Skip to main content

Advertisement

SpringerLink
Log in

Surgery for Metastatic Melanoma: an Evolving Concept

  • Melanoma (RJ Sullivan, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

This review describes the evolving role of surgery in stage III and IV melanoma.

Recent Findings

Surgery has been the first option to cure melanoma patients at initial diagnosis of metastatic spread: a complete surgical excision of the disease either in stage III or IV has been the gold standard for decades. A positive sentinel node biopsy (SNB) has been followed by a complete lymph node dissection (CLND) since the early stages of modern surgical oncology. However, since two randomized trials have indicated that a CLND does not improve survival in patients with a positive SNB, a CLND is no longer considered mandatory. A therapeutic lymph node dissection (TLND) is still offered to patients with macroscopic nodal disease and in highly selected cases, patients with distant melanoma metastases can be treated surgically as well. Also the availability of adjuvant, and in the future possibly neoadjuvant, systemic therapy have shifted the landscape to less extensive surgery in metastatic melanoma.

Summary

With the development of new systemic options, surgery in metastatic melanoma has become more and more part of a multidisciplinary treatment: surgical indications are moving from previous standards to a new role.

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

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 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.

    CAS  PubMed  Google Scholar 

  2. Morton DL, Cochran AJ, Thompson JF, Elashoff R, Essner R, Glass EC, et al. Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg. 2005;242(3):302–11 discussion 11-3.

    PubMed  PubMed Central  Google Scholar 

  3. • Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Nieweg OE, Roses DF, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599–609. The MSLT-I trial randomized patients between WLE of the primary tumor combined with either SN or nodal observation and failed to show a survival benefit between both arms.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Thomas JM. Prognostic false-positivity of the sentinel node in melanoma. Nat Clin Pract Oncol. 2008;5(1):18–23.

    PubMed  Google Scholar 

  5. van Akkooi AC. Sentinel node followed by completion lymph node dissection versus nodal observation: staging or therapeutic? Controversy continues despite final results of MSLT-1. Melanoma Res. 2014;24(4):291–4.

    PubMed  Google Scholar 

  6. Faries MB, Thompson JF, Cochran AJ, Andtbacka RH, Mozzillo N, Zager JS, et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med. 2017;376(23):2211–22.

    PubMed  PubMed Central  Google Scholar 

  7. •• Leiter U, Stadler R, Mauch C, Hohenberger W, Brockmeyer N, Berking C, et al. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2016;17(6):757–67. Both the MSLT-II and DeCOG-SLT trial were conducted after the MSLT-I trial showed that the SN alone was not a therapeutic procedure resulting in survival benefit. However, also performing a CLND in SN+ patients did not show a survival benefit over nodal observation in both trials.

    PubMed  Google Scholar 

  8. Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375(19):1845–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16(5):522–30.

    CAS  PubMed  Google Scholar 

  10. Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant Nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824–35.

    CAS  PubMed  Google Scholar 

  11. • Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, et al. Adjuvant Pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378(19):1789–801. The EORTC 1325 trial randomized patients between adjuvant pembrolizumab or placebo after complete resection of stage III (SN>1mm) melanoma. Apart from being one of the studies showing RFS benefit of adjuvant immunotherapy, this trial used a cross-over design. Giving patients in the placebo arm the opportunity to receive pembrolizumab after recurrence. Therefore, this study will answer the question whether if it is better to treat patients early, in the adjuvant setting, or if one can still wait to start treatment at the time of disease progression.

    CAS  PubMed  Google Scholar 

  12. Hauschild A, Dummer R, Schadendorf D, Santinami M, Atkinson V, Mandala M, et al. Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF V600-mutant stage III melanoma. J Clin Oncol. 2018:JCO1801219. https://doi.org/10.1200/JCO.18.01219.

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Long GV, Hauschild A, Santinami M, Atkinson V, Mandala M, Chiarion-Sileni V, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377(19):1813–23.

    CAS  PubMed  Google Scholar 

  14. Verver D, van Klaveren D, van Akkooi ACJ, Rutkowski P, Powell B, Robert C, et al. Risk stratification of sentinel node-positive melanoma patients defines surgical management and adjuvant therapy treatment considerations. Eur J Cancer. 2018;96:25–33.

    PubMed  Google Scholar 

  15. Madu MF, Franke V, Bruin MM, Berger DMS, Bierman C, Jozwiak K, et al. Immediate completion lymph node dissection in stage IIIA melanoma does not provide significant additional staging information beyond EORTC SN tumour burden criteria. Eur J Cancer. 2017;87:212–5.

    PubMed  Google Scholar 

  16. van Akkooi AC, Bouwhuis MG, van Geel AN, Hoedemaker R, Verhoef C, Grunhagen DJ, et al. Morbidity and prognosis after therapeutic lymph node dissections for malignant melanoma. Eur J Surg Oncol. 2007;33(1):102–8.

    PubMed  Google Scholar 

  17. Amaria RN, Prieto PA, Tetzlaff MT, Reuben A, Andrews MC, Ross MI, et al. Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Lancet Oncol. 2018;19(2):181–93.

    CAS  PubMed  Google Scholar 

  18. Long GV, Saw RPM, Lo S, Nieweg OE, Shannon KF, Gonzalez M, et al. Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB-C, BRAF(V600) mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial. Lancet Oncol. 2019;20:961–71.

    CAS  PubMed  Google Scholar 

  19. Amaria RN, Reddy SM, Tawbi HA, Davies MA, Ross MI, Glitza IC, et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med. 2018;24(11):1649–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Blank CU, Rozeman EA, Fanchi LF, Sikorska K, van de Wiel B, Kvistborg P, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med. 2018;24(11):1655–61.

    CAS  PubMed  Google Scholar 

  21. • Rozeman EA, Menzies AM, van Akkooi ACJ, Adhikari C, Bierman C, van de Wiel BA, et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 2019. The Opacin-neo study has identified an effective and tolerable neoadjuvant combination immunotherapy schedule, which in the future may provide patients with a better prognosis as well as the opportunity to undergo less extensive surgery. This will be studied in the extension cohort (reference 22).;20:948–60.

    CAS  PubMed  Google Scholar 

  22. Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) [Available from: https://clinicaltrials.gov/ct2/show/NCT02977052?term=opacin-neo&rank=1.

  23. Testori A, Soteldo J, Powell B, Sales F, Borgognoni L, Rutkowski P, et al. Surgical management of melanoma: an EORTC melanoma group survey. Ecancermedicalscience. 2013;7:294.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Verver D, Madu MF, Oude Ophuis CMC, Faut M, de Wilt JHW, Bonenkamp JJ, et al. Optimal extent of completion lymphadenectomy for patients with melanoma and a positive sentinel node in the groin. Br J Surg. 2018;105(1):96–105.

    CAS  PubMed  Google Scholar 

  25. Oude Ophuis CM, van Akkooi AC, Hoekstra HJ, Bonenkamp JJ, van Wissen J, Niebling MG, et al. Risk factors for positive deep pelvic nodal involvement in patients with palpable groin melanoma metastases: can the extent of surgery be safely minimized? : a retrospective, multicenter cohort study. Ann Surg Oncol. 2015;22(Suppl 3):S1172–80.

    PubMed  Google Scholar 

  26. Zdzienicki M, Rutkowski P, Nowecki ZI, van Akkooi AC, Michej W, Dziewirski W, et al. The analysis of the outcomes and factors related to iliac-obturator involvement in cutaneous melanoma patients after lymph node dissection due to positive sentinel lymph node biopsy or clinically detected inguinal metastases. Eur J Surg Oncol. 2013;39(3):304–10.

    CAS  PubMed  Google Scholar 

  27. van der Ploeg AP, van Akkooi AC, Schmitz PI, van Geel AN, de Wilt JH, Eggermont AM, et al. Therapeutic surgical management of palpable melanoma groin metastases: superficial or combined superficial and deep groin lymph node dissection. Ann Surg Oncol. 2011;18(12):3300–8.

    PubMed  PubMed Central  Google Scholar 

  28. Testori AA, Suciu S, van Akkooi ACJ, Suppa M, Eggermont AMM, de Vries E, et al. Lymph node ratio as a prognostic factor in melanoma: results from European Organization for Research and Treatment of Cancer 18871, 18952, and 18991 studies. Melanoma Res. 2018;28(3):222–9.

    PubMed  Google Scholar 

  29. Evaluation of Groin Lymphadenectomy Extent For Metastatic Melanoma (EAGLE FM) [Available from: https://clinicaltrials.gov/ct2/show/NCT02166788.

  30. Day CL Jr, Harrist TJ, Gorstein F, Sober AJ, Lew RA, Friedman RJ, et al. Malignant melanoma. Prognostic significance of “microscopic satellites” in the reticular dermis and subcutaneous fat. Ann Surg. 1981;194(1):108–12.

    PubMed  PubMed Central  Google Scholar 

  31. Harrist TJ, Rigel DS, Day CL Jr, Sober AJ, Lew RA, Rhodes AR, et al. “Microscopic satellites” are more highly associated with regional lymph node metastases than is primary melanoma thickness. Cancer. 1984;53(10):2183–7.

    CAS  PubMed  Google Scholar 

  32. Leon P, Daly JM, Synnestvedt M, Schultz DJ, Elder DE, Clark WH Jr. The prognostic implications of microscopic satellites in patients with clinical stage I melanoma. Arch Surg. 1991;126(12):1461–8.

    CAS  PubMed  Google Scholar 

  33. Singletary SE, Tucker SL, Boddie AW Jr. Multivariate analysis of prognostic factors in regional cutaneous metastases of extremity melanoma. Cancer. 1988;61(7):1437–40.

    CAS  PubMed  Google Scholar 

  34. Rutkowski P, Nowecki ZI, Zurawski Z, Dziewirski W, Nasierowska-Guttmejer A, Switaj T, et al. In transit/local recurrences in melanoma patients after sentinel node biopsy and therapeutic lymph node dissection. Eur J Cancer. 2006;42(2):159–64.

    CAS  PubMed  Google Scholar 

  35. Testori A, Faries MB, Thompson JF, Pennacchioli E, Deroose JP, van Geel AN, et al. Local and intralesional therapy of in-transit melanoma metastases. J Surg Oncol. 2011;104(4):391–6.

    PubMed  Google Scholar 

  36. Testori A, Ribero S, Bataille V. Diagnosis and treatment of in-transit melanoma metastases. Eur J Surg Oncol. 2017;43(3):544–60.

    CAS  PubMed  Google Scholar 

  37. 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(9):837–45.

    PubMed  Google Scholar 

  38. Lejeune FJ, Deloof T, Ewalenko P, Fruhling J, Jabri M, Mathieu M, et al. Objective regression of unexcised melanoma in-transit metastases after hyperthermic isolation perfusion of the limbs with melphalan. Recent Results Cancer Res. 1983;86:268–76.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  40. Lienard D, Ewalenko P, Delmotte JJ, Renard N, Lejeune FJ. High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol. 1992;10(1):52–60.

    CAS  PubMed  Google Scholar 

  41. Eggermont AM, Lienard D, Schraffordt KH. High dose tumor necrosis factor-alpha in isolation perfusion of the limb: highly effective treatment for melanoma in transit metastases or unresectable sarcoma. Reg Cancer Treat. 1995;7:32–6.

    Google Scholar 

  42. Rossi CR, Foletto M, Mocellin S, Pilati P, Lise M. Hyperthermic isolated limb perfusion with low-dose tumor necrosis factor-alpha and melphalan for bulky in-transit melanoma metastases. Ann Surg Oncol. 2004;11(2):173–7.

    PubMed  Google Scholar 

  43. Thompson JF, Hunt JA, Shannon KF, Kam PC. Frequency and duration of remission after isolated limb perfusion for melanoma. Arch Surg. 1997;132(8):903–7.

    CAS  PubMed  Google Scholar 

  44. Grunhagen DJ, de Wilt JH, van Geel AN, Eggermont AM. Isolated limb perfusion for melanoma patients--a review of its indications and the role of tumour necrosis factor-alpha. Eur J Surg Oncol. 2006;32(4):371–80.

    CAS  PubMed  Google Scholar 

  45. Madu MF, Deken MM, van der Hage JA, Jozwiak K, Wouters M, van Akkooi ACJ. Isolated limb perfusion for melanoma is safe and effective in elderly patients. Ann Surg Oncol. 2017;24(7):1997–2005.

    PubMed  Google Scholar 

  46. Thompson JF, Waugh RC. 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 

  47. Testori A, Intelisano A, Verrecchia F, Menicanti C, Tosti G, Grassi E, et al. Alternatives for the treatment of local advanced disease: electrochemotherapy, limb perfusion, limb infusion, intralesional IL2. What is the role? Dermatol Ther. 2012;25(5):443–51.

    PubMed  Google Scholar 

  48. Testori A, Rossi CR, Tosti G. Utility of electrochemotherapy in melanoma treatment. Curr Opin Oncol. 2012;24(2):155–61.

    CAS  PubMed  Google Scholar 

  49. Testori A, Tosti G, Martinoli C, Spadola G, Cataldo F, Verrecchia F, et al. Electrochemotherapy for cutaneous and subcutaneous tumor lesions: a novel therapeutic approach. Dermatol Ther. 2010;23(6):651–61.

    PubMed  Google Scholar 

  50. Campana LG, Testori A, Mozzillo N, Rossi CR. Treatment of metastatic melanoma with electrochemotherapy. J Surg Oncol. 2014;109(4):301–7.

    CAS  PubMed  Google Scholar 

  51. Campana LG, Testori A, Curatolo P, Quaglino P, Mocellin S, Framarini M, et al. Treatment efficacy with electrochemotherapy: a multi-institutional prospective observational study on 376 patients with superficial tumors. Eur J Surg Oncol. 2016;42(12):1914–23.

    CAS  PubMed  Google Scholar 

  52. Byrne CM, Thompson JF. Role of electrochemotherapy in the treatment of metastatic melanoma and other metastatic and primary skin tumors. Expert Rev Anticancer Ther. 2006;6(5):671–8.

    CAS  PubMed  Google Scholar 

  53. Kaufman HL, Bines SD. OPTIM trial: a phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma. Future Oncol. 2010;6(6):941–9.

    CAS  PubMed  Google Scholar 

  54. Perez MC, Miura JT, Naqvi SMH, Kim Y, Holstein A, Lee D, et al. Talimogene laherparepvec (TVEC) for the treatment of advanced melanoma: a single-institution experience. Ann Surg Oncol. 2018;25(13):3960–5.

    PubMed  PubMed Central  Google Scholar 

  55. Franke V, Berger DMS, Klop WMC, van der Hiel B, van de Wiel BA, Ter Meulen S, et al. High response rates for T-VEC in early metastatic melanoma (stage IIIB/C-IVM1a). Int J Cancer. 2019;145(4):974–8.

    CAS  PubMed  Google Scholar 

  56. Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, et al. Survival outcomes in patients with previously untreated BRAF wild-type advanced melanoma treated with nivolumab therapy: three-year follow-up of a randomized phase 3 trial. JAMA Oncol. 2019;5(2):187–194. https://doi.org/10.1001/jamaoncol.2018.4514.

    PubMed  Google Scholar 

  57. Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32(10):1020–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(11):1480–92.

    CAS  PubMed  Google Scholar 

  59. Howard JH, Thompson JF, Mozzillo N, Nieweg OE, Hoekstra HJ, Roses DF, et al. Metastasectomy for distant metastatic melanoma: analysis of data from the first multicenter selective lymphadenectomy trial (MSLT-I). Ann Surg Oncol. 2012;19(8):2547–55.

    PubMed  PubMed Central  Google Scholar 

  60. Faries MB, Mozzillo N, Kashani-Sabet M, Thompson JF, Kelley MC, DeConti RC, et al. Long-term survival after complete surgical resection and adjuvant immunotherapy for distant melanoma metastases. Ann Surg Oncol. 2017;24(13):3991–4000.

    PubMed  Google Scholar 

  61. Sosman JA, Moon J, Tuthill RJ, Warneke JA, Vetto JT, Redman BG, et al. A phase 2 trial of complete resection for stage IV melanoma: results of Southwest Oncology Group Clinical Trial S9430. Cancer. 2011;117(20):4740–06.

    PubMed  Google Scholar 

  62. Bello DM KSP, Hollmann TJ, Shoushtari AN, Chapman P, Postow MA, Callahan MK, et al. Outcomes of patients with metastatic melanoma selected for surgery after immunotherapy. SSO 2018 abstract2018.

  63. • Puza CJ, Bressler ES, Terando AM, Howard JH, Brown MC, Hanks B, et al. The emerging role of surgery for patients with advanced melanoma treated with immunotherapy. J Surg Res. 2019;236:209–15. This study is examplary for the evolving role of surgery in stage IV melanoma in the era of new systemic therapies. Patients with remaining lesions of a partial response or mixed response/oligoprogression might benefit from surgery.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dermatology, Fondazione IRCCS Policlinico San Matteo, v.le Golgi 19, 27100, Pavia, Italy

    Alessandro A. E. Testori

  2. Department of Surgical Oncology, Netherlands Cancer Institute – Antoni van Leeuwenhoek, Amsterdam, Netherlands

    Stephanie A. Blankenstein & Alexander C. J. van Akkooi

Authors
  1. Alessandro A. E. Testori
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephanie A. Blankenstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexander C. J. van Akkooi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alessandro A. E. Testori.

Ethics declarations

Conflict of Interest

Alessandro A.E. Testori declares that he has no conflict of interest.

Stephanie A. Blankenstein declares that she has no conflict of interest.

Alexander C.J. van Akkooi is supported by research funding from Amgen, Bristol-Myers Squibb, and Novartis; and has served as a consultant for and has participated on advisory boards sponsored by Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, and 4SC. All were unrelated to this work and all funds paid to his institution.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Melanoma

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Testori, A.A.E., Blankenstein, S.A. & van Akkooi, A.C.J. Surgery for Metastatic Melanoma: an Evolving Concept. Curr Oncol Rep 21, 98 (2019). https://doi.org/10.1007/s11912-019-0847-6

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11912-019-0847-6

Keywords

Search

Navigation