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Isolated Limb Perfusion with Melphalan and Tumour Necrosis Factor α for In-Transit Melanoma and Soft Tissue Sarcoma

  • Bone and Soft Tissue Sarcomas
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Isolated limb perfusion (ILP) is indicated in locally advanced melanoma and soft tissue sarcoma of the extremities. This series reports the outcome of patients undergoing ILP with melphalan and tumour necrosis factor α (TNFα) at a single centre.

Methods

All patients undergoing ILP from January 2005 to January 2015 were identified from a prospectively maintained database. Those undergoing ILP for in-transit melanoma (ITM) were grouped according to disease burden: low volume and bulky (>2 cm diameter).

Results

A total of 143 perfusions were attempted: 9 and 134 in the upper and lower limbs, respectively. A response was assessable in 129 patients with overall response rates for ITM and sarcoma of 81.8 and 61.1 %, respectively. No difference was found in response rates between low-volume and bulky ITM. Limb salvage rates in these cohorts were 97 and 62 %. Regional toxicity following ILP was minimal with 7 grade III (5.4 %), and 1 grade V (0.8 %) reactions. Median progression-free survival was 11 months in the ITM cohort and 12 months in the sarcoma cohort. In the ITM cohort, complete responses were significantly more durable than partial responses (p = 0.0004). Median disease-specific survival was 21 months in the ITM cohort and was not reached in the sarcoma cohort.

Conclusions

TNFα-based ILP is safe and provides excellent palliation of ITM due to rapid progression of systemic disease. It is less effective in sarcoma due to lower initial response rates and a lower incidence of disease dissemination.

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References

  1. Aigner K, Hild P, Henneking K, Paul E, Hundeiker M. Regional perfusion with cis-platinum and dacarbazine: recent results in cancer research. Fortschr Krebsforsch Prog Rech Cancer. 1983;86:239–45.

    CAS  Google Scholar 

  2. Vaglini M, Belli F, Marolda R, Prada A, Santinami M, Cascinelli N. Hyperthermic antiblastic perfusion with DTIC in stage IIIA-IIIAB melanoma of the extremities. Eur J Surg Oncol. 1987;13(2):127–9.

    CAS  PubMed  Google Scholar 

  3. Tjardes T, Neugebauer E. Sepsis research in the next millennium: concentrate on the software rather than the hardware. Shock. 2002;17(1):1–8.

    Article  PubMed  Google Scholar 

  4. de Wilt JH, ten Hagen TL, de Boeck G, van Tiel ST, de Bruijn EA, Eggermont AM. Tumour necrosis factor alpha increases melphalan concentration in tumour tissue after isolated limb perfusion. Br J Cancer. 2000;82(5):1000–3.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Eggermont AM, de Wilt JH, ten Hagen TL. Current uses of isolated limb perfusion in the clinic and a model system for new strategies. Lancet Oncol. 2003;4(7):429–37.

    Article  PubMed  Google Scholar 

  6. Lejeune FJ, Lienard D, Leyvraz S, Mirimanoff RO. Regional therapy of melanoma. Eur J Cancer. 1993;29A(4):606–12.

    Article  CAS  PubMed  Google Scholar 

  7. Cornett WR, McCall LM, Petersen RP, Ross MI, Briele HA, Noyes RD, et al. Randomized multicenter trial of hyperthermic isolated limb perfusion with melphalan alone compared with melphalan plus tumor necrosis factor: American college of surgeons oncology group trial Z0020. J Clin Oncol. 2006;24(25):4196–201.

    Article  CAS  PubMed  Google Scholar 

  8. Hayes AJ, Neuhaus SJ, Clark MA, Thomas JM. Isolated limb perfusion with melphalan and tumor necrosis factor alpha for advanced melanoma and soft-tissue sarcoma. Ann Surg Oncol. 2007;14(1):230–8.

    Article  PubMed  Google Scholar 

  9. Lans TE, de Wilt JH, van Geel AN, Eggermont AM. Isolated limb perfusion with tumor necrosis factor and melphalan for nonresectable Stewart-Treves lymphangiosarcoma. Ann Surg Oncol. 2002;9(10):1004–9.

    Article  CAS  PubMed  Google Scholar 

  10. Grunhagen DJ, de Wilt JH, Graveland WJ, van Geel AN, Eggermont AM. The palliative value of tumor necrosis factor alpha-based isolated limb perfusion in patients with metastatic sarcoma and melanoma. Cancer. 2006;106(1):156–62.

    Article  PubMed  Google Scholar 

  11. Eggermont AM, Schraffordt Koops H, Klausner JM, Kroon BB, Schlag PM, Lienard D, et al. Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas. The cumulative multicenter European experience. Ann Surg. 1996;224(6):756–64 (Discussion 764–765).

  12. Wieberdink J, Benckhuysen C, Braat RP, van Slooten EA, Olthuis GA. Dosimetry in isolation perfusion of the limbs by assessment of perfused tissue volume and grading of toxic tissue reactions. Eur J Cancer Clin Oncol. 1982;18(10):905–10.

    Article  CAS  PubMed  Google Scholar 

  13. Thompson JF, Waugh RC, Saw RP, Kam PC. Isolated limb infusion (ILI) with melphalan for recurrent limb melanoma. Reg Cancer Treat. 1993;6:51–2.

    Google Scholar 

  14. Beasley GM, Caudle A, Petersen RP, McMahon NS, Padussis J, Mosca PJ, et al. A multi-institutional experience of isolated limb infusion: defining response and toxicity in the US. J Am Coll Surg. 2009;208(5):706–15 (Discussion 715–717).

  15. Bonvalot S, Laplanche A, Lejeune F, Stoeckle E, Le Pechoux C, Vanel D, et al. Limb salvage with isolated perfusion for soft tissue sarcoma: could less TNF-alpha be better? Ann Oncol. 2005;16(7):1061–8.

    Article  CAS  PubMed  Google Scholar 

  16. Bonvalot S, Rimareix F, Causeret S, Le Pechoux C, Boulet B, Terrier P, et al. Hyperthermic isolated limb perfusion in locally advanced soft tissue sarcoma and progressive desmoid-type fibromatosis with TNF 1 mg and melphalan (T1-M HILP) is safe and efficient. Ann Surg Oncol. 2009;16(12):3350–7.

    Article  PubMed  Google Scholar 

  17. Brady MS, Brown K, Patel A, Fisher C, Marx W. A phase II trial of isolated limb infusion with melphalan and dactinomycin for regional melanoma and soft tissue sarcoma of the extremity. Ann Surg Oncol. 2006;13(8):1123–9.

    Article  PubMed  Google Scholar 

  18. Deroose JP, Eggermont AM, van Geel AN, Burger JW, den Bakker MA, de Wilt JH, et al. Long-term results of tumor necrosis factor alpha- and melphalan-based isolated limb perfusion in locally advanced extremity soft tissue sarcomas. J Clin Oncol. 2011;29(30):4036–44.

    Article  CAS  PubMed  Google Scholar 

  19. Kroon HM, Moncrieff M, Kam PC, Thompson JF. Outcomes following isolated limb infusion for melanoma: a 14-year experience. Ann Surg Oncol. 2008;15(11):3003–13.

    Article  PubMed  Google Scholar 

  20. Lindner P, Doubrovsky A, Kam PC, Thompson JF. Prognostic factors after isolated limb infusion with cytotoxic agents for melanoma. Ann Surg Oncol. 2002;9(2):127–36.

    Article  PubMed  Google Scholar 

  21. Moncrieff MD, Kroon HM, Kam PC, Stalley PD, Scolyer RA, Thompson JF. Isolated limb infusion for advanced soft tissue sarcoma of the extremity. Ann Surg Oncol. 2008;15(10):2749–56.

    Article  PubMed  Google Scholar 

  22. Noorda EM, Vrouenraets BC, Nieweg OE, van Geel AN, Eggermont AM, Kroon BB. Safety and efficacy of isolated limb perfusion in elderly melanoma patients. Ann Surg Oncol. 2002;9(10):968–74.

    Article  CAS  PubMed  Google Scholar 

  23. Alexander HR, Jr., Fraker DL, Bartlett DL, Libutti SK, Steinberg SM, Soriano P, et al. Analysis of factors influencing outcome in patients with in-transit malignant melanoma undergoing isolated limb perfusion using modern treatment parameters. J Clin Oncol. 2010;28(1):114–8.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Aloia TA, Grubbs E, Onaitis M, Mosca PJ, Cheng TY, Seigler H, et al. Predictors of outcome after hyperthermic isolated limb perfusion: role of tumor response. Arch Surg. 2005;140(11):1115–20.

    Article  PubMed  Google Scholar 

  25. Lienard D, Eggermont AM, Koops HS, Kroon B, Towse G, Hiemstra S, et al. Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases: a multicentre randomized phase II study. Melanoma Res. 1999;9(5):491–502.

    Article  CAS  PubMed  Google Scholar 

  26. Raymond AK, Beasley GM, Broadwater G, Augustine CK, Padussis JC, Turley R, et al. Current trends in regional therapy for melanoma: lessons learned from 225 regional chemotherapy treatments between 1995 and 2010 at a single institution. J Am Coll Surg. 2011;213(2):306–16.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Bonvalot S, Gronchi A. ILP and RT: the study that will never be. Ann Surg Oncol. 2011;18(2):303–5.

    Article  PubMed  Google Scholar 

  28. Folkert MR, Singer S, Brennan MF, Kuk D, Qin LX, Kobayashi WK, et al. Comparison of local recurrence with conventional and intensity-modulated radiation therapy for primary soft-tissue sarcomas of the extremity. J Clin Oncol. 2014;32(29):3236-41.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Hall EJ, Wuu CS. Radiation-induced second cancers: the impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys. 2003;56(1):83–8.

    Article  PubMed  Google Scholar 

  30. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.

    Article  CAS  PubMed  Google Scholar 

  31. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17.

    Article  PubMed  Google Scholar 

  32. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30.

    Article  CAS  PubMed  Google Scholar 

  33. Prieto PA, Yang JC, Sherry RM, Hughes MS, Kammula US, White DE, et al. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res. 2012;18(7):2039–47.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. The Sarcoma and Melanoma Units, The Department of Academic Surgery, The Royal Marsden Hospital NHS Foundation Trust, London, UK

    H. G. Smith MRCS, J. Cartwright MRCS, M. J. Wilkinson MRCS, D. C. Strauss FRCS, J. M. Thomas FRCS & A. J. Hayes FRCS, PhD

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  1. H. G. Smith MRCS
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  2. J. Cartwright MRCS
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  3. M. J. Wilkinson MRCS
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  4. D. C. Strauss FRCS
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  5. J. M. Thomas FRCS
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  6. A. J. Hayes FRCS, PhD
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Correspondence to H. G. Smith MRCS.

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Smith, H.G., Cartwright, J., Wilkinson, M.J. et al. Isolated Limb Perfusion with Melphalan and Tumour Necrosis Factor α for In-Transit Melanoma and Soft Tissue Sarcoma. Ann Surg Oncol 22 (Suppl 3), 356–361 (2015). https://doi.org/10.1245/s10434-015-4856-x

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  • DOI: https://doi.org/10.1245/s10434-015-4856-x

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