Medically reviewed by Dr. C.H. Weaver M.D. updated 9/2020
Stage III melanoma includes cancers of any thickness that have spread to the regional lymph nodes. Optimal treatment of stage III melanoma consists of surgical removal of the cancer followed by systemic adjuvant treatment to reduce the risk of cancer recurrence and prolong survival.
Surgical Treatment of Stage III Melanoma
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.(1-5)
Systemic Adjuvant Treatment of Stage III Melanoma
Systemic therapy is any treatment directed at destroying cancer cells throughout the body. Many patients with stage III melanoma are at high risk for disease recurrence because undetectable cancer cells referred to as micrometastases have already broken away from the primary cancer and traveled through the lymph and blood system to other locations in the body. The delivery of systemic cancer treatment following surgery is referred to as “adjuvant” therapy. (6,7,8)
Adjuvant treatment of stage III melanoma with newer precision cancer medicines and immunotherapy drugs is the standard of care because they delay the time to cancer recurrence and prolong survival.
Systemic Adjuvant Therapy for Stage III Melanoma
Precision Cancer Medicines
Precision cancer medicines that target the genetic makeup of the cancer and immuno-oncology (drugs that use your immune system to help fight cancer) improve the outcomes of individuals with melanoma when compared with traditional chemotherapy. These therapies are designed to target the cancer cells while minimizing damage to normal, healthy cells. Genomic testing of a patient’s cancer for unique biomarkers can identify differences at the genetic level, and determine which precision medicine is best.
The current NCCN guideline state that patients with stages IIIA, IIIB, IIIC/D melanoma (sentinel node positive) should be treated with a "Checkpoint Inhibitor" or the combination of Tafinlar/Mekinstfor patients with BRAFV600-activating mutation.
For patients who have stage III microscopic satellite or in-transit disease, systemic therapy can be considered if they have no evidence of disease after surgery or a less than complete resection. Local therapy options for less than complete excision include talimogene laherparepvec (T-VEC), Bacille Calmette-Guérin (BCG), interferon or interleukin-2, topical imiquimod for superficial dermal lesions and consideration of radiation therapy if not used previously. Regional therapy options include melphalan delivered by isolated limb perfusion or isolated limb infusion.
BRAF & MEK Kinase Inhibitors
The BRAF and MEK genes are known to play a role in cell growth, and mutations of these genes are common in several types of cancer. Approximately half of all melanomas carry a specific BRAF mutation known as V600E. This mutation produces an abnormal version of the BRAF kinase that stimulates cancer growth. Some melanomas carry another mutation known as V600K. BRAF and MEK inhibitors block the activity of the V600E and V600K mutations respectively.(8-12)
- 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. The combination of Taflinar plus Mekinist significantly improves survival compared to treatment with single agent Taflinar, when compared to no adjuvant therapy. The combination reduced the risk of disease recurrence or death by 53% and the 3-year overall survival rate was 86% in the combination-therapy group compared to 77%. Overall 4-year rates of relapse-free survival are reported to be 54% compared to 38% with placebo. (12)
Immunotherapy treatment of melanoma has also become a standard treatment. The immune system is a network of cells, tissues, and biologic substances that defend the body against viruses, bacteria, and cancer. The immune system recognizes cancer cells as foreign and can eliminate them or keep them in check—up to a point. Cancer cells are very good at finding ways to avoid immune destruction, however, so the goal of immunotherapy is to help the immune system eliminate cancer cells by either activating the immune system directly or inhibiting the mechanisms of suppression of the cancer.(6,7)
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. Opdivo (nivolumab) and Keytuda (pembrolizumab) are checkpoint inhibitors that block the PD-1 pathway and can enhance the ability of the immune system to fight cancer. Both Keytruda and Opdivo are approved as adjuvant therapy for melanoma because they improve survival. Opdivo has also been shown to be superior to Yervoy for the management of stage IIIb/c melanoma following complete surgical resection.(6,7)
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) Yervoy has also been demonstrated to be superior to Interferon treatment for stage III disease.(17)
Imlygic® (talimogene laherparepvec), the first ever FDA-approved oncolytic virus therapy, is approved for the treatment of melanoma sites in the skin and lymph nodes that cannot be surgically removed. Imlygic is given through a series of injections directly into the melanoma over the course of 6 months.
Imlygic is a genetically modified live oncolytic herpes virus therapy. When Imlygic is injected into the site of the cancer the modified herpes virus replicates inside cancer cells and causes the cancer cells to rupture and die. Imlygic may also promote tumor shrinkage, trigger a systemic immune response and prolong survival in some patients with advanced melanoma. After acting locally within the tumor, it is intended to prompt an immune response against cancer cells elsewhere in the body.
Preliminary results showed that 64 percent of injected tumors shrank by half. The vaccine shrank tumors that were directly injected as well as those that were not injected—indicating that the vaccine was triggering the immune system to fight the distant tumors.(15)
Strategies to Improve Treatment
The progress that has been made in the treatment of melanoma has resulted from patient participation in clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of melanoma.
Precision Cancer Medicines & Immunotherapy: As promising as all of the new, medicines are they typically stop working at some point because melanoma cells find another pathway that lets them start growing again. In many cancers, combination therapy improves survival and leads to cures when compared to single agent treatment. In addition to developing new precision cancer medicines and immunotherapies, researchers are testing various combinations of two or more drugs with encouraging results.
BRAF & MEK*:* The combination of a novel BRAF inhibitor Braftovi (encorafenib) with a MEK Mektovi (binimetinib) significantly delayed cancer recurrence compared to treatment with Zelboraf (vemurafenib) alone. Zelboraf was the first BRAF inhibitor approved for treatment of advanced melanoma and represented a breakthrough by significantly improving survival compared with chemotherapy, replaced the latter as a treatment option.(16)
Vaccines: Currently, no vaccine has been approved for the treatment melanoma. Melanoma vaccines produce responses, often dramatic, in some patients, but effects are far from consistent.
- Wagner JD, Gordon MS, Chuang TY, et al.: Current therapy of cutaneous melanoma. Plast Reconstr Surg 105 (5): 1774-99; quiz 1800-1, 2000.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma
- 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.
- 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.
- 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.
- 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.
- United States Food and Drug Administration. News Release. FDA approves first-of-its-kind product for the treatment of melanoma. Available here. Accessed October 27, 2015.
- [Dummer R et al “Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with](http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18%2930142-6/fulltext) [BRAF-mutant melanoma (COLUMBUS): A multicenter, open-label, randomized phase III trial”](http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18%2930142-6/fulltext) [Lancet Oncol](http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18%2930142-6/fulltext) [2018; DOI:10.1016/S1470-2045(18)30161-X.](http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18%2930142-6/fulltext)