NEW YORKThe folate antagonist trimetrexate(Drug information on trimetrexate) (TMTX) may be useful as a biochemical modulator of fluorouracil(Drug information on fluorouracil) (5-FU) in the treatment of advanced colorectal cancer, according to preliminary results of a phase III trial conducted by the European TMTX Study Group and discussed at the Chemotherapy Foundation Symposium XVII.
In preclinical models, trimetrexate is 10 times more cytotoxic than methotrexate(Drug information on methotrexate) when used in combination with 5-FU/leucovorin, said Cornelis J.A. Punt, MD, PhD, a researcher in the Department of Medical Oncology, University Hospital of Nijmegen, the Netherlands. In the synergism with 5-FU/leucovorin, trimetrexate has several advantages over methotrexate.
In phase II studies, the addition of trimetrexate to a 5-FU/leucovorin regimen showed promising response rates but resulted in a high incidence of severe diarrhea, Dr. Punt said. In the phase III trial, patients experiencing diarrhea were treated with intensive-dose loperamide(Drug information on loperamide).
Patients in the trimetrexate arm were given an intravenous trimetrexate dose of 110 mg/m² 24 hours before beginning 5-FU (500 mg/m²)/leucovorin (200 mg/m²), followed 6 hours later by oral leucovorin (6 × 15 mg). Patients in the control arm received a higher dose of 5-FU (600 mg/m²), reflecting the intention to investigate a meaningful biomod-ulation effect of trimetrexate, he said.
In the first 222 patients, with a median follow-up of 17 months, the overall response rate in the trimetrexate arm was 29% vs 26% in the control arm; overall survival in the trimetrexate arm was 13 months vs 10 months in the control arm. In addition, the incidence of severe diarrhea was significantly less in the tri-metrexate arm (15% vs 28%).
Quality of Life
We saw a positive difference in several quality of life parameters, Dr. Punt said. Although the response and survival advantages are not statistically significant, he said, there is a trend toward statistical significance in the survival data, which may become more apparent after full analysis of the data. Final results of the study will be available next year.