TNF-alpha and melphalan-based isolated limb perfusion: no evidence supporting the early destruction of tumour vasculature

Abstract

Background:Isolated limb perfusion with TNF-alpha and melphalan (TM-ILP) is a highly effective treatment for locally advanced tumours of the extremities. Previous research suggests an almost immediate disintegration of the blood supply of the tumour. The aim of the present study was to verify this hypothesis using non-invasive measurements of microvascular perfusion and tissue oxygenation.Methods:A total of 11 patients were included in the study. TM-ILP was performed under mildly hyperthermic conditions (39 °C) in the extremities via proximal vascular access. Capillary-venous microvascular blood flow, haemoglobin level (Hb) and oxygen saturation (SO2) were determined using laser Doppler and white-light spectroscopy, respectively, before TM-ILP and at 30 min, 4 h, 1 day, 4 days, 1 week, 2 weeks and 6 weeks after TM-ILP from tumour and healthy muscle tissues.Results:Blood flow and Hb were mostly higher, whereas SO2 was lower, in tumour tissue compared with muscle tissue. In both tumour and muscle tissues, blood flow significantly increased immediately after TM-ILP and remained elevated for at least 2 weeks, followed by a return to the initial values 6 weeks after the procedure.Conclusion:No signs were found of early destruction of the tumour vasculature. The observations suggest that an inflammatory reaction is one of the key elements of TM-ILP.

Cancer‐Related Systemic Inflammation: The Challenges and Therapeutic Opportunities for Personalized Medicine

“…High concentrations of TNF have been found to cause tumor necrosis via the destruction of tumor blood vessels and activation of tumor‐antigen‐specific T cells. In fact, TNF in combination with melphalan and isolated limb perfusion is used as a treatment for locally advanced soft‐tissue sarcoma . However, over the last decade, research has found that chronic levels of lower concentrations of TNF act as a tumor promotor in the tumor microenvironment.…”

Antitumor in situ vaccination effect of TNFα and IL-12 plasmid DNA electrotransfer in a murine melanoma model

“…Like IL-12, TNFα is a proinflammatory and immunostimulatory cytokine, but in contrast to IL-12, its antitumor activity is based primarily on its direct cytotoxicity to tumor cells and vascular disruption effects [ 13 ]. Due to the significant systemic toxicity, recombinant TNFα is currently used in the clinical practice in the setting of isolated limb perfusion only [ 14 ]. Tumor-targeted delivery of TNFα has been attempted by gene therapy approaches [ 15 , 16 ].…”