Background Sorafenib is the sole molecular-targeted agent showing a survival benefit in patients with advanced hepatocellular carcinoma (HCC). We evaluated the tolerability and effectiveness of a combination of S-1 with sorafenib in patients with advanced HCC. Methods S-1 was administered during days 1–14 and sorafenib was administered every day. This treatment was repeated every 21 days. In phase I, we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). The dose of each drug was planned as follows: cohort 1: S-1 48 mg/m2/day and sorafenib 400 mg/day, cohort 2a: S-1 48 mg/m2/day and sorafenib 800 mg/day, cohort 2b: S-1 64 mg/m2/day and sorafenib 400 mg/day, cohort 3: S-1 64 mg/m2/day and sorafenib 800 mg/day, and cohort 4: S-1 80 mg/m2/day and sorafenib 800 mg/day. In phase II, the patients were treated at the MTD to evaluate safety and efficacy. Results Nineteen patients were enrolled in phase I. One of the six patients in cohort 1 and one of the six patients in cohort 3 experienced DLT. None of the three patients in cohort 2a experienced DLT and three of the four patients in cohort 4 experienced DLT. Therefore, cohort 3 was considered the MTD. Subsequently, 26 patients were enrolled in phase II. The most common grade 3/4 toxicities were an increase of aspartate aminotransferase (38.5 %), thrombocytopenia (23.1 %), neutropenia (19.2 %), hyperbilirubinemia (15.4 %), an increase of alanine aminotransferase (15.4 %), hyponatremia (11.5 %), rash (11.5 %), and hypophosphatemia (11.5 %). Sudden death occurred in one patient (3.8 %). A patient (3.8 %) had a partial response, 15 (57.7 %) had stable disease, and 10 (38.5 %) had progressive disease. The median times to progression and overall survival were 2.4 and 10.5 months, respectively. Conclusion The MTD of S-1 and sorafenib in patients with advanced HCC was 64 mg/m2/day and 800 mg/day, respectively. This dose/regimen demonstrated substantial clinical activity among patients with advanced HCC.
Hepatocellular carcinoma Liver cancer S-1 Sorafenib Molecular-targeted agent
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Conflict of interest
Prof. Osamu Yokosuka received research grants from Bayer Healthcare. Yoshihiko Ooka, Tetsuhiro Chiba, Sadahisa Ogasawara, Kuniaki Arai, Eiichiro Suzuki, Akinobu Tawada, Tatsuya Yamashita, Fumihiko Kanai, and Shuichi Kaneko declare that they have no conflict of interest.
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