INTRODUCTION — Melanoma is a serious form of skin cancer that develops in the pigment-producing skin cells (melanocytes). Melanoma is the sixth most common cancer in the United States, and the number of melanoma cases diagnosed annually are increasing faster than for any other cancer. Although the explanation for this is unknown, it may be related, at least in part, to increased sun exposure and global changes such as ozone depletion.
After melanoma is diagnosed, the next step is to determine the stage or extent of disease spread. Accurate staging is important to determine the most appropriate treatment. Melanoma often starts as a single tumor or lesion (show figure 1). Cancer cells can spread to near-by lymph nodes and distant sites throughout the body. Once it spreads to distant locations, it is called advanced or metastatic melanoma.
This topic review discusses the treatment of stage IV (advanced or metastatic) melanoma. The diagnosis and treatment of localized melanoma is discussed separately. (See "Patient information: Treatment of localized melanoma").
STAGING — The American Joint Committee on Cancer (AJCC) has defined a staging system for melanoma (show table 1). Once the staging work-up is complete, a disease stage between I and IV is assigned, with stage IV meaning that there is more extensive disease (show table 2).
For patients with stage IV disease, the melanoma has spread beyond the local area into other areas or organs. The most common sites of metastases are the skin (subcutaneous tissue, show figure 2) and other soft tissues (including lymph nodes), the lungs, liver, brain, and bone. However, metastasis to organs such as the adrenal glands, spleen and gastrointestinal tract can also occur (show table 3).
TREATMENT — Treatment of advanced metastatic melanoma focuses on shrinking or eliminating the metastatic lesions, preventing further spread of the disease, and ensuring patient comfort. In most cases, it is not possible to completely eliminate the cancer. Depending on the location and extent of the metastases, treatment may involve the use of medical treatments (chemotherapy or immunotherapy), surgery, or radiation therapy.
Chemotherapy and immunotherapy treatments may be given alone or in combination. Most of these treatments must be given into a vein (intravenously) or injected under the skin, although a few can be given in pill form.
Each medication is given over a period of time, often several months or more, depending upon how the patient responds. Patients are monitored for signs of drug toxicity or side effects. Many side effects are temporary and can be managed so that patient discomfort is minimized.
Chemotherapy — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. These drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. 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.
Dacarbazine (DTIC) — DTIC is considered to be the most active chemotherapy drug for patients with metastatic melanoma. Although tumor shrinkage can be expected in about 20 percent of treated patients, the vast majority of these responses are only partial (that is, the tumor does not disappear entirely) and the average duration of benefit is only four to six months.
DTIC is given into a vein over one hour for five days every three weeks. It is generally well tolerated; nausea and vomiting are the most common side effects. Anti-nausea medications are administered with DTIC to reduce discomfort.
Temozolomide — Temozolomide is medication that is taken by mouth as a capsule. It is usually taken for five days every four weeks. It acts similar to DTIC. Unlike some other treatments, DTIC is able to penetrate into the brain and other structures in the nervous system. For this reason, it is often used to treat patients with metastases to the brain. However, clinical trials of temozolomide have produced mixed results; further study is needed to determine the optimal dose and schedule to temporarily slow or stop the growth of metastases.
Immunotherapy — In contrast to chemotherapy, immunotherapy works with the body's immune system to stop or slow the growth of cancer cells. Because immunotherapy works differently than chemotherapy, it has different side effects. Immunotherapy has less effect on the bone marrow, hair, and lining of the GI tract. However, many immunotherapy agents (eg, interferon alpha or IFNa) cause symptoms similar to the flu, such as low-grade fever, chills, muscle and/or joint aches, and headache.
Interleukin-2 (IL-2) — IL-2 is a form of immunotherapy that has been found to help some patients with metastatic melanoma when given in high doses. Although a significant benefit is seen only in a minority of patients, long-term follow-up of patients treated in early high-dose IL-2 trials confirms that the benefit can be long-lasting.
As an example, in an analysis of 270 patients treated in trials with high-dose IL-2 over eight years and followed for an additional 5 years,16 percent (about one in six) of all treated patients had shrinkage in the size of their tumors with treatment. The average duration of benefit was about nine months [2,3]. Sixty percent of those who achieved a complete response (no tumor was present after IL-2 treatment) remained progression-free at seven years. In addition, of the patients who responded to treatment for longer than 30 months, none had progression of their melanoma, suggesting that some patients may actually be "cured".
These encouraging results, although limited to a minority of patients, led to the approval of high dose IL-2 for patients with metastatic melanoma. However, high dose IL-2 can produce serious and toxic side effects and it is generally reserved for patients who are otherwise healthy (with good heart and lung function) who are treated in centers that specialize in this type of treatment.
Interferon alpha — IFNa is an immunotherapy agent that has limited effectiveness when used alone to treat metastatic melanoma; however, it does occasionally produce major tumor regressions, particularly in patients with a small amount of tissue affected by the melanoma. Thus, it is often used as an adjuvant treatment, following surgical removal of affected tissues.
Other treatments — Other medical treatment are being investigated for treatment of advanced and metastatic melanoma. These include monoclonal antibodies (specially formed proteins designed to attack cancer cells), melanoma vaccines, gene therapies, cellular therapies (adoptive immunotherapy) as well as various targeted (those that directly attack the growth of the melanoma) and anti-angiogenic agents (those that shrink the blood vessels of the cancer).
Surgery— Surgery may be recommended to remove the metastatic tumor in patients whose melanoma has spread to a limited or small number of sites. In some patients, surgery can prolong survival, particularly if the patient has a single site of metastasis. However, because metastatic melanoma usually spreads to many different locations, surgery is rarely curative. CT scans and/or PET scans are usually performed prior to surgery to evaluate the full extent of the disease and to help guide the plan for surgical treatment.
Surgery to remove brain metastases may be the best option for patients with a single brain metastasis. It may also be an option for patients with multiple brain metastases if a dominant lesion is present or if all the lesions are located within a single area of the brain.
Surgery can also be effective in relieving discomfort caused by a metastatic tumor, such as tumor in the lungs or brain. This type of surgery is often helpful in reducing symptoms and improving the patient's quality of life.
Whole brain radiation therapy — In some patients, surgery prolong survival, especially if the disease outside of the brain is controlled. A course of whole brain" radiation therapy or stereotactic radiation therapy (see below) to the tumor bed are generally administered after surgery to destroy any cancer cells that may remain in the brain.
Stereotactic radiosurgery — If the metastatic tumor or tumors are located in areas of the brain that cannot be reached by surgery, or if tumors are multiple and small, a procedure called stereotactic radiosurgery may be helpful in slowing or stopping the progression of brain metastases. Radiosurgery does not involve surgery, but instead uses precisely targeted radiation to destroy cancerous tissue. Stereotactic radiosurgery may be followed by a course of whole brain radiation therapy.
SURVIVAL — Modest progress has been made in the treatment of metastatic melanoma over the past decade. With the advent of high dose interleukin-2 (IL-2), it may be possible for a small number of patients to be cured of their disease (show figure 3).
Despite this, the average median survival in patients treated for metastatic disease may be as short as nine months (show figure 4). Because IL-2 treatment can have severe side effects, the risk of undergoing treatment with high dose IL-2 outweighs the small potential benefit for some patients (see "Interleukin-2 (IL-2)" above).
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
1-800-4-CANCER
(www.cancer.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The Melanoma Center, University of Pittsburgh Cancer Institute
(www.melanomacenter.org)
Melanoma Research Foundation
(www.melanoma.org)
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Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Elwood, JM, Jopson, J. Melanoma and sun exposure: an overview of published studies. Int J Cancer 1997; 73:198.
2. Atkins, MB, Lotze, MT, Dutcher, JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: Analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999; 17:2105.
3. Atkins, MB, Kunkel, L, Sznol, M, Rosenberg, SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: Long-term survival update. Cancer J Sci Am 2000; 6 Suppl 1:S11.
4. Gothelf, A, Mir, LM, Gehl, J. Electrochemotherapy: results of cancer treatment using enhanced delivery of bleomycin by electroporation. Cancer Treat Rev 2003; 29:371.
5. Crosby, T, Fish, R, Coles, B, Mason, MD. Systemic treatments for metastatic cutaneous melanoma. Cochrane Database Syst Rev 2000; :CD001215.
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