title: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis.
abstract: OBJECTIVE
  The modulation of fluorouracil (FU) by folinic acid (leucovorin [LV]) has been shown to be effective in terms of tumor response rate in patients with advanced colorectal cancer, but a meta-analysis of nine trials previously published by our group failed to demonstrate a statistically significant survival difference between FU and FU-LV. We present an update of the meta-analysis, with a longer follow-up and the inclusion of 10 newer trials.
  
  
  METHODS
  Analyses are based on individual data from 3,300 patients randomized in 19 trials on an intent-to-treat basis. Two trials had multiple comparisons, leading to a total of 21 pair-wise comparisons. FU doses were similar in both arms in 10 pair-wise comparisons, 15% to 33% higher in the FU-alone arm in six comparisons, and more than 66% higher in five comparisons.
  
  
  RESULTS
  Overall analysis showed a two-fold increase in tumor response rates (11% for FU-LV v 21% for FU-LV v 11% for FU [corrected] alone; odds ratio, 0.53; 95% CI, 0.44 to 0.63; P <.0001) and a small but statistically significant overall survival benefit for FU-LV over FU alone (median survival, 11.7 v 10.5 months, respectively; hazards ratio, 0.90; 95% CI, 0.87 to 0.94; P =.004), which were primarily seen in the first year. We observed a significant interaction between treatment benefit and dose of FU, with tumor response and overall survival advantages of FU-LV over FU-alone being restricted to trials in which a similar dose of FU was prescribed in both arms.
  
  
  CONCLUSIONS
  This updated analysis demonstrates, on a large data set, that FU-LV improves both response rate and overall survival compared with FU alone and that this benefit is consistent across various prognostic factors.
authors.affiliation: Saint Luc Hospital, Ireland.
authors.forename: P
authors.initials: P
authors.lastname: Thirion
authors.forename: S
authors.initials: S
authors.lastname: Michiels
authors.forename: J P
authors.initials: JP
authors.lastname: Pignon
authors.forename: M
authors.initials: M
authors.lastname: Buyse
authors.forename: A C
authors.initials: AC
authors.lastname: Braud
authors.forename: R W
authors.initials: RW
authors.lastname: Carlson
authors.forename: M
authors.initials: M
authors.lastname: O'Connell
authors.forename: P
authors.initials: P
authors.lastname: Sargent
authors.forename: P
authors.initials: P
authors.lastname: Piedbois
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D002955:Leucovorin; D005472:Fluorouracil