Journal of the National Cancer Institute Advance Access originally published online on June 9, 2009
JNCI Journal of the National Cancer Institute 2009 101(12):869-877; doi:10.1093/jnci/djp132
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© The Author 2009. Published by Oxford University Press.
ARTICLES |
Autoimmune Antibodies and Recurrence-Free Interval in Melanoma Patients Treated With Adjuvant Interferon
Affiliations of authors: Department of Surgical Oncology (MGB, TLMtH, AMME) and Department of Medical Oncology (WHK), Erasmus University Medical Center–Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; Statistics Department, EORTC Headquarters, Brussels, Belgium (SS, SC); Department of Medical Oncology, The Norwegian Radium Hospital, Oslo, Norway (SA); Department of Oncology, Odense University Hospital, Odense, Denmark (LB); Department of Medical Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden (US); Department of Surgery, Institut Jules Bordet, Brussels, Belgium (FS); Cancer Research UK Clinical Center, St. James's University Hospital, Leeds, UK (PP); Department of Medical Oncology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands (CJAP); Department of Oncology, University Central Hospital Helsinki, Helsinki, Finland (MH); Department of Pathology, Institut Gustave Roussy, Villejuif, France (AS); Department of Medical Oncology, Karolinska Institute, Stockholm, Sweden (JH)
Correspondence to: Alexander M. M. Eggermont, MD, PhD, Department of Surgical Oncology, Erasmus University MC–Daniel den Hoed Cancer Center, 301 Groene Hilledijk, 3075 EA Rotterdam, the Netherlands (e-mail: a.m.m.eggermont{at}erasmusmc.nl).
Background: Appearance of autoantibodies and clinical manifestations of autoimmunity in melanoma patients treated with adjuvant interferon (IFN)-
2b 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.
| CONTEXT AND CAVEATS Prior knowledge
The appearance of autoantibodies in melanoma patients treated with interferon- Study design Cox regression models, each treating the patient’s antibody status differently, were used to assess the association of seroconversion with recurrence-free survival. Contribution This study suggested that, contrary to previous reports, the appearance of autoantibodies is not strongly associated with improved outcome in melanoma patients treated with interferon. Implications Additional markers for selecting those melanoma patients who will benefit from interferon treatment will be needed. Limitations Only a subset of patients from the two clinical trials were included in this study, limiting the power to detect associations of a biomarker with outcome. From the Editors
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Manuscript received November 9, 2008; revised April 1, 2009; accepted April 20, 2009.
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