Interferon alfa in the postsurgical management of high-risk melanoma: is it worth it?

The incidence of cutaneous malignant melanoma is increasing in the United States. After resection, some patients, primarily those with relatively deep invasion by the primary tumor or regional lymph node involvement, have a substantial risk of future relapse and death from systemic disease. Accordingly, there has been a longstanding and growing need for an effective and feasible adjuvant systemic treatment to address micro-metastatic disease to reduce this risk. Despite decades of research resulting in the development of several therapies that initially seemed promising in uncontrolled or historically controlled clinical studies, the only approach that has consistently been shown in randomized controlled trials to have an impact on relapse risk compared with either no treatment or a control treatment believed to be ineffective has been interferon alfa. Unfortunately, interferon alfa administered at doses and durations shown to have efficacy as an adjuvant therapy for melanoma has significant toxicity. Moreover, although the improvement in relapse-free survival (RFS) associated with interferon alfa is now clearly established, this benefit is modest and has not been consistently coupled with a significant increase in observed overall survival (OS), even with relatively long follow-up. This has resulted in an unresolved controversy regarding the utility of adjuvant interferon in this setting and has left the clinician with a difficult dilemma when advising a patient with high-risk melanoma on postsurgical treatment options. The most frequently used interferon regimen in early-stage melanoma in the United States has been interferon alfa-2b, administered at a dose of 20 10 U/m 5 days a week for 4 weeks, followed by 10 10 U/m 3 days each week for 48 weeks. Because both interferon therapy and melanoma relapse can compromise quality of life, formal utility analyses have attempted to address the question of whether the observed benefit in terms of RFS justifies the toxicity of this schedule. Early on, it was shown that the net impact of high-dose interferon on quality-of-life-adjusted survival (QAS) varied from patient to patient and depended on the relative value placed by individual patients on time without relapse and time with toxicity. A subsequent study performed in patients with melanoma who were candidates for interferon therapy concluded that the median patient valued a 4% to 10% improvement in 5-year RFS highly enough to offset moderate to severe interferon toxicity. An analysis of data from the first two randomized trials of this interferon regimen concluded that most high-risk melanoma patients will experience an increase in QAS associated with high-dose interferon therapy, a finding consistent with the two previous reports. This study identified specific questions for the clinician to ask patients to identify a subset who would be likely to benefit in terms of QAS from high-dose interferon that remain potentially useful in practice but fall short of providing the validated tool for reliably predicting utility in each individual patient that clinicians really need. Throughout, for the high-dose interferon regimen currently in use in the United States for high-risk melanoma, both the clinical outcomes data (improved RFS without a consistent, statistically significant effect on observed OS) and the quality of life/utility data (effects on QAS that vary depending on an individual patient’s values, with many patients having improvements in QAS) have been remarkably consistent. What remains remarkably inconsistent is the conclusion drawn and communicated to patients by individual physicians involved in treating melanoma, caused in part by our desire to practice evidence-based medicine which we believe should result in our determining from the data what the correct treatment should be for all patients with a given specific clinical presentation and then recommending that approach to all patients with that condition. Paradoxically, with high-dose interferon therapy for high-risk melanoma, the evidence has consistently indicated that the correct treatment is not necessarily the same for two patients with identical clinical parameters but different individual values. All agree that we need a better adjuvant treatment for postsurgical management of high-risk melanoma. Optimally, this therapy would be more efficacious, with profound improvements in RFS and demonstrable increases in OS that stand the test of randomized, controlled trials. The attainment of this grail probably will have to await translation of the recent substantial advances in the molecular biology of melanoma and in basic immunology. In the meantime, some progress can be made by decreasing the toxicities associated with interferon alfa. Meticulous attention to supportive care during highdose interferon therapy is important. It may also be possible to truncate the schedule to 1 month of intravenous therapy, an approach under study for deep, but node-negative, melanomas in ECOG (Eastern Cooperative Oncology Group) E1697. There has been some evidence that therapy with pegylated interferon alfa, because of its pharmacokinetic profile, might achieve equal efficacy with less toxicity compared with treatment with the unmodified protein. In a recently published randomized trial (European Organisation for Research and Treatment of Cancer [EORTC] 18991) with a median follow-up of 3.8 years, pegylated interferon alfa-2b (peg-IFN-2b) administered weekly with a 2-month induction phase (6 mcg/kg/wk) followed by maintenance (3 mcg/kg/wk) for an JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 18 JUNE 2