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Originally published as JCO Early Release 10.1200/JCO.2009.21.2274 on January 26 2009 © 2009 American Society of Clinical Oncology.
Combining Docetaxel With Estramustine: Back to the Future?Medical Oncology Department, Georges Pompidou European Hospital; Rene Descartes University Paris; Ecole Nationale Vétérinaire d'Alfort, Paris, France
Department of Medicine, Institut Jean Godinot, Reims, France
Department of Medicine, Institut Gustave Roussy and University of Paris XI, Villejuif, France To the Editor: Based on the results of a randomized phase II trial of patients with docetaxel with or without estramustine in castration-resistant prostate cancer (CRPC), which was recently reported in Journal of Clinical Oncology, Machiels et al1 concluded that "the addition of estramustine to weekly docetaxel does not provide any clinically relevant advantage." Although the authors deserve be praise for conducting such a trial, we believe that this conclusion may not be completely accurate for a number of reasons. First, from a methodological point of view, the randomized phase II trial design used in this study does not allow a formal comparison between the two arms, and shall be rather used as a mean to explore two experimental arms in parallel.2 Secondly, the small number of patients (69 and 71 patients per arm, respectively) does not provide a large enough study base to detect a limited (eg, 20%), but still clinically meaningful, benefit related to the combination regimen over the single agent arm. Thirdly, a high proportion (approximately 25%) of patients included in this study had previously received estramustine and had a progression of their CRPC before entering the trial. This may have likely disfavored the docetaxel-estramustine arm, as the prostate-specific antigen (PSA) response rate to this regimen in patients who had received estramustine previously or not was 50% and 81%, respectively, in this trial.1 Finally, the docetaxel regimen used in both arms in this trial is a modified weekly schedule that is not considered as standard since the TAX 327 phase III trial reported better overall survival results with a 3-weekly regimen.3,4
The response rate of the docetaxel-estramustine regimen, as measured by the proportion of patients with a
More than 20 years after its approval for the treatment of patients with CRPC, whether the antitumor activity of estramustine is mostly related to its hormonal or cytotoxic effects is still largely unknown. A number of recent data indicate that CRPC is often still an androgen receptor–driven disease.8 The activity detected in the clinic with hormone-modulating agents like ketoconazole, diethylstilbestrol, and more recently, abiraterone acetate, act in a similar way, and the benefit of adding estramustine to chemotherapy over chemotherapy alone could well be explained by such an endocrine effect. Ideally, a large, well-designed phase III randomized trial would be required to properly answer this question. However, it is not certain that such a trial will be done in the future since other trial priorities exist, and estramustine, as a mature drug, has become an orphan drug with less support from the pharmaceutical industry. 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: Stéphane Oudard, Keocyt Lab (C); Jean Christophe Eymard, Keocyt Lab (C); Karim Fizazi, Keocyt Lab (C), Sanofi-aventis (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
1. Machiels JP, Mazzeo F, Clausse M, et al: Prospective randomized study comparing docetaxel, estramustine, and prednisone with docetaxel and prednisone in metastatic hormone-refractory prostate cancer. J Clin Oncol 26:5261–5268, 2008. 2. Rubinstein LV, Korn EL, Freidlin B, et al: Design issues of randomized phase II trials and a proposal for phase II screening trials. J Clin Oncol 23:7199–7206, 2005. 3. 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. 4. Oudard S, Banu E, Beuzeboc P, et al: Multicenter randomized phase II study of two schedules of docetaxel, estramustine, and prednisone versus mitoxantrone plus prednisone in patients with metastatic hormone-refractory prostate cancer. J Clin Oncol 23:3343–3351, 2005. 5. Caffo O, Sava T, Comploj E, et al: Docetaxel, with or without estramustine phosphate, as first-line chemotherapy for hormone-refractory prostate cancer: Results of a multicentre, randomized phase II trial. BJU Int 102:1080–1085, 2008.[CrossRef][Medline] 6. Eymard JC, Priou F, Zannetti A, et al: Randomized phase II study of docetaxel plus estramustine and single-agent docetaxel in patients with metastatic hormone-refractory prostate cancer. Ann Oncol 18:1064–1070, 2007. 7. Fizazi K, Le Maitre A, Hudes G, et al: Addition of estramustine to chemotherapy and survival of patients with castration-refractory prostate cancer: A meta-analysis of individual patient data. Lancet Oncol 8:994–1000, 2007.[CrossRef][Medline] 8. Nelson WG, De Marzo AM, Isaacs WB: Prostate cancer. N Engl J Med 349:366–381, 2003.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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50% decline in serum PSA, has been consistently reported in the 60% to 70% range, while that of docetaxel as a single agent was typically in the 40% to 50% range in randomized trials (summarized in 
