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Highlights from the 20th International Prostate Cancer Update

Per-Anders Abrahamsson, MD, PhD

William J. Catalona, MD

E. David Crawford, MD

Frans M.J. Debruyne, MD, PhD

Robert E. Donohue, MD

James A. Eastham, MD

Marc B. Garnick, MD

Leonard G. Gomella, MD

Paul H. Lange, MD

M. Scott Lucia, MD

Abraham Morgentaler, MD

Alan W. Partin, MD, PhD

Daniel P. Petrylak, MD

Neal D. Shore, MD

Matthew R. Smith, MD, PhD

H I G H L I G H T S Volume 9 Supplement 2 June 2010

GRAND ROUNDSin UROLOGY™

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Jointly sponsored by Grant/Downing Education and CJP Medical Communications.

a G r a n d R o u n d s

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Supported by an unrestricted educational grant from Watson Pharmaceuticals

OVERVIEWPatterns of care in prostate cancer have changed tremendously in the past 20 years, altering the way patients with this tumor present and how they are evaluated before and after diagnosis. With the use of new and combined treatments, the frequency and variety of complications have differed from those previously reported. Advances have been made in prostate cancer imaging, in biopsy methodology, in understanding causative factors and disease, in treatment-related quality of life, and in predicting the behavior of individual tumors using risk strata. Despite these advances, no con-sensus has emerged regarding the optimal treatment for the most common patient with prostate cancer.

There is a need for both oncologists and urologists to understand the rationale behind targeted therapy for the treatment of advanced prostate cancer and how trial entry could improve the effi cacy of drugs and decrease the toxicity. This activity seeks to educate urologists and other healthcare professionals about the latest advances in the prevention, screening, and treatment of prostate cancer. The International Pros-tate Cancer Update (IPCU) educational planning committee has identifi ed the fol-lowing educational gaps between recent research in prostate cancer and its integra-tion into professional practice at the inter-national, national, and community levels:

Current best practices in prevention • and screening of prostate cancer Promising therapies, issues, and • economic concerns in the treat-ment of local diseaseRole of androgen deprivation ther-• apy in 2010Emerging treatments for advanced • and castration-resistant prostate cancer

LEARNING OBJECTIVESThis educational initiative aims to reach urologists, oncologists, and urologic oncologists. Upon completion of this activity, participants will be able to:

Summarize the pathology of prostate • cancer and corresponding prevention

and screening strategies, including prostate-specifi c antigen (PSA) test-ing, the need for new biomarkers, and the watchful waiting optionCompare and contrast the use of radi-• ation and drug therapy for the man-agement of localized prostate cancerAnalyze the disease conditions that • can affect bone health, including hypogonadism, androgen depriva-tion, and bone metastasesExplain the role of hormone deprivation • therapy, including benefi ts, complica-tions, and the therapeutic approaches to the treatment of complicationsIdentify the scientifi c rationale and • clinical trial design of targeted agents for the treatment of advanced hor-mone refractory prostate cancerDefi ne recent developments in prostate • cancer surgery that improve patient oncologic and quality-of-life outcomesCompare and contrast the available • treatment options and effi cacy and safety of focal therapy

TARGET AUDIENCEThis activity has been developed and is intended for urologists, oncologists, uro-logic oncologists, and any medical pro-fessional who diagnoses or treats patients with prostate cancer.

SPONSORSHIPThis activity is jointly sponsored by CJP Medical Communications and Grant/Downing Education. It is funded by an unrestricted educational grant from Watson Pharmaceuticals.

GRANT/DOWNING EDUCATION DISCLOSUREGrant/Downing Education adheres to ACCME Essential Areas and Policies, including the Standards for Commercial Support regarding industry support of continuing medical education. In order to

resolve any identifi ed confl icts of interest, disclosure information is provided during the planning process to ensure resolution of any identifi ed confl icts. Disclosure of fac-ulty and commercial relationships, as well as the discussion of unlabeled/investiga-tional use of any drug, device, or procedure by the faculty, are made known below.

The employees of Grant/Downing Education have no fi nancial relationships to disclose.

CJP MEDICAL COMMUNICATIONS DISCLOSUREThe employees of CJP Medical Communi-cations and medical writer Anne Jacobson have no fi nancial relationships to disclose.

DISCLOSURE OF UNLABELED USE/INVESTIGATIONAL USEThe drug selection and dosage informa-tion presented in this activity are believed to be accurate. However, participants are urged to consult the full prescribing information on any drug presented in this activity for recommended dosage, indications, contra-indications, warn-ings, precautions, and adverse effects before prescribing any medication. This is particularly important when a drug is new or infrequently used.

FACULTY DISCLOSURES In accordance with the Accreditation Council for Continuing Medical Educa-tion (ACCME), Grant/Downing Educa-tion and CJP Medical Communications are required to disclose to the participants any fi nancial relationships the authors, fac-ulty, or planning committee members have with commercial interests whose products or healthcare services will be discussed in their presentations. It is Grant/Downing Education’s and CJP Medical Communica-tions’ policy to ensure that all continuing medical education activities are planned independent from commercial companies and are free from commercial bias. The fol-lowing disclosures of fi nancial relationships represent all people who were involved with the development or delivery of the content of this educational activity.

CONTINUING MEDICAL EDUCATION

Per-Anders Abrahamsson, MD, PhD, does not have any relevant fi nancial disclosures.

William J. Catalona, MD, discloses that during the past 12 months he has received research support and been a consultant, speaker, and study investigator for Beck-man Coulter; he receives research sup-port as a consultant and investigator from deCODE genetics; he received an hono-rarium as a speaker (once) for GlaxoSmith-Kline; he has received an honorarium as a speaker (once) for American Kidney Stone Management, Ltd.; and he has received research support from OHMX.

E. David Crawford, MD, discloses that he is a consultant or advisor for Eigen and Ferring; he is a meeting participant or lecturer for Watson, Endo, GlaxoSmith-Kline, Oncura, Endocare, Ferring, and Sanofi -Aventis; and he receives grant sup-port from NIH and University of Colo-rado Cancer Center.

Frans M.J. Debruyne, MD, PhD, dis-closes that he is a consultant for Steba Bio-tech and Vision Sciences; and he is on the advisory board for Ferring and Millenium-Takeda.

Robert E. Donohue, MD, does not have any relevant fi nancial disclosures.

James A. Eastham, MD, does not have any relevant fi nancial disclosures.

Marc B. Garnick, MD, discloses that he is the Editor-in-Chief for Harvard Health publications; he drafts manuscripts for CRICO/RMF; he is a consultant for Spe-ciality European Pharma; he is an advisor for Ferring; he directs screening for pros-tate cancer via the ACP point of care web-site PIER; and he serves as an adviser to Normoxys and Kalos.

Leonard G. Gomella, MD, discloses that he is an investigator and is an advisor for GlaxoSmithKline.

Paul H. Lange, MD, does not have any relevant fi nancial disclosures.

M. Scott Lucia, MD, discloses that he is a member of the advisory board for Gen-Probe.

Abraham Morgentaler, MD, discloses that he is a consultant for Slate; he is a speaker for Auxilium Pharmaceuticals,

Bayer, Solvay, and Watson; and he is a researcher for GlaxoSmithKline.

Alan W. Partin, MD, PhD, discloses that he receives research grants from Gen-Probe, Beckman Coulter, and the National Institutes of Health (NIH).

Daniel P. Petrylak, MD, discloses that he receives honorarium as the Chairman of the Sunfl u Advisory Board for eGenix; he is a consultant for Pfi zer, EUSA Pharma, Fer-ring, OncoGenex, GPC Biotech, Millen-nium, and MEDgenesis Inc.; and he is an investigator for Celgene and Sanofi -Aventis.

Neal D. Shore, MD, discloses that he is an investigator and on the advisory board for Dendreon.

Matthew R. Smith, MD, PhD, discloses that he is a consultant for Amgen, Novar-tis, and GTx.

INSTRUCTIONS FOROBTAINING CONTINUINGMEDICAL EDUCATION CREDITIn order to receive credit, participants must read this entire supplement, which is in a print and online medium. Participants must score at least a 70% on the post-test and submit it, along with the credit appli-cation and evaluation form, to the address/fax number indicated. Statements of credit will be mailed within 6 to 8 weeks.

ACCREDITATIONThis activity has been planned and imple-mented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Grant/Downing Education and CJP Medical Com-munications. Grant/Downing Education is accredited by the ACCME to provide con-tinuing medical education for physicians.

Grant/Downing Education designates this educational activity for a maximum of 3.0 AMA PRA Category 1 Credits™. Physi-cians should only claim credit commensu-rate with the extent of their participation in the activity.

DISCLAIMER STATEMENTThe views expressed in this activity are those of the faculty. It should not be

inferred or assumed that they are express-ing the views of the commercial support-ers, any other manufacturer of pharma-ceuticals, CJP Medical Communications, or Grant/Downing Education.

All rights reserved including transla-tion into other languages. No part of this activity may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval systems, without permission in writing from Grant/Downing Education.

PRIVACY POLICYGrant/Downing Education protects the privacy of personal and other informa-tion regarding participants, educational partners, and joint sponsors. Grant/Downing Education and CJP Medical Communications will not release person-ally identifi able information to a third party without the individual’s consent, except such information as is required for reporting purposes to the appropriate accrediting agency.

Grant/Downing Education and CJP Medical Communications maintain physical, electronic, and procedural safe-guards that comply with federal regula-tions to guard your nonpublic personal information.

TERM OF OFFERINGThe estimated time to complete this activ-ity is 3.0 hours. This activity was originally released on June 30, 2010, and is eligible for credit through June 30, 2011.

PUBLISHERCJP Medical Communications is a division of Carden Jennings Publishing Co., Ltd., 375 Greenbrier Drive, Ste 100, Charlottesville, VA, 22901. 434-817-2000; fax: 434-817-2020; www.grandroundseducation.com.

Copyright © June 30, 2010, to June 30, 2011, CJP Medical Communications. All Rights Reserved.

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GRAND ROUNDS IN UROLOGY™, please

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1 Session I: Prevention and ScreeningSession Editor: Per-Anders Abrahamsson, MD, PhDBiomarkers for Prostate CancerChemoprevention Trials: What Do the Results Mean?European View of Chemoprevention: ERSPC TrialsWatchful Waiting versus ChemopreventionPathology of Prostate Cancer: High-Grade Prostatic

Intraepithelial Neoplasia

15 Session II: Localized DiseaseSession Editor: E. David Crawford, MDProstate-Specifi c Antigen and Isoforms for Prostate CancerExpectant Management: The Johns Hopkins Program ExperienceThe Economics and Effectiveness of HIFU and RoboticsThe Emerging Role of Options for Targeted TherapyThe Role of Focal Therapy in Treating Localized Prostate Cancer

27 Session III: Issues with Hormone DeprivationSession Editor: E. David Crawford, MDThe 30th Anniversary of Leuprolide: Where Are We Now?An Update on LHRH Agonists and GnRH AntagonistsTreatment of Skeletal Related IssuesWhat Are the Major Issues with Hormone Replacement Therapy?

39 Session IV: Treatment of Advanced and

Castration-Resistant DiseaseSession Editor: Daniel P. Petrylak, MDImmunotherapy with VaccinesUpdate on Clinical Trials in CRPCEffective Testosterone Suppression for Prostate CancerBiology of Prostate Cancer Metastases

53 Post-Test for CME

55 Application for CME Credit

57 Directory of Meetings

Editorial BoardMEDICAL EDITOR

E. David Crawford, MDProfessor of Surgery, Urology, and Radiation OncologyHead, Urologic OncologyE. David Crawford Endowed Chair in Urologic OncologyUniversity of Colorado, DenverAurora, Colorado

ASSOCIATE EDITORS

Roger R. Dmochowski, MDProfessor of Urologic SurgeryVanderbilt University Medical CenterNashville, Tennessee

Glenn M. Preminger, MDProfessor of Urologic SurgeryDirector, Duke Comprehensive Kidney Stone CenterDuke University Medical CenterDurham, North Carolina

Jacob Rajfer, MDChief of Urology, Harbor/UCLA Medical CenterProfessor of Urology, David GeffenSchool of MedicineUniversity of California, Los AngelesLos Angeles, California

Mack Roach III, MDProfessor, Departments of RadiationOncology and UrologyChair, Department of Radiation OncologyUniversity of California, San FranciscoSan Francisco, California

Claus Roehrborn, MDE. E. Fogelson and Greer Garson Fogelson Distinguished Chair in UrologyUniversity of Texas Southwestern Medical SchoolDallas, Texas

Nicholas J. Vogelzang, MDDirectorNevada Cancer InstituteLas Vegas, Nevada

PublisherCJP Medical CommunicationsA Division of Carden Jennings Publishing Co., Ltd.375 Greenbrier Drive, Suite 100Charlottesville, Virginia 22901P: 434-817-2000; F: 434-817-2020www.grandroundseducation.com

GRAND ROUNDS IN UROLOGY™ is published by CJP Medical Communications, 375 Greenbrier Drive, Suite 100, Charlottesville, VA 22901, with an educational grant from Indevus. Copyright 2010 by CJP. All rights reserved. No part of this publication may be repro-duced or transmitted in any form or by any means, electronic or me-chanical, including photocopying, recording, or utilizing any storage and retrieval system without written permission from the copyright owner. GRAND ROUNDS IN UROLOGY™ is an exclusive trade-mark of CJP. All correspondence should be addressed to the Vice Presi-dent. Requests for change of address or deletion must include mailing label from latest issue.

Marc WeathersbyVice [email protected]

David UtzVice President, [email protected]

Jenny DeGraffProject [email protected]

Jenny [email protected]

C O N T E N T S

In this issue of Grand Rounds in Urology, we are pleased to provide readers with the highlights from the

20th International Prostate Cancer Update (IPCU), held January 27-30, 2010. This conference was the 20th anniversary of a meeting that began the year after prostate cancer became the most common cancer in American males and the second lead-ing cause of death. Much has happened in the last 20 years with regard to diag-nosis, surveillance, and prevention, as well as treatments for localized, advanced, and castration-resistant prostate cancer. This 3-day conference convened leading inter-national experts to review the most recent advances.

Back at the beginning, we were in the era of simply switching over from the subcuta-neous to the 1-month depots, the antian-drogens were just starting to break in, and a lot of exciting research was being con-ducted. Surgery also has come a long way. First we had retropubic and perineal surgery, which was followed by nerve-sparing sur-gery, after which we experienced the over-taking of the laparoscopic and robotic sur-gery options. In addition, the more recent options of focal therapy (high-intensity focused ultrasound and cryoablation) are being discussed at length. In terms of radi-ation therapy, the options have progressed from the pure external beam, from cobalt to the current intensity-modulated radia-tion therapy and treatment with gamma knives. Hormone therapy has evolved to the point where we now have an antago-nist, there are now antiandrogens, and a vaccine therapy has been approved. Thus, there have been many changes regarding how to treat patients with prostate cancer. Each is discussed within the pages of this highlights publication, as are the improve-ments in testing and diagnoses.

A discussion of clinical trials has been a hallmark of IPCU meetings, and this year was no exception. The clinical trials dis-cussed included the Cancer and Leukemia Group B study, which is a phase III trial of bevacizumab for prostate cancer; data on sipuleucel-T, which will be the fi rst immu-notherapeutic drug available for treatment; and a report on a recently completed

phase III trial involving abiraterone, a cytochrome P450 enzyme inhibitor that is also the focus of another ongoing phase III trial with chemotherapy.

Some of the disappointments in research over the past year were also discussed in January. They include the US Food and Drug Administration (FDA) decision not to more favorably review toremifene. This drug, a selective estrogen receptor modu-lator, or SERM, has potential in prostate cancer treatment as a side-effect drug (eg, for osteoporosis, hot fl ashes, and many of the estrogen-like side effects of androgen deprivation). The submitted study on toremifene was positive, yet the FDA did not grant their blessing for approval. Nor did they grant approval for denosumab, a RANK ligand that also is an exciting drug. Denosumab has been approved for osteo-porosis and is on hold for treating prostate cancer pending further review.

Another aspect of treatment I think in need of discussion is the cost of therapy in this whole system. We hope to soon pub-lish a retrospective analysis of the economic and clinical burden of prostate cancer. The bottom line is that prostate cancer costs money, with or without active treatment. In addition, the rates of both surgery and radiation therapy have increased, whereas the use of hormone therapy has declined. The average costs have increased, and so there has been some watchful waiting. There is probably still not a lot, but with an aging population, this concept will continue to grow.

Finally, the main focus of the annual IPCU conference is to gather multidis-ciplinary specialists to discuss and deter-mine the future landscape for diagnosing and treating prostate cancer. We hope you enjoy reading the expert opinions in this issue and that you use the discussion as a guideline in determining the best courses of treatment for your patients.

Sincerely,

E. David Crawford, MD

F R O M T H E E D I T O R I A L B O A R D

grandroundseducation.com 1grandroundseducation.com 1

S E S S I O N I Prevention and Screening

Biomarkers for Prostate Cancer

M. Scott Lucia, MD

Clinicians are challenged to select the best treatment plan for the large pro-

portion of men with prostate cancer who will not die from their disease. In 2010, approximately 192,000 men will be diag-nosed with prostate cancer in the US [1]. Most of these men, however, will die from causes other than this disease. Indeed, the lifetime risk of a prostate cancer diagnosis is approximately 17%, whereas the lifetime risk of prostate cancer mortality is approxi-mately 3%. Prostate cancer is expected to claim 27,360 lives this year [1].

Current options for prostate cancer detection are suboptimal. The prostate lies in a “blind spot” within the pelvis, bordered anteriorly and laterally by bones and by the bladder above, making access for examina-tion or imaging problematic. Digital rectal examination (DRE) can be insensitive, given that the exam is limited to the poste-rior aspect of the prostate. Although imag-ing techniques have improved in recent years, to date no imaging modality is appro-priate for widespread prostate cancer screen-ing. Biopsies are still performed blindly and

randomly, leading to signifi cant tissue sam-pling problems. With this approach to pros-tate biopsies, clinically insignifi cant cancers are being detected in excess (overdiagno-sis), and cancers that should be treated are missed (underdiagnosis).

Prostate specifi c antigen (PSA) is an important marker, but in the screening set-ting, PSA still lacks sensitivity and specifi c-ity for prostate cancer. Current National Comprehensive Cancer Network (NCCN) guidelines are controversial with respect to PSA screening. The NCCN recommends a baseline risk assessment, including PSA screening and DRE, at age 40. Men with a baseline PSA value <0.6 ng/mL can wait until age 45 for additional prostate cancer screen-ing, and men with a PSA of ≥0.6 ng/mL should proceed with annual follow-up screenings [2]. The NCCN also recom-mends a prostate biopsy for patients with a PSA level of 2.6 to 4.0 ng/mL and for those with a PSA velocity of ≥0.5 ng/mL per year when PSA is ≤2.5 ng/mL [2].

Patients are often confused about PSA levels, as our public-information campaigns have not caught up with recent PSA data. Some patients are still told that a PSA <4.0 ng/mL is considered “normal,” a PSA between 4.0 and 10.0 corresponds with a

Session Editor: Per-Anders Abrahamsson, MD, PhDChairman and ProfessorDepartment of UrologyLund UniversityMalmö, Sweden

Content Contributors: Per-Anders Abrahamsson, MD, PhDChairman and ProfessorDepartment of UrologyLund UniversityMalmö, Sweden

William Catalona, MDProfessor, Department of UrologyNorthwestern Feinberg School of MedicineDirector, Clinical Prostate Cancer ProgramRobert H. Lurie Comprehensive Cancer

Center at Northwestern UniversityChicago, Illinois

Leonard G. Gomella, MDBernard W. Godwin Jr. Professor of

Prostate CancerChairman, Department of UrologyDirector of Clinical Affairs, Kimmel Cancer

CenterThomas Jefferson UniversityPhilidelphia, Pennsylvania

M. Scott Lucia, MDAssociate Professor of PathologyDirector, Prostate Diagnostic LaboratoryDepartment of PathologyUniversity of Colorado, DenverAurora, Colorado

Figure 1. Prostate Cancer Prevention Trial (PCPT): cancer risk by prostate specifi c antigen (PSA) in the placebo group [4]. Insignifi cant cancer is defi ned as Gleason score ≤6, <3 cores with cancer, no core with >50% tumor.

0

10

20

30

40

50

60 Potentially incurable (pT3 or N1)

Insignificant cancer

>104.1-10.02.6-4.01.1-2.50-1.0

PSA, ng/mL

Per

cent

2 GRAND ROUNDS in UROLOGY™

low risk of cancer, and a PSA >10.0 ng/mL indicates a higher risk of prostate cancer. Findings from the Prostate Cancer Pre-vention Trial (PCPT), however, illustrate a very different pattern of risk [3]. As part of the PCPT protocol, all patients received an end-of-study biopsy, regardless of PSA. Among patients in the placebo group with a PSA of <4.0 ng/mL—supposedly the “normal” PSA group—15.2% were diag-nosed with prostate cancer as a result of the protocol-directed biopsy. Among these patients, some of whom had very low PSA levels, 14.9% had high-grade (Gleason score 7 to 10) cancer [3]. These fi ndings suggest that there is no PSA threshold below which patients are free from the risk of prostate cancer, including high-grade cancer.

Using PSA as a marker for prostate cancer involves a tradeoff between sensitivity and false-positive results. On one end of the spec-trum, the very low threshold of 1.0 ng/mL carries a high sensitivity for prostate cancer (82.0%), but is also associated with a high false-positive rate (59.4%). On the other end of the spectrum, the PSA threshold of 10.1 ng/mL has a very low false-positive rate (0.5%), but very low sensitivity (1.0%) [3].

PCPT investigators evaluated the associa-tion between PSA level and the prevalence of insignifi cant cancer, which was defi ned as a Gleason score of 6 or lower, <3 cores with cancer, and no core with >50% tumor. Even among patients with PSA levels of <1.0 ng/mL, only 50% of tumors fi t these criteria; the remainder were clinically signif-icant tumors (Figure 1) [4]. Many of these patients underwent treatment with pros-tatectomy, allowing researchers to exam-ine the pathologic features of the prostate. Potentially incurable disease, defi ned as pT3 or N1, was identifi ed in some patients with very low PSA levels (1.1 to 2.5 ng/mL) at the time of prostatectomy. All of the tumors examined in patients with the high-est PSA levels (>10 ng/mL) were potentially incurable [4].

Data from PCPT confi rm that PSA levels correspond with a continuum of risk across all values. Although PSA levels may refl ect tumor burden, this marker remains limited in the screening setting by the trade-off between sensitivity and false-positive rates. In PCPT, DRE was associated with very low sensitivity for prostate cancer (16%)[5]. Random biopsies are also inadequate

for screening, given sampling issues and the diffi culty in distinguishing clinically sig-nifi cant and clinically insignifi cant tumors. New approaches are needed to improve the diagnosis and assessment of prostate tumor aggressiveness.

BIOMARKERS FOR PROSTATE CANCERThe ideal biomarker for prostate cancer would be both sensitive and specifi c for the disease. In particular, the biomarker should be able to identify aggressive prostate cancer, rather than the clinically insignifi -cant tumors that do not require treatment. When modulated, the biomarker should also correlate with disease outcomes. The assay for the biomarker should be reproduc-ible, quick, low cost, and involve minimal invasiveness. Although it is unlikely that a single biomarker will carry all of these traits, it is important to clarify the goals.

Potential biomarker substrates—includ-ing urine, serum/plasma, and biopsy tis-sue—are associated with advantages and limitations. Urine is noninvasive, easy to obtain and handle, and contains prostate cells that drain from the prostatic ducts into the urethra; however, urine can be con-founded by pathologic activity in the blad-der and kidney. Serum/plasma sampling is more invasive, but blood samples are already routinely collected for serum PSA measure-ments. The major limitation with serum/plasma sampling is that tumor proteins are present in relatively low abundance, and are often obscured by high-abundance proteins such as albumin and immunoglobulins. Biopsy tissue can be informative, but pros-tate biopsy is invasive and often limited by sampling problems. Biomarkers that indi-cate the presence of a missed cancer would be helpful in directing repeat biopsies.

Prostate cancer antigen 3 (PCA3) is a genetic biomarker that was fi rst described in 1999 as differential display protein 3 (DD3) [6]. The PCA3 gene is located on a non-coding segment of mRNA, and its function remains unknown. PCA3 is prostate specifi c and highly overexpressed in more than 95% of prostate cancer. To date, it is has not been identifi ed in any other tissue or cancer [6].

Early studies of this biomarker evaluated the ratio of PCA3 mRNA to PSA mRNA (PCA3:PSA) in urinary sediments, using PSA mRNA as a surrogate for background

prostate epithelial cell nuclear material [7]. This ratio is sometimes referred to as the “PCA3 score” and is calculated as [PCA3 mRNA]/[PSA mRNA] x 1000. Researchers determined that a score 35 or higher is most appropriate for predicting a positive biopsy result. Validation studies of the PCA3 molecular urine assay showed good sensitiv-ity (66% to 82%), good specifi city (76% to 89%), and a high negative predictive value (84% to 90%) [7-10].

PCA3 may be useful in identifying aggressive disease in the form of large-volume/high-grade tumors. Nakanishi and colleagues have shown that the PCA3 score is higher in men with Gleason ≥7 tumors (versus Gleason <7), larger tumor volume (<0.5 cc versus 0.5-2.0 cc versus >2.0 cc), and “signifi cant” cancer (versus “insignifi -cant” cancer) [11].

Some clinicians have expressed a concern that patients may not widely accept PCA3 testing, given that it requires an atten-tive DRE—which is more complicated than a standard DRE—to release prostate cells into the urine. To address this con-cern, van Bokhoven and colleagues evalu-ated the feasibility of PCA3 screening in a community-based population of 349 men recruited during Prostate Cancer Aware-ness Week 2006 [12]. Multiple physicians were involved in the testing, and all were able to perform the test accurately. Nearly all tests (98.6%) yielded suffi cient mRNA for analysis. More than one-fourth of par-ticipants (28.1%) had positive PCA3 tests (PCA3:PSA ≥35). Importantly, the PCA3 and PSA tests appeared to identify different subpopulations of risk. In this study group, 16.6% of men had positive PCA3 tests but low PSA levels (<2.5 ng/mL). Conversely, 13.3% had high PSA levels (>2.5 ng/mL), but negative PCA3 tests [12]. Future studies will examine the correlation between PCA3-defi ned risk groups and clinical outcomes in prostate cancer to determine whether PCA3 will be useful in assisting with pros-tate cancer diagnosis and biopsy decisions, helping to identify clinically insignifi cant tumors, and monitoring patients following treatment.

Two other biomarkers are also receiving attention in prostate cancer. The gene fusion marker TMPRSS2:ERG/ETV1 is highly spe-cifi c for prostate tumors, present in approxi-mately 80% to 90% of prostate cancers, and

grandroundseducation.com 3

is detectable in prostate cells collected from urine sediments [13]. There is hope that a urine assay for TMPRSS2:ERG/ETV1 will be developed within the next few years.

Although it is not applicable to the screen-ing setting, the circulating tumor cell (CTC) test is currently used in the management of patients with metastatic prostate, colorectal, and breast carcinomas. Assays for CTC are highly sensitive for the presence of even a few CTCs in peripheral blood and can be used to monitor treatment effi cacy. Baseline CTCs also serve as prognostic markers in a variety of cancers. In 2008, de Bono and colleagues showed that baseline CTC levels independently predict overall survival in patients with metastatic hormone-refractory prostate cancer (HRPC) [14]. Patients with < 5 CTCs per 7.5 mL blood sample had a median survival of 21.7 months, compared with 11.5 months among patients with ≥5 CTCs per 7.5 mL blood sample (P < .0001) (Figure 2) [14]. On the basis of these fi nd-ings, the CTC assay is currently approved by the US Food & Drug Administration (FDA) for the evaluation of HRPC.

Emerging technologies will certainly advance the use of biomarkers in the diag-nosis and management of prostate cancer. Gene-expression profi ling with microarrays and other technologies allows researchers to characterize the molecular profi les of indi-vidual tumors, potentially directing the use

of highly specifi c targeted therapy. Based on the observation that benign and cancerous cells metabolize things differently, metabo-lomics is an emerging fi eld that seeks to identify cancer by detecting its unique metabolites [15].

Other technologies seek to identify molec-ular changes that occur in benign tissues of prostates containing cancer. Several candi-date markers that have cancer-associated changes have been identifi ed, including cadherin-11 [16], telomerase [17], HOXC5 [18], and GSTP1 methylation [19]. These markers may be most useful when evaluating a negative biopsy in a person with a rising PSA, particularly to determine whether they are at risk of having a nearby cancer that the biopsy missed.

Systems pathology is another tool that focuses on analyzing the interrelationships of multiple parameters in a system, such as molecular and pathological characteristics, rather than each parameter individually. In prostate cancer, a systems pathology study might incorporate data on pathologic fac-tors (eg, tumor grade and margins), clini-cal factors (PSA level and disease stage), and fi ndings from molecular and imaging analyses to calculate the risk of disease pro-gression. Using such an approach, Donovan and colleagues developed an algorithm of clinical, pathological, molecular, and imag-ing data that accurately predicted clinical

failure within 5 years after prostatectomy. The algorithm supported the predictive value of androgen receptor signaling in determining the duration of response to androgen-deprivation therapy [20].

In summary, biomarkers hold potential for clinical utility in prostate cancer beyond their use in screening and diagnosis. Bio-markers that also provide prognostic infor-mation may aid in decision-making in men with elevated PSA levels and negative biopsy results. In this setting, urine or blood bio-markers may identify which patients may benefi t from repeated biopsy and which patients can avoid overtreatment. Biomark-ers may also infl uence therapeutic decision-making by characterizing the risk of aggres-sive cancer and identifying candidates for targeted therapy. Ongoing therapeutic monitoring may also be improved with the use of biomarkers that track response to treatment.

Chemoprevention Trials: What Do the Results Mean?

Leonard G. Gomella, MD

Prostate cancer represents a signifi cant public health risk that has the poten-

tial to affect more than half of men aged 50 years or older. In autopsy studies of men who died of other causes, 55% of men aged 50 to 60 years and 64% of men aged 70 to 80 years had histologic evidence of pros-tate cancer [21]. Most of the risk factors for prostate cancer—age, race, genetic profi le—are not modifi able. Several observational studies have suggested that certain diet and lifestyle risk factors, namely red meat, dairy, and smoking, may increase the risk of prostate cancer, whereas certain vegetables, nutrients, and exercise appear to mitigate cancer risk. Without evaluation in prospec-tive randomized trials, these approaches cannot be recommended as evidence-based interventions for reducing the incidence of prostate cancer. With several primary pre-vention trials recently reporting fi ndings, however, a new era of scientifi cally rigorous chemoprevention may be beginning.

VITAMIN E AND SELENIUMThe Selenium and Vitamin E Cancer Pre-vention Trial (SELECT), the largest cancer

Figure 2. Circulating tumor cells (CTCs) and overall survival in hormone-refractory prostate cancer. Reproduced and adapted with permission from the American Association for Cancer Research: [13].


prevention trial to date, was designed to assess the effects of selenium and vitamin E alone and in combination on the incidence of prostate cancer [22]. SELECT enrolled 35,533 men age 50 or older (African Ameri-can men) or age 55 or older (all other men). All participants were considered to have a low baseline risk for prostate cancer, defi ned

as a PSA level <4 ng/mL and a nonsuspi-cious DRE at baseline. The men were ran-domly assigned to 1 of 4 treatment groups: selenium plus vitamin E; selenium plus placebo; vitamin E plus placebo; or placebo plus placebo.

Selenium or vitamin E, alone or in com-bination at the doses and formulations

used, did not prevent prostate cancer in this population of relatively healthy men. After a median follow-up of 5.46 years, there were no signifi cant differences in the incidence of prostate cancer across any of the study groups (Figure 3). Compared with placebo, the hazard ratios (HR) for prostate cancer were 1.13 (99% confi dence interval [CI], 0.95-1.35) for vitamin E, 1.04 (99% CI, 0.87-1.24) for selenium, and 1.05 (99% CI, 0.88-1.25) for vitamin E plus selenium [22].

5-ALPHA-REDUCTASE INHIBITORSObservational studies, animal models, and preclinical research have provided a strong rationale for hormonal manipulation as a strategy for prostate cancer prevention. High levels of dihydrotestosterone (DHT) have been implicated in the pathogenesis of both benign prostatic hyperplasia (BPH) and prostate cancer. The synthesis of DHT from testosterone requires the 5-alpha reductase (5AR) enzymes type 1 and 2. The type 1 isozyme is found predominantly in the sebaceous glands and prostatic epithelium, whereas type 2 is the principle isoenzyme found in the prostatic stroma. Two 5AR inhibitors (5ARIs) are currently available to prevent the synthesis of DHT, including dutasteride, a dual isozyme inhibitor, and fi nasteride, a selective type 2 inhibitor [23]. In addition to their use in the treatment of BPH, there has been much interest in the potential role of 5ARIs in the prevention of prostate cancer [24].

The PCPT was designed to determine if fi nasteride, taken for 7 years, could reduce the prevalence of prostate cancer com-pared with placebo. PCPT enrolled a total of 18,882 men aged 55 years or older with baseline PSA values of ≤3.0 ng/mL and a normal DRE. Patients were randomly assigned to treatment with fi nasteride 5 mg daily or placebo for 7 years, after which all study participants underwent a prostate biopsy. The primary endpoint was the incidence of histologically proven pros-tate cancer at 7 years [25].

Finasteride was associated with a 24.8% reduction in the incidence of prostate cancer over the 7 year trial period com-pared with placebo (18.4% versus 24.4%; P < .001). The reduction in incidence in the fi nasteride group was primarily restricted to low-grade tumors. Indeed,

Figure 3. Selenium and Vitamin E Cancer Prevention Trial (SELECT): prostate cancer incidence by treatment group. Compared with placebo, there was a statistically nonsignifi cant increase in prostate cancer in the vitamin E group (P = .06) and not in the selenium + vitamin E group (P = .52) or the selenium group (P = .62). Reprinted with permission from [21], copyright © 2010 American Medical Association. All rights reserved.

Figure 4. Reduction by Dutasteride of Prostate Cancer Events (REDUCE): proportion of men with prostate cancer during years 1-2 and 3-4. Relative risk reduction is 22.5% for Years 1-2 and 23.5% for Years 3-4 [29].

0

5

10

15

20

Dutasteride Group

Placebo Group

Years 1-2 Years 3-4

Pro

po

rtio

n o

f M

en w

ith

Pro

stat

e C

ance

r D

etec

ted

, % 17.2%

13.4%11.8%

9.1%


investigators found a greater proportion of biopsies with high-grade tumors (Glea-son score 7 to 10) in the fi nasteride group compared with the placebo group (37.0% versus 22.2%; P < .001) [25].

Dutasteride has been shown to reduce the risk of prostate cancer—reported as an adverse event—by 51% in phase III trials of BPH [26,27]. The Reduction by Dutas-teride of Prostate Cancer Events (REDUCE) trial was designed to determine whether treatment with dutasteride reduced the risk of biopsy-detectable prostate cancer in men who had an increased risk of developing the disease. The trial included 8200 men aged 50 to 75 years old with baseline PSA values of 2.5 to 10.0 ng/mL (ages 50-60) or 3.0 to 10.0 ng/mL (age >60), at least 1 negative prostate biopsy within 6 months, and a prostate volume ≤80 mL. After a 7-month run-in with placebo, patients were randomly assigned to treatment with dutas-teride 0.5 mg daily or placebo for 4 years.

All patients had a follow-up 10-core biopsy at 24 and 48 months; in addition, patients could undergo protocol-independent “for-cause” biopsies at any point during the study period. The primary endpoint was the incidence of biopsy-detectable prostate cancer [28,29].

Andriole and colleagues presented top-line fi ndings from REDUCE at the 2009 Amer-ican Urological Association (AUA) annual meeting [30]. Dutasteride reduced the risk of biopsy-detectable prostate cancer by 23% compared with placebo (P < .0001) in men at elevated risk of developing the disease. Prostate cancer was diagnosed in 17.2% of placebo patients and 13.4% of dutasteride patients during the fi rst 2 years of the trial, and in another 11.8% of placebo patients and 9.1% of dutasteride patients during the fi nal 2 years (Figure 4) [30].

REDUCE investigators have suggested a possible interpretation of these fi ndings. At the time of randomization, patients in both

treatment arms had an equal number of small volume cancers that were not detected on pre-study biopsy. During the fi rst round of biopsies (Years 1 and 2), however, 142 more cancers were detected in the placebo arm, suggesting that tumors in the placebo group grew more quickly than those in the dutasteride arm. Therefore, during the second round of biopsies (Years 3 and 4), more cancers were available to be detected in the dutasteride arm. Fewer cancer cases in dutasteride arm—despite the likely presence of more small cancers—suggests continued suppression of tumor growth by dutasteride throughout the study period.

The lower prevalence of prostate can-cers in the dutasteride arm was consistent across prespecifi ed subgroups, as defi ned by age, family history of prostate cancer, baseline International Prostate Symptom Score (IPSS), baseline prostate volume, and baseline PSA [30]. An analysis of the Gleason score distribution among tumors

Table 1. Comparison of the Prostate Cancer Prevention Trial (PCPT) and Reduction by Dutasteride of Prostate Cancer Events (REDUCE) Trials [24,29]*

Study Parameter PCPT REDUCE

Duration, y 7 4

Number of patients 18882 8250

Location USA International

Enrollment criteria

Age, y ≥55 50-75

PSA at entry, ng/mL ≤3 2.5-10

5ARI type Type 2 Types 1 and 2

Biopsy protocol

Baseline biopsy No Yes

Follow-up biopsy 1 per protocol (year 7 or FC) 2 per protocol (24 and 48 months); any FC

Number of cores per protocol biopsy 6 10

Demographics and biopsy outcomes

Median baseline PSA, ng/mL 1.1 5.9

Total biopsies, n (%) 8997 (47.6) 6276 (82.8)

Biopsies performed FC, % 39 12

Cancers diagnosed with FC biopsies, % 52 10

Demographics in placebo arms only

Patients biopsied, % 49 84

Biopsies performed for cause, % 39 12

Number CaP/number biopsied (%) 1147/4692 (24.4) 857/2987 (29.6)

Gleason score ≤6, % 77.8 72.6

Gleason score 7, % 17.2 25.2

Gleason score 8-10, % 4.9 2.2

Summary FC biopsies more likely to show cancer and more likely to be high-grade than protocol biopsies

FC biopsies more likely to show cancer than protocol biopsies; similar grade distribution

*PSA indicates prostate-specifi c antigen; 5ARI, 5-alpha-reductase inhibitor; FC, for cause; CaP, prostate cancer.


diagnosed during the study showed no sig-nifi cant increase in high-grade tumors over 4 years. A similar proportion of patients in the placebo and dutasteride groups devel-oped high-grade tumors, defi ned as Gleason score 7 to 10 (6.8% versus 6.7%; P = .81) or as Gleason score 8 to 10 (0.6% versus 0.9%; P = .15) [30].

Other cancer-related endpoints also favored treatment with dutasteride. Can-cers among men in the dutasteride group were smaller than those in the placebo group in terms of number of positive core biopsies, percentage of the core involved by prostate cancer, and total tumor volume. Dutasteride also reduced the appearance of adverse pathological fi ndings, including high-grade prostatic intraepithelial neo-plasia (HGPIN) and atypical small acinar proliferation (ASAP). The dutasteride group showed a 39% relative risk reduc-tion (RRR) in HGPIN versus placebo (P < .0001), as well as a 21% RRR in ASAP versus placebo (P < .04) [30].

Chemoprevention also improved out-comes related to PSA and BPH. Particu-larly among those with high-grade prostate cancer, treatment with dutasteride was asso-ciated with improved PSA performance, including mean PSA levels and rate of PSA

increase. In addition, dutasteride was asso-ciated with signifi cantly fewer BPH events, including acute urinary retention (1.6% versus 6.7%, P < .0001), BPH-related sur-gery (1.4% versus 5.1%, P < .0001), and urinary tract infection (5.3% versus 8.8%; P < .0001) [30].

Treatment with dutasteride was associ-ated with some toxicity. Patients in the dutasteride group were more likely than those in the placebo arm to report a range of drug-related adverse events, including decreased libido (3.3% versus 1.6%), loss of libido (1.9% versus 1.3%), erectile dysfunc-tion (9.0% versus 5.7%), decreased semen volume (1.4% versus 0.2%), and gyneco-mastia (1.9% versus 1.0%) (P < .05 for all comparisons) [30].

Findings from both the PCPT and REDUCE trials support the use of 5ARIs for risk reduction in prostate cancer, without the risk of masking incident cancer [25,30]. It is important, however, to consider differ-ences between the PCPT and REDUCE trials (Table 1). Compared with PCPT, the REDUCE trial enrolled men with a higher baseline risk of prostate cancer, as shown by the higher allowable PSA level at entry [25,30]. The biopsy protocols also differed. In PCPT, no baseline biopsy was required,

and sextant biopsy was more common [25]. By comparison, the REDUCE trial included a baseline biopsy, allowed for biopsies off protocol, and was more likely to include the superior 10-core biopsy technique [30].

The PCPT and REDUCE trials also dif-fered in the relationship between baseline PSA level and magnitude of benefi t with 5ARI use. In PCPT, the overall risk reduc-tion was 25% with treatment compared with placebo, but this ranged from 34% in the lowest baseline PSA group (0.0 to 1.0 ng/mL) to 19% in the highest baseline PSA group (2.1 to 3.0 ng/mL) [25]. By comparison, baseline PSA levels did not correlate with the magnitude of benefi t in the REDUCE trial. Dutasteride reduced the risk of prostate cancer by 23% in the lowest PSA tertile (2.5 to <4.9 ng/mL) and by 24% in the highest (6.8 to 10 ng/mL) [30].

Investigators will be publishing additional reports from the REDUCE trial, but the preliminary fi ndings provide several impor-tant conclusions [30]. In men at increased risk of prostate cancer, dutasteride signifi -cantly reduced the rate of prostate cancer on biopsy within the fi rst 2 years of treatment. Dutasteride showed no increase in the risk of high-grade tumors on biopsy. This is in con-trast to the PCPT trial, which—artifact or not—showed a 27% increase in high-grade tumors in the treatment group [25]. Dutas-teride also enhanced the utility of PSA in prostate cancer screening and showed ben-efi cial effects on BPH outcomes [30].

CHEMOPREVENTION IN CLINICAL PRACTICEThe next step is determining how to apply fi ndings from PCPT and REDUCE in the clinical setting. New tools for risk assessment may help to defi ne the best target population for chemoprevention. For example, investiga-tors from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial will be proposing a new nomogram for estimat-ing prostate cancer risk. In addition, Zheng and colleagues recently developed a risk score that incorporates family history and genetic profi le from 5 single-nucleotide polymor-phisms (SNIPs) to calculate future prostate cancer risk independent of PSA levels [31].

The chemoprevention landscape in pros-tate cancer is changing in favor of 5ARI use. In 2009, the American Society of Clinical Oncology (ASCO) and the AUA jointly

Figure 5. Modern strategies for risk reduction [34-39].

65%Cumulative risk of breast cancer in BRCA1 carriers by age 70 [34]

Drastic prevention measures to be considered(eg, mastectomy)

21% Risk of prostate cancer in men with prostate-specific antigen (PSA) 2.0-2.49 ng/mL, over 7-10 years [35]

13.2%Average risk of a cardiovascular (CV) event among subjects in

aspirin CV risk reduction studies (n = 72,139) [36]

5.1% Risk of prostate cancer in men with PSA = 1.5 ng/mL, over 5 years [37]

4.25% 7-year risk of invasive breast cancer in women enrolled in the tamoxifen breast cancer prevention study [39]

Average 6-year risk of stroke in subjects in the pravastatin stroke prevention study [38]4.5%


issued a guideline for risk reduction that incorporated 5ARIs as an option for risk reduction [32]. According to the updated guidelines, treatment with 5ARIs for 7 years is an appropriate option for chemopreven-tion for asymptomatic men with a PSA levels ≤3.0 ng/mL who undergo annual PSA screening. Clinicians should discuss the potential risks of 5ARI therapy—including the possibility of high-grade cancer—with men who are taking 5ARI therapy for chemoprevention or for benign conditions such as lower urinary tract symp-toms (LUTS). PSA levels should decrease by 50% within 12 months of starting therapy; however, given variations among men in PSA response, the guideline panel did not recommend a specifi c PSA threshold that should trigger a biopsy [32].

Patients who are interested in prostate cancer risk reduction should be counseled about a variety of options. Participation in clinical trials should be encouraged, as should screening among high-risk patients. Given that cardiovascular dis-ease is the leading cause of death in men with prostate cancer, patients should also be reminded of lifestyle modifi cations—low-fat diet, high vegetable consumption, exercise—to improve their cardiovascu-lar risk profi le. For now, the data do not support the use of vitamin E or selenium, although this may change with longer follow-up fi ndings from the SELECT trial. Vitamin D and soy supplementation, however, may have some benefi ts in pros-tate cancer reduction [33,34].

The ASCO/AUA guidelines now recom-mend fi nasteride or dutasteride with informed consent in appropriate patients [32]. Data from PCPT and REDUCE suggest that 7 years of treatment with 5ARIs reduces the risk of prostate cancer by approximately 21% [25,30]. The magnitude of risk reduction compares favorably to risk-reduction strate-gies in other therapeutic areas, including a 4.25% reduction in the 7-year risk of invasive breast cancer with tamoxifen, a 4.5% reduc-tion in the risk of stroke with pravastatin, and a 13.2% reduction in the risk of adverse cardiovascular events with aspirin (Figure 5) [35-40]. Chemoprevention of prostate cancer may soon be as commonplace as these more pervasive strategies for disease prevention.

European View of Chemoprevention: ERSPC Trial

Per-Anders Abrahamsson, MD, PhD

The management of prostate cancer presents a clinical paradox: only a

small portion of men with untreated pros-tate cancer will die from the disease, yet the prevalence of prostate cancer is so high that it is the second leading cause of cancer deaths among men. With their potential to reduce the morbidity and mortality associated with prostate cancer and its treatment, screening programs play a major role in improving clinical outcomes in prostate cancer.

Screening is often defi ned as a strategy used in a population to detect disease in

individuals without signs or symptoms of that disease. This seems straightforward, yet in prostate cancer, the optimal window for screening is narrow. The natural history of prostate cancer typically includes a stage in which the disease is localized and cure is possible, followed by stage marked by non-localized, incurable disease (Figure 6). Screening programs aim to move the time of diagnosis earlier, from the incurable to the potentially curable stage. Within the curable stage, however, there are some patients for whom the risks of treatment outweigh the benefi ts. Diagnosing prostate cancer within this stage presents a dilemma for both patients and providers. Indeed, although prostate cancer screening can save lives, it also leads to overdiagnosis and over-treatment for many patients.

Evidence-based decisions about screen-ing require real measures of the risks and benefi ts of prostate cancer screening. The European Randomized Study of Screening for Prostate Cancer (ERSPC) was a multi-national collaborative trial that compared an organized PSA-based screening pro-gram with current clinical practice among 182,160 men aged 50 to 74 years [41]. In particular, ERSPC measured the effects of screening on prostate cancer mortality, as well as the overdiagnosis and overtreatment of prostate cancer [41].

After a mean follow-up of 8.8 years, 20% fewer prostate cancer deaths were reported in the screening arm than in the control arm (relative risk [RR], 0.80; P = .04) [41]. During the trial, 85% of men with a biopsy indication accepted the biopsy. When the comparison between groups was narrowed in the screening arm to include only men who were compliant with the full screen-ing protocol, the survival benefi t increased to 27%. The screening program was par-ticularly effective for detecting advanced disease. Men in the screening group had a 22% lower incidence of T3 and T4 tumors (0.9 versus 1.15 per 1000 person years; P < .0001) and a 41% lower incidence of M1 disease (0.23 versus 0.39 per 1000 person years; P < .0001) compared with men in the control group [41].

Overdiagnosis and overtreatment are important adverse effects of screening. In the ERSPC study, 1410 men had to undergo screening and 48 needed to be treated to prevent 1 prostate cancer death [41].

Figure 6. The natural history of prostate cancer.

Localized Non-localized

Cure notnecessary

Cure possibleand necessary

Cure not possible

30

20

10

Life

exp

ecta

ncy

Screening

M110 years


For some, this balance between benefi t and risk may not favor screening. To explain the implications of these fi ndings to the urol-ogy community, the European Association of Urology (EAU) developed a consensus statement on prostate cancer screening. Given current data, the EAU recommends that men who are considering screening by PSA and biopsy should obtain information on the risks and benefi ts of screening and individual risk assessment [42]. With the publication of additional data from ERSPC and other screening trials, the EAU may advocate a more specifi c approach to pros-tate cancer detection. ERSPC investigators found a greater survival benefi t in patients with longer follow-up, including a 36% reduction in mortality for those who had been in the trial for 12 years (number needed to treat [NNT] = 500) (Figure 7) [41]. As the survival benefi t increases over time, the NNT and number needed to screen (NNS) estimates will fall, making widespread screening and treatment more acceptable to a greater number of physicians.

Before PSA screening can be recom-mended for all men, several additional research questions need to be answered. For example, researchers must measure the risk of overdiagnosis in a much larger cohort of men who might be newly eligible

for screening. Researchers must also defi ne the cost and quality of life implications of more widespread screening. Practical issues, such as the logistics and oversight of large-scale screening programs, must also be addressed.

In summary, with its potential for cure during a long indolent phase, prostate cancer is well suited for screening. Large intervention trials have now demonstrated that screening programs signifi cantly reduce prostate cancer mortality [41]. But given the potential human and fi nancial costs of screening, are healthcare systems ready to implement organized prostate cancer screening programs? If the successes of screening programs for cervical cancer and breast cancer are any indication, prostate cancer screening programs may be widely adopted in the near future.

Watchful Waiting versus Chemoprevention

William Catalona, MD

Prostate cancer is generally asymptomatic, existing in a curable stage for a time until it passes silently into an incurable stage (Figure 6). To improve clinical outcomes, screening programs must detect prostate

cancer while the disease is potentially cur-able. The ERSPC provided unequivocal evidence that screening reduces prostate cancer mortality. The intention-to-screen analysis of ERSPC data showed a 20% reduction in prostate cancer mortality among screened men [41]. Yet the magni-tude of this survival benefi t appeared to be diluted by non-compliance in the screen-ing arm and contamination from men who received screening in the control arm. After adjusting for these parameters, the reduc-tion in prostate mortality among screened men was 31% [4].

Other recent analyses have shown simi-larly impressive survival benefi ts of prostate cancer screening. Data from the National Cancer Institute Surveillance, Epidemi-ology, and End Results (SEER) Program suggest a 40% decrease in the prostate cancer mortality rate in the US since the implementation of prostate cancer screen-ing recommendations [44]. Internation-ally, the World Health Organization has documented a similar pattern of mortality reduction in countries where PSA screening is practiced, including a 54% reduction in prostate mortality in Tyrol, Austria [45,46].

Screening studies often use NNT as a variable to measure the potential for over-diagnosis and overtreatment as a result of screening. According to an initial analysis of the ERSPC trial, 1410 men would need to be screened and 48 treated (NNT = 48) to prevent 1 prostate cancer death [41]. With longer follow-up of the ERSPC trial, however, the NNT is expected to decrease. Estimates for NNT also fall when other outcomes other than death are considered. For example, comparing the results of the ERSPC screening arm with men in North-ern Ireland, where little screening is avail-able, the NNT to prevent 1 case of meta-static prostate cancer fell to 15 [43]. Falling NNT estimates in the prostate cancer set-ting are approaching those in the breast cancer fi eld (NNT = 10), where mammog-raphy screening with follow-up treatment is a widely acceptable prevention strategy.

ACTIVE SURVEILLANCE FOR PROSTATE CANCERThe drawbacks of active surveillance are well defi ned. No tools are available to pre-dict which cancers can be safely observed. As a result, there are no validated criteria

Figure 7. European Randomized Study of Screening for Prostate Cancer (ERSPC): greater survival with longer-follow up. Reprinted with permission from [40]. Copyright © 2010 Massachusetts Medi-cal Society. All rights reserved.


for selecting patients for surveillance and no validated prompts for switching from surveillance to active treatment. Active sur-veillance also requires repeated biopsies that often make subsequent nerve-sparing sur-gery more diffi cult or impossible. Moreover, many patients who are being managed with active surveillance experience anxiety about living with untreated cancer, thereby dimin-ishing their quality of life.

The primary limitation of active surveil-lance is that it can delay the prompt treat-ment of life-threatening tumors. Berglund and colleagues showed that among patients who were eligible for active surveillance, but instead were treated with prostatectomy, 27% had aggressive tumor features in their prostatectomy specimens [47]. In another study, Klotz and colleagues followed 299 patients who were monitored with active surveillance for favorable-risk prostate cancer (Gleason score ≤6, PSA <10 ng/mL, and T1c-T2a). After 8 years of follow-up, 65% remained on active surveillance. Of patients who underwent radical prostate-ctomy for progression, however, 58% had tumor extension beyond the prostate, and 8% had lymph node metastases [48].

Some patients with initially understaged disease will endure unnecessary morbidity and mortality from prostate cancer. This phenomenon begins with underdiagnosis (ie, the detection of tumors after they have spread beyond the prostate), and leads to undertreatment (ie, the unnecessary delay of adequate treatment for potentially cur-able disease). Given the inherent risk in underdiagnosis and undertreatment, active surveillance should be considered inves-tigational in healthy men with potentially curable prostate cancer and a long life expectancy. For these men, more research is needed to evaluate the tradeoffs before active surveillance can be considered legiti-mate treatment option.

On the other end of the spectrum, some patients who would not have suffered morbidity or mortality related to prostate cancer receive unnecessary treatment as a result of screening. As with all methods of early detection, overdiagnosis and over-treatment will occur as a result of active surveillance. Without strategies for early detection, however, many more men are underdiagnosed and treated too late, with dire consequences.

5ARIS AND CHEMOPREVENTIONFinasteride and dutasteride are currently approved for the treatment of BPH and are under active investigation for the preven-tion of prostate cancer. As described above, the PCPT was conducted to assess whether fi nasteride could prevent prostate cancer over a 7-year study period. Overall results from PCPT were positive, showing that treatment with fi nasteride reduced the inci-dence of prostate cancer by 25% compared with placebo [25].

Other fi ndings from PCPT, however, have been more diffi cult to interpret. In particular, the incidence of high-grade (Gleason score 7-10) tumors was 27% higher in the fi nasteride arm compared with the placebo group (6.4% versus 5.1%; P = .005) [25]. Critics noted that had the primary endpoint of PCPT been high-grade disease, the main fi nding would have been that fi nasteride increased risk for life-threatening prostate cancer. Although several investigators have offered inter-pretations of these results, these fi ndings remain controversial [4,49-52].

All study participants, most of whom maintained normal PSA levels and normal DRE results throughout the study, under-went end-of-protocol biopsies. In the clinical setting, such men would not receive biopsies. In PCPT, however, end-

of-protocol biopsies identifi ed cancer in 364 patients in the fi nasteride group and 564 patients in the placebo group [25]. In addition to the end-of-study biopsy mandated by the PCPT protocol, pros-tate biopsy was recommended for men with PSA > 4 ng/mL or suspicious DRE at any time during the study. Among men who underwent a for-cause biopsy, pros-tate cancer was diagnosed in 26.5% of those in the fi nasteride group and 29.5% of those in the placebo group [25]. In a clinical setting where biopsies are not rou-tinely performed as a result of an abnor-mal screening test, the 10% difference between treatment groups is not statisti-cally signifi cant [53].

Regardless of the means of cancer detec-tion, there was a higher prevalence of high-grade tumors in the fi nasteride group com-pared with the placebo arm: 48% versus 29% in cancers diagnosed in for-cause biopsies, and 25% versus 16% in cancers diagnosed in end-of-study biopsies [25]. In post-hoc analyses, PCPT researchers reported that that shrinkage of the pros-tate—an expected effect of therapy that is primarily used to treatment BPH—may enhance the performance characteristics of PSA and DRE. With smaller prostates, a greater proportion of the prostate is sam-pled, potentially leading to more accurate

Figure 8. Prostate Cancer Prevention Trial (PCPT): prostate cancer incidence and grading during year 7. Reprinted with permission from [24]. Copyright © 2010 Massachusetts Medical Society. All rights reserved.


Gleason scoring in the fi nasteride group. Statistical modeling showed that the increase in high-grade prostate cancer was most likely due to increased early detec-tion of high-grade tumors in men receiv-ing fi nasteride [49].

Another interpretation of PCPT data posits that fi nasteride does not prevent pros-tate cancer, but instead delays the progression of low-grade disease. Under this hypothesis, fi nasteride suppresses the growth of some tissue types—normal prostate tissue, BPH, and low-grade prostate cancer—but cannot control high-grade cancer. Over time, high-grade disease will emerge despite fi nasteride therapy. The relatively limited 7-year study period of PCPT does not provide suffi -cient follow-up time to evaluate this theory. Over a short period of observation, delayed cancer detection might mimic a decrease in cancer incidence; with longer follow-up, the apparent benefi t of treatment might diminish. Indeed, the differences between treatment groups began to diminish near the end of the PCPT follow-up period (Figure 8) [25]. During year 7 of PCPT, a similar proportion of patients in the fi nas-teride and placebo groups underwent for-cause biopsies (7.0% versus 7.1%, respec-tively), and a nearly equal number of cancers were diagnosed (122 versus 124, respectively). Among these tumors, however, the preva-lence of high-grade disease was 68% higher in the fi nasteride group than in the placebo group (52% versus 31%, respectively) [25].

In a recent analysis from the Finnish Prostate Cancer Screening Trial, Murtola and colleagues examined the incidence of prostate cancer among men who were receiving fi nasteride or alpha-blockers for the treatment of BPH [54]. Investigators found that fi nasteride reduced the risk of low-grade prostate cancer, but increased the risk of high-grade tumors among long-term users. Compared with men who did not use fi nasteride, those who used fi nasteride for longer than 4 years were more than twice as likely to be diagnosed with Gleason score 7 to 10 prostate cancer (HR, 2.61; P = .057 for trend). Alpha blockers had a neutral effect on prostate cancer incidence overall, but appeared to decrease the risk of high-grade tumors with long-term use (HR, 0.38; P = .044 for trend) [54].

In the REDUCE trial, dutasteride reduced the risk of prostate cancer over 4 years by

23% compared with placebo (19.9% versus 25.5%; P < .001) [30]. As described above, there was a discrepancy between treatment groups in the distribution of low-risk versus high-risk tumors. Among men who under-went a needle biopsy during the trial, 4.4% of patients in the dutasteride group and 2.2% of patients in the placebo group were diagnosed with Gleason score 8 to 10 tumors (P = .018). Looking more closely at the timing of diagnosis, however, investigators found that high-grade tumors were detected more frequently in the dutasteride group only after 2 years of treatment. During years 1 and 2, a similar proportion of patients in the dutasteride group and placebo group were diagnosed with high-grade tumors (3.9% versus 3.1%, respectively). By com-parison, signifi cantly more Gleason score 8 to 10 tumors were diagnosed in the dutas-teride group than in the placebo group in years 3 and 4 (5.4% versus 0.4%; P = .0008) [30]. Future studies will continue to exam-ine this disparity, particularly the hypothesis that 5ARIs render the higher-grade tumors easier to detect, allowing proportionately more of them to be diagnosed in the active-treatment arm of the trial.

When interpreting the fi ndings from REDUCE, it is important to consider base-line risk levels within the study population. In general, men with an elevated PSA level and a prior negative biopsy are at a lower risk for prostate cancer than men with an elevated PSA and no prior biopsy. The majority of men (83%) in REDUCE had negative biopsy results on baseline, indi-cating a relatively low baseline risk of pros-tate cancer [30]. Therefore, although some investigators argue that REDUCE enrolled a higher-risk population than PCPT, results from most REDUCE patients may not be applicable in truly high-risk men. Conversely, 17% of men in REDUCE did not undergo biopsy at randomization, and therefore their baseline risk was not well-defi ned [30]. Long-term follow-up data in this subgroup of patients may provide information on the optimal prevention strategies for patients with unknown or elevated risk. Until then, 5ARI use may not be appropriate in certain men, such as those with a family history of prostate cancer, particularly those with a family history of high-grade, aggressive prostate cancer.

Pathology of Prostate Cancer: High-Grade Prostatic Intraepithelial NeoplasiaM. Scott Lucia, MD

Major shifts in the typical clinical presentation and pathological char-

acteristics of prostate cancer have inspired important changes in treatment. In the past 2 decades, the proportion of prostate can-cers that are non-palpable (T1) at the time of diagnosis has risen markedly, while the proportion of T2 disease has fallen. At the same time, the proportion of patients with low (4-10 ng/mL) or very low (≤4.0 ng/mL) PSA values has also increased [55]. In gen-eral, patients are being diagnosed with pros-tate cancer earlier and with lower-risk dis-ease than in years past.

Urologists have recognized that not all can-cers need treatment, particularly those that are classifi ed as low-risk. For some patients, active surveillance or targeted focal therapy are attractive alternatives for managing low-risk disease. For these options to be most effective, physicians must be able to dif-ferentiate “signifi cant” from “insignifi cant” tumors. Although PSA levels are associated with aggressiveness, the association appears across the continuum of risk (Figure 1) [4]. To date, the PSA threshold separating sig-nifi cant and insignifi cant disease has not yet been defi ned. To improve the manage-ment of prostate cancer, clinicians need to fi nd better ways to identify subgroups of patients who require different approaches to therapy: those with low-risk, clinically innocuous tumors; those with signifi cant disease that can be eradicated by current treatments; and those whose cancers are so aggressive that therapy is likely to fail.

DETERMINING TUMOR AGGRESSIVENESSTraditional factors for evaluating tumor aggressiveness include histologic type and grade, pathologic state, margin status, and tumor volume. Recent changes in prostate cancer presentation, however, have altered the clinical utility of these tools.

The Gleason grading system is the most commonly used grading system for pros-tate cancer worldwide. Using normal pros-tate histology as a reference point, Gleason grading uses the microscopic appearance


of the tumor to estimate the degree of invasiveness. Tumor patterns are graded on a scale of 1 to 5, and Gleason scores are usually reported as the sum of the 2 most prevalent patterns (eg, 3 + 4 = 7) [56]. More recently, pathologists have discov-ered that the presence of at least 1 high-grade pattern, regardless of the total score, is strongly correlated with aggressiveness [57]. In one study, the combined per-centage of Gleason grades 4 and 5 pat-terns within a tumor sample was the best predictor of prostate cancer progression. When risk algorithms incorporated Glea-son grade 4/5 as a variable, traditional Gleason scoring no longer independently predicted treatment failure [58].

Within the past 2 decades, the preva-lence of tumors with Gleason scores of 2 to 4 at diagnosis has dropped considerably, while the prevalence of Gleason score 5 to 6 and Gleason score 7 tumors has risen [59]. Some of this change might be attributable to increased skill among pathologists. After gaining experience with the Gleason grading system, pathologists may have grown reluc-tant to give very low scores. Moreover, recent changes in biopsy technique may have also altered Gleason score patterns. For example, biopsies have grown smaller, and transure-thral resection of the prostate (TURP) biop-sies are performed less frequently.

Pathologists have also observed changes in tumor volume and other characteristics over time. In a study of biopsy samples collected prior to 1994, 56% of patients had multifocal tumors. The highest mean tumor volume was observed in patients with single-focus tumors (6.52 cc), fol-lowed distantly by bifocal tumors (1.48 cc). This fi nding indicates that the single tumors may in fact represent several indi-vidual tumors that had coalesced into a

single mass [60]. By comparison, in a study of tumors collected from 1997 to 2006, 20% of cases involved solitary tumors with a mean volume of 2.14 cc. The remain-ing 80% of cases involved 2 to 17 tumors per prostate. These studies illustrate how the typical presentation of prostate tumors has changed over time. In the pre-PSA era, tumors were larger, more confl uent masses with less HGPIN. Currently, tumors are smaller, more multifocal, and have more extensive HGPIN.

Changes in tumor characteristics have important implications for needle biopsy technique. The ability of a blind biopsy to sample malignant tissue depends on the ratio of tumor volume to the prostate volume. Random sampling of prostate tissue is more likely to detect a large tumor within a small prostate than a small tumor within a large prostate, even if 10 or more samples are taken. Therefore, with current techniques, a negative biopsy does not prove the absence of cancer.

Computer simulations of needle biopsies show that the standard sextant technique using random core biopsies has low sensitiv-ity for the presence of cancer (55%), mod-erate specifi city (89%), and a low negative predictive value (67%). By comparison, lat-erally directed sextant biopsy improves the sensitivity to 71%, the specifi city to 93%, and the negative predictive value to 77% (P < .0001) [61]. Despite this improvement, the laterally directed sextant biopsies missed signifi cant tumors in the anterior portion of the gland, which is undersampled with this technique. Another option for improving tumor detection is the use of 10 to 12 core biopsy schemes. Studies of 10 to 12 core biopsies show improved tumor detection compared with sextant biopsies, but with sen-sitivities only up to 71% to 85% [61-64].

The predictive value of HGPIN—for-merly a strong indicator of cancer risk—has decreased in recent years. In earlier stud-ies, 35% to 47% of patients with isolated HGPIN were diagnosed with cancer upon subsequent biopsy. Since the late 1990s, however, prostate cancer was reported in fewer patients (23% to 28%) with HGPIN who underwent subsequent biopsies [65]. The underlying reasons for this shift are unclear, although it may refl ect improved biopsy techniques that are better at detect-ing cancer on initial biopsies. Although the predictive value of HGPIN appears to be diminishing, PSA levels and ASAPs can be used to assess the risk of cancer detection after initial negative biopsies. In a study of 244 men with an initial negative biopsy and at least one follow-up biopsy, PSA level >5 ng/mL (P =.002) and the presence of ASAPs (P < .001) were predictive of a future cancer diagnosis. In this analysis, the pres-ence of HGPIN did not predict future biopsy outcomes [66].

Biopsy can reveal histologic features that predict biochemical recurrence or adverse pathology at prostatectomy, percent of cores with cancer, linear extent of cancer, and percent of tissue with cancer [67-70]. The number of positive biopsies can also help to distinguish organ-confi ned from nonorgan-confi ned disease [71].

Even if a biopsy manages to detect a tumor, the tumor grade assigned at biopsy may be wrong. One study compared attempts to score the same tumor at biopsy and at radical prostatectomy in the placebo arm of PCPT [50]. The Gleason score assigned at biopsy and at prostatectomy was the same in only 57% of cases (Table 2). For 30.5% of patients, the biopsy score increased when the tumor was examined at prostatectomy, and in 12.5% of cases, the Gleason score

Table 2. Prostate Cancer Prevention Trial (PCPT): Needle Biopsy versus Prostatectomy Gleason Scoring [49]*

Gleason Score at Radical Prostatectomy (N = 272)

Gleason Score on biopsy 2-5 6 7 8-10

2-5 10 28 8 1

6 12 100 43 0

7 1 13 38 3

8-10 0 3 5 7

Increased at RP 83/272 (30.5%)

Unchanged at RP 155/272 (57.0%)

Decreased at RP 34/272 (12.5%)

*RP indicates radical prostatectomy.


decreased [50]. Importantly, needle biopsy correctly identifi ed only 50.5% of can-cers that were high-grade (Gleason score 7 to 10) at prostatectomy [50]. These fi ndings underscore the dramatic limita-tions of needle biopsy in evaluating tumor aggressiveness.

The ability to correctly assess tumor grade has important consequences for the choice and effectiveness of therapy, particularly for targeted focal therapy. With current biopsy techniques, tumor grade and extent, including multifocality, volume, and location, can be assessed with only suboptimal sensitivity. Future imag-ing technology, particularly 3-dimensional (3-D) mapping, may improve biopsy sam-pling and pathological assessment for pros-tate cancer. Computer simulations show that 5- and 10-mm grid biopsies are able to detect 72% and 29% to 43%, respec-tively, of patients with disease localized to one side of the prostate [72]. By providing more accurate measurements of true tumor burden, grade and stage, 3-D mapping facilitates better selection of patients for targeted focal therapy and expectant man-agement. Further refi nements in screening and assessment techniques may improve the selection of successful therapies for patients with prostate cancer.

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