title: Individual 5-FU dose adaptation in metastatic colorectal cancer: results of a phase II study using a bimonthly pharmacokinetically intensified LV5FU2 regimen.
abstract: OBJECTIVE
  The aim of this phase II study was to determine the efficacy and tolerability of the bimonthly, pharmacokinetically intensified LV5FU2 regimen in the treatment of metastatic colorectal cancers.
  
  
  METHODS
  A total of 53 patients (23% second-line; 25 male/28 female; mean age 67 years; WHO performance status 0 in 38, 1 in 10 and 2 in 5) were treated in cycle 1 with the standard LV5FU2 regimen (leucovorin 200 mg/m2 per day followed by a 5-FU bolus 400 mg/m2 per day and a 22-h 5-FU continuous infusion 600 mg/m2 per day for two consecutive days every 2 weeks), and the AUC in mg.h/l.m2 was calculated. For cycle 2, according to a predefined schedule depending on the cycle-1 AUC value, in the absence of grade 3 toxicity, the 5-FU infusion dose was increased by 150% for AUC < or =5, by 100% for AUC >5-10, by 50% for AUC >10-15, and by 25% for AUC >15-20. 5-FU plasma concentrations were determined using high-performance liquid chromatography. A Bayesian methodology was used to assess individual pharmacokinetic parameters using the NONMEM computer program.
  
  
  RESULTS
  Among the 53 eligible patients, 87% (per-protocol population) received an increased dose in cycle 2 and 72% received the same dose. The median relative dose intensity was 1.28 (range 0.5-1.54) compared with the non-adapted theoretical total 5-FU dose. The objective response rate was 37% (95% CI 23-50%) in the intention-to-treat population and 47% (95% CI 29-65%) in the first-line per-protocol population. The median response duration was 10.4 months. The median progression-free survival (PFS) and overall survival (OS) were, respectively, 7 and 18.6 months. PFS and OS in first-line per-protocol patients were, respectively, 9.2 and 20 months. No deaths were attributed to toxicity of 5-FU despite the high doses administered. Of the 53 patients, 19% experienced gastrointestinal and 30% haematological grade 3/4 toxicities. Hand-foot syndrome was common but mild (grade 3 in one patient).
  
  
  CONCLUSIONS
  This strategy could be compared in a phase III trial with the standard LV5FU2 regimen.
authors.affiliation: Digestive Oncology Unit, CRLC Val d'Aurelle, Parc Euromédecine, 34298 Montpellier Cedex 5, France. mychou@valdorel.fnclcc.fr
authors.forename: Marc
authors.initials: M
authors.lastname: Ychou
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Duffour
authors.forename: Andrew
authors.initials: A
authors.lastname: Kramar
authors.forename: Charles
authors.initials: C
authors.lastname: Debrigode
authors.forename: Sophie
authors.initials: S
authors.lastname: Gourgou
authors.forename: Françoise
authors.initials: F
authors.lastname: Bressolle
authors.forename: Frédéric
authors.initials: F
authors.lastname: Pinguet
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016019:Survival Analysis
chemical_list: D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil