Brain Metastases

A. Basit Khan, B.A.
Joseph S. Kass, M.D., J.D.
Nicole J. Ullrich, M.D., PH.D.

Basic Information

Definition

Brain metastases result from a spread of cancers originating in other organs to the brain and are devastating complications of cancer. Brain metastases are the most common intracranial tumors in adults and account for more than one half of brain tumors.

ICD-10CM CODES
C80.0	Disseminated malignant neoplasm, unspecified
C80.9	Malignant neoplasm, unspecified
C79.89	Secondary malignant neoplasm of other specified sites

Epidemiology & Demographics

Incidence

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Accurate data on the incidence of metastatic brain disease are not available. Population studies based on review of epidemiological data show an overall incidence of 8.3 to 14.3 per 100,000 population per year. However, these studies underestimate the true incidence of brain metastases because they rely on historical data from times when diagnostic imaging was poor. Autopsy-based studies are thought to show higher incidence of brain metastases because they identify asymptomatic brain metastases. However, autopsy-based data are now more than 20 years old. Ultimately, the incidence of metastatic brain malignancy is rising, likely due to improved detection and better control of extracerebral disease.
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In the U.S., an estimated 98,000 to 170,000 new cases occur each year, representing 24% to 45% of all cancer patients. The incidence is higher in autopsy series, where 20% of patients with systemic disease have brain metastases.

Predominant Sex and Age

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In patients with systemic malignancies, brain metastases occur in 10% to 30% of adults and 6% to 10% of children. Of these, about 60% of patients are between the ages of 50 and 70 years.
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There is no definite gender predilection. Some data indicate that metastatic brain malignancy has a higher incidence in men because men have a higher incidence of primary lung cancer.

Risk Factors

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In adults, the cumulative incidence (CI) of metastases to the brain depends on the type of primary cancer as follows: lung cancer (16%-20% CI), renal cell carcinoma (7%-10% CI), melanoma (7% CI), breast cancer (5% CI), and colorectal cancers (1%-2% CI). Lymphoma is also known to metastasize to the brain. These metastatic lesions may or may not be present at the patient’s initial presentation. The majority of patients with metastases to the brain have greater than one metastasis. The cancers with the highest association of intracranial hemorrhage include renal cell carcinoma, melanoma, and the less common malignancies of thyroid carcinoma and choriocarcinoma.
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The most common primary pediatric solid tumors associated with metastatic spread include sarcomas, neuroblastoma, and germ cell tumors. Leukemias are well known to seed the CNS. Metastatic disease is usually never seen when a child first presents with malignancy, with the occasional exception of leukemia. For solid tumors, metastatic disease is seen at the time of disease recurrence. Neuroblastoma CNS lesions have a high propensity to hemorrhage.

Physical Findings & Clinical Presentation

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Clinical presentations vary depending on where the lesion is located. Brain metastases should be suspected in any cancer patient developing acute neurologic signs or symptoms. Neurologic symptoms, however, are common in patients with systemic cancer. In an analysis of more than 800 patients with neurologic symptoms, brain metastases were found in only 16%.
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Symptoms:
1. 1.
  
  Headache occurs in 40% to 50% of patients with brain metastases. Frequency is higher with metastases located in the posterior fossa, which may result in obstructive hydrocephalus. The headache can be accompanied by nausea, vomiting, focal neurologic signs, and postural variation.
2. 2.
  
  Focal neurologic signs/symptoms are the presenting symptom in 20% to 40% of patients. Hemiparesis is the most frequent complaint. However, the specific neurologic dysfunction depends on the location of the brain metastasis.
3. 3.
  
  Cognitive dysfunction, including memory problems or mood or personality changes, is the presenting problem in 30% to 45% of patients.
4. 4.
  
  Seizures are the presenting symptom for 10% to 20% of patients with metastatic brain tumors and indicate supratentorial metastases.
5. 5.
  
  Acute stroke secondary to hemorrhage into a metastasis, hypercoagulability, or local vascular invasion occurs in 5% to 10% of patients.

Etiology

The most common mechanism of metastasis to the brain is by hematogenous spread. The most common location is at the junction of the gray matter and white matter of the cerebral hemispheres (almost 80%). The blood vessels decrease in diameter in these regions, which is thought to act like a trap for clumps of tumor cells. Different tumor types have a tendency to metastasize to different regions of the brain. For example, metastases of small cell lung carcinoma are equally distributed in all regions, whereas pelvic (prostate and uterine) and gastrointestinal tumors more commonly metastasize to the posterior fossa.

Diagnosis

Differential Diagnosis

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Primary brain tumor
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Infection: bacterial abscess or fungal disease
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Progressive multifocal leukoencephalopathy
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Demyelinating disease: multiple sclerosis, post-infectious encephalomyelitis
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Cerebral infarction or bleeding
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Effects of treatment, such as radiation necrosis

Laboratory Tests

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Routine laboratory studies are not typically helpful.
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Lumbar puncture is generally contraindicated due to increased intracranial pressure and risk of herniation.
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Brain biopsy is necessary in some cases for a definitive diagnosis, particularly in the case of unknown primary tumor. Illustrating this situation is a study of cancer patients with solitary brain lesions that were presumed to be metastatic disease; in about 10% of study participants, the lesions were proved to be a different pathology.

Imaging Studies

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MRI (Fig. 1) with and without contrast is the imaging study of choice. Important features on MRI suggesting brain metastases include: presence of multiple lesions, localization at the junction of the gray and white matter, circumscribed margins, or large amounts of vasogenic edema. CT of the head with contrast (Fig. 2) can be used when MRI is contraindicated.

FIG.1

Brain magnetic resonance imaging (axial and coronal fluid-attenuated inversion recovery sequences) showing hemorrhagic metastatic deposition in the inferior right frontoparietal lobe (lobulated high signal focus) in a 40-year-old woman with metastatic choriocarcinoma to the brain.

(From Fielding JR, et al.: Gynecologic imaging, Philadelphia, 2011, Saunders.)

FIG.2

Intracranial metastatic disease.

Axial contrast-enhanced CT scan of head reveals multiple enhancing nodules throughout gray and white matter structures consistent with metastatic disease.

(From Vincent JL, et al. [eds]: Textbook of critical care, ed 6, Philadelphia, 2011, Saunders.)
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MR spectroscopy and PET are useful to differentiate tumor from either other space-occupying lesions or radiation necrosis.
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Newer experimental imaging studies, such as receptor-targeted and ligand-based molecular imaging, are on the horizon.
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In about 80% of patients, brain metastases develop after the diagnosis of systemic cancer. In the remaining patients, brain metastases are diagnosed either simultaneously or before the primary tumor is found. In patients without a known primary tumor, the lung should be the primary focus of evaluation. Other frequent primary cancer types include melanoma, colon cancer, and breast cancer. PET scan may be useful in these patients to help identify either the primary tumor or other sites of metastatic disease, which may be more amenable to biopsy.

Treatment

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Management of patients with brain metastases is influenced by the overall prognosis and may include treatments targeted at the metastases, management and prevention of complications (seizures, edema), and treatment of systemic malignancy.
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In patients considered to have a favorable prognosis (i.e., one to three metastases, good Karnofsky performance score, and controlled or absent systemic disease), treatment focuses on surgical resection and stereotactic radiation either to eradicate or control the brain metastases. Whole-brain radiation (WBRT) is widely used but has significant side effects. A study through the European Organisation for Research and Treatment of Cancer (EORTC), along with prior randomized studies, has shown the addition of WBRT did not improve overall survival but seemed to reduce the rates of disease relapse. A meta-analysis of five randomized controlled trials found that WBRT decreased the relative risk of intracranial disease progression at 1 year by 53% but did not improve survival. Additionally, the individuals who did not receive WBRT after stereotactic radiosurgery or surgery had better quality-of-life scores. Unfortunately, few patients with metastatic disease are able to meet inclusion criteria for such studies.
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In patients with poor prognosis, treatment focuses on symptom control and WBRT.

Acute General Rx

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Steroids are used to reduce peritumoral edema and intracranial pressure.
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Antiepileptics are started for patients who present with seizures. Prophylactic treatment for seizures is not indicated in patients without a prior history of seizure.
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Anticoagulants are sometimes used to prevent venous thromboembolic disease but should be used with caution in patients with brain metastases that are at increased risk of hemorrhage.

Chronic Rx

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Radiation therapy has become the mainstay of treatment for brain metastases, including whole brain radiation therapy and stereotactic radiosurgery (SRS).
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For highly chemosensitive tumors, chemotherapy has been integrated into the primary management of patients with disseminated disease.
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For other tumors (e.g., small cell and non-small cell lung cancers, breast cancer, melanoma) systemic chemotherapy or molecularly targeted agents may be of palliative value when surgery, whole brain radiation therapy, and SRS have failed or are inappropriate. In most cases, two to three agents in combination are used in conjunction with whole brain radiation therapy. A phase II trial has shown combination treatment of lapatinib, an epidermal growth factor receptor inhibitor (EGFR-inhibitor), and capecitabine, an antimetabolite prodrug that is converted to 5-fluorouracil, as active for first-line treatment of HER2-positive breast brain metastases. Another phase II trial showed sagopilone (low-molecular-weight epothilone B analogue) as showing modest activity in patients with metastatic breast cancer. Additionally, dabrafenib, a tyrosine kinase inhibitor of BRAF, had some activity and an acceptable safety profile for metastatic melanoma with BRAF^V600E mutations. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte antigen 4, was used for patients with metastatic melanoma and showed an improved median overall survival of 7 months in clinically asymptomatic lesions and 3.7 months in patients with neurologic symptoms. There are also other reports of its efficacy.

Disposition

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The median survival of patients who receive supportive care and are treated with corticosteroids only is approximately 1 to 2 months.
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Key prognostic factors are performance status, extent of systemic disease, and age. Most favorable outcome is found in patients with Karnofsky performance score ≥70, age younger than 70 years, no systemic disease or local control of primary tumor without extracranial metastases, and female gender. In this group, median survival is estimated at 7.1 months.

Referral

Treatment involves a multispecialty team. Consultations from oncology, neurosurgery, neurology, radiation oncology, psychiatry, and physical therapy are all warranted.

Pearls & Considerations

Comments

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Brain metastases are the most common intracranial tumors in adults, accounting for more than half of all brain tumors.
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Lung cancer, melanoma, renal cell carcinoma, and breast cancer are the most common primary tumors that metastasize to the brain.
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MRI of the brain with and without contrast is the most reliable imaging study.
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Treatment depends upon the patient’s overall prognosis.

Patient/Family Education

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American Brain Tumor Association (http://www.abta.org)
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National Brain Tumor Society (http://www.braintumor.org)

Ferri – Brain Metastases