Clinical studies of biochemical modulation of 5-fluorouracil by leucovorin in patients with advanced colorectal cancer by the North Central Cancer Treatment Group and Mayo Clinic.

The North Central Cancer Treatment Group (NCCTG) and Mayo Clinic are collaborating in an ongoing, prospective, randomized clinical trial of new approaches to the chemotherapy of advanced metastatic colorectal cancer. Single agent 5-fluorouracil (FUra) given by intensive-course rapid intravenous administration serves as a control. Included among the experimental treatments are two regimens consisting of FUra plus leucovorin (folinic acid). One of these regimens uses folinic acid at a dose level of 200 mg/m2 daily for 5 days based on earlier studies by Machover et al. (4). The second regimen uses folinic acid at 1/10 the dose level (20 mg/m2 daily for 5 days), since this lower dose of folinic acid has been shown to produce peak serum levels equivalent to the concentration of folinic acid required in culture medium to produce optimal inhibition of L1210 cells by FUra in vitro, and because of the great expense of folinic acid when given at the higher dose levels. As of January 1986, 78 patients had been randomized to receive treatment with FUra alone or one of the FUra-folinic acid regimens. The toxicity of the folinic acid regimens has been clinically tolerable, with stomatitis and, to a lesser extent, diarrhea being dose-limiting. Hematologic toxicity has been very mild. There is suggestive evidence that folinic acid given at the higher dose level in combination with FUra at a constant dose produces more severe effects on the oropharyngeal mucosa. Preliminary tumor response and survival data remain blinded in accordance with NCCTG policy. Further patient accrual and follow-up are required to assess the therapeutic effect of these folinic acid regimens compared to FUra given alone.