title: High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma.
abstract: OBJECTIVE
  To determine the toxicity and the therapeutic efficacy of the combination of the recombinant tumor necrosis factor alpha (rTNF alpha), recombinant interferon gamma (rIFN-gamma), and melphalan, we designed a protocol using isolation limb perfusion (ILP) with hyperthermia for in-transit metastases of melanoma and recurrent sarcoma. The triple combination was chosen because of the reported synergistic antitumor effect of rTNF alpha with IFN-gamma and of rTNF alpha with alkylating agents.
  
  
  METHODS
  Twenty-three patients received a total of 25 ILPs with the triple combination. There were 19 females and four males with either multiple progressive in-transit melanoma metastases of the extremities (stage IIIa or IIIab; 19 patients) or recurrent soft tissue sarcoma (five). The rTNF alpha was injected as a bolus in the arterial line, and total dose ranged between 2 and 4 mg, under hyperthermic conditions (40 degrees C to 40.5 degrees C) for 90 minutes. The rIFN-gamma was given subcutaneously (SC) on days -2 and -1 and in the perfusate, with rTNF alpha at the dose of 0.2 mg. Melphalan (Alkeran; Burroughs Wellcome Co, London, England) was administered in the perfusate at 40 micrograms/mL.
  
  
  RESULTS
  Toxicity observed during three ILPs in a pilot study with rTNF alpha included only two severe toxicities: one severe hypotension with tachycardia and transient oliguria and one moderate hypotension for 4 hours followed by severe kidney failure with complete recovery on day 29. In all 18 ILPs performed in the triple combination protocol, the patients received continuous infusion dopamine at 3 micrograms/kg/min from the start of ILP and for 72 hours and showed only mild hypotension and transient chills and temperature. Regional toxicity attributable to rTNF alpha was minimal. There have been 11 cases with hematologic toxicity consisting of neutropenia (one grade 4 and one grade 3) and neutropenia with thrombocytopenia (one grade 4 and three grade 2). Twelve patients had been previously treated with melphalan in ILP (11) or with cisplatin (one). The 23 patients are assessable: there have been 21 complete responses (CRs; range, 4 to 29 months; 89%), two partial responses (PRs; range, 2 to 3 months), and no failures. Overall disease-free survival and survival have been 70% and 76%, respectively, at 12 months. In all cases, softening of the nodules was obvious within 3 days after ILP and time to definite response ranged between day 5 and 30.
  
  
  CONCLUSIONS
  This preliminary analysis of a phase II study suggests that high-dose rTNF alpha can be administered with acceptable toxicity by ILP with dopamine and hyperhydration. Tumor responses can be evidenced in melanoma and sarcoma. Furthermore, combination of rTNF alpha, rIFN-gamma, and melphalan seems to achieve high efficacy with minimal toxicity, even after failure of prior therapy with melphalan alone.
authors.affiliation: Department of Surgery, Jules Bordet Institute, Université Libre de Bruxelles, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Lienard
authors.forename: P
authors.initials: P
authors.lastname: Ewalenko
authors.forename: J J
authors.initials: JJ
authors.lastname: Delmotte
authors.forename: N
authors.initials: N
authors.lastname: Renard
authors.forename: F J
authors.initials: FJ
authors.lastname: Lejeune
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001132:Arm; D010478:Chemotherapy, Cancer, Regional Perfusion; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D007371:Interferon-gamma / Q000008:administration & dosage; D007866:Leg; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008558:Melphalan / Q000008:administration & dosage; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D011994:Recombinant Proteins / Q000008:administration & dosage; D012509:Sarcoma / Q000188:drug therapy*; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
chemical_list: D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D008558:Melphalan