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Beating the odds: efficacy and toxicity of dihydropyrimidine dehydrogenase‐driven adaptive dosing of 5‐FU in patients with digestive cancer
Author(s) -
Launay Ma,
Dahan Laetitia,
Duval Ma,
Rodallec Anne,
Milano Gérard,
Duluc Muriel,
Lacarelle Bruno,
Ciccolini Joseph,
Seitz JeanFrancois
Publication year - 2016
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12790
Subject(s) - dosing , dihydropyrimidine dehydrogenase , medicine , exact test , gastroenterology , toxicity , cancer , odds ratio , incidence (geometry) , fluorouracil , pharmacogenetics , pharmacology , biology , thymidylate synthase , optics , physics , biochemistry , genotype , gene
Aims 5‐FU is the backbone of most regimens in digestive oncology. Administration of standard 5‐FU leads to 15–30% of severe side effects, and lethal toxicities are regularly reported with fluoropyrimidine drugs. Dihydropyrimidine dehydrogenase (DPD) deficiency is a pharmacogenetic syndrome responsible for most cases of life‐threatening toxicities upon 5‐FU intake, and pre‐treatment checking for DPD status should help to reduce both incidence and severity of side effects through adaptive dosing strategies. Methods We have used a simple method for rapidly establishing the DPD phenotype of patients with cancer and used it prospectively in 59 routine patients treated with 5‐FU‐based therapy for digestive cancers. No patient with total DPD deficiency was found but 23% of patients exhibited poor metabolizer phenotype, and one patient was phenotyped as profoundly deficient. Consequently, 5‐FU doses in poor metabolizer patients were cut by an average 35% as compared with non deficient patients (2390 ± 1225 mg vs . 3653 ± 1371 mg, P < 0.003, t ‐test). Results Despite this marked reduction in 5‐FU dosing, similar efficacy was achieved in the two subsets (clinical benefit: 40 vs . 43%, stable disease: 40 vs . 37%, progressive disease: 20% in both subsets, P = 0.893, Pearson's chi‐square). No difference in toxicities was observed ( P = 0.104, Fisher's exact test). Overall, only 3% of early severe toxicities were recorded, a value markedly lower than the 15‐30% ones usually reported with 5‐FU. Conclusions This feasibility study shows how simplified DPD‐based adaptive dosing of 5‐FU can reduce sharply the incidence of treatment‐related severe toxicities while maintaining efficacy as part of routine clinical practice in digestive oncology.