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Recent Results
in Cancer Research
Managing Editors
P. M. Schlag, Berlin В· H.-J. Senn, St. Gallen
Associate Editors
P. Kleihues, ZГјrich В· F. Stiefel, Lausanne
B. Groner, Frankfurt В· A. Wallgren, GГ¶teborg
Founding Editor
P. Rentchnik, Geneva
п›њп�їп�Ѕ
J. Ramon В· L. J. Denis (Eds.)
Prostate Cancer
With 47 Figures and 43 Tables
123
Jacob Ramon, MD
The Chaim Sheba Medical Center
Tel-Hashomer
Ramat-Gan 52621
Israel
Louis J. Denis, MD, FACS
Director Oncology Centre Antwerp
Secretary Europa Uomo
Lange Gasthuisstraat 35-37
2000 Antwerp
Belgium
Library of Congress Control Number: 2006932038
ISSN 0080-0015
ISBN 978-3-540-408970
Springer Berlin Heidelberg New York
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V
Preface
Prostate cancer treatment dates back almost
100 years. However, in an era of rapid developments and innovations in cancer research and
uro-oncology, there is an increasing need to
update our knowledge and especially to guide
our practice by innovations and evidence-based
medicine. Prostate cancer is still evolving following improvements in disease detection and
better understanding of disease characteristics.
This book addresses the current state of the art in
this still-developing field and presents the reader
with the information needed to make rational
patient decisions regarding treatment selection
and outcomes.
The growing body of knowledge regarding
epidemiology, pathogenesis, prevention, screening, diagnosis and staging is included in the first
half of the book.
To determine the most appropriate treatment
regimen for a prostate cancer patient, it is important to asses the individualвЂ™s risk factors. Patient
characteristics are one important factor in determining optimal therapy. Efficacy and survival
benefits need to be balanced against the patientвЂ™s
quality of life.
When diagnosed with prostate cancer, the
patient and his physician have to choose from
a wide range of therapies. Treatment can be deferred until progression or until symptoms appear (watchful waiting) or in indolent cancer
until curative treatment is indicated (active surveillance). The wide choice of treatment includes
radical prostatectomy (open or laparoscopic),
radiotherapy (interstitial or external), cryoablation, high-intensity focused ultrasound and
hormonal therapy. The choice of therapy may
influence survival as well as the risk of therapyinduced side effects.
To guide urologists and their patients with
prostate cancer in the selection of an appropriate treatment, the evidence surrounding current
treatment approaches is examined in the subsequent chapters of this volume.
The text addresses the time-honoured hormonal treatment, which has been the mainstay
of prostate cancer management for some decades. Due to the increased diagnosis of prostate
cancer at earlier stages and the increased use of
hormone therapy in earlier disease stages many
patients will receive hormone therapy for a long
period. These patients are at risk of acute and
chronic side effects of hormonal therapy. Therefore, the timing of initiating hormone therapy,
the type of hormone therapy and the monitoring
of patients on long-term hormone therapy have
become crucial in the appropriate management
of patients with prostate cancer.
Disease management in men with prostate
cancer has recently expanded to include maintenance of bone health. The role of urologists in
the management of patients with bone metastasis is changing. Symptom control and quality of
life are the priorities for patients with metastatic
disease. For patients with metastatic hormonerefractory prostate cancer (HRPC), there have
been relatively few advances recently in terms of
survival and quality of life.
In this book, therefore, we have covered in detail the main aspects of current prostate cancer
management, and we believe we have created a
comprehensive yet readable account of this rapidly expanding and fast-changing area. We hope
that it will be of value to all those who are involved in prostate cancer treatment.
Finally, we would like to thank the contributors, together with all the staff of Springer, without whose hard work and devotion this book
would not have been completed.
Jacob Ramon, MD
Louis J. Denis, MD
VII
International Prostate Health Council
The International Prostate Health Council
(IPHC) was established more than a decade ago
as an independent, non-governmental, nonprofit organization. Its main goals include assessment of the current knowledge base and practice
pattern of physicians concerned with prostate
disease, assessment of the level of awareness of
these diseases on the part of the public, and the
creation of worldwide educational programmes
and resource materials for urologists, medical
and radiation oncologists, primary care physicians and allied health workers.
This monograph, produced at the invitation
of the editors of the prestigious Springer series
Recent Results in Cancer Research, presents the
latest information for the care of prostate cancer in a general clinical setting. IPHC is an active and dedicated believer in multi-professional
collaboration to offer the best treatment and care
for patients. For this reason we invited experts
from outside the council to provide the reader
with updated information on optimizing patient
care and treatment. We are grateful for their contribution, which is yet another small step in facilitating the educational process aimed towards
knowledge and treatment of complex prostate
diseases.
In the spirit of modern health-care communication, we include the voice of Europa Uomo, the
European Prostate Cancer Coalition, to inform
readers of the coalitionвЂ™s vision and mission. We
hope the present manuscript addresses most of
our readersвЂ™ needs.
Louis J.Denis
Chairman IPHC
Contents
IX
Contents
1
Epidemiology of Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Vera Nelen
1
2
Natural History of Prostatic Carcinoma: The PathologistвЂ™s Perspective . . . .
Ferran Algaba, Isabel Trias, Yolanda Arce
9
3
Prognostic Factors in Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Johan Braeckman, Dirk Michielsen
25
4
The Prevention of Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Keith Griffiths, Domenico Prezioso, A. Turkes, Louis J. Denis
33
5
Prostate Cancer Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
P. Tenke, J. Horti, P. Balint, B. Kovacs
65
6
Diagnosis of Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Jehonathan H. Pinthus, Dalibor Pacik, Jacob Ramon
83
7
Does Localized Prostate Cancer Exist? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Bernard Lobel
101
8
Staging of Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Zohar A. Dotan, Jacob Ramon
109
9
Guidelines and Counselling for Treatment Options
in the Management of Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Axel Heidenreich
131
X
Contents
10
Choices for Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
StГ©phane LarrГ©, Laurent Salomon, Claude ClГ©ment Abbou
163
11
Radiation Therapy in Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Moshe E. Stein, Dirk Boehmer, Abraham Kuten
179
12
Cryoablation and High-Intensity Focused Ultrasound . . . . . . . . . . . . . . . . . . . .
Chris DвЂ™Hont
201
13
The Role of Hormonal Treatment in Prostate Cancer . . . . . . . . . . . . . . . . . . . . . .
Stephan H. FlГјchter, Ralf Weiser, Christoph Gamper
211
14
Androgen-Independent Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Dirk Schrijvers
239
15
Prostate Cancer Treatment and Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Domenico Prezioso, Raffaele Galasso, Mario Di Martino, Gennaro Iapicca
251
16
Europa Uomo: The European Prostate Cancer Coalition . . . . . . . . . . . . . . . . . .
Tom Hudson, Louis J. Denis
267
XI
List of Contributors
Claude ClГ©ment Abbou, Pr, MD
Director of the Department of Urology
University Hospital Henri Mondor
51 Av. de Lattre de Tassigny
94010 CrГ©teil
France
Johan Braeckman, MD
Department of Urology
AZ-VUB
Laarbeeklaan 101
1090 Brussels
Belgium
Dr. Ferran Algaba
Head of the Department of Pathology
Fundacion Puigvert
Department of Morphologic Sciences
Faculty of Medicine
Universitat AutГіnoma de Barcelona (UAB)
Cartagena 340вЂ“350
08025 Barcelona
Spain
Louis J. Denis, MD, FACS
Director Oncology Centre Antwerp
Secretary Europa Uomo
Lange Gasthuisstraat 35вЂ“37
2000 Antwerp
Belgium
Dr. Yolanda Arce
Pathology Section
Fundacion Puigvert вЂ“ Barcelona
Calle Cartagena 340вЂ“350
08025 Barcelona
Spain
Peter Balint, MD
Department of Urology
Jahn Ferenc South-Pest Hospital
KГ¶ves Utca 2вЂ“4
1204 Budapest
Hungary
Dirk BГ¶hmer, MD
UniversitГ¤tsmedizin Berlin
CharitГ© Campus Mitte
Klinik fГјr Strahlentherapie
Schumannstrasse 20/21
10117 Berlin
Germany
Chris DвЂ™Hont, MD
Department of Urology
ZNA Campus Middelheim
Lindendreef 1
2020 Antwerp
Belgium
Mario Di Martino, MD
Department of Urology
University of Naples вЂњFederico IIвЂќ
Via S. Pansini 5
80123 Naples
Italy
Zohar A. Dotan, MD, PhD
The Chaim Sheba Medical Center
Tel-Hashomer
Ramat-Gan 52621
Israel
Stephan H. FlГјchter, Prof. Dr. med.
Chefarzt der Klinik fГјr Urologie,
Kinderurologie und urologische Onkologie
Klinikum SaarbrГјcken
Winterberg 1
66119 SaarbrГјcken
Germany
XII
List of Contributors
Raffaele Galasso, MD
Department of Urology
University of Naples вЂњFederico IIвЂќ
Via S. Pansini 5
80123 Naples
Italy
Bela Kovacs, MD
Department of Urology
Jahn Ferenc South-Pest Hospital
KГ¶ves Utca 2вЂ“4
1204 Budapest
Hungary
Christoph Gamper, Dr. med
Klinik fГјr Urologie, Kinderurologie und
urologische Onkologie
Klinikum SaarbrГјcken
Winterberg 1
66119 SaarbrГјcken
Germany
Abraham Kuten, MD
Division of Oncology
Rambam Medical Center
and Faculty of Medicine
Technion вЂ“ Israel Institute
of Technology
Haifa
Israel
Keith Griffiths, DSc
Laurel Cottage
Castleton
Cardiff CF3 2UR
UK
Axel Heidenreich, Prof. Dr. med., MD
Division of Oncological Urology
Department of Urology
University of Cologne
Joseph-Stelzmann-Str. 9
50924 Cologne
Germany
Jozsef Horti, PhD
Department of Chemotherapy and Clinical
Pharmacology
National Institute of Oncology
Rath Gy. Utca 7вЂ“9
1122 Budapest
Hungary
Tom Hudson
Europa Uomo
Men Against Cancer
Cullahill, Killiney Road
Killiney
Dublin
Ireland
Gennaro Iapicca, MD
Department of Urology
University of Naples вЂњFederico IIвЂќ
Via S. Pansini 5
80123 Naples
Italy
StГ©phane LarrГ©, MD, PhM
Department of Urology
University Hospital Henri Mondor
51 Av. de Lattre de Tassigny
94010 CrГ©teil
France
Bernard Lobel
Head of the Department of Urology
HГґpital Pontchaillou
Rue Henri Le Guilloux
35033 Rennes
France
Dirk Michielsen, MD
Department of Urology
AZ-VUB
Laarbeeklaan 101
1090 Brussels
Belgium
Vera Nelen, MD
Public Health Department
Provinciaal Instituut voor HygiГ«ne
Kronenburgstraat 45
2000 Antwerp
Belgium
Dalibor Pacik, MD, CSc
Department of Urology
University Hospital Brno
JihlavskГЎ 20
62500 Brno
Czech Republic
XIII
Jehonathan H. Pinthus, MD, PhD
Department of Surgical Oncology
McMaster University
Juravinski Cancer Centre
699 Concession Street
Hamilton, Ontario
Canada
Domenico Prezioso, MD
Department of Urology
University of Naples вЂњFederico IIвЂќ
Via S. Pansini 5
80123 Naples
Italy
Jacob Ramon, MD
The Chaim Sheba Medical Center
Tel-Hashomer
Ramat-Gan 52621
Israel
Laurent Salomon, Pr, MD, PhD
University Hospital Henri Mondor
51 Av. de Lattre de Tassigny
94010 CrГ©teil
France
Dirk Schrijvers, MD, PhD
ZNA Campus Middelheim
Lindendreef 1
2020 Antwerp
Belgium
Moshe Stein, MD
Department of Oncology and Radiation Therapy
Rambam Medical Center
and Faculty of Medicine
Technion вЂ“ Israel Institute
of Technology
Haifa
Israel
PГ©ter Tenke, PhD
Department of Urology
Jahn Ferenc South-Pest Hospital
KГ¶ves Utca 2вЂ“4
1204 Budapest
Hungary
Dr. Isabel Trias
Director of the Department of Pathology
ClГnica PlatГі FundaciГі Privada
c/PlatГі 21
08006 Barcelona
Spain
Atilla Turkes, PhD
Department of Chemical Pathology
University Hospital of Wales
Heath
Cardiff
UK
Ralf Weiser, Dr. med. (FEBU)
Klinik fГјr Urologie, Kinderurologie
und urologische Onkologie
Klinikum SaarbrГјcken
Winterberg 1
66119 SaarbrГјcken
Germany
1
Epidemiology
of Prostate Cancer
Vera Nelen
Recent Results in Cancer Research, Vol. 175
В© Springer-Verlag Berlin Heidelberg 2007
Abstract
Prostate cancer is one of the most important cancers in men. With a worldwide incidence of 25.3
per 100,000 it is the second most common cancer in men, with large differences between countries. Important clues on risk factors remain to
be found. Age, genetic factors and environmental
influences have been studied. Incidence has been
increasing over the last few decades, largely due
to early detection procedures. The mortality rate
of 8.1 per 100,000 mainly affects men at older
ages; increases in this rate over time and differences between countries are markedly smaller
than for incidence. For the future, prostate cancer will remain an important andвЂ”through evolutions in incidence and demographyвЂ”growing
health problem.
Introduction
The burden of cancer can be expressed in three
measures: incidence, mortality and prevalence.
Incidence is the number of new cases occurring
in a population per year and can be expressed
as an absolute number or as a rate per 100,000
persons. Mortality is the number of deaths occurring and can also be expressed as a rate per
100,000 persons per year. Prevalence describes
the number of individuals alive with the disease
at a certain point in time. In the year 2002, estimates are that 10.9 million new cases of cancer
were detected worldwide, 6.7 million people died
of cancer and 24.6 million persons were alive
with cancer (within 5 years of diagnosis) (Parkin
et al. 2005). Figures for Europe for 2004 reveal
nearly 2.9 million new cases of cancer and 1.7
million cancer deaths (Boyle and Ferlay 2005).
In 2002 about 7.3 million people had cancer in
Europe (within 5 years of diagnosis) (Ferlay et al.
2004).
Prostate cancer is already one of the most
important cancers in men and is still increasing.
Therefore prostate cancer is an important public
health topic and the rest of this article will deal
with its epidemiology.
Prostate Cancer Incidence
Most recent world figures for prostate cancer
date from the year 2002. In that year 679,000
men developed prostate cancer worldwide. The
yearly prostate cancer incidence in the world is
25.3 per 100,000, which is an age-standardised
rate according to the world population. Since the
cancer risk increases with age, and demographics
differ widely around the world, rates corrected
for age improve comparability. This correction
can be done by using a standard age structure
called age standardisation. Of new cancer cases,
11.7% are prostate cancers. This makes prostate
cancer the fifth most common cancer and the
second most common cancer in men (Parkin et
al. 2005).
In Europe 238,000 men developed prostate
cancer in 2004, this is 15.5% of newly diagnosed
cancer cases in men. Prostate cancer is the second most frequent cancer in European men, after lung cancer. It is, however, the most common
cancer in men living in the European Union,
comprising 18.1% of all incident cases. The lifetime risk (0вЂ“74 years) of developing prostate
cancer in the European Union was 5.9% in 2004
(Boyle and Ferlay 2005).
2
Fig. 1.1 Prostate cancer incidence worldwide, Globocan 2002 (Ferley et al. 2004)
Fig. 1.2 Prostate cancer, age standardized incidence and mortality rates per
100,000 (Parkin et al. 2005)
Vera Nelen
1 Epidemiology of Prostate Cancer
Prostate cancer incidence differs between continents and from country to country (Figs. 1.1
and 1.2). Incidence is high in the United States,
Canada, Australia/New Zealand and Northern
and Western Europe. The lowest rates are found
in China and other parts of Asia (Parkin et al.
2005).
Very few cases of prostate cancer are found in
men under 50 years. Three-quarters of all cases
are found in men aged 65 or more, and rates increase steeply with age. It is therefore more common in populations with higher proportions of
elderly men. Prostate cancer amounts to 19% of
new cases in developed countries and only 5.3%
in developing countries (Quinn and Babb 2002).
Some part of the variability in the incidence of
prostate cancer is due to a different age structure
in the populations, but large variability remains
after age standardisation.
Latent cancer of the prostate, the slow growing intraprostatic microscopic foci of well-differentiated cancer cells, is comparatively common
in men of all ethnic groups. These cancers are
mostly discovered in autopsy or on microscopic
examination after prostatectomy for benign prostatic hyperplasia and can influence incidence
data reported to cancer registries. Nowadays
screening of asymptomatic individuals for prostate cancer has become very common in some
countries. This causes a temporary increased incidence when cancers are detected sub-clinically.
The increase persists if latent cancers that would
otherwise not clinically surfaceвЂ”and thus remaining undiagnosedвЂ”are discovered by needle
biopsies (SchrГ¶der et al. 2003a, b). In the United
States prostate cancer has become the most common cancer diagnosed in men, with an incidence
of 124.8 per 100,000 and presents 33% of all
newly diagnosed malignancies in men (Parkin
et al. 2005; Quinn and Babb 2002). The lifetime
risk for a man to develop prostate cancer in the
United States is 1 out of 6 (National Cancer Institute 2006).
Some of the differences between countries
might be due to interethnic differences in risk.
African Americans have a markedly higher incidence than whites (82.5 versus 49.6 per 100,000).
African Americans have a 9.8% lifetime risk of
developing prostate cancer compared to 8%
in whites. White people have higher rates than
3
Asian origin populations (Chinese 14.9, Japanese
16.5) (Prezioso et al. 2004). Similarly in Brazil the
risk for black males was 1.8 times that of whites
(Parkin et al. 2005).
Incidence can be influenced by several risk
factors including genetic susceptibility, environmental exposure in its largest sense and differences in health care and cancer registration (or
a combination of the these). More data on risk
factors will be discussed later in this chapter.
Prostate Cancer Mortality and Survival
Mortality rates are based on incidence and fatalityвЂ”the inverse of survivalвЂ”of a cancer and reflect prognosis. Prognosis for prostate cancer is
relatively good. With 221,000 deaths worldwide
in 2002 it is a less prominent cause of mortality
than might be expected consider the incidence.
Mortality per year is 8.1 per 100,000 (age standardised according to the world population)
(Parkin et al. 2005). Prostate cancer is responsible for 3.3% of all cancer deaths and 5.8% of
cancer deaths in men.
In Europe in 2004, 85,000 men died of prostate cancer, 8.9% of cancer deaths in men. The
lifetime risk (0вЂ“74 years) of dying from prostate
cancer in the European Union was 1.1% in 2004
(Boyle and Ferlay 2005).
Mortality rates for cancer in general differ less
between developing and developed countries
than incidence rates. For men, total cumulative
mortality for all cancers before age 65 is 18%
higher in developed countries. Differences in incidence are much larger. There are several reasons
for this. A large group of cancers that frequently
occur in developed countries and are associated
with a Western lifestyle have a good prognosis:
colon, rectum, breast and prostate cancer. Cancers of liver, stomach and oesophagus are more
common in developing countries and have a
poor prognosis. Prognosis in general is poorer
in developing countries and the ratio of deaths
to cases is less favourable, especially for cancers
where early detection and treatment have an impact on prognosis (Parkin et al. 2005).
Mortality as a result of prostate cancer differs
considerably around the world, but the differences are also much smaller than for incidence
4
(Quinn and Babb 2002). Survival for prostate
cancer is better in high-risk countries: 87% in the
United States versus 45% in developing countries. These figures are modified by inflation of
incidence through early detection programmes
that may cause lead-time and length-time bias,
and by treatment effects. Since prostate cancer is
a disease of the elderly, survival is impacted by
co-morbidity with increasing age (Coebergh et
al. 1999; Houterman et al. 2005). A Dutch study
showed 51% co-morbid conditions in prostate
cancer patients (Coebergh et al. 1999). Cancerspecific mortality is therefore variable by age. A
Swedish study showed an 80% risk of dying of
prostate cancer if diagnosed before age 60 years,
63% risk if diagnosed between 60 and 69, 53%
for ages 70 to 79 and 49% for ages 80 and older
(GrГ¶nberg et al. 1997).
Vera Nelen
The average 5-year survival for prostate cancer in Europe in the early 1990s was 67%. It
varied across Europe from less than 40 to more
than 80% with lowest rates in Eastern Europe,
the United Kingdom, Denmark, Malta and Portugal and highest in Austria, Iceland, Germany
and France (Fig. 1.3) (Coleman et al. 2003; Sant
et al. 2003). In the United States relative 5-year
survival for prostate cancer increased to 99.8% in
the period 1995вЂ“2001 (Surveillance, Epidemiology, and End Results Program 2006).
Crude mortality rates for prostate cancer are
an indication for the presence of invasive cancers
in a population. Mortality rates are high in the
Caribbean, Southern and Central Africa, Northern and Western Europe, Australia/New Zealand
and North and South America. They are low in
Asia and North Africa (Fig. 1.2). In particular,
Fig. 1.3 Five-year survival (%) from
prostate cancer, by country, Europe:
age-standardised relative survival, adults
(15вЂ“99 years) diagnosed in the period
1990вЂ“1994 and followed up to 1999 (Coleman et al. 2003)
1 Epidemiology of Prostate Cancer
prostate cancer mortality in the USA was not
very different from levels in other developed
countries despite the difference in incidence,
suggesting that a large proportion of cancers in
the USA have a good prognosis. However, mortality in Singapore, Japan, India and China was
lower than in other countries and consistent with
the pattern of incidence (Quinn and Babb 2002).
Prostate Cancer Prevalence
Since the number of men having prostate cancer
at a certain point in time and within a certain period from diagnosis depends on both incidence
and survival, it can differ largely between regions.
The world prevalence, 5 years from diagnosis,
in 2002 was 2,368,700 cases. Following breast
(17.9%) and colorectal cancer (11.5%), prostate
cancer is the third most prevalent cancer worldwide, with 9.6% of cases (Parkin et al. 2005).
Prevalence in Europe was 740,000 in 2002
and shows marked differences between countries
(Fig. 1.4) with the highest prevalence of 600 per
100,000 in Sweden contrasted with the lowest, 40
per 100,000, in Poland (Quinn and Babb 2002;
Ferlay et al. 2004).
5
Prostate Cancer Incidence and Mortality:
International Trends
Until the 1980s the rates of prostate cancer were
gradually increasing, partly due to a genuine rise
in risk, partly due to detection of asymptomatic
cancers by the increasing use of transurethral resection of the prostate (TURP) for treatment of
benign prostate hyperplasia (BPH) (Quinn and
Babb 2002). With the introduction of prostatespecific antigen (PSA) testing in the 1980s and
improved awareness of the disease there was
a huge rise in incidence, especially in localised
disease. The largest increases in incidence were
observed in high-risk countries, especially in
younger men, but there were also marked increases in China, Japan and Hong Kong (Parkin
et al. 2005; Newcomer et al. 1997; Mettlin 2000;
Sim and Cheng 2005). Since 1992вЂ“1993, incidence in the United States has been decreasing,
although it remains higher than in 1986.
The average increase in age-adjusted incidence worldwide from 1985 to 2002 was about
1.1% annually. A continued increase with this
magnitude will lead to almost 900,000 new cases
of prostate cancer annually by the year 2010 (Parkin et al. 2005). Even without changes in age-spe-
Fig. 1.4 Prevalence of prostate cancer in European countries by time since diagnosis, 1992 (Quinn and Babb 2002)
6
cific incidence and mortality, numbers in Europe
and other developed countries will continue to
rise due to ageing of the population (Quinn et al.
2003). Prostate cancer therefore remains a large
and growing health problem.
Mortality rates for prostate cancer increased
until the 1980s, but less marked than incidence,
averaging 2%вЂ“8% every 5 years (Stanford et al.
1999). Especially in countries with the highest
incidence increases, mortality rates did not follow the same pattern. Since the 1990s mortality
declined in several developed countries as a consequence of decreased diagnosis of distant-stage
disease and improved treatment (Parkin et al.
2005; Hsing et al. 1999; Newcomer et al. 1997;
Mettlin 2000; SchrГ¶der et al. 2003b).
In the European Union mortality for prostate cancer increased from 1980 to 1993 (from
13.9/100,000 to 15.7/100,000). From 1993 to
1999 the rate declined approximately 10% to
14.1/100,000. These trends were mainly observed
in the elderly and rates in the EU have remained
stable for men below age 65 (Levi et al. 2004).
Predictions for age-standardised rates mention a
continuing 11% decrease by 2015, although timing and the extent of the decreases vary widely
among countries. The number of cancer deaths
in the European Union, however, will increase
in the future when the older age groupsвЂ”where
incidence and mortality rates are the highestвЂ”
will become proportionally larger. By the year
2015 there will be a 20% increase of people aged
65 years and older and 50% more people will be
80 years and over. This demographic shift alone
results in a 25% increase in predicted cancer
deaths. The effect of the demographic shifts towards the elderly outweighs that of decreasing
trends in mortality rates in the predictions of
mortality towards 2015 (Quinn et al. 2003). For
prostate cancer, which mainly involves the elderly, these trends will be important.
Prostate Cancer Risk Factors
Large clues on risk factors for prostate cancer
are still to be found. Notions on this subject are,
however, important because they offer the possibility for primary prevention of the disease.
Prostate cancer is probably the result of a
combination of factors. One of them is age. Pros-
Vera Nelen
tate cancer rates increase with age faster than
many other cancers. Autopsy studies show that
histological cancer also increases with age, presenting 15%вЂ“30% in men older then 50 years
and 60%вЂ“70% in men older then 80 (Pienta and
Esper 1993). Although the incidence of clinical
prostate cancer varies greatly around the world,
this is not the case for histological cancer. The
age-specific incidence of histological cancer is
the same in the United States and Japan, while
clinical incidence differs largely. These data suggest that the initiation of prostate cancer is the
same around the world, and related to age. Differences between countries exist in progression
to clinical cancer, which is related to other risk
factors. Migration from low-risk to high-risk
areas in the world evokes a marked increase in
incidence in these populations and supports this
theory. Prostate cancer incidence in Chinese and
Japanese men respectively rose from 1.8 and 5.1
to 14.9 and 16.5 when migrating to North America (Prezioso et al. 2004).
Other risk factors include genetic factors. Several studies show an increased risk (OddвЂ™s ratioвЂ™s
from 2вЂ“6) for clinical prostate cancer in men with
affected relatives (Steinberg et al. 1990; CancelTassin and Cussenot 2005); concordance was reported higher for monozygotic versus dizygotic
twins (4 versus 19%) (GrГ¶nberg et al. 1994) and
large variations in prostate cancer incidence have
been noticed in different ethnic groups. African Americans have higher incidence rates than
white Americans of similar education and socioeconomic background (Baquet et al. 1991).
Environmental risk factors in the widest sense
were suggested: cigarette smoking, alcohol consumption, cadmium exposure, occupation, infectious agents, ionising radiation, ultraviolet light,
physical activity, body mass index and dietary
factors (Stanford et al. 1999). Most arguments are
found for the relation with dietary fat. High intake
of dietary fat seems to be related to a higher risk
for prostate cancer (Sonn et al. 2005; GrГ¶nberg et
al. 1996). Phyto-oestrogens, present in a soy-rich
diet, have been associated with a decreased risk
of prostate cancer. The low incidence in Asian
countries may partly be explained by effects of
a low animal fat and a soy-rich diet (Denis et al.
1999; Magee and Rowland 2004). Positive effects
of other dietary factors such as vitamins, minerals and anti-oxidants were suggested but need
1 Epidemiology of Prostate Cancer
further confirmation (Sonn et al. 2005; Quinn
and Babb 2002; Stanford et al. 1999; Pienta and
Esper 1993). Molecular mechanisms implicated
in inflammation of the prostate may provoke
adverse cell proliferation and play a role in carcinogenesis (Naber et al. 2004). One study found
that the risk of prostate cancer increased with the
lifetime number of female sexual partners and
with prior infection with gonorrhoea, supporting
the influence of infectious agents (Rosenblatt et
al. 2001). Studies have shown that prostate cancer
is more frequent in regions with less exposure to
sunlight. This may be in agreement with vitamin
D being protective against cancer (Hanchette and
Schwartz 1992; Polek and Weigel 2002).
Several studies report the interaction of endogenous hormones and prostate cancer. Higher
levels of serum testosterone are associated with
an increased risk of prostate cancer (Parsons et
al. 2005). Altered androgynous hormone metabolism may be the cause of the evolution of
histological to clinical prostate cancer. Oestrogens are also believed to play a role in the regulatory mechanisms of molecular growth in the
prostate. Oestrogen levels, or changed oestrogen/androgen balance, can therefore play a role
in the development of prostate disease in general
and prostate cancer in particular (Prezioso et al.
2004). The steroid hormone system is a complex
regulatory system that is influenced by genetic
mechanisms as well as environmental influences
(such as dietary fat, phyto-oestrogens, vitamins
and smoking) and plays a role in inflammation.
Other hormones, such as the insulin-like growth
factor (IGF) family, have also been described in
the regulation of physiological and pathological processes in the prostate and may play a role
in prostate cancer development (Gennigens et
al. 2005). The involvement of endogenous hormones would explain why unravelling the risk
factors that interact with the development of
prostate cancer has been so difficult (Naber et al.
2004; Pienta and Esper 1993).
Conclusion
Clues, derived from risk factors, for primary prevention of prostate cancer remain to be found.
Final level arguments, effect on mortality, for
the use of screening in the prevention of pros-
7
tate cancer are expected from the large randomised screening trials to be completed in the
near future. Meanwhile prostate cancer remains
a large and, through evolutions in incidence and
demography, growing health problem.
Epidemiology may be a more esoteric science compared to clinical practice, but studying
figures and their patterns over time helps us to
improve our understanding of the populationвЂ™s
health and the effects of interventions (preventive and curative). In the end, this provides us
with clues for individual patientвЂ™s care.
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2
Natural History of Prostatic Carcinoma:
The PathologistвЂ™s Perspective
Ferran Algaba, Isabel Trias, Yolanda Arce
Recent Results in Cancer Research, Vol. 175
В© Springer-Verlag Berlin Heidelberg 2007
Abstract
The stem (basal) cells of prostate acini are considered the origin of prostate cancer. Between these
cells and the final secretory cells, different intermediate or transit cells can be observed, and every one of them can evolve into malignant cells,
explaining the biological variability of prostatic
cancer. The exact changes between normal gland
and prostatic intraepithelial neoplasia (PIN) are
not yet known, but a post-inflammatory atrophy
lesion is being studied in this respect. The PIN
lesion is considered the pre-invasive change of
prostatic cancer and its presence in needle biopsy
is clinically used for follow-up of the patient. The
progressive knowledge of the stromal invasion
in prostate cancer (loss of some cellвЂ“cell adhesion molecules and expression of others) can be
correlated with the Gleason grading system, and
the molecular changes in the progression to androgen-independent carcinoma can be used as a
prognostic marker in conjunction with the classical pathological markers.
Introduction
Prostate cancer is a glandular malignant neoplasia (adenocarcinoma), mostly of secretory
or luminal cells. According to the current notion, the origin of such neoplasia is not to be
searched for in the secretory cells (that are final differentiation cells that will disappear after
serving their purpose) but in the precursor (or
stem) cells with secretory differentiation. This
hypothesis (hierarchical or stem cell model) [1]
opposes the theory that all neoplastic cells may
be tumour-initiating cells (stochastic model), but
some isolated evidence exists that questions the
hierarchical model [2]. Even so, in order to explain the pathologistвЂ™s perspective regarding the
natural history of prostate cancer, the stem cell
(hierarchical) model will be followed.
Morphological and Molecular Structure
of Normal Prostate Glands
The histological structure of acini and ducts
is identical, probably because the prostate is a
sparsely secreting gland, whereas the whole of it
should be secretory. The cells that form the gland
are arranged in two layers, basal and luminal
(Fig. 2.1).
The cells of the basal layer (basal cells) have little cytoplasm and show no microscopic differences
between each other. Most of them have growth
factor receptors of the growth factors produced
by the stromal prostate cells, they lack androgen
receptors and they express Bcl-2. These cells are
considered the stem cells. A small sub-population
of these cells have androgen receptors, which has
suggested the possibility that transit (intermediate) amplifying cells bearing stem cell characteristics exist, but the sensitivity to androgen enable
them to differentiate to luminal cells (secretory
cells), with androgen receptors in all of them [3].
This model is probably an over-simplistic definition of basal and luminal compartments, since
the currently existing immunohistochemical
tests are capable of stratifying the transit (intermediate) amplifying cells in early progenitors of
intermediate stem cells (CK5 and CK18 positive,
c-met positive, without androgen receptors), as
well as in late progenitors of intermediate stem
cells (K5 negative, CK18 with irregular expression, c-met positive and irregular expression of
androgenic receptors) [4] (Fig. 2.2).
10
Fig. 2.1 Prostate acini. Basal and luminal cells
Fig. 2.2 Stem cell model of the normal prostate acini
Ferran Algaba, Isabel Trias, Yolanda Arces
2 Natural History of Prostatic Carcinoma: The PathologistвЂ™s Perspective
11
Fig. 2.3 Stem cell model of the malignant transformation of prostate
acini, with stem cells loss, malignant transformation of intermediate
stem cells and secretory cells. Every one of these cells can be the final differentiation of the prostate cancer, and for this reason the prostate cancer
has different phenotypes
Molecular Definition of Tumoural Stem
Cells of the Prostate
The problem that arises in the prostate cancer
stem cell model is identifying which cells are
the target of carcinogenics. It is possible that the
early and late progenitors of the intermediate
stem cells, rather than the stem cells themselves,
justify the heterogeneity of prostate cancer, both
regarding the expression of androgen receptors
and the phenotypic characteristics [4]. These
cells probably represent a minimal percentage of
the tumour mass (<0.01%). It is quite difficult to
recognise them using the classical methods, and
they present with a differential phenotype with
high clonogenicity and therapeutic resistances
[5] (Fig. 2.3).
Pre-malignant Changes of Prostate Glands
The exact changes between a normal gland and
a neoplastic one are not yet known. There is increasing evidence that predisposing genetic factors, oxidative damage and dietary or environmental factors may play a role in this step of the
neoplastic transformation [6]. Very recent observations correlate phagocytic inflammatory cells
and cancer with the release of oxygen- and ni-
trogen-based radicals. Together with dietary factors, this leads to oxidative stress and causes cell
injury and regeneration with potential expansion
of early or late progenitor intermediate cells [7].
The above-mentioned observations have suggested that gland dilatations with flattening of
the secretory epithelium, previously considered
secretory cell atrophy unrelated to the hormonal status (Fig. 2.4), could be re-interpreted
differently when confirming that there may be
surrounding lymphocytes, and that the apparent atrophic morphologic appearance is not
consistent with its functional status due to the
expression of bcl-2 (anti-apoptotic status), ki67
(active proliferative status), decreased expression of p27 (cyclin-dependent kinase inhibitor),
and expression of glutathione-S-transferase p1
(GSTP1) and cyclooxygenase-2 (COX-2), all of
them potential signs that these cells are subjected
to oxidative stress [8]. For this reason these
changes [globally called proliferative inflammatory atrophy (PIA)] are considered the kind of
lesions that are potential precursors of prostatic
intraepithelial neoplasia [9]; however, the potential premalignant role of PIA is controversial and
the literature shows discrepancies that could be
caused either by the weak inter-relation of both
lesions or by the lack of homogeneous morphological criteria [10вЂ“12].
12
Ferran Algaba, Isabel Trias, Yolanda Arces
Fig. 2.4 Proliferative inflammatory atrophy (PIA)
Prostatic Intraepithelial Neoplasia
Prostatic intraepithelial neoplasia (PIN) includes
lesions characterised by neoplastic nuclear atypia
of the luminal cells with (total or partial) persistence of the basal layer and with no evidence
of basal membrane rupture [13]. This definition
spans from the mildest changes (low-grade PIN)
to the most obvious ones (high-grade PIN) (HGPIN) (Fig. 2.5). Due to the poor reproducibility
of the low-grade PIN, its diagnosis is usually
avoided, and HGPIN is only reflected in the pathology reports [14].
As already mentioned, certain observations
topographically relate PIA changes to HGPIN
(proximity between both lesions in 42.5% of
cases), and there is evidence of transition from
normal secretory epithelium to atrophic epi-
thelium and HGPIN changes (Fig. 2.6) [10],
which, jointly with GSTP1 inactivation by
hypermethylation, can explain the accumulation
of genomic changes to the cancer transformation
[7].
High-grade PINвЂ™s inter-relation with prostate
cancer shows itself through some epidemiologic
(both lesions undergo parallel increase with age),
topographic (proximity of both lesions in the
prostatectomy specimens in 70% of cases), morphologic (progressive loss of basal cells, atypia
with increased size and nuclear irregularity) and
genetic-molecular evidence (gain of chromosome 7q31 and 8q, loss of 8p, 10q, 16q and 18q
and expression of О±-methylacyl-CoA racemaseAMACR) [6, 15]. Together, these factors have
led to high-grade PIN being considered the most
likely precursor of prostatic carcinoma.
2 Natural History of Prostatic Carcinoma: The PathologistвЂ™s Perspective
13
Fig. 2.5 High-grade prostatic intraepithelial neoplasia (HGPIN). Malignant transformation of the
luminal cells with basal cells preserved
High-Grade PIN Evolution
Four architectural patterns of HGPIN (flat 28%,
tufting 87%, micropapillary 85% and cribriform
32%) have been described (Fig. 2.7) [16]. Even
though the patterns often merge with each other,
the possibility of a progressive transformation
of the flat pattern into a micropapillary one and
a cribriform one is a tempting thought. Some
authorsвЂ™ observation that the most central cells
of the papillary and cribriform patterns are more
undifferentiated and lose more heterozygosity
than those that are closer to the basement membrane, and also that carcinomas associated with
these patterns of HGPIN are clinically more
aggressive, reinforce this supposition [17, 18, 19],
which seems to be confirmed by the description
of unusual cell typesвЂ”such as signet ring cells
PIN, and small cells or neuroendocrine cell PIN
typesвЂ”in cribriform types (Fig. 2.8) [20] similar
to invasive carcinomas. All of these observations
have been the reason why some authors consider
the possibility that some of these changes indicate an intraductal carcinoma [21]. This notion, however, was rejected by consensus on
many occasions owing to lack of reproducible
criteria.
Another feature to be highlighted is the interrelation between HGPIN and the initial invasive
carcinoma. Continuity between carcinoma and
HGPIN was observed in 47.6% of cases with
small foci of invading carcinoma (Fig. 2.9) [22],
and some morphometric studies have linked the
initial microinvasion with the clonal selection
and the surfacing of clones that might be responsible for the invasive phenotype [23].
14
Ferran Algaba, Isabel Trias, Yolanda Arces
Fig. 2.6 HGPIN in continuity with PIA
However, and despite all that has been stated
above, some authors consider it possible that the
transition from normal epithelium to invasive
prostate cancer occurs without an intermediate
morphological stage [24].
Molecular Pathology of Stromal Invasion
in Prostate Cancer
Stromal invasion requires cellular detachment,
basal membrane degradation and the ability of
the cells to grow in a stromal environment.
The loss of cellвЂ“cell adhesion correlates with
the abnormal expression of adhesion molecules.
Amongst these, E-cadherin and N-cadherin play
the leading roles.
E-cadherin is coded at chromosome 16q21/22
and inter-relates with MUC-1 (EMA; episialin).
It is expressed in the prostatic normal secreting
cells. N-cadherin is coded at 18q 11.2 and it is
not expressed in the normal prostate [25].
The loss of E-cadherin seems to play quite an
important role in the invasive ability of prostate
carcinoma (Fig. 2.10) [26]. This loss of expression
of E-cadherin is accompanied by a progressive
N-cadherin expression, which in turn evolves
from a membrane pattern towards a dotted pattern, with intermediate stages of co-expression of
both cadherins in a same cell [25]. These changes
correlate with the progressive glandular pattern
loss (Gleason model). The progressive appearance of N-cadherin in the prostate cancer cell
membrane brings about a mesenchymal-like
transformation of the malignant cells [27], as if
such mimesis favoured the metastatic ability by
means of adherence to the stromal cells.
We may thus consider E-cadherin a tumoursuppressing gene, and its cellular recovery could
have great significance as a treatment of cancer,
which looks possible [26, 28].
The loss of cell-stromal adhesion is associated
with loss of hemidesmosome-forming proteins
and related adhesive molecules as integrins [29].
2 Natural History of Prostatic Carcinoma: The PathologistвЂ™s Perspective
Fig. 2.7 Flat, tufting, papillary and cribriform patterns of the HGPIN
Fig. 2.8 Cribriform HGPIN with neuroendocrine (small cells) differentiation in the luminal area
15
16
Ferran Algaba, Isabel Trias, Yolanda Arces
Fig. 2.9 HGPIN near to prostate carcinoma with microinvasion
To be able to proliferate, the cells need an attachment to the basal membrane, but cancer cells continue to proliferate when unattached, a phenomenon that is known as anchorage independence
[30]. Such independence requires a false message
to the nucleus that the cell is properly attached
when actually it is not; this message is probably
sent by the malignant cell with expression of laminin and collagen receptors through the synthesis
of the basal membrane material [31].
Gleason Grading System of Prostate
Cancer as a Model of Evolution
When the carcinoma becomes invasive, its aggressiveness increases with the increase of genetic (chromosomal) changes, evaluable through
the changes of the nuclear matrix (increased size,
contour abnormalities and nuclear chromatin
irregularity). All of these changes are included
within the notion of nuclear degree of differentiation; however, because the nuclear matrix,
the cytoplasmatic filaments and the intercellular
adhesion molecules are closely inter-related, the
above-mentioned nuclear changes may also be
expressed by means of changes in the architectural arrangement of the neoplastic cells [32].
In prostate cancer the most widely internationally accepted grading model is the Gleason
score [33] based on the progressive loss of the
gland pattern and the increased peritumoural
stroma invasion (Fig. 2.11). This grading system
can be considered a model of the invasive prostate cancer progress, since close relationship has
been shown with the progressive loss of E-cadherin expression, and also the abnormal expression of other adhesion molecules [34].
2 Natural History of Prostatic Carcinoma: The PathologistвЂ™s Perspective
17
Fig. 2.10 E-cadherin expression in well-differentiated prostate carcinoma and loss of the expression in badly differentiated cancer
Differences Between Transition
and Peripheral Zone Prostate Cancer
Following the GleasonвЂ™s progression model, we
may mention that 68.9% of carcinomas originated at the transition area show a Gleason score
of 4 or lower, whereas in 65.8% of the carcinomas originated at the peripheral area the Gleason
score is 7 or higher (authors observation). These
findings are concurrent with those published by
other authors, who found the average Gleason
score of the tumours of the transition area to be
5, whereas those of the peripheral area are 7, and
they correlate to indicators of lower cell activity
and lower aggressiveness in the tumours of the
transition area than in those of the peripheral
area (Mib1-Ki67 expression in 1.5 versus 5%, aneuploidy in 13.3% versus 53.3%, p53 overexpres-
sion in 2% versus 11%, and bcl-2 expression in
6% versus 27%) [35].
The reason for these differences is unknown.
One possible explanation could be the existence of
different precursory lesions at each of the areas.
We should remember that the transition area
is the one that develops benign prostate hyperplasia, and so the carcinomas in this area coincide with hyperplasia changes. There has been
some speculation that certain forms of microglandular hyperplasia with atypia (atypical adenomatous hyperplasia, AAH) may play a role as
cancer precursors [36]. This would explain why
the carcinomas of the transition area develop a
microglandular appearance very similar to GleasonвЂ™s patterns 1, 2 and 3A; nonetheless, there is
not enough scientific evidence of these lesions to
be inter-related [37].
18
Ferran Algaba, Isabel Trias, Yolanda Arces
Fig. 2.11 Gleason model with patterns from 1 to 4
However, the HGPIN being the most likely
precursor of prostatic carcinoma in the peripheral area, and observing the similitude between
the cribriform pattern of HGPIN and Gleason
patterns 3B and C with pattern 4 [38], it is not
difficult to assume that when these HGPIN lesions turn into invasive carcinoma, they already
show Gleason patterns 3, 4 and 5.
Molecular Pathology
of Prostate Cancer Progression
In prostate cancer, progression does not only
mean distant metastases but also the hormone
independence of its cells (hormone refractory
prostate cancer).
Metastasis
For a long time bone metastasis preference of
prostate cancer was thought to be caused by a
retrograde flow from the Batson plexus into the
pelvic area during the Valsalva manoeuvre, but
currently other metastatic factors are considered more important. Among them, the most
widely studied factor is the expression of adhesion molecules with an вЂњarea codeвЂќ for bone marrow (OB-cadherin and integrin О±2ОІ1), a selective
adhesion via integrin of prostate cancer cells to
bone marrow cells that probably contributes to
bone metastasis [39]. Other metastasis-associated genes are: KAI1 (11p11.2), whose loss is
associated with greater metastasis [40]; protein
p9Ka encodesd by calcium-binding protein gene,
2 Natural History of Prostatic Carcinoma: The PathologistвЂ™s Perspective
located in cytoskeletal components in a pattern
identical to actin filaments, which changes normal Ca++ metabolism [41], and the bone morphogenetic proteins that induce bone morphogenesis in vivo and are involved in the skeletal
metastases of advanced prostate cancer. Nm23H1 and CD44 are less solid factors [42].
Hormone-Refractory Prostate Cancer
The lack of response to hormone blockade may
be due to many causes. The stem cell model, discussed above, explains the possibility that, according to the transformed cell being either the
early or the late intermediate cell, the tumour
may be less or more sensitive, respectively, to
anti-androgen therapy [4]. Likewise, the extensive and multifocal neuroendocrine differentiation of prostate adenocarcinoma may represent
a different path to androgen independence because these cells can maintain cell proliferation
through a paracrine androgen-independent pathway [43].
Another explanation for hormone therapy
resistance is the multifocality and heterogeneity
of prostate carcinomas. Around 80% of prostate
carcinomas are multifocal, and this multiplicity
is not only topographic but may also correspond
with genetic and molecular variability [44], and
for this reason a patient may have hormone-dependent carcinoma foci concomitantly with hormone-refractory ones.
But not all the hormone-refractory neoplasias
have a specific phenotype; in order to survive
they may undergo a series of cellular adaptations,
and thus, by means of androgen receptor amplification (30% of the hormone-refractory cases),
they only need minimum amounts of androgens.
Amplification of 8q24 (through c-myc amplification?) and changes in chromosome 7 have also
been found in 80% of such cases [45, 46]. It is
possible as well to find androgen receptor mutations leading to oestrogen sensitivity, and also
overexpression of non-androgenic steroid androgen receptor coactivators [47, 48].
Bcl-2 could also play a role in the hormonal
independence mechanism because it is more frequent in these tumours than in hormone-sensitive neoplasias [49].
19
Prostate Cancer
Modifications After Treatment
At present there are various treatment alternatives to surgery, and also as adjuvants of radical
treatments. All of them are able to induce a series or morphological variations that modify the
characteristics of prostate cancer and make their
interpretation difficult when biopsy specimens
are taken.
Hormone therapy causes progressive atrophy
of cells with hormone receptors (luminal or secretory cells), be them neoplastic or not, leading to
an atrophic aspect of the whole glandular structure, with special emphasis on the basal cells. The
luminal cells lose their prostate-specific antigen
(PSA) expression of alpha-methylacyl-coenzyme
A racemase (AMACR) ability, but they retain
the expression of AMACR and of intermediate filaments such as CAM 5.2. (Fig. 2.12) [50].
Reduced incidence and extension of HGPIN
post-hormone therapy has also been verified.
Treatments with radiation therapy, either
external beam radiotherapy or brachytherapy,
induce variations similar to those of hormone
therapy, but with far more prominent nuclear
atypia (Fig. 2.13) [51], which entails that sometimes the prostatic biopsies show changes difficult to interpret called glands of the indeterminated category (Fig. 2.14). These gradually
disappear over time, and only 18% of the patients
show residual active prostate cancer [52]. Other
much newer treatments, such as cryotherapy and
high-intensity focussed ultrasound (HIFU) specifically elicit changes related to necrosis, fibrosis
and healing changes [53вЂ“55].
In view of all these variations, particularly
those that modify the gland structure, recommendation has been issued not to evaluate the
degree of differentiation (Gleason model) as we
do not know the biological significance of such
models after treatment [56].
Clinical Application of the Pathological
Natural History of Prostate Cancer
The body of observations commented upon above
is useful as an introduction to understanding the
natural history of prostate cancer; however, not
20
Fig. 2.12 Post-hormonotherapy expression of AMACR and CAM 5.2
Fig. 2.13 Prostate cancer after radiotherapy
Ferran Algaba, Isabel Trias, Yolanda Arces
2 Natural History of Prostatic Carcinoma: The PathologistвЂ™s Perspective
all of those observations are applicable in current
practice.
The PIA lesion may represent an interesting
preventive therapy target, provided it is shown
to be a usual step between a normal gland and
intra-epithelial neoplasia, and particularly if an
efficacious anti-inflammatory treatment without side-effects is attained. Additionally, HGPIN
is proving to be useful as a marker of probable
concomitant prostate carcinoma. Furthermore,
adhesion molecules enable us to know the dynamics of invasion and metastasis, but we still
do not have the methods that allow us to affect
progression.
By means of the Gleason model a correlation
can be established with pathological extension
(tumour volume) [57] and metastatic capacity
(score 2 to 5: 14% metastasis; score 6: 32%; score
7: 50%; score 8: 75% and score 9вЂ“10: 100%) [58].
But the most common clinical factor still associated with prognosis is the stage or level of ex-
21
tension of the carcinoma. Following the UICC (T
category) classification of 1992, we note that rates
of lymph node metastasis for incidental localized
carcinoma are respectively 2% (T1a), 26% (T1b),
and 4% (T1c), while the rates for clinically localized carcinomas are 1% (T2a) and 25% (T2b)
[59, 60]. This confirms that tumour volume remains quite reliable in terms of prognostic value
(the incidence of lymph node metastases is the
same in T1b tumours, i.e. involving more than
5% of the tissue, and T2b tumours, i.e. extensive
clinical tumours) even in the needle biopsy [61].
For this reason, one of the primary roles of the
pathologist is to determine extension (T stage).
As a refinement of local extension evaluation,
microvascular invasion can be an important marker. It is present in 38% of the radical prostatectomy specimens and is commonly associated
with extraprostatic extension (62%) and lymph
node metastases (67%), and correlates with
grade and progression [62]. Intraprostatic peri-
Fig. 2.14 Prostate glands of the indeterminated category, post-radiotherapy
22
neural invasion indicates tumour spread along
the path of least resistance; only 50% of these patients have extraprostatic extension, so it is not
very useful [63] and it is in relation to tumoural
volume [61].
The neuroendocrine differentiation somewhat implies a poor prognosis, and in some cases
it explains hormone independence [64], probably through the correlation with vascular endothelial growth factor (VEGF) and transforming
growth factor (TGF)-alpha (angiogenic factors)
[65], and the absence of androgenic receptors.
From all of the above we may conclude that
currently we are in front of the identification of a
series of molecular markers, some of which may
be of prognostic and therapeutic use. To date, the
refinement in grade and stage evaluation, as well
as hormone sensitivity determination, are the
most widely used methods to identify and assess
the severity of prostate cancer.
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3
Prognostic Factors in Prostate Cancer
Johan Braeckman, Dirk Michielsen
Recent Results in Cancer Research, Vol. 175
В© Springer-Verlag Berlin Heidelberg 2007
Abstract
In the nineteenth century the main goal of medicine was predictive: diagnose the disease and
achieve a satisfying prognosis of the patient's
chances. Today the effort has shifted to cure the
disease. Since the twentieth century, the word
prognosis has also been used in nonmedical
contexts, for example in corporate finance or
elections. The most accurate form of prognosis
is achieved statistically. Based on different prognostic factors it should be possible to tell patients
how they are expected to do after prostate cancer
has been diagnosed and how different treatments
may change this outcome.
A prognosis is a prediction. The word prognosis comes from the Greek word ПЂПЃПЊОіОЅП‰ПѓО· and
means foreknowing. In the nineteenth century
this was the main goal of medicine: diagnose the
disease and achieve a satisfying prognosis of the
patient's chances. Today the effort has shifted towards seeking a cure.
Prognostic factors in (prostate) cancer are defined as вЂњvariables that can account for some of
the heterogeneity associated with the expected
course and outcome of a diseaseвЂќ [1]. Bailey defined prognosis as вЂњa reasoned forecast concerning the course, pattern, progression, duration,
and end of the diseaseвЂќ [2]. Prognostic factors
are not only essential to understand the natural
history and the course of the disease, but also to
predict possible different outcomes of different
treatments or perhaps no treatment at all. This
is extremely important in a disease like prostate
cancer where there is clear evidence that a substantial number of cases discovered by prostatespecific antigen (PSA) testing are unlikely ever
to become clinically significant, not to mention
mortal [3]. Furthermore, prognostic factors are
of paramount importance for correct interpretation of clinical trials and for the construction of
future trials. Finally, according to WHO national
screening committee criteria for implementing a
national screening programme, widely accepted
prognostic factors must be defined before assessing screening [4].
Prognostic Factors May Be TumourRelated, Patient-Related or Independent
Variables
The anatomical extent or stage of the disease, measured with the International Union
Against Cancer (UICC) Tumour Node, Metastasis (TNM) classification [5], is our first guide
in prognosis, but does not include all relevant
prognostic factors in prostate cancer, especially
PSA and Gleason score [6]. Not surprisingly, the
post radical prostatectomy (RP) margin status is
also a very strong independent prognostic factor [6]. TNM stage, PSA, Gleason score and post
prostatectomy margin status are strong, independent and tumour-related prognostic factors.
Today it is obvious that patient or host-related
factors such as age, ethnic origin, general condition, co-morbidity (especially immune status)
and medication play an equivalent role in the
determination of the individual patientвЂ™s prognosis. Not to forget the personal preference of the
patient confronted with different treatment possibilities, todayвЂ™s patients are better informed and
more assertive, and participate more actively in
the therapeutic decision making than ever before.
The patientвЂ™s personal choice, variably influenced
by his subjective interpretation of treatment benefits and treatment risks, certainly has a greater
impact on prognosis too.
26
Johan Braeckman, Dirk Michielsen
Table 3.1 Components of the Veterans Administration
Cooperative Urological Research Group (VACURG)
system [41], the bin model [42] and the Partin tables for
prognosis of prostate cancer
VACURG
T+Gleason
Bin
TNM+Gleason
Partin
TNM+Gleason+PSA
Unfortunately, even today prognosis is also
affected by environment-related variables that
are completely independent of the patientвЂ™s life
expectancy and his tumour. In some places these
вЂњexternalвЂќ factors, such as demography, national
health-care policy and social obstruction to
medical care, may change the outcome of this
disease dramatically [7].
Patient assessment should include a complete personal and family history, co-morbidity
and medication, presence of lower urinary tract
symptoms, symptoms suggesting regional/distant spread, and a complete physical examination
with digital rectal exam. Serum PSA level should
be obtained, and depending on the risk category
(Table 3.1) an isotope bone scan or computed
tomographic examination (CT) of the abdomen
and pelvis may be indicated. In patients with low
risk of metastases the imaging studies are not
mandatory, although one might have them done
anyway, perhaps to obtain reference documents
to compare with possible later positive studies in
a given patient.
Standard treatment approaches for localized and locally advanced disease include active
monitoring, RP, brachytherapy, external beam
radiotherapy (EBRT), hormone therapy or a
combination of EBRT and hormones depending
on the tumour and patient characteristics. Estimated life expectancy is an important factor in
determining whether local treatment should be
utilized in management. Randomized clinical
trials have shown the efficacy of adjunctive hormonal therapy in patients with high-risk disease
treated with radiation therapy. In metastatic
disease hormonal therapy is the mainstay of
treatment and chemotherapy has recently been
shown to prolong survival in patients with hormone refractory disease [1].
Anatomical Extent of Disease
The local extent of disease in the prostate has
been demonstrated in multiple studies to be an
independent marker of prognosis in prostate
cancer [5]. It is assessed by digital examination
and/or transrectal ultrasound and described by
T category. Other methods include magnetic
resonance imaging (MRI) with endorectal coil,
ProstaScint(Cytogen, Princeton) [8] and positron emission tomography [9]. Each is being
evaluated, but to date the results are inconclusive. The volume of the tumour itself does not
seem to provide much useful prognostic information [10].
Certainly in the choice for brachytherapy and
sometimes also for RP, the total prostate volume
may be restrictive and then also becomes a prognostic factor. Pretreatment N and M categories
can be assessed by cross-sectional and skeletal
imaging. The sensitivity of both investigations
depends on serum PSA and Gleason score. Low
PSA values and Gleason scores are rarely associated with extraprostatic disease and in many
countries the imaging studies are not performed
when the odds are low. In Europe, increasing
numbers of centres no longer perform bone
scans in asymptomatic patients with PSA levels below 20. The presence and extent of pelvic
lymph node disease correlates clearly with outcome [11]. In more advanced disease, increased
tumour involvement on bone scan or visceral
organs is of prognostic importance [12].
Histology
The histological tumour grade plays a key role
in predicting progression and overall survival.
Over the past two decades the Gleason system
has become the preferred pathological grading system for prostate cancer [13]. Studies by
Albertsen et al. [14, 15] emphasize the prognostic value of Gleason score, especially in men with
localized disease. Young patients with high-grade
T1вЂ“T2 disease are best treated surgically, whereas
the therapeutic success rate of brachytherapy is
poor in these patients. The second study states
that aggressive treatment is not recommended
for low-grade localized prostate cancer.
3 Prognostic Factors in Prostate Cancer
Unfortunately the Gleason score is first assessed by light microscopy examination of core
biopsies and does not always correlate with the
final pathological grade resulting from the examination of the RP specimen; neither does it
prove to have perfect reproducibility [16]. Other
histopathological factors such as DNA ploidy,
microvascularization, perineural invasion and
the percentage of positive cores on needle biopsy have been assessed and confronted with the
outcome. Only the percentage of positive cores
has been shown to be of independent prognostic
significance in one study [17]. In another study
both the number of positive biopsy sites and the
highest percentage of adenocarcinoma at any biopsy site were significant predictors of small volume cancer in RP specimens [18].
Lymphovascular invasion, identified on the
RP specimen, is an independent predictor of
PSA relapse and cancer specific survival [19].
New histological assays are currently under
investigation. Zinc О±-2-glycoprotein (ZAG),
detected by immunohistochemical staining of
prostate cancer tissue, showed to be an independent prognostic factor, reversely correlated with
the Gleason score [20].
27
also significantly associated with the risk of biochemical progression [26].
PSA variables have been proposed in order
to increase its sensitivity to diagnose localized
disease. These have met with limited success,
with the possible exception of the measurement
of percentage of free PSA. The rate of change
of PSA over time, PSA velocity, and especially
its doubling time showed to hold some prognostic value, mostly in recurrent and hormone
refractory disease [27вЂ“30].
More work is being done on other derivates
such as complex PSA and PSA-specific membrane antigen. Recent and ongoing research is
also focussed on the prognostic role of cancerrelated gene products such as p53, p16INK4A,
p27KIP1, BCL-2, caspase proteins, cyclins,
E-cadherin, Ki-67, vascular endothelial growth
factor (VEGF), fibroblast growth factor (FGF),
angiogenesis inhibitors, and others [16, 31, 32,
33]. The prediction of the behaviour of prostate cancer with gene expression transcript profiles looks promising but has to be validated in
upcoming clinical trials.
Age and Life Expectancy
Prostate Specific Antigen
and Other Molecular Biomarkers
PSA is applied worldwide in the diagnosis and
monitoring of prostate cancer. It is appreciated
as an independent prognostic factor, both at
diagnosis and relapse, either for localized or
advanced disease [21, 22]. But as PSA is not
cancer specific, one must be somewhat cautious,
especially with lower PSA values in the early
stages of the disease. Currently, for newly diagnosed prostate cancer patients the prognostic
value of PSA becomes increasingly limited, as
the majority of these patients have a PSA of less
than 20 ng/ml.
A recent study found that PSA was only
weakly associated with prostate cancer volumes
in men treated with RP [23]. However, it is
helpful to predict the risk of marginally positive
disease at RP in conjunction with their T-stage
and the Gleason score [24, 25]. In men with
clinically localized disease selected for RP, PSA is
Although age is a well-known prognostic factor
for survival in prostate cancer in general, there is
considerable controversy regarding its effect on
outcome in patients with localized disease [34].
The controversy is highest in older patients. Life
expectancy is a much better parameter in this
situation. In more advanced disease older age
at presentation and poor performance status are
adverse prognostic features [12].
The presence of significant co-morbidity has
a definite impact on outcome both in early and
advanced stages [35].
Race
Race is also a well-known risk factor for developing prostate cancer, but surprisingly this disease
also behaves differently in men of different races.
Whether this is due to patient-related factors or
to external factors is not clear yet. A study from
Dayal et al. in 1985 suggested that the racial
28
difference between blacks and Caucasians in the
survival prognosis for prostate cancer was to a
large extent the result of differences in socio-economic status [36].
вЂќExternalвЂќ Factors
Some studies have suggested that reduced access
to health-care by lower socio-economic groups
contributes to a higher death rate from prostate
cancer [36, 37]. Whether this results directly from
the socio-economic status itself or rather from of
a higher awareness of the usefulness of early PSA
testing in the вЂњupper classвЂќ patients is not clear
yet. One should first check the true incidence of
prostate cancer in both groups, define the stage
distributions and compare the treatments offered
to the patients. Meanwhile, it has been shown
that in more educated populations a majority of
even the elderly patients with low-risk prostate
cancer receive some form of treatment [38].
It is clear that access to quality care, possibly influenced by socio-economics but also by
demography and national health-care politics,
has an important impact on prognosis. This is especially applicable in early disease, where the ability to achieve free surgical margins or to propose
appropriate radiation has shown to be of significance [39, 40]. In the first paper [39], Eastham et
al. conclude that the вЂњlower rates of positive surgical margins for high-volume surgeonsвЂќ suggest
that experience and careful attention to surgical
detail can decrease positive surgical margins and
improve cancer control with RP.
Combined Prognostic Factors
The obvious way to improve the usefulness of
prognostic factors is to combine them. Early experience was obtained with the VACURG system,
based upon T-category and Gleason score [41],
and the bin model, combining the TNM information and the Gleason score [42]. Today nomograms like the Partin tables [25], for the prediction of the pathological stage, the margin status
and possible lymph node involvement based on
the biopsy Gleason score, the clinical stage and
the PSA, are widely used in everyday urological
Johan Braeckman, Dirk Michielsen
practice. The components used in the VACURG,
bin and Partin tables are listed in Table 3.1. In
the late 1990s Kattan et al. presented useful
pretreatment nomograms for patients treated
with RP, conformal external radiotherapy or
brachytherapy [44вЂ“46]. Although these tables
are popular and widely used, at their best they
have an area under the ROC curve (AUR) of 0.75
[47]. Ramsden and Chodac analysed risk factors for biochemical progression in prostatectomized patients with seminal vesicle invasion to
validate KattanвЂ™s nomogram in this pathological
subgroup [48]. They found that the components
of the nomogram were not significant, but still
useful in helping to direct adjuvant therapy. Recently Kattan et al. noted that adding molecular
markers to the clinical parameters could improve
the AUR to 0.83 [49]. In the future, much is expected from artificial neural networks that may
be useful for simultaneous incorporation of the
many different prognostic variables associated
with prostate cancer [50].
Conclusion
The classical prognostic factors in prostate cancer
are its TNM stage category, the serum PSA level
and the Gleason score. In localized disease, low-,
intermediate- and high-risk groupings have been
proposed based upon these factors (Table 3.2).
The groupings have been shown to predict for
prostate cancer specific mortality [6]. The widespread introduction of PSA screening in many
counties caused an important diagnostic shift
towards early stage, low-risk prostate cancer.
In the United States the proportion of patients
presenting with high-risk disease dropped from
37% to 16% between 1989 and 2002 with a cor-
Table 3.2 Prognostic risk groupings for localized/locally
advanced prostate cancer categories
Risk group
PSA
(ng/ml)
Gleason
score
UICC T
category
Low (all of)
в‰¤10
в‰¤6
в‰¤T2a
Intermediate (any
of, if not low risk)
в‰¤20
7
High (any of)
>20
в‰Ґ8
T1/T2
в‰ҐT3
3 Prognostic Factors in Prostate Cancer
responding rise in the proportion of patients
with low-risk disease from 30% to 47% [51]. It
is clear that more and refined prognostic factors are necessary in order to select the proper
patients for the proper treatments. Recent collaborative initiatives addressed this issue in an
attempt to categorize different prognostic factors. From 1993 to 1999, under the auspices of
the World Health Organization (WHO), the
UICC or the College of American Pathologists
Table 3.3 Classification of prognostic factors for prostate
cancer: recommendations of the 1999 WHO consensus
conference. Modified from Bostwick and Foster [53]
Category 1
TNM stage
Histological grade (Gleason score and WHO nuclear
grade)
Surgical margin status
Perioperative PSA
Pathological effects of treatment
Location of cancer within prostate
Category II
DNA ploidy
Histological type
Cancer volume in needle biopsy specimens
Cancer volume in radical prostatectomy specimens
Category III
Prostate-specific membrane antigen
Other serum tests (P5 M, hK2, insulin-like growth
factor...)
Perineural invasion
Vascular/lymphatic invasion
Microvessel density
Stromal factors, including insulin-like growth factor ОІ,
integrins, ...
Proliferation markers and apoptosis
Nuclear morphometry and karyometric analysis
Androgen receptors
Neuroendocrine markers
Genetic markers
All other factors that do not appear in categories I and II
29
(CAP), seven international conferences were at
least partly organized with that intent [52]. The
most recent meeting of the WHO in Paris classified the prognostic factors [53] as category I
(factors that have been proved to be prognostic
or predictive based on evidence from multiple
published trails and that are recommended for
routine screening), category II (factors that show
promise as predictive factors based on evidence
from multiple published studies but that require
further evaluation before recommendation or
are recommended despite incomplete data as diagnostic or prognostic markers) and category III
(factors awaiting further study to clarify their
value in the prognostic arena). The selected factors are listed in Table 3.3.
These factors are all tumour-related, but prognosis is also determined by the patientвЂ™s personal
data related to his age and even more to his individual life expectancy. The benefit of any treatment with curative intent in patients with localized low- and intermediate-risk disease remains
controversial and is being addressed in ongoing
trials. A refinement of prognostic factors for disease progression will be critical in resolving this
therapeutic dilemma. In high-risk disease and
advanced disease, the role and the timing of adjunctive treatment to improve progression-free
and overall survival need to be evaluated. Ongoing and future trials should not only focus on
the therapeutic outcomes but also on the identification of more useful prognostic factors to tell
us which patient needs which treatment at what
time. A better combination of clinical, pathological and molecular вЂњdisease predictorsвЂќ should
enable us to distinguish harmless from lifethreatening prostate cancer. But even then, the
old adage, вЂњwe donвЂ™t treat tumours but patientsвЂќ,
should always lead our decision-making, with
respect to the patients individual life expectancy
and expectations.
The health provider can also be a prognostic factor. This was already hinted at when we
mentioned the relation between the skills of the
surgeon performing a RP and the chance of margin-free disease. But it is clear that optimal guide
counselling and commitment of treatment should
only be done by people who know their business.
Finally, efforts to provide optimal health-care
for everybody everywhere may seem a utopia,
30
but somehow it does not seem right when someoneвЂ™s socio-economic or demographic situation
affects his prognosis significantly.
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4
The Prevention of Prostate Cancer
Keith Griffiths, Domenico Prezioso, A. Turkes, Louis J. Denis
Recent Results in Cancer Research, Vol. 175
В© Springer-Verlag Berlin Heidelberg 2007
Abstract
From our better understanding of the natural
history of prostate cancer, it is not unreasonable
to believe that the disease is preventable. Prostate
cancer has become a major healthcare problem
worldwide, as life expectancy increases. Moreover, the cancer is slow growing, with a period
of about 20вЂ“25 years from initiation to the stage
when the clinically detectable phenotype can be
identified. This review provides a simple overview of the endocrinology of prostate cancer and
discusses some of the pharmaceutical agents that
have been or are being tested to restrain, possibly arrest, the progression of this slowly growing
cancer. Also discussed are many of the dietary
factors that may influence the molecular or endocrine events implicated in its development.
Dietary factors are considered responsible for
the geographical differences in prostate cancer
incidence and mortality. Since about 50% of all
men worldwide, from both East and West, show
evidence of microscopic cancer by 50 years of
age, growth restraint would appear to be the
pragmatic option to the possibility of preventing
initiation.
alent in Western developed countries, but rare in
Asia [2]. Until recently the concept that dietary
variability could influence the pathogenesis of
cancer was considered with scepticism, but now
interest centres on whether worldwide variability
is caused by dietary factors such as the high intake of fat in the West, or prevented by particular
constituents of the Asian diet.
Many constituents could impinge on the
molecular events implicated in prostate carcinogenesis to provide health benefit [3, 4],
and interest in chemoprevention has increased
spectacularly. As our understanding of prostate
growth regulation dramatically develops [5вЂ“8],
potential roles for dietary factors become easier
to appreciate [4, 9, 10] and there is little doubt
that geographical differences in diet and lifestyle
account for a large part of the worldwide variability in incidence.
The Natural History of Prostate Cancer
Prostate cancer is a disease of middle-aged men
which presents clinically beyond 50 years of age
and involves a slowly growing tumour that takes
Some Introductory Perspectives
The concept that prostate cancer is preventable is
by no means new. Questions posed by Huggins
[1] at one of the earliest meetings to specifically
discuss the biology of the gland are still relevant.
He highlighted certain unresolved problems
(Fig. 4.1) that today continue to exercise the
minds of investigators, none more so than the
reasons for the geographical differences in the
incidence of prostate cancer. The disease is prev-
Fig. 4.1 The perceived important issues relating to human
prostate disease in 1962 [1]
34
Keith Griffiths et al.
Fig. 4.2 Diagrammatic representation of the natural history of prostate disease that illustrates the slow-growing nature
of prostate cancer
more than 25 years to develop from a focal lesion
to the malignant phenotype (Fig. 4.2). Once
outside the confines of the capsule, the disease
is incurable. Its natural history is characterised
by a 20-year development phase, followed by a
10-year preclinical, asymptomatic period. Secondary prevention through early diagnosis using
serum prostate-specific antigen (PSA) analysis
and prostate biopsy has dramatically increased
incidence rates during the preclinical period,
creating interest in population screening. The results of international randomised screening trials
are awaited [11].
Particularly important, however, is that the
preclinical period offers the potential for primary chemoprevention, which will probably not
prevent initiation but certainly could suppress
the rate of cancer growth and progression. The
natural history highlights phases where preventive strategies can be focussed.
4 The Prevention of Prostate Cancer
вЂ“ Initiation would seem to occur soon after the
dramatic hormonal changes associated with
puberty and prostate growth. A maleвЂ™s developing sexuality through this time, possibly
afterwards [12], may also constitute an endogenous risk factor [13, 14], contributing to
the dysfunctional growth regulatory events
recognised at this time: prostatic intraepithelial hyperplasia (PIN), latent focal cancer, microscopic benign prostate hyperplasia (BPH)
and chronic inflammation associated with
prostatitis and proliferative inflammatory atrophy (PIA).
вЂ“ Inappropriate intrauterine oestrogen-mediated gene imprinting could significantly influence the prostate in later years by enhancing
its propensity to induce precancerous lesions
[15]. Genes associated with the insulin-like
growth factor (IGF)-network and other oestrogen-related events have been implicated in
imprinting, essentially comprising a mechanism by which certain genes are вЂ�silencedвЂ™.
вЂ“ After sustained prostate growth at puberty,
homeostasis should normally be established,
with a balance attained between the rates of
cell proliferation and cell death. The balance,
which should sustain a growth-quiescent
gland, despite high levels of circulating testosterone [16вЂ“18], is not always established, and
epithelial hyperplasia associated with microscopic BPH [19, 20] and PIN [21, 22], generally perceived as the precursor of microfoci of
latent cancer [23], are lesions which occur in
all men worldwide, irrespective of race.
вЂ“ The progression of latent cancer to the invasive
phenotype seems to be the feature of Western
men and results in the geographical variation
in prostate cancer incidence and mortality [9].
Relevant is that nearly 40% of all men worldwide will harbour latent prostate cancer.
вЂ“ A possible relationship between PIN and
cellular inflammatory lesions that characterise
prostatitis deserve consideration with regard
to adverse growth regulation [24, 25]. An important issue involves whether post-pubertal
consequences of oestrogen-related imprinting
relate to the induction of PIA [26вЂ“29].
вЂ“ Cancer progression to malignancy occurs
around the andropause [11], when plasma
levels of testosterone fall relative to those of
35
oestradiol-17ОІ, and the oestrogen/androgen
ratio can increase by up to 40%. Since this
enhanced oestrogenic status is considered responsible for the stromal hyperplasia characteristic of BPH, it is not unreasonable to consider that oestrogens may also be implicated
in the molecular events that support cancer
progression [9, 12, 27, 30].
вЂ“ Preventive measures that delay the development of clinical disease are clearly necessary,
and compelling evidence supports such a role
for certain isoflavonoids and flavonoids [4, 9,
27].
Pragmatically, of all the reported risk factors,
nutrition presents the most reasonable means of
rationalising the global variability of the disease.
Of interest are studies [31] of Asian migrants
to North America; within two generations they
assume an incidence closer to that of indigenous
males (Fig. 4.3). Moreover, as Asians acquire
Western dietary habits, changes in cancer incidence must be monitored [32, 33]. Already
in Japan a rising prostate cancer incidence [35]
is seen to relate to a rising intake of dietary fat.
Prostate cancer is a major health-care problem,
now exacerbated by increasing life expectancy
worldwide. Preventive strategies are being considered [34, 35, 36] through reviews of closed
and on-going trials of various dietary and hormonal factors that were established to assess efficacy and associated adverse effects. Few of these
have been completed and analysed.
Some Dietary Factors
for Chemoprevention
Isoflavonoids and Lignans
Phyto-oestrogens, certain isoflavonoids and lignans offer an exciting approach to prevention [3,
4]. They are bioactive (Fig. 4.4) and, as weak oestrogens, may act either as antagonists or agonists
[37вЂ“39] to modulate oestradiol-17ОІ-mediated
signalling. The presence of non-steroidal oestrogens in plants has long been known, with legumes such as soybean, lentils, beans and chickpeas being major sources of isoflavonoids [40].
These foodstuffs contain glycoside conjugates of
36
Keith Griffiths et al.
Fig. 4.3 Age-adjusted incidence rates for
prostate cancer for native Japanese in the Miyagi
Prefecture of Japan (1973вЂ“1981), for early and
later immigrants and for Japanese-Americans in
Los Angeles County (1972вЂ“1985), USA [31]
Fig. 4.4 A simple presentation of the formation of phyto-oestrogens from dietary constituents.
The formation of equol from daidzein is illustrated, together with reported biological effects and
structural relationships with oestrogens
4 The Prevention of Prostate Cancer
genistein and daidzein, which are metabolised
by normal gut microflora to produce the isoflavonoids. Soybean is a dietary staple in Asia, and
many traditional diets of India, Africa, Mediterranean countries, and South America have a
similar high legume content. The intake of legumes has fallen in Western countries over the
last century [41]. Plant lignans, matairesinol and
secoisolariciresinol, are similarly metabolised to
produce enterolactone and enterodiol, which are
also oestrogenic [4]. Flaxseed is a rich source of
lignans, as are other seeds such as sesame and
whole grain cereals like rye, fruits, berries and
vegetables.
The orientation of the hydroxyl groups of
oestradiol-17ОІ confers the moleculeвЂ™s oestrogenicity [9], and similarly that of phyto-estrogens
(Fig. 4.4). Although their oestrogenic properties
could influence prostate cancer progression, they
also demonstrate an imposing array of other biological effects [4, 9]. Their ability to restrain the
growth of experimental prostate cancer models
[34вЂ“36] may result from their capacity to act
as effective anti-oxidants, or as tyrosine kinase,
5О±-reductase (5AR) and aromatase inhibitors, or
to impede angiogenesis.
Enterolactone concentrations are high in
urine of vegetarians [42], and interestingly, substantial amounts are found in expressed prostatic
37
fluid of Portuguese men [43]. The plasma isoflavonoid content in Japan is high [44] relative
to levels in the United Kingdom (Fig. 4.5), with
higher levels in the elderly (Fig. 4.6) suggesting
that younger people are not eating as much soy
protein as their elders. Daily supplementation
with a cereal bar containing the soy protein appropriate to the daily Japanese intake shows the
rapid elevation of plasma concentrations of genistein and daidzein compared to those consistently sustained by Asian people (Fig. 4.7).
Trials are underway [34вЂ“36] to determine
whether soy protein supplementation restrains
the progression of HGPIN to invasive cancer;
another study aims to assess efficacy in preventing further development of cancer in patients
with stage I or II disease.
Flavonoids
Certain health benefits of polyphenolic flavonoids have also been known for a long time.
Unlike the isoflavonoids, however, flavonoids
are ubiquitous in nature and their influence on
health could be profound. Their complex chemistry is well studied [45, 46] and Fig. 4.8 certain
flavonoid structures relative to genistein. Onions
are a source of apigenin, apples of quercetin,
Fig. 4.5 Comparative mean concentrations of genistein and daidzein in Japanese
and British male and female plasma samples. Data from the Tenovus Institute for
Cancer Research, Cardiff
38
Keith Griffiths et al.
Fig. 4.6 Concentrations of genistein and daidzein in plasma samples from Japanese male and female subjects of varying
age. Data from the Tenovus Institute for Cancer Research, Cardiff
4 The Prevention of Prostate Cancer
39
Fig. 4.7 Daily supplementation for 3 days with a soy protein-containing biscuit (Prevacan, XiMed Group, Oxfordshire,
UK), showing concentrations of genistein and daidzein in plasma throughout the first day and during the next 3 days.
The levels of these isoflavonoids in Japanese subjects are illustrated for comparison
green tea of catechins and various anthocyanidins and resveratrol are constituents of red wine.
In ancient times, herbs and spices were synonymous with medicines, including the well-recognized thyme and parsley, garlic and chives and
the cruciferous vegetables [47]. Cinnamon may
suppress inflammatory disease. Curcumin, the
yellow pigment of turmeric, as well as capsaicin
in chilli pepper, are reported [48] to have cancerrestraining activity. Several flavonoidsвЂ”apigenin
and kaempferol, for example [49]вЂ”are also weak
oestrogens; the former, like many flavonoids, is
also an effective anti-oxidant. Others exercise a
range of biological actions, such as the inhibition
of angiogenesis or promotion of apoptosis [50,
51].
Selenium
For many years [52] seleniumвЂ”an essential
trace element found principally in fish, meat
and grainsвЂ”has been thought to be protective
against cancer, although this has never been confirmed unequivocally [53]. An inhibitory effect
on various experimental tumours was reported
40
Keith Griffiths et al.
Fig. 4.8 Chemical structures of certain flavonoids relative to that of genistein. Flavonoids
have a 2-phenylchroman nucleus, and isoflavonoids such as genistein have a 3-phenylchroman nucleus. Also illustrated are the structures of resveratrol, a constituent of red
wine, and one of the catechins present in tea
[54, 55], together with an ability to promote
apoptosis in prostate cancer cell lines [56]. Selenium, as selenocystein, is involved in catalysing
glutathione-S-transferase (GST) ПЂ-regulated reactions, which remove from cells the hydrogen
peroxide formed in tissues in response to inflammatory oxidative stress (Fig. 4.9). A recent study
[57] indicated that men with a high long-term
intake of selenium, as reflected in toenail paring
levels, were at lower risk of developing prostate
cancer. A daily intake of 86 Ојg was considered in
the lower range and 159 Ојg in the higher level.
More recently [58] a decreased incidence of
prostate cancer was reported after selenium supplementation. The daily selenium intake could
be 30вЂ“40 Ојg in the United Kingdom [59], low in
relation to the 1 Ојg/kg per day recommended intake [34].
Current interest centres on the SELECT trial
that is evaluating the efficacy of daily 200 Ојg
4 The Prevention of Prostate Cancer
41
Fig. 4.9 Representation of some molecular events relating to PIA, inflammation
and oxidative stress
selenomethionine intake on prostate cancer
risk, testing selenium against selenium and
О±-tocopherol, 400 mg daily, for 7 years [34, 35].
More than 30,000 North American males are to
be recruited, minimal age generally 55, but 50 for
African-Americans, valuable therefore, in determining whether they effectively restrain progression to clinical cancer. Also of interest would be
a study of early selenium and vitamin E supplementation on chronic inflammatory stress, the
prevention of PIN and progression to HGPIN
(Fig. 4.2).
Vitamins
Much of the epidemiological data relating to
the cancer protective value of vitamin supplementation would seem somewhat equivocal.
For example, in a meta-analysis of results from
12 case-control dietary intake studies and breast
cancer risk [60], a consistent protective effect
correlated with вЂ�fruit and vegetable intakeвЂ™, with
vitamin C considered the consistent factor. Conversely, another review [61] of data on vitamins
A, C and E, concluded that the association between vitamin C and breast cancer risk was
limited, although a modest, protective effect of
vitamin A was recognised. To compound the
inconsistency, results from the United States
Nurses Health Study [62] found no association
between the intake of vitamin C, vitamin E, nor
ОІ-carotene and risk, although again, a protective
effect of vitamin A was identified.
Boyle [63, 64] emphasised caution in accepting conclusions derived from such studies, outlining the need for controlled trials before, for
example, vitamin supplementation should be
recommended as protective against breast cancer. Care was also thought appropriate in relation
to data suggesting that prostate cancer risk increases with increasing intake of ОІ-carotene, the
conclusion from a study of 29,133 Finnish male
smokers [65] whose diet was supplemented with
vitamin E and ОІ-carotene. The data (Fig. 4.10)
suggest that vitamin E (50 mg/day) is protective in male smokers of this age group, whereas
ОІ-carotene supplementation is not, although
both are effective anti-oxidants. Vitamin E had
no effect on lung cancer risk.
Recent interest has centred on lycopene
(Fig. 4.11), responsible for the red colouration
of tomatoes and released by cooking and processing. Uncooked tomatoes are a less effective
source. Lycopene is another effective anti-oxidant [66, 67], with a recent analysis of anti-oxidants in biopsies of adipose tissue showing [68]
it to be the principal constituent. It restrains the
growth of cultured cancer cells [69], possibly
by inhibition of IGF-signalling networks [70].
Tomato powder, as distinct from purified lycopene, increased prostate cancer-specific survival,
in N-methyl-N-nitrosourea-treated rats [71].
Giovannucci [72] considers that tomato intake
42
Keith Griffiths et al.
Fig. 4.10 Data from a Finnish study [65] on the potential beneficial effects of О±-tocopherol and ОІ-carotene on the incidence of cancer in 29,133 male subjects at 6.1 years follow-up. Illustrated are the numbers of cases of prostate cancer,
also seen in relation to the incidence values for cancers of lung and bladder
consistently relates to a reduced risk of prostate
cancer, which is inversely associated with plasma
lycopene concentrations. As lycopene assumes
a potentially important role in prostate cancer
prevention, preliminary randomised trials are
underway [34вЂ“36] to determine the efficacy of
a tomato extract (30 mg lycopene/day) in suppressing progression of HGPIN lesions.
The influence of the carotenoids, vitamin A,
retinoids and retinoic acid on prostate carcinogenesis would seem complex. Although vitamin
A supports normal cellular differentiation and
controls proliferation, it has a limited influence
on established cancer. Various synthetic retinoid analogues have similar characteristics, and
despite high toxicity are thought by some to offer anti-cancer properties [73]. Although more
than 50 carotenoids manifest some вЂ�nutritional
activityвЂ™ [74, 75], only ОІ-carotene, derived from
vegetables and fruit, is generally recognised as
the principal source of vitamin A (Fig. 4.11) and
ОІ-carotene may have a role independent of vita-
min A. Although it seems that vitamin A supplementation may increase the risk of prostate cancer [63, 64], Schroeder [76] reported a significant
increased risk associated with a lower serum vitamin A levels.
Possibly relevant are the classical experiments
of Lasnitski [77, 78], which demonstrated that
methylcholanthrene-induced prostate epithelial hyperplasia was inhibited by retinoic acid as
well as vitamin A. The receptors for retinoids are
part of steroid superfamily, members of which
not only specifically bind 5О±-dihydrotestosterone (DHT) and oestradiol-17ОІ but also retinoic
acid and 1,25-dihydroxyvitamin D3 [79, 80].
DHT and oestradiol-17ОІ receptor complexes
specifically associate as homodimers to genomic
recognition sites (Fig. 4.12). Retinoic acid receptors (RARs) can bind as heterodimers with other
retinoic acid receptors, the RXRs [81, 82], to recognition sites composed of oestrogen response
element (ERE) half sites, the nucleotide sequence
AGGTCA вЂ�repeatingвЂ™ along the DNA chain. In-
4 The Prevention of Prostate Cancer
43
Fig. 4.11 Illustrated is the structure of lycopene, a dietary constituent of tomatoes and the synthetic relationship between ОІ-carotene, vitamin A and retinoic acid. Results of a chemopreventive study [71] of lycopene are also shown. Prostate cancer-specific survival curves for rats, treated with N-methyl-N-nitrosourea
and fed purified lycopene and a tomato powder are portrayed, indicating that at 50 weeks, 37% of controls
were alive, compared to 39% fed lycopene and 54% given the tomato powder
duction of differential regulatory responses is
thereby a consequence of different combinations
of receptors, ligands and recognition sites [83].
Moreover, ligand-independent dimeric receptors [84] can repress gene transcription [85],
with RARsвЂ”as well as the glucocorticoid receptor (GR) and 1,25-dihydroxyvitamin D3 receptor (VDR)вЂ”regulating AP-1 response elements
by a proteinвЂ“protein interaction (Fig. 4.13) with
the Jun proteins [86], each protein mutually inhibiting the activity of the other [87]. RARОІ expression in the prostate [88] is associated with
apoptosis [89]. Since AR or ER status relates to
RAR expression, any influence of ОІ-carotene
on cancer progression or any clinical effects of
retinoids may therefore be dependent on the
ER or AR content of the cancer [90, 91]. These
subtle genomic proteinвЂ“protein interactions
provide another insight into the complexity of
growth control in relation to prevention [92, 93].
Whereas retinoic acid can inhibit the expression
of ER-responsive genes, there is also evidence
that Fos and Jun proteins inhibit oestrogen responsive genes, with RAR and RXR, down-regulating transforming growth factor (TGF)-ОІ1 expression by antagonising AP-1 activity.
The bodyвЂ™s capacity to produce vitamin D is
also closely correlated to the risk of prostate can-
44
Keith Griffiths et al.
Fig. 4.12 A simple portrayal of the potential crosstalk between steroid hormone and growth factor signalling pathways with their capacity to influence the AP-1 recognition site through Fos-Jun action
cer [94], and Boyle [63, 64] refers to a 250,000
male cohort [95] in which 90 cases of prostate
cancer were identified in African-American men
and a similar number in Caucasians. The levels of
1,25-diOH-VitD3 in stored serum from these men
were compared to controls, matched for age, race
and for sample storage time. 1,25-diOH-VitD3
in cancer samples was reported to be a significant 1.81 pg/ml lower than controls; risk therefore decreases with higher levels of the vitamin.
Noteworthy, however, was that risk was associated only with palpable tumours, not incidental
cancer, suggesting that any influence is confined
to the later stages of tumour progression.
The skin, the only source of vitamin D3, is
where 7-dehydrocholesterol is converted by
solar UV irradiation to the provitamin D3.
Thermal isomerisation of provitamin D3 to vitamin D3, occurs in the epidermis from where
it enters the blood. It is hydroxylated at the C-25
position in the liver and then, primarily in the
kidney but also by keratinocytes, hydroxylated
to 1,25-diOH-VitD3, the biologically active
hormone, the biological effects of which are
mediated [96] through VDR. Like vitamin A,
it induces cellular differentiation and restrains
proliferation; both effects are associated with
the repression of the c-myc proto-oncogene [97]
and induction of TGF-ОІ expression [98]. VDR
is associated with enhanced apoptosis, increased
expression of Bcl-2 and G1S cell cycle blockade
in prostate cancer cell lines.
In the USA, prostate cancer mortality is inversely proportional to UV-radiation [99], and
in Finland, vitamin D deficiency similarly relates
to UV-radiation and cancer. Levels of plasma
25-OH-VitD3, which have been falling during
the past 25 years as prostate cancer incidence
has increased, are markedly different between
men in the rural north during winter than in the
southern region. The risk that relates to vitamin
D deficiency is higher in pre-andropausal men
than those over 50, suggesting a risk factor which
implicates androgens. This invokes the concept
that normalising vitamin D levels by administration of ergocalciferol or enhanced intake of fish
liver oil during the ages of 30вЂ“50 will provide
protection against prostate cancer.
4 The Prevention of Prostate Cancer
45
Fig. 4.13a,b Shown is a diagrammatic representation of the potential influence of retinoic acid receptors on the steroidand growth factor-mediated action on the genome. Depicted is the interaction between RAR RXR heterodimers on the
AP-1 response site. Also illustrated are some effects of retinoic acid on the proliferation of various prostate cell lines
in culture. The growth of the normal canine epithelial cell line (CAPE) is promoted by EGF and TGF-О± (a), an effect
inhibited by retinoic acid (b). Retinoic acid did not restrain the growth of the human prostate cancer cell lines PC3 and
DU145. Data taken from the Tenovus Institute for Cancer Research [90]
Hormonal Aspects of Prevention
Prevention with dietary factors offers an exciting prospect, but an anti-hormonal approach
is more pragmatic. Until recently the principal
risk factors for prostate cancer were functional
testes and an вЂ�age factorвЂ™, the latter derived from
the clinical manifestation of the disease beyond
the age of 50, the former on the concept that
cancer fails to develop in males castrated early
in life [100]. Androgen-dependence of prostate
cancer [101] and studies of men with an inherited 5О±-reductase 2 deficiency [102, 103] dem-
onstrated that the gland did not grow in the
absence of DHT. Such males did, however, develop acceptable secondary sex characteristics,
reasonable libido and a phallus, characteristics
promoted by testosterone. These and supporting studies centred on prostate growth regulation
[6], providing the incentive for an вЂ�anti-androgen
approachвЂ™ to prevention.
The use of anti-androgens such as flutamide,
bicalutamide or cyproterone acetate could offer
benefit to men at high risk, but loss of potency,
gynaecomastia, nausea and diarrhoea, are unwanted adverse features. Quite rightly, trials have
46
been instigated [34, 35], although anti-androgen
therapy cannot be perceived as an acceptable
preventive approach to recommend, for example, to all African-American males over the age
of 40, men who must by now believe themselves
at risk.
The development of finasteride [104, 105], a
5AR inhibitor, provided an innovative approach
to suppressing intraprostatic DHT levels without
compromising sexuality. Finasteride specifically
inhibits 5AR2, whereas alternatives, dutasteride
and epristeride, inhibit both 5AR1 and -2. The
Prostate Cancer Prevention Trial (PCPT) involved treating patients for 7 years with either
finasteride (5 mg daily) or placebo, followed by
an end-point prostate biopsy. Plasma testosterone levels are sustained. Rather than biopsy and
its confounding problems, some believe the only
acceptable end-points should be survival, metastasis-free survival or disease-specific survival,
which is an expensive approach requiring more
subjects and longer periods of study, but one that
could possibly offer unequivocal results. Second,
there is the question as to whether such a trial
should commence at an earlier age than 50. Such
issues have been considered recently [106].
Finasteride restrains cancer growth, with a 25%
reduced risk; the cumulative incidence of cancer
was 18.4% for finasteride-treated men and 24.4%
for those on placebo [107]. However, the greater
prevalence of high-grade cancer in the finasteride
group, with a Gleason score of 7 or more, tends to
compromise any unequivocal recommendation
regarding the clinical value of finasteride in preventive practise for men over 50.
The NCI-P01-0181 trial, which is evaluating
flutamide against the combination of flutamide
and the anti-oestrogen toremifene, offers a new
approach to preventive therapy. Since oestrogens
play a more significant role in prostate growth
regulatory events than hitherto thought [7, 9, 27],
the influence of an anti-oestrogen is awaited with
interest. Toremifene represses HGPIN development and decreased prostate cancer incidence
in TRAMP mice [108]. ERО± knock-out mice do
not develop HGPIN or invasive prostate cancer
after androgen and oestradiol administration,
whereas wild-type mice do [17, 109]. In a trial to
determine the effect of toremifene on men with
HGPIN, assessed by 6- and 12-month biopsy
Keith Griffiths et al.
[110], prostate cancer was detected in 31.2% of
the placebo group, compared to 24.4% in those
taking anti-oestrogen.
Is There a Genetic Approach to Prevention
Recognising the long preclinical phase in the natural history of prostate cancer, the identification
of men with a genetic predisposition to develop
the disease would clearly be beneficial. Familial
clustering [111] and evidence that family history constitutes a greater risk suggests underlying predisposing factors. Chromosomal analysis
mapped the loci of cancer susceptibility genes,
although segregation analysis [112, 113] indicates a low frequency, accounting for the 10% of
the hereditary cases within the population. To
date, hereditary disease has been mapped to the
HPC-1 locus (1q24вЂ“25), PCAP (1q42.2вЂ“43) and
CAPB (1p36), together with HPCX (Xq27вЂ“28)
on the long arm of chromosome X.
The search centred on point mutations, deletion or insertion of nucleotides within a gene
sequence that result in aberrant messenger
(m)RNA expression and thereby mutant proteins. The AF-1 transactivation function of the
N-terminal domain of AR is characterised by
polymorphic CAG repeats. Decreased repeats
from 24 to 18 relate to elevated AR transactivation activity and prostate cancer [114, 115],
with the prevalence of shorter alleles highest in
African-Americans and lowest in Asian men,
reflecting the geographical variation in incidence. Mutant ARs that inappropriately bind an
array of ligands [116] would seem rare in early
prostate cancer, although prevalent in metastatic
tissue. Gene amplification, whereby substantial
lengths of nucleotide sequences are copied,
sometimes more than a 100-fold, is a common
feature of cancer. If the sequence contains genes
encoding for growth regulatory proteins, the
effect could support cancer progression. Gene
deletion incurs cellular instability and restricted
growth restraint; the loss of growth suppressor
retinoblastoma (Rb) protein, for example, inevitably confers a growth advantage to the cancer cell. Loss of a p53 gene, which encodes the
protein that prevents a damaged cell entering
the cell cycle until DNA repair is complete, is
4 The Prevention of Prostate Cancer
generally an event related to the later refractory
phases of the disease.
Many low-penetrance susceptibility genes,
mapped to frequently deleted regions in prostate
cancers, are concerned with androgen metabolism. Genetic aberration of the SRD5A2 gene
would influence the prostate, and mutations have
been reported, with VL89 reducing enzyme activity, which is common in Asian men, whereas
A49T relates to increased activity and poor prognosis [117]. The latter mis-sense mutation is associated with a sevenfold greater risk of prostate
cancer in African-American men.
Aberrations of the HSD17B2 gene, 16q24.1вЂ“
24.2, encoding for 17ОІ-hydroxysteroid dehydrogenase type II, converting 17ОІ-hydroxy to
17-oxosteroidsвЂ”essentially the inter-conversions
of testosterone and androstenedione, and oestradiol-17ОІ and oestroneвЂ”could equally influence
the prostate. Gene polymorphisms may identify
men at risk, but also support the design of preventive strategies with shorter time-periods and
lower costs.
Dietary Factors: Causative or Protective?
Some Reflections on Obesity and Fat Intake
Possibly of significance is that prostate cancer
geographical variability is reflected in a similar
pattern for cancers of breast, ovary and endometrium, for which oestrogens are risk factors.
Sound arguments support some degree of homology between breast and prostate cancers [27,
118], and evidence has accumulated to suggest a
major role for oestrogens in prostate growth control [9, 27, 119].
Once again, geographical variability in incidence directs attention to Asian and Western
lifestyles, issues outlined by Doll [120] three decades ago, since when, after many retrospective
and prospective investigations, the consensus
viewpoint of three cancer agencies [121] was,
very simply, that the consumption of vegetables and fruit correlates with reduced risk. The
greater risk associated with red meat, primarily
beef, thereby allowed governmental institutions
to recommend frequent consumption of vegetables and fruit, with moderation in meat intake.
47
This and lots of exercise provide health benefits.
Broad recommendations, therefore, with the
International Agency for Research on Cancer
(IARC) suggest [121] that there is little support,
at present, for various supplementary cocktails
of vitamins and minerals, although the results of
the SELECT trial are eagerly anticipated.
The influence of dietary fat on cancer risk remains controversial. Obesity is stated to affect
more than 30% of adults in the USA [122], and
it has long been standard practise to implicate
dietary fat with cancer aetiology, particularly
breast [123], although Skrabanek [124], in a derisory manner, once referred to вЂ�the faddish infatuation with fat as the root of all dietary evilвЂ™. Some
researchers have not been convinced [125] that
eating a low-fat diet supports a longer life. Nonetheless, with greater fat intake in Japan, prostate
cancer incidence increases [33]; whether this relates to a decreased consumption of soy protein,
however, remains to be determined. A range of
prospective cohort studies on total dietary fat intake and prostate cancer risk [126] failed to identify an unequivocal relationship, although a correlation with animal fat intake was recognised, a
relationship believed by many to constitute the
principal risk factor responsible for geographical variability. Important, nonetheless, was that
obesity did relate to a greater risk of dying from
prostate cancer. Any link between risk and obesity, or increased body mass index (BMI), does,
however, remain controversial [126]. Whereas a
Norwegian study [127] suggested a higher BMI
increased risk, Giovannucci [128] indicated
the contrary. A 58% increased risk for obese
males, specifically between 50вЂ“59 years of age
and therefore вЂ�andropausalвЂ™, does identify an age
factor and suggests a possible adverse influence
of oestrogens produced by the aromatisation of
androgens in adipose tissue [9, 27]. Treatment
with an aromatase inhibitor is of clinical value in
the management of breast cancer; interestingly,
enterolactone, genistein and equol all inhibit the
aromatase enzyme in vitro [9, 129].
Possibly more important is the relationship of
risk to obesity during puberty and the immediate post-pubertal years, with a report [130] that
adolescent obesity increased the risk of dying
from prostate cancer. Poor nutrition and lack of
exercise through childhood, possibly leading to
48
some degree of insulin resistance in lifeвЂ™s early
years, could relate to prostate cancer aetiology
[131вЂ“133]. Such a lifestyle would lead to elevated
levels of androgens and IGF-I. Since the IGFnetwork supports proliferation and the progression of cells into the cell cycle (Fig. 4.14), IGF-I
could be implicated in prostate cancer initiation
and growth during the immediate post-pubertal
years [134, 135]. Various studies support a correlation between risk and levels of plasma IGF-I
[136вЂ“138], and Vihko [139] indicated that any
hyperandrogenicity developed through puberty
is retained into the third decade of life, possibly
supporting dysfunctional cellular proliferation
(Fig. 4.15).
Prostate Cancer: A Multifactorial Process
Prostate carcinogenesis is a multi-step process
involving multiple interactive factors and endocrine, genetic and nutritional features that impact on growth regulatory events [6] that either
support or restrain cancer progression through
the continuum from initiation to the invasive
phenotype. Interruption of these events is the
basis of prevention. Such a strategy using antihormonal drugs is clearly an important issue.
DHT is a predominant growth-promoting factor
in prostate cancer development, and the PCPT
trial provided evidence of a beneficial influence
of finasteride therapy for part of a group of men
treated beyond the age of 50. A controversial issue centres on whether the decline in intraprostatic DHT triggers a compensatory expression
of alternative, more aggressive growth-promoting signalling in the more progressive cancerous
lesions that will be harboured by a proportion of
such males, with the consequent development of
high-grade cancer. Selenium and vitamin E supplementation may provide benefit to men over
50, and this will be determined by the SELECT
trial, but their beneficial influence on PIA and
PIN for males in their 20s and 30s demands attention.
There is evidence that chronic, or recurrent
intraprostatic inflammation, a feature of asymptomatic prostatitis and PIA, could be implicated
in the early phases of prostate carcinogenesis
[24, 25, 27]. The induction of COX-2 as part of
Keith Griffiths et al.
the inflammatory response, with the consequent
production of prostaglandins (Fig. 4.9), a feature
of early cancer [140], together with the up-regulation of the enzyme in prostate cancer [141], has
directed attention to the potential of COX-2 inhibitors or other appropriate anti-inflammatory
agents [142] as an approach to chemoprevention. Moreover, a study by Coffey [27], emphasising a role for isoflavonoids in the suppression
of prostatic inflammation induced in rodents by
inappropriate intrauterine oestrogen imprinting,
highlights the need for trials of soy protein supplementation during the adolescent and post-pubertal years. Moreover, genistein may influence
the ERОІ-mediated effect [143] of oestrogens on
G5TПЂ activity. Certainly at the andropause, the
phyto-oestrogens may well suppress progression
of latent cancer to malignant disease, and trials
with soy protein would seem appropriate. Furthermore, soy protein supplements, as opposed
to genistein alone, may be relevant, since it appears that only certain males can convert daidzein to equol (Fig. 4.4), which could exercise a
specific, more effective preventive role [144] in
these individuals. There is evidence that the presentation of a higher-grade prostate cancer is associated with an ability to produce equol.
Many dietary constituents could impact on
prostate carcinogenesis, lycopene for one, but
others from the diverse range of flavonoids may
contribute to the bodyвЂ™s natural defences against
cancer. Although a recent study [145] found no
evidence that вЂ�flavonoid-rich foodsвЂ™ appeared to
influence breast cancer risk, a decreased prevalence did relate to a high intake of lentils and
beans, essentially legumes that provide a source
of isoflavonoids. Anthocyanidins and resveratrol
[146] of red wine offer health benefit [147, 148],
as might other polyphenols such as (в€’)epigallocatechin and (в€’)epigallocatechin-3-gallate, effective anti-oxidants and constituents of green tea
[149, 150]. Moreover, infusion of green tea leaves
with hot water liberates secoisolariciresinol
and matairesinol, precursors of enterolactone.
The proanthocyanidins are more effective antioxidants than vitamins C and E, whereas resveratrol has anti-inflammatory properties and
influences ER-signalling. The polyphenols of
green tea are reported to influence the prostate
of TRAMP mice [151] and an ongoing Italian
4 The Prevention of Prostate Cancer
49
Fig. 4.14 The cell cycle and some of the regulatory factors that determine the progression from G0 to G1 and through
the cycle
Fig. 4.15 Potential influence of insulin
resistance on the development of a
hyperandrogenic status in the younger
adult male
50
Keith Griffiths et al.
Fig. 4.16 The isoprenylation of Ras protein with products originating from hydroxymethylglutaryl (HMG)-CoA and
mevalonic acidвЂ”events that impact on the growth factor-mediated complex signalling pathways. Statins, tocotrienols
and limonene inhibit HMG-reductase. The mevalonic acid 6C-unit is the basic starter molecule of the cholesterol biosynthetic pathway, being converted first to the 5C-isopentyl pyrophosphate through two farnesyl units to lanosterol and
then cholesterol
study [152] provides evidence that they inhibit
the progression of HGPIN to clinical cancer. A
recent case control study in south-eastern China
[153] reports a significant correlation between
green tea consumption and the risk of prostate
cancer. There is evidence [154] that the tea polyphenols inhibit prostate cancer dissemination
by repressing the PSA-triggered activation of
matrix metalloproteinases that are concerned
with fibronectin and laminin degradation and
thereby support cancer cell invasion. Moreover, they can down-regulate AR expression
in LNCaP cells [155]. In passing, there is a notion [156] that alcohol itself may promote the
aromatisation of androgens.
The isothiocyanates of cruciferous vegetables,
constituents such as sulphoraphane, could also
exercise some degree of protection against prostate cancer initiation, possessing the capacity to
detoxify particular animal carcinogens such as
the heterocyclic aromatic amines produced by
the charring of red meat [27, 157]. This is somewhat controversial, since risk appears to relate to
the intake of red meat [10], despite such amines
4 The Prevention of Prostate Cancer
51
Fig. 4.17 Tocotrienols, the unsaturated
analogues of tocopherols
being produced by charring of chicken and fish.
Nevertheless, sulphoraphane promotes apoptosis, decreases cyclin B1 expression and induces
G2M cell cycle arrest in human prostate cancer
cell lines.
Although cancer was simply considered an
imbalance between cell proliferation and cell
death, more recently, failure of cancer cells to
undergo apoptosis has become the major issue
[158, 159]. Since cancer cells are dying more
slowly, therapy must be focussed on apoptosistriggering mechanisms and many of the вЂ�beneficialвЂ™ dietary factors that promote apoptosis in
experimental systems. Citrus fruits are seen as
beneficial and interesting; although d-limonene,
a monocyclic monoterpene in the peel of the
fruit also promotes apoptosis in model systems
[160], it is recognised thatвЂ”like the вЂ�statinsвЂ™вЂ”
d-limonene inhibits 3-hydroxymethylglutaryl
CoA (HMG CoA) reductase [161] and thereby
the synthesis of cholesterol (Fig. 4.16).
There is no doubt that the statins decrease
serum cholesterol and benefit those with cardiovascular problems, but can they decrease cancer
risk? HMGCoA reductase inhibition will suppress the synthesis of isoprenoid residues, thereby
inhibiting isoprenylation of the p21 Ras protein,
important for Ras GTP-ase signalling. Isoprenyl-
ation involves the transfer of either C15-farnesyl,
or C20-geranylgeranyl isoprene residues to the
p21-protein, thereby increasing its lipophobic
nature that enables GTPase to be anchored, then
re-located within the cell membrane. Ras mutations are a feature of prostate cancer, and repression of isoprenylation of the mutated p21 Ras
protein provides growth control. Transfection
of this mutated protein into mouse fibroblasts
in the presence of insulin and IGF-I results in
transformation and enhanced cell proliferation.
Also interesting is that prenylflavonoids [162]
such as isopentenyl-naringenin act as oestrogen
agonists.
The less well known tocotrienols, natural analogues of tocopherol (Fig. 4.17), also suppress
tumour growth, and the physiology that surrounds their preventive potential has been reviewed [163]. They also inhibit HMG-CoA reductase, promote apoptosis and inhibit DNA
synthesis.
Although the precise role of oestrogens within
the prostate remains somewhat of a conundrum,
they consistently feature in preventive strategies;
indole-3-carbinol, for example, a constituent of
cruciferous vegetables such as cabbage, cauliflower,
Brussels sprouts and broccoli, influences the metabolism of 2- and 16-hydroxylated oestrogens.
52
Keith Griffiths et al.
Fig. 4.18 The relationship of catechol oestrogens to angiogenesis and cell proliferation. Indole-3-carbinol is a product of
cruciferous vegetables. The indole-3-carbinol can prevent genotoxic agents from reaching their target site and, second,
induce 2-hydroxylase enzyme systems
Bradlow [164] reports that 16-hydroxylation
relates to cancer initiation, whereas 2-hydroxylation is associated with suppression. Indole-3carbinol induces the 2-hydroxylases (Fig. 4.18)
and, like genistein, 2-methoxyoestradiol inhibits
angiogenesis [165].
Important in the underlying events that control prostate growth is the recognition [38] that
genistein, through ERОІ-mediated signalling,
regulates the capacity of ERО± to promote AR expression and transactivation. This invokes interest in ERОІ-mediated signalling pathways relative
to those controlled by ERО±. They can be quite
distinct, sometimes complementary, but often
mutually antagonistic, with differing affinities
with various oestrogens [37, 39], and prostate
carcinogenesis will be influenced by the cellular
specificity and content of ER-isoforms. Can ge-
4 The Prevention of Prostate Cancer
nistein suppress AR levels and thereby epithelial cell proliferation during the early male adult
years? Loss of ERОІ-mediated signalling in PIN
lesions supports this putative role. Noteworthy is
that genistein, presumably through ERОІ, induces
G2M cell cycle arrest and apoptosis in association with p53-independent up-regulation of p21
and down-regulation of cyclin B1 [29]. Should
20-year-olds undertake soy protein supplementation? Important, however, is the report [166]
that the majority of primary prostate cancers, as
well as metastatic tissue, do express ERОІ.
Prevention: The Broader Acres
Despite a prevailing belief, inherited from folklore, traditional wisdom and possibly the words
of Confucius, that вЂ�an ounce of prevention is
better than a pound of cureвЂ™, the integration of
preventive practise into the modern healthorientated, medicine-based society is far from
complete. Scientifically credible preventive
measures must be inextricably linked to curative medicine, based on a precise understanding
of the natural history of a disease. Second, preventive strategies must be integrated into community screening programmes. The biological
essentials of such measures centre, very simply,
on the enhancement of the bodyвЂ™s own natural
defence mechanisms against disease. In the case
of prostate cancer these mechanisms would seem
reasonably effective during the extended preclinical period, when the glandвЂ™s own capacity to restrain carcinogenesis can be emphasized [167].
As to whether nutritional factors can prevent
initiation or extend the time to clinical disease
remains to be proved. Governmental agencies
recommend the benefits of a diet rich in fruit
and vegetables, a moderate red meat intake and
regular exercise. It is probably disappointing to
mention this, but caution is indicated with regard to the efficacy of supplementation with specific dietary constituents on the basis that doseresponses and adverse effects are yet unknown,
since few randomised controlled trials have been
completed. The medical community may also
believe the preventive concept to be a little premature. Such trials are costly and finances are
limited. Despite prostate cancerвЂ™s rise as a high-
53
profile diseaseвЂ”often presenting in the incurable, advanced stateвЂ”yet controversy flourishes
as to the value of population screening to reduce
mortality [11]. The concept that health gain can
be derived from diet-related intervention initiatives, even if scientifically sound, could be difficult to finance.
Prevention must, however, be the keystone of
medicine in the early decades of the twenty-first
century, and discussion must centre on real costs,
risks versus benefits of preventive strategies and
whether it is a worldwide issue for the entire
population, or merely appropriate for AfricanAmerican males, possibly Finns, who are recognised as high risk, or simply complementary to
current practise in the management of clinical
disease. Such an approach is not in any way an alternative option to recognised clinical practice. If
a preventive strategy could be offered to all men,
however, only few would derive benefit, and any
specific agent would have to be taken for a considerable period of time. The use of tamoxifen as
intervention therapy for breast cancer requires
400 appropriate North American females to take
the drug for a year to prevent one additional
case [168]. Assuming a dietary agent reduces
prostate cancer risk by 50%, a similar number
of American males would be treated to prevent
one additional case of prostate cancer [35]. Established drugs such as anti-oestrogens, 5AR
inhibitors and COX-2 inhibitors are being tested
with high-risk groups [34вЂ“36], and information
is accumulating on efficacy and appropriate endpoints. Nonetheless, such drugs are generally
perceived as вЂ�chemicalsвЂ™, whereas a more positive
but poorly perceived вЂ�consumer attitudeвЂ™ extends
to the вЂ�more naturalвЂ™ dietary factors, being seen
as purer and safer.
Rather than the broader advocacy of the
benefits of fruit and vegetables, if appropriate
specific dietary factors seem to provide some degree of protection against life threatening disease
and to better sustain menвЂ™s health, can such вЂ�scientific messagesвЂ™ be credibly conveyed to the
general public. Compelling evidence suggests
that isoflavonoids may well provide health benefit to Asian and other ethnic populations worldwide, either through the intake of soy protein by
healthy, reproducing Asians, or of other legumes,
by the people of India and South America.
54
Keith Griffiths et al.
Fig. 4.19 Standardised mortality rates for prostate cancer in Japan, illustrating within this population the influence of
regular intake of soybean soup. A similar influence was recognised by Hirayama [169] with regard to all cancers and
lung cancer, with an impact even on those who smoked. There were 265,118 subjects studied
Definitive evidence from controlled trials may
not be available for many years, so is it reasonable to suggest that since humans appear not to
be adversely affected by exposure to these phytooestrogens, that a greater intake of soybean, or
legumes, could be specifically recommended? A
similar argument could prevail for the polyphenols of green tea. The geographical variability between ethnic groups offers valuable data, but the
classical studies of Hirayama [169] that showed
differences in cancer incidence within an ethnic
groupвЂ”the differences being dependent on the
intake of soybean vegetable soup, daily, occasionally or rarely (Fig. 4.19)вЂ”provided particularly relevant information.
Undoubtedly, the importance of a properly
balanced diet is now better appreciated by the
general public, but any suggestion for the need
for specific dietary change must be accompanied
by readily assimilated science. People do not
find it easy to understand вЂ�scientific messagesвЂ™
although National Cancer Societies do provide
excellent guidelines on diet, nutrition and cancer
prevention. The вЂ�prevention of cancerвЂ™ can invoke
4 The Prevention of Prostate Cancer
serious emotional challenges, but dietary change
is not easy and a personвЂ™s ability to understand
the underlying science can be overestimated.
While emphasising, however, that 30% of the
500,000 cancer deaths in the United States annually are related to smoking, the substantial proportion that can be attributed to dietary factors,
very much a modifiable determinant of cancer
risk, cannot be overstated. The costs assumed by
a nationвЂ™s health services in managing the consequences of poor nutrition and the associated
lifestyle, especially cardiovascular disease and
cancer, are probably many fold higher than those
related to вЂ�smokingвЂ™. The signal-transduction
pathways that convey such salutary messages to
the man-in-the-street must be very professional
and the information scientifically sound, with
consideration given to the renowned inability
of the public to reach a consensus on almost any
subject. Open dissent through the media tends
to generate scepticism, upholding the view that
scientists rarely agree on any such issues.
Sporn [170] has most eloquently argued the
need for intervention initiatives directed to the
early phases of carcinogenesis. He intimates his
belief that a proportion of the medical community considers that cancer only вЂ�beginsвЂ™ when the
disease can be clinically detected, a time unfortunately when it may be invasive. Lots of vegetables
and fruit can be recommended for men through
their early years and possibly the three post-pubertal decades, but is this sufficient?
It would probably be naГЇve to advocate daily
helpings of Japanese miso soup made from fermented soybeans, five cups of green tea each day,
a bowl of blueberries and rye-bread toast sprinkled with cinnamon for breakfast, a vegetarianstyle lunch of broccoli and spinachвЂ”with walnuts for О±-linolenic acid, accompanied by two
glasses of red wineвЂ”and a venison-burger with
ketchup for supper. Alternatively, for the present, the government-sponsored production of
capsules that contain вЂ�dietary goodiesвЂ™ could offer a better way forward, the capsule containing
the appropriate amount of soy protein, flaxseed
for enterolactone, linolenic acid and selenium,
vitamin E, and lycopene, to combat oxidative
stress. It offers an interesting, precisely presented
вЂ�cocktailвЂ™ and invokes a challenging strategy. The
health benefits of statins as effective primary pre-
55
ventive agents against stroke [171] and for those
with hypercholesterolaemia, or at even moderate
risk of coronary or cerebrovascular problems,
might support their inclusion in such a capsule.
All this may be facetious comment and, clearly,
care is important [172]. The science is never simple. Although it might be presumed that all antioxidants, vitamin E, ОІ-carotene, vitamin C and
lycopene should demonstrate equal efficacy in restraining tissue damage induced by free radicals,
clearly they are not. Tellingly, the CHAOS investigation [173] and the GISSI-Prevenzione Trial
[174]вЂ”directed to vitamin E supplementation for
protection against cardiovascular diseaseвЂ”provided contradictory results. Moreover, a metaanalysis of 19 trials and 135,967 subjects suggested
[175] that a high vitamin E dose could enhance
all-cause mortality. A recent study [176] failed to
show any effect on prostate cancer risk, or any cancer, after supplementation with ОІ-carotene. Subsequent data evaluation then suggested, however,
that men with lower levels of plasma ОІ-carotene,
may benefit from supplementation, whereas those
with higher levels may develop cancer. Too much
ОІ-carotene may also be bad for men. A goody bag
capsule offers a logical way forward. But does society require unequivocal science from expensive
and time-consuming, randomised trials, before
forms of intervention can be established that do
not compromise the credibility of medical science? Another recent review (177) describes the
compelling evidence that dietary nutrients may
prevent the development and progression of prostate cancer, with a meta-analysis (178) indicating
that consumption of soy food was associated with
a lower risk of prostate cancer.
These confounding issues are part of societyвЂ™s
learning experience. The impact of intervention
therapy on the ageing process and mortality, or
premature death, could be profound; analysis is
therefore necessary on the costs vs benefits of
such strategies, which would change social structure. Research into the impact of dietary constituents on disease processes must be encouraged
and appropriate controlled intervention trials
quickly established as finance becomes available.
These trials will provide the real science-based
evidence of any benefit; but it is a fascinating
challenge for medical science as well as societies
to consider whether вЂ�eat more fruit and vegeta-
56
blesвЂ™ is going to be sufficient for those Web-savvy
consumers of today, who appear to demand
more information and a greater input into their
governmentsвЂ™ decision-making.
Keith Griffiths et al.
8.
Acknowledgements
9.
The authors would like to thank Mr. David
Griffiths, CompGraphics Services, Cardiff, UK,
for the kind use of the illustrations provided for
this chapter on prevention of prostate cancer.
10.
11.
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5
Prostate Cancer Screening
P. Tenke, J. Horti, P. Balint, B. Kovacs
Recent Results in Cancer Research, Vol. 175
В© Springer-Verlag Berlin Heidelberg 2007
Introduction
Prostate cancer is a major healthcare problem
worldwide, especially in the industrialized countries of the Western world. Prostate cancer has
become the most common type of cancer among
men and is the second leading cause of years of
life lost from cancer in males [58]. Incidence estimates for the year 2000 indicate prostate cancer
newly affected 542,990 men worldwide that year,
204,313 of whom have since died. Early detection and treatment of prostate cancer could theoretically reduce the burden of this potentially
disabling and deadly disease. However, because
no conclusive, direct evidence demonstrates that
early detection and treatment improve length or
quality of life, the value of prostate cancer screening remains controversial.
Prostate cancer is primarily a disease of elderly
men. About 85% of all cases of prostate cancer
are diagnosed in men older than 65 years, and
90% of deaths due to this disease are in men over
age 65. Prostate cancer is diagnosed in very few
men younger than 50 years (<0.1% of all patients
with prostate cancer) [2].
There are large differences in the incidence of
prostate cancer worldwide. Incidence is very high
in North America and northern Europe (peaking
at 63 per 100,000 white men and 102 per 100,000
African-Americans in the U.S.), but much lower
in Asia (10 per 100,000 men in Japan) [18]. The
lifetime risk for clinical prostate cancer among
men in the United States is approximately 10%;
approximately 3% die of this disease [43]. Despite
these differences, the microfocal incidence of
prostate cancer on autopsy is similar worldwide. Autopsy and cystoprostatectomy studies
have shown a prostate cancer prevalence of 30%
to 80%, depending on age, based on histologi-
cal examination. For men over age 50 years, the
weighted average of prostate cancer prevalence
based on autopsy studies is 30% [13]. Approximately 30% of these cancers are believed to be
clinically significant [48]. Thus, the risk for a
50-year-old man with a 25-year life expectancy of
having microscopic cancer is approximately 30%;
of having clinically evident disease, 10%; and of
dying of prostate cancer, 3% [60]. The disparity
between the 30% with microscopic cancer and
the 3% lifetime risk of death shows the difficulty
in distinguishing cancer as an indolent disease.
Patients with very aggressive tumors, (i.e., high
Gleason grade) have a significant risk of dying
of prostate cancer. Patients with relatively nonaggressive prostate cancer have a smaller risk of
dying of the disease [39, 49].
Epidemiology and Regional Variation
Prostate cancer is one of the few malignancies for
which the incidence varies widely across different
parts of the world. Hsing and colleagues classified 15 countries according to their level of prostate cancer risk. High-risk countries included the
United States, Canada, Sweden, Australia, and
France. Medium-risk countries included most of
Asia [27]. The same group of investigators also
examined trends in the incidence from 1973 to
1992. From 1998 to 1992, when prostate-specific
antigen (PSA) testing became widespread, the
incidence in the high-risk countries ranged from
48 to 137 per 100,000 person-years, while the
incidence in low-risk countries ranged from 2.3
to 9.8 per 100,000 person-years. In general, prostate cancer incidence rose in all countries during
these years, with the increment increasing by between 16.2% and 113.3% over the period [27].
66
The large geographical difference in the clinical incidence of prostate cancer, coupled with
the marked discrepancies between the incidence
of latent microfocal disease and clinical disease,
raises the concept that environmental factors
may play an important role in the prevention
and/or progression of the disease. In the majority
of men with pre-existing microfocal disease, the
growth is stimulated. It seems likely that these
differences are only rarely due to genetic factors
[36].
Among the environmental factors that are
supposed to be critical in the development of
prostate cancer, nutrition is suspected to play
a major role. Dietary habits vary greatly across
the world. There is increasing evidence to suggest that several elements of the diet may play an
important role in the prevention and/or progression of prostate cancer (Table 5.1) [53]. To date
there have been 14 well-performed, case-control
studies involving 4,797 prostate cancer patients
and 5,779 control subjects [18]. Eleven of these
studies have demonstrated a positive association
between increased dietary fat or specific fatty
foods and a higher risk of prostate cancer with
an odds ratio (OR) of 1.3вЂ“3.4. Epidemiological
studies have suggested that vitamin E may also
influence the development of prostate cancer
[25]. However, the preventative effect of dietary
components has not been definitely demonstrated in any specifically designed prostate cancer-focused studies that would withstand rigid
scientific scrutiny.
Screening and Early Detection
There is a worldwide attempt to improve the terrible outcome of prostate cancer. We think that
prostate cancer, when detected in a localized
stage, can be cured or the survival rate and the
patientsвЂ™ quality of life can be improved. If we diagnose prostate cancer in a late stage, it means an
incurable status. Two approaches are accepted to
achieve this goal at present: early detection and
systematic screening. The first means evaluation
on patientsвЂ™ request or as part of any other medical examination. The second is a planned examination of the affected population. The same
clinical examinations are used in both methods.
P. Tenke et al.
Table 5.1 Dietary factors and prostate cancer
Bad effect
Good effect
Fat
Antioxidants
High saturated fat
Vitamin E
High animal fat
Lycopene
Omega 6 fat
Carotenoids
Micronutrients
Micronutrients and
vitamins
Calcium/dairy
Selenium
Vitamin D
Soy/phytoestrogens
These are the digital rectal examination (DRE),
the serum PSA level measurement, and transrectal ultrasound.
The latest has not been used for years because
of the very low specificity, invasiveness, and high
cost. DRE has low sensitivity alone, so it is not
recommended for screening, but together with
(PSA) testing, it improves the detection rate.
PSA is a glycoprotein with serine protease activity produced primarily by epithelial cells lining
the acini and ducts of the prostate gland. PSA is
secreted into the lumina of the prostatic ducts
and is present in high concentrations in seminal fluid. Plasma concentrations are normally
low but are increased by conditions that disrupt
normal prostate structure and function (i.e.,
inflammation, infection, hyperplasia, prostate
cancer). Androgens regulate expression of the
PSA gene. Men who have regular PSA tests have
a much higher chance of finding out that they
have prostate cancer compared to men who do
not have PSA tests. With the use of an effective
testing procedure, systematic screening shows a
temporary but significant increase in the incidence, because we diagnose those patients whom
we would otherwise diagnose clinically at a later
time. Thus, lead-time is produced, which can
last from 4 to 10 years. After the second or third
screening round, lowering of the incidence is to
be expected. This was seen in the United StatesвЂ™
statistics very well [56]. The decreasing of mortality is expected only years after that. The cause of
the lead time and the aggressive early treatment
produce additional survival time, for which the
5 Prostate Cancer Screening
disease-specific mortality is the only endpoint in
evaluating the effectiveness of screening.
However, screening for prostate cancer remains controversial. In some countries, screening is standard healthcare policy; for example,
in the United States it is recommended that men
older than age 50 years (40 years for AfricanAmericans or first degree relatives of affected
men) have a PSA test and DRE at least once
every 1вЂ“3 years as long as their life expectancy
exceeds 10 years [21]. In other countries, such
as the United Kingdom, Austria, and the Netherlands, as well as in Scandinavian countries, there
are no screening policies because solid evidence
is lacking to support the effectiveness of screening and early treatment in terms of improving
mortality. Differences in healthcare systems and
other economic factors also have to be taken into
consideration when comparing countries with
high levels of testing with those that have a lower
level.
The American Urological Association and the
American Cancer Society recommend prostate
cancer screening annually, both PSA and DRE
from the age of 50 years for men who have at
least a 10-year life expectancy, and to younger
men who are at high risk. On the other hand,
according to the statement of the European
Association of Urology (guideline 2005), at the
present time there is a lack of evidence to support
or disregard widely adopted, population-based
screening programs for early detection of prostate cancer aimed at all men in a given population. The use of PSA in combination with DRE
as an aid to early diagnosis in well-informed
patients is less controversial and widely used in
clinical practice.
Effect of Screening
The decision about whether to pursue early
detection of prostate cancer is complex. In brief,
the dilemma exists because many men with prostate cancer will die of other causes. Treatment is
not necessary for some patients. On the other
hand, prostate cancer remains the second most
common cause of male cancer deaths. Therefore,
differentiating between patients whose cancer is
clinically insignificant and those whose disease
67
will progress is a challenge. To meet this challenge, a laboratory test must have maximum
sensitivity for detecting a clinically significant
disease and maximum specificity and positive
value to eliminate as many unnecessary biopsies
as possible.
Albertsen [1] in the United States and
Johansson [30] in Sweden examined the spontaneous history of early-localized prostate cancer
with conservative treatment. Albertsen found
that 29% of the patients regardless of the Gleason
score died of prostate cancer over the follow-up
20 years or more. He also scrutinized the mortality rates stratified by age and Gleason score at
the time of the diagnosis (Fig. 5.1). He does not
advise aggressive treatment of low-grade tumors.
Johansson, however, saw a markedly worsening outlook in case of disease-specific mortality and the generalization of the disease after
15 years, which was continuous up to 20 years,
both in low- and medium-grade (Fig. 5.2), so
he advised early aggressive treatment in patients
with long life expectancy. We should state that in
both studies the patients came from the pre-PSA
area, and the prostate cancers were mainly pT2.
We cannot know the exact outcome of the T1c
cancers, which are the most prominent part of
the screened population. We can hope that this
population could produce even more favorable
survival data.
In the United States the most complete information on the epidemiology of prostate cancer
has been assembled by the Surveillance, Epidemiology and End Results (SEER) database of
the National Cancer Institute (NCI) [58]. The
SEER incidence data for years 1973вЂ“1999 can
be divided into pre-PSA and PSA eras with the
PSA era beginning in the late 1980s. During
the pre-PSA era there was a gradual rise in the
incidence of prostate cancer, likely due to the
increasing number of transurethral resections
of the prostate (TURP) being performed. Once
TURP became a routine part of prostate management, prostate cancer rates stabilized in the late
1980s until the advent of the PSA era. At that
time, an abrupt rise in prostate cancer incidence
was observed. The incidence of newly diagnosed
prostate cancer peaked in 1992 with 237 cases
per 100,000 person-years. Thereafter, the annual
incidence rate declined until 1995, likely due to
68
P. Tenke et al.
Fig. 5.1 Survival and cumulative mortality from prostate cancer and other causes up to 20 years
after diagnosis, stratified by age at diagnoses and Gleason score [1]
the cull effect (removal of detectable cases in
prior years resulting in fewer available cases for
repeated screening). A relatively stable incidence
rate was observed in the pre-screening era.
The U.S. Preventive Services Task Force
(USPSTF) analyzed one randomized controlled
trial (RCT) and three case-control studies examining the effect of screening on prostate can-
cer mortality. The single RCT of PSA and DRE
screening, which reported a benefit from screening, was hampered by a low rate of acceptance of
screening in the intervention group (23%) and
by flaws in the published analysis [33]. No difference in the number of prostate cancer deaths
was observed between the groups randomized to
screening vs usual care using вЂњintention to treatвЂќ
5 Prostate Cancer Screening
69
Fig. 5.2 cause-specific survival by stage of disease and tumor grade at diagnosis [30]
analysis. Three case-control studies of screening
DRE produced mixed results [20, 29, 46]. In the
absence of better data about which treatments
are effective for which tumors, the USPSTF
could not determine whether the increased detection of prostate cancer from screening would
reduce mortality and morbidity.
A large, good-quality RCT, Bill-Axelson [5]
examined the course of localized prostate cancer
managed with radical prostatectomy or watchful
waiting over 10 years. Of the patients, 76% had
stage T2 tumor and only 12% had T1c. During
the follow-up, significantly fewer men in the
radical prostatectomy group than in the watchful
waiting group died of prostate cancer (30 vs 50,
p=0.01). They also found that the difference is
greatest and almost limited to patients younger
than 65 years. The difference in overall mortality
was also significant (83 vs 106, p=0.04). They also
stated the significant lowering of distant metastasis, local progression, and additional treatment
in the prostatectomy group. We can therefore
say that radical prostatectomy is able to reduce
cancer specific mortality in stage T2 tumors in
younger patients. This study does not establish a
benefit of screening because only 5.2% of cases
were found by screening.
The Canada Quebec trial was a populationbased trial that started in 1988. A total of 46,193
men aged 45 to 80 years were identified through
electoral lists, all residing in the province of Quebec; 30,956 were invited to be screened, of which
7,155 accepted. In the control group were 982 men
who were also screened. This meant only 23%.
The cutoff is a PSA level of 3 ng/ml; re-screening
was annual. The relative risk of dying of prostate
cancer was 3.7 times higher in the control group
than in the screening group. This showed a 69%
mortality rate reduction [20] among those who
were screened yearly. When others re-analyzed
this study according to screening principles (see
the following section), no significant difference
was found between the screening and control
group with respect to prostate cancer mortality
[6].
A reduction in prostate cancer mortality following the introduction of PSA screening has
been reported by Bartsch [3]. In this study PSA
testing was made freely available to men aged
45вЂ“75 years in Tyrol (Austria), and treatment
of curative intent was offered to every patient
diagnosed with prostate cancer between 1993
and 1998. There was a 44% decrease in prostate
cancer mortality in 2000. The decreasing started
in 1995. This was not freely observed in the rest
of Austria, where PSA testing was not freely
available (Fig. 5.3). However, it is difficult to
prove the benefit of PSA screening in such a confined population. When age-adjusted prostate
cancer mortality rates from the Austrian Central Statistics Office for Tyrol are compared with
those for the rest of the country, most deaths
and the greatest improvements in mortality occurred in the group aged 70вЂ“79 years (Fig. 5.4).
70
Fig. 5.3 Mortality from prostate cancer in Tyrol and the rest of Austria. Between 1993 and
1999 prostate cancer mortality decreased by 42% in Tyrol, where PSA testing was freely
available, compared with modest downward trend observed in the rest of Austria, where
it was not [3]
Fig. 5.4a,b Age-adjusted mortality from prostate cancer in: a Tyrol and the rest of Austria;
and b Tyrol and Carinthia. a Most deaths and the greatest improvements in prostate cancer
mortality in both Tyrol and rest of Austria occurred in the group aged 70вЂ“79 years, with
very little difference in other groups. b There was no difference in prostate cancer mortality
between Tyrol and Carinthia, an Austrian province of similar size to Tyrol with no formal
screening program, in men aged 60вЂ“69 or 70вЂ“79 years [3]
P. Tenke et al.
5 Prostate Cancer Screening
This is a trend that is also observed worldwide
and reflects the general improvement in medical
care of this age group. In the other groups (50вЂ“59
and 60вЂ“69 years) there was very little difference
in prostate cancer mortality between Tyrol and
the rest of Austria. The other problem with this
study is that the mortality decrease started too
early, which makes uncertain the cause-effect relationship [9]. If we look at the morbidity dates
of these areas from 1988 we can also assume a
heavily pre-screened status of the inhabitants.
The Olmsted County Study analyzed the
prostate cancer incidence and mortality between
1983 and 1995 in three different periods [47].
From 1991 a downward trend was noted in the
mortality rate. The study had an 80% power to
detect a 44% decline in mortality. Contrary to the
changes in incidence, a 22% decline in mortality
was seen, which was statistically insignificant.
Two big randomized prospective studies are
ongoing in the field of prostate cancer screening,
the European Randomized Study for Screening
for Prostate Cancer (ERSPC) and Prostate, Lung,
Colorectal, and Ovarian Cancer Screening trial
(PLCO), but for the results we will have to wait
till the end of this decade.
The European Randomized Study for Screening for Prostate Cancer is a multicenter trial initiated in 1994 that plans to enroll up to 251,000
men in eight different countries [15, 50]. Enrolling criteria vary somewhat between centers, with
the age of men ranging from 50 to 74 years, but
mainly it comprises men 55вЂ“69 years of age. The
first screening policy included a DRE, a PSA
level with cutoff 4 ng/ml, and transrectal ultrasonography (TRUS). In 1997 there was a protocol change; the PSA cutoff level was lowered to
3 ng/ml and DRE and TRUS were omitted. The
screening interval is also different between countries, ranging from 2 to 7 years, mainly 4 years. To
date, 251,133 men have been randomized, 74,568
of whom are being screened. In the screened
group, 3,928 cases of prostate cancer have been
found, and there have been 2,291 cases in the
control arm. Expected completion of the trial is
2008. In the Finnish arm of the trial, more than
5,000 participants have been screened; PSA levels exceeded 4 ng/ml in 8.5% of men aged 55 to
69 years. The cancer detection rate was 2.1% with
a positive predictive value of 27%. More than
71
80% of the cancers were localized and well or
moderately differentiated [37].
The PLCO trial started at the end of 1993 in
the United States. Randomized into the screened
were 37,000 men, with 37,000 in the control arm.
Recruitment was completed in June 2001. The
starting age group was aged 60вЂ“74, which was
changed later 55 to 67 years, with a screening interval of 5 years.
A review of the age-specific incidence of
prostate cancer shows that most countries report few cases for men younger than 50 years
of age, with the incidence rising exponentially
with advancing age and reaching a maximum
after age 80. The incidence rate in men over the
age of 75 is 20 to 83 times higher than in men
aged 50вЂ“54 [27]. The rise in prostate cancer incidence in the PSA era has been most prominent
in men between 50 and 59 years old, whereas
the incidence in men above 60 years has gradually declined since 1992 [24]. These trends are
characteristic of the screening effect. However,
the available ecologic studies have not provided
sufficient evidence that the decline in prostate
cancer in the United States or other countries is
attributable to screening; differences in prostate
cancer treatment, underlying risk factors, and
how deaths are classified can each introduce bias
into ecological comparisons.
Principles of Screening
Screening is defined as the application of suitable screening tests to a general population at
risk. Screening procedures for prostate cancer
are used widely in North America and many European countries, in spite of the fact that their
value has not been proved definitively by adequate randomized controlled trials.
Screening represents the use of laboratory
tests, physical examination, or imaging modalities carried out on asymptomatic patients with
the aim of identifying subclinical disease. Early
detection involves discovery of a disease or condition before the appearance of obvious signs or
symptoms; in patients with cancer this would
lead to the detection of localized disease. Screening is usually further subdivided into mass
screening or individualized screening [51]. The
72
former is performed with little regard for the risk
profile of the individual patient. Most physicians
are involved in the latter, which consists of recommending screening tests maintaining a constant patientвЂ“physician relationship.
The sensitivity and specificity of a specific test
help to establish its effectiveness. Sensitivity is the
equivalent of the proportion of the disease population who has a positive test (true-positive rate).
The particularity of a test equals the proportion
of healthy patients who have a negative test (truenegative rate). The terms sensitivity and specificity are only applied to situations in which the total
number of cancers present in a given population
is known. This is not the case in screening populations. The number needed in the denominator of the formulas that calculate sensitivity and
specificity is often replaced by the number of men
with positive or negative biopsy, which is usually
obtained by the use of a standard biopsy indication such as abnormal DRE or a PSA greater than
or equal to 4.0 ng/ml. More accurately, if this expression is chosen for comparison purposes, it
should be termed вЂњrelative sensitivityвЂќ and вЂњrelative specificity.вЂќ Patients and clinicians are often
more interested in the positive predictive value
of a test, which equals the proportion of patients
with a positive test result who actually have the
disease. The use of the term specificity in a situation in which the underlying prevalence of cancer
is not known may be acceptable because of the
usually large number of men who, in fact, do not
have cancer. This minimizes the mistake made by
applying this formula [40].
Criteria of Effective Screening Tests
For a screening test to be effective, certain criteria
should be fulfilled [40]:
вЂ“ The disease must constitute a significant public
health problem with significant morbidity
and mortality. It should have an available and
acceptable treatment, and the potential for
cure must be greater among screen-detected
patients.
вЂ“ It is essential that the screening test have
appropriate sensitivity, specificity, and positive predictive value, making it capable of
detecting a sufficiently high proportion of the
cancers in their detectable preclinical phase.
P. Tenke et al.
вЂ“ The screening test should be acceptable to the
patient and society.
вЂ“ There must be demonstrable improved health
outcomes related to screening.
вЂ“ The screening procedure should have a
reasonable cost; adequate resources and health
services should be available to accomplish the
screening and to provide the necessary interventions triggered by a positive test result.
The degree to which prostate cancer screening tests fulfill the above-mentioned criteria is
controversial. It is leading to different specific
policy recommendations from various organizations, although all groups agree that the testing
process should be conducted within the context
of an informed patientвЂ“physician relationship.
Patients should be informed of the known risks
and the potential benefits.
Factors That Have an Impact
on the Assessment of Screening Tests
Lots of biases can be hidden in the conduct
of screening tests that can have an impact on
apparent survival measures. These can affect
the valid assessment of screening test effectiveness [59]. In particular, lead time bias makes the
assessment of mortality improvements difficult.
Early detection of cancer causes a backward
shift in the starting point for measuring survival
(earlier diagnosis), which may artificially raise
the incidence and lengthen survival.
Autopsy studies have shown that at least 30%
to 80% (depends on age) of men who die have
latent prostate carcinoma. This rate is much
higher than the mortality rate (3%) due to prostate cancer. Screen-detected incidental cancers
represent length bias. Individuals with slower
progressive disease will tend to be detected.
Length bias increases the incidence of early-stage
disease and lengthens apparent survival, but has
no effect on mortality rates or advanced-stage
disease. Over-diagnosis might also be problematic since non-life-threatening prostate cancer
is found in every PSA range, though it is more
common in men with a PSA level of less than
3.0 ng/ml. In the ERSPC Rotterdam section,
approximately 15% of men with a PSA level of
3.0вЂ“3.9 ng/ml had possibly unharmful disease,
5 Prostate Cancer Screening
defined as a tumor volume of less than 0.5 ml
and no Gleason scores at 4 or 5 [59]. The diagnosis of nonorgan-confined disease can be another
restriction of prostate cancer screening. For example, the result from a randomized study in
Canada of screening vs no screening found that
approximately 25% of patients had clinical stage
T3вЂ“4 metastatic disease [14]. Moreover, during
an 8-year follow-up a further 9% of patients were
diagnosed with nonorgan confined disease.
Another complication of screening for prostate cancer is the fact that sextant biopsy can
miss up to 25% of detectable prostate cancer
that might be of significant value or become so
with time.
People who agree to take part in screening are a self-selected group who may be more
worried of the disease in question and more
health conscious. Selection bias can happen
whenever the group actually screened differs
from the potential population of individuals to
be screened. This bias also can cause apparent
increases in survival of individuals with screendetected cancers. Inattentive misclassification of
the cause of death or attribution bias can occur
when a screen-detected abnormality is labeled as
вЂњcancerвЂќ on the patientвЂ™s chart when in fact this
abnormality would never have been clinically
diagnosed in the absence of screen detection.
Because of these biases, case survival cannot
be used to estimate the effect of screening on
mortality. Instead, prospectively determined
mortality from the disease over a follow-up
period beginning with randomization should
be used. Also, one generally cannot make valid
estimations by comparing people screened with
those who were unscreened in the past. The only
way to find out the advantages without bias is
by comparing people who are offered screening
with a group of truly comparable people who are
not offered screening.
Some common methodologies used in observational epidemiology, particularly case-control
and cohort studies, are sometimes used to assess
screening. With the purpose of valid application
of these approaches screening should take place
in a community for a sufficient length of time so
that the benefit is detectable if there is any. This
period for PSA is probably just approaching.
Case-control studies have limitations because
differentiating a screening test from a diagnostic
73
test for prostate cancer can be difficult, and this
inaccuracy in classification can distort the results
of such studies.
National Trends in the Epidemiology
of Prostate Cancer
Proponents of the benefits of PSA screening
have found evidence of its effectiveness based
on the recent trends in prostate cancer incidence
and mortality. Based on data obtained from the
SEER program of the NCI, age-adjusted rates for
prostate cancer incidence increased significantly
in the late 1980s, reached the peak in 1992, and
then declined through 1996 [28]. Age at diagnosis for whites became lower after the introduction of PSA screening. Stage at diagnosis also
showed a downward shift to more organ-confined and less metastatic disease. An increase
in the incidence of moderately differentiated
tumors (Gleason score 5 to 7) seems to be leading the overall incidence trend [51]. After 1991,
the incidence of well-differentiated tumors has
been decreasing faster than tumors with higher
grades. Blacks exhibited similar trends but with a
1-year lag time, although they experienced a relative increase in high-grade, poorly differentiated
disease. These data confirm studies conducted in
smaller regions [16, 28].
Prostate cancer mortality increased an average
of 1% per year between 1973 and 1990. Since 1990
the prostate cancer death rate in the United States
has fallen to an average of 1.1% annually, the decrease totaling 6.7% from 1991 to 1995 [51].
With the successful screening test now in use,
prostate cancer incidence is constantly changing.
This PSA test can detect slower growing tumors
with an effect of lead-time bias due to early detection of prostate cancer beginning in the late
1980s and early 1990s [19]. Some of the increased
incidence of localized stage disease may be due
to length bias. The decrease in early-stage cancer
in recent years also suggests that lead-time bias
has taken place. The effect of lead-time bias is
further supported by the fact that the increase in
early-stage disease was followed by a decrease in
advanced-stage disease.
However, other factors also may be involved in
these trends. For example, the increase in moderately differentiated tumors actually began in 1986
74
before PSA testing became widespread. Changes
in treatment practices also may be confounding
the view of mortality. In the late 1980s and early
1990s the use of gonadotrophin-releasing hormone analogs and androgenic receptor blockers
became prevalent, replacing the use of castration
therapy or estrogen supplements. This change in
treatment patterns could bring about the recent
declines in mortality rates for prostate cancer.
Other factors also could have contributed to
the shift in the tumor grade distribution before
1992, including an increase in the radical prostatectomy rate, a decline in TURP rates for benign
prostate hyperplasia (BPH), and an increase in
biopsy rates. The changes in prostate cancer mortality experienced since the introduction of PSA
testing in the general population are also consistent with the hypothesis that a fixed percentage
of the rising and falling pool of recently diagnosed patients who die of other causes may be
mislabeled as dying from prostate cancer [19].
Effectiveness of Screening Tests
Digital Rectal Examination
The DRE is still the basis in the diagnosis of prostate cancer due to its prompt availability, low cost
and risk, and contribution to detect cancer in
males with normal or minimally high PSA levels. The DRE has been well known in the last few
centuries and was termed as palpatio per anum in
Latin. Several physicians precisely explained the
use of DRE in the diagnosis, staging, and followup of prostate cancer almost a century ago. The
prostate allows for easy access due to its anatomic
position in the pelvis, below the bladder neck for
palpation using finger placed per rectum. DRE
should also be used to diagnose benign prostate
hyperplasia, prostatitis. Generally, DRE is useful to detect prostate cancer because the majority of cancers arise from the peripheral zone of
the prostate. Nevertheless, DRE is moderately
sensitive at diagnosing small, early-stage prostate cancer and it is not sensitive in identifying
disease minimally extended beyond the prostate
capsule. Indeed, early studies indicate only 26%
to 34% of men with suspicious finding with DRE
have positive histology after biopsy for cancer,
P. Tenke et al.
and the overall positive predictive value is 28.0%
for DRE [38]. In a most recent trial the positive
predictive value (PPV) of an abnormal DRE was
8.8%, among a cohort of patients with less than
4 ng/ml PSA [7].
The sensitivity of the DRE in the detection of
prostate cancer is low, and the results diverge with
selection of patients, their age, symptoms, and
the clinical experience of the physician. Urological associations commonly recommend routine
annual DRE. Doubtful DRE should be followed
by transrectal echography and prostate biopsy.
Prostate-Specific Antigen Testing
PSA is a serine protease produced by epithelial
cells of the prostate gland. Releasing from prostatic stroma, PSA appears in the blood. Like
other serine proteases, serum PSA exists mostly
in a complex and inactive form; however, a small
proportion remains in a free but inactive form.
PSA is finally metabolized by the liver with a 2.2to 3.2-day serum half-life. There are several major
causes of increased serum PSA, including BPH,
prostate cancer, prostate inflammation or infection, and prostate or perineal trauma. BPH is still
the most common cause of elevated serum PSA.
Despite the fact that PSA is not cancer-specific,
the PPV for prostate cancer even in asymptomatic men is approximately 30%. Using PSA test
combined with DRE the results are significantly
better. In a screening trial, Catalona combined
serial measurements with DRE and found out
that the organ-confined rates of tumor increased
to 75% compared to 50% or less when screening
was performed with DRE alone [54].
Prostate-Specific Antigen Velocity
PSA velocity (PSAV) is defined as a change in
PSA value within a time frame. It was observed
more than a decade ago that PSA will go on rising more rapidly in men with significant cancer
than in males with benign prostate hypertrophy.
The acceptable rate of slope cannot be precisely
determined. Carter et al. [10] suggested a value
of 0.75 ng/ml as an indicator of the presence of
prostate cancer. They demonstrated that in men
5 Prostate Cancer Screening
with prostate cancer the early linear PSAV slope
turned to an exponential phase of PSAV beginning 7.3 years before the diagnosis in men with
localized disease and 9.2 years before the diagnosis in men with advanced stage disease. Using PSAV, 10%вЂ“30% of biopsies can be avoided
among men with elevated serum PSA and prior
negative biopsy. The specificity of diagnosis increases to over 90% with 72% sensitivity in predicting occult prostate cancer in men with PSA
less than 10.0 ng/ml. To obtain maximal benefit
from using PSAV measurements, at least three
PSA measurements should be taken at intervals
of 1.7вЂ“2.0 years. On the other hand, an exponential increase in serum PSA level is an independent risk factor for early relapses. DвЂ™Amico et
al. [34] have demonstrated that men whose PSA
level increases by more than 2.0 ng/ml during the
year before the diagnosis of prostate cancer may
have a relatively high risk of death from prostate
cancer, despite the early diagnosis and radical
prostatectomy.
As a conclusion, the significant intraindividual variability and frequent inconsistency in
PSA measurement, particularly in the setting of
relatively short time intervals between PSA tests
and PSA in the low ranges, may impede the performance and use of PSAV [44]. The clinical application of PSA doubling time (PSADT) arises
from the hypothesis that the growth of prostate
cancer is exponential and the doubling time
will indicate biologic tumor activity. It has been
presumed that prostate cancer has a constant
growth rate that is often relatively slow. Although
assessments of changes in serum PSA have a
well-established role in follow-up patients who
have undergone treatment, its role as a marker
for early diagnosis in untreated patients remains
controversial.
Prostate-Specific Antigen Density
PSA density (PSAD) is the ratio of the serum
PSA and prostate gland volume measured by
TRUS. Using this ratio PSAD adjusts for PSA
changes contributing to the benign prostatic
enlargement. There have been several reports
on improved differentiation between patients
with BPH and prostate cancer. These reports
75
have demonstrated that average PSAD in men
with prostate cancer is significantly higher than
in men with prostate hypertrophy. Benson et al.
enrolled 595 patients into a large screening study
with a PSA values between 4.1 and 10.0 ng/ml.
Within this intermediate range of PSA, Benson
et al. were not able to identify malignant prostatic disease by PSA values. However, there was
a strongly significant difference in PSAD values
between patients with positive or negative biopsy
(0.297 vs 0.208), respectively [4]. Furthermore,
of patients with a PSAD of 0.1 or greater, 97%
had prostate cancer [11]. Regardless of these
promising early results, the calculation of PSAD
involves the use of measurements that may vary
because of ultrasound operator variability or
sampling bias. In a large multicenter study, PSA
and PSAD were compared for early detection of
prostate cancer. If a PSAD cutoff of 0.15 were
to be used in a group of men with a PSA count
from 4 to 10 ng/ml, 47% of the cancers would be
missed. In summary, although applying PSAD
may achieve increased specificity and avoidance
of up to 37% of biopsies, the risk is unacceptable
to ignore large number of clinically significant
cancers.
Age-Specific Prostate-Specific Antigen Range
Age-specific PSA reference ranges (ASRR) were
recognized by the rationale that the prostate
gland normally enlarges with age. Even though
the incidence of prostate cancer increases
noticeably in men older than 60 years of age, the
presumption is that using a higher total PSA cut
point for older men is unlikely to result higher
morbidity or mortality from this disease. The
use of age-specific PSA levels also implies that
it is more important to diagnose prostate cancer
in younger men because their longer life expectancy and greater number of risk years puts them
at greater risk of disease progression, metastasis, and death. Using a higher upper-cut limit
for older men, it was believed that the number
of biopsies in this group would decline while the
detection of prostate cancer would not be jeopardized. Initially the upper limit of PSA, 4 ng/ml,
was set up by the test manufacturer based on
measurements of PSA levels in 860 healthy vol-
76
unteers. ASRR were recommended by Partin and
Oesterling over the standard 4 ng/ml cut point
based on their findings [41]. Using age-specific
cut points of 2.5, 3.5, 4.5, and 6.5 ng/ml for the
age groups 40 to 49, 50 to 59, 60 to 69, and 70 to
79 years, they were able to identify an additional
18% of prostate cancers in the groups under the
age of 60 years. On the other hand, using these
references ranges 22% of the cancer would have
been missed in older men. Adjusting the PSA
cutoff from 4.0 to 4.5 ng/ml for men in the 60вЂ“69
age group would eliminate 15% of biopsies, while
missing 3% of cancers. Of the cancers missed,
95% were considered as clinically insignificant.
Several publications highlighted disturbing numbers of clinically serious cancers or
advanced stage disease is missed in older men
when using similar age-specific ranges. The percentage of avoided biopsies was also not as significant in numerous follow-up studies. For the
time being a widely accepted, ideal cutoff point
to define a serum PSA level as normal does not
exist. Recent studies have shown that up to 25%
of men with prostate cancer have a PSA value of
less than 4 ng/ml, and 32% of the men with cancer have normal PSA levels [8]. In a large study
of 6,000 men over the age of 50, it was found that
increasing the PSA thresholds in older men may
result in 44% fewer biopsies, but at the expense
of missing up to 47% of organ-confined cancer
[45]. In general, although this modification may
increase the test sensitivity in younger men, it
will also decrease the sensitivity in the older
population.
Free Prostate-Specific Antigen
PSA exists in numerous different molecular
forms in the serum or in seminal fluid. The total
PSA contains all the measurable PSA in the serum. A large proportion of total PSA is complex
and inactive; however, a smaller fraction remains
in a free but also inactive form. This free PSA can
be measured by monoclonal antibodies. It was
postulated by Stenman that men with prostate
cancer tend to have higher ratios of complex PSA
to total PSA than men without prostate cancer
[57]. Several studies demonstrated a significantly lower free PSA to total PSA ratio in cancer
P. Tenke et al.
patients as compared to BPH. The representative
free PSA ratio was 15%вЂ“18% in cancer patients,
which significantly differed from the average of
free PSA ratio of 28%вЂ“30% in patients with BPH.
More recently, a prospective multicenter trial was
designed to assess the optimal free PSA threshold using 773 men aged 50 to 75 years with PSA
levels between 4 and 10 ng/ml [12]. There was no
difference in total PSA concentrations between
the men with benign prostate hypertrophy vs
malignant disease (total PSA 5.6 vs 5.9, respectively). The free PSA was able to distinguish the
group of men with benign disease (mean free
PSA of 18%) from those with cancer (12% free
PSA). A 25% cutoff identifies 95% of cancers
while avoiding 20% of unnecessary biopsies. The
few amounts of cancers associated with a free
PSA greater than 25%, were more often observed
in older patients with a lower grade and volume
of the disease. Free PSA has an inverse correlation with tumor aggressiveness; a lower free PSA
is associated with a more aggressive form of prostate cancer. The ability of this molecular form to
differentiate between prostate cancer and benign
conditions has proved to be the most useful PSA
modification to increase the performance of PSA
testing.
Imaging for Detection and Early Diagnosis
Although imaging studies do not have a basic
role in the early detection of prostate cancer,
imaging technique plays a role in the diagnosis
of the disease. Transrectal ultrasound is used to
guide biopsies of the prostate gland in patients
with an abnormal DRE or elevated serum PSA
level. The prostate can be imaged with transrectal
approach. In healthy young men, the zones of
the prostate are not sonographically evident.
The transition zone usually becomes distinguishable in patients with benign hyperplasia.
Prostate cancer placed in the peripheral zone
can be consistently observed by sonography.
Prostate cancer most commonly appears in the
hypoechoic zone compared to the normal surrounding [17]. However, lesions up to 40% are
isoechoic; therefore they are not detectable by
sonography. The finding of a hypoechoic lesion
on transrectal ultrasound sonography is not spe-
5 Prostate Cancer Screening
cific for carcinoma. The low positive predictive
value of TRUS (20%вЂ“50%) for the diagnosis of
prostate cancer makes it unsuitable as a screening tool at the present technical level. Computer
tomography lacks the soft tissue contrast resolution needed for the detection of intraprostatic
cancer and offers no advantages over TRUS in
biopsy guidance through screening procedures.
Although at present magnetic resonance imaging (MRI), as well as TRUS, are the best imaging
modalities for demonstrating the normal zonal
anatomy of the prostate, they have no established
role in prostate cancer detection [26]. Prostate
cancer usually appears as an area of abnormal
low signal intensity surrounded by the normal
homogeneous high signal intensity background
of the peripheral zone. Low signal intensity lesions in the peripheral zone display a sensitive
but not specific finding for cancer. In addition,
prostate biopsy may cause bleeding and irregularity in signal intensity that lead to false-positive
and false-negative results. To avoid this source
of bias, MRI should be postponed for at least
3 weeks after biopsy. Proton three-dimensional
magnetic resonance spectroscopic imaging (3DMRSI) is a newly developed technique to obtain
metabolic information about the prostate gland.
MRSI assesses prostatic metabolites, such as
choline and citrate. Within cancer tissue there
are significantly higher choline and significantly
lower citrate levels compared to the healthy field
in the peripheral zone. When the metabolic data
from 3D-MRSI is combined with morphologic
data from the MRI, it is possible to make a more
reliable diagnosis and much more precise localization of prostate cancer than with the data from
MRI alone [32]. A combined positive result from
the MRI and 3D-MRSI argue the presence of tumors. If both MRI and 3D-MRSI provide combined negative results the presence of cancer can
be excluded. The lack of an adequately high positive predictive value for cancer detection, combined with its high cost and limited availability
makes MRI inappropriate for cancer screening.
Potential Adverse Effects of Screening
The screening process is likely associated with
some increase in anxiety, but the number of
77
men affected and the magnitude of the increased
anxiety are largely unknown. The possible harms
associated with screening must consider the
psychological consequences of positive screening results or an actual cancer diagnosis, and the
reality of false reassurance with negative biopsy
results [31,35]. Some screening procedures cause
transient discomfort. Fewer than 10% of men
have ongoing interference with daily activities after biopsy, and fewer than 1% suffer more serious
complications, including infections [27].
At present, over-diagnosis probably represents the biggest problem related to prostate cancer screening. Over-diagnosis can be defined in
many ways, such as the diagnosis of cancers that
will not be diagnosed clinically, the diagnosis of
a cancer that will not kill a given patient, and, in
an epidemiologic sense, the difference in incidence in a screened population and a matched
unscreened population. Over-diagnosis is closely
related to the production of lead-time by screening, but also to comorbidity and the risk of intercurrent deaths in population of men who
undergo screening tests. The risk of over-detection has been estimated between 16% and 56%.
At present, there is clear evidence that screening
increases, at least temporarily, the incidence/
mortality ratio from 2 to approximately 5 in the
United States, where screening is prevalent [22].
In the controlled setting of the ERSPC (Rotterdam section) during the prevalence screening, a
crude incidence ratio of 6.51 per 1,000 personyears was seen between the screening and control
groups. Estimates from the ERSPC suggest that
for a screening program with a 4-year screening
interval from age 55 to 67 the estimated mean
lead time is 11.2 years (time from detection to
the cancer that becomes clinically apparent)
and the over-detection rate is 48% (range, 44%
to 55%) [37, 50]. In the same setting, taking into
consideration the prostate cancer mortality rate
in the Netherlands in 1997, an incidence/mortality ratio of 14.6 was found [52].
Perhaps more important are morbidity and
mortality associated with the cascade of procedures from diagnosis to treatment. The complications of radical prostatectomy include a low
mortality risk (0.2% to 0.4%), but considerable
morbidity affecting the quality of life may be
associated with this surgery (incontinence and
78
erectile dysfunction) or from radiation (bowel
dysfunction and rectal bleeding). Penson [42]
examined the five-year outcomes of the urinary
and sexual function after radical prostatectomy.
He found that only 45% of the patients had no
incontinence problems, 14% had frequent leakage or total incontinence, and 71% of the patients did not have firm enough erections for
intercourse. Steineck [55] found 80% of erectile
dysfunction and 49% of urinary leakage after
radical prostatectomy in Sweden. One year after
radiation therapy, 28.9% of the patients experienced decline in sexual function and 5.4% had
bowel functional problems [23].
At present, the true extent of over-diagnosis
in cases that do not require treatment and how
these can be avoided is not known.
Cost and Cost-effectiveness
Given the uncertainties about the effectiveness of
screening and the balance of benefits and harms,
the cost-effectiveness of screening for prostate
cancer is impossible to determine. If one makes
favorable assumptions about efficacy of screening, PSA screening may be cost-effective for men
aged 50 to 69 [58]. If efficacy of early treatment
is lower, harms could exceed benefits and PSA
screening would not be cost-effective. Current
models show that men older than 70 to 75 are
unlikely to benefit substantially from screening
because of their shorter life expectancy and
higher false-positive rates [58]. Cost-effectiveness of different screening intervals or variations
of PSA measurement is unknown.
Summary and Conclusion
Prostate cancer incurs a substantial incidence
and mortality burden, similarly to breast cancer,
and it ranks among the top ten specific causes of
death in the United States. It is inherent as we
maximize the detection of early prostate cancer
that we increase the detection of both nonaggressive (slow growing) and aggressive (faster
growing) prostate cancers. The evidence clearly
supports the use of PSA screening in conjunction with DRE as a means of early detection of
prostate cancer. Widespread implementation of
P. Tenke et al.
prostate cancer screening in the United States
has led to the phenomenon of stage migration
with more cancers being detected at a lower
stage. Such a trend has decreased the incidence
of metastatic disease at diagnosis and paralleled
the decrease of the mortality rate from prostate
cancer.
Our understanding of the natural history of
prostate cancer is progressing over time, but the
question of its length is unanswerable. The relatively long doubling time (on average) of early
prostate cancer of 3 to 4 years or more indicates a
relatively good prognosis for many men with this
disease, even without early detection and treatment. Unfortunately, the poor specificity of the
PSA test in men with benign prostatic hyperplasia (BPH) leads to high rates of prostate biopsy
and attendant illnesses and costs.
Early detection is more apt to detect a slowgrowing prostate cancer than a faster growing
cancer that is associated with a more rapid course
of progression to metastatic disease. Hence, the
launching of mass screening programs for the
early detection of prostate cancer is premature.
However, in the absence of solid evidence of
benefit, one reasonable approach to screening
at the individual level is to involve the patient
in decisions about whether or not to perform a
PSA test. Thus, вЂњofferingвЂќ PSA testing must be
accompanied by informed discussion within
the context of an ongoing patientвЂ“physician
relationship. This is to be distinguished from
the use of PSA testing for the purpose of вЂњmass
screening.вЂќ Concepts that must be explored with
the patient include:
1. The long-term ramifications of screening
2. The relatively high probability of further evaluation and biopsy with positive results
3. Potentially difficult decisions that may arise
about using treatments that are associated
with considerable morbidity and uncertain
benefits (at the time) if cancer is discovered
We should identify a future path that is evidence-based, focused on the issues that make a
difference to patients, and results in better and
longer lives of those with the disease and those
who are at risk of getting it. If that path leads
to treating fewer patients in the future, even if
sometimes more aggressively, we should pursue
it definitely and consequently.
5 Prostate Cancer Screening
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6
Diagnosis of Prostate Cancer
Jehonathan H. Pinthus, Dalibor Pacik, Jacob Ramon
Recent Results in Cancer Research, Vol. 175
В© Springer-Verlag Berlin Heidelberg 2007
Abstract
The contemporary challenge of prostate cancer
diagnosis has been changed in the past decade
from the endeavor to increase detection to that
of detecting only those tumors that are clinically
significant. Better interpretation of the role of
prostate-specific antigen (PSA) and its kinetics
as a diagnostic tool, the adoption of extended
prostate biopsy schemes, and perhaps implementation of new transrectal ultrasound (TRUS)
technologies promote the achievement of this
clinical mission. This chapter reviews these issues as well as the change in practice of patient
preparation for TRUS-biopsy and analgesia during it, the role of repeat and saturation prostate
biopsies, and the interpretation of an incidental
prostate cancer finding.
Currently, the lifetime risk of a diagnosis
of prostate cancer for North American men is
16%, compared to the lifetime risk of death from
prostate cancer, which is 3% (Carter 2004). The
advent of prostate-specific antigen (PSA) screening and transrectal ultrasonography (TRUS) has
significantly impacted the detection of prostate
cancer over the last 20 years. The mean age at
diagnosis has decreased (Hankey et al. 1999; Stamey et al. 2004) and the most common stage at
diagnosis is now localized disease (Newcomer et
al. 1997; Stamey et al. 2004). The goal of prostate
cancer screening is to detect only those men at
risk for death from the disease at an early curable phase. The ambiguous natural history of this
most common malignancy in men, being latent
with questionable life-threatening potential in a
large number of cases on the one hand, with only
a relatively small number (though not negligible)
of highly malignant cases on the other, propels
many doubts about whether this is possible. This
was famously phrased more than 20 years ago by
Whitmore who asked: вЂњIs cure possible for those
in whom it is necessary; and is it necessary for
those in whom it is possible?вЂќ This is probably
even more relevant nowadays. During the past
decade two factors influenced significantly the
increased detection rate of prostate cancer in
general and that of clinically insignificant prostate cancers in particular: the widespread use of
serum PSA as a screening tool to a large extent
and to a lesser though significant extent the application of extended multiple core biopsy schemes
(Master et al. 2005). In fact, 75% of men in the
United States aged 50 years and older have been
screened with the PSA test (Sirovich et al. 2003).
Outside of the screening context, which is dealt
with in depth in Chap. 5, clinical suspicion of
prostate cancer is raised usually by abnormal digital rectal examination (DRE) and/or by abnormal
levels of serum PSA. Final diagnosis is achieved
only based on positive prostate biopsies.
Serum PSA Levels as a Diagnostic Tool
The indications for prostate biopsy in patients
with elevated/abnormal PSA are in transition
due to emerging data on its performance as a
screening tool in serum levels of less than 10 ng/
ml in general and less than 4 ng/ml in particular.
The Prostate Cancer Prevention Trial (PCPT)
(Thompson et al. 2003) afforded the examination of PSA as a marker for prostate cancer.
Almost 9,500 healthy men with negative DRE
and serum PSA levels lower than 3 ng/ml were
receiving placebo and were followed by annual
DRE and serum PSA examination. At the end
of the study period (7 years) routine prostate
biopsies, parts of the study design, found that
almost a quarter were diagnosed with prostate
cancer. Subanalysis of prostate cancer incidence
84
among 2,950 men treated with placebo and who
never had a PSA level of more than 4.0 ng/ml or
an abnormal digital rectal examination revealed
that biopsy-detected prostate cancer, including
high-grade cancers, is not rare among men with
PSA levels of 4.0 ng/ml or lessвЂ”levels generally
thought to be in the normal range (Thompson
et al. 2004). The prevalence of prostate cancer
was 6.6% among men with a PSA level of up to
0.5 ng/ml, 10.1% among those with values of 0.6
to 1 ng/ml, 17% among those with values of 1.1
to 2.0 ng/ml, 23.9% among those with values of
2.1 to 3 ng/ml, and 26.9% among those with values of 3.1 to 4.0 ng/ml. The prevalence of highgrade cancers increased from 12.5% of cancers
associated with a PSA level of 0.5 ng/ml or less
to 25.0% of cancers associated with a PSA level of
3.1 to 4.0 ng/ml.
Accordingly, there is no serum PSA level below which there is no risk of having prostate cancer, although the risk of prostate cancer increases
with the levels of serum PSA. The question as to
whether we should lower the serum PSA threshold for detection would remain a matter of personal opinion at this point due to lack of firm data
to support or defer early detection. Lowering the
PSA value will lead unequivocally to the detection of an enormous number of inconsequential
tumors leading to a вЂњprostate cancer epidemicвЂќ
on the one hand, but will also result in the detection of clinically significant tumors, as supported
by the finding that almost a quarter of prostate
cancers detected in men with PSA between 2.1
and 3 ng/ml are of a Gleason score (GS) of 7 or
more (Thompson et al. 2004).
To add to this complexity, the drastic change
in the disease characteristic of prostate cancer
over the past decade with more patients that are
diagnosed with small-volume cancers at lower
stages and with lower PSA levels impose caution in analyzing previous data from populationbased studies of the early 1990s and adopting
it to current practice in an attempt to redefine
the indication for biopsy based on PSA levels.
Accordingly, Stamey recently radically criticized
the overusage of PSA for prostate cancer diagnosis, stating that the PSA era in the United States is
over for prostate cancer (Stamey et al. 2004).
Ignoring the dilemma of what is the adequate
PSA threshold that should promote biopsy, it is
Jehonathan H. Pinthus, Dalibor Pacik, Jacob Ramon.
worthwhile to acknowledge several inherited
caveats of serum PSA levels as a diagnostic tool:
intra-individual day-to-day variation in PSA is
34% (Bunting 1995). This as well as unavoidable analytical variation obviously creates inherent problems, particularly in the interpretation
of PSA kinetics in certain values (Nixon et al.
1997).
Biologic variability in PSA levels may often
stem from inflammation and infection. Moreover, prostatic manipulations are notoriously
known for alarming variations in PSA level: DRE,
TRUS, cystoscopy, and ejaculation have minimal
effects. However, since some authors showed that
it may have an effect on serum PSA levels, at least
when one interprets interindividual PSA dynamics, one should be aware of potential influences
of such manipulations: PSA testing within 24 h
after ejaculation may lead to an erroneous interpretation of the results of measurements of both
total and percentage of free PSA in a small proportion of men (Herschman et al. 1997). DRE
may result in a change of free but not of complex
PSA levels (Lechevallier et al. 1999). On the other
hand, prostatic massage, needle biopsy, TURP,
and prostatitis can cause significant elevations
of serum PSA (Klein and Lowe 1997). Additionally, in patients who receive intravesicle therapy
for superficial bladder TCC, serum PSA levels
should also be evaluated with caution: intravesical bacille Calmette-GuГ©rin (BCG) therapy may
be associated with significantly elevated PSA in
up to 40% of cases. This effect is self-limited and
PSA reverts to normal in 3 months (Leibovici et
al. 2000).
PSA levels are influenced by body weight. Recently, Baillargeon et al. (2005) showed in a cohort of 2,770 men without prostate cancer that
the mean PSA values decrease linearly as body
mass index increases. This important association
should be remembered, as obesity becomes a major public health problem in the Western world.
Digital Rectal Examination
as a Diagnostic Tool
Although abnormal DRE is considered an absolute indication for prostate biopsy, its central role
as a diagnostic tool was superceded by the wide-
6 Diagnosis of Prostate Cancer
spread application of serum PSA. Analyzing data
from the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer,
Schroder et al. evaluated the usefulness of DRE
as a standalone screening test and in conjunction
with measured serum PSA levels of 0вЂ“3.9 ng/ml
and TRUS (Schroder et al. 1998). Although they
showed that DRE has a poor performance in low
PSA ranges with a calculated positive predictive
value of DRE and TRUS at PSA 0 to 4.0 ng/ml of
only 9.7%. (Schroder et al. 2000), 17.3% of the
cancers identified in their cohort would have
remained undetected by PSA-based screening
alone (Schroder et al. 1998).
Regardless of serum PSA levels, a DRE finding of a firm nodule or diffusely firmed prostate
should promote prostate biopsy, as 5%, 14%,
and 30% of men with PSA 0вЂ“1.0, 1.1вЂ“2.5, and
2.6вЂ“4.0 ng/ml, respectively, have prostate cancer
(Carvalhal et al. 1999). Carvalhal et al. found that
the majority of cancer cases detected by DRE in
patients with serum PSA of less than 4 ng/ml
have features of clinically important and potentially curable disease (Carvalhal et al. 1999). Although for screening purpose DRE is fairly inferior to PSA, its role in combination with PSA
for diagnosis is imperative, as it gives essential
clinical information for staging.
Transrectal Ultrasound
as a Diagnostic Tool
TRUS was introduced in 1968 (Watanabe 1989)
and rapidly gained popularity among the practicing urologist as a tool for volume measurement of the prostate and to direct the biopsy
needle to various locations within the prostate.
Apparently its role as an additional diagnostic
tool is limited due to low specificity and sensitivity for detection of prostate cancer. Using grayscale ultrasound analysis, Dahnert et al. (1986)
demonstrated that 54% of prostate cancers are
echopenic, 22% are hypoechoic, and 24% are
isoechoic. Later reports classified most (60%)
prostate cancers as hypoechoic (Shinohara et al.
1989). In one recent analysis of 3,912 consecutive TRUS-guided prostate biopsies, Onur et al.
confirmed that despite the higher prevalence of
cancers discovered in prostates with hypoechoic
85
areas, the hypoechoic lesion itself was not associated with increased cancer prevalence compared
with biopsy cores from isoechoic areas (Onur et
al. 2004). Moreover, the echogenic features of the
tumor on TRUS do not impact on its prognosis
(Scherr et al. 2002).
In attempts to increase the accuracy of TRUS
as a diagnostic tool, several authors tried to integrate new technologies (Sedelaar et al. 2001).
These techniques include color Doppler, power
Doppler, three-dimensional (3D) ultrasound
imaging of the prostate alone or in combination
with ultrasound contrast agents with some encouraging results. The rational is that adding vascular information could improve the detection of
cancerous lesions, as tumor growth is associated
with neovascularization that could possibly result in altered blood flow. Indeed, several studies
demonstrated that color Doppler ultrasound of
the prostate might improve biopsy yield by directing systemic biopsies to distinct areas in patients with elevated PSA and no focal gray-scale
abnormalities as well as in the detection of diffuse
prostate lesions (Sedelaar et al. 2001). Moreover,
nonpalpable cancers with hypervascularized lesions were shown to have a significantly higher
GS than nonhypervascularized lesions (Cornud
et al. 1997). In their review of the literature,
Sedelaar et al. (2001) calculated that Doppler
ultrasound of the prostate increased the sensitivity and specificity of detecting prostate cancer from 17%вЂ“57% and 40%вЂ“63% achieved by
conventional gray-scale TRUS, to 75%вЂ“78% and
80%вЂ“87% respectively. The application of contrast-enhanced Doppler ultrasound also showed
promising results (Ragde et al. 1997; Goossen et
al. 2003) but the number of studies that examine
its role is very limited.
Unal et al. suggested that the combination of
transrectal 3D contrast-enhanced power Doppler ultrasonography can significantly increase
the sensitivity and specificity of prostate cancer
detection and in particular its combination with
PSA level (Unal et al. 2000). Caveats of these
promising technologies are that they are relatively complicated to interpret and are dependent
on expert observers. In addition, they are subject
to motion artifacts and false positive results due
to inflammatory processes like prostatitis, which
decrease their specificity as a diagnostic tool. Ac-
86
cordingly, none of these technologies can currently replace systemic biopsies for the early detection of prostate cancer (Sedelaar et al. 2001)
and none of them is ready yet to be adopted into
routine clinical practice.
Prostate Biopsy
TRUS-guided systematic prostate biopsy is the
standard test for prostate cancer diagnosis. Prostate biopsy strategies have significantly evolved
over the past decade. The current practice for
initial biopsy using extended biopsy schemes
(10вЂ“13 cores) including laterally directed biopsies has significantly reduced the false-negative
rate of the previous dominant classic sextant
biopsy. The increased diagnostic scheme of this
state-of-the-art approach not only results in
lower detection rates of re-biopsies but was demonstrated to provide valuable staging information (Singh et al. 2004; Naya et al. 2004).
Patient Preparation to the Biopsy
With the widespread application of TRUSguided prostate biopsy it became evident that
anesthesia and/or analgesia improve the patientвЂ™s
tolerance and comfort. The procedure can be
painful (Irani et al. 1997). Thus, especially with
the introduction of extended schemes of primary
and repeat biopsies, the application of anesthesia
and/or analgesia is the gold standard in clinical
practice with several randomized studies proving
its necessity (Leibovici et al. 2002; Chang et al.
2001). Indeed, up to 90% of patients undergoing
TRUS-guided biopsy of the prostate claim to
experience discomfort (Clements et al. 1993).
Many methods to decrease pain during the
procedure were described and are meticulously
reviewed by Autorino et al. (2005). Of the
various methods, periprostatic nerve block
alone or with lidocaine gel has been shown to
be safe, easy to perform, and highly effective.
The application of gel instillation should not
replace periprostatic nerve block, as prospective
randomized studies comparing the two methods
clearly demonstrated the superiority of the latter
(Autorino et al. 2005).
Jehonathan H. Pinthus, Dalibor Pacik, Jacob Ramon.
The use of antibiotic prophylaxis for transrectal prostate biopsy significantly reduces the incidence of infective complications (Sieber et al.
1997). Taylor and Bingham (1997) reviewed the
literature and found that oral antibiotics are inexpensive, well-tolerated, and effective for reducing the incidence of urinary tract infection and
fever following transrectal prostate biopsy. Their
recommendations, which are widely practiced,
are to use oral quinolones such as ciprofloxacin
or norfloxacin (Taylor and Bingham 1997). The
duration of treatment varies between different
institutions and was demonstrated to be effective even with the use of levofloxacin at 600 mg
for 1 day as prophylaxis (Shigemura et al. 2005).
Similar data from a prospective randomized trail
in Canada support that there is neither clinically
nor statistically a significant difference between a
1-day and 3-day antibiotic prophylaxis regimen
for patients undergoing TRUS-guided biopsies
(Sabbagh et al. 2004). Moreover, Griffith et al.
showed that a single 500-mg dose of levofloxacin
before transrectal needle biopsy of the prostate is
effective and safe in patients at low risk (Griffith
et al. 2002). Obviously those patients considered
at risk for endocarditis need a strictly different
parental regimen in accordance with published
American Heart Association recommendations.
The application of cleaning enemas before the
procedure is recommended to facilitate the transrectal prostate imaging and to reduce infectious
complications, although there is no substantial
evidence to prove it (Scherr et al. 2002).
Transrectal Ultrasound-Guided Prostate
Biopsy Techniques
The traditional sextant biopsy as described by
Hodge et al. (1989) comprises six core biopsies
taken from the apex, mid and base of the right
and left prostate at the parasagittal plane. With
this sextant biopsy approach that was widely
practiced in the 1990s, false-negative rates were at
the range of 30%вЂ“35% (Levine et al. 1998; Karakiewicz et al. 2005). Decreasing yield of sextant
biopsy was strongly associated with increasing
gland volume (Karakiewicz et al. 1997). Another
cause for the reduced detection rate with the routine application of the sextant biopsy scheme was
6 Diagnosis of Prostate Cancer
that the parasagittal plane of sampling does not
sample the more lateral peripheral zones. As a
result, Stamey suggested shifting the sextant biopsies template laterally in order to better sample
the peripheral zone where most of the cancers
are located (Stamey 1995). However, application of StameyвЂ™s modification for sextant biopsies
alone, with a single set of lateral sextant biopsies,
may miss clinically detectable prostate cancer in
more medial parts of the peripheral zone.
Similarly, Chang et al. found that in 20% of
men diagnosed with prostate cancer, the tumor
was found exclusively in the laterally directed
biopsies (Chang et al. 1998). These data are supported by elegant computer-based analysis studies (Chen et al. 1997; Zeng et al. 1999), which
clearly demonstrated that laterally directed biopsies that can sample the anterior horn increase
the detection rate. Indeed, Epstein et al. (2001)
demonstrated the importance of posterolateral
prostate biopsies in an ex vivo model. In their
study, using ex vivo needle biopsies of 150 specimens removed by radical prostatectomy, 25%
of the cancers were missed by sextant biopsy
scheme. Maximum cancer detection was yielded
from combining both routine sextant and posterolateral needle biopsies (Epstein et al. 2001).
Acknowledging the significance of a larger
number of cores as well as for more lateral location of needle placement, different investigators
studied alternative extended prostate biopsy
schemes to the traditional sextant biopsy. Presti
(Chon et al. 2002) introduced a 10-core systemic
biopsy scheme comprising four laterally directed
biopsies of the peripheral zone plus the conventional sextant biopsy template. Patients with
prostate volume larger than 50 cc underwent also
transitional zone (TZ) biopsy, which increased
the detection rate by 5.5% (Presti et al. 2000).
The sextant biopsy component of their scheme
missed 20% of the cancers ultimately detected.
Discarding the parasagittal base biopsies from
this 10-core template had only minimal effect on
the cancer detection rate (96% to 95%), thus leaving an 8-core biopsy scheme (Presti et al. 2000).
Later, Meng et al. suggested another scheme for
an 8-core prostate biopsy. They claimed that apical anterior horn prostate biopsies can target
cancers that are in a region that is usually undersampled using traditional schemes and recom-
87
mended adding it to the classic sextant biopsy
pattern (Meng et al. 2003).
Chen et al. (1999) used a computer model to
evaluate different prostate biopsy schemes. Their
simulation suggests that a multisite-directed
11-core biopsy is superior to all others. Eskew
showed that a 13-core biopsy scheme has a significantly better detection rate compared to that
of the sextant scheme (Eskew et al. 1997). In his
biopsy template Eskew added to the traditional
sextant scheme additional biopsy cores from the
far lateral and mid regions of the gland to improve the sampling of the peripheral zone. His
technique, named the 5-region prostate biopsy,
includes sampling 5 separate regions of the peripheral zone (laterally directedвЂ”base, mid and
apical coresвЂ”plus mid lobar sampling of the
apex and base). This scheme was shown to result
in significantly better diagnostic yield compared
to the sextant biopsy template but equivalent to
the 12-core scheme (Gore et al. 2001). In a recent study, Elabbady compared the diagnostic
yield and accuracy of final GS prediction (i.e.,
at radical prostatectomy) between 113 patients
who underwent TRUS-guided lateral sextant
biopsy and 176 patients who underwent extended 12-core biopsy who had similar clinical
characteristics (Elabbady and Khedr 2006). The
cancer detection rate was 24.8% and 36.4% in
those who underwent sextant and 12-core biopsy
respectively. The agreement between the biopsy
and prostatectomy specimen was significantly
higher in patients who underwent 12-core biopsy (82.5%) than those who underwent sextant
biopsy (50%).
Altogether, the well-proven role of extended
scheme prostate biopsy in increasing the detection
rate of prostate cancer stems from the fact that it
reduces the odds for sampling error. Whether it
also translates to providing better prognostic information is still questionable to some extent. In
the era of increased awareness of the clinically
insignificant nature of many newly diagnosed
early prostate cancers and consequently to the
viable option of expectant management (watchful waiting), adequateвЂ“informative prostate biopsies play a key role (Klotz 2002). Accordingly,
a finding of a small focus of cancer in a sextant
biopsy set reflects similar finding in radical prostatectomy only in the extreme minority of the
88
casesвЂ”10%. In another words, up to 90% of these
patients would suffer from clinically significant
cancer in terms of cancer volume. Furthermore,
the volume of prostate cancer in the biopsy specimen cannot reliably predict the volume of cancer
in the radical prostatectomy specimen (Cupp et
al. 1995; Weldon et al. 1995; Gardner et al. 1998).
However, when analyzing the relationship between the numbers of positive cores obtained at
extended biopsy (10вЂ“11 cores) and tumor volume
in radical prostatectomy specimens, Ochiai et al.
(2005) could clearly demonstrate that the number of positive cores was significantly related to
total tumor volume. Moreover, the probability of
insignificant cancer (defined as volume less than
0.5 cc and GS6 or less) was directly related to the
number of positive cores. Tumor length in a core,
GS, and prostate volume significantly enhanced
the prediction model for insignificant cancer in
men with one positive core who underwent extended biopsy.
Unfortunately, the inclusive tumorsвЂ™ GS as
obtained from radical prostatectomy specimen
is often higher than that determined by the prostate biopsy with the most common error being
underscoring of tumors, which are subsequently
shown to be GS7 tumors (Sved et al. 2004). Several studies using different methodologies for
prostate biopsy documented a wide range of
12%вЂ“92% rate of up-scoring from prostate biopsy GS6 to radical prostatectomy GS7, with
most reporting discordance rates in the range
of 30%вЂ“50% (Pinthus et al., 2006). Some reports
suggest that increasing the total numbers of
cores taken at the prostate biopsy could reduce
undergrading (Emiliozzi et al. 2004; Elabbady
and Khedr 2006).
Other studies, however, do not support this
(King and Long 2000; Fukagai et al. 2001). King
et al. could not demonstrate an advantage of extended biopsy patterns of as many as 18 cores in
improving grading error rate (King and Long
2000). However, following sextant prostate biopsy of GS6 tumors, Fleshner et al. found that
the rate of undergrading decreased from 58% (32
of 55 patients) to 28% (5 of 18 patients; Fleshner
et al. 1998). Thus, re-biopsy may be warranted
when the presence of GS7 would alter an individualвЂ™s treatment plan.
Jehonathan H. Pinthus, Dalibor Pacik, Jacob Ramon.
An inevitable consequence of the routine use
of extended pattern prostate biopsy templates is
the detection of smaller volume prostate cancers,
independent of PSA and Gleason grade. In a recent study, Master et al. compared the pathological characteristics of tumors, removed at radical
prostatectomy by a single surgeon, following
biopsies with at least 6 cores. Both groups were
evenly matched in terms of age, PSA, and biopsy
GS. The authors found that the use of increased
number of prostate biopsies contributes to the
detection of smaller tumors, and contributes to
over-detection independent of serum PSA. In
contrast, Siu et al. (2005) could not find a significant association between an increased numbers
of needle cores at initial prostate biopsy and finding of smaller and clinically insignificant cancer
in their retrospective analysis of 740 cases.
Using a computer simulation, Karakiewicz
et al. could clearly demonstrate that regardless
of the gland volume, detection of minimal volume disease increases with increasing amount
of sampling, although as expected this was more
frequent in smaller glands (Karakiewicz et al.
1998).
Taken together, extended biopsy templates
have certainly contributed to the downward stage
migration of prostate cancer detection and perhaps also to the risk of over-detection. However,
increased detection of clinically insignificant disease is an unavoidable trade-off for the improved
detection of clinically significant prostate cancer.
Role of Transitional Zone Biopsies
There is some debate as to the role of additional
TZ biopsies at the time of the initial biopsy. In
general, tumors arising in the TZ of the prostate
gland are well-differentiated and considered clinically unimportant. However, a study from StameyвЂ™s group that examined 79 volume-matched
cases of TZ prostate cancer to 79 pure peripheral
zone cancers (with no secondary tumors) demonstrated that cancer volume and the percentage
of Gleason grade 4/5 diseases were the same in
both groups. However, at 5 years of post-radical
prostatectomy follow-up, 49.2% of the men with
peripheral zone cancer had undetectable PSA
compared with 71.5% of those with TZ cancer
6 Diagnosis of Prostate Cancer
(Noguchi et al. 2000). Shannon et al. (2003) reviewed 187 cases of TZ cancers from radical prostatectomy specimens of which 76 represented the
index (main) tumor. These were compared with
a volume-matched group of 76 peripheral zone
(PZ) carcinomas. Of 76 TZ index carcinomas,
59 had additional minor tumors mainly located
in the PZ. Compared to PZ tumors of similar
size, TZ tumors had significantly lower GS, less
Gleason grade 4/5, and lower rates of capsular
penetration and positive surgical margins. Nevertheless, a subset of TZ carcinoma (10%), characterized by high tumor grade was found to have
a significant risk of extra-prostatic spread, margin positivity, and possible biochemical failure.
Interestingly, the best method to pre-operatively
diagnose these tumors was by transperineal biopsy. For patients initially evaluated because of
high PSA, a positive DRE, or both, the incidence
of having cancer exclusively in the TZ only in the
first set of biopsies was found to be merely 2.1%
but was increased to 18.7% in repeat biopsy that
included sampling of the TZ when the patients
had already at least one previous negative biopsy
of the peripheral zone (Deliveliotis et al. 2002).
Based on their study, Deliveliotis et al. (2002)
concluded that the low yield of transitional zone
biopsies (2.1%) during first-time sampling of the
prostate does not warrant their systematic use
for the early detection of prostate cancer. Instead,
the effectiveness of biopsies in that area is higher
when the biopsy is repeated after an initial previous negative biopsy of the peripheral zone.
Abdel-Khalek et al. (2005) also evaluated the importance of TZ biopsy in benign prostatic hyperplasia (BPH) patients with serum PSA more than
10 ng/ml and prior negative PZ biopsy and to estimate the sensitivity of TZ biopsy. A total of 273
BPH patients with PSA more than 10 ng/ml and
prior negative PZ biopsy underwent an extended
biopsy protocol. In patients with a TZ volume of
less than 25 cc, four TZ biopsies were taken (two
cores per side from the apex and base). In patients with a TZ volume greater than or equal to
25 cc, six TZ biopsies were taken (three cores per
side from the apex, middle, and base). TZ biopsy
detected only 61.3% (19/31) of TZ cancers, and
the incidence of pure TZ cancers was 7.3%, with
the majority (74%) of TZ cancers detected at the
apex site. Patient age, serum PSA, TRUS findings,
89
and PSA density did not correlate significantly
with the detection rate of TZ cancer, but prostate
volume (p=0.023), TZ volume (p=0.027), and
PSA/TZ density (p=0.007) were predictive of TZ
cancers. Similarly, Durkan et al. (2002) showed
that routine TZ biopsies should be considered in
the framework of extended prostate biopsy for
men with serum PSA levels exceeding 10 ng/ml
whom they found to be at increased risk for TZ
prostate cancer. It seems therefore that TZ biopsy
should be performed in the setting of repeat biopsy, especially in a selected group of patients.
Nonetheless, others could not show any advantage to TZ sampling at the initial biopsy
(Bazinet et al. 1996; Lui et al. 1995). In general,
the addition of TZ biopsies to the initial biopsy
strategy increases detection rates by only 1.8% to
4.3%, and there are few data to support the recommendation for routine TZ sampling (Matlaga
et al. 2003).
Based on a literature review, Karakiewicz et
al. (2005) recommended 12-core peripheral zone
biopsies as standard care. This scheme incorporates the traditional sextant biopsy plus six laterally directed biopsies taken from the base, mid,
and apex. In prostates larger than 60 cc they add
a biopsy core for each additional 5 cc of peripheral zone tissue, based on their computer simulation studies, which showed that maximum detection rates are obtained when one biopsy core
was taken for each 1.5 to 3.5 cc of prostatic tissue
(Karakiewicz et al. 1998). Similarly, Basillote et
al. (2003) demonstrated that the percentage of
prostate cancer missed on the initial biopsy and
detected on the repeat biopsy increases as the
prostate volume increases. Their conclusions
were based on their institutional experience with
4,376 men who underwent TRUS-guided sextant
biopsy of the prostate, of whom 556 underwent
a repeat sextant biopsy. Of the men who underwent a repeat biopsy, 22% were found to have
prostate cancer. The percentage of men with
cancer missed on the initial biopsy but detected
on the repeat biopsy for each volume was investigated. Using the cutoff volume of 50 cc (mean
gland volume of all the men in their study), a
statistically significant difference was found in
the percentage of prostate cancer not detected
between men with prostate volumes less than
50 cc and those with volumes of 50 cc or greater.
90
This statistically significant difference was maintained when the cutoff volume of 37.5 cc (the
median prostate volume of all the men found to
have cancer in their study) was used. Specifically,
prostate cancer was missed and subsequently diagnosed on the repeat biopsy in 13.7% and 6.5%
of men with a prostate volume 50 cc or greater
and less than 50 cc, respectively. Consequently,
the false-negative rate more than doubled as the
prostate volume exceeded 50 cc.
Using data from the European Prostate Cancer Detection Study (EPCDS) for PSA counts
less than 10 ng/ml, Remzi et al. recently developed their Vienna nomogram (VN) prostate biopsy model (Remzi et al. 2005). This model optimizes the number of biopsy cores taken based
on patient age and total prostate volume in the
PSA range 2вЂ“10 ng/ml. The number of cores
ranges from 6 to 18 based on the patientвЂ™s age
and prostate volume. Accordingly, the older the
patient the lower the number of cores needed
for optimal prostate cancer detection, whereas
more cores are taken for larger prostates. Thus,
for a given prostate volume equal to or less than
30 cc, for example, a 50-year-old or younger patient would undergo an 8-core biopsy, whereas
a patient older than 70 years would need only a
6-core biopsy. For prostates larger than 70 cc, 18core and 14-core biopsies would be needed for an
optimal detection of prostate cancer in a 50-yearold or younger patient and a 70-year-old or older
patient, respectively. The overall prostate cancer
detection rate in this model is 36.7%, which is
comparable to other extensive biopsy protocols
(Scherr et al. 2002). The clear advantage of this
model, though, is that it may reduce the detection of clinically insignificant tumors, as their
detection inevitably increases with more extensive templates of prostate biopsy (Remzi et al.
2005). Accordingly, in the VN, less biopsy cores
are taken from older men, avoiding oversampling
and over-treatment of small-volume tumors that
are not likely to cause cancer-specific mortality,
unlike young men in whom these tumors are expected to grow and even affect survival.
It is imperative to emphasize that regardless
of the number of cores taken, any suspicious
area (whether by DRE or because of TRUS finding of hypo-echogeneity in the peripheral gland)
should undergo separate directed biopsy and
Jehonathan H. Pinthus, Dalibor Pacik, Jacob Ramon.
should be sent as a separate specimen for pathological examination.
Repeat Biopsy
One of the most complex clinical decisions in
prostate cancer diagnosis is when one should
repeat a prostate biopsy in the presence of solid
clinical suspicions of prostate cancer. The data
used by most authors to construct algorithms to
address this issue were based on first-set negative sextant biopsy. It is tempting to consider that
the risk of prostate cancer diagnosis on repeat
biopsy following extended initial prostate biopsy
is lower than that following initial sextant biopsy
merely due to the reduction in sampling error.
Along this rationale, when Djavan et al. (2001)
examined the risk for prostate cancer in the first,
second, and third repeat biopsies following initial negative sextant biopsy they found a sharp
decrease in detection rates between the first repeated biopsy (22%) and the following repeated
biopsies (5% and 4% respectively; Djavan et al.
2001). Indeed, Brossner et al. showed that the use
of an extended (10-core) biopsy protocol at the
initial evaluation reduces the number of prostate
cancers in repeat biopsy as compared to the use
of sextant core biopsy in the first biopsy (Brossner et al. 2005). Several clinical and pathological risk factors have been identified as predictors
of prostate carcinoma in repeat biopsies. Wellestablished clinical risk factors are suspicious
DRE, total serum PSA levels, percentage of free
PSA, hypoechoic lesion on TRUS, PSA density
(PSAD), and TZ-PSAD. Pathological risk factors
that traditionally promoted repeat biopsy were
the presence of high-grade prostatic intraepithelial neoplasia (HGPIN) and of atypical small
acinar proliferation (ASAP) on initial sextant
biopsy (Epstein and Potter 2001). Nowadays,
however, when sextant biopsy is not considered
adequate for primary diagnosis as detailed above
(and even more so for repeat biopsies), and as
greater numbers of patients with different clinical characteristics (normal DRE and lower levels
of serum PSA) are subjected to prostate biopsies,
some of these pathological factors are not as valid
as factors that encourage a repeat biopsy. In the
era of sextant biopsy, the presence of HGPIN in
6 Diagnosis of Prostate Cancer
the initial biopsy was associated with up to 79%
of prostate cancers on subsequent repeat biopsy
(Epstein and Potter 2001). With an initial 11-core
biopsy scheme, this risk is reduced to 22% (Kamoi et al. 2000) and not higher than the general
risk of having prostate cancer on repeat biopsy
(Fowler et al. 2000). Based on their literature review, Karakiewicz et al. concluded that with an
extended initial prostate biopsy (11вЂ“13 cores),
the presence of HGPIN by itself is no longer an
indication for repeat biopsy (Karakiewicz et al.
2005). Unlike HGPIN, in the era of extended initial prostate biopsy the presence of ASAP is still
an indication for repeat biopsy, as it was shown
to be associated with 43% of prostate cancer diagnosis on repeat saturation biopsy (Stewart et
al. 2001).
Interestingly, Djavan et al. showed that with
an 8-core (sextant biopsy and two additional TZ
biopsies) biopsy scheme, biochemical and pathological features of cancers detected on initial and
repeat biopsy in the PSA range 2.0 to 4 ng/ml are
comparable in terms of PSA, grade, stage, and
cancer volume (Djavan et al. 2005). This implies
that a prostate cancer undiagnosed in a low-risk
patientвЂ™s first set of biopsy, but rather on his repeat biopsy, does not mean that it has more favorable tumor characteristics. Thus, at least for
this limited sampling scheme, a repeat prostate
biopsy in case of a negative finding on initial biopsy is strongly recommended.
In order to stratify the risk factors for detection of prostate cancer in repeat biopsy, using
recursive partitioning analysis, Garzotto et al.
recently constructed a model of four distinct risk
groups that can practically serve to characterize
high-risk, intermediate-risk, and low-risk groups
for the subsequent detection of prostate carcinoma (Garzotto et al. 2005). This model segregates patients into distinct 2- and 5-year cancer
detection rate according to their PSAD, PSADT,
and the presence and absence of HGPIN. Patients
in the highest risk group (those with a PSADT of
в‰¤5 years and a PSAD of >0.25 ng/ml per cc) have
an estimated carcinoma detection rate of 66В±9%
and 100%, respectively at 2 years and 5 years.
Therefore, these patients should be strongly considered for a repeat prostate biopsy within a few
months. Conversely, patients in the lowest-risk
group (those with a PSAD of <0.25 ng/ml per
91
cc, a PSADT of >5 years, and no HGPIN) can
be considered for less rigorous follow-up because the estimated carcinoma detection rate in
this group was found to be only 3В±1% at 2 years.
Patients with a PSADT of >5 years and a PSAD
of <0.25 ng/ml per cc with HGPIN detected in
the initial biopsy specimen had a 28%В±5% risk
of carcinoma detection at 2 years compared with
only 3%В±1% when HGPIN was absent. The presence of HGPIN lost significance when either the
PSADT was short or the PSAD was increased
(Garzotto et al. 2005).
It is imperative to emphasize that in any case
of repeat biopsy, the extended biopsy scheme
is indicated. The recommendation is to include
also TZ biopsies in the repeat biopsy. Keetch
and Catalona found a yield of 10% by sampling
the TZ in repeat biopsies (Keetch and Catalona
1995). Higher yield is expected if PSA values are
high and DRE is negative as indicated by Lui et
al., who found 53% of prostate cancers to be detected only in the TZ in this clinical scenario (Lui
et al. 1995).
Some authors have suggested performing
saturation biopsy in cases where the repeat biopsies are negative in the presence of strong clinical
suspicion of prostate cancer.
Saturation Biopsy
The indications for saturation biopsy are undefined yet. Patients who are considered at
increased risk for prostate cancer, but had previously negative biopsies, cause a diagnostic
challenge. The introduction of a saturation biopsy approach increased the detection of prostate cancer at the expense of a potentially higher
detection rate of clinically insignificant prostate
cancer. Stewart et al. from the Mayo clinic were
the first to developed a saturation needle biopsy
method for repeat prostate biopsy following negative sextant biopsy and a persistent indication
for repeat biopsy (Stewart et al. 2001). Patients
underwent this procedure in an outpatient surgical setting under general, regional, or intravenous sedative anesthesia. A mean of 23 cores
(range 14 to 45) were obtained at each biopsy.
Larger prostates underwent more biopsies than
smaller prostates. A total of 3 TZ biopsies were
92
obtained. Technically, the saturation biopsy was
performed using an inward radial step approach,
starting at the far lateral peripheral zone (anterior horn) and continuing until the mid gland
was reached. The process was then repeated on
the contralateral side. Diagnostic yield was 34%.
However, the incidence of insignificant cancer
detected by saturation biopsy increased from
11.1% to 15.4% or to 22.2% in patients with 1,
2, or more than 2 previous negative biopsies, respectively. Of the 49 tumors removed at prostatectomy, 15 (30.6%) were less than 0.5 cc. Rabets
et al. reported their experience with office saturation biopsy in 166 patients at increased risk for
prostate cancer who had at least one negative
prior biopsy (Rabets et al. 2004). In their series,
most patient underwent more extensive prior
sampling of the prostate as compared to Stewart
et al. (2001). Using periprostatic nerve block, 24
biopsies were obtained in the first 80 patients.
The 12 locations on either side were the lateral
base (2), lateral mid zone (3), apex (3), parasagittal mid zone (2) and parasagittal base. In the last
36 patients they changed their biopsy scheme to
include only 1 parasagittal mid zone and 1 parasagittal base biopsy from each side, thus decreasing the total number of cores sampled from 24 to
20, since in the first 80 patients medial parasagittal cores were never positive in the absence of
apical, lateral mid zone, or lateral base positivity.
In this scheme the TZ was visualized and sampled in medial parasagittal biopsies by advancing the needle through the surgical capsule and
sampling the most anterior tissue. The apex was
well sampled, including the anterior horn tissue,
and the adjacent lateral mid zone and parasagittal mid zone biopsies. Overall diagnostic yield
was 29%. But this was increased to a 64% cancer detection rate in patients who underwent a
single prior sextant biopsy. They also noted an
inverse correlation between the cancer detection
rate and the number of prior biopsies (33% with
1 biopsy and 23% with 2 or more). Importantly,
they showed that the risk of diagnosing clinically
insignificant prostate cancer with their technique
of saturation biopsy was similar to that in other
series in which the diagnosis of prostate cancer was made with fewer biopsy cores. Fleshner
and Klotz (Fleshner and Klotz 2002) evaluated
the role of saturation biopsy in 37 patients who
Jehonathan H. Pinthus, Dalibor Pacik, Jacob Ramon.
had undergone at least three prior sets of TRUSguided biopsies (ranging up to 6), including TZ
assessment. In all cases, the PSA parameters
were significantly changing from baseline levels,
including rising total PSA or a significant lowering (less than 0.10) of the free/total PSA ratio. All
procedures were done under general or spinal
anesthesia. The biopsy scheme included 24 laterally (4 from each sextant) placed TRUS-guided
peripheral zone cores, 6 to 12 TZ cores, and 2
transurethral samples from the lateral prostatic
lobes under resectoscopic guidance. However,
despite this extensive sampling protocol among
this high-risk cohort, only five (13.5%) of the
37 patients demonstrated carcinoma at saturation biopsy. Other notable pathologic features
at saturation biopsy were acute prostatitis (n=7),
chronic prostatitis (n=11), and HGPIN (n=1). In
3 of 5 cases, carcinoma was detected in the first
12 peripheral zone coresвЂ”transurethral and TZ
cores were positive in only 2 patients who also
had positive peripheral zone cores. Analyzing
the pattern of this aggressive prostate assessment
by looking at each separate biopsy location, the
authors noted that all cases of cancer were identified in the first 18 peripheral zone cores. In addition, only 1 case would have been missed had
only 12 cores been taken. They concluded that
12- to 18-core peripheral zone sampling should
suffice among patients deemed candidates for
repeated biopsy.
Thus, the indications for saturation biopsy are
still questionable, specifically when contemporary protocols already apply extended (10вЂ“13)
cores for the first biopsy.
Transperineal Prostate Biopsy
Transperineal prostate biopsy has a particular
role in two distinct clinical scenarios: as a mode
for repeat biopsy usually in the setting of saturation biopsy and in patients who have no rectum.
One of the advantages of transperineal biopsies,
particularly in the setting of repeat biopsy, is that
transperineal approaches are appropriate for
sampling from the anterior half of the prostate
gland (Satoh et al. 2005; Demura et al. 2005), and
it was also shown to enhance the identification of
TZ cancers not detected by previous transrectal
6 Diagnosis of Prostate Cancer
prostate biopsy in patients at high risk of prostate
cancer (Pinkstaff et al. 2005). Similar to transrectal prostate biopsy, prostate volume is the most
relevant variable in the planning of the optimal
number of cores in the extensive first biopsy set
(Ficarra et al. 2005). Pinkstaff et al. demonstrated
that systematic transperineal template biopsy of
the prostate has an overall cancer detection rate
of 37% in patients at high risk of prostate cancer
despite negative findings on previous biopsies
(Pinkstaff et al. 2005). The transperineal saturation biopsy is done under general anesthesia in
a setup similar to that of standard brachytherapy
techniques, namely using TRUS guidance and a
template fixation device, grid, and probe cradle
positioned adjacent to the perineum. Eighteengauge biopsy cores are obtained transperineally
through the template grid moving anteriorly
to posteriorly with the addition of more cores
in larger volume prostates to improve the sampling in the apical region. A relatively frequent
complication of transperineal prostate biopsy is
urinary retention (11%). The number of needle
incursions and prostate size are predictors of
post-procedure urinary retention (Buskirk et al.
2004).
In patients who have lost the rectum to malignancy or inflammatory bowel disease and present
with high or rising PSA, transperineal prostate
biopsies are applied (Matlaga et al. 2003). This is
done either the guidance of transperineal (Shinghal and Terris 1999) or transurethral (Seaman
et al. 1996) ultrasound. Worldwide experience
is relatively low, but it seems that the diagnostic
yield is lower than with TRUS-guidance biopsies,
emphasizing the need for prostate cancer screening before removal of the rectum (Matlaga et al.
2003).
Incidental Prostate Cancer
Incidental prostate cancer is defined as prostate
cancer that is not diagnosed clinically but is
rather diagnosed incidentally from histopathologic examination of a surgically obtained specimen. Two common clinical scenarios can lead to
incidental diagnosis of prostate cancer. The first
is through specimens obtained by transurethral
resection of the prostate (TURP) or open enucle-
93
ation of the prostate, and the second is following
radical cystoprostatectomy (RCP) for transitional cell carcinoma of the bladder. The UICC
Tumour Node, Metastasis (TNM) classification
of prostate cancer relates to the first scenario,
classifying tumors as T1a or T1b if the tumor
is found in less or more than 5% of the resected
prostatic tissue respectively. Another criteria to
differentiate between T1a and T1b tumors is the
tumor grade, which has to be of a GS equal to or
less than 7 to be T1a, or more than 7 to define
it as T1b. The incidental finding of T1a or T1b
tumor was reported in about 15% of patients
undergoing transurethral or open surgery for
BPH (Bostwick 1995). However, nowadays the
incidence of such a finding is probably lower, as
many patients undergo PSA screening and there
is an increase use of medical therapy (О± blockers and 5 О± reductase inhibitors) for BHP. In an
elegant comparative analysis, Mai et al. (2000)
reviewed consecutive TURP specimens from the
two time periods (before and during the PSA
screening era) to identify incidental PCA; they
showed that some prostate cancers previously
staged as T1b are now staged as T2 carcinomas,
as a result of PSA screening and earlier clinical
detection. The introduction of PSA screening
has had no influence on the incidence of T1a
prostate cancer. While it is clear from previous
studies that T1a and T1b tumors have a different
progression rate (Zincke et al. 1991), the recommended work-up and treatment plan for both
stages is not clear.
Previous studies demonstrate progression
rates without treatment as high as 16%вЂ“25% at
8вЂ“10 years (Matzkin et al. 1994). Cheng et al.
(1999) attempted to identify clinical predictors
of cancer progression in a large series of untreated T1a prostate adenocarcinoma patients
with lengthy follow-up (median 9 years). Interestingly, the only potential predictor that was
associated with progression was the amount of
resected prostate tissue (TURP weight). Patients
with a TURP weight greater than or equal to 30 g
had 100% progression-free survival at 10 years
compared with a progression-free survival rate
of 73% in patients with a TURP weight of less
than 12 g. GS, tumor volume, number of chips
involved by tumor, number of tumor foci, and
the presence of high-grade prostatic intraepithe-
94
lial neoplasia were not significant in predicting
cancer progression.
Serum PSA levels should significantly decrease after TURP (Wolff et al. 2000; Aus et al.
1996) or prostatic enucleation, but their application as a prognostic marker for the follow-up of
incidental prostate cancer is not reliable (Feneley
et al. 1995; Aus et al. 1996). Thus, in the absence
of adequate clinical predictors, it seems reasonable to follow patients who were just diagnosed
with stage T1a or T1b prostate cancer by prostate biopsy to gain more satisfactory data on the
tumor characteristics that by being detected in
the prostate biopsy will become a stage T1c, for
which treatment recommendations are more established. Without classifying these incidental
tumors by proper prostate biopsy, their clinical
behavior is unpredicted and often underestimated as reflected by previous studies like that of
Epstein et al., who reported their experience with
radical prostatectomy for T1a and T1b prostate
cancers (Epstein et al. 1994). Of the 64 cases of
stage T1a disease, 13 (20%) showed substantial
tumor, including 7 with more than 1 cc of tumor,
5 with capsular penetration, and 1 with a Gleason grade 4+5=9 tumor. Based on preoperative
pathological parameters, one could not predict
which cases had minimal versus substantial tumor. For cases with stage T1b carcinoma, Epstein et al. (1994) found that 26% had capsular
penetration and 10% had invasion of the seminal
vesicles.
Coexistent prostate cancer in RCP specimens
has been reported as high as 46% (Tal and Baniel
2005). The majority of these cancers were clinically insignificant. Indeed Ohori et al. (1994)
compared the characteristics of PC found incidentally in the prostates of 88 patients who underwent RCP for bladder cancer to 307 prostate
cancers that were detected clinically and treated
by radical prostatectomy. Normal DRE served as
the only pre-RCP screening test. The authors defined clinically important prostate cancer as a tumor with one or more of the following characteristics: volume of 0.5 cc or more, Gleason grades
equal to or greater than 4, or a tumor that is not
confined to the prostate. Important tumors were
farther defined as curable or advanced based on
the extent of extra-capsular extension and the
presence of seminal vesicle invasion or lymph
Jehonathan H. Pinthus, Dalibor Pacik, Jacob Ramon.
node metastases. Only 23% of the prostate cancers that were diagnosed in the RCP specimens
were clinically important. All were curable and
none was advanced, as opposed to most (91%)
clinically detected tumors.
Conclusions
Prostate cancer, always considered the most
common noncutaneous malignancy among men,
is becoming even more commonly diagnosed at
the present time due to PSA screening followed
by extended prostate biopsy protocols. Consequently, overdiagnosis of clinically insignificant
tumors occurs and should be regarded now as an
inevitable trade-off for the potential detection of
clinically significant tumors. Thus, in the absence
of alternative noninvasive diagnostic tools, extended biopsy schemes should be performed not
only at first biopsy but especially when repeated
biopsy is needed. The widespread use of local anesthesia makes the procedure more comfortable.
Future improvement of imaging techniques, the
development of better clinical algorithms, and
hopefully the discovery of better prostate cancer
markers may decrease the rate of unnecessary
biopsies.
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7
Does Localized Prostate Cancer Exist?
Bernard Lobel
Recent Results in Cancer Research, Vol. 175
В© Springer-Verlag Berlin Heidelberg 2007
Abstract
Does localized prostate cancer exist, and how
do we diagnose it? Early diagnosis and screening programs for prostate cancer (PC) have led to
a greater proportion of patients with a low-stage
disease at diagnosis. More men are treated with
curative intent by radical prostatectomy (RP),
external beam radiotherapy, or brachytherapy.
However, a substantial percentage of patients still
experience a prostate-specific antigen (PSA) relapse within 5 years. Biochemical recurrence is
observed in approximately 40% of patients who
undergo RP, with 95% of those relapses in the first
5 years. To avoid the risk of recurrence, the recent
tendency has been to detect PC at a lower PSA
level than the level widely accepted (в‰Ґ4.0 ng/ml).
But the risk of overdiagnosis and overtreatment
is a real problem in the PSA era. Discussion
around the wide discrepancy between the high
prevalence of histological changes recognizable
as cancer and the much lower prevalence of clinical disease is prominent. The recent experience
from studies on watchful waiting and the results
of randomized trials between surgery and active
surveillance have clearly demonstrated that many
localized PC are overtreated. New screening and
management strategies are required to target aggressive disease at an early stage while avoiding
overdiagnosis and overtreatment.
radiotherapy, or brachytherapy. However, a substantial percentage of patients still experience a
prostate-specific antigen (PSA) relapse within
5 years [3]. Biochemical recurrence is observed
in approximately 40% of patients who undergo
radical prastaectony (RP) with 95% of those relapses in the first 5 years [8]. To avoid the risk of
recurrence, the recent tendency has been to detect PC at a lower PSA level than the level widely
accepted (в‰Ґ4.0 ng/ml). The rationale for screening at a low PSA value is supported by the more
favorable expected characteristics of tumors
detected in the range of PSA between 2.4 ng/ml
and 4.0 ng/ml. However, the concept of localized
PC is highly controversial as an entity situated
between вЂњpotentially insignificant cancerвЂќ and
what is already вЂњnon-organ confined tumor.вЂќ The
risk of overdiagnosis and overtreatment is a real
problem in the PSA era. Discussion around the
wide discrepancy between the high prevalence of
histological changes recognizable as cancer and
the much lower prevalence of clinical disease is
prominent. Does localized PC exist and how do
we diagnose it?
How to Define Localized Prostate Cancer?
We have learned from our experience with RP
how difficult accurate preoperative staging and
evaluation of tumor aggressiveness can be.
Introduction
Early diagnosis and screening programs for
prostate cancer (PC) have led to a greater proportion of patients with a low-stage disease at
diagnosis. More men are treated with curative
intent by radical prostatectomy, external beam
Clinical and Pathological Criteria
(TNM Classification)
Localized PC is a cancer confined within the
prostate gland (T1вЂ“2) without extension through
the prostatic capsule (T3) in the extracapsular
102
tissue (T3a), the seminal vesicle (T3b), or adjacent structures (as bladder neck, external sphincter, rectum, levatori ani or pelvic wall). This cancer confined to the prostate gland is in principle
eradicated by RP. In the other cases, cancer is
locally advanced and surgical treatment is not
indicated.
How can we be sure that cancer is confined to
the prostate gland? Rectal examination alone is
inaccurate in up to 60% of cases, leading to both
under- and overstaging. Rectal ultrasound does
not offer any advantage over rectal examination
with a sensitivity of 50% and a specificity varying from 40% to 70%. Number and percentage
of prostate biopsies specimen involved by the
tumor is a more accurate parameter but underestimates the presence and grade of PC in 30% of
cases. Magnetic resonance imaging (MRI) is still
in evaluation.
Despite the numerous diagnostic parameters
used, the final report after RP is still disappointing, with surgical margins involved by tumor in
11% to 46% of patients [4]. Moreover, PC features
have evolved over the past 20 years: palpable
nodules have become less frequent (from 91%
to 17%) and index cancer volume has decreased
(from 5.3 to 2.4 cm3) [20]. The widespread use
of PSA testing associated with the extensive
Bernard Lobel
use of transrectal prostate biopsy have led to a
spectacular stage migration of PC. Catalona [2]
compared typical pathology diagrams of prostates with cancers in 1991 and 2005 (Fig. 7.1).
The diagram shows what the typical PC looked
like in the pre-PSA era as compared with today.
A decade ago it was frequent to find a large (but
probably incurable) index tumor. The PSA level
correlated strongly with the size of the tumor.
Today the dramatic decrease in the index tumor,
despite the multifocality of the lesions, gives the
PSA less importance in the staging of the cancer. The total tumor volume or the percentage of
carcinoma in the RP specimen may have more
prognostic value in the modern era. Although
clinical and pathological stages correlate with
outcome, a large percentage of patients thought
to have organ-confined disease will have evidence of disease beyond the prostate identified
at the time of surgery. This is due to our relative
inability to accurately stage the cancer. Digital
rectal examination is not reliable. Imaging modalities can identify tumor or metastatic lesions
half a centimeter in diameter, but are not able to
demonstrate microscopic foci of neoplastic cells
that have migrated to lymph nodes or perivesical
fatty tissue [26].
Fig. 7.1a, b Typical pathology diagrams of prostates with cancers in a 1991, compared with b 2005
7 Does Localized Prostate Cancer Exist?
вЂќLow-вЂќ and вЂњHigh-RiskвЂќ Tumors
The concept of a low- and high-risk tumor appears more appealing in the pretherapeutic
period. Epstein [5] described in 1994 criteria
predictive of organ-confined disease in nonpalpable prostate tumors (stage T1c). The criteria
are based on Gleason grade (defining tumor
differentiation), PSA density (level of PSA in relation to the size of the prostate gland) and the
extension of tumor infiltration in prostate biopsies. A PSA density that is less than 0.1 ng/ml,
the absence of a high-score tumor (Gleason
score в‰¤7), the presence of tumor in no more
than 3 out of 6 sampled biopsy specimens, and
tumor infiltration that is less than 50% of each
core biopsy correlates well with organ-confined
disease.
Partin [15] in 1997 designed the вЂњPartins
tableвЂќ evaluating a multi-institutional cohort of
4,000 patients who underwent RP. He compared
the data known before the operation (PSA level,
clinical stage and Gleason score from the biopsy
specimen) with the final pathological stage of the
prostate specimen in clinically localized PC. LetвЂ™s
give two examples of patients evaluated with
PartinвЂ™s table:
1. A 55-year-old patient underwent prostate
biopsies because of a PSA increase from 2
to 4.5 ng/ml over a year, with a normal DRE
(T1c): a Gleason score 8 tumor was found in 2
out of 6 biopsies.
The risk for the patient to have an extraprostatic extension is 40%, seminal vesicle infiltration 6%, and lymph node involvement 1%.
The chance for organ-confined lesion is 52%
(41% to 63%).
2. A 65-year-old asymptomatic patient with a
PSA of 7 ng/ml has normal DRE (T1c). Prostate biopsies show a Gleason score 7 (4+3)
tumor. The chance for organ-confined lesion
is 43% [35%вЂ“51%]. The risk for extraprostatic
extension is 47%, seminal vesicle infiltration
8%, and lymph node involvement, 2%.
The chance for both patients to have localized
PC are limited to 50%. Finally given the independent prognostic significance of pretreatment
PSA, Gleason score, and stage, various algorithms have been developed to provide point-
103
estimates of recurrence risk. Patients with a PSA
of less than 10 ng/ml, Gleason 6, and T1 or T2a
disease appear to be вЂњlow-risk patientsвЂќ with a
6% to 20% of recurrence rate after local treatment. Such patients are likely to be cured with
monotherapies such as external beam radiation
therapy, brachytherapy, or prostatectomy.
Patients with a PSA exceeding 20 ng/ml, Gleason 8вЂ“10, and T3b disease are considered to be at
вЂњhigh risk,вЂќ with recurrence rates of 50% to 100%
after definitive local therapy.
Identifying patients with вЂњlow-riskвЂќ characteristics appears the better way to treat patients
with organ-confined lesions according to Epstein
who had already described in 1994 clinical and
pathological criteria predictive of local extension
in nonpalpable prostate tumors (stage T1c).
Criteria for Insignificant Localized PC
Examining the feature of cancers detected after
RP, Epstein et al. [5] designed the criteria for insignificant PC: PC less than 0.2 cm3, confined
to the prostate with a Gleason sum less than 7.
Ohori [14] is more flexible proposing for unimportant cancer, a tumor less or equal to 0.5 cm3,
confined to the prostate, with no primary or secondary Gleason pattern 4 or 5.
A careful evaluation of the pathologic profile
of a patient diagnosed with a potentially вЂњinsignificantвЂќ cancer may help to distinguish those
with a truly вЂњinsignificantвЂќ tumorвЂ”well differentiated (Gleason в‰¤6) of low volume (0.2вЂ“0.5 ml),
manageable initially by surveillanceвЂ”from those
with a potentially life-threatening tumor requiring active treatment [25].
Localized PC is an entity situated between
вЂњpotentially insignificantвЂќ cancer and what is already вЂњnon-organ-confined tumor.вЂќ
How to Improve Diagnosis
of Localized PC?
PSA is a valuable tool for detecting early stage
PC and for staging men with newly diagnosed
tumor. In the last few years it rapidly became
obvious that men with higher PSA were significantly more likely to have higher clinical stages,
104
Bernard Lobel
Table 7.1 Relationship of the prostate-specific antigen (PSA) level to the prevalence of prostate cancer and high-grade
disease. High-grade disease was defined by a Gleason score of 7 or greater. The population was restricted to men with a
PSA level of 4.0 ng/ml or less throughout the study. Used with permission [21]
PSA level
No. of men
(n=2,950)
Men with
prostate cancer
(n=449)
Men with highgrade prostate
cancer (n=67)
No. of men (%)
No./total No. (%)
20/170 (11.8)
Sensitivity
Specificity
0.75
0.33
1.1вЂ“2.0 ng/ml
998
170 (17.0)
2.1вЂ“3.0 ng/ml
482
115 (23.9)
22/115 (19.1)
0.37
0.73
3.1-4.0 ng/ml
193
52 (26.9)
13/52 (25.0)
0.12
0.92
higher grade cancers in the biopsy and final RP
specimen, positive surgical margins, capsular
penetration, seminal vesicle invasion, and lymph
node metastasis [6]. The incidence of distant
stage disease decreased at a dramatic rate since
1991 in the PSA era and today 75% of PC are discovered at a low stage. The 5-year survival rate
is nearly 100% for local or regional disease and
only 33.5% for distant stage disease [2].
After the PC Prevention Trial (PCPT) [21]
it became obvious that, biopsy-detected PC, including high-grade cancers, is not rare (15.2%)
among men with PSA в‰¤4.0 ng/ml, levels generally thought to be in the normal range (Table 7.1).
A screening for PC at low PSA levels (<4.0 ng/
ml) was suggested. Is it the solution to diagnose
localized PC?
Using a Low PSA Level (<4.0 ng/ml)
for Detecting Localized PC?
There is a debate about the optimal PSA cutoff
for recommending prostate biopsy. It is welldocumented that 7% to 27% men with PSA 1.0
to 4.0 ng have biopsy detectable PC and 14.9%
have a Gleason score of 7 or higher [21]. However, recommending a lower PSA threshold for
prostate biopsy to 2.6 ng/ml is not the right response according to Stamey [20], because this
is precisely the range of serum PSA for benign
prostatic hyperplasia currently (Table 7.2).
SchrГ¶der et al. [19] considered also that using a low PSA threshold (2.4 ng to 4.0 ng/ml)
might detect clinically insignificant PC that
would not pose a clinical threat to the patient
(overdiagnosis).
If the best cutoff remains unknown, use of
a normal threshold (4.0 ng/ml) risks missing
clinically relevant cancers that are still curable,
whereas the use of a lower threshold increases the
number of unnecessary biopsies and the number of clinically insignificant cases. What about
European Official Guidelines? According to the
German Guidelines [18] the decision to undergo
early PC detection needs to come from the patient. He should be thoroughly informed about
what options he has after being advised about the
risks and benefits. It seems medically warranted
to stipulate a PSA cutoff at 4.0 ng/ml (5 biopsies
needed to find 1 carcinoma). Reducing the cutoff
to 3 ng/ml increases detection of curable tumors
by only 2% (Table 7.2).
The EAU guidelines [1] confirm that the exact cutoff level of what is considered to be a normal PSA value has not yet been determined, but
values around 2.5вЂ“3 ng/ml are often used for
younger men (grade C recommendation).
Table 7.2 The probability of a positive biopsy and detecting organ-confined cancer can be correlated to PSA value
(from Luboldt et al. [18])
0вЂ“4 ng/ml: case finding in 10%, ca. 90% are organconfined malignancies
4вЂ“10 ng/ml: case finding in 25%, 70% are organconfined malignancies
>10 ng/ml: case finding in 50%, 50% are organconfined malignancies
7 Does Localized Prostate Cancer Exist?
What About Prostate Cancer Screening?
Screening for PC remains a controversial issue
in spite of recent evidence of a decreasing PC
mortality in geographic areas were screening is
prevalent [19].
Criticism includes the financial burden of
screening, the morbidity of prostate biopsy, the
low positive predictive value of screening, the
overtreatment of an indolent disease, and the
lack of evidence demonstrating a mortality benefit due to screening. If the PSA era has brought
great promise for improving the prognosis of PC,
we have to improve PC screening to better select
clinically significant localized PC [13].
PSA Velocity and PSA Doubling Time
A PSA velocity measurement is helpful because
clinically significant PC is more likely to be found
in men with a rapidly rising PSA. Recent studies
suggest that for men with a total PSA higher than
4 ng/ml, a PSA velocity of 0.75 ng/ml per year is
an indication for biopsy. However, in men whose
total PSA level is lower than 4 ng/ml, a lower PSA
velocity cutoff should be used, in the range of 0.1
to 0.5 ng/ml per year. More clinical research is
needed to evaluate PSA velocity cutoffs for men
with low PSA levels [2].
PSA doubling-time (DT) enhances prediction of the biological phenotype of the cancer. A
PSA-DT shorter than 3 months has apparently
a high predictive value for PC-specific mortality following surgery or radiation therapy in
patients with clinically localized PC [23]. Moreover, in the pretreatment period a PSA-DT of
less than 2 years appears to identify patients at
high risk for local progression despite otherwise
favorable prognostic factors. A patient with a
PSA-DT of around 3 years has a high chance of
remaining free of recurrence or progression for
many years.
Can We Improve Management
of Localized PC?
The situation today is a real paradox: men who
underwent radical treatment (RP of radiother-
105
apy) with curative intent for localized PC have
a 20%вЂ”40% risk of 5-year biochemical recurrence; on the other hand, a relevant number
of patients who are disease free at 5 years have
probably been overtreated for clinically nonsignificant tumors.
What About Biochemical Failure After RP?
Most investigators consider the biochemical failure (PSA) after RP to be due to positive surgical
margins, metastatic disease, and or local recurrence, but also to the presence of benign prostatic glands in the surgical margin. Positive cancer margins occur in 11% to 46% of patients after
RP [4, 17] and biochemical or clinical recurrence
appears for as many as 63% of patients in a 5-year
follow-up.
The quality of life for men with PSA progression is definitely affected. Most patients with biochemical failure will experience clinical pelvic
recurrence or even distant metastasis. Patients
with PSA failure within the first 2 years carry
the greatest risk of developing distant metastasis, and patients with a detectable serum PSA
level immediately after surgery most probably
had distant disease at the time of surgery. The
PSA-DT is significantly associated with the time
to PC-specific mortality and the time to overall
mortality [23, 24].
Improving the technique to reduce positive
margins is mandatory, but the risk of incontinence is high when dealing with apical tissue.
New Strategy with Active Surveillance
and Selective Delayed Intervention Using
PSA Doubling Time for Good Risk Patients
According to Klotz [10, 11] localized PC is overtreated, with some patients who have a favorablerisk disease not destined to experience PC death
or morbidity undergoing radical therapy.
The Canadian Consensus Conference on PC
defines good-risk PC as patients with a Gleason
score 6 or less, T1c-T2a, and PSA of less than
10 ng/ml. In this group of patients, it is possible
to estimate the biological aggressiveness of the
tumor based on PSA-DT. Most patients who
106
understand the basis for this approach will remain on observation in the long termвЂ”PSA-DT
varies widely and is not predicted by grade, stage,
or baseline PSA. Of the patients in the series,
33% had a PSA-DT of more than 10 yearsвЂ”PSADT appears to be an excellent marker of cancer
aggressivity in localized PC. A PSA-DT of less
than 2 years identifies patients at high risk for
local progression and who need active therapy.
A PSA-DT of 3 years or more in cases of localized PC gives the patient a high probability of
remaining free of progression for many years.
It is likely that most of these patients will die of
causes unrelated to PC. Active surveillance is
clearly appropriate for elderly patients, patients
with significant co-morbidity, or in the presence
of favorable PC parameters.
Conclusion
Screening and early detection of PC in the PSA
era have led to a greater proportion of earlystage PC at diagnosis and an increasing number
of patients being offered definitive treatment
with RP or radiotherapy. The recent experience
from studies on watchful waiting and the results
of randomized trials between surgery and active surveillance have clearly demonstrated that
many localized PC are overtreated.
вЂќGood riskвЂќ patients (with a Gleason score of
6 or less, PSA <10 ng and T1cвЂ“T2a tumors) now
constitute 50% of newly diagnosed PC patients.
The present challenge is to identify in this group
of patients the prognostic criteria that might predict the degree of threat involved.
The assumption that localized PC at diagnosis warrants active treatment with a curative
intent is now being challenged. In the group of
patients with supposedly localized PC, clinically
insignificant tumors coexist with aggressive lifethreatening cancers sometimes associated with
microscopic distant metastasis.
New screening and management strategies
are required to target aggressive disease at an
early stage while avoiding overdiagnosis and
overtreatment.
Bernard Lobel
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8
Staging of Prostate Cancer
Zohar A. Dotan, Jacob Ramon
Recent Results in Cancer Research, Vol. 175
В© Springer-Verlag Berlin Heidelberg 2007
Introduction
Prostate cancer, with an incidence that is correlated to age, is the most common cancer tumor
diagnosed among men older than 50 years, and
an even higher incidence is found among patients older than 75. It is estimated that 234,460
men will be diagnosed during 2006 and 27,350
deaths will be attributed to prostate cancer in the
United States. Thus, it is the 3rd most common
cause of cancer-specific death, following lung
cancer, in Western men (Jemal et al. 2006). The
lifetime risk for prostate cancer is estimated to be
one in six among countries with active screening
programs. Since 1990 there has been a decline in
prostate cancer death. Of the patients diagnosed
from 1995 to 2000, around 90% were diagnosed
during local or regional stages. The 5-year survival rate for those patients approached 100%,
while the overall survival rate for all stages increased during the past 20 years from 67% to
99%, with a 10-year survival rate of 92%. Usually,
the increase in survival rate for those patients is
attributed to early diagnosis (American Cancer
Society 2005). Many patients newly diagnosed
with prostate cancer will be evaluated for curative treatment, according to age at diagnosis and
comorbidities. Following histologic diagnosis of
prostate cancer, staging is used to determine the
extent of the patientвЂ™s cancer to predict prognosis
and to evaluate and select the appropriate treatment options. Accurate staging is helpful in assessing different treatment options and defining
prognostic models.
Historically the staging of prostate cancer was
based on the anatomical extent of the cancer
determined during physical examination. The
ability to better stage patients who are currently
being diagnosed with prostate cancer continues
to evolve because of improvements in imaging,
defining, and detection of tumor markers, and
creation of prediction tools based on currently
available clinical variables. Such tools are used to
better define the extent of cancer at time of diagnosis, the probability that the individual patient
will clinically progress following local therapy,
and the likelihood of prostate-related death.
They are also used to evaluate the use of neoadjuvant and adjuvant treatment prior to or following
local therapy.
Classification System
Since 1975 the UICC 2002 Tumour Node, Metastasis (TNM) classification system has been
used by the American Joint Committee for Cancer Staging (AJCC). The AJCC classification is
based on the extent of the primary tumor (T),
the presence and extent of involved lymph nodes
(N), and distant metastases (M). This system has
replaced the previously used staging classification of Whitmore and Jewett, which was based
on digital rectal examination (DRE) only and
just described the extent of the tumor. The different classifications of the tumor included: class
A [normal DRE, tissue obtained by transurethral
resection of the prostate (TURP)], class B (palpable disease confined to the prostate), and class
C (tumor extent beyond the prostate capsule)
(Jewett 1975).
The 1992 version of the TNM system (International Union Against Cancer 1992), an effort by the AJCC and the International Union
Against Cancer (UICC), included DRE, prostate-specific antigen (PSA), and transrectal ultrasound (TRUS) findings, and added a new
classificationвЂ”T1c, those tumors detected by
prostate biopsy and triggered by elevated serum
PSA. The proportion of tumors classified as T1c
110
was initially less then 10% of all cases (Ohori et
al. 1994) and has increased significantly since
then, accounting for more than 70% of all newly
diagnosed prostate cancer cases (Draisma et al.
2003; Stamey et al. 2004). Nonpalpable disease
identified by TRUS was classified as T2, similar
to patients with palpable T2 disease; despite no
difference in outcome compared with T1c with
no visibility on TRUS (Ohori et al. 1994). Nonpalpable tumors compared with palpable tumors
but had lower preoperative PSA (9.3 ng/ml vs
11.8 ng/ml), higher percentage of Gleason score
6 tumors (71.8% vs 52.5%), and reduced tumor
involvement of the submitted tissue (14.3% vs
22.4%) (Augustin et al. 2003). Recent analysis of patients operated on from 1983 to 1998
showed no differences in presence of Gleason
score of 7 and above, tumor volume, and presence of organ-confined disease at the radical
prostatectomy (RP) specimen for patients with
nonpalpable disease and no difference regarding biochemical failure between nonpalpable
tumor with and without visible tumor by TRUS
(Ohori et al. 2003). TRUS findings (T2a vs T2b
vs T3c) did not predict freedom from biochemical failure. Only the group of patients classified
as definitely having cancer, according to TRUS
(group V vs groups IвЂ“VI), experienced an increased rate of progression following RPвЂ”76%
vs 85%, respectively, at 5 years. Of the last 100
cases, only 4% were classified as group V according to TRUS findings. The percentage of low-volume palpable tumor (T2a) had similar progression-free probability compared with nonpalpable
tumor with and without visible tumor by TRUS,
suggesting that classifying patients with visible
tumor by TRUS as T2a is not justified. The correlation between the TRUS-detected hypoechoic
lesions and the pathology finding of RP is low.
Many clinically significant tumors are not visible
by TRUS, which diminishes the importance of
the classification of nonpalpable tumor by TRUS
finding (Garzotto et al. 2003). Other imaging
modalities, such as endorectal probe magnetic
resonance imaging (erMRI), might be more useful in staging nonpalpable tumors (Mullerad et
al. 2005).
The 1997 edition of the TNM system (Fleming
et al. 1997) combined the previous T2a and T2b
classifications into T2a (tumor occupied only one
Zohar A. Dotan, Jacob Ramon
lobe) and T3a and T3b to T3a (unilateral vs bilateral extracapsular extension of tumor). However,
debate exists regarding the use of the 1997 classification vs the 1992 version, since the 1992 classification demonstrated differences in outcome in
T2a vs T2b. The ability to differentiate between
those groups was eliminated by the 1997 classification (Han et al. 2000). The 1992 classification
was reported to predict better outcome following
RP compared with the 1997 classification (Cagiannos et al. 2002). In 2002, the TNM staging was
revised again. T2 lesions were classified as either
вЂњlesion with abnormal DRE without extracapsular extension (ECE) or seminal vesicle invasion
(SVI)вЂќ or вЂњhypoechoic lesion by TRUS.вЂќ T3 lesions are subclassified to T3a and T3b based on
the 1997 classification.
Evaluation of Local Disease and Presence
of Metastatic Disease
The extent of local disease and biopsy variables
are the most important variable used to define
the natural history of prostate cancer and predict its progression, and to estimate response
to definitive local therapy among patients with
clinically localized prostate cancer. Treatment
for locally advanced cancer in the presence of
ECE, seminal vesicle invasion, and lymph node
involvement definitely impact progression-free
probability (measured by freedom from PSA recurrence), clinical progression, and death from
prostate cancer. Patients with locally advanced
cancer are not eliminated from potential curable
treatments to control local disease and clinical
progression. Several modalities are used to assess
the local extent of the disease.
Digital Rectal Examination (DRE)
Used for more than 50 years, DRE represents the
most accessible staging test for evaluating the
local extension of prostate cancer (Jawet 1975).
Staging systems and prognostic models rely on
DRE for clinical staging of prostate cancer (Partin et al. 1997; DвЂ™Amico et al. 1998; Kattan et al.
1998). However, during the post-PSA period,
more than 80% of tumors will be diagnosed
8 Staging of Prostate Cancer
111
following elevated PSA, and more than 70% of
those will have normal DRE. The probability of
overstaging and understaging with use of DRE
is significant, demonstrated by the discrepancy
between DRE and pathology reports of RP specimens, and it is examiner-dependent. Organconfined tumor (pT2) following RP was found
among 59% to 77% of the patients classified as
T1c. This staging upgrade was mainly due to the
presence of ECE in 17% to 24% (Table 8.1).
Overstaging patients with prostate cancer
can be estimated by evaluating the pathology
Table 8.1 Clinical T1c disease
Years
N
OCD ECE
SVI
LNI
23.9
2.2
0.7
Antenor et 1989вЂ“ 2669 75.4
al. 2005a
2001
23.1
1.5
Jack et al.
2002
1998вЂ“
2000
228 77
17
4.3
Bastian et
al. 2004
2000вЂ“
2003
237 91.6
7.6
0.8
Southwick 1994вЂ“
et al. 1999a 1996
268 71.6
Ohori et
al. 2003
1983вЂ“
1998
865 59
Geltzer et
al. 2002
1988вЂ“ 1119 72.5
2000
1.3
ECE, extracapsular extension; LNI, lymph node involvement; OCD, organ-confined disease; SVI, seminal vesicle
invasion
a
report of RP specimens of patients classified as
clinical T3 disease (either presence of ECE [T3a],
SVI [T3b], or adjacent organ involvement [T4]).
Clinical T3, based on preoperative physical examination, will be correct for 76% to 87% of patients. However, up to approximately 1/4 of the
patients treated with RP as monotherapy will
have pathological organ-confined disease following RP (Table 8.2).
DRE sensitivity in staging patients with
prostate cancer is limited by the trend of using
screening to identify clinically nondetectable
small-volume tumor, areas of the prostate that
are inaccessible to the examiner (DRE sensitivity of 59%вЂ“91%), and year of diagnosis and PSA
level prior to cancer detection (Table 8.1). The
specificity of DRE for local advanced tumors is
reasonable, in the range of 76% to 87%. Only less
than 25% of the patients who are considered by a
urologist to have clinical T3 disease will present
with organ-confined disease following RP (Partin et al. 1993; Van Poppel et al. 2000). Clinical
T2a has similar tendencies for the presence of
a positive surgical margin, ECE, and SVI compared with T1c disease. Researchers have suggested that the rate of biochemical failure for patients with T1c disease is comparable to that for
patients with cT2a, according to the 1997 classification (Freedland et al. 2003b). Others have
shown a difference in biochemical failure rates
between T1c and T2a in a cohort of patients who
were treated by RP (Kattan et al. 1998).
Preoperative PSA level of 4 to 10 ng/ml
Table 8.2 Clinical T3 disease
Years
N
36
19
45
1966вЂ“1982
812
17
49
Partin et al. 1993
Lerner et al. 1995a
Amling et al. 1997
158
13
Powell et al. 2002b
1993вЂ“1996
58
62
c
1983вЂ“2003
112
24
Carver et al. 2006
ECE
SVI
25
Van Poppel et al. 2000
a
OCD
LNI
T3
31
75
71
25
31
19
31
21
Neoadjuvant treatment in 491 cases (60%): external radiotherapy in 61 (7%), hormonal therapy 348 (43%) and both
82 (10%)
b
Neoadjuvant hormonal therapy for all the patients (Goseralin and flutamide)
c
No adjuvant therapy
112
Prostate-Specific Antigen (PSA)
Total
PSA was introduced to clinical urology less
than 20 years ago and significantly changed
the screening and follow-up process for patients with prostate cancer. PSA is 33-kDa
serine protease of the kallikrein family, which
includes 15 proteins; PSA is also known as human kallikrein 3. PSA is produced predominantly by the prostate epithelium, although it
can be found in endometrium and breast tissue in limited amounts. PSA is secreted by the
normal prostate epithelium to the seminal fluid,
where the level of PSA reaches levels of milligrams per milliliter. Although traces of PSA
can be found in endometrial and breast tissue
by immunohistology assays, it is considered to
be organ-specific. Every prostate disease, such
as cancer, inflammation, trauma, infarct, and
others, can cause PSA levels to rise. Differences
in the expression and production of PSA by the
different lobes of the normal prostate were reported, with the highest levels produced at the
transitional zone. Therefore, the PSA level usually significantly decreases following surgery for
benign prostate hyperplasia, with changes associated with the amount of removed prostatic
tissue (Furuya et al. 2000).
The PSA level was found to have a negative
correlation with Gleason score adjusted to tumor
volume of patients treated by RP (Partin et al.
1990). However, since there is a correlation between tumor volume and increased rate of PSA
release to the circulation with high-grade tumor,
increased serum PSA level corresponds to the
Gleason score (Stamey et al. 1987; Partin et al.
1997). Despite its limitation, PSA can provide
useful information regarding pretreatment staging for prostate cancer.
Prediction of pathology stages as the presence
of organ-confined disease, isolated capsular penetration, SVI, and lymph node metastases were
associated with PSA level. Only 9% of patients
with PSA above 50 ng/ml will have organ-confined disease compared with 64% of patients with
PSA below 4 ng/ml. SVI and lymph node metastases were found among 3% and 1% and 32%
and 27% of patients with PSA below 4 ng/ml and
Zohar A. Dotan, Jacob Ramon
patients with PSA above 50 ng/ml, respectively
(Partin et al. 1997).
The vast majority of patients diagnosed with
prostate cancer in countries that perform PSA
screening for prostate cancer will have a PSA
level of less than 20 ng/ml (Draisma et al. 2003).
Stamey et al. have demonstrated that serum PSA
levels between 1999 and 2003 correlated primarily with prostate size, i.e., the amount of benign
prostate tissue. In addition, PSA level was demonstrated to correlate with the volume of cancer.
When taking into account prostate weight and
cancer volume, no correlation was found between PSA level and ECE, SVI, and pathology
percentage of Gleason 4/5 (Stamey et al. 2004).
Free-to-Total PSA Ratio
Using the free-to-total (f/t) PSA ratio has added
information about patients presenting with
normal DRE and elevated PSA (2.5вЂ“10 ng/ml)
(Catalona et al. 1998). The role of the f/tPSA ratio for prostate cancer staging prior to RP is unclear. Among 76 patients undergoing RP, f/tPSA
was significantly higher among patients with
organ-confined versus those with non-organconfined disease (11.9% vs 9.1%). A threshold of
11% in f/tPSA indicates organ-confined disease
with a hazard ratio (HR) of 2.7 compared with
f/tPSA below 11% (using monoclonal antibody
immunoassay) (Tandem and Tandem-free PSA,
Hybritech, Belgium) (Morote et al. 1999). Pannek and coworkers from Johns Hopkins demonstrated that using an f/tPSA ratio of 25% did not
improve the prediction of non-organ-confined
disease (Pannek et al. 1996). In a later study, the
same group used monoclonal immunoassays for
PSA and free (f) PSA for 255 patients prior to RP
(Tandem and Tandem-free immunoassay, Hybritech, San Diego). A significantly lower f/tPSA ratio was detected among patients with non-organconfined disease vs those with organ-confined
disease (12.3% vs 15%) (Veltri et al. 2002). Similarly, 75% of patients with an f/tPSA exceeding
15% had a favorable pathology (organ-confined
disease, Gleason score less than 7, and small tumors) compared with 34% when the f/tPSA was
15% or lower (Catalona et al. 2000). In contrast,
the percentage of fPSA was associated with total
8 Staging of Prostate Cancer
prostate and benign prostatic hyperplasia (BPH)
volume among 256 patients who underwent RP,
but was not associated with total cancer and
Gleason 4/5 volume (Haese et al. 2003). Thus,
there is still no clear answer regarding the utility
of f/tPSA as a predictive variable when used with
clinical DRE staging, and prostate biopsy results
vs total PSA only.
PSA Velocity and Doubling Time
The dynamic characteristics of PSA changes can
be described in terms of PSA velocity (PSAV),
PSA slope, and PSA doubling time (PSADT).
Those variables are calculated by using several
PSA values over time and have been shown to
be helpful in the prognosis and outcome of patients who failed biochemically following RP or
radiotherapy (Pound et al. 1999; Roberts et al.
2001a; Dotan et al. 2005). Recently, PSAV and
PSADT have proved to be important predictive
factors for the probability of biochemical failure
and prostate cancer-specific mortality (PCSM)
after local therapy. PSAV of 2 ng/ml per year and
above prior to RP was associated with increased
probability of SVI compared with PSAV below
2 ng/ml per year (8% vs 3%), lymph node metastases (5% vs 0.7%), and a Gleason score of 8
to 10 at the final pathology (7% vs 3%) (DвЂ™Amico
et al. 2004a). Those worsened characteristics
translated to an increased rate of PCSM among
patients with PSAV of at least 2 ng/ml per year,
with an HR of 9.8, compared with patients with
a PSAV below 2 ng/ml per year. Data for a large
cohort of patients treated with RP confirm the
additional predictive ability of preoperative
PSAV and PSADT (Patel et al. 2005; Sengupta et
al. 2005).
A similar effect was demonstrated for patients treated with external radiotherapy who
were stratified by pretreatment PSAV. PSAV of
at least 2 ng/ml per year prior to radiotherapy
was associated with increased probability of biochemical failure (HR 1.8), PCSM (HR 12.0), and
overall mortality (HR 2.1). PSAV provided prognostic information for PCSM after using known
risk factors. Among low-risk patients stratified
by PSAV of 2 ng/ml per year and above, PCSM
at 7 years was 19% and 0%, while among high-
113
risk patients the probability of PCSM was 24%
and 9%, respectively (DвЂ™Amico et al. 2005a). The
main limitation of using PSA dynamics prior to
local treatment is the significant variation of PSA
values at that time. PSA level has high variability among patients followed by PSA for prostate
cancer screening. Of 40% to 55% of patients with
an abnormal PSA level, repeated PSA testing
showed normal levels during 4 years of followup prior to any treatment (Eastham et al. 2003).
Conflicting data exist on the impact of PSAV on
PCSM prior to RP (Bianco et al. 2004).
Prostate Biopsy
Prostate biopsy is the main procedure used to
make an initial tissue diagnosis of prostate cancer,
indicated by elevated PSA in the majority of cases.
For less than 20% of patients, DRE is the only indicator for prostate biopsy. Among patients with
suspicious DRE and low PSA (<2 ng/ml), the
mean volume of tumors and Gleason score were
less than 0.5 cc and 6, respectively (Schroder et
al. 1998). Other procedures used to obtain prostate tissue that can be used to diagnose primary
prostate cancer include: (1) surgery for clinically
benign lesions of the prostate, such as TURP or
open prostatectomy (classified as stage T1a/b),
which contributeвЂ”since the introduction of PSA
as a screening method for prostate cancerвЂ”less
than 5% of newly diagnosed tumors (Stephenson
et al. 2005); (2) prostate biopsy for patients who
presented with metastatic disease of unknown
origin. Thus, the majority of the patients with
newly diagnosed prostate cancer will be diagnosed by prostate biopsy for clinically localized
disease. Biopsy results including grading, estimation of tumor size, and tumor extent; presence of
invasive components; and other factors provide
important information regarding staging, treatment outcome, and survival.
A questionnaire filled out by experienced urooncologists estimated the data of prostate biopsy
prior to performing RP. The following data were
classified in a decreasing order of importance:
Gleason score, percentage involvement of the
core by cancer, presence of perineural invasion,
number of involved cores by cancer, and the
length of core involvement (Rubin et al. 2004).
114
Zohar A. Dotan, Jacob Ramon
Table 8.3 Probability of biochemical failure following radical prostatectomy according to pathology Gleason score
(Partin et al. 1997)
Gleason score
OCD
ECE
SVI
LNI
2вЂ“4
68
30
2
0
5
6
54
44
1
1
59
34
3
4
7
29
51
8
12
8вЂ“10
29
33
10
28
Grading Prostate Cancer
The most common method used for grading
prostate cancer is the Gleason grading system,
which was first described in 1966 and adapted by
the American College of Pathologists as the preferred method of prostate cancer grading (Gleason 1966; Bostwick and Foster 1999). Gleason
grading is based on assigning a number between
1 and 5 to the two most common patterns following cancer diagnosis, creating nine different
groups (2вЂ“10), to determine the Gleason score.
Gleason grading is determined by the architectural patterns of the prostate cancer based on
standard light microscopic interpretation of
hematoxylin and eosin staining a tissue section
(Epstein 2004). Gleason score is one of the most
important variables for prostate cancer staging
that correlates with the final pathology (Partin et
al. 1997). An inverse correlation exists between
Gleason score and outcome following local therapy (DвЂ™Amico et al. 1998; Kattan et al. 1998) and
cancer-specific survival following observation
only or androgen deprivation therapy (Albertsen
et al. 2005).
The occurrence of organ-confined disease
(lack of extra-capsular extension, seminal vesicle
invasion, and lymph node involvement) inversely
related to Gleason score (Table 8.3) (Partin et al.
1997). The correlation between biopsy Gleason
score and the RP specimenвЂ™s score is limited, and
the differences between them were demonstrated
in up to 64% of patients. Upgrading was noted
in 46%, and downgrading in the remaining 18%
(Noguchi et al. 2001). The differences were more
pronounced with the low- and moderate-grade
compared with high-grade biopsies (Bostwick et
al. 1994; Steinberg et al. 1997). Among patients
with biopsy Gleason scores of 5 or 6 on biopsy,
only 64% correlated with prostatectomy specimen scores, while Gleason scores of 7 or higher
correlated with 88% of the prostatectomy Gleason scores (Steinberg et al. 1997). In contrast,
45% of patients who presented with high-grade
prostate biopsy (8вЂ“10) at Memorial Sloan-Kettering prior to RP demonstrated downgrade to
Gleason of 7 or less on final pathology. Predictors for downstaging of pathology Gleason score
were lower clinical stage and lower biopsy Gleason Score (8 vs. 9вЂ“10) (Donohue et al. 2006). The
discrepancy between biopsy and final pathology can be caused by sampling bias, variability
Table 8.4 Probability of biochemical failure following
radical prostatectomy according to pathology Gleason
score
Gleason
score
a
Han
2003a
Blute
2001b
Herman
2001c
Lau
2001d
3+4
26%
33%
4+3
38%
46%
2вЂ“4
89%
5
85%
6
88%
71%
7
54%
69%
8вЂ“10
29%
43%
Biochemical failure at 10 years (Han et al. 2003)
b
Biochemical failure at 5 years, for T2вЂ“3N0
c
Biochemical failure at 5 years
d
Biochemical failure at 7 years
8 Staging of Prostate Cancer
between pathologists, and borderline tumors
(Epstein and Potter 2001).
An elevated Gleason score was also associated
with increased likelihood of biochemical failure
(Kattan et al. 1998; Blute et al. 2001; Han et al.
2001), metastases progression (Pound et al. 1999;
Dotan et al. 2005), and PCSM (Freedland et al.
2005) following RP; however, most researchers
used the pathology grading. Similarly, the impact
of Gleason score was noted following external
radiotherapy and brachytherapy. PCSM following radiotherapy among patients with Gleason
scores of 7 and 8вЂ“10 according to pretreatment
biopsy had HRs of 3.1 and 10.8, respectively, on
multivariate analysis compared with patients
with Gleason score lower than 6 (DвЂ™Amico et al.
2005b).
Among patients with a Gleason score of 7,
the primary grade of 4 vs 3 was associated with
a lower rate of advanced pathology characteristicsвЂ”organ-confined disease (31.6% vs 48.6%),
ECE (48.7% vs 37%), and SVI/LVI (17.6% vs
14.7%) (Makarov et al. 2002).
Estimating the Amount of Cancer
According to Prostate Biopsy
Other prostate biopsy variables, such as the number of cores obtained at time of biopsy, number of involved cores, maximal length of cancer
among all cores, and percentage of cancer in the
submitted specimen can be used to estimate the
final RP results and progression-free probability
following local therapy.
The total number of biopsy cores was related
to the accuracy of final pathology. RP Gleason
score was better correlated with biopsy Gleason
score according to the total number of cores obtained during prostate biopsy; among patients
who had 10 or more cores, identical final score
was found among 76% of the patients compared
with 67% among patients with less then 10 cores
(San Francisco et al. 2003). A similar pattern was
seen when the cores numbered 6, 8, or 10; the
use of 10 cores was a better predictor for the final
Gleason score (Coogan et al. 2005).
The number of preoperative prostate biopsy
cores containing cancer and/or percentage of
cancer among the submitted cores correlated
115
with presence of ECE (Ravery et al. 1994; Peller
et al. 1995; Sebo et al. 2000; Lotan et al. 2004;
Naya et al. 2004; Ohori et al. 2004; Antunes
et al. 2005), SVI (Peller et al. 1995; Koh et al.
2003; Antunes et al. 2005) and positive surgical margin at the RP specimen (Cheng et al.
2005a). The number of preoperative prostate biopsy-positive cores seems to correlate with the
tumor volume and, therefore, with the presence
of non-organ-confined disease (Cheng et al.
2005a). Wills et al. reported that biopsy Gleason score and the number of involved cores predicted the presence of organ-confined disease
(Wills et al. 1998). For patients with a Gleason
score of 6 and below, 69% were organ-confined
if only one to two cores were involved by sextant biopsy, while 48% of them had organ-confined disease if more then two cores were involved. That information should be taken into
account when consulting the patient regarding
treatment options, including nerve-sparing surgery. However, the main limitation of using the
total number of involved biopsy cores is the lack
of side-specific and area-specific (base vs mid
gland vs apex) prediction of non-organ-confined disease, especially the presence of extracapsular involvement.
Preoperative clinical variables such as PSA,
clinical stage, and pathology variables of prostate
biopsy were used among patients with clinically
localized prostate cancer to predict site-specific
probability of ECE. Increased rate of ECE was
found at the site of positive core with moderate- and high-grade tumor, compared with lower
grade. Multivariate analysis revealed that the
site-specific positive core related to the presence
of ECE on the same side, with an HR of 3.17
(Taneja et al. 1999). However, the positive predictive value for the presence of ECE, according to
the individually labeled positive core, and for the
site-specific positive core was 8.9% and 12.9%,
respectively. The authors concluded that labeling
biopsy cores as вЂњright sideвЂќ or вЂњleft sideвЂќ was not
justified because of the low positive predictive
value and the significant increase in the expanses
for individually labeled cores. In contrast, the
group from Memorial Sloan-Kettering developed
a nomogram that can predict the side-specific location of ECE with better accuracy (Ohori et al.
2004). Of the 1,526 patients, 226 (30%) had ECE,
116
according to the RP specimen. Among them,
15% had bilateral ECE. Three different nomograms were developed using clinically available
preoperative variables. The most extended model
includes preoperative PSA, clinical stage on each
side, Gleason score on each side, percentage of
positive cores on each side, and percentage of
cancer involvement of the submitted specimen,
and better predicted the probability of ECE compared with the limited models. The areas under
the curves for predicting side-specific probability of ECE was 0.788 and 0.806 for the limited
and extended models, respectively. The authors
recommended performing wider dissection of
the neurovascular bundle around the lobe when
there is a predicted ECE of more than 10%, and
performing wide resection in the presence of
positive DRE when there is an ECE estimation
of 50% and above. With that approach one can
decrease the rate of positive surgical margin
to obtain a better progression-free probability
(Graefen et al. 2001). Those recommendations
need to be validated prior to their use. Predicting
the probability of SVI can be done by evaluating
preoperative data including site-specific prostate
biopsy. According to a multivariate analysis preoperative PSA, primary Gleason score, and percentage of cancer at the base were correlated with
presence of SVI. Presence of SVI was 12.8% and
1.2% among patients with positive and negative
cores from the prostate base; none of the patients
with negative base cores and PSA of less then
10 ng/ml had SVI (Koh et al. 2003).
Despite the association between preoperative
biopsy results and final pathology results following RP, the following should be noted: surgical
technique has an important impact on surgical
margin beyond parameters such as ECE, SVI,
and tumor volume (Ward et al. 2004; Swindle et
al. 2005). The presence of extraprostatic disease
is correlated with decreased probability of progression. However, the majority of patients with
ECE and negative margin and about a third of
patients with SVI will be free from disease at
5 years following RP (Han et al. 2001; Hall et al.
2003). In one study, the number of cores containing cancer was positive, and the percentage of
cancer among the submitted cores was also correlated with progression-free probability following radical prostatectomy (DвЂ™Amico et al. 2000;
Zohar A. Dotan, Jacob Ramon
Freedland et al. 2003a) and PCSM following external radiotherapy (DвЂ™Amico et al. 2004b). This
suggested improvement in the prediction of the
probability for biochemical failure following local therapy for prostate cancer.
Lymphovascular Invasion
Lymphovascular invasion (LVI) is known as a
prognostic factor for biochemical, metastases
progression, and disease-specific survival following RP (Herman et al. 2000). In addition, it can
predict failure of salvage radiation for biochemical failure following RP (Brooks et al. 2005).
Despite the importance of LVI in long-term
outcome prediction with RP specimens, we are
unaware of any report predicting RP pathology
and biochemical failure rate according to the
presence of LVI at the prostate biopsy. One of the
difficulties is the limited amount of tissue available at the time of prostate biopsy for assessment
of LVI.
Predicting Insignificant Tumors
Since the use of PSA for diagnosing prostate cancer, the incidence of the disease has risen sharply
in the United States compared with countries
without active screening programs (Schroder
2004). One possible disadvantage of identifying tumors by PSA screening is the possibility
of detecting clinically insignificant tumors. The
definitions of clinically insignificant tumors vary
and usually are based on the pathology report of
the radical prostate specimen. The commonly
usual criteria include lack of Gleason grade 4 to
5 and tumor volume of less the 0.5 cc (Epstein
et al. 1994; Goto et al. 1996). However, validation of those criteria is still needed. A clear trend
of decreased tumor volume and lower Gleason
grade has been demonstrated since the clinical use of PSA screening. The presence of lowgrade, small-volume tumors can potentially lead
to different treatments and, therefore, the identification of those patients prior to treatment can
be useful (Schmid et al. 1993; Epstein and Potter 2001; Carter et al. 2003; Patel et al. 2004; Albertsen et al. 2005). In a cohort of patients from
8 Staging of Prostate Cancer
Johns Hopkins Hospital treated by RP, indolent
tumors were found in up to 31% of T1c patients
Accordy to preoperative estimation (Epstein et
al. 1998). The preoperative criteria to determine
the presence of indolent tumor according to biopsy were: less than three positive cores, less than
50% length involvement of each positive core,
and lack of pattern 7 of the positive cores. The
positive predictive value and negative predictive value of the model were 94.4% and 77.2%,
respectively (Epstein et al. 1998). In a different
cohort, 55 (16%) of 336 patients treated with RP
had small tumors (<0.5 cc) at the final pathology.
Predictive factors for small tumors were number of positive cores and highest percentage of
cancer at any site (Cheng et al. 2005b). A nomogram for the determination of the probability of
indolent tumor was constructed by Kattan et al.
using preoperative variables, including the preoperative PSA, clinical stage, primary and secondary Gleason grade, prostate volume according to TRUS, and cancerous and benign tissue
(length in millilitres) of all the biopsy cores. The
modelвЂ™s ROC was 0.64 for the base model (preoperative PSA, primary, and secondary Gleason
grade) and 0.79 when all the variables were used
(Kattan et al. 2003a). All of the previously mentioned prediction models used the presence of
indolent tumor as an endpoint, rather than the
treatment outcome. Conducting a prospective
study using the patientвЂ™s co-morbidities, age,
and life expectancy in addition to the tumor
characteristics has been proposed. The recommendation for watchful waiting of patients with
life-expectancies of 10 years or more is limited
and should be used as part of a research protocol
(Klotz 2005).
Imaging Modalities
The clinical variables used for prostate cancer
staging include mainly the prebiopsy PSA level,
biopsy results, and clinical stage as determined
by DRE. The combination of those can be used
to predict the presence of non-organ-confined
disease and estimate biochemical recurrence following local therapy (Partin et al. 1997; DвЂ™Amico
et al. 1998; Kattan et al. 1998; Partin et al. 1997;
Kattan 1999; DвЂ™Amico et al. 1998b). However,
117
significant variability is found between the prediction ability of those variables and the actual
finding following surgical treatment by radical prostatectomy. To increase the pretreatment
information regarding the location and extent
of the primary tumor, to evaluate the presence
of distant metastases, to help plan the different
therapeutic options, and reduce postoperative
short- and long-term complications, several imaging modalities were used following the diagnosis of prostate cancer, including TRUS, computed
tomography (CT), MRI, bone scan, and positron
emission tomography (PET).
Transrectal Ultrasound
TRUS is the most common imaging modality
used to perform prostate biopsy. However, the
use of TRUS for staging newly diagnosed prostate cancer is limited. The sensitivity and specificity of TRUS is low, and no significant change
in predicting ECE and SVI was found between
DRE and TRUS (Smith et al. 1997). More then
50% of prostate cancer cases would have been
missed if a biopsy had targeted only prostatic lesions identified by TRUS (Flanigan et al. 1994).
Tiguert et al. have suggested a change in the clinical stage of patients with nonpalpable disease
by incorporating TRUS findings; they suggest
classifying the patients with nonpalpable tumor
but with a detected lesion by TRUS as T2 rather
than T1c (Tiguert et al. 2000). However, analysis of more then 1,600 patients staged by TRUS
prior to radical prostatectomy showed that although patients with nonpalpable and positive
TRUS are at a more advanced pathology stage
and have higher Gleason scores compared with
T1c patients with invisible lesion of TRUS, no
change in progression-free probability was found
between the two groups. Comparison of patients
with clinical T2 disease to patients with nonpalpable and visible lesion on TRUS showed better
preoperative and postoperative findings for the
latter group, with better biochemical outcome
(Augustin et al. 2003). These data suggest that
the classification of T1c disease by TRUS will not
add significant information to the current AJCC
TNM classification.
118
MRI and erMRI
The use of MRI in prostate cancer is of interest
since the details obtained from abdominal ultrasound, TRUS, and CT are limited regarding the
intra- and periprostatic anatomyвЂ”that is, zonal
anatomy, prostate capsule, periprostatic soft tissue, and the relationship between the prostate
and the urethra. Those details can be seen on T2weighted images. The peripheral zone has higher
signal intensity compared with the central and
transitional zones. Distinguishing between the
anterior aspect of the prostate and the anterior
periprostatic space can be done by identifying
the low-intensity signal anterior fibromuscular
zone that is covering the anterior aspect of the
prostate. The normal prostate capsule can be
identified as the thin edge with a low-intensity
signal surrounding the peripheral zone. The
periprostatic soft tissue can also be rendered
clearly by MRI. The venous plexus at the anterior
(dorsal vein complex) and lateral aspect of the
prostate (periprostatic venous complex) and the
neurovascular bundle (NVB) at the posterolateral aspect of the prostate are captured by MRI.
The advantages of MRI over CT are the ability
to create images at different planes in addition to
the axial plane, the potentially better resolution,
the lack of a need for nephrotoxic contract material, and the lack of radiation exposure. Cancer
can be seen as a low-intensity area among a highintensity normal peripheral zone on T2 weighted
images (Hricak 2005). However, the low-intensity area is not specific to cancer and can also be
seen with hemorrhage, infection, and as a result
of radiation or hormonal treatment. Delaying
MRI by 4 to 8 weeks after prostate biopsy will
lower the false-positive effect of hemorrhage secondary to biopsy (White et al. 1995). Also, MR
spectroscopy imaging (MRSI) can be used. MRSI
can identify metabolite levels at cross sections
of the prostate and reveal the presence of cancer
according to the ratio of choline and creatine to
citrate [(choline+creatine)/citrate]. Citude is elevated in the absence of cancer. Elevated choline
can be seen in the presence of cancer, especially
with high-grade tumor (Hricak 2005). Resolution
can be increased more effectively by using erMRI
compared with using external surface coil, although no significant differences were observed
Zohar A. Dotan, Jacob Ramon
when the diagnostic ability of the two methods
were compared between patients with newly diagnosed prostate cancer (Kaji et al. 2002).
The TNM staging system is based on imaging
modality. For prostate cancer, no effective imaging modality had been established for clinical
staging until recently, that is, the presence of
ECE and SVI. erMRI has been shown recently
to increase the accuracy of clinical staging
compared with the use of DRE and PSA among
90 patients scheduled for RP. The use of erMRI
proved to be better in detecting SV involvement
and exhibited greater accuracy than DRE and
TRUS for tumor localization at the mid-gland
and base (Mullerad et al. 2005). Researchers
evaluated the ability of erMRI to detect tumor
localization and size and the extent of disease
among 95 patients undergoing RP. Nakashima
and associates compared erMRI findings with
the prostatectomy pathology findings and found
that the erMRI data correlated with tumors with
diameters of 1 cm and above. The accuracy of
erMRI was 74.7% for showing ECE and 75.8% for
staging (Nakashima et al. 2004). Similar accuracy
in detecting ECE was shown by the group from
Memorial Sloan-Kettering that evaluated clinical
variables including PSA, clinical staging, prostate
biopsy variables, and erMRI results prior to
RP. By multivariate analysis, serum PSA level,
percentage of cancer in all core biopsy specimens,
and erMRI findings were predictors of ECE; the
areas under receiver operating characteristics
curve (ROC) with and without erMRI findings
were 0.838 and 0.772, respectively (p=.022)
(Wang et al. 2004). Those reports indicate the
ability of erMRI to detect tumor localization
and predict the presence of ECE and SVI prior
to RP. Similarly, erMRI was shown to be effective
regarding treatment planning prior to intensive
modulated radiotherapy and brachytherapy
(Chen et al. 2004; Menard et al. 2004). In those
series, the follow-up period and number of patients were small, and no data are yet available
regarding the outcome of erMRI-based radiotherapy planning for prostate cancer. Does the
use of erMRI lead to better patient selection for
local therapy? Will the information obtained
from erMRI lead to improvement in the surgical/
radiation performance, and what will be the
impact of it on the outcome of local therapy,
8 Staging of Prostate Cancer
rate of biochemical recurrence, local recurrence,
and metastases progression? The answers are
still unknown. In addition, the criteria used for
selecting patients for erMRI prior to local therapy
are unclear, especially considering the expenses
associated with the use of erMRI.
Computed Tomography
The use of CT for evaluating the extent of local
disease in patients newly diagnosed with prostate
cancer is limited. CT ability to image the prostate
and the periprostatic soft tissue is significantly
reduced compared with erMRI. The main potential advantage of CT is its use for detection of
pelvic lymph node adenopathy (+PLN) prior to
local therapy. However, the presence of +PLN in
contemporary series is low and the majority of
the positive lymph nodes represent microscopic
involvement only (Meng and Carroll 2000; Bader
et al. 2002).
119
the frequency of use of CT, MRI, and bone scan
for newly diagnosed prostate cancer did not
change from 1989 to 1997 (Kindrick et al. 1998).
A recent meta-analysis of 23 studies concerning
baseline bone scans of 8,644 patients stratified according to PSA level at diagnosis of prostate cancer showed that positive bone scans were found
among 16% of the screened patients. PSA was the
most commonly studied prognostic factor, whose
detection rates for positive bone scan were 2.3%,
5.3%, 16.2%, 39.2%, and 73.4% among patients
with PSA levels less than 10, 10вЂ“19.9, 20вЂ“49.9,
50вЂ“99.9, and 100 ng/ml or greater, respectively.
These findings support the avoidance of bone
scan in cases in which PSA is below 10 ng/ml and
there is no bone pain prior to local treatment for
newly diagnosed prostate cancer (Abuzallouf et
al. 2004). Clinical stage and Gleason score were
also important predictors for bone scan results.
Noting the above data, the recommendation was
to limit the use of staging bone scan for patients
with either clinical stage T3 and above, PSA of 20
and above, and a Gleason score of 8вЂ“10.
Bone Scan
FDG-Positron Emission Tomography
Bone scan is used frequently for patients newly
diagnosed with prostate cancer. Metastatic prostate cancer has a tendency to spread to bones,
predominantly in the axial skeleton, and the imaging of choice used to detect this is the radionuclide bone scan with 99mtechnetium methylene
diphosphonate (Dotan et al. 2005). The use of
bone scan among patients with newly diagnosed
prostate cancer is determined by their clinical
stage, PSA level, biopsy results, and year of diagnosis. Oesterling found that PSA can be used
to define the staging of newly diagnosed prostate cancer by bone scan. Only 3 of 561 patients
had positive bone scan if their PSA was lower
than 10 ng/ml, and none of them had PSA below
8 ng/ml (Oesterling et al. 1993). That observation
was validated by others who found that positive
bone scan rates for newly diagnosed prostate cancer was 0%, 4.5%, 8%, and 40% for PSA of less
than 10, 10 to 20, >20 to 50 and >50 ng/ml, respectively (Levran et al. 1995; Gleave et al. 1996).
Still others have suggested lower PSA thresholds
for ordering bone scans (Wymenga et al. 2001).
However, according to the CAPSURE database,
The use of 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET)
for prostate cancer staging is limited because of
its inability to differentiate between clinically
localized prostate cancer and BPH secondary
to low glycolytic rate and therefore low FDG
uptake, its decreased sensitivity for detection of
pelvic lymph node compared with CT and MRI,
and its reduced detection of bone metastases
compared with bone scan (Shreve et al. 1996; Yeh
et al. 1996; Liu et al. 2001). In contrast, it plays a
promising role in response to treatment of local
advanced and metastatic prostate cancer in both
animal models (Oyama et al. 2004) and with
other isotopes such as C-11 acetate, and is still
under investigation.
Combination Staging Methods
Clinically localized prostate cancer represents a
heterogeneous disease. The natural history and
outcome following different therapy options vary
120
according to known risk factors. Predictions of
treatment outcome will change according to the
chosen endpoint. In general, the preferred endpoint in oncology is a disease-specific survival
rate, since it estimates the direct and indirect cancer-associated mortality rate of the specific disease (Welch et al. 2000; DвЂ™Amico 2002). The main
limitation of estimating the rate of disease-specific
survival among patients with localized prostate
cancer is the relatively indolent natural history of
prostate cancer, that is, only a limited number of
patients will die of prostate cancer at 5 to 10 years
from local treatment. Up to 1/3 of the patients will
have detectable or rising PSA levels following RP
(Dillioglugil et al. 1997; Roberts et al. 2001b; Han
et al. 2003) and 15% to 57% will not reach a nadir
below 1 ng/ml or will have rising PSA following
a nadir caused by external radiotherapy, depending on their risk group (Pollack et al. 2003). In
one study, disease-specific survival rates were
93%, 75%, and 55% at 5, 10, and 15 years from
biochemical failure following RP (Freedland et
al. 2005) and 85% from biochemical failure following radiotherapy at 5 years (Kwan et al. 2004).
Comparison of any endpoints as progression-free
probability, freedom from metastases, and disease-specific survival rates between patients following surgery and radiotherapy are beyond the
scope of that chapter.
Multiple variables influence progression-free
probability, freedom from metastases progression, and disease-specific survival rates for prostate cancer at different disease states. Using multiple variables or вЂњcombined modality stagingвЂќ
has the advantage of increasing the accuracy of
prediction for prostate cancer patients. Combing
the clinical stage according to the AJCC, pretreatment PSA, and Gleason score of the prostate
biopsy and others has proved to be useful for
staging clinical disease. Outcomes can be described as final pathology according to data obtained from patients undergoing RP, biochemical
failure rate, metastases progression rate, and the
PCSM rate following RP or radiotherapy.
Partin Tables
The estimation of final pathology was first described by Partin and predicted the probability
Zohar A. Dotan, Jacob Ramon
of organ-confined disease, presence of ECE,
SVI, and LNI according to clinical AJCC staging
(T1a-c, T2a-c, T3a), biopsy Gleason score (2вЂ“4,
5, 6, 7, 8вЂ“10), and prebiopsy PSA (0вЂ“4.0, 4.1вЂ“10,
10.1вЂ“20, >20) (Partin et al. 1997). Data obtained
from a nomogram can be used to consult the patient prior to choosing a local treatment for active surveillance, since the nomogram was externally validated and found to be accurate (Blute et
al. 2000). An updated version, using the records
of 5,089 patients treated since 1994 by RP with
a median follow-up of 5.8 years, was recently
published to improve the direction for current
diagnosed patients (Partin et al. 2001). The nomogram was criticized for: (1) having endpoints
that are the pathological findings of the RP specimen. The nomogram is useful for surgical planning but does not predict the clinical outcome
following surgery. Although patients with local
advanced prostate cancer (i.e., presence of ECE,
SVI, and LNI) have increased probabilities of
biochemical failure and clinical progression, the
majority of patients with ECE and the major minority of patients with SVI will see no evidence
of disease at 5 years from RP as monotherapy; (2)
using an arbitrary preoperative PSA threshold
(0вЂ“4, 4.1вЂ“10, 10.1вЂ“20, and >20) and, thus, creating heterogeneous groups (Diblasio and Kattan
2003); (3) having a limited ability to predict for
patients with clinical stage T3вЂ“4 disease (Partin
et al. 2001).
DвЂ™Amico Risk Classification
DвЂ™Amico has suggested classifying patients with
clinical organ-confined disease by risk level and
clinical stage, PSA, and Gleason score (GS) (low
risk: GSв‰¤6 and PSAв‰¤10 and T1c/T2a; intermediate risk: GS 7 or PSA 10вЂ“20 or T2b; and high
risk: GS 8вЂ“10 or PSAв‰Ґ10 or T3вЂ“4) (DвЂ™Amico et
al. 1998). The classification is popular because
of its simplicity but, like the part in tables, was
criticized for using of arbitrary thresholds (e.g.,
PSA <10, 10вЂ“20, and >20). It is also criticized
for creating heterogeneous groups (Diblasio and
Kattan 2003) and ignoring risk factors for different groups (e.g., ignoring the biopsy Gleason
score and clinical stage when the prebiopsy PSA
is >20 ng/ml) (Kattan 2003).
8 Staging of Prostate Cancer
Kattan Nomograms
Kattan used a different approach for predicting
outcome of patients with different solid tumors,
namely, nomograms. Nomograms are developed
based on Cox proportional hazard regression
analysis and modified by restricted cubic splines.
Hence, the variables are not assumed to have linear relations. For example, an increase in PSA
level from 2 ng/ml to 4 ng/ml would represent
the same significance as an increase from 302 ng/
ml to 304 ng/ml (Diblasio and Kattan 2003). The
use of variables in a continuous manner avoids
the creation of heterogeneous groups in contrast
to the grouping approach. A more accurate prediction is achieved with the prediction created
for a specific patient rather than for his classification group (Diblasio and Kattan 2003). The
nomogram uses multiple variables and each contributes to some extent to the prediction ability
of the model. The variables are added according
to their clinical importance, rather than according to their significance by multivariate analysis
and, thus, add to the accuracy of the model. The
impact of each variable on the model outcome is
represented schematically by a vertical bar, and
the summary of all the variables is translated to
outcome probability at a specific time from treatment (e.g., freedom from progression at 5 years
from RP).
Nomograms are evaluated according to their
discrimination, calibration, and validation. Discrimination is the nomogramвЂ™s ability to predict
which patients will reach the desired endpoint.
It is estimated by the concordance index (CI)
and expressed by a number between 0 and 1; a
value of 0.5 represents a flipped-coin probability.
Calibration of the nomogram is the relationship
between the prediction and actual outcome, and
validation is the performance of the nomogram
with respect to a different data set.
Applicability of the nomogram is limited to
patient characteristics similar to those used for
the nomogram development; for example, the
pre-RP nomogram was developed with a cohort
of 983 patients treated at a single academic institute by a single surgeon. Applicability of the nomogram to other populations at other academic
institutes and community centers was validated
by those cohorts. In addition, most of the nomo-
121
grams used PSA relapse as an endpoint, except
a nomogram predicting metastases progression
following external radiotherapy (Kattan et al.
2003b) and the probability of bone metastases
following biochemical failure after RP (Dotan et
al. 2005). Comparison of PSA-based outcome according to local treatment is limited because of
the different definitions of PSA failure after surgery vs radiotherapy (Gretzer et al. 2002).
Different nomograms are available for staging
patients with prostate cancer prior to treatment.
Those nomograms include the following:
a. RPвЂ”pretreatment nomogram
The nomogram was based on 983 patients
treated by RP by a single surgeon from 1983
to 1996 with a median follow-up of 30 months
and predicted the freedom from biochemical
failure at 5 years following RP (Kattan et al.
1998). The variables used are prebiopsy PSA,
clinical stage, and biopsy Gleason score; clinical stage was based on the 1992 classification.
Freedom from biochemical failure for the
entire cohort was 73%. The definitions of biochemical failure were PSA level of 0.4 ng/ml
and above, 2nd treatment (radiotherapy and/
or ADT), and patients for whom surgery was
aborted because of lymph node metastases.
The nomogram concordance index was 0.75.
Validation was conducted by bootstrapping
and by an external cohort of 168 patients
treated by RP. External validation was performed with a cohort of 6,232 patients from
seven academic centers in the United States
and Europe treated with RP (Graefen et al.
2002). The CI was 0.75, and the prediction for
the different risk groups matched well with
the original nomogram. A cohort of 1,701
patients treated by RP from the CAPSURE
database, which includes mainly community practices, was also used for validation
(Greene et al. 2004). The CI was found to be
slightly lower (0.68); reasons for that might
include the lack of central pathology review
and diversity of treating physicians (mainly
community hospitals).
b. External radiotherapyвЂ”pretreatment nomogram
The nomogram was based on 1,042 patients
treated with 3D conformal radiotherapy at
122
Memorial Sloan-Kettering Cancer Center
from 1988 to 1998 with a median follow-up
of 30 months and predicted the freedom from
biochemical failure at 5 years following RP
(Kattan et al. 2000). The variables used are
prebiopsy PSA, clinical stage, biopsy Gleason
score, use of ADT, and radiotherapy dose. The
definition of biochemical failure was based
on the 1997 ASTRO definition (American
Society for Therapeutic Radiology and Oncology 1997). The nomogram CI was 0.73. The
nomogram was externally validated by a cohort of 912 patients treated at the Cleveland
clinic a CI of 0.76. The nomogram prediction
was found to be superior to other grouping
prediction models.
c. Transperineal interstitial permanent brachytherapyвЂ”pretreatment nomogram
The nomogram was based on 920 patients
treated by permanent brachytherapy and predicted the freedom from biochemical failure
at 5 years following RP (Kattan et al. 2001).
The variables used are pre-biopsy PSA, clinical stage, biopsy Gleason score, and use of
radiotherapy. Clinical stage was based on the
1997 classification and included patients categorized as T1c and T2 a/b. The definition of
biochemical failure was based on the ASTRO
definition (1997), the presence of clinical progression, and the use of ADT. The nomogram
was externally validated with cohorts of 1,827
patients from Seattle and Arizona with CIs of
0.61 and 0.64, respectively.
d. OtherвЂ”a nomogram that predicted the probability of the presence of indolent tumor, extracapsular extension, and seminal vesicle invasion was described in a previous part of the
chapter.
Pelvic Lymph Node Dissection
Imaging modalities such as pelvic CT and MRI
are relatively insensitive for detection of pelvic
lymph node dissection, since the majority of the
involved nodes at the PSA era have microscopic
involvement only. The only accurate method of
detecting lymph node metastases is lymph node
dissection. Despite the high prevalence for treat-
Zohar A. Dotan, Jacob Ramon
ing prostate cancer with RP, the incidence of positive lymph node (+PLN) at pelvic lymph node
dissection (PLND) and its indications, anatomical boundaries, and diagnostic and therapeutic
outcomes are still debated.
An important question is, Who are the patients who can benefit from omitting PLND during RP without damaging the staging process?
The potential morbidity of PLND was estimated
to be 7% (Meng and Carroll 2000) and included
more prolonged surgery, an increased rate of
deep vein thrombosis, injury to major pelvic vessels and nerves, lower extremity lymphoedema,
and additional surgery costs. Indications for
PLND were determined according to the probability of +PLN and included probability of less
than 1.5% for +PLN by Partin tables (Cagiannos
et al. 2003); probability of +PLN of less than 18%
(Meng and Carroll 2000); PSA less than 5 ng/ml
or Gleason score of less than 6; or a combination
of PSA less than 25, Gleason score of 7 or lower,
and negative DRE (Rees et al. 1997).
The incidence of +PLN during PLND ranges
between 1.1% and 24% and varies according to
patient characteristics, extent of the performed
PLND, pathological analysis of the submitted
lymph node package, and year of surgery (Meng
and Carroll 2000; Bader et al. 2002). The staging
implications of PLND are clear, because patients
with +PLN at the time of RP are associated with
a significantly lower progression-free probability rate and an increased probability of death of
prostate cancer (Cadeddu et al. 1997; Cheng et
al. 2001; Hull et al. 2002; Zwergel et al. 2004).
The therapeutic implications of PLND for prostate cancer in the setting of RP are still debated
(Burkhard and Studer 2004). The treatment of
patients with lymph node metastases at the time
of RP is beyond the extent of the current review;
however, reports with limited patient number
and no randomization regarding treatment options have found prolonged disease-specific survival rates following RP and PLND as monotherapy in the range of 74% to 94% and 47% to 83%
at 5 and 10 years, respectively (Cheng et al. 2001;
Zwergel et al. 2004).
Despite potential advantages for cancer-specific survival seen with therapy combining hormonal treatment and RP (compared with hormonal therapy only; Ghavamian et al. 1999) and
8 Staging of Prostate Cancer
for early hormonal therapy following RP (vs RP
and late hormonal therapy; Messing et al. 1999),
timing and the type of adjuvant therapy following RP for +PLN still inspire debate.
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9
Guidelines and Counselling for Treatment Options
in the Management of Prostate Cancer
Axel Heidenreich
Recent Results in Cancer Research, Vol. 175
В© Springer-Verlag Berlin Heidelberg 2007
Abstract
Prostate cancer is often a complex disease and
one in which many aspects of the disease and the
affected patient must be taken into consideration
before decisions about diagnostic work-up, treatments, follow-up, etc. can be made. The current
chapter reflects the current recommendations of
the European Prostate Cancer Guideline Group
made on the basis of criteria of evidence-based
medicine after extensive review of the literature
available up to December 2005.
Introduction
There are numerous treatment options with regard to the potentially optimal management of
patients with organ-confined, locally advanced
and metastatic prostate cancer (CaP), as has
been demonstrated and extensively discussed in
the previous chapters. However, the dilemma for
many patients and even physicians is based on
the fact that many treatment recommendations
are merely based on subjective feelings due to
the lack of valid prospective randomized clinical trials. This is especially concerning treatment
decisions in men with clinically localized low-,
intermediate- and high-risk CaP with the competing surgical, radio-oncological, medical and
conservative therapeutic options. Even with regard to the important clinical scenario of prostate-specific antigen (PSA) recurrence following
local treatment with curative intent, very few
prospective randomized trials exists comparing
different treatment options.
Clinical guidelines for the diagnosis and
management of cancer are thought to somehow
reduce the decision dilemma for both physicians and patients. Treatment decisions must
be based on the available evidence which might
form the basis for a consensus guideline delivering a clear proposal for diagnostic and treatment measures in the different stages of a given
cancer and individual clinical situations. Evidence-based and national as well as Europeanwide guidelines were first established in the
management of testicular cancer [1, 2]. Further
studies have demonstrated that the clinical application of guidelines in the daily routine will
help to reduce both over-treatment and treatment failure and/or relapse [3]. Evidence-based
guidelines might serve as an internal quality
control in institutions treating patients with any
given type of cancer.
The new EAU guidelines on CaP are evidencebased, summarize the most recent findings in
the management of CaP and put them into recent practice [4]. Therefore, integration of these
guidelines will help physicians to objectively
counsel their patients with regard to the most appropriate therapy in a given clinical situation.
This chapter summarizes the recent EAU
guidelines which can be read in their entirety on
Website for The European Association of Urology, www.uroweb.org.
In order for the reader to evaluate the quality
of the information provided, the evidence levels
and grade of each recommendation have been
inserted in this updated guidelines text according to the general principles of evidence-based
medicine (EBM) [5].
Classifications and Grade
of Recommendations
The UICC 2002 Tumour Node, Metastasis (TNM)
classification is used throughout these guidelines
[6].The most commonly used system for grading
132
of adenocarcinoma of the prostate is the Gleason
score [7]. The system describes a score between
2 and 10, with 2 being the least aggressive and
10 the most aggressive. This score is the sum of
the two most common patterns (grades 1вЂ“5) of
tumour growth found. To be counted, a pattern
(grade) needs to occupy more than 5% of the biopsy specimen. Biopsy material (core biopsy or
operative specimens) is required to be able to assess the Gleason score; cytological preparations
cannot be used.
Prostate Cancer Screening
Population or mass screening is defined as the examination of asymptomatic men (at risk). Usually, screening takes place within the framework
of a trial or study and is initiated by a screener.
Contrary to that, early detection or opportunistic
screening represents individual case findings. It is
initiated by the screenee (patient) or his physician.
The trends in mortality from CaP show a wide
variety from country to country all over the industrialized world [8]. A decrease in mortality
rates due to CaP is currently seen in the United
States and Austria, but also in the United Kingdom and France, which share a similar decrease
in CaP mortality rates [8]. Similarly, in Sweden,
the relative 5-year survival rates increased in the
period from 1960 to 1988, which was attributed
to increased diagnostic activities and the detection of more non-lethal tumours [9]. However,
this trend could not be confirmed in a similar
study from the Netherlands [10].
Currently, only a non-randomized screening project in Tyrol (Austria) may support the
hypothesis that screening can be effective in reducing CaP mortality. The early detection programme in combination with the availability of
free treatment was used as an explanation for the
33% decrease in the CaP mortality rate seen in
Tyrol as compared with the rest of Austria [11]
(level of evidence: 2b). Other studies have contradicted the positive findings attributed to screening, with a comparative study between the Seattle
area (highly screened population) and Connecticut (seldom screened population) by Lu-Yao and
coworkers [12] showing that, notwithstanding
Axel Heidenreich
the very large diversity in PSA testing and in use
of curative treatments, there was no difference in
the reduction in the rate of CaP mortality (level
of evidence: 2b).
Thus, at the present time there is a lack of
evidence to support or disregard widely adopted, population-based screening programmes
for early detection of CaP aimed at all men in a
given population (level of evidence: 3). The use
of PSA in combination with digital rectal examination (DRE) as an aid to early diagnosis in
well-informed patients is less controversial and
widely used in clinical practice [13] (level of evidence: 3). All patients, however, undergoing PSA
screening should be informed intensively about
the measures to be taken if a PSA serum value
turns out to be suspicious for the presence of
CaP.
Diagnosis and Staging of Prostate Cancer
The decision to proceed with further diagnostic
or staging work-up is guided by which treatment
options are available to the patient, taking age
and comorbidity into consideration. Procedures
that will not affect the treatment decision can
usually be avoided.
An abnormal DRE result or elevated serum
PSA measurement may indicate CaP. The exact
cut-off level of what is considered to be a normal PSA value has not yet been determined, but
values around 2.5вЂ“3 ng/ml are often used for
younger men (grade C recommendation).
In younger men, aged 50вЂ“66 years, the CaP
detection rate was 13.2% in the PSA interval
3вЂ“4 ng/ml; the majority of these cancers were
judged to be clinically significant [14]. Even lower
cut-off levels have been proposed by some authors,
still with a relatively high detection rate [15]. The
finding that many men may harbour CaP despite
low levels of serum PSA has been underscored by
the recent results from a United States prevention
study [16]. The rate of CaP in relation to serum
PSA for 2,950 men in the placebo-arm and with
normal PSA-values is presented in Table 9.1. The
age range at biopsy was 62вЂ“91 years.
The diagnosis of CaP depends on histopathological confirmation (grade B recommendation).
Biopsy and further staging investigations are
9 Guidelines and Counselling for Treatment Options in the Management
Table 9.1 Risk of CaP in relation to low PSA values
PSA level (ng/ml)
Risk of CaP
0вЂ“0.5
6.6%
0.6вЂ“1
10.1%
1.1вЂ“2
17.0%
2.1вЂ“3
23.9%
3.1вЂ“4
26.9%
only indicated if they affect the management of
the patient (grade C recommendation).
Ultrasound-guided transrectal 18G core biopsy has become the standard way to obtain
material for histopathological examination. Sextant biopsies, as described by Hodge et al., have
been used in the past. Lately, the standard way
of obtaining sextant biopsies has been replaced
by laterally directed sextant biopsies in order
to optimize the CaP detection rate [17, 18]. Biopsy cores obtained this way include biopsies
from the posterolateral aspect of the peripheral
zone, the most common location for early CaP.
The number of biopsies required for the optimal
detection of CaP is controversial. Several studies have examined the detection rate with more
biopsy cores at primary biopsy. Nearly all have
shown a higher cancer detection rate in comparison with the standard sextant technique. Eskew
and co-workers, for instance, demonstrated that
the five-region biopsy protocol with 13 to 18
cores increased the detection rate by 35% when
compared to standard, mid-lobar sextant biopsies [19]. Studies clearly show that the transition
zone should not be the target area for a first set
of prostate biopsies due to the consistently low
cancer detection rate, which may be as low as 2%
or less [20, 21].
If the first set of biopsies is negative, repeated
biopsies can be recommended. In the second set
of biopsies, a detection rate of about 10%вЂ“35%
has been reported in cases with a negative first
set of biopsies [22вЂ“24]. In cases where high-grade
prostatic intraepithelial neoplasia (PIN) or atypical small acinar proliferation (ASAP) is present,
as many as 50%вЂ“100% of prostates harbour a
concomitant cancer, and re-biopsy is indicated
[25, 26]. Djavan and co-workers found that two
133
sets of biopsies detected the majority of clinically
significant cancers [24]. Even patients who have
undergone more extensive biopsies may still
have a significant detection rate at repeat biopsy
[22]. Today, we have no proven biopsy scheme
that omits the need for re-biopsy in case of a persistent indication (level of evidence: 3).
With an increasing number of men undergoing more extensive biopsies at maybe two or
even more occasions, the need for some form
of analgesia has become more evident in clinical practice. Of the various methods examined,
the use of a periprostatic injection with a local
anaesthetic seems to combine high efficacy with
easy application and low complication rates (best
level of evidence: 1a).
Local staging (T-staging) of CaP is based on
findings from DRE, transrectal ultrasonography
(TRUS) and possibly magnetic resonance imaging (MRI). Further information is provided
by the number and sites of positive prostate biopsies, tumour grade and level of serum PSA
(grade C recommendation).
The most commonly used method for viewing the prostate is TRUS. However, only 60% of
tumours are visible at TRUS and the remainder
are not recognized due to their echogenicity.
Thus, differentiation between T2 and T3 tumours
should not be based on TRUS alone [27, 28] since
multi-institutional large studies have shown that
TRUS was no more accurate at predicting organconfined disease than DRE [29, 30].
Both computed tomography (CT) and MRI
are now of a high technical standard, but neither
modality is sufficiently reliable to make it mandatory to use them to assess local tumour invasion. MRI of the prostate appears to be the most
accurate non-invasive method of identifying locally advanced disease [31]. However, its routine
use for the pre-treatment staging of CaP remains
controversial and MRI is not always available.
For dose planning before external-beam radiation, CT is most useful.
Lymph node status (N-staging) is only important when potentially curative treatment
is planned for. Patients with Stage T2 or less, a
PSA less than 20 ng/ml and a Gleason score of
6 or less have less than a 10% likelihood of having node metastases and may be spared nodal
evaluation. The gold standard for N-staging is
134
operative lymphadenectomy, by either open or
laparoscopic techniques (grade B recommendation). It is worth pointing out that recent studies with more extensive lymphadenectomy have
shown that the obturator fossa is not always
the primary site for metastatic deposits in the
lymph nodes [32, 33]. Various studies have demonstrated recently that the use of Partin tables
or other preoperative nomograms does not accurately predict the presence or absence of pelvic lymph node metastases. Both CT and MRI
are considered of limited use due to their low
sensitivity, which varies from 0% to 70% [34,
35]. Quite recently, high-resolution MRI with
magnetic nanoparticles allows the detection of
small and otherwise undetectable lymph node
metastases in patients with CaP [36]. However,
further prospective studies comparing MRI and
extended lymph node dissection have to support
these initial encouraging results.
For the identification of skeletal metastases,
bone scintigraphy remains the most sensitive
method, being superior to clinical evaluation,
bone radiographs, serum alkaline phosphatase
measurement and prostatic acid phosphatase
(PAP) determination. Technetium diphosphonates are the optimum radiopharmaceuticals
currently available due to their extremely high
bone-to-soft-tissue ratio [37]. A semi-quantitative grading system based upon the extent of
disease observed on the bone scan was found
to correlate with survival [38]. This may not be
indicated in asymptomatic patients if the serum
PSA level is less than 20 ng/ml in the presence
of well-, or moderately, differentiated tumours
(grade B recommendation).
Treatment of Prostate Cancer
An overview of the primary treatment options in
patients with prostate cancer is provided in Tables 9.2, 9.3, 9.4 and 9.5. It is usually impossible
to state that one therapy is clearly superior over
another, as there is a profound lack of randomized controlled trials in this field. Furthermore, it
might be best to differentiate patients with low-,
intermediate- and high-risk CaP with regard to
the recommendation of specific treatment mo-
Axel Heidenreich
dalities. Based on the evidence of the available
literature, some recommendations can be made.
A summary, subdivided by stage at diagnosis, is
found below.
Active SurveillanceвЂ”Good Risk CaP
The term deferred treatment or active surveillance (WW) is used to describe a treatment
strategy that includes an active standpoint to
postpone treatment until it is required. The rationale for this type of treatment is based on the
fact that for many good-risk patients defined by a
Gleason score of 6 or less, a PSA of 10вЂ“15 ng/ml
and cT1cвЂ“2a CaP the disease is indolent and
slow-growing. The challenge is to identify those
patients with aggressive disease and offer them
curative treatment, while sparing other patients
the morbidity of unnecessary treatment. Patients
who are offered active surveillance must be followed-up carefully with serial PSA measurements and periodic prostate re-biopsies at 2, 5
and 10 years.
The earlier papers [39вЂ“44] describe cancerspecific survival and metastasis-free survival
after 5 and 10 years of follow-up [1] (level of
evidence: 2b). The importance of tumour grade
is clear, with very low survival rates for grade 3
tumours. Even if the 10-year cancer-specific survival rate is equally good (87%) for grade 1 and
2 tumours, the latter have a significantly higher
progression rate, with 42% of the patients having
developed metastases. In another paper [45], the
re-evaluation of all biopsy specimens using the
more widely accepted Gleason score showed that
the risk of CaP death was very high in Gleason
7вЂ“10 tumours (60%вЂ“87%), intermediate in Gleason 6 tumours (18%вЂ“30%), but low in Gleason
2вЂ“5 cancers (4%вЂ“7%) [45, 46] (level of evidence:
3). Quite recently, the results of a prospective
phase II trial of active surveillance of 299 patients have been reported [47, 48]. At 8 years,
overall actuarial survival was 85% and cancerspecific survival was 99%. A PSA doubling time
of less than 3 years based on three consecutive
measurements over 6 months has been identified
as an indicator for the presence of aggressive disease, making a radical intervention necessary.
9 Guidelines and Counselling for Treatment Options in the Management
135
Table 9.2 Guidelines for the primary treatment of prostate cancer. Management of incidental prostate cancer
Stage Treatment
Comment
T1a
Watchful
waiting
Standard treatment for well-, and moderately, differentiated tumours and <10-year life
expectancy. In patients with >10-year life expectancy, re-staging with TRUS and biopsy is
advised (grade B recommendation)
Radical
prostatectomy
Optional in younger patients with a long life expectancy, especially for poorly differentiated
tumours (grade B recommendation)
Radiotherapy
Optional in younger patients with a long life expectancy, especially for poorly differentiated
tumours. Higher complication risks after TURP, especially for interstitial radiation (grade B
recommendation)
Hormonal
Not an option (grade A recommendation)
Combination
Not an option (grade C recommendation)
Table 9.3 Guidelines for the primary treatment of prostate cancer. Management of clinically localized prostate cancer
T1bвЂ“T2b Watchful waiting
Asymptomatic patients with well-, and moderately, differentiated tumours
and a life expectancy <10 years. Patients who do not accept treatment-related
complications (grade B recommendation)
Radical
prostatectomy
Standard treatment for patients with a life expectancy >10 years who accept
treatment-related complications (grade A recommendation)
Radiotherapy
Patients with a life expectancy >10 years who accept treatment-related
complications. Patients with contraindications for surgery. Unfit patients with
a 5- to 10-year life expectancy and poorly differentiated tumours (combination
therapy is recommended; see below) (grade B recommendation)
Hormonal
Symptomatic patients who need palliation of symptoms and who are unfit for
curative treatment (grade C recommendation). Antiandrogens are associated
with poorer outcome compared to watchful waiting and are not recommended
(grade A recommendation)
Combination
NHT+radical prostatectomy: no proven benefit (grade A recommendation).
NHT+radiotherapy: better local control. No proven survival benefit (grade B
recommendation). Hormonal (2вЂ“3 years)+radiotherapy: better than radiotherapy
alone for poorly differentiated tumours (grade A recommendation)
Table 9.4 Guidelines for the primary treatment of prostate cancer. Management of locally advanced prostate cancer
T3-T4 Watchful
waiting
Option in asymptomatic patients with T3, well-differentiated and moderately differentiated
tumours, and a life expectancy <10 years (grade C recommendation)
Radical
prostatectomy
Optional for selected patients with T3a and a life expectancy >10 years (grade C
recommendation)
Radiotherapy
T3 with a life expectancy >5вЂ“10 years. Dose escalation >70 Gy. Seems to be of benefit. If
this is not available, a combination with hormonal therapy could be recommended (see
below) (grade A recommendation)
Hormonal
Symptomatic patients, extensive T3-T4, high PSA level (>25 ng/ml), unfit patients. Better
than watchful waiting (grade A recommendation)
Combination
Radiotherapy+hormonal treatment seems better than radiotherapy alone (grade A
recommendation). NHT+radical prostatectomy: no proven benefit (grade B
recommendation)
136
Axel Heidenreich
Table 9.5 Guidelines for the primary treatment of prostate cancer. Management of metastatic prostate cancer. (For
more detailed information and discussion on second-line therapy, please see the full text version of the guidelines)
N+, M0 Watchful
waiting
Radical
prostatectomy
M+
Asymptomatic patients. Patient driven. May have a negative influence on survival (grade C
recommendation)
No standard option (grade C recommendation)
Radiotherapy
No standard option (grade C recommendation)
Hormonal
Standard therapy (grade A recommendation)
Combination
No standard option. Patient driven (grade B recommendation)
Watchful
waiting
No standard option. May result in worse survival/more complications than with
immediate hormonal therapy (grade B recommendation)
Radical
prostatectomy
Not an option (grade C recommendation)
Radiotherapy
Not an option (given for cure) (grade C recommendation)
Hormonal
Standard therapy. Symptomatic patients should not be denied treatment (grade A
recommendation)
Combination
Not an option (grade C recommendation)
Combination, hormonal therapy given prior to and/or after radical prostatectomy or radiotherapy; hormonal, all forms
of hormonal therapy; NHT, neoadjuvant therapy; TRUS, transurethral ultrasonography; TURP, transurethral resection
of the prostate
Active SurveillanceвЂ”Locally Advanced
CaP
The literature reporting on deferred treatment
for locally advanced CaP is sparse. There are
no randomized studies that compare more aggressive treatments, such as radiation therapy
or surgery, eventually in combination with hormones. Most patients whose disease progresses
after deferred treatment of locally advanced CaP
will be candidates for hormonal therapy. There
are reports from non-randomized studies showing that hormonal treatment may safely be delayed until metastatic progression occurs, as no
survival advantage was noted between patients
treated with immediate orchiectomy compared
with delayed treatment. However, when early
and delayed treatments were compared in a large
randomized trial carried out by the Medical
Research Council (MRC), a survival benefit for
immediate hormonal therapy was demonstrated
[49] (level of evidence: 1b). Also, comparing placebo with bicalutamide 150 mg showed that in
patients with locally advanced CaP, progression-
free survival was better with early treatment [50]
(level of evidence: 1b).
The SAKK 08/88 trial prospectively randomized 196 patients with CaP who, for any reasons,
were no candidates for local treatment to receive
either immediate or deferred orchiectomy on
symptomatic progression [51]. Of the recruited
men, 67% and 20% demonstrated T3вЂ“4 tumours
and lymph node metastases, respectively. There
was a slight benefit for patients with immediate
treatment concerning cancer-specific, but not
overall survival and progression-free survival.
However, by careful follow-up, only 42% of the
men with the deferred approach never needed
any tumour-specific therapy (level of evidence:
1a).
Active SurveillanceвЂ”Metastatic CaP
The only candidates for such treatment should
be asymptomatic patients with a strong wish to
avoid treatment-related side-effects (level of evidence: 4). The MRC trial highlighted the risk of
9 Guidelines and Counselling for Treatment Options in the Management
developing symptoms (pathological fractures,
spinal cord compression) and even death from
CaP, without receiving the possible benefit from
hormonal treatment [49, 52] (level of evidence:
1b). If a deferred treatment policy is chosen for
the patient with advanced CaP, there must be a
possibility of close follow-up.
Radical Prostatectomy
Currently, radical prostatectomy (RP) is the only
treatment for localized CaP that has shown a
cancer-specific survival benefit when compared
to conservative management in a prospective,
randomized trial [53]. The retropubic approach,
either by open surgery or laparoscopically, is
more commonly performed, as it enables simultaneous pelvic lymph node assessment to be carried out. In men with localized CaP and a life
expectancy of 10 years or more, the goal of a RP
by any approach must be eradication of the disease and maintaining erectile function and continence [54]. In fact, there is no rigid age limit
for RP and a patient should not be denied this
procedure on the grounds of age alone [55].
Stage T1a-T1b CaP
Stage T1a CaP is an incidental histological finding of cancer in 5% or less of resected prostatic
tissue during transurethral resection of the prostate (TURP) or open adenomectomy, while T1b
is when more than 5% contains cancer, or when
the tumour is poorly differentiated. Although the
risk of disease progression of untreated T1a CaP
after 5 years is only 5%, these cancers can progress in about 50% of cases after 10вЂ“13 years [56].
Thus, in younger patients with a life expectancy
of 15 years or more, the chance of disease progression is real, requiring specific treatment.
In contrast, most patients with T1b tumours
are expected to show disease progression after
5 years and aggressive treatment is often warranted [56]. Patients with T1b lesions are offered
RP when they have a life expectancy of 10 years
or more; however, external beam radiotherapy
can be a valuable alternative treatment modality.
137
Stage T1c CaP
The clinically unapparent tumour identified by
needle biopsy because of an aberrant PSA level
has become the most frequent clinical stage in
the actual RP population. In an individual patient it is difficult to differentiate between clinically insignificant and life-threatening CaP. Most
reports, however, stress that PSA-detected tumours are mostly significant and should not be
left untreated, since up to 30% of T1c tumours
are locally advanced [57]. The proportion of insignificant tumours detected because of PSA elevation varies between 11% and 16% [58, 59].
While it might be reasonable to follow-up
some patients whose tumours are most likely to
be insignificant, RP should be advocated for most
patients with T1c tumours, keeping in mind that
significant tumours will be found in the majority
of these individuals.
Stage T2 CaP
RP is one of the recommended standard treatments for patients with stage T2 CaP and a life
expectancy of more than 10 years [60]. The prognosis is excellent when the tumour is confined to
the prostate based on pathological examination
[61, 62]. Although most poorly differentiated
tumours extend outside the prostate, patients
with high-grade tumours that are confined to
the prostate at histopathological examination
still have a good prognosis after RP [34], with a
10-year cancer-specific survival of 85%. T2a patients with a 10-year life expectancy should be
offered RP since 35%вЂ“55% of them will have disease progression after 5 years if not treated. T2b
cancer still confined to the prostate but involving
more than half of a lobe or both lobes will progress in more than 70% of patients within 5 years
[37]. These data have been confirmed by a large
randomized trial comparing RP and watchful
waiting that included mostly T2 CaP patients
showing a significant reduction in disease-specific mortality [53]. In young men with localized
CaP who are otherwise healthy, RP is an excellent
option, and if an experienced surgeon performs
it, the patientвЂ™s subsequent quality of life (QoL)
should be more satisfactory.
138
Stage T3 CaP
T3a cancer is defined as capsular perforation and
T3b cancer as invasion of the seminal vesicles.
In extracapsular tumours, RP often results in
incomplete tumour excision. Whether or not T3
CaP should be considered an indication for surgical treatment remains unclear. The published
reports on treatment outcomes in patients with
clinical T3 are few.
Combination treatment with hormonal and
radiation therapy is gaining popularity, although
it has not been demonstrated that this approach
is superior to surgical treatment. A randomized
study on radiotherapy with hormones vs radiotherapy alone showed a clear advantage for the
combination treatment, but did not show the
superiority over RP [63]. Another problem is
вЂњcontaminationвЂќ by the additional use of either
adjuvant radiotherapy or immediate or delayed
hormonal treatment in most of the series that reported on the treatment of clinical T3 CaP.
In the absence of data from randomized
clinical trials comparing possible options for definitive therapy in these patients, only single or
multi-centre reports can be used to define the
role of RP in this stage. Most studies have demonstrated that about 15% of all clinical stage T3
tumours were over-staged (cT3, pT2), while only
8% were under-staged (cT3, pT4).
For clinical T3 cancer, the overall PSA-free
survival rate is about 20% after 5 years. The
Gleason score of the tumour has a definite impact on progression, but there is not always a
reliable correlation between the biopsy and the
specimen Gleason score. On the other hand,
seminal vesicle invasion, lymph node invasion,
positive surgical margins and high PSA level
are independent prognostic factors of PSA-free
survival. Some authors have used a serum PSA
level of 25 ng/ml as the discriminator for outcome [64, 65]. Others have shown that RP for
clinical T3a cancer with a PSA below 10 ng/ml
can achieve a 5-year PSA-free survival rate exceeding 60% [66]. Therefore, surgery has to be
considered a therapeutic option for some patients with clinical T3a CaP. Not only clinically
over-staged patients (pT2) but also individuals
whose tumours actually are pT3a can benefit
from this treatment option. RP for clinical T3
Axel Heidenreich
cancer necessitates sufficient surgical expertise
in order to keep the level of morbidity acceptable, to improve oncological control and functional outcome, as has been described for the
extended variant of RP [67].
Nodal Disease
Lymph node-positive (N+) disease will mostly
be followed by systemic disease progression,
and all patients with significant N+ disease
will ultimately fail to be cured. Nevertheless,
the combination of RP and simultaneous hormonal treatment has been shown to achieve a
10-year cancer-specific survival rate of 80%
[68]. However, it is questionable whether or not
these results could be obtained with hormonal
treatment alone. The incidence of tumour progression is lower in patients with fewer positive
lymph nodes and in those with microscopic invasion only.
N+ patients usually have significant nodal
involvement and will be treated with hormonal
manipulation only. In patients who prove to be
pN+ after RP, adjuvant hormonal treatment can
be advocated, but the benefits should be judged
against side-effects of long-term hormonal therapy. PSA follow-up and hormonal treatment in
case of PSA rise is therefore an acceptable option
in selected cases.
Recently, an extended lymph node dissection
comprising not only the obturator fossa but also
the external and the internal iliac area with the
presacral nodes has been advocated [32, 33], but
this approach was not analysed in a prospective
randomized fashion. Nevertheless, the limited
value of a lymph node dissection as only a staging procedure without any therapeutic benefit is
being increasingly challenged.
Neoadjuvant Hormonal Therapy and Radical
Prostatectomy
Five prospective, randomized studies have shown
a decrease in positive surgical margin rates, with
the use of a short-term (6 weeksвЂ“4 months)
course of neoadjuvant hormonal therapy (NHT).
Follow-up of these randomized trials has indi-
9 Guidelines and Counselling for Treatment Options in the Management
cated that this has not resulted in any difference
in PSA-free failure after 3вЂ“5 years of follow-up
[69вЂ“72]. Since none of these studies was powered to study overall survival, the impact of neoadjuvant hormonal therapy (NHT) on overall
survival remains unclear. The expectation had
been that a longer duration of NHT could improve the PSA-free survival, but a well-designed
randomized trial was unable to demonstrate any
advantage of an 8-month vs a 3-month preoperative hormonal treatment [73]. With these results
in mind, NHT cannot be recommended for routine clinical use prior to RP.
Summary of Guidelines for RP
Indications
вЂ“ RP is indicated for patients with stage T1bвЂ“
T2, NxвЂ“N0, M0 disease and a life expectancy
exceeding 10 years (level of evidence: 1b).
139
adjuvant radiation therapy), has not been
evaluated (level of evidence: 4).
Definitive Radiation Therapy
There are no randomized studies that compare
RP with either external beam therapy or brachytherapy for localized CaP. In Europe, the 1990s
saw the introduction of three-dimensional conformal radiotherapy (3D-CRT) and a growing
interest in transperineal brachytherapy. At the
onset of the third millennium, intensity modulated radiotherapy (IMRT) is gradually gaining
ground in centres of excellence. After the appropriate assessment of tumour extension, the
choice of treatment must be made based on a
multidisciplinary approach, taking into account
the 2002 TNM classification, Gleason score,
baseline PSA, age of the patient, comorbidity,
life expectancy and QoL. Obtaining a patientвЂ™s
consent is essential after providing exhaustive
information regarding diagnosis, the therapeutic
modalities and morbidity.
Optional Indications
вЂ“ Patients with a long life expectancy and stage
T1a disease (level of evidence: 3).
вЂ“ Patients with stage T3a disease, a Gleason
score exceeding 8 and a PSA of less than
20 ng/ml.
Comments
вЂ“ Short-term (3 months) neoadjuvant therapy
with gonadotrophin releasing-hormone analogues is not recommended in the treatment
of stage T1-T2 disease (level of evidence: 1a).
вЂ“ Nerve-sparing surgery may be attempted in
pre-operatively potent patients with low risk
for extracapsular disease (T1c, Gleason score
<7 and PSA <10 ng/ml or see Partin tables/
nomograms) (level of evidence: 3).
вЂ“ Unilateral nerve sparing procedures is an option in stage T2a disease (level of evidence: 4).
вЂ“ The role of RP in patients with high-risk features, lymph node involvement (stage N1 disease) or as a part of a planned multimodality
treatment (with long-term hormonal and/or
Localized CaP T1вЂ“2c N0, M0
Low-Risk Group
T1aвЂ“T2a N0, M0 and a Gleason score of 6 or less
and a PSA of less than 10 ng/ml qualifies as lowrisk. For external radiotherapy, up to 70вЂ“72 Gy
is recommended as it offers the same results as
dose escalation [74].
Intermediate-Risk Group
Intermediate-risk group patients, with T2b or
PSA 10вЂ“20 ng/ml, or a Gleason score of 7, may
benefit from dose escalation, as shown by two
randomized trials. The MD Anderson Cancer Centre randomized study compared 78 Gy
3D-CRT to a 70 Gy conventional radiotherapy
including 305 stage T1вЂ“3 patients with a pretreatment PSA level of more than 10 ng/ml (median follow-up of 40 months). A significantly
higher 5-year free-from-failure rate was found in
75% of the patients who received 78 Gy vs 48%
140
of those who received 70 Gy (p=0.01) [75]. This
study has been confirmed by the PROG 95-09
interim analysis that evaluated 393 T1bвЂ“T2b patientsвЂ”75% of which had a Gleason score of 6 or
lessвЂ”and with a PSA less than 15 ng/ml. Patients
were randomized to receive an initial boost to the
prostate alone using conformal protons of either
19.8 or 28.8 Gy, then 50.4 Gy to a larger volume.
With a median follow-up of 4 years, there was
a significant decrease of the 5-year biochemical
failure rate (p=0.00001) in favour of the patients
assigned to the higher dose (79.2 GyE) vs those
receiving a conventional dose (70.2 GyE) [76].
In daily practice, although a consensus has not
been reached yet concerning the level of the dose
escalation, 78 Gy seems to represent a good compromise.
Axel Heidenreich
receive 3D-CRT plus ADT had a significantly
higher survival rate (p=0.04), lower CaP-specific
mortality rate (p=0.02), and higher survival rate
free of salvage ADT (p=0.002) [80].
Prophylactic Irradiation of Pelvic Lymph Nodes
in Intermediate- or High-Risk Localized CaP
Nowadays, due to individual screening, comprehensive clinical work-up and new imaging modalities, the risk of pelvic lymph node invasion
may be assessed by the Roach formula [81]. The
Roach formula estimates the risk of pelvic lymph
node involvement higher than 15%: positive
lymph node=2/3 PSA+(GS-6)Г—10.
Innovative Techniques
High-Risk Group
Intensity Modulated Radiotherapy
For the high-risk group (T2c, or Gleason score
greater than 7 or PSA greater than 20 ng/ml), external irradiation with dose escalation improves
5-year biochemical disease-free survival [75] but
seems insufficient to cover the risk of relapse outside the pelvis. Many studies aim to evaluate the
dose escalation with or without adjuvant hormonal therapy:
1. The MRC with neoadjuvant hormonal therapy comparing conventional radiotherapy of
64 Gy to high-dose (74 Gy) radical conformal
radiotherapy [77]
2. The FГ©dГ©ration Nationale des Centres de Lutte
Contre le Cancer (FNCLCC) comparing 70 to
80 Gy without hormonal therapy [78]
3. The European Organization for Research and
Treatment of Cancer (EORTC) with dose
stratification (70, 74 and 78 Gy) with or without neoadjuvant and concomitant hormonal
therapy [79]
A prospective randomized trial, which included 206 patients with a PSA of at least 10 ng/
ml (maximum 40 ng/ml), a Gleason score of at
least 7 (range 5вЂ“10), or radiographic evidence
of extra-prostatic disease, compared 3D-CRT
alone or in combination with 6 months of androgen deprivation therapy (ADT). After a median
follow-up of 4.5 years, patients randomized to
IMRT enables radiation oncologists to homogeneously increase the doses up to 80 Gy within
the target volume, while respecting the threshold
doses in organs at risk. The Memorial Sloan-Kettering Cancer Centre has the largest experience
with this technique, reporting on 772 patients
treated between 1996 and 2001 with doses ranging from 81 to 86.4 Gy using an inverse planning approach. With a median follow-up time
of 24 months (6вЂ“60 months), the 3-year actuarial likelihood of late grade 2 or higher rectal
toxicity was 4%; the 3-year actuarial likelihood
of grade 2 or higher urinary toxicity was 15%;
and the 3-year actuarial PSA relapse-free survival rates for favourable-, intermediate- and
unfavourable-risk group patients were 92%, 86%
and 81% respectively [82]. The use of IMRT is
opening the way to hypofractionated treatment,
with a shorter duration for the overall treatment
time, by delivering 70 Gy in 28 fractions over
5.5 weeks, with 2.5 Gy per fraction.
Transperineal Brachytherapy
Transperineal brachytherapy is a safe and efficient
technique, which generally requires less than
2 days of hospitalization. There is a consensus on
9 Guidelines and Counselling for Treatment Options in the Management
the following eligibility criteria: stage cT1bвЂ“T2a
N0, M0, a Gleason score of 6 of less assessed on
a sufficient number of random biopsies, an initial
PSA level of 10 ng/ml or lower, a prostate volume
of 50 cm3 or less and a good International prostatic symptom score (IPSS) [83].
In cases of permanent implants, iodine-125 in
granule form is the radio-element of reference;
palladium-103 may be used for less differentiated
tumours with high doubling time. The dose delivered to the planning target volume is in the order
of 160 Gy for iodine-125 and of 120 Gy for palladium-103. A Gleason score of 7 still remains a
вЂњgrey zoneвЂќ, but patients with GS 4+3 show no difference in outcome [84]. In cases of intermediate
or high-risk localized CaP, the combination with
external irradiation [85] or neoadjuvant hormonal
treatment [86] may be considered, but the potential positive impact of these treatments needs to
be assessed with randomized trials. Non-permanent transperineal interstitial prostate brachytherapy using a high-dose rate iridium-192 stepping
source and a remote after-loading technique can
be applied with a total dose of 12 to 20 Gy in 2 to
4 fractions combined with fractionated external
radiotherapy of 45 Gy [26].
Immediate Post-operative External Irradiation
for Pathological Tumour Stage T3 N0, M0
Only one prospective randomized trial has assessed the role of immediate post-operative
radiotherapy; The European Organisation for
Research and Treatment of Cancer (EORTC)
study 22911 compared immediate post-operative
radiotherapy (60 Gy) to radiotherapy delayed
until local recurrence (70 Gy) in patients classified as pT3 pN0 after retropubic RP. Immediate
post-operative radiotherapy proved to be well
tolerated with a risk of grade 3вЂ“4 and urinary
toxicity of under 3.5% [88], without significant
difference regarding incontinence and/or stricture of anastomosis. The study concludes that
immediate post-operative radiotherapy significantly improves 5-year clinical or biological survival: 72.2% vs 51.8% p<0.0001. Consequently,
for patients classified as T1вЂ“2 N0 (or T3 N0 with
selected prognostic factors), pT3 pN0 with a
high risk of local failure after RP due to rupture
141
of the capsule, positive margins and/or invasion
of the seminal vesicles, presenting with a PSA of
<0.1 ng/ml 1 month after surgery, one of the following may be recommended:
вЂ“ Immediate radiotherapy upon recovery of
urinary function
вЂ“ Clinical and biological monitoring followed
by salvage radiotherapy, when the PSA exceeds 0.5 ng/ml
Locally Advanced CaP: T3вЂ“4 N0, M0,
T1вЂ“4 N1 M0
The incidence of locally advanced CaP declined
as a result of individual or mass screening. Pelvic
lymph node irradiation is optional for N0 patients, due to the likelihood of infra-clinical disease and N1 patients (inter-iliac nodes). Results
of radiotherapy alone are dismal. This is why, because of the hormone dependence of CaP [89],
ADT has been combined with external irradiation with the dual objectives of:
вЂ“ Reducing the risk of distant metastases by potentially sterilizing micrometastases already
present at the moment of diagnosis
вЂ“ Decreasing the risk of non-sterilization and/
or local recurrence as a source of secondary
metastases through the effect of radiation-induced apoptosis
Neoadjuvant Hormonal Therapy
The Radiation Therapy Oncology Group (RTOG)
study 86-10 included 471 patients with stage
T2-4N0-X M0. ADT was administered 2 months
before irradiation and during irradiation, or, in
the case of relapse, in the control arm. Of the patients, 32% were diagnosed as T2, 70% as T3вЂ“4
and 91% N0. The hormone treatment consisted
of oral flutamide, 250 mg, 3 times daily and goserelin acetate (Zoladex) 3.6 mg every 4 weeks by
subcutaneous injection. The pelvic target volume
received 45 Gy and the prostatic target volume
received 20вЂ“25 Gy. At 8 years, ADT was associated with an improvement in local control (42%
vs 30%, p=0.016), disease-free survival (33% vs
21%, p=0.004) and biochemical disease-free survival [PSA <1.5 ng/ml, 24% vs 10% (p<0.0001)].
142
In patients with Gleason score 2вЂ“6, there was a
significant improvement in survival: 70% vs 52%
(p=0.015) [90].
Concomitant and Adjuvant Hormonal Therapy
The EORTC study 22863 recruited 415 patients
diagnosed with T1вЂ“2 grade 3 WHO, T3вЂ“4
N0, M0 and compared radiotherapy with adjuvant ADT to radiotherapy alone. ADT was allowed in cases of relapse. Of the patients, 82%
were diagnosed as T3, 10% as T4 and 89% as N0.
The hormone treatment consisted of oral cyproterone acetate, 50 mg 3 times daily for 1 month,
beginning 1 week before the start of radiotherapy, and subcutaneous injection of goserelin acetate 3.6 mg every 4 weeks for 3 years, starting
on the first day of radiotherapy.
The pelvic target volume received was 50 Gy
and the prostatic target volume was 20 Gy. With
a median follow-up of 66 months, combination
therapy compared with radiotherapy alone was
significantly better for both survival (78% vs 62%,
p=0.001) and survival without clinical relapse
(78% vs 40%, p<0.001) [63]. The 5-year cumulative incidence of locoregional failure was 1.7% vs
16.4% in the radiotherapy alone arm (p<0.0001),
and survival without clinical or biological failure
(nadir of 1.5 ng/ml) was 81% for the combined
treatment arm vs 43% in the radiotherapy alone
arm (p<0.001).
Axel Heidenreich
in favour of the adjuvant hormonal therapy arm,
76% vs 71% and 53% vs 38%, respectively [44].
In this study, 95 of the 173 pN1 patients who received pelvic radiotherapy with immediate hormonal therapy had a significantly better survival
rate without biochemical relapse at 5 years (PSA
<1.5 ng/ml) than those in the arm with delayed
hormonal therapy (p=0.0001) [92].
Neoadjuvant, Concomitant
and Adjuvant Hormonal Therapy
The RTOG 92-02 trial closed in 1995 after accruing 1,554 patients. Statistically significant
improvements were observed in biochemical
non-evidence (bNED; actuarial biochemical
freedom of disease) control, distant metastatic
failure, local control and disease-free survival for
patients receiving long-term ADT (before, during and 2 years after radiotherapy) compared
with short-term treatment (2 months before, and
during radiotherapy). With a median follow-up
of 5.8 years, the long-term ADT arm showed significant improvement in all efficacy end-points
except 5-year overall survival, 80% vs 78.5%
(p=0.73), compared with the short-term ADT.
In a subset of patients, who were not part of the
original study design, with Gleason score 8вЂ“10
tumours, after 5 years the long-term androgen
deprivation (LTAD) arm showed significantly
better overall survival: 81% vs 70.7%, (p=0,04)
[93].
Adjuvant Hormonal Therapy
Summary of Definitive Radiation Therapy
The RTOG study 85-31 recruited 977 patients
diagnosed with T3вЂ“4 N0-1 M0, or pT3 after
RP. ADT was started in the last week of irradiation and continued up to relapse (group I) or
started at recurrence (group II). Of the patients
in groups I and II, 15% and 29%, respectively,
had undergone RP, while 14% of the patients in
group I and 26% in group II were pN1. Goserelin
acetate 3.6 mg was administered every 4 weeks.
The pelvis received 45 Gy and the prostatic bed
received 20вЂ“25 Gy. Patients diagnosed with stage
pT3 received 60вЂ“65 Gy. With a median followup time of 7.3 years, a statistical significance was
reached for 5-year and 10-year overall survival
1. In localized CaP T1c-T2c N0 M0, 3D-CRT
with or without IMRT, definitive radiation
therapy is recommended, even for young patients who refuse surgical intervention. There
is fairly strong evidence that intermediate-risk
patients benefit from dose escalation (level
of evidence: 2). For patients in the high-risk
group, short-term ADT prior to and during
radiotherapy may result in increased overall
survival (level of evidence: 2a).
2. Transperineal interstitial brachytherapy with
permanent implants may be proposed to patients cT1вЂ“T2a, a Gleason score less than 7
9 Guidelines and Counselling for Treatment Options in the Management
(or 3+4), a PSA of 10 ng/ml or lower, prostate
volume of 50 ml or less, without a previous
TURP and with a good IPSS (level of evidence: 2b).
3. Immediate post-operative external irradiation after RP for patients with pathological
tumour stage T3 N0 M0 prolongs biochemical and clinical disease-free survival (level of
evidence: 2a). An alternative option is to give
radiation at the time of biochemical failure
but before PSA reaches above 1вЂ“1.5 ng/ml
(level of evidence: 3).
4. In locally advanced CaP, overall survival is
improved by concomitant and adjuvant hormonal therapy (with a total duration of 2 to
3 years) with external irradiation (level of
evidence: 1). For a subset of patients, T2cвЂ“T3
N0-x with Gleason score 2вЂ“6, short-term
ADT before, and during, radiotherapy may
favourably influence overall survival (level of
evidence: 1b).
Experimental Local Treatment
of Prostate Cancer
Besides RP, external beam radiation and/or
brachytherapy, cryosurgery of the prostate
(CSAP) and high-intensity focussed ultrasound
(HIFU) have emerged as alternative therapeutic
options in patients with clinically localized CaP.
Whereas HIFU is still considered to be an experimental treatment, CSAP has been recognized as
a true therapeutic alternative as recommended
by the guidelines of the American Urological Association. Both techniques have been developed
as minimally invasive procedures potentially
resulting in the same therapeutic efficacy as the
established surgical and non-surgical options associated with reduced therapy-associated morbidity.
The reader is referred to the full guidelines
published at http://www.uroweb.org.
Summary of Experimental Therapeutic
Options to Treat Clinically Localized CAP
1. CSAP has evolved from an investigational
therapy to a possible alternative to treat CaP
143
in patients unfit for surgery or in those with a
life expectancy of less than 10 years (grade C
recommendation).
2. All other minimally invasive treatment options, such as HIFU, RITA, microwaves and
electrosurgery, are still experimental or investigational. For all of these procedures, a longer
follow-up is mandatory to assess their true
role in the management of CaP (grade C recommendation).
Hormonal Therapy
In 1941, Huggins and Hodges assessed the favourable effect of surgical castration and oestrogen administration on the progression of metastatic CaP, demonstrating for the first time the
responsiveness of CaP to androgen deprivation
[94]. Since their pivotal studies, androgen-suppressing strategies have become the mainstay
for the management of advanced CaP, but recent years show an evolution towards increasing hormonal treatment of younger men with
earlier (i.e. non-metastatic) stages of disease or
recurrent disease after definitive treatment, either as primary single-agent therapy or as a part
of a multimodality approach. Even if hormonal
treatment effectively palliates the symptoms of
advanced disease, there is no conclusive evidence
at present that it can extend life.
Testosterone-Lowering Therapy (Castration):
Bilateral Orchiectomy
Surgical castration is still considered the вЂњgold
standardвЂќ for ADT against which all other treatments are rated.
By removing the testicular source of androgens, a hypogonadal status with a considerable
decline of testosterone concentrations is induced,
though a very low level of testosterone (known as
вЂњcastration levelвЂќ) does persist. Bilateral orchiectomy is a simple and virtually complication-free
surgical procedure, which can easily be performed under local anaesthesia. The main drawback of orchiectomy is that it may have a negative psychological effect; some men consider it to
be an unacceptable assault on their manhood.
144
Oestrogens
The most commonly used oestrogen was diethylstilboestrol (DES). In early studies by the Veterans Administration Co-operative Urological Research Group (VACURG) [95, 96], oral DES at a
dosage of 5, 3 and 1 mg/day was tested, but the
treatment was associated with high cardiovascular morbidity and mortality due to the first-pass
hepatic metabolism with formation of thrombogenic metabolites.
Renewed interest in oestrogens can be ascribed to three main reasons. First, as a response
to the number of deleterious side-effects and the
high costs of long-term ADT with the currently
widespread LHRH agonists: oestrogens suppress
testosterone levels and do not seem to lead to
bone loss and cognitive decline (97, level of evidence: 3). Second, oestrogenic compounds (DES,
DES-diphosphate and the herbal supplement PC
SPES) have been shown to induce PSA-response
rates as high as 86% in phase II trials with patients diagnosed with hormone-refractory prostate cancer (HRPC). Third, a new oestrogen receptor-beta (ER-b), possibly involved in prostate
tumourigenesis, has been discovered [98].
In conclusion, DES is one of the classic forms
of hormonal therapy. Although its efficacy was
demonstrated many years ago and recently reconfirmed in a meta-analysis as comparable to
that of bilateral orchiectomy (99, level of evidence: 1a), the significant cardiovascular side-effects, even at lower dosages, remain a concern.
Further data are needed before oestrogens will
be readmitted in clinical practice as a standard
first-line treatment option.
Luteinizing Hormone-Releasing
Hormone Agonists
Long-acting luteinizing hormone-releasing hormone (LHRH) agonists (buserelin, goserelin,
leuprorelin and triptorelin) have been used in
advanced CaP for more than 15 years and are
currently the predominant forms of ADT [100,
101]. Chronic exposure to LHRH agonists eventually results in down-regulation of LHRH-receptors, with subsequent suppression of pituitary
LH and follicle-stimulating hormone (FSH) secretion and testosterone production. The level of
Axel Heidenreich
testosterone decreases to castration levels usually
within 2 to 4 weeks [19, 20]. However, approximately 10% of patients treated with LHRH agonist fail to achieve castration levels [21].
In a recent meta-analysis evaluating singletherapy ADT for advanced CaP, LHRH agonists
have shown comparable efficacy to orchiectomy
and DES (99, level of evidence: 1a). In addition,
although only based on an indirect comparison,
all seemed equally effective (99, level of evidence: 3). Today, LHRH agonists have become
the вЂњstandard of careвЂќ in hormonal therapy because they avoid the physical and psychological
discomfort associated with orchiectomy and lack
the potential cardiotoxicity associated with DES.
However, the main concerns associated with
the administration of LHRH agonists are the
potentially detrimental effects associated with
the вЂњflare phenomenonвЂќ in advanced disease,
namely increased bone pain, acute bladder outlet obstruction, obstructive renal failure, spinal
cord compression and fatal cardiovascular events
due to hypercoagulation status. A recent review
[102] addressing these issues concluded that
clinical flare needs to be distinguished from the
more common biochemical flare (i.e. increasing
levels of PSA) and even from asymptomatic radiographic evidence of progression, and that patients at risk for clinical flare are overwhelmingly
those with high-volume, symptomatic, bony
disease, accounting for only 4%вЂ“10% of M1 patients. Concomitant therapy with an anti-androgen definitely decreases the incidence of clinical
relapse, but it does not completely remove the
possibility of their occurrence. Based on pharmacokinetic considerations, it is recommended
that administration of the anti-androgens should
be started on the same day as the depot injection,
and treatment should be continued for a 2-week
period. However, for patients with impending
spinal cord compression, alternative strategies
for immediately ablating testosterone levels must
be considered, such as bilateral orchiectomy or
LHRH-antagonists.
LHRH Antagonists
In contrast to the agonists, LHRH antagonists
bind immediately and competitively to LHRH
receptors in the pituitary gland. The effect is a
9 Guidelines and Counselling for Treatment Options in the Management
rapid decrease in LH, FSH, and testosterone levels without any flare.
This seemingly more desirable mechanism of
action has made LHRH antagonists very attractive since their introduction, but practical shortcomings have limited clinical studies. Indeed,
many of these compounds have been associated
with serious and life-threatening histamine-mediated side-effects and, until recently, no depot
formulation was available. Abarelix has recently
been licensed by the United States Food and
Drug Administration for clinical use, but its use
is restricted to those patients with metastatic and
symptomatic CaP for whom no other treatment
option is available [103].
Anti-androgens
Anti-androgens compete with testosterone and
DHT for binding sites on their receptors in the
prostate cell nucleus, thus promoting apoptosis
and inhibiting CaP growth [26]. These orally administered compounds are classified according
to their chemical structure as steroidal [e.g. cyproterone acetate (CPA), megestrol acetate and
medroxyprogesterone acetate] and non-steroidal
or pure (e.g. nilutamide, flutamide and bicalutamide). Both classes act as competitors of androgens at the receptor level, but while this is the sole
action of non-steroidal anti-androgens, steroidal
anti-androgens additionally have progestational
properties with central inhibition of the pituitary
gland. As a consequence, non-steroidal anti-androgens do not lower testosterone levels, which
remain normal or, conversely, slightly elevated.
Steroidal Anti-androgens
These compounds are synthetic derivatives of
hydroxyprogesterone. In addition to peripherally
blocking androgen receptors, they have progestational properties and inhibit gonadotrophin (LH
and FSH) release and suppress adrenal activity.
At high doses megestrol acetate is cytotoxic.
Since steroidal anti-androgens lower testosterone
levels, the main pharmacological side-effects are
loss of libido and erectile dysfunction. The nonpharmacological side-effects are cardiovascular
toxicity (4%вЂ“40% for CPA) and hepatotoxicity.
145
Cyproterone Acetate
There is only one randomized trial [104] comparing CPA to standard hormonal therapy (i.e.
medical castration): patients in arm A (no contraindications to DES) were randomly assigned
to CPA, goserelin or DES, while patients in arm B
(contraindications to DES) were assigned to CPA
or goserelin. In arm A, treatment with CPA was
associated with significantly poorer median
overall survival than goserelin only; adjusting for
baseline characteristics did not account for this
difference. The only comparative study on antiandrogens as monotherapy was recently published by EORTC protocol 30892 (a randomized
trial of 310 patients comparing CPA vs flutamide
in metastatic CaP), which showed no difference
in cancer-specific and overall survival at a median follow-up of 8.6 years, though the study was
underpowered (105, level of evidence: 1b).
Megesterol Acetate
and Medroxyprogesterone Acetate
Very limited information is available on megesterol acetate and medroxyprogesterone acetate.
The only prospective randomized trial evaluating medroxyprogesterone acetate as primary
therapy in advanced (M0вЂ“1) CaP is the EORTC
30761 study mentioned above [106], in which
236 patients were assigned to receive CPA, DES
or medroxyprogesterone acetate: While no difference in cancer-specific and overall survival
was evident between CPA and DES, treatment
with medroxyprogesterone acetate had a less favourable course with a shorter survival time and
time to progression than any of the other two
drugs tested.
Non-steroidal Anti-androgens
Non-steroidal anti-androgens have been promoted in monotherapy for QoL and compliance
benefits over castration since they do not suppress testosterone secretion; it is claimed that
libido, overall physical performance and bone
mineral density are preserved.
Although no direct comparisons have been
undertaken in a monotherapy setting, the three
146
available drugs do not appear to differ in the severity of pharmacological side-effects, namely
gynaecomastia, breast pain and hot flashes. However, there are differences in the non-pharmacological side-effects, with bicalutamide showing
a more favourable safety and tolerability profile
than nilutamide and flutamide [107].
Flutamide
Flutamide was the first non-steroidal anti-androgen available for clinical use and has been
studied as monotherapy for over 20 years, but
no dose-finding studies against a currently accepted endpoint (e.g. PSA response) have been
published. Flutamide is a pro-drug and the halflife of the active metabolite is 5 to 6 h, so it has
to be administered three times daily to maintain
therapeutic serum levels; the recommended daily
dosage is 750 mg.
The main advantage shown in these studies
was the preservation of sexual function, which
was maintained in up to 80% of patients with no
pre-treatment erectile dysfunction [108вЂ“111].
This rate has not been confirmed in the EORTC
trial 30892 [105], where as few as 20% of the men
treated with flutamide maintained sexual activity
for up to 7 years. Only two phase III randomized
trials comparing flutamide monotherapy to standard therapy (orchiectomy [112] and CAB [113])
for advanced CaP have reported survival data;
both showed no significant difference in overall
survival for flutamide or castration. Results are
eagerly awaited from an on-going Swedish study
in which 700 patients with M1 CaP have been
randomized to flutamide 250 mg three times
daily or CAB.
Bicalutamide
Early reports with bicalutamide monotherapy
related only to the 50 mg dosage, which was the
one licensed for use in CAB. An overall analysis
of these studies showed that, although bicalutamide 50 mg/day had clinical benefits, it was inferior to castration in terms of overall survival
(median difference 97 days) [114]. Subsequent
dose-ranging studies established that bicaluta-
Axel Heidenreich
mide 150 mg once daily achieved a PSA response
similar to that seen with castration while maintaining a good tolerability profile [115].
As primary monotherapy, bicalutamide 150 mg/
day has been compared to medical or surgical
castration in two large prospective randomized
trials with identical study design, including a total of 1,435 patients with locally advanced M0 or
M1 CaP [115]. A pooled analysis showed:
вЂ“ An improvement in overall survival with castration in M1 patients, although the difference in median survival between the groups
was only 6 weeks; a further post-hoc analysis
showed a survival benefit only for patients with
higher PSA level (>400 ng/ml) at study entry.
вЂ“ No significant difference was noted in overall
survival in M0 patients.
In two smaller randomized trials, high-dose
bicalutamide was compared to CAB. In the first
trial (251 patients with predominantly M1 stage),
no difference in overall survival was apparent
[116]. In the second trial (220 patients with M0
and M1 stage), there was no difference in overall
survival for well- or moderately well-differentiated tumours [117] (level of evidence: 1b), but
both studies were underpowered.
As for the adjuvant setting, the on-going Early
Prostate Cancer Programme including 8,113 patients worldwide was designated to evaluate the
efficacy and tolerability of high-dose (150 mg/
day) bicalutamide vs placebo given in addition
to standard primary care (i.e. RP, radiotherapy
and вЂњwatchful waitingвЂќ) in localized or locally
advanced CaP. The first combined analysis of the
programme showed that, after a median followup of 3 years, adjuvant bicalutamide provided a
reduction of 42% in the risk of objective disease
progression compared to standard care alone
[58]. After a median follow-up of 5.4 years, it was
shown that the positive effects of bicalutamide
were obvious in patients with locally advanced
disease (stage M0), whereas for patients with localized disease survival appeared to be reduced
as compared to those receiving placebo [50]. In
conclusion, high-dose bicalutamide has emerged
as an alternative to castration for patients with
locally advanced (M0) and in highly selected,
well-informed cases of M1 CaP, but should be
avoided in patients with localized CaP.
9 Guidelines and Counselling for Treatment Options in the Management
Combination Therapies
147
Intermittent Versus Continuous
Androgen Deprivation Therapy
Complete Androgen Blockade
A plethora of studies evaluating complete androgen blockade (CAB) over monotherapy have
been carried out with contrasting results. From
the most recent systematic reviews and metaanalyses it appears that at a follow-up of 5 years,
CAB provides a small survival advantage (less
than 5%) when compared to monotherapy
([119вЂ“123] level of evidence: 1a). It remains debatable whether this small advantage, if any, can
be meaningful when applied to everyday clinical
practice.
Several phase II trials have demonstrated the feasibility of intermittent androgen blockade (IAB)
in metastatic or biochemically recurrent disease,
with PSA-response rates and symptom improvement similar to that of CAB, but phase III prospective, randomized controlled trials are still
underway and data on survival endpoints and
QoL are not mature [130].
In conclusion, although IAB is at present
widely offered to patients with CaP in various
clinical settings, its status should be regarded as
investigational.
Minimal Androgen Blockade
(or Peripheral Androgen Blockade)
Immediate Versus Deferred
Androgen Deprivation Therapy
In several phase II trials [124вЂ“128], the association of finasteride and flutamide, either in a concomitant or sequential regimen, has been evaluated in terms of PSA-response rate in patients
with advanced or biochemically recurrent CaP.
Notwithstanding the small sample and short follow-up, the overwhelming majority of patients
experienced a substantial decline in PSA (by up
to 96% compared to the level at entry). An update of one of these studies, at a long-term follow-up, reported on stronger endpoints, such as
castration-free survival (median: 37 months),
androgen-independent CaP-free survival (median: 48.6 months) and overall survival rate
(65% at 5 years); the conclusion was that combination therapy can induce an overall period of
hormone-responsive disease exceeding 4 years
[129]. In all these trials, sexual function was reported to be preserved in the great majority (55%
to 86%) of men.
The preliminary data make this treatment
option most attractive in the management of
patients for whom QoL is the primary issue.
However, while awaiting the results of follow-up
and larger controlled trials, the treatment is still
regarded as investigational.
Evidence on immediate vs deferred ADT is provided by three systematic reviews of the literature
(one of which is a meta-analysis). The Agency
for Health Care Policy and Research report indicated that a possible survival advantage for
early ADT existed in single studies where hormone treatment was the primary therapy, while
the combined analysis showed no significant
benefit. Furthermore, androgen suppression was
shown to be most cost-effective if initiated after
patients experienced symptoms from metastatic
disease [131]. The Cochrane Library review extracted four good-quality randomized controlled
trials {VACURG I & II studies [95, 96], the MRC
trial [49] and the Eastern Cooperative Oncology
Group (ECOG) 7887 study [133]}, which were
all conducted in the pre-PSA era and included
patients with advanced CaP who received early
vs deferred ADT as primary therapy or adjuvant
to RP, but not to radiotherapy. According to the
analysis, early androgen suppression significantly
reduces disease progression and complication
rates due to the progression itself, but does not
improve cancer-specific survival and provides a
relatively small benefit in overall survival with an
absolute risk reduction of 5.5%, which does not
become evident until after 10 years [134]. Based
on a systematic review of the literature, the recently published American Society of Clinical
Oncology Guidelines on the initial hormonal
148
treatment for androgen-sensitive metastatic, recurrent or progressive CaP concluded that no
recommendation can be made as to when to start
hormonal therapy in advanced asymptomatic
CaP until data from studies using modern diagnostic and biochemical tests and standardized
follow-up schedules become available [135].
Summary of Guidelines of Hormonal Therapy
1. In advanced CaP, ADT delays progression,
prevents potentially catastrophic complications and effectively palliates symptoms, but
does not prolong survival (level of evidence:
1b).
2. In advanced CaP, all forms of castration as
monotherapy (orchiectomy, LHRH and DES)
have equivalent therapeutic efficacy (level of
evidence: 1b).
3. Non-steroidal anti-androgen monotherapy
(e.g. bicalutamide) is an effective alternative
to castration in patients with locally advanced
disease (level of evidence: 1b).
4. In advanced CaP, the addition of a non-steroidal anti-androgen to castration (CAB) results in a small advantage in overall survival
over castration alone but is associated with
increased adverse events, reduced QoL and
high costs (level of evidence: 1a).
Axel Heidenreich
5. Intermittent and вЂњminimalвЂќ ADT should still
be regarded as experimental therapies (level
of evidence: 3).
6. In advanced CaP, immediate (given at diagnosis) androgen suppression significantly reduces disease progression and complication
rate due to progression itself compared to deferred (delivered at symptomatic progression)
androgen deprivation (level of evidence: 1b).
7. Bilateral orchiectomy may be the most costeffective form of ADT, especially if initiated
after occurrence of symptoms from metastatic
disease (level of evidence: 3).
Tables 9.6 and 9.7 summarize the guidelines
for primary treatment of prostate cancer at different stages.
Follow-up of Prostate Cancer Patients
Patients diagnosed with prostate cancer are usually followed life-long or until high age makes
follow-up superfluous. Determination of serum
PSA and a disease-specific history supplemented
by DRE are the cornerstones in the follow-up of
prostate cancer patients. Routine imaging procedures in stable patients are not recommended
and should only be used in specific situations.
The follow-up intervals and necessary follow-
Table 9.6 Guidelines for follow-up after treatment with curative intent
1. In asymptomatic patients, a disease-specific history and a serum PSA measurement supplemented by DRE are the
recommended tests for routine follow-up. These should be performed at 3, 6 and 12 months after treatment, then
every 6 months until 3 years, and then annually (grade B recommendation)
2. After radical prostatectomy, a serum PSA level of more than 0.2 ng/ml can be associated with residual or recurrent
disease (grade B recommendation)
3. After radiation therapy, a rising PSA level, rather than a specific threshold value, is the most reliable sign of
persistent or recurrent disease (grade B recommendation)
4. Both a palpable nodule and a rising serum PSA level can be signs of local disease recurrence (grade B
recommendation)
5. Detection of local recurrence by TRUS and biopsy is only recommended if it will affect the treatment plan In most
cases; TRUS and biopsy are not necessary before second-line therapy (grade B recommendation)
6. Metastasis may be detected by pelvic CT/MRI or bone scan. In asymptomatic patients these examinations may be
omitted if the serum PSA level is less than 30 ng/ml, but data on this topic are sparse (grade C recommendation)
7. Routine bone scans and other imaging studies are not recommended in asymptomatic patients. If a patient has
bone pain, a bone scan should be considered irrespective of the serum PSA level (grade B recommendation)
9 Guidelines and Counselling for Treatment Options in the Management
up tests have not been well-studied; often these
need to be individualized. Table 9.6 outlines the
guidelines for follow-up after therapy of curative intent; Table 9.7 summarizes follow-up after
hormonal therapy. Patients initially managed by
active monitoring (no active therapy) need individual follow-up, depending on the future aims
of therapy and tumour characteristics.
149
Treatment of Relapse After Curative Therapies
Before reviewing treatments of relapse after curative therapy (Table 9.8), we need to define local
and systemic failure after RP.
вЂ“ Local failure following RP is predicted with
an 80% probability by PSA increase more
than 3 years after RP, a PSA doubling time
Table 9.7 Guidelines for follow-up after hormonal treatment
1. Patients should be evaluated at 3 and 6 months after initiating treatment. Tests should include at least serum PSA
measurement, DRE and careful evaluation of symptoms in order to assess the treatment response and the sideeffects of treatments given (grade B recommendation)
2. Follow-up should be tailored to the individual patient, according to symptoms, prognostic factors and the
treatment given (grade C recommendation)
3. In patients with stage M0 disease with a good treatment response, follow-up is scheduled every 6 months, and
should include at least a disease-specific history, DRE and serum PSA determination (grade C recommendation)
4. In patients with stage M1 disease with a good treatment response, follow-up is scheduled for every 3вЂ“6 months.
A minimal follow-up should include a disease-specific history, DRE and serum PSA determination, frequently
supplemented with haemoglobin, serum creatinine and alkaline phosphatase measurements (grade C
recommendation)
5. When disease progression occurs or if the patient does not respond to the treatment given, the follow-up needs to
be individualized (grade C recommendation)
6. Routine imaging in stable patients is not recommended (grade B recommendation)
Table 9.8 Guidelines on second-line therapy after curative treatments
Recommendations
Presumed local failure after RP: Patients with presumed local failure only may be candidates for salvage
radiotherapy. This should be given with at least 64 Gy and preferably before PSA
has risen above 1.5 ng/ml. Other patients are best offered a period of watchful
waiting (active monitoring) with possible hormonal therapy later on (grade B
recommendation)
Presumed local failure after RT: Selected patients may be candidates for salvage radical prostatectomy (or
other curative efforts), although patients should be informed concerning the
comparatively high risk of complications. Other patients are best offered a period
of watchful waiting (active monitoring) with possible hormonal therapy later on
(grade C recommendation)
Presumed distant В±/в€’ local
failure:
There is some evidence that early hormonal therapy may be of benefit in delaying
progression and possibly achieve a survival benefit in comparison with delayed
therapy. The results are not without controversy. Local therapy is not recommended
except for palliative reasons (grade B recommendation)
150
Axel Heidenreich
Table 9.9 Guidelines for secondary hormonal, cytotoxic and palliative management in patients with hormone refractory prostate cancer
Hormonal manipulations
1. Castration levels of testosterone should be maintained also in hormone refractory patients (grade C
recommendation)
2. Administration of all anti-androgens has to cease once PSA progression is documented (grade B
recommendation)
3. After discontinuation of flutamide or bicalutamide, after 4 weeks and 6 weeks, respectively, the anti-androgen
withdrawal (AAW) effect will become apparent (grade B recommendation)
4. The combination of ketoconazole and AAW results in significantly better PSA response rates and longer time
to progression than AAW alone, but the side-effects of ketoconazole need to be taken into account (grade B
recommendation)
5. No clear-cut recommendation can be made regarding the most effective drug for secondary hormonal
manipulations since no data from randomized trials are available (grade C recommendation)
Cytotoxic therapy
1. In patients with a PSA rise only two consecutive increases of PSA serum levels above a previous reference level
should be documented (grade B recommendation)
2. Prior to treatment PSA serum levels should be >5 ng/ml to assure correct interpretation of therapeutic efficacy
(grade B recommendation)
3. Potential benefits of cytotoxic therapy and expected side-effects should be discussed with each individual patient
(grade C recommendation)
4. In patients with metastatic HRPCA docetaxel at 75 mg/m2 every 3 weeks results in a significant survival benefit
and represents the reference treatment (grade A recommendation)
5. In patients with symptomatic osseous metastases due to HRPCA either docetaxel or mitoxantrone with
prednisone or hydrocortisone are viable therapeutic options (grade A recommendation)
Palliative management
1. Bisphosphonates may be offered to patients with skeletal metastases (mainly zoledronic acid has been studied) to
prevent osseous complications (grade A recommendation)
2. Palliative treatments such as radionuclides, external beam radiotherapy; adequate use of analgesics should be
considered early on in the management of painful osseous metastases (grade B recommendation)
(PSADT) of 11 months or more, a Gleason
score of 6 of higher, and stage being pT3a
pN0, pTx R1 or earlier (Table 9.8 and 9.9).
вЂ“ Systemic failure following RP is predicted
with a greater than 80% accuracy by a PSA
increase less than 1 year after RP, PSADT of
4вЂ“6 months, a Gleason score 8вЂ“10 and stage
pT3b, pTxpN1.
вЂ“ Local failure after radiation therapy is documented by a positive prostatic biopsy and
negative imaging studies.
вЂ“ Prostatic biopsy after radiation therapy is only
necessary if local procedures such as salvage
prostatectomy are indicated in an individual
patient.
Diagnostic Procedure in Patients with PSA Relapse
1. Following RP, CT scans of the pelvis and abdomen are of low sensitivity and specificity in
patients with PSA levels of less than 20 ng/ml
or a PSA velocity of less than 20 ng/ml per
year.
2. Endorectal MRI or PET scans may help to
detect local recurrences if PSA is greater than
1вЂ“2.0 ng/ml, but this is not yet part of routine
clinical use.
3. If available, the capromab pendetide scan
shows a diagnostic yield of 60% to 80% independent of the PSA serum level.
9 Guidelines and Counselling for Treatment Options in the Management
4. Following radiation therapy, local recurrence
is documented by a positive biopsy 18 months
or later after the procedure.
Management of PSA Relapse After RP
вЂ“ Local recurrences are best treated by salvage
radiation therapy with 64вЂ“66 Gy at a PSA serum level at 1.5 ng/ml or less (grade B recommendation).
вЂ“ Expectant management is an option for patients with presumed local recurrence unfit
for, or unwilling to undergo, radiation therapy
(grade B recommendation).
вЂ“ PSA recurrence indicative of systemic relapse is best treated by early ADT resulting
in decreased frequency of clinical metastases
(grade B recommendation).
вЂ“ LHRH analogues/orchiectomy or bicalutamide at 150 mg/day can both be used when
there is indication for hormonal therapy (Table 9.7; grade A recommendation).
151
offered a period of watchful waiting (active
monitoring) with possible hormonal therapy
later on (grade B recommendation).
2. Presumed local failure after RP
Selected patients may be candidates for salvage RP after radiotherapy, although patients
should be informed concerning the comparatively high risk of complications. Other
patients are best offered a period of watchful waiting (active monitoring) with possible
hormonal therapy later on (grade C recommendation).
3. Presumed distant
There is some evidence that early hormonal
therapy may be of benefit in local failure
combined with distant occult metastases delaying progression, and such patients may
possibly achieve a survival benefit in comparison with delayed therapy. The results are
not without controversy. Local therapy is not
recommended except for palliative reasons
(Table 9.8; grade B recommendation).
Treatment of Relapse After Hormonal Therapy
Management of PSA Relapse After Radiation
Therapy
вЂ“ Local recurrences may be treated by salvage
RP in carefully selected patients (grade C recommendation).
вЂ“ CSAP and interstitial brachytherapy are alternative experimental procedures in patients
not suitable for surgery (grade C recommendation).
вЂ“ ADT is an option in patients with presumed
systemic relapse (grade B recommendation).
Guidelines for Second-Line Management
After Curative Treatment
1. Presumed local failure after radical radiotherapy
Only patients with presumed local failure
may be candidates for salvage radiotherapy.
This should be given with at least 64 Gy and
preferably prostatectomy before PSA has
risen above 1.5 ng/ml. Other patients are best
Patients experiencing relapse after hormonal
therapy (Table 9.9) are usually in a more advanced disease stage and will usually become
symptomatic within a relatively short time after the start of PSA rise. First PSA rise following hormonal therapy refers to androgen-independent PCA being sensitive to secondary
hormonal manipulations, including anti-androgen withdrawal and the addition of anti-androgens, oestrogenic compounds and adrenolytic
agents, as well as other novel approaches [136].
PSA progression following secondary endocrine
treatment refers to the state of true hormone
refractory prostate cancer. Patients with hormone-refractory prostate cancer are not curable, and maintaining or improving QoL should
be a main goal. In most cases the decision to
treat or not to treat is made based on counselling of the individual patient, which limits the
role of guidelines.
152
Secondary Hormonal Manipulations
Anti-androgen Withdrawal Syndrome
In 1993, Kelly and Scher [137] reported clinical
and PSA responses in men who discontinued flutamide therapy upon development of progressive
disease. Approximately one-third of patients respond to anti-androgen withdrawal as indicated
by at least a 50% PSA decrease with a median
duration of response of approximately 4 months.
Anti-androgen withdrawal responses have also
been reported after treatment with bicalutamide
and megestrol acetate [138вЂ“140]. The availability
and more favourable toxicity profile of secondary hormonal therapies allow the clinician to
consider these drugs for the growing category of
asymptomatic patients for whom chemotherapy
is difficult to justify, but who, due to increasing
serum PSA level, want treatment outside clinical trials. However, observation remains a viable
choice for asymptomatic patients.
Approximately 10% of circulating androgen
in humans is secreted by the adrenal glands. In
androgen-independent states, some tumour cells
must retain sensitivity to androgens, as a further
decrease in circulating androgen levels by bilateral adrenalectomy or drugs that inhibit adrenal
steroidogenesis can induce a clinical response.
The simultaneous addition of ketoconazole to
anti-androgen withdrawal, however, results in
a significantly increased PSA response (32% vs
11%) and a longer time to PSA progression (8.6
vs 5.9 months) compared to anti-androgen withdrawal alone [141], as has been documented in
a recent, prospective, randomized phase III trial
including 260 patients with androgen-independent CaP. In a recent prospective randomized
clinical phase II trial, ketoconazole was demonstrated to be significantly more effective than
estramustine phosphate with regard to PSA response (67% vs 29%) and time to progression
(7.9 vs 3.2 months).
Non-hormonal Therapy (Cytotoxic Agents)
Based on prospective randomized clinical
phase III trials, several proven chemotherapeutic options are available for the management of
Axel Heidenreich
HRPC with metastatic disease. In two recent
phase III trials, a significant improvement in median survival of approximately 2 months could be
demonstrated for docetaxel-based chemotherapy
as compared to a combination of mitoxantrone
and prednisone [143, 144]. In the TAX 327 study
[143], 1,006 patients with metastatic HRPC
were randomly assigned to mitoxantrone at
12 mg/m2 every 3 weeks, docetaxel at 75 mg/m2
every 3 weeks, or docetaxel at 30 mg/m2 weekly
for 5 of every 6 weeks. The median survival was
16.5 months in the mitoxantrone group and
18.9 months (p<0.001) and 17.4 months in the
docetaxel 75 mg/m2 every 3 weeks and docetaxel
30 mg/m2 for 5 of every 6 weeks, respectively.
A 50% or greater PSA decline was achieved
in 45% and 48% of men in the docetaxel-treated
groups compared to 32% in the mitoxantrone
group (p<0.001). Significant pain reduction was
achieved in 22% of the patients in the mitoxantrone group compared to 35% (p=0.01) and 31%
(p=0.08) in the docetaxel-treated groups. Adverse
events were similar among the different treatment groups. However, QoL was significantly
improved in both docetaxel-treated groups.
In the Southwest Oncology Group (SWOG)
99-16 trial [143], 674 patients with metastatic
HRPC were randomly assigned to receive mitoxantrone at 12 mg/m2 every 3 weeks or docetaxel
and estramustine at 60 mg/m2 every 3 weeks. In
an intention-to-treat analysis, the median survival was 17.5 months and 15.6 months (p=0.02)
in the docetaxel and the mitoxantrone groups, respectively. Also, the median time to progression
was significantly longer in the docetaxel group
with 6.3 months compared with 3.2 months in
the mitoxantrone group (p<0.001). A PSA decline of 50% or more was achieved in 50% and
27% patients of the docetaxel and the mitoxantrone group, respectively. Pain relief was similar
between both groups, though side-effects occurred significantly more often in the docetaxel
group.
Despite these encouraging results, the time
point to initiate a cytotoxic regime in patients
with HRPC remains controversial. Although it
appears evident that chemotherapy should be
started in patients with metastatic HRPC, there
are no data available with regard to the therapeutic efficacy of early chemotherapy in patients
9 Guidelines and Counselling for Treatment Options in the Management
with PSA rise only. There at least exists the recommendation that two consecutive increases in
PSA over a previous reference value should exists and that the PSA level should exceed 5 ng/ml
[135]. Therefore, the indication for the initiation
of chemotherapeutic regimes has to made on an
individual basis.
Mitoxantrone with corticosteroids [145, 146]
has been extensively studied primarily in patients
with symptomatic osseous lesions due to HRPC.
In the Cancer and Leukemia Group B (CALGB)
9182 study [146], 244 patients with symptomatic
metastatic HRPC were randomized to either
receive mitoxantrone plus hydrocortisone at
12 mg/m2 every 3 weeks or to hydrocortisone
alone. Although no differences were observed
with regard to survival, PSA response and median time to progression, QoL was significantly
improved in the combination arm. In the other
trial [30], 161 men with painful osseous metastases due to HRPC were randomized to receive
mitoxantrone plus prednisone compared to
prednisone alone. A significant benefit in terms
of pain reduction was observed in the combination group (29%) compared to prednisone alone
(12%, p=0.01); furthermore, duration of palliation was longer in patients who received mitoxantrone (43 vs 18 weeks, p<0.0001). There were
no significant differences with regard to PSA response and median survival time. Although none
of the studies demonstrated any survival benefit
for the patients, QoL was improved significantly
due to pain reduction.
Palliative Therapeutic Options
The majority of patients with HRPC have painful
bone metastases. The two beta-emitting radioisotopes, strontium-89 and samarium-153, can partially or completely decrease bone pain in up to
70% of patients. Early use can make subsequent
administration of chemotherapy more difficult
because of myelosuppression [147, 148]. Critical
issues of palliation must be addressed while considering additional systemic treatment, including management of pain, constipation, anorexia,
nausea, fatigue and depression, which frequently
occur (i.e. with palliative external beam radiation, cortisone, analgesics and anti-emetics).
153
Common complications due to skeletal metastases include bone pain, vertebral collapse
or deformity, pathologic fractures and spinal
cord compression. Recently, the use of bisphosphonates to inhibit osteoclast-mediated bone
resorption and activity of osteoclast precursors
has demonstrated a clinically significant effect in
terms of prevention of skeletal complications and
reduction of pain, or even total pain relief, in patients with HRPC. In the largest single phase III
trial [149], 643 men with HRPC metastatic to
the bone were randomized to receive zoledronic
acid at 8 mg or 4 mg every 3 weeks for 15 consecutive months or placebo. At 15 months and
at 24 months of follow-up, there was a significant reduction in skeletal-related events in the
zoledronic acid-treated group as compared to
the placebo group (44% vs 33%, p=0.021). The
frequency of pathological fractures was significantly lower in the zoledronic acid group compared with the placebo group (13.1% vs 22.1%,
p=0.015). Furthermore, the time to first skeletalrelated event was significantly prolonged in the
zoledronate group thereby significantly improving QoL. Currently, bisphosphonates could be
proposed to patients with HRPC bone metastases in order to prevent skeletal complications.
Pain due to osseous metastases is one of
the most debilitating complications of HRPC.
Bisphosphonates have been proved to be highly
effective with a response rate of 70%вЂ“80%,
which, associated with a low frequency of sideeffects, makes bisphosphonates to be an ideal
medication for palliative therapy of advanced
HRPC [150, 151]. Bisphosphonates should be
considered early in the management of symptomatic HRPC.
Hormone refractory CaP is usually a debilitating disease, often affecting the elderly male. A
multidisciplinary approach is required with input
from medical oncologists, radiation oncologists,
urologists, nurses and social workers [90].
Summary on Treatment
After Hormonal Therapy
вЂ“ It is recommended to cease anti-androgen
therapy once PSA progression is documented
(grade B recommendation).
154
вЂ“ Four to six weeks after discontinuation of flutamide or bicalutamide, an eventual anti-androgen withdrawal (AAW) effect will become
apparent (grade B recommendation).
вЂ“ No clear-cut recommendation can be made
regarding the most effective drug for secondary hormonal manipulations since data from
randomized trials are scarce (grade C recommendation).
Guidelines and Recommendations
for Cytotoxic Therapy in HRPC
1. In patients with a PSA rise only, two consecutive increases of PSA serum levels above a previous reference level should be documented
(grade B recommendation).
2. Prior to treatment, PSA serum levels should
be greater than 5 ng/ml to assure correct interpretation of therapeutic efficacy (grade B
recommendation).
3. Potential benefits of cytotoxic therapy and expected side-effects should be discussed with
each individual patient (grade C recommendation).
4. In patients with metastatic HRPCA, and who
are candidates for cytotoxic therapy, docetaxel
at 75 mg/m2 every 3 weeks has shown a significant survival benefit (grade A recommendation).
5. In patients with symptomatic osseous metastases due to HRPCA, either docetaxel or
mitoxantrone with prednisone or hydrocortisone are viable therapeutic options (grade A
recommendation).
Axel Heidenreich
Recommendations for Palliative Management
of HRPC
1. Bisphosphonates may be offered to patients
with skeletal metastases (mainly zoledronic
acid has been studied) to prevent osseous
complications (grade A recommendation)
2. Palliative treatments such as radionuclides,
external beam radiotherapy, adequate use of
analgesics should be considered early on in
the management of painful osseous metastases (grade B recommendation).
Summary
The present text represents a summary and for
more detailed information and a full list of references, we refer to the full-text version. These
EAU guidelines (ISBN 90-70244-27-6) are available at the website of the European Association
of Urology: http://www.uroweb.org.
References
1.
2.
3.
Guidelines for Palliative Management of HRPC
1. Patients with symptomatic and extensive osseous metastases cannot benefit from medical
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10
Choices for Surgery
StГ©phane LarrГ©, Laurent Salomon, Claude ClГ©ment Abbou
Recent Results in Cancer Research, Vol. 175
В© Springer-Verlag Berlin Heidelberg 2007
Abstract
Surgical treatment of prostate cancer has seen
many improvements in the past two decades, including laparoscopy, robotic surgery, and better
assessment of quality of life and functional results.
The limits of surgery for locally advanced disease
and after failure of radiotherapy have been better
defined, together with the roles of neoadjuvant
and adjuvant treatment. Patients with clinically
organ-confined prostate cancer, reasonable life
expectancy, and little or no co-morbidity are the
best candidates for radical prostatectomy. This
chapter reviews the different technical options
for the treatment of prostate cancer, with their
respective indications and functional and oncological results.
Techniques of Radical Prostatectomy
Radical prostatectomy consists of removing the
whole prostate gland and the seminal vesicles.
Three approaches can be used: the retropubic
approach, the perineal approach, and the laparoscopic approach.
Retropubic Prostatectomy
The retropubic approach is the reference technique. It is widely used and is described in detail
elsewhere. The current вЂњgold standardвЂќ technique, described by Walsh in 1983, has been
combined with new nerve-sparing techniques
giving better preservation of erectile function
(Walsh et al. 1983). Blood loss has been limited
by better control of the Santorini venous complex (Barre et al. 1999; Avant et al. 2000), and
continence is now recovered sooner (Walsh and
Marschke 2002).
Perineal Prostatectomy
Radical perineal prostatectomy was the surgical
treatment of choice for localized adenocarcinoma
of the prostate until the 1980s, when radical retropubic prostatectomy began to gain popularity.
The perineal technique is extensively described
in the literature (Weldon and Tavel 1988; Weldon
2002). Compared to the suprapubic approach,
the perineal approach is associated with less
bleeding, less pain, shorter hospitalization, and
easier urethrovesical anastomosis (Weldon and
Tavel 1988; Frazier et al. 1992; Walther 1993;
Haab et al. 1994; Salomon et al. 1997; Weldon et
al. 1997; Kahn et al. 1998; Lance et al. 2001; RuizDeya et al. 2001; Korman et al. 2002). It seems
to be at least as easy to learn as retropubic prostatectomy (Mokulis and Thompson 1997) and is
less invasive.
The main problem with this approach is that
lymph node dissection cannot be performed via
the same incision, and some authors therefore
advocate laparoscopic lymph node dissection
prior to prostate surgery (Parra et al. 1994; Teichman et al. 1995).
In addition, the development of retropubic
radical prostatectomy has permitted surgeons to
better define the indications of the lymph nodes
dissection according to the clinical stage, the
prostate-specific antigen (PSA) level, and biopsy
findings. Lymph node involvement is very rare
when PSA is less than 10 ng/ml, rectal examination is normal, and the Gleason biopsy score
is less than 7 (Bishoff et al. 1995; Bluestein et al.
1994). Lymph node dissection is optional for
164
StГ©phane LarrГ©, Laurent Salomon, Claude ClГ©ment Abbou
such patients, and radical perineal prostatectomy
is thus a good option. Nonetheless, this approach
has not become as popular as the retropubic approach, and it is now being gradually discarded
in favor of the laparoscopic approach.
Laparoscopic Prostatectomy
The laparoscopic approach to radical prostatectomy was gradually developed in the second part
of the 1990s, initially by French surgeons. Abbou
et al. (2000), Gaston et al. (Curto et al. 2006) and
Guillonneau et al. (Guillonneau and Vallancien
2000) developed an intraperitoneal approach.
The extraperitoneal approach was not very
popular at the beginning of the epoch of laparoscopic prostatectomy, even if the technique was
described approximately at the same time as the
transperitoneal approach (Raboy et al. 1997).
Transperitoneal Laparoscopic
Radical Prostatectomy
The transperitoneal approach requires a marked
Trendelenburg position, and usually begins with
seminal vesicle dissection via a direct approach
above DouglasвЂ™ sac. Dissection of the prostate
is then usually performed by an antegrade approach from the seminal vesicles to the prostate
apex (Guillonneau and Vallancien 2000; Hoznek
et al. 2003; Curto et al. 2006), but retrograde dissection has also been described from the prostate
apex to the seminal vesicles (Dubernard et al.
2003; Rassweiler et al. 2004).
Extraperitoneal Radical Prostatectomy
Abbou et al. (Hoznek et al. 2003) and others (Bollens et al. 2001; Stolzenburg et al. 2005) switched
to the extraperitoneal approach for several reasons. First, it avoids abdominal complications
such as gastrointestinal wounds, peritoneal urine
leakage from the anastomosis, postoperative pain
from the pneumoperitoneum, and occlusion secondary to incarceration of small ileal loops in
front of the bladder. It also permits adjuvant radiotherapy sparing the gastrointestinal tract, and
avoids possible dissemination of tumor cells into
the peritoneal cavity. The Trendelenburg position
can be avoided, and the technique reproduces the
same approach as the open retropubic approach.
In case of laparoconversion, the surgeon finds
himself in a more familiar situation (Bollens et
al. 2001; Hoznek et al. 2003; Stolzenburg et al.
2005). Normal feeding can resume more rapidly
(Hoznek et al. 2003). Creation of the working
space and the lack of initial dissection of the seminal vesicles may shorten the operation (Hoznek
et al. 2003; Cathelineau et al. 2004), although this
is still controversial for some authors (Erdogru
et al. 2004). In case of gross obesity, previous abdominal surgery, or simultaneous inguinal hernia repair, the extraperitoneal approach is simpler than the intraperitoneal approach (Erdogru
et al. 2004). No randomized studies have so far
compared the two approaches, but the intraperitoneal approach does not seem to be associated
with any significant advantages or disadvantages
in terms of complications, functional outcomes,
or carcinological results. Therefore, the choice
of the laparoscopic approach will depend on
the preference and experience of the individual
surgeon (Cathelineau et al. 2004; Erdogru et al.
2004).
Robot-Assisted Radical Prostatectomy
One of the main difficulties associated with laparoscopic prostatectomy is the length of the learning curve. It has been suggested that at least 40
procedures are necessary to achieve an acceptable operating time and complication rate. Laparoscopic robotic assistance can restore two of
the six degrees of freedom that are missing with
standard laparoscopy. The feasibility and reproducibility of robot-assisted laparoscopic radical
prostatectomy are now well-documented (Abbou
et al. 2001; Binder and Kramer 2001; Pasticier et
al. 2001; Rassweiler et al. 2001; Gettman et al.
2003; Menon et al. 2003). The largest published
series comes from the Vattikuti Institute, where,
compared to the laparoscopic technique, the use
of the Da Vinci system was associated with less
operating-room time, less estimated blood loss,
and a shorter median time to urinary continence
(Menon et al. 2005). For the surgeon, robotic as-
10 Choices for Surgery
sistance offers a more ergonomic environment
that might shorten the learning curve. This technology is still under active development, and future developments, including 5-mm instruments
with enhanced articulation, the availability of a
fourth arm (for solo surgery), arms installed in
the roof, or three-channel optical systems allowing a panoramic view, may also help simplify
and securitize the procedure. The main problem
will be one of cost, especially for small centers.
At least 10 robotically assisted radical prostatectomies would have to be performed every week
to be cost-effective compared to open retropubic
radical prostatectomy (Scales et al. 2005).
Differences Between Open
and Laparoscopic Radical Prostatectomy
Only a few studies have prospectively compared
the open retropubic approach to the laparoscopic
approach, and none was randomized (Anastasiadis et al. 2003; Bhayani et al. 2003; Hara et al.
2003; Roumeguere et al. 2003).
The main advantages of the laparoscopic approach relative to the retropubic approach are
a lower risk of bleeding and lesser analgesic requirements, with patients becoming active more
rapidly (4 weeks instead of 6) (Bhayani et al. 2003;
Hara et al. 2003; Farnham et al. 2006; Roumeguere
et al. 2003). The main disadvantages are the longer operating time, the longer learning curve,
and shorter oncological follow-up (the results
are currently similar with the two approaches).
The excision margins are the same, and no major differences in long-term oncological outcome
are therefore expected (Bhayani et al. 2003; Hara
et al. 2003; Roumeguere et al. 2003; Salomon et
al. 2002; Anastasiadis et al. 2003; Hoznek et al.
2005). Likewise, no major differences in functional results have been observed. With the laparoscopic approach, some authors have reported
more rapid recovery of continence (Anastasiadis
et al. 2003) while other authors have found slower
recovery (Roumeguere et al. 2003). Concerning
erectile function, the laparoscopic approach has
been linked to lesser sildenafil use (Roumeguere
et al. 2003), but sexual dysfunction is still a problem with both approaches. There are probably no
major differences between the laparoscopic and
165
open approaches as regards recovery of potency,
based on a series of patients with the same age in
which the same principles and techniques were
used (meticulous tissue handling and avoidance
of electrocautery; Hoznek et al. 2005).
Complications of Radical Prostatectomy
Perioperative Complications
The surgical mortality rate is now below 0.5% in
most studies, whatever the technique, all deaths
being of cardiorespiratory origin (Lu-Yao et
al. 1999; Anastasiadis et al. 2003; Bhayani et al.
2003; Hara et al. 2003; Roumeguere et al. 2003).
Hemorrhage is the most common intraoperative problem with open prostatectomy, but the
proportion of patients who need blood transfusion has fallen from 30% to less than 5% (Barre
et al. 1999; Avant et al. 2000). The use of the laparoscopic approach is associated with less bleeding: mean estimated blood loss is 250вЂ“500 ml,
representing no more than two-thirds of the volume lost during retropubic approaches (Bhayani
et al. 2003; Roumeguere et al. 2003; Farnham
et al. 2006). Improved control of the Santorini
plexus can nonetheless reduce blood loss to below 400 ml in open procedures (Barre et al. 1999;
Avant et al. 2000). However, blood loss is difficult to estimate precisely, as blood is mixed with
urine, and the blood transfusion rate is therefore
a more reliable measure (even if some centers
systematically reinfuse autologous blood collected before prostatectomy).
Rectal injuries are less frequent but can be
responsible for significant morbidity when not
diagnosed immediately. These injuries are more
frequent with the perineal approach than with
other approaches (Lance et al. 2001). The overall
rates are approximately 1%вЂ“2% for the suprapubic and laparoscopic procedures, and 1%вЂ“6% for
the perineal approach. Obturator nerve injury
(<0.5%) and ureteral injury (0.1%) are other very
rare intraoperative complications. The transperitoneal laparoscopic approach can also be associated with occasional gastrointestinal lesions. The
perineal approach can be associated with hypesthesia of the lower limbs due to hyperflexion,
and with pelvic cellulites.
166
StГ©phane LarrГ©, Laurent Salomon, Claude ClГ©ment Abbou
Potential post-surgical complications include
delayed bleeding (0.5%), lymphocele (3.4%), scar
infection (1.5%), deep vein thrombosis (2.6%),
pulmonary artery thrombosis (<0.5%), and
myocardial infarction (0.6%). (Harpster et al.
1995; Haggman et al. 1996; Lu-Yao et al. 1999;
Hoznek et al. 2001; Lance et al. 2001; Fichtner et
al. 2003).
The risk of complications correlates with preexisting comorbidity and with blood loss, but
not with age or the length of the procedure. The
surgeonвЂ™s experience and skill are also key factors
(Dillioglugil et al. 1997; Begg et al. 2002; Bianco
et al. 2005).
Postoperative Complications
Urinary incontinence is common after surgery but usually resolves within 3 to 6 months.
When incontinence is still present after 1 year it
is unlikely to improve spontaneously. In a large
series, 81% of patients did not need protection after 1 year, but the results can be worse in
smaller centers (Murphy et al. 1994). Serious incontinence is reported in 3.4% of patients. The
artificial sphincter is then a good option, with
excellent long-term results (Elliott and Barrett
1998; Mottet et al. 1998). Risk factors for postoperative incontinence include older age, previous
transurethral resection of the prostate, and postoperative anastomotic stricture. Postoperative
anastomotic stricture may occur in 0.5%вЂ“9% of
cases, and is more frequent in patients with major intraoperative bleeding, a transanastomotic
fistula, or previous transurethral resection of the
prostate (Dillioglugil et al. 1997).
Erectile dysfunction is also frequent after
radical prostatectomy, whatever the approach
used. Impotence is the rule unless a nerve-sparing procedure is used. The results obtained with
nerve-sparing techniques are difficult to compare because of different definitions of erectile
dysfunction and the use of different assessment
methods. It seems that at least 18 months must
elapse before erectile function can be reliably
evaluated (Walsh et al. 2000; Kim et al. 2001).
Many factors may influence the results, such as
the surgical technique (unilateral or bilateral
nerve-sparing technique, or none), the patientвЂ™s
age, and erectile status prior to surgery (Walsh
et al. 2000). These factors explain why potency
rates vary from 30% to 86% 12вЂ“18 months following surgery with a nerve-sparing technique
(Stanford et al. 2000; Walsh et al. 2000; Kim et al.
2001; Hoznek et al. 2005).
Reduced penis size is another recently reported complication of prostatectomy (Fraiman
et al. 1999; Savoie et al. 2003). Stretched penile
length measured 3 months after radical retropubic prostatectomy diminished in two-thirds of
patients, from 13 cm (median) to 12.5 cm. One
in five patients had at least a 15% decrease in penis length (Savoie et al. 2003). The precise reasons for this decrease are unknown, but hypoxia
and denervation could lead to apoptosis of penile erectile tissue cells and cause fibrosis or loss
of cavernous smooth muscle cells (Klein et al.
1997); the latter was found in approximately 40%
of patients with erectile dysfunction after radical
prostatectomy (Ciancio and Kim 2000). However, no correlation between penile extensibility
and the degree of smooth muscle fibrosis in the
corpora cavernosa was found, making this explanation unlikely (Moreira de Goes et al. 1992).
Other parameters like prostate volume, previous
potency status, and nerve-sparing surgery were
not related to penile size changes (Savoie et al.
2003).
Oncological Results
The oncological results of surgery for prostate
cancer are best evaluated in terms of the percentage of patients who are still PSA-free after a
defined period, for example 5 or 10 years. Biochemical recurrence after surgery is generally diagnosed when two or more PSA values are higher
than 0.2 ng/ml. Global and specific survival rates
compared to watchful waiting are discussed below, along with locally advanced disease and salvage prostatectomy. Comparison to radiotherapy
is detailed in Chap. 11
Many factors may influence the risk of recurrence. The more advanced the tumor, the higher
the risk of recurrence. Advanced tumors are
more likely when preoperative PSA levels, clinical stage, pathological stage, and the Gleason
score are high. Positive margins are also associ-
10 Choices for Surgery
167
ated with a higher risk of recurrence. It is difficult to predict recurrence after prostatectomy,
but nomograms or artificial networks adapted
to each center may be of assistance (Partin et al.
1997; Crawford et al. 2000; Partin et al. 2001).
Globally, in the largest series, the 5-year PSAfree survival rate is 70%вЂ“84% and the 10-year
rate is 52%вЂ“74% (see Table 10.1; Zincke et al.
1994; Han et al. 2001; Roehl et al. 2004).
Role of Lymph Node Dissection
in Radical Prostatectomy
Advantages of Lymph Node Dissection
Lymph node dissection is the best way to assess
node status in the patient with prostate cancer.
Lymph node status is a prognostic factor in this
setting (Cheng et al. 1999). Specific mortality
correlates with the number of metastatic nodes
(Smith and Middleton 1985; Golimbu et al. 1987;
Bader et al. 2003). The prognosis is better for patients with microscopic rather than macroscopic
node involvement. It is also likely that removal
of the unique lymph node with microscopic involvement could have a curative effect when
combined with local treatment (Golimbu et al.
1987; Steinberg et al. 1990; Bader et al. 2003).
risk of finding lymph node involvement is very
low. The latter risk obviously correlates with the
extent of lymph node dissection, and with the
patientвЂ™s oncological characteristics (more advanced disease is more likely to have spread to
the lymph nodes).
The probability of finding metastatic lymph
nodes can be assessed with the help of nomograms and artificial networks (Partin et al. 1997;
Crawford et al. 2000; Partin et al. 2001). Because
the chances of finding a metastatic lymph node
is very low when the stage is below T2a, the PSA
is less than 10 ng/ml, the Gleason score is below
7 (with grade 4<50%), and the CT shows no evidence of lymph node enlargement, lymph node
dissection is optional in such cases.
When Is Frozen Section Analysis
of Removed Lymph Nodes Necessary?
Frozen section analysis of lymph nodes is usually
done systematically, as surgery cannot cure metastatic prostate cancer. However, the sensitivity
of the procedure is only about 67%. False-negative results can occur, especially in patients with
nonpalpable micrometastases (Davis 1995).
Therefore, when lymphadenectomy is performed during an open procedure, frozen section analysis is optional when there are no macroscopic signs of lymph node involvement.
When Is Lymph Node Dissection Indicated?
Lymph node dissection is recommended at the
same time as radical prostatectomy, unless the
Table 10.1 Oncological results of radical prostatectomy
Study
Number
of
patients
Mean
5-year
follow-up PSA-free
(months) survival
(%)
10-year
PSAfree
survival
(%)
Roehl et 3,478
al. (2004)
65
80
68
Zincke et 3,170
al. (1994)
60
70
52
Han et al. 2,404
(2001)
75
84
74
Extent of Node Dissection
Lymphadenectomy is currently performed in
one of two ways. Removal of the obturator and
external iliac nodes is known as the modified
way, and removal of both the internal and external iliac nodes is known as the extended way. The
modified way has been the reference for more
than 20 years (Stone et al. 1997; Brendler et al.
1980). The internal iliac nodes are most often involved, and 20%вЂ“30% of node metastases involve
only these nodes; modified lymphadenectomy
may therefore fail to identify such involvement
(Stone et al. 1997; Heidenreich et al. 2002; Bader
et al. 2003; Brenot-Rossi et al. 2005). The extent
of lymphadenectomy does not appear to affect
the outcome of prostate cancer in node-nega-
168
StГ©phane LarrГ©, Laurent Salomon, Claude ClГ©ment Abbou
tive patients, and extended lymphadenectomy
might thus be of limited interest when there is a
low probability of node metastasis (DiMarco et
al. 2005).
Complications of Lymph Node Dissection
Lymph node dissection itself is associated with
increased morbidity and a longer operating time
(Heidenreich et al. 2002; Kavoussi et al. 1993;
Dillioglugil et al. 1997; Link and Morton 2001).
Compared to open procedures, laparoscopic
node dissection is associated with more vascular
and colonic injuries, but with less nerve damage,
lymphocele, infections, deep venous thrombosis,
and bowel occlusion. Altogether, laparoscopy is
associated with only about half the morbidity of
the suprapubic procedure (Kavoussi et al. 1993;
Link and Morton 2001). However, according to
the number of lymph nodes removed, laparoscopic node dissection is generally less extensive
than open procedures.
Extended node dissection was associated with
a complication rate of 10%вЂ“20% in series published before the 1990s (Dillioglugil et al. 1997),
but in recent series published by experienced
teams the difference with limited dissection is
not significant (Heidenreich et al. 2002). The
complication rate of pelvic lymphadenectomy is
around 7%, symptomatic lymphocele being the
most common complication (Dillioglugil et al.
1997).
To prevent complications, lymphatics lateral
to the external artery should be preserved, the
distal ends of the lymphatics should be either ligated or clipped, drains should be placed in each
side of the pelvis, and heparin should be used to
prevent venous thrombosis.
Mini-invasive techniques (mini-open surgery
or laparoscopy) have been developed for removing the external and obturator nodes, with results
comparable to those of the open technique.
These procedures may be less promising than
first thought, as the current trend is toward extended lymph node dissection, which can discover up to 30% of additional metastatic lymph
nodes.
Radical Prostatectomy
for Locally Advanced Disease
Prostate cancer is locally advanced when the
prostate capsule has been breached or the seminal vesicles have been invaded, but without
evidence of metastasis. This stage is associated
with a higher risk of undetectable lymph node
involvement (Boccon-Gibod et al. 2003) in an
estimated 30%вЂ“50% of cases (Peneau et al. 1998).
Prostate cancer staging prior to surgery is inaccurate, however, and 9%вЂ“27% of cT3 patients are
over-staged (Peneau et al. 1998; van den Ouden
et al. 1998; Ward et al. 2005b). These over-staged
patients could probably be cured by surgery
alone, and small pT3 cancers may also be cured
by radical prostatectomy if the tumor and prostate are completely removed (van den Ouden and
Schroder 1998; Van Poppel et al. 2000). Radical
prostatectomy is thus a possible first-line treatment for suspected locally advanced disease in
selected patients (Aus et al. 2005). Surgery is also
more effective than nonsurgical therapies at reducing local morbidity associated with invasion
of surrounding structures. As is the case with
other local treatments performed alone, radical
prostatectomy results are often disappointing for
locally advanced prostate cancer, and hormone
treatment is either added or used alone (Meraney
et al. 2005).
Indications
For patients with clinical T3 stage disease, surgery can be proposed when the PSA is less than
10 ng/ml (up to 20 ng/ml for some authors),
when seminal vesicle invasion is absent, when
the Gleason score is below 8, and when life expectancy is more than 10 years (van den Ouden
and Schroder 2000; Van Poppel et al. 2000; Van
Popple 2005).
Neoadjuvant Hormone Therapy
The large number of locally advanced prostate
cancers that turn out to be metastatic has led
many physicians to use hormone therapy prior
to or after surgery in these cases. Neoadjuvant
10 Choices for Surgery
169
hormone therapy for 3 months reduced prostate
size and the surgical margins rate, but had little
impact on the T stage and no effect on the PSA
recurrence rate at 3 years. (Cher et al. 1995; Soloway et al. 1995; Goldenberg et al. 1996; Hugosson
et al. 1996; Rabbani et al. 1998; Bono et al. 2001).
Surgery was reported to be more difficult, but no
increase in blood loss, the transfusion rate, or the
length of the procedure was observed (Van Poppel et al. 1992; Soloway et al. 1995; Hugosson et
al. 1996).
These initial reports on 3-months neoadjuvant hormone therapy were disappointing, and
longer treatments lasting 4вЂ“8 months were therefore proposed. The results were at least as good
as with neoadjuvant hormone therapy combined
with radiotherapy (Powell et al. 2002), with a decrease in the T stage and specific survival rates
of 76%, 55%, and 32%, respectively, at 5, 10, and
15 years.
More recently, bicalutamide 150 mg daily has
been compared with a placebo in a randomized
study, after local treatment of pT1b-T4NxM0
prostate cancer (Iversen et al. 2004). After 5 years
of follow-up, the bicalutamide group had a 43%
lower risk of disease progression. There was also
a significant improvement in overall survival
among men with locally advanced prostate cancer. The Early Prostate Cancer Program, with
8,000 patients, gave similar results after 5 years
of follow-up, confirming the significant improvement in progression-free survival among men
with locally advanced prostate cancer, but with
no evidence of a beneficial impact on overall
survival (See et al. 2003; Wirth et al. 2005). It
had also been shown that adjuvant bicalutamide
is not appropriate for patients with localized
disease.
Adjuvant Chemotherapy
Adjuvant Hormone Therapy
Many randomized studies have shown that early
adjuvant hormone therapy improves survival in
patients with locally advanced prostate cancers,
with or without lymph node involvement. When
lymph node involvement is present, Messing et
al. have shown that, relative to delayed hormone
treatment, immediate hormone treatment is associated with better overall and specific survival
after 10 years of follow-up (Table 10.2; Messing
et al. 1999, 2006). These results confirmed those
of Seay et al., who reviewed the files of 790 patients with pTxN+ prostate cancer who underwent radical prostatectomy with or without hormone treatment (Seay et al. 1998).
Table 10.2 Survival rates after immediate and delayed
hormone therapy in men with pTxN+ prostate cancer
(Messing et al. 2004)
Overall
survival
Specific
survival
Immediate hormone 74.4%
therapy
87.2%
Delayed hormone
therapy
56%
49%
Adjuvant chemotherapy has proved effective on
progression-free survival in many studies. Estramustine (Akduman and Crawford 2003), mitoxantrone (Wang et al. 2000), epirubicin (Pummer et al. 1997), and, more recently, docetaxel
(Petrylak et al. 2004; Tannock et al. 2004) are
effective on locally advanced prostate cancer. In
hormone-refractory prostate cancer, docetaxel
increases overall survival. Nonetheless, it is not
yet possible to predict which patients will respond
to chemotherapy. Some studies have shown that
patients with muc1 gene overexpression in the
tumor have a higher risk of recurrence, and that
patients with AZGP1 gene overexpression have a
lower risk of recurrence, regardless of the Gleason score and PSA level (Lapointe et al. 2004).
It should eventually be possible in the future to
associate different molecular profiles with treatment responsiveness, as in breast cancer (van вЂ�t
Veer et al. 2002) and some lymphomas (Lossos
et al. 2004).
Technical Aspects
The success of radical prostatectomy for locally
advanced prostate cancer is due to more radical excision and extensive lymph node dissec-
170
StГ©phane LarrГ©, Laurent Salomon, Claude ClГ©ment Abbou
tion. Locally advanced prostate cancers are more
likely to extend into the posterolateral and rectal
periprostatic tissue, especially in the caudal area.
As the lymph ducts of this area drain into the
lymph nodes of the sacrum and the promontory
(Gil-Vernet 1996), it is recommended to perform
extensive resection, including the internal lymph
nodes (Heidenreich et al. 2002). For the same
reasons, the neurovascular bundles are usually
widely resected, especially on the side of the cancer. The contralateral bundle can be spared in
some men with small unilateral T3 prostate tumors. To reduce the risk of positive surgical margins, the posterior plane of resection should be
deep enough under DenonvilliersвЂ™ fascia so that
both layers of the fascia are completely excised.
It is also recommended to fully transect the puboprostatic ligaments in order to permit proper
apical dissection, to avoid positive apical margins, and to perform bladder neck resection with
reconstruction when the cancer is not localized
to the apex (Ward and Zincke 2003; Van Popple
2005).
Complications and Results
The outcome of radical prostatectomy in men
with locally advanced prostate cancer is well
documented in the Mayo Clinic series (Ward
et al. 2005b), which is the largest single-institution experience in the management of cT3 prostate cancer with a mean follow-up of more than
10 years.
Morbidity was similar to that in men with
clinically localized disease. Erectile dysfunction
was observed in 75% of cases, but nerve-sparing techniques were used in only 26% of cases.
Urinary continence at 1 year was achieved in
79% of men staged cT3, and only 6% of men
had severe urinary incontinence (в‰Ґ2 pads/day).
No significant difference in complication rates
was reported by other authors (Davidson et al.
1996). At 10 and 15 years after radical prostatectomy for cT3 disease, respectively 43% and 38%
of patients were free of biochemical recurrence
(vs 61% and 52% for stage cT2). Among patients
with T3/4N0 disease, 60% received adjuvant or
salvage hormone therapy and 40% received adjuvant or salvage radiotherapy. The 10- and 15-year
overall survival rates (76% and 53%) and cancer-specific survival rates (90% and 79%) among
patients with cT3 disease were only moderately
lower than in patients with cT2 disease (82% and
61%, and 96% and 92%, respectively).
Surgery is an effective treatment for locally
advanced disease, as a significant number of patients are at stage pT2 despite clinical signs of
stage T3 disease, and radical prostatectomy can
cure both T2 tumors and small pT3 tumors. In
more advanced cases, radiotherapy is still possible and more accurate information could be
delivered to patients using that strategy.
Salvage Radical Prostatectomy
After failure of radiotherapy, salvage radical
prostatectomy is the only potentially curative for
men with evidence of persistent localized prostate cancer (Stephenson et al. 2004b; Ward et al.
2005a). Showing that the cancer is still localized
is thus crucial for the success of the procedure,
and so is the management of complications.
The oncological results of salvage radical prostatectomy after 5 years follow-up are comparable
to those of first-line radical prostatectomy for a
given pathological stage (Stephenson and Eastham 2005). The probability of localized prostate
cancer is higher when the PSA level is less than
10 ng/ml, and when biopsies of the prostate are
positive at least 1 year after radiotherapy. To be
eligible for salvage radical prostatectomy, patients
must also have no evidence of metastasis, and
must have a life expectancy of at least 10 years
(Stephenson et al. 2004a; Ward et al. 2005a). Patients with troublesome radiation cystitis might
be considered for bladder removal as well. When
these recommendations are respected, 70% of
patients are progression-free at 5 years (Stephenson et al. 2004a; Ward et al. 2005a).
Nonetheless, this technique is challenging,
and surgeons encounter major complications,
especially at the beginning of their experience
(Rogers et al. 1995; Stein et al. 1992; Cheng et al.
1998). Blood transfusion (up to 73% of patients),
rectal injury (up to 15%), anastomotic strictures
(up to 32%), and reoperation (up to 15%) are
more frequent than with first-line radical prostatectomy, and the salvage procedure is associated
10 Choices for Surgery
171
with longer hospital stays. Incontinence is much
more frequent (up to 64%) and the potency rate
is low (less than 16%).
However, with experience, the frequency of
some of these complications can become acceptable, especially that of rectal injuries, blood transfusion, and reoperation (Stephenson et al. 2004a).
The complication rate also seems to be lower after
external beam radiotherapy than after interstitial
radiotherapy. Continence increased with experience, with an incontinence rate of 61% to 44%
after 5 years (Stephenson et al. 2004a; Ward et al.
2005a). The high risk of urinary incontinence is
probably the biggest hindrance to salvage radical
prostatectomy. The potency rate can be increased
by nerve-sparing techniques, but not by nervegrafting procedures. At 5 years, Stephenson et al.
reported a potency rate of 28% with nerve-sparing techniques, and 45% in previously potent patients (Stephenson et al. 2004a).
Laparoscopic techniques have also been used
by Vallancien and colleagues for salvage radical
prostatectomy, with encouraging results on the
first 7 patients after 11 months of follow-up (Vallancien et al. 2003). No major complications were
observed, the mean operating time was 190 min,
mean blood loss was 400 ml, and 5/7 patients remained continent.
Patient qualifying for salvage radical prostatectomy should be informed of the increased
incidence of complications associated with this
procedure. There must be strong evidence that
the prostate cancer is still localized to the prostate, and life expectancy should be more than
10 years. Many complications can occur, including urinary incontinence. Nonetheless, experienced teams can expect to obtain acceptable
complication rates.
Watchful Waiting
Unlike other cancers, prostate cancer is indolent in a significant proportion of men. No impact on longevity or health is observed for many
years when the cancer is diagnosed early. Watchful waiting strategies have thus been developed,
with the introduction of hormone treatment
only when clinical signs occur. Given the mean
age at diagnosis (between 65 and 70 years in
Western countries) there is a significant chance
that the patient will die from another cause. The
benefits of prostate cancer screening and radical
treatment are therefore linked to the patientвЂ™s life
expectancy and to the characteristics of his prostate cancer.
It is now well established that patients with
nonlocalized prostate cancer do not benefit from
local treatment, except for some patients with locally advanced disease (see preceding section).
In men with localized prostate cancer, the
Scandinavian Prostatic Cancer Group Study 4 has
published the first randomized controlled trial to
compare watchful waiting with radical prostatectomy (Holmberg et al. 2002; Steineck et al. 2002),
and the data were recently updated with a median follow-up of 8.2 years (Table 10.3; Steineck
et al. 2002). The trial randomized 695 men with a
mean age of 64.7 years, localized disease, a mean
PSA level of 13 ng/ml, and a Gleason score below
7 in 68% of cases. The trial showed a small advantage in terms of global survival and a strong
advantage in terms of disease-specific mortality
among patients who had radical prostatectomy.
The benefits of radical prostatectomy were
largest in patients under 65 years. It must be
underlined that the study population probably differed from the general population of
Table 10.3 Comparison of mortality rates after radical prostatectomy and watchful waiting, with 10 years of follow-up
(Bill-Axelson et al. 2005)
Radical
prostatectomy
group
Prostate cancer
mortality
Overall mortality
Watchful
waiting group
Relative risk
p-value
9.6%
14.9%
0.56
0.01
27.0%
32%
0.74
0.04
172
StГ©phane LarrГ©, Laurent Salomon, Claude ClГ©ment Abbou
men identified by prostate cancer screening. In
the Scandinavian population, only 11.7% of the
patients were T1c, and 18.7% had a PSA above
20 ng/ml. Screening populations generally have
less advanced disease, and radical treatment
should therefore give better oncological results
and less specific mortality. Ongoing randomized
trials are addressing this issue (Schroder et al.
1999; Donovan et al. 2003; Andriole et al. 2005).
As regards quality of life, compared to prostatectomy, watchful waiting is associated with
less erectile dysfunction (45% vs 80%), less urine
leakage (21% vs 49%) but more urinary obstruction (44% vs 28%) (Steineck et al. 2002). The
respective benefits and disadvantages of radical prostatectomy and watchful waiting must be
fully explained, so that patients can make an informed choice.
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11
Radiation Therapy in Prostate Cancer
Moshe E. Stein, Dirk Boehmer, Abraham Kuten
Recent Results in Cancer Research, Vol. 175
В© Springer-Verlag Berlin Heidelberg 2007
Abstract
Adenocarcinoma of the prostate is one of the
most frequently diagnosed cancers of men in the
Western hemisphere and is second only to lung
cancer for male cancer mortality. Most patients
are diagnosed in the early/clinically localized
stage, which can be treated curatively with radiation therapy alone. Innovative methods such
as brachytherapy, three-dimensional conformal
radiotherapy (3D-CRT), and IMRT (intensity
modulated radiotherapy) are able to deliver very
high tumoricidal doses to the diseased prostate,
with minimal side effects to the surrounding tissue. Radiation therapy combined with hormonal
treatment can be curative in locally advanced
disease. Radiation therapy is also very effective
in alleviating symptoms of metastatic prostate
cancer (bone metastases, spinal cord compression, and bladder outlet obstruction).
History of Radiation Therapy
in Prostate Cancer
In the 1930s, Smith and Peirson (1930) described
the therapeutic value of 200 kV percutaneous
roentgen therapy in prostate cancer. Widman
(1934) followed them in his 1934 study with
reasonable results using radium and roentgen
(X-ray) therapy, even in advanced-stage disease.
However, the further use of radiotherapy did not
gain popularity because of the poor skin-sparing
effect and the insufficient dose depth properties
of the kilovoltage equipment.
As the limitation of hormonal treatment became apparent in the early 1950s, radiation therapy (RT) was rediscovered. The development of
megavoltage equipment and improved physical
properties contributed to the re-implementation
of RT in localized early prostate cancer. A pioneering study conducted at MD Anderson Hospital in Houston, Texas, between 1966 and 1974
showed the effectiveness of radiotherapy for localized prostate cancer, although 8% developed
major complications, including severe proctosigmoid injury, necessitating diverting colostomies
(Hussey 1980).
Radiobiological Parameters
of Prostate Cancer
Read (1959) and Lea (1955) quantified biologic
response to irradiation in terms of a linear dose
coefficient (О±) and a coefficient for the square of
the dose (ОІ), according to the formula that effect is proportional to О±D+ОІD2. The linear component (О±D) of this dose survival relationship
dominates response at low doses; with a dose per
fraction in the order of 2 Gy, it has major significance. The lower the О±/ОІ ratio, the lower the dose
per fraction below which the sparing effect of
dose fractionation is lost.
The dose range over which the linear component dominates in a linear quadratic relationship
depends on the relative value of О± and ОІ, and the
О±/ОІ ratio defines the dose at which cell killing by
linear and quadratic components are equal. If the
О±/ОІ coefficient is low, the survival curve will go
down after a relatively small initial linear region,
and there will also be a marked sparing effect at
dose fractionation on cell survival.
Prostate tumors have the slowest natural
turnover rates of all tumors. The average tpot (potential cell number doubling time, before any cell
loss factor) measured before treatment is 40 days
(range, 15 to >60 days), compared with 5 days
180
for many other types of tumor (King 2000). The
fractionation sensitivity of prostatic carcinoma,
as quantified by the О±/ОІ ratio, is low comparable
to that for late-responding tissue (1.5 Gy) and
shows a large fractionation effect.
Generally speaking, hypofractionation regimens for prostate cancer, in addition to their
economical and logistic advantages, would be
expected to result in less acute sequelae and late
effects for a given level of tumor control and
probability. Estimated values of О±/ОІ ratios for
prostate cancer are 1.2 Gy, 1.5 Gy, or 1.49 Gy.
These estimated values are clearly lower than
for most other tumors and are comparable to
those of adjacent late-responding normal tissues
(Brenner and Hall 1999; Brenner et al. 2002).
The consequences might be that, in prostate
cancer patients, appropriate hypofractionation
schemes using intensity modulated RT (IMRT)
or high-dose radiotherapy (HDR) should produce tumor control and late sequelae that are as
good as or better than those currently achieved
with conventional fractionation, and may even
give reduced rates of early sequelae. According to Fowler et al. (2001, 2003), a satisfactory
tumor response might be expected from a 5вЂ“25
fraction scheduled external beam RT (EBRT) or
HDR brachytherapy. These authors showed that
10 fractions, each of 4.4 Gy, should give the same
biochemical control as 75 Gy in 2-Gy fractions,
with the same rate of late complications expected
from 66 Gy in 2-Gy fractions. Such appropriately designed schedules using approximately 10
large fractions can result in absolute increases
of 15%вЂ“20% in biochemical control with no
evidence of disease and with no increase in late
sequelae (Brenner and Hall 1999; Logue et al.
2001).
In conclusion, hypofractionation will increase
the therapeutic ratio between tumor control
and late sequelae, provided that the О±/ОІ ratio
for prostate cancer is lower than that for complications. However, hypofractionation given in
an unusually short overall time, without proper
phase I testing of the toxic effect of such a schedule, might result in unexpected and severe rectal
complications. It should be emphasized that the
high fraction-size modality must be used with
appropriate reduction of total dose.
Moshe E. Stein, Dirk Boehmer, Abraham Kuten
External Beam Radiotherapy
in Prostate Cancer
EBRT alone or in combination with other treatment modalities, such as hormonal therapy or
brachytherapy, has become an alternative treatment to radical prostatectomy in patients with
low-risk tumors. Yet the long natural history often observed in these patients makes an accurate
assessment of the impact of any therapy on survival more difficult.
The local failure rate following conventional
RT is likely to be due in large part to tumor-related factors [lymph node involvement, more
advanced stages, extracapsular involvement,
perineural and vascular invasion, high Gleason
score, high initial prostate-specific antigen (PSA)
level] and partly to technical factors related to
the delivery of the radiation (older equipment,
inaccurate planning and verification, insufficient
total dose, inadequate coverage of the target volume). These have been identified to be of importance with respect to prognosis. In an analysis by
Roach et al. (1999), the Gleason score was the
single most important predictor of death in the
first 10 years after therapy. Another example is
the study of de Crevoisier, which raised the question of local failure with regard to patient treatment preparation. They found strong evidence
that rectal distension on the treatment-planning
CT scan decreased the probability of biochemical control, local control, and rectal toxicity (de
Crevoisier et al. 2005).
A number of retrospective and prospective
studies support the long-term efficacy of EBRT
in the management of clinically localized and
locally advanced prostate cancer. It has become
widely accepted that overall dose is crucial to
tumor recurrence. Long-term treatment results
after EBRT show that an insufficient dose compromises efficacy. The value of dose escalation
has been clearly demonstrated by several nonrandomized and randomized trials (Pollack et
al. 2000, 2004, 2005; Peeters et al. 2005). Regarding failure-free survival, there was an advantage
to a higher total dose, in particular for patients
with intermediate- and high-risk tumors. Unfortunately there was also some increase in rectal
toxicity with rising radiation doses. The results
of these studies initiated important future de-
11 Radiation Therapy in Prostate Cancer
velopments. First, there is a need for improved
quality assurance protocols concerning patient
preparation, treatment planning and treatment
verification (i.e., image guided radiotherapy).
Second, there is a need for safer dose escalation
with the growing use of sophisticated radiation
techniques, such as IMRT (Ashman et al. 2005).
Standard Radiotherapy
Standard (non-conformal) RT was based mainly
on estimations of the anatomic boundaries of
the prostate defined by plain X-ray or a single
computed tomography (CT)-slice radiography.
Guidelines for treatment planning were based on
the location of the pelvic bones (mainly the pubic bone), insertion of a bladder catheter balloon,
and the use of bladder and rectal contrast media
Standard RT used open squares or rectangular
fields. It typically involved the initial use of a
вЂњ4-field boxвЂќ (box technique) followed by a boost
to the prostate using a bilateral 120В° arc on the
4-field box technique for the entire treatment or
brachytherapy. These methods limited the ability
of the radiation therapist to deliver biologically
active high doses to the clinically estimated extension of the tumor without causing acute and
long-term damage to sensitive organs (urinary
bladder, rectum, femoral heads, urethra, penile
bulb) in the immediate vicinity of the prostate.
The later use of conformal blocking was an attempt to optimize the dose distribution to correspond to the shape of the target volume (Ten
Haken et al. 1989).
Information about pelvic lymph node involvement could be obtained by imaging studies (only
macroscopic lymph nodes) or by performing
a lymph node dissection. The latter procedure
was not commonly performed, but the available
imaging studies were not able to decrease uncertainties regarding the risk of involvement.
With the help of the so-called Roach formula
[2/3 PSA+10Г—(Gleason scoreв€’6)] (Woo et al.
1988; Seaward et al. 1998), the risk of lymph node
involvement may be estimated, thus accelerating
decision-making. If pelvic irradiation is regarded
as necessary, simulation should be performed
when the patient is in the prone or supine position. Some institutions used rigid immobilization
181
devices (Kneebone et al. 2003) and performed an
urethrogram to identify the inferior extent of
the prostate apex. The superior field border was
L4/L5 or L5/S1 junction, and the inferior border
was set 1 cm inferior to both ischial tuberosities.
The lateral margins are approximately 1вЂ“2 cm
lateral to the bony margin of the lateral pelvic
wall. The posterior field border was placed at the
S2вЂ“3 junction. Appropriate corner blocking was
used to decrease the dose to the femoral heads,
small bowel, bladder, and the posterior wall of
the rectum. Following delivery of the appropriate
pelvic dose, the initial field size can be reduced to
a field encompassing the prostate (plus margins)
only. Total dose to the pelvic field used in standard radiotherapy was generally 45вЂ“50 Gy with
1.8вЂ“2.0 Gy per fraction, followed by a boost to
the prostate of 15вЂ“20 Gy. The rationale and results of combined radiotherapy and hormonal
treatment for intermediate- and high-risk prostate cancer patients are depicted below.
Results of Conventional External
Beam Radiation Therapy
Accumulating data indicate that conventional
(non-3D) techniques yield 10-year cause-specific survival rates for T1, T2, T3, and T4 tumors of 79.0%, 66.0%, 55%, and 22%, respectively (Duncan et al. 1993). These results were
confirmed by Perez et al. (1993a,b). One of the
EBRT studies with the longest follow-up is the
retrospective study of a cohort of 136 patients
treated with 60 Gy EBRT between 1964 and
1973 with a median follow-up of 25.6 years for
surviving patients. Disease-free survival curves
never reached a plateau and tumor recurrences
still occurred after 20 years (Swanson et al.
2004). The authors concluded that results from
studies with a median follow-up of less than
10 years must be regarded as preliminary. Furthermore, results from these studies indicate
that more than 25% of all tumor recurrences
occur after more than 10 years (Swanson et al.
1994). For locally advanced disease with higher
risks of extracapsular tumor extension or seminal vesicle involvement, data demonstrate poor
local control and long-term survival following
standard radiotherapy.
182
Moshe E. Stein, Dirk Boehmer, Abraham Kuten
It became obvious that radiotherapy with
standard dose levels in the range of 60вЂ“70 Gy
would not be sufficient to completely eradicate
local prostate cancer in a significant proportion
of patients. Furthermore, the delivery of higher
radiation doses would result in an increased rate
of genitourinary and gastrointestinal (GI) toxicities. Dearnaley et al. and Koper et al. compared
radiation-induced side effects of conventional
vs three-dimensional conformal RT (3D-CRT).
Both studies demonstrated a reduction in toxicity, mainly rectal toxicity, by using 3D-CRT. Dose
volume histogram (DVH) analysis demonstrated
a statistically significant dose reduction. For instance, the treated anal volume and thus anal
toxicity were markedly reduced by the 3D conformal treatment (Dearnaley et al. 1999; Koper et
al. 1999). Hence, delivering higher doses without
increasing toxicities promoted 3D-CRT.
3D Conformal Radiation Therapy
Nowadays, 3D-CRT may be considered standard
treatment in most institutions. Using multileaf-collimators (MLC) that are mounted on the
treatment machine, the photon beam may be
shaped irregularly according to the shape of the
target volume.
3D-CRT allows delivery of higher doses of
radiation to the target volume while sparing the
surrounding normal tissues. This is achieved by
CT scans of the treatment volume, which are
used to delineate target structures as well as or-
gans at risk. There are convincing data that favor
the use of additional imaging modalities such as
magnetic resonance imaging (MRI), as it provides superior soft tissue visualization compared
to CT (McLaughlin et al. 2005a, 2005b). Compared to MRI, CT leads to a larger volume than
that derived by MRI, which also facilitates a more
precise definition of the prostate apex (Kagawa et
al. 1997; Sannazzari et al. 2002).
Guidelines for the organs at risk and target
volume definitions are the International Commission on Radiation Units and Measurements
(ICRU) 50 and ICRU 62. Standard terms of both
classifications are summarized in Table 11.1
(ICRU 1993, 1999). Currently the European Organisation for Research and Treatment of Cancer
(EORTC) is preparing guidelines for target and
organs at risk definitions in prostate radiotherapy. Today most institutions use delineation procedures that depend on the individual patientвЂ™s
risk profile. After a 3D calculation of the dose,
modern planning systems are able to calculate
dose volume histograms that allow different
techniques to be compared and rated. Digitally
reconstructed radiographs (DRR) serve as virtual simulation images and may be used for verification procedures.
Since their first publication, the вЂњPartin tablesвЂќ
have evolved into the major prognostic prediction tool in radiotherapy. The latest publication
comprises the results of more than 4,000 men
with prostate cancer (Khan and Partin 2003).
These tables are not only useful for predicting
the probability of transcapsular tumor spread or
Table 11.1 Volume definitions
1. Gross tumor volume (GTV)
Tumor only, no margins. Gross extent of tumor as determined by palpation or
imaging studies. GTVp (primary tumor) should be distinguished from GTVn
(nodal areas)
2. Clinical target volume (CTV)
Includes margins around the GTV for regions of microscopic risk (subclinical
involvement)
3. Planning target volume (PTV) Includes margins around the CTV accounting for beam penumbra, patient and
organ movement, daily set-up inaccuracies
4. Dose-volume histograms
A method to evaluate the entire amount of dosimetric data obtained by using a
3-D-CRT treatment plan. It presents the data in an understandable format and
shows minimal, maximal and mean doses, the percentage volume receiving greater
than or equal to the prescription dose for target volumes, and the percentage
volume receiving greater than or equal to the established tolerance dose
11 Radiation Therapy in Prostate Cancer
seminal vesicle or lymph node involvement, they
are also of outstanding importance for target definition during radiotherapy treatment planning.
The question of whether or not to irradiate pelvic
lymph nodes may be further clarified by recent
studies on new imaging modalities, which provide evidence that pelvic nodal radiation portals
should be based on vascular rather than on bony
anatomy landmarks, because of the localization
of nodal metastases in prostate cancer along the
major pelvic vasculature. These results were obtained by lymphotropic nanoparticle enhanced
MRI (LNMRI) which has proved to be useful in
the detection of minimal disease in normal-sized
nodes at high sensitivity and specificity (Brassell
et al. 2005; Shih et al. 2005; Will et al. 2006).
The efficient implementation of conformal
techniques into prostate cancer treatment has
been promoted by systematic and accurate evaluation of internal organ motion, proper patient
preparation and positioning, and treatment verification procedures. Currently there is no patient
preparation procedure that can be regarded as
вЂњstandard.вЂќ Although recent publications have
clarified some obscurities, controversies remain
about many issues, such as bladder filling, feet
fixation, etc. Patient immobilization devices significantly reduce errors in patient positioning,
especially in the prone position. The question of
patient positioning has been an issue of controversy for some years. Currently there is only one
prospective randomized trial comparing supine
and prone position. Bayley et al. found a significant advantage in the supine treatment position
with respect to prostate movement, number of
set-up corrections, patient comfort and radiation
therapist convenience as well as for all dose levels for small bowel, rectal wall, and bladder wall
doses (Bayley et al. 2004).
Another issue in clinical quality assurance is
treatment verification. In recent years verification procedures have been established that provide improved patient set-up accuracy, such as
ultrasound localization systems, X-ray imaging
systems, cone beam CT scanners and implanted
gold markers. These systems offer the possibility
of visualizing the prostate (or markers within the
prostate) immediately before treatment to assure
optimal target positioning. This procedure is
called image-guided radiotherapy (IGRT).
183
Results of 3D-Conformal Radiation Therapy
Retrospective dose escalation studies using
3D-CRT provide clear evidence for a doseвЂ“response relationship in various subgroups of patients with prostate cancer. Two phase III randomized trials and several retrospective analyses
have confirmed the advantage of dose escalating
conformal RT for patients with localized prostate cancer. Hanks et al. (1996) found that doses
ranging from 66вЂ“79 Gy in patients treated with
3D-CRT alone showed a clear dose response in
intermediate- and high-risk cohorts, along with
an acceptable toxicity profile. These results were
confirmed in 2002. With a median follow-up
of more than 9 years, Gleason score, palpation
T-stage, pretreatment PSA levels between 10 and
20 ng/ml, and radiation dose were significant
predictors of biochemical control. GI late toxicity
grade 2 was the only factor that significantly increased with dose (Hanks et al. 2002). They furthermore demonstrated that patients with a PSA
level of 10вЂ“20 ng/ml showed a benefit with a radiation dose exceeding 75.6 Gy compared to less
than 71.5 Gy (84% vs 19% at 5 years, p=0.0003).
Pollack and colleagues demonstrated a significant
improvement for intermediate-risk patients with
respect to biochemical failure when the radiation
dose was escalated to 76 Gy or greater (Pollack et
al. 2004). Zelefsky and Eid (1998) published their
experience at Memorial Sloan-Kettering Cancer
Center in New York. A total of 743 patients with
prostate cancer classified as T1cвЂ“T3 were treated
with 3D-CRT. Doses ranged from 64.8 Gy up to
75.6 Gy and 81 Gy. They found a minimal incidence of severe late complications. Multivariate
analysis showed that doses exceeding 75.6 Gy, a
history of diabetes mellitus, and acute GI symptoms were independent predictors of grade 2 or
higher late toxicity. The phase I/II RTOG 9406
trial is investigating changes in toxicity with increasing radiation doses. In their latest report
there is no significant difference in acute and late
toxicity up to the highest dose level of 79.2 Gy
(Michalski et al. 2005). The vast majority of 3DCRT studies showed a direct relationship between high doses and no biochemical evidence
of disease. In his study using high doses, Zelefsky
et al. (2001) found that a radiation dose level exceeding or equal to 75.6 Gy had a significant im-
184
pact on PSA relapse-free survival, mainly in the
intermediate group. Pollack et al. (2000) found
that dose escalation (78 Gy vs 70 Gy) benefited
mainly patients with initial PSA counts higher
than 10 mg/ml. Updated data continued to indicate that improvement in freedom from failure
is most significant for patients with intermediate disease. It is noteworthy that the role of dose
escalation remains undefined for low- and highrisk patients. For the latter group, the combined
effects of dose escalation, pelvic radiation, and
adjuvant hormonalВ±chemotherapy are currently
under investigation.
The step-by-step process of 3D-CRT is depicted in Table 11.2. Generally, the prescription
isodose (100%) covers the PTV with an acceptable under- and over-dosage of 5% and 7%, respectively. Specific dose constraints are derived
from toxicity studies. Treatment plans should be
evaluated with respect to these constraints to prevent increasing rates of late toxicities. The dose to
25% of the rectum, for instance, should be limited to 70 Gy to prevent rectal bleeding. Maximal dose to the femoral head is limited to less
than 60 Gy; maximum dose to the large bowel is
Moshe E. Stein, Dirk Boehmer, Abraham Kuten
less than 60 Gy; maximal dose limit to the small
bowel should be kept below 50 Gy (Michalski et
al. 2000; Blanco and Michalski 2003).
Sequelae of Conventional External
Beam Radiation Therapy
External beam RT is generally well-tolerated;
the most common side effects are grades 1вЂ“2
acute rectal morbidity: discomfort, tenesmus,
diarrhea, and urinary symptoms (frequency, dysuria, urgency, nocturia) requiring conservative
medication. Serious persisting complications
that require corrective surgical intervention are
rare. Late chronic urinary sequelae (cystitis, hematuria, urethral stricture, bladder contracture)
or chronic intestinal sequelae (rectal bleeding,
chronic diarrhea, perineal pain, proctitis, fistulas, rectal/anal stricture, rectal wall ulcer) have
been described in 1%вЂ“3% of cases. Less than 1%
of treated patients demonstrated bowel obstruction or perforation. Most complications occur in
the first 3вЂ“4 years after treatment, and the rate
of fatal complications is about 0.2%. The risk of
Table 11.2 Process of 3D-CRT
i
Patient positioning and immobilization (i.e., specific mold)
ii
Supine position. Semi-filled bladder and empty rectum
iii
Establishing patient reference marks system
iv
Set-up and simulation
v
Acquisition/input CT (MRI or other imaging data) into 3D radiation therapy treatment planning system
vi
Anatomy definition; definition of volumes/surfaces of organs at risk, target volume (e.g., rectum contoured from
the anal region to the level of the inferior border of the sacroiliac joint)
vii
Dose prescription for the PTV and dose tolerance for the organs at risk. Dose specification (ICRU 50 Report)вЂ”
the PTV should be covered by 95% isodose
viii Determination of beam arrangement, field shape (blocks, multileaf collimation), beam modifiers, beam
weighting
ix
Generating digitally reconstructed radiographs
x
Plan evaluation
xi
Dose-volume histogram analysis and estimation of normal tissue complication probability (NTCP) and tumor
control probability (TCP)
xii
Plan review and documentation (before implementation)
xiii Implementation
xiv Verification (monitoring treatment alignment, at least weekly port films or electronic portal imaging)
11 Radiation Therapy in Prostate Cancer
complications is increased when doses exceed
70 Gy. The risk of rectal or urinary bladder toxicity has been correlated with the volume of the
anterior rectal wall or urinary bladder exposed
to the high dose (Leibel et al. 1984; Hanks et al.
1995).
Liu et al. (1997) reported low acute GI and
genitourinary toxicities in elderly (>70 years of
age) patients who were treated by conventional
whole pelvic irradiation (total dose 45 Gy), followed by a cone-down and a final boost, to a
total dose of 72 Gy. Comorbidities, in decreasing order of frequency, such as hypertension,
hemorrhoids, diabetes mellitus, cardiovascular
disease, diverticulitis/diverticulosis, and CrohnвЂ™s
disease, were associated with a higher rate of GI
toxicity.
Late Sequelae of High-Dose 3D
Conformal Radiation Therapy
Rectal Toxicity
There is a significant correlation between the
percentage of the rectum treated to 70 Gy or
higher and the likelihood of late rectal toxicity
(bleeding, rectal wall ulcer, severe diarrhea, incontinence). In the dose volume histogram studies described by Storey et al. (2000), patients with
more than 25% of the rectal wall treated to 70 Gy
or a higher dose had a 37% risk of grade 2 rectal
toxicity compared to 13% in patients who had
less than 25% of the rectal wall exposed to this
dose. Michalski et al. (2000) found that the relative risk of developing a late bowel complication
increased if the total rectal volume on the planning CT exceeded 100 cc.
On the other hand, Zelefsky et al. (1998,
1999) found a much lower incidence of grade 2
or 3 late toxicities in their series. Their multivariate analysis identified doses at 75.6 Gy or higher,
a history of diabetes mellitus, and the presence
of acute GI symptoms during treatment as independent predictors of grade 2 or higher late GI
toxicity. In their dose-escalation modality for patients treated to a dose of 81 Gy, a separate boost
plan was initiated after 72 Gy, which blocked the
anterior rectal wall in all fields. Other authors
(Roeske et al. 1995; Zelefsky et al. 1999) used
185
tighter PTV margins at the prostate-rectal interface or recommended the addition of rectal
shielding or the routine use of the prone position in an attempt to reduce the rectal volume
included in the irradiated field.
Identifying diabetes mellitus as an independent predicting factor for late grade 2 proctitis
after 3D-CRT supports the notion that radiationinduced proctitis is an ischemic phenomenon
that affects the rectal mucosa due to ischemic
events in the microvascular system.
Bladder Toxicity
In the preliminary report of toxicity encountered
in the 3DOG/RT0G 9406 study, Michalski et al.
(2000) described two major predicting factors
for acute bladder toxicity: more than 30% of the
bladder receiving doses of 65 Gy or higher and
neoadjuvant hormonal treatment (because of
rapid volume shrinkage and more normal tissue
exposed to irradiation). In addition, the relative
risk of developing late bladder complications
(bleeding, strictures) also increased as the percentage of the bladder receiving 65 Gy or more of
radiation increased. Zelefsky et al. (2001, 2002)
used a dose volume histogram to ensure that
no more than 50% of the bladder wall received
a maximum dose of 75.6 Gy. They also found
that prior transurethral resection of the prostate
(TURP) did not increase the incidence of late
grade 2 urinary complications. However, Sandhu
et al. (2000) found a 4% incidence of stricture
development after 3D-CRT treatment in patients
who previously had undergone TURP.
Potency
Potency was defined as the ability to achieve
erectile function adequate for penetration. The
rates of erectile dysfunction after external beam
RT range from 6% to 84%. With a median followup of 34 months, Mantz et al. (1997) found that
actuarial potency rates at 1, 20, and 60 months
were 96%, 75% and 53%, respectively. Zelefsky et
al. (1998, 1999, 2002) reported that 39% of their
pre-treatment potent patients became impotent,
and the 5-year actuarial risk of potency loss was
186
60%. Multivariate analysis demonstrated that the
most significant predictors of impotence were
doses exceeding or equal to 75.6 Gy, followed by
androgen deprivation treatment, while younger
age or prior history of TURP were not identified
as predictors. There are other causative factors
for erectile dysfunction that may be present in
this aging population (ischemic diseases, diabetes mellitus, high blood pressure), which may
add to an accelerated deterioration of erectile
function (Zelefsky et al. 1998).
Guidelines for Treatment
Planning and Set-Up
The standard terms recommended by the ICRU
(ICRU 50) for defining target volumes during
treatment planning appear in Table 11.1.
Androgen Deprivation Therapy
as an Adjunct to Radiation Therapy
It has been postulated that the biological activity of prostate-specific hormonal treatment may
lead to various classes of molecular effects when
combined with RT and may rapidly accelerate
tumor destruction.
Androgen deprivation results in significant
tumor volume reduction, enhancing response by
decreasing the total number of viable clonogenic
cells or by improving blood flow, with a decrease
in tumor cell hypoxia, rendering the remaining
cell more sensitive to RT. Androgen deprivation
can eradicate microscopic tumor deposits that lie
outside EBRT portals. Androgen-dependent cytoreduction results from a triggered, irreversible,
cascade response to a variety of agents leading to
programmed cell death (apoptosis). RT, through
DNA damage, may lead to alternative pathways
for apoptosis that might have an additive effect
(Joon et al. 1997; Lawton 2003).
The use of endocrine therapy in conjunction
with EBRT has been explored in two main directions: as neoadjuvant cytoreductive therapy in
patients with bulky, locally advanced (including
pelvic lymphadenopathy) prostate cancer or as
adjuvant therapy with EBRT in patients with a
high risk for occult metastatic disease [high PSA
Moshe E. Stein, Dirk Boehmer, Abraham Kuten
and Gleason score levels; early (T1, T2) grade 3
tumors (high-grade, poorly differentiated carcinoma)].
Several prospective, randomized trials of neoadjuvant androgen deprivation therapy (ADT)
strongly support this approach. In most studies, the neoadjuvant approach has consisted
of several months of ADT with the luteinizing
hormone-releasing hormone (LHRH)-agonist
goserelin acetate (Zoladex, 3.6 mg subcutaneously every 4 weeks); in some studies, flutamide
(Eulexin) 250 mg po three times daily, was also
given. All patients received pelvic irradiation
ranging from 45 to 50 Gy and an additional prostate boost of 20вЂ“25 Gy (Pilepich et al. 1997; Lawton et al. 2001).
The majority of phase III randomized trials
comparing EBRT alone to EBRT with neoadjuvant ADT or neoadjuvant and concurrent ADT
demonstrated the benefit of the addition of ADT.
All these studies demonstrated greater local control, disease-free survival, and overall survival
than with EBRT alone (Hanks et al. 2003; Roach
et al. 2003).
The Radiation Therapy Oncology Group
(RTOG 8610) (Pilepich et al. 2001) report was
the landmark study that demonstrated a survival benefit with neoadjuvant (2 months prior
to RT) and concurrent hormonal therapy combined with RT, as compared to RT alone. This
study demonstrated that the benefits of shortterm hormonal therapy consisting of combined
androgen suppression therapy were limited to
patients with bulky disease and Gleason scores
of 2вЂ“6. The study also showed a decreasing incidence of distant failure, longer biochemical, and
actuarial disease-free survival. Although there
was no significant difference in overall survival
in the two groups, there was a highly significant
improvement in survival in patients with a Gleason score 2вЂ“6 compared to higher (7вЂ“10) Gleason score patients. Treatment was well-tolerated,
no grade 4вЂ“5 toxicity from RT was observed, and
preservation of sexual potency was similar for
both treatment groups.
Further support for the use of adjuvant hormone manipulation came from the EORTC study
(Bolla et al. 1997) on a group of 415 patients with
locally advanced prostate cancer. Eligible patients were those whose disease was T1T2 N0,
11 Radiation Therapy in Prostate Cancer
MX, with World Health Organization grade 3
histology or T3T4 disease without any radiological or surgical evidence of involved lymph nodes.
Patients received treatment to the whole pelvis
using a 4-field technique (L5-S1 upper border, ischial tuberosities lower border, 1 cm beyond the
maximum width of the bony pelvis laterally) to
a total dose of 50 Gy, with a 20 Gy boost to the
prostate plus seminal vesicles. Hormonal therapy
consisted of goserelin starting on the first day of
RT and continuing for 3 years, along with the steroidal antiandrogen cyproterone acetate 150 mg
po for 1 month.
With a median follow-up of 45 months, the
overall survival at 5 years for the combined modality group was 79% vs 62% (p=0.001) for the
RT alone group. The authors also noted statistically improved disease-free survival (85% vs 48%,
p<0.001) and local control. An update of this trial
(Bolla et al. 2002) showed there to be continued
statistically significant improvement in survival
(78% vs 62%, p=0.0002) and clinical disease-free
survival (74% vs 62%, p=0.0001) with a median
follow-up of 66 months and a 5-year specific survival of 94% vs 79%. Another EORTC study conducted by Bolla et al. compared EBRT in combination with 3-year LHRH-agonist treatment vs
EBRT and 6 months of hormonal therapy. The
results of this study are not yet available, as follow-up has been too short.
The RTOG protocol 9413 (Roach et al. 2003a)
addressed the timing of hormonal manipulation. Eligible patients were those with adenocarcinoma of the prostate whose estimated risk of
pelvic lymph node involvement was greater than
15% or patients with T2CвЂ“T4 and a Gleason
score of 6 or higher. Randomized patients had
a mean PSA of 22.8 mg/ml, 67% had T2CвЂ“T4
clinically staged disease, and 72% had a Gleason
score of 7вЂ“10. Patients were randomized between
whole pelvis RT plus a boost to the prostate vs
RT to the prostate only, and between neoadjuvant hormone manipulation (LHRH agonist plus
an antiandrogen) for 2 months before and during RT or the same hormonal manipulation for
4 months after RT. With a median follow-up of
59.3 months, patients treated with neoadjuvant
hormonal manipulation and radiation had a 4year progression-free survival of 53% vs 48% for
the adjuvant hormone arm (p=0.33). Patients
187
treated with whole pelvis RT plus boost had a
4-year progression-free survival rate of 56% vs
46% for the prostate-only RT (p=0.014). An improved progression-free survival rate was also
noted in the whole pelvis RT plus neoadjuvant
hormonal treatment group, compared to other
arms of the study. Overall survival was not statistically different for any of the arms.
The update of the RTOG study 9413 (Roach
2003) proved that the intermediate risk subpopulation (T3, Gleason score 6, or T1вЂ“2, Gleason
score 7) will benefit from neoadjuvant concurrent hormone treatment in combination with
EBRT, while high-risk patients (bulky disease,
Gleason score 7 or higher, PSA >30 mg/ml) require the addition of long-term adjuvant hormone therapy.
DвЂ™Amico et al. (2004), from the Brigham and
WomenвЂ™s Hospital, conducted a phase III trial
evaluating the role of ADT in clinically localized
prostate cancer. They introduced neoadjuvant/
concurrent androgen deprivation plus EBRT and
continued ADT for 6 months vs EBRT alone. With
a follow-up of 4.5 years, they found a significantly
improved 5-year overall survival (88% vs 78%),
5-year cause-specific survival (100% vs 94%), and
5-year biochemical NED (79% vs 55%) in favor
of the combined modality group, especially in the
intermediate-risk patients.
In conclusion, based on the extensive scientific work that has been carried out regarding
the potential benefit of neoadjuvant hormonal
manipulation and RT for patients with prostate
carcinoma, it is clear that there are benefits to
the combination therapy. Both the potential for
cytoreduction as well as potential control of micrometastatic disease have been documented.
Patients with nonmetastatic, intermediate-risk
disease represent a group that benefits from
neoadjuvant and concurrent hormonal cytoreduction for at least 3вЂ“4 months. The addition
of short-term androgen deprivation confers no
benefit for high-risk patients who should receive
neoadjuvant and concurrent androgen deprivation and long-term adjuvant treatment (for at
least 2 years).
Several groups have prospectively evaluated
the role of adjuvant ADT in combination with
EBRT. The RTOG described the results of RTOG
85-31 (Lawton et al. 2001) in determining the
188
advantage of androgen deprivation as adjunctive therapy following standard EBRT in locally
advanced prostate cancer. A total of 977 patients
were randomized to receive radiation only (androgen deprivation started at disease relapse)
or radiation plus adjuvant goserelin. There was
a statistically significant decrease in local and
distant failure rates in favor of the combination
arm. The local failure rate at 8 years was 23%
for the combination-therapy arm and 37% for
the radiation-alone arm (p<0.0001). The distant
metastasis rate in the combination arm was 27%
and 37% in the radiation-alone arm (p<0.0001).
The disease-free survival favored the immediate
androgen deprivation arm, but overall survival
was not statistically different between the two
groups. These results were confirmed by Pilepich
et al. (2005).
An evidence-based oncology study (Pilepich
et al. 2005; Roach 2005) summarized the results
of several American hospitals in the treatment of
poor prognosis prostate cancer patients, including T1 and T2 stage patients with radiographic
or histological evidence of lymphadenopathy,
treated with adjuvant androgen suppression with
radiotherapy or radiotherapy alone (minimal
target dose 60вЂ“70 Gy, 1.8вЂ“2 Gy daily fractions),
followed by LHRH-agonist (goserelin 3.6 mg
subcutaneously) at relapse. Participants in the
adjuvant goserelin arm received goserelin for
the last week of radiotherapy until disease progression. It was demonstrated that radiotherapy
plus adjuvant goserelin significantly and statistically increased the 10-year absolute disease-free
survival (49% vs 39%; p=0.002), 10-year diseasefree survival (37% vs 23%; p<0.0001), reduced
10-year disease specific mortality (16% vs 22%;
p=0.005), and decreased both the 10-year local
failure rate (23% vs 38%; p<0.0001) and 10-year
incidence of distant metastases (24% vs 39%;
p<0.0001) compared to radiotherapy alone followed by goserelin at relapse. Several important
issues remain unresolved about:
1. What is the best use of adjuvant hormonal
therapy in higher risk patients, e.g., subpopulations of high-risk patients who do not need
long-term adjuvant hormone therapy or subset of intermediate-risk patients for whom
long-term adjuvant hormonal therapy should
be considered?
Moshe E. Stein, Dirk Boehmer, Abraham Kuten
2. What about considering neoadjuvant hormonal therapy in addition to adjuvant hormonal therapy?
3. Most importantly, what is the optimum duration of adjuvant hormone therapy use?
The long-term findings of RTOG 8513 have
answered some questions but many more remain
to be addressed.
Radiation Therapy Following
Radical Prostatectomy
Radical prostatectomy is widely used as the primary treatment for clinically localized prostate
cancer. The role of postoperative RT is still controversial. Some patients with pathological T2N0
and clear surgical margins enjoy long-term progression-free survival, ranging from 84% to 98%,
without a need for RT (Kupelian et al. 1996). On
the other hand, if disease extends beyond the
prostatic capsule (pT3) or is present at the surgical margins, disease-free survival rates are lower
because of the subclinical disease burden. For
these high-risk patients, RT plays an important
role (Valicenti et al. 2003).
Postoperative RT can be delivered in an adjuvant setting or as a salvage modality in the setting of a rising PSA. In the EORTC Trial 22911,
Collette et al. (2005) demonstrated that immediate postoperative RT significantly improved
biochemical disease-free survival compared to
a wait-and-see policy until relapse or pathological risk factors appeared in pT2вЂ“3 patients after
radical prostatectomy. Their risk model revealed
that positive margins, seminal vesicle invasion,
World Health Organization differentiation grade,
preoperative PSA (>10вЂ“20 ng/ml), and a postoperative (3 weeks) level of greater than 0.2 ng/ml
were independent factors for biochemical disease-free survival in a wait-and-see group. In the
majority of studies, the most consistent predicting factors for disease recurrence and overall
survival were penetration of the prostatic capsule, the presence of tumor at the inked surgical
margins, lymph node involvement, preoperative
PSA level, and surgical Gleason score. According
to DвЂ™Amico et al. (1998), who used multivariate analysis, a pretreatment PSA of 10 mg/ml or
11 Radiation Therapy in Prostate Cancer
higher and a Gleason score of 7 or higher were
adverse prognostic factors when biochemical
control was used as an endpoint. These high-risk
patients may benefit from the use of RT.
The main goal of adjuvant RT is the eradication of microscopic residual tumor in the periprostatic tissues or adjacent pelvic lymph nodes.
Using total doses in the range of 55вЂ“65 Gy
showed a 55% and 48% clinical or biochemical
disease-free interval at 10 and 15 years, respectively, compared with 37% and 33%, respectively, for radical prostatectomy alone. Paulson
et al. (1990) and Anscher et al. (1995) showed
that patients receiving postoperative RT have a
marked reduction in mortality, significantly better 10-year disease-free survival rates and fewer
incidences of distant metastatic disease in T3вЂ“T4
disease. In their randomized study, Leibovich
et al. (2000) demonstrated that patients with
pT2N0 disease and a single positive margin, who
received postoperative RT (without androgen
deprivation treatment) had higher 5-year clinical
and biochemical disease-free survival rates compared to patients not receiving RT (88% vs 59%).
None of their patients treated with postoperative
irradiation had local or distant recurrence. Most
beneficial effects of irradiation were evident in
patients with positive margins either at the base
or apex.
Irradiation techniques include the pelvis up to
the bifurcation of the common iliac vessels with
the вЂњboxвЂќ technique (antero-posterior/posteroanterior and right/left lateral field) to a dose of
45вЂ“50 Gy (1.8 Gy per fraction). The prostate bed
and margins should then be supplemented with
the same box technique or with a bilateral 120В°
arc rotation with a boost of 15вЂ“20 Gy in 2 Gy
daily fractions. These doses are effective when
postoperative PSA levels are less than 2 ng/ml.
Higher PSA levels are less likely to benefit from
higher irradiation doses alone and should be
considered for additional hormonal treatment.
The most effective total dose is controversial.
Median doses reported for both salvage and adjuvant irradiation are between 60 Gy and 64 Gy;
according to Valicenti et al. (1998), 64.8 Gy or
above should be used for appropriately selected
patients after radical prostatectomy.
Bolla et al. (EORTC Trial 22911) (2005) performed a randomized controlled trial to compare
189
RP alone to RP patients irradiated in an immediate setting for pT3 or positive surgical margins
patients. Patients were irradiated to a dose of
50 Gy/25 fractions/5 weeks (volume encompassing surgical limits from the seminal vesicles
to the apex with margins to include subclinical
disease in the periprostatic area) with a 10 Gy
boost in 5 fractions over a week to reduced volume circumscribing the previous landmarks of
the prostate with reduced security margins. Biochemical progression was defined as an increase
of more than 0.2 Ојg/l over the lowest postoperative value measured on three subsequent occasions. Biochemical disease-free survival was significantly improved in the irradiated group (74%
vs 52.6%). Clinical progression-free survival was
also improved in the irradiated group. Severe late
toxic effects (grade 3 or higher) were rare but the
side effects were more frequent in the irradiated
group. The EORTC will soon activate a trial in
which all pT3 patients will receive immediate irradiation following RP. Patients will be randomized between EBRT alone vs EBRT combined
with hormonal therapy.
The RTOG recently completed accrual to a
phase 3 trial (RTOG 96-01), comparing salvage
RT alone vs salvage RT plus 2 years of androgen
deprivation treatment in pT2вЂ“T3 patients and/
or positive surgical margins. These patients,
who must have had a rising PSA from 0.2 ng/
ml to 4 ng/ml, were randomized to receive hormonal monotherapy (Casodex, 150 mg daily) or
a placebo for 2 years. All patients receive irradiation to the prostatic bed to a dose of 64.8 Gy.
The RTOG is also carrying out a study to evaluate the value of adjuvant therapy in high-risk
prostatectomy patients prior to biochemical
progression. RTOG P-0011 is a randomized
study to test whether adding androgen deprivation to RT (total dose of 63вЂ“66 Gy) leads to a
better outcome than each modality used separately. Poor-risk factors were defined as capsular penetration and surgical Gleason scores of 7
or higher, positive surgical margins, or seminal
vesicle invasion. Eligible patients must have had
a postoperative PSA below 0.2 ng/ml before
randomization. Endpoints included overall survival, disease-free survival, freedom from distant metastases, and biochemical disease-free
failure.
190
Most side effects are mild or moderate in
severity: urinary stress incontinence, cystitis,
and proctitis, which can be treated successfully
with conservative management. Urethral stricture was observed in approximately 5%вЂ“10% of
these patients. Incidence of impotency (erectile
dysfunction) increased even in patients who retained potency after nerve-sparing radical prostatectomy.
In conclusion, determining postoperative PSA
levels might serve as the best indicator for irradiation in low-risk patients. Patients with intermediate-risk disease can benefit from pelvic and prostatic bed irradiation to a total dose of 55вЂ“60 Gy.
Replacing conventional external irradiation with
conformal radiotherapy can promote dose escalation up to 64вЂ“66 Gy. Appropriate patients for immediate irradiation are those with high-risk factors (positive margins, seminal vesicle invasion,
Gleason score>6 or PSA>20 ng/ml). On the other
hand, Hayes and Pollack (2005) established welldefined prognostic factors that should be used
to select patients appropriately for salvage RT: a
positive margin, no seminal vesicle invasion, PSA
doubling time exceeding 10 months, pre-radiation PSA level of less than 1.0 ng/ml, and a postsurgical Gleason score of less than 7. All these
factors suggest possible late local or locoregional
recurrence without metastatic disease.
Hormone-Induced
Gynecomastia Prophylaxis
Gynecomastia occurs in about 90% of patients
receiving estrogens or flutamide, but only in 8%
of patients undergoing orchiectomy. In patients
treated with combined androgen blockade on
high-dose antiandrogens, some 3%вЂ“15% developed gynecomastia (Kirschenbaum 1995). Others (Di Lorenzo et al. 2005; Kuten et al. 2004) described gynecomastia with breast tenderness in
61%вЂ“85% of patients treated with bicalutamide
(Casodex) monotherapy vs 19%вЂ“22% in patients
treated with LHRH agonist goserelin and the antiandrogen flutamide. Breast tenderness alone
was noted especially in the bicalutamide group
(13.1% vs 4.4%).
Prophylactic RT should be completed 2вЂ“3 days
before the initiation of hormone therapy. RT
Moshe E. Stein, Dirk Boehmer, Abraham Kuten
can be given with orthovoltage irradiation: appositional 9- to 12-MeV electrons or Co-60 or
4 MV photon beams (tangential portals); or a
single dose of 9 Gy or a total dose of 12вЂ“15 Gy
in 4вЂ“5 Gy fractions. With these methods, gynecomastia can be prevented in up to 50% of
patients (Tyrrell et al. 2004; Kuten et al. 2004).
Painful gynecomastia developing after estrogen
or nonsteroidal antiandrogen therapy could be
relieved with RT to a total dose of 20 Gy (5 fractions), 40 Gy (20 fractions), or 8вЂ“15 Gy (single
fraction). In these cases, pain relief was obtained
for an average of 3.6 months (Chou et al. 1988;
Tyrrell et al. 2004).
Some recent studies suggest that adding
tamoxifen (an antiestrogen) to the hormonal
treatment might prevent/reduce gynecomastia
or alleviate pain in a significant number of patients (Di Lorenzo et al. 2005).
History of Brachytherapy
in Prostate Cancer
Implantation techniques have evolved from intraurethral insertion of temporary radioactive
sources in the early decades of the last century.
In 1917, Pasteau described the use of interstitial radium (Pasteau and Degrais 1917) and, in
1917, Barringer combined radioactive radon
(222Rn) as permanent interstitial therapy with
external radiation. In 1965, radioactive iodine
(125I) was introduced for permanent implantation (Hilaris et al. 1977). Flocks et al. (1952)
described the direct insertions of radioactive
colloidal gold (198Au) into the prostate or the
tumor bed with good results. During the early
1970s and early 1980s, retropubic implants with
125I became popular but this method was later
partly abandoned in favor of transperineal methods. Prostate brachytherapy entered the modern
era with a preliminary report in 1983 by Holm
et al. (1983) who described the use of transrectal
ultrasonography to guide transperineal insertion
of needles into the prostate to permanently deposit 125I sources into the gland.
In clinical practice, brachytherapy for prostate
cancer can be performed either by temporary or
permanent implants. Temporary implants are
small radioactive sources surgically implanted
11 Radiation Therapy in Prostate Cancer
directly into the prostate or tumor bed. Most
common is iridium-192 (192Ir) which has a 73.8day half-life and a dominated ОІ-decay. Its photon spectrum includes characteristic X-rays and
gamma rays ranging from 63 KeV to 1.4 MeV. Its
average energy is 0.397 MeV. It is used in lowand high-dose rate implants (Nag et al. 1999).
Permanent implantation of iodine-125 (125I)
has been used for 35 years, and palladium-103
(103Pd) has been available for more than a decade. 125I is available in the form of seeds. Its
half-life is 59.6 days and its average energy is
0.028 MeV. It decays by electron capture producing a cascade of 27- to 32-KeV characteristic
X-rays. It is actually an X-ray emitter, and it has
therapeutic advantage in slow-growing prostate
carcinoma (Gleason score 2вЂ“6). 103Pd has a halflife of 17 days. Its average energy is 0.020 MeV
(X-rays) and is presented in the form of seeds.
Due to its short half-life, 103Pd should theoretically show better cell kill in rapidly proliferating
tumors (Gleason score>6) (Nag et al. 1999; Ponholzer et al. 2005). Generally, despite differences
in physical properties of these two isotopes, no
differences have been established in clinical outcome (e.g., effectiveness or complications).
Necessary investigational steps before conduction of temporary brachytherapy include history of pelvic surgeries, recurrent urinary tract
infections, and transurethral procedures. Generally, the volume of the gland should be smaller
than 60 cm3 and be more than 5 mm from the
rectal mucosa. Ultrasound should assess initial
prostate volume. Urodynamic studies to measure
maximum urinary flow rate and postvoidal residual urine are vital, especially in patients with
lower urinary tract infections. The symptom
score before treatment is an important predictor
of urinary morbidity after treatment.
Systemic staging, initial PSA level, pathology, and Gleason score are mandatory before any
decision is made. Transrectal ultrasound should
image the exact zonal anatomy within the gland,
evaluate extracapsular extension, and detect pubic arch interference. CT scan, MRI with rectal
coil, and surgical lymph node staging are not
mandatory (Kovacs et al. 2005).
Brachytherapy can be used as monotherapy,
mainly for low-risk patients with smaller prostate volumes. The 192Ir dosage is as high as
191
60 Gy. Combined EBRT, followed by a temporary brachytherapy (BT) boost, is effective in
low-risk patients (T2a, initial PSA <10 ng/ml,
Gleason score<6), but these patients also do
well with permanent BT alone. The greatest advantage of EBRT plus temporary BT (total dose
of 20вЂ“25 Gy) seems to be in intermediate- and
high-risk patients (T1bвЂ“T3b or PSA>10 ng/ml
or Gleason>6) (Borghede et al. 1997; Kovacs et
al. 2005).
Hormonal treatment has a role in reducing
prostate volume before treatment (вЂњdownsizingвЂќ), due to reduced benign prostate hyperplasia (BPH) of the gland. The role of a short course
of neo-adjuvant hormonal therapy combined
with EBRT and temporary BT is under investigation. So far, there is no clearly significant advantage of short hormonal treatment observed
in dose escalating studies (total biologic effective
dose >70 Gy) with regard to long-term results
(Kovacs et al. 2005). On the other hand, Stock et
al. (2004) demonstrated that trimodality therapy
(androgen deprivation, brachytherapy and external beam RT) for high-risk patients (Gleason
scores 7вЂ“10, PSA levels >10вЂ“>20 ng/ml, T2bвЂ“T3)
resulted in excellent biochemical and pathologically confirmed local control.
Implantation is almost always performed as
out-patient surgery under general or spinal anesthesia. A needle guide template is mounted
against the perineum. With the patient in the lithotomy position, the template acts as a guide for
needle placement. This allows for control over
the entire prostate target volume and specification of source placement at any point within the
gland. The position of the needle is checked with
transrectal ultrasound and/or fluoroscopy.
If the prostate is imaged as a 3D ellipsoid
within the pelvis, any point within the prostate
can be given a unique set of coordinates (x-, y-,
and z-axes). The images of the prostate are used
to calculate the approximate total radiation dose
needed for target coverage, by using nomograms
based on the orthogonal dimension of the prostate. Images are taken along the prostate at 5 mm
intervals.
Modern treatment planning computers can
use this planning target volume to develop a pattern for the most ideal radioactive source placement that will deliver the desired (prescribed)
192
dose. The three orthogonal dimensions are used
to calculate the total activity needed to achieve a
minimal peripheral dose (MPD). They can generate dose-volume histograms for target volume,
rectum, and urethra. If areas are found to be underdosed or higher urethral doses are observed
on the images, appropriate adjustments are made.
High central doses may lead to urethral damage.
Postoperative dosimetry must be performed to
assess the adequacy of implantation and to determine the actual dose received by the prostate and
normal surrounding tissues. The planning and
execution of the implant is evaluated using 3D
CT-based reconstruction of the prostate to optimally assess the dose coverage of the gland.
For the treating brachytherapist, there are
some guidelines and definitions which are of
crucial importance for successful treatment of
the tumor. The MPD is a dose enclosing a volume equal to the target volume, indicating the
lowest dose received within the prostate volume.
Physically, it is the minimum dose to the periphery of an ellipsoid with the same average dimensions of the prostate. D90 is a dose covering 90%
of prostate volume and V100 is the percentage of
prostate volume receiving prescription dose. A
urethral dose of less than 10 Gy/fraction, a rectal
dose less than 6 Gy/fraction, and a dose less than
50 Gy delivered to 50% of the penile bulb are
generally tolerable. It is also advisable to define
different target areas within the gland as CTV1
(prostate CTV), CTV2 (tumor in the peripheral
zone), and CTV3 (visible tumor infiltration areas) (Kovacs et al. 2005).
Because of the low О±/ОІ ratio (<2 Gy) of prostate
cancer, it might be appropriate to give treatment
with a high-fraction size. However, it should be
kept in mind that delivering the total dose in a
very few high-dose fractions has also radiobiological disadvantages, such as inadequate tumor
re-oxygenation and normal tissue damage. On
the other side, there are some important advantages of high-dose rate brachytherapy which have
gained popularity:
1. As efficacious as standard protraction
2. More convenient for the patient, both in terms
of logistics and acute morbidity
3. Less resource-intensive than standard protraction
Moshe E. Stein, Dirk Boehmer, Abraham Kuten
4. Loss of therapeutic differential between the
slow-responding tissue and tumor
5. Less early morbidity
6. Less radiation exposure to personnel
Conformal high-dose rate brachytherapy
(C-HDR BT) is an alternative means of precise
dose escalation that offers similar tumoricidal
effects as 3D conformal EBRT. By placing HDR
after-loading needles directly into the prostate
gland, a steep dose gradient between the prostate
and adjacent normal tissues can be generated
that is unaffected by organ motion and edema
or treatment set-up uncertainties. The ability to
control the amount of time the single radioactive
source dwells at each position along the length
of each brachytherapy catheter further enhances
the conformity of the dose (Kestin et al. 2000).
At the William Beaumont Hospital (Martinez
et al. 2002), HDR BT was used to boost patients
with locally advanced prostate cancer (>T2b,
PSAв‰Ґ10, Gleason scoreв‰Ґ7). External beam RT
(pelvic irradiation) amounted to 46 Gy, and 3
HDR implants of 5.5вЂ“6.5 Gy each were given,
to a total dose of 16.5вЂ“19.5 Gy. With a median
follow-up of 4.4 years, the biochemical control
rate was 74%, with 91.6% overall survival and
no chronic grade 3 GI toxicity. Other authors
(Vicini et al. 2003) gave, in addition to EBRT, an
HDR boost of 20вЂ“25 Gy, 6.5 Gy per fraction in
3вЂ“4 fractions, to intermediate- and high-risk patients. The low-risk group (T1bвЂ“c, T2a, Gleason
scoreв‰¤6, PSAв‰¤10) was boosted with a total dose
of 18вЂ“24 Gy, 5.5вЂ“6 Gy per fraction in 3вЂ“4 fractions.
In the William Beaumont and other hospitalsвЂ™
series, patients experienced between 1.5% and
7.4% urethral stricture, 5%вЂ“7% moderate frequency/urgency, and 2% severe urgency. There
was a very low incidence of chronic grade 3 GI
complications, 1.6%вЂ“3% rectal bleeding. 1.7%
recto-vesicle fistula, and less than 2% rectal wall
necrosis.
Permanent brachytherapy offers several practical and theoretical advantages over EBRT in
selected patients. Due to the physics of radiation
emanation from the implanted radio-isotopes,
there is dose escalation within the prostate, with
a rapid dose fall in surrounding normal tissues.
11 Radiation Therapy in Prostate Cancer
125I is given as monotherapy (145 Gy) to patients with stage T1aвЂ“2a, Gleason score 2вЂ“6, and
PSA of less than 10 ng/ml, and as a boost (110 Gy)
to EBRT (40вЂ“45 Gy) in clinical stage T2bвЂ“2c or
Gleason score 8вЂ“10 or PSA>20 ng/ml.
Exclusion criteria for permanent brachytherapy are: short life expectancy (<5 years); poorly
healed TURP defect; distant metastases and
unacceptable operative risks. Exclusion criteria
for temporary brachytherapy include: volume
exceeding 60 cm3; TURP within 6 months; infiltration of the external sphincter of the bladder
neck; significant urinary obstructive symptoms;
severe pubic arch interference; rectumвЂ“prostate
distance on TRUS of less than 5 mm; and lithotomy position not possible or high-risk patients
for general anesthesia.
Relative contraindications for brachytherapy
are: risk of developing complications or technical difficulties leading to inadequate dose coverage (Anscher et al. 1995); large/prominent
median lobes (Ashman et al. 2005); previous
pelvic irradiation/multiple pelvic surgeries (Barringer 1917); severe diabetes mellitus (Bayley
et al. 2004); previous transurethral resection of
prostate (TURP) (Beyer 1999); gland size greater
than 60 cc at time of implantation (Beyer 2001);
and involved seminal vesicles (Beyer 2003; Nag
et al. 1999).
Brachytherapy can also be used for recurrent
prostate cancer after RT. Indications include the
following parameters: histologically confirmed
local recurrence (Anscher et al. 1995); no distant metastases (Ashman et al. 2005); adequate
urinary function (Barringer 1917); 5- to 10-year
life expectancy (Bayley et al. 2004); prolonged
disease-free interval (>2 years) from primary
RT (Beyer 1999); long PSA doubling time
(>6вЂ“9 months) (Beyer 2001); Gleason score of 6
or less and a PSA count below 10 ng/ml at the
time of recurrence (Beyer 2003). Grado et al.
(1999) implanted a median of 31.76 mCi 125I
or 126 mCi 103PD to deliver a median-matched
peripheral dose of 160 Gy and 120 Gy, respectively. At 3 and 5 years, the biochemical diseasefree survival was 48% and 34%, respectively, for
patients who reached a PSA nadir of less than
0.5 after salvage brachytherapy. Urinary complications were observed in 30% of the patients
193
and included urethral strictures requiring TURP
(14% ), incontinence (6%), hematuria (4% ), and
dysuria (6%). Rectal ulcers were observed in 4%
of patients, and one patient required a colostomy
for therapy-resistant proctitis. Using lower doses
of 125I and 103PD, Beyer (1999) achieved 53%
biochemical disease-free survival and 93% prostate cancer-specific survival at 5 years. PSA level
and Gleason score at the time of salvage are the
best predictors of outcome. The most likely to respond are patients with PSA counts below 10 ng/
ml and a Gleason score of 6 or less.
Some authors reported an increase in the
severity and duration of acute morbidity after
salvage brachytherapy. However, with the introduction of transperineal ultrasound-guided
techniques and the use of lower activity 125I
and 103PD sources, the reported risks have diminished. Most side effects include pelvic/penile
pain, hematuria, and urinary incontinence. Rectal complications include proctitis and bleeding
or necrosis leading to colostomy at rates ranging
between 0% and 5%.
Side Effects
Transient urinary morbidity related to radiationinduced urethritis or prostatitis are the most
common side effects of brachytherapy. Irritative
and obstructive lower urinary tract symptoms
may develop over the first few weeks as a result of
implant trauma. These side effects are of a temporary nature. In addition to the urethral dose,
the presence of obstructive symptoms secondary
to preexisting benign prostatic hypertrophy before brachytherapy has been correlated with an
increased incidence of acute symptoms, including urinary retention.
Late side effectsвЂ”such as incontinence, chronic cystitis, urinary retention, dysuria, and frequency and late grade 3 urinary complicationsвЂ”
that require medical or surgical intervention may
occur in approximately 2%вЂ“5% of patients, with
stricture reported in 2%вЂ“3% of patients. Combined modality (with EBRT) can cause about
20% of patients grade 2 and 8% grade 3 toxicity.
Late rectal complications, including proctitis
with diarrhea, perineal pain, tenesmus, or rectal
194
bleeding may occur in 2%вЂ“19% of patients. Isolated cases of rectal fistula formation have been
also reported. A combined modality (EBRT and
BT) cause about 23% of the patients grade 2 rectal toxicity (Beyer 2001).
Compared to other standard RT modalities,
permanent brachytherapy has been reported to
give better preservation of potency. However,
with a continuous follow-up (>2 years), gradually declining erectile function has been reported.
Ponholzer et al. (2005) found, in early prostate
cancer patients treated with 103-palladium implantation and using the International Index of
Erectile Function-15 (Cappelleri et al. 1999), a
high prevalence of preexisting erectile dysfunction among his patients; albeit, 57% of men fully
potent or with mild erectile dysfunction before
brachytherapy had lost no function 30 months
after the therapy. In a multivariate analysis, age,
preoperative PSA level, prostate volume, D90,
hormonal treatment, diabetes, smoking, or hypertension were not predictive of preserving
potency (p>0.05). Zelefsky et al. (2000) reported
impotence rates of 21% and 42%, respectively, at
2 and 5 years after transperineal implantation.
The following parameters were generally
found to be significant predictors of erectile
dysfunction after brachytherapy: D50 to the
penile bulb, high dose delivered to the neurovascular bundles, postimplantation prostate
CT volume, patient age, vascular disorders, and
diabetes mellitus.
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12
Cryoablation and High-Intensity
Focused Ultrasound
Chris DвЂ™Hont
Recent Results in Cancer Research, Vol. 175
В© Springer-Verlag Berlin Heidelberg 2007
Abstract
The fight against prostate cancer goes beyond
radical prostatectomy, radiation therapy, and
hormonal therapy. Temperature can also kill
cells and proves to be highly successful in this
war on prostate cancer. There is no known insensitivity to extremely low or extremely high
temperatures.
Targeted CryoAblation of the Prostate
Targeted cryoablation of the prostate (TCAP)
[1вЂ“12] brings low temperature inside the prostate through transperineal hollow, closed needles
(same set-up as in brachytherapy). Everything is
controlled by transrectal ultrasound. By sending
argon gas through those needles the ThomsonJoule effect produces very low freezing temperatures of 180 В°C or lower at the tip of each needle, resulting in freezing the surrounding tissue.
Conic ice balls (1вЂ“2 cm) arise at the tip of each
needle, and by confluencing these ice balls the
entire glandвЂ”or part of the glandвЂ”can be frozen. The critical freezing point to kill the cells is
at в€’40 В°C and should be reached all through the
capsula of the prostate for sufficient tumor control. The temperature gradient from в€’180 В°C in
the center of each ice ball to 0 В°C at its periphery and the warming up of the frozen tissue by
sending extra blood supply from the periphery
into the prostate (normal protective body reaction against freezing) may compromise killing
temperatures all through the capsula. Therefore
temperature monitoring during freezing is absolutely mandatory for efficient tumor kill. A
double freeze (argon gas)/thaw (helium gas) cycle is usually recommended, and pullback of the
probes to treat the apical area is usually necessary
with two extra freezing cycles. The limitations are
the size of the prostate and the high cost of the
single-use material. Nerve sparing procedures are
possible in highly selected cases but may result in
lower tumor control [9, 10]. The treatment can be
repeated in case of local recurrence, TCAP can
also be done after irradiation failure [3, 7, 12]. A
urethral warming catheter seems to be absolutely
necessary to protect the urethra. Impotence rates
are very high, incontinence rates similar to those
after radical prostatectomy, and rectal fistula are
seen because of freezing the rectal wall (hence,
again, we emphasize the importance of temperature monitoringвЂ”since shape of the ice ball is opposite to the shape of the posterior prostate capsula). Patients can leave the hospital within 24 h.
Main complications are perineal edema and
numbness, sloughing, and impotence [5, 6, 8вЂ“11].
Within 3вЂ“6 months the necrotic tissue is transformed into firm fibrotic tissue around a normal urethra, and the size of the prostate usually
shrinks to less than 10 cc. Endocare and Galil
Medical are the main suppliers, and all machines
have a similar approach in that the use of liquid nitrogen has been abandoned. Importantly,
the learning curve is greater than 50 cases, and
knowledge of transrectal ultrasound is mandatory. TCAP is a minimally invasive treatment,
but still it:
1. Requires multiple punctures of the perineum
(cryoprobes) with a risk of bleeding and cracking of the prostate during the freezing cycle
2. Allows for no exact freezing control
3. Will require posttreatment catheterization for
2вЂ“3 weeks.
TCA can also be used for liver tumors and
kidney tumors by introducing the freezing
needle directly into the tumor tissue (via sur-
202
gery). Other variations and applications of
cryoablation (with skin, lung tumors) are well
known.
High-Intensity Focused Ultrasound
High-Intensity focused ultrasound (HIFU)
[13вЂ“45] kills the tumor cells by heat [14, 15, 21,
44]. By focusing ultrasound waves through the
rectal wall a heat wave arises from the buildup
of acoustical pressure at the focus point coming
down toward the rectal antenna, which destroys
the prostate tissue in a very tiny and controllable
area at temperatures of 85В°CвЂ“95В°C. This can be
compared to the shockwave in ESWL, focusing
energy and destroying prostate tissue without
damaging the interlaying rectal wall. With Ablatherm this heat wave kills by thermonecrosis
and controlled cavitation, and the single lesion
expands from the anterior to the posterior wall
of the prostate with a variable focus distance of
1.9вЂ“2.4 cm and a with of 1.7вЂ“2 mm (resulting
in a killing zone of 20вЂ“30 by 2 mm per lesion).
The safety distance from the rectal wall can also
be adjusted between 3 and 6 mm, and the entire
treatment is fully automated [15, 18вЂ“21, 25, 40,
42]. With the Sonablate the lesions are only 1 cm
in length and killing results from thermonecrosis alone. Manual repositioning of the rectal antenna is necessary with Sonablate [27, 32, 46]. By
reproducing these lesions, one next to the other
in one layer and then again in the next layer, the
urologist can truly shape the killing area to the
exact contour of the prostate or of the target area.
Theoretically a more focused approach becomes
possibleвЂ”a nerve-sparing procedure resulting
in high potency preservation rates. Comorbidity is extremely low. HIFU can be done after a
transurethral resection of the prostate (TURP),
in case of local recurrence after any former therapy [radical prostatectomy (RP), external beam
radiotherapy (EBRT), brachytherapy, cryotherapy, etc.] and patients can also be safely retreated
with HIFU in case of local recurrence. The rectal
wall is protected by a continuous cooling (5В°C),
and a specific software design in the Ablatherm
system guarantees safe and efficient, automated
treatment under real-time powerful transrectal
ultrasound control.
Chris DвЂ™Hont
The advantages of HIFU are the minimal
invasive approach, relatively low cost of the
single-use material (compared to TCAP and
brachytherapy), excellent results on tumor control [low and stable prostate-specific antigen
(PSA) counts and negative biopsy rates while
preserving quality of life (QoL)], and the excellent shaping possibilities of following the exact
shape of the prostate, even at the level of the rectal wall (resulting in very low comorbidity and
extremely rare fistula rates). Potency preservation is high and incontinence rates are extremely
low. Specific software programs guarantee safe
re-treatment after irradiation (EBRT or brachytherapy). Patients leave the hospital within 24 h
after treatment and can get back to normal activity very shortly after. Within 3вЂ“6 months the
necrotic tissue is transformed into firm fibrotic
tissue around a normal urethra and the size of
the prostate usually shrinks to less than 5вЂ“10 cc.
A short learning curve (5вЂ“10 cases) is involved,
and knowledge of transrectal ultrasound is
mandatory. HIFU is done by a truly minimal
invasive transrectal approach (no transperineal
needles). Practicioners get precise lesion control, and there is a limited need for post-HIFU
catheterization 3вЂ“10 days.
Immune Response?
There are indications that killing prostate cells by
TCAP or by HIFU produces an immune (T cell
stimulation) reaction that in some reported cases
seems to have led to disappearance of metastases [36]. These, however, are case reports and no
scientific studies have confirmed these findings
so far.
Long-Term Results?
Results over more than 10 years have been published on cryotherapy from a limited number of
centers. There is a difference in outcome between
centers that systematically apply TCAP under
temperature monitoring (better results by expanding the ice ball until killing temperatures are
reached throughout the target area) and centers
that rely only on the transrectal ultrasound im-
12 Cryoablation and High-Intensity Focused Ultrasound
age of the posterior wall of the ice ball (shadowing the rest of the prostate). The results are very
operator-dependent [5, 6, 8вЂ“11].
Only two centers (Lyon and Munich) have
results on Ablatherm-HIFU covering more than
10 years (newer technology), but they confirm
the durability of the short-term results over a
long follow-up period. Several short-term results
have been reported. They generally conform
across all the different centers (>65 so far), showing the procedure to be less operator-dependent.
Lots of very promising results are being published and have been presented at international
urology meetings from many new centers with
follow-ups dating back up to 5 years [19вЂ“21, 25,
28вЂ“35, 38вЂ“46].
Both TCAP and HIFU, however, are very
promising and show advantages over radiotherapy and brachytherapy. Both can be repeated in
cases of local recurrence, are possible after irradiation failure, show very promising results as
primary therapy in patients who cannot or do
not want to have radical surgery, and show good
results in low- and high-risk PCA patients and in
all Gleason scores.
Ablatherm-HIFU has the advantage of being
less operator dependent, more automated, and
less invasive and safer for the patient (specific
software programs for specific conditions, fully
automated computer safety control of all parameters prior to each individual lesion).
Further clinical follow-up will have to confirm these promising results and define the definite place of these new technologies in prostate
cancer managing.
Results
Results TCAP
Although different reports highlight different
study interests and outcomes, the overall results
of TCAP seem to be very similar to classical alternatives for radical prostatectomy (Tables 12.1
and 12.2).
A quick lowering of the PSA to reach nadir
within 1вЂ“3 months, with fairy long-term results,
seems to be the overall outcome of TCAP. DFS
rates around 65%.
203
Results HIFU
A Multicenter European study shows very high
negative biopsy rate of more than 85% after a
single HIFU treatment. The rate climbs to more
than 95% with a second HIFU treatment, which
is indicated for a proven local recurrence (Table 12.3) [31].
Multiple single center reports show similar
results on disease-free survival and success rates,
a quick lowering of the PSA with very low nadir PSA usually reached within 1вЂ“3 months after HIFU treatment, and negative biopsy rates of
80%вЂ“93% with stable DFSR (Table 12.4).
PSA stabilizes around the nadir value of less
than 0.5 ng/ml for more than 75% of HIFU patients for the entire follow-up period (Tables 12.5
and 12.6) [42].
Comparing the outcome of the different treatment options for localized PCA, the results of
HIFU prove to be at least as good as those of any
other classical treatment option (Table 12.7).
Complication rates with HIFU are extremely
low, as fistula have not been seen with the current
Ablatherm software and rectal cooling. These extremely low comorbidity data favor HIFU over
all other treatment options (Table 12.8).
With HIFU a more focal treatment is technically possible. Nerve sparing treatments in wellselected patients offer potency preservation to
more than 75% of patients along with full tumor
control (Table 12.9).
HIFU can be repeated without additional
comorbidity, any other local treatment remains
possible after HIFU treatment in case of local recurrence. Local recurrences after HIFU are rare
and show no upgrade in tumor aggressiveness.
HIFU also proves to be a good salvage treatment for local recurrences after radiotherapy.
With the development of specific software parameters for re-treatment after radiotherapy
(EBRT or brachytherapy) with the Ablatherm
equipment, HIFU seems to offer a safe second
line treatment option for those formerly lost patients. Negative biopsy rates in the Gelet series
are around 80%, and comorbidity is low and very
much acceptable (Table 12.10).
Fewer results are published with Sonablate,
with short follow-up periods. Success rates are
around 76% biological disease-free survival rate
204
Chris DвЂ™Hont
Table 12.1 Therapies for localized prostate cancer. Treatment options for local PCA 2005вЂ“2006
RP
RXT
Brachy
TCAP
HIFU
Min.inv
No
Yes
Yes?
Yes?
Yes!!!
Repeatable+choices
No
No
No
Yes
Yes
1 day
No
No
Yes
Yes
Yes
Biopsy neg
Yes
No?
No?
Yes
Yes
PSA<0.5
Yes
No?
No?
Yes
Yes
HIFU, high-intensity focused ultrasound; Min.inv, minimal invasive procedure; RP, radical prostatectomy; RXT, radiotherapy; Brachy, brachytherapy; TCAP, targeted cryoablation of the prostate
Table 12.2 Results TCAP
Bahn, Lee
[10]
Number
590
mfolow_up
5.43 years
Chinn [2]
5 years
Chin, Paulter
[7]
Prepelica,
Katz [13]
De la Taille
[3]
118 ebrt fail
65
43 ebrt fail
18.6 months
35 months
21.9 months
3-month MAB
PSA<0.5
Low
61%
76%
Med
68%
72%
High
61%
40%
34%
PSA<1
Low
87%
37%
96%
Med
79%
91%
High
71%
49%
Low
92%
Med
89%
High
89%
35%
ASTRO
83%
POSBX
2В°TCAP
Fistula
13%
PSA<0;5
68%
PSA<1
72%
ASTRO
91%
15%
0%
3.10%
3.30%
Table 12.3 European multicenter HIFU [31] study ThГјroff-AUA/WCE 2002
Negative biopsy rate
Overall T1вЂ“2
85.7%
Low risk
92.4%
Interm. risk
84.4%
High risk
72.1%
12.50%
66%
12 Cryoablation and High-Intensity Focused Ultrasound
205
Table 12.4 Results HIFU [21, 26, 29, 31, 33, 38, 34, 42]
ThГјroff
Chaussy
Poisonnier Vallencien Blana
DвЂ�Hont
Gelet
Conti
Nb
402
271
120
30
146
350
245
146
M nadir
PSA
1.8
0.8
0.9
0.9
0.07
0.5
0.9
0.07
Neg bx %
87.2
87.7
86
80
93.4
ND
86
93.4
Nb, number; Neg bx, negative biopsies
Table 12.5 PSA post HIFU [42]
Mean PSA (mPSA) per risk group [42]
PSAO
Low
Interm.
High
T3a
PSA1
PSA 3
PSA12
PSA18
PSA24
PSA30
PSA36
0.6
0.9
0.8
Full
6.4
0.3
0.2
0.5
0.6
NS
6.4
0.7
0.5
0.5
0.3
0.6
0.7
0.6
Mean
6.4
0.55
0.35
0.5
0.45
0.6
0.75
0.7
Full
8.2
0.6
0.4
0.6
1.3
1
1.2
1.1
NS
7.7
0.7
0.6
0.6
1.6
1
0.1
0.5
Mean
7.95
0.7
0.5
0.6
1.45
1
0.65
1
Full
12.8
0.7
0.8
1.3
1.5
1.5
1.7
1.6
MS
16.2
0.4
0.4
0.8
0.2
0.2
0.3
0.5
Mean
14.5
0.55
0.6
1.05
0.85
1
1.2
1.05
15.4
2.5
1.5
1.5
1.4
1.3
1.7
1.8
Table 12.6 PSA less than 0.5 ng/ml post HIFU [42]
PSA<0.5 ng/ml
Low
Interm.
High
T3a
F
82%
86%
88%
NS
84%
84%
82%
F
75%
83%
68%
NS
83%
84%
81%
F
63%
60%
60%
NS
74%
70%
74%
F
67%
60%
47%
PSA less than 1 ng/ml at 6 months: low risk, 100%; intermediate risk, more than 90%; high risk, more than 80%; T3
cancer, more than 70%
206
Chris DвЂ™Hont
Table 12.7 Adapted outcome after Katz and Newcastle [11]
Biochemical disease-free survival bDFS
Katz and Newcastle [11]
Gelet [20]
RP
Cryo
Brachy
3DCRT
XRT
HIFU
Low
76%вЂ“98%
60%вЂ“92%
78%вЂ“89%
76%вЂ“87%
81%вЂ“86%
84%
Moderate
37%вЂ“77%
61%вЂ“89%
66%вЂ“82%
51%вЂ“58%
26%вЂ“60%
68%
High
46%
Table 12.8 Complications post HIFU [42]
Risk
Low
Treat
Numb.
Loc rec
Micro
meta
Urge
Stress I
Stress II
TUR/
strict
>3 months
Mini
Fistula
Death
follow-up
Not rltd
Full
29
0
0
1
1
0
7
0
0
NS
33
1
0
1
2
0
2
0
0
56
0
4
1
10
0
8
41
3
4
1
5
0
4
0
Interm. Full
NS
0
1
0
0
0
High
Full
65
6
5
2
7
1
9
NS
21
2
1
0
2
0
3
0
0
0
0
0
T3
Total
82
8
13
2
3
1
8
0
3
327
20
27
8
30
2
41
0
4
2.4
9.1
0.6
12.5
0
1.2
%
6.1
8.2
Distant tumor activity, rise in PSA, biopsies negative after HIFU; Loc rec, local recurrence proved by positive biopsy(s)
after PSA-rise: all had successful 2В° HIFU treatment; NS, nerve sparing; rltd, related; Strict, stricture; TOT, total; TUR,
transurethral resection
Table 12.9 Potency preservation after HIFU [42]
Risk
Full/nerve
sparing
Pot. Pros.
Low
F
32%
NS
78%
F
25%
NS
F
Interm.
High
NS
T3a
F
Table 12.10 Salvage treatments of prostate cancer relapse
after definitive EBRT (Gelet [37])
Procedures
Surgery Cryo
Brachy
HIFU
Amiing Chin
et al.
et al.
Grado
et al.
Gelet
et al.
Patients (n)
108
118
37
106
73%
DFSR
43%
40%
34%
40%
35%
Incontinence 51%
20%
6%
21%
75%
Obstruction
21%
8.5%
14%
16%
8%
Rectal injury
6%
9%
6%
*New specific software program on Ablalherm
5%вЂ“0%*
12 Cryoablation and High-Intensity Focused Ultrasound
(BDFSR) at 2 years, with negative biopsy rates of
68% (Uchida et al).
207
fighting PCA, preserving quality of life without
compromising the chances for a cure to this alltoo-common malignancy.
Conclusion
References
Both TCAP and HIFU use temperature to kill
prostate cells. Freezing below в€’40 В°C or heating
the prostate over 50 В°C each seem to be an effective method to control PCA and kill off prostate
cells. Both are performed under transrectal ultrasound control.
TCAP is more aggressive, since perineal puncture is needed to stick the cryoprobes into the
prostate tissue; temperature monitoring seems to
be best way to obtain optimal results. The learning curve is long and the results are very much
operator-dependent.
HIFU is less aggressive and is performed
transrectally. No puncturing of the perineum or
the prostate is needed to obtain good tumor kill.
With Ablatherm (for which we have the most
publications and the largest documented experience) most of the results are standardized thanks
to the fully automatic computer-controlled treatment, with fully automatic safety checks before
each lesion and rectal cooling stage. There are also
specific software programs for safe re-treatment.
Thermonecrosis and controlled cavitation are at
the basis of good HIFU treatment. The learning
curve is extremely short for a urologist experienced in transrectal ultrasound. Comorbidity is
extremely low, and reconvalescence extremely
short. Therefore, HIFU seems to be taking over
TCAP very quickly, ensuring its position in the
treatment of localized PCA.
Both treatments have proved their value killing tumors in PCA and therefore no longer need
to be called experimental treatments. Their results have been established in numerous single
and multicenter studies, with clinical follow-up
dating back over 10 years.
Long term follow-up needs to confirm these
very promising data, but once that happens, both
treatments can be repeated and leave an opening
for any other second-line curative option in case
of local recurrence, which has not been the case
to date with any of the more classical treatments.
Both HIFU and TCAP are sure to play a role
in the future as less aggressive approaches to
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13
The Role of Hormonal Treatment
in Prostate Cancer
Stephan H. FlГјchter, Ralf Weiser, Christoph Gamper
Recent Results in Cancer Research, Vol. 175
В© Springer-Verlag Berlin Heidelberg 2007
Abstract
In 1941 Huggins and Hodges published for the
first time the favorable effects of surgical castration and estrogen treatment on the progression
of metastatic prostate cancer. However, this hormonal therapy is not without side effects. Since
this pioneering milestone in history of prostate
cancer, a further tremendous innovation did
not take place. Today, due to intensive clinical,
biochemical, nuclearвЂ“biological and molecularвЂ“biological research, many hormone active
treatment variations are available. Besides traditional hormonal therapy, surgical or chemical
castration, maximal androgen blockade, nontraditional forms of hormonal therapy, intermittent
hormonal therapy, antiandrogens, 5-О±-reductase
inhibitors, and their combinations, we discuss
options toward creating an increased number
of side effect-oriented offers of hormonal treatment options, guaranteeing a longer and more
comfortable exhaustion of the individual hormonal period of response and probably a longer
survival. The prerequisite is a closer-than-ever
monitoring by tumor marker and an early observation of symptomatic changes.
Abbreviations
AD
DES
DHT
HT
IHT
HRPC
MAB
NHT
Androgen deprivation therapy
(surgical or chemical castration)
Diethylstilbestrol
Dihydrotestosterone
Hormonal therapy
Intermittent hormonal therapy
Hormone-refractory prostate cancer
Maximal androgen blockade
Neoadjuvant hormonal treatment
PSA
RP
RT
T
Prostate specific antigen
Radical prostatectomy
Radiotherapy
Testosterone
History
The introduction of hormonal therapy (HT) in
the treatment of prostate cancer (PC) by Huggins and Hodges (1941) in the 1940s was like a
thunderbolt. However, despite intensive basic
research on the field of hormonal receptors and
of testosterone (T) bioconversion and a better
understanding of the endocrine mechanisms
of action and inhibition in endocrine-active
organs, a further pioneering development has
not been achieved. The first-line standard option in virginal metastatic PC remains the androgen blockade achieved today with minimal
side effects using luteinizing hormone-releasing
hormone (LHRH) analogs. Low-priced, equally
effective alternatives to hormone deprivation
such as orchiectomy with the disadvantage of
morbidity and irreversibility had to give way to
the demand for a better quality of life (Fowler et
al. 2002; Potosky et al. 2002). Due to their high
rate of cardiovascular and hepatogenic complications, estrogens had fallen out of favor until
recently. Today a renaissance may be expected
as the transdermal form of parenteral applications, avoiding hepatic first-pass metabolism,
seems to be as effective as LHRH analogs, prevents andropause symptoms, improves quality of
life scores, and increases bone density. It could
be shown recently that this estrogenic compound
induces a prostate-specific antigen (PSA)-response in patients with hormone-refractory PC
(HRPC). It is important to mention that the
212
transdermal application of estradiol costs a tenth
of current therapy (Ockrim et al. 2004, 2005).
In the last few years, survival and quality of life
have improved due to modern hormonal treatment options consisting of many endocrine-active drugs, closer monitoring of tumor markers,
early observation of symptomatic changes, and
use of different hormone-active substances in a
secondary and even tertiary setting before nonhormonal treatment is indicated. In the case of
metastatic PC, the average duration of response
to castration was between 18 and 24 months
20 years ago. Further survival was rarely longer
than 6 months. Nowadays these patients survive
twice as long on average (Sharifi et al. 2005).
Therefore, delaying the onset of a true hormonerefractory state and exhausting all possible forms
of hormonal manipulations before starting effective chemotherapy is a reasonable strategy. Today
PSA values are followed more closely in actively
treated patients. Early change from a treatment
that effectively has been exhausted to one that
may be by now of benefit is possible. In this paper we give a summarized report of todayвЂ™s treatment options for patients with locally confined
PC, for patients in PSA progress after curative
treatment, for those with locally advanced PC,
for those with distant metastases, and for those
progressing in hormonal relapse.
Locally Confined Prostate Cancer
(T1вЂ“2 N0 M0)
In T1/T2 PC, curative treatment is indicated. Especially in young patients, radical prostatectomy
(RP) is the first treatment option. In pT1 and pT2
tumors, no further therapy is needed. There is no
place for adjuvant androgen deprivation therapy
(AD) or maximal androgen blockade (MAB) because, due to the side effects, survival may even
worsen. Recently, the members of the Early Prostate Cancer (EPC) program (Wirth et al. 2004;
Iversen et al. 2004; Iversen 2005) reported experiences with patients with localized and locally
advanced PC. The EPC program comprised three
randomized, double-blind, placebo-controlled
trials. Altogether 8,113 patients had RP (55%),
radiotherapy (RT) (17%) or watchful waiting
(25%) as standard care, and thereafter they were
Stephan H. FlГјchter, Ralf Weiser, Christoph Gamper
randomized into a bicalutamide 150 mg/day arm
(n=4,052) or a standard care only arm (placebo;
n=4,061). Bicalutamide led to a significantly improved progression-free survival in the overall
population. Overall survival was similar in the
bicalutamide and placebo groups, across the program, and in each trial. However, in the patients
primarily treated with watchful waiting, overall
survival appeared to be reduced in patients with
localized tumors treated with bicalutamide. The
authors concluded that there is no indication for
RP and adjuvant HT in patients with localized
disease and with low risk.
RT is also a curative treatment option. In
low-risk T1aвЂ“T2b N0 M0 PC patients (Gleason
score<7, PSA<10 ng/ml), the recommendation
is for external RT up to 70вЂ“72 Gy. In intermediate-risk T2b PC patients (Gleason score 7, PSA
10вЂ“20 ng/ml), dose-escalating RT up to 76вЂ“81
Gy becomes necessary. Additive adjuvant HT
does not improve the outcome (Wirth et al. 2004;
Iversen et al. 2004; Tyrrell et al. 2005). However,
the high-risk tumor T2c and upward (Gleason
score>7, PSA>20 ng/ml) often has not been
treated sufficiently by dose escalating RT alone.
Adjuvant HT is of significant benefit when there
is a possibility of a not-yet-detectable lymph
node involvement, or tumor spread outside the
pelvis (Aus et al. 2005). DвЂ™Amico et al. (2004) reported a survival benefit in a randomized controlled study for the management of high-risk
patients with clinically localized PC treated with
70 Gy three-dimensional conformal RT in combination with 6 months of HT. Eligible patients
included those with PSA at least 10 ng/ml, a
Gleason score of at least 7, or radiographic evidence of extraprostatic disease. After a median
follow-up of 4.52 years, patients randomized to
receive RT plus HT had a significantly higher
survival (p<0.04), a lower PC-specific mortality
(p<0.02), and a higher survival free of salvage
HT (p<0,002). Granfors et al. (1998) confirmed
the above findings. In a prospective randomized
study they compared orchiectomy and external
RT versus RT alone for nonmetastatic PC with or
without pelvic lymph node involvement. There
were 91 patients enrolled. Patients with early
stage and well or moderately well differentiated
T1вЂ“2 N0 tumors were excluded from the study.
After a median follow-up of 9.3 years, clinical
13 The Role of Hormonal Treatment in Prostate Cancer
progression was seen in 61% of the control group
and 31% of the hormone group (p<0.005). The
overall mortality was 61% and 38% (p<0.02),
and cancer-specific mortality was 44% and 27%
(p<0.06), respectively. The differences in favor
of combined therapy were mainly observed in
lymph node-positive tumors. For node-negative tumors there was no significant differences
in survival rates. The two above-cited studies
clearly demonstrate that there is no benefit of adjuvant HT after RT in locally confined PC. These
statements were recently confirmed by Tyrrell et
al. (2005) who presented an exploratory analysis
of the subgroup of the EPC program consisting
of 1,065 patients with T1вЂ“2 PC. The patients received RT and were later randomized in a bicalutamide treated arm and RT only arm. No benefit
was seen in the bicalutamide arm.
The first randomized studies assessing the
impact of immediate HT alone in men with locally confined PC was reported by the Veterans
Administration Cooperative Urological Research Group (VACURG) in 1972 (Byar 1972).
The studies found higher mortality in patients
receiving 5 mg/day diethylstilbestrol (DES) as
compared to those receiving placebo. Cardiovascular complications induced by DES caused the
high mortality rate. Due to this concern, the use
of DES had fallen out of favor until recently (Aus
et al. 2005; Ockrim et al. 2004, 2005). A less morbid form of HT using an antiandrogen alone has
been examined by the EPC program in a large,
ongoing, randomized trial (Wirth et al. 2004;
Iversen et al. 2004; Iversen 2005). The program
design is described above. The authors confirmed again a trend toward a reduction of overall survival in patients with localized PC treated
with bicalutamide. This contention was especially derived from the Scandinavian subgroup
of the EPC program (Iversen et al. 2004). In this
trial, 1,218 patients were enrolled, of whom 81%
were given primarily standard care with watchful
waiting. Of the participants, 60% had stage T1вЂ“2
tumors, 38% T3 PC; 43% had a Gleason score in
the 2вЂ“4 range, and 44% a Gleason score of 5вЂ“6.
The authors calculated that the relative effect of
bicalutamide as compared to placebo on overall
survival was dependent on baseline prognostic
factors showing statistical significance. Low-risk
patients characterized by low baseline PSA and
213
localized disease showed a decrease in overall
survival when treated with bicalutamide. On the
other hand, patients with locally advanced disease and high baseline PSA showed trends toward an improved survival. They concluded that
watchful waiting remains a valid treatment option in low-risk patients with localized PC.
To date there is no indication for starting HT
alone or in combination with RP or RT in T1/T2
PC. In patients with poorly differentiated, aggressive tumors showing contraindications for RP
such as advanced age, comorbidity, or refusal of
RP, combination therapy consisting of any form
of HT and RT can be indicated, especially when
there is a suspicion of lymph node metastasis or
tumor spread outside the pelvis.
EUA comment (Aus et al. 2005):
вЂ“ For patients with localized PC T1cвЂ“T2c N0
M0 with high-risk short-term AD prior to, and
during, radiotherapy may result in increased
overall survival (level of evidence: 2a).
вЂ“ LHRH or bicalutamide at 150 mg/day can both
be used when there is an indication for hormone therapy (grade A recommendation).
Prostate Cancer in PSA Progress
After Curative Treatment
PSA has dramatically altered the epidemiology of
PC. For one, the incidence of PC has increased.
PC is detected at an earlier stage and in younger
men. Consequently there is a remarkable shift
toward curative treatment procedures such as
RP and RT. After a follow-up of about 10 years,
25% to 40% of patients who undergo RP or RT
will have biochemical recurrence, as detected
by early PSA monitoring. In the favorable early
stage of low tumor burden, the crucial question
is: Which is the best treatment strategy? PSA
doubling time after recurrence, Gleason score,
and time to early PSA relapse are helpful markers on which to base the decision whether curative treatment is still possible, or if hormonal
manipulations with the goal of palliation have to
be recommended (Pound et al. 1999; DвЂ™Amico et
al. 2003). Curative RT is indicated in case of local recurrence in the prostate bed. This situation
can be expected in case of a PSA increase after
more than 2 years, PSA doubling time of more
214
than 10 months, and a Gleason score below 7.
Otherwise HT is indicated, raising new questions: What kind of strategy is effective, cost-efficient, and can be performed with acceptable
side effects? When is the optimal time to start?
Decisions concerning treatment options have to
consider the experiences at Johns Hopkins Hospital (Pound et al. 1999) demonstrating a median
time of 8 years up to the onset of metastases in
patients with early PSA progress and a median
time to death after development of metastases
of 5 years. Gleason grade 8 to 10, PSA relapse
2 years or less after surgery, and PSA doubling
time of less than 10 months are adverse factors
that decrease metastase-free survival. Due to this
long natural history of cancer, patients have to be
fully informed about improvement of survival on
the one hand, and loss of quality of life (and sexuality) caused by treatment on the other hand.
Today, patients have to play an active role in the
treatment decisions.
Stephan H. FlГјchter, Ralf Weiser, Christoph Gamper
Radiation Therapy
Patients with a long life expectancy are candidates for salvage RT with curative intention,
when the possibility of either residual or recurrent tumor confined to the prostate bed is given.
In the first case, PSA levels often do not reach
normal values after operation. The second case
is characterized by a PSA relapse after more
than 2 years, a PSA doubling time of more than
10 months, and a Gleason score below 7. In this
situation there is no indication for HT. This step
should be reserved as second-line treatment for
men progressing despite salvage RT. A consensus
panel report (American Society for Therapeutic Radiology and Oncology, ASTRO) recommended that patients should receive salvage RT
with at least 66 Gy to the prostatic fossa before
PSA is greater than 1.5 ng/ml (Cox et al. 1999).
EUA comment (Aus et al. 2005):
вЂ“ Local recurrences are best treated by salvage radiation therapy with 64вЂ“66 Gy at a PSA serum
level <1.5 ng/ml (grade B recommendation).
Watchful Waiting
Duration of survival, quality of life, and cause
of death are considered important questions
for therapeutic decisions. If one remembers
that patients with PC treated by RP have a life
expectancy of more than 10 years, it must be
considered that the natural history of PC after
PSA relapse may be longer than 10 years (Pound
et al. 1999). So after the decision for palliative
treatment, two forms of HT appear to make sense
and be convenient: the watchful waiting strategy
with deferred hormone therapy beginning at
the time of symptomatic progression, or the
intermittent hormonal therapy (IHT) at the
time when PSA reaches values of an average of
5 ng/ml. Elderly men frequently die from other
comorbidities than cancer. So if the patientsвЂ™ life
expectancy at the time of PSA progress is less
than 10 years, watchful waiting is a convincing
option.
EUA comment (Aus et al. 2005):
вЂ“ Expectant management is an option for patients with presumed local recurrence unfit
for, or unwilling to undergo, radiation therapy
(grade B recommendation).
Hormonal Therapy
Patients whose PSA postoperatively never decreases to undetectable levels are generally considered to have either metastatic disease or residual tumor. In the latter, a decision for RT is
advisable, when there is the probability that PC
is confined to the prostate bed. Otherwise and
when there is a suspicion of metastatic spread,
HT is recommended. Furthermore, systemic
progress must be supposed when initially undetectable PSA levels increase in a period of less
than 2 years, when the PSA value doubles in less
than 10 months, and when the Gleason score
is 8вЂ“10. In case of systemic progress, HT is the
first option (DвЂ™Amico et al. 2003). No consensus
has been reached regarding the optimal time to
begin HT. Moreover, which kind of HT should
be administered? At which PSA level HT should
be initiated? Should patients be treated as soon
as possible, or at higher PSA levels such as 10,
20, or even 50 ng/ml? The favorable natural history of PC in patients with early PSA progress
after RP raises the question of whether early
hormonal therapy will improve the outcome?
13 The Role of Hormonal Treatment in Prostate Cancer
Today it must be accepted that long-time results
of studies aimed at cancer-free survival, overall
survival, and time to hormone resistance are
missing, and so definite treatment recommendations cannot be given. Therefore one should
attempt to work up the most effective strategy
by extrapolation of older trials with comparable
questions. Furthermore, new studies and the interim reports of running trials dealing with hormonal treatment in early PSA relapse should be
considered.
Traditional Hormonal Therapy
Since the 1980s, many authors have discussed the
effectiveness of MAB (Bertagna et al. 1994; Caubet et al. 1997; Bennett et al. 1999). The extent of
disease is seen as a prognostic factor for overall
survival with MAB, and some (Eisenberger et al.
1994; Soloway et al. 2000), although not all authors (Eisenberger et al. 1998), reported better
survival in patients with minimal metastatic disease. Meta-analyses (McLeod et al. 1997; Postate
Cancer TrialistsвЂ™ Collaborative Group 2000) with
the intention to evaluate the clinical benefit of
MAB for advanced PC ranged from no significant
survival benefit, up to 22% benefit. Some authors
demonstrated an advantage for patients with minimal metastatic disease. In performing an extrapolation of these results to treatment options for
PC in early PSA relapse, they concluded that there
might be a benefit of MAB in this stage as well.
Recently a randomized study from the British Medical Research Council (MRC) compared
immediate versus delayed HT in 938 patients
with newly diagnosed local advanced PC (M0)
or with asymptomatic metastatic disease (M1).
A significant advantage for the immediate treatment group could be seen in the lower progression rate from stage M0 to M1 and in lower cancer-specific mortality. This advantage was most
pronounced in those with M0 disease (Medical Research Council Prostate Cancer Working
Party Investigators Group 1997). These results
led to the assumption that immediate HT in men
with early PSA relapse may be advisable. However, the patients with M0 disease in this study
had a more advanced disease than patients with
early PSA recurrence after curative treatment. In
215
a prospective, randomized study, the Eastern Cooperative Oncology Group demonstrated significant advantages in case of immediate AD compared with delayed treatment in 98 patients who
underwent RP and pelvic lymphadenectomy and
who were found to have nodal metastases. After
a median follow-up of 7.1 years, clinically staged
recurrence-free survival was significantly better in the immediately treated group than in the
observation group (p<0,001). Overall survival
was significantly better among the men in whom
AD was initiated immediately, than among those
with delayed treatment (p<002) (Messing et al.
1999). If an extrapolation is possible it can be
speculated that there may be a benefit of early
HT for men with PSA-only recurrence after curative treatment. According to Moul (2000), an
extrapolation of these results to patients with
PSA recurrence makes sense.
In a retrospective study of a large observational multicenter database conducted by Moul
et al. (2004), 1,352 patients with PC in PSA relapse after RP (PSA>0.2 ng/ml) were enrolled.
Of the cohort, 355 received early HT (PSA
level<10 ng/ml). They were compared with 997
patients with delayed HT (PSA level>10 ng/ml).
Of the 1,352 patients with PSA relapse, clinical
metastases developed in 103 (7.6%). The interim
results demonstrated that early AD delayed the
metastatic progress in the patients with high-risk
(PSA doubling time<1 year or Gleason score>7).
However, by analyzing all patients, there has been
no difference so far concerning time to clinical
metastases. A longer follow-up will be needed to
evaluate whether there is a benefit for cancer-free
or overall survival. In some patients, low PSA
levels after curative treatment could be caused by
benign prostate cells, which remain in the prostate bed after operation. These cells could produce low and stable PSA levels over the time and
falsely manipulate the history of PC under trial
conditions (Ravery 1999; Djavan et al. 2000).
At the time PSA levels start to rise, patients are
often young and healthy, and quality of life plays
an important role. This has to be considered in
the design of the individual treatment strategy.
IHT starting at a low PSA level is one option to
reduce adverse events. Furthermore, it aims at
delaying the onset of androgen-independent PC
cells. Recently Kurek et al. (1999) reported on 44
216
patients treated in an IHT pilot study. Patients
with a PSA of more than 3 ng/ml were treated
for 9 months with continuous MAB. All reached
a PSA nadir of less than 0.5 ng/ml. When PSA
increased again to more than 3 ng/ml, HT was
restarted for a new 9-month cycle. At a mean follow-up of 48 months the average duration of HT
was 26.6 months. Due to the short duration of
the study, the results were good, as expected. No
patient progressed to hormone refractory disease. Peyromaure et al. (2005) stated that IHT for
biochemical recurrence after RP achieves satisfactory oncologic results. In his series of 57 men,
most were at high risk, explaining the 15.8% rate
of metastatic progression and the cancer-specific mortality rate of 12.3%. The group of Peyromaure had started their first treatment phase
(the вЂњonвЂќ phase) with an antiandrogen alone.
They explained the favorable results reported by
Kurek et al. (1999) by the use of MAB and/or by
the longer period of the first on-phase. Sciarra
et al. (2000) also mentioned that Gleason score
was important for the outcome. Of 12 patients
with early PSA progress after RP with Gleason
scores of 8 or higher, 9 failed to respond to IHT
and all developed metastatic and/or local failure.
No case with a Gleason score below 7 failed to
respond. Prapotnich et al. (2003) reported comparable results. There were 90 patients with early
PSA relapse after RP or RT who were initially
treated with MAB. After a median follow-up of
35 months, a metastatic progression rate of 23%
and a cancer specific mortality of 4% were found.
Pain (2.5%) and urinary complications remained
limited in patients with PSA relapse. It is remarkable that, overall, patients spent 32% of their
time in the treatment phase (on-phase) and 68%
in the surveillance phase (off-phase). Ongoing
large multicenter, randomized trials (AUO AP
17, 19, 20, SWOG 9346, NCIC PR7) have to confirm these encouraging results.
EUA comment (Aus et al. 2005):
Relapse after RP or RT:
вЂ“ PSA recurrence indicative of systemic relapse is
best treated by early AD resulting in decreased
frequency of clinical metastases (grade B recommendation).
вЂ“ LHRH/orchiectomy or bicalutamide at 150 mg/
day can both be used when there is indication for
hormone therapy (grade A recommendation).
Stephan H. FlГјchter, Ralf Weiser, Christoph Gamper
As endpoint studies concerning survival benefit in early PSA progression are missing, the real
advantages of early or delayed HT with MAB,
AD, or IHT have not been proved. Hence, benefits regarding these approaches are so far purely
speculative. Since the natural history of PC can
be calculated as extending up to 13 years, HT,
beginning at the time when PSA levels begin to
rise, will generally run for more than 10 years,
and the advantage of long-term treatment needs
to be questioned. The burdens of long-term treatmentвЂ”loss of libido, impotency, hot flashes, depression, lack of drive, cognitive decline, malaise,
mild anemia, fatigue, and long-term concern
for osteoporosis with risk of bone fracture and
decreased muscle massвЂ”are distressing for the
still young and otherwise healthy patients (Wei
et al. 1999; Potosky et al. 2001). One solution is
the above-mentioned IHT, and other options include single forms of nontraditional HT options
that are currently receiving increasing amounts
of attention and acceptance by patients.
Nontraditional Hormonal Therapy
Nontraditional HT includes nonsteroidal antiandrogens (bicalutamide, flutamide, nilutamide),
5-О±-reductase inhibitors (finasteride or dutasteride) and their combinations. These drugs do
not block the T synthesis in the testes, so that
longtime side effects of MAB or AD including
PADAM (partial androgen deficiency in the aging man) do not occur. Therefore, most patients
should retain libido, potency, muscle mass, erythropoiesis, and their psychological status. However, if gynecomastia and breast tenderness or
pain occur, prophylactic RT of the mammillary
glands can reliably prevent these side effects.
The growth of PC is regulated primarily by
dihydrotestosterone (DHT), which is converted
in the prostatic cells out of T by 5-О±-reductase.
A 5-О±-reductase inhibitor blocks this enzymatic
reaction. DHT has a higher binding affinity for
the intracellular androgen receptor than T. Antiandrogens occupy the cytoplasmatic DHT receptor in the PC cell by competitive binding. In
case of adequate concentration of antiandrogens,
DHT cannot find a binding place at the receptor. In this case there is no stimulating effect on
13 The Role of Hormonal Treatment in Prostate Cancer
PC cells growth by DHT. Both agents inhibit the
action of androgens secreted from the adrenal
glands and from the testes. Remarkably, they do
not decrease serum T.
Nonsteroidal Antiandrogens
Nonsteroidal antiandrogens (bicalutamide, flutamide, nilutamide) given alone in the treatment
of metastatic PC are currently not accepted as
standard therapy. While flutamide has a relatively short half-life and must be administered
three times per day, both nilutamide and bicalutamide are given once daily. None of these agents
causes a decrease in luteinizing hormone (LH)
production. Thus, serum T levels remain normal
or may slightly increase, and potency is spared
when these agents are used as monotherapy.
Bicalutamide given alone in a dose of 50 mg
once daily in patients with metastatic PC showed
a lower efficacy in the time to treatment failure,
time to progression, and survival as compared
to castration (Bales and Chodak 1996). Subsequently, it was administered in a higher dose of
150 mg. In this dose the effect of bicalutamide
as compared to castration was examined in two
large studies with M1 and M0 PC. In 805 patients
with M1 PC at a median follow-up of 1.9 years,
bicalutamide was not as effective as castration.
It is interesting to mention that especially in the
subgroup of patients with a PSA count of more
than 400 ng/ml the castration effect was dominant, whereas in the M1 cancer group with PSA
below 400 ng/ml bicalutamide and castration
had a comparable efficacy. In patients with M0
disease (n=480 patients) at a median follow-up
of 6.3 years, no statistical difference was found
between the two forms of HT (Tyrrell et al. 1998;
Iversen et al. 2000; Kaisary et al. 2001). It is still
unknown whether the results of these stages of
M1 PC with pretreatment PSA value of below
400 ng/ml or of M0 disease can be extrapolated
to prove a benefit of bicalutamide monotherapy
in patients with PSA relapse. However, bicalutamide monotherapy guarantees an acceptable
quality of life to a high degree.
In the ongoing EPC program, bicalutamide
was given 150 mg once daily as an adjuvant treatment to standard care consisting of RP, RT, or
217
watchful waiting. In a total of 8,113 men with
localized or locally advanced PC, effectiveness
was compared with standard care alone (See
et al. 2001). Primary endpoints were objective
progression-free survival and overall survival.
Although the two treatment arms did not differ with respect to overall survival, a significant
benefit of bicalutamide versus standard care in
progression-free survival could be demonstrated
at a median follow-up of 5.4 years. Analyzing
the subgroups, overall survival appeared to be
improved with bicalutamide in patients with
locally advanced disease, whereas in those with
localized disease survival was reduced with bicalutamide (Wirth et al. 2004). These results
were confirmed recently by Iversen in his third
analysis at a median follow-up of 7.4 years. The
EPC trial provides results on adjuvant bicalutamide treatment. Patients definitively cured by
RP or RT are part of the statistical analysis, and
therefore conclusions applied to PC patients in
early PSA progress may be trend-setting but still
speculative. It should be noted that this is a trial
dealing with a well-staged T1вЂ“2 PC population,
as less than 2% of the patients had lymph node
metastases. Nevertheless, bicalutamide in a dose
of 150 mg daily has not yet been extensively evaluated in patients with early PSA progress, and
therefore there is need for randomized clinical
trials. The trend in the analyses toward a reduced
overall survival after a follow-up of 5.4 years
(Wirth et al. 2004) and 7.4 years (Iversen 2005)
of bicalutamide treatment underlined the reservations of some authors to begin any form of
HT immediately at the time of early PSA relapse.
For flutamide monotherapy the published data
are rare and inconclusive. The reason may be the
many side effects caused by its gastrointestinaland hepato-toxicity.
EUA comment (Aus et al. 2005):
вЂ“ Bicalutamide at 150 mg/day can be used when
there is indication for hormonal therapy (grade
A recommendation).
5-О±-Reductase Inhibitor
The 5-О±-reductase inhibitor finasteride reduces
the enzymatic intraprostatic bioconversion of T
to DHT. Andriole et al. (1995) published the first
218
randomized trial dealing with this treatment option. In the first year, orally administered finasteride in a dose of 10 mg daily versus placebo was
given to 120 men with PSA only recurrence after
RP. Thereafter all patients were treated with finasteride for a further year. The drug was well-tolerated. A delayed marginal decrease in PSA levels
could be demonstrated. However, no significant
benefit concerning recurrence rates could be calculated for finasteride as compared to placebo.
From a biochemical point of view, a complete
inhibition of DHT synthesis is not possible.
In our opinion there is no place for finasteride
monotherapy in early PSA progress. A stimulating effect of PC growth due to the still persistent
DHT concentration cannot be excluded. On the
other hand, the combination of finasteride with
an antiandrogen seems worth examining. Consideration should be given to the fact that this
treatment is not inexpensive.
Combination Therapy of Nonsteroidal Antiandrogen
Plus 5-О±-Reductase Inhibitor
Combination therapy of nonsteroidal antiandrogen plus 5-О±-reductase inhibitor is also named
minimal androgen blockade or peripheral androgen blockade. The biological mechanisms of
action of each drug is described above. Additional synergistic effects were reported by Wang
et al. (2004). They performed experiments with
an established hormone-dependent PC cell line
(LNCaP). Due to the more complete inactivation of the androgen receptor, a diminished ability of the receptor to mutate and so to generate androgen-independent clones is discussed
in this section.
In two studies recruiting 71 (Barqawi et al.
2003) and 36 (Moul et al. 1998) patients, combination therapy was conducted with a low-dose
flutamide application of 2Г—125 mg plus 2Г—5 mg
finasteride daily in patients with early and only
PSA progress after RP or RT. In the first study,
58% of patients reached a PSA nadir below
0.1 ng/ml after a median time of 7.9 months. In
21 patients progress was found; 6 of them (28%)
did not reach the nadir of less than 0.1 ng/ml.
Comparable results are reported by Moul et al.
(1998). A change in libido or potency was not
Stephan H. FlГјchter, Ralf Weiser, Christoph Gamper
seen. Breast tenderness (90%), breast enlargement (72%), nipple tenderness (33%), gastrointestinal disturbance (22%), elevated liver function tests (9%), and chronic fatigue (10%) were
found. Kirby et al. (1999) conducted a randomized multicenter phase II study in patients with
M1 PC comparing a combination of finasteride
(2Г—5 mg, daily) and flutamide (250 mg, t.i.d.)
with two other arms. The second arm consisted
of 3.6 mg goserelin, administered monthly in
combination with 250 mg flutamide, t.i.d. and a
placebo, daily, instead of 2Г—5 mg finasteride. A
third arm consisted of 3.6 mg goserelin, monthly
in combination with finasteride, 10 mg (2Г—5 mg)
daily and a placebo (t.i.d.) instead of flutamide.
The reduction in concentration of serum PSA at
24 weeks was the endpoint of interest. Baseline
PSA of the patients in the three groups were very
similar. At the end of the study there were no
statistical differences in terms of PSA behavior
and decline between the centers nor among the
three treatment arms. WHO performance status
and pain score did not differ between the groups.
Comparable clinical results were reported for
the combination of finasteride and bicalutamide
in patients with advanced PC (Tay et al. 2004).
Longer follow-up of patients treated with oral
combination therapy is needed, and a randomized phase III trial in early PSA recurrence cases
is warranted. Combination therapy is not inexpensive. Therefore it should be clarified at the
beginning whether or not there is any advantage
in combination treatment compared to nonsteroidal antiandrogen alone.
It can therefore be summarized that in case of
early PSA progression after curative treatment, a
proven advantage of early or delayed HT has not
yet been documented. To date no randomized trial
has confirmed the effectiveness of early HT. Any
benefit regarding the best timing and treatment
options such as MAB, AD, IHT, or a nontraditional
hormonal therapy with antiandrogens or
antiandrogens plus 5-О±-reductase inhibitor is
currently purely speculative. Nevertheless, the
increasing application of nontraditional HT
underlines the claim that it will improve quality of
life in younger and mostly healthier patients who
are seeking nerve-sparing procedures. In cases
of early PSA progress, such patients pursue an
intention to preserve their potency.
13 The Role of Hormonal Treatment in Prostate Cancer
Locally Advanced Prostate cancer
(T3вЂ“4 NO/N1 M0)
The incidence of locally advanced PC declined as
a result of PSA screening. Men with locally advanced clinical T3 PC are generally offered active
treatment, consisting of RP, RT, HT alone, or HT
in combination with RP or RT. The goals of treatment are cure, longer survival, or metastasis-free
survival, as well as improvement of quality of life.
Watchful waiting and deferred treatment seem
dangerous and are not optimal options since
local and systemic progression occurs within
36 months in 87% and 100% of such cases, respectively (Allison et al. 1997). The watchful
waiting strategy is only acceptable in patients
with low-grade disease and with short life expectancy (Aus et al. 2005). However, there is no option for patients with intermediate or high risk
and with long life expectancy. Here local therapy
is warranted.
Radical Prostatectomy
According to the EAU guidelines, small unilateral T3 tumors with a PSA lower than 20 ng/ml,
a Gleason score lower than 8, and a life expectancy of more than 10 years demand more radical tumor extirpation including: an extensive
lymph node dissection, clean apical dissection,
neurovascular bundle resection, and often a large
resection of the bladder neck (Aus et al. 2005).
RT in combination with HT should no longer be
considered as the treatment of choice for all T3
PC, as recently reported data of the EPC group
presented at the ECCO in Paris 2005 confirmed
that after a median follow-up of 7.4 years in
terms of overall survival, there was no statistical
difference between the combined arm consisting
of RP and adjuvant bicalutamide as compared
to the RP-only arm. However, overall survival
could be statistically prolonged by the addition
of bicalutamide to RT compared with RT alone
(Iversen 2005; Tyrrell et al. 2005). So the first
option for T3 PC is RP (Hsu et al. 2005), and in
case of pT3 N0 adjuvant HT is not appropriate.
However, it is accepted today that the advanced
T3 tumor cannot be cured by surgery alone, and
therefore a combination of hormones and/or
219
RT is advocated. For more effective tumor treatment, neoadjuvant HT before RP, and adjuvant
HT after RP are controversial. The primary goal
of treatment is to extend a progression-free time
and the overall survival. Concerning T4 PC,
there is no indication for any attempt at active
curative treatment.
EUA comment (Aus et al. 2005):
вЂ“ Optional: patients with stage T3a disease, a
Gleason score of >8, and a PSA of <20 ng/ml.
вЂ“ The role of radical prostatectomy in patients
with high-risk features, lymph node involvement (stage N1 disease), or as part of a planned
multimodality treatment (with long-term hormonal and/or adjuvant radiation therapy), has
not been evaluated (level of evidence: 4).
Neoadjuvant Hormonal Treatment
The shortcoming of RP is that nonlocalized PC
is often found after the operation. This situation
is associated with a high rate of recurrence. For
this reason, the goal of neoadjuvant hormonal
treatment (NHT) is the improvement of operability of the tumor, better local cancer control,
and longer survival of the patients. It is clear that
this setting lowers the pathological stage and reduces positive margins (Labrie et al. 1994). An
effect of downgrading has not yet been convincingly proved (Van Poppel et al. 1995; Paul et al.
2001). Due to reduction of prostate size and tumor mass, an operation may be easier after NHT,
giving the surgeon better local control. On the
other hand, fibrosis could be induced and may
complicate surgery. Furthermore, pathological
evaluation of the Gleason score and subsequent
prediction of a patientвЂ™s prognosis is more difficult. Although Soloway et al. (2002) found significantly decreased positive margins in patients
treated 3 months before RP with NHT, there was
no significant difference in terms of the biochemical recurrence rates in the neoadjuvant-treated
group (64.8%) compared to the control group
(67.6%) (p=0.663) after a follow-up of 5 years.
Other authors confirmed these findings and
agreed that NHT neither improved the time to
clinical progression nor the rate of survival (Aus
et al. 1998; Schulmann et al. 2000). A randomized study was conducted by Gleave et al. (2001)
220
with the hypothesis of a better and maximal effect of AD after 8 months of NHT prior to RP. In
a recent abstract, he reported that there was no
advantage of an 8-month over a 3-month NHT
(Gleave et al. 2003). Therefore, neoadjuvant
treatment cannot be recommended in locally
advanced PC.
Adjuvant Hormonal Treatment
There is no need for adjuvant HT in the pT3 N0
M0 R0 PC. This could be clearly confirmed in
a comprehensive EPC study with an enrolment
of 8,113 patients. These men underwent a standard care consisting of RP (55%), RT (17%), and
watchful waiting (25%). Thereafter the patients
were randomly assigned to receive oral bicalutamide 150 mg/day or standard care alone. Less
than 2% of the patients had a lymph node involvement. After a median follow-up of 5.4 years
(Wirth et al. 2004) and 7.4 years (Iversen 2005)
there was a significant improvement in progression-free survival in the overall population, but
no advantage could be demonstrated in terms of
overall survival.
In case of lymph node metastasis, there is a
clear-cut treatment option. A randomized study
performed by Messing et al. (1999) beginning
immediately after RP with HT using orchiectomy
or LHRH-agonists, demonstrated that adjuvant
HT in case of positive lymph nodes significantly
increases patientsвЂ™ survival. Of 98 men with
N+PC randomized 12 weeks after RP, AD was
begun immediately in one arm and compared
with the other arm that was treated with delayed
HT. After a median of 7.1 years of follow-up, 7
out of 47 men who received immediate HT had
died, as compared to 18 out of 51 men in the
observation group (p=0.02). The cause of death
was PC in 3 patients in the immediately treated
arm and in 16 patients in the observation arm
(p<0.01). At the time of the last follow-up, 36 patients in the immediately treated arm (77%) and
9 patients in the observation arm (18%) were still
alive (p<0.001). The findings of Messing confirm
the results of several uncontrolled reports of the
Mayo Clinic group (Myers et al. 1992; Seay et al.
1998). Here only patients with N+ tumors bearing DNA diploid cells, and treated immediately
after RP with AD, had shown a survival benefit
Stephan H. FlГјchter, Ralf Weiser, Christoph Gamper
after a minimum of 10 years of therapy. If RP was
not performed because of lymph node infiltration of the tumor and the decision was made for
HT, Wijburg et al. (1999) reported a rise in the
cancer-caused death rate compared to delayed
HT. Altogether, the consequences of this procedure appear to be worse than those after RP, despite lymph node involvement and immediately
started HT. Cheng et al. (2001) underlined the
advantage of RP and adjuvant HT in stage pT3
N1вЂ“2 tumors. In relation to the extent of lymph
node involvement, they reported a 10-year cancer-specific survival rate of 74% after RP and
pN+ status. In case of minimal lymph node involvement there is only a slight improvement in
survival compared with patients without lymph
node involvement. These data are in agreement
with those of Bader et al. (2003) who report that
some patients with minimal metastatic disease
found by meticulous pelvic lymph node dissection remained free of PSA relapse for more than
10 years after RP without any adjuvant treatment. In summary, there are good reasons to
recommend RP and lymphadenectomy followed
by immediate HT in case of pN+. Since only less
than 2% of the 8,113 patients enrolled in the EPC
program have had lymph node involvement, the
efficacy of bicalutamide-only treatment in N+ PC
is not yet convincingly shown. The wait-and-see
strategy can be recommended only in a minimal
N1-disease clearly documented by meticulous
pelvic lymph node dissection. There is no need
for adjuvant HT after RP and pT3 N0 PC.
EUA comment (Aus et al. 2005):
вЂ“ In advanced PC, all forms of castration as
monotherapy (orchiectomy, LHRH-analogs
and DES) have equivalent therapeutic efficacy
(level of evidence: 1b).
вЂ“ Nonsteroidal antiandrogen monotherapy (e.g.,
bicalutamide) is an effective alternative to castration in patients with locally advanced disease (level of evidence: 1b).
Radiation Therapy
In clinical trials the evaluation of the stage-related prognosis in clinical staged cT3 tumors is
difficult. In case of RT the cT3 PC may consist of
a mixture of T2 to T4, N0 to N2 tumors. Ward et
al. (2005) found an overstaging in 27% (cT3 to
13 The Role of Hormonal Treatment in Prostate Cancer
pT2), an understaging in 8% (cT3 to pT4), and
an additional lymph node involvement in 27%.
Even when applied in high doses, RT appears to
have a limited curative potential in patients with
locally advanced PC. The results of RT can be
improved by combining RT with HT. Nowadays,
this is the вЂњgold standardвЂќ in RT of T3 PC (Lawton et al. 2001; Bolla et al. 2002). Still, it could
not be shown that combined radio-hormonal
therapy was superior to surgical treatment either
in monotherapy or in combination with postoperative RT or HT (Van Poppel 2005; Iversen
2005). Pelvic lymph node irradiation is optional
for N0 patients due to the possibility of occult N1
disease. However, in this stage the outcome of radiotherapy alone is dismal (Bagshaw et al. 1988).
AD therapy in combination with RT is recommended in order to kill clinically undetected micrometastases, because of the hormonal dependency. In addition, the risk of early progression
caused by not completely sterilized tumor cells in
the pelvic lymph nodes can be decreased. In this
situation a supra-additive apoptotic response depending on the timing of HT and RT could be
seen (Zietman et al. 1997; Joon et al. 1997). However, the real extent of the contribution of RT
to the patientsвЂ™ outcome in case of combination
therapy with hormones is still unknown, since an
HT-alone arm is missing in reported studies. For
this reason, the recently conducted NCIC/MRC/
SWOG PR.3/PR07 International Intergroup trial
is comparing HT alone with HT combined with
RT. The trial started 1995, has been expanded to
1,200 patients, and is expected to release survival
data from 2008 onwards.
Neoadjuvant Hormonal Therapy
In the Radiation Therapy Oncology Group
(RTOG) study 86-10, 471 patients were recruited
with stage T2вЂ“T4 N0-x, M0 PC. All patients received RT. In the neoadjuvant treated arm 3.6 mg
goserelin acetate was given every 4 weeks for
2 months before RT and during RT. In the control
group, HT was started in case of relapse. After
8.6 years the update of the neoadjuvant-treated
arm as compared to the control arm showed a
significant improvement in local control (42%
versus 39%, p=0.016), in disease-free survival
(33% versus 22%, p=0.0004), and in biochemical
221
disease-free survival (PSA<1.5 ng/ml; 24% versus 10%; p=0.0001). Still, a significant advantage
in survival (70% versus 52%; p=0.015) was only
seen in patients with favorable Gleason 2вЂ“6 PC
(Pilepich et al. 2001). The main conclusion of
this trial is that there is no significant benefit for
survival especially in the intermediate and highrisk groups. However, studies with a longer period of hormonal therapy for 8 months prior to
RT are missing. In contrast to NHT performed
prior to RP, where no advantage in NHT could
be demonstrated when comparing 3-month with
8-month-HT (Gleave et al. 2003), there may be
an advantage in case of RT. Pilepich et al. (2005)
discussed that tumor debulking caused by HT
leads to a better tumor control by RT. Up-to-date
randomized studies have not been conducted
that deal with a reduction in radiation dose and
radiation field caused by NHT as the prostate
is downsized. So RT could be milder and more
protective as the radiation field decreases. A decrease of acute complication rates could be expected. Finally, it is important to know if, after
NHT, a reduction in radiation dose is at all acceptable, as dose escalation in the high-stage and
-grade PC is indicated.
Concomitant and Adjuvant Hormonal Treatment
The European Organisation for Research and
Treatment of Cancer (EORTC) study No. 22863
included 415 patients with either T1вЂ“2 G3 cancer or with a T3вЂ“4 tumor of any histological
grade, and with or without nodal involvement.
In the first arm patients received 50 mg cyproterone acetate 3 times daily for 1 month and 3.6 mg
goserelin acetate every 4 weeks at the beginning
of RT. In the control group patients received RT
alone. Of the patients, 82% were staged as T3,
10% as stage T4, and 89% as N0. HT was finished
after 3 years. This study included men with higher
risk. After a median follow-up of 5.5 years, there
was a significant advantage for the combination
therapy concerning overall survival (78% versus
62%, p=0.001), clinical disease free-survival (74%
versus 40%, p<0.0001), locoregional progression
(1.7% versus 16.4%), metastatic progression (9.8
versus 29.2%), and survival without clinical or
biochemical progress (PSA<1.5 ng/ml; 81% versus 43%, p=<0.001) (Bolla et al. 2002). Compa-
222
rable results concerning overall survival in combination therapy consisting of only 6 months
of AD and three-dimensional conformed RT
of high-risk patients are reported by DвЂ™Amico
et al. (2004). A further, much smaller study of
HT (n=91 patients) conducted by Granfors et
al. (1998) supports these findings. The study
was designed to include up to 400 patients, but
after an interim analysis it was closed to further
recruitment due to high frequency of disease
progression in patients treated with RT alone, especially in the group with positive lymph nodes.
All patients underwent bilateral lymphadenectomy. Positive lymph nodes were found in 43%
of the subjects. Excluded from the study were
patients with early-stage, well-differentiated, or
moderately well differentiated lymph node-negative tumors. In the hormonally treated group
patients underwent orchiectomy about 3 weeks
after staging lymphadenectomy. RT was started
5 weeks later. In the control group, RT started 5
to 6 weeks after lymphadenectomy. After a median follow-up of 9.3 years, clinical progression
was seen in 61% of the control group and 31%
of the hormone group (p<0.005). The overall
mortality was 61% and 38% (p<0.02) and cancer-specific mortality 44% and 27%, respectively
(p<0.06). The differences in favor of combined
therapy were mainly caused by lymph nodepositive tumors. For node-negative tumors there
was no significant difference in survival rates.
Adjuvant Hormonal Treatment
In the RTOG study 85-31 (Pilepich et al. 1997),
977 patients with stage T3вЂ“4 N0вЂ“N1 Mo or pT3
patients after radical prostatectomy showing capsule penetration or involvement of the seminal
vesicles were enrolled. In the first arm, indefinite
AD therapy (Goserelin in a dose of 3.6 mg given
every 4 weeks) started in the last week of RT. In
the control arm, HT was delayed, beginning at
the time of recurrence. Of the patients, 15% in
the hormone group and 29% in the control arm
had undergone RP, while 14% of the patients in
the hormone arm and 26% in the control arm
had had pN1 PC. After a median follow-up
time of 7.3 years, statistically significant differences were found in the hormone arm versus the
Stephan H. FlГјchter, Ralf Weiser, Christoph Gamper
control arm concerning local progression rates
of 5 years in 15% versus 30% and of 10 years in
23% versus 39%, respectively (both p<0.0001).
Concerning metastatic progression, the ratios
were 15% versus 29% and in 25% versus 39%,
respectively (both p<0.0001). Overall survival of
5 years was found in 76% versus 71%; there was
survival of 10 years in 49% versus 38% (p<0.002).
An advantage concerning overall survival was
seen especially in patients with a Gleason score
of 7 to 10. In a subset of the study, 95 patients
of 173 with pN1 PC and immediately administered hormonal therapy in the last week of
radiation therapy had a significantly better survival rate without biochemical relapse at 5 years
(PSA<1.5 ng/ml) compared to the control arm
(p=0.0001) (Pilepich et al. 2001, 2005; Lawton et
al. 1997). Tyrrell et al. (2005) presented an analysis of the preplanned subgroup of the EPC program consisting of 305 patients who received RT
with curative intent in order to determine the efficacy of bicalutamide as adjuvant setting. After a
median follow-up of 5.3 years, bicalutamide significantly increased progression-free survival by
53% and reduced the risk of disease progression
by 42% (p<0,0035). Objective tumor progression
was experienced by 33% versus 48.6% in the control group. On the 13th European Cancer Conference in Paris, 31 October 2005, Iversen (2005)
confirmed these findings and underlined that after an actual follow-up of 7.4 months the overall
survival was prolonged by the addition of bicalutamide among men with locally advanced PC as
compared to those who had received RT alone.
In this context it must be stressed that less than
2% of the patients in this study have had lymph
node involvement. It could be concluded that
in this well-staged subgroup the antiandrogen
bicalutamide is an effective antiandrogen when
given immediately in an early stage of T3вЂ“4 PC.
Duration of Hormonal Treatment
Current studies do not give a clear indication for
the optimal duration of HT in combination with
RT. Is indefinite therapy (such as surgical castration) necessary? Is long-term treatment over 2 to
3 years more effective than short-term treatment
only around the time of radiation? There are few
13 The Role of Hormonal Treatment in Prostate Cancer
facts available; most questions are still open to
speculation. Today most data support the assumption that there is an advantage of long-term
over short-term HT (Horwitz et al. 2001). Two
studies dealing with this issue are running comparing long-term HT (2 years=RTOG 92-02 (97)
and 2.5 years=EORTC 22961) with short-term
HT (up to 6 months) at the time of RT. Preliminary data showed that tumor grade is apparently
a stratification parameter, as there are significant gains for long-term treatment concerning
survival in patients with Gleason score 8вЂ“10
PC (Hanks et al. 2003). However, the favorable
results of RT combined with HT limited to 2вЂ“
3 years could have been only due to the reduction
in the size of the primary tumor and the entire
prostate gland, which would thereby improve the
efficacy of RT. So we must reflect that, especially
in high-risk subgroups and those with clinically
undetected metastases, an indefinite HT may be
most effective. Furthermore, we have to consider
that the complications and side effects caused by
indefinite or long-term AD influence the overall
survival. Therefore the benefit of these traditional
forms of HT in low-risk patients must be evaluated. Consequently, the question is raised again
for the use of nontraditional HT (see page 216)
and again data given of the EPC program blaze a
trail to antiandrogen only treatment (Wirth et al.
2004; Iversen 2005).
EAU comment (Aus et al. 2005):
вЂ“ In locally advanced PC, overall survival is improved by concomitant and adjuvant hormonal
therapy (with a total duration of 2 to 3 years)
with external irradiation (level of evidence: 1).
вЂ“ For a subset of patients, T2cвЂ“T3 N0-x with
Gleason score 2вЂ“6, short-term AD before, and
during, radiotherapy may favorably influence
overall survival (level of evidence: 1b).
Hormonal Therapy Alone
The MRC (Medical Research Council Prostate Cancer Working Party Investigators Group
1997) PR03 study conducted in men with locally advanced or asymptomatic metastatic PC
recruited 938 patients between 1985 and 1993.
In all, 500 patients had a nonmetastatic disease.
The effect of immediate and deferred HT was
223
investigated. According to patientsвЂ™ preference,
orchiectomy or LHRH agonists were accepted.
The first analysis in August 1996, after 74% of the
patients had died, showed that 30% of the immediately treated patients and 22% of the patients
with deferred treatment were still alive (p<0.02).
In patients with nonmetastatic disease at the beginning of the study, survival was 41% in the immediately treated group as compared to 30% in
the deferred treatment group. In a new analysis
undertaken in 2000, when 86% of the patients
had died, the results continued to show significant overall and disease-specific survival. In the
subgroup of patients with nonmetastatic disease
at study entry however, no significant difference
could be demonstrated (Kirk 2000). However,
patients with immediate therapy benefited in
terms of reduced bone pain and risks of bone
metastatic progression, thus diminishing the risk
of complications such as pathological fracture
and spinal cord compression, as well as systemic
progression resulting in distant metastases and
urinary flow obstruction. The Cochrane Library
review analyzed four randomized controlled
studies of the pre-PSA era (Byar 1973; Medical Research Council Prostate Cancer Working
Party Investigators Group 1997; Jordan et al.
1977; Messing et al. 1999) comparing immediate
versus delayed HT and concluded that immediate HT significantly reduces cancer progression
and progression-caused complications. An improvement of cancer-specific survival could not
be demonstrated, but a slight benefit in overall
survival could be seen. Recently in the EPC program (Iversen et al. 2004) it was calculated that
the relative effect of 150 mg/day bicalutamide on
overall survival when given immediately as compared to placebo was dependent on the baseline
prognostic factors PSA and tumor stage. Patients
with locally advanced disease and high baseline
PSA showed trends toward improved survival.
On the other hand, in carefully reviewing the literature, the American Society of Clinical Oncology (ASCO) guidelines state that no recommendation could be made about when to start HT in
advanced asymptomatic PC (Loblaw et al. 2004).
The time to start HT in patients with locally
advanced and asymptomatic PC remains a matter of debate. However, because of the reduction
of disease progression and above-mentioned
224
complications, immediate hormonal therapy
may be recommended in locally advanced PC
(T3вЂ“4, NO/N1 M0). There is a difference concerning overall survival between N0 and N1 PC.
Due to the side effects of longtime or indefinite
treatment, AD plays a more remarkable role
than previously expected. Therefore considerations concerning treatment options such as
nontraditional HT, as discussed on page 216,
appear worthwhile. The second analysis of the
bicalutamide EPC program (Wirth et al. 2004)
supported the assumption that there is an advantage of early HT with bicalutamide (150 mg) in
patients with locally advanced PC after a followup of 7.4 months. At the 13th European Cancer
Conference in Paris, 31 October 2005, Iversen
(2005) actually underlined in his third analysis
the advantage of early HT with bicalutamide
150 mg/day. Although less than 2% of the patients were N+, a prolongation of overall survival
could be demonstrated in patients treated with
bicalutamide as compared to those with watchful
waiting alone. It remains difficult to predict the
best timing and the appropriate form of HT for
asymptomatic advanced disease.
In summary, it can be stated that the first option for locally advanced PC is RP. There is no
need for adjuvant HT after RP and pT3 N0 PC.
The advanced T3 tumor cannot be cured by surgery alone. If a decision is made for RP, no benefit in terms of survival can be expected by performing NHT. Adjuvant HT is clearly indicated
when lymph node metastases are proved. The
wait-and-see strategy can be recommended only
in a minimal N1 disease clearly documented by
meticulous pelvic lymph node dissection.
After a decision for RT, data suggest the combination with HT. Patients with locally confined
PC and low-risk disease (Gleason 2вЂ“6) might
benefit from NHT and short-time adjuvant HT.
Patients with intermediate or high risk (Gleason
7вЂ“10) need definitive RT and adjuvant long-term
HT. In this subset NHT is not effective.
If curative options are not sought, the advantage of early HT in all its forms is not really
proved in cT3 N0 M0 PC. Due to its minimal
adverse events, bicalutamide is of advantage for
prolongation of overall survival. In case of lymph
node involvement (cT3 N+) early and long-term
HT is recommended. In this stage an advantage
Stephan H. FlГјchter, Ralf Weiser, Christoph Gamper
of bicalutamide-only treatment has not yet been
proved. Watchful waiting and deferred HT is
only acceptable in asymptomatic patients with
low-grade disease and without lymph node metastases.
EAU comment (Aus et al. 2005):
вЂ“ In advanced PC, all forms of castration as
monotherapy (orchiectomy, LHRH-analogs
and DES) have equivalent therapeutic efficacy
(level of evidence: 1b).
вЂ“ In advanced PC, AD delays progression, prevents potentially catastrophic complications
and effectively palliates symptoms, but does not
prolong survival (level of evidence: 1b).
вЂ“ Nonsteroidal antiandrogen monotherapy (e.g.,
bicalutamide) is an effective alternative to castration in patients with locally advanced disease (level of evidence: 1b).
Metastatic Prostate Cancer
Hormone Therapy Alone: Immediate
Versus Deferred Hormone Therapy
The most appropriate time to begin HT is controversial. There is agreement that symptomatic
metastatic PC needs to be treated immediately
by HT. The clinical benefits include a reduction
of bone pain, an improvement in performance
status, and a reduction of urinary obstruction.
Considerable debate remains about the impact
of HT in men with asymptomatic metastases.
Properly conducted randomized and controlled
studies with convincing data outlining a clearly
defined stage and hormonal treatment schedules are missing. So the real outcome in terms of
survival and quality of life is still unclear. There
are single studies demonstrating an advantage in
survival for the immediately started HT. However, in the meta-analyses no significant benefit
could be demonstrated. Furthermore, four randomized controlled studies of the pre-PSA era
(Byar 1973; Jordan et al. 1977; Medical Research
Council Prostate Cancer Working Party Investigators Group 1997; Messing et al. 1999) comparing immediate versus delayed HT were analyzed
by the Cochrane Library review with the conclusion that immediate HT significantly reduces
cancer progression and progression-caused com-
13 The Role of Hormonal Treatment in Prostate Cancer
plications. An improvement of cancer-specific
survival could not be demonstrated, apart from
a slight benefit in overall survival (Schmitt et al.
2000). After a careful review of the literature, the
ASCO guidelines state today that no recommendation can be given as to when to start HT in advanced asymptomatic PC (Loblaw et al. 2004).
EAU comment (Aus et al. 2005):
вЂ“ In advanced PC, immediate (given at diagnosis) androgen suppression significantly reduces
disease progression and complication rate due
to progression itself compared to deferred (delivered at symptomatic progression) androgen
deprivation (level of evidence: 1b).
Maximal Androgen Blockade
or Castration Alone
MAB is the combination of surgical or chemical
castration effectively preventing testicular androgen synthesis (95%), and of antiandrogens blocking the activation of the androgen receptor in the
prostate cells caused by the persistent adrenal
androgens (5%) due to their competitive binding
affinity at the receptor level. Another important
effect of antiandrogens consists of the blockade
of the receptor by growth factors and other ligand-independent activators (Kuil et al. 1995).
The latter mechanism plays an important role in
receptor activation in the androgen-depleted environment of the prostate caused by castration.
The discussion concerning the benefit of
MAB began in the middle of the 1980s (Labrie et
al. 1985). There remain some vestiges of controversy by the advocates of MAB. Steroidal antiandrogens (cyproteronacetate) are considered to be
of no advantage due to their cardiovascular and
hepatotoxic side effects. Meta-analyses and systematic reviews of large trials using nonsteroidal
antiandrogens document a benefit of MAB only
in a small group of younger men with defined
small burdens of metastatic disease over pharmacological or surgical castration alone (Seidenfeld
et al. 1999; Schmitt et al. 2000; Prostate Cancer
TrialistsвЂ™ Collaborative Group 2000). Recently
Klotz et al. (2004) spoke about a reassessment of
the role of MAB for advanced PC after calculating an estimated benefit of 20% in favor of MAB
treatment using bicalutamide as compared to
225
castration alone. The background is that bicalutamide is said to be a more effective antiandrogen than both flutamide and nilutamide due first
to its clinically effective anticancerous properties, and second to its better-tolerated side effect
profiles. Data on bicalutamide are missing for
inclusion in the metaanalyses, as bicalutamide
was not available when most combined versus
monotherapy studies were conducted. In in vitro
binding studies, Bicalutamide has shown a 2вЂ“4
times higher binding affinity for the human androgen receptor than flutamide and a two times
higher affinity as compared to nilutamide (Kolvenbag et al. 1998). As a consequence, bicalutamide is much more potent in reducing the mass
of intact ventral prostates of the rat. Furthermore, nonsteroidal antiandrogens differ in their
interaction with the androgen receptor. For instance, bicalutamide activates the nuclear androgen receptor co-suppressor N-CoR and inhibits
the co-activator SRC-1, resulting in inhibition of
cell growth signals by activated androgen receptors. In contrast, flutamide activity is much more
muted in this system (Hu and Lazar 2000). There
are important biological differences between the
nonsteroidal antiandrogens in the androgen-depleted environment. Bicalutamide is superior to
flutamide and nilutamide in delaying androgenindependent progression. Bicalutamide appears
to be more favorable than other antiandrogens
in MAB, but its real advantage remains to be
proved. Nevertheless, recently reported information about cardiovascular side effects caused by
electrocardiographically proved QT-prolongation in men subjected to MAB have to be taken
into consideration when a decision is made in
favor of MAB. Patients with a baseline QT interval exceeding 450 ms or those taking class IA or
III antiarrhythmics have to be excluded from AD
plus bicalutamide, as they are at risk of sudden
death by arrhythmias (Garnick et al. 2004).
The minimal advantage in survival using
nonsteroidal antiandrogens (bicalutamide, flutamide, nilutamide) in the everyday clinical
practice does not justify the costs this treatment
generates in patients with metastatic PC. MAB
is not recommended as standard therapy, since
there is no general benefit to patients with metastatic disease as suggested originally by Labrie et
al. (1985).
226
EAU comment (Aus et al. 2005):
вЂ“ In advanced prostate cancer, the addition of
a nonsteroidal antiandrogen to castration results in a small advantage in overall survival
over castration alone but is associated with increased adverse events, reduced QoL and high
costs (level of evidence 1a).
Intermittent Hormone Therapy
The reversibility of chemical castration, the reduction of morbidity caused by long-term HT,
the amelioration of quality of life, the possibility
of monitoring the course of PC by PSA, and at
least the theoretical possibility of delaying hormone resistance as underlined by experimental data of IHT in murine models (LNCaP and
Shionogi) (Bruchovsky et al. 1990; Sato et al.
1996) were convincing facts for beginning trials
with IHT. In summarizing details of five phase II
studies, Goldenberger et al. (1999) reported that
the initial AD should last 9 months on average,
that some on/off cycles can generally be carried
out, and that quality of life in the AD-free offphase is clearly improved as compared to the
on-phase. Furthermore, we have learned that patients with initial bulky tumors, with numerous
lymph nodes or bone metastases, initial serum
PSA greater than 100 ng/ml, a rapid PSA progression slope of more than 5 ng/ml per month
or severe pain are apparently poor candidates for
IHT, since they frequently achieve only a partial
or short-term response (Prapotnich et al. 2003).
Encouraging results were reported by Lane
et al. (2004). They recruited 75 patients in an
open, nonrandomized study initiated 10 years
ago and treated them with IHT. Of the patients,
86% remain alive at a median of 134 months
(11 years) after initial histological diagnosis. The
authors calculated the survival time and the time
to hormone resistance (from first cycle of HT).
A median survival time of 95 months (8 years)
was found in patients with localized or locally
advanced PC. In patients with metastatic disease they reported a median survival time of
87 months (7 years). The median time to hormone resistance was calculated as 83 months in
the group of localized and locally advanced PC
and as 50 months in those with metastases. A
Stephan H. FlГјchter, Ralf Weiser, Christoph Gamper
100% 5-years actual survival rate was found for
those with localized and locally advanced PC
and a 70% 5-years actual survival rate for patients
with metastatic disease. The authorsвЂ™ opinion is
that IHT is safe and effective and they suggest an
apparent survival advantage related to a delay in
the onset of androgen resistance.
After having treated 72 men with localized, advanced, or metastatic PC, De La Taille
et al. (2003) recommend IHT for PC patients
aged more than 70 years with localized PC and
a Gleason score of 7 or lower. The 24 patients
with biochemical progression were younger than
those with no biochemical progression and had
a statistically higher Gleason score. Sciarra et al.
(2000) also mentioned that the Gleason score
is an important variable. Of the 12 cases with a
Gleason score of 8 or higher, 9 failed to respond
to IHT and all developed metastatic and/or local
failure. No case with Gleason score below 7 failed
to respond.
Strum et al. (2000) pointed out that hormonenaive patients who achieved and maintained an
undetectable PSA level for at least 1 year during HT might anticipate a prolonged off-phase.
Achievement of long, undetectable PSA levels
may serve as an in vivo sensitivity test of a patientвЂ™s tumor cell population and allow for a better selection of patients best suited for IHT.
The first randomized phase III trial was conducted by de Leval et al. (2002). They compared
the efficacy of total IHT (35 patients) with continuous MAB (33 patients). The study suggested
that IHT could maintain the androgen-dependent state of advanced PC at least as long as continuous MAB.
Another interesting option of IHT is the socalled intermittent triple androgen blockade,
reported by Leibowitz and Tucker (2001). There
were 110 patients with T1 to T3 PC treated with a
three-drug androgen blockade regimen, consisting of an LHRH agonist, an antiandrogen, and
finasteride, followed by finasteride maintenance
therapy in the off-phase. The long-term experiences were encouraging. In all patients PSA
levels declined to 0.1 ng/ml or less in a median
time of 3 months. After a median follow-up of
36 months after initiation of treatment, PSA levels have remained stable in 105 of 110 patients.
No patient has received a second cycle of hor-
13 The Role of Hormonal Treatment in Prostate Cancer
mone blockade. Recently Eggener et al. (2005) illustrated the theoretical background. In contrast
to DHT, T is a weak inducer of proliferation and
a more potent inducer of tumor differentiation.
Finasteride increases T and decreases DHT during the off-phase and enhances the efficacy. The
authors reported on experiments in which they
established LNCaP tumors in nude mice. Finasteride administered in the off-phase of IHT provided the most favorable tumor growth kinetics
and survival when compared to MAB or standard IHT.
The use of IHT is increasing, but despite theoretical advantages in terms of possible delay of
hormonal resistance and of quality of life, randomized clinical trials with large patient cohorts,
long follow-up, and comparable study designs
have to prove its superiority to continuous HT.
The available studies document the feasibility of
IHT in the treatment of patients with metastatic
disease, as well as of those with locally confined
PC with PSA relapse after RP or RT. Nevertheless, until more data regarding its safety and
impact on survival are available, IHT should be
considered experimental, and results of running
phase III prospective, randomized controlled
studies must be awaited. We need clear therapeutic strategies and trigger points guided by PSA
(Pether and Goldenberger 2004).
EAU comment (Aus et al. 2005):
вЂ“ Intermittent AD should still be regarded as experimental therapy (level of evidence: 3).
вЂ“ In advanced PC, all forms of castration as
monotherapy (orchiectomy, LHRH and DES)
have equivalent therapeutic efficacy (level of
evidence: 1b).
вЂ“ Bilateral orchiectomy may be the most cost-effective form of AD, especially if initiated after
occurrence of symptoms from metastatic disease (level of evidence: 3).
Hormone Refractory Prostate Cancer
The stage of the illness following progression after AD or MAB is termed hormone-refractory
disease. The median overall duration of response
to HT in patients with metastasizing PC is only
18 to 36 months, even when AD is given in combination with long-term antiandrogens.
227
The following EAU criteria of HRPC must be
fulfilled (Aus et al. 2005): (1) serum castration
levels of T; (2) three consecutive rises of PSA
2 weeks apart resulting in two 50% increases
over the nadir; (3) antiandrogen withdrawal for
at least 4 weeks (either antiandrogen withdrawal,
or one secondary hormonal manipulation should
have been done); (4) PSA progression, despite
secondary hormonal manipulations; (5) progression of osseous or soft tissue lesions.
In defining the status of HRPC, we must distinguish two forms. (1) The androgen-independent, but hormone-sensitive HRPC implies that
disease progression occurs despite castration.
However, the tumor remains sensitive against
further different forms of HT due to its tremendous heterogeneity. Small et al. (1997) could
demonstrate that certain hormone refractory
cases retain hormonal sensitivity even after progression following antiandrogen withdrawal or
change in antiandrogen application (second-line
hormonal therapy; duration 6вЂ“10 months) making possible an effective further treatment with
ketoconazole, aminoglutethimide, glucocorticoids, or estrogens (third-line hormonal therapy;
duration 4вЂ“8 months). Finally, PC will uniformly
become вЂњhormone refractoryвЂќ (Ryan and Small
2005). (2) The second form is the true HRPC
from the outset. This tumor is resistant to all hormonal manipulations.
Different forms of cancer resistance developing at different unpredictable time intervals can
be attributed to the heterogeneity of PC cells.
Reasons discussed are multifactor mechanisms
such as mutation and amplification of the androgen receptor gene, deregulation of apoptosis,
loss of microtubule integrity, and loss of autocrine stimulation of growth factors (Visakorpi
et al. 1995; Taplin et al. 1995; Fenton et al. 1997;
Isaacs 1999). The estimated natural mean survival of patients with HRPC is 18вЂ“20 months in
case of asymptomatic disease and high PSA level
in patients with no metastasis. With minimal
metastases it is 14 months, and with extensive
metastases 9вЂ“12 months. If metastases become
symptomatic, natural mean survival declines to
9 months in men with minimal metastases and
to 6вЂ“8 months in men with extensive metastases
(Aus et al. 2005). However, primary androgen
resistance does not mean that PC is resistant a
228
priori to further androgen stimulation. At the
time of androgen relapse some hormonal-sensitive clones may still exist. From the therapeutic
point of view it is advisable to continue AD treatment, for example with LHRH agonists during
the following treatment schedules, since after a
withdrawal of AD, DHT and T levels return to
normal after a median of 16.6 weeks (Gulley et
al. 2005). In this case, PC growth accelerates and
reduces survival (Taylor et al. 1993).
A valid therapeutic response is defined by
the following EAU guidelines (Aus et al. 2005):
PSA decline of more than 50% maintained for
8 weeks; assessment according to RECIST (Response Evaluation Criteria In Solid Tumors)
criteria in case of nonosseous metastases; in
patients with advanced symptomatic metastatic
HRPC, therapeutic response can be best assessed
by improvement of symptoms.
Each period of response may be short and may
last only a few months. Therefore it is important
to establish an effective long-term strategy for
HRPC. Despite the recently reported promising
outcome of a docetaxel-based regimen showing
a significant effect on survival, toxicity is grave
and hardly tolerated in elderly patients. The challenge is to better understand the multifactor
endocrinological, immunological, and genetic
correlations in the PC cells that make it possible
to open new pathways for effective combination
strategies and to develop better means to avert a
total hormone refractory PC.
Second-Line Hormonal Therapy
In case of hormone relapse after simple AD, additive treatment with antiandrogens is indicated
before starting second-line HT. However, flutamide (Fossa et al. 1990) as well as bicalutamide
(Joyce et al. 1998) administration in patients
previously untreated with antiandrogens have a
modest response. Joyce reported a response rate
of only 6% for those patients treated with 150 mg
bicalutamide after simple primary androgen deprivation failed. The mean duration of response
lasts 4 to 6 months on average.
Stephan H. FlГјchter, Ralf Weiser, Christoph Gamper
Progression Under Maximal Androgen Blockade
When progression occurs, the therapy must be
switched. If initial MAB was performed using
flutamide as antiandrogen, a substitution of flutamide with high-dose bicalutamide is advisable.
Scher et al. (1997), McLeod (1993), and Joyce et
al. (1998) reported that bicalutamide is a stronger and more effective antagonist of the native
androgen receptor than flutamide. Furthermore,
a 3 to 4 times higher dose (150 up to 200 mg
daily) should be applied to maximize androgen receptor blockade. If this maneuver fails, a
further promising step of second-line HT is the
withdrawal of antiandrogens after long-term
MAB. Approximately one-third of patients will
respond to antiandrogen withdrawal as indicated
by a decline of PSA exceeding 50%. The mean
duration of response amounts to 5 to 6 months
(Scher and Kelly 1993).
The androgen receptor activation may occur
by stimulation of hormones or antihormones
(Culig et al. 1993). These observations, taken together with the fact that the androgen receptor
continues to be expressed and is often overexpressed in PC metastases (Visakorpi et al. 1995),
have led to the hypothesis that continued stimulation of the androgen receptor pathway may still
be critical for cancer cell survival. There must be
a change in receptor function. How can we explain the paradoxical form of hormonal therapy
in HRPC in which 25%вЂ“40% of patients after
having profited for a long time from antiandrogen application with the aim of killing PC cells,
will suddenly reverse and respond with temporary tumor remission caused by antiandrogen
withdrawal (Scher and Kelly 1993)?
The mechanisms explaining the positive effects of antiandrogen withdrawal are not known
with certainty. But it must be assumed that longterm treatment of antiandrogens e.g., flutamide,
directly stimulates tumor cell growth in some
patients with androgen-independent PC due to
androgen receptor gene mutations and/or its amplification, supporting the paradoxical antiandrogen cancer stimulation. For instance, LNCaP
cells developed from a patient with androgen-independent disease provide a possible paradigm
for the flutamide withdrawal response. Due to
13 The Role of Hormonal Treatment in Prostate Cancer
an androgen receptor mutation, these cells are
stimulated in vitro by flutamide as well as estradiol and progesterone (Olea et al. 1990; Joyce et
al. 1998). Patients who have been treated with
flutamide or bicalutamide over a long period of
time are better responders to antiandrogen withdrawal. In case of flutamide, clinical impact can
be expected after a few days, in case of bicalutamide in a few weeks (Schellhammer et al. 1997).
EAU comment (Aus et al. 2005):
вЂ“ It is recommended to cease antiandrogen therapy once PSA progression is documented.
вЂ“ Four to 6 weeks after discontinuation of flutamide or bicalutamide, an eventual antiandrogen withdrawal effect will become apparent
(Grade B recommendation).
Progression After Antiandrogen Withdrawal
In addition to the above-described possibility of
androgen receptor mutation, it was found that
some mutant androgen receptors capable of being stimulated by flutamide were paradoxically
inhibited by the structurally different antiandrogen bicalutamide or vice versa. Joyce et al.
(1998) observed a dramatic response rate of 43%
exclusively in patients treated with long-term
flutamide as part of a MAB when administering
bicalutamide at 150 mg a day. Comparable results were reported by Scher et al. (1997). They
discussed that bicalutamide may be a more effective antagonist of the native androgen receptor
than flutamide, which has weak agonist activity for the wild-type receptor (Wong et al. 1995;
Fenton et al. 1997). Even if flutamide withdrawal
is not effective in progressive androgen-resistant PC, bicalutamide may succeed. If flutamide
withdrawal is successful, bicalutamide treatment
is recommended in case of a new relapse. Flutamide was administered after a first relapse of
MAB using bicalutamide and after a relapse of
bicalutamide withdrawal (Miyake et al. 2005). A
22% response rate was reported with a median
interval of response of 6 months. In this series,
nonresponders tended to have a higher incidence
of bone metastases and a shorter response period
to first-line therapy than responders. Kojima et
al. (2004) have reported better results with a 50%
229
response. However, this report was based on only
10 patients. Bicalutamide and flutamide are not
completely cross-resistant, and therefore their alternative use in MAB or as second-line HT after
MAB relapse may be reasonable in some cases
(Joyce et al. 1998).
The first two small retrospective studies that
evaluated the efficacy of nilutamide as a secondline therapeutic tool were presented by Desai
et al. (2001) and Kassouf et al. (2003). They reported a PSA level decrease of more than 50% in
50% and 43% of patients, with a median response
duration of 11 and 7 months, respectively. In another retrospective study, nilutamide appears to
work as second-line hormonal therapy, after bicalutamide or flutamide failed in 40% of patients.
The median time to progression was 4.4 months.
In this study some patients benefited from nilutamide even when it was used as fifth-line hormonal therapy (Nakabayashi et al. 2005). However, a recently published prospective phase II
study of nilutamide in men with PC after failure
of flutamide or bicalutamide was discontinued
after an interim analysis because nilutamide
had no apparent effect (Davis et al. 2005). Randomized clinical trials are necessary in order to
clarify these controversies and to assess whether
nilutamide offers any survival benefit.
Antiandrogens share a comparable common
chemical structure required for interaction with
the androgen receptor. Despite functional similarities, each antiandrogen appears to interact
uniquely with the androgen receptor as shown in
vitro in androgen-dependent LNCaP cells (Olea
et al. 1990). Compared to flutamide and bicalutamide, nilutamide has a unique interaction with
the ligand-binding domain of the receptor when
analyzed by three-dimensional crystal structure.
An Asn705 residue in the ligand-binding domain of the androgen receptor is crucial in anchoring flutamide and bicalutamide, but has not
such a role in the case of nilutamide (Marhefka et
al. 2001). This may be the reason why nilutamide
is discussed as the antiandrogen of choice when
other antiandrogens have failed (Nakabayashi et
al. 2005). Nilutamide side effects are: mild and
reversible visual changes (light-to-dark adaptation), fatigue, alcohol intolerance, and respiratory symptoms.
230
Third-Line Hormonal Therapy
The adrenal glands are the second source of androgen production in man. The androgens androstenedione and dehydroepiandrosterone are
converted in a first step to T in peripheral tissues
and in the prostate gland, and converted in a
second step to DHT. This androgen production
makes up approximately 5% of total androgens.
In HRPC some tumor clones remain sensitive
to these hormones even after progression following antiandrogen withdrawal or change in
antiandrogen medication. An elimination of the
androgen production in the adrenal glands and a
blocking of stimulation of these tumor clones is
possible using aminoglutethimide, ketoconazole,
estrogens, and glucocorticoids.
Aminoglutethimide together with hydrocortisone has a reported average response rate of 10%
(Dawson 1993). More favorable response rates
could be achieved when aminoglutethimide was
administered after flutamide withdrawal (Sartor
et al. 1994). Fatigue, sickness and nausea, erythema, orthostatic hypertension, and ataxia were
noted as side effects.
Ketoconazole blocks the testicular and adrenal production of androgens. A direct cytotoxic
effect on PC cells is discussed in Rocklitz et al.
(1988). Response rates of ketoconazole and hydrocortisone of 15%, lasting 6 to 9 months are
reported, when 400 mg oral ketoconazole is administered every 8 h and 20 mg oral hydrocortisone each morning plus 10 mg orally each evening (Small et al. 1997). In a recently published
randomized prospective study, Small et al. (2004)
reported a significant advantage of the combination therapy consisting of antiandrogen withdrawal and additive ketoconazole application, as
compared to ketoconazole alone. Furthermore,
ketoconazole is effective, especially when given
to patients who have responded to antiandrogen withdrawal. According to Wilkinson and
Chodak (2004), the daily ketoconazole dose in
combination with 30 mg oral hydrocortisone can
be reduced to 600вЂ“800 mg with comparable effectiveness. Ketoconazole is better tolerated than
aminoglutethimide. Toxicity is mild and includes
nausea, sickness, fatigue, edema, hepatotoxicity,
and rash.
Stephan H. FlГјchter, Ralf Weiser, Christoph Gamper
Glucocorticoids and estrogens caused a decrease of the adrenal androgen production as
regulated over the feedback mechanism. A response rate after administration of glucocorticoids can be expected in 10% of the cases (Tannock et al. 1996; Kantoff et al. 1996). The role of
estrogens in the treatment of HRPC is discussed
anew. The rationales are interesting as well as
speculative. However, a positive effect has been
reported only in single case experiences. On the
one hand, estrogen receptors are found in PC
cells and they can be upregulated by castration
in the animal model. On the other hand, Taplin
et al. (1995) demonstrated in vitro an activation
of a mutated androgen receptor isolated from
hormone-independent PC cells when estrogens
were added. These findings offer different therapeutical options for the HRPC. In a pilot study,
Horton et al. (1988) reported response rates of
10% after administration of antiestrogens. An
estrogen withdrawal may also be effective in
some cases. Finally, a high dose of intravenously
applied estrogen push therapy is an established
polypragmatic therapeutic tool in the painful
stage of metastatic HRPC. The mechanism of
palliation remains unclear. The most frequently
discussed explanation is a direct cytotoxic effect
caused by mitotic arrest (Ferro et al. 1989).
EAU comment to substitution of antiandrogen and third-line HT (Aus et al. 2005):
вЂ“ No clear cut recommendation can be made regarding the most effective drug for secondary/
tertiary hormonal manipulations since data
from randomized trials are scarce (grade C recommendation).
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14
Androgen-Independent
Prostate Cancer
Dirk Schrijvers
Recent Results in Cancer Research, Vol. 175
В© Springer-Verlag Berlin Heidelberg 2007
Abstract
Pathophysiology
Androgen-independent or hormone-refractory
prostate cancer (AIPC) is prostate cancer that
progresses after primary androgen-ablation
therapyвЂ”either orchiectomy or a gonadotropinreleasing hormone (LHRH) agonist, followed
by addition and subsequent withdrawal of an
antiandrogen. In the majority of patients, AIPC
appears after a median time of 18 months of hormone deprivation. Patients with AIPC have a median survival between 10 and 20 months and the
prognosis can be defined by using nomograms.
Standard treatment is continued castration by
LHRH agonists in combination with docetaxelcontaining chemotherapy. Other treatment options to palliate symptoms are hormones, other
chemotherapeutic agents, radioisotopes or radiotherapy and bisphosphonates. New targeted
drugs and vaccination strategies are evaluated in
the treatment of AIPC.
Androgens are the primary regulators of cell
growth and proliferation of prostate cancer cells.
When androgens are ablated or withdrawn,
apoptosis is observed in a proportion of cells,
while those that survive remain in the G1 phase
of the cell cycle. Clinical progression is the result
of regrowth of cells that are primarily resistant
to androgen ablation or which, after a period of
growth arrest, adapt to the low-androgen environment and resume proliferation (Scher and
Sawyers 2005).
Epidemiology
Androgen-independent or hormone-refractory
prostate cancer (AIPC) is defined as prostate
cancer that progresses after primary androgenablation therapy by either orchiectomy or a gonadotropin-releasing hormone (LHRH) agonist,
followed by addition and subsequent withdrawal
of an antiandrogen (Scher et al. 1995).
At diagnosis, AIPC is observed in less than
20% of patients with advanced prostate cancer (Mahler and Denis 1995). In the majority
of patients, AIPC appears after a median time
of 18 months of hormone deprivation. Patients
with AIPC have a median survival between 10
and 20 months.
Androgen Receptor-Related AIPC
The androgen receptor (AR) plays a critical role in
the development of AIPC. The androgen-receptor
gene is the only gene that is consistently upregulated during tumor progression in different AIPC
experimental models, and it seems that tumor
progression despite androgen deprivation is associated with an active AR signaling pathway.
In patients with AIPC, a number of changes
in the AR signaling pathway have been described
(Scher and Sawyers 2005; Fig. 14.1):
вЂ“ Changes in the level of ligand(s) in tumor tissue
вЂ“ Increased levels of the AR protein due to gene
amplification or altered messenger (m)RNA
expression
вЂ“ Activating mutations in the receptor that affect structure and function
вЂ“ Changes in coregulatory molecules including
coactivators and corepressors
вЂ“ Factors that lead to activation of the receptor
independent of the level of ligand or receptor
by kinase crosstalk
240
Dirk Schrijvers
Fig. 14.1 Classification of mechanisms associated with continued signaling through the androgen-signaling axis despite
castration
Incomplete Blockade of AR Ligand Production
AR Mutations
Medical and surgical therapies that ablate production or androgen action do not result in
undetectable androgen levels in tumor tissue.
Intratumoral testosterone levels in patients with
castration-resistant disease are similar to untreated benign prostatic disease, and the level of
dihydrotestosterone is sufficient to maintain AR
signaling and expression of prostate-specific antigen (PSA). Intratumoral androgens may come
from an adrenal source or from direct synthesis
within the tumor by an intracrine mechanism.
Therefore, prostate tumors rarely encounter
a completely androgen-depleted environment.
AR mutation rates in human prostate cancer
range from 5%вЂ“50% depending on tumor status
(primary versus metastatic, pre- versus post-androgen ablation) and prior therapy. The majority
of mutations are in the ligand-binding domain,
and most of the mutations are associated with
gains as opposed to a loss of function and produce a receptor that is more sensitive to native
ligand, or that can be activated by other steroid
hormones and/or by the specific antiandrogen.
Increased Levels of AR Protein Without Mutation
Amplification of the AR gene has been documented in 20%вЂ“25% of both castration-resistant
metastatic and recurrent primary tumors. The
increase in AR protein sensitizes prostate cancer
cells to respond to low levels of ligand.
Indirect Mechanisms of AR Activation
Coactivators that enhance or corepressors that
reduce receptor function mediate the transcriptional activity of the AR.
Coactivator proteins such as ARA54 and
ARA70 can selectively enhance the activity of the
receptor to alternative ligands such as estradiol
and hydroxyflutamide, can sensitize the receptor
to lower concentrations of native and non-na-
14 Androgen-Independent Prostate Cancer
tive ligands, or allow ligand-independent activation by receptor tyrosine kinases (RTKs) such as
HER2.
Decreased expression of corepressors such as
nuclear receptor corepressor (N-CoR) and silencing mediator of retinoid and thyroid receptors
(SMRT), which mediate, in part, the antagonist
action of bicalutamide, flutamide, and mifepristone, may contribute to the agonist activity that
can be observed with these agents.
A change in the coactivator-to-corepressor
ratio can alter AR transactivation activity in the
presence of low concentrations of dihydrotestosterone. Conversely, the corepressors SMRT and
N-CoR can inhibit AR function in a ligand-dependent manner.
Alterations in the coactivator-to-corepressor
ratio can explain the paradoxical agonist effects
of antiandrogens and other steroid hormones on
prostate cancer growth. Coactivators may play a
role in castration-resistant disease.
HER-2/neu, a member of the epidermal
growth factor receptor (EGFR) family of RTKs is
consistently overexpressed at a higher frequency
in castration-resistant as opposed to hormonenaГЇve primary tumors. HER2, and other growth
factors such as keratinocyte growth factor, insulin-like growth factor-1, and epidermal growth
factor, and cytokines such as interleukin-6, can
activate the AR and minimize or possibly even
negate the requirement for ligand. HER-2/neu is
thought to promote DNA binding and AR stability through activation of mitogen-activated
protein kinase (MAPK) and Akt, which can also
bind directly to the receptor.
Androgen Receptor-Independent Mechanisms
Neuroendocrine cells are present in prostate stem
cells and increase in AIPC. Neuroendocrine cells
have a low rate of proliferation, which permits
them to survive many different types of treatment. In addition, neuroendocrine cells secrete
neuropeptides such as serotonin and bombesin,
which can increase the proliferation of neighboring cancer cells, thereby allowing progression of
AIPC. Neuroendocrine cells are present in 40%вЂ“
100% of patients with AIPC (Debes and Tindall
2004).
241
Another pathway that bypasses the AR involves the deregulation of apoptotic genes. The
tumor-suppressor gene PTEN and the antiapoptotic gene Bcl-2 play important roles in AIPC.
PTEN inhibits the phosphatidylinositol 3-kinase pathway in normal cells. Activation of this
pathway stimulates a protein called Akt, which
inactivates several proapoptotic proteins, thus
enhancing cell survival.
In the normal prostate, PTEN allows cells to
undergo apoptosis, whereas in cancer cells and in
AIPC the loss of PTEN increases Akt activity and
blocks apoptosis. Loss of PTEN function is infrequent in androgen-dependent prostate cancer.
Inactivation of PTEN is considerably more likely
to occur in AIPC. One of the primary targets of
Akt, when it is blocking apoptosis, is Bcl-2. Activated Akt frees Bcl-2 (which is bound to a protein
called Bad), allowing it to increase cell survival.
Overexpression of Bcl-2 has been implicated in
the progression to AIPC (Gleave et al. 2002).
Evaluation
A patient is having AIPC if there is disease progression after treatment with a standard hormonal regimen with androgen-ablation therapy
(usually orchiectomy or LHRH agonist), followed by addition and subsequent withdrawal of
an antiandrogen. He should be treated with this
regimen for at least 4 weeks and his serum testosterone level should be below 30 ng/ml (Small
et al. 2004).
Baseline studies should include a complete
blood cell count, alkaline phosphatase, serial
PSA levels (Bubley et al. 1999; Sartor et al. 1999),
lactate dehydrogenase, albumin, testosterone
level, chest X-ray, plain radiographs of painful
bony sites, bone scan, and imaging of disease
(e.g., abdominal CT scan in case of retroperitoneal lymph node metastases).
In addition, quality of life [e.g., European Organisation for Research and Treatment of Cancer
(EORTC), QLQ-C32, and a module of ten questions specific for metastatic prostate cancer] and
symptom measures (e.g., pain, including present
pain intensity, visual analog scale), comorbid
conditions and a geriatric assessment should be
included in the evaluation of patients with AIPC
(Curran et al. 1997).
242
Dirk Schrijvers
Fig. 14.2 Nomogram for survival of patients with progressive castrate metastatic disease
Prognosis of AIPC
There are several prognostic models that are predictive of survival in men with AIPC.
вЂ“ In the model of Berry et al., a short survival
is seen in patients with an age exceeding
65 years, severe bone pain, poor performance status, presence of soft tissue metastases, anemia, and elevated levels of lactate
dehydrogenase (LDH), acid phosphatase,
alkaline phosphatase, and prolactin (Berry et
al. 1979).
вЂ“ In the model developed by Emrich et al.,
identified factors that were predictive of survival in order of importance were previous
hormone response, anorexia, elevated acid
phosphatase, pain, elevated alkaline phosphatase, obstructive symptoms, tumor grade, performance status, anemia, and age at diagnosis
(Emrich et al. 1985).
вЂ“ Kantoff et al. (1999) identified the following prognostic factors: alkaline phosphatase,
LDH, baseline PSA, and hemoglobin.
вЂ“ Other factors identified in other studies were
greater than 50% decline in PSA, changes in
PSA after therapy, weight loss, extent of bone
metastasis, pretreatment serum testosterone
level, and any decline in PSA. Biologic markers such as plasma and urine vascular endothelial growth factor and reverse transcriptase
polymerase chain reaction for PSA have been
identified as statistically significant predictors
of overall survival in patients with AIPC.
вЂ“ There have also been developed pretreatment
nomograms to predict survival in patients
with AIPC (Figs. 14.2 and 14.3) (Smaletz et al.
2002; Halabi et al. 2004).
Treatment
Standard treatment options for patients with
AIPC include secondary hormonal therapies or
chemotherapy. In patients without prior orchiectomy, castration with an LHRH agonist is maintained. The treatment choice depends on the
14 Androgen-Independent Prostate Cancer
243
Fig. 14.3 Pretreatment nomogram predicting probability of survival. Instructions to physicians: Please start from the
second top axis by identifying the disease measurability. Draw a vertical line to the points axis (top line) to represent
the number of prognostic points the patients will receive for measurable disease. Do the same for the other prognostic
variables. Once all prognostic points for the predictors have been determined, add up the prognostic points for each
prognostic variable. You can determine the 12-month survival probability by drawing a vertical line down from the вЂњtotal points axisвЂќ (fourth from the bottom) to the 12-month survival probability axis (third line from the bottom). The same
process can be done to estimate the 24-month survival probability
impact of the disease on the quality of life, the
expected beneficial effect, and the general condition of the patient.
In patients with painful bone metastases,
external radiotherapy, radionucleotides, and
bisphosphonates may be beneficial.
stilbestrol. Although secondary hormonal manipulation may produce a subjective response in
approximately 25%вЂ“50% of patients, it is shortlived (approximately 4 months).
Prednisone and Dexamethasone
Hormonal Manipulation
For patients that progress on both an LHRH
agonist and antiandrogen, the withdrawal of antiandrogen therapy results in a response in 25%вЂ“
50% of patients.
In patients with a frail condition and/or slowly
progressing disease, hormonal manipulations
may be useful. These hormonal manipulations
include prednisone or other glucocorticoids,
ketoconazole, and estrogens such as diethyl-
Glucocorticoids may lead to PSA responses or
relief of symptoms (or both) in patients with
late-stage prostate cancer. Corticosteroids depress adrenocorticotropic hormone secretion
leading to suppression of adrenal androgen release. A randomized EORTC phase III study
comparing flutamide with prednisone in patients with prostate cancer who were progressing
symptomatically after androgen ablative therapy
found similar PSA response rates (В±20%), and
prednisone was superior in terms of pain control
244
and overall quality of life (Fossa et al. 2001). In
most patients who have been treated with firstline chemotherapy, corticosteroids are added;
the potential benefit in these patients is therefore
probably minimal.
Ketoconazole
Ketoconazole is an inhibitor of steroid synthesis
and must be administered with hydrocortisone or
prednisone. It may increase the probability of an
antiandrogen withdrawal response, although this
does not result in improved survival. When used
after prior chemotherapy it is associated with occasional PSA responses, although these responses
are usually transient (Berthold et al. 2005).
Estrogens
Estrogens, such as oral diethylstilbestrol (DES)
have been shown to be associated with PSA responses and improved symptoms in several small
trials when used after failure of other hormonal
measures. However, they must be used with caution since they may cause thrombosis and cardiovascular events. These side effects are usually
not a major problem if the dose of DES is at or
below 3 mg/day (Berthold et al. 2005).
Dirk Schrijvers
teins (MAPs) in the nuclear matrix and inhibits
microtubule assembly and disassembly.
As a single agent, estramustine has shown an
overall response rate of 14%вЂ“48%, with subjective improvements in pain and performance
status. The addition of estramustine to other
spindle poisons such as vinblastine, vincristine,
and paclitaxel improves the response rates compared to these agents alone, although there is no
improvement of overall survival. Common side
effects of estramustine are nausea, vomiting, and
thrombosis secondary to the high estrogen content (Goodin et al. 2002).
Vinca Alkaloids
Vinblastine, an agent that binds to tubulin and
prevents microtubule assembly, is active in patients with prostate cancer and has a response rate
of 21% when used as a single agent in continuous
infusion. In combination with estramustine, the
response rate, as measured by PSA, has varied
from 40%вЂ“54% while several studies showed
an improvement in pain control. Vinorelbine, a
newer vinca alkaloid, has shown a clinical benefit
in 40% of 15 patients in a phase II study. Studies
combining vinorelbine with other agents are ongoing (Goodin et al. 2002).
Topoisomerase II Inhibitors
Chemotherapy
Several clinical trials have evaluated the role
of both single agent and combination chemotherapy in the treatment of AIPC. Some of these
trials have demonstrated encouraging results in
disease control, PSA response, radiological responses, overall survival, and improvement in
quality of life. At the moment, the combination
of docetaxel and prednisone is considered as the
standard treatment in men with AIPC.
Estramustine
Estramustine is a 17-ОІ-estradiol phosphate derivative linked to a nor-nitrogen mustard molecule and binds to microtubule-associated pro-
Etoposide is a topoisomerase II inhibitor that
acts at the nuclear matrix and has a synergistic effect with estramustine. In phase II studies,
a response rate of 39%вЂ“50% was seen with this
combination, but some of the regimens were associated with major toxicities including grade 3
or 4 leukopenia and nausea in 25% and 29% of
patients, respectively.
Doxorubicin is another a topoisomerase II inhibitor; it has a single agent activity of 5%вЂ“84%
in prostate cancer, depending on response criteria. Combinations of doxorubicin with either
ketoconazole (response rate 45%) or cyclophosphamide (response rate 33%вЂ“46%) have been
reported in phase II trials. These combinations
led to substantial hematologic toxicity (Goodin
et al. 2002).
14 Androgen-Independent Prostate Cancer
Mitoxantrone in combination with prednisone was approved for the treatment of AIPC
based on palliative endpoints in randomized
phase III trials (Tannock et al. 1996; Kantoff et
al. 1999). Patients with AIPC were given prednisone, 10 mg orally each day alone or in combination with mitoxantrone, 12 mg/m2 intravenously
every 3 weeks. Patients who received mitoxantrone plus prednisone achieved a statistically significant greater palliation of symptoms, including
pain, compared with those who received prednisone alone (29% versus 12%, p=0.01) along with
a significantly longer duration of symptom palliation (43 versus 18 weeks, p <0.0001). Toxicity
was mild, with the exception of a decreased left
ventricular ejection fraction in the mitoxantrone
group. There was no difference in survival between the groups.
Taxanes
Docetaxel induces apoptosis by interfering with
the microtubule formation during mitosis and
inhibiting Bcl-2. Docetaxel phosphorylates Bcl-2
at serine residues, which inactivates this protein
and leads to the activation of the caspase cascade
and apoptosis. Docetaxel also inhibits the growth
of Bcl-2-negative tumors by inducing overexpression of the cell cycle inhibitor p27, which is
frequently lost in AIPC.
Docetaxel treatment has become the new
standard treatment in patients with AIPC, replacing mitoxantrone based on the results of two
independent phase III trials showing that taxane-based chemotherapy led to a survival benefit
in men with AIPC (Tannock et al. 2004; Petrylak
et al. 2004).
In a large international trial, two schedules
of docetaxel and prednisone were compared
to mitoxantrone and prednisone in 1,006 men
with AIPC. They were randomly assigned to
docetaxel 75 mg/m2 every 3 weeks, docetaxel
30 mg/m2 once weekly for 5 weeks, or mitoxantrone 12 mg/m2 every 3 weeks. All patients
also received 5 mg oral prednisone twice daily.
The 3-week schedule of docetaxel increased
survival by 24% as compared to mitoxantrone.
The median survival was 18.9 months in the every-3-week docetaxel group, 17.4 months in the
245
weekly docetaxel group, and 16.5 months in the
mitoxantrone group. Pain reduction was most
pronounced in those that received docetaxel every 3 weeks (35% compared with 31% on weekly
docetaxel and 22% on mitoxantrone) (Tannock
et al. 2004).
Another trial compared docetaxel and estramustine to mitoxantrone and prednisone.
Of the 674 patients eligible for the trial, 338 received docetaxel (60 mg/m2 every 21 days) and
estramustine (280 mg three times daily over
5 days). The other 336 received mitoxantrone
(12 mg/m2 every 21 days) and prednisone (5 mg
twice daily). In an intention-to-treat analysis, the
median overall survival was longer for patients
receiving docetaxel and estramustine than with
mitoxantrone and prednisone, with a 20% reduction in the risk of death in favor of the docetaxel
group. Median survival in the docetaxel and estramustine arm was 17.5 months, compared to
15.6 months. The median time-to-progression
was 6.3 months compared to 3.2 months. PSA
declines of at least 50% occurred in 50% of the
patients treated with the docetaxel-based regimen, compared to about 25% of patients in the
mitoxantrone group. Grade 3 or 4 neutropenic
fever, nausea and vomiting, and cardiovascular
events were more common among patients receiving docetaxel and estramustine than among
those receiving mitoxantrone and prednisone
(Petrylak et al. 2004).
These studies show that a docetaxel-based
regimen can improve survival by a median of 2 to
2.5 months and reduce the risk of death by 20%
to 24% in comparison to mitoxantrone. In addition to an improvement in survival, docetaxel
was linked to an increase in time to disease progression, PSA declines, and quality of life.
Epothilones
Epothilones have significant antitumor activity in in vitro and in vivo models insensitive or
resistant to taxanes. They induce microtubule
bundling, formation of multipolar spindles, and
mitotic arrest. Although reversible neurotoxicity
is the predominant toxicity, an advantage is that
no corticosteroid premedication is required.
246
Ixabepilone is a new epothilone and has potent cytotoxic effects on paclitaxel-sensitive and
insensitive cells, and in taxane-resistant tumor
cell lines overexpressing P-glycoprotein. It is
given in an intravenous dose schedule of 40 mg/
m2 every 3 weeks and induces PSA responses in
patients with AIPC of В±40%.
The response rate increases when ixabepilone
is combined with estramustine with responses in
В±70% of patients with AIPC. Neutropenia and
neuropathy are the main adverse events, with 9%
of patients having a grade 3вЂ“4 thrombotic event
(Berthold et al. 2005).
Platinum Compounds
Several older phase II trials showed a moderate activity of cisplatin and carboplatin as single
agents or in combination with other chemotherapeutic agents, with response rates varying
between 14%вЂ“30%. The newer agent oxaliplatin
induced a PSA response rate of 8% with a clinical
benefit in 32% of patients.
Satraplatin is an orally bioavailable platinum
compound, and in an EORTC Genitourinary
Tract Group trial, a PSA decrease of more than
50% was seen in 8.7% on prednisone versus
33.3% on satraplatin, with better progressionfree survival on the satraplatin arm (Sternberg et
al. 2005).
Based on these data, docetaxel treatment in
combination with prednisone should be considered first-line standard treatment in patients with
AIPC. Currently, it is unclear how the effectiveness of mitoxantrone is affected when it is used
as second-line treatment after docetaxel compared with the results seen in first-line studies.
Overall, the PSA response rate to docetaxel
after initial treatment with mitoxantrone seems
similar to that achieved with first-line treatment
(response rate 44%вЂ“85%), whereas a relatively
low proportion of patients respond to mitoxantrone after first receiving docetaxel (response
rate 6%вЂ“15%). Tolerability seems to be somewhat worse than for first-line chemotherapy,
with about 45%вЂ“65% of patients requiring a
delay, dose reduction, or cessation of chemotherapy in the second-line setting (Berthold et
al. 2005).
Dirk Schrijvers
The role of the newer cytotoxic agents should
be evaluated in randomized clinical trials.
Targeted Therapies
Several new agents based on translational research are being tested in patients with AIPC.
Oblimersen
Bcl-2 is an important pro-survival regulator of
apoptotic cell death. Oblimersen is a phosphorothioate antisense oligonucleotide complementary to the Bcl-2 mRNA and a potent inhibitor
of Bcl-2 expression, which in pre-clinical testing
can significantly enhance the therapeutic effect of
chemo therapy, hormones, and radiation therapy.
The antisense oligonucleotide directed to BCL-2,
oblimersen sodium (Genasense, Genta, Berkeley
Heights) lowers Bcl-2 level (Chi 2005).
Thalidomide
Thalidomide and its analogs modulate the immune system in various ways. Some of these immunomodulatory activities, together with the antiangiogenic, antiproliferative, and proapoptotic
properties, are believed to mediate antitumor responses in some tumors. A randomized phase II
trial combining docetaxel with thalidomide
resulted in an encouraging PSA decline rate. At
18 months, overall survival in the docetaxel plus
thalidomide group was 68.2% compared to only
42.9% in the docetaxel alone group (Dahut et al.
2004).
Atrasentan
Endothelin-1, acting via the endothelin-A receptor, has been implicated in metastasis and progression of prostate cancer, particularly in bone.
Atrasentan is a potent, oral, selective endothelin-A receptor antagonist. A meta-analysis of
two large randomized placebo-controlled studies of atrasentan in men with metastatic AIPC
showed that atrasentan resulted in a significant
14 Androgen-Independent Prostate Cancer
reduction in disease progression, attenuation of
the rise of the biomarkers PSA and bone alkaline
phosphatase, delay in time to biochemical progression, decrease in time to bone pain and incidence of bone pain, and disease-specific quality
of life benefit (Vogelzang et al. 2005).
Vaccine Therapy
Prostate cancer cells express many unique differentiation-associated antigens that allow for
development of organ-specific targeted vaccines.
APC8015 utilizes prostatic acid phosphatase
(PAP), which is highly expressed in more than
90% of prostate tumors. It is an immunotherapy
cellular product consisting of autologous peripheral blood mononuclear cells enriched for
the dendritic cell fraction pulsed with a PAPGM-CSF construct. Patients with asymptomatic
metastatic AIPC were randomized (2:1) to receive APC8015 (n=82) or placebo (n=45) every
2 weeks for 6 weeks, and at 3 years 34% of those
vaccinated were alive compared to 11% in the
placebo arm. In a subset analysis, treatment with
APC8015 resulted in a 6.4-month survival advantage in patients with Gleason scores of less or
equal to 7 (Small et al. 2005).
Bisphosphonates
Bisphosphonates act by decreasing the rate of
bone turnover, reducing the number of osteoclasts, their recruitment, lifespan, and activity.
Bone complications in prostate cancer occur as a
result of skeletal metastases, long-term treatment
with androgen withdrawal, and radiotherapy.
Bisphosphonates have been shown to reduce
bone pain in prostatic cancer for 2вЂ“3 weeks after a single intravenous infusion, in up to 30%
of patients.
Promising results were observed with zoledronic acid, and in phase III trials there were
fewer skeletal events compared with placebo
(44.2% vs 33.2%, p=0.02) after a 15-min infusion
of zoledronic acid every 3 weeks. However, renal
function should be monitored carefully, and osteonecrosis of the yaw may occur with the use of
bisphosphonates (Goodin et al. 2002).
247
Radiotherapy
External radiotherapy may be useful for perineal
pain, bleeding, or bone pain.
A single fraction of external local radiotherapy is effective for pain relief in symptomatic bony metastases in up to 76% of patients. It
may, however, take several weeks for it to take
effect.
Hemibody irradiation is utilized where a large
treatment field is required, usually encompassing
the pelvis and upper femurs. However, this frequently results in diarrhea and nausea.
Strontium-89 is a ОІ-emitter and is used as an
intravenous injection for pain control in widespread bone metastases. It may be associated
with an initial pain flare, but approximately 10%
of treated patients do experience a complete
resolution of pain. However, the presence of any
critical metastases potentially able to cause spinal cord compression must be excluded, as strontium may cause edema at these sites. In addition,
the treatment commonly produces prolonged
myelosuppression, particularly thrombocytopenia, and in patients with already depleted marrow reserves, either due to disease or treatment,
this can be problematic. It may also limit future
use of chemotherapy.
In two randomized phase III studies, strontium-89 was shown to give better and more durable relief of pain than limited field radiotherapy, while in a recent study this effect could not
be confirmed (Bauman et al. 2005; Oosterhof et
al. 2003).
Newer radiopharmaceuticals e.g., Samarium159, are being tested for the treatment of painful
bone metastases in patients with AIPC.
Conclusions
The evaluation and treatment of patients with
AIPC should be performed by an integrated
multidisciplinary approach to allow optimal
symptomatic control. Recent advances in the understanding of the molecular mechanisms implicated in prostate cancer progression may lead to
new therapies.
248
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14 Androgen-Independent Prostate Cancer
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15
Prostate Cancer Treatment
and Quality of Life
Domenico Prezioso, Raffaele Galasso, Mario Di Martino, Gennaro Iapicca
Recent Results in Cancer Research, Vol. 175
В© Springer-Verlag Berlin Heidelberg 2007
Abstract
Prostate cancer is detected today at earlier stages
and in younger men than ever before. A lot of
men are asymptomatic and also physically and
sexually active at diagnosis, and most of them
are being treated by curative procedures. These
trends have led to increasing numbers of patients
undergoing disease management for longer periods of time. For many patients quality of life
(QoL) may be just as important as survival. Thus,
QoL considerations may well be the critical factor in medical decision-making for most of
them. Widespread interest in studying patientcentred outcomes has led to the development of
methods for health-related QoL measurements.
In fact, many questionnaires have been introduced in clinical practice to assess the impact of
QoL in patients (SF-36, CARES, FACT, EORTC
QLQ-C30, GRISS, UCLA PCI, PCOS). Herein
we evaluate the impact of QoL on patients affected by prostate cancer and treated with watchful waiting, radical prostatectomy, radiotherapy
and hormonal therapy; we have also considered
the role of supportive care, including the administration of analgesics, antidepressants, corticosteroids, bisphosphonates, antiemetics and
stool softeners, together with psychological support. The ultimate goal of QoL research should
strongly improve medical care and concretely
assist patients and physicians in treatment decision-making.
Introduction
Prostate cancer is the most common cancer in
men in Western countries and it is the second
leading cause of cancer death [1]. In 2002 there
were an estimated 189,000 new cases of prostate
cancer in the United States, with 30,200 deaths
caused by the disease [2]. Each year the American Cancer Society estimates the number of new
cancer cases and deaths expected in the United
States in the current year and compiles the most
recent data on cancer incidence, mortality and
survival based on incidence data from the National Cancer Institute and mortality data from
the National Center for Health Statistics. Incidence and death rates are age-standardized to the
2000 standard million population of the United
States. A total of 1,372,910 new cancer cases and
570,280 deaths are expected to have occurred in
the United States in 2005. Regarding prostatic
cancer, 232,090 new cases and 30,000 estimated
deaths are expected in the same period [3].
Prostate-specific antigen (PSA) testing has led
to prostate cancer being detected at earlier stages
and in younger men than was previously the case
(low-stage migration). A lot of men are asymptomatic and also physically and sexually active at
diagnosis and more of them are being treated by
curative procedures [4]. These trends have led to
increasing numbers of patients undergoing disease management for longer periods of time.
Traditionally, the primary endpoints in prostate cancer treatment have been cure and survival. The advent of the medical outcomes movement and the worldwide effort to contain the
rizing costs of care, however, have underscored
the importance of patient-centred outcomes,
such as health-related quality of life (QoL). This
trend is relevant in patients with prostate cancer,
who often live for years after diagnosis. Because
of the long survival time, even modest changes
in QoL may have a significant impact on the patient. For many patients, therefore, QoL may be
just as important as survival.
252
When making treatment choices, patients
with early prostate cancer must weigh the benefits, such as delay in time to progression and
an extended period without pain, against any
adverse events than may affect QoL. In the light
of evidence that survival outcomes may be similar for the various treatment options of the subgroups [5], QoL considerations may well be the
critical factor in medical decision-making for
some men with prostate cancer.
QoL Assessment
The impact of health-related QoL on therapeutic
decision-making is now considered so important
that some investigators consider a clinical cancer
trial incomplete without QoL assessment [6, 7].
Consequently, appropriate QoL questionnaires
have been introduced into large multi-centre
trials [8, 9]. A contemporary interpretation of
health-related QoL is based on the WHOвЂ™s definition of health as a state of complete physical,
mental and social well-being and not merely the
absence of disease [10]. Since prostate cancer and
its treatment can influence many aspects of QoL,
a wide spectrum of the components of well-being must therefore be addressed when treating
patients with cancer.
Health-related QoL encompasses the physical, emotional and social well-being of the patient and will be influenced by the psychological
and physical effects of the disease, as well as its
treatment [11, 12]. The psychological impact of
being diagnosed with prostate cancer, even when
asymptomatic, could have a marked impact on
QoL.
During recent years, widespread interest in
studying patient-centred outcomes has led to
the development of a rigorous set of methods
for health-related QoL measurement. The clear
lesson from this work is that researchers and clinicians need to ask, in a standardised manner,
about disease-specific impairments such as erectile dysfunction (ED) and urinary incontinence.
These are complex qualitative variables that are
not easy to standardize; in order to quantify such
subjective phenomena, data are collected from
health-related QoL surveys, with so-called вЂ�instrumentsвЂ™. They contain questions, or items, that
Domenico Prezioso et al.
are organized in scales, each scale measuring a
different aspect, or domain, of QoL. For example,
items of a particular instrument may address a
patientвЂ™s ability to have an erection and his satisfaction with ejaculation, both of which might
be included in a sexual domain. Some scales
comprise many items, while others include only
one or two. Each item contains a stem, which
may be a question or a statement, together with
a response set. Instruments are best when they
are self-administrated by the patient himself, but
if the assistance of an interviewer is required it
must be conducted from an impartial position.
In order to compare treatment efficacy in relation to health-related QoL, contemporaneous
longitudinal studies with randomized controls
provide not only an effective study, but also the
most valid results. Health-related QoL instruments must be shown to exercise reliability, validity and responsiveness [13].
The Medical Outcomes Study Group ShortForm Health Survey (SF-36) determines both
вЂ�functionвЂ™ and вЂ�botherвЂ™ in patients with prostate
cancer [14] and probably constitutes the вЂ�gold
standardвЂ™ generic tool. Nevertheless, cancer-targeted instruments such as Cancer Rehabilitation Evaluation System (CARES) Short-Form,
the functional Assessment of Cancer TherapyGeneral (FACT-G) form and the European Organisation for Research and Treatment of Cancer
(EORTC) QoL questionnaire (EORTC QLQC30), have been found to be more sensitive to
relevant changes in patients treated for localized
disease [15, 16, 17]. It is a 20-item questionnaire,
covering bowel, urinary and sexuality symptoms,
which has been validated in men with localized
[18, 19] and metastatic [20] disease. Certain tools
designed to assess the existence and severity of
sexual problems, such as the Golombok Rust Inventory of Sexual Satisfaction (GRISS) [21], have
been used in studies of anti-androgen therapy for
patients with prostate cancer [22, 23].
Several questionnaires have been designed
specifically for prostate cancer, the validated
Functional Assessment of Cancer Therapy-Prostate (FACT-P), for example, addressing weight
loss, appetite and urinary and erectile disorders
on a 12-item scale [24], whereas the University
of California, Los Angeles Prostate Cancer Index
(UCLA PCI), a validated 20-item questionnaire,
15 Prostate Cancer Treatment and Quality of Life
quantifies 6 separate domains, essentially urinary function, urinary bother, sexual function,
sexual bother, bowel function and bowel bother
[17, 25вЂ“27].
Lower rates of impotence in groups of men
who had nerve-sparing versus non-nerve-sparing radical prostatectomy and, moreover, lower
rates of potency and continence in older versus
younger patients who had undergone surgery
were characterized in the Prostate Cancer Outcomes Study (PCOS), using a modified type of
UCLA PCI questionnaire. Using the same tool
in a different group of patients from the PCOS,
men taking luteinizing hormone-releasing hormone (LH-RH) agonists as primary therapy
fared worse in several domains compared with
men who had been surgically castrated, although
similar rates of sexual function were identified
[28].
When comparing androgen-deprivation
therapy with no treatment of patients with newly
diagnosed prostate cancer, significantly higher
rates of impotence and reduced vitality were
found in the former group. Despite this, patients
on androgen-deprivation therapy were significantly more likely to be satisfied with their treatment decision than the latter group [29].
More comprehensive tools that include a hormonal domain with specific questions on breast
tenderness and gynaecomastia have been created
by expanding the UCLA PCI (Expanded Prostate
Index Composite, EPIC) [30, 31].
The components of QoL often thought to be
of greater concern to patients are impotence and
incontinence. Treatment choice surveys show
that only a minority of men are willing to accept
a treatment that has a greater than 50% risk of
impotence [32], and importantly, men will often
accept a certain degree of reduced life expectancy in return for preserved potency [33, 34].
Consequently, for treatments with similar outcomes in terms of survival or time to progression, a QoL tool that includes determinants of
both impotence and incontinence is, therefore,
an important endpoint to consider. QoL issues
assume greater importance as treatment for longer duration becomes more widely used and increasing numbers of men manifest fewer symptoms.
253
QoL Following Watchful Waiting
Although watchful waiting avoids the immediate harmful side-effects of early intervention,
an impact on QoL is often experienced by men
with untreated prostate cancer, who experience
troublesome local and systemic symptoms that
affect their daily routine [35]. The worst consequence of deferring active treatment is that the
cancer might progress beyond curability and
eventually kill the patient. This possibility cannot be excluded for any individual patient, but to
date there are few data that document this risk.
Regarding QoL, these patients appear to have the
same degree of sexual dysfunction and urinary
and bowel symptoms as do age-matched controls
[32, 36]. In one particular study [36] the overall
QoL was similar in patients on observation as
in age-matched controls; in another study [37]
it did not change during the first year of follow
up. Patients on watchful waiting seem to have
similar psychological morbidity as patients subjected to radical prostatectomy, when assessed
3 and 10 years after treatment [38]. A deferred
treatment option, with active monitoring and
periodic evaluation, can provide an appropriate
solution for well-informed patients who wish
to minimize the short-term risks of immediate
therapy and who accept the consequent risks. For
men with a short life expectancy, active monitoring may be appropriate for any stage of cancer in
the absence of symptoms, or signs of impending
morbidity from the disease. For those with a life
expectancy of 10 years or longer, active monitoring is an option for intermediate-risk cancer.
What is important is providing the correct information to the patient with regard to his decisions
and his possible anxiety.
QoL Following Radical Prostatectomy
Radical prostatectomy may result in a loss of
sexual function and incontinence, whereas radiotherapy can be associated with a loss of sexual
function and gastrointestinal side-effects [39].
Operative time, transfusion rates, admission to
the intensive care unit, patient length of hospital
stay and major and minor complications, as well
as the mortality rate of radical prostatectomy,
254
have all decreased over time [40]. The more recent mortality rate ranges from 0.16% to 0.66%,
rising with increasing age and co-morbidity [41].
In centres of excellence, operative mortality occurred in only 11 (0.29%) of 3,834 reported patients [40]. Although perineal and laparoscopic
prostatectomy are associated with a much lower
blood loss and fewer transfusions, severe bleeding can occur and complicate recovery [42].
Rectal injury occurs in less than 1% of patients.
Previous pelvic irradiation, rectal surgery and
transurethral resection of the prostate (TURP)
have all been cited as predisposing factors. Deep
venous thrombosis and pulmonary embolism
occur in approximately 1.1% of perineal prostatectomies and 1.2% of laparoscopic prostatectomies, respectively [40]. Concerning the later
complications, urinary incontinence and ED are
the most important. Nation-wide surveys using
validated patient-reported questionnaires reveal
вЂ�severeвЂ™ incontinence in 8% of men of all ages after radical prostatectomy [43, 44]. In centres of
excellence, complete continence is reported in
92%вЂ“95% of patients, with severe stress incontinence requiring an artificial urinary sphincter in
less than 1% [43, 45]. The preservation of sexual
potency is possible in the majority of patients,
depending on age and the extent of nerve sparing [46]. Older patients are less likely to experience an adequate recovery of sexual potency after surgery and clearly, unilateral is less effective
than bilateral nerve preservation [46]. Anastomotic stricture has been reported in 0.5%вЂ“9% of
patients, with one recent survey finding patientreported stricture in 15% of 337 patients during
the first year after surgery [47]. Previous TURP,
excessive intraoperative blood loss and urinary
extravasation at the anastomotic site may contribute to stricture development [48].
QoL Following Radiation Therapy
The most widely applicable outcomes information on the effect of radiation therapy on urinary,
bowel and sexual function has recently been reported by the Prostate Cancer Outcomes Study
Group [49вЂ“51]. The reported risk of patients
needing to wear pads to stay dry following external beam radiation therapy ranged from 2% to
Domenico Prezioso et al.
7% and was lowest following three-dimensional
(3D) conformal external beam radiotherapy
(EBRT). The risk of bowel urgency following
conventional EBRT was 35.7% [49], and 22%
following 3D conformal EBRT. The percentage
of patients bothered by bowel dysfunction was
lower following 3D conformal EBRT (4%) than
following conventional EBRT (8%). When 3D
conformal EBRT included 46.8 Gy to the pelvic
lymph nodes, the risk relative to prostate-only irradiation, of bowel urgency and frequent bowel
movements was 1.8 [51].
The identification of patients who will not
benefit from pelvic lymph node irradiation will
therefore raise long-term health outcomes. From
the recently reported Radiation Therapy Oncology Group (RTOG) protocol 94-13, patients with
high risk localized disease who were treated with
whole pelvis and prostate radiation therapy had a
significantly higher 4-year progression-free survival than those randomized to treatment with
prostate-only radiation [52]. Recently, Talcott and
colleagues [53] reported long-term treatmentrelated complications for men with localized
disease receiving EBRT or brachytherapy [53].
Patient-reported rates of diarrhoea or frequent
watery bowel movements were 6% following
brachytherapy alone, 12% following EBRT and
15% after brachytherapy together with EBRT. The
prevalence of a need for absorbent pads for urine
leakage, again reported by patients, was 5% following EBRT, 18% following brachytherapy alone
and 13% after brachytherapy together with EBRT.
The percentage of patients having an erection
inadequate for intercourse was 70% following
EBRT, 51% following brachytherapy alone, and
67% after brachytherapy and EBRT. Treatment by
brachytherapy causes few rectal symptoms, but
does significantly increase urinary incontinence.
Physician-assessed toxicity depends upon the
scoring system used, which includes the RTOG,
SOMAвЂ“LENT (subjective, objective, management, analytic/late effects on normal tissue) and
FC-LENT (Fox Chase modified LENT) scales
[54вЂ“56]. Other available questionnaires are the
general RAND SF-16, the general cancer-related
FACT-G and disease-specific questionnaires
such as FACT-P, American Urological Association (AUA) symptom index, UCLA PCI and the
more recent five-domain EPIC [14, 30].
15 Prostate Cancer Treatment and Quality of Life
QoL Following External Beam
Radiation Therapy
Late rectal toxicity appears to be the limiting
factor in dose escalation trials. Using generous
safety margins of 15 mm around the prostate, patients experienced FC-LENT grade 2 and 3 late
rectal toxicity in 34% and 5% of cases at 75 Gy,
and 55% and 13% at 80 Gy, respectively. Consequently, the rectal dose was limited to 72 Gy by
additional rectal shielding. The dose effect relationship to bladder toxicity is far less clear, which
to some extent can be explained by its decreased
radiosensitivity and also a longer median latency
period of 23 versus 14 months for late rectal toxicity [59, 60]. Of great interest for future dose escalation trials are the long-term follow-up data
from the randomized proton trial, which shows
a continually rising incidence of RTOG, with a
greater than grade II bladder toxicity reaching
59% at 15 years. ED following EBRT can vary
from 6% to 84% because of the absence of validated measuring instruments [61]. Men who
are sexually active before EBRT have the better
chance of remaining potent after treatment [62].
The International Index for Erectile Function
(IIEF), recently introduced as a validated [63]
instrument for measuring ED, has already been
used in a brachytherapy series [64] and will offer
reliable comparisons of different treatment modalities. The time point of assessment of ED after
EBRT is equally important, since it increases further between 1 and 2 years following EBRT [65].
Its aetiology after EBRT is believed to be mainly
arteriogenic [66], and the radiation dose to the
bulb of the penis may be the cause [67]. Bowel
dysfunction with cramps, bleeding, diarrhoea
and bowel urgency is reported in up to 20% of
patients after EBRT [68, 69].
QoL Following Three-Dimensional
Conformal RT
Side-effects are related to both the dose and volume of irradiated normal tissue [70]. 3D-conformal radiotherapy (3D-CRT) techniques attempt
to spare normal surrounding and juxtaposed tissue by providing a dose distribution that closely
approximates the planning target volume. Several
255
studies have reported low toxicity rates after 3DCRT [71, 72] and further improvement can be
expected from intensity-modulated radiotherapy
(IMRT) [73, 74]. However, 3D-CRT alone is no
guarantee against complications. The ability of
3D-CRT to spare healthy tissues is limited by the
borders of the planned target volume, which includes a normal tissue safety margin around the
clinical target to account for set-up error, prostate motion and dosimetric build-up [75].
QoL Following Prostate Brachytherapy
In one of the first analyses of the QoL of men
treated with prostate brachytherapy (PB),
Brandeis [76] compared generic and diseasespecific QoL in men treated with PB (with and
without EBRT) after radical prostatectomy. Generic QoL did not differ greatly between the
two groups, with only the physical function of
the QoL domain in the SF-36 showing differences; the radical prostatectomy patients scored
higher than the PB group. Disease-specific QoL
measures were very different. Urinary function,
essentially leakage and bowel function, were
worse in the PB group, while sexual function and
bother did not differ in the two groups.
QoL data were reported [77] for men treated
with either PB alone or EBRT and radical prostatectomy for clinically localized prostate cancer.
Examination of the urinary, bowel and sexual
function indicated that men treated with PB had
better results. Significant differences were identified [78] in sexual, urinary and bowel QoL parameters between the treatment of 842 patients
treated with PB and EBRT, or by radical prostatectomy, with better sexual and urinary function
as well as less sexual bother in the former. Men
treated with PB or EBRT, however, reported significantly worse bowel function, bowel bother
and urinary bother than men treated with radical prostatectomy.
Results from 1,000 patients [79] treated with
RP, PB or EBRT between 1995 and 1999 and
using the EPIC instrument, a specific questionnaire, showed the PB group to have the worse
urinary, bowel and sexual QoL compared to
controls. A comparison of QoL scores in men,
at least 1 year from completion of therapy, found
256
that the PB group had significantly worse urinary, bowel and sexual symptoms than the RP or
EBRT groups. When patients who had received
EBRT were excluded from the PB group, sexual
QoL parameters were similar to the EBRT group
and superior to the RP. Lee and colleagues [25]
reported a prospective study examining QoL in
a group of patients treated with PB, RP or EBRT.
Men treated with PB or RP experienced a greater
depreciation in QoL at 1 month than men treated
with EBRT, although there were no differences at
1 year. In a recent report [81] a significant improvement in QoL was seen after high dose rate
prostate brachytherapy (HDR-PB) at 1 year of
follow up.
QoL Following Hormonal Therapy
Hormonal therapies vary with respect to their
side-effect profiles with QoL influenced by effects on physical and sexual activity, sexual interest, anaemia, bone mineral density, gynaecomastia and breast pain [82, 83].
The treatment benefits observed with anti-androgen therapy require consideration in relation
to morbidity associated with long-term therapy.
Cyproterone acetate (CPA) is associated with a
high incidence of loss of libido and impotence,
whereas sexual interest and function are gener-
Domenico Prezioso et al.
ally preserved using non-steroidal anti-androgens
[84]. In addition, CPA is associated with adverse
effects associated with the cardiovascular system
and hepatotoxicity [84]. The principal pharmacologic effects of treatment with non-steroidal antiandrogens are gynaecomastia and breast pain
[85]. Differences also exist between the non-steroidal anti-androgens with respect to non-pharmacologic effects such as gastrointestinal symptoms, hepatotoxicity and pulmonary events [86].
Diarrhoea, for example, is more common with
flutamide than with either bicalutamide or nilutamide. Clinically significant hepatotoxicity is
rare with bicalutamide and nilutamide, whereas
the incidence with flutamide has been estimated
to be 3/10,000 [86]. Interstitial pneumonitis and
visual disturbances are unique adverse effects of
nilutamide [85]. Bicalutamide seems to have a
more favourable tolerability profile than the other
non-steroidal anti-androgens and CPA.
Bicalutamide monotherapy has been shown to
offer improved health-related QoL compared with
castration in patients with locally advanced nonmetastatic disease (M0) (Fig. 15.1). Using a brief,
self-administered, patient questionnaire covering
10 domains of health-related QoL [87], data from
two large studies showed that bicalutamide was
favoured in 8 of 9 evaluable parameters, with statistic significance associated with both sexual interest (p=0.029) and physical capacity (p=0.046),
Fig. 15.1 Percentage reduction from baseline in sexual interest after 12 months of treatment with bicalutamide or castration (M0 patients) [22]
15 Prostate Cancer Treatment and Quality of Life
evidence suggesting that this treatment may benefit patients with early disease [22, 88].
In the Scandinavian arm (SPCG-6) of the
on-going bicalutamide EPC programme, sexual
function, assessed using the GRISS [21], was
found to be retained in 74.9% of the bicalutamide (150 mg) group, compared to 85% of the
standard care-alone group.
In early prostate cancer, where many patients are asymptomatic, gynaecomastia and
257
breast pain causes significant bother to patients,
problems that are greater with anti-androgen
as monotherapy. In the bicalutamide EPC programme, the main side-effects of bicalutamide
(150 mg) were gynaecomastia and breast pain
(53%), breast pain alone (20%) and gynaecomastia alone (13%), although these were mild to
moderate in more than 90% of cases (Table 15.1)
[89]. Withdrawals due to breast pain and/or
gynaecomastia were 15.6% in the bicalutamide
Table 15.1 Adverse events following treatment with bicalutamide 150 mg or placebo of patients with localized or locally
advanced prostate cancer who have previously had no prior treatment or treatment of primary curative intent (median
follow-up was 2.6 years) [89]
Bicalutamide 150 mg % (n=1,798)
Placebo % (n=1,805)
Gynaecomastia alone
17.4
5.3
Breast pain alone
17.6
3.1
Gynaecomastia plus breast pain
47.5
2.1
9.3
4.6
Vasodilatation
Flu syndrome
8.6
9.5
Back pain
8.2
10.9
Impotence
8.0
5.3
Urinary tract infection
7.9
6.4
Constipation
7.8
5.7
Hypertension
7.5
7.1
Abdominal pain
7.3
6.7
Asthenia
7.2
6.1
Arthralgia
7.1
8.6
Pharyngitis
6.9
6.0
Infection
6.9
5.3
Urinary incontinence
6.3
5.1
Rash
6.3
4.8
Urinary tract disorder
5.8
7.1
Weight gain
5.6
2.6
Pain
5.4
6.7
Diarrhoea
5.1
6.3
Hernia
5.1
6.2
Bronchitis
5.1
4.8
Somnolence
5.1
3.1
Pelvic pain
5.0
5.2
Haematuria
3.9
5.8
258
(150 mg) group, compared to 0.7% in the standard care-alone group [90], although withdrawals due to objective disease progression were
2.6% and 9.3% in the two groups, respectively
[91]. The use of anti-oestrogens, radiotherapy
and surgery for the prophylaxis and/or treatment
of gynaecomastia and breast pain [92] have been
suggested, although these side-effects are reversible if therapy is withdrawn within a few months
of the onset of symptoms [31]. In future trials of
anti-androgen therapy in early prostate cancer, it
may be desirable to assess QoL using a tool such
as EPIC, which evaluates the patientвЂ™s own perception of breast tenderness and gynaecomastia.
The introduction of gonadotropin-releasing
hormone (GnRH) analogues and anti-androgens,
especially in combination, has greatly increased
the economic and biological costs of prostate
cancer without any concomitant decrease in overall mortality.
An EORTC group concluded from their study
of QoL in patients with newly diagnosed M1
prostate cancer that the physicianвЂ™s rating does
not accurately reflect the functional health and
symptom status of their patients [94]. The longterm impact of androgen withdrawal on QoL is
not well-defined and it can be difficult to differentiate effects of the disease from those of the
treatment. In EORTC trial 30853, an overall improvement in QoL was reported [94] following
androgen withdrawal therapy, specifically lower
urinary tract symptoms, although other outcomes were difficult to assess. During hormonal
treatment many patients reported a reduction of
sexual activity, although this was not consistently
related to overall QoL and many patients suffered
from ED before they started hormonal therapy.
Non-specific symptoms, such as fatigue and loss
of energy, can occur following androgen deprivation as well as slight anaemia and loss of muscle
mass, although the potential impact of androgen
withdrawal on central nervous system function
and cognition is uncertain.
Use of androgen deprivation at the time of
biochemical relapse following primary therapy
and for locally advanced disease is increasing,
and the cumulative impact of the side-effects
is likely to be higher the longer the duration of
therapy. Whereas a meta-analysis of 21 trials
found a slight advantage of complete androgen
blockade on 5-year survival [95], it remains
Domenico Prezioso et al.
unclear whether the minimal survival benefit
equates to a QoL improvement. The side-effects
and the rate of withdrawal from complete androgen blockade are more prevalent than with castration alone.
The Southwest Oncology Group (SWOG) trial
(INT 0105) showed [96] that patients randomized to complete androgen blockade reported
more problems than those assigned medical castration. One non-randomized study showed that
patients prefer treatment with a GnRH analogue
to orchiectomy for psychological reasons [97],
with the reversibility of this approach, avoidance
of surgery and the patientвЂ™s self-esteem underlying this preference.
Hot flashes, a prevalent side-effect of hormonal therapy, decreased the QoL of a large
number of patients who are often in a palliative
situation. As many as 75% of men treated with
either LH-RH agonists or non-steroidal anti-androgens, or by castration, experience hot flashes
and sweats. Several classes of drugs, from antidepressants to oestrogens, have been assessed
and advocated as treatment of hot flashes.
Osteoporosis is another important and debilitating side-effect of many prostate cancer
therapies, although precise estimates of the incidence, degree and cost of osteoporosis are not
completely known. Bone mineral density loss
can be as much as 3% to 5% yearly during the
first few years of androgen deprivation therapy
[98]. An emerging approach to control bone loss,
including that induced by treatment for prostate
cancer, is the use of intravenous bisphosphonate
therapy to block tumour-promoted osteoclast
activity. Patients with bone metastases often suffer from morbid skeletal-related events, such as
pain, pathologic fractures, radiation therapy, surgery to bone and changes due to anti-neoplastic
therapy for the management of bone pain. Unfortunately, advanced prostate cancer responds
poorly to current anti-neoplastic treatment and,
as skeletal disease progresses, patients may be
left with significant disability and loss of mobility and independence. When patients with advanced or recurrent cancer and bone metastases
were randomised [99] to leuprolide and pamidronate, or leuprolide alone, bone mineral density did not change significantly in men treated
with both drugs for 48 weeks. It was concluded
that pamidronate prevents bone loss in the hip
15 Prostate Cancer Treatment and Quality of Life
and lumbar spine in patients receiving treatment
with LH-RH agonist.
More recently, a new bisphosphonate, zoledronic acid, has been introduced into clinical
practice with good results [100, 101]. Intravenous bisphosphonates, including zoledronic
acid, are generally well-tolerated and can be administrated safety. The most common side-effect
is a transient flu-like syndrome characterized by
fever, arthralgias, myalgias and chills. Nausea,
fatigue and headache are among the other more
common adverse events. Bisphosphonate administration may also be associated with impairment
of renal function related to the precipitation of
calcium-bisphosphonate complexes in the kidney and also mandibular osteonecrosis.
Anaemia is a common problem for men being treated for metastatic disease, due to various causes, including invasion of the disease
into the bone marrow, side-effects of cytotoxic
drugs, radiation therapy and bisphosphonate
therapy. Epoetin-О± therapy (10,000 IU, three
times weekly), is associated with a significant
increase in haemoglobin level and decrease in
transfusion use within 4 weeks after initiation
of therapy [102].
259
Supportive Care
Supportive treatment includes the administration of analgesics, anti-depressants, corticosteroids, anti-emetics and stool softeners, together
with psychological support [103, 104]. Pain
management is a multidisciplinary concept.
Bisphosphonates are potent inhibitors of osteoclasts [105], and zoledronic acid, a new generation of nitrogen containing bisphosphonates, is
100- to 1,000-fold more potent than the previous
generation. It has been shown to be important
in the control and reduction of skeletal-related
events and pain in a variety of cancers, including
prostate cancer [106вЂ“109]. A recently completed,
multicentre, randomized, placebo-controlled
trial of zoledronic acid in hormone-refractory
prostate cancer with bone metastases provided
evidence [110, 111] of significant clinical benefit in reducing the risk of pathologic fractures
and other skeletal-related events (Figs. 15.2 and
15.3). The current recommended treatment with
zoledronic acid is 4 mg infused over 15 min every 3 or 4 weeks. A better dosage should be done
in consideration of the creatinine clearance, however, because the major risk in its use includes a
Fig. 15.2 Treatment with zoledronic acid reduces all types of skeletal-related events (SREs) compared with placebo in men with hormone-refractory prostate cancer metastatic to bone. Zoledronic acid (4 mg every weeks for 24 months) reduced the percentage of patients with SREs
compared with placebo. SREs included radiation to bone, pathologic fractures, spinal cord compression, antineoplastic therapy, surgery to bone, and hyperkalemia. Adapted by Saad et al. [111]
260
Domenico Prezioso et al.
Fig. 15.3 Treatment with zoledronic acid significantly reduces pain scores compared with placebo in men with hormone-refractory prostate cancer metastatic to bone. Zoledronic acid (4 mg every weeks for 24 months) consistently reduced pain scores compared with placebo throughout the course of the study. Graph depicts mean change from baseline
pain scores after initiation of treatment. Asterisks indicate significant differences at months 3 (p=0.003), 9 (p=0.030), 21
(p=0.014) and 24 (p=0.024). Adapted by Saad et al. [112]
low incidence of renal insufficiency, and serum
creatinine should therefore be checked prior to
each dose.
Conclusions
The increased popularity of QoL measurements
in prostate cancer clinical trials has led to improvements in the quality of patient care. When
physicians are attuned to the QoL concerns of
their patients, care is more comprehensive at
the bedside and in the clinic. As QoL studies are
extended to the screening environment, we may
learn that QoL is affected by anxiety in the prediagnosis phase. This factor must be considered
in assessments of the value of screening programmes. Beyond the descriptive analysis, QoL
outcomes must be compared in patients undergoing different modes of therapy. General and
disease-specific QoL must be measured to facilitate comparison with patients treated for other
common chronic conditions.
The ultimate goal of QoL research must be to
improve medical care and assist in medical decision-making. The QoL research objectives are to
assess overall treatment efficacy, including subjective morbidity, help to determine whether the
goals of treatment have been met, educate patients and clinicians about the full spectrum of
treatment outcomes, facilitate medical decisionmaking and provide the defining issue if treatments are otherwise equivalent.
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16
Europa Uomo:
The European Prostate Cancer Coalition
Tom Hudson, Louis J. Denis
Recent Results in Cancer Research, Vol. 175
В© Springer-Verlag Berlin Heidelberg 2007
Abstract
Europa Uomo is a patient-led, non-governmental
association (NGO), launched formally in Milan
in 2004 with a legal base in Antwerp. As a coalition of prostate cancer patient groups with representation in 18 European countries, the NGO
focusses on awareness, early detection, optimal
treatment, multi-professional care and, above all,
quality of life and patient advocacy.
In the majority of European countries prostate
cancer is the most commonly diagnosed cancer
affecting men beyond middle age. The incidence
and substantial mortality rises with age, peaking
in the seventh decade. Standards of diagnosis
and treatment vary across Europe and attitudes
differ. Information about the early detection and
awareness of prostate cancer available to the public leaves much to be desired.
Since 2002, involved individuals, patient support groups, patients, family members, physicians, urologists, oncologists and nurses joined in
the formation of an independent, international,
non-profit association of patient-led prostate
cancer support groups from European countries
known as Europa Uomo, the European Prostate
Cancer Coalition. This Coalition was legally established as an NGO in June 2004 in Milan with
the headquarters and secretariat in Antwerp,
Belgium.
Its membership represents 18 countries by the
national or regional groups listed in Table 16.1
with their respective contact persons. The coalition is led by a steering committee under the control of the annual general assembly. The steering
committee members and their co-ordinates are
listed in Table 16.2.
Scientific advice is given by a scientific committee chaired by Prof. H. Van Poppel as the li-
aison officer with the European Association of
Urology (EAU). The support for EAU guidelines
appears on the Web site and will be linked to all
members in their own language (www.cancerworld.org/europauomo).
The goals and activities of Europa Uomo have
been condensed in a series of slides at the request
of the Eurocan+Plus collaboration to facilitate
international collaboration. These slides have
been listed in Tables 16.3, 16.4 16.5, 16.6, 16.7,
16.8, 16.9, 16.10, 16.11, 16.12, 16.13 and 16.14.
It should be noted that membership includes
supporting activities for patients and adherence
to our 10 objectives listed in the manifest (Tables 16.4вЂ“16.6). The bottom line is that the coalition focuses on peer-to-peer support, information and education, as well as partnership with
professional associations.
We in Europa Uomo hope to see the decrease
in over-treatment and mortality of prostate cancer by the clinical activities, trials and research of
the professional organizations. We have the great
opportunity to be supported and sponsored by
the European School of Oncology (ESO) and
its director Dr. A. Costa. The European Society
of Medical oncology (ESMO), the International
Consultation of Urological Diseases (ICUD)
and the International Prostate Health Council
(IPHC) support our advice on scientific data.
It is quite natural that all of our members have
joined the European Cancer Patients Coalition
(ECPC) to speak for all European patients with
one voice.
We are a young association but ambitious
enough to launch several projects in addition
to the Web site, such as the Prostate Passport, a
global coalition of patient support organizations,
and a series of patient symposia. In this way we
are able to show our support and collaboration
268
Tom Hudson, Louis Denis
Table 16.1 Europa UomoвЂ™s groups
Country
Group
Contact person
Austria
Selbsthilfe Prostatakrebs
E. Buechler
Belgium
Wij Ook BelgiГ«вЂ”US TOO Belgium
L. Denis
Czech Republic
ArcusвЂ”Onko Centrum
J. Kozelska
Denmark
PROPA
E.P. Pyndt
Finland
PROPO
H. Tavio
France
ANAMACaP
R. Muntz
Germany
Bundesverband Prostatakrebs
Selbsthilfe e.V.
C. Ligensa
Ireland
Men Against Cancer
T. Hudson
Italy
Europa Uomo Italy
F. Sereni
Norway
PROPO Norway
J. Christie
Poland
Gladiator
T. Wlodarczyk
Portugal
AssociaГ§ГЈo Portuguesa dos Doentes
da PrГіstata
A. Pereira Pinto
Romania
Institute of Oncology Bucharest
S. Colovai
Slovak Republic
Europa Uomo Slovakija
V. Koprda
Spain
Fefoc
E. Valverde
Sweden
ProstatacancerfГ¶rbundet
L. Eliason
The Netherlands
United Kingdom
US TOO Forum
T. Eggenhuizen
SCP
A. van der Linden
PCaSO
M. Lockett
16 Europa Uomo: The European Prostate Cancer Coalition
Table 16.2 Steering committee legends
Name
Title
T. Hudson Chair
Street address, etc.
Cullahill
Killiney Road, Killiney
Dublin, Ireland
Tel: 00353 1 2852859
Fax : 00353 1 2852859
E-mail : rlthudson@eircom.net
269
Table 16.3 Europa UomoвЂ™s mission
The Coalition wants to mobilize the support and
solidarity of men towards better public and professional
education, early detection and optimal physical and
psychological treatment of prostate diseases and
prostate cancer in particular, to raise public awareness
and promote research on all aspects of these diseases
Keywords: awareness, education, peer support,
partnership, research
Oncology Centre Antwerp (OCA) 2006
C. Ligensa Vice chair RГ¶merstrasse 20
56412 Niederelbert, Germany
Tel: 00492602вЂ“2433
Fax: 00492602вЂ“2013
E-mail: ligensa@t-online.de
H. Tavio
Vice chair Haukikuja 3B
02170 Espoo, Finland
Tel: +358 40 765 3228 (mobile)
Table 16.4 First three of the ten objectives of Europa
Uomo (I)
1. To find ways and means to promote quality of life for
prostate cancer patients and their families
2. To promote the dissemination and exchange of
evidence-based information on prostate cancer
3. To promote prostate awareness and appropriate
diagnosis and prognosis
E-mail: hannu.tavio@cancer.fi
L. Denis
Secretary
Lange Gasthuisstraat 35вЂ“37
2000 Antwerpen, Belgium
F. Sereni
Treasurer
OCA 2006
Table 16.5 Further objectives of Europa Uomo (II)
Tel: +32 3 223.53.54
4. To emphasize the need for appropriate early detection
Fax: +32 3 223.53.52
E-mail: louis.denis@skynet.be
5. To campaign for provision of and access to optimum
treatment
Instituto di Pediatrica e
Neonatologia
6. To ensure quality supportive care throughout and
after treatment
dell Universita Degli Studi
7. To promote multi-professional quality care and
appropriate medical infrastructure
Via della Commenda 9
20122 Milano, Italy
OCA 2006
Tel: +39 02 57 99 28 49
E-mail : fabio.sereni@unimi.it
R. Muntz
Rue des CarriГЁres 11
B.P. 51
57400 Sarrebourg, France
Tel: +33 614 88 36 67
Fax: +33 387 03 34 60
E-mail: muntzr@sarremoselle.com
L. Eliason
Ekdungen 13
443 42 Grabo, Sweden
Tel: +46 302 40 598
E-mail: lars@eliason.se
Table 16.6 Ten objectives Europa Uomo (III)
8. To acknowledge good clinical practice and promote
its development
9. To ensure that all men fully understand any proposed
treatment options, including entry into clinical trials
and their right to a second opinion
10. To promote the advancement of prostate cancer
research
OCA 2006
270
Table 16.7 Health policy
The coalition will promote initiatives at all government
and professional levels (global to local) to give
appropriate priority to prostate diseases (with emphasis
on the specifics of prostate cancer) while respecting
cultural differences
The coalition aims to act as a clearinghouse of evidencebased information in partnership with the professional
organizations to provide access to new treatments and
clinical trials
Keywords: appropriate priority, centre of objective
information, access to drugs and trials
Tom Hudson, Louis Denis
Table 16.11 Training
The coalition supports appropriate medical
infrastructure and emphasizes the needed
communication skills for all health personnel towards
the patient. The outcome results of any given treatment
should be available to the patient with appropriate
emphasis on side-effects and their treatment
Keywords: appropriate functional good clinical
practice, outcome results
OCA 2006
OCA 2006
Table 16.8 Prevention
The coalition promotes the unity of primary and
secondary prevention including population screening
based on facts. The right to early detection is an
individual right preceded by complete information on
pros and cons confirmed by informed consent. Survival
vs quality of life is the choice of the patient
Keywords: primary and secondary prevent research,
complete information and consent
Table 16.12 Dissemination of information
There should be factual, up-to-date and evidence-based
information provided in simple, clear messages and
treated as strategic communication towards public,
patients and health workers. Professional advice is
needed to reflect expert authority
Keywords: factual updated and evidence-based
information, strategic to different cohorts
OCA 2006
OCA 2006
Table 16.9 Treatment and care
Table 16.13 Clinical trials
The coalition aims towards promotion of the provision
and access to optimal treatment with emphasis on the
holistic approach towards the patient and an effective
multi-professional treatment
The coalition supports the patientsвЂ� full understanding
of a clinical trial; the consent form is a basic right, while
access to trials should be made available for the patients
that meet the inclusion criteria
The quality care with emotional support has to be
continued after initial treatment. Men in support
groups and clinical trials receive optimal care
Keywords: consent and access are patient rights
OCA 2006
Keywords: holistic and multi-professional treatment,
access to support groups and clinical trials
OCA 2006
Table 16.10 Cancer research
Table 16.14 Europa Uomo membership
The coalition promotes basic and clinical research.
Causes of prostate cancer may derive from oestradial
17 beta and/or chronic infection, while clinical research
should include the psycho-oncology and emotional
aspects of patient and family
Only legally existing and active associations led by
patients are accepted as full members; individual
members (without voting rights) are reserved for
professionals in the scientific council, advisers or
sponsors
Keywords: basic and overall clinical research including
psycho-oncology
Keywords: support groups led by patients
OCA 2006
OCA 2006
16 Europa Uomo: The European Prostate Cancer Coalition
with all health workers, including nurses, social
workers, nutritionists and psychologists.
We like to conclude this contribution with a
list of questions to the experts from our participation in the 6th International Consultation of
Urological Diseases (ICUD) symposium in Paris
(Hudson et al. 2006).
Why?
Clearly there are many questions yet to be answered. Europa Uomo found when researching
and preparing the presentation for Paris that
there were many pressing questions; some of
them had been discussed and others needed to
be revisited. The conclusion was that there is a
series of questions that need to be posed to you
the professional. From the patientsвЂ™ perspective,
therefore, and to summarize what we had been
talking about in Paris:
вЂ“ If early detection is important for effective
treatment, why not develop better patientspecific early detection guidelines?
вЂ“ This is both in your hands and ours, as an organization; we need to work with you and, if
necessary, remind you that this is urgent,
вЂ“ If evidence suggests patients are over-treated,
why not develop better treatment protocols?
вЂ“ If patients are faced with so many different
choices, why not provide better education for
the patient and the public?
вЂ“ This is something that we as Europa Uomo
aim to do, but we can only do it in consultation with you because we need your guidance;
we would like to tap into your knowledge to
ensure that the information that we are passing on to the patient and the public is accurate, and we can only get that in consultation
with you.
вЂ“ If prostate cancer represents different diseases,
why not increase the use of multi-professional
teams and a more holistic patient outlook?
вЂ“ If treatments change so rapidly, why not increase the use of centres of excellence in complicated cases?
271
вЂ“ If evidence shows age-based treatment decisions can be effective, why do physicians continue to routinely suggest invasive treatments
on so many men over the age of 65?
вЂ“ This comes down to the quality-of-life issue,
which you are well aware of.
вЂ“ If patients control the choices they must make,
why are they largely uninformed about the
wide range of available treatment options?
вЂ“ If prostate cancer involves a slow-growing
tumour, why are patients often not given the
time to absorb the diagnosis, get other opinions and evaluate the correct course to take?
These questions can be well-addressed if patient and physician groups work together. This is
the key. We believe that by finding the time to
work together we will be able to make positive
progress for everybodyвЂ™s benefit.
Changes in Policy and Protocols Alone Can
Positively Save Lives
We hope to see most of these questions answered
in the future, as only optimal care should be the
standard of treatment and greatly facilitate our
dream of having each patient enjoy patient-centred and truly holistic care.
References
Denis LJ, Pais J (2004) News and views. From patients
and patient groups. Europa Uomo: the European
Prostate Cancer Coalition (uncorrected proof). J
Mens Health Gender xx:1вЂ“2
Hudson T, Faulds Wood L, Muntz R, Page J, Pais J,
Redmond K, Tavio H (2006) Committee 16: patientвЂ™s perspectives in prostate diseases. In: McConnell J, Denis L, Akaza H, Khoury S, Schalken J (eds)
Prostate cancer edition 2006. Health Publications,
p 363вЂ“368

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