A SEQUENTIAL 4-DRUG CHEMOTHERAPY AND BIOTHERAPY WITH INTERFERON-ALPHAAND GM-CSF - AN INNOVATIVE PROTOCOL FOR THE TREATMENT OF METASTATIC MELANOMA

We present the results of our chemo-biotherapy protocol for patients w ith metastatic melanoma. The rationale for the design of the combined therapy was induction of systemic anti-tumor immunity by: (a) priming with IFN-alpha for enhancement of tumor and histocompatibility antigen expression, (b) therapy by the 4-drug regimen (BCNU, DTIC, cisplatin and tamoxifen)for maximal tumor destruction, followed by (c) an immuno modulatory, low dose of GM-CSF. Treatment was given in cycles of three weeks: first IFN-alpha (3 x 10(6)U/day on days I, 3, and 5); then the 4-drug regimen given according to Del Prete et al., (4); followed by GM-CSF (20 mu g/m(2)/day on days 15 to 21). All patients were previous ly untreated by chemotherapy, and had a performance status of ECOG 0-2 Treatment was discontinued upon severe toxicity or disease progressio n. In responding patients - once maximal response was achieved - IFN a lpha treatment (3 x 10(6)U/day, three times weekly) was continued for a period of two years or until disease progression. All 40 patients (2 8 males and 12 females) who received the above program were evaluable for response and toxicity and received at feast two cycles of therapy. At a median follow-up of one year, 50% had achieved an objective resp onse, with 22.5% complete responses (CR), and 27.5% partial remissions (PR). Median duration of response is I I months (12 for CR and 9 for PR patients). Median survival for all patients is 14 months (range, 7 - 21), increasing to 22 months (range, 15 - 29) in responding patients . Activation of patients' peripheral blood Macrophages and Dendritic C ells was observed following GM-CSF treatment. I;the chemo-biotherapy p rotocol presented above - while associated with acceptable toxicity - resulted in a relatively high response rate with an increase in the nu mber of durable responses in patients with metastatic melanoma.