DOUBLE-MODULATION OF 5-FLUOROURACIL BY HIGH-DOSE LEUCOVORIN AND INTERFERON-ALPHA-2B IN ADVANCED COLORECTAL-CANCER - A PHASE-I AND A PHASE-II STUDY OF WEEKLY ADMINISTRATION

In an attempt to evaluate the feasibility of 5-fluorouracil (FU) treatment modulated by (R,S)-leucovorin (LV) and interferonc alpha (IFN alpha) in patients with advanced colorectal cancer, we conducted a phase I trial with increasing doses of subcutaneous IFNc alpha (3x1x10(6) U, 3x3x10(6) U, 3x3x10(6) U, 3x5x10(6) U and 3x10x10(6) U/week) and 500 mg/m(2) LV i.v. as a 2-h infusion with 600 mn/m(2) FU i.v. as a midpoint injection. Unacceptable side-effects occurred in all 3 patients at the highest dose level of IFN alpha, while toxicity was tolerable at 3x5x510(6) U IFN alpha/week. Thus, this dose was defined as the maximal tolerable dose for IFN alpha in combination with FU and LV. In a subsequent phase II study a total of 83 treatment courses (median: 2.8, range: 2-10) were administered to 30 evaluable patients. Side-effects were acceptable with no WHO grade IV toxicities. Grade III toxicities consited in thrombopenia (2/30), stomatitis (2/30), diarrhoea (3/30) and nausea/vomiting (4/30). After a median observation time of 17 months (range: 8-22 months), no complete remission was observed and 9 patients experienced a partial response lasting for a median of 6.6 months (range: 3-13+ months), for an overall response rate of 30% (95% confidence interval: 15%-49%). These results show that the described regiment of FU doubly modulated by LV and IFN alpha is active in colorectal cancer and can be safely administered in an out, patient setting with acceptable toxicity. Thus, this regimen is suitable to be used for further evaluation in clinical trials.