title: A rapid and inexpensive method for anticipating severe toxicity to fluorouracil and fluorouracil-based chemotherapy.
abstract: Dihydropyrimidine dehydrogenase (DPD) deficiency leads to dramatic overexposure to fluorouracil (5-FU), resulting in a potentially lethal outcome in patients treated with standard doses. The aim of this study was to validate, in a routine clinical setting, a simple and rapid method to determine the DPD status in a subset of cancer patients, all presenting with life-threatening toxicities following 5-FU or capecitabine intake. In this study, 80 out of 615 patients (13%) suffered severe toxicities, including 5 lethal ones (0.8%), during or after chemotherapy with a fluoropyrimidine drug. Patients with severe toxicities were treated with 5-FU (76 patients) or capecitabine-containing protocols (4 patients). Simplified uracil to di-hydrouracil (U/UH2) ratio determination in plasma was retrospectively performed in these 80 patients, as a surrogate marker of DPD activity. When possible, 5-FU Css determination was performed, and screenings for the canonical IVS14+1G>A mutation were systematically carried out. Comparison of the U/UH2 ratios with a reference, non-toxic population, showed abnormal values suggesting impaired DPD activity in 57 out of the 80 toxic patients (71%) included in this study, and in 4 out of 5 patients (80%) with a fatal outcome. Similarly, drug exposures up to 15 times higher than the range observed in the non-toxic population were also observed. Importantly, no IVS14+1G>A mutation was found in these patients, including those displaying the most severe or lethal toxicities. These data warrant systematic detection of DPD-deficient patients prior to fluoropyrimidine administration, including when oral capecitabine (Xeloda) is scheduled. Finally, the simplified methodology presented here proved to be a low cost and rapid way to identify routinely patients at risk of toxicity with 5-FU or capecitabine.
authors.affiliation: Clinical Pharmacokinetics Department, La Timone University Hospital, Marseille, France.
authors.forename: Joseph
authors.initials: J
authors.lastname: Ciccolini
authors.forename: Cédric
authors.initials: C
authors.lastname: Mercier
authors.forename: Alexandre
authors.initials: A
authors.lastname: Evrard
authors.forename: Laetitia
authors.initials: L
authors.lastname: Dahan
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Boyer
authors.forename: Florence
authors.initials: F
authors.lastname: Duffaud
authors.forename: Karine
authors.initials: K
authors.lastname: Richard
authors.forename: Carmelo
authors.initials: C
authors.lastname: Blanquicett
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
authors.forename: Aurore
authors.initials: A
authors.lastname: Blesius
authors.forename: Alain
authors.initials: A
authors.lastname: Durand
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Seitz
authors.forename: Roger
authors.initials: R
authors.lastname: Favre
authors.forename: Bruno
authors.initials: B
authors.lastname: Lacarelle
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D054067:Dihydropyrimidine Dehydrogenase Deficiency; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D010641:Phenotype; D012189:Retrospective Studies
chemical_list: D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil