title: Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial.
abstract: BACKGROUND
  Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment. Our aim was to determine whether pegylated interferon alfa-2b can facilitate prolonged exposure while maintaining tolerability.
  
  
  METHODS
  1256 patients with resected stage III melanoma were randomly assigned to observation (n=629) or pegylated interferon alfa-2b (n=627) 6 mug/kg per week for 8 weeks (induction) then 3 mug/kg per week (maintenance) for an intended duration of 5 years. Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness, sex, and centre. Randomisation was done with a minimisation technique. The primary endpoint was recurrence-free survival. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00006249.
  
  
  RESULTS
  All randomised patients were included in the primary efficacy analysis. 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses. The median length of treatment with pegylated interferon alfa-2b was 12 (IQR 3.8-33.4) months. At 3.8 (3.2-4.2) years median follow-up, 328 recurrence events had occurred in the interferon group compared with 368 in the observation group (hazard ratio 0.82, 95% CI 0.71-0.96; p=0.01); the 4-year rate of recurrence-free survival was 45.6% (SE 2.2) in the interferon group and 38.9% (2.2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the interferon group and 14 (2%) in the observation group. In the interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in 191 (31%) patients.
  
  
  CONCLUSIONS
  Adjuvant pegylated interferon alfa-2b for stage III melanoma has a significant, sustained effect on recurrence-free survival.
authors.affiliation: Erasmus University Medical Center, Rotterdam, Netherlands. Electronic address: a.m.m.eggermont@erasmusmc.nl.
authors.forename: Alexander Mm
authors.initials: AM
authors.lastname: Eggermont
authors.affiliation: EORTC Headquarters, Brussels, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Suciu
authors.affiliation: Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Santinami
authors.affiliation: Istituto Europeo di Oncologia, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Testori
authors.affiliation: Erasmus University Medical Center, Rotterdam, Netherlands.
authors.forename: Wim Hj
authors.initials: WH
authors.lastname: Kruit
authors.affiliation: University Hospital Birmingham, Birmingham, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Marsden
authors.affiliation: University Medical Center St Radboud, Nijmegen, Netherlands.
authors.forename: Cornelis Ja
authors.initials: CJ
authors.lastname: Punt
authors.affiliation: Institut Jules Bordet, Brussels, Belgium.
authors.forename: François
authors.initials: F
authors.lastname: Salès
authors.affiliation: Royal Marsden Hospital NHS, London, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Gore
authors.affiliation: University of Glasgow, Glasgow, UK.
authors.forename: Rona
authors.initials: R
authors.lastname: MacKie
authors.affiliation: University Hospital Sestre Milosrdnice, Zagreb, Croatia.
authors.forename: Zvonko
authors.initials: Z
authors.lastname: Kusic
authors.affiliation: University Clinic Zürich, Zürich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: University Hospital Kiel, Kiel, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Hauschild
authors.affiliation: EORTC Headquarters, Brussels, Belgium.
authors.forename: Elena
authors.initials: E
authors.lastname: Musat
authors.affiliation: Institut Gustave-Roussy, Villejuif, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Spatz
authors.affiliation: Charité, Benjamin Franklin Campus, Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keilholz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D008875:Middle Aged; D009362:Neoplasm Metastasis; D019370:Observation; D011092:Polyethylene Glycols; D016016:Proportional Hazards Models; D011994:Recombinant Proteins
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C417083:peginterferon alfa-2b