Phase I dose-finding and pharmacokinetic study of docetaxel and vinorelbine as first-line chemotherapy for metastatic breast cancer.

BACKGROUND AND PURPOSE: Anthracycline-containing regimens are widely used in advanced breast cancer. However, there is a need for new, non-anthracycline regimens that are active in patients for whom anthracyclines are contraindicated. The aim of this study was to determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs) and recommended doses of docetaxel and vinorelbine as first-line chemotherapy in patients with metastatic breast cancer. The pharmacokinetics of both drugs was also evaluated. PATIENTS AND METHODS: Thirty-four women with first-line metastatic breast cancer were treated with docetaxel, 60-100 mg/m2 (day 1), and vinorelbine, 20-22.5 mg/m2 (days 1 and 5), repeated every three weeks and administered on an outpatient basis. RESULTS: Two MTDs were determined: MTD1 was defined at the dose level using docetaxel 75 mg/m2, and vinorelbine 22.5 mg/m2 DLT being a grade 3 stomatitis that was more related to the dose of vinorelbine than that of docetaxel. Therefore, the study continued with a fixed dose of vinorelbine, 20 mg/m2, and docetaxel 85-100 mg/m2. MTD2 was defined at the dose level combining docetaxel, 100 mg/m2, and vinorelbine, 20 mg/m2; DLTs were grade 3 stomatitis and severe asthenia. Fluid retention was observed in 41% of patients but was never severe or a reason for patient discontinuation. In comparison with historical experience, Daflon 500 did not seem to increase the efficacy of the three-day corticosteroid premedication by further reducing the incidence or severity of fluid retention. No significant neurotoxicity was observed and no patient discontinued the study due to this site effect. Activity was observed at all dose levels and at all metastatic sites, with an overall response rate of 71% (95% CI: 52.0%-85.8%). The median time to progression was 31.4 weeks (95% CI: 12-48 weeks) and median survival was 15.6 months (95% CI: 2.6-26.6 months). The pharmacokinetics of docetaxel and vinorelbine were not modified between day 1 and day 3 when the two drugs were combined with the day 1 administration schedule used in this study. CONCLUSION: The recommended doses for phase II studies are docetaxel, 75 mg/m2 (day 1), plus vinorelbine, 20 mg/m2 (days 1 and 5), repeated every three weeks. At these doses, the combination was found to be active and well tolerated.

Phase II study of sequential administration of docetaxel followed by doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer.

PURPOSE: To evaluate the feasibility and efficacy of a sequential administration of four cycles of docetaxel (100 mg/m(2) every 3 weeks) followed by four cycles of doxorubicin and cyclophosphamide (AC; 60/600 mg/m(2) every 3 weeks), with subsequent consolidation with docetaxel or AC, as first-line chemotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-eight patients received 443 cycles of chemotherapy (median, 11 cycles/patient; range, 1 to 13 cycles). A total of 267 cycles of docetaxel (60.3%) and 176 of AC (39.7%) were given. Consolidation therapy was given to 33 patients (29 with docetaxel). RESULTS: Grade 4 neutropenia was the most frequent toxicity (83% of patients). This was not cumulative and was rarely complicated by febrile neutropenia or severe infection. The nonhematologic safety profile was favorable: there were no grade 4 adverse events, and grade 3 episodes were infrequent. Docetaxel-specific toxicities were generally not severe. With a median cumulative doxorubicin dose of 397 mg/m(2) (range, 150 to 543 mg/m(2)), two incidences of unrelated congestive heart failure after further treatment with anthracyclines and two of asymptomatic left ventricular ejection fraction decrease were observed. Among the 42 assessable patients, five (12%) had complete and 25 (60%) had partial responses, for an overall response rate of 71% (95% confidence interval, 55% to 84%). Median duration of response was 53 weeks (range, 12 to 72 weeks), and median time to progression was 46 weeks (range, 3 of 72 weeks). With a median follow-up of 40.4 months, median survival was 32 months (range, 2 to 55 months). CONCLUSION: This docetaxel-based sequential schedule is safe and effective in first-line therapy for MBC, without incurring cumulative toxicity, and provides a feasible chemotherapeutic option in this clinical setting.