SYSTEMIC LEAKAGE AND SIDE-EFFECTS OF TUMOR-NECROSIS-FACTOR-ALPHA ADMINISTERED VIA ISOLATED LIMB PERFUSION CAN BE MANIPULATED BY FLOW-RATE ADJUSTMENT

Background: The tolerated systemic dose of recombinant tumor necrosis factor alpha (rTNF-alpha) is very limited, since its administration le ads to a severe septic shock-like condition. Its implementation in iso lated limb perfusion (ILP) for metastatic melanoma or advanced soft-ti ssue sarcoma confined to the limb facilitates doses of rTNF-alpha 10 t imes higher than the systemic tolerated dose. However, with the tradit ional high flow rate used in ILP, systemic leakage and side effects ar e not eliminated. Objective: To determine if a lower perfusion flow ra te would reduce leakage and consequently toxic effects. Methods: Isola ted limb perfusion was performed for melanoma and soft-tissue sarcoma confined to the limb using a flow rate of 869+/-122 mL/min in nine pat ients (group 1) and a lower rate of 286+/-62 mL/min in six patients (g roup 2). Results: The systemic leakage rate was 12.5%+/-2.9% in group 1, compared with 2.3%+/-1.0% in group 2 (P=.003). Peak TNF-alpha level s were 29 000+/-2700 pg/mL in group 1, higher than 1580+/-1355 pg/mL i n group 2 (P=.02). The tachycardia, hypotension, increased cardiac out put, decreased systemic vascular resistance, bilirubinemia, elevation of liver enzyme levels, hypocholestrolemia, thrombocytopenia, and prol ongation of prothrombin and partial thromboplastin times all observed in group 1 were significantly attenuated or eliminated in group 2. The limb PO2, PCO2, pH, and viability remained similar in both groups. Al so, the tumor response rate remained high and was unaffected by the de crease in flow rate. Conclusions: Decreasing perfusion flow rate durin g ILP results in diminished leakage of TNF-alpha. Consequently, the sy stemic hemodynamic, metabolic, and hematologic toxic effects are virtu ally abolished.