Continuous regional treatment with fluoropyrimidines for metastases from colorectal carcinomas: influence of modulation with leucovorin.

Hepatic regional treatment represents an attempt to improve tumor response by increasing drug concentration with low systemic toxicities. Recently in vitro and clinical studies have shown that the cytotoxicity of 5-fluorodeoxyuridine (FUDR) and 5-fluorouracil (5FU) can be potentiated by high doses of leucovorin (LCV). Two pilot studies with intraarterial FUDR, 5FU, and LCV were initiated. Since 1982, 221 patients with colorectal liver metastases were treated by various forms of long-term monthly continuous regional treatment using implantable ports or pumps. FUDR (0.05 to 1.7 mg/kg/d) was administered alone or combined with 5-FU and leucovorin. In 61 patients curative liver resection was possible and was followed by adjuvant arterial treatment. Overall median survival time (MST) was 15 months and increased to 36 months after liver resection. This was influenced by the following important factors: treatment, number of metastases, extent of infiltration, tumor volume, and minimal intraoperatively diagnosed extrahepatic disease. The response rate varied from 69% to 23%. Time of development of extrahepatic progression was not delayed by additional systemic treatment. Local side effects significantly depended on the duration of arterial infusion. The rate of biliary sclerosis ranged from 19% to 0%. Occurrence of chemical hepatitis was between 7% and 38%. In contrast, after combined intraarterial treatment with LCV, systemic side effects, mainly stomatitis and diarrhea, were dose limiting. Despite the improvement of survival after regional treatment, further randomized trials are mandatory to compare regional with relevant systemic treatment.