Skip to main content
SpringerLink
Log in

Safety and Efficacy of Isolated Limb Infusion Chemotherapy for Advanced Locoregional Melanoma in Elderly Patients: An Australian Multicenter Study

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

Abstract

Background

Isolated limb infusion (ILI) offers a minimally invasive treatment option for locally advanced extremity melanoma.

Objective

The aim of the current study was to evaluate the safety and efficacy of ILI in elderly patients in an Australian multicenter setting.

Methods

The results of 316 first ILI procedures, performed between 1992 and 2008 in five Australian institutions, were identified and analyzed, with the main focus on elderly patients (≥75 years of age). All institutions used the same protocol: melphalan was circulated in the isolated limb for 20–30 min (±actinomycin D), and toxicity, responses, and survival were recorded.

Results

Characteristics of patients aged ≥75 years (n = 148) were similar to those aged <75 years (n = 168), except that older patients had more melanoma deposits (median 4 vs. 5; p = 0.035) and lower limb volumes (5.4 vs. 6.5 L; p = 0.001). Median drug circulation times were lower in the older group (21 vs. 24 min; p = 0.04), and older patients experienced less limb toxicity (grade III/IV in 22 and 37% of patients, respectively; p = 0.003). A complete response (CR) was seen in 27% of patients aged ≥75 years and in 38% of patients aged <75 years (p = 0.06), while overall response rates were 72 and 77%, respectively (p = 0.30). No difference in survival was seen (p = 0.69).

Conclusions

The ILI technique proved safe and effective in elderly patients. When present, toxicity was localized, and lower compared with younger patients, possibly due to shorter drug circulation times. CR rates were higher in younger patients, although not significantly, while overall response and survival were equal. Optimization of perioperative factors in elderly patients may allow response rates to be raised further, while maintaining low toxicity.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Adapted from Giles and Coventry14

Fig. 2

Similar content being viewed by others

References

  1. Whiteman DC, Green AC, Olsen CM. The growing burden of invasive melanoma: Projections of incidence rates and numbers of new cases in six susceptible populations through 2031. J Invest Dermatol. 2016;136:1161–71.

    Article  CAS  PubMed  Google Scholar 

  2. Lasithiotakis KG, Petrakis IE, Garbe C. Cutaneous melanoma in the elderly: epidemiology, prognosis and treatment. Melanoma Res. 2010;20:163–70.

    PubMed  Google Scholar 

  3. Vrouenraets BC, Nieweg OE, Kroon BBR. Thirty-five years of isolated limb perfusion for melanoma: indications and results. Br J Surg. 1996;83:1319–28.

    Article  CAS  PubMed  Google Scholar 

  4. Moreno-Ramirez D, de la Cruz-Merino L, Ferrandiz L, et al. Isolated limb perfusion for malignant melanoma: systematicreview on effectiveness and safety. Oncologist. 2010;15:416–27.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Vrouenraets BC, Klaase JM, Nieweg OE, et al. Toxicity and morbidity of isolated limb perfusion. Semin Surg Oncol. 1998;14:224–31.

    Article  CAS  PubMed  Google Scholar 

  6. McMasters KM. Isolated limb perfusion in elderly melanoma patients. Ann Surg Oncol. 2002;9:939–40.

    Article  PubMed  Google Scholar 

  7. Van Etten B, van Geel AN, de Wilt JH, et al. Fifty tumor necrosis factorbased isolated limb perfusions for limb salvage in patients older than 75 years with limb-threatening soft tissue sarcomas and other extremity tumors. Ann Surg Oncol. 2003;10:32–7.

    Article  PubMed  Google Scholar 

  8. Thompson JF, Kam PC, Waugh RC, et al. Isolated limb infusion with cytotoxic agents: a simple alternative to isolated limb perfusion. Semin Surg Oncol. 1998;14:238–47.

    Article  CAS  PubMed  Google Scholar 

  9. 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.

    Article  Google Scholar 

  10. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27:6199–206.

    Article  PubMed  PubMed Central  Google Scholar 

  11. 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.

    Article  CAS  PubMed  Google Scholar 

  12. Thompson JF, Kam PCA, de Wilt JHW, et al. Isolated limb infusion for melanoma. In: Thompson JF, Morton DL, Kroon BBR (eds). Textbook of melanoma. London: Martin Dunitz; 2004. pp. 429–37.

    Google Scholar 

  13. Kroon HM, Huismans AM, Kam PCA, et al. Isolated limb infusion: technical aspects. J Surg Oncol. 2014;109:352–6.

    Article  PubMed  Google Scholar 

  14. Giles MH, Coventry BJ. Isolated limb infusion chemotherapy for melanoma: an overview of early experience at the Adelaide Melanoma Unit. Cancer Manag Res. 2013;5:243–9.

    PubMed  PubMed Central  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. Lai DTM, Ingvar C, Thompson JF. The value of monitoring serum creatine phosphokinase values following hyperthermic isolated limb perfusion for melanoma. Reg Cancer Treat 1993;6:36–9.

    Google Scholar 

  17. World Health Organization. WHO handbook for reporting results of cancer treatments. WHO Offset Publication No. 48. Geneva: World Health Organization; 1979.

    Google Scholar 

  18. Kaplan L, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1985;53:457–81.

    Article  Google Scholar 

  19. Cox DR. Regression models and life table. J Stat Soc. 1972;34:187–220.

    Google Scholar 

  20. 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;240:205–13.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Testori A, Soteldo J, Sances D, et al. Cutaneous melanoma in the elderly. Melanoma Res. 2009;19:125–34.

    Article  PubMed  Google Scholar 

  22. Zenilman ME. Surgery in the elderly. Curr Probl Surg. 1998;35:99–179.

    Article  CAS  PubMed  Google Scholar 

  23. Thompson JF. Local and regional therapies for melanoma: many arrows in the quiver. J Surg Oncol. 2014;109:295.

    Article  PubMed  Google Scholar 

  24. Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene Laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33:2780–8.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  PubMed  Google Scholar 

  26. Sanki A, Kroon HM, Kam PC, Thompson JF. Isolated limb perfusion and isolated limb infusion for malignant lesions of the extremities. Curr Probl Surg. 2011;48:371–430.

    Article  PubMed  Google Scholar 

  27. Kroon HM, Moncrieff M, Kam PC, et al. Outcomes following isolated limb infusion for melanoma: a 14-year experience. Ann Surg Oncol. 2008;15:3003–13.

    Article  PubMed  Google Scholar 

  28. Kroon HM, Coventry BJ, Giles MH, et al. Australian multicenter study of isolated limb infusion for melanoma. Ann Surg Oncol. 2016;23:1096–103.

    Article  PubMed  Google Scholar 

  29. Kroon HM, Huismans AM, Kam PCA, et al. Isolated limb infusion with melphalan and actinomycin D for melanoma: a systematic review. J Surg Oncol. 2014;109:348–51.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  PubMed  Google Scholar 

  31. Knorr C, Melling N, Goehl J, Drachsler T, Hohenberger W, Meyer T. Long-term functional outcome after hyperthermic isolated limb perfusion (HILP). Int J Hyperth. 2008;24:409–14.

    Article  CAS  Google Scholar 

  32. 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.

    Article  PubMed  Google Scholar 

  33. Klaase JM, Kroon BB, Van Geel BN, et al. Patient- and treatment-related factors associated with acute regional toxicity alter isolated perfusion for melanoma of the extremities. Am J Surg. 1994;167:618–20.

    Article  CAS  PubMed  Google Scholar 

  34. Klaase JM, Kroon BB, Beijnen JH, et al. Melphalan tissue concentrations in patients treated with regional isolated perfusion for melanoma of the lower limb. Br J Cancer. 1994;70:151–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Huismans AM, Kroon HM, Haydu LE, Kam PCA, 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.

    Article  PubMed  Google Scholar 

  36. Sonneveld EJ, Vrouenraets BC, van Geel BN, et al. Systemic toxicity after isolated limb perfusion with melphalan for melanoma. Eur J Surg Oncol. 1996;22:521–7.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  PubMed  Google Scholar 

  38. Knorr C, Meyer T, Janssen T, et al. Hyperthermic isolated limb perfusion (HILP) in malignant melanoma: experience with 101 patients. Eur J Surg Oncol. 2006;32:224–7.

    Article  CAS  PubMed  Google Scholar 

  39. Sanki A, Kam PC, Thompson JF. Long-term results of hyperthermic, isolated limb perfusion for melanoma: a reflection of tumor biology. Ann Surg. 2007;245:591–6.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Muilenburg DJ, Beasley GM, Thompson ZJ, et al. Burden of disease predicts response to isolated limb infusion with melphalan and actinomycin d in melanoma. Ann Surg Oncol. 2015;22:482–8.

    Article  PubMed  Google Scholar 

  41. Puzanov I, Skitzki J. New does not always mean better: isolated limb perfusion still has a role in the management of in-transit melanoma metastases. Oncology. 2016;30(12):1053–4.

    PubMed  Google Scholar 

  42. 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.

    Article  Google Scholar 

  43. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30–9.

    Article  PubMed  Google Scholar 

  44. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Beasley GM, Coleman AP, Raymond A, et al. A phase I multi-institutional study of systemic sorafenib in conjunction with regional melphalan for in-transit melanoma of the extremity. Ann Surg Oncol. 2012;19:3896–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Disclosure

None.

Author information

Authors and Affiliations

  1. Department of Surgery, Royal Adelaide Hospital, University of Adelaide, Adelaide, SA, Australia

    Hidde M. Kroon MD, PhD, Brendon J. Coventry BMBS, PhD, FRACS, FACS, FRSM & Mitchell H. Giles BMBS

  2. Division of Surgical Oncology, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia

    Michael A. Henderson MD, FRACS, David Speakman MBBS & Mark Wall BMBS

  3. Queensland Melanoma Project, Discipline of Surgery, Princess Alexandra Hospital, University of Queensland, Brisbane, QLD, Australia

    Andrew Barbour MBBS, PhD, FRACS & Bernard M. Smithers MBBS, FRACS, FRCS

  4. Discipline of Surgery, The Alfred Hospital, Melbourne, VIC, Australia

    Jonathan Serpell MBBS, FRACS & Paul Paddle MBBS

  5. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia

    Hidde M. Kroon MD, PhD & John F. Thompson MD, FRACS, FACS

  6. Discipline of Surgery, The University of Sydney, Sydney, NSW, Australia

    John F. Thompson MD, FRACS, FACS

  7. Department of Surgical Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia

    John F. Thompson MD, FRACS, FACS

Authors
  1. Hidde M. Kroon MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brendon J. Coventry BMBS, PhD, FRACS, FACS, FRSM
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mitchell H. Giles BMBS
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael A. Henderson MD, FRACS
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Speakman MBBS
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mark Wall BMBS
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andrew Barbour MBBS, PhD, FRACS
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jonathan Serpell MBBS, FRACS
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Paul Paddle MBBS
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bernard M. Smithers MBBS, FRACS, FRCS
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. John F. Thompson MD, FRACS, FACS
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hidde M. Kroon MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kroon, H.M., Coventry, B.J., Giles, M.H. et al. Safety and Efficacy of Isolated Limb Infusion Chemotherapy for Advanced Locoregional Melanoma in Elderly Patients: An Australian Multicenter Study. Ann Surg Oncol 24, 3245–3251 (2017). https://doi.org/10.1245/s10434-017-6046-5

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-017-6046-5

Keywords

Search

Navigation