title: Increase of survival benefit in advanced resectable colon cancer by extent of adjuvant treatment: results of a randomized trial comparing modulation of 5-FU + levamisole with folinic acid or with interferon-alpha.
abstract: BACKGROUND
  The benefit of adjuvant therapy in curatively resected lymph node-positive colon cancer was established using 5-fluorouracil (5-FU) and levamisole (LEV) for 12 months. 5-FU cytotoxicity can be modulated by folinic acid (FA) or interferon-alpha (INF-alpha). The aim of this study was to investigate the efficacy of modulating 5-FU+ LEV by either FA or IFN-alpha in the adjuvant treatment of high-risk colon cancer.
  
  
  METHODS
  Patients with curatively resected colon cancer (stages UICC IIb and III) were stratified according to T, N, and participating center and randomized to receive a 12-month treatment using 5-FU + LEV alone or in combination with FA or IFN-alpha.
  
  
  RESULTS
  A total of 855 of 904 entered patients (94.6%) were eligible. The median follow-up of all eligible patients was 4.6 years. Addition of FA to 5-FU + LEV improved recurrence-free and overall survival in comparison with 5-FU + LEV alone (P = 0.007 and P = 0.004, respectively, 1-sided). The 5-year overall survival rates were 60.5% (95% confidence interval, 54.3-66.7) and 72.0% (95% confidence interval, 66.5-77.5) for 5-FU + LEV and 5-FU + LEV + FA, respectively. Addition of INF-alpha showed a tendency to improve recurrence-free survival, however, without altering overall survival. Toxicities (WHO III + IV) were generally tolerable except one toxic death in the control arm and were observed in 9.9% of the patients receiving 5-FU + LEV alone and in 13.3% and in 30.7% of patients receiving additional FA and IFN-alpha, respectively.
  
  
  CONCLUSIONS
  Addition of IFN-alpha was associated with increased toxicity without markedly influencing the outcome and should therefore not be recommended for adjuvant treatment. Addition of FA increased the 5-year recurrence-free and overall survival rate by 9.3 and 11.5 percentage points, respectively. 5-FU + LEV + FA for 12 months may be an effective adjuvant treatment option for locally advanced high-risk colon cancer.
authors.affiliation: Department of General Surgery, University of Ulm, Ulm, Germany.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Link
authors.forename: Marko
authors.initials: M
authors.lastname: Kornmann
authors.forename: Ludger
authors.initials: L
authors.lastname: Staib
authors.forename: Martin
authors.initials: M
authors.lastname: Redenbacher
authors.forename: Martina
authors.initials: M
authors.lastname: Kron
authors.forename: Hans Günter
authors.initials: HG
authors.lastname: Beger
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000401:mortality / Q000628:therapy*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000633:toxicity; D005500:Follow-Up Studies; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage; D002955:Leucovorin / Q000008:administration & dosage; D007978:Levamisole / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D010349:Patient Compliance; D015996:Survival Rate
chemical_list: D000964:Antimetabolites, Antineoplastic; D016898:Interferon-alpha; D007978:Levamisole; D002955:Leucovorin; D005472:Fluorouracil