Comparison of 4 Screening Methods for Detecting Fluoropyrimidine Toxicity Risk: Identification of the Most Effective, Cost-Efficient Method to Save Lives

• Published in: Dose-response Vol. 18; no. 3; p. 1559325820951367
• Main Authors: Capitain, Olivier, Seegers, Valérie, Metges, Jean-Philippe, Faroux, Roger, Stampfli, Claire, Ferec, Marc, Budnik, Tamara Matysiak, Senellart, Hélène, Rossi, Valérie, Blouin, Nadège, Dauvé, Jonathan, Campone, Mario
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01-07-2020; SAGE PUBLICATIONS, INC; SAGE Publishing
• Subjects: Cancer therapies; Health risk assessment; Original; Radiation therapy; Toxicity; toxicity; risk assessment; screening; comparison; DPD deficiency; fluoropyrimidines
• ISSN: 1559-3258; 1559-3258
• DOI: 10.1177/1559325820951367

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.