Melanoma

  • Dana-Farber/Brigham and Women's Cancer Care

    Melanoma is a form of skin cancer that begins in melanocytes (the cells that make the pigment melanin). Melanoma usually begins in a mole. Learn about melanoma and find information on how we support and care for people with melanoma before, during, and after treatment.

Treatment 

The specialists at the Center for Melanoma Oncology at Dana Farber/Brigham and Women's Cancer Center focus exclusively on melanoma treatment. We work closely together to evaluate and treat patients with confirmed or suspected melanoma.

Our team of health care professionals includes dermatologists, pathologists, surgical and medical oncologists, plastic surgeons, and radiation oncologists.

Our clinicians are experts in treating all types of melanoma, including intraocular melanoma and mucosal melanoma.

As part of our commitment to melanoma research, we also offer a variety of clinical trials that allow us to provide a broad range of treatment options for high-risk patients or patients with metastatic melanoma.

We understand that cancer treatment can be challenging both physically and emotionally. That knowledge informs how our specialists work with you to create a care plan that takes your individual needs into account.

Patients and their families have access to a range of support services, including nutrition counseling, support groups, and integrative therapies such as meditation and Reiki.

Learn more about our melanoma treatment and research 

Contact us 

 New patients 

If you have never been seen before at Dana-Farber/Brigham and Women's Cancer Center, please call 877-442-3324 or use this online form to make an appointment.

For other patient questions or information, call us at 617-632-5055.

Fax: 617-632-6727

Referring physicians: 617-632-6869

Mailing address
Dana-Farber Cancer Institute
Attn: Melanoma Disease Center
450 Brookline Ave.
Boston, MA 02215 

Information for: Patients | Healthcare Professionals

General Information About Merkel Cell Carcinoma

Merkel cell carcinoma is a very rare disease in which malignant (cancer) cells form in the skin.

Merkel cells are found in the top layer of the skin. These cells are very close to the nerve endings that receive the sensation of touch. Merkel cell carcinoma, also called neuroendocrine carcinoma of the skin or trabecular cancer, is a very rare type of skin cancer that forms when Merkel cells grow out of control. Merkel cell carcinoma starts most often in areas of skin exposed to the sun, especially the head and neck, as well as the arms, legs, and trunk.

Anatomy of the skin with Merkel cells; drawing shows normal skin anatomy, including the epidermis, dermis, hair follicles, sweat glands, hair shafts, veins, arteries, fatty tissue, nerves, lymph vessels, oil glands, and subcutaneous tissue. The pullout shows a close-up of the epidermis with Merkel cells above the dermis with a vein and artery. Nerves are connected to Merkel cells.  
Anatomy of the skin showing the epidermis, dermis, and subcutaneous tissue. Merkel cells are in the layer of basal cells at the deepest part of the epidermis and are connected to nerves.

Merkel cell carcinoma tends to grow quickly and to metastasize (spread) at an early stage. It usually spreads first to nearby lymph nodes and then may spread to lymph nodes or skin in distant parts of the body, lungs, brain, bones, or other organs.

Sun exposure and having a weak immune system can affect the risk of Merkel cell carcinoma.

Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn't mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Risk factors for Merkel cell carcinoma include the following:

  • Being exposed to a lot of natural sunlight.
  • Being exposed to artificial sunlight, such as from tanning beds or psoralen and ultraviolet A (PUVA) therapy for psoriasis.
  • Having an immune system weakened by disease, such as chronic lymphocytic leukemia or HIVinfection.
  • Taking drugs that make the immune system less active, such as after an organ transplant.
  • Having a history of other types of cancer.
  • Being older than 50 years, male, or white.

Merkel cell carcinoma usually appears as a single painless lump on sun-exposed skin.

This and other changes in the skin may be caused by Merkel cell carcinoma or by other conditions. Check with your doctor if you see changes in your skin.

Merkel cell carcinoma usually appears on sun-exposed skin as a single lump that is:

  • Fast-growing.
  • Painless.
  • Firm and dome-shaped or raised.
  • Red or violet in color.

Tests and procedures that examine the skin are used to detect (find) and diagnose Merkel cell carcinoma.

The following tests and procedures may be used:

  • Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
  • Full-body skin exam: A doctor or nurse checks the skin for bumps or spots that look abnormal in color, size, shape, or texture. The size, shape, and texture of the lymph nodes will also be checked.
  • Skin biopsy: The removal of skin cells or tissues so they can be viewed under a microscope by a pathologist to check for signs of cancer.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) and treatment options depend on the following:

  • The stage of the cancer (the size of the tumor and whether it has spread to the lymph nodes or other parts of the body).
  • Where the cancer is in the body.
  • Whether the cancer has just been diagnosed or has recurred (come back).
  • The patient's age and general health.

Prognosis also depends on how deeply the tumor has grown into the skin.

Stages of Merkel Cell Carcinoma

After Merkel cell carcinoma has been diagnosed, tests are done to find out if cancer cells have spread to other parts of the body.

The process used to find out if cancer has spread to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment.

The following tests and procedures may be used in the staging process:

  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. A CT scan of the chest and abdomen may be used to check for primarysmall cell lung cancer, or to find Merkel cell carcinoma that has spread. A CT scan of the head and neck may also be used to find Merkel cell carcinoma that has spread to the lymph nodes. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • PET scan (positron emission tomography scan): A procedure to find malignanttumorcells in the body. A small amount of radioactiveglucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
  • Lymph node biopsy: There are two main types of lymph node biopsy used to stage Merkel cell carcinoma.
    • Sentinel lymph node biopsy: The removal of the sentinel lymph node during surgery. The sentinel lymph node is the first lymph node to receive lymphatic drainage from a tumor. It is the first lymph node the cancer is likely to spread to from the tumor. A radioactive substance and/or blue dye is injected near the tumor. The substance or dye flows through the lymph ducts to the lymph nodes. The first lymph node to receive the substance or dye is removed. A pathologist views the tissue under a microscope to look for cancer cells. If cancer cells are not found, it may not be necessary to remove more lymph nodes.
      Sentinel lymph node biopsy of the skin. The first of three panels shows a radioactive substance and/or blue dye injected near the tumor; the middle panel shows that the injected material is followed visually and/or with a probe that detects radioactivity to find the sentinel nodes (the first lymph nodes to take up the material); the third panel shows the removal of the tumor and the sentinel nodes to check for cancer cells. 
      Sentinel lymph node biopsy of the skin. A radioactive substance and/or blue dye is injected near the tumor (first panel). The injected material is detected visually and/or with a probe that detects radioactivity (middle panel). The sentinel nodes (the first lymph nodes to take up the material) are removed and checked for cancer cells (last panel).
    • Lymph node dissection: A surgical procedure in which the lymph nodes are removed and a sample of tissue is checked under a microscope for signs of cancer. For a regional lymph node dissection, some of the lymph nodes in the tumor area are removed. For a radical lymph node dissection, most or all of the lymph nodes in the tumor area are removed. This procedure is also called lymphadenectomy.
     
  • Immunohistochemistry: A test that uses antibodies to check for certain antigens in a sample of tissue. The antibody is usually linked to a radioactive substance or a dye that causes the tissue to light up under a microscope. This type of test may be used to tell the difference between different types of cancer.

There are three ways that cancer spreads in the body.

Cancer can spread through tissue, the lymph system, and the blood:

  • Tissue. The cancer spreads from where it began by growing into nearby areas.
  • Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
  • Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

Cancer may spread from where it began to other parts of the body.

When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.

  • Lymph system. The cancer gets into the lymph system, travels through the lymph vessels, and forms a tumor (metastatic tumor) in another part of the body.
  • Blood. The cancer gets into the blood, travels through the blood vessels, and forms a tumor (metastatic tumor) in another part of the body.

The metastatic tumor is the same type of cancer as the primary tumor. For example, if Merkel cell carcinoma spreads to the liver, the cancer cells in the liver are actually cancerous Merkel cells. The disease is metastatic Merkel cell carcinoma, not liver cancer.

The following stages are used for Merkel cell carcinoma:

Tumor size compared to everyday objects; shows various measurements of a tumor compared to a pea, peanut, walnut, and lime  
Pea, peanut, walnut, and lime show tumor sizes.

Stage 0 (carcinoma in situ)

In stage 0, the tumor is a group of abnormalcells that remain in the place where they first formed and have not spread. These abnormal cells may become cancer and spread to lymph nodes or distant parts of the body.

Stage IA

In stage IA, the tumor is 2 centimeters or smaller at its widest point and no cancer is found when the lymph nodes are checked under a microscope.

Stage IB

In stage IB, the tumor is 2 centimeters or smaller at its widest point and no swollen lymph nodes are found by a physical exam or imaging tests.

Stage IIA

In stage IIA, the tumor is larger than 2 centimeters and no cancer is found when the lymph nodes are checked under a microscope.

Stage IIB

In stage IIB, the tumor is larger than 2 centimeters and no swollen lymph nodes are found by a physical exam or imaging tests.

Stage IIC

In stage IIC, the tumor may be any size and has spread to nearby bone, muscle, connective tissue, or cartilage. It has not spread to lymph nodes or distant parts of the body.

Stage IIIA

In stage IIIA, the tumor may be any size and may have spread to nearby bone, muscle, connective tissue, or cartilage. Cancer is found in the lymph nodes when they are checked under a microscope.

Stage IIIB

In stage IIIB, the tumor may be any size and may have spread to nearby bone, muscle, connective tissue, or cartilage. Cancer has spread to the lymph nodes near the tumor and is found by a physical exam or imaging test. The lymph nodes are removed and cancer is found in the lymph nodes when they are checked under a microscope. There may also be a second tumor, which is either:

  • Between the primary tumor and nearby lymph nodes; or
  • Farther away from the center of the body than the primary tumor is.

Stage IV

In stage IV, the tumor may be any size and has spread to distant parts of the body, such as the liver, lung, bone, or brain.

Recurrent Merkel Cell Carcinoma

RecurrentMerkel cell carcinoma is cancer that has recurred (come back) after it has been treated. The cancer may come back in the skin, lymph nodes, or other parts of the body. It is common for Merkel cell carcinoma to recur.

Treatment Option Overview

There are different types of treatment for patients with Merkel cell carcinoma.

Different types of treatments are available for patients with Merkel cell carcinoma. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Three types of standard treatment are used:

Surgery

One or more of the following surgical procedures may be used to treat Merkel cell carcinoma:

  • Wide local excision: The cancer is cut from the skin along with some of the tissue around it. A sentinel lymph node biopsy may be done during the wide local excision procedure. If there is cancer in the lymph nodes, a lymph node dissection also may be done.
  • Lymph node dissection: A surgical procedure in which the lymph nodes are removed and a sample of tissue is checked under a microscope for signs of cancer. For a regional lymph node dissection, some of the lymph nodes in the tumor area are removed; for a radical lymph node dissection, most or all of the lymph nodes in the tumor area are removed. This procedure is also called lymphadenectomy.

Even if the doctor removes all the cancer that can be seen at the time of the surgery, some patients may be given chemotherapy or radiation therapy after surgery to kill any cancer cells that are left. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant therapy.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping the cells from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.

New types of treatment are being tested in clinical trials.

Information about clinical trials is available from the NCI Web site.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI's listing of clinical trials.

Follow-up tests may be needed.

Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests. This is sometimes called re-staging.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.

Treatment Options by Stage

Stage I and Stage II Merkel Cell Carcinoma

Treatment of stage I and stage IIMerkel cell carcinoma may include the following:

  • Surgery to remove the tumor, such as wide local excision with or without lymph node dissection.
  • Radiation therapy after surgery.
  • A clinical trial of a new treatment.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I neuroendocrine carcinoma of the skin and stage II neuroendocrine carcinoma of the skin. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Stage III Merkel Cell Carcinoma

Treatment of stage IIIMerkel cell carcinoma may include the following:

  • Wide local excision with or without lymph node dissection.
  • Radiation therapy.
  • A clinical trial of chemotherapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III neuroendocrine carcinoma of the skin. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Stage IV Merkel Cell Carcinoma

Treatment of stage IVMerkel cell carcinoma may include the following as palliative treatment to relieve symptoms and improve quality of life:

  • Chemotherapy.
  • Surgery.
  • Radiation therapy.
  • A clinical trial of a new treatment.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV neuroendocrine carcinoma of the skin. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Treatment Options for Recurrent Merkel Cell Carcinoma

Treatment of recurrentMerkel cell carcinoma may include the following:

  • Wide local excision to remove a larger area of tissue than was removed in earlier surgery. A lymph node dissection may also be done.
  • Radiation therapy after surgery.
  • Chemotherapy.
  • Radiation therapy and/or surgery as palliative treatment to relieve symptoms and improve quality of life.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent neuroendocrine carcinoma of the skin. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

To Learn More About Merkel Cell Carcinoma

For more information from the National Cancer Institute about Merkel cell carcinoma, see the following:

For general cancer information and other resources from the National Cancer Institute, see the following:


This information is provided by the National Cancer Institute.

This information was last updated on May 5, 2014.


General Information About Melanoma

Melanoma is a malignant tumor of melanocytes, which are the cells that make the pigment melanin and are derived from the neural crest. Although most melanomas arise in the skin, they may also arise from mucosal surfaces or at other sites to which neural crest cells migrate, including the uveal tract. Uveal melanomas differ significantly from cutaneous melanoma in incidence, prognostic factors, molecular characteristics, and treatment. (Refer to the PDQ summary on Intraocular (Uveal) Melanoma Treatment for more information.)

Incidence and Mortality

Estimated new cases and deaths from melanoma in the United States in 2014:[1]

  • New cases: 76,100.
  • Deaths: 9,710.

Skin cancer is the most common malignancy diagnosed in the United States, with 3.5 million cancers diagnosed in 2 million people annually.[1] Melanoma represents less than 5% of skin cancers but results in most deaths.[1][2] The incidence has been increasing over the past four decades.[1] Elderly men are at highest risk; however, melanoma is the most common cancer in young adults aged 25 to 29 years and the second most common cancer in those aged 15 to 29 years.[3] Ocular melanoma is the most common cancer of the eye, with approximately 2,000 cases diagnosed annually.

Risk Factors

Risk factors for melanoma include both intrinsic (genetic and phenotype) and extrinsic (environmental or exposure) factors:

  • Sun exposure.
  • Pigmentary characteristics.
  • Multiple nevi.
  • Family and personal history of melanoma.
  • Immunosuppression.
  • Environmental exposures.

(Refer to the PDQ summaries on Skin Cancer Prevention and the Genetics of Skin Cancer for more information about risk factors.)

Anatomy

Schematic representation of normal skin; drawing shows normal skin anatomy, including the epidermis, dermis, hair follicles, sweat glands, hair shafts, veins, arteries, fatty tissue, nerves, lymph vessels, oil glands, and subcutaneous tissue. The pullout shows a close-up of the squamous cell and basal cell layers of the epidermis, the basement membrane in between the epidermis and dermis, and the dermis with blood vessels. Melanin is shown in the cells. A melanocyte is shown in the layer of basal cells at the deepest part of the epidermis. 
Schematic representation of normal skin. Melanocytes are also present in normal skin and serve as the source cell for melanoma. The relatively avascular epidermis houses both basal cell keratinocytes and squamous epithelial keratinocytes, the source cells for basal cell carcinoma and squamous cell carcinoma, respectively. The separation between epidermis and dermis occurs at the basement membrane zone, located just inferior to the basal cell keratinocytes.

Screening

Refer to the PDQ summary on Skin Cancer Screening for more information.

Clinical Features

Melanoma occurs predominantly in adults, and more than 50% of the cases arise in apparently normal areas of the skin. Although melanoma can occur anywhere, including on mucosal surfaces and the uvea, melanoma in women occurs more commonly on the extremities, and in men it occurs most commonly on the trunk or head and neck.[4]

Early signs in a nevus that would suggest a malignant change include the following:

  • Darker or variable discoloration.
  • Itching.
  • An increase in size or the development of satellites.
  • Ulceration or bleeding (later signs).
Melanoma Lesions

 

Photograph of a large, asymmetrical, red and brown lesion on the skin. 

 

 

Photograph of a brown lesion with a large and irregular border on the skin. 

 

 

Photograph of a large, asymmetrical, red and brown lesion on the skin. 

 

Diagnosis

A biopsy, preferably by local excision, should be performed for any suspicious lesions. Suspicious lesions should never be shaved off or cauterized. The specimens should be examined by an experienced pathologist to allow for microstaging.

Studies show that distinguishing between benign pigmented lesions and early melanomas can be difficult, and even experienced dermatopathologists can have differing opinions. To reduce the possibility of misdiagnosis for an individual patient, a second review by an independent qualified pathologist should be considered.[5][6] Agreement between pathologists in the histologic diagnosis of melanomas and benign pigmented lesions has been studied and found to be considerably variable.[5][6]

Evidence (discordance in histologic evaluation):

  1. One study found that there was discordance on the diagnosis of melanoma versus benign lesions in 37 of 140 cases examined by a panel of experienced dermatopathologists. For the histologic classification of cutaneous melanoma, the highest concordance was attained for Breslow thickness and presence of ulceration, while the agreement was poor for other histologic features such as Clark level of invasion, presence of regression, and lymphocytic infiltration.[5]
  2. In another study, 38% of cases examined by a panel of expert pathologists had two or more discordant interpretations.[6]

Prognostic Factors

Prognosis is affected by the characteristics of primary and metastatic tumors. The most important prognostic factors have been incorporated into the revised 2009 American Joint Committee on Cancer staging and include the following:[4][7][8][9]

  • Thickness and/or level of invasion of the melanoma.
  • Mitotic index, defined as mitoses per millimeter.
  • Ulceration or bleeding at the primary site.
  • Number of regional lymph nodes involved, with distinction of macrometastasis and micrometastasis.
  • Systemic metastasis.
    • Site—nonvisceral versus lung versus all other visceral sites.
    • Elevated serum lactate dehydrogenase level.
     

Patients who are younger, who are female, and who have melanomas on their extremities generally have better prognoses.[4][7][8][9]

Microscopic satellites, recorded as present or absent, in stage I melanoma may be a poor prognostic histologic factor, but this is controversial.[10] The presence of tumor infiltrating lymphocytes, which may be categorized as brisk, nonbrisk, or absent, is under study as a potential prognostic factor.[11]

The risk of relapse decreases substantially over time, although late relapses are not uncommon.[12][13]

Related Summaries

Other PDQ summaries containing information related to melanoma include the following:

  • Skin Cancer Prevention
  • Skin Cancer Screening
  • Skin Cancer Treatment
  • Intraocular (Uveal) Melanoma Treatment

References:

  1. American Cancer Society: Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed May 21, 2014.

  2. Melanoma. Bethesda, Md: National Library of Medicine, 2012. Available online. Last accessed May 15, 2014.

  3. Bleyer A, O’Leary M, Barr R, et al., eds.: Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival: 1975-2000. Bethesda, Md: National Cancer Institute, 2006. NIH Pub. No. 06-5767. Also available online. Last accessed May 27, 2014.

  4. Slingluff CI Jr, Flaherty K, Rosenberg SA, et al.: Cutaneous melanoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1643-91.

  5. Corona R, Mele A, Amini M, et al.: Interobserver variability on the histopathologic diagnosis of cutaneous melanoma and other pigmented skin lesions. J Clin Oncol 14 (4): 1218-23, 1996.

  6. Farmer ER, Gonin R, Hanna MP: Discordance in the histopathologic diagnosis of melanoma and melanocytic nevi between expert pathologists. Hum Pathol 27 (6): 528-31, 1996.

  7. Balch CM, Soong S, Ross MI, et al.: Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial. Ann Surg Oncol 7 (2): 87-97, 2000.

  8. Manola J, Atkins M, Ibrahim J, et al.: Prognostic factors in metastatic melanoma: a pooled analysis of Eastern Cooperative Oncology Group trials. J Clin Oncol 18 (22): 3782-93, 2000.

  9. Balch CM, Gershenwald JE, Soong SJ, et al.: Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27 (36): 6199-206, 2009.

  10. León P, Daly JM, Synnestvedt M, et al.: The prognostic implications of microscopic satellites in patients with clinical stage I melanoma. Arch Surg 126 (12): 1461-8, 1991.

  11. Mihm MC Jr, Clemente CG, Cascinelli N: Tumor infiltrating lymphocytes in lymph node melanoma metastases: a histopathologic prognostic indicator and an expression of local immune response. Lab Invest 74 (1): 43-7, 1996.

  12. Shen P, Guenther JM, Wanek LA, et al.: Can elective lymph node dissection decrease the frequency and mortality rate of late melanoma recurrences? Ann Surg Oncol 7 (2): 114-9, 2000.

  13. Tsao H, Cosimi AB, Sober AJ: Ultra-late recurrence (15 years or longer) of cutaneous melanoma. Cancer 79 (12): 2361-70, 1997.

Cellular and Molecular Classification of Melanoma

The descriptive terms for clinicopathologic cellular subtypes of malignant melanoma should be considered of historic interest only; they do not have independent prognostic or therapeutic significance. The cellular subtypes are the following:

  • Superficial spreading.
  • Nodular.
  • Lentigo maligna.
  • Acral lentiginous (palmar/plantar and subungual).
  • Miscellaneous unusual types:
    • Mucosal lentiginous (oral and genital).
    • Desmoplastic.
    • Verrucous.
     

Identification of activating mutations in the mitogen-activated protein (MAP) kinase pathway served as a catalyst to develop a molecular classification of melanoma. Such a classification provides potential drug targets, directions for future clinical trials, and the ability to select patients for targeted therapies.

BRAF gene mutations  

BRAF (V-raf murine sarcoma viral oncogene homolog B1) genes, first reported in 2002, are the most frequent mutations in cutaneous melanoma. Approximately 40% to 60% of malignant melanomas harbor a single nucleotide transversion in BRAF. Most have a mutation that results in a substitution from valine to glutamic acid at position 600 (BRAF V600E); less frequent mutations include valine 600 to lysine or arginine residues (V600K/R).[1]

Drugs that target this mutation by inhibiting BRAF are under evaluation in clinical trials. Vemurafenib was approved by the U.S. Food and Drug Administration (FDA) in 2011 for the treatment of unresectable or metastatic melanoma in patients who test positive for the BRAF mutation, as detected by an FDA-approved test (e.g., cobas 4800 BRAF V600 Mutation Test).

Other gene mutations  

In smaller subsets of cutaneous melanoma, other activating mutations have been described, including the following:

  • NRAS (neuroblastoma RAS viral [v-ras] oncogene homolog): Approximately 15% to 20% of melanomas harbor an oncogenic NRAS mutation.[2][3]
  • c-KIT: A c-KIT mutation, or increased copy number, is associated with mucosal and acral melanomas (which comprise 6%–7% of melanomas in whites but are the most common subtype in the Asian population).[4][5][6]
  • CDK4 (cyclin-dependent kinase 4): CDK4 mutations have been described in approximately 4% of melanomas and are also more common in acral and mucosal melanomas.[7][8]

Drugs developed to target these mutations are currently in clinical trials.

Additional oncogenes and tumor-suppressor gene candidates currently under evaluation include P13K, AKT, P53, PTEN, mTOR, Bcl-2, and MITF.

Uveal melanoma  

Uveal melanomas differ significantly from cutaneous melanomas; in one series, 83% of 186 uveal melanomas were found to have a constitutively active somatic mutation in GNAQ or GNA11.[9][10] (Refer to the PDQ summary on Intraocular (Uveal) Melanoma Treatment for more information.)

References:

  1. Pollock PM, Meltzer PS: A genome-based strategy uncovers frequent BRAF mutations in melanoma. Cancer Cell 2 (1): 5-7, 2002.

  2. Edlundh-Rose E, Egyházi S, Omholt K, et al.: NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing. Melanoma Res 16 (6): 471-8, 2006.

  3. Goel VK, Lazar AJ, Warneke CL, et al.: Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma. J Invest Dermatol 126 (1): 154-60, 2006.

  4. Hodi FS, Friedlander P, Corless CL, et al.: Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 26 (12): 2046-51, 2008.

  5. Guo J, Si L, Kong Y, et al.: Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 29 (21): 2904-9, 2011.

  6. Carvajal RD, Antonescu CR, Wolchok JD, et al.: KIT as a therapeutic target in metastatic melanoma. JAMA 305 (22): 2327-34, 2011.

  7. Curtin JA, Fridlyand J, Kageshita T, et al.: Distinct sets of genetic alterations in melanoma. N Engl J Med 353 (20): 2135-47, 2005.

  8. Stark M, Hayward N: Genome-wide loss of heterozygosity and copy number analysis in melanoma using high-density single-nucleotide polymorphism arrays. Cancer Res 67 (6): 2632-42, 2007.

  9. Van Raamsdonk CD, Bezrookove V, Green G, et al.: Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457 (7229): 599-602, 2009.

  10. Van Raamsdonk CD, Griewank KG, Crosby MB, et al.: Mutations in GNA11 in uveal melanoma. N Engl J Med 363 (23): 2191-9, 2010.

Stage Information for Melanoma

Clinical staging is based on whether the tumor has spread to regional lymph nodes or distant sites. For melanoma that is clinically confined to the primary site, the chance of lymph node or systemic metastases increases as the thickness and depth of local invasion increases, which worsens the prognosis. Melanoma can spread by local extension (through lymphatics) and/or by hematogenous routes to distant sites. Any organ may be involved by metastases, but lungs and liver are common sites.

The microstage of malignant melanoma is determined on histologic examination by the vertical thickness of the lesion in millimeters (Breslow classification) and/or the anatomic level of local invasion (Clark classification). The Breslow thickness is more reproducible and more accurately predicts subsequent behavior of malignant melanoma in lesions thicker than 1.5 mm and should always be reported.

Accurate microstaging of the primary tumor requires careful histologic evaluation of the entire specimen by an experienced pathologist.

Clark Classification (Level of Invasion)

Table 1. Clark Classification (Level of Invasion)

Level of Invasion

Description

Level I

Lesions involving only the epidermis (in situ melanoma); not an invasive lesion.

Level II

Invasion of the papillary dermis; does not reach the papillary-reticular dermal interface.

Level III

Invasion fills and expands the papillary dermis but does not penetrate the reticular dermis.

Level IV

Invasion into the reticular dermis but not into the subcutaneous tissue.

Level V

Invasion through the reticular dermis into the subcutaneous tissue.

American Joint Committee on Cancer (AJCC) Stage Groupings and TNM Definitions

Melanoma staging is defined by the AJCC's TNM classification system.[1]

Table 2. TNM Definitions for Stage 0 Melanoma
Stage TNM Description
Clinicala  Pathologicalb     
0 0 Tis Melanoma in situ 
N0 No regional metastases
M0 No detectable evidence of distant metastases
Stage 0 melanoma in situ; drawing shows skin anatomy with an abnormal area on the surface of the skin. Both normal and abnormal melanocytes and melanin are shown in the epidermis (outer layer of the skin). Also shown are the dermis (inner layer of the skin) and the subcutaneous tissue below the dermis. 
Stage 0 melanoma in situ; drawing shows skin anatomy with an abnormal area on the surface of the skin. Both normal and abnormal melanocytes and melanin are shown in the epidermis (outer layer of the skin). Also shown are the dermis (inner layer of the skin) and the subcutaneous tissue below the dermis.
T = primary tumor; N = regional lymph nodes; M = distant metastasis. 
Adapted with permission from AJCC: Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44. 
The explanations for superscripts a and b are at the end of Table 7. 
Table 3. TNM Definitions for Stage I Melanoma
Stage TNM Description
Clinicala  Pathologicalb     
IA IA T1a Melanomas ≤1.0 mm in thickness without ulceration; mitosis <1/mm2 
N0 No regional metastases detected
M0 No detectable evidence of distant metastases
IB IB T1b Melanomas ≤1.0 mm in thickness with ulceration or mitoses ≥1/mm2 
T2a Melanomas 1.01–2.0 mm in thickness without ulceration
N0 No regional metastases detected
M0 No detectable evidence of distant metastases
Two-panel drawing of stage I melanoma. The first panel shows a stage IA tumor that is not more than 1 millimeter thick, with no ulceration (break in the skin). The second panel shows two stage IB tumors. One tumor is not more than 1 millimeter thick, with ulceration, and the other tumor is more than 1 but not more than 2 millimeters thick, with no ulceration. Also shown are the epidermis (outer layer of the skin), the dermis (inner layer of the skin), and the subcutaneous tissue below the dermis. 
Two-panel drawing of stage I melanoma. The first panel shows a stage IA tumor that is not more than 1 millimeter thick, with no ulceration (break in the skin). The second panel shows two stage IB tumors. One tumor is not more than 1 millimeter thick, with ulceration, and the other tumor is more than 1 but not more than 2 millimeters thick, with no ulceration. Also shown are the epidermis (outer layer of the skin), the dermis (inner layer of the skin), and the subcutaneous tissue below the dermis.

T = primary tumor; N = regional lymph nodes; M = distant metastasis. 
Adapted with permission from AJCC: Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44. 
The explanations for superscripts a and b are at the end of Table 7. 
Table 4. TNM Definitions for Stage II Melanoma
Stage TNM Description
Clinicala  Pathologicalb     
IIA IIA T2b Melanomas 1.01–2.0 mm in thickness with ulceration
T3a Melanomas 2.01–4.0 mm in thickness without ulceration
N0 No regional metastases detected
M0 No detectable evidence of distant metastases
IIB IIB T3b Melanomas 2.01–4.0 mm in thickness with ulceration
T4a Melanomas >4.0 mm in thickness without ulceration
N0 No regional metastases detected
M0 No detectable evidence of distant metastases
IIC IIC T4b Melanomas >4.0 mm in thickness with ulceration
N0 No regional metastases detected
M0 No detectable evidence of distant metastases
Three-panel drawing of stage II melanoma. The left panel shows two stage IIA tumors. One tumor is more than 1 but not more than 2 millimeters thick, with ulceration (break in the skin); the other tumor is more than 2 but not more than 4 millimeters thick, with no ulceration. The right panel shows two stage IIB tumors. One tumor is more than 2 but not more than 4 millimeters thick, with ulceration; the other tumor is more than 4 millimeters thick, with no ulceration. The bottom panel shows a stage IIC tumor that is more than 4 millimeters thick, with ulceration. Also shown are the epidermis (outer layer of the skin), the dermis (inner layer of the skin), and the subcutaneous tissue below the dermis. 
Three-panel drawing of stage II melanoma. The left panel shows two stage IIA tumors. One tumor is more than 1 but not more than 2 millimeters thick, with ulceration (break in the skin); the other tumor is more than 2 but not more than 4 millimeters thick, with no ulceration. The right panel shows two stage IIB tumors. One tumor is more than 2 but not more than 4 millimeters thick, with ulceration; the other tumor is more than 4 millimeters thick, with no ulceration. The bottom panel shows a stage IIC tumor that is more than 4 millimeters thick, with ulceration. Also shown are the epidermis (outer layer of the skin), the dermis (inner layer of the skin), and the subcutaneous tissue below the dermis.
T = primary tumor; N = regional lymph nodes; M = distant metastasis. 
Adapted with permission from AJCC: Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44. 
The explanations for superscripts a and b are at the end of Table 7. 
Table 5. TNM Definitions for Stage III Melanoma: Clinical Staging
Stage TNM Description
III Any T TX = Primary tumor cannot be assessed (e.g., curettaged or severely regressed melanoma)
T0 = No evidence of primary tumor
Tis = Melanoma in situ 
T1a = Melanomas ≤1.0 mm in thickness without ulceration; mitosis <1/mm2 
T1b = Melanomas ≤1.0 mm in thickness with ulceration or mitoses ≥1/mm2 
T2a = Melanomas 1.01–2.0 mm in thickness without ulceration
T2b = Melanomas 1.01–2.0 mm in thickness with ulceration
T3a = Melanomas 2.01–4.0 mm in thickness without ulceration
T3b = Melanomas 2.01–4.0 mm in thickness with ulceration
T4a = Melanomas >4.0 mm in thickness without ulceration
T4b = Melanomas >4.0 mm in thickness with ulceration
≥N1 N1 = 1 regional lymph node metastasis
N2 = 2–3 regional lymph node metastases
N3 = ≥4 regional lymph node metastases; or matted nodes; or in transit met(s)/satellite(s) with metastatic lymph node(s)
M0 No detectable evidence of distant metastases
Stage III melanoma; drawing shows a primary tumor on the lower arm. In the top inset, cancer is shown (a) in lymph nodes near a blood vessel. In the bottom inset, cancer is shown (b) in lymph nodes that are joined together (matted), (c) in a lymph vessel, and (d) not more than 2 centimeters away from the primary tumor. 
Stage III melanoma; drawing shows a primary tumor on the lower arm. In the top inset, cancer is shown (a) in lymph nodes near a blood vessel. In the bottom inset, cancer is shown (b) in lymph nodes that are joined together (matted), (c) in a lymph vessel, and (d) not more than 2 centimeters away from the primary tumor.
T = primary tumor; N = regional lymph nodes; M = distant metastasis. 
Adapted with permission from AJCC: Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44. 
The explanations for superscripts a and b are at the end of Table 7. 
Table 6. TNM Definitions for Stage III Melanoma: Pathologic Stagingb

Stage

TNM

Description

IIIA

T1–4a

T1a = Melanomas ≤1.0 mm in thickness without ulceration; mitosis <1/mm2 

T1b = Melanomas ≤1.0 mm in thickness with ulceration or mitoses ≥1/mm2 

T2a = Melanomas 1.01–2.0 mm in thickness without ulceration

T2b = Melanomas 1.01–2.0 mm in thickness with ulceration

T3a = Melanomas 2.01–4.0 mm in thickness without ulceration

T3b = Melanomas 2.01–4.0 mm in thickness with ulceration

T4a = Melanomas >4.0 mm in thickness without ulceration

N1a

1 regional lymph node metastasis with micrometastasisc 

N2a

2–3 regional lymph node metastases with micrometastasisc 

M0

No detectable evidence of distant metastases

IIIB

T1–4b

T1a = Melanomas ≤1.0 mm in thickness without ulceration; mitosis <1/mm2 

T1b = Melanomas ≤1.0 mm in thickness with ulceration or mitoses ≥1/mm2 

T2a = Melanomas 1.01–2.0 mm in thickness without ulceration

T2b = Melanomas 1.01–2.0 mm in thickness with ulceration

T3a = Melanomas 2.01–4.0 mm in thickness without ulceration

T3b = Melanomas 2.01–4.0 mm in thickness with ulceration

T4a = Melanomas >4.0 mm in thickness without ulceration

T4b = Melanomas >4.0 mm in thickness with ulceration

N1a

1 regional lymph node metastasis with micrometastasisc 

N2a

2–3 regional lymph node metastases with micrometastasisc 

M0

No detectable evidence of distant metastases

IIIB

T1–4a

T1a = Melanomas ≤1.0 mm in thickness without ulceration; mitosis <1/mm2 

T1b = Melanomas ≤1.0 mm in thickness with ulceration or mitoses ≥1/mm2 

T2a = Melanomas 1.01–2.0 mm in thickness without ulceration

T2b = Melanomas 1.01–2.0 mm in thickness with ulceration

T3a = Melanomas 2.01–4.0 mm in thickness without ulceration

T3b = Melanomas 2.01–4.0 mm in thickness with ulceration

T4a = Melanomas >4.0 mm in thickness without ulceration

N1b

N1b = 1 regional lymph node metastasis with macrometastasisd 

N2b

N2b = 2–3 regional lymph node metastases with macrometastasisd 

N2c

N2c = 2–3 regional lymph node metastases and in transit met(s)/satellite(s) without metastatic lymph nodes

M0

No detectable evidence of distant metastases

IIIC

T1–4b

T1a = Melanomas ≤1.0 mm in thickness without ulceration; mitosis <1/mm2 

T1b = Melanomas ≤1.0 mm in thickness with ulceration or mitoses ≥1/mm2 

T2a = Melanomas 1.01–2.0 mm in thickness without ulceration

T2b = Melanomas 1.01–2.0 mm in thickness with ulceration

T3a = Melanomas 2.01–4.0 mm in thickness without ulceration

T3b = Melanomas 2.01–4.0 mm in thickness with ulceration

T4a = Melanomas >4.0 mm in thickness without ulceration

T4b = Melanomas >4.0 mm in thickness with ulceration

N1b

N1b = 1 regional lymph node metastasis with macrometastasisd 

N2b

N2b = 2–3 regional lymph node metastases with macrometastasisd 

N2c

N2c = 2–3 regional lymph node metastases and in transit met(s)/satellite(s) without metastatic lymph nodes

M0

No detectable evidence of distant metastases

IIIC

Any T

TX = Primary tumor cannot be assessed (e.g., curettaged or severely regressed melanoma)

T0 = No evidence of primary tumor

Tis = Melanoma in situ 

T1a = Melanomas ≤1.0 mm in thickness without ulceration; mitosis <1/mm2 

T1b = Melanomas ≤1.0 mm in thickness with ulceration or mitoses ≥1/mm2 

T2a = Melanomas 1.01–2.0 mm in thickness without ulceration.

T2b = Melanomas 1.01–2.0 mm in thickness with ulceration

T3a = Melanomas 2.01–4.0 mm in thickness without ulceration

T3b = Melanomas 2.01–4.0 mm in thickness with ulceration

T4a = Melanomas >4.0 mm in thickness without ulceration

T4b = Melanomas >4.0 mm in thickness with ulceration

N3

≥4 regional lymph node metastases; or matted nodes; or in transit met(s)/satellite(s) with metastatic lymph node(s)

M0

No detectable evidence of distant metastases

T = primary tumor; N = regional lymph nodes; M = distant metastasis.

Adapted with permission from AJCC: Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44.

The explanations for superscripts b–d are at the end of Table 7.

Table 7. TNM Definitions for Stage IV Melanoma
Stage TNM Description
Clinicala  Pathologicalb     
IV IV Any T TX = Primary tumor cannot be assessed (e.g., curettaged or severely regressed melanoma)
T0 = No evidence of primary tumor
Tis = Melanoma in situ 
T1a = Melanomas ≤1.0 mm in thickness without ulceration; mitosis <1/mm2 
T1b = Melanomas ≤1.0 mm in thickness with ulceration or mitoses ≥1/mm2 
T2a = Melanomas 1.01–2.0 mm in thickness without ulceration
T2b = Melanomas 1.01–2.0 mm in thickness with ulceration
T3a = Melanomas 2.01–4.0 mm in thickness without ulceration
T3b = Melanomas 2.01–4.0 mm in thickness with ulceration
T4a = Melanomas >4.0 mm in thickness without ulceration
T4b = Melanomas >4.0 mm in thickness with ulceration
Any N NX = Regional lymph nodes cannot be assessed (e.g., previously removed for another reason)
N1a = 1 regional lymph node metastasis with micrometastasisc 
N1b = 1 regional lymph node metastasis with macrometastasisd 
N2a = 2–3 regional lymph node metastases with micrometastasisc 
N2b = 2–3 regional lymph node metastases with macrometastasisd 
N2c = In transit met(s)/satellite(s) without metastatic lymph nodes
N3 = ≥4 regional lymph node metastases; or matted nodes; or in transit met(s)/satellite(s) with metastatic lymph node(s)
M1 M1a = Metastases to skin, subcutaneous, or distant lymph nodes and normal serum LDH
M1b = Metastases to lung and normal serum LDH
M1c = Metastases to all other visceral sites and normal serum LDH; or distant metastases to any site and elevated serum LDH
LDH = Lactate dehydrogenase; T = primary tumor; N = regional lymph nodes; M = distant metastasis.
Adapted with permission from AJCC: Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44.
aClinical staging includes microstaging of the primary melanoma and clinical and/or radiologic evaluation for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases.
bPathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial or complete lymphadenectomy. Pathologic stage 0 or stage IA patients are the exception; they do not require pathologic evaluation of their lymph nodes.
cMicrometastases are diagnosed after sentinel lymph node biopsy and complete lymphadenectomy (if performed).
dMacrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.
Stage IV melanoma; drawing shows that the primary tumor has spread to other parts of the body, such as the brain, lung, liver, lymph nodes, small intestine, or bone. The pullout shows cancer in the lymph nodes, lymph vessels, and blood vessel. 
Stage IV melanoma; drawing shows that the primary tumor has spread to other parts of the body, such as the brain, lung, liver, lymph nodes, small intestine, or bone. The pullout shows cancer in the lymph nodes, lymph vessels, and blood vessel.

References:

  1. Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44.

Treatment Option Overview for Melanoma

Table 8. Standard Treatment Options for Melanoma

Stage (TNM Staging Criteria)

Standard Treatment Optionsa 

Stage 0 melanoma

Excision

Stage I melanoma

Excision +/− lymph node management

Stage II melanoma

Excision +/− lymph node management

Resectable Stage III melanoma

Excision +/− lymph node management

Unresectable Stage III, Stage IV, and Recurrent melanoma

Immunotherapy

Signal transduction inhibitors

Chemotherapy

Palliative local therapy

aClinical trials are an important option for patients with all stages of melanoma because advances in understanding the aberrant molecular and biologic pathways have led to rapid drug development. Standard treatment options are available in many clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Excision

Surgical excision remains the primary modality for treating melanoma. Cutaneous melanomas that have not spread beyond the site at which they developed are highly curable. The treatment for localized melanoma is surgical excision with margins proportional to the microstage of the primary lesion.

Lymph node management

Sentinel lymph node biopsy (SLNB)

Lymphatic mapping and SLNB can be considered to assess the presence of occult metastasis in the regional lymph nodes of patients with primary tumors larger than 1 to 4 mm, potentially identifying individuals who may be spared the morbidity of regional lymph node dissections (LNDs) and individuals who may benefit from adjuvant therapy.[1][2][3][4][5][6]

To ensure accurate identification of the sentinel lymph node (SLN), lymphatic mapping and removal of the SLN should precede wide excision of the primary melanoma.

Multiple studies have demonstrated the diagnostic accuracy of SLNB, with false-negative rates of 0% to 2%.[1][6][7][8][9][10][11] If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure.

Complete lymph node dissection (CLND)

Patients can be considered for CLND if the sentinel node(s) is microscopically or macroscopically positive for regional control or considered for entry into the Multicenter Selective Lymphadenectomy Trial II (NCT00297895) to determine whether CLND affects survival. SLNB should be performed prior to wide excision of the primary melanoma to ensure accurate lymphatic mapping.

Adjuvant Therapy

High-dose interferon alpha-2b was approved by the U.S. Food and Drug Administration (FDA) in 1995 for the adjuvant treatment of patients with melanoma who have undergone a complete surgical resection but who are considered to be at a high risk of relapse (stages IIB, IIC, and III). However, prospective, randomized, multicenter treatment trials have demonstrated that high-dose interferon alpha-2b and pegylated interferon improve relapse-free survival but do not improve overall survival (OS).

Therapies that have improved OS in patients with recurrent or metastatic disease are now being tested as adjuvant therapy in clinical trials, including NCT01274338, NCT01667419, and NCT01682083.

Limb Perfusion

A completed, multicenter, phase III randomized trial (SWOG-8593) of patients with high-risk primary stage I limb melanoma did not show a disease-free survival or OS benefit from isolated limb perfusion with melphalan, when compared with surgery alone.[5]

Systematic Treatment for Unresectable Stage III, Stage IV, and Recurrent disease

Although melanoma that has spread to distant sites is rarely curable, treatment options are rapidly expanding. Two approaches—checkpoint inhibition and targeting the mitogen-activated protein kinase pathway—have demonstrated improvement in OS in randomized trials in comparison to dacarbazine (DTIC). Although none appear to be curative when used as single agents, early data of combinations are promising. Given the rapid development of new agents and combinations, patients and their physicians are encouraged to consider treatment in a clinical trial for initial treatment and at the time of progression.

Immunotherapy

Checkpoint inhibitors: Ipilimumab has demonstrated an improvement in progression-free survival (PFS) and OS in international, multicenter, randomized trials in patients with unresectable or advanced disease, resulting in FDA approval in 2011. In an international, multicenter, randomized trial, pembrolizumab received accelerated approval in 2014 for demonstrating durable responses in patients whose disease had progressed after they received ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Multiple phase III trials of PD-1 (programmed cell death-1) and PD-L1 (programmed death-ligand 1) checkpoint inhibitors alone and in combination (e.g., with ipilimumab) are in progress to assess their ability to improve PFS and OS.

Interleukin-2 (IL-2): IL-2 was approved by the FDA in 1998 on the basis of durable complete response (CR) rates in a minority of patients (6%–7%) with previously treated metastatic melanoma in eight phase I and II studies. Phase III trials comparing high-dose IL-2 with other treatments and providing an assessment of relative impact on OS have not been conducted.

Signal transduction inhibitors

Studies to date indicate that both BRAF and MEK inhibitors can significantly impact the natural history of melanoma, although they do not appear to be curative as single agents.

BRAF inhibitors

Vemurafenib

Vemurafenib, approved by the FDA in 2011, has demonstrated an improvement in PFS and OS in patients with unresectable or advanced disease. Vemurafenib is an orally available, small-molecule, selective BRAF V600E kinase inhibitor, and its indication is limited to patients with a demonstrated BRAF V600E mutation by an FDA-approved test.[11]

Dabrafenib

Dabrafenib, an orally available, small-molecule, selective BRAF inhibitor that was approved by the FDA in 2013, showed improvement in PFS when compared with DTIC in an international, multicenter trial (BREAK-3 [NCT01227889]).

MEK inhibitors

Trametinib

Trametinib is an orally available, small-molecule, selective inhibitor of MEK1 and MEK2 that was approved by the FDA in 2013 for patients with unresectable or metastatic melanoma with BRAF V600E or K mutations. Trametinib demonstrated improved PFS over DTIC.

Combination signal transduction therapy

In 2014, the combination of dabrafenib and trametinib received accelerated approval from the FDA for patients with unresectable or metastatic melanomas that carry the BRAF V600E or V600 K mutation. The combination demonstrated improved durable response rates over single-agent dabrafenib. Full approval is pending completion of ongoing clinical trials and demonstration of clinical benefit on OS.

c-KIT inhibitors

Early data suggest that mucosal or acral melanomas with activating mutations or amplifications in c-KIT may be sensitive to a variety of c-KIT inhibitors.[12][13][14] Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.

Chemotherapy

DTIC: DTIC was approved in 1970 on the basis of overall response rates. Phase III trials indicate an overall response rate of 10% to 20%, with rare CRs observed. An impact on OS has not been demonstrated in randomized trials.[15][16][17][18] When used as a control arm for recent registration trials of ipilimumab and vemurafenib in previously untreated patients with metastatic melanoma, DTIC was shown to be inferior for OS.

Temozolomide: Temozolomide, an oral alkylating agent, appeared to be similar to intravenous DTIC in a randomized phase III trial with a primary endpoint of OS; however, because the trial was designed to demonstrate the superiority of temozolomide, which was not achieved, the trial was left with a sample size that was inadequate to provide statistical proof of noninferiority.[16]

Palliative local therapy

Melanoma metastatic to distant, lymph node–bearing areas may be palliated by regional lymphadenectomy. Isolated metastases to the lung, gastrointestinal tract, bone, or sometimes the brain may be palliated by resection, with occasional long-term survival.[19][20][21]

References:

  1. Shen P, Wanek LA, Morton DL: Is adjuvant radiotherapy necessary after positive lymph node dissection in head and neck melanomas? Ann Surg Oncol 7 (8): 554-9; discussion 560-1, 2000.

  2. Hochwald SN, Coit DG: Role of elective lymph node dissection in melanoma. Semin Surg Oncol 14 (4): 276-82, 1998.

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

  4. Cascinelli N, Morabito A, Santinami M, et al.: Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet 351 (9105): 793-6, 1998.

  5. Koops HS, Vaglini M, Suciu S, et al.: Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 16 (9): 2906-12, 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. 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.

  8. 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.

  9. 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 randomised phase III trial. Lancet 372 (9633): 117-26, 2008.

  10. Hancock BW, Wheatley K, Harris S, et al.: Adjuvant interferon in high-risk melanoma: the AIM HIGH Study--United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma. J Clin Oncol 22 (1): 53-61, 2004.

  11. Chapman PB, Hauschild A, Robert C, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364 (26): 2507-16, 2011.

  12. Hodi FS, Friedlander P, Corless CL, et al.: Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 26 (12): 2046-51, 2008.

  13. Guo J, Si L, Kong Y, et al.: Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 29 (21): 2904-9, 2011.

  14. Carvajal RD, Antonescu CR, Wolchok JD, et al.: KIT as a therapeutic target in metastatic melanoma. JAMA 305 (22): 2327-34, 2011.

  15. Chapman PB, Einhorn LH, Meyers ML, et al.: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17 (9): 2745-51, 1999.

  16. Middleton MR, Grob JJ, Aaronson N, et al.: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18 (1): 158-66, 2000.

  17. Avril MF, Aamdal S, Grob JJ, et al.: Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 22 (6): 1118-25, 2004.

  18. Robert C, Thomas L, Bondarenko I, et al.: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364 (26): 2517-26, 2011.

  19. Leo F, Cagini L, Rocmans P, et al.: Lung metastases from melanoma: when is surgical treatment warranted? Br J Cancer 83 (5): 569-72, 2000.

  20. Ollila DW, Hsueh EC, Stern SL, et al.: Metastasectomy for recurrent stage IV melanoma. J Surg Oncol 71 (4): 209-13, 1999.

  21. Gutman H, Hess KR, Kokotsakis JA, et al.: Surgery for abdominal metastases of cutaneous melanoma. World J Surg 25 (6): 750-8, 2001.

Stage 0 Melanoma Treatment

Standard Treatment Options for Stage 0 Melanoma

Standard treatment options for stage 0 melanoma include the following:

  1. Excision.

Excision

Patients with stage 0 disease may be treated by excision with minimal, but microscopically free, margins.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Stage I Melanoma Treatment

Standard Treatment Options for Stage I Melanoma

Standard treatment options for stage I melanoma include the following:

  1. Excision with or without lymph node management.

Excision

Evidence suggests that lesions no thicker than 2 mm may be treated conservatively with radial excision margins of 1 cm.

Depending on the location of the melanoma, most patients can now have the excision performed on an outpatient basis.

Evidence (excision):

  1. A randomized trial compared narrow margins (1 cm) with wide margins (≥3 cm) in patients with melanomas no thicker than 2 mm.[1][2][Level of evidence: 1iiA]
    • No difference was observed between the two groups in the development of metastatic disease, disease-free survival (DFS), or overall survival (OS).
     
  2. Two other randomized trials compared 2-cm margins with wider margins (4 cm or 5 cm).[3][4][Level of evidence:1iiA]
    • No statistically significant difference in local recurrence, distant metastasis, or OS was found; the median follow-up was at least 10 years for both trials.
     
  3. In the Intergroup Melanoma Surgical Trial, the reduction in margins from 4 cm to 2 cm was associated with both of the following:[5][Level of evidence: 1iiA]
    • A statistically significant reduction in the need for skin grafting (from 46% to 11%; P < .001).
    • A reduction in the length of hospital stay.
     
  4. A multicenter, phase III randomized trial (SWOG-8593) of patients with high-risk stage I primary limb melanoma did not show a DFS or OS benefit from isolated limb perfusion with melphalan, when compared with surgery alone.[6][7]

Lymph node management

Elective regional lymph node dissection is of no proven benefit for patients with stage I melanoma.[8]

Lymphatic mapping and sentinel lymph node biopsy (SLNB) for patients who have tumors of intermediate thickness and/or ulcerated tumors may identify individuals with occult nodal disease. These patients may benefit from regional lymphadenectomy and adjuvant therapy.[6][9][10][11]

Evidence (immediate lymphadenectomy vs. observation with delayed lymphadenectomy):

  1. The International Multicenter Selective Lymphadenectomy Trial (MSLT-1 [JWCI-MORD-MSLT-1193]) included 1,269 patients with intermediate-thickness (defined as 1.2 mm–3.5 mm in this study) primary melanomas.[12][Level of evidence: 1iiB]
    • There was no melanoma-specific survival advantage (primary endpoint) for patients randomly assigned to undergo wide excision plus SLNB, followed by immediate complete lymphadenectomy for node positivity versus nodal observation and delayed lymphadenectomy for subsequent nodal recurrence at a median of 59.8 months.
    • This trial was not designed to detect a difference in the impact of lymphadenectomy in patients with microscopic lymph node involvement.
     
  2. The Sunbelt Melanoma Trial (UAB-9735 [NCT00004196]) was a phase III trial to determine the effects of lymphadenectomy with or without adjuvant high-dose interferon alpha-2b versus observation on DFS and OS in patients with submicroscopic sentinel lymph node (SLN) metastasis detected only by the polymerase chain reaction assay (i.e., SLN negative by histology and immunohistochemistry).
    • No survival data have been reported from this study.
     

Treatment Options Under Clinical Evaluation for Stage I Melanoma

Treatment options under clinical evaluation for patients with stage I melanoma include the following:

  1. Clinical trials evaluating new techniques to detect submicroscopic SLN metastasis. Because of the higher rate of treatment failure in the subset of clinical stage I patients with occult nodal disease, clinical trials have evaluated new techniques to detect submicroscopic SLN metastasis to identify patients who may benefit from regional lymphadenectomy with or without adjuvant therapy.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Veronesi U, Cascinelli N: Narrow excision (1-cm margin). A safe procedure for thin cutaneous melanoma. Arch Surg 126 (4): 438-41, 1991.

  2. Veronesi U, Cascinelli N, Adamus J, et al.: Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. N Engl J Med 318 (18): 1159-62, 1988.

  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. Balch CM, Urist MM, Karakousis CP, et al.: Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial. Ann Surg 218 (3): 262-7; discussion 267-9, 1993.

  6. Essner R, Conforti A, Kelley MC, et al.: Efficacy of lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection as a therapeutic procedure for early-stage melanoma. Ann Surg Oncol 6 (5): 442-9, 1999 Jul-Aug.

  7. Koops HS, Vaglini M, Suciu S, et al.: Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 16 (9): 2906-12, 1998.

  8. Hochwald SN, Coit DG: Role of elective lymph node dissection in melanoma. Semin Surg Oncol 14 (4): 276-82, 1998.

  9. Gershenwald JE, Thompson W, Mansfield PF, et al.: Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 17 (3): 976-83, 1999.

  10. Mraz-Gernhard S, Sagebiel RW, Kashani-Sabet M, et al.: Prediction of sentinel lymph node micrometastasis by histological features in primary cutaneous malignant melanoma. Arch Dermatol 134 (8): 983-7, 1998.

  11. Morton DL, Thompson JF, Cochran AJ, et al.: Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 355 (13): 1307-17, 2006.

  12. Morton DL, Thompson JF, Cochran AJ, et al.: Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 370 (7): 599-609, 2014.

Stage II Melanoma Treatment

Standard Treatment Options for Stage II Melanoma

Standard treatment options for stage II melanoma include the following:

  1. Excision with or without lymph node management.

Excision

For melanomas with a thickness between 2 mm and 4 mm, surgical margins need to be 2 cm to 3 cm or smaller.

Few data are available to guide treatment in patients with melanomas thicker than 4 mm; however, most guidelines recommend margins of 3 cm whenever anatomically possible.

Depending on the location of the melanoma, most patients can have the excision performed on an outpatient basis.

Evidence (excision):

  1. The Intergroup Melanoma Surgical Trial Task 2b compared 2-cm versus 4-cm margins for patients with melanomas that were 1 mm to 4 mm thick.[1]
    • With a median follow-up of more than 10 years, no significant difference in local recurrence or survival was observed between the two groups.
    • The reduction in margins from 4 cm to 2 cm was associated with the following:
      • A statistically significant reduction in the need for skin grafting (from 46% to 11%; P < .001).
      • A reduction in the length of the hospital stay.
       
     
  2. A study conducted in the United Kingdom randomly assigned patients with melanomas thicker than 2 mm to undergo excision with either 1-cm or 3-cm margins.[2]
    • Patients treated with excision with 1-cm margins had higher rates of local regional recurrence (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.00–1.59; P = .05).
    • No difference in survival was seen (HR, 1.24; 95% CI, 0.96–1.61; P = .1).
    • This study suggests that 1-cm margins may not be adequate for patients with melanomas thicker than 2 mm.
     

Lymph Node Management

Lymphatic mapping and sentinel lymph node biopsy (SLNB)

Lymphatic mapping and SLNB have been used to assess the presence of occult metastasis in the regional lymph nodes of patients with stage II disease, potentially identifying individuals who may be spared the morbidity of regional lymph node dissections (LNDs) and individuals who may benefit from adjuvant therapy.[3][4][5][6][7]

To ensure accurate identification of the sentinel lymph node (SLN), lymphatic mapping and removal of the SLN should precede wide excision of the primary melanoma.

With the use of a vital blue dye and a radiopharmaceutical agent injected at the site of the primary tumor, the first lymph node in the lymphatic basin that drains the lesion can be identified, removed, and examined microscopically. Multiple studies have demonstrated the diagnostic accuracy of SLNB, with false-negative rates of 0% to 2%.[3][8][9][10][11][12] If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure.

Regional lymphadenectomy

No published data on the clinical significance of micrometastatic melanoma in regional lymph nodes are available from prospective trials. Some evidence suggests that for patients with tumors of intermediate thickness and occult metastasis, survival is better among patients who undergo immediate regional lymphadenectomy than it is among those who delay lymphadenectomy until the clinical appearance of nodal metastasis.[13] This finding should be viewed with caution because it arose from a post hoc subset analysis of data from a randomized trial.

Evidence (regional lymphadenectomy):

  1. The International Multicenter Selective Lymphadenectomy Trial (MSLT-1 [JWCI-MORD-MSLT-1193]) included 1,269 patients with intermediate-thickness (defined as 1.2 mm–3.5 mm in this study) primary melanomas.[14][Level of evidence: 1iiB]
    • There was no melanoma-specific survival advantage (primary endpoint) for patients randomly assigned to undergo wide excision plus SLNB, followed by immediate complete lymphadenectomy for node positivity versus nodal observation and delayed lymphadenectomy for subsequent nodal recurrence at a median of 59.8 months.
    • This trial was not designed to detect a difference in the impact of lymphadenectomy in patients with microscopic lymph node involvement.
     
  2. Three other prospective randomized trials have failed to show a survival benefit for prophylactic regional LNDs.[15][16][17]

Adjuvant therapy  

High-dose interferon  

High-dose interferon alpha-2b was approved in 1995 for the adjuvant treatment of patients with melanoma who have undergone a complete surgical resection but are considered to be at a high risk of relapse. Evidence was based on a significantly improved relapse-free survival (RFS) and marginally improved overall survival (OS) that were seen in EST-1684.

Subsequent large, randomized trials have not been able to reproduce a benefit in OS. Ongoing trials are testing therapies that have demonstrated improved OS in patients with stage IV disease.

Clinicians should be aware that the high-dose regimens have significant toxic effects.

Evidence (high-dose interferon alpha-2b):

  1. A multicenter, randomized, controlled study (EST-1684) compared a high-dose regimen of interferon alpha-2b (20 mU/m2 of body surface per day given intravenously 5 days a week for 4 weeks, then 10 mU/m2 of body surface per day given subcutaneously 3 times a week for 48 weeks) with observation.[8][Level of evidence: 1iiA]
    • This study included 287 patients at high risk of recurrence after potentially curative surgery for melanoma (patients with melanomas thicker than 4 mm without involved lymph nodes or patients with melanomas of any thickness with positive lymph nodes).
    • Patients who had recurrent melanoma involving only the regional lymph nodes were also eligible.
    • At a median follow-up of 7 years, this trial demonstrated a significant prolongation of RFS (P = .002) and OS (P = .024) for patients who received high-dose interferon.
    • The median OS for patients who received the high-dose regimen of interferon alpha-2b was 3.8 years, compared with 2.8 years for those in the observation group.
    • A subset analysis of the stage II patients failed to show any RFS or OS benefit from high-dose interferon. Because the number of stage II patients was small in this subset analysis, it is difficult to draw meaningful conclusions from this study for this specific group.
     
  2. A multicenter, randomized, controlled study (EST-1690) conducted by the same investigators compared the same high-dose interferon alpha regimen with either a low-dose regimen of interferon alpha-2b (3 mU/m2 of body surface per day given subcutaneously 3 times per week for 104 weeks) or observation. The stage entry criteria for this trial included patients with stage II and III melanoma. This three-arm trial enrolled 642 patients.[9][Level of evidence: 1iiA]
    • At a median follow-up of 52 months, a statistically significant RFS advantage was shown for all patients who received high-dose interferon (including the clinical stage II patients) when compared with the observation group (P = .03).
    • No statistically significant RFS advantage was seen for patients who received low-dose interferon when compared with the observation group.
    • The 5-year estimated RFS rate was 44% for the high-dose interferon group, 40% for the low-dose interferon group, and 35% for the observation group.
    • Neither high-dose nor low-dose interferon yielded an OS benefit when compared with observation (HR, 1.0; P = .995).
     

Treatment Options Under Clinical Evaluation for Stage II Melanoma

Postsurgical adjuvant treatment (e.g., with interferons) has not been shown to affect survival.

Treatment options under clinical evaluation for patients with stage II melanoma include the following:

  1. Clinical trials are testing therapies of postsurgical adjuvant treatment that have improved OS in patients with stage IV disease, including NCT01274338, NCT01667419, and NCT01682083. Postsurgical adjuvant treatment (e.g., with interferons) has not been shown to affect survival; therefore, clinical trials are an important therapeutic option for patients at high risk for relapse.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Balch CM, Urist MM, Karakousis CP, et al.: Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial. Ann Surg 218 (3): 262-7; discussion 267-9, 1993.

  2. Thomas JM, Newton-Bishop J, A'Hern R, et al.: Excision margins in high-risk malignant melanoma. N Engl J Med 350 (8): 757-66, 2004.

  3. Gershenwald JE, Thompson W, Mansfield PF, et al.: Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 17 (3): 976-83, 1999.

  4. McMasters KM, Reintgen DS, Ross MI, et al.: Sentinel lymph node biopsy for melanoma: controversy despite widespread agreement. J Clin Oncol 19 (11): 2851-5, 2001.

  5. Cherpelis BS, Haddad F, Messina J, et al.: Sentinel lymph node micrometastasis and other histologic factors that predict outcome in patients with thicker melanomas. J Am Acad Dermatol 44 (5): 762-6, 2001.

  6. Essner R: The role of lymphoscintigraphy and sentinel node mapping in assessing patient risk in melanoma. Semin Oncol 24 (1 Suppl 4): S8-10, 1997.

  7. Chan AD, Morton DL: Sentinel node detection in malignant melanoma. Recent Results Cancer Res 157: 161-77, 2000.

  8. Morton DL, Wen DR, Wong JH, et al.: Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127 (4): 392-9, 1992.

  9. Reintgen D, Cruse CW, Wells K, et al.: The orderly progression of melanoma nodal metastases. Ann Surg 220 (6): 759-67, 1994.

  10. Thompson JF, McCarthy WH, Bosch CM, et al.: Sentinel lymph node status as an indicator of the presence of metastatic melanoma in regional lymph nodes. Melanoma Res 5 (4): 255-60, 1995.

  11. Uren RF, Howman-Giles R, Thompson JF, et al.: Lymphoscintigraphy to identify sentinel lymph nodes in patients with melanoma. Melanoma Res 4 (6): 395-9, 1994.

  12. Bostick P, Essner R, Glass E, et al.: Comparison of blue dye and probe-assisted intraoperative lymphatic mapping in melanoma to identify sentinel nodes in 100 lymphatic basins. Arch Surg 134 (1): 43-9, 1999.

  13. Cascinelli N, Morabito A, Santinami M, et al.: Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet 351 (9105): 793-6, 1998.

  14. Morton DL, Thompson JF, Cochran AJ, et al.: Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 355 (13): 1307-17, 2006.

  15. Veronesi U, Adamus J, Bandiera DC, et al.: Delayed regional lymph node dissection in stage I melanoma of the skin of the lower extremities. Cancer 49 (11): 2420-30, 1982.

  16. Sim FH, Taylor WF, Ivins JC, et al.: A prospective randomized study of the efficacy of routine elective lymphadenectomy in management of malignant melanoma. Preliminary results. Cancer 41 (3): 948-56, 1978.

  17. Balch CM, Soong SJ, Bartolucci AA, et al.: Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger. Ann Surg 224 (3): 255-63; discussion 263-6, 1996.

Resectable Stage III Melanoma Treatment

Standard Treatment Options for Resectable Stage III Melanoma

Standard treatment options for resectable stage III melanoma include the following:

  1. Excision with or without lymph node management.

Excision

The primary tumor may be treated with wide local excision with 1-cm to 3-cm margins, depending on tumor thickness and location.[1][2][3][4][5][6][7] Skin grafting may be necessary to close the resulting defect.

Lymph node management

Sentinel lymph node biopsy (SLNB)

Lymphatic mapping and SLNB can be considered to assess the presence of occult metastases in the regional lymph nodes of patients with primary tumors larger than 1 mm to 4 mm, potentially identifying individuals who may be spared the morbidity of regional lymph node dissections (LNDs) and individuals who may benefit from adjuvant therapy.[3][8][9][10][11][12]

To ensure accurate identification of the sentinel lymph node (SNL), lymphatic mapping and removal of the SLN should precede wide excision of the primary melanoma.

Multiple studies have demonstrated the diagnostic accuracy of SLNB, with false-negative rates of 0% to 2%.[8][12][13][14][15][16][17] If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure.

Complete lymph node dissection (CLND)

Patients can be considered for CLND if the sentinel node(s) is microscopically or macroscopically positive for regional control or considered for entry into the Multicenter Selective Lymphadenectomy Trial II to determine whether CLND affects survival. SLNB should be performed prior to wide excision of the primary melanoma to ensure accurate lymphatic mapping.

Adjuvant Therapy  

Interferon alpha-2b  

Prospective, randomized, multicenter treatment trials have demonstrated that high-dose interferon alpha-2b and pegylated interferon, both approved for the adjuvant treatment of patients at high risk for relapse, can improve relapse-free survival (RFS) but do not improve overall survival (OS). Agents that have demonstrated improved OS in patients with recurrent or metastatic disease are now being tested in clinical trials of adjuvant therapy in patients at high risk for relapse after surgical resection of tumor. These trials include NCT01274338, NCT01667419, and NCT01682083.

Evidence (high-dose alpha interferon):

  1. A multicenter, randomized, controlled study (EST-1690) compared a high-dose interferon alpha regimen with either a low-dose regimen of interferon alpha-2b (3 mU/m2 of body surface per day given subcutaneously three times per week for 104 weeks) or observation. The stage entry criteria for this trial included patients with stage II and III melanoma. This three-arm trial enrolled 642 patients.[14][Level of evidence: 1iiA]
    • At a median follow-up of 52 months, a statistically significant RFS advantage was shown for all patients who received high-dose interferon (including the clinical stage II patients) when compared with the observation group (P = .03).
    • No statistically significant RFS advantage was seen for patients who received low-dose interferon when compared with the observation group.
    • The 5-year estimated RFS rate was 44% for the high-dose interferon group, 40% for the low-dose interferon group, and 35% for the observation group.
    • Neither high-dose nor low-dose interferon yielded an OS benefit when compared with observation (hazard ratio [HR], 1.0; P = .995).
    • Pooled analyses (EST-1684 and EST-1690) of the high-dose arms versus the observation arms suggest that treatment confers a significant RFS advantage but not a significant benefit for survival.
     
  2. A randomized, multicenter, national trial, ECOG-1697 [NCT00003641], evaluated high-dose intravenous interferon for a short duration (1 month) versus observation in patients with node-negative melanoma at least 2 mm thick or with any thickness and positive sentinel nodes. This trial was closed at interim analysis because of the lack of benefit from treatment with interferon.

Pegylated interferon alpha-2b  

In 2011, pegylated interferon alpha-2b, which is characterized by a longer half-life and can be administered subcutaneously, was approved by the U.S. Food and Drug Administration for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of complete surgical resection, including complete lymphadenectomy.

Evidence (pegylated interferon alpha-2b):

  1. Approval of pegylated interferon alpha-2b was based on EORTC-18991 [NCT00006249], which randomly assigned 1,256 patients with resected stage III melanoma to observation or weekly subcutaneous pegylated interferon alpha-2b for up to 5 years.[15][Level of evidence: 1iiDii]
    • RFS, as determined by an independent review committee, was improved for patients receiving interferon (34.8 months vs. 25.5 months in the observation arm; HR, 0.82; 95% confidence interval [CI], 0.71–0.96; P = .011).
    • No difference in median OS between the arms was observed (HR, 0.98; 95% CI, 0.82–1.16).
    • One-third of the patients receiving pegylated interferon discontinued treatment because of toxicity.
     

Treatment Options Under Clinical Evaluation for Resectable Stage III Melanoma

Treatment options under clinical evaluation for patients with resectable stage III melanoma include the following:

  1. Adjuvant therapy that can impact OS.
  2. Intralesional therapies.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Veronesi U, Cascinelli N: Narrow excision (1-cm margin). A safe procedure for thin cutaneous melanoma. Arch Surg 126 (4): 438-41, 1991.

  2. Veronesi U, Cascinelli N, Adamus J, et al.: Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. N Engl J Med 318 (18): 1159-62, 1988.

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

  4. 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.

  5. 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.

  6. 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.

  7. Balch CM, Urist MM, Karakousis CP, et al.: Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial. Ann Surg 218 (3): 262-7; discussion 267-9, 1993.

  8. Shen P, Wanek LA, Morton DL: Is adjuvant radiotherapy necessary after positive lymph node dissection in head and neck melanomas? Ann Surg Oncol 7 (8): 554-9; discussion 560-1, 2000.

  9. Hochwald SN, Coit DG: Role of elective lymph node dissection in melanoma. Semin Surg Oncol 14 (4): 276-82, 1998.

  10. Cascinelli N, Morabito A, Santinami M, et al.: Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet 351 (9105): 793-6, 1998.

  11. Koops HS, Vaglini M, Suciu S, et al.: Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 16 (9): 2906-12, 1998.

  12. 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.

  13. 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.

  14. 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.

  15. 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 randomised phase III trial. Lancet 372 (9633): 117-26, 2008.

  16. Hancock BW, Wheatley K, Harris S, et al.: Adjuvant interferon in high-risk melanoma: the AIM HIGH Study--United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma. J Clin Oncol 22 (1): 53-61, 2004.

  17. Chapman PB, Hauschild A, Robert C, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364 (26): 2507-16, 2011.

Unresectable Stage III, Stage IV, and Recurrent Melanoma Treatment

Treatment Options for Unresectable Stage III, Stage IV, and Recurrent Melanoma

Treatment options for unresectable stage III, stage IV, and recurrent melanoma include the following:

  1. Immunotherapy.
    1. Checkpoint inhibitors.
      • Anti–CTLA-4 (cytotoxic T-lymphocyte antigen-4): ipilimumab.
      • Anti–PD-1 (programmed cell death-1) and PD-L1 (programmed death ligand 1).
       
    2. High-dose interleukin-2 (IL-2).
    3. Dual immunomodulation.
     
  2. Signal transduction inhibitors.
    1. BRAF (V-raf murine sarcoma viral oncogene homolog B1) inhibitors (for patients who test positive for the BRAF V600 mutation).
      • Vemurafenib.
      • Dabrafenib.
       
    2. MEK inhibitors.
      • Trametinib.
       
    3. Combination therapy with signal transduction inhibitors.
      • Dabrafenib plus trametinib.
      • Multikinase inhibitors.
       
    4. KIT inhibitors.
     
  3. Chemotherapy.
  4. Palliative local therapy.

Although melanoma that has spread to distant sites is rarely curable, treatment options are rapidly expanding. Two approaches—checkpoint inhibition and targeting the mitogen-activated protein kinase (MAPK) pathway—have demonstrated improvement in overall survival (OS) in randomized trials versus the use of dacarbazine (DTIC) or in comparison to DTIC. Although none appear to be curative when used as single agents, early data of combinations are promising. Given the rapid development of new agents and combinations, patients and their physicians are encouraged to consider treatment in a clinical trial for initial treatment and at the time of progression.

Immunotherapy

Checkpoint inhibitors

Anti–CTLA-4: ipilimumab

Ipilimumab is a human monoclonal antibody that binds to CTLA-4, thereby blocking its ability to down-regulate T-cell activation, proliferation, and effector function.

Ipilimumab has demonstrated clinical benefit by prolonging OS in randomized trials, and was approved by the U.S. Food and Drug Administration (FDA) in 2011. Two prospective, randomized, international trials, one each in previously untreated and treated patients, supported the use of ipilimumab.[1][2]

Evidence (ipilimumab):

  1. Previously treated patients: A total of 676 patients with previously treated, unresectable stage III or stage IV disease, and who were HLA-A*0201 positive, were entered into a three-arm, multinational, randomized (3:1:1), double-blind, double-dummy trial. A total of 403 patients were randomly assigned to receive ipilimumab (3 mg/kg every 3 weeks for 4 doses) with glycoprotein 100 (gp100) peptide vaccine. One hundred thirty-seven patients received ipilimumab (3 mg/kg every 3 weeks for 4 doses), and 136 patients received the gp100 vaccine. Patients were stratified by baseline metastases and previous receipt or nonreceipt of interleukin-2 (IL-2) therapy. Eighty-two of the patients had metastases to the brain at baseline.[2][Level of evidence: 1iA]
    • The median OS was 10 months among patients receiving ipilimumab alone and 10.1 months among those receiving ipilimumab with the gp100 vaccine, compared with 6.4 months for patients receiving the vaccine alone (hazard ratio [HR] of ipilimumab alone vs. gp100 alone, 0.66; P <.003; HR of ipilimumab plus vaccine vs. gp100 alone, 0.68; P < .001).
    • An analysis at 1 year showed that among patients treated with ipilimumab, 44% of those treated with ipilimumab and 45% of those treated with ipilimumab and the vaccine were alive, compared with 25% of the patients who received the vaccine only.
    • Grade 3 or grade 4 immune-related adverse events (irAEs) occurred in 10% to 15% of patients treated with ipilimumab. These irAEs most often included diarrhea or colitis, and endocrine-related events (e.g., inflammation of the pituitary). These events required cessation of therapy and institution of anti-inflammatory agents such as corticosteroids or, in four cases, infliximab (an antitumor necrosis factor-alpha antibody).
    • There were 14 drug-related deaths (2.1%), and seven deaths were associated with irAEs.
     
  2. Previously untreated patients: A multicenter, international trial randomly assigned 502 patients untreated for metastatic disease (adjuvant treatment was allowed) in a 1:1 ratio to receive ipilimumab (10 mg/kg) plus DTIC (850 mg/m2) or placebo plus DTIC (850 mg/m2) at weeks 1, 4, 7, and 10 followed by DTIC alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary endpoint was survival. Patients were stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS) and metastatic stage. Approximately 70% of the patients had an ECOG PS of 0, and the remainder of the patients had an ECOG PS of 1. Approximately 55% of patients had stage M1c disease.[1][Level of evidence: 1iA]
    • The median OS was 11.2 months (95% confidence interval [CI], 9.4–13.6) for the ipilimumab-DTIC group, versus 9.1 months (95% CI, 7.8–10.5) for the placebo-DTIC group. Estimated survival rates in the ipilimumab-DTIC group were 47.3% at 1 year, 28.5% at 2 years, and 20.8% at 3 years (HR for death, 0.72; P < .001); and in the placebo-DTIC group, the rates were 36.3% at 1 year, 17.9% at 2 years, and 12.2% at 3 years.
    • The most common study-drug–related adverse events (AEs) were those classified as immune related. Grade 3 or grade 4 irAEs were seen in 38.1% of patients treated with ipilimumab plus DTIC versus 4.4% of patients treated with placebo plus DTIC, the most common events were hepatitis and enterocolitis.
    • No drug-related deaths occurred.
     

Clinicians and patients should be aware that immune-mediated adverse reactions may be severe or fatal. Early identification and treatment, including potential administration of systemic glucocorticoids or other immunosuppressants according to the immune-mediated adverse reaction management guide provided by the manufacturer, are necessary.[3]

Anti–PD-1 and PD-L1

The PD-1 pathway is a key immunoinhibitory mediator of T-cell exhaustion. Blockade of this pathway can lead to T-cell activation, expansion, and enhanced effector functions. PD-1 has 2 ligands, PD-L1 and PD-L2 (Programmed Death-2 Ligand 2).

Pembrolizumab

Pembrolizumab was granted accelerated approval by the FDA in September 2014 for patients with unresectable or metastatic melanoma who have progressed despite therapy with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Pembrolizumab is a human monoclonal antibody that binds to the PD-1 receptor, preventing it from binding to its ligands, PD-L1 and PD-L2. The FDA granted accelerated approval based on the surrogate endpoint of durable response rate in an international, multicenter, open-label, randomized, dose-comparative trial. As a condition to accelerated approval, randomized trials to assess clinical benefit, e.g., improvement in progression-free survival (PFS) and OS versus standard therapy, is required.

Evidence (pembrolizumab):

  1. Previously treated patients. A total of 173 patients with unresectable or metastatic melanoma with disease progression within 24 weeks of the last dose of ipilimumab and, if BRAF V600 mutation positive, previous treatment with a BRAF inhibitor, were randomly assigned to one of two doses of pembrolizumab—2 mg/kg or 10 mg/kg—every 3 weeks. The trial excluded patients with an autoimmune disease, a condition requiring immunosuppression, or a history of severe irAEs from treatment with ipilimumab.
    • The median age was 61 years; 60% were male; 67% had an ECOG PS of 0, and 33% had an ECOG PS of 1. Eighteen percent of patients had tumors that were BRAF V600 mutation positive, 39% had an elevated lactate dehydrogenase (LDH), 64% had M1c disease, 9% had brain metastases, and 72% had undergone two or more therapies for advanced disease. The primary outcome measure was overall response rate (ORR) according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) criteria as assessed by blinded independent central review.[4][Level of evidence: 1iiDiv]
    • The ORR determined by independent central review was 26% (95% CI, -14–13; P = .96) in the 2 mg/kg arm, consisting of one complete response (CR) and 20 partial responses (PRs) in 81 patients. Median follow-up was 8 months, and all patients had a minimum of 6 months of follow-up. Among the 21 patients with an objective response, 18 had ongoing responses, ranging from 1.4+ months to 8.5+ months.
    • Response rate in the 10 mg/kg arm was similar at 26%, consisting of 20 responses in 76 patients. Responses were seen in patients with and without BRAF V600 mutations.
    • The approved dose was 2 mg/kg administered as an intravenous (IV) infusion for 30 minutes every 3 weeks.

    Pembrolizumab was discontinued because of AEs in 7% of the patients treated with 2 mg/kg, with 3% considered drug-related AEs by the investigators. The most common AEs in the 2 mg/kg versus 10 mg/kg arms were:

    • Fatigue (33% vs. 37%).
    • Pruritus (23% vs. 19%).
    • Rash (18% vs. 18%).

    Other common AEs included cough, nausea, decreased appetite, constipation, arthralgia, and diarrhea. The most frequent and serious AEs that occurred in more than 2% of a total of 411 patients treated with pembrolizumab included renal failure, dyspnea, pneumonia, and cellulitis. Additional clinically significant irAEs included pneumonitis, colitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and hepatitis.

The FDA label provides recommendations for suspected irAEs, including withholding drug and administering corticosteroids.

High-dose interleukin-2 (IL-2)

IL-2 was approved by the FDA in 1998 on the basis of durable CRs in eight phase I and II studies. Phase III trials comparing high-dose IL-2 to other retreatments, providing an assessment of relative impact on OS, have not been conducted.

Evidence (high-dose IL-2):

  1. Based on a pooled analysis of 270 patients from eight single- and multi-institutional trials in 22 institutions conducted between 1985 and 1993:
    • High-dose IL-2 demonstrated a 6% to 7% CR rate.[5]
    • With a median follow-up time for surviving patients of at least 7 years, the median duration of CRs was not reached but was at least 59 months.[6]
     

Strategies to improve this therapy are an active area of investigation.

Dual immunomodulation

T-cells coexpress several receptors that inhibit T-cell function. Preclinical data and early clinical data suggest that coblockade of the two inhibitory receptors, CTLA-4 and PD-1, may be more effective than blockade of either alone. This has led to a phase III trial comparing each single agent to the combination (NCT01844505).

Signal transduction inhibitors

Studies to date indicate that both BRAF and MEK (mitogen-activated ERK-[extracellular signal-regulated kinase] activating kinase) inhibitors, as single agents and in combination, can significantly impact the natural history of melanoma, although they do not appear to provide a cure.

BRAF inhibitors

Vemurafenib

Vemurafenib is an orally available, small molecule, selective BRAF kinase inhibitor that was approved by the FDA in 2011 for patients with unresectable or metastatic melanoma who test positive for the BRAF V600E mutation.

Treatment with vemurafenib is discouraged in wild-type BRAF melanoma because data from preclinical models have demonstrated that BRAF inhibitors can enhance rather than down-regulate the MAPK pathway in tumor cells with wild-type BRAF and upstream RAS mutations.[7][8][9][10]

Evidence (vemurafenib):

  1. Previously untreated patients: The approval of vemurafenib was supported by an international, multicenter trial (BRIM-3 [NCT01006980]) that screened 2,107 patients with previously untreated stage IIIC or IV melanoma for the BRAF V600 mutation and identified 675 patients via the cobas 4800 BRAF V600 Mutation Test.[11] Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or DTIC (1,000 mg/m2 IV every 3 weeks). Coprimary endpoints were rates of OS and PFS. At the planned interim analysis, the Data and Safety Monitoring Board determined that both the OS and PFS endpoints had met the prespecified criteria for statistical significance in favor of vemurafenib and recommended that patients in the DTIC group be allowed to cross over to receive vemurafenib.[11][Levels of evidence: 1iiA and 1iiDiii]
    • A total of 675 patients were evaluated for OS; although the median survival had not yet been reached for vemurafenib and the data were immature for reliable Kaplan-Meier estimates of survival curves, the OS in the vemurafenib arm was clearly superior to that in the DTIC arm.
    • The HR for death in the vemurafenib group was 0.37 (95% CI, 0.26–0.55; P < .001). The survival benefit in the vemurafenib group was observed in each prespecified subgroup, for example, age, sex, ECOG PS, tumor stage, lactic dehydrogenase, and geographic region.
    • The HR for tumor progression in the vemurafenib arm was 0.26 (95% CI, 0.20–0.33; P < .001). The estimated median PFS was 5.3 months in the vemurafenib arm versus 1.6 months in the DTIC arm.
    • Twenty patients had non-BRAF V600E mutations: 19 with BRAF V600K and 1 with BRAF V600D. Four patients with a BRAF V600K mutation had a response to vemurafenib.
    • AEs required dose modification or interruption in 38% of patients receiving vemurafenib and 16% of those receiving DTIC. The most common AEs with vemurafenib were cutaneous events (i.e., arthralgia and fatigue). Cutaneous squamous cell carcinoma (SCC), keratoacanthoma, or both developed in 18% of patients and were treated by simple excision. The most common AEs with DTIC were fatigue, nausea, vomiting, and neutropenia. (Refer to the PDQ summaries on Supportive and Palliative Care for more information on coping with cancer.)
     
  2. Previously treated patients: A total of 132 patients with a BRAF V600E or BRAF V600K mutation were enrolled in a multicenter phase II trial of vemurafenib, which was administered as 960 mg orally twice daily. Of the enrolled patients, 61% had stage M1c disease, and 49% had an elevated LDH level. All patients had received one or more prior therapies for advanced disease. Median follow-up was 12.9 months.[12][Level of evidence: 3iiiDiv]
    • An independent review committee (IRC) reported a 53% response rate (95% CI, 44–62), with eight patients (6%) achieving CR.
    • Median duration of response per IRC assessment was 6.7 months (95% CI, 5.6–8.6). Most responses were evident at the first radiologic assessment at 6 weeks; however, some patients did not respond until after receiving therapy for more than 6 months.
     

Dabrafenib

Dabrafenib is an orally available, small molecule, selective BRAF inhibitor that was approved by the FDA in 2013 for patients with unresectable or metastatic melanoma who test positive for the BRAF V600E mutation as detected by an FDA-approved test. Dabrafenib and other BRAF inhibitors are not recommended for treatment of BRAF wild type melanomas, as in vitro experiments suggest there may be a paradoxical stimulation of MAPK signaling resulting in tumor promotion.

Evidence (dabrafenib):

  1. An international, multicenter trial (BREAK-3 [NCT01227889]) compared dabrafenib with DTIC. A total of 250 patients with unresectable stage III or IV melanoma and BRAF V600E mutations were randomly assigned in a 3:1 ratio (dabrafenib 150 mg orally twice a day or DTIC 1,000 mg/m2 IV every 3 weeks). IL-2 was allowed as prior treatment for advanced disease. The primary endpoint was PFS; patients could cross over at the time of progressive disease after confirmation by a blinded IRC.[13][Level of Evidence: 1iiDiii]
    • With 126 events, the HR for PFS was 0.30 (95% CI, 0.18–0.51; P < .0001). The estimated median PFS was 5.1 months for dabrafenib versus 2.7 months for DTIC. OS data are limited by the median duration of follow-up and crossover. The PR rate was 47% versus 5%, and CR was 3% versus 2% in patients receiving dabrafenib versus DTIC, respectively.
    • The most frequent AEs in patients treated with dabrafenib were cutaneous findings (i.e., hyperkeratosis, papillomas, palmar-plantar erythrodysesthesia), pyrexia, fatigue, headache, and arthralgia. Cutaneous SCC or keratoacanthoma occurred in 12 patients, basal cell carcinoma occurred in four patients, mycosis fungoides occurred in one patient, and new melanoma occurred in two patients.
     

MEK inhibitors

Trametinib

Trametinib is an orally available, small-molecule, selective inhibitor of MEK1 and MEK2. BRAF activates MEK1 and MEK2 proteins, which in turn, activate MAP kinases. Preclinical data suggest that MEK inhibitors can restrain growth and induce cell death of some BRAF-mutated human melanoma tumors. BRAF activates MEK1 and MEK2 proteins, which, in turn, activate MAPK.

In 2013, trametinib was approved by the FDA for patients with unresectable or metastatic melanoma with BRAF V600E or K mutations, as determined by an FDA-approved test.

Evidence (trametinib):

  1. A total of 1,022 patients were screened for BRAF mutations, resulting in 322 eligible patients (281 with BRAF V600E, 40 with BRAF V600K, and one with both mutations).[14] One previous treatment (biologic or chemotherapy) was allowed; however, no previous treatment with a BRAF or MEK inhibitor was permitted. Patients were randomly assigned in a 2:1 ratio to receive trametinib (2 mg once daily) or IV chemotherapy (either DTIC 1,000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks). Crossover for patients randomly assigned to chemotherapy was allowed; therefore, the primary endpoint was PFS.
    • The investigator-assessed PFS was 4.8 months in patients receiving trametinib versus 1.5 months in the chemotherapy group (HR for PFS or death, 0.45; 95% CI, 0.33–0.63; P < .001). A radiology review blinded-to-treatment arm resulted in similar outcomes. Median OS has not been reached.
    • AEs leading to dose interruptions occurred in 35% of patients in the trametinib group and 22% of those in the chemotherapy group. AEs leading to dose reductions occurred in 27% of patients receiving trametinib and in 10% of those receiving chemotherapy.
    • The most common AEs included rash, diarrhea, nausea, vomiting, fatigue, peripheral edema, alopecia, hypertension, and constipation. Cardiomyopathy (7%), interstitial lung disease (2.4%), central serous retinopathy (<1%), and retinal-vein occlusion (<1%) are uncommon but serious AEs associated with trametinib. On-study cutaneous SCCs were not observed. (Refer to the PDQ summaries on Supportive and Palliative Care for more information on coping with cancer.)
     

Combination therapy with signal transduction inhibitors

Resistance to BRAF inhibitors, in patients with BRAF V600 mutations, may be associated with reactivation of the MAPK pathway. Combinations of signal transduction inhibitors that block different sites in the same pathway or sites in multiple pathways are an active area of research.

Evidence (combination therapy with signal transduction inhibitors):

  1. In January 2014, the FDA granted accelerated approval to dabrafenib and trametinib in combination to treat patients with unresectable or metastatic melanomas who carry the BRAF V600E or V600K mutation as detected by an FDA-approved test. Accelerated approval was granted on the basis of objective response rates from an open-label phase II trial that randomly assigned 162 patients with unresectable or metastatic melanoma with the BRAF V600E or V600K mutation in a 1:1:1 ratio to receive dabrafenib alone (150 mg twice a day) or with trametinib (at a dose of either 1 mg or 2 mg twice a day).[15] Patients who had disease progression on dabrafenib monotherapy could cross over to receive the combination of dabrafenib 150 mg plus trametinib 2 mg twice a day. Patients were allowed to have received one previous therapy other than a BRAF or MEK inhibitor.[15][Level of evidence: 1iiDiv].
    • Patients treated with the combination had a response rate of 76%, with an average duration of 10.5 months. Patients treated with dabrafenib alone had a response rate of 54%, with an average duration of 5.6 months.
    • The development of a new SCC of the skin associated with single-agent dabrafenib was reduced in the combination arm (19% with dabrafenib and 7% with the combination).
    • The most frequent AEs in the combination were pyrexia and chills, fatigue, nausea, vomiting, and diarrhea, although symptoms were rarely grade 3 or grade 4.
    • In the combination group, 58% of patients required dose reductions because of AEs, most associated with pyrexia. Re-escalation was possible in most patients.
    • Rare, serious AEs with the combination included decreased ejection fraction (<2%) and chorioretinopathy (<1%).
     

Full approval for the combination will depend on demonstration of improvements in PFS and survival from ongoing trials.

These early phase II data with combinations of BRAF and MEK inhibitors, in addition to the mechanistic understanding of pathways, have led to testing this combination in multiple phase III trials, such as NCT01584648, NCT01597908, and NCT01689519.[15] Combination therapy to address other mechanisms of resistance (e.g., via activation of the PI3K/Akt pathway) are in early-phase trials.

Multikinase inhibitors

Sorafenib

The multikinase inhibitor sorafenib has activity against both the vascular endothelial growth-factor signaling and the Raf/MEK/ERK pathway at the level of RAF kinase.

This agent had minimal activity as a single agent in melanoma treatment. Two large, multicenter, placebo-controlled, randomized trials of carboplatin and paclitaxel plus or minus sorafenib showed no improvement over chemotherapy alone as either first-line treatment or second-line treatment.[13][16]

KIT inhibitors

Early data suggest that mucosal or acral melanomas with activating mutations or amplifications in c-KIT may be sensitive to a variety of c-KIT inhibitors.[17][18][19] Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.

Chemotherapy

DTIC was approved in 1970 on the basis of overall response rates. Phase III trials indicate an overall response rate of 10% to 20%, with rare CRs observed. An impact on OS has not been demonstrated in randomized trials.[1][11][20][21][22] When used as a control arm for recent registration trials of ipilimumab and vemurafenib in previously untreated patients with metastatic melanoma, DTIC was shown to be inferior for OS.

Temozolomide (TMZ), an oral alkylating agent that hydrolyzes to the same active moiety as DTIC, appeared to be similar to DTIC (IV administration) in a randomized, phase III trial with a primary endpoint of OS; however, the trial was designed for superiority, and the sample size was inadequate to prove equivalency.[21]

The objective response rate to DTIC and the nitrosoureas, carmustine and lomustine, is approximately 10% to 20%.[20][23][24][25] Responses are usually short-lived, ranging from 3 to 6 months, although long-term remissions can occur in a limited number of patients who attain a CR.[23][25]

A randomized trial compared IV DTIC with TMZ, an oral agent; OS was 6.4 months for DTIC versus 7.7 months for TMZ (HR, 1.18; 95% CI, 0.92–1.52). While these data suggested similarity between DTIC and TMZ, no benefit in survival has been demonstrated for either DTIC or TMZ; therefore, demonstration of similarity did not result in approval of TMZ by the FDA.[21][Level of evidence: 1iiA]

An extended schedule and escalated dose of TMZ was compared with DTIC in a multicenter trial randomly assigning 859 patients (EORTC-18032 [NCT00101218]). No improvement was seen in OS or PFS for the TMZ group, and this dose and schedule resulted in more toxicity than standard-dose, single-agent DTIC.[26][Level of evidence: 1iiA]

Two randomized, phase III trials in previously untreated patients with metastatic melanoma (resulting in FDA approval for vemurafenib [11] and ipilimumab [1]) included DTIC as the standard therapy arm. Both vemurafenib (in BRAF V600 mutant melanoma) and ipilimumab showed superior OS compared with DTIC in the two separate trials.

Other agents with modest, single-agent activity include vinca alkaloids, platinum compounds, and taxanes.[23][24]

Attempts to develop combination regimens that incorporate chemotherapy (e.g., multiagent chemotherapy,[27][28] combinations of chemotherapy and tamoxifen,[29][30][31] and combinations of chemotherapy and immunotherapy [5][6][27][32][33][34][35]) have not demonstrated an improvement in OS.

A published data meta-analysis of 18 randomized trials (15 of which had survival information) that compared chemotherapy with biochemotherapy (i.e., the same chemotherapy plus interferon alone or with IL-2) reported no impact on OS.[36][Level of evidence:1iiA]

Palliative local therapy

Melanoma metastatic to distant, lymph node–bearing areas may be palliated by regional lymphadenectomy. Isolated metastases to the lung, gastrointestinal tract, bone, or sometimes the brain may be palliated by resection, with occasional long-term survival.[33][34][35]

Although melanoma is a relatively radiation-resistant tumor, palliative radiation therapy may alleviate symptoms. Retrospective studies have shown that symptom relief and some shrinkage of the tumor with radiation therapy may occur in patients with the following:[37][38]

  • Multiple brain metastases.
  • Bone metastases.
  • Spinal cord compression.

The most effective dose-fractionation schedule for palliation of melanoma metastatic to the bone or spinal cord is unclear, but high-dose-per-fraction schedules are sometimes used to overcome tumor resistance. (Refer to the PDQ summary on Pain for more information.)

A phase I and II clinical trial (MCC-11543 [NCT00005615]) evaluated adjuvant radiation therapy plus interferon in patients with recurrent melanoma; results are pending.

Treatment Options Under Clinical Evaluation for Unresectable Stage III, Stage IV, and Recurrent Melanoma

  1. Immunotherapy, single agent, and combination immunomodulation.
  2. Targeted therapy—single-agent and combination therapy.
    1. Signal transduction inhibitors, including P13K (phosphoinositide-3 kinase) and Akt (protein kinase B) inhibitors, CDK (cyclin-dependent kinase) in addition to BRAF and MEK.
    2. Antiangiogenesis agents. Preclinical data suggest that increased vascular endothelial growth factor production may be implicated in resistance to BRAF inhibitors.[39]
    3. Targeted therapy for specific melanoma populations.
      • In smaller subsets of melanoma, activating mutations may occur in NRAS (neuroblastoma RAS viral [v-ras] oncogene homolog) (15%–20%), c-KIT (28%–39% of melanomas arising in chronically sun-damaged skin, or acral and mucosal melanomas), and CDK4 (cyclin-dependent kinase 4) (<5%), whereas GNAQ is frequently mutated in uveal melanomas. Drugs developed to target the pathways activated by these mutations are currently in clinical trials.
       
     
  3. Intralesional injections (for example, oncologic viruses).
  4. Complete surgical resection of all known disease versus best medical therapy.
  5. Isolated limb perfusion for unresectable extremity melanoma.
  6. Systemic therapy for unresectable disease.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III melanoma, stage IV melanoma and recurrent melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Robert C, Thomas L, Bondarenko I, et al.: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364 (26): 2517-26, 2011.

  2. Hodi FS, O'Day SJ, McDermott DF, et al.: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363 (8): 711-23, 2010.

  3. Yervoy (Ipilimumab): Serious and Fatal Immune-Mediated Adverse Reactions [Medication Guide]. Princeton, NJ: Bristol-Myers Squibb, 2011. Available online. Last accessed May 15, 2014.

  4. Robert C, Ribas A, Wolchok JD, et al.: Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet : , 2014.

  5. Atkins MB, Lotze MT, Dutcher JP, et al.: High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17 (7): 2105-16, 1999.

  6. Atkins MB, Kunkel L, Sznol M, et al.: High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 6 (Suppl 1): S11-4, 2000.

  7. Heidorn SJ, Milagre C, Whittaker S, et al.: Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140 (2): 209-21, 2010.

  8. Hatzivassiliou G, Song K, Yen I, et al.: RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464 (7287): 431-5, 2010.

  9. Poulikakos PI, Zhang C, Bollag G, et al.: RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464 (7287): 427-30, 2010.

  10. Su F, Viros A, Milagre C, et al.: RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 366 (3): 207-15, 2012.

  11. Chapman PB, Hauschild A, Robert C, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364 (26): 2507-16, 2011.

  12. Sosman JA, Kim KB, Schuchter L, et al.: Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366 (8): 707-14, 2012.

  13. Hauschild A, Grob JJ, Demidov LV, et al.: Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380 (9839): 358-65, 2012.

  14. Flaherty KT, Robert C, Hersey P, et al.: Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367 (2): 107-14, 2012.

  15. Flaherty KT, Infante JR, Daud A, et al.: Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367 (18): 1694-703, 2012.

  16. Flaherty KT, Lee SJ, Zhao F, et al.: Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol 31 (3): 373-9, 2013.

  17. Hodi FS, Friedlander P, Corless CL, et al.: Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 26 (12): 2046-51, 2008.

  18. Guo J, Si L, Kong Y, et al.: Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 29 (21): 2904-9, 2011.

  19. Carvajal RD, Antonescu CR, Wolchok JD, et al.: KIT as a therapeutic target in metastatic melanoma. JAMA 305 (22): 2327-34, 2011.

  20. Chapman PB, Einhorn LH, Meyers ML, et al.: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17 (9): 2745-51, 1999.

  21. Middleton MR, Grob JJ, Aaronson N, et al.: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18 (1): 158-66, 2000.

  22. Avril MF, Aamdal S, Grob JJ, et al.: Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 22 (6): 1118-25, 2004.

  23. Anderson CM, Buzaid AC, Legha SS: Systemic treatments for advanced cutaneous melanoma. Oncology (Huntingt) 9 (11): 1149-58; discussion 1163-4, 1167-8, 1995.

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

  25. Mays SR, Nelson BR: Current therapy of cutaneous melanoma. Cutis 63 (5): 293-8, 1999.

  26. Patel PM, Suciu S, Mortier L, et al.: Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). Eur J Cancer 47 (10): 1476-83, 2011.

  27. 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.

  28. 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.

  29. Kirkwood JM, Ibrahim J, Lawson DH, et al.: High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: results of the Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696. J Clin Oncol 19 (5): 1430-6, 2001.

  30. Hancock BW, Wheatley K, Harris S, et al.: Adjuvant interferon in high-risk melanoma: the AIM HIGH Study--United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma. J Clin Oncol 22 (1): 53-61, 2004.

  31. Koops HS, Vaglini M, Suciu S, et al.: Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 16 (9): 2906-12, 1998.

  32. Lee ML, Tomsu K, Von Eschen KB: Duration of survival for disseminated malignant melanoma: results of a meta-analysis. Melanoma Res 10 (1): 81-92, 2000.

  33. Leo F, Cagini L, Rocmans P, et al.: Lung metastases from melanoma: when is surgical treatment warranted? Br J Cancer 83 (5): 569-72, 2000.

  34. Ollila DW, Hsueh EC, Stern SL, et al.: Metastasectomy for recurrent stage IV melanoma. J Surg Oncol 71 (4): 209-13, 1999.

  35. Gutman H, Hess KR, Kokotsakis JA, et al.: Surgery for abdominal metastases of cutaneous melanoma. World J Surg 25 (6): 750-8, 2001.

  36. Ives NJ, Stowe RL, Lorigan P, et al.: Chemotherapy compared with biochemotherapy for the treatment of metastatic melanoma: a meta-analysis of 18 trials involving 2,621 patients. J Clin Oncol 25 (34): 5426-34, 2007.

  37. Rate WR, Solin LJ, Turrisi AT: Palliative radiotherapy for metastatic malignant melanoma: brain metastases, bone metastases, and spinal cord compression. Int J Radiat Oncol Biol Phys 15 (4): 859-64, 1988.

  38. Herbert SH, Solin LJ, Rate WR, et al.: The effect of palliative radiation therapy on epidural compression due to metastatic malignant melanoma. Cancer 67 (10): 2472-6, 1991.

  39. Martin MJ, Hayward R, Viros A, et al.: Metformin accelerates the growth of BRAF V600E-driven melanoma by upregulating VEGF-A. Cancer Discov 2 (4): 344-55, 2012.


This information is provided by the National Cancer Institute.

This information was last updated on September 12, 2014.

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