Treatment for metastatic melanoma
– 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
– 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 largely 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 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, colitis (causing diarrhea or bleeding), 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 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 the following settings: in combination with nivolumab, after disease progression on nivolumab or pembrolizumab, or following surgical resection of disease (called "adjuvant therapy") in patients at high risk for disease recurrence.
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 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 (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) and dabrafenib (brand name: Tafinlar), and the MEK inhibitors trametinib (brand name: Mekinist) and cobimetinib (brand name: Cotellic). 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 fevers, rash, fatigue, and liver test abnormalities. The most significant side effects for the vemurafenib and cobimetinib combination are fatigue, rash, photosensitivity
, liver abnormalities, visual changes, and joint pain.
Chemotherapy — Chemotherapy uses medicines such as dacarbazine
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.