Phase I study of adjuvant gemcitabine or S-1 in patients with biliary tract cancers undergoing major hepatectomy: KHBO1003 study.

ABSTRACT

BACKGROUND: Standardized adjuvant therapy is not performed after major hepatectomy for biliary tract cancer (BTC) because of frequent adverse events, which may be caused by insufficient liver function. Therefore, the aim of this multicenter study (KHBO1003) was to determine the safety protocol for adjuvant chemotherapy after major hepatectomy. METHODS: Within 12 weeks of R0 or R1 major hepatectomy (hemihepatectomy or trisectionectomy) for BTC, the following adjuvant chemotherapy was performed for 6 months 800-1,000 mg/m(2) gemcitabine on days 1, 8, and 15 and then every 3-4 weeks or 40-80 mg/m(2)/day S-1 on days 1-28 and every 3-6 weeks. Major dose-limited toxicity (DLT) was defined as grade 4 hematotoxicity, grade 3/4 febrile neutropenia, grade 3/4 non-hematotoxicity, skipped gemcitabine on days 8 and 15, or halting the course at or after 14 days. Dose-escalation and de-escalation decisions were based on the continual reassessment method. Every three patients were alternately assigned to each arm. RESULTS: Thirty-three patients (14 intrahepatic bile duct, 1 gall bladder, 18 extrahepatic bile duct) were enrolled in this study from February 2011 to July 2012 (n = 18 gemcitabine, n = 15 S-1). At 10% of DLT, the recommended dose was 1,000 mg/m(2) gemcitabine biweekly and 80 mg/m(2)/day S-1 on days 1-28 and every 6 weeks. Major DLT and adverse drug reactions were neutropenia. No grade 3 or 4 non-hematological adverse events were noted. CONCLUSION: We determined RDs for gemcitabine and S-1 adjuvant chemotherapy after major hepatectomy with a DLT that does not exceed 10%.