Technical Basis of Radiation Therapy Practical Clinical

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Contents V

To my wife and children,

whose support and
encouragement make it all happen.

Seymour H. Levitt
Contents VII

Foreword

This fourth revised edition of “Technical Basis of Radiation Therapy: Practical Clinical
Applications”, edited by S. H. Levitt, J. A. Purdy, C. A. Perez, and S. Vijaykumar, continues
this publication’s outstanding excellence in the definition of the technical advances for
radiation therapy. The previous three editions were milestones in the definition of new
technologies and how they would be applied in clinical practice. The present volume
presents significant and important concepts of treatment planning, not only with regard
to appropriate treatment plans but also how various auxiliary technologies can be used to
achieve the best clinical outcome with the minimum complication.
The first portion of the book deals not only with the advances in imaging technology
and their role in defining more precisely the extent of the tumor but also how these imag-
ing techniques can be used in devising treatment plans. Clearly, three-dimensional treat-
ment planning and conformal therapy along with intensity-modulated radiation therapy,
stereotactic radiosurgery and radiotherapy, new technologies in brachytherapy as well
as advances in cyberknife, tomotherapy and image-guided radiation therapy can lead to
better outcomes. Consonant with these considerations is the impact on second malignan-
cies following radiation therapy and the clinical applications for chemoradiation.
In the second part of the book, the practical clinical applications are defined precisely
for essentially all major tumor sites. Each tumor site is dealt with in depth, and the authors
show how the new techniques can improve the potential outcome in terms of manage-
ment. In 2005, 60% of all malignant tumors were cancers of the lung, breast, prostate, and
colorectum. Particular attention is directed toward these tumor sites and how the new
methods can improve the overall outcome.
There is significant emphasis on the utilization of various brachytherapy techniques
and how they may be integrated to produce better outcomes at each tumor site.
The excellence of the text is obvious, the data submitted important. This volume makes
a major contribution to patient management.

Luther W. Brady
Hans-Peter Heilmann
Michael Molls
Contents IX

Preface

This is the 4th edition of a book which was originally initiated as a supplement to a post-
graduate refresher course in radiation oncology held at the University of Minnesota. This
program was instituted in 1970 and ended 25 years later. The idea of the course and the
book that followed was to acquaint radiation oncologists with the concepts, policies and
treatment methods in the cutting-edge radiation oncology departments.
The inspiration for this program came from Dr. Gilbert Fletcher and from Dr. Norah
Tapley. Indeed, the first edition of this book was entitled “Levitt and Tapley’s”. Unfortu-
nately these wonderful colleagues are no longer with us and their friendship and advice and
contributions are much missed.
This edition has been completely rewritten. There are several new chapters, and all of
the original chapters have been updated. We, the editors and authors, feel that this edition
truly reflects the best approach to the technical basis of radiation oncology at this time.
Obviously our discipline is moving forward at break-neck speed, and it is essential for
the practitioners of radiation oncology to have as many tools as possible to help them be at
the cutting edge of our practice. We believe this edition achieves just that.
All of the chapter authors are experts in their areas, and have many high demands on
their time. We are grateful for their efforts..

Minneaopolis Seymour H. Levitt

Sacramento James A. Purdy
St. Louis Carlos A. Perez
Sacramento Srinivasan Vijayakumar
Contents XI

Contents

Part I: Basic Concepts in Treatment Planning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 001

1 Practical Time-Dose Evaluations, or How to Stop Worrying and Learn to

Love Linear Quadratics
Jack F. Fowler . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003

2 Second Malignancies Following Radiotherapy

Eric J. Hall . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 033

3 Clinical Principles and Applications of Chemoirradiation

Dan P. Garwood, L. Chinsoo Cho, and Hak Choy . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

4 Imaging in Radiation Therapy. Recent Advances and Their Role in Radiotherapy

Filip Claus and Hedvig Hricak . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

5 Physics of Treatment Planning in Radiation Oncology

James A. Purdy, Srinivasan Vijayakumar, Carlos A. Perez,
and Seymour H. Levitt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

6 The Simulation Process in the Determination and Definition

of the Treatment Volume and Treatment Planning
Sasa Mutic, James A. Purdy, Jeff M. Michalski, and Carlos A. Perez . . . . . . . 107

7 Clinical Applications of High-Energy Electrons

Bruce J. Gerbi. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

8 Treatment Aids for External Beam Radiotherapy

Eric Klein, Sasa Mutic, and James A. Purdy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

9 Three-Dimensional Treatment Planning and Conformal Therapy

James A. Purdy, Jeff M. Michalski, Jeffrey Bradley,
Srinivasan Vijayakumar, Carlos A. Perez, and Seymour H. Levitt . . . . . . . . . 179

10 Intensity-Modulated Radiation Therapy

Daniel A. Low, Wei Lu, James A. Purdy, Carlos A. Perez,
and Seymour H. Levitt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

11 Stereotactic Radiosurgery and Radiotherapy

Joseph R. Simpson, Robert E. Drzymala, and Keith M. Rich . . . . . . . . . . . . . . . . 233

12 Physics and Clinical Aspects of Brachytherapy

Zuofeng Li. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
XII Contents

13 Radiobiology of Low- and High-Dose-Rate Brachytherapy

Eric J. Hall and David J. Brenner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291

14 Clinical Applications of Low Dose Rate and Medium Dose Rate Brachytherapy
Carlos A. Perez, Robert D. Zwicker, and Zuofeng Li . . . . . . . . . . . . . . . . . . . . . . 309

15 Clinical Applications of High-Dose-Rate Brachytherapy

Subir Nag. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379

16 Quality Assurance in Radiation Oncology

James A. Purdy, Eric Klein, Srinivasan Vijayakumar, Carlos A. Perez,
and Seymour H. Levitt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395

Part II: Practical Clinical Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423

17 Central Nervous System Tumors

Volker W. Stieber, Kevin P. McMullen, Michael T. Munley,
and Edward G. Shaw . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425

18 Head and Neck Cancer

William M. Mendenhall, Robert J. Amdur, and Jatinder R. Palta . . . . . . . . . 453

19 Breast Cancer
Sabin B. Motwani, Eric A. Strom, Marsha D. McNeese,
and Thomas A. Buchholz. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485

20 Carcinoma of the Esophagus

Jeffrey D. Bradley and Sasa Mutic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511

21 Carcinoma of the Lung

Samir Narayan, Srinivasan Vijayakumar. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525

22 Cancers of the Colon, Rectum, and Anus

James A. Martenson Jr., Michael G. Haddock, and Leonard L. Gunderson . . 545

23 Bladder Cancer - Technical Basis of Radiation Therapy

Alan R. Schulsinger, Ron R. Allison, Walter H. Choi,
and Marvin Rotman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561

24 Radiation Therapy for Cervical Cancer

Kathryn E. Dusenbery and Bruce J. Gerbi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579

25 Technical Aspects of Radiation Therapy in Endometrial Carcinoma

Higinia R. Cardenes and Brent Tinnel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599

26 Vulva
Carlos A. Perez and Imran Zoberi. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631

27 Carcinoma of the Vagina

Higinia R. Cardenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657
Contents XIII

28 Prostate
Jeff M. Michalski, Gregory S. Merrick, and Sten Nilsson . . . . . . . . . . . . . . . . . 687

29 Testicular Cancer
Maria Pearse and Gerard C. Morton . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 739

30 Extremity Soft Tissue Sarcoma in Adults

Thomas F. DeLaney, David C. Harmon, Andrew E. Rosenberg,
and Francis J. Hornicek . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 755

31 Total Body Irradiation Conditioning Regimens in Stem Cell Transplantation

Kathryn E. Dusenbery and Bruce J. Gerbi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785

32 Radiotherapy for Hodgkin’s Disease

Chung K. K. Lee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805

33 Techniques of Intravascular Brachytherapy

Sri Gorty and Prabhakar Tripuraneni . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 837

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843

List of Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857

Practical Time-Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics 1

Part I:
Basic Concepts in Treatment Planning
Practical Time-Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics 3

1 Practical Time-Dose Evaluations, or How to Stop

Worrying and Learn to Love Linear Quadratics
Jack F. Fowler

CONTENTS 1.5.8 Conclusions Re Head-and-Neck Schedules 21

1.5.9 Concurrent Chemotherapy 22
Glossary 3 1.6 Hypofractionation for Prostate Tumors 22
1.1 Introduction 6 1.7 Summary 23
1.2 The Simplest Modeling 7 1.8 Appendix: Is This a Mistaken Dose
1.2.1 The Seven Steps to LQ Heaven – Brief Summary 7 Prescription? 24
1.3 The Seven Steps to LQ Heaven – The Details 8 1.8.1 For Equal “Late Complications” 25
1.3.1 Development of the Simple LQ Formula E = nd 1.8.2 For Equal Tumor Effect 25
(1+d/D/E) 9 1.8.3 Acute Mucosal Effects 26
1.3.2 Biologically Effective Dose 10 1.9 Line-by-Line Worked Examples:
1.3.3 Relative Effectiveness 11 Details of Calculations of the Schedules
1.3.4 Overall Treatment Time 12 Discussed in This Appendix 27
1.3.5 Acute Mucosal Tolerance 13 References 29
1.3.6 To Convert from BED to NTD or EQD2 Gy 14
1.3.7 One Example 14
1.3.8 What is the Standard of Precision of These This chapter is written mainly for those who say “I
Estimates of BED or NTD? Gamma Slopes 15 don’t understand this DE business – I can’t be both-
1.4 Rejoining Point for Those Who Skipped: How to ered with Linear Quadratic and that sort of stuff.”
Evaluate a New Schedule – Brief Summary 15
1.5 Now Let Us Study Some of the Best-Known Schedules
Well, it might seem boring – depending on your per-
for Head-And-Neck Tumor Radiotherapy 16 sonality – but it is easy, and it makes so many things in
1.5.1 Standard Fractionation 16 radiation therapy wonderfully and delightfully clear.
1.5.2 Hyperfractionation 17 Experienced readers can turn straight to Section 1.4.
1.5.3 Radiation Therapy Oncology Group Four-Arm
Fractionation Trial (RTOG 90-03) 17
1.5.4 Head-and-Neck Schedules That Were Initially
“Too Hot” in Table 1.2 18
1.5.5 Shortening the Wang 2-Fraction-a-Day Schedule J. F. Fowler, DSc, PhD
Using BED to Adjust Individual Doses 19 Emeritus Professor of Human Oncology and Medical Physics,
1.5.6 General Considerations of Medical School of University of Wisconsin, Madison, Wiscon-
Head-and-Neck Radiotherapy 19 sin, USA; Former Director of the Gray Laboratory, Northwood,
1.5.7 A Theoretical Calculation of “Close to Optimum” London, UK
Head & Neck Schedules: 3 Weeks at Five Fractions Present address:
per Week 20 150 Lambeth Road, London, SE1 7DF, UK

Glossary

D, alpha Intrinsic radiosensitivity. Loge of the number of cells sterilized non-repairably per
gray of dose of ionizing radiation.
E, beta Repair capacity. Loge of the number of cells sterilized in a repairable way per gray
squared.
DE, alpha/beta ratio the ratio of “intrinsic radiosensitivity” to “repair capability” of a specified tissue.
This ratio is large (>8 Gy) for rapidly proliferating tissues and most tumors. It is
small (<6 Gy) for slowly proliferating tissues, including late normal-tissue complica-
tions. This difference is vital for the success of radiotherapy. When beta (E) is large,
both mis-repair and good-repair are high. It is the mis-repair that causes the cell
survival curve to bend downward.
4 J. F. Fowler

Accelerated fractionated schedules with shorter overall times than the conventional 7 (or 6)
fractionation weeks.
BED Biologically effective dose, proportional to log cell kill and therefore more conceptu-
ally useful as a measure of biological damage than physical dose, the effects of which
vary with fraction size and dose rate. Formally, “the radiation dose equivalent to an
infinite number of infinitely small fractions or a very low dose-rate”. Corresponds
to the intrinsic radiosensitivity (D) of the target cells when all repairable radia-
tion damage (E) has been given time to be repaired. In linear quadratic modeling,
BED=total dose×relative effectiveness (RE), where RE=(1+dDE), with d=dose
per fraction, D=intrinsic radiosensitivity, and E=repair capacity of target cells.
bNED Biochemically no evidence of disease. No progressive increase of prostate specific
antigen (PSA) level in patients treated for prostate cancer.
CI Confidence interval (usually ±95%).
CTV Clinical tumor volume. The volume into which malignant cells are estimated to have
spread at the time of treatment, larger than the gross tumor volume (GTV) by at least
several millimeters, depending on site, stage, and location. See also GTV and plan-
ning treatment volume (PTV).
't Time interval between fractions, recommended to be not less than 6 h.
EBR External beam radiation.
EGFR Epithelial growth factor receptor, one of the main intracellular biochemical path-
ways controlling rate of cell proliferation.
EQD Biologically equivalent total dose, usually in 2-Gy dose fractions. The total dose of a
schedule using, for example, 2 Gy per fraction that gives the same log cell kill as the
schedule in question. If so, should be designated by the subscript EQD2 Gy.
EUD Equivalent uniform dose. A construct from the DVH of a non-uniformly irradiated
volume of tissue or tumor that estimates the surviving proportion of cells for each
volume element (voxel), sums them, and calculates that dose which, if given as a
uniform dose to the same volume, would give the same total cell survival as the given
non-uniform dose. Local fraction size is taken into account by assuming an DE
ratio for the tissue concerned.
Gamma, J-50, J-37 Slope of a graph of probability, usually tumor control probability (TCP), versus total
fractionated dose (NTD or EQD), as percentage absolute increase of probability per 1%
increase in dose. The steepest part of the curve is at 50% for logistic-type curves and
at 37% for Poisson-type curves. Tumor TCP is usually between a gamma-50 (or -37) of
1.0 and 2.5. The difference between J-50 and J-37 is rarely clinically significant.
Gy, gray The international unit of radiation dose: one joule per kilogram of matter. Com-
monly used radiotherapy doses are approximately 2 Gy on each of 5 days a week.
Gy10, Gy3, Gy1.5 Biologically effective dose (BED), with the subscript representing the value of that
tissue’s DE ratio=10 Gy for early radiation effects, 3 Gy for late radiation effects and
1.5 Gy for prostate tumors. The subscript confirms that this is a BED, proportional
to log cell kill, and not a real physical dose.
GTV Gross tumor volume. The best estimate of tumor volume visualized by radiologi-
cal, computed tomography (CT) scan, magnetic resonance, ultrasound imaging, or
positron emission tomography.
HDR High dose rate. When the dose fraction is delivered in less than five or ten
minutes; that is, much shorter than any half-time of repair of radiation damage.
Hyperfractionation More (and smaller) dose fractions than 1.8 Gy or 2 Gy.
Hypofractionation Fewer (and larger) dose fractions than 1.8 Gy or 2 Gy.
Isoeffect Equal effect.
Practical Time-Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics 5

LC Local control (of tumors).

LDR Low dose rate. Officially (ICRU), less than 2 Gy/h; but this is deceptive because any
dose rate greater than 0.5 Gy/h will give an increased biological effect compared with
the traditional 0.42 Gy/h (1000 cGy per day). For example at 2 Gy/h, the biological
effects will be similar to daily fractions of 3.3 Gy and 2.8 Gy on late complications
and on tumors respectively.
Linear effect Directly proportional to dose.
Ln loge Natural logarithm, to base e. One log10 is equal to 2.303 loge.
Log10 Common logarithm, to base 10. “Ten logs of cell kill” are 23.03 loge of cell kill.
LQ Linear quadratic formula: loge cells killed=Dudose+Eudose-squared.
Logistic curve A symmetrical sigmoid or S-shaped graph relating the statistically probable incidence
of “events”, including complications, or tumors controlled, at a specified time after
treatment, to total dose (NTD). This curve is steepest at the probability of 50%.
LRC Loco-regional tumor control. LC would be local control.
NTCP Normal tissue complication probability.
NTD Normalized total dose of any schedule. The total dose of a schedule using 2 Gy per
fraction that gives the same log cell kill as the schedule in question. The NTD will be
very different for late effects (with DE=3 Gy and no overall treatment time factor)
than for tumor effect (with DE=10 Gy and an appropriate time factor).
Poisson curve A near-sigmoid graph of probability of occurrence of “events”, such as tumor control
at X years, versus total dose or NTD. Based on random chance of successes among
a population of tumors or patients, the probability of curve P=exp (–n), where an
average of n cells survive per tumor after the schedule, but 0 cells must survive to
achieve 100% cure. If an average of 1 cell survives per tumor, P=37%. If 2 cells sur-
vive, P=14%. If 0.1 cells survive on average, P=90%. This curve is steepest at the
probability of 37%.
PTV Planning treatment volume – larger than CTV to allow for set-up and treatment-
planning errors.
PSA Prostate-specific antigen: can be measured in a blood specimen as a measure of activ-
ity of the prostate gland. Often taken as a measure of activity of prostate cancer.
Quadratic Effect proportional to dose squared, for example from two particle tracks passing
through a target.
QED Quod Erat Demonstrandum – Latin for “That’s what we wanted to show!”
RE Relative effectiveness. We multiply total dose by RE to obtain BED. RE=(1+d[DE])
where d is the dose per fraction.
RTOG Radiation Therapy Oncology Group, USA.
SF Surviving fraction after irradiation, usually of cells.
Tpot Potential doubling time of cells in a population; before allowing for the cell loss
factor. Tpot is the reciprocal of cell birth rate. It can only be measured in a tissue
before any treatment is given to disturb its turnover time.
Tp Cell doubling time in a tissue during radiotherapy; probably somewhat faster than Tpot.
Determined from gross tumor (or other tissue) results when overall time is altered.
Tk Kick-off or onset time: the apparent starting time of rapid compensatory repopula-
tion in tumor or tissue after the start of treatment, when it is assumed that there
are just two rates of cell proliferation during radiotherapy: zero from start to Tk,
then constant doubling each Tp days until end of treatment at T days. Accelerating
repopulation is discussed in Section 1.5.6.
TCP Tumor control probability.
6 J. F. Fowler

1.1 In the early years of the development of the LQ

Introduction formulation, there was no overall treatment-time
factor (Douglas and Fowler 1976; Barendsen
It is well known that the simplest description of radi- 1982; Withers et al. 1983). This was added later
ation dose, the total dose, is not adequate because (Travis and Tucker 1987; van de Geijn 1989;
its effect varies with size of dose per session (the Fowler 1989), based on LQ-aided analyses of animal
dose fraction) and with dose rate. If we double the and clinical data (Denekamp 1973; Turesson and
dose per fraction from 2 Gy to 4 Gy (keeping total Notter 1984a,b; Thames and Hendry 1987). Since
dose constant), the effect is 20% greater for tumors then, the strong effect of repopulation of tumor
but 100% greater for late complications. Further, cells during radiotherapy has been well substanti-
if a given physical dose is spread evenly over 24 h ated so that a repopulation term has been added for
instead of 2 min, its effect is reduced by 20% for most tumors (Fowler 1978, 1989; Withers et al. 1988;
tumors, but to about half for late complications. We Fowler and Lindstrom 1992; Hendry et al. 1996).
need a way of expressing radiation “dose” in some More recently, a different set of parameters has been
quantitative way that is more proportional to the described to predict acute mucosal reactions in
observed biological effect. This is the object of cal- human patients (Fowler et al. 2003c).
culating a biologically effective dose (BED), and an Although the accuracy and even the nature of the
equivalent dose in 2 Gy fractions (EQD or NTD), so LQ factors has been queried a few times, for example
that a 20% increase or decrease of BED or NTD or whether the parameters are unique or distributed
EQD2 Gy will lead to a reasonable approximation of a (King and Mayo 2000; Brenner and Hall 1999,
20% increase or decrease of the expected biological 2000; King and Fowler 2002; Dasu et al. 2003;
effect. The interesting point is that the same change Moiseenko 2004), the LQ formulation has remained
in physical dose is likely to alter the incidence of solidly useful and has aided in the design of clinical
late complications to double or half of its effect on trials that have changed the practice of radiotherapy
tumors. So how can we deal with that? (Thames et al. 1983). Examples include the design of
The basic truth in radiotherapy is that any change hyperfractionated (more and smaller fractions) and
in the schedule of dose delivery has a different effect accelerated fractionation (shorter) trials, the avoid-
on tumors from its effect on late complications, ance of gaps in radiation treatment, the development
unless both dose per fraction and dose rate are kept of high dose-rate brachytherapy, and a better under-
constant. These differences provide some of the standing of when to use or avoid hypofractionation
remarkable advantages of radiation therapy, and (fewer and larger fractions). The recent growth of
also some puzzles until they are explained. BED can stereotactic body radiotherapy is a subset of the
take these differences into account, and preferably latter category (Fowler et al. 2004).
explain them. One of the most interesting series of modeling
In the 25 years since the linear quadratic (LQ) investigations concerns oral and laryngeal cancers
formula has been used for the evaluation of radio- in which the overall times were deliberately short-
therapy schedules, it has proved remarkably reliable. ened until the acute reactions became too severe,
It is now the main and generally accepted method of in several well known schedules in different coun-
rationalizing the improved time–dose-fractionation tries. Each schedule was then moderated in some
schedules that have been developed to replace, in way until it became tolerable. The modeling then
some body sites, the standard “2 Gy given five times showed that not only the acute mucosal reactions
a week for 6 or 7 weeks” schedules. It was first of all fell into a narrow band of BED, but the modeled
useful in identifying the important difference in the tumor responses were then all close to 11 log10 of
effect of dose-fraction size between rapidly prolifer- predicted tumor cell kill for a variety of different
ating tissues (most tumors) and slowly proliferating time–dose schedules. This story will be told in this
tissues (most late complications). This explained the chapter.
blindly used, but not always wrong, predominance Although the numerical results of modeling
of multi-small-fraction schedules, such as 1.8 or depend to some extent on the values assumed for the
2 Gy five times a week for 6 or 7 weeks. As explained parameters, ratios of parameters such as DEratios
below, the theoretically ideal overall time would be and time–dose trade-offs (grays per day) are often
close to the time at which rapid repopulation in the known sufficiently well for reasonable variations to
tumor kicks off, designated Tk days after starting lead to no clinically significant differences in pre-
treatment. dicted total dose or BED or NTD. In the modeling
Practical Time-Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics 7

described below, we take care to limit the assumed they are not a strong function of cells sterilized. The
values of parameters to a small library of values phantom of immunological response keeps rear-
selected from experience, avoiding “elegant varia- ing its head, with little practical effect. The addi-
tion”. Then, results that are useful and self-consis- tive effect of chemotherapy seems to apply most
tent are obtained. effectively when it is used concomitantly, and up to
Unlike some other attempts at modeling, the now amounts to some 10% of the total cell kill com-
number of initially viable cells per mm3 is not pared with radiotherapy. The strength of radiation
essential in LQ modeling for time–dose evaluations, as a treatment strategy is that it can and does reach
because it is largely cancelled out against radiosensi- wherever the physical plan puts it, with increasing
tivity D in the standard BED formulation. This is also efficiency of positional accuracy.
true of equivalent uniform dose (EUD; Niemierko The object of the present modeling is to find simi-
1997). Both BED and EUD enjoy similar stability for lar biological effects to the radiotherapy treatments
this reason. The most essential biological factor in LQ with which we are familiar, from different schedul-
formulation is the DE ratio of the tissue concerned, ing of time and dose. That is the “isoeffect modeling”
which appears in the BED with weighting equal to that has much history, passing through the “cube
dose per fraction. The other significant factors are root law” of the 1930s, the “Strandqvist slope” of the
the “kick-off time” of rapid tumor repopulation Tk 1940s, and the “Nominal Standard Dose” (NSD) or
and the doubling time of repopulating tumor cells “Time-dose Factor” (TDF) of Dr Frank Ellis in the
Tp, which together with the D value all appear in the 1960s and 1970s – and then to evaluate methods of
repopulation term which is usually, but not always, doing better. We shall start by writing down some
a small proportion of BED. ideas for explaining the non-linear action of ioniz-
A glossary is attached at the beginning of this ing radiation in damaging biological cells.
chapter of terms that are best for readers to know Radiation sterilizes cells, meaning that they do
when reading about these topics. not die immediately, but at the time of the next cell
division, or a few divisions later. An important factor
is the repair occurring in the cells between irradia-
tion and their next cell division. This repair in cells,
1.2 i.e., recovery in tissues, depends on the turnover rate
The Simplest Modeling of renewing tissues – a day or so for rapidly prolifer-
ating tissues and most tumors, but many months for
Years ago, mathematical models were regarded with the organs that normally proliferate slowly. That is
suspicion, or with derision as playthings for chil- the important difference in the tissues that LQ mod-
dren – but not any more. Modeling has become an eling helped to bring out, with the help of the famous
important scientific tool in the design and evalua- or infamous ratio D over E.
tion of topics from global warming to engineering
design of aircraft and the pharmacological develop-
ment of drugs, replacing expensive experimentation 1.2.1
in many cases (Prof. Gordon Steel 1990, personal The Seven Steps to LQ Heaven – Brief Summary
communication). With the aid of computers, math-
ematical modeling using optimization and new First, before explaining them in detail, we list here
imaging are continuing to revolutionize treatment the “Seven (algebraic) Steps to LQ Heaven”, so that
planning in radiotherapy, as other chapters in this readers who wish to do so can skip several pages
book will show. and turn to Section 1.4. That’s where the story gets
“There are good reasons for believing that the exciting.
primary effects of radiation on biological tissues Alpha is the intrinsic radiosensitivity of the
are cell damage and cell depopulation in renewing cells, defined as how many logs (to the exponential
populations” (Thames and Hendry 1987). This is base “e”) are killed (sterilized) per gray, in a “non-
still true whether the concern is damage to normal repairable” way. Beta is the repairable portion of the
tissues or the elimination of every malignant cell radiation damage, requiring 6 h or more for com-
in tumors. However, certain indirect biological end plete repair. It can be regarded as the result of two
points, such as radiation sickness or extent of late charged-particle tracks passing through a sensitive
fibrosis, do not appear to depend only on numbers target in the cell nucleus in less than 6 h, so this term
of cells sterilized, although it does not mean that has to be multiplied by d squared. E is the loge sum of
8 J. F. Fowler

the non-repairable D term and the partly repairable for which tissue each BED or EQD2 Gy or NTD is cal-
E term. So for n fractions of d Gy dose each: culated. We should state each time “late” or “tumor”
or “early” BED or NTD (Fowler 1989).
E = n (αd + βd 2 ) [1.1] A further measure of radiation damage from
these formulae is:
E = nd (α + βd) [1.2]
Loge cell kill = E = BEDuD, so that in the
E / α = nd (1+ dβ / α) [1.3] “common log to base 10 scale, log10 cell kill = loge
cell kill/2.303.
Dividing through by D to express DE as a ratio.
E d To convert from BED to EQD 2 Gy or NTD (total
= nd (1 + ) E = nd (1 + d) [1.4] equivalent dose in 2 Gy fractions):
α α /β
For late complications, divide Gy3 by 1.667. For
With no repopulation considered; as for most types tumor or early effects, divide Gy10 by 1.2.
of late complication. The explanation comes from the identity
BED1=BED2, where “1” is for “d Gy per fraction”
This is the limited definition of BED. It applies and “2” is for “2 Gy per fraction”, so for identical
to late effects. BED=E/D=total doseuRE where BEDs, we have:
RE=(1+d/[DE@), and it is very useful.
Next, we subtract the log cell kill due to repopu- Total dose 1uRE1=total dose 2u(RE for 2 Gy and
lation of any cells during radiotherapy, after the the same DE).
“kick-off” or onset time Tk, where T is overall time NTDu(1+2/DE)=BED. Then solve for NTD!
and Tp is the average cell-number doubling time (in
days) between Tk and T.

E = nd (D+Ed)–(T – Tk)u rate of repopulation per 1.3

day [1.5] The Seven Steps to LQ Heaven – The Details

E = nd (D+Ed)–loge2(T–Tk)/Tp [1.6] This is the section that experienced modelers might

(loge2 = 0.693) wish to skip by several pages, and go to Sections 1.4
and 1.5, where comparisons of actual schedules are
To transform the total log cell kill E into the total tabulated and discussed.
BED requires the same division throughout by D The mathematics of the LQ formula are very simple
that we carried out in step 3 (Eq. 1.3) above: and are taught in courses before the end of the high
school syllabus at age 15 or 16 years. Solving an alge-
Ε d 0, 693
BED = = nd (1 + ) − (T − Tk) [1.7] braic quadratic equation and manipulating the con-
α α /β αTp version of an exponential to a logarithmic form are
Final step = LQ heaven! the only steps requiring an effort of memory and are
only necessary if you get into more calculations than
BED can be expressed as Gy3 (or Gy2) for late you will normally need. If you don’t deal with this
complications, or as Gy10 (or Gy x) for tumor or early sort of arithmetic every week, you normally need no
normal-tissue reactions, the subscript referring to the more than the four simplest keys (+, –, u,) on your
DE value used in its calculation. Gy3 and Gy10 values hand calculator, or even just the back of an enve-
must not be mixed, as USA and Canadian or Hong lope. The “Seven Steps to LQ Heaven” are intended
Kong dollars cannot. However, several segments of to ensure that you, the reader, are never puzzled by
a schedule can have their Gy10 values added together such simple calculations again. Having followed,
and, separately, their Gy3 values added, for a compar- and understood, the seven steps that follow, you
ison of total BEDs amounting to a “therapeutic ratio” should be able to use them with confidence for any
of Gy10Gy3 – representing tumor cell damage divided comparisons of radiotherapy schedules you wish to
by late normal-tissue damage. This notation should make in terms of BED (Fowler 1989, 1992).
always be used, or confusion quickly sets in. It both BED is proportional to log cell kill for cells of the
reminds us that this is a BED, not the real physical specified DE ratio, and so is a strong function of
dose; and confirms which DE ratio was used, thus biological effect. BED is itself a ratio (E/D), the two
Practical Time-Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics 9

parameters of which are not individually important. minus D/Do. This would be called a “single-hit”
Mathematically, E/D is simply a linkage term show- curve. The dose Do would reduce survival by one loge
ing equivalence between two schedules – their “iso- which is to 37% survival. You can see that Do=1/D
effect” in the time-dose scale – as well as providing in the LQ formula, that is 1/(the dose to reduce cell
a useful number, the BED. Its numerical value is a survival by one loge).
convenient number, representing a dose without Plotting graphically the proportion of surviving
the repairable component, that is avoiding dose per mammalian cells against single dose of radiation
fraction or dose rate, until relative effectiveness (RE) gives a curve, not a straight line. This curve starts
is built in. We could talk about D=0.35 loge per Gy from zero dose with a definite non-zero slope, gradu-
and E=10 log10 of cell kill, or equally D=0.035 loge ally bending downward into a “shoulder” at less than 1
per Gy and E=one log10 of cell kill, and the BED gray of dose, and continuing to bend downward until
would be the same because it is ED at least 10 or 20 grays. At higher doses, the cell sur-
vival curve appears to become nearly straight again
but of course steeper than at the origin (Gilbert et
1.3.1 al. 1980). This is the well-known “cell survival curve”
Development of the Simple LQ Formula where the logarithm of the surviving proportion of
E = nd (1+d/D/E) cells is plotted downward, against radiation dose on
the horizontal axis (Fig 1.1). It is the same curve as
Cell depopulation is the main effect of radiation, both the negative logarithm of the fraction of cells “killed”
for eliminating tumors and for damaging normal – actually “sterilized” so that they die later, after the
tissues. In addition, some genes are activated, which next cell division or a few divisions.
can be relevant in those cells that survive irradia-
tion, and some apoptosis (cell death independent of This is the plot of loge proportion of cells surviv-
mitosis) may be caused. Although apoptosis does ing: S=–Dd–Ed 2.
not appear to be the major effect of radiation, when
it happens it adds to the effect. The promising strat- Therefore also: loge proportion of cells sterilized
egy of damaging tumors by depleting their blood (killed)=+Dd+Ed 2.
supply, with pharmacological or enzyme-pathway
aid (Fuks et al. 1994), can be regarded as consider- It is this logarithm of the number of cells steril-
ing the neovasculature (that is, rapidly proliferating ized that can be divided into one part proportional
endothelial cells (Hobson and Denekamp 1984) as to dose Dd; and another part proportional to dose-
legitimate oncogenic targets, as well as the directly
malignant tumor clonogens (Hahnfeldt et al.
1999). Radiation can reach them all.
If a dose of radiation D sterilizes a proportion of
cells in a given tumor or normal organ so that the
number of viable cells is reduced from the initial No
to Ns: the surviving proportion is Ns/No, which is
designated S.
This process is represented as S=e–D/Do =
exp(–D/Do), in its simplest form, where Do is the
average dose that would sterilize one cell. This
shows that the surviving proportion of cells is
reduced exponentially with radiation dose. That
is, each successive equal increment of dose reduces
the surviving cells by the same proportion, not by
the same number. The proportion of surviving cells
would then decrease from 1 to 0.5, to 0.25, to 0.125,
etc.; if higher doses per fraction were used, from 0.1 Fig. 1.1. The simple cell survival curve for linear quadratic cell
kill versus radiation dose, for a single dose of radiation deliv-
to 0.01 to 0.001.
ered within a few minutes. The alpha component increases as
Another way of writing this is: loge S= D/Do, shown linearly with dose. The beta component is added to this
which plots out as a graph of loge S vertically versus in a curving pattern, increasing with the square of the dose.
dose horizontally to give a straight line of slope This example is numerically correct for the DE ratio of 3 Gy
10 J. F. Fowler

squared Ed 2 (that is “quadratically”, where two sub- you understand the LQ steps well enough not to
lesions combine, each produced in number propor- forget them within the next few days.
tional to dose). The logarithm (proportion) of lethal The next step is the simple one of adding several
events caused by a dose d is then: fractions of daily doses, each of d grays, to obtain
the total dose if n fractions (daily doses) are given.
E=Dd+Ed 2 Figure 1.2 illustrates the sequence of equal fractions,
giving a total curve that is made up of a sequence of
The linear component is found to be not repair- small shoulders, in toto an exactly linear locus, of
able beyond a few milliseconds after the irradia- slope depending on the value of Eq. 1.1 at each dose
tion, but this does not mean it cannot be altered, by d:
oxygen if present at the time of irradiation as one
major example. However, the dose-squared damage E = n (αd + βd 2 ) [1.1]
gradually fades over a few hours. It is repaired by
several processes within the biological cells, mostly The dose per fraction d can be taken outside the
within the DNA, so that cell survival recovers toward parentheses, nd being of course the total dose:
the straight initial D slope. Cells and tissues are said
to “recover” and biochemical lesions in DNA are E = nd (α + βd) [1.2]
said to be “repaired”.
Let us call this cell-number damage E, the loga- We usually know the ratio of the two coefficients,
rithm of the number of cells sterilized by a dose d in DE, for given cells and tissues much better than
grays (Gy). Then, we just write the first equation as: we know their individual values, so the next step
is to express E in terms of this ratio. It is most use-
E=Dd+Ed 2 fully done by dividing both sides of Eq. 1.3 by D
(Barendsen 1982). If instead we divided by E, then
where Dand E are the coefficients of the linear com- the resulting BED would be in terms of dose squared,
ponent and the dose-squared component, respec- which would be awkward.
tively. This is the first step on the ladder to explain-
ing the LQ formulation, commonly taught as the E/D=nd(1+dED) [1.3]
“Seven Steps to Heaven”. If you remember this little
starting formula you will have no trouble at all with which is also of course identical to:
the next three steps. “LQ Heaven” is reached when E d
= nd (1 + ) E = nd (1 + d) [1.4]
α α /β
Because D is defined as a number (log number
of cells sterilized) “per gray”, the term E/D has the
dimensions of dose. It is in fact the BED that we are
seeking to calculate, so Eq. 1.4 gives it to us. We are
halfway up the “Steps to Heaven” and this equation
enables us to do many useful things in predicting
biological damage (Fowler 1989; also Chapters 12
& 13 in Steel 2002).

1.3.2
Biologically Effective Dose

The basic concept of BED was defined by Barendsen

Fig. 1.2. The survival curve for four equal radiation doses given (1982), who at first called it extrapolated tolerance
sequentially, with sufficient time – at least 6 h – between them dose (ETD), meaning that dose which, if given as an
to allow complete repair of the beta component of radiation infinite number of infinitely small fractions (along
damage. Since the shape of each is then a repetition of the
previous dose, the track of the result after each dose fraction the initial slope of the cell survival curve), or at a
is a straight line when plotted as log cell kill against dose as very low dose rate (so that all the quadratic damage
shown has been repaired), would cause the same log cell kill