title: Oxaliplatin plus irinotecan and FU-FOL combination and pharmacokinetic analysis in advanced colorectal cancer patients.
abstract: This phase I-II trial was designed to assess the effect of irinotecan on oxaliplatin pharmacokinetics and to determine the MDT of both drugs when administered in combination. Treatment was repeated every 2 weeks. Pharmacokinetic studies were performed on cycle 1 and 2 to assess the best sequence and detect any interaction between the two drugs. Thirty-four patients with advanced colorectal cancer were enrolled; 28 of them (82%) had liver involvement. The main toxicities were neutropenia and delayed diarrhea; 5 patients (14%) experienced febrile neutropenia. Dose-limiting toxicity was experienced at levels 1/2/3/4/5 by 4/10, 1/6, 3/6, 3/8, and 3/4 patients, respectively. Fifteen patients responded (2 CR; 13 PR) for an ORR of 44%. No pharmacokinetic interactions between irinotecan and oxaliplatin were detected. The recommended dose for future phase II trials is oxaliplatin 85 mg/m and irinotecan 180 mg/m2 on day 1 combined with 5FU/leucovorin according to the de Gramont regimen at days 2 and 3. Twenty-nine percent of patients underwent secondary hepatectomy with curative intent, and two of them are long-term disease-free survivors. It would appear that the dose and schedule defined by this trial could be proposed as front-line therapy for advanced colorectal carcinoma to establish rapid disease control and to permit patients to proceed to surgery.
authors.affiliation: SOMPS, Salpetriere Hospital, Paris, France. marian.gil-delgado@psl.ap-hop-paris.fr
authors.forename: Marian A
authors.initials: MA
authors.lastname: Gil-Delgado
authors.forename: Gerard
authors.initials: G
authors.lastname: Bastian
authors.forename: François
authors.initials: F
authors.lastname: Guinet
authors.forename: Jean Phillippe
authors.initials: JP
authors.lastname: Spano
authors.forename: Sophie
authors.initials: S
authors.lastname: Taillibert
authors.forename: Marie Ange
authors.initials: MA
authors.lastname: Rocher
authors.forename: Denis
authors.initials: D
authors.lastname: Castaing
authors.forename: René
authors.initials: R
authors.lastname: Adam
authors.forename: Saik
authors.initials: S
authors.lastname: Urien
authors.forename: Henry
authors.initials: H
authors.lastname: Bismuth
authors.forename: David
authors.initials: D
authors.lastname: Khayat
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D000077150:Oxaliplatin; D016019:Survival Analysis
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin