Skip to main content

Advertisement

Log in

Isolated Limb Perfusion for Melanoma is Safe and Effective in Elderly Patients

  • Melanomas
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Data on isolated limb perfusion (ILP) in elderly melanoma patients are scarce. We aimed to evaluate the efficacy and safety of ILP in our institutional cohort of melanoma patients.

Methods

We performed retrospective analysis of stage IIIB/C melanoma patients who underwent ILP for melanoma in-transit metastases (ITMs) in our institution between 2000 and 2016. Normothermic ILP was performed with either melphalan or melphalan and tumor necrosis factor. Baseline and treatment characteristics, locoregional progression-free survival (LPFS) and melanoma-specific survival (MSS) were assessed and prognostic factors for response, recurrence, and survival were analyzed using univariable and multivariable analysis.

Results

Overall, 91 patients were included in this study. Based on the median age of 70 years, we split patients into younger and elderly groups. No differences in response rates were observed between age groups, with an overall response rate of 81% and complete response (CR) rate of 47%. LPFS did not differ between age groups, and median LPFS was 16 months for patients with a CR. Median MSS was 38 months and differed between younger (45 months) and elderly patients (18 months). Toxicity was generally mild and did not differ between age groups. Two patients (2.2%) suffered Wieberdink IV toxicity, while no patients required amputation because of severe toxicity. CR was prognostic for improved LPFS and MSS, while patients >70 years of age and patients with stage IIIC disease had a higher risk of melanoma-specific death.

Conclusions

Because of its safety profile and high CR rates, ILP is a viable option for patients with bulky or multiple melanoma ITMs, including elderly (>70 years of age) patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Read RL, Haydu L, Saw RP, Quinn MJ, Shannon K, Spillane AJ, et al. In-transit melanoma metastases: incidence, prognosis, and the role of lymphadenectomy. Ann Surg Oncol. 2015;22(2):475–81.

    Article  PubMed  Google Scholar 

  2. Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355(13):1307–17.

    Article  CAS  PubMed  Google Scholar 

  3. Grunhagen 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:e528–34.

  4. Nieweg OE, Kroon BB. Isolated limb perfusion with melphalan for melanoma. J Surg Oncol. 2014;109(4):332–7.

    Article  PubMed  Google Scholar 

  5. Moreno-Ramirez D, de la Cruz-Merino L, Ferrandiz L, Villegas-Portero R, Nieto-Garcia A. Isolated limb perfusion for malignant melanoma: systematic review on effectiveness and safety. Oncologist. 2010;15(4):416–27.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199–206.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Noorda EM, Takkenberg B, Vrouenraets BC, Nieweg OE, van Geel BN, Eggermont AM, et al. Isolated limb perfusion prolongs the limb recurrence-free interval after several episodes of excisional surgery for locoregional recurrent melanoma. Ann Surg Oncol. 2004;11(5):491–9.

    Article  PubMed  Google Scholar 

  8. 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 

  9. Noorda EM, Vrouenraets BC, Nieweg OE, van Geel AN, Eggermont AM, Kroon BB. Repeat isolated limb perfusion with TNFalpha and melphalan for recurrent limb melanoma after failure of previous perfusion. Eur J Surg Oncol. 2006;32(3):318–24.

    Article  CAS  PubMed  Google Scholar 

  10. Noorda EM, Vrouenraets BC, Nieweg OE, van Geel BN, Eggermont AM, Kroon BB. Isolated limb perfusion for unresectable melanoma of the extremities. Arch Surg. 2004;139(11):1237–42.

    Article  PubMed  Google Scholar 

  11. Klaase JM, Kroon BB, van Geel AN, van Wijk J, Franklin HR, Eggermont AM, et al. Limb recurrence-free interval and survival in patients with recurrent melanoma of the extremities treated with normothermic isolated perfusion. J Am Coll Surg. 1994;178(6):564–72.

    CAS  PubMed  Google Scholar 

  12. Klaase JM, Kroon BB, van Geel AN, Eggermont AM, Franklin HR, van Dongen JA. Is there an indication for a double perfusion schedule with melphalan for patients with recurrent melanoma of the limbs? Melanoma Res. 1994;4 Suppl 1:13–6.

    PubMed  Google Scholar 

  13. Dossett LA, Ben-Shabat I, Olofsson Bagge R, Zager JS. clinical response and regional toxicity following isolated limb infusion compared with isolated limb perfusion for in-transit melanoma. Ann Surg Oncol. 2016;23(7):2330–5.

    Article  PubMed  Google Scholar 

  14. Smith HG, Cartwright J, Wilkinson MJ, Strauss DC, Thomas JM, Hayes AJ. Isolated limb perfusion with melphalan and tumour necrosis factor alpha for in-transit melanoma and soft tissue sarcoma. Ann Surg Oncol. 2015;22 Suppl 3:S356–61.

    Article  PubMed  Google Scholar 

  15. Paulsen IF, Chakera AH, Drejoe JB, Klyver H, Dahlstrom K, Oturai PS, et al. Tumour response after hyperthermic isolated limb perfusion for locally advanced melanoma. Dan Med J. 2014;61(1):A4741.

    PubMed  Google Scholar 

  16. Olofsson R, Mattsson J, Lindner P. Long-term follow-up of 163 consecutive patients treated with isolated limb perfusion for in-transit metastases of malignant melanoma. Int J Hyperth. 2013;29(6):551–7.

    Article  CAS  PubMed  Google Scholar 

  17. Deroose JP, Grunhagen DJ, van Geel AN, de Wilt JH, Eggermont AM, Verhoef C. Long-term outcome of isolated limb perfusion with tumour necrosis factor-alpha for patients with melanoma in-transit metastases. Br J Surg. 2011;98(11):1573–80.

    Article  CAS  PubMed  Google Scholar 

  18. 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  PubMed Central  Google Scholar 

  19. 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  Google Scholar 

  20. 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 

  21. Hoekstra HJ, Veerman K, van Ginkel RJ. Isolated limb perfusion for in-transit melanoma metastases: melphalan or TNF-melphalan perfusion? J Surg Oncol. 2014;109(4):338–47.

    Article  CAS  PubMed  Google Scholar 

  22. Pace M, Gattai R, Mascitelli EM, Millanta L. Results of isolated lower limb perfusion for loco-regional advanced/recurrent melanoma using borderline true hyperthermia plus additional bolus of melphalan. A critical analysis of homogeneous cases. J Surg Oncol. 2011;104(7):718–23.

    Article  PubMed  Google Scholar 

  23. Rossi CR, Pasquali S, Mocellin S, Vecchiato A, Campana LG, Pilati P, et al. Long-term results of melphalan-based isolated limb perfusion with or without low-dose TNF for in-transit melanoma metastases. Ann Surg Oncol. 2010;17(11):3000–7.

    Article  PubMed  Google Scholar 

  24. Deroose JP, Eggermont AM, van Geel AN, de Wilt JH, Burger JW, Verhoef C. 20 years experience of TNF-based isolated limb perfusion for in-transit melanoma metastases: TNF dose matters. Ann Surg Oncol. 2012;19(2):627–35.

    Article  PubMed  Google Scholar 

  25. Deroose JP, Grunhagen DJ, Eggermont AM, Verhoef C. Repeated isolated limb perfusion in melanoma patients with recurrent in-transit metastases. Melanoma Res. 2015;25(5):427–31.

    Article  CAS  PubMed  Google Scholar 

  26. Lidsky ME, Turley RS, Beasley GM, Sharma K, Tyler DS. Predicting disease progression after regional therapy for in-transit melanoma. JAMA Surg. 2013;148(6):493–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Boesch CE, Meyer T, Waschke L, Merkel S, Goehl J, Hohenberger W, et al. Long-term outcome of hyperthermic isolated limb perfusion (HILP) in the treatment of locoregionally metastasised malignant melanoma of the extremities. Int J Hyperth. 2010;26(1):16–20.

    Article  PubMed  Google Scholar 

  28. Sharma K, Beasley G, Turley R, Raymond AK, Broadwater G, Peterson B, et al. Patterns of recurrence following complete response to regional chemotherapy for in-transit melanoma. Ann Surg Oncol. 2012;19(8):2563–71.

    Article  PubMed  Google Scholar 

  29. Grunhagen DJ, Brunstein F, Graveland WJ, van Geel AN, de Wilt JH, Eggermont AM. One hundred consecutive isolated limb perfusions with TNF-alpha and melphalan in melanoma patients with multiple in-transit metastases. Ann Surg. 2004;240(6):939–47; discussion 47–8.

  30. Brobeil A, Berman C, Cruse CW, De Conti R, Cantor A, Lyman GH, et al. Efficacy of hyperthermic isolated limb perfusion for extremity-confined recurrent melanoma. Ann Surg Oncol. 1998;5(4):376–83.

    Article  CAS  PubMed  Google Scholar 

  31. 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(4):348–51.

    Article  CAS  PubMed  Google Scholar 

  32. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.

  34. 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 

  35. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus Ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32.

    Article  CAS  PubMed  Google Scholar 

  36. Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(13):1270–1.

    Article  PubMed  Google Scholar 

  37. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–16.

    Article  CAS  Google Scholar 

  38. 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 

  39. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240(2):205–13.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Disclosures

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alexander C. J. van Akkooi MD, PhD.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 17 kb)

Supplementary material 2 (DOCX 13 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Madu, M.F., Deken, M.M., van der Hage, J.A. et al. Isolated Limb Perfusion for Melanoma is Safe and Effective in Elderly Patients. Ann Surg Oncol 24, 1997–2005 (2017). https://doi.org/10.1245/s10434-017-5803-9

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-017-5803-9

Keywords

Navigation