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 Melanoma

Melanoma is a disease in which malignant (cancer) cells form in the skin cells called melanocytes (cells that color the skin).

Melanocytes are found throughout the lower part of the epidermis. They make melanin, the pigment that gives skin its natural color. When skin is exposed to the sun, melanocytes make more pigment, causing the skin to tan, or darken.

Anatomy of the skin with melanocytes; 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 above 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.
Anatomy of the skin, showing the epidermis, dermis, and subcutaneous tissue. Melanocytes are in the layer of basal cells at the deepest part of the epidermis.

The skin is the body’s largest organ. It protects against heat, sunlight, injury, and infection. The skin has 2 main layers: the epidermis (upper or outer layer) and the dermis (lower or inner layer).

There are 3 types of skin cancer:

  • Melanoma.
  • Basal cell skin cancer.
  • Squamous cell skin cancer.

When melanoma starts in the skin, the disease is called cutaneous melanoma. Melanoma may also occur in mucous membranes (thin, moist layers of tissue that cover surfaces such as the lips). This PDQ summary is about cutaneous (skin) melanoma and melanoma that affects the mucous membranes. When melanoma occurs in the eye, it is called intraocular or ocular melanoma. (See the PDQ summary on Intraocular (Eye) Melanoma Treatment for more information.)

Melanoma is more aggressive than basal cell skin cancer or squamous cell skin cancer. (See the PDQ summary on Skin Cancer Treatment for more information on basal cell and squamous cell skin cancer.)

Melanoma can occur anywhere on the body.

In men, melanoma is often found on the trunk (the area from the shoulders to the hips) or the head and neck. In women, melanoma forms most often on the arms and legs. Melanoma is most common in adults, but it is sometimes found in children and adolescents. (See the PDQ summary on Unusual Cancers of Childhood for more information on melanoma in children and adolescents.)

Unusual moles, exposure to sunlight, and health history can affect the risk of melanoma.

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 melanoma include the following:

  • Having a fair complexion, which includes the following:
    • Fair skin that freckles and burns easily, does not tan, or tans poorly.
    • Blue or green or other light-colored eyes.
    • Red or blond hair.
  • Being exposed to natural sunlight or artificial sunlight (such as from tanning beds) over long periods of time.
  • Being exposed to certain factors in the environment (in the air, your home or workplace, and your food and water). Some of the environmental risk factors for melanoma are radiation, solvents, vinyl chloride, and PCBs.
  • Having a history of many blistering sunburns, especially as a child or teenager.
  • Having several large or many small moles.
  • Having a family history of unusual moles (atypical nevussyndrome).
  • Having a family or personal history of melanoma.
  • Being white.
  • Having a weakened immune system.
  • Having certain changes in the genes that are linked to melanoma.

Being white or having a fair complexion increases the risk of melanoma, but anyone can have melanoma, including people with dark skin.

Signs of melanoma include a change in the appearance of a mole or pigmented area.

These and other signs and symptoms may be caused by melanoma or by other conditions. Check with your doctor if you have any of the following:

  • A mole that:
    • changes in size, shape, or color.
    • has irregular edges or borders.
    • is more than one color.
    • is asymmetrical (if the mole is divided in half, the 2 halves are different in size or shape).
    • itches.
    • oozes, bleeds, or is ulcerated (a hole forms in the skin when the top layer of cells breaks down and the tissue below shows through).
  • A change in pigmented (colored) skin.
  • Satellite moles (new moles that grow near an existing mole).

For pictures and descriptions of common moles and melanoma, see Common Moles, Dysplastic Nevi, and Risk of Melanoma.

Tests that examine the skin are used to detect (find) and diagnose melanoma.

If a mole or pigmented area of the skin changes or looks abnormal, the following tests and procedures can help find and diagnose melanoma:

  • Skin exam: A doctor or nurse checks the skin for moles, birthmarks, or other pigmented areas that look abnormal in color, size, shape, or texture.
  • Biopsy: A procedure to remove the abnormal tissue and a small amount of normal tissue around it. A pathologist looks at the tissue under a microscope to check for cancer cells. It can be hard to tell the difference between a colored mole and an early melanoma lesion. Patients may want to have the sample of tissue checked by a second pathologist. If the abnormal mole or lesion is cancer, the sample of tissue may also be tested for certain gene changes.

A biopsy should be done on any abnormal areas of the skin. These areas should not be shaved off or cauterized (destroyed with a hot instrument, an electric current, or a caustic substance).

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

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

  • The thickness of the tumor and where it is in the body.
  • How quickly the cancer cells are dividing.
  • Whether there was bleeding or ulceration at the primary site.
  • Whether cancer has spread to the lymph nodes or to other places in the body.
  • The number of places cancer has spread to in the body and the level of lactate dehydrogenate (LDH) in the blood.
  • The patient’s general health.

Stages of Melanoma

After melanoma has been diagnosed, tests are done to find out if cancer cells have spread within the skin or to other parts of the body.

The process used to find out whether cancer has spread within the skin or 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. Talk with your doctor about what the stage of your cancer is.

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

  • 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.
  • Lymph node mapping and sentinel lymph node biopsy: Procedures in which a radioactive substance and/or blue dye is injected near the tumor. The substance or dye flows through lymphducts to the sentinel node or nodes (the first lymph node or nodes where cancer cells are likely to have spread). The surgeon removes only the nodes with the radioactive substance or dye. A pathologist views a sample of tissue under a microscope to check for cancer cells. If no cancer cells are found, it may not be necessary to remove more nodes.
  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the neck, chest, and abdomen, 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. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography. For melanoma, pictures may be taken of the chest, abdomen, and pelvis.
  • PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (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.
  • MRI (magnetic resonance imaging) with gadolinium: A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as the brain. A substance called gadolinium is injected into a vein. The gadolinium collects around the cancer cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. For melanoma, the blood is checked for an enzyme called lactate dehydrogenase (LDH). LDH levels that are higher than normal may be a sign of melanoma.

The results of these tests are viewed together with the results of the tumor biopsy to find out the stage of the melanoma.

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 melanoma spreads to the lung, the cancer cells in the lung are actually melanoma cells. The disease is metastatic melanoma, not lung cancer.

The method used to stage melanoma is based mainly on the thickness of the tumor and whether cancer has spread to lymph nodes or other parts of the body.

The staging system is based on the following:

  • The thickness of the tumor. The thickness is described using the Breslow scale.
  • Whether the tumor is ulcerated (has broken the skin).
  • Whether the tumor has spread to the lymph nodes and if the lymph nodes are joined together (matted).
  • Whether the tumor has spread to other parts of the body.

The following stages are used for melanoma:

Stage 0 (Melanoma in Situ)

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. Abnormal melanocytes are in the epidermis (outer layer of the skin).

In stage 0, abnormalmelanocytes are found in the epidermis. These abnormal melanocytes may become cancer and spread into nearby normal tissue. Stage 0 is also called melanoma in situ.

Millimeters; drawing shows millimeters (mm) using everyday objects. A sharp pencil point shows 1 mm, a new crayon point shows 2 mm, and a new pencil-top eraser shows 5 mm.
Millimeters (mm). A sharp pencil point is about 1 mm, a new crayon point is about 2 mm, and a new pencil eraser is about 5 mm.

Stage I

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.
Stage I melanoma. In stage IA, the tumor is not more than 1 millimeter thick, with no ulceration (break in the skin). In stage IB, the tumor is either not more than 1 millimeter thick, with ulceration, OR more than 1 but not more than 2 millimeters thick, with no ulceration. Skin thickness is different on different parts of the body.

In stage I, cancer has formed. Stage I is divided into stages IA and IB.

  • Stage IA: In stage IA, the tumor is not more than 1 millimeter thick, with no ulceration.
  • Stage IB: In stage IB, the tumor is either:
    • not more than 1 millimeter thick and it has ulceration; or
    • more than 1 but not more than 2 millimeters thick, with no ulceration.

Stage II

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.
Stage II melanoma. In stage IIA, the tumor is either more than 1 but not more than 2 millimeters thick, with ulceration (break in the skin), OR it is more than 2 but not more than 4 millimeters thick, with no ulceration. In stage IIB, the tumor is either more than 2 but not more than 4 millimeters thick, with ulceration, OR it is more than 4 millimeters thick, with no ulceration. In stage IIC, the tumor is more than 4 millimeters thick, with ulceration. Skin thickness is different on different parts of the body.

Stage II is divided into stages IIA, IIB, and IIC.

  • Stage IIA: In stage IIA, the tumor is either:
    • more than 1 but not more than 2 millimeters thick, with ulceration; or
    • more than 2 but not more than 4 millimeters thick, with no ulceration.
  • Stage IIB: In stage IIB, the tumor is either:
    • more than 2 but not more than 4 millimeters thick, with ulceration; or
    • more than 4 millimeters thick, with no ulceration.
  • Stage IIC: In stage IIC, the tumor is more than 4 millimeters thick, with ulceration.

Stage III

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. The tumor may be any thickness, with or without ulceration (a break in the skin), and (a) cancer has spread to one or more lymph nodes; (b) lymph nodes with cancer may be joined together (matted); (c) cancer may be in a lymph vessel between the primary tumor and nearby lymph nodes; and/or (d) very small tumors may be found on or under the skin, not more than 2 centimeters away from the primary tumor.

In stage III, the tumor may be any thickness, with or without ulceration. One or more of the following is true:

  • Cancer has spread to one or more lymph nodes.
  • Lymph nodes may be joined together (matted).
  • Cancer may be in a lymph vessel between the primary tumor and nearby lymph nodes.
  • Very small tumors may be found on or under the skin, not more than 2 centimeters away from where the cancer first started.

Stage IV

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. The tumor has spread to other parts of the body.

In stage IV, the cancer has spread to other places in the body, such as the lung, liver, brain, bone, soft tissue, or gastrointestinal (GI) tract. Cancer may have spread to places in the skin far away from where it first started.

Recurrent Melanoma

Recurrentmelanoma is cancer that has recurred (come back) after it has been treated. The cancer may come back in the area where it first started or in other parts of the body, such as the lungs or liver.

Treatment Option Overview

There are different types of treatment for patients with melanoma.

Different types of treatment are available for patients with melanoma. 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.

Five types of standard treatment are used:

Surgery

Surgery to remove the tumor is the primary treatment of all stages of melanoma. The doctor may remove the tumor using the following operations:

  • Wide local excision: Surgery to remove the melanoma and some of the normal tissue around it. Some of the lymph nodes may also be removed.
  • Lymphadenectomy: A surgical procedure in which the lymph nodes are removed and a sample of tissue is checked under a microscope for signs of cancer.
  • Sentinel lymph node biopsy: The removal of the sentinel lymph node (the first lymph node the cancer is likely to spread to from the tumor) during surgery. A radioactive substance and/or blue dye is injected near the tumor. The substance or dye flows through the lymphducts 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).

Skin grafting (taking skin from another part of the body to replace the skin that is removed) may be done to cover the wound caused by surgery.

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

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them 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).

One type of regional chemotherapy is hyperthermicisolated limb perfusion. With this method, anticancer drugs go directly to the arm or leg the cancer is in. The flow of blood to and from the limb is temporarily stopped with a tourniquet. A warm solution with the anticancer drugs is put directly into the blood of the limb. This gives a high dose of drugs to the area where the cancer is.

The way the chemotherapy is given depends on the type and stage of the cancer being treated.

See Drugs Approved for Melanoma for more information.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiationtherapy 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.

Biologic therapy

Biologic therapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.

Interferon and interleukin-2 (IL-2) are types of biologic therapy used to treat melanoma. Interferon affects the division of cancer cells and can slow tumor growth. IL-2 boosts the growth and activity of many immune cells, especially lymphocytes (a type of white blood cell). Lymphocytes can attack and kill cancer cells.

Tumor necrosis factor (TNF) therapy is a type of biologic therapy used with other treatments for melanoma. TNF is a protein made by white blood cells in response to an antigen or infection. Tumor necrosis factor can be made in the laboratory and used as a treatment to kill cancer cells.

See Drugs Approved for Melanoma for more information.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. The following types of targeted therapy are being used in the treatment of melanoma:

  • Monoclonal antibody therapy: A cancer treatment that uses antibodies made in the laboratory, from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells. Monoclonal antibodies may be used with chemotherapy as adjuvant therapy. Ipilimumab is a monoclonal antibody used to treat melanoma. Other monoclonal antibodies are being studied in the treatment of melanoma.
  • Signal transduction inhibitor therapy: A type of targeted therapy. Signal transduction inhibitors block signals that are passed from one molecule to another inside a cell. Blocking these signals may kill cancer cells. Vemurafenib is a signal transduction inhibitor used to treat some patients with advanced melanoma or tumors that cannot be removed by surgery.
  • Oncolytic virus therapy: A type of targeted therapy that is being studied in the treatment of melanoma. Oncolytic virus therapy uses a virus that infects and breaks down cancer cells but not normal cells. Radiation therapy or chemotherapy may be given after oncolytic virus therapy to kill more cancer cells.
  • Angiogenesis inhibitors: A type of targeted therapy that is being studied in the treatment of melanoma. Angiogenesis inhibitors block the growth of new blood vessels. In cancer treatment, they may be given to prevent the growth of new blood vessels that tumors need to grow.

See Drugs Approved for Melanoma for more information.

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 0 (Melanoma in Situ)

Treatment of stage 0 is usually surgery to remove the area of abnormalcells and a small amount of normal tissue around it.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 melanoma. 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 I Melanoma

Treatment of stage I melanoma may include the following:

  • Surgery to remove the tumor and some of the normal tissue around it. Sometimes lymph node mapping and removal of lymph nodes is also done.
  • A clinical trial of new ways to find cancercells in the lymph nodes.
  • A clinical trial of lymphadenectomy with or without adjuvant therapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I melanoma. 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 II Melanoma

Treatment of stage II melanoma may include the following:

  • Surgery to remove the tumor and some of the normal tissue around it.
  • Lymph node mapping and sentinel lymph node biopsy, followed by surgery to remove the tumor and some of the normal tissue around it. If cancer is found in the sentinel lymph node, a second surgery may be done to remove more nearby lymph nodes.
  • A clinical trial of new types of treatment to be used after surgery.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II melanoma. 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 Melanoma

Treatment of stage III melanoma that can be removed by surgery may include the following:

  • Surgery to remove the tumor and some of the normal tissue around it. Skin grafting may be done to cover the wound caused by surgery.
  • Surgery followed by biologic therapy with interferon if there is a high risk that the cancer will come back.

Treatment of stage III melanoma that cannot be removed by surgery may include the following:

  • Targeted therapy with ipilimumab or vemurafenib.
  • Regional chemotherapy (hyperthermicisolated limb perfusion). Some patients may also have biologic therapy with tumor necrosis factor.

Treatments that are being studied in clinical trials for stage III melanoma include the following:

  • New kinds of treatments to be used after surgery.
  • Treatment with injections into the tumor, such as oncolytic virus therapy.
  • Systemic chemotherapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III melanoma. 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 and Recurrent Melanoma

Treatment of stage IV and recurrentmelanoma may include the following:

  • Targeted therapy with ipilimumab or vemurafenib.
  • Biologic therapy with interleukin-2 (IL-2).
  • Chemotherapy.
  • Palliative therapy to relieve symptoms and improve the quality of life. This may include:
    • Surgery to remove lymph nodes or tumors in the lung, gastrointestinal (GI) tract, bone, or brain.
    • Radiation therapy to the brain, spinal cord, or bone.

Treatments that are being studied in clinical trials for stage IV and recurrent melanoma include the following:

  • A new treatment or combination of treatments.
  • Different biologic therapy agents.
  • Targeted therapy with other signal transduction inhibitors.
  • Angiogenesis inhibitors.
  • Treatment with injections into the tumor, such as oncolytic virus therapy.
  • Surgery to remove all known cancer.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV melanoma and recurrent melanoma. 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 Melanoma

For more information from the National Cancer Institute about melanoma, 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 February 7, 2014.


General Information About Melanoma

Incidence and Mortality

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

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

Risk Factors

The incidence of melanoma has been increasing over the past four decades. Risk factors for melanoma include the following:

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

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

Histopathology

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. Melanoma occurs predominantly in adults, and more than 50% of the cases arise in apparently normal areas of the skin. Early signs in a nevus that would suggest malignant change include darker or variable discoloration, itching, an increase in size, or the development of satellites. Ulceration or bleeding are later signs. Melanoma in women occurs more commonly on the extremities and in men, it occurs most commonly on the trunk or head and neck, but it can arise from any site on the skin surface. A biopsy, preferably by local excision, should be performed for any suspicious lesions, and the specimens should be examined by an experienced pathologist to allow for microstaging. Suspicious lesions should never be shaved off or cauterized. 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.[2]

Prognostic Factors

Prognosis is affected by clinical and histological factors and by anatomic location of the lesion. Thickness and/or level of invasion of the melanoma, mitotic index, presence of tumor infiltrating lymphocytes, number of regional lymph nodes involved, and ulceration or bleeding at the primary site affect the prognosis.[3][4][5][6] Microscopic satellites in stage I melanoma may be a poor prognostic histologic factor, but this is controversial.[7] Patients who are younger, female, and who have melanomas on the extremities generally have a better prognosis.[3][4][5][6]

Follow-up and Survival

Clinical staging is based on whether the tumor has spread to regional lymph nodes or distant sites. For disease clinically confined to the primary site, the greater the thickness and depth of local invasion of the melanoma are, the higher the chance of lymph node or systemic metastases, and the worse the prognosis is. 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 risk of relapse decreases substantially over time, though late relapses are not uncommon.[8][9]

Related Summaries

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

  • Genetics of Skin Cancer
  • Skin Cancer Prevention
  • Skin Cancer Screening
  • Skin Cancer Treatment

References:

  1. American Cancer Society.: Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed February 14, 2014.

  2. 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.

  3. 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.

  4. 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.

  5. Balch CM, Buzaid AC, Soong SJ, et al.: Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19 (16): 3635-48, 2001.

  6. 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.

  7. 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.

  8. 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.

  9. 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

Following is a list of clinicopathologic cellular subtypes of malignant melanoma. These should be considered descriptive terms of historic interest only as they do not have independent prognostic or therapeutic significance.

  • 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 kinase pathway has led to the definition of molecular subtypes of melanoma and provided potential drug targets.

BRAF (V-raf murine sarcoma viral oncogene homolog B1) gene, first reported in 2002, are the most frequent mutation in cutaneous melanoma. Approximately 40% to 60% of malignant melanomas harbor a single nucleotide transversion. The majority 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. One such drug, 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).

In smaller subsets of cutaneous melanoma, other activating mutations have been described, including NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog], c-KIT, and CDK4 (cyclin-dependent kinase 4).

  • Approximately 15% to 20% of melanomas harbor an oncogenic NRAS mutation.[2][3]
  • A c-KIT mutation, or increased copy number, is associated with mucosal and acral melanomas (which comprise 6% to 7% of melanomas in Caucasians but are the most common subtype in the Asian population).[4][5][6]
  • 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, MITF.

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]

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

Agreement between pathologists in the histologic diagnosis of melanomas and benign pigmented lesions has been studied and found to be considerably variable. One such 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.[1] 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. In another study, 38% of cases examined by a panel of expert pathologists had two or more discordant interpretations. These studies convincingly show that distinguishing between benign pigmented lesions and early melanoma 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.[2]

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 larger than 1.5 mm in thickness and should always be reported. Accurate microstaging of the primary tumor requires careful histologic evaluation of the entire specimen by an experienced pathologist. Estimates of prognosis should be modified by sex and anatomic site as well as by clinical and histologic evaluation.

Clark Classification (Level of Invasion)

  • Level I: Lesions involving only the epidermis (in situ melanoma); not an invasive lesion.
  • Level II: Invasion of the papillary dermis but 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.

Definitions of TNM

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification to define melanoma.[3]

Table 1. Primary Tumor (T)a

TX

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

T0

No evidence of primary tumor.

Tis

Melanoma in situ.

T1

Melanomas ≤1.0 mm in thickness.

T2

Melanomas 1.01–2.0 mm.

T3

Melanomas 2.01–4.0 mm.

T4

Melanomas >4.0 mm.

Note: a and b subcategories of T are assigned based on ulceration and number of mitoses per mm2 as shown below:

T classification

Thickness (mm)

Ulceration Status/Mitoses

T1

≤1.0

a: w/o ulceration and mitosis <1/mm2.

b: with ulceration or mitoses ≥1/mm2.

T2

1.01–2.0

a: w/o ulceration.

b: with ulceration.

T3

2.01–4.0

a: w/o ulceration.

b: with ulceration.

T4

>4.0

a: w/o ulceration.

b: with ulceration.

aReprinted 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.

Table 2. Regional Lymph Nodes (N)a

NX

Patients in whom the regional nodes cannot be assessed (e.g., previously removed for another reason).

N0

No regional metastases detected.

N1–3

Regional metastases based upon the number of metastatic nodes and presence or absence of intralymphatic metastases (in transit or satellite metastases).

Note: N1–3 and a–c subcategories assigned as shown below:

N Classification

No. of Metastatic Nodes

Nodal Metastatic Mass

N1

1

a: micrometastasis.b

b: macrometastasis.c

N2

2–3

a: micrometastasis.b

b: macrometastasis.c

c: in transit met(s)/satellites(s) without metastatic nodes.

N3

≥4 metastatic nodes, or matted nodes, or in transit met(s)/satellite(s) with metastatic node(s).

No = number.

aReprinted 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.

bMicrometastases are diagnosed after sentinel lymph node biopsy and completion lymphadenectomy (if performed).

cMacrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.

Table 3. Distant Metastasis (M)a

M0

No detectable evidence of distant metastases.

M1a

Metastases to skin, subcutaneous, or distant lymph nodes.

M1b

Metastases to lung.

M1c

Metastases to all other visceral sites or distant metastases to any site combined with an elevated serum LDH.

Note: Serum LDH is incorporated into the M category as shown below:

M Classification

Site

Serum LDH

M1a

Distant skin, subcutaneous, or nodal mets.

Normal.

M1b

Lung metastases.

Normal.

M1c

All other visceral metastases.

Normal.

Any distant metastasis.

Elevated.

LDH = lactate dehydrogenase.

aReprinted 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.

Table 4. Anatomic Stage/Prognostic Groupsa

Stage

T

N

M

Stage

T

N

M

Clinical Stagingb

Pathologic Stagingc

0

Tis

N0

M0

0

Tis

N0

M0

IA

T1a

N0

M0

IA

T1a

N0

M0

IB

T1b

N0

M0

IB

T1b

N0

M0

T2a

N0

M0

T2a

N0

M0

IIA

T2b

N0

M0

IIA

T2b

N0

M0

T3a

N0

M0

T3a

N0

M0

IIB

T3b

N0

M0

IIB

T3b

N0

M0

T4a

N0

M0

T4a

N0

M0

IIC

T4b

N0

M0

IIC

T4b

N0

M0

III

Any T

≥N1

M0

IIIA

T1–4a

N1a

M0

T1–4a

N2a

M0

IIIB

T1–4b

N1a

M0

T1–4b

N2a

M0

T1–4a

N1b

M0

T1–4a

N2b

M0

T1–4a

N2c

M0

IIIC

T1–4b

N1b

M0

T1–4b

N2b

M0

T1–4b

N2c

M0

Any T

N3

M0

IV

Any T

Any N

M1

IV

Any T

Any N

M1

aReprinted 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.

bClinical 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.

cPathologic 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.

References:

  1. 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.

  2. 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.

  3. 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

Melanomas that have not spread beyond the site at which they developed are highly curable. Most of these are thin lesions that have not invaded beyond the papillary dermis (Clark level I–II; Breslow thickness ≤1 mm). The treatment of localized melanoma is surgical excision with margins proportional to the microstage of the primary lesion; for most lesions 2 mm or less in thickness, this means 1 cm radial re-excision margins.[1][2]

Melanomas with a Breslow thickness of 2 mm or more are still curable in a significant proportion of patients, but the risk of lymph node and/or systemic metastasis increases with increasing thickness of the primary lesion. The local treatment for these melanomas is surgical excision with margins based on Breslow thickness and anatomic location. For most melanomas more than 2 mm to 4 mm in thickness, this means 2 cm to 3 cm radial excision margins. These patients should also be considered for sentinel lymph node biopsy followed by complete lymph node dissection if the sentinel node(s) are microscopically or macroscopically positive. Sentinel node biopsy should be performed prior to wide excision of the primary melanoma to ensure accurate lymphatic mapping. Patients with melanomas that have a Breslow thickness more than 4 mm should be considered for adjuvant therapy.

Some melanomas that have spread to regional lymph nodes may be curable with wide local excision of the primary tumor and removal of the involved regional lymph nodes.[3][4][5][6] A completed, multicenter, phase III randomized trial (SWOG-8593) of patients with high-risk primary limb melanoma did not show a benefit from isolated limb perfusion with melphalan in regard to disease-free survival (DFS) or overall survival (OS) when compared to surgery alone.[7] Systemic treatment with high dose and pegylated interferon alpha-2b are approved for the adjuvant treatment of patients who have undergone a complete surgical resection but are considered to be at high risk for relapse. Prospective, randomized, controlled trials with both agents have not shown an increase in OS when compared with observation.[8][9][10] Clinicians should be aware that high-dose and pegylated interferon regimens have substantial side effects, and patients should be monitored closely. Adjuvant therapy with lower doses of interferon have not been consistently shown to have an impact on either relapse-free survival or OS.[11] Therapies that have impacted OS in patients with recurrent or metastatic disease are now being tested as adjuvant therapy in clinical trials, including NCT01274338, NCT01667419, and NCT01682083.

Although melanoma that has spread to distant sites is rarely curable, both ipilimumab and vemurafenib have demonstrated an improvement in progression-free survival (PFS) and OS in international, multicenter, randomized trials in patients with unresectable or advanced disease, resulting in U.S. Food and Drug Administration (FDA) approval in 2011. These single agents are rarely curative; however, clinical trials that incorporate these agents are testing combinations in an attempt to prevent development of drug resistance. Vemurafenib is a selective BRAF V600E kinase inhibitor, and its indication is limited to patients with a demonstrated BRAF V600E mutation by an FDA-approved test. Clinical trials are testing targeted therapies in the smaller patient subsets (e.g., those with mutations in NRAS, c-KIT, CDK4, GNAQ or GNA11). Information about ongoing clinical trials is available from the NCI Web site.

Interleukin-2 (IL-2) was approved by the FDA in 1998 on the basis of durable complete response (CR) rates in a minority of patients (0% –8%) with previously treated metastatic melanoma in eight phase I and II studies. No improvement in OS has been demonstrated in randomized trials.

Dacarbazine (DTIC) was approved in 1970 based on 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.[12][13][14][15][16] Temozolomide, an oral alkylating agent, appeared to be similar to DTIC (intravenous 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.[13]

Patients with all stages of melanoma may be considered candidates for ongoing clinical trials. Information about ongoing clinical trials is 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. 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.

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

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

  6. 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.

  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. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

Stage 0 Melanoma

Stage 0 melanoma is defined by the American Joint Committee on Cancer's TNM classification system:[1]

  • Tis, N0, M0

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.

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.

Stage I Melanoma

Stage I melanoma is defined by the American Joint Committee on Cancer's TNM classification system:[1]

  • T1a, N0, M0
  • T1b, N0, M0
  • T2a, N0, M0

Standard Treatment Options for Patients With Stage I Melanoma

  • Current evidence suggests that lesions 2 mm or less in thickness may be treated conservatively with radial excision margins of 1 cm. A randomized trial compared narrow margins (1 cm) with wide margins (at least 3 cm) in patients with melanomas no thicker than 2 mm.[2][3] No difference was observed between the two groups in respect to the development of metastatic disease, disease-free survival (DFS), or overall survival (OS). Two other randomized trials compared 2 cm margins with wider margins (i.e., 4 cm or 5 cm) and found no statistically significant difference in local recurrence, distant metastasis, or OS with a median follow-up of 10 years or more for both trials.[4][5][6][Level of evidence:1iiA] In the Intergroup Melanoma Surgical Trial, the reduction in margins from 4 cm to 2 cm was associated with a statistically significant reduction in the need for skin grafting (46% to 11%, P < .001) and a reduction in the length of the hospital stay.[6] Depending on the location of the melanoma, most patients can now have this procedure performed on an outpatient basis.

    Elective regional lymph node dissection is of no proven benefit for patients with stage I melanoma. Lymphatic mapping and sentinel lymph node (SNL) biopsy for patients who have tumors of intermediate thickness and/or ulcerated tumors, however, may allow the identification of individuals with occult nodal disease who might benefit from regional lymphadenectomy and adjuvant therapy.[7][8][9][10]

    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.[11] There was no melanoma-specific survival advantage (the primary endpoint) for those patients randomly assigned to wide excision plus SLN biopsy followed by immediate complete lymphadenectomy for node positivity versus patients randomly assigned to nodal observation and delayed lymphadenectomy for subsequent nodal recurrence at a median of 59.8 months.[11][Level of evidence: 1iiB]

    This trial was not designed to detect a difference in the impact of lymphadenectomy in patients with microscopic lymph node involvement.[11]

Treatment Options Under Clinical Evaluation for Patients With Stage I Melanoma

  • Because of the higher rate of treatment failure in the subset of clinical stage I patients with occult nodal disease, clinical trials are evaluating new techniques to detect submicroscopic SLN metastasis to identify those patients who may benefit from regional lymphadenectomy with or without adjuvant therapy. One of the objectives of the phase III Sunbelt Melanoma Trial (UAB-9735) was 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 SLN metastasis detected only by the polymerase chain reaction (PCR) (i.e., SLN negative by histology and immunohistochemistry). No survival data have been reported from this study. A diagnostic study (UCCRC-9308) tested the combination of reverse transcription and PCR in the detection of melanoma tumor antigen transcripts in lymph nodes and peripheral blood samples.

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. 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.

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

  3. 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.

  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. 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.

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

  8. 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.

  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.

Stage II Melanoma

Stage II melanoma is defined by the American Joint Committee on Cancer's TNM classification system:[1]

  • T2b, N0, M0
  • T3a, N0, M0
  • T3b, N0, M0
  • T4a, N0, M0
  • T4b, N0, M0

Standard Treatment Options for Patients With Stage II Melanoma

  • Current evidence suggests that for melanomas with a thickness between 2 mm and 4 mm, the surgical margins need to be 2 cm or less.

    The Intergroup Melanoma Surgical Trial compared 2-cm margins versus 4-cm margins for patients with 1-mm thick melanomas to 4-mm thick melanomas. With a median follow-up of more than 10 years, no significant difference was observed between the two groups in terms of local recurrence or survival. The reduction in margins from 4 cm to 2 cm was associated with a statistically significant reduction in the need for skin grafting (46% to11%; P < .001) and a reduction in the length of the hospital stay.[2] Depending on the location of the melanoma, most patients can now have this surgery performed on an outpatient basis.

    A study conducted in the United Kingdom randomly assigned patients with melanomas more than 2 mm in thickness to excision with either 1 cm margins or 3 cm margins.[3] Patients treated with 1 cm margins of excision had a higher rate of local regional recurrence (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.00–1.59; P = .05), but no difference in survival was seen (HR, 1.24; 95% CI, 0.96–1.61; P = .1).

    This suggests that 1 cm margins may not be adequate for patients with melanomas that are more than 2 mm in thickness. Few data are available to guide treatment in patients with melanomas more than 4 mm thick; however, most guidelines recommend margins of 3 cm whenever anatomically possible. Although prophylactic regional lymph node dissections (LNDs) have been used in patients with stage II melanomas, four prospective randomized trials have failed to show a benefit for this procedure in terms of survival.[4][5][6][7]

    Lymphatic mapping and sentinel lymph node (SLN) biopsy have been used to assess the presence of occult metastasis in the regional lymph nodes of patients with stage II disease, which potentially identifies individuals who may be spared the morbidity of regional LND and individuals who may benefit from adjuvant therapy.[8][9][10][11][12] The diagnostic accuracy of SLN biopsy has been demonstrated in several studies with a false-negative rate of 0% to 2%.[8][13][14][15][16][17] Using a vital blue dye and a radiopharmaceutical agent, which are 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. If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure. To ensure accurate identification of the SLN, lymphatic mapping and removal of the SLN should be performed prior to wide excision of the primary melanoma.

    To date, no published data from prospective trials are available on the clinical significance of micrometastatic melanoma in regional lymph nodes, but some evidence suggests that for patients with tumors of intermediate thickness and occult metastasis, survival is better among those patients who undergo immediate regional lymphadenectomy than it is among those who delay lymphadenectomy until the clinical appearance of nodal metastasis.[7] Because this finding arose from a post-hoc subset analysis of data from a randomized trial, it should be viewed with caution.

    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.[18] There was no melanoma-specific survival advantage (the primary endpoint) for those patients randomly assigned to wide excision plus SLN biopsy followed by immediate complete lymphadenectomy for node positivity versus patients randomly assigned to nodal observation and delayed lymphadenectomy for subsequent nodal recurrence at a median of 59.8 months.[18][Level of evidence: 1iiB]

    This trial was not designed to detect a difference in the impact of lymphadenectomy in patients with microscopic lymph node involvement.[18]

Adjuvant Treatment Options for Patients With Stage II Melanoma

  • Adjuvant treatment after resection (e.g., with interferons) has not been shown to impact survival.

Treatment Options Under Clinical Evaluation for Patients With Stage II Melanoma

  • Clinical trials testing adjuvant treatment following surgery.

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. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

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

  13. 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.

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

  15. 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.

  16. 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.

  17. 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.

  18. 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.

Stage III Melanoma

Stage III melanoma is defined by the American Joint Committee on Cancer's TNM classification system:[1]

  • Any T, N1, M0
  • Any T, N2, M0
  • Any T, N3, M0

Standard Treatment Options for Patients With Stage III Melanoma

  1. Wide local excision of the primary tumor with 1 cm to 3 cm margins, depending on tumor thickness and location.[2][3][4][5][6][7][8] Skin grafting may be necessary to close the resulting defect.
  2. High-dose or pegylated interferon alpha-2b as adjuvant treatment for patients who have undergone a complete surgical resection but are considered to be at high risk for relapse.
  3. Ipilimumab for patients with unresectable disease.
  4. Vemurafenib for patients with unresectable disease who test positive for the BRAF V600 mutation in a U.S. Food and Drug Administration-approved test.

Adjuvant Treatment Options for Patients With Resected Stage III Disease

Prospective, randomized, multicenter treatment trials have demonstrated that high-dose interferon alpha-2b and pegylated interferon 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.

  1. 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 who are considered to be at a high risk of relapse. Evidence was based on a significantly improved relapse-free survival (RFS) and marginally improved OS that were seen in the completed EST-1684 trial. Subsequent large, randomized trials have not been able to reproduce a benefit in OS.
    • 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 for 5 days a week every week for 4 weeks, then 10 mU/m2 of body surface per day given subcutaneously 3 times a week every week for 48 weeks) to observation.[9] This study included 287 patients at high risk for recurrence after potentially curative surgery for melanoma (patients with melanoma >4 mm thick 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 receiving 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.[9][Level of evidence: 1iiA] A subset analysis of the stage II patients, however, failed to show any benefit from high-dose interferon in terms of RFS or OS. 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.

    • A subsequent multicenter, randomized, controlled study (EST-1690) conducted by the same investigators compared the same high-dose regimen of interferon alpha-2b to either a low-dose regimen (3 mU/m2 of body surface per day given subcutaneously 3 times a week every week for 104 weeks) or observation.[10] The stage entry criteria for this trial were the same as for the initial study. This three-arm trial entered 642 patients. 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); however, no statistically significant RFS advantage was seen for low-dose interferon when compared with the observation group. The 5-year estimated RFS rates for the high-dose interferon, low-dose interferon, and observation groups were 44%, 40%, and 35%, respectively. Neither high-dose interferon nor low-dose interferon yielded an OS benefit when compared with observation (hazard ratio [HR], 1.0; P = .995).[10][Level of evidence: 1iiA]
    • Pooled analyses of the two high-dose arms versus the two observation arms from both studies (EST-1684 and EST-1690) suggest that treatment confers a significant RFS advantage but not a significant benefit for survival.[10][Level of evidence: 1iiA]
    • E-1697, a randomized, multicenter, national trial evaluated high-dose intravenous interferon for a short duration (1 month) versus observation in patients with node-negative melanoma at least 2 mm in thickness 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.

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

  2. Pegylated Interferon. Pegylated interferon alpha-2b, which is characterized by a longer half-life and can be administered subcutaneously, was approved by the FDA in 2011 for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of complete surgical resection, including complete lymphadenectomy. Approval was based on EORTC-18991, 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. 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).[11][Level of evidence: 1iiDii] One-third of the patients receiving pegylated interferon discontinued treatment because of toxicity.

Treatment Options for Patients With Unresectable Stage III Disease

  1. Ipilimumab. (Refer to the Standard Treatment Options for Patients with Stage IV and Recurrent Melanoma section of this summary for more information.)
  2. Vemurafenib for patients who test positive for the BRAF V600 mutation by an FDA-approved test. (Refer to the Standard Treatment Options for Patients with Stage IV and Recurrent Melanoma section of this summary for more information.)
  3. Local therapy for extremity melanoma. For patients with in-transit and/or satellite lesions (stage IIIC) of the extremities, hyperthermic isolated limb perfusion (ILP) with melphalan (L-PAM) with or without tumor necrosis factor-alpha (TNF-alpha) has resulted in high tumor response rates and palliative benefit.[4] No impact on OS has been convincingly demonstrated in randomized controlled studies.[12][13]

Treatment Options Under Clinical Evaluation for Patients With Stage III Melanoma

  • Clinical trials exploring the following:
    • Adjuvant therapy after local control of the tumor in high-risk tumors.
    • Intralesional therapies for local control of lesions.
    • Isolated limb perfusion for unresectable extremity melanoma.
    • 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. 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. 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.

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

  3. 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.

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

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. Lens MB, Dawes M: Isolated limb perfusion with melphalan in the treatment of malignant melanoma of the extremities: a systematic review of randomised controlled trials. Lancet Oncol 4 (6): 359-64, 2003.

Stage IV and Recurrent Melanoma

Stage IV melanoma is defined by the American Joint Committee on Cancer's TNM classification system:[1]

  • Any T, any N, M1

Treatment Options for Patients With Stage IV and Recurrent Melanoma

  1. Immunotherapy.
    • Checkpoint inhibitors.
    • Interleukin-2 (IL-2).
  2. Signal transduction inhibitors.
    • BRAF (V-raf murine sarcoma viral oncogene homolog B1) inhibitors (for patients who test positive for the BRAF V600 mutation).
    • MEK inhibitors.
    • Multikinase inhibitors.
    • KIT inhibitors.
  3. Chemotherapy.
  4. Palliative local therapy.
  5. Clinical trials should be strongly considered because of the rapid advances in the development of novel agents and combinations of agents designed to reverse or interrupt aberrant molecular pathways that support tumor growth.

Treatment option overview for patients with stage IV and recurrent melanoma

Although melanoma that has spread to distant sites is rarely curable, two approaches have demonstrated clinical benefit by prolonging overall survival (OS) in randomized trials: immunotherapy (e.g., ipilimumab) and inhibition of the mitogen-activated protein (MAP) kinase pathway (e.g., with vemurafenib in patients whose tumors have a V600 mutation in the BRAF gene). Both ipilimumab and vemurafenib were approved by the U.S. Food and Drug Administration (FDA) in 2011. Although neither appears to be curative when used as a single agent, clinical trials are currently testing combinations of these and similar agents to prevent the development of resistance. Ipilimumab and vemurafenib are available to newly diagnosed and previously treated patients.

IL-2 was approved by the FDA in 1998 on the basis of durable complete response (CR) rates in a minority of patients (0%–8%) with previously treated metastatic melanoma in eight phase I and II studies. No improvement in OS has been demonstrated in randomized trials.

Dacarbazine (DTIC) was approved in 1970 based on 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.[2][3][4][5][6] Temozolomide, an oral alkylating agent, appeared to be similar to DTIC (intravenous administration) in a randomized phase with a primary endpoint of OS; however, the trial was designed for superiority, and the sample size was inadequate to prove equivalency.[3]

Attempts to develop combination regimens that incorporate chemotherapy, for example, multiagent chemotherapy;[7][8] combinations of chemotherapy and tamoxifen;[9][10][11] and combinations of chemotherapy and immunotherapy [7][12][13][14][15][16][17] have not demonstrated an improvement of the combination on OS.

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.

Malignant melanoma has been reported to spontaneously regress; however, the incidence of spontaneous complete regressions is less than 1%.[18]

Immunotherapy

Checkpoint inhibitors

Anti-CTLA-4: ipilimumab

Ipilimumab is a human monoclonal antibody that blocks the activity of CTLA-4, blocking the function of CTLA-4 as a down regulator of T-cell activation. It is approved for the treatment of unresectable or metastatic melanoma and supported by two prospective, randomized, international trials, one each in previously untreated and treated patients.[6][19]

Previously treated patients. A total of 676 patients with previously treated, unresectable stage III or stage IV disease, who were HLA-A*0201-positive patients, were entered into a three-arm, multinational, randomized, double-blind trial comparing ipilimumab with or without glycoprotein 100 (gp100) peptide vaccine to the gp100 vaccine plus placebo.[19] Patients were stratified by baseline metastases and prior receipt or nonreceipt of IL-2 therapy. Of the patients, 82 had metastases to the brain at baseline. The median OS was 10 months and 10.1 months among patients receiving ipilimumab alone or with the gp100 vaccine, respectively, versus 6.4 months for patients receiving the vaccine alone (hazard ratio [HR], 0.68; P < .001; HR, 0.66; P < .003).

An analysis at 1 year showed that among those patients treated with ipilimumab, 44% and 45% of them were alive compared with 25% of the patients who received vaccine only. Grade 3 to grade 4 immune-related adverse events (AEs) occurred in 10% to 15% of patients treated with ipilimumab. These immune-related AEs most often included diarrhea or colitis, and endocrine-related events (i.e., inflammation of the pituitary) that required cessation of therapy and institution of anti-inflammatory agents, such as corticosteroids or in four cases, infliximab (i.e., an anti-tumor necrosis factor-alpha antibody). There were 14 deaths related to study drugs (2.1%), and seven were associated with immune-related AEs.[19][Level of evidence: 1iA]

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 ipilimumab (10 mg/kg) plus dacarbazine (850 mg/m2) or placebo plus dacarbazine (850 mg/m2) at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22.[6] 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 the patients had stage M1c disease. The median OS was 11.2 months (95% confidence interval [CI], 9.4–13.6) versus 9.1 months (95% CI, 7.8–10.5). Estimated survival rates in the two groups respectively were 47.3% and 36.3% at 1 year; 28.5% and 17.9% at 2 years; and 20.9% and 12.2% at 3 years (HR for death with ipilimumab-dacarbazine, 0.72; P < .001). The most common study-drug–related AEs were those classified as immune related. Grade 3 to 4, immune-related AEs were seen in 38.1% of patients treated with ipilimumab plus dacarbazine versus 4.4% in patients treated with placebo plus dacarbazine, the most common being hepatitis and enterocolitis. No drug-related deaths occurred.[6][Level of evidence: 1iA]

Clinicians and patients should be aware that immune-mediated adverse reactions may be severe and 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, is necessary.[20]

Anti-PD-1 and PD-L1

Anti-PD-1 and PD-L1 are immune checkpoint inhibitors; however, they inhibit different targets than ipilimumab. Promising early data have supported testing anti-PD-1 against DTIC in a phase III trial (NCT01721772).[21]

IL-2

Response to high-dose IL-2 regimens generally ranges from 10% to 20%.[12][13][22] Approximately 4% to 6% of patients may obtain a durable complete remission and be long-term survivors; these results were the basis for approval by the FDA in 1998. Phase III confirmatory trials have not been conducted, and there are currently no predictive biomarkers to select who is likely to respond to treatment.

Attempts to improve on this therapy have included the addition of lymphokine-activated killer cells (i.e., autologous lymphocytes activated by IL-2 ex vivo) and tumor-infiltrating lymphocytes (TIL) (i.e., lymphocytes derived from tumor isolates cultured in the presence of IL-2). A single-institution trial reports that adoptive cell therapy (ACT) with lymphodepletion (using cyclophosphamide plus fludarabine with or without total-body irradiation) followed by autologous TIL transfer and high-dose IL-2 may improve durable response.[23][Level of evidence: 3iiiDiv] A multicenter, randomized trial of high-dose IL-2 with and without a peptide vaccine [gp100:209–217(210M)] in patients with locally advanced stage III or stage IV melanoma who were HLA*A0201-positive reported an increase in response rate with the combination.[24][Level of evidence:1iiDiv] Multicenter, phase III trials powered for an assessment on OS are needed for validation, because response rates are not known to be a surrogate for OS in melanoma.

Signal transduction inhibitors

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

BRAF inhibitors

Vemurafenib

Vemurafenib is an orally available, small molecule, selective BRAF inhibitor that is approved by the FDA for patients with unresectable or metastatic melanoma that tests positive for the BRAF V600E mutation. Treatment with vemurafenib is discouraged in wild-type BRAF melanoma because data from preclinical models has demonstrated that BRAF inhibitors can enhance rather than downregulate the MAPK (mitogen-activated protein kinase) pathway in tumor cells with wild-type BRAF and upstream RAS mutations.[25][26][27][28]

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 by the cobas® 4800 BRAF V600 Mutation Test.[5] Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m2 intravenously [ IV] every 3 weeks). Coprimary endpoints were rates of OS and PFS.[5][Levels of evidence: 1iiA and 1iiDiii]

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 dacarbazine group be allowed to cross over to receive vemurafenib. 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 dacarbazine 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 versus 1.6 months in the vemurafenib and dacarbazine arms, respectively.

Twenty patients had non-V600E mutations: 19 with V600K and 1 with 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 dacarbazine. The most common AEs with vemurafenib were cutaneous events, 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 dacarbazine were fatigue, nausea, vomiting, and neutropenia.

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.[29] Of the enrolled patients, 61% percent had stage M1c disease, and 49% had an elevated lactate dehydrogenase level. All patients had received one or more prior therapies for advanced disease. Median follow-up was 12.9 months. 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 they received therapy for more than 6 months.[29][Level of evidence: 3iiiDiv]

Dabrafenib

Dabrafenib is an orally available, small molecule, selective BRAF inhibitor that has been compared with DTIC in an international, multicenter trial (BREAK-3 [NCT01227889]). 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 1000 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.[30]

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 versus 2.7 months for dabrafenib and DTIC, respectively. OS data are limited by the median duration of follow up and crossover. Partial response was 47% versus 5%, and CR was 3% versus 2% in patients receiving dabrafenib versus DTIC, respectively.[30][Level of Evidence: 1iiDiii]

The most frequent AEs in patients treated with dabrafenib were cutaneous (i.e., hyperkeratosis, papillomas, palmar-plantar erythrodysesthesia), pyrexia, fatigue, headache, and arthralgia. Cutaneous SCC or keratoacanthoma occurred in twelve patients, basal cell carcinoma occurred in four patients, mycosis fungoides occurred in one patient, and new melanoma occurred in two patients.[30]

MEK inhibitors

Trametinib

Trametinib is an orally available, small molecule, selective inhibitor of MEK1 and MEK2. 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 MAP kinases.

A total of 1,022 patients were screened for BRAF mutations, resulting in 322 eligible patients (281 with V600E, 40 with V600K and 1 with both mutations).[31] Patients were randomly assigned in a 2:1 ratio to receive trametinib (2 mg once daily) or IV chemotherapy (either DTIC 1000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks). Crossover was allowed, and 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). Median OS has not yet 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 10% of those receiving chemotherapy. The most common AEs included rash, diarrhea, nausea, vomiting, fatigue, peripheral edema, alopecia, hypertension, and constipation. Central serous retinopathy and retinal-vein occlusion are uncommon, but serious, AEs associated with trametinib. On-study cutaneous SCCs were not observed.

Combinatorial therapy with signal transduction inhibitors

Resistance to BRAF inhibitors, in patients with BRAF V600 mutations, may be associated with reactivation of the MAP kinase pathway. Early phase II data with combinations of BRAF and MEK inhibitors have supported testing this combination in phase III trials, such as NCT01584648, NCT01597908, and NCT01689519.[32] 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 and two large, multicenter, placebo-controlled, randomized trials of carboplatin and taxol plus or minus sorafenib showed no improvement over chemotherapy alone as either first-line treatment or second-line treatment.[33][34]

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.[35][36][37] Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.

Chemotherapy

The objective response rate to DTIC and the nitrosoureas, carmustine and lomustine, is approximately 10% to 20%.[2][38][39][40] Responses are usually short-lived, ranging from 3 to 6 months, though long-term remissions can occur in a limited number of patients who attain a CR.[38][40] A randomized trial compared IV DTIC with temozolomide (TMZ), an oral agent that hydrolyzes to the same active moiety as DTIC; OS was 6.4 months versus 7.7 months, respectively (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 and therefore, demonstration of similarity did not result in approval from the FDA.[3][Level of evidence: 1iiA] An extended schedule and escalated dose of TMZ was compared with DTIC in a multicenter trial (NCT00091572) that randomly assigned 859 patients. 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.[41][Level of evidence: 1iiA]

The design of two recent randomized, phase III trials in previously untreated patients with metastatic melanoma included DTIC as the standard therapy arm. 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.[38][39]

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.[15][16][17]

Although melanoma is a relatively radiation-resistant tumor, palliative radiation therapy may alleviate symptoms. Retrospective studies have shown that patients with multiple brain metastases, bone metastases, and spinal cord compression may achieve symptom relief and some shrinkage of the tumor with radiation therapy.[42][43] (Refer to the PDQ summary on Pain for more information.) 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. A phase I and II clinical trial (MCC-11543 [NCT00005615]) evaluated adjuvant radiation therapy plus interferon in patients with recurrent melanoma and results are pending.

Biochemotherapy

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) demonstrated no impact on OS.[44][Level of evidence:1iiA]

Other Treatment Options Under Clinical Evaluation for Patients With Stage IV and Recurrent Melanoma

  1. Immunotherapy, including anti-PD-1 and vaccines.
  2. Signal transduction inhibitors, including P13K (phosphoinositide-3 kinase) and Akt (protein kinase B inhibitors).
  3. Antiangiogenesis agents. Preclinical data suggest that increased vascular endothelial growth factor production may be implicated in resistance to BRAF inhibitors.[45]
  4. Intralesional injections; for example, oncologic viruses.
  5. Complete surgical resection of all known disease versus best medical 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 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:

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  3. 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.

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This information is provided by the National Cancer Institute.

This information was last updated on May 16, 2013.

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