Nelson N.

Stone
E. David Crawford Editors

The Prostate
Cancer Dilemma

Selecting Patients
for Active Surveillance,
Focal Ablation
and Definitive Therapy

123
The Prostate Cancer Dilemma
Nelson N. Stone • E. David Crawford
Editors

The Prostate Cancer

Dilemma
Selecting Patients for Active Surveillance,
Focal Ablation and Definitive Therapy
Editors
Nelson N. Stone E. David Crawford
Professor of Urology and Radiation Professor of Urology/Surgery,
Oncology Radiation Oncology
Department of Urology University of Colorado
The Icahn School of Medicine Denver, Aurora, CO, USA
at Mount Sinai
New York, NY, USA

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Preface

The Prostate Cancer Dilemma: Selecting Patients for Active Surveillance, Focal
Ablation and Definitive Therapy is the first textbook to provide a complete descrip-
tion of the newest technologies to diagnose and manage the most common prostate
cancer diagnosed today: low risk disease. Over 50 % of men diagnosed with pros-
tate cancer by transrectal biopsy appear to have this type of cancer. But do they
really? And if they do, is it safe to observe them or should they have more aggres-
sive therapy? Follow a typical patient and see how these issues are addressed by
reading the valuable contributions of all of the coauthors of this textbook. In addi-
tion to the many state-of-the-art photographs accompanying this book, several pro-
cedure videos are also available online.
A 52-year-old man visits his primary care physician for his annual checkup. He
asks her about being tested for prostate cancer. She tells him about the controversy
surrounding PSA testing and that the USPTF has given PSA a grade D recommen-
dation. In Chap. 1, Drs. Andriole and Manley summarize the history of the discov-
ery of PSA and how it became such an integral part of prostate cancer management.
Basic biology and physiology of PSA is discussed to provide insights about its
current and future applications. Salient points in the arguments for and against PSA
screening are presented. A thorough review of the randomized trials (both US and
European) that led to the “D” recommendation is undertaken. Lastly, new PSA
markers that may help distinguish between benign, low grade, and aggressive can-
cer are evaluated.
The patient asks about prostate cancer pathology. He wants to know if he has a
biopsy and it is positive what type of cancer and how dangerous might it be. In
Chap. 2, Dr. Lucia discusses how prostate cancer pathology has changed over the
last 30 years. In 1966, Donald Gleason described the varied architectural appear-
ances of a large number of prostatic adenocarcinomas and demonstrated that the
degree of glandular differentiation and infiltration of the surrounding stroma by
tumor cells reflected the biology of the tumor. Those tumors that displayed well-
formed acinar structures had favorable outcomes compared with those that had pro-
gressively more poorly formed acini. Those tumors that formed only sheets,
cords, or single cell arrangements behaved aggressively and were often lethal.

v
vi Preface

Over the ensuing years modifications of Dr. Gleason’s original system arose from
outcomes experience with prostate cancer grading on biopsy and prostatectomy
specimens evolved. In 2005, 80 genitourinary pathologists from around the world
(members of the International Society of Urologic Pathologists) participated in a
survey of practice patterns and a consensus conference to document and assess
cancer grading trends and refined the guidelines for Gleason grading. Most notable
among the items addressed were (1) restrictions on assigning very low-grade pat-
terns (grades 1 and 2) on biopsy specimens, (2) refining the separation between
patterns 3 and 4, (3) assigning grade to cribriform patterns of cancer, and (4) scoring
biopsies that contain minor amounts of high-grade patterns or tertiary-grade pat-
terns. By the mid-1990s, it was recognized that prostate cancer often has multiple
foci of discrete tumors in surgical prostatectomy specimens in more than 50 % of
the cases. These findings increased the risk that standard transrectal biopsies, where
limited tissue is removed, might mislead the clinician as to the type and extent of
cancer present. Dr. Lucia also discusses the new role of molecular pathology and
how what appears to the eye of the pathologist as low-grade cancer might have a
more ominous clinical course.
The primary care physician examines the patient and finds a sizable lesion occu-
pying the entire left lobe of the prostate. She tells him that her suspicion for prostate
cancer is increased. He asks what the implications of these findings are. In Chap. 3,
Drs. Leapman and Cooperberg discuss the American Joint Commission on Cancer
Tumor, Lymph Node, Metastasis (TNM) clinical staging systems and compare it to
the newer Cancer of the Prostate Risk Assessment (CAPRA) method. CAPRA is
based on a 10-point system, designed to provide an approximate doubling of risk
with every 2-point increase in the total score. Tissue-based assays and how their
addition to the CAPRA score improves outcome predictability are also discussed.
The patient’s physician now orders a PSA and refers the patient to a urologist for
further evaluation.
In Chap. 4, Drs. Leapman and Shinohara discuss the “gold standard” for diag-
nosing prostate cancer, the transrectal ultrasound-guided prostate biopsy. The urolo-
gist tells the patient that a 12-core biopsy procedure incorporating the apical and
lateral peripheral zone improves cancer detection rates over a 6-core procedure.
Despite taking an increased number of samples, limitations of systematic TRUS
prostate biopsy include both over- and under-sampling of disease, misrepresenta-
tion of the removed tissue, and an increased rate of biopsy-related complications.
The urologist explains that additional ultrasonographic parameters including
contrast-enhancement, power Doppler imaging, and elastography may improve the
discrimination of suspicious lesions during biopsy. He also tells the patient new
technology allows him to refine the selection for biopsy candidates by utilizing
novel serum biomarkers which offer specificity beyond PSA and clinical parameters
alone. The patient’s PSA is 8.5 ng/ml and he agrees to have a 12-core TRUS biopsy.
On the left 2 of 6 cores are positive for Gleason 6 prostate cancer with 33 % of both
cores positive; all 6 cores are negative on right.
The urologist tells the patient he may qualify for active surveillance but he is not
sure if the transrectal biopsy may have missed more significant disease. He tells him
Preface vii

about transperineal mapping biopsy (TPMB) and mpMRI-targeted biopsy. In

Chaps. 5 and 6 TPMB is discussed. The TPMB technique uses a grid placed against
the perineum and in a sterile fashion directs biopsy specimens be taken at 5 mm
intervals using a combination of transverse and sagittal imaging. In contrast to the
TRUS method where 12–18 samples are typically taken, with the TPMB 50 or more
biopsies can be taken. On average the TPMB finds 30 % more cancers when a
TRUS biopsy is negative, upgrades low risk cancers that were initially diagnosed by
TRUS, and excludes patients from focal therapy because of a high incidence of
multifocality. Dr. Crawford introduces a new software program which creates a
real-time 3D model of the prostate generated from intraoperative axial (transverse)
images. Once the 3D representation is obtained, a biopsy plan is generated. During
the biopsy phase, the image position and the virtual biopsy sites (in axial and longi-
tudinal) can be adjusted to match the US contours of the prostate, urethra, and rec-
tum. This “real-time” image-guided procedure also allows matching of the virtual
biopsy sites to the biopsy needle in the gland. The 3D reconstruction creates a
highly accurate method to biopsy the gland and to provide a roadmap for focal
therapy. Dr. Skouteris reviews their experience with elastography and how it can
improve the diagnosis and staging of prostate cancer in Chap. 7. He compares the
biopsy results of elastography suspicious lesions to those detected by mapping tech-
nique in a number of men biopsied at is center in Athens, Greece.
While interested in the TPMB procedure, the patient already knows he has pros-
tate cancer and is looking for a less invasive method of further assessing his gland.
In Chap. 8, Dr. Taneja and associates describe the advantages of utilizing mpMRI in
both the diagnosis and focal treatment of prostate cancer. This chapter provides a
detailed review of the different aspects of an mpMRI, for example diffusion
weighted imaging (DWI) and the apparent diffusion coefficient (ADC) and how
these “parameters” improve the differentiation between benign and malignant tis-
sue. These authors also compare mpMRI biopsy results to radical prostatectomy
specimens and provide important data about tumor volume and location setting the
stage for using mpMRI for focal ablation. An mpMRI is ordered and a Pi-RADS 4/5
0.5 cm3 lesion is seen in the anterior of the gland. An mpMRI-targeted biopsy is
performed on this lesion which demonstrated a Gleason 3 + 4 lesion.
Finally to help the patient decide how aggressive the cancer is the urologist tells
him about a variety of new genetic markers. In Chap. 9, Drs. Shore and Ventii dis-
cuss the use of genomic and proteomic markers/assays and their ability to improve
the precision of risk assessment and shared educational patient–physician review,
thus enhancing decision-making for physicians and patients, especially when the
traditional clinical parameters (PSA, DRE, pathology) may not provide the most
accurate assessment of indication for biopsy nor indication for treatment option.
A patient with low-risk, newly diagnosed prostate cancer may benefit from a more
precise, personalized assessment of their individual tumor biology. Even patients
with a histologic diagnosis of Gleason 3 + 4 tumors can have a more indolent course
once analyzed with these new genetic markers.
The patient now has a clearer understanding of his disease characteristics and is
deciding on treatment. He knows he has intermediate to low risk disease and realizes
viii Preface

that there are advantages to active surveillance. In Chap. 10, Dr. Klotz tells us that
active surveillance is an effective solution to the widely recognized problem of
overtreatment of screen detected prostate cancer and that it could reduce overall
mortality without an increase in prostate cancer deaths and provide substantial cost
savings. However, the patient is a little reluctant to “leave” his cancer untreated and
is concerned about the side effects of entire gland treatment. He inquires about a
“lumpectomy” where only the lesions are treated. Dr. Barqawi (Chap. 11) summa-
rizes the morbidity associated with conventional treatment of prostate cancer by
radical prostatectomy or radiation therapy and argues for a less invasive method of
treating the disease. Accurate lesions location by TPMB and resolving multifocality
by treating just the index lesion are proposed. In Chap. 12, Dr. Onik discusses dif-
ferent energy modalities for applying focal therapy and makes a case for treating
high-grade disease by inducing an immunologic system response. Finally, in Chap. 13,
Dr. Pinto et al. show how mpMRI-guided therapies can potentially achieve equiva-
lent oncologic efficacy to traditional whole gland therapies such as surgery and
radiation, while avoiding the side effects of conventional treatment.

New York, NY, USA Nelson N. Stone, M.D.

Aurora, CO, USA E. David Crawford, M.D.
Contents

Part I Diagnosis
1 History of Prostate-Specific Antigen, from Detection
to Overdiagnosis ...................................................................................... 3
Brandon J. Manley and Gerald L. Andriole
2 Pathology of Prostate Cancer: What Has Changed
in the Last 30 Years ................................................................................. 17
M. Scott Lucia
3 Clinical Risk Prediction Tools for Prostate Cancer:
TNM to CAPRA—Should Risk Be Redefined? ................................... 33
Michael S. Leapman and Matthew R. Cooperberg
4 TRUS Biopsy: Is There Still a Role? ..................................................... 53
Michael S. Leapman and Katsuto Shinohara
5 Transperineal Biopsy Technique ........................................................... 69
Nelson N. Stone, Vassilios M. Skouteris, and E. David Crawford
6 3D Biopsy: A New Method to Diagnose Prostate Cancer.................... 83
Kevin Krughoff, Nelson N. Stone, Jesse Elliott, Craig Baer,
Paul Arangua, and E. David Crawford
7 Elastography: Can It Improve Prostate Biopsy Results? .................... 93
Vassilios M. Skouteris, Spyros D. Yarmenitis,
and Georgios P. Zacharopoulos
8 Multiparametric MRI of the Prostate as a Tool for Prostate
Cancer Detection, Localization, and Risk Assessment ........................ 107
Marc A. Bjurlin, Neil Mendhiratta, and Samir S. Taneja
9 Genomic Markers ................................................................................... 127
Neal D. Shore and Karen Ventii

ix
x Contents

Part II Treatment
10 Current Status of Clinical Trials in Active Surveillance ..................... 141
Laurence Klotz
11 Focused Targeted Therapy in Prostate Cancer .................................... 153
Kevin Krughoff and Al Barqawi
12 Technologies and Methods in Primary Ablation
with Focal Therapy ................................................................................. 167
Gary Onik
13 Multiparametric MRI (mpMRI): Guided Focal Therapy .................. 187
Michele Fascelli, Amichai Kilchevsky, Arvin K. George,
and Peter A. Pinto

Conclusions ...................................................................................................... 201

Index ................................................................................................................. 203

Contributors

Gerald L. Andriole, M.D. Division of Urologic Surgery, Washington University

in St. Louis, Barnes Jewish Hospital, St. Louis, MO, USA
Paul Arangua, B.S., M.P.H. Urologic Oncology, University of Colorado Denver,
Aurora, CO, USA
Craig Baer, Ph.D. BCSi Inc., Colorado Springs, CO, USA
Al Barqawi, M.D., F.R.C.S. Division of Urology, Department of Surgery,
University of Colorado Denver School of Medicine, Aurora, CO, USA
Marc A. Bjurlin, D.O. Division of Urologic Oncology, Department of Urology,
NYU Langone Medical Center, New York, NY, USA
Matthew R. Cooperberg, M.D., M.P.H. Department of Epidemiology, University
of California, San Francisco, San Francisco, CA, USA
Epidemiology & Biostatistics, University of California, San Francisco, San
Francisco, CA, USA
E. David Crawford, M.D. Professor of Urology/Surgery, Radiation Oncology,
University of Colorado, Aurora, CO, USA
Jesse Elliott, B.A. Software Development, BSCi Inc., Colorado Springs, CO, USA
Michele Fascelli, B.A. Urologic Oncology Branch, National Cancer Institute –
National Institutes of Health, Bethesda, MD, USA
Arvin K. George, M.D. Urologic Oncology Branch, National Cancer Institute—
National Institutes of Health, Bethesda, MD, USA
Amichai Kilchevsky, M.D. Urologic Oncology Branch, National Cancer
Institute – National Institutes of Health, Bethesda, MD, USA
Laurence Klotz, M.D. Sunnybrook Health Sciences Centre, Toronto, ON, Canada

xi
xii Contributors

Kevin Krughoff, B.A. Division of Urology, Department of Surgery, University of

Colorado Denver School of Medicine, Aurora, CO, USA
Michael S. Leapman, M.D. Department of Urology, University of California, San
Francisco, San Francisco, CA, USA
M. Scott Lucia, M.D. Anatomic Pathology, Department of Pathology, University
of Colorado School of Medicine, Aurora, CO, USA
Brandon J. Manley, M.D. Division of Urologic Surgery, Washington University
in St. Louis, Barnes Jewish Hospital, St. Louis, MO, USA
Neil Mendhiratta, B.A. School of Medicine, NYU Langone Medical Center,
New York, NY, USA
Gary Onik, M.D. Mechanical Engineering, Carnegie Mellon University,
Ft. Lauderdale, FL, USA
Peter A. Pinto, M.D. Prostate Cancer Division, Urologic Oncology Branch,
National Cancer Institute, Bethesda, MD, USA
Katsuto Shinohara, M.D. Department of Urology, University of California, San
Francisco, San Francisco, CA, USA
Neal D. Shore, M.D., F.A.C.S. Carolina Urologic Research Center, Myrtle Beach,
SC, USA
Vassilios M. Skouteris, M.D. Prostate Brachytherapy Department, Hygeia
Hospital, Hygeia Group, Maroussi, Athens, Greece
Nelson N. Stone, M.D. Professor of Urology and Radiation Oncology, Department
of Urology, The Icahn School of Medicine at Mount Sinai, New York, NY, USA
Samir S. Taneja, M.D. Division of Urologic Oncology, Department of Urology,
NYU Langone Medical Center, New York, NY, USA
Karen Ventii, Ph.D. Emory University, Atlanta, GA, USA
Spyros D. Yarmenitis, M.D. Radiology Department, Hygeia Hospital, Hygeia
Group, Maroussi, Athens, Greece
Georgios P. Zacharopoulos, M.D., M.Sc., Ph.D. Ultrasound Department, Hygeia
Hospital, Hygeia Group, Maroussi, Athens, Greece
Editor’s Biography

Nelson N. Stone, M.D. Dr. Stone, an internationally recognized entrepreneur and

academician, is Professor of Urology and Radiation Oncology at the Icahn School
of Medicine at Mount Sinai, NY. Professor Stone earned his medical degree from
the University of Maryland in 1979. He completed a general surgical residency in
1981 at the University of Maryland, followed by residency in urology at the
University of Maryland. Dr. Stone then completed a fellowship in urologic oncol-
ogy at Memorial Sloan Kettering Cancer Center and a research fellowship in bio-
chemical endocrinology at Rockefeller University in 1986. He then became chief of
urology at Elmhurst City Hospital, eventually being promoted to full professor of
Urology and Radiation Oncology at Mount Sinai in NYC.
From the outset, Dr. Stone recognized the need to develop innovative technolo-
gies for urologic diseases and specifically prostate cancer. He was one of the first
adopters combining academic achievement with medical inventions. He recog-
nized the need to develop an alternative to radical surgery for his patients with
prostate cancer and invented the real-time 3D brachytherapy (radioactive seed)
program in 1990. Now he has turned his attention to the development of a 3D imag-
ing and biopsy system to more accurately diagnose and localize individual prostate
cancer lesions.
Dr. Stone serves on the editorial board of many scientific journals and is a mem-
ber of many professional societies, including the Prostate Conditions Education
Council, the Society for Minimally Invasive Therapy, the New York State Urological
Society, the American Association of Clinical Urologists, and the American Urologic
Association. Dr. Stone has participated in approximately 25 research studies on
prostate cancer and has authored over 400 articles, abstracts, and book chapters,
most on prostate cancer.

E. David Crawford, M.D. With his vast experience and knowledge in the urology
field, Dr. Crawford is Professor of Surgery, Professor of Radiation Oncology, and
Head of the Section of Urologic Oncology at the University of Colorado Denver
Health Sciences Center and School of Medicine. He serves as associate director of
the University of the Colorado Comprehensive Cancer Center, also in Denver.

xiii
xiv Editor’s Biography

Dr. Crawford received his medical degree from the University of Cincinnati. His
postgraduate training included an internship and residency in Urology at the Good
Samaritan Hospital in Cincinnati. He was subsequently awarded a Genitourinary
Cancer fellowship with Dr. Donald G. Skinner at the University of California
Medical Center in Los Angeles.
Dr. Crawford is a nationally recognized expert in prostate cancer. The recipient
of more than 69 research grants, he has conducted research in the treatment of
advanced bladder cancer, metastatic adenocarcinoma of the prostate, hormone-
refractory prostate cancer, and other areas of urological infections and malignan-
cies. He has authored or coauthored over 400 articles, which have been published in
such journals as Urology, the New England Journal of Medicine, and the Journal of
the National Cancer Institute. He has published five textbooks. He is also an edito-
rial reviewer or consultant for a large number of publications, including Urology,
Journal of Urology, the New England Journal of Medicine, Cancer, and the Journal
of Clinical Oncology.
Dr. Crawford is an active member of many national and international organiza-
tions, including the American Society of Clinical Oncology, American Urological
Association (AUA), and the American Association for the Advancement of
Science. Within the AUA, he is a member of the Committee to Study Urologic
Research Funding and the Prostate Cancer Clinical Trials Subcommittee. He cur-
rently serves on the board of governors, the GU committee, and the scientific advi-
sory board of the Southwest Oncology Groups, and chairs the Prostate Conditions
Education Council.
 Part I
Diagnosis
Chapter 1
History of Prostate-Specific Antigen,
from Detection to Overdiagnosis

Brandon J. Manley and Gerald L. Andriole

Abbreviations

PSA Prostate-specific antigen

PAP Prostatic acid phosphatase
DRE Digital rectal exam
kDa Kilodaltons
hK2 Human kallikrein 2
FDA Federal Drug Administration
WHO World Health Organization
IRP International Reference Preparation
BPH Benign prostatic hyperplasia
AUA American Urological Association
ACA American Cancer Association
USA United States of America
CPDR Center for Prostate Disease Research
SEER Surveillance epidemiology, and end results
PLCO Prostate lung, colorectal and ovarian screening
ERSPC European randomized study of screening for prostate cancer
PIVOT Prostate cancer intervention versus observation trial
PCPT Prostate cancer prevention trial
REDEEM Reduction by dutasteride of clinical progression events in expect-
ant management
TRUS Transrectal ultrasound
CAP/ProtecT Comparison arm for prostate testing for cancer and treatment trial
PCOS Prostate cancer outcomes study

B.J. Manley, M.D. • G.L. Andriole, M.D. (*)

Division of Urologic Surgery, Washington University in St. Louis, Barnes Jewish Hospital,
4960 Children’s Place, Campus Box 8242, St. Louis, MO 63110, USA
e-mail: [email protected]

© Springer International Publishing Switzerland 2016 3

N.N. Stone, E.D. Crawford (eds.), The Prostate Cancer Dilemma,
DOI 10.1007/978-3-319-21485-6_1
4 B.J. Manley and G.L. Andriole

The discovery and integration of prostate-specific antigen (PSA) has substantially

changed the diagnosis, treatment, and management of prostate cancer. Only a few
discoveries in the medical field over the last half century can rival the profound
impact of PSA. While the current opinions of the appropriate use of PSA as a
screening tool can be debated, its impact and the way it has directed the course of
prostate cancer research can not.
For many younger clinicians it may be hard to imagine managing a prostate can-
cer patient without the use of PSA. Prior to the identification of PSA, there were
many attempts to identify tumor markers for prostate cancer by several research
groups around the world.

The Pursuit and Discovery of PSA

Many trace the initial pursuit for a prostate cancer marker to Gutman and Gutman
in 1938 when they found elevated serum phosphatase levels in metastatic prostate
cancer patients [1]. Later in 1941, Huggins and Hodges demonstrated this finding
was likely related to the presence of bony metastasis in such patients [2]. While the
use of serum phosphatase in prostate cancer was eventually found to be limited as a
clinically useful tumor marker due to its poor sensitivity and specificity, it did pave
the way for many groups to began focused research in the field.
Over the next decade, prostatic acid phosphatase (PAP) was identified as a poten-
tial tumor marker. Several different assays to measure PAP were developed to aid in
the clinical management of prostate cancer patients. Early assays measured total
enzyme activity of PAP, mainly calorimetric, which involved the use of reagents that
change color in the presence of a specific substrate [3]. Later, newer techniques
using radioimmunoassays were able to moderately improve the specificity of testing
for PAP [4]. Ultimately, while PAP was found to be a more specific marker, it lacked
the sensitivity for prostate cancer needed to be clinically useful, as it was noted to
be elevated in several benign prostatic diseases and even after digital rectal exam
(DRE) [5]. It was also found only to be elevated in 20–30 % of patients with clini-
cally localized prostate cancer.
The work with PAP and other markers brought to light the need for a more sensi-
tive and reliable tumor marker. There was also a shift in focus to find a marker that
was present or elevated in those patients with clinically localized disease, as these
patients could possibly benefit from a serum assay test that could be useful to moni-
tor or even initiate treatment.
Many groups claimed to have conducted the research that led to the discovery of
PSA. One of the earliest reports on the identification of prostate-specific antigens
was by Rubin Flocks in 1960 [6]. In 1966, a Japanese forensic scientist, Mitsuwo
Hara, partially characterized and reported on a protein many consider similar to
PSA. He labeled the protein “gamma-seminoprotein” and proposed its use as foren-
sic evidence in rape cases because of its presence in seminal fluid [7]. Later Li and
Beling further purified this protein and reported it to have a molecular weight of
1 History of Prostate-Specific Antigen, from Detection to Overdiagnosis 5

31 kilodaltons (kDa) [8]. Similar reports and characterization were done by

Sensabaugh and his group confirming this protein to have specificity for human
semen [9]. Years later, through the work of Wang and Papsidero the purification of
this protein demonstrated that it was identical to that of PSA found in human serum
[10, 11]. More definitively, in 1970 and 1972 Albin published his reports of a puri-
fied antigen isolated from prostate tissue [12, 13].
In 1979, T. Ming Chu and his research group purified and characterized PSA and
demonstrated its presence in both benign and malignant prostate tissue [11, 14].
These studies confirmed that PSA was highly specific for prostate tissue and was
produced by prostatic epithelial cells. This group was also credited with the first
development of an immunoassay that could be used for human serum testing
although it was much less sensitive than those used today detecting PSA at a mini-
mal concentration of 500 ng/ml compared to modern assay’s detecting PSA at
<0.01 ng/ml [11]. In 1987, early work in the clinical applications of PSA by Chu’s
group and Thomas Stamey demonstrated a use for PSA in monitoring the course of
patients known to have prostate cancer [15].
More precise testing using protein sequencing has determined that many of the
groups from the 1960s and 1970s were most likely describing prostate-specific anti-
gen or one of its natural analogues [16].
Shortly after its discovery much of the interest on PSA focused on determination
of its physiologic role. In 1984 Chu et al. reported that PSA was a protease and later
through studies by Lilja its role in the proteolytic cleavage of seminal vesicle pro-
teins was published [17, 18]. They described the role of PSA as cleaving the gel-
forming proteins from the seminal vesicles (semenogelins I, II and fibronectin)
which initiates liquefaction of the ejaculate, thereby increasing the motility of sperm
and aiding in fertilization. These studies and others also identified several other
prostatic proteins similar to PSA, notably human kallikrein 2 (hK2). Similar to
PSA, it is expressed by prostatic tissue and has a similar role in cleaving of seminal
vesicle proteins, although it is much more potent enzymatically [19].
Later in the 1980s PSA was confirmed to belong to the human kallikrein family
of serine proteases, and it was given formal nomenclature and labeled human kal-
likrein 3 (hK3) [20]. There are currently 15 other members of this family that have
been described in the literature and many of them are believed to play some role in
many human cancers [21]. The relationship between PSA and hK2 is worth noting.
These two share many common features but also some key differences. PSA and
hK2 share 80 % amino acid sequence homology but hK2 is present in 1–2 % of the
amount of PSA found in typical prostate tissue [22]. In vitro studies have demon-
strated that hK2 has the ability to autoactivate, while PSA does not have this char-
acteristic and for this reason some have proposed a role for hK2 in regulating the
activity of PSA [23].
Further studies into the physiologic role of PSA also uncovered two forms of PSA
most commonly found in patients serum. One form was smaller than the other (36
kDa compared to 90–100 kDa) and it was found later by Lilja and Stenman that the
smaller form was that of free PSA and the larger was complexed PSA (also known as
bound PSA) [24]. Studies showed that PSA was most commonly complexed with
6 B.J. Manley and G.L. Andriole

alpha-1-antichymotrypsin, a protease inhibitor [25]. Only 10–30 % of PSA was pres-

ent in an uncomplexed form. Free PSA represented the inactive form and was typi-
cally higher in patients with begin prostatic conditions. Other studies demonstrated
that the level of free PSA was lower in prostate cancer patients and this subsequently
led to the development of immunoassays to test specifically for it [26]. The ratio of
free PSA to total PSA has proven useful in its clinical application and ability to
increase the positive predictive value for positive prostate biopsies [27].

The Golden Years of PSA Testing

The Federal Drug Administration (FDA) approved the first commercial immunoas-
say for PSA testing in 1987. Around this time Stamey et al. and Oesterling reported
the half-life of PSA to be 2.2 ± 0.8 and 3.2 ± 0.1 days respectively [15, 28].
Subsequently several assays were developed for PSA testing including Tandem-R
PSA®, Pros-check PSA®, Tandem-E PSA®, IRMA-count PSA®, and Abbott IMX
PSA®. Myrtle et al. was one of the first to attempt to give the reference range for a
“normal” PSA value with the use of the Tandem R PSA® assay [29]. He studied the
reported PSA values in a population of 472 men without a history of prostate cancer,
most of which were below the age of 60 years. Other larger studies attempted to find
the ideal value for initiating prostate biopsy looking at more clinically relevant
patient populations (i.e., over 50 years of age) and varied in their suggested cutoff
values between 2.8 and 4.0 ng/ml using a standard deviation of ±2 [30, 31].
Ultimately it was the screening test reported from a cohort of 6630 men aged 50–74
years of age using a cutoff value of 4.0 ng/ml that led to the FDA’s approval of
screening with PSA [32–35]. Consequently the value of 4.0 ng/ml became most
commonly used for initiating prostate biopsy, although at the time several groups
felt this value to be too aggressive and proposed a cutoff value of 10 ng/ml. Notably
in 2004 the National Comprehensive Cancer Network recommended a lower cutoff
of 2.5 ng/ml citing the number of cancers missed with higher cutoffs and the bene-
fits in patient outcomes reported at that time.
Early use of these commercial assays used in the clinical setting led to inconsis-
tent results and created the need for standardization of PSA testing. Graves et al.
called for an international standardization of PSA assays in 1990, which led to the
principles used in PSA testing today [36]. The issue he described centered around
the fact that each assay detected different molar ratios of the various forms of PSA
found in the serum (free vs. bound to proteins) and therefore different results were
obtained with different assays from the same serum [37]. As many of the initial PSA
screening trials were done using the Tandem R PSA® assay from Hybritech, newer
assays that came on the market were initially “standardized” to the values of this
assay. With time it became apparent that there was increasing variability between
these assays and their reported PSA values. Naturally this raised many concerns,
especially when following patients’ PSA values could dictate the decision to per-
form a prostate biopsy. In an effort to mitigate these effects, a group of researchers
1 History of Prostate-Specific Antigen, from Detection to Overdiagnosis 7

and experts convened at Stanford University in 1994 and proposed a method of

standardization that later was adopted by the World Health Organization (WHO)
who issued the First International Reference Preparation (IRP) for PSA in 1999.
Unknowingly the standardization from the WHO produced PSA values that were
approximately 22 % lower than that of the traditional results from the Tandem R
PSA assay®. These discrepancies had the potential to cause serious confusion among
physicians and potentially resulted in some patients not being offered biopsy, espe-
cially when following patients by such metrics as PSA velocity.
In 1990, the idea for the incorporation of PSA as part of the initial work up for
diagnosing prostate cancer was introduced by Cooner [38]. He described using PSA
testing as part of a “three-legged stool” which included DRE and transrectal ultra-
sound guided prostate biopsies. This algorithm was believed to be superior for pros-
tate cancer screening since DRE alone found that 70–80 % of patient had locally
advanced or metastatic disease at diagnosis [39]. Subsequent to his initial study,
Cooner and several other groups attempted to improve the specificity of PSA testing
for prostate cancer by reporting on age-specific PSA values [40–42]. These studies
were done in part due to the fact that patients with benign prostatic hyperplasia
(BPH) had increased PSA levels making one “normal” value for all men unreliable.
The introduction of PSA density (prostate volume/PSA) and PSA velocity (changes
over time) was an attempt to compensate for these limitations [43].
In 1991, Catalona et al. used a PSA cutoff of 4.0 ng/mL in the initial screening
of prostate cancer patients and suggested the use of PSA as a screening test for
prostate cancer [32, 40]. Over the next couple of years several medical groups
including the American Urological Association (AUA) and American Cancer
Association (ACA) endorsed annual PSA screening for men over 50 years of age.
During this time PSA screening was hailed as dramatically improving the detec-
tion of curable prostate cancer. Gann et al. found in men diagnosed with prostate
cancer an elevated PSA preceded an abnormal DRE by an average of 6.2 years [42].
Incorporation of PSA screening into clinical practice resulted in an increase of pros-
tate cancer detection from 1987 to 1992 of 85 %. By 1997, 75 % of prostate cancers
were diagnosed by elevated or abnormal PSAs in the United States of America
(USA) [44, 45]. Stage migration of prostate cancer also dramatically shifted during
this time with Catalona et al. publishing a report in 1993 that 70–80 % of men were
being diagnosed with organ confined disease compared to historical cohorts of
20–30 % [33]. The Center for Prostate Disease Research (CPDR) reported that the
percentage of patients presenting with metastatic disease decreased from 19.8 % in
1989 to 3.3 % by 1998 [46].

The Trials and Tribulations of PSA Screening

After PSA screening came into practice in the USA in the late 1980s and especially
in the early 1990s, the incidence of prostate cancer diagnosis rapidly increased, with
mortality rates subsequently declining [47]. Etzioni and colleagues used modeling
8 B.J. Manley and G.L. Andriole

data from Surveillance, Epidemiology, and End Results (SEER) Medicare and
screening standards used in the Prostate, Lung, Colorectal and Ovarian screening
trial (PLCO) to show that PSA screening alone could not account for the decrease
in prostate cancer mortality seen during the 1990s [48]. Their work and others high-
lighted the fact that while PSA screening certainly played a role in the mortality
decrease for prostate cancer patients, especially in the USA, the increase in new and
more aggressive treatments also contributed to this decline. Tapering enthusiasm for
PSA screening, Albertsen and colleagues published data that showed that many
patients in the pre-PSA screening era, when followed without treatment, were des-
tined to die of causes other than prostate cancer [49].
Opposition to PSA’s use and specifically PSA screening became more common
by the late 1990s and early 2000s. Concern grew that the results of the emerging
retrospective studies showing improved diagnosis and survival of prostate cancer
patients using PSA screening were confounded by lead time and length time biases.
Around this time several large randomized studies testing the hypothesis that PSA
screening could decrease prostate cancer-specific mortality were initiated.
The two largest and most discussed studies regarding PSA screening are the
Prostate, Lung, Colorectal and Ovarian screening trial (PLCO) in the USA and the
European Randomized Study of Screening for Prostate Cancer (ERSPC) [50, 51].
Several other large studies also contributed to the evaluation of the benefits and risks
of PSA screening including Prostate Cancer Intervention Versus Observation Trial
(PIVOT), Prostate Cancer Prevention Trial (PCPT), and Reduction by Dutasteride
of Clinical Progression Events in Expectant Management (REDEEM) trial [52–54].
It is essential that all physicians who treat or manage prostate cancer patients read
and understand the results of these trials.
The primary objectives of both ERSPC and PLCO were nearly identical. The
main endpoint in both studies was prostate cancer mortality. One of the main differ-
ences between the two studies was the population in Europe, at least during the
early years of the study, had less exposure to PSA testing and thus offered a less
“contaminated” control group. Unfortunately, men enrolling in the US study had
significant exposure to PSA testing compromising the PLCO control group. In this
regard many consider the PLCO trial to be one of comparing systematic PSA
screening to “opportunistic” screening as evidenced by the fact that the absolute
difference in those who underwent PSA screening at anytime during the study
between the screening and control group was only 33 %.
There was also some other differences between the trials that deserve mention.
In PLCO the contamination rate was reported to be 54.8 % with patients obtaining
a PSA outside the trials design [55]. The best reported rate of contamination in
ERSPC published was 30.7 %, although this data is hard to come by in Europe [56].
It should be mentioned that for the power calculations used in the design of the
ERSPC trial a contamination rate of 20 % was employed. There was also a large
difference between the two trials with regard to performing indicated prostate biop-
sies. In PLCO the rate of biopsy was 41 % in patients indicated for biopsy during
the first year of the study and rose to 64 % with the third year of screening. In
ERSPC the rate was 85.8 % for patients indicated within its trial design [57]. This
1 History of Prostate-Specific Antigen, from Detection to Overdiagnosis 9

difference likely contributes to the lower rate of cancer detection seen in the PLCO
screening arm and may have impacted comparison between the two arms in regard
to prostate cancer mortality.
The randomization of patients in both trials also had some notable differences,
along with the indications for biopsy. Patients aged 50–74 years were randomized
to the two arms but later a “core age group” was defined in reporting much of the
data from ERSPC, which had patients aged 55–69. Men in the screening arm were
screened at 4-year interval, except in Sweden in which they were screened at 2-year
intervals. Indications for biopsy varied among the constitute centers for the ERSPC
trial. Initially some centers required a PSA over 4.0 ng/dl and an abnormal DRE as
an indication for biopsy. After 1997, all centers, minus Finland, recommended
biopsy for a PSA over 3.0 ng/dl. In Finland DRE was required to be positive for
PSA in the 3–3.9 ng/dl range and later this changed to having a free/total ratio of
PSA of equal to or less than 0.16. In Italy patients with a PSA of 2.5–3.9 ng/dl had
DRE and transrectal ultrasound (TRUS) performed. When performing biopsies a
lateral sextant method was applied in all centers but the execution of these was left
to individual study groups within ERSPC. Medical contraindications were the only
exception listed for not performing an indicated biopsy. After a diagnosis of pros-
tate cancer, treatment decisions were left to the discretion of local providers.
PLCO initially randomized patients aged 60–74 years old, later they included
patients aged 55–60 and also used prior PSA testing with 3 years of entry to the trial
to reduce contamination between the two arms. In PLCO screening with DRE and
PSA was offered yearly for the first 4 years and then with PSA alone for another 2
years. Recommended indications for prostate biopsy were “community standard”
where initially a PSA value above 4.0 ng/dl and/or abnormal DRE. In later years a
significant percentage of patients underwent biopsy for a PSA 2.5–4.0 ng/dl. The
biopsy extent and the number of cores were left to the individual providers in the
community.
In 2009 both trials published their initial results. ERSPC reported it findings after
its data monitoring committee found a significant difference in prostate cancer mor-
tality in favor of the screening arm at the time of its third predetermined interim
analysis. The publishing of the results for the PLCO trial was done after the safety
monitoring committee found a continuing lack of significant difference in the death
rates between the two study groups and felt that this presented concerns in regard to
public health. The PLCO trial was updated in 2012 with 13-year follow-up between
the two arms of the study and continued to show no statistical difference between
the intervention arm (organized screening) and the control arm (opportunistic
screening) [58]. Recent updates from ERSPC in 2014, now with 13-year follow-up,
have continued to show a survival benefit for patients undergoing PSA screening
and in fact that benefit has increased modestly [59]. Their findings reported a sig-
nificant 21 % relative reduction in prostate cancer in intention to screen analyses,
and a 27 % relative reduction in men who actually had screening. These recent
updates showed an improved benefit of PSA screening with longer follow-up dem-
onstrated by the number needed to screen and number needed to be diagnosed with
prostate cancer to prevent one prostate cancer death. As seen in the table below,
10 B.J. Manley and G.L. Andriole

Table 1.1 Trending the number needed to screen and diagnose with ERSPC updates
ERSPC Number needed to be screened Number needed to be
follow-up data (per 1000 patients) diagnosed (per 1000 patients)
9 years 1410 48
11 years 979 35
13 years 781 27

Table 1.1, both numbers in the case of the ERSPC trial have become substantially
lower in their most recent follow-up data at 13 years compared to the numbers
reported at 11 years and 9 years of follow-up [60]. For reference, the number needed
to be screened with digital mammography to save one life from breast cancer was
reported as 1339 (CI: 322–7455) and 377 (CI 230 to 1050) in women aged 50–59
years old and 60–69 years old, respectively [61]. Similarly the reported number
needed to screen for colorectal cancer with fecal occult blood testing is 1176 [62].
The Göteborg screening trial, which was comprised of a significant number of
patients who were enrolled in the ERSPC trial, also further supported these findings
and reported a number of approximately 300 patients needing to be screened to
prevent one death from prostate cancer at 14 years [63]. In contrast a study that
looked at the largest center that participated in ERSPC, Finland, which by itself had
a larger number of study patients than PLCO, showed only a non-statistically sig-
nificant benefit in prostate cancer mortality among patients in the screening arm of
the study [64]. This finding along with treatment patterns favoring men in the
screened arm continues to cause concern about the real benefit of PSA-based
screening.
Several other groups have used modeling data to estimate the improved benefits
of PSA screening with longer follow-up. Gulati et al. projected 25-year estimates of
the number needed to screen and to treat to prevent one prostate cancer death for
men aged 55–69 years at diagnosis using data from ERSPC and PLCO [65]. They
reported that in Europe, the number needed to screen was 262 and number needed
to treat was nine after 25 years. Attempting to control for rates of overdiagnosis in
the USA, they reported the number needed to screen was 186–220 and number
needed to treat being 2–5. These statistics are markedly lower than the most recent
13-year follow-up data from the ERSPC.
We strongly encourage the reader to become familiar with both trials as the
debate regarding their results and their impact on PSA screening is likely to con-
tinue for years to come. The results of future studies, particularly the Comparison
Arm for Prostate Testing for Cancer and Treatment trial (CAP/ProtecT) of 450,000
men from the United Kingdom, will likely add to our current data on the use of PSA
screening and prostate cancer [66].
At the center of the PSA screening debate is the attempt to realize the beneficial
and adverse effects of screening. Finding the equilibrium between these two results
is unlikely to be found in the scientific or medical literature but must be valued
within the political and social systems in which screening is practiced.
1 History of Prostate-Specific Antigen, from Detection to Overdiagnosis 11

The Effects of Screening with PSA and Overdiagnosis

Some of the issues surrounding screening with PSA revolve around the risk of over-
treatment for low grade and low-risk prostate cancer patients. With the influx of new
cases in the early 1990s after the integration of regular PSA screening, there was
also a natural increase in the number of patient undergoing definitive treatment.
Concerns about the long-term effects of these treatments, especially those patients
that are younger and those with low-risk disease, gave rise to an emerging field of
study in prostate cancer, cancer survivorship. The product of early screening and
treatment along with the frequency and high survival rates of prostate cancer patients
has created a growing population of prostate cancer survivors [67]. Both the
American Cancer Society and a recent study by Mariotto et al. estimate that there
are now more than two million prostate cancer survivors living in the USA and that
number is expected to climb [68, 69].
Recently several groups have published long-term data regarding the effects of
prostate cancer treatment [70]. One of the largest populations that have been
reported on for these effects is the Prostate Cancer Outcomes Study (PCOS) which
follows 1164 men who underwent treatment with surgery and 491 who had radio-
therapy. The study assessed functional status immediately after treatment and at 2,
5, and 15 years after diagnosis. Resnick et al. reported data for this group at 15 years
and found the prevalence of erectile dysfunction was very high, affecting 87.0 % of
men in the prostatectomy group and 93.9 % of those in the radiotherapy group [71].
This study was somewhat limited by the lack of a control group (e.g., active surveil-
lance) and reliable pretreatment baseline data. Regardless this study and others have
placed a spotlight on the long-term effects of invasive procedures needed to treat
and cure prostate cancer.
Dealing with the sequelae of prostate cancer treatment, especially long-term sur-
vivors, can place a significant burden on patients, both financially and in terms of
time and efforts. De Oliveria et al. looked at a population of prostate cancer survi-
vors in Canada and found higher total health care expenses among younger patients,
metastatic patients, and those who underwent treatment with surgery [72]. They
also found lower costs in patients with better urinary function. Similar findings in a
study of prostate cancer patients in the USA who were recently diagnosed, within
1–3 years, found total out of pocket expenses and overall costs were inversely
related to most of the commonly employed prostate-specific health-related quality
of life survey scores [73].
The long-term effects of prostate cancer treatment are not limited to those under-
going surgery or radiation. Morgans et al. showed that in patients undergoing pro-
longed androgen deprivation the risk of developing comorbidities, specifically
diabetes and cardiovascular disease, is increased well above those of age matched
controls [74]. This risk was especially high among those patients who already had
significant comorbidities prior to treatment.
The risks of long-term morbidity from prostate cancer treatment need to be con-
sidered by both the physician and patient prior to initiating screening. Several
12 B.J. Manley and G.L. Andriole

Table 1.2 Risk of mortality Comorbidity count

from causes other than
Age 0 1 2 3+
prostate cancer
Under 60 (%) 9 19 30 35
60–70 (%) 26 26 48 53
Older than 70 (%) 49 57 66 74
Comorbidity counts were calculated using the
Charlson comorbidity index. Other cause mortality at
14 years [77]

groups have attempted to better define those patients suitable for treatment and
screening. Using data from the PCOS, Daskivich et al. have published their findings
in an attempt to better understand competing risk for mortality in patients with pros-
tate cancer [75]. The cumulative incidence of other cause mortality at 14 years was
modeled based on comorbidities (Table 1.2). Prostate cancer mortality at 14 years
using the same analysis was 5, 8, and 23 % for men with low-, intermediate-, and
high-risk disease respectively using the D’Amico classification [76].

The Evolution of Prostate Tumor Markers

While the exact role for PSA, especially in regard to screening, continues to evolve,
the ongoing development of even more specific and ideally more applicable tumor
markers for prostate cancer continues to progress. Many of these improvements sur-
round PSA itself. Of these, the prostate health index, which is an assay using the
concentration of a molecular isoform of free PSA, total PSA, and proPSA, has a
greater specificity than total PSA or percentage-free PSA in select patients [78].
Addition of the four kallikrein protein assay has shown promise in being able to
discriminate patients at risk for high grade prostate cancer [79]. Many of these assays
are being introduced and appear to be making a clinical impact in the management
and diagnosis of prostate cancer patients with a particular focus on their integration
into screening algorithms. How they will compare to the current methods for screen-
ing and diagnosis will need to be investigated in randomized trials [80].

References

1. Gutman AB, Gutman EB. An acid phosphatase occurring in the serum of patients with metas-
tasizing carcinoma of the prostate gland. J Clin Invest. 1938;17(1):473–9.
2. Huggins HR, Hodges CV. Studies on prostatic cancer: the effects of castration of estrogen and
of androgen injection on serum phosphatases on metastatic carcinoma of the prostate. Cancer
Res. 1941;1(1):293–7.
3. Fishman WH, Lerner F. A method for estimating serum acid phosphatase of prostatic origin.
J Biol Chem. 1953;200(1):89–97.
1 History of Prostate-Specific Antigen, from Detection to Overdiagnosis 13

4. Griffiths JC. Prostate-specific acid phosphatase: re-evaluation of radioimmunoassay in diag-

nosing prostatic disease. Clin Chem. 1980;26(3):433–6.
5. Li CY, Chuda RA, Lam WK, Yam LT. Acid phosphatases in human plasma. J Lab Clin Med.
1973;82(3):446–60.
6. Flocks R, Urich V, Patel C, Opitz J. Studies on the antigenic properties of prostatic tissue.
J Urol. 1960;84:134–43.
7. Hara M, Koyanagi Y, Inoue T, Fukuyama T. Some physico-chemical characteristics of “ -semi-
noprotein”, an antigenic component specific for human seminal plasma. Forensic immunologi-
cal study of body fluids and secretion. VII. Nihon Hoigaku Zasshi. 1971;25(4):322–4.
Japanese.
8. Li TS, Beling CG. Isolation and characterization of two specific antigens of human seminal
plasma. Fertil Steril. 1973;24(2):134–44.
9. Sensabaugh GF. Isolation and characterization of a semen-specific protein from human semi-
nal plasma: a potential new marker for semen identification. J Forensic Sci.
1978;23(1):106–15.
10. Wang MC, Valenzuela LA, Murphy GP, Chu TM. Tissue specific and tumor specific antigens
in human prostate. Fed Proc. 1977;36:1254.
11. Papsidero LD, Wang MC, Valenzuela LA, Murphy GP, Chu TM. A prostate antigen in sera of
prostatic cancer patients. Cancer Res. 1980;40(7):2428–32.
12. Ablin RJ, Bronson P, Soanes WA, Witebsky E. Tissue- and species-specific antigens of normal
human prostatic tissue. J Immunol. 1970;104(6):1329–39.
13. Ablin RJ, Soanes WA, Bronson P, Witebsky E. Precipitating antigens of the normal human
prostate. J Reprod Fertil. 1970;22(3):573–4.
14. Wang MC, Valenzuela LA, Murphy GP, Chu TM. Purification of a human prostate specific
antigen. Invest Urol. 1979;17(2):159–63.
15. Stamey TA, Yang N, Hay AR, McNeal JE, Freiha FS, Redwine E. Prostate-specific antigen as
a serum marker for adenocarcinoma of the prostate. N Engl J Med. 1987;317:909–16.
16. Sokoll LJ, Chan DW. Prostate-specific antigen. Its discovery and biochemical characteristics.
Urol Clin North Am. 1997;24(2):253–9. Review.
17. Ban Y, Wang MC, Watt KW, Loor R, Chu TM. The proteolytic activity of human prostate-
specific antigen. Biochem Biophys Res Commun. 1984;123(2):482–8.
18. Lilja H. A kallikrein-like serine protease in prostatic fluid cleaves the predominant seminal
vesicle protein. J Clin Invest. 1985;76(5):1899–903.
19. Lilja H. Structure and function of prostatic- and seminal vesicle-secreted proteins involved in
the gelation and liquefaction of human semen. Scand J Clin Lab Invest Suppl.
1988;191:13–20.
20. Berg T, Bradshaw RA, Carretero OA, Chao J, Chao L, Clements JA, et al. A common nomen-
clature for members of the tissue (glandular) kallikrein gene families. Agents Actions Suppl.
1992;38(Pt 1):19–25.
21. Borgoño CA, Michael IP, Diamandis EP. Human tissue kallikreins: physiologic roles and
applications in cancer. Mol Cancer Res. 2004;2(5):257–80. Review.
22. De Angelis G, Rittenhouse HG, Mikolajczyk SD, Blair Shamel L, Semjonow A. Twenty years
of PSA: from prostate antigen to tumor marker. Rev Urol. 2007;9(3):113–23. Summer.
23. Mikolajczyk SD, Millar LS, Marker KM, Grauer LS, Goel A, Cass MM, et al. Ala217 is
important for the catalytic function and autoactivation of prostate-specific human kallikrein 2.
Eur J Biochem. 1997;246(2):440–6.
24. Stenman UH, Leinonen J, Alfthan H, Rannikko S, Tuhkanen K, Alfthan O. A complex between
prostate-specific antigen and alpha 1-antichymotrypsin is the major form of prostate-specific
antigen in serum of patients with prostatic cancer: assay of the complex improves clinical
sensitivity for cancer. Cancer Res. 1991;51(1):222–6.
25. Lilja H, Christensson A, Dahlén U, Matikainen MT, Nilsson O, Pettersson K, et al. Prostate-
specific antigen in serum occurs predominantly in complex with alpha 1-antichymotrypsin.
Clin Chem. 1991;37(9):1618–25.
14 B.J. Manley and G.L. Andriole

26. Chen Z, Chen H, Stamey TA. Prostate specific antigen in benign prostatic hyperplasia: purifi-
cation and characterization. J Urol. 1997;157(6):2166–70.
27. Toubert ME, Guillet J, Chiron M, Meria P, Role C, Schlageter MH, et al. Percentage of free
serum prostate-specific antigen: a new tool in the early diagnosis of prostatic cancer. Eur J
Cancer. 1996;32A(12):2088–93.
28. Oesterling JE, Chan DW, Epstein JI, Kimball Jr AW, Bruzek DJ, Rock RC, et al. Prostate spe-
cific antigen in the preoperative and postoperative evaluation of localized prostatic cancer
treated with radical prostatectomy. J Urol. 1988;139(4):766–72.
29. Myrtle JF, Klimley PG, Ivor LP, Brun JF. Clinical utility of prostate-specific antigen (PSA) in
the management of prostate cancer. Advances in Cancer Diagnosis. Hybritech. 1986.
30. Kane RA, Littrup PJ, Babaian R, Drago JR, Lee F, Chesley A, et al. Prostate-specific antigen
levels in 1695 men without evidence of prostate cancer. Findings of the American Cancer
Society National Prostate Cancer Detection Project. Cancer. 1992;69(5):1201–7.
31. Dalkin BL, Ahmann FR, Kopp JB. Prostate specific antigen levels in men older than 50 years
without clinical evidence of prostatic carcinoma. J Urol. 1993;150(6):1837–9.
32. Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuan JJ, et al. Measurement of
prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med.
1991;324(17):1156–61. Erratum in: N Engl J Med 1991 Oct 31;325(18):1324.
33. Catalona WJ, Smith DS, Ratliff TL, Basler JW. Detection of organ-confined prostate cancer is
increased through prostate-specific antigen-based screening. JAMA. 1993;270(8):948–54.
34. Dalkin BL, Ahmann FR, Kopp JB, Catalona WJ, Ratliff TL, Hudson MA, et al. Derivation and
application of upper limits for prostate specific antigen in men aged 50-74 years with no clini-
cal evidence of prostatic carcinoma. Br J Urol. 1995;76(3):346–50.
35. Catalona WJ, Richie JP, Ahmann FR, Hudson MA, Scardino PT, Flanigan RC, et al.
Comparison of digital rectal examination and serum prostate specific antigen in the early
detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. J Urol.
1994;151(5):1283–90.
36. Graves HC, Wehner N, Stamey TA. Comparison of a polyclonal and monoclonal immunoas-
say for PSA: need for an international antigen standard. J Urol. 1990;144(6):1516–22.
37. Punglia RS, D'Amico AV, Catalona WJ, Roehl KA, Kuntz KM. Effect of verification bias on
screening for prostate cancer by measurement of prostate-specific antigen. N Engl J Med.
2003;349(4):335–42.
38. Cooner WH, Mosley BR, Rutherford Jr CL, Beard JH, Pond HS, Terry WJ, et al. Prostate
cancer detection in a clinical urological practice by ultrasonography, digital rectal examination
and prostate specific antigen. J Urol. 1990;143(6):1146–52. discussion 1152-4.
39. Brawer MK. Prostate specific antigen. New York, NY: Marcel Dekker; 2001.
40. Brawer MK, Chetner MP, Beatie J, Buchner DM, Vessella RL, Lange PH. Screening for pros-
tatic carcinoma with prostate specific antigen. J Urol. 1992;147(3 Pt 2):841–5.
41. Carter HB, Pearson JD, Metter EJ, Brant LJ, Chan DW, Andres R, et al. Longitudinal evalua-
tion of prostate-specific antigen levels in men with and without prostate disease. JAMA.
1992;267(16):2215–20.
42. Gann PH, Hennekens CH, Stampfer MJ. A prospective evaluation of plasma prostate-specific
antigen for detection of prostatic cancer. JAMA. 1995;273(4):289–94.
43. Carter HB, Ferrucci L, Kettermann A, Landis P, Wright EJ, Epstein JI, et al. Detection of life-
threatening prostate cancer with prostate-specific antigen velocity during a window of cur-
ability. J Natl Cancer Inst. 2006;98(21):1521–7.
44. Potosky AL, Miller BA, Albertsen PC, Kramer BS. The role of increasing detection in the ris-
ing incidence of prostate cancer. JAMA. 1995;273(7):548–52.
45. Plawker MW, Fleisher JM, Vapnek EM, Macchia RJ. Current trends in prostate cancer diagno-
sis and staging among United States urologists. J Urol. 1997;158(5):1853–8.
46. Sun L, Gancarczyk K, Paquette EL, McLeod DG, Kane C, Kusuda L, et al. Introduction to
Department of Defense Center for Prostate Disease Research Multicenter National Prostate
Cancer Database, and analysis of changes in the PSA-era. Urol Oncol. 2001;6(5):203–9.
1 History of Prostate-Specific Antigen, from Detection to Overdiagnosis 15

47. Hankey BF, Feuer EJ, Clegg LX, Hayes RB, Legler JM, Prorok PC, et al. Cancer surveillance
series: interpreting trends in prostate cancer--part I: evidence of the effects of screening in
recent prostate cancer incidence, mortality, and survival rates. J Natl Cancer Inst.
1999;91(12):1017–24.
48. Etzioni R, Legler JM, Feuer EJ, Merrill RM, Cronin KA, Hankey BF. Cancer surveillance
series: interpreting trends in prostate cancer – part III: quantifying the link between population
prostate-specific antigen testing and recent declines in prostate cancer mortality. J Natl Cancer
Inst. 1999;91(12):1033–9.
49. Albertsen PC, Fryback DG, Storer BE, Kolon TF, Fine J. Long-term survival among men with
conservatively treated localized prostate cancer. JAMA. 1995;274(8):626–31.
50. Andriole GL, Crawford ED, Grubb 3rd RL, Buys SS, Chia D, Church TR, et al. Mortality
results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360(13):
1310–9.
51. Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. Screening and
prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360(13):
1320–8.
52. Wilt TJ, Brawer MK, Jones KM, Barry MJ, Aronson WJ, Fox S, et al. Radical prostatectomy
versus observation for localized prostate cancer. N Engl J Med. 2012;367(3):203–13.
53. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, et al. The influence
of finasteride on the development of prostate cancer. N Engl J Med. 2003;349(3):215–24.
54. Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M, Montorsi F, REDUCE
Study Group, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med.
2010;362(13):1192–202.
55. Pinsky PF, Black A, Kramer BS, Miller A, Prorok PC, Berg C. Assessing contamination and
compliance in the prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO)
cancer screening trial. Clin Trials. 2010;7(4):303–11.
56. Roobol MJ, Kerkhof M, Schröder FH, Cuzick J, Sasieni P, Hakama M, et al. Prostate cancer
mortality reduction by prostate-specific antigen-based screening adjusted for nonattendance
and contamination in the European Randomised Study of Screening for Prostate Cancer
(ERSPC). Eur Urol. 2009;56(4):584–91.
57. Schröder FH, Roobol MJ. ERSPC and PLCO prostate cancer screening studies: what are the
differences? Eur Urol. 2010;58(1):46–52.
58. Andriole GL, Crawford ED, Grubb 3rd RL, Buys SS, Chia D, Church TR, et al. Prostate can-
cer screening in the randomized prostate, lung, colorectal, and ovarian cancer screening trial:
mortality results after 13 years of follow-up. J Natl Cancer Inst. 2012;104(2):125–32.
59. Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Zappa M, Nelen V, et al. Screening and
prostate cancer mortality: results of the European Randomised Study of Screening for Prostate
Cancer (ERSPC) at 13 years of follow-up. Lancet. 2014;384(9959):2027–35.
60. Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. Prostate-cancer
mortality at 11 years of follow-up. N Engl J Med. 2012;366(11):981–90.
61. US Preventive Services Task Force. Screening for breast cancer: U.S. Preventive Services Task
Force recommendation statement. Ann Intern Med. 2009;151(10):716–26, W-236.
62. Hewitson P, Glasziou P, Irwig L, Towler B, Watson E. Screening for colorectal cancer using
the faecal occult blood test. Hemoccult. Cochrane Database Syst Rev. 2007;1, CD001216.
Review.
63. Hugosson J, Carlsson S, Aus G, Bergdahl S, Khatami A, Lodding P, et al. Mortality results
from the Göteborg randomised population-based prostate-cancer screening trial. Lancet
Oncol. 2010;11(8):725–32.
64. Kilpeläinen TP, Tammela TL, Malila N, Hakama M, Santti H, Määttänen L, et al. Prostate
cancer mortality in the Finnish randomized screening trial. J Natl Cancer Inst.
2013;105(10):719–25.
65. Gulati R, Mariotto AB, Chen S, Gore JL, Etzioni R. Long-term projections of the harm-benefit
trade-off in prostate cancer screening are more favorable than previous short-term estimates.
J Clin Epidemiol. 2011;64(12):1412–7.
16 B.J. Manley and G.L. Andriole

66. Lane JA, Donovan JL, Davis M, Walsh E, Dedman D, Down L, ProtecT study group, et al.
Active monitoring, radical prostatectomy, or radiotherapy for localised prostate cancer: study
design and diagnostic and baseline results of the ProtecT randomised phase 3 trial. Lancet
Oncol. 2014;15(10):1109–18.
67. Heijnsdijk EA, Wever EM, Auvinen A, Hugosson J, Ciatto S, Nelen V, et al. Quality-of-life
effects of prostate-specific antigen screening. N Engl J Med. 2012;367(7):595–605.
68. American Cancer Society: What is prostate cancer?. http://www.cancer.org/cancer/prostatecan-
cer/. Accessed 28 Nov 2014.
69. Mariotto AB, Yabroff KR, Shao Y, Feuer EJ, Brown ML. Projections of the cost of cancer care
in the United States: 2010-2020. J Natl Cancer Inst. 2011;103(2):117–28.
70. Taylor KL, Luta G, Miller AB, Church TR, Kelly SP, Muenz LR, et al. Long-term disease-
specific functioning among prostate cancer survivors and noncancer controls in the prostate,
lung, colorectal and ovarian cancer screening trial. J Clin Oncol. 2012;30(22):2768–75.
71. Resnick MJ, Koyama T, Fan KH, Albertsen PC, Goodman M, Hamilton AS, et al. Long-term
functional outcomes after treatment for localized prostate cancer. N Engl J Med.
2013;368(5):436–45.
72. de Oliveira C, Bremner KE, Ni A, Alibhai SM, Laporte A, Krahn MD. Patient time and out-of-
pocket costs for long-term prostate cancer survivors in Ontario, Canada. J Cancer Surviv.
2014;8(1):9–20.
73. Jayadevappa R, Schwartz JS, Chhatre S, Gallo JJ, Wein AJ, Malkowicz SB. The burden of out-
of-pocket and indirect costs of prostate cancer. Prostate. 2010;70(11):1255–64.
74. Morgans AK, Fan KH, Koyama T, Albertsen PC, Goodman M, Hamilton AS, et al. Influence of
age on incident diabetes and cardiovascular disease among prostate cancer survivors receiving
androgen deprivation therapy. J Urol. 2014;pii: S0022–5347(14)04835–6.
75. Daskivich TJ, Fan KH, Koyama T, Albertsen PC, Goodman M, Hamilton AS, et al. Prediction
of long-term other-cause mortality in men with early-stage prostate cancer: results from the
Prostate Cancer Outcomes Study. Urology. 2015;85(1):92–100.
76. D'Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, et al. Biochemical outcome
after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for
clinically localized prostate cancer. JAMA. 1998;280(11):969–74.
77. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic
comorbidity in longitudinal studies: development and validation. J Chronic Dis.
1987;40(5):373–83.
78. Loeb S, Sanda MG, Broyles DL, Shin SS, Bangma CH, Wei JT, et al. The Prostate Health Index
(phi) selectively identifies clinically-significant prostate cancer. J Urol. 2014;pii:
S0022–5347(14)04900–3.
79. Carlsson S, Maschino A, Schröder F, Bangma C, Steyerberg EW, van der Kwast T, et al.
Predictive value of four kallikrein markers for pathologically insignificant compared with
aggressive prostate cancer in radical prostatectomy specimens: results from the European
Randomized Study of Screening for Prostate Cancer section Rotterdam. Eur Urol.
2013;64(5):693–9.
80. Nordström T, Vickers A, Assel M, Lilja H, Grönberg H, Eklund M. Comparison between the
four-kallikrein panel and Prostate Health Index for predicting prostate cancer. Eur Urol.
2014;pii: S0302–2838(14)00752–0.
Chapter 2
Pathology of Prostate Cancer: What Has
Changed in the Last 30 Years

M. Scott Lucia

Introduction

Thirty years have brought about enormous growth in our understanding of the
pathobiology of prostate cancer. For instance, while it was known that prostate can-
cer development and growth is dependent on androgens since the groundbreaking
work of Huggins and Hodges [1], more data is surfacing on the importance of
androgen receptor (AR) signaling in prostate cancer progression and the role of
genetic variants of AR in resistance to hormone therapy [2, 3]. A number of key
molecular abnormalities have been identified that occur with high frequency in
prostate cancer including loss of the tumor suppressor PTEN, amplification of the
oncogene cMYC, and TMPRSS2:ETS translocations [4, 5]. Evidence of a role for
chronic inflammation and oxidative stress in the development and progression of
prostate cancer is emerging [6–8]. The last 30 years have also seen striking advance-
ments in the manner in which we diagnose and manage prostate cancer.
The identification of prostate-specific antigen (PSA), and the recognition that
increases in serum levels of PSA portend an increased risk of prostate cancer, her-
alded an era of widespread prostate cancer screening in the United States and a
dramatic rise in the number of men diagnosed with prostate cancer in the 1990s [9].
During this time, as more men were diagnosed earlier in the natural history of pros-
tate cancer, there was a marked shift in stage towards clinically localized disease
[9–12]. Whereas tumors removed by prostatectomy in the pre-PSA era tended to be
large, occupying the majority of the prostate volume, often with extensive extra-
prostatic extension, more tumors seen today are smaller in volume, more often
organ-confined, and associated with improved therapeutic outcomes [11, 12]. It is
now clear that the natural history of prostate cancer is quite variable [13]. While a

M.S. Lucia, M.D. (*)

Anatomic Pathology, Department of Pathology, University of Colorado School of Medicine,
12801 East 17th Avenue, Mail Stop 8104, Aurora, CO, USA
e-mail: [email protected]

© Springer International Publishing Switzerland 2016 17

N.N. Stone, E.D. Crawford (eds.), The Prostate Cancer Dilemma,
DOI 10.1007/978-3-319-21485-6_2
18 M.S. Lucia

small subset of cancers are highly aggressive and progress rapidly, the majority of
cancers have a more protracted course over many years. Some cancers may never
become life threatening during the expected lifetime of the patient. Thus, more men
die with prostate cancer than of prostate cancer. Concern now arises that we are detect-
ing many small, slow-growing cancers that would otherwise not be a health threat to
the patient. Such tumors could be managed expectantly and monitored rather than
treated radically to reduce the overall morbidity associated with therapy. The key to
appropriate therapeutic decision-making lies in the ability of pathological examina-
tion of prostate biopsy tissue to accurately identify those cancers that are of low risk
to progress from those that are potentially lethal. The evolution of new management
strategies including active surveillance and targeted focal therapy necessitates greater
emphasis in assessing the biological aggressiveness and extent of the tumor from the
prostate needle biopsy. Herein we review the advancements made over the last few
decades in the pathological examination and reporting of prostate cancer.

Histopathology of Prostate Cancer and Evolving Concepts

in Grading

The vast majority of prostate cancers are adenocarcinomas composed of glandular

cells exhibiting variable degrees of differentiation into glandular acini that infiltrate
the fibromuscular stroma of the prostate gland. The degree of differentiation can
range from tumors with well-formed glandular acini to poorly formed ragged appear-
ing acini to sheets, cords, or even single infiltrating cells without true acinar forma-
tions (Fig. 2.1). The morphologic or cytologic differentiation of a tumor reflects its

Fig. 2.1 The architectural patterns of prostate cancer reflect the biological aggressiveness of the
tumor. (a) Low-grade cancers are composed of well-formed, discrete glandular acini that are dis-
tributed within the fibromuscular stroma. The tumor in (a) depicts Gleason pattern 3 (H&E, 200×).
(b, c) High-grade cancer patterns show variable degrees of glandular fusion and poorly formed
acini. The tumor in (b) (H&E, 200×) shows glandular fusion (Gleason grade pattern 4), while the
tumor in (c) (H&E, 400×) shows absence of well-formed acini with tumor cells infiltrating as cords
(Gleason pattern 5)
2 Pathology of Prostate Cancer: What Has Changed in the Last 30 Years 19

biologic aggressiveness. In general, the more poorly differentiated the tumor, the
more aggressive is its behavior. Much of what we have learned regarding tumor biol-
ogy and natural history comes from the pathological analyses of prostatectomy spec-
imens. In 1966, Donald Gleason described the varied architectural appearances of a
large number of prostatic adenocarcinomas and demonstrated that the degree of glan-
dular differentiation and infiltration of the surrounding stroma by tumor cells
reflected the biology of the tumor [14]. Those tumors that displayed well-formed
acinar structures had favorable outcomes compared with those that had progressively
more poorly formed acini. Those tumors that formed only sheets, cords, or single cell
arrangements behaved aggressively and were often lethal. These observations
formed the basis for the Gleason grading system that has been the most important
and widely used grading system for prostate cancer since his landmark publication.
The Gleason grading system contains five tiers or grade ranks and categorizes
tumors by their architectural pattern of growth rather than cytologic features.
Individual tumors often display more than one pattern. This was addressed by
Gleason by adding the most prevalent pattern (the primary pattern) with the second
most prevalent pattern (the secondary pattern) to obtain a Gleason “score.” If only
one pattern was present, then the pattern rank was doubled to result in Gleason scores
for each tumor ranging from 2 (grade 1 + grade 1) to 10 (grade 5 + grade 5). The
higher the score, the more aggressive is the tumor. Tumors do not necessarily prog-
ress from low grade (patterns 1–3) to high grade (patterns 4–5) during their natural
course. Tumors can arise as high grade or may remain as low-grade tumors [15, 16].
Over time, the Gleason system has undergone a number of modifications by
Gleason and others [17, 18]. The basis for these modifications comes from years of
experience with prostate cancer grading on biopsy and prostatectomy specimens by
academic pathologists and a plethora of studies relating Gleason grade to disease
outcomes and responses to therapy. In 2005, 80 genitourinary pathologists from
around the world as members of the International Society of Urologic Pathologists
(ISUP) participated in a survey of practice patterns and a consensus conference to
document and assess cancer grading trends and refine the guidelines for Gleason
grading [18]. Most notable among the items addressed by the ISUP were (1) restric-
tions on assigning very low-grade patterns (grades 1 and 2) on biopsy specimens,
(2) refining the separation between patterns 3 and 4, (3) assigning grade to cribri-
form patterns of cancer, and (4) scoring biopsies that contain minor amounts of
high-grade patterns or tertiary-grade patterns.
Gleason’s original work in developing the grading system was based upon exam-
ination of prostatectomy specimens, transurethral resections, and large caliber nee-
dle biopsies. Contemporary needle biopsies are thin (~18 gauge) and relatively short
producing core fragments that average ~1.5 cm in length and 0.6 mm in thickness.
Thus, tumor sampling is limited and, as discussed further below, this has an impact
on the accuracy of Gleason grading when compared to subsequent prostatectomy
specimens. Because of this, assigning grades of 1 or 2 on needle biopsies usually
results in upgrading at prostatectomy [19, 21]. In addition, most tumors that would
have been graded as 1 + 1 (score = 2) in the past would today be recognized as benign
adenoses with the use of basal cell markers. This trend was noted in studies looking
20 M.S. Lucia

Fig. 2.2 Cribriform cancer

showing nests of cells with
distinctive sharply outlined
holes

at grading trends over time [20, 21]. Gleason scores of 2–4 represented 21 % of
cases diagnosed on prostatectomy and TURP specimens between 1983 and 1984
but only 11 % of cases diagnosed in 1992–1993 [20]. By 2001, the number had
fallen to less than 5 % [21]. Therefore, the ISUP recommended that Gleason grades
1 and 2 rarely if ever be used on biopsies.
In contrast, the most important grade patterns to recognize on needle biopsies are
the high-grade patterns 4 and 5. Tumors that contain even small amounts of pattern
4 or 5 (corresponding to Gleason scores of 7–10 depending on the relative amount
of pattern 3) behave more aggressively than those graded with Gleason scores of
2–6 [22, 23]. Thus, it is important to be able to separate architectural patterns that
behave more aggressively than typical grade 3 patterns and include them as pattern
4 or 5 appropriately. Unlike the original Gleason system, it was recommended by
the ISUP that ill-defined acini with poorly formed lumens and tumors containing
single cells should not be allowed within Gleason pattern 3. Single cells represent
pattern 5, while poorly formed glands represent pattern 4. Pattern 3 is reserved for
tumors with discrete, well-formed acini with prominent lumens and separated by
variable amounts of stroma. When holding to this standard, the outcomes for
Gleason score 3 + 3 tumors are very favorable [24, 25].
More problematic is what to do with tumors that display cribriform morphology
(Fig. 2.2). In the original Gleason system, these were grouped within grade 3. The
ISUP consensus was that cribriform cancers represent a mixed bag of tumor aggres-
siveness. Most cribriform tumors behave similar to tumors with pattern 4 and there-
fore should be graded as pattern 4. Only tumors with small, well-rounded
arrangements should warrant the designation of pattern 3. However, more recently
this notion has been challenged [26, 27]. In our experience, all cribriform cancers
behave aggressively regardless of the size or shape of the cribriform structures [27].
Lastly, the 2005 ISUP Consensus Group recommended modifications as to assign-
ing Gleason scores on prostate biopsies. It was recommended that any amount of
high-grade patterns seen on a biopsy be recorded as part of the Gleason score even if
it was not the primary or secondary grade pattern present or represented less than
2 Pathology of Prostate Cancer: What Has Changed in the Last 30 Years 21

5 % of the tumor. In the classic Gleason system, tumor patterns that represented less
than 5 % of the tumor or were a tertiary pattern were ignored. For example, a tumor
that consists of 75 % pattern 3, >20 % pattern 4, and <5 % pattern 5 would be scored
as 3 + 5 under the 2005 recommendations but 3 + 4 using the classic Gleason system.
These modifications were recommended to attempt to reduce the number of cancers
that would otherwise be upgraded upon prostatectomy, a situation that unfortunately
occurs frequently when comparing the Gleason grade on presurgical biopsies with
the subsequent prostatectomy [28, 29]. However, applying these modifications also
resulted in a shift towards higher Gleason scores reported on biopsies in some studies
[30, 31]. Nevertheless, the recommendations documented in the 2005 ISUP
Consensus Conference report represent a synthesis of grading practices by leading
genitourinary pathologists around the world rather than a new grading scheme per se.
Despite the 2005 ISUP modifications, there are still problems associated with the
Gleason grading of biopsies that impact patient care. Since Gleason patterns 1 and
2 are not usually reported on biopsies, the lowest Gleason grade typically assigned
to a biopsy is 3 + 3 (score = 6). Gleason score 6 lies halfway between Gleason score
2 and 10; therefore, patients may perceive a Gleason score 6 tumor as being inter-
mediate in aggressiveness. Large population studies clearly indicate that Gleason
score 6 tumors have an excellent prognosis, and patients with such tumors represent
good candidates for active surveillance [13]. Patients may be reluctant to choose
active surveillance if they perceive their cancer to be in the middle of the grading
scale. Furthermore, data suggest that the amount of tumor that displays high-grade
features is most important prognostically [22, 27, 32]. Classifying a tumor as 3 + 4
versus 4 + 3 may indicate that the latter has relatively more pattern 4 than the former
on a particular biopsy, but since both are Gleason scores of 7, it does not really con-
vey prognostic information in a clear way. In 2013, Epstein and colleagues from the
Johns Hopkins Medical Center reviewed prognostic variables in the biopsies of
7869 men that underwent radical prostatectomy at their institution [25]. They found
that meaningful stratification of biochemical-free survival by Kaplan–Meier analy-
sis was achieved by amalgamating Gleason scores into 5 prognostic groups. Group
1 was composed of tumors with biopsy Gleason score ≤3 + 3. This group had the
best overall biochemical-free survival at 5 years (94.6 %). Groups 2 (Gleason score
3 + 4), 3 (Gleason score 4 + 3), and 4 (Gleason score 8) had 5-year biochemical-free
survivals of 82.7, 65.1, and 63.1 % respectively. The worst biochemical-free sur-
vival (34.5 %) was seen in Group 5 (Gleason score 9–10). By defining Prognostic
Group 1 as the group with the most favorable prognosis, they emphasize a patient
population that could be the ideal candidates for active surveillance. The other
prognostic groups indicate categorically greater relative amounts of the high-grade
patterns 4 and 5 that impact treatment outcomes. From these data, a new grading
scheme, based upon the architectural features inherent in the Gleason grades, has
been proposed to classify tumors by the amount of high-grade patterns that make up
the tumor. Table 2.1 compares this new grading scheme with the classic Gleason
system and 2005 ISUP Gleason modifications. This concept was presented to 85
pathologists from 17 countries in November 2014 and endorsed by the ISUP. It is
anticipated that the new scheme will eventually replace Gleason scoring within the
next 5–10 years.
22 M.S. Lucia

Table 2.1 Comparison of the classical, ISUP modified Gleason grading systems, and proposed
new system
Classical Gleason system 2005 ISUP modified Gleason 2014 Proposed grading
(1977) system system
Pattern 1: Small, uniform, and Pattern 1: Closely packed, Grade 1: Tumor purely
closely packed acini in tight separate, uniform round–oval, composed of individual
circumscribed masses medium-sized acini in separate well-formed acini
circumscribed nodules
Pattern 2: Mild-moderate Pattern 2: Mild acinar Grade 2: Tumor with
variation in size and shape of irregularity with minimal predominantly well-formed
acini and some cellular atypia; infiltration at edges of tumor individual acini with lesser
acini more loosely packed than nodule; more loosely packed component of poorly
pattern 1, but still relatively than pattern 1 formed, fused or cribriform
circumscribed acini
Pattern 3: Small infiltrating Pattern 3: Small infiltrative Grade 3: Tumor with
acini with irregularity of size individual glandular acini with predominantly poorly
and shape; individual cells marked variation in size and formed, fused or cribriform
invading stroma away from shape; smoothly circumscribed acini with lesser component
circumscribed glandular small cribriform cellular of well-formed acini
masses; papillary and structures
cribriform arrangements
ranging from small to large
with smooth rounded edges
Pattern 4: Infiltrating fused Pattern 4: Fused microacini Grade 4: Tumor composed
acini that coalesce and branch and ill-defined acini with of only poorly formed,
(no longer single and separate); poorly formed luminae; fused or cribriform acini;
acini with large clear cells cribriform structures that are tumor with predominantly
resembling hypernephroma large or have irregular borders; well-formed acini but with
ductal or hypernephromatoid lesser component lacking
tumors acini
Pattern 5: Poorly differentiated Pattern 5: Infiltrating cells with Grade 5: Tumor formed of
cells infiltrating in solid or essentially no acinar cells lacking any acinar
diffuse masses; individual cells differentiation arranged in solid formations (e.g., cords or
with essentially no acinar sheets, cords, or single cells; single cells) with or
differentiation; Signet ring comedocarcinoma with central without component of
cells; comedocarcinoma with necrosis poorly formed, fused or
central necrosis cribriform acini;
comedonecrosis
Gleason scoring:
Gleason score: add together the Prostatectomy: add together the Gleason scoring not
most prominent pattern most prominent pattern necessary
(primary) with the second most (primary) with the second most
prominent pattern (secondary) prominent pattern (secondary)
Same scoring method used for Biopsies: add together the most
prostatectomy and biopsy prominent pattern (primary)
with the highest remaining
grade pattern regardless of
amount: Gleason scores 2–4
should rarely (if ever) be
assigned
2 Pathology of Prostate Cancer: What Has Changed in the Last 30 Years 23

Multifocality and Heterogeneity

Although prostate cancers can arise anywhere within the prostate, most (70–80 %)
arise in the peripheral lobe [33]. However, in the mid-1990s, it was recognized that
prostate cancer often has multiple foci of discrete tumors in surgical prostatectomy
specimens. Using computer-assisted three-dimensional reconstructions of prosta-
tectomy specimens obtained from 1987 to 1991, Miller and Cygan found multifocal
cancer in more than half of all cases, and concluded that most cases in which the
prostate only contained one tumor resulted from the assimilation of multiple smaller
tumors when they grew to confluence [15]. As more patients are now diagnosed
earlier in the course of the disease, multifocal disease is now seen in over 64–87 %
of cases [34] supporting the conclusions of Miller and Cygan. In our database of
over 300 prostates that have been whole-mount processed and reconstructed since
2005, multifocal tumor is present in >70 % while the average tumor volume has
decreased from over 6 cm3 in the early 1990s to approximately 2 cm3. Individual
tumor foci are somatically independent and display differences in the degree of dif-
ferentiation (grade), molecular characteristics, and DNA ploidy [35–37]. These dif-
ferences do not just exist between separate tumor foci, but even between different
regions within an individual tumor focus. Figure 2.3 depicts a representative pros-
tate from our database that has been three-dimensionally reconstructed. Panel (a)
shows the intact prostate while in Panel (b) the benign prostate has been stripped
away leaving multiple discrete tumor foci. The different colors correspond to the
different Gleason grade patterns present. It has also become apparent that tumors
can arise deep in the anterior portion of the prostate in either the transition zone or
anterior horns of the peripheral zone where they become difficult to detect by digital
rectal examination (DRE) or routine prostate needle biopsy protocols. Such anterior

Fig. 2.3 Three-dimensional reconstruction of prostate containing multiple tumor foci. (a) Whole-
mount reconstruction showing benign prostate (dark blue) and colored foci of tumor extending to
surface. (b) Prostate from (a) with benign prostate removed to demonstrate multiple tumor foci.
The different colors indicate areas with different Gleason grade patterns (Red = pattern 3,
Green = pattern 4, orange = pattern 5) and prostatic intraepithelial neoplasia (PIN-yellow)
24 M.S. Lucia

tumors appear similar to tumors arising in the posterior periphery and may attain
relatively large size and potentially more advanced stage before being detected [33,
38]. The orange tumor in Fig. 2.3b is an anterior tumor that is high grade (Gleason
pattern 5) and present at the resection margin.

The Role of Pathological Examination of the Prostate Biopsy

in Management Decisions

The role of the pathologist in the examination of prostate biopsies is to (1) establish
the presence or absence of cancer, (2) determine the expected biologic aggressive-
ness of the tumor, and (3) estimate the extent of the tumor present. Our ability to
provide this information is complicated by the nature of the prostate biopsy itself.
Before the advent of PSA screening, most prostate cancers, due to their relatively
large volume, were discovered by DRE with subsequent directed biopsy. Now with
PSA screening, the majority of prostate cancers are diagnosed when serum eleva-
tions in PSA prompt a prostate biopsy. Since most of these tumors are not palpable
and, as noted above, are smaller and multifocal making them difficult to image, a
series of individual prostate needle biopsies are taken transrectally using transrectal
ultrasound (TRUS) guidance in a systematic but largely random manner from the
left and right sides of the prostate fanning from apex to base. The manner in which
these biopsies are taken has undergone a number of changes over the last few
decades. For years obtaining six biopsy cores, three on each side, was routine. As it
became increasingly clear that cancers were often missed, biopsy schemes were
extended to 10, 12, or even more cores and concentrated on sampling the lateral
portions of the gland [39, 40]. While these modifications have increased the sensi-
tivity for diagnosing prostate cancer, extended biopsy protocols can still miss cancer
foci [39, 40]. Consequently, many men undergo repeated biopsy after a negative
biopsy due to concerns that they might have a cancer that was simply missed on the
first biopsy. When a cancer is detected on a needle biopsy, the pathologist gives the
tumor a Gleason score, and some measure of extent is provided such as the number
of cores positive for cancer and the percent (or millimeter extent) the tumor encom-
passes on each core. Unfortunately, this critical information is also affected by
biopsy sampling. For example, the biopsy may not sample the highest grade of
tumor present. It has been shown that the Gleason score of the cancer on subsequent
prostatectomy often is one, two, or even three grades higher than the presurgical
biopsy specimen [28, 29]. The primary reason is that the biopsy needle only sam-
pled a portion of the tumor and missed foci of high-grade tumor readily apparent
when the entire gland was examined. Moreover, a biopsy is a poor staging tool, and
although the number of cores positive for cancer in a given set of biopsy cores cor-
relates with tumor volume, the finding of a small amount of tumor on a single biopsy
core does not necessarily indicate a clinically inconsequential tumor will be found
on the subsequent prostatectomy [41].
2 Pathology of Prostate Cancer: What Has Changed in the Last 30 Years 25

Table 2.2 Pathological and clinical features at time of biopsy used to predict potentially limited
tumor of prostate and determine eligibility for active surveillance protocols
PSADb
Clinical PSAa (ng/ Gleason No. of cores Corec percent
Reference stage (ng/ml) ml/g) score positive positive
Epstein 1994 [45] T1c NSd ≤0.15 ≤3 + 3 ≤2 <50 %
Van den Bergh 2009 T1c/2 ≤10 <0.2 ≤3 + 3 ≤2 NS
[46]
Soloway 2010 [47] T1/2 ≤10 NS ≤3 + 3 ≤2 ≤20 %
Adamy 2011 [48] T1/2a ≤10 NS ≤3 + 3 ≤3 ≤50 %
Whitson 2011 [49] T1c/2 ≤10 NS ≤3 + 3 ≤33 % ≤50 %
a
PSA = prostate-specific antigen
b
PSAD = PSA density
c
Core percent positive = percent linear extent of any core
d
NS = not stated

These sampling issues are particularly problematic when considering active sur-
veillance or targeted focal therapy as management options. Thirty years ago when
treatment options were limited, merely rendering a diagnosis of cancer on prostate
biopsy or transurethral resection led to radical definitive therapy. In contemporary
practice, patients with low-grade, low volume organ-confined tumors may be candi-
dates for active surveillance or targeted focal therapy. The most commonly used
definition of a low-risk tumor is a tumor of <0.5 cm3 (some have expanded this to
1.3 cm3) that is confined to the prostate and has a Gleason score of 6 or less (no pat-
tern 4 or 5) at prostatectomy [42–44]. A number of investigators have attempted to
predict such low-risk tumors by defining thresholds on the grade and extent of dis-
ease present on the biopsy, and then using these criteria for active surveillance pro-
tocols (Table 2.2) [45–49]. Perhaps the most stringent and accepted definition is
that of Epstein and colleagues which defines a tumor as “potentially insignificant”
if the following criteria are met: (1) clinical stage T1c, (2) PSA density of <0.15 ng/
ml/gm as calculated by TRUS, (3) biopsy Gleason score ≤6 (no pattern 4 or 5), and
(4) tumor involving less than three cores with no core containing more than 50 %
linear involvement [45]. Unfortunately, attempts to predict low volume, low-grade
organ-confined tumor using these biopsy criteria are imperfect. The performance of
the active surveillance protocols as defined in Table 2.2 was compared on common
patient cohorts [50, 51] and demonstrated upgrading to Gleason scores of 7 or
greater anywhere from 42 to 51 % of cases, while upstaging to non-organ-confined
disease was reported in 5–9 % of cases [50]. Sensitivities for predicting insignifi-
cant tumors ranged from 45 to 83 % with specificities of 39–82 % [51]. Sensitivities
for just predicting organ-confined, low-grade tumors at prostatectomy ranged from
34 to 73 % with specificities of 39–83 % [51].
The biologic aggressiveness of a tumor combined with its volume or extent of
spread determines the outcome for a patient following treatment. Therefore, accu-
rate assessment of biologic potential and tumor extent at the time of biopsy is cru-
cial in order to identify those tumors that should be treated aggressively from those
26 M.S. Lucia

Fig. 2.4 Ultrasound image of prostate fused with transperineal mapping biopsy results. (a) views
the prostate from the apex. (b) views the prostate from above. A cluster of three positive biopsies
is present in left posterior base of the prostate. The positive needle locations (represented in blue)
show foci of 3 + 3 cancer, shown in yellow indicating the amount of the core positive for tumor, and
3 + 4 cancer, shown in green with the amount of core represented by the length of the bar.

tumors that could be focally ablated or be monitored by active surveillance. Due to

the limited tumor sampling inherent with current TRUS biopsy methods, accurate
identification of tumors that can be assured not to progress remains a challenge.
Physicians are faced with uncertainty as to whether or not the tumor biology is
accurately captured in the biopsy sample taken, the true volume of tumor present,
and whether or not there are additional foci of tumor, particularly in anterior portions
of the prostate, that may have been missed. To better address these issues, a recent
approach that has been used by us and others is to “map” the prostate for areas of
cancer using a transperineal template-guided method with biopsies taken at regular
intervals across all three dimensions of the prostate [52, 53]. Each core is separately
graded, measured for extent, and then grid-mapped to produce a three-dimensional
representation of the prostate with all tumor foci (Fig. 2.4). This method requires a
relatively large number of biopsies to completely map a prostate, but results in
improved grade accuracy when compared to TRUS-guided transrectal biopsies
upon subsequent prostatectomy. Comparison of TRUS-guided transrectal biopsy
(TRB) with three-dimensional template-guided transperineal mapping biopsies
(TPMB) in 215 patients undergoing both procedures showed Gleason score ≤6
tumor in the TRB of 73 % of the patients, but in only 50 % of TPMB [53]. Upgrading
to Gleason score 7 or higher from TRB to TPMB occurred in 27 %, while 46 % of
tumors were upstaged on TPMB compared to TRB. In 25 patients that underwent
prostatectomy after having both TRB and TPMB, the tumors were upgraded from
the TRB in 52 % of cases, but upgraded from the TPMB in only 12 % of the cases
[54]. This method also allows for improved determination of the location of all
tumor foci which is necessary for proper targeting for focal ablation. Efforts to
improve the precision of this approach and reduce the labor-intensiveness are under-
way to promote wider acceptance for patients considering active surveillance or
targeted focal therapy.
2 Pathology of Prostate Cancer: What Has Changed in the Last 30 Years 27

Advances in Molecular Pathology: The New Frontier

While the grade of a tumor reflects its biologic aggressiveness, the mechanistic
basis for a tumor’s biology lies at the molecular level. A thorough understanding of
the molecular events that lead to the aggressive cancer phenotype has been elusive.
This is due in part to the heterogeneity of prostate cancer. Compounding the prob-
lem has been the difficulty in obtaining sufficient quantities of fresh cancerous tis-
sue from surgical specimens and biopsies for analyses. Recent advances in
technology have largely overcome this barrier allowing for robust analysis of pro-
gressively smaller quantities of DNA and RNA even from formalin-fixed and
paraffin-embedded (FFPE) pathological specimens. This has led to the identifica-
tion of a number of genetic abnormalities associated with prostate cancer including
alterations in PTEN, cMyc, and the TMPRSS2:ETS gene fusions found in many
prostate cancers [4, 5]. However, the utility of these abnormalities as prognostic or
predictive markers has not been proven. More progress has been made in the devel-
opment of gene expression assays on RNA isolated from FFPE biopsy tissue as
prognostic markers for prostate cancer.
Commercially offered gene expression assays are now available for use on as
little as 1 mm of tumor on prostate needle biopsies. For example, one such assay
determines a cell cycle progression (CCP) score derived from 31 genes across the
spectrum of the cell proliferation cycle normalized to 15 reference housekeeping
genes (Prolaris®, Myriad Genetics, Salt lake City, UT). In a cohort of 349 men con-
servatively managed following prostate biopsy, the CCP score was independently
predictive of cancer-specific mortality within 10 years and showed additive value
when combined with Gleason score and PSA [55]. In patients treated with prostatec-
tomy, the CCP score as calculated from the pretreatment needle biopsy was a strong
predictor of biochemical recurrence and metastasis-free survival [56]. Thus, combin-
ing the CCP score with other pathological prognostic variables such as grade and
number of cores positive may better identify patients who would be the ideal candi-
dates for active surveillance from those requiring definitive treatment. However,
most prostate cancers are heterogeneous not only in grade but also in terms of genetic
abnormalities and molecular expression [35–37], and concern remains as to how
sampling bias for such prostate cancers affects the results for individual patients. In
this context, mapping biopsies may help to improve the performance of molecular
tissue biomarkers by limiting the impact of tumor heterogeneity and sampling.
Another commercially available prognostic gene expression assay was recently
developed specifically to address the concerns regarding tumor heterogeneity and
under-sampling. This assay (Oncotype DX®, Genomic Health, Inc., Redwood City,
CA) calculates a genomic prostate score (GPS) using a 17-gene expression panel
including 5 reference genes and 12 genes across multiple molecular pathways that
have been shown to be predictive of metastasis and death in prostatectomy tissue
while also being predictive of having high-grade or advanced stage cancer of the
prostate regardless of the grade of tumor sampled [57, 58]. The gene expression
panel covers pathways associated with poor outcomes (e.g., stromal response and
28 M.S. Lucia

proliferation genes) as well as favorable outcomes (e.g., androgen signaling and

cellular organization genes). The assay was validated on a set of men who were
considered by National Comprehensive Cancer Network (NCCN) criteria to be very
low risk (Stage T1c, PSA density ≤0.15, Gleason score ≤3 + 3, <3 cores positive
with no core having ≥50 % tumor involvement; n = 37), low risk (stage T1-T2a,
PSA < 10 ng/ml, Gleason score ≤3 + 3; n = 191), or intermediate risk (stage T2b/c or
Gleason score 7 or PSA 10–20 ng/ml; n = 160). For each risk group, the GPS added
independent prognostic value and identified men whose scores indicated a more
favorable prognosis and also men whose scores indicated a less favorable prognosis
than expected for their NCCN risk group, thereby providing improved discrimina-
tory power for selecting men who could be managed conservatively versus those
who would benefit best from definitive therapy [58].
The examples of gene expression assays described above represent some of the
first generation of molecular tests that serve as adjuncts to traditional pathology. It
is anticipated that continuing advances in technology will ultimately better define
the aggressive phenotype for prostate cancer at the molecular level improving our
ability to predict tumor behavior and grant the clinician more tools to guide treat-
ment strategies for individual patients in the new era of precision medicine.

Conclusion

The last 30 years has given us a better understanding of the biology of prostate can-
cer. We now know that not all tumors are destined to be life threatening, and defined
a subset of tumors from a pathologic basis that could be better managed conserva-
tively. We have also refined our ability to predict the aggressiveness and extent of
tumors at the time of biopsy using traditional pathologic features and the develop-
ment of newer molecular investigations. However, our ability to do so accurately
for every patient at the time of biopsy is still hampered by limitations in the amount
of information that can be obtained from routine prostate biopsies. While the pro-
cess of carcinogenesis and cancer progression evolves over time, a biopsy can only
capture a glimpse of the tumor at a single time point. Maximizing the amount of
information that can be gleaned from the biopsy is paramount in order to identify
those patients that may be candidates for active surveillance or targeted focal ther-
apy. Continued refinements in our ability to recognize the histologic and molecular
features of cancer that contribute to its aggressiveness will ultimately improve the
predictive accuracy of prostate biopsies.

References

1. Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and
androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer
J Clin. 1972;22:232–40.
2 Pathology of Prostate Cancer: What Has Changed in the Last 30 Years 29

2. Lonergan PE, Tindall DJ. Androgen receptor signaling in prostate cancer development and
progression. J Carcinog. 2011;10:20. Epub 2011 August 23.
3. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA,
Chen Y, Fedor HL, Lotan TL, Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller
CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J. AR-V7 and resistance to enzalu-
tamide and abiraterone in prostate cancer. N Engl J Med. 2014;371(11):1028–38.
4. Gurel B, Iwata T, Koh CM, Yegnasubramanian S, Nelson WG, De Marzo AM. Molecular
alterations in prostate cancer as diagnostic, prognostic, and therapeutic targets. Adv Anat
Pathol. 2008;15:319–31.
5. Barbieri CE, Tomlins SA. The prostate cancer genome: perspectives and potential. Urol Oncol
2014;32(1):53.e15-22.
6. Koul HK, Kumar B, Koul S, Deb AA, Hwa JS, Maroni P, van Bokhoven A, Lucia MS, Kim FJ,
Meacham RB. The role of inflammation and infection in prostate cancer: importance in pre-
vention, diagnosis and treatment. Drugs Today (Barc). 2010;46:929–43.
7. Lucia MS, Lambert JR, Platz EA, De Marzo AM. Inflammation as a target in prostate cancer.
In: Figg WD, Chau CH, Small EJ, editors. Drug management of prostate cancer. New York,
NY: Springer; 2010. p. 375–86.
8. Paschos A, Pandya R, Duivenvoorden WC, Pinthus JH. Oxidative stress in prostate cancer:
changing research concepts towards a novel paradigm for prevention and therapeutics. Prostate
Cancer Prostatic Dis. 2013;16:217–25.
9. Crawford ED. Epidemiology of prostate cancer. Urology. 2003;62(6 Suppl 1):3–12.
10. Stephenson RA. Population-based prostate cancer trends in the PSA era: data from the
Surveillance, Epidemiology, and End Results (SEER) Program. Monogr Urol. 1998;19:3–19.
11. Falzarano SM, Magi–Galluzzi C. Prostate cancer staging and grading at radical prostatectomy
over time. Adv Anat Pathol. 2011;18(2):159–64.
12. Moul JW, Wu H, Sun L, et al. Epidemiology of radical prostatectomy for localized prostate
cancer in the era of prostate-specific antigen: an overview of the Department of Defense Center
for Prostate Disease Research national database. Surgery. 2002;132(2):213–9.
13. Eggener SE, Scardino PT, Walsh PC, Han M, Partin AW, Trock BJ, Feng Z, Wood DP, Eastham
JA, Yossepowitch O, Rabah DM, Kattan MW, Yu C, Klein EA, Stephenson AJ. Predicting
15-year prostate cancer specific mortality after radical prostatectomy. J Urol. 2011;185:869–75.
14. Gleason DF. Classification of prostatic carcinomas. Cancer Chemother Rep. 1966;50(3):
125–8.
15. Miller GJ, Cygan JM. Morphology of prostate cancer: the effects of multifocality on histologi-
cal grade, tumor volume and capsule penetration. J Urol. 1994;152(5 Pt 2):1709–13.
16. Klotz L. Active surveillance for prostate cancer: a review. Curr Urol Rep. 2010;11(3):
165–71.
17. Gleason DF. Histological grading and clinical staging of prostatic carcinoma. In: Tannenbaum
M, editor. Urologic pathology: the prostate. Philadelphia, PA: Lea & Febiger; 1977. p. 171–98.
18. Epstein JI, Allsbrook Jr WC, Amin MB, Egevad LL, ISUP Grading Committee. The 2005
International Society of Urological Pathology (ISUP) consensus conference on gleason grad-
ing of prostatic carcinoma. Am J Surg Pathol. 2005;29(9):1228–42.
19. Epstein JI. Gleason score 2-4 adenocarcinoma of the prostate on needle biopsy: a diagnosis
that should not be made. Am J Surg Pathol. 2000;24(4):477–8.
20. Gilliland FD, Gleason DF, Hunt WC, Stone N, Harlan LC, Key CR. Trends in Gleason score
for prostate cancer diagnosed between 1983 and 1993. J Urol. 2001;165:846–50.
21. Ghani KR, Grigor K, Tulloch DN, Bollina PR, McNeal SA. Trends in reporting Gleason score
1991 to 2001: changes in the pathologist’s practice. Eur Urol. 2005;47:196–201.
22. Pan CC, Potter SR, Partin AW, Epstein JI. The prognostic significance of tertiary Gleason pat-
terns of higher grade in radical prostatectomy specimens. A proposal to modify the Gleason
grading system. Am J Surg Pathol. 2000;24:563–9.
23. Servoll E, Saeter T, Vlatkovic L, Lund T, Nesland J, Waaler G, Axcrona K, Beisland
HO. Impact of a tertiary Gleason pattern 4 or 5 on clinical failure and mortality after radical
prostatectomy for clinically localised prostate cancer. BJU Int. 2012;109(10):1489–94.
30 M.S. Lucia

24. Miyamoto H, Hernandez DJ, Epstein JI. A pathological reassessment of organ-confined,

Gleason score 6 prostatic adenocarcinomas that progress after radical prostatectomy. Hum
Pathol. 2009;40(12):1693–8.
25. Pierorazio PM, Walsh PC, Partin AW, Epstein JI. Prognostic Gleason grade grouping: data
based on the modified Gleason scoring system. BJU Int. 2013;111:753–60.
26. Sarbay BC, Kir G, Topal CS, Gumus E. Significance of the cribriform pattern in prostatic
adenocarcinomas. Pathol Res Pract. 2014;210(9):554–7.
27. Iczkowski KA, Torkko KC, Kotnis GR, Wilson RS, Huang W, Wheeler TM, Abeyta AM, La
Rosa FG, Cook S, Werahera PN, Lucia MS. Digital quantification of five high-grade prostate
cancer patterns, including the cribriform pattern, and their association with adverse outcome.
Am J Clin Pathol. 2011;136:98–107.
28. Sved PD, Gomez P, Manoharan M, Kim SS, Soloway MS. Limitations of biopsy Gleason
grade: implications for counseling patients with biopsy Gleason score 6 prostate cancer. J
Urol. 2004;172(1):98–102.
29. King CR, McNeal JE, Gill H, Presti Jr JC. Extended prostate biopsy scheme improves reli-
ability of Gleason grading: implications for radiotherapy patients. Int J Radiat Oncol Biol
Phys. 2004;59(2):386–91.
30. Guimaraes MS, Billis A, Quintal MM, et al. The impact of the 2005 International Society of
Urological Pathology (ISUP) consensus conference on standard Gleason grading of prostatic
carcinoma. Mod Pathol. 2006;19:139A.
31. Zareba P, Zhang J, Yilmaz A, Trpkov K. The impact of the 2005 International Society of
Urological Pathology (ISUP) consensus on Gleason grading in contemporary practice.
Histopathology. 2009;55:384–91.
32. Stamey TA, McNeal JE, Yemoto CM, Sigal BM, Johnstone IM. Biological determinants of
cancer progression in men with prostate cancer. JAMA. 1999;281:1395–400.
33. Jack GS, Cookson MS, Coffey CS, Vader V, Roberts RL, Chang SS, Smith Jr JA, Shappell
SB. Pathological parameters of radical prostatectomy for clinical stages T1c versus T2
adenocarcinoma: decreased pathological stage and increased detection of transition zone
tumors. J Urol. 2002;168:519–24.
34. Algaba F, Montironi R. Impact of prostate cancer multifocality on its biology and treatment. J
Endourol. 2010;24(5):799–804.
35. Karavitakis M, Ahmed HU, Abel PD, Hazell S, Winkler M. Tumor focality in prostate cancer:
implications for focal therapy. Nat Rev Clin Oncol. 2011;8(1):48–55.
36. Liu J, Lau SK, Varma VA, Moffitt RA, Caldwell M, Liu T, Young AN, Petros JA, Osunkoya
AO, Krogstad T, Leyland-Jones B, Wang MD, Nie S. Molecular mapping of tumor heterogene-
ity on clinical tissue specimens with multiplexed quantum dots. ACS Nano. 2010;4:2755–65.
37. Lindberg J, Klevebring D, Liu W, Neiman M, Wiklund F, Mills IG, Egevad L, Gronberg
H. Exome sequencing of prostate cancer supports the hypothesis of independent tumour ori-
gins. Eur Urol. 2013;63:347–53.
38. Sundi D, Kryvenko ON, Carter HB, Ross AE, Epstein JI, Schaeffer EM. Pathological exami-
nation of radical prostatectomy specimens in men with very low risk disease at biopsy reveals
distinct zonal distribution of cancer in black American men. J Urol. 2014;191(1):60–7.
39. Presti JC. Prostate biopsy: current status and limitations. Rev Urol. 2007;9(3):93–8.
40. Raja J, Ramachandran N, Munneke G, Patel U. Current status of transrectal ultrasound-guided
prostate biopsy in the diagnosis of prostate cancer. Clin Radiol. 2006;61(2):142–53.
41. Quann P, Jarrard DF, Huang W. Current prostate biopsy protocols cannot reliably identify
patients for focal therapy: correlation of low-risk prostate cancer on biopsy with radical pros-
tatectomy findings. Int J Clin Exp Pathol. 2010;3(4):401–7.
42. Stamey TA, Freiha FS, McNeal JE, Redwine EA, Whittemore AS, Schmid HP. Localized pros-
tate cancer: relationship of tumor volume to clinical significance for treatment of prostate
cancer. Cancer. 1993;71(3 Suppl):933–8.
43. Epstein JI, Chan DW, Sokoll LJ, Walsh PC, Cox JL, Rittenhouse H, Wolfert R, Carter
HB. Nonpalpable stage T1c prostate cancer: prediction of insignificant disease using free/total
prostate specific antigen levels and needle biopsy findings. J Urol. 1998;160(6 Pt 2):2407–11.
2 Pathology of Prostate Cancer: What Has Changed in the Last 30 Years 31

44. Sengupta S, Blute ML, Bagniewski SM, Inman B, Leibovich BC, Slezak JM, Myers RP,
Zincke H. After radical retropubic prostatectomy 'insignificant' prostate cancer has a risk of
progression similar to low-risk ‘significant’ cancer. BJU Int. 2008;101(2):170–4.
45. Epstein JI, Walsh PC, Carmichael M, Brendler CB. Pathologic and clinical findings to predict
tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA. 1994;271(5):368–74.
46. Van den Bergh RC, Roemeling S, Roobol MJ, Aus G, Hugosson J, Rannikko AS, Tammela TL,
Bangma CH, Schroder FH. Outcomes of men with screen-detected prostate cancer eligible for
active surveillance who were managed expectantly. Eur Urol. 2009;55:1–8.
47. Soloway MS, Soloway CT, Eldefrawy A, Acosta K, Kava B, Manoharan M. Careful selection
and close monitoring of low-risk prostate cancer patients on active surveillance minimizes the
need for treatment. Eur Urol. 2010;58:831–5.
48. Adamy A, Yee DS, Matsushita K, Maschino A, Cronin A, Vickers A, Guillonneau B, Scardino
PT, Eastham JA. Role of prostate specific antigen and immediate confirmatory biopsy in pre-
dicting progression during active surveillance for low risk prostate cancer. J Urol.
2011;185:477–82.
49. Whitson JM, Porten SP, Hilton JF, Cowan JE, Perez N, Cooperberg MR, Greene KL, Meng
MV, Simko JP, Shinohara K, Carroll PR. The relationship between prostate specific antigen
change and biopsy progression in patients on active surveillance for prostate cancer. J Urol.
2011;185:1656–60.
50. Kim TH, Jeon HG, Choo SH, Jeong BC, Seo SI, Jeon SS, Choi HY, Lee HM. Pathological
upgrading and upstaging of patients eligible for active surveillance according to currently used
protocols. Int J Urol. 2014;21:377–81.
51. Iremashvili V, Pelaez L, Manoharan M, Jorda M, Rosenberg DL, Soloway MS. Pathologic
cancer characteristics in patients eligible for active surveillance: a head-to-head comparison of
contemporary protocols. Eur Urol. 2012;62:462–8.
52. Crawford ED, Wilson SS, Torkko KC, Hirano D, Stewart JS, Brammell C, Wilson RS, Kawata
N, Sullivan H, Lucia MS, Werahera PN. Clinical staging of prostate cancer: a computer-
simulated study of transperineal prostate biopsy. BJU Int. 2005;96:999–1004.
53. Barqawi AB, Rove KO, Gholizadeh S, O’Donnell CI, Koul H, Crawford ED. The role of
3-dimensional mapping biopsy in decision making for treatment of apparent early stage pros-
tate cancer. J Urol. 2011;186:80–5.
54. Crawford ED, Rove KO, Barqawi AB, Maroni PD, Werahera PN, Baer CA, Koul HK, Rove
CA, Lucia MS, La Rosa FG. Clinical-pathologic correlation between transperineal mapping
biopsies of the prostate and three-dimensional reconstruction of prostatectomy specimens.
Prostate. 2013;73:778–87.
55. Cuzick J, Berney DM, Fisher G, Mesher D, Moller H, Reid JE, Perry M, Park J, Younus A,
Gutin A, Foster CS, Scardino P, Lanchbury JS, Stone S, Transatlantic Prostate Group.
Prognostic value of a cell cycle progression signature for prostate cancer death in a conserva-
tively managed needle biopsy cohort. Br J Cancer. 2012;106:1095–9.
56. Bishoff JT, Freedland SJ, Gerber L, Tennstedt P, Reid J, Welbourn W, Graefen M, Sangale Z,
Tikishvili E, Park J, Younus A, Gutin A, Lanchbury JS, Sauter G, Brawer M, Stone S, Schlomm
T. Prognostic utility of the cell cycle progression score generated from biopsy in men treated
with prostatectomy. J Urol. 2014;192:409–14.
57. Knezevic D, Goddard AD, Natraj N, Cherbavaz DB, Clark-Langone KM, Snable J, Watson D,
Falzarano SM, Magi–Galluzzi C, Klein EA, Quale C. Analytical validation of the oncotype
DX prostate cancer assay – a clinical RT-PCR assay optimized for prostate needle biopsies.
BMC Genomics. 2013;14:690.
58. Klein EA, Cooperberg MR, Magi–Galluzzi C, Simko JP, Falzarano SM, Maddala T, Chan JM,
Li J, Cowan JE, Tsiatis A, Cherbavaz DB, Pelham RJ, Tenggara-Hunter I, Baehner FL,
Knezevic D, Febbo PG, Shak S, Kattan MW, Lee M, Carroll PR. A 17-gene assay to predict
prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor mulitfo-
cality, and biopsy undersampling. Eur Urol. 2014;66:550–60.
Chapter 3
Clinical Risk Prediction Tools for Prostate
Cancer: TNM to CAPRA—Should Risk
Be Redefined?

Michael S. Leapman and Matthew R. Cooperberg

Introduction: Rationale for Consistent Risk Stratification

in Research and Clinical Practice

Prostate cancer is a remarkably heterogeneous disease, ranging from a slow-growing,

organ-confined tumor to an aggressive malignancy capable of metastasis and death
[1]. Uniform treatment of all individuals with newly diagnosed prostate cancer each
year—some 240,000 men in the United States alone—would expose many with
indolent tumors to the morbidities of treatment and would not effect cure for many
with aggressive disease [2, 3]. From this vantage, accurate risk stratification—
approximating extant disease and future behavior—is of clear importance: clinicians
may tailor the method and intensity of treatment and provide patients useful prog-
nostic information during counseling. Those with a sufficiently high probability of
favorable risk profiles may opt for surveillance strategies, while those at higher risk
can be guided towards a growing array of interventions, perhaps applied in combi-
nation as appropriate.
The value of accurate risk prediction tools applies to both clinical decision
making and in the design and interpretation of research studies. Given the biological
basis for variable clinical phenotypes it is critically important that accurate methods
are used to stratify study subjects, thereby delineating participants by disease status.

M.S. Leapman, M.D.

Department of Urology, University of California, San Francisco,
550 16th Street, 6th Floor, Box 1695, San Francisco, CA 94109, USA
M.R. Cooperberg, M.D., M.P.H. (*)
Department of Epidemiology, University of California, San Francisco,
550 16th Street, 6th Floor, Box 1695, San Francisco, CA 94109, USA
Epidemiology & Biostatistics, University of California, San Francisco,
550 16th Street, 6th Floor, Box 1695, San Francisco, CA 94109, USA
e-mail: [email protected]

© Springer International Publishing Switzerland 2016 33

N.N. Stone, E.D. Crawford (eds.), The Prostate Cancer Dilemma,
DOI 10.1007/978-3-319-21485-6_3
34 M.S. Leapman and M.R. Cooperberg

Beyond limiting the heterogeneity within research cohorts and offering “apples to
apples” comparisons, consistency in risk assessment is increasingly important for
optimal interpretation of the many emerging prognostic assays which are intended
to be interpreted within the context of standard clinical risk assessment.
Paralleling our understanding of the complexity of prostate cancer outcomes, an
expanding selection of tools have been developed that enable researchers and clini-
cians to stratify men with prostate cancer, or at risk for its diagnosis. These range
from classically utilized staging tools including digital rectal examination (DRE),
biopsy histopathology (Gleason score), and serum assays (prostate-specific antigen,
PSA) to modern iterations of biomarkers (e.g., Kallikrein-related peptidase 2, and
[-2]proPSA), tissue-based gene expression tests, and advanced imaging. A clear
benefit exists in the integration of multiple clinically relevant factors that function
to offer improvements in risk estimation that surpass single variables alone.
As a result, a trove of clinical risk prediction tools has been presented in the
urological literature. In 2008 Shariat and colleagues published a compendium of
111 prediction models relating to prostate cancer outcomes [4], and this number has
grown considerably since that time; a conservative estimate may be obtained from
a PubMed search for “prostate cancer nomogram” which offers over several hun-
dred articles addressing risk prediction. These include tools to stratify individuals in
numerous disease contexts including pathological outcomes at surgery, likelihood
of biochemical recurrence (BCR) or mortality following treatment, to functional
recovery after definitive intervention. In this chapter we will review the trajectory of
risk prediction tools in prostate cancer, from early clinical staging schema, to the
integration of multivariate models and novel assays receiving present-day assess-
ment and clinical utilization. We argue that while risk classification systems like
the D’Amico/AUA/NCCN risk groups are still widely used, they are inadequate for
use in contemporary practice for a variety of reasons and should be replaced with
validated, multivariable risk stratification tools.

Principles of Instrument Evaluation

Risk prediction tools reflect the population from which they are derived. The criteria
used to evaluate these instruments relate to the characteristics of their development,
observed performance, and ease of use. These considerations are therefore relevant
to their utilization, in that one must consider whether a clinical or research context
maintains a meaningful resemblance to the conditions under which a risk stratifica-
tion tool was devised. Properties of risk instruments used in their critical appraisal
include discrimination, calibration, applicability, validation, and parsimony.
The discrimination of a particular risk assessment tool refers to its accuracy in
the prediction of a specified endpoint. This may be seen as a statistical measure of
the likelihood of experiencing a particular clinical outcome. Naturally, a perfect
model would offer 100 % accuracy; it would predict the result in all instances
3 Clinical Risk Prediction Tools for Prostate Cancer… 35

(sensitivity) without incorrectly identifying negative results as positive (specificity).

Overall discriminatory ability reflects the likelihood of predicting an event across
all risk thresholds and may be nonuniform among lower and higher risk patients,
for example [5]. Common measures of discrimination include receiver operating
characteristic (ROC) curve analysis for binary outcomes (e.g., does a diagnostic test
identify the cancer) and Harrell’s concordance (c) index for survival analysis ana-
lyzing outcomes over time.
Calibration refers to an objective assessment of observed versus predicted out-
comes based on a model, offering a valuable indication of performance in various
settings. Calibration plots can be generated that depict predicted and observed fre-
quencies among training or discovery cohorts as well as external validation popula-
tions. A given instrument might have high discrimination in that it will consistently
identify which man in a pair is more likely to have an adverse outcome—but simul-
taneously poor calibration if it is consistently over-optimistic or under-optimistic
across a range of risk strata.
Standard metrics of discrimination (ROC or c-index) that provide an aggregate
measure of a risk instrument’s ability to predict a desired outcome may be alone
inadequate to gauge the broader implications of its clinical implementation.
Management decisions vary considerably by perceived disease risk level, in addition
to other factors including age, comorbid conditions, and patient preference. Therefore,
the true performance of a risk prediction model may best be viewed as dynamic, and
varying by risk and benefit levels. The decision curve analysis (DCA) method has
been advanced as a statistical means to evaluate the benefit of a particular test in
influencing decision making across a spectrum of hypothetical probability thresholds
[6]. This modeling approach was initially conceived for the evaluation of prediction
models and has since been applied to numerous diagnostic and prognostic schema.
Applied to newly diagnosed prostate cancer, net benefit reflects the difference
between anticipated benefit (treatment efficacy) and anticipated harm (cost, morbid-
ity, inconvenience), while probability thresholds represent a scaled probability of
predictive accuracy of a particular instrument that may lead to treatment. DCA curves
offer an opportunity to graphically compare risk prediction tools, plotting net benefit
on the Y-axis, and probability threshold on the X-axis [7]. In comparison, an instru-
ment of superior performance will possess the highest net benefit across a range of
probabilities; some may demonstrate greater value in all situations, while others may
appear advantageous within particular thresholds of probability.
Applicability refers to the generalizability of an instrument to other study popu-
lations or samples. Because prostate cancer incidence, treatment, and outcomes
vary considerably among various factors including year of diagnosis, patient age,
and race, one must also therefore be mindful of the population from which a par-
ticular risk prediction instrument is derived [8, 9]. For example, models drawn
from patients in the pre-PSA era may not perform equally well today, where early
detection has driven a migration in favor of earlier stage disease. The same is true
for many clinical risk tools that were created in academic institutions and draw
from high-volume centers that may not apply equally in clinical practice. Because
36 M.S. Leapman and M.R. Cooperberg

nonuniformity among various populations must be expected, the evaluation of

clinical instruments should occur in an initial development or training set that
reflects the initial test population and should be also evaluated in an external
validation study. Such measures ensure that the findings of a discovery phase are
not limited to the circumstances and particularities of that population and serve to
provide an evaluation of the viability of the instrument, as well a secondary assessment
of applicability.
The parsimony of a particular test is a qualitative judgment of its complexity in
practical application. Seen from the perspective of real-world utilization, it is impor-
tant that the number of variables entered and the interpretation of these factors are
not overly cumbersome. In the research setting, intricate models may not appear as
limiting as their computation may be performed by most statistical platforms used
in clinical research—though even in research, a cumbersome or opaque instrument
may be difficult to validate, reproduce, or apply in other settings. However, in the
attempt to provide crossover to clinical practice, complex instruments that require
the iterative performance of calculations for individual patient will likely not see
uptake in the face of simpler methods. Increasingly, as a function of the diffusion of
handheld devices, prostate cancer nomograms have been offered on smartphone
devices that seek to offer added convenience and portability—but even using such
an application may still be seen as a break in the clinic workflow, depending on the
speed and performance of the software. As such, a balance is to be struck between
accounting maximally for all clinically relevant variables that may offer value in
predicting an outcome while simultaneously providing a nimble and intuitive system
that will enjoy broad appeal.

TNM Staging

Early attempts at estimating prognosis were performed on the basis of clinical

stage and histological grade [10, 11]. The 1992 American Joint Committee on
Cancer (AJCC) tumor, lymph node, metastasis (TNM) staging classification was
updated from the 1987 system which grouped prostate cancer histologic diagnosis
by T1a versus T1b: greater than or less than three microscopic foci, and T2a versus
2b based on size threshold of 1.5 cm (Table 3.1) [12]. The 1992 update (since
modified in 2002 and most recently in 2010) categorizes nonpalpable/nonvisible
lesions as T1, and palpable/visible lesions as T2. It is important to stress that sub-
dividing stage T2 is based on physical exam and imaging, not biopsy findings. It is
common for stage to be misreported, for example, as T2c based on the bilateral
presence of disease on biopsy, when in fact this designation actually requires visi-
ble or palpable disease on both sides of the prostate [13]. In any event, clinical
stage has proved a relatively unimportant prognostic factor, compared to PSA,
Gleason grade, and measures of tumor burden which are better proxies for tumor
volume than clinical stage [14].
3 Clinical Risk Prediction Tools for Prostate Cancer… 37

Table 3.1 Comparison of the American Joint Commission on Cancer Tumor, Lymph Node,
Metastasis (TNM) clinical staging systems
1987 1992, 2002, 2010
T1 Incidental histologic finding T1 Clinically unapparent; tumor not
palpable or visible by imaging
T1a ≤3 microscopic foci T1a Incidental finding ≤5 % of tissue
resected
T1b >3 microscopic foci T1b Incidental finding in >5 % of tissue
resected
T2 Palpable tumor, limited to the gland T1c Tumor identified by needle biopsy
(e.g., because of elevated PSA)
T2a Tumor ≤1.5 cm T2 Tumor confined within prostate
(palpable or visible on TRUS)
T2b Tumor >1.5 cm or in more than one lobe T2a Involves half of a lobe or less
T3 Tumor invades apex, into or beyond T2b Involves more than half of a lobe but
capsule, bladder neck, or seminal vesicle not both lobes
T2c Tumor involves both lobes
T3 Tumor extends through prostatic
capsule
T3a Unilateral extracapsular extension
T3b Bilateral extracapsular extension
T3c Tumor invades seminal vesicle(s)
Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois.
The original and primary source for this information is the AJCC Cancer Staging Manual, Seventh
Edition (2010) published by Springer Science + Business Media

Epstein Criteria

The Epstein criteria, described initially in 1994, remain a commonly utilized rubric
for defining “insignificant” prostate cancer, specifying tumor volume <0.2 cm3,
absent Gleason pattern 4 or 5, and clinically organ-confined disease (<cT3) as insig-
nificant, and tumors between 0.2 and 0.5 cm3 as minimally significant. This frame-
work was developed by Epstein and colleagues from patients with nonpalpable
(≤T1c) prostate cancer treated with prostatectomy at the Johns Hopkins Medical
Center, where tumor volume estimates were derived from observational studies of
palpable tumors without extraprostatic extension or BCR at 5-year follow-up [15–17].
Many have argued that these criteria are too restrictive, and that tumors of larger
volume, if low grade and organ confined, may be equally indolent as those under
0.5 cc [18, 19].
The Johns Hopkins investigators have also proposed an expanded criteria includ-
ing: PSA density <0.15 ng/mL, Gleason score <7, fewer than two cores positive for
tumor, no single core with >50 % prostate cancer involvement, and clinically organ-
confined (≤cT2) disease. This model was evaluated in a case series of 157 men with
38 M.S. Leapman and M.R. Cooperberg

T1c disease, where the positive predictive and negative predictive values were 95
and 66 %, respectively. Overall, the yield for prediction of insignificant and minimal
cancer was 73 % [20]. A clear advantage of such criteria is the ability to render a
dichotomous judgment based on intuitive and easy to mobilize clinical variables.
However, these are also very restrictive criteria, and in longitudinal assessment, the
Epstein criteria have been questioned in their ability to predict more meaningful
prostate cancer endpoints beyond pathological stage alone [21].

Risk Groupings

Many of the commonly utilized pretreatment risk groupings offer easy to conceptu-
alize (and to calculate) classification schemes that broadly distinguish patients with
Prostate cancer on empiric clinical criteria. The rationale for their development
reflects the integration of PSA testing as well as the ascendency and standardization
of the Gleason histological classification schemes. These schemata include the
D’Amico classification, and its modifications reflected in the American Urological
Association (AUA) and National Comprehensive Caner Network (NCCN) risk
classifications.

D’Amico

The D’Amico classification system was initially proposed in 1998 as a means to

stratify patients according to risk of BCR following treatment with radical prosta-
tectomy, external beam radiotherapy, or brachytherapy. These groupings are defined
on the basis of biopsy Gleason score, categorical PSA, and clinical stage. Low risk
includes individuals with PSA ≤10ng/mL, stage ≤cT2a, and Gleason ≤3 + 3; inter-
mediate risk includes those with stage T2b, PSA >10 and ≤20 ng/ml, or Gleason 7;
and high risk includes those with stage ≥T2c, PSA >20, or Gleason score ≥8 [22].
A subsequent validation study was performed in a cohort of 1100 patients treated at
Brigham and Women’s Hospital with radical prostatectomy. In a Cox regression
model, the relative risk for biochemical failure after treatment was 3.3 for interme-
diate versus low disease, and 6.3 for high versus low categories [23]. Numerous
additional studies have emerged in recent years that demonstrate a consistent and
statistically significant stratification among group, though reflect the well-known
stage migration associated with early detection and efficacious treatment [24–26].
In a critical appraisal, the D’Amico risk groups are clearly exemplary in their
ease of use and parsimony. The initial groupings require no calculation to be per-
formed and can readily be recalled by providers in a clinical context. Yet while vali-
dation studies have demonstrated that separation of outcomes does indeed exist, the
discriminative ability and accuracy of this three-tiered scheme is suboptimal due to
the heterogeneity within these groupings. This effect, termed spectrum bias, is illus-
trated by Pierorazio et al., among others, who demonstrated that among patients
meeting D’Amico criteria for high-risk disease, there is considerable variability in
3 Clinical Risk Prediction Tools for Prostate Cancer… 39

outcomes determined by the number of criteria that are possessed [27–30]. There
are multiple reasons for this: the classification over-weights T-stage which, as noted
above, is frequently inaccurate. It also fails to distinguish Gleason 3 + 4 from 4 + 3
disease; if anything Gleason 7 disease should be considered at even more granular
levels [31]. Most importantly, the risk groupings do not comprise a true multivari-
able model. A patient with a Gleason 3 + 4, PSA 4.1, cT2a tumor and one with a
Gleason 4 + 3, PSA 18.3, cT2b tumor are both classified as “intermediate” risk.
Moreover, it has become clear that other pretreatment factors add additional
value in the prediction of prostate cancer outcome. Lee et al. reported on the pres-
ence of >50 % positive biopsies for cancer as associated with pathologic upgrading
at surgery and poorer BCR free survival outcomes among a concordance testing of
427 patients treated with RP within the low-risk category [32]. Further refinements
to this classification scheme based on tumor volume within low and intermediate
categories based on tumor volume were also made based on data from prostatec-
tomy patients [33].

AUA and NCCN Risk Groupings

Risk groupings in the style of the D’Amico classification are employed by the
American Urological Association (AUA) and National Comprehensive Cancer
Network (NCCN) Guidelines for prostate cancer [34, 35]. The AUA and NCCN
provide risk groupings in the context of management guidelines and differ from the
D’Amico classification in that the systems were not subject to validation within a
training or external dataset. Thus, the rationale by which the clinical criteria were
selected reflects a consensus of relevant variables but was not derived from a multi-
variate model attuned to a particular endpoint. One important difference is that stage
T2c is not assigned to high risk under the NCCN or AUA classifications. Updates to
the NCCN Guidelines for Prostate Cancer Initial Clinical Assessment and Staging
Evaluation seek to add discrimination between categories and specify five groupings:
very low, low, intermediate, high, and very high risk. These groupings incorporate
numerous clinical criteria derived from individual variables that bear prognostic
significance, yet are not shared among all categories.
This is perhaps best illustrated by examining the distinction between very
low- and low-risk disease, where “very low risk” is specified by men possessing all
of the following: clinical stage T1c, biopsy Gleason score ≤6, PSA <10 ng/mL, less
than three biopsy cores with disease, ≤50 % prostate cancer in any single core, and
PSA density <0.15 ng/ml/g. In contrast, low-risk patients are defined as clinical
T1–T2a, Gleason ≤6, PSA <10 without a designation of tumor volume or PSA
density [36]. These criteria are similar to the Epstein “insignificant disease” criteria
discussed above, but have not been externally validated. While the rationale for
these groupings is individually evidence based, an important caveat must be applied
for the use of these groupings to generate probabilistic determinations of outcome,
be they for the purposes of clinical counseling or research. It is critical to emphasize
40 M.S. Leapman and M.R. Cooperberg

that while these risk classification systems are still widely used, they ultimately are
inadequate for all the reasons delineated above, and going forward, prostate cancer
risk really must be considered and assessed using a true multivariable instrument.

Nomograms

In this context of prediction instruments, a nomogram refers to a graphic depiction of

a risk calculation formula that is typically derived from multivariate models yielding
quantitative estimates of a proposed outcome. As a result, such tools provide a clear
benefit over risk groupings in the prediction of treatment outcomes after surgery or
radiotherapy and have been used to predict BCR, metastatic progression, and can-
cer-specific mortality (CSM). They are usually generated from time-dependent sur-
vival models (e.g., Cox proportional hazards) or statistical classification models
(e.g., logistic regression), as appropriate. The consequence of incorporating
continuous variables is that nomograms limit spectrum bias by accounting for the
contribution of variables along a range of values, as opposed to groupings where
values are dichotomized.
In 1998 Kattan and colleagues reported on a nomogram to predict biochemical
recurrence 5 years following radical prostatectomy. The authors evaluated clinical
data associated with BCR in a Cox proportional hazards model comprised of 983
men treated with RP for clinically localized prostate cancer between 1983 and 1996
including 196 experiencing PSA failure, yielding an area under the ROC curve
(AUC) of 0.79 [37]. This initial model incorporated PSA (scaled 0.1–110), clinical
stage, and biopsy Gleason score and has since received external validation in vari-
ous settings [38]. In these assessments, the Kattan nomogram has demonstrated
robust performance as a risk prediction instrument in the academic setting, with
slightly lower discrimination in a community-based cohort (c-index = 0.68), poten-
tially reflecting bias within the training set from which it was derived [39, 40].
A multitude of nomograms have since emerged in the style of Kattan, often apply-
ing a similar methodology to other prostate cancer endpoints including likelihood of
seminal vesicle or lymph node invasion at prostatectomy, BCR, and metastatic pro-
gression after radiation therapy or surgery [41–45]. A plain benefit to the use of
nomograms is the ability to offer a visual depiction of generated risk scores as well
as an appreciation for the constituent components of the model. Moreover, nomo-
grams clearly represent a step forward as compared with risk groupings with respect
to methodology and discrimination. Ultimately, though, nomograms have not
gained widespread acceptance in clinical practice, an observation that may be attrib-
utable to their requirement of a multi-step paper instrument or computer software,
as well as the necessity of obtaining abstruse code for large-scale calculations in an
academic setting, since the regression equations underlying the nomograms are
rarely published.
Because they are usually derived from high-volume academic cohorts, nomograms
tend to calibrate suboptimally—specifically they tend to be over-optimistic in their
3 Clinical Risk Prediction Tools for Prostate Cancer… 41

predictions for any given outcome when validated in a community-based setting [46].
The other problem is that nomogram generation has become very simple, requiring
no more than a single command issued to standard statistical software following a
regression procedure. This phenomenon has fed a proliferation of nomograms, most
of which are never validated, and very few of which actually find their way into
either clinical practice or subsequent research studies.

UCSF-CAPRA Score

In 2005, the Cancer of the Prostate Risk Assessment (CAPRA) Score was developed
at the University of California San Francisco (UCSF) in response to the growing
appreciation of an unmet need for a risk prediction instrument that offers robust
performance, yet can be applied without the necessity of a drawn paper tool or
online calculator. The cohort used for initial development set was the Cancer of the
Prostate Strategic Urologic Research Endeavor (CaPSURE), a community practice
database drawing from over 40 US sites with longitudinal follow-up. This initial
cohort included 1439 men diagnosed with prostate cancer between 1992 and 2001
who received treatment with radical prostatectomy without neoadjuvant or adjuvant
radiation therapy or hormonal therapy. Significant clinical factors associated with
BCR or secondary treatment in a Cox proportional hazards regression model
included age, pretreatment PSA, Gleason score, percentage of biopsy cores positive
for cancer, and clinical stage. The resulting 10-point system, designed to provide an
approximate doubling of risk with every 2-point increase in the total score, is derived
from logarithmic parameter estimates yielded in the final Cox model. The final system
is detailed in Table 3.2. Strong correlations were seen between the UCSF-CAPRA
score and the D’Amico and Kattan tools, and the c-index appeared comparable for all:
CAPRA (0.66), D’Amico (0.63), and Kattan nomogram (0.65) [47].
Several external validations of the CAPRA score have been performed to date.
Among a racially diverse Veterans Affairs and military population of 1346 men, the
c-index for the prediction of clinical recurrence after RP was 0.68 [48]. The CAPRA
score has performed slightly better in external validation studies from academic insti-
tutions (c-index 0.76–0.81), a finding that appears to invert the findings of nomograms
derived from academic cohorts in community-based populations [40, 49–51]. It
should also be stressed, with respect to calibration, that the CAPRA score is intended
to indicate relative rather than absolute risk. For example, a patient with a CAPRA
score of 4 or 2 may have better outcomes in a high-volume academic center than in a
lower volume community context, but a patient with the score of 4 will always have
higher risk of recurrence and progression than a patient with the score of 2.
In addition, the CAPRA score has been externally evaluated in international
populations (Table 3.3) [50, 52]. Beyond BCR, the CAPRA score has also been
validated to predict pathological stage, as well as significant oncological endpoints
including metastatic progression and prostate cancer mortality (PCSM) following
treatment [53]. The CAPRA score is also one of the only risk stratification systems
42 M.S. Leapman and M.R. Cooperberg

Table 3.2 PScoring systems for the Cancer of the Prostate Risk Assessment (CAPRA), CAPRA-S,
and J-CAPRA tools
CAPRA CAPRA-S J-CAPRA
Variable Points Variable Points Variable Points
Age (years) Margin status Biopsy
Gleason score
<50 0 Negative 0 3+3 0
≥50 1 Positive 2 3 + 4/4 + 3 1
8–10 2
PSA (ng/mL) PSA (ng/mL) PSA (ng/mL)
<6 0 0–6 0 0–20 0
6.1–10 1 6.01–10 1 > 20–100 1
10.1–20 2 10.01–20 2 >100–500 2
20.1–30 3 >20 3 >500 3
>30 4
Biopsy Gleason score Pathologic Gleason score T-stage
1–3/1–3 0 2–6 0 ≤T2a 0
1–3/4–5 1 3+4 1 ≤T3a 1
4–5/1–5 3 4+3 2 T3b 2
8–10 3 T4 3
Percent of biopsy cores Seminal vesicle invasion N-stage
positive for cancer
<34 % 0 No 0 N1 1
≥34 % 1 Yes 2
T-stage Extracapsular extension M-stage
T1/T2 0 No 0 M1 3
≥T3a 1 Yes 1
Lymph node invasion
No 0
Yes 1
Sum of all points /10 /12 /12

to have been evaluated successfully following prostatectomy, radiation therapy,

hormonal therapy, and other management approaches [48, 54–56].
A 2013 meta-analysis of seven studies evaluating the prediction of risk among
trichotomized categories—low risk (0–2), intermediate risk (3–5), and high risk
(6–10)—recapitulated the ability of the CAPRA score to predict clinical recurrence
after RP, though appeared to suggest an underprediction of risk at 5 years [57]. It
should be noted though that while these risk groupings represent validated compres-
sions, the CAPRA score represents a near continuous risk prediction model and the
meta-analysis did not look at these groupings. Variability in the performance among
cohorts may also be related to the quality of the clinical data utilized in the model,
considerations which are less of an issue for variables that are reliably measured
(i.e., age, PSA) a significant factor to consider with respect to Gleason score,
3 Clinical Risk Prediction Tools for Prostate Cancer… 43

Table 3.3 External validation studies of the UCSF CAPRA, CAPRA-S, and J-CAPRA risk
assessment instruments
Instrument Author, year Country N Setting Endpoint Performance
CAPRA Coopberberg USA 1346 Veterans BCR after c-index 0.68
[48], 2006 affairs/ RP
SEARCH
May [50], Germany 1296 Academic BCR after c-index 0.81
2007 RP (7-grouped
CAPRA score);
0.78, three-tiered
CAPRA scorea
Zhao [49], USA 6737 Academic BCR after c-index 0.78
2008 RP
Lughezzani Germany 1976 Academic BCR after 3- and 5-year
[52], 2010 RP c-index 0.743,
0.729 respectively
Halverson USA 612 Academic 5-year BCR c-index 0.69
[56], 2011 after EBRT
Ishizaki [73], Japan 211 Academic 5-year BCR c-index 0.755
2011 after RP
Tamblyn Australia 635 Academic BCR after c-index 0.787
[74], 2011 RP
Budäus [75], Germany 2937 Academic BCR, MR BCRFS: c-index
2012 after RP 0.762; MR:
c-index 0.785
Yoshida Japan 503 Academic 5-year BCR BCRFS: c-index
[76], 2012 after RP 0.673
Krishnan Canada 345 Academic BCR after HR per continuous
[55], 2014 EBRT or CAPRA score
LDR BT 1.37 (95 % CI
1.10–1.72,
p = 0.006)
Seo [77], Korea 115 Academic BCR after 3- and 5-year:
2014 RP c-index 0.74, 0.77,
respectively
Delouya Canada 744 Academic BCR after AUC 3-year
[54], 2014 EBRT or BCRFS 0.66;
BT 5-year, 0.62
CAPRA-S Seong [78], Korea 134 Academic 5-year c-index 0.776
2013 BCRFS
Punnen [46], USA 2670 Veterans 5-year c-index, BCR
2014 Affairs/ BCR, CSM 0.73; CSM, 0.85
SEARCH after RP
Cooperberg USA 1010 Academic PCSM c-index 0.75
[79], 2014
Tilki [62], Germany 14,532 Academic 5-year c-index, BCR:
2014 BCR, 0.80; metastasis:
metastasis, 0.85; CSM: 0.88
mortality
(continued)
44 M.S. Leapman and M.R. Cooperberg

Table 3.3 (continued)

Instrument Author, year Country N Setting Endpoint Performance
J-CAPRA Seo [80], Korea 130 Academic 5-year PFS c-index 0.80
2014
Kitagawa Japan 319 Academic PFS, PCSM c-index CSS
[81], 2013 0.833; OS, 0.665
Akakura Japan 426 Academic 10-year Categories 1–2
[82], 2014 PFS, PCSM (75.6, 98.9 %)
versus 3–6 (52.6,
93.1 %), p < 0.001
and p = 0.044
Shiota [83], Japan 248 Academic PFS, c-index PFS
2015 PCSM, OS 0.890; PCSM
0.836; OS 0.700
Yamaguchi Japan 255 Academic PFS, c-index PFS
[84], 2015 PCSM, OS 0.847; PCSM
0.820; OS 0.669
PSM positive surgical margins, RFS recurrence free survival, c-index concordance index, RP radi-
cal prostatectomy, RARP robotic assisted radical prostatectomy, MR metastatic recurrence,
BT brachytherapy, EBRT external beam radiation therapy, PCSM prostate cancer-specific mortal-
ity, SEARCH Shared Equal Access Regional Cancer Hospital
a
Three-tiered CAPRA score (0–2 = low risk; 3–5 = intermediate risk; 6–10 = high risk)

clinical stage, and the percentage of biopsy cores positive which are subject to
interpretation by clinicians [58].
The CAPRA score was designed to perform in research and clinical settings, and
has been reflected in a system that can be calculated rapidly, without pen, paper, or
computer, and may be committed to memory with relative ease, while functioning
on par with other risk assessment instruments. Beyond calibration alone, prognostic
tests are practically held to a standard that is proportional to their clinical value.
Such insights may be appreciated by examining the DCA comparison of prostate
cancer risk assessment tools. Lughezzani et al. compared calibration and DCA
models among the D’Amico, Stephenson, and CAPRA instruments among 1976
patients among a European RP cohort. While the CAPRA and Stephenson systems
demonstrated c-indices of 72.9 and 73.5 %, respectively, a benefit was seen with the
CAPRA score, implying a potential advantage in clinical performance [52].

CAPRA-S

Following radical prostatectomy, the enhanced pathological staging information

offered by surgery may often inform further management decisions based on the risk
for recurrence or other ensuing events. The value of this new information has been
previously incorporated in nomograms tailored to the post-RP setting [59, 60]. Kattan
et al. first described a postoperative nomogram for disease recurrence derived from a
3 Clinical Risk Prediction Tools for Prostate Cancer… 45

Cox proportional hazards regression analysis from a cohort of 996 men treated with
RP [61]. The performance of this nomogram was excellent, with an AUC in an initial
separate validation cohort of 332 men of 0.89, yet is subject to the same limitations in
utilization and scalability that affect nomograms in the pretreatment setting.
The postsurgical CAPRA-S score was developed and published in 2011 as an
analogous model to CAPRA that can be readily calculated on-demand, based largely
on pathological data. Like CAPRA, the training set used for the development of
CAPRA-S was a cohort of 3837 men from the CaPSURE database, where putative
clinical and pathological variables were entered into a multivariate Cox propor-
tional hazards model. These included categorical preoperative PSA (0–6; 6.01–10;
10.01–20; >20), pathological Gleason score (3 + 3; 3 + 4; 4 + 3; 8–10), as well the
presence or absence of seminal vesicle invasive, positive surgical margins, extracap-
sular extension (pT3a), or lymph node positivity. The point values obtained for the
final model were derived from the log hazard ratio parameter estimates, yielding a
theoretical maximum of 12-point scale, though very few patients fall above 10,
allowing scores ≥9 to be grouped together (Table 3.3). Within the initial analytic
CaPSURE cohort, the bootstrap corrected c-index was 0.77 (95 % CI 0.75–0.79).
The CAPRA-S score has since been externally validated in US and international
populations (Table 3.3). Punnen et al. performed a multi-institutional validation in
the VA SEARCH database comprising 2670 with complete data and median follow-
up of 58 months. In this ethnically diverse population, including 42 % non-
Caucasians, the c-index for BCR was 0.73. In a DCA comparison to the Stephenson
nomogram, the CAPRA-S demonstrated greater net benefit, particularly in situations
of threshold probabilities >40 % [46]. The CAPRA-S score has also demonstrated
robust performance in the prediction of downstream oncologic endpoints. Within the
original validation set the sub-hazard ratio for PCSM per unit-increase in CAPRA-S
was 1.42 (95 % CI 1.27–1.60); when applied to a European population, the c-index
for BCR was 0.80, systemic progression (c-index 0.85), and for PCSM, 0.88 [62].

J-CAPRA

Prostate cancer screening has catalyzed a shift in the nature of disease at presenta-
tion, favoring the detection of clinically localized disease [63]. However, for patients
with metastatic or locally advanced disease at presentation—accounting for approx-
imately one-fifth of new diagnoses in Japan—treatment is initially approached with
androgen deprivation therapy (ADT). While this approach is not endorsed by
Western guidelines, it is endorsed and widely practiced in Asia. The J-CAPRA
score was developed from data including CaPSURE and the Japan Study Group of
Prostate Cancer (J-CaP) registries to offer risk estimation for patients receiving
primary ADT, capturing nearly half of all Japanese men diagnosed with prostate
cancer during the study period, as well as nearly all patients treated with ADT.
The J-CAPRA score was derived from a Cox proportional hazards regression model
of progression free survival (PFS). The J-CAPRA was thereby rendered using the
46 M.S. Leapman and M.R. Cooperberg

following variables: Gleason score, PSA, T-stage, N-stage, and M-stage. The c-index
for PFS was 0.71 in J-CaP; and 0.84 for PCSM among CaPSURE patients. A summary
of J-CAPRA validation studies is presented in Table 3.3.

Future Directions: Novel Biomarkers, Gene Expression

Testing, Advanced Imaging

Advances in the molecular and genetic characterization of prostate cancer have

recently paid dividends in the form of novel assays that offer risk prediction in various
settings. The pace of innovation appears to reflect an appreciation for the limitations
of even the highest performing risk prediction instruments derived from standard
clinical variables to accurately characterize all patients. To this end, progress has been
seen on several fronts, including the nomination and assessment of new biomarkers
that aim to mitigate the vaunted over-detection and over-treatment associated with
contemporary PSA screening. Following diagnosis, opportunities exist to better
characterize disease across risk spectra utilizing prostate magnetic resonance imaging
(MRI) and tissue-based assays evaluating unique genomic signatures.
Prostate magnetic resonance imaging (MRI) interrogating multiple parameters
including T2 intensity, dynamic contrast enhancement (DCE), diffusion weighted
sequences, and magnetic resonance spectroscopy also represents a powerful tool
for risk prognostication. The ability of baseline prostate MRI to predict
non-organ-confined disease (pT3a) has been extensively studied and is subject to
issues of nonstandardization relating to technology (3 Tesla versus 1.5 Tesla),
interobserver variability, and sequences performed. Nomograms incorporating
MRI and MRSI have demonstrated improved performance when compared to stan-
dard clinical models. Among 181 low D’Amico risk patients, the incorporation of
MR findings into a basic clinical model consisting only of PSA, clinical stage, and
biopsy Gleason score resulted in a significantly improved performance; however
these differences were not maintained among a more sophisticated clinical model
inclusive of the percentage of biopsy cores positive [64]. mpMRI has also demon-
strated considerable potential to change risk prediction at the time of detection by
facilitating MR-ultrasound fusion biopsy. This modality has shown improved
detection of Gleason ≥7 tumors at biopsy though the optimal manner in which to
incorporate the pathological data from these high-probability biopsies in existing
risk prediction instruments remains to be determined [65, 66].
Tissue-based gene expression assays derived from genes highly associated with
prostate cancer aggressiveness have also been developed that can assist in the prog-
nostication of extant disease in various contexts including from prostate biopsy
specimens or radical prostatectomy tissue. Central to the evaluation of these prom-
ising new tools is the benchmark for comparison where new assays are tasked to
offer an improvement in risk assessment over currently available clinical instruments.
Therefore, in the development and validation phases of study, it is particularly
critical that subjects are appropriately stratified by the nature of their presumed risk.
3 Clinical Risk Prediction Tools for Prostate Cancer… 47

A putative marker that merely associates with known risk factors may be interesting
from a scientific standpoint but will have little clinical value; what is needed is tests
that improve over a multivariable gold standard in terms of discrimination and/or
calibration.
The Prolaris assay (Myriad Genetics, Salt Lake City, UT) generates a cell cycle
progression score (CCP) derived from a 31 gene signature associated with prostate
cancer outcome. In validation studies derived from archival biopsy radical prostatec-
tomy specimens, the CCP score was associated with adverse outcomes after prosta-
tectomy including BCR and metastatic progression [67, 68]. The importance of
accurate clinical assessment is underscored in the evaluation of this assay, where the
predictive performance was assessed in relation to CAPRA-S score. While the CCP
score alone was not superior to the clinical model, a composite score (derived from a
weighting of CAPRA-S and CCP) demonstrated improved performance across risk
spectra, a benefit that was maintained as well for low-risk patients [69].
Decipher (GenomeDX Biosciences, San Diego, CA), a genomic classifier (GC)
comprised of 22 genes highly associated with prostate cancer aggressiveness, devel-
oped from high density transcriptosome-wide microarrays and has been validated in
a high-risk cohort for the prediction of metastatic progression after RP (AUC 0.79)
[70]. In a subset of 185 high-risk patients from a cohort utilized for discovery and
validation, CAPRA-S and the GC were independent predictors of PCMS (c-indices
0.75 and 0.78 respectively). While the combination of the two did not improve the
AUC for predicting PCSM, the GC was able to further sub-stratify clinically high-
risk men (CAPRA-S ≥6, p < 0.001) as well as CAPRA-S to re-stratify high GC
scores (>0.6, p = 0.005) [71]. The findings gleaned from the Prolaris and Decipher
studies serve to illustrate the value of improved methods to predict risk in the post-
treatment setting where considerable heterogeneity in outcomes exists, even among
patients with high-risk features by clinical criteria.
The Oncotype DX Genomic Prostate Score (GPS) assay (Genomic Health,
Redwood City, CA) utilizes a 17-gene signature, including 12 genes highly associ-
ated with prostate cancer outcome along four biological pathways. Amplification of
minute tumor volumes (1 mm) yield quantitative gene expression levels that are
calculated into a scaled (0–100) GPS score. In a validation study of 395 patients
with CAPRA <5 disease and biopsy Gleason pattern ≤3 + 4, GPS score was com-
pared against CAPRA score for the prediction of favorable pathology at radical
prostatectomy (defined as Gleason pattern <4 + 3, and pathological stage <pT3a).
The AUC for this endpoint was 0.63 for CAPRA alone, and improves to 0.67 in a
model incorporating both GPS and CAPRA [72].
Tumor-based gene expression tests represent a new frontier for risk assessment
in prostate cancer and have been adapted at all stages of disease, including clinically
localized to locally advanced. While offering new insights, these do not supplant
existing clinical models which appear to perform nearly as well, though net benefits
have been projected in DCA modeling studies. One must also be mindful of the
growing complexity and health care infrastructure expense that is associated with
their development and widespread integration. Just as overly complex clinical mod-
els that offer strong predictive performance may not meet universal clinical utilization
48 M.S. Leapman and M.R. Cooperberg

such considerations also apply to emerging biomarkers and tissue expression assays.
Thus, while numerous platforms may seek to exist within these clinical spaces,
those that offer strong clinical performance, parsimony, and intuitive use may be
best suited to enjoy empiric success.

Conclusion

Clinical staging of prostate cancer is complex, reflecting the shifting sands of disease
epidemiology, therapeutics, and an ever-expanding armamentarium of tools with
which to estimate risk at various junctures of clinical impact. From early risk estima-
tion models, relying on relatively crude means of digital rectal examination alone, to
the integration of histopathology and biomarkers (PSA), risk prediction has evolved
past risk groups to multivariable instruments integrating all known clinical informa-
tion, with some models like the CAPRA score nearly as easy to apply as the risk
groups. A new era of advancement, heralded by innovative leaps in biomarker vali-
dation, advanced imaging, and cancer genomics, is positioned to add predictive
accuracy to clinical models and may deliver higher degrees of predictive certainty
at several intersections of prostate cancer decision making.

References

1. Wyatt AW, Mo F, Wang K, et al. Heterogeneity in the inter-tumor transcriptome of high risk
prostate cancer. Genome Biol. 2014;15(8):426.
2. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.
3. Resnick MJ, Koyama T, Fan KH, et al. Long-term functional outcomes after treatment for
localized prostate cancer. N Engl J Med. 2013;368(5):436–45.
4. Shariat SF, Karakiewicz PI, Roehrborn CG, Kattan MW. An updated catalog of prostate cancer
predictive tools. Cancer. 2008;113:3075–99.
5. Shariat SF, Karakiewicz PI, Margulis V, Kattan MW. Inventory of prostate cancer predictive
tools. Curr Opin Urol. 2008;18(3):279–96.
6. Vickers AJ, Elkin EB. Decision curve analysis: a novel method for evaluating prediction models.
Med Decis Making. 2006;26(6):565–74.
7. Fitzgerald M, Saville BR, Lewis RJ, et al. Decision curve analysis. JAMA. 2015;313(4):
409–10.
8. Chu DI, Moreira DM, Gerber L, et al. Effect of race and socioeconomic status on surgical
margins and biochemical outcomes in an equal-access health care setting: results from the
Shared Equal Access Regional Cancer Hospital (SEARCH) database. Cancer.
2012;118(20):4999–5007.
9. Kattan MW. Comparison of Cox regression with other methods for determining prediction
models and nomograms. J Urol. 2003;170(6 pt 2):S6–S9; discussion S10.
10. Gleason DF, Mellinger GT. Prediction of prognosis for prostatic adenocarcinoma by combined
histological grading and clinical staging. J Urol. 1974;111(1):58–64.
11. Spigelman SS, McNeal JE, Freiha FS, Stamey TA. Rectal examination in volume determina-
tion of carcinoma of the prostate: clinical and anatomical correlations. J Urol. 1986;
136(6):1228–30.
3 Clinical Risk Prediction Tools for Prostate Cancer… 49

12. Edge S, Byrd DR, Compton CC, et al. American Joint Committee on Cancer staging manual.
7th ed. New York, NY: Springer; 2010.
13. Reese AC, Sadetsky N, Carroll PR, et al. Inaccuracies in assignment of clinical stage for
localized prostate cancer. Cancer. 2011;117(2):283–9.
14. Reese AC, Cooperberg MR, Carroll PR. Minimal impact of clinical stage on prostate cancer
prognosis among contemporary patients with clinically localized disease. J Urol.
2010;184(1):114–9.
15. Epstein JI, Pizov G, Walsh PC. Correlation of pathologic findings with progression following
radical retropubic prostatectomy. Cancer. 1993;71:3582–93.
16. Bastian PJ, Mangold LA, Epstein JI, Partin AW. Characteristics of insignificant clinical T1c
prostate tumors: a contemporary analysis. Cancer. 2004;101:2001–5.
17. Epstein JI, Carmichael M, Partin AW, Walsh PC. Is tumor volume an independent predictor of
progression following radical prostatectomy? A multivariate analysis of 185 clinical stage B
adenocarcinomas of the prostate with five years follow-up. J Urol. 1993;149:1478–81.
18. Wolters T, Roobol MJ, van Leeuwen PJ, et al. A critical analysis of the tumor volume threshold
for clinically insignificant prostate cancer using a data set of a randomized screening trial.
J Urol. 2011;185(1):121–5.
19. Porten SP, Cooperberg MR, Carroll PR. The independent value of tumour volume in a contem-
porary cohort of men treated with radical prostatectomy for clinically localized disease. BJU
Int. 2010;105(4):472–5.
20. Epstein JI, Walsh PC, Carmichael M, Brendler CB. Pathologic and clinical findings to predict
tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA. 1994;271:368–74.
21. Lee MC, Dong F, Stephenson AJ, et al. The Epstein criteria predict for organ-confined but not
insignificant disease and a high likelihood of cure at radical prostatectomy. Eur Urol.
2010;58(1):90–5.
22. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prosta-
tectomy, external beam radiation therapy, or interstitial radiation therapy for clinically local-
ized prostate cancer. JAMA. 1998;280:969–74.
23. D’Amico AV, Whittington R, Malkowicz SB, et al. Predicting prostate specific antigen out-
come preoperatively in the prostate specific antigen era. J Urol. 2001;166:2185–8.
24. Boorjian SA, Karnes RJ, Rangel LJ. Mayo Clinic validation of the D’amico risk group clas-
sification for predicting survival following radical prostatectomy. J Urol. 2008;179(4):1354–
60. discussion 1360-1.
25. Hernandez DJ, Nielsen ME, Han M, Partin AW. Contemporary evaluation of the D’amico risk
classification of prostate cancer. Urology. 2007;70(5):931–5.
26. D’Amico AV, Whittington R, Malkowicz SB, et al. Pretreatment nomogram for prostate-
specific antigen recurrence after radical prostatectomy or external-beam radiation therapy for
clinically localized prostate cancer. J Clin Oncol. 1999;17(1):168–72.
27. Shariat SF, Karakiewicz PI, Suardi N, et al. Comparison of nomograms with other methods for
predicting outcomes in prostate cancer: a critical analysis of the literature. Clin Cancer Res.
2008;14(14):4400–7.
28. Kattan MW. Nomograms. Introduction. Semin Urol Oncol. 2002;20:79–81.
29. Mitchell JA, Cooperberg MR, Elkin EP, et al. Ability of 2 pretreatment risk assessment meth-
ods to predict prostate cancer recurrence after radical prostatectomy: data from CaPSURE. J
Urol. 2005;173(4):1126–31.
30. Pierorazio PM, Ross AE, Han M, et al. Evolution of the clinical presentation of men undergo-
ing radical prostatectomy for high-risk prostate cancer. BJU Int. 2012;109(7):988–93.
31. Reese AC, Cowan JE, Brajtbord JS, et al. The quantitative Gleason score improves prostate
cancer risk assessment. Cancer. 2012;118(24):6046–54.
32. Lee AK, Schultz D, Renshaw AA, et al. Optimizing patient selection for prostate monother-
apy. Int J Radiat Oncol Biol Phys. 2001;49(3):673–7.
33. Lieberfarb ME, Schultz D, Whittington R, et al. Using PSA, biopsy Gleason score, clinical
stage, and the percentage of positive biopsies to identify optimal candidates for prostate-only
radiation therapy. Int J Radiat Oncol Biol Phys. 2002;53(4):898–903.
50 M.S. Leapman and M.R. Cooperberg

34. Mohler JL, Kantoff PW, Armstrong AJ, et al. Prostate cancer, version 2.2014. J Natl Compr
Canc Netw. 2014;12(5):686–718.
35. American Urological Association Education and Research, Inc. (AUA). Guideline for the
management of clinically localized prostate cancer: AUA guideline. Linthicum, MD: American
Urological Association Education and Research, Inc.; 2007.
36. Reese AC, Pierorazio PM, Han M, Partin AW. Contemporary evaluation of the National
Comprehensive Cancer Network prostate cancer risk classification system. Urology.
2012;80:1075–9.
37. Kattan MW, Eastham JA, Stapleton AM, et al. A preoperative nomogram for disease
recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst.
1998;90(10):766–71.
38. Graefen M, Karakiewicz PI, Cagiannos I, et al. A validation of two preoperative nomograms
predicting recurrence following radical prostatectomy in a cohort of European men. Urol
Oncol. 2002;7(4):141–6.
39. Graefen M, Karakiewicz PI, Cagiannos I, et al. International validation of a preoperative
nomogram for prostate cancer recurrence after radical prostatectomy. J Clin Oncol.
2002;20:3206–12.
40. Greene KL, Meng MV, Elkin EP, et al. Validation of the Kattan preoperative nomogram for
prostate cancer recurrence using a community based cohort: results from Cancer of the Prostate
Strategic Urological Research Endeavor (CaPSURE). J Urol. 2004;171(6 Pt 1):2255–9.
41. Stephenson AJ, Scarcino PT, Eastham JA, et al. Preoperative nomogram predicting the 10-year
probability of prostate cancer recurrence after radical prostatectomy. J Natl Cancer Inst.
2006;98:715–7.
42. Dotan ZA, Bianco Jr JF, Rabbani F, et al. Pattern of prostate-specific antigen (PSA) failure
dictates the probability of a positive bone scan in patients with an increasing PSA after radical
prostatectomy. J Clin Oncol. 2005;23:1962–8.
43. Briganti A, Chun FK, Salonia A, et al. Validation of a nomogram predicting the probability of
lymph node invasion among patients undergoing radical prostatectomy and an extended pelvic
lymphadenectomy. Eur Urol. 2006;49(6):1019–26. discussion 1026-7.
44. Kattan MW, Potters L, Blasko JC, et al. Pretreatment nomogram for predicting freedom
from recurrence after permanent prostate brachytherapy in prostate cancer. Urology.
2001;58(3):393–9.
45. Koh H, Kattan MW, Scardino PT, et al. A nomogram to predict seminal vesicle invasion by the
extent and location of cancer in systematic biopsy results. J Urol. 2003;170(4 pt 1):1203–8.
46. Punnen S, Freedland SJ, Presti Jr JC, et al. Multi-institutional validation of the CAPRA-S
score to predict disease recurrence and mortality after radical prostatectomy. Eur Urol.
2014;65(6):1171–7.
47. Cooperberg MR, Pasta DJ, Elkin EP, et al. The University of California, San Francisco Cancer
of the Prostate Risk Assessment score: a straightforward and reliable preoperative predictor of
disease recurrence after radical prostatectomy. J Urol. 2005;173(6):1938–42.
48. Cooperberg MR, Freedland SJ, Pasta DJ, et al. Multiinstitutional validation of the UCSF can-
cer of the prostate risk assessment for prediction of recurrence after radical prostatectomy.
Cancer. 2006;107(10):2384–91.
49. Zhao KH, Hernandez DJ, Han M, Humphreys EB, Mangold LA, Partin AW. External valida-
tion of University of California, San Francisco, Cancer of the Prostate Risk Assessment score.
Urology. 2008;72:396–400.
50. May M, Knoll N, Siegsmund M, et al. Validity of the CAPRA score to predict biochemical
recurrence-free survival after radical prostatectomy. Results from a European multicenter sur-
vey of 1296 patients. J Urol. 2007;178:1957–62.
51. Loeb S, Carvalhal GF, Kan D, et al. External validation of the cancer of the prostate risk
assessment (CAPRA) score in a single-surgeon radical prostatectomy series. Urol Oncol.
2012;30(5):584–9.
52. Lughezzani G, Budäus L, Isbarn H, et al. Head-to-head comparison of the three most commonly
used preoperative models for prediction of biochemical recurrence after radical prostatectomy.
Eur Urol. 2010;57(4):562–8.
3 Clinical Risk Prediction Tools for Prostate Cancer… 51

53. Cooperberg M, Broering J, Carroll P. Risk assessment for prostate cancer metastasis and
mortality at the time of diagnosis. J Natl Cancer Inst. 2009;101:878–87.
54. Delouya G, Krishnan V, Bahary JP, et al. Analysis of the Cancer of the Prostate Risk Assessment
to predict for biochemical failure after external beam radiotherapy or prostate seed brachy-
therapy. Urology. 2014;84(3):629–33.
55. Krishnan V, Delouya G, Bahary JP, et al. The Cancer of the Prostate Risk Assessment (CAPRA)
score predicts biochemical recurrence in intermediate-risk prostate cancer treated with exter-
nal beam radiotherapy (EBRT) dose escalation or low-dose rate (LDR) brachytherapy. BJU
Int. 2014;114(6):865–71.
56. Halverson S, Schipper M, Blas K, et al. The Cancer of the Prostate Risk Assessment (CAPRA)
in patients treated with external beam radiation therapy: evaluation and optimization in patients
at higher risk of relapse. Radiother Oncol. 2011;101:513–20.
57. Meurs P, Galvin R, Fanning DM, Fahey T. Prognostic value of the CAPRA clinical prediction
rule: a systematic review and meta-analysis. BJU Int. 2013;111(3):427–36.
58. Goodman M, Ward KC, Osunkoya AO, et al. Frequency and determinants of disagreement
and error in Gleason scores: a population-based study of prostate cancer. Prostate.
2012;72(13):1389–98.
59. Bauer JJ, Connelly RR, Seterhenn IA, et al. Biostatistical modeling using traditional preop-
erative and pathological prognostic variables in the selection of men at high risk for disease
recurrence after radical prostatectomy for prostate cancer. J Urol. 1998;159:929–33.
60. Stephenson AJ, Scardino PT, Eastham JA, et al. Postoperative nomogram predicting the
10-year probability of prostate cancer recurrence after radical prostatectomy. J Clin Oncol.
2005;23:7005–12.
61. Kattan MW, Wheeler TM, Scardino PT. Postoperative nomogram for disease recurrence after
radical prostatectomy for prostate cancer. J Clin Oncol. 1999;17(5):1499–507.
62. Tilki D, Mandel P, Schlomm T et al. External validation of the CAPRA-S score to predict bio-
chemical recurrence, metastasis and mortality after radical prostatectomy in a European cohort.
J Urol. 2014;pii: S0022–5347(14)05061–7. doi: 10.1016/j.juro.2014.12.020. [Epub ahead of print].
63. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29.
64. Shukla-Dave A, Hricak H, Akin O, et al. Preoperative nomograms incorporating magnetic
resonance imaging and spectroscopy for prediction of insignificant prostate cancer. BJU Int.
2012;109(9):1315–22.
65. Siddiqui MM, Rais-Bahrami S, Truong H, et al. Magnetic resonance imaging/ultrasound-
fusion biopsy significantly upgrades prostate cancer versus systematic 12-core transrectal
ultrasound biopsy. Eur Urol. 2013;64(5):713–9.
66. Wysock JS, Rosenkrantz AB, Huang WC, et al. A prospective, blinded comparison of Magnetic
Resonance (MR) imaging-ultrasound fusion and visual estimation in the performance of
MR-targeted prostate biopsy: the PROFUS trial. Eur Urol. 2014;66(2):343–51.
67. Cuzick J, Swanson GP, Fisher G, et al. Prognostic value of an RNA expression signature
derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective
study. Lancet Oncol. 2011;12(3):245–55.
68. Bishoff JT, Freedland SJ, Gerber L, et al. Prognostic utility of the cell cycle progression score
generated from biopsy in men treated with prostatectomy. J Urol. 2014;192(2):409–14.
69. Cooperberg MR, Simko JP, Cowan JE, et al. Validation of a cell-cycle progression gene panel
to improve risk stratification in a contemporary prostatectomy cohort. J Clin Oncol.
2013;31(11):1428–34.
70. Karnes RJ, Bergstralh EJ, Davicioni E, et al. Validation of a genomic classifier that predicts
metastasis following radical prostatectomy in an at risk patient population. J Urol.
2013;190(6):2047–53.
71. Cooperberg MR, Davicioni E, Crisan A, et al. Combined value of validated clinical and
genomic risk stratification tools for predicting prostate cancer mortality in a high-risk prosta-
tectomy cohort. Eur Urol. 2015;67(2):326–33.
72. Klein EA, Cooperberg MR, Magi-Galluzzi C, et al. A 17-gene assay to predict prostate cancer
aggressiveness in the context of gleason grade heterogeneity, tumor multifocality, and biopsy
undersampling. Eur Urol. 2014;66(3):550–60.
52 M.S. Leapman and M.R. Cooperberg

73. Ishizaki F, Hoque MA, Nishiyama T, et al. External validation of the UCSF-CAPRA
(University of California, San Francisco, Cancer of the Prostate Risk Assessment) in Japanese
patients receiving radical prostatectomy. Jpn J Clin Oncol. 2011;41(11):1259–64.
74. Tamblyn DJ, Chopra S, Yu C, et al. Comparative analysis of three risk assessment tools in
Australian patients with prostate cancer. BJU Int. 2011;108 Suppl 2:51–6.
75. Budäus L, Isbarn H, Tennstedt P, et al. Risk assessment of metastatic recurrence in patients
with prostate cancer by using the Cancer of the Prostate Risk Assessment score: results from
2937 European patients. BJU Int. 2012;110(11):1714–20.
76. Yoshida T, Nakayama M, Takeda K, et al. External validation of the cancer of the prostate risk
assessment score to predict biochemical relapse after radical prostatectomy for prostate cancer
in Japanese patients. Urol Int. 2012;89(1):45–51.
77. Seo WI, Kang PM, Chung JI. Predictive value of the cancer of the prostate risk assessment
score for recurrence-free survival after radical prostatectomy in Korea: a single-surgeon series.
Korean J Urol. 2014;55(5):321–6.
78. Seong KT, Lim JH, Park CM, et al. External validation of the cancer of the prostate risk assess-
ment-s score in Koreans undergoing radical prostatectomy. Korean J Urol. 2013;54(7):433–6.
79. Cooperberg MR, Davicioni E, Crisan A et al. Combined value of validated clinical and
genomic risk stratification tools for predicting prostate cancer mortality in a high-risk prosta-
tectomy cohort. Eur Urol. 2014; pii: S0302–2838(14)00521–1. doi: 10.1016/j.
eururo.2014.05.039. [Epub ahead of print].
80. Seo WI, Kang PM, Kang DI, et al. Cancer of the Prostate Risk Assessment (CAPRA)
Preoperative Score Versus Postoperative Score (CAPRA-S): ability to predict cancer progres-
sion and decision-making regarding adjuvant therapy after radical prostatectomy. J Korean
Med Sci. 2014;29(9):1212–6.
81. Kitagawa Y, Hinotsu S, Shigehara K, et al. Japan Cancer of the Prostate Risk Assessment for
combined androgen blockade including bicalutamide: clinical application and validation. Int J
Urol. 2013;20(7):708–14.
82. Akakura K, Tsuji H, Suzuki H, et al. Usefulness of J-CAPRA score for high-risk prostate
cancer patients treated with carbon ion radiotherapy plus androgen deprivation therapy. Jpn J
Clin Oncol. 2014;44(4):360–5.
83. Shiota M, Yokomizo A, Takeuchi A, et al. The oncological outcome and validation of Japan
Cancer of the Prostate Risk Assessment score among men treated with primary androgen-
deprivation therapy. J Cancer Res Clin Oncol. 2015;141(3):495–503.
84. Yamaguchi Y, Hayashi Y, Ishizuya Y, et al. A single-center study on predicting outcomes of
primary androgen deprivation therapy for prostate cancer using the Japan Cancer of the
Prostate Risk Assessment (J-CAPRA) score. Jpn J Clin Oncol. 2015;45(2):197–201.
Chapter 4
TRUS Biopsy: Is There Still a Role?

Michael S. Leapman and Katsuto Shinohara

Introduction

Transrectal ultrasound-guided prostate needle biopsy (TRUS-Bx) is the standard for

obtaining a histological diagnosis of prostate cancer (PCa) and thereby represents a
cornerstone in subsequent treatment planning by dictating Gleason score and measures
of tumor volume [1]. Systematic biopsy of the prostate in men with clinical suspi-
cion of PCa has been recognized as a problematic element in the management algo-
rithm due to limitations on two fronts: undersampling clinically significant disease
in a proportion of patients, and oversampling biologically low-risk cancers [2].
Consequential undertreatment and overtreatment have been identified as significant
concerns in modern PCa management, driving the development of novel strategies
to limit biopsies that may be regarded as unnecessary in that they detect tumors with
little clinical significance. These concerns, as well as the growing appreciation for
biopsy-related complications, and the incorporation of image-targeted biopsy
modalities have culminated in the broader questioning of the relevance of TRUS-Bx
in the contemporary era [3].
In this chapter, we will address the current role for TRUS-Bx in the initial evalu-
ation of men with clinical suspicion of PCa, giving treatment to issues relating to
observed diagnostic performance, and complications associated with its utilization.
In addition, we will review current methods under investigation to improve the
initial diagnostic accuracy of systematic TRUS-Bx, measures to lowering compli-
cation rates, increasing diagnostic yield, patient discomfort, and examine the inte-
gration of hybrid image-guided techniques exploiting advancements in magnetic
resonance imaging (MRI) and TRUS.

M.S. Leapman, M.D. • K. Shinohara, M.D. (*)

Department of Urology, University of California, San Francisco,
UCSF Box 1695, 550 16th Street, 6th Floor, San Francisco, CA 94143, USA
e-mail: [email protected]

© Springer International Publishing Switzerland 2016 53

N.N. Stone, E.D. Crawford (eds.), The Prostate Cancer Dilemma,
DOI 10.1007/978-3-319-21485-6_4
54 M.S. Leapman and K. Shinohara

Principles of Evaluation

The performance of a given prostate biopsy strategy may be assessed on several

levels. Typically, the principal question to be answered by biopsy is an appraisal of
the presence of cancer, its grade, and extent of disease within the prostate, often
compared to a gold standard reference of step-sectioned radical prostatectomy speci-
mens. In this context these findings can be regarded in a dichotomous fashion
(i.e., upgrading versus downgrading, or significant cancer versus nonclinically
significant cancers). Sensitivity, a measure of the true positive rate, refers to the sta-
tistical likelihood of detecting such an event while specificity is a measure of the true
negative rate that reflects the percentage of negative results which are appropriately
identified. Furthermore, the positive predictive value (precision) reflects the propor-
tion of true positives divided by true and false positives and the negative predictive
rate reflects the true negatives divided by all negatives. A classification model for a
prostate biopsy strategy to predict a dichotomous endpoint may also be represented
by the area under the receiver operator characteristic curve (AUC), represented
graphically as a plot of true positive rate (Y-axis) by false positive rate (X-axis).
Many initial studies evaluate the performance of a biopsy method in relation to
overall cancer yield of any Gleason score or volume. However, in light of the rec-
ognition of the variability of cancer-related outcomes and the nearly uniformly
favorable longitudinal experience with pathological Gleason 3 + 3 disease, an
increasing trend towards active surveillance or non-treatment a distinction may be
made between significant prostate tumors (regarded to be those possessing a vari-
able component of Gleason 4) and those with limited biological potential [4, 5].
Moreover, given the prevalence of PCa and the associated frequency biopsy, other
relevant issues bear consideration on a population scale including healthcare
expense, adverse health-related quality of life (HRQOL) outcomes, and procedure-
related complications.

Rationale for Systematic Biopsy

By its nature, adenocarcinoma is a multifocal disease within the prostate [6, 7]. On this
basis, systematic sampling of the peripheral zone represents a means by which mul-
tiple areas may be examined in one setting and offer a broader appreciation for tumor
status beyond a targeted palpable or visualized nodule. The sophistication of prostate
biopsy techniques has improved dramatically from an initial 1953 report by Grabstald
and Elliot in JAMA reporting on 50 cases utilizing a rectal speculum [8]. Early tar-
geted biopsy of palpable lesions has given way to systematic templates incorporating
prostate sextants, and ultimately to extended templates offering improved diagnostic
yields, and serving as the standard in contemporary clinical practice [9–12].
In a meta-analysis of 20,698 patients derived from 87 studies including 68 studies
comparing extended sampling schemes with sextant biopsy, diagnostic yield was
4 TRUS Biopsy: Is There Still a Role? 55

improved with the inclusion of additional cores [13]. Moreover, the inclusion of
apical and lateral biopsy cores has been associated with the detection of significantly
more cancer than central cores [14, 15]. The use of 10–12 core extended sampling
methods has been shown to result in improved cancer detection; however initial
sampling strategies that extend beyond 12 cores appear to confer little additional
value [16, 17]. Moreover, it does not appear that overdetection of clinically insig-
nificant disease is a direct consequence of extended sampling techniques [18].
The superior yield of extended systematic sampling techniques over sextant
biopsy has been established, culminating in the majority of guideline statements
recommending extended biopsy templates as the approach of choice. The American
Urological Association White Paper on “Optimal Techniques of Prostate Biopsy
and Specimen Handling” offers an expert recommendation on the use of protocols
involved 10–12 cores in men with an abnormal digital rectal examination (DRE) or
elevated PSA [19]. The National Comprehensive Cancer Network recommendation
panel recommends an extended-pattern biopsy including standard sextants including
the peripheral base, mid-gland, apex, as well as directed biopsy of nodules or radio-
graphically suspicious lesions [20].

Sampling Limitations of Systematic Biopsy

A considerable limitation associated with systematic TRUS prostate biopsy relates

to mischaracterization of the true grade, stage, and volume of PCa within the gland
seen at radical prostatectomy. This discordance in staging is often cited as a justifi-
cation for early treatment in ostensibly favorable risk disease, and may conversely
result in undertreatment for patients who are undersampled [21, 22]. Epstein and
colleagues evaluated the concordance between radical prostatectomy specimens
and biopsy. Among 7643 men with prostate biopsy specimens evaluated under the
rubric of the 2005 modified ISUP Gleason scoring system, 36.3 % with Gleason ≤6
tumors were upgraded at surgery. Among biopsy Gleason 3 + 4 = 7 biopsies, 49.7
were concordant at final pathology while 24.4 % were downgraded, and 25.8 %
upgraded [23]. From a Surveillance, Epidemiology, and End Results (SEER) study
of 10,273 men treated with radical prostatectomy for clinical low-risk disease,
upgrading was observed in 44 %, where biopsy core volume was a significant clinical
predictor of upgrading [24].
Despite the use of extended biopsy templates, the false negative rate has been
reported in the range of 16–41 % seen among men undergoing repeat biopsy [25–28].
In light of the frequency of TRUS-Bx—approximately one million performed annu-
ally in the United States—this may be appreciated as a considerable proportion of
repeated procedures, with associated costs and morbidity. Therefore, an interest
exists in identifying patients in whom an initial negative biopsy result may warrant
additional investigation. To this end, clinical risk factors associated with subsequent
positive findings have been investigated and include serum PSA, PSA density, and
% free PSA and prostate volume [29].
56 M.S. Leapman and K. Shinohara

Histological findings within the spectrum of negative pathology have been asso-
ciated with findings on repeat biopsy. The presence of atypical small acinar prolif-
eration (ASAP) on biopsy has been associated with a likelihood of cancer in nearly
one half of repeat biopsies which informs the recommendation to perform repeat
sampling within 1 year [30, 31]. High-grade prostatic intraepithelial neoplasia
(HGPIN), a pathological diagnosis given to structurally benign prostatic glands that
are lined by atypical cells believed to be a precursor for adenocarcinoma, has been
associated with a variable detection rate of PCa on subsequent biopsy [32, 33].

Procedure-Related Complications

TRUS biopsy is associated with a low but non-inconsequential complication rate

when considered in aggregate. With biopsy undertaken with such frequency,
concerns beyond sampling metrics are relevant to the discussion. While many
biopsy-related complications are rare, or transient, taken in aggregate they represent
a significant potential burden [34]. Infectious complications following TRUS
biopsy occur in a rate of 1–10 %. Loeb et al. recently conducted a comprehensive
analysis of reported complications following TRUS-Bx identifying a range of
reported incidences. A study from the Rotterdam section of the European
Randomized Study of Prostate Cancer indicated a 4.2 % rate of febrile episodes
among 10,474 biopsies, where risk factors for infection included diabetes and larger
prostates. Most patients who experience an infection were treated with an outpatient
course of antibiotics; however severe sepsis requiring hospitalization was reported
in less than 1 % of procedures [35]. Fluoroquinolone use and resistance is a com-
monly recognized risk factor for infectious complications following biopsy [36, 37].
As a result, many authors advocate consulting a hospital or local antibiogram to
assess patterns of antibiotic resistance patterns to better direct prophylaxis.
The association between repeat TRUS biopsy and erectile dysfunction has
been explored. Fujita and colleagues examined urinary and sexual quality of life
functional scores among 231 men with PCa managed with active surveillance
(AS) at Johns Hopkins. Decreased Sexual Health Inventory for Men (SHIM)
scores were observed in men receiving three or greater biopsies when compared
with men receiving two or fewer (p = 0.02); however when stratified by baseline
erectile function increasing number of biopsies trended towards but did not reach
statistical significance [38]. A UCSF study of 427 men with PCa managed with
AS receiving multiple prostate biopsies however demonstrated a considerable
variation in sexual activity within AS cohorts, with no association between erec-
tile dysfunction and prostate biopsy exposure when adjusting for clinical factors
including age, sexual activity, clinical stage, and diagnostic period [39]. Such
findings have been supported by other studies suggesting a small decrease in erec-
tile function over time and increased use of PDE5 inhibitors in this demographic
which may be in part attributable to the aging process [40].
4 TRUS Biopsy: Is There Still a Role? 57

Patient anxiety discomfort during biopsy is an important consideration particu-

larly for men facing repeat biopsies. Factors associated with reported levels of pain
also appear to include pre-biopsy anxiety state, use of local anesthetic, and prostate
size [41, 42]. Among one study 289 men administered a visual analog questionnaire
prior to ten core biopsy, 47.6 % reported the procedure as painful [43]. Moreover, a
subset of patients report pain or discomfort limiting enough that they would not
accept a second biopsy [44]. Measures to mitigate procedural discomfort have been
examined, including the addition of diclofenac suppositories to periprostatic nerve
blockade. In 2005 Ragayan et al. reported on 65 patients receiving 12-core biopsy,
demonstrating that the combination of suppository provided a modest improvement
in procedural pain compared to lidocaine block alone (pain scores of 1.8/10 on a
visual analog scale compared with 1.95 for lidocaine alone) without added risk of
bleeding complications [45]. However, a randomized trial of 96 patients comparing
lidocaine periprostatic block with or without combined diclofenac suppositories
found no significant benefit to pain levels or tolerability [46]. Other well-reported
sequelae of TRUS-Bx include urinary retention, hematuria, and hematospermia
[47]. Urinary retention has been noted in a small percentage (<2 %) and does not
appear to correlate with number of cores sampled, though a saturation techniques
may reasonably pose a greater risk than very limited sampling [48]. Gross hematu-
ria following TRUS-Bx represents a common entity that has been reported in
between 8.1 % and 8.4 % of patients [49]. Incidence rates were compared among
men undergoing 12 vs. 18 vs. more than 24-core biopsies, where rates of hematuria
were 8.1, 9.7, and 10.4 % respectively with the majority being self-limiting and not
requiring hospitalization.

Measures to Improve Biopsy

Rectal Swab Cultures

In response to an increasing appreciation for antibiotic resistance among patients

receiving TRUS-Bx, publications have examined the use routine rectal swab cul-
tures from patients to guide prophylaxis [50]. In a study of 457 men undergoing
TRUS prostate biopsy, antibiotic selection derived from rectal swab cultures to
examine fluoroquinolone resistance. Of 112 patients receiving targeted antimicro-
bial prophylaxis experienced no infectious complications were observed, com-
pared with nine among men treated with empirical ciprofloxacin therapy; however
these differences did not reach statistical significance (p = 0.12) [51]. In a random-
ized prospective trial of preprocedural povidone-iodine rectal cleansing consisting
of 885 patients, patients in the intervention group had a slight, though nonstatisti-
cally significant reduction in the percentage of infectious complications (3.5 % vs.
4.5 %) [52].
58 M.S. Leapman and K. Shinohara

Refined Selection

Improved methods for selecting men for initial prostate biopsy are a promising
means to reduce the number of unnecessary biopsies. Pre-biopsy nomograms
have been developed using PSA screening data to predict the likelihood of cancer
on biopsy, thereby allowing greater ability to select patients for biopsy beyond
dichotomous PSA thresholds alone. For example, the Prostate Cancer Prevention
Trial (PCPT) Risk Calculator is a validated and widely used risk prediction instru-
ment derived from 5088 men within the PCPT study for men who are aged 55 and
older, have no prior history of prostate cancer, and have PSA and DRE results within
1 year [53]. The nomogram utilizes the following variables: race, age, PSA level,
family history of prostate cancer, DRE findings, and status of prior prostate
biopsy. Additional calculators have been generated that incorporate other clinical
characteristics including BMI, finasteride usage, and AUA symptom score [54, 55].
Other factors including % free PSA and [-2]proPSA have also been incorporated.
In an external validation study derived from 446 men undergoing TRUS-Bx from
the San Antonio Center of Biomarkers of Risk for Prostate Cancer (SABOR)
cohort, the AUC for detection of PCa was 65.5 % (95 % CI 60.2–70.8 %,
p < 0.0001) [56]. In a larger cohort of 3482 men receiving an extended biopsy
scheme, the AUC for cancer detection appeared more modest: 0.57 for any tumor,
and 0.60 for Gleason ≥7 [57].

Biomarkers for Biopsy Selection

Biomarkers with improved sensitivity and specificity for PCa including the
4-Kallikrein panel (4Kscore) offer promise for the detection of significant PCas
while potentially limiting overdetection of lower grade disease. This assay includes
measurement of free PSA, total PSA, intact PSA, and human kallikrein 2 (hK2) in
addition to clinical staging risk factors associated with risk of PCa (age, digital rec-
tal examination, and prior biopsy status) to generate a numerical likelihood of sig-
nificant PCa. Among 1012 men prospectively scheduled for prostate biopsy, the
4Kscore yielded an AUC of 0.82 for the detection of Gleason ≥7 disease, and out-
performed the multivariable Prostate Cancer Prevention Trial Risk Calculator in
decision curve analysis [58, 59]. The Prostate Health Index (PHI) is another assay
calculated from multiple serum markers: [-2]proPSA, free and total PSA that has
been examined in independent prospective cohorts of biopsy naïve men. In a multi-
center evaluation of 956 total patients, the AUC for detection of Gleason ≥7 pros-
tate cancer was 0.815 [60]. These tools hold promise in assessing risk of significant
disease prior to biopsy with improved accuracy and may potentially refine the sub-
sequent path to biopsy, diagnosis, and treatment in these individuals. Future studies
are warranted to determine how these novel biomarkers add to clinical risk predic-
tion of oncological events beyond the detection of disease.
4 TRUS Biopsy: Is There Still a Role? 59

Improved US Imaging Techniques

Power Doppler Ultrasound

The use of power Doppler enhanced TRUS to guide biopsy has also been evaluated
in the setting of initial diagnosis. Power Doppler Imaging generates a visual depiction
of total signal and is believed to allow for improved detection of tumor vascularity
that may not be appreciated on conventional color Doppler studies [61, 62]. In a
study of 136 patients with initial PSA between 2.5 and 10 ng/mL, the sensitivity and
specificity for PCa detection was 82.8 and 78.8 % for PDI-TRUS [63]. Sauvain
et al. evaluated 243 patients undergoing PDI-TRUS with a 4-tier grading system of
vascularity in which normal Doppler signal was strongly associated with the likeli-
hood of detecting favorable risk PCa [64].

Contrast-Enhanced Ultrasound

Prostatic tumors appear as hypoechoic lesions on TRUS examination, though the

predictive value of biopsy targeted of these lesions has been suboptimal in most
series [65, 66]. In terms of staging, B-mode TRUS has been shown to offer similarly
favorable abilities at staging when compared with T2-MRI [67]. Interest has
emerged in enhancing TRUS imaging using additional imaging modalities. Contrast
agents for ultrasound imaging have been devised using micrometer scale bubbles
(MB) arranged in a concentric fashion around high density compounds including
perfluorocarbon and sulfur hexafluoride that are delivered intravascularly [68–71].
In a randomized, blinded, placebo-controlled trial of oral dutasteride pretreatment
272 total patients underwent a systematic and targeted biopsy following contrast
administration using liposome encapsulated perfluoropropane microbubbles. The
area under the ROC curve for the detection of any cancer was 0.60 for TRUS alone
imaging compared with 0.64 following contrast enhancement, and 0.74 and 0.80,
respectively, for the detection of Gleason score ≥7 [72]. The potential to add ligand
specificity for microbubble contrast agents has been explored with PSMA monoclo-
nal antibodies targeting nanoscale MBs that appear to bind PCa cells with high
specificity [73].

Elastography

Ultrasound elastography exploits differences in stiffness between benign and

malignant tissue that can be visually depicted on an elastogram wherein regions
resisting deformation are represented more darkly, while elastic areas are shown in
60 M.S. Leapman and K. Shinohara

brighter colors [74–76]. The clinical performance has been assessed in several studies
including a prospective study of 353 patients with clinical suspicion for PCa ran-
domized 1:1 to real-time elastography or standard gray-scale TRUS receiving
10-core prostate biopsy with extended targeted biopsy of hypoechoic (gray-scale
TRUS) or relatively inelastic (blue) lesions. Elastographic guided approaches
detected PCa in 51.1 % compared with 39.4 % (p = 0.027), demonstrating sensitivity
of 60.8 % and specificity of 68.4 % [77]. The combination of multiple ultrasound
parameters has also been examined. Brock et al. examined 86 patients undergoing
combined real-time elastography and CE-TRUS, which decreased the false-positive
rate of elastography from 34.9 to 10.3 %, and resulted in a positive predictive value
of cancer detection of 89.7 % [78].

Improving Negative Predictive Value

Commercial applications have explored the premise that a field effect within histologi-
cally benign prostate tissue can identify occult PCa missed due to sampling errors.
The confirmMDX assay evaluates epigenetic changes within GSTP1, APC, and
RASSF1 and has been examined in two blinded studies of men with negative biopsies
[79]. In a study of the methylation assay among 498 European patients with negative
biopsies undergoing subsequent repeat biopsy within 30 months, a negative predictive
value of 90 % (95 % CI 87–93) was demonstrated where a strong independent associa-
tion was observed when adjusting for age, PSA, DRE, and histopathological character-
istics [80]. Similarly, in a study of 350 patients from five US centers undergoing
repeat biopsy within 2 years of a negative study, the negative predictive value of the
assay was 88 % (95 % CI 85–91) [81]. The clinical utility of such tools in the transla-
tion to reducing subsequent biopsy has also been estimated in an observational study
of 138 men with negative assay results in which the repeat biopsy rate was 4 %, an
estimated tenfold decrease from previous observed patterns in that setting [82, 83].

MR Fusion Biopsy Techniques

Prostate MRI reflecting multiple imaging parameters is a highly promising means

with which to improve on the yield of conventional biopsy by identifying lesions for
biopsy with a greater likelihood of harboring significant PCa [84, 85]. Recently,
novel techniques have been developed to align previously obtained MR images with
real-time TRUS [86]. Improvements in magnetic field strength (a transition from
1.5 to 3 T) have been associated with associated benefits in anatomic resolution on
T2 weighted sequences. The integration of multiple imaging parameters including
diffusion weighted imaging (DWI), dynamic contrast enhancement (DCE) imaging,
and MR-spectroscopy imaging (MRSI) appears to offer additional insights with
regard to the detection of intraprostatic tumors [87–89]. Thus, prospectively identified
4 TRUS Biopsy: Is There Still a Role? 61

MR lesions with high suspicion for significant cancer have been proposed as an
efficacious means to select lesions for high probability biopsy.
Cognitive biopsy techniques in which lesion location obtained from MR is
tracked and targeted with TRUS have represented an early means to integrate on
the multiparametric MRI findings within TRUS-Bx. In a study of 95 patients
undergoing cognitive versus systematic biopsy, detection of clinically significant
PCa was 67 % versus 52 %, respectively (p = 0.0011). Fusion MR-Ultrasound tech-
niques have been developed which superimpose MR images with TRUS offering
electromagnetic tracking that facilitates 3D recognition in space and biopsy
(Fig. 4.1) [90, 91].
The comparative performance of systematic biopsy versus MR fusion biopsy has
been evaluated in several well-designed studies comparing the two modalities.

Fig. 4.1 Multiparametric MRI images of a 67-year-old man with Gleason grade 3 + 3 cancer PSA
5.9 ng/ml on active surveillance. (a) T2 weighed image shows a hypo-intense lesion at right ante-
rior mid-gland (arrows). (b) Average diffusion co-efficiency map shows marked restricted diffu-
sion in the corresponding lesion represented by a dark area (arrows). (c) Diagram of MRI fusion
biopsy showing 3D prostate shape in red, suspicious lesion in green line, and a biopsy tract going
through the lesion in yellow line. Biopsy revealed Gleason grade 4 + 3 cancer from the lesion
62 M.S. Leapman and K. Shinohara

Siddiqui et al. reported on 1003 men receiving systematic and MR fusion biopsies
in the setting of clinical suspicion of PCa. MR fusion biopsy resulted in the detection
of 30 % more high-risk tumors than systematic TRUS while missing 17 % fewer
low-risk cancers. When compared to radical prostatectomy pathology among 170
men treated surgically, the AUC for detection of high-grade disease was 0.73 for a
targeted MR/Ultrasound fusion approach compared with 0.59 for a standard
extended template TRUS biopsy, and 0.67 for a combined approach [92].

Future Directions

The optimal sequence and timing of imaging and biopsy in men with clinical suspicion
of PCa remains to be definitively determined. While studies addressing the improved
diagnostic yield of MR-guided biopsy are encouraging in their improved specificity
for high-risk disease, barriers to a widespread pre-biopsy imaging approach do exist
that reflect healthcare expenditure, convenience, and patient discomfort. However,
if sufficient predictive value can be demonstrated with MR imaging alone, a poten-
tial to forego biopsy altogether is particularly enticing, though the viability of such
a framework has not yet been empirically demonstrated. In the context of men
undergoing AS for clinically favorable PCa who have already received histologic
diagnosis via biopsy, the ability to pursue an mpMRI-alone system without routine
biopsy has also been proposed [93]. Longitudinal evidence from the Prostate Cancer
Research International Active Surveillance (PRIAS) study suggests that MRI posi-
tivity may represent a valuable predictor for disease reclassification, and a robust
area of future investigation [94].

Conclusions

TRUS-Bx is a highly utilized method for PCa detection and risk assessment, offering
multifocal gland sampling in one setting. Despite improvements in diagnostic
yield associated with extended biopsy templates, sampling limitations with sys-
tematic methods may drive overtreatment of nonlethal disease, or may mischarac-
terize more significant tumors. Viewed from a population level, relatively
infrequent procedure-related complications including pain, infection, and hematu-
ria bear relevance to whole-scale PSA-driven biopsy schema. Measures to improve
the performance of TRUS biopsy, including the integration of novel biomarkers to
enable better patient selection for biopsy and advancements in ultrasound imaging,
may afford improved diagnostic yield. Simultaneously, multiparametric MRI
imaging has demonstrated superior detection of clinically significant disease when
combined with TRUS localization. With refinements in its application and method-
ology, TRUS-Bx is poised to receive continued integration in the PCa detection
algorithm.
4 TRUS Biopsy: Is There Still a Role? 63

References

1. Dugan JA, Bostwick DG, Myers RP, et al. The definition and preoperative prediction of
clinically insignificant prostate cancer. JAMA. 1996;275(4):288–94.
2. Tilki D, Schlenker B, John M, et al. Clinical and pathologic predictors of Gleason sum
upgrading in patients after radical prostatectomy: results from a single institution series. Urol
Oncol. 2011;29(5):508–14.
3. Ploussard G, de la Taille A. Prostate biopsies: let’s move forward. Eur Urol. 2013;64(6):
893–4.
4. Lecornet E, Ahmed HU, Hu Y, et al. The accuracy of different biopsy strategies for the detec-
tion of clinically important prostate cancer: a computer simulation. J Urol. 2012;188(3):
974–80.
5. Klotz L, Vesprini D, Sethukavalan P, et al. Long-term follow-up of a large active surveillance
cohort of patients with prostate cancer. J Clin Oncol. 2015;33(3):272–7.
6. Swanson GP, Epstein JI, Ha CS, Kryvenko ON. Pathological characteristics of low risk pros-
tate cancer based on totally embedded prostatectomy specimens. Prostate. 2015;75(4):424–9.
7. Miller GJ, Cygan JM. Morphology of prostate cancer: the effects of multifocality on histologi-
cal grade, tumor volume and capsule penetration. J Urol. 1994;152(5 Pt 2):1709–13.
8. Grabstald H, Elliott JL. Transrectal biopsy of the prostate. JAMA. 1953;153(6): 563–565
9. Hodge KK, McNeal JE, Terris MK, Stamey TA. Random systematic versus directed ultra-
sound guided transrectal core biopsies of the prostate. J Urol. 1989;142:71.
10. Siu W, Dunn RL, Shah RB, Wei JT. Use of extended pattern technique for initial prostate
biopsy. J Urol. 2005;174:505–9.
11. Norberg M, Egevad L, Holmberg L, Sparen P, Norlen BJ, Busch C. The sextant protocol for
ultrasound-guided core biopsies of the prostate underestimates the presence of cancer. Urology.
1997;50:562.
12. Hodge KK, McNeal JE, Stamey TA. Ultrasound guided transrectal core biopsies of the palpably
abnormal prostate. J Urol. 1989;142(1):66–70.
13. Eichler K, Hempel S, Wilby J, et al. Diagnostic value of systematic biopsy methods in the
investigation of prostate cancer: a systematic review. J Urol. 2006;175(5):1605–12.
14. Gore JL, Shariat SF, Miles BJ, et al. Optimal combinations of systematic sextant and laterally
directed biopsies for the detection of prostate cancer. J Urol. 2001;165(5):1554–9.
15. Babaian RJ, Toi A, Kamoi K, et al. A comparative analysis of sextant and an extended 11-core
multisite directed biopsy strategy. J Urol. 2000;163:152–7.
16. Elabbady AA, Khedr MM. Extended 12-core prostate biopsy increases both the detection of
prostate cancer and the accuracy of Gleason score. Eur Urol. 2006;49:49–53.
17. de la Taille A, Antiphon P, Salomon L, et al. Prospective evaluation of a 21-sample needle
biopsy procedure designed to improve the prostate cancer detection rate. Urology.
2003;61:1181.
18. Meng MV, Elkin EP, DuChane J, Carroll PR. Impact of increased number of biopsies on the
nature of prostate cancer identified. J Urol. 2006;176:63–8.
19. AUA. Optimal Techniques of Prostate Biopsy and Specimen Handling. White Paper. http://
www.auanet.org/common/pdf/education/clinical-guidance/Prostate-Biopsy-WhitePaper.pdf.
Accessed 22 Feb, 2015.
20. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology
(NCCN guidelines(r)): prostate cancer early detection. Version 1.2014. http://www.nccn.org/
professionals/physician_gls/pdf/prostate_detection.pdf. Accessed 22 Feb 2015.
21. Capitanio U, Karakiewicz PI, Valiquette L, et al. Biopsy core number represents one of foremost
predictors of clinically significant gleason sum upgrading in patients with low-risk prostate
cancer. Urology. 2009;73(5):1087–91.
22. Chun FK, Steuber T, Erbersdobler A, et al. Development and internal validation of a nomo-
gram predicting the probability of prostate cancer Gleason sum upgrading between biopsy and
radical prostatectomy pathology. Eur Urol. 2006;49(5):820–6.
64 M.S. Leapman and K. Shinohara

23. Epstein JI, Feng Z, Trock BJ, Pierorazio PM. Upgrading and downgrading of prostate cancer
from biopsy to radical prostatectomy: incidence and predictive factors using the modified
Gleason grading system and factoring in tertiary Grades. Eur Urol. 2012;61(5):1019–24.
24. Dinh KT, Mahal BA, Ziehr DR et al. Incidence and predictors of upgrading and upstaging
among 10,000 contemporary patients with low-risk prostate cancer. J Urol. 2015;pii: S0022–
5347(15)00254–2. doi: 10.1016/j.juro.2015.02.015. [Epub ahead of print].
25. Borboroglu PG, Comer SW, Riffenburgh RH, Amling CL. Extensive repeat transrectal
ultrasound guided prostate biopsy in patients with previous benign sextant biopsies. J Urol.
2000 Jan;163(1):158–62
26. Serefoglu EC, Altinova S, Ugras NS, et al. How reliable is 12-core prostate biopsy procedure
in the detection of prostate cancer? Can Urol Assoc J. 2012;2:1–6.
27. Clyne M. Prostate cancer: does a negative second biopsy give patients false hope? Nat Rev
Urol. 2013;10(6):310.
28. Presti Jr JC, O’Dowd GJ, Miller MC, et al. Extended peripheral zone biopsy schemes increase
cancer detection rates and minimize variance in prostate specific antigen and age related cancer
rates: results of a community multi-practice study. J Urol. 2003;169(1):125–9.
29. Ploussard G, Nicolaiew N, Marchand C, et al. Risk of repeat biopsy and prostate cancer
detection after an initial extended negative biopsy: longitudinal follow-up from a prospective
trial. BJU Int. 2013;111(6):988–96.
30. Iczkowski KA, MacLennan GT, Bostwick DG. Atypical small acinar proliferation suspicious
for malignancy in prostate needle biopsies: clinical significance in 33 cases. Am J Surg Pathol.
1997;21(12):1489–95.
31. Alsikafi NF, Brendler CB, Gerber GS, et al. High-grade prostatic intraepithelial neoplasia with
adjacent atypia is associated with a higher incidence of cancer on subsequent needle biopsy
than high-grade prostatic intraepithelial neoplasia alone. Urology. 2001;57(2):296–300.
32. Netto GJ, Epstein JI. Widespread high-grade prostatic intraepithelial neoplasia on prostatic
needle biopsy: a significant likelihood of subsequently diagnosed adenocarcinoma. Am J Surg
Pathol. 2006;30(9):1184–8.
33. Lee MC, Moussa AS, Yu C, et al. Multifocal high grade prostatic intraepithelial neoplasia is a
risk factor for subsequent prostate cancer. J Urol. 2010;184(5):1958–62.
34. Raaijmakers R et al. Complication rates and risk factors of 5802 transrectal ultrasound-guided
sextant biopsies of the prostate within a population-based screening program. Urology.
2002;60(5):826–30.
35. Loeb S, van den Heuvel S, Zhu X, et al. Infectious complications and hospital admissions after
prostate biopsy in a European randomized trial. Eur Urol. 2012;61(6):1110–4.
36. Williamson DA, Masters J, Freeman J, Roberts S. Travel-associated extended-spectrum
β-lactamase-producing Escherichia coli bloodstream infection following transrectal
ultrasound-guided prostate biopsy. BJU Int. 2012;109(7):E21–2.
37. Dalhoff A. Global fluoroquinolone resistance epidemiology and implications for clinical use.
Interdiscip Perspect Infect Dis. 2012;2012:976273.
38. Fujita K, Landis P, McNeil BK. Serial prostate biopsies are associated with an increased risk
of erectile dysfunction in men with prostate cancer on active surveillance. J Urol.
2009;182(6):2664–9.
39. Hilton JF, Blaschko SD, Whitson JM, Cowan JE, Carroll PR. The impact of serial prostate
biopsies on sexual function in men on active surveillance for prostate cancer. J Urol.
2012;188(4):1252–8.
40. Braun K, Ahallal Y, Sjoberg DD, et al. Effect of repeated prostate biopsies on erectile function
in men on active surveillance for prostate cancer. J Urol. 2014;191(3):744–9.
41. Macefield RC, Lane JA, Metcalfe C, et al. Do the risk factors of age, family history of prostate
cancer or a higher prostate specific antigen level raise anxiety at prostate biopsy? Eur J Cancer.
2009;45:2569–73.
42. Tekdogan U, Tuncel A, Nalcacioglu V, Kisa C, Aslan Y, Atan A. Is the pain level of patients
affected by anxiety during transrectal prostate needle biopsy? Scand J Urol Nephrol.
2008;42:24–8.
4 TRUS Biopsy: Is There Still a Role? 65

43. Peyromaure M, Ravery V, Messas A, Toublanc M, Boccon-Gibod L. Pain and morbidity of an

extensive prostate 10-biopsy protocol: a prospective study in 289 patients. J Urol.
2002;167:218–21.
44. Mkinen T, Auvinen A, Hakama M, Stenman UH, Tammela TL. Acceptability and complica-
tions of prostate biopsy in population-based PSA screening versus routine clinical practice: a
prospective, controlled study. Urology. 2002;60(5):846–50.
45. Ragavan N, Philip J, Balasubramanian SP, et al. A randomized, controlled trial comparing
lidocaine periprostatic nerve block, diclofenac suppository and both for transrectal ultrasound
guided biopsy of prostate. J Urol. 2005;174(2):510–3. discussion 513.
46. Ooi WL, Hawks C, Tan AH, Hayne D. A randomised controlled trial comparing use of ligno-
caine periprostatic nerve block alone and combined with diclofenac suppository for patients
undergoing transrectal ultrasound (TRUS)-guided prostate biopsy. BJU Int. 2014;114 Suppl
1:45–9.
47. Loeb S, Carter HB, Berndt SI, et al. Complications after prostate biopsy: data from SEER-
Medicare. J Urol. 2011;186:1830–4.
48. Berger AP, Gozzi C, Steiner H, et al. Complication rate of transrectal ultrasound guided pros-
tate biopsy: a comparison among 3 protocols with 6, 10 and 15 cores. J Urol. 2004;171(4):1478–
80. discussion 1480-1.
49. Loeb S, Vellekoop A, Ahmed HU, et al. Systematic review of complications of prostate biopsy.
Eur Urol. 2013;64(6):876–92.
50. Liss MA, Taylor SA, Batura D, et al. Fluoroquinolone resistant rectal colonization predicts risk
of complications after transrectal prostate biopsy. J Urol. 2014;192(6):1673–8.
51. Taylor AK, Zembower TR, Nadler RB, et al. Targeted antimicrobial prophylaxis using rectal
swab cultures in men undergoing transrectal ultrasound guided prostate biopsy is associated
with reduced incidence of postoperative infectious complications and cost of care. J Urol.
2012;187(4):1275–9.
52. Abughosh Z, Margolick J, Goldenberg SL, et al. A prospective randomized trial of povidone-
iodine prophylactic cleansing of the rectum before transrectal ultrasound guided prostate
biopsy. J Urol. 2013;189(4):1326–31.
53. Prostate Cancer Prevention Trial (PCPT) Prostate Cancer Risk Calculator. Available at http://
deb.uthscsa.edu/URORiskCalc/Pages/uroriskcalc.jsp. Accessed 25 Feb, 2015.
54. Thompson IM, Chi C, Ankerst DP, Goodman P, Tangen C, Lippman S, et al. Effect of finasteride
on the sensitivity of PSA for detecting prostate cancer. J Natl Cancer Inst. 2006;98:1128–33.
55. Ankerst DP, Till C, Boeck A, Goodman P, Tangen CM, Feng Z, et al. The impact of prostate
volume, number of biopsy cores, and AUA symptom score on the sensitivity of cancer detec-
tion using the Prostate Cancer Prevention Trial Risk Calculator. J Urol. 2013;190(1):70–6.
56. Parekh DJ, Ankerst DP, Higgins BA, et al. External validation of the Prostate Cancer Prevention
Trial risk calculator in a screened population. Urology. 2006;68(6):1152–5.
57. Nguyen CT, Yu C, Moussa A, Kattan MW, Jones JS. Performance of prostate cancer preven-
tion trial risk calculator in a contemporary cohort screened for prostate cancer and diagnosed
by extended prostate biopsy. J Urol. 2010;183(2):529–33.
58. Parekh DJ, Punnen S, Sjoberg DD et al. A multi-institutional prospective trial in the USA
confirms that the 4Kscore accurately identifies men with high-grade prostate cancer. Eur Urol.
2014;pii: S0302–2838(14)01035–5. doi: 10.1016/j.eururo.2014.10.021. [Epub ahead of print].
59. Vedder MM, de Bekker-Grob EW, Lilja HG, et al. The added value of percentage of free to
total prostate-specific antigen, PCA3, and a kallikrein panel to the ERSPC risk calculator for
prostate cancer in prescreened men. Eur Urol. 2014;66(6):1109–15.
60. Nordström T, Vickers A, Assel M et al. Comparison between the four-kallikrein panel and
prostate health index for predicting prostate cancer. Eur Urol. 2014;pii: S0302–2838(14)00752–0.
doi: 10.1016/j.eururo.2014.08.010. [Epub ahead of print].
61. Bilger SA, Deering RE, Brawer MK. Comparison of microscopic vascularity in benign and
malignant prostate tissue. Hum Pathol. 1993;24:220–6.
62. Donnelly EF, Geng L, Wojcicki WE, Fleischer AG, Hallahan DE. Quantified power Doppler
US of tumor blood flow correlates with microscopic quantification of tumor blood vessels.
Radiology. 2001;219:166–70.
66 M.S. Leapman and K. Shinohara

63. Remzi M, Dobrovits M, Reissigl A, et al. Can Power Doppler enhanced transrectal ultrasound
guided biopsy improve prostate cancer detection on first and repeat prostate biopsy? Eur Urol.
2004;46(4):451–6.
64. Sauvain JL, Sauvain E, Rohmer P, et al. Value of transrectal power Doppler sonography in the
detection of low-risk prostate cancers. Diagn Interv Imaging. 2013;94(1):60–7.
65. Rifkin MD, Dahnert W, Kurtz AB. State of the art: endorectal sonography of the prostate
gland. AJR Am J Roentgenol. 1990;154:691–700.
66. Engelbrecht MR, Barentsz JO, Jager GJ, et al. Prostate cancer staging using imaging. BJU Int.
2000;86 Suppl 1:123–34.
67. Jung AJ, Coakley FV, Shinohara K, et al. Local staging of prostate cancer: comparative
accuracy of T2-weighted endorectal MR imaging and transrectal ultrasound. Clin Imaging.
2012;36(5):547–52.
68. Xie SW, Li HL, Du J, et al. Contrast-enhanced ultrasonography with contrast-tuned imaging
technology for the detection of prostate cancer: comparison with conventional ultrasonogra-
phy. BJU Int. 2012;109:1620–6.
69. Jiang J, Chen YQ, Zhu YK, et al. Factors influencing the degree of enhancement of prostate
cancer on contrast-enhanced transrectal ultrasonography: correlation with biopsy and radical
prostatectomy specimens. Br J Radiol. 2012;85:e979–86.
70. Sano F, Terao H, Kawahara T, et al. Contrast-enhanced ultrasonography of the prostate: various
imaging findings that indicate prostate cancer. BJU Int. 2011;107:1404–10.
71. Cosgrove D. Ultrasound contrast agents: an overview. Eur J Radiol. 2006;60:324–30.
72. Halpern EJ, Gomella LG, Forsberg F, et al. Contrast enhanced transrectal ultrasound for the
detection of prostate cancer: a randomized, double blind trial of dutasteride pretreatment.
J Urol. 2012;188(5):1739–45.
73. Wang L, Li L, Guo Y, et al. Construction and in vitro/in vivo targeting of PSMA-targeted
nanoscale microbubbles in prostate cancer. Prostate. 2013;73(11):1147–58.
74. Barr RG, Memo R, Schaub CR. Shear wave ultrasound elastography of the prostate: initial
results. Ultrasound Q. 2012;28:13–20.
75. Salomon G, Köllerman J, Thederan I, et al. Evaluation of prostate cancer detection with ultra-
sound real-time elastography: a comparison with step section pathological analysis after radical
prostatectomy. Eur Urol. 2008;54(6):1354–62.
76. Zhang M, Nigwekar P, Castaneda B, Hoyt K, Joseph JV, di Sant’Agnese A, et al. Quantitative
characterization of viscoelastic properties of human prostate correlated with histology.
Ultrasound Med Biol. 2008;34:1033–42.
77. Brock M, von Bodman C, Palisaar RJ, et al. The impact of real-time elastography guiding a
systematic prostate biopsy to improve cancer detection rate: a prospective study of 353
patients. J Urol. 2012;187(6):2039–43.
78. Brock M, Eggert T, Palisaar RJ, et al. Multiparametric ultrasound of the prostate: adding con-
trast enhanced ultrasound to real-time elastography to detect histopathologically confirmed
cancer. J Urol. 2013;189(1):93–8.
79. Troyer DA, Lucia MS, de Bruine AP, et al. Prostate cancer detected by methylated gene mark-
ers in histopathologically cancer-negative tissues from men with subsequent positive biopsies.
Cancer Epidemiol Biomark Prev. 2009;18(10):2717–22.
80. Stewart GD, Van Neste L, Delvenne P, et al. Clinical utility of an epigenetic assay to detect
occult prostate cancer in histopathologically negative biopsies: results of the MATLOC study.
J Urol. 2013;189(3):1110–6.
81. Partin AW, Van Neste L, Klein EA, et al. Clinical validation of an epigenetic assay to predict
negative histopathological results in repeat prostate biopsies. J Urol. 2014;192(4):1081–7.
doi:10.1016/j.juro.2014.04.013. Epub 2014 Apr 18.
82. Wojno KJ, Costa FJ, Cornell RJ, et al. Reduced rate of repeated prostate biopsies observed in
ConfirmMDx Clinical Utility Field Study. Am Health Drug Benefits. 2014;7(3):129–34.
83. Pinsky PF, Crawford ED, Kramer BS, et al. Repeat prostate biopsy in the prostate, lung,
colorectal and ovarian cancer screening trial. BJU Int. 2007;99:775–9.
4 TRUS Biopsy: Is There Still a Role? 67

84. Numao N, Yoshida S, Komai Y, et al. Usefulness of prebiopsy multiparametric magnetic

resonance imaging and clinical variables to reduce initial prostate biopsy in men with suspected
clinically localized prostate cancer. J Urol. 2013;190:502–8.
85. Jambor I, Kahkonen E, Taimen P, et al. Prebiopsy multiparametric 3T prostate MRI in patients
with elevated PSA, normal digital rectal examination, and no previous biopsy. J Magn Reson
Imaging. 2015;41(5):1394–404.
86. Rastinehad AR, Turkbey B, Salami SS, et al. Improving detection of clinically significant
prostate cancer: magnetic resonance imaging/transrectal ultrasound fusion guided prostate
biopsy. J Urol. 2014;191(6):1749–54.
87. Oto A, Yang C, Kayhan A, et al. Diffusion-weighted and dynamic contrast-enhanced MRI of
prostate cancer: correlation of quantitative MR parameters with Gleason score and tumor
angiogenesis. AJR Am J Roentgenol. 2011;197(6):1382–90.
88. Testa C, Schiavina R, Lodi R, et al. Accuracy of MRI/MRSI-based transrectal ultrasound
biopsy in peripheral and transition zones of the prostate gland in patients with prior negative
biopsy. NMR Biomed. 2010;23(9):1017–26.
89. Donati OF, Mazaheri Y, Afaq A, et al. Prostate cancer aggressiveness: assessment with whole-
lesion histogram analysis of the apparent diffusion coefficient. Radiology. 2014;271(1):143–52.
90. Pokorny MR, de Rooij M, Duncan E, et al. Prospective study of diagnostic accuracy compar-
ing prostate cancer detection by transrectal ultrasound-guided biopsy versus magnetic reso-
nance (MR) imaging with subsequent MR-guided biopsy in men without previous prostate
biopsies. Eur Urol. 2014;66(1):22–9.
91. Wysock JS, Rosenkrantz AB, Huang WC, et al. A prospective, blinded comparison of mag-
netic resonance (MR) imaging-ultrasound fusion and visual estimation in the performance of
MR-targeted prostate biopsy: the PROFUS trial. Eur Urol. 2014;66(2):343–51.
92. Siddiqui MM, Rais-Bahrami S, Turkbey B, et al. Comparison of MR/ultrasound fusion-guided
biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA.
2015;313(4):390–7.
93. Moore CM, Petrides N, Emberton M. Can MRI replace serial biopsies in men on active
surveillance for prostate cancer? Curr Opin Urol. 2014;24(3):280–7.
94. Bul M, Zhu X, Valdagni R, et al. Active surveillance for low-risk prostate cancer worldwide:
the PRIAS study. Eur Urol. 2013;63:597–603.
Chapter 5
Transperineal Biopsy Technique

Nelson N. Stone, Vassilios M. Skouteris, and E. David Crawford

Abbreviations

AS Active surveillance
EBRT External beam irradiation
RP Radical prostatectomy
TPMB Transperineal prostate mapping biopsy
TRUS Transrectal ultrasound

Electronic supplementary material: The online version of this chapter (doi:10.1007/978-3-

319-21485-6_5) contains supplementary material, which is available to authorized users. Videos
can also be accessed at http://link.springer.com/chapter/10.1007/978-3-319-21485-6_5.
N.N. Stone, M.D. (*)
Professor of Urology and Radiation Oncology, Department of Urology,
The Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place,
New York, NY 10029, USA
675 Lionshead Place, Unit 622, Vail, CO 81657, USA
e-mail: [email protected]
V.M. Skouteris, M.D.
Prostate Brachytherapy Department, Hygeia Hospital, Hygeia Group,
4 Er. Stavrou Str. Kifissias Av., Marousi, Athens 15123, Greece
e-mail: [email protected]
E.D. Crawford, M.D.
Professor of Urology/Surgery, Radiation Oncology, University of Colorado,
Mail Stop # F 710, 6510, Denver, Aurora, CO 80045, USA
e-mail: [email protected]

© Springer International Publishing Switzerland 2016 69

N. Stone, E.D. Crawford (eds.), The Prostate Cancer Dilemma,
DOI 10.1007/978-3-319-21485-6_5
70 N.N. Stone et al.

Introduction

Transrectal ultrasound guided biopsy (TRUS) has been the gold-standard for
diagnosing prostate cancer for over 30 years. The introduction of the biplanar ultra-
sound probe combined with a spring loaded biopsy needle facilitated what was
before a painful procedure associated with a high complication rate [1]. Adoption of
this technique coincided with the introduction of PSA testing, first identified by
immunoperoxidase staining of prostate tissue, its application as a monoclonal anti-
body test to detect serum levels, and its eventual utility as a screening test for pros-
tate cancer [2–6]. In 1987 the American Cancer Society estimated 96,000 new
prostate cancer cases [7]. Coinciding with the widespread application of PSA test-
ing, new cases increased to 165,000 in 1993, 244,000 in 1995 and peaked in 1997
at 334,500 [8–10]. Since then the number of new cases has steady declined and had
remained fairly constant at 200,000–250,000 with 2014 projected at 233,000 [8]. In
1987, only 65 % of prostate cancers were considered local at diagnosis compared to
81 % for years 2003–2009 [11–12]. In a report on 226,046 men who attended
Prostate Cancer Awareness Weeks 1989–1993, 13.1 % of the attendees had an
abnormal digital rectal exam (DRE) and 24.5 % of these were diagnosed with pros-
tate cancer [9]. Today most localized prostate cancers are diagnosed with non-pal-
pable (T1c) disease which is directly related to the widespread application of both
PSA testing and TRUS guided biopsy over the last three decades.
The increasing incidence of newly diagnosed non-palpable prostate cancer has
made its detection more difficult. Larger lesions were more easily discovered
because of their hypoechoic appearance on ultrasound and their predilection within
the peripheral zone of the gland (close to the optimal focal point of the transducer).
Lesions have dramatically decreased in size without a concomitant reduction in the
percent of high grade, potentially lethal cancers. Finding these smaller aggressive
lesions, which comprise 20–25 % of newly detected disease, has become a priority.
In addition, the 75 % of prostate cancers diagnosed with low grade disease are
potential candidates for active surveillance. However, mixed in with these apparent
“low risk cancers” are a substantial number of high grade lesions that were “missed”
by the TRUS biopsy. The transperineal prostate mapping biopsy (TPMB) presents
an opportunity to find these lesions and better stratify patients into active treatment
or surveillance.

Transperineal Prostate Mapping Biopsy Technique

The hallmark of the TPMB technique is taking the prostate biopsy by puncture of
the skin in the perineum rather than through the anterior rectal wall. When transrec-
tal ultrasound was introduced as an adjunct to prostate biopsy, both techniques were
initially described in 1987. Lee described the TRUS approach while Vallancien
described a transperineal technique [1, 13]. The TRUS biopsy quickly became the
favorite because it could be easily and quickly performed in an office setting without
5 Transperineal Biopsy Technique 71

Fig. 5.1 Template setup

against perineum. US
probe is in rectum

the need for anesthesia which has resulted in over 1,200,000 yearly TRUS biopsies
performed in the USA [14]. It is estimated that over 3.7 million TRUS biopsy are
performed worldwide.
The TPMB procedure performed today is markedly different from that described
by Vallancien. Clinicians utilize a brachytherapy setup and the procedure is
performed in the operating theater under general, spinal, or regional anesthesia. The
patient is placed in dorsal lithotomy position with the ultrasound probe placed in a
stepping device with the template attached and applied to a sterile field (Fig. 5.1).
The outer template is aligned to the puncture sites as depicted on the ultrasound
image (Fig. 5.2). The urologist starts at the upper left on the template (11 o’clock
position on the prostate) and punctures the perineum and pushes the biopsy needle
so it is visualized on the axial prostate image (Fig. 5.3). Imaging is switched to
sagittal and the needle is pulled back to the apex before it is fired (Fig. 5.4). When
sampling longer lengths of the prostate (for example in the midline) the standard
TRUS needle is limited to a 17–20 mm core bed. This necessitates re-puncture in
the same grid point in order to biopsy from the longitudinal midpoint to the base
(Fig. 5.5). In cases of very large prostates this could require 3 or more punctures
(17 mm × 3 = 51 mm prostate length). Re-puncture of the prostate increases error as
72 N.N. Stone et al.

Fig. 5.2 Ultrasound grid is aligned to outer template puncture holes (Fig. 5.1)

Fig. 5.3 Each 5 mm site is punctured and observed on the US transverse image. The urologist is
viewing the needle puncture site at the 11 o’clock position
5 Transperineal Biopsy Technique 73

Fig. 5.4 Sagittal image with tip of biopsy needle at apex before it is fired

Fig. 5.5 Sagittal image of biopsy needle after firing. The specimen only includes tissue from apex
to mid prostate. Another biopsy needle will need to be introduced in same grid point to sample
same longitudinal path from mid prostate to base of gland

each reentry results in some drift in the longitudinal plane. Each biopsy specimen is
inked at its end and placed in individual vials (Fig. 5.6). A record of lesion location
can be used if focal therapy is contemplated. A video of a TPMB procedure is pro-
vided (Video 5.1).
74 N.N. Stone et al.

Fig. 5.6 Each specimen is inked and put in individual vials allowing recording of lesion position
within the prostate

Rationale for TPMB

Recent data suggests that active surveillance (AS) in low risk patients may offer
similar survival advantages as definitive therapy [15]. Selecting candidates most
appropriate for surveillance has been an ongoing problem. In the Klotz study more
than 1/3 of men went off surveillance or were treated by 10 years [15]. Part of the
problem is that prostate cancer is known to be a multifocal disease. Meiers found
that more than 2/3 of men undergoing radical prostatectomy had multiple bilateral
lesions [16]. A number of studies have reviewed their prostatectomy experiences in
men who were AS candidates. Ploussard studied 177 men who underwent a 21-core
TRUS biopsy protocol and had less than 3 positive cores and less than 3 mm tumor
length or less than 50 % involvement or less than 33 % positive cores [17]. Over 25
% had adverse pathology. In a literature search Shapiro found more than 1/3 men
with low risk disease where upgraded on their prostatectomy specimen [18]. In a
retrospective analysis of 10,785 consecutive radical prostatectomy performed in 10
university hospitals, Beauval found 919 patients with T1c, PSA <10 ng/mL, a single
positive biopsy, tumor length <3 mm, and Gleason score <7 [19]. Only 26 % of
patients had “insignificant” tumors and would have been ideal candidates for
AS. Thus the data seems to indicate that TRUS biopsy does not properly differenti-
ate low risk patients who would be ideal candidates for AS versus definitive therapy.
This statement holds true even when a saturation strategy is utilized with more than
20 biopsies taken [20].
5 Transperineal Biopsy Technique 75

Validation of TPMB as a More Accurate Prostate Cancer

Detection Technique

Brede conducted a study to evaluate the reliability of TPMB [21]. They sought to
determine if bevel position, tissue deformity and technique affected its accuracy. He
noted substantial deviation of the needle which increased at increasing depths and
concluded that proper technique was critical to improve accuracy. Huo sought to
compare the results of TPMB to 414 RP specimens [22]. The sensitivity and speci-
ficity of detecting cancer in all biopsy zones was only 48 % and 84.1 %, respec-
tively. Rather than follow a 5 mm grid plan these authors took an average of 22
biopsies through 12 regions. This study and several others like it reinforce the need
to follow a strict sampling plan so all prostate is evaluated. Katz evaluated 17 men
who had TPMB then subsequent RP [23]. Sensitivity and specificity for prostate
cancer detection was 86 % and 83 %. However, four quadrants negative for cancer
on TPMB were positive on prostatectomy, and six positive on TPMB were negative
on prostatectomy. Compared to the previous study many more cores were taken
(17–114) as well as multiple samples when prostate core length exceeded core bed.
Crawford analyzed 64 men who had TPMP followed by RP [24]. The specimens
were whole-mounted and reconstructed in 3D. When comparing Gleason score
between the two 72 % were identical, 12 % upgraded, and 16 % downgraded.
TPMB missed 16/64 lesions but only one was clinically significant.

Comparison of TPMB to TRUS Biopsy

The most common application of TPMB is re-biopsy of patients diagnosed with low
risk disease based on TRUS biopsy. There are two basic techniques for TPMB. The
prostate is divided into zones and a set number of cores are taken from each one.
Alternatively, cores are taken at 5 mm intervals starting at the upper right edge (on
axial) of the gland (Table 5.1). Both techniques need to consider that biopsy needle
is limited to a maximum of 2 cm of specimen. The zonal approach usually divides
the length of the gland into basal and apical zones, whereas the grid approach
requires multiple cores through the same puncture site if the gland length exceeds
2 cm at that point.
Symons evaluated 409 men using a 14-region technique [25]. Indications for
biopsy included elevated PSA level (75 %, median 6.5 ng/ml), abnormal digital
rectal examination (8 %), and active surveillance restaging (18 %). Typically, 22
cores were taken from 14 biopsy locations as designated by a standardized biopsy
scheme. Stratified between those having their first TPMB or a repeat procedure
(after a previous negative biopsy), the detection rates were 64.4 % and 35.6 %,
respectively. Significantly higher detection rates were found in prostates <50 mL in
volume than in larger prostates (65.2 % vs. 38.3 %, respectively, p < 0.001). Li
reported on 303 cases that had an 11-region template-guided transperineal saturation
76 N.N. Stone et al.

Table 5.1 Prostate cancer detection rates following transperineal prostate mapping biopsy
(TPMB)
Detection Detection
Number rate as rate as Overall Gleason
Number cores initial repeat detection score
Study Technique patients [mean] biopsy (%) biopsy (%) rate (%) ≥7 (%)
Symons Zonal 409 22 64.4 35.6 56.7 74
[25]
Li [26] Zonal 303 23.7 37.6 37.6 66.4
Moran Zonal 180 NS – 38 38 31
[27]
Novara Zonal 143 24 – 26 26 25
[28]
Pal [29] Zonal 40 36 – 68 68 40.7
Pinkstaff Zonal 210 21.2 – 37 37 45
[30]
Taira [31] Zonal 373 54 75.9 46.9 69.7 55.5

biopsy of the prostate as their first biopsy [26]. The inclusion criteria included a
PSA ≥ 4.0 ng/ml (median 13.7), suspicious findings on the digital rectal examina-
tion, or abnormal prostate gland findings on ultrasonography, computed tomogra-
phy, or magnetic resonance imaging. A mean of 23.7 cores (range, 11–44) were
obtained, with an overall prostate cancer detection rate of 37.6 % (114 of 303).
Moran investigated 180 patients with a median PSA of 8.1 ng/ml and 2 prior nega-
tive TRUS biopsies in which the prostates were equally divided into eight sections
(four axial, two sagittal) [27]. TPMB yielded positive biopsies identifying adenocar-
cinoma in 68 of 180 (38 %). Novara re-biopsied 143 men using a 24-core scheme
[28]. The inclusion criteria were a previous negative biopsy and a PSA ≥ 10.0 ng/ml
(median 9.0), free/total ratio of <20 % or an abnormal digital rectal examination or
previous high-grade prostatic intraepithelial neoplasia (HGPIN) or atypical small
acinar proliferation (ASAP). The number of previous biopsies was one in 59 % of
patients, two in 26 % and three or more in 15 %. Prostate cancer was detected in 26
%, ASAP in 5.6 % and HGPIN in 2.1 %. Pal investigated 40 patients with a mean
PSA 21.9 ng/ml (range 4.7–87) and two previous sets of negative TRUS biopsies
who underwent 36 core template-assisted transperineal prostate biopsies (6 zones)
[29]. In total, 27 of 40 (68 %) patients were found to have adenocarcinoma. Of the
210 men who were re-biopsied by Pinkstaff 170 (81 %) had undergone two or more
TRUS biopsies [30]. The mean number of prostate cores obtained before the tem-
plate biopsy was 17.4. A mean of 21.2 cores (range 12–41) were obtained at the
template biopsy, depending on prostate size. The study inclusion criteria included
PSA of 10 ng/ml or greater, prostate-specific antigen velocity of 0.75 ng/mL per year
or greater, or the presence of prostatic intraepithelial neoplasia and/or atypical small
cell acinar proliferation on the previous biopsy. Prostate cancer was detected in 78
men (37 %) and was in the transition zone in 60 (77 %). Taira performed TPMB in
5 Transperineal Biopsy Technique 77

Table 5.2 Results of TPMB in men with low risk prostate cancer being considered for active
surveillance (AS)
Bilateral
disease or Not AS
increased Upgrading candidates
Number tumor Gleason score after
Study Patients Technique cores volume (%) 7 or higher (%) TPMB (%)
Onik [32] 180 5 mm 50 61.1 22.7 44.4
Ayers [33] 101 5 mm 47 34 29 33.7
Barqawi [34] 180 5 mm 56 45.6 27.2 75.6
Vyas [35] 307 Zone 24–38 NS 29 29

373 men of whom 294 had prior negative biopsy and 79 men as the initial biopsy [31].
The biopsies were taken from 24 zones. Cancer detection rate for the initial biopsy
was 75.9 %. For men with 1, 2, and 3 prior negative biopsies detection rates were
55.5, 41.7, and 34.4 % (Table 5.2).
The use of TPMB to improve intra-prostatic staging and better identify candi-
dates for AS is becoming more common. Onik performed TPMB on 180 patients
with unilateral cancer on TRUS biopsy, who were considering conservative man-
agement [32]. Biopsies were taken every 5 mm throughout the volume of the pros-
tate, and labeling of the specimen coordinates allowed accurate reconstruction of
the location and extent of a patient’s cancer. A median of 50 cores were taken and
110 patients (61.1 %) were positive bilaterally, and 41 patients (22.7 %) had Gleason
scores increased to 7 or higher. Of the initial 180 patients, 100 (55.6 %) were still
considered AS candidates after TPMB. Ayers restaged 101 men on active surveil-
lance using TPMB. Criteria for active surveillance were ≤75 years, Gleason ≤3 + 3,
PSA ≤ 15 ng/mL, clinical stage T1-2a, and ≤50 % ultrasound-guided transrectal
biopsy cores positive for cancer with ≤10 mm of disease in a single core [33]. More
significant prostate cancer was found in 34, and 44 % had disease predominantly in
the anterior part of the gland. Barqawi prospectively performed 3-dimensional map-
ping biopsy on 180 men early stage, organ confined prostate cancer based on tran-
srectal ultrasound guided 10–12-core biopsy [34]. Gleason score was upgraded in
49 of 180 cases (27.2 %) and up-stage in 82 (45.6 %). After TPMB 38 men elected
radical prostatectomy, 11 received radiation therapy, 45 underwent whole gland
cryotherapy, 60 were enrolled in a targeted focal cryotherapy clinical study and 44
elected AS. Vyas reviewed 634 patients who underwent TPMB for prior negative
transrectal biopsy (174), primary biopsy in men at risk of sepsis (153); further eval-
uation after low-risk disease diagnosed based on a 12-core TRUS biopsy (307) [35].
Prostate cancer was found in 36 % of men after a negative TRUS with 17 % of these
had disease solely in anterior sectors. As a primary diagnostic strategy, prostate
cancer was diagnosed in 54 % of men (median PSA 7.4 ng/ml). Of men with
Gleason 3 + 3 disease on TRUS biopsy, 29 % were upgraded and went on to have
radical treatment.
78 N.N. Stone et al.

Taking more biopsies (by TRUS or TPMB) potentially increases the risk of
diagnosing more low risk disease resulting in more definitive treatments. In this
scenario, over-detection leads to over-treatment. This has been one of the criticisms
of widespread use of PSA for screening. Too many men with minimally elevated
PSA undergo TRUS biopsy and, despite low risk features, a large percent opt for
surgery or radiation. However, the goal of TPMB is not to diagnose more cancers,
but rather to improve the intra-prostatic staging so a more educated decision can be
made about treatment choice. Valerio investigated 391 men who underwent TPMB
(20 zones). The goal of this study was to define the index lesions [36]. Deploying a
median of 1.2 (IQR = 0.9–1.7) cores/ml, cancer was diagnosed in 82.9 % (324/391)
with a median of 6 (IQR = 2–9) positive cores, median maximum cancer core length
at 5 mm (IQR = 3–8) and total cancer core length per zone at 7 mm (IQR = 3–13).
26.3–42.9 % had insignificant disease. When a stringent spatial relationship was
used to define individual lesions, 44.4–54.6 % had one index lesion and 12.7–19.1
% had more than one area with clinically significant disease.
Precise localization of index lesions using TPMB offers the opportunity to con-
sider focal ablation. Onik re-biopsied 110 men who were candidates for focal ther-
apy because of low volume unilateral disease [37]. Biopsies were performed at
5 mm intervals and a median of 46 cores were taken. Bilateral cancers were demon-
strated in 55 % and Gleason score was increased in 23 %. 84 patients (76 %) had at
least one factor that would have potentially changed their management.

Morbidity Associated with TPMB

While the data suggests that TPMB improves cancer detection, accuracy of Gleason
score, and disease volume and multifocality over TRUS biopsy, morbidity associated
with the procedure has the potential to be greater than the standard TRUS biopsy.
More cores are obtained, the access is transcutaneous (perineum), and patients
require general or spinal anesthesia. Each of these factors could have their own com-
plications. Complications include infection, bleeding, and urinary retention.
An increase in incidence in fluoroquinolone-resistant infections following TRUS
biopsy has generated an interest in alternative biopsy and imaging modalities. Loeb
performed a review of the SEER database and identified 17,472 men who under-
went prostate biopsy to 134,977 matched controls [38]. Initial and repeat biopsies
were associated with a significantly increased risk of hospitalization within a 30-day
period compared to randomly selected controls (p < 0.0001). In the repeat biopsy
group the mean number of biopsy procedures was 2.5. Compared to no biopsy, for
every biopsy there was a 1.7-fold increase in overall hospitalizations, a 1.7-fold
increase in serious infectious complications and a 2.2-fold increased risk of nonin-
fectious urological complications. Thus, the more TRUS biopsies that a man under-
goes, the greater his cumulative risk of experiencing a serious complication [38].
Minamida analyzed the prospective data from 100 patients who underwent TRUS-
guided prostate biopsy from April to December 2010. A stool culture was obtained
5 Transperineal Biopsy Technique 79

1 month before biopsy. Patients received 500 mg levofloxacin orally once daily for
3 days, beginning 2 h before biopsy [39]. Of the 100 patients, 13 (13 %) had a stool
culture positive for fluoroquinolone-resistant E. coli. In 4 (31 %) of these 13 patients,
acute bacterial prostatitis was detected after TRUS-guided prostate biopsy. Batura
started adding Amikacin to the prophylaxis of TRUS biopsy because he noted a 3.9
% infection rate (seven urinary tract infections [UTIs] and seven bacteremias).
However, this approach did not eliminate all infections as 1.4 % of the subsequent
540 biopsies still developed 6 UTIs and 2 bacteremias [40]. Mosharafa evaluated
the frequency and potential risk factors for infection-related complications after
transrectal prostate biopsy [41]. Of the 107 patients, acute prostatitis developed in
10 (9.3 %). The most significant risk factor was prior use of a fluoroquinolone anti-
microbial, with acute prostatitis developing in 7 (17.1 %) of 41 patients who had
used a fluoroquinolone compared with 3 (4.5 %) of 66 patients who had not
(p = 0.042). Patients who received an enema before the procedure were slightly less
likely to develop prostatitis (p = 0.061). Of eight positive specimens, the organisms
isolated were Escherichia coli in six, Klebsiella pneumoniae in one, and
Staphylococcus epidermidis in one. Isolated gram-negative organisms were
fluoroquinolone-resistant in 85.7 % of samples.
In contrast to the high infection rate associated with TRUS biopsy, especially
for subsequent “confirmatory” biopsies done in the setting of AS, the TPMB,
which is done as a sterile procedure, should have a very low rate of this complica-
tion. Grummet reviewed 245 TPMB biopsies that were performed at seven institu-
tions in Australia and noted no hospital readmission for infections [42]. He also
performed a literature review of 6609 TPMBs and found an infection readmission
rate of 0.076 %.
While infectious complications with TPMB appear to be low, the increase num-
ber of samples taken does increase the risk of bleeding and prostate swelling lead-
ing to urinary retention. Losa reviewed 87 patients with low-risk prostate cancer
who were candidates for focal therapy who underwent re-biopsy by TPMB [43].
He observed 37 cases of grade 1 complications, including 5 (6.1 %) cases of mac-
rohematuria, 13 (16 %) of hemospermia, 11 (13.5 %) of perineal hematoma, 3 (3.7
%) of perineal hematoma and hemospermia, and 5 (6.1 %) of macrohematuria and
hemospermia. Three patients (3.7 %) developed acute urinary retention. In 10
studies reporting on 2113 patients, the average urinary retention rate was 4.7 %
(Table 5.3). An increase number of cores and advanced patient age were associated
with higher retention rates. Of 1956 men from 9 studies, 19 (1 %) required catheter
placement for clot retention or hospitalization.

Conclusions

Transperineal prostate mapping biopsy offers several advantages over TRUS biopsy
including improved intra-prostatic staging, improved identification of men who are
candidates for active surveillance, and better stratification of treatment selection for
80 N.N. Stone et al.

Table 5.3 Complications associated with TPMB. The average retention and hospitalization rates
were 4.7 and 1 %
Gross hematuria [catheter or
Study Number Urinary retention [%] hospitalization required (%)]
Onik [32] 180 14 [7.7] 2 [1.1]
Symons [25] 409 17 [4.2] 0 [0]
Losa [43] 87 3 [3.7] 0 [0]
Onik [37] 110 9 [8] 1 [0.9]
Vyas [35] 634 11 [1.7] 2 [0.3]
Barqawi [24] 180 9 [4.2] 9 [4.2]
Novara [28] 143 4 [3] 3 [2]
Merrick [44] 129 9 [7.1] 1 [0.8]
Buskirk [45] 157 18 [11.5] NR
Tsivian [46] 84 5 [6] 1 [1.2]

definitive and focal therapy. There is a higher urinary retention rate with this modality
compared to TRUS biopsy, but this should be weighed against the substantial reduc-
tion in UTIs and sepsis. TPMB costs more than TRUS biopsy, but is competitive
with mpMRI guided biopsy. Which modality may eventually be superior will need
to be determined by clinical trials.

References

1. Lee F. Transrectal ultrasound in the diagnosis, staging, guided needle biopsy, and screening for
prostate cancer. Prog Clin Biol Res. 1987;237:73–109.
2. Stein BS, Vangore S, Petersen RO, Kendall AR. Immunoperoxidase localization of prostate-
specific antigen. Am J Surg Pathol. 1982;6(6):553–7.
3. Horoszewicz JS, Kawinski E, Murphy GP. Monoclonal antibodies to a new antigenic marker
in epithelial prostatic cells and serum of prostatic cancer patients. Anticancer Res. 1987;
7(5B):927–35.
4. Stamey TA, Yang N, Hay AR, McNeal JE, Freiha FS, Redwine E. Prostate-specific antigen as
a serum marker for adenocarcinoma of the prostate. N Engl J Med. 1987;317(15):909–16.
5. Brawer MK, Lange PH. Prostate-specific antigen and premalignant change: implications for
early detection. CA Cancer J Clin. 1989;39(6):361–75.
6. Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuan JJ, Petros JA, Andriole
GL. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer.
N Engl J Med. 1991;324(17):1156–61.
7. Silverberg E, Lubera J. CA Cancer J Clin. 1987;37(1):2–19.
8. Garfinkel L. CA Cancer J Clin. 1993;43(1):5–6.
9. Garfinkel L. CA Cancer J Clin. 1995;45(1):5–7.
10. Cunningham MP. CA Cancer J Clin. 1997;47(1):3–4.
11. Siegel R, Ma J, Zou Z, Jemal A. CA Cancer J Clin. 2014;64(1):9–29.
12. Stone NN, Crawford ED, DeAntoni EP, Prostate Cancer Education Council. Screening for
prostate cancer by digital rectal exam and prostate specific antigen: results of prostate cancer
awareness week, 1989–1992. Urology. 1994;44(6):18–25.
13. Vallancien G, Leo JP, Brisset JM. Transperineal prostatic biopsy guided by transrectal ultraso-
nography. Prog Clin Biol Res. 1987;243B:25–7.
5 Transperineal Biopsy Technique 81

14. United States biopsy procedures outlook to 2020, Global Data, July 2014.
15. Klotz L, Vesprini D, Sethukavalan P, Jethava V, Zhang L, Jain S, Yamamoto T, Mamedov A,
Loblaw A. Long-term follow-up of a large active surveillance cohort of patients with prostate
cancer. J Clin Oncol. 2015;33:272–7.
16. Meiers I, Waters DJ, Bostwick DG. Preoperative prediction of multifocal prostate cancer and
application of focal therapy: review 2007. Urology. 2007;70(6 Suppl):3–8.
17. Ploussard G, Salomon L, Xylinas E, Allory Y, Vordos D, Hoznek A, Abbou CC, de la Taille
A. Pathological findings and prostate specific antigen outcomes after radical prostatectomy in
men eligible for active surveillance--does the risk of misclassification vary according to biopsy
criteria? J Urol. 2010;183(2):539–44.
18. Shapiro RH, Johnstone PA. Risk of Gleason grade inaccuracies in prostate cancer patients
eligible for active surveillance. Urology. 2012;80(3):661–6.
19. Beauval JB, Ploussard G, Soulié M, Pfister C, Van Agt S, Vincendeau S, Larue S, Rigaud J,
Gaschignard N, Rouprêt M, Drouin S, Peyromaure M, Long JA, Iborra F, Vallancien G, Rozet
F, Salomon L, Members of Committee of Cancerology of the French Association of Urology
[CCAFU]. Pathologic findings in radical prostatectomy specimens from patients eligible for
active surveillance with highly selective criteria: a multicenter study. Urology. 2012;80(3):
656–60.
20. Giannarini G, Autorino R, di Lorenzo G. Saturation biopsy of the prostate: why saturation
does not saturate. Eur Urol. 2009;56(4):619–21.
21. Brede CM, Douville NJ, Jones S. Variable correlation of grid coordinates to core location in
template prostate biopsy. Curr Urol. 2013;6(4):194–8.
22. Huo AS, Hossack T, Symons JL, PeBenito R, Delprado WJ, Brenner P, Stricker PD. Accuracy
of primary systematic template guided transperineal biopsy of the prostate for locating prostate
cancer: a comparison with radical prostatectomy specimens. J Urol. 2012;187(6):2044–9.
23. Katz DJ, Pinochet R, Richards KA, Godoy G, Udo K, Nogueira L, Cronin AM, Fine SW,
Scardino PT, Coleman JA. Comparison of transperineal mapping biopsy results with whole-
mount radical prostatectomy pathology in patients with localized prostate cancer. Prostate
Cancer. 2014;2014:781438.
24. Crawford ED, Rove KO, Barqawi AB, Maroni PD, Werahera PN, Baer CA, Koul HK, Rove
CA, Lucia MS, La Rosa FG. Clinical-pathologic correlation between transperineal mapping
biopsies of the prostate and three-dimensional reconstruction of prostatectomy specimens.
Prostate. 2013;73(7):778–87.
25. Symons JL, Huo A, Yuen CL, Haynes AM, Matthews J, Sutherland RL, Brenner P, Stricker
PD. Outcomes of transperineal template-guided prostate biopsy in 409 patients. BJU Int.
2013;112(5):585–93.
26. Li H, Yan W, Zhou Y, Ji Z, Chen J. Transperineal ultrasound-guided saturation biopsies using
11-region template of prostate: report of 303 cases. Urology. 2007;70(6):1157–61.
27. Moran BJ, Braccioforte MH, Conterato DJ. Re-biopsy of the prostate using a stereotactic
transperineal technique. J Urol. 2006;176(4 Pt 1):1376–81.
28. Novara G, Boscolo-Berto R, Lamon C, Fracalanza S, Gardiman M, Artibani W, Ficarra V.
Detection rate and factors predictive the presence of prostate cancer in patients undergoing
ultrasonography-guided transperineal saturation biopsies of the prostate. BJU Int. 2010;105(9):
1242–6.
29. Pal RP, Elmussareh M, Chanawani M, Khan MA. The role of a standardized 36 core template-
assisted transperineal prostate biopsy technique in patients with previously negative transrectal
ultrasonography-guided prostate biopsies. BJU Int. 2012;1099(3):367–71.
30. Pinkstaff DM, Igel TC, Petrou SP, Broderick GA, Wehle MJ, Young PR. Systematic transperi-
neal ultrasound-guided template biopsy of the prostate: three-year experience. Urology.
2005;65(4):735–9.
31. Taira AV, Merrick GS, Galbreath RW, Andreini H, Taubenslag W, Curtis R, Butler WM,
Adamovich E, Wallner KE. Performance of transperineal template-guided mapping biopsy in
detecting prostate cancer in the initial and repeat biopsy setting. Prostate Cancer Prostatic
Dis. 2010;13(1):71–7.
82 N.N. Stone et al.

32. Onik G, Miessau M, Bostwick DG. Three-dimensional prostate mapping biopsy has a potentially
significant impact on prostate cancer management. J Clin Oncol. 2009;27(26):4321–6.
33. Ayres BE, Montgomery BS, Barber NJ, Pereira N, Langley SE, Denham P, Bott SR. The role
of transperineal template prostate biopsies in restaging men with prostate cancer managed by
active surveillance. BJU Int. 2012;109(8):1170–6.
34. Barqawi AB, Rove KO, Gholizadeh S, O’Donnell CI, Koul H, Crawford ED. The role of
3-dimensional mapping biopsy in decision making for treatment of apparent early stage pros-
tate cancer. J Urol. 2011;186(1):80–5.
35. Vyas L, Acher P, Kinsella J, Challacombe B, Chang RT, Sturch P, Cahill D, Chandra A, Popert
R. Indications, results and safety profile of transperineal sector biopsies [TPSB] of the pros-
tate: a single centre experience of 634 cases. BJU Int. 2014;114(1):32–7.
36. Valerio M, Anele C, Freeman A, Jameson C, Singh PB, Hu Y, Emberton M, Ahmed
HU. Identifying the index lesion with template prostate mapping biopsies. J Urol.
2015;193:1185. pii: S0022-5347[14]04859-9.
37. Onik G, Barzell W. Transperineal 3D mapping biopsy of the prostate: an essential tool in
selecting patients for focal prostate cancer therapy. Urol Oncol. 2008;26(5):506–10.
38. Loeb S, Carter HB, Berndt SI, Ricker W, Schaeffer EM. Complications after prostate biopsy:
data from SEER-Medicare. J Urol. 2011;186(5):1830–4.
39. Minamida S, Satoh T, Tabata K, Kimura M, Tsumura H, Kurosaka S, Matsumoto K, Fujita T,
Iwamura M, Baba S. Prevalence of fluoroquinolone-resistant Escherichia coli before and inci-
dence of acute bacterial prostatitis after prostate biopsy. Urology. 2011;78(6):1235–9.
40. Batura D, Rao GG, Bo Nielsen P, Charlett A. Adding amikacin to fluoroquinolone-based anti-
microbial prophylaxis reduces prostate biopsy infection rates. BJU Int. 2011;107(5):760–4.
41. Mosharafa AA, Torky MH, El Said WM, Meshref A. Rising incidence of acute prostatitis fol-
lowing prostate biopsy: fluoroquinolone resistance and exposure is a significant risk factor.
Urology. 2011;78(3):511–4.
42. Grummet JP, Weerakoon M, Huang S, Lawrentschuk N, Frydenberg M, Moon DA, O’Reilly
M, Murphy D. Sepsis and ‘superbugs’: should we favour the transperineal over the transrectal
approach for prostate biopsy? BJU Int. 2014;114(3):384–8.
43. Losa A, Gadda GM, Lazzeri M, Lughezzani G, Cardone G, Freschi M, Lista G, Larcher A,
Nava LD, Guazzoni G. Complications and quality of life after template-assisted transperineal
prostate biopsy in patients eligible for focal therapy. Urology. 2013;81(6):1291–6.
44. Merrick GS, Taubenslag W, Andreini H, Brammer S, Butler WM, Adamovich E, Allen Z,
Anderson R, Wallner KE. The morbidity of transperineal template-guided prostate mapping
biopsy. BJU Int. 2008;101(12):1524–9.
45. Buskirk SJ, Pinkstaff DM, Petrou SP, Wehle MJ, Broderick GA, Young PR, Weigand SD,
O’Brien PC, Igel TC. Acute urinary retention after transperineal template-guided prostate
biopsy. Int J Radiat Oncol Biol Phys. 2004;59(5):1360–6.
46. Tsivian M, Abern MR, Qi P, Polascik TJ. Short-term functional outcomes and complications
associated with transperineal template prostate mapping biopsy. Urology. 2013;82(1):
166–70.
Chapter 6
3D Biopsy: A New Method to Diagnose
Prostate Cancer

Kevin Krughoff, Nelson N. Stone, Jesse Elliott, Craig Baer,

Paul Arangua, and E. David Crawford

Introduction

Both transrectal ultrasound guided biopsy (TRUS) and transperineal mapping biopsy
(TPMB) provide valuable information on the presence and grade of prostate cancer.
However, both have limitations that make educated recommendations difficult for
patients. TRUS biopsy identifies the correct grade and number of lesions between 30
and 50 % of the time. TPMB, in its current form, while a substantial improvement
over TRUS in accurate grading and lesion identification is not optimal because of
lack of standardization and antiquated technology. Additionally, TPMB usually
requires anesthesia and an outpatient OR. An ideal mapping program should incor-
porate user friendly software to direct and record the biopsy sites, a biopsy needle
and gun to sample the prostate along its length as a single specimen and a pathology
component that preserve’s the integrity of the core and facilitates processing.

Electronic supplementary material: The online version of this chapter (doi:10.1007/978-3-

319-21485-6_6) contains supplementary material, which is available to authorized users. Videos
can also be accessed at http://link.springer.com/chapter/10.1007/978-3-319-21485-6_6.

K. Krughoff, B.A.
Division of Urology, Department of Surgery, University of Colorado Denver School of
Medicine, 12631 East 17th Ave., Room L15-5602, Aurora, CO 80045, USA
e-mail: [email protected]
N.N. Stone, M.D.
Professor of Urology and Radiation Oncology, Department of Urology, The Icahn School of
Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA
e-mail: [email protected]
J. Elliott, B.A.
Software Development, BSCi, Inc.,
721 N. Tejon St., #200, Colorado Springers, CO 80903, USA
e-mail: [email protected]

© Springer International Publishing Switzerland 2016 83

N.N. Stone, E.D. Crawford (eds.), The Prostate Cancer Dilemma,
DOI 10.1007/978-3-319-21485-6_6
84 K. Krughoff et al.

3D Mapping Software

An ideal mapping software program should provide a biopsy plan that directs sam-
pling of the gland to provide a high degree of probability of encountering a lesion
of a specific size. Kepner and Kepner performed an analysis of uniform core sam-
pling to yield data on tumor volume limits on negative biopsies [1]. Based on their
calculations it is possible to construct a probability graph utilizing sequential spac-
ing and core diameter size. The requirements needed to achieve the depicted prob-
abilities include even spacing between successive biopsy sites and one full length
sample from base to apex (Fig. 6.1). For example, using a 15 gauge biopsy needle
to take full core samples (base to apex) using 5 mm grid spacing would yield a prob-
ability of detecting a lesion with a radius of 2.5 mm at 90–95 %.

Probability of Detection vs. Tumor Radius

1mm 2.5mm 5mm 10mm
1.2

1
Probability of Detection

0.8

0.6

0.4

0.2

0
0 0.5 1 1.5 2 2.5 3 3.5 4
Tumor Radius (mm)

Fig. 6.1 Probability of detecting a negative biopsy based on grid spacing and needle size. In this
example a 15 gauge biopsy needle is used to take full core samples (base to apex) using 5 mm grid
spacing (blue line). The probability of detecting a lesion as indicated by the black arrow assumes
perfectly spaced biopsies, no loss due to urethra intercept and perfect handling of capsule borders

C. Baer, Ph.D.
BCSi Inc., Colorado Springs, CO, USA
e-mail: [email protected]
P. Arangua, B.S., M.P.H.
Urologic Oncology, University of Colorado Denver,
1665 Aurora Court, Room 1004, Aurora, CO 80045, USA
e-mail: [email protected]
E.D. Crawford, M.D. (*)
Professor of Urology/Surgery, Radiation Oncology, University of Colorado,
Mail Stop # F 710, PO Box # 6510, Aurora, CO 80045, USA
e-mail: [email protected]
6 3D Biopsy: A New Method to Diagnose Prostate Cancer 85

There are several constraints to using this approach with the current methodology
of TPMB. When the biopsy needles are inserted in the outer template through the
skin their entrance into the prostate will depend on the perineal anatomy, needle
deflection, and gland movement from the needle and respiration. Stone has previ-
ously shown that brachytherapy needles, similarly placed through a perineal tem-
plate can deform and deflect the prostate gland [2]. He found the median change in
the base position of the prostate was 1.5 cm (range of 0–3.0 cm; p = 0.0034). The
mean X and Y deformation was 6.8 mm (median, 7.9 mm; range, 4.3–8.1 mm) and
3.6 mm (median, 3.3 mm; range, 1.0–5.5 mm), respectively. Given the variable and
significant movement of the gland when brachytherapy needles were placed, which
were 17 gauge in that study, the likelihood more movement will be experienced if
15 gauge biopsy needles are used needs to be accounted for if the biopsy sites are to
be uniformly distributed throughout the prostate.
A software program was developed to create a real-time 3D model of the prostate
generated from intraoperative axial (transverse) image capture. Once the 3D
representation is obtained a biopsy plan is generated. During the biopsy phase, the
image position and the virtual biopsy sites (in axial and longitudinal) can be adjusted
to match the US contours of the prostate, urethra and rectum as well the virtual
biopsy sites are matched to the biopsy needle in the gland. The steps in the software
program are described below in a patient undergoing TPMB.
Three-dimensional mapping biopsy (3DMB) is performed under general anes-
thesia with the patient in the dorsal lithotomy position. The ultrasound (US) probe
is connected to a laptop running the software (3D Biopsy LLC) using a video cap-
ture card and S-video cable. After attaching the probe to a stepping device and
brachytherapy grid, the probe is advanced into the rectum in 5 mm increments to
visualize the prostate.
Selecting “Live Feed” broadcasts the US image in real-time to the laptop running
the program (Fig. 6.2).
Once the base of the prostate is identified, the software is calibrated to the posi-
tion of the US probe and dimensions of the prostate using the “Machine Calibration”
function. This generates a biopsy template superimposed onto the US image with
demarcations for the center of the US probe and the US field-of-view which are
toggled to match the real-time US image. While the default spacing between biopsy
probe positions is set to match that of a 5 mm brachytherapy template, the software-
generated template can be moved, expanded, or collapsed to fit the needs of the case
at hand (Fig. 6.3) .
Following calibration, the user is ready to begin outlining the prostatic capsule into
the software. Using the touchscreen or mouse, the center of the prostate is demarcated
and the user traces the outline of the prostatic capsule onto each axial image, moving
through the prostate in axial view at 5 mm intervals from base to apex. Various options
with the contouring tool allow smooth or nodal contouring (Fig. 6.4).
After outlining the capsule and position of the urethra and rectum on each axial
image, the user is ready to begin planning biopsy coordinates using the “Generate
Biopsy Plan” feature. In this window the biopsy needle length, spacing between
needles, minimum distance from the urethra, and option for multiple biopsies at the
same location are indicated. Given that the current prostate biopsy needle only takes
86 K. Krughoff et al.

Fig. 6.2 Urologist views US image fed live into the 3D mapping program

Fig. 6.3 Alignment calibration of ultrasound probe center, field of view, and grid adjustment
6 3D Biopsy: A New Method to Diagnose Prostate Cancer 87

Fig. 6.4 Contouring of prostatic capsule in 5 mm slices

a 17–20 mm specimen length, this information needs to be entered into the program
so the biopsy plan will generate enough in-line needles to cover the entire length of
the prostate at each biopsy site. The software generates a biopsy plan covering the
volume of the prostate with the user’s predetermined settings, after which the user
can modify specified biopsy locations as needed (Fig. 6.5).
With the biopsy plan set, the urologist is ready to begin taking needle biopsies.
On axial view, the urologist approximates each biopsy location generally starting at
the top left-most position on the grid corresponding to biopsy site 1. When clicking
on biopsy site 1 the coordinates are displayed. The screen also displays how many
in-line needles are required or in the case of a variable biopsy needle (discussed
below) how long the length of the prostate is at that site. If the inserted needle is not
on the grid point (it may be a 1 or 2 mm away), rather than removing the needle and
reinserting it the urologist can move the virtual needle to overlap the inserted nee-
dle. When the probe switches to sagittal view the auto-plane feature of the software
automatically resets to sagittal. The biopsy needle tip will be in the middle of the
gland. The virtual image of this needle will also be displayed and just like in axial,
the needle image needs to be matched to the inserted biopsy needle (Fig. 6.6).
The position of each biopsy is recorded and the specimen is inked at its proximal
end. In general it will take approximately 1.5–2 biopsy cores per gram of prostate
for adequate coverage using the brachytherapy template. Once all biopsies have
been taken the user can view the overall biopsy coverage of the prostate in each
88 K. Krughoff et al.

Fig. 6.5 (a) Dialogue box where specifications are entered before plan is generated. (b) Biopsy
plan is generated. Biopsy site 1 is indicated in the dialogue box and by the bright point in the plan

axial slice or in full three-dimensional imaging to determine if any areas appear to

be under-sampled. The urologist can add a new biopsy location if needed (Fig. 6.7).
The pathology is read for each core and the depth of each cancer from the inked
end is recorded, giving each cancer foci a specific location along the specimen. This
information for each positive biopsy, including its Gleason score and linear location
is entered into the patient’s 3D file creating a three-dimensional model of the can-
cerous lesion locations (Fig. 6.8).
6 3D Biopsy: A New Method to Diagnose Prostate Cancer 89

Fig. 6.6 Sagittal view of virtual needle with biopsy needle behind it

Fig. 6.7 Three-dimensional image of the prostate with biopsy core locations generated to help
determine overall biopsy coverage

The 3DMB procedure allows accurate intra-prostate staging of the cancer. Of the
200–220,000 men diagnosed with prostate cancer with Gleason 6/7 disease this
procedure will find that approximately one-third would be ideal AS candidates, one-
third would need definitive therapy and the rest could be considered for focal ther-
apy. If a patient is found to have cancer amenable to targeted focal therapy, the 3D
map can be utilized in the OR to locate the sites to be ablated. For example, cryo-
therapy probes can be inserted in the proper needle tracts and advanced to the
appropriate depth utilizing the 3D map in a real-time mode. Video 6.1 demonstrates
a short video of the procedure.
90 K. Krughoff et al.

Fig. 6.8 3D model of prostate gland with biopsy results entered into patient’s file. This patient
who had 1/12 core positive for Gleason score 7 had 4 Gleason 6 and 3 Gleason 7 (darker lesions)
on final pathology after 3DMB

Other Considerations

One of the difficulties in reproducing the high probability of finding small lesions is
the uncertainty introduced by multiple in-line sticks in rows longer than the current
biopsy needle will permit. Brede et al. found that deviation of the biopsy needle
course increases at further depths of sampling [3–6]. This uncertainty can be over-
come by the introduction of a biopsy needle specifically designed for this approach.
Such a needle would require a variable length core bed and gun to fire the needle the
correct distance. For example if the urologist were to click on needle #5 and the
distance specified at that point was 3.2 cm, the gun would be “dialed” to that dis-
tance and fired so the core taken is 3.2 cm. This technology is under development.
Lastly, placing a long tissue specimen on telfa or directly into a formalin filled
vial will not permit the pathologist to precisely identify the cancer site along the
core. Handling and transport to the lab results in tissue fragmentation. To prevent
this, a 6 cm fenestrated cassette which snaps closed and secures the specimen until
it arrives at the lab has been developed. Upon arrival in the lab, the pathologist
opens the cassette and removes the core intact on a specially developed medium.

Conclusions

The 3DMB software can identify lesions as small as 2.5 mm radius with high prob-
ability. Combined with the new needle and tissue cassette, the procedure can be
performed quickly and accurately. The concern for over-diagnosis of low grade
lesions should not be an issue because a patient with a few low grade lesions can
elect active surveillance and not worry about repeat biopsies or risk of progression
6 3D Biopsy: A New Method to Diagnose Prostate Cancer 91

because of missed high volume or high grade disease. In this scenario, active surveil-
lance becomes “accurate surveillance.” The apparent “low risk” patient who under-
goes a 3BMB and is found with high grade lesions is no longer “under diagnosed”
and is referred for definitive therapy. Finally, a large number of men, who don’t
qualify for AS or RP, can be offered focal ablation, where a hemi-ablation or hockey-
stick ablation is replaced by precise focused ablation of the individual lesions.

References

1. Kepner GR, Kepner JV. Transperineal prostate biopsy: analysis of a uniform core sampling
pattern that yields data on tumor volume limits in negative biopsies. Theor Biol Med Model.
2010;17(7):23.
2. Stone NN, Roy J, Hong S, Lo YC, Stock RG. Prostate gland motion and deformation caused
by needle placement during brachytherapy. Brachytherapy. 2002;1:154–60.
3. Brede CM, Douville NJ, Jones S. Variable correlation of grid coordinates to core location in
template prostate biopsy. Curr Urol. 2013;6(4):194–8. doi:10.1159/000343538.
4. Huo ASY, Hossack T, Symons JLP, et al. Accuracy of primary systematic template guided
transperineal biopsy of the prostate for locating prostate cancer: a comparison with radical
prostatectomy specimens. J Urol. 2012;187(6):2044–9. doi:10.1016/j.juro.2012.01.066.
5. Brawer MK. The influence of prostate volume on prostate cancer detection. Eur Urol Suppl.
2002;1(6):35–9. doi:10.1016/S1569-9056(02)00055-6.
6. Symons JL, Huo A, Yuen CL, et al. Outcomes of transperineal template‐guided prostate biopsy
in 409 patients. BJU Int. 2013;112(5):585–93. doi:10.1111/j.1464-410X.2012.11657.x.
Chapter 7
Elastography: Can It Improve Prostate
Biopsy Results?

Vassilios M. Skouteris, Spyros D. Yarmenitis,

and Georgios P. Zacharopoulos

Introduction

The optimal way to biopsy prostate gland is still evolving. The ultrasound technol-
ogy has evolved by adding several tools that improve the identification of the dis-
ease at early stages and avoid unnecessary biopsies.
Since original sextant scheme introduced by Hodge et al. [1], extended protocols
with laterally directed biopsies have been described that considerably increased
cancer detection rates [2]. Although the positivity rate was also increased by increas-
ing the number of cores taken, the anterior part of the gland still remained the most
frequent region missed by conventional TRUS biopsy [3]. Transperineal template
guided biopsy having the advantage of easy access to the anterior region of the
gland revealed the importance of transitional zone sampling of which its uniquely
involvement in prostate cancer can exceed 50 % [4]. Pinkstaff et al. in 2005 pub-
lished a study where 210 men underwent transperineal ultrasound template guided

Electronic supplementary material: The online version of this chapter (doi:10.1007/978-3-

319-21485-6_7) contains supplementary material, which is available to authorized users. Videos
can also be accessed at http://link.springer.com/chapter/10.1007/978-3-319-21485-6_7.
V.M. Skouteris, M.D. (*)
Prostate Brachytherapy Department, Hygeia Hospital, Hygeia Group,
4 Er. Stavrou Str. And Kifissias Av., Maroussi, Athens 15123, Greece
e-mail: [email protected]
S.D. Yarmenitis, M.D.
Radiology Department, Hygeia Hospital, Hygeia Group,
4 Er. Stavrou Str. And Kifissias Av., Maroussi, Athens 15123, Greece
e-mail: [email protected]
G.P. Zacharopoulos, M.D., M.Sc., Ph.D.
Ultrasound Department, Hygeia Hospital, Hygeia Group,
4 Er. Stavrou Str. And Kifissias Av., Maroussi, Athens 15123, Greece
e-mail: [email protected]

© Springer International Publishing Switzerland 2016 93

N.N. Stone, E.D. Crawford (eds.), The Prostate Cancer Dilemma,
DOI 10.1007/978-3-319-21485-6_7
94 V.M. Skouteris et al.

prostate biopsy. All of them had at least one negative transrectal biopsy in the past
with 81 % of them having more than one. The mean number of cores obtained was
21. Prostate cancer in the transitional zone was detected in 77 % of the patients and
in 46 % of them cancer was solely localized in that region [5].
Transperineal prostate biopsy guided by a template represents the most accurate
and uniform way to sample the entire gland [6–8]. One of the advantages of this
technique is that is a transcutaneous procedure performed through the perineum and
not through the anterior rectal wall, diminishing the risk of infection to negligible
levels. Grummet et al. reported almost zero percent of sepsis and hospital readmis-
sion rate after 245 transperineal prostate biopsies [9]. Another advantage is that
puncture sites are guided by a template (or grid) similar to the one used for brachy-
therapy or cryotherapy. This allows a uniform mapping of the gland at constant
5 mm intervals increasing the cancer detection rate from 25 to 60 %. Ayres et al.
reported in 2012 that 101 patients already diagnosed with prostate cancer by tran-
srectal biopsy and were on active surveillance, they underwent restaging by trans-
perineal template guided biopsy. The criteria used for surveillance were:
age ≤ 75 years, PSA ≤ 15 ng/ml, clinical stage ≤T2a, ≤50 % cores positive on tran-
srectal biopsy and ≤10 mm positive in each core. The results showed that 34 % of
the patients had more significant disease than falsely originally estimated and 44 %
of them had disease predominantly in the anterior part of the gland. As a result of the
above, 33 % of them stopped surveillance and proceed to a radical treatment [10].
In 2009, Onik and his colleagues restaged 180 patients who were considering
conservative management of their disease by transperineal mapping biopsy. All
patients had unilateral, Gleason 6, prostate cancer found on TRUS biopsy. The map-
ping biopsy was carried out transperineally using a brachytherapy grid and biopsies
were taken every 5 mm throughout the volume of the gland, under TRUS guidance.
Median 50 cores were obtained. Their results showed that in 61.1 % (110 patients)
the disease was bilateral and in 25 % (45 patients) Gleason score was upgraded to 7
or higher [11].
Initially puncture sites of biopsy schemes were guided solely by grey scale imag-
ing. Afterwards the addition of Doppler ultrasound improved blood flow informa-
tion to the suspicious areas. Elastography is a technique that produces images about
the mechanical characteristics of the tissues. It uses ultrasound imaging modality to
detect and visually record shear deformation of a tissue by the shearing forces of an
ultrasonic waveform and the elastic restoring forces of the tissue against this defor-
mation. Two types of shearing effects may be observed, simple shear that displaces
a single dimension of a tissue body resulting in simple shape deformation and pure
shear that displaces a whole surface of the tissue body resulting in horizontal expan-
sion of it.
In clinical practice ultrasound (US) elastograms may be illustrated as static
images of the tissue strain usually under the term “Strain or Compression
Elastography” or as dynamic tissue displacement measurements. The latter method
comprises various techniques that are commonly grouped under the term “Shear
Wave Elastography” and offer the capability to quantitatively measure the shear
7 Elastography: Can It Improve Prostate Biopsy Results? 95

wave properties. Both elastography methods can be used to detect the elastographic
properties of normal prostate tissue against those of cancerous lesions.
Several publications report a significant improvement in the detection of prostatic
cancer by the use of strain elastography and also a better performance in the guidance
of targeted needle biopsy sampling [12–18]. However, some controversial reports
exist that show inability of the method to satisfactorily distinguish prostate cancer
from chronic prostatitis or to confirm improvements of biopsy guidance [19, 20].
In regard with Shear Wave elastography, a few reports at the moment with prom-
ising results, support an improved Negative Predictive Value rate by using a cut-off
stiffness value of 35–37 kPa of malignant lesions [18, 20].
Major limitations of Strain Elastography are the non-uniform compression force
over the prostate gland and the intra- and inter-operator dependency. Limitations of
Shear Wave elastography mainly include the slower real time frame rate and the
small elasticity sampling box that cannot include the whole organ.

Transrectal Ultrasound and Elastography

In our institution prostate transrectal US elastography is obtained with a Hitachi

Hi-Vision Preirus machine (Hitachi Hi Vision Preirus, Hitachi Medical Corporation,
Tokyo, Japan) with an EUP-U531 intracavity probe, performing at 8.0–4.0 MHz
with Tissue Harmonics and Compound Imaging in b-mode and the fourth genera-
tion Hitachi Real-Time Elastography (HI-RTE) technique.
In a period of 10 months, 153 consecutive male patients were evaluated (mean
age: 63.6 years, range: 37–84). In all patients a standard b-mode TRUS scan was
followed by a color Doppler scan and Real-Time Compression Elastography
(RTCE). The b-mode TRUS findings were categorized as type 1: no focal lesions,
type 2: ill-defined focal lesions and type 3: definite focal lesion(s) (Fig. 7.1).
Using the Hitachi elasticity color code mapping that encodes stiff tissues as blue
and soft as red (Fig. 7.2), elastic properties of the peripheral zone were classified as
type 1: normal stiffness (evenly mixed red, orange, yellow, and green hues), type 2:
inhomogeneous/inconclusive stiffness, and type 3: definite focal lesions of increased
stiffness (blue). Intact prostate fibrofatty margin (capsule) was illustrated as an
Orange/Red rim in the RTCE images (Figs. 7.3 and 7.4).
An US guided needle biopsy was then performed. In 122/153 patients 12 core
biopsies were taken. The rest 31 patients had 6–8 core biopsies. In both B-mode and
RTCE scans, type 1 images were interpreted as negative, type 3 images as positive and
type 2 images as inconclusive. Ultrasound findings were compared to the results of the
core biopsies. Inconclusive were the B-mode TRUS scans in 14/153 (9 %) patients.
Three of these were among the 46 prostate cancer patients (7 %) while 11 were among
the 107 non-cancer patients (10 %). Inconclusive were the RTCE scans in 8/153 (5 %)
patients. Three of these were among the 46 cancer patients (7 %) while five were
among the 107 non-cancer patients (5 %). Disruption of the normal prostatic capsule
red rim in RTCE was found in 11 (73 %) of the 15 cancer patients that were histologi-
96 V.M. Skouteris et al.

Fig. 7.1 (a) B mode TRUS findings classification. Type 1, no focal lesion. (b) B mode TRUS
findings classification. Type 2, intermediate or ill-defined focal lesions. (c) B mode TRUS findings
classification. Type 3, definite focal lesion (blue arrow)

Fig. 7.2 Color coding of

strain or compression
elastography
7 Elastography: Can It Improve Prostate Biopsy Results? 97

Fig. 7.3 (a) Prostatic peripheral zone RTCE TRUS findings classification. Normal stiffness. (b)
Prostatic peripheral zone RTCE TRUS findings classification. Inhomogeneous/inconclusive stiff-
ness. (c) Prostatic peripheral zone RTCE TRUS findings classification. Definite focal lesion of
increased stiffness (white arrow), capsule disruption (black arrow)

cally proven to have neoplasia extended beyond the prostatic capsule. Sensitivity,
specificity, positive and negative predictive values are summarized in Table 7.1.
These data suggest that RTCE improves the diagnostic rate of TRUS in detecting
peripheral zone prostatic cancer and yields more robust information in the presence
of cancer lesions. It can discriminate the inconclusive results of baseline B-mode
images. Thus the number of needle core samples may be reduced. It also may
enhance the role of TRUS in prostatic cancer local staging (Video 7.1). Even our
data show that addition of elastography to TRUS increases accuracy it’ s efficacy has
never been compared to the pathologic result obtained through transperineal tem-
98 V.M. Skouteris et al.

Fig. 7.4 An important characteristic or advantage of strain elastography is the ability of assessing
the integrity of prostatic capsule. In this figure we can see that the capsule looks normal, intact on
both sides. Peripheral zone has normal elastographic appearance and we can see few hard lesions
in the transitional zone, bilaterally, which proved to be non cancerous

Table 7.1 Results of TRUS biopsy with elastography

Needle biopsy Needle biopsy
positive negative
TRUS positive 39 21 PPV 65 %
TRUS negative or inconclusive 8 85 NPV 91 %
(Sensitivity 83 %) (Specificity 80 %)
RTCE positive 43 9 PPV 83 %
RTCE negative or inconclusive 4 97 NPV 96 %
(Sensitivity 91 %) (Specificity 92 %)

plate guided prostate biopsy. As previously mentioned, this biopsy technique pro-
vides the most reliable and uniform access to all regions of the prostate and for this
reason we believe it represents a highly accurate method for assessing the effective-
ness of elastography and its capability in distinguishing cancerous foci from normal
prostate parenchyma. Our institution started offering transperineal mapping biopsy
to patients in 2008 and elastography was added to the procedure in 2011, a year after
ultrasound department was equipped with the ultrasound elastography machine.
7 Elastography: Can It Improve Prostate Biopsy Results? 99

Fig. 7.5 Radiologist

marks hard-suspicious area
on elastography (e.g.,
RPL). He will then
reassure that this area is
sampled during mapping
biopsy and the samples
marked accordingly

Technique of Transperineal Biopsy and Elastography

Patients at risk for prostate cancer were referred for transrectal ultrasound elastog-
raphy followed by a transperineal biopsy. The patient is placed at a right lateral
decubitus position with the knees elevated towards the chest and a local anesthetic
gel is introduced in the rectum. Prostate is divided in six quadrants in each lobe,
anterior-lateral (AL), anterior/medial (AM), middle/lateral (ML), middle/medial
(MM), posterior/lateral (PL) and posterior/medial (PM). The radiologist performing
the ultrasound locates suspicious-hard lesions on elastography areas and carefully
maps the quadrant in which they are present in order after to note which sample
taken during the transperineal biopsy corresponds to that area (Fig. 7.5). After com-
pletion of elastography, the patient is brought in the operating room where the team
is present consisting of an urologist and the radiologist who previously performed
the elastographic evaluation. The patient is now placed in the dorsal lithotomy posi-
tion and a Foley catheter is placed, draining in the bladder. The purpose of the ure-
thral catheter is to clearly identify the anatomic relations and to prevent any urethral
injury during the procedure. The stepping device is attached to the table and ultra-
sound probe fixed to it (B&K Leopard, model 8558 probe, B&K Medical, Winthrop,
Mass) and inserted to the rectum. Prostate image is adjusted to fit template’s coor-
dinates on the ultrasound screen. That is a crucial adjustment since the holes of the
100 V.M. Skouteris et al.

Fig. 7.6 Superimposed template on transverse ultrasound image of prostate. Samples were
obtained at 5 mm intervals throughout whole prostate volume. Sampling starts from right lobe and
anterior lateral part (e.g., C capital 4) working our way down till the most medial/posterior part
(e.g., D capital 1)

grid have to have access to all parts of the prostate. Sampling then starts under
general anesthesia, in transverse plane beginning from the right lobe and most ante-
rior/lateral part, working our way down till the most medial/posterior part (Fig. 7.6).
Once the needle is visible, image is switched to sagittal and the needle is pulled
back until the tip reaches the apex of the gland. The biopsy device is then fired and
the sample taken. In cases where prostate length exceeds sample length (1.8 cm),
e.g., in a gland with 4 cm length, two cores are taken one from the base till middle
of the gland and one from the middle till the base. If length extends beyond 4 cm, a
third core at the same level can be taken to cover the entire sagittal distance of the
gland. The biopsy instrument used (“gun”) was the disposable 18G “Max-Core”,
with 25 cm long needle (CR Bard, Covington, GA, USA). When right lobe is fin-
ished, we switch and biopsy the left side. Samples are carefully put to the corre-
sponding labeled vials according to their region and the radiologist is reassuring that
positive-hard areas on elastography are mapped correctly, sampled and marked
(Figs. 7.5 and 7.7). Once the procedure is finished, patient is brought to the recovery
room and Foley catheter is removed. If the patient is unable to urinate catheter is
reinserted the same day. When the pathology report is available urologist and radi-
ologist check if cancerous areas correspond to the positive elastographic quadrants
(Figs. 7.8, 7.9, 7.10, and 7.11).
7 Elastography: Can It Improve Prostate Biopsy Results? 101

Fig. 7.7 Radiologist reassures during mapping biopsy that area RPL is sampled and marks down
names of cores (e.g., B capital 1, B small 1, B capital 1½, B small 1½)

Fig. 7.8 Normal elastographic appearance of peripheral zone, few hard areas present in the tran-
sitional zone. Mapping biopsy revealed 3/15 positive cores from the right lobe (RAL, RML,
RMM) and 5/19 positive from the left lobe (LAL, LAM, LML, LPL, LMM), Gleason 7 (4 + 3)
102 V.M. Skouteris et al.

Fig. 7.9 Normal elastographic appearance of peripheral zone, few hard areas present in the tran-
sitional zone. Mapping biopsy revealed a Gleason 7 (3 + 4) prostate cancer, with 4/25 cores positive
from the right lobe (4xRAM) and 8/31 positive from the left lobe (2xLAM, LAL, 4xLMM, LML)

Fig. 7.10 Normal elastographic appearance of peripheral zone, few hard areas present in the tran-
sitional zone not pathologic. Mapping biopsy revealed one core positive for adenocarcinoma out
of 20 (total 44) in the right lobe (RPL quadrant), Gleason 6 (3 + 3)
7 Elastography: Can It Improve Prostate Biopsy Results? 103

Fig. 7.11 Extensive hard lesion occupying the right peripheral zone with signs of capsular disrup-
tion on both sides. Few hard areas also present on the transitional zone bilaterally. Mapping biopsy
revealed 9/17 positive cores on the right lobe (2xRML, 5xRPL, 1xRMM, 1xRPM) and 9/23 posi-
tive from the left lobe (1xLAL, 7xLPL, 1xLPM), Gleason 9 (5 + 4)

Results of Transperineal Template-Guided Biopsy

with Elastography

From July 2008 till December 2014, 149 consecutive patients underwent transperi-
neal mapping biopsy. In the last 15 of them “3D biopsy” software (see Chap. 6) was
used to guide and record the biopsy procedure. 73 patients (49 %) had abnormal
findings on digital rectal examination (DRE) and 52 of them previously underwent
negative transrectal biopsies in 1–3 occasions (one: 33 patients, two: 16 patients,
three: 3 patients). 83 (55.7 %) of the patients were submitted to TRUS compression
elastography before the mapping biopsy and the pathology results were used to
make comparisons between elastography and transperineal biopsy findings. Median
patient age was 66 years (range 48–86), mean PSA 8 ng/dl (range 1–118), mean
prostate volume (PV) 46 cm3 (range 18–137) and mean PSA density (PSAD) 0.2037
(range 0.02–4.21) (Table 7.2).
Preparation the night before the biopsy included a fleet enema around 19:00 and
light, low in fiber supper was suggested. Patients were prescribed an a-blocker and
oral fluoroquinolone for 10 days total (five pre and five post-procedure). PV, resid-
ual urine, international prostate symptom score (IPSS) and quality of life measure-
ments were determined prior and 1 week after procedure (Table 7.3). Associations
were tested by ANOVA and two-tail T test and correlations/odds ratios estimated by
chi-square (Pearson).
104 V.M. Skouteris et al.

Table 7.2 Patient Variable Mean Median Range

characteristics of 149 men
Age (years) 66 66 48–86
undergoing transperineal
mapping biopsy PSA (ng/ml) 8.1 6.3 1–118
PSAD 0.193 0.129 0.02–4.21
Prostate Volume (cm3) 46 45.5 18–147

Table 7.3 Factors Variable IPSS Residual volume Prostate volume

comparison before and after
Before TPMB 4.6 14.1 49.1
(1 week) transperineal biopsy
After TPMB 6.6 18.9 57.2
p value <0.001 <0.001 <0.001

A median 46 cores (range 18–84) were obtained, 23 from each lobe. 67 men
(44.96 %) were diagnosed with prostate cancer and of the 52 with prior negative
transrectal biopsy, 25 (48.1 %) were proved positive for prostate adenocarcinoma
through the transperineal route. 20 (80 %) of them, were characterized as clinical
significant cancers according to Epstein criteria (2005). Mean number of positive
cores was 6.7 (range 1–26), Gleason score was 6 in 25 (37.3 %), 7 in 36 (53.7 %)
and 8–10 in 6 (9 %). Positive biopsy was associated only with a positive DRE
(61.5 % vs. 26.5 %, p < 0.001, OR 4.5), and a positive family history (88.9 % vs.
36.5 %, p = 0.002, OR 13.9). PSA level, prior negative biopsy and number of cores
taken were not significant predictors of a positive biopsy. Mean PSAD for negative
biopsy was 0.1359 and for positive biopsy 0.2885 (p = 0.057). Of the Gleason scores
6, 10/24 (41.6 %) had PSAD ≤ 0.15 and ≤2 positive cores (p = 0.004) but 16/35
(45.7 %) with Gleason score 7 also had PSAD ≤ 0.15.
Compression elastography was positive in 33/46 (71.7 %) of the positive biop-
sies in the peripheral zone (p = 0.007, OR 5.1, 95 % CI 1.5–17.1) and had an ROC
area of 0.690. But efficacy of elastography in the other zones of prostate as well as
in determining bilateral disease was lower than in the periphery. Mapping biopsy
found cancer located in the remaining zones of prostate where elastography was
negative in 18/40 (45 %) of patients. Elastography also incorrectly evaluated that
disease existed only in one lobe in 19/36 (52.7 %) patients where transperineal route
proved that bilateral localization was present. When results in the peripheral zone
where stratified according to prostate volume we found out that in patients with
PV < 40 cm3 (n = 28) elastography could identify cancer in 85.7 % of the cases (24
patients) compared to 44.4 % (8/18 patients) in glands with PV ≥ 40 cm3.

Conclusions

Prostate elastography gives valuable information in the peripheral zone of the

prostate where the majority of prostate cancers arise but efficacy in prediction of
bilateral disease and cancer involvement in other zones of the gland is limited. It
improves the detection rate over b-mode TRUS guided biopsy.
7 Elastography: Can It Improve Prostate Biopsy Results? 105

Gland size significantly affects elastography results, as in smaller glands predict-

ing of cancerous areas is more accurate. When prostate volume is increasing effi-
cacy of elastography is diminished.

References

1. Hodge KK, McNeal JE, Stamey TA. Ultrasound guided transrectal core biopsies of the palpa-
bly abnormal prostate. J Urol. 1989;142(1):66–70.
2. Chon CH, Lai FC, McNeal JE, Presti Jr JC. Use of extended systematic sampling in patients
with a prior negative prostate needle biopsy. J Urol. 2002;167(6):2457–60.
3. Meng MV, Franks JH, Presti Jr JC, Shinohara K. The utility of apical anterior horn biopsies in
prostate cancer detection. Urol Oncol. 2003;21(5):361–5.
4. Merrick GS, Gutman S, Andreini H, Taubenlag W, et al. Prostate cancer distribution in patients
diagnosed by transperineal template-guided saturation biopsy. Eur Urol. 2007;52(3):723–4.
5. Pinkstaff DM, Igel TC, Petrou SP, Broderick GA, Wehle MJ, Young PR. Systematic transperi-
neal ultrasound-guided template biopsy of the prostate: three-year experience. Urology.
2005;65(4):735–9.
6. Dimmen M, Vlatkovic L, Hole KH, Nesland JM, Brennhovd B, et al. Transperineal prostate
biopsy detects significant cancer in patients with elevated prostate-specific antigen (PSA) lev-
els and previous negative transrectal biopsies. BJU Int. 2012;110:E69.
7. Epstein JI, Sanderson H, Carter HB, Scharfstein DO. Utility of saturation biopsy to predict
insignificant cancer at radical prostatectomy. Urology. 2005;66(2):356–60.
8. Nafie S, Mellon JK, Dormer JP, Khan MA. The role of transperineal template prostate biopsies
in prostate cancer diagnosis in biopsy naïve men with PSA less than 20ng/ml. Prostate Cancer
Prostatic Dis. 2014;17(2):170–3.
9. Grummet JP, Weerakoon M, Huang S, Lawrentschuk N, Frydenberg M, Moon DA, O’Reilly
M, Murphy D. Sepsis and ‘superbugs’: should we favour the transperineal over the transrectal
approach for prostate biopsy? BJU Int. 2014;114(3):384–8.
10. Ayres BE, Montgomery BS, Barber NJ, Pereira N, Langley SE, Denham P, Bott SR. The role
of transperineal template prostate biopsies in restaging men with prostate cancer managed by
active surveillance. BJU Int. 2012;109(8):1170–6.
11. Onik G, Miessau M, Bostwick DG. Three-dimensional prostate mapping biopsy has a poten-
tially significant impact on prostate cancer management. J Clin Oncol. 2009;27(26):4321–6.
12. Salomon G, Kollerman J, Thederan I, et al. Evaluation of prostate cancer detection with ultra-
sound real-time elastography: a comparison with step section pathological analysis after radi-
cal prostatectomy. Eur Urol. 2008;54:1354–62.
13. Pallwein L, Mitterberger M, Struve P, et al. Real-time elastography for detecting prostate can-
cer: preliminary experience. BJU Int. 2007;100:42–6.
14. Brock M, von Bodman C, Sommerer F, et al. Comparison of real-time elastography with grey-
scale ultrasonography for detection of organ-confined prostate cancer and extra capsular exten-
sion: a prospective analysis using whole mount sections after radical prostatectomy. BJU Int.
2011;108:E217–22.
15. Brock M, von Bodman C, Palisaar RJ, et al. The impact of real-time elastography guiding a
systematic prostate biopsy to improve cancer detection rate: a prospective study of 353
patients. J Urol. 2012;187:2039–43.
16. Walz J, Marcy M, Pianna JT, et al. Identification of the prostate cancer index lesion by real-
time elastography: considerations for focal therapy of prostate cancer. World J Urol. 2011;29:
589–94.
17. Aigner F, Pallwein L, Junker D, et al. Value of real-time elastography targeted biopsy for pros-
tate cancer detection in men with prostate specific antigen 1.25 ng/ml or greater and 4.00 ng/
ml or less. J Urol. 2010;184:913–7.
106 V.M. Skouteris et al.

18. Aboumarzouk OM, Ogston S, Huang Z, et al. Diagnostic accuracy of transrectal elastosonog-
raphy (TRES) imaging for the diagnosis of prostate cancer: a systematic review and meta-
analysis. BJU Int. 2012;110:1414–23.
19. Kapoor A, Mahajan G, Sidhu BS. Real-time elastography in the detection of prostate cancer in
patients with raised PSA level. Ultrasound Med Biol. 2011;37:1374–81.
20. Kamoi K, Okihara K, Ochiai A, et al. The utility of transrectal real-time elastography in the
diagnosis of prostate cancer. Ultrasound Med Biol. 2008;34:1025–32.
Chapter 8
Multiparametric MRI of the Prostate as a Tool
for Prostate Cancer Detection, Localization,
and Risk Assessment

Marc A. Bjurlin, Neil Mendhiratta, and Samir S. Taneja

Introduction

Advances in multiparametric magnetic resonance imaging (mpMRI) hold promise

for the improved detection and characterization of prostate cancer [1]. MpMRI
combines diffusion-weighted imaging, dynamic contrast-enhanced sequences, or
spectroscopy with conventional T2-weighted sequences. With a combination of
anatomic and functional imaging sequences to identify suspicious regions in the
prostate, pre-biopsy mpMRI has the potential to improve prostate cancer detection
and risk stratification through MRI-targeted biopsy [2]. In this chapter we review
the role of mpMRI in prostate cancer detection, the outcomes of MRI-targeted
biopsy, and the critical concepts currently under evaluation in validation of an MRI-
based prostate cancer risk stratification strategy.

Limitations of Contemporary Systematic Biopsy Technique

and Methods for Prostate Cancer Detection

The contemporary random 12-core systematic biopsy strategy relies on sampling

efficiency for cancer detection and is consequently subject to sampling error. Cancers
are often small, intermingled with benign stroma, and not uniformly distributed

M.A. Bjurlin, D.O. • S.S. Taneja, M.D. (*)

Division of Urologic Oncology, Department of Urology, NYU Langone
Medical Center, 150 E 32nd Street, 2nd Floor, New York, NY 10016, USA
e-mail: [email protected]; [email protected]
N. Mendhiratta, B.A.
School of Medicine, NYU Langone Medical Center,
550 1st Avenue, New York, NY 10016, USA
e-mail: [email protected]

© Springer International Publishing Switzerland 2016 107

N.N. Stone, E.D. Crawford (eds.), The Prostate Cancer Dilemma,
DOI 10.1007/978-3-319-21485-6_8
108 M.A. Bjurlin et al.

within the gland. As a result, clinically significant cancers frequently go undetected.

Under-sampling of the prostate during ultrasound-guided biopsy also leads to incor-
rect risk stratification in a subset of men with a potential for categorization of clini-
cally significant tumors as low volume or low grade. Random non-targeted prostate
biopsies risk inadequate sampling of a cancer lesion often at its periphery. This may
reveal a small length of tumor in a core with a low Gleason score, when in fact a
clinically significant lesion may exist adjacent to the biopsy site. Approximately
30–50 % of men over age 50 years harbor clinically insignificant PCa at autopsy.
These clinically insignificant cancers are often identified by chance during a system-
atic biopsy approach, contributing, in part, to the problem of over-detection and
over-treatment of indolent PCa. Repeat biopsy increases detection of clinically insig-
nificant PCa. The recent trend of overcoming sampling error through increasing core
number, or repeating biopsies, further escalates the risk of identifying small, indolent
cancers which may have little to do with the patient’s PSA elevation [3].
Introducing pre-biopsy mpMRI and MRI-targeted biopsy in the evaluation of
men at risk for prostate cancer has the potential to address many of the shortcom-
ings of contemporary clinical approaches to prostate cancer diagnosis using system-
atic biopsy. Potential advantages of pre-biopsy mpMRI and MRI-targeted biopsy
include increased detection of high-risk prostate cancer, reduced detection of low
risk, indolent disease, utilization of fewer biopsy cores, reduction of the number of
men needing biopsy, and better sampling of cancer leading to more accurate risk
stratification [4, 5].

Multiparametric MRI: Image Sequences

T2-Weighted Imaging

T2-weighted MR images, reflecting tissue water content, have high spatial resolution
and clearly define the prostate’s zonal anatomy, distinguishing the peripheral zone
(high signal intensity) from the central zone (surrounding the ejaculatory ducts in the
posterior prostate base and exhibiting decreased T2 signal intensity) and transition
zones (surrounding the urethra, extending anteriorly and superiorly from the level of
the verumontanum, and exhibiting heterogeneous, often swirled, signal intensity)
(Fig. 8.1) [6]. In the peripheral zone, PCa can appear as an area of low signal inten-
sity. The degree of intensity decrease differs with the Gleason score, with higher
Gleason score components showing lower signal intensities [7]. T2-weighted imag-
ing results in false-positive findings, as low signal intensity can also be the conse-
quence of benign abnormalities including acute and chronic prostatitis, atrophy,
scars, post-irradiation or hormonal treatment effects, hyperplasia, and post-biopsy
hemorrhage. Partly related to the heterogeneous appearance of BPH with areas of
both increased and decreased signal intensity, cancer in transition zone may be more
difficult to discern than in the peripheral zone, particularly for the less experienced
radiologist. However, morphological features such as homogeneously low signal
8 Multiparametric MRI of the Prostate as a Tool for Prostate Cancer Detection… 109

Fig. 8.1 Sixty-six year-old biopsy naïve male with a PSA of 6.2 underwent mpMRI demonstrat-
ing a Likert scale suspicion score of 5/5 in the left posterolateral base to mid peripheral zone
lesion: T2WI (a), ADC (b), DWI (b-value 1500) (c), and DCE (single time-point (d)). Systematic
biopsy demonstrated Gleason score 6 (3 + 3) prostate cancer while MRI-targeted biopsy demon-
strated Gleason score 8 (4 + 4) cancer in 4/4 cores. Red arrow points to lesion

intensity, ill-defined irregular edges of the suspicious lesion, invasion into the urethra
or the anterior fibromuscular stroma, and lenticular shape are helpful for detection of
transition zone tumor [8].

Diffusion-Weighted Imaging

Diffusion-weighted (DW) MRI measures random motion of water molecules. The

strength of the gradient that determines the degree of diffusion-weighting is reflected
by the sequence’s b-value. By performing DWI with multiple b-values, it is possible
to compute the apparent diffusion coefficient (ADC) based on the signal intensity
measured at each b-value image to quantify the restriction of water diffusion
(Fig. 8.1). Traditionally, a maximal b-value of around 1000 s/mm2 has been used.
More recent data show that use of higher b-values up to 2000 s/mm2 helps eliminate
background signal from normal prostate and may increase the accuracy of PCa
detection [9], within both the peripheral zone and transition zone [10]. However,
modern MRI hardware and careful attention to sequence optimization is required to
110 M.A. Bjurlin et al.

maintain image quality when using these very high b-values. On ADC maps, PCa
frequently shows low ADC [11], and an inverse correlation exists between quantita-
tive ADC values and the Gleason score [12]. While ADC does correlate with final
Gleason score, the confidence intervals are widely overlapping, limiting the ability
to use ADC as a surrogate of Gleason score. This is an area of ongoing investigation
and technical optimization aimed to improve ADC’s predictive ability in the future.
Limitations of DWI include low signal-to-noise ratio and image distortion, both of
which become more problematic at higher b-values. Nonetheless, DWI is a widely
available technique with relatively straightforward acquisition and post-processing.
Moreover, given its strong association with tumor aggressiveness, it may prove to be
the primary sequence for tumor detection and characterization [13].

Perfusion Imaging

Dynamic contrast-enhanced (DCE) MRI consists of a series of fast T1-weighted

sequences covering the prostate before and after rapid injection (2–4 mL/s) of a
bolus of a gadolinium chelate. Given the serial rapid imaging of the prostate, DCE-
MRI allows assessment of contrast kinetics within focal lesions (Fig. 8.1). PCa typi-
cally enhances faster and to a greater extent than surrounding prostate, and will also
show more rapid washout of contrast in a fraction of cases. Even though prostatitis-
related enhancement is usually diffuse and non-focal in nature, and BPH-related
enhancement is often well-encapsulated and spherical, the non-specific nature of
these patterns limits the utility of DCE findings in isolation, resulting in DCE often
being applied largely as an adjunct to interpretations based primarily on findings on
T2WI and DWI. A simple approach to evaluating DCE-MRI is through a subjective
visual assessment of the raw dynamic images. Alternatively, semi-quantitative
parameters, such as the time-to-peak, wash-in rate, and washout rate, may be com-
puted to allow pixel-wide construction of parametric perfusion maps. A compartment-
based model may also be performed to generate truly quantitative metrics. This has
largely been performed using a Tofts model, which provides the parameter ktrans
(transfer constant), reflecting the forward transfer rate constant between the plasma
and extravascular extracellular space and is elevated in PCa [14].
One limitation of DCE-MR imaging relates to overlap of cancer with prostatitis in
the peripheral zone and marked overlap with vascularized BPH nodules in the transi-
tion zone. Another limitation is the reduced spatial resolution due to fast imaging.

Accuracy in Detection/Performance Characteristics

While these individual sequences all have utility in PCa detection, results are opti-
mized by multiparametric (mp) MRI, combining all of the sequences in an inte-
grated fashion (Fig. 8.1). MpMRI offers superior diagnostic power for PCa detection
8 Multiparametric MRI of the Prostate as a Tool for Prostate Cancer Detection… 111

and can assist risk stratification based on lesion size, extent, and ADC value [15]. In
one study, mpMRI sensitivity exceeded 80 % for detecting 0.2 cm3 of Gleason 4 + 3
or above and 0.5 cm3 of ≥Gleason 3 + 4 [16]. In another study using a 3 T magnet,
addition of DCE and/or DW imaging to T2-weighted MRI significantly improved
sensitivity from 63 % to 79–81 % in the peripheral zone, while maintaining a stable
specificity [17]. Yoshizako et al. demonstrated the combined use of DW, DCE, and
T2-weighted MRI to increase accuracy in detection of transition zone cancer com-
pared to T2WI alone, from 64 to 79 % [18]. Nevertheless, given moderate specific-
ity, mpMRI findings require biopsy to confirm the presence of tumor and assess
Gleason score [15]. PCa MRI suspicion scores have been developed for improved
standardization of MRI interpretation and reporting [19, 20].

MRI Suspicion Score

Prostatic abnormalities, often termed regions of suspicion, identified on mpMRI

have the potential to localize high-risk prostate cancer. Lesions are commonly
scored on a Likert scale as 2 (low probability), 3 (equivocal), 4 (high probability),
or 5 (very high probability), or the standard-based Prostate Imaging-Reporting and
Data System (PI-RADS) as I (very low), II (low), III (indeterminate), IV (high), V
(very high), as previously described [21–23]. The performance characteristics of
MRI suspicion score in predicting the likelihood of cancer are highly interpreter-
dependent. Individual institutional variation in reporting of Likert scales of suspi-
cion results in variability in cancer detection rates observed on biopsy. This serves
as a primary impetus for the implementation of a standardized reporting scheme
such as PI-RADS. Most recently in version 2 of PI-RADS (Tables 8.1 and 8.2), the
standardized scheme has been greatly simplified [23].
MRI suspicion score strongly predicts the likelihood of cancer on MRI-targeted
biopsy. In a study of 105 subjects with prior negative biopsy and elevated PSA
values who underwent mpMRI targeted biopsy, a highly suspicious MRI abnor-
mality was the most significant predictor of significant cancer on multivariate
analysis [24]. Yerram et al. evaluated 125 patients with only low suspicion pros-
tatic lesions on mpMRI and determined these lesions are associated with either
negative biopsies or low-grade tumors suitable for active surveillance [25]. Our
institution has also reported a positive trend between increasing suspicion score on
mpMRI and detection of high-grade (GS ≥ 7 PCa) disease, but not with detection
of Gleason score 6 cancer [5].

Negative Predictive Value of MRI

One potential benefit of the utilization of pre-biopsy MRI in clinical practice would
be the opportunity to reduce biopsy utilization among men at risk. A growing body
of literature has begun to address the negative predictive value (NPV) of MRI in
 112

Table 8.1 PI-RADS 2.0 mpMRI interpretation

Score T2W (PZ) T2W (TZ) DWI (PZ and TZ) Score DCE (PZ and TZ)
1 Uniform hyperintense signal Homogenous intermediate signal No abnormality on ADC and (−) No early enhancement, or
intensity intensity high b-value DWI Diffuse enhancement not
2 Linear/wedge-shaped Circumscribed hypointense or Indistinct hypointense on corresponding to a focal finding on
hypointensity or diffuse mild heterogenous encapsulated ADC T2 and/or DWI or
hypointensity nodules Focal enhancement corresponding
3 Heterogenous signal intensity Heterogenous signal intensity Focal mildly/moderately to a lesion demonstrating features
or non-circumscribed, rounded, with obscured margins hypointense on ADC and of BPH on T2WI
moderate hypointensity isointense/mildly hyperintense
on high b-value DWI
4 Circumscribed, homogenous Lenticular or non-circumscribed, Focal markedly hypointense (+) Focal, and;
moderate hypointense focus/ homogenous, moderately on ADC and markedly Earlier than or contemporaneously
mass confined to prostate and hypointense, and <1.5 cm in hyperintense on high b-value with enhancement of adjacent
<1.5 cm in greatest dimension greatest dimension DWI; <1.5 cm in greatest normal prostatic tissues, and;
dimension Corresponds to suspicious finding
on T2W and/or DWI
5 Same as 4 but ≥1.5 cm in Same as 4 but ≥1.5 cm in greatest Same as 4 but ≥1.5 cm in
greatest dimension or definite dimension or definite greatest dimension or definite
extraprostatic extension/ extraprostatic extension/invasive extraprostatic extension/
invasive behavior behavior invasive behavior
Adapted from Radiology ACo. MR Prostate Imaging Reporting and Data System version 2.0. 2015; http://www.acr.org/Quality-Safety/Resources/PIRADS/,
(2015). Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License
M.A. Bjurlin et al.
8 Multiparametric MRI of the Prostate as a Tool for Prostate Cancer Detection… 113

Table 8.2 PI-RADS 2.0 scoring rubric

Peripheral zone Transition zone
Score DWI T2W DCE DWI T2W DCE
1 1 Any Any Any 1 Any
2 2 Any Any Any 2 Any
3 3 Any (−) ≤4 3 Any
4 3 Any (+) 5 3 Any
4 Any Any Any 4 Any
5 5 Any Any Any 5 Any
Adapted from Radiology ACo. MR Prostate Imaging Reporting and Data System version
2.0. 2015; http://www.acr.org/Quality-Safety/Resources/PIRADS/, (2015). Creative
Commons Attribution-NonCommercial-NoDerivatives 4.0 International License

ruling out cancer in men for whom there is clinical suspicion. A normal or low sus-
picion MRI has the potential to allow men to avoid an unnecessary prostate biopsy,
and secondarily to reduce the over-detection of indolent disease.
Kumar et al. evaluated 36 men who had a PSA between 4 and 10 ng/mL and a
magnetic resonance spectroscopic image (MRSI) that did not show any malignant
voxels [26]. Of the 26 men who met follow-up criteria, an initial MRSI negative for
a lesion suspicious for malignancy maintained a high negative predictive value
(96.2 %), even after an average period of more than 2 years. The authors concluded
that a prostate biopsy can be deferred in patients with an increased serum PSA of
4–10 ng/mL and a negative MRSI. Squillaci et al. reported on suspicious lesion on
transrectal ultrasound that was further evaluated by mpMRI with proton MR spec-
troscopy (MRSI). This study reported a NPV for overall cancer detection of T2W-
MRI alone, MRSI alone, and combined MRI/MRSI as 69 %, 91 %, and 74 %,
respectively [27]. Manenti et al. also showed the prostate biopsy results of 39 men
undergoing mpMRI with MRSI, reporting a similar NPV of T2W-MRI, MRSI, and
combined MRI/MRSI of 77 %, 74 %, and 74 %, respectively [28].
Although the NPV of mpMRI is high in terms of overall cancer detection rates
(CDR), a paucity of data exists on the NPV of mpMRI for clinically significant
prostate cancer. In our institutional experience we evaluated 75 men presenting for
prostate biopsy who underwent pre-biopsy mpMRI that was negative for suspicious
foci, defined as a MRI suspicion score of 1/5 as previously described [21]. Overall,
cancer was detected in 14 (18.7 %) men [29]. One (1.3 %) was found to have
Gleason 3 + 4 and the remaining 13 (17.3 %) were found to have Gleason sum 6
(GS6). No Gleason sum ≥ 7 (GS ≥ 7) were detected in men without prior biopsy or
on active surveillance. Overall, the NPV for detecting any cancer on systematic
12-core biopsy for men with a negative MRI was 81.3 % and 98.7 % for detecting
GS ≥ 7. These NPV were 86.2 % and 100 % for men without prior biopsy, 88.0 %
and 96 % for men with a prior negative biopsy, and 61.9 % and 100 % for men on
active surveillance. On multivariate analysis, no prior biopsy and a prior negative
biopsy were significantly associated with decreased cancer detection on systematic
prostate biopsy with a negative mpMRI.
114 M.A. Bjurlin et al.

In a recent prospective trial of 226 men who had 3 T mpMRI prior to primary
biopsy, Pokorny et al. reported negative biopsies in 56/81 (69 %) men with normal
mpMRI [30]. However, this group included men with both PIRADS 1 and 2 mpMRI
scores. Among the 25 men with normal mpMRI and prostate cancer on biopsy,
80 % had low-risk disease (low volume Gleason score 3 + 3 or very low volume
Gleason score 3 + 4), making the NPV for intermediate/high risk disease 94 %. The
authors highlight that mpMRI with MRI targeted prostate biopsy reduces the detec-
tion of low-risk prostate cancer and reduces the number of men requiring biopsy
while improving the overall rate of detection of intermediate/high-risk prostate can-
cer, a conclusion that is supported by several additional studies [31, 32].
These findings, taken together, lend further support to the utility of mpMRI in
predicting negative biopsy among men with clinical suspicion for prostate cancer.
The performance characteristics of mpMRI appear to have a high clinical NPV
where mpMRI may ultimately be a useful tool to rule out clinically significant pros-
tate cancer on initial evaluation, therefore avoiding unnecessarily prostate biopsies.
Validation of this concept will require standardized prospective study.

Correlation of MRI with Surgical Pathology: Disease

Localization

There is strong evidence that mpMRI accurately localizes prostate cancer foci larger
than 0.2 mL and/or high-grade disease [30, 33]. Accurate identification of index
tumor location on mpMRI, followed by fusion of the MR image with a transrectal
ultrasound image, could potentially guide targeted biopsy of such index tumors with
greater accuracy. Moreover, for image-guided focal therapy, imaging must be able
to guide therapy and accurately define margins of the tumor to allow accurate treat-
ment and follow-up. The findings of mpMRI have been compared with whole mount
radical prostatectomy specimens and have been evaluated to address the concor-
dance of the index tumor location and the index tumor volume.
In initial studies comparing MRI with whole mount radical prostatectomy spec-
imens to determine tumor site and size concordance, Villers et al. assessed the
value of pelvic phased array DCE MRI for predicting the intraprostatic location
and volume of clinically localized prostate cancers [16]. Sensitivity, specificity,
and positive and negative predictive values for cancer detection by magnetic reso-
nance imaging were 77 %, 91 %, 86 % and 85 % for foci greater than 0.2 cc, and
90 %, 88 %, 77 % and 95 % for foci greater than 0.5 cc, respectively. Kim et al.
[34] and Nakashima et al. [35] observed similar performance characteristics of
MRI in determining cancer foci location and size. More recent studies which have
incorporated modern multiparametric sequences have shown that mpMRI has
>90 % specificity in detecting index tumors [36, 37]. In a multi-institutional study
of 135 men who had pre-biopsy MRI, MR-TRUS image-fusion biopsy, and robotic
radical prostatectomy, followed by whole mount step section of the specimen,
MR-TRUS fusion biopsy accurately identified the location of the index tumor in
8 Multiparametric MRI of the Prostate as a Tool for Prostate Cancer Detection… 115

95 % of patients. In the remaining 5 % of patients, the index tumor was invisible

on MRI; each of these tumors was very small (histological tumor volume ≤0.4 mL
for radical prostatectomy specimens). These data suggest that MR-TRUS image-
fusion biopsies could become a valuable tool in identifying the location of clini-
cally important prostate cancer. However, not all prostate cancer lesions are
detectable on MRI, even when using advanced technology. The MRI visibility of
prostate cancer depends on cancer volume, grade, histology, and location in com-
parison to the histological architecture of normal adjacent prostate tissue.
Determining tumor volume concordance, rather than the index lesions site,
appears to be a more challenging undertaking with varied success. In a series of 75
men, Isebaert et al. correlated mpMRI and histopathological tumor volumes after
radical prostatectomy [38]. Tumor volume was found to be the most accurately
assessed by means of DW MRI (r = 0.75). In a retrospective analysis of 135 men,
Baco et al. determined a coefficient for correlation between index lesion volume on
MRI and histology was r = 0.663 [39]. The authors acknowledge the absence of
significant agreement between the two and additional MRI variables are necessary
to improve tumor volume estimations. Turkbey et al. evaluated 135 patients who
underwent multiparametric 3 T endorectal coil magnetic resonance imaging of the
prostate and subsequent radical prostatectomy [37]. They observed a positive cor-
relation between histopathology tumor volume and MRI tumor volume (Pearson
coefficient 0.633). MRI accurately estimated the index tumor volume independent
of Gleason score. MRI had a better accuracy than clinical variables (serum PSA,
patient age) in the distinction of tumors larger than 0.5 cm3.
In our institutional experience, Le Nobin et al. evaluated the level of agreement in
volumes of prostate cancer index lesions between histopathology and MRI in 37 men
[40]. The authors addressed many of the shortcoming of previous whole mount stud-
ies, such as imprecise estimates of pathological volume as the reference standard,
suboptimal techniques for achieving co-registration of MRI and pathological images,
and the use of correlative statistical methods (such as the Pearson correlation coeffi-
cient), by investigating the accuracy of volume estimates from 3 T multiparametric
MRI using novel co-registration software. The volume estimates of prostate cancer
using MRI tended to substantially underestimate histopathological volumes, with a
wide variability in extent of underestimation across cases. Rud et al. similarly com-
pared tumor volume and tumor burden between MRI and histology from radical
prostatectomy specimens in 199 men and observed MRI underestimates both tumor
volume and tumor burden compared with histology [36]. The rate of detection of the
index tumor was 92 %, while the overall rate of detection of tumors with a histology
tumor volume of >0.5 mL was 86 %. Cornud et al. studied 84 men who had a mpMRI
prior to prostatectomy and analyzed mpMRI and pathological tumor volume [41].
The authors similarly observed a wide variation in overestimation and underestima-
tion of MRI tumor volume compared to pathological volume.
In the context of potential focal ablation, Anwar et al. analyzed mpMRI of 20
men who underwent radical prostatectomy with the aim of defining the contour of
treatable intraprostatic tumor foci in prostate cancer [42]. By comparing histopatho-
logical tumor maps from whole-mount step sections the authors calculated the
116 M.A. Bjurlin et al.

margin of error between imaging and histopathological contours at both capsular

and non-capsular surfaces and the treatment margin required to ensure at least 95 %
tumor coverage if the patient was to undergo targeted therapy. They concluded
mpMRI can be used to accurately contour these tumor foci; complete tumor cover-
age is achieved by expanding the treatment contour at the non-capsular margin by
5 mm. Our institutional experience has shown that MRI underestimates histologi-
cally determined tumor boundaries, especially for high MRI suspicion score and
high Gleason score lesions [43]. A 9 mm treatment margin around an MRI-visible
lesion consistently ensures treatment of the entire histological tumor volume during
focal ablative therapy. In assessing tumor volume and tumor margins, mpMRI
tended to underestimate lesion size for high-grade tumors while overestimating the
size of low-grade tumors. The latter may relate, in part, to stromal reaction and
inflammation in the surrounding tissues.

Outcomes of MRI-Targeted Biopsy in Clinical Practice

There are a number of potential benefits of MRI-targeted biopsy which are

reported in the literature; however, these still need to be proven though further
studies. In theory, accurate localization of significant cancer prior to biopsy may
potentially correct limitations of systematic biopsy. Accurate targeting of biopsy
cores should reduce false-negative biopsies and improve accuracy in risk classifi-
cation through better sampling of tumor, with the intent of detecting high-risk
disease and avoiding indolent cancer (Table 8.3). Secondarily, a reduction in
false-negative biopsies could reduce the necessity for repeat biopsies, thereby
reducing cost. Because targeted biopsy relies upon image guidance, fewer cores
potentially would be required, additionally reducing cost. Finally, if metrics can
be established to demonstrate the lowest risk parameters for detection of clinically
significant disease, avoidance of biopsy among men falling below that threshold
may reduce the number of biopsies performed and secondarily reduce over-detec-
tion. These principles remain to be fully proven, but there is a growing body of
evidence to support the assertion.
Several institutions, including our own, have now accrued a mature dataset high-
lighting the outcomes of MRI-targeted biopsy. In our institutional experience of 601
men, we also found that MRI-US fusion-targeted biopsy detects more high-grade
cancer compared to systematic biopsy while limiting over-detection of indolent dis-
ease in all men presenting for prostate biopsy [5]. The National Cancer Institute has
shown an increased detection of high-risk prostate cancer and decreased detection
of low-risk prostate cancer in their experience of 1003 targeted MR/ultrasound
fusion biopsies [4]. Collectively, the published literature suggests that overall can-
cer detection is decreased by MR-targeted biopsy compared to systematic biopsy,
but higher grade cancers are detected with fewer cores, and insignificant cancers are
detected less often [24, 44].
 8

Table 8.3 Summary of trials of MRI-ultrasound fusion-targeted biopsy in which the cancer detection rate (CDR) of clinically significant cancer was reported
MRI field
strength and Definition of Clinically Clinically
Study Biopsy additional clinically Overall Overall significant significant
Investigators size history sequencesa TB technique SB technique significant cancer CDR (TB) CDR (SB) CDR (TB) CDR (SB)
Mozer et al. 152 100 % BN 1.5 T Transrectal 12-core TRUS CCL ≥ 4 mm or 54 % 57 % 43 % 37 %
[47] GS ≥ 3 + 4
Sonn et al. 105 100 % PNB 3.0 T Transrectal 12-core TRUS CCL ≥ 4 mm or 24 % 28 % 22 % 15 %
[24] GS ≥ 3 + 4
Wysock 125 54 % BN 3.0 T Transrectal 12-core TRUS GS ≥ 3 + 4 Cohort: Cohort: Cohort: Cohort: NR
et al. [59] 27 % PNB 36 % NR 23 % BN: 33 %
19 % AS BN: 40 % BN: 55 % BN: 33 %
Kuru et al. 347 51 % BN 3.0 T Transperineal 24-core NCCN criteria 51 % 50 % 41 % 38 %
[61] 49 % PNB Transperineal (intermediate or
high risk)
Fiard et al. 30 43 % BN 3.0 T Transrectal 12-core TRUS ≥10 mm cancer 55 % 43 % 50 % 33 %
[64] 57 % PNB or GS ≥ 3 + 4
Rastinehad 105 33 % BN 3.0 T Transrectal 12-core TRUS Epstein criteria 51 % 49 % 45 % 32 %
et al. [65] 67 % PNB
Sonn et al. 171 38 % PNB 3.0 T Transrectal 12-core TRUS GS ≥ 3 + 4 35 % 44 % 13 % 12 %
[66] 62 % AS
Siddiqui 1003 20 % BN 3.0 T Transrectal 12-core TRUS GS ≥ 4 + 3 46 % 47 % 17 % 12 %
et al. [4] 43 % PNB Spectroscopy
37 % AS
Multiparametric MRI of the Prostate as a Tool for Prostate Cancer Detection…

TB MR-targeted biopsy, SB systematic biopsy, BN biopsy naive, PNB prior negative biopsy, AS active surveillance, CCL cancer-core length, GS Gleason score
a
All studies used T2-weighted, diffusion-weighted, and dynamic contrast-enhanced magnetic resonance imaging sequences, with any additional sequences
listed above
117
118 M.A. Bjurlin et al.

Among Men with No Previous Biopsy

The use of MRI among men with no previous biopsy has been studied but currently
its cost-effectiveness and true benefit are yet to be determined by larger randomized
studies, as such its use is currently investigational. Haffner et al. reported a seminal
series of 555 consecutive patients undergoing pre-biopsy MRI followed by system-
atic biopsy and visual estimation biopsy of MRI abnormalities. The overall cancer
detection rate (CDR) was 54 % using extended systematic biopsy and 63 % amongst
the 351 cases with an abnormal MRI [2]. Although systematic biopsy detected 66
more cases of cancer, 53 were deemed clinically insignificant. The MRI-targeted
approach detected more high-grade cases and better quantified the cancer through
increased cancer length per biopsy core. Delongchamps et al. also examined the use
of pre-biopsy mpMRI in 391 consecutive patients and reported CDR of 41 % using
systematic biopsy and 43 % using cognitive or fusion-targeted biopsy [45]. Targeted
biopsy was significantly better at detecting high Gleason score (>3 + 3) cancer, miss-
ing only 2/63 (3 %) high-grade cancers detected by systematic biopsy while detect-
ing an additional 17 high-grade cancers missed by systematic biopsy and avoiding
detection of 39 Gleason 6 cancers [45]. Among 1448 men with pre-biopsy DW-MRI
prior to initial biopsy, Watanabe et al. reported a CDR of 70.1 % in 890 patients with
MRI lesions who underwent both targeted and systematic biopsy, compared to a
CDR of only 13.1 % in 558 patients with no MRI lesions who only underwent sys-
tematic biopsy [46]. CDR was 90.1 % in 141 patients with anterior cancers found on
MRI, an area easily missed with standard systematic biopsy [46]. A number of addi-
tional studies have demonstrated similar results (Table 8.1) [2, 47, 48].

Among Men with Previous Negative Biopsy

In a series of 438 consecutive patients with elevated PSA and at least one prior
negative biopsy who underwent mpMRI, Hoeks et al. reported a CDR of 41 %
(108/265) using in-bore targeted biopsy, with 87 % (94/108) of these cancers found
to be clinically significant [49]. Vourganti et al. report on 195 patients with previous
negative biopsy and suspicious mpMRI, finding a CDR of 37 % (73/195) using a
combination of MRI-US fusion biopsy and systematic biopsy [50]. In addition to
detecting nine additional high-grade cancers missed by systematic biopsy, fusion
biopsy leads to pathological upgrading in 28/73 (38.4 %) patients [50]. Sonn et al.
found a CDR of 34 % (36/105) in men with previous negative biopsy with 72 %
(26/36) being clinically significant [24]. MRI-US fusion biopsy detected clinically
significant cancer in 21/23 (91 %) men compared to only 15/28 (54 %) men with
systematic biopsy. A highly suspicious MRI lesion was the most significant predic-
tor of significant cancer on multivariate analysis [24]. Even in patients with up to
four prior negative biopsies, Labanaris et al. found that among 170/260 (65 %) of
patients with a suspicious MRI, PCa was detected on 96/170 (56 %) targeted
8 Multiparametric MRI of the Prostate as a Tool for Prostate Cancer Detection… 119

biopsies compared to only 30/170 (18 %) systematic biopsies [51]. A subgroup

analysis of our institutional cohort demonstrated that among 172 men with prior
negative biopsies and suspicious lesions on MRI, targeted biopsies missed no high-
grade cancers, while detecting 15/31 (48 %) additional high-grade cancers missed
by systematic biopsy. Additionally, the majority of cancers detected by systematic
biopsy and missed or mischaracterized by targeted biopsy was found to be low vol-
ume and met clinical criteria for insignificant disease [52].

Among Men with Low-Risk Cancer

The performance of mpMRI and MRI-US fusion biopsy for monitoring patients
with prostate cancer on active surveillance has yielded positive results which may
improve risk stratification in these men [53, 54]. In a study of 388 consecutive
patients with low-risk disease who underwent mpMRI and confirmatory visual esti-
mation co-registration biopsy, Vargas et al. reported that 20 % (79/388) of patients
were upgraded on confirmatory biopsy [55]. A 5-point MRI suspicion scale demon-
strated excellent risk stratification, with a high sensitivity for upgrading on confir-
matory biopsy (0.87–0.98) for a score of 5/5 [55]. In a study of 281 men, Ouzzane
et al. showed mpMRI-targeted biopsy reclassified 10 % of patients who were eligi-
ble for active surveillance based on systematic biopsy [54]. In a recent study of 152
men meeting active surveillance criteria who underwent MRI-US fusions biopsy,
Walton Diaz et al. determined that stable findings on mpMRI are associated with
Gleason score stability and mpMRI appears promising as a useful aid for reducing
the number of biopsies in the management of patients on active surveillance [56].
Additionally, Kim et al. demonstrated that among 287 men on active surveillance,
high ADC values on DWI were strongly predictive of clinically insignificant, organ-
confined disease [57]. MpMRI-based nomograms may further confirm eligibility
for active surveillance and may decrease the number of repeat biopsies in patients
on active surveillance by as much as 68 % [58].

Limitations of MRI-Targeted Biopsy

While MRI-targeted biopsy has the potential to overcome the limitations of stan-
dard TRUS-guided biopsy, it is not without several potential limitations itself. MRI-
targeted biopsy incurs additional cost which remains to be justified through larger
cohort studies. Imaging quality and quality of image-interpretation serves as a major
barrier to widespread implementation in the community. Targeting methods are not
purely defined and may still miss cancer. This targeting strategy may result in addi-
tional biopsies due to a false-positive MRI. Lastly, MRI-targeted biopsy may over-
estimate cancer risk, where further studies are needed to define the significance of
pathology findings within the targeted biopsy.
120 M.A. Bjurlin et al.

Technique of MRI-Targeted Biopsy

Visual Estimation MR-Targeted TRUS Biopsy

Visual estimation allows adaptation of MRI-targeted biopsy in clinical practice

without significant upfront cost, but carries a significant learning curve and lacks
real-time feedback regarding accuracy. The effectiveness of visual estimation-
targeted biopsy in detecting PCa varies between studies, likely reflecting inconsis-
tencies in targeting precision, but generally visual estimation appears inferior to
software co-registration [59, 60]. In a series of 351/555 (63 %) patients with a posi-
tive MRI, Haffner et al. detected clinically significant PCa in 45 % (248/555) of
patients by systematic biopsy compared to 43 % (236/555) by visual estimation
biopsy, but 53/66 cancers missed by targeted biopsy were clinically insignificant
[2]. In contrast, Labanaris et al. reported CDR of 56 % by targeted visual estimation
MRI-targeted biopsy alone but only 18 % by systematic biopsy alone in 170/260
(65 %) patients with a positive MRI [51]. Collectively, the currently published stud-
ies suggest improved accuracy and efficiency compared to systematic biopsy but
also demonstrate that experience with visual estimation biopsy varies by investiga-
tor experience and likely, in part, due to variable practices in imaging approach.

Software Co-registered MRI-Targeted TRUS Biopsy

Software co-registration potentially overcomes the limitation of cognitive fusion

through reproducible methods for identification of MRI lesions on ultrasound. A
number of commercial platforms have become available [56]. These applications
vary by method of co-registration (mechanical, electromagnetic, or real-time) and
utilize different hardware platform for aligning the biopsy with the co-registered
image. MRI/US fusion biopsy potentially has greater reproducibility due to less
operator dependence and by providing real-time feedback of actual biopsied loca-
tions. Disadvantages include a high upfront cost for the software/device, dependence
on the software for accuracy, and associated learning curve and operator training.
Table 8.3 summarizes reported outcomes of systematic biopsy vs. targeted biopsy
using MRI/US fusion platforms evaluating clinically significant PCa. Siddiqui et al.
recently reported that the combination of extended systematic and targeted biopsy
using the Philips/PercuNav device resulted in diagnosing 30 % more high-risk
cancers vs. standard biopsy (173 vs. 122 cases, P < 0.001) and 17 % fewer low-risk
cancers (213 vs. 258 cases, P < 0.001) [4]. Sonn et al. report similar positive results
using the Eigen/Artemis device, reporting a CDR of 53 % (90/171) with a higher
percentage of positive cores (21 % vs. 7 %) and higher detection of Gleason ≥ 7
(38 % vs. 31 %) cancers using targeted biopsy [24]. Our institution experience with
the Eigen/Artemis device has yielded similar results (Fig. 8.2) [5]. Patients with
highly suspicious MRI lesions (5/5 grade) had a 94 % rate of cancer diagnosis com-
pared to only 43 % in patients with low suspicious lesions (2/5 grade) [24]. High
8 Multiparametric MRI of the Prostate as a Tool for Prostate Cancer Detection… 121

Fig. 8.2 Suspicious lesion visualized as (a) hypointense area on T2W image, (b) restricted diffu-
sion with low ADC, and (c) high signal on diffusion-weighted image. Targeted biopsy workflow
showing segmented prostate and lesion on (d) T2-weighted MRI, (e) transrectal ultrasound, and (f)
3D reconstruction of prostate and suspicious region

detection rates have also been demonstrated with transperineal MRI/US fusion
biopsy. Kuru et al. reported a CDR of 58 % (200/347) (58 %) using the MedCom/
BiopSee device, with a CDR of 82.6 % (86/104) in patients with highly suspicious
lesions compared to only 15 % (14/94) in patients with a normal mpMRI [61].

In Bore MRI-Guided Biopsy

Hoeks et al. reported on 265 patients with suspicious lesions on mpMRI with prior
negative TRUS biopsies that underwent transrectal in-bore MRGB, resulting in
CDR of 41 % with 87 % of these detected cancers found to be clinically significant
[49]. Multiple studies have corroborated this result, demonstrating that in-bore
MRGB is a feasible diagnostic technique in patients with prior negative biopsy with
a median detection rate of 42 %, significantly higher than reported detection rates
for repeat systematic biopsy [62]. This in-bore biopsy strategy has the advantages
of real-time feedback of needle placement, fewer sampled cores, and a low likeli-
hood of missed target. It has the disadvantage of increased cost, use of scanner time
(opportunity cost), and an inability to routinely sample the remaining gland.
Additionally, in applying in bore MRI-guided biopsy, urologists are largely removed
from the diagnostic pathway with concerning implications for the ultimate manage-
ment of the disease.
122 M.A. Bjurlin et al.

Comparative Studies

While many studies compare targeted to systematic biopsy, only a few studies have
compared the CDR between different targeted techniques. Recently, Cool and col-
leagues analyzed 225 simulated targeted biopsies by both visual estimation and
MRI–ultrasound fusion and found MRI-targeted TRUS-guided prostate biopsy
using cognitive registration appears to be inferior to MRI-TRUS fusion, with fewer
than 50 % of clinically significant PCA lesions successfully sampled [60]. Wysock
et al. prospectively compared MRI/US fusion biopsy using the Eigen/Artemis sys-
tem vs. visual estimation targeting for 125 consecutive men with suspicious regions
on pre-biopsy mpMRI and found that fusion targeting had improved accuracy for
smaller MRI lesions and trended toward increased detection compared to visual
targeting for all cancer (32.0 % vs. 26.7 %) as well as Gleason sum ≥ 7 cancers
(20.3 % vs. 15.1 %) [59]. Delongchamps et al. reported that cognitive fusion was
not significantly better than systematic random biopsies, while both software co-
registration devices tested (Esaote/MyLabTMTwice and Koelis/Urostation) signifi-
cantly increased CDR compared to systematic biopsies using conditional logistic
regression analysis in a cohort of 391 patients [45]. Yet to be explored are the rela-
tionship of clinical factors such as prostate size, PSA, and location of MRI lesion on
the accuracy of targeting by cognitive or co-registered approach. While more com-
parative studies examining the efficacy of different techniques are needed, it is pos-
sible that the decision for an institution or practice to utilize a particular type of
MRI-targeted biopsy will be largely influenced by local factors such as cost, space,
and operator experience with MRI interpretation. Recently through a consensus
meeting, guidelines were published regarding conduct and standards in reporting
MRI-targeted biopsy studies [63].

Conclusions

MpMRI represents a potential tool for addressing many of the limitations of con-
temporary systematic biopsy as MRI suspicion score correlated with significant dis-
ease. MpMRI appears to have a high negative predictive value, potentially reducing
the need for a prostate biopsy in men with a normal MRI. However, there appears
to be substantial variation in estimation of MRI tumor volume compared to patho-
logical volume. Among men with no previous biopsy, targeted prostate biopsy using
MRI guidance has the potential to reduce false negatives, improve risk classifica-
tion, and contribute to reduction of repeat biopsies and over-detection. Among men
with previous negative biopsy, but persistent suspicion, it has the potential to
increase cancer detection and reduce further repeat biopsy. Among men with cancer
contemplating surveillance, MR-targeted biopsy potentially improves risk stratifi-
cation and reduces the need for repetitive biopsy. The optimal method for
MR-targeted biopsy is not yet established, but emerging methods of co-registration
8 Multiparametric MRI of the Prostate as a Tool for Prostate Cancer Detection… 123

may offer wider accessibility to the approach. Further comparative studies to standard
of practice and evaluation of cost-effectiveness are warranted prior to consideration
of wide adoption.

Acknowledgement Neil Mendhiratta and Samir S. Taneja are supported by the Joseph and Diane
Steinberg Charitable Trust.

References

1. Bjurlin MA, Meng X, Le Nobin J, et al. Optimization of prostate biopsy: the role of magnetic
resonance imaging targeted biopsy in detection, localization and risk assessment. J Urol.
2014;192(3):648–58.
2. Haffner J, Lemaitre L, Puech P, et al. Role of magnetic resonance imaging before initial
biopsy: comparison of magnetic resonance imaging-targeted and systematic biopsy for signifi-
cant prostate cancer detection. BJU Int. 2011;108(8 Pt 2):E171–8.
3. Bjurlin MA, Carter HB, Schellhammer P, et al. Optimization of initial prostate biopsy in clini-
cal practice: sampling, labeling and specimen processing. J Urol. 2013;189(6):2039–46.
4. Siddiqui MM, Rais-Bahrami S, Turkbey B, et al. Comparison of MR/ultrasound fusion-guided
biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA. 2015;313(4):
390–7.
5. Meng X, Rosenkrantz AB, Mendhiratta N et al. Relationship of pre-biopsy multiparametric
MRI and biopsy indication with MRI-US fusion-targeted prostate biopsy outcomes. Paper pre-
sented at: American Urological Association Annual Meeting, New Orleans, LA, 17 May 2015.
6. Hricak H, Dooms GC, McNeal JE, et al. MR imaging of the prostate gland: normal anatomy.
AJR Am J Roentgenol. 1987;148(1):51–8.
7. Wang L, Mazaheri Y, Zhang J, Ishill NM, Kuroiwa K, Hricak H. Assessment of biologic
aggressiveness of prostate cancer: correlation of MR signal intensity with Gleason grade after
radical prostatectomy. Radiology. 2008;246(1):168–76.
8. Akin O, Sala E, Moskowitz CS, et al. Transition zone prostate cancers: features, detection,
localization, and staging at endorectal MR imaging. Radiology. 2006;239(3):784–92.
9. Kim CK, Park BK, Kim B. High-b-value diffusion-weighted imaging at 3 T to detect prostate
cancer: comparisons between b values of 1,000 and 2,000 s/mm2. AJR Am J Roentgenol.
2010;194(1):W33–7.
10. Katahira K, Takahara T, Kwee TC, et al. Ultra-high-b-value diffusion-weighted MR imaging
for the detection of prostate cancer: evaluation in 201 cases with histopathological correlation.
Eur Radiol. 2011;21(1):188–96.
11. Mazaheri Y, Vargas HA, Akin O, Goldman DA, Hricak H. Reducing the influence of b-value
selection on diffusion-weighted imaging of the prostate: evaluation of a revised monoexponen-
tial model within a clinical setting. J Magn Reson Imaging. 2012;35(3):660–8.
12. Hambrock T, Hoeks C, Hulsbergen-van de Kaa C, et al. Prospective assessment of prostate
cancer aggressiveness using 3-T diffusion-weighted magnetic resonance imaging-guided biop-
sies versus a systematic 10-core transrectal ultrasound prostate biopsy cohort. Eur Urol. 2012;
61(1):177–84.
13. Turkbey B, Shah VP, Pang Y, et al. Is apparent diffusion coefficient associated with clinical risk
scores for prostate cancers that are visible on 3-T MR images? Radiology. 2011;258(2):488–95.
14. Parker GJ, Tofts PS. Pharmacokinetic analysis of neoplasms using contrast-enhanced dynamic
magnetic resonance imaging. Top Magn Reson Imaging. 1999;10(2):130–42.
15. Turkbey B, Choyke PL. Multiparametric MRI and prostate cancer diagnosis and risk stratifica-
tion. Curr Opin Urol. 2012;22(4):310–5.
16. Villers A, Puech P, Mouton D, Leroy X, Ballereau C, Lemaitre L. Dynamic contrast enhanced,
pelvic phased array magnetic resonance imaging of localized prostate cancer for predicting
124 M.A. Bjurlin et al.

tumor volume: correlation with radical prostatectomy findings. J Urol. 2006;176(6 Pt 1):
2432–7.
17. Delongchamps NB, Rouanne M, Flam T, et al. Multiparametric magnetic resonance imaging
for the detection and localization of prostate cancer: combination of T2-weighted, dynamic
contrast-enhanced and diffusion-weighted imaging. BJU Int. 2011;107(9):1411–8.
18. Yoshizako T, Wada A, Hayashi T, et al. Usefulness of diffusion-weighted imaging and dynamic
contrast-enhanced magnetic resonance imaging in the diagnosis of prostate transition-zone
cancer. Acta Radiol. 2008;49(10):1207–13.
19. Jung JA, Coakley FV, Vigneron DB, et al. Prostate depiction at endorectal MR spectroscopic
imaging: investigation of a standardized evaluation system. Radiology. 2004;233(3):701–8.
20. Barentsz JO, Richenberg J, Clements R, et al. ESUR prostate MR guidelines 2012. Eur Radiol.
2012;22(4):746–57.
21. Rosenkrantz AB, Kim S, Lim RP, et al. Prostate cancer localization using multiparametric MR
imaging: comparison of Prostate Imaging Reporting and Data System (PI-RADS) and Likert
scales. Radiology. 2013;269(2):482–92.
22. Rosenkrantz AB, Lim RP, Haghighi M, Somberg MB, Babb JS, Taneja SS. Comparison of inter-
reader reproducibility of the prostate imaging reporting and data system and likert scales for
evaluation of multiparametric prostate MRI. AJR Am J Roentgenol. 2013;201(4):W612–8.
23. Radiology ACo. MR Prostate Imaging Reporting and Data System version 2.0. 2015. http://
www.acr.org/Quality-Safety/Resources/PIRADS/
24. Sonn GA, Natarajan S, Margolis DJA, et al. Targeted biopsy in the detection of prostate cancer
using an office based magnetic resonance ultrasound fusion device. J Urol. 2013;189(1):86–91.
25. Yerram NK, Volkin D, Turkbey B, et al. Low suspicion lesions on multiparametric magnetic
resonance imaging predict for the absence of high-risk prostate cancer. BJU Int. 2012;110(11
Pt B):E783–8.
26. Kumar R, Nayyar R, Kumar V, et al. Potential of magnetic resonance spectroscopic imaging in
predicting absence of prostate cancer in men with serum prostate-specific antigen between 4
and 10 ng/ml: a follow-up study. Urology. 2008;72(4):859–63.
27. Squillaci E, Manenti G, Mancino S, et al. MR spectroscopy of prostate cancer. Initial clinical
experience. J Exp Clin Cancer Res. 2005;24(4):523–30.
28. Manenti G, Squillaci E, Carlani M, Mancino S, Di Roma M, Simonetti G. Magnetic resonance
imaging of the prostate with spectroscopic imaging using a surface coil. Initial clinical experi-
ence. Radiol Med. 2006;111(1):22–32.
29. Wysock JS, Zattoni F, Meng X et al. Predictive value of negative 3T multiparametric prostate
MRI on 12 core biopsy results. Submitted.
30. Pokorny MR, de Rooij M, Duncan E, et al. Prospective study of diagnostic accuracy compar-
ing prostate cancer detection by transrectal ultrasound-guided biopsy versus magnetic reso-
nance (MR) imaging with subsequent MR-guided biopsy in men without previous prostate
biopsies. Eur Urol. 2014;66(1):22–9.
31. Itatani R, Namimoto T, Atsuji S, et al. Negative predictive value of multiparametric MRI for
prostate cancer detection: outcome of 5-year follow-up in men with negative findings on initial
MRI studies. Eur J Radiol. 2014;83(10):1740–5.
32. Villeirs GM, De Meerleer GO, De Visschere PJ, Fonteyne VH, Verbaeys AC, Oosterlinck
W. Combined magnetic resonance imaging and spectroscopy in the assessment of high grade
prostate carcinoma in patients with elevated PSA: a single-institution experience of 356
patients. Eur J Radiol. 2011;77(2):340–5.
33. Hoeks CM, Barentsz JO, Hambrock T, et al. Prostate cancer: multiparametric MR imaging for
detection, localization, and staging. Radiology. 2011;261(1):46–66.
34. Kim CK, Park BK, Kim B. Localization of prostate cancer using 3T MRI: comparison of
T2-weighted and dynamic contrast-enhanced imaging. J Comput Assist Tomogr. 2006;30(1):
7–11.
35. Nakashima J, Tanimoto A, Imai Y, et al. Endorectal MRI for prediction of tumor site, tumor
size, and local extension of prostate cancer. Urology. 2004;64(1):101–5.
8 Multiparametric MRI of the Prostate as a Tool for Prostate Cancer Detection… 125

36. Rud E, Klotz D, Rennesund K, et al. Detection of the index tumour and tumour volume in
prostate cancer using T2-weighted and diffusion-weighted magnetic resonance imaging (MRI)
alone. BJU Int. 2014;114(6b):E32–42.
37. Turkbey B, Mani H, Aras O, et al. Correlation of magnetic resonance imaging tumor volume
with histopathology. J Urol. 2012;188(4):1157–63.
38. Isebaert S, Van den Bergh L, Haustermans K, et al. Multiparametric MRI for prostate cancer
localization in correlation to whole-mount histopathology. J Magn Reson Imaging. 2013;37(6):
1392–401.
39. Baco E, Ukimura O, Rud E, et al. Magnetic resonance imaging-transectal ultrasound image-
fusion biopsies accurately characterize the index tumor: correlation with step-sectioned radical
prostatectomy specimens in 135 patients. Eur Urol. 2015;67:787–94.
40. Le Nobin J, Orczyk C, Deng FM, et al. Prostate tumour volumes: evaluation of the agreement
between magnetic resonance imaging and histology using novel co-registration software. BJU
Int. 2014;114(6b):E105–12.
41. Cornud F, Khoury G, Bouazza N, et al. Tumor target volume for focal therapy of prostate
cancer-does multiparametric magnetic resonance imaging allow for a reliable estimation? J
Urol. 2014;191(5):1272–9.
42. Anwar M, Westphalen AC, Jung AJ, et al. Role of endorectal MR imaging and MR spectro-
scopic imaging in defining treatable intraprostatic tumor foci in prostate cancer: quantitative
analysis of imaging contour compared to whole-mount histopathology. Radiother Oncol.
2014;110(2):303–8.
43. Le Nobin J, Rosenkrantz AB, Villers A et al. Image guided focal therapy of MRI-visible pros-
tate cancer: defining a 3D treatment margin based on MRI-histology co-registration analysis.
J Urol. 2015. doi: 10.1016/j.juro.2015.02.080.
44. Puech P, Rouviere O, Renard-Penna R, et al. Prostate cancer diagnosis: multiparametric
MR-targeted biopsy with cognitive and transrectal US-MR fusion guidance versus systematic
biopsy—prospective multicenter study. Radiology. 2013;268:461–9.
45. Delongchamps NB, Peyromaure M, Schull A, et al. Prebiopsy magnetic resonance imaging
and prostate cancer detection: comparison of random and targeted biopsies. J Urol.
2013;189(2):493–9.
46. Watanabe Y, Terai A, Araki T, et al. Detection and localization of prostate cancer with the
targeted biopsy strategy based on ADC map: a prospective large-scale cohort study. J Magn
Reson Imaging. 2012;35(6):1414–21.
47. Mozer P, Rouprêt M, Le Cossec C, et al. First round of targeted biopsies using magnetic reso-
nance imaging/ultrasonography fusion compared with conventional transrectal ultrasonography-
guided biopsies for the diagnosis of localised prostate cancer. BJU Int. 2015;115(1):50–7.
48. Numao N, Yoshida S, Komai Y, et al. Usefulness of pre-biopsy multiparametric magnetic reso-
nance imaging and clinical variables to reduce initial prostate biopsy in men with suspected
clinically localized prostate cancer. J Urol. 2013;190(2):502–8.
49. Hoeks CM, Schouten MG, Bomers JG, et al. Three-Tesla magnetic resonance-guided prostate
biopsy in men with increased prostate-specific antigen and repeated, negative, random, sys-
tematic, transrectal ultrasound biopsies: detection of clinically significant prostate cancers. Eur
Urol. 2012;62(5):902–9.
50. Vourganti S, Rastinehad A, Yerram NK, et al. Multiparametric magnetic resonance imaging
and ultrasound fusion biopsy detect prostate cancer in patients with prior negative transrectal
ultrasound biopsies. J Urol. 2012;188(6):2152–7.
51. Labanaris AP, Engelhard K, Zugor V, Nutzel R, Kuhn R. Prostate cancer detection using an
extended prostate biopsy schema in combination with additional targeted cores from suspi-
cious images in conventional and functional endorectal magnetic resonance imaging of the
prostate. Prostate Cancer Prostatic Dis. 2010;13(1):65–70.
52. Mendhiratta N, Meng X, Rosenkrantz AB, et al. Pre-biopsy MRI and MRI-ultrasound fusion-
targeted prostate biopsy in men with previous negative biopsies: improved cancer detection
and risk stratification. Paper presented at American Urological Association Annual Meeting,
New Orleans, LA, 17 May 2015.
126 M.A. Bjurlin et al.

53. Turkbey B, Mani H, Aras O, et al. Prostate cancer: can multiparametric MR imaging help
identify patients who are candidates for active surveillance? Radiology. 2013;268(1):144–52.
54. Ouzzane A, Renard-Penna R, Marliere F, et al. MRI-targeted biopsy improves selection of
patients considered for active surveillance for clinically low-risk prostate cancer based on
systematic biopsies. J Urol. 2015. doi: 10.1016/j.juro.2015.02.2938.
55. Vargas HA, Akin O, Afaq A, et al. Magnetic resonance imaging for predicting prostate biopsy
findings in patients considered for active surveillance of clinically low risk prostate cancer. J
Urol. 2012;188(5):1732–8.
56. Logan JK, Rais-Bahrami S, Turkbey B, et al. Current status of magnetic resonance imaging
(MRI) and ultrasonography fusion software platforms for guidance of prostate biopsies. BJU
Int. 2014;114(5):641–52.
57. Kim TH, Jeong JY, Lee SW, et al. Diffusion-weighted magnetic resonance imaging for predic-
tion of insignificant prostate cancer in potential candidates for active surveillance. Eur Radiol.
2015;25:1786–92.
58. Siddiqui MM, Truong H, Rais-Bahrami S, et al. Clinical implications of a multiparametric MRI
based nomogram applied to prostate cancer active surveillance. J Urol. 2015;193:1943–9.
59. Wysock JS, Rosenkrantz AB, Huang WC, et al. A prospective, blinded comparison of mag-
netic resonance (MR) imaging-ultrasound fusion and visual estimation in the performance of
MR-targeted prostate biopsy: the PROFUS Trial. Eur Urol. 2014;66(2):343–51.
60. Cool DW, Zhang X, Romagnoli C, Izawa JI, Romano WM, Fenster A. Evaluation of MRI-
TRUS fusion versus cognitive registration accuracy for MRI-targeted, TRUS-guided prostate
biopsy. AJR Am J Roentgenol. 2015;204(1):83–91.
61. Kuru TH, Roethke MC, Seidenader J, et al. Critical evaluation of MRI-targeted TRUS-guided
transperineal fusion biopsy for detection of prostate cancer. J Urol. 2013;190(4):1380–6.
62. Overduin CG, Futterer JJ, Barentsz JO. MRI-guided biopsy for prostate cancer detection: a
systematic review of current clinical results. Curr Urol Rep. 2013;14(3):209–13.
63. Moore CM, Kasivisvanathan V, Eggener S, et al. Standards of reporting for MRI-targeted
biopsy studies (START) of the prostate: recommendations from an International Working
Group. Eur Urol. 2013;64(4):544–52.
64. Fiard G, Hohn N, Descotes JL, Rambeaud JJ, Troccaz J, Long JA. Targeted MRI-guided pros-
tate biopsies for the detection of prostate cancer: initial clinical experience with real-time
3-dimensional transrectal ultrasound guidance and magnetic resonance/transrectal ultrasound
image fusion. Urology. 2013;81(6):1372–8.
65. Rastinehad AR, Turkbey B, Salami SS, et al. Improving detection of clinically significant
prostate cancer: magnetic resonance imaging/transrectal ultrasound fusion guided prostate
biopsy. J Urol. 2014;191(6):1749–54.
66. Sonn GA, Chang E, Natarajan S, et al. Value of targeted prostate biopsy using magnetic
resonance-ultrasound fusion in men with prior negative biopsy and elevated prostate-specific
antigen. Eur Urol. 2014;65(4):809–15.
Chapter 9
Genomic Markers

Neal D. Shore and Karen Ventii

Introduction

Patients being evaluated for the detection of prostate cancer often face critical inter-
ventional decisions, such as whether or not to do an initial biopsy or perform a
repeat biopsy after an initial negative one. Furthermore, if diagnosed with prostate
cancer, a decision to choose an interventional treatment vs. an active surveillance
strategy has now become an appropriate discussion.
Use of genomic and proteomic markers/assays may improve the precision of risk
assessment and shared educational patient–physician review, thus enhancing
decision-making for physicians and patients, especially when the traditional clinical
parameters (PSA, DRE, pathology) may not provide the most accurate assessment
of indication for biopsy nor indication for treatment option. Certainly, a patient with
low-risk, newly diagnosed prostate cancer may benefit from a more precise, person-
alized assessment of their individual tumor biology.
The currently commercially available array of biomarkers aims to improve risk
assessment, guide diagnostic strategies and ultimately enhance treatment outcomes
through more targeted screening, more accurate diagnosis, and improved risk strati-
fication, which should lead to improved treatment recommendations and subsequent
selection of therapy [1].

N.D. Shore, M.D., F.A.C.S. (*)

Carolina Urologic Research Center,
823 82nd Parkway, 4 Nelson Court, Myrtle Beach, SC 29572, USA
e-mail: [email protected]
K. Ventii, Ph.D.
Emory University, 1510 Clifton Rd., Atlanta, GA 30322, USA
e-mail: [email protected]

© Springer International Publishing Switzerland 2016 127

N.N. Stone, E.D. Crawford (eds.), The Prostate Cancer Dilemma,
DOI 10.1007/978-3-319-21485-6_9
128 N.D. Shore and K. Ventii

Who Is Best Suited for an Initial Biopsy?

• PSA testing became the cornerstone of early prostate cancer detection after its
approval approximately 30 years ago. However, due to the low disease mortality
rate, controversies have emerged with early detection strategies, and concerns
regarding subsequent overdiagnosis with the attendant concern of overtreatment
with the associated morbidities for the patient and additional cost to the healthcare
system.
• Biomarker assays have been developed to help reduce unnecessary initial biop-
sies, unnecessary repeat biopsies, and enhanced information for ultimate treat-
ment strategies when prostate cancer is newly diagnosed.

PSA

After its approval by the Food and Drug Administration (FDA) in 1986, the avail-
ability of PSA dramatically influenced prostate cancer early diagnosis [2, 3]. In the
United States, approximately 19 million men receive annual PSA testing, which
resulted in more than 1.3 million biopsy procedures and a resultant 240,890 new
prostate cancer diagnoses [4].
Nonetheless, reliance on PSA testing alone for the detection of prostate cancer
has inherent limitations. First, the test is prostate-specific but not prostate cancer,
and it often gives false-positive or false-negative results. Most men with an elevated
PSA level (above 4.0 ng/mL) [5] are not found to have prostate cancer; only approx-
imately 25 % of men undergoing biopsy for an elevated PSA level actually have the
disease. Conversely, a negative result may give false assurances that the tumor is not
detected, when, in fact, a cancer may still exist. Secondly, the test does not always
differentiate indolent from aggressive cancers and thus its early detection may not
impact eventual mortality from the disease [5] and can lead to overtreatment. This
limitation of PSA testing was largely responsible for the recent recommendation of
the USPTF against continued routine screening [6].
The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening trial was
a large, population-based randomized trial designed and sponsored by the National
Cancer Institute to determine the effects of screening on cancer-related mortality
and secondary endpoints in men and women aged 55–74. Regarding the prostate
cancer arm of the trial, after 13 years of follow-up, there was no evidence of a sur-
vival benefit for planned annual screening compared with mandated screening.
Additionally, there was no clinical impact with benefit for scheduled vs. unplanned
screening related to age, baseline comorbidity, or pretrial PSA testing [7]. PLCO
had a high rate of previous screening (~50 %) in the control arm, thus limiting its
conclusions. However, Crawford and colleagues have reported a survival benefit for
screening in men without significant comorbidities [8].
Eleven-year follow-up results from the European Randomized Study of Screening
for Prostate Cancer study demonstrated that screening does significantly reduce
9 Genomic Markers 129

death from prostate cancer [9]. A potential reason for these differing results is that
in the US-based PLCO Cancer Screening trial, at least 44 % of participants in the
control arm were already PSA-tested prior to being randomized into the study [7],
confounding the interpretation of the results.
Roobol and colleagues [10] stated that there was “poor compliance with biopsy
recommendations” in PLCO, as the trial did not mandate biopsies. Screening test
results were sent to the participant and his physician, and together they decided
upon subsequent biopsy.
In order to improve the sensitivity and specificity of serum PSA, several PSA
derivatives and isoforms (e.g., PSA isoforms, PSA density, etc.) have been used.
The National Comprehensive Cancer Network (NCCN) recommends PSA density
when assessing for very low-risk prostate cancer patients [11].
Of note, the Goteborg trial, a prospective randomized trial of 20,000 men born
between 1930 and 1944, showed that the benefit of prostate cancer screening com-
pared favorably to other cancer screening programs. Prostate cancer mortality was
reduced by almost half, over 14 years of follow-up [12].

Prostate Health Index (Phi)

Efforts have been made to reduce PSA-associated over-biopsying, which may lead
to overtreatment in very-low- and low-risk patients. Phi was approved by the FDA
for use in 2012 in those with serum PSA values between 4 and 10 ng/mL in an effort
to reduce the burden of biopsies in men with a low probability of prostate cancer.
NCCN guidelines describe Phi as markers of specificity (along with PCA3 and
percent-free PSA) to be used in those considered for additional biopsy [13].
The Phi (Phi = [−2] proPSA/fPSA × PSA1/2); proPSA is a PSA subtype and
fPSA is free PSA initially developed as an additional diagnostic biomarker in men
with a serum PSA level of 2–10 ng/mL in European trials; an elevated proPSA/
fPSA ratio is associated with prostate cancer [14].
Phi score trials have reported a high diagnostic accuracy rate and can be used in
prostate cancer diagnosis. Phi score may be useful as a tumor marker in predicting
patients harboring more aggressive disease and guiding biopsy decisions [15].
Phi also predicts the likelihood of progression during active surveillance. Tosoian
and colleagues showed that both baseline and longitudinal values of Phi predicted
which men would be reclassified to higher-risk disease on repeat biopsy during a
median follow-up of 4.3 years after diagnosis. Baseline and longitudinal measure-
ments of Phi had confidence indices of 0.788 and 0.820 for upgrading on repeat
surveillance biopsy, respectively. In contrast, an earlier study in the Johns Hopkins
active surveillance program, PCA3 did not reliably predict short-term biopsy pro-
gression during active surveillance [16].
In patients with persistent suspicion of prostate cancer and a negative biopsy,
testing with PCA3 and Phi has been proposed as a way to reduce the number of
unnecessary repeat biopsies [17].
130 N.D. Shore and K. Ventii

4KScore

4KScore is a newly available commercial assay panel that is designed to help pre-
dict which men with an elevated PSA will have high-grade disease upon tumor
biopsy. By combining measures of total, free, and intact PSA with human kallikrein
2 (hK2) and other clinical parameters, the 4KScore was shown to be better than
PCPT (Prostate Cancer Prevention Trial) at predicting the occurrence of high-grade
disease on biopsy [18]. The 4Kscore Test results have recently been validated in a
prospective, blinded clinical study conducted at 26 urology centers across the
United States on 1012 patients [19]. The test has been shown to identify the risk of
aggressive prostate cancer for the individual patient, including high-grade prostate
cancer pathology and poor prostate cancer clinical outcomes within 20 years, with
both high sensitivity and negative predictive value for aggressive prostate cancer
[20]. Ongoing clinical utility trials are still pending.

Who Can Safely Avoid a Repeat Biopsy?

• For patients with an initial negative prostate biopsy, who are still believed to be
at risk for prostate cancer, biomarker tests (PCA3 and ConfirmMDx) may be
considered to clarify avoiding proceeding to a repeat (second) biopsy.
• In the presence of persistent risk factors (e.g., elevated PSA), repeat prostate
biopsies are frequently used to detect occult cancer in men with previous nega-
tive findings, leading to unnecessary morbidity and increased healthcare costs
[21].
• Some studies on repeated biopsy procedures have shown that initial prostate
biopsy histopathology has a 20–30 % false-negative rate [21].

PCA3

PCA3 is a noncoding messenger RNA that has been demonstrated to be elevated in

>90 % of men with known prostate cancer, but not significantly elevated in normal
prostatic glands or in benign prostatic hypertrophy. The PCA3 test is a urine-based
assay approved by the FDA as a diagnostic test in the setting of a previous negative
prostate biopsy. It may be helpful in deciding when to proceed or not re-biopsy, and
thus avoid the attendant potential morbidity and associated healthcare costs, while
supplementing the diagnostic information obtained from monitoring a patient’s
PSA kinetics [22]. The higher the PCA3 score, the higher the probability of prostate
cancer, whereas a lower score suggests a lower likelihood. The mean PCA3 score
was statistically significantly higher in men with a positive prostate cancer biopsy,
or those with atypical small acinar proliferation and/or high-grade prostatic intraep-
ithelial neoplasia (HGPIN), compared with men who had a negative biopsy in a
9 Genomic Markers 131

large cohort of prospectively evaluated men [23]. PCA3 testing may fail to identify
transition zone cancers because the DRE may not elude cells for the assay evalua-
tion into the urine.

ConfirmMDx

ConfirmMDx is a tissue-based epigenetic assay designed to improve decision-

making for a repeat prostate biopsy after an initial negative biopsy when there
remains concern that a cancer may still be present. It is performed on the paraffin-
embedded blocked biopsy samples, and has had assay validation extending back to
24 months from the prior biopsy. The assay detects an epigenetic field effect result-
ing from increased hypermethylation of three distinct prostate cancer-specific genes.
The field effect, or halo effect of cancerization, purports to detect significant genetic
abnormalities within/around the cancerous lesion, and thus may be detected despite
the normal histologic appearance of the epithelium, hence, effectively extending the
interpretative coverage of the biopsy core. This test may help in the identification of
men who should proceed to a repeat biopsy while also assist in the avoidance of
many unnecessary repeat biopsies [24, 25]. Use of this assay on initial biopsies has
been reported to enhance the negative predictive value over histopathologic review
[26]. A prospective clinical utility trial (Prostate Assay Specific Clinical Utility at
Launch; PASCUAL) is underway to assess the role of this assay in lowering the
repeat biopsy rate. With favorable trial findings, it is expected that unrestricted
Medicare coverage will be granted (with the Registry requirement removed) [27].

PCMT

PCMT is a tissue-based test that identifies a deletion in mitochondrial DNA that indi-
cates cellular change associated with prostate cancer. It detects the presence of malig-
nant cells in normal-appearing tissue across an extended area. Recent clinical data
indicate that this test may be useful for identifying men who do not require a repeat
biopsy [28]. A nested case-controlled study demonstrates that the deletion has clinical
utility in identifying those patients who may have had cancer missed by sampling
error on a prior biopsy procedure. The sensitivity of the assay is 85 % and importantly
it has a negative predictive value of 92 % [28, 29]. Additional trials are still pending.

PTEN

Dysregulation of PTEN, a tumor suppressor gene, which is remarkably common

deletion for many solid tumor malignancies, has been associated with poor progno-
sis in prostate cancer. Evidence suggests that loss (homozygous/heterozygous) of
132 N.D. Shore and K. Ventii

PTEN is associated with higher Gleason grade, risk of progression, and recurrence
after therapy [30]. Additionally, it has been reported to be associated with increased
risk with advanced localized and metastatic disease [31]. The PTEN assay is a prog-
nostic fluorescence in situ hybridization test, typically ordered in conjunction with
prostate biopsy tests which will indicate partial or complete deletions of the gene.
Understanding the deletion presence with regard to homozygosity and heterozygos-
ity requires further clinical validation and clinical utility trials.

Who Should Undergo Interventional Therapy or Consider

Active Surveillance?

• Physicians and patients can evaluate disease monitoring (active surveillance) as

an alternative to interventional treatment after careful consideration of the
patient’s prostate cancer risk, general health, and age. Biomarkers should assist
with this shared decision-making.

Oncotype DX®

The Oncotype DX® is a multi-gene RT-PCR expression assay that has been prospec-
tively validated in several contemporary cohorts as an accurate predictor of adverse
pathology in men with NCCN very-low-, low- and low-intermediate-risk prostate
cancer [32]. Using very small biopsy tumor volumes, the assay measures expression
of 17 cancer-related genes from four relevant biological pathways, employing five
reference genes as threshold validation. These are combined to calculate a Genomic
Prostate Score (GPS), which adds independent predictive information beyond stan-
dard clinical and pathologic parameters. The report that generates a score between 0
and 100 reveals the patient’s underlying tumor, which may help guide initial treat-
ment decision at the time of biopsy. The assay has been clinically validated in two
separate independent cohorts confirming Oncotype DX® as a predictor of adverse
pathology from the prostate needle biopsy and demonstrating the test’s ability to
predict the risk of biochemical recurrence after surgery [33, 34]. There is an ongoing
clinical utility trial designed to demonstrate the assay’s usefulness with physician–
patient shared decision making regarding a decision to proceed with interventional
therapy vs. active surveillance.

Prolaris®

Prolaris® is a tissue-based cell cycle progression signature test that assesses 31 cell
cycle progression genes to provide a risk assessment of prostate cancer-specific
progression and 10-year disease-specific mortality when combined with standard
9 Genomic Markers 133

pathologic parameters [35]. It is designed as a risk stratification tool to help refine

treatment/monitoring strategy for patients with prostate cancer. Prolaris has been
validated in both the biopsy and post-prostatectomy settings. The prognostic value
of the Prolaris score has been validated in nine cohorts and over 6000 patients. Data
from these studies demonstrate that Prolaris is more predictive of mortality than
Gleason score, PSA, age, clinical stage or extent of disease individually and almost
doubles the total predictive information when they are combined [36–41].
PROCEDE 500 is a prospective registry study that was designed to evaluate the
impact of the Prolaris test on physician treatment recommendations for patients
with prostate cancer. It demonstrated that 65 % of physicians changed their original
treatment plans for men with prostate cancer based on results from the Prolaris test
[42]. A larger prospective clinical utility trial, PROCEDE 1000, has been com-
pleted and the final analysis has been accepted for presentation at the AUA Annual
Meeting 2015.

Decipher®

The Decipher® RNA assay directly measures the biological risk for metastatic pros-
tate cancer after radical prostatectomy. The test assesses the activity of 22 RNA
markers associated with metastatic disease and has been demonstrated to be inde-
pendently prognostic of prostate cancer death in a high-risk surgical cohort. It gen-
erates a genomic risk score to predict the probability of the patient developing
metastasis within 5 years of surgery or 3 years of biochemical recurrence. Patients
are identified as high, average or low risk based on their predicted probability of
developing metastasis. In a validation study, over 70 % of high-risk patients had low
genomic classifier (GC) scores and good prognosis, whereas patients with high GC
scores had a cumulative incidence of metastasis over 25 % [43, 44]. The test has
also demonstrated clinical utility. In a recent study, an average of 39 % of physicians
changed patient treatment planning with the benefit of Decipher results [45]. The
assay has recently received an LCD (Local Coverage Determination) approval for
its indications in assessing post-prostatectomy risk for adjuvant therapy.

ProMark

ProMark is a prognostic biopsy-based prostate cancer test. It uses immunofluores-

cent imaging analysis to quantify protein biomarker expression and classify patients’
tumors. A clinical validation study demonstrated that ProMark can differentiate
indolent from aggressive disease, based on data from standard formalin-fixed, par-
affin-embedded tissue. The ability to monitor treatment effects and to identify thera-
peutic targets at the time of treatment consideration is a major unmet need in prostate
cancer. Additional assay validation and clinical utility trials are underway [46].
134 N.D. Shore and K. Ventii

Markers to Assist Post-prostatectomy Evaluation

Both Prolaris® and Decipher® are approved in the post-prostatectomy space, to help
enable application of directed, multimodal or adjuvant therapy for patients follow-
ing radical prostatectomy (RP). Prolaris® testing is particularly well-suited for post-
prostatectomy patients with higher risk features to better estimate the risk of
biochemical recurrence (BCR) [36, 47]. For Decipher®, 60 % of clinically high-risk
men post prostatectomy were reclassified as low risk by Decipher and 98.5 % of
men classified as low risk by Decipher did not develop metastasis within 5 years of
radical prostatectomy [48].

Clinical Utility and Value of Biomarkers

A biomarker must be measurable, reproducible, linked to relevant clinical out-

comes, and demonstrate clinical utility. Clinical utility demonstrates how much
additional information the biomarker provides relative to what is currently avail-
able; both cost and clinical utility affect reimbursement. Although the FDA does not
formally request clinical utility in the biomarker development process, it is a vital
consideration that will impact on how widely the marker is used and ultimately
reimbursed by private and public payers. For example, clinical utility would be a
deciding factor when comparing the value of a costly molecular analysis of a tumor
compared to inexpensive clinical parameters routinely available in practice to assess
prognosis [49].
Molecular diagnostic researchers should ensure that the analytic validity of a
biomarker test has been established prior to the evaluation of clinical utility. In plan-
ning clinical utility studies for biomarkers, protocols should specify the patient
population intended to benefit from the decision guided by the test result. For vali-
dation studies of all types, prior evidence from early studies must be obtained from
cohorts relevant to the intended use population.
Ideally, clinical validation studies should use metrics that are clinically useful to
physicians in order to assess the strength of association between the biomarker
assay and prostate cancer. Ideally, such studies should include outcome measures
that assess the potential benefits and challenges from the patient perspective, recog-
nizing that these outcomes may occur at different time points and are the result of
clinical management decisions guided by test results.
Biomarker platforms that enable healthcare professionals to accurately interpret
and communicate the results of biomarker diagnostic and predictive testing for
patients and their caregivers must be prospectively validated before their contempo-
raneous use should be promoted.
9 Genomic Markers 135

Conclusion

Prostate cancer biomarkers have the potential to assist clinicians in improving deci-
sions regarding whom to biopsy, whom to avoid a repeat biopsy, whom to enhance
risk assessment, and thereby reduce unnecessary biopsy strategies as well as over
overtreatment, thus achieving more selective therapy for patients with high-risk dis-
ease. In effect, clinicians can strive for better outcomes and hopefully remain cost
neutral or better yet, achieve cost savings to the healthcare system. In the last few
years, there has been rapid development of many new and novel biomarkers. These
biomarkers should offer and assist clinicians with improved decision-making on when
to biopsy, whom to re-biopsy and how to assist patients with treatment decisions.

References

1. Crawford ED, Ventii K, Shore ND. New biomarkers in prostate cancer. Oncology.
2014;28:135–42.
2. Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum
as a screening test for prostate cancer. N Engl J Med. 1991;324(17):1156–61.
3. Chou R, Croswell JM, Dana T, et al. Screening for prostate cancer: a review of the evidence
for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155(11):762–71.
4. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.
5. Institute NC: Prostate-specific antigen (PSA) test.
6. Moyer VA, U.S. Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive
Services Task Force recommendation statement. Ann Intern Med. 2012;157(2):120–34.
7. Andriole GL, Crawford ED, Grubb III RL, et al. Prostate cancer screening in the randomized
Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13
years of follow-up. J Natl Cancer Inst. 2012;104(2):125–32.
8. Crawford ED, Grubb III R, Black A, et al. Comorbidity and mortality results from a random-
ized prostate cancer screening trial. J Clin Oncol. 2011;29(4):355–61.
9. Schroder FH, Hugosson J, Roobol MJ, et al. Prostate-cancer mortality at 11 years of follow-up.
N Engl J Med. 2012;366(11):981–90.
10. Roobol MJ, Bangma CH, Loeb S. Prostate-specific antigen screening can be beneficial to
younger and at-risk men. CMAJ. 2013;185(1):47–51.
11. Oncology NCPGI: Prostate Cancer. Version 2.2014. 2014.
12. Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Goteborg randomised
population-based prostate-cancer screening trial. Lancet Oncol. 2010;11(8):725–32.
13. NCCI: Updates Prostate Cancer Early Detection. Version 1.2014. 2014.
14. Le BV, Griffin CR, Loeb S, et al. [-2]Proenzyme prostate specific antigen is more accurate than
total and free prostate specific antigen in differentiating prostate cancer from benign disease in
a prospective prostate cancer screening study. J Urol. 2010;183(4):1355–9.
15. Wenying Wang MW, Wang L, Adams TS, Tian Y, Xu J. Diagnostic ability of %p2PSA and
prostate health index for aggressive prostate cancer: a meta-analysis. Sci Rep. 2014;4:5012.
16. Tosoian JJ, Loeb S, Feng Z, et al. Association of [-2]proPSA with biopsy reclassification dur-
ing active surveillance for prostate cancer. J Urol. 2012;188(4):1131–6.
17. Porpiglia F, Russo F, Manfredi M, et al. The roles of multiparametric magnetic resonance
imaging, PROSTATE CANCER3 and prostate health index-which is the best predictor of pros-
tate cancer after a negative biopsy? J Urol. 2014;192:60–6.
136 N.D. Shore and K. Ventii

18. Daniel WL. The 4KscoreTM test as a predictor of high-grade prostate cancer on biopsy.
American Urological Association Annual Meeting; 2014.
19. Lin DW. The 4Kscore test as a predictor of high-grade prostate cancer on biopsy. AUA; 2014.
20. Lilja HJ, Vickers AJ, Sjoberg D, et al. Improving the specificity of prostate cancer screening
for early detection of lethal disease. J Clin Oncol. 2014;32:5s. suppl; abstr 5081.
21. Wojno KJ, Costa FJ, Cornell RJ, et al. Reduced rate of repeated prostate biopsies observed in
ConfirmMDx clinical utility field study. Am Health Drug Benefits. 2014;7(3):129–34.
22. De La Taille A, Irani J, Graefen M, et al. Clinical evaluation of the PROSTATE CANCER3
assay in guiding initial biopsy decisions. J Urol. 2011;185(6):2119–25.
23. Crawford ED, Rove KO, Trabulsi EJ, et al. Diagnostic performance of PROSTATE CANCER3
to detect prostate cancer in men with increased prostate specific antigen: a prospective study of
1,962 cases. J Urol. 2012;188(5):1726–31.
24. Stewart G, et al. Clinical utility of a multiplexed epigenetic gene assay to detect cancer in
histopathologically negative prostate biopsies: results of the multicenter MATLOC study.
American Urological Association (AUA) 2012 Annual Scientific Meeting, 211; 2012.
25. Trock BJ, Brotzman MJ, Mangold LA, et al. Evaluation of GSTP1 and APC methylation as
indicators for repeat biopsy in a high-risk cohort of men with negative initial prostate biopsies.
BJU Int. 2012;110(1):56–62.
26. Stewart GD, Van Neste L, Delvenne P, et al. Clinical utility of an epigenetic assay to detect
occult prostate cancer in histopathologically negative biopsies: results of the MATLOC study.
J Urol. 2013;189(3):1110–6.
27. Clinicaltrials.Gov., Nct02250313.: PASCUAL (Prostate Assay Specific Clinical Utility at
Launch) Study.
28. Robinson K, Creed J, Reguly B, et al. Accurate prediction of repeat prostate biopsy outcomes
by a mitochondrial DNA deletion assay. Prostate Cancer Prostatic Dis. 2010;13(2):126–31.
29. Parr RL, Mills J, Harbottle A, et al. Mitochondria, prostate cancer, and biopsy sampling error.
Discov Med. 2013;15(83):213–20.
30. Lotan TL, Carvalho FL, Peskoe SB, et al. PTEN loss is associated with upgrading of prostate
cancer from biopsy to radical prostatectomy. Mod Pathol. 2015;28:128–37.
31. Chaux A, Peskoe SB, Gonzalez-Roibon N, et al. Loss of PTEN expression is associated with
increased risk of recurrence after prostatectomy for clinically localized prostate cancer. Mod
Pathol. 2012;25(11):1543–9.
32. Knezevic D, Goddard AD, Natraj N, et al. Analytical validation of the Oncotype DX prostate
cancer assay—a clinical RT-PCR assay optimized for prostate needle biopsies. BMC
Genomics. 2013;14:690.
33. Cullen J, Rosner IL, Brand TC, et al. A biopsy-based 17-gene genomic prostate score predicts
recurrence after radical prostatectomy and adverse surgical pathology in a racially diverse
population of men with clinically low- and intermediate-risk prostate cancer. Eur Urol.
2015;68(1):123–31.
34. Klein EA, Cooperberg MR, Magi-Galluzzi C, et al. A 17-gene assay to predict prostate cancer
aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy
undersampling. Eur Urol. 2014;66:550–60.
35. Kar AJ, Scholz MC, Fegan JE, David Crawford E, Scardino PT, Kaldate RR, Brawer MK. The
effect of cell cycle progression (CCP) score on treatment decisions in prostate cancer: results
of an ongoing registry trial. J Clin Oncol 32, 2014 (suppl 4; abstr 277).
36. Cuzick J, Swanson GP, Fisher G, et al. Prognostic value of an RNA expression signature
derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective
study. Lancet Oncol. 2011;12(3):245–55.
37. Cuzick J, Stone S, Yang ZH, et al. Validation of a 46-gene cell cycle progression RNA signa-
ture for predicting prostate cancer death in a conservatively managed watchful waiting needle
biopsy cohort. American Urological Association; 2014.
38. Bishoff JT, Freedland SJ, Gerber L, et al. Prognostic utility of the cell cycle progression score
generated from biopsy in men treated with prostatectomy. J Urol. 2014;192(2):409–14.
9 Genomic Markers 137

39. Freedland SJ, Gerber L, Reid J, et al. Prognostic utility of cell cycle progression score in men
with prostate cancer after primary external beam radiation therapy. Int J Radiat Oncol Biol
Phys. 2013;86(5):848–53.
40. Cooperberg MR, et al. Development and validation of the biopsy-based genomic prostate
score (GPS) as a predictor of high grade or extracapsular prostate cancer to improve patient
selection for active surveillance. AUA; 2013.
41. Cuzick J, Berney DM, Fisher G, et al. Prognostic value of a cell cycle progression signature
for prostate cancer death in a conservatively managed needle biopsy cohort. Br J Cancer.
2012;106(6):1095–9.
42. Crawford ED, Scholz MC, Kar AJ, et al. Cell cycle progression score and treatment decisions
in prostate cancer: results from an ongoing registry. Curr Med Res Opin. 2014;30(6):1025–31.
43. Badani K, Thompson DJ, Buerki C, et al. Impact of a genomic classifier of metastatic risk on
postoperative treatment recommendations for prostate cancer patients: a report from the
DECIDE study group. Oncotarget. 2013;4(4):600–9.
44. Karnes RJ, Bergstralh EJ, Davicioni E, et al. Validation of a genomic classifier that predicts
metastasis following radical prostatectomy in an at risk patient population. J Urol.
2013;190(6):2047–53.
45. Lobo JM, Dicker AP, Buerki C, et al. Evaluating the clinical impact of a genomic classifier in
prostate cancer using individualized decisionanalysis. PLoS One. 2015;10(3):e0116866.
46. Fred Saad MS, Choudhury S, Capela T, Ernst C, Hurley A, Small C, Kaprelyants A, Hussain
S, Chang H, Giladi E, Dunyak J, Coupal L, Nifong T, Latour M, Berman D, Blume-Jensen
P. Distinguishing aggressive versus nonaggressive prostate cancer using a novel prognostic
proteomics biopsy test, ProMark. 2014 ASCO Annual Meeting J Clin Oncol 2014;32:5s.
(suppl; abstr 5090).
47. Cooperberg MR, Simko JP, Cowan JE, et al. Validation of a cell-cycle progression gene panel
to improve risk stratification in a contemporary prostatectomy cohort. J Clin Oncol.
2013;31(11):1428–34.
48. Ross AE, Feng FY, Ghadessi M, et al. A genomic classifier predicting metastatic disease pro-
gression in men with biochemical recurrence after prostatectomy. Prostate Cancer Prostatic
Dis. 2014;17(1):64–9.
49. Scher HI, Morris MJ, Larson S, Heller G. Validation and clinical utility of prostate cancer
biomarkers. Nat Rev Clin Oncol. 2013;10(4):225–34.
 Part II
Treatment
Chapter 10
Current Status of Clinical Trials in Active
Surveillance

Laurence Klotz

Background

The identification of men with indolent, clinically insignificant prostate cancer

began in the 1950s, when TURP became widely adopted for BPH. Ten percent of
men having this operation were found to have clinically unsuspected prostate cancer;
in most cases this was small volume, low-grade disease (stage T1a). Remarkably,
there was a widespread and uncontroversial consensus that this cancer did not war-
rant treatment [1]. The incidence of micro-focal low grade disease increased dra-
matically with the advent of PSA testing in North America and Europe in the late
1980s. This continued unabated until 2012, when the US Preventive Services Task
Force announced a level D recommendation against PSA screening [2], followed by
equivocal recommendations regarding PSA screening by several other respected
national health policy organizations [3]. Screening remains a topic of intense con-
troversy and disagreement. (Most experts believe that PSA screening provides a
mortality benefit at the cost of significant overdiagnosis; if overtreatment is avoided,
the mortality benefit is compelling.) However, the consequences of the USPSTF
recommendation (and that of other groups) have been a steady drop in the rate of
PSA testing and referral for biopsy over the last few years.
The USPSTF recommendation against PSA screening was driven in large part by
concerns about overdiagnosis and overtreatment of clinically insignificant disease
[3]. Despite the historical consensus about conservative management of T1a disease
post TURP, from the beginning of the PSA era around 1988 until the task force
recommendation in 2012, more than 90 % of patients diagnosed with low-risk pros-
tate cancer by PSA and biopsy in the US were treated with definitive therapy.

L. Klotz, M.D. (*)

Sunnybrook Health Sciences Centre,
2075 Bayview Ave., MG408, Toronto, ON, Canada, M4N 3M5
e-mail: [email protected]

© Springer International Publishing Switzerland 2016 141

N.N. Stone, E.D. Crawford (eds.), The Prostate Cancer Dilemma,
DOI 10.1007/978-3-319-21485-6_10
142 L. Klotz

However, following the task force recommendation, and bolstered by substantial

evidence regarding the indolent nature of low-grade disease and the favorable outcome
with expectant management, an increasing consensus about the value and benefit of
active surveillance has emerged. The most recent available data are that the propor-
tion of patients with low-risk disease managed conservatively increased from about
10 % in 2000 to 35 % in 2010 [4, 5].

Metastatic Potential of Low-Risk Prostate Cancer

Prostate cancers have heterogeneous biology and behavior. Some cancers are
aggressive, and others have little or no metastatic potential. Some small cancers,
due to lack of telomerase, VEGF, or other biological machinery conferring cellular
immortality, may even undergo spontaneous involution and disappear [6]. Several
large clinical series have reported a rate of metastasis for surgically confirmed
Gleason 6 (where there is no possibility of occult higher grade cancer lurking in the
prostate) that is virtually zero [7]. Occult higher grade cancer is present in about
25–40 % of men initially diagnosed with Gleason 6 on biopsy [8, 9].
A natural limitation of assessing the outcome of conservative (no treatment)
series is that, since the diagnosis is based on needle biopsy, it is possible, indeed
probable, that occult higher grade cancer present at the time of diagnosis was
responsible for disease progression in the subset of patients who proceed to develop
metastases. The long-term mortality reported for biopsy Gleason 6 managed with
no intervention is remarkably similar, about 25 % [10]. The occult high-grade can-
cers thus are likely responsible for most of the prostate cancer deaths reported in
conservative management series.
One way to address the under-grading problem in assessing the true natural history
of Gleason 6 is to examine the outcome when the entire prostate has been evaluated,
i.e., by surgical pathological grading after radical prostatectomy. One multicenter
study of 24,000 men with long-term follow up after surgery included 12,000 with
surgically confirmed Gleason 6 cancer [7]. The 20-year prostate cancer mortality was
0.2 %. About 4000 of these were treated at MSKCC; of these, 1 died of prostate can-
cer; a pathological review of this patient revealed Gleason 4 + 3 disease in the primary;
in other words, it was misclassified as Gleason 6 [11]. A second study of 14,000 men
with surgically confirmed Gleason 6 disease found only 22 with lymph node metasta-
ses; review of these cases showed that all 22 were misclassified, and had higher grade
cancer in the primary tumor. The rate of node-positive disease in the 14,000 patients
with no Gleason 4 or 5 disease in their prostates was therefore zero. (A limitation of
this study was that patients had, in most cases, a limited node dissection; but given the
large cohort size, the message is still clear) [12].
Of course, an alternative explanation for the very low rate of metastasis fol-
lowing surgery for Gleason 6 cancer is the treatment effect, i.e., that the intervention
is completely successful, and commonly alters the natural history of the disease.
This is analogous to the surgical management of basal cell carcinomas of the skin,
10 Current Status of Clinical Trials in Active Surveillance 143

which may become lethal due to the effects of local invasion if neglected, but in
early cases are almost always cured by surgical resection. An important distinction
is that basal cell carcinomas do not metastasize, even when locally advanced. Higher
grade prostate cancer clearly does metastasize. Thus, one would expect, if Gleason 6
had metastatic potential occasional Gleason 6 cancers would have micro-metastasized
prior to surgery or recur locally with subsequent metastasis. This has rarely if ever
been observed. Further, if resection of a small basal cell carcinoma of the skin had the
same effects on quality of life as a radical prostatectomy, dermatologists would also
be considering conservative management in the “low-risk” cases! Notwithstanding
that absence of a metastatic potential does not preclude categorizing a lesion as
cancer, it has been proposed to change the designation “cancer” for micro-focal
Gleason 6 to “Indolent Lesions of Epithelial Origin” (IDLE tumors) [13].
An interesting case report with longitudinal genetic sequencing described a
patient who was managed stably on surveillance for Gleason 6 disease for 15 years,
including 12 sets of biopsies showing Gleason 6 only or normal tissue. Fifteen years
after diagnosis he was re-biopsied for a sharp rise in PSA and found to have Gleason
9 and 10 cancer with metastases. The expression of PTEN, ERG, P53, and Ki-67
switched from uniformly normal in the first 12 biopsies to abnormal in the last one.
This case confirms that the activation of genetic switches resulting in histological
grade progression can occur in low-grade cancer (or in normal prostate epithelium).
Fortunately, these kinds of cases are rare in clinical practice [14].
The published literature on surveillance includes 23 prospective studies. The
largest and most mature 14 studies encompassing about 5000 men are summarized
in Table 10.1 [15–29]. The conclusions to be drawn from these studies and the areas
of continued uncertainty are summarized as below:
The studies use a range of eligibility criteria, from inclusive to stringent. This
heterogeneity with respect to eligibility reflects a difference in risk tolerance by the
investigators. Inclusion criteria include all low-risk patients (Gleason 6 and
PSA < 10 ng/mL, regardless of cancer volume), and selected intermediate risk
(Gleason 7 with small amounts of pattern 4, or PSA between 10 and 20 ng/mL).
For those groups with more inclusive criteria, particularly the Toronto, Rotterdam,
and UCSF series, the potential advantages of surveillance outweigh what is hoped
to be a small increased risk of metastasis occurring during the period of surveil-
lance. In contrast, the centers adopting a more stringent inclusion approach restrict
surveillance to very low-risk patients by NCCN guidelines (1–2 cores positive,
<50 % of core involvement, and PSA density <0.15). For these groups, the
increased risk of metastatic disease outweighs the benefits of surveillance for the
low- and intermediate-risk groups. Several decision analyses suggest that a very
substantial increase in prostate cancer mortality with surveillance compared to
radical intervention for all would be required before surveillance would not have a
net benefit for the low- and intermediate-risk groups [30]. However, this remains
an area of debate.
The rate of radical intervention in men on active surveillance is consistently
around 30 % at 5–10 years. This is remarkably similar to the rate of occult higher grade
cancer known to be present in men found to have Gleason 6 on systematic biopsy.
144 L. Klotz

Table 10.1 Outcomes of AS in large prospective series

Median % treated Overall/disease % BCR post
follow-up overall; % specific deferred
References n (months) treatment free survival (%) treatment
Klotz et al. [15, 16], 993 92 30 %; 72 % at 79/97 at 10 25 % (6 %
University of Toronto 5 years years overall)
Bul et al. [17], 2500 47 32 %; 43 % at 77/100 at 10 20 %
Multicentre, Europe 10 years years
Dall’Era et al. [18] 328 43 24 %; 67 % at 100/100 at 5 NR
UCSF 5 years years
Kakehi et al. [19], 118 36 51 %; 49 % at NR NR
Multicentre, Japan 3 years
Tosian et al. [20], Johns 407 NR 36 %; NR NR NR: 50 %
Hopkins, USA “incurable”
based on RP
pathology
Roemeling et al. [21], 273 41 29 %; 71 % at 89/100 at 5 NR [31 % of
Rotterdam Netherlands 5 years years 13 RP positive
margins]
Soloway et al. [22], 99 35 8 %; 85 % at NR NR
Miami, USA 5 years
Patel et al. [23], 88 35 35 %; 58 % at NR NR
Memorial Sloan 5 years
Kettering, USA
Barayan [24] McGill, 155 65 20 % NR NR
Canada
Rubio-Briones [25] 232 36 27 % 93 % at 5
Spain years/99.5 %
Godtman [26] 439 63 % 81/99.8 14 %
Thomsen [27] Denmark 167 40 35 %/60 % 5
years
Selvadurai [28] UK 471 67 30 % 98/99.7 12 %
Eggener [29] 262 29 15 %; 25 % at NR 5%
5 years

The intervention rate does vary between series, reflecting differences in eligibility
criteria and triggers for intervention.
Most groups have reported a consistent rate of re-classification and radical
treatment for at least 5 years after diagnosis, typically around 5 %/year. Most
patients who are re-classified in the first 5 years likely harbored higher grade cancer
at the time of diagnosis. This experience defines an opportunity for improvement in
the surveillance algorithm. It is likely that the increasing use of MRI will identify
those patients harboring higher grade, usually anterior cancers, earlier, resulting in
a shift of the intervention curve to the left. This should result in improved outcome
for those patients with a “wolf in sheep’s clothing,” i.e., an occult higher grade
cancer present but not detected by the TRUS biopsy.
Death from prostate cancer is uncommon. Most of these studies have a duration
of follow up that is insufficient to preclude an increased risk of prostate cancer
10 Current Status of Clinical Trials in Active Surveillance 145

mortality as a result of surveillance with certainty. In the most mature surveillance

cohort with a median follow up of 8 years and range of 2–18 years, the actuarial
prostate cancer mortality at 15 years was 5 % [16]. The commonest cause of death
in AS cohorts is cardiovascular disease. In the Toronto cohort, the cumulative
hazard ratio (or relative risk) of non-prostate-cancer death rate with a median follow
up of 9 years was ten times that for prostate cancer.
A challenge to the surveillance concept is the pivotal Swedish study reported that
the risk of prostate cancer mortality in patients managed by watchful waiting was
low for many years, but tripled after 15 years of follow up [31]. (“Watchful waiting”
meant no opportunity for selective delayed intervention, whereas about 30 % of
patients in the surveillance series have had radical treatment.) In the Toronto experi-
ence, 70 patients have been followed for 14 years; about 1.5 % have had late disease
progression (metastasis developing 8 or more years after diagnosis) but there is no
evidence of a sharp increase in mortality to date. Thus a critical question in this field
is what the long-term prostate cancer mortality will be beyond 15 years. It will be
5–7 years before the most mature existing cohorts have a median of 15 years of
follow-up. To date, however, there is no evidence of a dramatic increase in late
prostate cancer mortality.
PSA density has been identified by many groups as a biomarker for higher risk
disease, including in the most recent update of the Epstein criteria [32]. A low PSA
density is a proxy for low volume of disease, and vice versa; this, in turn, is corre-
lated with the risk of higher grade cancer. A PSA density of <0.15 is an indicator of
a more benign phenotype.
If Gleason 6 does not metastasize, and therefore is generally not a threat to the
patient’s life, what is the significance of higher volume of Gleason 6? This has
become clear in several recent publications. Higher volume Gleason 6 is a predictor
for an increased risk of occult higher grade cancer [33–35]. In one study, total can-
cer biopsy length of >8 mm predicted for a significantly increased risk of high-grade
disease [36]. Thus, high volume Gleason 6 patients require close scrutiny to exclude
as accurately as possible the presence of higher grade disease. With the exception of
very young patients, they otherwise do not require treatment.
Race is relevant. African Americans on AS have a higher rate of risk
re-classification and PSA failure after treatment than Caucasian men [37]. Black
men who are surveillance candidates also have a higher rate of large anterior can-
cers than Caucasians. Another study suggested that AA men may be at higher risk
for disease reclassification [38]. Japanese men younger than age 60 have a lower
rate of histological cancer than Caucasian men [39]. Thus, the finding of low-grade
prostate cancer in young Asian men is less common, and the risk of overdiagnosis
may be less. However, Black and Asian patients diagnosed with low-grade prostate
cancer includes men who have little or no probability of a prostate cancer-related
death during their remaining lives, and active surveillance is still an appealing
option for those who have been appropriately risk-stratified.
The utility of surveillance compared to surgery and radiation has been modeled
by several groups. One propensity score analysis compared 452 men from the
Toronto surveillance cohort to 6485 men who had RP, 2264 treated with external
beam radiotherapy and 1680 with brachytherapy. There was no difference in prostate
146 L. Klotz

cancer mortality between the groups while there was improved overall survival in
the surveillance group due to an increase in other cause mortality in the radiation
patients [40]. A decision analysis of surveillance compared to initial treatment
showed that surveillance had the highest QALE even if the relative risk of prostate
cancer-specific death for initial treatment vs. active surveillance was as low as 0.6
[30]. (In fact, it is almost certainly 0.95 or better at 15 years.)
An attempt to carry out a prospective randomized trial comparing active surveil-
lance to radical intervention (surgery or radiation) for men with low-risk prostate
cancer was undertaken by the NCIC, the intergroup mechanism (CTEP) in the US,
and the UKCCR beginning in 2004 (the START trial). The START trial was to enroll
2100 patients, with a primary outcome of prostate cancer mortality. Unfortunately,
despite the widespread co-operative group support for the trial, it failed to accrue
sufficiently, closing after 4 years with only 240 patients registered.
While surveillance has become more widely accepted over the last decade, the
modification of the Gleason system in 2005 has resulted in a decrease in the number
of newly diagnosed Gleason 6 compared to 7. Many Gleason 7 cases, who would
have been graded as Gleason 6 before 2005, also have clinically insignificant dis-
ease. In particular, where the component of pattern 4 is small (<10 %), these patients
are likely to have a similar natural history to those with Gleason 3 + 3, reflecting
stage migration [41]. A recent analysis of Gleason 7 patients having radical prosta-
tectomy found that those who otherwise fulfilled criteria for very low-risk disease
(PSA < 10, T1c, ≤positive cores, and PSA density <0.15) had only a 12 % chance of
Gleason 4 + 3 or higher cancer [42].

Active Surveillance Technique

Implementation of AS has evolved over the last 15 years. The published series
reflect an approach which relied on serial systematic biopsies and PSA kinetics.
All groups mandate a confirmatory biopsy within the first 3–12 months, targeting
the areas of the prostate that have been shown to harbor significant cancer in patients
initially diagnosed with Gleason 6. These are the regions that are typically under-
sampled on the initial diagnostic biopsy, namely the anterior prostate, prostatic apex
and base. The interval of biopsy after this varied between annual (Johns Hopkins)
and 4–5 years (Toronto).
A major development in the field is the increasing use of multiparametric
MRI. We emphasize that none of the favorable results reported in the 14 cohorts
summarized herein employed mpMRI until recently. However, the ability to identify
large high-grade cancers by imaging is compelling. Some groups are now using
mpMRI routinely in men who are surveillance candidates, with biopsy of a target
when present. Others use MRI selectively, i.e., in those patients whose biopsy shows
substantial volume increase, those who are upgraded to Gleason 3 + 4 and surveil-
lance is still desired as a management option, or whose PSA kinetics suggest more
aggressive disease (usually defined as a PSADT < 3 years). Multiparametric MRI,
10 Current Status of Clinical Trials in Active Surveillance 147

including T2-weighted image, dynamic contrast-enhanced image, and diffusion-

weighted image, should be performed. Identification of an MRI target suspicious
for high-grade disease should warrant a targeted biopsy; or, if the lesion is large and
unequivocal, intervention.
Eighty-five to 90 % of patients who are upgraded are increased to Gleason 3 + 4
[33]. Upgrading to Gleason 8 or higher occurs in 10 % or less of upgraded patients.
In many of these patients, the presence of a small amount of Gleason 4 cancer does
not alter the indolent course, and conservative management may still be feasible.
MRI has an emerging and potentially game-changing role in the management of
AS patients. There are two potential benefits: reassurance that no higher risk disease
is present in those with no visualized disease; and, in the subset harboring higher
grade disease, earlier identification of this cancer. With respect to the former, the
key metric is the negative predictive value. This has been reported to be 97 % for a
group of about 300 surveillance candidates at MSKCC [43]. A study of the perfor-
mance of MRI in the Toronto cohort showed that a non-suspicious MRI was highly
correlated with a lack of clinically significant lesions. MRI-targeted biopsy was
6.3× more likely to yield a core positive for GS7 cancer compared with TRUS Bx
(25 % of 141 vs. 4 % of 874, P < 0.001). The negative predictive value of mpMRI
for Gleason 7 or greater cancer was 100 % [44]. A recent report from Hopkins con-
firmed that a non-suspicious MRI was highly correlated with a lack of pathologi-
cally significant lesions in an AS population [45]. Another recent study showed that
the performance of MRI was particularly effective in men with a PSA > 5.2 (which
includes most men with diagnosed untreated prostate cancer) [46].
If these results of single-centre cohorts are validated, the performance of MRI as
a diagnostic test would permit a level of confidence in a negative MRI that would
allow it to replace the biopsy in men with an elevated PSA. This would decrease the
number of men requiring biopsies (a major unmet need) and facilitate earlier iden-
tification of clinically significant disease. A limitation is that the skill set for accu-
rate interpretation of mpMRI is demanding and not yet widely prevalent.
PSA kinetics are now used as a guide to identify patients at higher risk, but not
to drive the treatment decision. This is a shift in practice. In most centers reporting
surveillance outcomes, prior to the availability of mpMRI, men with worrisome
PSA kinetics (doubling time < 3 years or PSA velocity > 2 ng/mL/year) were treated.
In the PRIAS multi-institutional AS registry, 20 % of men being treated had inter-
vention based on a PSA doubling time <3 years [17].
A rapid rise in PSA is sensitive for aggressive disease but lacks sufficient specific-
ity to be reliable. For example, in a report of the five men dying of metastatic prostate
cancer in the Toronto cohort, all had a PSA doubling time <2 years [47]. However,
the lack of specificity is a critical flaw. In a study of PSA kinetics in a large surveil-
lance cohort, false-positive PSA triggers (doubling time < 3 years, or PSA velocity > 2 ng/
mL/year) occurred in 50 % of stable untreated patients, none of whom went on to
progress, require treatment, or died of prostate cancer [48]. An overview of all of the
studies of more than 200 patients examining the predictive value of PSA kinetics
in localized prostate cancer concluded that PSA kinetics had no independent predic-
tive value beyond the absolute value of PSA [49].
148 L. Klotz

Active surveillance is highly cost-effective. A recent economic analysis estimated

that avoiding treatment in men with clinically insignificant prostate cancer would
save $1.32 billion per year in the US alone [50].

Ongoing Clinical Trials

The Protect trial, a randomized phase 3 study [51], recruited men between age 50
and 69 for a PSA test, and mandated biopsies for those with a PSA ≥ 3.0 ng/
mL. Those diagnosed with prostate cancer were randomized between active surveil-
lance, radical prostatectomy, or conformal radiotherapy. Two thousand eight hun-
dred and ninety-six men were diagnosed with prostate cancer (4 % of tested men
and 39 % of those who had a biopsy), of whom 2417 (83 %) had clinically localized
disease (mostly T1c, Gleason score 6). One thousand six hundred and forty-three
(62 %) agreed to be randomly assigned (545 to active monitoring, 545 to radio-
therapy, and 553 to radical prostatectomy). The primary end point is prostate cancer
mortality at 10 years, and the data from this pivotal study are expected to be reported
in 2016.
Diet may play a role in preventing progression of low-risk disease, and many
epidemiological studies suggest that a vegetable based diet may be beneficial. The
MEAL study is a 2-year randomized, phase 3 clinical trial in 464 patients allocated
to receive either a validated telephone-based diet counseling intervention for 2 years
or a published diet guideline [52]. The primary outcome is clinical progression
defined by PSA value and pathological findings on follow-up prostate biopsy.
Secondary outcome variables include incidence of surgical and non-surgical treat-
ments for prostate cancer, prostate cancer-related patient anxiety and health-related
quality of life.
The Study of Active Monitoring in Sweden (SAMS) is a prospective, multicentre
study of active surveillance for low-risk prostate cancer, consisting of randomiza-
tion between standard re-biopsy and follow-up and extensive initial re-biopsy cou-
pled with less intensive follow-up and no further scheduled biopsies (SAMS-FU)
[53]. There is also an observational arm (SAMS-ObsQoL). SAMS-FU is planned to
randomize 500 patients and SAMS-ObsQoL to include at least 500 patients during
5 years. The primary endpoint is conversion to active treatment.

Conclusion

Active surveillance is an effective solution to the widely recognized problem of

overtreatment of screen-detected prostate cancer. Many prospective phase 2 studies
including more than 5000 patients have reported a low rate of prostate cancer
metastasis and death. A randomized phase 3 trial comparing surveillance to radi-
cal intervention was launched in 2007—it failed to accrue adequately and closed
10 Current Status of Clinical Trials in Active Surveillance 149

unsuccessfully. Mild uncertainty remains related to the outcome after >15 years
follow-up. Adoption of an active surveillance program for low-risk disease could
reduce overall mortality without an increase in prostate cancer deaths and provide
substantial cost savings (estimated at up to $1.32 billion/year in the US). The
approach to surveillance continues to evolve, and the incorporation of improved
imaging and molecular biomarkers is certain to improve individual risk characteriza-
tion, and therefore long-term outcome. This should also reduce the need for periodic
biopsies. A dispassionate re-assessment of PSA screening based on these improved
metrics should lead to a re-consideration of the value of early detection by organiza-
tions such as the USPSTF. The minimum standard currently is a confirmatory biopsy
targeting the anterolateral horn and anterior prostate within 6–12 months. PSA
should be performed every 6 months and subsequent biopsies every 3–5 years until
the patient is no longer a candidate for definitive therapy. The role of mpMRI in men
on surveillance is currently the subject of intensive investigation, and should be
clarified within the next few years. Currently it is indicated for men with a grade or
volume increase, or adverse PSA kinetics. Treatment should be offered for most
patients with upgraded disease.

References

1. Byar DA, The VA Cooperative Urology Research Group. Survival of patients with incidentally
found microscopic cancer of the prostate: results of a clinical trial of conservative treatment.
J Urol. 1972;108:908.
2. http://www.uspreventiveservicestaskforce.org/uspstf12/prostate/prostateart.htm
3. https://www.auanet.org/education/guidelines/prostate-cancer-detection.cfm
4. Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary
treatment of localized prostate cancer. J Clin Oncol. 2010;28(7):1117–23.
5. Weiner AB, Patel SG, Etzioni R, Eggener SE. National trends in the management of low and
intermediate risk prostate cancer in the United States: SEER and NCDB et al. J Urol. 2015
Jan;193(1):95–102.
6. Serrano M. Cancer: a lower bar for senescence. Nature. 2010;464(7287):363–4.
7. Eggener S, Scardino P, Walsh P, et al. 20 year prostate cancer specific mortality after radical
prostatectomy. J Urol. 2011;185(3):869–75.
8. Vellekoop A, Loeb S, Folkvaljon Y, Stattin P. Population based study of predictors of adverse
pathology among candidates for active surveillance with Gleason 6 prostate cancer. J Urol.
2014;191(2):350–7.
9. Truong M, Slezak JA, Lin CP, Iremashvili V, Sado M, Razmaria AA, Leverson G, Soloway MS,
Eggener SE, Abel EJ, Downs TM, Jarrard DF. Development and multi-institutional validation
of an upgrading risk tool for Gleason 6 prostate cancer. Cancer. 2013;119(22):
3992–4002.
10. Albertsen PC, Hanley JA, Fine J. 20-year outcomes following conservative management of
clinically localized prostate cancer. JAMA. 2005;293(17):2095–101.
11. Scott Eggener. Personal communication.
12. Ross HM, Kryvenko ON, Cowan JE, Simko JP, Wheeler TM, Epstein JI. Do adenocarcinomas
of the prostate with Gleason score (GS) <= 6 have the potential to metastasize to lymph nodes?
Am J Surg Pathol. 2012;36(9):1346–52.
13. Esserman LJ, Thompson IM, Reid B, Nelson P, Ransohoff DF, Welch HG, Hwang S, Berry
DA, Kinzler KW, Black WC, Bissell M, Parnes H, Srivastava S. Addressing overdiagnosis and
overtreatment in cancer: a prescription for change. Lancet Oncol. 2014;15(6):e234–42.
150 L. Klotz

14. Haffner MC, De Marzo AM, Yegnasubramanian S, Epstein JI, Carter HB. Diagnostic
challenges of clonal heterogeneity in prostate cancer. J Clin Oncol. 2015;33(7):e38–40.
15. Klotz L, Zhang L, Lam A, Nam R, Mamedov A, Loblaw A. Clinical results of long-term
follow-up of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol.
2010;28(1):126–31.
16. Klotz L, Vesprini D, Sethukavalan P, Jethava V, Zhang L, Jain S, Yamamoto T, Mamedov A,
Loblaw A. Long-term follow-up of a large active surveillance cohort of patients with prostate
cancer. J Clin Oncol. 2015;33(3):272–7.
17. Bul M, Zhu X, Valdagni R, Pickles T, Kakehi Y, Rannikko A, Bjartell A, van der Schoot DK,
Cornel EB, Conti GN, Boevé ER, Staerman F, Vis-Maters JJ, Vergunst H, Jaspars JJ, Strölin P,
van Muilekom E, Schröder FH, Bangma CH, Roobol MJ. Active surveillance for low-risk
prostate cancer worldwide: the PRIAS study. Eur Urol. 2013;63(4):597–603.
18. Dall’Era MA, Konety BR, Cowan JE, Shinohara K, Stauf F, Cooperberg MR, Meng MV, Kane
CJ, Perez N, Master VA, Carroll PR. Active surveillance for the management of prostate can-
cer in a contemporary cohort. Cancer. 2008;112(12):2664–70.
19. Kakehi Y, Kamoto T, Shiraishi T, Ogawa O, Suzukamo Y, Fukuhara S, Saito Y, Tobisu K,
Kakizoe T, Shibata T, Fukuda H, Akakura K, Suzuki H, Shinohara N, Egawa S, Irie A, Sato T,
Maeda O, Meguro N, Sumiyoshi Y, Suzuki T, Shimizu N, Arai Y, Terai A, Kato T, Habuchi T,
Fujimoto H, Niwakawa M. Prospective evaluation of selection criteria for active surveillance
in Japanese patients with stage T1cN0M0 prostate cancer. Jpn J Clin Oncol. 2008;
38(2):122–8.
20. Tosoian JJ, Trock BJ, Landis P, et al. Active surveillance program for prostate cancer: an
update of the Johns Hopkins experience. J Clin Oncol. 2011;29:2185–90.
21. Roemeling S, Roobol MJ, de Vries SH, Wolters T, Gosselaar C, van Leenders GJ, Schröder
FH. Active surveillance for prostate cancers detected in three subsequent rounds of a screening
trial: characteristics, PSA doubling times, and outcome. Eur Urol. 2007;51(5):1244–50.
22. Soloway MS, Soloway CT, Eldefrawy A, et al. Careful selection and close monitoring of low-
risk prostate cancer patients on active surveillance minimizes the need for treatment. Eur Urol.
2010;58:831–5.
23. Patel MI, DeConcini DT, Lopez-Corona E, Ohori M, Wheeler T, Scardino PT. An analysis of
men with clinically localized prostate cancer who deferred definitive therapy. J Urol.
2004;171(4):1520–4.
24. Barayan GA, Brimo F, Bégin LR, Hanley JA, Liu Z, Kassouf W, Aprikian AG, Tanguay S.
Factors influencing disease progression of prostate cancer under active surveillance: a McGill
University Health Center Cohort. BJU Int. 2014;114:E99–104.
25. Rubio-Briones J, Iborra I, Ramírez M, Calatrava A, Collado A, Casanova J, Domínguez-Escrig
J, Gómez-Ferrer A, Ricós JV, Monrós JL, Dumont R, López-Guerrero JA, Salas D, Solsona
E. Obligatory information that a patient diagnosed of prostate cancer and candidate for an
active surveillance protocol must know. Actas Urol Esp. 2014;38:559–65.
26. Godtman RA, Holmberg E, Khatami A, Stranne J, Hugosson J. Outcome following active
surveillance of men with screen-detected prostate cancer. Results from the Göteborg ran-
domised population-based prostate cancer screening trial. Eur Urol. 2013;63(1):101–7.
27. Thomsen FB, Røder MA, Hvarness H, Iversen P, Brasso K. Active surveillance can reduce
overtreatment in patients with low-risk prostate cancer. Dan Med J. 2013;60(2):A4575.
28. Selvadurai ED, Singhera M, Thomas K, Mohammed K, Woode-Amissah R, Horwich A,
Huddart RA, Dearnaley DP, Parker CC. Medium-term outcomes of active surveillance for
localised prostate cancer. Eur Urol. 2013;64:981–7.
29. Eggener SE, Mueller A, Berglund RK, Ayyathurai R, Soloway C, Soloway MS, Abouassaly R,
Klein EA, Jones SJ, Zappavigna C, Goldenberg L, Scardino PT, Eastham JA, Guillonneau
B. A multi-institutional evaluation of active surveillance for low risk prostate cancer. J Urol.
2013;189(1 Suppl):S19–25. discussion S25.
30. Hayes JH, Ollendorf DA, Pearson SD, Barry MJ, Kantoff PW, Stewart ST, Bhatnagar V,
Sweeney CJ, Stahl JE, McMahon PM. Active surveillance compared with initial treatment for
men with low-risk prostate cancer: a decision analysis. JAMA. 2010;304(21):2373–80.
10 Current Status of Clinical Trials in Active Surveillance 151

31. Popiolek M, Rider JR, Andrén O, Andersson SO, Holmberg L, Adami HO, Johansson
JE. Natural history of early, localized prostate cancer: a final report from three decades of
follow-up. Eur Urol. 2013;63(3):428–35.
32. Kryvenko ON, Carter HB, Trock BJ, Epstein JI. Biopsy criteria for determining appropriateness
for active surveillance in the modern era. Urology. 2014;83(4):869–74.
33. Porten SP, Whitson JM, Cowan JE, Cooperberg MR, Shinohara K, Perez N, Greene KL, Meng
MV, Carroll PR. Changes in prostate cancer grade on serial biopsy in men undergoing active
surveillance. J Clin Oncol. 2011;29(20):2795–800.
34. Dall’Era MA, Cowan JE, Simko J, Shinohara K, Davies B, Konety BR, Meng MV, Perez N,
Greene K, Carroll PR. Surgical management after active surveillance for low-risk prostate
cancer: pathological outcomes compared with men undergoing immediate treatment. BJU Int.
2011;107(8):1232–7.
35. Choo R, Danjoux C, Morton G, Szumacher E, Sugar L, Gardner S, Kim M, Choo CM, Klotz L.
How much does Gleason grade of follow-up biopsy differ from that of initial biopsy in untreated,
Gleason score 4–7, clinically localized prostate cancer? Prostate. 2007;67(15):1614–20.
36. Bratt O, Folkvaljon Y, Loeb S, Klotz L, Egevad L, Stattin P. Upper limit of cancer extent on
biopsy defining very low risk prostate cancer. BJU Int. 2015 Aug;116(2):213–9.
37. Sundi D, Ross AE, Humphreys EB, Han M, Partin AW, Carter HB, Schaeffer EM. African
American men with very low-risk prostate cancer exhibit adverse oncologic outcomes after
radical prostatectomy: should active surveillance still be an option for them? J Clin Oncol.
2013;31(24):2991–7.
38. Odom BD, Mir MC, Hughes S, Senechal C, Santy A, Eyraud R, Stephenson AJ, Ylitalo K,
Miocinovic R. Active surveillance for low-risk prostate cancer in African American men: a
multi-institutional experience. Urology. 2014;83(2):364–8.
39. Zlotta AR, Egawa S, Pushkar D, Govorov A, Kimura T, Kido M, Takahashi H, Kuk C, Kovylina
M, Aldaoud N, Fleshner N, Finelli A, Klotz L, Sykes J, Lockwood G, van der Kwast
TH. Prevalence of prostate cancer on autopsy: cross-sectional study on unscreened Caucasian
and Asian men. J Natl Cancer Inst. 2013;105(14):1050–8.
40. Stephenson A, Klotz L. Comparative propensity analysis of active surveillance vs initial
treatment. AUA 2013.
41. Cooperberg MR, Cowan JE, Hilton JF, Reese AC, Zaid HB, Porten SP, Shinohara K, Meng
MV, Greene KL, Carroll PR. Outcomes of active surveillance for men with intermediate-risk
prostate cancer. J Clin Oncol. 2011;29(2):228–34.
42. Ploussard G, Isbacbrrn H, Briganti A, Sooriakumaran P, Surcel CI, Salomon L, Freschi M,
Mirvald C, van der Poel HG, Jenkins A, Ost P, van Oort IM, Yossepowitch O, Giannarini G,
van den Bergh RC. Can we expand active surveillance criteria to include biopsy Gleason 3 + 4
prostate cancer? A multi-institutional study of 2,323 patients. Urol Oncol. 2015;33:71.e1–9.
pii: S1078-1439(14)00263-4.
43. Vargas HA, Akin O, Afaq A, Goldman D, Zheng J, Moskowitz CS, Shukla-Dave A, Eastham
J, Scardino P, Hricak H. Magnetic resonance imaging for predicting prostate biopsy findings
in patients considered for active surveillance of clinically low risk prostate cancer. J Urol.
2012;188(5):1732–8.
44. Da Rosa MR, Milot L, Sugar L, Vesprini D, Chung H, Loblaw A, Pond GR, Klotz L, Haider MA.
A prospective comparison of MRI-US fused targeted biopsy versus systematic ultrasound-
guided biopsy for detecting clinically significant prostate cancer in patients on active surveil-
lance. J Magn Reson Imaging. 2015;41(1):220–5.
45. Mullins JK, Bonekamp D, Landis P, Begum H, Partin AW, Epstein JI, Carter HB, Macura
KJ. Multiparametric magnetic resonance imaging findings in men with low-risk prostate
cancer followed using active surveillance. BJU Int. 2013;111(7):1037–45.
46. Shakir NA, George AK, Siddiqui MM, Rothwax JT, Rais-Bahrami S, Stamatakis L, Su D,
Okoro C, Raskolnikov D, Walton-Diaz A, Simon R, Turkbey B, Choyke PL, Merino MJ,
Wood BJ, Pinto PA. Identification of threshold prostate specific antigen levels to optimize the
detection of clinically significant prostate cancer by magnetic resonance imaging/ultrasound
fusion guided biopsy. J Urol. 2014;192(6):1642–8.
152 L. Klotz

47. Krakowsky Y, Loblaw A, Klotz L. Prostate cancer death of men treated with initial active
surveillance: clinical and biochemical characteristics. J Urol. 2010;184(1):131–5.
48. Loblaw A, Zhang L, Lam A, Nam R, Mamedov A, Vesprini D, Klotz L. Comparing prostate
specific antigen triggers for intervention in men with stable prostate cancer on active surveil-
lance. J Urol. 2010;184(5):1942–6.
49. Vickers A. Systematic review of pretreatment PSA velocity and doubling time as PCA predictors.
J Clin Oncol. 2008;27:398–403.
50. Aizer AA, Gu X, Chen MH, Choueiri TK, Martin NE, Efstathiou JA, Hyatt AS, Graham PL,
Trinh QD, Hu JC, Nguyen PL. Cost implications and complications of overtreatment of
low-risk prostate cancer in the United States. J Natl Compr Canc Netw. 2015;13(1):61–8.
51. Lane JA, Donovan JL, Davis M, Walsh E, Dedman D, Down L, Turner EL, Mason MD,
Metcalfe C, Peters TJ, Martin RM, Neal DE, Hamdy FC, ProtecT study group. Active moni-
toring, radical prostatectomy, or radiotherapy for localised prostate cancer: study design and
diagnostic and baseline results of the ProtecT randomised phase 3 trial. Lancet Oncol.
2014;15(10):1109–18.
52. Parsons JK, Pierce JP, Mohler J, Paskett E, Jung SH, Humphrey P, Taylor JR, Newman VA,
Barbier L, Rock CL, Marshall J. A randomized trial of diet in men with early stage prostate
cancer on active surveillance: rationale and design of the Men’s Eating and Living (MEAL)
Study (CALGB 70807). Contemp Clin Trials. 2014;38(2):198–203.
53. Bratt O, Carlsson S, Holmberg E, Holmberg L, Johansson E, Josefsson A, Nilsson A, Nyberg
M, Robinsson D, Sandberg J, Sandblom D, Stattin P. The Study of Active Monitoring in
Sweden (SAMS): a randomized study comparing two different follow-up schedules for active
surveillance of low-risk prostate cancer. Scand J Urol. 2013;47(5):347–55.
Chapter 11
Focused Targeted Therapy in Prostate Cancer

Kevin Krughoff and Al Barqawi

Introduction

Prostate cancer is the second most common cancer in men at 28 % of all non-
cutaneous malignancies and the second most common cause of cancer death in men,
yet most men diagnosed with prostate cancer will not die of their disease [1, 2].
Partially accounting for this is the well-recognized stage migration that took place
after the advent of PSA testing, where the proportion of metastatic prostate cancer
diagnoses decreased substantially while localized disease diagnoses took prece-
dence [3]. One large-scale study demonstrated as much as a 75 % reduction in meta-
static prostate cancer diagnoses from 1993 to 2003 [4]. Given exceedingly high
prostate-cancer specific survival rates for localized disease, the push for increased
utilization of Active Surveillance (AS) instead of treatment is stronger than ever [5].
Despite this, overdiagnosis and overtreatment remain a problem, and non-curative
initial management (NCIM) strategies, either AS or watchful waiting (WW), have
for decades continued to meet minimal enrollment success [6–10]. Even though
more cancers continue to be found at lower stages and are associated with lower
PSA levels, epidemiological data demonstrates the opposite to be true with regard
to grade, a situation that would make increases in NCIM more worrisome. An
increase in Gleason 3 + 4, 4 + 3, or 8–10 has been noted in recent biopsies relative to

K. Krughoff, B.A.
1663 Vine St., Denver, CO 80206, USA
Division of Urology, Department of Surgery, University of Colorado Denver
School of Medicine, 12631 East 17th Ave., Room L15-5602, Aurora, CO 80045, USA
e-mail: [email protected]
A. Barqawi, M.D., F.R.C.S. (*)
Division of Urology, Department of Surgery, University of Colorado Denver
School of Medicine, 12631 East 17th Ave., Room L15-5602, Aurora, CO 80045, USA
e-mail: [email protected]

© Springer International Publishing Switzerland 2016 153

N.N. Stone, E.D. Crawford (eds.), The Prostate Cancer Dilemma,
DOI 10.1007/978-3-319-21485-6_11
154 K. Krughoff and A. Barqawi

1999–2001 [11]. It’s been speculated that a proposed modification to the Gleason
grading system in 2005 and the increase in the number of cores taken per biopsy may
account for this; however, the effect was documented prior to such recommendations
[12–14]. In any event, the upward trend in Gleason grading implies trouble for the
already disproportionately low AS enrollment rates as fewer men will meet eligibil-
ity criteria if grade migration continues.
Results from the more recently aggregated Michigan Urological Survey
Improvement Collaborative (MUSIC) registry are encouraging for AS enrollment,
and the reported 50 % AS enrollment amongst D’Amico low-risk patients may sug-
gest a shifting tide in AS acceptance. Long-term follow-up success remains to be
seen, however, given the sparse use of follow-up biopsy regimens in these patients
[15]. Moreover, the MUSIC registry demonstrated that AS was still a relatively
infrequent option for younger, healthier men, reflecting a not-uncommon bias
against AS use in this population and a continuing problem for AS success [16].
Data from both the Surveillance, Epidemiology, and End Results Program (SEER)
and the National Cancer Database (NCDB) did show that the proportion of men
with Gleason ≤6 cancers electing NCIM strategies increased over the last 10 years,
but when changes to the Gleason grading system were accounted for (i.e., looking
at both Gleason 6 and 7 cancers) there was no overall significant change in the pro-
portion of men using NCIM strategies. On the contrary, the proportion of men elect-
ing a surgical approach increased substantially over time [17].
As of today, most men who are diagnosed with clinically localized prostate can-
cer continue to receive radical surgical, radiation, and/or hormonal treatments, pos-
sibly due to prevailing attitudes about taking an active approach to fixing the
problem, the psychological burden of living with cancer, pressure from relatives and
friends, and a lack of clarity regarding clinical significance of individual cancer
prognosis and impact on overall mortality [17–19]. The side effect profile from
whole gland treatment arises from collateral damage to sensitive structures such as
the bladder neck, neurovascular bundles, external sphincter, and rectum.
Complication rates varies considerably across published data; however, the rates of
urinary incontinence, erectile dysfunction, and other quality-of-life-reducing side
effects and overall cost associated with these treatments remain substantial, a fact
which played heavily into the recent recommendation against routine PSA screen-
ing [20–25].
Due to a high-risk side effect profile, it has been argued that such traditional
treatment should be reserved only for men with significant risk of disease progres-
sion or relegated only to high-volume centers where surgical expertise can reduce
complication rates [20, 26]. The difficulty in doing so lies in the sheer volume of
prostatectomies that would have to be addressed by such a small proportion of sur-
geons. While approximately 60,000 prostatectomies take place in the USA every
year, less than half of these are performed by the 7 % of surgeons that one might
consider high volume (over 24 RPs per year) [27]. Robot assisted laparoscopic radi-
cal prostatectomy (RALP) became an attractive option after initial reports of less
postoperative pain, less blood loss, and shorter length of stay, and since the 2000
FDA approval of the Da Vinci surgical system 42 % of high volume surgeons have
11 Focused Targeted Therapy in Prostate Cancer 155

adopted RALP [27, 28]. To this end, RALP has demonstrated at best equivocal
continence and potency rates but with a ballooning cost increase [26].
In the face of problematic AS enrollment, the most likely scenario for men diag-
nosed with localized prostate cancer is the eventual pursuit of one of many treat-
ment options with a high side effect profile and poor cost effectiveness. Given that
most therapeutic options for localized cancer have virtually equivalent survival
rates, it is precisely this side effect profile and the post-therapeutic quality of life
(QOL) that becomes the dominant determining factor in treatment, a concept widely
reflected in the literature [29–32]. Decision-making analyses find that when patients
present with low grade prostate cancer, physicians place much more importance on
patient preferences, and one of the most important patient concerns is how QOL is
affected by treatment [33]. Of those who prefer nonsurgical options, their decision
is found to be most significantly guided by concerns surrounding the impact of
treatment on daily life [34].
Among the impacts to QOL from traditional treatments, most significant are
urinary and sexual side effects. A systematic review of 18 randomized controlled
trials and 473 observational studies found variable rates of incontinence (Table 11.1).
With regard to erectile dysfunction, results from the Prostate Cancer Outcomes
Study (PCOS) found rates ranging from 33 to 86 % depending on therapeutic
modality (Table 11.2).
With regard to recovery from such symptoms, a QOL evaluation of 580 patients
performed over 24 months following RP, EBRT, and brachytherapy found variable
results (Table 11.3).
Extended follow-up for this group was conducted out to 48 months, finding that
return to sexual function remained minimal for RP patients while EBRT subjects
began to demonstrate progressively worsening urinary function after 24 months but
steadily improved in sexual function [36].
After 15 years following patients who received RP or EBRT for clinically localized
prostate cancer, it was found that patients continue to have symptoms (Table 11.4).

Table 11.1 Incontinence RP EBRT Brachytherapy

rates—Wilt et al. [24]
5–35 % 2–6 % 2–32 %
RP radical prostatectomy, EBRT electron beam radiation therapy

Table 11.2 Erectile RP ADT WW

dysfunction rates—PCOS
58 % 86 % 33 %
[23]
ADT androgen deprivation therapy

Table 11.3 Return to baseline following therapy—Litwin et al. [37]

RP (%) EBRT (%) Brachytherapy (%)
Return to sexual function baseline 39 70 60
Return to urinary control baseline 65 95 90
156 K. Krughoff and A. Barqawi

Table 11.4 Complication RP (%) EBRT (%)

rates 15-years following
Frequent leakage or no control 18.3 9.4
therapy—Resnick et al. [39]
Bowel urgency 21.9 35.8
Poor erectile quality 87 3.9

The study by Resnick et al. demonstrates that the urinary, sexual, and bowel
related side effects only continue to decline after 2 years. In addition, the hypothesis
that men become accustomed to these problems over the years does not hold, as
bothersome indices for urinary, sexual, and bowel related side effects were shown
to steadily and consistently increase over the years [37].
When considering the side effect profiles and literature on decision making in the
face of localized prostate cancer, the demand for therapeutic options with minimal
effects on quality of life are abundantly clear, and this is the problem that focal
therapy aims to solve. By bridging the gap between surveillance and whole gland
therapy, focal therapy offers the chance for cancer control while decreasing the
common side effects associated with definitive therapy.

Patient Selection

The crux of successful focal therapy is proper patient selection and accurate identi-
fication and characterization of the lesion.
In regard to grade, many differing opinions exist on the ideal candidate for focal
therapy and inclusion criteria was initially very limited, as established by the
International Task Force on Prostate Cancer in 2007 [38]. Today, the momentum of
focal therapy is moving from clinically insignificant disease and progressing
towards prostate-confined intermediate disease [39]. In a meta-analysis of focal
therapy covering 25 studies using focal therapy in the primary setting, 5 in the sal-
vage setting, and 13 registered trials found that nearly half of focal therapy studies
employed eligibility criteria of Gleason ≤4 + 3, one-quarter used Gleason ≤3 + 4,
and the remaining used Gleason ≤3 + 3 and one of Gleason ≤8 [40].
With regard to PSA the consensus on inclusion criteria is for a PSA value <15 ng/
mL, however, some studies have used values exceeding 20 [39, 40]. The baseline
PSA may, however, be more helpful as a marker of progression rather than as a strict
inclusion criterion.
It is well known that most prostate cancer is multifocal and the issue of staging
warrants further discussion [41]. It has been demonstrated, for instance, that when
RP specimens are closely examined approximately 80 % will harbor multifocal can-
cer [42–44]. As for the nature of these secondary lesions, an analysis of 100 RP
specimens found that 43 % of secondary lesions are clinically significant [45].
Moreover, such secondary lesions are likely not restricted to one side of the prostate,
which questions the utility of hemi-ablation. While stage migration towards unilateral
11 Focused Targeted Therapy in Prostate Cancer 157

disease has been documented since the PSA era, the absolute magnitude of that
change and the overall proportion of unilateral prostate cancer are questionable
[46]. Two large pathological studies demonstrated that 14.3 % of 3676 RP speci-
mens from 1988 to 2006 were unilateral compared to just 21.3 % of 1467 RP speci-
mens from 2000 to 2007 [44, 46]. There also lies a difficulty in identifying this
population of unilateral cancers as unilateral cancer is extremely difficult to predict
based on traditional transrectal ultrasound guided (TRUS) biopsy schemes and
serum markers [47, 48].
Thus the current landscape of localized prostate cancer is one of multifocal ori-
gin, rarely limited to one side, and even if present, unlikely to be correctly identified
using the traditional tools of prostate cancer screening (i.e., TRUS biopsy and serum
markers). How, then, should focal therapy proceed?
Fortunately, the growing sense of utility for concept of focal therapy has ushered
in an impressive array of new targeting efforts. Extensive data shows that the “gold-
standard” TRUS biopsy is insufficiently accurate for the purposes of focal therapy,
even when the number of biopsy cores is advanced [49–51]. To this end, new tech-
nologies emerged that demonstrate significant advances in the accuracy of prostate
cancer localization, staging and grading (see Chaps. 6, 7 and 9). Chief among these
are transperineal template guided mapping biopsies (TPM and multiparametric
MRI (mpMRI).
The second concept of focal therapy centers around index lesion treatment rather
than curative ablation of all cancer foci—a concept that has fallen out of favor
amongst focal therapy experts [52]. The prevalence of index lesions was demon-
strated by one evaluation of 1832 whole-mount RP specimens, in which it was
found that for those with multifocal disease, 80 % of tumor burden was focused in
one dominant tumor, and in those with extracapsular extension, 92 % arose from
this same index lesion [53]. The literature on index lesion characteristics reveals
that progression-free survival is associated with index lesion volume but not with
that of the secondary tumor foci [42]. Biochemical failure was also found to be
determined by index lesion characteristics and Gleason 4/5 tumor volume, whereas
secondary tumors were insignificant in this regard [54, 55].
Evidence now suggests that metastatic potential can be directly related to the
index tumor as well. As part of the Project to Eliminate Lethal Prostate Cancer
(PELICAN), researchers analyzed single-nucleotide and copy-number polymor-
phism at 94 anatomically separate malignant cancer sites from 30 men who died of
disseminated prostate cancer, concluding that lethal prostate cancer cells can be
traced back to a common parent cell [56]. In a separate report, an extensive patho-
logical workup of metastatic prostate cancer in one man found that metastatic foci
were of the same clonal origin as a smaller secondary focus of prostate cancer.
However, a nearby larger tumor of higher Gleason grade harbored the same muta-
tion, leading the authors to believe that the clonal origin came from a small area of
this larger tumor that later developed subsequent malignant potential [57].
Researchers speculate a day where the temporal sequence of genomic lesions
might be tracked, and a “molecular time stamp” established whereby progression
could be better defined and identification and risk stratification of the index tumor
158 K. Krughoff and A. Barqawi

more accurately tailored [58]. This may become especially important in cases where
high grade tumors exist at small volumes, which has been demonstrated in other
studies [41]. If and when this may arrive is unclear, but due to the growing body of
evidence relating index tumor characteristics to overall prostate cancer behavior, the
consensus is that therapy should be directed towards identification and treatment of
the index lesion [39, 52].

Technique

The initial phase of focal therapy is accurate cancer localization; this is best per-
formed via 3-dimensional mapping biopsy (3DMB) with 3D-reconstruction or
mpMRI.
The 3D-reconstruction is usually rendered by a specialized software program
that reconstructs the cancerous foci within the prostate in three dimensions. This
virtual visual representation helps the patient and physician visualize the extent and
grade of cancer foci and tailor a treatment plan. Targeted focal therapy (TFT) usu-
ally takes place 8–12 weeks following 3DMB to allow sufficient time to account for
reduction of swelling and allow the prostate to return to its original position and
dimensions. Positioning of the prostate has been accurately obtained using at least
two fiducial markers inserted at predetermined coordinates during the mapping
biopsy; however, preliminary use of recent software advances and real-time imag-
ing suggests that the same level of accuracy can be obtained without such markers.
Patients can be treated with one of a variety of energies to achieve the aims of focal
therapy, and a variety of approaches are used based on the patient’s individual tumor
characteristics. The most commonly used ablation schemes, in order of frequency,
are focal/zonal ablation, hemi-ablation, or an extended “hockey-stick” approach
(which includes the posterior zone of the contralateral lobe), and bilateral focal
ablation [40]. Each modality has variations in approach.
During focal laser ablation patients undergo multiparametric 3.0 T prostate MRI
the day before the focal laser ablation utilizing an endorectal coil and 8-channel pelvis
phased array surface coil. Using proprietary software, 3D images from 3DMB ultra-
sound are fused with 3D rendering of the prostate by MRI to match the cancer loca-
tions from both imaging modalities. After an appropriate needle path is identified, the
patient is placed under general anesthesia in lithotomy position and a urethral catheter
is placed. A laser shelter with an MR-compatible titanium trocar is inserted transperi-
neally through the appropriate template hole and advancement is monitored using
ultrasound. The metal insert is then replaced with a laser applicator and the patient is
transferred to the MR suite for real-time MR guided laser ablation.
In the supine position T1 weighted MR imaging of the prostate is obtained to
localize and confirm the position of the laser probe and laser ablation is performed
in real-time using continuously updated MR temperature mapping using MR ther-
mometry software. Energy from the laser probe induces irreversible cell injury and
coagulative necrosis at ≥50 °C, while the surrounding area undergoes a heat-sink
11 Focused Targeted Therapy in Prostate Cancer 159

Fig 11.1 Focal laser

ablation with real-time
MRI thermal guidance.
Borders of ablation zone
are precisely visualized via
MRI, critical structures are
untouched

Fig 11.2 Targeted focal cryotherapy 3D reconstruction (left) and corresponding ablative lesion
(right)

effect and high temperatures are dissipated. Post-procedure MRI is performed with
and without IV contrast to assess ablation sites (Fig. 11.1).
Cryotherapy takes place under general anesthesia as well, and the position of the
prostate is again recreated using pre-implanted fiducial markers. Thermosensors are
placed at the apex, external sphincter, left and right neurovascular bundles, and
Denonvilliers’ fascia to monitor temperature protect these areas from damage from
the cryoprobes. In addition, a urethral continued irrigation warmer is placed to pro-
tect the urethra. Cryoprobes are placed in respective cancerous zones of the prostate
and ablation is performed using two cycles of argon gas freezing with helium thaw-
ing. This ensures that the targeted tissue reaches a temperature of −40 °C to ensure
necrosis. Real-time monitoring with US can identify the 0 °C line, 6 mm from
which exists the true −40 °C destructive zone [59]. A urethral catheter is left in place
for 1 week to minimize tissue sloughing and urinary retention (Fig. 11.2).
160 K. Krughoff and A. Barqawi

Follow-Up

Follow-up for TFT varies by institution and there is currently no standardized fol-
low-up regimen in regard to serum markers, biopsies, or imaging.
While many definitions for biochemical failure have been used, there has yet to be
established a standardized definition of biochemical failure following focal therapy
[60]. This makes sense given that various degrees of prostate tissue are ablated for each
given technique and should correlate with varying levels of baseline PSA following
each procedure. Some use the Phoenix (nadir + 2 ng/mL) or ASTRO (three consecutive
rises in PSA) to define failure after therapy; however, these were developed for RT
purposes and data exists to suggest that these may not be suitable pathological corre-
lates for recurrence in the arena of focal therapy [61]. Focal therapy encompasses many
different modalities, with options to boil, burn, freeze, necrose, or stimulate apoptosis
of cancer cells, the effects of which on PSA have yet to be determined. Due to the
expansive set of biochemical failure definitions in the literature, sensitivity analyses are
needed to determine a suitable definition of PSA failure following focal therapy.
Technological advances in MRI have increased the sensitivity and specificity for
prostate cancer to a significant degree [62]. Some advocate for the use of MRI
6 months, 2 weeks, or even immediately after surgery; however, there is again no
standard approach [63]. Even though most studies employ the use of biopsy, a
consensus on this has still yet to evolve. Given the wide array of treatment modali-
ties and quantity of prostate ablated, it is possible that there may not evolve such a
standard protocol that encompasses TFT as a whole (Table 11.5) and instead we find
that a standard set of follow-up regimens come to light to encompass for example
hemi-ablation versus focal ablation.

Future Trends and Challenges

Focal therapy seeks to achieve the trifecta of cancer control, continence, and
potency, and the cornerstone of achieving this lies in accurate identification and
ablation of cancerous zones. To this end more accurate imaging and biopsy schemes
have been developed which identify the index lesion and a variety of primary meth-
ods of ablation are employed to eradicate such lesions. In addition, focal therapy has
opened doors to new discussions on cancer management. As discussed, the aggres-
siveness of focal therapy varies from situation to situation. This, combined with the
fact that focal therapy can be applied multiple times throughout a patient’s life and/
or combined with different modalities, lends significant flexibility to the therapeutic
approach. Older comorbid men who may not be suitable for whole gland treatment
could instead opt for cancer control with a focal approach, avoiding the complica-
tions of progressive disease and the side effects of radiation therapy. At the same
time, younger men could pursue more aggressive ablative options while still pre-
serving function and living many symptom-free years.
11 Focused Targeted Therapy in Prostate Cancer 161

Table 11.5 Focal Ablation and follow-up procedures

Variation in follow-up regimens for TFT
Study Modality N Follow-up
Barret HIFU, VTP, Cryo = 50 Serial PSA and DRE at 3, 6, and 12 months then
(2013) [64] cryo, BT VTP = 23 every 6 months for 2 years, then yearly. Bx at
HIFU = 21 12 months then yearly or if BF
BT = 12
Nguyen MR-guided MR-BT = 318 PSA/DRE every 3 months for 2 years then every
(2012) [65] BT 6 months. Endorectal coil MRI if BF (PSA
increase by 2 ng/ml above nadir when
PSAV > 0.75 ng/ml per year), TRUS 12 core bx if
suspicious MRI
Ahmed Transrectal HIFU = 42 mpMRI 10–14 days s/p HIFU, at 6 months (w/
(2012) [66] HIFU targeted bx) and at 12 months. PSA at 1, 3, 6, 9,
12 months
Bahn Cryo Cryo = 73 PSA every 3–6 months. TRUS-Doppler imaging
(2012) [67] hemi-ablation every 6 months. Sextant and image-targeted bx at
6–12 months, then yearly or as indicated
Truesdale Unilateral Cryo = 77 Physical exam and PSA at 3 and 6 months, then
(2010) [61] nerve-sparing every 6 months. 12 core TRUS-bx if clinical
cryo suspicion of recurrence based on abnormal DRE,
biochemical failure (nadir + 2 ng/mL) or as
otherwise indicated
Lambert US guided Cryo = 25 PE and PSA at 3, 6, and 12 months then every
(2007) [68] percutaneous 6 months thereafter. 12-core bx if BF (PSA nadir
cryo plus 2 ng/mL or PSA nadir of less than 50 %)
Muto HIFU Whole Sextant bx and testosterone level at 6 and
(2008) [69] HIFU = 41 12 months. PSA at 3, 6, 12, 18, 24, and
Focal 36 months. BF = 3 consecutive increases in PSA
HIFU = 29 after a nadir
Ellis Focal cryo Cryo = 60 PSA at 3, 6, 9, 12 months and ever 6 months
(2007) [70] thereafter. bDFS = 3 successive rises in PSA
HIFU high-intensity focused ultrasound, VTP vascular targeted photodynamic therapy, BT
brachytherapy, MR-BT magnetic resonance-guided brachytherapy, US ultrasound, bx biopsy, BF
biochemical failure, bDFS biochemical disease-free status

While further refinement of focal therapy techniques continues to demonstrate

improvement in the side effect profile of focal therapy, and data such as that in the
COLD registry continues to demonstrate that treatment goals are being met, the
methods, modalities, and follow-up regimens employed in focal therapy vary sub-
stantially across studies. For focal therapy to succeed, the multitude of practitioners
involved in its use need to establish common ground for the evaluation of oncologi-
cal and functional success. Until that happens, success will continue to be evaluated
in a piecemeal approach, hindering consensus on the state of focal therapy. There
exists a strong need for sensitivity analyses of biomarkers and/or investigation into
pretest driven monitoring approaches which can more accurately guide follow-up.
162 K. Krughoff and A. Barqawi

In addition, the current momentum of focal therapy is to include more intermediate

risk patients, and for the purposes of comparison of long-term data and analyzing
outcomes, more universalized eligibility criteria should be established.
With regard to pathological aspects of focal therapy, the definition of the index
lesion is still problematic. Where once it was defined simply as the largest lesion, an
idea is emerging that it may not be the size so much as the dominant aggressive
clone that should count as the index lesion [42, 56, 58]. Furthermore, the concept
that treatment of the index lesion corresponds to treatment of the cancer as a whole
has not been proven, and it remains to be seen whether or not the potentially lethal
clone can be reliably identified.
Multifocality is also a concern, and while the aforementioned evidence suggests
that treating the index tumor alone guides progression and prognosis, the nature of
the field effect and the behavior of small lesions potentially left behind during index
lesion treatment require further study, despite consensus on the appropriateness of
this approach [52]. The analogy of focal therapy as “male lumpectomy” has met
criticism due to the fact that a pillar of breast lumpectomy is adjuvant therapy. The
argument for chemopreventative considerations following focal therapy is valid due
to the multifocal nature of prostate cancer and these options should be pursued.
New markers continue to be developed that can reduce negative biopsies and
help differentiate patients suitable for AS from those requiring further biopsy for
focal or radical therapy [71, 72]. Others may aid in assessing the probability that
high grade prostate cancer exists in a given patient, or attempt to risk stratify those
with cancer into groups with less or more aggressive cancer [73, 74]. New imaging
techniques like histoscanning, shear wave elastography, may also help with
follow-up. Combined B-mode, Doppler, and contrast-enhanced US (CEUS) recently
demonstrated an 82 % detection rate [75].
Focal therapy is not without challenges, and many steps are needed to refine this
budding therapeutic option; however, the need for QOL-sparring techniques has
never been stronger. As new imaging techniques, biomolecular markers, and biopsy
strategies continue to advance, further consensus may be reached on appropriate
patient selection and treatment regimens.

References

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):

11–30. doi:10.3322/caac.21166.
2. Lu-Yao GL, Albertsen PC, Moore DF, Shih W, Lin Y, DiPaola RS, et al. Outcomes of localized
prostate cancer following conservative management. JAMA. 2009;302(11):1202–9.
doi:10.1001/jama.2009.1348.
3. Cooperberg MR, Lubeck DP, Mehta SS, Carroll PR. CaPSURE. Time trends in clinical risk
stratification for prostate cancer: implications for outcomes (data from CaPSURE). J Urol.
2003;170(6 Pt 2):S21–5. doi:10.1097/01.ju.0000095025.03331.c6. discussion S26–7.
4. Bartsch G, Horninger W, Klocker H, Pelzer A, Bektic J, Oberaigner W, et al. Tyrol Prostate
Cancer Demonstration Project: early detection, treatment, outcome, incidence and mortality.
BJU Int. 2008;101(7):809–16. doi:10.1111/j.1464-410X.2008.07502.x.
11 Focused Targeted Therapy in Prostate Cancer 163

5. Ganz PA, Barry JM, Burke W, Col NF, Corso PS, Dodson E, et al. National Institutes of Health
state-of-the-science conference: role of active surveillance in the management of men with
localized prostate cancer. Ann Intern Med. 2012;156:591–5. Available at: http://annals.org/
article.aspx?articleid=1103897.
6. Welch HG, Albertsen PC. Prostate cancer diagnosis and treatment after the introduction of
prostate-specific antigen screening: 1986-2005. J Natl Cancer Inst. 2009;101(19):1325–9.
doi:10.1093/jnci/djp278.
7. Loeb S, Bjurlin MA, Nicholson J, Tammela TL, Penson DF, Carter HB, et al. Overdiagnosis and
overtreatment of prostate cancer. Eur Urol. 2014;65(6):1046–55. doi:10.1016/j.eururo.2013.12.062.
8. Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment
of localized prostate cancer. J Clin Oncol. 2010;28(7):1117–23. doi:10.1200/JCO.2009.26.0133.
9. Harlan SR, Cooperberg MR, Elkin EP, Lubeck DP, Meng M, Mehta SS, et al. Time trends and
characteristics of men choosing watchful waiting for initial treatment of localized prostate
cancer: results from CaPSURE. J Urol. 2003;170(5):1804–7. doi:10.1097/01.
ju.0000091641.34674.11.
10. Wu X, Chen VW, Andrews PA, Chen L, Ahmed MN, Schmidit B, et al. Initial treatment pat-
terns for clinically localized prostate cancer and factors associated with the treatment in
Louisiana. J La State Med Soc. 2005;157(4):188–94.
11. Glass AS, Cowan JE, Fuldeore MJ, Cooperberg MR, Carroll PR, Kenfield SA, et al. Patient
demographics, quality of life, and disease features of men with newly diagnosed prostate can-
cer: trends in the PSA era. Urology. 2013;82(1):60–5. doi:10.1016/j.urology.2013.01.072.
12. Weiner AB, Etzioni R, Eggener SE. Ongoing Gleason grade migration in localized prostate can-
cer and implications for use of active surveillance. Eur Urol. 2014;66(4):611–2. doi:10.1016/j.
eururo.2014.02.051.
13. Epstein JI. An update of the Gleason grading system. J Urol. 2010;183(2):433–40.
doi:10.1016/j.juro.2009.10.046.
14. Crawford ED. Epidemiology of prostate cancer. Urology. 2003;62(6):3–12. doi:10.1016/j.
urology.2003.10.013.
15. Womble PR, Montie JE, Ye Z, Linsell SM, Lane BR, Miller DC, et al. Contemporary use of
initial active surveillance among men in Michigan with low-risk prostate cancer. Eur Urol.
2015;67(1):44–50. doi:10.1016/j.eururo.2014.08.024.
16. Bechis SK, Carroll PR, Cooperberg MR. Impact of age at diagnosis on prostate cancer treat-
ment and survival. J Clin Oncol. 2011;29(2):235–41. doi:10.1200/JCO.2010.30.2075.
17. Weiner AB, Patel SG, Etzioni R, Eggener SE. National trends in the management of low and
intermediate risk prostate cancer in the United States. J Urol. 2015;193(1):95–102.
doi:10.1016/j.juro.2014.07.111.
18. Chapple A, Ziebland S, Herxheimer A, McPherson A, Shepperd S, Miller R. Is “watchful waiting”
a real choice for men with prostate cancer? A qualitative study. BJU Int. 2002;90(3):257–64.
19. Latini DM, Hart SL, Knight SJ, Cowan JE, Ross PL, Duchane J, et al. The relationship between
anxiety and time to treatment for patients with prostate cancer on surveillance. J Urol.
2007;178(3):826–32. doi:10.1016/j.juro.2007.05.039.
20. Cooperberg MR. Prostate cancer: a new look at prostate cancer treatment complications. Nat
Rev Clin Oncol. 2014;1:304–5. doi:10.1038/nrclinonc.2014.58.
21. Kumar RJ, Barqawi A, Crawford ED. Adverse events associated with hormonal therapy for
prostate cancer. Rev Urol. 2005;7 Suppl 5:S37–43.
22. Nam RK, Cheung P, Herschorn S, Saskin R, Jiandong S, Klotz L, et al. Incidence of complica-
tions other than urinary incontinence or erectile dysfunction after radical prostatectomy or
radiotherapy for prostate cancer: a population-based cohort study. Lancet Oncol.
2014;15(2):223–31. doi:10.1016/S1470-2045(13)70606-5.
23. Hoffman RM, Hunt WC, Gilliland FD, Stephenson RA, Potosky AL. Patient satisfaction with
treatment decisions for clinically localized prostate carcinoma. Results from the Prostate
Cancer Outcomes Study. Cancer. 2003;97(7):1653–62. doi:10.1002/cncr.11233.
24. Wilt TJ, MacDonald R, Rutks I, Shamliyan TA, Taylor BC, Kane RL. Systematic review:
comparative effectiveness and harms of treatments for clinically localized prostate cancer. Ann
Intern Med. 2008;148(6):435–48.
164 K. Krughoff and A. Barqawi

25. Chou R, Croswell JM, Dana T, Bougatsos C, Blazina I, Fu R, et al. Screening for prostate
cancer: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med.
2011;155(11):762. doi:10.7326/0003-4819-155-11-201112060-00375.
26. Coelho RF, Rocco B, Patel MB, Orvieto MA, Chauhan S, Ficarra V, et al. Retropubic, laparo-
scopic, and robot-assisted radical prostatectomy: a critical review of outcomes reported by
high-volume centers. J Endourol. 2010;24(12):2003–15. doi:10.1089/end.2010.0295.
27. Chang SL, Kibel AS, Brooks JD, Chung BI. The impact of robotic surgery on the surgical
management of prostate cancer in the USA. BJU Int. 2015;115:929. doi:10.1111/bju.12850.
28. Nelson B, Kaufman M, Broughton G, Cookson MS, Chang SS, Herrell SD, et al. Comparison
of length of hospital stay between radical retropubic prostatectomy and robotic assisted lapa-
roscopic prostatectomy. J Urol. 2007;177(3):929–31. doi:10.1016/j.juro.2006.10.070.
29. D’Amico AV, Whittington R, Malkowicz SB, Cote K, Loffredo M, Schultz D, et al. Biochemical
outcome after radical prostatectomy or external beam radiation therapy for patients with clini-
cally localized prostate carcinoma in the prostate specific antigen era. Cancer. 2002;95(2):281–
6. doi:10.1002/cncr.10657.
30. Birkhahn M, Penson DF, Cai J, Groshen S, Stein JP, Lieskovsky G, et al. Long-term outcome
in patients with a Gleason score ≤6 prostate cancer treated by radical prostatectomy. BJU Int.
2011;108(5):660–4. doi:10.1111/j.1464-410X.2010.09978.x.
31. Sylvester JE, Grimm PD, Blasko JC, Millar J, Orio 3rd PF, Skoglund S, et al. 15-Year bio-
chemical relapse free survival in clinical Stage T1-T3 prostate cancer following combined
external beam radiotherapy and brachytherapy; Seattle experience. Int J Radiat Oncol Biol
Phys. 2007;67(1):57–64. doi:10.1016/j.ijrobp.2006.07.1382.
32. Alicikus ZA, Yamada Y, Zhang Z, Pei X, Hunt M, Kollmeier M, et al. Ten-year outcomes of
high-dose, intensity-modulated radiotherapy for localized prostate cancer. Cancer.
2011;117(7):1429–37. doi:10.1002/cncr.25467.
33. Song L, Chen RC, Bensen JT, Knafl GJ, Nielsen ME, Farnan L, et al. Who makes the decision
regarding the treatment of clinically localized prostate cancer-the patient or physician? Cancer.
2012;119(2):421–8. doi:10.1002/cncr.27738.
34. Zeliadt SB, Moinpour CM, Blough DK, Penson DF, Hall IJ, Smith JL, et al. Preliminary treat-
ment considerations among men with newly diagnosed prostate cancer. Am J Manag Care.
2010;16(5):e121–30.
35. Litwin MS, Gore JL, Kwan L, Brandeis JM, Lee SP, Withers HR, et al. Quality of life after
surgery, external beam irradiation, or brachytherapy for early-stage prostate cancer. Cancer.
2007;109(11):2239–47. doi:10.1002/cncr.22676.
36. Gore JL, Kwan L, Lee SP, Reiter RE, Litwin MS. Survivorship beyond convalescence:
48-month quality-of-life outcomes after treatment for localized prostate cancer. J Natl Cancer
Inst. 2009;101(12):888–92. doi:10.1093/jnci/djp114.
37. Resnick MJ, Koyama T, Fan K-H, Albertsen PC, Goodman M, Hamilton AS, et al. Long-term
functional outcomes after treatment for localized prostate cancer. N Engl J Med.
2013;368(5):436–45. doi:10.1056/NEJMoa1209978.
38. Eggener SE, Scardino PT, Carroll PR, Zelefsky MJ, Sartor O, Hricak H, et al. Focal therapy
for localized prostate cancer: a critical appraisal of rationale and modalities. J Urol.
2007;178(6):2260–7. doi:10.1016/j.juro.2007.08.072.
39. van den Bos W, Muller BG, Ahmed H, Bangma CH, Barret E, Crouzet S, et al. Focal therapy
in prostate cancer: international multidisciplinary consensus on trial design. Eur Urol.
2014;65(6):1078–83. doi:10.1016/j.eururo.2014.01.001.
40. Valerio M, Ahmed HU, Emberton M, Lawrentschuk N, Lazzeri M, Montironi R, et al. The role
of focal therapy in the management of localised prostate cancer: a systematic review. Eur Urol.
2014;66(4):732–51. doi:10.1016/j.eururo.2013.05.048.
41. Epstein JI, Carmichael MJ, Partin AW, Walsh PC. Small high grade adenocarcinoma of the
prostate in radical prostatectomy specimens performed for nonpalpable disease: pathogenetic
and clinical implications. J Urol. 1994;151(6):1587–92.
42. Wise AM, Stamey TA, McNeal JE, Clayton JL. Morphologic and clinical significance of
multifocal prostate cancers in radical prostatectomy specimens. Urology. 2002;60(2):264–9.
11 Focused Targeted Therapy in Prostate Cancer 165

43. Mouraviev V, Mayes JM, Sun L, Madden JF, Moul JW, Polascik TJ. Prostate cancer laterality
as a rationale of focal ablative therapy for the treatment of clinically localized prostate cancer.
Cancer. 2007;110(4):906–10. doi:10.1002/cncr.22858.
44. Tareen B, Sankin A, Godoy G, Temkin S, Lepor H, Taneja SS. Appropriate candidates for
hemiablative focal therapy are infrequently encountered among men selected for radical pros-
tatectomy in contemporary cohort. Urology. 2009;73(2):351–4. doi:10.1016/j.urology.2008.08.504.
discussion 354–5.
45. Bott SRJ, Ahmed HU, Hindley RG, Abdul-Rahman A, Freeman A, Emberton M. The index
lesion and focal therapy: an analysis of the pathological characteristics of prostate cancer. BJU
Int. 2010;106(11):1607–11. doi:10.1111/j.1464-410X.2010.09436.x.
46. Polascik TJ, Mayes JM, Sun L, Madden JF, Moul JW, Mouraviev V. Pathologic stage T2a and
T2b prostate cancer in the recent prostate‐specific antigen era: implications for unilateral abla-
tive therapy. Prostate. 2008;68(13):1380–6. doi:10.1002/pros.20804.
47. Isbarn H, Karakiewicz PI, Vogel S, Jeldres C, Lughezzani G, Briganti A, et al. Unilateral pros-
tate cancer cannot be accurately predicted in low-risk patients. Int J Radiat Oncol Biol Phys.
2010;77(3):784–7. doi:10.1016/j.ijrobp.2009.05.068.
48. Briganti A, Tutolo M, Suardi N, Gallina A, Abdollah F, Capitanio U, et al. There is no way to
identify patients who will harbor small volume, unilateral prostate cancer at final pathology.
Implications for focal therapies. Prostate. 2012;72(8):925–30. doi:10.1002/pros.21497.
49. Berg KD, Toft BG, Røder MA, Brasso K, Vainer B, Iversen P. Is it possible to predict low-
volume and insignificant prostate cancer by core needle biopsies? APMIS. 2013;121(4):257–
65. doi:10.1111/j.1600-0463.2012.02965.x.
50. Gallina A, Maccagnano C, Suardi N, Capitanio U, Abdollah F, Raber M, et al. Unilateral posi-
tive biopsies in low risk prostate cancer patients diagnosed with extended transrectal
ultrasound-guided biopsy schemes do not predict unilateral prostate cancer at radical prosta-
tectomy. BJU Int. 2012;110(2 Pt 2):E64–8. doi:10.1111/j.1464-410X.2011.10762.x.
51. Sinnott M, Falzarano SM, Hernandez AV, Jones JS, Klein EA, Zhou M, et al. Discrepancy in
prostate cancer localization between biopsy and prostatectomy specimens in patients with uni-
lateral positive biopsy: implications for focal therapy. Prostate. 2012;72(11):1179–86.
doi:10.1002/pros.22467.
52. Donaldson IA, Alonzi R, Barratt D, Barret E, Berge V, Bott S, et al. Focal therapy: patients,
interventions, and outcomes - a report from a consensus meeting. Eur Urol. 2015;67:771.
doi:10.1016/j.eururo.2014.09.018.
53. Ohori M, Eastham JA, Koh H. Is focal therapy reasonable in patients with early stage prostate
cancer (CaP): an analysis of radical prostatectomy (RP) specimens. J Urol. 2006;175(Suppl):507.
doi:10.1002/cncr.22858/full.
54. Stamey TA, McNeal JM, Wise AM, Clayton JL. Secondary cancers in the prostate do not
determine PSA biochemical failure in untreated men undergoing radical retropubic prostatec-
tomy. Eur Urol. 2001;39 Suppl 4:22–3. doi:10.1159/000052577.
55. Masterson TA, Cheng L, Mehan RM, Koch MO. Tumor focality does not predict biochemical
recurrence after radical prostatectomy in men with clinically localized prostate cancer. J Urol.
2011;186(2):506–10. doi:10.1016/j.juro.2011.03.106.
56. Liu W, Laitinen S, Khan S, Vihinen M, Kowalski J, Yu G, et al. Copy number analysis indi-
cates monoclonal origin of lethal metastatic prostate cancer. Nat Med. 2009;15(5):559–65.
doi:10.1038/nm.1944.
57. Haffner MC, Mosbruger T, Esopi DM, Fedor H, Heaphy CM, Walker DA, et al. Tracking the
clonal origin of lethal prostate cancer. J Clin Invest. 2013;123(11):4918–22. doi:10.1172/
JCI70354.
58. Barbieri CE, Demichelis F, Rubin MA. The lethal clone in prostate cancer: redefining the
index. Eur Urol. 2014;66(3):395–7. doi:10.1016/j.eururo.2013.12.052.
59. Georgiades C, Rodriguez R, Azene E, Weiss C, Chaux A, Gonzalez-Roibon N, et al.
Determination of the nonlethal margin inside the visible “ice-ball” during percutaneous
cryoablation of renal tissue. Cardiovasc Intervent Radiol. 2013;36(3):783–90. doi:10.1007/
s00270-012-0470-5.
166 K. Krughoff and A. Barqawi

60. Phillips JM, Catarinicchia S, Krughoff K, Barqawi AB. Cryotherapy in prostate cancer. J Clin
Urol. 2014;7(5):308–17. doi:10.1177/2051415814521806.
61. Truesdale MD, Cheetham PJ, Hruby GW, Wenske S, Conforto AK, Cooper AB, et al. An
evaluation of patient selection criteria on predicting progression-free survival after primary
focal unilateral nerve-sparing cryoablation for prostate cancer. Cancer J. 2010;16(5):544–9.
doi:10.1097/PPO.0b013e3181f84639.
62. Heijmink SWTPJ, Fütterer JJ, Hambrock T, et al. Prostate cancer: body-array versus endorec-
tal coil MR imaging at 3 T--comparison of image quality, localization, and staging perfor-
mance. Radiology. 2007;244(1):184–95. doi:10.1148/radiol.2441060425.
63. Muller BG, Fütterer JJ, Gupta RT, Takahashi S, Scheenen TW, Huisman HJ, et al. The role of
magnetic resonance imaging (MRI) in focal therapy for prostate cancer: recommendations
from a consensus panel. BJU Int. 2014;113:218–27. doi:10.1111/bju.12243.
64. Barret E, Ahallal Y, Sanchez-Salas R, Galiano M, Cosset JM, Validire P, et al. Morbidity of
focal therapy in the treatment of localized prostate cancer. Eur Urol. 2013;63(4):618–22.
doi:10.1016/j.eururo.2012.11.057.
65. Nguyen PL, Chen M-H, Zhang Y, Tempany CM, Cormack RA, Beard CJ, et al. Updated
results of magnetic resonance imaging guided partial prostate brachytherapy for favorable risk
prostate cancer: implications for focal therapy. J Urol. 2012;188(4):1151–6. doi:10.1016/j.
juro.2012.06.010.
66. Ahmed HU, Hindley RG, Dickinson L, Freeman A, Kirkham AP, Sahu M, et al. Focal therapy
for localised unifocal and multifocal prostate cancer: a prospective development study. Lancet
Oncol. 2012;13(6):622–32. doi:10.1016/S1470-2045(12)70121-3.
67. Bahn D, de Castro Abreu AL, Gill IS, Hung AJ, Silverman P, Gross ME, et al. Focal cryo-
therapy for clinically unilateral, low-intermediate risk prostate cancer in 73 men with a median
follow-up of 3.7 years. Eur Urol. 2012;62(1):55–63. doi:10.1016/j.eururo.2012.03.006.
68. Lambert EH, Bolte K, Masson P, Katz AE. Focal cryosurgery: encouraging health outcomes for
unifocal prostate cancer. Urology. 2007;69(6):1117–20. doi:10.1016/j.urology.2007.02.047.
69. Muto S, Yoshii T, Saito K, Kamiyama Y, Ide H, Horie S. Focal therapy with high-intensity-
focused ultrasound in the treatment of localized prostate cancer. Jpn J Clin Oncol.
2008;38(3):192–9. doi:10.1093/jjco/hym173.
70. Ellis DS, Manny TB, Rewcastle JC. Focal cryosurgery followed by penile rehabilitation as
primary treatment for localized prostate cancer: initial results. Urology. 2007;70(6 Suppl):9–
15. doi:10.1016/j.urology.2007.07.036.
71. Loeb S, Catalona WJ. The Prostate Health Index: a new test for the detection of prostate can-
cer. Ther Adv Urol. 2014;6(2):74–7. doi:10.1177/1756287213513488.
72. Crawford ED, Rove KO, Trabulsi EJ, Qian J, Drewnowska KP, Kaminetsky JC, et al.
Diagnostic performance of PCA3 to detect prostate cancer in men with increased prostate
specific antigen: a prospective study of 1,962 cases. J Urol. 2012;188(5):1726–31.
doi:10.1016/j.juro.2012.07.023.
73. Parekh DJ, Punnen S, Sjoberg DD, Asroff SW, Bailen JL, Cochran JS, et al. A multi-institutional
prospective trial in the USA confirms that the 4kscore accurately identifies men with high-grade
prostate cancer. Eur Urol. 2014. pii: S0302-2838(14)01035-5. doi: 10.1016/j.eururo.2014.10.021.
[Epub ahead of print]
74. Cooperberg MR, Simko JP, Cowan JE, Reid JE, Djalilvand A, Bhatnagar S, et al. Validation of
a cell-cycle progression gene panel to improve risk stratification in a contemporary prostatec-
tomy cohort. J Clin Oncol. 2013;31(11):1428–34. doi:10.1200/JCO.2012.46.4396.
75. Xie SW, Li HL, Du J, Xia JG, Guo YF, Xin M, et al. Contrast-enhanced ultrasonography with
contrast-tuned imaging technology for the detection of prostate cancer: comparison with conven-
tional ultrasonography. BJU Int. 2012;109(11):1620–6. doi:10.1111/j.1464-410X.2011.10577.x.
Chapter 12
Technologies and Methods in Primary
Ablation with Focal Therapy

Gary Onik

Introduction

The introduction of breast-sparing surgery (i.e., “lumpectomy”) revolutionized the

management of breast cancer. The use of lumpectomy showed that quality of life
could be optimized without compromising treatment efficacy. In 2002, Onik et al.
introduced the concept of focal therapy for prostate cancer utilizing cryosurgery,
i.e., a male lumpectomy [1]. Following the lead of breast cancer management, the
intention was to limit prostate cancer treatment morbidity while maintaining good
cancer results. A number of short term studies regarding focal therapy using a
variety of ablation methods have been reported confirming that incontinence can be
virtually eliminated as a complication of prostate cancer treatment and that potency
can be maintained in up to 85 % of patients [2–5].
These results have now established focal therapy as a major trend in prostate
cancer management, resulting in the publication of scientific articles and topical
textbooks, and the convening of international scientific forums and consensus con-
ferences of experts to define the approach [6–8].
Until recently long-term data on patients who have undergone focal therapy
has not been available. The two seminal questions associated with the strategy
have always been (1) the cancer control efficacy of focal therapy compared to
radical treatments, and (2) which patients might benefit from this conservative
approach. A recent study published by Onik et al. [9] following 70 patients treated
with focal cryoablation for an average of 10 years has shown that the results of
focal therapy can be successfully used in even medium- and high-risk patients
suggesting that better biochemical disease-free survival are obtainable in these

G. Onik, M.D. (*)

Center for High Risk and Recurrent Prostate Cancer, Carnegie Mellon University,
401 East Las Olas Blvd Suite 130-407 Ft, Lauderdale, FL 33301, USA
e-mail: [email protected]

© Springer International Publishing Switzerland 2016 167

N.N. Stone, E.D. Crawford (eds.), The Prostate Cancer Dilemma,
DOI 10.1007/978-3-319-21485-6_12
168 G. Onik

patient groups than with traditional treatments, such as robotic radical prostatectomy
and IMRT [10, 11].
This chapter which deals with the methods of primary ablation used in focal
therapy, in its narrowest terms could be a listing and discussion of the various tissue
destructive technologies now being used for focal therapy, but the real issue to be
dealt with is whether there are any lessons that can be learned from the literature as
to how to optimize the results of focal therapy in respect to whatever technology is
used. The recommendations to be made are based on my own 18-year experience
doing focal therapy. The chapter therefore proceeds as follows:
1. A review of the methods that are common to all the technologies under investigation
for performing focal therapy that might be optimized for success,
2. The techniques particular to cryoablation, as this is the only method that is
generally available for anyone contemplating starting to utilize focal therapy
clinically, and
3. A review of what the ideal technology for prostate ablation might be and a
comparison of the various technologies available.

General Issues for Optimizing Focal Therapy

Patient Population for Focal Therapy

Focal therapy has been suggested as a middle ground between active surveillance and
radical whole gland treatment. The ideal candidate according to this thinking would
therefore be the patient who has low-risk prostate cancer who chooses not to undergo
active surveillance or the patient who has eventually progressed on an active surveil-
lance program and seeks treatment. There are various methods of stratifying patients
as to risk levels based on pathology, genetic profile of the cancer, and a combination
pathologic (Gleason score), PSA, and stage (the D’Amico stratification).
From the very start of my experience with this modality I felt that focal therapy
should not be limited to patients with low grade and low volume disease but rather it
should be considered in many cases of higher grade and volume tumors. The majority
of patients who experience systemic relapse are those with higher risk disease and
were treated by IMRT or EBRT [12]. Application of focal therapy in this patient group
grew out of my experience treating patients with unresectable terminal cancer in
whom focal therapy resulted in long-term disease-free survival [13].
In a recent publication of long term which followed patients for a mean of 10
years results of focal therapy the patient population treated with focal therapy was
representative of all risk levels of disease (Table 12.1). The majority of patients
that had focal therapy had intermediate- and high-risk disease (57 %). This distri-
bution is similar to patients in other long-term series with other treatments [10, 11].
The survival curves demonstrate show that no statistically significant difference
between the risk levels in these long-term results by risk level (Fig. 12.1). Our
updated latest survival statistics are shown in Table 12.2.
12 Technologies and Methods in Primary Ablation with Focal Therapy 169

Table 12.1 Patient demographics for a representative focal therapy series

Patient demographics
Patients 70
Follow-up 8–18 years Mean 10.1 years
D’Amico risk level
Low 29
Medium 32
High 9
Gleason score
Gleason 6 or less 41
Gleason 7 24
Gleason 8 or greater 5
Stage
T1c 56
T2a 6
T2b 3
T2c 4
T4 1
PSA level at DX
Less than 10 54
10–20 13
Greater than 20 2
Adapted from Onik Gary, et al. Long-term results of optimized focal therapy
for prostate cancer: average 10-year follow-up in 70 patients. J Mens Health.
2014;11(2):64–74

Fig 12.1 Shows the Kaplan–Meier curves of 70 patients treated with focal cryoablation followed
for 10 years. There is no significant difference in BDFS between the risk groups. Adapted from
Onik G, et al. Long-term results of optimized focal therapy for prostate cancer: average 10-year
follow-up in 70 patients. J Mens Health. 2014;11(2):64–74
170 G. Onik

Table 12.2 The results of 75 patients treated with focal therapy with cryoablation follow-up
between 8–18 years with average 10-year follow-up
Results
Overall actuarial survival N = 75 71/75 (94.6 %)
Disease-specific survival N = 71 71/71 (100 %)
Biochemical disease-free survival N = 75 67/75 (90 %)
BDFS high risk (D’Amico) N = 10 9/10 (89 %)
BDFS med risk (D’Amico) N = 33 29/33 (88 %)
BDFS low risk (D’Amico) N = 32 29/32 (90 %)
P = .965 no difference risk levels
Bilateral multi focal N = 20 19/20 (95 %)
Local recurrence N = 10 9/10 (90 %)
Complications
Continent after primary procedure N = 75 75/75 100 %)—no pads
Retained potency after first treatment N = 58 53/58 (94 %)

When historical controls are examined from other long-term series reported for
RP and IMRT focal cryoablation shows at least equivalent results to traditional
therapies for all risks levels but actually improved results in medium- and high-risk
patients [10, 11]. Why this might be is discussed later in the chapter since it has
implications for the various technologies utilized for focal therapy but suffice to say
all risk levels should be considered when applying focal therapy, particularly in an
investigative setting.
A subset of high-risk patients has gross extra-capsular extension. These patients
are particularly well suited to focal ablation since ablation carried outside the mar-
gins into the peri-prostatic tissue is not difficult to accomplish (Fig. 12.2).
What about those patients that have bilateral multifocal disease? In our series we
treated 20 patients with bilateral multifocal disease with 19 of them being BDFS
at an average of 10 years (Fig. 12.3). There was no statistical difference between
bilateral multifocal and the unifocal group. Considering inclusion of these patients
it has been estimated that over 90 % of patients could be considered candidates for
focal therapy [14]. Thus it appears that focal therapy is not a marginally applicable
technique for a narrow group of patients but potentially competitive to all whole
gland radical treatments in a diverse patient population.

Patient Staging for Focal Therapy

The staging of a patient for focal therapy is the most critical issue associated with
focal therapy. Long-term results are going to be dependent on knowing the full
extent and location of a patient’s disease and adequately treating it. The more accu-
rate the localization the more targeted the approach can be applied whatever the
ablation technology being used. This ultimately will apply the destructive energy
12 Technologies and Methods in Primary Ablation with Focal Therapy 171

Fig. 12.2 (a) MRI

showing a large extra-
capsular tumor (arrow)
invading the bladder base
and left SV. Tumor was a
Gleason 10. The patient
had failed androgen
deprivation therapy. (b) CT
scan 3 years later shows
the mass is gone with
residual scar remaining.
The patient remained
disease free 8 years later

Fig. 12.3 (a) The image on the left shows a patient with bilateral multifocal disease with the posi-
tive areas indicated on the US image taken at the time of 3D Prostate Mapping Biopsy. (b) The
image on the right taken during the freezing showing a temp of +26 °C at the Neurovascular bundle
on the right and a temp of −61 °C at the left Neurovascular bundle
172 G. Onik

Fig. 12.4 On the left is a whole mount slide with a tumor outlined in white in the left peripheral
zone. The ablation probes are positioned to destroy the left side of the gland in a hemi-ablation.
Note that the probes are not optimally placed to destroy the tumor. On the right side is the same
tumor now with the probes optimally grouped to focally destroy the tumor. The power of the
3D-Mapping biopsy is the ability to target the tumor as in the right hand slide

where it is needed most improving results and limiting the extent of the ablation
needed and therefore minimizing side effects (Fig. 12.4). This is why hemi-ablation
while it seems the more conservative approach will ultimately yield poorer results
than a targeted approach.
Based on our experience the use of TRUS biopsy, even in a saturation fashion is
not adequate for staging and locating tumors for focal therapy. Our experience with
TRUS biopsy, even with an additional staging biopsy obtained on the side opposite
the known cancer prior to a hemi-ablation leads to a long-term recurrence a recur-
rence rate of 33 %. Even with a high level of expertise in TRUS with color Doppler
a recurrence rate of 25 % [3] can be expected.
The most accurate modality for staging and localization of cancer for targeting
by focal therapy is transperineal 3D-prostate mapping biopsy. This subject is well
covered in other sections of this book; however, our experience confirms that when
applied in this setting 3D-PMB lowers the long-term local recurrence rate from
33 % to just 4 %. This is consistent with the theoretical sensitivity of 95 % shown
for significant cancers in previous studies [15, 16].
I know that the major trend at academic centers is to use mpMRI and fusion
directed biopsies as the standard for guiding focal therapy but based on our experi-
ence and a review of the mpMRI literature in which mpMRI was compared to the
gold standard of RP specimens, mpMRI as it stands now, the role for mpMRI for
staging and guiding focal therapy should be approached with caution at this time.
The excellent studies by Delongchamps et al. and Bratan et al. compare mpMRI to
the gold standard of whole mount radical prostatectomy specimens [17, 18].
Delongchamps et al. show that its sensitivity for picking up clinically significant
tumors in the peripheral zone of the prostate was 85 % and just 62 % in the transi-
tion zone. These results were confirmed in a study by Bratan et al. comparing
mpMRI in 175 patients with radical prostatectomy specimens.
Focal abnormalities observed on mpMRI were localized using a 27-point
grid diagram. RP whole mount sections were digitized, and regions of cancer were
12 Technologies and Methods in Primary Ablation with Focal Therapy 173

highlighted. Focal abnormalities on mpMRI were considered true positives if their

diameters corresponded to 50–150 % with a histologic cancer in an overlapping
region. The lesson here is that based on this data there is not a 1 to 1 correlation to
prostate cancer on pathology to the lesion seen on mpMRI. This theoretically could
lead to over or under treatment of lesions based on mpMRI lesion borders.
In addition, overall mpMRI detected only 25, 48, and 71 % of Gleason 6 diam-
eter tumors <0.5, 0.5–2, and >2 cm, respectively. Taking the traditional definition of
a tumor that is 0.5 mm [19] in diameter being clinically significant, mpMRI is miss-
ing 50 % of tumors 0.5–2 cm and 30 % of those over 2 cm. Caution should be used
in discounting such large tumors even though they may be Gleason 6 now that they
may be further characterized with genetic profiling. For Gleason 7 tumors, mpMRI
detected 63, 85, and 97 % of Gleason 7 tumors, diameter tumors <0.5, 0.5–2, and
>2 cm, respectively; and 80, 93, and 100 % of Gleason 8 or greater.
At this time the use of mpMRI as the sole means of guidance for focal therapy is
most likely inadequate for reproducing the long-term results recently published
using the 3D-mapping biopsy.

The Immune Response Associated with Tumor Ablation

There is a growing body of evidence that there is a tumor-specific immune response

associated with tumor ablation particularly cryoablation. This response was first
described by Ablin et al. [20] in relation to cryoablation, who reported the sponta-
neous remission of metastatic prostate cancer after freezing of the primary tumor
for palliation. There is a growing body of literature describing this phenomenon.
The essential concept is that the dead tumor left in situ exposes unique tumor anti-
gens to the patient’s immune system, acting as an in vivo tumor vaccine. The belief
is that cryoablation, since it does not denature proteins such as heat based ablation
modalities is able to elicit this response. Whether cryoablation acts as an immune
stimulator or actual suppressant is a complex interplay of many factors which is
covered very well by Sabel [21]. An indication that cryoablation might be having
such an effect can be appreciated by the whole gland cryoablation data published
by Bahn [22] which compared favorably to our own survival data and in which
the failure rates were the same regardless of risk category. This is in contrast to
radiation and RP series whose survival curves have an ongoing downward trend
over time [23].
Literature is now emerging showing that cryoablation in combination with other
immune enhancing approaches, such as CTLA-4 blockade with drugs such as
Ipilimumab, Treg suppression with cyclophosphamide, or autologous dendritic cell
therapy, work synergistically to prevent metastatic disease or even treat existing
metastatic disease in both animals and humans [24–26].
This is perhaps the most exciting and profound aspect of focal therapy. Might the
biology of prostate cancer be manipulated by treating the primary cancer with an
immune enhancing ablation to improve overall survival?
174 G. Onik

Technical Considerations for Optimizing Focal Therapy

Using Cryoablation

Cryoablation is the ablation modality most practitioners are going to have access
to so it behooves us to consider some technical aspects of the technology that are
critical to consistently good results.
Since no imaging modality can reliably determine microscopic extra-capsular
extension, when a tumor is adjacent to structures that are known weaknesses in the
capsule, tumor destruction should be planned to prophylactically include areas of
potential extension. Such areas include the NVB or the central seminal vesicles
when cancer is in the midline and has access to the ejaculatory ducts and the apex
of the gland. This is designed to prevent local recurrences particularly in intermedi-
ate- and high-risk patients.
Another critical technical adjunct is to separate the rectum from the prostate with
a saline injection into Denonvilliers’ fascia [27] (Fig. 12.5). This technique, which
many cryosurgeons do not employ, ensures that tumors in the posterior peripheral
zone can be adequately frozen without stopping the freezing prematurely for fear of
causing rectal damage and potential urethrorectal fistula, the occurrence of which
can be virtually eliminated with this technique.
The freezing process itself has a number of important technical issues that have
to be followed for optimal results. Two freeze–thaw cycles to −40 °C has been the
standard recommended protocol [28]. However, over time we have modified our
approach and now use three freeze–thaw cycles to −10 °C. This provides equivalent
tumor destruction while minimizing the area that needs to be frozen. Cryosurgical
literature confirms that the parameters for optimal tissue destruction include a slow
passive thaw. Current cryoprobes have a warming feature to disengage them from
the tissue at the end of the last freeze. Most surgeons now use this feature to actively

Fig. 12.5 On the left is an ultrasound showing a needle placed into Denonvilliers’ fascia
(arrowheads). On the right saline has been injected markedly increasing the space between the
rectum and the prostate
12 Technologies and Methods in Primary Ablation with Focal Therapy 175

thaw the tissue to save time during the procedure, a technique which might possibly
compromise long-term results.
More than a few physicians carrying out cryoablation do not monitor tempera-
tures using just US imaging to determine the adequacy of freezing. Based on the
fact that the certain goals of temperature have to be met in order to reliably kill
prostate cancer [29] and to prevent injury to the external sphincter, temperature
monitoring is essential. Adequate temp robe monitoring is one of the most challeng-
ing technical aspects of cryoablation and literally differences of millimeters can
mean the difference between success and failure.

The Technologies of Tumor Ablation for Focal Therapy

Once the patient has been chosen and staged and the tumor is ready to be targeted
there are a number of technologies that can be used to ablate the tumor. The ideal
ablation modality should have the following characteristics:
1. Clinical evidence of efficacy,
2. Reliable tissue destruction,
3. Accurate monitoring to confirm tissue destruction and prevent complications,
4. General availability and cost effective, and
5. Ability to stimulate a tumor-specific immune response.
The main tumor ablation modalities that are available for focal therapy can be
grouped by those readily available in the USA with FDA approval and those that are
considered experimental. The former group includes cryoablation, irreversible elec-
troporation, laser ablation, and radiation. Experimental therapies include HIFU and
photodynamic therapy.

Cryoablation

Technological advances in prostate cryoablation, such as the addition of the urethral

warmer and argon based cryosurgical systems with greater freezing control helped
propel the procedure to an effective and safe alternative in treating prostate cancer.
In July 1999, prostate cryoablation was approved by Medicare as a treatment for
primary prostate cancer (removing it from the investigational category) and it is
paid for by all insurance companies.
Level one evidence is now available on the efficacy of cryoablation. Donnelly
et al. reported in 2010 a randomized study of 244 patients to either cryoablation or
external beam radiation therapy [30]. The median follow-up was 100 months. 92 %
of patients had intermediate to high-risk disease. Disease progression at 36 months
was observed in 23.9 % (PSA nadir + 2 ng/mL) of men in the cryoablation arm and
in 23.7 % (PSA nadir + 2 ng/mL) of men in the radiotherapy arm. No differences in
overall or disease-specific survival were observed. At 60 months, the observed
176 G. Onik

failure rates in the two groups were equal; but at 84 months, the observed difference
was in favor of cryoablation. At 36 months, more patients in the radiotherapy arm
had a cancer-positive biopsy (28.9 %) compared with patients in the cryoablation
arm (7.7 %). It should also be noted that in the cryoablation arm six patients
remained disease free 7–9 years later after a re-treatment with cryoablation (one of
the major advantages of this type of therapy) but were counted as failures based on
the criteria accepted at the start of the study. The authors concluded that the long-
term trend in the data favored cryoablation.
Using cryoablation a number of focal therapy series have been published and a
recent review of the focal cryo literature by Shah et al. showed 9 series of focal cryo-
ablation published with a total of 1582 patients treated [31]. The BDFS ranged from
71 to 93 % at 9–70 months follow-up. Incontinence rates were 0–3.6 % and potency
rates were 58–100 %. Urethrorectal fistula occurred in three patients (0.2 %). Ward
et al. [32] recently published data accumulated from the COLD registry, a coopera-
tive collection of outcomes from several clinicians. These data showed a marked
increase in the use of focal therapy vs whole gland cryo between 2004 and 2007.
Low-risk disease was present in 541 (47 %), intermediate risk in 473 (41 %) and 143
(12 %) had high risk, clearly indicating that practitioners felt that medium- and high-
risk patients were candidates for focal therapy. The biochemical disease-free rate at
36 months was 75.7 % using the ASTRO criteria. There was no significant difference
in results between the risk levels. In addition there was no significant difference
between whole gland cryosurgery and focal therapy (Fig. 12.6). A look at the KM

Time to Failure * (ASTRO) for Full Gland/Focal Gland by Risk

100

75
Percent Survived

50
Results stable after 24 months

25

0
0 6 12 18 20 30 35 42 48 54 60
Time in Months
Full Gland - Low Risk Full Gland - Intermediate Risk Full Gland - High Risk
Focal Gland - Low Risk Focal Gland - Intermediate Risk Focal Gland - High Risk

Fig. 12.6 This shows the Kaplan–Meier curves reported from the COLD registry for both focal
and whole gland cryoablation. Note that there is no difference in the results between risk groups
for either the full gland cryo or the focal cryo. Also note the similarities of these curves to the
curves in Fig. 12.1, where after approximately 2 years the curves flatten and maintain the same
level of success. This is a unique characteristic that has been demonstrated in all the long-term cryo
results. Adapted from Ward JF, Jones JS. Focal cryotherapy for localized prostate cancer a report
from the National Cryo On-Line database. BJU Int 2012;109:1648–1654
12 Technologies and Methods in Primary Ablation with Focal Therapy 177

curves for the various groups demonstrate stable results after 24 months, a finding
characteristic of cryoablation. The positive biopsy rate for the whole cohort was only
3.7 %. Urinary continence defined as 0 pads was 98.4 % and potency was 58.1 %.
The reliability of cryo tissue destruction is very high. In Ward et al. the overall
positive biopsy rate was just 3.7 % of 1160 patients treated. In our series we did not
have a positive biopsy in any of the frozen regions, local recurrences were found
only in previously unfrozen tissue [1]. The reliability of cryo is, however, greatly
dependent on placement of probes correctly into the cancer focus (targeted focal vs
hemi-gland ablation), the use and accuracy of temperature monitoring, the routine
use of hydro dissection of Denonvilliers’ fascia, and the freezing protocol (2–3
freezes).
Cryoablation is widely available, relatively cheap, and any practitioner can start
a cryoablation program with few barriers. Specific CPT codes for cryoablation are
available and mobile services can provide equipment on a per case basis. With US
guidance and a relatively cheap per probe cost, cryoablation is extremely cost
effective.

Irreversible Electroporation (IRE)

IRE is a non-thermal ablation modality that uses microsecond pulses of DC electrical

current to perforate the cell membrane. The animal work on prostate IRE showed it
had certain advantages in relation to prostate ablation including rapid resolution of
ablated tissue [33]. IRE being a non-thermal ablation modality spares tissue structures
such as the rectum, urethra, ejaculatory ducts, and nerves (Figs. 12.7 and 12.8).

Fig. 12.7 Pathology of the prostate taken after an IRE treatment. The arrows indicate glands that
still have their basic morphology. Ghosts of the cell nucleus can still be seen. IRE is a structure
sparing non thermal ablation which causes cell death by apoptosis
178 G. Onik

Fig. 12.8 Pathology showing an intact nerve (arrow) after an IRE treatment

There is little clinical data associated with prostate IRE; most information comes
from the treatment of pancreatic carcinoma where IRE’S structure sparing qualities
has allowed safe ablation of this disease [34]. A single study recently published by
Valerio et al. [35] reports initial results on 34 patients the majority of whom had
intermediate-risk disease (74 %). The median follow-up was 6 months. Seventeen
percent of the patients failed and went on to another therapy. Continence was 100 %
and potency was 95 % in those who were potent before treatment.
My personal unpublished experience comprises 17 patients. All were staged with
3D-PMB and 16 of the 17 had a post-op 3D-PMB to cover the area of treatment and
a 5 mm margin around it. Of the 16 patients biopsied 15 of the 16 were negative for
cancer and 1 had a residual microscopic focus. Continence was 100 % and potency
was maintained in the 14 patients who were potent preoperatively. Of interest is that
one of the patients treated was actually a whole gland treatment (Fig. 12.9) and he
regained full potency at 7 months post-IRE which would be highly unlikely if he
had been treated by whole gland cryoablation based on my experience.
IRE is a challenging technology since there is a complex interplay between the
electrical parameters such as pulse number, pulse width, voltage and the arrange-
ment and the length of the conducting portion of the probe exposed. The inability
to monitor and confirm an adequate treatment at the time of the procedure is the
biggest inadequacy of the technology although parameters for an adequate treatment
have been elucidated in prostate cancer cell studies allowing some degree of
pre-procedure planning [36].
I currently use IRE in those patients in whom the tissue sparing aspects of IRE
are important (such as patients with bilateral disease adjacent to the NVB’s) or dis-
ease adjacent to the urethra in which I am worried that the urethral warmer would
spare cancer in a cryoablation. In these setting I often combine using cryo and IRE
in the same procedure.
12 Technologies and Methods in Primary Ablation with Focal Therapy 179

Fig. 12.9 The image on the left shows a ultrasound with 12 IRE probes in place ready to treat the
whole gland in a patient with diffuse Gleason 4 + 3 cancer throughout both lobes. The image on the
right shows post IRE the gland is obscured by gas created during the treatment but color Doppler
shows the neuro vascular bundles are intact with flow still occurring (arrows). The patient had full
potency return and 7 years later maintains a PSA of .1

Compared to cryoablation the equipment is very expensive (approximate cost

$250,000) and the probe cost of $2,000/probe (2–6 probes per case) is almost
prohibitive. If you want to take advantage of IRE the best strategy is to create a
program where it is used for multiple areas of the body.
Lastly while we originally thought that IRE would provide an immunologic
response similar to cryoablation, IRE’s main cell destructive mechanism of apoptosis
is not an optimal immunologic stimulatory method and studies looking at this aspect
of IRE has been mixed.

Laser Ablation

Studies are now just emerging using laser ablation for focal therapy. The technology
is approved for general tissue ablation but not specifically for prostate and there are
currently no CPT codes for payment. The first series published with over ten patients
was reported by Lindner et al. [37]. In this study the area to be ablated was con-
firmed and targeted using MR imaging with US MRI fusion software. The proce-
dure was monitored using contrast enhanced ultrasound. Twelve patients were
treated. The procedure was well tolerated with 75 % of the patients were discharged
home without a catheter the same day. There were no perioperative complications
and minimal morbidity. All patients who were potent before the procedure main-
tained potency after the procedure. Continence was 100 %. Based on multicore total
prostate biopsy carried out at 6 months, however, only 67 % of patients were free of
tumor in the targeted area and 50 % were free of disease overall.
180 G. Onik

Laser therapy is now being carried out under MRI guidance and monitoring. By
using special MR sequences such as proton-resonance frequency (PRF) shift MR
thermometry, near real-time quantification of temperature using changes in the
phase of gradient-recalled echo (GRE) images to estimate relative temperature
changes can be made [38]. The laser being used is 980-nm diode surrounded by a
1.65-mm cooling catheter manufactured by Visualase, Inc. (Houston, TX). The
technical considerations are well beyond the scope of this chapter but I refer the
reader to the excellent review on the subject by Lee et al. [39]. In this article they
also report their first series of 23 patients of laser ablated focal therapy. The inclu-
sion criteria for the study included, a 10-year life expectancy, between one to two
focal abnormalities on mpMRI consistent with prostate cancer, no dominant Gleason
pattern 4 disease on random TRUS-guided biopsies of the normal appearing pros-
tate on mpMRI, focal abnormality on MRI <15 mm, and no Gleason score over 7.
The procedures were well tolerated with 100 % continence and no change in
sexual function. Follow-up was very short with only 14 of the patients reaching 6
month follow-up. Of the 14 patients 2 were noted to have positive biopsies (one
Gleason 6 and one Gleason 7 (3 + 4).
The trend in focal therapy as indicated by the above study is toward using MRI
guided biopsies followed by MRI guided ablation. Based on the previous discussion
of multiparametric MRI the investigators using this modality may in the end be
biasing the results against laser ablation. With that said each investigator and prac-
titioner will have to make their own judgment as to whether mpMRI guided biopsy
as the sole staging and guidance method for focal therapy is sufficient. From a cost
effectiveness and availability standpoint mpMRI guidance of focal therapy is obvi-
ously problematic. Our approach to focal therapy has always been and remains to
stage as accurately as possible and leave no known cancer untreated.
From an immunologic standpoint heating lesions are least likely to illicit a therapeu-
tic immunologic response due to the denaturing of the unique cancer protein/antigens.
As with all other focal therapy modalities, laser ablation appears to have an
excellent morbidity profile.

Focal Radiation Therapy

There is minimal data relating to the use of focal radiation therapy as the primary
treatment for prostate cancer. No studies have been carried relating to any external
beam technology for focal therapy although it appears to be technically feasible [40].
Only a few have been published on focal brachytherapy with the largest series by
Nguyen et al. [41] with 318 patients. In this study, however, there was not targeting of
specific lesion but partial treatment of the gland by just treating the peripheral zone.
With a median follow-up of 5.1 years, the BDSF for intermediate-risk cases was 73 %
at 5 years and 66 % at 8 years. High recurrence rates would be expected with such an
approach since 30 % of tumors are expected to be found in the transition zone of the
gland and would not be adequately treated with such an approach. No other series
12 Technologies and Methods in Primary Ablation with Focal Therapy 181

reporting the cancer control results of primary brachytherapy have been published as
yet. For further considerations on this topic I refer the reader to an excellent review of
the theoretical considerations of the subject by Kovacs et al. [40].
Clearly with the advent of new technologies such a proton beam therapy and the
Cyberknife trials with focal therapy using radiation will be pursued. Just as clearly,
however, the major limitations to radiation therapy, including radiation scatter, vari-
able effectiveness in high Gleason grade tumors, the delayed effect of radiation, and
dose limitations for re-treatment, make the competitiveness of this modality
questionable.

Photodynamic Therapy

Vascular-targeted photodynamic (VTP) therapy comprises three elements: a pho-

tosensitizing agent to enhance the sensitivity of tumor vasculature to light energy;
light of a specific wavelength; and sufficient oxygen to drive the reaction. VTP
uses an intravenous administered photo sensitizer. TOOKAD® Soluble (WST11)
(padeliporfin; palladium bacteriopheophorbide monolysotaurine) is the drug currently
being studied for prostate ablation. Optical fibers within hollow plastic needles
allow accurate positioning in the prostate. The light activates the TOOKAD within
the prostate, which creates reactive oxygen species that cause thrombosis within
the vessels. This results in destruction of the microvasculature with resultant depri-
vation of oxygen and destruction of the prostate cancer cells.
Azzouzi et al. [42] reported the results of 83 patients treated with VTP with
TOOKAD. The patients were divided into two main groups those treated with 4 mg/kg
and those with 6 mg/kg doses. Approximately a quarter of the patients were treated
bilaterally. At the 6-month follow-up, 61/83 (74 %) patients had negative biopsies.
The most successful group were the patients treated with 4 mg/kg TOOKAD® Soluble
and 200 J/cm light (unilateral), 38/46 of which (83 %) patients had negative biopsies
at the 6-month follow-up. Complications were in general minor and self-limited and
were felt to be related to the procedure; however, there were two complications felt to
be related to the drug itself, one of which was ischemic optic neuropathy resulting in
a visual field defect for the patient. Being dependent on a drug given systemically cre-
ates added regulatory hurdles making the availability of VTP in the near future not
likely. With many excellent alternatives for thermal and non-thermal ablation avail-
able, VTP is unlikely to gain significant interest.

High Intensity Focused US-HIFU

HIFU has a long history only second to cryoablation in follow-up and volume of
patients treated. HIFU uses sound waves to achieve coagulative necrosis and destruc-
tion of the targeted tissue by heating which denatures proteins and destroys cellular
182 G. Onik

membranes. This results in instantaneous and irreversible coagulative necrosis.

At the present time two systems are available the Sonoblate-500 produced by Focus
Surgery (Indianapolis, IN) and Ablatherm produced by EDAP TMS (Lyons, France)
for treating prostate cancer. Neither system has been approved for use in the USA,
and patients who want the treatment are taken to centers outside of the country. Due
to the limits of the ultrasound wave depth penetration there can be difficulty in ablat-
ing anterior cancers [43].
No level one data is available for HIFU but several studies treating the whole
gland report on the technology’s efficacy. A multicenter trial using the Ablatherm
was reported in 2003 [43]. Although 28 % of the patients required two treatment
sessions, 87 % of the patients had a negative biopsy with 92, 86, and 82 % in the
low-, intermediate-, and high-risk groups, respectively. Gelet et al. [44] analyzed the
long-term results in patients with low-risk disease. Patients demonstrated negative
biopsy of 78 % and 5-year disease-free survivals of 83 %, but for those in intermedi-
ate- and high-risk groups, the disease-free survival rate was just 53 and 36 %,
respectively. Blana et al. [45] reported a large group of patients with low- and
intermediate-risk disease. The overall 5-year disease-free probability was 66 %.
A number of small series have been published using HIFU as focal therapy. In 2008,
Muto et al. [46] compared the results of whole gland to hemi gland HIFU. 57 % of
the patients had whole gland therapy and 45 % focal therapy. At 12 months post
procedure whole gland patients had an 84.4 % negative biopsy rate and in the focal
therapy group 76.5 % had negative biopsy rate. The 2-year biochemical DFS rates
in patients at low, intermediate and high-risk were 85.9, 50.9 and 0 %, respectively.
No significant differences were noted in the 2-year biochemical DFS rates for the
patients at low and intermediate risk treated for the whole and hemi treated patients.
All patients were continent. Sexual potency was not evaluated. There were no major
complications.
In 2011, El Fegoun et al. [47] presented a series of 12 cases of low and intermedi-
ate risk treated with hemiablation by HIFU. The mean follow-up was 10 years.
BDFS at 5 and 10 years was 90 and 38 % with 4 of the 12 patients on hormonal
therapy. All patients were continent. Sexual function was not reported. Finally,
Ahmed et al. published two series [48, 49]. The first was in 2011, where he evalu-
ated 20 low- and intermediate-risk patients over 12 months. The protocol included
the use of MRI and transperineal biopsies with template mapping. The recurrence in
the follow-up biopsy at 6 months was 11 %, 2 of the 20 patients were incontinent
and required use of pads and 95 % maintained potency. Another series by Ahmed
et al. was published in 2012 using the Sonoblate machine [49]. 41 low- and
intermediate-risk patients were assessed during a period of 12 months. The positive
biopsy rate at 6 months was 23 %. Continence was ultimately 100 % but at 1 month
30 % of the patients were using pads and full continence was not achieved by all the
patients until 9 months post-op. In all, the focal therapy experience with HIFU is
fairly limited in numbers and follow-up. Short term positive biopsy rates appear
rather high, but the most disturbing factor is the tendency toward incontinence
requiring pads in both the short and long term.
Being a heat based ablation there would minimal positive immunologic effect
expected from HIFU treatment.
12 Technologies and Methods in Primary Ablation with Focal Therapy 183

Conclusion

Based on the current available data, focal therapy appears to offer consistent if not
superior cancer control results, compared with whole gland ablation. It accom-
plishes this with extremely low morbidity. The long-term results that are just being
reported with focal therapy can give some degree of comfort that patient outcomes
are not compromised. Many technologies are being investigated for focal therapy
and time will tell the utility of each. The most exciting future possibility associated
with focal therapy is the harnessing of a specific tumor immune response to improve
results in the high-risk patients.

References

1. Onik G, Narayan P, Vaughan D, Dineen M, Brunelle R. Focal “nerve-sparing” cryosurgery for

treatment of primary prostate cancer: a new approach to preserving potency. Urology.
2002;60:109–14.
2. Bahn DK, Silverman P, Lee Sr F, Badalament R, Bahn ED, Rewcastle JC. Focal prostate cryo-
ablation: initial results show cancer control and potency preservation. J Endourol.
2006;20:688–92.
3. Bahn D, de Castro Abreu AL, Gill IS, Hung AJ, Silverman P, Gross ME. Focal cryotherapy for
clinically unilateral, low-intermediate risk prostate cancer in 73 men with a median follow-up
of 3.7 years. Eur Urol. 2012;62:55–63.
4. de Castro Abreu AL, Bahn D, Leslie S, et al. Salvage focal and salvage total cryoablation for
locally recurrent prostate cancer after primary radiation therapy. BJU Int.
2013;112:298–307.
5. Hale Z, Miyake M, Palacios DA, Rosser CJ. Focal cryosurgical ablation of the prostate: a
single institute’s perspective. BMC Urol. 2013;13:2.
6. Ahmed HU, Arya M, Carroll PR, Emberton M, editors. Focal therapy in prostate cancer.
Chichester, West Sussex: Wiley-Blackwell; 2012.
7. van den Bos W, Muller BG, Ahmed H, et al. Focal therapy in prostate cancer: international
multidisciplinary consensus on trial design. Eur Urol. 2014;65:1084–5.
8. Bostwick DG, Waters DJ, Farley ER, et al. Group consensus reports from the Consensus con-
ference on focal treatment of prostatic carcinoma, Celebration, Florida, February 24, 2006.
Urology. 2007;70:42–4.
9. Gary O, Karen B, Matthew M, David B, David V, Jeff B, et al. Long-term results of optimized
focal therapy for prostate cancer: average 10-year follow-up in 70 patients. J Mens Health.
2014;11(2):64–74.
10. Alicikus ZA, Yamada Y, Zhang Z, et al. Ten-year outcomes of high-dose, intensity-modulated
radiotherapy for localized prostate cancer. Cancer. 2011;117:1429–37.
11. Ginzburg S, Nevers T, Staff I, et al. Prostate cancer biochemical recurrence rates after robotic-
assisted laparoscopic radical prostatectomy. JSLS. 2012;16:443–50.
12. Onik G, Vaughan D, Lotenfoe R, Dineen M, Brady J. “Male lumpectomy”: focal therapy for
prostate cancer using cryoablation. Urology. 2007;70(6 Suppl):16–21.
13. Onik G, Rubinsky B, Zemel R, et al. Ultrasound guided hepatic cryosurgery in the treatment
of metastatic colon carcinoma: Preliminary results. Cancer. 1991;67:901–7.
14. Singh PB, Anele C, Dalton E, et al. Prostate cancer tumour features on template prostate map-
ping biopsies: implications for focal therapy. Eur Urol. 2014;66(1):12–9.
15. Crawford ED, Wilson SS, Torkko KC, et al. Clinical staging of prostate cancer: a computer-
simulated study of transperineal prostate biopsy. BJU Int. 2005;96:999–1004.
184 G. Onik

16. Crawford ED, Rove KO, Barqawi AB, et al. Clinical-pathologic correlation between transperineal
mapping biopsies of the prostate and three-dimensional reconstruction of prostatectomy
specimens. Prostate. 2013;73:778–87.
17. Delongchamps NB, Beuvon F, Eiss D, et al. Multiparametric MRI is helpful to predict tumor
focality, stage, and size in patients diagnosed with unilateral low-risk prostate cancer. Prostate
Cancer Prostatic Dis. 2011;14:232–7.
18. Bratan F, Niaf E, Melodelima C, et al. Influence of imaging and histological factors on prostate
cancer detection and localisation on multiparametric MRI: a prospective study. Eur Radiol.
2013;23:2019–29.
19. Noguchi M, Stamey TA, McNeal JE, Nolley R. Prognostic factors for multifocal prostate
cancer in radical prostatectomy specimens: lack of significance of secondary cancers. J Urol.
2003;170:459–63.
20. Ablin RJ, Fontana G. Cryoimmunotherapy: continuing studies toward determining a rational
approach for assessing the candidacy of the prostatic cancer patient for cryoimmunotherapy
and postoperative responsiveness. An interim report. Cryobiology. 1980;17:170–7.
21. Sabel MS. Cryo-immunology: a review of the literature and proposed mechanisms for stimula-
tory versus suppressive immune responses. Cryobiology. 2009;58:1–11.
22. Bahn DK, Lee F, Badalament R, Kumar A, Greski J, Chernick M. Targeted cryoablation of the
prostate: 7-year outcomes in the primary treatment of prostate cancer. Urology. 2002;60:3–11.
23. Grimm P, Billiet I, Bostwick D, et al. Comparative analysis of prostate-specific antigen free
survival outcomes for patients with low, intermediate and high risk prostate cancer treatment
by radical therapy. Results from the Prostate Cancer Results Study Group. BJU Int.
2012;109:22–9.
24. Waitz R, Solomon SB, Petre EN, et al. Potent induction of tumor immunity by combining
tumor cryoablation with anti-CTLA-4 therapy. Cancer Res. 2012;72:430–9.
25. Kawano M, Nishida H, Nakamoto Y, Tsumura H, Tsuchiya H. Cryoimmunologic antitumor
effects enhanced by dendritic cells in osteosarcoma. Clin Orthop Relat Res. 2010;46.
26. Niu L-Z, Li J-L, Zeng J-Y, Feng M, et al. Combination treatment with comprehensive cryoab-
lation and immunotherapy in metastatic hepatocellular cancer. World J Gastroenterol.
2013;19(22):3473–80.
27. Onik G, Narayan P, Brunelle R, Vaughn D, Dineen M, Brown T. Saline injection into
Denonvilliers’ fascia during prostate cryosurgery. J Min Inv Ther Relat Tech. 2000;6:423–7.
28. Tatsutani K, Rubinsky B, Onik G, Dahiya R, Narayan P. The effect of thermal variables on
frozen human primary prostatic adenocarcinoma cells. Urology. 1996;48(3):441–7.
29. Larson TR, Rrobertson DW, Corica A, Bostwick DG. In vivo interstitial temperature mapping
of the human prostate during cryosurgery with correlation to histopathologic outcomes.
Urology. 2000;55(4):547–52.
30. Donnelly BJ, Saliken JC, Brasher PM, et al. A randomized trial of external beam radiotherapy
versus cryoablation in patients with localized prostate cancer. Cancer. 2010;116:323–30.
31. Shah TT, Ahmed H, Kanthabalan A, Lau B, Ghei M, Maraj B, et al. Focal cryotherapy of
localized prostate cancer: a systematic review of the literature. Expert Rev Anticancer Ther.
2014;14(11):1337–47.
32. Ward JF, Jones JS. Focal cryotherapy for localized prostate cancer a report from the National
Cryo On-Line database. BJU Int. 2012;109:1648–54.
33. Onik G, Mikus P, Rubinsky B. Irreversible electroporation: implications for prostate ablation.
Technol Cancer Res Treat. 2007;6:295–300.
34. Martin 2nd RC, McFarland K, Ellis S, Velanovich V. Irreversible electroporation therapy in
the management of locally advanced pancreatic adenocarcinoma. J Am Coll Surg. 2012;
215(3):361–9.
35. Valerio M, Stricker PD, Ahmed HU. Dick Initial assessment of safety and clinical feasibility
of irreversible electroporation in the focal treatment of prostate cancer. Prostate Cancer
Prostatic Dis. 2014;17(4):343–7.
36. Rubinsky B, Onik G, Mikus P. Irreversible electroporation: a new ablation modality—clinical
implications. Technol Cancer Res Treat. 2007;6(1):37–48.
12 Technologies and Methods in Primary Ablation with Focal Therapy 185

37. Lindner U, Weersink RA, Haider MA, Gertner MR, Davidson SR, Atri M, et al. Image guided
photothermal focal therapy for localized prostate cancer: phase I trial. J Urol. 2009;182(4):
1371–7.
38. Rieke V, Vigen KK, Sommer G, et al. Referenceless PRF shift thermometry. Magn Reson
Med. 2004;51:1223–31.
39. Lee T, Mendhiratta N, Sperling D, Lepor H. Focal laser ablation for localized prostate cancer:
principles, clinical trials, and our initial experience. Rev Urol. 2014;16(2):55–66.
40. Kovács G, Cosset JM, Carey B. Focal radiotherapy as focal therapy of prostate cancer. Curr
Opin Urol. 2014;24:231–5.
41. Nguyen PL, Chen MH, Zhang Y, et al. Updated results of magnetic resonance imaging guided
partial prostate brachytherapy for favorable risk prostate cancer: implications for focal therapy.
J Urol. 2012;188:1151–6.
42. Azzouzi AR, Barret E, Moore CM, Villers A, Allen C, Scherz A, et al. TOOKAD(®) Soluble
vascular-targeted photodynamic (VTP) therapy: determination of optimal treatment conditions
and assessment of effects in patients with localised prostate cancer. BJU Int. 2013;112(6):766–74.
doi:10.1111/bju.12265.
43. Thüroff S, Chaussy C, Vallancien G, et al. High-intensity focused ultrasound and localized
prostate cancer: efficacy results from the European multicentric study. J Endourol. 2003;
17(8):673–7.
44. Gelet A, Chapelon JY, Poissonier L, et al. Prostate cancer control with transrectal HIFU in 242
consecutive patients: 5-year results. Eur Urol. 2004;3(Suppl):214.
45. Blana A, Murat FJ, Walter B, et al. First analysis of the long-term results with transrectal HIFU
in patients with localised prostate cancer. Eur Urol. 2008;53(6):1194–203.
46. Muto S et al. Focal therapy with high-intensity focused ultrasound in the treatment of localized
prostate cancer. Jpn J Clin Oncol. 2008;38:192–9.
47. Fegoun E et al. Focal therapy with high intensity focused ultrasound for prostate cancer in the
elderly. A feasibility study with 10 years follow-up. Int Braz J Urol. 2011;37:213–22.
48. Ahmed HU et al. Focal therapy for localized prostate cancer: a phase I/II trial. J Urol.
2010;185:1246–54.
49. Ahmed HU, Hindley RG, Dickinson L, et al. Focal therapy for localised unifocal and multifocal
prostate cancer: a prospective development study. Lancet Oncol. 2012;13(6):622–32.
Chapter 13
Multiparametric MRI (mpMRI): Guided
Focal Therapy

Michele Fascelli, Amichai Kilchevsky, Arvin K. George, and Peter A. Pinto

Introduction

Approximately one in seven men will be diagnosed with prostate cancer (PCa) dur-
ing his lifetime, with roughly 50 % of newly diagnosed patients presenting with
low-risk disease features [1]. The ubiquitous use of PSA screening has been respon-
sible for increased rates of cancer detection, with concurrent increase of definitive
therapy, namely radical prostatectomy (RP) and radiation therapy (RT). Increasing
rates of treatment for clinically localized prostate cancer via RP or RT have caused
both escalating healthcare costs and patient morbidity, including erectile dysfunc-
tion, urinary incontinence, and anxiety associated with decreased quality of life [2].
Approximately half of all men enrolled in the European Randomized Study for
Screening Prostate Cancer (ERSPC) trial underwent surgery for cancers found to
meet criteria for “clinically indolent disease” (<0.5 cm3 tumor volume, organ con-
fined, and Gleason score ≤6) [3]. Focal therapy thus emerged as a safe treatment
alternative to spare patients the morbidity of established definitive treatment meth-
ods while preserving oncologic control.
The Prostate Intervention Versus Observation Trial (PIVOT) was among the first
studies to reveal a limited benefit of treatment in the subset of patients identified by PSA

Electronic supplementary material: The online version of this chapter (doi:10.1007/978-3-

319-21485-6_13) contains supplementary material, which is available to authorized users. Videos
can also be accessed at http://link.springer.com/chapter/10.1007/978-3-319-21485-6_13.
M. Fascelli, B.A. • A. Kilchevsky, M.D. • A.K. George, M.D.
Urologic Oncology Branch, National Cancer Institute—National Institutes of Health,
9000 Rockville Pike, Building 10, Room 1-5940, Bethesda, MD 20892, USA
e-mail: [email protected]; [email protected]; [email protected]
P.A. Pinto, M.D. (*)
Prostate Cancer Division, Urologic Oncology Branch, National Cancer Institute,
10 Center Drive, MSC 1210, Bethesda, MD 20892-1210, USA
e-mail: [email protected]

© Springer International Publishing Switzerland 2016 187

N.N. Stone, E.D. Crawford (eds.), The Prostate Cancer Dilemma,
DOI 10.1007/978-3-319-21485-6_13
188 M. Fascelli et al.

and TRUS biopsy [4]. PIVOT elucidated the role of observation in the management of
patients with low-grade, low-volume disease, discouraging unnecessary biopsies and
treatment-related morbidity without tangible benefit; however, many patients ultimately
go on to definitive therapy because of uncertainty regarding the reliability of PSA and
random biopsies for detecting lethal cancers and reluctance to defer treatment.
Fundamental to the application of focal therapy is reliable and accurate imaging
to patient selection, treatment guidance, and patient follow-up while preserving
oncologic efficacy, sexual potency, and urinary continence. Multiparametric mag-
netic resonance imaging (mpMRI), an imaging modality demonstrating improved
detection rates of prostate cancer, has been utilized to guide clinical decision-
making, touting accurate tumor localization and improved staging of disease [5–8].
The parameters of mpMRI include: T2-weighted imaging (T2W), dynamic contrast
enhancement (DCE), apparent diffusion coefficient (ADC) on diffusion weighted
imaging (DWI), and MR spectroscopic imaging (MRSI) (Fig. 13.1). T2W imaging,

Fig. 13.1 Example of multiparametric MRI and all parameters. A 78-year-old male was referred to
our institution for elevating PSA, measured at 6.21 ng/mL at time of biopsy. Multiparametric MRI
revealed a 4.8 cm lesion encompassing most of the peripheral zone, positive on all mpMRI parame-
ters: T2 (a), diffusion weighted imaging (b), permeability mapping on dynamic contrast enhancement
(c), and MR spectroscopy (d). In (d), the yellow box in the upper right corner depicts the choline (cho)
and citrate (cit) peaks measured for the yellow/green square highlighted in the prostate imaged. This
patient had a high choline–citrate ratio, consistent with a positive MR spectroscopy parameter
13 Multiparametric MRI (mpMRI): Guided Focal Therapy 189

reflecting tissue water content, provides the highest spatial resolution and zonal
anatomy. DWI reflects the diffusion of water within tissue and is given an order of
magnitude, referred to as the apparent diffusion coefficient (ADC); diffusion of
water is restricted within tumors representing hypercellularity, making DWI very
sensitive for detecting cancers, especially in the peripheral zone of the prostate.
Moreover, lower ADC values on DWI correlate with higher Gleason grade at histol-
ogy, allowing for risk stratification of patients. Dynamic contrast enhanced MRI
consists of a series of fast T1-weighted sequences before and after injection of con-
trast, assessing the focal kinetics of enhancement within prostatic lesions. Lastly,
MRSI detects relative levels of the prostate metabolites, choline and citrate, in
which altered concentrations exist in benign and malignant disease. Among these
parameters, MRSI is the least often employed, and current protocols have moved
away from it due to limited additional benefits when accounting for time and cost.
MpMRI has reliably shown diagnostic accuracy with an ability to localize dis-
ease and correctly characterize and identify multifocal disease using its multiple
parameters. Success utilizing mpMRI stems from accurate disease localization and
subsequent histopathological correlation, reliable identification of index lesions,
and matching the tumor volumes of these suspicious lesions to their final pathology,
therein providing ample measurement when applying therapies.
MpMRI may specifically identify those patients harboring intermediate–high-
grade, high-volume disease who would benefit from definitive treatment, simultane-
ously reducing unnecessary detection of patients with low-grade, low-volume
disease. Correlating histological lesions and MRI findings had been previously dif-
ficult to determine as angles varied between section intervals on MRI images and
prostatectomy specimens. Despite this hurdle, the Turkbey et al. group corrected for
this variability with a shrinkage factor as well as co-registration between histology
and imaging; furthermore, in order to confirm the accuracy of mpMRI targeted
lesions, the group assessed cancer detection using whole mount sectioning from
customized three-dimensional prostatic molds to register specimen pathology and
MRI [9]. Cancer detection using whole mount sectioning from the 3D prostatic
molds allowing registration between specimen pathology and MRI found that
mpMRI had high sensitivity for tumors larger than 5 mm in diameter and with
Gleason scores greater than 3 + 4 = 7, while low suspicious lesions identified on MRI
reliably represented benign tissue or low-grade prostate cancer [9, 10]. Additionally,
mpMRI has shown superiority in predicting active surveillance eligibility (no tumor
larger than 0.5 cc or possessing any Gleason 4 or 5 pattern disease) with sensitivity
and overall accuracy of 93 and 92 %, respectively [8]. These findings suggest that
imaging supplements clinicopathologic criteria and improves disease identification
in patients while encouraging a potential union of mpMRI and focal therapy.
Focal therapy operates on the pathophysiologic principle of prostate cancer exist-
ing as a multifocal disease, wherein the highest suspicious lesions identified on imag-
ing can be defined as index lesions, or those responsible for driving disease biology,
and thus targeted for curative treatment. Targeted biopsy of MR-identified lesions is
becoming the new standard technique for diagnosis of any prostate cancer and of
clinically significant prostate cancer [11]. Baco and colleagues posited that index
190 M. Fascelli et al.

lesions could be precisely identified on multiparametric MRI in comparison to radical

prostatectomy specimen, yielding successful characterization of 95 % (128/135) of
males with high concordance (κ = 0.76) between primary Gleason pattern on targeted
biopsy and RP specimen, and suggesting there exist means to identify disease using
diagnostic imaging to provide pertinent prognostic information [12]. Several groups
have shown mpMRI does reliably estimate index lesion tumor volumes and these
mpMRI estimates correlated with histopathologic volumes [13, 14].
Different focal therapy techniques for localized disease have emerged as poten-
tial means to eradicate these foci of cancer, including cryotherapy, high-intensity
focused ultrasound (HIFU), and laser interstitial therapy. The objective of this chap-
ter is to review the current status and role of multiparametric magnetic resonance
imaging in these focal therapy techniques.

Cryotherapy

Cryotherapy, also known as cryoablation or cryosurgery, is a thermoablative tech-

nique using rapid cycles of freezing and thawing of cells to induce coagulative
necrosis at targeted areas. First described in the 1850s when James Arnott used ice-
salt mixtures to treat cancers, cryoablation underwent drastic modernization by
Irving Cooper in the 1960s when the use of liquid nitrogen was adopted [15, 16]. By
2008, the American Urologic Association acknowledged cryotherapy as a treatment
option for newly diagnosed or recurrent organ-confined prostate cancer [17].
Typically, cryotherapy is performed using transrectal ultrasound (TRUS)-guided
needles inserted via a transperineal approach. Pressurized gases that freeze (argon)
and actively warm (helium) are used, operating under the Joule–Thompson effect
wherein different gases undergo temperature changes when depressurized. Ice crys-
tals form in targeted cells surrounding argon-based probes, reaching temperatures
lower than −40 °C, and causing rapid thermal expansion. Thawing of the ice crys-
tals induces cell damage and death by dehydration, protein denaturation, and cell
membrane rupture; localized glandular ischemia and microthrombi also occur as a
result of vascular stasis [18].
More recently, improved control of freezing and thawing has been coupled with
MRI thermometry. MRI thermometry serves a unique advantage over ultrasound,
accurately detecting temperature changes in real-time and allowing intraoperative
assessment of tissue damage (Fig. 13.2). During the freezing, the location of the
probe tip is considered the most effective region for therapy and therefore depends
upon accurate visualization of technique and treatment. On real-time MRI, “ice-
balls” formed by application of cryoprobe tips to cancerous lesions can be seen as a
signal void due to the absence of free hydrogen atoms in frozen tissue water. This
tracking information allows the cryotherapy operator to determine the distance and
extent of treatment coverage. The iceball needs to extend beyond the border of the
tumor in order to fully treat all margins of disease [19]. Should the iceball configu-
ration inadequately cover the area of gland in question, the probe position could be
13 Multiparametric MRI (mpMRI): Guided Focal Therapy 191

Fig. 13.2 Sagittal view of MR thermometry. Sagittal view of T2 MR pre-ablation (a) with the
laser probe visible in the prostate and post-ablation (b). MR thermometry allows real-time
temperature mapping during this focal laser ablation (c), later providing a post-ablation tissue
damage map (d)

readjusted in real-time. Moreover, if the ice ball is seen approaching the rectal wall,
then the corresponding cryoprobe could be slowed down or stopped [20].
MRI compatible cryoprobes used in liver and kidney cancer treatment, as well as
experimental robots used to insert needles into the prostate, have allowed for more
development of MRI-real time monitoring and technique application to patients
[21, 22]. Early work done in canine models using 0.5 T MRI showed technically
feasible MRI-guided cryosurgery, but initial cryoprobes scattered T1 and T2 signals
[23, 24]. Information from canine models revealed that T1 sequences of MRI did
not reliably correlate tissue necrosis volume with that induced. Rather, contrast-
enhanced sequences were more consistent at predicting tissue damage after cryosur-
gery with an accuracy rate of 91 % (Pearson r2 = 0.97) [24].
192 M. Fascelli et al.

Initial work done in 29 patients with prostate cancer using MRI-guided cryosur-
gery has revealed minor complications, including hematuria, dysuria, scrotal pain,
and urinary retention [20, 25] while reporting one major instance of urethrorectal
fistula that healed within 3 months of surgery [20]. MRI guidance instead of tran-
srectal ultrasound allows for insertion of a rectal balloon with warm saline to protect
the rectal wall from freezing. Additionally, published follow-up literature has shown
these initial cohorts had no change in erectile function but worsening incontinence
in three of 18 patients [25].
There is a paucity of long-term follow-up in patients receiving prostate cryoabla-
tion with MRI guidance as primary treatment for prostate cancer thereby making
long-term outcomes difficult to assess. In fact, only Gangi et al. looked at cancer
recurrence in this patient population. While the researchers did not routinely per-
form a systematic post-cryoablation prostate biopsy as part of the study, follow-up
MRI revealed no suspected region for remaining prostate cancer in any of the 11
treated patients [20]. The hope is that their long-term results will be as good, if not
better, than the previous cohort of patients treated with cryoablation. In that popula-
tion, a multicenter registry (the Cryoablation-On-Line-Database registry) has
reported pooled 5-year biochemical disease-free rate using the Phoenix definition of
nadir plus 2 as: 91 % in the low-risk group at 5 years, 78 % in the intermediate-risk
group, and 62 % in the high-risk group [26].

High-Intensity Focal Ultrasound

High-intensity focal ultrasound (HIFU) is a minimally invasive procedure directing

increased intensity ultrasound waves compared to those used during imaging explo-
ration. Ultrasound waves are focused on specific pathologic regions from a trans-
ducer, generating high local tissue temperatures. Absorbed ultrasound energy is
rapidly converted to heat in prostatic tissue, via a thermal effect, yielding cellular
disruption and coagulative necrosis. Tissue is heated for approximately 5 seconds,
attaining temperatures up to 90 °C (194 °F), and its focal application to targets
allows for preservation of the surrounding tissue. In addition to the thermal effect of
HIFU, cavitation results from ultrasound waves interacting with intraprostatic,
intracellular water to cause microbubbles, which are responsible for dispersion of
energy and enhancement of tissue ablation. Use of ultrasound waves to destroy
human tissue was first proposed in the 1940s by John G. Lynn before its implemen-
tation in soft-tissue tumor ablation in the 1950s, followed by the use of MRI guid-
ance with HIFU in prostate cancer in the 1990s [27–30].
While MRI-guided HIFU is not approved in the USA as of 2015, the therapy is
approved for use in 30 countries and clinical trials are underway. The utility of MRI-
guided HIFU is in real-time monitoring using quantitative MRI thermometry to
report tissue temperature and ensure accurate ablation without compromising other
key structures of the pelvis, including the urethra and neurovascular bundles [31].
Additionally, coregistration of ultrasound and mpMRI has been used in identifying
13 Multiparametric MRI (mpMRI): Guided Focal Therapy 193

treatment margins, up to 5 mm in one study [31], both prior to and during HIFU
therapy [32–34], providing a means for serial follow-up imaging to detect recur-
rence and to assess need for re-treatment.
Prior work applying MRI-guided focused ultrasound that led to its application in
prostate cancer was performed in uterine fibroids before extending to other organs,
including breast, liver, and bone [35–38]. Preliminary work in canine prostate mod-
els again confirmed the feasibility of MRI-guided HIFU with small transition zones
between ablated and viable tissue ranging from 0.4 to 2.0 mm [39–41]. Two cohorts
of males underwent initial MRI-guided HIFU in 2010 prior to radical prostatec-
tomy; approximately 30 % of the prostate volume was ablated post-prostatectomy
with no complications during or after surgery [40, 42]. MRI guidance proved to be
advantageous in overcoming rectal damage and urethral damage previously docu-
mented in patients undergoing HIFU sans MRI [43]. Despite this, the initial cohorts
did reveal technological limitations: average ablation times were extensive, ranging
from 2–2.5 hours, with incidental peaks greater than 6 hours [44] and tumor and
prostate mobility allowed aberrant movement to create focal spot losses and mis-
align treatment. A similar study by Napoli et al. found no evidence of disease on
follow-up MRI or residual viable tumor in the ablation area on final pathology [31].
However, histologic examination revealed a nonsignificant bilateral residual tumor
according to the Epstein criteria outside the treated area in three out of five patients
and bilateral Gleason 7 tumor in the other two patients.
HIFU has also been implicated in a promising future clinical application with
targeted drug delivery. It has been proposed that systemic therapeutic agents, like
chemotherapy, can be delivered to the body in encapsulated form and then stimu-
lated to locally release upon activation by the heat from the mechanical oscillation
of the focused ultrasound waves [45].

Laser Interstitial Therapy

Laser interstitial therapy (LIT) is also commonly referred to as focal laser ablation
(FLA). This thermoablative technique employs high-energy laser light to generate
rapid heat and incite coagulation in target tissue. Previously popularized as a means
to destroy hepatic and renal lesions, most recent adaptations of FLA in tumor
destruction have arisen in the field of neuro-oncology, with applications in several
brain lesions—both primary gliomas and cerebral metastases have been treated with
promising outcomes [46]. First attempts at FLA of prostate cancer were documented
in the 1980s when neodymium-doped yttrium aluminum garnet (Nd:YAG) lasers
were employed, but FLA has since come to use 980 nm diode lasers [47–49]. Energy
is delivered to the prostate using transperineally inserted laser fibers that produce
and spread laser energy from the fiber tip through the immediate surrounding
absorption zone, causing an increase in temperature to exposed tissues. Initial
results in canine and cadaveric prostate models demonstrated easy handling and
good penetrating laser fiber power [50–52].
194 M. Fascelli et al.

The first patients to undergo FLA under MRI-guidance did so in 2010, using a
1.5 T MRI, 980 nm diode lasers, and the assistance of MRI thermometry, similar to
cryoablation. Both of these males underwent in-bore treatment, were discharged
within 3 hours of undergoing therapy, and suffered no adverse events within 1
month of follow-up [49]. The application of transperineal focal laser treatment in
these two patients represented initial feasibility work with regard to this focal ther-
apy technique. Subsequently, in-gantry multiparametric MRI was employed to
locate tumors, guide laser placement, and confirm optical laser application. Use of
MRI thermometry provided precise assessment of ablated zones. Use of post-
treatment multiparametric MRI therefore should be able to confirm overlap of can-
cerous lesions and necrotic areas [53] (Fig. 13.3).
Since its inception, results of phase I laser interstitial therapy trials have shown
potential, as developments of phase II trials are underway. Two phase I trials con-
cluded in 2013, applying laser interstitial therapy to a total of 47 men. In one study,
seven of nine showed no signs of cancer at the ablation site after 6 months of follow-
up, while the remaining two individuals showed recurrence of Gleason 3 + 3 disease
[54]. The second study reported nearly identical results, mirroring minimal compli-
cations post-treatment; the group published that 26 % of their 38 male cohort
showed positive biopsy at the time of their 4-month follow-up appointment, with no
incidences of incontinence, rectal wall injury, or other complications [55]. Both
study groups on retrospective review cited failure to completely cover the lesions
using the ablation zone produced by FLA as likely cause for cancer recurrence.
A concern about the accuracy of ablation zones therefore arises as MRI-identified
tumor volumes must correlate with treatment volumes for sufficient treatment appli-
cation. Preclinical trials were performed in dogs and rats; these studies aimed to
assess efficacy of FLA prior to their human counterparts. One study in dogs showed
that histological examination of ablation zones consistently showed central areas of
unviable tissue surrounded by coagulative necrosis and strong correlations of ther-
mal damage on MRI thermometry and post-treatment MRI volume with histologic
volumes (r2 = 0.94) [51]. A study in rats found that the mean necrosis volume on
MRI at 48 hours after FLA strongly correlated with histologic volumes as well,
again revealing ellipsoid lesions consistent with coagulative necrosis [56]. In an
early case series, ablated volumes measured on MRI correlated strongly with the
ablation volume in four patients who underwent FLA 1 week prior to RP [57].
These pathology findings support accurate volume correlations and have since
spurred assessment of mpMRI in distinguishing tissue response to treatment.
MpMRI modalities, including T2 and ADC, were analyzed for co-occurrence of
tissue-specific responses and indicated to have a high sensitivity for identifying
change in tissue patterns [58]. This suggests that mpMRI alone may continue to
improve in hopes of functioning as a sole quantitative assessment of prostate cancer
burden in post-focal therapy patients, in addition to aid in clinical planning and
treatment application.
Major criticism of these initial studies has come from inconsistent selection cri-
teria for men treated with FLA. Generally, patients have low to intermediate-risk
prostate cancer: PSA <15 ng/mL, Gleason score 6–7, and clinical stage T1c–T2a;
disease burden assessed by mpMRI is fundamental to determining eligibility and
13 Multiparametric MRI (mpMRI): Guided Focal Therapy 195

Fig. 13.3 Example of Focal Laser Ablation (FLA). A 58-year-old gentleman presented with mul-
tiple prior negative biopsies, an elevated PSA, as high as 12.7 ng/mL, and referred for mulitpara-
metric MRI. On imaging, he was found to have a 1.3 cm lesion in the right apical to mid-central
gland lesion; preoperative T2 (a) and DWI (b) sequences of his multiparametric MRI are shown.
On biopsy, he was found to have Gleason 3 + 3 = 6 disease. He consented for focal laser ablation.
Images 1 day post-treatment (T2 in (c), DWI in (d)) and at 1 year of follow-up (T2 in (e), DWI in
(f)) are also shown. At 1 year of follow-up, his imaging reported diffuse hypointensity suggestive
of tissue necrosis in the ablated area. Subsequent multiparametric MRI/TRUS fusion-guided
biopsy of the target did not show disease

planning treatment as FLA maximum ablation zones have been cited to be up to

approximately 2 cm3 [59]. As such, patient selection and treatment planning addi-
tionally require specialized prostate MRI radiologists that work in conjunction with
urologists, merging anatomical location of lesions on mpMRI with those on prostate
biopsy. During the FLA, radiologists aid in MRI thermometry interpretation and
further assist with laser repositioning feedback; this highlights the dependence of
FLA on MRI in gantry performance of focal therapy (Video 13.1).
196 M. Fascelli et al.

Acutely, the side-effect profile of FLA appears to be minimal, but long-term onco-
logical outcomes remain to be seen. The short treatment times, MRI-visualized dis-
tinct ablation zones, and promising success rates using real-time MRI remain key
features of laser ablation therapy, as future work hopes to elucidate the therapeutic
efficacy of laser interstitial therapy. At present, post-treatment quality of life scores do
not suggest a significant change from baseline in symptom scores or mean sexual
function scores [60]. Phase II trials to investigate oncologic efficacy are in progress.

Future Directions

Other focal therapies are on the verge of development, similarly utilizing multipara-
metric MRI to benefit patient selection, treatment application, and assess outcomes.
One such example is focal photodynamic therapy whereby free radicals and antioxi-
dant enzymes are stimulated from the interaction of light from laser fibers and pho-
tosensitive agents administered orally or intravenously [61]. Reactive oxidative
species directly induce damage to tumor cells, propagating cell apoptosis and necro-
sis and producing an acute inflammatory reaction. This cytotoxic method of induced
cell destruction requires intraprostatic fibers to target lesions in a darkened room
under MRI guidance, allowing for strong correlation between MRI-volumes and
lesion targeting [62]. Several agents currently under investigation include temopor-
fin, padoporfin, and padeliporfin. Concerns with these agents include vessel con-
striction and thrombosis [63].
Similarly, use of localized radiation sources can be placed near or inside the
treatment area, as is the case for brachytherapy and brachytherapy seed implanta-
tion. MRI guidance of seed implantation aided in MRI-guided microwave and
radiofrequency ablation techniques. The first focal therapy modality, microwave
ablation, applies an applicator emitting electromagnetic waves that generate heat
and cause tissue destruction. These electromagnetic waves, however, can create
noise and interfere with the MRI signals themselves. Initial work regarding the
signal-to-noise ratio and accuracy of MRI thermometry revealed a negative influ-
ence in patient outcomes [64]. Radiofrequency ablation (RFA) utilized a needle
electrode inserted into tumor to again use electromagnetic waves producing friction-
generated rising of temperature and subsequent cell death. MRI-guided prostate
RFA is still very limited, but initial work in liver malignancies showed technical
feasibility with no signal-to-noise effects [65].

Conclusion

Use of mpMRI and focal therapy techniques employed in targeting other types of
malignancies (i.e., breast, liver cancer) provide promise in developing new alterna-
tive therapies applicable to prostate cancer in hope of replacing current standards of
13 Multiparametric MRI (mpMRI): Guided Focal Therapy 197

care, including surgical intervention and radiation therapy. Focal therapy was once
referred to as the “lumpectomy” of prostate cancer [66], as urologists hope to hone
multiparametric magnetic resonance imaging, providing better detection of disease,
localization and extent of disease involvement, and spatial accuracy to determine
optimal candidates for targeted therapy. By melding imaging and intervention in a
minimally invasive and centralized manner, these focal therapy techniques and tech-
nologies will continue to improve; more results of long-term oncologic outcomes
will aid in clinical decision-making for improved patient disease management.

Disclosures This work was supported by the Intramural Research Program of the National
Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research, and the Center
for Interventional Oncology. NIH and Philips Healthcare have a cooperative research and develop-
ment agreement. NIH and Philips share intellectual property in the field.
This work was also made possible through the National Institutes of Health Medical Research
Scholars Program, a public–private partnership supported jointly by the NIH and generous contri-
butions to the Foundation for the NIH from Pfizer Inc., The Doris Duke Charitable Foundation, The
Alexandria Real Estate Equities, Inc. and Mr. and Mrs. Joel S. Marcus, and the Howard Hughes
Medical Institute, as well as other private donors. For a complete list, please visit the Foundation
website at: http://fnih.org/work/education-training-0/medical-research-scholars-program.

References

1. Klotz L. Active surveillance: patient selection. Curr Opin Urol. 2013;23(3):239–44.

2. Chou R, Croswell JM, Dana T, Bougatsos C, Blazina I, Fu R, et al. Screening for prostate
cancer: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med.
2011;155(11):762–71.
3. Schröder FH, Hugosson J, Roobol MJ, Tammela TLJ, Zappa M, Nelen V, et al. Screening and
prostate cancer mortality: results of the European Randomised Study of Screening for Prostate
Cancer (ERSPC) at 13 years of follow-up. Lancet. 2014;384(9959):2027–35.
4. Wilt TJ, Brawer MK, Jones KM, Barry MJ, Aronson WJ, Fox S, et al. Radical prostatectomy
versus observation for localized prostate cancer. N Engl J Med. 2012;367(3):203–13.
5. Stephenson SK, Chang EK, Marks LS. Screening and detection advances in magnetic reso-
nance image-guided prostate biopsy. Urol Clin North Am. 2014;41(2):315–26.
6. Da Rosa MR, Milot L, Sugar L, Vesprini D, Chung H, Loblaw A, et al. A prospective compari-
son of MRI-US fused targeted biopsy versus systemic ultrasound-guided biopsy for detecting
clinically significant prostate cancer in patients on active surveillance. J Magn Reson Imaging.
2014;21:00.
7. Fradet V, Kurhanewicz J, Cowan JE, Karl A, Coakley FV, Shinohara K, et al. Prostate cancer
managed with active surveillance: role of anatomic MR imaging and MR spectroscopic imag-
ing. Radiology. 2010;256(1):176–83.
8. Turkbey B, Rastinehad AR, Linehan WM, Wood BJ, Pinto PA. Prostate cancer: can multipa-
rametric MR imaging help identify patients who are candidates for active surveillance?
Radiology. 2013;268(1):144–52.
9. Turkbey B, Mani H, Shah V, Rastinehad AR, Bernardo M, Pohida T, et al. Multiparametric 3T
prostate magnetic resonance imaging to detect cancer: histopathological correlation using
prostatectomy specimens processed in customized magnetic resonance imaging based molds.
J Urol. 2011;186(5):1818–24.
10. Yerram NK, Volkin D, Turkbey B, Nix J, Hoang AN, Vourganti S, et al. Low suspicion lesions
on multiparametric magnetic resonance imaging predict for the absence of high-risk prostate
cancer. BJU Int. 2012;110(11 Pt B):E783–8.
198 M. Fascelli et al.

11. Siddiqui MM, Rais-Bahrami S, Turkbey B, George AK, Rothwax J, Shakir N, et al. Comparison
of MR/ultrasound fusion–guided biopsy with ultrasound-guided biopsy for the diagnosis of
prostate cancer. JAMA. 2015;313(4):390.
12. Baco E, Ukimura O, Rud E, Vlatkovic L, Svindland A, Aron M, et al. Magnetic resonance
imaging-transectal ultrasound image-fusion biopsies accurately characterize the index tumor:
correlation with step-sectioned radical prostatectomy specimens in 135 patients. Eur Urol.
2014;17.
13. Turkbey B, Mani H, Aras O, Rastinehad AR, Shah V, Bernardo M, et al. Correlation of mag-
netic resonance imaging tumor volume with histopathology. J Urol. 2012;188(4):1157–63.
14. Cornud F, Khoury G, Bouazza N, Beuvon F, Peyromaure M, Flam T, et al. Tumor target vol-
ume for focal therapy of prostate cancer-does multiparametric magnetic resonance imaging
allow for a reliable estimation? J Urol. 2014;191(5):1272–9.
15. Cooper SM, Dawber RP. The history of cryosurgery. J R Soc Med. 2001;94(4):196–201.
16. Copper IS. Cryogenic surgery: a new method of destruction or extirpation of benign or malig-
nant tissues. N Engl J Med. 1963;268:743–9.
17. Finley DS, Pouliot F, Miller DC, Belldegrun AS. Primary and salvage cryotherapy for prostate
cancer. Urol Clin North Am. 2010;37(1):67–82. Table of Contents.
18. Rees J, Patel B, MacDonagh R, Persad R. Cryosurgery for prostate cancer. BJU Int.
2004;93(6):710–4.
19. Tatli S, Acar M, Tuncali K, Morrison PR, Silverman S. Percutaneous cryoablation techniques
and clinical applications. Diagn Interv Radiol. 2010;16(1):90–5.
20. Gangi A, Tsoumakidou G, Abdelli O, Buy X, de Mathelin M, Jacqmin D, et al. Percutaneous
MR-guided cryoablation of prostate cancer: initial experience. Eur Radiol. 2012;22(8):1829–35.
21. Abdelaziz S, Esteveny L, Renaud P, Bayle B, Barbé L, De Mathelin M, et al. Design consider-
ations for a novel MRI compatible manipulator for prostate cryoablation. Int J Comput Assist
Radiol Surg. 2011;6(6):811–9.
22. Caviezel A, Terraz S, Schmidlin F, Becker C, Iselin CE. Percutaneous cryoablation of small
kidney tumours under magnetic resonance imaging guidance: medium-term follow-up. Scand
J Urol Nephrol. 2008;42(5):412–6.
23. Josan S, Bouley DM, van den Bosch M, Daniel BL, Butts PK. MRI-guided cryoablation: In vivo
assessment of focal canine prostate cryolesions. J Magn Reson Imaging. 2009;30(1):169–76.
24. Van den Bosch MAAJ, Josan S, Bouley DM, Chen J, Gill H, Rieke V, et al. MR imaging-
guided percutaneous cryoablation of the prostate in an animal model: in vivo imaging of
cryoablation-induced tissue necrosis with immediate histopathologic correlation. J Vasc Interv
Radiol. 2009;20(2):252–8.
25. Woodrum DA, Kawashima A, Karnes RJ, Davis BJ, Frank I, Engen DE, et al. Magnetic reso-
nance imaging-guided cryoablation of recurrent prostate cancer after radical prostatectomy:
initial single institution experience. Urology. 2013;82(4):870–5.
26. Babaian RJ, Donnelly B, Bahn D, Baust JG, Dineen M, Ellis D, et al. Best practice statement
on cryosurgery for the treatment of localized prostate cancer. J Urol. 2008;180:1993–2004.
27. Lynn JG, Zwemer RL, Chick AJ. The biological application of focused ultrasonic waves.
Science. 1942;96(2483):119–20.
28. Bradley WG. MR-guided focused ultrasound: a potentially disruptive technology. J Am Coll
Radiol. 2009;6(7):510–3.
29. Hynynen K, Damianou C, Darkazanli A, Unger E, Schenck JF. The feasibility of using MRI to
monitor and guide noninvasive ultrasound surgery. Ultrasound Med Biol. 1993;19(1):91–2.
30. Cline HE, Hynynen K, Watkins RD, Adams WJ, Schenck JF, Ettinger RH, et al. Focused US
system for MR imaging-guided tumor ablation. Radiology. 1995;194(3):731–7.
31. Napoli A, Anzidei M, De Nunzio C, Cartocci G, Panebianco V, De Dominicis C, et al. Real-
time magnetic resonance-guided high-intensity focused ultrasound focal therapy for localised
prostate cancer: preliminary experience. Eur Urol. 2013;63(2):395–8.
32. Dickinson L, Ahmed HU, Kirkham AP, Allen C, Freeman A, Barber J, et al. A multi-centre
prospective development study evaluating focal therapy using high intensity focused ultrasound
for localised prostate cancer: the INDEX study. Contemp Clin Trials. 2013;36(1):68–80.
13 Multiparametric MRI (mpMRI): Guided Focal Therapy 199

33. Dickinson L, Hu Y, Ahmed HU, Allen C, Kirkham AP, Emberton M, et al. Image-directed,
tissue-preserving focal therapy of prostate cancer: a feasibility study of a novel deformable
magnetic resonance-ultrasound (MR-US) registration system. BJU Int. 2013;112(5):594–601.
34. Partanen A, Yerram NK, Trivedi H, Dreher MR, Oila J, Hoang AN, et al. Magnetic resonance
imaging (MRI)-guided transurethral ultrasound therapy of the prostate: a preclinical study
with radiological and pathological correlation using customised MRI-based moulds. BJU Int.
2013;112(4):508–16.
35. Funaki K, Fukunishi H, Sawada K. Clinical outcomes of magnetic resonance-guided focused
ultrasound surgery for uterine myomas: 24-month follow-up. Ultrasound Obstet Gynecol.
2009;34(5):584–9.
36. Furusawa H, Namba K, Thomsen S, Akiyama F, Bendet A, Tanaka C, et al. Magnetic
resonance-guided focused ultrasound surgery of breast cancer: reliability and effectiveness. J
Am Coll Surg. 2006;203(1):54–63.
37. Liberman B, Gianfelice D, Inbar Y, Beck A, Rabin T, Shabshin N, et al. Pain palliation in
patients with bone metastases using MR-guided focused ultrasound surgery: a multicenter
study. Ann Surg Oncol. 2009;16(1):140–6.
38. Kopelman D, Inbar Y, Hanannel A, Dank G, Freundlich D, Perel A, et al. Magnetic resonance-
guided focused ultrasound surgery (MRgFUS). Four ablation treatments of a single canine
hepatocellular adenoma. HPB (Oxford). 2006;8(4):292–8.
39. Jolesz FA. MRI-guided focused ultrasound surgery. Annu Rev Med. 2009;60:417–30.
40. Siddiqui K, Chopra R, Vedula S, Sugar L, Haider M, Boyes A, et al. MRI-guided transurethral
ultrasound therapy of the prostate gland using real-time thermal mapping: initial studies.
Urology. 2010;76(6):1506–11.
41. Chopra R, Burtnyk M, N’djin WA, Bronskill M. MRI-controlled transurethral ultrasound ther-
apy for localised prostate cancer. Int J Hyperthermia. 2010;26(8):804–21.
42. Chopra R, Colquhoun A, Burtnyk M, N’djin WA, Kobelevskiy I, Boyes A, et al. MR imaging-
controlled transurethral ultrasound therapy for conformal treatment of prostate tissue: initial
feasibility in humans. Radiology. 2012;265(1):303–13.
43. Rouvière O, Souchon R, Salomir R, Gelet A, Chapelon J-Y, Lyonnet D. Transrectal high-
intensity focused ultrasound ablation of prostate cancer: effective treatment requiring accurate
imaging. Eur J Radiol. 2007;63(3):317–27.
44. Uchida T, Shoji S, Nakano M, Hongo S, Nitta M, Murota A, et al. Transrectal high-intensity
focused ultrasound for the treatment of localized prostate cancer: eight-year experience. Int J
Urol. 2009;16(11):881–6.
45. Deckers R, Rome C, Moonen CTW. The role of ultrasound and magnetic resonance in local
drug delivery. J Magn Reson Imaging. 2008;27(2):400–9.
46. Rahmathulla G, Recinos PF, Kamian K, Mohammadi AM, Ahluwalia MS, Barnett GH. MRI-
guided laser interstitial thermal therapy in neuro-oncology: a review of its current clinical
applications. Oncology. 2014;87(2):67–82.
47. Sander S, Beisland HO. Laser in the treatment of localized prostatic carcinoma. J Urol.
1984;132(2):280–1.
48. Sander S, Beisland HO, Fossberg E. Neodymion YAG laser in the treatment of prostatic can-
cer. Urol Res. 1982;10(2):85–6.
49. Raz O, Haider MA, Davidson SRH, Lindner U, Hlasny E, Weersink R, et al. Real-time mag-
netic resonance imaging-guided focal laser therapy in patients with low-risk prostate cancer.
Eur Urol. 2010;58(1):173–7.
50. Woodrum DA, Gorny KR, Mynderse LA, Amrami KK, Felmlee JP, Bjarnason H, et al.
Feasibility of 3.0T magnetic resonance imaging-guided laser ablation of a cadaveric prostate.
Urology. 2010;75(6):1514.e1–6.
51. Stafford RJ, Shetty A, Elliott AM, Klumpp SA, McNichols RJ, Gowda A, et al. Magnetic reso-
nance guided, focal laser induced interstitial thermal therapy in a canine prostate model.
J Urol. 2010;184(4):1514–20.
52. Peters RD, Chan E, Trachtenberg J, Jothy S, Kapusta L, Kucharczyk W, et al. Magnetic reso-
nance thermometry for predicting thermal damage: an application of interstitial laser coagula-
tion in an in vivo canine prostate model. Magn Reson Med. 2000;44(6):873–83.
200 M. Fascelli et al.

53. Hoang AN, Volkin D, Yerram NK, Vourganti S, Nix J, Linehan WM, et al. Image guidance in
the focal treatment of prostate cancer. Curr Opin Urol. 2012;22(4):328–35.
54. Oto A, Sethi I, Karczmar G, McNichols R, Ivancevic MK, Stadler WM, et al. MR imaging-
guided focal laser ablation for prostate cancer: phase I trial. Radiology. 2013;267(3):932–40.
55. Cepek J, Chronik BA, Lindner U, Trachtenberg J, Davidson SRH, Bax J, et al. A system for
MRI-guided transperineal delivery of needles to the prostate for focal therapy. Med Phys.
2013;40(1):012304.
56. Colin P, Nevoux P, Marqa M, Auger F, Leroy X, Villers A, et al. Focal laser interstitial thermo-
therapy (LITT) at 980 nm for prostate cancer: treatment feasibility in Dunning R3327-AT2 rat
prostate tumour. BJU Int. 2012;109(3):452–8.
57. Lindner U, Lawrentschuk N, Weersink RA, Davidson SRH, Raz O, Hlasny E, et al. Focal laser
ablation for prostate cancer followed by radical prostatectomy: validation of focal therapy and
imaging accuracy. Eur Urol. 2010;57(6):1111–4.
58. Viswanath S, Toth R, Rusu M, Sperling D, Lepor H, Futterer J, et al. Identifying quantitative
in vivo multi-parametric MRI features for treatment related changes after laser interstitial ther-
mal therapy of prostate cancer. Neurocomputing. 2014;144:13–23.
59. Wenger H, Yousuf A, Oto A, Eggener S. Laser ablation as focal therapy for prostate cancer.
Curr Opin Urol. 2014;24(3):236–40.
60. Lee T, Mendhiratta N, Sperling D, Lepor H. Focal laser ablation for localized prostate cancer:
principles, clinical trials, and our initial experience. Rev Urol. 2014;16(2):55–66.
61. Bozzini G, Colin P, Nevoux P, Villers A, Mordon S, Betrouni N. Focal therapy of prostate
cancer: energies and procedures. Urol Oncol. 2013;31(2):155–67.
62. Betrouni N, Lopes R, Puech P, Colin P, Mordon S. A model to estimate the outcome of prostate
cancer photodynamic therapy with TOOKAD soluble WST11. Phys Med Biol. 2011;56(15):
4771–83.
63. Da Rosa MR, Trachtenberg J, Chopra R, Haider MA. Early experience in MRI-guided thera-
pies of prostate cancer: HIFU, laser and photodynamic treatment. Cancer Imaging. 2011;11
Spec No:S3–8.
64. Chen JC, Moriarty JA, Derbyshire JA, Peters RD, Trachtenberg J, Bell SD, et al. Prostate can-
cer: MR imaging and thermometry during microwave thermal ablation-initial experience.
Radiology. 2000;214(1):290–7.
65. Terraz S, Cernicanu A, Lepetit-Coiffé M, Viallon M, Salomir R, Mentha G, et al. Radiofrequency
ablation of small liver malignancies under magnetic resonance guidance: progress in targeting
and preliminary observations with temperature monitoring. Eur Radiol. 2010;20(4):886–97.
66. Onik G, Vaughan D, Lotenfoe R, Dineen M, Brady J. The “male lumpectomy”: focal therapy
for prostate cancer using cryoablation results in 48 patients with at least 2-year follow-up. Urol
Oncol. 2008;26(5):500–5.
Conclusions

Prior to the mid-1980s, prostate cancer was most commonly diagnosed when
patients presented with systemic symptoms or if found by digital rectal exam with
locally extensive disease. Within 10 years of the introduction of PSA testing, pros-
tate cancer death rates had declined and local disease was more often confined to the
gland. Today cancer death rates are down 40 % from their high, and most cancers
are detected with no palpable disease present. The 5-year survival rate for locally
detected disease approaches 100 %.
The dilemma today is who not to treat once prostate cancer is diagnosed. The
authors of The Prostate Cancer Dilemma: Selecting Patients for Active Surveillance,
Focal Ablation and Definitive Therapy have presented a detailed description of the
newest technology and thinking regarding this problem. From pathology, new serum
and genetic markers, diagnostic modalities such as elastography and mpMRI, to
novel biopsy strategies utilizing a mapping and targeted MRI approach and lastly to
no longer treating the entire gland but rather providing a focal approach, the authors
have covered it all.
This project was conceived after the editors and authors Drs. Stone and Crawford
taught a course on this subject matter at the 2014 American Urologic Association meet-
ing. The need for a concise, state-of-the-art book became obvious. We wish to thank all
of the coauthors for their valuable contributions. Each of them and their colleagues are
the best and brightest in their areas of expertise, and it was no small endeavor for them
to take the time out of their busy schedules to write their respective chapters.
We hope you have learned from and enjoyed reading the text. Whether you are a
primary care physician, urologist, radiation oncologist, or other health care pro-
vider, we believe this book provided helpful and meaningful insight on how to best
manage men diagnosed with early prostate cancer.
Sincerely,

The Editors

© Springer International Publishing Switzerland 2016 201

N.N. Stone, E.D. Crawford (eds.), The Prostate Cancer Dilemma,
DOI 10.1007/978-3-319-21485-6
Index

A DRE, 7
ACA. See American Cancer Association (ACA) ERSPC and PLCO, 10
Active surveillance (AS), 90, 129, 132 prostate cancer, 7
Adverse effects, 10 Diffusion weighted (DW) imaging, 109, 110
American Cancer Association (ACA), 7 Digital rectal examination (DRE), 23, 24
American Urological Association (AUA), 7 3-Dimensional mapping biopsy (3DMB), 158
Androgen receptor (AR), 17 DRE. See Digital rectal examination (DRE)
AUA. See American Urological Association
(AUA)
E
Elastography, 98–104
B B-mode and RTCE, 95
Benign prostatic hyperplasia (BPH), 7 B mode TRUS findings classification, 96
hitachi elasticity color code mapping, 95
mapping biopsy, 94
C peripheral zone, 101
Cancer detection rates (CDR), 113 puncture sites, 94
CAP/ProtecT. See Comparison Arm for RTCE, 95, 97
Prostate Testing for Cancer and shearing effects, 94
Treatment trial (CAP/ProtecT) strain elastography, 98
CCP score. See Cell cycle progression (CCP) strain/compression, 96
score transperineal prostate biopsy, 94
Cell cycle progression (CCP) score, 27 transrectal ultrasound, 95–98
Center for Prostate Disease Research (CPDR), 7 TRUS biopsy, 98
Comparison Arm for Prostate Testing for Cancer ultrasound technology, 93
and Treatment trial (CAP/ProtecT), 10 ERSPC. See European Randomized Study
Compression elastography, 104 of Screening for Prostate Cancer
ConfirmMDx, 131 (ERSPC)
Cryotherapy, general anesthesia, 159 European Randomized Study of Screening
for Prostate Cancer (ERSPC)
“core age group”, 9
D data monitoring committee, 9
Decipher®, 133 digital mammography, 10
Diagnosis power calculations, 8

© Springer International Publishing Switzerland 2016 203

N.N. Stone, E.D. Crawford (eds.), The Prostate Cancer Dilemma,
DOI 10.1007/978-3-319-21485-6
204 Index

F Molecular pathology, 27–28

Federal Drug Administration (FDA), 6 MRI targeted biopsy, 120, 121
FFPE. See Formalin-fixed and paraffin- limitations, 119
embedded (FFPE) men, low risk cancer, 119
Focal therapy men, no previous biopsy, 118
index lesion, 157 men, previous negative biopsy, 118, 119
“male lumpectomy”, 162 technique
meta-analysis, 156 in-bore biopsy strategy, 121
side effect, 161 software co-registration, 120
TFT, 158 visual estimation, 120
trifecta, 160 ultrasound fusion biopsies, 116
Formalin-fixed and paraffin-embedded MRI-ultrasound fusion-targeted biopsy, 117
(FFPE), 27 Multiparametic magnetic resonance imaging
(mpMRI), 157
contemporary systematic biopsy technique,
G 107
Genomic classifier (GC) scores, 133 description, 107
Genomic markers detection/performance characteristics, 110,
active surveillance, 132 111
clinical utility and value, 134 DW, 109
ConfirmMDx, 131 index tumor location, 114
PCA3, 130 NPV, 111, 113, 114
PCMT, 131 perfusion imaging, 110
PHI, 129, 130 PI-RADS 2.0 mpMRI interpretation, 112
post-prostatectomy evaluation, 134 PI-RADS 2.0 scoring rubric, 113
and proteomic markers/assays, 127 suspicion score, 111
PSA testing, 128 targeted biopsy, 116
PTEN, 132 tumor volume, 114, 115
Genomic prostate score (GPS), 27 T2-weighted imaging, 108
Gleason grading, 19, 21
Gleason score components, 108
GPS. See Genomic prostate score (GPS) N
National Cancer Database (NCDB), 154
National Comprehensive Cancer Network
H (NCCN), 28
HGPIN. See High-grade prostatic Needle biopsy, 18–20, 23, 24, 27
intraepithelial neoplasia (HGPIN) Negative predictive value (NPV), 111
High-grade prostatic intraepithelial neoplasia Non-curative initial management (NCIM), 153
(HGPIN), 76, 130
History, 6
Hitachi elasticity color code mapping, 95 O
Oncotype DX®, 132

I
Index tumor location, 114 P
International prostate symptom score (IPSS), 103 PAP. See Prostatic acid phosphatase (PAP)
ISUP Consensus Group, 20 Patient selection, 83, 85, 89
PCA3 test, 130, 131
PCMT, 131
M PLCO. See Prostate, Lung, Colorectal and
Macrohematuria, 79 Ovarian screening trial (PLCO)
Mapping biopsy, 103 Project to Eliminate Lethal Prostate Cancer
Michigan Urological Survey Improvement (PELICAN), 157
Collaborative (MUSIC) registry, 154 Prolaris®, 132, 133
Index 205

ProMark, 133 development, immunoassays, 5, 6

Prostate biopsy ERSPC and PLCO, 8
acute bacterial prostatitis, 78 FDA, 6
infection-related complications, 78 “gamma-seminoprotein”, 4
TPMB technique, 70 human kallikrein family, 5
Prostate cancer, 24–26 limitation, 128
acini, 20 long-term effects, 11
adenocarcinomas, 18 long-term morbidity, 11
AR signaling, 17 NCCN, 6
chronic inflammation and oxidative stress, 17 PAP, 4
cribriform cancer, 20 PLCO, 8, 128
DRE, 70 prostate cancer, 128
focal therapy, 79 prostate tumor markers, 12
Gleason grading system, 19, 21 protein sequencing, 5
ISUP Consensus Group, 20 screening tests, 6
ISUP modified Gleason grading systems, seminal vesicle proteins, 5
21, 22 serum phosphatase, 4
Kaplan–Meier analysis, 21 Tandem R PSA assay®, 7
management strategies, 18 “three-legged stool”, 7
metastatic, 153 Prostate, lung, colorectal and ovarian (PLCO)
molecular pathology, 27–28 cancer, 8, 128
MRI, 160 “community standard”, 9
multifocal disease, 74 safety monitoring committee, 9
multifocality and heterogeneity, 23–24 Prostatic acid phosphatase (PAP), 4
non-cutaneous malignancies, 153 Prostatitis, 78
pathological examination PTEN, 131
active surveillance protocols, 25
biologic aggressiveness, 25, 26
focal therapy, 25 R
Gleason score, 24 Real-time compression elastography (RTCE), 95
“potentially insignificant”, 25 Robot assisted laparoscopic radical
role, 24 prostatectomy (RALP), 154
TRB, 26 RTCE. See Real-time compression
TRUS, 24 elastography (RTCE)
PCOS, 155
PELICAN, 157
prostatectomy specimens, 19 S
TRUS, 69 Shear wave elastography, 94
tumors, 17 Strain elastography, 95
Prostate Cancer Outcomes Study (PCOS), 155 Surveillance, Epidemiology and End Results
Prostate elastography, 104 Program (SEER), 154
Prostate health index (PHI)
active surveillance, 129
4Kscore, 130 T
NCCN guidelines, 129 Targeted ablation
proPSA/fPSA ratio, 129 clinically localized prostate cancer in men,
score trials, 129 154
Prostate-specific antigen (PSA) complication rates, 154
ACA, 7 decision-making analyses, 155
AUA, 7 EBRT, 155
benefits and risks, 8 erectile dysfunction, 155
benign and malignant prostate tissue, 5 follow-up, 160
bony metastasis, 4 Gleason grading system in 2005, 154
BPH, 7 MUSIC registry, 154
206 Index

Targeted ablation (cont.) accurate prostate cancer detection

overdiagnosis and overtreatment, 153 technique, 74–75
patient selection, 156–158 adenocarcinoma, 76
problematic AS enrollment, 155 anesthesia, 70
prostate cancer, 153 AS, 73, 76, 77
RALP, 154 axial prostate image, 71, 72
SEER and NCDB, 154 bilateral cancers, 78
technique, 158–160 biopsy specimen, 71, 74
trends and challenges, 160–162 brachytherapy, 70
urinary, sexual and bowel related side “confirmatory” biopsies, 79
effects, 156 digital rectal examination/abnormal
Template-guided biopsy prostate gland, 76
digital rectal examination, 100 dorsal lithotomy position, 71
IPSS, 103 fluoroquinolone antimicrobial, 78
positive biopsy, 104 fluoroquinolone-resistant infections, 78
Three-dimensional mapping biopsy (3DMB) gland cryotherapy, 77
alignment calibration, 85, 86 Gleason score, 77
biopsy needles, 85 grade 1 complications, 79
biopsy plan, 87 prophylaxis, 78
brachytherapy needles, 85 prostate cancer detection rates, 75
contouring, prostatic capsule, 85, 87 prostatectomy specimen, 74
cryotherapy probes, 89 PSA, 77
dorsal lithotomy position, 85 stool culture, 78
focal therapy, 89 transcutaneous, 78
intraoperative axial (transverse) image transrectal ultrasound, 70
capture, 85 ultrasound grid, outer template, 71, 72
"live feed” broadcasts the US image, Transrectal ultrasound (TRUS), 24
85, 86 biplanar ultrasound probe, 69
“machine calibration” function, 85 immunoperoxidase staining, 70
probability, 84 “low risk cancers”, 70
prostate gland, 85, 88, 90 TRUS-guided transrectal biopsy (TRB), 26
sagittal view, virtual needle, 87, 89 TRUS. See Transrectal ultrasound (TRUS)
TRUS and TPMB, 83
Traditional transrectal ultrasound guided
(TRUS) biopsy, 157 U
Transperineal biopsy, 103 Urinary retention, 78, 79
elastographic evaluation, 99
stepping device, 99
Transperineal prostate mapping biopsy W
(TPMB) technique World Health Organization (WHO), 7