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Prospective Randomized Trial of Interferon Alfa-2b and Interleukin-2 as Adjuvant Treatment for Resected Intermediate- and High-Risk Primary Melanoma Without Clinically Detectable Node Metastasis

Axel Hauschild, Michael Weichenthal, Bernd-Rüdiger Balda, Jürgen C. Becker, Helmut H. Wolff, Wolfgang Tilgen, Klaus-Werner Schulte, Johannes Ring, Dirk Schadendorf, Stephan Lischner, Günter Burg, Reinhard Dummer

From the Department of Dermatology, University of Kiel, Kiel; St. Georg Hospital, Hamburg; Klinikum Augsburg, Augsburg; University of Würzburg, Würzburg; University of Lübeck, Lübeck; University of Heidelberg and University of Homburg/Saar, Heidelberg/Homburg; University of Düsseldorf, Düsseldorf; Technical University of München, München; Rudolf-Virchow Hospital, Berlin; Skin Cancer Unit, DKFZ Heidelberg; and University Hospital of Mannheim, Germany; and University of Zürich, Switzerland.

Address reprint requests to Axel Hauschild, MD, University of Kiel, Department of Dermatology, Schittenhelmstrasse 7, 24105 Kiel, Germany; email: ahauschild{at}dermatology.uni-kiel.de.

Purpose: Low-dose interferon alfa (IFN) has been shown to have limited effects in the adjuvant treatment of patients with intermediate- and high-risk primary melanoma. We hypothesized that a combination regimen with low-dose interleukin-2 (IL-2) may improve survival prospects in these patients.

Patients and Methods: After wide excision of primary melanoma without clinically detectable lymph node metastasis (pT3 to 4, cN0, M0), 225 patients from 10 participating centers were randomly assigned to receive either subcutaneous low-dose IFN2b (3 million international units [MU]/m²/d, days 1 to 7, week 1; three times weekly, weeks 3 to 6, repeated all 6 weeks) plus IL-2 (9 MU/m²/d, days 1 to 4, week 2 of each cycle) for 48 weeks, or observation alone. The primary end point was prolongation of a relapse-free interval.

Results: Of the 225 enrolled patients, 223 were found to be eligible. Median follow-up time was 79 months. All evaluated prognostic factors were well balanced between the two arms of the study. Relapses were noticed in 36 of 113 patients treated with IFN2b plus IL-2 and in 34 of 110 patients with observation alone. Five-year disease-free survival of those who had routine surgery supplemented by IFN2b and IL-2 treatment was 70.1% (95% confidence interval [CI], 61.3% to 78.9%), compared with 69.9% in those receiving surgery and observation alone (95% CI, 60.7% to 79.1%) in the intention-to-treat analysis. Evaluation of the overall survival did not show any difference between treated and untreated melanoma patients (P = .93).

Conclusion: Adjuvant treatment of intermediate- and high-risk melanoma patients with low-dose IFN2b and IL-2 is safe and well tolerated by most patients, but it does not improve disease-free or overall survival.

Supported by grants from Essex Pharma GmbH (Munich, Germany) and Chiron Therapeutics (Ratingen, Germany).

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