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Originally published as JCO Early Release 10.1200/JCO.2008.16.9524 on September 15 2008 © 2008 American Society of Clinical Oncology. Prospective Randomized Study Comparing Docetaxel, Estramustine, and Prednisone With Docetaxel and Prednisone in Metastatic Hormone-Refractory Prostate Cancer
From the Departments of Medical Oncology and Urology, Centre du Cancer, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain; Department of Medical Oncology, Centre Hospitalier Interrégional Edith Cavell Site Parc Leopold, Brussels; Department of Medical Oncology, Clinique Saint-Luc, Bouge; Department of Medical Oncology, Hôpital de Jolimont, Haine-St Paul; Department of Medical Oncology, Hôpital St-Joseph, Gilly; Department of Medical Oncology, Clinique Notre Dame, Charleroi; Department of Medical Oncology, Clinique Notre Dame, Tournai; Department of Medical Oncology, Clinique Notre Dame de Grâce, Gosselies; Department of Medical Oncology, Clinique St-Pierre, Ottignies; Department of Medical Oncology, AZ Klina, Brasschaat; Department of Medical Oncology, St Nikolaus-Hospital, Eupen; and Department of Medical Oncology, Université Catholique de Louvain, Mont-Godinne and Saint-Elisabeth, Yvoir and Namur, Belgium Corresponding author: Jean-Pascal Machiels, MD, PhD, Medical Oncology Unit, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium; e-mail: Jean-pascal.Machiels{at}uclouvain.be
Purpose To assess the efficacy and toxicity of the addition of estramustine to docetaxel (D) for the treatment of metastatic hormone-refractory prostate cancer.
Patients and Methods One hundred fifty patients were randomly assigned to D alone (35 mg/m2 on days 2 and 9, every 3 weeks) or D in combination with estramustine (D/E; 280 mg orally three times a day on days 1 to 5 and 8 to 12, every 3 weeks). All patients received prednisone (10 mg/d). The primary end point was prostate-specific antigen (PSA) response rate, which was defined as a decrease in PSA Results The PSA response rate was not statistically different between the two groups. PSA of less than 4 ng/mL occurred in 29 (41%) of 71 patients receiving D/E and in 17 (25%) of 69 patients receiving D (P = .05). No significant differences were found for median time to PSA progression (D/E, 6.9 months; D, 7.3 months) or median overall survival time (D/E, 19.3 months; D, 21 months). More patients had at least one grade 3 or 4 toxicity with D/E (45%) compared with D (21%; P = .005), mainly as a result of grade 3 or 4 GI toxicity (P = .05). Serious adverse events were more frequent with D/E (n = 20) than with D (n = 9; P = .04). Conclusion The addition of estramustine to weekly D does not provide any clinically relevant advantage. Both regimens are well tolerated, although the toxicity profile favors D without estramustine.
Prostate cancer is the most frequent cancer and the second most common cause of cancer death in men. Metastatic hormone-refractory prostate cancer (M+ HRPCa) is an incurable disease. As demonstrated in the TAX 327 and Southwest Oncology Group (SWOG) 99-16 studies, treatment with mitoxantrone and corticosteroids results in an overall survival time of approximately 16 months.1-3 In older studies, this combination improved bone pain but did not increase survival.4,5 Docetaxel (D), a semisynthetic taxoid that promotes tubulin assembly and inhibits microtubule depolymerization, has been shown to improve median survival and clinical outcome in patients with M+ HRPCa.1-3,6 In the TAX 327 study, median survival increased from 16.3 months in the mitoxantrone group to 19.2 months in the D group (administered every 3 weeks).1,2 In the SWOG 99-16 study, median survival was longer in patients treated with D and estramustine (D/E) compared with those treated with mitoxantrone alone (17.5 v 15.6 months, respectively).3 Estramustine phosphate is a nitrogen mustard derivative of estradiol-17-β-phosphate, which exerts an antineoplastic effect by interfering with microtubule dynamics and by reducing testosterone plasma levels.7,8 Estramustine has minor activity in M+ HRPCa but shows synergistic activity in vitro and in preclinical models with other antimicrotubule agents such as vinblastine, paclitaxel, and D.8-12 In routine clinical practice, the combination of D/E is controversial. Indirect comparisons between the SWOG 99-16 and the TAX 327 studies suggest that D monotherapy offers similar improvements in survival and prostate-specific antigen (PSA) response rate as the D/E combination.1-3 In contrast, various phase II studies, small randomized trials, and a meta-analysis support the hypothesis that D/E could improve the PSA response rate compared with D alone.6,13-20 To assess the impact of the addition of estramustine to D for PSA response rate and toxicity, we conducted a randomized, prospective, multicenter study comparing D versus D/E in M+ HRPCa patients.
Eligibility Criteria Eligibility criteria included histologically proven prostate adenocarcinoma, Eastern Cooperative Oncology Group performance status of 0 to 2, documented metastatic disease, effective androgen deprivation (testosterone level < 50 ng/dL), compliance with the antiandrogen withdrawal period if applicable (at least 4 weeks for flutamide or nilutamide and at least 6 weeks for bicalutamide), no prior chemotherapy (with the exception of estramustine phosphate and a wash-out period of at least 6 weeks), neutrophil count more than 1.5 x 109/L, hemoglobin level more than 9 g/dL (after transfusion, if required), platelet count more than 100 x 109/L, total bilirubin less than the institution's upper normal limit, and ALT and AST less than 2.5x the upper normal limit. Patients with disease progression who had started bisphosphonate therapy before inclusion were allowed to continue this medication, but the initiation of a bisphosphonate at inclusion or during the study was not permitted. Patients were required to have documented radiologic progression (Response Evaluation Criteria in Solid Tumors) or biochemical disease progression (defined as at least two consecutive increases in PSA over a baseline value taken at least 1 week apart). The exclusion criteria were as follows: prior radionuclide therapy, prior radiotherapy to more than 25% of the bone marrow, known brain or leptomeningeal involvement, symptomatic peripheral neuropathy more than grade 1, and other serious illness or medical conditions. The study was approved by the independent ethics committee and the Belgian Health Authority and was conducted in accordance with the Declaration of Helsinki (October 2000).
Study Objectives
Pretreatment Evaluation and Follow-Up
Design
D, D/E, and Prednisone Administration
Outcome Secondary end points were time to PSA progression, PSA response duration, event progression-free survival, survival, response rate according to RECIST criteria, toxicity, and quality of life. In PSA nonresponders, PSA progression was defined as a 25% increase (at least 5 ng/mL) over the nadir value confirmed by a second value. In patients experiencing progression after a first PSA response, PSA progression was defined as a 50% increase (at least 5 ng/mL) over the nadir value, confirmed by a second value. The time to PSA progression was measured from the date of random assignment to the date of PSA progression. The PSA response duration was the time interval between the date of the first 50% decline in PSA until the date at which the PSA value increased by 50% above the nadir (provided that the increase was at least 5 ng/mL). Event progression-free survival was the time interval between the date of random assignment and the date of event progression or the date of death. An event was defined as either PSA progression or tumor progression. Overall survival was the time interval between the date of random assignment and the date of death or the date of last follow-up. In patients with measurable disease, the objective response rate was calculated according to the RECIST criteria.23 Adverse effects were recorded according to the National Cancer Institute Common Toxicity Criteria (version 2). Quality of life was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30.24,25 The relative dose-intensity for D and estramustine was calculated as the dose-intensity divided by the planned dose-intensity and then multiplied by 100.
Statistical Methods
Patient Characteristics A total of 150 M+ HRPCa patients from 19 Belgian centers were randomly assigned between February 2004 and August 2006. One patient randomly assigned to the D arm was ineligible because of an error in diagnosis (lung cancer). This patient was not analyzed for toxicity or response because no data were collected. Thus, 149 patients, 74 in the D arm and 75 in the D/E arm, were assessable for toxicity and efficacy. Seventy-one patients were assessable for PSA response rate in the D/E group and 69 were assessable in the D group, in accordance with the consensus guidelines (Fig 1).21 Baseline characteristics were not significantly different between the two arms (Table 1). Eighteen patients in the D/E arm and 20 patients in the D arm had been previously treated with estramustine before enrollment.
Acute Adverse Events and Dose-Intensity The most frequent grade 1 or 2 toxicities were fatigue (D/E: 61%, D: 61%), anemia (D/E: 57%, D: 48%), diarrhea (D/E: 36%, D: 28%), and peripheral neuropathy (D/E: 23%, D: 17%). These complications did not result in any treatment interruption or dose modification and were not statistically different between the two arms. Grade 3 or 4 adverse events are listed in Table 2. In the D/E group, the most frequent grade 3 or 4 toxicities were venous thrombosis (n = 9, 12%) and digestive toxicity (n = 11, 15%), which included nausea (n = 3, 4%), vomiting (n = 4, 5%), diarrhea (n = 4, 5%), and esophagitis (n = 3, 4%). In patients receiving D, the most frequent grade 3 or 4 toxicities were anemia (n = 7, 9%) and venous thrombosis (n = 6, 8%). More patients receiving D/E had at least one grade 3 or 4 toxicity (n = 33, 45%) compared with D alone (n = 16, 21%; P = .005), with the main difference relating to grade 3 or 4 digestive toxicity (D/E: 15%, D: 4%; P = .05). Thirteen (17%) and six patients (8%) had at least one grade 3 or 4 cardiovascular event on the D/E and D arms, respectively, but this difference was not statistically significant (P = .14). Of note, four patients who received D/E developed cardiac infarction or ischemia, but these adverse events did not occur in patients receiving D alone. Serious adverse events were reported more frequently in patients treated with D/E than with D (20 v nine serious adverse events, respectively; P = .04).
The relative dose-intensity of D was 93% and 91% for the D/E and D arms, respectively. The relative dose-intensity of estramustine was 83%. The median number of chemotherapy cycles administered was six in both groups.
Efficacy
Median follow-up time at the time of assessing survival was 16 months (range, 0.5 to 44.1 months). Median survival time was the same between the two groups (D/E, 19.3 months; D, 21 months; Fig 2).
In this study, the addition of estramustine to weekly D did not demonstrate any clinically relevant advantage. The primary objective of this study was to compare the response between D/E combination therapy and D monotherapy, as determined by a decrease in PSA of  50%. In contrast with two smaller randomized phase II trials that showed an improvement in the PSA response rate when D was combined with estramustine, this study found no significant difference between the two groups.18,19 Eymard et al18 randomly assigned 92 patients to either D 75 mg/m2 (day 1, every 3 weeks) or D 70 mg/m2 (day 2, every 3 weeks) plus oral estramustine 280 mg twice daily (days 1 through 5). A PSA response 50% was found in 68% of the patients receiving D/E compared with only 30% of the patients receiving D. Similarly, Caffo et al19 evaluated D 70 mg/m2 every 3 weeks with or without estramustine (280 mg three times daily on days 1 through 5) in 95 hormone-refractory patients. The PSA response 50% occurred in 75% of the D/E patients compared with 40% of the D alone patients. However, there are some differences between these two last trials and this study; fewer patients were enrolled, and D was administered every 3 weeks compared with weekly in our study. This is of importance because the TAX 327 study showed that, in contrast to the D regimen of every 3 weeks, the weekly regimen did not improve survival when compared with mitoxantrone. We used the regimen developed by Oudard et al6 that divided the every 3 week regimen into two administrations (days 2 and 9). This D administration schedule has been shown to significantly improve the PSA response rate and the median time to PSA progression compared with mitoxantrone. In the Oudard et al6 study, survival favored D versus mitoxantrone, but it did not reach statistical significance (18.4 v 13.4 months, respectively; P = .3), most probably because of the low number of patients included. Compared with the Caffo et al19 and Eymard et al18 studies, we also used a higher dose of estramustine. However, the relevance of this higher dose is highly questionable because no difference was found in a randomized phase II trial that compared low-dose estramustine (140 mg three times daily on days 1 to 5) with high-dose estramustine (280 mg three times daily on days 1 to 5) in combination with D 70 mg/m2 (day 2, every 3 weeks). This suggests that lose-dose estramustine is sufficient or that the addition of estramustine to D is not beneficial.
Survival is the only validated end point in clinical trials investigating patients with M+ HRPCa. Although our study was not powered to detect a survival advantage, the survival curves for both D/E and D looked similar. It is unlikely that greater patient numbers would have detected any difference in survival (Fig 2). PSA response, as a surrogate for survival after D-based chemotherapy, was investigated in the TAX 327 and SWOG 99-16 trials.26,27 In both studies, a PSA decrease Both regimens were well tolerated, although the toxicity profile favored D alone. More patients in the D/E group (45%) had at least one grade 3 or 4 toxicity compared with patients who received D (21%; P = .005). Indirect comparisons between the two large phase III trials (SWOG 99-16 and TAX 327) comparing either D/E or D with mitoxantrone also suggested that estramustine increases toxicity, particularly with regard to cardiovascular, digestive, and metabolic toxicities.1-3 This is in contrast with previous reports that showed that no significant toxicity differences were found between D/E and D.18,19 Given that our study included more patients, it was easier to detect a significant difference. Additionally, quality-of-life scores evaluated during treatment were not in favor of D/E (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30); the mean items score favored patients not receiving estramustine at all time points throughout the study except at baseline where the scores were identical (data not shown). However, the score did not reach statistical significance at any time point. Of importance, we recorded a nonsignificant increased rate of cardiac (infarction/ischemia) and venous thromboembolic events in the D/E arm compared with the D arm (17% v 8%, respectively), despite the preventative administration of acenocoumarol. Our findings are in accordance with the data published by Oudard et al6 using the same regimens and with the SWOG trial, where the rate of cardiovascular events in patients receiving D/E was 15%. This raises the question concerning an optimal thromboprophylaxis regimen to prevent estramustine thrombotic events. When we initiated our trial, it was common practice to add low-dose vitamin K antagonists to estramustine based on the positive findings of small trials.13,28 Prophylactic anticoagulation therapy was not planned in the SWOG 99-16 study, but because of the high incidence of cardiovascular thrombotic events, the protocol was amended to include prophylactic low-dose warfarin and aspirin. Unfortunately, the addition of these drugs failed to reduce the number of thromboembolic events.5 Low-dose administration of warfarin and aspirin can produce a variable effect on the international normalized ratio as a result of genetic polymorphisms, diet, concomitant medications, vitamin K intake, and so on.5,6,13,18,29 This makes it difficult to standardize anticoagulation therapy using this approach, especially in the absence of a planned target international normalized ratio. It is also unlikely that vitamin K antagonists, which are more effective with venous complications, could prevent the arterial thrombotic events observed. Some studies combined low-dose aspirin with warfarin, but their prophylactic effect was unclear.5,13 The impact of prophylactic vitamin K antagonists, as well as the efficacy of other antithrombotic agents, such as low molecular weight heparin and clopidogrel, needs to be investigated prospectively in randomized trials. In conclusion, the addition of estramustine to D in our study did not demonstrate any efficacy advantage. Both regimens were well tolerated, although the toxicity profile favored D without estramustine. The addition of estramustine to D cannot be recommended to treat patients with M+ HRPCa outside of a clinical trial setting.
The author(s) indicated no potential conflicts of interest.
Conception and design: Jean-Pascal Machiels, Filomena Mazzeo, Marylene Clausse, Bertrand Filleul, Luc Marcelis, Brigitte Honhon, Lionel D’Hondt, Catherine Dopchie, Vincent Verschaeve, Lionel Duck, Didier Verhoeven, Peter Jousten, Marie-Alix Bonny, Anne-Marie Moxhon, Bertrand Tombal, Joseph Kerger Administrative support: Anne-Marie Moxhon Provision of study materials or patients: Jean-Pascal Machiels, Filomena Mazzeo, Marylene Clausse, Bertrand Filleul, Luc Marcelis, Brigitte Honhon, Lionel D’Hondt, Catherine Dopchie, Vincent Verschaeve, Lionel Duck, Didier Verhoeven, Peter Jousten, Marie-Alix Bonny, Bertrand Tombal, Joseph Kerger Collection and assembly of data: Jean-Pascal Machiels, Marie-Alix Bonny, Bertrand Tombal Data analysis and interpretation: Jean-Pascal Machiels, Marie-Alix Bonny, Bertrand Tombal Manuscript writing: Jean-Pascal Machiels, Bertrand Filleul, Didier Verhoeven, Anne-Marie Moxhon, Bertrand Tombal Final approval of manuscript: Jean-Pascal Machiels, Filomena Mazzeo, Marylene Clausse, Bertrand Filleul, Luc Marcelis, Brigitte Honhon, Lionel D’Hondt, Catherine Dopchie, Vincent Verschaeve, Lionel Duck, Didier Verhoeven, Peter Jousten, Marie-Alix Bonny, Anne-Marie Moxhon, Bertrand Tombal, Joseph Kerger
We are grateful to the following doctors in Luxembourg and Belgium for including patients in this study: Dr Berchem, Dr Richard, Dr Rojas, Dr Holbrechts, Dr Kains, and Dr Hamdan. We also thank Aileen Eiszele, BA(Hons), DipEd, for assistance with editing this manusript.
published online ahead of print at www.jco.org on September 15, 2008. Supported by an educational grant from Sanofi-Aventis, Brussels, Belgium. Preliminary results were presented at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical trial information can be found for the following: NCT00541281 [ClinicalTrials.gov] .
1. Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 35:1502-1512, 2004 2. Berthold DR, Pond GR, Soban F, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: Updated survival in the TAX 327 study. J Clin Oncol 26:242-245, 2008 3. Petrylak DP, Tangen CM, Hussain MH, et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced prostate cancer. N Engl J Med 35:1513-1520, 2004 4. Kantoff PW, Halabi S, Conaway M, et al: Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: Results of the Cancer and Leukemia Group B 9182 study. J Clin Oncol 17:2506-2513, 1999 5. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: A Canadian randomized trial with palliative end points. 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Williams JF, Muenchen HJ, Kamradt JM, et al: Treatment of androgen-independent prostate cancer using antimicrotubule agents docetaxel and estramustine in combination: An experimental study. Prostate 44:275-278, 2000[CrossRef][Medline] 11. Oudard S, Legrier ME, Boye K, et al: Activity of docetaxel with or without estramustine phosphate versus mitoxantrone in androgen dependent and independent human prostate cancer xenografts. J Urol 169:1729-1734, 2003[CrossRef][Medline] 12. Hamilton A, Muggia F: Estramustine potentiates taxane in prostate and refractory breast cancers. Oncology 15:S40-S43, 2001 (suppl 7) 13. 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] 14. Weitzman AL, Shelton G, Zuech N, et al: Dexamethasone does not significantly contribute to the response rate of docetaxel and estramustine in androgen independent prostate cancer. J Urol 163:834-837, 2000[CrossRef][Medline] 15. 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 16. Boehmer A, Anastasiadis AG, Feyerabend S, et al: Docetaxel, estramustine and prednisone for hormone-refractory prostate cancer: A single-center experience. Anticancer Res 25:4481-4486, 2005 17. Sitka Copur M, Ledakis P, Lynch J, et al: Weekly docetaxel and estramustine in patients with hormone-refractory prostate cancer. Semin Oncol 28:S16-S21, 2001 (suppl 15)[CrossRef] 18. 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 19. Caffo O, Sava T, Comploj E, et al: Docetaxel and estramustine as first-line chemotherapy for patients with hormone-refractory advanced prostate cancer: Final results of a multicentric phase II randomized trial. J Clin Oncol 25:654s, 2007 (suppl; abstr 15552) 20. 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] 21. Bubley GJ, Carducci M, Dahut W, et al: Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: Recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 17:3461-3467, 1999 22. Pocock SJ, Simon R: Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 31:102-115, 1975 23. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 24. Fayers P, Bottomley A: Quality of life research within the EORTC: The EORTC QLQ-C30. Eur J Cancer 38:125-133, 2002[CrossRef] 25. Fayers P, Aaronson NK, Bjordal K, et al: EORTC QLQ-C30 Scoring Manual (ed 3). Brussels, Belgium, European Organisation for Research and Treatment of Cancer, 2001 26. Armstrong AJ, Garrett-Mayer E, Yang Y, et al: Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer. J Clin Oncol 25:3965-3970, 2007 27. Petrylak DP, Ankerst DP, Jiang CS, et al: Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99-16. J Natl Cancer Inst 98:516-521, 2006 28. Petrylak DP, Shelton GB, England-Owen C, et al: Response and preliminary survival results of a phase II study of docetaxel (D) + estramustine (E) in patients (Pts) with androgen-independent prostate cancer (AIPCA). Proc Am Soc Clin Oncol 19:334s, 2000 (abstr 1312) 29. Bodin L, Verstuyft C, Tregouet DA, et al: Cytochrome P450 2C9 and vitamin K epoxide reductase genotypes as determinants of acenocoumarol sensitivity. Blood 106:135-140, 2005 Submitted February 26, 2008; accepted June 19, 2008.
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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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ABSTRACT
INTRODUCTION
