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

Mirjam Crul, Nadja E. Schoemaker, Dick Pluim, Marc Maliepaard, René W.M. Underberg, Margaret Schot, Rolf W. Sparidans, Paul Baas, Jos H. Beijnen, Nico Van Zandwijk, Jan H.M. Schellens

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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/m2 gemcitabine in combination with cisplatin 90 mg/m2. 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/ m2) with cisplatin at a dose intensity of 50 mg/m 2/week is feasible on a two-weekly administration scheme in NSCLC patients.

Original languageEnglish
Pages (from-to)3526-3533
Number of pages8
JournalClinical Cancer Research
Issue number10 I
Publication statusPublished - 1 Oct 2003

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