How does interferon work? Does it even matter?

Adjuvant therapy for patients with melanoma using interferon remains controversial despite numerous randomized clinical trials. There can be no doubt that interferon works—that is, it has biologic activity sufficient to alter the natural history of resected melanoma. Multiple randomized trials have demonstrated that adjuvant interferon prolongs recurrence free survival compared with observation or compared with a defined antigen vaccine. The effect on overall survival is more contentious— only two studies have demonstrated a significant effect on overall survival, and only one of those studies included an untreated control group. Nonetheless, prolonged recurrence free survival is clear-cut evidence of a biologic effect of the therapy. From a clinical standpoint, however, this demonstrated recurrence free survival and presumptive overall survival benefit must be weighed against the substantial toxicity of therapy. It is interesting to note that, in the ongoing debate over the clinical role of adjuvant interferon , little attention has been paid to the question of how interferon works. Most clinicians seemingly accept at face value the notion that interferon acts as an immunomodulator, augmenting the host immune response to melanoma-associated antigens on residual tumor cells. However, because interferon has multiple known activities, this simple notion may not be as straightforward as it first appears. Perhaps the most salient reason to question a purely immunomodulatory role for interferon is the failure of interferon to prolong recurrence free survival in two randomized trials. Interferon at the doses administered in those two trials is a documented immunomodulator, one that many tumor immunologists would say is superior to interferon . Thus, if the mechanism of action were purely immunostimulatory, then we would anticipate an equal or greater effect for interferon . However, even if we accept the fact that the mechanism of action of interferon is uncertain, why should we care? A better understanding of the mechanism of action of adjuvant interferon may help with three unresolved but closely interrelated clinical questions: 1) What is the optimum dose of interferon ? 2) What is the optimum duration of therapy, and should therapy be stopped or continued in the event of a resectable recurrence? 3) How can we minimize the toxicity of interferon without losing efficacy? In this issue of Cancer, Kirkwood et al. present the results of a biologic companion trial to Intergroup Trial E1690, which compared high-dose and low-dose interferon 2b with observation after sur947