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

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.