title: Cytokine levels and systemic toxicity in patients undergoing isolated limb perfusion with high-dose tumor necrosis factor, interferon gamma, and melphalan.
abstract: OBJECTIVE
  Isolated limb perfusion (ILP) with tumor necrosis factor (TNF), interferon gamma, and melphalan (M) has been reported to result in high response rates for extremity melanoma and sarcoma. We have evaluated the relationship of systemic TNF exposure to induction of several secondary mediators and incidence of systemic toxicity.
  
  
  METHODS
  Nineteen patients with extremity melanoma (n = 16) or sarcoma (n = 3), underwent 90-minute ILP with TNF-alpha, interferon gamma (0.2 mg), and M (10 to 13 mg/L of limb volume) (TNF/IFN/M) (n = 12), or M alone (n = 7). Continuous intraoperative monitoring (CIM) for systemic leak from the perfusion circuit was performed using radioactive iodine-131 albumin. Cytokine levels in the perfusate and systemic circulation during and after ILP were measured by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Systemic leaks > or = 1% from the perfusion circuit occurred in six patients who received TNF/IFN/M and in four who received M alone. Hypotension that required vasopressor support occurred in six of six patients with evidence of a leak (> or = 1%) and zero of six patients without a leak (< 1%). These six patients had significantly higher peak systemic TNF levels during and after perfusion than patients without a leak (2.8 and 8.2 ng/mL v 0.7 and 2.0 ng/mL, respectively; P < .05). All patients who received TNF/IFN/M had significantly greater increases in systemic interleukin-6 (IL-6) levels than in patients with M alone (12,395 +/- 10,374 pg/mL v 79.4 +/- 7.2 pg/mL, respectively; P < .001). Intracellular adhesion molecule (ICAM), IL-8, and TNF-R levels were also increased after ILP with TNF/IFN/M.
  
  
  CONCLUSIONS
  ILP with TNF/IFN/M can be safely performed, as I131 albumin provides a sensitive measure of systemic leakage from the perfusion circuit. Patients with a measured leak of > or = 1% develop mild and transient postoperative hypotension with significantly higher systemic TNF levels and lower perfusate TNF levels than in patients without leaks.
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: A K
authors.initials: AK
authors.lastname: Thom
authors.forename: H R
authors.initials: HR
authors.lastname: Alexander
authors.forename: M P
authors.initials: MP
authors.lastname: Andrich
authors.forename: W C
authors.initials: WC
authors.lastname: Barker
authors.forename: S A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: D L
authors.initials: DL
authors.lastname: Fraker
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001132:Arm; D010478:Chemotherapy, Cancer, Regional Perfusion; D016207:Cytokines / Q000097:blood*; D005260:Female; D018219:Histiocytoma, Benign Fibrous / Q000097:blood / Q000628:therapy*; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage*; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D007866:Leg; D007890:Leiomyosarcoma / Q000097:blood / Q000628:therapy*; D008297:Male; D008545:Melanoma / Q000097:blood / Q000628:therapy*; D008558:Melphalan / Q000008:administration & dosage*; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000097:blood / Q000628:therapy*; D012878:Skin Neoplasms / Q000097:blood / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D008558:Melphalan