Randomized Multicenter Trial of Hyperthermic Isolated Limb Perfusion With Melphalan Alone Compared With Melphalan Plus Tumor Necrosis Factor: American College of Surgeons Oncology Group Trial Z0020

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Abstract
Purpose To determine in a randomized prospective multi-institutional trial whether the addition of tumor necrosis factor alpha (TNF-α) to a melphalan-based hyperthermic isolated limb perfusion (HILP) treatment would improve the complete response rate for locally advanced extremity melanoma. Patients and Methods Patients with locally advanced extremity melanoma were randomly assigned to receive melphalan or melphalan plus TNF-α during standard HILP. Patient randomization was stratified according to disease/treatment status and regional nodal disease status. Results The intervention was completed in 124 patients of the 133 enrolled. Grade 4 adverse events were observed in 14 (12%) of 129 patients, with three (4%) of 64 in the melphalan-alone arm and 11 (16%) of 65 in the melphalan-plus-TNF-α arm (P = .0436). There were two toxicity-related lower extremity amputations in the melphalan-plus-TNF-α arm, and one disease progression–related upper extremity amputation in the melphalan-alone arm. There was no treatment-related mortality in either arm of the study. One hundred sixteen patients were assessable at 3 months postoperatively. Sixty-four percent of patients (36 of 58) in the melphalan-alone arm and 69% of patients (40 of 58) in the melphalan-plus-TNF-α arm showed a response to treatment at 3 months, with a complete response rate of 25% (14 of 58 patients) in the melphalan-alone arm and 26% (15 of 58 patients) in the melphalan-plus-TNF-α arm (P = .435 and P = .890, respectively). Conclusion In locally advanced extremity melanoma treated with HILP, the addition of TNF-α to melphalan did not demonstrate a significant enhancement of short-term response rates over melphalan alone by the 3-month follow-up, and TNF-α plus melphalan was associated with a higher complication rate.