Regional chemotherapy of nonresectable colorectal liver metastases with mitoxantrone, 5-fluorouracil, folinic acid, and mitomycin C may prolong survival

BACKGROUND. Regional chemotherapy of isolated, nonresectable colorectal. li ver metastases (CRLMs) by hepatic artery infusion (HAI) has the advantages of high response rates and the possibility of downstaging and resection of CRLMs. 5-Fluorodeoxyuridine (5-FUDR) has been the drug studied in most Phas e II and III trials. The meta-analysis of the Phase III trials comparing HA I with systemic or supportive therapy confirmed an advantage for response a nd even survival for HAI. Hepatic artery infusion with 5-FUDR, however, is hepatotoxic, inducing sclerosing cholangitis (SC). The authors have introdu ced 5-fluorouracil (5-FU) with folinic acid for HAI and found equal effecti vity but no SC when compared with HAI with 5-FUDR. Now, they report a new c ombination chemotherapy protocol based on HAI with 5-FU with FA and on in v itro Phase II studies suggesting mitoxantrone and mitomycin. C as active dr ugs for HAI in CRLM. PATIENTS AND METHODS. Between February 1993 and August 2000, 63 patients wi th CRLM were treated with HAI using mitoxantrone, 5-FU with FA, and mitomyc in C (MFFM) via port catheters with a protocol planing up to 11 cycles of t reatment. Toxicity and response were analyzed according to World Health Org anization (WHO) criteria, and survival was analyzed according to Kaplan-Mei er. All patients were treated with more than two HAI cycles. RESULTS. The objective response rate (complete remission and partial remiss ion) was 54% and primary intrahepatic progression (progressive disease) occ urred in 4.8%, whereas in 41.3% of the patients the intrahepatic disease wa s evaluated as no change. Median survival times from the first diagnosis of CRLM or start of HAI were 25.7 months and 23.7 months, respectively, and 7 patients lived longer than 40 months. Grade 3 toxicity according to WHO oc curred in 34.9%, and Grade 4 occurred in 3.2%. No toxic death or SC occurre d. CONCLUSIONS. Our new HAI protocol with MFFM seems to be superior to HAI wit h 5-FUDR, 5-FU with FA, and systemic chemotherapy with 5-FU and FA at accep table toxicity. Currently, HAI with MFFM is compared with systemic chemothe rapy using 5-FU and FA intravenously in a randomized Phase III trial. Cance r 2001;92: 2746-53. (C) 2001 American Cancer Society.