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

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.

[Dihydropyrimidine dehydrogenase deficiency screening for management of patients receiving a fluoropyrimidine: Results of two national practice surveys addressed to clinicians and biologists]. / Intérêts et limites de la recherche du déficit en dihydropyrimidine déshydrogénase dans le suivi des patients traités par fluoropyrimidines : résultats de deux enquêtes nationales de pratiques réalisées auprès des médecins et des biologistes.

Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of early severe toxicities induced by fluoropyrimidines (FP). The French Group of Clinical Oncopharmacology (GPCO)-Unicancer and the French Pharmacogenetics Network (RNPGx) initiated two surveys, one addressed to oncologists, the other to biologists, in order to evaluate routine practices regarding DPD deficiency screening at national level, as well as compliance, motivations and obstacles for implementation of these tests. These anonymized online surveys were performed with the logistic assistance of the Francophone Federation of Digestive Oncology (FFCD) and the support of numerous medical and biological societies. The surveys were conducted in 2016-2017 before the creation of the French INCa/HAS expert panel, which contributed to the drafting of rules and recommendations for DPD deficiency screening published in December 2018. In all, 554 questionnaires from clinicians were analyzed (23% participation) and 35 from biologists. The main arguments raised by clinicians for justifying the limited practice of DPD deficiency screening were: the lack of recommendations from medical societies or Health Authorities, delays in obtaining results, and the lack of adequate reimbursement by the health insurance system. The goal of these surveys was to provide the French Health Authorities with an overview on nationwide DPD-deficiency screening practices and thus help to design recommendations for the standardization and improvement of the management and safety of cancer patients receiving FP-based chemotherapy.

Prevention of 5-fluorouracil-induced early severe toxicity by pre-therapeutic dihydropyrimidine dehydrogenase deficiency screening: Assessment of a multiparametric approach.

5-Fluorouracil (5-FU)-based treatments can lead to early-onset severe (4%-5%) even fatal (0.3%) toxicities in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. This multicenter prospective cohort study aimed to assess the clinical benefit of pretherapeutic screening for DPD deficiency using a multiparametric approach. Two parallel cohorts of patients treated with 5-FU-based chemotherapy for colorectal carcinoma were compared in a prospective nonrandomized study. In arm A, patients had DPD deficiency screening before treatment, whereas in arm B no pretherapy screening was performed. Dosing was based on 5-FU administration guidelines of each institution. DPD deficiency screening was performed using a combined multiparametric approach (5-FUODPM Tox). The frequency of early grade 4-5 toxic events potentially induced by 5-FU was compared in the two groups. At total of 1,142 patients (n = 1,116 evaluable) were enrolled. In arm A, out of 718 evaluable patients, nine grade 4 early toxicities potentially related to 5-FU were reported in nine patients (1.2%) with no toxic death despite one complete DPD deficiency and 24 partial deficiencies. The 24 patients with partial deficiency had safe pharmacokinetics (PK)-monitored 5-FU. In arm B, among 398 evaluable patients, 17 grade 4-5 toxic early events potentially related to 5-FU were reported in 12 patients (4.2%). The incidence of early severe toxicity was significantly higher in arm B (P = .0019), confirming the positive impact of pretherapeutic DPD assessment. The percent of patients with a toxicity grade 3 or higher observed in arm A was 10.8% (n = 78) compared to 17.55% (n = 69)  in arm B (P = .0497). The percentage of death was reduced from 2.5/1,000 in arm B to 0 in arm A. The time to occurrence of all grade ≥3 toxicities was determined in both arms and the difference between the two arms was significant (P = .047). Overall, one patient with complete DPD deficiency confirmed retrospectively died within 13 days from grade 5 multivisceral toxicity. Enrollment was prematurely closed after external experts' decision. In conclusion, multiparametric pretherapeutic DPD deficiency screening significantly lowered the risk of early severe toxicity and avoided an early toxic death. This approach should be used for safe administration of 5-FU-based treatments.