NEW YORKThe folate antagonist trimetrexate (TMTX) may be useful
as a biochemical modulator of 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 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
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.