Journal of the National Cancer Institute Advance Access originally published online on April 29, 2008
JNCI Journal of the National Cancer Institute 2008 100(9):681-682; doi:10.1093/jnci/djn104
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© The Author 2008. Published by Oxford University Press.
CORRESPONDENCE |
Re: Adaptive Therapy for Androgen-Independent Prostate Cancer: A Randomized Selection Trial of Four Regimens
Affiliations of authors: Duke University Comprehensive Cancer Center and the Duke Prostate Center, Duke University, Durham, NC (AJA); Hollings Cancer Center, Department of Biostatistics, Medical University of South Carolina, Charleston, SC (ELGM); Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD (ME)
Correspondence to: Andrew J. Armstrong, MD, ScM, Duke University Comprehensive Cancer Center and the Duke Prostate Center, Duke University, Durham, NC (e-mail: andrew.armstrong{at}duke.edu).
We commend Thall et al. (1) for their report on a four-arm crossover randomized phase II study of complex multiagent chemotherapy regimens in men with castration-resistant prostate cancer. The sequentially randomized design proposed by Thall et al. (1) is an attractive method that may enhance our ability to select a potentially active new regimen that deserves further testing. Indeed, they show that this design is feasible.
This study was conducted before the US Food and Drug Administration approval of docetaxel and prednisone, which demonstrated improved overall survival and palliative ability in this population (2). Combination chemotherapy regimens in prostate cancer, which have been studied for many years, culminated in the Southwest Oncology 99-16 randomized phase III trial, which showed higher overall survival with combination treatment of docetaxel, estramustine, and prednisone than with combination treatment of mitoxantrone and prednisone, the historic standard palliative regimen for this disease (3). However, the combination regimen of docetaxel, estramustine, and prednisone produced only a modest survival benefit that was similar in magnitude to the benefit observed with docetaxel and prednisone alone in the multicenter TAX327 study (2). The additional cardiovascular, thrombotic, and gastrointestinal toxic effects associated with estramustine treatment have led to the conclusion that this agent likely has a minimal, if any, additive benefit in the first-line treatment of patients with metastatic castration-resistant prostate cancer. This assessment has been confirmed in a subsequent smaller randomized trial that evaluated treatment with docetaxel, estramustine, and prednisone vs that with docetaxel and prednisone alone, which showed no clinically significant differences in patient outcomes (4).
It is against this historic backdrop that the regimens in this phase II trial must be assessed (1). Because there was no docetaxel single-agent comparator arm in the study by Thall et al. (1), it is difficult to judge the merits of this aggressive and toxic approach. The authors claim that the rates for "overall success" and 5-year survival of 10% in their study justify this approach and that, in TAX327, no survival was observed beyond 48 months. However, this statement was not accurate, given that survival beyond 48 months as reported in the recently updated analysis of this trial was observed in 4.1% of patients in the every 3-week docetaxel and prednisone arm; only 1.5% of patients treated with mitoxantrone and prednisone survived beyond 4 years (5). A nomogram derived from the TAX327 trial may allow one to predict long-term survival by use of known baseline prognostic factors (6). Although nomograms may enhance our ability to predict 1-, 2-, and 5-year survival probabilities, routine use of such instruments in this context to evaluate the results of other trials still requires validation in carefully conducted prospective randomized trials.
Reliance on prostate-specific antigen (PSA)–based outcomes and other "response parameters" in the sequential randomized design may be a limitation of this design. Indeed, the use of non-standardized measures of PSA declines reported by Thall et al. (1) are difficult to assess because of the lack of supportive data on the surrogate value of these intermediate outcomes for the prediction of survival in patients with castration-resistant prostate cancer (7). More information on baseline prognostic characteristics of the patients, such as volume or burden of disease and known prognostic factors, should be reported, with particular emphasis on those characteristics associated with better survival. This data would allow a more rigorous assessment of the merits of the intensive regimens used in the study by Thall et al. (1). Finally, a description of the rates of progression-free survival, time to progression, and overall survival for each of the initial chemotherapy regimens would provide useful comparative data against currently approved therapies. Given that the median time to progression for the overall cohort was short at 4.9 months, selection bias may have played a relatively strong role in the favorable long-term outcomes in this trial.
REFERENCES
1. Thall PF, Logothetis C, Pagliaro LC, et al. Adaptive therapy for androgen-independent prostate cancer: a randomized selection trial of four regimens. J Natl Cancer Inst (2007) 99(21):1613–1622.
2. Tannock IF, de WR, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med (2004) 351(15):1502–1512.
3. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med (2004) 351(15):1513–1520.
4. Machiels JH, Mazzeo F, Clausse M, et al. Phase III trial of docetaxel (D), estramustine (E), and prednisone versus docetaxel plus prednisone in patients with metastatic hormone-refractory prostate cancer (HRPC). Proc Am Soc Clin Oncol (2007) 25. (18S). Abstract 5067.
5. Berthold DR, Pond GR, Soban F, de WR, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol (2008) 26(2):242–245.
6. Armstrong AJ, Garrett-Mayer ES, Yang YC, de WR, Tannock IF, Eisenberger M. A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis. Clin Cancer Res. (2007) 13(21):6396–6403.
7. 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 (2007) 25(25):3965–3970.
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J Natl Cancer Inst 2008 100: 682-683.
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