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Update on Adjuvant Interferon Therapy for High-Risk Melanoma

Update on Adjuvant Interferon Therapy for High-Risk Melanoma

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.

Key Issues

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.[1] 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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