BACKGROUND No effective systemic salvage therapy exists for patients with advanced colorectal cancer who progress after receiving bolus fluorouracil (FU) and leucovorin (LV) chemotherapy. In vitro data suggest that bolus FU resistance can be overcome by continuous infusion (CI) FU, and that the cytotoxic effects of Mitomycin-C (MMC) and FU are synergistic. Based on this data, a Phase II trial of CI FU and LV with bolus MMC in patients with advanced colorectal carcinoma who progressed on only one previous chemotherapy regimen was performed. METHODS Twenty-eight patients with advanced colorectal carcinoma who had progressed after one previous chemotherapy regimen of bolus FU/LV were treated with bolus MMC 10 mg/m2 every 6 weeks and CI FU 200 mg/m2/day admixed with LV 10 mg/m2/day given 14 days on/7 days off. RESULTS The partial response rate in 24 evaluable patients was 17% (95% confidence interval, 2-32%) with a median response duration of 9.5 months (range, 4.2-12.0 months). Twelve (50%) additional patients achieved disease stabilization. Median survival was 9.9 months in the whole group (28 patients) and 11.5 months in the 24 evaluable patients. The major toxicities were grade 4 diarrhea occurring in two patients and grade 3 mucositis occurring in five patients. There was minimal myelosuppression (grade 3 thrombocytopenia in one patient) and no occurrences of hand-foot syndrome or cardiotoxicity. CONCLUSIONS This regimen demonstrates modest activity with acceptable toxicity in colorectal cancer patients who have failed a single-bolus FU/LV regimen. Modifications of this and other infusional FU-based chemotherapy regimens should be explored as potential salvage chemotherapy regimens in advanced colorectal cancer.