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Supported by an unrestricted educational grant from Endo Pharmaceuticals

Selected Highlights from

the 2009 Future Directions in Urology Symposium

Benign Prostatic HyperplasiaNeal D. Shore, MDM. Scott Lucia, MD

Basic Science and Research: Biomarkers Addressing Pragmatic HurdlesJack A. Schalken, PhD

Prostate Cancer Screening and Prevention: Mixed MessagesE. David Crawford, MD

Testosterone Replacement Facing New FrontierAbraham Morgentaler, MD

Local and Locally Advanced Prostate CancerGary M. Onik, MDMack Roach III, MDM. Scott Lucia, MD

H I G H L I G H T S Volume 8 Issue 4 December 2009

GRAND ROUNDSin Urology™

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

E d u c a t i o n

P u b l i c a t i o n

STATeMeNT oF NeedUrology experts generally agree that the urological patient will benefit greatly if the treatment provided is the result of a combined effort among the special-ists involved in patient care. The col-laboration of experts from various fields is thus necessary to improve urological research and enhance medical practice worldwide and to close the practice gap found among current treatment pro-tocols. The 2009 Future Directions in Urology Symposium (FDUS) brought together leading urologists, radiolo-gists, radiation oncologists, and medi-cal oncologists to provide a forum for sharing knowledge and experience with the objective of facilitating multidis-ciplinary approaches that aim to opti-mize disease prevention and diagnostic therapeutic interventions. A four-day symposium was held, featuring state-of-the-art lectures, case reports, a review of clinical trials, and treatment guideline analysis. Group discussion assisted in improving competence and knowledge and addressed four Institute of Medi-cine (IOM) Universal Physician com-petencies: to provide patient-centered care, to work in interdisciplinary teams, to employ evidence-based practice, and to apply quality improvement.

Meetings such as FDUS are of great value in promoting further scientific col-laboration between the various experts working in the challenging and rapidly evolving fields of prostate, bladder, and renal cell cancer. The FDUS format enabled experts to present and discuss the most recent advances in prostate, blad-der, and renal cell cancer. Topics covered included both bench research and clini-cal applications that will be of interest to both clinicians and basic scientists and that provide a roadmap to future prac-tice guidelines and updates on ongoing clinical trial research. A multidisciplinary approach to patient care is an essential part of routine urological care. For that reason, collaboration between urologists, radiation oncologists, and medical oncol-ogists will be important for the future of the practice of urology. This activ-ity provides a review and analysis of the

presentations and discussions of the 2009 Future Directions in Urology Symposium in a self-learning format designed to pres-ent the most important points of debate and discussion in prevention, screening, treatment, and overall patient care.

LeARNiNg oBjeCTiveSUpon completion of this educational activity, participants should be able to:

Evaluate the potential role of experi-•mental BPH treatmentsIdentify the potential advantages •of LHRH antagonists in treating obstructive urinary symptomsExplain the need for and potential •impact of more effective biomarkers on prostate cancer treatmentDescribe the role of 5-alpha reductase •inhibitors as a means of preventing prostate cancerReview the costs, outcomes, and mor-•bidity associated with current prostate cancer treatment patternsExplain the impact of raising testoster-•one levels on prostate cancer growthDescribe how the saturation model •explains the impact of testosterone supplementation in non-castrated menCompare appropriate clinical situa-•tions for use of adjuvant radiotherapyAppraise the potential of IRE as a tar-•geted therapy

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The contributing faculty disclose the following:

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.

M. Scott Lucia, MD, discloses that he is a consultant for GlaxoSmithKline and 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 lec-turer for Auxilium Pharmaceuticals, Wat-son, and Bayer; and he is on the advisory board for Solvay and Endo.

CONTINUING meDICAL eDUCATION

Gary M. Onik, MD, discloses that he is in a relationship with Bostwick Labs and he has an ownership interest in Endocare, Inc. (now HealthTronics).

Mack Roach III, MD, discloses that he receives funding from GlaxoSmithKline for investigator initiated grant research support; he is a member of the Speaker’s Bureau for Siemens and AstraZeneca; he is a health care consultant for CareCore National, LLC; he is a product develop-ment consultant for Molectular Insight, TROFEX; and he is a consultant for General Electric (G.E.).

Jack A. Schalken, PhD, discloses that he is a consultant for Gen-Probe.

Neal D. Shore, MD, discloses that he is a consultant for Boston Scientific, Nymox, and AbbeyMoor Medical; and he a researcher for Urglasty.

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5 From the Editorial Board

6 Highlights Benign Prostatic Hyperplasia

Neal D. Shore, MD

M. Scott Lucia, MD

9 Highlights Basic Science and Research: Biomarkers Addressing Pragmatic Hurdles

Jack A. Schalken, PhD

11 Highlights Prostate Cancer Screening and Prevention: Mixed Messages

E. David Crawford, MD

14 Highlights Testosterone Replacement Facing New Frontier

Abraham Morgentaler, MD

17 Highlights Local and Locally Advanced Prostate Cancer

Gary M. Onik, MD

Mack Roach III, MD

M. Scott Lucia, MD

21 Application for CME Credit

23 Post-Test

C O N T e N T S

Editorial BoardMediCAL ediToR

E. David Crawford, MDProfessor of Surgery, urology, and Radiation OncologyHead, urologic Oncologyuniversity of Colorado Health Sciences CenterAurora, Colorado

ASSoCiATe ediToRS

Roger R. Dmochowski, MD, FACSProfessor 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 G. 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 2009 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.

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grandroundseducation.com 5

In this issue of Grand Rounds in Urology we offer a selected high-lights of the 2009 Future Directions in

Urology Symposium (FDUS), held August 19-22, 2009, in Colorado Springs, Colo-rado. This four-day symposium, also known as the “Think Tank” meeting, brought together 19 leading experts in many different areas of urology to discuss current and future directions in research and treatment. It provided an open exchange of information that will hope-fully lead to new and innovative modali-ties for patients. Although there are many large society-based meetings in urology, there is still an unmet need for more inti-mate independent educational programs like FDUS. These types of meetings can bring together multidisciplinary specialists in an informal format that often can create roadmaps for research and treatment. The 2009 Future Directions in Urology Sympo-sium program focused on the areas of pro-static diseases (BPH and prostate cancer), kidney and bladder cancer, and areas such as prevention and screening, testosterone replacement therapy, focal therapy, and radiation oncology.

Discussions from previous FDUS programs have resulted in implementa-tion of an International Phase III trial in

hormone refractory prostate cancer. Past discussions also have focused on appro-priate treatment for the increasing num-ber of men with low-risk prostate cancer. Others have resulted in the launching of a comprehensive focal therapy program, and expert interactions regarding unmet opportunities in bladder cancer have lead to the development of two phase III trials in the disease. The 2002 meeting’s open forum format resulted in the develop-ment of two novel therapies for renal cell carcinoma.

There are many new developments in urology within the last year that will pro-vide hope for future breakthroughs, and the highlights of this year’s Future Direc-tions in Urology Symposium will hopefully lead to ideas for clinical progress to the benefit of urology patients worldwide. I hope you enjoy reading this issue, and can apply some of what the experts discussed to your practice.

Sincerely,


f R O m T H e e D I T O R I A L b O A R D

6 GRAND ROUNDS in Urology™

H I G H L I G H T S


Benign Prostatic Hyperplasia

Contributing Authors:

Neal D. Shore, MD

DirectorCarolina urologic Research CenterMyrtle Beach, South Carolina, uSA

M. Scott Lucia, MD

ChiefGenitourinary & Renal PathologyDirectorProstate Diagnostic Labuniversity of Colorado at DenverDenver, Colorado, uSA

Benign Prostatic Hyperplasia Therapies Are Increasingly Less InvasiveNeal D. Shore, MD

Over the past 2 decades, the number and type of treatments available for benign prostatic hyperplasia (BPH) has grown to the point that urologists, primary care physicians, and educators might find it difficult to properly assess the role of each treatment. One thing that’s clear, however, is that the standard of care has evolved from transurethral resec-tion of the prostate (TURP) toward less invasive options, a trend that likely will continue.

As of 2003, estimates place the num-ber of US patients afflicted with BPH at 17 million. Only about half of these patients are diagnosed [1], however, and of this group only about one-third receive treatment. The remaining two-thirds of patients diagnosed with BPH manage the condition with watchful waiting, under their urologists’ supervision [2].

Among patients actually treated for BPH, 88% choose pharmacologic ther-apy. Presently, 3 million patients take drug therapy for BPH, usually combining an alpha blocker and a 5-alpha reductase inhibitor (5-ARI) at a cost of about $170 per month, depending on drug plan. With direct costs of BPH totaling more than $1 billion annually [3], BPH certainly has caught the attention of the Centers for Medicare and Medicaid Services (CMS) as a target for potential cost savings.

The aging of the baby boomer gener-ation coupled with the politics of health care reform have further highlighted the economic burden of diseases including prostate cancer, a topic that academic and continuing medical education (CME) forums frequently mention but very rarely discuss in full. In this climate, urologists must participate in—and in fact take control of—these discussions. Regulators might not appreciate, for example, that even watchful waiting creates long-term costs. A recent analysis estimates that over a 20-year period, watchful waiting costs in our society approximately $4 million, versus $15 million for combination treat-ments, which relieve symptoms but have little effect on clinical outcomes. TURP and transurethral microwave thermother-apy (TUMT) cost even more in the first 5 to 7 years of the analysis, but their costs actually decrease if patients have a 10-year or longer life expectancy [4].

Additionally, several experimental treat-ments for BPH show promise and one day might factor into patients' and poli-cymakers' decisions. For instance, a Phase 2 study comparing the pro-apoptotic pro-tein NX-1207 to finasteride found that after 90 days, a single 2.5 mg/kg injection of NX-1207 achieved a mean American Urological Association symptom score (AUA SS) decrease of 9.71, versus 4.13 for finasteride 5 mg/kg (P = .001) [5]. As a 90-second, office-based procedure that requires no catheter, analgesic or anes-thetic, NX-1207 one day could represent the ultimate minimally invasive therapy for BPH (Table).

NX-1207 Results: American urological Association Symptom Index (AuASI) Analysis by Intention to Treat.

Cohort NAuA Score

Baseline/90 days Mean improvement

NX-1207 2.5 mg 48 23.15/13.44 9.71

NX-1207 0.125 mg 7 22.29/18.0 4.29 (P = .034)

Finasteride 5 mg p.o. 24 20.17/16.04 4.13 (P = .001)

*Versus NX-1207 2.5 mg

Key words:

Benign prostatic hyperplasia (BPH)5-alpha reductase inhibitor (5-ARI)Cost savingsSymptomatology


Somewhat similarly, a 12-week phase 2 trial of transrectal botulinum toxin for BPH management found that injections of 100 or 300 units achieved at least a 30% improvement in patients’ American Uro-logical Association (AUA) symptom score (SS) and Qmax scores for 73% and 81% of patients, respectively [6]. Additionally, an office-based device that provides percutane-ous tibial nerve stimulation (PTNS; Urgent PC, Uroplasty, Minnetonka, MN) shows promise as a bridge therapy (before using an implantable device) for patients who fail or cannot tolerate overactive bladder (OAB) drugs. In one study, 80% of patients said that PTNS improved or cured their OAB symptoms, versus 55% of patients treated with tolderodine [7]. In a retrospective analysis, the addition of maintenance nerve stimulation sustained improvement in nearly all patients treated for OAB for up to 3 years [8].

By the same token, luteinizing hormone-releasing hormone (LHRH) antagonists including ozarelix, degarelix, and cetrorelix quickly reduce luteinizing hormone (LH) and follicle-stimulating hormone (FSH) without producing the initial testosterone flares associated with LHRH agonist use. In patients with obstructive urinary symp-toms, sub-castrate doses of these agents do not appear to impact prostate volume, but they have shown success in improving flow rates. Further research with these drugs ultimately could produce safe, in-office injections given no more than twice yearly. Somewhat similarly, although herbal thera-pies including Serenoa repens (saw palmetto) and Pygeum africanum have yielded mixed results in BPH thus far, they clearly may have potential and merit further study in well-designed trials.

BPH Pathology Gives Insights into Disease ProgressionM. Scott Lucia, MD

Pathologists’ understanding of what causes BPH has changed little since the 1950s, when Franks examined nodules found in the transition zones of enlarged prostates and concluded that these nodules were highly heterogeneous in composition: they could have stromal, smooth muscle, and epithelial elements, and these elements often occurred together in variable combinations [9].

Recent research further elucidates poten-tial relationships between BPH composi-tion and its clinical impact. In particular, many BPH nodules contain increased vas-cularity, which is particularly prevalent in stromal nodules, as are significant amounts of inflammation. Although data regarding the clinical significance of increased vascu-larity are scarce, researchers are beginning to understand that vascularity might be an important BPH treatment target. Some 5-ARIs indeed have effects on vessels and may reduce the amount of angiogenesis occurring in BPH nodules.

More recently, we used whole mounts of prostatectomy specimens to examine the morphology of transition-zone BPH nod-ules and to examine the relationship between 3 crucial elements—epithelial, smooth mus-cle, and fibroblastic/stromal—and AUA SS. Not surprisingly, nodules taken from patients with AUA scores of 18 or higher tended to have larger nodules. These findings, how-ever, were far from absolute: people with high symptom scores could have small nod-ules, and vice versa. When we examined the stromal to epithelial ratio, we found it was significantly higher in subjects who had high AUA scores, suggesting that stromal com-ponents might play a particular role in BPH symptomatology [10].

We performed the same analysis on biop-sies from more than 1000 men in the Medi-cal Therapies of Prostate Cancer (MTOPS) study, attempting to correlate disease symp-toms and outcomes with stromal-epithelial ratios discovered through image analysis. In random transition zone (not necessar-ily nodule) biopsies, we found correlations between the percentage of stroma and the stromal-epithelial ratio with prostate or transition zone volume and prostate-specific antigen (PSA) [11]. Even though these cor-relations were highly clinically or statisti-cally significant, they were relatively mod-est; however, our analysis also showed that men who progressed in the MTOPS study clearly had lower epithelial percentages and higher stromal-epithelial ratios, further sug-gesting that stromal overgrowth may play a major role in symptomatology, although we do not yet know why.

We also used staining and image analysis on whole mounts of prostatectomy speci-mens to determine if there is any associa-tion between inflammation and BPH. We found that normal tissues could contain

inflammation, usually in low amounts. Con-versely, our research uncovered a highly sig-nificant correlation between chronic inflam-mation and lesions such as BPH, atrophy, and cancer [12]. Moreover, baseline biopsies of men from the MTOPS trial who had not yet been put on any treatment revealed that not only were subjects with baseline inflam-mation more likely to progress, but also that subjects with baseline inflammation were 4 times as likely to suffer an acute urinary retention event [13]. Additional research will help determine whether the inflamma-tion is a cause or effect of BPH.

Presently, it’s too soon to begin emphasiz-ing a pathologic diagnosis of inflammation of the prostate—urologists do not yet know what this implies clinically. Rather, urolo-gists should view the situation in terms of healthy versus unhealthy prostates: signifi-cant amounts of atrophy and inflammation represent signs of the latter. Research has not yet established what makes a prostate unhealthy. Some experts theorize that early events in prostate diseases such as cancer and BPH may involve an initial stimulus that triggers an autoimmune response. This initial stimulus could be infectious, hor-monal, or dietary. More research to explore the pathogenesis of BPH is desperately needed.

ReFeReNCeS1. AUA Practice Guidelines Committee. AUA

guideline on management of benign pros-tatic hyperplasia (2003). Chapter 1: Diag-nosis and treatment recommendations. J Urol. 2003;170:530-547.

2. Roehrborn CG, Marks L, Harkaway R. Enlarged prostate: a landmark national sur-vey of its prevalence and impact on US men and their partners. Prostate Cancer Prostatic Dis. 2006;9:30-34.

3. Wei JT, Calhoun E, Jacobsen SJ. Urologic diseases in America project: benign pros-tatic hyperplasia. J Urol. 2005;173:1256-1261.

4. DiSantostefano RL, Biddle AK, Lavelle JP. An evaluation of the economic costs and patient-related consequences of treatments for benign prostatic hyperplasia. BJU Int. 2006;97:1007-1016.

5. Shore ND, Freedman SJ, Kalota SJ, et al. A prospective randomized two dose level comparison of single-injection transrectal intraprostatic NX-1207 and finasteride in men with lower urinary tract symptoms


due to benign prostatic hyperplasia. Pre-sented at the American Urological Associa-tion South Central Sectional Meeting, Sep-tember 5-9, 2007, Colorado Springs, CO. Abstract number unavailable.

6. Crawford DE, Donnell R, Hirst K, et al. 12-week results of a phase II trial of 100 and 300 units botulinum toxin type A (BONT-A) for the management of benign prostatic hyperplasia (BPH) [abstract]. J Urol. 2009;181:649-650. Abstract 1800.

7. Peters KM, Leong FC, Shobeiri SA, et al. Randomized multicenter study comparing percutaneous tibial nerve stimulation with pharmaceutical therapy for the treatment of overactive bladder. Presented at the Ameri-can Urologic Association Annual Meeting,

May 17-22, 2008, Orlando, FL. Abstract number unavailable.

8. Cappellano F, Finazzi Agro E, Giollo A, et al. Percutaneous tibial nerve stimulation (PTNS): results at long term follow-up. Presented at the Societa Italiana di Urody-namica (SIUD) Congresso Nationale, Sep-tember 27-30, 2006, Rome, Italy. Abstract number unavailable.

9. Franks LM. Atrophy and hyperplasia in the prostate proper. J Pathol Bacteriol. 1954;68:617-621.

10. Werahera PN, van Bokhoven A, La Rosa FG, et al. Association of stromal, epithelial, smooth muscle, and luminal compositions to nodule size and symptom severity of benign prostatic hyperplasia [abstract]. J Urol. 2006;175(4 Suppl):464. Abstract 1440.

11. Lucia MS, Noble WD, McConnell JD, et al. Tissue composition analysis in baseline transition zone biopsies in the MTOPS trial [abstract]. J Urol. 2005;173(4 Suppl):388. Abstract 1432.

12. La Rosa FG, Wilson S, Genova EE, et al. Evaluation of inflammation in prostate cancer by digital image analysis. Presented at the Keystone Symposium on Inflamma-tion and Cancer, February 27-March 3, 2005, Breckenridge, CO. Abstract number unavailable.

13. Roehrborn CG, Kaplan SA, Noble WD, et al. The impact of acute or chronic inflam-mation in baseline biopsy on the risk of clinical progression of BPH: results from the MTOPS study. J Urol. 2005;173(4 Suppl):346. Poster 1277.


H I G H L I G H T S Basic Science and Research: Biomarkers Addressing Pragmatic Hurdles

Contributing Author:

Jack A. Schalken, PhD

Professor of Experimental urologyRadboud university Nijmegen Medical CollegeNijmegen, The Netherlands

iNTRoduCTioNFor biomarkers to fulfill their promise of reducing overtreatment of prostate cancer (PCa), translational research must focus on developing useful therapies hand-in-hand with the biomarkers that will guide their use. Rather than identifying new biomarkers then seeking clinical applica-tions for them, researchers increasingly must keep the clinical goals of identify-ing aggressive cancers and pinpointing patients who would benefit from new (targeted) therapies in the front of their minds from the start.

Copious data make clear that physicians overtreat PCa. Despite a declining US death rate from PCa over the past 2 to 3 years, the United States still has a higher incidence to mortality ratio than any portion of Europe. Northern Europe achieves the West’s low-est incidence to mortality ratio, 1.79; the corresponding ratio in the United States is 5.39. Of about 193,000 patients diagnosed annually, 35,800 will die. Such evidence suggests that to avoid costs associated with needless biopsies and other treatments, we must more accurately identify the clinically significant PCas for which more aggressive treatment is appropriate.

Large studies published in 2009 further highlight the need for effective biomark-ers. The European Randomized Study of Screening for Prostate Cancer (ERSPC) shows that population-based screening can reduce mortality 20%—but at a cost of significant overtreatment [1]. Similarly, the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study indicates that chemoprevention with dual 5-alpha reductase inhibitor (5-ARI) therapy can reduce PCa incidence in 4 years by 23% [2]. A biomarker or series of biomarkers could help identify at-risk patients for whom this therapy, or at least close moni-toring, should be advised (Table).

gSTP1 MeTHyLATioNPresently, 3 biomarkers have successfully navigated the development process into

commercial development, or very close to it. One is the GSTP1 methylation panel, currently in the final phases of clinical evaluation. Although there is currently very little peer-reviewed literature regard-ing urinary methylated genes and PCa, recent conferences including the Euro-pean Association of Urology (EAU) and American Urological Association (AUA) annual meetings and the Prostate Cancer Translational Research in Europe meet-ing (held in Amsterdam) featured poster presentations suggesting that this panel could be clinically useful to predict biopsy outcome.

PCA3Additionally, prostate cancer antigen 3 (PCA3) testing, a project which our team at Nijmegen has worked on over the past decade, is available in Europe as Progensa PCA3 (Gen-Probe, San Diego, CA). The PCA3 study that should lead to FDA approval is underway.

Molecular profiling during the 1990s first identified PCA3, also known as DD3, a gene we found to be overexpressed 66-fold in PCa [3]. PCA3 is an atypical gene in that rather than being translated into a messen-ger RNA, then into a protein, PCA3 is not translated into a protein at all.

We hypothesized that finding such a cancer-specific marker in the urine of patients with PCa could have prognostic value. In the first test of this hypothesis, research showed that patients with low-volume, low-grade tumors had a mean PCA3 score of 26, versus a score of nearly 60 in patients with significant tumors (P = .004) [4].

Additionally, a European study involv-ing 463 patients found a significantly lower median PCA3 score in indolent PCa than in significant PCa: 21.4 versus 42.1, respectively; the 95% confidence interval (CI) was 14.9 to 34.0 versus 50.3 to 101.5, respectively (P = .0059) [5]. A 233-patient study in the United States found similar results [6]. As such, urine-based PCA3

Key words:

Prostate cancer (PCa)BiomarkersTargeted therapyGSTP1 methylationProstate cancer antigen 3 (PCA3)Gene fusion


assays could prove quite useful in the clini-cal setting, with a cutoff of 35 providing the greatest diagnostic accuracy regarding the likelihood of a positive repeat biopsy.

geNe FuSioNGene fusion panels, on the other hand, already are being used in clinical studies with new endocrine therapies. Gene fusions typically involve an oncogene, usually ERG, fused to an androgen regulated gene, usually TMPRSS2, creating a new genetic element, TMP RSS2-erg [7]. These fusions occur in roughly 50% of patients with PCa. In a proof of principle study, combining markers for ERG and TMPRSS2 yielded a sensitivity of 0.38 and a specificity of 0.94 [8]. A later test of the T2:ERG urine test yielded a sensitiv-ity of 41%, which is consistent with T2:ERG prevalence in prostate tumors, and a specific-ity of 95% (J.A.S. unpublished data).

In the same study, combining the T2:ERG and PCA3 tests yielded a sensitivity of 75% and a specificity of 83%, which were simi-lar to findings of Hessels et al [8]. Similarly, researchers are already testing several prom-ising candidates that could complement PCA3 in a panel of 2 to 4 biomarkers, and these candidates are achieving similar results. Also, in the ERSPC Rotterdam cohort, researchers performed PCA3 tests on 1300 patients entering the third round of screen-ing and found that they could significantly reduce the number of biopsies they took while missing fewer significant cancers than they would with prostate-specific antigen (PSA) alone [9].

Likewise, David Bostwick, MD, MBA, chairman, CEO, and president of Bostwick Laboratories (Glen Allen, VA), says research has shown that the metabolic marker sar-cosine, an N-methyl derivative of the amino acid glycine, is highly increased during PCa progression to metastasis and can be detected non-invasively in urine [10].

The Prostate PX test (Aureon, yonkers, Ny) combines morphometry, immunos-tains, and clinical data from biopsy speci-mens to make prognostic predictions,

Dr. Bostwick adds. Although it has not been FDA cleared, it has proven equivalent to other models for predicting 5-year clini-cal failure after radical prostatectomy, with a concordance index of 0.81 to 0.85 [11]. Similarly, a 4-gene test called the Prostate Gene Expression Profile (Health Discovery Corporation, Savannah, GA) has shown the ability to identify grade 3 or higher cancer with 90% sensitivity and, more importantly, can distinguish benign from malignant tis-sue with 97% specificity [12].

Additionally, Dr. Bostwick says that after being quietly withdrawn during the late 1990s because of assay variability issues, cir-culating tumor cells (CTCs) have reemerged with greater accuracy and reproducibility thanks largely to flow cytometry and static image analysis. Several studies have shown that one can find CTCs at sensitivity levels of 1 in 1 million or higher; the question that ongoing research must answer is how best to apply this information clinically.

CoNCLuSioNNot all of the biomarkers discussed above ultimately will prove useful or cost-effective. It is clear, however, that with continued development, cancer-specific markers such as GSTP1 methylation, gene fusions, and PCA3 likely will have a significant impact on the diagnosis and staging of PCa and could provide surrogate endpoints for clini-cal trials of new PCa therapies.

ReFeReNCeS1. Roobol MJ, Kerkhof M, Schröder FH, et

al. Prostate cancer mortality reduction by prostate-specific antigen-based screening adjusted for nonattendance and contamina-tion in the European Randomised Study of Screening for Prostate Cancer (ERSPC). Eur Urol. 2009 Jul 28. [Epub ahead of print]

2. Andriole GL, Bostwick D, Brawley O, et al. Further analysis from the REDUCE pros-tate cancer risk reduction trial. Presented at the American Urologic Association Annual Meeting; April 25-30, 2009; Chicago. Abstract LBA1.

3. Bussemakers MJ, van Bokhoven A, Verhaegh GW, et al. DD3: a new prostate-specific gene, highly overexpressed in prostate can-cer. Cancer Res. 1999;59:5975-5979.

4. Nakanishi H, Groskopf J, Fritsche HA, et al. PCA3 molecular urine assay correlates with prostate cancer tumor volume: impli-cation in selecting candidates for active sur-veillance. J Urol. 2008;179:1804-1809.

5. Haese A, de la Taille A, van Poppel H, et al. Clinical utility of the PCA3 urine assay in European men scheduled for repeat biopsy. Eur Urol. 2008;54:1081-1088.

6. Marks LS, Fradet y, Deras IL, et al. PCA3 molecular urine assay for prostate cancer in men undergoing repeat biopsy. Urology. 2007;69:532-535.

7. Tomlins SA, Rhodes DR, Perner S, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate can-cer. Science. 2005;310:644-648.

8. Hessels D, Smit FP, Verhaegh GW, Witjes JA, Cornel EB, Schalken JA. Detection of TMPRSS2-ERG fusion transcripts and pros-tate cancer antigen 3 in urinary sediments may improve diagnosis of prostate cancer. Clin Cancer Res. 2007;13:5103-5108.

9. Roobol M. Biomarker update: the PCA3 test in the diagnosis of prostate cancer. Pre-sented at the European Association of Urol-ogy 24th Annual Congress; March 17-21, 2009. Stockholm, Sweeden. [Plenary Ses-sion 2: Focus on Prostate Cancer, Friday, March 20, 2009]

10. Sreekumar A, Poisson LM, Rajendiran TM, et al. Metabolomic profiles delineate poten-tial role for sarcosine in prostate cancer pro-gression. Nature. 2009;457:910-914.

11. Eggener SE, Vickers AJ, Serio AM, et al. Comparison of models to predict clinical failure after radical prostatectomy. Cancer. 2009;115:303-310.

12. Guyon I, Fritsche HA, Choppa P, yang L-y, Barnhill SD. A four-gene expression signa-ture for prostate cancer cells consisting of UAP1, PDLIM5, IMPDH2, and HSPD1. UroToday Int J. 2009 Aug;2(4). Available from www.urotoday.com (accessed Novem-ber 9, 2009).

The Current Evaluation Status of Biomarkers

Biomarker Substrate Phase 1 Phase 2 Phase 3 Phase 4 Phase 5 Phase 6

gSTP1 + methylation urine/Bx yes yes ongoing ongoing yes no

PCA3dd3 urine yes yes yes yes end 2006 Progensa™ gen-Probe Ce-marked

2007/2008 Progensa™ gen-Probe

T2-erg urine yes yes yes ongoing yes no


H I G H L I G H T S Prostate Cancer Screening and Prevention: Mixed Messages



Professor of Surgeryurology & Radiation OncologyHeadurologic OncologyE. David Crawford Endowed Chair of urologic Oncologyuniversity of ColoradoDenver, Colorado, uSA

SCReeNiNgAlthough some studies do not support the use of routine prostate cancer (PCa) screening, prevention strategies clearly could reduce the economic burden and mortality associated with PCa.

In 1989, PCa became the most com-monly diagnosed cancer—and the sec-ond leading cause of death—in American men. Therefore, the Prostate Conditions Education Council (PCEC) instituted Prostate Cancer Awareness Week, employ-ing celebrity spokesmen to publicize the importance of detecting PCa early. As a result of such efforts, the next few years witnessed declining PCa mortality rates in many countries, as reflected by the Sur-veillance, Epidemiology and End Results (SEER) database, the landmark Olmsted County study, and others. Conversely, PCa mortality did not fall in countries that have not embraced screening, such as Mexico.

Screening studies yielded conflicting results and were not randomized, how-ever, so their evidence was not strong enough to support public policy. As a

result, conflicting recommendations have emerged. On one side, the American Urologic Association (AUA) and other groups recommend some form of routine PCa screening. For instance, the PCEC recommends a baseline prostate health assessment, including prostate-specific antigen (PSA) and digital rectal exami-nation (DRE), for all men at age 40 (35 for high-risk men), followed by annual screening starting at age 50 for men with PSA less than 1 ng/mL or, for those with PSA greater than 1 ng/mL, perhaps addi-tional testing. Conversely, the American Cancer Society and the Centers for Dis-ease Control and Prevention consider the evidence insufficient to support routine screening.

Recently reported long-term data from the European Randomized Study of Screening for Prostate Cancer (ERSPC) study show that screening reduces PCa mortality by 20% [1]. The largest PCa screening study to date, the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, however, has raised doubts about the utility of PCa

Figure 1. Type of treatment. Of men who were treated, the most common treatment was surgery. The percentages add to more than 100% because there were patients who received more than one treatment. Misc indicates ketoconazole, aminogluetethimide, and any corticosteroid.

0

10

20

30 Initial Tx

23%

Hormones Surgery Misc

Type of Treatment

27%

0%1%

12%

20%

Radiation Chemotherapy

9%

17%

14%

17%

Key words:

Prostate cancer (PCa)ScreeningMortalityCost savingsFinasteride


screening in preventing PCa deaths. In this trial, researchers randomized 77,000 men to undergo either 6 years of annual screen-ing, through PSA testing and DRE, or care-as-usual from their family physicians. At 7 and 10 years’ follow-up, investigators found no significant mortality benefit to screening [2].

Popular media outlets trumpeted this apparent failure of annual screening, but these discussions ignored the fact that at baseline, about 33% of all study patients had already had at least one PSA test or DRE, which suggests that their physicians already suspected that they might have PCa. Addi-tionally, about 50% of men in the usual-care cohort underwent prostate screening at their primary physician’s behest. Also overlooked was the fact that few patients in either the treatment or control groups died of PCa (92 versus 82 at 10 years, respectively). This suggests that usual care provided by family physicians works just as well as doing yearly PSAs and DREs.

Nevertheless, many clinicians feel that the cost and morbidity associated with PCa treatment presently outweigh the benefits of routine screening, even if one assumes that screening reduces PCa mortality (which appears to be the case). Perhaps more accurately, screening does not work for all

cancers, as research has shown in lung can-cer, neuroblastoma, and some breast can-cers. Moreover, not everyone diagnosed with PCa requires treatment. But urolo-gists must remember that in 2008, 28,000 men succumbed to PCa. To help reduce this figure, PLCO investigators presently are analyzing the histories of patients who died of PCa during the clinical trial to see if information can be gleaned about who dies of prostate cancer.

Meanwhile, the US health care system spends $8 billion annually to treat PCa, which afflicts 16% of American men. A more detailed assessment comes from an analysis of data from 85 health care plans including 45 million lives nationally (E.D.C. unpub-lished data). For this analysis, investigators followed treatment costs and outcomes of more than 23,000 men age 40 years or older who had been diagnosed with PCa (and no other cancers) since 1995.

Overall, 80% of men had PSA tests at some point during the study, and 58% of men underwent some form of treatment, as opposed to watchful waiting. Surgery ranked as the most popular treatment option, and the men who chose surgery as their first option tended to be younger than those who chose hormonal treatments: 58 years versus 65 years, respectively. It’s disconcerting,

though, that more than 33% of patients required more than 1 treatment, usually because of a complication. Surgery created the most complications, including urinary retention, incontinence, and urethral stric-ture. Total per-patient treatment costs in the first year after diagnosis averaged $40,873 for patients who got any treatment, versus $12,000 for watchful-waiting patients and $29,000 on average (Figures 1 and 2).

PReveNTioNBecause PCa treatments carry significant cost and morbidity, and because the mortal-ity benefit of screening remains unproven, it is perhaps wiser to prevent PCa in the first place. Arguments that support prevention include the fact that men cannot alter many PCa risk factors, such as race and genetics. Conversely, diet clearly plays a role: obesity is associated with more aggressive PCas.

Large trials of primary PCa prevention strategies include the Selenium and Vita-min E Cancer Prevention Trial (SELECT), which showed that these supplements had no effect. In fact, selenium was associ-ated with increased rates of diabetes, and vitamin E with a higher incidence of PCa [3]. Additionally, vitamins E and C failed to prevent PCa in the Physicians Health Study II [4].

Figure 2. Average total monthly medical costs. Costs peak in the month following diagnosis and are highest for patients who receive treatment. WW indicates watchful waiting; Tx indicates treatment.


In the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study, dutasteride reduced the incidence of PCa by 23% among high-risk men [5]. The Prostate Cancer Prevention Trial (PCPT) showed for the first time that medical intervention—finasteride—reduced the risk of developing PCa by 25% compared to placebo [6].

These findings gave rise to the recom-mendation that for men who are concerned about PCa, it’s appropriate to discuss pre-vention with finasteride, while also high-lighting both its potential benefits and side effects [7]. While European urologists have embraced this practice, their Ameri-can counterparts have largely ignored the prevention message, and not just in PCa. Well-designed studies have highlighted many effective means of preventing heart attacks, yet heart disease remains the top cause of US mortality. If this message is fall-ing on deaf ears, how will the nuances of PCa prevention play? M. Scott Lucia, MD, Associate Professor of Pathology at the Uni-versity of Colorado Denver, has said, “I’m very concerned about the future of PCa prevention.”

Among FDUS participants, 73% say they now consult with patients regarding PCa prevention, and 87% say they will place patients on chemoprevention for PCa in the next 5 years. Half of participants report having made dietary/lifestyle changes to that effect in their own lives; 30% presently take 5-ARIs, with 21% doing so for preven-tive purposes.

Finasteride as a preventative treatment remains controversial partly because in the PCPT, men treated with finasteride developed more high-grade cancers than placebo-treated patients did (90 versus 53, respectively). However, follow-up studies

tend to refute this finding. It appears to be a product of volume reduction, and PSA per-forms better when the patient is on a drug like finasteride.

One could argue that merely delay-ing the development of PCa is beneficial because men likely will die of other causes long before their PCa reaches advanced stages; however, Dr. Lucia says that all the PCPT really showed was that “Finasteride prevented the diagnosis of PCa during the time of the study.” As such, it’s unclear whether prescribing 5-ARIs preventively improves mortality rates (for practicality’s sake, 5-ARI studies typically use intermedi-ate endpoints).

Moreover, Marc Garnick, MD, and Howard E. LeWine, MD, of Harvard Med-ical School, say the costs of PCa prevention with finasteride would be prohibitive. With 42 million US men older than 50 years, “If one assumes that the cost per product is $1 per pill per day, and chemopreven-tion prevents 5% of deaths that would otherwise have occurred, the cost per year per life saved is $10 million.” Dr. Garnick is Clinical Professor of Medicine, Harvard Medical School, and Dr. LeWine is Clinical Instructor of Medicine at Harvard Medical School and Brigham & Women’s Hospital in Boston.

“However,” counters E. David Crawford, MD, “if chemoprevention also reduces benign prostatic hyperplasia (BPH) progression and associated consequences such as uri-nary retention 50%, $1 per day seems a bargain.” Crawford is Professor of Surgery, Urology and Radiation Oncology and head of Urologic Oncology at the University of Colorado, Denver.

One agent that researchers perhaps should study for PCa prevention (Dr. Crawford

says) is the gonadotropin-releasing hor-mone (GnRH) antagonist cetrorelix. So far, low doses of this agent used in BPH trials have produced only mild side effects. Should cetrorelix be found to prevent PCa, it would require injection every 6 months, which men likely would find easier than taking a daily tablet.

ReFeReNCeS1. Schröder FH, Hugosson J, Roobol MJ, et

al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:1320-1328.

2. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Mortality results from a random-ized prostate-cancer screening trial. N Engl J Med. 2009;360:1310-1319.

3. Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009;301:39-51.

4. Gaziano JM, Glynn RJ, Christen WG, et al. Vitamins E and C and the prevention of prostate and total cancers in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2009;301:52-62.

5. Andriole G, Bostwick D, Brawley O, et al. Further analysis from the REDUCE pros-tate cancer risk reduction trial. Presented at the American Urological Association Annual Meeting; April 25-30, 2009; Chi-cago. Abstract LBA1.

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

7. Teillac P, Abrahamsson PA. The Prostate Cancer Prevention Trial and its implications for clinical practice: a European consensus. Eur Urol Supp. 2006;5:627-646.


H I G H L I G H T S


Testosterone Replacement Facing New Frontier


Abraham Morgentaler, MD

Associate Clinical Professor of urologyHarvard Medical School and Beth Israel Deaconess Medical CenterDirectorMen’s Health BostonBoston, Massachusetts, uSA

iNTRoduCTioNA growing body of evidence shows that rather than fueling prostate cancer (PCa), testosterone replacement therapy in non-castrated men—even some who have or have had prostate cancer—delivers ben-efits such as improved sexual health and mood without raising PCa risk.

Most urologists were taught that high testosterone levels cause PCa growth. This idea came from Huggins and Hodges, who showed nearly 70 years ago that castration causes PCa regression. They also claimed that supplementing testosterone enhanced PCa growth [1]. These notions remained unchallenged until relatively recently.

In 1996, sextant biopsies in 77 hypogo-nadal men with normal prostate-specific antigen (PSA) and digital rectal examina-tion (DRE) who were being considered for testosterone therapy showed that 14% already had PCa, which contradicted the long-standing idea that low testosterone levels protect against PCa [2]. Further-more, a complete literature review of testosterone and PCa between 1985 and 2004 showed no compelling evidence that high levels of testosterone—endogenous or via testosterone supplementation—increased the risk of PCa or caused PCa progression [3].

Additionally, 3 small retrospective studies of testosterone treatment in post- radical retroperitoneal prostatectomy (RRP) patients showed no PCa recurrences in up to 12 years of follow-up [4-6]. More daring was a study that showed no PCa recurrences after medians of 4.5 years of testosterone therapy and 5 years of follow-up in 31 patients treated with brachyther-apy, which leaves the prostate in situ [7].

Such findings sparked a closer reading of Huggins and Hodges’ original text, which revealed that the authors actually gave testosterone to only 3 men with met-astatic PCa. The paper provided results for 2 of them—1 of whom already had been castrated. Since then, intermittent luteinizing hormone-releasing hormone

(LHRH) therapy has proven that if one discontinues chemical castration, PSA will rise. Focusing more appropriately on the non-castrated population, it turns out that decades of prohibition against testosterone therapy stemmed from results observed in a single patient (whose acid phosphatase levels were not particularly convincing).

Subsequent research appeared to rein-force testosterone’s bad reputation. For example, when researchers published data on testosterone given to 10 men with met-astatic PCa, the report emphasized that within weeks, 5 had died or shown clear evidence of progression; however, these 10 men already had been castrated and had re-presented with problems. In the same publication, investigators found no progression in 26 non-castrated or recently castrated men with bony metastases who took testosterone [8].

Similarly, a Memorial Sloan-Kettering study showed that among 52 men with metastatic disease given testosterone, 45 had “unfavorable” responses [9]. How-ever, only 1 of 4 intact men among the original 52 had an unfavorable response. The other 3 received daily injections of testosterone for up to 300 days without incident. These findings led the authors to suggest that normal testosterone levels suffice to maximally stimulate PCa. And if normal testosterone levels do not fuel PCa in an individual, neither will additional testosterone.

THe SATuRATioN ModeLAlthough urologists historically have

understood the relationship between serum testosterone and PCa growth to be fairly linear, one actually sees a significant rise in PCa growth in the near-castrate range, but little additional growth past it. This happens because in the human pros-tate, dihydrotestosterone (DHT) saturates the androgen receptor (AR) at serum con-centrations of 120 ng/dL. Simply stated, at some point, the prostate has enough testosterone to do whatever it will—if

Key words:

Prostate cancer (PCa)Testosterone replacement therapySerum testosteroneSaturation model


cancer has not developed by this point, it is unlikely to do so at higher concentrations.

In the saturation model, castration leads to PSA declines and shrinking of PCa (and benign prostate tissue). At very low concen-trations, PCa exhibits exquisite sensitivity to changes in serum testosterone. Conversely, PCa shows little or no sensitivity to changes in serum testosterone at higher concentra-tions [10-12].

While no study has definitively validated the saturation model, a pooled analysis of data from 18 prospective studies regarding androgens and PCa found no association between PCa and serum androgens [13]. Men with the highest testosterone concen-trations turned out to have no greater risk of developing PCa than men with the lowest testosterone concentrations. Additionally, in a meta-analysis of 19 placebo-controlled studies, men who received testosterone had no worse voiding symptoms, nor rates of PCa or elevated PSA, than counterparts not given testosterone [14].

Conversely, several studies show a trou-bling association between PCa and low tes-tosterone levels. One such study reveals that the lower the testosterone level, the greater the risk of a positive biopsy [15]. Low

testosterone, not high testosterone, also has been correlated with higher tumor grade and Gleason stage at the time of RP, greater risk of biochemical recurrence after RP, and lower survival rates.

Additional research shows that even sup-raphysiologic testosterone doses do not increase PSA levels in young [16] or older patients [17]. Moreover, in a case series involving 13 older surveillance patients with PCa, testosterone therapy caused no significant PSA changes after 12.7 months’ mean follow-up. In this study, 4 of the first 6 follow-up biopsies showed no identifi-able cancer [18]. Subsequently, researchers have observed no progression in 11 of the 13 patients. A wealth of studies also shows that hypogonadal men who receive testos-terone supplementation tend to experi-ence better sexual and psychological health. Several studies have even demonstrated greater longevity among men with normal testosterone compared to men with low testosterone.

CoNCLuSioNThus the weight of evidence suggests that in non-castrated men, testosterone delivers sig-nificant health benefits without raising PCa

risk. In light of a cancer risk that has proven theoretical at best, it is perhaps even unethi-cal to deny appropriately selected men the benefits of testosterone therapy.

Accordingly, universities should begin teaching urologists that rather than feed-ing a hungry tumor, testosterone in non-castrated men functions more like water for a thirsty plant. Deprived, the plant shriv-els. Watered adequately, it thrives. But no amount of water will turn a snapdragon into a Sequoia.

Already, the above data are changing some physicians’ and other experts’ minds. The proportion of FDUS attendees who believe it is reasonable to offer testosterone therapy to men with definitively treated local PCa rose from 76% before learning about the saturation model to 95% after. Similarly, the proportion who believe it is reasonable to offer testosterone therapy to men with untreated PCa who are on surveillance rose from 24% to 60%.

However, L. Michael Glodé, MD, Profes-sor of Medical Oncology at the University of Colorado, Denver, says it is premature to accept the saturation model because in breast cancer, it took tens of thousands of patients to show conclusively that estro-gen replacement increases the risk of breast cancer.

Dr. Morgentaler replies that in the Wom-en’s Health Initiative (WHI) estrogen plus progesterone study, no single adverse event reached statistical significance. “Only when one adds up the potpourri do they reach statistical significance. Therefore, we must be careful about making the comparison” between breast cancer and PCa.

Nevertheless, Jack A. Schalken, PhD, Pro-fessor of Experimental Urology, Radboud University, Nijmegen Medical College, says extrapolation of testosterone concentrations should be done with care because it ignores what happens in the microenvironment of the prostate, where local enzymes determine how much testosterone and particularly DHT are synthesized regardless of serum levels.

“The local microenvironment ‘titrates’ particularly DHT to the level that it needs, and with an amplified AR, that may well be 30% of normal levels,” Dr. Schalken says. Conversely, he says provocative ideas that require animal testing suggest that for castration-resistant PCa, supraphysiologic testosterone doses could have therapeutic

Serum testosterone and prostate cancer prevalence. N = 345. Reprinted from [15] with permission from Elsevier.


benefit. Because these doses overload the AR and the genes it drives, he explains, this strategy eventually could kill the cancer.

ReFeReNCeS1. Huggins C, Hodges CV. Studies on pros-

tatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol. 2002;167:948-951.

2. Morgentaler A, Bruning CO 3rd, DeW-olf WC. Occult prostate cancer in men with low serum testosterone levels. JAMA. 1996;276:1904-1906.

3. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and rec-ommendations for monitoring. N Engl J Med. 2004;350:482-492.

4. Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostate-ctomy for prostate cancer in hypogonadal men. J Urol. 2004;172:920-922.

5. Agarwal PK, Oefelein MG. Testosterone replacement therapy after primary treatment for prostate cancer. J Urol. 2005;173:533-536.

6. Khera M, Grober ED, Najari B, et al. Testosterone replacement therapy fol-lowing radical prostatectomy. J Sex Med. 2009;6:1165-1170.

7. Sarosdy MF. Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy. Cancer. 2007;109:536-541.

8. Prout GR Jr, Brewer WR. Response of men with advanced prostatic carcinoma to exog-enous administration of testosterone. Can-cer. 1967;20:1871-1878.

9. Fowler JE Jr, Whitmore WF Jr. The response of metastatic adenocarcinoma of the prostate to exogenous testosterone. J Urol. 1981;126:372-375.

10. Morgentaler A. Testosterone and prostate cancer: an historical perspective on a mod-ern myth. Eur Urol. 2006;50:935-939.

11. Reply to A. Edward Friedman’s Letter to the Editor re: Abraham Morgentaler, Abdulmaged M. Traish. Shifting the Para-digm of Testosterone and Prostate Cancer: The Saturation Model and the Limits of Androgen-Dependent Growth. Eur Urol. 2009;55:310-321. Published online 1 April 2009, page e5.

12. Marks LS, Mazer NA, Mostaghel E, et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA. 2006;296:2351-2361.

13. Endogenous Hormones and Prostate Can-cer Collaborative Group, Roddam AW,

Allen NE, Appleby P, Key TJ. Endogenous sex hormones and prostate cancer: a collab-orative analysis of 18 prospective studies. J Natl Cancer Inst. 2008;100:170-183.

14. Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci. 2005;60:1451-1457.

15. Morgentaler A, Rhoden EL. Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen levels of 4.0 ng/mL or less. Urology. 2006;68:1263-1267.

16. Woodhouse LJ, Reisz-Porszasz S, Javan-bakht M, et al. Development of models to predict anabolic response to testos-terone administration in healthy young men. Am J Physiol Endocrinol Metab. 2003;284:E1009-E1017.

17. Gray PB, Singh AB, Woodhouse LJ, et al. Dose-dependent effects of testosterone on sexual function, mood, and visuospatial cognition in older men. J Clin Endocrinol Metab. 2005;90:3838-3846.

18. Morgentaler A et al. Testosterone therapy in men with untreated prostate cancer. Poster presented at Sexual Medicine Society of North America Meeting; October 16-19, 2008, Toronto. Poster 49.


H I G H L I G H T S


Local and Locally Advanced Prostate Cancer

Contributing Authors:

Gary M. Onik, MD

DirectorThe Center for Safer Prostate Cancer TherapyCelebration Heatlh/Florida HospitalCelebration, Florida, uSA

Mack Roach III, MD

ProfessorRadiation OncologyMedical Oncology, and urologyChairRadiation Oncologyuniversity of CaliforniaSan Francisco, California, uSA

M. Scott Lucia, MD

ChiefGenitourinary & Renal PathologyDirectorProstate Diagnostic Labuniversity of Colorado at DenverDenver, Colorado, uSA

Targeted Focal Therapy: Moving Beyond Low-Risk, Unifocal CancersGary M. Onik, MD

As targeted focal therapy (TFT) contin-ues to prove its mettle in treating low-risk, unifocal prostate cancers, evidence is beginning to show that it also might be effective for higher-risk cancers, even those with multiple foci. Additionally, 1 technology—irreversible electroporation (IRE)—appears particularly well-suited for focal ablation.

To succeed, targeted focal ablation requires the guidance of a 3D mapping biopsy, which involves inserting needles through a brachytherapy grid and sam-pling every 5 mm throughout the pros-tate. In a recent study, this technique found bilateral cancer in 61% of patients who were diagnosed by 12-core transrec-tal ultrasound (TRUS) biopsies as having only unilateral disease [1]. These patients generally would have proceeded to watch-ful waiting. But going forward, no patient should choose watchful waiting without having a 3D mapping biopsy to determine whether his case truly is low risk.

Thomas Keane, MBBCh, Chairman and Professor of Urology at the Medical University of South Carolina, says that many patients are choosing focal therapy or radiotherapy based on 12-core biop-sies. “If one is selectively going after high-risk disease or areas where one thinks the disease is primarily located,” he asks, “should the patient not undergo a map-ping biopsy?”

Cancer sampling by random needle biopsy is a function of tumor volume to prostate volume, adds M. Scott Lucia, MD, Associate Professor of Pathology at the University of Colorado, Denver. A standard 12-core biopsy conceivably could miss a small tumor in a large prostate, he adds.

In an ongoing study of 120 patients (treated by Dr. Onik) with varying Gleason

grades treated with focal cryotherapy and mapping biopsy, at an average of 3 years postsurgery, 99% of patients—including 9 who required retreatment—had achieved local control with no demonstrable resid-ual disease. Radiation failures are faring particularly well, suggesting that focal cryotherapy be considered the preferred salvage treatment for these patients. At 12 years postsurgery, Kaplan-Meier curves reveal no difference in the rate of bio-chemical disease-free survival for patients with unifocal or multifocal disease, the latter being 37% of the patient popula-tion. Moreover, every patient has been 100% continent immediately postsurgery. Accordingly, it appears that for local and locally advanced prostate cancer, targeted cryoablation works as well as whole-gland cryoablation.

Going forward, IRE offers poten-tially the best uniformity, predictability, and safety of any targeted therapy. This technology uses dual probes to apply an electrical field to targeted tissue, thereby creating irreversible pores in cell mem-branes that ultimately kill cells. Fur-thermore, IRE uses no thermal energy, relying instead on the fact that prostate cancer cells perish at a current density that spares nerves, microvasculature, and other surrounding tissues [2].

In an initial series of 16 high-risk patients treated with IRE, 100% were continent immediately postsurgery, and 90% of patients who were potent pre-operatively were potent immediately post-surgery. Only 1 patient required re-treatment, for a Gleason 6 cancer discovered outside the treatment area. As patients continue to be monitored, E. David Crawford, MD, plans to institute the first investigational device exemption (IDE) study and safety study with IRE in December 2009 (Figure 1).

A diSSeNTiNg voiCeHowever, Mack Roach III, MD, Professor of Radiation Oncology, Medical Oncology,

Key words:

Benign prostatic hyperplasia (BPH)5-alpha reductase inhibitor (5-ARI)Cost savingsSymptomatology


and Urology, University of California, San Francisco, says of IRE that it is highly improbable that a modality that nonspecifi-cally destroys tissue is able to recognize and spare normal tissues. Dr. Onik counters that through 5 years of research, “We have deter-mined that individual cell types have differ-ent resistance levels to electroporation, with nervous tissue showing a higher resistance than any epithelial tissue.”

Dr. Roach adds that in the ongoing 120-patient study, the 9 patients retreated with focal cryotherapy should count as failures. “In practical terms,” Dr. Onik replies, “if one re-treats a patient at low risk, it should count as a success for the modality.”

As for the tumor-grade independence of cryotherapy over other therapies, Dr. Roach says there’s no evidence that radiation does not work against high-grade tumors.

Another area of controversy involves treating the primary cancer in the face of known or probable metastatic disease, says Dr. Onik. Traditionally, many urologists believed local control of local and locally advanced prostate cancers mattered little because metastases likely were already pres-ent at initial diagnosis. New studies, how-ever, show that better local control leads to better overall survival [3,4]. Conversely, if one leaves high-grade cancer in place, it stands to reason that the patient could prog-ress to metastatic disease.

In gaining local control, cryoablation or even IRE offers advantages over surgery and

radiotherapy. Cryoablation is tumor grade–independent, repeatable, and extremely well-suited for extracapsular disease.

Radiotherapy Standards EvolvingMack Roach III, MD

Several recent studies are changing the standard of care in adjuvant radiotherapy (ART). In particular, the Southwest Oncol-ogy Group (SWOG) study and others showed that radiotherapy in post–radical prostatectomy (RP) patients can improve survival, reduce the risk of metastasis, and reduce the risk that patients will require hormone therapy. Such studies support pre-scribing ART particularly for any post-RP patient who has adverse pathologic features including positive margins, pathological T3 status, or seminal vesicle involvement.

For intermediate-risk prostate cancer, 4 Phase 3 trials pitting radiation alone versus radiation plus neoadjuvant hormone ther-apy (NADT) all show benefit in terms of survival and prostate-specific antigen (PSA) control to incorporating NADT [5-8]. Similarly, an 880-patient Swedish trial com-paring long-term ADT versus ADT plus radiation showed that adding radiotherapy improved overall survival and cause-specific survival [9].

Regarding the prevailing notion that short-term hormone therapy raises cardio-vascular risk, no evidence supports this link. An often-cited study in this area concluded

that men older than 65 years who under-went 6 or 8 months of hormone therapy had an increased risk of fatal myocardial infarction (MI) versus peers who did not receive hormone therapy [10]. This con-clusion, however, is largely statistical noise: plotting these authors’ 3-, 6-, and 8-month curves on the same graph reveals that 8 years out, the risk of fatal MI is twice as high if one took 0 or 6 months of ADT than if one had taken 8 months, which is counterintui-tive. These incongruities stem from pooling patients from different studies with differ-ent eligibility requirements, and in small numbers at that [11].

The strongest refutation of the purported short-term ADT/MI link comes from a Canadian study comparing 19,000 prostate cancer patients treated with ADT against 19,000 who were not treated with ADT. Although researchers discovered increased risk of diabetes and fractures with hormone therapy, they saw no increased risk of fatal MI [12].

Similarly, though dose escalation has become many a radiation oncologist’s man-tra, evidence shows that raising radiation doses produces fewer biochemical failures but to date has not been shown to prolong survival. Because data supporting NADT are stronger than those supporting dose escalation, treating oncologists should con-sider treating high-risk patients with dose escalation plus hormone therapy.

Another radiation oncology trend worth questioning is proton therapy. A recent

Figure 1. Bilateral irreversible electroporation (IRE) 18 months postsurgery. The patient had a prostate-specific antigen (PSA) level of .04 and was both potent and continent.


analysis comparing low-risk prostate can-cers treated with brachytherapy against similar cancers treated with conformal protons showed virtually identical survival curves [13]. Brachytherapy also reduced PSA more effectively, and it’s far cheaper and more available than proton therapy. Brachytherapy also has produced excellent 5-year results based on an analysis of more than 1000 patients with Gleason scores of 7 to 10 treated at the University of California, San Francisco, and other centers [14].

Of note, a commonly cited study con-cluded that brachytherapy is less effective than external beam RT or radical pros-tatectomy for patients with intermedi-ate and high-risk prostate cancer [15]. Its authors overlooked what is now known as the benign blip: PSA increases after brachytherapy often quickly subside. This study also is based on data for which it is unclear whether computed tomography (CT)-based post-implant dosimetry was performed (Figure 2).

Regarding whole-pelvic (WP) radia-tion, 2 prominent studies have not shown benefit [16,17]; however, neither of the

institutions involved with these studies actually uses WPRT. Rather, researchers there treat only the so-called “true pelvis,” from the lower border of the ischial tuber-osities. To update, there are many more studies supporting WPRT than there are studies that refute it in patients undergo-ing external beam RT. Studies that support WPRT include RTOG 9413, as well as reports by Seaward et al from the Univer-sity of California, San Francisco; Pan et al from the University of Michigan; Spiotto et al from Stanford; Da Pozzo from Italy; Aizer from yale; and Milecki et al from Poland. RTOG 0924, which will use over-all survival as its primary endpoint, hope-fully will finally answer the question.

Biopsies AdvancingM. Scott Lucia, MD

Research continues to refine the prognos-tic utility of biopsy in local and locally advanced prostate cancer (PCa). In par-ticular, urology is witnessing rapid growth in terms of biomarkers and molecular determinants used not only for predicting

treatment responses, but also for prognostic purposes. For example, expression of molec-ular targets (eg, androgen receptor) or cyto-genetic alterations may become increasingly used for prognosis or selection of therapy. In the next 5 to 10 years, urologic oncolo-gists will see many more of these types of determinants being incorporated into their practices.

Pathologists also are getting more out of tissue samples by applying multiple newer modalities to them. For example, a patholo-gist can cut a paraffin block into sections for separate submission to mutational analysis, image analysis, nuclear morphometry, and tissue morphometry. When combined with clinical and classic pathologic data, this multivariate approach yields more accurate risk stratification.

ReFeReNCeS1. Onik G, Miessau M, Bostwick DG. Three-

dimensional prostate mapping biopsy has a potentially significant impact on pros-tate cancer management. J Clin Oncol. 2009;27:4321-4326.

2. Rubinsky J, Onik G, Mikus P, Rubinsky B. Optimal parameters for the destruction of prostate cancer using a reversible electropo-ration. J Urol. 2008;180:2668-2674.

3. Zelefsky MJ, yamada y, Fuks Z, et al. Long-term results of conformal radiotherapy for prostate cancer: impact of dose escalation on biochemical tumor control and distant metastases-free survival outcomes. Int J Radiat Oncol Biol Phys. 2008;71:1028-1033.

4. Trock BJ, Han M, Freedland SJ, et al. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008;299:2760-2769.

5. Roach M 3rd, Bae K, Speight J, et al. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J Clin Oncol. 2008;26:585-591.

6. Laverdière J, Nabid A, De Bedoya LD, et al. The efficacy and sequencing of a short course of androgen suppression on freedom from biochemical failure when administered with radiation therapy for T2-T3 prostate cancer. J Urol. 2004;171:1137-1140.

7. D’Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW.

Figure 2. Examples of nodal areas that need to be covered by whole-pelvic radiotherapy (WPRT) in high-risk patients: peri-prostatic (orange), external iliac (green), external iliac (yellow), pre-sacral (blue midline), common iliac (red), para-aortic (light blue, top midline), and peri-rectal posterior (not shown).


6-month androgen suppression plus radia-tion therapy vs radiation therapy alone for patients with clinically localized pros-tate cancer: a randomized controlled trial. JAMA. 2004;292:821-827.

8. Denham JW, Stiegler A, Wilcox C, et al. Time to biochemical failure and prostate-specific antigen doubling time as surrogates for prostate cancer-specific mortality: evi-dence from the TROG 96.01 randomised controlled trial. Lancet Oncol. 2008;9:1058-1068.

9. Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radio-therapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet. 2009;373:301-308.

10. D’Amico AV, Denham JW, Crook J, et al. Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarction. J Clin Oncol. 2007;25:2420-2425.

11. Roach M 3rd. Regarding the risk of adju-vant suppression therapy for prostate can-cer on the frequency and timing of fatal myocardial infarction: how real is the risk? J Clin Oncol. 2007;25:5325-2326; author reply 5326.

12. Alibhai SM, Duong-Hua M, Sutradhar R, et al. Impact of androgen deprivation ther-apy on cardiovascular disease and diabetes. J Clin Oncol. 2009;27:3452-3458.

13. Jabbari S, Weinberg VK, Shinohara K, et al. Equivalent biochemical control and improved prostate-specific antigen nadir after permanent prostate seed implant brachytherapy versus high-dose three-dimensional conformal radiother-apy and high-dose conformal proton beam radiotherapy boost. Int J Radiat Oncol Biol Phys. 2009 Apr 29. [Epub ahead of print]

14. Stone NN, Potters L, Davis BJ, et al. Mul-ticenter analysis of effect of high biologic

effective dose on biochemical failure and survival outcomes in patients with Gleason score 7-10 prostate cancer treated with per-manent prostate brachytherapy. Int J Radiat Oncol Biol Phys. 2009;73:341-346.

15. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radi-cal prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969-974.

16. Jacob R, Hanlon AL, Horwitz EM, Mov-sas B, Uzzo RG, Pollack A. Role of prostate dose escalation in patients with greater than 15% risk of pelvic lymph node involvement. Int J Radiat Oncol Biol Phys. 2005;61:695-701.

17. Pommier P, Chabaud S, Lagrange JL, et al. Is there a role for pelvic radiation in local-ized prostate adenocarcinoma? Prelimi-nary results of GETUG-01. J Clin Oncol. 2007;25:5366-5373.

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