title: Limb salvage with isolated perfusion for soft tissue sarcoma: could less TNF-alpha be better?
abstract: BACKGROUND
  The optimal dose of TNF-alpha delivered by isolated limb perfusion (ILP) in patients with locally advanced soft tissue sarcoma is still unknown.
  
  
  METHODS
  Randomised phase II trial comparing hyperthermic ILP (38-40 degrees ) with melphalan and one of the four assigned doses of TNF-alpha: 0.5 mg, 1 mg, 2 mg, and 3/4 mg upper/lower limb. The main end point was objective tumour response on MRI. Secondary end points were histological response, rate of amputation and toxicity. Resection of the remnant tumour was performed 2-3 months after ILP. The sample size was calculated assuming a linear increase of 10% in the objective response rates between each dose level group.
  
  
  RESULTS
  One hundred patients (25 per arm) were included. Thirteen per cent of patients had a systemic leakage with a cardiac toxicity in six patients correlated with high doses of TNF-alpha. Objective tumour responses were: 68%, 56%, 72% and 64% in the 0.5 mg, 1 mg, 2 mg and 3 or 4 mg arms, respectively (NS). Sixteen per cent of patients were not operated, 71% had a conservative surgery and 13% were amputated with no difference between the groups. With a median follow-up of 24 months, the 2 year overall and disease-free survival rates (95% CI) were 82% (73% to 89%) and 49% (39% to 59%), respectively.
  
  
  CONCLUSIONS
  At the range of TNF-alpha doses tested, there was no dose effect detected for the objective tumour response, but systemic toxicity was significantly correlated with higher TNF-alpha doses. Efficacy and safety of low-dose TNF-alpha could greatly facilitate ILP procedures in the near future.
authors.affiliation: Department of Surgery, Institut Gustave Roussy, Villejuif, France. bonvalot@igr.fr
authors.forename: S
authors.initials: S
authors.lastname: Bonvalot
authors.forename: A
authors.initials: A
authors.lastname: Laplanche
authors.forename: F
authors.initials: F
authors.lastname: Lejeune
authors.forename: E
authors.initials: E
authors.lastname: Stoeckle
authors.forename: C
authors.initials: C
authors.lastname: Le Péchoux
authors.forename: D
authors.initials: D
authors.lastname: Vanel
authors.forename: P
authors.initials: P
authors.lastname: Terrier
authors.forename: J
authors.initials: J
authors.lastname: Lumbroso
authors.forename: M
authors.initials: M
authors.lastname: Ricard
authors.forename: G
authors.initials: G
authors.lastname: Antoni
authors.forename: A
authors.initials: A
authors.lastname: Cavalcanti
authors.forename: C
authors.initials: C
authors.lastname: Robert
authors.forename: N
authors.initials: N
authors.lastname: Lassau
authors.forename: J Y
authors.initials: JY
authors.lastname: Blay
authors.forename: A
authors.initials: A
authors.lastname: Le Cesne
mesh_terms: D000328:Adult; D000368:Aged; D010478:Chemotherapy, Cancer, Regional Perfusion; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005121:Extremities; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology / Q000628:therapy; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000628:therapy; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D014409:Tumor Necrosis Factor-alpha