What`s new in research and treatment of melanoma skin cancer?

Research into the causes, prevention, and treatment of melanoma is being done in medical centers throughout the world.

Causes, prevention, and early detection

Sunlight and ultraviolet (UV) radiation

Recent studies suggest there may be 2 general ways that UV exposure is linked to melanoma, but there is likely some overlap.

The first link is to sun exposure to as a child and teenager. People with melanoma often have an early history of sunburns or other intense sun exposures, although not everyone does. This early sun exposure may cause changes in the DNA of skin cells (melanocytes) that starts them on a path to becoming melanoma cells many years later. Some doctors think this might help explain why melanomas often occur on the legs and trunk, areas that generally aren’t exposed to the sun as much in adulthood.

The second link is to melanomas that occur on the arms, neck, and face. These areas are chronically exposed to sun, particularly in men. Tanning booths may encourage either kind of melanoma to develop.

Researchers are looking to see how melanomas that develop as a result of these types of UV exposure may differ. For example, they may have different gene changes that would require them to be treated differently.

Public education

Most skin cancers can be prevented. The best way to reduce the number of skin cancers and the pain and loss of life from this disease is to educate the public, especially parents, about skin cancer risk factors and warning signs. It is important for health care professionals and skin cancer survivors to remind everyone about the dangers of excess UV exposure (from the sun and from man-made sources such as tanning beds) and about how easy it can be to protect your skin against too much UV radiation.

Melanoma can often be detected early, when it is most likely to be completely cured. Monthly skin self-exams and awareness of the warning signs of melanomas may be helpful in finding most melanomas when they are at an early, curable stage.

The American Academy of Dermatology (AAD) sponsors annual free skin cancer screenings throughout the country. Many local American Cancer Society offices work closely with the AAD to provide volunteers for registration, coordination, and education efforts related to these free screenings. Look for information in your area about these screenings or call the American Academy of Dermatology for more information. Their telephone number and Web site are listed in the “Additional resources” section.

Along with recommending staying in the shade, the American Cancer Society uses a slogan popularized in Australia as part of its skin cancer prevention message in the United States. “Slip! Slop! Slap! and Wrap” is a catchy way to remember when going outdoors to slip on a shirt, slop on sunscreen, slap on a hat, and wrap on sunglasses to protect your eyes and the sensitive skin around them.

Melanoma DNA research

Scientists have made a great deal of progress during the past few years in understanding how UV light damages DNA and how changes in DNA cause normal skin cells to become cancerous.

Some people, though, may inherit mutated (damaged) genes from their parents. For example, changes in the CDKN2A (p16) gene cause some melanomas to run in certain families. People who have a strong family history of melanoma should speak with a cancer genetic counselor or a doctor experienced in cancer genetics to discuss the possible benefits, limits, and downsides of testing for changes in this gene.

Molecular staging

Advances in melanoma DNA research are also being applied to molecular staging. In ordinary staging, a lymph node removed from a patient is looked at under a microscope to see if melanoma cells have spread to the lymph node.

In molecular staging, RNA (a chemical related to DNA), is extracted from cells in the lymph node. Certain types of RNA are made by melanoma cells but not by normal lymph node cells. A sophisticated test called reverse transcription polymerase chain reaction (RT-PCR) is used to detect these types of RNA.

Early studies have found that RT-PCR is better than routine microscopic testing at detecting the spread of melanoma to lymph nodes. This test could eventually help identify some patients who might benefit from additional treatment such as immunotherapy after surgery. However, some doctors are concerned that this test may lead to unnecessary treatment for some patients, which is why this test is not currently recommended. Studies are now in progress to learn more about how results should influence choice of treatment.

Treatment

Early-stage melanomas can often be cured with surgery, but more advanced melanomas are often much harder to treat because standard cancer treatments such as chemotherapy are not very effective. Newer types of treatment have shown a great deal of promise in treating more advanced melanomas.

Immunotherapy

This type of treatment includes several approaches for helping the body’s immune system attack melanoma cells more effectively. Some forms of immune therapy, such as ipilimumab (Yervoy), cytokines (interferon-alpha and interleukin-2), and the BCG vaccine are already used to treat some melanomas (see “Immunotherapy for melanoma skin cancer”). These treatments work by generally boosting the immune system.

Ipilimumab targets CTLA-4, a protein that normally suppresses the T-cell immune response, which might help melanoma cells survive. This drug has been shown to help some people with advanced melanomas live longer. Researchers are now trying to determine if it might be useful earlier in the course of the disease. Other drugs that counteract CTLA-4 are now being studied as well.

Drugs that block PD-1 and PD-L1

Melanoma cells may also use other natural pathways in the body to help avoid detection and destruction by the immune system. For example, they often have a protein called PD-L1 on their surface that helps them evade the immune system. New drugs that block the PD-L1 protein, or the corresponding PD-1 protein on immune cells called T cells, can help the immune system recognize the melanoma cells and attack them.

In early studies, an anti-PD-1 drug known as BMS-936558 shrank tumors in about 3 out of 10 people with melanoma, while a drug targeting PD-L1 (known as BMS-936559) shrank tumors in about 2 out of 10 people. Many of the tumor responses have been long-lasting so far. Larger studies of these new drugs are now being done.

Melanoma vaccines

Vaccines directed at melanoma are being studied in clinical trials. They are experimental therapies that do not yet have proven benefit.

These vaccines are, in some ways, similar to the vaccines used to prevent diseases such as polio, measles, and mumps that are caused by viruses. Such vaccines usually contain weakened viruses or parts of a virus that cannot cause the disease. The vaccine stimulates the body's immune system to destroy the more harmful type of virus.

In the same way, killed melanoma cells or parts of cells (antigens) can be injected into a patient as a vaccine to try to stimulate the body's immune system to destroy other melanoma cells in the body. Usually, the cells or antigens are mixed with other substances that help boost the body's immune system as a whole. But unlike vaccines that are meant to prevent infections, these vaccines are meant to treat an existing disease.

Making an effective vaccine against melanoma has proven to be harder than making a vaccine to fight a virus. The results of studies using vaccines to treat melanoma have been mixed so far, but newer vaccines may hold more promise.

In a recent clinical trial of patients with advanced melanoma, adding a vaccine to high-dose interleukin-2 (IL-2) increased the portion of tumors that shrank and the length of time before they started growing again better than just giving IL-2 alone. But it's not yet clear if this vaccine can help people live longer.

Other immunotherapies

Other forms of immunotherapy are also being studied. Some early studies have shown that treating patients with high doses of chemotherapy and radiation therapy and then giving them tumor-infiltrating lymphocytes (TILs), immune system cells found in tumors, can shrink melanoma tumors and possibly prolong life as well. Newer studies are looking at changing certain genes in the TILs before they are given to see if this can make them more effective at fighting the cancer. This approach has looked promising in early studies, but it is complex and is only being done in a few centers. These new treatments are being studied further.

Another potential approach to treatment is to combine different types of immunotherapy, which may be more effective than any single treatment for advanced melanoma.

Targeted drugs

As doctors have discovered some of the gene changes in melanoma cells, they have begun to develop drugs that attack these changes. These targeted drugs work differently from standard chemotherapy drugs. They may work in some cases when chemotherapy doesn't. They may also have less severe side effects.

Drugs that target changes in the BRAF gene: As noted in the section, “Targeted therapy for melanoma skin cancer” about half of all melanomas have changes in the BRAF gene, which helps the cells grow. A drug called vemurafenib (Zelboraf) has been shown to shrink many of these tumors and is now often used in melanomas that test positive for this gene change.

Other drugs that target BRAF gene changes are now being studied as well. A drug called dabrafenib has shown results similar to those for vemurafenib in studies. It may have an added benefit of causing fewer squamous cell carcinomas of the skin, but further testing is needed to be sure. This drug is only available through clinical trials at this time.

The MEK gene is in the same signaling pathway inside cells as the BRAF gene. A drug that blocks MEK, known as trametinib, has been shown to cause some melanomas with BRAF mutations to shrink. It’s not yet clear if this drug will be as effective as the BRAF inhibitors, or if it might work against some melanomas that do not respond to BRAF inhibitors. This drug is also only available through clinical trials.

One approach now being studied is to combine a BRAF inhibitor with a MEK inhibitor in the hope of causing tumors to shrink for longer periods of time. Early results have been promising, showing that some side effects (such as the development of other skin cancers) might actually be less common with the combination, but further research is needed.

Drugs that target changes in the c-kit gene: Certain types of melanomas often have unusual gene changes. This often includes melanomas that start:

• On the palms of the hands, soles of the feet, or under fingernails
• Inside the mouth or in other mucosal areas
• In areas that get chronic sun exposure

About one third of these uncommon melanomas have changes in a gene called c-kit. Some drugs that are already used to treat other cancers, such as imatinib (Gleevec) and nilotinib (Tasigna), are known to target cells with changes in c-kit. Clinical trials are now looking to see if these and other drugs might help people with these types of melanoma.

Drugs that target other gene or protein changes: Several drugs that target other abnormal genes or proteins, such as sorafenib (Nexavar), bevacizumab (Avastin), temsirolimus (Torisel), and everolimus (Afinitor), are now being studied in clinical trials as well.

Researchers are also looking at combining some of these targeted drugs with other types of treatments, such as chemotherapy or immunotherapy.