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Journal of Clinical Oncology, Vol 26, No 21 (July 20), 2008: pp. 3648-3649 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.2494
In ReplySidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY
Duke University Medical Center, Durham, NC
Princess Margaret Hospital, Toronto, Ontario, Canada
Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY
Sam Camillo Forlanini Hospital, Rome, Italy
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
University of Washington, Seattle, WA
Beth Israel Deaconess Medical Center, Boston, MA
Cleveland Clinic, Cleveland, OH
Columbia Presbyterian Medical Center, New York, NY
Dana-Farber Cancer Institute, Boston, MA
Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY
Yale Cancer Center, New Haven, CT
National Cancer Institute, Bethesda, MD
UCSF Comprehensive Cancer Center, San Francisco, CA
Oregon Health and Science University, Portland, OR
University of Wisconsin Comprehensive Cancer Center, Madison, WI
National Cancer Institute, Bethesda, MD
University of Michigan Comprehensive Cancer Center, Ann Arbor, MI Consensus guidelines are designed to reduce confounding so that clinical trials are more informative. In phase II, this translates to the demonstration of treatment effects that can be attributed reliably to the agent under study, and in phase III, the demonstration of clinical benefit. The authors raise issues of trial eligibility and the reporting of outcomes in the new Prostate Cancer Working Group 2 (PCWG2) guidelines.1 They are addressed in turn. PCWG2 recommends controlling for a withdrawal response because they can be clinically meaningful, and to avoid the false attribution of response to a study agent. Doing so is of particular importance in phase II trials, and the guidelines highlight the scenarios where they are most likely to occur to minimize treatment delays. The fact that a survival benefit has not been shown does not apply in this context, nor does the issue of trial accrual. Note as well that prostate-specific antigen (PSA) declines have been observed with megestrol acetate,2 although the frequency that it occurs has not been well studied. Controlling for withdrawal responses is less of an issue in phase III trials, where the potential effect can be balanced by randomization and response is not usually the primary end point. Washout periods are included in eligibility to ensure that a drug has been eliminated and to allow for potential delayed toxicities to occur and to resolve. A washout period also reduces the possibility of untoward interactions that might occur with the concurrent administration of a second agent, which in some cases may negate the effects of a study drug. The duration of the washout must consider the half-life of the agent that is being discontinued, which exceeds 1 week for the most commonly used antiandrogens. PCWG2 does not recommend a specific observation period after discontinuation of ketoconazole, aminoglutethimide, or systemic steroids. Given the half-life of these agents, investigators could consider and incorporate a shorter off-treatment interval into a trial design as they deem appropriate. The PCWG2 recommendations highlight the importance of recording historical information—both clinical and biologic—that might affect prognosis at trial entry. The recommendation was derived from noted inconsistencies in reporting this information, and is of particular importance for trials using delay/prevent end points. The authors suggest that the PSA nadir on androgen depletion be used to stratify patients on trials for patients with castration-resistant disease. This suggestion is premature, as there are no data at this time to indicate whether the PSA nadir observed on androgen depletion will have prognostic significance in trials of interventions initiated in castrate-resistant patients. The PCWG2 recommendation to record the nadir will allow the potential significance of this factor to be explored for future trials. Similarly, a detailed discussion of all potential prognostic factors is beyond the scope of these guidelines. PCWG2 recommends recording the presence or absence of disease in the primary site based on recent controversies regarding the impact of disease control in this area on long-term outcomes.3,4 Even if they were identified, trials could not stratify for every factor shown to have prognostic significance in the context of a survival analysis related to the treatment with a specific drug. Further, factors that are prognostic of survival may not predict for sensitivity to a drug, and the randomization itself will reduce the chance for important imbalances. An additional concern is the PCWG2 recommendation to avoid reporting PSA response rates and to use waterfall plots instead. The recommendation was based on the fact that as stand-alone criteria, the outcome has no meaning, and has been misconstrued by both patients and physicians to indicate clinical benefit. PCWG2 also points out that the clinical significance of the 3-month 30% decline from the Southwest Oncology Group trial 99-165 and, separately, TAX 327,6 is being studied prospectively in phase III trials ongoing in the Southwest Oncology Group and the Cancer and Acute Leukemia Group B. Ultimately, prospective validation in multiple trials with a variety of interventions will be required before this or any outcome measure can be considered a potential surrogate of clinical benefit. The use of waterfall plots is not a matter of validation, rather it is to allow any data set to be analyzed on the basis of any degree of decline be it 90%, 50%, or 30%, which allows the results to be considered in the context of other trials conducted for this patient group. PCWG2 disagrees with the suggestion that post-therapy changes in PSA doubling time are an appropriate end point for a phase II trial. PSA doubling time is a pretreatment prognostic factor,7 but there is little to no evidence that the agents cited modulate their effects on growth through PSA, and doing so would only increase the likelihood that the antitumor effects of such drugs would be missed. Resource constraints are well recognized, which makes it all the more imperative to design trials with meaningful end points that inform the decision whether the outcomes observed are worthy of further study. Given the modest association of PSA declines and outcome—not to mention the difficulty keeping patients on trial with rising values—change in PSA slope is a slippery slope indeed. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Ian F. Tannock, Sanofi-aventis (U), Algeta ASA (U), GPC Biotech (U); Michael A. Carducci, Abbott Laboratories (C), Sanofi-aventis (U), Methylgene (C), Cougar Biotechnology (C); Mario A. Eisenberger, Sanofi-aventis (C), GPC Biotech (C), Celgene (C); Robert Dreicer, Merck (C), Sanofi-aventis (C), Bristol-Meyers Squibb Co (C); Daniel P. Petrylak, Sanofi-aventis (C), GPC Biotech (C), Abbott Laboratories (C); Eric J. Small, Cougar Biotechnology (C), Poniard Pharmaceuticals (C); Tomasz M. Beer, Novacea (C) Stock Ownership: Tomasz M. Beer, Novacea Honoraria: Michael A. Carducci, Sanofi-aventis, Abbott Laboratories; Mario A. Eisenberger, Sanofi-aventis, Ipsen, GPC Biotech; Robert Dreicer, Berlex; Daniel P. Petrylak, Sanofi-aventis, Celgene, Abbott Laboratories; Wm Kevin Kelly, Sanofi-aventis, Genentech; Tomasz M. Beer, Sanofi-aventis Research Funding: Ian F. Tannock, Sanofi-aventis, Novacea; Mario A. Eisenberger, Sanofi-aventis, Celgene, Cytogen; Robert Dreicer, Sanofi-aventis, Eli Lilly & Co, Millenium; Daniel P. Petrylak, Sanofi-aventis, Celgene, GPC Biotech; Wm Kevin Kelly, Sanofi-aventis, Genentech, Curagen; Eric J. Small, Dendreon, Novartis; Tomasz M. Beer, Sanofi-aventis Expert Testimony: None Other Remuneration: None REFERENCES
1. Scher HI, Halabi S, Tannock I, et al: Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 26:1148-1159, 2008 2. Dawson NA, McLoed DG: Dramatic prostate specific antigen decrease in response to discontinuation of megestrol acetate in advanced prostate cancer: Expansion of the antiandrogen withdrawal syndrome. J Urol 153:1946-1947, 1995[CrossRef][Medline] 3. Thompson IM, Tangen C, Basler J, et al: Impact of previous local treatment for prostate cancer on subsequent metastatic disease. J Urol 168:1008-1012, 2002[CrossRef][Medline] 4. Halabi S, Vogelzang NJ, Ou SS, et al: The impact of prior radical prostatectomy in men with metastatic castration recurrent prostate cancer: A pooled analysis of 9 Cancer and Leukemia Group B Trials. J Urol 177:531-534, 2007[CrossRef][Medline] 5. Petrylak D, Ankerst DP, Jiang CS, et al: Evaluation of prostate-specific antigen declines for surrogacy in patients on SWOG 99-16. J Natl Cancer Inst 98:516-521, 2006 6. Armstrong AJ, Garrett-Mayer E, Ou Yang YC, et al: Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer. J Clin Oncol 25:3965-3970, 2007 7. Armstrong AJ, Garrett-Mayer ES, Yang YC, et al: A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: A TAX327 study analysis. Clin Cancer Res 13:6396-6403, 2007 Related Correspondence
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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