Securing Fluoropyrimidine-based chemotherapy: comparison of three methods of screening for dihydropyrimidine dehydrogenase deficiency.

Abstract

OBJECTIVE: 5-Fluorouracil is a widely used antimetabolite in oncology but can be toxic, particularly in patients with dihydropyrimidine dehydrogenase deficiency. A plasma uracil level exceeding 16 ng/mL and a metabolic ratio (dihydrouracil/uracil) below 6 are indicators of DPD deficiency. This study compares different screening methods for dihydropyrimidine dehydrogenase deficiency. MATERIALS AND METHODS: One hundred and eighty-eight Algerian patients with colorectal cancer treated with 5-Fluorouracil were screened for dihydropyrimidine dehydrogenase deficiency using DPYD genotyping, phenotyping with uracil levels and metabolic ratio, and a multiparametric approach. Moderate-to-severe toxicities were investigated, and predictive performances of screening method was compared using likelihood ratios. RESULTS: No mutations were found except a heterozygous c.1905+ 1G>A (2A*) mutation in one patient. Uracil and metabolic ratio values ranged from [3.52-18.63] ng/mL and [4.33-30.74], respectively. The likelihood ratios for uracil, metabolic ratio, and multiparametric method were 5.7/0.13, 10.6/0.05, and 11.3/0.04, respectively. The multiparametric method reduced false-negative rates by more than half compared to uracil. Gender and weight significantly impacted toxicity (p=0.023 and p=0.013, respectively). CONCLUSIONS: The multiparametric method outperforms plasma uracil levels in predicting moderate-to-severe fluoropyrimidines toxicities. A more complex predictive model, considering factors like weight, sex, uracil, and metabolic ratio, is recommended. Further investigation into the DPYD gene in North African populations is needed.

Graphical abstract: https://www.europeanreview.org/wp/wp-content/uploads/110-122-scaled.jpg.