Affiliation:
1. Institut de Cancérologie de l’Ouest, Angers, France
2. CHU Hôpital Morvan, Brest, France
3. CH Départemental Vendée La Roche sur Yon, France
4. CH Laval, France
5. CH Pays de Morlaix, Morlaix, France
6. CHU Hôtel Dieu, Nantes, France
7. CH Château Gontier, France.
Abstract
Background: Fluoropyrimidines (FPs) carry around 20% risk of G3-5 toxicity and 0.2-1% risk of death, due to dihydropyrimidine dehydrogenase (DPD) deficiency. Several screening approaches exist for predicting toxicity, however there is ongoing debate over which method is best. This study compares 4 screening approaches. Method: 472 patients treated for colorectal, head-and-neck, breast, or pancreatic cancers, who had not been tested pre-treatment for FP toxicity risk, were screened using: DPYD genotyping (G); phenotyping via plasma Uracil (U); phenotyping via plasma-dihydrouracil/uracil ratio (UH2/U); and a Multi-Parametric Method (MPM) using genotype, phenotype, and epigenetic data. Performance was compared, particularly the inability to detect at-risk patients (false negatives). Results: False negative rates for detecting G5 toxicity risk were 51.2%, 19.5%, 9.8% and 2.4%, for G, U, UH2/U and MPM, respectively. False negative rates for detecting G4-5 toxicity risk were 59.8%, 36.1%, 21.3% and 4.7%, respectively. MPM demonstrated significantly (p < 0.001) better prediction performance. Conclusion: MPM is the most effective method for limiting G4-5 toxicity. Its systematic implementation is cost-effective and significantly improves the risk-benefit ratio of FP-treatment. The use of MPM, rather than G or U testing, would avoid nearly 8,000 FP-related deaths per year globally (500 in France), and spare hundreds of thousands from G4 toxicity.
Funder
Ligue Contre le Cancer comité départemental du Maine et Loire, France
Subject
Chemical Health and Safety,Health, Toxicology and Mutagenesis,Public Health, Environmental and Occupational Health,Toxicology
Cited by
8 articles.
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