High dose tumor necrosis factor alpha in isolation perfusion of the limb: Highly effective treatment for melanoma in transit metastases or unresectable sarcomas

Tumor Necrosis Factor-alpha (TNFα) is a very toxic substance with potent antitumor activity in some experimental animal tumor models. Its systemic application in patients with disseminated malignancies was associated with such severe toxicity that only 5-10% of the dose required for antitumor effects in mice could be administered, and a 5% response rate was observed. In the setting of an isolated limb perfusion high doses of TNFα can be delivered and thus in this closed system the tumors can be exposed to ultrahigh concentrations of TNFα over a period of 1-1.5 hours. TNFα was administered in combination with Interferon-gamma (IFN) and Melphalan in 83 patients in 4 perfusion centers. In this setting TNFα appeared a remarkably effective antitumor agent in humans as is illustrated by an 88% CR rate in 58 patients with melanoma in transit metastases confined to the limb. Also large tumor masses, such as irresectable soft tissue sarcomas in the extremities, reacted very favorably to ILP with TNFα. In 25 patients with locally far advanced or multiple irresectable soft tissue sarcomas of the extremities 10 CR, 12 PR and 3 MR, usually rendering the tumors resectable, were observed. Thus in 23 patients (88%) limb salvage was achieved. Angiographic and (immuno)histological studies suggest that the TNFα-mediated destruction of the endothelium of the tumor associated vessels and the subsequent total destruction of the tumor associated vascular bed is key to the dramatic antitumor effects. TNFα can be safely and effectively applied in the treatment of advanced tumors by isolation perfusions of extremities.