title: Integrated analysis of overall survival in two randomised studies comparing 5-fluorouracil/leucovorin with or without trimetrexate in advanced colorectal cancer.
abstract: BACKGROUND
  Two randomised studies were performed with trimetrexate (TMTX) as a biochemical modulator of 5-fluorouracil (5-FU)/leucovorin (LV) in advanced colorectal cancer (ACC), one in Europe and one in the United States. Both studies were similarly designed to detect a statistically significant difference in progression-free survival (PFS). Overall survival (OS), however, was later adopted as the primary outcome measure for approvability of agents for first-line treatment of ACC. Therefore, an integrated analysis of survival data from the European and USA trials was performed to detect a clinically relevant difference in survival.
  
  
  METHODS
  The experimental arm was identical in both studies and consisted of TMTX 110 mg/m2 intravenously (i.v.) followed 24 h later by i.v. LV 200 mg/m2/5-FU 500 mg/m2 plus oral LV rescue. The 5-FU dose in the control arm was 600 mg/m2 in the European study and 500 mg/m2 in the USA study, and the USA study was placebo-controlled. Treatment was given weekly for 6 weeks every 8 weeks.
  
  
  RESULTS
  A total of 746 patients were analysed. Median OS was 13.0 months for 5-FU/LV and 14.6 months for TMTX/5-FU/LV (P = 0.15; Wilcoxon). Median PFS was 4.4 months and 5.4 months, respectively (P = 0.07; Wilcoxon).
  
  
  CONCLUSIONS
  The addition of TMTX to a weekly regimen of 5-FU/LV does not improve the outcome for patients with ACC.
authors.affiliation: University Medical Centre, St Radboud, Nijmegen, The Netherlands. c.punt@onco.azn.nl
authors.forename: C J A
authors.initials: CJ
authors.lastname: Punt
authors.forename: C D
authors.initials: CD
authors.lastname: Blanke
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: L
authors.initials: L
authors.lastname: Hammershaimb
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D018450:Disease Progression; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use*; D008297:Male; D016019:Survival Analysis; D015996:Survival Rate; D013997:Time Factors; D016597:Trimetrexate / Q000627:therapeutic use*
chemical_list: D002955:Leucovorin; D005472:Fluorouracil; D016597:Trimetrexate