Docetaxel in combination chemotherapy for metastatic breast cancer

Due to its novel mechanism of action, docetaxel has significant in vitro activity against a variety of solid tumors, including breast cancer. In phase II clinical trials, docetaxel 100 mg/m2 every 3 weeks has shown substantial single-agent activity in patients with both previously untreated and heavily pretreated metastatic breast cancer. As single-agent chemotherapy is rarely curative in this setting, docetaxel has been combined with other anticancer agents with proven efficacy against breast cancer (doxorubicin, vinorelbine, fluorouracil, cyclophosphamide, cisplatin, and doxorubicin plus cyclophosphamide) in an attempt to increase efficacy and prolong patient survival. The aims of these phase I dose-finding studies were to define the maximum tolerated dose, the dose-limiting toxicity, the recommended dose, and the safety profile of each combination. All patients had previously untreated metastatic breast cancer. Each study followed a dose-escalation design; patients were initially assigned to the lowest dose level, with at least three patients treated at each level before enrolling patients at the next level. All patients received corticosteroid-based premedication, but granulocyte colony-stimulating factor was not routinely used. The docetaxel/doxorubicin and docetaxel/ vinorelbine studies have been recently completed; in both studies, the dose-limiting toxicity was neutropenia. Other adverse events were generally mild. No significant cardiotoxicity (with docetaxel/doxorubicin) or neurotoxicity (with docetaxel/vinorelbine) was observed, and no patients discontinued treatment because of fluid retention. Both combinations are well tolerated without granulocyte colony-stimulating factor support. The recommended dose for docetaxel/doxorubicin in phase II studies is either 75/50 or 60/60 mg/m2 administered on day 1 every 3 weeks; impressive response rates of 90% and 66%, respectively, were achieved with these dose levels. The recommended dose for docetaxel/vinorelbine is docetaxel 85 mg/m2 on day 1 and vinorelbine 20 mg/m2 on days 1 and 5, repeated every 3 weeks; the efficacy of this combination is still being evaluated, but preliminary results are promising. For both combinations, the time to disease progression and median response duration were not available at the time of this report. Combination studies with fluorouracil, cisplatin, and cyclophosphamide, and a study of sequential administration with doxorubicin + cyclophosphamide, are ongoing. Interim results indicate that these docetaxel-based combinations have acceptable safety profiles and encouraging levels of antitumor activity. The full results of these studies will help to elucidate the potential contribution of docetaxel-based combination chemotherapy to the management of metastatic breast cancer.