title: Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas. The cumulative multicenter European experience.
abstract: OBJECTIVE
  The objective of the study was to achieve limb salvage in patients with locally advanced soft tissue sarcomas that can only be treated by amputation or functionally mutilating surgery by performing an isolated limb perfusion (ILP) with tumor necrosis factor (TNF) + melphalan (M) as induction biochemotherapy to obtain local control and make limb-sparing surgery possible.
  
  
  BACKGROUND
  To increase the number of limb-sparing resections in the treatment of locally advanced extremity soft tissue sarcoma, preoperative radiation therapy or chemotherapy or a combination of the two often are applied. The ILP with cytostatic agents alone is another option but rarely is used because of rather poor results. The efficacy of the application of TNF in ILP markedly has changed this situation.
  
  
  METHODS
  In 8 cancer centers, 186 patients were treated over a period of almost 4.5 years. There were 107 (57%) primary and 79 (43%) recurrent sarcomas, mostly high grade (110 grade III; 51 grade II; and 25 very large, recurrent, or multiple grade I sarcomas). The composition of this series of patients is unusual: 42 patients (23%) had multifocal primary or multiple recurrent tumors; median tumor size was very large (16 cm); 25 patients (13%) had known systemic metastases at the time of the ILP. Patients underwent a 90-minute ILP at 39 to 40 C with TNF + melphalan. The first 55 patients also received interferon-tau. A delayed marginal resection of the tumor remnant was done 2 to 4 months after ILP.
  
  
  RESULTS
  A major tumor response was seen in 82% of the patients rendering these large sarcomas resectable in most cases. Clinical response rates were: 33 complete response (CR) (18%), 106 partial response (PR) (57%), 42 no change (NC) (22%), and 5 progressive disease (PD) (3%). Final outcome was defined by clinical and pathologic response: 54 CR (29%), 99 PR (53%), 29 NC (16%), and 4 PD (2%). At a median follow-up of almost 2 years (22 months; range, 6-58 months), limb salvage was achieved in 82%. Regional toxicity was limited and systemic toxicity minimal to moderate, easily managed, with no toxic deaths.
  
  
  CONCLUSIONS
  In the setting of isolated limb perfusion, TNF is an active anticancer drug in patients. The ILP with TNF + melphalan can be performed safely in many centers and is an effective induction treatment with a high response rate that can achieve limb salvage in patients with locally advanced extremity soft tissue sarcoma.
authors.affiliation: Department of Surgical Oncology, University Hospital Rotterdam, Daniel den Hoed Cancer Center, The Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: Eggermont
authors.forename: H
authors.initials: H
authors.lastname: Schraffordt Koops
authors.forename: J M
authors.initials: JM
authors.lastname: Klausner
authors.forename: B B
authors.initials: BB
authors.lastname: Kroon
authors.forename: P M
authors.initials: PM
authors.lastname: Schlag
authors.forename: D
authors.initials: D
authors.lastname: Liénard
authors.forename: A N
authors.initials: AN
authors.lastname: van Geel
authors.forename: H J
authors.initials: HJ
authors.lastname: Hoekstra
authors.forename: I
authors.initials: I
authors.lastname: Meller
authors.forename: O E
authors.initials: OE
authors.lastname: Nieweg
authors.forename: C
authors.initials: C
authors.lastname: Kettelhack
authors.forename: G
authors.initials: G
authors.lastname: Ben-Ari
authors.forename: J C
authors.initials: JC
authors.lastname: Pector
authors.forename: F J
authors.initials: FJ
authors.lastname: Lejeune
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D010478:Chemotherapy, Cancer, Regional Perfusion; D005121:Extremities; D005260:Female; D018219:Histiocytoma, Benign Fibrous / Q000601:surgery; D006801:Humans; D008080:Liposarcoma / Q000601:surgery; D008297:Male; D008558:Melphalan / Q000008:administration & dosage*; D008875:Middle Aged; D012509:Sarcoma / Q000188:drug therapy / Q000601:surgery*; D013584:Sarcoma, Synovial / Q000601:surgery; D012983:Soft Tissue Neoplasms / Q000188:drug therapy / Q000601:surgery*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D008558:Melphalan