Treatment for melanoma depends on various factors, including:
- The site of the original lesion
- The stage of the cancer
- The patient's age and general health
Treatment options include:
- Surgery to remove the tumor or tumors
- Radiation therapy
- Symptom relief (palliative therapy)
Surgery is the primary treatment for all stages of melanoma. Some or all of the melanoma is often removed during the initial biopsy. After the biopsy, a surgeon will cut away additional tissue from the surrounding area to remove any stray cancer cells and have clear margins. The margin of normal skin around the melanoma is determined by the size and staging of the tumor. Sentinel lymph node biopsy is also determined by these factors.
Surgical management of melanoma that develops in rare sites, such as the vagina, cervix and ovaries, is becoming less aggressive. Studies have shown that wide local removal works as well as radical surgery in many of these cases. Melanoma of the urethra, bladder, and ureter often requires extensive surgery, however.
Mohs Micrographic Surgery
A technique used to remove very thin layers of skin, one at a time. Each layer is examined immediately under a microscope. When the layers are shown to be cancer-free, the surgery is complete. This is usually reserved only for melanomas in areas where wide margins are not possible, such as near the eyes or ears.
The amount of tissue removed depends on the size, depth, and degree of invasion:
- Stage I lesions that are less than 1 mm thick require the smallest surgical cuts, with 1 cm around each side and down just above the muscle.
- For melanomas that are 2 mm or thicker, a margin of 2 to 3 cm is important for reducing the risk that the cancer will return.
- Thicker lesions require wider surgical cuts.
Doctors used to remove a large area, regardless of the cancer stage. This potentially disfiguring approach has been abandoned because studies have shown that removing wider margins does not improve survival. Nevertheless, sometimes skin grafts may need to be taken from other body sites to help cover the wound.
Lymph Node Removal
If there is evidence that melanoma has spread to nearby lymph nodes but has not spread beyond them, removing those lymph nodes may reduce the chance of recurrence and help patients live longer.
Surgery for Metastatic Melanoma
In some cases, surgical removal of distant tumors may be possible. This may extend survival, since often in melanoma the cancer spreads first only to a single site, such as the lung or brain.
Cryosurgery freezes skin tissue and destroys it. This procedure is not used as a primary treatment for melanomas of the skin, but it might have some value in specific situations. For example, it may be effective for smaller melanomas in the eye, a location that is difficult to treat with traditional surgery. It may be useful to eliminate cancer cells that remain after standard surgery for lentigo maligna melanomas, an unusual form of melanoma that has a wide surface and is difficult to treat.
Surgery for Lentigo Maligna
Recurrence rates are very high with lentigo maligna after conservative surgery. Although this cancer grows very slowly, lentigo maligna can develop into melanoma. Most of these lesions appear on the face and neck, where extensive surgery can be disfiguring. Patients should carefully discuss with their doctor having surgery to remove all diseased tissue while causing as little cosmetic harm as possible. Mohs surgery is a useful tool when treating lentigo maligna.
Chemotherapy is often used to treat melanomas that return or spread. This type of therapy is not intended as a cure, but it can prolong life and improve its quality. Chemotherapy tends to work better than radiotherapy for advanced stage cancers and tumors.
Chemotherapy may also be given after surgical removal (excision) of melanoma when there is increased risk for recurrence based on size of the lesion, location, or presence of cancer cells in the local lymph nodes. This is called adjuvant chemotherapy.
The following are some of the chemotherapy drugs used to treat melanoma. They may be used alone or in combination under specific situations. Chemotherapy is usually given in cycles, with rest periods between treatment periods.
- Methylating agents impair the ability of cancer cells to divide. Dacarbazine (DTIC) and temozolomide (Temodar) are the drugs most often used.
- Nitrosoureas, which include carmustine (BCNU), and lomustine (CCNU), are often used.
- Taxanes, such as docetaxel (Taxotere) and paclitaxel (Taxol), are showing some activity against melanoma.
- Biochemotherapy treatment regimens combine traditional chemotherapy agents, such as cisplatin, vinblastine, carboplatin, and dacarbazine, with biologic agents such as interferon alpha or interleukin 2. This combination may be tried for patients with large primary tumors or disease that has spread locally.
Researchers continue to investigate other chemotherapy drugs and combinations of drugs to see which ones work best.
Side effects occur with all chemotherapy drugs. They are more severe with higher doses and increase over the course of treatment.
Common side effects include the following:
- Nausea and vomiting
- Temporary hair loss
- Weight loss
- Easy bruising
Serious short- and long-term complications can also occur, and may vary depending on the specific drugs used. They include the following:
- Abnormal blood clotting (thrombocytopenia).
- Allergic reaction.
- Increased chance for infection because the drugs suppress the immune system.
- Liver and kidney damage.
- Menstrual abnormalities and infertility in women. A natural hormone medication called a gonadotropin-releasing hormone analogue, which puts women in a temporary prepubescent state during chemotherapy, may preserve fertility in some women.
- Severe drops in white blood cells (neutropenia). Certain chemotherapy drugs, such as taxanes, pose a higher risk for this side effect. White blood cell count may be improved by adding a drug called granulocyte colony-stimulating factor (either filgrastim or lenograstim).
- Problems in concentration, motor function, and memory, which may be long-term.
- Rarely, secondary cancers such as leukemia.
- Nerve damage
Treating Side Effects
Drugs known as serotonin antagonists, especially ondansetron (Zofran) can relieve nausea and vomiting in nearly all patients given moderate drugs, and in most patients who take more powerful drugs.
Benefits of Chemotherapy
About 20% of cancers shrink in response to one or more of these drugs, but the effects last only 3 to 6 months. If the tumors completely disappear, the cancer may stay in remission much longer, but in virtually all cases it returns.
Chemotherapeutic Regional Perfusion
Chemotherapeutic regional perfusion (also called isolated limb perfusion) is a technique used to give a person very high-dose chemotherapy. It is often used effectively for melanoma that returns or spreads and that occurs on the arm or leg. It does not appear to be useful for preventing cancer spread after a first occurrence of melanoma in one of these locations.
This technique involves the following:
- The blood supply to the limb with melanoma is temporarily interrupted using a tourniquet and then rechanneled through a heart-lung machine.
- Anticancer drugs are added to the blood in up to 10 times the standard doses.
- The blood is then heated to enhance the drug's potency.
- The chemo-infused blood is sent directly to the melanoma site, minimizing the likelihood of drug toxicity. By the end of the treatment, the chemotherapy agents are completely washed away.
- Adverse effects occur in less than 1% of cases, and include severe problems in the treated limb (rarely leading to amputation) and drug leakage into the bloodstream. This can severely reduce white blood cells and lead to serious infection.
Perfusion techniques have also been tested for the pelvis, head, neck, skin of the breast, and abdomen.
Immunotherapy uses drugs to boost the patient's own immune system to recognize and kill the cancerous cells. Immunotherapy after surgery may help prevent recurrence in certain people with melanoma. This is called adjuvant therapy. If there is improvement in overall survival with this therapy, it is small. These medicines are often given along with chemotherapy, other immunotherapies, or both.
Immunotherapy drugs being used include:
- Interferon alpha is an FDA-approved postoperative immunotherapy for stage III melanoma. Both interferon alpha-2b and pegylated interferon alpha-2b have shown positive effects on relapse-free survival (and to a modest extent, overall survival rates for stage III melanoma). Although interferon drugs have provided some benefit, their use is controversial because of significant side effects. Additional drugs are being tested.
- Interleukin-2 is a hormone-like substance that stimulates the growth of cancer-fighting white blood cells. High-dose interleukin-2 has been shown to help patients with melanoma that has spread. The drug can cause significant side effects, including very low blood pressure, heart rhythm abnormalities, flu like symptoms, severe infections, and shortness of breath. The side effects are manageable, however, and are nearly always reversible.
Vaccine immunotherapy is the use of a specific vaccine to treat an existing cancer. In this case, the vaccine targets one or more proteins that are produced by melanoma cells.
Vaccine immunotherapy requires the body to build up its own defenses. It can take months before benefits occur, but when they do, tumor reduction is more lasting than with chemotherapy. Vaccines also seem to have fewer side effects than interleukin and interferon.
Many therapeutic melanoma vaccines are in the advanced stages of testing, but none is approved for use in the United States at this time. So far trials have shown:
- No response at all
- The cancer completely disappearing
- Some shrinking of the melanoma
- Some slowing of the melanoma growth rate
Combined vaccine and biologic therapies are under study and show promising results.
Monoclonal antibodies work in different ways. They can attach to cancer cells, allowing your immune system to better attack the cancer cells, block the cancer cells from growing, or deliver chemotherapy or radiation to the cancer cells.
The monoclonal antibody ipilimumab (Yervoy) is approved by the FDA for use in adult patients with high-risk melanoma. This antibody allows the immune cells to attack tumors more effectively by blocking a regulator gene of the immune system. Fatigue and diarrhea are common side effects. However, the drug carries the risk of potentially fatal side effects, which include intestinal inflammation (colitis) and inflammation of the liver (hepatitis).
The monoclonal antibody pembrolizumab (Keytruda), which targets PD1, has recently been approved by FDA for treatment of melanoma that spread to lymph nodes. Another antibody targeting PD1 called nivolumab (Opdivo) is also approved for treatment of melanoma that is advanced or cannot be removed by surgery. Nivolumab is sometimes used together with ipilimumab.
- The PD1 receptor is found on certain immune system cells (known as T cells) that normally fight cancers. This receptor prevents the T cells from fighting other cells in the body.
- Anti-PD1 agents block this receptor, and as a result, the T cells are more likely to respond and fight against the cancer.
- Clinical trials of anti-PD1 monoclonal antibodies have shown them to be effective in patients with advanced, metastasized melanoma, and they seem to be less toxic than ipilimumab.
- These drugs are also being studied as adjuvant therapy to shrink tumors.
Several studies are under way to assess new monoclonal antibodies, such as KIT inhibitors, as well as to determine when, in what sequence, and which combination of these antibodies is most effective. It appears that combination treatment is the best way of using these medications.
BRAF and MEK inhibitors target proteins in the BRAF mutation, which is specific for melanoma cells so that normal cells are not targeted by these medications.
Vemurafenib (Zelboraf) is an inhibitor of the mutated BRAF protein, which is found in approximately 50% of metastatic melanoma cases. Vemurafenib is approved by the FDA for treating metastatic or inoperable melanoma in patients with the BRAF mutation, and has proven superior to chemotherapy. Dabrafenib (Tafinlar), seems equally effective, but it has fewer skin side effects. Enocrafenib (Braftovi) is another BRAF inhibitor. These medications shrink down tumors or slow the growth of metastatic lesions. These help prolong life but do not cure the melanoma.
Trametinib (Mekinist) is an MEK inhibitor. It targets the MEK protein found in the BRAF mutation. It was approved in 2013 for patients with BRAF mutation melanoma that cannot be surgically removed or that becomes metastatic. Other MEK inhibitors are binimetinib (Mektovi) and cobimetinib (Cotellic). These are pills taken daily.
Several combinations of BRAF and MEK inhibitors have been approved for patients with melanoma with BRAF mutation that are metastatic or that cannot be removed by surgery:
- MEK inhibitor trametinib (Mekinist) with BRAF inhibitor dabrafenib (Tafinlar)
- MEK inhibitor binimetinib (Mektovi) with BRAF inhibitor encorafenib (Braftovi)
- MEK inhibitor cobimetinib (Cotellic) with BRAF inhibitor vemurafenib (Zelboraf)
Medications that Target C-Kit
Some melanomas have mutations in the C-Kit gene that cause them to grow. This mutation is more commonly found in melanomas on the hands, feet, or inside the mouth. Imatinib (Gleevec) and nilotinib (Tasigna) are medicines that target this gene defect.
In general, radiation is used to help relieve pain and discomfort caused by cancer that has spread or recurred. Radiation is not used as often for melanoma as it is for other forms of cancer, because melanoma cells tend to be more resistant to its effects. It may be useful in some cases.
- Radiation may help in patients who are unwilling or unable to have surgery.
- In some patients with tumors less than 3 cm deep, radiation may help slow down cancer spread when combined with a super-heating process using microwaves.
- In some high risk patients with melanoma that has spread to lymph nodes, surgery combined with regional radiation (adjuvant radiotherapy) may reduce the rate of recurrence.
- Brachytherapy, in which radioactive seeds are implanted close to the tumor, has been successfully used for melanoma of the eye.
- Lentigo maligna may sometimes be treated successfully with specific radiation treatments called soft, or Grenz, x-rays.
- Radiotherapy using a gamma knife (very focused gamma radiation) is also effective for cancer that has spread to the brain. In some cases it halts the cancer growth and, in rare situations, even eliminates it.
The goal of palliative therapy is to improve the patient's quality of life and relieve symptoms. It is not a cure. Advanced melanoma that has spread to distant sites often cannot be cured, although surgery to remove tumors that have spread may provide some benefit by easing pain, increasing the general quality of life, and lengthening survival.
Patients should ask their doctors about clinical trials, studies that examine new immunotherapies (vaccines, cytokines), gene therapies, chemotherapy combinations, or other treatments.