Immune checkpoint and BRAF-targeted inhibitors have demonstrated significant survival benefits for advanced melanoma patients within the context of clinical trials. We sought to determine their impact on overall survival (OS) at a population level in order to better understand the current landscape for patients diagnosed with clinical stage III melanoma.
A retrospective study was performed using the National Cancer Database. Patients diagnosed with clinical stage III melanoma were categorized by diagnosis year into two cohorts preceding the advent of novel therapies (P1: 2004–2005, P2: 2008–2009) and a contemporary group (P3: 2012–2013). OS was estimated using standard time-to-event statistical methods.
Of 3720 patients, 525 (14%) were diagnosed in P1, 1375 (37%) in P2, and 1820 (49%) in P3. Median age at diagnosis increased over time (58, 59, and 61 years in P1, P2, and P3, respectively, P = 0.004). OS increased between P2 (median 49.3 months) and P3 (median 58.2 months, Bonferroni-corrected log-rank P < 0.001) but did not differ between P1 (median 50.5 months) and P2 (Bonferroni-corrected log-rank P > 0.99). These differences persisted on multivariable analysis. OS improved for patients diagnosed in P3 compared with P1 [hazard ratio (HR) 0.76, P < 0.001] but not P2 compared with P1 (HR 0.96, P = 0.52).
OS has significantly improved nationally for patients newly diagnosed with clinical stage III melanoma in the era of novel melanoma therapies. OS outcomes will likely continue to evolve as these agents are increasingly utilized in the adjuvant setting. These data may help to better inform affected patients with respect to prognosis.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30. https://doi.org/10.3322/caac.21442
Balch CM, Buzaid AC, Soong S-J, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19(16):3635–48. https://doi.org/10.1200/jco.2001.19.16.3635
Balch CM, Gershenwald JE, Soong S-J, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199–206. https://doi.org/10.1200/jco.2009.23.4799.
Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eight edition cancer staging manual. CA Cancer J Clin. 2017;67(6):472–92. https://doi.org/10.3322/caac.21409.
Bartlett EK, Karakousis GC. Current staging and prognostic factors in melanoma. Surg Oncol Clin N Am. 2015;24(2):215–27. https://doi.org/10.1016/j.soc.2014.12.001.
Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16. https://doi.org/10.1056/nejmoa1103782.
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. https://doi.org/10.1056/nejmoa1003466.
Hauschild A, Grob J-J, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–65. https://doi.org/10.1016/s0140-6736(12)60868-x.
Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30. https://doi.org/10.1056/nejmoa1412082.
Eggermont AM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378(19):1789–801. https://doi.org/10.1056/nejmoa1802357.
Wolchok JD, Kluger H, Callahan MK, et al. Safety and clinical activity of combined PD-1 (nivolumab) and CTLA-4 (ipilimumab) blockade in advanced melanoma patients. N Engl J Med. 2013;369(2):122–33. https://doi.org/10.1056/nejmoa1302369.
Eggermont AM, Chiarion-Sileni V, Grob J-J, 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. https://doi.org/10.1016/s1470-2045(15)70122-1.
Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824–35. https://doi.org/10.1056/nejmoa1709030.
Eggermont, Alexander M., Chiarion-Sileni V, Grob J-J, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375(19):1845–55. https://doi.org/10.1056/nejmoa1611299.
Sinnamon AJ, Neuwirth MG, Gimotty PA, et al. Association of first-in-class immune checkpoint inhibition and targeted therapy with survival in patients with stage IV melanoma. JAMA Oncol. 2018;4(1):126–8. https://doi.org/10.1001/jamaoncol.2017.3462.
Bilimoria KY, Stewart AK, Winchester DP, Ko CY. The National Cancer Data Base: a powerful initiative to improve cancer care in the United States. Ann Surg Oncol. 2008;15(3):683–90. https://doi.org/10.1245/s10434-007-9747-3.
About the National Cancer Database. National Cancer Database. https://www.facs.org/quality-programs/cancer/ncdb/about. Accessed 1 Oct 2018.
R Core Team (2018). R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing https://www.R-project.org/. Accessed 1 July 2018.
Balch CM, Soong S-J, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19(16):3622–34. https://doi.org/10.1200/jco.2001.19.16.3622.
Balch CM, Gershenwald JE, Soong S-J, 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. https://doi.org/10.1200/jco.2009.27.1627.
Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107–114. https://doi.org/10.1056/nejmoa1203421.
White RR, Stanley WE, Johnson JL, Tyler DS, Seigler H. Long-term survival in 2,505 patients with melanoma with regional lymph node metastasis. Ann Surg. 2002;235(6):879–887.
Balch CM, Soong S-J, Gershenwald JE, et al. Age as a prognostic factor in patients with localized melanoma and regional metastases. Ann Surg Oncol. 2013;20(12):3961. https://doi.org/10.1245/s10434-013-3100-9.
Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer. 1998;83(8):1664–78.
Cormier JN, Xing Y, Feng L, et al. Metastatic melanoma to lymph nodes in patients with unknown primary sites. Cancer. 2006;106(9):2012–20. https://doi.org/10.1002/cncr.21835.
Lee CC, Faries MB, Wanek LA, Morton DL. Improved survival after lymphadenectomy for nodal metastasis from an unknown primary melanoma. J Clin Oncol. 2008;26(4):535–41. https://doi.org/10.1200/jco.2007.14.0285.
Bae JM, Choi YY, Kim DS. Metastatic melanomas of unknown primary show better prognosis than those of known primary: a systematic review and meta-analysis of observational studies. J Am Acad Dermatol. 2015;72(1):59–70. https://doi.org/10.1016/j.jaad.2014.09.029.
Burmeister BH, Henderson MA, Ainslie J, 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. https://doi.org/10.1016/s1470-2045(12)70138-9.
There are no relevant conflicts of interest or disclosures.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Song, Y., Tieniber, A.D., Gimotty, P.A. et al. Survival Outcomes of Patients with Clinical Stage III Melanoma in the Era of Novel Systemic Therapies. Ann Surg Oncol 26, 4621–4630 (2019). https://doi.org/10.1245/s10434-019-07599-y