Absence of severe systemic toxicity after leakage-controlled isolated limbperfusion with tumor necrosis factor-alpha and melphalan

Background: Severe systemic toxicity and hemodynamic changes after isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF-alpha) and melp halan, with or without interferon-gamma, have been reported in several seri es. We studied whether these side effects could be precluded by preventing leakage from the isolated circuit into the systemic circulation. Methods: Clinical and pharmacokinetic data for 20 consecutive patients with recurrent melanoma of the limbs who were treated by ILP with TNF-alpha (3- 4 mg) and melphalan, with or without interferon-gamma, were studied. Leakag e rates and TNF-alpha levels were determined during and after ILP and were correlated with systemic toxicity and hemodynamic changes. Results: Only two patients experienced leaks (2% and 13%) during ILP. For 1 8 patients without leakage, the mean peak systemic TNF-alpha level was 2.8 ng/ml at 10 minutes after ILP. After leakage, the peak systemic TNF-alpha l evels were 31.9 and 88.3 ng/ml at 5 minutes. Toxicity was mild and consiste d mainly of fever (n = 17) and nausea/vomiting (n = 19) during the first da y after ILP. Some patients developed tachycardia (n = 6), hypotension (n = 3; responding immediately to fluid challenge), a decrease in the WBC count (n = 3; grade I) or thrombocyte count (n = 11; grade I/II, no hemorrhage or therapeutic intervention), or hepatotoxicity [cytolysis (n = 15; 14 grade I/II and 1 grade IV) or hyperbilirubinemia (n = 7; grade I/II, all resolvin g spontaneously)]. Patients with tachycardia or hepatotoxicity exhibited si gnificantly higher TNF-alpha levels after ILP, compared with other patients . Conclusions: Systemic toxicity after ILP with TNF-alpha is minimal and does not differ from that after ILP with melphalan alone when leakage is adequa tely controlled.