title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 86 Asanbyeongwon-gil, Songpa-gu, Seoul 138-736, Korea.
authors.forename: K-p
authors.initials: KP
authors.lastname: Kim
authors.forename: G
authors.initials: G
authors.lastname: Jang
authors.forename: Y S
authors.initials: YS
authors.lastname: Hong
authors.forename: H-S
authors.initials: HS
authors.lastname: Lim
authors.forename: K-s
authors.initials: KS
authors.lastname: Bae
authors.forename: H-S
authors.initials: HS
authors.lastname: Kim
authors.forename: S S
authors.initials: SS
authors.lastname: Lee
authors.forename: J-G
authors.initials: JG
authors.lastname: Shin
authors.forename: J-L
authors.initials: JL
authors.lastname: Lee
authors.forename: M-H
authors.initials: MH
authors.lastname: Ryu
authors.forename: H-M
authors.initials: HM
authors.lastname: Chang
authors.forename: Y-K
authors.initials: YK
authors.lastname: Kang
authors.forename: T W
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000502:physiology; D065637:Cytochrome P-450 CYP2A6; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000077150:Oxaliplatin; D010094:Oxonic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D005641:Tegafur / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D004338:Drug Combinations; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6