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

F. Bouchenak, N.R. Laoufi, K. Sobhi, R. Djidjik, M. Oukkal, S. Adjmi, M. Hazi, S. Adane, H. Chader, K. Mansouri, K. Bouzid

Toxicology Laboratory, Central Army Hospital Doctor Mohamed Seghir Nekkache, Algiers, Algeria. f.bouchenak@univ-alger.dz

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• Oncology

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.

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