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Originally published as JCO Early Release 10.1200/JCO.2005.11.933 on February 28 2005 © 2005 American Society of Clinical Oncology.
Prostate Cancer Chemotherapy: Emerging From the ShadowsVanderbilt-Ingram Comprehensive Cancer Center, Nashville, TN Until recently, the label placed on advanced prostate cancer as being chemoresistant seemed to be a valid summation of 30 years of clinical trials experience. That history is littered with changing end points, varied definitions of response, and a patient population perceived as being sufficiently fragile because of age or comorbidity to be poor candidates for aggressive, innovative therapeutic approaches. Until the early 1990s, the vast majority of single-agent cytotoxics provided single-digit objective response rates by the usual criteria. Although formal quality-of-life assessments were rare, the proportion of patients obtaining symptomatic benefit from chemotherapy in advanced disease seemed to be similarly low. The 1990s witnessed the approval of mitoxantrone and the introduction of palliative end points as appropriate primary objectives of clinical trials. Two large phase III trials of mitoxantrone demonstrated that approximately one third of symptomatic patients with metastatic prostate cancer experienced improvement in pain, although the objective response rate in bidimensionally measurable disease was less than 10%; not surprisingly, there was no evidence of survival benefit.1,2 Because of this demonstrated palliative benefit from a drug with minimal side effects, mitoxantrone became the standard of care for nearly a decade. A new era in prostate cancer chemotherapy was ushered in by clinical trials of the taxanes, in general, and docetaxel, in particular. Single-agent docetaxel results hinted at higher prostate-specific antigen (PSA) and objective response rates,3,4 whereas preclinical data suggested that some synergy might be observed by combining a taxane with the microtubular-associated protein inhibitor estramustine phosphate.5 Clinical trials of docetaxel combined with estramustine routinely resulted in higher PSA response rates than docetaxel alone, with possibly an improvement in measurable disease response rates.6-8 What remained to be proven was whether the improvement in serologic response rates could be translated into meaningful improvement in either progression-free or overall survival. In this issue, Oudard et al9 report the results of a randomized phase II trial in which patients with advanced prostate cancer were treated with one of two schedules of docetaxel (weekly or every 3 weeks) in combination with either estramustine plus prednisone or mitoxantrone plus prednisone. This report adds to a rapidly growing body of data establishing the benefit of docetaxel-based therapy. Recently, two more definitive phase III trials have demonstrated, for the first time, a survival benefit in advanced disease with docetaxel administered every 3 weeks,10,11 which resulted in the Food and Drug Administration’s approval of docetaxel for patients with advanced prostate cancer in May 2004. The trial by Oudard et al9 used PSA response superiority as the primary end point for docetaxel compared with mitoxantrone, whereas the phase III trials10,11 mentioned earlier used survival. Even if the arms of this randomized phase II trial could be statistically formally compared, as in a phase III trial, some of the superiority for docetaxel observed in this trial may be the result of a worse than expected outcome for the mitoxantrone patients. In terms of PSA response, only 18% of the patients in the Oudard et al trial had a 50% decline in PSA, compared with 37.5%,2 32%,10 and 27%11 in three phase III trials. Similarly, the time to progression for mitoxantrone patients in the Oudard et al trial was unusually short at 1.7 months, which is half the time observed in the phase III trials.10,11 Finally, the overall survival time of patients treated with mitoxantrone in the Oudard et al trial was shorter (13.4 months) than in the phase III trials (16.5 months and 15.6 months).10,11 Such differences are not surprising given the small sample size and the design of randomized phase II trials. This trial’s conclusions regarding the superiority of docetaxel-based therapy compared with mitoxantrone are predictive of the results of the definitive phase III trials. However, it is the differences in the results compared with those trials that force us to question both the trial design and the continued use of PSA response as a primary end point. Using a randomized phase II design, this trial has neither sufficient power to make statistically valid comparisons between the treatment arms nor a large enough sample size to accurately compare differences in survival with the two, more definitive phase III trials. The randomized phase II trial design has been perceived by many as a poor man’s phase III trial because it is more economical (from the view of the sponsor) than a true phase III trial that requires much larger numbers of patients, with more rapid access (from the view of the investigator) to what superficially appears to be truly comparative data. The results of such trials, unfortunately, have been too often embraced with the same practice-changing gusto as the results of a phase III trial. The randomized phase II trial remains primarily a hypothesis-generating design, with definitive data awaiting a subsequent phase III trial. If clinical practice had changed based on the trial of Oudard et al, 9 in the absence of confirmatory phase III data, we would have incorrectly concluded that docetaxel-based regimens did not provide survival benefit compared with mitoxantrone, that there was no difference between a weekly and an every-3-weeks schedule, and that docetaxel provides a higher measurable disease response rate. Is PSA reduction an appropriate end point, even in a hypothesis-generating trial design? Although many have assumed that PSA has fulfilled the requirements for surrogacy with respect to survival, the results from two recent trials have called this into question. First, in the TAX 327 trial,10 the arm with a schedule of every 3 weeks for docetaxel and the arm with weekly administration had virtually identical PSA response rates (45% and 48%, respectively), and yet the every-3-weeks arm had an overall survival advantage compared with mitoxantrone, whereas the weekly arm did not. This would suggest the possibility of missing true benefit in terms of survival if one used only PSA response as a screening tool to decide which regimens should be studied in phase III trials. Conversely, estramustine-containing docetaxel combination regimens routinely have higher PSA response rates than regimens with docetaxel alone, as evidenced most recently by a randomized phase II trial in which docetaxel plus estramustine resulted in a PSA response rate of 68%, whereas docetaxel alone showed a 29% PSA response rate.12 However, comparison of the data from the two definitive phase III trials would suggest that there is likely little, if any, survival benefit from the addition of estramustine to a docetaxel-containing regimen.10,11 Such false-negative and false-positive results necessitate a serious re-evaluation of PSA response as an adequate tool to screen novel regimens. The benefit of docetaxel-based therapy in advanced prostate cancer has now been well established. Although the gains have been modest and incremental by some standards, they nevertheless, for the first time, have broken the barrier of achieving an overall survival benefit from treatment with cytotoxics in hormone-refractory prostate cancer. Many more patients will now likely be offered chemotherapy as the perception of this disease’s chemosensitivity changes. Perhaps more importantly, there is now clear direction for further improvements in chemotherapy in advanced disease, as well as an impetus for the study of the effects of chemotherapy in earlier stages of disease. Finally, it has raised the bar for evaluating further improvements in chemotherapy because survival benefit is clearly now an achievable goal. Author’s Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES
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2. Kantoff PW, Halabi S, Conoway M, et al: Hydrocortisone with or without mitoxantrone in with hormone-refractory prostate cancer: Results of the Cancer and Leukemia Group B 9182 study. J Clin Oncol 17:2506-2513, 1999 3. Picus J, Schultz M: Docetaxel (Taxotere) as monotherapy in the treatment of hormone-refractory prostate cancer: Preliminary results. Semin Oncol 26:14-18, 1999 (suppl 17)[Medline]
4. Beer TM, Pierce WC, Lowe BA, et al: Phase II study of weekly docetaxel in symptomatic androgen-independent prostate cancer. Ann Oncol 12:1273-1279, 2001
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6. Petrylak DP, Macarthur RB, O’Connor J, et al: Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol 17:958-967, 1999
7. Savarese DM, Halabi S, Hars V, et al: Phase II study of docetaxel, estramustine and low-dose hydrocortisone in men with hormone-refractory prostate cancer: A final report of CALGB 9780. J Clin Oncol 19:2509-2516, 2001 8. Sinibaldi VJ, Carducci MA, Moore-Cooper S, et al: Phase II evaluation of docetaxel plus one-day oral estramustine phosphate in the treatment of patients with androgen-independent prostate carcinoma. Cancer 94:1457-1465, 2002[CrossRef][Medline]
9. 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
10. Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004
11. Petrylak DP, Tangen CM, Hussain MHA, et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513-1520, 2004 12. Eymard J-C, Joly F, Priou F, et al: Phase II randomized trial of docetaxel + estramustine versus docetaxel alone in patients with hormone-refractory prostate cancer: A final report. Proc Am Soc Clin Oncol 23:406, 2004 (abstr 4603)
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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