title: Intrapleural administration of tumour necrosis factor-alpha (TNFalpha) in patients with mesothelioma: cytokine patterns and acute-phase protein response.
abstract: BACKGROUND
  Tumour necrosis factor-alpha (TNFalpha) has been found to be very effective in the isolated limb perfusion setting for advanced extremity tumours. In a phase I study of intrapleural administration of TNFalpha 5 patients were followed for inflammatory response patterns.
  
  
  METHODS
  Malignant mesothelioma patients were treated with repeated intrapleural administration of 0. 1-0.2 mg recombinant TNFalpha. Samples of serum and pleural fluid were taken at different time-points before and after TNFalpha-administration. Levels of TNFalpha, interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP) and secretory phospholipase A2 (sPLA2) were measured using enzyme-linked immunosorbent assays (ELISAs). Alpha 1-acid glycoprotein (alpha1-AG) was measured by nephelometry.
  
  
  RESULTS
  In pleural fluid TNFalpha and IL-8 reached peak levels, up to 50-700 ng mL-1 and 6-60 ng mL-1, respectively, 24 h after administration of TNFalpha. IL-6 (peak levels up to 250 ng mL-1) and sPLA2 peaked after 48 h. A slower and less dramatic pattern was observed for the levels of CRP and alpha1-AG. In serum no detectable levels of TNFalpha and no IL-8 were observed, whereas serum levels of IL-6, sPLA2 and CRP showed a clear increase after intrapleural administration of TNFalpha. Cytokines and acute-phase proteins showed the same pattern during subsequent cycles even up to 12 cycles. Tumour regression was not observed.
  
  
  CONCLUSIONS
  In the setting of a phase I study of repetitive intrapleural administration of TNFalpha in mesothelioma patients, we studied the characteristics of the inflammatory response. Intrapleural administration was followed by a clear inflammatory response locoregionally. In spite of TNFalpha peak levels as high as 700 ng mL-1 systemic levels were never detectable. The secondary cytokine response led to very high intrapleural IL-6 and IL-8 levels. Systemically IL-8 levels were never detectable whereas high IL-6 levels were induced systemically initially, with a decreased response to each intrapleural TNFalpha administration over time. The acute-phase response in contrast remained remarkably constant throughout the course of repeated intrapleural administrations of TNFalpha. Intrapleural administration of TNFalpha is well tolerated but associated with inconsistent and rather moderate impact on production of pleural fluid. This can be achieved by other simpler and cheaper treatment, thus we see no justification for further studies.
authors.affiliation: University Hospital Rotterdam, Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands.
authors.forename: T C
authors.initials: TC
authors.lastname: Stam
authors.forename: A J
authors.initials: AJ
authors.lastname: Swaak
authors.forename: W H
authors.initials: WH
authors.lastname: Kruit
authors.forename: G
authors.initials: G
authors.lastname: Stoter
authors.forename: A M
authors.initials: AM
authors.lastname: Eggermont
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism*; D000368:Aged; D002097:C-Reactive Protein / Q000378:metabolism; D016207:Cytokines / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015552:Injections, Intralesional; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D008654:Mesothelioma / Q000097:blood / Q000188:drug therapy* / Q000276:immunology*; D008875:Middle Aged; D009367:Neoplasm Staging; D009961:Orosomucoid / Q000378:metabolism; D010741:Phospholipases A / Q000097:blood; D054467:Phospholipases A2; D010997:Pleural Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000276:immunology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D009961:Orosomucoid; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D010741:Phospholipases A; D054467:Phospholipases A2