Stages of Melanoma
Treatment of Stage I-II Melanoma
Stage I-II Melanoma is treated with surgery and some individuals may benefit from adjuvant therapy.1,2,3,4
Surgical treatment of stage II melanoma
Treatment of stage I-II melanoma typically involves a single surgical procedure in which a local excision of the cancer is performed as well as a sentinel lymph node biopsy (SLNB). When melanoma spreads it typically first invades the local lymph nodes so their evaluation is essential for treatment planning. If the lymph nodes are involved with cancer, additional systemic adjuvant treatment may be necessary. Approximately 15% of patients undergoing SLNB have a positive SLN for stage II disease(pathologically stage III).5
Adjuvant treatment of stage I-II melanoma
Despite undergoing sentinel lymph node evaluations that are negative, some patients with stage II melanoma are at increased risk for having small amounts of cancer that have not been detected. Patients with thick melanomas (> 4 mm) who have evidence of ulceration are considered at high risk for recurrence. The delivery of cancer treatment aimed at killing micrometastases following local treatment with surgery is referred to as “adjuvant” therapy.
Patients should discuss the role of adjuvant interferon and participation in clinical trials evaluating newer precision cancer medicines and immunotherapy which have improved the outcomes of patients with stage III melanoma and are currently being evaluated in stage II disease. Patients should ask their doctor about these advances and if they should undergo genomic testing of their cancer and /or participate in a clinical trial evaluating newer adjuvant therapy treatments.6,7,8,9
References
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 Kirkwood JM, Strawderman MH, Ernstoff MS, et al.: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14 (1): 7-17, 1996.
7 Kirkwood JM, Ibrahim JG, Sondak VK, et al.: High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18 (12): 2444-58, 2000.
8 Eggermont AM, Suciu S, Santinami M, et al.: Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomized phase III trial. Lancet 372 (9633): 117-26, 2008.
9 Ribas A, Hodi FS, Kefford R, et al. Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL). J Clin Oncol 32:5s, 2014.
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.1,2,3,4,5
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
BRAF inhibitors
- Zelboraf® (vemurafenib) BRAF V600E kinase inhibitor
- Tafinlar® (dabrafenib) BRAF V600E kinase inhibitor
- Braftovi® (enorafenib) BRAF inhibitor
MEK inhibitors
- Mekinist® (trametinib) MEK V600 kinase inhibitor
- Cotellic® (cobimetinib) MEK V600 kinase inhibitor
- Mektovi® (binimetinib) MEK inhibitor
Combination therapy
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
References
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.
8 https://www.nejm.org/doi/full/10.1056/NEJMoa1708539
9 http://news.cancerconnect.com/fda-approves-mekinist-in-combination-with-tafinlar-for-advanced-melanoma/
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.
Treatment of Stage IV – Metastatic Melanoma
Individuals with stage IV, or metastatic, melanoma have cancer that has spread from its site of origin to distant lymph nodes or other distant sites in the body, such as the liver, lungs, or brain. Significant advances in the treatment of advanced melanoma including the development of precision cancer medicines and immunotherapy have largely replaced chemotherapy and many patients are living for years as a result of these newer treatments.
Newer precision cancer medicines and immunotherapy drugs are 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 Melanoma include:
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.1,2,3,4,5 Combinations of a BRAF and a MEK inhibitor appear to decrease the emergence of disease resistance that occurs in patients treated with BRAF inhibition alone.5
BRAF inhibitors
- Zelboraf®(vemurafenib) BRAF V600E kinase inhibitor
- Tafinlar®(dabrafenib) BRAF V600E kinase inhibitor
- Braftovi® (enorafenib) BRAF inhibitor
MEK inhibitors
- Mekinist®(trametinib) MEK V600 kinase inhibitor
- Cotellic® (cobimetinib) MEK V600 kinase inhibitor
- Mektovi® (binimetinib) MEK inhibitor
Immuno-Oncology
Immunotherapy treatment of melanoma has also progressed considerably and 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
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.
PD-1 “Checkpoint Inhibitors”: Drugs 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. Opdivo (nivolumab) and Keytruda (pembrolizumab) is a checkpoint inhibitors that are approved for treatment of advanced melanoman and are superior to Yervoy.7,8
Proleukin® (interleukine 12) is an immunotherapy agent has traditionally been given in high doses to patients with melanoma, administered either intravenously by rapid infusion or by continuous infusion. Although high doses of Proleukin® historically have been associated with severe side effects management of these has significantly improved over the past decade making this treatment more tolerable.9
Chemotherapy
Although once the standard of care, chemotherapy has largely been replaced by the newer precision cancer medicines and immunotherapies in the management of advanced melanoma. Chemotherapy is still being used in some situations and may represent an appropriate treatment option for selected patients alone or in combination with newer targeted immunotherapies. DTIC (dacarbazine) has been the standard chemotherapy for the treatment of metastatic melanoma, with an overall response rate of approximately 15-20% and no clinical trials directly comparing DTIC to different chemotherapy combinations have demonstrated clear superiority of drug combinations over DTIC alone.10,11
- DTIC (dacarbazine)
- Platinum
- Tamadol (temazolamide)
- Avastin
References
1 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.
2 Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomized controlled trial. Lancet. 2012;380(9839):358-65. doi: 10.1016/S0140-6736(12)60868-X.
3 Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. New England Journal of Medicine. 2012;367(2):107-14. doi: 10.1056/NEJMoa1203421.
4 http://news.cancerconnect.com/fda-approves-mekinist-in-combination-with-tafinlar-for-advanced-melanoma/
5 https://www.nejm.org/doi/full/10.1056/NEJMoa1708539
6 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.
8 http://abstracts.asco.org/199/AbstView_199_187297.html
9 Cancer, Vol 88, No 9, pp 2042-2046, 2003
10 Rao RD, Holtan SG, Ingle JN et al. Combination of Paclitaxel and Carboplatin as Second-Line Therapy for Patients with Metastatic Melanoma. Cancer. 2006;106:375-82.
11 Perez DG, Suman VJ, Fitch TR, et al. Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma. Cancer. 2009; 115: 119-127.