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.

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.

• Authors: K-p Kim, G Jang, Y S Hong, H-S Lim, K-s Bae, H-S Kim, S S Lee, J-G Shin, J-L Lee, M-H Ryu, H-M Chang, Y-K Kang, T W Kim
• Journal: British journal of cancer (Br J Cancer) Vol. 104 Issue 4 Pg. 605-12 (Feb 15 2011) ISSN: 1532-1827 [Electronic] England
• PMID: 21326246 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Pharmacological
• Biomarkers, Tumor
• Drug Combinations
• Organoplatinum Compounds
• Oxaliplatin
• S 1 (combination)
• Tegafur
• Oxonic Acid
• Aryl Hydrocarbon Hydroxylases
• CYP2A6 protein, human
• Cytochrome P-450 CYP2A6

Topics

• Adenocarcinoma (drug therapy, genetics, metabolism, pathology)
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics, therapeutic use)
• Aryl Hydrocarbon Hydroxylases (genetics)
• Biliary Tract Neoplasms (drug therapy, genetics, metabolism, pathology)
• Biomarkers, Pharmacological (analysis, metabolism)
• Biomarkers, Tumor (genetics, physiology)
• Cytochrome P-450 CYP2A6
• Drug Combinations
• Female
• Humans
• Inactivation, Metabolic (genetics, physiology)
• Male
• Middle Aged
• Organoplatinum Compounds (administration & dosage, adverse effects, pharmacokinetics)
• Oxaliplatin
• Oxonic Acid (administration & dosage, adverse effects, pharmacokinetics)
• Polymorphism, Single Nucleotide (physiology)
• Tegafur (administration & dosage, adverse effects, pharmacokinetics)
• Treatment Outcome
• Young Adult