The Value of Dihydrouracil/Uracil Plasma Ratios in Predicting 5-Fluorouracil-Related Toxicity in Colorectal Cancer Patients

Abstract

This study investigated the relationship between the dihydrouracil/uracil (UH(2)/U) plasma ratio, a surrogate marker of dihydropyrimidine dehydrogenase (DPD) activity, and 5-fluorouracil (5-FU)-related early toxicity. Plasma UH(2)/U ratios were determined in 68 colorectal cancer patients and 100 healthy controls. A cut-off value indicative of DPD deficiency was calculated using receiver operator characteristics. Patients experiencing toxicity were screened for the DPD G-to-A point mutation within the 5'-splicing donor site of intron 14 (IVS14+1G>A). Overall, 24/68 patients (35%) experienced toxicity (all grades) and abnormal UH(2)/U ratios were demonstrated in 21/24 (87.5%) patients. Drug concentrations up to 130 times the recommended level were found in 13/24 (54%) patients experiencing toxicity. One patient experiencing toxicity was a heterozygous carrier of the IVS14+1G>A mutation. A low UH(2)/U plasma ratio had a sensitivity of 0.87 and specificity of 0.93 for predicting 5-FU-induced toxicity. Systematic detection of DPD-deficient patients using the UH(2)/U ratio could optimize 5-FU-based chemotherapy and minimize life-threatening toxicity.