A Phase I Study of Estramustine, Weekly Docetaxel, and Carboplatin Chemotherapy in Patients with Hormone-Refractory Prostate Cancer
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284 Vol. 11, 284–289, January 1, 2005 Clinical Cancer Research A Phase I Study of Estramustine, Weekly Docetaxel, and Carboplatin Chemotherapy in Patients with Hormone-Refractory Prostate Cancer William K. Oh,1 Elizabeth Hagmann,1 docetaxel is 43 mg/m2 combined with estramustine and Judith Manola,2 Daniel J. George,1 carboplatin. PSA declines were seen at every dose level. Timothy D. Gilligan,1 Joseph O. Jacobson,4 Matthew R. Smith,3 Donald S. Kaufman,3 and INTRODUCTION Philip W. Kantoff 1 Prostate cancer remains the second leading cause of cancer 1Lank Center for Genitourinary Oncology, Department of Medical death in men in the United States (1). Although initially Oncology and 2Department of Biostatistical Science, Dana-Farber responsive to androgen deprivation therapy, prostate cancer Cancer Institute; 3Department of Medical Oncology, Massachusetts almost always becomes refractory to hormonal manipulation (2) 4 General Hospital Cancer Center, Boston, Massachusetts; and North Mitoxantrone chemotherapy combined with corticosteroids Shore Cancer Center, Peabody, Massachusetts provides palliative benefit in the management of symptomatic disease, but no improvement in survival (3, 4). Phase I and II ABSTRACT trials have shown that the combination of docetaxel and Purpose: To define the maximal tolerated dose, safety, estramustine is effective and well tolerated in patients with and efficacy of docetaxel, carboplatin, and estramustine in hormone refractory prostate cancer (HRPC; refs. 5–9). Two patients with hormone-refractory prostate cancer (HRPC). recently reported large phase III trials showed that docetaxel Methods: Patients with HRPC received docetaxel for 3 combined with either prednisone or estramustine was associated weeks, followed by a rest week. Docetaxel (20, 25, 30, 36, or with a survival benefit compared with mitoxantrone and 43 mg/m2) was given on days 2, 9, and 16 of a 28-day cycle. prednisone in the treatment of HRPC (10, 11). Platinum compounds have been studied both as single Patients also received estramustine (140 mg p.o. three times agents and in combination regimens in the treatment of daily on days 1-5, 8-12, and 15-19) and carboplatin [area hormone refractory prostate cancer (12–22). Yagoda et al. under the curve, AUC (5) or (6) on day 2]. (12) reported a 12% partial remission and 24% stable disease Results: Thirty patients were treated. Five patients rate in 25 patients with measurable HRPC treated with cisplatin. received carboplatin [AUC (6)] but experienced delayed Merrin (13) noted partial or complete responses in 17 of 54 thrombocytopenia. After a protocol amendment, 25 subse- (31%) patients treated with weekly cisplatin, whereas Moore quent patients received carboplatin [AUC (5)]. Median age et al. (14) found a 10% response rate in 29 patients treated with was 64 years. Median prostate-specific antigen (PSA) was a similar regimen. Carboplatin has a distinct toxicity profile from 117 ng/mL. Fifty-three percent received prior ketoconazole cisplatin that allows for potentially equivalent antitumor effect with less toxicity (15). Miglietta et al. (16) treated 35 patients and 10% had mitoxantrone. No dose-limiting toxicities were 2 noted. Although maximal tolerated dose was not reached, with weekly carboplatin at a dose of 150 mg/m . Prostate- z docetaxel dose escalation was stopped at 43 mg/m2. specific antigen (PSA) declines of 50% were seen in 28%, with a mean duration of about 6 months. Also, 27% with Significant myelosuppression was not seen until the highest measurable disease had a partial response. Jungi et al. (17) dose level, when seven and four patients experienced grade treated 27 patients with carboplatin 400 mg/m2 every 28 days 3 and 4 toxicities, respectively. Among all patients, PSA and noted decreased pain and/or an improved performance declines of z50% occurred in 63%. At the recommended status in 48%. phase II dose, PSA declines of z50% occurred in 75% (95% Platinum compounds also have been studied in combina- confidence interval, 43-95). Four of 14 (29%) patients with tion regimens. Cisplatin or carboplatin was combined with measurable disease had partial responses. Median survival etoposide and estramustine in men with poorly differentiated was 14.6 months. HRPC (18). Fifteen of 30 patients experienced tumor response Conclusions: Estramustine, docetaxel, and carboplatin by PSA declines or decrease in measurable disease. Several are well tolerated and active in HRPC. Myelosuppression is trials have evaluated the efficacy of estramustine, paclitaxel, and the primary toxicity. The recommended phase II dose of carboplatin (19–21). In one multicenter trial, 56 patients were treated with estramustine, weekly paclitaxel, and carboplatin every 4 weeks. PSA declines of z50% were seen in 67%, and Received 7/28/04; revised 9/24/04; accepted 10/21/04. measurable responses were noted in 15 of 33 patients (45%; ref. Grant support: Aventis Pharmaceuticals. 19). The Cancer and Leukemia Group B completed a phase II The costs of publication of this article were defrayed in part by the triall of estramustine, docetaxel and carboplatin given on an payment of page charges. This article must therefore be hereby marked every 3 week schedule and showed PSA declines >50% in 68% advertisement in accordance with 18 U.S.C. Section 1734 solely to of patients and measurable responses in 52% (22). indicate this fact. Requests for reprints: William K. Oh, Lank Center for Genitourinary In summary, platinum compounds have modest but distinct Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA single agent activity in HRPC. However, combined with taxanes 02115; E-mail: [email protected]. and estramustine, carboplatin may offer the greatest potential for D2005 American Association for Cancer Research. benefit. In addition, since weekly docetaxel chemotherapy is Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2005 American Association for Cancer Research. Clinical Cancer Research 285 associated with less myelotoxicity than every 3 week docetaxel, pelvis, bone scans, and chest X-ray s. Treatment toxicity was particularly in older patients who may have received prior graded according to the National Cancer Institute Common radiotherapy, we undertook this phase I trial to determine the Toxicity Criteria. All patients with evidence of measurable maximum tolerated dose as well as the safety and efficacy of disease underwent tumor response evaluated by the Response weekly docetaxel in combination with estramustine and Evaluation Criteria in Solid Tumors (26). PSA response was carboplatin. defined according to the PSA Working Group and required a z50% reduction in PSA sustained for at least 4 weeks (23). PATIENTS AND METHODS Statistical Methods. Descriptive statistics were used to Eligibility. Patients had histologically confirmed prostate characterize patients at baseline. Exact binomial confidence cancer and showed progression despite androgen deprivation intervals were provided for response rates. The method of therapy. Progression was defined as either an increase in the Kaplan-Meier (27) was used to estimate overall survival. product of bidimensional diameters of one or more radiograph- ically documented sites of measurable disease or by PSA progression according to the PSA Working Group criteria (23). RESULTS Patients had Eastern Cooperative Oncology Group performance Thirty-two patients were registered for this trial. Two statuses of 0 to 2. Required laboratory values included a WBC patients withdrew prior to starting therapy; one who was count z3,000/mL, platelet count z100,000/mL, serum creatinine ineligible before treatment because of a deep venous thrombosis V2.0 mg/dL, bilirubin less than or equal the upper limit of normal, diagnosed within 1 year and a second who began treatment for AST V1.5 times the upper limit of normal, and testosterone levels brain metastases. Therefore, 30 patients are included in this V50 ng/mL. Prior chemotherapy was allowed if it did not include analysis. Baseline patient characteristics are listed in Table 1. taxanes or platinum derivatives. Patients with significant Most patients had received prior secondary hormonal therapies peripheral neuropathy and current congestive heart failure (New (53% ketoconazole, 33% PC-SPES) and 10% of patients had York Heart Association Class 2 or higher) were excluded. At least received prior chemotherapy with mitoxantrone. All patients had 4 weeks must have elapsed from radiation or antiandrogen a performance status of 0 or 1. therapies. No patients were allowed with myocardial infarction or This study was initiated with a carboplatin dose of AUC deep venous thrombosis within 1 year or significant change in (6). Five patients were treated at this dose of carboplatin, three anginal pattern within 6 months of study entry. All patients signed at the first dose level, and two at the second dose level. Two of an informed consent form approved by the institutional review three patients in the first dose level experienced significant dose board of the Dana-Farber/Partners Cancer Care before partici- pating in this trial. Treatment Plan. Patients were treated with one of five escalating doses of docetaxel for three consecutive weeks Table 1 Baseline patient characteristics followed by a rest week. Docetaxel was given i.v. on days 2, Characteristic % 9, and 16 of a 28-day cycle. Patients received the same dose of Age Median 64 treatment to which they were assigned for each cycle of Range 46–82 chemotherapy, unless a dose-reduction was instituted secondary Performance status 0 10 33 to toxicity. Dexamethasone was given orally at a dose of 8 mg, 12067 f Time since diagnosis Median (y) 6 12 hours and 1 hour prior to and again 12 hours after Range (y) 0.5–10.5 docetaxel. Carboplatin was given i.v. at a dose AUC (6) or (5), Unknown 7 over 60 minutes, on day 2 of each cycle (24). Creatinine PSA at study entry Median 117.5 clearance was estimated using the Cockcroft-Gault formula (25). Range 5.9–6,290.0 Testosterone at study Median 20 Estramustine was given orally at a dose of 140 mg three times entry daily on days 1 to 5, 8 to 12, and 15 to 19 of each cycle.