HIGH-DOSE TUMOR-NECROSIS-FACTOR-ALPHA AND MELPHALAN ADMINISTERED VIA ISOLATED LIMB PERFUSION FOR ADVANCED LIMB SOFT-TISSUE SARCOMA RESULTS IN A GREATER-THAN-90-PERCENT RESPONSE RATE AND LIMB PRESERVATION

BACKGROUND, Recombinant tumor necrosis factor-alpha (rTNF-alpha) is a highly potential antineoplastic agent. However, its systemic administr ation in humans has resulted in a life-threatening septic shock-like s yndrome, and its use has been abandoned. The administration of high do se rTNF-alpha and melphalan via isolated limb perfusion (ILP) eliminat ed the systemic side effects and was shown to be very effective for me tastatic melanoma confined to the limb. The purpose of the current stu dy was to assess the role of rTNF-alpha and melphalan administered via ILP in patients with soft tissue sarcoma. Amputation is unavoidable i n 10% of these patients despite aggressive conventional therapy. Limb preservation was the objective in this select group of candidates for amputation or mutilating surgery. METHODS, During a 36-month period, 3 5 patients with high grade soft tissue sarcoma underwent 41 ILPs with high dose rTNF-alpha (3-4 mg) and melphalan (1-1.5 mg/kg). There were 21 males and 14 females. The mean age was 48 years (range, 14-80 years ). Histologic subtypes included malignant fibrous histiocytoma, synovi al, liposarcoma, malignant schwannoma, desmoid, clear cell, epithelioi d, rhabdomyosarcoma, leiomyosarcoma, and unclassifiable. Twenty-one pa tients presented with recurrent and 14 with very extensive primary tum ors. The tumors were located in the upper extremity in 8 patients and in the lower extremity in 27 patients. Twenty-five patients were candi dates for amputation and 10 for extensive mutilating surgery. ILP was performed via the corresponding vessels proximal to the tumor. Six pat ients with partial response (PR) insufficient to render them resectabl e underwent a second ILP. With the exception of 4 of 9 patients with m ultifocal lesions and 1 who refused surgery, resection of the residual tumor or tumor bed or limb was performed 6-8 weeks after ILP. RESULTS , Marked tumor softening occurred within 48 hours, and in tumors protr uding through the skin hemorrhagic necrosis was evident within 24 hour s. The overall response rate was 91%. Thirteen patients (37%) had a co mplete response and 19 (54%) had a PR; in 5 of these patients > 90% ne crosis of the tumor occurred. In 3 patients (8.5%), only minimal regre ssion was observed (stabilization of disease). The rate of limb sparin g was 85% (29 of 34 patients). CONCLUSIONS, The combination of high do se rTNF-alpha and melphalan given via ILP appears to be effective in p atients with advanced soft tissue sarcoma confined to the limb, achiev ing a high response rate and limb preservation. (C) 1997 American Canc er Society.