title: Beating the odds: efficacy and toxicity of dihydropyrimidine dehydrogenase-driven adaptive dosing of 5-FU in patients with digestive cancer.
abstract: OBJECTIVE
  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.
authors.affiliation: Laboratoire de Pharmacocinétique La Timone University Hospital of Marseille, Marseille.
authors.forename: Manon
authors.initials: M
authors.lastname: Launay
authors.affiliation: Digestive Oncology Unit, La Timone University Hospital of Marseille, Marseille.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Dahan
authors.affiliation: Laboratoire de Pharmacocinétique La Timone University Hospital of Marseille, Marseille.
authors.forename: Manon
authors.initials: M
authors.lastname: Duval
authors.affiliation: Laboratoire de Pharmacocinétique La Timone University Hospital of Marseille, Marseille.
authors.forename: Anne
authors.initials: A
authors.lastname: Rodallec
authors.affiliation: Oncopharmacology Unit, Centre Antoine Lacassagne, Nice.
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
authors.affiliation: Digestive Oncology Unit, La Timone University Hospital of Marseille, Marseille.
authors.forename: Muriel
authors.initials: M
authors.lastname: Duluc
authors.affiliation: Laboratoire de Pharmacocinétique La Timone University Hospital of Marseille, Marseille.|SMARTc Unit, U911 Cro2 Aix-Marseille Univ., Marseille, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Lacarelle
authors.affiliation: Laboratoire de Pharmacocinétique La Timone University Hospital of Marseille, Marseille.|SMARTc Unit, U911 Cro2 Aix-Marseille Univ., Marseille, France.
authors.forename: Joseph
authors.initials: J
authors.lastname: Ciccolini
authors.affiliation: Digestive Oncology Unit, La Timone University Hospital of Marseille, Marseille.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Seitz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D004067:Digestive System Neoplasms / Q000188:drug therapy*; D054067:Dihydropyrimidine Dehydrogenase Deficiency / Q000378:metabolism; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000502:physiology*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil
keywords: 5-FU; DPD deficency; adaptive dosing; digestive oncology; efficacy; toxicity