title: Isolated limb perfusion for extremity soft-tissue sarcomas, in-transit metastases, and other unresectable tumors: credits, debits, and future perspectives.
abstract: Isolated limb perfusion (ILP) with melphalan is effective against melanoma in-transit metastases but has failed in the treatment of limb-threatening extremity sarcomas. Tumor necrosis factor-alpha (TNF) has changed this situation completely. Now, ILP with TNF + melphalan is a very successful treatment to prevent amputation. In a multicenter European trial, ILP with TNF + melphalan resulted in a 76% response rate and a 71% limb salvage rate in patients with limb-threatening soft-tissue sarcomas, deemed unresectable by independent review committees, leading to approval of TNF in Europe. We have also reported on the success of this regimen against bulky melanomas, multifocal skin cancers, and drug-resistant bony sarcomas. High-dose TNF destructs tumor vasculature, and, most importantly, it enhances tumor-selective drug uptake (ie, melphalan and doxorubicin) by threefold to sixfold. Similar synergy is observed in well-vascularized liver metastases after isolated hepatic perfusion with TNF and melphalan. New (vasoactive) drugs and mechanisms of action and interaction with chemotherapy are in development. ILP is also a promising treatment modality for adenoviral vector-mediated gene therapy. Many clinical phase I/II evaluations in ILP are now underway.
authors.affiliation: Department of Surgical Oncology, University Hospital Rotterdam, Daniel den Hoed Cancer Center, 301 Groene Hilledijk, 3075 EA Rotterdam, The Netherlands. E-mail: eggermont@chih.azr.nl
authors.forename: A M
authors.initials: AM
authors.lastname: Eggermont
authors.forename: T L
authors.initials: TL
authors.lastname: ten Hagen
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods*; D005121:Extremities; D005544:Forecasting; D006801:Humans; D008558:Melphalan / Q000627:therapeutic use*; D009362:Neoplasm Metastasis; D051381:Rats; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014409:Tumor Necrosis Factor-alpha; D008558:Melphalan