¹Department of Medical Oncology and Clinical Pharmacology, INSERM U564 Centre Paul Papin, Centre Régional de Lutte Contre le Cancer, Angers, Cedex, France

Correspondence: Professor E Gamelin, Department of Clinical Pharmacology, CRLCC Paul Papin, INSERM U564, 2 Rue Moll, Angers 49933, France. E-mail: e.gamelin@unimedia.fr

Received 20 March 2007; Revised 20 June 2007; Accepted 6 July 2007; Published online 14 August 2007.

Abstract

The purpose of this study was to determine simple genetic factors helpful to tailor 5-FU administration and determine strategy in first-line chemotherapy of advanced colorectal cancer. In 76 patients initially treated by 5-FU, thymidylate synthase, dihydropyrimidine dehydrogenase and methylene tetrahydrofolate reductase germinal polymorphisms, dihydrouracil/uracil plasma ratio and 5-FU plasma clearance were investigated and correlated for tolerance (10.5% grade 3 and 4 toxicity) and efficacy (32.9% objective response rate and 20 months median overall survival time). Toxicity was linked to performance status >2 (P=0.004), low UH₂/U ratio, 2846 A>T, IVS 14+1G>A for DPD (P=0.031), and homozygoty C/C for MTHFR 1298 A>C (P=0.0018). The overall survival of the patients with a 3R/3R TS genotype associated with C/C for 677 C>T or A/A for 1298 A>C was statistically shorter (log-rank test P=0.0065). Genetic factors permit the tailoring of 5-FU treatment. They should occupy center stage in future clinical trials for specifically designing treatment for patients with a given biologic feature.