Trimetrexate: Review and current clinical experience in advanced colorectal cancer

Unresectable metastatic colorectal cancer remains a significant cause of morbidity and mortality in both the United States and Europe. To date, no chemotherapeutic regimen for this disease has demonstrated a definitive survival advantage compared with 5-fluorouracil (5-FU) plus leucovorin (LV). However, recent trials have raised the possibility that the combination of trimetrexate (TMTX) plus 5-FU/LV may improve response rates and survival in patients with metastatic colorectal cancer. Trimetrexate is a nonclassical antifolate that has demonstrated antitumor activity against a number of malignancies, including those resistant to the classical antifolate methotrexate. While the single-agent activity of TMTX remains modest in metastatic colorectal cancer, the combination of TMTX/5-FU/LV has shown significant activity in several phase II trials. Reported studies include a phase II trial in chemotherapy failures that demonstrated a 20% response rate, and two multicenter phase II trials in previously untreated patients that demonstrated 50% and 38% overall response rates, respectively. Diarrhea was the dose-limiting toxicity in all trials although a regimen of scheduled loperamide was quite effective in mitigating this complication. These studies are being followed up with two confirmatory phase II studies in chemorefractory patients and two randomized phase III trials comparing TMTX/5-FU/LV with standard 5-FU/LV.