Combination paclitaxel and vinorelbine therapy: in vitro cytotoxic interactions and dose-escalation study in breast cancer patients previously exposed to anthracyclines

The objectives of the present study were first to analyse the in vitro cyto toxic interactions between paclitaxel and vinorelbine in order to approach the optimal clinical scheduling in cancer patients, and second to determine the maximum-tolerated doses of this combination without haematopoietic gro wth factor in breast cancer patients previously exposed to anthracyclines. The in vitro cytotoxicity of paclitaxel and vinorelbine alone, in combinati on and in sequence, was evaluated against the established human doxorubicin -resistant MCF7 (MCF7-R) breast carcinoma cell line using the standard isob ologram methodology. Regarding the simultaneous exposure to vinorelbine and paclitaxel, the combined data points fell mainly on the left side of the e nvelope of additivity suggesting a synergistic interaction. Conversely the representative isobologram of MCF7-R cells for sequential exposure to vinor elbine followed by paclitaxel or paclitaxel followed by vinorelbine indicat ed antagonism. These results prompted us to perform a trial of paclitaxel/v inorelbine combination using the administration of these drugs on the same day directly one after the other. The dose-escalation trial included 20 wom en with metastatic breast cancer who were treated by paclitaxel every 3 wee ks (135 mg/m(2) starting dose) with 20 mg/m(2) steps in subsequent cohorts of patients and vinorelbine (30 mg/m(2) fixed dose). Patients were treated every 21 days. A total of 91 courses of therapy were administered to patien ts at three dose levels. Neutropenic fever was the dose-limiting toxicity a t level 3 (paclitaxel 175 mg/m(2)). Other significant toxicities included s ensory neuropathy, myalgias and fatigue. We conclude that paclitaxel 155 mg /m(2) the other on the same day, every 21 days, are the doses recommended f or further study.