Systemic toxicity of tumor necrosis factor administered via high flow isolated limb perfusion

Tumor necrosis factor (TNF) is a very potent antineoplastic drug, but its tolerated systemic dose is very limited since its administration leads to a severe septic shock-like condition and multi-organ failure. Its implementation in isolated limb perfusion (ILP) for metastatic melanom or advanced soft tissue sarcoma confned to the limb facilitates doses of TNF ten times that of the sytemic tolerated dose. However, we have learned that with the traditional high flow used in ILP, systemic leakage and side effects are not eliminated. Nine consecutive patients underwent ILP using a flow rate of 869±122 ml/min. Systemic leakage was 12.5±2.9% and peak sytemic serum TNF levels were 29,000±2.700 pg/ml. This unique group of patients provided us with the opportunity to study the systemic side effects of TNF. A good correlation was found between rTNF-α. levels and the severity of systemic side effects, which may be divided into three categories:cardiovascular: tachycardia, hypotension, increased cardiac output, decreased sytemic vascular resistance, metabolic: increased temperature, bilirubinemia, elevation of liver enzymes, hypocholesterolemia, and hematologic: leukopenia, thrombocytopenia and prolongation of PT and PTT. In subsequent patients, isolation techniques were improved and now rates adjusted to decrease pressure, which abolished the systemic side effects. However, these side effects should be taken into consideration when ILP with TNF is planned, and extreme caution and adherence to meticulous isolation techniques implemented.