title: Systemic leakage and side effects of tumor necrosis factor alpha administered via isolated limb perfusion can be manipulated by flow rate adjustment.
abstract: BACKGROUND
  The tolerated systemic dose of recombinant tumor necrosis factor alpha (rTNF-alpha) is very limited, since its administration leads to a severe septic shock-like condition. Its implementation in isolated limb perfusion (ILP) for metastatic melanoma or advanced soft-tissue sarcoma confined to the limb facilitates doses of rTNF-alpha 10 times higher than the systemic tolerated dose. However, with the traditional high flow rate used in ILP, systemic leakage and side effects are not eliminated.
  
  
  OBJECTIVE
  To determine if a lower perfusion flow rate would reduce leakage and consequently toxic effects.
  
  
  METHODS
  Isolated limb perfusion was performed for melanoma and soft-tissue sarcoma confined to the limb using a flow rate of 869 +/- 122 mL/min in nine patients (group 1) and a lower rate of 286 +/- 62 mL/min in six patients (group 2).
  
  
  RESULTS
  The systemic leakage rate was 12.5% +/- 2.9% in group 1, compared with 2.3% +/- 1.0% in group 2 (P = .003). Peak TNF-alpha levels were 29,000 +/- 2700 pg/mL in group 1, higher than 1580 +/- 1355 pg/mL in group 2 (P = .02). The tachycardia, hypotension, increased cardiac output, decreased systemic vascular resistance, bilirubinemia, elevation of liver enzyme levels, hypocholestrolemia, thrombocytopenia, and prolongation of prothrombin and partial thromboplastin times all observed in group 1 were significantly attenuated or eliminated in group 2. The limb PO2, PCO2, pH, and viability remained similar in both groups. Also, the tumor response rate remained high and was unaffected by the decrease in flow rate.
  
  
  CONCLUSIONS
  Decreasing perfusion flow rate during ILP results in diminished leakage of TNF-alpha. Consequently, the systemic hemodynamic, metabolic, and hematologic toxic effects are virtually abolished.
authors.affiliation: Department of Intensive Care and Anesthesiology, Ichilov Hospital, Tel Aviv, Israel.
authors.forename: P
authors.initials: P
authors.lastname: Sorkin
authors.forename: S
authors.initials: S
authors.lastname: Abu-Abid
authors.forename: D
authors.initials: D
authors.lastname: Lev
authors.forename: M
authors.initials: M
authors.lastname: Gutman
authors.forename: D
authors.initials: D
authors.lastname: Aderka
authors.forename: P
authors.initials: P
authors.lastname: Halpern
authors.forename: A
authors.initials: A
authors.lastname: Setton
authors.forename: N
authors.initials: N
authors.lastname: Kudlik
authors.forename: J
authors.initials: J
authors.lastname: Bar-On
authors.forename: V
authors.initials: V
authors.lastname: Rudich
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000032:analysis; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001132:Arm; D001772:Blood Cell Count / Q000187:drug effects; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods*; D002784:Cholesterol / Q000097:blood; D004334:Drug Administration Schedule; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007866:Leg; D008111:Liver Function Tests; D008297:Male; D008545:Melanoma / Q000503:physiopathology / Q000556:secondary / Q000628:therapy*; D008558:Melphalan / Q000627:therapeutic use; D008660:Metabolism / Q000187:drug effects; D008875:Middle Aged; D011994:Recombinant Proteins; D012509:Sarcoma / Q000503:physiopathology / Q000628:therapy*; D012983:Soft Tissue Neoplasms / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000009:adverse effects* / Q000032:analysis
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol; D008558:Melphalan