ISOLATED LIMB PERFUSION WITH HIGH-DOSE TUMOR-NECROSIS-FACTOR-ALPHA INCOMBINATION WITH INTERFERON-GAMMA AND MELPHALAN FOR NONRESECTABLE EXTREMITY SOFT-TISSUE SARCOMAS - A MULTICENTER TRIAL

Purpose: 16 determine the efficacy of isolated limb perfusion (ILP) wi th tumor necrosis factor-alpha (TNF) in combination with interferon-ga mma (IFN) and melphalan as induction therapy to render tumors resectab le and avoid amputation in patients with nonresectable extremity soft tissue sarcomas (STS). Patients and Methods: Among 55 patients with 30 sarcomas, primary and 25 recurrent sarcomas, there were 48 high-grade and seven grade I sarcomas (very large, recurrent, or multiple), The composition of this series of patients is unusual: 13 patients (24%) h ad multifocal primary sarcomas or multiple recurrent tumors; tumors we re very large (median, 18 cm); and nine patients (16%) had known syste mic metastases, IFN was administered subcutaneously on the 2 days befo re ILP with TNF, IFN, and melphalan. A delayed marginal resection of t he tumor remnant was usually performed 2 to 3 months after ILP. Result s: A major tumor response was seen in 87% of patients and rendered the sarcomas resectable in most cases, Clinical response rates were as fo llows: 10 (18%) completes responses (CRs), 35 (64%) partial responses (PRs), and 10 (18%) no change (NC), Final outcome was defined as follo ws by clinical and pathologic response: 20 (36%) CRs, 28 (51%) PRs, an d seven (13%) NC, Limb salvage was achieved in 84% (follow-up duration , 20+ to 50+ months). In 39 patients, resection of the tumor remnant ( n = 31) or of two to eight tumors (n = 8) after ILP was performed; loc al recurrence developed in five (13%), When no resection was performed (multiple tumors or systemic metastases), local recurrences were freq uent (five of 16), but limb salvage was often achieved as patients die d of systemic disease, Regional toxicity was limited and systemic toxi city minimal to moderate with no toxic deaths, Histology showed hemorr hagic necrosis; angiographies showed selective destruction of tumor-as sociated vessels. Conclusion: ILP with TNF, IFN, and melphalan is a sa fe and highly effective induction biochemotherapy procedure that can a chieve limb salvage in patients with nonresectable extremity STS, TNF is an active anticancer drug in humans in the setting of ILP.