The influence of fluorouracil outcome parameters on tolerance and efficacy in patients with advanced colorectal cancer

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 42 (P ¼ 0.004), low UH 2 /U ratio, 2846 A4T, IVS 14 þ 1G4A for DPD (P ¼ 0.031), and homozygoty C/C for MTHFR 1298 A4C (P ¼ 0.0018). The overall survival of the patients with a 3R/3R TS genotype associated with C/C for 677 C4T or A/A for 1298 A4C was statistically shorter (log-rank test P ¼ 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.

Therapeutic drug monitoring of 5-fluorouracil

“…Capitain and colleagues analyzed the potential effect of genetic factors on 5-FU metabolism and the correlation with tolerance and efficacy in 76 patients with mCRC receiving PK-monitored infusional 5-FU chemotherapy [78]. In this patient cohort, 3.9% (3 patients) were heterozygous for DPD variants.…”

Combinations of Polymorphisms in Genes Involved in the 5-Fluorouracil Metabolism Pathway Are Associated with Gastrointestinal Toxicity in Chemotherapy-Treated Colorectal Cancer Patients

“…Previous studies have shown contradicting results with regard to the role of MTHFR in toxicity in relation to 5-FU chemotherapy (6,13,17,(33)(34)(35). The contradictory results may reflect that the MTHFR 677C>T and MTHFR 1298A>C SNPs were not combined according to phenotypic effects, differences in treatment regimens, and inadequate statistical analyses.…”

Variants in the Dihydropyrimidine Dehydrogenase, Methylenetetrahydrofolate Reductase and Thymidylate Synthase Genes Predict Early Toxicity of 5-Fluorouracil in Colorectal Cancer Patients

“…These results are in accordance with previously published results indicating an effect on toxicity of decreased MTHFR activity. 29,61 A curious finding, also noted by Gene variants in DPYD, MTHFR and TYMS predict 5-FU-related toxicity Sharma et al,62 was that the MTHFR 677 C/T heterozygous genotype significantly predicted toxicity (RR 1.38; P = 0.03).…”