Interferon-α and interleukin-2 in the treatment of metastatic melanoma. Comparison of two phase II trials

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Abstract
Background. Interferon‐α (IFNα) and interleukin‐2 (IL‐2) are active agents against malignant melanoma. There is, however, no consensus on the optimal dosing schedule of both drugs. This is a report of two sequential immunotherapy trials in patients with metastatic melanoma using two different IL‐2 dosing schedules. Methods. Schedule A consists of IFNα, 10 million U/m2/day subcutaneously for 5 days, followed by continuous intravenous infusion of IL‐2, 1 mg/m2/24 hours for 5 days. Schedule B consists of the same dose of IFNα, but a modified regimen of IL‐2. To improve the induction of high‐affinity IL‐2 receptors, the initial IL‐2 dose was increased (1 mg/m2/6 hours, followed by 1 mg/m2/12 hours, and 1 mg/m2/24 hours). To reduce toxicity, the dose was reduced thereafter to 0.25 mg/m2/24 hours for the following 3 days. Both regimens were repeated after 4 weeks. Results. 27 patients were treated with schedule A with a response rate of 18% (1 complete response [CR], 4 partial responses [PR]), 95% confidence interval, 6–36%. The response rate in 27 patients treated with schedule B was 41% (3 CR, 8 PR), 95% confidence interval 22–61%. Severe, often dose‐limiting toxicity was associated with IL‐2 in schedule A, particularly hypotension and fluid retention. Toxicity was reduced significantly in schedule B. Maximal serum levels of soluble CD25 were 17,022 ± 13,070 U/ml in schedule A, and 31,148 ± 4227 U/ml in schedule B (P ± 0.01). Serum levels of TNFα were significantly lower in schedule B than in schedule A, as were the side effects. Conclusions. Toxicity of IL‐2 is reduced by modifying the schedule of administration, which also enhances the immunologic response and appears to increase the response rate.

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