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Role of Tumor Necrosis Factor on Toxicity and Cytokine Production after Isolated Hepatic Perfusion¹

Surgery Branch, Division of Clinical Sciences and the Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland 20892

Purpose: Isolated limb or liver perfusion with tumor necrosis factor (TNF) and melphalan results in regression of advanced cancers in the majority of treated patients. However, the contribution of TNF to the efficacy of isolation perfusion with melphalan has not been demonstrated conclusively in random assignment trials. Furthermore, TNF is an inflammatory cytokine and may be associated with significant systemic and regional toxicity. This study was conducted to characterize the toxicity and secondary cytokine production attributable to TNF by comparing these parameters in patients undergoing isolated hepatic perfusion (IHP) using melphalan with or without TNF.

Experimental Design: Thirty-two patients with unresectable colorectal cancer confined to the liver underwent a 60-min hyperthermic IHP using 1.5 mg/kg melphalan alone (n = 17) or with 1.0 mg of TNF (n = 15) with inflow via the gastroduodenal artery and outflow via an isolated segment of inferior vena cava. Complete vascular isolation was confirmed using the I-131 radiolabeled albumin-monitoring technique. Post-IHP parameters of hepatic and systemic toxicity and cytokine levels [TNF, interleukin (IL)-6 and IL-8] in perfusate and serum were measured.

Results: Levels of IL-6 and IL-8 in perfusate at the end of the 60-min IHP were significantly higher in TNF-treated patients (P 0.001). Peak systemic IL-6 and IL-8 levels post-IHP were also significantly higher in TNF-treated compared with non-TNF-treated patients (P < 0.0001) by 28- and 268-fold, respectively. The peak levels of these cytokines were associated with significantly lower systolic blood pressure and higher heart rate and mean pulmonary artery blood pressure in TNF-treated patients during the first 48 h post-IHP (P 0.03). Serum bilirubin levels were significantly higher (P = 0.017) and platelets lower (P = 0.03) in TNF-treated compared with non-TNF-treated patients. However, elevations in aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase were not significantly different between groups and returned toward baseline within 1 week after IHP.

Conclusions: Addition of TNF to melphalan during IHP results in significant differences in post-IHP production of IL-6 and IL-8 with associated changes in mean arterial blood pressure and greater regional toxicity, as reflected in higher levels of serum bilirubin. However, these measurable differences were transient and did not appear to be of major clinical consequence. Prior to its routine use, the benefit of TNF in isolation perfusion should be demonstrated in random assignment trials.

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