title: Isolated limb perfusion with high-dose tumor necrosis factor-alpha in combination with interferon-gamma and melphalan for nonresectable extremity soft tissue sarcomas: a multicenter trial.
abstract: OBJECTIVE
  To determine the efficacy of isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF) in combination with interferon-gamma (IFN) and melphalan as induction therapy to render tumors resectable and avoid amputation in patients with nonresectable extremity soft tissue sarcomas (STS).
  
  
  METHODS
  Among 55 patients with 30 primary and 25 recurrent sarcomas, there were 48 high-grade and seven grade 1 sarcomas (very large, recurrent, or multiple). The composition of this series of patients is unusual: 13 patients (24%) had multifocal primary sarcomas or multiple recurrent tumors; tumors were very large (median, 18 cm); and nine patients (16%) had known systemic metastases. IFN was administered subcutaneously on the 2 days before ILP with TNF, IFN, and melphalan. A delayed marginal resection of the tumor remnant was usually performed 2 to 3 months after ILP.
  
  
  RESULTS
  A major tumor response was seen in 87% of patients and rendered the sarcomas resectable in most cases. Clinical response rates were as follows: 10 (18%) completes responses (CRs), 35 (64%) partial responses (PRs), and 10 (18%) no change (NC). Final outcome was defined as follows by clinical and pathologic response: 20 (36%) CRs, 28 (51%) PRs, and 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; local recurrence developed in five (13%). When no resection was performed (multiple tumors or systemic metastases), local recurrences were frequent (five of 16), but limb salvage was often achieved as patients died of systemic disease. Regional toxicity was limited and systemic toxicity minimal to moderate with no toxic deaths. Histology showed hemorrhagic necrosis; angiographies showed selective destruction of tumor-associated vessels.
  
  
  CONCLUSIONS
  ILP with TNF, IFN, and melphalan is a safe and highly effective induction biochemotherapy procedure that can achieve limb salvage in patients with nonresectable extremity STS. TNF is an active anticancer drug in humans in the setting of ILP.
authors.affiliation: Department of Surgical Oncology, University Hospital Rotterdam-Daniel den Hoed Cancer Center, The Netherlands. eggermont@chih.azr.nl
authors.forename: A M
authors.initials: AM
authors.lastname: Eggermont
authors.forename: H
authors.initials: H
authors.lastname: Schraffordt Koops
authors.forename: D
authors.initials: D
authors.lastname: Liénard
authors.forename: B B
authors.initials: BB
authors.lastname: Kroon
authors.forename: A N
authors.initials: AN
authors.lastname: van Geel
authors.forename: H J
authors.initials: HJ
authors.lastname: Hoekstra
authors.forename: F J
authors.initials: FJ
authors.lastname: Lejeune
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000627:therapeutic use*; D010478:Chemotherapy, Cancer, Regional Perfusion; D005121:Extremities; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008558:Melphalan / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D012074:Remission Induction; D016879:Salvage Therapy; D012509:Sarcoma / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D008558:Melphalan