Phase I and pharmacokinetic study of 5-fluorouracil administered by 5-day continuous infusion in patients with hepatocellular carcinoma

Purpose: In this study the maximum tolerated dose of 5-fluorouracil administered by 5-day (120-h) continuous infusion every 4 weeks was investigated and the pharmacokinetics in patients with hepatocellular carcinoma were evaluated. Methods: Patients with hepatocellular carcinoma no longer amenable to established forms of treatment were eligible for the study. The starting dose of 5-fluorouracil was 300 mg/m² per day and doses were escalated in 50 mg/m² per day increments in successive cohorts of three new patients if tolerated. Pharmacokinetic studies were performed at the time of the first course of therapy. Results: Enrolled in the study were 20 patients. The maximum tolerated dose was 500 mg/m² per day and the dose-limiting toxicity was stomatitis. Other toxicities were mild and well tolerated. Age, gender and associated liver cirrhosis were significant factors influencing 5-fluorouracil clearance. With regard to biochemical parameters, serum alanine aminotransferase and cholesterol levels were correlated with 5-fluorouracil clearance. Conclusions: The maximum tolerated dose for 5-day continuous infusion of 5-fluorouracil in hepatocellular carcinoma patients was 500 mg/m² per day. The recommended dose for phase II studies using this schedule is 450 mg/m² per day. Furthermore, the pharmacokinetic data obtained in this study may be useful in determining chemotherapy dosage adjustments for reduction of toxicity.