title: Clinical impact of pharmacokinetically-guided dose adaptation of 5-fluorouracil: results from a multicentric randomized trial in patients with locally advanced head and neck carcinomas.
abstract: A significant link between 5-fluorouracil (5FU) plasma concentration and its therapeutic activity has been demonstrated in colon and head and neck cancer patients for 5FU used as a continuous infusion. Dose adjustment based on pharmacokinetic follow-up has been proposed to decrease hematological and digestive toxicities, but the clinical impact of this approach has not yet been demonstrated. A randomized multicentric study was conducted to evaluate the clinical interest of 5FU dose adaptation guided by pharmacokinetics. One hundred twenty-two head and neck cancer patients were randomly assigned to receive induction chemotherapy with cisplatin (100 mg/m2, day 1) and 5FU (96-h continuous infusion), either at standard dose (St-arm; 4 g/m2) or at a dose adjusted according to the 5FU area under the curve (AUC0-48h; PK-arm). In total, 106 patients were evaluable for toxicity and response. In the PK-arm (n = 49), 5FU doses and area under the curve were significantly reduced during cycle 2 and cycle 3 (P < 0.001) as compared with the St-arm (n = 57). Grade 3-4 neutropenia and thrombopenia were significantly more frequent in the St-arm as compared with the PK-arm (17.5% versus 7.6%, respectively; P = 0.013). No grade 3-4 mucositis occurred in the PK-arm, whereas 5.1% was observed in the St-arm (P < 0.01). The objective response rate was comparable in the two treatment arms: 77.2% in the St-arm versus 81.7% in the PK-arm. The present study is the first to demonstrate, in a randomized design, the clinical interest of an individual 5FU dose adaptation based on pharmacokinetic survey, in terms of therapeutic index improvement.
authors.affiliation: Centre René Gauducheau, Nantes, France. r-fety@gauducheau-nantes.fnclcc.fr
authors.forename: R
authors.initials: R
authors.lastname: Fety
authors.forename: F
authors.initials: F
authors.lastname: Rolland
authors.forename: M
authors.initials: M
authors.lastname: Barberi-Heyob
authors.forename: A
authors.initials: A
authors.lastname: Hardouin
authors.forename: L
authors.initials: L
authors.lastname: Campion
authors.forename: T
authors.initials: T
authors.lastname: Conroy
authors.forename: J L
authors.initials: JL
authors.lastname: Merlin
authors.forename: A
authors.initials: A
authors.lastname: Rivière
authors.forename: G
authors.initials: G
authors.lastname: Perrocheau
authors.forename: M C
authors.initials: MC
authors.lastname: Etienne
authors.forename: G
authors.initials: G
authors.lastname: Milano
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
chemical_list: D000964:Antimetabolites, Antineoplastic; D002945:Cisplatin; D005472:Fluorouracil