HIGH-DOSE RECOMBINANT TUMOR-NECROSIS-FACTOR-ALPHA IN COMBINATION WITH INTERFERON-GAMMA AND MELPHALAN IN ISOLATION PERFUSION OF THE LIMBS FOR MELANOMA AND SARCOMA

Purpose: To determine the toxicity and the therapeutic efficacy of the combination of the recombinant tumor necrosis factor alpha (rTNFα), recombinant interferon gamma (rIFN-γ), and melphalan, we designed a protocol using isolation limb perfusion (ILP) with hyperthermia for in-transit metastases of melanoma and recurrent sarcoma. The triple combination was chosen because of the reported synergistic antitumor effect of rTNFα with IFN-γ and of rTNFα with alkylating agents. Patients and Methods: Twenty-three patients received a total of 25 ILPs with the triple combination. There were 19 females and four males with either multiple progressive in-transit melanoma metastases of the extremities (stage IIIa or IIIab; 19 patients) or recurrent soft tissue sarcoma (five). The rTNFα was injected as a bolus in the arterial line, and total dose ranged between 2 and 4 mg, under hyperthermic conditions (40°C to 40.5°C) for 90 minutes. The rIFN-γ was given subcutaneously (SC) on days -2 and -1 and in the perfusate, with rTNFα at the dose of 0.2 mg. Melphalan (Alkeran; Burroughs Wellcome Co, London, England) was administered in the perfusate at 40 μg/mL. Results: Toxicity observed during three ILPs in a pilot study with rTNFα included only two severe toxicities: one severe hypotension with tachycardia and transient oliguria and one moderate hypotension for 4 hours followed by severe kidney failure with complete recovery on day 29. In all 18 ILPs performed in the triple combination protocol, the patients received continuous infusion dopamine at 3 μg/kg/min from the start of ILP and for 72 hours and showed only mild hypotension and transient chills and temperature. Regional toxicity attributable to rTNFα was minimal. There have been 11 cases with hematologic toxicity consisting of neutropenia (one grade 4 and one grade 3) and neutropenia with thrombocytopenia (one grade 4 and three grade 2). Twelve patients had been previously treated with melphalan in ILP (11) or with cisplatin (one). The 23 patients are assessable: there have been 21 complete responses (CRs; range, 4 to 29 months; 89%), two partial responses (PRs; range, 2 to 3 months), and no failures. Overall disease-free survival and survival have been 70% and 76%, respectively, at 12 months. In all cases, softening of the nodules was obvious within 3 days after ILP and time to definite response ranged between day 5 and 30. Conclusion: This preliminary analysis of a phase II study suggests that high-dose rTNFα can be administered with acceptable toxicity by ILP with dopamine and hyperhydration. Tumor responses can be evidenced in melanoma and sarcoma. Furthermore, combination of rTNFα, rIFN-γ, and melphalan seems to achieve high efficacy with minimal toxicity, even after failure of prior therapy with melphalan alone. © 1992 by American Society of Clinical Oncology.