Intrapleural administration of tumour necrosis factor alpha (TNFα) in patients with mesothelioma: Cytokine patterns and acute-phase protein response

Background. Tumour necrosis factor-alpha (TNFα) 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 TNFα 5 patients were followed for inflammatory response patterns. Patients and methods. Malignant mesothelioma patients were treated with repeated intrapleural administration of 0.1-0.2 mg recombinant TNFα. Samples of serum and pleural fluid were taken at different time-points before and after TNFα-administration. Levels of TNFα, 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 (α1-AG) was measured by nephelometry. Results. In pleural fluid TNFα 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 TNFα. 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 α1-AG. In serum no detectable levels of TNFα and no IL-8 were observed, whereas serum levels of IL-6, sPLA₂ and CRP showed a clear increase after intrapleural administration of TNFα. 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 TNFα in mesothelioma patients, we studied the characteristics of the inflammatory response. Intrapleural administration was followed by a clear inflammatory response locoregionally. In spite of TNFα 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 TNFα administration over time. The acute-phase response in contrast remained remarkably constant throughout the course of repeated intrapleural administrations of TNFα. Intrapleural administration of TNFα 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.