Autoimmune antibodies and recurrence-free interval in melanoma patients treated with adjuvant interferon.
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.
Bouwhuis
Marna G
MG
Department of Surgical Oncology, Erasmus University MC-Daniel den Hoed Cancer Center, 301 Groene Hilledijk, Rotterdam, the Netherlands.
Suciu
Stefan
S
Collette
Sandra
S
Aamdal
Steinar
S
Kruit
Wim H
WH
Bastholt
Lars
L
Stierner
Ulrika
U
Salès
François
F
Patel
Poulam
P
Punt
Cornelis J A
CJ
Hernberg
Micaela
M
Spatz
Alain
A
ten Hagen
Timo L M
TL
Hansson
Johan
J
Eggermont
Alexander M M
AM
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
D000276:Adjuvants, Immunologic; D017153:Antibodies, Anticardiolipin; D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D016898:Interferon-alpha; C006606:anti-thyroglobulin