title: Phase I/II Study of Sorafenib in Combination with Hepatic Arterial Infusion Chemotherapy Using Low-Dose Cisplatin and 5-Fluorouracil.
abstract: We conducted a phase I/II study in patients with advanced hepatocellular carcinoma (HCC) to determine the recommended dose, as well as the safety and efficacy, of combination therapy of sorafenib with hepatic arterial infusion chemotherapy (HAIC) using low dose cisplatin (CDDP) and 5-fluorouracil (5FU). Cohorts consisting of 3-6 patients with HCC received an escalated dose of CDDP and 5-FU until a maximum-tolerated dose was achieved. The treatment regimen was as follows: oral administration of sorafenib (400 mg twice daily for 28 days) combined with HAIC using CDDP (14-20 mg/m(2), on days 1 and 8) and 5-FU (170-330 mg/m(2), continuously on days 1-5 and 8-12) via an implanted catheter system). Each treatment cycle consisted of 28 days and three cycles of combination therapy. At the end of the first cycle, adverse events were evaluated and future dose escalation was determined. Eighteen patients with advanced HCC were enrolled. Dose-limiting toxicity was observed in two patients from cohort 1 (erythema multiforme and grade 4 thrombocytopenia) and in one patient from cohort 2 (erythema multiforme). Seven of the 18 patients achieved a partial response, seven showed stable disease, two were diagnosed as progressive disease, and two were not assessable. The response rate was 38.9% and the disease control rate was 77.8%. The time-to-progression was 9.7 months and the 1-year survival rate was 88.2%. Oral administration of 400 mg of sorafenib twice daily, 20 mg/m(2) of intra-arterial infusion of CDDP, and 5-FU at 330 mg/m(2) are the recommended doses for combination therapy, which was well tolerated and efficacious. This combination therapy may be a promising treatment for patients with advanced HCC. A large prospective randomized multicenter study (ClinicalTrials.gov Identifier NCT01214343) is ongoing.
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Kazuomi
authors.initials: K
authors.lastname: Ueshima
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
authors.affiliation: Department of Hepatology, Yokokura Hospital, Fukuoka, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterology, Ogaki Municipal Hospital, Gifu, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kumada
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Hobyung
authors.initials: H
authors.lastname: Chung
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Hagiwara
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Yada
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kitai
keywords: Cisplatin; Fluorouracil; Hepatic arterial infusion; Hepatocellular carcinoma; Sorafenib