Primum non nocere: Screening patients for fluoropyrimidine-related toxicity risk: The most effective method
Authors: M. Boisdron-Celle, J. Metges, O. Capitain, R. Faroux, C. Stampfli, M. Ferec, P. Laplaige, T. Lecomte, T. Matysiak-Budnik, H. Senellart, M. Campone, A. Morel, E. Gamelin
Journal: Annals of Oncology (2018)

Introduction: Fluoropyrimidines carry a 3% to 5% risk of grade 3 or higher early toxicities and a 0.2% risk of death linked to dihydropyrimidine dehydrogenase (DPD) deficiency, related to genetic and epigenetic factors. Methods: 462 patients were tested after the first or second cycle: 254 because of grade 3 or greater toxicities, among them, 27 deaths, and 208 after grade 2 or lower toxicity. Patients were treated with several regimens. Colorectal cancer patients received fluoropyrimidines using the protocols LV5FU2, FOLFIRI, or FOLFOX over 46 hours, with or without EGFR or VEGF monoclonal antibodies. Breast cancer patients were treated by either FEC50, FEC100, or capecitabine. Head & neck cancer, and pediatric cancer patients were treated by continuous infusion of fluoropyrimidines over 96 hours along with cisplatin. Toxicity evaluation was performed after the first or second chemotherapy cycle and given a Common Terminology Criteria for Adverse Events (CTCAE) grade according to the National Cancer Institute adverse reactions to cancer drugs. Six methods were compared: genotyping DPYD*2 alone, four SNPs, uracil plasma levels, dihydrouracil/uracil ratio, GPCP-RNPGx and multiparametric approach. Results: All six methods yield a high specificity. However, when the sensitivity is considered, it is markedly insufficient to test only for the DPYD*2 mutation. Screening for the four selected mutations was more sensitive; nonetheless, 66% of patients had a DPD deficiency which did not involve any of the four selected DPYD SNPs. The UH2/U ratio alone was more sensitive but not sufficient either. The multiparametric algorithm, combining all of these approaches was clearly the best method with 96% sensitivity. Interestingly, all the methods yield a reasonable positive predictive value (probability that patients with a positive screening test truly will experience an adverse reaction), but all, except the multiparametric algorithm have a low negative predictive value (probability that patients with a negative screening test truly will not have an adverse reaction). Comparing the positive likelihood ratio (LR+, which is the probability of an individual with the condition having a positive test result divided by the probability of an individual without the condition having a positive test result) for all four methods shows that although the multiparametric algorithm was not better than the UH2/U ratio, it is close. The negative likelihood ratio (LR-) is defined as the probability of a patient having a high risk of a toxic response divided by the probability of a patient at low risk having a negative test. Once again, the algorithm, which considered multiple parameters, gave the most accurate prediction of the four approaches. Conclusion: Finally, the high value (610) of the diagnostic odds ratio for the multiparametric test confirms it is the superlative method for predicting a patient's risk of having a toxic reaction to fluoropyrimidines.