Does adjuvant systemic therapy with interferon-alpha for stage II-III melanoma prolong survival?

Abstract

The experience with interferon-alpha in malignant melanoma resembles, to some degree, the experience with various kinds of adjuvant immunotherapeutic agents where 25 years of phase III trials of adjuvant therapy in stage II-IIII melanoma have not defined a standard therapy. Most trials failed to demonstrate an impact on disease-free survival and overall survival. Currently, data from 12 randomized interferon-alpha trials are available. The data in almost 3000 patients, approximately 50% of the total patient population, is immature and thus, inconclusive. Mature trials show that interferon-alpha significantly prolongs disease-free survival, but does not prolong overall survival, across different dose levels. Ultra-low-dose (1 MIU flat dose), interferon-alpha failed to even have an effect on disease-free survival. Although two trials with high-dose (10-20 MIU/m(2)) interferon-alpha have shown an impact on overall survival, these data are inconclusive since this impact was transient, inconsistent in subsequent trials, and the data was somewhat immature. Inconsistent results have also been observed for intermediate- (5-10 MIU flat dose) and low-dose (3 MIU flat dose) interferon-alpha regimens. The results, overall, suggest that these doses do have an impact on disease-free survival, but not on overall survival. Preliminary results regarding distant metastasis-free survival (the closest surrogate for overall survival available) of the very large European Organisation for Research and Treatment of Cancer (EORTC) 18952 trial suggests that there is a benefit with long-term low intermediate doses and support the anti-angiogenic concept of long-term maintenance treatment with interferon-alpha. The efficacy of short-term high-dose and long-term intermediate-dose treatment is being investigated in new trials. For now the role of interferon-alpha still remains to be determined and its use should be restricted to the setting of clinical trials.