title: DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity.
abstract: BACKGROUND
  Fluoropyrimidine drugs are widely used in head and neck cancer (HNC). DPD deficiency is a pharmacogenetics syndrome associated with severe/lethal toxicities upon 5-FU or capecitabine intake. We have developed a simple, rapid, and inexpensive functional testing for DPD activity, as a means to identify deficient patients and to anticipate subsequent 5-FU-related toxicities. We present here the impact of fluoropyrimidine dose tailoring based on DPD functional screening in a prospective, open, non-controlled study, both in term of reduction in severe toxicities and of treatment efficacy.
  
  
  METHODS
  About 65 patients with HNC (59 ± 9 years, 52M/13F, Prospective Group) were entered into the study. Screening for DPD deficiency was performed prior to the beginning of the chemotherapy or radiochemotherapy. DPD status was evaluated by monitoring U/UH2 ratio levels in plasma as a surrogate marker for enzymatic functionality. 5-FU doses were reduced according to the extent of the detected DPD impairment, and adjusted on the basis of age, general condition, and other clinical/paraclinical covariates, if required. Treatment-related toxicities and subsequent impact on treatment delay were carefully monitored next for comparison with a retrospective, Reference subset of 74 other patients with HNC (mean age: 59 ± 10, 58M/16F, Reference Group), previously treated in the same institute with similar schedule but using standard 5-FU dosage.
  
  
  RESULTS
  Thirty-one out of 65 patients (48%) were identified as mildly (28%) to markedly (20%) DPD deficient. Subsequently, dose reductions ranging from 10 to 100% with 5-FU were applied in those patients. In this group, six patients (9%) experienced severe toxicities, none of them being life threatening, and no toxic death was encountered. In comparison, 16 out of 74 patients (22%) of the Reference Group displayed severe side effects after standard 5-FU administration, 13% being life-threatening toxicities (e.g., G4 neutropenia + sepsis). Moreover, one toxic death was observed in this Reference Group. No postponement or cancelation of forthcoming chemoradiotherapy courses occurred in the Prospective Group, whereas treatment had to be disrupted in six patients (8%) from the Reference Group. No difference in first-line therapy efficacy was evidenced between the two subsets (78 vs. 79% response, P = 0.790).
  
  
  CONCLUSIONS
  Although non-randomized, this study strongly suggests that prospective determination of DPD status has an immediate clinical benefit by reducing the drug-induced toxicities incidence in patients treated with 5-FU, allowing an optimal administration of several courses in a row, while maintaining efficacy. Our preliminary results thus advocate for systematic DPD screening in patients eligible for treatment with fluoropyrimidine drugs in HNC.
authors.affiliation: Medical Oncology Unit, La Timone University Hospital, 234 Rue St Pierre, 13385 Marseille cedex 05, France.
authors.forename: Chen Guang
authors.initials: CG
authors.lastname: Yang
authors.forename: Joseph
authors.initials: J
authors.lastname: Ciccolini
authors.forename: Aurore
authors.initials: A
authors.lastname: Blesius
authors.forename: Laetitia
authors.initials: L
authors.lastname: Dahan
authors.forename: Danielle
authors.initials: D
authors.lastname: Bagarry-Liegey
authors.forename: Caroline
authors.initials: C
authors.lastname: Brunet
authors.forename: Arthur
authors.initials: A
authors.lastname: Varoquaux
authors.forename: Nicolas
authors.initials: N
authors.lastname: Frances
authors.forename: Hafedh
authors.initials: H
authors.lastname: Marouani
authors.forename: Antoine
authors.initials: A
authors.lastname: Giovanni
authors.forename: Rose-Marie
authors.initials: RM
authors.lastname: Ferri-Dessens
authors.forename: Mohamed
authors.initials: M
authors.lastname: Chefrour
authors.forename: Roger
authors.initials: R
authors.lastname: Favre
authors.forename: Florence
authors.initials: F
authors.lastname: Duffaud
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Seitz
authors.forename: Michel
authors.initials: M
authors.lastname: Zanaret
authors.forename: Bruno
authors.initials: B
authors.lastname: Lacarelle
authors.forename: Cédric
authors.initials: C
authors.lastname: Mercier
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D054067:Dihydropyrimidine Dehydrogenase Deficiency / Q000235:genetics*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011446:Prospective Studies; D012189:Retrospective Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil