2011 ANNUAL MEETING HIGHLIGHTS Prostate Cancer Course #9IC
Management of Castration Resistant Prostate Cancer
Prostate Cancer Update 2011
The Role of Radical Prostatectomy and Pelvic Lymph Node Dissection in an Integrated Treatment Program of High Risk Prostate Cancer
Update on AUA Cancer Related Guidelines: Preparation for Certification
Late Breaking News: Denosumab to Prevent Bone Metastases (Dmab 147 Study) Highlights: Prostate Cancer Ramon Guiteras Lecture: Early Diagnosis of Prostate Cancer Through PSA Testing Saves Lives Take Home Message: Localized Prostate Cancer
AUA 2011 ANNUAL MEETING HIGHLIGHTS
Robert C. Flanigan, M.D.
American Urological Association 1000 Corporate Boulevard Linthicum, MD 21090 Copyright © 2011 by American Urological Association None of the contents may be reproduced in any form without prior written permission of the publisher. The opinions expressed in this publication are those of the speakers and do not necessarily reflect the opinions or recommendations of their affiliated institutions, the publisher, the American Urological Association or any other persons. Some articles in this publication may discuss unapproved or “off-label” uses of products. Any procedures, medications or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients’ conditions and of possible contraindications or dangers in use, review of any applicable manufacturers’ product information and comparison with the recommendations of the authorities.
This publication is supported by educational grants from Abbott Laboratories, Amgen Inc., Dendreon, and Janssen Biotech Inc.
AUA 2011 WASHINGTON, DC ANNUAL MEETING HIGHLIGHTS
Highlights on Prostate Cancer (from courses #9IC, #63PG, #92IC and #70IC, 2011 AUA Annual Meeting)
Method of Participation
This CME enduring material activity consists of a printed overview of the content presented at a live course at the 2011 AUA Annual Meeting, and an online posttest and evaluation.
activity planners and presenters) provided by the AUAER are required to disclose to the provider any relevant financial relationships they have with any commercial interest. The AUAER must determine if an individual’s commercial relationships may influence the educational content with regard to exposition or conclusion, and resolve any conflicts of interest prior to the commencement of the educational activity. The intent of this disclosure is not to prevent individuals with relevant financial relationships from serving as planners or presenters, but rather to provide the audience with information on which they can make informed judgments about the material presented.
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The opinions and recommendations expressed by faculty, authors and other experts whose input is included in this program are their own and do not necessarily represent the viewpoint of the AUAER.
To receive CME credit/hours of participation, participants must read the overview of the course, complete the online posttest, passing with a score of at least 80%, and submit the evaluation and the credit request form by visiting http:// www.AUANet.org/cme/PROSTATECANCER11.
Estimated time to complete this CME enduring material activity: 1.5 hours Release Date: October 2011 Expiration Date: October 31, 2012
AUA Disclosure Policy As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), the American Urological Association Education & Research Inc. (AUAER) must ensure balance, independence, objectivity and scientific rigor in all its activities. All persons in a position to control the content of an educational activity (ie
Course #9IC: Management of Castration Resistant Prostate Cancer Faculty Fred Saad, M.D. Course Director Professor of Urology Chief, Division of Urology University of Montreal Montreal, Canada Disclosures: Amgen, Astellas, Millenium, Novartis, Sanofi Aventis: Consultant/ Advisor Mario Eisenberger, M.D. R. Dale Hughes Professor of Oncology and Urology Johns Hopkins Medical Institutions Baltimore, MD Disclosures: Sanofi Aventis: Investigator; Ipsen, Millenium: Consultant/Advisor
Learning Objectives At the conclusion of this CME enduring material activity, participants should be able to: • review present and future therapeutic options for patients with castration resistant prostate cancer (CRPC) • acquire the basic knowledge required to integrate systemic and nonsystemic therapies in their clinical practice • describe side effects of current and future therapies as well as strategies in managing and preventing these side effects • integrate a more systematic approach to dealing with the complexity of patients with CRPC
Course #63PG: Prostate Cancer Update 2011 Faculty William J. Catalona, M.D. Course Director Professor of Urology Director of Clinical Prostate Cancer Program Northwestern University Feinberg School of Medicine Chicago, IL Disclosures: Beckman Coulter, Inc.: Consultant/Advisor, Investigator, Meeting Participant/Lecturer, Scientific Study/ Trial; Nanosphere, Inc.: Scientific Study/ Trial; deCODE Genetics: Consultant/ Advisor, Scientific Study/Trial; OHMX: Consultant/Advisor, Investigator, Scientific Study/Trial Douglas M. Dahl, M.D. Associate Professor of Surgery/Urology Chief, Division of Urologic Oncology Massachusetts General Hospital Boston, MA Disclosures: Nothing to disclose Stanley Liauw, M.D. Assistant Professor ▼ Continued on page 2
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Department of Radiation and Cellular Oncology University of Chicago Hospitals Chicago, IL Disclosures: Nothing to disclose Stacy Loeb, M.D. Chief Resident Brady Urological Institute Johns Hopkins Medical Institutions Baltimore, MD Disclosures: Nothing to disclose Robert B. Nadler, M.D. Professor of Urology Director of Minimally Invasive Urology Northwestern University Chicago, IL Disclosures: Angio Dynamics, Intuitive Surgical (Da Vinci): Consultant /Advisor; Boston Scientific Corp: Fellowship Support
Learning Objectives At the conclusion of this CME enduring material activity, the participant should be able to: • cite important new publications in this field during the past year • identify the relative strengths and weaknesses of the reports • appraise how new studies relate to the existing state-of-the-art in clinical practice • analyze whether they and their colleagues should consider changing their practice based on the new information
Course #92IC: The Role of Radical Prostatectomy and Pelvic Lymph Node Dissection in an Integrated Treatment Program of High-Risk Prostate Cancer Faculty Peter T. Scardino, M.D. Course Director Chair, Department of Surgery David H. Koch Chair Memorial Sloan-Kettering Cancer Center New York, NY
Disclosures: NCI, NIH, Prostate Cancer Foundation: Investigator; Steba Biotechnology: Consultant/Advisor Vincent P. Laudone, M.D. Associate Attending Co-Director Robotic Surgery Memorial Sloan-Kettering Cancer Center New York, NY Disclosures: Nothing to disclose
Learning Objectives At the conclusion of this CME enduring material activity, the participant should be able to: • outline the pitfalls of risk stratification schemes for localized and locally advanced prostate cancer • appraise staging and evaluation of patients with a high risk of locally recurrent cancer • describe the indications for radical prostatectomy in men with high risk cancers • identify optimal surgical techniques for high risk cancers, including seminal vesicle resection and pelvic lymph node dissection • compare adjuvant to salvage radiation therapy after radical prostatectomy, and develop management strategies for high risk cancers, incorporating surgery, radiation and hormonal therapy
Course #70IC: Update on AUA Cancer-Related Guidelines: Preparation for Certification Faculty Sam S. Chang, M.D. Course Director Professor of Urologic Surgery Department of Urologic Surgery Vanderbilt University Medical Center Nashville, TN Disclosures: ENDO, Centocor Ortho Biotech, Dendreon, Amgen, Spectrum: Consultant/Advisor Peter E. Clark, M.D. Associate Professor of Urology
Vanderbilt University Medical Center Nashville, TN Disclosures: Tengion, Galil Medical: Consultant/Advisor Daniel W. Lin, M.D. Associate Professor Chief of Urologic Oncology University of Washington Seattle, WA Disclosures: Caris Life Sciences: Consultant/Advisor; Dendreon: Meeting Participant/Lecturer
Learning Objectives At the conclusion of this CME enduring material activity, the participant should be able to: • illustrate difficult case scenarios that are elucidated by the AUA cancer related guidelines • measure core knowledge of these guidelines and appropriate situations to use • prepare for upcoming examinations
Statement of Need Urologists and other health care providers of prostate cancer treatment need to be aware of the latest developments and research in diagnosis and therapy, including the latest prostate specific antigen screening guidelines, prognosis and management of localized and advanced prostate cancer. There is no clear “right” answer for the typical patient diagnosed with prostate cancer, but as the population ages, there is a continued need to educate urologists on the treatment options available.
Target Audience Urologists, urologists in training and nonphysician providers involved in urology.
Accreditation The American Urological Association Education & Research, Inc. is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. ▼ Continued on page 3
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Credit Designation The AUAER designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. The AUAER takes responsibility for the content, quality and scientific integrity of this CME enduring material activity.
Commercial Support This CME enduring material activity is supported by an educational grant from Abbott Laboratories, Amgen Inc., Janssen Biotech, Inc. and Dendreon.
Statement of Evidence-Based Content As a provider of continuing medical education accredited by the ACCME, it is the policy of the AUAER to review and certify that the content contained in this CME enduring material activity is valid, fair, balanced, scientifically rigorous and free of commercial bias.
Off-Label or Unapproved Use of Drugs or Devices It is the policy of the AUAER to require the disclosure of all references to off-label or unapproved uses of drugs or devices prior to the presentation of educational content. The audience is advised that
this CME enduring material activity may contain reference(s) to off-label or unapproved uses of drugs or devices. Please consult the prescribing information for full disclosure of approved uses. Copyright © 2011 by the American Urological Association
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AUA 2011 WASHINGTON, DC ANNUAL MEETING HIGHLIGHTS
Management of Castration Resistant Prostate Cancer Fred Saad, M.D., Director; Marion Eisenberger, M.D., Faculty
Definition of Castration Resistant Prostate Cancer Castration resistant prostate cancer (CRPC) is defined by disease progression despite androgen depletion therapy (ADT) and may present as either a continuous increase in serum prostate specific antigen (PSA), progression of preexisting disease and/or appearance of new metastases.
Management of CRPC Secondary hormonal manipulations. To date, no study of secondary hormone treatment has shown benefits in terms of survival but most trials have been smaller and heavily confounded by future treatments used. Of patients treated with luteinizing hormone-releasing hormone (LH-RH) agonist monotherapy or who have undergone orchiectomy, total androgen blockade (TAB) with testosterone antagonists such as bicalutamide can offer PSA responses in 30% to 35%.1, 2 For patients who have undergone TAB and have signs of progression, the antiandrogen may be discontinued in an attempt to obtain an antiandrogen withdrawal response (AAWD), which can be observed in 20% to 30% of patients. Other options may include a change to a different antiandrogen, such as nilutamide or flutamide, or the use of ketoconazole.3 For all of these modalities, transient PSA reductions have been reported in approximately 30% of patients. Because the androgen receptor remains active in most patients who have castration resistant disease, it is recommended that ADT be continued. Consequently, most if not all clinical trials of patients with CRPC have mandated continued ADT. Novel agents that potently affect the androgen axis have recently been developed and have renewed the enthusiasm for effective hormone manipulation. Currently, accrual has been completed for men with CRPC in phase 3 clinical
trials evaluating whether prednisone and abiraterone acetate, a potent and irreversible inhibitor of CYP-17, a critical enzyme in androgen biosynthesis, can improve survival compared to prednisone and placebo.4-6 In the post-docetaxel setting abiraterone/prednisone was shown to significantly prolong median overall survival compared to placebo/prednisone by 4.1 months (range 14.9 vs 10.8 months, HR 0.61, p=0.0001). In light of these positive results abiraterone was approved by the Food and Drug Administration (FDA) as second line treatment in patients with CRPC. Oternerol, an inhibitor of CYP-17, and MDV-3100, a potent inhibitor of the androgen receptor, are also being evaluated in the predocetaxel and post-docetaxel settings in international randomized clinical trials. Systemic corticosteroid therapy. Corticosteroid therapy with low dose prednisone or dexamethasone may also offer improvement in PSA values and/or palliative outcomes in up to 30% of symptomatic and asymptomatic men.7 Prednisone therapy in patients with CRPC has been evaluated in several studies, although most address the symptomatic patient.8 PSA response rates, defined by a posttreatment decrease of 50% or more from baseline, vary from 21% to 34%. In asymptomatic men Heng and Chi reported a 22.4% response rate to prednisone, defined as a 50% or greater decrease in PSA decline.9 An additional 16.3% of patients had a PSA decline of less than 50%. Of the patients 90% had no documented side effects. Of all PSA responders 27% had a time to progression greater than 1 year and 45% did not require chemotherapy for the duration of the study. First line systemic chemotherapy. Docetaxel and prednisone are currently considered the standard of care for men with CRPC and detectable metastatic disease based largely on the simultaneous publication of 2 large randomized
controlled trials comparing this combination to the previously established standard of mitoxantrone and prednisone.10,11 Docetaxel is a taxane drug that induces polymerization of microtubules and phosphorylation of bcl-2 protein. Tannock et al reported improved survival with docetaxel and prednisone (every 3 weeks) compared to mitoxantrone and prednisone (median survival 18.9 vs 16.5 months, HR 0.76, 95% CI 0.62–0.94, 2-sided p = 0.009).11 No overall survival benefit was observed with docetaxel given on a weekly schedule (HR 0.91, 95% CI 0.75–1.11, 2-sided p = 0.36). Petrylak et al reported longer survival time with docetaxel and estramustine (EMP) combination chemotherapy compared with mitoxantrone (median survival 17.5 vs 15.6 months, HR 0.80, 95% CI, 0.67–0.97, 2-sided p = 0.02).10 This trial also had a median progression-free interval of 6.3 vs 3.2 months (HR 0.73, 95% CI, 0.63–0.86, 2-sided p <0.0001) favoring docetaxel and EMP compared with mitoxantrone. Pain response was assessed in both trials. Significantly more patients treated with docetaxel (every 3 weeks) achieved a pain response compared with those receiving mitoxantrone (35% vs 22%, p = 0.01). Quality of life response, defined as a sustained 16-point or greater improvement from baseline on 2 consecutive measurements, was higher with docetaxel given every 3 weeks (22% vs 13%, p = 0.009) or weekly (23% vs 13%, p = 0.005) compared with mitoxantrone. In both trials PSA response rates were also statistically significantly higher with docetaxel compared to mitoxantrone. Based on the results of these 2 trials, it is now recommended that men with metastatic CRPC be given 75 mg/m2 docetaxel intravenously every 3 weeks with 5 mg prednisone orally twice daily to improve overall survival, disease control, symptom palliation and quality of life.12 Immunotherapy. In April 2010 sipu▼ Continued on page 5
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leucel-T became the first immunotherapeutic agent to be approved by the FDA based on consistent observed improvements in overall survival. Sipuleucel-T is an autologous “vaccine” that requires the collection of white blood cells from patients to obtain antigen presenting cells (APCs). These APCs are then exposed to the prostatic acid phosphatase-granulocyte macrophage colony stimulating factor (PAP-GM-CSF) fusion protein and reinfused into the patient. Patients entered onto the studies of sipuleucelT have had excellent to good performance status (ECOG 0-1), have been asymptomatic or minimally symptomatic and have not had visceral metastases. Improvements in overall survival were noted in the integrated analysis of D9901 and D9902A, which demonstrated a 33% reduction in the risk of death (HR 1.50, 95% CI 1.10–2.05, p = 0.011 log-rank).13 FDA approval was finally granted when the confirmatory trial D9902B that randomized 512 patients to sipuleucel-T or placebo in a 2:1 ratio also found a 22.5% improvement in mortality risk (median survival 25.8 vs 21.7 months, HR 0.775, 95% CI 0.614–0.979, p = 0.032).14 The treatment appears well tolerated and the most common complications include transient mild to moderate chills, pyrexia and headaches. Second line systemic chemotherapy. Until 2010 mitoxantrone was considered the de facto second line chemotherapy agent but published series suggested that it has limited activity and increased toxicity in that setting with response rates from retrospective series ranging from 9% to 20%.15-17 For patients who have not demonstrated definitive evidence of resistance to docetaxel, re-treatment with docetaxel can be considered.18-21 Cabazitaxel is a potent taxane agent, which has been selected in preclinical studies by virtue of its high cytotoxicity and low affinity to the adenosine triphosphate dependent drug efflux pump P-glycoprotein 1, which can be responsible for resistance to docetaxel.22 Results from a large, phase III trial evaluating
the efficacy of cabazitaxel were recently published.23 A total of 755 patients with CRPC pretreated with docetaxel were recruited for this randomized, placebo controlled trial. Patients were randomized to receive 10 mg prednisone daily with either 12 mg/m2 mitoxantrone or 25 mg/m2 cabazitaxel every 3 weeks. Grade 3 to 4 neutropenia occurred in 81.7% of patients in the cabazitaxel arm and 58.0% of those in the mitoxantrone arm, with an overall incidence of febrile neutropenia of 7.5% and 1.3%, respectively. A statistically significant and clinically relevant advantage in survival emerged in favor of the cabazitaxel group, with a median survival of 15.1 months vs 12.7 months for the mitoxantrone group (HR 0.70, 95% CI 0.59–0.83, p <0.0001). In light of these positive results cabazitaxel was approved by the FDA as second line treatment in CRPC patients. Bone targeted therapy. Bone loss in patients with prostate cancer may be attributed to the disease itself, which is a risk factor for osteoporosis and ADT.24, 25 Bone loss associated with ADT and the presence of bone metastases lead to a fragile bone state and significant risk of skeletal complications, including pathological fractures, debilitating bone pain and spinal cord compression. Bisphosphonates and denosumab, a human monoclonal antibody RANK ligand inhibitor,26 are inhibitors of osteoclast mediated bone resorption that can prevent bone loss and increase bone mineral density in patients with prostate cancer receiving ADT.27-29 Zoledronic acid and denosumab also reduce the risk of skeletal related events (SREs) in patients with bone metastatic CRPC. In men with castration recurrent prostate cancer and bone metastases 4 mg zoledronic acid intravenously and 120 mg denosumab subcutaneously every 4 weeks are recommended to prevent SREs including pathological fractures, spinal cord compression, surgery or radiation therapy to bone.30 Results from this randomized study indicated that fewer men receiving zoledronic acid had SREs
than those in the placebo group (38% vs 49%, p=0.02). Zoledronic acid also increased the median time to first event (488 vs 321 days, p=0.01), and the overall reduction in the rate of SREs in treated patients was 36%. Denosumab in a randomized controlled study demonstrated an 18% (p=0.001) improvement in time to first SRE compared to zoledronic acid. No dose modification for renal function is necessary for denosumab but the risk of hypocalcemia is increased, and calcium supplementation and dosing are recommended. Zoledronic acid and denosumab are associated with a 1% to 2% risk of osteonecrosis of the jaw (ONJ).31-33 Most but not all patients who have ONJ have preexisting dental problems. Excellent oral hygiene, baseline dental evaluation for high risk individuals and avoidance of invasive dental surgery during therapy are recommended to reduce risk of ONJ.
Clinical Trials and Future Directions Men with CRPC are living longer with improved quality of life but most, if not all, eventually die of disease. Therefore, better treatments are necessary. To date, there is no standard of care for nonmetastatic CRPC. However, this may soon change with the recently reported results of a placebo controlled randomized clinical trial using denosumab in patients with CRPC without bone metastases. The study showed a statistically significant delay in time to first bone metastasis of 4 months (p=0.03). Several trials are ongoing in the pre-chemotherapy setting with the objective of delaying progression, and the need for chemotherapy and improving overall survival. Novel agents are also being tested in phase 3 trials in combination with docetaxel in the first line setting. A number of trials for patients who had previous treatment with docetaxel are evaluating novel antiandrogens, cytotoxic agents and targeted therapies. Because CRPC remains an incurable and ultimately fatal illness, participation in clinical trials at all stages of the disease remains paramount. ▼ Continued on page 6
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Conclusion CRPC is a multifaceted problem that needs a multidisciplinary approach. The role of the urologist is likely to increase in the near future with the hope that new noncytotoxics may prove to be effective in the early stages of CRPC. ♦ 1. Sciarra A, Cardi A and Di Silverio F: Antiandrogen monotherapy: recommendations for the treatment of prostate cancer. Urol Int 2004; 72: 91. 2. Cox RL and Crawford ED: Estrogens in the treatment of prostate cancer. J Urol 1995; 154: 1991. 3. Small EJ, Halabi S, Dawson NA et al: Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol 2004; 22: 1025. 4. Hartmann R, Ehmer P, Haidar S et al: Inhibition of CYP 17, a new strategy for treatment of prostate cancer. Arch Pharm (Weinheim) 2002; 335: 119. 5. De Bono JS, Attard G, Reid AH et al: Anti-tumor activity of abiraterone acetate (AA), a CYP17 inhibitor of androgen synthesis, in chemotherapy naive and docetaxel pre-treated castration resistant prostate cancer (CRPC). J Clin Oncol 2008; 26: 251s, abstract 5005. 6. Danila DC, Rathkopf DE, Morris MJ et al: Abiraterone acetate and prednisone in patients (Pts) with progressive metastatic castration resistant prostate cancer (CRPC) after failure of docetaxelbased chemotherapy. J Clin Oncol 2008; 26: 254s, abstract 5019. 7. Storlie JA, Buckner JC, Wiseman GA et al: Prostate specific antigen levels and clinical response to low dose dexamethasone for hormone-refractory metastatic prostate carcinoma. Cancer 1995; 76: 96. 8. Tannock IF, Osoba D, Stockler MR et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative endpoints. J Clin Oncol 1996; 14: 1756. 9. Heng DY and Chi KN: Prednisone monotherapy in asymptomatic hormone refractory prostate cancer. Can J Urol 2006; 13: 3335. 10. Petrylak DP, Tangen CM, Hussain MHA et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351: 1513. 11. Tannock IF, de Wit R, Berry WR et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502.
12. Winquist E, Waldron T, Berry S et al: Nonhormonal systemic therapy in men with hormonerefractory prostate cancer and metastases: a systematic review from the Cancer Care Ontario Program in Evidence-based Care’s Genitourinary Cancer Disease Site Group. BMC Cancer 2006; 6: 112. 13. Higano CS, Schellhammer PF, Small EJ et al: Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 2009; 115: 3670. 14. Schellhammer PF, Higano C, Berger ER et al: A randomized, double-blind, placebo-controlled, multi-center, phase III trial of sipuleucel-T in men with metastatic, androgen independent prostatic adenocarcinoma (AIPC). Presented at the annual meeting of the American Urological Association,Chicago, Illinois, April 25-30, 2009. 15. Michels J, Montemurro T, Murray N et al: Firstand second-line chemotherapy with docetaxel or mitoxantrone in patients with hormone-refractory prostate cancer: does sequence matter? Cancer 2006; 106: 1041.. 16. Oh WK, Manola J, Babcic V et al: Response to second-line chemotherapy in patients with hormone refractory prostate cancer receiving two sequences of mitoxantrone and taxanes. Urology 2006; 67: 1235. 17. Berthold DR, Pond G, De Wit R et al: Survival and PSA response of patients in the TAX 327 study who crossed over to receive docetaxel after mitoxantrone or vice versa. Ann Oncol 2008; 19: 1749. 18. Beer TM, Ryan CW, Venner PM et al: Intermittent chemotherapy in patients with metastatic androgen-independent prostate cancer: results from ASCENT, a double-blinded, randomized comparison of high-dose calcitriol plus docetaxel with placebo plus docetaxel. Cancer 2008; 112: 326. 19. Jankovic B, Beardsley E and Chi KN: Rechallenge with docetaxel as second-line chemotherapy in patients with metastatic hormone refractory prostate cancer (HRPC) after previous docetaxel: a population based analysis. Presented at the American Society of Clinical Oncology 2008 ASCO Genitourinary Cancers Symposium, San Francisco, California, February 14-16, 2008; abstract 196. 20. Ansari J, Hussain SA, Zarkar A et al: Docetaxel chemotherapy for metastatic hormone refractory prostate cancer as first-line palliative chemotherapy and subsequent re-treatment: Birmingham experience. Oncol Rep 2008; 20: 891. 21. Eymard J, Oudard S, Gravis G et al: Docetaxel reintroduction in patients with metastatic castration-resistant docetaxel-sensitive prostate cancer: a retrospective multicentre study. BJU Int 2010; 106: 974.
22. Di Lorenzo G, Buonerba C, Autorino R et al: Castration-resistant prostate cancer: current and emerging treatment strategies. Drugs 2010; 70: 983. 23. Sartor AO, Oudard S, Ozguroglu M et al: Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: final results of a multinational phase III trial (TROPIC). Presented at the American Society of Clinical Oncology 2010 ASCO Genitourinary Cancers Symposium, San Francisco, California, Mar 5-7, 2010; abstract 9. 24. Diamond TH, Higano CS, Smith MR et al: Osteoporosis in men with prostate carcinoma receiving androgen-deprivation therapy: recommendations for diagnosis and therapies. Cancer 2004; 100: 892. 25. Preston DM, Torrens JI, Harding P et al: Androgen deprivation in men with prostate cancer is associated with an increased rate of bone loss. Prostate Cancer Prostatic Dis 2002; 5: 304. 26. Saad F, Markus R and Goessl C: Targeting the receptor activator of nuclear factor-kB (RANK) ligand in prostate cancer bone metastases. BJU Int 2007; 101: 1071. 27. Smith MR, McGovern FJ, Zietman AL et al: Pamidronate to prevent bone loss during androgendeprivation therapy for prostate cancer. N Engl J Med 2001; 345: 948. 28. Smith MR, Eastham J, Gleason DM et al: Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 2003; 169: 2008. 29. Smith MR, Egerdie B, Hernández Toriz N et al: Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009; 361: 745. 30. Saad F, Gleason DM, Murray R et al: Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone refractory prostate cancer. J Natl Cancer Inst 2004; 96: 879. 31. Sarin J, DeRossi SS and Akintoye SO: Updates on bisphosphonates and potential pathobiology of bisphosphonate-induced jaw osteonecrosis. Oral Dis 2008; 14: 277. 32. Pazianas M, Miller P, Blumentals WA et al: A review of the literature on osteonecrosis of the jaw in patients with osteoporosis treated with oral bisphosphonates: prevalence, risk factors, and clinical characteristics. Clin Ther 2007; 29: 1548. 33. Migliorati CA, Siegel MA and Elting LS: Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment. Lancet Oncol 2006; 7: 508.
Prostate Cancer Update 2011 William J. Catalona, M.D., Course Director; Douglas Dahl, M.D., Robert Nadler, M. D., Staby Loeb, M.D. and Stan Liauw, M. D., Faculty
The purpose of this course was to highlight some of the important epidemiological trends and research in prostate cancer (CaP) which were published during the last year. In 2010 prostate cancer was the most common noncutaneous malignancy in U.S. men, accounting
for 28% of cancers and 11% of cancer deaths.1 The majority of prostate cancers are diagnosed through screening with PSA, which has resulted in a substantial reduction in the prevalence of advanced disease at diagnosis. Furthermore, the age adjusted PSA mortality rate has
decreased by approximately 40% during the PSA era.2 Due to changing population demographics, an increase in years of potential life lost from prostate cancer deaths is projected in the future.3 Correspondingly, there has been major ongoing investigation into different aspects of ▼ Continued on page 7
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prostate cancer care, from chemoprevention and screening to novel diagnostic and treatment modalities.
The Good News In the screening arena new data were reported in 2010 from the Göteborg randomized population based screening trial.4 Consistent with the results of the overall European Randomized Study of Screening for Prostate Cancer,5 a significant mortality benefit with screening was demonstrated. However, with the longer followup in this report (14 years), the magnitude of benefit was much greater as screening led to a 44% relative reduction in CaP mortality and only 12 men needed to be diagnosed to prevent 1 CaP death. Interestingly, a followup study from the previously considered “negative” U.S. PLCO (Prostate, Lung, Colorectal and Ovarian) cancer screening trial also demonstrated a significant 44% lower CaP mortality rate for men in the screening arm with none or 1 comorbid condition.6 As more data on screening continued to mature, several professional organizations published new screening guidelines this past year. The American Cancer Society recommends that asymptomatic men with a life expectancy of 10 years or more should have the opportunity to make an informed decision on prostate cancer screening beginning at age 50 years.7 In contrast, the National Comprehensive Cancer Network recommends offering a baseline screening at age 40 years to assess individual risk that can be used to guide the screening protocol8 as does the the AUA Best Practice Statement.9 Although screening has been shown to save lives, many studies have also examined ways to further improve screening, such as reducing the potential for over diagnosis. For example, PSA velocity was shown to enhance the prediction of life threatening disease beyond that provided by total PSA alone.10 Another adjunctive marker, [-2] proPSA, and a mathematical algorithm called the “prostate health index” (abbreviated “phi”) also correlate
with aggressive CaP.11,12 Additional studies are ongoing to evaluate the role for imaging for the identification of aggressive prostate cancer13 and to develop better predictive tools to use for active surveillance.14 An update of the Swedish randomized trial of radical prostatectomy vs watchful waiting in patients with localized disease was recently reported.15 As in the prior publications, surgery was associated with significant reductions in metastases, prostate cancer mortality and all-cause mortality. Although this study primarily reflects a clinically detected patient cohort, these same benefits of radical prostatectomy were reported in the subset of men with low risk disease. For patients with high risk localized disease, radiation therapy with hormonal therapy (RT/HT) has traditionally been the preferred management option. Indeed, updated studies have confirmed the long-term efficacy of combined RT/HT in high risk disease.16 Nevertheless, an increasing number of studies have shown favorable long-term outcomes with radical prostatectomy for selected men with high risk disease, a strategy that may avoid or delay the need for hormonal therapy in a proportion of patients.17, 18 Also, new 5-year followup data have been published for high frequency ultrasound and cryotherapy.19, 20 The accrual of additional patients and followup will be necessary to fully evaluate and compare these outcomes with traditional management options. The last year also witnessed great strides in the treatment of patients with advanced disease, with the approval of several new drugs for castration resistant prostate cancer. Abiraterone acetate (irreversible inhibitor of androgen biosynthesis), sipuleucel T (immunotherapy) and cabazitazel (chemotherapy) were all shown to benefit patients with CRPC after docetaxel failed.21-23 However, the cost and side effect profiles differ among the agents, and the optimal treatment sequence remains to be determined. Interestingly, even re-treatment with docetaxel (rather than switching to
cabazitaxel) may be associated with partial biochemical or objective responses in some patients with CRPC.24 Several other promising new drugs targeting the androgen receptor axis are in the pipeline, including MDV3100.25
The Bad News Unfortunately, last year witnessed a step backward in terms of efforts at prostate cancer chemoprevention with 5α-reductase inhibitors (5-ARIs). Findings from the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial, in which men were randomized to dutasteride or placebo, revealed that although dutasteride was associated with a reduction in prostate cancer diagnoses overall, it was due entirely to a decrease in Gleason 6 or less cancers.26 In contrast, there were significantly more Gleason 8-10 cancers in the dutasteride arm by year 4 of the study. Following an extensive re-review of data from REDUCE and the earlier PCPT (Prostate Cancer Prevention Trial), the FDA ultimately ruled against the use of 5-ARIs for prostate cancer prevention.27 Their reanalysis of the data suggested that for every 200 men treated with a 5-ARI, there would be 3 fewer Gleason 6 tumors and 1 more Gleason 8-10 cancer. Nevertheless, there is considerable investigation into other potential agents for use in prostate cancer chemoprevention. For example, in a Finnish screening trial of 23,320 participants the incidence of prostate cancer was 38% lower among statin users.28 Other studies revealed lower rates of biochemical failure after radical prostatectomy in statin users.29 However, unlike 5-ARIs, prospective studies have not been performed to evaluate statins as chemopreventive agents. Another negative issue that received considerable attention last year is an apparent increase in complications after prostate biopsy. A large Canadian study reported a dramatic increase in hospitalization rates following prostate biopsy over time, particularly for infectious complications.30 These trends have been attributed largely to increasing fluoroqui▼ Continued on page 8
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nolone resistance,31 prompting investigation into new strategies to increase the safety of prostate biopsy.
Conclusion During the last year significant advances have been made in many aspects of prostate cancer care. Long-term data from randomized studies have confirmed that PSA screening saves lives, radical prostatectomy reduces morbidity and mortality of men with localized disease compared to watchful waiting, and radiation therapy with combined hormonal therapy improves long-term survival of men with high risk localized disease. Other significant advances are the approvals of several new drugs for castration resistant prostate cancer. Despite disappointment in chemoprevention with 5-ARIs, considerable investigation is ongoing into alternative agents such as statins. Overall, as we move forward in 2012, the horizon is much brighter for men at all different stages of prostate cancer. ♦ 1. American Cancer Society. Cancer Facts and Figures 2010. http://www.cancer.org/acs/groups/ content/@epidemiologysurveilance/documents/ document/acspc-026238.pdf. Accessed September 20, 2010. 2. National Cancer Institute Surveillance Research Program SEER*Stat software, 6.2.4 edn. Available at: http://www.seer.cancer.gov/seerstat. Accessed September 20, 2010. 3. Li C and Ekwueme DU: Years of potential life lost caused by prostate cancer deaths in the United States-Projection from 2004 through 2050. Cancer Epidemiol 2010; 34: 368 4. Hugosson J, Carlsson S, Aus G et al: Mortality results from the Goteborg randomised populationbased prostate-cancer screening trial. Lancet Oncol 2010; 11: 725. 5. Schroder FH, Hugosson J, Roobol MJ et al: Screening and prostate-cancer mortality in a randomized
European study. N Engl J Med 2009; 360: 1320. 6. Crawford ED, Grubb R 3rd, Black A et al: Comorbidity and mortality results from a randomized prostate cancer screening trial. J Clin Oncol 2011; 29: 355. 7. American Cancer Society recommendations for prostate cancer early detection. http://www.cancer. org/Cancer/ProstateCancer/MoreInformation/ProstateCancerEarlyDetection/prostate-cancer-earlydetection-acs-recommendations. Accessed May 21, 2011. 8. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. http://www.nccn. org/professionals/physician_gls/pdf/prostate_detection.pdf. Accessed June 25, 2011. 9. Prostate-Specific Antigen Best Practice Statement: 2009 Update. http://www.auanet.org/content/ media/psa09.pdf. Accessed March 21, 2011. 10. Loeb S, Carter HB, Schaeffer EM et al: Distribution of PSA velocity by total PSA levels: data from the Baltimore Longitudinal Study of Aging. Urology 2011; 77: 143. 11. Sokoll LJ, Sanda MG, Feng Z et al: A prospective, multicenter, National Cancer Institute Early Detection Research Network study of [-2]proPSA: improving prostate cancer detection and correlating with cancer aggressiveness. Cancer Epidemiol Biomarkers Prev 2010; 19: 1193. 12. Catalona WJ, Partin AW, Sanda MG et al: A multicenter study of [-2] pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range. J Urol 2011; 185: 1650. 13. Woodfield CA, Tung GA, Grand DJ et al: Diffusion-weighted MRI of peripheral zone prostate cancer: comparison of tumor apparent diffusion coefficient with Gleason score and percentage of tumor on core biopsy. AJR Am J Roentgenol 2010; 194: W316. 14. San Francisco IF, Werner L, Regan,MM et al: Risk stratification and validation of prostate specific antigen density as independent predictor of progression in men with low risk prostate cancer during active surveillance. J Urol 2011; 185: 471. 15. Bill-Axelson A, Holmberg L, Ruutu M et al: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011; 364: 1708. 16. Bolla M, Van Tienhoven G, Warde P et al: External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol 2010; 11: 1066. 17. Loeb S, Schaeffer EM, Trock BJ et al: What are the outcomes of radical prostatectomy for high-risk prostate cancer? Urology 2010; 76: 710.
18. Cooperberg MR, Vickers AJ, Broering JM et al: Comparative risk-adjusted mortality outcomes after primary surgery, radiotherapy, or androgen-deprivation therapy for localized prostate cancer. Cancer 2010; 116: 5226. 19. Donnelly BJ, Saliken JC, Brasher PM et al: A randomized trial of external beam radiotherapy versus cryoablation in patients with localized prostate cancer. Cancer 2010; 116: 323. 20. Crouzet S, Rebillard X, Chevallier D et al: Multicentric oncologic outcomes of high-intensity focused ultrasound for localized prostate cancer in 803 patients. Eur Urol 2010; 58: 559. 21. de Bono JS, Logothetis CJ, Molina A et al: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995. 22. de Bono JS, Oudard S, Ozguroglu M et al: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376: 1147. 23. Kantoff PW, Higano CS, Shore ND et al: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411. 24. Di Lorenzo G, Buonerba C, Faiella A et al: Phase II study of docetaxel re-treatment in docetaxelpretreated castration-resistant prostate cancer. BJU Int 2011; 107: 234. 25. Scher HI, Beer TM, Higano CS et al: Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 2010; 375: 1437. 26. Andriole GL, Bostwick DG, Brawley OW et al: Effect of dutasteride on the risk of prostate cancer. N Engl J Med 2010; 362: 1192. 27. Theoret MR, Ning YM, Zhang JJ et al: The risks and benefits of 5α-reductase inhibitors for prostatecancer prevention. N Engl J Med 2011; 365: 97. 28. Murtola TJ, Tammela TL, Määttänen L et al: Prostate cancer and PSA among statin users in the Finnish prostate cancer screening trial. Int J Cancer 2010; 127: 1650. 29. Hamilton RJ, Banez LL, Aronson WJ et al: Statin medication use and the risk of biochemical recurrence after radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) Database. Cancer 2010; 116: 3389. 30. Nam RK, Saskin R, Lee Y et al: Increasing hospital admission rates for urological complications after transrectal ultrasound guided prostate biopsy. J Urol 2010; 183: 963. 31. Zhanel GG, Hisanaga TL, Laing NM et al: Antibiotic resistance in Escherichia coli outpatient urinary isolates: final results from the North American Urinary Tract Infection Collaborative Alliance (NAUTICA). Int J Antimicrob Agents 2006; 27: 468.
The Role of Radical Prostatectomy and Pelvic Lymph Node Dissection in an Integrated Treatment Program for High Risk Prostate Cancer Peter T. Scardino, M.D. Director; Vincent P. Laudone, M. D., Faculty
The optimal role of surgical intervention in the treatment of prostate cancer continues to evolve. The growing recognition that active surveillance is a viable
option for select patients with low risk, low volume disease, as well as evidence from studies such as the PIVOT (Prostate Cancer Intervention Versus Observation
Trial) reported at this year’s annual AUA meeting suggest that the benefit of surgery may be greatest in those men with more aggressive disease. Traditionally, urolo▼ Continued on page 9
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gists have recommended radiotherapy with androgen deprivation therapy over radical prostatectomy (RP) for men with high risk disease, not because oncologic outcomes were better with radiotherapy, but because rates of incontinence and erectile dysfunction with RP were high and cure rates were discouraging. More recently, risk stratification schemes that more accurately predict disease extent have improved our ability to appropriately select patients for treatment. Radical prostatectomy and pelvic lymph node dissection (PLND) effectively treat high risk prostate cancer either alone or as part of integrated multimodality strategy. Surgery allows early use of adjuvant or salvage radiation therapy for improved local control, and the long-term outcomes are at least as good if not better than primary radiation therapy with hormones. Maximizing the appropriate outcomes in these high risk patients requires a thorough understanding of the indications for RP as well as a particular emphasis on the specific surgical techniques that must be incorporated into either an open or minimally invasive surgical approach. Consensus recommendations for the identification and treatment of organ confined prostate cancer with high risk features are lacking. Ideally, such a definition would reliably distinguish patients whose cancer is curable with local therapy alone from those who already harbor micrometastases at diagnosis and, therefore, whose disease is not amenable to cure by localized treatment. Although terms such as “locally advanced” and “poorly differentiated” are often used as synonyms for high risk disease, no single criterion adequately identifies cancers with a high probability of progression after local treatment. While clinical stage, biopsy results and pretreatment prostate specific antigen as individual variables each provides some prognostic information, the combination of these variables markedly increases the ability to predict treatment outcome. For many risk-grouping strategies, patients are classified into 1 of 3 risk groups
based on predefined levels for 1, 2 or all 3 of these variables. Grouping together patients with similar but not identical risk features in this way obscures the fact that individuals within each group actually have varying risks of recurrence. A preferable strategy is to use multivariable models such as nomograms to calculate individual risk. These models incorporate data from all risk factors relevant to the probability of treatment failure and proportionately weigh their relative contribution to calculate a risk score for each individual. Nomograms are more accurate than a risk-group approach and can incorporate additional information such as biopsy core data. This feature makes them the best method currently available for estimating pathological stage and prognosis, and for making informed decisions on treatment strategies and enrollment in clinical trials. After RP, the majority of men, regardless of the definition of high risk disease, remain free of clinical metastasis more than 10 years later. Followup information on 11,521 patients treated with RP at 4 academic centers from 1987 to 2005 demonstrated an overall 15-year prostate cancer specific mortality (PCSM) rate of only 7%.1 A nomogram predicting 15-year PCSM based on standard pathological parameters was accurate and discriminating with an externally validated concordance index of 0.92. For organ confined cancer, extraprostatic extension, seminal vesicle invasion and lymph node metastasis, the 15-year PCSM risk was 0.8% to 1.5%, 2.9% to 10%, 15% to 27% and 22% to 30%, respectively. Less than a third of patients will die of prostate cancer within 15 years of RP even in the presence of highly adverse pathological features. The goals of RP, regardless of the surgical technology or approach, are to remove the cancer completely with negative surgical margins, minimal blood loss, no serious perioperative complications, and complete recovery of potency and urinary continence. From an oncologic standpoint, when dealing with high risk patients, the issues of lymph node
involvement and surgical margin status are of critical importance. Evidence from long-term followup of large series of patients undergoing RP has suggested a therapeutic benefit from PLND, particularly in those with a low burden of cancer in the pelvic lymph nodes. During the short term, biochemical recurrence-free rates of better than 75% can be achieved with proper lymph node dissections in patients with limited nodal disease and, for up to a third of these patients, this result is durable for the long term.2 Unwarranted controversy exists regarding the appropriate extent of the PLND. Lymphatic drainage of the prostate is known to be highly variable and involves regions not sampled during a limited (external iliac) PLND. Nodal metastases will be detected exclusively in areas outside the boundaries of a limited template and up to 60% of node positive cases will be missed with a limited dissection. A thorough “standard” PLND should be performed in all patients with high risk features and must include the external iliac, hypogastric and obturator node packets. Of men at our institution with a preoperative nomogram risk of 2% or greater for lymph node involvement (70% of surgical patients) 14% will have positive nodes. Of major concern is a report that men treated with open RP were at least 5 times more likely to undergo lymphadenectomy vs men treated with laparoscopic or robotic RP, even after controlling for patient and tumor characteristics.3 Performing a proper PLND does require an added degree of technical proficiency and will increase the operative duration, but these facts do not justify forgoing this part of the operation in the surgical treatment of high risk cancer regardless of approach. Obtaining negative surgical margins is critically important. A positive surgical margin has been associated with as much as a fourfold higher risk of biochemical recurrence, even after adjusting for other prognostic factors such as Gleason grade, extracapsular extension, seminal vesicle invasion and lymph node metastasis. Furthermore, of all the adverse patho▼ Continued on page 10
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logical features status of the surgical margins is the only one that can be influenced by the surgical technique. In men with high risk cancer avoiding a positive margin while preserving the neurovascular bundles may be challenging, as large tumors tend to abut the prostatic capsule along the posterolateral surface area. Dissection of the neurovascular bundles is rarely an all-or-none phenomenon. Even in a patient with a high risk of extraprostatic extension a portion of the neurovascular bundle can often be preserved and is likely preferable in terms of functional recovery compared to complete nerve resection and graft placement. Use of endorectal magnetic resonance imaging along with predictive models developed to identify patients at high risk for neurovascular bundle involvement allows surgeons to choose a proper plane of dissection in an individual based on tumor location and extent. Dissection beneath Denonvilliers’ fascia posteriorly should be performed routinely, as few nerves are present in this area and deep dissection will reduce the incidence of positive posterolateral margins. While blunt dissection is quicker, it is discouraged because it frequently leaves all or part of Denonvilliers’ fascia
on the rectum rather than the prostate, thus increasing the likelihood of positive posterior margins. For high risk cancers located posteriorly, this dissection beneath Denonvilliers’ fascia can be further extended to keep perirectal fat on the prostate as well. When done robotically, this is most readily accomplished using a posterior approach to the seminal vesicles. High grade cancers near the base of the prostate or in the anterior transition zone often invade the bladder neck. Maintaining a generous margin of bladder neck tissue by dividing the bladder neck a centimeter or more from its junction with the prostate helps reduce the risk of a positive margin in this area. Long-term urinary continence is not improved by preservation of the bladder neck, which risks positive margins even in intermediate risk cancers. Finally, careful division of the dorsal vascular complex is paramount to avoid dissection into the apex. This step is particularly important with open surgery as it also reduces bleeding, facilitating visualization during the remainder of the procedure. With a laparoscopic/robotic approach, transection of the dorsal vascular complex and apex is often left until the end of the dissec-
tion. Using the pneumoperitoneum as a tamponade, the complex can be divided without initial ligation. This allows the surgeon to select the precise point of transection and conform the dissection to the apical anatomy without being restricted by a previously placed ligature. These steps have allowed us to keep the rate of positive margins below 20% in pT3 cancers at our institution. The role of RP in high risk patients is expanding with the understanding that they do not uniformly have a poor prognosis and that surgery provides oncologic outcomes similar to or better than other treatment options. Surgery must be tailored to the particular anatomy and risk profile of the individual. Surgery can be performed by an open or laparoscopic/ robotic approach with equivalent results, but only if proper oncologic principles and surgical techniques are used. ♦ 1. Eggener SE, Scardino PT, Walsh PC et al: Predicting 15-year prostate cancer specific mortality after radical prostatectomy. J Urol 2011; 185: 869. 2. von Bodman C, Godoy G, Chade DC et al: Predicting biochemical recurrence-free survival for patients with positive pelvic lymph nodes at radical prostatectomy. J Urol 2010; 184: 143. 3. Feifer AH, Elkin EB, Lowrance WT et al: Temporal trends and predictors of pelvic lymph node dissection in open or minimally invasive radical prostatectomy. Cancer 2011; Epub ahead of print.
Update on AUA Cancer-Related Guidelines: Preparation for Certification Sam Chang, M.D., Course Director; Peter Clark, M.D. and Daniel Lin, M.D., Faculty
Although this course covered different urological malignancies, we will focus on prostate cancer related highlights of our course which attempted to synthesize key diagnostic and treatment related issues for the practicing clinician. The 2007 AUA Guideline for the Management of Clinically Localized Prostate Cancer addressed the management of organ confined prostate cancer at the time of diagnosis and, thus, was restricted to those patients with clinical stage T1 or T2 disease.1 Specifically there was
no discussion of patients with suspected extraprostatic disease (clinical T3 disease or higher), local regional spread to the pelvic lymph nodes or systemic metastases. This guideline also did not address patients in whom disease recurred after failed primary therapy. Due to a lack of sufficient supporting evidence at that time, the panel elected not to include within the guideline cryotherapy, high intensity focused ultrasound, high dose rate interstitial brachytherapy or primary androgen deprivation therapy. The thera-
peutic options that are discussed include active surveillance (AS), radical prostatectomy, external beam radiation therapy (EBRT) and low dose rate brachytherapy. The first Standard applicable to all patients is that before initiating therapy, life expectancy, overall health status and tumor characteristics must be considered. Across all risk strata there is no convincing evidence to demonstrate the clear superiority of any single therapeutic modality over another. Estimates of ▼ Continued on page 11
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benefit and harm for each intervention and consideration should include patient preferences and health conditions related to urinary, sexual and bowel function. For patients who choose AS, the aim and goals of any second line therapy should be determined in advance so that followup may be tailored appropriately. Across all risk strata it is important to remember that the panel called for randomized, controlled trials to answer key management questions. In addition, the various techniques of RP and EBRT are not stratified, and the indications, followup and definitions of progression for AS are not elucidated. The panel did offer some specific conclusions from randomized controlled trials for each risk stratum. Thus, for patients in the lower risk stratum (PSA 10 ng/ml or less, Gleason score 6 or less and clinical stage T1c or T2a) considering EBRT, higher dose radiation may decrease the risk of PSA recurrence.2 In addition, when compared to watchful waiting, RP may lower disease recurrence, cancer specific death and overall risk of death.3 For patients with intermediate risk disease (PSA 10 to 20 ng/ml, Gleason score 7 or clinical stage T2b) who are considering EBRT, 6 months of combined hormonal therapy with EBRT may prolong survival.4 Finally, in high risk patients (PSA greater than 20 ng/ml, or Gleason score 8 or greater, or stage T2c or higher) considering EBRT, 2 to 3 years of combined hormonal therapy with EBRT may prolong survival.5 This panel also stated that first line hormone therapy for patients with clinically localized prostate cancer is seldom indicated except for those symptomatic patients with locally advanced and/or poorly differentiated cancer whose life expectancy is too short to benefit from attempts at curative treatment. Finally, the panel called for more patients to be enrolled in clinical trials in order to answer the critical management questions in this patient population. Shortly after this guideline was published, the AUA released a Best Practice Policy addressing the use of cryotherapy
for prostate cancer.6 The policy indicated that recent improvements in cryotherapy have been critically dependent on several advances including the use of argon based systems, better thermocouples to monitor temperature and use of urethral warming devices. The principles of treatment included rapid freezing is better than slow freezing, the use of thermocouples is strongly encouraged, the appropriate nadir temperature is -40C, slow/passive thaw is better than active/ fast thaw and a double freeze-thaw cycle is recommended. The panel reported that cryotherapy was an option when treatment was appropriate in men with organ confined disease. Nevertheless, some consideration should be given to gland size since larger glands are more difficult to treat and prior transurethral resection of the prostate is a relative contraindication to cryotherapy. In addition, for patients at high risk, a lymph node evaluation should be performed and for patients being considered for salvage cryotherapy after failed radiation, treatment is best done in those with biopsy proven recurrence, PSA less than 10 ng/ml and no evidence of seminal vesicle involvement. The panel acknowledged that there is no consensus on a definition of biochemical failure, making estimations of long-term efficacy difficult. This is further complicated by a lack of data on long-term metastasis-free or disease specific survival. Complication rates have been substantially lowered using modern techniques, although erectile dysfunction remains a common problem after cryotherapy. The panel called for enrolling patients undergoing cryotherapy into prospective trials to verify the promising, but early, outcomes data presently available. In 2009 the American Urological Association released an update of the PSA Best Practice Policy originally reported in 2000.7 The purpose of the update was to provide current information on the use of PSA testing 1) for evaluation of men at risk for prostate cancer, 2) for risks and benefits of early detection, 3) for assistance in pretreatment staging
or risk assessment, 4) for posttreatment monitoring and 5) as a guide in management of recurrent disease after primary or secondary therapy. We discuss the notable differences in the current policy.
Use of PSA for Early Detection of Prostate Cancer The goal of early prostate cancer detection is to decrease morbidity and mortality. While 2 recent trials reported different results with regard to the impact of prostate cancer screening on mortality, both suggest that prostate cancer screening leads to over detection and overtreatment of some patients.8, 9 Therefore, the AUA strongly supports that men be informed of the risks and benefits of prostate cancer screening before biopsy, and the option of active surveillance in lieu of immediate treatment for some men with newly diagnosed prostate cancer. Men who wish to be screened for prostate cancer should undergo PSA testing and digital rectal examination (DRE). A variety of factors can affect PSA levels, eg prostatitis, benign prostatic hyperplasia and medications, and should be considered in the interpretation of results. While several modifications of PSA have been proposed and put into practice, eg free/total PSA ration, age adjusted PSA, PSA density and PSA velocity, because of potential tradeoffs between sensitivity and specificity, there is no consensus on optimal strategies for using the different PSA modifications. Importantly, the current policy no longer recommends a single, threshold value of PSA to prompt prostate biopsy. Rather, the decision to proceed to prostate biopsy should be based primarily on PSA and DRE results but multiple factors, including free and total PSA, patient age, PSA velocity, PSA density, family history, ethnicity, prior biopsy history and comorbidities, should also be considered. Thus, the decision to use PSA for the early detection of prostate cancer should be individualized. Lastly, early detection and risk assessment of prostate cancer should be offered to asymptomatic men who wish to be screened and who are 40 â–ź Continued on page 12
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years old or older with an estimated life expectancy of more than 10 years.
Use of PSA in Posttreatment Management of Prostate Cancer
Use of PSA for Pretreatment Staging of Prostate Cancer
Periodic PSA determinations should be offered to detect disease recurrence. For example, serum PSA should decrease and remain at undetectable levels after radical prostatectomy. The AUA defines biochemical recurrence as PSA 0.2 ng/ml or less followed by a subsequent confirmatory PSA of the same value. Similarly, serum PSA should decrease to a low level after radiation therapy, high intensity focused ultrasound and cryotherapy with no successive increases. The precise definition of PSA failure after radiotherapy has been controversial. The American Society for Therapeutic Radiation and Oncology definition of failure is 3 successive increases above nadir level, while the Phoenix definition is PSA 2.0 ng/ml or greater above the nadir that predicted true failure with greatest sensitivity and specificity. Upon PSA failure, the kinetics of PSA increase (ie PSA doubling time) can help distinguish between local and distant recurrence. For patients with PSA failure after surgery or radiation for localized prostate cancer, the absolute PSA to trigger a bone scan is uncertain. For advanced disease, the PSA nadir after
In general, serum PSA levels correlate with the stage of prostate cancer and the response to all forms of therapy. Routine use of a bone scan is not required for staging asymptomatic men with clinically localized prostate cancer and PSA 20.0 ng/ml or less. As metastatic disease is significantly more common in cases of locally advanced or high grade disease, it is reasonable to consider bone scans at the time of diagnosis when the patient has Gleason 8 or greater, or stage T3 or greater disease, even with PSA less than 10.0 ng/ml. Similarly, computerized tomography or magnetic resonance imaging may be considered for staging of disease in men with high risk, clinically localized prostate cancer when the PSA is greater than 20.0 ng/ml, disease is locally advanced or Gleason score is 8 or greater. Lastly, pelvic lymph node dissection for clinically localized prostate cancer may not be necessary when PSA is less than 10.0 ng/ml and Gleason score is 6 or less.
initiation of androgen deprivation therapy predicts mortality, and PSA kinetics at the time of castrate resistant disease further predict prostate cancer specific mortality. ♦ 1. Thompson I, Thrasher JB, Aus G et al: Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol 2007; 177: 2106. 2. Zietman AL, DeSilvio ML, Slater JD et al: Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA 2005; 294: 1233. 3. Bill-Axelson A, Holmberg L, Ruutu M et al: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005; 352: 1977. 4. D’Amico AV, Manola J, Loffredo M et al: 6-Month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA 2004; 292: 821. 5. Bolla M, Collette L, Blank L et al: Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002; 360: 103. 6. Babaian RJ, Donnelly B, Bahn D et al: Best practice statement on cryosurgery for the treatment of localized prostate cancer. J Urol 2008; 180: 1993. 7. Greene KL, Albertsen PC, Babaian RJ et al: Prostate specific antigen best practice statement: 2009 update. J Urol 2009; 182: 2232. 8. Andriole GL, Crawford ED, Grubb RL 3rd et al: Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009; 360: 1310. 9. 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.
Late Breaking News: Denosumab to Prevent Bone Metastases (Dmab 147 Study) Matthew R. Smith, M.D., Ph.D., Department of Hematology-Oncology, Massachusetts General Hospital, Boston, Massachuetts
(Reprinted from AUA Daily News 2011; Wednesday, p. 1) A new randomized, controlled phase III trial reported at Tuesday’s Plenary Session found that denosumab, a novel RANK ligand inhibitor, significantly improved bone metastasis-free survival in men with castrate resistant prostate cancer (CRPC). “This is the first large, randomized trial to demonstrate that targeting the bone microenvironment prevents bone
metastasis in men with prostate cancer,” said Matthew R. Smith, M.D., Ph.D., Associate Professor of Medicine at Harvard Medical School and Director of the Genitourinary Malignancies Program at the Massachusetts General Hospital Cancer Center, Boston. “Compared to placebo, denosumab significantly increased bone metastasis-free survival, time to first bone metastasis and time to symptomatic bone metastasis. Overall rates of adverse events were similar between the groups. Hypocalcemia and osteonecrosis of the
jaw, the known adverse effects of denosumab, were frequently observed,” Dr. Smith said. “Based on the results of this global randomized, controlled trial, we conclude that denosumab is a potentially new and important treatment option for men with castrate resistant prostate cancer,” he added. The study, known as Dmab 147, compared the treatment effect of denosumab with placebo on prolonging bone metastasis-free survival in 1,432 men with hormone refractory, ▼ Continued on page 13
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or castrate resistant, prostate cancer and rapidly rising prostate specific antigen (PSA) levels who had no bone metastases at baseline. The primary end point of the trial was time to first occurrence of bone metastasis or death from any cause, with secondary end points including time to first occurrence of bone metastasis (excluding death) and overall survival. “Bone metastases are common in men with advanced prostate cancer and represent a major cause of morbidity and mortality. Bone metastases result in significant health and economic burdens,” Dr. Smith said.“There have been meaningful advances in the management of metastatic, castrate resistant prostate cancer, including new chemotherapy, immunotherapy and androgen inhibitors. To date, however, no therapy has been shown to be effective in delaying the development of bone metastases in men with non-metastatic CRPC. Prevention of bone metastasis, therefore, represents an important unmet medical need,” he added. “The development of bone metastasis involves reciprocal interactions between tumor cells and bone, the socalled vicious cycle of bone metastasis. Denosumab is a human monoclonal antibody that binds and activates the RANK ligand, a key mediator of osteoclast differentiation and survival,” Dr. Smith explained.“Denosumab is superior to zoledronic acid for the prevention of skeletal negative events in men with CRPC and bone metastasis, and is
approved for use in this setting,” he said. The Dmab 147 study included men with castrate resistant prostate cancer who were at high risk for bone metastasis based on a PSA serum concentration less than 50 ng/ml and/or a PSA doubling time of less than 10 months. The median age of the patients was 74 years, and the median time from prostate cancer diagnosis to study entry was 6.1 years. Denosumab treatment was discontinued if bone metastases developed. About 42 percent of the patients in the placebo group and 35 percent of patients in the denosumab group developed bone metastases. “The median bone metastasis-free survival was 25.2 months in the placebo group and 29.5 months in the denosumab group,” Dr. Smith said. “The difference in median bone metastasisfree survival between the groups was 4.2 months.” The median time to first bone metastasis was 29.5 months in the placebo group and 33.2 months in the denosumab group. Overall survival was similar between the denosumab and placebo groups. The median overall survival time in both groups was approximately 44 months. The study investigators defined progression-free survival as freedom from bone metastasis and investigator determined progression. “Compared with placebo, denosumab tended to improve the overall progression-free survival, with a hazard ratio of 0.89 and a p value of 0.93,” Dr. Smith said. “The most common adverse events
were distributed equally between the placebo and denosumab groups,” he continued. “Hypocalcemia and osteonecrosis of the jaw are recognized adverse events with denosumab and other osteoclast targeted therapies, and as expected, we observed higher rates of these conditions in the denosumab treated subjects. Among men who received denosumab, 12—or 1.7 percent—had hypocalcemia and 33—or 4.6 percent—experienced osteonecrosis of the jaw.” The risk factors for osteonecrosis of the jaw include prior tooth extraction and poor dental hygiene. “Most of these cases were managed conservatively, and only two subjects required bone resection. As of February 2011, 13 cases—or 39 percent—had resolved,” Dr. Smith said. The RANK ligand pathway, first discovered in the mid 1990s, is believed to play a central role in cancer induced bone destruction, regardless of cancer type. Data suggest that in bone metastasis cancer invasion is facilitated by bone destruction. Hence, increased bone resorption due to increased RANK ligand expression appears to augment bone metastasis. Denosumab prevents the RANK ligand from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and halting the release of growth factors, making the environment less conducive to tumor growth, according to the drug’s manufacturer. ♦
2011 Highlights from Podium/Poster Sessions: Prostate Cancer Thomas J. Guzzo, M.D., MPH, Department of Surgery, Division of Urology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
The prostate cancer highlights from this year’s poster and podium sessions were presented on May 18, 2011 at the AUA Annual Meeting in Washington, DC. There were a number of fantastic studies presented throughout the meeting and I would encourage the readers to browse the abstracts in the Program Abstract Supplement to the April issue
of The Journal of Urology® (http://www. aua2011.org/abstracts/abstracts.cfm) for more detailed information about the presentations mentioned here as well as those that could not be included in this highlights due to space and time limitations. Vickers et al from Memorial SloanKettering Cancer Center presented
“Individualized Estimation of the Benefit of Radical Prostatectomy: Data from the SPCG4” (abstract 1783). They evaluated data from 650 men with prostate cancer in the SPCG4 study who were randomized to either radical prostatectomy (RP) or watchful waiting. Risk scores were modeled using Gleason grade, clinical stage and prostate specific antigen. The ▼ Continued on page 14
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risk scores and patient age were included in competing risk models to predict metastasis or death in each treatment group. A total of 250 deaths occurred during the study period, of which 115 were related to prostate cancer. In older men radical prostatectomy was associated less with a reduction in risk of death from prostate cancer independent of stage and grade. Younger men with more aggressive disease experienced a larger reduction in absolute risk of prostate cancer death with radical prostatectomy than older men with a lower risk disease. For example, using the authors’ model, the 10-year risk of death from prostate cancer was reduced by surgery from 24% to 9% for a 60-yearold man with Gleason score 7, stage T2 prostate cancer. The authors concluded that based on this model it is difficult to justify surgery in patients with clinical stage T1, Gleason 6 tumors or in those older than 70 years. A multi-institutional study was described by Khurana et al from The Cleveland Clinic entitled “Overall Survival and Prostate Cancer-Specific Mortality Among Contemporary Men with Screen-Detected, Localized Prostate Cancer Managed by Active Surveillance Versus Definitive Local Therapy” (abstract 1460). In this retrospective analysis the authors presented data on more than 8,000 men with clinically localized prostate cancer treated with radical prostatectomy, external beam radiation, brachytherapy or active surveillance between 1996 and 2007. Multivariable Cox regression, and Fine and Gray competing risk regression were used to measure the association between initial treatment strategy, and prostate cancer specific mortality and overall survival in
this cohort. Of the active surveillance and treated patients 67.3% and 49.6%, respectively, had low risk disease as defined by D’Amico criteria. Median followup was 47 and 74 months for the active surveillance and treatment groups, respectively. On multivariable analysis active surveillance was not associated with an increased risk of prostate cancer specific mortality compared to that of definitive therapy (HR 0.8, p=0.7). Of note, external beam radiation (HR 2.2, p <0.001) and brachytherapy (HR 2.0, p <0.001) were associated with worse survival. In this retrospective study active surveillance was not associated with an inferior overall survival or prostate cancer specific mortality compared to that of patients undergoing definitive local therapy. Such results are encouraging for properly selected active surveillance patients with low risk prostate cancer, although less than 20% of the patients in the active surveillance arm of this study had 10 years or more of followup and, therefore, longer term data are needed to validate these results. Ross et al from The Johns Hopkins Medical Institutions presented “Effects of 5-Alpha-Reductase Inhibitor Use in Monitored Men with Very Low Risk Prostate Cancer” (abstract 1638). Patients in a large active surveillance program were evaluated to determine the influence of 5α-reductase inhibitor (5-ARI) use and the risk for Gleason grade progression or increased cancer volume at the time of annual surveillance prostate biopsy. The authors also evaluated 587 men with low risk prostate cancer who did not have a history of 5-ARI use before enrolling in their active surveillance program. The primary outcome was reclassification by
biopsy upgrade only and not patient preference to come off of active surveillance. A total of 47 men in this cohort started a 5-ARI during the study period with a mean time on the medication of 2.4 years. Using multivariate proportional hazard models in which the time of 5-ARI initiation and duration of use were accounted for, the authors observed no significant reduction in the risk of biopsy reclassification overall (HR 0.55, p=0.164) by the presence of Gleason grade 4 or greater on biopsy (HR 0.8, p=0.7) or increased tumor extent (HR 0.37, p=0.08). Importantly, if the timing and duration of drug exposure were not accounted for, 5-ARI use artificially appeared to reduce the risk of disease progression. Spahn et al discussed “Micro-RNA-221 is a Strong and Independent Predictor of Clinical Progression and CancerSpecific Survival in High-Risk Prostate Cancer” (abstract 1630). They evaluated 214 patients with preoperative high risk prostate cancer (PSA greater than 20, cT3/T4, Gleason score 8-10) treated with radical prostatectomy and pelvic lymph node dissection to determine the association between micro-RNA (miRNA)-221 and prostate cancer specific survival. Median followup was 82 months. MiRNA-221 down-regulation was associated with worse cancer specific survival on multivariable analysis. This study demonstrates the potential usefulness of biomarkers such as miRNA-221 in selecting patients with high risk prostate cancer for multimodal treatment, and may represent a potential treatment target in this patient population. ♦
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Ramon Guiteras Lecture: Early Diagnosis of Prostate Cancer through PSA Testing Saves Lives William J. Catalona, M.D., Department of Urology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
There would be no point in early prostate cancer (PC) detection if there were no effective treatment. The study on the long-term results of a Swedish randomized trial of radical prostatectomy versus watchful waiting (WW) for early PC shows that RP can reduce metastases and PC deaths, and increase overall survival.1 Accumulating evidence shows that PSA screening can reduce PC deaths. The “holy grail” of screening is the randomized trial. In the initial report from the ERSPC (European Randomized Study of Screening for Prostate Cancer ) 40% of screened men had less advanced PC at diagnosis and a 20% lower PC death rate.2 Not surprisingly, the benefit was observed largely in men younger than 70 years. However, the sobering estimate that the number needed to treat (NNT) to prevent 1 prostate cancer death (48) raised eyebrows. The risk of dying of PC is influenced by life expectancy. Therefore, the NNT to save 1 life is influenced by patient age, health, duration of screening and the length of followup of the trial. The NNT is lower in younger, healthier men and in trials that continue screening and have longer followup. The PC mortality curves of the ERSPC were reported at 9 years of followup, just as the curves began to separate. Schröder reported at the 2011 AUA Meeting that at 12 years of followup the NNT in the ERSPC had decreased from 48 to 12. The PLCO (Prostate, Lung, Colorectal, Ovarian) cancer screening trial initially reported results for all enrollees– young and old, healthy and not so healthy –and concluded “…we now know that PC screening provided no reduction in death rates at 7 years…” These 2 trials have been interpreted as conflicting but a subsequent data analysis of healthier PLCO participants revealed a far different result. There was a 44% mortality
benefit in screened PLCO participants with minimal or no comorbidities and the NNT to save 1 life was 5.4 The Norrkoping trial was also widely publicized as being a negative screening trial.5 However, this trial has important limitations, such as only 85 screen detected PC cases, screening was performed every 3 years with the first 2 screens involving only digital rectal examination (DRE), fine needle aspiration cytology was used for PC diagnosis, median age of patients with PC was nearly 70 years, median followup of patients with PC was only 6 years, and nearly half of the screen detected cases were managed with WW, while only a third were treated with RP. Nevertheless, Norrkoping data provide considerable support for screening as screened men had far fewer advanced tumors at diagnosis, a strong trend for better PC specific survival (p = 0.065) and a lower risk ratio for PC death (p= 0.024). The screening trial with the best methodology is the Göteborg trial.6 Unlike either PLCO or ERSPC, it is population based. Participants were younger, with 20,000 men 50 to 64 years old. It is cleaner with a contamination rate, ie opportunistic prostate specific antigen screening of controls, of only 3% when the trial started in contrast to 15% in ERSPC and 40% to 50% in PLCO. Screening occurred every 2 years with progressively lower PSA cutoffs over time (3.4 to 2.5 ng/ml). Moreover, 93% of patients had a biopsy when they had an abnormal screening test (only 40% of PLCO participants underwent prompt biopsies). In Göteborg 77% of patients had 14 years of followup. Of the screened participants 41% fewer presented with advanced disease and they had a 44% lower PC death rate. The NNT was 12, comparing favorably with NNT of 10 for breast cancer.
What epidemiological evidence suggests that PSA screening saves lives? In the SEER (Surveillance and End Results)-Medicare database there has been a 75% decrease in metastatic disease at diagnosis during the PSA era and a 40% decrease in the age-adjusted PC death rate.7 In 1992 there were 131 million U.S. males and the age-adjusted PC mortality rate was 39.2/100,000 males, accounting for more than 51,000 PC deaths. By 2007, the population had grown to 149 million men but the ageadjusted PC mortality rate decreased from 39.2 to 23.5, which amounts to about 35,000 fewer PC deaths. Thus, 17,000 fewer men died of PC in 2007 than in 1992, the beginning of the PSA era. What would have happened if the PC mortality rate had not decreased during the PSA era? From 1990 to 2007 the male population increased from 122 to 151 million. If the PC death rate had remained at 39, there would have been 59,000 PC deaths in 2007 rather than 35,000. Thus, there actually occurred 24,000 fewer PC deaths than there would have been had the PC mortality rate not decreased. Envision a basketball arena with 24,000 people in attendance, which is the number of men who would have died of PC in a single year if the death rate had not decreased during the PSA era. Does PSA screening deserve credit for the decreasing PC death rate? In a study conducted by teams from the National Cancer Institute (NCI) modeling network 45% to 70% of the PC mortality benefit was attributed directly to PSA screening.8 In the rest of the world similar trends have been observed in countries where PSA screening is widespread but not in those where it is not practiced.9 In the 5 Nordic countries, coinciding with the introduction of PSA, there was a rapid ▼ Continued on page 16
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increase in PC incidence during the early 1990s, except in Denmark where they were slow to adopt PSA screening. In Denmark PSA screening occurred 5 years later. PC death rates stabilized or declined in the 4 countries where PSA testing was adopted but continued to increase in Denmark.10 In Tyrol, Austria regular PSA testing was available to the public at no cost but not elsewhere in Austria. In Tyrol there has been a 54% reduction in PC deaths during the PSA era vs a 29% decrease in the rest of Austria.11 Only about 6% of men are screened in Northern Ireland. Comparing these Irish men to the 94% in the screening arm of the ERSPC, the PC death rate was 37% lower in the ERSPC.12 The extent to which PSA screening causes over diagnosis and overtreatment is exaggerated. The widely quoted epidemiological estimate that 66% of all PC cases are over diagnosed is derived from the statistical model and data from Rotterdam. In a study, also involving the NCI modeling network teams from Michigan and Seattle and using their statistical models with the U.S. SEER data, the estimated over diagnosis rate was 23% to 28%.13 Using surgical pathology criteria, the rates of over diagnosis are even lower. In fact, there is more under diagnosis of PC than over diagnosis in patients treated with RP.14, 15 Recently, there has been a virtual tsunami of anti-PSA screening articles in newspapers, magazines, medical journals, newscasts and on the Internet, which discourage men from PSA screening16 and which I believe does a disservice to the public. Screening is necessary to give patients the full range of treatment options at the earliest possible time. It is not necessary to treat aggressively every man diagnosed with PC to save lives. In the Göteborg trial WW was used in 28% of the screened patients and they still achieved a 44% lower PC death rate by treating those who needed active treatment.6
The US Preventive Services Task Force (USPSTF) is a government agency, and its panel is now reviewing PC screening recommendations. The previous USPSTF panel included no urologist or medical oncologist. In 2008 they concluded that there was insufficient evidence to recommend for or against PSA screening in men older than 75 years but recommended that those men should not be screened.17 On the other hand, the AUA18 and the American Cancer Society19 have adopted cautiously positive recommendations for PC screening, and the National Comprehensive Cancer Center Network has produced guidelines to help physicians implement screening in men who have decided they want to be screened.20 However, with the USPSTF and other organizations claiming there is insufficient evidence, the medical community has become polarized, and patients and physicians have become confused. Several current guidelines suggest that men with a 10-year life expectancy should have an informed discussion of the benefits and risks of PSA screening. If they decide to be screened, a baseline PSA and DRE should be performed at age 40 years to assess individual risk. If the risk is high (ie strong family history of PC, African-American race, baseline PSA greater than 1 or PSA velocity greater than 0.35 ng/ml per year), annual screening is indicated. If the risk is average, repeat screening is recommended at age 45 years and then, if it remains average, annual screening begins at age 50 years.20 Urologists should try to educate our primary care physician colleagues and patients that PSA screening performed intelligently will save lives. Thus, the bottom line is that we should encourage screening because it will give men more time to spend with their families, listen to the music, sail their boats and smell the roses. ♦ 1. Bill-Axelson A, Holmberg L, Ruutu M et al: Radical prostatectomy versus watchful waiting in early
prostate cancer. N Engl J Med 2011; 364:1708. 2. 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. 3. Andriole GL, Crawford ED, Grubb RL 3rd et al: Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009; 360: 1310. 4. Crawford ED, Grubb R III, Black A et al: Comorbidity and mortality results from a randomized prostate cancer screening trial. J Clin Oncol 2010; 29: 355. 5. Sandblom G, Varenhorst E, Rosell J et al: Randomized prostate cancer screening trial: 20 year follow-up. BMJ 2011; 342: d1539 6. Hugosson J, Carlsson S, Aus G et al: Mortality results from the Göteborg randomized populationbased screening trial. Lancet Oncol 2010; 11:725. 7. FastStats: Age-adjusted U.S. mortality rates by cancer site: all ages, all races, male, prostate 1992-2007. Mortality source: U.S. Mortality Files. National Center for Health Statistics, DCD. http:// www.seer.cancer/gov. Accessed September 8, 2010. 8. Etzioni R, Tsodikov A, Mariotto A et al: Quantifying the role of PSA screening in the US prostate cancer mortality decline. Cancer Causes Control 2008; 19:175. 9. Bouchardy C, Fioretta G, Rapiti E et al: Recent trends in prostate cancer mortality show a continuous decrease in several countries. Int J Cancer 2008; 123: 421. 10. Kvale R, Auvinen A, Adami HO et al: Interpreting trends in prostate cancer incidence and mortality in the five Nordic countries. J Natl Cancer Inst 2007; 99:1881. 11. Bartsch G, Horninger W, Klocker H et al: Tyrol Prostate Cancer Demonstration Project: early detection, treatment, outcome, incidence and mortality. BJU Int 2008; 101: 809. 12. van Leeuwen PJ, Connolly D, Gavin A et al: Prostate cancer mortality in screen and clinically detected prostate cancer: estimating the screening benefit. Eur J Cancer 2010; 46: 377. 13. Draisma G, Etzioni R, Tsodikov A et al: Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context. J Natl Cancer Inst 2009; 101: 374. 14. Graif T, Loeb S, Roehl KA et al: Under diagnosis and over diagnosis of prostate cancer. J Urol 2007; 178: 88. 15. Pelzer AE, Bektic J, Akkad T et al: Under diagnosis and over diagnosis of prostate cancer in a screening population with serum PSA 2 to 10 ng/ml. J Urol 2007; 178: 93. 16. Zeliadt SB, Hoffman RM, Etzioni R et al: Influence of publication of US and European prostate cancer screening trials on PSA testing practices. J Natl Cancer Inst 2011; 103: 520. 17. U.S. Preventive Services Task Force: Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2008; 149: 185. 18. Greene KL, Albertsen PC, Babaian RJ et al: Prostate specific antigen best practice statement 2009 update. J Urol 2009; 182: 2232. 19. Wolf AMD, Wender RC, Etzioni RB et al: American Cancer Society guideline for the early detection of prostate cancer: update 2010. Ca Cancer J Clin 2010; 60: 70. 20. Kawachi MH, Bahnson RR, Barry M et al: NCCN clinical practice guidelines in oncology: prostate cancer early detection. J Natl Compr Canc Netw 2010; 8: 240.
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Take Home Message: Localized Prostate Cancer E. David Crawford, M.D. and Paul Arangua, M.D., Aurora, Colorado, provided the audience with highlights of the AUA meeting on Localized Prostate Cancer. The abstract numbers are indicated in parentheses
(Reprinted from AUANews 2011; Vol. 16, No. 6, pp. 3-4) The 2011 AUA meeting offered an exciting program with a wide variety of presentations. More than 140 abstracts on localized prostate cancer were accepted for presentation this year. We will attempt to cover a broad application of a small segment of these excellent presentations.
Diagnosis HistoScanningâ„˘, an ultrasound technology that detects cancerous tissues in back scattered waves, showed promise for detecting and diagnosing small cancer foci (1092). The HistoScanning results of 27 patients preparing to undergo radical prostatectomy were compared to whole mount sections. Of 23 foci 0.5 cc or larger 21 were identified during whole mount and detected via the HistoScanning technology, demonstrating a 90% sensitivity and 72% specificity for locating foci 0.2 cc or greater. The effects of pretreatment depressive symptoms on posttreatment urinary and sexual function were studied in nearly 900 patients (1000). Of the patients who experienced clinically elevated levels of depressive symptoms at baseline 19.7% fared significantly worse in terms of urinary and sexual function 6 months postoperatively than their counterparts, controlling for factors such as prostate specific antigen, Gleason score, demographics and preexisting baseline urinary or sexual dysfunction. Physicians should account for these findings and counsel patients on appropriate interventions before they undergo treatment.
Local Therapies The effect of media coverage and marketing of robotic assisted radical prosta-
tectomy (RARP) was reviewed (1463). The bulk of direct to consumer advertising revolved around RARP, whereas 0% was related to open surgery. The authors concluded that media and marketing have contributed to the increase in the performance of RARP but the quality of the information is poor. The outcomes of 255 patients treated with high intensity focused ultrasound (HIFU) from 1996 to 2010 indicated a secondary therapy-free survival of HIFU at 84% for low risk, 72% for intermediate risk and 45% for high risk disease, demonstrating that HIFU is a reliable treatment option for men with low risk prostate cancer but not a viable treatment for those with intermediate or high risk cancer due to high recurrence rates (1298).
Pelvic Lymph Node Dissection Omission of pelvic lymphadenectomy has remained common among patients presenting with low risk prostate cancer. A total of 211 patients were analyzed after RP to determine whether the 5-year biochemical-free survival rate differed in men treated with or without lymphadenectomy (473). The findings suggest that the only predictor of biochemical recurrence (BCR) was preoperative PSA, whereas pelvic lymph node dissection, year of surgery, age at surgery, race or clinical staging preoperatively did not have a significant role. Similar results on the effects of pelvic lymph node dissection and the number of lymph nodes sampled during prostatectomy confirmed no significant association between all-cause mortality or prostate cancer specific mortality (PCSM) among 13,000 men with N0 or NX disease (474). However, in 425 men with lymph node positive disease the number of lymph nodes removed at surgery initially demonstrated improved
PCSM but statistical significance was not achieved.
Positive Surgical Margins A meta-analysis compared the positive surgical margin (PSM) and complication rates of more than 110,000 open retropubic, laparoscopic or RARP cases between 2002 and 2008 (349). The robotic prostatectomy group had overall lower PSM and complication rates, indicating decreased perioperative morbidity compared to the open and laparoscopic approaches. However, long-term outcomes and cost-benefit analysis are needed before making a recommendation. A report on 15-year PCSM in men with positive surgical margins revealed no increased PCSM risk due to positive margins alone (470). Between 1987 and 2005 the PCSM for patients with positive surgical margins and those with negative surgical margins was 10% and 6%, respectively. Interestingly, the extent of postoperative radiotherapy or late radiotherapy did not offer any additional protective effects against recurrence. Conversely, of 1,747 patients with high risk prostate cancer (PSA greater than 20 ng/ml, cT3a or greater, or biopsy Gleason score 8 or greater) who underwent RP between 1987 and 2009 approximately 1,257 had PSMs (471). A multivariate analysis demonstrated that an increased number of PSMs was an independent predictor of lower overall cancer specific survival and overall survival (OS). All patients had undergone RP with pelvic lymph node dissection, and 57.3% had negative margins, 23.5% had 1 PSM, 7.6% had 2 PSMs and 11.6% had 3 PSMs. Analysis of the disease recurrence rate of a positive apical margin (PAM) in low grade prostate cancer in 174 patients treated with RP between 1988 and 2003 â–ź Continued on page 18
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revealed a 10-year biochemical-free survival rate of 85% (1097). An isolated PAM, primary Gleason grade and area of tumor in contact with the margin showed potential use for identifying patients at higher risk for recurrence, whereas the length of an isolated PAM was not a significant predictor of disease progression.
Biochemical Failure Little information exists on the effects of BCR vs biochemical persistence (BCP, PSA 0.2 ng/ml or greater) in patients after primary treatment. A total of 3,711 patients underwent RARP from 2001 to 2008 at a single institution (472). Those with BCP experienced significantly more aggressive disease than patients with BCR alone (higher preoperative PSA, greater disease burden, higher disease grade and lymphovascular invasion), demonstrating that patients with BCP, especially those with Gleason 8 cancer, are more likely to have distant metastasis. Based on the Shared Equal Access Regional Cancer Hospital database, 921 men with a history of statin use were analyzed before undergoing RP to determine the role of cholesterol in long-term survival outcomes (997). When controlling for men with total cholesterol 200 mg/dl or greater, the results indicated a significant association with elevated BCR risk, whereas accounting for all factors (total cholesterol, high-density
lipoprotein, low-density lipoprotein and triglycerides) in all men did not demonstrate increased BCR risk.
Active Surveillance It has been well established that early failure in men undergoing active surveillance (AS) is usually due to an initial under grading. Research aimed at determining the accuracy and potential role of endorectal coil magnetic resonance imaging (MRI) in locating higher grade disease among patients on AS was initiated (1292). Of 60 patients with localized prostate cancer findings on MRI showed no cancer in 38%, were similar to the initial diagnosis in 40% and demonstrated large volume disease in 22%, which was confirmed in 10 of 12 cases with followup biopsy. Statistical significance existed between increased PSA density among cases upstaged during MRI compared to those with normal MRI findings. Approximately 40% of men initially eligible for an AS protocol underwent RP and were found to have Gleason score upgrading that would have made them ineligible for AS (1094). Analysis revealed that preoperative PSA, number of positive biopsy cores and prostate volume were significant predictors of Gleason score upgrading. A nomogram was subsequently developed to aid physicians in determining which patients on AS may be at risk for Gleason score upgrading.
A multicenter study was initiated to better evaluate patients for AS protocols using confirmatory biopsies of at least 16 cores approximately 9 to 12 months after initial diagnosis (1095). Approximately 36% of patients initially eligible for AS were excluded from study due to upgrading (11.6%), more than 2 positive cores (23.8%) or cancer foci greater than 3 mm (50 of 56 men). This study demonstrates the value of performing a second biopsy to validate the initial diagnosis. The difference of overall and prostate cancer specific mortality was compared among 8,292 men treated with AS, RP, external beam radiation therapy (EBRT) or brachytherapy (1460). AS was not associated with increased PCSM compared to definitive local therapy, yet little difference existed between the survival of patients treated with AS and RP. However, survival was actually diminished between the EBRT and brachytherapy cohorts, demonstrating that AS should be considered a viable first line treatment for men with organ confined prostate cancer. We need simple tissue or serum markers to help determine favorable risk men for AS (1293). The Prostate Px+ used in 100 patients on AS demonstrated an excellent correlation with identifying those in whom AS would fail. â™Ś
Highlights of Prostate Cancer courses offered at AUA2011.