Journal of Surgical Oncology 2011;103:648–655 TNF Dose Reduction and Shortening of Duration of Isolated Limb Perfusion for Locally Advanced Soft Tissue Sarcoma of the Extremities Is Safe and Effective in Terms of Long-Term Patient Outcome MIRIAM L. HOVEN-GONDRIE, MD, 1 ESTHER BASTIAANNET, MSc, 1 ROBERT J. VAN GINKEL, MD, PhD, 1 ALBERT J.H. SUURMEIJER, MD, PhD, 2 AND HARALD J. HOEKSTRA, MD, PhD 1 * 1 Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands 2 Department of Pathology, University Medical Center Groningen, Groningen, The Netherlands Background and Objectives: Dose reduction and shortening of duration of perfusion in isolated limb perfusion with TNF-a and Melphalan (TM- ILP) are associated with less systemic toxicity and seem to be safe and effective on short-term. However, data on long-term patient outcome are scarce. Methods: From 1991 to 2008, 102 TM-ILPs were performed in 98 patients for a locally advanced soft tissue sarcoma of the extremity. Perfusions were categorized in three groups: (A) high dose and long duration (n ¼ 59), (B) high dose and short duration (n ¼ 16), and (C) low dose and short duration (n ¼ 27). Long-term local control rates and (limb)-survival were evaluated. Results: Limb salvage rates were in group A 76.3%, B 62.5%, and C 85.2% (P ¼ 0.2). With a median follow up of 76 (range 4–203) months, 50 patients were still alive (51%). Disease-specific 5-year survival was not different between the three groups: A 55.4%, B 52.5%, and C 57.3% (P ¼ 0.9). There was no difference in local recurrence-free 5-year survival (adjusted P ¼ 0.1) and distant metastases-free survival (P ¼ 0.9). Conclusions: Dose reduction and shorter duration of TM-ILP seem to be safe and effective regarding long-term patient outcome, as 5-year local control rates and (limb)-survival are not compromised. J. Surg. Oncol. 2011;103:648–655. ß 2011 Wiley-Liss, Inc. KEY WORDS: soft tissue sarcoma; limb perfusion; dose reduction; tumor necrosis factor; long-term outcome INTRODUCTION Isolated limb perfusion (ILP) was introduced by Creech in 1957 [1]. With the use of Melphalan as single therapeutic agent, complete response (CR) rates of 50–65% can be achieved in patients with locore- gional recurrent melanoma patients [2]. However, because of poor and inhomogeneous drug uptake in soft tissue sarcomas (STS), ILP with chemotherapy alone has failed in the treatment of unresectable extrem- ity STS [3,4]. In the early 1990s, TNF-a was successfully added to Melphalan in ILP (TM-ILP) for the treatment of locally advanced STS as well as for in transit metastases of melanoma of the limbs [5]. This combined treatment proved to be successful with excellent response rates especially for locally advanced STS of the limbs [6]. After a multicenter European trial this led to the approval of TNF-a for the treatment of unresectable STS in Europe [7]. Currently, TM-ILP is performed in 36 centers in Europe, but less than 10 centers have long- lasting experience of more than 15 years. TNF-a has selective destruc- tive effects on tumor-associated vessels and, by increasing vascular permeability, acts synergistic with Melphalan by enhancing its uptake in the tumor. Furthermore it has a small direct cytotoxic effect by inducing hemorrhagic necrosis [8,9]. However, the administration of TNF-a can lead to severe systemic toxicity and leakage to the systemic circulation should therefore be strictly controlled [10,11]. The initial approved doses of 4 mg TNF-a for ILP in the lower extremity and 3 mg TNF-a for ILP in the upper extremity are arbitrarily based on the proportional translation that, like for Melphalan, drug concentrations 10 times higher than systemically tolerated were well tolerated in the limb [5]. Former studies showed, however, that dose reduction to 1 or 2 mg TNF-a is associated with less systemic toxicity and seems to be as effective as high-dose TNF-a [12,13]. At the University Medical Center Groningen (UMCG) TM-ILP with reduced dosage of TNF-a has been applied since 2003. Furthermore, since the last decade, the overall duration of the perfusion was shortened from 90 to 60 min. This was based on the fact that TNF-a concentrations remain stable during perfusion but that after 30 min, the effect of Melphalan is dramatically decreased [13,14]. These two changes in ILP technique have proven to be safe and effective in terms of response rate and short-term patient outcome [15,16]. However, since data on long-term patient outcome are not widely available, the aim of this study was to evaluate if long-term local control rates and survival are not compromised by dose reduction of TNF-a and shortened duration of the perfusion. MATERIALS AND METHODS Patients From 1991 to 2008, 102 TM-ILPs were performed in 98 patients with a locally advanced soft tissue sarcoma of the extremity. A combination of TNF-alpha (TNF) and Melphalan was used, with (n ¼ 20) or without (n ¼ 82) interferon gamma (IFN). Two patients underwent a double ILP for the same tumor because of no clinical response after the first ILP. Two patients had a second ILP for a local recurrence. The WHO 2002 Classification of soft tissue tumors was used for histopathologic typing. Presented at the 63rd Annual Cancer Symposium, Society of Surgical Oncology, Saint Louis 2010. *Correspondence to: Harald J. Hoekstra, MD, PhD, Division of Surgical Oncology, Department of Surgery, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. Fax: þ31- 503614873 E-mail: h.j.hoekstra@chir.umcg.nl Received 22 August 2010; Accepted 18 January 2011 DOI 10.1002/jso.21885 Published online 17 February 2011 in Wiley Online Library (wileyonlinelibrary.com). ß 2011 Wiley-Liss, Inc.