Present status and future prospects for adjuvant therapy of melanoma: time to build upon the foundation of high-dose interferon alfa-2b.

Melanoma is the fourth most frequent cancer among males and the second most frequent cancer in females age 25 to 34 years [1]. The distribution of disease at presentation has evolved during the last 50 years, with thin lesions ( 1.0-mm Breslow depth) increasing in both sexes, leading to resultant cure in more than 86% of patients. Despite the reduction in case fatality rate, more than 8,000 deaths per year are still attributable to melanoma in the United States, and the death rate and incidence continue to rise among subpopulations, such as older men with thick lesions ( 4.0-mm) [2], suggesting the need for better detection, secondary chemoprevention, and adjuvant treatment strategies. The beneficial effect of high-dose interferon alfa-2b (HDI) adjuvant therapy after resection of thick (American Joint Committee on Cancer [AJCC] stage IIB or IIC) or lymph-node-positive (stage III) melanoma was demonstrated a decade ago and has been widely evaluated in rigorous multicenter randomized controlled trials that have shown statistically significant benefits from HDI on relapsefree survival (RFS), an end point in relation to which the impact of HDI has been confirmed and unquestioned in any quarter [3-5]. The statistically significant impact of HDI on overall survival (OS), first observed in the Eastern Cooperative Oncology Group trial comparing HDI with observation (E1684), has been confirmed in the recent Intergroup American trial (E1694), comparing HDI to GM2 vaccine [5]. Although this benefit has been accepted by the United States Food and Drug Administration (FDA) and regulatory agencies worldwide, the impact of HDI on longterm survival has been questioned, partly because of the cost and toxicity of the regimen, and partly to the absence of a survival benefit in another Intergroup trial (E1690) [4]. In this trial, conducted after FDA approval of HDI as adjuvant therapy, crossover treatment with interferon alfa-2b (IFN-2b) at relapse among patients who had been assigned to observation has been put forth as a confounding variable in interpreting the overall survival data [4]. As a consequence of the cost and toxicity of this regimen, trials outside the US have only recently evaluated HDI, with studies performed by the Association of Dermatologic Oncologists in Germany, the Italian Melanoma Intergroup, and the Hellenic Oncology Group in Greece. A number of randomized controlled studies have evaluated lower doses of IFN-2b (LDI) for intermediateand highrisk resected melanoma (AJCC stages II and III) and have shown no effect in high-risk melanoma, a transient delay in relapse for intermediate-risk melanoma, and no survival benefit in intermediate and high-risk disease [4,6-10]. The results of these trials of LDI led to the AIM HIGH trial in the United Kingdom, reported in this issue of the Journal of Clinical Oncology. AIM HIGH is the seventh negative randomized controlled study of LDI and the largest single study of LDI published to date, with a median follow-up of 6.8 years. Accrual was terminated before reaching the targeted accrual goal because of the early lack of sufficient evidence of benefit in terms of either RFS or OS [11]. This trial might have been the end of LDI adjuvant therapy for melanoma, save for the European Organization for Research and Treatment of Cancer (EORTC) Trial 18952, testing “intermediate” doses of IFN-2b given for 1 or 2 years. At 3 years’ median follow-up, there was neither OS nor RFS benefit for the two “intermediate” dosages of 5 MU three times per week for 2 years (5 MU/m) and 10 MU three times per week administered subcutaneously (communication by A.M.M. Eggermont to the Milan ESO Melanoma Congress, May, 2003). JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 1 JANUARY 1 2004