title: Prevention of 5-fluorouracil-induced early severe toxicity by pre-therapeutic dihydropyrimidine dehydrogenase deficiency screening: Assessment of a multiparametric approach.
abstract: 5-Fluorouracil (5-FU)-based treatments can lead to early-onset severe (4%-5%) even fatal (0.3%) toxicities in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. This multicenter prospective cohort study aimed to assess the clinical benefit of pretherapeutic screening for DPD deficiency using a multiparametric approach. Two parallel cohorts of patients treated with 5-FU-based chemotherapy for colorectal carcinoma were compared in a prospective nonrandomized study. In arm A, patients had DPD deficiency screening before treatment, whereas in arm B no pretherapy screening was performed. Dosing was based on 5-FU administration guidelines of each institution. DPD deficiency screening was performed using a combined multiparametric approach (5-FUODPM Tox). The frequency of early grade 4-5 toxic events potentially induced by 5-FU was compared in the two groups. At total of 1,142 patients (n = 1,116 evaluable) were enrolled. In arm A, out of 718 evaluable patients, nine grade 4 early toxicities potentially related to 5-FU were reported in nine patients (1.2%) with no toxic death despite one complete DPD deficiency and 24 partial deficiencies. The 24 patients with partial deficiency had safe pharmacokinetics (PK)-monitored 5-FU. In arm B, among 398 evaluable patients, 17 grade 4-5 toxic early events potentially related to 5-FU were reported in 12 patients (4.2%). The incidence of early severe toxicity was significantly higher in arm B (P = .0019), confirming the positive impact of pretherapeutic DPD assessment. The percent of patients with a toxicity grade 3 or higher observed in arm A was 10.8% (n = 78) compared to 17.55% (n = 69)  in arm B (P = .0497). The percentage of death was reduced from 2.5/1,000 in arm B to 0 in arm A. The time to occurrence of all grade ≥3 toxicities was determined in both arms and the difference between the two arms was significant (P = .047). Overall, one patient with complete DPD deficiency confirmed retrospectively died within 13 days from grade 5 multivisceral toxicity. Enrollment was prematurely closed after external experts' decision. In conclusion, multiparametric pretherapeutic DPD deficiency screening significantly lowered the risk of early severe toxicity and avoided an early toxic death. This approach should be used for safe administration of 5-FU-based treatments.
authors.affiliation: Oncopharmacologie, ICO Paul Papin, Angers, France. Electronic address: michele.boisdron@ico.unicancer.fr.
authors.forename: Michele
authors.initials: M
authors.lastname: Boisdron-Celle
authors.affiliation: Service d'Oncologie Médicale, ICO Paul Papin, Angers, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Capitain
authors.affiliation: Service de Gastro-Entérologie, Centre Hospitalier Départemental Les Oudairies, La Roche sur Yon, France.
authors.forename: Roger
authors.initials: R
authors.lastname: Faroux
authors.affiliation: Service d'Oncologie Médicale, CHU Jean Minjoz, Besançon, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Borg
authors.affiliation: Service d'Oncologie et de Radiothérapie, Institut de Cancérologie et d'Hématologie, Brest, France.
authors.forename: Jean Philippe
authors.initials: JP
authors.lastname: Metges
authors.affiliation: Service d'Oncologie Médicale, Centre François Baclesse, Caen, France.
authors.forename: Marie Pierre
authors.initials: MP
authors.lastname: Galais
authors.affiliation: Service d'Hépatologie et de Gastroentérologie, Centre Hospitalier, Cholet, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Kaassis
authors.affiliation: Service d'Oncologie Médicale, ICO René Gauducheau, Saint Herblain, France.
authors.forename: Jaafar
authors.initials: J
authors.lastname: Bennouna
authors.affiliation: Service d'Hépato-Gastro-Entérologie, Centre Hospitalier Universitaire, Caen, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Bouhier-Leporrier
authors.affiliation: Service d'Hépato-Gastro-Entérologie, Centre A. Lacassagne, Nice, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Francois
authors.affiliation: Service d'Oncologie Médicale, Hôpital Henri Mondor, Creteil, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Baumgaertner
authors.affiliation: Service d'Oncologie Médicale, Centre Hospitalier, Saumur, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Guerin-Meyer
authors.affiliation: Service d'Onco-Hématologie, Centre Hospitalier, Le Mans, France.
authors.forename: Oana
authors.initials: O
authors.lastname: Cojocarasu
authors.affiliation: Service d'Oncologie Médicale, Clinique Gentilly, Nancy, France.
authors.forename: Celia
authors.initials: C
authors.lastname: Roemer-Becuwe
authors.affiliation: Service d'Hépato-Gastro-Entérologie, Proctologie et Oncologie Digestive 5B, Centre Hospitalier, Laval, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Stampfli
authors.affiliation: Unité d'Hépato-Gastro-Entérologie, Centre Hospitalier Sarthe et Loir, La Fleche, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Rosenfeld
authors.affiliation: Service d'Hépato-Gastro-Entérologie, CHU Hôpital Trousseau, Tours, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lecompte
authors.affiliation: Centre Evaluation Clinique, ICO Paul Papin, Angers, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Berger
authors.affiliation: Oncopharmacologie, ICO Paul Papin, Angers, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Morel
authors.affiliation: Oncopharmacologie, ICO Paul Papin, Angers, France.
authors.forename: Erick
authors.initials: E
authors.lastname: Gamelin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D015331:Cohort Studies; D054067:Dihydropyrimidine Dehydrogenase Deficiency / Q000175:diagnosis*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D005472:Fluorouracil / Q000633:toxicity*; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies
chemical_list: D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil
keywords: 5-Fluorouracil; DPD deficiency; Genotyping, UH2/U; Lethal toxicity; Multiparametric approach