgkin lymphoma Surveillance for relapse
Surveillance/intervention for late effects after [ 5 years
Annual blood pressure, serum glucose, lipids screening
Consider baseline echo/stress echo after 10 years
Pneumococcal revaccination q 5–7 years in patients who had splenectomy or splenic irradiation
Meningococcal/H. flu vaccination in selected patients
Consider annual influenza vaccine in high-risk patients
Annual TSH if neck irradiated
Annual chest imaging for patients at increased risk for lung cancer
Mammogram/Breast MRI screening 8–10 years after irradiation or by age 40
Counseling on reproduction, health habits, psychosocial, cardiovascular, breast self-exam, skin cancer risk
Kidney cancer Surveillance for relapse only
Melanoma Surveillance for relapse
Surveillance/intervention for late effects
Patient education on skin self-exam, protection, and subsequent skin cancer risksa
Structured follow-up program to detect subsequent second primary melanoma and non-melanoma primary
skin malignances; at least annual skin examination for lifea
Multiple myeloma Surveillance for relapse only
Myelodysplastic Surveillance for relapse only
syndrome
Neuroendocrine tumor Surveillance for relapse only
Non-Hodgkin’s Surveillance for relapse only
lymphoma
Non-melanoma skin Surveillance for relapse
cancer Surveillance/intervention for late effects:
Basal cell and squamous Complete skin examination q 6–12 months, annually for life after 3 yearsa
cell
Dermatofibrosarcoma Patient education on sun exposure and self examinationa
protuberans
Merkel cell cancer Prevention with oral retinoids in high-risk patients to reduce risk of subsequent skin cancersa
Aggressive treatment of precancers can prevent development of subsequent invasive tumorsa
Surveillance for relapse only
Surveillance for relapse only
Non-small cell lung Surveillance for relapse only
cancer
Occult primary Surveillance for relapse only
Ovarian cancer Surveillance for relapse only
Pancreatic Surveillance for relapse only
adenocarcinoma
Prostate cancer Surveillance for relapse
Surveillance/intervention for late effects:
Increased risk of osteoporosis after either medical or surgical castration; recommended baseline bone density
test and supplementation with calcium and vitamin D
If osteopenia or osteoporosis, strongly consider bisphosphonate therapy
Small cell lung cancer Surveillance for relapse
Surveillance/intervention for late effects:
Smoking cessation intervention after recovery from primary therapya
New pulmonary nodules after 2 years follow-up should initiate work-up for potential new primarya
(continued)
 BioSurveillance and Longitudinal Lifelong Guidelines 161

Table 2 (continued)
Disease site Surveillance guidelines
Soft tissue sarcoma Surveillance for relapse only
Testicular cancer Surveillance for relapse only
Thymic cancer Surveillance for relapse only
Thyroid cancer Surveillance for relapse only
Uterine cancer Surveillance for relapse only
a
Surveillance/intervention recommendations for late events unrelated to cancer treatment exposures but related to other underlying risk factors

reduction and prevention of these late effects may play an traditional breast cancer risk factors may further modify the
important role in improving the well-being of long-term risk (Travis et al. 2003; van Leeuwen et al. 2003). Mam-
cancer survivors. mography screening is a widely accepted screening
modality that has been shown to significantly reduce breast
cancer mortality in the general population (Frisell et al.
4.1 Second Malignancy 1997; Tabar et al. 2000; Duffy et al. 2005). Although its
efficacy has not been specifically assessed in cancer survi-
Second malignancy is one of the most serious late effects in vors with breast cancer mortality as an endpoint, given the
patients who had survived their first cancer. There is a large known significantly increased risk, mammography screen-
body of literature describing the increased risk of second ing 8–10 years after chest irradiation is recommended in
malignancy among survivors of childhood cancers (Cardous- most follow-up guidelines for survivors. Breast MRI has
Ubbink et al. 2007; Davies 2007; MacArthur et al. 2007), as been shown to be more sensitive than mammogram in high-
well as survivors of several adult-onset cancers, with most risk women based on their genetic predisposition, although
information available in survivors of Hodgkin lymphoma its role in detecting treatment-related breast cancer has not
(Biti et al. 1994; Doria et al. 1995; Donaldson et al. 1999; been assessed. Nevertheless, the ACS currently recom-
Swerdlow et al. 2000; van Leeuwen et al. 2000; Dores et al. mends yearly breast MRI imaging as an adjunct to mam-
2002; Ng et al. 2002; Franklin et al. 2006; Hodgson et al. mography in women who received chest radiation between
2007). Increasing data are also available on second malig- the age of 10 and 30 years (Saslow et al. 2007).
nancy risk after treatment for testicular cancer (Kollmanns- Chemoprevention with selective estrogen-receptor
berger et al. 1999; Travis et al. 2000, 2005), breast cancer modulators (SERMS) have been evaluated in high-risk
(Boice et al. 1992; Fisher et al. 1994; Neugut et al. 1994; populations, mostly based on genetic predisposition but also
Roychoudhuri et al. 2004; Kirova et al. 2007), prostate cancer including survivors of breast cancers, for breast cancer risk
(Brenner et al. 2000; Pickles et al. 2002; Chrouser et al. 2005; reduction (Cuzick 2008). Although it has not been assessed
Moon et al. 2006), cervical cancer (Boice et al. 1987; in other cancer survivors, in women at high risk due to their
Kleinerman et al. 1995; Chaturvedi et al. 2007), and non- treatment history and other risk factors, tamoxifen for
Hodgkin’s lymphoma (Travis et al. 1995; Mudie et al. 2006; women who have completed child-bearing, and raloxifene
Tward et al. 2006). The following lists a number of second in post-menopausal women can be considered on a case-by-
malignancies that have been shown to have an increased case basis.
incidence among specific cancer survivors, and in which
screening and/or prevention may be warranted. 4.1.2 Lung Cancer as a Second Malignancy
An increased risk for lung cancer have been shown in
4.1.1 Breast Cancer as a Second Malignancy survivors of Hodgkin lymphoma (Swerdlow et al. 2000; van
An increased risk of breast cancer is clearly shown in sur- Leeuwen et al. 2000; Dores et al. 2002; Ng et al. 2002;
vivors of a number of childhood malignancies and Hodgkin Travis et al. 2002; Hodgson et al. 2007), non-Hodgkin’s
lymphoma, largely as a result of prior chest irradiation lymphoma (Andre et al. 2004; Mudie et al. 2006; Tward
(Travis et al. 2003; van Leeuwen et al. 2003; Kenney et al. et al. 2006), breast cancer (Neugut et al. 1994; Kaufman
2004). An excess risk of contralateral breast cancer related et al. 2008), lung cancer (Rubin et al. 2007), testicular
to radiation therapy has also been demonstrated in women cancer (Argiris et al. 2004), and cervical cancer (Boice et al.
treated with breast or chest wall irradiation (Boice et al. 1987; Kleinerman et al. 1995; Chaturvedi et al. 2007).
1992; Gao et al. 2003; Hemminki et al. 2007). In addition to Radiation therapy and alkylating chemotherapy both con-
young age at treatment, hormonal exposures as well as other tribute to the risk, as has been demonstrated in survivors of
162 A. K. Ng and M. M. Hudson

Hodgkin and non-Hodgkin’s lymphoma (Swerdlow et al. 4.1.4 Endometrial Cancer as a Second Malignancy
2001; Travis et al. 2002; Andre et al. 2004). The increased Tamoxifen is commonly used as adjuvant therapy in women
risk seen in survivors of cancers of the head and neck, with estrogen-receptor positive breast cancer, and has been
lungs, and cervix is more likely to be related to tobacco shown to reduce the risk of contralateral breast cancer by
history being a common etiologic factor for both the pri- 30–40 % (Swerdlow et al. 2001). It is also an effective
mary malignancy and the subsequent lung cancer. chemoprevention agent, reducing the risk of breast cancer
The role of low-dose chest CT screening in other high- by 50 % in high-risk women (Fisher et al. 1998). However,
risk populations has been studied and reported in nonran- several large studies have shown that tamoxifen therapy is
domized studies, and the results are conflicting and con- associated with a 2- to 4-fold significantly increased risk of
troversial (Bach 2008; Henschke et al. 2008; Midthun et al. endometrial caner (Magriples et al. 1993; Fisher et al. 1994;
2008). The National Lung Screening Trial, a randomized Bergman et al. 2000). In most cases, the endometrial can-
study comparing chest X-ray versus chest CT screening in cers are detected an early, resectable stage. Although there
the noncancer population showed a 20 % reduction in lung are no proven effective screening tests for endometrial
cancer-specific mortality with chest CT screening (Aberle cancer, survivors of breast cancer who have received
et al. 2011). The role of chest CT screening in cancer sur- tamoxifen should be made aware of the increased risk,
vivors has not been studied. However, for selected survivors encouraged to undergo regular gynecological examinations,
who are deemed at high risk based on the their treatment and have prompt evaluation of any vaginal spotting or
and smoking history, and in whom further radiation therapy abdominal/pelvic pain.
is not feasible because of their prior chest irradiation, they
may particularly benefit from early detection through a 4.1.5 Colorectal Cancer as a Second Malignancy
more sensitive screening modality such as CT scan, with the An increased risk of colorectal cancer is seen among
goal of detecting lung cancers at an early, operable, and childhood cancer survivors who had received prior
presumably more curable stage. abdominal/pelvic irradiation, most notably in survivors of
Given the known contribution of smoking to lung cancer Wilms’ tumor (Densmore et al. 1996; Metayer et al. 2000;
risk, and the multiplicative effect of smoking on lung cancer Bhatia et al. 2003). In addition, the risk of colorectal cancer
risk after cancer therapy (Travis et al. 2002; Kaufman et al. has been shown to be significantly elevated among survi-
2008), survivors who continue to be smokers would greatly vors of Hodgkin lymphoma, testicular cancer, cervical
benefit from smoking cessation counseling and referral to cancer and prostate cancer (Brenner et al. 2000; Travis et al.
smoking cessation programs. 2005; Chaturvedi et al. 2007; Hodgson et al. 2007). Cur-
rently, the COG guidelines recommend colonoscopy
4.1.3 Skin Cancer as a Second Malignancy screening in patients who have received radiation therapy to
An increased risk of non-melanomatous skin cancer, in par- the abdominal/pelvic region for childhood malignancies, to
ticular basal cell carcinoma, within prior radiation treatment be performed every 5 years beginning at 10 years after
fields have been demonstrated (Colman et al. 1988; Levi et al. radiation or by age 35. Although recommendations for
2006a). Synchronous or metachronous skin malignancies are colorectal cancer screening prior to age 50 in survivors of
also commonly seen in patients who already have a skin adult-onset malignancies are not available, the COG rec-
cancer diagnosis (Karagas et al. 1996; Goggins et al. 2003; ommendations may apply to selected young adult cancer
Revenga et al. 2004; Levi et al. 2006b; Titus-Ernstoff et al. survivors based on their primary cancer diagnosis, radiation
2006; Cardous-Ubbink et al. 2007), as well as in patients with therapy history, time since treatment and other risk factors
history of non-Hodgkin’s lymphoma (Goggins et al. 2001; such as family history.
Hemminki et al. 2003; Loriot et al. 2006), chronic leukemia
(Travis et al. 1992), and in patients status bone marrow or
stem cell transplantation (Hasegawa et al. 2005; Cavalier 4.2 Cardiovascular Disease
et al. 2006). The increased risk of skin cancer in these patients
are likely related to sun exposure and compromised immune A broad spectrum of cardiovascular complications after
status, rather than from prior cancer therapy. In cancer sur- cancer therapy can be seen after exposure to chest radiation
vivors at high risk of developing a skin malignancy, risk- therapy, specific chemotherapeutic agents and targeted
reduction through sun-safety practice, and early-detection therapy, and hormonal therapy. An increased risk of car-
through regular self-examination and at least annual skin diovascular disease has been demonstrated in survivors of
examination by a dermatologist are essential. childhood malignancies (Krischer et al. 1997; Pein et al.
 BioSurveillance and Longitudinal Lifelong Guidelines 163

2004; Guldner et al. 2006), Hodgkin lymphoma (Heidenr- appropriateness criteria recommended routine exercise tol-
eich et al. 2003, 2005, 2007; Hull et al. 2003; Aleman et al. erance testing and echocardiography in symptomatic
2007), non-Hodgkin’s lymphoma (Moser et al. 2006), breast patients and periodic screening in patients depending on the
cancer (Jones et al. 1989; Seidman et al. 2002; Ewer et al. mediastinal radiation dose, cumulative anthracycline dose,
2005) and more recently prostate cancer (Smith 2004; and presence of other cardiac risk factors.
Smith 2007; Tsai et al. 2007) and testicular cancer (Huddart ASCO recently reviewed the clinical evidence for
et al. 2003; van den Belt-Dusebout et al. 2006, 2007). In ongoing care related to cardiac and pulmonary late effects
general, prior chest irradiation is associated with an (Carver et al. 2007). Potential strategies for monitoring of
increased risk of coronary vessel disease, pericardial dis- chemotherapy-related cardiac complications, including
ease, valvular dysfunction, cardiomyopathy, conduction serial endocardial biopsy, serial B-type natriuretic peptide
defects (Benoff et al. 1995; Adams et al. 2003), while (BNP) and troponin level testing, radionucleotide MUGA or
exposure to anthracyclines is associated with ventricular radionucleotide angiography, exercise testing, and echo-
dysfunction in a dose-related fashion (Shan et al. 1996; cardiogram were discussed, although it was concluded that
Keefe 2001; Steingart 2005). Among breast cancer survi- at the present time evidence supporting the use of any of
vors, earlier data had shown that patients treated with left- these screening tools as standard monitoring for long-term
sided breast or chest wall irradiation had an increased risk survivors of cancer is lacking. In addition, it was deter-
for ischemic heart disease and cardiac deaths, although for mined that the value of any treatment, including combina-
patients treated in recent years with modern techniques and tions of beta blockers, angiotensin-converting enzyme
conformal therapy, an increased risk was no longer seen (ACE) inhibitors, angiotensin receptor blockers, spirono-
(Cuzick et al. 1994; Nixon et al. 1998; Patt et al. 2005). lactone, diuretics, nitrates, and hydralazine in altering the
Trastuzumab (Herceptin) has been shown to significantly natural history of cardiac disease in the asymptomatic sur-
improve disease-free and overall survival in women with vivor remains to be clarified.
HER-2/neu positive breast cancer in both metastatic and
adjuvant therapy settings. However, it is also associated
with an increased risk of congestive heart failure and ven- 4.3 Endocrine Function
tricular dysfunction (Seidman et al. 2002; Tan-Chiu et al.
2005). Unlike anthracycline-related cardiac dysfunction, Reproductive health is often affected by cancer therapy, and
however, the long-term cardiac risk Herceptin use is not this is especially relevant for survivors of cancers diagnosed
clear. For survivors of testicular cancer, an increased risk of during childhood or young adulthood. Both alkylating-agent
small and large artery disease has been demonstrated after based chemotherapy and radiation therapy to the pelvic
cisplatin-based chemotherapy, which may be related to region increase the risk of early ovarian failure in women
direct endothelial damage (van den Belt-Dusebout et al. and permanent azospermia in men. In addition, history of
2006). For patients with prostate cancer, treatment with cranial irradiation, particularly in childhood cancer survi-
gonadotropin-releasing hormone agonists increases subcu- vors, can lead to growth hormone deficiencies and hypo-
taneous fat mass, decreases insulin sensitivity, increases gonadism. The COG guidelines recommend baseline
serum lipoproteins, leading to greater risk of diabetes, car- screening follicle-stimulating hormone (FSH), luteinizing
diovascular disease, and cardiac deaths (Smith 2007). hormone (LH), testosterone or estradiol levels at age 14 or
The COG guidelines recommend baseline and periodic as clinically indicated in patients with delayed puberty or
screening with echocardiogram and MUGA scans after clinical signs and symptoms of hormone deficiency (2006).
exposure to anthracyclines, and for patients treated with chest A number of adult-onset cancers can occur in patients in
irradiation, fasting blood glucose, lipid profile every their reproductive age, and in whom treatment can affect
3–5 years, as well as baseline and periodic echocardiogram their reproductive function. Examples include patients with
(2006). breast cancer (Partridge et al. 2008), gynecological cancers
The NCCN guidelines provide some cardiac-related (Carter et al. 2007), testicular cancer (Taksey et al. 2003)
follow-up recommendations after treatment for breast can- and lymphoma (Howell et al. 2002; Franchi-Rezgui et al.
cer and Hodgkin lymphoma (2008). Specifically, for breast 2003; Sieniawski et al. 2008). These patients would benefit
cancer patients treated with trastuzumab-containing regi- from baseline evaluation by reproductive endocrinology to
mens, cardiac monitoring at baseline, 3 , 6 , and 9 months discuss options of preserving fertility prior to treatment
was recommended, although the type of cardiac monitoring initiation, and in their follow-up, referral to specialists, as
was not specified. For survivors of Hodgkin lymphoma, the applicable, for counseling and to review reproductive
NCCN recommended annual blood pressure, serum glucose options (Demeestere et al. 2006).
and lipid screening, and that baseline stress test/echocar- Several primary cancer sites involve radiation therapy that
diogram at 10 years should be considered (2008). The ACR included treatment to the neck region. In these patients, there
164 A. K. Ng and M. M. Hudson

is a 30–40 % risk of developing hypothyroidism over time patients (Recklitis et al. 2006). Data on psychosocial function
(Chin et al. 1997). Screening thyroid stimulating hormone of long-term survivors of several individual adult-onset
(TSH) levels should be obtained in all patients with prior cancers are also available, most notably for survivors of
radiation exposure to the neck as part of their follow-up for breast cancer, Hodgkin lymphoma and testicular cancer
detection and treatment of subclinical hypothyroidism. (Fobair et al. 1986; Rieker et al. 1989; Bloom et al. 1993;
Arai et al. 1996; Loge et al. 1997; Dorval et al. 1998; Ozen
et al. 1998; Ganz et al. 2002, 2003; Wettergren et al. 2004;
4.4 Bone Health Helgeson et al. 2005; Thorsen et al. 2005). The influence of
the time from treatment on the level of distress appears to
Bone health can be compromised through different mech- vary, with some studies showing improvement in psycho-
anisms after cancer therapy. In the COG guidelines, social function over time (Bloom et al. 2004), while others
screening bone density evaluation is recommended as part showing persistent distress beyond 7–10 years after treat-
of long-term follow-up in patients who had received anti- ment (Loge et al. 1997; Mehanna et al. 2006). In a study
metabolites or corticosteroids (2006). examining the risk of significant depressive symptoms over
This recommendation may also apply to survivors of an 8-year period among 8,387 adults after a diagnosis of
adult-onset cancer including women with treatment-induced cancer, diabetes, hypertension, heart disease, arthritis,
ovarian failure, and men with prostate cancer treated with chronic lung disease, or stroke, only patients with an initial
gonadotropin-releasing hormone agonists, which can diagnosis of cancer or heart disease continued to have sig-
increase bone turnover, decrease bone mineral density, and nificant depressive symptoms beyond 4– 8 years (Polsky
increase fracture risk. The role of preventative treatment et al. 2005). These findings highlight the importance of
against osteopenia, including bisphosphonates and selective implementing routine psychological screening and access to
estrogen receptor modulators in high risk cancer survivors mental health professionals for long-term cancer survivors.
remain to be determined. In the NCCN Task Force Report
on Bone Health and Cancer Care, the role of imaging
techniques to assess bone health and potential therapeutic 5 Conclusions
strategies to maintain bone health in high-risk cancer sur-
vivors were discussed (Theriault et al. 2006). Successful cancer therapy often comes at the price of
History of exposure to radiation doses of 60 Gy or higher increased risk of adverse late events. In addition to lifelong
region places patients at increased risk of osteoradionecrosis follow-up of cancer survivors with reducing the risks of,
(Ramli et al. 2006; Goldwaser et al. 2007). Similar doses of monitoring for, and prompt treatment of late effects, early
radiation to weight-bearing bones have been associated with education of newly diagnosed patients regarding potential
an increased risk of bone fractures. This has been demon- future events are essential. Survivors may also benefit from
strated in survivors of gynecological cancers who have being regularly evaluated at dedicated survivorship clinics
received pelvic irradiation (Ikushima et al. 2006), and sur- where pertinent experts for addressing specific late effects
vivors of soft tissue sarcoma treated with radiation therapy and from the most up-to-date information on management
(Holt et al. 2005), who typically receive doses of 60 Gy or of cancer survivors are available. In addition, follow-up at
higher to at least part of the bone. Survivors with this treat- survivorship clinics may facilitate patient participation in
ment history should be made aware of the increased fracture survivorship research, allowing further improvement in the
risk and should have prompt attention to and evaluation of care of long-term cancer survivors.
any bone pain or swelling, or non-healing wounds.

6 Future Directions
4.5 Psychosocial Issues
It is important to recognize that currently available guide-
Cancer survivors face a broad range of psychosocial chal- lines in the follow-up of cancer survivors are largely based
lenges related to their prior cancer diagnosis and treatment. on the known late effects after specific treatment exposures.
Survivors can be distressed by fear of recurrence, adverse Little are available on the feasibility, level of compliance,
health consequences related to cancer treatment, disruption efficacy, and cost-effectiveness of the recommended sur-
or alteration of social support, difficulties at the workplace, veillance strategies. The optimal types of testing and
and barriers in obtaining health and life insurance. Consid- intervention, as well as their timing and frequency also need
erable data are available describing psychological distress in to be better defined. Prospective evaluation of these strat-
childhood cancer survivors. In one study on pediatric cancer egies represents an important component of survivorship
survivors, alarmingly, suicidal ideation was found in 18 % of research.
 BioSurveillance and Longitudinal Lifelong Guidelines 165

To optimize care for cancer survivors and for successful Aziz NM, Oeffinger KC, Brooks S, Turoff AJ (2006) Comprehensive
conduction of survivorship research, the ability to reach out long-term follow-up programs for pediatric cancer survivors.
Cancer 107(4):841–848
to long-term cancer survivors is crucial. It can be logisti- Bach PB (2008) Lung cancer screening. J Natl Compr Cancer Netw
cally difficult for survivors who no longer live locally to 6(3):271–275
return to their oncology center for regular follow up visits. Benoff LJ, Schweitzer P (1995) Radiation therapy-induced cardiac
Long-term survivors, especially for those who are young injury. Am Heart J 129(6):1193–1196
Bergman L, Beelen ML, Gallee MP, Hollema H, Benraadt J, van
and asymptomatic, may also be less motivated in main- Leeuwen FE (2000) Risk and prognosis of endometrial cancer after
taining contact with their health care providers. An inno- tamoxifen for breast cancer. Comprehensive Cancer Centres’
vative approach is to utilize the Internet, which has the ALERT Group. Assessment of liver and endometrial cancer risk
potential to stay in contact with a large number of patients following tamoxifen. Lancet 356(9233):881–887
Bhatia S, Landier W (2005) Evaluating survivors of pediatric cancer.
and provide individualized and interactive information at Cancer J 11(4):340–354
considerably lower costs than in-person contact. Research- Bhatia S, Yasui Y, Robison LL, Birch JM, Bogue MK, Diller L,
ers at Texas Children’s Cancer Center and Baylor College, DeLaat C, Fossati-Bellani F, Morgan E, Oberlin O, Reaman G,
in conjunction with COG, are developing an interactive Ruymann FB, Tersak J, Meadows AT (2003) High risk of
subsequent neoplasms continues with extended follow-up of
internet resource for childhood cancer survivors, entitled childhood Hodgkin’s disease: report from the late effects study
‘‘Passport for Care’’ (2006). Data are also beginning to Group. J Clin Oncol 21(23):4386–4394
become available on the use Internet-based survivorship Biti G, Cellai E, Magrini SM, Papi MG, Ponticelli P, Boddi V (1994)
care plans for survivors of adult-onset malignancies (Hill- Second solid tumors and leukemia after treatment for Hodgkin’s
disease: an analysis of 1121 patients from a single institution. Int J
Kayser et al. 2008). The role of the Internet to provide Radiat Oncol Biol Phys 29(1):25–31
follow-up and preventative care for cancer survivors need to Bloom JR, Fobair P, Gritz E, Wellisch D, Spiegel D, Varghese A,
be further investigated. Hoppe R (1993) Psychosocial outcomes of cancer: a comparative
Finally, as cancer therapy evolve, it is imperative to analysis of Hodgkin’s disease and testicular cancer. J Clin Oncol
11(5):979–988
continue the long-term follow-up of survivors with careful Bloom JR, Stewart SL, Chang S, Banks PJ (2004) Then and now: quality
documentation of types of late effects associated with new of life of young breast cancer survivors. Psycho oncol 13(3):147–160
treatments, their temporal trend, and modifying effect of Boice JD Jr, Blettner M, Kleinerman RA, Stovall M, Moloney WC,
other existing risk factors, efforts which will allow advances Engholm G, Austin DF, Bosch A, Cookfair DL, Krementz ET et al
(1987) Radiation dose and leukemia risk in patients treated for
in the care of future cancer survivors. cancer of the cervix. J Natl Cancer Inst 79(6):1295–1311
Boice JD Jr, Harvey EB, Blettner M, Stovall M, Flannery JT (1992)
Cancer in the contralateral breast after radiotherapy for breast
References cancer. N Engl J Med 326(12):781–785
Brenner DJ, Curtis RE, Hall EJ, Ron E (2000) Second malignancies in
prostate carcinoma patients after radiotherapy compared with
Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom surgery. Cancer 88(2):398–406
RM, Gareen IF, Gatsonis C, Marcus PM, Sicks JD (2011) Reduced Cardous-Ubbink MC, Heinen RC, Bakker PJ, van den Berg H,
lung-cancer mortality with low-dose computed tomographic Oldenburger F, Caron HN, Voute PA, van Leeuwen FE (2007)
screening. N Engl J Med 365(5):395–409 Risk of second malignancies in long-term survivors of childhood
Adams MJ, Hardenbergh PH, Constine LS, Lipshultz SE (2003) cancer. Eur J Cancer 43(2):351–362
Radiation-associated cardiovascular disease. Crit Rev Oncol Carter J, Lewin S, Abu-Rustum N, Sonoda Y (2007) Reproductive
Hematol 45(1):55–75 issues in the gynecologic cancer patient. Oncology (Williston Park)
Aleman BM, van den Belt-Dusebout AW, De Bruin ML, van ‘t Veer 21(5): 598–606; discussion 606–609
MB, Baaijens MH, de Boer JP, Hart AA, Klokman WJ, Kuenen Carver JR, Shapiro CL, Ng A, Jacobs L, Schwartz C, Virgo KS,
MA, Ouwens GM, Bartelink H, van Leeuwen FE (2007) Late Hagerty KL, Somerfield MR, Vaughn DJ (2007) American society
cardiotoxicity after treatment for Hodgkin lymphoma. Blood of clinical oncology clinical evidence review on the ongoing care
109(5): 1878–1886 of adult cancer survivors: cardiac and pulmonary late effects. J Clin
Andre M, Mounier N, Leleu X, Sonet A, Brice P, Henry-Amar M, Oncol 25(25):3991–4008
Tilly H, Coiffier B, Bosly A, Morel P, Haioun C, Gaulard P, Reyes Cavalier M, Shmalo JA, Yu M, Billings SD, Abonour R, Nelson RP Jr
F, Gisselbrecht C (2004) Second cancers and late toxicities after (2006) Skin cancer after nonmyeloablative hematopoietic cell
treatment of aggressive non-Hodgkin lymphoma with the ACVBP transplantation. Bone Marrow Transpl 37(12):1103–1108
regimen: a GELA cohort study on 2837 patients. Blood Chaturvedi AK, Engels EA, Gilbert ES, Chen BE, Storm H, Lynch CF,
103(4):1222–1228 Hall P, Langmark F, Pukkala E, Kaijser M, Andersson M, Fossa
Arai Y, Kawakita M, Hida S, Terachi T, Okada Y, Yoshida O (1996) SD, Joensuu H, Boice JD, Kleinerman RA, Travis LB (2007)
Psychosocial aspects in long-term survivors of testicular cancer. Second cancers among 104,760 survivors of cervical cancer:
J Urol 155(2):574–578 evaluation of long-term risk. J Natl Cancer Inst 99(21):1634–1643
Argiris A, Brockstein BE, Haraf DJ, Stenson KM, Mittal BB, Kies Chin D, Sklar C, Donahue B, Uli N, Geneiser N, Allen J, Nirenberg A,
MS, Rosen FR, Jovanovic B, Vokes EE (2004) Competing causes David R, Kohn B, Oberfield SE (1997) Thyroid dysfunction as a
of death and second primary tumors in patients with locoregionally late effect in survivors of pediatric medulloblastoma/primitive
advanced head and neck cancer treated with chemoradiotherapy. neuroectodermal tumors: a comparison of hyperfractionated versus
Clin Cancer Res 10(6):1956–1962 conventional radiotherapy. Cancer 80(4):798–804
166 A. K. Ng and M. M. Hudson

Chrouser K, Leibovich B, Bergstralh E, Zincke H, Blute M (2005) V, Eghbali H, Ferme C, Henry-Amar M, Hoppe R, Howard S,
Bladder cancer risk following primary and adjuvant external beam Meyer R, Niedzwiecki D, Pavlovsky S, Radford J, Raemaekers J,
radiation for prostate cancer. J Urol 174(1): 107–110; discussion Ryder D, Schiller P, Shakhtarina S, Valagussa P, Wilimas J,
110–111 Yahalom J (2006) Second malignancy risk associated with
Colman M, Easton DF, Horwich A, Peckham MJ (1988) Second treatment of Hodgkin’s lymphoma: meta-analysis of the random-
malignancies and Hodgkin’s disease–the Royal Marsden Hospital ised trials. Ann Oncol 17(12):1749–1760
experience. Radiother Oncol 11(3):229–238 Frisell J, Lidbrink E, Hellstrom L, Rutqvist LE (1997) Followup after
Cuzick J (2008) Chemoprevention of breast cancer. Breast Cancer 11 years–update of mortality results in the Stockholm mammo-
15(1):10–16 graphic screening trial. Breast Cancer Res Treat 45(3):263–270
Cuzick J, Stewart H, Rutqvist L, Houghton J, Edwards R, Redmond C, Ganz PA, Desmond KA, Leedham B, Rowland JH, Meyerowitz BE,
Peto R, Baum M, Fisher B, Host H et al (1994) Cause-specific Belin TR (2002) Quality of life in long-term, disease-free survivors
mortality in long-term survivors of breast cancer who participated of breast cancer: a follow-up study. J Natl Cancer Inst 94(1):39–49
in trials of radiotherapy. J Clin Oncol 12(3):447–453 Ganz PA, Greendale GA, Petersen L, Kahn B, Bower JE (2003) Breast
Davies SM (2007) Subsequent malignant neoplasms in survivors of cancer in younger women: reproductive and late health effects of
childhood cancer: childhood cancer survivor study (CCSS) studies. treatment. J Clin Oncol 21(22):4184–4193
Pediatr Blood Cancer 48(7):727–730 Gao X, Fisher SG, Emami B (2003) Risk of second primary cancer in
Demeestere I, Simon P, Emiliani S, Delbaere A, Englert Y (2006) the contralateral breast in women treated for early-stage breast
Options to preserve fertility before oncological treatment: cryo- cancer: a population-based study. Int J Radiat Oncol Biol Phys
preservation of ovarian tissue and its clinical application. Acta Clin 56(4):1038–1045
Belg 61(5):259–263 Geenen MM, Cardous-Ubbink MC, Kremer LC, van den Bos C, van
Densmore TL, Langer JC, Molleston JP, Dehner LP, Coffin CM (1996) der Pal HJ, Heinen RC, Jaspers MW, Koning CC, Oldenburger F,
Colorectal adenocarcinoma as a second malignant neoplasm Langeveld NE, Hart AA, Bakker PJ, Caron HN, van Leeuwen FE
following Wilms’ tumor and rhabdomyosarcoma. Med Pediatr (2007) Medical assessment of adverse health outcomes in long-
Oncol 27(6):556–560 term survivors of childhood cancer. JAMA 297(24):2705–2715
Donaldson SS, Hancock SL, Hoppe RT (1999) The Janeway lecture. Goggins WB, Finkelstein DM, Tsao H (2001) Evidence for an
Hodgkin’s disease–finding the balance between cure and late association between cutaneous melanoma and non-Hodgkin lym-
effects. Cancer J Sci Am 5(6):325–333 phoma. Cancer 91(4):874–880
Dores GM, Metayer C, Curtis RE, Lynch CF, Clarke EA, Glimelius B, Goggins WB, Tsao H (2003) A population-based analysis of risk
Storm H, Pukkala E, van Leeuwen FE, Holowaty EJ, Andersson M, factors for a second primary cutaneous melanoma among mela-
Wiklund T, Joensuu T, van’t Veer MB, Stovall M, Gospodarowicz noma survivors. Cancer 97(3):639–643
M, Travis LB (2002) Second malignant neoplasms among long- Goldwaser BR, Chuang SK, Kaban LB, August M (2007) Risk factor
term survivors of Hodgkin’s disease: a population-based evaluation assessment for the development of osteoradionecrosis. J Oral
over 25 years. J Clin Oncol 20(16): 3484–3494 Maxillofac Surg 65(11):2311–2316
Doria R, Holford T, Farber LR, Prosnitz LR, Cooper DL (1995) Guldner L, Haddy N, Pein F, Diallo I, Shamsaldin A, Dahan M,
Second solid malignancies after combined modality therapy for Lebidois J, Merlet P, Villain E, Sidi D, Sakiroglu O, Hartmann O,
Hodgkin’s disease. J Clin Oncol 13(8):2016–2022 Leftakopoulos D, de Vathaire F (2006) Radiation dose and long
Dorval M, Maunsell E, Deschenes L, Brisson J, Masse B (1998) Long- term risk of cardiac pathology following radiotherapy and anthra-
term quality of life after breast cancer: comparison of 8-year cyclin for a childhood cancer. Radiother Oncol 81(1):47–56
survivors with population controls. J Clin Oncol 16(2):487–494 Hasegawa W, Pond GR, Rifkind JT, Messner HA, Lau A, Daly AS,
Duffy SW, Smith RA, Gabe R, Tabar L, Yen AM, Chen TH (2005) Kiss TL, Kotchetkova N, Galal A, Lipton JH (2005) Long-term
Screening for breast cancer. Surg Oncol Clin N Am 14(4):671–697 follow-up of secondary malignancies in adults after allogeneic
Ewer MS, Vooletich MT, Durand JB, Woods ML, Davis JR, Valero V, bone marrow transplantation. Bone Marrow Transpl 35(1):51–55
Lenihan DJ (2005) Reversibility of trastuzumab-related cardiotox- Heidenreich PA, Hancock SL, Lee BK, Mariscal CS, Schnittger I
icity: new insights based on clinical course and response to medical (2003) Asymptomatic cardiac disease following mediastinal irra-
treatment. J Clin Oncol 23(31):7820–7826 diation. J Am Coll Cardiol 42(4):743–749
Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Heidenreich PA, Hancock SL, Vagelos RH, Lee BK, Schnittger I
Cronin WM (1994) Endometrial cancer in tamoxifen-treated breast (2005) Diastolic dysfunction after mediastinal irradiation. Am
cancer patients: findings from the National Surgical Adjuvant Heart J 150(5):977–982
Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst Heidenreich PA, Schnittger I, Strauss HW, Vagelos RH, Lee BK,
86(7):527–537 Mariscal CS, Tate DJ, Horning SJ, Hoppe RT, Hancock SL (2007)
Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Screening for coronary artery disease after mediastinal irradiation
Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, for Hodgkin’s disease. J Clin Oncol 25(1):43–49
Wieand S, Tan-Chiu E, Ford L, Wolmark N (1998) Tamoxifen for Helgeson VS, Tomich PL (2005) Surviving cancer: a comparison of 5-
prevention of breast cancer: report of the National Surgical year disease-free breast cancer survivors with healthy women.
Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst Psycho Oncol 14(4):307–317
90(18):1371–1388 Hemminki K, Ji J, Forsti A (2007) Risks for familial and contralateral
Fobair P, Hoppe RT, Bloom J, Cox R, Varghese A, Spiegel D (1986) breast cancer interact multiplicatively and cause a high risk. Cancer
Psychosocial problems among survivors of Hodgkin’s disease. Res 67(3):868–870
J Clin Oncol 4(5):805–814 Hemminki K, Jiang Y, Steineck G (2003) Skin cancer and non-
Franchi-Rezgui P, Rousselot P, Espie M, Briere J, Pierre Marolleau J, Hodgkin’s lymphoma as second malignancies. markers of impaired
Gisselbrecht C, Brice P (2003) Fertility in young women after immune function? Eur J Cancer 39(2):223–229
chemotherapy with alkylating agents for Hodgkin and non- Henschke CI, Yankelevitz DF (2008) CT screening for lung cancer:
Hodgkin lymphomas. Hematol J 4(2):116–120 update 2007. Oncologist 13(1):65–78
Franklin J, Pluetschow A, Paus M, Specht L, Anselmo AP, Aviles A, Hill-Kayser C, Vachani C, Hampshire MK, Jacobs LA, Metz J (2008)
Biti G, Bogatyreva T, Bonadonna G, Brillant C, Cavalieri E, Diehl First report of internet-based survivorship care plans and utilization
 BioSurveillance and Longitudinal Lifelong Guidelines 167

by colorectal cancer (CRC) survivors. Gastrointest Cancers Symp Landier W, Bhatia S (1999) Long-term complications following
Abstract No. 398 childhood cancer. Indian Pediatr 36(10):975–980
Hodgson DC, Gilbert ES, Dores GM, Schonfeld SJ, Lynch CF, Storm Landier W, Bhatia S, Eshelman DA, Forte KJ, Sweeney T, Hester AL,
H, Hall P, Langmark F, Pukkala E, Andersson M, Kaijser M, Darling J, Armstrong FD, Blatt J, Constine LS, Freeman CR,
Joensuu H, Fossa SD, Travis LB (2007) Long-term solid cancer Friedman DL, Green DM, Marina N, Meadows AT, Neglia JP,
risk among 5-year survivors of Hodgkin’s lymphoma. J Clin Oncol Oeffinger KC, Robison LL, Ruccione KS, Sklar CA, Hudson MM
25(12):1489–1497 (2004) Development of risk-based guidelines for pediatric cancer
Holt GE, Griffin AM, Pintilie M, Wunder JS, Catton C, O’Sullivan B, survivors: the Children’s Oncology Group Long-Term Follow-Up
Bell RS (2005) Fractures following radiotherapy and limb-salvage Guidelines from the Children’s Oncology Group Late Effects
surgery for lower extremity soft-tissue sarcomas. a comparison of Committee and Nursing Discipline. J Clin Oncol
high-dose and low-dose radiotherapy. J Bone Joint Surg Am 22(24):4979–4990
87(2):315–319 Landier W, Wallace WH, Hudson MM (2006) Long-term follow-up of
Howell SJ, Shalet SM (2002) Fertility preservation and management pediatric cancer survivors: education, surveillance, and screening.
of gonadal failure associated with lymphoma therapy. Curr Oncol Pediatr Blood Cancer 46(2):149–158
Rep 4(5):443–452 Levi F, Moeckli R, Randimbison L, Te VC, Maspoli M, La Vecchia C
Huddart RA, Norman A, Shahidi M, Horwich A, Coward D, Nicholls (2006a) Skin cancer in survivors of childhood and adolescent
J, Dearnaley DP (2003) Cardiovascular disease as a long-term cancer. Eur J Cancer 42(5):656–659
complication of treatment for testicular cancer. J Clin Oncol Levi F, Randimbison L, Maspoli M, Te VC, La Vecchia C (2006b)
21(8):1513–1523 High incidence of second basal cell skin cancers. Int J Cancer
Hudson MM (2008) Survivors of childhood cancer: coming of age. 119(6):1505–1507
Hematol Oncol Clin North Am 22(2): 211–231, v–vi Loge JH, Abrahamsen AF, Ekeberg O, Hannisdal E, Kaasa S (1997)
Hull MC, Morris CG, Pepine CJ, Mendenhall NP (2003) Valvular Psychological distress after cancer cure: a survey of 459 Hodgkin’s
dysfunction and carotid, subclavian, and coronary artery disease in disease survivors. Br J Cancer 76(6):791–796
survivors of hodgkin lymphoma treated with radiation therapy. Loriot Y, Chaoui D, Dorval T, Vincent-Salomon A, Lumbroso-Le
JAMA 290(21):2831–2837 Rouic L, Dendale R, Desjardins L, Levy C, Decaudin D (2006)
Ikushima H, Osaki K, Furutani S, Yamashita K, Kishida Y, Kudoh T, Association between lymphoma and melanoma: report of a single-
Nishitani H (2006) Pelvic bone complications following radiation center series of eight patients and a review of the literature. Leuk
therapy of gynecologic malignancies: clinical evaluation of Lymphoma 47(6):1023–1028
radiation-induced pelvic insufficiency fractures. Gynecol Oncol MacArthur AC, Spinelli JJ, Rogers PC, Goddard KJ, Phillips N,
103(3):1100–1104 McBride ML (2007) Risk of a second malignant neoplasm among
Jones JM, Ribeiro GG (1989) Mortality patterns over 34 years of 5-year survivors of cancer in childhood and adolescence in British
breast cancer patients in a clinical trial of post-operative radio- Columbia, Canada. Pediatr Blood Cancer 48(4):453–459
therapy. Clin Radiol 40(2):204–208 Magriples U, Naftolin F, Schwartz PE, Carcangiu ML (1993) High-
Kadan-Lottick NS, Robison LL, Gurney JG, Neglia JP, Yasui Y, grade endometrial carcinoma in tamoxifen-treated breast cancer
Hayashi R, Hudson M, Greenberg M, Mertens AC (2002) Childhood patients. J Clin Oncol 11(3):485–490
cancer survivors’ knowledge about their past diagnosis and treat- Mehanna HM, Morton RP (2006) Deterioration in quality-of-life of
ment: childhood cancer survivor study. JAMA 287(14):1832–1839 late (10-year) survivors of head and neck cancer. Clin Otolaryngol
Karagas MR, McDonald JA, Greenberg ER, Stukel TA, Weiss JE, 31(3):204–211
Baron JA, Stevens MM (1996) Risk of basal cell and squamous cell Mertens AC (2007) Cause of mortality in 5-year survivors of
skin cancers after ionizing radiation therapy. for the skin cancer childhood cancer. Pediatr Blood Cancer 48(7):723–726
prevention study group. J Natl Cancer Inst 88(24):1848–1853 Metayer C, Lynch CF, Clarke EA, Glimelius B, Storm H, Pukkala E,
Kaufman EL, Jacobson JS, Hershman DL, Desai M, Neugut AI (2008) Joensuu T, van Leeuwen FE, van’t Veer MB, Curtis RE, Holowaty
Effect of breast cancer radiotherapy and cigarette smoking on risk EJ, Andersson M, Wiklund T, Gospodarowicz M, Travis LB
of second primary lung cancer. J Clin Oncol 26(3):392–398 (2000) Second cancers among long-term survivors of Hodgkin’s
Keefe DL (2001) Anthracycline-induced cardiomyopathy. Semin disease diagnosed in childhood and adolescence. J Clin Oncol
Oncol 28(4 Suppl 12):2–7 18(12): 2435–2443
Kenney LB, Yasui Y, Inskip PD, Hammond S, Neglia JP, Mertens AC, Midthun DE, Jett JR (2008) Update on screening for lung cancer.
Meadows AT, Friedman D, Robison LL, Diller L (2004) Breast Semin Respir Crit Care Med 29(3):233–240
cancer after childhood cancer: a report from the childhood cancer Moon K, Stukenborg GJ, Keim J, Theodorescu D (2006) Cancer
survivor study. Ann Intern Med 141(8):590–597 incidence after localized therapy for prostate cancer. Cancer
Kirova YM, Gambotti L, De Rycke Y, Vilcoq JR, Asselain B, 107(5):991–998
Fourquet A (2007) Risk of second malignancies after adjuvant Moser EC, Noordijk EM, van Leeuwen FE, le Cessie S, Baars JW,
radiotherapy for breast cancer: a large-scale, single-institution Thomas J, Carde P, Meerwaldt JH, van Glabbeke M, Kluin-
review. Int J Radiat Oncol Biol Phys 68(2):359–363 Nelemans HC (2006) Long-term risk of cardiovascular disease
Kleinerman RA, Boice JD Jr, Storm HH, Sparen P, Andersen A, after treatment for aggressive non-Hodgkin lymphoma. Blood
Pukkala E, Lynch CF, Hankey BF, Flannery JT (1995) Second 107(7):2912–2919
primary cancer after treatment for cervical cancer. an international Mudie NY, Swerdlow AJ, Higgins CD, Smith P, Qiao Z, Hancock
cancer registries study. Cancer 76(3):442–452 BW, Hoskin PJ, Linch DC (2006) Risk of second malignancy after
Kollmannsberger C, Hartmann JT, Kanz L, Bokemeyer C (1999) non-Hodgkin’s lymphoma: a British cohort study. J Clin Oncol
Therapy-related malignancies following treatment of germ cell 24(10):1568–1574
cancer. Int J Cancer 83(6):860–863 NCCN clinical practice guidelines in oncology (2008) www.nccn.org
Krischer JP, Epstein S, Cuthbertson DD, Goorin AM, Epstein ML, Neugut AI, Murray T, Santos J, Amols H, Hayes MK, Flannery JT,
Lipshultz SE (1997) Clinical cardiotoxicity following anthracy- Robinson E (1994) Increased risk of lung cancer after breast
cline treatment for childhood cancer: the pediatric oncology group cancer radiation therapy in cigarette smokers. Cancer 73(6):
experience. J Clin Oncol 15(4):1544–1552 1615–1620
168 A. K. Ng and M. M. Hudson

Ng AK, Bernardo MV, Weller E, Backstrand K, Silver B, Marcus KC, Robison LL (2005) The Childhood Cancer Survivor Study: a resource
Tarbell NJ, Stevenson MA, Friedberg JW, Mauch PM (2002) for research of long-term outcomes among adult survivors of
Second malignancy after Hodgkin disease treated with radiation childhood cancer. Minn Med 88(4):45–49
therapy with or without chemotherapy: long-term risks and risk Roychoudhuri R, Evans H, Robinson D, Moller H (2004) Radiation-
factors. Blood 100(6):1989–1996 induced malignancies following radiotherapy for breast cancer. Br
Nixon AJ, Manola J, Gelman R, Bornstein B, Abner A, Hetelekidis S, J Cancer 91(5):868–872
Recht A, Harris JR (1998) No long-term increase in cardiac-related Rubins J, Unger M, Colice GL (2007) Follow-up and surveillance of
mortality after breast-conserving surgery and radiation therapy the lung cancer patient following curative intent therapy: ACCP
using modern techniques. J Clin Oncol 16(4):1374–1379 evidence-based clinical practice guideline (2nd edition). Chest
Oeffinger KC (2003) Longitudinal risk-based health care for adult 132(3 Suppl):355S–367S
survivors of childhood cancer. Curr Probl Cancer 27(3):143–167 Saslow D, Boetes C, Burke W, Harms S, Leach MO, Lehman CD,
Oeffinger KC, Hudson MM (2004) Long-term complications follow- Morris E, Pisano E, Schnall M, Sener S, Smith RA, Warner E,
ing childhood and adolescent cancer: foundations for providing Yaffe M, Andrews KS, Russell CA (2007) American Cancer
risk-based health care for survivors. CA Cancer J Clin 54(4): Society guidelines for breast screening with MRI as an adjunct to
208–236 mammography. CA Cancer J Clin 57(2):75–89
Oeffinger KC, Mertens AC, Hudson MM, Gurney JG, Casillas J, Chen Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, Murphy
H, Whitton J, Yeazel M, Yasui Y, Robison LL (2004) Health care M, Stewart SJ, Keefe D (2002) Cardiac dysfunction in the
of young adult survivors of childhood cancer: a report from the trastuzumab clinical trials experience. J Clin Oncol 20(5):
childhood cancer survivor study. Ann Fam Med 2(1):61–70 1215–1221
Oeffinger KC, Mertens AC, Sklar CA, Kawashima T, Hudson MM, Shan K, Lincoff AM, Young JB (1996) Anthracycline-induced
Meadows AT, Friedman DL, Marina N, Hobbie W, Kadan-Lottick cardiotoxicity. Ann Intern Med 125(1):47–58
NS, Schwartz CL, Leisenring W, Robison LL (2006) Chronic Sieniawski M, Reineke T, Josting A, Nogova L, Behringer K,
health conditions in adult survivors of childhood cancer. N Engl J Halbsguth T, Fuchs M, Diehl V, Engert A (2008) Assessment of
Med 355(15):1572–1582 male fertility in patients with Hodgkin’s lymphoma treated in the
Ozen H, Sahin A, Toklu C, Rastadoskouee M, Kilic C, Gogus A, German Hodgkin Study Group (GHSG) clinical trials. Ann Oncol
Kendi S (1998) Psychosocial adjustment after testicular cancer 19(10):1751–1801
treatment. J Urol 159(6):1947–1950 Skinner R, Wallace WH, Levitt GA (2005) Therapy based long-term
Partridge AH, Gelber S, Peppercorn J, Gunsburg E, Sampson E, follow-up practice statement. http://www.ukccsg.org/public/follow
Rosenberg R, Przypyszny M, Winer EP (2008) Fertility and up/PracticeStatement/index.html (2nd edn)
menopausal outcomes in young breast cancer survivors. Clin Smith MR (2004) Changes in fat and lean body mass during androgen-
Breast Cancer 8(1):65–69 deprivation therapy for prostate cancer. Urology 63(4):742–745
Passport for care: an internet-based survivorship care plan (2006) Smith MR (2007) Androgen deprivation therapy for prostate cancer:
http://www.cancer.gov/ncicancerbulletin/NCI_Cancer_Bulletin_06 new concepts and concerns. Curr Opin Endocrinol Diabetes Obes
0606/page9. 14(3):247–254
Patt DA, Goodwin JS, Kuo YF, Freeman JL, Zhang DD, Buchholz TA, Steingart R (2005) Mechanisms of late cardiovascular toxicity from
Hortobagyi GN, Giordano SH (2005) Cardiac morbidity of adjuvant cancer chemotherapy. J Clin Oncol 23(36):9051–9052
radiotherapy for breast cancer. J Clin Oncol 23(30):7475–7482 Swerdlow AJ, Barber JA, Hudson GV, Cunningham D, Gupta RK,
Pein F, Sakiroglu O, Dahan M, Lebidois J, Merlet P, Shamsaldin A, Hancock BW, Horwich A, Lister TA, Linch DC (2000) Risk of
Villain E, de Vathaire F, Sidi D, Hartmann O (2004) Cardiac second malignancy after Hodgkin’s disease in a collaborative
abnormalities 15 years and more after adriamycin therapy in 229 British cohort: the relation to age at treatment. J Clin Oncol
childhood survivors of a solid tumour at the Institut Gustave 18(3):498–509
Roussy. Br J Cancer 91(1):37–44 Swerdlow AJ, Schoemaker MJ, Allerton R, Horwich A, Barber JA,
Pickles T, Phillips N (2002) The risk of second malignancy in men Cunningham D, Lister TA, Rohatiner AZ, Vaughan Hudson G,
with prostate cancer treated with or without radiation in British Williams MV, Linch DC (2001) Lung cancer after Hodgkin’s
Columbia, 1984–2000. Radiother Oncol 65(3):145–151 disease: a nested case-control study of the relation to treatment.
Polsky D, Doshi JA, Marcus S, Oslin D, Rothbard A, Thomas N, J Clin Oncol 19(6):1610–1618
Thompson CL (2005) Long-term risk for depressive symptoms Tabar L, Vitak B, Chen HH, Duffy SW, Yen MF, Chiang CF, Krusemo
after a medical diagnosis. Arch Intern Med 165(11):1260–1266 UB, Tot T, Smith RA (2000) The Swedish two-county trial twenty
Ramli R, Ngeow WC, Rahman RA, Chai WL (2006) Managing years later. Updated mortality results and new insights from long-
complications of radiation therapy in head and neck cancer term follow-up. Radiol Clin North Am 38(4):625–651
patients: part IV. Management of osteoradionecrosis. Singap Dent Taksey J, Bissada NK, Chaudhary UB (2003) Fertility after chemo-
J 28(1):11–15 therapy for testicular cancer. Arch Androl 49(5):389–395
Recklitis CJ, Lockwood RA, Rothwell MA, Diller LR (2006) Suicidal Tan-Chiu E, Yothers G, Romond E, Geyer CE Jr, Ewer M, Keefe D,
ideation and attempts in adult survivors of childhood cancer. J Clin Shannon RP, Swain SM, Brown A, Fehrenbacher L, Vogel VG,
Oncol 24(24):3852–3857 Seay TE, Rastogi P, Mamounas EP, Wolmark N, Bryant J (2005)
Revenga F, Paricio JF, Vazquez MM, Del Villar V (2004) Risk of Assessment of cardiac dysfunction in a randomized trial comparing
subsequent non-melanoma skin cancer in a cohort of patients with doxorubicin and cyclophosphamide followed by paclitaxel, with or
primary basal cell carcinoma. J Eur Acad Dermatol Venereol without trastuzumab as adjuvant therapy in node-positive, human
18(4):514–515 epidermal growth factor receptor 2-overexpressing breast cancer:
Rieker PP, Fitzgerald EM, Kalish LA, Richie JP, Lederman GS, Edbril NSABP B-31. J Clin Oncol 23(31):7811–7819
SD, Garnick MB (1989) Psychosocial factors, curative therapies, Theriault RL, Biermann JS, Brown E, Brufsky A, Demers L, Grewal
and behavioral outcomes. A comparison of testis cancer survivors RK, Guise T, Jackson R, McEnery K, Podoloff D, Ravdin P,
and a control group of healthy men. Cancer 64(11):2399–2407 Shapiro CL, Smith M, Van Poznak CH (2006) NCCN Task Force
Ries L, Melbert D, Krapcho M, al E (2007) SEER Cancer Statistics Report: Bone Health and Cancer Care. J Natl Compr Canc Netw 4
Review, 1975–2004. National Cancer Institute, Bethesda Suppl 2: S1–20
 BioSurveillance and Longitudinal Lifelong Guidelines 169

Thorsen L, Nystad W, Stigum H, Dahl O, Klepp O, Bremnes RM, Wist Van’t Veer MB, Glimelius I, Storm H, Pukkala E, Stovall M,
E, Fossa SD (2005) The association between self-reported physical Curtis R, Boice JD Jr, Gilbert E (2003) Breast cancer following
activity and prevalence of depression and anxiety disorder in long- radiotherapy and chemotherapy among young women with Hodg-
term survivors of testicular cancer and men in a general population kin disease. JAMA 290(4):465–475
sample. Support Care Cancer 13(8):637–646 Tsai HK, D’Amico AV, Sadetsky N, Chen MH, Carroll PR (2007)
Titus-Ernstoff L, Perry AE, Spencer SK, Gibson J, Ding J, Cole B, Androgen deprivation therapy for localized prostate cancer and the
Ernstoff MS (2006) Multiple primary melanoma: two-year results risk of cardiovascular mortality. J Natl Cancer Inst
from a population-based study. Arch Dermatol 142(4):433–438 99(20):1516–1524
Travis LB, Andersson M, Gospodarowicz M, van Leeuwen FE, Tward JD, Wendland MM, Shrieve DC, Szabo A, Gaffney DK (2006)
Bergfeldt K, Lynch CF, Curtis RE, Kohler BA, Wiklund T, Storm The risk of secondary malignancies over 30 years after the
H, Holowaty E, Hall P, Pukkala E, Sleijfer DT, Clarke EA, Boice treatment of non-Hodgkin lymphoma. Cancer 107(1):108–115
JD Jr, Stovall M, Gilbert E (2000) Treatment-associated leukemia van den Belt-Dusebout AW, de Wit R, Gietema JA, Horenblas S,
following testicular cancer. J Natl Cancer Inst 92(14):1165–1171 Louwman MW, Ribot JG, Hoekstra HJ, Ouwens GM, Aleman BM,
Travis LB, Curtis RE, Glimelius B, Holowaty EJ, Van Leeuwen FE, van Leeuwen FE (2007) Treatment-specific risks of second
Lynch CF, Hagenbeek A, Stovall M, Banks PM, Adami J et al malignancies and cardiovascular disease in 5-year survivors of
(1995) Bladder and kidney cancer following cyclophosphamide testicular cancer. J Clin Oncol 25(28):4370–4378
therapy for non-Hodgkin’s lymphoma. J Natl Cancer Inst van den Belt-Dusebout AW, Nuver J, de Wit R, Gietema JA, ten
87(7):524–530 Bokkel Huinink WW, Rodrigus PT, Schimmel EC, Aleman BM,
Travis LB, Curtis RE, Hankey BF, Fraumeni JF Jr (1992) Second van Leeuwen FE (2006) Long-term risk of cardiovascular disease
cancers in patients with chronic lymphocytic leukemia. J Natl in 5-year survivors of testicular cancer. J Clin Oncol
Cancer Inst 84(18):1422–1427 24(3):467–475
Travis LB, Fossa SD, Schonfeld SJ, McMaster ML, Lynch CF, Storm van Leeuwen FE, Klokman WJ, Stovall M, Dahler EC, van’t Veer
H, Hall P, Holowaty E, Andersen A, Pukkala E, Andersson M, MB, Noordijk EM, Crommelin MA, Aleman BM, Broeks A,
Kaijser M, Gospodarowicz M, Joensuu T, Cohen RJ, Boice JD Jr, Gospodarowicz M, Travis LB, Russell NS (2003) Roles of
Dores GM, Gilbert ES (2005) Second cancers among 40,576 radiation dose, chemotherapy, and hormonal factors in breast
testicular cancer patients: focus on long-term survivors. J Natl cancer following Hodgkin’s disease. J Natl Cancer Inst 95(13):
Cancer Inst 97(18):1354–1365 971–980
Travis LB, Gospodarowicz M, Curtis RE, Clarke EA, Andersson M, van Leeuwen FE, Klokman WJ, Veer MB, Hagenbeek A, Krol AD,
Glimelius B, Joensuu T, Lynch CF, van Leeuwen FE, Holowaty E, Vetter UA, Schaapveld M, van Heerde P, Burgers JM, Somers R,
Storm H, Glimelius I, Pukkala E, Stovall M, Fraumeni JF Jr, Boice Aleman BM (2000) Long-term risk of second malignancy in
JD Jr, Gilbert E (2002) Lung cancer following chemotherapy and survivors of Hodgkin’s disease treated during adolescence or
radiotherapy for Hodgkin’s disease. J Natl Cancer Inst young adulthood. J Clin Oncol 18(3):487–497
94(3):182–192 Wettergren L, Bjorkholm M, Axdorph U, Langius-Eklof A (2004)
Travis LB, Hill DA, Dores GM, Gospodarowicz M, van Leeuwen FE, Determinants of health-related quality of life in long-term survi-
Holowaty E, Glimelius B, Andersson M, Wiklund T, Lynch CF, vors of Hodgkin’s lymphoma. Qual Life Res 13(8):1369–1379
 BioPediatric Complexities of Growth
and Development
Arnold C. Paulino, Sughosh Dhakal, and Louis S. Constine

Contents Abstract
Although increased survival and ultimately cure of
1 Introduction.......................................................................... 171 cancer remains the primary goal of treatment, the quality
2 Organogenesis: Sensitivity to Late Effects According of survival is largely dependent on the toxicities of
to Stage of Development ..................................................... 172 treatment. In particular, the late effects of treatment,
2.1 Embryo and Fetus.................................................................. 172 which may manifest months to years or even decades
2.2 Postnatal Period and Childhood............................................ 173
after therapy, have been a driving force in the evolution
2.3 Adulthood .............................................................................. 173
of the treatment of many curable cancers. Advances in
3 Growth Patterns of Normal Tissues: Influence radiation oncology and diagnostic radiology have led to
on Manifestations of Normal Tissue Effects .................... 173
3.1 Lymphoid Growth Pattern..................................................... 174 more conformal treatments that spare adjacent normal
3.2 Brain Growth Pattern ............................................................ 174 structures, and chemotherapy regimens have likewise
3.3 Gonadal Growth Pattern........................................................ 175 evolved. In addition, in many cancers, perhaps most
3.4 General Growth Pattern......................................................... 177 notably Hodgkin lymphoma, favorable subsets of
4 Growth Patterns in Adults ................................................. 178 patients are now treated with decreased doses of
4.1 Maintenance of Homeostasis ................................................ 178 chemotherapy and radiation while maintaining overall
4.2 Confounding Factors in Adults............................................. 178
efficacy.
5 Summary............................................................................... 179
References...................................................................................... 179

1 Introduction

Although increased survival and ultimately cure of cancer

remains the primary goal of treatment, the quality of sur-
vival is largely dependent on the toxicities of treatment. In
particular, the late effects of treatment, which may manifest
months to years or even decades after therapy, have been a
driving force in the evolution of the treatment of many
curable cancers. Advances in radiation oncology and diag-
L. S. Constine (&) nostic radiology have led to more conformal treatments that
Department of Radiation Oncology, James P. Wilmot Cancer
Center, University of Rochester Medical Center, 647, Rochester, spare adjacent normal structures, and chemotherapy regi-
NY 14642, USA mens have likewise evolved. In addition, in many cancers,
e-mail: [email protected] perhaps most notably Hodgkin lymphoma, favorable sub-
A. C. Paulino sets of patients are now treated with decreased doses of
Radiation Oncology, Department of Radiation Oncology, chemotherapy and radiation while maintaining overall
The Methodist Hospital, 6565 Fannin St, 77030 efficacy.
Houston, TX, USA
The development and manifestation of late effects in
S. Dhakal children differ greatly when compared to adults. The late
Radiation Oncology, Department of Radiation Oncology,
University of Rochester School of Medicine and Dentistry, effects in adults are primarily a result of inflammatory and
601 Elmwood Ave, Box 647, Rochester, NY 14642, USA fibrogenic processes. While these processes can also occur

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 171
DOI: 10.1007/978-3-540-72314-1_11, Ó Springer-Verlag Berlin Heidelberg 2014
172 A. C. Paulino et al.

in children, the inability of an organ to grow and mature effects of radiation and occurs within the first 2 weeks
properly is a late complication which is unique to children. postconception. In some mammals, this can be manifested
Differences in tissue and organ development explain many by a decrease in litter size secondary to prenatal death of the
of the susceptibilities to and manifestations of radiation- accompanying progeny. The irradiated preimplanted
induced injury when delivered throughout the early years of embryo that survives until term grows normally in the
life, whereas a differential ability to repair injury is the prepartum and postpartum periods. Growth is not affected
primary determinant of chronic tissue injury in the mature by irradiation at this period as only a few cells are present;
and senescing adult. Furthermore, comorbid illness and if substantial numbers of cells die, the embryo is resorbed.
prolonged environmental and lifestyle factors are much In those that have survived, cells usually divide to ‘‘make-
more likely to affect the development of treatment related up’’ what cells were destroyed. Data regarding the effects of
injury in adults. radiation therapy during this phase of development are
Many of these principles are illustrated by the example largely derived from animal models and in vitro experi-
of chest wall irradiation. Both the adult and child will be ments, utilizing mouse embryos grown in tissue culture
prone to pulmonary consequences, such as inflammation (Streffer and Molls 1987). Doses as low as 5–15 cGy can
and fibrosis; however, the child also will be susceptible to a kill fertilized eggs in mice and rats (Rugh 1962; Brent and
direct restriction of lung compliance from bone hypoplasia Ghorson 1972).
and malformation in the developing ribs and spine, as well The second phase of development in utero is prenatal
as indirect effects of compliance due to greater levels of organogenesis, which occurs immediately after implanta-
atelectasis and air trapping. Such is not the case in the adult, tion and extends through the first 60 days after conception.
where the bones are fully grown and hypoplasia and mal- It is a period of marked radiosensitivity as this corresponds
formation are not an issue. However, comedical factors to differentiation of body structures. Irradiation during this
generally absent in children but oftentimes present in adults, period has resulted in malformations secondary to disrup-
such as smoking or other environment exposures, will affect tion of morphogenesis of different organ systems. Most of
the risk of treatment-related pneumonitis. In addition, the the clinical information regarding malformations occurring
capacity for tissue repair may be relatively limited in the in this period come from atomic bomb survivors in Hiro-
elderly. shima. Reported anomalies have largely affected a few
This chapter will review organogenesis in the developing organ systems including the central nervous system, skeletal
human, from the embryo to adulthood, and the complexities system and dentition, eye and genitalia. The gastrointesti-
involved in manifestation of late effects from radiation nal, cardiovascular, and renal systems, which are common
therapy according to stage of development. It will review sites of anomalies, are not particularly involved in those
the four classic growth curves for normal tissues in children receiving radiation (Metler and Upton 1995). This may be
and briefly discuss a selected number of confounding fac- related to the length and time of organ development. If
tors that may influence the degree of late effects in the death occurs as a result of irradiation during organogenesis,
pediatric and adult population. Secondary malignant neo- it is likely to manifest as neonatal death or death occurring
plasms will not be covered in this chapter as they are dis- at time of or around birth, in contrast to death during irra-
cussed extensively elsewhere. diation at time of preimplantation or implantation, in which
case the embryo is resorbed.
The fetal period occurs from 60 days after conception
2 Organogenesis: Sensitivity to Late through parturition. Body and organ growth predominates
Effects According to Stage as differentiation becomes more complete; hence, structural
of Development malformations gradually decrease while disturbances of
growth are more prominent. Much higher doses are required
2.1 Embryo and Fetus to cause death during this phase compared to earlier periods
of development. Irradiation of an early fetus results in the
Growth starts after fertilization of the egg by the sperm. largest degree of permanent growth retardation, in contrast
Radiotherapy to the developing embryo or fetus may affect to an irradiated early embryo, which will exhibit greater
growth depending on its stage of development. There are growth retardation at birth but largely recover later in life.
three recognized phases of the developmental period in As can be expected, tissues undergoing the most rapid cell
utero: (1) preimplantation, (2) prenatal organogenesis, and division at the time of exposure are the most susceptible to
(3) fetal period (Russell and Russell 1954). growth disturbances. For example, the highest incidence of
Preimplantation starts from the time of fertilization to the mental retardation in atomic bomb survivors are seen in
time when the embryo attaches to the uterine wall those exposed at 8–15 weeks of intrauterine life, with a
(implantation). It is the most sensitive phase to the lethal relative risk four times higher than those exposed at
BioPediatric Complexities of Growth and Development 173

16 weeks or greater. Mental retardation was not seen in have been described: (1) maturation, (2) renewal, and (3)
subjects irradiated at \8 weeks in utero (Otake et al. 1991). senescence. Radiotherapy during these adult phases will
Irradiation of the fetus between 16 and 20 weeks of gesta- lead to reactions that are primarily both inflammatory and
tion may also lead to microcephaly and stunting of growth. fibrogenic.
Irradiation after 30 weeks of gestation is not likely to pro- Maturation occurs from approximately 18–40 years of
duce gross structural abnormalities leading to serious age. It is a time when the normal tissues are fully regen-
problems in early life. erative and functional units are replaced. Repair recovery is
usually rapid. This phase can also be defined as a balance of
2.2 Postnatal Period and Childhood regenesis. Losses of molecular fidelity that occur during this
phase are maintained by a repair and turnover system that is
Unlike the prenatal stage, postnatal development after capable of achieving a homeostatic state until reproductive
radiation exposure has been less studied, both in animal maturation is totally achieved (Hayflick 2007). This assures
models and humans. The majority of our information comes that the species would be able to survive.
from descriptive studies of children irradiated for cancer The renewal phase refers to the period from 40–60 years
with adjacent normal tissue incidentally receiving dose. The of age in which some cellular senescence starts occurring
postnatal period and childhood span years where organs and and normal tissue regeneration loses its capacity to restore
functional subunits continue to proliferate and develop. This cells. As a result, some parenchymal atrophy occurs as
period is divided into three growth phases: neogenesis, senescence sets in. Cellular senescence is the phenomenon
genesis, and pubogenesis. This period covers the time from where normal diploid differentiated cells lose the ability to
birth to the beginning of adulthood which, for simplicity, is divide, generally after about 50 cell divisions in vitro
arbitrarily set at 18 years of age in this chapter. (Hayflick 1965). In response to deoxyribonucleic acid
Neogenesis refers to the time between birth and (DNA) damage, cells either age or self-destruct through
approximately 5 years of age, when most normal tissues are apoptosis if the damage cannot be repaired. It is believed
newly formed and their development consists of rapid that the death of a fraction of the cells may benefit the tissue
growth of their functional subunits. Brain tissue is rapidly and ultimately the organism as a whole. The renewal phase
developing during this phase and is hence more susceptible is also the time after the female has achieved reproductive
to radiation injury. Musculoskeletal growth, likewise, is maturation. The imbalance that occurs in youth where
more vulnerable when bone growth is most rapid, during repair and maintenance of molecules exceeds any loss of
neogenesis and pubogenesis; however, mitotic potential is fidelity slowly shifts after reproductive maturation to a state
greater for neogenesis rather than pubogenesis. Therefore, it where the loss of molecular fidelity begins to exceed repair
is not surprising that the neonatal bone would be more capacity (Hayflick 2007).
susceptible to growth retardation than adolescent bone The senescence phase refers to the period from
given the same dose of radiation. 60–80 years of age and beyond, during which time cellular
Genesis refers to the time between 5 years of age and senescence exceeds the normal tissue capacity to regener-
just prior to the onset of puberty. Growth is more stable ate. Thus, normal tissue atrophy or compensatory hyper-
during this period, and the organs have full complement of trophy or hyperplasia occurs in order to compensate for loss
functional subunits. Irradiation at this time would in general of functional subunits. Table 1 lists some of the bodily
be less detrimental to different organ systems compared to changes which occur during the senescence phase.
neogenesis as mitotic potential decreases.
Pubogenesis refers to the time from the onset of puberty
to the beginning of adulthood. It is the phase when sexual
organs grow as well as the second growth spurt in the 3 Growth Patterns of Normal Tissues:
musculoskeletal system. As will be discussed later, genitalia Influence on Manifestations of Normal
and breast tissues undergo rapid change. Certain organs Tissue Effects
such as the brain have less growth during pubogenesis, and
irradiation at this time has less potential detrimental effects The growth period for the human body is unusually long
on neurocognitive function. among mammalian species, extending for more than a
quarter of the normal life span. This long growth period is
2.3 Adulthood associated with a delay in most aspects of bodily develop-
ment, especially skeletal and endocrine maturation. Total
Adulthood can be defined as a time of normal tissue body mass continues to increase after maturity, but the rate
regeneration to maintain homeostasis rather than true of increase is slowed considerably after about age 18 years
growth in size and content of an organ system. Three phases in males and about age 16 years in females.
174 A. C. Paulino et al.

Table 1 Bodily changes during the senescence phase growth during the postnatal period and puberty. Figure 1
Cessation of organ growth shows the growth relationships according to time and type
Wrinkling of skin of organ in the neonatal period and childhood (Tanner
Loss of teeth
1962), while Table 2 provides specific data for a broader
number of organs and systems.
Graying of hair
In general, one can expect the timing of radiation therapy
Atrophy of gonads
along the curve to influence the type and severity of pos-
Weakening of muscles sible late effects, with more pronounced and severe com-
Bent posture plications occurring if radiation is administered during the
Slowed reaction time periods of increased mitotic activity. These growth curves
Presbyopia provide a context in which to explore and discuss the
Reduction in rapid eye movement (REM) sleep incidence and differential responses of children with respect
Diminution of sense of smell
to the normal tissue effects.
Loss of fine coordination
Decline of memory and mental efficiency
3.1 Lymphoid Growth Pattern
Loss of hearing, particularly for higher frequencies
Decline in ability to taste, particularly salt and bitter This type of growth pattern is characterized by gradual
Diminution of vibratory sense in toes and feet evolution and involution to the time of puberty. An example
of an organ that follows this pattern is the thymus. It reaches
its greatest relative weight at birth, but its absolute weight
continues to increase until the onset of puberty. In fact in
the renewal phase of adulthood, it is estimated that the
thymus gland is only about 5–10 % of its original size. No
significant late effects from RT occur in the lymphoid
system. In particular, there are no age-specific effects,
perhaps because the inherent radiation sensitivity of lym-
phoid tissues outweighs any differential that could be
observed due to age.

3.2 Brain Growth Pattern

This type of growth pattern is characterized by rapid post-

natal growth which slows down and is almost complete in
adolescence. Naturally, the head and neck also follow this
pattern of growth.
The brain is most sensitive to ionizing radiation in the
early fetal period, but postnatally during the first few years
of life. Brain growth during the first 3 years of life is not
secondary to increase in number of neurons but due to
axonal growth, dendritic arborization, and synaptogenesis.
Fig. 1 Four classic growth curves according to age and organ size. Myelinization, though well developed at about the second
Modified with permission from Tanner (1962) year of life, is not complete until the second to third decade
of life (Dobbing and Sands 1963). By 6 years of age, the
The growth of specific tissues from birth to adulthood child’s brain has reached adult size. Several studies have
has been categorized by four classic patterns: (1) lymphoid, shown greater cognitive impairment in younger children
with accelerated growth followed by involution at the time compared to older children receiving cranial irradiation (Ris
of puberty; (2) brain, with rapid postnatal growth that slows et al. 2001; Conklin et al. 2008). It is for this reason that for
and essentially completes by early adolescence; (3) gonadal, many years prior to the era of conformal radiotherapy, in an
with little change during early life but rapid development effort to avoid the deleterious effects of radiotherapy, che-
just before and coincident with puberty; and (4) a more motherapy after surgery was the treatment for chil-
general pattern characterized by two major periods of rapid dren \3 years of age with medulloblastoma, ependymoma,
BioPediatric Complexities of Growth and Development 175

Table 2 Anatomy and physiology: relative rate of development

Age 0–5 years Age 5–10 years Age 10–15 years Age 15–Adult
Brain 4 1 1 1
Thyroid 2 3 3 4
GI 4 3 3 2
Gonadal 1 1 4 4
Lung 3 2 3 4
Urinary system 4 3 3 2
Skin 3 2 4 4
Lymphoid tissues 4 4 hypoplasia hypoplasia
Liver 4 2 3 2
Musculoskeletal 3 2 4 2
Head and neck 4 2 2 1
Circulatory 3 2 4 2
1 static, 2 mild, 3 moderate, 4 significant

have more effect during the time when there is greater

growth of the brain. Table 3 shows the growth and devel-
opment of the brain according to time of irradiation.
In adulthood, late effects of RT to the brain involve
neurocognitive dysfunction which is discussed in greater
detail elsewhere in this textbook.

3.3 Gonadal Growth Pattern

This type of growth pattern is characterized by little change

during early life but rapid development just before and
Fig. 2 Intelligence quotient (IQ) scores after conformal radiotherapy coincident with puberty. Examples of organs with this
in children with low grade glioma. Reprinted with permission from growth pattern are the testicle, ovary, and breast.
Merchant et al. (2009)
This unique growth pattern explains why, unlike in other
sites where children are more vulnerable to the late effects
and high-grade gliomas (Duffner et al. 1993). A report from of radiotherapy compared with their adult counterparts, the
St. Jude Children’s Research Hospital showed cognitive ovary is different with respect to sterility. The ovary con-
decline after conformal radiotherapy for children under tains a fixed pool of primordial oocytes, maximal at
12 years of age with low-grade glioma (Fig. 2). In fact, age 5 months of gestational age, declining with increasing age
at time of irradiation was more important than radiation in an exponential fashion, culminating at menopause
dose in predicting cognitive decline. Children \5 years old (Wallace and Kelsey 2010) (Fig. 3). In contrast to other
show the most cognitive decline (Merchant et al. 2009). organs that are able to maintain homeostasis, the ovary does
Consistent with this, most children who are affected with not replenish oocytes, similar to other organs in cellular
radiation-induced Moyamoya syndrome were irradiated senescence during the past years.
when they were \5 years of age, a time when brain growth A classic study showed that the effective sterilizing dose
is rapid (Desai et al. 2006). to the ovary after fractionated radiotherapy decreased at
One study attributed a greater degree of deficient increasing age of irradiation: 20.3 Gy at birth, 18.4 Gy at
development with loss of white matter, and this was pre- 10 years, 16.5 Gy at 20 years, and 14.3 Gy at 30 years of
sumptively correlated with the impaired cognitive outcome age (Wallace et al. 2005). The study authors estimated the
of younger children (Mulhern et al. 2001). This description sterilizing dose of radiotherapy at any given age by inte-
of white matter changes is consistent with the classic find- grating known data on the radiosensitivity of human
ing after radiation insult of the normal brain of a focal or oocytes with their model for natural oocyte decline (Fig. 4).
diffuse area of white matter necrosis (Martins et al. 1977). It This finding is also supported by the Childhood Cancer
is also consistent with the premise that radiotherapy would Survivor Study, which showed that cyclophosphamide
176 A. C. Paulino et al.

Table 3 Growth and development of brain with respect to time of irradiation

Phase Time Manifestation after radiation therapy
Preimplantation First 2 weeks post-conception Death of pre-implanted embryo
Prenatal organogenesis 2 weeks to parturition Microcephaly, mental retardation (greatest risk at 8–15 weeks post-conception)
and fetal period
Neogenesis Birth to 6 years Mental retardation, severe cognitive deficits especially in children \3 years of
age when myelin formation is still not nearly complete. Hypoplasia of portion
of skull and soft tissues which receive radiation therapy
Genesis 6 years to puberty Mild to moderate cognitive deficits. Mild or no hypoplasia of skull as brain
reaches its adult size at 6 years of age
Pubogenesis Puberty to 18 years Mild cognitive deficits. No hypoplasia of skull
Maturation 18–40 years Mild cognitive deficits. No hypoplasia of skull
Renewal and 40 years + Brain atrophy, cognitive deficits seen but a combination of senescence and
senescence phase radiotherapy effect

Fig. 3 The average non-growing follicles population at ages the respective 95 % PI. Max, maximum. Reprinted from Wallace and
20 weeks after conception, birth, 13, 25, and 35 years is given, along Kelsey (2010)
with predicted average age of menopause at 49.6 years, together with

exposure was a risk factor for sterility in older Similarly, children and adults have different manifesta-
(13–20 years), but not younger (\13 years) children (Che- tions of late radiation injury in the breast, with breast
maitilly et al. 2006). Finally, data exist showing that ovarian hypoplasia being the most common type of late toxicity in
dysfunction may be less in children receiving total body children. In 129 children, \4 years of age receiving a mean
irradiation at an age before menarche, compared with those dose of 2.3 Gy for hemangioma, breast hypoplasia was
who were older and received radiotherapy after menarche observed in 53 % (Furst et al. 1989). Others have also
(Ogilvy-Stuart et al. 1992), although this difference is observed breast hypoplasia after relatively low doses of
temporary as longer follow-up of patients reveals the same radiation, such as for pulmonary metastases from Wilms’
incidence of permanent ovarian dysfunction. tumor where children receive bilateral lung irradiation to
BioPediatric Complexities of Growth and Development 177

Fig. 4 Effective (red line) and mean (blue line) estimates of the dose
required to sterilize a patient at a known age of treatment. Gy, gray.
Reprinted with permission from Wallace et al. (2005) Fig. 5 Testicular volume/Livi index curve as the function of age in a
non-gypsy sample. Modified from Beres (1989)

doses of 10–12 Gy (Macklis et al. 1991). Although the dose 3.4 General Growth Pattern
was quite low, the breast in the young has not fully devel-
oped, with hyperplasia of the breast not occurring till This type of growth pattern is characterized by peak growth
puberty. The development of secondary breast malignancies rates in the early postnatal period and during puberty. It is
is discussed in great detail elsewhere in this text. perhaps best exemplified by the musculoskeletal system;
With regard to the testes, it is important to note that however, the liver and gastrointestinal tract, kidneys, and
unlike in the ovary, where fertility and hormone production urinary system, and skin also follow this pattern.
are closely related because of their dependence on the ova Bone growth is not a uniform process and does not grow
and primary follicle, these functions differ in the testes at a gradual rate. There is accelerated growth from birth to
because of the differing sensitivity of the spermatogonia and about 5 years old, steady slow growth from 5 to 10, and
Leydig cells to cytotoxic therapy. Because the spermato- accelerated growth during the pubertal years, which of
gonia are exquisitely sensitive to radiation, even small course generally occurs a few years earlier for females
dosages can produce measurable damage. Depression of compared to males. Radiation damage to bone is expressed
sperm counts is discernible at dosages as low as 15 cGy. in the epiphysis by arrested chondrogenesis, in the
This decrease in sperm counts may evolve 3–6 weeks after metaphysis by deficient absorptive processes in the calcified
irradiation, and, depending on the dosage, recovery may bone and cartilage, and in the diaphysis by an alteration in
take 1–3 years. The germinal epithelium is damaged by periosteal activity causing abnormal bone modeling (Prob-
much lower dosages (less than 1 Gy) of RT than Leydig ert and Parkers 1975). Doses [20 Gy are usually necessary
cells (20–30 Gy) (Sklar et al. 1990). Complete sterilization to arrest endochondral bone formation. In a classic study of
may occur with fractionated irradiation to a dosage of spinal growth after radiotherapy, the greatest retardation of
1–2 Gy. Spermatocytes generally fail to complete matura- growth was seen during the periods of most active growth in
tion division at dosages of 2–3 Gy and are visibly damaged children \ 6 years of age and those undergoing puberty
after 4–6 Gy with resulting azoospermia. Higher dosages (Probert and Parker 1975). In another study of slipped
are necessary to damage spermatids than will damage the epiphysis secondary to radiation therapy, doses
more sensitive spermatocytes. At the highest dosages, per- of [2500 cGy and young age at time of irradiation were the
manent sterility is common. At lower dosages, this reduced main risk factors for this complication (Silverman et al.
sperm count is seen 60–80 days after exposure, which is the 1981), which occurred in 50 % of children \4 years and
time at which maturation would otherwise be complete 5 % of children 5–15 years of age. In contrast to children
(Shalet et al. 1976). and adolescents, adult bone is much more tolerant to radi-
The growth of the testicle reflects its functional evolu- ation damage; doses of 6000 cGy or more are needed to
tion. While at the ages of 0–9 the volume does not signif- cause osteoradionecrosis.
icantly change, there is a rapid (about tenfold) increase Muscular growth parallels bone growth, and is bimodal,
between 10 and 15 years. The maximum size is attained at again occurring during the early postnatal and pubertal
17–22 years depending on race (Beres 1989) (Fig. 5). periods. Muscular hypoplasia and atrophy have been
178 A. C. Paulino et al.

reported in young children receiving radiotherapy to the of adults than hyperplasia, which refers to the increase in
spine and extremities. the number of cells due to division when stressed or stim-
Another example of the general growth pattern is the ulated to increase activity. The skin and intestinal epithe-
urinary system, although its radiosensitivity varies widely, lium, hepatocytes, fibroblasts, and bone marrow cells can
with the ureter being the most resistant, the bladder having undergo hyperplasia whereas nerve cells and cardiac and
intermediate sensitivity, and the kidney the most sensitive. skeletal muscle have relatively no capacity for hyperplastic
The tolerance of dose for the adult kidney appears to be growth.
approximately 23 Gy in 5 weeks to the parenchyma of both Atrophy of an organ is a result of impaired repair pro-
kidneys, with 28 Gy to both kidneys in 5 weeks carrying a cess. Atrophy refers to the shrinkage of a cell by loss of cell
high risk of severe radiation nephritis (Luxton and Kunkler substance, or shrinkage of tissue or an organ from cell
1964). It is not clear whether renal injury is more severe in atrophy or death. Several factors can contribute to atrophic
children than adults or during varying points of the growth organs or tissues such as decreased workload, loss of
curve, with the possible perhaps exception of irradiation innervation, diminished blood supply, inadequate nutrition,
during neogenesis (Cassady 1995; Peschel et al. 1981). This or loss of endocrine stimulation (Robbins et al. 1984).
comparison is greatly confounded by the fact that much of
the data in regards to the effect of radiation therapy on the
pediatric kidney has been collected from survivors of 4.2 Confounding Factors in Adults
pediatric Wilms tumor, who undergo resection and/or irra-
diated for their primary renal malignancy (and also some- Many changes occur in various organ systems during the
times present with bilateral disease), as opposed to adults aging process. For example, in the musculoskeletal system,
whose kidneys are often only tangentially or incidentally collagen undergoes stiffening and loss of elasticity, result-
irradiated during the treatment of a range of abdominal/ ing in decreased integrity and function. Both men and
pelvic malignancies. women lose bone mass, starting at around the renewal phase
of adulthood. Physical inactivity and malnutrition (espe-
cially for calcium and Vitamin D) of the elderly can also
4 Growth Patterns in Adults result in bone loss. In postmenopausal women, decrease in
estrogen production can lead to osteoporosis. By the time an
Hayflick’s studies with human fibroblasts in cell culture adult has reached the peak of the senescence phase, it is not
have demonstrated that the capacity to divide becomes less unusual to see a decrease in height of 1–3 inches, with
as a person gets older; an infant’s cells divide about 50 women having more loss.
times, those of a 20-year old about 30 times and those of an For many organs in the body, specific disease states
80-year old about 20 times (Hayflick 1974). This decline in associated with aging are of more significance than gen-
the ability to repair damage, together with cell attrition and eralized deterioration. Generalized reduction in blood flow
the effects of comorbid illness are particularly important in due to atherosclerosis, accelerated by hypertension and
the manifestation of late effects in the elderly. diabetes, has an adverse effect on most organ systems. For
example, after radiation treatment to the extremity in a child
bone and muscle growth are the primary late toxicities
4.1 Maintenance of Homeostasis whereas in an adult, soft tissue or bone necrosis, atrophy of
the extremity and fracture may be the concern because of
Achieving homeostasis is a delicate balance between cell change of cellular composition and diminished blood flow
proliferation and attrition. When stem cells move beyond to the irradiated area. A recent study from Florence showed
the pleuripotent stage, under the influence of intrinsic and that seven of 214 patients treated for extremity soft tissue
extrinsic factors they follow one of two paths: (1) self sarcoma and postoperative radiotherapy developed a frac-
renewal or multipotency or (2) differentiation, giving rise to ture. The fractures were all in older patients [55 years of
more specialized cells. In the final stages of life, differen- age. Interestingly these seven fractures were seen only in
tiated or nondividing cells play a greater role in injury postmenopausal women, indicative of the interaction
response as cells within the proliferative compartment move between age and coexisting hormonal changes on bone
toward a quiescent or senescent state. density and late radiotherapy complications (Livi et al.
Hypertrophy and hyperplasia can occur in response to 2006).
injury. Hypertrophy, which refers to the increase in the size Other organs can also be more susceptible in older adults
of cells and ultimately the tissue and organ in response to because of comorbidities and the aging process where the
function demand or hormonal stimulation, becomes rela- inability to repair normal tissues and maintain homeostasis
tively more important in the maintenance of normal tissues is problematic. In the kidney, chronic renal failure is more
BioPediatric Complexities of Growth and Development 179

common in older patients ([30 years) after total body age, fludarabine and total body irradiation in the incidence and
irradiation (Delgado et al. 2006). In the radiotherapeutic severity of chronic renal failure after allogeneic hematopoietic cell
transplantation. Biol Blood Marrow Transplant 12:75–83
management of brain tumors, cognitive function is severely Desai SS, Paulino AC, Mai WY, Teh BS (2006) Radiation-induced
affected in young children while in the older adult, cogni- Moyamoya syndrome. Int J Radiat Oncol Biol Phys
tive loss can occur but not necessarily from the treatment 65:1222–1227
but because of other disease states affecting the brain as Dobbing J, Sands J (1963) The quantitative growth and development
of the human brain. Arch Dis Child 48:757–767
well as part of normal aging process when a small amount Duffner PK, Horowitz ME, Krischer JP, Friedman HS, Burger PC,
of neurons are lost. Both age and educational level, for Cohen ME, Sanford RA, Mulhern RK, James HE, Freeman CR,
example, are included in the determination of cognitive Seidel FG, Kun LE (1993) Postoperative chemotherapy and
impairment after whole brain radiotherapy for brain delayed radiation in children less than three years of age with
malignant brain tumors. N Engl J Med 328:1725–1731
metastases using the Folstein Mini-Mental status examina- Furst CJ, Lundell M, Ahlback SO, Holm LE (1989) Breast hypoplasia
tion (Corn et al. 2008). following irradiation of the female breast in infancy and early
childhood. Acta Oncol 28:519–523
Hayflick L (1965) The limited in vitro lifetime of human diploid cell
strains. Exp Cell Res 37:614–636
5 Summary Hayflick L (1974) The longevity of human cultured cells. J Am Geriatr
Soc 22:1–12
The developing human organism is complex with multiple Hayflick L (2007) Biological aging is no longer an unsolved problem.
organ systems developing at different times and rates. Late Ann N Y Acad Sci 1100:1–13
Livi L, Santoni R, Paiar F, Bastiani P, Beltrami G, Caldora P, Capanna
effects of radiotherapy are influenced not only by total dose, R, De Biase P, Detti B, Fondelli S, Meldolesi E, Pertici M, Polli C,
volume, and fractionation but also the stage of normal tissue Simontacchi G, Biti G (2006) Late treatment-related complications
development, comorbid disease, and various host factors, in 214 patients with extremity soft-tissue sarcoma treated by
both intrinsic and extrinsic. While late effects in adults are surgery and postoperative radiation therapy. Am J Surg
191:230–234
primarily inflammatory and fibrogenic, in children a major Luxton RW, Kunkler PB (1964) Radiation nephritis. Acta Radiol Ther
and unique contributor to late toxicity is impairment of Phys Biol 66:169–178
maturation of the organ. Confounding factors such as Macklis RM, Oltikar A, Sallan SE (1991) Wilms’ tumor patients with
comorbid disease, physiologic changes, and environmental pulmonary metastases. Int J Rad Onc Biol Phys 21:1187–1193
Martins AN, Johnston JS, Henry MJ, Stoffel TJ, Dichiro G (1977)
factors play a big part in the determination of late toxicity in Delayed radiation necrosis of the brain. J Neurosurg 47:336–345
the adult patient. Knowledge of the growth and develop- Merchant TE, Conklin HM, Wu S, Lustig RH, Xiong X (2009) Late
ment of various organ systems will help the radiation effects of conformal radiotherapy for pediatric patients with low-
oncologist to understand potential degree of late effects both grade glioma: prospective evaluation of cognitive, endocrine and
hearing deficits. J Clin Oncol 27:3691–3697
in children and adults. Metler FA, Upton AC (1995) Medical effects of ionizing radiation, 2nd
edn. WB Saunders Co, Philadelphia
Mulhern RK, Palmer SL, Reddick WE, Glass JO, Kun LE, Taylor J,
References Langston J, Gajjar A (2001) Risks of young age for selected
neurocognitive deficits in medulloblastoma are associated with
white matter loss. J Clin Oncol 19:472–479
Beres J (1989) Testicular volume variations from 0 to 28 years of age. Ogilvy-Stuart AL, Clark DJ, Wallace WH, Gibson BE, Stevens RF,
Int Urol Nephrol 21:159–167 Shalet SM, Donaldson MD (1992) Endocrine deficit after frac-
Brent RL, Ghorson RO (1972) Radiation exposure in pregnancy. Curr tionated total body irradiation. Arch Dis Child 67:1107–1110
Probl Radiol 2:1–48 Otake M, Schull WJ, Yoshimura H (1991) Brain damage among the
Cassady JR (1995) Clinical radiation nephropathy. Int J Radiat Oncol prenatally exposed. J Radiat Res (Suppl) 32:249–264
Biol Phys 31:1249–1256 Peschel RE, Chen M, Seashore J (1981) The treatment of massive
Chemaitilly W, Mertens AC, Mitby P (2006) Acute ovarian failure in hepatomegaly in stage IV-S neuroblastoma. Int J Radiat Oncol Biol
the Childhood Cancer Survivor Study. J Clin Endo Metab Phys 7:549–553
91:1723–1728 Probert JC, Parker BP (1975) The effects of radiation therapy on bone
Conklin HM, Li C, Xiong X, Ogg RJ, Merchant TE (2008) Predicting growth. Radiology 114:155–162
change in academic abilities after conformal radiation therapy for Ris MD, Packer R, Goldwein J, Jones-Wallace D, Boyett JM (2001)
localized ependymoma. J Clin Oncol 26:3965–3970 Intellectual outcome after reduced-dose radiation therapy plus
Corn BW, Moughan J, Knisely JPS, Fox SW, Chakravarti A, Yung adjuvant chemotherapy for medulloblastoma: a Children’s Cancer
WKA, Curran WJ, Robins HI, Brachman DG, Henderson RH, Group study. J Clin Oncol 19:3470–3476
Mehta MP, Movsas B (2008) Prospective evaluation of quality of Robbins SL, Cotran RS, Kumar V (1984) Pathologic basis of disease,
life and neurocognitive effects in patients with multiple brain 3rd edn. WB Saunders, Philadelphia
metastases receiving whole-brain radiotherapy with or without Rugh R (1962) The impact of ionizing radiation on the embryo and
thalidomide on Radiation Therapy Oncology Group (RTOG) Trial fetus. Am J Roentgenol 87:559–566
0118. Int J Radiat Oncol Biol Phys 71:71–78 Russell LB, Russell WL (1954) An analysis of the changing radiation
Delgado J, Cooper N, Thomson K, Duarte R, Jarmulowicz M, Cassoni response of the developing mouse embryo. J Cell Physiol (Suppl 1)
A, Kottaridis P, Peggs K, Mackinnon S (2006) The importance of 43:103–149
180 A. C. Paulino et al.

Shalet SM, Beardwell CG, Pearson D, Jones PH (1976) The effects of Streffer C, Molls M (1987) Cultures of preimplantation mouse embryos:
varying doses of cerebral irradiation on growth hormone produc- a model for radiobiological studies. Adv Radiat Biol 13:169–213
tion in childhood. Clin Endocrinol (Oxf) 5:287–290 Tanner JM (1962) Growth at adolescence. Blackwell Scientific
Silverman CL, Thomas PRM, McAlister WH, Walker S, Whiteside Publications, Oxford
LA (1981) Slipped capital femoral epiphysis in irradiated children: Valentin J (2002) Basic anatomical and physiological data for use in
dose volume and age relationships. Int J Radiat Oncol Biol Phys radiological protection: reference values. ICRP Publication 89.
7:1357–1363 Ann ICRP 32:5–265
Sklar CA, Robison LL, Nesbit ME, Sather HN, Meadows AT, Ortega Wallace WH, Kelsey TM (2010) Human ovarian reserve from
JA, Kim TH, Hammond GD (1990) Effects of radiation on conception to menopause. PLoS ONE 5:e8772
testicular function in long-term survivors of childhood acute Wallace WH, Thomson AB, Saran F, Kelsey TW (2005) Predicting
lymphoblastic leukemia: a report from the Children’s Cancer Study age of ovarian failure after radiation to a field that includes the
Group. J Clin Oncol 8:1981–1987 ovaries. Int J Radiat Oncol Biol Phys 62:738–744
 BioGenetic and Host Implications

Barry S. Rosenstein

Contents Abstract
It has been of substantial interest to identify the inherent
1 Introduction.......................................................................... 182 factors that individuals may possess which could render
2 Diseases Associated with Adverse Responses them more likely to suffer adverse effects resulting from
to Radiotherapy ................................................................... 182 a standard radiation therapy treatment for cancer. Case
2.1 Collagen Vascular Disease.................................................... 182 reports have been published suggesting that patients with
2.2 Diabetes and Hypertension ................................................... 183
certain diseases, including collagen vascular diseases,
2.3 Inflammatory Bowel Disease ................................................ 183
diabetes, and inflammatory bowel disease, are at greater
3 Genetic Factors .................................................................... 184 risk for developing normal tissue toxicities following
3.1 Skin Fibroblast Radiosensitivity ........................................... 184
3.2 Lymphocyte Assays............................................................... 184 radiation therapy. However, retrospective studies have
3.3 Gene Expression Profiling .................................................... 184 generally not found substantial increases in the suscep-
3.4 Identification of Single Nucleotide Polymorphisms ............ 185 tibility of these patients for the development of normal
References...................................................................................... 187 tissue toxicities following radiotherapy. The focus of
many research studies has been to develop cell-based
assays to identify radiosensitive patients, but the only
approach that appears promising in this regard is the
lymphocyte apoptosis assay. On the genomic level,
expression studies have suggested that altered expression
of certain genes may correlate with adverse radiation
effects. A major focus of the effort to identify markers
for potential radiosensitivity, is the identification of
genetic alterations, primarily single nucleotide polymor-
phisms (SNPs) that are associated with the development
of radiation-induced toxicities. A series of candidate
gene SNP studies has been performed whose results are
supportive of the role for genetic factors conferring an
increased risk for the development of radiation injuries.
The current emphasis in this area of research is to
perform genome wide association studies involving
simultaneous screening of a broad range of genes for
each patient using high density microarrays to identify
SNPs that have the strongest associations with adverse
effects arising from radiotherapy. Identification of such
genetic markers may be of clinical significance as it
B. S. Rosenstein (&) could lead to the development of a predictive assay that
Radiation Oncology, Dermatology and Community will permit identification of potential radiotherapy
and Preventive Medicine, Mount Sinai School of Medicine,
NYU School of Medicine, 1 Gustave L. Levy Place, patients that are at greatest risk for the development of
New York, NY 10029, USA radiation injuries. In addition, the discovery of genes
e-mail: [email protected]

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 181
DOI: 10.1007/978-3-540-72314-1_12, Ó Springer-Verlag Berlin Heidelberg 2014
182 B. S. Rosenstein

whose products alter the susceptibility of patients for the 2.1 Collagen Vascular Disease
development of normal tissue toxicities may provide
valuable information as to the molecular pathways Collagen vascular disease (CVD) represents a spectrum of
through which these radiation effects arise. disorders characterized by abnormalities in immunoregula-
tory processes resulting in the production of autoantibodies
and anomalies in cell-medicated immunity (Hamilton
1 Introduction 2005). The autoantibodies are typically formed against
components of the extracellular matrix, including collagen
A substantial degree of variability among patients in the and elastin. Patients with CVDs may exhibit skin rash,
response to a standard course of radiotherapy has long been fibrosis, arthritis, and in more severe cases, organ damage.
observed. When a patient exhibits an unusual reaction to a A series of case reports, often of pronounced and even
conventional protocol, generally the first approach is to dramatic radiation reactions and toxicity, initially suggested
examine whether any tissues received an excessively high that patients diagnosed with CVDs were at an increased risk
dose due to overlapping fields or a dosimetric error was for radiation injuries resulting from radiotherapy (Nilsen
made in treatment planning. However, more often than not, et al. 1967; Glasenapp 1968; Urtasun 1971; Ransom and
there is not a clear explanation for an excessive normal Cameron 1987; Olivotto et al. 1989; Robertson et al. 1991;
tissue response. Therefore, it has generally been assumed Varga et al. 1991; Rathmell and Taylor 1992; Abu-Shakra
when treating patients to a dose which represents tolerance and Lee 1993; Hareyama et al. 1995; Bliss et al. 1996; Mayr
for a normal tissue, that by chance, some patients will and Riggs 1997; Rakfal and Deutsch 1998; Khoo et al.
develop a radiation injury. This has often been ascribed to 2004; Wo and Taghian 2007). In response to these case
the random nature of cell killing and the stochastic nature of reports, radiation oncologists have been cautious in treating
the pathways leading to the expression of radiation injury. patients with CVDs. In addition, based upon these findings,
However, a number of studies have suggested that often the the American College of Radiology stated in their guide-
explanation for the development of an adverse response is lines concerning breast cancer (Winchester and Cox 1998)
not simply random, but may be more a reflection of some that ‘‘a history of collagen vascular disease is a relative
genetic attribute of the patient that confers a susceptibility contraindication to breast conservation treatment because
for the development of an adverse response (Safwat et al. published reports indicate that such patients tolerate irra-
2002). Thus, if it were possible to identify the ‘‘host’’ fac- diation poorly’’.
tors that render certain patients more likely to develop To examine the question as to whether patients with
complications from a radiation treatment, it could then be CVD are at increased risk for radiation injuries following
feasible to adjust the treatment protocols for these patients. radiotherapy, several retrospective studies were performed
Thus, depending upon the cancer being treated, it may be (Ross et al. 1993; Morris and Powell 1997; Chen and
prudent to use a lower total dose or attempt a more con- Obedian 2001; Phan et al. 2003; Gold et al. 2007, 2008;
formal treatment. Alternatively, for those patients who Pinn et al. 2008). The patients studied primarily included
could be reasonably treated with surgery alone, it may be those affected with rheumatoid arthritis (RA), systemic
best to avoid the use of radiotherapy. The purpose of this lupus erythematosus (SLE), dermatomyositis, polymyositis,
chapter is to review the evidence that certain inherent and systemic sclerosis (scleroderma). In addition, some of
genetic patient factors may play a role in the response of these patients exhibited overlapping syndromes, referred to
normal tissues and organs to radiotherapy. as mixed connective tissue disorders. In a study of 20
patients specifically diagnosed with scleroderma, Gold et al.
(2007) reported that only 15 % of the subjects developed
2 Diseases Associated with Adverse late radiation toxicities, which is similar to the rates of
Responses to Radiotherapy historical controls. In addition, only a small percentage of
patients displayed grade 3 or worse acute toxicities, com-
Patients with certain underlying conditions or diseases may parable to the rates in historic control populations. How-
be more susceptible for the development of adverse respon- ever, in a subsequent publication, Gold et al. (2008)
ses to a standard course of radiotherapy. The main groups of reported in a study of 41 patients with either scleroderma or
patients that have been investigated are radiotherapy patients SLE, that patients who were diagnosed with high severity
who had been diagnosed with either collagen vascular dis- CVD were at greater risk to develop radiation-induced
eases, diabetes/hypertension, or inflammatory bowel disease. toxicities resulting from radiotherapy compared with
BioGenetic and Host Implications 183

patients with low-severity CVD. In addition, the manifes- Thus, although some studies have suggested an increased
tations of radiation injury appeared earlier in the high- risk of late effects in certain patients, particularly those
severity CVD group. In a study of 21 patients with SLE, people diagnosed with scleroderma, none of the retrospec-
Pinn et al. (2008) reported that patients with SLE renal tive series has confirmed the substantial increase in the
involvement were at a greater risk for the development of susceptibility of patients with CVDs to radiation-induced
chronic radiation toxicity resulting from radiotherapy. normal tissue toxicities that were reported in earlier case
These authors concluded that both acute and chronic tox- reports.
icities resulting from radiotherapy were moderate among
patients with SLE and therefore the use of RT should not be
avoided in these patients, although patients with more 2.2 Diabetes and Hypertension
advanced SLE may be at an increased risk for the devel-
opment of adverse effects resulting from RT. Diabetes and hypertension often have similar vascular
In order to reach a more definitive conclusion as to whether pathologies to patients with CVDs, although without an
CVDs predispose patients to complications from RT, the autoimmune etiology. Herold et al. (1999); Chon and Loeffler
results of three matched case–control studies (Ross et al. (2002) reported upon radiation toxicities in a population of
1993; Chen and Obedian 2001; Phan et al. 2003) and one 944 patients treated with EBRT for prostate cancer, 121 of
large retrospective study (Morris and Powell 1997) have been whom had diabetes. They found that the rates of gastroin-
published. Ross et al. (1993) reported the results for 61 testinal and genitourinary morbidity were somewhat higher
patients with CVDs (39 RA, 13 SLE, 4 scleroderma, 4 der- in the diabetic patients compared with men not exhibiting
matomyositis, and 1 polymyositis) treated with radiotherapy. evidence of diabetes. Maruyama et al. (1974) reviewed the
No significant difference was found between the group of records of 271 patients treated with RT for cervical cancer
patients with CVDs and matched controls in terms of either and concluded that patients with diabetes were more likely to
acute or late effects of radiation. Phan (2003) performed a develop small bowel obstructions following RT. VanNagell
case–control study of 38 patients with CVDs (21 SLE, two et al. (1974) also reported on cervical cancer RT patients with
scleroderma, four Raynaud’s phenomena, three fibromyalgia, the finding of a correlation between diabetes with the
three polymyalgia, three Sjogren’s syndrome, two polymyo- development of radiation-induced bladder and rectal injuries.
sitis-dermatomyositis) and reported no significant differences
in the incidence of either early or late complications between
the case and control groups, although the patients with 2.3 Inflammatory Bowel Disease
scleroderma exhibited an increase in both acute and late
effects. Chen et al. (2001) performed a case control study of Inflammatory bowel diseases (IBD) comprise patients with
patients diagnosed with CVDs who received breast conserv- ulcerative colitis and Crohn’s disease. IBD has been con-
ing therapy. Similar to previous studies, no significant dif- sidered a relative contraindication for pelvic or abdominal
ferences were found in the incidence of acute effects between RT since this disease is characterized by an inflammatory
the cases and controls. However, this study found an reaction in the mucosa and it has been thought that radiation
increased risk of late radiation toxicity in the CVD patients would exacerbate this condition. Willet et al. (2000) reported
compared with controls. This was primarily due to the on 28 patients with IBD (10 Crohn’s disease and 18 ulcera-
development of late morbidity in 75 % of the scleroderma tive colitis). A higher rate of radiation toxicities was observed
patients, although this group consisted of only four subjects. in IBD patients who underwent abdominal or pelvic RT
A retrospective report from Morris and Powell (1997) of 209 compared with morbidity rates of non-IBD patients who
patients diagnosed with CVDs (136 RA, 28 SLE, 17 poly- received similar treatments. Thus, these authors suggested
myositis-dermatomyositis, 16 scleroderma, 8 ankylosing that RT should be used judiciously in these patients. Green
spondylitis, 4 mixed tissue disorders) reported a similar rate of et al. (1999) reported on the outcomes for 47 IBD patients (35
acute reactions to the Ross et al. study (1993). However, this ulcerative colitis and 12 Crohn’s disease) treated with RT for
study found that severe late radiation toxicity was signifi- rectal cancer. The rates of acute and late complications were
cantly associated with non-RA CVDs. Thus, these authors similar in this group to those reported in randomized trials of
concluded that aside from RA, CVD may be associated with RT for rectal cancer. In addition, two studies (Grann and
an enhanced risk of late effects following standard radio- Wallner 1998; Peters et al. 2006) of patients with IBD who
therapy. Holscher et al. (2006) performed a review of the received brachytherapy for prostate cancer reported that
literature and calculated a pooled relative risk of 2.0 (95 % these patients tolerated this treatment and exhibited similar
confidence interval, 0.99–4.1) for the development of late rates of rectal complications to non-IBD patients.
effects in patients diagnosed with CVDs following radio- In summary, a series of case reports have described
therapy compared with RT patients without a history of CVD. radiotherapy-related injuries in patients with CVDs, diabetes,
184 B. S. Rosenstein

hypertension, and IBD, thereby raising concerns about between dermal fibroblast radiation sensitivity with the
patients diagnosed with these types of diseases as to their severity for both early and late effects (Loeffler et al. 1990;
suitability for radiotherapy. However, retrospective series, Oppitz et al. 2001). However, replication studies generally
with several exceptions, have generally reported a tolerable were not able to validate these initial findings as there was a
incidence of complications among these patients. In addition, lack of correlation between fibroblast radiosensitivity with
publication bias may have prevented some negative studies late effects and only a weak association with early skin
from being reported. Thus, the avoidance of radiotherapy for responses (Begg et al. 1993).
patients diagnosed with these diseases based upon case
reports may have resulted in overly cautious treatment rec-
ommendations. However, it must be recognized that some 3.2 Lymphocyte Assays
people, in particular patients with active CVD, IBD, or a
combination of uncontrolled hypertension with diabetes, The initial results examining lymphocyte radiosensitivity
may be at a greater risk for the development of normal tissue did not suggest a correlation with adverse radiotherapy
injuries resulting from a standard course of radiotherapy and effects. In addition, because lymphocytes display differen-
should be treated with particular care. tial radiation sensitivity, the changes in the levels of dif-
ferent lymphocyte cell-types resulted in large experimental
variation (Stewart et al. 1988; Crompton and Ozsahin
3 Genetic Factors 1997). However, in more recent work that takes into
account the cell-type specific radiosensitivities, it has been
It has long been speculated that genetic factors could play reported that the response of CD4 and CD8 T-lymphocytes
an important role influencing the susceptibility of a patient to irradiation correlates with radiation-induced morbidity in
for the development of a radiation injury (Andreassen et al. a breast cancer patient population treated with radiotherapy
2002, 2005; Baumann et al. 2003; Fernet and Hall 2004; (Crompton et al. 1999, 2001; Ozsahin et al. 1997; Azria
Bourguignon et al. 2005; Jones et al. 2005). To examine the et al. 2004; Ozsahin et al. 2005). In particular, an inverse
role of potential genetic influences, the incidence and time correlation has been reported between radiation-induced
to development of radiation-induced telangiectasia in breast T-lymphocyte apoptosis, especially in CD8 cells, with the
cancer patients treated with radiotherapy was examined development of late effects in patients from whom the
(Safwat et al. 2002). A large range in the severity and latent lymphocytes were derived.
times prior to the manifestation of telangiectasia was
observed in this population despite a uniform radiotherapy
treatment. Consistent with previous results (Tucker et al. 3.3 Gene Expression Profiling
1992, 1996; Turesson and Joiner 1996), it was estimated
that 80–90 % of the variability among patients could be With the development of gene expression microarrays that
attributed to deterministic effects, associated possibly with provide the ability to measure the expression of a large
individual genetic differences. By comparison, it was cal- number of genes following irradiation, it is now possible to
culated that only about 10–20 % of the variation resulted examine whether differential expression of certain genes
from stochastic events associated with the random varia- following irradiation correlates with the development of
tions in dosimetry and dose delivery. radiation-induced injuries resulting from radiotherapy.
Expression was studied in fibroblast cell lines derived from
breast cancer patients exhibiting a range of subcutaneous
3.1 Skin Fibroblast Radiosensitivity fibrotic reactions following post-mastectomy radiotherapy
(Alsner et al. 2007; Rodningen et al. 2008). RNA was
As a manifestation of an inherent genetic susceptibility to isolated 2 h following irradiation of fibroblasts and analyzed
radiation toxicity, studies were performed in which the using a 15 K cDNA microarray. The results were compared
in vitro radiosensitivity of skin fibroblasts was measured. It with gene expression in unirradiated fibroblasts. A mini-
should be noted that although it could be expected that cell mum set of 18 genes was identified that could differentiate
killing by radiation may play a central role in the etiology of patients who were at low risk for fibrosis compared with
early effects, late radiation effects in the skin are more likely patients at high risk based upon the differential expression
a manifestation of a cytokine cascade induced by radiation of these genes in the two populations. Using quantitative
resulting in an inflammatory response leading to a fibrotic real time PCR, it was found that the relative magnitude of
reaction (Bentzen 2006). Thus, a correlation between killing the increase in irradiated compared with unirradiated
of skin fibroblasts with late effects would be unlikely. fibroblasts provided even greater discrimination between
Nevertheless, several initial studies reported an association patients who were either sensitive or resistant to the
BioGenetic and Host Implications 185

development of subcutaneous fibrosis following radiother- SNPs were screened. Thus, it is likely that some SNPs
apy. The results of this study indicated that differential gene reported as being significantly associated with a particular
expression of specific genes could distinguish between form of radiation injury were actually false positives.
patients at low risk from those at high risk for a fibrotic It should be noted that when reference is made to possession
response. of a SNP in the following discussion, this indicates that the
patients were either heterozygous or homozygous for the
minor SNP allele.
3.4 Identification of Single Nucleotide
Polymorphisms 3.4.1 Prostate Cancer
Hall et al. (1998) first reported an association between the
The most direct way to identify the genetic factors associated possession of ‘‘significant mutations’’ in ATM with proctitis
with susceptibility for the development of radiation-induced and cystitis in prostate cancer patients treated with radio-
adverse effects is to identify the genetic variants that correlate therapy. This was followed by two studies by Cesaretti et al.
with the manifestation of different forms of radiation- (2005, 2006) in which they discovered an association
induced injuries resulting from radiotherapy. Putting aside between missense SNPs (causes substitution of the encoded
copy number variants, humans are 99.9 % identical in their amino acid) in ATM with rectal bleeding and erectile dys-
genetic makeup. Thus, about once every 1,000 nucleotides at function and that the impact of the SNPs upon proctitis was
least 1 % of the population exhibits a change in the DNA radiation dose dependent. In contrast to these positive
sequence that is the result of an ancestral mutation which has findings, Meyer et al. (2007) found no association between
spread throughout the population resulting in substitution of the codon 1054 SNP in ATM with either urinary morbidity
a variant base pair at a specific nucleotide in the human or erectile dysfunction. Damaraju et al. (2006) screened for
genome for the one observed in the majority of the population SNPs in multiple genes and identified an association
(Frazer et al. 2007). These are referred to as single nucleotide between SNPs in LIG4, ERCC2 and CP2D6*4 with bladder
polymorphisms or SNPs. Therefore, each individual is either and rectal toxicity. Peters et al. (2007) detected a correlation
homozygous for the major allele (the more common base between SNPs in TGFB1 with both erectile dysfunction and
pair), homozygous for the minor allele (less common pair rectal bleeding. Burri et al. (2008) reported that patients
base) or heterozygous for the allele (possessing the more with a particular SNP in XRCC1 were more likely to
common base pair in one copy of the chromosome and the develop erectile dysfunction and that men who harbored
less common base pair in the other chromosome of the pair). either a specific SNP in SOD2 or a combination of SNPs in
Although many of the SNPs in the human genome have little SOD2 and XRCC3 displayed an increased incidence of
or no functional consequence, it is thought that some number rectal bleeding.
of these genetic variants are associated with a susceptibility
to the development of a diversity of biological end-points 3.4.2 Breast Cancer
including physical attributes such height, weight and intel- The first report of a positive association between possession
ligence, an increased risk for a particular disease, and vari- of SNPs and radiation injury in breast cancer patients
ation in the response to drugs and radiotherapy. This forms treated with radiotherapy was from Iannuzzi et al. (2002)
the basis of personalized medicine, which is the use of a followed later by Ho et al. (2007) who reported a correla-
person’s genotype to select a medical treatment for a certain tion between missense SNPs in ATM with subcutaneous
disease or a preventative measure against the development of fibrosis and telangiectasias. In contrast, Bremer (2003) did
a specific disorder that is most appropriate for that particular not detect an association between SNPs in ATM with radi-
person. ation effects. Edvardsen (2007) found a correlation between
In order to identify the SNPs associated with adverse an ATM SNP with a reduced frequency of telangiectasia,
radiation effects, a series of case–control studies has been indicating a protective effect associated with possession of
performed over the past 10 years in which SNPs in specific this SNP. Andreassen (2003, 2005, 2006) reported an
candidate genes have been screened in radiotherapy patients association between SNPs in TGFB1, SOD2, XRCC3,
who developed complications from radiotherapy and con- XRCC1 and ATM with subcutaneous fibrosis. However, in a
trol subjects who received similar treatments, but did not validation study in which a separate replication set of sub-
develop adverse responses. Although associations of certain jects was screened, this group was unable to confirm their
SNPs with normal tissue toxicities resulting from radio- initial findings (Andreassen et al. 2006). Angele et al.
therapy have been detected, it should be noted that few of (2003), Moullan et al. (2003), Quarmby et al. (2003) and
these studies have been validated. Another important limi- Giotopulos et al. (2007) found associations between adverse
tation of these findings is that generally corrections were not radiation responses with SNPs in either ATM, XRCC1,
made for multiple testing, even though routinely multiple TGFB1, and TGFB1/XRCC1, respectively. In addition,
186 B. S. Rosenstein

Edvardsen et al. (2007) reported that possession of a SNP in whose presence confers susceptibility to the development of
GSTP1 was associated with pleural thickening. the end-point of interest. The other important event that has
fueled the tremendous increase in GWAS during recent
3.4.3 Other Sites years has been the development of relatively low cost SNP
De Ruyck et al. (2005, 2006) reported a correlation between genotyping arrays. These arrays permit the simultaneous
SNPs in XRCC3 and TGFB1 with an increase risk of late genotyping of roughly one million SNPS in each person.
radiation effects following treatment for either cervical or Using this approach, the cost of SNP genotyping has fallen
endometrial cancers whereas a SNP in XRCC1 with asso- nearly 10,000-fold in the past decade. It is therefore now not
ciated with a reduced incidence of late effects. Severin et al. necessary to limit screening to only a handful of genes and
(2001) published an association between a SNP in RAD21 SNPs. Thus, there has been virtually an explosion of GWAS
with radiation effects following treatment at any one of published over the past few years reporting associations
multiple sites. between SNPs with a variety of traits and susceptibility to a
range of diseases (Manolio et al. 2008). It must also be
3.4.4 Multiple SNP Screening recognized that the technology for DNA re-sequencing is
In order to expand the number of SNPs being screened, developing rapidly with a commensurate drop in price.
Suga et al. (2007) have reported results performed as part of Hence, the time is likely not very far into the future when it
the Japanese RadGenomics Project in which breast cancer may be possible to determine the complete nucleotide
patients treated with radiotherapy were screened for 999 sequence for an individual at a modest cost.
SNPs in a total of 137 candidate genes. It was discovered in In addition to the identification of most SNPs and the
this study that haplotypes in six loci were associated with ability to genotype at a relatively low cost, there are several
the development of early skin reactions. In a separate study other reasons why the preferred approach for SNP associ-
performed by this group (Suga et al. 2008), prostate cancer ation studies is to perform this research on a genome-wide
patients who had undergone carbon ion radiotherapy were basis. The first is recognition of the relative ignorance as to
screened for 450 SNPs in 118 genes and an association was genes involved in the pathways leading to normal tissue
found between SNPs in SART1, ID3, EPDR1, PAH, and effects. A candidate gene approach permits examination of
XRCC6 with urinary morbidity. only a limited number of genes whose proteins play known
roles in the development of radiation injuries. In contrast,
3.4.5 Genome Wide Association Studies GWAS will facilitate the discovery of new genes and pro-
In recent years, an effort has been made to expand the list of teins involved in etiology of radiation effects and help to
genes and SNPs that are being screened. The logical elucidate novel pathways for the development of radiation
extension of this work is to perform genome wide associ- responses. In addition, it has been found in some GWAS
ation studies (GWAS). Thus, work has been initiated to that the critical SNPs were not located within coding
conduct GWAS by the GENE-PARE (Ho et al. 2006), regions of genes, but in non-coding portions of the genome.
GENEPI (Baumann et al. 2003; West et al. 2005) and Presumably, in these instances, the changes in DNA
RadGenomics (Suga et al. 2007) consortia to identify SNPs sequence exert some type of regulatory control over a
associated with adverse radiotherapy responses. Each of particular gene. These SNPs clearly would not have been
these groups has developed a large biorepository and identified using a candidate gene approach. Also, it must be
databank of radiotherapy patients. This area of research has appreciated that it is not adequate for a certain protein to
only recently become feasible due to two major scientific play an important role in a radiation-response pathway, but
and technical breakthroughs. The first is the HapMap pro- the gene that encodes that protein must also possess a
ject (Frazer et al. 2007) which has now identified roughly 3 SNP(s) that exerts an important functional impact for there
million of the estimated 10 million SNPs that are thought to to be a genetic basis associated with clinical radiosensitivity
exist in the human population. In addition, HapMap has related to that particular gene.
demonstrated that SNPs are inherited in ‘‘haplotype blocks’’ In addition to SNPs, the other major source of genetic
which represent groups of SNPs that are in linkage dis- variation between people is copy number variants. These
equilibrium and are thus inherited together since they are represent relatively long nucleotide stretches in which more
rarely separated through recombination. Therefore, it is in than one copy for that portion of the genome may be present
fact not necessary to genotype all possible SNPs, but just a in an individual. If a copy number variant is present in greater
portion, since one SNP in a haplotype block can serve than 1 % of a population, it is referred to as a copy number
essentially as a ‘‘tag’’ SNP. Once this tag SNP has been polymorphism. Although there are relatively few studies
identified, comprehensive sequencing in the area sur- which have correlated specific effects with CNPs, it is pos-
rounding the SNP will identify the actual functional SNP sible to use SNP microarrays to also analyze CNPs. Thus,
BioGenetic and Host Implications 187

most GWAS are also screening for association between Begg AC, Russell NS, Knaken H, Lebesque JV (1993) Lack of correlation
CNPs and the particular end-point of interest since this of human fibroblast radiosensitivity in vitro with early skin reactions
in patients undergoing radiotherapy. Int J Radiat Biol 64(4):393–405
source of genetic variation may prove to be of importance. Bentzen SM (2006) Preventing or reducing late side effects of
In summary, there is evidence to support the hypothesis radiation therapy: radiobiology meets molecular pathology. Nat
that much of the individual variation in susceptibility for the Rev Cancer 6(9):702–713
development of radiation-induced normal tissue toxicities is Bliss P, Parsons CA, Blake PR (1996) Incidence and possible aetiological
factors in the development of pelvic insufficiency fractures following
the result of inherent host or genetic susceptibilities, which radical radiotherapy. Br J Radiol 69(822):548–554
each patient brings into radiotherapy. Thus, the develop- Bourguignon MH, Gisone PA, Perez MR et al (2005) Genetic and
ment of complications resulting from a treatment with epigenetic features in radiation sensitivity. Part II: implications for
radiation does not necessarily arise from random chance, clinical practice and radiation protection. Eur J Nucl Med Mol
Imaging 32(3):351–368
but may be a manifestation of predisposing factors that Bremer M, Klopper K, Yamini P, Bendix-Waltes R, Dork T, Karstens
render certain patients more likely to suffer injuries from JH (2003) Clinical radiosensitivity in breast cancer patients
radiotherapy. It is anticipated that identification of the carrying pathogenic ATM gene mutations: no observation of
genetic and host factors that predispose individuals to the increased radiation-induced acute or late effects. Radiother Oncol
69(2):155–160
development of adverse effects from radiotherapy will Burri RJ, Stock RG, Cesaretti JA et al (2008) Association of single
greatly facilitate the ability to optimize cancer treatment for nucleotide polymorphisms in SOD2, XRCC1 and XRCC3 with
each patient on an individual basis. susceptibility for the development of adverse effects resulting from
radiotherapy for prostate cancer. Radiat Res 170(1):49–59
Cesaretti JA, Stock RG, Lehrer S et al (2005) ATM sequence variants are
References predictive of adverse radiotherapy response among patients treated
for prostate cancer. Int J Radiat Oncol Biol Phys 61(1):196–202
Cesaretti J, Stock R, Atencio D et al (2006) A genetically determined
Abu-Shakra M, Lee P (1993) Exaggerated fibrosis in patients with dose volume histogram predicts for rectal bleeding among patients
systemic sclerosis (scleroderma) following radiation therapy. treated with prostate brachytherapy. Int J Radiat Oncol Biol Phys
J Rheumatol 20(9):1601–1603 66(3):S37–S50
Alsner J, Rodningen OK, Overgaard J (2007) Differential gene Chen AM, Obedian E, Haffty BG (2001) Breast-conserving therapy in
expression before and after ionizing radiation of subcutaneous the setting of collagen vascular disease. Cancer J 7(6):480–491
fibroblasts identifies breast cancer patients resistant to radiation- Chon BH and Loeffler JS (2002) The effect of nonmalignant systemic
induced fibrosis. Radiother Oncol 83(3):261–266 disease on tolerance to radiation therapy. Oncologist 7(2):136–143
Andreassen CN (2005) Can risk of radiotherapy-induced normal tissue Crompton NE and Ozsahin M (1997) A versatile and rapid assay of
complications be predicted from genetic profiles? Acta Oncol radiosensitivity of peripheral blood leukocytes based on DNA and
44(8):801–815 surface-marker assessment of cytotoxicity. Radiat Res 147(1):55–60
Andreassen CN, Alsner J, Overgaard J (2002) Does variability in Crompton NE, Miralbell R, Rutz HP et al (1999) Altered apoptotic
normal tissue reactions after radiotherapy have a genetic basis– profiles in irradiated patients with increased toxicity. Int J Radiat
where and how to look for it? Radiother Oncol 64(2):131–140 Oncol Biol Phys 45(3):707–714
Andreassen CN, Alsner J, Overgaard M, Overgaard J (2003) Predic- Crompton NE, Shi YQ, Emery GC et al (2001) Sources of variation in
tion of normal tissue radiosensitivity from polymorphisms in patient response to radiation treatment. Int J Radiat Oncol Biol
candidate genes. Radiother Oncol 69(2):127–135 Phys 49(2):547–554
Andreassen CN, Alsner J, Overgaard J et al (2005) TGFB1 polymor- Damaraju S, Murray D, Dufour J et al (2006) Association of DNA
phisms are associated with risk of late normal tissue complications repair and steroid metabolism gene polymorphisms with clinical
in the breast after radiotherapy for early breast cancer. Radiother late toxicity in patients treated with conformal radiotherapy for
Oncol 75(1):18–21 prostate cancer. Clin Cancer Res 12(8):2545–2554
Andreassen CN, Overgaard J, Alsner J et al (2006a) ATM sequence De Ruyck K, Van Eijkeren M, Claes K et al (2005) Radiation-induced
variants and risk of radiation-induced subcutaneous fibrosis after damage to normal tissues after radiotherapy in patients treated for
postmastectomy radiotherapy. Int J Radiat Oncol Biol Phys gynecologic tumors: association with single nucleotide polymor-
64(3):776–783 phisms in XRCC1, XRCC3, and OGG1 genes and in vitro
Andreassen CN, Alsner J, Overgaard M, Sorensen FB, Overgaard J chromosomal radiosensitivity in lymphocytes. Int J Radiat Oncol
(2006b) Risk of radiation-induced subcutaneous fibrosis in relation Biol Phys 62(4):1140–1149
to single nucleotide polymorphisms in TGFB1, SOD2, XRCC1, De Ruyck K, Van Eijkeren M, Claes K et al (2006) TGFbeta1
XRCC3, APEX and ATM–a study based on DNA from formalin polymorphisms and late clinical radiosensitivity in patients treated
fixed paraffin embedded tissue samples. Int J Radiat Biol for gynecologic tumors. Int J Radiat Oncol Biol Phys 65(4):
82(8):577–586 1240–1248
Angele S, Romestaing P, Moullan N et al (2003) ATM haplotypes and Edvardsen H, Kristensen VN, Grenaker Alnaes GI et al (2007)
cellular response to DNA damage: association with breast cancer Germline glutathione S-transferase variants in breast cancer:
risk and clinical radiosensitivity. Cancer Res 63(24):8717–8725 relation to diagnosis and cutaneous long-term adverse effects after
Azria D, Gourgou S, Sozzi WJ et al (2004) Concomitant use of two fractionation patterns of radiotherapy. Int J Radiat Oncol Biol
tamoxifen with radiotherapy enhances subcutaneous breast fibrosis Phys 67(4):1163–1171
in hypersensitive patients. Br J Cancer 91(7):1251–1260 Edvardsen H, Tefre T, Jansen L et al (2007) Linkage disequilibrium
Baumann M, Holscher T, Begg AC (2003) Towards genetic prediction pattern of the ATM gene in breast cancer patients and controls;
of radiation responses: ESTRO’s GENEPI project. Radiother association of SNPs and haplotypes to radio-sensitivity and post-
Oncol 69(2):121–125 lumpectomy local recurrence. Radiat Oncol 2:25
188 B. S. Rosenstein

Fernet M, Hall J (2004) Genetic biomarkers of therapeutic radiation Maruyama Y, Van Nagell JR, Utley J, Vider ML, Parker JC (1974)
sensitivity. DNA Repair (Amst) 3(8–9):1237–1243 Radiation and small bowel complications in cervical carcinoma
Frazer KA, Ballinger DG, Cox DR et al (2007) A second generation therapy. Radiology 112(3):699–703
human haplotype map of over 3.1 million SNPs. Nature Mayr NA, Riggs CE Jr., Saag KG, Wen BC, Pennington EC, Hussey
449(7164):851–861 DH (1997) Mixed connective tissue disease and radiation toxicity.
Giotopoulos G, Symonds RP, Foweraker K et al (2007) The late a case report. Cancer 79(3):612–618
radiotherapy normal tissue injury phenotypes of telangiectasia, Meyer A, Wilhelm B, Dork T et al (2007) ATM missense variant
fibrosis and atrophy in breast cancer patients have distinct P1054R predisposes to prostate cancer. Radiother Oncol
genotype-dependent causes. Br J Cancer 96(6):1001–1007 83(3):283–288
Glasenapp GB (1968) Osteomyelitis of the maxilla following radio- Morris MM and Powell SN (1997) Irradiation in the setting of collagen
therapy for facial lupus. HNO, 16(2):46–49 vascular disease: acute and late complications. J Clin Oncol
Gold DG, Miller RC, Petersen IA, Osborn TG (2007) Radiotherapy for 15(7):2728–2735
malignancy in patients with scleroderma: the mayo clinic experi- Moullan N, Cox DG, Angele S, Romestaing P, Gerard JP, Hall J
ence. Int J Radiat Oncol Biol Phys 67(2):559–567 (2003) Polymorphisms in the DNA repair gene XRCC1, breast
Gold DG, Miller RC, Pinn ME, Osborn TG, Petersen IA, Brown PD cancer risk, and response to radiotherapy. Cancer Epidemiol
(2008) Chronic toxicity risk after radiotherapy for patients with Biomarkers Prev 12(11 Pt 1):1168–1174
systemic sclerosis (systemic scleroderma) or systemic lupus Nilsen LB, Missal ME, Condemi JJ (1967) Appearance of Hodgkin’s
erythematosus: association with connective tissue disorder sever- disease in a patient with systemic lupus erythematosus. Cancer
ity. Radiother Oncol 87(1):127–131 20(11):1930–1933
Grann A and Wallner K (1998) Prostate brachytherapy in patients with Olivotto IA, Fairey RN, Gillies JH, Stein H (1989) Fatal outcome of
inflammatory bowel disease. Int J Radiat Oncol Biol Phys pelvic radiotherapy for carcinoma of the cervix in a patient with
40(1):135–138 systemic lupus erythematosis. Clin Radiol 40(1):83–84
Green S, Stock RG, Greenstein AJ (1999) Rectal cancer and Oppitz U, Baier K, Wulf J, Schakowski R, Flentje M (2001) The
inflammatory bowel disease: natural history and implications for in vitro colony assay: a predictor of clinical outcome. Int J Radiat
radiation therapy. Int J Radiat Oncol Biol Phys 44(4):835–840 Biol 77(1):105–110
Hall EJ, Schiff PB, Hanks GE et al (1998) A preliminary report: Ozsahin M, Ozsahin H, Shi Y, Larsson B, Wurgler FE, Crompton NE
frequency of A-T heterozygotes among prostate cancer patients (1997) Rapid assay of intrinsic radiosensitivity based on apoptosis
with severe late responses to radiation therapy. Cancer J Sci Am in human CD4 and CD8 T-lymphocytes. Int J Radiat Oncol Biol
4(6):385–389 Phys 38(2):429–440
Hamilton CD (2005) Immunosuppression related to collagen-vascular Ozsahin M, Crompton NE, Gourgou S et al (2005) CD4 and CD8 T-
disease or its treatment. Proc Am Thorac Soc 2(5):456–460 lymphocyte apoptosis can predict radiation-induced late toxicity: a
Hareyama M, Nagakura H, Tamakawa M et al (1995) Severe reaction prospective study in 399 patients. Clin Cancer Res
after chemoradiotherapy of nasopharyngeal carcinoma with colla- 11(20):7426–7433
gen disease. Int J Radiat Oncol Biol Phys 33(4):971 Peters CA, Cesaretti JA, Stone NN, Stock RG (2006) Low-dose rate
Herold DM, Hanlon AL, Hanks GE (1999) Diabetes mellitus: a prostate brachytherapy is well tolerated in patients with a history of
predictor for late radiation morbidity. Int J Radiat Oncol Biol Phys inflammatory bowel disease. Int J Radiat Oncol Biol Phys
43(3):475–479 66(2):424–429
Ho AY, Atencio DP, Peters S et al (2006) Genetic predictors of Peters CA, Stock RG, Cesaretti JA et al (2007) TGFB1 single
adverse radiotherapy effects: the Gene-PARE project. Int J Radiat nucleotide polymorphisms are associated with adverse quality of
Oncol Biol Phys 65(3):646–655 life in prostate cancer patients treated with radiotherapy. Int J
Ho AY, Fan G, Atencio DP et al (2007) Possession of ATM sequence Radiat Oncol Biol Phys 70:752–759
variants as predictor for late normal tissue responses in breast Phan C, Mindrum M, Silverman C, Paris K, Spanos W (2003)
cancer patients treated with radiotherapy. Int J Radiat Oncol Biol Matched-control retrospective study of the acute and late compli-
Phys 69:677–684 cations in patients with collagen vascular diseases treated with
Holscher T, Bentzen SM, Baumann M (2006) Influence of connective radiation therapy. Cancer J 9(6):461–466
tissue diseases on the expression of radiation side effects: a Pinn ME, Gold DG, Petersen IA, Osborn TG, Brown PD, Miller RC
systematic review. Radiother Oncol 78(2):123–130 (2008) Systemic lupus erythematosus, radiotherapy, and the risk of
Iannuzzi CM, Atencio DP, Green S, Stock RG, Rosenstein BS (2002) acute and chronic toxicity: the mayo clinic experience. Int J Radiat
ATM mutations in female breast cancer patients predict for an Oncol Biol Phys 71(2):498–506
increase in radiation-induced late effects. Int J Radiat Oncol Biol Quarmby S, Fakhoury H, Levine E et al (2003) Association of
Phys 52(3):606–613 transforming growth factor beta-1 single nucleotide polymor-
Jones IM, Thomas CB, Xi T, Nelson DO, Mohrenweiser HW (2005) phisms with radiation-induced damage to normal tissues in breast
The genetic basis for variation in radiation sensitivity in the general cancer patients. Int J Radiat Biol 79(2):137–143
population. Radiat Res 163(6):700–701 Rakfal SM, Deutsch M (1998) Radiotherapy for malignancies
Khoo VS, Saunders MP, Gowda R, Price P, Cummings BJ (2004) Anal associated with lupus: case reports of acute and late reactions.
canal cancer and chemoradiation treatment in two patients with Am J Clin Oncol 21(1):54–57
systemic lupus erythematosus treated by chronic therapeutic Ransom DT and Cameron FG (1987) Scleroderma–a possible contra-
immunosuppression. Clin Oncol (R Coll Radiol) 16(1):1–5 indication to lumpectomy and radiotherapy in breast carcinoma.
Loeffler JS, Harris JR, Dahlberg WK, Little JB (1990) In vitro Australas Radiol, 31(3):317–318
radiosensitivity of human diploid fibroblasts derived from women Rathmell AJ and Taylor RE (1992) Enhanced normal tissue response
with unusually sensitive clinical responses to definitive radiation to radiation in a patient with discoid lupus erythematosus. Clin
therapy for breast cancer. Radiat Res 121(2):227–231 Oncol (R Coll Radiol) 4(5):331–332
Manolio TA, Brooks LD, Collins FS (2008) A HapMap harvest of Robertson JM, Clarke DH, Pevzner MM (1991) Breast conservation
insights into the genetics of common disease. J Clin Invest therapy. Severe breast fibrosis after radiation therapy in patients
118(5):1590–1605 with collagen vascular disease. Cancer 68(3):502–508
BioGenetic and Host Implications 189

Rodningen OK, Borresen-Dale AL, Alsner J, Hastie T, Overgaard J Tucker SL, Geara FB, Peters LJ, Brock WA (1996) How much could
(2008) Radiation-induced gene expression in human subcutaneous the radiotherapy dose be altered for individual patients based on a
fibroblasts is predictive of radiation-induced fibrosis. Radiother predictive assay of normal-tissue radiosensitivity? Radiother Oncol
Oncol 86(3):314–320 38(2):103–113
Ross JG, Hussey DH, Mayr NA, Davis CS (1993) Acute and late Turesson I and Joiner MC (1996) Clinical evidence of hypersensitivity
reactions to radiation therapy in patients with collagen vascular to low doses in radiotherapy. Radiother Oncol 40(1):1–3
diseases. Cancer 71(11):3744–3752 Urtasun RC (1971) A complication of the use of radiation for
Safwat A, Bentzen SM, Turesson I, Hendry JH (2002) Deterministic malignant neoplasia in chronic discoid lupus erythematosus. J Can
rather than stochastic factors explain most of the variation in the Assoc Radiol, 22(2): 168–169
expression of skin telangiectasia after radiotherapy. Int J Radiat van Nagell JR, Parker JC, Maruyama Y, Utley J, Vider ML, Luckett P
Oncol Biol Phys 52(1):198–204 (1974) Bladder or rectal injury following radiation therapy for
Severin DM, Leong T, Cassidy B et al (2001) Novel DNA sequence cervical cancer. Am J Obstet Gynecol 119(6):727–732
variants in the hHR21 DNA repair gene in radiosensitive cancer Varga J, Haustein UF, Creech RH, Dwyer JP (1991) and Jimenez, SA
patients. Int J Radiat Oncol Biol Phys 50(5):1323–1331 Exaggerated radiation-induced fibrosis in patients with systemic
Stewart CC, Stevenson AP, Habbersett RC (1988) The effect of low- sclerosis. JAMA 265(24):3292–3295
dose irradiation on unstimulated and PHA-stimulated human West CM, McKay MJ, Holscher T et al (2005) Molecular markers
lymphocyte subsets. Int J Radiat Biol Relat Stud Phys Chem predicting radiotherapy response: report and recommendations
Med 53(1):77–87 from an International Atomic Energy Agency technical meeting.
Suga T, Ishikawa A, Kohda M et al (2007) Haplotype-based analysis Int J Radiat Oncol Biol Phys 62(5):1264–1273
of genes associated with risk of adverse skin reactions after Willett CG, Ooi CJ, Zietman AL et al (2000) Acute and late toxicity of
radiotherapy in breast cancer patients. Int J Radiat Oncol Biol Phys patients with inflammatory bowel disease undergoing irradiation
69(3):685–693 for abdominal and pelvic neoplasms. Int J Radiat Oncol Biol Phys
Suga T, Iwakawa M, Tsuji H et al (2008) Influence of multiple genetic 46(4):995–998
polymorphisms on genitourinary morbidity after carbon ion Winchester DP and Cox JD (1998) Standards for diagnosis and manage-
radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys ment of invasive breast carcinoma. American College of Radiology.
72(3):808–813 American College of Surgeons. College of American Pathologists.
Tucker SL, Turesson I, Thames HD (1992) Evidence for individual Society of Surgical Oncology. CA Cancer J Clin 48(2): 83–107
differences in the radiosensitivity of human skin. Eur J Cancer Wo J and Taghian A (2007) Radiotherapy in setting of collagen
28A(11):1783–1791 vascular disease. Int J Radiat Oncol Biol Phys 69(5):1347–1353
 Bioengineering of Irradiated Normal Tissues
by Bone Marrow Stem Cells
Joel S. Greenberger and Michael W. Epperly

Contents Abstract
Irradiation damage of normal tissue during radiation
1 Introduction.......................................................................... 191 therapy is repaired by stem cells and differentiated
2 Bone Marrow Stem Cell Reconstitution progeny derived from both the irradiated tissue and from
of the Irradiated Bone Marrow......................................... 192 cells migrating through the blood from the bone marrow.
3 Endothelial Progenitor Cell Involvement in Tissue The bone marrow contains both pluripotential hematopoi-
Regeneration and Bioengineering...................................... 194 etic stem cells and their committed progenitors, and bone
marrow stromal cells (mesenchymal stem cells). Using
4 Epithelial Progenitor Cells Derived from the Bone
Marrow ................................................................................. 194 defined conditions in vitro or in animal model systems
in vivo, each of these marrow origin cell populations has
5 Bone Marrow-Derived Mesenchymal Stem Cells............ 197
been shown to differentiate into multiple cell lineages.
6 The Irradiated Tissue Microenvironment: Niche Irradiation of epithelial organs stimulates migration of
or Vascular Space?.............................................................. 198
bone marrow cells to sites of injury where incorporation
References...................................................................................... 198 leads to either repair of acute injury or to formation of late
fibrosis. The degree to which marrow origin stem and
committed progenitor cells contribute to repair of irradi-
ation damage is not known. This chapter discusses the
roles of the different marrow origin cell populations in
repair of irradiation-induced damage to epithelial organs.

1 Introduction

There has always been a fascination with tissue healing.

Scientists and physicians have made tremendous discover-
ies over the past several decades with respect to the
molecular and cellular mechanisms of wound repair and
methods by which to optimize recovery of tissue function
and minimize late fibrosis or scarring (Rubin and Cassarett
1968; Hall 1988; Epperly et al. 2003; Dileto and Travis
1996; Franko and Sharplin 1994). The fields of tissue
Supported by Research Grants: RO1CA11927 and RO1CA083876.
engineering (Lanza and Atala 2002), bioengineering (Stripp
J. S. Greenberger (&)
M. W. Epperly and Reynolds 2005), and regenerative medicine (Lagasse
Department of Radiation Oncology, University of Pittsburgh et al. 2001) have evolved from the wealth of basic science,
Cancer Institute, UPMC Cancer Pavilion, POB2, 5th Floor, and clinical data obtained from a variety of disciplines
Rm. 533, 5150, Centre Avenue, Pittsburgh, PA 15232, USA
e-mail: [email protected]
including both medical and tissue physiology.

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 191
DOI: 10.1007/978-3-540-72314-1_13, Ó Springer-Verlag Berlin Heidelberg 2014
192 J. S. Greenberger and M. W. Epperly

In the medical field, pioneering studies in plastic and O’Sullivan 2009)), and volume effects. Tissue and organ
reconstructive surgery (Stripp and Reynolds 2005), wound volume effects of ionizing irradiation present a complex
and burn management (Lagasse et al. 2001), ischemia and challenge in explaining the mechanism of total body irra-
reperfusion damage (Kaminski et al. 2004), organ failure diation damage from a specific dose of irradiation that is
(Novakova-Jiresova et al. 2004), regeneration following significantly more severe than the same dose delivered to
functional organ reduction (Giangreco et al. 2009), and hemibody or partial body volumes. For example, the length
others have uncovered clear evidence of age-related chan- of spinal cord receiving a given irradiation dose determines
ges in the biological repair process, the critical role of tissue capacity for recovery (van der Kogel et al. 1982).
inflammatory cytokines in tissue regeneration, and the role However, the cellular and molecular mechanisms of the
of stem cells in the process of repair. volume effect are poorly understood (Prise and O’Sullivan
In the basic science disciplines of cellular physiology 2009).
and stem cell biology, many revolutionary changes in the It is now clear that damage to self-renewing cell popu-
past decades have occurred most prominently. The dis- lations that have a supportive role in the microenvironment
covery of the multilineage epithelial differentiating capacity can significantly limit recovery capacity not only by effects
of subsets of bone marrow stem cells that were previously on other surviving cells within the irradiated volume, but
thought to be restricted to the lymphohematopoietic lineage also with respect to hosting reparative cells that migrate in
(Petersen et al. 1999; Krause et al. 2001). Fibroblasts of the from distant sites through the circulation (Greenberger
bone marrow microenvironment (Friedenstein et al. 1982), 1991). This chapter will review both the state of knowledge
renamed mesenchymal stem cells (Pittenger et al. 1999) and future challenges with respect to exploiting the poten-
were shown to have a capacity not only for multilineage tial effectiveness of bone marrow-derived stem cells to
differentiation to osteoblasts, chondrocytes, and adipocytes, reconstitute irradiated tissues.
but also to display migratory and homing capacity to dif-
ferent sites within the bone marrow and other organs (Erices
et al. 2000; Anklesaria et al. 1989; Quesenberry et al. 2005; 2 Bone Marrow Stem Cell Reconstitution
Werts et al. 1980). Both intrinsic genetic (Boggs et al. 1981) of the Irradiated Bone Marrow
and microenvironmentally determinative (Tjwa et al. 2009;
Hazen et al. 2009; Heissig et al. 2002) influences on stem The role of bone marrow-derived stem cells in what is now
cell differentiation have been established. called regenerative medicine in fact began in radiation
Tissue damage from ionizing irradiation parallels many biology. The pioneering studies of Till and McCulloch
features of injury from other insults including thermal burn, (1961) first demonstrated a direct cell dose response curve
ultraviolet irradiation damage, and ischemia/reperfusion with respect to the capacity of bone marrow-derived cells to
injury (Kaminski et al. 2004). Common to each form of produce hematopoietic cell foci in the total body irradiated
tissue injury is the phenomenon of oxidative stress (Tyurina mouse spleen. This assay called the colony forming unit
et al. 2008, Tyurin 2008; Kagan et al. 2009; Jiang et al. spleen was the first clear demonstration that bone marrow
2007; Greenberger and Epperly 2007). The antioxidant pool could quantitatively restore tissue and organ function
within cells, tissues, and organs has been shown to critically (McCulloch and Till 1962). Over the next several decades,
influence the capacity of the repair process following each researchers established several basic principles of the biol-
form of injury (Epperly et al. 2004). However, ionizing ogy of bone marrow transplantation, each of which serves
irradiation injury is unique in several aspects. Ionizing as a focus for continuing research efforts:
irradiation-induced DNA strand breaks that initiate cellular 1. There is a bone marrow toxic dose of total body ionizing
death are highly localized within the nucleus (Olive and irradiation, below which marrow transplantation can
Banath 2004), and have been shown to activate a set of facilitate survival. Above that threshold total body irra-
signal transduction events that lead to a unique form of diation dose, damage to other organs overrides the
injury (Bakkenist and Kastan 2003). The direct irradiation reconstitution capacity of bone marrow stem cells to
dose–response relationships of cellular, tissue, and organ rescue the animal/human from lethality. There remains
injury are influenced by radiation quality (high-linear great controversy as to the mechanism of the ‘‘dose
energy transfer particle damage compared to X-ray photon- threshold for survival by bone marrow transplantation’’.
induced damage (Ibanez et al. 2009)), direct and indirect 2. A subset of cells in the bone marrow contains totipo-
bystander effects (Mothersill and Seymour 2004) (Unirra- tential or pluripotential hematopoietic stem cells. Sepa-
diated cells can facilitate and stimulate repair of irradiated ration and concentration of this subset of cells, then
cells, and conversely irradiated cells can release cytokines injected intravenously after total body irradiation will
and/or communicate damage through cell contact to induce promote survival as well as will whole bone marrow
cell death in unirradiated cells, respectively (Prise and (Krause et al. 2001; Tsao et al. 2009; Zaibak et al. 2009;
Bioengineering of Irradiated Normal Tissues by Bone Marrow Stem Cells 193

Montini et al. 2009; Dickson et al. 2009; Carotta et al. 2003; Ara et al. 2003; Kiel et al. 2005; Wright et al.
2004; Cerdan et al. 2004; Yoyooka et al. 2003; Torres 2001). Controversy persists as to whether these homing
et al. 2007). The other subsets of cells (usually those signals are microenvironment cell type-specific (endo-
already displaying differentiation markers on the cell thelial cell (Kiel et al. 2005), osteoblast progenitor cell
surface) may provide short-term protection, but do not (Calvi et al. 2003), and bone marrow fibroblast (Ara
result in donor cell origin mediated long-term reconsti- et al. 2003)) or common to all cells and are rather
tution of hematopoiesis in the irradiated recipient. Non- dependent on expression of adhesion molecules
stem cell subpopulations within the bone marrow are (Greenberger 1991). Homing can be transient, such as
referred to as committed progenitors and sub-sets have the known initial concentration of intravenously injected
been shown to be unilineage (granulocyte progenitors, bone marrow-derived stem cells in the recipient lung
macrophage progenitors), bilineage (granulocyte–mac- (Albera et al. 2005). However, for stable engraftment to
rophage progenitors), and multilineage hematopoietic or the marrow the trafficking or homing cell must arrive at a
lymphohematopoietic progenitors. The genetic profile of specific microenvironmental space or niche. Controversy
the true totipotential, lymphohematopoietic reconstitut- also persists as to the physical site within the bone
ing stem cell has been a subject of intense investigation marrow space of this stem cell niche, whether it is
(Terskikh et al. 2003). Gene-Array and proteomics periosteal, contained within the vascular space of retic-
studies have shown specific gene expression (Terskikh ular adventitial cells, or involves sites of osteoblast
et al. 2003) and protein profiles (Unwin et al. 2006) with activity (Jones and Wagers 2008). Attentively, the site
true stem cells; however, the precise identification of this may be a region of relative hypoxia (Parmar et al. 2007).
cell subset is still unknown. 4. Transplanted bone marrow stem cells must return to a
3. The irradiated microenvironment into which bone mar- state of quiescence to provide stable reconstitution
row stem cells migrate significantly influences the (Zipori 2004; Roy and Verfaillie 1999). The mechanism
parameters of engraftment. Stem cell introduction by which engrafted cells return to a nondividing state
through the circulation leads to the phenomena of (G0, or quiescence) is unknown. Several observations
migration and homing. Before the identification of bone suggest that this phenomenon is absolutely required for
marrow-derived stem cells, it was known that other stable bone marrow transplantation (van Hennik et al.
differentiated nucleated committed cells within the 1999). Manipulation of purified hematopoietic stem cells
peripheral circulation (polymorphonuclear leukocytes, in tissue culture, in bioreactors, or by rapid in vitro serial
monocytes, and lymphocytes) respond to inflammatory transplantation, using tissue culture dishes or other
cytokines, peptide signals, and endothelial cell surface materials produces cells that are altered and rendered
adhesion molecules which influence their attachment and insufficient to allow homing and return to quiescence,
stable residence within a particular tissue or organ. The and results in loss of the stem cell phenotype and often
past decades have identified other primitive cell types inability to stably engraft.
which also migrate through the circulation including Another proof of the need for quiescence of stem cells is
bone marrow stromal cell progenitors (bone marrow that those hematopoietic cells surviving chemotherapy
fibroblasts, mesenchymal stem cells), committed hema- using drugs that target cycling or dividing cells, leave a
topoietic progenitor cells, and true pluripotential hema- residual population that is still capable of in vivo
topoietic stem cells. Factors which induce migration of transplantation (Rice et al. 1993).
cell populations from one site in the bone marrow to 5. Toxicity to the engraftment site (hematopoietic micro-
another site in marrow or other organs have clearly been environment) can prevent engraftment of healthy stem
shown to include several cytokines, the most prominent cells. Radiation dose dependent toxicity has been shown
granulocyte-colony stimulating factor. Migration which to limit healthy stem cell engraftment to a high dose
has also been called ‘‘trafficking’’ leads to the enhanced irradiated marrow site compared to a lower dose irradi-
availability of tissue regenerating cells in the circulation ated site (Werts et al. 1980). The recovery capacity of a
(Bonig et al. 2009; Schmitz et al. 1996; Switzer et al. high dose irradiated site can be observed over time, or a
2001; Semerad et al. 2005; Kim et al. 2006; Carlo-Stella late toxic effect to the irradiated microenvironment can
et al. 2000). permanently prevent the return of hematopoiesis at this
Migration is not always followed by homing. Homing site. The late toxic effect involves fibrosis and replace-
(stable residence and return to an integrated basal state) ment of functioning tissue with proliferating fibroblasts.
of bone marrow-derived stem cells to specific sites is Fibrosis is a common phenomenon to many irradiated
dependent upon specific microenvironmental factors in organs and prevents both recovery of resident in situ
the target site (Calvi et al. 2003; Matsuzaki et al. 2004; stem populations as well as engraftment of circulating
Cancelas et al. 2005; Adams et al. 2007; Zhang et al. progenitors derived from bone marrow (Dileto and
194 J. S. Greenberger and M. W. Epperly

Travis 1996; Franko and Sharplin 1994; Werts et al. 2002). The capacity of endothelial progenitors to revascu-
1980). larize the damaged cardiac vasculature and central nervous
There are bone marrow stem cell and microenviron- system vasculature has been shown (Young et al. 2007).
mental niche cell specific genetic determinants of tissue The role of endothelial progenitors in revascularization
repair (Boggs et al. 1981; Tjwa et al. 2009; Hazen et al. of irradiation damaged tissue remains controversial. A
2009; Heissig et al. 2002). Mouse genotype specific common factor limiting bone marrow-derived endothelial
factors can determine total body radiosensitivity of the progenitor cell reconstitution of irradiation in damaged
hematopoietic system. Specific genes have been shown tissue is toxicity to the microenvironment. Revasculariza-
to modulate transplantation capacity (Christopherson II tion has been shown to depend upon both vascular budding
et al. 2004; Boggs et al. 1973), but also genetic factors of of intrinsic endothelial cells (Hirschi and Goodell 2002) as
the hematopoietic microenvironment or niche can be well as the involvement of migrating, circulation/bone
specific modulators of engraftment (Anklesaria et al. marrow-derived endothelial cell progenitors (Takakura
1989). et al. 2000). Revascularization of cutaneous wounds has
The genetic factors influencing both stem cell and been shown to depend upon vascular bud recruitment into
microenvironment specific components of stem cell the repairing tissue (Hirschi and Goodell 2002). The reac-
transplantation appear to be independent of the intrinsic tion of neurons, fibroblast progenitor cells (mesenchymal
radiosensitivity of each of those cell types (Anklesaria stem cells), and budding endothelial cells within irradiation-
et al. 1989). damaged tissue influences whether vascular repair will
occur or attentively whether deleterious fibrosis will limit
vascular extension (Lei et al. 2006). Within the local tissue,
3 Endothelial Progenitor Cell cells migrating into the wound area through the circulation
Involvement in Tissue Regeneration include not only endothelial progenitors, but those involved
and Bioengineering in the inflammatory response (Miyahara et al. 2006). In
thermal, ultraviolet irradiation, and ischemia reperfusion
There continues to be controversy over the distinct pheno- injury (Link et al. 1996), dead and dying cells within the
type of the circulating endothelial progenitor cell of bone tissue recruit inflammatory cells through the circulation to
marrow origin. Initial studies suggested that the hemato- serve a role in limiting tissue damage, but also in the clean-
poietic stem cell was capable of differentiation to endo- up process of removing dead and damaged cells (Jackson
thelial cells (Takakura et al. 2000; Sakai et al. 2009). A et al. 2001). A successful revascularization depends upon
subset of circulating, bone marrow-derived hematopoietic limitation of the fibrotic response, but also on rapid and
cells containing FLT1 receptors was shown to be specific efficient removal of dead cells (Lei et al. 2006). Tipping the
for endothelial differentiation capacity (Shimonaka et al. balance away from successful revascularization and toward
2003). The ability of these cells to migrate through the organ failure can result from continued inflammatory
circulation and reconstitute blood vessels at a distant site cytokine production by cells of the irradiated microenvi-
was documented (Bompais et al. 2004). However, the ronment (Greenberger 1991). A chronic inflammatory
unique cells surface phenotype of the endothelial progenitor phenomenon may limit the capacity of both in situ surviving
remains controversial. vascular progenitor cells that produce the budding phe-
Bone marrow-derived cells are known to contribute to nomenon, as well as circulatory stem cells from providing
the vasculature within tumors (Murayama et al. 2002). In tissue repair.
several in vivo orthotopic tumor models, migration of bone
marrow-derived cells into the tumor microenvironment has
been shown (Murayama et al. 2002). Tumor-derived 4 Epithelial Progenitor Cells Derived
endothelial cells share many properties with endothelial from the Bone Marrow
cells from normal organs including liver and brain (Aird
et al. 1995). However, organ-specific endothelial cells have The studies of Peterson et al. (1999) first demonstrated that
been shown to be dependent in their response to specific bone marrow cells could differentiate to regenerating liver.
transcriptional factors including Von Willebrand factor These studies were followed by those of Krauss et al. (2001)
(Jahroudi et al. 1996). Fetal endothelial cells share micro- demonstrating that single bone marrow cell reconstituted,
environmental properties with those endothelial cells of the lethally irradiated recipient, mice had rare cells in multiple
adult brain (Aird et al. 1995). These observations suggest epithelial organs which were epithelial and had markers of
the potential capacity of bone marrow-derived endothelial the donor hematopoietic cell (Krause et al. 2001).
progenitors to be involved in critical aspects of tissue repair, Numerous studies followed demonstrating the evidence of
namely revascularization following injury (Murayama et al. non-hematopoietic organ reconstitution capacity of bone
Bioengineering of Irradiated Normal Tissues by Bone Marrow Stem Cells 195

Table 1 Published reports of donor bone marrow-derived progenitor/stem cell origin of normal tissues
Tissue Reference Methodology demonstration of differentiation self-renewal
In situ In situ In Demonstration
localization by localization by vitro in vivo
donor cell functional explant
marker marker
Hematopoietic Till and McCulloch (1961), McCulloch and Till + + + +
stem cell (1962)
Endothelial cell Bompais et al. (2004), Lombaert et al. (2008) + + + -
(blood vessel)
Liver Petersen et al. (1999), Krause et al. (2001), + + + -
(hepatocyte, oval Spyridonidis et al. (2004), Korbling et al. (2002),
cell, biliary duct Theise et al. (2000)
cell)
Esophagus Epperly et al. (2004), Niu et al. (2008) + + + +
Lung Albera et al. (2005), Engelhardt (2001), Kyung et al. + + + -
(2004), Reynolds et al. (2004)
Skeletal muscle Proksch et al. (2009), Mookerjee et al. (2009), + + + -
Gussoni et al. (1999)
Cardiac muscle Yoon et al. (2005) + + + -
Marrow stromal Anklesaria et al. (1989) + + + +
cell
Osteoblast Sasportas et al. (2009), Gronthos et al. (1994), + + + -
Prockop (1997)
Chondrocyte Zhou et al. (2005) + + + -
Pancreas Hess et al. (2003), Chen et al. (2004), Zeng et al. + + + -
(2006)
Intestine Ishikawa et al. (2004) + + + -
Skin (dermis) Deng et al. (2005) + + + -
Central nervous Barberi et al. (2003), Lim et al. (2009), Cheng et al. + + + -
system (2009), Brazelton et al. (2000), Mezey et al. (2000),
neurological cell Kamishina et al. (2008), Davoust et al. (2006), Munoz
et al. (2005), Simard and Rivest (2004), Habich et al.
(2006), Goolsby et al. (2003), Ohtaki et al. (2008)
Retina Chadderton et al. (2009), Lamba et al. (2006) + + + -
Peripheral Sigurjonsson et al. (2005), Lin et al. (2008), Barnabe- + + + -
nervous system Heider and Frisen (2008), Park et al. (2005)
neurons, spinal
cord
Ear Li et al. (2003) + + + -
Germ cell Lue et al. (2007) + + + -
Breast Li et al. (2009), Woodward et al. (2007) + + + -
Salivary gland Lombaert et al. (2008) + - + -

marrow fibroblast or hematopoietic cells (Table 1). These Bone marrow transplantation can result in epithelial
reports document the capacity of bone marrow cells to organ recovery, but this need not be attributed to trans-
differentiate to cells of the brain, spinal cord, skin, eye, planted stem cells (Fig. 1). The stem cell is not the same as
lung, esophagus, oral cavity, salivary gland, osteoblast/ committed progenitor cells. Bone marrow committed pro-
bone, glandular tissues, and germ cells. A problem with genitor cells can migrate into an irradiated tissue, prolifer-
many reports in this area has been the failure to properly ate, and assume characteristics of that tissue either through
apply the correct definition of ‘‘stem cell’’ when using a the inductive microenvironment causing differentiation, or
conclusion that stated evidence of bone marrow ‘‘stem cell’’ through cell fusion (Ogle et al. 2005). However, stabiliza-
origin of organ-specific cells. tion of tissue damage and transient early appearance of
196 J. S. Greenberger and M. W. Epperly

Fig. 1 Irradiation-induced bone marrow stem cell migration to bone marrow-derived cells (not true stem cells) moving into the
epithelial tissues via the circulation serves as a restorative counter- irradiated esophagus restoring committed esophageal progenitor cells
measure to stimulate organ recovery. a Esophagus stem cells and (red). True esophageal stem cells remain in their niche and repopulate
stromal cells in a basal state. b Esophagus irradiation depletes basal the esophagus at a later time pushing out the marrow origin cells
stem cells causing proliferative response. c The effect of bone marrow (Greenberger and Epperly 2009, reproduced with permission of the
stem cell regenerative migration (red) into the esophagus restoring the publisher (Elsevier, Inc.).)
epithelial stem cell niche. d The effect of differentiated/committed

donor cell-derived marked cells within tissue does not prove circulation has been shown to be critically dependent on the
that bone marrow-derived stem cells were responsible. functional status of the microenvironment of that target
The true definition of a stem cell is that it retains capacity organ.
for not only differentiation but self-renewal to generate Irradiation damage to a specific organ includes both
other stem cells. Studies in which self-renewal has been acute and chronic side effects (van Rongen et al. 1993). The
documented represent a small subset of the total published eclipse or quiet phase between the disappearance of acute
studies reporting bone marrow stem cells derived regener- irradiation effects and appearance of late effects has been
ation of epithelial organs (Table 1). It is well established shown to be attributable to a second phase of cytokine
that damage to the microenvironment of the irradiated organ production that is associated with the initiation of the late
can limit bone marrow-derived stem cell or differentiated effects (Leask and Abraham 2004). It is generally accepted
cell homing and proliferative capacity in that organ (Fig. 2) that for bone marrow-derived stem cells to have a functional
(Quesenberry et al. 2005; Epperly et al. 2004; Niu et al. role in tissue reconstitution of an epithelial organ, the del-
2008). eterious effect of continuous free radical production by the
Damage to the irradiated tissue microenvironment can be microenvironment in that tissue must be ameliorated
decreased by treatment of that organ with agents that reduce (Oberley and Buettner 1979). Research efforts have focused
oxidative stress and production of free radicals (Greenber- on development of techniques by which to supply stable
ger 1991; Demedts et al. 2005; Naparstek et al. 1985; antioxidant delivery to cells of the irradiated microenvi-
Greenberger et al. 1988). The capacity of an irradiated tis- ronment to facilitate stem cell homing. At the present time,
sue to favorably support the migration, homing, and stable there still remain challenges for proof of the concept that
functioning of bone marrow-derived cells, arriving from the bone marrow-derived cells can reconstitute an epithelial
Bioengineering of Irradiated Normal Tissues by Bone Marrow Stem Cells 197

a b

Fig. 2 ROSA positive male donor bone marrow-derived squamous fixed in 10 % formalin, sectioned, and stained for LacZ expression
epithelium in MnSOD-PL treated irradiated esophagus of C57BL/ using goat anti-LacZ antibody followed by biotinylated labeled
6HNsd female mouse. LacZ expression in ROSA positive cells (brown antigoat antibody and ExtrAvidin-Peroxidase reagent (Sigma Chem-
color arrows). Female C57BL/6NHsd mice were administered ical Co., St. Louis, MO). Nuclei were stained with hematoxylin.
MnSOD-PL (100 lg plasmid DNA in 100 ll lipofectin) at the top a Esophagus section from an MnSOD-PL treated, irradiated control
of the esophagus and the mice were permitted to swallow. 24 h later mouse. b Section from a mouse receiving MnSOD-PL before
mice were irradiated to 27 Gy to the upper body. Five days later mice irradiation and injected ROSA bone marrow. LacZ positive foci of
were injected with 1 9 106 bone marrow cells from a ROSA (LacZ+) ROSA bone marrow (arrows) (b) (940)
male mouse. Mice were sacrificed 14 days later, esophagus removed,

organ. These challenges include the demonstration that 1977). Hematopoietic stem cells derived from long-term
functional cellular physiologic units within the recipient’s bone marrow culture were shown to have the properties of
irradiated tissue are derived from donor bone marrow cells. freshly derived stem cells from donor mice (Dexter et al.
Some representative challenges include: 1977). Hematopoietic reconstitution of lethally irradiated
1. Alveolar respiratory complexes in the lung must be mice by transplant of stem cells derived from long-term
shown to be of donor marrow cellular origin. bone marrow cultures that had been in vitro for months,
2. Functioning muscle bundles producing muscle contrac- demonstrated the capacity of an in vitro culture system to
tion and contributing to muscle strength must be shown contain persistent totipotential stem cells. Within the
to be associated with skeletal myocytes derived from hematopoietic niche of these marrow cultures ‘‘cobblestone
donor bone marrow origin cells. islands’’ were shown to contain quiescent cells that har-
3. Elements of glandular secretion/glandular buds and bored true stem cells (Greenberger 1978; Mauch et al. 1980;
production of donor bone marrow genotype-derived Sakakeeny and Greenberger 1982). The aging of continuous
secretary products must be shown to be derived from bone marrow cultures was associated with decline in the
bone marrow genotype specific cells. number of stem cells and production of committed hema-
These criteria have been met in few situations including topoietic progenitors (Sakakeeny and Greenberger 1982).
at present only the target recipient organs of liver and bone The long-term bone marrow culture system remains the
marrow itself (Wagers et al. 2002). only in vitro system for maintenance of true stem cells
outside the body for long durations (Sakakeeny and
Greenberger 1982).
5 Bone Marrow-Derived Mesenchymal Other organ explant systems have been shown to share
Stem Cells some properties of the long-term bone marrow culture
system (Kataoka et al. 2003; Kalabis et al. 2008; Engelhardt
Bone marrow fibroblasts were originally thought to be those et al. 1993). The success of the long-term bone marrow
cells supporting the homing and proliferation of hemato- culture system allowed focus on those cells of the micro-
poietic cells (Friedenstein et al. 1982). Continuous bone environment (nonhematopoietic) which were responsible
marrow cultures provided a system by which to study cells for stable quiescence of hematopoietic stem cells (Mauch
of the hematopoietic microenvironment and their interac- et al. 1980). Following explant to culture, long-term marrow
tion with hematopoietic stem cells in vitro (Dexter et al. cultures were shown to contain cells with endothelial
198 J. S. Greenberger and M. W. Epperly

markers, fibroblast markers, as well as macrophage markers induced lung damage such as that by bleomycin injury
(Sakakeeny and Greenberger 1982). The hematopoietic (Ortiz et al. 2003). Under one set of conditions, bone
microenvironment was thought to be composed of these marrow-derived cells can be involved in tissue repair and
three cell types (Dexter et al. 1977). Accumulation of potentially organ reconstitution, and under another set of
neutral fat/lipid in bone marrow stromal cell association of conditions a distinct mesenchymal stem cell subset can
lipid containing droplets in stromal cells near hematopoietic contribute to late fibrotic damage which limits organ
niches, suggested that the adipocyte was the critical he- recovery. The subtle dynamics of cell migration into an
mopoiesis supporting stromal cell (Greenberger 1978). irradiated microenvironment can be either beneficial or
Further information indicated that lipid accumulation was in deleterious depending on the cell population and the timing.
fact the toxic response of bone marrow to the high con-
centrations of fat and corticosteroid in horse serum used to
establish the cultures (Greenberger 1978). Cultures with
limited fat accumulation led to longer duration of hemato- 6 The Irradiated Tissue
poiesis (Sakakeeny and Greenberger 1982). This data was Microenvironment: Niche
consistent with the clinical observation that accumulation of or Vascular Space?
yellow fat occurs in bone marrow during aging, and the
fatty repopulation of the marrow microenvironment was It is clear that above a toxic threshold dose of irradiation
associated with hematopoietic failure (Sakakeeny and (which may differ between tissues and organs) spontaneous
Greenberger 1982). tissue reconstitution may not follow. The protection or
Ionizing irradiation effects on the hematopoietic micro- replacement by bone marrow cells of the irradiation dam-
environment were shown to be similar to those in natural aged tissue microenvironment after such a toxic dose may
aging (Zhou et al. 2008). Irradiated cells accumulated fat lead to improved tissue recovery. There is controversy as to
more quickly (Greenberger 1991), irradiated cells in culture whether the microenvironment for stem cells is in fact a
showed upregulation of p53 and p21, stress response ele- vascular space (Lombaert et al. 2008) or a specific cell type
ments also shown to be upregulated during aging of bone which functions as the niche (Anklesaria et al. 1989; Adams
marrow stromal cells (Zhou et al. 2008). Factors which et al. 2007; Zhang et al. 2003). There is further controversy
reversed fat accumulation and aging effects in bone marrow over whether the cells of the microenvironment as well as
stromal cells were shown to enhance hematopoiesis the stem cell population itself can be replaced by bone
(Lechpammer et al. 2005; Epperly et al. 2007). marrow.
There is evidence that the cells of bone marrow micro- Reconstitution of irradiated epithelial and nonepithelial
environment can be repopulated/replenished by cells of tissues is dependent upon a subtle interplay between
donor bone marrow origin (Anklesaria et al. 1989; Werts migratory beneficial cells (tissue reparative stem cells) and
et al. 1980). Replacement of the microenvironment was first deleterious late damage inducing cells (fibrosis inducing
demonstrated by Werts and Degowin (Werts et al. 1980) mesenchymal stem cells). One approach toward tipping the
and confirmed by Anklesaria et al. (1989) who showed that balance toward repair may be to limit oxidative stress
bone marrow stromal cells engrafted less effectively to high responses in the irradiated tissue microenvironment which
dose irradiated sites compared to low dose irradiated sites. change the makeup of cytokine production and release.
These cells were called bone marrow fibroblasts, but later Therefore, in addition to marrow-derived stem cell trans-
were shown to be those cells capable of multilineage dif- plant, local delivery of antioxidants by stimulation of the
ferentiation (Pittenger et al. 1999). in situ replenishment of antioxidant stores, by specific
Bone marrow stromal cells can engraft into a fracture/ antioxidant diets, or by direct perfusion with antioxidants
bone wound healing defect in vivo (Gokhale et al. 2010) may facilitate tissue repair. Research is ongoing and
and they are involved in regeneration/osteogenesis in irra- important to achieve the goal of replacing irradiation-
diation damage tissue. Higher irradiation doses limit the damaged tissue through donor stem cell transplantation.
capacity of migratory cells to be involved in bone healing
(Gokhale et al. 2010). Antioxidant administration facilitates
improved mesenchymal stem cell engraftment. However, References
serious negative effect of bone marrow stromal cell
engraftment is the role of these cells in late tissue irradiation Adams GB, Martin RP, Alley IR et al (2007) Therapeutic targeting of
a stem cell niche. Nat Biotechnol 25:238–242
damage. Bone marrow stromal cells have been shown to
Aird WC, Jahroudi N, Weiler-Guettler H, Rayburn HB, Rosenberg RD
contribute significantly to the fibrosis in irradiated lung (1995) Human von Willebrand factor gene sequences target
(Epperly et al. 2003). Bone marrow stromal cell involve- expression to a subpopulation of endothelial cells in transgenic
ment in fibrosis is also a factor in chemotherapeutic drug mice. Proc Natl Acad Sci U S A 92:4567
Bioengineering of Irradiated Normal Tissues by Bone Marrow Stem Cells 199

Albera C, Polak JM, Janes S, Griffiths MJD, Alison MR, Wright NA, Chen LB, Jiang XB, Yang L (2004) Differentiation of rat marrow
Navaratnarasah S, Poulsom R, Jeffrey R, Fisher C, Burke M, mesenchymal stem cells into pancreatic islet beta-cells. World J
Bishop AE (2005) Repopulation of human pulmonary epithelium Gastroenterol 10:3016–3020
by bone marrow cells: a potential means to promote repair. Tissue Cheng L-C, Pastrana E, Tavazoie M, Doetsch F (2009) miR-124
Eng 11:7–8 regulates adult neurogenesis in the subventricular zone stem cell
Anklesaria P, FitzGerald TJ, Kase K et al (1989) Improved hemato- niche. Nat Neurosci 12(4):399–405
poiesis in anemic S1/S1d mice by therapeutic transplantation of a Christopherson II KW, Hangoc G, Mantel CR, Broxmeyer HE (2004)
hematopoietic microenvironment. Blood 74:1144–1152 Modulation of hematopoietic stem cell homing and engraftment by
Ara T, Tokoyoda K, Sugiyama T, Egawa T, Kawabata K, Nagasawa T CD26. Science 305:1000–1004
(2003) Long-term hematopoietic stem cells require stromal cell- Davoust N, Vuaillat C, Cavillon G, Domenget C, Hatterer E, Bernard
derived factor-1 for colonizing bone marrow during ontogeny. A, Dumontel C, Jurdic P, Malcus C, Confavreux C, Belin MF,
Immunity 19:257–267 Nataf S (2006) Bone marrow CD34+/B220+ progenitors target the
Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM inflamed brain and display in vitro differentiation potential toward
through intermolecular autophosphorylation and dimer association. microglia. FASEB J 20:2081–2092
Nature 30(421):499–506 Demedts M, Behr J, Buhl R, Costabel U, Dekhuijzen R, Jansen HM,
Barberi T, Klivenyi P, Calingasan NY, Lee H, Kawamata H, Loonam MacNee W, Thomeer M, Wallaert B, Laurent F, Nicholson AG,
K, Perrier AL, Bruses J, Rubio ME, Topf N, Tabar V, Harrison NL, Verbeken EK, Verschakelen J, Flower CDR, Capron F, Petruzzelli
Beal MF, Moore MAS, Studer L (2003) Neural subtype specifi- S, DeVuyst P, van den Bosch JMM, Rodriguez-Becerra E,
cation of fertilization and nuclear transfer embryonic stem cells and Corvasce G, Lankhorst I, Sardina M, Montanari M (2005) High-
application in parkinsonian mice. Nat Biotechnol 21(10): dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med
1200–1210 353:2229–2242
Barnabe-Heider F, Frisen J (2008) Stem cells for spinal cord repair. Deng W, Han Q, Liao L, Li C, Ge W, Zhao Z, You Sheng, Deng H,
Cell Stem Cell 3:16–20 Murad F, Zhao RCH (2005) Engrafted bone marrow-derived Flk-
Boggs SS, Wilson SM, Smith WW (1973) Effects of endotoxin on 1+ mesenchymal stem cells regenerate skin tissue. Tissue Eng
hematopoiesis in irradiated and non-irradiated W/Wv mice. Rad 11:110–119
Res 56:481 Dexter TM, Allen TD, Lajtha LG (1977) Conditions controlling the
Boggs DR, Boggs SS, Ruscetti FW (1981) The W/Wv mouse as a proliferation of hematopoietic stem cells in vitro. J Cell Physiol
model system for the study of aplastic anemia. In: Levine AS (ed) 91:335–344
Proceedings of the conference on aplastic anemia: a stem cell Dickson GJ, Kwasniewska A, Mills KI, Lappin TRJ, Thompson A
disease, No. 81-1008. NIH Publication, San Francisco, p 197 (2009) Hoxa6 potentiates short-term hematopoietic cell prolifera-
Bompais H, Chagraoui J, Canron X, Crisan M, Liu XH, Anjo A, tion and extended self-renewal. Exp Hematol 37:322–333
Tolla-Le Port C, Leboeuf M, Charbord P, Bikfalvi A, Uzan G Dileto C, Travis EL (1996) Fibroblast radiosensitivity in vitro and lung
(2004) Human endothelial cells derived from circulating fibrosis in vivo: comparison between a fibrosis-prone and fibrosis-
progenitors display specific functional properties compared resistant mouse strain. Radiat Res 146:61–67
with mature vessel wall endothelial cells. Blood 103(7): Engelhardt JF (2001) Stem cell niches in the mouse airway. Am J
2577–2584 Respir Cell Mol Biol 24:649–652
Bonig H, Chudziak D, Priestley G, Papayannopoulou T (2009) Insights Engelhardt JF, Yang Y, Stratford-Perricaudet LD, Allen ED, Kozarsky
into the biology of mobilized hematopoietic stem/progenitor cells K, Perricaudet M, Yankaskas JR, Wilson JM (1993) Direct gene
through innovative treatment schedules of the CXCR4 antagonist transfer of human CFTR into human bronchial epithelia of
AMD3100. Exp Hematol 37:402–415 xenografts with E1-deleted adenoviruses. Nat Genet 4:27–34
Brazelton TR, Rossi FM, Keshet GI, Blau HM (2000) From marrow to Epperly MW, Sikora CA, Defilippi S, Gretton JE, Greenberger JS
brain: expression of neuronal phenotypes in adult mice. Science (2003) Bone marrow origin of myofibroblasts in irradiation
290:1775–1779 pulmonary fibrosis. Am J Resp Mol Cell Biol 29:213–224
Calvi LM, Adams GB, Weibrecht KW et al (2003) Osteoblastic cells Epperly MW, Osipov AN, Martin I, Kawai K, Borisenko GG,
regulate the haematopoietic stem cell niche. Nature 425:844–848 Jefferson M, Bernarding M, Greenberger JS, Kagan VE (2004a)
Cancelas JA, Lee AW, Prabhakar R et al (2005) GTPases differentially Ascorbate as a ‘‘redox-sensor’’ and protector against irradiation-
integrate signals regulating hematopoietic stem cell localization. induced oxidative stress in 32D cl 3 hematopoietic cells and
Nat Med 11:886–894 subclones overexpressing human manganese Superoxide Dismu-
Carlo-Stella C, Cesana C, Regazzi E et al (2000) Peripheral blood tase. Int J Radiat Oncol Biol Phys 58(3):851–861
progenitor cell mobilization in healthy donors receiving recombi- Epperly MW, Goff JP, Sikora CA, Shields DS, Greenberger JS (2004b)
nant human granulocyte colony-stimulating factor. Exp Hematol Bone marrow origin of cells with capacity for homing and
28:216–224 differentiation to esophageal squamous epithelium. Radiat Res
Carotta S, Pilat S, Mairhofer A, Schmidt U, Dolznig H, Steinlein P, 162:233–240
Beug H (2004) Directed differentiation and mass cultivation of Epperly MW, Cao S, Zhang X, Franicola D, Kanai AJ, Greenberger
pure erythroid progenitors from mouse embryonic stem cells. EE, Greenberger JS (2007) Increased longevity of hematopoiesis in
Blood 104:1873–1880 continuous bone marrow cultures derived from mtNOS-/-
Cerdan C, Rouleau A, Bhatia M (2004) VEGF-A165 augments homozygous recombinant negative mice correlates with increased
erythropoietic development form human embryonic stem cells. radioresistance of hematopoietic and bone marrow stromal cells.
Blood 103:2504–2510 Exp Hematol 35:137–145
Chadderton N, Millington-Ward S, Palfi A, O’Reilly M, Tuohy G, Erices A, Conget P, Minguell JJ (2000) Mesenchymal progenitor cells
Humphries MM, Li T, Humphries P, Kenna PF, Farrar GJ (2009) in human umbilical cord blood. Br J Haematol 109:235–242
Improved retinal function in a mouse model of dominant retinitis Franko AJ, Sharplin J (1994) Development of fibrosis after lung
pigmentosa following AAV-delivered gene therapy. Mol Ther irradiation in relation to inflammation and lung function in a mouse
17(4):593–599 strain prone to fibrosis. Radiat Res 140:347–355
200 J. S. Greenberger and M. W. Epperly

Friedenstein AJ, Lat-Zink NW, Grosheva AG, Gorskaya VF (1982) Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW,
Microenvironment transfer by heterotopic transplantation of freshly Entman ML, Michael LH, Hirschi KK, Goodell MA (2001)
cultured cells in porous sponges. Exp Hematol 10:217–227 Regeneration of ischemic cardiac muscle and vascular endothelium
Giangreco A, Arwert EN, Rosewell IR, Snyder J, Watt FM, Stripp BR by adult stem cells. J Clin Invest 107:1395–1402
(2009) Stem cells are dispensable for lung homeostasis but restore Jahroudi N, Ardekani AM, Greenberger JS (1996) Ionizing irradiation
airways after injury. PNAS 106(23):9286–9291 increases transcription of the von Willebrand factor gene in
Gokhale AS, Epperly M, Glowacki J, Wang H, Wipf P, Pierce JG, endothelial cells. Blood 88:3801–3814
Dixon T, Patrene K, Greenberger JS (2010) Small molecule GS- Jiang J, Kurnikov I, Belikova NA, Xiao J, Zhao Q, Vlasova IL,
nitroxide ameliorate ionizing irradiation-induced delay in bone Amoscato AA, Braslau R, Studer A, Fink MP, Greenberger JS,
wound healing in a novel murine model. In vivo 24:377–384 Wipf Pe, Kagan VE (2007) Structural requirements for optimized
Goolsby J, Marty MC, Heletz D, Chiappelli J, Tashko G, Yarnell D, delivery, inhibition of oxidative stress an anti-apoptotic activity of
Fishman PS, Dhib-Jalbut S, Bever CT, Pessac B, Trisler D (2003) targeted nitroxides. J Pharmacol Exp Ther 320(5):1050–1060
Hematopoietic progenitors express neural genes. PNAS 100: Jones DL, Wagers J (2008) No place like home: anatomy and function
14926–14931 of the stem cell niche. Mol Cell Biol 9:11–20
Greenberger JS (1978) Sensitivity of corticosteroid-dependent, insulin- Kagan VE, Bayir A, Bayir H, Stoyanovsky D, Borisenko GG,
resistant lipogenesis in marrow preadipocytes of mutation diabetic- Tyurina YY, Wipf P, Atkinson J, Greenberger JS, Chapkin RS,
obese mice. Nature 275:752–754 Belikova NA (2009) Mitochondria-targeted disruptors and inhib-
Greenberger JS (1991) Toxic effects on the hematopoietic microen- itors of cytochrome c/cardiolipin peroxidase complexes: a new
vironment. Exp Hematol 19:1101–1109 strategy in anti-apoptotic drug discovery. Mol Nutr Food Res
Greenberger JS, Epperly MW (2007) Antioxidant therapeutic 53:104–114
approaches toward amelioration of the pulmonary pathophysiolog- Kalabis J, Oyama K, Okawa T, Nakagawa H, Michaylira CZ, Stairs
ical damaging effects of ionizing irradiation. Curr Respir Med Rev DB, Figueiredo J-L, Mahmood U, Diehl JA, Rustgi AK (2008) A
3:29–37 subpopulation of mouse esophageal basal cells has properties of
Greenberger JS, Epperly MW (2009) Bioengineering in the repair of stem cells with the capacity for self-renewal and lineage specifi-
irradiated normal tissue by bone marrow derived stem cell cation. J Clin Invest 118:3860–3868
populations. Semi Radiat Oncol (19(2):133–139 Kaminski A, Pohl CB, Sponholz C, Ma N, Stamm C, Vollmar B,
Greenberger JS, FitzGerald TJ, Kleason V, Anklesaria P, Bushnell D, Steinhoff G (2004) Up-regulation of endothelial nitric oxide
Kase K, Sakakeeny MA (1988) Alteration in hematopoietic stem synthase inhibits pulmonary leukocyte migration following lung
cell seeding and proliferation by low-dose-rate irradiation of bone ischemia-reperfusion in mice. Am J Pathol 164(6):2241–2249
marrow stromal cells in vitro. Int J Radiat Oncol Biol Phys Kamishina H, Cheeseman JA, Clemmons RM (2008) Nestin-positive
14:85–94 spheres derived from canine bone marrow stromal cells generate
Gronthos S, Graves SE, Ohta S, Simmons PJ (1994) The STRO-1+ cells with early neuronal and glial phenotypic characteristics. In
fraction of adult human bone marrow contains the osteogenic Vitro Cell Dev Biol Animal 44:140–144
precursors. Blood 84:4164–4173 Kataoka K, Medina RJ, Kageyama T, Miyazaki M, Yoshino T,
Gussoni E, Soneoka Y, Strickland CD et al (1999) Dystrophin Makino T, Huh Nam-ho (2003) Participation of adult mouse bone
expression in the mdx mouse restored by stem cell transplantation. marrow cells in reconstitution of skin. Am J Pathol 163(4):
Nature 401:390–394 1227–1231
Habich A, Jurga M, Markiewicz I, Lukomska B, Bany-Laszewicz U, Kiel MJ, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst C, Morrison SJ
Domanska-Janik K (2006) Early appearance of stem/progenitor (2005) SLAM family receptors distinguish hematopoietic stem and
cells with neural-like characteristics in human cord blood mono- progenitor cells and reveal endothelial niches for stem cells. Cell
nuclear fraction cultured in vitro. Exp Hematol 34:914–925 121:1109–1121
Hall EJ (ed) (1988) Radiobiology for the radiobiologist, 3rd edn. JB Kim HK, De La Luz Sierra M, Williams CK, Gulino AV, Tosato G
Lippincott Company, Philadelphia (2006) G-CSF down-regulation of CXCR4 expression identified as
Hazen AL, Smith MJ, Desponts C, Winter O, Moser K, Kerr WG a mechanism for mobilization of myeloid cells. Blood
(2009) SHIP is required for a functional hematopoietic stem cell 108:812–820
niche. Blood 113:2924–2930 Korbling M, Katz RL, Khanna A, Ruifrok AC, Rondon G, Albitar M,
Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR, Champlin RE, Estrov Z (2002) Hepatocytes and epithelial cells of
Crystal RG, Besmer P, Lyden D, Moore MAS, Werb Z, Rafii S donor origin in recipients of peripheral-blood stem cells. N Engl J
(2002) Recruitment of stem and progenitor cells from the bone Med 346:738–746
marrow niche requires MMP-9 mediated release of Kit-Ligand. Krause D, Theise N, Collector M et al (2001) Multi-organ, multi-
Cell 109:625–637 lineage engraftment by a single bone marrow-derived stem cell.
Hirschi KK, Goodell MA (2002) Hematopoietic, vascular, and cardiac Cell 105:369–377
fates of bone marrow-derived stem cells. Gene Ther 9:648–652 Kyung UH, Reynolds SD, Watkins S, Fuchs E, Stripp BR (2004) Basal
Ibanez IL, Bracalente C, Molinari BL, Palmieri MA, Policastro L, cells are a multipotent progenitor capable of renewing the
Kreiner AJ, Burlon AA, Valda A, Navalesi D, Davidson J, bronchial epithelium. Am J Pathol 164:577–588
Davidson M, Vazquez M, Ozafran M, Duran H (2009) Induction Lagasse E, Shizuru JA, Uchida N, Tsukamoto A, Weissman IL (2001)
and rejoining of DNA double strand breaks assessed by H2AX Toward regenerative medicine. Immun 14:425–436
phosphorylation in melanoma cells irradiated with proton and Lamba BA, Karl MO, Ware CB, Reh TA (2006) Efficient generation
lithium beams. Int J Radiat Oncol Biol Phys 74:1226–1235 of retinal progenitor cells from human embryonic stem cells. PNAS
Ishikawa F, Yasukawa M, Yoshida S, Nakamura KI, Nagatoshi Y, 103:12769–12774
Kanemaru T, Shimoda K, Shimoda S, Miyamoto T, Okamura J, Lanza RP, Atala A (eds) (2002) Methods of tissue engineering.
Shultz LD, Harada M (2004) Human cord blood- and bone Academic Press, New York
marrow-derived CD34+ cells regenerate gastrointestinal epithelial Leask A, Abraham DJ (2004) TGF-B signaling and the fibrotic
cells. FASEBJ 18:1958–1960 response. FASEB J 18:816–827
Bioengineering of Irradiated Normal Tissues by Bone Marrow Stem Cells 201

Lechpammer S, Epperly MW, Zhou S, Nie S, Glowacki J, Greenberger endothelial progenitor cell significance in angiogenic growth
JS (2005) Antioxidant pool regulated adipocyte differentiation factor-induced neovascularization in vivo. Exp Hematol
Sod2-/- bone marrow stromal cells. Exp Hematol 33:1201–1208 30:967–972
Lei Ye, Haider HKA, Sim EKW (2006) Adult stem cells for cardiac Naparstek E, Donnelly T, Kase K, Greenberger JS (1985) Biologic
repair: a choice between skeletal myoblasts and bone marrow stem effects of in vitro x-irradiation of murine long-term bone marrow
cells. Exp Biol Med 231:8–19 cultures on the production of granulocyte-macrophage colony
Li H, Liu H, Heller S (2003) Pluripotent stem cells from the adult stimulating factors. Exp Hematol 13:701–708
mouse inner ear. Nat Med 9(10):1293–1299 Niu Y, Epperly MW, Shen H, Smith T, Lewis D, Gollin S,
Li W, Ferguson BJ, Khaled WT, Tevendale M, Stingl J, Poli V, Rich Greenberger JS (2008) Intraesophageal MnSOD-plasmid liposome
T, Salomoni P, Watson CJ (2009) DML depletion disrupts normal administration enhances engraftment and self-renewal capacity of
mammary gland development and skews the composition of the bone marrow derived progenitors of esophageal squamous epithe-
mammary luminal cell progenitor pool. PNAS 106:4725–4730 lium. Gene Therapy 15:347–356
Lim DA, Huang Y-C, Swigut T, Mirick AL, Garcia-Verdugo JM, Novakova-Jiresova A, van Gameren MM, Coppes RP, Kampinga HH,
Wysocka J, Ernst P, Alvarez-Bo (2009) Chromatin remodeling Groen HJM (2004) Transforming growth factor-B plasma dynam-
factor Mll1 is essential for neurogenesis from postnatal neural stem ics and post-irradiation lung injury in lung cancer patients.
cells. Nature 458:529–336 Radiother Oncol 71:183–189
Lin W, Chen X, Wang X, Liu J, Gu X (2008) Adult rat bone marrow Oberley LW, Buettner GR (1979) Role of superoxide dismutase in
stromal cells differentiate into Schwann cell-like cells in vitro. In cancer: a review. Cancer Res 39:1141–1149
Vitro Cell Dev Biol Animal 44:31–40 Ogle BM, Cascalho M, Platt JL (2005) Biological implications of cell
Link CJ, Orren D, Muldoon R, Cook JA, Bohr VA (1996) Pentox- fusion. Mol Cell Biol 6:567
ifylline inhibits gene-specific repair of UV-induced DNA damage Ohtaki H, Ylostalo JH, Foraker JE, Robinson AP, Reger RL, Shioda S,
in hamster cells. Rad Onc Invest 4:115–121 Prockop DJ (2008) Stem/progenitor cells from bone marrow
Lombaert IMA, Brunsting JF, Wierenga PK, Kampinga HH, de Haan decrease neuronal death in global ischemia by modulation of
G, Coppes RP (2008) Cytokine treatment improves parenchymal inflammatory/immune responses. PNAS 105:14638–14643
and vascular damage of salivary glands after irradiation. Clin Olive PL, Banath JP (2004) Phosphorylation of histone H2AX as a
Cancer Res 14(23):7741–7748 measure of radiosensitivity. Int J Radiat Oncol Biol Phys
Lue Y, Erkkila K, Liu PY, Ma K, Wang C, Hikim AS, Swerdloff RS 58:331–335
(2007) Fate of bone marrow stem cells transplanted into the testis: Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N,
potential implication for men with testicular failure. Am J Pathol, Phinney DG (2003) Mesenchymal stem cell engraftment in lung is
170(3):899–908 enhanced in response to bleomycin exposure and ameliorates its
Matsuzaki Y, Kinjo K, Mulligan RC et al (2004) Unexpectedly fibrotic effects. PNAS 100(14):8407–8411
efficient homing capacity of purified murine hematopoietic stem Park HC, Shim YS, Ha Y, Yoon SH, Park SR, Choi BH, Park HS
cells. Immunity 20:87–93 (2005) Treatment of complete spinal cord injury patients by
Mauch P, Greenberger JS, Botnick LE, Hannon EC, Hellman S (1980) autologous bone marrow cell transplantation and administration of
Evidence for structured variation in self-renewal capacity within granulocyte-macrophage colony stimulating factor. Tissue Eng
long-term bone marrow cultures. PNAS 77:2927–2930 11:913–922
McCulloch EA, Till JE (1962) The sensitivity of cells from normal Parmar K, Mauch P, Vergilio Jo-A, Sackstein R, Down JD (2007)
mouse bone marrow to gamma radiation in vitro and in vivo. Distribution of hematopoietic stem cells in the bone marrow
Radiat Res 16:822–832 according to regional hypoxia. PNAS 104:5431–5436
Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR (2000) Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Boggs
Turning blood into brain: cells bearing neuronal antigens generated SS, Greenberger JS, Goff JP (1999) Bone marrow as a potential
in vivo from bone marrow. Science 290:1779–1783 source of hepatic oval cells. Science 284:1168–1170
Miyahara Y, Nagaya N, Kataoka M, Yanagawa B, Tanaka K, Hao H, Pittenger MF, Mackay AM, Beck SC et al (1999) Multilineage
Ishino K, Ishida H, Shimizu T, Kangawa K, Sano S, Okano T, potential of adult human mesenchymal stem cells. Science
Kitamura S, Mori H (2006) Monolayered mesenchymal stem cells 284:143–147
repair scarred myocardium after myocardial infarction. Nat Med Prise KM, O’Sullivan JM (2009) Radiation-induced bystander signal-
12(4):459–468 ing in cancer therapy. Nat Rev Cancer 9:351–365
Montini E, Cesana D, Schmidt M, Sanvito F, Bartholomae CC, Prockop DJ (1997) Marrow stromal cells as stem cells for nonhemat-
Ranzani M, Benedicenti F, Sergi LS, Ambrosi A, Ponzoni M, opoietic tissues. Science 276:71
Doglioni C, Di SC, von Kalle C, Naldini L (2009) The genotoxic Proksch S, Bel A, Puymirat E, Pidial L, Bellamy V, Peyrard S,
potential of retroviral vectors is strongly modulated by vector Larghero J, Augereau-Vacher B, Menasche P (2009) Does the
design and integration site selection in a mouse model of HSC gene human skeletal muscle harbor the murine equivalents of cardiac
therapy. J Clin Invest 110:964–975 precursor cells? Mol Ther 17(4):733–741
Mookerjee I, Hewitson TD, Halls ML, Summers RJ, Mathai ML, Quesenberry PJ, Colvin G, Abedi M (2005) Perspective fundamental
Bathgate RAD, Tregear GW, Samuel CS (2009) Relaxin inhibits and clinical concepts on stem cell homing and engraftment: a
renal myofibroblast differentiation via RXFP1, the nitric oxide journey to niches and beyond. Exp Hematol 33:9–19
pathway and Smad2. FASEBJ 23:1219–1229 Reynolds SD, Giangreco A, Hong KU, McGrath KE, Ortiz LA, Stripp
Mothersill C, Seymour CB (2004) Radiation-induced bystander BR (2004) Airway injury in lung disease pathophysiology:
effects-implications for cancer. Nat Rev Cancer 4:158–164 selective depletion of airway stem and progenitor cell pools
Munoz JR, Stoutenger BR, Robinson AP, Spees JL, Prockop DJ (2005) potentiates lung inflammation and alveolar dysfunction. Am J
Human stem/progenitor cells from bone marrow promote neuro- Physiol Lung Cell Mol Physiol 287:L1256–L1265
genesis of endogenous neural stem cells in the hippocampus of Rice A, Barbot C, Lacombe F, Dubosc-Marchenay N, Marit G, Hau F,
mice. PNAS 102:18171–18176 Boiron JM, Reiffers J (1993) 5-fluorouracil permits access to a
Murayama T, Tepper OM, Silver M, Ma H, Losordo DW, Isner JM, primitive subpopulation of peripheral blood stem cells. Stem Cells
Asahara T, Kalka C (2002) Determination of bone marrow-derived 11:326–335
202 J. S. Greenberger and M. W. Epperly

Roy V, Verfaillie CM (1999) Expression and function of cell adhesion hematopoietic stem/progenitor cells. J Clin Invest 119(4):
molecules on fetal liver, cord blood and bone marrow hematopoi- 1008–1018
etic progenitors: implications for anatomical localization and Torres P, Maria E, Parfitt David E, Kouzarides T, Zernicka-Goetz M
developmental stage specific regulation of hematopoiesis. Exp (2007) Histone arginine methylation regulates pluripotency in the
Hematol 27:302–312 early mouse embryo. Nature 445:214–220
Rubin P, Cassarett GW (1968) Clinical radiation pathology, vol 1. WB Tsao GJ, Allen JA, Logronio KA, Lazzeroni LC, Shizuru JA (2009)
Saunders, Philadelphia Purified hematopoietic stem cell allografts reconstitute immunity
Sakai E, Kitajima K, Sato A, Nakano T (2009) Increase of superior to bone marrow. PNAS 106:3288–3293
hematopoietic progenitor and suppression of endothelial gene Tyurin VA, Tyurina YY, Kochanek PM, Hamilton R, DeKosky ST,
expression by Runx1 expression during in vitro ES differentiation. Greenberger JS, Bayir H, Kagan VE (2008) Oxidative lipidomics
Exp Hematol 37:334–345 of programmed cell death. Methods Enzymol 442:375–393
Sakakeeny MA, Greenberger JS (1982) Granulopoiesis longevity in Tyurina YY, Tyurin VA, Epperly MW, Greenberger JS, Kagan VE
continuous bone marrow cultures and factor dependent cell line (2008) Oxidative lipidomics of c-irradiation induced intestinal
generation: significant variation among 28 inbred mouse strains injury. Free Radic Biol Med 44:299–314
and outbred stocks. J Nat Cancer Inst 68:305–317 Unwin RD, Smith DL, Blinco D, Wilson CL, Miller CJ, Evans CA,
Sasportas LS, Kasmieh R, Wakimoto H, Hingtgen S, van de Water Jaworska E, Baldwin SA, Barnes K, Pierce Andrew, Spooncer
Jeroen AJM, Mohapatra G, Figueiredo JL, Martuza RL, Weissleder Elaine, Whetton Anthony D (2006) Quantitative proteomics
R, Shah K (2009) Assessment of therapeutic efficacy and fate of reveals posttranslational control as a regulatory factor in primary
engineered human mesenchymal stem cells for cancer therapy. hematopoietic stem cells. Blood 107:4687–4693
Proc Natl Acad Sci U S A 106(12):4822–4827 van der Kogel AJ, Sissingh HA, Zoetelief J (1982) Effect of x-rays and
Schmitz N, Linch DC, Dreger P et al (1996) Randomized trial of neutrons on repair and regeneration in the rat spinal cord. Int J
filgrastim-mobilized peripheral blood progenitor cell transplanta- Radiat Oncol Biol Phys 8:2095–2097
tion versus autologous bone-marrow transplantation in lymphoma van Hennik PB, de Koning AE, Ploemacher RE (1999) Seeding
patients. Lancet 347:353–357 efficiency of primitive human hematopoietic cells in nonobese
Semerad CL, Christopher MJ, Liu F et al (2005) G-CSF potently diabetic/severe combined immune deficiency mice: implications
inhibits osteoblast activity and CXCL12 mRNA expression in the for stem cell frequency assessment. Blood 94(9):3055–3061
bone marrow. Blood 106:3020–3027 van Rongen E, Thames HD, Travis EL (1993) Recovery from radiation
Shimonaka M, Katagiri K, Nakayama T, Fujita N, Tsuruo T, Yoshie O, damage in mouse lung: Interpretations in terms of two rates of
Kinashi T (2003) Rap1 translates chemokine signals to integrin repair. Radiat Res 133:225–233
activation, cell polarization, and motility across vascular endothe- Wagers AJ, Christensen JL, Weissman IL (2002) Cell fate determi-
lium under flow. J Cell Biol 161(2):417–427 nation from stem cells. Gene Ther 9:606–612
Sigurjonsson OE, Perreault MC, Egeland T, Glover JC (2005) Adult Werts ED, Gibson DP, Knapp SA et al (1980) Bone marrow fibroblasts
human hematopoietic stem cells produce neurons efficiently in the circulate to replace damaged marrow sites. Radiat Res 81:20–30
regenerating chicken embryo spinal cord. PNAS 102:5227–5232 Woodward WA, Chen MS, Behbod F, Alfaro MP, Buchholz TA,
Simard AR, Rivest S (2004) Bone marrow stem cells have the ability Rosen JM (2007) WNT/b-catenin mediates radiation resistance of
to populate the entire central nervous system into fully differen- mouse mammary progenitor cells. PNAS 104:618–623
tiated parenchymal microglia. FASEB J 18:998–1000 Wright DE, Wagers AJ, Gulati AP, Johnson FL, Weissman IL (2001)
Spyridonidis A, Schmitt-Graff A, Tomann T, Dwenger A, Follo M, Physiological migration of hematopoietic stem and progenitor
Behringer D, Finke J (2004) Epithelial tissue chimerism after cells. Science 294:1933–1936
human hematopoietic cell transplantation is a real phenomenon. Hess D, Li L, Martin M, Sakano S, Hill D, Strutt B, Thyssen S, Gray
Am J Pathol 164:1147–1155 DA, Bhatia M (2003) Bone marrow-derived stem cells initiate
Stripp BR, Reynolds SD (2005) Bioengineered lung epithelium: pancreatic regeneration. Nat Biotechnol 21:763–770
implications for basic and applied studies in lung tissue regener- Yoon Y, Wecker A, Heyd L, Park J, Tkebuchava T, Kusano K, Hanley
ation. Am J Respir Cell Mol Biol 32:85–86 A, Scadova H, Qin G, Cha D, Johnson KL, Aikawa R, Asahara T,
Switzer GE, Goycoolea JM, Dew MA, Graeff EC, Hegland J (2001) Losordo DW (2005) Clonally expanded novel multipotent stem
Donating stimulated peripheral blood stem cells vs. bone marrow: cells from human bone marrow regenerate myocardium after
do donors experience the procedures differently? Bone Marrow myocardial infarction. J Clin Invest 115:326–338
Transplant 27:917–923 Young PP, Vaughan DE, Hatzopoulos AK (2007) Biologic properties
Takakura N, Watanabe T, Suenobu S, Yamada Y, Noda T, Ito Y, of endothelial progenitor cells and their potential for cell therapy.
Satake M, Suda T (2000) A role for hematopoietic stem cells in Prog Cardiovasc Dis 49:421–429
promoting angiogenesis. Cell 102:199–209 Yoyooka Y, Tsunekawa N, Akasu R, Noce T (2003) Embryonic stem
Terskikh AV, Miyamoto T, Chang C, Diatchenko L, Weissman IL cells can form germ cells in vitro. PNAS 100:11457–11462
(2003) Gene expression analysis of purified hematopoietic stem Zaibak F, Kozlovski J, Vadolas J, Sarsero JP, Williamson R, Howden
cells and committed progenitors. Blood 102:94–102 SE (2009) Integration of functional bacterial artificial chromo-
Theise ND, Badve S, Saxena R, Henegariu O, Sell S, Crawford JM, somes into human cord blood-derived multipotent stem cells. Gene
Krause DS (2000) Derivation of hepatocytes from bone marrow Ther 16:404–414
cells in mice after radiation-induced myeloablation. Hepatology Zeng F, Chen M, Baldwin DA, Gong Z, Yan J, Qian H, Wang J, Jiang
31:235–240 X, Ren Z, Sun Deming, Huang S (2006) Multiorgan engraftment
Till JE, McCulloch EA (1961) Developmental aspects of the cell and differentiation of human cord blood CD34+ Lin- cells in goats
cycle, vol 971. Academic Press, New York, pp 297–313 assessed by gene expression profiling. PNAS 103:7801–7806
Tjwa M, Sidenius N, Moura R, Jansen S, Theunissen K, Andolfo A, Zhang J, Niu C, Ye L et al (2003) Identification of the haematopoietic
DeMol M, Dewerchin M, Moons L, Blasi F, Verfailie C, Carmeliet stem cell niche and control of the niche size. Nature 425:836–841
P (2009) Membrane-anchored uPAR regulates the proliferation, Zhou S, Yates KE, Eid K, Glowacki J (2005) Demineralized bone
marrow pool size, engraftment, and mobilization of mouse promotes chondrocyte or osteoblast differentiation of human
Bioengineering of Irradiated Normal Tissues by Bone Marrow Stem Cells 203

marrow stromal cells cultured in collagen sponges. Cell Tissue marrow-derived mesenchymal stem cells and their differentiation
Banking 6:33–44 to osteoblasts. Aging Cell 7:335–343
Zhou S, Greenberger JS, Epperly MW, Goff JP, Adler C, LeBoff MS, Zipori D (2004) The nature of stem cells: state rather than entity. Nat
Glowacki J (2008) Age-related intrinsic changes in human bone Rev 5:873–883
 Radiotherapy-Induced Carcinogenesis
and Leukemogenesis: Mechanisms
and Quantitative Modeling
David J. Brenner, Igor Shuryak, and Rainer K. Sachs

Contents Abstract
Biologically-based modeling of spontaneous and radia-
1 Introduction.......................................................................... 206 tion-induced carcinogenesis has a history spanning sev-
2 Short-Term Biologically Based Models ............................ 206 eral decades. Such models are important conceptual and
2.1 The Linear Quadratic Exponential Model............................ 207 quantitative tools, particularly useful whenever cancer
2.2 Semi-Empirical Models with Cell Proliferation................... 208 risks must be estimated under exposure situations for
2.3 Initiation, Inactivation, and Proliferation Models ................ 209
which no data yet exist, e.g., for novel and prospective
3 Long-Term Biologically Based Models ............................. 210 radiotherapy protocols. Direct extrapolation from existing
3.1 Multistage Models Without Clonal Expansion .................... 210 data is often not possible due to complex differences
3.2 Two-Stage Models with Clonal Expansion .......................... 211
3.3 Multistage Models with Genomic Instability ....................... 213 between the data sets, but quantitative models can
3.4 Old Age Effects..................................................................... 214 accommodate such extrapolation. Many carcinogenesis
3.5 Some Generalizations ............................................................ 215 models can be characterized as short-term, in that they
4 Integration of Short-Term and Long-Term Models ....... 217 focus on those processes occurring during and shortly
4.1 An Example of Short-Term and Long-Term Model after irradiation. The main advantage of this class of
Unification ............................................................................. 217 models is that they provide a detailed initial dose response
4.2 Model Comparisons............................................................... 219
for short-term endpoints which are used as surrogates for
5 Radiation-Induced Leukemia ............................................. 220 carcinogenesis. The main disadvantage is that the possibly
6 Conclusions ........................................................................... 222 substantial modulations of the magnitude and shape of this
initial dose response during the lengthy period between
References...................................................................................... 223
irradiation and manifestation of typical solid tumors are
not considered. In contrast with the short-term models,
another class of biologically-motivated models can be
characterized as long-term, in the sense that they track
carcinogenesis mechanisms throughout the entire human
life span. The main advantages of long-term models are:
(1) modulation of the radiation dose response during the
long latency period between exposure and diagnosis of
cancer is included; and (2) extensive data on spontaneous
cancers can be used to help determine the adjustable
parameters needed to estimate cancer risks. The main
disadvantage is that the early radiation response is
typically treated in a less-mechanistic manner than in
D. J. Brenner (&)
I. Shuryak the short-term models. Here we review some short- and
Center for Radiological Research, long-term model examples and the carcinogenesis mech-
Columbia University Medical Center,
New York, NY, USA anisms which they incorporate. We also discuss an
e-mail: [email protected] example of unification of both model classes, focusing
R. K. Sachs on application of such formalisms for quantifying radio-
Departments of Mathematics and Physics, therapy-induced second cancer risks.
University of California, Berkeley, CA, USA

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 205
DOI: 10.1007/978-3-540-72314-1_14, Ó Springer-Verlag Berlin Heidelberg 2014
206 D. J. Brenner et al.

1 Introduction protocols, can address this problem by predicting risks of

current (and prospective) treatment regimens.
Ionizing radiation is a well-known cytotoxic and carcino- A systematic review of the epidemiological data on sec-
genic agent. As such, it is effective as a treatment for cancer, ond cancers has been given in the chapter titled
but can also induce secondary malignancies (Curtis et al. ‘‘Understanding and Predicting Radiation-Associated
2006) (see also the chapter titled ‘‘Understanding and Normal Tissue Injury: A Global and Historical Perspective
Predicting Radiation-Associated Normal Tissue Injury: A ’’. Here, we discuss some biologically based models of
Global and Historical Perspective’’). As more patients spontaneous and radiation-induced carcinogenesis in the
undergo cancer radiotherapy, and live longer after treatment, literature, and analyze their potential for predicting second
the number of cancer survivors has tripled over the past three cancers due to modern treatment protocols. Most of the dis-
decades and continues to increase, reaching [10 million cussion focuses on solid tumors. Leukemias, which can be
(Curtis et al. 2006; Anonymous 2004). The lifetime risk of substantially different from solid tumors in terms of latency
radiation-induced second cancers in these individuals is not period and dose–response relationships, are treated sepa-
negligible (Brenner et al. 2007), and these second cancers can rately. We also discuss an example of a potentially useful
result in high mortality and morbidity—for example, breast approach for improving biologically based second cancer
cancer radiotherapy can cause lung cancer, and lung cancer modeling by unifying some current model concepts to pro-
has a poor prognosis. Consequently, second malignancies duce a formalism which includes both short- and long-term
induced by radiotherapy are becoming a growing concern mechanisms important for radiation carcinogenesis.
(Brenner et al. 2000; Ron 2006). This is the case particularly
for patients irradiated in childhood, who have a long life
expectancy during which second cancers can develop, and in 2 Short-Term Biologically Based Models
whom the relative risk of some radiogenic second cancers is
on the order of 10–100 (Ron 2006; Ronckers et al. 2006; Biologically motivated mathematical modeling of sponta-
Neglia et al. 2006). neous and ionizing radiation-induced carcinogenesis has a
It has recently become clearer (Lindsay et al. 2001; Sachs history spanning more than 50 years (Nordling 1953;
and Brenner 2005) that even at high radiation doses—tens of Armitage and Doll 1954). Many biologically based models
Gy—radiation-induced cancer risk remains substantial, pre- can be characterized as short-term, in that they focus on those
sumably due to cellular repopulation, instead of dropping processes occurring during and shortly (i.e., about 1 month
essentially to zero due to cell inactivation (killing), as was or less) after irradiation (Sachs and Brenner 2005; Nilsson
previously thought by many radiobiologists (Bennett et al. et al. 1990; Thames 1985; Dale 1986; Sontag 1997; Lange
2004; Dasu et al. 2005). Thus, tissues surrounding the tumor, et al. 1997; Zaider and Wuu 1995; Stewart 2001; Curtis 1986;
which unavoidably receive doses not much smaller than the Tobias 1985; Radivoyevitch et al. 2001; Hahnfeldt and
prescribed treatment dose, may be a source of much of the Hlatky 1996, 1998; Mebust et al. 2002; Schollnberger et al.
second cancer risk attributable to radiotherapy (Hodgson 2002; Hofmann et al. 2006; Sachs et al. 2007; Shuryak et al.
et al. 2007; Koh et al. 2007). The remaining portion of the 2006; Little 2007; Schneider and Kaser-Hotz 2005;
radiation-induced risk is derived from large volumes of tis- Schneider and Walsh 2008). These models typically analyze
sues more distant from the treatment target, which receive the induction of short-term endpoints which are used as
lower radiation doses. An example of the estimated relative surrogates for carcinogenesis, such as mutations or
contributions of high- and low-dose regions to overall chromosome aberrations (Radivoyevitch et al. 2001;
radiogenic cancer risk is shown in Fig. 1. Ottolenghi et al. 1999). Different short-term models analyze
A reasonable approach to minimizing radiation-induced DNA damage induction and DNA repair/misrepair (Nilsson
second cancers would be to compare radiotherapy protocols et al. 1990; Sontag 1997; Stewart 2001; Curtis 1986; Tobias
of equal efficacy against the primary tumor, and identify the 1985). Short-term models take into account a variety of
ones with the lowest second cancer risk. However, because phenomena such as dose rate effects (Thames 1985; Rossi
the latency period for radiation-induced solid tumors is long and Kellerer 1986; Brenner et al. 1996), induction and/or
(Curtis et al. 2006; Brenner et al. 2000; BEIR VII Report saturation of particular repair pathways (Schollnberger et al.
2005; Ivanov et al. 2004), the carcinogenic effects of 2002), and alterations of the cell cycle distribution during/
radiotherapy have been directly measured only for regimens after irradiation (Zaider and Wuu 1995; Hahnfeldt and
used several decades ago. The risks which may be associ- Hlatky 1996, 1998). Many short-term models are motivated
ated with newer treatment methods are for the most part not toward radiation-induced cancer risk estimation at low
yet observable. Biologically motivated mathematical/com- radiation doses (Bennett et al. 2004), but some have also been
putational models, calibrated using data from older adapted to predict radiotherapy-induced second cancers
Radiotherapy-Induced Carcinogenesis and Leukemogenesis 207

a b

ERR contribution / unit dose

Volume exposed to given dose

0 10 20 30 40 0 10 20 30 40

Dose (Gy) Dose (Gy)

Fig. 1 Estimation of radiation-induced second-cancer risks based on intervals within the irradiated breast to the overall excess relative risk
a dose-volume histogram (DVH). The DVH (a) is for the left breast of (ERR), assuming the dose–response relationship for the ERR is
a female treated for breast cancer by radiotherapy; the doses are in approximately linear in dose
0.5 cGy intervals. b The estimated contribution of different dose

(Dasu et al. 2005; Dale 1986; Schneider and Kaser-Hotz 2.1 The Linear Quadratic Exponential Model
2005; Schneider and Walsh 2008). The common feature of
these short-term models is that the long-term processes The assumption that radiation-induced carcinogenesis is
involved in carcinogenesis, which are dominant before primarily governed by a balance of cell mutation (also
radiation exposure and in the long latency period after initial commonly referred to as initiation) and cell killing (often
tissue recovery from radiation damage, are typically treated referred to as inactivation) has been used for many years
indirectly, nonmechanistically, or not at all. Often a (Gray 1957). It has generally been quantified by use of the
proportional hazards assumption is used to justify taking the so called linear-quadratic-exponential (LQE) equation. This
shape of the cancer incidence dose–response curve as being equation uses the classic linear-quadratic form both for
the same, apart from an overall scaling factor, as the shape radiation induced initiation (i.e., a D ? b D2, where D is
of the dose–response curve for some short-term surrogate radiation dose and a and b are adjustable parameters) and
endpoint (BEIR VII Report 2005; Upton 2003; NCRP Report for radiation-induced inactivation (exp[- a D - b D2],
136 2001). where a and b are adjustable parameters). It has been
The main advantage of this class of models is that they applied to data from Japanese atomic bomb survivors
provide a detailed initial dose response for short-term end- (Bennett et al. 2004), and to radiotherapy-treated cancer
points which are used as surrogates for carcinogenesis. The patients (Dasu et al. 2005).
main disadvantage is that the possibly substantial modula- At very low doses (1 Gy), the quadratic terms for both
tions of the magnitude and shape of this initial dose response initiation and inactivation in the LQE equation are negli-
during the lengthy period (multiple years-decades in gible, given realistic parameter values. The dose response
humans) between irradiation and manifestation of typical is, therefore, effectively linear. This qualitatively agrees
solid tumors are not considered; a simple proportional haz- with the linear-no-threshold (LNT) approach generally used
ards assumption, plausible at low doses, becomes question- for radiation protection estimates at low doses (BEIR VII
able at the high doses responsible for some second cancers. Report 2005; NCRP Report 136 2001). At intermediate
Among the great variety of mathematical formalisms radiation doses (i.e., up to a few Gy), the equation predicts
which can be classified as short-term radiation carcino- that the radiogenic cancer risk is an increasing function of
genesis models, we here focus on those models designed dose. This is because at such doses the risk is dominated by
specifically for analyzing radiotherapy-induced second initiation, and inactivation has a limited effect since the
cancers. majority of cells can survive the exposure. At high doses
208 D. J. Brenner et al.

100

Excess absolute risk × 10-4 person-years

12
80
Predicted risk (%)

60
8

40

4
20

0 0
0 5 10 15
0 4 8 12 16 20
Dose (Gy)
Dose (Gy)
Fig. 3 Predicted cancer incidence as a function of organ absorbed
Fig. 2 Typical dose responses for radiogenic cancer risk predicted by dose of the atomic bomb survivors (squares). Shown are the fits to the
the LQE model involving competition between cell mutation and combined dataset of A-bomb survivor data and Hodgkin’s patients
killing for single radiation doses (SD) and fractionated doses (FX), using a linear-exponential model (solid line) and a plateau-dose model
using the same parameters. A strictly linear dose response that neglects (dashed line). The data and fits are presented for a neutron RBE of 10.
cell killing is shown for comparison. The figure is reproduced from The figure and caption are reproduced from Schneider and Walsh
Dasu et al. (2005) (2008)

(e.g. 5 Gy), however, the exponential inactivation term exponentially decreasing term can be interpreted as the
leads to a very small predicted radiogenic risk, because combination of cell inactivation and proliferation, along
essentially all radiation-initiated cells would be inactivated with possible other contributing factors. At low doses,
by the radiation. These model behaviors are illustrated the predicted risk grows approximately linearly. At
graphically in Fig. 2, for both single and for fractionated higher doses it turns over, and tends to zero at very high
radiation doses. doses.
(2) A phenomenological plateau-dose model, which
assumes that the dose response grows linearly at low
2.2 Semi-Empirical Models with Cell doses and saturates at high doses by asymptotically
Proliferation approaching a plateau. The plateau can be interpreted as
a balance of inactivation and proliferation, which tend
The LQE model often underestimates the risks of high to equilibrium by cancelling each other. The main dif-
radiation doses (Sachs and Brenner 2005), presumably ference from the linear-exponential model is that this
because it describes only the processes of cell initiation and formalism predicts a substantial radiogenic cancer risk
inactivation. A biologically plausible explanation for the even at very large doses.
persistence of large risks at high fractionated doses deliv- One or other of these alternative models can potentially
ered during cancer radiotherapy is that cell proliferation be applied to any dose distribution if the dose-volume his-
during the time intervals between dose fractions and shortly togram is available. They can also be used to calculate
after treatment stops negates much of the effect of cell the organ equivalent dose (OED), which is defined as the
inactivation. The recent models by Schneider and Kaser- integral of the dose-volume distribution weighted by the
Hotz (2005), Schneider and Walsh (2008) address this issue predicted cancer risk (Schneider and Kaser-Hotz 2005;
by providing a semi-empirical or phenomenological treat- Schneider and Walsh 2008). For a strictly linear dose
ment of cell proliferation (and possibly other relevant fac- response, OED is proportional to mean dose. For inhomo-
tors that alter the dose response at high doses) by means of geneous dose distributions, it may differ considerably from
the following alternative assumptions: the mean dose. Best fits of the two model versions to data
(1) A linear-exponential model, which assumes that the on atomic bomb survivors and patients treated with radio-
dose response consists of a linearly increasing term and therapy for Hodgkin’s disease are shown in Fig. 3. This
an exponentially decreasing term. The linearly approach describes the atomic bomb survivor and second
increasing term can be interpreted as a combination of cancer data adequately and is potentially useful for addi-
all the factors leading to cell initiation, and the tional second cancer risk estimation.
Radiotherapy-Induced Carcinogenesis and Leukemogenesis 209

2.3 Initiation, Inactivation, and Proliferation remains high even at doses [10 Gy. The latter situation is
Models supported by some recent epidemiological data on radio-
therapy-induced second cancers (Travis, the chapter titled ‘‘
In contrast to phenomenological models, the so called ini- Understanding and Predicting Radiation-Associated Normal
tiation, inactivation, and proliferation (iip) models (Lindsay Tissue Injury: A Global and Historical Perspective’’ this
et al. 2001; Sachs and Brenner 2005; Sachs et al. 2007; volume, and Curtis et al. 2006; Sachs and Brenner 2005;
Shuryak et al. 2006; Little 2007; Wheldon et al. 2000) Travis et al. 2002, 2003). Therefore, modeling cell prolifer-
involve a relatively detailed mechanistic treatment of the ation of normal and initiated cells appears to be an important
three short-term processes that give the models their name component of reasonably predicting the risks of second
throughout the course of a typical high-dose (tens of Gy) malignancies caused by radiotherapy for existing tumors.
fractionated radiotherapy regimen, and during a subsequent The iip modeling approach for solid tumors was further
tissue recovery period of a number of weeks. refined by Sachs and Brenner (2005). Here a typical frac-
The model developed by Wheldon and Lindsay (Lindsay tionated dosing radiotherapy regimen was modeled, and the
et al. 2001; Wheldon et al. 2000) is based on familiar two- iip processes were tracked in detail throughout the radio-
stage concepts: Normal stem cells can be mutated to a pre- therapy and subsequent tissue recovery periods. In partic-
malignant (initiated) state, either spontaneously or by ular, cell proliferation of both normal and pre-malignant
radiation. These once-mutated cells can, with a certain cells was calculated in the time gaps between dose frac-
probability, acquire the second mutation, which makes them tions, as well as during a recovery period after radiotherapy
fully malignant. In addition to elevating the initiation rate, ends. Eventual risk of cancer was assumed to be propor-
radiation can inactivate (kill, i.e., reproductively sterilize) tional to the number of pre-malignant (initiated) cells
both normal and initiated cells. present after radiotherapy and recovery, by the time when
A key concept in the model involves compensatory homeostatic organ repopulation has been completed. The
proliferation of both normal and initiated cells after some of relevant proportionality constants were estimated by using
these cells have been inactivated by radiation. This process data on atomic bomb survivors. The main adjustable
is assumed to occur in response to intercellular signals, parameter in the model was the relative proliferation rate of
restoring the homeostatically controlled total number of initiated cells compared with normal ones, there called
stem cells in the organ which existed before irradiation. r. The model was fitted to epidemiological data on lung and
Partial or complete impairment of the homeostatic mecha- breast cancers in patients irradiated for Hodgkin’s disease.
nism by radiation is allowed in the model: Under complete The fits were adequate, as shown in Fig. 5.
impairment, no proliferation occurs after cell killing, and The fits shown in Fig. 5 were produced using the relative
under no impairment surviving cells repopulate to exactly proliferation rate of initiated cells compared with normal
the same number, as was present before exposure. Inter- ones of r B 1, e.g., r = 0.8. If r was [1, the model gen-
mediate scenarios are easily accommodated. The prolifer- erated cancer excess relative risk (ERR) curves that increase
ation rate of initiated cells relative to normal ones is also faster than linearly with radiation dose, which was contrary
treated as an adjustable parameter. They can proliferate as to the data. This means that the model successfully
fast as, faster than or slower than normal cells. The model is describes the data only if initiated cells have a growth
mainly deterministic, but an approximation for stochastic disadvantage during the tissue recovery period, rather than
extinction of all initiated cells after high doses of radiation an advantage, which contrasts with the more commonly
is made. If all initiated cells in the organ are killed, then made assumption of clonal expansion. One explanation
only normal cells participate in repopulation. could be that the growth disadvantage occurs only on the
Typical radiation dose responses generated by the Whel- relatively short-term time scale of a few weeks-months
don-Lindsay model are shown in Fig. 4. The figure demon- during and after radiotherapy, for example because some
strates the following important consequence of detailed initiated cells could be selectively eliminated during inter-
modeling of cell proliferation in addition to initiation and actions with surrounding normal cells. On the long-term
inactivation: If compensatory cell proliferation is not time scale of multiple years on the pathway towards cancer,
accounted for, cell inactivation by radiation begins to over- this disadvantage could disappear and a small growth
power cell initiation at relatively low radiation doses of a few advantage for initiated cells could emerge.
Gy. At higher doses (e.g., 10 Gy), predicted radiogenic An alternative explanation is that the slope of the cancer
cancer incidence would therefore quickly decline. However, ERR dose–response relationship is reduced at high doses by
cell proliferation stimulated by homeostatic mechanisms can stochastic effects, i.e. due to stochastic extinction of a
compensate for much of the cell killing. So when prolifera- substantial proportion of initiated cells during radiotherapy.
tion is taken into account, radiogenic cancer incidence This possibility was explored in a stochastic extension of
210 D. J. Brenner et al.

1.0 a 20 b
16
Incidence (%)

0.8

12
0.6

0.4 8

0.2 4

4 8 12 16 20 4 8 12 16 20

Dose (Gy) Dose (Gy)

Fig. 4 The percentage incidence of carcinogenesis 20 years after irradiation is illustrated for a no cell repopulation and b full cell repopulation
to 108 cells, using the Wheldon-Lindsay model. The figure and caption are reproduced from Wheldon et al. (2000)

the deterministic iip model (Sachs et al. 2007). Indeed, it carcinogenesis is usually treated as just a perturbation of
was found that, with realistic parameter values, stochastic background carcinogenesis, so that extensive data on
effects due to cell killing during radiotherapy could be spontaneous cancers can be used to help determine the
substantial. The variance of the number of live initiated adjustable parameters needed to estimate cancer risks. The
cells after the multifraction radiotherapy protocol was typ- main disadvantage is that the early radiation response is
ically much larger than the mean, and the probability that typically treated in a less-mechanistic, more phenomeno-
the simulated organ contains zero such cells after repopu- logical, manner than in the short-term models, and similarly
lation has run its course was quite high. This stochastic for the dose-rate response. This disadvantage can be par-
model allowed the epidemiological second cancer data to be tially alleviated by suitable semi-mechanistic assumptions
fitted well even if a growth advantage for initiated cells was about the short-term aspects of the dose response, e.g., the
present during the recovery period (i.e., r [ 1). It showed effects of cell repopulation which partially compensates for
that reducing the overall radiotherapy treatment time, e.g., cell killing by radiation (Heidenreich and Hoogenveen
by treating on weekends, can reduce the second cancer risk 2001), cell–cell interactions which can accelerate the pro-
by increasing the probability of stochastic extinction of pre- liferation of pre-malignant cells causing radiogenic pro-
malignant clones. motion, etc. Some examples of long-term models that are
relevant or potentially relevant to second-cancer estimation
are discussed below.
3 Long-Term Biologically Based Models

By contrast with the short-term models described so far, 3.1 Multistage Models Without Clonal
another class of biologically motivated quantitative models Expansion
can be characterized as long-term, in the sense that they
track carcinogenesis mechanisms throughout the entire This class includes the earliest of the commonly used
human or animal life span, e.g., the Armitage-Doll model mathematical models of carcinogenesis—the pioneering
(Armitage and Doll 1954; Armitage 1985), the Moolgavkar- models of Nordling (1953) and Armitage and Doll (1954).
Venzon-Knudson two-stage clonal expansion (TSCE) They are based on the concept that cancer originates from
model (Moolgavkar 1980; Moolgavkar 1978; Moolgavkar an ancestral target somatic cell, whose lineage has accu-
and Knudson 1981), the two-stage logistic (TSL) model mulated several relevant alterations (i.e., changes that are
(Sachs et al. 2005), and many others (Little and Li 2007; passed on to daughter cells). In current applications of these
Little and Wright 2003; Pierce and Mendelsohn 1999; models, the target cells are usually thought of as organ-
Pierce and Vaeth 2003; Ritter et al. 2003; Yakovlev and specific stem cells; the relevant alterations are thought to be
Polig 1996). The main advantages of long-term models are: mutations occurring in oncogenes and tumor suppressor
(1) including the modulation of the radiation dose response genes, though chromosome rearrangements such as bal-
during the long latency period between radiation exposure anced translocations or inversions, copy number changes, or
and diagnosis of cancer; and (2), the fact that radiation epigenetic changes are also sometimes discussed. Once a
Radiotherapy-Induced Carcinogenesis and Leukemogenesis 211

Lung cancer excess relative risk 15

Hodgkins data
Repopulation model
Simplified model

10

5
Fig. 6 A schematic representation of the assumptions for the
Armitage-Doll model. The various mutations in the stem cell lineage
produce pre-malignant changes. The last (black) mutation produces a
0 fully malignant cell, which can grow into a tumor (grey mass)
0 10 20 30 40
Dose to tumor location (Gy) 1986), referring to the fact that the age-specific incidence of
these cancers can be described by a power function of age.
The number of mutations needed for full malignancy is
Hodgkins data usually considered an adjustable parameter in the Nordling
Repopulation model
Breast cancer excess relative risk

Simplified model and Armitage-Doll models. Fitting the models to sponta-

40 neous cancer incidence data suggests that this number is on
the order of 5–6 for many solid tumors. This estimate agrees
with experimental evidence in some cases (Tahara 2004;
Tamura 2006; Midorikawa et al. 2007; Feitelson et al. 2004;
Bockmuhl and Petersen 2002; Trosko 2006; Michor et al.
20
2004, 2005).
Variants of the Armitage-Doll model intended for pre-
diction of radiation-induced cancer risk have been applied
to data sets such as the Japanese atomic bomb survivors
0 (Pierce and Mendelsohn 1999; Pierce and Vaeth 2003). The
0 10 20 30 40
main finding is that the effect of relatively low acute radi-
Dose to tumor location (Gy)
ation doses, such as those experienced by survivors of the
Fig. 5 Measured and predicted excess relative risks for lung cancer Hiroshima and Nagasaki bombings, can be approximated
and female breast cancer induced by high doses of ionizing radiation, based on the assumption that radiation effectively ‘‘accel-
using the Sachs-Brenner iip model (solid curves). The data points are erates’’ normal aging. In other words, a given dose of
from studies of second cancers after radiotherapy of Hodgkin’s disease
patients. The dashed lines are the predictions of the simplified radiation is roughly equivalent to a certain amount of time
repopulation model based on the slope at low doses derived from the with spontaneous mutation rates (Fig. 7). The excess cancer
excess relative risks of the atomic bomb survivors. The figure and risk is described solely as a function of age and radiation
caption are reproduced from Sachs and Brenner (2005) dose, and variables such as age at exposure and time since
exposure are not individually important. After irradiation,
cell has accumulated all the necessary mutations, it the ERR decreases approximately as the reciprocal of age.
becomes fully malignant, and can subsequently (after some These conclusions are reasonably well supported by atomic
lag period) develop into a clinical cancer. A pictorial rep- bomb survivor data.
resentation of these models is provided in Fig. 6.
Given realistic parameter values, the two models
numerically behave very similarly over most of the human 3.2 Two-Stage Models with Clonal Expansion
lifetime: they predict that cancer incidence should be
approximated by a power function of age, where the power The models in this class are based on the broad paradigm of
is equal to the number of necessary mutations minus one. initiation, promotion, transformation, and progression in
When both age and predicted cancer incidence are plotted carcinogenesis, which has been applied to numerous studies
on a logarithmic scale, an approximately straight line is of chemically induced and radiation-induced tumors in
produced. These models fit the spontaneous age-dependent experimental animals. They are also sometimes motivated
cancer incidence data for many adult-onset solid tumors by the concept of ‘‘two-hit’’ recessive oncogenesis, devel-
reasonably well, particularly in the age range of 20–70. This oped by Knudson to describe the data on sporadic and
observation led to the term ‘‘log–log cancers’’ (Moolgavkar inherited forms of human retinoblastoma (Knudson 1971).
212 D. J. Brenner et al.

10 2
deterministic

Cases per person-year

10 0
β= 0, q =μ

10 -2 -5
q = 10
-4
q = 10
10 -4

10 -6

0 20 40 60 80
Age (years)

Fig. 9 The spontaneous cancer hazard function as function of age

predicted by the TSCE model with various parameter values, from
Heidenreich and Hoogenveen (2001). The deterministic version refers
Fig. 7 Male and female age-specific cancer rates on transformed age
to the simplified case where clonal expansion is modeled determin-
scales, using the Pierce-Mendelsohn model (a derivative of the
istically, rather than stochastically, i.e., using only a net expansion rate
Armitage-Doll model), for the four dose categories of 0, 0.005, 0.5,
instead of individual birth and death rates
and 1 Sv. The data are for non-sex-specific solid tumors in atomic
bomb survivors. The four upper curves are for males, with age scale
age ? 4.1 dose, and lower curves are for females with age scale cells and transformation that makes malignant cells) on the
age ? 6.4 dose. The figure and caption are reproduced from Pierce pathway to cancer. It focuses on tracking over time the
and Vaeth (2003)
number of once-mutated, initiated, pre-malignant cells.
Usually this is done stochastically, i.e. an initiated cell can
proliferate or die/differentiate or transform with certain
probabilities per unit time. The clonal expansion rate is
Normal stem cell
approximately the difference between the birth and death
Malignancy probabilities. Incidence of malignant cells is proportional to
Clonal expansion the number of initiated cells. A malignant cell gives rise to
Fig. 8 A representation of the TSCE model, adapted from Luebeck
clinical cancer after a lag period, which is sometimes
and Hazelton (2002), Curtis et al. (2006). l0 and l1 are rate constants assumed to be constant (e.g., 10 years).
for initiation or transformation, respectively The TSCE model has been fitted to numerous data sets
on spontaneous and carcinogen-induced tumors in animals
The most widely used representative of this class is the and humans (Heidenreich et al. 1999, 2002, 2007; He-
TSCE model (Moolgavkar 1978, 1980). It assumes that a idenreich and Paretzke 2001). Spontaneous cancer inci-
stem cell which has acquired a single relevant mutation has dence in humans over the age range of 20–70 is typically
a slight growth or survival advantage relative to normal described very well, marginally better than by the previ-
cells (e.g., can proliferate at a faster rate and/or is more ously discussed multistage models without clonal expan-
resistant to apoptotic signals). Over time, the growth sion, although the small differences in quality of fit are
advantage leads to clonal expansion of the mutated pre- typically not statistically significant. The mechanistic
malignant cell. When any cell within the clone acquires a implications are, however, different: In the models without
second oncogenic mutation, it becomes a fully malignant clonal expansion, the ‘‘slope’’ of the spontaneous age-
cell, which can grow into a clinical cancer. Acquisition of dependent cancer incidence curve is determined by the
the first mutation, leading from a normal to a pre-malignant number of stages (mutations) on the pathway toward cancer.
cell, is called initiation. Clonal expansion of the pre- In the TSCE model, it is determined mainly by the net
malignant cells is called promotion. Acquisition of the clonal expansion rate of initiated cells (i.e., by the differ-
second mutation, leading from a pre-malignant to a malig- ence between proliferation and death/differentiation rates
nant cell, is called transformation. Exogenous agents such for these cells). The typical cancer hazard function pre-
as chemicals or ionizing radiation can affect these three dicted by the TSCE model is shown in Fig. 9.
processes, e.g., by initiating more normal cells and/or The TSCE model has also been applied to radiogenic
accelerating clonal expansion of the mutant ones. The cancer risks in atomic bomb survivors, and many other
general TSCE model assumptions are shown in Fig. 8. radiation-related data sets. The fits have generally been good.
As its name implies, the TSCE model therefore considers The mechanistic interpretations of the observed patterns are,
only two stages (i.e. initiation that makes pre-malignant as for the spontaneous tumors, different from those using
Radiotherapy-Induced Carcinogenesis and Leukemogenesis 213

Armitage-Doll-type models: The radiogenic risk depends on accelerates the acquisition of mutations relevant for carci-
age at exposure and time since exposure, and also on the nogenesis, such as activation of oncogenes and loss of
degree to which radiation affects initiation versus promotion. tumor suppressor genes. However, it remains unclear at
If radiation affects predominantly (or exclusively) the initi- what point, i.e., early or late, genomic instability usually
ation step, as is sometimes assumed, ERR decreases with age appears during cancer development (Michor et al. 2003a, b;
at exposure. If it affects predominantly promotion (i.e. Nishimura et al. 2000; Finley et al. 2006). If it appears
accelerates the clonal expansion of already initiated cells), early, in the form of the so-called ‘‘mutator phenotype’’, it
ERR is much less dependent on age at exposure. Predomi- may be a very important driving force for carcinogenesis
nance of initiation modulation is often inferred from analysis because it accelerates subsequent mutation rates. If it
of atomic bomb survivors, although the possible role of appears late, by the time most of the mutational steps
promotion by low-LET photon radiation has recently drawn toward cancer have already occurred, it is probably less
more attention (Heidenreich et al. 2007). Predominance of important, although destabilization of the genome even at a
promotion modulation is usually inferred from analysis of late stage may affect properties of the tumor such as resis-
long-term exposure to high-LET radiation, e.g., radon- tance to therapy and acquisition of metastatic potential.
exposed underground miners (Curtis et al. 2001). Many recent models of spontaneous carcinogenesis
The TSCE model explicitly addresses clonal expansion (Michor et al. 2004, 2005) focus on genomic instability. It
of pre-malignant cells, which has been observed or pre- has also been included in models of radiation-induced
sumed in many organs, e.g., colon (Leedham and Wright cancers (Little and Li 2007; Little and Wright 2003; Ohtaki
2008; Leedham et al. 2005; McDonald et al. 2006), liver and Niwa 2001). Typically, in such models genomic
(Kohle 2008; Rusyn et al. 2006), skin (Brash 2006; Brash instability is added to a multistage framework that essen-
et al. 2005), esophagus (Maley 2007; Maley and Reid tially represents an extension of the concepts used in both
2005), bladder (Spiess and Czerniak 2006), and others the stochastic TSCE model and the Armitage-Doll model.
(Perez-Ordonez et al. 2006), supporting the general con- The number of stages is an adjustable parameter, as for the
clusion that hyperplasia is a common property of pre- Armitage-Doll model. The cells in each stage, however, can
malignant cells. The ability of certain nongenotoxic sub- clonally expand by a stochastic process of births and deaths,
stances (promoters) to produce cancers by inducing prolif- as in the TSCE model. At some point, genomic instability
eration of already initiated cells also supports an important can be acquired, presumably by a random mutation in some
role for clonal expansion during carcinogenesis (Kohle genome-guardian gene(s) (e.g., genes responsible for DNA
2008; Shaw and Jones 1994; Yamasaki 1992). repair, cell cycle checkpoints, etc.). Once this occurs, the
The TSCE model does not consider the possibly important unstable cell clone can proceed more quickly to subsequent
effects of limitations of clonal expansion, e.g., due to tissue stages leading to malignancy.
architecture (Michor et al. 2004; Leedham and Wright 2008; Because they include several phenomena, i.e., multiple
Leedham et al. 2005; Michor et al. 2003a; Calabrese et al. mutational stages, clonal expansion, and genomic instabil-
2004; Komarova and Cheng 2006; Bennett et al. 2003; Potten ity, such models are very flexible and can involve a very
and Booth 2002; Slack 2000) and diffusion-based size large number of potentially adjustable parameters (e.g.,
restrictions for pre-angiogenic tumors (Almog et al. 2006; number of stages, mutation, and clonal expansion rates for
Brem et al. 1977; Thomlinson and Gray 1955; Naumov et al. each stage with or without genomic instability). Conse-
2006; Hlatky et al. 1996). A recent TSL model (Sachs et al. quently, it is not surprising that they can adequately fit the
2005) attempts to include these factors. data on age-dependent spontaneous cancer incidence.
However, the quality of fit is usually no better than (or
sometimes marginally worse than) that for simpler models
3.3 Multistage Models with Genomic such as the TSCE model (Little and Li 2007). This occurs in
Instability part because the simpler models already fit the data very
well, so further improvement will always be marginal and
It is well known that cells in many tumors are genomically may not reach statistical significance. This phenomenon is
unstable. There are different types of genomic instability, illustrated in Fig. 10. A more detailed discussion of some
such as chromosomal instability (CIN), which leads to loss conclusions that can be drawn from comparing the fits of
or duplication of large pieces of chromosomes, and different models to spontaneous cancer incidence curves is
microsatellite instability (MIN), which leads to accumula- presented below, in Sect. 4.
tion of more subtle DNA sequence changes. In either case, Some inference about the potential role of genomic
mutation rates throughout the genome can be elevated by instability in radiation-induced cancers can be made using
several orders of magnitude above the normal values (No- available data. One consequence of genomic instability is
wak et al. 2002, 2006). Presumably, this phenotype greatly the prediction that cancer ERR should increase with time
214 D. J. Brenner et al.

Males Females

Annual incidence rate (×10 -5 )

Observed + 95% CI
2-stage 1-destabilization
3-stage 1-destabilization
5-stage 2-destabilization
Nowak et al (2002)
Luebeck and Moolgavkar (2002)

Age (years)

Fig. 10 Spontaneous colon cancer hazards predicted by models of destabilizing mutation, three cancer-stage mutations and one destabi-
Nowak et al. (2002) (with two cancer-stage mutations and one lizing mutation, five cancer-stage mutations and two destabilizing
destabilizing mutation), of Luebeck and Moolgavkar (2002) (with four mutations), with stem cell population fixed to 108 cells, fitted to SEER
cancer-stage mutations and no destabilizing mutations), and of Little colon cancer data. The figure and caption are reproduced from Little
and Wright (2003) (with two cancer-stage mutations and one and Li (2007)

since exposure because the mutation rate(s) would remain The reasons for these old age phenomena are not fully
elevated. This intuitive conclusion is supported by mathe- understood. For cancers of hormonally sensitive organs,
matical results (Little and Wright 2003). The data from such as the female breast, a decrease in incidence at old age
atomic bomb survivors generally do not support this: in the may be due to large changes in hormonal status: e.g., clonal
long run ERR for most cancers remains constant or expansion of pre-malignant cells may slow down and many
decreases with time since exposure. A plausible interpre- clones may become extinct when estrogenic stimulation is
tation is that low-LET radiation may not induce genomic reduced. For cancers where population incidence is domi-
instability that persists long enough to substantially affect nated by some exogenous risk factor, such as smoking in
cancer incidence. This does not mean that genomic insta- male lung cancer, cohort effects of different exposure to this
bility is unimportant in spontaneous incidence of the cancer factor may complicate true age effects: For example, indi-
in question—for example, instability could be already viduals who are now in the oldest age groups may have, on
present before irradiation, and the exposure would have no average, smoked less during their lifetime than individuals
substantial impact on this phenomenon. Also, an increase of in somewhat younger cohorts, producing an apparently
ERR with time since exposure is suggested by some second lower cancer incidence at older ages. Variations in spon-
cancer data sets, e.g., for colon cancer in radiotherapy- taneous carcinogenesis rates between individuals can also
treated cervical cancer patients (Chaturvedi et al. 2007). be important: If some individuals are more susceptible to
Such findings may support the alternative interpretation that getting cancer, e.g. because of some subtle defects in anti-
radiation-induced genomic instability may be important for neoplastic cell signaling or DNA repair capacity, they will
carcinogenesis, at least for some tumor types. get cancer at an earlier age. The oldest age groups will be
depleted of these individuals, and enriched for those with
lower cancer susceptibility (Fig. 11).
3.4 Old Age Effects
There may also be true physiological reasons for a
turnover in cancer incidence at old age. A likely mechanism
As mentioned above, the incidence of typical adult-onset
is senescence of stem cells and/or deterioration of stem cell
solid tumors rises quite steeply with age in the age range of
function, or niche function, with age (Brunet and Rando
20–70. At older ages, however, the increase in incidence
2007; Carlson and Conboy 2007; Sharpless and DePinho
slows down and, for some cancers (e.g., breast, lung), is
2007). The number of viable normal stem cells may not
apparently reversed—incidence decreases for ages[80 (e.g.
necessarily decrease at old age, but their ability to prolif-
SEER database, http://seer.cancer.gov). Similar trends are
erate may become impaired due to senescence of the stem
seen in some animal cancer data sets (Pompei et al. 2001).
Radiotherapy-Induced Carcinogenesis and Leukemogenesis 215

this model to spontaneous cancer data sets are shown in

C = 1.0 Fig. 13.
C = 0.1
An important qualitative implication of the Pompei-
C = 0.05
Incidence (×10-5, log scale)
Wilson model is that lifetime cancer incidence is predicted
to be less than unity, i.e., cancer is not a certainty even in
the absence of competing risks.

3.5 Some Generalizations

C = 0.01 To summarize, the main biological concepts represented in

current long-term models, often with different emphases, are:
(1) Solid tumor carcinogenesis involves accumulation of
several—two or more—mutational/epigenetic events in
target, e.g., stem, cells. To become fully malignant, a
cell must contain all the critical mutations, not neces-
Age (years, log scale)
sarily in one order.
Fig. 11 Predicted cancer incidence trends with age using a model of (2) Some mutations may cause the cell to become ge-
heterogeneous cancer susceptibility by Cook et al. (1969), reproduced nomically unstable, thereby making future mutations
from Ritter et al. (2003). The variable C represents the fraction of more likely.
cancer-susceptible individuals
(3) Cells that have undergone at least one mutational event,
which are often called ‘‘initiated’’ or ‘‘pre-malignant’’
cells themselves and/or loss of function of surrounding stem cells, may have some net proliferative/survival advan-
cell niche-forming cells (Fig. 12). Similar mechanisms may tage over their normal counterparts, e.g., they are more
apply to some extent to mutated pre-malignant stem cells as resistant to apoptotic signals and/or less dependent on
well, leading to reduced carcinogenesis rates at old age. growth factors. Consequently, these pre-malignant cells
The old age effects on cancer incidence are handled and can undergo clonal expansion over time. All cells in a
explained differently in the context of the commonly used clone contain the same mutations as the clone’s foun-
carcinogenesis models described above. For example, the der, so as the number of cells in the clone grows, the
Armitage-Doll model with realistic parameters predicts that clone becomes an ever larger target for accumulation of
cancer incidence should continue to increase roughly as a additional mutations on the pathway to full malignancy.
power of age for ages beyond 80 years. The TSCE and TSL Available data on spontaneous carcinogenesis, though
models predict an asymptotic flattening of the incidence very extensive, are generally not sufficient to statistically
hazard function at old age. This prediction is somewhat at reject any of the competing long-term models, because
odds with the data mentioned before, which suggest a different mechanisms can predict similar realistic cancer
decrease in cancer incidence at very old ages. Such data are incidence functions, i.e., a rapid increase in incidence with
becoming progressively more difficult to ignore, because as increasing age over a wide range of ages (Little and Li
more people survive to older ages, the incidence statistics 2007; Heidenreich et al. 2002; Kopp-Schneider and Portier
for ages beyond 80 are becoming more accurate and more 1991). For example, fits of comparable quality are gener-
difficult to explain by poor diagnosis and incomplete ated by:
adjustment for competing risks. (1) Models with multiple mutational stages ([2), but
The mathematical structure of 2-stage and multistage without genomic instability or clonal expansion (Nor-
cancer models discussed so far precludes them from pre- dling 1953; Armitage and Doll 1954; Armitage 1985).
dicting a decrease in cancer incidence at old ages (reviewed (2) Models with fewer stages (e.g., 2), with genomic
by Ritter et al. 2003). A new model which explicitly instability, with or without clonal expansion (Little and
addresses this issue was developed by Pompei and Wilson Li 2007; Little and Wright 2003; Ohtaki and Niwa
(Pompei et al. 2001; Pompei and Wilson 2002; Harding et al. 2001; Meza et al. 2008).
2008). The model assumes that carcinogenesis proceeds (3) Models with only 2 stages, with or without genomic
according to Armitage-Doll multistage principles throughout instability, but with clonal expansion (Moolgavkar
most of the life span of an individual. At old ages, it is 1978, 1980, 1983; Moolgavkar and Knudson 1981;
modified by a ‘‘cancer extinction’’ term, where the proba- Sachs et al. 2005).
bility of nonextinction is described by the term 1 - b t, These different approaches produce numerically similar
where t is age and b is an adjustable parameter. Some fits of fits to spontaneous cancer incidence data because different
216 D. J. Brenner et al.

Fig. 12 A schematic Stem cell Progenitors Effectors

representation of stem cell/stem
cell niche aging, from Sharpless
and DePinho (2007)

Young

Physiological ageing, mutagen

exposure or forced regeneration

Old

mutational stages, clonal expansion, and genomic instability

approximately compensate for one another—if one or two
3000
of these mechanisms are absent from a model, a reasonable
fit to the data can still be produced by increasing the role of
Incidence rate ( Χ 10^ -5)

the remaining mechanism(s).

Modeling approaches also differ in the interpretation of
2000
old age effects on carcinogenesis rates. For example, in the
Armitage-Doll model and its derivatives, the flattening or
decrease of cancer incidence at old ages is explained solely
1000
by population heterogeneity and other exogenous factors
(e.g. poor cancer diagnosis at old age). In other words, the
old age effects are assumed not to occur in individuals, but
0 result from population-level phenomena. In the TSCE and
0 10 20 30 40 50 60 70 80 90 100 110
TSL models, these effects are explained by the stochastics
Age (years)
of clonal expansion or by physiological constraints on the
Fig. 13 Fits of the Pompei-Wilson model to the sum of all cancers for number of pre-malignant cells in an organ, respectively.
males (green) and females (red) using data from the SEER database. Finally, some models (e.g., the Pompei-Wilson model)
The curves in the figure are reproduced from Harding et al. (2008) assume that cancer risks are explicitly affected by the age of
the individual.
mechanisms can have approximately compensatory effects This situation shows that current understanding of the
for one another. For example, increasing the number of complex processes involved in carcinogenesis is quite
necessary mutational stages and increasing the clonal limited. Experimental or epidemiological data which could
expansion rate of mutant cells during some or all of these help to elucidate the relative contributions of various pro-
stages both have a roughly similar consequence—the pre- cesses such as clonal expansion and genomic instability are
dicted age-dependent cancer incidence curve becomes often limited as well. Therefore, the various models are
steeper. Increasing the mutation rate leading from a given usually applied to spontaneous or carcinogen-induced can-
stage to the next, e.g. by invoking genomic instability, has a cer incidence data, which represent only the ultimate net
roughly similar numerical effect to increasing the clonal result of these processes. Although such data may not have
expansion rate during this stage—i.e. the transition rate to adequate power to reject any of the models, they can allow
the next stage is elevated either because the next mutation is some useful inferences.
more likely per cell per unit time, or because there are more One potentially important conclusion can be drawn from
cells in the target clone. Therefore, the number of the fact that very simple models such as the TSCE model fit
Radiotherapy-Induced Carcinogenesis and Leukemogenesis 217

most data sets reasonably even though they ignore numer-

ous biologically plausible aspects of carcinogenesis. Intro-
ducing some of these aspects, e.g., extending the models to
more stages with or without genomic instability, usually
does not improve the fit substantially (Little and Li 2007).
This implies that some processes in carcinogenesis (e.g.,
clonal expansion) may dominate over others, so that cap-
turing these key processes may be more important than
increasing model complexity by incorporating numerous
lesser contributors. Such an approach may be useful at the
current stage of knowledge of carcinogenesis, where intro-
ducing too many mechanisms into the model has the prin- Fig. 14 A general scheme of short- and long-term processes govern-
ing the total number of pre-malignant cells, adapted from Shuryak
cipal effect of increasing the number of adjustable et al. (2009). As an unirradiated individual ages, the number of viable
parameters, because there is often insufficient information pre-malignant cells grows, but may turn over and decrease at very old
to estimate the values of the extra parameters from sources age (blue line in the main graph). Radiation exposure (e.g., radiother-
independent of the data set being fitted. apy for an existing cancer nearby) initially causes the number of pre-
malignant cells to decrease due to cell killing (red line). After
exposure stops, the irradiated tissues recover, allowing pre-malignant
cells to repopulate and reach a number somewhat higher, than was
4 Integration of Short-Term and Long- present before irradiation, i.e., a net excess radiogenic cancer risk is
Term Models produced. Fluctuations in the number of pre-malignant cells through-
out the irradiation and recovery periods (i.e., during the short-term
processes) are shown in the inset graph. The number of pre-malignant
The lack of detailed treatment of radiation-specific effects cells determines the incidence of malignant cells and thereby cancer
typically limits risk predictions from long-term models to incidence later
exposure conditions where a known shape for the early
dose–response relationship, e.g., a linear shape, holds. Sit- The long-term part of the model approximates carcino-
uations where this dose–response relationship itself requires genesis by a two-stage process, where normal stem cells can
mechanistic analyses, such as at high fractionated radio- be initiated to become pre-malignant cells, which can clon-
therapeutic doses, are difficult to describe solely with long- ally expand and mutate into fully malignant cells, which then
term models. Conversely, the more detailed dose responses give rise to cancer after some lag period. The basic
produced by short-term models can be converted into can- assumptions are similar to those of several models discussed
cer risk at much later times only by considering the effects above, including the TSCE model. However, the long-term
of factors such as age at exposure and time since exposure, formalism differs from the TSCE model in three main ways:
which are not explicitly taken into account by the short-term (1) Normal and pre-malignant stem cells are considered as
formalisms. Probably a unified approach of integrating localized in distinct stem cell niches or compartments
short- and long-term formalisms is needed, where a detailed (Bennett et al. 2003; Potten and Booth 2002; Slack
initial dose response for pre-malignant cell numbers is 2000; Borthwick et al. 2001; Fuchs et al. 2004; Ghaz-
produced over a wide range of doses, and changes to the izadeh and Taichman 2005; Li and Xie 2005). The
shape of this dose response over the latency period before number of such niches per organ, and the number of
the development of cancer are also analyzed. A schematic stem cells per niche, are homeostatically regulated
representation of model unification is provided in Fig. 14. (Fuchs et al. 2004; Li and Xie 2005). Niche boundaries
can affect the rate of clonal expansion of pre-malignant
cells (Brash et al. 2005; Zhang et al. 2001). By com-
4.1 An Example of Short-Term and Long- parison, the TSCE model and previously discussed
Term Model Unification multi-stage models do not directly consider the effects
of tissue compartmentalization or homeostatic regula-
Here we provide one specific example of unifying the two tion of pre-malignant cells.
different model classes (Shuryak 2009a, b). The goal was to (2) Pre-malignant cells in all niches are assumed to lose
produce a simple formalism with the smallest possible their carcinogenic potential with age, so that at old age
number of adjustable parameters, which would illustrate the they have a progressively smaller probability of being
idea of a unified short-long-term approach and allow inte- transformed to malignant cells. This assumption is
grated analysis of background cancers, atomic bomb sur- suggested by a decrease in incidence of most cancers at
vivors, and second cancers. Alternative examples of very old age, e.g., [80 years in humans (SEER data-
unifying long- and short-term models are certainly possible. base, http://seer.cancer.gov; see Fig. 13) and[800 days
218 D. J. Brenner et al.

Fig. 15 Fits of the unified Stomach Cancer Lung Cancer

Yearly cancer incidence

model of Sect. 4.1 to

Yearly cancer incidence

0.12% Data 0.60% Data
spontaneous and radiation- Model Model
induced incidence of selected
0.08% 0.40%
cancers: stomach, lung, colon,
and thyroid. a–d Spontaneous
cancer incidence from SEER. e– 0.04% 0.20%
h The radiation-induced cancer
ERRs for atomic bomb survivors.
0.00%
a b
0.00%
i–l The ERRs for high-dose
20 40 60 80 100 20 40 60 80 100
radiotherapy-induced second
cancers Age (years) Age (years)

Yearly cancer incidence Colon Cancer Thyroid Cancer

Yearly cancer incidence

0.50% 0.020%
Data Data
0.40% Model Model
0.015%
0.30%
0.010%
0.20%

0.10% 0.005%

0.00%
c d
0.000%
20 40 60 80 100 20 40 60 80 100
Age (years) Age (years)

Stomach Cancer Lung Cancer

ERR/Gy at age 70 years

ERR/Gy at age 70 years

Data Data f
0.8 Model
e 0.6 Model

0.6
0.4
0.4
0.2
0.2

0.0 0.0
0 20 40 60 0 20 40 60
Age at exposure (years) Age at exposure (years)

Colon Cancer Thyroid Cancer

ERR/Gy at age 70 years

4
ERR/Gy at age 70 years

Data g Data
1.5 Model Model
h
3
1.0
2
0.5
1

0.0
0
0 20 40 60 0 20 40 60
Age at exposure (years) Age at exposure (years)

in mice (Pompei et al. 2001). The likely mechanism is a prediction of negative cancer incidence at very old
senescence of stem cells and/or deterioration of stem age is removed.
cell function, or niche function, with age (Brunet and (3) To reduce the number of adjustable model parameters,
Rando 2007; Carlson and Conboy 2007; Sharpless and clonal expansion of pre-malignant stem cells is treated
DePinho 2007). As discussed above, standard two-stage deterministically, using a net proliferation rate. In other
and multistage models cited above do not reproduce words, clonal expansion is estimated by a deterministic
this trend very well. The unified formalism addresses ‘‘exponential model’’, instead of the stochastic TSCE
this issue by introducing an age-dependent senescence model. Until the onset of old age, both approaches
probability for pre-malignant cells, which mathemati- produce numerically similar results with realistic
cally differs from one used by Pompei and Wilson parameter values (Heidenreich and Hoogenveen 2001).
(Pompei et al. 2001; Pompei and Wilson 2002), so that At old age, the stochastic TSCE model predicts a
Radiotherapy-Induced Carcinogenesis and Leukemogenesis 219

Fig. 15 continued Stomach Cancer Lung Cancer

12
i Data j Data
6 Model Model

8
4

ERR
ERR
2 4

0 0
0 20 40 60 0 20 40 60
Dose (Gy) Dose (Gy)

Colon Cancer Thyroid Cancer

3 25
k Data Data
Model Model
20
2
ERR

15

ERR
1 10

5
0 l
0
0 20 40 60 0 20 40 60
Dose (Gy) Dose (Gy)

plateau in the cancer hazard, whereas the deterministic of radiation doses at any point during the lifetime of the
approximation predicts further growth. However, in the individual. Its main disadvantages are those common to all
unified formalism, the hazard at old age decreases due two-stage carcinogenesis models, namely very simplistic
to the senescence assumption mentioned above. So, the treatment of many aspects of carcinogenesis such as mul-
stochastically generated plateau is not necessary to tiple mutational stages.
explain old age effects and was neglected because its
analysis would require an extra adjustable parameter.
The short-term part of the model is based on the stochastic
initiation-inactivation-proliferation (iip) model cited earlier 4.2 Model Comparisons
(Sachs et al. 2007). Some improvements relative to previous
iip models are introduced: in mathematical approach, by A comparison of the unified model of Sect. 4.1 with some
using analytic solutions for stochastic birth–death processes commonly used carcinogenesis models described above, by
in place of Monte-Carlo simulations; and in biological fitting models to spontaneous cancer incidence data for
assumptions, by emphasizing pre-malignant niches and selected sites, is shown in Fig. 16. Colon cancer in males
clones, rather than individual pre-malignant cells. was chosen as an example where the rate of increase of
The model was applied to data for several common solid cancer incidence slows down at old age, but absolute inci-
cancer types. For each tumor type, the data included dence does not decline. Lung cancer in males was chosen as
spontaneous US cancer incidence from SEER and radio- an example of the opposite case, where incidence does peak
genic excess risks in atomic bomb survivors at doses of a and declines at very old age.
few Gy or less, and in radiotherapy-treated patients at much In the first case, exemplified by colon cancer, all the
higher fractionated doses. Model fits to clinical data for carcinogenesis models tested here fit the data quite well
some selected cancer types are shown in Fig. 15. The goal (Fig. 16a). They differ only in their predictions at very old
of the figure is to display the various age, time and dose age, beyond the range of the data set: some predict con-
patterns of spontaneous and radiogenic cancer risks, and the tinued increase in cancer incidence (e.g., the Armitage-Doll
ability of the model to describe these patterns using one set model), other predict a plateau (e.g., the TSCE model), and
of parameters for each cancer. yet others predict a decline (e.g., the unified and Pompei-
Because the unified model integrates some features of Wilson models). In the second case exemplified by lung
short- and long-term modeling approaches, it should, in cancer, where incidence declines at old ages, the best fits are
principle, share the advantages of both: i.e., it can predict understandably generated by those models that can
spontaneous and radiogenic cancer risks over a wide range accommodate such a decline (Fig. 16c).
220 D. J. Brenner et al.

Fig. 16 Best fits of several Colon cancer Colon cancer

1.0% -2
carcinogenesis models to 10
SEER data a b

Yearly cancer incidence

spontaneous cancer incidence

Yearly cancer incidence

Shuryak et al. model, 2 stages
data from SEER for selected 0.8% TSCE model 10
-3
Nordling model
cancer types. a, b Data and model Armitage-Doll model
fits for colon cancer in males, and 0.6% Pompei-Wilson model
10
-4

c, d the analogous information

for male lung cancer 0.4%
10
-5
SEER data
Shuryak et al. model, 2 stages
0.2% -6 3 stages
10 4 stages
5 stages
0.0% -7
10
10 30 50 70 90 10 30 50 70 90
Age (years) Age (years)

Lung cancer Lung cancer

-2
1.0% 10
SEER data c d
Yearly cancer incidence

Yearly cancer incidence

Shuryak et al. model, 2 stages
0.8% TSCE model -3
Nordling model
10
Armitage-Doll model
0.6% Pompei-Wilson model -4
10

0.4% -5
10
SEER data
Shuryak et al. model, 2 stages
0.2% -6 3 stages
10 4 stages
5 stages
0.0% -7
10
10 30 50 70 90 10 30 50 70 90
Age (years) Age (years)

Panels b and d in Fig. 16 refer to extensions of the considered separately. For example, the period between
unified model to more than two stages, designed to explore radiation exposure and the development of leukemia is
the effects of multiple mutations. Clearly, the differences typically only a few years (Curtis et al. 1994), much less
between the versions with different numbers of stages are than for the development of most solid tumors (Boice et al.
marginal. The simplest two-stage version fits the data 1988), which may imply certain mechanistic differences
essentially no worse than, or even marginally better than, between these two cancer classes, e.g., the number of
those with more stages. This result is in qualitative agree- mutations needed for malignancy and/or the proliferation
ment with those of (Little and Li 2007; Little and Wright kinetics of pre-malignant cells.
2003), cited earlier, where several two-stage and multistage Many epidemiological studies of leukemia risks after
models were also compared on the same data. Mechanisti- radiation therapy have been reported. However, treatment
cally, this finding may imply that one of the mutational techniques for radiation therapy are changing rapidly, par-
stages is dominant in determining the rate of carcinogenesis. ticularly with increasing use of escalated treatment doses,
For example, this key stage may be the first to result in a altered dose fractionation or protraction, and altered dose
growth advantage, leading to clonal expansion, which distributions in normal tissues (Zelefsky et al. 2002; Ngu-
increases the probability of subsequent mutations by yen and Ang 2002; Hall and Wuu 2003). Thus, as with the
increasing the target cell number. In general, it may be that solid tumors, results from these epidemiological studies,
one or a few events produce sufficient deregulation of cell which typically analyze data from treatments that took place
signaling/proliferation, so that further deregulation proceeds several decades ago, cannot be applied directly to modern-
as a cascade leading towards cancer. day protocols. Thus evaluating leukemia risks associated
with modern-day and future treatments also requires the
development of mechanistic models that use organ doses or
5 Radiation-Induced Leukemia dose distributions as the basis for predicting cancer risks.
The iip approach described above for solid tumors was
The previous sections dealt exclusively with cancers of shown to be superior in fitting recent second cancer data on
solid organs. Radiation-induced leukemia (Curtis et al. solid tumors at high doses, compared with the older linear
1994, 2006; Travis et al. 2000; Weiss et al. 1995; Inskip quadratic exponential (LQE) approach, which neglected cell
et al. 1993; Boice et al. 1987; Little et al. 1999) needs to be proliferation and underestimated the risks at these doses
Radiotherapy-Induced Carcinogenesis and Leukemogenesis 221

Fig. 17 A schematic
representation of the concepts of
initiation, inactivation,
proliferation and migration of
normal and pre-leukemic mutated
stem cells in bone marrow
compartments and blood.
Adapted from Shuryak et al.
(2006)

(Sachs and Brenner 2005). However, measured ERRs for

radiation therapy-induced leukemia are lower than those
predicted by the iip model, although still higher than those
predicted by the LQE model (Travis et al. 2000; Little
2001). A potential reason for this difference between the
risk patterns for high-dose radiation-induced solid tumors
and leukemias is the difference in repopulation mechanisms
for the relevant target cells. For solid tumors, the target cells
are assumed to be the stem cells for that organ; for leuke-
mias, the cells at risk for radiation-induced initiation to a
preleukemic state are probably hematopoietic stem cells
(HSCs) and/or pluripotent progenitor cells. Like other stem
cells, HSCs in a given location can repopulate by symmetric
proliferation; unlike other stem cells, they can also repop-
ulate by migrating through the blood stream from distant
Fig. 18 Model predictions from Shuryak et al. (2006), using param-
locations (Hanks 1964; Croizat et al. 1980; Fliedner et al.
eter values estimated from the literature, compared with epidemio-
2002). Migration of HSCs, occurring primarily through the logical data on radiation-induced leukemia after radiotherapy for
blood stream, is more rapid and longer ranged than uterine cancer from Curtis et al. (1994)
migration of solid organ stem cells (Fliedner et al. 2002;
Fliedner 1998). A substantial fraction of the repopulating 2001). Consequently, the iip approach was extended to
HSCs will, therefore, originate far from the radiation apply to leukemias, by adding an analysis of long-range
treatment volume, in regions in which they were much less HSC migration to improve the accuracy of risk estimation
likely to have been initiated by radiation to become pre- for leukemias associated with radiation therapy, and to
leukemic HSCs (Fig. 17). In contrast, repopulating stem increase mechanistic understanding of radiation leukemo-
cells in solid organs will generally have originated in genesis (Shuryak 2009a, b). In this model, the bone marrow
heavily irradiated regions and would, therefore, include an is divided into several compartments, corresponding to
appreciable fraction of premalignant cells. Thus, long-range skeletal regions. Each compartment contains some number
HSC migration would partially offset the carcinogenic of target stem cells, estimated from the literature. The blood
effects of proliferation and would be expected to result in an is considered as an additional compartment. With some
ERR for leukemia associated with high-dose radiation that probability per unit time, some stem cells can exit from a
is intermediate between the ERR predicted by the iip model, given bone marrow compartment, remain transiently in the
which neglects migration, and the ERR predicted by the blood, and return to some bone marrow compartment. The
standard LQE model, which neglects both proliferation and compartments of origin and return do not have to be the
migration. In fact, such an intermediate ERR has been same. For example, it is possible for a stem cell to migrate
observed in epidemiologic studies (Travis et al. 2000; Little through the bloodstream from the femur to the ribs.
222 D. J. Brenner et al.

Table 1 A comparison of the properties of some biologically based models potentially useful for radiotherapy-induced second-cancer risk
estimation
Model References Short-term processes Long-term processes
Init Inact Prolif NS CE GI TA OA
LQE Bennett et al. (2004), Dasu et al. (2005) + +
Schneider et al. Schneider and Kaser-Hotz (2005), Schneider and Walsh (2008) + + +
iip Lindsay et al. (2001), Sachs and Brenner (2005), Sachs et al. + + +
(2007), Wheldon et al. (2000)
Nordling, Nordling (1953), Armitage (1954, 1985) + [2
Armitage-Doll
TSCE Moolgavkar (1978, 1980, 1983) + + + 2 +
Little-Wright Little and Li (2007), Little and Wright (2003) + + C2 + + +
Pompei-Wilson Pompei et al. (2001), Pompei and Wilson (2002) + [2 +
Shuryak et al. Shuryak (2009a, b) + + + C2 + + +
Details of the model assumptions are discussed in the main text. The + symbols indicate that the model focuses on this particular aspect of
carcinogenesis. In most cases, models including more effects or more stages have more adjustable parameters
Init initiation, Inact cell inactivation, Prolif cell repopulation through proliferation
NS number of stages, CE clonal expansion, GI genomic instability, TA tissue architecture effects, OA old age effects

Without excess radiation exposure, the rate of such The main disadvantages of the model are the same as for
migration is relatively small. However, when radiation kills the general short-term model class, to which it belongs.
a substantial proportion of stem cells in some compart- Specifically, to account for the effects of age at exposure
ment(s), the cells in other compartments, even in distant and time since exposure on leukemia risk, the model relies
ones, are assumed to exit into the bloodstream and home on proportionality factors derived from additional data, i.e.,
into the damaged compartments with the goal of repopu- from atomic bomb survivors.
lating them. In other words, the entire hematopoietic system
is considered as a single integrated unit that attempts to
maintain a homeostatically determined total number of
6 Conclusions
HSCs in the body. When a certain bone marrow region is
A comparison of the properties of some models discussed in
depopulated by radiation, the system responds in two ways:
this chapter is provided in Table 1. Although the field of
(1) by local proliferation of surviving cells in the damaged
mathematical modeling of spontaneous and radiation-
region and (2) by accelerated migration of cells from
induced carcinogenesis has existed for a half-century, the
undamaged regions to the damaged one. These concepts are
current models are still far from being able to explain many
schematically illustrated in Fig. 17.
complexities of this process. Because multiple phenomena
This initiation, inactivation, proliferation, and migration
in carcinogenesis are still poorly understood and their
model of radiogenic leukemia can explain the ERR dose
quantitative contributions under various conditions are dif-
responses observed for inhomogeneous high-dose fraction-
ficult to estimate experimentally or epidemiologically,
ated irradiation, which occurs during cancer radiotherapy
incorporating them into mathematical models is difficult.
(Fig. 18). In this situation, some bone marrow regions,
When several such phenomena are included in a single
which are in close proximity to the radiotherapy field,
model, the consequence is often ‘‘overfitting’’, i.e., the
receive very high radiation doses. In contrast, other more
model contains numerous adjustable parameters, many
distant regions receive essentially zero doses. The mean
combinations of which can adequately fit the available data
dose to the bone marrow, which is frequently estimated in
sets. This situation leads to models that focus only on a few
epidemiological studies, is, therefore, of limited utility in
specific aspects of carcinogenesis and explain the observed
predicting the excess cancer risk, if the dose distribution is
patterns only in light of these aspects. Unfortunately,
not known. When the distribution is known, the model
models that focus on quite different mechanisms, e.g.,
predicts the observed risks adequately even without fitting
genomic instability versus clonal expansion of pre-malig-
to the data, using only biologically plausible parameter
nant cells, can describe usual data sets approximately
values on stem cell radiosensitivity, proliferation, migration
equally well, making it difficult to discriminate between the
etc., obtained from independent sources (Fig. 18).
more and less important mechanisms.
Radiotherapy-Induced Carcinogenesis and Leukemogenesis 223

Despite their shortcomings, mechanistic mathematical Boice JD Jr, Engholm G, Kleinerman RA et al (1988) Radiation dose
models of carcinogenesis are important conceptual and and second cancer risk in patients treated for cancer of the cervix.
Radiat Res 116:3–55
quantitative tools, for which, in some situations, there are no Borthwick DW, Shahbazian M, Krantz QT et al (2001) Evidence for
good alternatives. They are particularly useful whenever stem-cell niches in the tracheal epithelium. Am J Respir Cell Mol
cancer risks must be estimated under exposure situations for Biol 24:662–670
which no data yet exist, e.g., for novel and prospective Brash DE (2006) Roles of the transcription factor p53 in keratinocyte
carcinomas. Br J Dermatol 154(Suppl 1):8–10
radiotherapy protocols. Direct extrapolation from existing Brash DE, Zhang W, Grossman D et al (2005) Colonization of
data is often not possible due to complex differences adjacent stem cell compartments by mutant keratinocytes. Semin
between the data sets, but mathematical models can Cancer Biol 15:97–102
accommodate such extrapolation. Of course, the level of Brem SS, Gullino PM, Medina D (1977) Angiogenesis: a marker for
neoplastic transformation of mammary papillary hyperplasia.
confidence in model-based extrapolations depends on how Science 195:880–882
well the model describes existing data, and on how bio- Brenner DJ, Hahnfeldt P, Amundson SA et al (1996) Interpretation of
logically plausible are its mechanistic assumptions. inverse dose-rate effects for mutagenesis by sparsely ionizing
For second cancers, such modeling has already suggested radiation. Int J Radiat Biol 70:447–458
Brenner DJ, Curtis RE, Hall EJ et al (2000) Second malignancies in
two preliminary but important insights: prostate carcinoma patients after radiotherapy compared with
(1) Additional minimization of regions outside the primary surgery. Cancer 88:398–406
tumor experiencing high doses, comparable to the Brenner DJ, Shuryak I, Russo S et al (2007) Reducing second breast
treatment dose, may be as important as minimizing the cancers: a potential role for prophylactic mammary irradiation.
J Clin Oncol 25:4868–4872
much larger volumes experiencing small doses, con- Brunet A, Rando TA (2007) Ageing: from stem to stern. Nature
trary to the idea that, due to cell killing, very high doses 449:288–291
do not contribute much to the second cancer risk. Calabrese P, Tavare S, Shibata D (2004) Pretumor progression: clonal
(2) Radiotherapy-induced second cancer risks are generally evolution of human stem cell populations. Am J Pathol
164:1337–1346
particularly relevant for patients treated in childhood Carlson ME, Conboy IM (2007) Loss of stem cell regenerative
because their expected survival time can be sufficiently capacity within aged niches. Aging Cell 6:371–382
long for second cancers to develop. However, the Chaturvedi AK, Engels EA, Gilbert ES et al (2007) Second cancers
radiotherapy-induced risks in adults can also be sub- among 104,760 survivors of cervical cancer: evaluation of long-
term risk. J Natl Cancer Inst 99:1634–1643
stantial, particularly if radiation acts by promotion of Cook PJ, Doll R, Fellingham SA (1969) A mathematical model for the
the growth of background pre-malignant cells. age distribution of cancer in man. Int J Cancer 4:93–112
Croizat H, Frindel E, Tubiana M (1980) The effect of partial body
irradiation on haemopoietic stem cell migration. Cell Tissue Kinet
References 13:319–325
Curtis SB (1986) Lethal and potentially lethal lesions induced by
radiation—a unified repair model. Radiat Res 106:252–270
Almog N, Henke V, Flores L et al (2006) Prolonged dormancy of Curtis RE, Boice JD Jr, Stovall M et al (1994) Relationship of
human liposarcoma is associated with impaired tumor angiogen- leukemia risk to radiation dose following cancer of the uterine
esis. Faseb J 20:947–949 corpus. J Natl Cancer Inst 86:1315–1324
Anonymous (2004) Cancer survivors: living longer, and now, better. Curtis SB, Luebeck EG, Hazelton WD et al (2001) The role of
Lancet 364:2153–2154 promotion in carcinogenesis from protracted high-LET exposure.
Armitage P (1985) Multistage models of carcinogenesis. Environ Phys Med 17(Suppl 1):157–160
Health Perspect 63:195–201 Curtis R, Freedman D, Ron E et al (2006) New malignancies among
Armitage P, Doll R (1954) The age distribution of cancer and a multi- cancer survivors: SEER Cancer Registries, 1973–2000. National
stage theory of carcinogenesis. Br J Cancer VIII:1–12 Cancer Institute, Bethesda
BEIR VII Report, Phase 2 (2005) Health risks from exposure to low Dale RG (1986) The application of the linear-quadratic model to
levels of ionizing radiation. The National Academic Press, fractionated radiotherapy when there is incomplete normal tissue
Washington recovery between fractions, and possible implications for treat-
Bennett WR, Crew TE, Slack JM et al (2003) Structural-proliferative ments involving multiple fractions per day. Br J Radiol 59:919–927
units and organ growth: effects of insulin-like growth factor 2 on Dasu A, Toma-Dasu I, Olofsson J et al (2005) The use of risk
the growth of colon and skin. Development 130:1079–1088 estimation models for the induction of secondary cancers following
Bennett J, Little MP, Richardson S (2004) Flexible dose-response radiotherapy. Acta Oncol 44:339–347
models for Japanese atomic bomb survivor data: Bayesian Feitelson MA, Pan J, Lian Z (2004) Early molecular and genetic
estimation and prediction of cancer risk. Radiat Environ Biophys determinants of primary liver malignancy. Surg Clin North Am
43:233–245 84:339–354
Bockmuhl U, Petersen I (2002) DNA ploidy and chromosomal Finley JC, Reid BJ, Odze RD et al (2006) Chromosomal instability in
alterations in head and neck squamous cell carcinoma. Virchows Barrett’s esophagus is related to telomere shortening. Cancer
Arch 441:541–550 Epidemiol Biomarkers Prev 15:1451–1457
Boice JD Jr, Blettner M, Kleinerman RA et al (1987) Radiation dose Fliedner TM (1998) The role of blood stem cells in hematopoietic cell
and leukemia risk in patients treated for cancer of the cervix. J Natl renewal. Stem Cells 16(Suppl 1):13–29
Cancer Inst 79:1295–1311
224 D. J. Brenner et al.

Fliedner TM, Graessle D, Paulsen C et al (2002) Structure and Lange CS, Mayer PJ, Reddy NM (1997) Tests of the double-strand
function of bone marrow hemopoiesis: mechanisms of response to break, lethal-potentially lethal and repair-misrepair models for
ionizing radiation exposure. Cancer Biother Radiopharm mammalian cell survival using data for survival as a function of
17:405–426 delayed-plating interval for log-phase Chinese hamster V79 cells.
Fuchs E, Tumbar T, Guasch G (2004) Socializing with the neighbors: Radiat Res 148:285–292
stem cells and their niche. Cell 116:769–778 Leedham SJ, Wright NA (2008) Expansion of a mutated clone—from
Ghazizadeh S, Taichman LB (2005) Organization of stem cells and stem cell to tumour. J Clin Pathol 61(2):164–171
their progeny in human epidermis. J Invest Dermatol 124:367–372 Leedham SJ, Schier S, Thliveris AT et al (2005) From gene mutations
Gray LH (1957) Radiobiology and cancer. Nature 179:991–994 to tumours–stem cells in gastrointestinal carcinogenesis. Cell Prolif
Hahnfeldt P, Hlatky L (1996) Resensitization due to redistribution of 38:387–405
cells in the phases of the cell cycle during arbitrary radiation Li L, Xie T (2005) Stem cell niche: structure and function. Annu Rev
protocols. Radiat Res 145:134–143 Cell Dev Biol 21:605–631
Hahnfeldt P, Hlatky L (1998) Cell resensitization during protracted Lindsay KA, Wheldon EG, Deehan C et al (2001) Radiation
dosing of heterogeneous cell populations. Radiat Res carcinogenesis modelling for risk of treatment-related second
150:681–687 tumours following radiotherapy. Br J Radiol 74:529–536
Hall EJ, Wuu CS (2003) Radiation-induced second cancers: the impact Little MP (2001) Comparison of the risks of cancer incidence and
of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys 56:83–88 mortality following radiation therapy for benign and malignant
Hanks GE (1964) In vivo migration of colony-forming units from disease with the cancer risks observed in the Japanese A-bomb
shielded bone marrow in the irradiated mouse. Nature survivors. Int J Radiat Biol 77:431–464
203:1393–1395 Little MP (2007) A multi-compartment cell repopulation model
Harding C, Pompei F, Lee EE et al (2008) Cancer suppression at old allowing for inter-compartmental migration following radiation
age. Cancer Res 68:4465–4478 exposure, applied to leukaemia. J Theor Biol 245:83–97
Heidenreich WF, Hoogenveen R (2001) Limits of applicability for the Little MP, Li G (2007) Stochastic modelling of colon cancer: is there a
deterministic approximation of the two-step clonal expansion role for genomic instability? Carcinogenesis 28:479–487
model. Risk Anal 21:103–105 Little MP, Wright EG (2003) A stochastic carcinogenesis model
Heidenreich WF, Paretzke HG (2001) The two-stage clonal expansion incorporating genomic instability fitted to colon cancer data. Math
model as an example of a biologically based model of radiation- Biosci 183:111–134
induced cancer. Radiat Res 156:678–681 Little MP, Weiss HA, Boice JD Jr et al (1999) Risks of leukemia in
Heidenreich WF, Jacob P, Paretzke HG et al (1999) Two-step model Japanese atomic bomb survivors, in women treated for cervical
for the risk of fatal and incidental lung tumors in rats exposed to cancer, and in patients treated for ankylosing spondylitis. Radiat
radon. Radiat Res 151:209–217 Res 152:280–292
Heidenreich WF, Luebeck EG, Hazelton WD et al (2002) Multistage Luebeck EG, Hazelton WD (2002) Multistage carcinogenesis and
models and the incidence of cancer in the cohort of atomic bomb radiation. J Radiol Prot 22:A43–A49
survivors. Radiat Res 158:607–614 Luebeck EG, Moolgavkar SH (2002) Multistage carcinogenesis and
Heidenreich WF, Cullings HM, Funamoto S et al (2007) Promoting the incidence of colorectal cancer. Proc Natl Acad Sci U S A
action of radiation in the atomic bomb survivor carcinogenesis 99:15095–15100
data? Radiat Res 168:750–756 Maley CC (2007) Multistage carcinogenesis in Barrett’s esophagus.
Hlatky L, Hahnfeldt P, Tsionou C et al (1996) Vascular endothelial Cancer Lett 245:22–32
growth factor: environmental controls and effects in angiogenesis. Maley CC, Reid BJ (2005) Natural selection in neoplastic progression
Br J Cancer Suppl 27:S151–S156 of Barrett’s esophagus. Semin Cancer Biol 15:474–483
Hodgson DC, Koh ES, Tran TH et al (2007) Individualized estimates McDonald SA, Preston SL, Greaves LC et al (2006) Clonal expansion
of second cancer risks after contemporary radiation therapy for in the human gut: mitochondrial DNA mutations show us the way.
Hodgkin lymphoma. Cancer 110:2576–2586 Cell Cycle 5:808–811
Hofmann W, Crawford-Brown DJ, Fakir H et al (2006) Modeling lung Mebust M, Crawford-Brown D, Hofmann W et al (2002) Testing
cancer incidence in rats following exposure to radon progeny. extrapolation of a biologically based exposure-response model
Radiat Prot Dosimetry 122:345–348 from in vitro to in vivo conditions. Regul Toxicol Pharmacol
Inskip PD, Kleinerman RA, Stovall M et al (1993) Leukemia, 35:72–79
lymphoma, and multiple myeloma after pelvic radiotherapy for Meza R, Jeon J, Moolgavkar SH et al (2008) Age-specific incidence of
benign disease. Radiat Res 135:108–124 cancer: phases, transitions, and biological implications. Proc Natl
Ivanov VK, Gorski AI, Tsyb AF et al (2004) Solid cancer incidence Acad Sci U S A 105:16284–16289
among the Chernobyl emergency workers residing in Russia: Michor F, Iwasa Y, Komarova NL et al (2003a) Local regulation of
estimation of radiation risks. Radiat Environ Biophys 43:35–42 homeostasis favors chromosomal instability. Curr Biol 13:581–584
Knudson AG Jr (1971) Mutation and cancer: statistical study of Michor F, Frank SA, May RM et al (2003b) Somatic selection for and
retinoblastoma. Proc Natl Acad Sci U S A 68:820–823 against cancer. J Theor Biol 225:377–382
Koh ES, Tran TH, Heydarian M et al (2007) A comparison of mantle Michor F, Iwasa Y, Rajagopalan H et al (2004) Linear model of colon
versus involved-field radiotherapy for Hodgkin’s lymphoma: cancer initiation. Cell Cycle 3:358–362
reduction in normal tissue dose and second cancer risk. Radiat Michor F, Iwasa Y, Lengauer C et al (2005) Dynamics of colorectal
Oncol 2:13 cancer. Semin Cancer Biol 15:484–493
Kohle C, Schwarz M, Bock KW (2008) Promotion of hepatocarcino- Midorikawa Y, Makuuchi M, Tang W et al (2007) Microarray-based
genesis in humans and animal models. Arch Toxicol 82:623–631 analysis for hepatocellular carcinoma: from gene expression
Komarova NL, Cheng P (2006) Epithelial tissue architecture protects profiling to new challenges. World J Gastroenterol 13:1487–1492
against cancer. Math Biosci 200:90–117 Moolgavkar SH (1978) The multistage theory of carcinogenesis and
Kopp-Schneider A, Portier CJ (1991) Distinguishing between models the age distribution of cancer in man. J Natl Cancer Inst 61:49–52
of carcinogenesis: the role of clonal expansion. Fundam Appl Moolgavkar S (1980) Multistage models for carcinogenesis. J Natl
Toxicol 17:601–613 Cancer Inst 65:215–216
Radiotherapy-Induced Carcinogenesis and Leukemogenesis 225

Moolgavkar SH (1983) Model for human carcinogenesis: action of Ronckers CM, Sigurdson AJ, Stovall M et al (2006) Thyroid cancer in
environmental agents. Environ Health Perspect 50:285–291 childhood cancer survivors: a detailed evaluation of radiation dose
Moolgavkar SH (1986) Carcinogenesis modeling: from molecular response and its modifiers. Radiat Res 166:618–628
biology to epidemiology. Annu Rev Public Health 7:151–169 Rossi HH, Kellerer AM (1986) The dose rate dependence of oncogenic
Moolgavkar SH, Knudson AG Jr (1981) Mutation and cancer: a model transformation by neutrons may be due to variation of response
for human carcinogenesis. J Natl Cancer Inst 66:1037–1052 during the cell cycle. Int J Radiat Biol Relat Stud Phys Chem Med
Naumov GN, Bender E, Zurakowski D et al (2006) A model of human 50:353–361
tumor dormancy: an angiogenic switch from the nonangiogenic Rusyn I, Peters JM, Cunningham ML (2006) Modes of action and
phenotype. J Natl Cancer Inst 98:316–325 species-specific effects of di-(2-ethylhexyl)phthalate in the liver.
NCRP Report 136 (2001) Evaluation of the linear-nonthreshold dose- Crit Rev Toxicol 36:459–479
response model for ionizing radiation. The National Academic Sachs RK, Brenner DJ (2005) Solid tumor risks after high doses of
Press, Washington ionizing radiation. Proc Natl Acad Sci U S A 102:13040–13045
Neglia JP, Robison LL, Stovall M et al (2006) New primary neoplasms Sachs RK, Chan M, Hlatky L et al (2005) Modeling intercellular
of the central nervous system in survivors of childhood cancer: a interactions during carcinogenesis. Radiat Res 164:324–331
report from the Childhood Cancer Survivor Study. J Natl Cancer Sachs RK, Shuryak I, Brenner D et al (2007) Second cancers after
Inst 98:1528–1537 fractionated radiotherapy: stochastic population dynamics effects.
Nguyen LN, Ang KK (2002) Radiotherapy for cancer of the head J Theor Biol 249:518–531
and neck: altered fractionation regimens. Lancet Oncol Schneider U, Kaser-Hotz B (2005) Radiation risk estimates after
3:693–701 radiotherapy: application of the organ equivalent dose concept to
Nilsson P, Thames HD, Joiner MC (1990) A generalized formulation plateau dose-response relationships. Radiat Environ Biophys
of the ‘incomplete-repair’ model for cell survival and tissue 44:235–239
response to fractionated low dose-rate irradiation. Int J Radiat Biol Schneider U, Walsh L (2008) Cancer risk estimates from the combined
57:127–142 Japanese A-bomb and Hodgkin cohorts for doses relevant to
Nishimura M, Furumoto H, Kato T et al (2000) Microsatellite radiotherapy. Radiat Environ Biophys 47:253–263
instability is a late event in the carcinogenesis of uterine cervical Schollnberger H, Mitchel RE, Crawford-Brown DJ et al (2002)
cancer. Gynecol Oncol 79:201–206 Nonlinear dose-response relationships and inducible cellular
Nordling CO (1953) A new theory on the cancer inducing mechanism. defence mechanisms. J Radiol Prot 22:A21–A25
Br J Cancer 7:68–72 Sharpless NE, DePinho RA (2007) How stem cells age and why this
Nowak MA, Komarova NL, Sengupta A et al (2002) The role of makes us grow old. Nat Rev Mol Cell Biol 8:703–713
chromosomal instability in tumor initiation. Proc Natl Acad Sci U Shaw IC, Jones HB (1994) Mechanisms of non-genotoxic carcino-
S A 99:16226–16231 genesis. Trends Pharmacol Sci 15:89–93
Nowak MA, Michor F, Iwasa Y (2006) Genetic instability and clonal Shuryak I, Sachs RK, Hlatky L et al (2006) Radiation-induced
expansion. J Theor Biol 241:26–32 leukemia at doses relevant to radiation therapy: modeling mech-
Ohtaki M, Niwa O (2001) A mathematical model of radiation anisms and estimating risks. J Natl Cancer Inst 98:1794–1806
carcinogenesis with induction of genomic instability and cell death. Shuryak I, Hahnfeldt P, Hlatky L, Sachs RK, Brenner DJ (2009a) A
Radiat Res 156:672–677 new view of radiation-induced cancer: integrating short- and long-
Ottolenghi A, Ballarini F, Merzagora M (1999) Modelling radiation- term processes. Part I: approach. Radiat Environ Biophys
induced biological lesions: from initial energy depositions to 48(3):263–274 (Erratum in: Radiat Environ Biophys 50(4):
chromosome aberrations. Radiat Environ Biophys 38:1–13 607–608)
Perez-Ordonez B, Beauchemin M, Jordan RC (2006) Molecular Shuryak I, Hahnfeldt P, Hlatky L, Sachs RK, Brenner DJ (2009b) A
biology of squamous cell carcinoma of the head and neck. J Clin new view of radiation-induced cancer: integrating short- and long-
Pathol 59:445–453 term processes. Part II: second cancer risk estimation. Radiat
Pierce DA, Mendelsohn ML (1999) A model for radiation-related Environ Biophys 48(3):275–286 (Erratum in: Radiat Environ
cancer suggested by atomic bomb survivor data. Radiat Res Biophys 50(4):607–608)
152:642–654 Slack JM (2000) Stem cells in epithelial tissues. Science
Pierce DA, Vaeth M (2003) Age-time patterns of cancer to be 287:1431–1433
anticipated from exposure to general mutagens. Biostatistics Sontag W (1997) A discrete cell survival model including repair after
4:231–248 high dose-rate of ionizing radiation. Int J Radiat Biol 71:129–144
Pompei F, Wilson R (2002) A quantitative model of cellular Spiess PE, Czerniak B (2006) Dual-track pathway of bladder
senescence influence on cancer and longevity. Toxicol Ind Health carcinogenesis: practical implications. Arch Pathol Lab Med
18:365–376 130:844–852
Pompei F, Polkanov M, Wilson R (2001) Age distribution of cancer in Stewart RD (2001) Two-lesion kinetic model of double-strand break
mice: the incidence turnover at old age. Toxicol Ind Health rejoining and cell killing. Radiat Res 156:365–378
17:7–16 Tahara E (2004) Genetic pathways of two types of gastric cancer.
Potten CS, Booth C (2002) Keratinocyte stem cells: a commentary. IARC Sci Publ 157:327–349
J Invest Dermatol 119:888–899 Tamura G (2006) Alterations of tumor suppressor and tumor-related
Radivoyevitch T, Kozubek S, Sachs RK (2001) Biologically based risk genes in the development and progression of gastric cancer. World
estimation for radiation-induced CML. Inferences from BCR and J Gastroenterol 12:192–198
ABL geometric distributions. Radiat Environ Biophys 40:1–9 Thames HD (1985) An ‘incomplete-repair’ model for survival after
Ritter G, Wilson R, Pompei F et al (2003) The multistage model of fractionated and continuous irradiations. Int J Radiat Biol Relat
cancer development: some implications. Toxicol Ind Health Stud Phys Chem Med 47:319–339
19:125–145 Thomlinson RH, Gray LH (1955) The histological structure of some
Ron E (2006) Childhood cancer—treatment at a cost. J Natl Cancer human lung cancers and the possible implications for radiotherapy.
Inst 98:1510–1511 Br J Cancer 9:539–549
226 D. J. Brenner et al.

Tobias CA (1985) The repair-misrepair model in radiobiology: carcinogenesis model incorporating cellular repopulation. Int J
comparison to other models. Radiat Res Suppl 8:S77–S95 Radiat Biol 76:699–710
Travis LB, Andersson M, Gospodarowicz M et al (2000) Treatment- Yakovlev A, Polig E (1996) A diversity of responses displayed by a
associated leukemia following testicular cancer. J Natl Cancer Inst stochastic model of radiation carcinogenesis allowing for cell
92:1165–1171 death. Math Biosci 132:1–33
Travis LB, Gospodarowicz M, Curtis RE et al (2002) Lung cancer Yamasaki H, Mesnil M, Nakazawa H (1992) Interaction and
following chemotherapy and radiotherapy for Hodgkin’s disease. distinction of genotoxic and non-genotoxic events in carcinogen-
J Natl Cancer Inst 94:182–192 esis. Toxicol Lett 64–65 Spec No:597–604
Travis LB, Hill DA, Dores GM et al (2003) Breast cancer following Zaider M, Wuu CS (1995) The effects of sublethal damage recovery
radiotherapy and chemotherapy among young women with Hodg- and cell cycle progression on the survival probability of cells
kin disease. JAMA 290:465–475 exposed to radioactive sources. Br J Radiol 68:58–63
Trosko JE (2006) From adult stem cells to cancer stem cells: Oct-4 Zelefsky MJ, Fuks Z, Hunt M et al (2002) High-dose intensity
Gene, cell–cell communication, and hormones during tumor modulated radiation therapy for prostate cancer: early toxicity and
promotion. Ann N Y Acad Sci 1089:36–58 biochemical outcome in 772 patients. Int J Radiat Oncol Biol Phys
Upton AC (2003) The state of the art in the 1990’s: NCRP Report No. 53:1111–1116
136 on the scientific bases for linearity in the dose-response Zhang W, Remenyik E, Zelterman D et al (2001) Escaping the stem
relationship for ionizing radiation. Health Phys 85:15–22 cell compartment: sustained UVB exposure allows p53-mutant
Weiss HA, Darby SC, Fearn T et al (1995) Leukemia mortality after keratinocytes to colonize adjacent epidermal proliferating units
X-ray treatment for ankylosing spondylitis. Radiat Res 142:1–11 without incurring additional mutations. Proc Natl Acad Sci U S A
Wheldon EG, Lindsay KA, Wheldon TE (2000) The dose-response 98:13948–13953
relationship for cancer incidence in a two-stage radiation
 The Bioepidemiology of Multiple
Primary Cancers
Lois B. Travis and Andrea K. Ng

Contents Abstract

1 Introduction.......................................................................... 227 • The number of cancer survivors with second or higher

2 Methods to Evaluate Second Cancer Risk ....................... 228 order cancers is increasing, with these malignancies now
2.1 Cohort Studies ....................................................................... 228 comprising about 16 % (or 1 in 6) incident cancers
2.2 Case–Control Studies ............................................................ 229 reported to the population-based registries of the National
3 Selected Results in the NCI SEER Program, Cancer Institute’s (NCI’s) Surveillance, Epidemiology,
1973–2000.............................................................................. 229 and End Results (SEER) Program.
3.1 Overview................................................................................ 229 • In a recent review of over two million cancer survivors
3.2 Summary of Overall Risks of Subsequent Cancers ............. 230
3.3 Overall Patterns of Multiple Primary Cancers ..................... 230 who were reported to the NCI’s SEER Program
(1973–2000), the relative risk of subsequent neoplasms
4 Second Malignancies Among Survivors of Selected
was significantly elevated (Observed to expected
Adult Cancers ...................................................................... 232
4.1 Hodgkin Lymphoma.............................................................. 232 ratio = 1.14; 95 % C.I. = 1.14–1.15.). Twenty-five
4.2 Testicular Cancer................................................................... 234 years after first cancer diagnosis, the cumulative inci-
4.3 Breast Cancer......................................................................... 234 dence of all second cancers was 13.7 %.
4.4 Prostate Cancer ...................................................................... 236
• Second cancers can reflect the late effects of therapy, the
5 Comment............................................................................... 237 impact of lifestyle choices (e.g., tobacco use), host fac-
References...................................................................................... 237 tors, environmental determinants, and the operation of
joint effects, including gene–environment and gene–gene
interactions. A sizable proportion of all subsequent can-
cers in the review of the SEER program data developed
among cancer survivors with initial cancers that are
strongly related to tobacco and/or alcohol use.
• In the SEER program review, cancer treatment among all
older adults taken together did not appear to be linked
with a sizable excess of subsequent cancers, but children
and young adults appeared to be particularly susceptible
to the carcinogenic effects of therapy. In the present
chapter, we highlight recent analytic studies of sub-
sequent malignancies following HL and testicular cancer
as well as cancers of breast and prostate.
L. B. Travis (&)
Department of Radiation Oncology, University of Rochester
Medical Center, 265 Crittenden Boulevard, Rochester, 1 Introduction
NY CU 420318, USA
e-mail: [email protected]
Significant improvements in cancer detection, supportive care,
A. K. Ng
Department of Radiation Oncology, Harvard Medical School, and treatment in the past few decades have resulted in
Brigham and Women’s Hospital, Dana-Farber Cancer Institute, increasing numbers of cancer survivors. In the U.S. alone in
75 Francis Street ASB1-L2, Boston, MA 02115, USA

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 227
DOI: 10.1007/978-3-540-72314-1_15,  Springer-Verlag Berlin Heidelberg 2014
228 L. B. Travis and A. K. Ng

2005, there were an estimated 10.8 million cancer survivors, means of specified inclusion criteria, e.g., all one-year sur-
who have a 5-year relative survival rate overall of almost 66 % vivors of testicular cancer reported to selected population-
(Ries et al. 2007). In view of the improved survival for based cancer registries (Travis et al. 2005). These patients
increasing numbers of patients (Anonymous [No authors lis- can then be either prospectively or retrospectively followed
ted] 2004), the identification and quantification of the late for a diagnosis of second cancer. Sources of cohort investi-
sequelae of cancer and its treatment have become imperative. gations include population-based cancer registries such as
The development of a new primary malignancy is one of the the NCI SEER Program and nation-wide cancer registries in
most serious events experienced by cancer survivors, with an Scandinavia. Strengths of these registries include the large
increasing number of survivors diagnosed with second or numbers of subjects, which allows detection of even small
higher order cancers, which now comprise about 16 % (or 1 in second cancer risks, the evaluation of site-specific risks, and
6) incident cancers reported to the National Cancer Institute’s the opportunity to describe the effect(s) of latency, sex, and
(NCI’s) Surveillance, Epidemiology, and End Results (SEER) age at first and at second cancer diagnosis (Travis et al. 2005).
program (Ries et al. 2007). Further, second solid cancers are a Moreover, the observed and expected numbers of second
leading cause of death among several populations of long-term cancers are derived from the same population. The popula-
survivors, especially those with Hodgkin lymphoma (HL) tion-based nature of the registries precludes the selection or
(Dores et al. 2005). Second cancers can reflect the late effects of referral bias that may confound clinical series. A major
therapy, the influence of lifestyle choices (e.g., tobacco or weakness of these registries, however, is that cancer treat-
excessive alcohol use), host factors, environmental determi- ment data are limited, usually comprising only the initial
nants, and the operation of joint effects, including gene–envi- course of therapy, and then in terms of broad categories, such
ronment and gene–gene interactions (Travis et al. 2006). as radiotherapy or chemotherapy. Data for radiotherapy
Travis et al. (2006) recently categorized second primary can- fields or the names and doses of cytotoxic drugs are not
cers into three major groups according to predominant etio- collected. Further, information on additional courses of
logic factor i.e., therapy-related; syndromic; and those due to therapy is not gathered. Although underascertainment of
shared etiologic influences. These authors underscored the second cancers can result from migration of patients from
non-exclusivity of these groups. SEER Program catchment regions, this is an almost negli-
In the present chapter, we summarize the overall results gible concern in nation-wide registries, such as those in
of a systematic review of subsequent cancers conducted Scandinavia. Information derived from population-based
among over 2 million cancer survivors reported to the registries facilitate an evaluation of site-specific second
population-based cancer registries which comprise the NCI cancer risk according to a number of relevant parameters and
SEER Program, 1973–2000 (Curtis et al. 2006). Methodo- enable observation of trends in risk as cancer therapies
logic issues involved in this form of cohort study (as well as evolve (Schonfeld et al. 2006). Registries also serve as a
case–control investigations) will also be summarized. In foundation for nested case–control investigations in which
addition, we highlight recent findings of subsequent thorough evaluations of treatment effects, including a
malignancies following Hodgkin lymphoma, testicular description of dose–response relations with radiation and
cancer, breast cancer, and prostate cancer, malignancies for chemotherapy, can be undertaken.
which a relatively large amount of data has been generated. Other sources of patient cohorts in which second cancer
Second tumors among childhood cancers were recently risks can be evaluated include hospital-based cancer regis-
described by Bhatia et al. (2003). For additional informa- tries and clinical trials. Hospital-based cancer registries
tion, the reader is referred to comprehensive reviews of provide the advantage of detailed patient data, although
multiple primary cancers (Travis 2002; Bhatia and Landier inconsistent follow-up, administration of differing therapies,
2005; Behrens et al. 2000), including discussions of possi- and underascertainment of second cancers can restrict the
ble underlying genetic mechanisms (Travis et al. 2006; usefulness of these sources. If follow-up is more complete for
Allan and Travis 2005). patients with second cancers than for patients who remain
well, elevated risks result. Strengths of clinical trial data
include the availability of detailed data for protocol treat-
2 Methods to Evaluate Second Cancer ments, and the potential for direct comparisons between
Risk treatment effectiveness and second cancer risk in randomized
groups. Weaknesses include the lack of information on off-
2.1 Cohort Studies protocol therapy, limited follow-up, and frequently incom-
plete ascertainment of long-term adverse events, including
Two epidemiologic study designs (cohort and case–control) second cancers. The relatively small number of patients in
have been applied in most studies of therapy-related cancers. many clinical trials also does not permit adequate statistical
In a cohort study, a group of cancer patients is identified by power to accurately evaluate long-term treatment sequelae.
 The Bioepidemiology of Multiple Primary Cancers 229

Several risk measures can be estimated from cohort then compared. One drawback of case–control studies is
studies. A commonly used comparison in relation to the that statistical methods require specification of a reference
general population is the observed to expected ratio (O/E) group. An optimal group would be non-exposed patients,
[or standardized incidence ratio (SIR)] of second cancers. however, this choice is usually unavailable. An alternative
Person-years of observation in the cohort, stratified by age, approach is to choose patients managed with surgery only
sex, calendar year, etc., are used to estimate the expected or a low-dose exposure group, bearing in mind that with the
numbers of second cancers, based on cancer incidence rates latter choice, the estimates may be diminished. An alter-
in the general population. The observed number of second native approach is to use continuous variables (e.g., radia-
cancers is then compared with the number expected. A tion dose) to model second cancer risk (Gilbert et al. 2003).
second type of calculation is the excess absolute risk (EAR), A potential weakness of nested case–control studies is
which is calculated by subtracting the expected number of overmatching. The intent of matching is to ensure compa-
second cancers from the observed number, dividing by the rability of cases and controls on confounding variables.
person-years at risk, and then multiplying by 10,000. In Overmatching occurs when a matching factor is not a
order to allow for a refined adjustment of the effects of age confounder, such as cancer stage, since stage commonly
at first and second cancer diagnosis, latency, and calendar influences therapy. The drawbacks of overmatching include
year, multivariable statistical methods have been effectively diminished statistical power to detect associations and lar-
applied (Travis et al. 2005). ger standard errors. A bias in the relative risk estimates
Even a large O/E ratio can translate into a small absolute typically does not occur.
risk, if the second cancer is rare in the general population.
For example, in an international registry-based study of HL
(Dores et al. 2002), the EAR of acute myeloid leukemia 3 Selected Results in the NCI SEER
(AML) was about 6 excess cases per 10,000 patients per Program, 1973–2000
year, although the SIR was over 20. Thus, the EAR is
especially useful in demonstrating which second cancers 3.1 Overview
account for the largest disease burden in a population, and
facilitates comparison with other late sequelae. In late 2006, the NCI published a systematic review of all
Other methods to measure risk in cohort studies involve subsequent neoplasms among cancer survivors reported
actuarial techniques in which censored data methods are from 1973 through 2000 to the nine original cancer regis-
used to evaluate in-cohort risk, e.g., the proportion of tries of the SEER Program (the states of Connecticut,
patients in whom a second cancer is diagnosed in a specified Hawaii, Iowa, New Mexico, and Utah; and the metropolitan
time period. A standard measure is the cumulative risk, in areas of Detroit, Atlanta, Seattle-Puget Sound, and San
which methods that allow for competing risks (Gooley et al. Francisco) (Curtis et al. 2006). These areas cover more than
1999) are usually used, since a patient may die of another 10 % of the U.S. population. This comprehensive review
cause before a second cancer is diagnosed. Even with provided information on more than 2 million cancer patients
actuarial estimation procedures, second cancer risk may be who survived at least 2 months, with nearly 390,000
overestimated if follow-up is more complete for patients patients surviving at least 10 years, and 76,000 patients
with complications who re-enter the health care system than surviving 20 or more years. Almost 11 million person-years
for those who remain well. at risk were accrued over the follow-up period.
The NCI monograph (Curtis et al. 2006) reported on the
risk of subsequent cancers following first primary cancers,
2.2 Case–Control Studies with one chapter each devoted to first cancers of the fol-
lowing sites: buccal cavity and pharynx; digestive tract
Nested case–control studies of cancer survivors provide an (excluding colorectal cancer); colon, rectum, and anus;
efficient approach to investigate in detail the role of treat- respiratory tract, breast cancer; uterine cervix, vagina, and
ment in second cancer risk, including quantification of the vulva; uterine corpus and ovary; male genital tract; urinary
dose–response relation with radiation or cumulative drug tract; bone, soft tissue, and Kaposi sarcoma; melanoma; brain
dose (Travis et al. 2003; van Leeuwen et al. 2003). In this and central nervous system; thyroid and other endocrine
type of study design, the diagnoses of second cancers glands; Hodgkin lymphoma, non-Hodgkin lymphoma, and
(cases) are ascertained in a well-defined cohort of cancer myeloma; leukemia; and childhood cancer. The risks of
survivors. Controls are a stratified, random matched sample subsequent cancers were evaluated by gender, age at diag-
of subjects without a second cancer derived from the same nosis of the initial cancer, and time since diagnosis, as well as
cohort. Therapies between cases and matched controls are the initial treatment and histologic type for selected cancers.
230 L. B. Travis and A. K. Ng

Table 1 Risk of subsequent primary cancer after any initial cancer, by age at initial diagnosis, SEER 1973–2000
Total Males Females
Age at initial diagnosis O O/E EAR O O/E EAR O O/E EAR
a a a
All ages 185,407 1.14 21 100,428 1.11 22 84,979 1.17 21
00–17 351 6.13a 15 176 6.44a 15 175 5.84a 15
a a a
18–29 1,401 2.92 22 562 3.39 22 839 2.67 23
30–39 4,909 2.37a 39 1,530 2.88a 40 3,379 2.20a 38
a a a
40–49 13,537 1.61 39 4,466 1.83 52 9,071 1.52 34
50–59 34,159 1.27a 32 15,957 1.33a 46 18,202 1.21a 24
a a a
60–69 62,286 1.13 23 35,986 1.11 25 26,300 1.14 22
70–79 52,321 1.02a 4 32,419 1.00 0 19,902 1.05a 9
a a a
80–115 16,443 0.92 -19 9,332 0.92 -26 7,111 0.93 -14
Notes All first primary cancers, except for non-melanoma skin, are included in the analysis. Subsequent cancers include second, third, and later
primaries and encompass all cancer sites, except for non-melanoma skin and subsequent prostate cancers following first primary prostate cancer.
Due to their large impact on subsequent cancer risks for males, O, O/E, and EAR were adjusted by excluding observed and expected numbers of
subsequent prostate cancers following an initial prostate cancer (O = 44, E = 15,185). The population at risk includes 2,036,597 patients who
survived 2 or more months after initial diagnosis during 1973–2000 (1,038,089 males and 998,508 females, 9 SEER registries). Numbers of
patients surviving at least 5, 10, and 20 years were 789, 221, 387, 436, and 75,859 patients, respectively. The age distribution at initial diagnosis
was 3.4, 14.2, 44.2, 25.6, and 12.6 % for age groups \30, 30–49, 50–69, 70–79, and [80 years, respectively. The average age at initial cancer
diagnosis was 64.6 years for men and 62.5 years for women
O observed number of subsequent (second, third, etc.) primary cancers, E expected numbers of subsequent cancers, O/E ratio of observed to
expected cancers, PYR person-years at risk, EAR excess absolute risk (excess cancers per 10,000 person-years, calculated as [(O-E)/
PYR]910,000)
a
P \ 0.05
Reproduced from (Curtis et al. 2006), which is a U.S. government work that may be reproduced or copied without permission

3.2 Summary of Overall Risks of Subsequent Although children (ages \18 years) demonstrated a 3.5 %
Cancers cumulative incidence of second cancer at 25 years, it is
expected that risk will continue to rise as these patients enter
Overall, 185,404 new primary cancers were observed com- the age period of increasing cancer incidence.
pared with 162,602 expected (O/E = 1.14; 95 %
C.I. = 1.14–1.15; excess absolute risk (EAR) 21 excess
subsequent cancer cases per 10,000 person-years) (Table 1). 3.3 Overall Patterns of Multiple Primary
A sizable percentage (93 %) of patients with multiple can- Cancers
cers had microscopic confirmation of each malignancy,
ensuring a low probability that metastasis from the first Tobacco and Alcohol. The risk of subsequent cancers fol-
malignancy would be misclassified as a new primary cancer. lowing initial primary cancers that have been typically
Notable differences were apparent by age at first cancer associated with tobacco and/or alcohol (e.g., cancers of oral
diagnosis with 6-fold relative risks for survivors of child- cavity/pharynx, esophagus, larynx, and lung) is shown in
hood cancer (O/E = 6.13) (Table 1), 2- to 3-fold increased Table 2. It should be noted that over 11,000 of the 24,688
risks for patients diagnosed as young adults (ages subsequent cancers among these patients similarly devel-
18–39 years), and 1.2- to 1.6-fold elevated risks for ages oped at these sites (O/E = 3.62). Curtis et al. (2006)
40–59 years. However, the largest burden of new malig- pointed out that tobacco/alcohol-related cancer sites
nancies in general was experienced by patients initially accounted for more than 35 % of the total excess cancers
diagnosed with cancer at ages 30–49 years, with an EAR of occurring in the SEER Program. The rate of excess cancers
39 per 10,000 person-years. (EAR) was estimated at 114 cases per 10,000 person-years.
For all cancers considered together, almost 14 % of SEER Curtis and colleagues also reported a differential influence
patients were diagnosed with a second cancer by 25 years of of tobacco or alcohol when the initial cancers were evalu-
follow-up (cumulative incidence of 5.0, 8.4, 10.8, and ated by histologic type (e.g., squamous cell carcinoma
13.7 % at 5, 10, 15, and 25 years, respectively). Cumulative versus adenocarcinoma of the esophagus), by cancer subsite
incidence of second cancer also varied by age at first cancer (e.g., renal pelvis versus renal parenchyma), or by earlier
diagnosis, and was highest among those diagnosed between age at initial diagnosis (e.g., age \70 versus older ages).
50 and 69 years of age (16.4 % at 25 years of follow-up). Further, the known impact of tobacco and alcohol on second
 The Bioepidemiology of Multiple Primary Cancers 231

Table 2 Risk of subsequent primary cancers following first primary cancers that are strongly related to tobacco and/or alcohol exposure (oral
cavity and pharynx, esophagus, larynx, lung, and bronchus), by sex, SEER 1973–2000
Total Males Females
Subsequent primary cancer O O/E EAR O O/E EAR O O/E EAR
All subsequent cancers 24,688 1.64a 114 17,491 1.58a 120 7,197 1.82a 105
Oral/pharynx, esophagus, larynx, and lung/bronchus 11,593 3.62a 99 8,184 3.20a 105 3,409 5.33a 90
a a
Oral/pharynx 2,510 9.04 26 1,742 7.78 28 768 14.29a 23
a a a
Larynx, lung/broncus 8,084 2.95 63 5,704 2.62 66 2,380 4.26 59
Esophagus 999 5.49a 10 738 4.74a 11 261 9.94a 8
a a a
Bladder, renal pelvis, ureter, and kidney parenchyma 1,772 1.44 6 1,449 1.39 8 323 1.71 4
Bladder, renal pelvis, ureter 1,325 1.42a 5 1,116 1.38a 6 209 1.68a 3
a a a
Kidney parenchyma 447 1.48 2 333 1.40 2 114 1.78 2
Pancreas 531 1.36a 2 346 1.28a 1 185 1.55a 2
Cervix uteri 60 1.16 \1 – – – 60 1.16 \1
Stomach 474 1.39a 2 395 1.44a 2 79 1.17 \1
All other cancers 10,258 1.05a 5 7,117 1.03a 4 3,141 1.08a 8
Notes The population at risk includes 336,929 patients who survived 2 or more months after an initial diagnosis of cancer of the oral cavity/
pharynx, esophagus, larynx, or lung/bronchus during 1973–2000 (221,000 males and 115,929 females, 9 SEER registries). Cancers of the oral
cavity/pharynx are defined to include cancers of the tongue, tonsil, mouth/floor of mouth, oropharynx, and hypopharynx. All subsequent cancers
include second, third, and later primaries and encompass all cancer sites, except for non-melanoma skin
O observed number of subsequent (second, third, etc.) primary cancers, E expected numbers of subsequent cancers, O/E ratio of expected
cancers; PYR person-years at risk, EAR excess absolute risk (excess cancers per 10,000 person-years, calculated as [(O-E)-PYR]910,000)
a
P \ 0.05
Reproduced from Curtis et al. (2006), which is a U.S. government work that may be reproduced or copied without permission

cancer risk is also shown by the risk reductions that have information that may influence on cancer risk. However,
been observed with cessation of exposures following the these variables likely played a role in the increased risk of
initial cancer diagnosis (Do et al. 2004). new malignancies among patients with cancers of the
Therapeutic Effects. Based on the systematic review of female breast, reproductive organs, and the upper and lower
all SEER program data, Curtis et al. (2006) concluded that digestive tract. In particular, Curtis et al. (2006) pointed out
cancer treatment among older adults did not appear to be that, in addition to tobacco and alcohol, a low intake of
linked with a sizable excess of subsequent cancers. In vegetables and fruits may have had an impact on the
contrast, children and young adults appeared to be espe- excesses of multicentric tumors along the upper aerodi-
cially susceptible to the carcinogenic effects of intensive gestive tract. Moreover, it was suggested that physical
treatment, as reviewed earlier (Travis et al. 2008). In the inactivity, excess caloric intake, obesity, and reproductive
SEER program, 5-year survivors of childhood cancer given variables likely influenced the patterns of hormone-depen-
radiotherapy initially had the largest risks of solid tumors, dent tumors (e.g., breast, uterine corpus, ovary, and pros-
consistent with the long latency period associated with tate), as well as colon cancer (Curtis et al. 2006).
radiogenic solid cancers. Radiotherapy appeared to con- Genetic Predisposition. Several patterns of multiple pri-
tribute to the heightened risk for solid tumors arising in mary cancers in the SEER Program appeared consistent with
areas in which high-dose, large-field radiotherapy had been previously reported familial cancer syndromes. In children
used in the past, in particular, for second cancers of breast, and young adults, the association of breast cancer, sarcoma,
lung, and other sites among patients with Hodgkin lym- and other cancers was likely reflective of Li-Fraumeni syn-
phoma, as reported previously (Travis et al. 2002, 2003, drome, which has been mainly linked with germline muta-
2005, 2008; Gilbert et al. 2003). Elevated risks of acute tions of p53 (reviewed in Travis et al. (2006)). Excess
leukemia were observed after radiotherapy for cancers of subsequent cancers of uterine corpus, ovary, bile ducts, small
cervix and uterine corpus. Among patients treated with intestine, and renal pelvis observed among patients with
radiotherapy for breast cancer, excesses cancers of the lung early-onset colon cancer were consistent with hereditary
and esophagus, as well as sarcomas, occurred. nonpolyposis colon cancer (Lynch syndrome), due to inher-
Dietary Factors and Hormones. Information reported to ited mutations in mismatch repair genes [reviewed in Travis
the SEER program does not include lifestyle factors (such et al. (2006)]. The sizable risks of contralateral breast and
as obesity, physical inactivity, and diet) or reproductive ovarian cancer among younger women with breast cancer are
232 L. B. Travis and A. K. Ng

consistent with heritable syndromes associated with germ- with lymphocyte predominant HL have been shown to be at
line mutations of BRCA1/2. higher risk for developing NHL than those with other histo-
Infection and Immunosuppression. Several constellations logic types. The prognosis of NHL after HL appears to be
of cancers may have reflected the influence of viruses [e.g., comparable to patients with de novo advanced-stage NHL
human papillomavirus (HPV), human immunodeficiency (Rueffer et al. 2001).
virus, human herpesvirus 8, Epstein-Barr virus, hepatitis B Solid tumors have emerged as the major type of second
and C, and Helicobacter pylori, together with immune malignancy after HL, comprising up to 75–80 % of all cases
dysregulation and inflammation (Hisada and Rabkin 2005; (Hodgson et al. 2007). Radiotherapy-associated solid tumors
Morgan et al. 2006)]. For example, cancers of cervix and usually develop after a considerably longer latency period (at
anogenital tract likely reflected a role of HPV infections. least 5–9 years) from the time of primary treatment of HL
The immune dysfunction inherent to chronic lymphocytic than do secondary leukemias, with increased risks persisting
leukemia probably contributed to the excess risks of cuta- for at least three decades (Hodgson et al. 2007). The majority
neous melanoma, as reported earlier (Travis et al. 1992). of second primary solid cancer arise within or at the edges of
prior HL radiotherapy fields, supporting an important role for
antecedent irradiation. Recent studies have also reported
4 Second Malignancies Among Survivors significant relationships with radiation dose for HL to the site
of Selected Adult Cancers of second tumor occurrence for selected solid cancers. In a
large international case–control investigation of women
4.1 Hodgkin Lymphoma treated for HL before age 30 years who developed breast
cancer (105 cases; 266 matched controls), radiation dose to
Given the high curability of HL and the generally young age the area of the breast where the tumor developed in the case
at diagnosis, a considerable body of work has documented (and a comparable area in matched controls) was estimated
the large risk of subsequent malignancies among these for each case–control set (Travis et al. 2003). Breast cancer
patients. The largest excesses of therapy-related leukemias risk increased significantly with increasing radiation dose to
in HL patients occur in the first decade after treatment (van reach 8-fold for the highest category (median dose 42 Gy)
Leeuwen and Travis 2005), with the initial reports dating compared to the lowest dose group (\4 Gy) (p trend for dose
back to the early 1970s (Arseneau et al. 1972). The elevated \0.001). In a separate Dutch study of women treated for HL
risk is largely accounted for by the antecedent alkylating before the age of 40 years (van Leeuwen et al. 2003), similar
agent chemotherapy, for which strong dose–response rela- results were found, with most of the latter patients also
tionships have been documented (Kaldor et al. 1990; van included in the international investigation (Travis et al.
Leeuwen et al. 1994). Data with regard to splenectomy for 2003). In both studies (Travis et al. 2003; van Leeuwen et al.
HL as well as the addition of radiation therapy to chemo- 2003), women who received both chemotherapy and radia-
therapy as additional risk factors for therapy-related leu- tion therapy had a significantly reduced risk (about 50 %)
kemia are conflicting (Henry-Amar 1992; Andrieu et al. compared to women given with radiation therapy alone;
1990). The prognosis after a diagnosis of secondary leu- moreover, the radiation-associated risks were decreased
kemia among HL patients is poor, with a median survival of among women given alkylating agents and/or who received a
less than 1 year (Ng et al. 2002). The replacement of radiation dose of 5 Gy or more to the ovaries. The Dutch
mechlorethamine, vincristine, procarbazine, and prednisone study, in particular, clearly showed that the marked risk
(MOPP) combination chemotherapy by adriamycin, bleo- reduction associated with chemotherapy was secondary to
mycin, vinblastine, and dacarbazine (ABVD) has substan- the high number of women who developed premature men-
tially reduced the risk of leukemia (Schonfeld et al. 2006). opause. Findings in both investigations indicated that ovarian
Possibly leukemogenic agents, however, are still given hormones are an important influence in promoting tumori-
during salvage therapy, and are often included in newer genesis, with radiation producing an initiating event (Travis
regimens, such as bleomycin, etoposide, adriamycin, et al. 2003; van Leeuwen et al. 2003).
cyclophosphamide, procarbazine, and prednisone (BEA- A highly significant dose–response relationship with
COPP) (Diehl et al. 2003). Thus, excess secondary leuke- radiation has similarly been shown for the development of
mias may eventually occur in subgroups of HL patients lung cancer after HL. In an international study by Travis
given selected new chemotherapy regimens. et al. (2002), lung cancer risk increased with increasing
Although an elevated risk of non-Hodgkin’s lymphoma radiation dose to the area of the lung in which cancer
(NHL) after HL has been reported (van Leeuwen and Travis developed, even among HL patients who received 40 or
2005), the relationship with prior therapy is unclear. Patients more Gy (p trend with dose \0.001); risk reached 7- to 9-
 The Bioepidemiology of Multiple Primary Cancers 233

fold at doses of 30 or more Gy. All risks were calculated in prompted a need for informed counseling. Estimates of the
relation to patients who received \5 Gy to the area of the cumulative absolute risk of breast cancer among young
lung in which cancer developed. women treated for HL at age 30 years or younger, however,
It should be pointed out that the data on solid tumors have varied widely ranging from 4.2 to 34 % at 20–25 years
after radiotherapy for HL are based on patients treated in an after treatment (Bhatia et al. 2003; Swerdlow et al. 2000;
era during which large treatment fields and very high Aisenberg et al. 1997; Sankila et al. 1996). Most estimates
radiation doses were used. In contrast, radiation treatment have not taken into account the influence of alkylating agent
fields are now significantly smaller with the current stan- therapy, which can reduce breast cancer risk (Travis et al.
dard consisting of involved-field radiation therapy given as 2003; van Leeuwen et al. 2003), or the effect of competing
part of combined modality therapy. Further, ongoing causes of mortality (Gooley et al. 1999). Accurate projec-
investigations are examining the effect of further reductions tions of breast cancer risk, as available for women in the
in radiation treatment dose for HL. Both these dose general population (Gail et al. 1989), are important to predict
reductions and the trend toward the use of involved-node the disease burden among the growing population of HL
radiation therapy will result in additional reductions in the survivors treated with past regimens and to facilitate the
exposure of normal tissue to radiation (Girinsky et al. development of risk-adapted long-term follow-up recom-
2006). Thus, it is likely that HL patients who receive mendations. Estimates of the cumulative absolute risk of
radiotherapy in the modern treatment era will incur a lower breast cancer for women treated for HL at age 30 years or
risk of solid tumors. younger were recently provided in terms of measures of
Given the historically important role of radiation therapy radiation dose and chemotherapy recorded in medical charts
in the treatment of HL, there is a deficit of long-term data on (Travis et al. 2005). The estimates also took into account age
late effects in those patients treated with chemotherapy and calendar year of HL diagnosis, age at counseling, base-
alone. In a British survey of 1,693 HL patients given che- line breast cancer incidence rates, and competing causes of
motherapy only, the relative risk of lung cancer was ele- mortality. For example, a HL survivor treated at age 25 years
vated 3-fold (RR = 3.3; 95 % C.I., 2.2–4.7) (Swerdlow with a chest radiation dose of at least 40 Gy without alkyl-
et al. 2000). The increased risk of lung cancer was com- ating agents had an estimated cumulative absolute risks of
parable in magnitude to HL patients who received either breast cancer by age 35, 45, and 55 years of 1.4, 11.1, and
radiation therapy alone (RR, 2.9, 95 % C.I., 1.9–4.1) or 29.0 %, respectively. Cumulative absolute risks were pre-
combined modality therapy (RR, 4.3, 95 % C.I., 2.9–6.2). dictably lower in women also treated with alkylating agents
Most HL patients in this study were treated with alkylating- used in the past, which frequently caused in ovarian failure.
agent based chemotherapy. The important role of alkylating In comparison, in the general population the absolute risks of
agents given for HL in the subsequent occurrence of lung breast cancer in white women from age 20 years to ages 30,
cancer was confirmed in a case–control study by the same 40, 50, and 60 years are, respectively, 0.04, 0.5, 2.0, and
British group (Swerdlow et al. 2001), and in the NCI- 4.3 %. Travis et al. (2005) emphasized that the risk estimates
international case–control study described above (Travis are most relevant for HL survivors treated with past regi-
et al. 2002); both investigations demonstrated significant mens, and should be used circumspectly in women treated
dose–response relationships between cumulative amount of with more recent approaches, including limited-field radio-
alkylating agent chemotherapy and lung cancer risk. therapy and/or ovary-sparing chemotherapy.
Age is an important modifying factor in the risk of Tobacco use is another important factor that modifies the
selected treatment-related second cancers after HL. Young risk of treatment-related lung cancer among HL survivors. In
age at mantle irradiation has consistently been shown to be the NCI-International case–control study of lung cancer
associated with a significantly increased risk of breast described above (Travis et al. 2002), in which the reference
cancer in patients with HL (Travis et al. 2003; Ng et al. (comparison) group was comprised of HL patients with
2002; Hodgson et al. 2007; van Leeuwen et al. 2000), which minimal radiation exposure and who were non-smokers or
is not consistent with the known radiosensitivity of the light smokers, those patients given either alkylating agent
breast in young women. In a recent population-based cohort chemotherapy alone or 5 or more Gy of radiation therapy
study by Hodgson et al., the absolute risks of breast cancer alone to the region of the lung in which cancer developed
in women diagnosed with HL at ages 15–25 were 34–47 per later experienced 4.3- and 7.2-fold increased risks of lung
10,000 person-years at 10 years, which was higher than the cancer, respectively. These relative risks increased to 16.8-
absolute risks of women in the general population between and 20.2-fold, respectively, among those HL patients who
50 and 54 years, the typical age at which screening mam- also smoked at least one pack of cigarettes per day. For those
mography is recommended (Hodgson et al. 2007). cigarette smokers (at least one pack per day) also given
The increasing awareness of the substantial excesses of alkylating agent chemotherapy and 5 or more Gy of radiation
breast cancer after therapy for HL at a young age has therapy to the area of the lung in which cancer developed, a
234 L. B. Travis and A. K. Ng

significantly increased 50-fold relative risk of lung cancer Excess leukemias after testicular cancer have been
was evident, consistent with a multiplicative effect of linked to both antecedent chemotherapy and radiation
smoking on the risk of treatment-related lung cancer. therapy (van den Belt-Dusebout et al. 2007; Travis et al.
As data on second malignancy risk after HL therapy have 2000; Pedersen-Bjergaard et al. 1991; Kollmannsberger
been generated, increasing research and clinical efforts have et al. 1999). Chemotherapeutic agents that have been
been directed toward the development of programs for early associated with the development of leukemia in testicular
detection and prevention of a new cancer and for risk factor cancer patients include cisplatin and etoposide (Travis et al.
modification (e.g., smoking cessation) as well as treatment 2000; Pedersen-Bjergaard et al. 1991; Kollmannsberger
refinements (described above) (Mauch et al. 2005). These et al. 1999). An international population-based study by
iterative efforts may provide a useful model for managing Travis et al. examined treatment-associated leukemia in
survivors of other primary cancers for whom long-term data 18,567 men with testicular cancer who had survived at least
on excess second malignancies are only now emerging. one year. The risk of leukemia increased significantly with
increasing radiation field size, which was reflected in total
dose to active bone marrow. Further, after taking into
4.2 Testicular Cancer account the dose of radiation to active bone marrow, the
risk of leukemia was also significantly associated with
Testicular cancer is highly curable and largely affects young cumulative amount of cisplatin (Travis et al. 2000), with too
patients, who currently have a 95 % 5-year relative survival few patients exposed to etoposide to reliably evaluate risk.
rate. Past treatments for testicular cancer included the use of
relatively large radiotherapy fields, and second malignan-
cies are an important cause of death among these patients 4.3 Breast Cancer
(Schairer et al. 2007; van den Belt-Dusebout et al. 2007).
Increased risks for secondary leukemias have been Women with breast cancer comprise about 20 % of all
reported in survivors of testicular cancer, as well as excess cancer survivors. An extensive amount of data exist for
solid tumors, including malignant mesothelioma, and can- contralateral breast cancer, which is related in large part to
cers of the lung, thyroid, esophagus, stomach, pancreas, pre-existing breast cancer risk factors (Kirova et al. 2007;
colon, rectum, kidney, bladder, and connective tissue Boice et al. 1992; Storm et al. 1992). Prior radiation therapy
(Travis et al. 2005). Excess contralateral testicular cancers may also contribute to excess risks, especially among
have also been observed, which are likely due to underlying women treated at a young age. Endometrial cancer is
predisposition rather than treatment. In a large population- another second malignancy that is related to both shared
based study of 29,515 U.S. testicular cancer survivors, the risk factors and breast cancer therapy, in particular,
15-year cumulative risk of contralateral testicular cancer tamoxifen. Lung cancer and sarcoma are other solid tumors
was 1.9 %, and represented a 12.4-fold higher risk than that that have been reported in breast cancer survivors, with
expected in the general population (Fossa et al. 2005). risks largely related to radiotherapy exposure. An increased
Many solid tumors which follow testicular cancer, risk of leukemia after breast cancer has been associated with
depending on site, are likely due in part to the historical use antecedent chemotherapy and radiation therapy.
of para-aortic and pelvic radiation therapy for testicular The risk of contralateral breast cancer is increased 2- to
cancer; mediastinal irradiation was also given through the 5-fold among breast cancer survivors (Boice et al. 1992).
1970s. In the largest international population-based study of Conflicting information exists on the contribution of radi-
testicular cancer survivors to date, Travis et al. described ation therapy to the excess risks (Kirova et al. 2007; Boice
site-specific solid tumor risk among 40,576 testicular cancer et al. 1992; Gao et al. 2003; Hill-Kayser et al. 2006). In a
patients (Travis et al. 2005) who were followed for an case–control study by Boice et al., the overall relative risk
average of 11.8 years. The relative risks of developing a of contralateral breast cancer was not significantly elevated
solid tumor were significantly increased after both radiation after radiation therapy (RR, 1.19, 95 % C.I., 0.94, 1.15)
therapy alone and chemotherapy alone (RR, 2.0 and 1.8, (Boice et al. 1992). Among those patients who were under
respectively). Although the relative risk was somewhat 45 years of age at the time of irradiation, however, the
higher among patients who received both chemotherapy and relative risk was significantly elevated (RR, 1.59; 95 % C.I.
radiation therapy (RR, 2.9), the risk did not differ signifi- 1.07–2.36). In contrast, in a separate large case–control
cantly from those patients treated with single-modality study undertaken in Denmark, there was no significant
therapy. For the group of infradiaphragmatic solid tumors difference in the risk of contralateral breast cancer in
that were likely related to prior radiation treatment (based women who did and did not receive radiation therapy,
on anatomic site of development), the relative risks regardless of age at treatment (Storm et al. 1992). In the
increased significantly with increasing follow-up time. latter investigation, contralateral tumors were uniformly
 The Bioepidemiology of Multiple Primary Cancers 235

distributed in the medial, lateral, and central portions of the ipsilateral lung also supports a contributing role of radiation
breast, a pattern which was also not consistent with a causal therapy to the elevated risk (Zablotska and Neugut 2003).
role of radiotherapy. In a report from the Early Breast Several studies showed an even greater increase in lung
Cancer Trialists’ Collaborative Group, a significantly cancer risk among smokers given breast irradiation (Neugut
increased risk of contralateral breast cancer was reported et al. 1994; Ford et al. 2003), although any interaction
after radiotherapy, primarily during the period 5–14 years between tobacco exposure and prior radiation therapy on
after randomization (RR, 1.43, p = 0.00001), a latency subsequent lung cancer risk is not as well-delineated as in
pattern which is not consistent with the late effects of HL survivors.
radiotherapy; significant excesses following radiotherapy The 15-year cumulative incidence of sarcoma after
were reported even among women aged 50 years or older breast cancer is low (\0.5 %), although the relative risk has
(RR, 1.25, p = 0.002) (Clarke et al. 2005). A recent large been estimated to be as high as 7-fold, given the low
survey of 13,472 breast cancer patients treated at the Institut background incidence in the general population (Kirova
Curie did not demonstrate an increased overall risk of et al. 2005, 2007; Huang and Mackillop 2001; Karlsson
contralateral tumors among women who received radiation et al. 1998). In an Italian study of breast cancer survivors
therapy compared to those who did not receive irradiation conducted by Rubino et al. (2003), all subsequent sarcomas
(RR, 1.1, 95 % C.I., 0.96–1.27); however, analyses by were either localized to the previously irradiated fields or to
patient age were not performed (Kirova et al. 2007). the upper extremity of the arm ipsilateral to the treated
Tamoxifen, which is prescribed as adjuvant therapy for breast among women given radiotherapy. By estimating the
many breast cancer patients with estrogen-receptor positive initial radiation dose to the site of sarcoma development,
tumors, has been shown to reduce the risk of contralateral using a dose of \14 Gy as reference, women who received
tumors by 30–40 % (Fisher et al. 2005). Nonetheless, a 14–44 Gy had a 1.6-fold increased risk of sarcoma, while
number of large studies have clearly shown a 2- to 4-fold those who received [45 Gy to the site had a 30.6-fold
increased risk of endometrial cancer after tamoxifen therapy increased risk (p trend for dose \0.001). Angiosarcoma
(Fisher et al. 1994, 1998). Whereas early studies suggested after breast cancer was initially shown to be associated with
that endometrial cancer after tamoxifen therapy might have chronic lymphedema following radical mastectomy (Jessner
a more favorable prognosis compared with de novo tumors, et al. 1952). Given the increasing use of radiotherapy with
more recent data have suggested that tamoxifen-related breast-conserving surgery, a growing number of reports
endometrial cancers may demonstrate more aggressive now document the occurrence of cutaneous angiosarcoma
behavior (Magriples et al. 1993; Bergman et al. 2000; of the breast arising in the radiation field (Kirova et al.
Saadat et al. 2007). However, because most endometrial 2005; Esler-Brauer et al. 2007; Virtanen et al. 2007; Si-
cancers that develop after tamoxifen therapy are detected at monart and Heenen 2004). Dissimilar to other radiation-
an early stage and are thus able to be surgically resected related soft tissue sarcomas, breast angiosarcoma appears to
(Saadat et al. 2007), these cancers do not appear to be have a short latency period, with diagnoses documented in
associated with poorer endometrial cancer-specific survival. the first 5 years after therapy.
Radiation therapy is an important modality in the treat- Excess leukemias following breast cancer are related to
ment of breast cancer, either as part of breast-conserving prior chemotherapy and radiation therapy (Boice et al.
therapy or as post-mastectomy radiation therapy. Other 1992; Curtis et al. 1992; Praga et al. 2005; Campone et al.
solid tumors have also been linked to radiotherapy for 2005). In a population-based, nested case–control study of
breast cancer, including lung cancer, soft tissue sarcoma, women treated for breast cancer between 1973 and 1985,
and esophageal cancer. In a number of studies (Kirova et al. Curtis et al. (1992) showed that compared to women who
2007; Roychoudhuri et al. 2004; Neugut et al. 1993), did not receive alkylating agent chemotherapy or radiation
women who received radiation therapy have been shown to therapy, the relative risks of acute myelogenous leukemia
be at a 1.5- to 3-fold increased risk of developing lung after radiation therapy alone, alkylating chemotherapy
cancer compared to women who did not receive radiation alone, and both chemotherapy and radiation therapy were
therapy. The increased risk appeared to be more clearly 2.4, 10.0, and 17.4, respectively. A significant dose–
related to post-mastectomy radiation therapy, in which the response relation was observed for either cumulative dose
target volume often also includes the supraclavicular, axil- of melphalan, cyclophosphamide, or radiation to the active
lary and/or internal mammary nodal region, thus exposing a bone marrow, and subsequent leukemia risk. This study,
larger volume of underlying lung tissue to radiation, while however, was conducted in a period when higher cumula-
the existence of any increased risk after post-lumpectomy tive doses of chemotherapy and larger field radiation ther-
radiation therapy is less certain (Zablotska and Neugut apy were used than are presently given. Further, melphalan-
2003; Deutsch et al. 2003). The observation that lung cancer containing regimens are no longer used in the treatment of
after breast cancer therapy is more frequently found in the breast cancer. Recent data demonstrate that the risk of
236 L. B. Travis and A. K. Ng

secondary acute leukemia is more significantly related to does not collect data on type of radiotherapy. A more recent
the dose-intensity of cyclophosphamide than with cumula- investigation using the linked SEER-Medicare database
tive dose (Smith et al. 2003), an observation which is studied a larger group of prostate cancer patients, including
noteworthy in view of the increasing trend toward the use of those treated in the more recent era (Moon et al. 2006). Men
dose-intensified regimens for breast cancer. Even as evo- given external beam radiotherapy demonstrated signifi-
lutions in systemic chemotherapy for breast cancer may cantly increased risks of malignant melanoma, and cancers
eventually affect the risk of second malignancies, recent of bladder, rectum, colon, brain, stomach, and lung, with
advances in radiation therapy, including the use of intensity odds ratios ranging from 1.25 to 1.85, when compared with
modulated therapy radiation, and the growing interest in men who did not receive external beam radiation therapy.
partial breast irradiation (Chen and Vicini 2007) may also Patients who received radioactive implants with or without
influence the risk profile. The degree to which second external beam radiation therapy, however, did not show
cancer risk will be affected by these newer radiation therapy significant excesses of second cancers, when compared with
approaches and techniques will have to be documented those who did not receive radiation.
through long-term follow-up of sufficiently large cohorts of Another updated survey of prostate cancer patients
breast cancer survivors, which will enable sufficient statis- reported to the SEER program (1973–2001) focused on the
tical power for the detection of increased risks. risk of rectal cancer following irradiation (Kendal et al.
2006). Unlike previous studies, a significant association
between radiation therapy and subsequent excesses of rectal
4.4 Prostate Cancer cancer were not found. Results of Cox proportional hazards
analysis (with prostate irradiation, prostate surgery and age
Given the large number of prostate cancer survivors, the at diagnosis entered as covariates) showed that only
issue of the late effects of cancer and its treatment have increasing age was associated with an increased risk of
become critically important. In recent years, an increasing subsequent rectal cancer.
number of reports have documented an increased risk of Among prostate cancer patients given radiotherapy and
second cancers after radiation therapy for prostate cancer reported to the British Columbia Tumor Registry (Pickles
[reviewed in van Leeuwen and Travis (2005)]. In an early and Phillips 2002), significantly increased risks of sarcoma
report (Neugut et al. 1997), the risk of second cancers fol- (RR = 1.7, p \ 0.05), colorectal cancer (RR = 1.21,
lowing radiotherapy for prostate carcinoma was evaluated p \ 0.01), and pleural cancer (RR = 2.28, p \ 0.01) were
among patients reported to the population-based registries observed. Although significant bladder cancer excesses
which comprise the NCI’s Surveillance, Epidemiology, and were not apparent in the radiotherapy cohort, risks for both
End Results (SEER) program (1973–1990). Patients treated bladder cancer (RR = 1.32, p \ 0.01) and testicular cancer
with radiation therapy had significant excesses of bladder (RR = 2.82, p \ 0.05) were significantly increased in the
cancer after a latent period of 8 years (RR, 1.5, 95 % C.I., non-irradiated cohort, which were attributed to heightened
1.1–2.0), while excesses were not apparent among men who surveillance.
did not receive radiation therapy. In a more recent survey, Most of the investigations to date that evaluate the risk of
utilizing the Mayo Clinic Cancer Registry (Chrouser et al. malignancies among prostate cancer survivors are based on
2005), the overall relative risk of bladder cancer after data reported to population-based tumor registries. The
radiation therapy was not significantly increased. However, conflicting observations with regard to the contribution of
among those men given adjuvant radiation therapy after a radiotherapy to various second malignancies after prostate
radical prostatectomy, the relative risk of bladder cancer cancer may reflect a number of factors, including the stan-
was 5-fold higher than expected (p = 0.05), which may dard procedure of most registries to gather data only on
reflect the larger volume of bladder tissue exposed to initial course of therapy, the incomplete registration of this
radiation in the post-operative setting. initial treatment, and misclassification. Moreover, selection
In an updated study of prostate cancer patients reported bias may be operant in decisions to manage patients with
to the SEER Program (1973–1993), second cancer risks either surgery alone or radiation therapy, and the limited
among men who were initially given radiation therapy were data available in most population-based registries do not
compared with those observed after surgery alone (Brenner permit the identification of confounding factors. Patients
et al. 2000). Men given radiotherapy demonstrated signifi- with significant co-morbid illnesses and/or a history of
cant excesses of sarcoma and cancers of lung, bladder, and heavy tobacco use may not be treated with surgery and may
rectum. The elevated risks of lung cancer were hypothe- be more likely to be given radiation therapy. Further, among
sized to reflect low scatter doses of radiation to the lungs. prostate cancer patients given radiation therapy, treatment-
This finding may be more relevant to men given Cobalt related sequelae such as cystitis, hematuria, proctitis, and
irradiation to the whole pelvis, although the SEER program rectal bleeding may lead to additional cystoscopies or
 The Bioepidemiology of Multiple Primary Cancers 237

colonoscopies, which can then result in an apparent increase consequence of success, and not observed unless a patient
in the incidence of urologic and colorectal cancers. survives an initial cancer diagnosis. Thus, it must be kept in
In those studies that show significant excesses of cancers mind that the survival benefits provided by many cancer
after radiotherapy for prostate cancer, the overall risk treatments greatly outweigh the risk of developing a second
appears to be low. In the investigation by Brenner and primary cancer. Moreover, as so clearly shown in the recent
colleagues, which included prostate cancer patients given systematic review of the SEER program data (Curtis et al.
larger field Cobalt irradiation, the risk of developing a 2006), lifestyle choices such as alcohol or tobacco use have a
second malignancy was estimated at 1 in 290 (Brenner et al. sizable impact on the risk of second cancers, as well as on the
2000). In the last few years, intensity modulated radiation occurrence of first primary cancers. Results in the SEER
therapy (IMRT) has been increasingly utilized to treat program also confirm that multiple primary cancers can
prostate cancer in order to permit more conformal dose reflect the late effects of therapy, the influence of other factors
distribution and dose escalation (Guckenberger and Flentje including nutrition and hormones, infections and immuno-
2007). Depending on treatment energy, IMRT is associated suppression, genetic predisposition, other host factors,
with a 3- to 5-fold higher number of monitor units as environmental determinants, and the operation of joint
compared with conventional treatment. Applying risk effects, including gene–environment and gene–gene inter-
coefficients from the National Council of Radiation Pro- actions (Travis et al. 2006; Travis 2002).
tection and Measurements for specific anatomic sites to this
configuration, the risks of second malignancy using IMRT
techniques have been estimated to be 2–3 times higher than References
that after conventional radiation therapy (Kry et al. 2005).
These preliminary estimates remain to be confirmed in Aisenberg AC, Finkelstein DM, Doppke KP et al (1997) High risk of
epidemiologic studies which include large numbers of breast carcinoma after irradiation of young women with Hodgkin’s
patients given IMRT who have been followed for sufficient disease. Cancer 79:1203–1210
Allan JM, Travis LB (2005) Mechanisms of therapy-related carcino-
periods of time to permit detection of any increased radio- genesis. Nat Rev Cancer 5:943–955
therapy-associated risk. Andrieu JM, Ifrah N, Payen C et al (1990) Increased risk of secondary
acute nonlymphocytic leukemia after extended-field radiation
therapy combined with MOPP chemotherapy for Hodgkin’s
disease. J Clin Oncol 8:1148–1154
5 Comment Anonymous [No authors listed] (2004) Cancer survivors: living longer,
and now, better [editorial]. Lancet 364:2153–2154
Arseneau JC, Sponzo RW, Levin DL et al (1972) Nonlymphomatous
In view of the increasing numbers of cancer survivors, the
malignant tumors complicating Hodgkin’s disease. Possible asso-
development of second malignant neoplasms has emerged as ciation with intensive therapy. N Engl J Med 287:1119–1122
a significant complication that can affect quality of life and Behrens C, Travis LB, Wistuba II et al (2000) Molecular changes in
long-term survival. It is critical to continue to describe and second primary lung and breast cancers after therapy for Hodgkin’s
disease. Cancer Epidemiol Biomark Prev 9:1027–1035
quantify the site-specific risks of second malignancies.
Bergman L, Beelen ML, Gallee MP et al (2000) Risk and prognosis of
Moreover, the evolving patterns have important implications endometrial cancer after tamoxifen for breast cancer. Comprehen-
for patient counseling and the recommendation of behavioral sive cancer centres’ ALERT group. Assessment of liver and
changes (e.g., smoking cessation), cancer screening and endometrial cancer risk following tamoxifen. Lancet 356:881–887
Bhatia S, Landier W (2005) Evaluating survivors of pediatric cancer.
prevention strategies. Where efficacious screening methods
Cancer J 11:340–354
(e.g., mammographic examination) are available, these Bhatia S, Yasui Y, Robison LL et al (2003) High risk of subsequent
modalities should be included in patient follow-up, as indi- neoplasms continues with extended follow-up of childhood Hodg-
cated, e.g., for women treated for HL at a young age with the kin’s disease: report from the late effects study group. J Clin Oncol
21:4386–4394
wide-field, high-dose chest radiotherapy treatments of the
Boice JD Jr, Harvey EB, Blettner M et al (1992) Cancer in the
past [reviewed in Travis et al. (2008)]. Preventive approaches contralateral breast after radiotherapy for breast cancer. N Engl J
will also decrease the risk of selected second cancers, and Med 326:781–785
cancer survivors should be strongly advised to implement Brenner DJ, Curtis RE, Hall EJ et al (2000) Second malignancies in
prostate carcinoma patients after radiotherapy compared with
practices consistent with a healthy lifestyle. An improved
surgery. Cancer 88:398–406
recognition and understanding of second malignancies can Campone M, Roche H, Kerbrat P et al (2005) Secondary leukemia
inform changes in regimens to minimize exposure to cyto- after epirubicin-based adjuvant chemotherapy in operable breast
toxic agents. Modification or reduction of current treatments cancer patients: 16 years experience of the French adjuvant study
group. Ann Oncol 16:1343–1351
that have established efficacy, however, should not be
Chen PY, Vicini FA (2007) Partial breast irradiation. Patient selection,
undertaken outside the context of clinical trials. Further, it is guidelines for treatment, and current results. Front Radiat Ther
important to remember that second malignancies are a Oncol 40:253–271
238 L. B. Travis and A. K. Ng

Chrouser K, Leibovich B, Bergstralh E et al (2005) Bladder cancer risk Girinsky T, van der Maazen R, Specht L et al (2006) Involved-node
following primary and adjuvant external beam radiation for radiotherapy (INRT) in patients with early Hodgkin lymphoma:
prostate cancer. J Urol 174:107–110, discussion 110–101 concepts and guidelines. Radiother Oncol 79:270–277
Clarke M, Collins R, Darby S et al (2005) Effects of radiotherapy and Gooley TA, Leisenring W, Crowley J et al (1999) Estimation of failure
of differences in the extent of surgery for early breast cancer on probabilities in the presence of competing risks: new representa-
local recurrence and 15-year survival: an overview of the tions of old estimators. Stat Med 18:695–706
randomised trials. Lancet 366:2087–2106 Guckenberger M, Flentje M (2007) Intensity-modulated radiotherapy
Curtis RE, Boice JD Jr, Stovall M et al (1992) Risk of leukemia after (IMRT) of localized prostate cancer: a review and future perspec-
chemotherapy and radiation treatment for breast cancer. N Engl J tives. Strahlenther Onkol 183:57–62
Med 326:1745–1751 Henry-Amar M (1992) Second cancer after the treatment for
Curtis RE, Ron E, Hankey BA et al (2006) New malignancies Hodgkin’s disease: a report from the International Database on
following breast cancer. In: Curtis RE, Freedman DM, Ron E et al Hodgkin’s Disease. Ann Oncol 3(Suppl 4):117–128
(eds) New malignancies among cancer survivors: SEER cancer Hill-Kayser CE, Harris EE, Hwang WT et al (2006) Twenty-year
registries, 1973–2000. NIH publication no. 05-5302. National incidence and patterns of contralateral breast cancer after breast
Cancer Institute, Bethesda, pp 181–205 conservation treatment with radiation. Int J Radiat Oncol Biol Phys
Deutsch M, Land SR, Begovic M et al (2003) The incidence of lung 66:1313–1319
carcinoma after surgery for breast carcinoma with and without Hisada M, Rabkin CS (2005) Viral causes of cancer. In: Shields PG
postoperative radiotherapy. Results of national surgical adjuvant (ed) Cancer risk assessment. Taylor and Francis, Boca Raton,
breast and bowel project (NSABP) clinical trials B-04 and B-06. pp 287–311
Cancer 98:1362–1368 Hodgson DC, Gilbert ES, Dores GM et al (2007) Long-term solid
Diehl V, Franklin J, Pfreundschuh M et al (2003) Standard and increased- cancer risk among 5-year survivors of Hodgkin’s lymphoma. J Clin
dose BEACOPP chemotherapy compared with COPP-ABVD for Oncol 25:1489–1497
advanced Hodgkin’s disease. N Engl J Med 348:2386–2395 Huang J, Mackillop WJ (2001) Increased risk of soft tissue sarcoma
Do KA, Johnson MM, Lee JJ et al (2004) Longitudinal study of after radiotherapy in women with breast carcinoma. Cancer
smoking patterns in relation to the development of smoking-related 92:172–180
secondary primary tumors in patients with upper aerodigestive tract Jessner M, Zak FG, Rein CR (1952) Angiosarcoma in postmastectomy
malignancies. Cancer 101:2837–2842 lymphedema (Stewart-Treves syndrome). AMA Arch Dermatol
Dores GM, Metayer C, Curtis RE et al (2002) Second malignant Syphilol 65:123–129
neoplasms among long-term survivors of Hodgkin’s disease: a Kaldor JM, Day NE, Clarke EA et al (1990) Leukemia following
population-based evaluation over 25 years. J Clin Oncol Hodgkin’s disease. N Engl J Med 322:7–13
20:3484–3494 Karlsson P, Holmberg E, Samuelsson A et al (1998) Soft tissue
Dores G, Schonfeld S, Chen J et al (2005) Long-term cause-specific sarcoma after treatment for breast cancer—a Swedish population-
mortality among 41–146 one-year survivors of Hodgkin lymphoma based study. Eur J Cancer 34:2068–2075
(HL). Proc Am Soc Clin Oncol 23:562S Kendal WS, Eapen L, Macrae R et al (2006) Prostatic irradiation is not
Esler-Brauer L, Jaggernauth W, Zeitouni NC (2007) Angiosarcoma associated with any measurable increase in the risk of subsequent
developing after conservative treatment for breast carcinoma: case rectal cancer. Int J Radiat Oncol Biol Phys 65:661–668
report with review of the current literature. Dermatol Surg 33:749–755 Kirova YM, Vilcoq JR, Asselain B et al (2005) Radiation-induced
Fisher B, Costantino JP, Redmond CK et al (1994) Endometrial cancer sarcomas after radiotherapy for breast carcinoma: a large-scale
in tamoxifen-treated breast cancer patients: findings from the single-institution review. Cancer 104:856–863
national surgical adjuvant breast and bowel project (NSABP) B-14 Kirova YM, Gambotti L, De Rycke Y et al (2007) Risk of second
[see comments]. J Natl Cancer Inst 86:527–537 malignancies after adjuvant radiotherapy for breast cancer: a large-
Fisher B, Costantino JP, Wickerham DL et al (1998) Tamoxifen for scale, single-institution review. Int J Radiat Oncol Biol Phys
prevention of breast cancer: report of the national surgical adjuvant 68:359–363
breast and bowel project P-1 Study [see comments]. J Natl Cancer Kollmannsberger C, Hartmann JT, Kanz L et al (1999) Therapy-
Inst 90:1371–1388 related malignancies following treatment of germ cell cancer. Int J
Fisher B, Costantino JP, Wickerham DL (2005) Effects of chemo- Cancer 83:860–863
therapy and hormonal therapy for early breast cancer on recurrence Kry SF, Salehpour M, Followill DS et al (2005) The calculated risk of
and 15-year survival: an overview of the randomised trials. Lancet fatal secondary malignancies from intensity-modulated radiation
365:1687–1717 therapy. Int J Radiat Oncol Biol Phys 62:1195–1203
Ford MB, Sigurdson AJ, Petrulis ES et al (2003) Effects of smoking Magriples U, Naftolin F, Schwartz PE et al (1993) High-grade
and radiotherapy on lung carcinoma in breast carcinoma survivors. endometrial carcinoma in tamoxifen-treated breast cancer patients.
Cancer 98:1457–1464 J Clin Oncol 11:485–490
Fossa SD, Chen J, Schonfeld SJ et al (2005) Risk of contralateral Mauch P, Ng A, Aleman B et al (2005) Report from the Rockefellar
testicular cancer: a population-based study of 29,515 U.S. men. Foundation Sponsored International Workshop on reducing mor-
J Natl Cancer Inst 97:1056–1066 tality and improving quality of life in long-term survivors of
Gail MH, Brinton LA, Byar DP et al (1989) Projecting individualized Hodgkin’s disease. Bellagio, Italy, 9–16 July 2003. Eur J Haematol
probabilities of developing breast cancer for white females who are (supp):68–76
being examined annually. J Natl Cancer Inst 81:1879–1886 Moon K, Stukenborg GJ, Keim J et al (2006) Cancer incidence after
Gao X, Fisher SG, Emami B (2003) Risk of second primary cancer in localized therapy for prostate cancer. Cancer 107:991–998
the contralateral breast in women treated for early-stage breast Morgan GJ, Linet MS, Rabkin CS (2006) Immunologic factors. In:
cancer: a population-based study. Int J Radiat Oncol Biol Phys Schottenfeld D, Fraumeni JFJ (eds) Cancer epidemiology and
56:1038–1045 prevention. Oxford University Press, New York, pp 549–561
Gilbert ES, Stovall M, Gospodarowicz M et al (2003) Lung cancer Neugut AI, Robinson E, Lee WC et al (1993) Lung cancer after
after treatment for Hodgkin’s disease: focus on radiation effects. radiation therapy for breast cancer [see comments]. Cancer
Radiat Res 159:161–173 71:3054–3057
 The Bioepidemiology of Multiple Primary Cancers 239

Neugut AI, Murray T, Santos J et al (1994) Increased risk of lung Swerdlow AJ, Barber JA, Hudson GV et al (2000) Risk of second
cancer after breast cancer radiation therapy in cigarette smokers malignancy after Hodgkin’s disease in a collaborative British
[see comments]. Cancer 73:1615–1620 cohort: the relation to age at treatment. J Clin Oncol 18:498–509
Neugut AI, Ahsan H, Robinson E et al (1997) Bladder carcinoma and Swerdlow AJ, Schoemaker MJ, Allerton R et al (2001) Lung cancer
other second malignancies after radiotherapy for prostate carci- after Hodgkin’s disease: a nested case-control study of the relation
noma. Cancer 79:1600–1604 to treatment. J Clin Oncol 19:1610–1618
Ng AK, Bernardo MV, Weller E et al (2002) Second malignancy after Travis LB (2002) Therapy-associated solid tumors. Acta Oncol
Hodgkin disease treated with radiation therapy with or without 41:323–333
chemotherapy: long-term risks and risk factors. Blood Travis LB, Curtis RE, Hankey BF et al (1992) Second cancers in
100:1989–1996 patients with chronic lymphocytic leukemia. J Natl Cancer Inst
Pedersen-Bjergaard J, Daugaard G, Hansen SW et al (1991) Increased 84:1422–1427
risk of myelodysplasia and leukemia after etoposide, cisplatin, and Travis LB, Andersson M, Gospodarowicz M et al (2000) Treatment-
bleomycin for germ-cell tumours. Lancet 338:359–363 associated leukemia following testicular cancer. J Natl Cancer Inst
Pickles T, Phillips N (2002) The risk of second malignancy in men 92:1165–1171
with prostate cancer treated with or without radiation in British Travis LB, Gospodarowicz M, Curtis RE et al (2002) Lung cancer
Columbia, 1984–2000. Radiother Oncol 65:145–151 following chemotherapy and radiotherapy for Hodgkin’s disease.
Praga C, Bergh J, Bliss J et al (2005) Risk of acute myeloid leukemia J Natl Cancer Inst 94:182–192
and myelodysplastic syndrome in trials of adjuvant epirubicin for Travis LB, Hill DA, Dores GM et al (2003) Breast cancer following
early breast cancer: correlation with doses of epirubicin and radiotherapy and chemotherapy among young women with Hodg-
cyclophosphamide. J Clin Oncol 23:4179–4191 kin disease. JAMA 290:465–475
Ries L, Melbert D, Krapcho M et al (2007) SEER cancer statistics Travis LB, Fossa SD, Schonfeld SJ et al (2005a) Second cancers
review, 1975–2004. National Cancer Institute, Bethesda among 40,576 testicular cancer patients: focus on long-term
Roychoudhuri R, Evans H, Robinson D et al (2004) Radiation-induced survivors. J Natl Cancer Inst 97:1354–1365
malignancies following radiotherapy for breast cancer. Br J Cancer Travis LB, Hill D, Dores GM et al (2005b) Cumulative absolute breast
91:868–872 cancer risk for young women treated for Hodgkin lymphoma.
Rubino C, de Vathaire F, Shamsaldin A et al (2003) Radiation dose, J Natl Cancer Inst 97:1428–1437
chemotherapy, hormonal treatment and risk of second cancer after Travis LB, Rabkin CS, Brown LM et al (2006) Cancer survivorship—
breast cancer treatment. Br J Cancer 89:840–846 genetic susceptibility and second primary cancers: research strat-
Rueffer U, Josting A, Franklin J et al (2001) Non-Hodgkin’s egies and recommendations. J Natl Cancer Inst 98:15–25
lymphoma after primary Hodgkin’s disease in the German Travis LB, Hodgson D, Allan J et al (2008) Second cancers. In:
Hodgkin’s lymphoma study group: incidence, treatment, and Cancer: Principles and practice of oncology. Lippincott Williams
prognosis. J Clin Oncol 19:2026–2032 and Wilkins, Philadelphia (in press)
Saadat M, Truong PT, Kader HA et al (2007) Outcomes in patients van den Belt-Dusebout AW, de Wit R, Gietema JA et al (2007)
with primary breast cancer and a subsequent diagnosis of Treatment-specific risks of second malignancies and cardiovascular
endometrial cancer : comparison of cohorts treated with and disease in 5-year survivors of testicular cancer. J Clin Oncol
without tamoxifen. Cancer 110:31–37 25:4370–4378
Sankila R, Garwicz S, Olsen JH et al (1996) Risk of subsequent van Leeuwen FE, Travis LB (2005) Second cancers. In: DeVita VT Jr
malignant neoplasms among 1,641 Hodgkin’s disease patients et al (eds) Cancer: principles and practice of oncology, 7th edn.
diagnosed in childhood and adolescence: a population-based cohort Lippincott Williams & Wilkins, Philadelphia, pp 2575–2602
study in the five Nordic countries. Association of the Nordic van Leeuwen FE, Chorus AM, van den Belt-Dusebout AW et al (1994)
Cancer Registries and the Nordic Society of Pediatric Hematology Leukemia risk following Hodgkin’s disease: relation to cumulative
and Oncology. J Clin Oncol 14:1442–1446 dose of alkylating agents, treatment with teniposide combinations,
Schairer C, Hisada M, Chen BE et al (2007) Comparative mortality for number of episodes of chemotherapy, and bone marrow damage.
621 second cancers in 29,356 testicular cancer survivors and J Clin Oncol 12:1063–1073
12,420 matched first cancers. J Natl Cancer Inst 99:1248–1256 van Leeuwen FE, Klokman WJ, Veer MB et al (2000) Long-term risk
Schonfeld SJ, Gilbert ES, Dores GM et al (2006) Acute myeloid of second malignancy in survivors of Hodgkin’s disease treated
leukemia following Hodgkin lymphoma: a population-based study during adolescence or young adulthood. J Clin Oncol 18:487–497
of 35,511 patients. J Natl Cancer Inst 98:215–218 van Leeuwen FE, Klokman WJ, Stovall M et al (2003) Roles of
Simonart T, Heenen M (2004) Radiation-induced angiosarcomas. radiation dose, chemotherapy, and hormonal factors in breast
Dermatology 209:175–176 cancer following Hodgkin’s disease. J Natl Cancer Inst 95:971–980
Smith RE, Bryant J, DeCillis A et al (2003) Acute myeloid leukemia Virtanen A, Pukkala E, Auvinen A (2007) Angiosarcoma after
and myelodysplastic syndrome after doxorubicin-cyclophospha- radiotherapy: a cohort study of 332,163 Finnish cancer patients.
mide adjuvant therapy for operable breast cancer: the national Br J Cancer 97:115–117
surgical adjuvant breast and bowel project experience. J Clin Oncol Zablotska LB, Neugut AI (2003) Lung carcinoma after radiation
21:1195–1204 therapy in women treated with lumpectomy or mastectomy for
Storm HH, Andersson M, Boice JD Jr et al (1992) Adjuvant primary breast carcinoma. Cancer 97:1404–1411
radiotherapy and risk of contralateral breast cancer. J Natl Cancer
Inst 84:1245–1250
 Radiation-Related Second Primary Cancers:
Clinical Perspectives
David C. Hodgson, Andrea Ng, and Lois B. Travis

Contents Abstract
Radiation therapy (RT) is a major treatment used in the
1 Introduction.......................................................................... 241 curative management of many cancer types. As survival
2 Analytic Issues Influencing the Clinical Interpretation rates for many forms of cancer continue to improve,
of Second Cancer Studies ................................................... 242 there is increasing clinical attention being directed
2.1 Relative versus Absolute Risks............................................. 242 toward the risk of delayed radiation-induced second
2.2 Cumulative Incidence and Competing Risks ....................... 242
cancer (SC). Survivors of Hodgkin lymphoma, leukemia,
3 Radiation Dose-Risk Relationships and Implications cervix cancer, and breast cancer treated with RT have
for Radiation Therapy ........................................................ 243 been shown, to varying degrees, to experience increased
4 Intensity Modulated Radiation Therapy and Second risks of SC. Important improvements in the analysis of
Cancer Risk .......................................................................... 244 risk can aid clinical interpretation: in particular, empha-
5 Second Malignancy Risk in Survivors of Adult-Onset sis on the cumulative incidence of SC, and appropriate
Cancers.................................................................................. 245 adjustment for competing causes of death can provide
5.1 Radiation-Related Malignancies After Hodgkin more clinically meaningful insight into the burden of SC
Lymphoma ............................................................................. 245
5.2 Radiation-Related Malignancies After Testicular Cancer ... 246 than descriptions of the relative risk. The nature of the
5.3 Radiation-Related Malignancy After Cervical Cancer ........ 247 dose-risk relationship for normal tissues exposed to
5.4 Radiation-Related Malignancy After Breast Cancer............ 248 intermediate and high dose is uncertain, although there
5.5 Radiation-Related Malignancy After Prostate Cancer ......... 249 are emerging data that the risk may increase with
6 Pediatric Malignancies ........................................................ 250 increasing dose above 10 Gy. A better understanding of
6.1 Risk of Second Cancer in Survivors of Acute the risk associated with doses in this range will be an
Lymphoblastic Leukemia ...................................................... 251
6.2 Retinoblastoma ...................................................................... 251
important component of developing RT treatments that
limit the risk of SC and also for understanding the
7 Summary............................................................................... 252
potential risk associated with newer treatments, such as
References...................................................................................... 252 intensity modulated radiation therapy (IMRT). Further
research is required to better understand how the
interaction of RT and chemotherapy or biologic agents
may affect SC risk, and to identify the genetic contrib-
utors to the development of SC.
D. C. Hodgson (&)
Department of Radiation Oncology, University of Toronto,
Princess Margaret Hospital, 610 University Ave, Toronto,
ON M5G 2M9, Canada
e-mail: [email protected] 1 Introduction
A. Ng
Department of Radiation Oncology, Harvard Medical School, There are an estimated 10.7 million cancer survivors in the
Brigham and Women’s Hospital and Dana-Farber Cancer
United States, and this population is growing by roughly
Institute, 75 Francis street L2, Boston, MA 02115, USA
2 % annually (Ries et al. 2006). As more patients experi-
L. B. Travis
ence prolonged survival after an initial cancer diagnosis, the
Department of Radiation Oncology, University of Rochester,
James P. Wilmot Cancer Center, 265 Crittenden Boulevard; late effects of treatment have emerged as an increasingly
CU 420318, Rochester, NY 14642-0318, USA important clinical concern.

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 241
DOI: 10.1007/978-3-540-72314-1_16, Ó Springer-Verlag Berlin Heidelberg 2014
242 D. C. Hodgson et al.

One of the most serious late effects of cancer and its in SIR. In contrast, the SIR may be lower for more common
treatment is the development of second cancers (SC), which cancers (e.g., breast cancer) that affect a greater number of
accounted for approximately 16 % of incident malignancies patients in the general population. In this regard, the SIR
reported to the National Cancer Institute’s (NCI’s) Sur- may obscure the true excess morbidity caused by a partic-
veillance, Epidemiology, and End Results (SEER) Program ular second cancer. A more clinically meaningful expres-
in 2003 (Ries et al. 2006). SC are also a leading cause of sion of risk is the absolute excess risk (AER), typically
mortality among several populations of long-term survivors defined as the number of excess cases occurring per 10,000
(Bhatia et al. 2003; Capra et al. 2007; Guerin et al. 2007; person-years of follow-up: (observed number of cases per
Hodgson et al. 2007a, b; Travis et al. 2005; Travis and year – expected number of cases per year)/total person-
Gilbert 2005; Tward et al. 2007). Development of a SC can years at risk 9 10,000). Since the AER better reflects the
reflect the cellular and tissue damage caused by cancer actual number of patients affected, it is generally considered
treatment, as well as the influence of environmental expo- to be a more clinically relevant indicator of the burden of
sures, biological determinants, and combinations of effects, morbidity caused by SC.
including gene-environment and gene–gene interactions
(Travis et al. 2006).
The focus of this chapter will be the influence of radia- 2.2 Cumulative Incidence and Competing
tion therapy (RT) on the risk of SC. RT is associated with Risks
elevated risks of second cancer among survivors of Hodgkin
lymphoma (Aleman et al. 2003; Bhatia et al. 2003; Capra Both SIR and AER present risks in terms different from
et al. 2007; Hodgson et al. 2007), non-Hodgkin lymphoma those used to describe most other cancer-related clinical
(Bluhm et al. 2008; Sacchi et al. 2008; Travis et al. 1991, outcomes, such as 5-year disease-free survival or overall
1993), testicular cancer (Kaldor et al. 1987; Schairer et al. survival. This can make it a challenge to weigh the risks and
2007; Travis et al. 2005; van Leeuwen et al. 1993), cervix benefits of treatment. For example, clinical trials have
cancer (Boice et al. 1985; Chaturvedi et al. 2007) and breast demonstrated that following chemotherapy for early stage
cancer (Brown et al. 2007; Deutsch et al. 2007; Gao et al. HL, radiation therapy improves disease-free survival by
2003; Schaapveld et al. 2008) as well as several forms of about 5–10 % (Meyer et al. 2003; Nachman et al. 2002),
childhood cancer. (Bassal et al. 2006; Dinu et al. 2008; while epidemiologic studies have reported that this treat-
Neglia et al. 2001). Increased risks of second cancer have ment is associated with a 2- to 6-fold increased risk of
also been reported among patients receiving RT for prostate second cancer (Dores et al. 2002; Ng et al. 2002). It is easier
cancer, (Brenner et al. 2000; Moon et al. 2006; Pickles and to make a clinically meaningful evaluation of risk–benefit
Phillips 2002; Rapiti et al. 2008) and cancer of the naso- concerns if the second cancer risk is also expressed as a
pharynx, (Kong et al. 2006) reflecting in part the increasing cumulative incidence (e.g., the 20-year risk of second
awareness and concern regarding late effects of treatment as cancers after wide field mantle ± para-aortic RT is
the control of the primary disease improves. approximately 20 % (Ng et al. 2002).
The Kaplan–Meier method has been used to estimate the
cumulative incidence of second cancers over time (Bhatia
et al. 1996; Dores et al. 2002; Ng et al. 2002). Studies using
2 Analytic Issues Influencing the Clinical this approach have typically censored patients who die prior
Interpretation of Second Cancer Studies to developing SC. However, one of the assumptions of the
Kaplan–Meier estimate is that censored patients do not
2.1 Relative versus Absolute Risks differ systematically from non-censored patients with regard
to their risk of developing the outcome of interest (i.e., the
Elevated risks of SC are often expressed as the ratio of assumption of ‘‘non-informative’’ censoring). This
observed number of cases/expected number cases (O/E assumption is not met when deceased patients are censored,
ratio), where the expected number of cases is typically since they have no further risk of developing a SC. Clinical
based on the cancer incidence reported in the general pop- readers should be aware that the Kaplan–Meier estimate of
ulation, standardized to the sex, age, race, and calendar year cumulative incidence can significantly inflate the apparent
distribution of the study cohort. This ratio is also referred to risk of SC, particularly among patient groups with worse
as the standardized incidence ratio (SIR). overall survival rates, and the magnitude of this overesti-
One limitation of the SIR as a measure of risk is its mate increases with follow-up time. (Pintilie 2006) (Fig. 1).
sensitivity to the baseline incidence of the cancer type being Notably, most estimates of the AER also censor patients at
evaluated: for uncommon cancers (such as leukemia) a the time of death, and so multiplying the annual AER x the
small number of excess cases can produce a large increase number of years of follow-up as an approximation of the
Radiation-Related Second Primary Cancers: Clinical Perspectives 243

Fig. 1 Cumulative incidence of second cancers among patients treated Fig. 2 Relative risk of subsequent glioma and meningioma within the
at the Princess Margaret Hospital for Hodgkin lymphoma, aged C30 - Childhood Cancer Survivor Study cohort by radiation dose (open
years at HL diagnosis. The Kaplan–Meier method does not adequately boxes, mean observed relative risk for meningioma; closed boxes,
account for competing causes of death that can occur prior to developing mean observed relative risk for glioma; solid line, fitted line for
a second cancer. As a result, the cumulative incidence of second cancers meningioma risk; hatched line, fitted line for glioma risk). P \ 0.001
is overestimtated compared to models that account for competing risks, (likelihood ratio test, two-sided). Reproduced with permission from
particularly with prolonged follow-up. Reproduced with permission Neglia et al. 2006
from Neglia et al. 2006

cumulative incidence also does not adequately account for occur at the edge of RT fields because increased cell killing
competing causes of death. results in lower SC risk for tissues in the ‘‘high dose’’
Several methods to account for competing causes of (i.e., [35 Gy) volume. However, analytic studies of selec-
death that may influence the cumulative incidence of late ted second solid cancers among patients receiving RT have
effects have been described (Pintilie 2006). While a detailed demonstrated that this is often not the case (Travis and
review of these methods are beyond the scope of this Gilbert 2005; Travis et al. 2003; van Leeuwen et al. 2003).
review, appropriate clinical interpretation of SC studies For example, following mediastinal RT for HL, the risks of
requires an understanding that competing risks should be breast- and lung cancer have been shown to increase with
accounted for in study analyses. increasing doses above 30 Gy (Gilbert et al. 2003; Travis
et al. 2002), although the slope of the dose-risk curve
appears to be less steep in this dose range. Similarly, the
3 Radiation Dose-Risk Relationships risks of soft-tissue sarcoma (Rubino et al. 2005), osteosar-
and Implications for Radiation Therapy coma (Hawkins et al. 1996), glioma and meningioma (Ne-
glia et al. 2006) have also been found to rise with increasing
The relationship between low-dose radiation exposures and radiation doses above 20 Gy. In a CCSS study, increasing
cancer risk has been studied extensively in studies of Jap- radiation dose-risk relationships were apparent for both
anese atomic bomb survivors (Ron et al. 1994; Thompson glioma and meningioma, with no downturn of the risk at
et al. 1994), and those experiencing occupational radiation high doses. At radiation doses of 30–45 Gy to the site of
exposures (Cardis et al. 2007; Lie et al. 2008). Conse- CNS tumor development, the RRs of glioma and meningi-
quently, the relationship between radiation dose and cancer oma were 21.0 and 96.3, respectively, compared with
risk is better understood for low-dose exposures than for exposure to less than 1 Gy (Fig. 2). The radiation dose
doses typically prescribed for RT. For most solid tumors response for glioma was significantly stronger for patients
and leukemia, there is an approximately linear increase in irradiated before age five (Neglia et al. 2006).
risk with increasing radiation dose up to about 5 Gy (Boice In contrast, radiation-induced thyroid cancer risk appears
et al. 1988; Curtis et al. 1994; Preston et al. 2002). At higher to increase with increasing doses up to 10–20 Gy (Ron et al.
doses, cell killing offsets the induction of malignancy in 1995; Sigurdson et al. 2005), and then plateaus or declines
hematopoietic tissue, and the risk of developing leukemia with increasing dose. The dose-risk relationship for radia-
declines (Boice et al. 1987). In part due to this observation, tion-induced leukemia is quite different from that seen for
it has been a common clinical precept that second cancers solid tumor induction: the risk of leukemia is much higher
244 D. C. Hodgson et al.

at low doses, and there is little or no increased risk at higher

dose (i.e. [20 Gy), likely due to bone marrow ablation
(Curtis et al. 1992; Little et al. 1999).
These findings suggest two clinically important conclu-
sions relating to RT-related SC risk. First, no single dose-
risk relationship will apply to all exposed tissues: there is
variation in the sensitivity of different tissues with regard to
cancer induction by radiation. Second, for many tissues, the
risk of radiation-induced SC increases with increasing doses
up to and exceeding doses typically occurring at the edge of
treatment fields.

4 Intensity Modulated Radiation Therapy

and Second Cancer Risk

An understanding of the radiation dose-risk relationship has

important implications when considering the potential
therapeutic gains that may be achieved with intensity
modulated radiation therapy (IMRT). Compared to con-
ventional RT, IMRT typically achieves more conformal
(i.e., smaller) high-dose volumes at the expense of exposing
a larger volume of normal tissues to low/intermediate doses.
This occurs in part because IMRT often employs more
treatment fields than conventional RT, thereby exposing
additional tissue to intermediate-dose radiation from these
added fields. Further, IMRT may be associated with long
‘‘beam on’’ times (i.e. more monitor units) than conven-
tional RT, and can thereby increase the low-dose total body
exposure caused by radiation leakage during treatment (Hall
2006). Finally, use of high energy beams (e.g., 18 MV) may
increase total body neutron dose due to the interaction of
Fig. 3 Scatter dose to normal tissues associated with breast RT,
high energy X-rays with the components of the linear comparing physical wedges and dynamic wedges/IMRT. Because
accelerator. A small number of studies have predicted that, physical wedges are placed close to the patient, they can produce
in spite of the improved conformality of the high-dose greater scatter dose to normal tissues than techniques that employ
segmented multileaf collimation to modify beam intensity. Repro-
volume, the additional low-dose exposure may increase the
duced with permission from Woo et al. (2006)
risk of second cancers compared to conventional RT (Hall
2006; Schneider 2006).
Radiation oncologists prescribing IMRT should be aware scatter dose to the patient. (Woo et al. 2006) Consequently,
of these issues when weighing the merits of different RT it is not a necessary feature of IMRT that it increases total
plans. In many cases, a well-designed IMRT plan can body exposure compared to conventional RT given histor-
deliver an integral dose to the irradiated volume comparable ically. (See Fig. 3 comparing IMRT vs. conventional tan-
to a non-IMRT plan, with a larger low/intermediate dose gent RT for breast cancer treatment).
volume, but a smaller high-dose volume. In view of the Appropriate utilization of IMRT requires both the con-
dose-risk data presented above, it remains to be determined sideration of primary tumor control as well as the risk of
how increasing low-dose tissue volume while decreasing other radiation-related toxicities. The potential increase in
the high-dose volume will affect the overall increase in SC absolute risk of SC associated with IMRT over conventional
risk with IMRT. Also, since externally mounted beam RT (estimated to be \3 % for patients with prostate IMRT
modifying devices (e.g., wedges) attenuate the RT beam, (Kry et al. 2007)), should be considered within the context
segmented IMRT beams may in some cases require com- of a patient’s competing risk of death from the primary
paratively less ‘‘beam on’’ time to treat the same volume cancer, and the potential benefit that IMRT may provide in
than older techniques. Furthermore, these wedges are often properly treating the primary tumor and reducing the risk of
placed in close proximity to the patient and are a source of serious chronic organ damage (e.g., xerostomia, rectal
Radiation-Related Second Primary Cancers: Clinical Perspectives 245

toxicity, osteopenia/bone fractures). In particular, clinicians Unlike leukemias after Hodgkin lymphoma, which typ-
should be aware of the potential for IMRT to increase SC ically arise within the first 10 years after treatment, solid
risk, and the features of an IMRT plan that may influence tumors are associated with a longer latency, ranging from 5
this risk, such as dose to the entire irradiated volume, and to over 15 years, depending on the subtype of solid tumors.
the number of monitor units required to deliver treatment. In addition, the risks appear to persist for prolonged periods
Further research is required to quantify the potential for of time. In more recent studies with longer follow-up time,
IMRT to increase the risk of SC compared to conventional solid tumors account for over three-quarters of all cases of
RT in order to facilitate more thoughtful balancing of the second malignancies after Hodgkin lymphoma.
potential risks and benefits. The contribution of RT to the development of SC after
Hodgkin lymphoma is supported by several studies dem-
onstrating increased risks among patients receiving RT as
5 Second Malignancy Risk in Survivors part of their initial treatment (Aleman et al. 2003; Bhatia
of Adult-Onset Cancers et al. 2003; Capra et al. 2007; Hodgson et al. 2007). As
noted previously, studies have reported a significant radia-
Radiation therapy plays a central role as part of curative tion dose–response relationship in the development of
treatment in a considerable number of adult-onset malig- specific types of solid tumors after HL. Two case–control
nancies. Most of the data on radiation-related second studies examined in detail the relationship between radia-
malignancy risks derive from patients with primary cancers tion dose and the risk of breast cancer after Hodgkin lym-
in whom RT is routinely (or was historically) used as phoma therapy (Travis et al. 2003; van Leeuwen et al.
definitive or adjuvant treatment, and on primary cancers 2003). In both studies, the radiation dose at the site of the
that tend to affect young patients, have a high cure rate, and/ breast cancer was estimated in the case patients and com-
or a long natural history. Among survivors of various adult- pared to the dose in a comparable location in the control
onset malignancies, the largest amount of data with regard subjects. In the study by van Leeuwen et al., which con-
to SC risk exist for survivors of Hodgkin lymphoma. Data sisted of 48 cases of breast cancer and 175 matched con-
on radiation-related second malignancy risks are also trols, the breast cancer risk was significantly increased only
available in survivors of testicular cancer, cervical cancer, after a radiation dose of 38.5 Gy or higher, but not at lower
and more recently breast cancer and prostate cancer. doses (van Leeuwen et al. 2003). In the large, international
case–control study by Travis et al. (Travis et al. 2003),
which consisted of 105 breast cancer cases and 266 matched
controls, a radiation dose of [4 Gy to the breast was
5.1 Radiation-Related Malignancies After associated with a 3.2-fold breast cancer risk compared with
Hodgkin Lymphoma women who received lower doses of radiation and no
alkylating chemotherapy. The risk increased to 8-fold for
The cure of Hodgkin lymphoma (HL) using large-field women who received [40 Gy to the breast (p
radiation therapy was first demonstrated over 50 years ago trend \ 0.001). The comparable results of these studies is
(Peters and Middlemiss 1958), with ensuing decades wit- due in part to overlap of breast cancer cases evaluated in the
nessing a considerable evolution of treatment. Excess sec- Dutch study (40 of 48 cases) (van Leeuwen et al. 2003) that
ond malignancies after successful treatment of Hodgkin were also included in the international series by Travis et al.
lymphoma were first reported in the early 1970s (Arseneau (2003).
et al. 1972). These early reports focused mostly on A significant radiation dose–response relationship has
increased leukemia risks that were largely related to the use similarly been shown for the development of lung cancer
of alkylating chemotherapy in a dose-dependent manner. after Hodgkin lymphoma. Travis et al. conducted a case–
The use of large-field radiation therapy was also initially control study of 222 cases of lung cancer and 444 matched
suggested as a contributing factor to excess leukemias. controls in patients who had been treated for Hodgkin
However, in a case–control study by van Leeuwen et al. lymphoma (Travis et al. 2002). Using patients who recei-
(van Leeuwen et al. 1994), the addition of RT to chemo- ved \5 Gy to the area of the lung in which the cancer
therapy did not significantly increase the risk of leukemia developed as the reference group, the lung cancer risk
(relative risks of chemotherapy alone versus combined increased with increasing dose to the lung (p trend \ .001),
modality therapy: 44.6 vs. 20.9. p = 0.16). Although total- although the increased risk was statistically significant only
nodal irradiation in combination with chemotherapy was after exposure to doses of 30 Gy or higher.
associated with a 2.5-fold elevated risk of leukemia com- A number of factors have modifying effects on radiation-
pared with patients treated with chemotherapy alone, the related second malignancy after Hodgkin lymphoma. For
increase was not statistically significant (p = 0.39). breast cancer after Hodgkin lymphoma, young age at mantle
246 D. C. Hodgson et al.

irradiation has consistently been shown to be associated contemporary IFRT for patients with mediastinal disease
with significantly increased risk for breast cancer in women found that the latter was associated with a reduction in
(Ng et al. 2002; Travis et al. 2003). In addition to age at radiation dose to female breast tissue of approximately 65,
treatment, ovarian hormonal exposures also have a signifi- and a 35 % reduction in lung dose (Koh et al. 2007).
cant modifying effect on breast cancer risk after Hodgkin Radiobiologic modeling predicted comparable reductions in
lymphoma therapy. In the studies by both Travis et al. 2003 the breast- and lung cancer risks associated with the tran-
and van Leeuwen et al. 2003 patients who received che- sition from mantle RT to IFRT (Hodgson et al. 2007). A
motherapy and radiation therapy had significantly a reduced meta-analysis showed that the risk of breast cancer is sig-
risk of breast cancer compared with those treated with nificantly higher after extended-field than involved-field
radiation therapy alone, and the radiation-related risks were radiation therapy (OR, 3.25, p = 0.04), which is likely
also attenuated by a radiation dose of 5 Gy or more deliv- related to the reduced amount of breast tissue in a more
ered to the ovaries. The Dutch study also clearly showed limited treatment field (e.g., exclusion of the axillae)
that the substantial risk reduction associated with chemo- (Franklin et al. 2006). Ongoing clinical efforts are exploring
therapy was attributable to the high frequency of premature the possibility of further reductions in radiation treatment
menopause in chemotherapy-treated patients (van Leeuwen doses for HL. More recently, there is a trend toward
et al. 2003). Taken together, results in both studies showed involved-node radiation therapy that further reduces the
that ovarian hormones play a critical role in promoting exposure of normal tissue to radiation (Girinsky et al.
breast tumorigenesis once radiation has produced an initi- 2006). It is thus expected that patients who receive RT in
ating event. the modern era will likely experience lower risks for second
The striking effect of smoking on the treatment-related malignancies than those reported in long-term follow-up
risk for lung cancer among HL survivors merits emphasis. studies of now outdated treatment.
In a case–control study by Travis and colleagues (2002), in
which the reference group consisted of patients who had HL
who had minimal radiation exposure and who were non- 5.2 Radiation-Related Malignancies After
smokers or light smokers, those patients who received either Testicular Cancer
alkylating agent chemotherapy alone or 5 Gy or more of
radiation therapy alone to the area of the lung in which Historically, treatment for testicular cancer included the use
cancer developed later experienced 4.3-fold and 7.2-fold of large-field radiation therapy including treatment to the
increased risks for lung cancer, respectively. These relative mediastinum and paraaortic and pelvic lymph nodes. Sim-
risks increased to 16.8-fold and 20.2-fold, respectively, in ilar to Hodgkin lymphoma, testicular cancer typically affect
those patients who also smoked at least one pack of ciga- young adults and has a high cure rate. In addition, as in
rettes per day. For cigarette smokers (at least one pack per survivors of Hodgkin lymphoma, second malignancy has
day) who had also received alkylating chemotherapy and been associated with excess mortality among selected long-
5 Gy or more of radiation therapy to the area of the lung in term survivors of testicular cancer (Schairer et al. 2007).
which cancer developed, the relative risk for subsequent The types of second malignancy documented in survivors of
lung cancer was 49.1, consistent with a multiplicative effect testicular cancer include leukemia and several solid tumors,
of tobacco use on the risk for treatment-related lung cancer. including mesothelioma, cancers of the lung, thyroid,
In view of these findings, clinicians should be diligent in esophagus, stomach, pancreas, colon, rectum, kidney,
facilitating smoking cessation among both new HL patients bladder, and connective tissue (Pedersen-Bjergaard et al.
and survivors. 1991; Travis et al. 2005; van den Belt-Dusebout et al.
In considering SC risk after Hodgkin lymphoma, it 2007). Much of the existing data on treatment-related sec-
should be noted that while RT is a major contributor to ond malignancy after testicular cancer may reflect the his-
excess risks, a number of other factors also influence risk, torical routine use of large field RT, although chemotherapy
including chemotherapy (Swerdlow et al. 2000; Travis et al. has also been shown to contribute to the risk. An excess risk
2002), underlying immune dysfunction and genetic predis- for contralateral testicular cancer has also been observed,
position. Further, much of the data on solid tumors after which is likely related to underlying predisposition rather
radiation therapy for Hodgkin lymphoma was based on than prior treatment (Fossa et al. 2005).
patients treated in an era when large treatment fields and A population-based case–control study by Travis et al.
higher radiation doses were routinely employed. A signifi- explored treatment-associated leukemia in men with tes-
cantly reduced volume of normal tissue is exposed with the ticular cancer who had survived at least one year (Travis
current standard of care, which includes involved-field et al. 2000). The risk for leukemia increased significantly
radiation therapy as part of combined modality therapy with increasing radiation field size, which was reflected in
(Fig. 4). A comparative study of mantle RT fields versus dose to active bone marrow. In addition, after taking into
Radiation-Related Second Primary Cancers: Clinical Perspectives 247

Fig. 4 Dose to normal tissues

associated with mantle field
(a) and involved-field RT (b) for
a female patient with mediastinal
HL. Historically used mantle
fields contributed significant dose
to normal tissue by electively
treating the axillae. Restriction of
RT to lymph node regions
initially involved with disease
can significantly reduce normal
tissue exposure (c). Many north
american pediatric protocols also
reduce dose to &20 Gy, further
reducing normal tissue dose
compared to 35 Gy mantle RT.
Reproduced with permission
from Koh et al. (2007), and
Hodgson et al. (2007b)

account the amount of radiation exposure to active bone survived testicular cancer for more than 5 years were at
marrow, the risk for leukemia was also significantly asso- particularly high risk of developing stomach cancer (RR,
ciated with cumulative dose of cisplatin received. 6.9; 95 % CI, 3.3–12.7). In a update from the same group
In the largest cohort study on testicular cancer survivors based on 2,707 5-year testicular cancer survivors (van den
to date, Travis et al. reported on the solid tumor risk among Belt-Dusebout et al. 2007), followed for a median of
40,576 patients (Travis et al. 2005). At a mean follow-up of 17.6 years, the relative risk of second malignancy was 1.7
11.8 years, the relative risks of developing a solid tumor (95 % C.I., 1.5–1.9), with subdiaphragmatic radiotherapy
were significantly increased after both radiation therapy and being strongly associated with increased risk of SC.
chemotherapy alone (RR, 2.0 and 1.8, respectively). Among
10-year survivors of testicular cancer initially treated with
radiation therapy, the relative risks of solid tumors at sites 5.3 Radiation-Related Malignancy After
included in typical infradiaphragmatic fields (e.g., bladder, Cervical Cancer
stomach, pancreas, and kidneys) were considerably higher
than those at sites not in field. Significantly increased risks Both definitive RT and radical surgery are accepted options
of cancers of the esophagus, pleura, or lung were also in the treatment of nonbulky early-stage cervical cancer,
found, likely reflecting the historical use of prophylactic while primary RT is typically the treatment of choice for
mediastinal irradiation. In a cohort study from the Nether- women with bulky stage IB and IIA cervical cancer. Sur-
lands based on 1,909 patients with testicular cancer, the vivors of cervical cancer are at increased risk for developing
relative risk of second malignancy was 1.6 (95 % CI, several second malignancies, some of which can be
1.3–2.1) (Travis et al. 1993). Patients who had received explained by shared infectious causes or environmental risk
radiation therapy to the paraaortic lymph nodes and who factors, whereas others are attributable to previous
248 D. C. Hodgson et al.

treatment exposures. Kleinerman and colleagues were increased after radiation therapy (RR = 1.19; 95 % CI,
among the first to report on the risk of second malignancies 0.94–1.15). Among women who were younger than
following cervical cancer (Kleinerman et al. 1982). Com- 45 years of age at the time of irradiation, however, the
pared with the general population, survivors of cervical relative risk was significantly elevated (RR 1.59; (95 % CI,
cancer had a 1.4-fold increased risk for a second malig- 1.07–2.36). In the Early Breast Cancer Trialists’ Collabo-
nancy. A history of radiation therapy was associated with rative Group report, which evaluated the effects of RT, a
significant excesses of several cancers arising in the pelvic significantly increased risk for contralateral breast cancer
radiation field, including tumors of bladder, kidney, rectum, was found, mainly during the period 5 –14 years after
corpus uteri, and ovary. Since then, several studies have randomization (RR = 1.43; P = .00001), and the increased
confirmed these findings (Boice et al. 1985; Chaturvedi risk associated with RT was significant elevated among
et al. 2007). Chaturvedi and colleagues updated and women aged 50 years or older when randomized
expanded these data based on 104,760 1-year survivors of (RR = 1.25; P = .002) (Clarke et al. 2005). In contrast, in
cervical cancer reported to 13 population-based cancer another large case–control study from Denmark, there was
registries in Denmark, Finland, Norway, Sweden, and the no significant difference in the risk for contralateral breast
United States (Chaturvedi et al. 2007). In this larger study cancer in women who did and did not receive RT, regard-
with longer follow-up time, a significantly elevated relative less of age at treatment (Storm et al. 1992). In the Danish
risk (RR = 1.3; 95 % CI, 1.28–1.33) for second malig- study, it was found that the second breast cancers were
nancy was again found. Moreover, the authors showed that evenly distributed in the medial, lateral, and central portions
following radiation therapy for cervical cancer, the risks for of the breast, which also argued against a causal role of
second cancers of the rectum/anus, colon, urinary bladder, radiotherapy in tumorigenesis. A large-scale, single-insti-
ovary, and other female genital sites remained significantly tution study from Institut Curie which included 13,472
elevated for more than 40 years. Several second cancers women, similarly failed to show an increased risk for con-
were likely related to shared etiologic factors rather than tralateral breast cancer when comparing women who did or
radiation therapy, because an increased risk was also did not receive radiation therapy (RR = 1.1; 95 % CI,
observed among the non-radiation therapy cohort. These 0.96–1.27). Analysis by age, however, was not performed in
included cancers of the pharynx, genital sites, and rectum/ that study (Kirova et al. 2007).
anus, which are related to human papillomavirus infections; In addition to contralateral breast cancer, several other
and cancers of the lungs, pancreas, and urinary bladder, solid tumors have also been linked to a history of radiation
which are related to tobacco use. In this study, younger age therapy for breast cancer. These include cancers of the lung,
at cervical cancer treatment was associated with a signifi- thyroid and esophagus, and soft tissue sarcoma (Huang and
cantly higher cumulative risk for second cancer. After Mackillop 2001; Huang et al. 2001; Levi et al. 2005;
adjustment for competing mortality, the 40-year cumulative Neugut et al. 1993; Roychoudhuri et al. 2004; Zablotska
risk of any second cancer was higher among women diag- and Neugut 2003). An increased risk for leukemia after
nosed with cervical cancer before age 50 than among breast cancer has also been observed, which is associated
women diagnosed after age 50 (22.2 vs. 16.4 %). with exposure to both chemotherapy and radiation therapy.
Women who receive RT for breast cancer have been
shown to be at a 1.5- to 3-fold increased risk for developing
5.4 Radiation-Related Malignancy After lung cancer compared with women who did not receive
Breast Cancer radiation therapy (Neugut et al. 1993; Zablotska and Neugut
2003). The increased risk seemed to be more clearly related
Radiation therapy is an important modality in the treatment to postmastectomy radiation therapy, in which the radiation
of breast cancer, either as part of breast-conserving therapy target volume often also include the supraclavicular, axil-
or postmastectomy treatment. Among the various types of lary, or internal mammary nodal region, thus exposing a
second cancers observed in survivors of breast cancer, the larger volume of underlying lung tissue to the radiation,
largest amount of data exists for contralateral breast cancer, whereas the risk after post-lumpectomy RT is less certain
which is partly related to preexisting breast cancer risk (Deutsch et al. 2003; Zablotska and Neugut 2003). The
factors (Boice et al. 1992; Gao et al. 2003; Hemminki et al. observation that lung cancer after breast cancer therapy is
2007; Kirova et al. 2007; Storm et al. 1992). The increased more frequently found in the ipsilateral lung also supports
risk has been estimated to range from two- to five-fold the contributing role of radiation to the risk (Zablotska and
among breast cancer survivors, with conflicting data on the Neugut 2003). Several studies showed further increases in
contribution of RT to these excesses. In a case–control the risk for lung cancer among smokers who received breast
study by Boice and colleagues (1992), the overall relative irradiation (Ford et al. 2003; Neugut et al. 1994), although
risk for contralateral breast cancer was not significantly the interaction between tobacco exposure and prior
Radiation-Related Second Primary Cancers: Clinical Perspectives 249

radiation therapy on subsequent lung cancer risk is not as alone, and both chemotherapy and radiation therapy were
well elucidated as in survivors of HL. 2.4, 10.0, and 17.4, respectively. With regard to the con-
Adjuvant radiation therapy for breast cancer has also tribution of radiation therapy, a significant dose–response
been related to excess esophageal cancers (Levi et al. 2005; effect was observed for the cumulative dose of radiation to
Roychoudhuri et al. 2004). In a cohort study from the the active bone marrow and the subsequent risk for
Thames Cancer Registry on 64,782 cases of breast cancer leukemia.
diagnosed between 1961 and 2000, the incidence of There has been significant progress in the radiation
esophageal cancer among the 33,763 patients who received treatment techniques for breast cancer. Much of the data on
radiation therapy and the 31,019 patients who did not second malignancy risks were based on outdated treatment
receive radiation therapy was compared (Roychoudhuri including use of large-field treatments, such as the hockey-
et al. 2004). The relative risk for esophageal cancer was stick technique (Harris and Hellman 1988), which has since
found to be significantly increased at 2.19 (95 % C.I. been abandoned, and cobalt therapy. In addition, advances
1.10–4.62) at 15 or more years after initial breast cancer in radiation therapy (Chen and Vicini 2007), including use
treatment. A significantly increased excess risk of esopha- of intensity modulated therapy radiation (IMRT), and the
geal cancer after breast cancer therapy with increasing growing interest in partial breast irradiation may also alter
follow-up time from initial diagnosis was also demonstrated the second malignancy risk of breast cancer survivors. The
in other population-based studies (Ahsan and Neugut 1998; risks associated with these newer radiation therapy
Levi et al. 2005). approaches and techniques remain to be clarified.
Sarcoma after breast cancer is a rare event, with a 15
year incidence rate of less than 0.5 %, although the relative
risk has been estimated to be as high as seven, because of 5.5 Radiation-Related Malignancy After
the low background incidence in the general population Prostate Cancer
(Huang and Mackillop 2001; Kirova et al. 2005). In a study
by Rubino and colleagues (2005), all observed sarcomas Radiation therapy has a curative role in selected patients
occurred among women who had initially received radiation with localized disease. Patients are also routinely offered
therapy, and in all cases the sarcomas were located in the adjuvant radiation therapy for rising prostate specific anti-
irradiated fields or in the upper extremity of the arm ipsi- gen after radical prostatectomy in the absence of evidence
lateral to the treated breast. Further, a significant dose– of distant metastasis. There has been increasing attention to
response relationship was demonstrated. By estimating the the risk for SC after radiation therapy for prostate cancer
initial radiation dose to the site of sarcoma development, (Brenner et al. 2000; Chrouser et al. 2005; Liauw et al.
using a dose of 14 Gy or less to the site as reference, women 2006; Moon et al. 2006; Neugut et al. 1997; Pickles and
who received 14–44 Gy had a 1.6-fold increased risk for Phillips 2002). Neugut and colleagues were the first to
sarcoma, whereas those who received 45 Gy or more to the report on the effect of RT for prostate carcinoma on the risk
site had a 30.6-fold increased risk (P \ .001). Angiosar- for second cancers in a population-based study using data
coma was initially shown to be associated with chronic from the SEER program (Neugut et al. 1997). Men who
lymphedema following radical mastectomy (Jessner et al. received radiation therapy had a significantly increased risk
1952). With the increasing use of radiation therapy, there for developing bladder cancer after a latent period of
have been a growing number of reports of cutaneous 8 years (RR = 1.5; 95 % CI, 1.1–2.0), whereas the risk was
angiosarcoma of the breast arising in the radiation field not increased among men who did not receive RT. An
(Brenn and Fletcher 2005; Esler-Brauer et al. 2007; Fodor increased risk for rectal cancer or leukemia after RT was not
et al. 2006; Virtanen et al. 2007). Unlike other radiation- seen (Neugut et al. 1997). In a more recent study based on
related soft tissue sarcoma, angiosarcoma has a short the Mayo Clinic Cancer Registry (Chrouser et al. 2005),
latency and can occur in the first 5 years after therapy. whereas the overall relative risk for bladder cancer after
The increased risk for leukemia following breast cancer radiation therapy was not significantly increased, among the
is related to both chemotherapy and RT (Campone et al. subset of patients who received adjuvant radiation therapy
2005; Curtis et al. 1992; Praga et al. 2005; Smith et al. after a radical prostatectomy the relative risk for bladder
2003). In a case–control study by Curtis and colleagues of cancer was fivefold higher than expected (P = 0.05), which
women treated for breast cancer between 1973 and 1985 may be because of the larger volume of bladder exposed to
(Curtis et al. 1992), 90 women who developed leukemia and the radiation in the postoperative setting.
264 matched controls were studied. Compared with women In a subsequent study by Brenner and colleagues
who did not receive alkylating chemotherapy or radiation (Brenner et al. 2000), which also used data from the SEER
therapy, the relative risk for acute myelogenous leukemia program, men who were treated initially with radiation
after radiation therapy alone, alkylating chemotherapy therapy were compared with men treated with surgery
250 D. C. Hodgson et al.

alone. Patients who received radiation therapy had a sig- with increasing risk of malignancy, incomplete adjustment
nificantly increased risk for bladder cancer, rectal cancer, for the age differences between patients undergoing RT
sarcoma, and lung cancer. The finding of a significant versus surgery will erroneously elevate the apparent SC risk
association between irradiation for prostate cancer and lung associated with RT. Similarly, patients who have significant
cancer risk was attributed to low scatter doses of radiation comorbid illnesses or heavy smoking histories may not be
to the lungs. This observation may be more pertinent in selected for surgery and may be more likely to undergo
patients who received cobalt irradiation to the whole pelvis. radiation therapy. Consequently, increased risks of lung
A study using the linked SEER-Medicare database included cancer may in part relate to unmeasured confounders such
a larger number of patients, including those treated in the as smoking status. Further, among patients who received
more recent era (Moon et al. 2006). Men who received radiation therapy, treatment-related effects, including
external beam radiation therapy had a statistically signifi- proctitis, rectal bleeding, cystitis, and hematuria may lead to
cantly increased risk for developing cancers of the bladder, additional colonoscopies or cystoscopies, which in turn can
rectum, colon, brain, stomach, and lung, and melanoma, produce a detection bias and an apparent increased inci-
with odds ratios ranging from 1.25 to 1.85, when compared dence of colorectal or other urologic cancers. Even so,
with men who did not receive external beam radiation radiation is a known carcinogen, and the risk of SC among
therapy. Patients who received radioactive implants with or long-term survivors of prostate RT should be considered in
without external beam radiation therapy, however, did not the clinical context in which prostate cancer treatment
have a significantly increased risk for second cancer when decisions are being made.
compared with those not receiving RT. In studies that demonstrate a significant risk for cancers
In a study from the British Columbia Tumor Registry, after radiation therapy for prostate cancer, the absolute
among patients who received RT, significantly elevated incidence seems to be low. In the study by Brenner and
risks for colorectal cancer (RR = 1.21; P \ .01), pleural colleagues that included patients who received larger-field
cancer (RR = 2.28; P \ .01) and sarcoma (RR = 1.7; cobalt irradiation, the risk for developing a radiation-asso-
P \ .05) were observed. Although the bladder cancer risk ciated second malignancy was estimated at 1 in 290
was not significantly increased in the radiation therapy (Brenner et al. 2000). In the last several years, IMRT has
cohort, the risks for bladder cancer (RR = 1.32; P \ .01) been increasingly adopted in the treatment of prostate
and testicular cancer (RR = 2.82; P \ .05) were signifi- cancer to allow more conformal dose distribution and dose
cantly increased in the non-irradiation cohort, which was escalation (Guckenberger and Flentje 2007). Depending on
believed to be related to heightened surveillance (Pickles treatment energy, IMRT is associated with a 3- to 5 -fold
and Phillips 2002). larger number of monitor units as compared with conven-
Another report also based on data from the SEER pro- tional treatment. Using the National Council of Radiation
gram focused on the risk for rectal cancer after prostatic Protection and Measurements risk coefficients for specific
irradiation (Kendal et al. 2006). Unlike previous studies, a anatomic sites, the risk for second malignancy using IMRT
significant association between radiation therapy and a techniques has been estimated to be two to three times
subsequently increased risk for rectal cancer was not found. higher than that after conventional radiation therapy (Kry
Results of Cox proportional hazards analysis (with prostate et al. 2007). These estimates are yet to be confirmed in
irradiation, prostate surgery, and age at diagnosis entered as epidemiologic studies with sufficient follow-up time for
covariates) showed that only age was associated with an those patients who have received IMRT.
increased risk for subsequent rectal cancer.
Most studies on malignancies after prostate cancer
therapy used data from population-based registries. The 6 Pediatric Malignancies
conflicting findings on the contribution of radiation therapy
to various second malignancies after prostate cancer may Second cancer risk in survivors of childhood malignancy
reflect the fact that most registries collect data only on have been the subject of large cohort studies in North
initial course of therapy, registration of initial treatment is America and Europe (de Vathaire et al. 1999; Neglia et al.
incomplete in some registries, and selection criteria differ 2001; Olsen et al. 1993). The Childhood Cancer Survivor
for patients given surgery versus radiation therapy. More- Study (CCSS) (Neglia et al. 2001), reported SC risks in a
over, given the limited data available in most population- cohort of 13,581 five-year survivors of childhood and
based registries, it is not possible to identify or to control for adolescent cancer, diagnosed between 1970 and 1986. The
confounding factors. Incomplete adjustment for attained age risk of developing a second malignancy was increased 6.4-
is the most obvious of these: patients who receive RT for fold compared with the general population, and the cumu-
prostate cancer are consistently older than those who lative risk was 3.2 % at 20 years (median follow-up time of
undergo surgery alone. Since advancing age is associated 15 years). In a population-based British cohort of 16,541
Radiation-Related Second Primary Cancers: Clinical Perspectives 251

three-year survivors of childhood cancer, the absolute CNS tumors is higher in children 5 years of age or younger
excess risk of SC was 12 per 10,000 patients per year, and at first treatment (Loning et al. 2000; Walter et al. 1998).
the 28-year cumulative risk was 4.2 % (Jenkinson et al. In part due to these concerns, prophylactic cranial RT
2004). Similarly, a population-based European study of has been largely replaced by intrathecal chemotherapy and
30,880 children diagnosed 1943–1987 reported a 3.6-fold high-dose intravenous methotrexate in contemporary ALL
increased risk of SC (95 % CI: 3.1–4.1) and a 35-year treatment protocols. A study of SC among 8,831 ALL
cumulative incidence of 3.7 % (Olsen et al. 1993). The survivors treated on risk-based Children’s Cancer Group
largest RRs have been reported for second primary bone protocols between 1983 and 1995 (i.e. using intensive
tumors, soft tissue sarcoma, leukemia, and cancers of the chemotherapy and limited use of radiation) reported a RR of
brain, thyroid, and breast. second cancer of 7.2-fold, with a cumulative risk of 1.2 %
Notably, some young adult survivors of pediatric at 10 years (Bhatia et al. 2002). Notably, this result is not
malignancy appear to be at increased risk of cancers typi- dramatically different from prior studies, and in other
cally diagnosed in late adulthood, and the excess relative clinical situations, chemotherapy alone or in combined
risk of radiation-related cancers of the breast, lung, thyroid, modality regimens may also increase this risk of solid
and gastrointestinal tract are greater for children and ado- cancers (Menu-Branthomme et al. 2004). Longer follow-up
lescents than for adults. will be needed to fully elucidate the extent to which risk-
For example, the CCSS found significant excess risks of adapted treatments using high dose methotrexate will
cancers of the breast (RR = 12.5) (Kenney et al. 2004), reduce the risk of SC among ALL survivors.
nonmelanoma skin (RR = 6.3 after RT) (Perkins et al. In ALL survivors, treatment with epipodophyllotoxin
2005), head and neck (RR = 13.6), kidney (RR = 10.6), agents (e.g., etoposide) has been associated with the
colon and rectum (RR = 2.7), lung (RR = 3.1), and blad- development of acute myeloid leukemia (AML). A study of
der (RR = 5.1). Remarkably, the median age at diagnosis 734 children with ALL who received epipodophyllotoxin
of these adult-type carcinomas was 27 years (Bassal et al. maintenance reported a 6-year cumulative incidence of
2006). AML of 3.8 % (Pui et al. 1991). Continual treatment is
A complete review of the risks of SC following each major risk factor: patients who received weekly or twice-
primary malignancy of childhood is beyond the scope of weekly doses of epipodophyllotoxins had a significantly
this chapter. However, examination of SC risk following greater risk of AML than those treated less frequently (e.g.,
acute lymphoblastic leukemia and retinoblastoma reveals courses lasting 3–5 consecutive days given every
issues specific to the pediatric population. 3–4 weeks) (Le Deley et al. 2003; Pui et al. 1991).

6.1 Risk of Second Cancer in Survivors 6.2 Retinoblastoma

of Acute Lymphoblastic Leukemia
Only a portion of the excess second cancer risk in survivors
Since ALL is the most common childhood cancer, and has a of childhood cancer is related to treatment. Largely
high cure rate, risks of SC among ALL survivors have been uncharacterized biologic variability in the population is
studied extensively. Several investigations have demon- thought to substantially modify the risk of treatment-related
strated an increased risk of SC, and central nervous system SC. Retinoblastoma (RB) is a classic example: familial
tumors in particular (Bhatia et al. 2002; Loning et al. 2000; retinoblastoma is caused by inherited mutations of the RB-1
Maule et al. 2007; Pui et al. 2003; Walter et al. 1998). tumor suppressor gene, which is located on the long arm of
A German study of 5,006 ALL patients treated between chromosome 13q14 (Friend et al. 1986). In a study of 1,604
1979 and 1995 reported a 15-year cumulative incidence of one-year survivors of RB, the risk of SC was increased 19-
SC of 3.3 % following completion of initial treatment fold in hereditary retinoblastoma survivors (88 % of whom
(Loning et al. 2000). Cranial radiation increases the risk of had received RT) while the risk was not elevated in non-
high-grade astrocytomas, particularly during the first decade hereditary patients (RR = 1.2), compared to the general
after treatment, but can also increase the risk of low-grade population. Fifty years after retinoblastoma diagnosis, the
brain tumors or meningiomas among 10-year survivors of cumulative incidence of second malignancy, adjusting for
ALL (Walter et al. 1998). As noted above, the risk of a competing risks of death, was 36 % in hereditary patients,
second brain tumor increases with increasing cranial radi- and 5.7 % in nonhereditary patients (Wong et al. 1997). In
ation dose (Walter et al. 1998). The CCSS study reported patients with hereditary retinoblastoma, RT significantly
20-year cumulative risks of 1.0 %, 1.7 %, and 3.2 % for increases the cumulative incidence of second cancers to
patients who received radiation doses of 10–21 Gy, approximately 40 % at 50 years, versus 20 % in nonirra-
21–30 Gy, and greater than 30 Gy, respectively. Risk of diated patients. RT does not appear to significantly affect
252 D. C. Hodgson et al.

risk in nonhereditary retinoblastoma patients (Kleinerman Arseneau JC et al (1972) Nonlymphomatous malignant tumors
et al. 2005; Wong et al. 1997). complicating Hodgkin’s disease. Possible association with inten-
sive therapy. N Engl J Med 287:1119–1122
While RB is a classic example genetic defect associated Bassal M et al (2006) Risk of selected subsequent carcinomas in
with an increased risk of SC, very few SC can be attributed survivors of childhood cancer: a report from the childhood cancer
to the presence of such high-penetrance genetic changes. survivor study. J Clin Oncol 24:476–483
There is some evidence that patients with neurofibromatosis Bhatia S et al (1996) Breast cancer and other second neoplasms after
childhood Hodgkin’s disease. N Engl J Med 334:745–751
Type 1 treated for optic pathway gliomas have and Bhatia S et al (2002) Low incidence of second neoplasms among
increased incidence of second central nervous system children diagnosed with acute lymphoblastic leukemia after 1983.
tumors, and particularly after receiving RT (Sharif et al. Blood 99:4257–4264
2006). Mutations in the ataxia-telangiectasia (ATM) gene Bhatia S et al (2003) High risk of subsequent neoplasms continues
with extended follow-up of childhood hodgkin’s disease: report
are associated with increased radiation sensitivity, however from the late effects study group. J Clin Oncol 21:4386–4394
existing studies indicate ATM mutation carriers do not Bluhm EC et al (2008) Cause-specific mortality and second cancer
account for a significant proportion of patients with radia- incidence after non-Hodgkin lymphoma: a report from the
tion-induced second cancers following HL treatment (Bro- childhood cancer survivor study. Blood 111:4014–4021
Boice JD Jr et al (1985) Second cancers following radiation treatment
eks et al. 2000; Nichols et al. 1999). A better understanding for cervical cancer. An international collaboration among cancer
of the influence of common low-penetrance genetic factors registries. J Natl Cancer Inst 74:955–975
on the risk of treatment-related SC could potentially be an Boice JD Jr et al (1987) Radiation dose and leukemia risk in patients
important advance in tailoring cancer treatments to not only treated for cancer of the cervix. J Natl Cancer Inst 79:1295–1311
Boice JD Jr et al (1988) Radiation dose and second cancer risk in
maximize initial cure rates, but to also reduce the resulting patients treated for cancer of the cervix. Radiat Res 116:3–55
late toxicity for the majority of patients (Travis et al. 2006). Boice JD Jr et al (1992) Cancer in the contralateral breast after
radiotherapy for breast cancer. N Engl J Med 326:781–785
Brenn T, Fletcher CD (2005) Radiation-associated cutaneous atypical
vascular lesions and angiosarcoma: clinicopathologic analysis of
7 Summary 42 cases. Am J Surg Pathol 29:983–996
Brenner DJ et al (2000) Second malignancies in prostate carcinoma
As increasing numbers of patients who have cancer are patients after radiotherapy compared with surgery. Cancer
cured, the occurrence of SC has emerged as a problem 88:398–406
Broeks A et al (2000) Increased risk of breast cancer following
limiting long-term survival and quality of life, particularly irradiation for Hodgkin’s disease is not a result of ATM germline
among young patients. A significant proportion of cancer mutations. Int J Radiat Biol 76:693–698
survivors do not receive routine screening examinations Brown LM et al (2007) Risk of second non-hematological malignan-
(e.g., mammography), in spite of routine contact with the cies among 376,825 breast cancer survivors. Breast Cancer Res
Treat 106:439–451
health care system. At a minimum, these should be per- Campone M et al (2005) Secondary leukemia after epirubicin-based
formed as part of follow-up, in accordance with accepted adjuvant chemotherapy in operable breast cancer patients: 16 years
guidelines. Survivor-specific guidelines for follow-up care experience of the french adjuvant study group. Ann Oncol
are emerging (Children’s Oncology Group, 2008). although 16:1343–1351
Capra M et al (2007) Long-term outcome in children with Hodgkin’s
the evidence base supporting many of these guidelines is lymphoma: the united kingdom children’s cancer study group
weak, especially in survivors of adult-onset cancers. Future HD82 trial. Eur J Cancer 43:1171–1179
refinement of observational studies, with greater focus on Cardis E et al (2007) The 15-country collaborative study of cancer risk
absolute risks among identifiable patient groups, will assist among radiation workers in the nuclear industry: estimates of
radiation-related cancer risks. Radiat Res 167:396–416
patient counseling and rational screening strategies among Chaturvedi AK et al (2007) Second cancers among 104,760 survivors
cancer survivors. Further, improved understanding of ther- of cervical cancer: evaluation of long-term risk. J Natl Cancer Inst
apy-related second malignancies can guide the development 99:1634–1643
of new treatment regimens that have the potential to mini- Chen PY, Vicini FA (2007) Partial breast irradiation. Patient selection,
guidelines for treatment, and current results. Front Radiat Ther
mize late effects while maintaining or improving initial cure Oncol 40:253–271
rates. Children’s Oncology Group (2008) http://www.
survivorshipguidelines.1062_org/. Accessed April, 2013
Chrouser K, et al. (2005) Bladder cancer risk following primary and
adjuvant external beam radiation for prostate cancer. J Urol 174:
References 107–110, (discussion 110–111)
Clarke M et al (2005) Effects of radiotherapy and of differences in the
Ahsan H, Neugut AI (1998) Radiation therapy for breast cancer and extent of surgery for early breast cancer on local recurrence and 15-
increased risk for esophageal carcinoma. Ann Intern Med year survival: an overview of the randomised trials. Lancet
128:114–117 366:2087–2106
Aleman BM et al (2003) Long-term cause-specific mortality of Curtis RE et al (1992) Risk of leukemia after chemotherapy and
patients treated for Hodgkin’s disease. J Clin Oncol 21:3431–3439 radiation treatment for breast cancer. N Engl J Med 326:1745–1751
Radiation-Related Second Primary Cancers: Clinical Perspectives 253

Curtis RE et al (1994) Relationship of leukemia risk to radiation dose Hodgson DC et al (2007b) Individualized estimates of second cancer
following cancer of the uterine corpus. J Natl Cancer Inst risks after contemporary radiation therapy for Hodgkin lymphoma.
86:1315–1324 Cancer 110:2576–2586
de Vathaire F et al (1999) Second malignant neoplasms after a first Huang J, Mackillop WJ (2001) Increased risk of soft tissue sarcoma
cancer in childhood: temporal pattern of risk according to type of after radiotherapy in women with breast carcinoma. Cancer
treatment. Br J Cancer 79:1884–1893 92:172–180
Deutsch M et al (2007) An association between postoperative Huang J et al (2001) Risk of thyroid carcinoma in a female population
radiotherapy for primary breast cancer in 11 National Surgical after radiotherapy for breast carcinoma. Cancer 92:1411–1418
Adjuvant Breast and Bowel Project (NSABP) studies and the Jenkinson HC et al (2004) Long-term population-based risks of second
subsequent appearance of pleural mesothelioma. Am J Clin Oncol malignant neoplasms after childhood cancer in Britain. Br J Cancer
30:294–296 91:1905–1910
Deutsch M et al (2003) The incidence of lung carcinoma after surgery Jessner M et al (1952) Angiosarcoma in postmastectomy lymphedema
for breast carcinoma with and without postoperative radiotherapy. (Stewart-Treves syndrome). AMA Arch Derm Syphilol 65:123–129
Results of National Surgical Adjuvant Breast and Bowel Project Kaldor JM et al (1987) Second malignancies following testicular
(NSABP) clinical trials B-04 and B-06. Cancer 98:1362–1368 cancer, ovarian cancer and Hodgkin’s disease: an international
Dinu I et al (2008) Prediction of second malignant neoplasm incidence collaborative study among cancer registries. Int J Cancer
in a large cohort of long-term survivors of childhood cancers. 39:571–585
Pediatr Blood Cancer 50:1026–1031 Kendal WS et al (2006) Prostatic irradiation is not associated with any
Dores GM et al (2002) Second malignant neoplasms among long-term measurable increase in the risk of subsequent rectal cancer. Int J
survivors of Hodgkin’s disease: a population-based evaluation over Radiat Oncol Biol Phys 65(3):661–668
25 years. J Clin Oncol 20:3484–3494 Kenney L et al (2004) Breast cancer after childhood cancer: a report
Esler-Brauer L et al (2007) Angiosarcoma developing after conserva- from the Childhood Cancer Survivor Study. Ann Intern Med
tive treatment for breast carcinoma: case report with review of the 141(8):590–597
current literature. Dermatol Surg 33:749–755 Kirova YM et al (2007) Risk of second malignancies after adjuvant
Fodor J et al (2006) Angiosarcoma after conservation treatment for radiotherapy for breast cancer: a large-scale, single-institution
breast carcinoma: our experience and a review of the literature. review. Int J Radiat Oncol Biol Phys 68:359–363
J Am Acad Dermatol 54:499–504 Kirova YM et al (2005) Radiation-induced sarcomas after radiotherapy
Ford MB et al (2003) Effects of smoking and radiotherapy on lung for breast carcinoma: a large-scale single-institution review.
carcinoma in breast carcinoma survivors. Cancer 98:1457–1464 Cancer 104:856–863
Fossa SD et al (2005) Risk of contralateral testicular cancer: a Kleinerman RA et al (1982) Second cancers following radiotherapy for
population-based study of 29,515 U.S. men. J Natl Cancer Inst cervical cancer. J Natl Cancer Inst 69:1027–1033
97:1056–1066 Kleinerman RA et al (2005) Risk of new cancers after radiotherapy in
Franklin J et al (2006) Second malignancy risk associated with long-term survivors of retinoblastoma: an extended follow-up.
treatment of Hodgkin’s lymphoma: meta-analysis of the random- J Clin Oncol 23:2272–2279
ised trials. Ann Oncol 17:1749–1760 Koh ES et al (2007) A comparison of mantle versus involved-field
Friend SH et al (1986) A human DNA segment with properties of the radiotherapy for Hodgkin’s lymphoma: reduction in normal tissue
gene that predisposes to retinoblastoma and osteosarcoma. Nature dose and second cancer risk. Radiat Oncol 2:13
323:643–646 Kong L et al (2006) The risk of second primary tumors in patients with
Gao X et al (2003) Risk of second primary cancer in the contralateral nasopharyngeal carcinoma after definitive radiotherapy. Cancer
breast in women treated for early-stage breast cancer: a population- 107:1287–1293
based study. Int J Radiat Oncol Biol Phys 56:1038–1045 Kry SF et al (2007) Uncertainty of calculated risk estimates for
Gilbert E et al (2003) Lung cancer after treatment for Hodgkin’s secondary malignancies after radiotherapy. Int J Radiat Oncol Biol
disease: focus on radiation effects. Radiat Res 159(2):161–173 Phys 68:1265–1271
Girinsky T et al (2006) Involved-node radiotherapy (INRT) in patients Le Deley MC et al (2003) Risk of secondary leukemia after a solid
with early Hodgkin lymphoma: concepts and guidelines. Radiother tumor in childhood according to the dose of epipodophyllotoxins
Oncol 79:270–277 and anthracyclines: a case-control study by the Societe Francaise
Group CsO (2006) www.survivorshipguidelines. Accessed Nov 2007 d’Oncologie Pediatrique. J Clin Oncol 21:1074–1081
Guckenberger M, Flentje M (2007) Intensity-modulated radiotherapy Levi F et al (2005) Increased risk of esophageal cancer after breast
(IMRT) of localized prostate cancer: a review and future perspec- cancer. Ann Oncol 16:1829–1831
tives. Strahlenther Onkol 183:57–62 Liauw SL et al (2006) Second malignancies after prostate brachyther-
Guerin S et al (2007) Treatment-adjusted predisposition to second apy: incidence of bladder and colorectal cancers in patients with
malignant neoplasms after a solid cancer in childhood: a case- 15 years of potential follow-up. Int J Radiat Oncol Biol Phys
control study. J Clin Oncol 25:2833–2839 66:669–673
Hall EJ (2006) Intensity-modulated radiation therapy, protons, and the Lie JA et al (2008) Ionizing radiation exposure and cancer risk among
risk of second cancers. Int J Radiat Oncol Biol Phys 65:1–7 Norwegian nurses. Eur J Cancer Prev 17:369–375
Harris JR, Hellman S (1988) Put the ‘‘hockey stick’’ on ice. Int J Little MP et al (1999) Risks of leukemia in Japanese atomic bomb
Radiat Oncol Biol Phys 15:497–499 survivors, in women treated for cervical cancer, and in patients
Hawkins MM et al (1996) Radiotherapy, alkylating agents, and risk treated for ankylosing spondylitis. Radiat Res 152:280–292
of bone cancer after childhood cancer. J Natl Cancer Inst Loning L et al (2000) Secondary neoplasms subsequent to Berlin-
88:270–278 Frankfurt-Munster therapy of acute lymphoblastic leukemia in
Hemminki K et al (2007) Risks for familial and contralateral breast childhood: significantly lower risk without cranial radiotherapy.
cancer interact multiplicatively and cause a high risk. Cancer Res Blood 95:2770–2775
67:868–870 Maule M et al (2007) Risk of second malignant neoplasms after
Hodgson DC et al (2007a) Long-term solid cancer risk among 5-year childhood leukemia and lymphoma: an international study. J Natl
survivors of Hodgkin’s lymphoma. J Clin Oncol 25:1489–1497 Cancer Inst 99:790–800
254 D. C. Hodgson et al.

Menu-Branthomme A et al (2004) Radiation dose, chemotherapy and Ries L et al (2006) SEER cancer statistics review 1975–2003. National
risk of soft tissue sarcoma after solid tumours during childhood. Int Cancer Institute, Bethesda
J Cancer 110:87–93 Ron E et al (1995) Thyroid cancer after exposure to external radiation:
Meyer R et al (2003) A Randomized phase III comparison of single - a pooled analysis of seven studies. Radiat Res 141:259–277
modality ABVD with a strategy that includes radiation therapy in Ron E et al (1994) Cancer incidence in atomic bomb survivors. Part
patients with early-stage Hodgkins disease: The HD-6 trial of the IV: Comparison of cancer incidence and mortality. Radiat Res
national cancer institute of canada clinical trials group. abstr 81. 137:S98–S112
J Clin Oncol (accepted for publication) Roychoudhuri R et al (2004) Radiation-induced malignancies follow-
Moon K et al (2006) Cancer incidence after localized therapy for ing radiotherapy for breast cancer. Br J Cancer 91:868–872
prostate cancer. Cancer 107:991–998 Rubino C et al (2005) Radiation dose and risk of soft tissue and bone
Nachman JB et al (2002) Randomized comparison of low-dose sarcoma after breast cancer treatment. Breast Cancer Res Treat
involved-field radiotherapy and no radiotherapy for children with 89:277–288
Hodgkin’s disease who achieve a complete response to chemo- Sacchi S et al (2008) Secondary malignancies after treatment for
therapy. J Clin Oncol 20:3765–3771 indolent non-Hodgkin’s lymphoma: a 16-year follow-up study.
Neglia JP et al (2001) Second malignant neoplasms in five-year Haematologica 93:398–404
survivors of childhood cancer: childhood cancer survivor study. Schaapveld M et al (2008) Risk of new primary nonbreast cancers
J Natl Cancer Inst 93:618–629 after breast cancer treatment: a Dutch population-based study.
Neglia JP et al (2006) New primary neoplasms of the central nervous J Clin Oncol 26:1239–1246
system in survivors of childhood cancer: a report from the Schairer C et al (2007) Comparative mortality for 621 second cancers
childhood cancer survivor study. J Natl Cancer Inst 98:1528–1537 in 29356 testicular cancer survivors and 12420 matched first
Neugut AI et al (1997) Bladder carcinoma and other second cancers. J Natl Cancer Inst 99(16):1248–1256
malignancies after radiotherapy for prostate carcinoma. Cancer Schneider U (2006) Calculated risk of fatal secondary malignancies
79:1600–1604 from intensity-modulated radiotherapy: In regard to Kry et al. (Int J
Neugut AI et al (1994) Increased risk of lung cancer after breast cancer Radiat Oncol Biol Phys 2005;62:1195–1203). Int J Radiat Oncol
radiation therapy in cigarette smokers. Cancer 73:1615–1620 Biol Phys 64: 1290; (author reply 1290–1291)
Neugut AI et al (1993) Lung cancer after radiation therapy for breast Sharif S et al (2006) Second primary tumors in neurofibromatosis 1
cancer. Cancer 71:3054–3057 patients treated for optic glioma: substantial risks after radiother-
Ng AK et al (2002) Second malignancy after Hodgkin disease treated apy. J Clin Oncol 24:2570–2575
with radiation therapy with or without chemotherapy: long-term Sigurdson AJ et al (2005) Primary thyroid cancer after a first tumour in
risks and risk factors. Blood 100:1989–1996 childhood (the childhood cancer survivor study): a nested case-
Nichols KE et al (1999) Heterozygous germline ATM mutations do control study. Lancet 365:2014–2023
not contribute to radiation-associated malignancies after Hodgkin’s Smith RE et al (2003) Acute myeloid leukemia and myelodysplastic
disease. J Clin Oncol 17:1259 syndrome after doxorubicin-cyclophosphamide adjuvant therapy
Olsen JH et al (1993) Second malignant neoplasms after cancer in for operable breast cancer: the national surgical adjuvant breast and
childhood or adolescence. Nordic society of paediatric haematol- bowel project experience. J Clin Oncol 21:1195–1204
ogy and oncology association of the nordic cancer registries. BMJ Storm HH et al (1992) Adjuvant radiotherapy and risk of contralateral
307:1030–1036 breast cancer. J Natl Cancer Inst 84:1245–1250
Pedersen-Bjergaard J et al (1991) Increased risk of myelodysplasia and Swerdlow AJ et al (2000) Risk of second malignancy after Hodgkin’s
leukaemia after etoposide, cisplatin, and bleomycin for germ-cell disease in a collaborative British cohort: the relation to age at
tumours. Lancet 338:359–363 treatment. J Clin Oncol 18:498–509
Perkins JL et al (2005) Nonmelanoma skin cancer in survivors of Thompson DE et al (1994) Cancer incidence in atomic bomb survivors.
childhood and adolescent cancer: a report from the childhood Part II: solid tumors, 1958–1987. Radiat Res 137:S17–S67
cancer survivor study. J Clin Oncol 23:3733–3741 Travis LB et al (1991) Second cancers following non-Hodgkin’s
Peters MV, Middlemiss KC (1958) A study of Hodgkin’s disease lymphoma. Cancer 67:2002–2009
treated by irradiation. Am J Roentgenol Radium Ther Nucl Med Travis LB et al (1993) Second cancers among long-term survivors of
79:114–121 non-Hodgkin’s lymphoma. J Natl Cancer Inst 85:1932–1937
Pickles T, Phillips N (2002) The risk of second malignancy in men Travis LB et al (2000) Treatment-associated leukemia following
with prostate cancer treated with or without radiation in British testicular cancer. J Natl Cancer Inst 92:1165–1171
Columbia, 1984–2000. Radiother Oncol 65:145–151 Travis LB et al (2002) Lung cancer following chemotherapy and
Pintilie M (2006) Competing risks: a practical perspective. Wiley, radiotherapy for Hodgkin’s disease. J Natl Cancer Inst 94:182–192
West Sussex Travis LB et al (2003) Breast cancer following radiotherapy and
Praga C et al (2005) Risk of acute myeloid leukemia and myelodys- chemotherapy among young women with Hodgkin disease. JAMA
plastic syndrome in trials of adjuvant epirubicin for early breast 290:465–475
cancer: correlation with doses of epirubicin and cyclophosphamide. Travis LB, Gilbert E (2005) Lung cancer after Hodgkin lymphoma: the
J Clin Oncol 23:4179–4191 roles of chemotherapy, radiotherapy and tobacco use. Radiat Res
Preston DL et al (2002) Radiation effects on breast cancer risk: a 163:695–696
pooled analysis of eight cohorts. Radiat Res 158:220–235 Travis LB et al (2005a) Second cancers among 40,576 testicular
Pui CH et al (2003) Extended follow-up of long-term survivors of cancer patients: focus on long-term survivors. J Natl Cancer Inst
childhood acute lymphoblastic leukemia. N Engl J Med 97:1354–1365
349:640–649 Travis LB et al (2005b) Cumulative absolute breast cancer risk for
Pui CH et al (1991) Acute myeloid leukemia in children treated with young women treated for Hodgkin lymphoma. J Natl Cancer Inst
epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J 97:1428–1437
Med 325:1682–1687 Travis LB et al (2006) Cancer survivorship—genetic susceptibility and
Rapiti E et al (2008) Increased risk of colon cancer after external second primary cancers: research strategies and recommendations.
radiation therapy for prostate cancer. Int J Cancer 123:1141–1145 J Natl Cancer Inst 98:15–25
Radiation-Related Second Primary Cancers: Clinical Perspectives 255

Tward J et al (2007) Incidence, risk factors, and pathogenesis of Virtanen A et al (2007) Angiosarcoma after radiotherapy: a cohort
second malignancies in patients with non-Hodgkin lymphoma. study of 332,163 Finnish cancer patients. Br J Cancer 97:115–117
Leuk Lymphoma 48:1482–1495 Walter AW et al (1998) Secondary brain tumors in children treated for
van den Belt-Dusebout AW et al (2007) Treatment-specific risks of acute lymphoblastic leukemia at st jude children’s research
second malignancies and cardiovascular disease in 5-year survivors hospital. J Clin Oncol 16:3761–3767
of testicular cancer. J Clin Oncol 25:4370–4378 Wong FL et al (1997) Cancer incidence after retinoblastoma.
van Leeuwen FE et al (1994) Second cancer risk following Hodgkin’s Radiation dose and sarcoma risk. JAMA 278:1262–1267
disease: a 20-year follow-up study. J Clin Oncol 12:312–325 Woo TC et al (2006) Body radiation exposure in breast cancer
van Leeuwen FE et al (2003) Roles of radiation dose, chemotherapy, radiotherapy: impact of breast IMRT and virtual wedge compen-
and hormonal factors in breast cancer following Hodgkin’s disease. sation techniques. Int J Radiat Oncol Biol Phys 65:52–58
J Natl Cancer Inst 95:971–980 Zablotska LB, Neugut AI (2003) Lung carcinoma after radiation
van Leeuwen FE et al (1993) Second cancer risk following testicular therapy in women treated with lumpectomy or mastectomy for
cancer: a follow-up study of 1,909 patients. J Clin Oncol primary breast carcinoma. Cancer 97:1404–1411
11:415–424
 The Psychosocial and Functional Impact
of Radiation Therapy
Jason Q. Purnell, Karen Mustian, Pascal Jean-Pierre, Oxana Palesh,
Luke J. Peppone, Supriya G. Mohile, Tom V. Darling,
and Gary R. Morrow

Contents 8 Psychosocial Effects of Cancer Among Ethnic

Minorities and Underserved Populations ......................... 267

1 Introduction.......................................................................... 257 References...................................................................................... 268

2 Symptom Burden During Radiation Therapy ................. 258

3 Cancer-Related Fatigue ...................................................... 259
Abstract
4 Sleep Problems During Radiation Therapy ..................... 261
5 Radiation Oncology and Psychological Functioning....... 263 • Cancer treatment, including radiation therapy, can cause
6 Patient Information Needs During immediate side effects as well as persistent disruptions
Radiation Therapy............................................................... 264 across several domains of functioning.
7 Radiotherapy and Cognitive Functioning ........................ 265
• Symptoms, and side effects related to radiation therapy
should be conceptualized, assessed, and addressed as co-
occurring rather than in isolation.
• Cancer-related fatigue and sleep problems associated
J. Q. Purnell (&) with radiation therapy are increasingly amenable to
The Brown School/Institute for Public Health, Washington
behavioral and pharmacological treatments, however,
University in St. Louis, Campus Box 1196, Brown Hall,
Room 215,One Brookings Drive, St. Louis, MO 63130, USA more research is needed to establish standards of care.
e-mail: [email protected] • Psychological problems, while significant for some can-
K. Mustian cer patients, appear to abate during and after treatment.
Departments of Radiation Oncology & Community and Radiation oncologists are encouraged to assess for psy-
Preventive Medicine, University of Rochester Medical Center, chological problems and refer patients for appropriate
601 Elmwood Avenue, Box 704 Rochester, NY 14642, USA
treatment.
P. Jean-Pierre • Patient anxiety regarding radiation therapy can be alle-
Department of Psychology, University of Notre Dame,
viated to a significant extent by providing appropriate
109 Haggar Hall, Notre Dame, IN 46556, USA
information throughout the treatment process.
O. Palesh
• Cancer-related cognitive dysfunction has also been
Department of Psychiatry & Behavioral Sciences,
Stanford School of Medicine, 401 Quarry Road, associated with radiotherapy, but systematic interventions
Stanford, CA 94305, USA for cancer patients are still lacking.
L. J. Peppone
T. V. Darling • Racial and ethnic minorities and other underserved pop-
Department of Kinesiology and Physical Education, Valdosta ulations face unique challenges that can be addressed by
State University, 1500 N. Patterson St., Valdosta, GA 31698, radiation oncology.
USA
S. G. Mohile
Department of Medical Hematology/Oncology, USA,
601 Elmwood Avenue, Rochester, NY 14642, USA
1 Introduction
G. R. Morrow
This year alone, more than 1.4 million Americans will be
Departments of Radiation Oncology & Psychiatry,
DirectorUniversity of Rochester Cancer Center Community diagnosed with cancer Jemal et al. (2008). Cancer and its
Clinical Oncology Program Research Base, 601 Elmwood treatments can produce multiple distressing symptoms and
Avenue, Rochester, NY 14642, USA

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 257
DOI: 10.1007/978-3-540-72314-1_17,  Springer-Verlag Berlin Heidelberg 2014
258 J. Q. Purnell et al.

impairments in function: patients often experience physical and the impact of these symptoms on daily activities
and psychological symptoms both during and after aggres- (Cleeland et al. 2007).
sive cancer treatments. Those undergoing radiation and Although symptoms of cancer and cancer treatment have
chemotherapy suffer from a myriad of physical side effects, been studied as single entities, certain symptoms occur
including nausea, alopecia, pain, and fatigue, as well as a together and can influence one another. Multiple symptoms
variety of psychiatric problems such as depression and additively and synergistically affect overall quality of life
anxiety. Improvements in medical technologies, develop- (Cleeland et al. 2000, 2007; Dodd et al. 2001). Dodd et al.
ment and availability of more effective drugs, and techno- (2001) defined a ‘‘symptom cluster’’ as three or more con-
logical innovations in radiotherapy equipment and delivery current symptoms that are related to each other. Typical
have facilitated more timely identification and management symptoms that co-occur include fatigue, pain, insomnia,
of malignancies. Progress in oncology research and clinical anorexia, and psychological distress. Given et al. reported
practice has contributed to increased survival rates for that clusters of symptoms, such as insomnia, fatigue, and
patients with many types of cancer. Unfortunately, the pain in 826 elderly patients had a consistent and significant
effective management of cancer creates side effects (e.g., effect on QOL unrelated to the type of cancer, treatment,
cognitive dysfunction, fatigue, nausea, and vomiting) that stage of disease, or comorbid conditions (Given et al. 2001).
affect important dimensions of patients’ psychosocial It has been hypothesized that symptoms may occur together
functioning and quality of life (Ahles et al. 2002; Bender due to common underlying inflammatory or neuroimmu-
et al. 2001; Saykin et al. 2003). nologic mechanisms (Cleeland et al. 2003; Lee et al. 2004).
Symptoms may not always occur in the same patterns and
may not develop or disappear with the same temporal
course, making necessary thoughtful longitudinal studies to
2 Symptom Burden During Radiation identify coexisting symptoms.
Therapy Several multiple-symptom assessment scales have been
developed and validated to assess not only the most fre-
Symptom burden is a quantitative measure of the overall quent symptoms but also symptoms that co-occur, and the
effect of symptoms on a patient’s function and health- interference of symptoms with quality of life and daily
related quality of life (HRQOL). Early recognition of, and activities. The ideal scale is brief, easy to understand, and
effective intervention directed against, treatment-related able to be administered for both clinical and research pur-
symptoms is essential, as these symptoms can lead to poses (Cleeland et al. 2000, 2007). Kirkova et al. (2006)
treatment delays or early discontinuation. Symptom control systematically reviewed cancer symptom assessments and
is an integral component of cancer care during and after identified 21 tools most appropriate for clinical use in
treatment. cancer patients. Although this review did not identify any
HRQOL, as utilized in cancer care, is a multidimensional that met all the criteria of an ideal instrument, thirteen of the
construct that includes four dimensions: physical function, available symptom assessment tools evaluated more than
psychological function, social role function, and disease- or five symptoms and also assessed interference of symptoms
treatment-related symptoms. Patient ratings of symptom with overall quality of life and daily activities. The M.D.
severity and their impact on function are important subsets Anderson Symptom Inventory (MDASI) is one such tool
of HRQOL. Unlike objective ‘‘signs’’ of disease noted on frequently utilized to rate the severity of 13 symptoms
physical examination or imaging scans, symptoms are common in cancer patients and the impact of these symp-
dependent on the observations of the patient and can only be toms on various aspects of a patient’s life. Research
elicited through patient report. It is often difficult to define investigating the properties of the inventory revealed that
or characterize symptoms because the underlying etiology the most severe symptoms (i.e., fatigue, insomnia, lack of
could derive from the disease, the treatment, comorbid appetite, pain, psychological distress) were similar regard-
medical conditions, or a combination thereof. Whereas less of cancer type (Cleeland et al. 2000).
many symptoms are caused by the underlying cancer, Several studies have assessed the prevalence of symp-
treatment may lead to commonly recognized side effects toms and the impact of overall symptom burden on the QOL
including fatigue, neuropathy, insomnia, cognitive dys- of cancer patients undergoing radiotherapy (RT). In a study
function, psychological distress, and depression. While evaluating the longitudinal relationship between chemora-
these symptoms may occur during treatment, residual diation for non-small-cell lung cancer and patient symp-
treatment-related symptoms can persist even after effective toms, 63 % of patients suffered from moderate to severe
treatment has been completed. All causes of discomfort play levels of multiple symptoms by the end of treatment (Wang
a part in the total symptom burden, which consists of the et al. 2006). While all symptoms interfered with daily
patient’s global impressions of disease or treatment burden activities, fatigue, distress, and sadness caused the most
The Psychosocial and Functional Impact of Radiation Therapy 259

Fig. 2 Percentage increase in symptom interference following radi-

ation therapy

Fig. 1 Mean severity of symptoms at baseline and at weeks 3 and 5

during the course of RT (n = 419) (with permission from Hickok et al. treatment (Miaskowski et al. 2004). Given the negative
2005a) effects of high symptom burden on daily activities and
HRQOL, more research is necessary to evaluate the effect
significant disruption to daily life. Investigators at the of interventions that target common symptom clusters
University of Rochester characterized the longitudinal rather than individual symptoms. Ideally, the development
course of 12 common symptoms in 1,129 consecutive of such interventions will lead to a reduction of overall
patients during radiotherapy (Hickok et al. 2005a). Eighty- symptom burden in cancer patients.
four percent of patients experienced symptoms before
treatment. During the five-week course of treatment, the
419 patients who completed both pre- and post-RT assess- 3 Cancer-Related Fatigue
ments reported that the frequency of all symptoms increased
significantly (Fig. 1). In another study by the same inves- Cancer-related fatigue (CRF) is a global term used to refer
tigators, fatigue was highly prevalent in patients undergoing to fatigue resulting from cancer and/or its treatments
RT; only 13 % reported no fatigue (Hickok et al. 2005b). including surgically-induced, chemotherapy-induced, and
The same University of Rochester research team recently radiation-induced fatigue. CRF is a multifaceted, psycho-
utilized a modified version of the MDASI to assess the social and physiological state characterized by an over-
prevalence of multiple symptoms and their interference whelming sensation of exhaustion that is accompanied by a
with daily life activities in patients undergoing radiother- decreased capacity for mental and physical energy expen-
apy. The primary goals were to determine the prevalence diture (Ahlberg et al. 2003; Barton-Burke and Barton-Burke
and the pattern of change in specific symptoms during and 2006; Berger 1998; Broeckel et al. 1998; Carroll et al. 2007;
after radiation therapy and to evaluate the impact of Cella 1998; Cella et al. 1998, 2001, 2002; Curt et al. 2000;
symptoms on QOL and daily activities. All age groups and Escalante 2003; Hickok et al. 2003, Hickok et al. 2005b;
tumor types were included in the analysis. The investigators Hofman et al. 2004, 2007; Irvine et al. 1991; Jacobsen et al.
found a significant increase in the severity of almost all 2007; Jean-Pierre et al. 2007; Jereczek-Fossa et al. 2001;
symptoms and their impact on QOL and daily activities. Kroenke et al. 1988; Mock 2004; Mock and Olsen 2003;
The overall symptom burden score (a sum of the individual Morrow 2007; Morrow et al. 2002, 2005; Mustian et al.
symptom scores) significantly increased post-radiotherapy 2007; National Comprehensive Cancer Network 2008;
(Fig. 2). In addition, higher symptom burdens correlated Piper et al. 1987; Portenoy and Itri 1999; Ryan et al. 2007).
with deficits in patients’ impressions of their own QOL. CRF is differentiated from the fatigue experienced by
The majority of previous symptom research has focused healthy individuals because of its severity, persistence, and
on individual symptoms, yet in reality patients often expe- impact on quality of life among cancer patients and survi-
rience many different symptoms simultaneously. Research vors (Carroll et al. 2007; Hofman et al. 2007; Morrow 2007;
in patients undergoing radiotherapy has illustrated a high Mustian et al. 2007; Ryan et al. 2007). Unlike the fatigue
prevalence of symptoms that significantly impact QOL and stemming from physical or mental exertion that can be
daily activities. Moreover, high symptom burden and spe- relieved with rest or sleep, CRF is not alleviated by resting
cific symptom clusters can have a deleterious effect on or sleeping (Carroll et al. 2007; Hofman et al. 2007; Mor-
patient outcomes due to delays or discontinuation of row 2007; Mustian et al. 2007; National comprehensive
260 J. Q. Purnell et al.

Cancer Network 2008; Ryan et al. 2007). Cancer patients activities, a reduced capacity to sustain meaningful rela-
and survivors report that CRF begins with diagnosis, tionships and activities with families, a reduced ability to
worsens during the course of treatment, and can persist for continue working and a reduction in engagement in social
months and years after treatments are completed (Carroll and other activities (Carroll et al. 2007; Hofman et al. 2007;
et al. 2007; Hofman et al. 2007; Morrow 2007; Mustian Jacobsen et al. 2007; Jean-Pierre et al. 2007; Meyerowitz
et al. 2007; Ryan et al. 2007). CRF can also immerge for the et al. 1979; Mock 2004; Morrow 2007; Morrow et al. 2002,
first time months or years after treatments are completed 2005; Mustian et al. 2007, 2008; National Comprehensive
(Carroll et al. 2007; Hofman et al. 2007; Morrow 2007; Cancer Network 2008; Rhodes et al. 1988; Ryan et al.
Mustian et al. 2007; National Comprehensive Cancer Net- 2007). These signs and symptoms occur both during and
work 2008; Ryan et al. 2007). As such CRF can be char- after treatment for cancer (Carroll et al. 2007; Hofman et al.
acterized as an acute or chronic side effect as well as an 2007; Jacobsen et al. 2007; Jean-Pierre et al. 2007; Morrow
early or late side effect resulting from cancer and its treat- 2007; Mustian et al. 2007, 2008; Ryan et al. 2007). CRF is
ments (Mustian et al. 2007). often reported as more distressing and having a greater
From 60 to 100 % of cancer patients and survivors with a negative impact on patients’ and survivors’ daily activities
variety of diagnoses who are receiving different types of and QOL than other cancer-related symptoms such as
treatments report some degree of CRF, with 41 % or more vomiting, nausea, pain, and depression (Carroll et al. 2007;
indicating a severe level of CRF (0 = no CRF to 10 = CRF Curt et al. 2001; Hofman et al. 2007; Jacobsen et al. 2007;
as bad as you can imagine; a score [7 = severe on this 11- Jean-Pierre et al. 2007; Mock 2004; Morrow 2007; Morrow
point Likert Scale) during treatment (Ahlberg et al. 2003; et al. 2002, 2005; Mustian et al. 2007, 2008; National
Barton-Burke and Barton-Burke 2006; Berger 1998; Comprehensive Cancer Network 2008; Ryan et al. 2007).
Broeckel et al. 1998; Cella 1998; Cella et al. 1998, 2001, While great advances have been made in cancer treatments
2002; Curt et al. 2000; Escalante 2003; Hickok et al. 2001, over the past decade, the negative impact of CRF is mag-
2003; Hofman et al. 2004; Irvine et al. 1991; Jereczek-Fossa nified because life expectancy has increased among cancer
et al. 2001; Kroenke et al. 1988; Mock 2004; Mock and survivors. The experience of CRF is prolonged and there is
Olsen 2003; Piper et al. 1987; Portenoy and Itri 1999). More no effective cure (Carroll et al. 2007; Hofman et al. 2007;
than 80 % of cancer survivors report that the CRF they Jacobsen et al. 2007; Jean-Pierre et al. 2007; Morrow 2007;
experience persists for months and even years after treat- Mustian et al. 2007, 2008; Ryan et al. 2007).
ments are completed, with 17–38 % indicating that their Cancer-related fatigue was first acknowledged as an
CRF persists well beyond 6 months post-treatment (Barton- official diagnosis in the International Classification of Dis-
Burke and Barton-Burke 2006; Carroll et al. 2007; Frank- ease (ICD-10) in 1998. The National Comprehensive Can-
Stromberg and Wright 1984; Hofman et al. 2007; Jacobsen cer Network (NCCN) published the first set of guidelines
et al. 2007; Meyerowitz et al. 1983; Morrow 2007; Mustian for the management of CRF in 2000. These guidelines were
et al. 2006; Mustian et al. 2007; Padilla and Grant 1985; based on a synthesis of the best and most currently available
Prue et al. 2006; Ryan et al. 2007). CRF is associated with a research and clinical experience in oncology. These NCCN
poorer prognosis among patients and often continues even Practice Guidelines were recently updated in 2008 and
when a survivor’s cancer is undetectable or in remission provide concise, up-to-date, evidence-based and clinically-
(Carroll et al. 2007; Hofman et al. 2007; Jacobsen et al. based recommendations for the management of CRF based
2007; Jean-Pierre et al. 2007; Morrow 2007; Mustian et al. on current knowledge of the symptom and development of
2007; Ryan et al. 2007). new therapies (National Comprehensive Cancer Network
CRF has a considerable negative impact on an individ- 2008).
ual’s ability to perform important normal daily activities The current NCCN guidelines for the management of
and overall QOL (Carroll et al. 2007; Hofman et al. 2007; CRF (National Comprehensive Cancer Network 2008)
Jacobsen et al. 2007; Jean-Pierre et al. 2007; Morrow 2007; suggest that clinicians frequently screen for CRF in patients
Mustian et al. 2007, 2008; Ryan et al. 2007). This impact with cancer and, when present, first treat possible contrib-
stems from the physiological and psychosocial signs and uting factors (e.g., pain, emotional distress, sleep disruption,
symptoms of CRF which typically include: anemia, hypo- anemia, nutrition, physical activity levels), including
thyroidism, shortness of breath, muscle atrophy, physical comorbid conditions (e.g., infection, cardiac dysfunction,
weakness, decreased aerobic capacity, decreased ability to pulmonary dysfunction, renal dysfunction, hepatic dys-
walk, reduced capacity to bathe, dress or cook, sleep dis- function, neurologic dysfunction, endocrine dysfunction,
ruption, pain, self-reported tiredness, mood disturbance, hypothyroidism), which is typically done via pharmacologic
depression, anxiety, hopelessness, negative outcome therapies (National Comprehensive Cancer Network 2008).
expectancies, impaired memory, the inability to concen- Many patients with cancer continue to experience CRF even
trate, a reduction in patients’ ability to participate in leisure after successful clinical management of these contributing
The Psychosocial and Functional Impact of Radiation Therapy 261

factors (Carroll et al. 2007; Hofman et al. 2007; Jacobsen depression and anxiety), physical complaints, substance
et al. 2007; Jean-Pierre et al. 2007; Morrow 2007; Mustian abuse, reduced quality of life, and cognitive impairment
et al. 2007, 2008; Ryan et al. 2007). Patients may also (Breslau et al. 1996; Katz and Mchorney 2002; Lee et al.
experience CRF in the absence of any clinically discernable 2005; Leger et al. 2001, 2002; Ohayon and Zulley 2001;
contributing factors (Carroll et al. 2007; Hofman et al. Walsh and Engelhardt 1999; Zee and Walsleben 2004).
2007; Jacobsen et al. 2007; Jean-Pierre et al. 2007; Morrow Some data also suggest that sleep difficulty may negatively
2007; Mustian et al. 2007, 2008; Ryan et al. 2007). In influence cardiovascular conditions, reduce immune func-
instances where no specific causal factors can be identified, tion, and affect the respiratory and musculoskeletal systems
or when the patient continues to have moderate-to-severe (Burgos et al. 2006; Katz and Mchorney 2002; Schwartz
fatigue and/or persistent chronic fatigue after treatments for et al. 1999; Suka et al. 2003). Katz and MChorney (2002)
the cancer are complete and the other possible contributing report that insomnia is independently associated with
factors have been clinically treated, the NCCN guidelines reduced health-related quality of life to the same extent as
(National Comprehensive Cancer Network 2008) recom- other serious chronic conditions such as diabetes and heart
mend that physicians consider both pharmacologic inter- disease.
ventions and nonpharmacologic behavioral interventions Although the full impact of insomnia on cancer patients
including maintaining physical activity, psychosocial ther- and on disease progression is largely unknown, it is rea-
apies, and other integrative therapies. Some of the most sonable to assume that it would create similar adverse
promising therapies that are still under investigation include psychiatric and physiological consequences in cancer
exercise (Jacobsen et al. 2007; Mustian et al. 2007), psy- patients as in the general population. Insomnia may exac-
chosocial therapies (Jacobsen et al. 2007; Mustian et al. erbate other cancer-related symptoms (i.e., fatigue, nausea,
2007), and Modafinil (Morrow et al. 2008). depressive mood, pain, and/or reduced pain tolerance), and
Despite the existence of the NCCN guidelines and a disrupted circadian rhythms may influence disease inci-
growing body of literature that has identified some prom- dence, progression, and survival (Anderson et al. 2003;
ising treatments, there is currently no evidence-based, Fortner et al. 2002; Koopman et al. 2002; Mormont et al.
effective cure for CRF, and there is no specific standard of 2000; Spiegel and Sephton 2002).
care for CRF in the medical community. Moreover, very While the literature on the prevalence of insomnia in
little attention has been given to the unique pathophysio- cancer patients is scant, two early studies found that the
logical and treatment nuances of CRF as an acute versus proportion of people who had difficulty staying asleep was
chronic side effect or an early versus late effect. More sci- significantly higher among cancer patients (40–45 %) than
entific research is needed to discern the pathophysiology of among healthy controls (14–25 %) (Kaye et al. 1983;
all types of CRF and to develop effective cures for all types Malone et al. 1994). Although both of these studies
of CRF. This knowledge will provide the evidence upon underscored the importance of studying sleep in cancer
which the standards of care for CRF in oncology will patients, the sample size in Kaye et al. (1983) was insuffi-
eventually be based. cient to draw any definitive conclusions about insomnia in
cancer patients, and Malone et al. (1994) failed to undertake
a detailed examination of sleep concerns.
4 Sleep Problems During Radiation A more recent study conducted by Savard and colleagues
Therapy in 2001 focused specifically on the prevalence, clinical
characteristics, and risk factors for insomnia in the context
Relatively little attention has been devoted to sleep distur- of breast cancer. They surveyed 300 breast cancer survivors
bance, one of the most distressing symptoms patients with a median time since diagnosis of 49 months (Savard
experience (Savard and Morin 2001). The spectrum of sleep et al. 2001). Nearly 51 % reported insomnia symptoms,
disorders ranges from insomnia to sleep apnea, parasom- 19 % met diagnostic criteria for insomnia disorder, 33 %
nias, restless leg syndrome, and circadian rhythm disorders. reported that insomnia occurred after they were diagnosed
Insomnia is defined as difficulty falling asleep, staying with cancer, and for 58 % of patients, insomnia became
asleep or waking up earlier than intended, resulting in worse during the course of their cancer. This study was one
daytime complaints of fatigue or sleepiness for at least of the first to note that insomnia prevalence is significantly
1 month and not due to another mental disorder. Insomnia is higher in women with breast cancer than in the general
prevalent; several epidemiological studies report that population. Savard and colleagues also identified risk fac-
15–20 % of the population has insomnia (Ohayon 2007). In tors for the development of insomnia in breast cancer
general, population sleep loss and/or insomnia are associ- patients. The study found that unemployment, being on sick
ated with several negative physical and psychiatric conse- leave, and being widowed were significant contributors to
quences including fatigue, psychiatric illness (e.g., major the development of insomnia in this population. In addition,
262 J. Q. Purnell et al.

they reported that chemotherapy either caused or aggra- 10

Sleep problems at their worst
vated sleep difficulties. The authors hypothesized that the
spike in symptoms during chemotherapy might be 8
explained either by the antiemetic drugs used in treatment Chemotherapy with/without radiation (n = 388)
Radiation alone (n = 256)
or the onset of menopause brought on by chemotherapy.
The most comprehensive insomnia prevalence study 6

Sleep
(Davidson et al. 2002) included 982 cancer patients (with a
mean age of 65 years) with six different types of cancer 4
(gastrointestinal, gynecologic, genitourinary, breast, lung,
and nonmelanoma skin). Patients completed a ‘‘Sleep Sur-
vey’’ questionnaire that was used to evaluate the presence or 2

absence of various sleep problems (e.g., insomnia, restless leg

syndrome, fatigue) and to define their type of sleep problem 0
(i.e., difficulty falling asleep, difficulty staying asleep, or Pre-Treatment During Treatment Post-Treatment
waking up too early) (Davidson et al. 2002). Three hundred
Fig. 3 Sleep problems by treatment type
patients reported insomnia (30.5 %), and the majority (76 %)
reported the greatest difficulty with frequent awakening. The
authors found that the prevalence of insomnia was highest in versus radiation are at higher risk for developing sleep
the surgery group (45 %), followed by chemotherapy problems and, furthermore, that difficulties with sleep
(34.5 %) and radiation (29.5 %); these differences, however, increase during cancer treatment.
were not statistically significant. The authors also noted that All of these studies taken together indicate that insomnia
cancer patients who reported marked fatigue were 2.5 times is a prevalent and distressing symptom for cancer patients.
more likely to have insomnia than others. Multiple studies indicate that insomnia rates among cancer
The most recent study, conducted by Mao and col- patients are two to three times higher than rates in the
leagues, describes the symptom burden in cancer survivors general population. Increasing evidence suggests that can-
(Mao et al. 2007). The author’s evaluated data collected cer treatment might cause or exacerbate existing insomnia
from 1904 cancer survivors from the 2002 National Health complaints and that the use of radiation and/or chemother-
Interview Survey. Nearly 52 % of the survivors were six or apy may cause these complaints to increase. To date, no
more years past their initial diagnosis of cancer, and nearly definitive studies have evaluated insomnia in cancer
30 % reported insomnia symptoms, compared to 17 % of patients undergoing radiation. It is still unclear whether
healthy controls. Younger patients (age \ 50 years) had an insomnia precedes cancer or whether insomnia develops as
increased symptom burden compared to older patients a result of cancer diagnosis and/or treatment. Diagnosis and
(age [ 64 years), and the adjusted odds ratios for insomnia treatment of cancer and concerns about survival are severe
were 2.7 and 1.44, respectively. stressors that in themselves might precipitate the develop-
A recent study conducted by the URCC CCOP group ment of insomnia; multiple additional biological and psy-
(Palesh et al. 2007) surveyed 648 cancer patients (mean chological ‘‘insults’’ (e.g., tumor biology, anti-cancer
age = 61) who completed questionnaires evaluating fati- medications, early menopause, and fatigue) might also
gue, pain, depression, and difficulty sleeping. Sixty percent precipitate the development of insomnia symptoms. Given
received chemotherapy and 40 % received radiation ther- the high rate of insomnia in cancer patients, more investi-
apy. Participants rated the severity of their symptoms at gation into its precipitating and perpetuating factors is
their worst on an 11-point Likert Scale (0 = Not present to needed in order to design effective interventions.
10 = As bad as you can imagine) prior to treatment, during Within the general population, insomnia is highly treat-
treatment, and 6 months following treatment. Patients able with pharmacological and psychological therapies (i.e.,
reported significantly more sleep problems during treatment zolpidem and cognitive-behavioral therapy for insomnia).
(median = 4) than either prior to or following treatment Several studies conducted in cancer survivors indicate that
(both, median = 2). Women reported more sleep problems pharmacological and behavioral interventions are also
than men before, during, and after treatment (all p \ 0.01). effective in this group (Espie et al. 2008; Jacobsen et al.
Younger patients (age B 60) reported more problems with 1994; Savard et al. 2005). Additional research is needed to
sleep at all time points (all p \ 0.001). Patients receiving uncover physiological, psychological, and behavioral fac-
chemotherapy had more difficulties with sleep at all time tors that contribute to the development of insomnia during
points than patients undergoing radiation alone (all radiation. Such studies will increase understanding of the
p \ 0.001) (Fig. 3). These results show that women, natural course of insomnia disorder and allow the devel-
younger patients, and patients undergoing chemotherapy opment of effective interventions.
The Psychosocial and Functional Impact of Radiation Therapy 263

5 Radiation Oncology and Psychological cancer sites (e.g., breast, head and neck, prostate, bladder,
Functioning cervix) and other adjuvant treatments (e.g., chemotherapy
and hormone therapy).
A cancer diagnosis and its subsequent treatment represent Prior to RT, the studies reported that 10–20 % of patients
major sources of stress that can lead to a variety of psy- had anxiety symptoms and only 1.5–8 % had depressive
chological difficulties (Dunn et al. 2004; Steginga et al. symptoms. The authors attribute the difference to anticipa-
1998). Two major themes characterize the psychological tory anxiety about treatment and its side effects prior to
distress of cancer patients: first, the fear of the unknown, treatment and suggest that the absence of treatment side
and second, the patient’s belief that the treatment will cause effects may account for relatively low levels of depression
pain, discomfort, and/or adverse effects (Poroch 1995). (Stiegelis et al. 2004).
While no consensus exists on the prevalence of psycho- During RT, anxiety symptoms were reported in 21–54 %
logical morbidity among cancer patients, seminal research of patients; these symptoms, however, showed relatively
in this area places the estimate as high as 47 % (Derogatis consistent declines as treatment progressed. For example,
et al. 1983). Major depression, the most investigated psy- Rahn et al. (1998) showed that 40 % of patients were
chiatric disorder in cancer, has been reported in 0–38 % of anxious on the first day of treatment, while only 19 % were
patients, and ‘‘depression spectrum disorders’’ in 0–58 % still anxious by the last day. It is likely that patients’ anxiety
(Massie 2004). This wide range of prevalence estimates is decreased as they gained more familiarity with treatment. In
largely due to the highly variable methods of assessment contrast to the pre-treatment phase, depressive symptoms
(e.g., self-report paper-and-pencil instruments, structured were relatively high during RT, with 12-31 % of patients
interviews, clinical interviews, and DSM diagnoses) and the reporting such symptoms.
differences in study design used by research teams since the Data were less consistent in studies examining anxiety
1960s. Investigation has also focused on anxiety disorders, and depression following radiation treatment. Reports of
with prevalence estimates ranging from 1.7–23 % and anxiety symptoms ranged from 0 to 52 % of patients, with
similar patterns of variability in study approach (Stark and assessments of anxiety covering time points from immedi-
House 2000). ately after RT to as many as 13 years post-treatment. There
Though other psychiatric illnesses (e.g., Posttraumatic was also significant variability in depression, ranging from
Stress Disorder and Adjustment Disorder) have also 8 to 48 % of patients. However, most studies found that
received research attention, depression and anxiety are between 8 and 21.5 % of patients reported depressive
widely considered the most important comorbidities for symptoms. The authors suggest that, in some instances,
cancer patients because of their potential for interference differences in cut-off scores and response format may have
with treatment and association with poor health outcomes elevated reporting (Stiegelis et al. 2004).
(Frick et al. 2007). Anxiety and stress have been associated Longitudinal studies also showed inconsistencies, with
with reduced survival and poorer prognosis, although the some (Monga et al. 1999) finding an improvement in
association is inconsistent (De Boer et al. 1999). There is depressive symptoms over the course of RT and others
also evidence that depression predicts progression and (Chawla et al. 1999) finding a worsening of symptoms. Stie-
mortality and can affect immune function (Spiegel and gelis and colleagues suggest that this difference may be
Giese-Davis 2003). Psychological comorbidities may attributable to varying baseline levels of psychological func-
impair adherence to medical treatment, which could tioning and point to Andersen and Tewfik’s (1985) observa-
account for poorer outcomes (Spiegel and Giese-Davis tion that: (a) patients with high levels of anxiety at baseline are
2003). Psychological distress among cancer patients has more likely to see a substantial decrease in symptoms; (b)
also been linked to impaired social functioning, nausea, and patients with low anxiety are likely to worsen; and (c) patients
vomiting (Smith et al. 2003), all of which have a negative with moderate anxiety are unlikely to see much change in
effect on quality of life (Frick et al. 2007; Smith et al. 2003). symptoms. However, the majority of both cross-sectional and
In terms of psychological distress in response to radia- longitudinal studies found declines in anxiety, depressive
tion treatment (RT), an instructive review of the literature symptoms, and psychological distress after RT compared to
has been conducted by Stiegelis et al. (2004). They divided the periods prior to and during treatment.
45 studies, obtained through Medline and Psychlit databases The literature has also addressed the particular distress
between 1980 and 2002, into four categories representing that may accompany the end of RT (Deshields et al. 2005).
studies that assessed psychological functioning: (a) prior to This treatment termination distress may be occasioned both
RT, (b) during RT, (c) after RT, and (d) using longitudinal by the loss of support from medical staff, family, and
designs. The studies included patients receiving both cura- friends once treatment is completed and by anxiety about
tive and palliative external radiation therapy with a range of returning to a regular routine (Culver et al. 2002; Lampic
264 J. Q. Purnell et al.

et al. 1994; Leedham and Ganz 1999). In a study of breast psychological distress for a variety of medical procedures
cancer patients at the end of RT, Deshields and colleagues including dental surgery, postoperative recovery, and MRI
found elevated levels of depression and somewhat dimin- usage (Davis et al. 1994; Hartfield et al. 1982; Mogan et al.
ished quality of life, but lower levels of anxiety compared to 1985; Selim 2001; Sime and Libera 1985). Early informa-
healthy population norms. Consistent with the studies tional and educational programs were implemented in trials
reviewed by Steigelis et al., the authors speculate that among cancer patients, with some success (Lilja et al. 1998;
anxiety associated with diagnosis and treatment had sub- Mcquellon et al. 1998; Wells et al. 1995; Williams and
sided by the end of RT. In addition, both depression and Schreier 2004; Wilson et al. 2006). More recent research
quality of life improved substantially within 2 weeks of the has shown that providing information and education to
end of treatment. patients on both the disease and the course of treatment can
Despite the evidence that depression, anxiety, and improve psychological well-being (Helgeson et al. 1999;
quality of life concerns are significant problems for cancer Helgeson et al. 2001).
patients, especially in the early phases of diagnosis and The desire of cancer patients to be informed and edu-
treatment, barriers remain in terms of recognition and cated about their treatment is well-documented. Information
treatment of these symptoms in radiation oncology practice. and education are particularly significant in the case of RT,
These barriers include lack of communication about emo- because the treatment is frequently misunderstood by the
tional issues between oncologists and their patients (Pollak general public (Chapman et al. 2003; Dunn et al. 2004).
et al. 2007), stigmatization and devaluation of mental health Research has shown that patients undergoing RT have fears
concerns and treatment (Holland 2003), belief that psy- directly related to the treatment itself and its perceived
chological problems are a ‘‘natural’’ part of the cancer negative side-effects (Andersen et al. 1984; Frith 1991;
experience (Spiegel 1996), and a tendency to dismiss O’rourke 1999). One study found that of 50 patients who
somatic complaints thought to be associated with the cancer were prescribed curative RT, the majority did not expect it
itself that may be indicative of psychological distress (Hahn to be effective (Haggmark et al. 2001). Of patients who
et al. 2004; Jackson and Jackson 2007). Addressing these considered themselves ‘‘well informed,’’ over two-thirds
barriers to treatment of psychological problems in radiation wanted more information, while only 2 % did not want any
oncology requires the concerted efforts of oncologists to information on their treatment or its potential side effects
properly assess these symptoms and to intervene when (Cassileth et al. 1980). When providing informational
necessary. materials to patients, clinicians must consider a number of
Hahn et al. (2004) have demonstrated the effectiveness factors (e.g., gender, age, ability to comprehend, family
of the Beck Depression Inventory-II for identifying clini- support) that influence patients’ preferences (Meredith et al.
cally depressed patients and strongly urge its routine use. 1996). The lack of information and educational materials
Jackson and Jackson (2007) offer a helpful review of can intensify existing fears resulting from the initial diag-
comorbid depression in adult oncology and note that both nosis and can cause patients to misinterpret symptoms and
psychotherapeutic and pharmacologic treatments have been the side effects of treatments (Cimprich and Ronis 2001;
shown to be effective in this patient population. Similar Peck and Boland 1977).
brief measures and interventions are available for treatment Harrison et al. assessed the information needs of breast
of anxiety. In an historical retrospective on the field of cancer patients over their first course of radiation therapy
psycho-oncology, Holland (2003) notes that the number of (Harrison et al. 1999). Thirty-three women were inter-
empirically supported psychosocial interventions has never viewed about their informational needs and preferences
been as great as it is now, making it relatively easy for during the first, third, and final week of treatment and again
radiation oncologists to refer patients for the appropriate 1 month post-treatment. In general, patients had high
treatment for psychological distress. These treatments not information needs throughout the entire course of RT. This
only increase patient quality of life but enhance compliance study also demonstrated that most women undergoing RT
with treatment, which may affect survival. had a strong desire for information on both the disease and
the treatment. Based on these findings, the authors recom-
mend continually assessing the informational needs of
6 Patient Information Needs During patients throughout the course of their treatment.
Radiation Therapy There is also evidence that the provision of appropriate
information has an impact on treatment-related side effects.
One way to ameliorate psychological distress and improve A randomized trial conducted in 2002 examined the effects
quality of life for cancer patients is by providing appropriate of information on the severity of treatment side effects in
information regarding the disease and its treatment. Edu- 152 RT patients (Kim et al. 2002). The intervention took
cational and informational materials have been used to ease place during the first and fifth radiation treatments and
The Psychosocial and Functional Impact of Radiation Therapy 265

provided patients with specific, objective information about standard care or standard care plus an information audio-
what to expect during treatment, while the control group tape. The results demonstrated that patients who received
was given only general information. The results demon- the audiotapes were more knowledgeable, used more self-
strated that the brief, targeted information was successful in care measures, and practiced more helpful self-care
reducing both fatigue and sleep problems among those who behaviors than the control group. The audiotapes had a
received it. This trial demonstrated that targeted informa- positive effect because of their convenience; patients could
tion can have a positive impact on certain side effects, receive the information at the time and place of their
which may represent a method of improving quality of life choosing.
among those receiving RT. Clinicians can use a variety of information media, rather
The timing of information dissemination can affect how than just the standard printed materials. A recent clinical
patients use that information. A trial conducted in 2000 trial randomized 310 patients beginning radiotherapy to
sought to determine the optimal timing of information receive standard care or standard care plus a 15-minute
provision to radiotherapy patients (D’haese et al. 2000). educational videotape, a 12-page informational booklet, and
Sixty-eight patients were randomized to receive either a an audiotape of relaxation techniques (Krischer et al. 2007).
description of RT procedures and sensations or teaching The results did not show an overall reduction in psycho-
sheets with treatment-site information. Patients received the logical distress for the informational intervention versus
information either all at once or in a stepwise manner. The standard care, but they did show a reduction in psycho-
analyses revealed that patients who received all the infor- logical distress among those who had higher levels of
mation at once were more anxious and less satisfied with psychological distress at baseline. These findings demon-
their radiation therapy. The authors believed this negative strate that informational and educational materials can
outcome resulted from the timing of the intervention. benefit patients with heightened distress.
Receiving the information only a short time before the A diagnosis of cancer and its subsequent treatment are
commencement of RT did not give the patients the oppor- stressful, life-changing events. The anxiety and depression
tunity to discuss the information with a clinician. The that result can have detrimental effects. The evidence is
authors also noted that it was important to maintain contact clear that patients have a strong desire for informational and
with the patients post-treatment, since some evidence sug- educational materials concerning their diagnosis and course
gests that anxiety increases during this period. of treatment. Unfortunately, these informational needs are
A recent trial of 525 patients undergoing RT assessed the often unmet. Research has shown the importance of pro-
impact of different forms of information on anxiety (Jones viding patients with information both before they begin
et al. 1999). This randomized trial utilized two groups who treatment and throughout treatment. All media (booklets,
each received information via computer. One group audiotapes, videotapes) can be effective, as long as the
received personalized information while the other group patient can comprehend the message. Personalized infor-
received only general information. The patients assigned the mation is more effective than general information. In certain
personalized information found they learned something new studies, education reduced side effects and increased self-
and were more likely to share the information with others. care measures. Nevertheless, although information eased
In addition, those who received the personalized informa- psychological distress in some studies, none has linked the
tion showed a greater reduction in anxiety than those provision of information to improved prognosis or survival.
receiving the general information. The authors suggest that However, it is clear that providing information to patients
clinicians should offer personalized information via com- has positive effects during treatment and may help to alle-
puter as a cost-effective way to educate patients and pos- viate anxiety.
sibly reduce patient anxiety.
The next two studies used informational audio- and
videotapes to educate patients undergoing radiation therapy. 7 Radiotherapy and Cognitive
The first study was a quasi-experimental design of 92 Functioning
patients beginning RT, which assessed the effects of a
patient education video on psychological distress (Dunn Cancer-related cognitive dysfunction (CRCD) is an inca-
et al. 2004). The study found those in the intervention group pacitating and enduring side effect of cancer treatment (e.g.,
reported high levels of utilization and satisfaction. Never- radiation therapy) with critical social/relational and eco-
theless, the video had no effect on coping or psychological nomic implications. Many cancer patients have reported
distress throughout the course of treatment. A 1996 study mild to moderate CRCD in important neuropsychological
used informational audiotapes to increase knowledge and and cognitive domains of attention, concentration, pro-
self-care behaviors in those undergoing RT (Hagopian cessing speed, and memory (Paraska and Bender 2003).
1996). Seventy-five patients were assigned to receive Incidence rates of CRCD range from 17 to 75 %. Previous
266 J. Q. Purnell et al.

studies have reported a higher incidence of cognitive dys- cognitive status and verbal memory function during and
function among cancer patients than in matched healthy after WBRT. Specifically, during and after WBRT verbal
controls (Brezden et al. 2000). A recent prospective, lon- memory function was primarily influenced by pretreatment
gitudinal study reported that 61 % of patients undergoing cognitive status and to a lesser extent by WBRT. Acute (T1)
cancer treatment demonstrated diminished neuropsycho- radiation effects on verbal memory function were only
logical function in multiple domains of cognition 6 months observed in TCI patients, whereas subacute (T3) radiation
following initiation of treatment (Wefel et al. 2004). effects on verbal memory function were observed in both
Many hypotheses have been put forth to explain the TCI and prophylactic cranial irradiation patients. Visual
etiologies of CRCD. Some of the hypotheses include a memory and attention, however, were not influenced by
genetic predisposition, such as an absence of epoetin alfa WBRT. Welzel et al. (in press) reported that observed
(O’shaughnessy 2002, 2003; Weiss 2003), direct and/or effects of irradiation were more pronounced in patients with
indirect toxic effects of cancer treatment on the central the above-average performance at baseline. WBRT causes
nervous system (Ahles et al. 2002; Meyers et al. 2005; cognitive dysfunction immediately after the beginning of
Wefel et al. 2004), differences in estrogen secretion (Bender radiation therapy only in patients with brain metastases.
et al. 2007), the effects of cytokine activities in the brain, Lilja et al. (2001) examined the short-term effects of
microvasculature obstruction, and infarction of brain tissue radiotherapy (RT) on attention and memory performance in
(Meyers 2000). Other psychologically-based explanations patients with primary brain tumors. Participants were sub-
include the relationship between CRCD and cancer-related jected to neuropsychological assessment at baseline (before
fatigue and mood states such as anxiety and depression RT, which lasted for 6 weeks), within 2 weeks after the
(Bender et al. 2001; Saykin et al. 2003; Staat and Segatore completion of radiotherapy, and at 3 months after the
2005; Tannock et al. 2004). completion of radiotherapy. Healthy control individuals
CRCD has been associated with radiotherapy for were assessed at baseline and follow-up. The findings
malignant tumors with primary sites within (e.g., brain) and showed that at baseline, cancer patients scored significantly
outside the central nervous system (e.g., lung, breast). lower than the controls in tests of semantic memory, vi-
Researchers have classified the negative effects of radio- suoconstructive skill, and visual and verbal memory. Can-
therapy on the central nervous system (CNS) in three broad cer patients performed significantly more poorly than
categories: acute reactions, short-term delayed reactions, individuals in the control group on a two-choice reaction
and long-term delayed reactions (Lilja et al. 2001). Acute time test, a subtraction test, and a vigilance test. The authors
reactions occur within hours or days immediately following concluded, however, that RT was not associated with neg-
radiotherapy and are associated with increased intracranial ative short-term effects in attention and memory function in
pressure. Short-term delayed reactions occur within a few patients with brain tumors who received a radiation dose of
weeks or months after completion of radiotherapy. Last, 54.5 grays. They noted that the cognitive deficits experi-
long-term delayed reactions occur from months to years enced by cancer patients were evident at baseline, before
after completion of radiotherapy. RT. Therefore, they concluded that the observed problems
Both prophylactic and therapeutic whole brain radio- in cognitive performance were associated with the malig-
therapy (WBRT) are associated with cognitive problems in nancy itself and/or prior surgical procedures.
cancer patients. Welzel et al. (2008) conducted a prospec- CRCD is a significant problem for many cancer patients.
tive study comparing the effects of prophylactic and thera- As with other cancer and treatment-related side effects such
peutic RT (WBRT) on memory function among adults with as cancer-related fatigue, CRCD can have an enduring
and without brain metastases. The authors performed serial negative effect on psychosocial performance (Ahles et al.
cognitive evaluations of patients before (T0), after starting 2002). Despite increasing recognition of the negative
(T1), at the end of treatment (T2), and at 6–8 weeks after impact of CRCD on patients’ well-being and psychosocial
completion of radiotherapy (RT) (T3). The sample included functioning, systematic interventions to control CRCD are
small-cell lung cancer patients treated with prophylactic still lacking. Patients with CRCD could benefit from
cranial irradiation, patients with brain metastases treated behavioral interventions, and longitudinal studies to inform
with therapeutic cranial irradiation (TCI), and breast cancer the development of neuropsychological therapies to control
patients treated with RT to the breast (control group). CRCD are needed. In the meantime, neuropsychological
Interestingly, the authors reported that before therapy, and cognitive techniques that have been applied to help
patients treated with prophylactic cranial irradiation per- improve cognitive performance in other populations with a
formed worse on most tests than patients treated with TCI similar profile of cognitive dysfunction (e.g., mild cognitive
and patients from the control group. The findings also impairment) could be adapted for cancer patients struggling
showed a significant relationship between pretreatment with CRCD.
The Psychosocial and Functional Impact of Radiation Therapy 267

8 Psychosocial Effects of Cancer Among 10–15 % lower five-year cancer survival rate than individ-
Ethnic Minorities and Underserved uals of higher socioeconomic status (American Cancer
Populations Society 2000). Poverty is commonly associated with lower
levels of education, low-paying jobs and unemployment,
The impact of cultural beliefs on cancer treatment and lack of health insurance and limited access to healthcare,
survival is evident in a number of cultures. Culture can inadequate transportation and resources, lack of adequate
affect psychosomatic processes, which can have a negative health information, risky health behaviors, and various
impact on cancer survival. In a study of 28,169 Chinese other factor that can result in advanced cancer stage and a
Americans, researchers discovered that those who had a diminished health status (Haynes and Smedley 1999;
specific combination of disease and birth year considered Smedley et al. 2003). Factors associated with poverty make
ill-fated by Chinese astrology died younger than the quality cancer care difficult for both the healthcare profes-
control population, and that individuals with stronger sional and the patient.
Chinese traditions died even earlier (Phillips et al. 1993). A panel discussion (Dana-Farber Cancer Institute and
While these study results cannot be fully explained, Beth Israel Deaconess Medical Center) presented several
investigators concluded that the findings were partly due to examples of cancer experiences in minority and under-
psychosomatic processes. The findings seemed consistent represented communities (Gilligan et al. 2003). Cancer
with other studies (Dean and Surtees 1989; Derogatis et al. survivors from different racial and ethnic backgrounds
1979; Greer 1991; Greer et al. 1979; Hislop et al. 1987) used their personal experiences to address many of the
that found that cancer patients who displayed stoic issues and concerns regarding cancer care disparities. The
acceptance or helplessness/hopelessness about their disease general mistrust of healthcare providers, was repeatedly
died earlier than patients without these psychological mentioned during discussions. One individual reported that
characteristics. she was so worried about staff attitudes toward minority
A cultural study of cancer beliefs among American patients that she avoided calling for assistance at night
Samoans (Hubbell et al. 2005) produced several unexpected while in the hospital. Another individual stated that
answers to the basic questions: (1) What is cancer?, (2) ‘‘people are frightened when they come for care.’’ She
What causes cancer?, and (3) What can you do to prevent explained that many people, specifically women from
cancer? Answers included the following: (1) Cancer is not a other countries, will not see male physicians and will not
Samoan disease, but a new illness brought by the West- return if they are assigned a male provider. Conversely,
erners (there is no word for cancer in the Samoan language); men from some countries may not respect female doctors,
(2) Departure from the Samoan lifestyle fa’aSamoa is a and many may refuse service.
major factor in causing cancer (including eating nontradi- The panel moderators addressed specific cancer disparity
tional foods such as canned goods or refrigerated items); (3) issues (access to medical care, poverty, outreach and edu-
Lifestyle modifications can prevent cancer but prevention is cational programs, screening, research, and personal sup-
not part of the Samoan culture (the majority depend on port). Specific comments from cancer survivors included:
traditional remedies and traditional healers; few see medical Access: ‘‘Some patients cannot afford the cost of treat-
doctors, and only if symptoms are severe). ments; a few cannot even afford a cab. Also, medical ser-
The impact of cultural beliefs, mores, and norms on the vices occur at night…but taxicabs are reluctant to come into
cancer experience is understudied (Aziz and Rowland our communities.’’
2002). Studies suggest that cultural beliefs and attitudes Poverty: ‘‘People on hourly wages live from paycheck to
toward cancer, seem to affect the individual sufficiently to paycheck, so they cannot afford to take time off. If there are
produce measurable change in physiological outcomes children, child care is needed in order for parents to come.’’
(advanced cancer stage and diminished survival). Research Language: ‘‘For the Hispanic population, the language
is needed to confirm these findings, and new investigations barrier is an obvious obstacle to communicating effectively
examining cultural influences may aid in the overall with healthcare professionals. Having providers learn to
understanding of cancer disparities. speak other languages is not a viable solution. I think that
Of course, culture is just one aspect of the cancer we should expand resources for teaching immigrants to
experience for many minorities and underserved individu- learn English.’’
als. There is a growing consensus that socioeconomic status Screening: ‘‘After my surgery for prostate cancer, I met
is a greater determinant of cancer disparities than either with my three brothers in Spain to discuss PSA examina-
ethnicity or race (American Cancer Society 2000). Poor tions. My youngest brother left the room, because he didn’t
individuals, regardless of race or ethnic background, have a want to listen, and my older brothers had little to say. The
268 J. Q. Purnell et al.

cultural norm in Spain is that you go for medical tests only diagnosed with prostate cancer were 11 % less likely to
when you are sick.’’ get surgical or radiation treatment (Dunham 2008).
Research: ‘‘Minority communities are often skeptical of • Although black and white rectal cancer patients were
these trials…Many members of my support group are equally likely to consult an oncologist, the use of adju-
skeptical, because treatments might not be effective. Also, vant therapy was significantly different. Radiation ther-
they do worry about being harmed by the new medicines.’’ apy was administered for 73.7 % of black patients versus
While these statements do not describe the entire cancer 83.4 % of white patients (Morris et al. 2008).
experience for ethnic minorities and underserved groups, Results from these studies point to opportunities to
they certainly send a strong message that cancer care dis- improve treatment for underserved and minority patients in
parities do exist. Additionally, cancer experiences may radiation oncology, an imperative that has been recognized
differ within ethnic and racial subgroups, and these differ- as a national priority. Interventions designed to aid clini-
ences magnify the complexity of providing high quality and cians in provision of optimal treatment and to encourage
equitable cancer care. patient acceptance of such treatment is sorely needed.
The combination of certain cultural and socioeconomic
factors leads to a variety of negative cancer experiences,
which contribute to inadequate and unequal cancer care.
The challenges for healthcare professionals and cancer References
patients include identifying current and potential causes of
cancer care disparities, increasing awareness among Ahlberg K et al (2003) Assessment and management of cancer-related
healthcare providers of various cultural and socioeconomic fatigue in adults [Review] [140 refs]. Lancet 362:640–650
influences, targeting and developing strategies for Ahles TA et al (2002) Neuropsychologic impact of standard-dose
systemic chemotherapy in long-term survivors of breast cancer and
improvement, implementing effective programs, and mon-
lymphoma. J Clin Oncol 20:485–493
itoring success. American Cancer Society (2000) Fighting cancer in the poor and
Radiation oncology is a ‘‘fertile ground for conducting underserved. American Cancer Society, New York
disparities research’’ (Greenwood 2005). The following are Andersen BL, Tewfik HH (1985) Psychological reactions to radiation
study findings regarding disparities in radiation oncology: therapy: reconsideration of the adaptive aspects of anxiety. J Pers
Soc Psychol 48:1024–1032
• Case study: 41-year-old African American female with Andersen BL et al (1984) Anxiety and cancer treatment: response to
schizophrenia received several interruptions in radiation stressful radiotherapy. Health Psychol 3:535–551
treatment and less than half of the recommended che- Anderson KO et al (2003) Fatigue and sleep disturbance in patients
motherapy regimen due to missed appointments (Garner with cancer, patients with clinical depression, and community-
dwelling adults. J Pain Symptom Manag 25:307–318
2003). Aziz NM, Rowland JH (2002) Cancer survivorship research among
• Women with disabilities do not receive standard post- ethnic minority and medically underserved groups. Oncol Nurs
surgical therapy including radiation therapy, resulting in Forum 29:789–801
a higher risk for recurrence and cancer-related morbidity Barton-Burke M, Barton-Burke M (2006) Cancer-related fatigue and
sleep disturbances. Further research on the prevalence of these two
(Beth Israel Deaconess Medical Center 2006). symptoms in long-term cancer survivors can inform education,
• Among older patients with rectal cancer, blacks are 23 % policy, and clinical practice. [Review] [31 refs]. Am J Nurs
less likely to receive radiation therapy than whites 106:72–77
(Morris et al. 2008). Bender CM et al (2001) Cognitive function and reproductive hormones
in adjuvant therapy for breast cancer: a critical review. J Pain
• In a study of 93 Native American radiation therapy Symptom Manag 21:407–424
patients the median one-way travel distance for treatment Bender CM et al (2007) Memory impairments with adjuvant
was 109 miles, 37 % traveled at least 150 miles; 28 % anastrozole versus tamoxifen in women with early-stage breast
had treatment delays of six or more days; 15 % had cancer. Menopause J North Am Menopause Soc 14:995–998
Berger AM (1998) Patterns of fatigue and activity and rest during
delays of 11 or more days; 50 % experienced grade 2 adjuvant breast cancer chemotherapy. Oncol Nurs Forum
radiation treatment toxicities; and 10 patients had grade 3 25:51–62
radiation treatment toxicities (Rogers and Petereit 2005). Beth Israel Deaconess Medical Center (2006) Press release: disparities
• Significant disparities occur in the management of early- in breast cancer treatment for women with disabilities. Beth Israel
Deaconess Medical Center, Boston
stage breast cancer among Asian Americans and Pacific Breslau N et al (1996) Sleep disturbance and psychiatric disorders: a
Islanders, with Japanese, Hawaiians, and Filipinos being longitudinal epidemiological study of young adults. Biol Psychi-
particularly less likely to receive standard-of-care treat- atry 39:411–418
ment (i.e., breast conserving surgery, radiation therapy, Brezden CB et al (2000) Cognitive function in breast cancer patients
receiving adjuvant chemotherapy. J Clin Oncol 18:1–7
and chemotherapy) (Gelber et al. 2006). Broeckel JA et al (1998) Characteristics and correlates of fatigue after
• Black women who had a lumpectomy were 7 % less adjuvant chemotherapy for breast cancer. J Clin Oncol
likely than whites to receive radiation therapy. Black men 16:1689–1696
The Psychosocial and Functional Impact of Radiation Therapy 269

Burgos I et al (2006) Increased nocturnal interleukin-6 excretion in Dodd MJ et al (2001) Symptom clusters and their effect on the
patients with primary insomnia: a pilot study. Brain Behav Immun functional status of patients with cancer. Oncol Nurs Forum
20:246–253 28:465–470
Carroll JK et al (2007) Pharmacologic treatment of cancer-related Dunham W (2008) Racial disparities persist in U.S. cancer treatment.
fatigue. Oncologist 12(Suppl 1):43–51 National Prostate Cancer Coalition, Reuters
Cassileth BR et al (1980) The effect of experience on radiation therapy Dunn J et al (2004) Evaluating patient education materials about
patients’ desire for information. Int J Radiat Oncol Biol Phys radiation therapy. Patient Educ Couns 52:325–332
6:493–496 Escalante CP (2003) Treatment of cancer-related fatigue: an update.
Cella D (1998) Factors influencing quality of life in cancer patients: Support Care Cancer 11:79–83
anemia and fatigue. Semin Oncol 25:43–46 Espie CA et al (2008) Randomized controlled clinical effectiveness
Cella D et al (1998) Progress toward guidelines for the management of trial of cognitive behavior therapy compared with treatment as
fatigue. Oncology 12:369–377 usual for persistent Insomnia in patients with cancer. J Clin Oncol
Cella D et al (2001) Cancer-related fatigue: prevalence of proposed 26:1–9
diagnostic criteria in a United States sample of cancer survivors. Fortner BV et al (2002) Sleep and quality of life in breast cancer
J Clin Oncol 19:3385–3391 patients. J Pain Symptom Manag 24:471–480
Cella D et al (2002) Fatigue in cancer patients compared with fatigue Frank-Stromberg M, Wright P (1984) Ambulatory cancer patients’
in the general United States population. Cancer 94:528–538 perception of the physical and psychosocial changes in their lives
Chapman K et al (2003) Lay understanding of terms used in cancer since the diagnosis of cancer. Cancer Nurs 7:117–130
consultations. Psychonosology 12:557–566 Frick E et al (2007) Anxiety, depression and quality of life of cancer
Chawla S et al (1999) Temporal assessment of quality of life of head patients undergoing radiation therapy: a cross-sectional study in a
and neck cancer patients receiving radical radiotherapy. Qual Life community hospital outpatient centre. Eur J Cancer Care
Res 8:73–78 16:130–136
Cimprich B, Ronis DL (2001) Attention and symptom distress in Frith B (1991) Giving information to radiotherapy patients. Nurs Stand
women with and without breast cancer. Nurs Res 50:86–94 5:33–35
Cleeland CS et al (2000) Assessing symptom distress in cancer Garner EI (2003) Cervical cancer: disparities in screening, treatment,
patients: the M.D Anderson symptom inventory. Cancer and survival. Cancer Epidemiol Biomarkers Prev 12:242s–247s
89:1634–1646 Gelber RP et al (2006) Ethnic disparities in breast cancer management
Cleeland CS et al (2003) Are the symptoms of cancer and cancer among Asian Americans and Pacific Islanders. Ann Surg Oncol
treatment due to a shared biologic mechanism? A cytokine- 13:977–984
immunologic model of cancer symptoms. Cancer 97:2919–2925 Gilligan TD et al (2003) Cancer survivorship issues for minority and
Cleeland CS et al (2007) Symptom burden: multiple symptoms and underserved populations. Cancer Epidemiol Biomarkers Prev
their impact as patient-reported outcomes. J Natl Cancer Inst 12:284s–286s
Monogr 37:16–21 Given CW et al (2001) Predictors of pain and fatigue in the year
Culver JL et al (2002) Coping and distress among women under following diagnosis among elderly cancer patients. J Pain Symp-
treatment for early stage breast cancer: comparing African tom Manag 21:456–466
Americans, Hispanics and non-Hispanic whites. Psycho-Oncology Greenwood A (2005) NCI radiation oncology program tackles cancer
11:495–504 disparaties www.cancer.gov 2(6):16–26
Curt GA et al (2000) Impact of cancer-related fatigue on the lives of Greer S (1991) Psychological response to cancer and survival. Psychol
patients: new findings from the fatigue coalition. Oncologist Med 21:43–49
5:353–360 Greer S et al (1979) Psychological response to breast cancer: effect on
Curt GA et al (2001) Impact of cancer-related fatigue on the lives of outcome. Lancet 2:785–787
patients: new findings from the fatigue coalition. In: Marty M, Haggmark C et al (2001) Effects of information supply on satisfaction
Pecorelli S (eds) Fatigue and cancer. Elsevier, Amsterdam, with information and quality of life in cancer patients receiving
pp 3–16 curative radiation therapy. Patient Educ Couns 45:173–179
Davidson JR et al (2002) Sleep disturbance in cancer patients. Social Hagopian GA (1996) The effects of informational audiotapes on
Sci Med 54:1309–1321 knowledge and self-care behaviors of patients undergoing radiation
Davis TM et al (1994) Undergoing cardiac catheterization: the effects therapy. Oncol Nurs Forum 23:697–700
of informational preparation and coping style on patient anxiety Hahn CA et al (2004) Routine screening for depression in radiation
during the procedure. Heart Lung 23:140–150 oncology patients. Am J Clin Oncol Cancer Clin Trials 27:497–499
De Boer MF et al (1999) Psychosocial correlates of cancer relapse and Harrison DE et al (1999) Information needs and preference for
survival: a literature review. Patient Educ Couns 37:215–230 information of women with breast cancer over a first course of
Dean C, Surtees PG (1989) Do psychological factors predict survival radiation therapy. Patient Educ Couns 38:217–225
in breast cancer? J Psychosom Res 33:561–569 Hartfield MT et al (1982) Effects of information about a threatening
Derogatis LR et al (1979) Psychological coping mechanisms and procedure on patients’ expectations and emotional distress. Nurs
survival time in metastatic breast cancer. JAMA 242:1504–1508 Res 31:202–206
Derogatis LR et al (1983) The prevalence of psychiatric disorders Haynes A, Smedley B (1999) The unequal burden of cancer: an
among cancer patients. JAMA 249:751–757 assessment of NIH research and programs for ethnic minorities and
Deshields T et al (2005) Ending treatment: the course of emotional the medically underserved. National Academy Press, Washington
adjustment and quality of life among breast cancer survivors Helgeson VS et al (1999) Education and peer discussion group
immediately following radiation therapy. Support Care Cancer interventions and adjustment to breast cancer. Arch Gen Psychiatry
13:1018–1026 56:340–347
D’haese S et al (2000) The effect of timing of the provision of Helgeson VS et al (2001) Long-term effects of educational and peer
information on anxiety and satisfaction of cancer patients receiving discussion group interventions on adjustment to breast cancer.
radiotherapy. J Cancer Educ 15:223–227 Health Psychol 20:387–392
270 J. Q. Purnell et al.

Hickok JT, Morrow GR, Roscoe JA, Pierce HI, Rosenbluth RJ (2001) Lampic C et al (1994) Anxiety and cancer-related worry of cancer-
Prevalence and severity of acute and delayed NV associated with 3 patients at routine follow-up visits. Acta Oncol 33:119–125
highly emetogenic chemotherapies. In: Supportive care in cancer, Lee B-N et al (2004) A cytokine-based neuroimmunologic mecha-
13th international symposium 9, 289 nism of cancer-related symptoms. Neuroimmunomodulation
Hickok JT, Roscoe JA, Morrow GR Bushunow P, Shelke AR, 11:279–292
Matteson S, Dakhil SR, Flynn PJ (2003) Occurrence of severe Lee KA et al (2005) Critical components of a sleep assessment for
nausea in 194 women treated with doxorubicin for breast cancer. clinical practice settings [Review] [27 refs]. Issues Ment Health
Support Care Cancer 11:393 Nurs 26:739–750
Hickok JT et al (2005a) Occurrence, severity, and longitudinal course Leedham B, Ganz PA (1999) Psychosocial concerns and quality of life
of twelve common symptoms in 1129 consecutive patients during in breast cancer survivors. Cancer Invest 17:342–348
radiotherapy for cancer. J Pain Symptom Manag 30:433–442 Leger D et al (2001) SF-36: Evaluation of quality of life in severe and
Hickok JT et al (2005b) Frequency, severity, clinical course, and mild insomniacs compared with good sleepers. Psychosom Med
correlates of fatigue in 372 patients during 5 weeks of radiotherapy 63:49–55
for cancer. Cancer 104:1772–1778 Leger D et al (2002) Medical and socio-professional impact of
Hislop TG et al (1987) The prognostic significance of psychosocial insomnia. Sleep 25:625–629
factors in women with breast cancer. J Chronic Dis 40:729–735 Lilja Y et al (1998) Effects of extended preoperative information on
Hofman M et al (2004) Cancer patients’ expectations of experiencing perioperative stress: an anaesthetic nurse intervention for patients
treatment-related side effects: a university of Rochester cancer with breast cancer and total hip replacement. Intensive Crit Care
center–community clinical oncology program study of 938 patients Nurs 14:276–282
from community practices. Cancer 101:851–857 Lilja AM et al (2001) Short-term effects of radiotherapy on attention
Hofman M et al (2007) Cancer-related fatigue: the scale of the and memory performances in patients with brain tumors. Cancer
problem. Oncologist 12:4–10 91:2361–2368
Holland JC (2003) Psychological care of patients: psycho-oncology’s Malone M et al (1994) Assessment of the impact of cancer on work,
contribution. J Clin Oncol 21:253S–265S recreation, home management and sleep using a general health
Hubbell FA et al (2005) Exploring beliefs about cancer among status measure. J R Soc Med 87:386–389
American Samoans: focus group findings. Cancer Detect Prev Mao JJ et al (2007) Symptom burden among cancer survivors: impact
29:109–115 of age and comorbidity. J Am Board Fam Med 20:434–443
Irvine DM et al (1991) A critical appraisal of the research literature Massie MJ (2004) Prevalence of depression in patients with cancer.
investigating fatigue in the individual with cancer. Cancer Nurs J Natil Cancer Inst Monogr 32:57–71
14:188–199 McQuellon RP et al (1998) Reducing distress in cancer patients with
Jackson CW, Jackson KH (2007) Comorbid depression in adult an orientation program. Psychooncology 7:207–217
oncology. J Pharm Pract 20:360–367 Meredith C et al (1996) Information needs of cancer patients in west
Jacobsen PB et al (1994) Hypnotic efficacy and safety of Triazolam Scotland: cross sectional survey of patients’ views. BMJ
administered during the postoperative period. Gen Hosp Psychiatry 313:724–726
16:419–425 Meyerowitz BE et al (1979) Adjuvant chemotherapy for breast
Jacobsen PB et al (2007) Systematic review and meta-analysis of carcinoma. Cancer 43:1613–1618
psychological and activity-based interventions for cancer-related Meyerowitz BE et al (1983) Quality of life for breast cancer patients
fatigue [Review] [70 refs]. Health Psychol 26:660–667 receiving adjuvant chemotherapy. Am J Nurs 83:232–235
Jean-Pierre P et al (2007) Assessment of cancer-related fatigue: Meyers CA (2000) Neurocognitive dysfunction in cancer patients.
implications for clinical diagnosis and treatment. Oncologist Oncology 14:75–79
12:11–21 Meyers CA et al (2005) Cognitive impairment, fatigue, and cytokine
Jemal A et al (2008) Cancer statistics, 2008. CA Cancer J Clin levels in patients with acute myelogenous leukemia or myelodys-
58:71–96 plastic syndrome. Cancer 104:788–793
Jereczek-Fossa BA et al (2001) Radiotherapy-related fatigue: how to Miaskowski C et al (2004) Symptom clusters: the new frontier in
assess and how to treat the symptom: a commentary. Tumori symptom management research. J Natl Cancer Inst Monogr
87:147–152 32:17–21
Jones R et al (1999) Randomised trial of personalised computer based Mock V (2004) Evidence-based treatment for cancer-related fatigue
information for cancer patients. BMJ 319:1241–1247 [Review] [70 refs]. J Natl Cancer Inst Monogr 32:112–118
Katz DA, McHorney CA (2002) The relationship between insomnia Mock V, Olsen M (2003) Current management of fatigue and anemia
and health-related quality of life in patients with chronic illness. in patients with cancer [Review] [33 refs]. Semin Oncol Nurs
J Fam Pract 51:229–235 19:36–41
Kaye J et al (1983) Sleep patterns in patients with cancer and patients Mogan J et al (1985) Effects of preoperative teaching on postoperative
with cardiac disease. J Psychol 114:107–113 pain: a replication and expansion. Int J Nurs Stud 22:267–280
Kim Y et al (2002) The effects of information and negative affect on Monga U et al (1999) Prospective study of fatigue in localized prostate
severity of side effects from radiation therapy for prostate cancer. cancer patients undergoing radiotherapy. Radiat Oncol Investig
Support Care Cancer 10:416–421 7:178–185
Kirkova J et al (2006) Cancer symptom assessment instruments: a Mormont MC et al (2000) Marked 24-h rest/activity rhythms are
systematic review. J Clin Oncol 24:1459–1473 associated with better quality of life, better response, and longer
Koopman C et al (2002) Sleep disturbances in women with metastatic survival in patients with metastatic colorectal cancer and good
breast cancer. Breast J 8:362–370 performance status. Clin Cancer Res 6:3038–3045
Krischer MM et al (2007) Self-administered stress management Morris AM, Billingsley KG, Hayanga AJ, Matthews B, Baldwin LM,
training in patients undergoing radiotherapy. J Clin Oncol Birkmeyer JD (2008) Residual treatment disparities after oncology
25:4657–4662 referral for rectal cancer. J Natl Cancer Inst 100:738–744
Kroenke K et al (1988) Chronic fatigue in primary care. Prevalence, Morrow GR (2007) Cancer-related fatigue: causes, consequences, and
patient characteristics, and outcome. JAMA 260:929–934 management. Oncologist 12:1–3
The Psychosocial and Functional Impact of Radiation Therapy 271

Morrow GR et al (2002) Fatigue associated with cancer and its Rhodes VA et al (1988) Patients’ descriptions of the influence of
treatment. Support Care Cancer 10:389–398 tiredness and weakness on self-care abilities. Cancer Nurs
Morrow GR et al (2005) Management of cancer-related fatigue. 11:186–194
Cancer Invest 23:229–239 Rogers D, Petereit DG (2005) Cancer disparities research partnership
Morrow GR, Jean-Pierre P, Roscoe JA, Heckler CE, Schwartzenberger in Lakota country: clinical trials, patient services, and community
PO, Giguere JK, Dakhil SRA (2008) Phase III randomized, education for the Oglala, Rosebud, and Cheyenne River Sioux
placebo-controlled, double-blind trial of a eugeroic agent in 642 tribes. Am J Public Health 95:2129–2132
cancer patients reporting fatigue during chemotherapy: a URCC Ryan JL et al (2007) Mechanisms of cancer-related fatigue. Oncologist
CCOP study. J Clin Oncol 26:504s 12:22–34
Mustian KM, Hofman M Morrow GR, Griggs JJ, Jean-Pierre P, Kohli Savard J, Morin CM (2001) Insomnia in the context of cancer: a
S, Roscoe JA, Simondet J, Bushunow P (2006) Cancer-related review of a neglected problem. J Clin Oncol 19:895–908
fatigue and shortness of breath among cancer survivors: a Savard J et al (2001) Prevalence, clinical characteristics, and risk
prospective URCC CCOP study. In: NCI cancer survivorship factors for insomnia in the context of breast cancer. Sleep
conference 24:583–590
Mustian KM et al (2007) Integrative nonpharmacologic behavioral Savard J et al (2005) Randomized study on the efficacy of cognitive-
interventions for the management of cancer-related fatigue. behavioral therapy for insomnia secondary to breast cancer, part I:
Oncologist 12:52–67 Sleep and psychological effects. J Clin Oncol 23(25):6083–6096
Mustian KM et al (2008) Cancer-related fatigue interferes with Saykin AJ et al (2003) Mechanisms of chemotherapy-induced
activities of daily living among 753 patients receiving chemother- cognitive disorders: neuropsychological, pathophysiological, and
apy: a URCC CCOP study. J Clin Oncol 26:(May 20 suppl; abstr neuroimaging perspectives. Semin Clin Neuropsychiatry
9500) 8:201–216
National Comprehensive Cancer Network (2008) National compre- Schwartz S et al (1999) Insomnia and heart disease: a review of
hensive cancer network practice guidelines. Cancer related fatigue epidemiologic studies. J Psychosom Res 47:313–333
panel 2008 guidelines. National comprehensive cancer network Selim MA (2001) Effect of pre-instruction on anxiety levels of patients
version 1 (March 2004; Rockledge, PA) undergoing magnetic resonance imaging examination. East Med-
Ohayon MM (2007) Prevalence and comorbidity of sleep disorders in iterr Health J 7:519–525
general population. Rev Prat 57:1521–1528 Sime AM, Libera MB (1985) Sensation information, self-instruction
Ohayon MM, Zulley J (2001) Correlates of global sleep dissatisfaction and responses to dental surgery. Res Nurs Health 8:41–47
in the German population. Sleep 24:780–787 Smedley B, Stith A, Nelson A (2003) Unequal treatment: confronting
O’Rourke ME (1999) Narrowing the options: the process of deciding racial and ethnic disparities in healthcare. National Academic
on prostate cancer treatment. Cancer Invest 17:349–359 Press, Washington
O’Shaughnessy JA (2002) Effects of epoetin alfa on cognitive Smith EM et al (2003) Assessing the independent contribution to
function, mood, asthenia, and quality of life in women with breast quality of life from anxiety and depression in patients with
cancer undergoing adjuvant chemotherapy. Clin Breast Cancer advanced cancer. Palliat Med 17:509–513
Suppl 3:S116–S120 Spiegel D (1996) Cancer and depression. Br. J Psychiatry Suppl 109-
O’Shaughnessy JA (2003) Chemotherapy-induced cognitive dysfunc- 116
tion: a clearer picture. Clin Breast Cancer Suppl 2:S89–S94 Spiegel D, Giese-Davis J (2003) Depression and cancer: mechanisms
Padilla G, Grant M (1985) Quality of life as a cancer nursing outcome and disease progression. Biol Psychiatry 54:269–282
variable. Adv Nurs Sci 8:45–49 Spiegel D, Sephton S (2002) Re: night shift work, light at night, and
Palesh O, Mustian K, Roscoe JA, Morrow G, Perlis M, Issel B, risk of breast cancer. J Natl Cancer Inst 94:530–533
Banerjee T, Delmore JE (2007) Prevalence and severity of sleep Staat K, Segatore M (2005) The phenomenon of chemobrain. Clin J
disturbance in 596 cancer patients: a URCC CCOP study. J Clin Oncol Nurs 9:713–721
Oncol 25:18S Stark DPH, House A (2000) Anxiety in cancer patients. Br J Cancer
Paraska K, Bender CM (2003) Cognitive dysfunction following 83:1261–1267
adjuvant chemotherapy for breast cancer: Two case studies. Oncol Steginga S et al (1998) Domains of distress: the experience of breast
Nurs Forum 30:473–478 cancer in Australia. Oncol Nurs Forum 25:1063–1070
Peck A, Boland J (1977) Emotional reactions to radiation treatment. Stiegelis HE et al (2004) Psychological functioning in cancer patients
Cancer 40:180–184 treated with radiotherapy. Patient Educ Couns 52:131–141
Phillips DP et al (1993) Psychology and survival. Lancet Suka M et al (2003) Persistent insomnia is a predictor of hypertension
342:1142–1145 in Japanese male workers. J Occup Health 45:344–350
Piper BF et al (1987) Fatigue mechanisms in cancer patients: Tannock IF et al (2004) Cognitive impairment associated with
developing nursing theory. Oncol Nurs Forum 14:17–23 chemotherapy for cancer: report of a workshop. J Clin Oncol
Pollak KI et al (2007) Oncology communication about emotion during 22:2233–2239
visits with patients with advanced cancer. J Clin Oncol Walsh JK, Engelhardt CL (1999) The direct economic costs of
25:5748–5752 insomnia in the United States for 1995. Sleep 22:S386–S393
Poroch D (1995) The effect of preparatory patient education on the Wang XS et al (2006) Longitudinal study of the relationship between
anxiety and satisfaction of cancer patients receiving radiation chemoradiation therapy for non-small-cell lung cancer and patient
therapy. Cancer Nurs 18:206–214 symptoms. J Clin Oncol 24:4485–4491
Portenoy RK, Itri LM (1999) Cancer-related fatigue: guidelines for Wefel JS et al (2004) ‘Chemobrain’ in breast carcinoma? A prologue.
evaluation and management. Oncologist 4:1–10 Cancer 101:466–475
Prue G et al (2006) Cancer-related fatigue: a critical appraisal Weiss MJ (2003) New insights into erythropoietin and epoetin alfa:
[Review] [84 refs]. Eur J Cancer 42:846–863 mechanisms of action, target tissues, and clinical applications.
Rahn AN et al (1998) Influence of radiotherapy on psychological Oncologist 8:18–29
health in breast cancer patients after breast conserving surgery. Wells ME et al (1995) Reducing anxiety in newly diagnosed cancer
Anticancer Res 18:2271–2273 patients: a pilot program. Cancer Pract 3:100–104
272 J. Q. Purnell et al.

Welzel G, Fleckenstein K, Schaefer J, Hermann B, Kraus-Tiefenb- Wilson RW et al (2006) Pilot study of a self-administered stress
acher U, Mai SK, Wenz F (2008) Memory function before and management and exercise intervention during chemotherapy for
after whole brain radiotherapy in patients with and without brain cancer. Support Care Cancer 14:928–935
metastases. Int J Radiat Oncol Biol Phys 72:1311–1318 Zee P, Walsleben J (2004) Toward optimal health: the experts
Williams SA, Schreier AM (2004) The effect of education in managing discuss sleep sufficiency and health. J Women’s Health
side effects in women receiving chemotherapy for treatment of 13:764–769
breast cancer. Oncol Nurs Forum 31:E16–E23
 Nursing

Sheila Judge Santacroce and Madelyn Rubin

Contents Abstract
Nursing is a discipline that comprises a sizeable number
1 Introduction.......................................................................... 273 of the qualified health professionals who interact with
2 The Pediatric Oncology Experience.................................. 274 survivors throughout the cancer continuum. Nurses can
2.1 Treatment Advancements and Recognition also exert great influence in alleviating the personal and
of Late Effects ....................................................................... 274 societal burdens attributable to cancer through the
2.2 Establishment of Late Effects Clinics .................................. 274
integration of clinical care, education, and research. With
2.3 Clinical Care of Childhood Cancer Survivors ..................... 274
2.4 Models of Care for Childhood Cancer Survivors ................ 275 increasing survival rates and the growing numbers of
2.5 Summary ................................................................................ 275 long-term survivors, the mild to life-threatening conse-
3 Nursing Roles in the Care of Adult quences of cancer treatment regimens have become more
Cancer Survivors ................................................................. 276 evident. Through systematic collaborative research, more
3.1 Clinical Care .......................................................................... 276 associations are now known about the relationship
3.2 Education ............................................................................... 280 between treatment exposures and late effects, thus
3.3 Research................................................................................. 281
highlighting the need for life-long follow-up care.
4 Conclusion ............................................................................ 282 Pediatric oncology nursing has established guidelines
References...................................................................................... 282 for risk-based monitoring and standardized survivorship
education, allowing for the nursing care of adult cancer
survivors to be built upon what has already been
implemented in pediatrics. Nurses and nurse practitioners
(NPs) are well equipped to play a key role in survivorship
care plan (SCP) management, including the promotion of
health behaviors, treatment adherence, and regular
screening for prompt recognition of potential late effects.

1 Introduction

With approximately 12 million people living with a history

of cancer, understanding and attending to the needs of
cancer survivors is a major public health concern.
According to the National Cancer Institute (NCI), National
Coalition of Cancer Survivors, and the Lance Armstrong
Foundation (LAF), individuals are cancer survivors from
the day of diagnosis through the rest of their lives. Nursing,
S. J. Santacroce
M. Rubin (&) a discipline that comprises a sizeable number of the quali-
Yale University School of Nursing, fied health professionals who come in contact with survi-
100 Church Street South PO, New Haven,
CT, Box 974006536-0740, USA vors throughout the cancer continuum, can wield great
e-mail: [email protected] influence in alleviating the personal and societal burdens

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 273
DOI: 10.1007/978-3-540-72314-1_18, Ó Springer-Verlag Berlin Heidelberg 2014
274 S. J. Santacroce and M. Rubin

that are attributable to cancer and its treatment. The usual The children’s oncology group (COG) Nursing Discipline
roles of nurses and nurse practitioners (NP) in clinical care, and Late Effects Committee (Children’s Oncology Group
education, and research can be put into practice with diverse Nursing Discipline and Late Effects Committee Children’s
populations of adult cancer survivors using, as Rowland has Oncology Group Nursing Discipline and Late Effects
suggested (Rowland 2005), the pediatric oncology experi- Committee 2007) have created a guide to develop com-
ence as a model. prehensive LTFU clinical programs. This guide can also
steer development of LTFU programs for adult cancer
survivors.
2 The Pediatric Oncology Experience

2.1 Treatment Advancements 2.3 Clinical Care of Childhood Cancer

and Recognition of Late Effects Survivors

Foremost among advancements in the treatment and control Clinical care of childhood cancer survivors includes atten-
of cancer are those that have been made in childhood can- tion to parental caregivers and indirect care of the popula-
cer. Currently, 5-year survival is expected for roughly 80 % tion of survivors and the community through education
and 10-year survival is likely for about 75 % of children advocacy (Hobbie and Hollen 1993). As with pediatrics in
newly diagnosed with cancer (Rowland et al. 2004). As general (Rowland 2005), pediatric oncology nurses take
survival rates and the number of long-term survivors development and function into account. Their nursing care
increased, mild to life-threatening persistent or late onset is informed by: (a) knowledge about typical development
consequences of effective regimens became evident, and and important functions for the various age-stage groups
later, through systematic collaborative research, associa- they encounter, including adults, (b) sensitivity to how
tions were made between treatment exposures and late development and function can be altered by the cancer
effects. Early on, the late effects of radiation therapy were experience, and (c) the design and application of nursing
understood to be subtler in nature and later in onset than actions that aim to support favorable developmental and
those of surgery and possibly chemotherapy, thus life-long functional outcomes. Characteristically, pediatric oncology
follow-up of patients who received this therapy is required nurses conduct anticipatory guidance and monitor for
for early detection of late effects and to guide therapy to the potential difficulties with regards to physical, psychological,
minimum necessary to attain cure (D’Angio 1975). developmental, and social outcomes of childhood cancer
and its treatment.

2.2 Establishment of Late Effects Clinics 2.3.1 Long-Term Follow-up Guidelines

for the Care of Childhood Cancer Survivors
The necessity of ‘‘late effects clinics’’ that could provide Recognizing the importance of anticipation in limiting
methodical evaluation and treatment as indicated for the adverse outcomes, that is, late effects, the COG Nursing
continuously expanding population of childhood cancer Discipline and Late Effects Committee collaborated to
survivors was recognized in the early 1980s (Meadows develop LTFU Guidelines for Survivors of Child, Adoles-
2006), and the first one was established in 1983 at The cent, and Young Adult Cancers (Children’s Oncology
Children’s Hospital of Philadelphia. Since then, the number Group Nursing Discipline and Late Effects Committee
of such clinics and the scope of their services have greatly 2009; Landier et al. 2004). These guidelines, which are
expanded aided by nursing (Institute of Medicine 2006; organized by the therapeutic exposure, are derived from
Hobbie and Hollen 1993). At least 50 long-term follow-up evidence about associations between exposures and late
(LTFU) programs for childhood cancer survivors exist in effects. They are then integrated with opinions from clinical
the United States (Childhood Cancer Guides 2007). Key experts to establish risk-based, exposure-related recom-
qualities of these programs are shown in Table 1. The usual mendations about monitoring for potential late effects. Most
referral pattern is that a survivor is referred by the treatment (88%) guidelines recommend minimal assessments that can
team to an LTFU program at the treating institution when he be obtained via thorough history and physical examination
or she is 3–5 years post-diagnosis and/or 2 years post- (Landier et al. 2004). Further evaluation is performed as
treatment completion with no evidence of active disease. indicated for survivors with concerning screening results or
Some childhood cancer survivors may have been lost to signs and symptoms. To extend the impact of the clinical
follow-up for many years and self-refer when life circum- visits and standardize the health education and anticipatory
stances, for example, thinking about marriage and child- guidance, the COG Nursing Discipline and Late Effects
bearing, bring concerns about late effects to the forefront. Committee also created Health Links, Health Links is
Nursing 275

Table 1 Key qualities of long- Draws on a philosophy of care that attends to

term follow-up programs
The whole person
The effects of the cancer experience on the family
Wellness versus illness
Staffed by multidisciplinary team consisting of but not limited to
Nurse practitioner and physician with expertize in late effects
Nurse coordinator/case manager
Medical social worker
Services include
Medical record abstraction and treatment summary preparation
Risk-based screening of individuals for physiological and psychosocial late effects
Referrals to other providers for evaluation and treatment as clinically indicated
Care coordinator
Patient and family education about
cancer diagnosis and treatment, potential late effects
current health status including actual late effects
recommendations regarding risk-reduction and regular monitoring
Help obtaining insurance, and educational and vocational services
Opportunities for participation in survivorship research
Assistance with transitioning to another care setting
Tracking of survivors post-transition in case there is need to notify
Education of providers-in-training and non-oncology providers about late effects

comprised of, standardized patient and family educational consultation with the pediatric oncology treatment team or
materials on 33 topics including risk-reduction behaviors to LTFU program (Bhatia and Meadows 2006). Additional
help control potential late affects (Landier et al. 2004). This models of LTFU have been developed based on the indi-
tool can empower childhood cancer survivors and their vidual survivor’s level of complexity of need for care/care
caregivers to take steps in daily life to control late effects. coordination or risk for late effects. For example, a model of
One concern about the COG guidelines is that, although care that offers same-day, same-clinic access to multiple
they are based on evidence regarding associations between subspecialists has been developed for survivors with actual
treatments and late effects, the efficacy of the recommended late effects or at highest risk for late effects based on
screenings suggested risk-reduction behaviors have not treatment intensity (Carlson et al. 2008). In contrast, mail
been well evaluated (Institute of Medicine 2006; Landier and telephone follow-up have been used with childhood
et al. 2004). Pediatric oncology health professionals none- cancer survivors who do not attend LTFU (Parkes et al.
theless agree that is reasonable to recommend that survivors 2007), and has been proposed for use with childhood cancer
adopt behaviors that have been shown to reduce health risks survivors who are at low risk for late effects (Skinner et al.
in the general population. 2007).

2.4 Models of Care for Childhood Cancer 2.5 Summary

Survivors
To summarize, increasing rates of survival and numbers of
As LTFU for childhood cancer survivors has matured, four childhood cancer survivors made late effects and the need
basic models of care have been developed especially for for long-term follow-up apparent. Nursing care of child-
adolescent and young adult survivors: (a) pediatric oncol- hood cancer survivors includes family caregivers, uses a
ogy directed care within the general program or through a developmental perspective and is anticipatory. Pediatric
distinct but allied LTFU program, (b) transitional care that oncology nursing has played critical roles in establishing
aims to assist with the shift to adult oncology or commu- and carrying out LTFU including development of guide-
nity-based care, (c) adult oncology care, and (d) commu- lines for risk-based monitoring and standardized health
nity-based care by an adult primary care provider in education. Despite the lack of evidence about the efficacy of
276 S. J. Santacroce and M. Rubin

screening, nursing care of adult survivors of adult cancer (NCI)-designated comprehensive cancer center where it is
can rapidly advance by building on what has been done in responsible for coordinating the design, development,
pediatrics. evaluation, and integration of programs that aim to meet the
needs of cancer survivors into the range of services offered
(Lance Armstrong Foundation 2008). Names and locations
3 Nursing Roles in the Care of Adult of Network member institutions and where to access more
Cancer Survivors information about them are shown in Table 2. To address
needs that have been largely unmet by conventional
The implications for nurses and nurse practitioners in the oncology or primary care, the focus of the Network to date
realm of cancer survivorship care are plentiful. Nurses has been those survivors who have completed therapy
already play a key role in the application and delivery of (Shapiro et al. 2009).
treatment summaries and care plans. Additionally, the Three models of clinical care for adult cancer survivors
incorporation of holistic wellness promotion and disease are being tested by the Network (Shapiro et al. 2009), and
prevention counseling is a natural part of the nursing scope the NP carries out key clinical care roles in each of them. In
of practice (Ganz et al. 2008). With the growing number of the first model, the ‘‘consult model’’, the survivor is seen
cancer survivors and the accompanying shortage of on- once by an NP or physician with survivorship expertize.
cologists, the burden of cancer symptom management and The visit typically includes universal screening for psy-
supportive survivorship care is starting to fall on primary chosocial late effects, treatment-specific clinical assess-
care providers and nurse practitioners (Potosky et al. 2011; ments (medical and family history, review of systems,
Rowland and Ganz 2011). The 2006 IOM survivorship physical examination, clinical laboratory evaluation, imag-
report acknowledged that survivorship care planning is ing and other studies) with referrals and other follow-up as
congruent with the education and skill set of nurse prac- clinically indicated. Following the visit, a form of the
titioners and that they are very willing to assume the role, individualized SCP and results of any assessments are sent
but that they are concerned about the continuously to the patient, referring primary care provider, and oncology
changing nature of cancer surveillance guidelines (Hewitt treatment team. The goal is to empower survivors with
et al. 2007, p. 38). Primary care NPs and oncology NPs are information about their cancer treatment, their future health
well versed in routine health maintenance, and can help by risks, and what can be done to manage those risks including
advising cancer survivors on issues such as nutrition, healthy behaviors and regular health care. Responsibility for
exercise, weight management, mental health, smoking the care of the survivor remains with the oncology treatment
cessation, alcohol consumption and cancer screening. team and/or primary care provider, who through the con-
Furthermore, nurse practitioners are well suited to provide sultation are also educated about the survivor’s treatment
cancer survivorship care through the integration of clinical history and health risks and can apply the consultant’s
care, education and research. With the Affordable Care recommendations about regular monitoring. In the second
Act, combined with the growing number of cancer survi- model, the ‘‘ongoing care model’’, the oncology treatment
vors and the increased need for medical providers, nurse team hands responsibility for the care of the survivor over to
practitioners will be assuming more roles and responsi- a survivorship nurse practitioner or physician, at an estab-
bilities, so their involvement in survivorship care planning lished point in time post-treatment completion. The patient
is critical. is seen on a regular basis, usually annually, by the survi-
vorship health professional for ongoing monitoring and
education about survivorship issues. Communication is
maintained between treatment teams and primary care
3.1 Clinical Care providers. In the third model, the ‘‘integrated care model’’,
survivorship care is provided by the oncology treatment
Compared to pediatrics, clinical programs that address the team. An SCP is prepared when the patient completes
needs of adult cancer survivors are emergent. Model clinical treatment, and then discussed with the patient at a sub-
programs for adult survivors exist in a few academic centers sequent ‘‘survivorship’’ visit and annually thereafter by a
and the development of eight of these, starting with a pilot treatment team NP. Responsibility for the care of the sur-
at University of Pennsylvania have been supported in part vivor remains with the treatment team in the short term.
by funding from the LIVESTRONGTM Survivorship Center Patients who are at low risk for late onset versus persistent
of Excellence (COE) Network initiative of the LAF. This treatment effects can be identified and eventually transi-
Network was created to focus attention on adult cancer tioned to primary care with recommendations for regular
survivors, its primary goal being to develop and disseminate screenings and ongoing communication between providers
best clinical practices. Each Network member is located at a (Shapiro et al. 2009).
Nursing 277

Table 2 LIVESTRONGTM survivorship center of excellence network members

Institution/Location Web address
University of Pennsylvania (UPenn) Abramson Cancer http://www.penncancer.org/cancerprograms_detail2.cfm?id=56
Center Philadelphia PA
Dana Farber Cancer Institute (DFCI) Boston MA www.dana-farber.org/pat/surviving
Fred Hutchinson Cancer Research Center (FHCRC) http://www.fhcrc.org/patient/support/survivorship/
Seattle WA
University of California at Los Angeles (UCLA) Jonsson http://www.cancer.ucla.edu/Index.aspx?page=221
Comprehensive Cancer Center Los Angeles CA
Memorial Sloan Kettering Cancer Center (MSKCC) New www.mskcc.org/mskcc/html/58022.cfm
York NY
Ohio State University (OSU) Comprehensive Cancer http://www.jamesline.com/patientsandvisitors/survivorship/Pages/index.aspx
Center Columbus OH
University of North Carolina (UNC) Lineberger http://cancer.med.unc.edu/patient/support/carolinawel
Comprehensive Cancer Center Chapel Hill NC
University of Colorado (UC) Comprehensive Cancer www.uccc.info/for-healthcare-professional/cancercenter/prevention/survivorship/
Center Denver CO uccc-livestrong.aspx

Although yet to be systematically evaluated through whose actual or potential late effects are numerous or
research, the integrated model of care for adults with cancer complex, for example, survivors who have been treated
may have disadvantages that resemble those previously with cranial or mantle radiation.
observed, in the care of childhood cancer survivors. Some The role of the nurse to date has been fairly constant
of disadvantages could be that: (a) the needs of patients in across COE clinical programs. Ideally, following the IOM
active treatment are prioritized over survivors’ typically recommendations (Institute of Medicine 2006), a treatment
non-urgent needs, and more so as the number of patients in summary is completed and distributed to the patient at the
active treatment continues to grow (Shulman 2009), (b) the completion of therapy. Therefore, a role for nursing in the
main area of concern at treatment completion is disease clinical care of cancer survivors within the realm of medical
recurrence and so when information about late effects is record review and abstraction is to create a treatment
presented at the end of treatment survivorship visit, patients summary. Network members have created institution-spe-
and family caregivers may not absorb it, (c) survivors can cific treatment summary templates that are intended to be
feel social pressure to express only gratitude for successful completed by an oncology health professional such as a
treatment completion, and therefore lack willingness to nurse, and if at all possible may become part of the survi-
discuss negative aspects of their treatment with those who vor’s electronic medical record. Alternatively, ‘‘A Pre-
delivered it. Furthermore, as the literature expands, oncol- scription for Living’’ (Haylock et al. 2007), is a generic
ogy nurses and other health professionals may find it template that any nurse or survivor can use to create an
challenging to keep up with innovations in treatments and individualized treatment summary based on the official
growing knowledge about survivorship. The benefits of the medical record or the survivor’s personal records. Along
integrated approach include increased opportunities for these same lines, the Network is collaborating with Uni-
direct communication and collaboration among health versity of Pennsylvania’s OncoLink to expand its Web-
professionals. based treatment summary and Survivorship Care Plan
Nurse Practitioners who provide clinical care for survi- (SCP) (see Table 3), which is called OncoLifeTM (Shapiro
vors can examine the survivor’s treatment summary to et al. 2009).
determine his or her cancer-related health risks, and thus In creating the treatment summary, the nurse should
offer an approach to clinical care. Survivors who are at low address all of the essential elements including: the cancer
risk for late effects might participate in annual postal diagnosis and date, treating oncologist(s), elements of the
assessments apropos to health-related quality of life and treatment regimen (type and date of any surgeries to control
risk-based interim history. Postal assessments are reviewed the cancer; chemotherapy agents, routes of administration,
by the nurse or NP who then initiates clinical evaluation for and total dose when indicated; radiation type, field, frac-
the patients reporting concerning signs and symptoms. At tionation, and total dose; transplant type and date), major
the other end of the risk spectrum, the NP may do ongoing acute treatment effects including psychosocial difficulties,
symptom management and care coordination for survivors date of treatment completion, current health status including
278 S. J. Santacroce and M. Rubin

Table 3 Sources for clinical practice guidelines related to adult cancer

Resource Organization Web address
‘‘Putting evidence into practice’’ Oncology Nursing Society (ONS) http://www.ons.org/outcomes/
Clinical practice guidelines American Society of Clinical Oncology (ASCO) http://www.asco.org
Clinical practice guidelines National Comprehensive Cancer Network (NCCN) http://www.nccn.org

non-cancer related comorbid conditions, and persistent 3.1.2 Health Behaviors

treatment effects and known late effects. Essential elements Nursing care of cancer patients, survivors, and their family
of the SCP include all of the components of the treatment caregivers should include regular assessments of tobacco
summary plus recommendations about cancer and treat- use and second-hand smoke exposure, alcohol consumption,
ment-specific screenings, advice about lifestyle changes to lifestyle, weight, and diet (American Cancer Society 2008;
optimize the survivor’s health, and information about the Mayer et al. 2008). During active treatment, nurses can help
availability of psychosocial resources and referrals (Institute patients avoid unhealthy weight and physical decondition-
of Medicine 2007). ing that can complicate therapy in the short term and ulti-
Unlike pediatrics, widely accepted exposure driven evi- mately compromise survival. Nurses and NPs are in an ideal
dence-based or consensus-based guidelines are not yet position to provide guidance and support concerning diet
available to guide creation of the SCP for adult cancer and physical activity, direction to established guidelines
survivors. Based on the need for consensus-based guide- and, for patients who need them, referrals to nutritionists,
lines, work is in progress through the American Society of dietitians, and physical therapists. They can also counsel
Clinical Oncology (ASCO) and the National Comprehen- patients on the importance of immunizations a regular
sive Cancer Network (see Table 3), to standardize care and health screenings.
study its effects has been recognized (Earle 2007).
3.1.3 Treatment Adherence
Treatment adherence is fundamental to survivorship. Nurses
3.1.1 ‘‘Upstreaming’’ Survivorship can expect that patients will experience difficulties achiev-
Aside from the initial diagnosis, the transition from active ing at least 95 % adherence, and should therefore conduct
treatment can be the most frightening and warrants special regular assessments using an understanding and hopeful
attention to survivorship care planning (Institute of Medi- approach (Williams 2001). Acknowledging that patients
cine 2006; Campbell 2008). It is a time when ‘‘upstrea- and their family caregivers are doing their best given the
ming’’ of nursing attention to survivorship must occur, just complexities of life while employing a non-judgmental
as conversations about palliative care should commence at approach to problem-solving is important to establish
diagnosis and not end-of-life (Ferrell et al. 2008). Toward patient-provider relationships aimed to optimize adherence
this goal, several Network members led by MSKCC are (Thorne et al. 2004). At diagnosis and on a regular basis,
conducting educational programs for their office practice nurses should encourage patients and their family caregiv-
and hospital-based oncology nurses in anticipation of ers to discuss their understanding of the cancer and its
stimulating a shift in thinking about the timing of nursing prognosis, treatment goals, and beliefs about treatment
attention to survivorship. With today’s treatment regimens, efficacy, and to define their various roles and responsibili-
about 65 % of newly diagnosed adult patients overall will ties in adherence (Malbasa et al. 2007). Nurses can also help
survive their cancer for 5 years or more. Thus, it is rea- patients establish acceptable and supportive roles for their
sonable to encourage, beginning at diagnosis, a forward- family caregivers and other concerned individuals with
looking perspective that allows attention to maintenance or regards to supporting adherence. Nurses can also help
development of behaviors that can optimize health and patients to access medications and other aspects of their
well-being during active treatment and survivorship. Con- treatment regimen, as well as help them develop reminders
sistent messages from nurses that convey a sense of hope systems (Malbasa et al. 2007). Nurses should supply precise
for the future can be a source of comfort and focus during written information about treatment and copies of treatment
treatment (Thorne et al. 2008), and may enhance a patient’s calendars and instructions, and may consider providing
outcomes by reducing risks for late effects. Furthermore, regular reminders via cell phone and other electronic means
helping patients and their family caregivers to maintain or (Puccio et al. 2006).
increase healthy behaviors and lessen risky behaviors at
‘‘teachable moments’’ (Demark-Wahnefried et al. 2005) 3.1.4 Symptoms and Symptom Clusters
earlier in the cancer continuum may be more achievable Related to adherence, nurses should conduct regular
than later on in survivorship. assessments of symptoms and/or symptom clusters that can
Nursing 279

emerge as side effects of cancer and its treatment and that medicine (CAM) as a means to manage symptoms includ-
may compromise adherence. Symptom clusters are group- ing pain, symptoms of premature menopause, and psycho-
ings of two or more symptoms that commonly occur toge- social symptoms such as anxiety and depression. The use of
ther and may share causation (Barsevick 2007), an example CAM seems particularly prevalent among ethnic and racial
being the cluster of pain, depression, and fatigue. Such minority group members and those whose beliefs and
symptom/symptom clusters can produce distress and impact practices lack correspondence with prevailing approaches to
key functions such as the ability to work or do activities of care (Fletcher et al. 2008). Nurses should increase their
daily living across the cancer continuum. knowledge about CAM therapies, explicitly ask cancer
Nurses should use widely available standardized mea- patients and survivors and family caregivers about their use
sures to conduct symptom assessments. Kirkova and col- of CAM, particularly considering the potential for detri-
leagues have identified 21 instruments that are available and mental supplement-drug herbal and dietary supplement
appropriate for clinical assessment of specific symptoms or interactions, and also consider recommending CAM thera-
groups of symptoms that have been related to cancer and its pies. For example, mindfulness-based stress reduction, art
treatment (Kirkova et al. 2006). Moreover, the Patient- therapy, and music therapy that have reasonable mecha-
Reported Outcomes Measurement Information System nisms of action, are safe and have been shown to improve
(PROMIS) Network is developing what will be a publicly symptoms (Monti et al 2008).
available resource of standardized accurate and efficient
measures of physical symptoms, emotional distress, physi-
cal function, and social function. This measure can be used 3.1.6 A Special Clinical Population: Adolescent-
to assess responses to medical treatment and supportive care Young Adult Cancer Patients and Survivors
across the cancer continuum (Monti et al. 2008). Symptoms Adolescent and young adult (AYA) cancer patients and
including depression, anxiety, posttraumatic stress, sleep survivors are an at risk population that deserves particular
disturbances, fatigue, and pain have been shown to occur in attention from nursing. The NCI AYA Oncology Group has
family caregivers and may affect the caregiver’s ability to defined the AYA population as including 15–39 year olds
provide key aspects of care (Garcia et al. 2007). Nurses can (Monti et al. 2008), based on SEER data showing that
identify the patient’s primary family caregivers, conduct people in this age group have not shared in improvements in
regular assessments of caregiver symptoms, and encourage cancer survival to the same extent as others (Adolescent and
referral to a primary care and/or mental health provider as Young Adult Oncology Progress Review Group 2006). This
indicated. lack of progress has been attributed to AYA having low
Assessments can be used to target and also evaluate rates of enrollment in clinical trials, wherein much of the
outcomes of nursing interventions aimed at symptom improvement in outcomes for children is attributed to
management. Nurses should apply or recommend evidence- clinical trials (O’Leary et al. 2006), and also to usual
based symptom management interventions when possible. developmental characteristics of AYA.
The Oncology Nursing Society (ONS) has developed a set Characteristically, AYA perceive their selves to be
of evidence-based resources, ‘‘Putting Evidence into Prac- immortal and unique, and therefore not susceptible to can-
tice (PEP)’’, intended for use by nurses, NPs, and nurse cer-related health threats or the consequences of risky
researchers in the evidence-based care of people with can- health behaviors such as lack of adherence to medical rec-
cer and their families (see Table 3). The PEP resources ommendations. With normative increases in cognitive
include reference cards, definitions, integrated reviews and abilities, a central task for AYAs is to become independent.
meta-analyses, existing guidelines and standards, tables of In pursuing independence, AYAs can be wary of parental
instruments for measuring intervention outcomes and ref- assistance with health care communications, health care
erences, summaries of key evidence and gaps in evidence, decision-making and adherence to medical recommenda-
recommendations, and links to current research and other tions. Moreover, AYAs can lack regular primary care pro-
relevant resources. Extant evidence-based guidelines are viders who might provide crucial guidance in these matters.
directed at anxiety, caregiver strain and burden, constipa- As an age group, AYA have the highest rates of being
tion, depression, dyspnea, fatigue, functional status, under- or uninsured (Bleyer et al. 2006).
lymphedema, mucositis, nausea and vomiting, pain, Development tasks for AYA also include establishing a
peripheral neuropathy, nutritional status, and sleep-wake career, a sense of self as a sexual being, and commitment to
disturbances. another person (Albritton and Eden 2007). Achievements in
these areas can be impeded by the effects of cancer and its
3.1.5 Complementary and Alternative Medicine treatment such as fatigue, changes in physical appearance,
In addition to conventional medicine, cancer patients and altered cognitive and psychological function, and problems
survivors can make use of complementary and alternative with sexual functioning. Existential issues may be
280 S. J. Santacroce and M. Rubin

particularly intense for AYA who typically can grasp the seem to have great potential to enhance outcomes for AYA
potentially fatal nature of cancer but can lack the expec- (Rowland 1990).
tancy of personal vulnerability to cancer, substantial expe-
rience with health care, and the social support that can help
them form a cognitive schema for making sense of their 3.2 Education
situation (Rowland 1990).
Nurses should endeavor to develop age-appropriate Education of cancer patients, survivors, and family care-
clinical environments that allow AYA patients and survi- givers about the potential effects of cancer and its treatment,
vors to interact with their age-peers, convey a sense of hope and what can be done to manage them, is a central element
for the future, and provide assistance with navigating health of oncology clinical care and thus addressed throughout the
care, payment for care and educational systems. Nurses previous section. As the population of cancer patients and
should also support AYA enrollment in clinical trials by survivors continues to grow with diagnostic and treatment
introducing the option and helping them locate suitable advances, it is increasingly apparent that the oncology
treatment and supportive care clinical trials through workforce is insufficient to supply all cancer-related care.
resources such as that available online through the NCI at (Shulman et al. 2009) Oncology nurses and NP can help
http://www.cancer.gov/clinicaltrials/search or LAF at: expand this workforce by enhancing their communications
http://www.livestrong.org/site/c.khLXK1PxHmF/ with primary care providers as a means to educate them
b.4012249/. Nurses should also advocate for the develop- about issues for cancer patients and survivors including
ment of clinical trials that target issues of salience to AYA. potential late effects and promote their involvement in
Given their age-based heightened risk for depression and survivorship care.
posttraumatic stress disorder (PTSD), nurses should regu-
larly assess AYA patients and survivors for these conditions 3.2.1 Education for Referring Primary Care
and make referrals as clinically indicated (Santacroce Providers
2010). Nurses should also ask methodically about current After acute cancer treatment and initial follow-up visits, the
academic, work, social, and sexual functioning. Addition- care of cancer survivor patients is often transitioned from
ally, Nurses should repeatedly assess the concerns and the oncologist to a primary care provider (PCP), however,
information needs of AYA patients and survivors and their the role of the PCP in survivorship care is currently not well
capacity for information processing; these can vary across defined (Haylock et al. 2007). Recent research highlights
the illness trajectory and with developmental advancement. that when oncologists gradually become less involved in
Nurses should assume that AYA patients and survivors survivorship care, the patient’s cancer-related surveilance,
are neither secure in their health care communications nor including late effects, declines significantly (Snyder et al.
that they will ask even the most burning that they may have 2008). This finding implicates the need for a survivorship
questions. Nurses can assist AYA patients and survivors by care plan (SCP) that explicitly outlines pertinent medical
bringing up usual areas of concern for the age group, such information and guidelines for how PCPs and oncologists
as concerns about fertility preservation, and by helping are going to coordinate the follow-up care. Rather than
AYA identify and write down their questions in anticipation requiring PCPs to extract brief summaries of care from
of communications with physicians. When parents are multiple sources and synthesize the information themselves,
involved, nurses should assume that AYA and parental it is preferable for the oncology team to provide a com-
perspectives and questions will differ, given differences in prehensive summary and plan to facilitate a smooth tran-
their developmental characteristics and tasks, understand- sition (Horning 2008; Del Giudice et al. 2009). To illustrate
ings of cancer, and life experiences (Santacroce 2008). this point, the 2006 Institute of Medicine (IOM) report on
Nurses must determine, as early as feasible, to what ‘Implementing Cancer Survivorship Care Planning’ found
extent the AYA wishes to involve their parents in their care that out of all ambulatory cancer care visits, most are with
and decision making. Nurses can help AYA see that primary care providers, but noted that many PCPs do not
parental involvement is often necessary, principally during feel adequately prepared for the task. However, the per-
treatment. Nurses can help parents by guiding them on how ceived ability to care for cancer survivors increases when
to continue to support their AYA child’s development in the PCPs are given some form of treatment summary or SCP
context of cancer. Having permission from the AYA, the from oncologists. Unfortunately they rarely do receive
nurse could give information to the patient first and then, to these, and the transfer of care is continually rated very
the extent specified, to parents and patient together (Palmer poorly (Hewitt and Ganz 2007, p.11; Nissen et al. 2007).
et al. 2007). Nursing interventions for AYA could include After the diagnostic evaluation is completed, the oncol-
those that promote functional coping and favorable devel- ogy nurse/NP should assure that the patient’s primary care
opment. Interventions that aim to enhance social support provider receive information about the diagnosis and
Nursing 281

treatment plan, potential acute effects of cancer and its 3.3 Research
treatment, implications of the diagnosis for other family
members for example when there is a known genetic basis The scope of survivorship research has recently been
for the cancer, and available supportive care services. The redefined by Aziz 2007 as that which aims to: (a) identify,
oncology nurse/NP should encourage cancer patients and examine, prevent, and control the adverse effects of cancer
their family caregivers to maintain the patient’s relationship and its treatment; (b) define and examine the effects of
with his or her primary care provider during cancer therapy guidelines for follow-up and methods of surveillance for all
for routine health maintenance and ongoing management of cancer survivors; (c) prevent, control, and treat co-morbid
co-existing conditions not under specialty care. When conditions; (d) offer health promotion and lifestyle inter-
treatment is completed, the oncology nurse/NP should ventions as potential means to optimize health after cancer
assure that the patient’s SCP is made available to the pri- treatment; (e) explore the effects of the cancer experience
mary care provider. For survivors who in time are dis- on the family; and (f) reduce disparities in cancer outcomes
charged from oncology care, the oncology nurse/NP should that may be attributable to factors such as age, ethnicity,
initiate explicit referrals back to primary care providers for and income (Grinyer 2003). Opportunities for nursing to
regular monitoring for potential late effects according to an contribute to survivorship research are abundant.
updated SCP, with a request for ongoing communication Within their workplace or through nursing and multi-
about the patient’s health status and referral back to disciplinary professional groups, nurses can collaborate in
oncology if problems arise. The oncology nurse/NP can also or lead research that looks at the nature and prevalence of
conduct continuing education sessions about survivorship late effects of established therapies, and work in partnership
that target primary care providers and spotlight their roles. with colleagues from other disciplines to review and sum-
Equipped with education and up-to-date information, pri- marize the literature toward the development of evidence-
mary care providers will be well positioned to make based practice guidelines, or at least evidence-informed
important contributions to the care of cancer patients and consensus-based recommendations, for the management of
survivors. late effects. Nurses can also use the resultant guidelines to
standardize nursing practices concerning the care of cancer
3.2.2 Education for Nurses survivors and then collaborate with nursing and other col-
Survivorship has long been a subspecialty area within leagues to evaluate the outcomes, costs, and implications of
pediatric oncology nursing (Hobbie and Hollen 1993), and applying the guidelines to large numbers of survivors.
the same may happen in oncology nursing as a whole, Nurses should also conduct research on the creation and
potentially limiting interactions and knowledge exchange psychometric evaluation of measures that can be used in
between oncology nurses who specialize in different aspects practice and in research to comprehensively assess cancer
of the cancer continuum. However, nursing expertise in patients and survivors for symptoms that may indicate the
cancer survivorship and the care of survivors should inform development of acute and long-term effects of innovative
cancer patients, for example, of the value of health educa- therapies, especially symptoms which are nurse-sensitive,
tion throughout the cancer continuum. Along with educat- that is, can be influenced by nursing actions. Additionally,
ing patients, families and primary care providers, nurses nurses can conduct intervention research that aims to
who specialize in survivorship should regularly conduct establish best nursing practices for managing the range of
educational sessions for nurses who care for cancer patients symptoms that people can develop across the cancer con-
during active treatment. Such sessions could be required as tinuum. Nurses should also do research that examines fea-
part of a required orientation program for oncology nursing sibility and effectiveness of translating evidence-based
staff and also a regular topic in Nursing Grand Rounds or interventions into oncology nursing education and practice.
unit-based educational programs. Nurses with expertise in No standardized or evidence-based model of survivor-
survivorship should regularly participate in patient care ship care exists (Aziz 2007), although the need for research
rounds and treatment decision-making conferences where that examines and compares outcomes for various models
they can raise implications for survivorship. Finally, nurse of care by oncologists and primary care physician is gen-
faculty with expertise in survivorship should champion the erally accepted. However, current third-party payment
addition of survivorship didactic content and clinical structures and other forces can pressure oncologists to focus
experiences in the curriculum at the baccalaureate level as on patients who are in active treatment versus survivors
well in Master’s and clinical doctorate programs that pre- (Shulman et al. 2009), and nursing, predominantly the NP,
pare primary care and oncology NPs, and for inclusion of has grown to be the core discipline providing survivorship
survivorship content on state licensure and national certifi- clinical care across the various models. Yet there has been
cation examinations. no call from nursing to examine and compare outcomes for
282 S. J. Santacroce and M. Rubin

various models of nurse-delivered survivorship care nor is careers or working fulltime at jobs with benefits that include
much known about the economic feasibility of NP-provided health insurance and/or disability insurance, and potentially
survivorship care compared to care by an oncologist or have many work years ahead of them. Yet symptoms such
primary care physician. Nursing must take the lead in as fatigue, pain, and neuro-cognitive impairments have the
conducting survivorship research that has to do with the potential to compromise their ability to complete essential
nature, outcomes, and financial feasibility of nursing mod- educational programs and/or engage in work that in quantity
els of care. and quality allows them to achieve financial security and
Supporting adherence to medical recommendations other gratifications (Rowland 1990). Additionally, family
concerning cancer treatment, participation in regular fol- caregivers may have to cut back on work for pay or decline
low-up and primary care, adoption and maintenance of opportunities for education and/or career advancement and
healthy lifestyle behaviors, and the management of co- higher pay in order to provide care. Similarly, their work
morbid conditions is a means through which nursing can performance may be adversely affected by the burdens or
contribute to beneficial outcomes for survivors. Yet, symptoms that can be associated with providing care for
research about the assessment of adherence, development, cancer patients and survivors. Nurses should conduct
and evaluation of nursing interventions that aim to promote research that seeks to: (a) identify factors such as work and
adherence and systematic incorporation of evidence-based insurance that can affect financial security across the cancer
interventions into usual oncology practice and educational continuum for individuals who have been diagnosed with
programs has not been a major focus in oncology nursing. cancer as well as their family caregivers, (b) describes
Adherence has a been a focus of nursing research about potential barriers and facilitators of work, insurance, and
people with other chronic conditions notably diabetes. Thus other factors that can affect financial security, and (c)
an area through which nursing can be a factor in survivor- develop and test interdisciplinary inventions that aim to
ship research is through research on the aforesaid aspects of support financial security.
adherence, and this research should build on what has been
learned through nursing research on adherence in other
chronic illness populations. 4 Conclusion
Nursing as a discipline characterized by concern with
whole individuals including their social circumstances, in Cancer survivors and their family caregivers are at risk for
which the family and family caregivers can occupy a central adverse outcomes that can be related to cancer or its treat-
position. As previously discussed, symptoms are prevalent ment. Nurses and NPs who care for people and their families
in family caregivers in response to the caregiver burden, and who have been diagnosed with cancer must cultivate
these symptoms may compromise the caregiver’s ability to awareness and sensitivity to the potential for adverse out-
provide care and thus outcomes for cancer patients and comes throughout the cancer continuum. Nurses can educate
survivors. Nurses should conduct research that describes patients and health professionals about these risks, and
caregiver symptoms and associations with cancer outcomes, encourage the adoption of health behaviors that can prevent
and also develop and test interventions that are intended to or minimize the severity of adverse outcomes. They can also
improve outcomes for cancer patients and survivors by conduct regular assessments including screening for poten-
preventing the development of or controlling caregiver tial late effects, apply evidence-based interventions, and
symptoms. conduct/collaborate in survivorship research that aims to
In addition to developing symptoms in response to their maximize health and function after the diagnosis of cancer.
cancer experience, family caregivers may be at risk for
developing malignancy based on shared factors including
genetic endowment. Another focus for nursing research is
the development and testing of behavioral interventions that References
aim to: assist with decision making around cancer genetic
testing, sharing of genetic information and potential Adolescent and Young Adult Oncology Progress Review Group
responses to that information, participation in screenings (2006). Closing the gap: research and care imperatives for
adolescents and young adults with cancer. NCI , Bethesda,
that can facilitate early detection of cancers that have been pp 06–6067
linked to a genetic mutation and other behaviors that can Albritton K, Eden T (2007) Access to care before and during therapy.
minimize family members’ risks for malignancy. In: Bleyer A, Barr R (eds) Cancer in Adolesc and Young Adults.
Social circumstances also include factors that can affect Springer, New York, pp 61–69
American Cancer Society (2008) Cancer facts and figures.
finances, for example, work and insurance. Work and http://www.cancer.org/docroot/STT/content/
insurance are especially salient issues for young adult STT_1x_Cancer_Facts_and_Figures_2008.asp?from=fast. Acces-
cancer patients who may not yet be established in their sed 17 Jan 2009
Nursing 283

Aziz N (2007) Cancer survivorship research: State of knowledge, Horning SJ (2008) Follow-up of adult cancer survivors: new
challenges and opportunities. Acta Oncol 46:417–432 paradigms for survivorship care planning.Hematol Oncol Clin N
Barsevick A (2007) The concept of symptom cluster. Semin Oncol Am 22:201–210
Nurs 23:89–98 Institute of Medicine (2006) From cancer patient to cancer survivor:
Bhatia S, Meadows A (2006) Long-term follow-up of childhood lost in transition. National Academies Press, Washington
cancer survivors: Future directions for clinical care and research. Institute of Medicine (2007) Implementing cancer survivorship care
Pediatr Blood Cancer 46:143–148 planning. The National Academies Press, Washington
Bleyer A, Budd T, Montello M (2006) Adolescents and young adults Kirkova J, Davis M, Walsh D et al (2006) Cancer symptom assessment
with cancer: the scope of the problem and criticality of clinical instruments: A systematic review. J Clin Oncol 24:1459–1473
trials. Cancer 107:1645–1655 Lance Armstrong Foundation (2008) Survivorship centers
Campbell M, Mayer D, Abernethy A, Carroll S (2008) Cancer http://www.livestrong.org/site/c.khLXK1PxHmF/b.2661103/
survivorship. NC Med J. 69:322–324 k.7D72/Survivorship_Centers.htm. Accessed 17 Jan 2009
Carlson C, Hobbie W, Brogna M, Ginsburg J (2008) A multidisci- Landier W, Bhatia S, Eshelman D et al (2004) Development of risk-
plinary model of care for childhood cancer survivors with complex based guidelines for pediatric cancer survivors: The Children’s
medical needs. J Pediatr Oncol Nurs 25:7–13 Oncology Group Long-Term Follow-up Guidelines from the
Childhood Cancer Guides. (2007) Survivorship resource center: Children’s Oncology Group Late Effects Committee and Nursing
follow-up clinics. http://www.acor.org/ped-onc/treatment/ Discipline. J Clin Oncol 22:4979–4990
surclinics.html. Accessed 17 Jan 2009 Malbasa T, Kodish E, Santacroce S (2007) Adolescent adherence to
Children’s Oncology Group Nursing Discipline and Late Effects oral therapy for leukemia: a focus group study. J Pediatr Oncol
Committee (2007) Establishing and enhancing services for child- Nurs 24:139–151
hood cancer survivors: long–term follow up program resource Mayer D, Terrin N, Menon U et al (2008) Health behaviors in cancer
guide. http://www.survivorshipguidelines.org/pdf/LTFUResource survivors. Oncol Nurs Forum 34:643–651
Guide.pdf. Accessed 17 Jan 2009 Meadows A (2006) Pediatric cancer survivorship: research and clinical
Children’s Oncology Group Nursing Discipline and Late Effects care. J Clin Oncol 24:5160–5165
Committee (2007) Children’s oncology group long-term follow-up Monti D, Sulfian M, Peterson C (2008) Potential role of mind-body
guidelines for survivors of childhood, Adolescent, and Young therapies in cancer survivorship. Cancer 2008(112):2607–2616
Adult Cancers V.2. http://www.survivorshipguidelines. Nissen MJ, Beran MS, Lee MW, Mehta SR, Pine DA, Swenson KK
org/pdf/LTFUGuidelines.pdf. Accessed 17 Jan 2009 (2007) Views of primary care providers on follow-up care of
D’Angio G (1975) Pediatric cancer in perspective: cure is not enough. cancer patients. Fam Med 39(7):477–482
Cancer 35:866–870 O’Leary M, Barr R, Ries LAG (eds) (2006) Cancer epidemiology in
Del Giudice ME, Grunfeld E, Harvey BJ, Piliotis E, Verma S (2009) older adolescents and young adults 15 to 29 years of age, including
Primary care physicians’views of routine follow-up care of cancer SEER incidence and survival: 1975–2000. NCI, Bethesda
survivors. J Clin Oncol 27(20):3338–3345 Palmer S, Mitchell S, Thompson K (2007) Unmet needs among
Demark-Wahnefried W, Aziz N, Rowland J et al (2005) Riding the adolescent cancer patients: a pilot study. Palliat Support Care.
crest of teachable moments: promoting long-term health after the 5:127–134
diagnosis of cancer. J Clin Oncol 23:5814–5830 Parkes S, Jenkinson H, Griffiths A, Kinch D (2007) Mann. Is postal
Earle C (2007) Cancer survivorship research and guidelines: Maybe follow-up of childhood cancer survivors worthwhile? Pediatr
the cart should be beside the horse. J Clin Oncol 25:3800–3801 Blood Cancer 50:80–84
Ferrell B, Paice J, Koczywas M (2008) New standards and implica- Potosky AL, Han PKJ, Rowland J, Klabunde CN, Smith T, Aziz N,
tions for improving the quality of supportive oncology practice. Earle C et al (2011) Differences between primary care physician’
J Clin Oncol 23:3824–3831 and oncologists’ knowledge, attitudes and practices regarding the
Fletcher B, Dodd M, Schumacher K, Miakowski C (2008) Symptom care of cancer survivors. J Gen Intern Med 26(12):1403–1410
experience of family caregivers of patients with cancer. Oncol Nurs Puccio J, Belzer M, Olson J et al (2006) The use of cell phone
Forum 35:23–44 reminder calls for assisting HIV infected adolescents and young
Ganz PA, Casillas J, Hahn EE (2008) Ensuring quality care for cancer adults to adhere to highly active antiretroviral therapy: a pilot
survivors: implementing the survivorship care plan. Sem Oncol study. AIDS Patient Care STD 20:438–444
Nurs 24(3):208–217 Rowland J (1990) Developmental stage and adaptation: adult model.
Garcia S, Cella D, Lauser S et al (2007) Standardizing patient-reported In: Holland JC, Rowland JH (eds) Psycho-oncology. Oxford
outcomes assessment in cancer clinical trials: a patient-reported University Press, New York
outcomes measurement information system initiative. J Clin Oncol Rowland J (2005) Looking forward: beyond cure: pediatric cancer as a
32:5106–5112 model. J Pediatr Psychol 30:1–3
Grinyer A (2003) Young adults with cancer: parent interactions with Rowland J, Mariotto A, Aziz N et al (2004) Cancer survivorship-
health care providers. Eur J Cancer Care. 33:622–630 United States, 1971–2001. Morbid Mortal 53:526–530
Haylock PJ, Mitchell SA, Cox T, Temple SV, Curtiss CP (2007) Rowland JH, Ganz PA (eds) (2011) Cancer survivorship plans: a
The cancer survivor’s prescription for living. Am J Nurs 107(4): paradigm shift in the delivery of quality cancer care (Ch. 8). In:
58–70 Feuerstein M, Ganz P (eds) Health services for cancer survivors.
Hewitt ME, Greenfield S, Stovall E (eds), National Research Council, Springer Science & Business Media, LLC, New York
Institute of Medicine(2006) From cancer patient to cancer survivor: Rubin M (2012) Cancer survivorship in primary care (Unpublished
lost in transition. TheNational Academies Press, Washington N757 Research Paper Assignment). Yale University School of
Hewitt ME, Ganz P (eds), Institute of Medicine (2007) Implementing Nursing, New Haven
cancer survivorship care planning: workshop summary. National Santacroce S (2008) Late effects case report: the young adult
Academies Press, Washington childhood cancer survivor with symptoms of posttraumatic stress.
Hobbie W, Hollen P (1993) Pediatric nurse practitioners specializing Oncol Nurs Ed 22:22–30
with survivors of childhood cancer. J Pediatr Health Care. Santacroce S, Zebrack B (2010) Adolescent and Young Adult Patients.
7:24–30 In J. Holland, W.S. Breitbart, P.B. Jacobsen, M.S. Lederberg, M.J.
284 S. J. Santacroce and M. Rubin

Loscalzo, R. McCorkle (eds.), Psycho-Oncology, New York, Snyder CF, Earle CC, Herbert RJ, Neville BA, Blackford AL, Frick
Oxford University Press KD (2008) Preventive care for colorectal cancer survivors: a 5-year
Shapiro C, McCabe M, Syrjala K et al (2009) The LIVESTRONGTM longitudinal study. J Clin Oncol 26(7):1073–1079
Survivorship center of excellence network. J Cancer Surviv (in Thorne S, Harris S, Mahoney K, Con A, McGuinness L (2004) The
press) context of health communication in chronic illness. Patient Educ
Shulman L, Jacobs L, Greenfield S, et al. (2009) Cancer care and Counsel. 54:299–306
cancer survivorship in the US: Will we be able to care for these Thorne S, Hislop T, Armstrong E, Oglov V (2008) Cancer care
patients in the future? JOP 5(3):119–123 communication: the power to harm and the power to heal. Patient
Skinner R, Wallace W, Levitt G (2007) Long-term follow-up of Educ Couns 71:34–40
children treated for cancer: why is it necessary, by whom, where Williams A (2001) Adherence to HIV regimens: 10 vital lessons. Am J
and how? Arch Dis Child 92:257–260 Nurs 10:37–44
 Economic Consequences of Late Effects

Andre Konski

Contents Abstract
Late effects of cancer treatment can have economic
1 Introduction.......................................................................... 285 consequences on patients and their families. The reduc-
2 Employment Reduction....................................................... 286 tion in employment opportunities is directly related to
2.1 Breast Cancer Survivors........................................................ 286 the type of cancer and treatment received. Patients
2.2 Lung Cancer Survivors.......................................................... 286 undergoing combinations of surgery, chemotherapy and
2.3 Head and Neck Cancer Survivors......................................... 286
radiotherapy experience far greater employment oppor-
2.4 Gastric Cancer ....................................................................... 287
tunities when compared to those patients surviving after
3 Pediatric Cancer Survivors ................................................ 287 having only single modality therapy. Employment status
3.1 General Economic Effects of Cancer Therapy .................... 287
also can be influenced by social support provided by
4 Long-Term Economic Consequences of Cancer.............. 288 governments with patient’s living in countries with more
4.1 Genitourinary Cancer ............................................................ 288
liberal social support not feeling as much pressure when
4.2 Head and Neck Cancer ......................................................... 288
4.3 Anemia/Neutropenic-Related Costs ...................................... 289 compared to patients living in countries with very little
4.4 Targeted Agents..................................................................... 289 support. In addition to reduced employment potential,
5 Conclusion ............................................................................ 290 survivors with late effects of cancer therapy will also
require additional treatment to treat the late effects
References...................................................................................... 290
thereby increasing the cost of care. This too is also
dependent upon type of cancer and treatment received.

1 Introduction

The adverse effect of radiation (RT) on normal tissues has

been well documented. What have not been highlighted are
the economic consequences these late effects have on
patients and families. The direct economic cost of RT-
induced late effects includes the cost of treatment to repair
damaged tissue and organs as well as to ameliorate the
symptoms of damage. For late effects occurring early in life,
such as in the pediatric population, these costs would
accumulate for longer periods of time with potentially
staggering economic consequences to society. There are
also the indirect medical costs to consider in addition to the
direct cost of medical care.
A. Konski (&) The cost of transportation to/from hospitals/physician-
Department of Radiation Oncology, offices and the cost of child or elder care to attend these
Wayne State University School of Medicine
Barbara Ann Karmanos Cancer Center, visits are but two of many examples of indirect medical
Detroit, Michigan, USA cost. The impact to society in general is even harder to
e-mail: [email protected]

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 285
DOI: 10.1007/978-3-540-72314-1_19, Ó Springer-Verlag Berlin Heidelberg 2014
286 A. Konski

quantify. Lost wages or reductions in potential earning survivors and normal matched controls although cancer
capacity in patients unable to fully work can be difficult to survivors reported significantly poorer work ability, poorer
measure but have been found to be less in long-term breast health status, greater numbers of disease symptoms, more
cancer survivors as a result of reduced work effort (Chirikos anxiety, and reduced physical quality of life (Berg Gud-
et al. 2002). A number of studies have investigated the bergsson et al. 2008). An analysis of long-term costs asso-
relationship between symptoms and productivity reductions ciated with breast cancer in a population of Canadian
in survivors of breast cancer. A 3.1 % reduction in pro- women from 3 Quebec cities revealed that costs occurred
ductivity was reported by breast cancer survivors compared over a long time period and were not borne by just the
to a healthy worker; with fatigue and hot flashers account- patient but by the whole family with wage losses being one
ing for productivity reductions of 1.6–2.2 %, respectively of the principal cost sources (Lauzier et al. 2005). In another
(Lavigne et al. 2008). Another study found breast cancer study from Quebec, women between 18 and 59 who were
survivors finding return to work difficult not because of working at the time of the breast cancer diagnosis between
discrimination by employers or colleagues but because of 1996 and 1997 were studied and compared to a randomly
sequelae of their disease and it’s treatment (Molina Vil- selected group of patients without breast cancer. It was
laverde et al. 2008). reported 85% of breast cancer survivors who remained free
This chapter will review the available literature per- of disease during the 3-year study period were absent from
taining to the cost of treating complications or late effects of work for 4 weeks or more when compared to 18% of the
cancer and its therapy. It is important to quantify the cost of healthy women (Drolet et al. 2005). After 3 years, there was
treating complications or late effects as it is only then can no difference between the two groups in work absence,
the true total cost of cancer treatment be known for certain. although women with breast cancer who recurred had more
In addition, knowing the exact cost of late effects is required eventual absences. This would cause a disruption in any
for cost-effectiveness analyses of therapies to prevent or workplace with higher cost to replace the sick worker and
treat late effects. lower productivity for the company as part-time employees
are never as productive as compared to full-time employees.

2 Employment Reduction
2.2 Lung Cancer Survivors
2.1 Breast Cancer Survivors
The impact of lung cancer on working lives was studied
The ability to work after a diagnosis of breast cancer was with the aid of a postal survey in Britain. Two hundred and
investigated in a cohort of Korean breast cancer survivors sixty-seven eligible patients returned a consent form and
who had been working prior to the diagnosis of breast questionnaire, for a response rate of 50 %. The majority of
cancer. Compared to a group of 20–60-year-old Korean respondents were women with breast cancer but 6 % of the
women without breast or any type of cancer, employment respondents had lung cancer. 82 % of the respondents did
rates decreased from 47.6 % pretreatment to 33.2 % post- return to work and treatment modality (absence of surgery),
treatment (Ahn et al. 2009). Fatigue and exhaustion were i.e patients who did not receive surgery had the longest sick
the most frequent difficulties encountered during occupa- leave, and length of sick-leave were the only significant
tional work. There was no mention other than mastectomy factors related to return to work (Amir et al. 2007). Males
on treatment-related factors affecting the survivor’s ability were more likely than females to return to work, and not
to return to work. In another study, radiotherapy, shorter take sick leave, but they were more likely to take longer
time since surgery and endocrine therapy predicted daily periods of absence when they did.
activity and work limitations due to sequelae in an age- A diagnosis of lung cancer, as well as blood, liver, and
stratified random sample of 2000 Danish female breast brain cancer, as well as older age, company employee, and
cancer survivors (Peuckmann et al. 2009). Bradley et al. on lower income were significant predictors of early job loss or
the other hand reported women surviving breast cancer had delayed re-employment in a study of Korean patients
a 10 % less chance of working compared to women without diagnosed with cancer (Park J.H. et al. 2008).
breast cancer, but those women who did work were found to
work on average approximately 3 more hours per week
compared to women who did not have cancer (Bradley et al. 2.3 Head and Neck Cancer Survivors
2002). Similarly, Berg et al. explored the work engagement
of employed tumor free patients, including breast cancer The quality of life of 36 patients with primary squamous
survivors, compared to matched controls. They found no cell carcinoma of the base of the tongue treated with pri-
differences in work engagement rates between cancer mary radiotherapy was evaluated with a variety of quality of
Economic Consequences of Late Effects 287

life instruments. The annual incomes of these 36 patients at Full-time employment was normal, however, among sur-
the time of follow-up were similar to the income at the time vivors of hematologic malignancies who did not receive
of presentation (Harrison et al. 1997). The majority of radiation. Hays et al, however, found with the exception of
patients achieved excellent functional status and quality of survivors treated for CNS tumors, patients treated between
life and could maintain their pre-diagnosis earning poten- 1945 and 1975 had few economic sequelae of cancer or its
tial. What was not clear from the report was how these therapy that extended beyond the first decades after treat-
patients were selected from all of the patients treated ment (Hays et al 1992). Fifty-six of 60 long-term survivors
between 1981 and 1990. Patients surviving head and neck of pediatric brain tumors, exclusive of craniopharyngiomas
cancer were among the highest to report an adjusted risk of and pituitary tumors, were evaluated a mean of 10 (range:
disability or quitting work, however, among 1,433 patients 5–16) years after diagnosis. 66 % had no or mild disability
surviving cancer and interviewed 1–5 years after complet- compatible with active life and employment (Lannering
ing treatment (Short et al. 2005). et al 1990). Eighty-nine survivors of Ewing’s sarcoma
Employment in head and neck survivors was studied in family tumors were compared to 97 sibling controls with
The Netherlands where they found 83% of patients initially the cancer survivors to be less likely to be employed full-
employed at the time of diagnosis returned to work. At a time (Odds ratio 0.4, p\0.01) (Novakovic et al 1997).
median of 6 months after completing therapy, the majority Education, employment, insurance, and marital status were
of patients returned to the same type of work while 7/53 to studied among 694 survivors of pediatric lower extremity
adapted work and 9/53 to other work (Verdonck-de Leeuw bone tumors in a long-term follow-up study of the Child-
IM et al 2012). It was reported that anxiety, oral dysfunc- hood Cancer Survivor Study. When compared with siblings,
tion, trismus, problems with teeth and loss of appetite were patients who had undergone amputation had significant
some of the symptoms significantly associated with deficits in education, employment, and health insurance
employment after treatment. This would be particularly (Nagarajan et al 2003).
problematic in patients who use oral communication skills
in their line of work.
3.1 General Economic Effects of Cancer
Therapy
2.4 Gastric Cancer
In a study of 964 cancer survivors in Denmark, a trend was
Employment status and work-related difficulties comparing noted that male cancer survivors were less likely than other
stomach cancer survivors and the general population was men without cancer to be currently employed and more
studied in 408 gastric cancer survivors in Korea. A greater likely to be retired as compared to men without cancer
percentage of nonworking was found among gastric cancer (25.2% vs 29.7%, p=0.06 (Norredam et al. 2009). In addi-
survivors, 46.6 %, compared to the general population, tion to having less of an ability to return to work after being
36.5 % (Lee et al. 2008). In addition, survivors reported more successfully treated for cancer, cancer survivors may not
fatigue, had reduced working hours, and had reduced work- receive needed medical care because of financial concerns.
related ability compared to the general population. This is In a study of data from the US National Health Interview
most likely a result of the extent of surgery and subsequent Survey (NHIS) from 2003 to 2006, 6602 adult cancer sur-
treatment that occurs in patients with stomach cancer. vivors were identified and compared to 104,364 individuals
without cancer. Approximately 8% of cancer survivors did
not receive medical care because of cost, 9.9% did not fill
3 Pediatric Cancer Survivors prescriptions, 11.3% did not receive medical care and 2.7%
did not receive mental care (Weaver et al. 2010). Chal-
Functional outcomes and life satisfaction in long-term sur- lenges in obtaining employment after a cancer diagnosis
vivors of pediatric sarcomas was assessed in 32 participants and treatment were also noted in a cohort of patients with
in National Cancer Institute clinical trials. Eight patients Hodgkin Lymphoma as compared to siblings. Patients with
reported cancer had negatively impacted work while 17 [4 physician visits within 2 years, \10 years from diag-
reported that it negatively impacted their vocational paths nosis, or with permanent hair loss from treatment were more
(Gerber L.H. et al 2006). Full-time employment was also likely to report inability to change jobs due to fear of losing
found to be below the natural norms in a survey of 1,437 insurance and compared to siblings, survivors of Hodgkin
children who survived cancer treated at St. Jude’s Research Lymphoma were more likely to face challenges in obtaining
Hospital (Crom et al. 2007). This cohort was compared to employment and insurance (Chen et al. 2012).
normative data in the Medical Expenditure Panel Survey Another potential for additional economic cost is the cost
and the U.S. Census Bureau’s Current Population Surveys. associated with care provided by caregivers. This cost is not
288 A. Konski

usually calculated or collected during the majority of eco- metastasis and 1 SRE (Lage et al. 2008). There was no
nomic studies of cancer care because it is time consuming mention as to how many patients were receiving androgen
and difficult to collect but the economic impact can be deprivation but one has to assume the great majority of
substantial. Patients with complications from cancer treat- patients must have been receiving androgen deprivation,
ment can require increased care from not only healthcare since this is the standard treatment for bone metastasis in
providers but can require care from family members that is patient with prostate cancer.
not captured. The opportunity cost of this care can be Extreme variation in the cost of continuing care of
substantial as the caregivers may not be able to work while patients with prostate cancer was thought to be responsible
giving care to family members. Cost of caregiver care was for potentially unnecessary excess cost to the health care
tabulated from a national survey of caregivers of cancer system in an analysis of [100,000 patients diagnosed with
patients between 2003 and 2006. On average, caregivers prostate cancer between 1992-2005 in the SEER-Medicare
provided care for 8.3 hours per day for 13.7 months (Ya- database (Skolarus et al. 2010). Office visits and the use of
broff and Kim 2009). The number of months and daily androgen deprivation comprised the most physician-related
hours spent caregiving were the highest for cancer survivors payments for prostate cancer survivorship care (Skolarus
diagnosed with distant disease when compared to survivors et al 2010).
with regional or localized disease, p\0.05. Cost of informal The lifetime costs of treating bladder cancer and asso-
caregiver time over the 2-year period after diagnosis was ciated complications were studied via a model in 208
highest for caregivers of patients with lung and ovarian patients with bladder cancer registered at MD Anderson
cancer and lowest for caregivers of patients with breast Cancer Center between 1991 and 1999. Although the
cancer (Yabroff and Kim 2009). majority of cost was associated with surveillance and
treatment of the primary malignancy, 30 % was attributable
to treatment of complications (Avritscher et al. 2006).
4 Long-Term Economic Consequences Unfortunately, the authors did not separate complication
of Cancer cost by procedure or treatment that was responsible for it.

A review of the literature found a significant number of

articles dealing with the complications of therapy, but rel- 4.2 Head and Neck Cancer
atively few articles dealing with the cost of complications of
cancer therapy, either radiation therapy, chemotherapy or Head and neck cancer treatment can cause considerable
surgery. One can extrapolate and use simple assumptions morbidity, especially if combined with cytotoxic chemo-
that patients with complications incur more healthcare costs therapy resulting in higher cost due to increased rates of
compared to patients without complications but these data hospitalization, opioid use and a greater need for fluid and
are not published as of yet. The available literature is nutritional support (Murphy et al. 2007). Higher costs were
highlighted below. found in patients with head and neck cancer receiving
radiochemotherapy experiencing severe mucositis/pharyn-
gitis compared to patients without severe mucositis/phar-
4.1 Genitourinary Cancer yngitis, $39,313 versus $20,798, p = 0.007 (Nonzee et al.
2008). The total increased incremental cost for patients with
Healthcare costs of men receiving androgen deprivation mucositis was $17,244. This study technically, however, did
therapy were analyzed in a cohort of 8,577 men with not investigate the cost of late complications as data were
prostate cancer; 3,055 who had initiated androgen depri- collected from the initiation of radiochemotherapy to
vation therapy. The mean unadjusted total cost of health 2 months afterward. Similar results were noted in a study of
care during the 36-month period was $48,350 per person for 204 patients with head and neck cancer treated with RT
men receiving androgen deprivation compared to men not with or without chemotherapy. Oral mucositis was found to
receiving androgen deprivation (Krupski et al. 2007). After be associated with an incremental increase of cost ranging
controlling for differences in health status, the majority of between $1,700 and $6,000 depending upon on the muco-
excess cost was attributable to the androgen deprivation, sitis grade (Elting et al. 2007). Once again, cost of treatment
with a minority of cost attributable to fractures. Another was measured from the start of RT to 6 weeks from com-
study found radiation therapy to be the highest cost of pletion of treatment. In a more recent observation, an
treating a skeletal-related event (SRE) followed by patho- increased risk of cerebrovascular disease was noted in older
logic fracture and then surgery in a retrospective claims patients treated with head and neck cancer treated with
analysis of 342 patients with a diagnosis of prostate cancer definitive radiation (Smith et al. 2008). Although compli-
and at least 2 subsequent claims with a diagnosis of bone cation costs were not calculated, it is intuitive that patients
Economic Consequences of Late Effects 289

Table 1 Cost associated with treatment, recurrence, and complications for patients with medicare insurance treated on RTOG 91–11
Treatment No recurrence and no No recurrence but with Recurrence but no Recurrence and
related costs complication n = 7 complication n = 27 complication n = 6 complication
n = 26
RT only $11,662 $21,770 $37,577 $61,804 $92,050
Induction $17,439 $36,045 $43,958 $38,453 $65,208
chemotherapy and
radiation
Concurrent $12,433 n/a $58,224 $42,581 $50,576
chemoradiation

experiencing cerebrovascular complications will exhibit (Norum and Moen 2008). Anemia treatment costs, eryth-
higher healthcare costs compared to patients not exhibiting ropoietin versus blood transfusion, were analyzed in 12
these complications. patients with cervical cancer. Treatment was given either
It is also intuitive, but has never been fully substantiated, before or during the cancer therapy. Average transfusion-
that patients with recurrences and complications cost more related costs were $990, compared to the projected eryth-
to treat as compared to patients who do not recur or expe- ropoietin-related costs of $3,869 (Kavanagh et al. 2001).
rience a complication. This hypothesis was tested using The impact of anemia and its treatment on employee
Medicare Part A and Part B costs for patients with Medicare disability and medical costs was evaluated in patients
insurance treated on Radiation Therapy Oncology Group receiving chemotherapy within 6 months of cancer diag-
(RTOG) protocol 91-11 (Konski 2007). This clinical trial nosis. The data were also linked to their employer’s short-
investigated three different treatments for larynx preserva- term disability records. Twenty-five percent of patients had
tion in patients with locally advanced laryngeal cancer. chemotherapy-induced anemia. The presence of anemia and
Only 66 of the 547 patients randomized to the protocol had longer length of transfusion therapy were associated with
Medicare insurance. Patients were classified as having a increased expenditures (Berndt et al. 2005). Longer length
complications if they had experienced a [ Grade 3 com- of erythropoietin alpha use, however, was associated with
plication. Table 1 shows the costs by category and by lower expenditures. The incremental cost of anemia was US
treatment arm. Patients with no recurrence but with a $5,538 per month for the first 6 months following cancer
complication had higher mean costs compared to treatment- diagnosis, 10.8 % of which were costs related to short-term
related costs with no recurrence or complication. The costs disability leave (Berndt et al. 2005). Costs of neutropenic
were the highest for patients who received radiation only complications secondary to chemotherapy was evaluated
having experienced a recurrence and a complication and using a US healthcare claims database. Costs of neutrope-
second highest for patients experiencing a recurrence but no nia-related care were $12,397 higher for neutropenia versus
complication. Likewise, the costs were also highest for comparison patients (Weycker et al. 2008). Cost of all
patients receiving induction chemotherapy and radiation subsequent neutropenia-related care averaged $6,594
who experienced a recurrence and a complication. These (Weycker et al. 2008). Cost of neutropenic complications in
results need to be further confirmed in other patient groups women with metastatic breast cancer treated with chemo-
and treatment types.. therapy was studied in a retrospective cohort design and a
US healthcare claims data. Chemotherapy-induced neutro-
penic complications were experienced in 11% of subjects
4.3 Anemia/Neutropenic-Related Costs with cost for inpatient care (88% of patients with compli-
cations) averaging $12,869 US Dollars, while the cost for
Anemia secondary to anti-neoplastic treatment including outpatient care was significantly less at $2030 US Dollars
radiotherapy can adversely affect treatment efficacy as well (Weycker et al. 2012).
as decrease a patient’s quality of life. Treatment of the
anemia includes red blood cell (RBC) transfusions and use
of growth factors such as epoetin. Epoetin beta with con- 4.4 Targeted Agents
comitant IV iron in anemic patients with lymphoprolifera-
tive malignancies not receiving chemotherapy resulted in Newer agents targeting specific areas of the cell have gained
better outcomes at lower cost compared to epoetin beta increasing use in cancer care. They normally have few side
without iron (Hedenus et al. 2008). RBC transfusion in an effects but some have specific toxicities. Certain targeted
oncology unit was studied in 118 patients in Norway. The agents result in dermatologic toxicity. A recent analysis of
annual cost of transfusions was calculated at Euro 1,069 132 patients treated between 2005 and 2008 having a cancer
290 A. Konski

treated with 1 molecularly targeted agent showed patients Berndt E, Crown W, Kallich J, Long S, Song X, Lyman GH (2005)
with a dermatologic toxicity had a median of 3 visits for The impact of anaemia and its treatment on employee disability
and medical costs. Pharmacoeconomics 23(2):183–192
management of the dermatologic toxicity with a median Borovicka JH, Calahan C, Gandhi M et al (2011) Economic burden of
cost of $1,920 US Dollars. Sorafenib had the highest overall dermatologic adverse events induced by molecularly targeted
median cost per patient ($2,509 per patient) while imatinib cancer agents. Arch Dermatol 147(12):1403–1409
had the lowest overall median cost per patient ($1,263 per Bradley CJ, Bednarek HL, Neumark D (2002) Breast cancer and
women’s labor supply. Health Serv Res 37(5):1309–1328
patient) (Borovicka et al. 2011). Although small in cost Burudpakdee C, Zhao Z et al (2012) Economic burden of toxicities
relative to other more costly complications, this is just the associated with metastatic colorectal cancer treatment regimens
start of use of these type of agents and more informations containing monoclonal antibodies. J MedEcon 15(2):371–377
will be forthcoming as their use increases. Chen AB, Feng Y, Neuberg D, Recklitis C, Diller LR, Mauch PN, Ng
AK et al (2012) Employment and insurance in survivors of
Another recent analysis evaluated the economic burden Hodgkin lymphoma and their siblings: a questionnaire study. Leuk
of the use of monoclonal antibodies, bevacizumab, cetux- Lymphoma 53(8):1474–1480
imab, panitumumab, associated with treatment of metastatic Chirikos TN, Russell-Jacobs A, Cantor AB (2002) Indirect economic
colorectal cancer. The highest inpatient cost per event was effects of long-term breast cancer survival. Cancer Pract 10(5):
248–255
for treatment of GI perforation ($32,443 US Dollars), fol- Crom DB, Lensing SY, Rai SN, Snider MA, Cash DK, Hudson MM
lowed by fistula ($29,062 US Dollars), and wound-healing (2007) Marriage, employment, and health insurance in adult
complications ($13,240 US Dollars) (Burudpakdee et al. survivors of childhood cancer. J Cancer Surviv 1(3):237–245
2012). Inpatient costs to treat hypomagnesemia and skin Drolet M, Maunsell E, Mondor M, Brisson C, Brisson J, Masse B, et al
(2005) Work absence after breast cancer diagnosis: a population-
rash were the lowest with outpatient treatment for skin rash based study. CMAJ 173(7):765–71
was among the least costly at $185 US Dollars Elting LS, Cooksley CD, Chambers MS, Garden AS (2007) Risk,
(Burudpakdee et al. 2012). outcomes, and costs of radiation-induced oral mucositis among
patients with head-and-neck malignancies. Int J Radiat Oncol Biol
Phys 68(4):1110–1120
Gerber LH, Hoffman K, Chaudhry U, Augustine E, Parks R, Bernad M
5 Conclusion et al (2006) Functional outcomes and life satisfaction in long-term
survivors of pediatric sarcomas. Arch Phys Med Rehabil
The economic cost of late effects of cancer therapy include 87(12):1611–1617
Harrison LB, Zelefsky MJ, Pfister DG, Carper E, Raben A, Kraus DH
not only the cost of treatment the actual complication, such et al (1997) Detailed quality of life assessment in patients treated
as diarrhea, perforation or neutropenia, but also includes with primary radiotherapy for squamous cell cancer of the base of
lost productivity of not being able to work and caregiver the tongue. Head Neck 19(3):169–175
costs. Unfortunately, the economic consequences of radio- Hays DM, Landsverk J, Sallan SE, Hewett KD, Patenaude AF,
Schoonover D et al (1992) Educational, occupational, and insur-
therapy late effects have not been studied extensively to ance status of childhood cancer survivors in their fourth and fifth
date. With the advent of healthcare reform, studies docu- decades of life. J Clin Oncol 10(9):1397–1406
menting the economic effect of all cancer therapies, Hedenus M, Nasman P, Liwing J (2008) Economic evaluation in
including late effects, need to be performed to decide which Sweden of epoetin beta with intravenous iron supplementation in
anaemic patients with lymphoproliferative malignancies not
treatments provide the most economic use of scarce receiving chemotherapy. J Clin Pharm Ther 33(4):365–374
healthcare dollars. Kavanagh BD, Fischer BAT, Segreti EM, Wheelock JB, Boardman C,
Roseff SD et al (2001) Cost analysis of erythropoietin versus blood
transfusions for cervical cancer patients receiving chemoradiother-
apy. Int J Radiat Oncol Biol Phys 51(2):435–441
References Konski A, Bhargavan M, Owen J et al (2007) The price of failure:
economic analysis of recurrence and complicaitons of patients
Ahn E, Cho J, Shin DW, Park BW, Ahn SH, Noh DY, Nam SJ, Lee treated on RTOG 91-11. Oncology (Williston Park) 21(5 Suppl.
ES, Yun YH (2009) Impact of breast cancer diagnosis and 2):3
treatment on work-related life and factors affecting them. Breast Krupski TL, Foley KA, Baser O, Long S, Macarios D, Litwin MS
Cancer Res Treat 116(3):609–616 (2007) Health care cost associated with prostate cancer, androgen
Amir Z, Moran T, Walsh L, Iddenden R, Luker K (2007) Return to deprivation therapy and bone complications. J Urol 178(4 Pt 1):
paid work after cancer: a British experience. J Cancer Surviv 1423–1428
1(2):129–136 Lage MJ, Barber BL, Harrison DJ, Jun S (2008) The cost of treating
Avritscher EB, Cooksley CD, Grossman HB, Sabichi AL, Hamblin L, skeletal-related events in patients with prostate cancer. Am J
Dinney CP et al (2006) Clinical model of lifetime cost of treating Manag Care 14(5):317–322
bladder cancer and associated complications. Urology Lannering B, Marky I, Lundberg A, Olsson E (1990) Long-term
68(3):549–553 sequelae after pediatric brain tumors: their effect on disability and
Berg Gudbergsson S, Fossa SD, Dahl AA (2008) Is cancer survivor- quality of life. Med Pediatr Oncol 18(4):304–310
ship associated with reduced work engagement? A NOCWO study. Lauzier S, Maunsell E, De Koninck M, Drolet M, Hebert-Croteau N,
J Cancer Surviv 2(3):159–168 Robert J (2005) Conceptualization and sources of costs from breast
Economic Consequences of Late Effects 291

cancer: findings from patient and caregiver focus groups. Psych- Novakovic B, Fears TR, Horowitz ME, Tucker MA, Wexler LH
ooncology 14(5):351–360 (1997) Late effects of therapy in survivors of Ewing’s sarcoma
Lavigne JE, Griggs JJ, Tu XM, Lerner DJ (2008) Hot flashes, fatigue, family tumors. J Pediatr Hematol Oncol 19(3):220–225
treatment exposures and work productivity in breast cancer Park JH, Park EC, Kim SG, Lee SY et al (2008) Job loss and re-
survivors. J Cancer Surviv 2(4):296–302 employment of cancer patients in Korean employees: a nationwide
Lee MK, Lee KM, Bae JM, Kim S, Kim YW, Ryu KW et al (2008) retrospective cohort study. J Clin Oncol 26(8):1302–1309
Employment status and work-related difficulties in stomach cancer Peuckmann V, Ekholm O, Sjøgren P, Rasmussen NK, Christiansen P,
survivors compared with the general population. Br J Cancer Møller S, Groenvold M (2009) Health care utilisation and
98(4):708–715 characteristics of long-term breast cancer survivors: Nationwide
Molina Villaverde R, Feliu Batlle J, Villalba Yllan A, Jimenez Gordo survey in Denmark. Eur J Cancer 45(4):625–633. doi:
AM, Redondo Sanchez A, San Jose Valiente B et al (2008) 10.1016/j.ejca.2008.09.027 (Epub 2008 Nov 25)
Employment in a cohort of breast cancer patients. Occup Med Short PF, Vasey JJ, Tunceli K (2005) Employment pathways in a large
58(7):509–511 cohort of adult cancer survivors. Cancer 103(6):1292–1301
Murphy BA (2007) Clinical and economic consequences of mucositis Skolarus TA, Zhang Y, Miller DC et al (2010) The economic burden
induced bychemotherapy and/or radiation therapy. J Support Oncol of prostate cancer survivorship care. J Urol 184(2):532–538
5(9 Suppl 4):13–21 Smith GL, Smith BD, Buchholz TA, Giordano SH, Garden AS,
Nagarajan R, Neglia JP, Clohisy DR, Yasui Y, Greenberg M, Hudson Woodward WA et al (2008) Cerebrovascular disease risk in older
M et al (2003) Education, employment, insurance, and marital head and neck cancer patients after radiotherapy. J Clin Oncol
status among 694 survivors of pediatric lower extremity bone 26(31):5119–5125
tumors: a report from the childhood cancer survivor study. Cancer Verdonck-de Leeuw IM, Bleek WJ, Leemans CR, Bree R et al (2010)
97(10):2554–2564 Employment and return to work in head and neck cancer survivors.
Nonzee NJ, Dandade NA, Markossian T, Agulnik M, Argiris A, Patel Oral Oncol 46(1):56–60
JD et al (2008) Evaluating the supportive care costs of severe Weaver KE, Rowland JH, Bellizzi KM, Aziz NM et al (2010)
radiochemotherapy-induced mucositis and pharyngitis: results Forgoing medical care because of cost: assessing disparities in
from a Northwestern University Costs of Cancer Program pilot healthcare access among cancer survivors living in the United
study with head and neck and nonsmall cell lung cancer patients States. Cancer 116(14):3493–3504
who received care at a county hospital, a Veterans Administration Weycker D, Malin J, Edelsberg J, Glass A, Gokhale M, Oster G (2008)
hospital, or a comprehensive cancer care center. Cancer Cost of neutropenic complications of chemotherapy. Ann Oncol
113(6):1446–1452 19(3):454–460
Norredam M, Meara E, Landrum MB et al (2009) Financial status, Weycker D et al (2012) Risk and healthcare costs of chemotherapy-
employment, and insurance among older cancer survivors. J Gen induced neutropenic complications in women with metastatic
Intern Med 24 Suppl 2:S438-45 breast cancer. Chemotherapy 58(1):8–18.
Norum J, Moen MA (2008) Practice and costs of red blood cell (RBC) Yabroff KR, Kim Y (2009) Time costs associated with informal
transfusion in an oncological unit. Anticancer Res 28(1B):459–464 caregiving for cancer survivors. Cancer 115(18 Suppl):4362–4373.
 Radiological and Nuclear Terrorism: Relevance
to the Radiation Oncology and Biology
Communities
C. Norman Coleman, Nathaniel Hafer, Bert Maidment, Ronald Manning,
Pat Prasanna, and Paul Okunieff

Contents 6.4 Integrated National Biodefense Medical Countermeasures

Portfolio: Promoting a One-Portfolio Approach .................. 303
6.5 The MCM Requirements Process ......................................... 304
1 Introduction.......................................................................... 294 6.6 BARDA Radiological and Nuclear Activities...................... 304
2 Preparedness and Planning ................................................ 295 7 Conclusions ........................................................................... 308
3 Biodosimetry......................................................................... 297 References...................................................................................... 309
4 Medical Countermeasures Against Radiological
and Nuclear Threats- NIAID ............................................. 299
5 Normal Tissue Injury Research Program-Centers Abstract
for Medical Countermeasures Against Radiation ........... 301 There are now unique opportunities for research and
6 Product Development: Biomedical Advanced Research community service for radiation experts based on a
and Development Authority ............................................... 302 confluence of needs for reducing radiation toxicity for
6.1 BARDA.................................................................................. 302
cancer care and preparing a medical response to a
6.2 Project BioShield................................................................... 302
6.3 Pandemic and All-Hazards Preparedness Act ...................... 302 potential nuclear or radiological incident. The new
opportunities include: (a) the need for agents (e.g.,
drugs, biologics, and natural products) to prevent and/or
mitigate radiation injury; (b) the discovery and validation
*Katherine Casey-Sawicki from University of Florida provided of biomarkers to predict radiation susceptibility and
editorial assistance.Conflicts of interest-none.
provide diagnostics for measuring dose (biodosimetry)
C. N. Coleman (&) and guiding clinical care; (c) basic research on mecha-
Department of Health and Human Services (HHS), nisms of radiation injury that are in common with other
Office of the Assistant Secretary for Preparedness fields, such as inflammation, regenerative medicine,
and Response (ASPR), Washington, USA
e-mail: [email protected] cancer, and aging; and (d) radiation biology research
on mechanisms of radiation injury at the molecular,
C. N. Coleman
P. Prasanna
Division of Cancer Treatment and Diagnosis cellular, and organismal levels. The radiological/nuclear
(DCTD)/Radiation Research Program (RRP), medical preparedness and response field is moving
National Cancer Institute (NCI), Bethesda, USA rapidly with a multipronged goal of ever-improving
N. Hafer
B. Maidment medical preparedness and response. This effort involves
National Institutes of Health (NIH), National Institute basic and translational science, device and medical
of Allergy and Infectious Diseases (NIAID), Bethesda, USA countermeasure development, deployment of personnel
N. Hafer and medical resources, access to up-to-date, just-in-time
The American Association for the Advancement information for medical management, post-event recov-
of Science (AAAS) Science and Technology Policy Fellow,
Washington, USA ery and resilience, and complex policy issues. The
breadth of challenges provides an opportunity for a wide
R. Manning
ASPR, Biomedical Advanced Research and Development range of experts to participate. This chapter highlights
Authority (BARDA), Washington, USA the current state of the radiological/nuclear medical
P. Okunieff preparedness and response field. Given the rapidity with
Department of Radiation Oncology, University of Florida which research, development, and system solutions are
Shands Cancer Center, Gainesville, USA

P. Rubin et al. (eds.), ALERT – Adverse Late Effects of Cancer Treatment, Medical Radiology. Radiation Oncology, 293
DOI: 10.1007/978-3-540-72314-1_20,  Springer-Verlag Berlin Heidelberg 2014
294 C. N. Coleman et al.

evolving, this chapter emphasizes where to find up- MTA Material threat assessment
to-date information. MTD Material threat determination
NIA National Institute on Aging
NCI National Cancer Institute
Abbreviations and Acronyms NHP Non-human primate
AC Assembly centers (predetermined site in NIAID National Institute of Allergy and Infectious
RTR system) Diseases
AFRRI Armed forces radiobiology research NIH National Institutes of Health
institute NSBRI National Space Biomedical Research
ALC Absolute lymphocyte count Institute
ARS Acute radiation syndrome OPEO Office of Preparedness and Emergency
ASPR Office of the Assistant Secretary for Pre- Operations
paredness and Response PAHPA Pandemic and all-hazards preparedness act
BAA Broad Agency announcement (BARDA) PDA Personal digital assistant
BARDA Biomedical Advanced Research and PHEMCE Public Health Emergency Medical Coun-
Development Authority (ASPR) termeasures Enterprise
CBRN Chemical, biological, radiological, nuclear PRO-CTCAE Patient related outcomes-common toxicity
CDC Centers for Disease Control and Prevention criteria for adverse events
CMCR Centers for Medical Countermeasures R&D Research and development
against Radiation (NIAID) RCP Radiation countermeasures program
CTCAE Common toxicity criteria for adverse (NIAID)
events RDD Radiological dispersal device
DARPA Defense Advanced Research Products REMM Radiation emergency medical management
Agency RERF Radiation effects research foundation
DEARE Delayed effects of acute radiation exposure RFA Request for application
DF Dangerous fallout zone RFI Request for information (BARDA)
DHS Department of Homeland Security RFP Request for proposal (BARDA)
DHHS Department of Health and Human Services RITN Radiation injury treatment network
(also HHS) RTR Radiation triage, treatment and transport
DoD Department of Defense system
DOE Department of Energy SALT Sort, assess, life-saving intervention, treat/
DTPA Diethylenetriaminepentaacetate triage/transport
EPR Electron paramagnetic resonance SBIR Small business innovation research (grant)
FDA Food and drug administration SD Severe damage zone
FY Fiscal year SNS Strategic national stockpile (CDC)
GI Gastrointestinal SSN Sources sought notice (BARDA)
GIS Geographic information system TRL Technology readiness level
GLP Good laboratory practice (required by WHO World Health Organization
FDA)
GMP Good manufacturing practice (required by
FDA)
Gy Gray 1 Introduction
HHS Department of Health and Human Services
IAEA International Atomic Energy Agency The spectrum of a terrorist attack includes biological,
IMAAC Interagency Modeling and Atmospheric chemical, and radiological/nuclear events. As the Cold War
Advisory Center came to a close, the interest and investment in the conse-
LD Light damage zone quences of a nuclear attack waned, although there was
LINAC Linear accelerator fortunately ongoing support for long-term epidemiological
MC Medical care sites (predetermined site in studies (Mettler et al. 2007; Preston et al. 2007, 2008; I-
RTR system) vanov et al. 2008; Little 2009). However, a National Cancer
MCM Medical countermeasures Institute (NCI) workshop in 2000 stimulated renewed
MD Moderate damage zone interest in normal tissue injury (Stone et al. 2002) as new
Radiological and Nuclear Terrorism 295

information was emerging from other fields, such as • Severe Damage (SD) zone—close to the epicenter with
inflammatory response and imaging. Although limited, extensive physical damage and radiation with few sur-
there was some ongoing investment at the Armed Forces vivors likely, although people sheltered deep within some
Radiobiology Research Institute (AFRRI) in developing modern structures may survive.
radiation protectors (Ledney and Elliott 2010) and biodos- • Moderate Damage (MD) zone—physical damage and
imetric assessment. The terrorist attack on September 11, some radiation, particularly where the dangerous fallout
2001 and the recent growth in the number of actual and (DF) crosses the zone. Many people in this zone will be
potential countries with nuclear weapons have lead to injured but salvageable.
renewed interest and investment in nuclear and radiological • Light Damage (LD) zone—glass damage and car acci-
terrorism response. The majority of the investment in ter- dents but a limited number of serious injuries. It will have
rorism response is in biological agents, but there is also radiation only where the DF crosses this zone. Most
solid interest in all-hazards response planning (PHEMC victims will be ambulatory and few will have any radi-
2010), including natural and man-made disasters since there ation exposure.
are response commonalities among all hazards and threats. • Dangerous Fallout (DF) zone—the exposure rate will be
Over the past 8 years, detailed planning for nuclear and sufficiently high to potentially cause acute radiation
radiological incidents has been undertaken, and there is now syndrome (Homeland Security Council 2010; Waselenko
investment in the discovery and development of radiologi- et al. 2004; Fliedner 2006) in which a person may
cal/nuclear medical countermeasures and diagnostics. This receive *2 Gy or more from fallout. Sheltering in place
work has been supported largely by a funding stream is important for reducing dose. The footprint of the DF
through NIAID (NIAID 2010) that is separate from the zone is determined by about 1–2 h and dose rate declines
National Institutes of Health (NIH) budget. It is specifically rapidly thereafter so that it becomes smaller (Homeland
dedicated to terrorism response and normal tissue medical Security Council Interagency Policy Coordination Sub-
countermeasure (called MCM) development. committee for Preparedness and Response to Radiologi-
This chapter highlights the preparedness and response cal and Nuclear Threats 2010).
challenges, the spectrum of programs for response to a • A Time Limited zone (Fig. 1)—zone above 10 mR/h
nuclear detonation, and the relevance of these programs to where responders can work; however, the Incident
the radiation oncology, biology, and physics communities. Commander limits time based on protective action prin-
In that these are rapidly moving areas of research and ciples (Homeland Security Council 2010).
development, this chapter will emphasize key references The medical response is a complex system that has two
and websites where opportunities and progress can be fol- general components developed by the Office of Prepared-
lowed. The components of the United States’ overall ness and Emergency Operations (OPEO) in the Office of the
response to radiological/nuclear threats include detection, Assistant Secretary for Preparedness and Response (ASPR)
interdiction, render safe, community planning, response, (ASPR 2010) in the Department of Health and Human
and resilience. Experts from the radiation oncology, biol- Services (HHS). One is the set of spontaneously forming
ogy, physics, hematology, and transplantation fields have sites at which people will congregate and/or victims may be
the opportunity to be involved in these activities as part of found; the other is a set of predetermined response sites.
their formal work or through volunteerism. The importance This RTR system, which defines functional sites for Radi-
of such involvement is significant (Coleman and Parker ation TReatment, TRiage, and TRansport (Hrdina et al.
2009) since well-informed expertise must be available to 2009; Coleman et al. 2009), is not a medical triage system.
local communities as well as to advisory groups to the Figure 1 illustrates the five response zones and RTR sites
federal, state, local, and tribal governments. (Homeland Security Council 2010; Buddemeier and Dillion
2010). RTR 1 sites have both physical damage and high
radiation (will be near SD and MD zones); RTR 2 has
limited or no damage and fallout (will be near DF zone);
2 Preparedness and Planning RTR 3 has limited or no damage, has no radiation, and is
where people may spontaneously gather or be sent as the
The Planning Guidance for Response to a Nuclear Deto- response gets organized (will be near LD zone and beyond).
nation (Homeland Security Council 2010; Buddemeier and Medical care sites (MC) are predetermined sites that will
Dillion 2010) contains detailed information regarding the include alternate care sites. Assembly centers (AC) are
physical impact of a nuclear detonation using 10 kT as the predetermined places where people without medical needs
example. There are five general damage zones that are will be sent to assemble after the Shelter-in-Place period.
considered for response: Given the initial high exposure rate from fallout, sheltering
296 C. N. Coleman et al.

Fig. 1 Response zones and RTR medical system. The five physical 1–3, medical care sites (MC), assembly centers (AC), evacuation
damage zones are noted: severe, moderate, and light damage, centers, and outside facilities/expert centers (Homeland Security
dangerous fallout, and hot zone. The RTR sites are overlaid, RTR Council 2010; ASPR 2010)

in place is the default recommendation for 12–24 h as severity is not dose dependent. The deterministic injuries
responders develop situational awareness. RTR 3 and AC are often called Acute Radiation Syndrome (ARS) and
differ in that AC are predetermined; whereas, RTR 3 will include hematological, gastrointestinal, dermatological, and
form during the event, although they may end up being used neurovascular effects (Coleman et al. 2009, 2003; Fliedner
as ACs. HHS has advanced geographic information system et al. 2009). The delayed effects of acute radiation exposure
(GIS) mapping capabilities by which to manage the event in (DEARE) occur over time and include lung and kidney
the Med Map system (Homeland Security Council 2010). injury and soft tissue fibrosis (Homeland Security Council
Comprehensive medical management and triage are 2010; Coleman et al. 2009; Pellmar and Rockwell 2005)
beyond the purpose and scope of this chapter and references (See Table 1). While radiation injuries are often described
are provided below. In addition to the Planning Guidance as separate organ system injury with differential sensitivity,
(Homeland Security Council Interagency Policy Coordina- we now recognize that this is a multiorgan issue, for both
tion Subcommittee for Preparedness and Response to diagnostic biomarkers and therapeutic interventions, in
Radiological and Nuclear Threats 2010), another key ref- which all organs are responding to the radiation (Fliedner
erence tool is the Radiation Emergency Medical Manage- et al. 2009, 2009). The stochastic effect of concern is
ment (REMM) website (Coleman et al. 2009), which can be radiation-induced cancer (Suit et al. 2007) for which
downloaded to a computer or personal digital assistant appropriate biomarker and surveillance studies will be
(PDA). Some key underlying principles and useful refer- needed. The spectrum of injuries will include one or more
ences for medical management are presented below. of the following: blast, burn, radiation, and secondary
Radiation injury is often described as consisting of two trauma (e.g., glass injury and car accidents). Medical
general types—deterministic, in which the complication management includes appropriate supportive care, specifi-
severity increases with dose, and stochastic, in which the cally hematological growth factors, antibiotics, blood
probability of the complication increases with dose but the products, and other approaches often used in oncology
Radiological and Nuclear Terrorism 297

Table 1 Basic radiation medicine responders, and a person’s symptoms. Evaluating the
Hematological syndrome ([2 Gy) severity of and time to vomiting is helpful but unreliable for
Occurs after whole-body or substantial partial-body dose definitive triage (Demidenko et al. 2009) due to the possi-
Shielding part of the body reduces impact bility other causal factors. After initial sorting of victims,
Aggressive treatment can be life saving
Death can occur within a few days at high doses but more
there will be assessment, life-saving intervention, and
commonly in 3–8 weeks treatment/transport/triage using a variation of the SALT
Gastrointestinal syndrome (5–10 Gy, although GI dysfunction occurs approach (Lerner et al. 2008). Clearly, a very complex and
at lower doses) rapidly changing scarce resources situation will exist
Occurs after whole-body or if only part of the abdomen is irradiated (AHRQ 2007). A critical component of medical response is
Can cause immediate symptoms reassessment, especially as conditions change in that
If untreated death occurs in 3–10 days
someone triaged to receive palliative care only may be
Dermatological syndrome (5–6 Gy)
changed to aggressive management as resource setting
From the prompt flash to exposed areas
Beta-burns can occur from fallout improves. A detailed discussion of triage, medical man-
Thermal burns may also occur from secondary fires agement in a scarce resources setting, crisis standards of
Pulmonary syndrome (5–10 Gy) care (IOM 2009), ethical considerations, the importance of
Considered a delayed effect—can be months to years after exposure serial reassessment (Homeland Security Council 2010), and
Occurs if part of the lung is irradiated the need for the Radiation Injury Treatment Network
Central nervous system syndrome ([10 Gy) (RITN) (Davids et al. 2010) are in a recent issue of Disaster
Complex brain and cardiovascular collapse
Med (Coleman et al. 2011).
Can be fatal immediately and within first few days
The radiation oncology and biology communities, the
Combined injury = radiation plus trauma and/or burns
Lowers the threshold for acute radiation syndrome
National Institutes of Health (NCI and NIAID), AFRRI, and
Enhances likelihood of death—prompt intervention needed the Radiation Research and Health Physics Societies have
Multiorgan dysfunction and failure responded to the challenge of nuclear terrorism by bringing
All organs respond to radiation so that the ‘‘syndromes’’ above together the research communities to help determine the
describe dominant cause of clinical syndrome preparedness and response and develop research plans
Diagnostics such as biomarkers will be impacted by multiple organ (Coleman et al. 2001, 2003; Pellmar and Rockwell 2005;
changes
Stone et al. 2004; Augustine et al. 2005; Williams et al.
Phases
Exposure may be followed by latent phase before full syndrome
2010). Aspects of these programs are described below.
occurs A recent effort has begun to explore the possibility of using
Latent period can be days to weeks for acute radiation syndromes the medical countermeasures developed for normal tissue
Radiation medical countermeasures (MCM) mitigation for terrorism response for clinical cancer care
Protectors—used before radiation (not likely of major use in (Mosvas et al. 2010).
nuclear event)
Mitigators—used after exposure but before development of major
dysfunction to reduce injury
Treatment—used as syndrome is developing 3 Biodosimetry
Internal contamination—issue for a radiological dispersal device
but not a nuclear detonation. Using biological methods to assess the dose received by an
individual is essential when physical dosimetry is lacking,
(Waselenko et al. 2004; Fliedner 2006; REMM 2010; particularly in a radiation mass casualty setting. Even when
Fliedner et al. 2009a, 2009b; Dainiak et al. 2003; Koenig there is a physical estimate of exposure, laboratory confir-
et al. 2005; Weinstock et al. 2008; Weisdorf et al. 2006; mation is necessary for medical management. Hematolog-
AFRRI 2009, 2008; REAC/TS 2010). The REMM provides ical analysis, particularly absolute lymphocyte count (ALC)
detailed medical management algorithms for radiation and the change in ALC over time, are important indicators
injury (Homeland Security Council 2010). and this may be sufficient information for managing the
Medical triage will be based on the physical injury and higher-radiation dose ranges. In general, the initial goal is to
the best possible assessment for radiation dose. Given the sort or ‘‘bin’’ people with potential exposure to radiation
size of the event and the limited number of emergency into three bins: (a) \2 Gray (Gy) where no intervention is
responders, it is expected that the vast majority of those needed (except in the presence of combined injury); (b)
who reach medical care will do so by self-evacuation. The 2–4 Gy where observation and potential treatment for ARS
estimation of possible exposure will come from the mod- is needed over the next few weeks; and (c) [4 Gy where
eling of the incident by the Interagency Modeling Atmo- immediate medical management is needed. A fourth cut off
spheric and Advisory Center (IMAAC) (Homeland Security of [8–10 Gy would likely be used to triage a victim into
Council 2010), physical dose measurement of the area by the expectant category (Lerner et al. 2008). The use of
298 C. N. Coleman et al.

hematological growth factors is appropriate only at doses However, in order to rapidly diagnosis- or bin- who may be
of [2 Gy (and for serious combined injury). at risk for ARS, rapid and preliminary dose estimation for
While crude assessment of absorbed dose can be made triage may be needed for scores of 20–50 metaphases per
from the clinical signs and symptoms, such as skin subject. For example, in the Chernobyl accident, an
responses (erythema) and peripheral blood cell counts, approximate dosimetry was achieved by a preliminary
uncertainties in these dose predictions are quite large examination of 50 metaphases per person for several indi-
because of variability among individuals, potential presence viduals (Pyatkin et al. 1989).
of infection or trauma, and comorbid medical illnesses. Frequency of metaphase spreads without dicentric
Methods are needed to help assess the stochastic risk of aberrations and distribution of dicentrics among metaphase
radiation-induced cancer to determine who might require spreads can help determine whether exposure is uniform,
long-term follow-up. At present, cytogenetic-based methods whole-body, or partial-body and help identify patients’
are widely used to measure radiation dose and occupy a appropriate treatments (Lloyd 1997). Radiation exposures
unique niche in biological dosimetry. Several molecular from accidents or terrorist incidents are likely to be partial-
biomarker and biophysical dosimetric approaches are also body from the prompt radiation (the initial blast) but rela-
rapidly evolving, as noted below. tively homogenous for fallout radiation. Recently, a model
Radiation induces many types of chromosomal aberra- for triage dose prediction in radiation mass casualties,
tions in an exposed individual’s peripheral blood lympho- which is based on determination of equivalent whole-body
cytes. Due to their radiation specificity, the presence of doses under partial-body exposure conditions, has been
dicentrics, a common structural aberration, indicates radi- proposed (Prasanna et al. 2010). According to the model, an
ation exposure and provides an excellent measure of initial screening of metaphases can confirm radiation
absorbed dose. It shows a very low background level, low exposure above 2 Gy and analysis of 50 metaphases will
interindividual variation, and good dose-frequency rela- allow risk-based stratification of the exposed cohort.
tionship. Exposure of lymphocytes in vitro or in vivo pro- However, cytogenetic biodosimetry is labor-intensive,
duces similar levels of dicentrics per Gy; therefore, dose can time-consuming, and expertise-driven. Therefore, automa-
be predicted from observed dicentric yield in an exposed tion of sample preparation analysis is essential to improve
subject’s peripheral blood lymphocytes by comparison with throughput for mass casualty events. In addition, laboratory
a suitable in vitro generated calibration curve. The assay is automation improves quality control and assurance. Use of
also useful in determining full- versus partial-body expo- robotic instruments, as well as laboratory information
sures (International Atomic Energy Agency 2001). management systems to address data management and
Biological dosimetry using dicentrics following an sample-tracking, is being established (Martin et al. 2007).
accidental overexposure has been used since the 1962 Re- National and international cooperative cytogenetic networks
cuplex criticality accident at Hanford (Bennder and Gooch are already established to increase throughput in radiation
1966), as well as several other radiation accidents involving mass casualties (Wilkins et al. 2008; Miller et al. 2007).
mass casualties. Estimated doses using cytogenetic methods Exposure to radiation induces stable radicals in teeth and
correlated well with the severity of ARS (Sevankaev 2000). fingernails. These changes are highly reliable and electron
Several countries have established laboratories for chro- paramagnetic resonance (EPR) analysis can provide useful
mosome aberration-based biological dosimetry. In addition, information for retrospective dose reconstruction (IAEA
harmonized technical manuals (Williams et al. 2010) and 2002). The EPR technology may provide rapid capability
laboratory accreditation standards are now available (ISO for dose assessment in mass casualties (Trompier et al.
2004). Recently, an interlaboratory comparison study fur- 2007); however, complete mapping of partial-body expo-
ther validated the assay by determining variability and sures may not be possible. Currently, bulky instrumentation
accuracy among five laboratories (Wilkins et al. 2008). requires miniaturization.
Referral guidance for cytogenetic biodosimetry for Alternative biomarkers of DNA damage may be assessed
determining who may need subsequent treatment or sur- relatively quickly and easily compared to traditional cyto-
veillance is based on the person’s location from knowledge genetic tools providing clinically useful information.
of physical dosimetry, onset of prodromal signs and Examples of potential alternative methods include: (a)
symptoms, and lymphocyte depletion kinetics. Small vol- gamma-H2AX assay (Dicky et al. 2009); (b) measurement
umes of peripheral blood are collected from exposed sub- of micronuclei along with other damage in cytokinesis-
jects and sent to a cytogenetic laboratory where the blocked binucleated cells (Fenech 2007); and (c) a rapid
peripheral blood lymphocytes are grown in cultures to interphase chromosome assay (RICA), which measures
harvest cells in metaphase, and the frequency of dicentrics damage to specific chromosomes in interphase cells by
is estimated by analysis of 500–1,000 metaphases for dose fluorescence in situ hybridization after premature chromo-
prediction by comparison with a calibration curve. somal condensation by mitosis promotion and phosphatase
Radiological and Nuclear Terrorism 299

are the most critical issues, physicians with experience in

oncology care are necessary.
Additional information is available on multiparameter
triage (Blakely et al. 2010; Ossetrova and Blakely 2009;
Ossetrova et al. 2010), partial-body exposure (Prasanna
et al. 2010), the establishment of laboratory networks
(Blakely et al. 2009; Ainsbury et al. 2009), and the criteria
for rapid techniques (Grace et al. 2010).

4 Medical Countermeasures Against

Radiological and Nuclear Threats- NIAID
Fig. 2 Biodosimetry and radiobioassay for medical management.
The current techniques available include hematology, dicentric- Safeguarding people against the threat of nuclear or radio-
cytogenetic assay, and radio bioassay for some of the radionuclides. logical agents is not only a priority for U.S. national security
There is limited laboratory capacity such that a Radiation Laboratory but also a major public health concern. Should mass expo-
Network (Rad-LN) has been proposed. Newer approaches include
automation of current techniques and novel markers
sure to these hazards occur, medical countermeasures that
prevent or repair tissue damage will need to be widely
available. Because it is unlikely that people will have
inhibition (Prasanna et al. 2000). Early gene expression advanced warning, and it will take time to muster the
changes, proteomics, metabolomics, and organ-specific response, these countermeasures must be effective when
biomarkers may also be useful in the near future (Zhang given days after radiation exposure. Healthcare providers
et al. 2009). must be equipped to treat both the acute and long-term
Any single assay may not be able to address dose effects of radiation damage. However, there are currently no
assessment needs in all radiation exposure scenarios, which licensed medical products to mitigate or treat the injuries that
can be often complex. Therefore, when multiple assays are can result from a nuclear or radiological accident or attack.
involved, a multiparameter, comprehensive, and integrated The Secretary of the HHS, through the Project BioShield
approach for predicting dose is essential (Fig. 2). Some of Act of 2004 (Project Bioshield 2010), directed NIAID to
these approaches to estimate dose are available on REMM develop a strategic plan and research agenda to guide all
(REMM 2010). In a mass casualty event there will be two NIH activities contributing to the development of medical
sets of screens; assays that produce risk assessment for countermeasures against radiological and nuclear threats.
significant radiation exposures (i.e., binning) would be The final document, The National Institutes of Health (NIH)
followed by systems that produce a reliable actual physical Strategic Plan and Research Agenda for Medical Coun-
dose. Because some casualties will have combined injuries, termeasures Against Radiological and Nuclear Threats, was
including some degree of trauma, and since combined published in June 2005 and describes NIAID’s priorities in
injuries greatly alter the need for triage for even low-dose this area (NIH 2005). Over the past 5 years, the radiation
whole-body exposures, the first screen should be sensitive countermeasures program (RCP) has made significant pro-
to prognosis rather than just radiation dose. Triage will be gress toward the goals described within the Strategic Plan,
done based on standard medical triage (trauma, burns, and and this section highlights the recent activities supported by
level of consciousness), radiation-alone triage (dose), and the RCP. Current information can be found on RCP’s
some estimate of the adverse impact of combined injury. website (NIAID 2010).
When exposure is not homogeneous, the specification of the The RCP is primarily focused on developing mitigators
dose is not possible. For example, individuals with ingestion and treatments for ARS and DEARE, developing biodosi-
or inhalation exposures from a Radiological Dispersal metric tools that can rapidly assess the dose of radiation
Device (RDD), or those partially shielded from prompt absorbed by a person post-exposure and also decorporation
radiation by physical structures like cars and walls, will agents that can speed the removal of internalized radio-
have some marrow protection. The partial-marrow protec- nuclides from the body (Ramakrishnan 2009; Cassatt et al.
tion will lead to a much greater tolerance to whole-body 2010). Since the type and severity of radiation injury can
exposure. Here again, it will be important to have a first vary greatly due to the nature of the exposure, ARS/DEARE
screen that determines both medical risk as well as a sec- does not represent a single pathological condition, but rather
ondary accurate measure of radiation dose. Medical man- describes a variety of syndromes affecting the hematopoi-
agement will be guided by dose; nevertheless, since the etic system, gastrointestinal system, lungs, kidneys, skin,
actual patient’s clinical progression and organ dysfunction and central nervous system (Table 1). Broad classes of
300 C. N. Coleman et al.

compounds that might enhance repair of radiation-induced reinvigorated the field of normal tissue radiobiology by
damage and increase survival include growth factors, cell- developing educational tools, recruiting new investigators
signaling molecules, antioxidants, anti-apoptotics, anti- to study radiation biology, and providing funds for pilot
inflammatory agents, and antibiotics. A number of studies research projects. The CMCR program was recompeted in
in the literature demonstrate that radiation combined with 2010 and will be supported for another 5 years.
other trauma (such as a burn or wound) significantly alters In addition to the CMCRs, the RCP supports a number of
the course of tissue recovery and survival (Ledney and grant programs focused on topics including radiation com-
Elliott 2010; DiCarlo et al. 2008). It is also important to bined injury, immune reconstitution, gastrointestinal (GI)
consider that survivors of acute radiation exposure are at injury, radiation-induced thrombocytopenia, radiation-
risk to develop a variety of late effects, such as cataracts, induced lung injury, cutaneous radiation syndrome, under-
cardiovascular disease, tissue fibrosis, and cancer. Biodos- standing the mechanism of radiation injury, and novel de-
imetry must accurately assess the amount of radiation corporation agents. These programs to date have funded
received by an individual and must be useful during a mass nearly 60 individual projects. To help provide funding
casualty event. Thus, the signal for a putative biomarker opportunities for small businesses, a focused radiation/
must persist long enough to be measured and must be robust nuclear medical countermeasures small business innovation
enough to be detected in a population with a great amount research (SBIR) grant program was initiated in 2009 with
of genetic diversity and variability in underlying health expanded funding limits and timelines compared to tradi-
status. Decorporation agents, useful for a RDD but not a tional SBIR awards. These are more attractive to small
nuclear detonation, must be developed for a variety of ra- industry and enable companies to achieve more significant
dionuclides that constitute a realistic threat, and each has a progress and results. The success of the CMCR and grant
unique pharmacokinetic and target organ injury profile programs sponsored by NIAID is demonstrated by the fact
(Cassatt et al. 2008; Hafer 2009a, b). that multiple RCP awardees have gone on to win additional
Given that a sizable and diverse group of people may funds from the Biomedical Advanced Research and
need treatment after a large-scale radiological or nuclear Development Authority (BARDA) (BARDA 2010) and the
incident, products that address these three scientific needs Department of Defense (DoD) to support the advanced
must also be easily administered to large numbers of people, development of radiation countermeasures.
including special populations (e.g., children, pregnant Early stage product development. In addition to sponsor-
women, the elderly and immuno-compromised people). It is ing research, the RCP is also responsible for the early stage
also likely that Federal Government resources will not be product development of radiation medical countermeasures.
immediately available after a major incident, so medical In order to operate efficiently and reduce the risk and cost to
products and regimens must be effective even when they are the Federal Government, the RCP has developed a product
administered at least 24 h after radiation exposure. The RCP development support services contract to perform product
products must meet all these requirements; consequently, development tasks for specific MCM candidates in partner-
decisions on which candidate product to advance are based ship with industry. To achieve these goals, in 2005 NIAID
on the ability of the product to meet these priority needs. awarded a contract to the University of Maryland School of
Research programs. The RCP supports research and Medicine for these services (NIAID 2010; Advanced Radi-
product development through a number of funding mecha- ation Therapeutics- Radiation Injury Mitigation 2010). The
nisms and flexible approaches. Research is supported contractor, under the direction of NIAID, can perform a
through grants for basic, translational, and small business number of pre-clinical and early clinical studies with specific
research programs. The primary grant program is the Cen- MCMs to support licensure by the Food and Drug Adminis-
ters for Medical Countermeasures against Radiation tration (FDA). If a product demonstrates efficacy in initial
(CMCRs). Awarded for the first time in 2005, the eight studies, additional evaluations are performed to optimize the
CMCRs operate under a cooperative agreement and serve as dose, schedule, and route of administration. Capabilities also
an early stage research and discovery engine for the pro- exist in the contract to evaluate toxicology, pharmacology,
gram. The CMCR accomplishments over the past 5 years, and safety parameters. Manufacturing facilities capable of
detailed in the next section, include the publication of compliance with current Good Manufacturing Practice
nearly 200 papers and the submission of over 20 patents. (GMP) are available to provide formulation and stability
Rodent, canine, non-human primate (NHP), and knockout testing. Finally, the contract can support regulatory services
models of radiation injury have been developed and more to assist with the preparation of Investigational New Drug and
than 100 MCMs are currently under various stages of New Drug Application submissions.
development to mitigate/treat radiation injuries. Several Currently, the contract supports five facilities that are
investigators are developing portable and automated capable of performing Good Laboratory Practice (GLP)-
biodosimeters with promising results. The CMCRs have compliant pivotal animal efficacy studies and nonclinical
Radiological and Nuclear Terrorism 301

safety studies. Animal models for hematological and GI ARS the reversible components of both acute and late radiation-
have been developed for the mouse and NHP. Screening related and combined modality-mediated toxicity, there are
facilities have evaluated nearly 20 compounds for efficacy in still few agents ready for the strategic national stockpile
mitigating the hematological syndrome and almost 10 com- (SNS) despite efficacy in animal models. The later is largely
pounds for the GI syndrome in mice and have identified due to the inability of these agents to overcome the many
several promising candidates for further development. Four regulatory hurdles required for approval under the FDA’s
compounds have been tested for their ability to decorporate ‘‘Animal Rule’’ (Williams et al. 2010; Food and Drug
Americium-241 from rats. The RCP, through this contract, Administration, HHS 2009, 2002). More recently, however,
has assisted with one pre-Investigational New Drug appli- it has become clear that many of these agents can also
cation and two pre-Investigational Device Exemption sub- improve wound healing. Other data for some agents indicate
missions to the FDA and performed a GLP efficacy study in that they improve tumor response to radiation and/or che-
NHP for the mitigation of hematological ARS. motherapy, while also reducing radiation and combined
Collaborations. The RCP actively promotes research and modality toxicities (Mosvas et al 2010). Indeed, the
collaborates with other organizations to expand research approach of the radiation MCM effort has been to empha-
capacity. Since 2005, RCP has sponsored and participated size the potential ‘‘multi-clinical use’’ agents that have other
in almost 30 meetings related to radiation injury and indications. This approach might have the benefits of (a)
countermeasure development. One recent meeting of par- facilitating drug approval, (b) having doctors with experi-
ticular interest was sponsored by the RCP and the NCI and ence using the agents, (c) having drugs already available in
held in January 2010 (Mosvas et al. 2010). This joint hospitals and pharmacies, and (d) encouraging investment
workshop was designed to examine how compounds being in drug development by industry as it would have a rea-
developed for a radiation MCM indication might also be sonable market beyond that of government stockpiles.
developed for a radiation therapy indication (Mosvas et al. Biodosimetry technologies are also finding use in
2010). MCM development is often considered a poor oncology clinics. In local radiation treatments, the tumor is
business opportunity due to the projected low volume and the organ largely exposed to the majority of the radiation;
low margin of product sales and unpredictable need for the thus, damage detection by biodosimetry techniques are
product. This problem can be addressed by developing under investigation as markers of tumor response. Since the
products that could be used for multiple clinical indications. approaches being studied by the CMCR require turnaround
In the case of radiation countermeasures, the radiation within minutes and must be evaluable shortly after expo-
oncology market represents an additional clinical opportu- sure, these technologies have the potential for measuring
nity to reduce treatment toxicity for patients treated with tumor response within hours or days after exposure, instead
radiation therapy or radiation plus chemotherapy. of the usual long delays currently experienced clinically
The RCP has established a number of active collabora- between staging laboratory or radiographic studies and
tions with research groups inside and outside the U.S., response evaluation.
including the Radiation Effects Research Foundation The impact of supportive measures has also made
(RERF), the National Space Biomedical Research Institute important strides over the past 5 years since the CMCR
(NSBRI), the Armed Forces Radiobiology Research Institute inception. Perhaps more than any other type of mitigation or
(AFRRI), the World Health Organization (WHO), and other therapeutic intervention, supportive care to cover the usu-
institutes at NIH, including the NCI, the National Institute on ally short period of highest mortality risk can be very
Aging (NIA), and the National Institute of Diabetes and effective (Williams et al. 2010). This includes measures that
Digestive and Kidney Diseases. Additional information are easy to implement, such as dietary modification, anti-
about these programs and collaborations can be found in the biotics, and hydration, although the surge in the number of
reference section (NIAID 2010; Cassatt et al. 2010). patients will stress the healthcare system. As a result, a
second category of agents has been identified that prolongs
the median survival after otherwise lethal exposure (Wil-
5 Normal Tissue Injury Research liams et al. 2010). Such agents can allow for the time
Program-Centers for Medical needed to evacuate patients to intensive care units nation-
Countermeasures Against Radiation ally. Indications are that some antibiotic medications also
have an independent direct mitigation effect against radia-
The CMCRs have reinvigorated translational research for tion toxicity allowing them to work on two levels (Epperly
diagnostic technologies and pharmaceuticals to be used for et al. 2010; Kim et al. 2009; Xiao et al. 2006).
post-exposure mitigation of radiation injury. While these The CMCRs have put a great deal of thought into animal
centers have been very successful at increasing under- models that might best identify agents and instruments for
standing of the mechanisms of radiation toxicity, including and justify agents in the SNS (Augustine et al. 2005;
302 C. N. Coleman et al.

Williams et al. 2010). While publications developed threats, an interagency group of experts recommended the
through these workshops are not necessarily used by the use of the Special Reserve Fund, described below, autho-
FDA to approve agents, the concepts defined at those rized under Project BioShield to acquire the following
meetings provide some guidance to entities trying to additional countermeasures for the Strategic National
develop nuclear or radiological mitigation technologies. Stockpile (SNS):
The organ of interest must clearly be protected in the • A liquid form of potassium iodide (KI) that can be taken
identification of appropriate animal models. While a num- more easily than tablets by children. KI is a drug that
ber of radiation toxicities are common to multiple organs, blocks absorption of radioactive iodide in the thyroid
most injury is organ specific; thus, mitigation agents tend to gland.
be different for different organs and tend to require different • Calcium-diethylenetriaminepentaacetate (DTPA) and
schedules to be most efficacious. Therefore, mitigation and Zinc-DTPA, 2 forms of a decorporation agent which help
treatment will need cocktails of agents for the multiple remove transuranic radioactive particles from the body.
organs at risk. Along with these needs, it will be necessary • Treatments to address the neutropenia associated with
to identify technologies that assess the organ that was most ARS.
critically damaged by radiation and to be able to follow and The Secretaries of HHS and the Department of Home-
measure any organ-specific beneficial effects of the inter- land Security (DHS) jointly recommended these acquisi-
vention. The multi-clinical use application of these agents tions; the Director of the Office of Management and Budget
and technologies are obvious for the cancer clinic (Mosvas approved the purchases under delegated authority from the
et al. 2010). Figure 3 includes some of the agents currently President; and, HHS implemented these acquisition
under development through the CMCRs. programs.
Project BioShield provided unprecedented legislation to
facilitate CBRN preparedness. The law authorized HHS to
6 Product Development: Biomedical support late-stage procurement programs (8 years to licen-
Advanced Research and Development sure); in addition, it appropriated $5.6 billion in the Special
Authority Reserve Fund for fiscal years (FY) 2004–2013, facilitated
the NIH mission to develop countermeasures, and permitted
6.1 BARDA use of MCMs not yet FDA approved (under Emergency Use
Authorization). However, there were insufficient incentives
The Biomedical Advanced Research and Development to entice large pharmaceutical companies due to the risk
Authority (BARDA) (BARDA 2010) provides an inte- being placed primarily on developers. Advance payments
grated, systematic approach to the development and pur- refundable upon contract failure and insufficient support for
chase of the necessary vaccines, drugs, therapies, and advanced product development caused products to languish
diagnostic tools for public health medical emergencies. in the so-called ‘‘Valley of Death’’.
BARDA manages Project BioShield (Project Bioshield
2010), which includes the procurement and advanced
development of medical countermeasures for chemical, 6.3 Pandemic and All-Hazards
biological, radiological, and nuclear (CBRN) agents, as well Preparedness Act
as the advanced development and procurement of MCMs
for pandemic influenza and other emerging infectious dis- In 2006, the Pandemic and All-Hazards Preparedness Act
eases that fall outside the auspices of Project BioShield. In (PAHPA) (PAHPA 2010) established BARDA as the focal
addition, BARDA manages the Public Health Emergency point within HHS for the advanced development and
Medical Countermeasures Enterprise (PHEMCE) (PHEMC acquisition of MCMs to protect the American civilian
2010). population against CBRN and naturally occurring threats to
public health. Using its advanced research and development
authority, BARDA strengthens HHS efforts to bridge the
6.2 Project BioShield ‘‘Valley of Death’’ funding gap that exists between the early
stages of product development and the acquisition of
The Project BioShield Act of 2004 (Project Bioshield 2010) approved or approvable MCMs for the SNS. The PAHPA
is part of a broader strategy to defend the United States provided for the establishment of the Biodefense MCM
against weapons of mass destruction. Its purpose is to Development Fund ($1.07 billion of funding were autho-
accelerate the research, development, purchase, and avail- rized but funds were not provided, i.e. appropriated,), and
ability of effective MCMs for the adverse health effects of PAHPA authorized milestone-payments under Project
CBRN agents. In addressing radiological and nuclear BioShield (up to 50 % nonrefundable).
Radiological and Nuclear Terrorism 303

Fig. 3 Radiation mitigators under development through the CMCRs. the normal tissue toxicity. Regarding the anti-inflammatory agents, the
This is a partial list of agents that have been studied by various CMCR mechanism of this apparently contradictory effect appears to be a
as potential protection, mitigation, or therapeutic agents against reduction in inflammatory cytokines. In tumors, these cytokines
radiation. These agents generally come in classes including anti- augment tumor aggressiveness and in normal tissue they promote
inflammatory, antioxidant, antiapoptotic, and growth factors. Those deleterious normal tissue reactions. Thus, inhibition of these signaling
agents in the first two categories have commonly shown a doubly molecules after radiation benefits both processes
beneficial effect wherein tumor response to radiation is improved as is

6.4 Integrated National Biodefense Medical different missions and foci. DoD’s focus is on protecting the
Countermeasures Portfolio: Promoting armed forces prior to exposure; whereas, HHS’s focus is on
a One-Portfolio Approach response to threats to the civilian population after exposure in
a CBRN event. However, there are areas of common
Under the Integrated National Biodefense Medical Coun- requirements or interest where MCM candidates, resources,
termeasure Portfolio ‘‘One-Portfolio Approach’’, the DoD and information can be appropriately shared to maximize
and HHS each identify MCM requirements to address their opportunities for success in the development of MCMs for
304 C. N. Coleman et al.

the highest priority threats. BARDA, in partnership with 2. Under Pillar 2, HHS evaluates medical and public health
other HHS and DoD partners, is leading an Integrated consequences based on DHS scenarios. Questions to be
National Biodefense Medical Countermeasure Portfolio to answered include: How many people will require diag-
leverage resources and programs across the agencies that nostics and MCMs? What is the potential public health
develop and acquire CBRN MCMs to more effectively impact (i.e., reductions in morbidity/mortality) of exist-
address the broad range of common threats and requirements. ing or future medical countermeasures? How do
Members of this Integrated Portfolio include BARDA, NI- response times at the federal, state, and local levels affect
AID and other Institutes of NIH, and multiple elements of the MCM effectiveness?
DoD Chemical and Biological Defense Program. 3. Pillar 3 is the establishment of MCM requirements.
Integrated Portfolio objectives include: Deliverables are based on a scientific background
• Collect information and report on the overall state of the assessment in which the biochemical, epidemiological,
Integrated Portfolio CBRN MCM programs. and pathogenic characteristics of threat agents are
• Evaluate portfolio probability of success and articulate examined. A follow-on deliverable is then a scenario-
required investment. based requirement in which medical-consequence mod-
• Identify portfolio gaps and overlaps. eling defines classes and quantities of necessary MCMs.
• Develop recommendations for portfolio (‘‘Implementa- Product-specific requirements are determined next.
tion Planning’’). Minimum and desired features for individual MCM
• Implement joint portfolio oversight. products (e.g., characteristics and quantity) for devel-
• Enhance intradepartmental and interdepartmental opment and acquisition are identified. Next, a utilization
collaboration. policy is developed. This policy consists of a framework
• Build portfolio plan into budget planning. of operational policies and procedures for MCM utili-
Accomplishments to date: zation and deployment.
• DoD and HHS harmonization of a common set of 4. Pillar 4 involves determination of near-, mid-, and long-
Technology Readiness Levels (TRLs - discussed below, term development and acquisition strategies. In stage 1
Table 2) (Project BioShield 2006) to define the research (strategy), overarching guiding principles and frame-
pipeline and candidate maturity. work for priority-setting are determined. In stage 2
• An improved understanding of the expected impact of the (implementation planning), near- (FY07 - 08), mid-
FDA ‘‘Animal Rule’’ on MCM product development. (FY09 - 13), and long-term (FY14 - 23) goals for
• Mapping of pipelines for several biological threat MCMs. research, development, and acquisition of MCMs were
• Establishment by program officers of focused networks developed.
with colleagues in other agencies.
• MCM development of ‘‘projects in common’’ between
DoD and HHS and across HHS. 6.6 BARDA Radiological and Nuclear
• Approaches to portfolio integration: cost-sharing, Activities
knowledge sharing, and program sharing.
• Establishment of memorandums of understanding 6.6.1 Biodosimetry
(MOUs) between agencies to facilitate cooperation. A request for information (RFI) was issued in May 2008 in
Federal Business Opportunities for Physical and Biological
Dosimetry Techniques and Devices Useful in Initial Triage
6.5 The MCM Requirements Process after Radiologic and Nuclear Events (https://www.fbo.gov/
index?s=opportunity&mode=form&id=3e7743eb3535970
MCMs are developed and acquired in a requirements pro- 91efeb4194cb685b4&tab=core&_cview=1). In February
cess. This consists of four pillars: 2009, a Broad Agency Announcement (BAA) was issued
1. Pillar 1 is to identify and assess threats. This includes for Point of Care or High-Throughput Biological Assays for
development of Material Threat Assessments (MTAs) Determining Absorbed Ionizing Radiation Dose (Biodosi-
and Material Threat Determinations (MTDs). In the metry) After Radiologic and Nuclear Events (https://www.
former, DHS and HHS collaborate to identify and model fbo.gov/index?id=9079d4e9d8f113c4b79b8785051d69f4).
plausible, high consequence scenarios, and the number Subsequently, BARDA awarded contracts for tests and
of individuals likely to be exposed to each threat agent devices to help the nation respond to a radiological
under those scenarios. The latter are issued by the Sec- emergency. Nine contracts for the advanced research and
retary of Homeland Security for threat agents deemed to development of more effective tests and devices to
pose a material threat to national security; these are determine the level of radiation a person has absorbed
necessary for Project BioShield acquisitions. after a nuclear or radiological incident were awarded. The
Radiological and Nuclear Terrorism 305

Table 2 Technology Readiness Levels (TRLs) For Medical Countermeasure Products (Drugs And Biologics)a,b. Based on October 2004 DOD
Medical TRLs and May 2008 HHS PHEMCE TRLs
TRL 1 Review of scientific knowledge Base
Active monitoring of scientific knowledge base. Scientific findings are reviewed and assessed as a foundation for characterizing new
technologies
TRL 2 Development of hypotheses and experimental designs
Scientific ‘‘paper studies’’ to generate research ideas, hypotheses, and experimental designs for addressing related scientific issues.
Focus on practical applications based on basic principles observed. Use of computer simulation or other virtual platforms to test
hypotheses
TRL 3 Target/Candidate identification and characterization of preliminary candidate(s)
Begin research, data collection, and analysis in order to test hypothesis. Explore alternative concepts, identify and evaluate critical
technologies and components, and begin characterization of candidate(s). Preliminary efficacy demonstrated in vivo
3A Identify target and/or candidate
3B Demonstrate in vitro activity of candidate(s) to counteract the effects of the threat agent
3C Generate preliminary in vivo proof-of-concept efficacy data (non-Good Laboratory Practice (GLP))
TRL 4 Candidate optimization and non-GLP in vivo demonstration of activity and efficacy
Integration of critical technologies for candidate development. Initiation of animal model development. Non-GLP in vivo toxicity
and efficacy demonstration in accordance with the product’s intended use. Initiation of experiments to identify markers, correlates of
protection, assays, and endpoints for further nonclinical and clinical studies
Animal models. Initiate development of appropriate and relevant animal model(s) for the desired indications
Assays. Initiate development of appropriate and relevant assays and associated reagents for the desired indications
Manufacturing. Manufacture laboratory-scale (i.e., non-GMP (Good Manufacturing Practice)) quantities of bulk product and
proposed formulated product
4A Demonstrate non-GLP in vivo activity and potential for efficacy consistent with the product’s intended use (i.e., dose, schedule,
duration, route of administration, and route of threat agent challenge)
4B Conduct initial non-GLP toxicity studies and determine pharmacodynamics and pharmacokinetics and/or immune response in
appropriate animal models (as applicable)
4C Initiate experiments to determine assays, parameters, surrogate markers, correlates of protection, and endpoints to be used during
nonclinical and clinical studies to further evaluate and characterize candidate(s)
TRL 5 Advanced characterization of candidate and initiation of GMP process development
Continue non-GLP in vivo studies and animal model and assay development. Establish draft Target Product Profiles. Develop a
scalable and reproducible manufacturing process amenable to GMP
Animal models. Continue development of animal models for efficacy and dose-ranging studies
Assays. Initiate development of in-process assays and analytical methods for product characterization and release, including
assessments of potency, purity, identity, strength, sterility, and quality as appropriate
Manufacturing. Initiate process development for small-scale manufacturing amenable to GMP
Target product profile. Draft preliminary Target Product Profile. Questions of shelf life, storage conditions, and packaging should be
considered to ensure that anticipated use of the product is consistent with the intended use for which approval will be sought from
FDA
5A Demonstrate acceptable Absorption, Distribution, Metabolism and Elimination characteristics and/or immune responses in non-
GLP animal studies as necessary for IND filing
5B Continue establishing correlates of protection, endpoints, and/or surrogate markers for efficacy for use in future GLP studies in
animal models. Identify minimally effective dose to facilitate determination of ‘‘humanized’’ dose once clinical data are obtained
TRL GMP pilot lot production, IND submission, and phase 1 clinical trial(s)
6 Manufacture GMP-compliant pilot lots. Prepare and submit Investigational New Drug (IND) package to FDA and conduct Phase 1
clinical trial(s) to determine the safety and pharmacokinetics of the clinical test article
Animal models. Continue animal model development via toxicology, pharmacology, and immunogenicity studies
Assays. Qualify assays for manufacturing quality control and immunogenicity, if applicable
Manufacturing. Manufacture, release, and conduct stability testing of GMP-compliant bulk and formulated product in support of the
IND and clinical trial(s)
Target Product Profile. Update target product profile as appropriate.
6A Conduct GLP nonclinical studies for toxicology, pharmacology, and immunogenicity as appropriate
6B Prepare and submit full IND package to FDA to support initial clinical trial(s)
6C Complete phase 1 clinical trial(s) that establish an initial safety, pharmacokinetics, and immunogenicity assessment as appropriate
TRL 7 Scale-up, initiation of GMP process validation, and phase 2 clinical 3
Trial(s) Scale-up and initiate validation of GMP manufacturing process Conduct animal efficacy studies as appropriate.d Conduct
Phase 2 clinical trial(s)c
Animal models. Refine animal model development in preparation for pivotal GLP animal efficacy
Assays. Validate assays for manufacturing quality control and immunogenicity if applicable
Manufacturing. Scale-up and validate GMP manufacturing process at a scale compatible with USG requirements. Begin stability
studies of the GMP product in a formulation, dosage form, and container consistent with Target Product Profile. Initiate
manufacturing process validation and consistency lot production
Product profile. Update target product profile as appropriate
7A Conduct GLP animal efficacy studies as appropriate for the product at this staged
7B Complete expanded clinical safety trials as appropriate for the product (e.g., Phase 2)c
(continued)
306 C. N. Coleman et al.

Table 2 (continued)
TRL 8 Completion of GMP validation and consistency lot manufacturing, pivotal animal efficacy studies or clinical trials 3, and FDA
approval or licensure
Finalize GMP manufacturing process. Complete pivotal animal efficacy studies or clinical trials (e.g., Phase 3), and/or expanded
clinical safety trials as appropriate. Prepare and submit NDA/BLA
Manufacturing. Complete validation and manufacturing of consistency lots at a scale compatible with USG requirements. Complete
stability studies in support of label expiry dating
Target product profile. Finalize target product profile in preparation for FDA approval
8A Complete pivotal GLP animal efficacy studies or pivotal clinical trials (e.g., Phase 3) and any additional expanded clinical safety
trials as appropriate for the productc
8B Prepare and submit New Drug Application (NDA) or Biologics Licensing Application (BLA) to the FDA.
8C Obtain FDA approval or licensure
TRL 9 Post-Licensure and post-approval activities
9A Commence post-licensure/post-approval and phase 4 studies (post-marketing commitments), such as safety surveillance, studies
to support use in special populations, and clinical trials to confirm safety and efficacy as feasible and appropriatee
9B Maintain manufacturing capability as appropriate
Note When using these criteria, a medical countermeasure product should be rated at a particular level only after the sponsor has completed all
activities listed in that level (e.g., a product is rated at TRL 4 once it completes all of the activities listed in TRL 4)
a
This document is designed for evaluating the maturity of medical countermeasure development programs. For a detailed description of
development processes for assays and animal models, please consult the Technology Readiness Levels for Product Development Tools (PDTs),
developed by the PDT Working Group of the HHS Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) and available at
http://www.medicalcountermeasures.gov
b
This document does not serve as official FDA Guidance nor does it represent FDA’s current thinking on this topic. For the purposes of a
regulatory application seeking licensure or approval for a specific medical product, additional data may be required by FDA
c
Identification of later regulatory stages of clinical development in this document (e.g., Phase 2, Phase 3) may not apply to some products being
developed under the ‘‘Animal Rule.’’ Other than human safety studies, no additional clinical data may be feasible or ethical to obtain. For
additional information on the ‘‘Animal Rule,’’ please see http://www.fda.gov/OHRMS/DOCKETS/98fr/053102a.htm
d
These could include GLP animal efficacy studies required by the FDA at this stage in support of an Emergency Use Authorization (EUA). The
scientific evidence required for issuance of an EUA will be handled on a case-by-case basis and will depend on, among other things, the nature
and extent of the threat at any point during the product development timeline, from the initiation of Phase 1 studies through licensure or approval.
GLP animal efficacy study requirements may also vary by product type (e.g., vaccine, therapeutic, prophylactic) and U.S. government agency
program office
e
For products approved under the ‘‘Animal Rule,’’ confirmatory efficacy data are required, if such studies are feasible and ethical, and may be
obtained from use during an event

contracts total $35 million for the initial phase and up to and Thrombocytopenia Associated with the Acute Radiation
$400 million over 5 years (names of awardees available Syndrome (ARS) (http://grants.nih.gov/grants/guide/notice-
on BARDA website) (BARDA 2010). files/not-ai-05-007.html). A sources sought notice (SSN) for
Each contract awardee identified particular physical or Therapeutics Applicable for the Treatment of Neutropenia
biological characteristics, known as biomarkers, of radiation Resulting from Exposure to Ionizing Radiation (https://
dose to help health care responders determine the most www.fbo.gov/index?s=opportunity&mode=form&tab=core
appropriate treatment. In the first year of the contract, the &id=13c9de1649a4a12754124bd0e5cf02ee&_cview=1)
contractors conduct tests of the accuracy of the biomarkers as was issued in May 2007. A Request for Application (RFA)
an indicator for the level of absorbed radiation and determine for BARDA/NIAID Medical Countermeasures to Mitigate
if their proposed devices measure these biomarkers effec- and/or Treat Ionizing Radiation-Induced Pulmonary Injury:
tively. If successful, the contractors develop prototypes of Project Bioshield (http://grants.nih.gov/grants/guide/rfa-
portable devices that can be used in the field by responders. files/rfa-ai-07-040.html) was issued in December 2007 and
These are developed under the U.S. Food and Drug Admin- a Request for Proposal (RFP) for Advanced Therapeutics
istration (FDA) Investigational Device Exemption process for Treating Neutropenia Resulting from Acute Exposure to
that allows the devices to be used in a clinical study to collect Ionizing Radiation (https://www.fbo.gov/index?id=7d5aae
safety and effectiveness data required to support a premarket 491592d213faf9489aaceab5eb) was posted in March 2009.
approval application or a premarket notification submission One or more contract awards are pending.
to FDA. If the products are approved by the FDA in future A BAA was posted in 2008 for Therapies for Hematopoi-
years, the products may become eligible for consideration etic Syndrome, Bone Marrow Stromal Cell Loss, And Vascular
and procurement by the U.S. government. Injury Resulting From Acute Exposure to Ionizing Radiation (
https://www.fbo.gov/index?s=opportunity&mode=form&id=
6.6.2 Acute Radiation Syndrome a8f8740158d15c32d4f9f4a8defdfcb2&tab=core&_cview=1).
In October 2004 and May 2005, Requests for Information Over $20 Million was awarded to seven respondents in Sep-
(RFIs) were issued for Therapeutics to Treat Neutropenia tember 2008. The BAA targeted the following 3 R & D areas:
Radiological and Nuclear Terrorism 307

1. Area 1 was for the development of MCMs that can 6.6.5 BARDA Animal Model Development RFI-
replenish the normal hematopoietic profile, in whole or BARDA-2010-Animal Models-001
in part (i.e., treat neutropenia, lymphopenia, and Under this RFI, the USG is seeking appropriate facilities
thrombocytopenia), following acute radiation exposure that are adequate and available to develop new animal tests
that induces lethal hematopoietic dysfunction. or models and also update existing animal tests or models
2. Area 2 targeted the development of MCMs to replenish that are accepted by FDA (https://www.fbo.gov/index?s=
bone marrow niche and progenitor cells that normally opportunity&mode=form&id=399f56eafb7b181ff66327e21
populate the bone marrow stroma and niche environ- 34e34fe&tab=core&_cview=0). Laboratories that can con-
ments and that can restore normal functioning hemato- duct pilot studies to establish the natural history of selected
poietic cell lineages following acute exposure to ionizing CBRN agents in appropriate animal species are included.
radiation that induces lethal hematopoietic dysfunction. Also of interest are laboratories that can perform efficacy
3. Area 3 aimed at the development of MCMs that address evaluations in various species on candidate compounds.
injury to the vascular system induced following acute BARDA is seeking laboratories that can provide analytical
exposure to ionizing radiation, including changes in support to monitor the progression of the disease in animal
intimal integrity and clotting propensity, macrophage models and demonstrate prospective correlates of protec-
repair mechanisms and trafficking, vascular leak, endo- tion. Finally, BARDA seeks laboratories with the capability
thelial repair, endovascular surface chemistry, alteration to perform radiation exposure studies using Cs-137, Co-60,
of angiogenesis, and other changes in anatomical or Linear Accelerator (LINAC), X-ray, or other accepted
molecular pathology. instrumentation for controlled exposures of animals to
lethal radiation within the constraint of acceptable dose
6.6.3 Chronic Effects of Radiation Exposure rates and with uniform field flux and field sizes for both
BARDA awarded a contract for a Pediatric Formulation large and small animals.
(Liquid) Potassium Iodide (KI) in March 2005 and a contract
for acquisition of Calcium and Zinc Diethylenetriamine-
pentaacetate (Ca DTPA and Zn DTPA) in December 2005. 6.6.6 Continuum between BARDA and NIAID
The experience with the initial efforts in Project Bioshield
6.6.4 Rolling BAA (Project Bioshield 2010) demonstrated that translational
BARDA has reissued a long-range BAA: (BARDA-CBRN- science, typically interpreted as bench to bedside and back,
BAA-10-100-SOL-00012) (https://www.fbo.gov/index?id= required a component of technology transfer to be suc-
c1d5b56d7a9026456191e372b856f469) to identify innova- cessful. There are few if any customers or demand for
tive and promising MCM technologies for advanced radiological and nuclear terrorism products other than the
development across several CBRN Research Areas. The government; thus, there is little incentive for major phar-
focus is on TRLs 5–7 (pre-IND to Phase 2) (https://www. maceutical companies to enter the business of creating
fbo.gov/index?s=opportunity&mode=form&id=3e7743eb expensive and hard-to-test terrorism products. The CMCR
353597091efeb4194cb685b4&tab=core&_cview=1) in the and related grantees funded by NIAID were found to be
following areas: fertile breeding places for the identification of mechanisms
• Vaccines and example products but were not sufficiently large or
• Antitoxins and Therapeutics focused enough for commercialization. Since BARDA
• Antimicrobial Drugs funds advanced research required to reach a commerciali-
• Radiological/Nuclear Threat Countermeasures zation stage, it was able to fill the gap between the research
• Chemical Threat Countermeasures funded by NIAID and that required for regulatory approval
• Diagnostics. and commercialization.
The BAA application is a two stage process. The initial The rigorous distinction between NIAID- and BARDA-
stage involves submission of a 5–15 page white paper/quad funded efforts are usually based on TRLs that range from
chart that is reviewed for BARDA program relevance, the most basic level 1 to a final level of FDA approval in
technical merit, and capabilities. Within 90 days, BARDA level 9 (Table 2) (Project BioShield 2006). BARDA funds
provides specific technical feedback to the offeror if the TRLs that are typically higher than those supported by the
white paper/quad chart is deemed acceptable. If acceptable, CMCRs and NIAID. The focus of BARDA is to oversee the
the offeror will receive an invitation letter to submit a full steps and help guide the studies needed to create a product
proposal based on technical guidance provided by BARDA. of interest to the government with FDA approval.
The second stage of the BAA process involves submission Figure 4 illustrates the continuum of effort among the
of a full proposal (technical and cost) based on guidance federal agencies ranging from basic science to translational
provided by BARDA. work to product development and implementation.
308 C. N. Coleman et al.

Fig. 4 Continuum of product

development by the Federal
agencies. The funding for MCM
and biodosimetric development
comes from several different
funding streams. It builds on the
research and development of NIH
and other agencies, such as the
Department of Energy (DOE),
the Department of Defense
(DoD), and the Defense
Advanced Research Products
Agency (DARPA)

Fig. 5 Medical
countermeasures and diagnostics
for medical response to a nuclear
detonation. A typical scenario
after a radiation event will
include a triage stage (best if
within 1–2 days), wherein
identification of individuals who
might have had significant
radiation exposure are identified.
These individuals will likely be
offered a dose of the appropriate
growth factor until validation of
their exposure is obtained. They
will be followed with more
detailed biodosimetry and
supportive and mitigative care.
At present, the gold standard
biodosimetry remains
cytogenetics, which will be
available later for
epidemiological study

normal tissue radiation biology; (b) the description of new

7 Conclusions mechanisms of injury, including inflammation; (c) the
inclusion of late toxicity into clinical toxicity criteria for
Over the last 6–7 years, there has been substantial progress in cancer care (Common Toxicity Criteria for Adverse Events,
the organization of the medical response to a nuclear/radio- or CTCAE and now Patient Related Outcomes- PRO-
logical incident built on (a) a resurgence in the interest in CTCAE) (https://www.fbo.gov/index?s=opportunity&mode
Radiological and Nuclear Terrorism 309

=form&id=3e7743eb353597091efeb4194cb685b4&tab= Buddemeier BR, Dillion MB (2010) Key response planning factors for
core&_cview=1); (d) programs developed through NI- the aftermath of a nuclear detonation. LLNL-TR-410067.
http://www.remm.nlm.gov/IND_ResponsePlanning_LLNL-TR-
AID, BARDA, AFRRI, NCI, and others; and (e) the 410067.pdf. Accessed 07 May 2010
‘‘multi-clinical use’’ concept whereby technologies and Cassatt DR, Kaminski JM, Hatchett RJ, DiCarlo AL, Benjamin JM,
medicines that are used to treat injuries caused by ter- Maidment BW (2008) Medical countermeasures against nuclear
rorism are also used in day-to-day medical care. Figure 5 threats: radionuclide decorporation agents. Radiat Res 170:
540–548
illustrates how the ongoing research and development can Coleman CN, Parker GW (2009) Radiation terrorism: what society
impact the current state of the art. needs from the radiobiology-radiation protection and radiation
There are tools available for those involved in medical oncology communities. J Radiol Prot 29(2A):A159-69
response preparedness and planning, including REMM Coleman CN, Blakely WF, Fike JR, MacVittie TJ, Metting NF,
Mitchell JB et al (2003) Molecular and cellular biology of
(REMM 2010), the Planning Guidance (Homeland Security moderate-dose (1–10 Gy) radiation and potential mechanisms of
Council 2010), and the Scare Resources project soon to be radiation protection: report of a workshop at Bethesda, Maryland,
published (Coleman, personal communication). Those December 17–18. Radiat Res 159(6):812–834
interested in these areas of research can find information on Coleman CN, Stone HB, Alexander GA, Barcellos-Hoff MH, Bedford
JS, Bristow RG et al (2003) Education and training for radiation
the websites noted in this chapter. There are substantial scientists: radiation research program and American Society of
opportunities for research and development, community Therapeutic Radiology and Oncology Workshop, Bethesda, Mary-
participation, public communication and education, and land, May 12–14. Radiat Res 160(6):729–737
recruitment/retention of talented people to assist in the Coleman CN, Hrdina C, Bader JL, Norwood A, Hayhurst R, Forsha J
et al (2009) Medical response to a radiologic/nuclear event:
science, policy, and clinical application of these advances integrated plan from the office of the assistant secretary for
for both terrorism preparedness and spin-off benefits to preparedness and response, Department of Health and Human
cancer care. Services. Ann Emerg Med 53(2):213–222
Coleman CN, Knebel AR, Hick JL, Weinstock DM, Casagrande R,
Jaime Caro J, DeRenzo EG, Dodgen D, Norwood AE, Sherman SE,
Cliffer KD, McNally R, Bader JL, Murrain-Hill P (2011) Scarce
References resources for nuclear detonation: project overview and challenges.
Disaster Med Public Health Preparedness (Suppl 1):13–19
Dainiak N, Waselenko JK, Armitage JO, MacVittie TJ, Farese AM
AFRRI (2008) AFRRI emergency radiation medicine pocket guide.
(2003) The hematologist and radiation casualties. Hematology/the
http://www.afrri.usuhs.mil/outreach/pdf/AFRRI-Pocket-Guide.pdf.
Education Program of the American Society of Hematology,
Accessed 07 May 2010
pp 473–496
Advanced Radiation Therapeutics- Radiation Injury Mitigation (2010).
Davids MS, Case C Jr, Hornung R 3rd, Chao NJ, Chute JP, Coleman
National Cancer Institute and the National Institute of Allergy and
CN, Weisdorf D, Confer DL, Weinstock DM (2010) Assessing
Infectious Disease. http://www3.cancer.gov/rrp/workshop_2010/
surge capacity for radiation victims with marrow toxicity. Biol
rrp_workshop.pdf. Accessed 07 May 2010
Blood Marrow Transplant. [Epub ahead of print]
Ainsbury EA, Livingston GK, Abbott MG, Moquet JE, Hone PA,
Demidenko E, Williams BB, Swartz HM (2009) Radiation dose
Jenkins MS, Christensen DM, Lloyd DC, Rothkamm K (2009)
prediction using data on time to emesis in the case of nuclear
Interlaboratory variation in scoring dicentric chromosomes in a
terrorism. Radiat Res 171(3):310–319
case of partial-body X-ray exposure: implications for biodosimetry
DiCarlo AL, Hatchett RJ, Kaminski JM, Ledney GD, Pellmar TC,
networking and cytogenetic ‘‘triage mode’’ scoring. Radiat Res
Okunieff P, Ramakrishnan N (2008) Medical countermeasures for
172(6):746–752
radiation combined injury: radiation with burn, blast, trauma and/or
Armed Forces Radiobiology Research Institute (AFRRI), US Depart-
sepsis. Report of an NIAID Workshop, 26–27 March 2007. Radiat
ment of Defense AFRRI (2009) Medical Management of Radio-
Res 169:712–721
logical Casualties, 3rd edn. http://www.afrri.usuhs.mil/outreach/
Dicky JS, Redon CE, Nakumara AJ, Baird BJ, Sedelnikova OA,
pdf/2edmmrchandbook.pdf. Accessed 07 May 2010
Bonner WM (2009) H2AX: Functional roles and potential
Augustine AD, Gondre-Lewis T, McBride W, Miller L, Pellmar TC,
applications. Chromosoma 118:683–692
Rockwell S (2005) Animal models for radiation injury, protection
Epperly MW, Franicola D, Shields D, Rwigema JC, Stone B, Zhang X,
and therapy. Radiat Res 164(1):100–109
McBride W, Georges G, Wipf P, Greenberger JS (2010) Screening
Bennder MA, Gooch PC (1966) Somatic chromosome aberrations
of antimicrobial agents for in vitro radiation protection and
induced by human whole-body irradiation: The ‘‘Recuplex’’
mitigation capacity, including those used in supportive care
criticality accident. Radiat Res 18:389–396
regimens for bone marrow transplant recipients. In Vivo 24(1):9–19
Biomedical Advanced Research and Development Authority
Fenech M (2007) Cytokinesis-block micronucleus cytome assay. Nat
(BARDA). Available at: http://www.hhs.gov/aspr/barda/index.
Protoc 2:1084–1104
html. Accessed 14 May 2010
Fliedner TM (2006) Nuclear terrorism: the role of hematology in
Blakely WF, Carr Z, Chu MC, Dayal-Drager R, Fujimoto K, Hopmeir
coping with its health consequences. Curr Opin Hematol
M et al (2009) WHO 1st consultation on the development of a
13(6):436–444
global biodosimetry laboratories network for radiation emergencies
Fliedner TM, Friesecke I, Beyrer K. Medical management of radiation
(BioDoseNet). Radiat Res 171(1):127–139
accidents: manual on the acute radiation syndrome. (METREPOL)
Blakely WF, Ossetrova NI, Whitnall MH, Sandgren DJ, Krivokry-
http://vts.uni-ulm.de/docs/2009/6891/vts_6891_9572.pdf Compen-
senko VI, Shakhov A et al (2010) Multiple parameter radiation
dium to the main METREPOL document http://vts.uni-ulm.de/
injury assessment using a nonhuman primate radiation model-
docs/2009/6891/vts_6891_9573.pdf Accessed 07 May 2010
biodosimetry applications. Health Phys 98(2):153–159
310 C. N. Coleman et al.

Fliedner TM, Chao NJ, Bader JL, Boettger A, Case C Jr, Chute J, Confer International Atomic Energy Agency (2001) Cytogenetic analysis for
DL, Ganser A, Gorin NC, Gourmelon P, Graessle DH, Krawisz R, radiation dose assessment: a manual. Technical Report Series No
Meineke V, Niederwieser D, Port M, Powles R, Sirohi B, Weinstock 405, IAEA, Vienna, Austria
DM, Wiley A, Coleman CN (2009) Stem cells, multiorgan failure in Institute of Medicine (IOM) (2009) Guidance for establishing crisis
radiation emergency medical preparedness: a U.S./European Con- standards of care for use in disaster situations http://www.iom.
sultation Workshop. Stem Cells 27(5):1205–1211 edu/Reports/2009/DisasterCareStandards.aspx. Accessed 07 May
Food and Drug Administration, HHS (2002) New drug and biological 2010
drug products; evidence needed to demonstrate effectiveness of ISO (2004) Radiation protection—performance criteria for service
new drugs when human efficacy studies are not ethical or feasible. laboratories performing biological dosimetry by cytogenetics, ISO
http://www.fda.gov/OHRMS/DOCKETS/98fr/053102a.htm. 19238. International Standardization Organization, Geneva
Accessed 10 May 2010 Ivanov VK, Chekin SY, Kashcheev VV, Maksioutov MA, Tumanov
Food and Drug Administration, HHS (2009, January) Guidance for KA (2008) Risk of thyroid cancer among chernobyl emergency
industry: animal models—essential elements to address efficacy workers of Russia. Radiat Environ Biophys 47(4):463–467
under the animal rule. http://www.fda.gov/downloads/Drugs/ Kim K, Pollard JM, Norris AJ, McDonald JT, Sun Y, Micewicz E,
GuidanceComplianceRegulatoryInformation/Guidances/UCM Pettijohn K, Damoiseaux R, Iwamoto KS, Sayre JW, Price BD,
078923.pdf. Accessed 10 May 2010 Gatti RA, McBride WH (2009) High-throughput screening iden-
Grace MB, Moyer BR, Prasher J, Cliffer KD, Ramakrishnan N, tifies two classes of antibiotics as radioprotectors: tetracyclines and
Kaminski J, Coleman CN, Manning RG, Maidment BW, Hatchett fluoroquinolones. Clin Cancer Res 15(23):7238–7245
R (2010) Rapid radiation dose assessment for radiological public Koenig KL, Goans RE, Hatchett RJ, Mettler FA Jr, Schumacher TA,
health emergencies: roles of NIAID and BARDA. Health Phys Noji EK et al (2005) Medical treatment of radiological casualties:
98(2):172–178 current concepts. Ann Emerg Med 45(6):643–652
Hafer, N. Cassatt, D, DiCarlo, A, Ramakrishnan, N, Kaminski, J, Ledney GD, Elliott TB (2010) Combined injury: factors with potential
Norman,M-K, Maidment, B and Hatchett, R. (2010) NIAID/NIH to impact radiation dose assessments. Health Phys 98:145–152
radiation/nuclear medical countermeasures product research and Lerner EB, Schwartz RB, Coule PL, Weinstein ES, Cone DC, Hunt
development program. Health Phys J 98(6):903–905 RC, Sasser SM, Liu JM, Nudell NG, Wedmore IS, Hammond J,
Hafer N (2009a) Radionuclide medical countermeasures development Bulger EM, Salomone JP, Sanddal TL, Markenson D, O’Connor
programs. Paper presented at tenth international meeting on the RE (2008) Mass casualty triage: an evaluation of the data and
conference on the health effects of incorporated radionuclides. May development of a proposed national guideline. Disaster Medicine
10–14, 2009. http://www.lrri.org/heir/Program/HEIR/Presentations/ and Public Health Preparedness 2:S25–S34
Tuesday/11%20-%20Tue%20-%201340%20-%20HaferNathaniel Little MP (2009) Cancer and non-cancer effects in Japanese atomic
24421.pdf. Accessed 07 May 2010 bomb survivors. J Radiol Prot 29(2A):A43–59
Hafer N (2009b) NIH/NIAID radionuclide decorporation agent Lloyd DC (1997) Chromosomal analysis to assess radiation dose. Stem
development program. Nov 5, 2009. Paper presented at: GHSI Cells 15(Suppl. 2):195–201
public health emergency medical countermeasures workshop. Martin PR, Berdechevsky RE, Subramanian U, Blakely WF, Prasanna
http://www.blsmeetings.net/2009GHSImeetingsmcm/ PGS (2007) Sample tracking in an automated cytogenetic biodos-
presentations/RadNuc/Hafer-GHSIpresentationFINAL.pdf. Acces- imetry laboratory for radiation mass casualties. Radiat Meas
sed 07 May 2010 42:1119–1124
Homeland Security Council Interagency Policy Coordination Sub- Mettler FA Jr, Gus’kova AK, Gusev I (2007) Health effects in those
committee for Preparedness and Response to Radiological and with acute radiation sickness from the chernobyl accident. Health
Nuclear Threats (2010). Planning guidance for response to a Phys 93(5):462–469
nuclear detonation. http://www.whitehouse.gov/files/documents/ Miller SM, Ferrarotto CL, Vlahovich S, Wilkins RC, Boreham DR,
ostp/press_release_files/Planning%20Guidance%20for%20Nuclear Dolling JA (2007) Canadian cytogenetic emergency network
%20Detonation%20Response.pdf. Accessed 07 May 2010 (CEN) for biological dosimetry following radiological/nuclear
Hrdina CM, Coleman CN, Bogucki S, Bader JL, Hayhurst RE, Forsha accidents. Int J Radiat Biol 83:353–361
JD et al (2009) The ‘‘RTR’’ medical response system for nuclear Mosvas B et al. (2010) Decreasing the adverse effects of cancer
and radiological mass-casualty incidents: a functional TRiage- therapy: National Cancer Institute Guidance for the Clinical
TReatment-TRansport medical response model. Prehosp Disaster Development of Radiation Injury Mitigators (submitted).
Med 24(3):167–178 Advanced radiation therapeutics-radiation injury mitigation.
https://www.fbo.gov/index?id=7d5aae491592d213faf9489aaceab5eb http://www3.cancer.gov/rrp/workshop_2010/rrp_workshop.pdf.
https://www.fbo.gov/index?id=c1d5b56d7a9026456191e372b856f469 Accessed 07 May 2010
https://www.fbo.gov/index?s=opportunity&mode=form&id=399f56 NIAID-National Institute of Allergy and Infectious Diseases, (2010)
eafb7b181ff66327e2134e34fe&tab=core&_cview=0 Medical countermeasures against radiological and nuclear threats.
https://www.fbo.gov/index?s=opportunity&mode=form&tab=core&id Available at:
=13c9de1649a4a12754124bd0e5cf02ee&_cview=1 http://www.niaid.nih.gov/topics/radnuc/Pages/default.aspx. Acces-
https://www.fbo.gov/index?s=opportunity&mode=form&id=3e7743 sed 07 May 2010
eb353597091efeb4194cb685b4&tab=core&_cview=1 National Institutes of Health (2005). NIH Strategic Plan and
https://www.fbo.gov/index?id=9079d4e9d8f113c4b79b8785051d69f4 Research Agenda for medical countermeasures against radiolog-
http://grants.nih.gov/grants/guide/notice-files/not-ai-05-007.html ical and nuclear threats (online). Washington, DC: U.S. Depart-
http://grants.nih.gov/grants/guide/rfa-files/rfa-ai-07-040.html ment of Health and Human Services; NIH Publication No. 05-
https://www.fbo.gov/index?s=opportunity&mode=form&id=a8f8740 5608; 2005. Available at: http://www.niaid.nih.gov/about/whoWe
158d15c32d4f9f4a8defdfcb2&tab=core&_cview=1 Are/Documents/radnucstrategicplan.pdf. Accessed 14 May 2010
IAEA (2002) Use of electron paramagnetic resonance dosimetry with Ossetrova NI, Blakely WF (2009) Multiple blood-proteins approach
tooth enamel for retrospective dose assessment. TECDOC-1331, for early-response exposure assessment using an in vivo murine
IAEA, Vienna, Austria radiation model. Int J Radiat Biol 85(10):837–850
Radiological and Nuclear Terrorism 311

Ossetrova NI, Sandgren DJ, Gallego S, Blakely WF (2010) Combined Sevankaev AV (2000) Results of cytogenetic studies of the conse-
approach of hematological biomarkers and plasma protein SAA for quences of the chernobyl accident. Radiat Biol Radioecol
improvement of radiation dose assessment triage in biodosimetry 40:589–595
applications. Health Phys 98(2):204–208 Stone HB, McBride WH, Coleman CN (2002) Modifying normal
Office of the Assistant Secretary for Preparedness and Response tissue damage postirradiation. Report of a workshop sponsored by
(ASPR) (2010). http://www.hhs.gov/aspr/. Accessed 07 May 2010 the radiation research program, National Cancer Institute,
Pandemic and All-Hazards Preparedness Act (PAHPA). http://www. Bethesda, Maryland, Sept 6–8 2000. Radiat Res 157(2):204–223
hhs.gov/aspr/opsp/pahpa/index.html. Accessed 07 May 2010 Stone HB, Moulder JE, Coleman CN, Ang KK, Anscher MS,
Patient-Reported Outcomes Version of the Common Terminology Barcellos-Hoff MH et al (2004) Models for evaluating agents
Criteria for Adverse Events (PRO-CTCAE). http://outcomes. intended for the prophylaxis, mitigation and treatment of radiation
cancer.gov/tools/pro-ctcae.html. Accessed 07 May 2010 injuries. Report of an NCI Workshop, Dec 3–4 2003. Radiat Res
Pellmar TC, Rockwell S (2005) Priority list of research areas for 162(6):711–728
radiological nuclear threat countermeasures. Radiat Res 163(1): Suit H, Goldberg S, Niemierko A, Ancukiewicz M, Hall E, Goitein M
115–123 et al (2007) Secondary carcinogenesis in patients treated with
PHEMC,(2010) Public health emergency medical countermeasures radiation: a review of data on radiation-induced cancers in human,
(PHEMC) enterprise. http://www.hhs.gov/aspr/barda/phemce/ non-human primate, canine and rodent subjects. Radiat Res
index.html. Accessed 07 May 2010 167(1):12–42
Prasanna PGS, Escalada ND, Blakely WF (2000) Induction of Trompier F, Kornak L, Calas C, Romanyuka A, Leblanc B, Mitchell
premature chromosome condensation by a phosphatase inhibitor CA, Swartz HM, Clairand I (2007) Protocol for emergency EPR
and a protein kinase in unstimulated human peripheral blood dosimetry in fingernails. Radiat Meas 42:1085–1088
lymphocytes: a simple and rapid technique to study chromosome US DHHS. Agency for Healthcare Research and Quality (AHRQ)
aberrations using specific DNA hybridization probes for biological (2007) Mass medical care with scarce resources: a community
dosimetry. Mutat Res 466:131–141 guide. http://www.ahrq.gov/research/mce/mceguide.pdf. Accessed
Prasanna PGS, Moroni M, Pellmar TC (2010a) Triage dose assessment 07 May 2010
for partial-body exposure: dicentric analysis. Health Phys 98: Waselenko JK, MacVittie TJ, Blakely WF, Pesik N, Wiley AL,
244–251 Dickerson WE et al (2004) Medical management of the acute
Prasanna PG, Blakely WF, Bertho JM, Chute JP, Cohen EP, Goans radiation syndrome: recommendations of the strategic national
RE, Grace MB, Lillis-Hearne PK, Lloyd DC, Lutgens LC, Meineke stockpile radiation working Group. Ann Intern Med
V, Ossetrova NI, Romanyukha A, Saba JD, Weisdorf DJ, Wojcik 140(12):1037–1051
A, Yukihara EG, Pellmar TC (2010b) Synopsis of partial-body Weinstock DM, Case C Jr, Bader JL, Chao NJ, Coleman CN, Hatchett
radiation diagnostic biomarkers and medical management of RJ et al (2008) Radiologic and nuclear events: contingency
radiation injury workshop. Radiat Res 173(2):245–253 planning for hematologists/oncologists. Blood 111(12):5440–5445
Preston DL, Ron E, Tokuoka S, Funamoto S, Nishi N, Soda M et al Weisdorf D, Chao N, Waselenko JK, Dainiak N, Armitage JO,
(2007) Solid cancer incidence in atomic bomb survivors: McNiece I et al (2006) Acute radiation injury: contingency
1958–1998. Radiat Res 168(1):1–64 planning for triage, supportive care, and transplantation. Biol
Preston DL, Cullings H, Suyama A, Funamoto S, Nishi N, Soda M Blood Marrow Transplant 12(6):672–682
et al (2008) Solid cancer incidence in atomic bomb survivors Williams JP, Brown SL, Georges GE, Hauer-Jensen M, Hill RP, Huser
exposed in utero or as young children. J Natl Cancer Inst AK, Kirsch DG, Macvittie TJ, Mason KA, Medhora MM, Moulder
100(6):428–436 JE, Okunieff P, Otterson MF, Robbins ME, Smathers JB, McBride
Project Bioshield. http://www.hhs.gov/aspr/barda/bioshield/index.html WH (2010) Animal models for medical countermeasures to
. Accessed 07 May 2010 radiation exposure. Radiat Res 173(4):557–578
Project BioShield: Annual Report to Congress (2006–2007) Wilkins RC, Romm H, Kao TC, Awa AA, Yoshida MA, Livingston
http://www.hhs.gov/aspr/barda/documents/ GK, Jenkins MS, Oestereicher U, Pellmar TC, Prasanna PGS
bioshieldannualreport2006.pdf. Accessed 07 May 2010 (2008) Inter-laboratory comparison of the dicentric chromosome
Pyatkin EK, Nugis VY, Chrikov AA (1989) Absorbed dose estimation assay for radiation biodosimetry in mass casualty events. Radiat
according to the results of cytogenetic investigation of lymphocyte Res 169:551–560
cultures of persons who suffered in the accident at Chernobyl Xiao Z, Su Y, Yang S, Yin L, Wang W, Yi Y, Fenton BM, Zhang L,
atomic power station. Radiat Med 4:52–58 Okunieff P (2006) Protective effect of esculentoside A on radiation-
Radiation Emergency Medical Management (REMM). http://www. induced dermatitis and fibrosis. Int J Radiat Oncol Biol Phys
remm.nlm.gov/. Accessed 07 May 2010 65(3):882–889
Radiation Emergency Assistance Center/Training Site (REAC/TS). Zhang H, Zhang SB, Sun W, Yang S, Zhang M, Wang W, Liu C,
http://orise.orau.gov/reacts/. Accessed 07 May 2010 Zhang K, Swarts S, Fenton BM, Keng P, Maguire D, Okunieff P,
Ramakrishnan, N (2009) NIAID/NIH radiation/nuclear medical coun- Zhang L (2009) B1 sequence-based real-time quantitative PCR: a
termeasures development program. GHSI public health emergency sensitive method for direct measurement of mouse plasma DNA
medical countermeasures workshop, Nov 4 2009. http://www. levels after gamma irradiation. Int J Radiat Oncol Biol Phys
blsmeetings.net/2009GHSImeetingsmcm/presentations/RadNuc/ 74(5):1592–1599
Ramakrishnan-GHSIRamakrishnanNov4.pdf. Accessed 07 May
2010