Patient information: Melanoma treatment; advanced or metastatic melanoma (Beyond the Basics)
- Jeffrey A Sosman, MD
Jeffrey A Sosman, MD
- Professor of Medicine
- Vanderbilt University Medical Center
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.
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 information: Melanoma treatment; localized melanoma (Beyond the Basics)".)
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.
Treatment of metastatic melanoma focuses on:
●Eliminating the cancer
●Shrinking or stopping the growth of known metastases
●Controlling symptomatic or risky sites of disease
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 improve survival for most patients and now are the preferred approaches for patients 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 [Opdivo], pembrolizumab [Keytruda], ipilimumab [Yervoy]), which have largely replaced high-dose interleukin-2 (IL-2). These have important benefits for some patients, although each can cause significant side effects.
Anti-PD-1 checkpoint inhibitors — The anti-PD-1 checkpoint inhibitors (nivolumab, pembrolizumab) unleash the body’s immune system so that it can be able reject the melanoma. Nivolumab is given once every two weeks, while pembrolizumab is given once every three weeks. Both are continued unless there is evidence of disease progression or severe side effects. Nivolumab may be given in combination with ipilimumab. 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 that occasionally (<5 percent of all treated patients) 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, colitis (causing diarrhea or bleeding), and inflammation of endocrine organs (pituitary, thyroid, or adrenal, leading to diminished hormone production).
If one takes one of these drugs, it is important to tell your doctor about any side effects they experience, even mild ones. This will help to avoid more serious complications.
Ipilimumab — Ipilimumab is a drug 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 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.
Ipilimumab can also cause the body to develop an immune reaction against its own tissues. Principal immune-related toxicities from ipilimumab 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 largely 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 (oncogene addiction).
Three drugs, vemurafenib (Zelboraf), dabrafenib (Taflinar), and trametinib (Mekinist) block this protein or the pathway it stimulates and cause tumors with this specific mutation in BRAF to shrink. Generally, dabrafenib is 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. Vemurafenib is currently being studied with a MEK inhibitor, cobimetinib, and this combination is more effective than vemurafenib alone and will likely be approved shortly.
These drugs thus prolong the time until there is disease growth and extend overall survival in patients with BRAF-mutant melanoma. However, tumors eventually start to grow again despite continuation of treatment with this targeted therapy. The most significant side effects with vemurafenib are development of other kinds of skin cancers (non-melanoma), which can be managed with routine skin cancer care and do not require interruption of treatment; skin photosensitivity; joint pain; and fatigue. The most significant side effects for dabrafenib and trametinib combination are fevers, rash, fatigue, and liver test abnormalities.
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), the hair, and the lining of the gastrointestinal (GI) tract. 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 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. Surgery can also help to relieve pain caused by a metastatic tumor, such as in the lung or brain.
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 the tumors and prevent the development of additional 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 be used in some cases following surgery to destroy any cancer cells that remain in the brain.
Radiation therapy may also have a role in controlling symptoms from a particular site of metastasis, such as bone.
In some people with metastatic melanoma, the disease cannot be controlled or stops being controlled. 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 usually involves multiple people, including a clinician, registered nurse, nursing aide, a chaplain or religious leader, a social worker, and volunteers.
These providers work together to meet the patient and family's needs and significantly reduce their suffering. For more information about hospice, see www.hospicenet.org. (See "Hospice: Philosophy of care and appropriate utilization in the United States".)
Significant progress has been made in the treatment of patients with metastatic melanoma over the past decade. The anti-PD-1 checkpoint inhibitors (nivolumab, pembrolizumab) and the combination of nivolumab plus ipilimumab are effective for controlling metastatic melanoma and prolonging life in some people. 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, dabrafenib, and/or trametinib 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 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.
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:
Videos addressing common questions about clinical trials are available from the American Society of Clinical Oncology (http://www.cancer.net/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.
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.
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.
Evaluation and treatment of regional lymph nodes in melanoma
Imaging studies in melanoma
Initial surgical management of melanoma of the skin and unusual sites
Management of brain metastases in melanoma
Cutaneous melanoma: Management of local recurrence
Cutaneous melanoma: In transit metastases
Pathologic characteristics of melanoma
Radiation therapy in the management of melanoma
Staging work-up and surveillance after treatment of melanoma
Interleukin-2 and experimental immunotherapy approaches for advanced melanoma
Molecularly targeted therapy for metastatic melanoma
Immunotherapy of advanced melanoma with immune checkpoint inhibition
Cytotoxic chemotherapy for metastatic melanoma
Surgical management of metastatic melanoma
Hospice: Philosophy of care and appropriate utilization in the United States
The following organizations also provide reliable health information.
●National Cancer Institute
●The American Society of Clinical Oncology
●National Comprehensive Cancer Network
●American Cancer Society
●National Library of Medicine
●The Melanoma Center, University of Pittsburgh Cancer Institute
All topics are updated as new information becomes available. Our peer review process typically takes one to six weeks depending on the issue.