title: Long term follow up of the EORTC 18952 trial of adjuvant therapy in resected stage IIB-III cutaneous melanoma patients comparing intermediate doses of interferon-alpha-2b (IFN) with observation: Ulceration of primary is key determinant for IFN-sensitivity.
abstract: BACKGROUND
  We report on the long term outcome of the EORTC 18952 adjuvant interferon (IFN) trial in 1388 resected stage IIB/III melanoma patients and identify key predictive factors for outcome.
  
  
  METHODS
  We analysed outcome of the EORTC 18952 trial (4 weeks of IFN, 10 MU, 5 times/week for 4 weeks followed by 12 months IFN at 10 MU, 3 times/week versus followed by 24 months IFN at 5 MU 3 times/week versus observation) regarding relapse-free survival (RFS), distant metastasis-free interval/survival (DMFI/DMFS), and overall survival (OS), and analysed potential predictive factors of outcome.
  
  
  RESULTS
  At a median follow-up of 11 years, the comparison of IFN 13 months versus IFN 25 months versus observation yielded estimated hazard ratios (HR) for RFS of 0.94 versus 0.84 (p = 0.06); for DMFI 0.95 versus 0.82 (p = 0.027); for DMFS 0.95 versus 0.84 (p = 0.07); and for OS 0·95 versus 0.84 (p = 0.08), respectively. The impact of treatment was greatest in the ulceration group, whereas in patients with non-ulcerated primaries the impact was null (HR ≥ 1.0). In patients with ulcerated melanoma the HR for IFN 13 months versus 25 months versus observation were for: RFS 0.82 (p = 0.16) versus 0.61 (p = 0.0008); DMFS 0.76 (p = 0.06) versus 0.57 (p = 0.0003); OS 0.80 (p = 0.13) versus 0.59 (p = 0.0007). In stage IIB/III-N1 (microscopic nodal involvement only) patients with ulcerated melanoma the HR estimates were for: RFS 0.85 versus 0.62; DMFS 0.80 versus 0.56; OS 0.77 versus 0.54.
  
  
  CONCLUSIONS
  This long term report of the EORTC 18952 trial demonstrates the superiority of the 25-month IFN schedule and defines ulceration of the primary as the overriding predictive factor for IFN-sensitivity.
authors.affiliation: Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. Electronic address: alexander.eggermont@gustaveroussy.fr.
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
authors.affiliation: EORTC Headquarters, Brussels, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Suciu
authors.affiliation: Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Rutkowski
authors.affiliation: Erasmus MC Cancer Institute - Location Daniel den Hoed, Rotterdam, The Netherlands.
authors.forename: Willem H
authors.initials: WH
authors.lastname: Kruit
authors.affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam, Amsterdam, The Netherlands.
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Punt
authors.affiliation: Universitaetsspital Zurich, Zürich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Institut Jules Bordet, Brussels, Belgium.
authors.forename: François
authors.initials: F
authors.lastname: Salès
authors.affiliation: Charité, Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keilholz
authors.affiliation: EORTC Headquarters, Brussels, Belgium.
authors.forename: Gaetan
authors.initials: G
authors.lastname: de Schaetzen
authors.affiliation: Istituto Europeo di Oncologia, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Testori
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D017024:Chemotherapy, Adjuvant; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D008197:Lymph Node Excision; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000401:mortality / Q000556:secondary / Q000628:therapy*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012878:Skin Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D012883:Skin Ulcer / Q000473:pathology*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins
keywords: Adjuvant; Interferon; Melanoma; Predictive factors; Randomised trial; Ulceration