MELANOMA OVERVIEW — Melanoma is a serious form of skin cancer that develops in the cells (melanocytes) that make our skin color. Melanoma is the sixth most common cancer in the United States, and the number of melanoma cases diagnosed annually is increasing faster than for any other cancer.

After melanoma is diagnosed, the next step is to determine the cancer's stage, which is based upon the thickness of the tumor, the extent of its spread, and its aggressiveness. Staging is important to determine the most appropriate treatment.

Melanoma generally starts as a single tumor or lesion. Cancer cells can then spread to nearby lymph nodes and/or distant sites throughout the body. Once melanoma spreads to distant locations, it is called advanced or metastatic. Rarely, melanoma is diagnosed when a person presents with distant metastases, and no primary site on the skin or elsewhere can be found.

This article discusses the treatment of stage IV (advanced or metastatic) melanoma. The diagnosis and treatment of localized (stage I or II) or regional (stage III) melanoma is discussed separately. (See "Patient education: Melanoma treatment; localized melanoma (Beyond the Basics)".)

CANCER CARE DURING THE COVID-19 PANDEMIC — COVID-19 stands for "coronavirus disease 2019." It is an infection caused by a virus called SARS-CoV-2. The virus first appeared in late 2019 and has since spread throughout the world. Especially at the beginning of the pandemic, and while the virus was spreading quickly in a lot of places, people in many areas were told to stay home as much as possible in order to slow the spread of the virus. This has been particularly important for people with cancer, as many of them are at increased risk of severe illness if they get COVID-19. However, this risk must be balanced against the importance of continuing to get regular medical care to monitor and treat their cancer. 

If you live in an area where there are still a lot of cases of COVID-19 and are undergoing treatment for cancer, your oncologist can talk to you about whether you should make any changes to your usual regimen or schedule. In some cases, it may be an option to reduce the number of appointments you need to attend in person. This will depend on several different things, including where you live, how much the virus is still spreading in your community, the type and stage of your cancer, available treatment options, and your overall health.

MELANOMA STAGING — For people with stage IV disease, the melanoma has spread beyond the local area and regional nodes into other parts of the body or internal organs. The most common sites of such spread (metastases) are under the skin (subcutaneous tissue), lymph nodes away from those that drain the site of the original tumor, the lungs, liver, brain, and bone. However, metastasis to other sites in the body (such as the adrenal glands, spleen, gastrointestinal tract, and heart) can also occur.

MELANOMA TREATMENT — Treatment of metastatic melanoma focuses on:

●Prolonging survival

●Eliminating the cancer

●Shrinking or stopping the growth of known metastases

●Controlling symptomatic or risky sites of disease

●Providing comfort

Depending upon where and how big the metastases are, treatment may involve drug treatments, surgery, and/or radiation therapy.

Drug treatments — There are three main categories of drug treatments:

●Immunotherapy – Drugs that stimulate or unleash your immune system to attack and kill the cancer cells

●Targeted therapy – Drugs that inhibit specific enzymes or molecules important to the cancer cells

●Chemotherapy – Drugs that stop or slow the growth of cancer cells by interfering with their ability to divide or reproduce themselves

Advances in the use of immunotherapy and targeted therapy have improved survival for most patients, and they now are the preferred approaches for people with metastatic melanoma. Although chemotherapy was widely used in the past, it now has a limited role for patients whose disease can no longer be controlled with either immunotherapy or targeted therapy.

Immunotherapy — Several different types of immunotherapy have been developed, the most important of which are checkpoint inhibitors (nivolumab [brand name: Opdivo], pembrolizumab [brand name: Keytruda], ipilimumab [brand name: Yervoy]), which have replaced high-dose interleukin-2 (IL-2) (see 'Interleukin-2 (IL-2)' below). These have important benefits for some patients, although each can cause significant side effects.

Anti-PD-1 checkpoint inhibitors — The anti-programmed cell death 1 (PD-1) checkpoint inhibitors (nivolumab, pembrolizumab) unleash the body's immune system to reject the melanoma. Nivolumab is given once every two or four weeks, while pembrolizumab is given once every three weeks. Both are usually continued for one to two years unless there is evidence of disease progression or severe side effects. Nivolumab may be given in combination with ipilimumab (see 'Ipilimumab' below). Treatment with nivolumab, pembrolizumab, or the combination of nivolumab plus ipilimumab may decrease the extent of your melanoma and help you live longer.

Both nivolumab and pembrolizumab can cause the body to develop an immune reaction against its own tissues. This can result in a wide range of side effects, which occasionally (in less than 5 percent of people) can be severe or life threatening. The most important of these side effects include lung inflammation (causing difficulty breathing), rash or inflammation of the skin, hepatitis, inflammation of the kidneys causing decreased kidney function, inflammation of the gastrointestinal tract causing diarrhea or bleeding (colitis), and inflammation of endocrine organs (pituitary, thyroid, or adrenal, leading to diminished hormone production). These inflammatory conditions can usually be controlled with medications that suppress the immune system (eg, corticosteroids), often without interfering with the effectiveness of the checkpoint inhibitors.

If you take one of the anti-PD-1 checkpoint inhibitors, it is important to tell your doctor about any side effects that you experience, even if they are mild. This will help to avoid more serious complications.

Ipilimumab — Ipilimumab is another checkpoint inhibitor that stimulates the body's immune system to react against the melanoma. Ipilimumab is given once every three weeks for a total of four doses. Although treatment with ipilimumab alone may decrease the extent of your melanoma and help you live longer, it is less effective than nivolumab or pembrolizumab and is used primarily in combination with nivolumab or after disease progression on nivolumab or pembrolizumab.

Ipilimumab can also cause the body to develop an immune reaction against its own tissues. Possible side effects include colitis, rash, hepatitis, and inflammation of the endocrine organs, each occurring in 5 to 30 percent of patients. These ipilimumab-related side effects tend to be both more frequent and more severe than those seen with the anti-PD-1 pathway checkpoint inhibitors.

Interleukin-2 (IL-2) — IL-2 is a form of immunotherapy that was found to help some people with metastatic melanoma when given in high doses. In some people treated with high-dose IL-2, the disease disappeared completely or stopped growing for a prolonged period. Treatment usually required being in the hospital. IL-2 has been replaced by checkpoint inhibitors, which are safer and more effective.

Targeted therapy — About one-half of metastatic melanomas contain a specific mutation in one gene (BRAF) that causes the cell to make a particular protein that drives the growth of cancer cells. The melanoma actually becomes addicted to the actions of this protein (this is known as "oncogene addiction").

There are several drugs that block this protein or the pathway it stimulates and cause tumors with this specific mutation in BRAF to shrink. These include the BRAF inhibitors vemurafenib (brand name: Zelboraf); dabrafenib (brand name: Tafinlar); and encorafenib; and the MEK inhibitors trametinib (brand name: Mekinist), cobimetinib (brand name: Cotellic), and binimetinib (brand name: Mektovi). Generally, dabrafenib should be given in combination with trametinib, as the two agents together have been shown to be more effective and no more toxic than single-agent dabrafenib or vemurafenib. Similarly, vemurafenib is given with cobimetinib, and this combination is more effective than vemurafenib alone.

These drugs prolong the time until there is disease growth and extend overall survival in patients with BRAF-mutant melanoma. However, in the vast majority of patients, tumors eventually start to grow again, despite continuation of treatment.

The most significant side effects for the dabrafenib and trametinib combination are high fevers, rash, fatigue, and liver test abnormalities. The most significant side effects for the vemurafenib and cobimetinib combination are fatigue, rash, sensitivity to light, liver test abnormalities, visual changes, and joint pain. The most significant side effects for encorafenib and binimetinib include risk of new skin cancers, heart problems, liver test abnormalities, muscle damage, visual changes, breathing difficulties, and bleeding or clotting issues.

Chemotherapy — Chemotherapy uses medicines such as dacarbazine or temozolomide to stop or slow the growth of cancer cells by interfering with the ability of cancer cells to divide or reproduce. Because most of an adult's normal cells are not actively growing, they are not affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), hair, and the lining of the gastrointestinal tract. The effects of chemotherapy on these and other normal tissues result in side effects during treatment.

Chemotherapy is less effective than immunotherapy or targeted therapy, and it generally is not used as the initial treatment for patients with advanced disease. (See 'Immunotherapy' above and 'Targeted therapy' above.)

Surgery — Surgery may be recommended if melanoma has spread to only one or a very limited number of sites. Surgery may prolong survival or relieve symptoms caused by the melanoma. However, surgery is rarely curative because metastatic melanoma usually spreads to many different places throughout the body. Consequently, surgery for metastatic disease is increasingly being delayed until after other therapies (this is known as "salvage surgery") in situations where only localized disease remains.

Radiation therapy — Melanoma frequently spreads to the brain. If the spread is limited to one or a very limited number of spots within the brain, surgery may be indicated to remove the tumor. However, if the tumor is in a location in the brain that cannot be easily removed, or if there are several tumors, radiation therapy may be useful to shrink and/or control the tumors.

Radiation therapy may be given to only the parts of the brain containing tumor using a technique called radiosurgery (or stereotactic radiation therapy). This approach is generally more useful than a technique called "whole brain" radiation therapy, as it delivers more radiation to the tumor cells while sparing exposure and potential damage to normal brain cells.

Radiation therapy may also have a role in controlling symptoms from a particular site of metastasis, such as bone.

END-OF-LIFE CARE — In some people with metastatic melanoma, the disease progresses despite treatment. Deciding when to stop treating a patient with melanoma can be difficult, and this decision should involve the patient, family, friends, and the healthcare team.

Ending treatment does not mean ending care for the patient. Hospice care is frequently recommended when a person is unlikely to live longer than six months. Hospice care involves treatment of all aspects of a patient and family's needs, including the physical (eg, pain relief), psychological, social, and spiritual aspects of suffering. This care may be given at home or in a nursing home or hospice facility, and it usually involves multiple people, including a clinician, registered nurse, nursing aide, chaplain or religious leader, social worker, and volunteers.

These providers work together to meet the patient and family's needs and significantly reduce their suffering. (See "Hospice: Philosophy of care and appropriate utilization in the United States".)

MELANOMA SURVIVAL — Significant progress has been made in the treatment of patients with metastatic melanoma over the past decade.

The anti-programmed cell death 1 (PD-1) checkpoint inhibitors (nivolumab, pembrolizumab) and the combination of nivolumab plus ipilimumab are effective for controlling metastatic melanoma and prolonging life in nearly half of all patients. However, immunotherapy (nivolumab, pembrolizumab, ipilimumab) can be associated with severe side effects. Fortunately, these can usually be controlled with a brief course of immunosuppressive drugs without interfering with the control of the tumor in most cases.

Targeted therapy with vemurafenib plus cobimetinib, dabrafenib plus trametinib, or encorafenib and binimetinib has also been shown to improve overall survival in the majority of patients whose tumors contain BRAF mutations. However, continued treatment with targeted therapy is usually required for benefit to persist, and most patients eventually experience tumor progression.

In deciding what treatment is right for you, you and your family must consider the risks and benefits of each option according to your values and preferences. In addition, clinical trials are available to help address this situation. (See 'Clinical trials' below.)

CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:

●www.cancer.gov/about-cancer/treatment/clinical-trials

●https://clinicaltrials.gov/

Videos addressing common questions about clinical trials are available from the American Society of Clinical Oncology (https://www.cancer.net/research-and-advocacy/clinical-trials/welcome-pre-act).

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

●(See "Patient education: Melanoma skin cancer (The Basics)".)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

●(See "Patient education: Melanoma treatment; localized melanoma (Beyond the Basics)".)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Systemic treatment of metastatic melanoma lacking a BRAF mutation
Systemic treatment of metastatic melanoma with BRAF and other molecular alterations
Evaluation and treatment of regional lymph nodes in melanoma
Imaging studies in melanoma
Surgical management of primary cutaneous melanoma or melanoma at other unusual sites
Management of brain metastases in melanoma
Cutaneous melanoma: Management of local recurrence
Cutaneous melanoma: In-transit metastases
Radiation therapy in the management of melanoma
Staging work-up and surveillance of cutaneous melanoma
Cytotoxic chemotherapy for metastatic melanoma
Metastatic melanoma: Surgical management
Hospice: Philosophy of care and appropriate utilization in the United States

The following organizations also provide reliable health information.

●National Cancer Institute

      1-800-4-CANCER

      (www.cancer.gov)

●The American Society of Clinical Oncology

     (www.cancer.net)

●American Cancer Society

      1-800-ACS-2345

     (www.cancer.org)

●National Library of Medicine

     (https://medlineplus.gov/healthtopics.html)

●The Melanoma Center, University of Pittsburgh Cancer Institute

(http://hillman.upmc.com/cancer-care/melanoma-skin/program)

●Melanoma Research Foundation

     (https://melanoma.org/)