Adjuvant Interferon Therapy for Melanoma: High-Dose, Low-Dose, No Dose, Which Dose?

Melanoma presents formidable problems across the clinical spectrum—from prevention and early detection to treatment of high-risk and metastatic disease. In white populations, the worldwide incidence of invasive primary cutaneous melanoma has been rising for decades, making it a public health issue of growing importance. In the United States, almost 50,000 new cases are expected in 2003 [1]. Recently, clinical management of melanoma has advanced through more precise staging. The use of sentinel lymph node biopsy for accurate staging of regional lymph nodes and, more recently, the recognition of the prognostic significance of ulceration have greatly refined the precision with which clinicians can determine prognosis [2]. Two of the most important predictors of relapse (and, therefore, survival) are Breslow’s thickness of the primary melanoma, and regional lymph node status. Patients with melanomas larger than 4 mm thick have an approximately 50% risk of relapse, while those with lymph node involvement have a 50% to 85% risk of metastasis depending on the number of lymph nodes involved and other factors [3]. Thus, a group of patients can be defined who are appropriate candidates for postsurgical adjuvant therapy. During the past 20 years, numerous agents have been evaluated in a series of both nonrandomized and randomized adjuvant therapy trials in melanoma patients. Many of these clinical trials suffered from serious methodological problems such as inadequate statistical power, use of inappropriate controls, and lack of stratification for known prognostic factors. However, the major obstacle to the success of adjuvant therapy of melanoma has been the lack of active agents. Agents that have demonstrated little or no benefit include BCG, levamisole, interferon gamma, interleukin-2, retinoids, dacarbazine, and megestrol acetate [4]. While controversies are common in medicine, few aspects of the treatment of malignant melanoma have stimulated as much controversy as the interpretation of the adjuvant interferon alfa (IFN ) trials for patients with resected high-risk melanoma. This has resulted largely from conflicting results of successive randomized controlled trials, the first of which demonstrated a statistically significant overall survival benefit for high-dose IFN compared with surgery alone [5-7]. Interpretations of these data and the resultant treatment recommendations vary widely, with proponents proclaiming high-dose IFN as standard therapy, while opponents, analyzing the same data, believe that the routine use of IFN cannot be recommended outside of the context of a clinical trial. Interestingly, the interpretation of the same clinical trial data varies widely geographically. In the United States, a high-dose IFN regimen, with a 1-month induction course, is most commonly used. In Europe and the UK, a low-dose, prolonged duration schedule has been more widely used. However, even in the United States, there has not been widespread acceptance of highdose IFN, with clinicians and patients often believing that this treatment is either ineffective or too toxic. As with most controversies, the truth lies somewhere in between, and this story is no less complex than many other medical controversies. What is generally agreed on by both the skeptics and the true believers? First, the data from the completed randomized clinical trials consistently demonstrate that high-dose IFN is associated with an approximate 10% improvement in relapse-free survival (RFS). This favorable effect of high-dose IFN on RFS should no longer be debated. Multiple randomized trials have shown that HDI for one year improves RFS compared with surgery alone [5,6]. Second, given general agreement on the benefit of surviving without relapse, there would probably be little controversy about the use of high-dose IFN were it not for the high incidence of serious toxicity. The most common acute side effects are flu-like syndrome with constitutional symptoms of fever, chills, headache, and myalgias. More chronic toxicities include anorexia, malaise, depression, abJOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 1 JANUARY 1 2004