Ebook Prostate cancer - Diagnosis and clinical management: Part 1

(BQ) Part 1 book Prostate cancer - Diagnosis and clinical management has contents: Prostate cancer epidemiology, diagnosis and screening, understanding the histopathology, markers in prostate cancer, radical surgery, radiation therapy in the management of prostate cancer,... and other contents.

PROSTATE

CANCER

Edited by Ashutosh K Tewari,

Peter Whelan and John D Graham

Prostate Cancer

Diagnosis and clinical management

Center for Prostate Cancer

Weill Cornell Medical College and New York Presbyterian Hospital Director

LeFrak Center of Robotic Surgery, NYPH

Weill Cornell Medical College

New York Presbyterian Hospital

New York, USA

Community Urologist, Leeds, UK

Emeritus Consultant Urological Surgeon

Pyrah Department of Urology

St James’s University Hospital

This edition first published 2014  2014 by John Wiley & Sons, Ltd.

Registered office: John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester,

West Sussex, PO19 8SQ, UK

Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK

The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK

111 River Street, Hoboken, NJ 07030-5774, USA

For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at

www.wiley.com/wiley-blackwell

The right of the author to be identified as the author of this work has been asserted in accordance with the

UK Copyright, Designs and Patents Act 1988.

All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher.

Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners The publisher is not associated with any product or vendor mentioned in this book It is sold on the understanding that the publisher is not engaged in rendering professional services If professional advice or other expert assistance is required, the services of a competent professional should be sought.

The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by health science practitioners for any particular patient The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents

of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions Readers should consult with a specialist where appropriate The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read No warranty may be created or extended by any promotional statements for this work Neither the publisher nor the author shall be liable for any damages arising herefrom.

Library of Congress Cataloging-in-Publication Data

Prostate cancer (Tewari)

Prostate cancer : diagnosis and clinical management / edited by Ashutosh K Tewari,

Peter Whelan, John Graham.

p ; cm.

Includes bibliographical references and index.

ISBN 978-1-118-34735-5 (pbk.)

I Tewari, Ashutosh, editor of compilation II Whelan, Peter, 1947– editor of compilation.

III Graham, John, 1955– editor of compilation IV Title.

[DNLM: 1 Prostatic Neoplasms–diagnosis 2 Prostatic Neoplasms–therapy.

3 Patient Care Management 4 Prostate–pathology 5 Prostate–surgery WJ 762]

RC280.P7

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not

be available in electronic books.

Cover image: back drop  C author Ch 03; inserts  C author Ch 05

Cover design by Meaden Creative

Set in 9.5/13pt Meridien by Aptara Inc., New Delhi, India

Contributors, vii

Preface, x

1 Prostate Cancer Epidemiology, 1

Annie Darves-Bornoz, Joe Park, and Aaron Katz

2 Diagnosis and Screening, 16

Yiannis Philippou, Harveer Dev, and Prasanna Sooriakumaran

3 Understanding the Histopathology, 34

Nicholas James Smith and William Richard Cross

7 Active Surveillance in the Management of Low-Risk Prostate

Cancer, 136

L Boccon-Gibod

8 Radical Surgery, 145

Adnan Ali and Ashutosh Tewari

9 Radiation Therapy in the Management of Prostate Cancer, 170

J Conibear and P.J Hoskin

10 Novel Therapies for Localized Prostate Cancer, 191

Massimo Valerio, Mark Emberton, Manit Arya, and

Hashim U Ahmed

v

vi Contents

11 Posttherapy Follow-up and First Intervention, 211

Ernesto R Cordeiro, Anastasios Anastasiadis, Matias Westendarp, Jean J.M.C.H de la Rosette, and Theo M de Reijke

12 Managing Rising PSA in Naive and Posttherapy Patients, 230

George Thalmann and Martin Spahn

13 Diagnosis and Management of Metastatic Prostate Cancer, 245

Bertrand Tombal and Frederic Lecouvet

14 New Therapies in Hormone Relapsed Disease, 265

Carmel Pezaro, Aurelius Omlin, Diletta Bianchini, and

17 The Future: What’s in the Toolkit for Prostate Cancer

Diagnosis and Treatment?, 313

Norman J Maitland

Index, 331

Color plate section can be found facing page 148

Division of Surgery and Interventional Science,

University College London, London, UK; and

Department of Urology,

University College London Hospitals NHS

Foundation Trust, London, UK

Adnan Ali, MBBS

Clinical Research Fellow

Center for Prostate Cancer,

Weill Cornell Medical College,

New York Presbyterian Hospital,

New York, NY, USA

Anastasios Anastasiadis, MD, FEBU

Fellow in Endourology and Laparoscopy

Clinical Research Fellow

EAU Section of Uro-Technology (ESUT),

Academic Medical Center

Amsterdam, The Netherlands

Manit Arya, MBChB, MD(Res),

London, UK; and

Barts Cancer Institute,

Queen Mary University London,

London, UK

Diletta Bianchini, MD

Specialist Oncologist

Prostate Cancer Targeted Therapy Group and

Drug Development Unit,

The Royal Marsden NHS Foundation Trust and

The Institute of Cancer Research, Surrey, UK

L Boccon-Gibod, MD

Former Chairman and former head of surgery Department of Urology,

CHU Bichat, Paris, France

Philippa J Cheetham, MD

Attending Urologist Department of Urology, Winthrop University Hospital, New York, NY, USA

J Conibear, MBBCh, BSc, MSc, MRCP, FRCR

Clinical Oncology Specialist Registrar Mount Vernon Cancer Center, Middlesex, UK

Ernesto R Cordeiro, MD, FEBU

Fellow in Endourology and Laparoscopy Clinical Research Fellow

Endourological Society, Academic Medical Center, Amsterdam, The Netherlands

William Richard Cross, BMedSci, BMBS, FRCS(Urol.), PhD

Consultant Urological Surgeon Department of Urology,

St James’s University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK

Annie Darves

Medical Student Stony Brook University and Winthrop University Hospital, New York

vii

viii Contributors

Johann de Bono, MD, FRCP, MSc,

PhD, FMedSci

Professor of Experimental Cancer Medicine

Prostate Cancer Targeted Therapy Group and

Drug Development Unit,

The Royal Marsden NHS Foundation Trust and

The Institute of Cancer Research,

Surrey, UK

Jean J.M.C.H de la Rosette, MD,

PhD

Chairman Department of Urology

Chairman Clinical Research Office

Endourology Society

Executive Board Member Soci ´et ´e

Internationale d’Urologie

Academic Medical Center,

Amsterdam, The Netherlands

Theo M de Reijke, MD, PhD, FEBU

Senior Staff Urology Department

Academic Medical Center,

Amsterdam, The Netherlands

Harveer Dev MA, MB BChir, MRCS

NIHR Academic Clinical Fellow in Urology

Cambridge

University Hospitals NHS Foundation Trust

Cancer, Research UK Cambridge,

Institute Cambridge Biomedical Campus

Division of Surgery and Interventional Science,

University College London, London, UK; and

Somerset, UK; and

Director, National Collaborating Centre for

Northwood UK; and

Professor in Clinical Oncology University College London

Norman Maitland, PhD

YCR Professor of Molecular Biology and Director

Department of Biology, YCR Cancer Research Unit, University of York, York, UK

Aurelius Omlin, MD

Clinical Research Fellow Prostate Cancer Targeted Therapy Group and Drug Development Unit,

The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research,

Surrey, UK

Jon Oxley, BSc, MD, FRCPath

Consultant in Cellular Pathology Southmead Hospital,

North Bristol NHS Trust, Bristol, UK

Joe Park

Medical Student Stony Brook University and Winthrop University Hospital, New York

Carmel Pezaro, MBChB, FRACP, DMedSc

Clinical Research Fellow Prostate Cancer Targeted Therapy Group and Drug Development Unit,

The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research,

Jonathan Richenberg, BM, BcH, MA,

MRCP, FRCR (Hon Sen Lect.), BSMS

St James’s University Hospital,

Leeds Teaching Hospitals NHS Trust,

Leeds, UK

Prasanna Sooriakumaran, MD, PhD,

FRCSUrol, FEBU

Senior Fellow in Robotics and Urology

Honorary Consultant Urological Surgeon

Nuffield Department of Surgical Sciences,

University of Oxford,

Oxford, UK; and

Visiting Assistant Professor

Department of Molecular Medicine and

Center for Prostate Cancer,

Weill Cornell Medical College, New York Presbyterian Hospital;

New York, NY, USA; and

Director LeFrak Center of Robotic Surgery, Weill Cornell Medical College,

New York Presbyterian Hospital, New York, NY, USA

George Thalmann, MD

Professor of Urology Director and Chairman Department of Urology, University Hospital Bern, Inselspital Anna Seiler-Haus,

Bern, Switzerland

Bertrand Tombal, MD, PhD

Professor of Urology Division of Urology, Cliniques universitaires Saint Luc, Institut de Recherche clinique, Universit ´e catholique de Louvain, Brussels, Belgium

Massimo Valerio, MD, FEBU

Clinical Research Fellow, PhD candidate Division of Surgery and Interventional Science,

University College London, London, UK; and

Department of Urology University College London Hospitals NHS Foundation Trust,

London, UK; and

Centre Hospitalier Universitaire Vaudoi, Lausanne, Switzerland

Peter Whelan, MS, FRCS,

Community Urologist, Leeds, UK Emeritus Consultant Urological Surgeon, Pyrah Department of Urology,

St James’s University Hospital, Leeds, UK

With the advent of new drugs and innovative technologies with which totreat prostate cancer in the last few years, and the realization that over-diagnosis and hence overtreatment have been a feature of the recent past;

it was felt timely to produce a short, comprehensive book on all aspects

of prostate cancer, leaving the details for the expert to the many excellentcontemporary monographs

We are privileged to have had an internationally known team of tributors ranging across the field Aaron Katz and colleagues set the scenewith the all important review of the epidemiology and natural history ofthe disease Jon Oxley sets the contemporary context of histopathology;Philippa J Cheetham gives us an exhaustive review of the current state ofmarkers in this disease, whereas Jonathan Richenberg brings us up to datewith imaging of the disease both locally and distantly In an innovatorychapter, William Richard Cross reviews what informed consent means andthe evidence we have, stage by stage, with which to advise our patients.The management of localized disease is discussed from all aspects ofpossible therapies, starting with a discussion on active monitoring, a coun-terintuitive concept when dealing with cancer in not offering treatmentimmediately, and why it is valid in prostate cancer, by L Boccon-Gibod.Ashutosh Tewari gives an authoritive description of surgical treatment,whereas P.J Hoskin examines both external beam radiotherapy andbrachytherapy to help us understand why, numerically, these are themost frequent treatments utilized Hashim U Ahmed and Mark Embertonreview the role of emerging therapies to which they have contributed

con-so much

In linked chapters, Theo M de Reijke, George Thalmann, and BertrandTombal, together with their colleagues, explore what options there arewhen definitive therapies appear to have failed It is hoped that these,taken together with William Richard Cross’s chapter, will allow all readers

to reflect on the two important components of prostate cancer treatment:

x

Preface xi

evidence and timescale Johann de Bono brings his immense experienceand expertise to discuss the exciting developments of new therapies inthis disease Peter Whelan looks at the progress and lack of it, from thebeginning of anatomical radical prostatectomy through the PSA era to thecurrent day, whereas John D Graham reminds us that this is a malignantdisease with which we are dealing and some patients progress and somedie from it In a sensitive account, he sets out how our patients may besupported to have a “good death.”

Finally, we thought it appropriate to ask a scientist, Norman Maitland,who has spent more than 30 years in this field, to give a scientific ratherthan a clinical take on future prospects

We hope this book will prove useful to the experts to enable them

to understand where other experts are “coming from,” what their apies have to offer, and what are these therapies’ inevitable limitations

ther-to the generalist who can use this book ther-to help guide patients throughthe bewildering options available, and sincerely to include the lay reader,both patient and their relatives We hope that it will provide a comprehen-sive summary, an accessible narrative, and a starting point for discussionspatients will have with their treating physicians

Andrew von Eschenbach, a urologist and ex-director of the US NationalInstitute of Cancer, stated that the hope was to turn prostate cancer into

a chronic disease This has largely been achieved in the current era withmany men living a quarter or even a third of their lives after the diagnosis

We hope this book shows how this came about and how men can andmust be persuaded to live out their lives as fully as possible, and that thereare always options, and one will probably fit an individual’s needs

We are grateful to all at Wiley especially Oliver Walter who sioned this volume, and to Kate Newell and Claire Brewer

commis-C H A P T E R 1

Prostate Cancer Epidemiology

Annie Darves-Bornoz1, Joe Park1, and Aaron Katz2

1 Stony Brook University and Winthrop University Hospital, New York

2 Department of Urology, Winthrop University Hospital, New York

United States—recent trends in incidence

and mortality

Incidence

Prostate cancer is the most common non-skin cancer diagnosed amongAmerican males, affecting roughly one in six men (16.15%) over thecourse of their lifetime Prostate cancer is also the second leading cause ofcancer-related deaths in American men According to the most recent datafrom the Surveillance Epidemiology and End Results (SEER) database, anestimated 241 740 men were diagnosed with prostate cancer and over

28 000 died of it in the United States in 2012 [1] The incidence of prostatecancer spiked in the United States in the early 1990s because of the advent

of more aggressive prostate-specific antigen (PSA) screening [2] This wasfollowed by a sharp decline from 1992 to 1995 during which incidencerates returned to a new baseline which remained approximately two and ahalf times the pre-PSA era rate, likely due to the fact that increased screen-ing in prior years had successfully diagnosed much of the previously unde-tected prostate cancer patients in the population

Mortality and survival

Most recent data show that mortality rates due to prostate cancer havebeen declining, with a 3.5% decrease between 2000 and 2009 [3] In addi-tion, 5-year survival rates have also been increasing, jumping from 76%between 1983 and 1985 to 98% between 1992 and 1998 [4] While thisstaggering rise in survival and decline in mortality can in part be attributed

Prostate Cancer: Diagnosis and Clinical Management, First Edition.

Edited by Ashutosh K Tewari, Peter Whelan and John D Graham.

C

1

2 Chapter 1

to the recent trend in earlier detection and more aggressive treatment [5],screening overdiagnosis of preclinical prostate cancers which may neverprogress clinically is likely a major contributor as well Overall, 5-year rel-ative survival is nearly 100%, relative 10-year survival is 98%, and relative15-year survival is 93%

The stage of the prostate cancer is a major contributor to survival,

as patients with local and regional disease had relative 5-year survivalrates nearing 100%, while patients with distant metastasis had a relative5-year survival of only 28% [6] As screening is advancing, there has been

an increase in incidence of organ-confined and regional diseases and adecrease in incidence of metastatic diseases [7]

International trends

Prostate cancer is the second most common cancer among men in theUnited States and fifth most common cancer worldwide [8] However,incidence and mortality of this disease differ greatly depending on thegeographical area Incidence is highest in Scandinavia and North Amer-ica (especially among African-Americans, with an annual rate of 236.0per 100 000 men) and lowest in Asia (1.9 cases per 100 000 annually)[1, 8] With respect to mortality rates, the highest rates are found in theCaribbean (at 26.3 deaths per 100 000 annually) and the lowest rates arefound in Asia (⬍3 deaths per 100 000 annually) There are numerousexplanations for these drastically different mortality rates among coun-tries Two major factors are differences in treatment and misattribution ofcause of death Environment is likely to play a role as well One studycomparing Japanese men living in the United States with Japanese menliving abroad found that Japanese men living in the United States hadmore similar rates of prostate cancer to persons of similar ancestry living

in the United States than to the Japanese men living in Japan [9]

Advancing age

Advancing age is the principal risk factor for acquiring prostate cancer.From 2005 to 2009, the median age of diagnosis was 67 years, withapproximately 90% of diagnoses occurring at the age of 55 years andabove In addition, older men are more likely to be diagnosed withhigh-risk prostate cancer leading to lower overall and cancer-specificsurvival [1]

Prostate Cancer Epidemiology 3

Race/ethnicity

Race is a major risk factor for prostate cancer, both with respect to dence and mortality; however, the reasons as to why are less clear.African-Americans have the highest incidence of prostate cancer than anyother race or ethnicity in the United States (between 2005 and 2009, 236.0per 100 000 men annually) This is in contrast to other groups living inthe United States, including white American males (146.9 per 100 000men annually), Asian/Pacific Islanders (85.4 per 100 000 men annually),American Indian/Alaska Natives (78.4 per 100 000 men annually), andHispanics (125.9 per 100 000 men annually) African-Americans also havethe highest mortality rate (between 2005 and 2009, 53.1 per 100 000men annually) once diagnosed with prostate cancer Again, white Ameri-can males (21.7 per 100 000 men annually), Asian/Pacific Islanders (10.0per 100 000 men annually), American Indian/Alaska Natives (19.7 per

inci-100 000 men annually), and Hispanics (17.8 per inci-100 000 men annually)all had significantly lower mortality rates in comparison [1]

There are numerous explanations for this disparity in outcomes amongraces Higher mortality in African-Americans has been attributed to lowersocioeconomic status [10–12], less frequent PSA screening [13], lessaggressive treatment [14], and a lack of access to advanced treatmentfacilities [15] However, even in studies which seemingly control for eco-nomic status, PSA screening, diagnostic approaches, and treatment barriersworse outcomes are still found in African-American males [16, 17] Fur-ther research is warranted to elucidate both biologic and societal causes ofsuch disparate outcomes among races

Family history

Family history is one of the strongest risk factors when considering whowill develop prostate cancer Having an affected relative, the number ofaffected relatives, and the age of onset of prostate cancer in the affectedrelative are all risk factors for developing prostate cancer Risk of prostatecancer doubles for a male who has one affected first-degree relative[18–22] For males with more than one affected relatives, the risk is fur-ther increased [20] Age of onset in affected first-degree relatives is alsoimportant, as younger age of onset correlates with increased risk as well[20, 23] Another study from Sweden found prognostic correlation in

4 Chapter 1

families where both the father and son had prostate cancer When ing fathers who survived for 5 or more years versus fathers who survivedless than 2 years, sons of fathers who survived for 5 or more years had ahazard ratio of 0.62 (95% CI) [24]

compar-These familial factors point to a possible hereditary component in thedevelopment of prostate cancer This notion is corroborated by a study of

45 000 twin pairs from Sweden, Denmark, and Finland which found thatthere was a higher concordance for prostate cancer diagnosis in monozy-gotic twins (18%) versus dizygotic twins (3%) This study estimated thatpotentially 42% of the risk of developing prostate cancer could be due toheritable causes [25] Inheritance patterns of prostate cancer are not yetwell understood, although segregation analyses of prostate cancer fami-lies point to an autosomal dominant [26], X-linked, or recessive inheri-tance [27]

Hormonal factors

Androgens

Androgens are important for the normal development of the prostategland and are likely important in the carcinogenesis of the prostate aswell The results of the Prostate Cancer Prevention Trial demonstratedthat inhibition of the conversion of testosterone to dihydrotestosterone byfinasteride, a 5␣-reductase inhibitor, significantly decreased incidence ofprostate cancer, thus confirming the role of androgens in the development

of prostate cancer [28] However, a meta-analysis of 18 studies showedthat normal variations in serum androgen levels were not correlated with

an increased risk of developing prostate cancer [29]

Insulin-like growth factor-1

Higher concentrations of insulin-like growth factor-1 (IGF-1), which mally promotes proliferation and apoptotic inhibition of normal prostatecells [30], have been associated with an increased risk of prostate cancer[31] A pooled analysis of 12 studies also found that IGF binding protein 3was weakly associated with increased risk of prostate cancer as well [31].IGF-1 levels are both genetically and nutritionally dependent, which may

nor-be a reason why certain countries and populations have higher or lowerrates of prostate cancer

Prostate Cancer Epidemiology 5

Lifestyle decisions

Smoking cigarettes

A meta-analysis determined that smoking was not associated withincreased risk of developing prostate cancer, but was associated with fatalprostate cancer [32] Smokers had a 24–30% increased risk of death due

to prostate cancer compared with nonsmokers A large study also foundthat smokers actually had an 18% decreased risk of developing prostatecancer, but a 67% increased risk of mortality due to prostate cancer [33]

Alcohol

Most studies have shown that there is no effect of alcohol consumption

on the incidence or mortality of prostate cancer [34–36] Additionally, redwine has not been shown to have any protective effect on prostate cancer[35] These studies suggest that alcohol consumption does not play a majorrole in the development of prostate cancer

Diet

Obesity

The role of obesity, as defined by high body mass index (BMI), in thepathogenesis of prostate cancer is not well defined Many studies showthat excess body weight does not lead to increased cases of prostate cancer[37–39], although some have shown a positive association [40, 41] Whatstudies have shown more conclusively is that obesity is associated withcases of higher-grade and fatal prostate cancer [42, 43]

Fats

Early studies found a positive correlation between fat consumption andprostate cancer incidence and mortality [44] Subsequent case–controlstudies, including one comparing various races [20], also found a posi-tive association between increased fat consumption and risk of develop-ing prostate cancer [45] In addition to increased incidence, a handful ofprospective studies have shown that fat intake correlated with the higher-stage disease [20, 46] The causes of these findings are likely multifacto-rial, including increased oxidative stress due to increased adipose tissue,increased difficulty of prostate detection in obese men, and increased pro-duction of IGF-1 However, the European Prospective Investigation into

6 Chapter 1

Cancer and Nutrition (EPIC) study, a meta-analysis of seven prospectivestudies, failed to demonstrate any association between fat consumptionand incidence of disease or stage of disease [47] Currently, it is unclear iffat consumption does indeed raise the risk of developing prostate cancer

Lycopene

Lycopene, a carotenoid with potent antioxidant properties found primarily

in tomatoes, has been hypothesized to reduce the risk of prostate cancer,but the results have been inconclusive A meta-analysis found that whencomparing the group with the lowest consumption of raw tomato productswith the highest-consumption group, there was an 11% reduction in therisk of prostate cancer This reduction was increased to 19% when cookedtomato products were considered [48] However, a recent nested case–control study examining the effect of lycopene on various cancers found

no reduction in prostate cancer risk [49]

Soy

Soy is high in phytoestrogens, compounds which may reduce 5␣-reductaseactivity, induce differentiation of prostate cells, and modulate estrogenreceptors which inhibit androgen activity [50] A meta-analysis of six case–control and two cohort studies [51], as well as the US Multiethnic CohortStudy [52], showed a reduction in the risk of prostate cancer in males withhigh soy consumption The latter study also found a 30% reduction inthe risk of being diagnosed with advanced disease Thus, Asian soy-baseddiets may be contributing to lower rates of prostate cancer in this popula-tion However, active surveillance studies have failed to produce the sameresults [53] Although promising, the benefit of soy in reducing prostatecancer risk has not been substantiated

Vitamins/minerals/trace elements

Vitamin D/calcium

No association between vitamin D intake and prostate cancer has beenfound in studies which have examined this relationship [54–56] Con-versely, numerous studies, including the Cancer Prevention Study IINutrition Cohort, have reported positive associations between high cal-cium intake and increased incidence of as well as increased mortal-ity from prostate cancer [55, 57, 58] With the abundance of calcium

Prostate Cancer Epidemiology 7

supplementation in the United States, more studies are needed to uate these potentially increased risks

eval-Vitamin E

Results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT)

as well as the Physicians’ Health Study II were equivocal when examiningthe effect of vitamin E on the risk of prostate cancer [59, 60] However,

␣-tocopherol, the most potent form of naturally occurring vitamin E, hasshown to decrease the risk of prostate cancer in smokers [61] Interestinglythough, subsequent follow-up of this same cohort showed no association

of vitamin E with incidence of prostate cancer [62], blurring the validity ofthis association

Selenium

The Nutritional Prevention of Cancer Study showed that selenium plementation reduced the risk of prostate cancer by 65% compared withplacebo [63]; these results have been corroborated by subsequent studies[64, 65] However, these findings conflict with the results of the SELECTtrial [59] Further research is needed before any steadfast conclusions can

sup-be made regarding selenium’s protective role in prostate cancer

Genetics

Single-nucleotide polymorphisms (8q24 region)

Genome-wide association studies have demonstrated that certain geneticvariations called single-nucleotide polymorphisms (SNPs) when found inaggregate in a male are associated with an increased risk of developingprostate cancer [66] Allelic foci have been found in the 8q24 [67, 68] and17q regions [66]

BRCA1/BRCA2 mutations

Risk of developing prostate cancer is increased if a BRCA1 (17q21) orBRCA2 (13q12) mutation is present BRCA1 mutations roughly doublethe risk of prostate cancer [69, 70] BRCA2 mutation carriers have a five-

to sevenfold increase in risk [71], an early onset of disease [72], a worseprognosis [72, 73], and a higher Gleason score [74]

8 Chapter 1

Natural history of prostate cancer

The natural history of a disease is the course a disease takes if leftuntreated In other words, it is the prognosis of the disease and the inci-dence of parameters of interest over time It is of great interest that physi-cians are aware of the natural history of diseases, and particularly that ofprostate cancer, as many prostate cancers grow slowly and the treatment

is not without any side effects A cost–benefit analysis must be done todetermine whether treatment at all and what treatment is appropriate on

an individual basis

The incidence of prostate cancer is high Autopsy studies have strated that 60–70% of older men have some area showing cancer withinthe prostate [75, 76] It is estimated that a 50-year-old man has a lifetimerisk of 42% of developing prostate cancer, but only a 9.5% risk of devel-oping the disease clinically and being diagnosed and a 2.9% risk of dyingfrom prostate cancer [77] This shows the highly protracted course andnatural history of prostate cancer However, our understanding of prostatecancer’s natural history is incomplete and an individual’s prognosis provesdifficult to predict With the advent of PSA screening, prostate cancer isbeing detected at earlier stages The clinical behavior can vastly differ indifferent men with prostate cancer of similar staging, PSA levels, and his-tological appearance Of the 234 460 men diagnosed with prostate canceryearly, 91% present with localized disease [78] Clinicians are faced withthe challenge of predicting more aggressive forms of localized disease and

demon-“clinically insignificant” forms of disease (organ-confined cancer⬍0.5 mL,

no Gleason grade 4 or 5)

A majority of prostate cancers turn out to be small, low grade, and invasive with doubling times of 2–4 years It has been shown that up to20% of cancers found on pathology after prostatectomy fit in this categoryand pose no immediate risk to the patient’s health [79], suggesting pos-sible overtreatment of prostate cancer Making the diagnosis of prostatecancer more complicated is the fact that it can be a multifocal disease.Studies have shown the presence of multiple carcinomas in at least 50%

non-of radical prostatectomy specimens, typically having different grades [80].This can lead to sampling errors and difficulty predicting the true grade

of a patient’s prostate from a standard biopsy Standard TRUS biopsy mayunderestimate the grade and extent of disease, thus many physicians rec-ommend curative treatment for even low-risk cancers found on biopsy

It is unknown whether low-risk tumors over time acquire the necessarymutations to progress or if they undergo a dedifferentiation process In one

Prostate Cancer Epidemiology 9

study of patients undergoing active surveillance for the prostate cancer,17% were found to have higher-grade cancers (poorer differentiation) onrepeat biopsies within 6 years [81] However, it is difficult to concludewhether this is due to dedifferentiation of the initial cancer biopsied orreflect prostate heterogeneity and a sampling error in the initial diagnosis

us to look at the natural history of prostate cancer

Outcomes of 828 men with prostate cancer who were conservativelymanaged with watchful waiting were assessed in a pooled analysis In thisstudy, they measured disease-specific survival 10 years after the diagnosis,which was found to be 87% for low-grade cancers, and 34% for thosewith high-grade cancers About 81% of those with low-grade cancers atdiagnosis remained metastasis-free, whereas only 26% of those with high-grade cancers were metastasis-free [82]

In a prospective cohort study done in Sweden [83–85], 223 men werefollowed for over three decades A total of 223 subjects were diagnosedwith localized prostate cancer and initial treatment was deferred It wasinitially found that these men had good disease-specific survival after 15years [83], demonstrating an indolent course at first; however, mortalityrates increased with further follow-up between 15 and 20 years after diag-nosis Survival without metastases decreased from 76.9% at 15 years to51.2% at 20 years, and disease-specific survival decreased from 78.7% to54.4% At 15 years, the prostate cancer mortality rate was 15 per 1000person-years and increased to 44 per 1000 person-years at 20 years post-diagnosis The authors concluded from this prospective study that watch-ful waiting may be appropriate for men who have less than 15 years of lifeexpectancy, as prostate cancer seemed to rapidly progress after 15 years

As of June 2011, this cohort had been followed for 32 years at whichpoint only 3 of the 223 original patients were alive As per the initialprotocol of the study, men who developed symptomatic progression or

10 Chapter 1

metastasis of prostate cancer were treated with hormone therapy About

142 of the 223 men (64%) remained untreated over the course of thetrial They remained metastasis-free and did not die of prostate cancer,indicating that a majority of the men had a cancer that never becameclinically significant In contrast to this good prognosis, 38 of the 79 men(almost 50%) who were hormonally treated died of prostate cancer [85]

In contrast to their prior study, no increase in the rate of progression andmortality was found when follow-up was extended beyond 20 years It islikely that the increase in progression after 15 years was likely due to thesmall size of the surviving subjects Supporting this is another watchfulwaiting study, a retrospective cohort review of 767 men diagnosed withlocalized prostate cancer followed up with a mean observation of 24 years

No significant difference in the rate of progression or mortality after 15years was found [86] In this cohort, men with high-grade cancer (Glea-son score 8–10) at the time of diagnosis had a much higher probability ofdying from prostate cancer (121 deaths per 1000 person-years) comparedwith those with low-grade cancer (Gleason score 2–4, 6 deaths per 1000person-years) [86]

The diagnoses of the subjects in these studies were made prior to theuse of PSA screening, which makes it difficult to correlate it to today’spatients Tumors detected by PSA screening have a lead time between 5and 7 years [87] and may progress differently than those found clinically

as in the studies above The first watchful waiting study done in the PSAera found the highest predictive parameters for progression of localizeddisease were PSA level at time of diagnosis and Gleason score of the initialbiopsy [88] In a prospective cohort study done during the contemporaryPSA era, disease-specific survival rates were found to be more favorable,reflecting the lead time discussed above and the indolent course of prostatecancer The 10-year prostate-cancer-specific mortality was 8.3% for menwith well-differentiated tumors, 9.1% for those with moderately differen-tiated tumors, and 25.6% for those with poorly differentiated tumors [89].The natural history of prostate cancer still leaves much to the unknown.Although localized cancer often remains clinically insignificant, progres-sion and metastasis may still develop after several years Factors includ-ing PSA level, Gleason score, patient’s age, and overall health should beassessed when determining appropriate treatment However, it is impor-tant to consider that these are not concrete risk factors, as some men whopossess the high-risk factors do not progress to a clinically significant can-cer and, similarly, the low-risk men do not always maintain an indolentcourse

Prostate Cancer Epidemiology 11

References

1 Howlader N, Noone AM, Krapcho M, et al (eds) SEER Cancer Statistics Review,

1975–2009 (Vintage 2009 Populations) SEER Fact Sheets: Prostate Available at http://seer.cancer.gov/statfacts/html/prost.html 2012–2013 Last accessed January

2, 2013.

2 Potosky AL, Miller BA, Albertsen PC, Kramer BS The role of increasing detection in

the rising incidence of prostate cancer J Am Med Assoc 1995;273(7):548–552.

3 Jemal A, Simard EP, Dorell C, et al Annual Report to the Nation on the Status

of Cancer, 1975–2009 Featuring the burden and trends in human papillomavirus

(HPV)-associated cancers and HPV vaccination coverage levels J Natl Cancer Inst

and survival rates J Urol 2000;163(1):364–365.

6 Survival rates for prostate cancer http://www.cancer.org/cancer/prostatecancer/ detailedguide/prostate-cancer-survival-rates: American Cancer Society; 2013 [cited

19 Hemminki K, Czene K Age specific and attributable risks of familial prostate

carci-noma from the family-cancer database Cancer 2002;95(6):1346–1353.

20 Whittemore AS, Wu AH, Kolonel LN, et al Family history and prostate cancer risk

in black, white, and Asian men in the United States and Canada Am J Epidemiol

1995;141(8):732–740.

21 Zeegers MP, Jellema A, Ostrer H Empiric risk of prostate carcinoma for relatives of

patients with prostate carcinoma: a meta-analysis Cancer 2003;97(8):1894–1903.

22 Johns LE, Houlston RS A systematic review and meta-analysis of familial prostate

cancer risk BJU Int 2003;91(9):789–794.

23 Gronberg H, Damber L, Damber JE Familial prostate cancer in Sweden A

nation-wide register cohort study Cancer 1996;77(1):138–143.

24 Hemminki K, Ji J, Forsti A, et al Concordance of survival in family members with prostate cancer J Clin Oncol 2008;26(10):1705–1709.

25 Lichtenstein P, Holm NV, Verkasalo PK, et al Environmental and heritable factors

in the causation of cancer–analyses of cohorts of twins from Sweden, Denmark, and

Finland N Engl J Med 2000;343(2):78–85.

26 Gong G, Oakley-Girvan I, Wu AH, et al Segregation analysis of prostate cancer in

1,719 white, African-American and Asian-American families in the United States

and Canada Cancer Causes Control 2002;13(5):471–482.

27 Monroe KR, Yu MC, Kolonel LN, et al Evidence of an X-linked or recessive genetic component to prostate cancer risk Nat Med 1995;1(8):827–829.

28 Thompson IM, Goodman PJ, Tangen CM, et al The influence of finasteride on the development of prostate cancer N Engl J Med 2003;349(3):215–224.

29 Endogenous Hormones and Prostate Cancer Collaborative Group, Roddam AW.

Allen NE, et al Endogenous sex hormones and prostate cancer: a collaborative ysis of 18 prospective studies J Natl Cancer Inst 2008;100(3):170–183.

anal-30 Cohen P, Peehl DM, Rosenfeld RG The IGF axis in the prostate Horm Metab Res

1994;26(2):81–84.

31 Roddam AW, Allen NE, Appleby P, et al Insulin-like growth factors, their

bind-ing proteins, and prostate cancer risk: analysis of individual patient data from 12

prospective studies Ann Intern Med 2008;149(7):461–471.

32 Huncharek M, Haddock KS, Reid R, Kupelnick B Smoking as a risk factor for

prostate cancer: a meta-analysis of 24 prospective cohort studies Am J Public Health

Prostate Cancer Epidemiology 13

36 Chao C, Haque R, Van Den Eeden SK, et al Red wine consumption and risk of prostate cancer: the California men’s health study Int J Cancer 2010;126(1):171–

179.

37 Nilsen TI, Vatten LJ Anthropometry and prostate cancer risk: a prospective study of

22,248 Norwegian men Cancer Causes Control 1999;10(4):269–275.

38 Habel LA, Van Den Eeden SK, Friedman GD Body size, age at shaving initiation,

and prostate cancer in a large, multiracial cohort Prostate 2000;43(2):136–143.

39 Giovannucci E, Rimm EB, Stampfer MJ, et al Height, body weight, and risk of prostate cancer Cancer Epidemiol Biomarkers Prev 1997;6(8):557–563.

40 Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ Overweight, obesity, and

mortality from cancer in a prospectively studied cohort of U.S adults N Engl J Med

2003;348(17):1625–1638.

41 Veierod MB, Laake P, Thelle DS Dietary fat intake and risk of prostate cancer: a

prospective study of 25,708 Norwegian men Int J Cancer 1997;73(5):634–638.

42 Gong Z, Neuhouser ML, Goodman PJ, et al Obesity, diabetes, and risk of prostate cancer: results from the prostate cancer prevention trial Cancer Epidemiol Biomarkers

Prev 2006;15(10):1977–1983.

43 MacInnis RJ, English DR Body size and composition and prostate cancer risk:

sys-tematic review and meta-regression analysis Cancer Causes Control 2006;17(8):989–

47 Crowe FL, Allen NE, Appleby PN, et al Fatty acid composition of plasma

phos-pholipids and risk of prostate cancer in a case–control analysis nested within

the European Prospective Investigation into Cancer and Nutrition Am J Clin Nutr

2008;88(5):1353–1363.

48 Etminan M, Takkouche B, Caamano-Isorna F The role of tomato products and lycopene in the prevention of prostate cancer: a meta-analysis of observational stud-

ies Cancer Epidemiol Biomarkers Prev 2004;13(3):340–345.

49 Peters U, Leitzmann MF, Chatterjee N, et al Serum lycopene, other carotenoids, and

prostate cancer risk: a nested case–control study in the prostate, lung, colorectal,

and ovarian cancer screening trial Cancer Epidemiol Biomarkers Prev 2007;16(5):962–

14 Chapter 1

54 Chan JM, Giovannucci EL Dairy products, calcium, and vitamin D and risk of

prostate cancer Epidemiol Rev 2001;23(1):87–92.

55 Kristal AR, Cohen JH, Qu P, Stanford JL Associations of energy, fat, calcium, and

vitamin D with prostate cancer risk Cancer Epidemiol Biomarkers Prev 2002;11(8):719–

725.

56 Giovannucci E, Rimm EB, Wolk A, et al Calcium and fructose intake in relation to risk of prostate cancer Cancer Res 1998;58(3):442–447.

57 Skinner HG, Schwartz GG Serum calcium and incident and fatal prostate cancer in

the National Health and Nutrition Examination Survey Cancer Epidemiol Biomarkers

Prev 2008;17(9):2302–2305.

58 Rodriguez C, McCullough ML, Mondul AM, et al Calcium, dairy products, and risk

of prostate cancer in a prospective cohort of United States men Cancer Epidemiol

Biomarkers Prev 2003;12(7):597–603.

59 Lippman SM, Klein EA, Goodman PJ, et al Effect of selenium and vitamin E on risk

of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention

Trial (SELECT) J Am Med Assoc 2009;301(1):39–51.

60 Gaziano JM, Glynn RJ, Christen WG, et al Vitamins E and C in the prevention of

prostate and total cancer in men: the Physicians’ Health Study II randomized

con-trolled trial J Am Med Assoc 2009;301(1):52–62.

61 Heinonen OP, Albanes D, Virtamo J, et al Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial J

Natl Cancer Inst 1998;90(6):440–446.

62 Virtamo J, Pietinen P, Huttunen JK, et al Incidence of cancer and mortality following

alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up.

J Am Med Assoc 2003;290(4):476–485.

63 Clark LC, Combs GF, Jr., Turnbull BW, et al Effects of selenium

supplementa-tion for cancer prevensupplementa-tion in patients with carcinoma of the skin A randomized

controlled trial Nutritional Prevention of Cancer Study Group J Am Med Assoc

70 Warner E, Foulkes W, Goodwin P, et al Prevalence and penetrance of BRCA1 and

BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer.

J Natl Cancer Inst 1999;91(14):1241–1247.

71 Cancer risks in BRCA2 mutation carriers The Breast Cancer Linkage Consortium J

Natl Cancer Inst 1999;91(15):1310–1316.

Prostate Cancer Epidemiology 15

72 Tryggvadottir L, Vidarsdottir L, Thorgeirsson T, et al Prostate cancer progression and survival in BRCA2 mutation carriers J Natl Cancer Inst 2007;99(12):929–935.

73 Narod SA, Neuhausen S, Vichodez G, et al Rapid progression of prostate cancer in men with a BRCA2 mutation Br J Cancer 2008;99(2):371–374.

74 Mitra A, Fisher C, Foster CS, et al Prostate cancer in male BRCA1 and BRCA2 tion carriers has a more aggressive phenotype Br J Cancer 2008;98(2):502–507.

muta-75 Rullis I, Shaeffer JA, Lilien OM Incidence of prostatic carcinoma in the elderly

Urol-ogy 1975;6(3):295–297.

76 Sakr WA, Grignon DJ, Crissman JD, et al High grade prostatic intraepithelial

neopla-sia (HGPIN) and prostatic adenocarcinoma between the ages of 20–69: an autopsy

study of 249 cases In Vivo 1994;8(3):439–443.

77 Scardino PT Early detection of prostate cancer Urol Clin North Am 1989;16(4):635–

80 Miller GJ, Cygan JM Morphology of prostate cancer: the effects of multifocality

on histological grade, tumor volume and capsule penetration J Urol 1994;152(5 Pt

86 Albertsen PC, Hanley JA, Fine J 20-year outcomes following conservative

manage-ment of clinically localized prostate cancer J Am Med Assoc 2005;293(17):2095–2101.

87 Draisma G, Etzioni R, Tsodikov A, et al Lead time and overdiagnosis in specific antigen screening: importance of methods and context J Natl Cancer Inst

prostate-2009;101(6):374–383.

88 Kattan MW, Cuzick J, Fisher G, et al Nomogram incorporating PSA level to predict

cancer-specific survival for men with clinically localized prostate cancer managed

without curative intent Cancer 2008;112(1):69–74.

89 Lu-Yao GL, Albertsen PC, Moore DF, et al Outcomes of localized prostate cancer following conservative management J Am Med Assoc 2009;302(11):1202–1209.

C H A P T E R 2

Diagnosis and Screening

Yiannis Philippou1, Harveer Dev2, and Prasanna

Sooriakumaran3

1 Department of Urology, East Surrey Hospital, Redhill, UK

2 Department of Surgery, Cambridge University Hospital, Cambridge, UK

3 Surgical Intervention Trials Unit, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK

Prostate cancer is a significant burden to men’s health It represents themost frequently diagnosed nondermatological malignancy and the secondleading cause of death due to cancer in men [1] In 2009, just over 40 000patients were diagnosed with prostate cancer in the United Kingdom,with approximately 10 000 deaths occurring each year Global rates forprostate cancer generally mirror those found in the United Kingdom, withthe highest primarily in the developed countries of Europe, North andSouth America, and the Oceanic nations

The natural progression of prostate cancer in most men is relatively slow.Most tumors remain organ confined and will never surface clinically dur-ing the patient’s lifetime, either because they are indolent or because deathoccurs from competing causes before clinical manifestation of the malig-nancy

The causes of prostate cancer most likely reflect a complex interplaybetween environmental and hereditary genetic factors, most of whichremain to be identified, that interact and lead to a critical acquisition

of DNA mutations in prostate cancer cells As the growth of prostaticcancer cells initially relies on circulating testosterone metabolites, hor-monal factors are likely to have an important role in the natural his-tory of the disease A slight increase in incidence of prostate cancer hasbeen predicted with high consumption of meat, dairy products, and fats[2] Although the evidence reveals at best, weak associations are incred-ibly difficult to interpret in the face of multiple confounding factors

Prostate Cancer: Diagnosis and Clinical Management, First Edition.

Edited by Ashutosh K Tewari, Peter Whelan and John D Graham.

C

16

Diagnosis and Screening 17

Hitherto, major environmental risk factors that are amenable to primaryprevention measures have not been identified [3] The Selenium and Vita-min E Cancer Prevention Trial (SELECT), the largest ever cancer preven-tion trial, countered evidence from previous epidemiological studies thatsuggested that daily selenium and vitamin E taken alone or in combina-tion could decrease the risk of prostate cancer In fact, the trial reportedthat taking vitamin E or selenium supplement alone or in combinationmight increase the risk of developing prostate cancer [4] Dutasteride,

a 5-alpha-reductase inhibitor (used in the treatment of benign prostatichyperplasia, BPH), can reduce serum prostate-specific antigen (PSA) lev-els by approximately 50% at 6 months and total prostatic volume by 25%after 2 years The Reduction by Dutasteride of Prostate Cancer Events(REDUCE) trial suggested that dutasteride might potentially play a role as

a chemoprevention agent in individuals at high risk of developing prostatecancer [5]

Symptoms

The diagnosis of prostate cancer can be made in a number of stages toms due to prostate cancer are rarely the cause for patient presentationand investigation If symptomatic, localized prostate cancer can result inurinary symptoms including hematospermia, although the presence ofvoiding lower urinary tract symptoms (LUTS), hematuria, and/or per-ineal/voiding discomfort is likely to result from coexisting BPH/prostatitis.Advanced disease may present with rectal obstruction, bone pain, andmore systemic features of malignancy [6]

Symp-First line investigations

First line tests include completion of the physical examination with a tal rectal examination (DRE), and measurement of serum PSA; suspiciousfindings on either of these tests is followed by more sophisticated diagnos-tic techniques, beginning with transrectal ultrasound (TRUS) and guidedsystematic biopsy Until as recently as the early 1990s, prostate cancer wastypically diagnosed as a result of symptomatic metastases or when foundduring DRE in a patient presenting with urinary complaints In addition,the biomarker “prostatic acid phosphatase” would often be elevated withthe presence of bone metastases However, the advent of the PSA blood

digi-18 Chapter 2

test assay, developed by Kurlyama et al in the 1980s, transformed the

diag-nostic landscape for prostate cancer, as the antigen became one of the mostcommonly used tumor markers in modern medicine

Prostate-specific antigen

Prostate-specific antigen (PSA) is a glycoprotein consisting of 240 aminoacids It is a serine protease secreted by prostate into semen where itcauses lysis of seminal coagulum, although its function in the serum isless well understood PSA in blood occurs in three forms: free PSA, PSAcomplexed with alpha-1 antichymotrypsin, and PSA complexed with␤1-antichymotrypsin [7] In conjunction with DRE, PSA has since become awidely used clinical tool to help identify men with prostate cancer [8],

as well as its subsequent staging and monitoring post-diagnosis PSA els may be elevated in men with prostate cancer because PSA produc-tion is increased within the cancerous tissue and in addition tissue barriersbetween the prostate gland lumen and the capillary are disrupted, releas-ing more PSA into the serum Studies have estimated that PSA elevationscan precede clinical disease by 5–10 years [9]

lev-Although PSA was originally introduced as a tumor marker to detectcancer recurrence or disease progression following treatment, it waswidely adopted for cancer screening by the early 1990s [10] Subsequently,various professional organizations issued guidelines condoning the rou-tine use of PSA in the detection of prostate cancer [11] The routineuse of the PSA blood test as a diagnostic/screening tool has resulted in

a substantial increase in the incidence of prostate cancer recorded wide Although the PSA test allows for earlier detection of prostate can-cer, critics state that such numbers represent overdetection of subclini-cal disease, with the potential for widespread use of relatively aggressivecurative treatments by radical surgical, chemotherapeutic, and radiationstrategies [12]

world-The traditional cutoff for an abnormal PSA level has been 4.0 ng/mL [11,13] The American Cancer Society systematically reviewed the literature

to assess the PSA test performance [14] When reviewing the performance

of a diagnostic test, several parameters need to be assessed These includesensitivity (probability of identifying true positives with the disease), speci-ficity (probability of identifying the true negatives), and positive/negativepredictive values (probability that a test positive/negative individual

Diagnosis and Screening 19

actually has/does not have the disease) According to the American cer Society, the estimated sensitivity of a PSA cutoff of 4.0 ng/mL is 21%for detecting any prostate cancer and 51% for detecting high-grade can-cers (Gleason≥8) Using a cutoff of 3.0 ng/mL increased the sensitivities

Can-to 32% and 68%, respectively The estimated specificity was 91% for aPSA cutoff of 4.0 ng/mL and 85% for a cutoff of 3.0 ng/mL PSA testinghowever has poorer discriminating ability in men with symptomatic BPH[15] Overall, the positive predictive value for a PSA level⬎4.0 ng/mL isapproximately 30%, meaning that slightly less than one in three men with

an elevated PSA will have prostate cancer detected on biopsy [16] For PSAlevels between 4.0 and 10.0 ng/mL, the positive predictive value is about25% and this increases to 42–64% for PSA levels⬎10 ng/mg [17] Severalfactors have been reported to affect the measured level of serum PSA thusaffecting the specificity of the PSA blood test These include BPH, diagnos-tic examinations such as DRE, physical exercise, ejaculation, and prostati-tis PSA levels have also been shown to correlate with prostate volume andthe age of the patient

Many studies have used DRE and PSA to screen for the presence ofprostate cancer [17–19] The results of these studies are twofold First

of all, the studies suggest that DRE alone can detect some tumors notdetectable by PSA testing, but overall its levels of sensitivity and speci-ficity are inferior to PSA These results suggest that the PSA test is a moreaccurate screening tool in detecting prostate cancer compared with DRE,with significantly greater sensitivity, specificity, and positive predictive val-ues As expected, these studies highlight that on combining DRE and PSA,the testing results in better prostate cancer detection rates A multicenter

screening study by Catalona et al of 6630 men reported a detection rate of

3.2% for DRE, 4.6% for PSA, and 5.8% for the two methods combined.PSA detected significantly more of the cancers than DRE (82% vs 55%)[17] Overall, 45% of the cancers were detected only by PSA, whereasjust 18% were detected solely by DRE In a separate study of 1000 men

by Gali´c et al., the positive predictive value for prostate cancer was 48.7%

for abnormal finding of DRE, 47% for PSA⬎ 4 ng/mL, and 80% for thecombination of both [20] Further manipulations of PSA, based on density(PSA/unit volume of prostate), kinetics (change in PSA/unit time), andfree:bound ratios have all been used to attempt to further improve thepredictive value of PSA, although no one measure has been established

as superior In general, large trials looking at the efficacy of screening forprostate cancer have relied on the level of PSA alone

20 Chapter 2

Transrectal ultrasound

Transrectal ultrasound (TRUS) is the most commonly used imaging nique for evaluating prostate cancer In addition to its role in diagnosingprostate cancer, it also allows estimation of prostate size, guides needlebiopsies, provides local staging information, and monitors disease prior toand after treatment TRUS is not normally used as a primary screeningmeasure but to confirm the diagnosis of prostate cancer in combinationwith prostate biopsy for those with raised PSA or lesions suspicious onDRE Technical advances, selection biases, observer differences in TRUSscanning, and the lack of UK studies mean that the evidence concerningthe accuracy and effectiveness of TRUS for the detection and diagnosis

tech-of prostate cancer remains variable It is however generally accepted thatwhen used in conjunction with DRE and PSA measurement, TRUS canadd to the detection rate of localized prostate cancer

Transrectal ultrasound-guided biopsy

Needle biopsy is used to confirm the diagnosis of prostate cancer and toprovide histological grading information In the context of the increasinguse of the PSA assay, the number of biopsies undertaken in urologicalpractice has increased considerably in recent years Core biopsy involvesthe use of a spring-loaded automatic biopsy gun, equipped with an 18-gauge needle The needle is reliably placed into suspicious lesions in thegland using TRUS which helps to ensure accurate targeting [21] Foci ofcancerous cells within the prostate can appear as hypo- (or even hyper-)echoic lesions on TRUS, although are frequently isoechoic, warranting astandard protocol biopsy (e.g., 12-core) Biopsy does not have a role infirst line screening, although it is considered the gold standard diagnosticinvestigation for histological confirmation of prostate cancer

The ability to grade and stage prostate cancer accurately is of vital tance for prognosis and the choice of suitable treatment options Biopsyspecimens are graded histologically based on the architectural differen-tiation of the tumor cells [22] The predominant histological system isthe Gleason grading system in which sections of tumor are graded from

impor-1 (least aggressive) to 5 (most aggressive) The two highest grades fromeach tumor are added to give a score ranging from 2 to 10 In addi-tion to using the Gleason score as a predictor of the biological aggressive-ness of prostate cancer, other parameters can also be combined with the

Diagnosis and Screening 21

Gleason score to estimate disease severity D’Amico et al suggested a

strat-ification of patients into low, intermediate, and high-risk groups by bining the Gleason score, the PSA measurement, and the clinical stage[23] The TNM system is the major method used for the staging of prostatecancer Although physical examination and the DRE provide the basis forclinical staging, imaging in the form of TRUS, MRI, CT, radionuclide bonescans, and pelvic lymph node evaluation are used to further evaluate thestage of prostate cancer

com-Evaluating population screening for prostate cancer

A number of criteria are commonly used to determine the suitability of acondition for population screening for disease as outlined by Wilson andJungner in 1968 [24] We can consider each of these criteria together withthe available evidence from randomized control trials (RCTs) and observa-tion trials in order to evaluate a prostate cancer screening program

r Epidemiology: It is of no doubt that prostate cancer is indeed a major

health problem and a public health concern, as the second mostcommon cause of cancer death among men With an increasing lifeexpectancy, improvements in diagnostic techniques, and a rise in pub-lic knowledge and demand for testing, the incidence and prevalence ofdisease will continue to rise

r Natural history: In contrast to breast and cervical cancer (where national

screening programs are established), the natural history of prostate cer remains poorly understood The severity of prostate cancer rangesfrom nonfatal slow-growing tumors, which remain asymptomatic andprobably require no treatment, to aggressive fast-growing tumors thatmetastasize quickly, often before symptoms become evident In betweenare those cancers that are confined to the prostate in the early stages and

can-in these a screencan-ing program would seek to target

r Diagnostic tests: Diagnostic screening tests need to be simple to

per-form, relatively inexpensive, and provide accurate information aboutthe presence or absence of the disease The front-line screening testsfor prostate cancer include DRE and PSA (see above), both of whichare relatively inexpensive and easy to perform but show wide variations

in specificity and sensitivity between studies In addition, the intervalbetween screening tests also proves problematic to define, due to ourlimited understanding of the natural history of the disease, and requiresfurther careful evaluation

22 Chapter 2

r Acceptability of test: The initial diagnostic tests need to be acceptable

to both the population to be tested and the clinicians performing thetests In the first stage of screening for prostate cancer, these tests wouldinvolve taking a blood sample and a DRE It is generally assumed thatthese are acceptable to most patients and clinicians, although little workhas been published to confirm this Further evaluation is required relat-ing to quality of life in screened and nonscreened men with prostatecancer to assess the social and psychological effects of the screeninginvestigations, as well the impact of additional year(s) of knowledge of

a diagnosis during active surveillance or watchful waiting

r Case selection: There should be an agreed policy on whom to treat as

patients

r Treatment: Broadly, there are three main treatments for localized

prostate cancer each with its own risk–benefit profile: radical ctomy, radiotherapy, and conservative management where surveillance

prostate-is preferred with active treatment if symptoms then develop Althoughthere is evidence that all of the above treatment modalities can beeffective in the treatment of localized prostate cancer, the question stillremains as to whether early detection and active treatment of prostatetumors can significantly enhance life expectancy and the quality of life[25]

r Resources and services: Currently, there is no national screening

ser-vice for prostate cancer in the United Kingdom, although ad hoc

screen-ing by general physicians has increased due to patient-led demand forPSA testing This has resulted in increasing referrals to hospital urol-ogy clinics, which may not currently have the facilities to accommo-date population screening If screening were to be introduced, furthersubstantial investment in diagnostic and treatment facilities would benecessary

r Costs: Cost analyses for establishing and maintaining a prostate cancer

screening service has yet to be performed; however, estimates suggestthat the funding of such a service would be considerable A recent study

by Benoit et al estimated that the cost per year life saved by prostate

cancer screening with PSA and DRE results in a cost per year life saved

of$2339–$3005 for men aged 50–59 years,$3905–$5070 for men aged60–69 years, and$3574–$4627 overall for men aged 50–69 years [26]

It is also likely that costs of following up false positives in a prostatescreening program would also be considerable in addition to the costincurred on managing the complications associated with treatment oflocalized prostate cancer

Diagnosis and Screening 23

Screening studies

A number of observational trials and RCTs have been performed to assessthe effectiveness of screening, mainly in North America and Europe Overthe last few years, several large multicenter RCTs have been undertaken toassess whether screening for prostate cancer using PSA and DRE has hadany impact on prostate cancer mortality One of the first was a Canadiantrial called the Quebec Prospective Randomized Controlled Trial, whichwas originally reported in 1999 [27] The Prostate, Lung, Colorectal andOvarian (PLCO) Cancer Screening Trial and the European RandomizedStudy of Screening for Prostate Cancer (ERSPC) were both larger mul-ticenter trials published in 2009 [28, 29] The results from these lattertwo trials have been the most quoted by health organizations, both inEurope and the United States when making recommendations for nationalprostate cancer screening programs

The Quebec Prostate Cancer Trial involved 46 193 men aged 45–

80 years who were randomized to no screening, or screening with PSAand DRE at their initial visit (and with PSA alone thereafter); a PSA level

of 3 ng/mL prompted further workup with TRUS and biopsy The endpoint was prostate cancer mortality and the patients were followed upfor 7 years The study reported 137 deaths due to prostate among 38 056nonscreened men and only 5 deaths among 8137 screened individuals

An odds ratio of 3.25 (p-value⬍.01) in support of prostate screening wasfound The analysis of data as an observational study instead of a RCTinvited criticism by the introduction of several biases that were felt toultimately overestimate the effects of screening and as a result this studyhas fallen out of favor [30]

The PLCO Screening Trial was a US-based multi-institutional RCT of

76 693 men between the ages of 55 and 74 years who were randomlyassigned to annual screening with PSA and DRE or their usual care [28]

A PSA level above 4.0 ng/mL or an abnormal DRE were indications forbiopsy A total of 7 years of follow-up was provided The PCLO trialreported information on prostate cancer incidence, cancer-specific mortal-ity, all-cause mortality, and cancer staging and is one of few studies withhigh compliance rates and total patient accrual The reported incidence ofprostate cancer per 10 000 person-years in the screening group was 116compared with 95 in the control group (rate ratio, RR= 1.22; 95%CI =1.16–1.29) The cancer-specific mortality per 10 000 person-years was 2.0

in the screened group and 1.7 in the unscreened population (RR= 1.13;95%CI= 0.75–1.70) The percentage of those diagnosed with low stage

24 Chapter 2

I or II cancers was also similar regardless of the group Based on theseresults, neither prostate cancer incidence nor cancer-specific mortalitydemonstrated significant differences due to screening Although the PLCOTrial has several methodological strengths, mainly the high number

of participants and high compliance rates, there are some weaknesses.While the trial appears to be equally randomized between the studygroups, approximately 44% of patients had received a PSA test prior torandomization in the control group and in addition by the sixth year ofthe study 52% of the control population had been screened The fact that

a significant proportion of the control population had already receivedscreening prior to randomization suggests that men who are less likely tohave prostate cancer and in addition less likely to have higher-stage orlife-threatening disease may have been introduced into the control arm ofthe RCT, hence contributing to the lack of a significant difference in cancerincidence and mortality due to screening A further weakness of the PLCOTrial was the short follow-up period of 7 years, which was addressedwith the publication of 13-year follow-up data (92% follow-up through

10 years; 57% through 13 years); this found a 12% higher incidence ofprostate cancer in the intervention arm (RR= 1.12; 95%CI = 1.07–1.17)with no significant difference in prostate cancer mortality compared withthe control group (RR = 1.09; 95%CI = 0.87–1.36) [31] Furthermore,the PLCO Trial used a PSA level of 4 ng/mL to trigger further workup,although it is generally accepted that lower cutoff PSA values may lead todetection of more cancers

The ERSPC Trial was an European multi-institutional RCT initiated inthe 1990s with participation of 182 160 men aged 50–74 years who wererandomly assigned to PSA screening every 4 years or a control group thatwas offered no screening; median follow-up was 9 years [29] This studyused different recruiting and randomization procedures across seven cen-ters in Europe and used a PSA cutoff of 2.5–4.0 ng/mL (with most cen-ters using cutoff of 3.0 ng/mL) as indication for referral for TRUS andbiopsy After a median follow-up of 11 years, for the 162 243 men aged55–69 years, the primary outcome of prostate cancer mortality was 21%lower in the group offered screening (RR= 0.79; 95%CI = 0.68–0.91)

To prevent one death from prostate cancer at 11 years follow-up, 1055men would need to be invited for screening and 37 cancers would need to

be detected [32] Furthermore, there was a 41% reduction of metastaticcancers detected in the screening group in addition to the identification

of a higher percentage of patients with low-risk disease (Gleason scores 6and 7 of 72.2% and 27.8%, respectively, in the screened group vs 54.8%

Diagnosis and Screening 25

and 45.2% in the control group) All-cause mortality was not reducedwith screening (18.2 vs 18.5 deaths per 1000 person-years; RR= 0.99;95%CI= 0.97–1.01) In 2012, Schroder et al consolidated their previous

finding about ERSPC Trial published in 2009 that PSA-based screeningsignificantly reduced mortality from prostate cancer but did not affect all-cause mortality

Several factors could have contributed to this finding of no effect inall-cause mortality About 24% of subjects invited for screening did notundergo PSA testing [29] and in addition a substantial proportion of thecontrol group received PSA testing as 31% of cancers in the control groupwere in fact detected through PSA screening Furthermore, additionalanalysis of the ERSPC data may further improve the mortality reductionand screening benefit found in the study A subsequent analysis of theRotterdam site data estimated that after adjustment for noncompliance inthe screening population and contamination in the control arm, the mor-tality benefit found in the ERSPC population might be as high as 30% [33].Furthermore, similar to the PLCO Trial, the 5–10-year lead time associatedwith PSA testing may mean the follow-up duration was insufficient toaccurately estimate the survival benefit A modeling study using data fromall ERSPC sites concluded that the screening benefit could increase overtime, with numbers needed to screen (NNS) of 837 at year 10 and 503 atyear 12 [34]

Like all screening trials, the results of the ERSPC should be examinedwith certain caveats First, several biases could have favored the screen-ing group A higher proportion of cancers diagnosed in the screeninggroup was aggressively treated in a tertiary setting with radical prosta-tectomy compared with the control group where aggressive cancers weremostly treated with radiotherapy, expectant management, or hormonaltherapy, so some of the survival outcome differences could be relatedmore to improved treatment than screening [35] While demonstrat-ing a mortality benefit associated with screening, the ERSPC Trial alsorevealed a high likelihood of overdiagnosis and overtreatment with risk

of overdiagnosis estimated to reach about 50% It is of vital tance to note that any survival benefit from screening would not berealized for many years, while the burdens of screening and treat-ment, including harms from overdiagnosis and overtreatment, wouldoccur immediately and potentially have lifelong consequences Finally,

impor-of the seven individual centers included in the mortality analysis, two(Sweden and the Netherlands) demonstrated statistically significant reduc-tions in prostate cancer deaths with PSA screening The magnitude

14 years of follow-up (RR for death of 0.56 in those screened vs screened) Additionally, compared with the results reported by the ERSPCstudy, the NNS and numbers needed to treat (NNT) were 293 and 12,respectively, in the G ¨oteborg Trial.

non-The G ¨oteborg study demonstrated better outcomes with screening pared with both the larger ERSPC and PLCO trials Different parameters inthe G ¨oteborg Trial design included a younger patient population (median

com-56 years of age compared with⬎60 years in ERSPC/PLCO trials), shorterinterval of screening (every 2 years compared with 4 years in the ERSPCTrial), a lower rate of PSA testing prior to entry (approximately 3% com-pared with 44% in the PLCO Trial), a lower rate of contamination inthe control group, and a longer duration of follow-up from randomiza-tion (median 14 years); these may contribute to the finding of a benefitfor prostate cancer screening The 44% relative risk reduction in deaths asdemonstrated from this study may be the strongest evidence that screeningfor prostate cancer with PSA can be effective in lowering cancer-specificmortality

Despite the publication of the results of several long-awaited RCTs, thecontroversy surrounding prostate cancer continues because the interpre-tation of this level-one evidence is varied Although the ERSPC and the

G ¨oteborg Sweden trials suggest that screening with PSA can be effective inlowering cancer-specific mortality rates, there are still concerns over statis-tical analyses issues, contamination of control groups, insufficient follow-

up time, differing levels of PSA triggering further workup, and ate screening intervals

inappropri-In addition to the recent publication of RCTs to determine whetherscreening for prostate cancer will reduce prostate cancer mortality, cer-tain RCTs have compared active treatments for localized prostate cancerwith watchful waiting These studies endeavored to determine whetheraggressive treatment of localized prostate cancers detected by PSA willreduce morbidity and mortality when compared with watchful waiting.The PIVOT study, conducted in the United States, included men with