Recent Progress in the Clinical Development of Docetaxel (Taxotere)

As a result of their substantial antitumor activity, clinical development of the taxanes has moved rapidly from second-line treatment of anthracycline-refractory metastatic breast cancer to current evaluation in large, adjuvant trials. New information suggests that the mechanism of action of taxanes may include cell death by induction of apoptosis and by antiangiogenic properties. In vitro analyses demonstrate docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) to be 100-fold more potent than paclitaxel in bcl-2 phosphorylation and apoptotic cell death. Antiangiogenic effects of docetaxel are mediated by endothelial cell migration, proliferation, and microtubule formation, which occur at drug concentrations achieved clinically with standard dose. Current initiatives involve the development of the weekly schedules of taxane administration. Potential advantages to weekly docetaxel over paclitaxel include reduction in peripheral neuropathies and lack of arthralgia/myalgia syndrome. The recommended doses for phase II testing of weekly docetaxel are 35 to 45 mg/m2/wk, levels at which grade 3/4 neutropenia and nonhematologic toxicities are minimal. Weekly regimens under investigation combine docetaxel with alternative agents, including trastuzumab (Herceptin; Genentech, San Francisco, CA). The docetaxel plus trastuzumab combination demonstrates synergy in vitro, in contrast to additivity demonstrated with paclitaxel plus trastuzumab. Several trials of the docetaxel (every 3 week and weekly) plus trastuzumab combination are ongoing for which the preclinical observations of synergy are hoped to translate into greater clinical activity and improved survival. The development of additional docetaxel combinations, schedules, and regimens as a result of the newly available therapies in the management of breast cancer holds promise for the future.