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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 Cancer¹

Netherlands Cancer Institute, Departments of Medical Oncology [M. C., N. E. S., D. P., M. M., R. W. M. U., M. S., J. H. M. S.] and Thoracic Oncology, Amsterdam [P. B., N. v. Z.]; Slotervaart Hospital, Department of Pharmacy, 1066 EC Amsterdam [M. C., N. E. S., J. H. B.]; Faculty of Pharmacy, Department of Biomedical Analysis, Utrecht University, Utrecht [R. W. S.]; and Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht [J. H. B., J. H. M. S.], the Netherlands

ABSTRACT

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/m²/week is feasible on a two-weekly administration scheme in NSCLC patients.

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				J. M. Rademaker-Lakhai, M. Crul, L. Zuur, P. Baas, J. H. Beijnen, Y. J.W. Simis, N. van Zandwijk, and J. H.M. Schellens Relationship Between Cisplatin Administration and the Development of Ototoxicity J. Clin. Oncol., February 20, 2006; 24(6): 918 - 924. [Abstract] [Full Text] [PDF]