Isolation limb perfusion with tumor necrosis factor alpha and chemotherapy for advanced extremity soft tissue sarcomas

The unique property of high dose recombinant tumor necrosis factor alpha (rTNFα) is to activate and selectively destroy the tumor-associated microvasculature. For the systemic application of rTNFα it has been shown that the maximum tolerated dose (MTD) is 10 times less than the effective close in animals. The main toxicity corresponds to systemic inflammatory response syndrome with a decrease in vascular resistance and hypotension. We found that it is possible to administer rTNFα at 10 times the MTD in an isolated limb perfusion (ILP) system with heart-lung machine, for locally advanced extremity soft tissue sarcomas. One hundred forty patients received an ILP with high-dose TNFα. In 55 patients treated with the combination of high-dose rTNFα + interferon-γ + melphalan an overall objective response rate of 87% with 36% complete responses was observed; it was 81% and 28%, respectively, in a group treated with TNFα and melphalan (n = 85). Angiographic and immunohistological studies showed the selective and early damage of the sarcoma-associated microvasculature preceded by the upregulation of adhesion molecules and intratumoral leak of von Willebrand factor. Tumor invasion by platelets and, in some cases, by polymorphonuclear cells, appeared within hours after the application of rTNFa long before the lysis of the tumor. Thus, ILP with high-dose TNFα and chemotherapy seems to act through a dual targeting: TNF hits the tumor associated vasculature, and chemotherapy attacks the tumor cells. Therefore, ILP with TNF is a new option in the management of locally advanced soft tissue sarcoma of the extremities.