Docetaxel (Taxotere) in combination: a step forward

Abstract

Docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) is a hemisynthetic derivative from European yew that inhibits tubulin depolymerization and enhances the formation of microtubule bundle aggregates, causing cell death. Activity against a variety of tumor types has been reported. Single-agent chemotherapy is rarely curative; hence, combination regimens are the logical next step in the attempt to improve tumor reduction and prolong survival. In preclinical studies, docetaxel has shown synergism with vinorelbine (Navelbine; Burroughs Wellcome Company, Research Triangle Park, NC), etoposide, cyclophosphamide, 5-fluorouracil, and methotrexate against a variety of murine tumors; in each case, at least 60% of the maximum tolerated dose could be administered without additional toxicity. Similar studies indicated an overlap in dose-limiting toxicity for docetaxel with cisplatin or doxorubicin, whereas with vincristine at least 80% of the maximum tolerated dose could be administered without additional toxicity. A number of docetaxel combinations are currently undergoing clinical evaluation and preliminary results appear to be encouraging. In a phase I trial, the docetaxel/5-fluorouracil combination exhibited activity against refractory solid tumors; grade IV neutropenia was observed, but there was no increase in gastrointestinal toxicity. The docetaxel/doxorubicin combination demonstrated impressive antitumor activity as front-line therapy for metastatic breast cancer (response rate, 70%), with little evidence of mucositis and dose-limiting toxicity experienced by only a minority of patients. Among 12 heavily pretreated phase I patients, the docetaxel/cyclophosphamide combination produced two partial responses in patients with breast cancer; three patients had febrile neutropenia and two had grade II mucositis. The docetaxel/vinorelbine combination produced responses at all dose levels as front-line therapy for metastatic breast cancer; dose-limiting toxicity was experienced by two patients, but only when the vinorelbine dose was raised to 22.5 mg/m2. In phase II studies in non-small cell lung cancer, preliminary results have shown the docetaxel/cisplatin combination to have a promising level of activity and an acceptable toxicity profile. Future trials will continue to evaluate the role of docetaxel in combination and in sequential regimens, most particularly in metastatic breast cancer and non-small cell lung cancer.