AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

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.¹ 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.

Pathophysiology

To metastasize, tumor cells have to gain access to the circulation, survive while circulating, pass through the microvasculature of the adopted organs, extravasate 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 themselves 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.²

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, 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.³ 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.

Frequency

United States

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. Likewise, 11% of patients with a solitary mass in the brain have lesions other than metastatic disease.

Mortality/Morbidity

• Most metastatic tumors in the brain and spinal cord originate from systemic disease. Only a few primary high-grade brain tumors traverse the CSF space or ventricles to metastasize to other parts of the neuraxis. These include high-grade gliomas (10-25%), primitive neuroectodermal tumors (PNETs, 10-20%), ependymomas (11%), oligodendrogliomas (1%), and pineal tumors (rare). These types of tumor account for <4-9% of all primary brain tumors. The inability of brain tumors to metastasize to extracranial organs is attributed to the absence of an intracranial lymphatic system and the readily collapsible capillaries in the brain. Hence, the conduits through which tumor cells may leave their innate environment are few. 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.
• The most common origins of brain metastasis are systemic cancer of the lung, breast, skin, or GI tract. In 2700 cases from 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.

  Table 1 shows other data for sources of brain metastases.

  Table 1. Sources of Primary Tumor in Brain Metastases

  Primary Tumor Site	Percentage (%)
  Lung	21
  Breast	9
  Melanoma	40
  Lymphoma, mainly non-Hodgkin	1
  GI tract	3
  Genitourinary tract	11
  Osteosarcoma	10
  Head and neck	6

• 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 metastasis.

  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 commonly metastasizes to the brain. 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.

Sex

Although melanoma spreads to the brain more commonly in males than in females, gender does not affect the overall incidence of brain metastases.

Age

• 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.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

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.

Physical

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.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

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.

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• 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.
• Recent advancement in proteomics and the use of serum markers may be useful in the future for target treatment and diagnosis.

Imaging Studies

• 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.
  • 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
• • Diffusion-perfusion MRI has been used to differentiate poorly enhancing lesions.
  • Tien et al reported that peritumoral edema and nonenhancing tumor have distinguishable features.⁴
  • 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 matastasis 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.

Procedures

• Tissue diagnosis
• • 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.
• Brain biopsy
• • The morbidity rate for stereotactic brain biopsy is 3% overall; 1% is due to hemorrhage and 1% to deficits without bleed. The mortality rate is 3%.
  • The morbidity rate for tumor resection is 20%, and the mortality rate is 2%.
  • With recent advances in intraoperative navigation, the morbidity and mortality rates of excision biopsy have been reduced to 10% and 0.5-2%, respectively, which are slightly higher than the rates of stereotactic brain biopsy alone.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical treatments consist of symptomatic and systematic treatments. Other options are surgical treatments, radiation therapy (whole brain radiation, focal beam and stereotactic radiation therapy such as radiosurgery), chemotherapy, combined therapies, experimental therapies, and integration therapy.

Integration therapy is a multidiscipline approach with joint therapy of behavioral modification/coping, nutritional counseling, alternative medicine (herbal), in addition to physical and occupational therapy. Integration therapy has become more accessible to most health care providers in the past few years. It was once looked upon as therapy that was in the fringe of pseudo-sciences; it is now an important element in major cancer centers. It serves as a resource and reference center to most of the cancer patients.

Medical Care

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 infarction.
    • 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 kappa. 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's starting 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.
  • See the following eMedicine articles for more information about the diagnosis and treatment of seizures: Complex Partial Seizures and Status Epilepticus.
• Chemotherapy
  • 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.
• Radiation therapy
  • Radiation therapy has become a mainstream therapy for brain metastasis. Radiation therapy includes WBRT, multiplanar fractionated radiation, 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 histologic 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.
• Stereotactic radiosurgery
  • 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 configuration 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 17-18 Gy.
  • Median survival after radiosurgery is 11 months. The size of metastatic tumors may not change until months afterward. The lesion may appear to grow immediately after treatment. Treatment can worsen peritumoral edema, which can be controlled with a prolonged course of a high-dose steroid.
  • The prophylactic use of anti-inflammatory drugs to reduce edema is still being debated.
  • 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 tumoral size, edema, or mass effect with or without frank necrosis. It can be difficult to distinguish from the tumor.
  • Emerging data has suggested multiplanar focal radiation and radiosurgery can be equally effective. These modalities have been offered to patients with low Karnofsky scores and to patients with life expectancies of 3 months. They are also used as adjuvant therapies in patients who have undergone metastatic brain-tumor resection. The effectiveness of this treatment depends on the histology of the tumor.

Surgical Care

• Indications for surgical resection include the following:
• • Solitary lesions > 3 cm
  • Lesions in noneloquent areas of the brain
  • Limited and/or controlled systemic disease
  • Karnofsky score >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 <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.⁵ 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 > 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.^{6, 7}
  • Read more on Stereotactic Radiosurgery in the Management of Brain Metastasis.
• Multimodality therapy
  • 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 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.

Read more on Surgical Management of Brain Metastases.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Corticosteroids

These agents reduce edema around tumor, frequently leading to symptomatic and objective improvement.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Prognosis

• In summary, outcome factors associated with an improved prognosis are the following:
• • High Karnofsky score (>70%)
  • Age younger than 60 years
  • No systemic disease or systemic disease controlled
  • No systemic metastases within 1 year of diagnosis of primary lesion
  • Female patients
• 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. Table 2 provides an overview of data from several RTOG studies.

  Table 2. Overview of RPA Data from RTOG Studies
  

  Group	Karnofsky Performance Status	Systemic Disease	Median Survival (mo)
  1 (age 65 y or younger)	70 or higher	Controlled primary disease, no extracranial metastases	7.1; 13.5 for single metastasis, 6.0 for multiple metastases
  2*	Not group 1 or 3	Not group 1 or 3	4.2; 8.1 for single metastasis, 4.1 for multiple metastases
  3	<70		2.3

  ^*Patients in group 2 were those who did not meet the criteria for groups 1 and 3.

• 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.

• Median survival durations for resection, WBRT, and/or stereotactic radiosurgery are as follows:
• • Surgical resection and WBRT - 36 months
  • Surgical resection - 22 months
  • Surgical resection and WBRT - 16 months
  • Stereotactic radiosurgery - 11 months
  • WBRT - 6 months

Patient Education

• For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Brain Cancer.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Special Concerns

• Metastatic brain tumors are most commonly intracranial tumors.
• • Because many of the widely used chemotherapeutic agents do not cross the BBB, the brain is a safe haven for tumor growth.
  • Increasing incidence of brain metastasis is a result of the increasing age of the population (and thus an increase in the incidence of cancer overall) and improvements in treating systemic disease.
• To date, treatment options for metastatic disease to the brain are mainly palliative, but 20% of the total yearly cost of cancer treatment in the United States is for patients with primary or secondary cancer of the CNS.
• • A good proportion of this money is used for comfort and supportive care; the latter includes counseling for both patients and their families, which is an essential element in comprehensive care for this population of patients.
  • Given the increasing cost of treating cancer patients, specialists must justify their practice patterns on the basis of outcome analysis, and they must base their management plans on published guidelines, which may or may not apply to the needs of the individual patient.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Management of recurrent metastasis.
	View Full Size Image
Media type:  Chart

Media file 2:  Multiple brain metastasis in a patient with known non-small cell lung adenocarcinoma. There was also systemic disease in the liver.
	View Full Size Image
Media type:  Radiograph

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

1. Nussbaum ES, Djalilian HR, Cho KH, Hall WA. Brain metastases. Histology, multiplicity, surgery, and survival. Cancer. Oct 15 1996;78(8):1781-8. [Medline].
2. Santarelli JG, Sarkissian V, Hou LC, Veeravagu A, Tse V. Molecular events of brain metastasis. Neurosurg Focus. 2007;22(3):E1. [Medline].
3. Rusciano D, Burger MM. Mechanisms of Metastases. In: levine AJ, Schmidek HH (eds). In Molecular Genetics of Nervous System Tumors. New York: John Wiley & Son; 1993.
4. Tien RD, Felsberg GJ, Friedman H, Brown M, MacFall J. MR imaging of high-grade cerebral gliomas: value of diffusion-weighted echoplanar pulse sequences. AJR Am J Roentgenol. Mar 1994;162(3):671-7. [Medline].
5. Bindal RK, Sawaya R, Leavens ME, Lee JJ. Surgical treatment of multiple brain metastases. J Neurosurg. Aug 1993;79(2):210-6. [Medline].
6. Cho KH, Hall WA, Lee AK. Stereotactic radiosurgery for patients with single brain metastasis. J Radiol. 1998;1:79-85.
7. Auchter RM, Lamond JP, Alexander E, Buatti JM, Chappell R, Friedman WA, et al. A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis. Int J Radiat Oncol Biol Phys. Apr 1 1996;35(1):27-35. [Medline].
8. Bindal AK, Bindal RK, Hess KR, Shiu A, Hassenbusch SJ, Shi WM, et al. Surgery versus radiosurgery in the treatment of brain metastasis. J Neurosurg. May 1996;84(5):748-54. [Medline].
9. DeAngelis LM, Mandell LR, Thaler HT, Kimmel DW, Galicich JH, Fuks Z, et al. The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery. Jun 1989;24(6):798-805. [Medline].
10. Galicich JH, French LA. Use of dexamethasone in the treatment of cerebral edema resulting from brain tumors and brain surgery. Am Pract Dig Treat. Mar 1961;12:169-74. [Medline].
11. Rusciano D, Burger MM. Mechanisms of metastases. In: Levine AJ, Schmidek HH, eds. In: Molecular Genetics of Nervous System Tumors. New York, NY: Wiley-Liss; 1993.

Article Last Updated: Jan 28, 2008