BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)

Type I IFNs, including IFNα, are natural proteins produced by immune cells in response to infectious agents. Durable responses seen in patients treated with IFNα for metastatic melanoma, particularly in those patients with small volume and soft tissue only disease, led to investigations in the adjuvant setting for patients with high-risk resected melanoma [77]. The majority of studies with high-dose IFNα have been conducted by the Eastern Cooperative Oncology Group (ECOG). The first trial (E1684) randomized 287 patients with resected Stage IIB or III melanoma to either observation or high-dose IFNα with an induction phase of daily intravenous IFN-a at 20 million international units (MU)/m2 for 4 weeks followed by 48 weeks of maintenance therapy at 10 MU/m2 subcutaneously 3 days a week [78].This study demonstrated statistically significant improvement in both relapsed free and overall survival (one-sided p = 0.0237) for the IFNα treated patients relative to those on observation at a median follow-up time of 6.9 years. On the basis of these results, the US FDA approved this high-dose IFNα regimen as the first postsurgical adjuvant therapy for stage IIB (T4) and III melanoma in 1996. However, the benefits of IFNα therapy on overall survival decreased, and eventually disappeared, in patients who were followed for a median of 12.6 years based on a pooled analysis [79]. This called into question the impact of high-dose IFNα on overall survival. The controversy regarding the survival benefits of adjuvant IFNα was further heightened by subsequent ECOG led studies showing conflicting results. For example, E1690 randomized patients with Stage II and III melanoma to high-dose IFNα, lower dose IFNα or observation and showed an improvement in relapse free survival for the high-dose IFNα arm, but no difference in overall survival [80], while E1694 (as noted above) showed significant improvement in both relapse free and overall survival for high-dose IFNα compared to a ganglioside vaccine [72]. Large meta-analyses have tried to address this controversy. Mocellin et al confirmed that IFNα has a substantial, if limited, benefit [81]. This analysis, which included trials with high, intermediate, and low-dose interferon, showed an overall hazard ratio of 0.82 for relapse-free survival (?P < 0.001), with a smaller, but still significant risk reduction of 0.89 for overall survival (?P = 0.002). In the review, no optimal dose, treatment duration, or subset of patients was identified as being more responsive to adjuvant interferon therapy. More recently, the Melanoma Disease Site Group in Canada published an analysis of high-dose IFNα regimens and found a mean relapse free survival hazard ratio of 0.76 (95% confidence interval 0.67, 0.87) and mean overall survival hazard ratio of 0.87 (95% confidence interval 0.75, 1.01) which just failed to reach statistical significance [82]. Taken together these data suggest a risk reduction for relapse of around 25% and for death of about 10% associated with high-dose IFNα. However, the usefulness of this data is further compromised by the fact that these studies took place in the era before routine sentinel lymph node staging and therefore do not provide any information on patients with currently defined N1 (Stage IIIA) melanoma, the most commonly identified high risk population in the current era.

Efforts to improve upon the therapeutic index for high-dose IFNα have focused on the use of longer acting IFN compounds, such as Pegylated IFNα, and shorter duration treatment regimens. Pegylated IFNα has been used to treat hepatitis B or C, and EORTC 18991 investigated its use in patients with resected stage III melanoma in a randomized phase III trial compared to observation [83]. Pegylated IFNα was administered subcutaneously at a dose 6 µg/kg once a week for 8 weeks followed by 3 µg/kg for 5 years. Although there was no difference in overall survival or distant metastases-free survival (DMFS), pegylated IFNα improved recurrence free survival, which led to the approval of this agent for adjuvant treatment of stage III melanoma in the US in 2011. This benefit was particularly apparent in the subset of patients with microscopic involvement of 1 lymph node and ulcerated primaries. These retrospective subset analyses, however, have yet to have independent or prospective validation.

Two studies have looked at shorter duration regimens. A study conducted in Greece examined the use of a regimen in which patients with resected high-risk melanoma were randomized to receive either a year of high-dose IFNα or a truncated regimen in which IFNα was given for only the 4-week induction period [84]. At a median follow-up of 63 months (95% CI 58.1—67.7), the median relapse free and overall survival were essentially equivalent between the two arms while patients in the 12-month treatment arm had more grade 1 to 2 hepatotoxicity, nausea/vomiting, alopecia, and neurologic toxicity. This study, while provocative, was felt to be too small to confirm equivalence. To further investigate the utility of this shortened regimen, E1697 compared 4-week high-dose IFNα induction only with observation in 1150 patients with resected intermediateand high-risk melanoma [85]. The median relapse-free survival was 7.3 years (95% CI 5.3, 9.8) in the observation arm and 6.8 years (95% CI 5.1, 9.0) for IFNα, while the 5-year overall survival rate was 85% (95% CI 81, 89) for observation and 82% (95% CI 78, 86) for IFNα. Because of the lack of any apparent treatment benefit, this trial was terminated early. These data call into question the value of abbreviated and modified IFN regimens and leave the original HD IFNα regimen as the, albeit controversial, standard of care for adjuvant treatment of patients with intermediate or high risk melanoma.

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