Randomized phase I clinical and pharmacologic study of weekly versus twice-weekly dose-intensive cisplatin and gemcitabine in patients with advanced non-small cell lung cancer.

PURPOSE To establish the maximum dose intensity of cisplatin plus gemcitabine on a weekly or two-weekly schedule in patients with advanced non-small cell lung cancer (NSCLC). METHODS Patients with NSCLC stage IIIB or IV were randomized to receive weekly or two-weekly courses of gemcitabine on day 1 and cisplatin on day 2. An interpatient dose escalation scheme was used, and pharmacokinetics were determined for both agents in plasma and WBCs. RESULTS Seventy-three patients were included, 32 on the weekly schedule and 41 on the two-weekly schedule. Fifty patients received all planned courses. Dose-limiting toxicities were leukocytopenia, neutropenia, and trombocytopenia on the weekly schedule and ototoxicity on the two-weekly schedule. Most common nonhematological toxicities consisted of nausea, vomiting, and fatigue. The highest dose intensity of cisplatin could be achieved on the two-weekly schedule, and therefore, further development of the weekly schedule was abandoned. The maximum tolerated dose was established at 1500 mg/m(2) gemcitabine in combination with cisplatin 90 mg/m(2). More than half (53%) of patients achieved an objective response on the two-weekly schedule, versus 23% in the weekly treatment arm. The pharmacokinetic studies revealed a significant interaction: gemcitabine reduced both GG and AG platinum-DNA intrastrand adducts in WBCs. CONCLUSION The combination of gemcitabine (1500 mg/m(2)) with cisplatin at a dose intensity of 50 mg/m(2)/week is feasible on a two-weekly administration scheme in NSCLC patients.