title: Regional chemotherapy of nonresectable colorectal liver metastases with mitoxantrone, 5-fluorouracil, folinic acid, and mitomycin C may prolong survival.
abstract: BACKGROUND
  Regional chemotherapy of isolated, nonresectable colorectal liver 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 Phase II and III trials. The meta-analysis of the Phase III trials comparing HAI with systemic or supportive therapy confirmed an advantage for response and even survival for HAI. Hepatic artery infusion with 5-FUDR, however, is hepatotoxic, inducing sclerosing cholangitis (SC). The authors have introduced 5-fluorouracil (5-FU) with folinic acid for HAI and found equal effectivity but no SC when compared with HAI with 5-FUDR. Now, they report a new combination chemotherapy protocol based on HAI with 5-FU with FA and on in vitro Phase II studies suggesting mitoxantrone and mitomycin C as active drugs for HAI in CRLM. PATIENTS AND METHODS Between February 1993 and August 2000, 63 patients with CRLM were treated with HAI using mitoxantrone, 5-FU with FA, and mitomycin C (MFFM) via port catheters with a protocol planing up to 11 cycles of treatment. Toxicity and response were analyzed according to World Health Organization (WHO) criteria, and survival was analyzed according to Kaplan-Meier. All patients were treated with more than two HAI cycles.
  
  
  RESULTS
  The objective response rate (complete remission and partial remission) was 54% and primary intrahepatic progression (progressive disease) occurred in 4.8%, whereas in 41.3% of the patients the intrahepatic disease was 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 occurred in 34.9%, and Grade 4 occurred in 3.2%. No toxic death or SC occurred.
  
  
  CONCLUSIONS
  Our new HAI protocol with MFFM seems to be superior to HAI with 5-FUDR, 5-FU with FA, and systemic chemotherapy with 5-FU and FA at acceptable toxicity. Currently, HAI with MFFM is compared with systemic chemotherapy using 5-FU and FA intravenously in a randomized Phase III trial.
authors.affiliation: Department of General Surgery, University of Ulm, Ulm, Germany. wiesbaden@asklepios.com
authors.forename: K H
authors.initials: KH
authors.lastname: Link
authors.forename: E
authors.initials: E
authors.lastname: Sunelaitis
authors.forename: M
authors.initials: M
authors.lastname: Kornmann
authors.forename: M
authors.initials: M
authors.lastname: Schatz
authors.forename: F
authors.initials: F
authors.lastname: Gansauge
authors.forename: G
authors.initials: G
authors.lastname: Leder
authors.forename: A
authors.initials: A
authors.lastname: Formentini
authors.forename: L
authors.initials: L
authors.lastname: Staib
authors.forename: J
authors.initials: J
authors.lastname: Pillasch
authors.forename: H G
authors.initials: HG
authors.lastname: Beger
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008113:Liver Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage / Q000009:adverse effects; D008942:Mitoxantrone / Q000008:administration & dosage / Q000009:adverse effects; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D016685:Mitomycin; D008942:Mitoxantrone; D002955:Leucovorin; D005472:Fluorouracil