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Neoadjuvant Treatment of Regional Stage IIIB Melanoma With High-Dose Interferon Alfa-2b Induces Objective Tumor Regression in Association With Modulation of Tumor Infiltrating Host Cellular Immune Responses

Stergios J. Moschos, Howard D. Edington, Stephanie R. Land, Uma N. Rao, Drazen Jukic, Janice Shipe-Spotloe, John M. Kirkwood

From the Melanoma and Skin Cancer Program; Division of Medical Oncology, Department of Medicine; Department of Surgery, Division of Surgical Oncology; Department of Biostatistics, Graduate School of Public Health; Department of Pathology; and the Department of Dermatology, Division of Dermatopathology, University of Pittsburgh School of Medicine, Pittsburgh, PA

Address reprint requests to John M. Kirkwood, MD, Department of Medicine, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Research Pavilion, Suite 1.32, 5117 Centre Avenue, Pittsburgh, PA 15213-2584; e-mail: kirkwoodjm{at}upmc.edu

PURPOSE: Adjuvant high-dose interferon-alfa-2b (HDI) improves disease-free and overall survival in patients with high-risk melanoma. However, its mechanism of action is largely unknown. Therefore, HDI was investigated in the neoadjuvant setting to assess clinical and pathologic responses after 4 weeks of HDI and to perform immunohistochemical evaluation of immune cell subsets and melanoma-associated antigens.

PATIENTS AND METHODS: Patients with palpable regional lymph node metastases from melanoma (American Joint Committee on Cancer stage IIIB-C) underwent surgical biopsy at study entry and then received standard intravenous HDI (20 million units/m², 5 days per week) for 4 weeks followed by complete lymphadenectomy and standard maintenance subcutaneous HDI (10 million units/m² 3 times per week) for 48 weeks. Biopsy samples were obtained before and after intravenous HDI and subjected to immunohistochemical analysis as well as routine pathologic study.

RESULTS: Twenty patients were enrolled, and biopsy samples were informative for 17. Eleven patients (55%) demonstrated objective clinical response, and 3 patients (15%) had complete pathologic response. At a median follow-up of 18.5 months (range, 7 months to 50 months) 10 patients had no evidence of recurrent disease. Clinical responders had significantly greater increases in endotumoral CD11c⁺ and CD3⁺ cells and significantly greater decreases in endotumoral CD83⁺ cells compared with nonresponders. No changes in the expression of melanoma-associated lineage antigens, tumor cell proliferation, angiogenesis, or apoptosis were evident.

CONCLUSION: Neoadjuvant HDI is highly effective for the treatment of palpable stage IIIB-C melanoma, and the findings of this study implicate an indirect immunomodulatory mechanism rather than a direct antitumor mechanism.

Supported by a research scholarship from the Robert Johnson Foundation for Melanoma Research and the Grant Channel Memorial Melanoma Research Fund (S.J.M.), and by National Institutes of Health National Cancer Institute Grant No. P30 CA4790413 (J.M.K. and S.R.L.). Costs for radiographic and laboratory analyses were funded in part by a research grant from Schering-Plough Research Institute to the University of Pittsburgh.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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