In Vitro and Clinical Studies: Paclitaxel and Vinorelbine in Non-Small-Cell Lung Cancer

Paclitaxel (Taxol) and vinorelbine (Navelbine) are both microtubule toxins but with opposite mechanisms of action, Paclitaxel promotes the assembly of microtubules, whereas vinorelbine prevents microtuble assembly. Paclitaxel and vinorelbine are synergistic against human breast cancer cells and murine P388 leukemia. We have evaluated the cytotoxicity of both drugs and changes in cell-cycle distribution in A549 human adenocarcinoma cells of the lung. The cytotoxicity was dose- and exposure-time dependent. Synergism was observed at low doses and was sequence dependent but did not correlate with the degree of blockage observed in the G₂M phase of the cell cycle. We then modeled clinical treatment on our in vitro results. A total of 19 patients with stage IV refractory non-small-cell lung cancer (NSCLC) were treated with 25 mg/m² of vinorelbine on days 1 and 8 plus 175 mg/m² of paclitaxel, intravenously over 3 hours on day 2 every 3 weeks, with granulocyte colony-stimulating factor (G-CSF, filgrastim [Neupogen]) support. To date, response has been evaluated in 14 patients and toxicity in 18 patients. Three patients (21%) exhibited partial responses. Neutropenia was the most common side effect (grade 4 in six patients and grade 3 in three patients). Five patients had leukopenic fever, and one died of sepsis. Other toxicities were mostly mild or moderate. The median survival was 165 days, and the actuarial 1-year survival rate was 26.7%. We conclude that paclitaxel and vinorelbine have a dose- and sequence-dependent synergistic cytotoxicity in vitro, and that the combination is active in refractory NSCLC.