title: Trimetrexate as biochemical modulator of 5-fluorouracil/leucovorin in advanced colorectal cancer: final results of a randomised European study.
abstract: BACKGROUND
  Trimetrexate (TMTX) is a biochemical modulator of 5-fluorouracil (5-FU) and leucovorin (LV). Phase II trials have shown promising activity of 5-FU/LV/TMTX in patients with advanced colorectal cancer (ACC). This trial evaluated the effect of TMTX in combination with 5-FU/LV as first-line treatment in ACC.
  
  
  METHODS
  Patients with ACC were randomised to receive either intravenous LV 200 mg/m2/5-FU 600 mg/m2 or TMTX 110 mg/m2 followed 24 h later by LV 200 mg/m2/5-FU 500 mg/m2 plus oral LV rescue. Both schedules were given weekly for 6 weeks every 8 weeks. Patients were evaluated for progression-free survival (PFS), overall survival (OS), tumour response, quality of life (QoL) and toxicity.
  
  
  RESULTS
  A total of 365 patients were randomised. A statistically significant prolongation of median PFS was seen in patients treated with TMTX/5-FU/LV compared with 5-FU/LV (5.4 months versus 4.1 months, respectively; P = 0.03), and a trend towards a significant benefit for OS (13.4 months versus 10.5 months, respectively; P = 0.08). Tumour response, QoL and toxicity were comparable between the two arms. Diarrhoea was the most frequently occurring grade 3 or 4 toxicity (22% and 30%, respectively).
  
  
  CONCLUSIONS
  The addition of TMTX to a weekly regimen of 5-FU/LV results in a small but significant improvement in PFS without adding toxicity or worsening QoL in 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: H J
authors.initials: HJ
authors.lastname: Keizer
authors.forename: J
authors.initials: J
authors.lastname: Douma
authors.forename: T
authors.initials: T
authors.lastname: Skovsgaard
authors.forename: J
authors.initials: J
authors.lastname: Schüller
authors.forename: E W
authors.initials: EW
authors.lastname: Muller
authors.forename: C H H
authors.initials: CH
authors.lastname: Ten Napel
authors.forename: J J
authors.initials: JJ
authors.lastname: Croles
authors.forename: H
authors.initials: H
authors.lastname: Lochs
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: L
authors.initials: L
authors.lastname: Hammershaimb
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D005060:Europe; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D015996:Survival Rate; D016597:Trimetrexate / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D002955:Leucovorin; D005472:Fluorouracil; D016597:Trimetrexate