Treatment & Management of Melanoma

Treatment of melanoma may consist of surgery, immunotherapy, chemotherapy and precision cancer medicines.

Medically reviewed by Dr. C.H. Weaver M.D. 12/2018

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.

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)

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.

Surgical Treatment of Melanoma: Learn More...

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.

Precision Cancer Medicine Treatment of Melanoma: Learn More...

  • 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.

Learn about immunotherapy.

  • 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.

  • 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: 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.

Recurrent or Relapsed: The melanoma has been detected or returned (recurred/relapsed) following an initial treatment.

Surgery For Melanoma

Surgery is an integral component in the management of melanoma and is used to confirm a diagnosis, determine prognosis, and treat the cancer.

Surgical Biopsy A biopsy is a procedure to remove the abnormal tissue and a small amount of normal tissue around it. Patients may want to have the sample of tissue checked by a second pathologist. If the abnormal mole or lesion is cancer, the sample of tissue may also be tested for certain genomic changes and biomarkers.

The most important initial feature that is obtained from biopsy at the time that the melanoma is diagnosed is the thickness of the melanoma (Breslow thickness, measured in millimeters). A pathologist determines this thickness by examining the melanoma under a microscope and measuring the lesion from the top to the bottom. Based on the thickness of the tumor, melanoma is divided into 3 general categories:

  • Thin melanomas, which are less than or equal to 1 mm in thickness
  • Intermediate thickness melanomas, which are between 1 mm to 4 mm
  • Thick melanomas, which are greater than 4 mm

The thicker a melanoma is determined to be at the time of diagnosis, the greater the chance that it has spread. In general, melanoma spreads to the lymph nodes in the region of the primary cancer first.(1-4)

Lymph Node Mapping & Sentinel Lymph Node Biopsy

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 following surgical removal of the cancer.

A SLNB is typically performed in patients with a primary melanoma greater than 1 mm and considered in patients with thin melanomas (< 1 mm) and adverse prognostic factors, such as vertical growth phase, Clark Level IV, regression, and ulceration.

During a SLNB a radioactive substance or blue dye is injected near the cancer. The substance or dye flows through the lymph tubes and nodes where cancer may have spread. The nodes with the radioactive substance or dye are then removed and a pathologist evaluates a sample of tissue from the removed node to check for cancer cells. If no cancer cells are found, it may not be necessary to remove more nodes.

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 CLND if the sentinel node(s) is microscopically or macroscopically positive.(5)

Complete Lymph Node Dissection

A complete lymph node dissection (CLND) may be performed in the neck, armpit or groin, depending on the site of the primary tumor and presence of palpable lymph nodes. Chronic side effects of removing lymph nodes vary, depending on the extent of disease, body habits of the patient, and inclusion of postoperative radiation to the site, but may include numbness, and swelling of the associated extremity, which is called lymphedema. Patients should discuss the risk of lymphedema and potential benefit of CLND with their doctor as there is some controversy regarding the role of CLND.(5)

Surgical Treatment of Stage I-II Melanoma

Stage I-II Melanoma – surgical removal with pathologically confirmed negative margins. Efforts been made to reduce the amount of normal skin removed without compromising the cure rate achieved with surgery. A melanoma greater than 1 millimeter appears to require a greater surgical margin to reduce the rate of recurrence at the site of origin. Most surgeons recommend a surgical margin of 2 centimeters (almost an inch) surrounding the entire cancer for melanomas greater than 1 mm. The need for skin grafting occurs in approximately 10% of patients. Over 90% of patients with melanomas of less than 1 mm are cured following surgical removal of the melanoma.(1-4)

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.(1-4)

Stage IV Melanoma – Surgery plays a role in the management of some patients with metastatic melanoma. Patients who have a limited number of lung metastases may benefit from surgical removal if they have favorable other prognostic features, such as a long period of time between diagnosis and recurrence. Surgery in some patients can eradicate disease that has incompletely responded to systemic therapy and some of these patients will survive cancer-free. Surgery can also relieve symptoms of obstruction and bleeding. Selected patients with metastatic melanoma to the gastrointestinal tract can experience prolonged survival following surgical removal of the melanoma.(1,5,6)

Recurrent Melanoma – A frequently asked question is whether a second surgery can also provide benefit to patients who have a recurrence, or return of the cancer, after already having one surgery for metastatic melanoma. Researchers reviewed the treatment outcomes for 211 patients with stage IV metastatic melanoma who were deemed clinically free of cancer after surgery. The melanoma recurred in 131 of these patients after an average of 8 months but ranging up to 7.5 years following initial treatment. After a second surgical removal of cancer from 1 to 3 sites to which the cancer had spread in the body, the average survival time after surgery was 18 months. At 5 years after surgery, 20% of patients in whom removal of all detectable cancer was complete were alive. The longer the interval between the initial treatment and the recurrence, the longer the survival time was after the repeat surgery. These findings show that a second surgery may benefit patients who have a recurrence of metastatic melanoma, provided that the surgical removal of all detectable cancer was complete. This is an important treatment option for patients with metastatic melanoma for whom other treatments are ineffective or for those who have a partial response to biologic therapies (or immunotherapies) or chemotherapy.(6)

The available data suggests that surgery plays a role in the management of some patients with metastatic melanoma. Patients who have a limited number of lung metastases may benefit from surgical removal if they have favorable other prognostic features, such as a long period of time between diagnosis and recurrence. Surgery in some patients can eradicate disease that has incompletely responded to chemotherapy and/or biological therapy and some of these patients will survive cancer-free for over 5 years. Surgery can also relieve symptoms of obstruction and bleeding. Selected patients with metastatic melanoma to the gastrointestinal tract can experience prolonged survival following surgical removal of the melanoma.(6)

Immunologic Therapy or Immuno-oncology

Immunotherapy treatment of melanoma has progressed considerably over the past few decades and has now 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. Recent promising clinical results have generated an explosion of interest and research in the field of immuno-oncology.

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.

There are several substances that boost, direct or restore normal immune defenses and include interferons, interleukins, vaccines and newer monoclonal antibodies, which are in essence a targeted or precision immunotherapy.

Researchers are mainly focused on two promising types of immunotherapy. One type creates a new, individualized treatment for each patient by removing some of the person’s immune cells, altering them genetically to kill cancer, and then infusing them back into the bloodstream. This procedure has been pioneered mainly in the treatment of leukemia or lymphoma.

The second type of immunotherapy is a group of drugs that do not have to be tailored to each patient; these are called checkpoint inhibitors. These drugs block a mechanism, called a checkpoint, that cancer uses to shut down the immune system. These drugs have been approved by the US Food and Drug Administration (FDA) to treat several types of cancer, including melanoma.(7,8)

PD-1 Checkpoint Inhibitors

Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the cancer. A diagnostic test to measure the level of PD-L1 is available and checkpoint inhibitors are effective in the management of melanoma.(7)

Keytruda® (pembrolizumab) and Opdivo (nivolumab) are sthe first anti-PD-1 drug, aimed at re-energizing a patient’s protective immune response to cancer to have received FDA approval in the U.S for the treatment of cancer.(8,9)

Opdivo® is superior to Yervoy® as initial treatment of patients with advanced melanoma. Opdivo nearly doubled the rate of progression-free survival compared to patients treated with Yervoy.(7,10)

Researchers suspect that checkpoint inhibitors might work better if they are combined with treatments that kill tumor cells because debris from dead cancer cells may help the immune system recognize its target. Studies are under way to test checkpoint inhibitors in combination with chemotherapy. But it is a delicate balance to adjust the timing and doses because in addition to killing cancer cells, chemotherapy treatments can knock out the immune system just when it is needed most.

  • Keytruda® (pembrolizumab)
  • Opdivo (nivolumab)
  • Imfinzi (durvalumab)
  • Tecentriq® (atezolizumab)

One significant side effect of checkpoint inhibitors will require further research: in addition to causing lung inflammation, checkpoint inhibitors can lead to autoimmune disease, including colitis and rheumatoid arthritis, which result from an attack on other tissues by the revved-up immune system.(11)

Yervoy® (ipilimumab) is a targeted immunotherapy directed at a protein that prevents the body’s immune system from recognizing and killing melanoma cells. It was the first contemporary immunotherapy drug shown to extend the lives of patients with advanced melanoma.[5]

More-detailed and in-depth results of the recent clinical trials evaluating checkpoint inhibitors is forth coming, and this will provide better guidance regarding their optimal use in the treatment of melanoma. Importantly, there are also ongoing clinical trials evaluating these and other novel targeted and immunotherapies for the management of melanoma; patients should discuss the potential role of these trials with their treating physician.

Precision Cancer Medicine

Not all cancer cells are alike: Cancer cells may differ from one another based on what genes have mutations. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Currently this “genomic testing” is performed on a biopsy sample of the cancer.

Once a genetic abnormality is identified, a specific precision cancer medicine or targeted therapy can be developed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells.

Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed. Precision cancer medicines can be used both instead of and in addition to chemotherapy to improve treatment outcomes.

By testing an individual’s melanoma for specific unique biomarkers doctors can offer the most personalized treatment approach utilizing precision medicines.

Melanoma Biomarkers & Medicines to Target Them

BRAF & MEKKinase 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. Lung cancers may carry the BRAFmutation known as V600E. This mutation produces an abnormal version of the BRAF kinase that stimulates cancer growth. Another mutation known as V600K may also be present. BRAF and MEK inhibitors are precision cancer medicines that block the activity of the V600E and V600K mutations respectively.(13-17)

  • 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

A combination of a BRAF and a MEK inhibitor appears to decrease the emergence of disease resistance that occurs in patients treated with a BRAF mutation. The combination of Taflinar plus Mekinist has been evaluated and FDA approved.(15,16)

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.(6)

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. mavendoctors.io/cancerconnect/melanoma/fda-approves-mekinist-in-combination-with-tafinlar-for-advanced-melanoma-Tjpp3YHBi0-oOxvOqAHcOA/

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

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