Trimetrexate as biochemical modulator of 5-fluorouracil/leucovorin in advanced colorectal cancer:: final results of a randomised European study

Background: Trimetrexate (TMTX) is a biochemical modulator of 5-fluorcuracil (5-FU) and leucovorin (LV). Phase 11 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. Patients and methods: Patients with ACC were randomised to receive either intravenous LV 200 m/mg/m(2)/5-FU 600 mg/m(2) or TMTX I 10 mg/m(2) followed 24 h later by LV 200 mg/m(2)/5-FU 500 mg/m(2) 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.