Melanoma

Treatment options

Stage III and IV melanoma

An advanced melanoma diagnosis of Stage III or Stage IV disease indicates that the primary tumor cells have spread beyond the original site to lymph nodes in the region (known as regional disease) or to distant sites in the body (known as advanced disease). The type of treatment your doctor recommends will depend primarily on the specific stage and location of the melanoma, as well as your overall health. Your treatment regimen may include surgery, targeted therapy, immunotherapy, chemotherapy, radiation therapy or a combination of treatments.

Talk to your doctor about the risks and benefits of each treatment option to select the most appropriate treatment for you, based on your diagnosis. Many of the treatments used for Stage III and IV melanoma require specialized knowledge and should be managed by an appropriately trained medical oncologist, surgical oncologist, dermatologist or other specialized physician. Talk to your team about who will be delivering your treatments, the possible side effects you may experience and how they can be managed.

Treatment of stage IIIA, IIIB and IIIC melanomas

Surgery is the initial treatment for Stage III melanoma and usually involves the removal of involved lymph nodes. Additional treatment after surgery, which is called adjuvant therapy, is often recommended, especially in higher-risk patients. The goal of adjuvant therapy is to kill any remaining melanoma cells to decrease the chance that the melanoma will return and to improve survival rates. Adjuvant treatment usually includes a form of interferon (high-dose or pegylated). Adjuvant therapy may also include targeted therapy or immunotherapy drugs. Radiation therapy to the area where the lymph nodes were removed may be given if melanoma cells have spread outside the lymph node or are found in many lymph nodes, or if the tumors are very large or have invaded surrounding tissues.

For Stage III in-transit melanoma, the preferred primary treatment is the surgical removal of all melanoma metastases (when only a few lesions are present), and an SLN biopsy, if it has not already been performed. For locally advanced or recurrent melanoma on an arm or leg, procedures known as hyperthermic isolated limb perfusion and isolated limb infusion may be options when multiple, large or recurrent lesions are present. These involve isolating the blood flow to the limb and treating it directly with high-dose chemotherapy.

If surgical removal of all melanoma metastases is not possible, other treatment options include injections of the bacillus Calmette-Guerin vaccine to stimulate an immune response; radiation therapy; laser treatment using a carbon dioxide laser to remove the melanoma; or systemic therapy. Targeted therapy or immunotherapy may also be options for you.

Treatment of stage IV melanoma

Management of Stage IV melanoma typically includes targeted therapy, immunotherapy and chemotherapy. Until 2011, only two immunotherapy drugs and one chemotherapy drug were approved in the United States for treating melanoma. Options for systemic therapy (treatment that travels through the body via the bloodstream), however, have greatly expanded with the subsequent approval of several new drugs (see Table 1).

Combinations of treatments, such as surgery with radiation therapy, or chemotherapy with immunotherapy (called biochemotherapy), are often used. Radiation therapy may also be included to treat symptoms of metastatic cancer, primarily to the brain or bones.

Table 1. FDA-approved systemic therapies for stage III and IV melanoma

Type of systemic therapy Generic (brand) drug name
Immunotherapy
• aldesleukin (Proleukin)

• bacillus Calmette-Guerin (BCG) vaccine

• high dose interleukin-2 (IL-2)

• interferon-alfa (Intron A)

• ipilimumab (Yervoy)

• nivolumab (Opdivo)

• peginterferon alfa-2b (Sylatron)

• pembrolizumab (Keytruda)
 
• talimogene laherparepvec (Imlygic/TVEC)
Chemotherapy
• dacarbazine (DTIC-Dome)
Targeted therapy
• cobimetinib (Cotellic)
 
• dabrafenib (Tafinlar)

• trametinib (Mekinist)

• vemurafenib (Zelboraf)

 

Surgical removal of melanoma metastases is usually done when possible, especially if the tumor is limited in size and confined to one organ, if the person has symptoms and if the risk of surgery-related complications is acceptable. When melanoma has spread to the brain, radiation therapy or surgery sometimes can relieve symptoms or prevent future symptoms.

If surgery is not possible, immunotherapy may be used as first-line treatment, and second-line immunotherapy treatment options are available if the first-line drugs are not effective. Targeted therapy may be another option for people with Stage IV melanoma with the BRAF  or MEK gene mutations. Combinations of immunotherapies and targeted therapies are also under evaluation in clinical trials. Talk to your doctor to see if volunteering for a clinical trial is right for you.

Targeted therapy

Targeted therapy is treatment with drugs or other substances that block the growth and progression of cancer. They do so by interfering with specific molecules involved in tumor growth and progression. The targeted therapy agents block or modify the molecules on or inside cancer cells that alter signaling pathways, which are complex systems that direct basic cell functions, such as cell division and cell death.

The development of certain targeted therapy drugs used to treat melanoma began after researchers identified a specific genetic mutation, called BRAF V600, in about half of all people with metastatic melanoma. The mutation affects the BRAF gene and causes tumor cells to grow and divide more quickly. Drugs known as BRAF inhibitors specifically attack the mutated form of BRAF and are approved for use only in people who have melanoma with the BRAF mutation. Because the attack is so targeted, molecular testing must be done on a sample of melanoma tissue before treatment begins to see if the mutation is present.

The identification of the BRAF and MEK mutations and the development of drugs to target these two mutations is a significant advancement in the treatment of Stage IV melanoma. Clinical studies have shown that using the combination of a BRAF plus a MEK inhibitor resulted in higher response rates and improved progression-free and overall survival compared either drugs as a single agent or standard chemotherapy. And the side effects are more manageable. Thus, the combination is generally used together in patients with BRAF-mutated metastatic melanoma.

Some melanomas have mutations in another gene, C-KIT, that help them grow.

Because targeted drugs are meant to attack only the cancer cells and not normal cells (unlike traditional chemotherapy), side effects are typically more manageable.

Immunotherapy

Although advanced melanoma can be difficult to treat using standard therapies, it’s been one of the most responsive cancers to newly developed immunotherapy treatments. Immunotherapy is a type of cancer treatment that seeks to stimulate your own immune system to fight cancer.

The use of the body’s own immune system makes immunotherapy fundamentally different from other cancer treatments. Many immunotherapy strategies currently exist (see Table 2). Additional immunotherapies, used alone and in conjunction with other treatments, are being studied in clinical trials (see Find Clinical Trials).

Immunotherapy depends on a functioning immune system, so it will likely be important to make sure that you do not have an autoimmune disorder or are not taking any immunosuppressive medications. After taking into consideration these and other factors, such as your overall health, type and stage of your melanoma and your treatment history, your doctor will recommend one or a combination of treatments.

Once treatment begins, monitoring is key. More monitoring and follow-up occur with immunotherapy than with most other forms of treatment. You will likely undergo testing to allow your doctor to evaluate how well treatment is working by measuring the size of the tumor as treatment progresses.

If immunotherapy is not suggested for you, do not be disappointed. All of the approved treatments for melanoma are extremely effective strategies. In addition, you may be a candidate for a clinical trial that offers access to a leading-edge treatment that is not yet available (see Find Clinical Trials). Ask your doctor about all your options, taking into consideration possible side effects, before making any treatment decisions.

The use of immunotherapy to treat melanoma began in the 1990s with interferon alfa (Intron A) and interleukin-2 (Proleukin), which are both types of cytokine treatment. Cytokines are the messengers of the immune system, aiding in communication between immune cells to induce an immune response. Cytokine immunotherapy treatments involve introducing large amounts of manufactured cytokines to the immune system to stimulate it to respond, including boosting certain cells’ abilities to attack cancer. When used alone, both interferon alfa and interleukin-2 have been shown to shrink advanced melanoma tumors in some patients. They are often combined with additional treatments such as other immunotherapy or chemotherapy drugs. In 2011, another type of cytokine therapy was approved to prevent malignant melanoma from recurring after surgery. Peginterferon alfa-2b (Sylatron) is a pegylated drug, which stays in the blood longer than non-pegylated cytokines. Because it stays in the blood longer, peginterferon alfa-2b can be taken less often than other cytokines and still be as or more effective than they are.

Cytokines have the potential to cause substantial immune-related side effects especially when given in high doses. Because of this, certain patients must receive treatment in a hospital so they can be monitored closely by their physician.

Recent advancements in immunotherapy treatment for melanoma include drugs known as checkpoint inhibitors. Immune cells communicate with other cells (including tumor cells) through several proteins on the surface of each cell that connect to one another. Immune checkpoints are specific connections between cells that help regulate the immune response, specifically when to shut down the response once it’s no longer necessary. Immune checkpoint inhibitors are drugs that block the checkpoint from being engaged (see Figure 1), which essentially turns the immune system back on so it can fight the melanoma. These types of drugs have shown significant promise, with the approval of three checkpoint inhibitor drugs to treat melanoma since 2011: ipilimumab (Yervoy), pembrolizumab (Keytruda) and nivolumab (Opdivo). New immunotherapy treatments are quickly becoming first-line and second-line therapy options, above other treatment types that have long been considered standard therapy.

Another type of immunotherapy treatment for advanced melanoma is oncolytic virus immunotherapy. In this treatment, an oncolytic virus (a virus that infects and kills cancer cells) is injected into tumors. Talimogene laherparepvec (Imlygic), often called T-VEC, is the first FDA-approved oncolytic virus immunotherapy to treat melanomas that cannot be removed with surgery.

Cancer vaccines are substances that stimulate the immune system to fight infection or disease. Cancer vaccines strengthen the immune system against cancer cells. The bacillus Calmette-Guérin (BCG) vaccine is approved to treat melanoma. The BCG vaccine is sometimes used to treat Stage III melanomas by injecting it directly into the tumors to stimulate the immune system.

Immunotherapy is commonly associated with side effects such as flu-like symptoms (chills, fever, muscle and joint aches and fatigue), nausea, vomiting, rash and diarrhea, but may also cause serious, immune-related side effects. Talk to your doctor about how to prevent, monitor and manage side effects during and after treatment with immunotherapy.

Table 2. FDA-Approved Immunotherapy Strategies for Melanoma

Class of treatment Purpose Type of treatment Drug
Checkpoint inhibitors Prevent the immune system from shutting down in the body and restore the immune response against melanoma cells CTLA-4 inhibitor ipilimumab (Yervoy)
PD-1 inhibitor
nivolumab (Opdivo)
pembrolizumab (Keytruda)
Combination therapy of ipilimumab with nivolumab
Cytokines Boost the immune system overall   interferons, interleukins, hematopoietic growth factors aldesleukin (interleukin-2; Proleukin); peginterferon alfa-2b (Sylatron)
Oncolytic viruses Kill tumors, primarily those that cannot be surgically removed Oncolytic virus therapy talimogene laherparepvec (Imlygic/T-VEC)
Vaccines Activate the immune system Vaccine bacillus Calmette-Guerin (BCG) vaccine
Non-specific immune stimulators Boost the immune system overall Toll-like receptor agonists imiquimod (Aldara)

Table 3. Common Side Effects of Immunotherapies For Melanoma

Name or Type of Drug Side Effects
bacillus Calmette-Guerin (BCG) vaccine Injection-site pain; flu-like symptoms with a headache, aches and high temperature
imiquimod (Aldara) Injection-site reactions or local skin reactions such as itching, burning, superficial reddening of the skin, flaking/scaling/dryness, scabbing/crusting, swelling, hardening of normally soft tissues or organs as a reaction to inflammation
interferons, interleukins, hematopoietic growth factors aldesleukin (Interleukin-2; Proleukin) Flu-like symptoms such as fever, chills, aches and fatigue; severe allergic reaction; lowered blood counts; changes in blood chemistry; organ damage (usually to heart, lungs, kidneys, liver or brain)
ipilimumab (Yervoy) Fatigue, diarrhea, itching, rash, and other immune-mediated adverse reactions such as enterocolitis, hepatitis, dermatitis, neuropathy and endocrinopathy
peginterferon alfa-2b (Sylatron) Depression and other neuro-psychiatric disorders, fatigue, elevated liver enzymes, fever, headache, decreased appetite, muscle pain, nausea, chills, injection-site reaction
pembrolizumab (Keytruda) Fatigue, itchy skin, rash, constipation, diarrhea, nausea, decreased appetite, change in thyroid function
nivolumab (Opdivo) Rash, fatigue, muscle or joint pain, bone pain, diarrhea, itchy skin, nausea, change in thyroid function
talimogene laherparepvec (Imlygic, T-VEC) Fatigue, chills, fever, nausea, flu-like symptoms, injection-site pain

 

For more information about immunotherapy, see Understanding Immunotherapy.

Chemotherapy

Chemotherapy involves the use of drugs to kill rapidly multiplying cells, including cancer cells. This type of treatment has not been as effective for melanoma as for other types of cancer, and studies have shown that chemotherapy has no benefit after surgery for Stage III melanoma. Thus, chemotherapy is primarily used to relieve symptoms related to Stage IV melanoma, and may help shrink melanomas in a small percentage of patients with Stage IV disease.

Chemotherapy is often associated with side effects such as nausea, vomiting and a decrease in the number of healthy blood cells, but these effects are usually temporary and manageable.

Radiation therapy

Radiation therapy uses high-energy X-rays or other forms of radiation to destroy cancer cells. Radiation has been shown to reduce the risk of relapse when multiple lymph nodes are involved with the tumor, when a tumor is very large, or if it has invaded surrounding tissues, but it has not shown benefit in overall survival. It can, however, shrink tumors and reduce symptoms of metastatic melanoma in the bones, brain, skin and underlying tissues.

Radiation can be delivered in multiple ways. External-beam radiation is delivered from a source outside the body; it may cause sunburn-like skin changes in the area being treated, and can also cause swelling, a feeling of heaviness in the irradiated area, and overall fatigue. Stereotactic radiation is the use of focused radiation delivered through a device (e.g., Gamma Knife, CyberKnife). This type of treatment has been highly effective in controlling limited numbers of brain metastases where surgery may be difficult. Stereotactic radiation may also be used to relieve symptoms related to metastatic disease in bone.

Clinical trials

New treatments are being evaluated every day in clinical trial research. A clinical trial is an important option for any stage of disease. Participants in cancer clinical trials will receive the standard of care as a foundation and then the experimental treatment or a placebo will be added to it. Learn more about clinical trials here.

 

Questions to ask your medical team when discussing treatment options

  • Will you be my only doctor or will I have a team of oncologists?
  • What are my treatment options?
  • What are the possible side effects of each treatment?
  • How common are these side effects?
  • When are these side effects most likely to occur and how long will they likely last?
  • Is there a way to prevent or manage my side effects?
  • When should I contact a member of my health care team about a side effect?
  • How long will my treatment plan last? Where will my treatments be done?
  • Will I need to make any lifestyle changes before, during or after treatment?
  • How do the benefits of the recommended cancer treatment compare with the risks?

 

Additional Resources

 

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