Standard surgical treatment for patients with stage III melanoma is removal of the primary cancer with up to 2-centimeter (over an inch) margins of the adjacent skin, depending on the thickness of the primary tumor, and removal of all of the regional lymph nodes. Outcomes of patients with stage III melanoma relate primarily to the extent of lymph node metastasis.
Lymphatic mapping and sentinel lymph node biopsy (SLNB) are used to assess the presence of melanoma cells in the regional lymph nodes in order to help determine which patients may require regional lymph node dissections (LNDs) and systemic adjuvant therapy.
SLNB should be performed prior to wide excision of the primary melanoma to ensure accurate lymphatic mapping. If metastatic melanoma is detected, a complete lymph node dissection (CLND) can be performed in a second procedure. Patients can be considered for a CLND if the sentinel node(s) is microscopically or macroscopically positive.1,2,3,4,5
Systemic Adjuvant Treatment of Stage III Melanoma
Systemic therapy is any treatment directed at destroying cancer cells throughout the body. The delivery of systemic cancer treatment following surgery is referred to as “adjuvant” therapy and improves survival.6,7,8
Adjuvant treatment of stage III melanoma with newer precision cancer medicines and immunotherapy drugs have rapidly become the standard of care because they delay the time to cancer recurrence and prolong survival. Patients should discuss the role of genomic testing for determining the best therapy to be used.
Systemic therapies commonly used in the treatment of stage III melanoma include Keytruda, Opdivo, Yervoy and BRAF-MEK Inhibitors.8,9,10,11
- Zelboraf® (vemurafenib) BRAF V600E kinase inhibitor
- Tafinlar® (dabrafenib) BRAF V600E kinase inhibitor
- Braftovi® (enorafenib) BRAF inhibitor
- Mekinist® (trametinib) MEK V600 kinase inhibitor
- Cotellic® (cobimetinib) MEK V600 kinase inhibitor
- Mektovi® (binimetinib) MEK inhibitor
Combination of a BRAF and a MEK inhibitor appears to decrease the emergence of disease resistance that occurs in patients treated with BRAF inhibition alone.12
Yervoy® (ipilimumab) is a monoclonal antibody that targets CTLA4, found on the surface of T cells. CTLA4 is thought to inhibit immune responses. By targeting this molecule, Yervoy enhances the immune system’s response against tumor cells. Yervoy has been demonstrated to improve survival in stage III melanoma patients who are at high risk of recurrence following complete surgical resection.7
PD-1 “Checkpoint Inhibitors”: PD-1 is a protein that inhibits certain types of immune responses, allowing cancer cells to evade an attack by immune cells. Drugs like Opdivo (nivolumab) and Keytuda (pembrolizumab) that block the PD-1 pathway can enhance the ability of the immune system to fight cancer and are referred to as checkpoint inhibitors for their ability to help the immune system recognize and attack cancer.6,7,13
1 Wagner JD, Gordon MS, Chuang TY, et al.: Current therapy of cutaneous melanoma. Plast Reconstr Surg 105 (5): 1774-99; quiz 1800-1, 2000.
2 Cohn-Cedermark G, Rutqvist LE, Andersson R, et al.: Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm. Cancer 89 (7): 1495-501, 2000.
3 Balch CM, Soong SJ, Smith T, et al.: Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol 8 (2): 101-8, 2001.
4 Heaton KM, Sussman JJ, Gershenwald JE, et al.: Surgical margins and prognostic factors in patients with thick (>4mm) primary melanoma. Ann Surg Oncol 5 (4): 322-8, 1998.
5 Wong SL, Balch CM, Hurley P, et al.: Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J Clin Oncol 30 (23): 2912-8, 2012.
6 Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. September 10, 2017DOI: 10.1056/NEJMoa1709030.
7 Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. New England Journal of Medicine. 2011;364(26):2517-26. doi: 10.1056/NEJMoa1104621.
10 Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New England Journal of Medicine. 2011;364(26):2507-16. doi: 10.1056/NEJMoa1103782.
11 Hauschild A, Grob JJ, 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. doi: 10.1016/S0140-6736(12)60868-X.
12 Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. New England Journal of Medicine.2012;367(18):1694-703. doi: 10.1056/NEJMoa1210093.
13 Robert C, Long GV, Brady B, et al. Nivolumab in Previously Untreated Melanoma without BRAF Mutation. New England Journal of Medicine [early online publication]. November 16, 2014.
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