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Technology Insight: utility of TNF-α-based isolated limb perfusion to avoid amputation of irresectable tumors of the extremities

Nature Clinical Practice Oncology volume 3, pages 94–103 (2006)Cite this article

Abstract

Isolated limb perfusion (ILP) with melphalan is effective in the treatment of small multiple melanoma intransit metastases and is utilized widely for this indication. The treatment is much less effective against bulky melanoma metastases and has uniformly failed in the treatment of irresectable extremity soft tissue sarcomas. The addition of tumor-necrosis factor-α (TNF-α) to this treatment approach has changed the situation dramatically. High response rates and limb-salvage rates have been reported in multicenter trials that combined ILP with TNF-α plus melphalan; these trials resulted in the approval of TNF-α for bulky melanoma metastases and soft tissue sarcomas in Europe in 1998. Subsequently, many doctors working in European centers have been trained, and a series of confirmatory reports from single institutions have now been published regarding the efficacy of the procedure. TNF-α has an early and a late effect; it enhances tumor-selective drug uptake during the perfusion, and plays an essential role in the subsequent selective destruction of the tumor vasculature. These effects result in a high response rate in bulky tumors, soft tissue sarcomas, bulky melanomas, and various other tumor types. This induction therapy therefore allows tumor remnants to be resected some 3 months after ILP thus avoiding limb amputation. TNF-α-based ILP is a well-established treatment that aims to avoid amputations regardless of the tumor size and type. It represents an important example of combination therapy that modulates the tumor vasculature and should be offered in high-volume tertiary referral centers.

Key Points

  • The use of tumor-necrosis factor-α (TNF-α) in the isolated limb perfusion (ILP) setting for soft tissue sarcoma (STS) treatment showed impressive response rates, and subsequent confirmation in multicenter trials led to the approval and registration of this regimen in Europe

  • Data from studies assessing dosage in STS showed that TNF-α doses of 1 mg (for the arm) and 1–2 mg (for the leg) are sufficient

  • High limb-salvage and response rates were seen in patients with metastatic disease who received TNF-α-based ILP palliative therapy

  • In patients with melanoma intransit metastases, amputation is seldom beneficial and TNF-α-based ILP therapy is an attractive option, with very high reported response rates (95%) and limb salvage rates (99%)

  • TNF-α-based ILP is an excellent tool for achieving local control and avoiding limb amputations in patients with limb-threatening tumors

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Figure 1: Schematic isolated limb perfusion for large soft tissue sarcoma in the upper leg.
Figure 2: Selective eradication of the tumor vasculature by tumor-necrosis-factor-α-based isolated limb perfusion (ILP).

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Authors and Affiliations

  1. Department of Surgical Oncology,

    Dirk J Grünhagen, Johannes HW de Wilt, Timo LM ten Hagen & Alexander MM Eggermont

  2. Department of Surgical Oncology,

    Dirk J Grünhagen, Johannes HW de Wilt, Timo LM ten Hagen & Alexander MM Eggermont

  3. Laboratory for Experimental Surgical Oncology in the Department of Surgical Oncology,

    Dirk J Grünhagen, Johannes HW de Wilt, Timo LM ten Hagen & Alexander MM Eggermont

  4. Department of Surgical Oncology, Erasmus MC–Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

    Dirk J Grünhagen, Johannes HW de Wilt, Timo LM ten Hagen & Alexander MM Eggermont

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Correspondence to Alexander MM Eggermont.

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Grünhagen, D., de Wilt, J., ten Hagen, T. et al. Technology Insight: utility of TNF-α-based isolated limb perfusion to avoid amputation of irresectable tumors of the extremities. Nat Rev Clin Oncol 3, 94–103 (2006). https://doi.org/10.1038/ncponc0426

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