Hepatic Arterial Chemotherapy with Oxaliplatin, Folinic Acid and 5-Fluorouracil in Pre-treated Patients with Liver Metastases from Colorectal Cancer

Background: Hepatic arterial chemotherapy (HAC) is an effective treatment of liver metastases from colorectal cancer (CRC). Phase I and II studies have already shown the feasibility and efficacy of intra-arterial oxaliplatin (OXA). Patients and Methods: Twenty-one pre-treated patients with liver metastases who received HAC with OXA/folinic acid (FA)/5- fluorouracil (5-FU) at our Division between March 2000 and November 2003, were clinically examined. Most patients were heavily pre-treated with two or more systemic chemotherapeutic regimes. All patients received a percutaneously implanted catheter into the hepatic artery through femoral or transaxillary access. Treatment was administered every 14 days: OXA 100 mg/m 2 as a 12-hour infusion on day 1; FA 100 mg/m 2 as a 2- hour infusion on days 2 and 3; 5-FU 2600 mg/m 2 as a continuous infusion on days 2 and 3. Results: Grade 3-4 toxicities were: asthenia (2 out of 21), transaminase elevation (2 out of 21) and pain (2 out of 21), nausea and vomiting (1 out of 21), neutropenia (1 out of 21), thrombocytopenia (1 out of 21) and neurotoxicity (1 out of 21). Main dose limiting toxicity was right upper quadrant pain. Response rates were: 5% complete response, 19% partial response, 28% stable disease and 48% progressive disease. Two patients became operable and underwent complete resection of liver disease. The median overall survival was 36.1 months. Two-year and 3-year survival rates were 62% and 52%, respectively. Conclusion: This regimen is feasible with low toxicity and with an encouraging overall tumor growth control (52%) in a subset of heavily pre-treated patients. Intra-arterial OXA/FA/5-FU should be considered for the treatment of patients pre-treated with systemic chemotherapies with liver metastases from CRC. Liver metastases from colorectal cancer (CRC) are present at diagnosis in 15-20% of patients or developed during disease progression in about another 50% of patients. Radical surgery remains the only curative treatment, while systemic chemotherapy is offered to the unresectable patients (1). Because of the poor outcome associated with metastatic CRC, alternative strategies have been explored. One such strategy is hepatic arterial chemotherapy (HAC) for patients with liver-only metastases (2). Multiple trials over the past decades have shown that HAC is an effective treatment for liver metastases with superior response rates (RR) compared to systemic chemotherapy even if there is no significant improvement in survival (3). Thus, clinical use of this regimen has not been recommended. Recently, in a randomised trial, HAC with floxuridine, FA and dexamethasone has been compared with an intravenous (i.v.) bolus regimen with 5-fluorouracil (5-FU) and folinic acid (FA) in patients with metastases confined to the liver, and a significant advantage in overall survival (OS) was shown for HAC versus systemic treatment (24.4 vs. 20 months) and time to hepatic progression (9.8 vs. 7.3 months) (4). Oxaliplatin (OXA) is a new platinum compound with significant activity in CRC. For patients with unresectable and/or extrahepatic disease, systemic chemotherapy with OXA combined with FA and 5-FU has produced RR greater than 50% and OS of more than 20 months. Two- year survival rate, however, remained poor (25-30%) and long-term survivors were rare (5-7). In a rabbit tumor model intra-arterial (i.a.) hepatic OXA has shown a significant pharmacokinetic advantage compared with i.v. infusion (8). Several phase I and II studies of HAC with OXA have been published to date. Tolerability and efficacy in heavily pre-