Effects of isolated limb perfusion with tumor necrosis factor-alpha on circulating levels of proinflammatory cytokines

Hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF alpha) and cytotoxic drugs is currently used for treatment of melanom a and sarcoma of the limbs. Tumor necrosis factor-alpha is involved in the systemic inflammatory response syndrome as a result of activation of inflam matory cells and production of bioactive substances. The goal of this study was to determine the circulating levels of proinflammatory cytokines and s oluble adhesion molecules in 19 patients with limb melanoma or sarcoma unde rgoing ILP with (n = 9) or without TNF alpha (n = 10). The results obtained demonstrated that ILP with TNF alpha was responsible for a leakage of TNF alpha in the systemic circulation, followed by a rise in interleukin (IL)-6 and IL-8 levels within 1 h. Elevated soluble (s)P-selectin levels were fou nd 1-3 h after ILP. Plasma sE-selectin peaked 6-9 h after ILP, and soluble vascular cell adhesion molecule (sVCAM) levels reached a maximum after 24 h . Significant correlations were observed among these variables, confirming the interdependence of all changes observed. On the other hand, ILP with cy totoxic drugs alone induced only a modest release of TNF alpha, which was n ot followed by an immediate rise in IL-6 and IL-8. Four of the 9 patients u ndergoing ILP with TNF had severe systemic toxicity. No association was fou nd between systemic TNF levels and the clinical outcome, whereas elevated T NF perfusion levels as well as systemic IL-6 and IL-8 levels were constantl y elevated in patients with severe toxicity. These results are suggestive o f an important role of TNF alpha levels in the perfusion system (more than leakage of perfusate) in causing postoperative toxicity, although other ILP -related factors should not be excluded.