Recombinant interleukin-2-based treatments for advanced melanoma: The experience of the European organization for research and treatment of Cancer Melanoma Cooperative Group

PURPOSE This article reviews the currently available data on phase II and III trials regarding the efficacy of recombinant interleukin-2 (rIL-2)-based regimens in the treatment of stage IV melanoma, and discusses the rationale and outcome of past and currently ongoing rIL-2-based chemoimmunotherapy phase III trials conducted by the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group. PATIENTS AND METHODS In the first EORTC-MCG phase III trial, stage IV melanoma patients were stratified on the basis of serum lactate dehydrogenase levels and tumor burden and randomized to receive rIL-2 (decrescendo regimen) plus interferon-alpha (IFN-alpha) plus or minus cisplatin. In the second trial, which is still ongoing, patients ate being randomized to receive dacarbazine plus cisplatin plus IFN-alpha plus or minus rIL-2. These studies are designed to address the relative impact of cisplatin and rIL-2, respectively, on response and survival. RESULTS The addition of cisplatin to immunotherapy (rIL-2 plus IFN-alpha) doubled the response rate from 18% to 35%, but had no impact on survival. The second trial is still ongoing, and no data is available yet on the contribution of rIL-2 to response and survival. CONCLUSIONS Review of the literature and the outcome of our first trial indicate that the addition of single-agent cisplatin or polychemotherapy regimens to immunotherapy with rIL-2 and/or IFN-alpha can dramatically improve response rates. However, what impact, if any, these regimens have on overall survival is not known at this time. We could not demonstrate a survival benefit in the cisplatin-containing arm in spite of the increased response rate. Chemotherapy may yield only short-term responses, whereas immunotherapy appears to yield durable complete responses in a subset of patients. Further randomized phase III studies are needed to identify the essential components in combination regimens and to determine whether the toxicity associated with these regimens is outweighed by potential cure or a significant survival benefit.