Despite more than 2 decades of active clinical study, the use of interferon as adjuvant therapy for high-risk melanoma remains controversial. The controversy has centered on dose, schedule, and toxicity of treatment. Agarwala and Kirkwood superbly summarize the clinical studies to date and highlight many of the salient issues relevant to clinicians.
As background, it is important to emphasize the issues that have affected melanoma adjuvant trials. First, melanoma trials are significantly smaller than breast and colon cancer adjuvant trials due to the lower incidence of the disease. This results in studies that are generally underpowered to detect small survival differences.
Second, sentinel lymph node mapping has revolutionized surgical staging of melanoma. Although this is a critical advancement in risk stratification of clinical trials, sentinel node mapping and improved radiographic staging of distant disease have resulted in a stage-migration effect in serial clinical trials. This is evident in the improvement in survival in the observation arms of more recent randomized trials.
Third, the lack of consensus for an optimal dose and schedule of interferon in metastatic disease has resulted in a range of adjuvant clinical trial designs. Finally, philosophical differences among clinicians assessing efficacy and toxicity tradeoffs of biological therapy have led to conflicting interpretations of randomized trial results.
The authors summarize the series of US melanoma trials conducted by the Eastern Cooperative Oncology Group (ECOG) over 2 decades—E1684, E1690, and E1697—concluding that high-dose interferon is the standard of care for the adjuvant treatment of high-risk stage IIb and III disease.
E1684 is a pivotal study demonstrating an improvement in disease-free and overall survival favoring high-dose interferon. Critics of this study focus on the small (10%), absolute 5-year survival benefit, and the toxicity, duration, and cost of treatment. However, the proportional survival benefit (25%) and treatment cost analyses are similar to those of other accepted adjuvant therapies. The crucial difference in this study was the prolonged duration of moderate-to-severe constitutional toxicities specific to biological therapy. Despite an emphasis on supportive care and dose modifications, many patients and physicians are reluctant to pursue high-dose interferon therapy.
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