New applications of cancer immunotherapy.

THE INCIDENCE of malignant melanoma continues to rise throughout the world. In the United States, the incidence of melanoma has increased significantly, up from 5.7 per 100,000 in 1973 to 13.8 per 100,000 in 1996. This represents a 4% rise per year. In 2001, new cases of malignant melanoma are estimated at 51,400 and deaths are estimated at 7,800.1 Although the prognosis for patients with clinically localized disease is relatively good, the outlook is dismal for patients with American Joint Committee on Cancer (AJCC) stage IV disease, with a 5-year survival rate of 6% and a median duration of survival of 7.5 months.2,3 Within the AJCC stage IV category, patients with visceral disease have an even worse prognosis of 4 to 6 months, a fact reflected in the recent modification of the AJCC staging system.4 Involvement of the liver, in particular, has portended a poor prognosis in some studies, with a possible time of survival of 2 to 6 months.5-7 Malignant melanoma is resistant to many forms of therapy. Most single-agent chemotherapeutics provide only low tumor response rates. Dacarbazine, the most commonly used single agent, yields a response rate of 10% to 20%, but has not been shown to bestow survival benefit.8 Temozolomide, an analogue of dacarbazine with the potential advantages of central nervous system penetration and oral administration, has been essentially equivalent to the latter agent in randomized trials.9 Combination chemotherapy has not proved a successful strategy in metastatic melanoma. The Dartmouth regimen (cisplatin/dacarbazine/tamoxifen/carmustine) has produced response rates up to 55%; however, the duration of the response is short and survival is not impacted.10-12 A recent randomized trial of this combination versus dacarbazine alone did not show a significant improvement in response rates or survival.13 Several other trials of combination chemotherapy have had the same outcome.14-16 Interleukin-2 (IL-2) has been shown to have activity against melanoma,17,18 as detailed by Michael Atkins in this supplement. In clinical studies, high-dose, intravenous, bolus IL-2 was administered at 600,000 to 720,000 IU/kg every 8 hours on days 1 to 5 with up to 14 doses per cycle. Overall tumor responses were observed in 15% to 20% of patients who received IL-2.19-21 Long-term survival data for 270 assessable patients enrolled into eight clinical trials showed tumor responses in 16% of patients.22 However, dose-related toxicities have prevented this regimen from being extensively used and this treatment option is currently restricted to patients presenting to major melanoma treatment centers. Lower-dose, subcutaneous IL-2 has lower toxicity but has not been adequately studied as a single agent in this disease. IFNhas also shown activity against metastatic melanoma; overall response rates of 15% have been observed at nonvisceral sites.23,24 The report by John Kirkwood in this issue expands on the IFNexperience in cancer immunotherapy. IL-2 has been combined with IFNand other chemotherapeutic agents (biochemotherapy) for the treatment of metastatic melanoma. Three recent trials testing this strategy against chemotherapy alone have either not proven successful25-27 or have produced marginal benefits with extreme toxicity.28,29 This approach must therefore be considered to be investigational until the results of the ongoing intergroup trial, E3695, looking at cispla-