title: Modulation of high-dose infusional fluorouracil by low-dose methotrexate in patients with advanced or metastatic colorectal cancer: final results of a randomized European Organization for Research and Treatment of Cancer Study.
abstract: OBJECTIVE
  Methotrexate (MTX) has been described to modulate the activity of fluorouracil (5-FU) in patients with metastatic colorectal cancer. The European Organization for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Cooperative Group (GITCCG) conducted a phase III trial to investigate the efficacy and tolarability of the addition of low-dose MTX (40 mg/m2) to high-dose infusional 5-FU (60 mg/kg over 48 hours) given weekly for 4 weeks and thereafter every 2 (for 4 weeks) and 3 weeks.
  
  
  METHODS
  Three hundred ten patients were randomized between 1987 and 1992. Eligible patients had measurable advanced or metastatic colorectal cancer and had not been pretreated with antifolates or fluorodinated pyrimidines. All 297 eligible patients were evaluated for survival; toxicity was assessed in 292 patients who received at least one course of treatment. Patients with bidimensionally measurable disease (n = 230) were also evaluated for response according to standard criteria.
  
  
  RESULTS
  The addition of low-dose MTX to high-dose infusional 5-FU led to a doubling of the response rate from 10% to 21% (P = .025). The median survival time also increased from 9.3 to 12.5 months, but this difference was not statistically significant (P = .12). High-dose infusional 5-FU with or without low-dose MTX was well tolerated, with grade 3 to 4 toxicity in greater than 10% of patients only occurring for stomatitis with the combination treatment. Performance status was the sole prognostic factor for survival in a multivariate analysis.
  
  
  CONCLUSIONS
  Low-dose MTX effectively modulated high-dose infusional 5-FU in a large, randomized trial in which less than 5% of patients received leucovorin.
authors.affiliation: European Organization for Research and Treatment of Cancer, Gastrointestinal Tract Cancer Cooperative Group, Brussels, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Blijham
authors.forename: T
authors.initials: T
authors.lastname: Wagener
authors.forename: J
authors.initials: J
authors.lastname: Wils
authors.forename: J
authors.initials: J
authors.lastname: de Greve
authors.forename: M
authors.initials: M
authors.lastname: Buset
authors.forename: H
authors.initials: H
authors.lastname: Bleiberg
authors.forename: A
authors.initials: A
authors.lastname: Lacave
authors.forename: M
authors.initials: M
authors.lastname: Dalmark
authors.forename: J
authors.initials: J
authors.lastname: Selleslag
authors.forename: L
authors.initials: L
authors.lastname: Collette
authors.forename: T
authors.initials: T
authors.lastname: Sahmoud
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D005060:Europe; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007262:Infusions, Intravenous; D017567:Karnofsky Performance Status; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D011379:Prognosis; D016016:Proportional Hazards Models; D012074:Remission Induction; D015996:Survival Rate
chemical_list: D005472:Fluorouracil; D008727:Methotrexate