title: High dose tumor necrosis factor-alpha and melphalan administered via isolated limb perfusion for advanced limb soft tissue sarcoma results in a >90% response rate and limb preservation.
abstract: BACKGROUND
  Recombinant tumor necrosis factor-alpha (rTNF-alpha) is a highly potential antineoplastic agent. However, its systemic administration in humans has resulted in a life-threatening septic shock-like syndrome, and its use has been abandoned. The administration of high dose rTNF-alpha and melphalan via isolated limb perfusion (ILP) eliminated the systemic side effects and was shown to be very effective for metastatic melanoma confined to the limb. The purpose of the current study was to assess the role of rTNF-alpha and melphalan administered via ILP in patients with soft tissue sarcoma. Amputation is unavoidable in 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, 35 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, synovial, liposarcoma, malignant schwannoma, desmoid, clear cell, epithelioid, rhabdomyosarcoma, leiomyosarcoma, and unclassifiable. Twenty-one patients presented with recurrent and 14 with very extensive primary tumors. The tumors were located in the upper extremity in 8 patients and in the lower extremity in 27 patients. Twenty-five patients were candidates for amputation and 10 for extensive mutilating surgery. ILP was performed via the corresponding vessels proximal to the tumor. Six patients with partial response (PR) insufficient to render them resectable underwent a second ILP. With the exception of 4 of 9 patients with multifocal 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 protruding through the skin hemorrhagic necrosis was evident within 24 hours. The overall response rate was 91%. Thirteen patients (37%) had a complete response and 19 (54%) had a PR; in 5 of these patients > 90% necrosis of the tumor occurred. In 3 patients (8.5%), only minimal regression was observed (stabilization of disease). The rate of limb sparing was 85% (29 of 34 patients).
  
  
  CONCLUSIONS
  The combination of high dose rTNF-alpha and melphalan given via ILP appears to be effective in patients with advanced soft tissue sarcoma confined to the limb, achieving a high response rate and limb preservation.
authors.affiliation: Department of Surgery, Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Gutman
authors.forename: M
authors.initials: M
authors.lastname: Inbar
authors.forename: D
authors.initials: D
authors.lastname: Lev-Shlush
authors.forename: S
authors.initials: S
authors.lastname: Abu-Abid
authors.forename: M
authors.initials: M
authors.lastname: Mozes
authors.forename: S
authors.initials: S
authors.lastname: Chaitchik
authors.forename: I
authors.initials: I
authors.lastname: Meller
authors.forename: J M
authors.initials: JM
authors.lastname: Klausner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D010478:Chemotherapy, Cancer, Regional Perfusion; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007866:Leg; D008297:Male; D008558:Melphalan / Q000008:administration & dosage*; D008875:Middle Aged; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014409:Tumor Necrosis Factor-alpha; D008558:Melphalan