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Extranodal Spread is Associated with Recurrence and Poor Survival in Stage III Cutaneous Melanoma Patients

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

Abstract

Background

Inconsistent data suggests extranodal spread (ENS) is an adverse prognostic factor in Stage III melanoma patients but it remains contentious. By rigorously matching cohorts, this study sought to clarify associations with recurrence and survival.

Methods

Melanoma patients with lymph node metastases (AJCC Stage III), with or without ENS, sub-classified on the basis of known (MKP) or unknown primary (MUP), were identified from a single institution prospective database. Of 725 ENS patients identified, 567 were able to be precisely matched 1:1 with a non-ENS cohort. Clinicopathologic factors were analyzed for associations with outcome.

Results

There were 481 MKP and 86 MUP patients in each cohort. ENS, compared to non-ENS, was an independent predictor of worse melanoma specific survival (MSS) (HR = 1.71, 95% CI = 1.39–2.11, P < 0.0001) with median MSS 56.4 versus 175.2 months, P < 0.001; worse disease free survival (DFS) (HR = 1.16, 95%CI = 1.00–1.34, P = 0.044) with median DFS 15.6 versus 21.5 months, P = 0.009; and worse post-recurrence survival (PRS) (HR = 1.66, 95%CI = 1.37–2.02, P < 0.0001) with median PRS 20.1 versus 51.1 months, P < 0.001. ENS was also associated with reduced time to distant recurrence (Distant Disease Free Survival [DDFS]) (HR = 2.00, 95% CI = 1.24–3.24, P = 0.0047), however median time to distant recurrence not reached within the study time period.

Conclusions

ENS represents a significant independent predictor of worse MSS, DFS, PRS and DDFS in Stage III melanoma patients. ENS should be considered in the stratification of patients in adjuvant therapy trials.

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References

  1. 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 

  2. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Ding S, Byrd DR et al. Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases. J Clin Oncol. 2010;28(14):2452–9.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Khosrotehrani K, van der Ploeg AP, Siskind V, Hughes MC, Wright A, Thomas J et al. Nomograms to predict recurrence and survival in stage IIIB and IIIC melanoma after therapeutic lymphadenectomy. Eur J Cancer. 2014;50(7):1301–9.

    Article  PubMed  Google Scholar 

  4. Grotz TE, Huebner M, Pockaj BA, Perkins S, Jakub JW. Limitations of lymph node ratio, evidence-based benchmarks, and the importance of a thorough lymph node dissection in melanoma. Ann Surg Oncol. 2013;20(13):4370–7.

    Article  PubMed  Google Scholar 

  5. Henderson MA, Burmeister BH, Ainslie J, Fisher R, Di Iulio J, Smithers BM et al. Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial. Lancet Oncol. 2015.

  6. Spillane AJ, Pasquali S, Haydu LE, Thompson JF. Patterns of recurrence and survival after lymphadenectomy in melanoma patients: clarifying the effects of timing of surgery and lymph node tumor burden. Ann Surg Oncol. 2014;21(1):292–9.

    Article  PubMed  Google Scholar 

  7. Koopal SA, Tiebosch AT, Daryanani D, Plukker JT, Hoekstra HJ. Extra nodal growth as a prognostic factor in malignant melanoma. Eur J Surg Oncol. 2005;31(1):88–94.

    Article  CAS  PubMed  Google Scholar 

  8. Burmeister BH, Henderson MA, Ainslie J, Fisher R, Di Iulio J, Smithers BM et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial. Lancet Oncol. 2012;13(6):589–97.

    Article  PubMed  Google Scholar 

  9. Niebling MG, Haydu LE, Karim RZ, Thompson JF, Scolyer RA. Pathology review significantly affects diagnosis and treatment of melanoma patients: an analysis of 5011 patients treated at a melanoma treatment center. Ann Surg Oncol. 2014;21(7):2245–51.

    Article  PubMed  Google Scholar 

  10. Murali R, Cochran AJ, Cook MG, Hillman JD, Karim RZ, Moncrieff M et al. Interobserver reproducibility of histologic parameters of melanoma deposits in sentinel lymph nodes: implications for management of patients with melanoma. Cancer. 2009;115(21):5026–37.

    Article  PubMed  PubMed Central  Google Scholar 

  11. van der Ploeg AP, van Akkooi AC, Haydu LE, Scolyer RA, Murali R, Verhoef C et al. The prognostic significance of sentinel node tumour burden in melanoma patients: an international, multicenter study of 1539 sentinel node-positive melanoma patients. Eur J Cancer. 2014;50(1):111–20.

    Article  PubMed  Google Scholar 

  12. Hughes MC, Wright A, Barbour A, Thomas J, Smithers BM, Green AC et al. Patients undergoing lymphadenectomy for stage III melanomas of known or unknown primary site do not differ in outcome. Int J Cancer. 2013;133(12):3000–7.

    CAS  PubMed  Google Scholar 

  13. Shen P, Wanek LA, Morton DL. Is adjuvant radiotherapy necessary after positive lymph node dissection in head and neck melanomas? Ann Surg Oncol. 2000;7(8):554, 9; discussion 560-1.

  14. Calabro A, Singletary SE, Balch CM. Patterns of relapse in 1001 consecutive patients with melanoma nodal metastases. Arch Surg. 1989;124(9):1051–5.

    Article  CAS  PubMed  Google Scholar 

  15. Lee RJ, Gibbs JF, Proulx GM, Kollmorgen DR, Jia C, Kraybill WG. Nodal basin recurrence following lymph node dissection for melanoma: implications for adjuvant radiotherapy. Int J Radiat Oncol Biol Phys. 2000;46(2):467–74.

    Article  CAS  PubMed  Google Scholar 

  16. Guadagnolo BA, Zagars GK. Adjuvant radiation therapy for high-risk nodal metastases from cutaneous melanoma. Lancet Oncol. 2009;10(4):409–16.

    Article  PubMed  Google Scholar 

  17. Garbe C, Peris K, Hauschild A, Saiag P, Middleton M, Spatz A et al. Diagnosis and treatment of melanoma: European consensus-based interdisciplinary guideline. Eur J Cancer. 2010;46(2):270–83.

    Article  PubMed  Google Scholar 

  18. Barbour S, Mark Smithers B, Allan C, Bayley G, Thomas J, Foote M et al. Patterns of recurrence in patients with stage IIIB/C cutaneous melanoma of the head and neck following surgery with and without adjuvant radiation therapy: is isolated regional recurrence salvageable? Ann Surg Oncol. 2015.

  19. Bibault JE, Dewas S, Mirabel X, Mortier L, Penel N, Vanseymortier L et al. Adjuvant radiation therapy in metastatic lymph nodes from melanoma. Radiat Oncol. 2011;6:12,717X-6-12.

  20. Agrawal S, Kane JM, 3rd, Guadagnolo BA, Kraybill WG, Ballo MT. The benefits of adjuvant radiation therapy after therapeutic lymphadenectomy for clinically advanced, high-risk, lymph node-metastatic melanoma. Cancer. 2009;115(24):5836–44.

  21. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877–88.

    Article  PubMed  Google Scholar 

  22. 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 

  23. Grimaldi AM, Simeone E, Festino L, Vanella V, Palla M, Ascierto PA. Novel mechanisms and therapeutic approaches in melanoma: targeting the MAPK pathway. Discov Med. 2015;19(107):455–61.

    PubMed  Google Scholar 

  24. Grob JJ, Amonkar MM, Karaszewska B, Schachter J, Dummer R, Mackiewicz A et al. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. Lancet Oncol. 2015;16(13):1389–98.

    Article  CAS  PubMed  Google Scholar 

  25. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444–51.

    Article  CAS  PubMed  Google Scholar 

  26. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–9.

    Article  PubMed  Google Scholar 

  27. John L, Cowey CL. The rapid emergence of novel therapeutics in advanced malignant melanoma. Dermatol Ther (Heidelb). 2015;5(3):151–69.

    Article  Google Scholar 

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Ackowledgment

The authors thank the various medical and clinical staff at Melanoma Institute Australia, particularly Hazel Burke and John F Thompson, as well as the patients and their families.

Funding

Grant support from the Australian National Health and Medical Research Council and Cancer Institute New South Wales is gratefully acknowledged. RAS is supported by an NHMRC Practitioner Fellowship. Andrew Spillane’s academic position is funded by the Friends of the Mater Hospital Foundation.

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Authors and Affiliations

  1. Melanoma Institute Australia, 40 Rockland Roads, North Sydney, NSW, 2060, Australia

    Thomas R. Crookes MBBS, Richard A. Scolyer MD, Serigne Lo PhD, Martin Drummond MDM, MBiostat & Andrew J. Spillane MD

  2. Sydney Medical School, The University of Sydney, Sydney, Australia

    Richard A. Scolyer MD, Martin Drummond MDM, MBiostat & Andrew J. Spillane MD

  3. School of Medicine Sydney, The University of Notre Dame, Sydney, Australia

    Thomas R. Crookes MBBS

Authors
  1. Thomas R. Crookes MBBS
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  2. Richard A. Scolyer MD
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  3. Serigne Lo PhD
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  4. Martin Drummond MDM, MBiostat
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  5. Andrew J. Spillane MD
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Corresponding author

Correspondence to Andrew J. Spillane MD.

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Crookes, T.R., Scolyer, R.A., Lo, S. et al. Extranodal Spread is Associated with Recurrence and Poor Survival in Stage III Cutaneous Melanoma Patients. Ann Surg Oncol 24, 1378–1385 (2017). https://doi.org/10.1245/s10434-016-5723-0

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  • DOI: https://doi.org/10.1245/s10434-016-5723-0

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