A dose-escalation phase II clinical trial of infusional mitomycin C for 7 days in patients with advanced measurable colorectal cancer refractory or resistant to 5-fluorouracil.

Chemotherapy for 5-fluorouracil (5-FU)-resistant colorectal cancer is largely ineffective with new and innovative therapeutic strategies needed to benefit patients developing progressive disease while receiving 5-FU or 5-FU-based programs. The tumor antibiotic mitomycin C is an alkylating agent with a broad range of clinical activity in a variety of gastrointestinal malignancies and is therefore a reasonable agent to test for clinical activity in the setting of 5-FU-resistant or -refractory colorectal cancer. The principal goal of this study is to investigate the logistical feasibility and clinical efficacy of a 7-day infusion of mitomycin C, delivering an equitoxic dose to the standard bolus delivery in patients with progressive disease while receiving 5-FU-based chemotherapy. Twenty-five patients with advanced measurable colorectal cancer, resistant or refractory to 5-FU-based chemotherapy, were treated with a 7-day intravenous infusion of mitomycin C. Doses ranged between 1.5 and 3.0 mg/M2/day for total cumulative mitomycin C, ranging between 10.5 and 21.0 mg/M2 per chemotherapy cycle. Forty-four courses of infusional mitomycin C were delivered to 25 patients via surgically implanted venous access devices. The median age of all patients was 63 years (range, 27-83); there were 11 men and 14 women. Eleven patients had received two or more prior chemotherapy combinations, with the average number of prior therapies before mitomycin C being 1.6. The median number of cycles of mitomycin C administered was two (range, one to six). Thirty-seven of 44 cycles were administered at the dose range of 2.0-3.0 mg/M2/day. Hematologic toxicity was mild, with only three courses associated with grade III thrombocytopenia and one course with grade III neutropenia. No extrahematologic toxicities were observed. No patient had a complete response; two patients (8%) showed partial responses that lasted for 145 and 190 days. One patient had stable disease for 180 days. Twenty-two of 25 patients (88%) developed progressive disease during mitomycin C administration. Infusional mitomycin C for 7 days, cycled every 42 days, is logistically feasible and associated with minimal clinical toxicity. Used on this schedule and with these doses in 5-FU-resistant/refractory colorectal cancer, however, there is no meaningful clinical activity for this agent, and it cannot be recommended as a salvage or second-line therapy in the treatment of metastatic colorectal cancer.