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

A significant link between 5-fluorouracil (5FU) plasma concentration a nd its therapeutic activity has been demonstrated in colon and bead an d neck canter patients for 5FU used as a continuous infusion. Dose adj ustment based on pharmacokinetic follow-up has been proposed to decrea se hematological and digestive toxicities, but the clinical impact of this approach has not Set been demonstrated. A randomized multicentric study was conducted to evaluate the clinical interest of 5FU dose ada ptation guided by pharmacokinetics. One hundred twenty-two head and ne ck cancer patients were randomly assigned to receive induction chemoth erapy with cisplatin (100 mg/m(2), day 1) and 5FU (96-h continuous inf usion), either at standard dose (St-arm; 4 g/m(2)) or at a dose adjust ed according to the 5FU area under the curve (AUC(0-48h); PK-arm),In t otal, 106 patients were evaluable for toxicity and response. In the PK -arm (n = 49), 5FU doses and area under the curve were significantly r educed during cycle 2 and cycle 3 (P < 0.001) as compared with the St- arm (n = 57), Grade 3-4 neutropenia and thrombopenia were significantl y more frequent in the St-arm as compared with the PK-arm (17.5% versu s 7.6%, respectively; P = 0.013) No grade 3-4 mucositis occurred in th e PK-arm, whereas 5.1% was observed in the St-arm (P < 0.01), The obje ctive 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 i ndividual 5FU dose adaptation based on pharmacokinetic survey, in term s of therapeutic index improvement.