The success of TNFα in isolated limb perfusion (ILP) in the management of locally advanced tumors: Lessons from a clinical-preclinical interactive program and future prospects for TNFα in isolated organ perfusions

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Abstract

TNF-based Isolated Limb Perfusion. The efficacy of Isolated Limb Perfussions with Tumor Necrosis Factor and Malphalan for Limb Salvage in Patients with Locally Advanced Soft Tissue Extremity Sarcomas has been established by the multicenter European Experience reported by Eggermont et al, in J. Clin. Oncol. 14: 2653-2665, 1996 and in Ann. Surg. 224: 756-765, 1996. Patients and methods: In 8 cancer-centers 200 perfusions were performed in 186 pts over a period of 4.5 years. There were 107 (57%) primary and 79 (43%) recurrent sarcomas, mostly high grade tumors; 42 pts (23%) had multifocal primary or multiple recurrent tumors; median tumor size was very large (16 cm); 25 pts (13%) had known systemic metastases at the time of the ILP. Pts underwent a 90 minutes ILP at 39-40 °C with TNF + melphalan. The first 55 pts also received IFNγ. A delayed marginal resection of the tumor remnant was done 2-4 months after ILP. Results: A major tumor response was seen in 82% of the pts rendering these large sarcomas resectable in most cases. Clinical response rates were: 33 CR (18%), 106 PR (57%), 42 NC (22%) and 5 PD (3%). Final outcome was defined by clinical + pathological response: 54 CR (29%), 99 PR (53%), 29 NC (16% and 4 PD (2%). At a median flow up of almost 2 years (22 months; NC (16%) and 4 PD (2%). At a median follow up of almost 2 years (22 month; range 6-58) limb salvage was achieved in 82%. Other tumors: Similar response rates have been observed in the treatment of patients with melanoma in transit metastasis or other malignant limb tumors. These results achieved by TNF-based ILPs are far superior to the generally low clinical response rate (35%) reported after ILP with cytostatic agents alone of after systemic therapy (response rate <20%). Preclinical perfusion models: In Rotterdam we have developed isolated limb, kidney and hepatic perfusion models in rats using three tumors differing in histological type and vascularity. Factors that determine antitumor efficacy are drug concentration, perfusion time, temperature, use of vasoactive agents. Moreover, in pigs we have developed isolated pelvic, abdominal and hepatic perfusions using ballooncatheter technology to minimize surgery. Pharmakokinetic profiles with the latter methods predict the possible introduction of a TNFα in these systems. Conclusions: The success of TNFα in isolated limb perfusions in patients shown that TNFα can be used very effectively in patients and has renewed interest in it's use in other systems.

Original languageEnglish
Pages (from-to)536
Number of pages1
JournalBiotherapy
Volume12
Issue number5
Publication statusPublished - 1998
Externally publishedYes

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