In transit metastases of malignant melanoma treated by high dose rTNFα in combination with interferon‐γ and melphalan in isolation perfusion

Abstract To increase the therapeutic efficacy of recombinant tumor necrosis factor alpha (rTNFα) and reduce the systemic side effects, a protocol was designed using isolation perfusion of the limbs with hyperthermia for in transit metastases of melanoma. A triple combination of high dose rTNFα + recombinant interferon‐gamma (rIFN‐γ) + melphalan was chosen because of a synergistic anti‐tumor effect of rTNFα with rIFN‐γ and of rTNFα with alkylating agents reported in the literature. Twenty‐nine patients of mean age 60 years (range 22–82 years) entered the study after informed consent and received a total of 31 isolation perfusions with the triple combination. There were 24 women and 5 men with multiple progressive in transit melanoma metastases of the lower limb (stage IIIa or IIIab). rTNFα at the unique dose of 4 mg was injected as a bolus in the arterial line, under mild hyperthermic conditions (40 to 40.5°C) for 90 minutes. rIFN‐γ was given subcutaneously on days −2 and −1 and in the perfusate, with rTNFα, at the dose of 0.2 mg. Melphalan was administered in the perfusate at dose giving a concentration of 40 µg/ml. In all the 31 isolation perfusions performed in the triple combination protocol, in order to prevent a septic shock‐like syndrome which had been encountered in 2 patients treated outside this protocol for sarcoma and carcinoma, the patients received dopamine continuous infusion at 3 µg/kg/min from the start of isolation perfusion and for 48 hours, and only showed mild hyptension and very transient chills and temperature. Regional toxicity attributable to rTNFα was minimal. There have been 16 patients with hematologic toxicity consisting of neutropenia (11 cases, 1 case grade 4 and 1 case grade 3) and neutropenia with thrombocytopenia (12 cases, 1 case grade 4 and 4 cases grade 2). Eighteen of 29 patients had been previously treated with melphalan in isolation perfusion (n=13) or with cisplatinum (n=2), rTNFα‐Melphalan (n=1), or rTNFα alone (n=2). Median follow‐up has been 41 weeks. The 29 patients are evaluable: there have been 26 (90%) complete remissions (CR), 3 (10%) partial remissions (PR), and no failures. Actuarial disease‐free survival and total survival have been 63% and 73%, respectively, at 12 months. In all cases, softening of the nodules was obvious within 3 days after isolation perfusion and time to definite response ranged between day 6 and 22. This interim analysis of a phase II study suggests that high dose of rTNFα can be administered with acceptable toxicity by isolation perfusion with dopamine and hyperhydration. Tumor responses can be evidenced in all patients, with 90% CR. 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.