title: Autoimmune antibodies and recurrence-free interval in melanoma patients treated with adjuvant interferon.
abstract: BACKGROUND
  Appearance of autoantibodies and clinical manifestations of autoimmunity in melanoma patients treated with adjuvant interferon (IFN)-alpha2b was reported to be associated with improved prognosis. We assessed the association of the appearance of autoantibodies after initiation of treatment with recurrence-free interval in two randomized trials that compared intermediate doses of IFN with observation for the treatment of melanoma patients.
  
  
  METHODS
  Serum levels of anticardiolipin, antithyroglobulin, and antinuclear antibodies were determined using enzyme-linked immunosorbent assays in 187 and 356 patients in the European Organization for Research and Treatment of Cancer (EORTC) 18952 and Nordic IFN trials, respectively, immediately before and up to 3 years after random assignment. The association of the presence of at least one of the three autoantibodies with risk of recurrence was assessed by three Cox models in patients negative for all three autoantibodies at baseline (125 from the EORTC 18952 trial and 230 from the Nordic IFN trial): 1) a model that considered appearance of autoantibodies as a time-independent variable, 2) one that considered a patient autoantibody positive once a positive test for an autoantibody was obtained, and 3) a model in which the status of the patient was defined by the most recent autoantibody test. All statistical tests were two-sided.
  
  
  RESULTS
  When treated as a time-independent variable (model 1), appearance of autoantibodies was associated with improved relapse-free interval in both trials (EORTC 18952, hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.25 to 0.68, P < .001; and Nordic IFN, HR = 0.51, 95% CI = 0.34 to 0.76, P < .001). However, on correction for guarantee-time bias, the association was weaker and not statistically significant (model 2: EORTC 18952, HR = 0.81, 95% CI = 0.46 to 1.40, P = .44; and Nordic IFN, HR = 0.85, 95% CI = 0.55 to 1.30, P = .45; model 3: EORTC 18952, HR = 1.05, 95% CI = 0.59 to 1.87, P = .88; and Nordic IFN, HR = 0.78, 95% CI = 0.49 to 1.24, P = .30).
  
  
  CONCLUSIONS
  In two randomized trials of IFN for the treatment of melanoma patients, appearance of autoantibodies was not strongly associated with improved relapse-free interval when correction was made for guarantee-time bias.
authors.affiliation: Department of Surgical Oncology, Erasmus University MC-Daniel den Hoed Cancer Center, 301 Groene Hilledijk, Rotterdam, the Netherlands.
authors.forename: Marna G
authors.initials: MG
authors.lastname: Bouwhuis
authors.forename: Stefan
authors.initials: S
authors.lastname: Suciu
authors.forename: Sandra
authors.initials: S
authors.lastname: Collette
authors.forename: Steinar
authors.initials: S
authors.lastname: Aamdal
authors.forename: Wim H
authors.initials: WH
authors.lastname: Kruit
authors.forename: Lars
authors.initials: L
authors.lastname: Bastholt
authors.forename: Ulrika
authors.initials: U
authors.lastname: Stierner
authors.forename: François
authors.initials: F
authors.lastname: Salès
authors.forename: Poulam
authors.initials: P
authors.lastname: Patel
authors.forename: Cornelis J A
authors.initials: CJ
authors.lastname: Punt
authors.forename: Micaela
authors.initials: M
authors.lastname: Hernberg
authors.forename: Alain
authors.initials: A
authors.lastname: Spatz
authors.forename: Timo L M
authors.initials: TL
authors.lastname: ten Hagen
authors.forename: Johan
authors.initials: J
authors.lastname: Hansson
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D017153:Antibodies, Anticardiolipin / Q000097:blood; D000974:Antibodies, Antinuclear / Q000097:blood; D001323:Autoantibodies / Q000097:blood*; D015982:Bias; D015986:Confounding Factors, Epidemiologic; D018572:Disease-Free Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology*; D008875:Middle Aged; D016017:Odds Ratio; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D013997:Time Factors
chemical_list: D000276:Adjuvants, Immunologic; D017153:Antibodies, Anticardiolipin; D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D016898:Interferon-alpha; C006606:anti-thyroglobulin