Adjuvant Interferon in Melanoma: Is Duration of Therapy Important?
Authors: Grant A. McArthur
Journal: Journal of Clinical Oncology (2013)

Thirty-five years ago, cancer research was captivated by the complex biology of interferons, a family of cytokines with direct and indirect antitumor activity in a broad range of preclinical models. Subsequent clinical trials showed activity in a variety of malignancies, including melanoma. Activity in patients with advanced disease was modest. However, it was the eventual application of interferon alfa 2b (IFN-2b) to patients at high risk of developing distant metastases in the adjuvant setting that provided the first and, to date, the only worldwide approval of an adjuvant therapy for melanoma. Nonetheless, to this day, IFN-2b remains a controversial therapy. Toxicity is substantial with neuropsychiatric, constitutional, and hepatic toxicity being the major issues. Efficacy is seen by many as modest, particularly when balanced against the toxicity that has substantial impact on quality of life—some patients will either relapse from their disease despite the use of IFN-2b, and some patients will be cured regardless of the use of IFN-2b. Meta-analyses have shown highly significant effects of IFN-2b therapy on relapse-free survival (hazard ratios, 0.82-0.87) and small, but statistically significant, improvements in overall survival (hazard ratios, 0.89-0.93) in patients with predominantly regional nodal metastases. As such, ongoing efforts to maximize benefit and limit toxicity by examining dose and schedule remain relevant. Despite well more than four decades of research into IFN-2b biology, the mechanism of antitumor activity remains far from certain. IFN-2b is immunomodulatory and antiangiogenic and can directly promote apoptosis of melanoma cells. Understanding these mechanisms would be of benefit for optimizing the dose and schedule. Intermittent therapy maybe of use when immunomodulatory activities dominate, whereas longer durations of activity maybe required if antiangiogenic mechanisms are the major mechanism of delaying recurrence and improving survival. Moreover, a clear understanding of mechanism of action would allow examination of surrogate biomarkers to explore optimal dose. Indeed, both long and short duration of therapy and low and higher doses have been evaluated in different randomized trials. The study by Payne et al compared a short duration of highdose IFN-2b therapy delivered intravenously 5 days per week for 4 weeks to the conventional duration and schedule (initially developed by the Eastern Cooperative Oncology Group) of 4 weeks of intravenous therapy 5 days per week followed by 48 weeks of subcutaneous therapy three times per week. This pilot study was designed to examine the feasibility of a phase III trial and included patients with high-risk localized stage II disease (stage IIB and IIC) as well as patients with high-risk regional metastases (stage IIIB and IIIC). Although the study was not statistically powered to demonstrate superiority of the longer regimen, there was a strong trend favoring the longer regimen in overall survival. This result is consistent with the reported negative result of the Eastern Cooperative Oncology Group E1697 study that compared 4 weeks of IFN-2b with observation but clearly contrasts with the slightly larger study reported by Pectasides et al who used a lower dose of IFN-2b and found no difference in survival between intravenous therapy 5 days per week for 4 weeks when compared with the same induction treatment followed by 48 weeks of subcutaneous therapy three times per week. An explanation for the difference between the studies is not clear but may relate to IFN-2b dose and/or the dose delivered given that grade 3 toxicity was lower in the longerduration arm of the study by Pectasides et al when compared with the longer-duration arm of the study by Payne et al. The lack of clarity regarding dose and schedule is compounded by meta-analyses suggesting that dose may not play a significant role in the efficacy of IFN-2b in the adjuvant therapy of melanoma. However, the data from Payne et al clearly questions the use of IFN-2b for short durations. For those patients who choose treatment with adjuvant IFN-2b, I am personally reluctant to prospectively plan any shorter duration than 52 weeks of therapy. One additional difference between the studies by Payne et al and Pectasides et al is the inclusion of patients with stage IIIA disease in the study by Pectasides et al. Might IFN-2b be more active in a shorter duration for patients with stage IIIA disease? This seems unlikely given that only 11% of patients in the study by Pectasides et al had stage IIIA disease; furthermore in a large study, Eggermont et al showed substantial improvements in distant metastasis–free survival from a long duration of therapy with pegylated IFN-2b in patients with stage IIIA but not in those with stages IIIB and IIIC. Given the expanding role of sentinel lymph node biopsy to accurately stage patients’ disease, clear understanding of the efficacy of existing adjuvant therapies and the development of novel therapies for patients with stage IIIA disease remains a high priority. Sentinel lymph node biopsy provides an opportunity to treat micrometastatic disease in patients with intermediate-thickness primary melanomas at an earlier stage of disease with presumably lower micrometastatic tumor load and can potentially improve outcomes for a high proportion of patients at risk of distant metastases. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 3 JANUARY 2