Urological Oncology: Prostate Cancer

Urological Survey

Urological Oncology: Prostate Cancer Can Dutasteride Delay or Prevent the Progression of Prostate Cancer in Patients With Biochemical Failure After Radical Therapy? Rationale and Design of the Avodart After Radical Therapy for Prostate Cancer Study F. H. Schroder, C. H. Bangma, J. M. Wolff, A. Alcaraz, F. Montorsi, P. Mongiat-Artus, P. A. Abrahamsson, T. A. McNicholas, R. S. Castro and I. M. Nandy Erasmus MC, Rotterdam, The Netherlands BJU Int 2009; 103: 590 –596.

Objective: To describe the Avodart after Radical Therapy for prostate cancer Study (ARTS), investigating the use of dutasteride (a dual 5alpha-reductase inhibitor that suppresses intraprostatic dihydrotestosterone, reduces tumour volume and improves other markers of tumour regression in prostate cancer) to prevent or delay disease progression in patients with biochemical recurrence after therapy with curative intent. Patients and Methods: An increasing serum prostate-specific antigen (PSA) level after radical prostatectomy (RP) or radiotherapy (RT) is indicative of recurrent prostate cancer and typically pre-dates clinically detectable metastatic disease by several years. ARTS is an ongoing European multicentre trial in which patients are stratified by previous therapy (RP with or without salvage RT vs primary RT) and randomized to double-blind treatment with dutasteride 0.5 mg or placebo once daily for 2 years. Eligible patients will have a PSA doubling time (DT) of 3–24 months. Biochemical recurrence is defined as three increases in PSA level from the nadir, with each increase ⱖ4 weeks apart and each PSA level ⱖ0.2 ng/mL, and a final PSA level of ⱖ0.4 ng/mL (after RP) or ⱖ2 ng/mL (after primary RT). Study endpoints include time to PSA doubling, time to disease progression, treatment response (PSA decrease or an increase of ⱕ15% from baseline), changes in PSA and PSADT, and changes in anxiety (Memorial Anxiety Scale for Prostate Cancer). Conclusions Arts: Will be the first study to evaluate the effects of dutasteride on PSADT, disease progression and treatment response in patients with biochemical failure after RP or RT, and should help to elucidate the potential role of dual 5alpha-reductase inhibition in prostate cancer. Editorial Comment: This paper describes a study that will evaluate the ability of a dual 5␣-reductase inhibitor (dutasteride) to prevent or delay progression in men with a rising PSA following radical prostatectomy or radiation. A similar trial was reported 15 years ago using finasteride.1 Although finasteride delayed increases in PSA by about 9 months, it had no effect on clinical end points such as local recurrence and distant metastases. I have seen many men with rising PSA levels following definitive treatment who were placed on 5␣-reductase inhibitors mainly for the psychological benefit they provide by lowering PSA levels. I know of no other trials that have evaluated their efficacy in terms of clinical progression. Unfortunately this trial, which is only 2 years long, is unlikely to be informative on this important end point as well. Patrick C. Walsh, M.D. 1. Andriole G, Lieber M, Smith J et al: Treatment with finasteride following radical prostatectomy for prostate cancer. Urology 1995; 45: 491.

0022-5347/09/1825-2311/0 THE JOURNAL OF UROLOGY® Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 182, 2311-2318, November 2009 Printed in U.S.A. DOI:10.1016/j.juro.2009.08.007

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External Beam Radiotherapy for Prostate Cancer Patients on Anticoagulation Therapy: How Significant is the Bleeding Toxicity? K. S. Choe, A. B. Jani and S. L. Liauw Department of Radiation and Cellular Oncology, University of Chicago Pritzker School of Medicine, Chicago, Illinois Int J Radiat Oncol Biol Phys 2009; Epub ahead of print.

Purpose: To characterize the bleeding toxicity associated with external beam radiotherapy for prostate cancer patients receiving anticoagulation (AC) therapy. Methods and Materials: The study cohort consisted of 568 patients with adenocarcinoma of the prostate who were treated with definitive external beam radiotherapy. Of these men, 79 were receiving AC therapy with either warfarin or clopidogrel. All patients were treated with three-dimensional conformal radiotherapy or intensitymodulated radiotherapy. Bleeding complications were recorded during treatment and subsequent follow-up visits. Results: With a median follow-up of 48 months, the 4-year actuarial risk of Grade 3 or worse bleeding toxicity was 15.5% for those receiving AC therapy compared with 3.6% among those not receiving AC (p ⬍ .0001). On multivariate analysis, AC therapy was the only significant factor associated with Grade 3 or worse bleeding (p ⬍ .0001). For patients taking AC therapy, the crude rate of bleeding was 39.2%. Multivariate analysis within the AC group demonstrated that a higher radiotherapy dose (p ⫽ .0408), intensity-modulated radiotherapy (p ⫽ 0.0136), and previous transurethral resection of the prostate (p ⫽ .0001) were associated with Grade 2 or worse bleeding toxicity. Androgen deprivation therapy was protective against bleeding, with borderline significance (p ⫽ 0.0599). Dose-volume histogram analysis revealed that Grade 3 or worse bleeding was minimized if the percentage of the rectum receiving ⱖ70 Gy was ⬍10% or the rectum receiving ⱖ50 Gy was ⬍50%. Conclusion: Patients taking AC therapy have a substantial risk of bleeding toxicity from external beam radiotherapy. In this setting, dose escalation or intensity-modulated radiotherapy should be used judiciously. With adherence to strict dose-volume histogram criteria and minimizing hotspots, the risk of severe bleeding might be reduced. Editorial Comment: I have always viewed men with localized prostate cancer who were on AC therapy as undesirable surgical candidates because of the comorbidity associated with AC therapy and the potential complications when it is temporarily discontinued. For this reason I usually encourage them to undergo radiation therapy. This article was an eyeopener for me. Although radiation therapy may offer short-term advantages, at 4 years 39% of men on AC therapy had rectal bleeding, and in 16% it was severe, requiring intervention, transfusions or surgery. Of men not on AC therapy only 4% had severe bleeding. Furthermore, beyond 4 years 39% of the men on AC therapy who had bled continued to bleed. These sobering findings will modify my advice in the future. Patrick C. Walsh, M.D.

Duration of Androgen Suppression in the Treatment of Prostate Cancer M. Bolla, T. M. de Reijke, G. Van Tienhoven, A. C. Van den Bergh, J. Oddens, P. M. Poortmans, E. Gez, P. Kil, A. Akdas, G. Soete, O. Kariakine, E. M. van der Steen-Banasik, E. Musat, M. Pierart, M. E. Mauer and L. Collette; EORTC Radiation Oncology Group and Genito-Urinary Tract Cancer Group Centre Hospitalier Regional Universitaire de Grenoble, Grenoble, France N Engl J Med 2009; 360: 2516 –2527.

Background: The combination of radiotherapy plus long-term medical suppression of androgens (ⱖ 2 years) improves overall survival in patients with locally advanced prostate cancer. We compared the use of radiotherapy plus short-term androgen suppression with the use of radiotherapy plus longterm androgen suppression in the treatment of locally advanced prostate cancer. Methods: We randomly assigned patients with locally advanced prostate cancer who had received external-beam radiotherapy plus 6 months of androgen suppression to two groups, one to receive no further

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treatment (short-term suppression) and the other to receive 2.5 years of further treatment with a luteinizing hormone-releasing hormone agonist (long-term suppression). An outcome of noninferiority of short-term androgen suppression as compared with long-term suppression required a hazard ratio of more than 1.35 for overall survival, with a one-sided alpha level of 0.05. An interim analysis showed futility, and the results are presented with an adjusted one-sided alpha level of 0.0429. Results: A total of 1113 men were registered, of whom 970 were randomly assigned, 483 to short-term suppression and 487 to long-term suppression. After a median follow-up of 6.4 years, 132 patients in the short-term group and 98 in the long-term group had died; the number of deaths due to prostate cancer was 47 in the short-term group and 29 in the long-term group. The 5-year overall mortality for short-term and long-term suppression was 19.0% and 15.2%, respectively; the observed hazard ratio was 1.42 (upper 95.71% confidence limit, 1.79; P⫽0.65 for noninferiority). Adverse events in both groups included fatigue, diminished sexual function, and hot flushes. Conclusions: The combination of radiotherapy plus 6 months of androgen suppression provides inferior survival as compared with radiotherapy plus 3 years of androgen suppression in the treatment of locally advanced prostate cancer. Editorial Comment: A number of studies have shown that hormonal therapy in combination with radiotherapy prolongs survival in men with high risk disease. However, how long after completion of radiotherapy should men continue treatment with hormones? This well-done randomized trial of men with locally advanced prostate cancer shows that men who received hormonal therapy for 3 years following radiation therapy had improved survival over those men who only received it for 6 months. This was accomplished without any increase in cardiovascular mortality. In another recently published study a hypothesis generating analysis suggested that men who received hormonal therapy for more than 5 years had significant improvement in survival over men who received it for less time.1 Although these data were not from a predetermined randomized trial, it does look like long-term treatment is better. Patrick C. Walsh, M.D. 1. Souhami L, Bae K, Pilepich M et al: Impact of the duration of adjuvant hormonal therapy in patients with locally advanced prostate cancer treated with radiotherapy: a secondary analysis of RTOG 85-31. J Clin Oncol 2009; 27: 2137.

Twenty-Four-Month Postradiation Prostate Biopsies are Strongly Predictive of 7-Year Disease-Free Survival: Results From a Canadian Randomized Trial J. M. Crook, S. Malone, G. Perry, L. Eapen, J. Owen, S. Robertson, C. Ludgate, S. Fung and G. Lockwood Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada Cancer 2009; 115: 673– 679.

Background: The objective of this study was to evaluate the predictive value of prostate biopsies that were obtained 24 months after the completion of radiotherapy (RT) with respect to disease-free survival (DFS) in a randomized trial that compared 3 months versus 8 months of neoadjuvant hormone therapy before conventional dose external RT. Methods: From February 1995 to June 2001, 378 men were randomized to receive either 3 months or 8 months of combined flutamide and goserelin before they received 66 Gray of RT at 4 participating centers. By risk group, 26% of patients were categorized as low risk, 43% were categorized as intermediate risk, and 31% were categorized as high risk. The 2 treatment arms were balanced in terms of age, Gleason score, clinical tumor classification, risk group, and presenting prostate-specific antigen level. The median follow-up for the patients who remained alive was 6.6 years (range, 1.6 –10.1 years). Of 361 evaluable patients, 290 patients remained alive. Post-RT prostate biopsies were performed between 24 and 30 months after the completion of RT in 3 of the 4 centers. Biopsies that had residual tumor with severe treatment effect were considered indeterminate, and biopsies that had minimal or no treatment effect were considered positive. Results: The 5-year rate of actuarial freedom from any failure for the 3-month arm versus the 8-month arm was 72% versus 75% (P ⫽ .18). The DFS for patients who had negative and indetermi-

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nate biopsies was similar. Two-year post-treatment biopsy status was a strong predictor of 5-year DFS rate (82% and 83% for negative and indeterminate biopsies, respectively, vs 27% for positive biopsies; P ⬍ .0001). Multivariate analysis indicated that biopsy status (P ⬍ .0001) and Gleason score (P ⬍ .0001) were the strongest determinates of biochemical DFS. Conclusions: Two-year post-RT prostate biopsies were strongly predictive of subsequent DFS. Biopsies with severe treatment effect were considered negative. Editorial Comment: I become concerned when young men elect to have definitive radiation therapy for the treatment of localized prostate cancer because if radiation therapy fails to control their disease, the window of curability might be missed for pursuing salvage treatment. This study suggests that biopsies at 2 years might be useful in predicting those patients destined to fail. In the future I will advise young men who elect radiation therapy to consider this. Patrick C. Walsh, M.D.

Socioeconomic Factors, Urological Epidemiology and Practice Patterns Primary Care Physicians’ Reported Use of Pre-Screening Discussions for Prostate Cancer Screening: A Cross-Sectional Survey S. K. Linder, S. T. Hawley, C. P. Cooper, L. E. Scholl, M. Jibaja-Weiss and R. J. Volk Department of Family and Community Medicine, Baylor College of Medicine, Houston, Texas BMC Fam Pract 2009; 10: 19.

Background: Professional medical organizations recommend individualized patient decision making about prostate cancer screening. Little is known about primary care physicians’ use of pre-screening discussions to promote informed decision making for prostate cancer screening. The aim of this study is to explore physicians’ use of pre-screening discussions and reasons why physicians would or would not try to persuade patients to be screened if they initially refuse testing. Methods: Primary care physicians completed a self-administered survey about prostate cancer screening practices for informed decision making. Results: Sixty-six physicians (75.9%) completed the survey, and 63 were used in the analysis. Thirteen physicians (20.6%) reported not using prescreening discussions, 45 (71.4%) reported the use of prescreening discussions, and 3 (4.8%) reported neither ordering the PSA test nor discussing it with patients. Sixty-nine percent of physicians who reported not having discussions indicated they were more likely to screen African American patients for prostate cancer, compared to 50% of physicians who reported the use of discussions (Chi-square(1) ⫽ 1.62, p ⫽ .20). Similarly, 91% of physicians who reported not having discussions indicated they are more likely to screen patients with a family history of prostate cancer, compared to 46% of those who reported the use of discussion (Chi-square(1) ⫽ 13.27, p ⬍ .001). Beliefs about the scientific evidence and efficacy of screening, ethical concerns regarding patient autonomy, and concerns about time constraints differed between physicians who would and would not try to persuade a patient to be tested. Conclusion: Although guidelines recommend discussing the risks and benefits of prostate cancer screening, physicians report varying practice styles. Future research needs to consider the nature of discussions and the degree to which informed decision making is being achieved in clinical practice.