Surgical therapy for patients with distant metastases

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For many years patients with metastatic melanoma to sites beyond the draining regional lymph nodes have had a bad prognosis with low rates of long term survival. Therapies have included a range of systemic treatments including chemotherapy, immune therapies such as interferon and vaccines, as well as other conventionally developed and alternative “non-scientifically” developed treatments. High level evidence for clinically relevant efficacy of any of these interventions has been missing. Patients have been best managed within a multidisciplinary team environment with all appropriate clinicians and support staff attending. Depending on the distribution and kinetics of the disease evolution, choices have been made as to whether the patient was offered systemic therapy or control of disease with local therapies such as surgery or radiotherapy or in some situations just offered best supportive care. Clearly the choice of therapy or combinations and sequencing of interventions has been based on the distribution and biological aggressiveness of the disease. The favoured systemic therapy has been “Clinical Trial Agent”, because the standard systemic therapy for many years, Dacarbazine, was clearly inadequate in terms of efficacy. Despite these attempts to prolong the lives of patients with stage 4 metastatic melanoma the vast majority usually succumbed to their disease within 12–18 months depending on the site (refer to the American Joint Committee on Cancer [AJCC] staging categories).[1]

From around 2010 onwards, advances in targeted and immune check point inhibitor systemic therapy have revolutionised the treatment of patients with stage 4 metastatic melanoma. These agents and their improvements in overall survival rates for patients are documented separately. As these changes have only occurred in recent times there is a dearth of studies with meaningful follow-up that indicate the preferred sequencing of multimodality interventions for patients with stage 4 metastatic melanoma. The practical reality is that patients are still best discussed within a multidisciplinary team that has access to all modalities, in a group that actively collects data to document outcomes and is that is actively engaged in clinical trials (see Multidisciplinary care section). As the goal posts have been moving so quickly with systemic therapy alone the ability to do studies on patients with combinations of effective systemic therapy and surgery and/or radiotherapy is limited but clearly will become more important when the rapid advances in systemic therapy plateau.

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Systematic review evidence

For patients with distant metastases, when is surgical therapy indicated?

There are no randomised controlled trials that have accrued and reported on the sequencing of surgery with systemic therapy options.

The literature evaluated during this evidence-based review process reported on patients who did not have access to effective systemic therapy. Due to the nature of the presentation of these patients, nearly all reported series would have been open to selection bias, with those patients with lower volume metastatic disease and less aggressive biology being more likely to be suitable for surgery, and those with worse disease being managed with largely ineffective systemic therapy.[2][3][4]

As reflected in the AJCC staging system, the site of the metastastic disease has a major impact on survival in patients managed with surgery or systemic therapies, especially prior to the availability of effective targeted and immunotherapy.[1][4] Nevertheless some information can be gleaned regarding situations where the clinical presentation mandates immediate removal of the disease causing life-threatening complications. Examples include:

1. symptomatic brain metastasis [5] – see Recommended surgical approach to brain metastases

2. small bowel metastasis (or less commonly other GI sites) causing obstruction or major bleeding[6]

3. bone metastasis causing fracture or impending fracture[7]

4. spine causing actual or threatened spinal cord compression.

Other situations where the preference is still to use surgery as an initial therapy may include isolated or a small number of metastases in surgically accessible sites after a long disease-free interval, e.g. lung metastasis,[8][9] liver metastasis,[10][11][12][13][14][9] adrenal metastasis,[15][16][17] brain metastasis, bowel metastasis,[9] distant soft tissue metastasis[4] and bone metastasis.[7]

Recommendations and practice points

Consensus-based recommendationQuestion mark transparent.png

Situations where surgery should be considered for stage 4 disease include the following, but when possible all cases should be discussed in an experienced multidisciplinary team setting:

1. Isolated site of metastatic disease that are causing life threatening symptoms or likely to cause irreversible damage if not treated immediately, eg. brain, small bowel, spine/causing spinal cord compression.

2. Isolated or a few resectable sites of metastatic disease after a meaningful disease-free interval.

3. Isolated progression or resistance in the face of otherwise effective systemic therapy.

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Multidisciplinary team discussion is required for all melanoma patients with isolated or a small number of metastases. Patients should be informed of the nature of the multidisciplinary discussion including the range of options discussed and why the final recommendation was reached.

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The multidisciplinary discussion would seek to consider the balance between surgical morbidity and likelihood of immediate reversal of symptoms or achievement of disease free status compared to the side effects, outcome and long-term results that would be achieved with other treatment modalities.

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In the case of isolated or a small number of metastases in a surgically accessible sites, particularly after a long disease-free interval, surgery may be the preferred initial therapy, e.g. isolated lung metastasis, isolated liver metastasis, isolated adrenal metastasis, isolated brain metastasis, isolated distant soft tissue metastasis, isolated bone metastasis with impending fracture.

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  1. 1.0 1.1 Gershenwald JE, Scolyer RA, Hess KR, Sondak VK, Long GV, Ross MI, et al. Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 2017 Nov;67(6):472-492 Available from:
  2. 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 Aug;19(8):2547-55 Available from:
  3. Deutsch GB, Flaherty DC, Kirchoff DD, Bailey M, Vitug S, Foshag LJ, et al. Association of Surgical Treatment, Systemic Therapy, and Survival in Patients With Abdominal Visceral Melanoma Metastases, 1965-2014: Relevance of Surgical Cure in the Era of Modern Systemic Therapy. JAMA Surg 2017 Jul 1;152(7):672-678 Available from:
  4. 4.0 4.1 4.2 Forschner A, Eichner F, Amaral T, Keim U, Garbe C, Eigentler TK. Improvement of overall survival in stage IV melanoma patients during 2011-2014: analysis of real-world data in 441 patients of the German Central Malignant Melanoma Registry (CMMR). J Cancer Res Clin Oncol 2017 Mar;143(3):533-540 Available from:
  5. Carrubba CJ, Vitaz TW. Factors affecting the outcome after treatment for metastatic melanoma to the brain. Surg Neurol 2009 Dec;72(6):707-11 Available from:
  6. Chua TC, Saxena A, Morris DL. Surgical metastasectomy in AJCC stage IV M1c melanoma patients with gastrointestinal and liver metastases. Ann Acad Med Singapore 2010 Aug;39(8):634-9 Available from:
  7. 7.0 7.1 Colman MW, Kirkwood JM, Schott T, Goodman MA, McGough RL 3rd. Does metastasectomy improve survival in skeletal melanoma? Melanoma Res 2014 Aug;24(4):354-9 Available from:
  8. Neuman HB, Patel A, Hanlon C, Wolchok JD, Houghton AN, Coit DG. Stage-IV melanoma and pulmonary metastases: factors predictive of survival. Ann Surg Oncol 2007 Oct;14(10):2847-53 Available from:
  9. 9.0 9.1 9.2 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 Oct 10 Available from:
  10. Hameed AM, Ng EE, Johnston E, Hollands MJ, Richardson AJ, Pleass HC, et al. Hepatic resection for metastatic melanoma: a systematic review. Melanoma Res 2014 Feb;24(1):1-10 Available from:
  11. Hau HM, Tautenhahn HM, Schoenberg MB, Atanasov G, Wiltberger G, Morgül MH, et al. Liver resection in multimodal concepts improves survival of metastatic melanoma: a single-centre case-matched control study. Anticancer Res 2014 Nov;34(11):6633-9 Available from:
  12. Faries MB, Leung A, Morton DL, Hari D, Lee JH, Sim MS, et al. A 20-year experience of hepatic resection for melanoma: is there an expanding role? J Am Coll Surg 2014 Jul;219(1):62-8 Available from:
  13. Frenkel S, Nir I, Hendler K, Lotem M, Eid A, Jurim O, et al. Long-term survival of uveal melanoma patients after surgery for liver metastases. Br J Ophthalmol 2009 Aug;93(8):1042-6 Available from:
  14. Gomez D, Wetherill C, Cheong J, Jones L, Marshall E, Damato B, et al. The Liverpool uveal melanoma liver metastases pathway: outcome following liver resection. J Surg Oncol 2014 May;109(6):542-7 Available from:
  15. Collinson FJ, Lam TK, Bruijn WM, de Wilt JH, Lamont M, Thompson JF, et al. Long-term survival and occasional regression of distant melanoma metastases after adrenal metastasectomy. Ann Surg Oncol 2008 Jun;15(6):1741-9 Available from:
  16. Flaherty DC, Deutsch GB, Kirchoff DD, Lee J, Huynh KT, Lee DY, et al. Adrenalectomy for Metastatic Melanoma: Current Role in the Age of Nonsurgical Treatments. Am Surg 2015 Oct;81(10):1005-9 Available from:
  17. Mittendorf EA, Lim SJ, Schacherer CW, Lucci A, Cormier JN, Mansfield PF, et al. Melanoma adrenal metastasis: natural history and surgical management. Am J Surg 2008 Mar;195(3):363-8; discussion 368-9 Available from:

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