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Hyperthermic Isolated Perfusion With Low-Dose Tumor Necrosis Factor and Doxorubicin for the Treatment of Limb-Threatening Soft Tissue Sarcomas

¹ Surgery Branch, Department of Oncological and Surgical Sciences, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy
² Department of Pharmacology and Anesthesiology, University of Padova, Largo Meneghetti, 2, 35131 Padova, Italy
³ Clinical Epidemiology Unit, Regional Oncology Centre, Via Gattamelata, 6, 4 35128 Padova, Italy

Correspondence: Address correspondence and reprint requests to: Carlo Riccardo Rossi, MD; E-mail: carlor.rossi{at}unipd.it.

Background: Tumor necrosis factor (TNF)-–based hyperthermic isolated limb perfusion (HILP) is one of the most active available approaches for locally advanced soft tissue sarcomas (STS) of the limbs. The aim of this study was to investigate the anticancer activity of a novel drug regimen including doxorubicin (DXR) and low-dose TNF-.

Methods: HILP with low-dose TNF- (1 mg) and DXR (8.5 mg/L of limb volume) was given to 21 patients with limb-threatening STS: 14 had primary and 7 had recurrent STS, most of which were high grade (grade 1, n = 3; grade 2, n = 6; grade 3, n = 12). Resection of the tumor remnant was performed 6 to 8 weeks after HILP. TNF- concentrations in plasma and perfusate were measured throughout perfusion.

Results: A major tumor response was observed at histology and clinical evaluation in 90% and 62% of patients, respectively. After a median follow-up of 30 months, limb salvage and local disease control were achieved in 71% and 81% of cases, respectively. Fourteen patients had moderate regional toxicity, which was resolved in all cases. One patient had severe limb toxicity, which did not require amputation. Systemic side effects were minimal, and there were no postoperative deaths. The perfusate/plasma area under the curve ratio for TNF- was 56.

Conclusions: HILP with low-dose TNF- and DXR seems to be an active neoadjuvant drug regimen against limb-threatening STS. This therapeutic approach can achieve high limb-sparing surgery rates with acceptable local and negligible systemic toxicity.

Key Words: Limb-threatening soft tissue sarcoma • Isolated limb perfusion • TNF- • Doxorubicin

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