title: Fluoropyrimidine toxicity in patients with dihydropyrimidine dehydrogenase splice site variant: the need for further revision of dose and schedule.
abstract: Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolic catabolism of 5-fluorouracil (5-FU) and its derivatives (capecitabine and tegafur). Complete or partial deficiency of DPD activity has been demonstrated to induce severe toxicities in cancer patients treated with fluoropyrimidine therapy. We analyzed 180 individuals that were candidates for a treatment with 5-FU class drugs for the most common DPD mutation, IVS14+1G>A, and detected four heterozygous patients. We recorded the toxicities for all 180 individuals after the first two chemotherapy cycles and found that three of the four patients, although they were treated with a dose reduction in 50 % on the basis of the genetic analysis, all showed severe toxicities that resulted in hospitalization of patient and premature discontinuation of treatment. One patient with mutated DPD was not treated with chemotherapy upon the clinician's decision because of his DPD mutated genotype and the presence of microsatellite instability. Our data suggest that greater dose reductions or alternative therapies are needed for patients with DPD IVS14+1G>A mutations.
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliera ASMN, IRCCS, Reggio Emilia, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Magnani
authors.forename: Enrico
authors.initials: E
authors.lastname: Farnetti
authors.forename: Davide
authors.initials: D
authors.lastname: Nicoli
authors.forename: Bruno
authors.initials: B
authors.lastname: Casali
authors.forename: Luisa
authors.initials: L
authors.lastname: Savoldi
authors.forename: Chiara
authors.initials: C
authors.lastname: Focaccetti
authors.forename: Corrado
authors.initials: C
authors.lastname: Boni
authors.forename: Adriana
authors.initials: A
authors.lastname: Albini
authors.forename: Maria
authors.initials: M
authors.lastname: Banzi
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism*; D000069287:Capecitabine; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism; D054067:Dihydropyrimidine Dehydrogenase Deficiency / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D018579:Patient Selection; D016133:Polymerase Chain Reaction
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil