TNFa-based isolated limb perfusion in the rat : development of a model and analysis of efficacy determining factors

Isolated limb perfusion (lLP) with high dose TNFa in combination with IFNr and melphalan in patients with melanoma in transit metastases confined to the limb has recently been reported to result in much higher complete tumor response rates than after the standard therapy of ILP with melphalan alone: 90 % vs 54 % complete remissionl .'. Moreover the same protocol of ILP when applied as an induction bio-chemotherapy in patients with irresectabIe extremity soft tissue sarcomas. was reported to result in about 85 % response rates rendering most tumors resectable and resulting in a > 80% limb salvage rate'·'. The tumor response in many patients in both patient groups was characterized by an immediate (within 3 days) and grossly visible reaction to treatment, which shows a remarkable similarity to that observed in animal tumor models after systemic administration of TNFa. ILP became the first setting, in which effective concentrations of TN Fa could be reached and a reproducible antitumor effect could be measured. In patients Lv. administration of TN Fa is limited to much lower doses than the effective doses in mice, since TNFa causes severe hypotension in man and is known to play a key role as a mediator in septic shock. Pathophysiologically, TNFa is a paracrine (and autocrine) mediator that is released at the inflammation site, with severe hypotensive effects when it is released systemically. Therefore the trials of systemic administration of TNFa, either alone or in combination with other cytokines or chemotherapy had marginal results.

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