Metastatic Melanoma

Synonyms

2

Overview

Metastatic melanoma is a term used when melanoma cells of any kind (cutaneous, mucosal or ocular) have spread through the lymph nodes to distant sites in the body and/or to the body's organs. The most dangerous aspect of melanoma is its ability, in later stages, to spread (or metastasize) to other parts of the body.

Three groups of patients are identified: those with cutaneous, nodal, or gastrointestinal tract metastases; those with isolated pulmonary metastases; and those with liver, brain, or bone metastases.

Symptoms

If your melanoma has spread to other areas, you may have signs and symptoms listed below:

  • Hardened lumps under your skin
  • Swollen or painful lymph nodes
  • Trouble breathing, or a cough that doesn't go away
  • Swelling of your liver (under your lower right ribs) or loss of appetite
  • Bone pain or, less often, broken bones
  • Headaches, seizures, or weakness or numbness in your arms or legs
  • Weight loss
  • Fatigue

Causes

Melanoma usually starts as a single lesion on the skin or mucous membranes. This lesion can progress to formation of metastases if it is not recognised and treated effectively at its early stages.

Risk factors for development of melanoma include:

  • age (risk increases with age)
  • history of previous skin cancer
  • family history of melanoma
  • having large numbers of moles especially atypical moles
  • having fair skin which burns easily
  • having sun damaged skin.

The risk of melanoma becoming metastatic is higher in individuals who have advanced primary melanomas, melanomas that are not fully removed or are not removed at all, and those who have suppression of the immune system.

Prevention

You can reduce your risk of melanoma and other types of skin cancer by avoiding certain risks such as:

  • Avoid the sun during the middle of the day. The sun's rays are strongest between about 10 a.m. and 4 p.m. Schedule outdoor activities for other times of the day, even in winter or when the sky is cloudy.

    You absorb UV radiation year-round, and clouds offer little protection from damaging rays. Avoiding the sun at its strongest helps you avoid the sunburns and suntans that cause skin damage and increase your risk of developing skin cancer. Sun exposure accumulated over time also may cause skin cancer.

  • Wear sunscreen year-round. Sunscreens don't filter out all harmful UV radiation, especially the radiation that can lead to melanoma. But they play a major role in an overall sun protection program.

    Use a broad-spectrum sunscreen with an SPF of at least 15. Apply sunscreen generously, and reapply every two hours — or more often if you're swimming or perspiring. The American Academy of Dermatology recommends using a broad-spectrum, water-resistant sunscreen with an SPF of at least 30.

  • Wear protective clothing. Sunscreens don't provide complete protection from UV rays. So cover your skin with dark, tightly woven clothing that covers your arms and legs and a broad-brimmed hat, which provides more protection than a baseball cap or visor does.

    Some companies also sell photoprotective clothing. A dermatologist can recommend an appropriate brand.

    Don't forget sunglasses. Look for those that block both types of UV radiation — UVA and UVB rays.

  • Avoid tanning lamps and beds. Tanning lamps and beds emit UV rays and can increase your risk of skin cancer.

  • Become familiar with your skin so that you'll notice changes. Examine your skin regularly for new skin growths or changes in existing moles, freckles, bumps and birthmarks.

    With the help of mirrors, check your face, neck, ears and scalp. Examine your chest and trunk and the tops and undersides of your arms and hands. Examine both the fronts and backs of your legs and your feet, including the soles and the spaces between your toes. Also check your genital area and between your buttocks.

Diagnosis

Metastatic melanoma may be diagnosed on the basis of characteristic skin lesions. Other clues are enlarged lymph nodes and/or symptoms related to other organs.

Biopsy: Suspicious skin and subcutaneous lesions can be biopsied and show characteristic features of metastatic melanoma pathology. A sentinel node biopsy is sometimes performed after a primary melanoma is diagnosed. This is a biopsy of a regional lymph node to determine whether there are occult (not palpable) lymph node metastases.

Blood tests: The serum LDH is a marker for progressive metastatic disease at distant sites. When it is elevated it confers a worse prognosis, but often the LDH remains normal even in late-stage metastatic melanoma. Other laboratory tests are not routinely used because their value as pointers to the presence of metastases and/or prognosis is limited.

Chest x-ray: Lung metastases may be visible on chest x-ray, but, as melanoma metastases resemble other types of lung lesion, there are also a significant number of false positives meaning that this is not a very helpful investigation.

Ultrasound scanning: Can reveal liver metastases and lymph node metastases.

CT and MRI: Can show metastatic deposits in most body sites.

Positron emission tomography (PET) scanning: This is an important advance in imaging for metastatic disease. It shows up “hot spots” of tissue that are metabolising faster than normal tissue. It has been found to have good diagnostic accuracy for metastatic melanoma.

Prognosis

Significant progress has been made in the treatment of metastatic melanoma over the past decade.

The prognosis of melanoma depends on the disease staging, which is based around characteristics of the primary tumour, nodal and distant metastases. The prognosis is poorer with higher numbers of involved nodes and with metastases to internal organs and distant sites. The 10-year survival rate for patients with metastatic melanoma is still very low.

Treatment

Although Metastatic melanoma continues to be a challenging disease to treat there are several options. Choosing what's right, will depend on where and how big the cancer is, what your health is like, and what your wishes are. Since most cases of metastatic melanoma can't be cured, the goals of treatment are to:

  • Prolonging survival
  • Shrinking or stopping the growth of known metastases
  • Preventing the development of new sites of disease
  • Providing comfort

In most cases, it is not possible to completely eliminate or cure the cancer. 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 work with your immune system to stop or slow the growth of 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 have been shown to potentially improve survival and have become the preferred approaches for most patients with metastatic melanoma. Although chemotherapy was widely used in the past, it now has a secondary role for patients whose disease can no longer be controlled with either immunotherapy or targeted therapy.

  • Immunotherapy: Two different types of immunotherapy have been developed, high dose interleukin-2 (IL-2) and ipilimumab. Both of these have important benefits in some patients, although each can cause significant side effects.

- Interleukin-2 (IL-2): IL-2 is a form of immunotherapy that has been found to help some people with metastatic melanoma when given in high doses. In some people treated with high dose IL-2, the disease may disappear completely or stop growing for a prolonged period in excess of five years. IL-2 is usually given into a vein three times per day for five days twice per month. Treatment is usually completed while you are in the hospital. However, high dose IL-2 can cause serious side effects, including low blood pressure, irregular heart rhythms, accumulation of fluid in the lungs, fever, and rarely death. Because of this, treatment with high dose IL-2 is generally reserved for younger patients who are otherwise healthy and have good heart and lung function.

- Ipilimumab (Yervoy) 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. Treatment with ipilimumab may decrease the extent of your melanoma and help you live longer. However, ipilimumab can also cause the body to develop an immune reaction against its own tissues. This can result in a wide range of side effects that may be severe or life threatening. The most important of these include colitis (causing diarrhea, bleeding, or more serious complications), hepatitis, rash or inflammation of the skin, and inflammation of endocrine organs (pituitary, thyroid, or adrenal) leading to diminished hormone production. If this occurs, you might have to stop the ipilimumab and receive additional treatment for the complications. If one takes this drug, it is important to tell their doctor about any side effects they experience, even mild ones. This will help to avoid more serious complications.

  • 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. 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 are the development of other kinds of skin cancers (non-melanoma), which can be managed with routine skin cancer care and do not require interruption of vemurafenib treatment, skin photosensitivity, joint pain, and fatigue.

  • 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 with ipilimumab and targeted therapy with vemurafenib, and it generally is not used as the initial treatment for patients with advanced disease.

 

Surgery: Resection of distant metastases may also be considered for selected patients in whom a survival benefit might be expected with surgical rather than medical treatment. Surgery may potentially improve outcomes in patients with fully resectable oligometastatic disease. Although surgery alone probably won't cure the cancer, it can help you live longer and have fewer symptoms. 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: These can help some people, depending on the size and location of the cancer. Melanoma is considered a relatively radioresistant tumor, but patients may derive clinical benefit from radiation of symptomatic metastases. Radiation therapy is usually used as an adjunct to the use of systemic therapy. Radiation therapy is especially useful in patients with central nervous system (CNS) metastases, as most systemic therapies have limited penetration into the CNS. 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). Alternatively, if more extensive disease is present in the brain, a technique called “whole brain” radiation therapy may be useful. 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.

Many novel therapies are currently under investigation. Researchers are studying other drugs that spur the immune system to fight melanoma.

In some people with metastatic melanoma, the disease cannot be cured. Deciding when to stop treating the melanoma can be difficult, and this decision should involve the patient, family, friends, and the healthcare team.

Resources

Refer to Research Publications.