Journal of the National Cancer Institute Advance Access published online on October 30, 2007
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm189
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© The Author 2007. Published by Oxford University Press.
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Adaptive Therapy for Androgen-Independent Prostate Cancer: A Randomized Selection Trial of Four Regimens
Affiliations of authors: Departments of Biostatistics (PFT, SW) and Genitourinary Medical Oncology (CL, LCP, MAB, DW, REM), The University of Texas M. D. Anderson Cancer Center, Houston, TX
Correspondence to: Randall E. Millikan, PhD, MD, Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, PO Box 301439, 1155 Herman P. Pressler, Houston, TX 77030 (e-mail: rmillika{at}mdanderson.org).
Background: Physicians typically switch therapies unless clinically relevant thresholds of response are observed, and treatments that produce high-quality responses and that are active in the salvage setting are generally felt to be promising. With the goal of efficiently selecting promising regimens for more advanced trials, we conducted a randomized selection trial of four regimens to identify promising treatments for androgen-independent prostate cancer.
Methods: Patients without prior exposure to cytotoxic therapy were randomly assigned to one of four regimens (i.e., cyclophosphamide, vincristine, and dexamethasone [CVD]; ketoconazole plus doxorubicin alternating with vinblastine plus estramustine [KA/VE]; weekly paclitaxel, estramustine, and carboplatin [TEC]; paclitaxel, estramustine, and etoposide [TEE]). Patients were evaluated every 8 weeks to assess response and adverse events. Patients who responded continued with the same treatment; those who did not were randomly assigned to one of the other three treatments. Response was assessed by considering tumor-specific symptoms, tumor regression, and prostate-specific antigen (PSA) changes. Treatment was continued until two consecutive courses induced a response (i.e., overall success, the major criterion for which was 80% PSA reduction) or until patients were given two different regimens that failed to induce such a response.
Results: Median overall survival from registration among all 150 patients was 22 months (95% confidence interval [CI] = 19 to 26 months). Estimated survival at 3 and 5 years, respectively, was 26% (95% CI = 20% to 35%) and 10% (95% CI = 5% to 16%). Overall success was achieved in 35 patients with the initial treatment (i.e., four treated with CVD, seven with KA/VE, 14 with TEC, and 10 with TEE) and in nine more patients with a second-line regimen (i.e., two with CVD, five with KA/VE, and two with TEC). For all 44 (29%, 95% CI = 23% to 37%) patients with overall success, median survival was 30 months (95% CI = 26 to 40 months); for the other 106 patients, it was 19 months (95% CI = 17 to 22 months). TEC produced the greatest number and proportion of successful courses of treatment, and TEC followed by KA/VE was the most promising two-stage strategy.
Conclusions: Some patients responded to particular treatments, and responses to second-line treatments were not rare. We propose that TEC be considered for phase III evaluation.
| CONTEXT AND CAVEATS Prior knowledge Defined methods to select promising therapeutic agents for advanced trials (such as phase III randomized trials) are lacking. Study design An algorithm was designed for a randomized selection trial to identify promising treatments for androgen-independent prostate cancer for more advanced trials. Four different chemotherapy regimens were studied, taking account of both first-line and second-line treatments. Contribution Some patients responded to particular treatments, and responses to second-line treatments were not rare. The regimen of weekly paclitaxel, estramustine, and carboplatin (TEC) produced the greatest number and proportion of successful courses of treatment, and TEC followed by a regimen of ketoconazole plus doxorubicin alternating with vinblastine plus estramustine was the most promising two-stage strategy. Implications The algorithm and analysis used in this study appear to be a useful method for the selection of promising therapies. Limitations This is a single-institutional study among a population of prostate cancer patients that is more highly motivated and resourceful than the general population of such patients. Validation of this method in independent populations of patients is required.
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Manuscript received February 14, 2007; revised July 30, 2007; accepted September 12, 2007.
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J Natl Cancer Inst 2008 100: 681-682.
J Natl Cancer Inst 2007 99: 1561.
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  A. J. Armstrong, E. L. Garrett-Mayer, and M. Eisenberger Re: Adaptive Therapy for Androgen-Independent Prostate Cancer: A Randomized Selection Trial of Four Regimens J Natl Cancer Inst, May 7, 2008; 100(9): 681 - 682. [Full Text] [PDF]
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