Phase II study of S-1 combined with oxaliplatin as therapy for patients with metastatic biliary tract cancer: influence of the CYP2A6 polymorphism on pharmacokinetics and clinical activity

Background: Advanced biliary cancer is often treated with fluoropyrimidine-based chemotherapy. In this study, we evaluated the efficacy and tolerability of a combination of S-1, an oral fluoropyrimidine prodrug, and oxaliplatin in patients with metastatic biliary cancer. Methods: Patients with histologically confirmed metastatic biliary cancer and no history of radiotherapy or chemotherapy were enrolled. Oxaliplatin was administered intravenously (130 mg m −2 ), followed by 14-day administration of oral S-1 (40 mg m −2 twice daily) with a subsequent 7-day rest period every 21 days. Pharmacokinetic analysis of S-1 was performed at cycle 1. Patients were genotyped for CYP2A6 polymorphisms ( * 1, * 4, * 7, * 9 or * 10), and pharmacokinetic and clinical parameters compared according to the CYP2A6 genotype. Results: In total, 49 patients were evaluated, who received a median of four cycles. The overall response rate was 24.5%. Median progression-free and overall survival was 3.7 and 8.7 months, respectively. The most common haematological grade 3 out of 4 toxicity was neutropenia (14%), while non-hematological grade 3 out of 4 toxicities included anorexia (14%), nausea (12%), asthenia (10%), vomiting (10%), and diarrhoea (4%). Biotransformation of S-1 (AUC 0−24 h of 5-fluorouracil/AUC 0−24 h of tegafur) was 1.85-fold higher for the *1/*1 group than for the other groups (90% confidence interval 1.37–2.49). Diarrhoea ( P =0.0740), neutropenia ( P =0.396), and clinical efficacy (response rate, P =0.583; PFS, P =0.916) were not significantly associated with CYP2A6 genotype, despite differences in 5-FU exposure. Conclusion: The combination of S-1 and oxaliplatin appears to be active and well tolerated in patients with metastatic biliary cancer, and thus is feasible as a therapeutic modality. CYP2A6 genotypes are associated with differences in the biotransformation of S-1. However, the impact of the CYP2A6 polymorphism on variations in clinical efficacy or toxicity requires further evaluation.