RATIONALE FOR USING TNF-ALPHA AND CHEMOTHERAPY IN REGIONAL THERAPY OFMELANOMA

Recombinant tumor necrosis factor-alpha (rTNF alpha) has potent antitu mor activity in experimental studies on human tumor xenografts. Howeve r, in humans, the administration of rTNF alpha is hampered by severe s ystemic side-effects. The maximum tolerated dose ranges from 350 to 50 0 mg/m(2), which is at least 10-fold less than the efficient dose in a nimals. Isolation perfusion of the limbs (ILP) allows the delivery of high dose rTNF alpha in a closed system with acceptable side-effects. A protocol with a triple-drug regimen was based on the reported synerg ism of rTNF alpha with chemotherapy, with interferon-gamma, and with h yperthermia. In melanoma-in-transit metastases (stage IIIA or AB) we o btained a 91% complete response, compared with 52% after ILP with melp halan alone. Release of nanograms levels of TNF alpha in the systemic circulation was evident but control of this leakage and appropriate in tensive care resulted in acceptable toxicity. Angiographic, immunohist ological, and immunological studies suggest that the efficacy of this protocol is due to a dual targeting: rTNF alpha activates and elective ly lyses the tumor endothelial cells while melphalan is mainly cytotox ic to the tumor cells. ILP with rTNF alpha appears to be a useful mode l for studying the biochemotherapy of cancer in man. (C) 1994 Wiley-Li ss, Inc.