Prolonged infusion of gemcitabine in advanced solid tumors: a phase-I-study.

BACKGROUND: Gemcitabine is a pro-drug that has to be phosphorylated to gemcitabine-triphosphate in order to exhibit its antineoplastic activity. This reaction involves the enzyme deoxycytidine kinase which is saturated at plasma concentrations following standard 30-min infusions. Pharmacological studies indicate that prolonged administration of gemcitabine might result in higher intracellular concentrations of active metabolites. This phase I trial was therefore initiated to determine the optimal dose of gemcitabine administered over 4 h in patients with advanced solid tumors. PATIENTS AND METHODS: Patients were treated with gemcitabine as 4 h-infusion on day 1, 8 and 15 in 4 week intervals. The starting dose was 350 mg/m(2). Doses were escalated in 50 mg/m(2) increments.
RESULTS: Twenty-one patients were treated at doses ranging from 350 to 450 mg/m(2). The maximum tolerated dose was 400 mg/m(2) with neutropenia, thrombocytopenia, stomatitis and elevation of liver enzymes being dose limiting toxicities (DLTs). Hematologic and nonhematological toxicities were generally mild to moderate. Most common side effects were myelosuppression, nausea, elevation of liver enzymes and asthenia. Objective responses were noted in patients with hepatocellular carcinoma and cholangio-carcinoma.
CONCLUSION: In this phase I study of gemcitabine as 4h-infusion, DLTs were neutropenia, thrombocytopenia, stomatitis and elevation of liver enzymes. The recommended dose for phase II studies is 400 mg/m(2).