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

Background Tumour necrosis factor-alpha (TNFa) 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 TNFa 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 TNFa. Samples of serum and pleural fluid were taken at different time-points before and after TNFa-administration. Levels of TNFa, 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 (a1-AG) was measured by nephelometry. Results In pleural fluid TNFa and IL-8 reached peak levels, up to 50‐700 ng mL π1 and 6‐ 60 ng mL π1 , respectively, 24 h after administration of TNFa. IL-6 (peak levels up to 250 ng mL π1 ) and sPLA2 peaked after 48 h. A slower and less dramatic pattern was observed for the levels of CRP and a1-AG. In serum no detectable levels of TNFa and no IL-8 were observed, whereas serum levels of IL-6, sPLA2 and CRP showed a clear increase after intrapleural administration of TNFa. 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 TNFa in mesothelioma patients, we studied the characteristics of the inflammatory response. Intrapleural administration was followed by a clear inflammatory response locoregionally. In spite of TNFa peak levels as high as 700 ng mL π1 systemic levels were never detectable. The secondary cytokine response led to very high intrapleural IL-6 and IL8 levels. Systemically IL-8 levels were never detectable whereas high IL-6 levels were induced systemically initially, with a decreased response to each intrapleural TNFa administration over time. The acute-phase response in contrast remained remarkably constant throughout the course of repeated intrapleural administrations of TNFa. Intrapleural administration of TNFa 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.