The incidence of cutaneous melanoma has risen rapidly over the last 30 years, with an annual rate increase among the Caucasian population of approximately 3%. Melanoma is now the third most prevalent cancer, representing about 7% of tumors in both men and women. The median age at diagnosis for melanoma is 63 years in men and 56 years for women. Although melanoma is rare before the age of 30 years, it is the second and third most commonly diagnosed cancer in women and men, respectively, in the 20 to 29 years age group. The 5-year and 10-year relative survival rates for patients with melanoma are 91.2% and 89.1%, respectively. For those with localized melanoma, the 5-year survival rate is 98.2%; 5-year survival rates for individuals with regional and distant stage disease decline to 61.7% and 15.2%, respectively .
Treatment options for patients with advanced melanoma are limited and non-curative in the majority of cases. In a meta-analysis of 42 phase II trials including more than 2100 patients, the median survival time was 6.2 months [95% confidence interval (CI), 5.9−6.5 months), with 25.5% of the patients (95% CI, 23.6−27.4%) alive at 1 year . Median progression-free survival (PFS) was 1.7 months (95%CI, 1.6−1.8 months), with 14.5% of the patients (95% CI, 12.9−16.1%) progression-free at 6 months.
Dacarbazine (DTIC) was the first approved chemotherapeutic agent for the treatment of metastatic melanoma and, for more than 30 years, was the standard treatment for such disease. Fotemustine is the most active nitrosourea in metastatic melanoma, with an objective response rate of 20–25%, with 5–8% of complete responses, and was the first drug to show significant efficacy in brain metastases [3, 4]. One hypothesis to explain this is that fotemustine, thanks to the phosphoalanine group, is highly lipophilic and so able to diffuse across the blood–brain barrier. Another explanation could be the potential effect of fotemustine in inhibiting vascular endothelial growth factor (VEGF)-C release and thereby reducing tumor diffusion . In a phase III study, fotemustine was associated with a higher overall response rate (ORR) than dacarbazine in the intention-to-treat (ITT) population (15.2% vs 6.8%, p=0.043). However, the response duration (time to disease progression and overall survival [OS]) was not statistically significantly different between groups .
Interferon-α (IFN) has been suggested to exert activity against melanoma through immunomodulatory mechanisms , although it also has an anti-proliferative effect. Evidence for the involvement of different immunomodulatory mechanisms has been derived from several studies which have shown an increase in tumor infiltrating cells , the development of autoantibodies and clinical manifestations of autoimmunity (~30%) [9, 10], a decrease in circulating Treg cells , modulation of the STAT1/STAT3 balance in tumor cells and host lymphocytes , changes in serum cytokine concentrations , and normalization of T-cell signaling defects in peripheral blood lymphocytes [14, 15]. In the adjuvant setting, a meta-analysis of randomized melanoma trials using a wide range of IFN dose regimens revealed that the benefits of IFN are independent of dose or therapy duration, and translate into an absolute OS benefit of approximately 3% (95% CI: 1–5%) at 5 years [16, 17].
In our previous experience , 43 patients with advanced melanoma received first-line therapy with a combination of fotemustine 100 mg/m2 on day 1, intravenous (IV) dacarbazine 250 mg/m2 on days 2–5 every three weeks, and subcutaneous (SC) α2a 3 MIU three times a week until progression. The ORR was 40% (95% CI, 25-56%), and the median duration of response was 24 weeks. Median survival time was 40 weeks, with a 13% 2-year survival rate. Similar results (ORR, 38.3% [95% CI, 26.1–51.8%], median duration of response, 28 weeks; median survival, 36 weeks) were observed in a subsequent study in which cisplatin was added to fotemustine, dacarbazine and IFN , suggesting the addition of cisplatin was not clinically beneficial. In both these studies, some patients achieved a durable complete response (CR). On this basis, and supported by findings from other studies , we considered that IFN may have contributed to prolonging the median duration of response (by about 6 months in both studies).
In this prospective, randomized, controlled study, we assessed the effect of adding fotemustine and/or IFN to standard therapy with dacarbazine alone in patients with advanced malignant melanoma.