Melanoma pp 451-465 | Cite as

Isolated Limb Infusion for Recurrent and Locally Metastatic Limb Melanoma

  • Hidde M. Kroon
  • Anna M. Huismans
  • Brendon J. Coventry
  • John F. Thompson


Recurrent and metastatic melanoma confined to a limb is a frequently encountered clinical problem in patients with initial primary limb melanoma. Regional chemotherapy using isolated limb perfusion (ILP) provides effective treatment, but is invasive, complex, and costly. Isolated limb infusion (ILI) chemotherapy is a simple, minimally invasive, and effective alternative to ILP.

ILI involves drug administration into a limb via percutaneously inserted catheters after vascular isolation of the limb with a tourniquet. The infused drugs, normally melphalan and actinomycin D, are circulated for 30 minutes via a simple extracorporeal circuit incorporating a heater to produce mild hyperthermia of the limb, but with no oxygenation.

Limb tumor remission rates following ILI are similar to those achieved by conventional ILP. ILI is well tolerated and, in contrast to ILP, elderly patients and those with major medical comorbidities and peripheral vascular disease can be treated with satisfactory results.

The development of effective systemic treatment options for patients with melanoma in the past decade has provided new melanoma therapy options. However, the response and control rates of ILI are still superior to those achieved following systemic therapy. Nevertheless, there is great potential value in combining regionally applied ILI with systemically administered agents to achieve an optimal and sustained response, and clinical trials of combined regional and systemic therapies are in progress.


Melanoma Metastasis Extremity Unresectable Isolated limb infusion Melphalan Actinomycin D 


  1. 1.
    Creech O Jr, Krementz ET, Ryan RF, Winblad JN. Chemotherapy of cancer: regional perfusion utilizing an extracorporeal circuit. Ann Surg. 1958;148:616–32.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Vrouenraets BC, Nieweg OE, Kroon BB. Thirty-five years of isolated limb perfusion for melanoma: indications and results. Br J Surg. 1996;83:1319–28.CrossRefPubMedGoogle Scholar
  3. 3.
    Schraffordt Koops H, Lejeune FJ, Kroon BBR, Klaase JM, Hoekstra HJ. Isolated limb perfusion for melanoma: technical aspects. In: Thompson JF, Morton DL, Kroon BBR, editors. Textbook of melanoma. London: Martin Dunitz; 2004. p. 404–9.Google Scholar
  4. 4.
    Sanki A, Kroon HM, Kam PCA, Thompson JF. Isolated limb perfusion and isolated limb infusion for malignant lesions of the extremities. Curr Probl Surg. 2011;48:371–430.CrossRefPubMedGoogle Scholar
  5. 5.
    Noorda EM, Vrouenraets BC, Nieweg OE, Van Coevorden F, Kroon BB. Isolated limb perfusion: what is the evidence for its use? Ann Surg Oncol. 2004;11:837–45.CrossRefPubMedGoogle Scholar
  6. 6.
    Moreno-Ramirez D, de la Cruz-Merino L, Ferrandiz L, et al. Isolated limb perfusion for malignant melanoma: systematic review on effectiveness and safety. Oncologist. 2010;15:416–27.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Karakousis CP, Kanter PM, Lopez R, Moore R, Holyoke ED. Modes of regional chemotherapy. J Surg Res. 1979;26:134–41.CrossRefPubMedGoogle Scholar
  8. 8.
    Bland KI, Kimura AK, Brenner DE, et al. A phase II study of the efficacy of diamminedichloroplatinum (cisplatin) for the control of locally recurrent and intransit malignant melanoma of the extremities using tourniquet outflow-occlusion techniques. Ann Surg. 1989;209:73–80.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Karakousis CP, Kanter PM, Park HC, Sharma SD, Moore R, Ewing JH. Tourniquet infusion versus hyperthermic perfusion. Cancer. 1982;49:850–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Thompson JF, Waugh RC, Saw RP, Kam PC. Isolated limb infusion with melphalan for recurrent limb melanoma: a simple alternative to isolated limb perfusion. Reg Cancer Treat. 1994;7:188–92.Google Scholar
  11. 11.
    Thompson JF, Kam PC, Waugh RC, Harman CR. Isolated limb infusion with cytotoxic agents: a simple alternative to isolated limb perfusion. Semin Surg Oncol. 1998;14:238–47.CrossRefPubMedGoogle Scholar
  12. 12.
    Kroon HM, Coventry BJ, Giles MH, et al. Australian multi-center study of isolated limb infusion for melanoma. Ann Surg Oncol. 2016;23:1096–103.CrossRefPubMedGoogle Scholar
  13. 13.
    Beasley GM, Caudle A, Petersen RP, et al. A multi-institutional experience of isolated limb infusion: defining response and toxicity in the US. J Am Coll Surg. 2009;208:706–15.CrossRefPubMedGoogle Scholar
  14. 14.
    Cecchini S, Sarti D, Ricci S, et al. Isolated limb infusion chemotherapy with or without hemofiltration for recurrent limb melanoma. World J Clin Oncol. 2015;6:57–63.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kroon HM, Huismans AM, Kam PCA, Thompson JF. Isolated limb infusion: technical aspects. J Surg Oncol. 2014;109:352–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Beasley G, Kroon HM, Ross M, Kam PCA, Thompson JF, Tyler D. Isolated limb infusion for melanoma (Chapter 27). In: Balch C, Houghton AN, Sober AJ, Soong SJ, Atkins MB, Thompson FJ, editors. Cutaneous melanoma. 5th ed. St. Louis, MO: Quality Medical Publishing Inc.; 2009. p. 541–60. ISBN: 978-1-57626-276-4.Google Scholar
  17. 17.
    Koops HS, Vaglini M, Suciu S, et al. Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. EORTC Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol. 1998;16:2906–12.CrossRefPubMedGoogle Scholar
  18. 18.
    Kroon HM, Coventry BJ, Giles MH, Henderson MA, Speakman D, Wall M, Barbour A, Serpell J, Paddle P, Smithers BM, Thompson JF. Safety and efficacy of isolated limb infusion chemotherapy for advanced locoregional melanoma in elderly patients: an Australian multicenter study. Ann Surg Oncol. 2017;24:3245–51.CrossRefPubMedGoogle Scholar
  19. 19.
    Kroon HM, Lin DY, Kam PC, Thompson JF. Safety and efficacy of isolated limb infusion with cytotoxic drugs in elderly patients with advanced locoregional melanoma. Ann Surg. 2009;246:1008–13.CrossRefGoogle Scholar
  20. 20.
    Madu MF, Deken MM, van der Hage JA, Jóźwiak K, Wouters MW, van Akkooi AC. Isolated limb perfusion for melanoma is safe and effective in elderly patients. Ann Surg Oncol. 2017;24:1997–2005.CrossRefPubMedGoogle Scholar
  21. 21.
    Noorda EM, Vrouenraets BC, Nieweg OE, et al. Safety and efficacy of isolated limb perfusion in elderly melanoma patients. Ann Surg Oncol. 2002;9:968–74.CrossRefPubMedGoogle Scholar
  22. 22.
    Kroon HM, Lin DY, Kam PC, Thompson JF. Isolated limb infusion as palliative treatment for advanced limb disease in patients with AJCC stage IV melanoma. Ann Surg Oncol. 2009;16:1193–201.CrossRefPubMedGoogle Scholar
  23. 23.
    Takkenberg RB, Vrouenraets BC, van Geel AN, et al. Palliative isolated limb perfusion for advanced limb disease in stage IV melanoma patients. J Surg Oncol. 2005;91:107–11.CrossRefPubMedGoogle Scholar
  24. 24.
    Wieberdink J, Benckhuysen C, Braat RP, et al. 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;18:905–10.CrossRefPubMedGoogle Scholar
  25. 25.
    Beasley GM, Petersen RP, Yoo J, et al. Isolated limb infusion for in-transit malignant melanoma of the extremity: a well-tolerated but less effective alternative to hyperthermic isolated limb perfusion. Ann Surg Oncol. 2008;15:2195–205.CrossRefPubMedGoogle Scholar
  26. 26.
    Brys AK, Bhatti L, Bashir MR, et al. Computed tomography based limb volume measurements for isolated limb infusion in melanoma. Ann Surg Oncol. 2016;23:1090–5.CrossRefPubMedGoogle Scholar
  27. 27.
    Siemann DW, Chapman M, Beikirch A. Effects of oxygenation and pH on tumor cell response to alkylating chemotherapy. Int J Radiat Oncol Biol Phys. 1991;20:287–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Kroon HM, Thompson JF. Isolated limb infusion: a review. J Surg Oncol. 2009;100:169–77.CrossRefPubMedGoogle Scholar
  29. 29.
    Thompson JF, Ramzan I, Kam PCA, Yau DF. Pharmacokinetics of melphalan during isolated limb infusion for melanoma. Reg Cancer Treat. 1996;9:13–6.Google Scholar
  30. 30.
    Skarsgard LD, Skwarchuk MW, Vinczan A, Kristl J, Chaplin DJ. The cytotoxicity of melphalan and its relationship to pH, hypoxia and drug uptake. Anticancer Res. 1995;15:219–23.PubMedGoogle Scholar
  31. 31.
    Lindner P, Doubrovsky A, Kam PCA, et al. Prognostic factors after isolated limb infusion with cytotoxic agents for melanoma. Ann Surg Oncol. 2002;9:127–36.CrossRefPubMedGoogle Scholar
  32. 32.
    Kroon HM, Moncrieff M, Kam PC, et al. Outcomes following isolated limb infusion. A 14-year experience. Ann Surg Oncol. 2008;15:3003–13.CrossRefPubMedGoogle Scholar
  33. 33.
    Kroon HM, Moncrieff M, Kam PC, Thompson JF. Factors predictive of acute regional toxicity after isolated limb infusion with melphalan and actinomycin D in melanoma patients. Ann Surg Oncol. 2009;16:1184–92.CrossRefPubMedGoogle Scholar
  34. 34.
    Wu ZY, Smithers BM, Parsons PG, Roberts MS. The effects of perfusion conditions on melphalan distribution in the isolated perfused rat hindlimb bearing a human melanoma xenograft. Br J Cancer. 1997;75:1160–6.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Roberts MS, Wu ZY, Siebert GA, Thompson JF, Smithers BM. Saturable dose-response relationships for melphalan in melanoma treatment by isolated limb infusion in the nude rat. Melanoma Res. 2001;11:611–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Cheng TY, Grubbs E, Abdul-Wahab O, et al. Marked variability of melphalan plasma drug levels during regional hyperthermic isolated limb perfusion. Am J Surg. 2003;186:460–7.CrossRefPubMedGoogle Scholar
  37. 37.
    McMahon N, Cheng TY, Beasley GM, et al. Optimizing melphalan pharmacokinetics in regional melanoma therapy: does correcting for ideal body weight alter regional response or toxicity? Ann Surg Oncol. 2009;16:953–61.CrossRefPubMedGoogle Scholar
  38. 38.
    Klaase JM, Kroon BB, Beijnen JH, van Slooten GW, van Dongen JA. Melphalan tissue concentrations in patients treated with regional isolated perfusion for melanoma of the lower limb. Br J Cancer. 1994;70:151–3.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Wong J, Chen YA, Fisher KJ, Beasley GM, Tyler DS, Zager JS. Resection of residual disease after isolated limb infusion (ILI) is equivalent to a complete response after ILI-alone in advanced extremity melanoma. Ann Surg Oncol. 2014;21:650–5.CrossRefPubMedGoogle Scholar
  40. 40.
    Huismans AM, Kroon HM, Haydu LE, Kam PC, Thompson JF. Is melphalan dose adjustment according to ideal body weight useful in isolated limb infusion for melanoma? Ann Surg Oncol. 2012;19:3050–6.CrossRefPubMedGoogle Scholar
  41. 41.
    Santillan AA, Delman KA, Beasley GM, et al. Predictive factors of regional toxicity and serum creatine phosphokinase levels after isolated limb infusion for melanoma: a multi-institutional analysis. Ann Surg Oncol. 2009;16:2570–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Kroon HM, Huismans AM, Kam PC, Thompson JF. Isolated limb infusion with melphalan and actinomycin D for melanoma: a systematic review. J Surg Oncol. 2014;109:348–51.CrossRefPubMedGoogle Scholar
  43. 43.
    Jiang BS, Speicher PJ, Thomas S, Mosca PJ, Abernethy AP, Tyler DS. Quality of life after isolated limb infusion for in-transit melanoma of the extremity. Ann Surg Oncol. 2015;22:1694–700.CrossRefPubMedGoogle Scholar
  44. 44.
    Huismans AM, Kroon HM, Kam PC, Thompson JF. Does increased experience with isolated limb infusion for advanced limb melanoma influence outcome? A comparison of two treatment periods at a single institution. Ann Surg Oncol. 2011;18:1877–83.CrossRefPubMedGoogle Scholar
  45. 45.
    World Health Organization. WHO handbook for reporting results of cancer treatments (WHO offset publication no. 48). Geneva: World Health Organization; 1979.Google Scholar
  46. 46.
    Barbour AP, Thomas J, Suffolk J, et al. Isolated limb infusion for malignant melanoma: predictors of response and outcome. Ann Surg Oncol. 2009;16:3463–72.CrossRefPubMedGoogle Scholar
  47. 47.
    Grünhagen DJ, Kroon HM, Verhoef C. Perfusion and infusion for melanoma in-transit metastases in the era of effective systemic therapy. Am Soc Clin Oncol Educ Book. 2015;35:e528–34.CrossRefGoogle Scholar
  48. 48.
    Coventry BJ, Kroon HM, Giles MH, et al. Australian multi-center experience outside of the Sydney Melanoma Unit of isolated limb infusion chemotherapy for melanoma. J Surg Oncol. 2014;109:780–5.CrossRefPubMedGoogle Scholar
  49. 49.
    Raymond AK, Beasley GM, Broadwater G, 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;213:306–16.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Kroon HM, Lin DY, Kam PC, Thompson JF. Efficacy of repeat isolated limb infusion with melphalan and actinomycin D for recurrent melanoma. Cancer. 2009;115:1932–40.CrossRefPubMedGoogle Scholar
  51. 51.
    Beasley GM, Sharma K, Wong J, Miller M, Turley RS, Lidsky M, Masoud M, Dewhirst MW, Mosca PJ, Zager JS, Tyler DS. A multi-institution experience comparing the clinical and physiologic differences between upper extremity and lower extremity melphalan-based isolated limb infusion. Cancer. 2012;118:6136–43.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Ueno T, Ko SH, Grubbs E, et al. Modulation of chemotherapy resistance in regional therapy: a novel therapeutic approach to advanced extremity melanoma using intra-arterial temozolomide in combination with systemic O6-benzylguanine. Mol Cancer Ther. 2006;5:732–8.CrossRefPubMedGoogle Scholar
  53. 53.
    Beasley GM, Speicher P, Augustine CK, et al. A multicenter phase I dose escalation trial to evaluate safety and tolerability of intra-arterial temozolomide for patients with advanced extremity melanoma using normothermic isolated limb infusion. Ann Surg Oncol. 2015;22:287–94.CrossRefPubMedGoogle Scholar
  54. 54.
    Testori A, Faries MB, Thompson JF, et al. Local and intralesional therapy of in-transit melanoma metastases. J Surg Oncol. 2011;104:391–6.CrossRefPubMedGoogle Scholar
  55. 55.
    Thompson JF, Agarwala SS, Smithers BM, et al. Phase 2 study of intralesional PV-10 in refractory metastatic melanoma. Ann Surg Oncol. 2015;22:2135–42.CrossRefPubMedGoogle Scholar
  56. 56.
    Feldman AL, Alexander HR Jr, Bartlett DL, Fraker DL, Libutti SK. Management of extremity recurrences after complete responses to isolated limb perfusion in patients with melanoma. Ann Surg Oncol. 1999;6:562–7.CrossRefPubMedGoogle Scholar
  57. 57.
    Hegazy MA, Kotb SZ, Sakr H, et al. Preoperative isolated limb infusion of doxorubicin and external irradiation for limb-threatening soft tissue sarcomas. Ann Surg Oncol. 2007;14:568–76.CrossRefPubMedGoogle Scholar
  58. 58.
    Menzies AM, Long GV. Recent advances in melanoma systemic therapy. BRAF inhibitors, CTLA4 antibodies and beyond. Eur J Cancer. 2013;49:3229–41.CrossRefPubMedGoogle Scholar
  59. 59.
    Menzies AM, Long GV. Recent developments in melanoma therapy. JAMA Oncol. 2016;2:1259–60.CrossRefPubMedGoogle Scholar
  60. 60.
    Beasley GM, Riboh JC, Augustine CK, et al. Prospective multicenter phase II trial of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with advanced extremity melanoma. J Clin Oncol. 2011;29:1210–5.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Turley RS, Fontanella AN, Padussis JC, et al. Bevacizumab-induced alterations in vascular permeability and drug delivery: a novel approach to augment regional chemotherapy for in-transit melanoma. Clin Cancer Res. 2012;18:3328–39.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Mian R, Henderson MA, Speakman D, et al. Isolated limb infusion for melanoma: a simple alternative to isolated limb perfusion. Can J Surg. 2001;44:189–92.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Marsden J, Samarasinghe V, Duddy M, et al. Regional chemotherapy for inoperable limb cancer using isolated limb infusion. Br J Dermatol. 2008;159:10.Google Scholar
  64. 64.
    Duprat Neto JP, Mauro AC, Molina AS, et al. Isolated limb infusion with hyperthermia and chemotherapy for advanced malignancy: factors influencing toxicity. ANZ J Surg. 2014;84:677–82.CrossRefPubMedGoogle Scholar
  65. 65.
    Wong J, Chen YA, Fisher KJ, et al. Isolated limb infusion in a series of over 100 infusions: a single‐center experience. Ann Surg Oncol. 2013;20:1121–7.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Coventry BJ, Kroon HM, Giles MH, Henderson M, Speakman D, Wall M, Barbour A, Serpell J, Paddle P, Coventry AG, Sullivan T, Smithers BM. Multi-center experience outside of the Sydney Melanoma Unit of isolated limb infusion chemotherapy for melanoma. J Surg Oncol. 2014;109:780–5.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Hidde M. Kroon
    • 1
    • 2
  • Anna M. Huismans
    • 1
  • Brendon J. Coventry
    • 3
  • John F. Thompson
    • 1
  1. 1.Melanoma Institute AustraliaThe University of SydneySydneyAustralia
  2. 2.Department of General SurgeryFlinders Medical CentreAdelaideAustralia
  3. 3.Department of Surgery, Royal Adelaide HospitalUniversity of AdelaideAdelaideAustralia

Personalised recommendations