Brain metastases are cancer cells that have spread to the brain from primary tumors in other organs in the body . Metastatic tumors are among the most common mass lesions in the brain. An estimated 24-45% of all cancer patients in rethe United States have brain metastases.
Signs and symptoms
Approximately 60% of patients with brain metastases have subacute symptoms. Symptoms are usually related to the location of the tumor and may include the following:
- Nuchal rigidity
- Cognitive dysfunction
- Motor dysfunction
Laboratory investigations include blood work, such as CBC, electrolyte panel, coagulation screen, and liver function panel.
Images provide information on tumor burden in the brain and associated structures, in addition to the rest of the body, and are integral part in formulating the optimal treatment plan.
Imaging studies include the following:
- Chest radiography
- Computerized tomography (CT)
- Positron emission tomography (PET)
- Magnetic Resonance Imaging (MRI)
Medical treatments consist of symptomatic and systematic treatments. Medical management of metastatic diseases has mainly focused on the treatment of cerebral edema, headache, and seizure.
Other options are radiation therapy (whole brain radiation, focal beam, and stereotactic radiation therapy), chemotherapy, combined therapies, experimental therapies, and integration therapy.
Most tumors that metastasize to the brain are not chemosensitive, though small-cell lung cancer, breast cancer, and lymphoma respond to chemotherapy. In most cases, 2-3 chemotherapeutic agents are used in combination and in conjunction with whole-brain radiation therapy (WBRT).
Radiation therapy has become a mainstream therapy for brain metastasis. Radiation therapy includes WBRT and stereotactic radiosurgery.
Stereotactic radiosurgery is a more preferred treatment modality for radio-resistant lesions such as nonsmall cell lung cancer, renal cell carcinoma, and melanoma. It is also more frequently used to treat the resection cavity of brain metastasis, particularly in patients with breast metastatic disease.
Surgical resection is considered standard care for solitary metastases larger than 3 cm and in noneloquent areas of the brain.
Other indications for surgical resection include the following:
- Limited and/or controlled systemic disease
- Karnofsky score greater than 70
- One symptomatic lesion with multiple asymptomatic lesions
- Contraindications to surgery include a radiosensitive tumor (e.g.,
small-cell lung tumor), patient life expectancy < 3 months (WBRT
indicated), and multiple lesions.
Metastatic tumors are among the most common mass lesions in the brain. In the United States, an estimated 98,000-170,000 cases occur each year. This is about 24-45% of all cancer patients. 
The prevalence of brain metastasis is thought to be 120,000-140,000 per year. This disease accounts for 20% of cancer deaths annually, a rate that can be traced to an increase in the median survival of patients with cancer because of modern therapies, increased availability of advanced imaging techniques for early detection, and vigilant surveillance protocols for monitoring recurrence. In addition, most systemic treatments (eg, the use of chemotherapeutic agents, which may penetrate the brain poorly) can transiently weaken the blood-brain barrier (BBB) and allow systemic disease to be seeded in the CNS, leaving the brain a safe haven for tumor growth.
Metastases from systemic cancer can affect the brain parenchyma, its covering, and the skull. This discussion is restricted to the incidence, pathophysiology, and management of metastases to the brain parenchyma.
Multiple brain metastasis in a patient with known non-small cell lung adenocarcinoma. There was also systemic disease in the liver.
To metastasize, tumor cells have to gain access to the circulation, survive while circulating, pass through the microvasculature of the adopted organs, xtravasate into the organ parenchyma, and reestablish themselves at the secondary site. This process requires the tumor cells to penetrate the basement membrane and cross the subendothelial membrane. Tumor cells achieve this by producing proteolytic enzymes, particularly metalloproteinases and cathepsins to help them to break down the basal matrix and enhance their invasiveness. Tumor cells modulate the expression of fibronectin, collagen, or laminin, and change the type of integrin receptor on their surface and on the surface of the surrounding stromal cells, resulting in desegregation of the stromal cells and creating a permissive environment for them to expand and invade.
Invading cells detach from the tumor mass, disperse, and traverse the epithelial/endothelial boundary; they will use the vascular conduit to colonize distant organs. Furthermore, they have to survive intravascular circulation and avoid immune surveillance during this journey. They accomplish that by coating t hemselves with a shield made out of the coagulating elements such as fibrin and platelets in the blood. These metastatic emboli also produce adherens to slow
themselves down to a halt in the blood stream. These adheren molecules allow the circulating cancer cells to reattach onto the vascular wall and gain entry to the host tissue by disruption of the endothelial barrier. This leads to re-establishment of distant micrometastasis.
Tumor cells can survive in environments of low oxygen tension. When a tumor increases in volume by more than 2-3 times, the tumor expresses angiogenic factors such as angiopoietin-2 and vascular endothelial growth factors. These angiogenic modulators promote sprouting of surrounding blood vessels, which results in tumor angiogenesis. Additionally, these paracrine factors influence the readiness of target organs to accept tumor growth to prepare a favorable microenvironment for the tumor to undergo exponential growth and become a macrometastasis. 
Different tumors metastasize preferentially to different organs. Cells with similar embryologic origins are generally believed to have similar growth constraints and express similar sets of adhesion molecules, such as addressins. An example is melanoma; the cells are closely related to CNS cells (they are derived from the neural crest cells), and melanoma commonly metastasizes to the brain. Certain cell-surface markers in cancer are indicators and/or predictors of distant metastasis, eg, nm23 and CD44 in breast cancer. 
Similarly, breast cancer cells that are HER positive are more likely to metastasis to the brain. 
Renal, gastrointestinal, and pelvic cancer tend to metastasize to the cerebellum, whereas breast cancer is more commonly found in the posterior pituitary. Thus, the trafficking of cancer cells to their final destination is not entirely random and may be guided by factors produced by stromal cells of their host organ.
Recently, it has been shown that metastases may have originated from cancer initiating cells, which are more resistant to therapy by virtue of their stemlike properties. 
Additionally, cancer cells recruit bone marrow–derived cells to modify the microenvironment of distant recipient sites, forming a premetastatic niche by alternating the level of fibronectin and making the site more favorable for the colonization of metastatic tumor. 
Cancer cells have been shown to recruit bone marrow—derived cells to modify the microenvironment of distant recipient site; the formation of a premetastatic niche by alternating the level of fibronectin and making the site more favorable for the colonization of metastatic tumor. 
The incidence of metastatic brain tumors exceeds that of primary brain tumors, accounting for 50% of total brain tumors and for as many as 30% of tumors seen on imaging studies alone. An estimated 100,000 new cases are diagnosed per year in the United States; about 60% of patients are aged 50-70 years.
More than 20% of patients with systemic disease have brain metastasis on autopsy. About 15% of patients with cancer present with neurologic symptoms before their systemic cancer is diagnosed. Among them, 43-60% have an abnormal chest radiograph suggestive of bronchogenic primary or other metastases to the lung. In 9%, the CNS is the only site of spread. About 10% of patients with proven metastatic disease have no identifiable primary source.
The most common origins of brain metastasis are systemic cancer of the lung, breast, skin, or GI tract. In 2700 cases from the Memorial Sloan-Kettering Cancer Center in New York, the distribution of primary cancers was as follows: 48% lung, 15% breast, 9% melanoma, 1% lymphoma (mainly non-Hodgkin), 3% GI (3% colon and 2% pancreatic), 11% genitourinary (21% kidney, 46% testes, 5% cervix, 5% ovary), 10% osteosarcoma, 5% neuroblastoma, and 6% head and neck tumor. Of note, renal, GI, and pelvic cancers tend to metastasize to the cerebellum, whereas breast cancer most commonly affects the posterior pituitary. Cancer-cell trafficking may not be entirely random, and factors produced by stromal cells may guide their final destination in the brain.
Primary lung tumors account for 50% of all metastatic brain tumors. Lung cancer is the most common origin of metastatic disease. Of lung cancer patients who survive for more than 2 years, 80% will have brain metastases.
The average time interval between the diagnosis of primary lung cancer and brain metastases is 4 months. Interestingly, small cell carcinomas, which are only 20% of all lung cancers, account for 50% of brain metastases from lung cancer. In a retrospective study, 6.8% of the first cancer recurrence was in the brain.
Breast tumor is the main source of metastatic disease in women, followed by melanoma, renal, and colorectal tumors. Breast cancer is a heterogeneous disease demonstrating genotypic and phenotypic diversity. The interval between the diagnosis of primary breast cancer and brain metastasis can be up to 3 years. The first site of distant failure is the brain, alone or as a component of metastatic disease, and a proportionately high number are ER- or HER2 negative. Yet HER
positive cancer is twice as common to metastasize to the brain. Additionally, it has been shown that nm23 and CD44 in breast cancer are indicators for distant m etastasis.
Melanoma commonly metastasizes to the brain. Melanoma has an increased incidence among other systemic cancers in terms of metastasizing to the brain. About 40-60% of patients with melanoma will have brain metastasis. Melanoma cells are closely related to CNS cells due to their embryonic origin and neural crest cells, and they share common antigens such as MAG-1 and MAG-2. After melanoma is detected in the brain, median survival is 3 months. These metastases are poorly responsive to all treatments. Approximately 14% of cases have no identifiable primary tumor. Melanomagenic tumors also involve the
pial/arachnoid. In CT imaging, they are marginally enhanced with contrast compared with bronchogenic cancer. They are distinctive in MRI because of the melanin or due to hemorrhage. Others metastatic tumors that commonly bleed are thyroid and renal cell carcinoma. Unfortunately, patients with brain metastasis from melanoma are known to do poorly despite therapy.
Metastatic disease from the breast, thyroid, renal cells, and colon are more commonly found as a single metastatic lesion, whereas metastatic disease from lung cancer and melanoma are more commonly found to be multiple lesions. Testicular tumor is a uncommon cancer and yet it more frequently metastasizes to the brain as compared with lung cancer.
Patients with brain metastasis at the same time of having systemic cancer (synchronous metastasis) tend to do worse as compared with patients with metachronous metastatic disease.
Although melanoma spreads to the brain more commonly in males than in females, gender does not affect the overall incidence of brain metastases.
About 60% of patients are aged 50-70 years.CNS metastasis is not common in children; it accounts for only 6% of CNS tumors in children.Leukemia accounts for most metastatic CNS lesions in young patients, followed by lymphoma, osteogenic sarcoma, and rhabdomyosarcoma.Germ-cell tumors are common in adolescents and young adults aged 15-21 years.
Approximately 60% of patients with brain metastases have subacute symptoms. Symptoms are usually related to the location of the tumor. About 85% of the lesions are in the cerebrum, 15% are in the cerebellum, and 5% are in the brainstem. Morning headache with nausea and vomiting together with papilledema are suggestive of intracranial hypertension. Features such as headache, nuchal rigidity and photophobia indicate meninges involvement. The timing of the onset of these symptoms is subacute rather than acute.
Acute onset of symptoms suggests vascular or electrical etiology such as bleeding or seizure. Dementia and cognitive deficits of a gradual onset most likely indicate a demyelination problem, radiation necrosis. Paraneoplastic syndromes include limbic encephalopathy and cerebellar degeneration. The latter is commonly associated with ovarian cancer. Progressive weight loss and general fatigue can be ominous and highly suggestive of recurrent systemic cancer. Similarly, neurologic problems such as polyneuropathy or myopathy can be sinister.
Headache (42%) and seizure (21%) are the 2 most common presenting symptoms.
New onset of seizures in a patient older than 35 years is highly suggestive of primary or metastatic disease.
In addition, 35% of patients have cognitive dysfunction, and 30% have motor dysfunction.
About 10% of patients present with hemorrhage. Metastases commonly derive from choriocarcinoma, melanoma, bronchogenic carcinoma, thyroid carcinoma, and renal carcinoma bleeding; most of these hemorrhages are intramural.
Findings on the neurologic examination depend on the location of the metastatic lesions. Focal findings are common. Findings consistent with generalized CNS dysfunction also can occur secondary to the cumulative effects of multiple CNS lesions, edema associated with large single or multiple CNS lesions, and/or adverse effects of medications.
Any subacute neurological disease: About 11% of mass lesions in patients with cancer are not metastases. Mass lesions that can masquerade as brain metastasis include abscess (20%) and granuloma (less common and mostly associated with mycobacterial or fungal infection).
Acute demyelinating diseases (mostly secondary to acute postinfective demyelination)
Progressive multifocal leukoencephalopathy (PML)
Radiation necrosis, if patient had prophylactic radiotherapy for previous metastases to the brain
Nonbacterial thrombotic endocarditis (NBTE) and intravascular thrombosis: This is frequently encountered in patients with disseminated disease of the lung, breast, or GI or genitourinary tract or with tumors of hematopoietic origin. NBTE is uncommon in patients whose disease is in remission.
Resolving hematoma due to coagulopathy secondary to NBTE or intravascular thrombosis from associated coagulation disorder
Coagulopathy: Coagulopathies have been associated with breast cancer and leukemia. In some cases, cardiolipin antibodies are present; in other cases, abnormalities in viper-venom coagulation results have been documented.
- Differential Diagnoses
- Blood Dyscrasias and Stroke
- Brainstem Gliomas
- Cardioembolic Stroke
- Cerebral Venous Thrombosis
- Glioblastoma Multiforme
- Imaging in Oligodendroglioma
- Low-Grade Astrocytoma
- Multiple Sclerosis
- Neurological Sequelae of Infectious Endocarditis00
Laboratory investigations include blood work, such as CBC, electrolyte panel, coagulation screen, and liver function panel.
Specific markers, such as anti-Hu antibody in limbic encephalopathy, anti-Yo antibody in cerebellar degeneration, and anti-Ri antibody in opsoclonus and ataxia are of some value, especially in patients with small-cell lung cancer, ovarian cancer, and breast or lung cancers.
Chronic anemia is common in systemic disease.
Electrolyte imbalance, such as in hyponatremia (hypothyroidism or syndrome of inappropriate secretion of antidiuretic hormone [SIADH]), can be found in patients with metastasis to the pituitary gland and meninges.
Abnormal coagulopathy can be observed in patients with breast cancer or leukemia.
Abnormal liver function is common in patients with advanced systemic diseases or in those receiving chemotherapy.
Specific markers, such as anti-Hu antibody in limbic encephalopathy, anti-Yo antibody in cerebellar degeneration, and anti-Ri antibody in opsoclonus and ataxia, are of some diagnostic value, especially in patients with small-cell lung cancer, ovarian cancer, breast cancer, or lung cancers.
The recent advancement in genomic and proteomic medicine allows the use of a molecular signature to gauge the risk of developing brain metastasis. For example, in young breast cancer patients, an ER-positive, PR-positive, and HER2 -negative profile incurs a higher brain metastasis risk compared with a triple-negative or HER2 -positive profile. 
It is especially true if the patient has a short interval between initial diagnosis and systemic metastasis; this risk is noted to be even higher if there are multiple sites of systemic metastasis. In current practice, this is beginning to be used as a method to guide personalized therapy.
Imaging study for metastatic disease to the brain can be divided into systemic imaging and imaging of the neuraxis. Images provide information on tumor burden in the brain and associated structures, in addition to the rest of the body, and are integral part in formulating the optimal treatment plan.
Systemic imaging studies
Chest radiography should be included in the workup of any mass lesion in the brain, specifically in patients without a history of systemic cancer.
Chest radiographs may reveal the primary cancer and suggest an alternative site for obtaining tissue for histologic diagnosis.
Additional imaging modalities such as CT, positron emission tomography (PET), and bone scanning are used to stage the systemic disease.
Imaging of the neuraxis (brain and spinal cord)
Head CT imaging of the brain is not as reliable as MRI in determining the extent of brain metastases.
Head CT can cause underestimation of the number of brain lesions. In 20% of cases and even when contrast medium is used, head CT shows a
solitary lesion but subsequent MRI shows multiple lesions.
High-resolution MRI can be used to detect additional brain metastases in patients undergoing Gamma Knife surgery. 
Contrast medium enhances visualization of mass lesions in the brain and should be used in both CT and MRI.
Newer imaging modalities, such as magnetization transfer imaging and perfusion imaging, are not particularly useful.
Diffusion-perfusion MRI has been used to differentiate poorly enhancing lesions.
Tien et al reported that peritumoral edema and nonenhancing tumor have distinguishable features. 
The utility of this imaging technique in metastatic diseases is not established, though peritumoral edema is prominent in most cases.
Magnetic resonance (MR) spectrometry and PET scan (positron emission tomography).
MR spectroscopy uses the chemical signature of rapid membrane turnover of proliferative cells to reveal the presence of cancer cells.
Multiple voxel analysis is more commonly used because it has an advantage over signal voxel study to yield more information about the region of interest and to differentiate edema and possible necrosis.
CT-PET and bone scans are used to stage the extent of the systemic disease. This helps to formulate the extensiveness of future treatments (see Treatment) and their justification. Patients with multiple systemic metastasis do not do well in intensive therapy.
Other experimental imaging studies such as receptor-targeted and ligands-based molecular imaging are on the horizon. These imaging modalities are cancer specific.
Both MRI spectrometry and PET studies are useful to differentiate radiation necrosis from tumor.
Thallium-201 chloride PET seems to have high specificity (91%) in this regard.
Neither of these methods is useful for differentiating metastasis from primary brain tumors, but they are helpful whenever the possibility of an abscess is being considered.
Eleven percent of cancer patients with a solitary mass in the brain have lesions other than metastatic disease. Hence, tissue diagnosis is sometimes necessary to resolve this diagnostic uncertainty, especially when there is ambiguity in the imaging study.
Tissue diagnosis should be performed in cases of uncertain etiology. Of note, most surgeons advocate excision biopsy for a solitary lesion in an accessible area of the brain.
For stereotactic brain biopsy, the morbidity rate is 3% with a 1% rate of hemorrhage and a 1% rate of deficit without hemorrhage. The mortality rate is 3%.
In the past, the morbidity rate associated with tumor resection was 20%, and mortality rate was 2%. With recent advances in intraoperative navigation, the morbidity and mortality rates of excisional biopsy have been reduced to 10% and 0.5-2%, respectively, which are still higher than the rates with biopsy alone.
Medical treatments consist of symptomatic and systematic treatments. Other options are surgical treatments, radiation therapy (whole brain radiation, focal beam and stereotactic radiation therapy, eg, radiosurgery), chemotherapy, combined therapies, experimental therapies, and integration therapy.
Integration therapy is a multidisciplinary approach with combination therapy of behavioral modification/coping, nutritional counseling, alternative medicine (herbal), physical therapy, and occupational therapy. Integration therapy has become more accessible to most healthcare providers in the past few years. It was once looked upon as therapy that was in the fringe of pseudosciences; it is now an important element in major cancer centers. It serves as a resource and reference center to most cancer patients.
Medical management of metastatic diseases has mainly focused on the treatment of cerebral edema, headache, and seizure. Headache and cerebral edema are interrelated and are discussed as such.
Management of headache and edema
Causes of headache are cerebral edema with increased intracranial pressure and meningeal irritation secondary to infiltration of cancer cells. Other causes, such as hydrocephalus and hemorrhage, require surgical intervention.
The diagnosis is normally confirmed with radiographic studies.
Hydrocephalus is uncommon in metastatic disease. In most cases, carcinomatosis meningitis is the cause. In rare cases, obstruction of the aqueduct of Sylvan or the fourth ventricle is the cause.
Shunting of the ventricle is the treatment of choice. The most common concern with this maneuver is the possibility of systemic seeding of
tumor cells into the peritoneal cavity. Cerebral edema of metastatic disease is mainly vasogenic. Brain swelling causes a secondary insult to the surrounding healthy brain, which may worsen cognitive function and/or motor and sensory deficits. If severe, it compromises cerebral perfusion and results in cerebral
Dexamethasone is the treatment of choice.  It has the least mineralocorticoid effect of all steroids and is less likely than other steroids to be associated with infection or cognitive dysfunction. It does not increase the risk of myopathy. Common adverse effects are psychotic reaction (5%), GI bleed (less than 1%), and glucose intolerance (19%). The frequency of steroid complications depends on the duration of treatment (>3 wk increases risk). It is also associated with hypoalbuminemia, which increases the risk of adverse effects associated with steroid treatment.
The optimal dosage of dexamethasone vasogenic edema is 4 mg given intravenously or orally every 6 hours after a loading dose of 10 mg. Symptoms improve in 70-80% of patients within 48 hours of the start of treatment. High doses of steroid (6-10 mg q6h) may improve functional scores (70 vs 54) after 7-10 days of treatment. However, this trend is reversed after 3-4 weeks. Most physicians advocate an initial dose of 16 mg/day, which is tapered after 4-28 days. Adverse effects of steroids include GI bleeding, an increased rate of opportunistic infection, diabetes, and myopathy. In patients with cancer, one must be aware of the catabolic effect of steroids and provide nutritional supplements as needed.
Management of seizures
The frequency of seizures in patients with metastatic brain tumor is 30-40%. One half of patients who have seizures present with them.
The type of seizure guides treatment. Prophylactic treatment for seizure is not necessary in patients with no history of seizure.
The most commonly used drug is phenytoin, especially for patients with generalized motor seizures. Valproate has also been used, as have newer medications, such as levetiracetam. Phenytoin should be started before radiation therapy. The incidence of allergic reaction increases if it is started after radiation. An allergic reaction can be acute or delayed; it commonly appears within 3-6 weeks after the patient has started the medication.
Status epilepticus occurs infrequently in patients with metastasis, but it is associated with a high mortality rate (6-35%). Status epilepticus should be considered the cause in patients with a prolong postictal state or in stuporous or comatose patients whose imaging study does not show significant mass effect of edema. Status epilepticus should be treated aggressively. Ativan or Diazepam is the common medication. Propofol infusion has also been used.
Medical treatment directed at cancer cells that have seeded into the brain is ineffective. The failure of chemical therapy has always been attributed to an intact BBB and the acquisition of drug resistance by the cancer cells. Most tumors that metastasize to the brain are not chemosensitive, though small-cell lung cancer, breast cancer, and lymphoma respond to chemotherapy. Hence, management and treatment depend on the systemic disease, the tumor type, and the stage of the disease.
A variety of chemotherapeutic agents have been used to treat brain metastasis from lung, breast, and melanoma, including cisplatin, cyclophosphamide, etoposide, teniposide, mitomycin, irinotecan, vinorelbine, etoposide, ifosfamide, temozolomide, fluorouracil (5FU), and prednisone.
In most cases, 2-3 of these agents are used in combination and in conjunction with whole-brain radiation therapy (WBRT). The outcome with this approach is not promising. The mean survival for chemotherapy alone for small-cell lung and breast cancer and melanoma is about 3.2-8 months. Survival with the combination of chemotherapy and WBRT is about 3.5-13 months.
Chemotherapy can have a remission rate of above 10%, a partial-response rate of about 40%, and a local-control rate of about 9%.
Temozolomide has recently been used as a single agent to treat brain metastasis from breast cancer. The result is encouraging. Complete remission was achieved in 36% of patients, and an additional 58% had a partial response.
The advent in small-molecule tyrosine kinase inhibitors (tyrKi) and monoclonal antibodies has helped transform the management of brain metastasis. Gefitinib and erlotinib, epidermal growth factor receptor (EGFR) tryKis, have shown promising results in treating nonsmall cell lung cancers that metastasize to the brain, especially if they have the EGFR mutation.  The use of lapatinib in combination with capecitabine is effective in treating HER2 -positive brain metastasis; similarly, the use of vemurafenib in treating BRAF V600E–positive melanoma that has brain metastasis is also found to be effective.  It is noteworthy that a recent study at Memorial Sloan-Kettering has shown that the use of sorafenib or sunitinib can lower the incidence of metastasis of renal cell carcinoma to the brain.  Monoclonal antibodies such as trastuzumab have been used in treating metastatic breast cancer. The latter, however, is not that effective in crossing the blood-brain barrier and results in relapse within the central nervous system. Ipilimumab, on the other hand, has been found to be effective in treating metastatic melanoma to the brain.
Radiation therapy has become a mainstream therapy for brain metastasis. Radiation therapy includes WBRT and stereotactic radiosurgery.
For decades, WBRT has been advocated for patients with multiple lesions. WBRT is also advocated for patients with a low Karnofsky score or a life expectancy of < 3 months. Effectiveness of this treatment depends on the histological type of the tumor. Small-cell lung tumor and germ-cell tumors are highly susceptible to radiation, other types of lung cancer and breast cancers are less sensitive, and melanoma and renal-cell carcinoma are not sensitive at all.
Regarding the effectiveness of radiation therapy, the Radiation Therapy Oncology Group (RTOG) has recommended a treatment schedule of 30 Gy delivered in 10 fractions over 2 weeks. With this treatment, median survival is 3-6 months depending on number of lesions, their radiosensitivity, and the status of systemic disease. Disadvantages are short- and long-term adverse effects. Besides hair loss, headache, nausea, otitis media, and cerebral edema, patients may have increased somnolence. After 6 months, patients may have evidence of radiation necrosis, leukoencephalopathy, and/or dementia.
Hippocampal avoidance (HA), a modification of WBRT, may preserve short-term memory in cancer patients with brain metastases. In a study involving 113 adult cancer patients with a measurable brain metastasis outside a 5-mm margin around the hippocampus, the HA-WBRT group showed a 7% performance decline on a standardized memory test at 4 months, whereas the control group showed a 30% decline.  At 6 months, the decline averaged 2%.
This modality makes use of multiple, well-collimated beams converging on a small lesion with a steep dose gradient at the edge of the beam. This conformity allows a high dose of radiation to be delivered to the target in a single fraction without causing excessive radiation damage to surrounding healthy brain. Several lesions can theoretically be treated on a single clinic visit. As the number of lesions increase, the overlapping of fields exceeds tolerance of healthy brain to radiation injury. For lesions 1-3 cm, the median dose is 15-24 Gy.
Stereotactic radiosurgery is a more preferred treatment modality for radio-resistant lesions such as nonsmall cell lung cancer, renal cell carcinoma, and melanoma. It is also more frequently used to treat the resection cavity of brain metastasis, particularly in patients with breast metastatic disease. The latter population of patients has a higher survival potential, thus whole brain radiation or EBRT, with their long-term cognitive adverse effects, make these modalities a less favorable choice.
Median survival after radiosurgery is 14.1 months. Twenty-four percent of patients with brain metastasis from breast cancer have 24-month overall survival. The overall control rate in breast metastasis in the brain is 82-90%. Unfortunately, 47% of the patients have new brain metastasis 11-15 months after initial radiosurgery. This is especially true in melanoma. The median tumor control for most brain metastasis is about 10 months.
The size of metastatic tumors may not change until months after radiation. The lesion may appear to grow slightly immediately after treatment. Treatment can worsen peritumoral edema, which can be controlled with a prolonged course of high-dose steroids. The prophylactic use of anti-inflammatory drugs to reduce edema is still being debated. If cerebral edema becomes symptomatic, then craniotomy and resection is warranted.
Acute reactions due to edema occur within 2 weeks in 7-10% of patients. These reactions include headache, nausea, vomiting, worsening of preexisting neurological deficits, and seizure. Radiation necrosis happens later, 6 months after treatment in 4% of patients. It can manifest as a transient increase in tumor size, edema, or mass effect with or without frank necrosis. It can be difficult to distinguish from the tumor itself.
In a recent study, the radiation complication rate for stereotactic radiosurgery in treating metastatic brain tumors is estimated to be 6%. It has been shown that the risk of having imaging-documented radiation necrosis is proportional to the volume of nontumor brain tissue exposed to 10 or 12 Gy of radiation. For volume more than 10 cm3 in a single session of radiosurgery, the risk of necrosis is 47% and is about 24% when the volume is less than 10 cm3. 
Fortunately, only 5.8% of the patients are symptomatic.
Collectively, these merging data confirm that radiosurgery is equally effective in treating brain metastasis. Radiosurgery is particularly useful in treating patients with limited systemic disease and higher Karnofsky scores and in patients with life expectancies of more than 6 months. However, radiosurgery is now commonly offered to patients with higher systemic tumor burden when a shorter treatment regimen is more desirable.
Radiosurgery is also increasingly used as the adjuvant therapy in patients who have undergone metastatic brain-tumor resection. The effectiveness of this treatment depends on the histology of the tumor.
Indications for surgical resection include the following:
- Solitary lesions larger than 3 cm
- Lesions in noneloquent areas of the brain
- Limited and/or controlled systemic disease
- Karnofsky score greather than 70
One symptomatic lesion with multiple asymptomatic lesions (The symptomatic lesion should be resected, and remaining lesions should be treated with radiotherapy.)
The surgical morbidity rate is about 10%, and the mortality rate is less than 5%. The outcome of resection can be improved by applying intraoperative navigation and monitoring with cortical mapping; this allows for aggressive resection, even in eloquent regions.
Contraindications to surgery include a radiosensitive tumor (eg, small-cell lung tumor), patient life expectancy < 3 months (WBRT indicated), and multiple lesions. However, Bindal et al recently indicated that patients who underwent resection of multiple lesions fared better than patients with multiple lesions who did not undergo surgery.  Morbidity and mortality rates are essentially the same as those in patients with a solitary lesion.
Surgical resection versus radiosurgery
Surgical resection is considered standard care for solitary metastases larger than 3 cm and in noneloquent areas of the brain.
Surgical resection is superior to radiosurgery, with a median survival nearly twice that of radiosurgery. About 13% of surgically treated patients have local recurrence, whereas 39% of patients treated with radiosurgery have local progression of disease.
Cho and Auchter reported that combined therapies (eg, resection plus radiosurgery or radiosurgery plus WBRT) yield outcomes better than those of WBRT alone. [20, 21]
Read more in Stereotactic Radiosurgery in the Management of Brain Metastasis.
In 2 prospective randomized trials, surgical resection plus WBRT was more effective than WBRT alone in controlling disease. The combination had a median survival of 8-16 months and 7-15% local recurrence rates. The role of adjunctive WBRT after surgery for a solitary lesion is controversial.
Postoperative WBRT reduces the recurrence rate but does not affect overall survival.
In 1 comparison of radiosurgery plus WBRT versus WBRT alone in patients with multiple metastases (2-4 tumors, < 25-mm total diameter), combined therapy was most effective in controlling disease and that it had a survival advantage (median time to local failure of 36 vs 6 mo).
WBRT after surgery or radiosurgery is controversial. Local control is best with a combined approach, but functional scores and overall survival were not clearly different.
The growing trend is to postpone WBRT until recurrence and to use fractionated stereotactic radiotherapy with radiosensitizers (eg, gadolinium texaphyrin, RSR13).
Management of recurrent metastasis
The local recurrence rate of brain metastasis is relatively high. It can be as high as 85% in patients undergoing craniotomy without WBRT.
For patients given radiation therapy and stereotactic radiosurgery, the relapse rate can be as much as 67%.
The recurrence rate of brain metastasis is related to the duration of survival, which in turn mostly depends on the nature and the course of the systemic disease.
Treatment outcomes for patients with brain metastases who live 24 months or longer after initial treatment include primary tumor control, single-organ metastasis, and a long latency period between primary treatment and recurrence.
The management paradigm for recurrent brain metastasis is highly controversial.
Management of single/solitary brain metastasis in patients without prior WBRT
The algorithm for the management of a solitary brain tumor (patient with no or stable systemic disease) is easier than that of a single metastatic tumor. If the solitary lesion is symptomatic and/or in a noneloquent area, then surgical resection is the best option; this provides tissue confirmation and reduces mass effect.
Even then, the use of WBRT or radiosurgery as adjuvant therapy remains controversial. It is a general belief that adjuvant radiotherapy is indicated since the hazard ratios for local recurrence and distance recurrence in patients without WBRT are 3.14 and 2.16 (as compared to 0.58 and 0.42), respectively. However, the use of stereotactic radiosurgery as an adjuvant therapy is gaining momentum. A body of clinical evidence suggests that radiosurgery to the rim of the tumor resection cavity is equally effective in achieving local control. An upcoming NCCTG-N107C study is designed to categorically address this issue.
Radiosurgery has been used effectively in treating multiple lesions as an upfront therapy; therefore, there is no reason to doubt it will not be able to control local diseases around the resection cavity if an adequate marginal dose is achievable; thus, reserve WBRT to be used in distance relapse with multiple lesions, local progression, or in cases in which leptomeningeal spread is suspected. It is also possible to perform re-resection in cases in which local progression is evidenced, as well as in cases in which the differentiation of local recurrence and radiation necrosis is not possible.
Management of brain metastasis with unknown primary diseases
Metastatic cancer of an unknown primary lesion accounts for 3-5% of all cancers, and makes it the seventh most common malignancy. About 15% of brain metastasis is included in this category.
Metastasis without a primary lesion is considered present when a complete history, physical examination (including breast and pelvic examination in female patients and prostate and testicular examination in male patients), standard laboratory investigations, and histologic examination fail to confirm systemic disease before any form of treatment is given. In this situation, the likelihood of identifying the primary disease is about 30-82%.
The general belief is that the primary lesion has become involuted or that the phenotype and/or genotype of the tumor suggest metastatic potency instead of a slow local expansion of the tumor.
This designation creates uncertainty regarding treatment and an assumption of a poor prognosis. In fact, this condition represents a subgroup of cancers with widely divergent prognoses.
Serum markers, such as cancer antigen (CA)15.3 for breast tumor, CA19.9 for pancreatic tumors, and CA125 for ovarian cancers have helped to focus the search of the primary disease and have empirically guided treatment.
Brain metastases of unknown primary origin are often adenocarcinomas or squamous cell carcinomas (31% and 9%, respectively). A search for occult head and neck cancer frequently reveals the origin of the systemic disease. Nevertheless, in 42% of cases, the origin remains unclear after extensive investigation.
The median survival of patients with brain metastasis without a primary cancer is about 6 months; those with solitary lesions have a better prognosis.
Surgery in combination of WBRT is the most common mode of therapy. Chemotherapy is infrequently used when serum markers and histological clues indicate the most likely source of the disease.
The goals of pharmacotherapy are to induce remission, reduce morbidity and prevent complications.
These agents reduce edema around tumor, frequently leading to symptomatic and objective improvement.
Dexamethasone (Active Injection D, Dexamethasone Intensol, DexPak, DoubleDex)
The postulated mechanisms of action of corticosteroids in brain tumors include reduction in vascular permeability, cytotoxic effects on tumors, inhibition of tumor formation, and decreased CSF production.
Prednisone (Deltasone, Rayos, Prednisone Intensol)
Used adjunctively with chemotherapeutic medications. Glucocorticosteroid; elicits mild mineralocorticoid activity and moderate anti-inflammatory effects; controls or prevents inflammation by controlling rate of protein synthesis, suppressing migration of polymorphonuclear leukocytes (PMNs) and fibroblasts, reversing capillary permeability, and stabilizing lysosomes at cellular level; in physiologic doses, corticosteroids are administered to replace deficient endogenous hormones; in larger (pharmacologic) doses, they decrease inflammation.
Prednisolone (Pediapred, Orapred ODT, Millipred, Millipred DP, Veripred 20)
Used adjunctively with chemotherapeutic medication, reversing capillary permeability, and stabilizing lysosomes at cellular level; Coticosteroids also decrease inflammation.
Anticonvulsants are employed in management of seizures presenting as complication of disease
Valproic acid (Depacon, Depakene, Depakote, Depakote ER, Depakote Sprinkles)
May increase levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in brain; may enhance or mimic action of GABA at postsynaptic receptor sites; may also inhibit sodium and calcium channelsUsed to control seizures, including generalized motor seizures and complex partial seizures
Levetiracetam (Keppra, Keppra XR, Roweepra, Spritam)
Antiepileptic mechanism unknown; may inhibit voltage-depedent N-type calcium channels; may bind to synaptic proteins that modulate neurotransmitter release; through displacement of negative modulators may facilitate GABA-ergic inhibitory transmission
Lorazepam (Ativan, Lorazepam Intensol)
A benzodiazepine. A sedative hypnotic with short onset of effects and relatively long half-life. Increases the action of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain; May depress all levels of CNS, including limbic and reticular formation. Indicated for status epilepticus as complication of disease.
Diazepam (Diastat, Diastat AcuDial, Diazepam Intensol, Valium)_
A benzodiazepine. Extremely lipid-soluble agent that quickly enters brain in first pass and often stops seizures in 1-2 min. Rapidly distributes to other stores of body fat. Increases the action of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain; Indicated for status epilepticus as complication of disease.
Phenytoin (Dilantin, Phenytek, Dilantin Infatabs, Phenytoin Infatabs)
Sodium transport inhibitor indicated for management of generalized motor seizures and complex partial seizures
General Anesthetics, Systemic
These agents stabilize the neuronal membrane so the neuron is less permeable to ions. This prevents the initiation and transmision of nerve impulses, thereby producing anesthetic effect
Propofol (Diprivan, Fresenius Propoven)
Propofol, an IV anesthetic agent, is active on the glutamate and GABA-A receptors, whereas benzodiazepines are active only against the GABA receptors. Only slightly soluble in water, but highly soluble in lipids. CNS penetration primarily depends on cerebral blood flow. Emergence from anesthesia is relatively fast, even with prolonged infusions. Causes global CNS depression, presumably through agonist actions of GABA receptors; Indicated for treatment of status
epilepticus presenting as complication of disease.
Antineoplastic agents are employed to reduce tumor burden and induce remission. Some agents may also reduce angiogenesis, and metastasis. Selection and use depends on systemic disease, tumor type, and stage.
Platinum coordination compound that inhibits DNA synthesis, cross-links and denatures strands of DNA and disrupts DNA function by covalently binding to DNA bases
Metabolites interfere with malignant cell growth by cross-linking tumor cell DNA; non-cell cycle specific with potent immunosuppressive activity
Synthetic analog of cyclophosphamide. Exerts its cytotoxic effect via alkylation of DNA, leading to interstrand and intrastrand DNA crosslinks, DNA-protein crosslinks, and inhibition of DNA replication.
Imidazotetrazine derivative prodrug whose active metabolite, the reactive compound 5-(3-methyltriazen-1-yl),
A glycosidic derivative of podophyllotoxin that exerts a cytotoxic effect by stabilizing the normally transient covalent intermediates formed between the DNA substrate and topoisomerase II. The drug leads to single-stranded and double-stranded DNA breaks that arrest cellular proliferation in the late S or early G2 phase of cell cycle.
Semisynthetic podophyllotixin derivative which inhibits topoisomerase II to cause DNA strand breaks by inhibiting DNA strand-passing and DNA ligase activity., Prevents cells from entering mytosis by delaying the transit of cells through the S phase and causing arrest in late S or early G2 phase of the cell cycle.
Anthracycline antibiotic which crosslinks DNA,,primarily with guanine and cytosine, preventing replication and transcription. Cell-cycle nonspecific but acts primarily against cells in late G and early S phases.
Semisynthetic derivative of camptothecin, an alkaloid extract from the Camptotheca acuminate tree. Inactive in its parent form. Converted by the carboxylesterase enzyme to its active metabolite from, SN-38.SN-38 binds to and stabilizes the topoisomerase I-DNA complex and prevents the relegation of DNA after it has been cleaved by topoisomerase I, inhibiting DNA replication.
Semi-synthetic vinca alkaloid which inhibits mitosis at metaphase by depolymerizing microtubules. Disrupts the mitotic spindle, causing the cell to arrest at metaphase. It is specific for the M and S phase of the cell cycle. By blocking glutamic acid utilization may also interfere with nucleic acid and protein synthesis
Fluoropyrimidine analog. Cell cycle-specific with activity in the S-phase as single agent and has for many years been combined with biochemical modulator leucovorin. Has activity as single agent that inhibits DNA replication and transcription. Classic antimetabolite anticancer drug with chemical structure similar to endogenous intermediates or building blocks of DNA or RNA synthesis.
Fluoropyrimidine carbamate prodrug form of 5-fluorouracil (5-FU). Capecitabine itself is inactive. Undergoes hydrolysis in liver and tissues to form the active moiety (fluorouracil), inhibiting thymidylate synthetase, which in turn blocks methylation of deoxyuridylic acid to thymidylic acid. This step interferes with DNA and to a lesser degree with RNA synthesis.
EGF receptor is present on normal and cancer cells and plays a role in cell growth and proliferation. Gefitinib reversibly inhibits the kinase activity of wild-type and certain activating mutations of epidermal growth factor receptor (EGFR) preventing autophosphorylation of tyrosine residues associated with the receptor, thereby inhibiting further downstream signaling and blocking of EGFR-dependent proliferation.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor; may also block angiogenesis and cellular proliferation. Erlotinib exhibits higher binding activity for EGR exon 19 deletion or exon 21 L858R mutations than for the wild type receptor. Causes apoptosis by inhibiting intracellular phosphorylation, which in turn prevents downstream signaling.
Multikinase inhibitor of intracellular ((CRAF, BRAF, and mutant BRAF) and cell surface (KIT, FLT-3, RET, RET/PTC, vascular endothelial growth factor receptor [VEGFR]-1, VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor-beta) kinases. which are involved in tumor angiogenesis, cell signaling and apoptosis
Sunitinib inhibits cellular signaling by targeting multiple receptor tyrosine kinases, such as platelet-derived growth factor receptors, and vascular endothelial growth factor receptors, which play a role in both tumor angiogenesis and tumor cell proliferation.
Tyrosine kinase inhibitor, blocking phosphorylation of EGF-receptor and HER2 kinase, which in turn blocks the activation of downstream second messengers responsible for cell proliferation and survival in ErbB- and ErbB-expressing tumors., Indicated in combination with capecitabine for patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including anthracycline, a taxane, and trastuzumab.
Inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF V600E, reducing cellular proliferation; Also inhibits other kinases in vitro (eg CRAF, ARAF, wild-type BRAF, SRMS, ACK 1, MAP4K5, FGR) at similar concentrations.
This is a form of drug delivery that specifically targets the tumor cells, thus reducing the systemic side effects of chemotherapy and at the same time being more effective than routine forms of chemotherapy agents.
Trastuzumab is a monoclonal antibody that binds to the human epidermal growth factor receptor 2 protein (HER-2) extracellular domain. It inhibits the proliferation of cells overexpressing HER-2 protein.
In summary, outcome factors associated with an improved prognosis  are the following:
- High Karnofsky score (>70%)
- Age younger than 70 years
- No systemic disease or systemic disease controlled
- No systemic metastases within 1 year of diagnosis of primary lesion
Generalizing median survival data for resection, WBRT, and/or stereotactic radiosurgery from available study reports is difficult.
Median survival after any therapy must be judged by means of recursive partitioning analysis (RPA) of the patients’ data and by evaluating the tumor type included in the study groups.
Surgery and WBRT remain the standard of care. Emerging data suggest that WBRT and radiosurgery is as promising as surgery and WBRT, especially in patients with more than 1 lesion in the brain. Furthermore, no significant difference has been observed between stereotactic radiosurgery and combined WBRT and radiosurgery in this population of patients. Hence, patients of RAP 2 or 3 may not have any survival advantage with aggressive and prolonged treatment, and radiosurgery alone may be a more sensible therapeutic option.
To date, treatment options for metastatic disease to the brain are mainly palliative, but this is changing. With newer chemotherapeutic agents, the repetitive use of stereotactic radiosurgery, and the growing trend in developing comprehensive cancer centers and integrative medicine to address emotional, nutritional, and cognitive/social issues of cancer patients, physicians and auxiliary staffs caring for cancer patients are more equipped to meet the personal needs of the patients.