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Annals of Oncology 13:81-86, 2002
© 2002 European Society for Medical Oncology

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

C. J. A. Punt1,+, H. J. Keizer2,§, J. Douma3, T. Skovsgaard4, J. Schüller5, E. W. Muller6, C. H. H. Ten Napel7, J. J. Croles8, H. Lochs9, J. Zhang10 and L. Hammershaimb10

1University Medical Centre, St. Radboud, Nijmegen; 2University Medical Centre, Leiden; 3Rijnstate Hospital, Arnhem, The Netherlands; 4Herlev Hospital, University Hospital of Copenhagen, Denmark; 5Rudolf Hospital, Vienna, Austria; 6Slingeland Hospital, Doetinchem; 7Medisch Spectrum, Twente Enschede; 8Bosch Medicentrums, Hertogenbosch, The Netherlands; 9University Hospital Charite, Berlin, Germany; 10MedImmune Oncology, Inc., Gaithersburg, MD, USA

Received 7 September 2001; accepted 11 September 2001.

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.

Patients and 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.

Key words: biochemical modulation, colorectal cancer, 5-fluorouracil, leucovorin, trimetrexate, randomised trial


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