Role of isolated limb perfusion with recombinant human tumor necrosis factor α and melphalan in locally advanced extremity soft tissue sarcoma

Abstract

Isolated limb perfusion with recombinant human tumor necrosis factor α and melphalan (TNF-ILP) is a highly effective regional treatment for locally advanced soft tissue sarcoma. This review critically discusses the indication for TNF-ILP. AbstractManagement of locally advanced extremity soft tissue sarcoma of the limbs is challenging particularly in recurrent tumors and those adjacent to neurovascular bundles and joints. Typically the tumors are large, below the fascia and of high grade (T2b, stage III according to AJCC) and thus require multimodal therapy. Treatment options must be tailored to patient and tumor characteristics.Isolated limb perfusion with recombinant human tumor necrosis factor α (TNF-ILP) adds a therapeutic option to radiation therapy and systemic chemotherapy. Although the procedure is somewhat sophisticated to learn, it is a safe method working for now almost two decades in more than 50 centers worldwide. TNF-ILP yields a high rate of pathologic complete or near-complete tumor remission. Combined with post-ILP surgical resection of the tumor remnant the limb salvage rate is close to 90%. Often adjuvant radiation therapy can be spared without compromising longterm local tumor control rates. Nevertheless, TNF-ILP has never been compared to other treatment regimen in a randomized trial. This review summarizes the mode of action and the standard application of TNF-ILP and focuses on a critical discussion on the role of TNF-ILP in multimodal treatment of locally advanced primary and recurrent extremity sarcoma.

Neoadjuvant chemotherapy plus radiation versus chemotherapy plus regional hyperthermia in high-grade soft tissue sarcomas: a retrospective comparison

“…When comparing the pathological tumor response with other published data, HCT achieved a (nearly) complete response rate of 45.2%, defined as less than 10% vital tumor cells after neoadjuvant treatment. This rate compares favorable to more invasive treatment approaches like isolated limb perfusion with tumor necrosis factor a and melphalan with nearly complete response rates between 17 and 47% [44]. Histopathological treatment results after HCT or CRT in our study are comparable to studies investigating CRT: Kraybill et al [18] reported a rate of 27% complete pathological response, DeLaney et al [45] reported a complete response rate of only 8% (4 of 48 patients).…”

Systemic delivery of the tumor necrosis factor gene to tumors by a novel dual DNA-nanocomplex in a nanoparticle system

“…In this context, TNF is a pleiotropic cytokine that promotes immune surveillance and directly kills cancer cells (5). Despite the promise of TNF as an anti-tumor agent, systemic TNF-induced toxicity precluded clinical development of this cytokine, other than in the setting of isolated limb perfusion for sarcomas (8). Noteworthy, however, are the findings that intratumoral administration of TNFerade has activity in the treatment of diverse human cancers (10), supporting the premise that a system for the delivery of TNF to tumors, while circumventing the systemic toxicity, could be an effective anti-cancer therapy.…”

“…We and others investigated the effectiveness of recombinant human TNF as a clinical anti-cancer agent; however, systemic side effects, such as fever, fatigue and hypotension, precluded its further development (6, 7). As a way of ameliorating the systemic toxicities, TNF has been approved in Europe for administration by isolated limb perfusion in the treatment of patients with locally advanced extremity soft tissue sarcoma (8). Another approach for the clinical development of TNF involved intratumoral delivery of an adenoviral vector encoding TNF under the control of a radio- and chemo-inducible promoter (TNFerade) (9).…”

Comparative evaluation of bolus and fractionated administration modalities for two antibody-cytokine fusions in immunocompetent tumor-bearing mice

“…vascular leak syndrome, nausea and fever) are frequently observed [13][14][15]. Recombinant TNF (Beromun ® ) has been approved for the treatment of soft-tissue sarcoma patients only for isolated limb perfusion procedures [16][17][18][19], whereas recombinant interferons have received marketing authorization for the treatment of various types of malignancies [20,21].…”

“…This feature, which may initially appear as paradoxical, is easy to understand considering the fact that only a small amount of product (in absolute terms) reaches the tumor mass (approximately 5-20 percent injected dose per gram in mice and 0.01-0.1 percent injected dose per gram in patient) [39,40]. Exposure of blood and normal organs to pro-inflammatory cytokines may cause hypotension, flu-like symptoms, nausea and vomiting [13][14][15][16][17][18][19][20][21]. Intense research activities are devoted to the search for methods which preserve the therapeutic activity of engineered cytokine products, while decreasing systemic toxicity [24].…”