Most patients with melanoma that is localized to the skin can be cured with surgery. Patients with spread of melanoma to local lymph nodes or to other organs have historically been difficult to treat and often considered to be incurable. Recent advances in immune-oncology and precision cancer medicine however have vastly improved patient outcomes and many patients with advanced disease are now cured or survive for years with a high quality of life. The treatment of melanoma is tailored to each individual and may consist of surgery, precision cancer medicines, immunotherapy and chemotherapy. The specific treatment will depend on the stage and genomic profile of the cancer.1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20

Surgery for Melanoma

Surgical excision remains the primary treatment for early stage melanomas which are highly curable. Evaluating whether the melanoma has spread is important to define whether additional treatment is necessary. This can be accomplished by lymphatic mapping and a sentinel lymph node biopsy (SLNB) to assess for the presence of cancer that has spread to the regional lymph nodes. This is currently recommended for patients with primary cancers larger than 1 to 4 mm.1,2,3,4,5,6,7

Patients should be considered for complete lymph node dissection (CLND) if the sentinel node(s) has evidence of cancer. The SLNB should be performed before additional wide excision of the primary melanoma to ensure accurate lymphatic mapping.

Systemic Therapy: Precision Cancer Medicine, Chemotherapy, and Immunotherapy

Precision cancer medicines, chemotherapy, and immunotherapy are all systemic therapies commonly used in the treatment of stage II, III, and IV melanoma patients. A systemic therapy is any treatment directed at destroying cancer cells throughout the body. Systemic therapy is different from surgery in that the cancer-fighting treatments circulate in the blood to parts of the body where the cancer may have spread and can kill or eliminate cancers cells at sites great distances from the original cancer. Systemic therapy is necessary to treat any cancer that may have already spread and escaped local treatment with surgery or radiation. Systemic therapy may consist of single drugs or combinations and can be administered through a vein or delivered orally in the form of a pill, however most systemic therapies are given intravenously.

Precision Cancer Medicines

The purpose of precision cancer medicine is to define the genomic (genetic) alterations in the cancers DNA that are driving that specific cancer. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Several precision cancer medicines have been developed and improved the treatment of melanoma and include the following.8,9,10,11,12,13,14,15,16,17,18

  • Zelboraf® (vemurafenib) BRAF inhibitor
  • Tafinlar® (dabrafenib) BRAF inhibitor
  • Mekinist® (trametinib) MEK inhibitor
  • Cotellic® (cobimetinib) MEK inhibitor
  • Braftovi® (enorafenib) BRAF inhibitor
  • Mektovi® (binimetinib) MEK inhibitor

Immunotherapy

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 immune system. Several immunotherapy drugs have improved the treatment of melanoma and include the following.9,10,11,12,18,19,20

  • Opdivo (nivolumab)
  • Keytruda (pembrolizumab)
  • Yervoy® (ipilimumab)
  • Proleukin (interleukin-12)
  • Interferon

Chemotherapy

Chemotherapy is a general term used to describe any systemic treatment involving the use of drugs to kill cancer cells. Chemotherapy medications used for the management of melanoma are relatively ineffective when compared to precision cancer medicines and immunotherapy but include the following and may be used in certain circumstances.19,20

  • DTIC
  • Temador (temozolamide)

The Stage of The Melanoma Determines Primary Treatment

Stage 0: Patients with melanoma in situ (stage 0) have melanoma cells only in the outer layer of skin (epidermis). There is no invasion of the deeper layer (dermis) and therefore essentially no potential for spread.

Stage I: Patients with stage I malignant melanoma have cancer that is found in the outer layer of the skin (epidermis) and/or the upper part of the inner layer of skin (dermis) but has not spread to lymph nodes. The primary melanoma is less than 2 millimeters (1/16 of an inch) thick.

Stage II: Patients with stage II melanoma have cancer that is 1 to 2 millimeters with ulceration or greater than 2 mm with or without ulceration. Stage II melanoma has spread to the lower part of the inner layer of skin (dermis), but not into the tissue below the dermis or into nearby lymph nodes.

Stage III: Includes cancers of any thickness that have spread to the regional lymph nodes.

Stage IV-Metastatic: 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.

References

 

1 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.

2 Wagner JD, Gordon MS, Chuang TY, et al.: Current therapy of cutaneous melanoma. Plast Reconstr Surg 105 (5): 1774-99; quiz 1800-1, 2000.

3 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.

4 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.

5 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.

6 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.

7 Journal of Surgical Oncology, Vol 71, No 4, pp 209-213, 1999

8 news.bms.com/press-release/bmy/opdivo-nivolumab-combination-yervoy-ipilimumab-and-opdivo-monotherapy-significantl

9 abstracts.asco.org/199/AbstView_199_187297.html

10 news.bms.com/press-release/bmy/opdivo-nivolumab-combination-yervoy-ipilimumab-and-opdivo-monotherapy-significantl

11 Cappelli L et al. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis 2017;76:43.

12 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.

13 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.

14 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.

15 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.

16 news.cancerconnect.com/melanoma/fda-approves-mekinist-in-combination-with-tafinlar-for-advanced-melanoma-Tjpp3YHBi0-oOxvOqAHcOA/

17 nejm.org/doi/full/10.1056/NEJMoa1708539

18 Journal of Clinical Oncology, Vol 18, No12, 2000.

19 Bottomley A, Coens C, Suciu S et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation in resected Stage III melanoma: A Phase II randomized controlled trial of health-related quality of life and symptoms by the European Organisation for Research and Treatment of Cancer Melanoma Group. Journal of Clinical Oncology. 2009;27:2916-2923.

20 Viragen’s Multiferon® Demonstrates Statistically Significant Increase in Overall Survival in Melanoma Study. Available at: . Accessed October 2004.

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