Paclitaxel couplets with cyclophosphamide or cisplatin in metastatic breast cancer

Determining active combinations containing paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to treat metastatic breast cancer has been the focus of recent clinical development. Paclitaxel combined with either cyclophosphamide or cisplatin has several potential advantages: cisplatin and cyclophosphamide are active single agents against previously untreated metastatic breast cancer, colony-stimulating factors can modulate overlapping toxicities like myelosuppression, and no mechanisms of cross-resistance between paclitaxel and these agents are yet known. Major questions include the optimal schedule of administration and the sequence dependence of toxicities with these combinations. Paclitaxel schedules with cisplatin include either two dose levels using the 24-hour infusion or a novel biweekly 3-hour infusion. The sequence in the three available studies was paclitaxel followed by cisplatin. Hematologic toxicities were dose limiting with the biweekly and low-dose 24-hour paclitaxel/cisplatin combinations; with granulocyte colony-stimulating factor, neurotoxicity became a prominent cumulative toxicity of the high-dose paclitaxel/cisplatin combination. Response rates in the first-line treatment of metastatic breast cancer ranged from 49% to 85%. In the three completed studies with cyclophosphamide, paclitaxel has been administered over either 72, 24, or 3 hours. Paclitaxel followed by cyclophosphamide had greater hematologic toxicity than the opposite schedule or concurrent administration. Pharmacokinetic factors do not seem to account for this sequence-dependent toxicity. As expected, dose-limiting toxicity in all studies has been hematologic. However, granulocyte colony-stimulating factor has ameliorated myelosuppression and allowed considerable dose escalation of cyclophosphamide. This combination has demonstrated activity in previously treated patients with metastatic breast cancer, including the anthracycline-refractory subpopulation that will be reviewed.