Brain Metastases

What is Brain Metastases?

Who Is At Risk?

More than 60% of all Stage IV melanoma patients will develop brain metastases at some point, but certain factors increase the risk [1,2]:

• The primary tumor was on the head, neck, trunk, or abdomen
• The primary tumor was ulcerated, deep, or invasive
• The LDH is elevated at diagnosis of unresectable Stage III or Stage IV 
• The presence of NRAS or BRAF mutation
• The melanoma has spread to the internal organs

Why Are Brain Metastases So Difficult To Treat?

There are several potential reasons:

• There is growing evidence that brain tumors are very different from tumors in other parts of the body and may need to be treated differently.
• The brain looks familiar. Melanocytes arise from the same part of the early embryo as the brain, so the brain might be a very natural environment for melanoma tumors to grow in.
• Often, by the time a patient first exhibits symptoms, s/he already has multiple lesions, not just one.
• Brain metastases tend to be very aggressive and even a small increase in their size can cause more symptoms.
• The brain has many defenses to reduce the penetration of harmful substances. This system is called the blood-brain-barrier, and also it prevents many medications from entering the brain.
• Treatment options may damage surrounding normal tissue and have significant impact on the quality of life.

What Determines the Treatment Options and Prognosis For Patients With Brain Metastases?

Certain characteristics of both the patient and the cancer will affect the patient’s prognosis as well as eligibility for treatment. The following factors are associated with better outcomes [3,4,5]:

• Younger age: less than 60 years old
• Fewer vs. more brain metastases: fewer than three lesions
• No extracranial disease (extracranial is the presence of disease outside the cranium)
• Normal LDH 
• High—greater than 70—Karnofsky Performance Status (KPS) score (Karnofsky assesses the functional status of a patient)

Diagnosis

Many patients do not have any symptoms from the presence of brain metastases. Based on their location and size, however, patients may experience headaches, nausea, vomiting, fatigue, weakness or unsteadiness from the presence of brain metastases. Patients may also experience symptoms known to result from strokes such as facial droop, slurred speech, or even seizures.

If your doctor suspects that your melanoma has spread to your brain, he or she may recommend a number of tests and procedures.

A neurological exam. A neurological exam may include, among other things, checking your vision, hearing, balance, coordination, strength, and reflexes. Difficulty in one or more areas may provide clues about the part of your brain that could be affected by a brain tumor.

Imaging tests. Magnetic resonance imaging (MRI) is commonly used to help diagnose brain metastases. A dye may be injected through a vein in your arm during your MRI study.  Other imaging tests may include computerized tomography (CT) but the gold standard for diagnosis is MRI.

Biopsy. If a suspicious lesion is found but the diagnosis is uncertain, a biopsy may be performed to obtain a tissue sample for evaluation. This information is critical to establish a diagnosis, a prognosis and to guide treatment. Often times, however, if a patient already carries a diagnosis of Stage IV melanoma, brain metastases can be diagnosed by imaging and will not require a biopsy to confirm.

 

Treatment Options

Your doctor will discuss a treatment plan with you. The treatment options for brain metastases are determined by the number of metastases, their size and location, the presence of extracranial metastases (melanoma outside of the brain and spinal cord), any prior treatment for melanoma, whether your melanoma is known to have a BRAF mutation, and your performance status. Treatment plans may involve a single approach or combine multiple approaches but ideally the decision should be taken by a team of specialists including a neurosurgeon, a radiation oncologist, and a melanoma medical oncologist.

Surgery

Surgery is a standard treatment for melanoma brain metastases. It is potentially curative for patients whose melanoma is otherwise controlled and who have a limited number of brain metastases. 

Generally, surgery is reserved for patients with fewer than three metastases, particularly if they are too large to be effectively treated with focal radiation therapy (described below) or for patients that are having significant symptoms from the tumor It may also be used for tumors that re-grow after previously being treated with radiation or that are causing bleeding in the brain.

Patients with many tumors, or tumors in critical areas of the brain, are usually not candidates for surgery.

Radiation: SRS

Stereotactic radiosurgery (SRS) targets certain spots in the brain. One newer type, gamma knife, is able to treat metastases more quickly than previous radiation machines. Compared to whole brain radiation therapy, it has a significantly lower risk of damage to normal brain tissue and subsequent impact on cognitive function. SRS can result in long-term control of brain metastases for some patients.

In the past, SRS was reserved for patients with three or fewer brain metastases; at some institutions, gamma knife is now being used to treat higher numbers of brain metastases. Generally, it is most effective for brain tumors that are less than two centimeters in diameter, but specific size limits/guidelines can vary between different institutions. It may also be used after surgical removal of a brain tumor to reduce the risk of tumor recurrence.

Radiation: WBRT

Whole-brain radiation treatment (WBRT) treats brain metastases that can be seen, as well as tumor cells that are too small to be identified by MRI or CT scans. WBRT is likely to slow the growth of tumors, but it is generally not thought to be curative. WBRT works better for patients with brain metastases from other cancers like breast cancer or lung cancer but has lower efficacy for melanoma.

WBRT is typically used in patients who have too many brain metastases to be suitable for surgery or SRS, patients with leptomeningeal disease, or in patients who have several tumors grow after having been previously treated with SRS.

WBRT has a significant risk of causing damage to normal brain tissue, resulting in neurocognitive decline. New techniques (hippocampal sparing RT) and medications (memantine) are often used to reduce the impact of WBRT on cognitive function.

Steroids

Brain metastases can cause swelling in the brain which can result in a variety of symptoms, including headache, nausea, vomiting, and/or confusion. Steroids can reduce swelling in the brain and, therefore, are often used to treat the symptoms caused by brain metastases. The steroids will not treat or eradicate the tumors themselves.

Steroids can reduce the effectiveness of immunotherapy, and they can cause a variety of side effects (fluid retention, difficulty sleeping, increased, or excessive energy). For patients who need steroids to control swelling in the brain, there are good reasons to try to find the lowest possible dose that will be successful in controlling the swelling.

For patients who have been on steroids for a prolonged period of time (more than three to four weeks), it can be dangerous to suddenly stop steroid treatment, as the body’s ability to make normal amounts of steroids may be suppressed by prolonged treatment. For these patients, steroids are decreased (“tapered”) over time to allow the body to recover its ability to make steroids itself.

Immunotherapy

Most FDA-approved checkpoint inhibitor-based immunotherapies can achieve significant shrinkage of melanoma brain metastases. These responses often last for more than two years. Immunotherapies that have shown such benefit include Yervoy, Opdivo, Keytruda and combination treatment with Yervoy and Opdivo. Most patients who experience significant shrinkage of their brain metastases also experience similar shrinkage or control of tumors growing in other parts of the body.

In clinical trials in patients who did not require steroids to control swelling of the brain and/or symptoms from brain metastases, significant shrinkage of melanoma brain metastases was seen in approximately 20% of patients treated with single-agent Yervoy, single-agent Opdivo, and single-agent Keytruda, and more than 50% of patients treated with combination immunotherapy with Yervoy and Opdivo.

Immunotherapy may not be the best initial treatment for patients who need to take steroids to control swelling of the brain or other symptoms caused by brain metastases. Clinical trials have shown that for patients who require treatment with steroids, the rates of tumor shrinkage were much lower with Yervoy (approximately 5%) and with Opdivo (approximately 5%). Limited results in patients on steroids have been reported on combination immunotherapy with Yervoy and Opdivo showing decreased rates of response.

Targeted Therapy

There are multiple FDA-approved targeted therapies for patients with metastatic melanoma with a BRAF mutation in their tumor. Standard of care targeted therapy regimens for such patients include combined treatment with a BRAF inhibitor and a MEK inhibitor. The three approved combination regimens are Tafinlar (dabrafenib) and Mekinist (trametinib); Zelboraf (vemurafenib) and Cotellic (cobimetinib); and Braftovi (encorafenib) and Mektovi (binimetinib).

These treatments are NOT to be used in patients who do not have a BRAF mutation in their tumor.

In a phase II clinical trial of Tafinlar and Mekinist in melanoma patients with new or growing brain metastases, more than 50% of patients showed significant shrinkage of their brain metastases, and approximately 80% of patients achieved at least slowing of tumor growth. The treatment can be used and be effective in patients who need to take steroids to control brain swelling and/or symptoms from their brain metastases.

Although initially effective in most patients, data from clinical trials suggest that the response to targeted therapy in the brain is less durable (long lasting) than the response to targeted therapy in tumors in other parts of the body. 

Chemotherapy

Drugs such as Temodar and Fotemustine are able to get into the brain tissue and may be used to treat patients with brain metastases. These therapies achieve significant tumor shrinkage in only a minority (less than 10%) of patients, and they generally are not durable or curative.

Supportive Care

Supportive care is used when the physician feels that active treatment will do more harm than good, or if it is the patient’s preference not to be treated. It’s intended to reduce pain, confusion, and/or seizures, but not to slow or eliminate the growth of the tumors.

Steroids are an example of supportive care, as they are frequently used to reduce swelling in the brain caused by metastases, which may help ease symptoms of pain, nausea, and confusion. Other medicines may be used to control seizures, which can be caused by brain metastases.

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Rehabilitation After Treatment

Because brain tumors can develop in parts of the brain that control motor skills, speech, vision and thinking, rehabilitation may be a necessary part of recovery. Your doctor may refer you to services that can help:

• Physical therapy can help you regain lost motor skills or muscle strength.
• Occupational therapy can help you get back to your normal daily activities, including work, after a brain tumor or other illness.
• Speech therapy (speech pathologists) can help if you have difficulty speaking.

Coping and Support

Coping with brain metastasis involves coming to terms with the news that your cancer has spread beyond its original site as well as enduring challenging symptoms and side effects. Your doctor will work to minimize your pain and to maintain your function so that you can continue your daily activities.

Each person finds his or her own way to cope with brain metastases. Until you find what works best for you, consider trying to:

• Find out enough about brain metastasis to make decisions about your care. Ask your doctor about the details of your cancer and your treatment options.
• Be aware of potential limits on activities. Talk with your doctor about whether it’s okay for you to drive, if that is something you regularly do. Your decision may depend on whether your neurological exam shows that your judgment and reflexes haven’t been affected too much.
• Express your feelings. Find an activity that allows you to write about or discuss your emotions, such as writing in a journal, talking to a friend or counselor, or participating in a support group. Contact our Community Engagement Director to find support groups in your area.
• Review AIM’s Survivorship and Palliative Care pages

What to Ask Your Doctor about Brain Metastases

Preparing a list of questions can help you make the most of your time with your doctor. For brain metastases, some basic questions to ask your doctor include:

References:

1. Zakrzewski J, Geraghty LN, Rose AE, et al. Clinical Variables and Primary Tumor Characteristics Predictive of the Development of Melanoma Brain Metastases and Post-Brain Metastases Survival. Cancer. 2011; 117:1711-1720.
2. Bedikian AY, Wei C, Detry M, et al. Predictive Factors for the Development of Brain Metastasis in Advanced Unresectable Metastatic Melanoma. Am J Clin Oncol 2010. Dec 13.
3. Fife KM, Colman MH, Stevens GN, Firth IC, Moon D, Shannon KF, et al. Determinants of Outcome in Melanoma Patients with Cerebral Metastases. J Clin Oncol. 2004;22:1293-1300.
4. Nieder C, Marienhagen K, Geinitz H, Grosu AL. Can Current Prognostic Scores Reliably Guide Treatment Decisions in Patients with Brain Metastases From Malignant Melanoma?. J Can Res Ther [serial online] 2011 [cited 2011 Aug 18];7:47-51. Available from: http://www.cancerjournal.net/text.asp?2011/7/1/47/80458
5. Sperduto PW, Chao ST, Sneed PK, et al. Diagnosis-Specific Prognostic Factors, Indexes, and Treatment Outcomes for Patients With Newly Diagnosed Brain Metastases: A Multi-Institutional Analysis of 4,259 Patients. Int J Radiat Oncol Biol Phys 2010;77:655-61.