Phase I/II study of the pharmacokinetics, safety and efficacy of S‐1 in patients with advanced hepatocellular carcinoma

S‐1, an oral fluoropyrimidine derivative, has been shown to be clinically effective against various solid tumors, and preclinical studies have demonstrated activity against hepatocellular carcinoma. We conducted a phase I/II study in patients with advanced hepatocellular carcinoma to examine the pharmacokinetics, recommended dose, safety and efficacy of S‐1. In phase I, the administered dose of S‐1 was approximately 64 mg/m2 per day in three patients (level 1) and approximately 80 mg/m2 per day in six patients (level 2). There was no dose‐limiting toxicity at level 1, but two patients had dose‐limiting toxicity at level 2 (grade 3 anorexia and grade 2 rash requiring eight or more consecutive days of rest). The recommended dose was finally estimated to be 80 mg/m2 per day. There were no significant differences in the pharmacokinetics of S‐1 between patients with Child‐Pugh A and those with B. In phase II, five of 23 patients (21.7%) had partial responses. The median progression‐free survival and overall survival were 3.7 and 16.6 months, respectively. The most common toxicities of grade 3 or 4 were elevated serum aspartate aminotransferase levels, hypochromia and thrombocytopenia. In conclusion, S‐1 showed an acceptable toxicity profile and promising antitumor activity for hepatocellular carcinoma, warranting further evaluation in randomized clinical trials. (Cancer Sci 2010; 101: 2606–2611)