Brain metastases

I. Problem/Condition.

Brain metastases are the most common intracranial tumor in adults and may affect up to 200,000 patients per year. The three most common primary malignancies that metastasize to the brain are lung, breast, and melanoma. Additional cancers with brain metastases include renal cell, colorectal cancer, and gynecologic cancers. Brain metastases are typically associated with advanced stage cancer, although they can happen with early stage lung cancer, melanomas or renal carcinomas. The frequency of brain metastases appears to be rising due to longer survival of cancer patients, better imaging modalities, and earlier detection.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

One can break up the differential into infectious causes, vascular causes and other neoplastic causes.

Among infectious possibilities, abscess remains on the differential for any intracranial mass lesion. It should be considered in an individual with a malignancy unlikely to go to the brain, in thick walled cavitary intracranial lesions, or in the proper clinical scenario (sepsis). Toxoplasmosis can cause ring-enhancing lesions; tuberculous meningitis can cause plaque-like accumulations on the meninges mimicking leptomeningeal carcinomatosis; and tuberculomas can occur intracranially, although this is rare in the United States.

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Neoplastic causes include metastases, central nervous system (CNS) lymphoma, solitary or multifocal glioblastoma, leptomeningeal disease, and meningioma.

Vascular causes include venous anomalies, side effects from therapy (reversible posterior leukoencephalopathy, associated with bevacizumab (Avastin), hemorrhage, or evolving cerebrovascular accident.

B. Describe a diagnostic approach/method to the patient with this problem

Patients who present with focal neurologic signs, headache or seizure in the setting of a known cancer with predilection for intracranial spread (lung, breast, kidney, melanoma) should be considered to have a brain metastasis.

Patients who have a malignancy that uncommonly spreads to the brain (cervix, prostate, ductal carcinoma in situ of the breast, colon), have no prior tissue confirmed metastatic disease, or have imaging features suggestive of other causes may require tissue confirmation through brain biopsy before treatment can be safely begun.

Although brain biopsy seems invasive, it is actually a fairly low risk procedure and can be accomplished in superficial lesions.

At times, the presentation of brain metastases can be fairly subtle, as in patients who have a mild persistent headache or word finding difficulties. Other times, there is a more fulminant presentation, such as severe headaches associated with vomiting, seizures, or acute impairment in activities of daily living.

1. Historical information important in the diagnosis of this problem.

The presence of headache, cognitive disruptions, expressive aphasias, motor, or sensory deficits should be queried. Ataxia suggests cerebellar involvement. Nausea and vomiting, especially worse in the morning, is suggestive of increased intracranial pressure as the cerebrospinal fluid (CSF) redistributes to the intracranial vault with recumbency. Seizures may also be present; approximately 15% of patients have seizure as the presenting sign of brain metastases and 30-40% experience seizures during their course.

Fever should point towards an infectious cause, although intracranial abscesses can often be walled off and non-pyrogenic. A recent history of dental procedure suggests a risk for intracranial abscess within the frontal lobes. A sinus infection of the frontal or ethmoid sinuses can spread to the frontal lobe. Otitis media/mastoiditis can spread to the inferior temporal lobes or cerebellum. Previously implanted foreign bodies can also result in abscess. No underlying cause is found in up to 40% of cases of those with brain abscess.

Patients with a history of immunosuppression (transplant – solid organ or stem cell, human immunodeficiency virus (HIV) with acquired immune deficiency syndrome (AIDS) defining illness) or injection drug use should have a thorough work-up to exclude atypical infectious causes. Injection drug users in particular can present with multiple intracranial abscesses, although any infection resulting in bacteremia can do the same.

CNS lymphoma is often accompanied by B symptoms like systemic lymphomas of fevers, night sweats and loss of weight.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Neurologic examination should be performed. Focal neurologic deficits in strength or sensory exam may occur as a result of destruction or displacement of brain tissue due to metastases. Diplopia can be detected by patients more readily than by clinicians, so when performing extraocular eye movement testing, one should ask if diplopia is elicited. The presence of dysdiadokinesis or ataxia suggests a cerebellar mass. Visual symptoms may indicate an occipital lobe tumor. Meningeal signs are uncommon. Ophthalmologic exam should be performed to assess for papilledema in the setting of significantly increased intracranial pressure.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Although computed tomography (CT) of the head is typically the first test ordered, gadolinium-enhanced magnetic resonance imaging (MRI) is the test of choice when there is a high index of suspicion for brain metastases. Patients with contraindications to MRI (certain implanted devices, shrapnel in the head) should undergo contrast enhanced CT scan. With a high level of clinical suspicion, a negative non-contrast head CT does not provide clinically useful information.

The distribution of metastases is proportional to relative blood flow in the regions: 80% are located in the cerebral hemispheres, 10-15% in the cerebellum, and 1-5% in the brainstem. Most brain metastases are often well-circumscribed and solid on appearance. Extensive edema may be present and some metastases can develop enhancement due to necrosis or haemorrhage.

Neuropsychological testing may be performed as cognitive impairment can be seen in 65% of patients with brain metastases.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Complicating the picture is that hematogenously seeded brain abscesses arise in the grey-white junction, similar to brain metastases. The most common location for brain abscesses is the frontal or temporal lobes, with the least common location being the occipital lobes. Abscesses tend to be thick-walled cavities radiologically. Diffusion weight imaging and magnetic resonance spectroscopy can be very helpful in making a distinction between the two entities.

Toxoplasmosis can be ruled out by the absence of serum toxoplasma antibodies or the absence of significant immunosuppression. The lesions tend to be multiple and more prevalent in the frontal lobes, parietal lobes, thalamus, basal ganglia, and the corticomedullary junction.

The presence of Epstein-Barr virus deoxyribonucleic acid (EBV DNA) in the CSF is highly suggestive of lymphoma. The lesions on MRI tend to occur in a periventricular location and in periependymal locations.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Non-contrast head CT in a patient with a high pre-test probability of brain metastases is often a wasted step. If you would proceed to MRI regardless, start with MRI unless it is unavailable. Even if a non-contrast head CT shows metastatic disease, MRI is often necessary so that the radiation oncologist has a baseline by which to monitor disease response following radiation treatment.

The clinical situation of a patient following brain radiation with “new” lesions seen on MRI when the only comparison is a prior CT is a clinical conundrum to be avoided. The two tests have dramatically different sensitivities and even among MRI machine sensitivity they differ depending on technical parameters (magnetic strength 1.5 tesla versus 3 tesla, sequence 3D magnetization-prepared, rapid acquisition, gradient echo imaging (MPRAGE) versus 2D secondary electron (SE)).

III. Management while the Diagnostic Process is Proceeding

A. Management of brain metastases.

The management of brain metastases can be divided into two strategies – symptomatic and therapeutic.

  • Acute management consists of symptomatic relief. Patients with midline shift or hydrocephalus should be evaluated by neurosurgery for possible decompression.

Steroid therapy with dexamethasone 10 mg intravenous (IV) load and 4 mg IV every 6 hours should be instituted. Steroid therapy can reduce edema until antitumor treatment can start. Patients usually improve within hours after the first dose and attain maximal benefit after 3-7 days. Once patients are asymptomatic or maximal benefit is reached, steroid doses should be tapered. Patients with few symptoms, little edema and no mass effect can have steroids withheld. If CNS lymphoma and abscess are being considered in the differential, particularly in the setting of an immunocompromised patient, steroid therapy should be withheld. Even a single dose of steroids can cause regression of lymphoma and obviate the ability to diagnose the problem. Patients with intracranial abscess masquerading as brain metastases have substantial mortality, and failure to identify these individuals can be fatal.

Anticonvulsant therapy should be considered for any patient with brain metastases who experiences a seizure. Prophylactic anticonvulsant agents are not recommended.

  • Therapeutic management of brain metastases can include surgery, whole brain radiation, sterotactic radiosurgery, and chemotherapy. Decisions on treatment depend on prognostic factors such as age, performance status, number of brain metastases, tumor type, and systemic tumor activity.

Patients with a single lesion have been shown in randomized trials to have a survival benefit with neurosurgical resection and whole brain radiation therapy versus radiation therapy alone. In those with a good performance status and reasonably well-controlled or absent systemic disease, neurosurgical consultation should be offered. Likewise, patients with a bulky mass causing obstructive hydrocephalus benefit from a neurosurgical opinion, as debulking can give rapid palliation in appropriate patients. In patients with multiple metastases, surgery may be considered in patients with a symptomatic or life-threatening lesion and/or those who may need tissue diagnosis before proceeding with therapy.

In those with a limited number of brain metastases, radiosurgery with or without whole brain radiation should be considered. The definition of “limited” is somewhat subjective, but usually means somewhere under ten metastases. This is also tempered by the fact that screening brain MRIs are typically 3-5 mm slice intervals and when double dose gadolinium screening is performed and 1mm slice intervals are obtained, there is a high rate of detection of previously occult lesions. In other words, patients who have ten metastases within the brain on a head CT are not likely to be good candidates for stereotactic radiotherapy.

Whole brain radiation therapy has been the mainstay of multiple intracranial metastatic lesions. As it is associated with some neurocognitive impact, ways of avoiding whole brain radiation therapy are being investigated. For patients with limited metastases to the brain, there is accumulating evidence that whole brain radiotherapy may be safely avoided with the appropriate close subsequent imaging, as randomized trials have failed to show an overall survival benefit.

Such patients are treated with stereotactic radiation therapy, which gives large, usually single dose treatments (“fractions” in the radiotherapy vernacular), that precisely target only the visualized lesion. Patients with more than three lesions are somewhat more controversial and some institutions are using stereotactic radiation in a more aggressive fashion.

The radiation oncologist should have a detailed discussion with the patient and family regarding pros (avoiding neurocognitive side effects, hair loss, risk of somnolence syndrome, less of a break in chemotherapy) and cons (risk of radionecrosis, potentially leaving micrometastatic disease untreated and a higher rate of “elsewhere” failure) of avoiding whole brain radiotherapy according to the individual patient’s risk tolerance.

Brain metastases, although sometimes a neurosurgical emergency, are rarely a radiotherapeutic emergency. Emergent radiation (often after hours) typically means that the standard physics review, quality assurance checks and computerized dose distributions are not performed prior to initiation of therapy. As such, it should be avoided to preserve patient safety.

Radiotherapy can cause transient increased edema in the first 48-72 hours, and in patients with significant edema or imaging or symptoms of increased intracranial pressure, 24 hours of premedication with steroids is advocated.

Patients who refuse biopsy in the absence of a known cancer are not appropriate for empiric radiotherapy. In contrast, a patient with a malignancy known for intracranial spread (e.g., small cell lung cancer, advanced melanoma) and the appropriate clinical and radiographic scenario does not usually require tissue confirmation.

Chemotherapy may play a role in the treatment of brain metastases. While chemotherapy agents are often thought to not penetrate the blood-brain barrier, some studies show intracranial response to chemotherapy agents. The utility of chemotherapy agents for brain metastases depends on the primary tumor type.

In summary, the management of brain metastases is often complicated and patients should have thorough multidisciplinary evaluation by oncology, radiation oncology and sometimes neurosurgery, to determine the most appropriate treatment.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

Patients without a demonstrable primary malignancy site should be strongly considered for tissue confirmation. Administration of brain radiotherapy to a patient with infectious causes delays diagnosis of the infection and intracranial abscess has considerable mortality.

Anticonvulsants are well known to impact neurocognition negatively. They should not be given prophylactically.

Patients without a histologic diagnosis of cancer despite radiographic evidence of a malignancy should undergo tissue confirmation of malignancy prior to beginning radiotherapy whenever feasible. Most pathologists are able to provide a verbal confirmation of malignancy as soon as slides are made.

Side effects of whole brain radiation therapy should be distinguished from those resulting from more localized radiation approaches (stereotactic radiosurgery).

The most dreaded complication of whole brain radiotherapy is cognitive decline related to brain atrophy and leukoencephalopathy. True radiation-induced dementia consists of the triad of dementia, ataxia and urinary incontinence. The most quoted, but strongly misleading, study gives a rate of 11% for radiation-induced dementia; however, this study included patients getting twice the daily dose that is usually admitted per day (5-6 Gy versus the standard 2.5-3 Gy per day) and also concurrent Adriamycin.

No patients treated in the standard fashion of modern radiotherapy within this study developed this complication with the classic triad and debilitating dementia. The degree of this complication is related to the age of the patient at administration (age less than 3 being more profound), fraction size (larger being associated with more significant late effects) and presence of concurrent chemotherapy (no longer routinely done, except for some primary brain tumors that have been shown to be safe).

Modern series studying this prospectively established that whole brain radiation produces learning and memory deficits at 4 months (52% versus 24%). However, in our clinical experience, patients are still functional albeit somewhat more reliant on accessory memory aids (notes to self, calculators for higher math). There is active clinical investigation in the area of hippocampal sparing whole brain radiation, with the idea that the hippocampus is a source of neural progenitor cells and sparing this area may reduce neurocognitive sequelae.

Stereotactic radiation (given under various brand names of machines used to deliver it – GammaKnife, CyberKnife, Brain Lab, Novalis Perfexion, Varian Trilogy) has excellent local control rates for the lesions treated. The predominant risk is radionecrosis, which increases with lesion size. Lesions above 3-4 cm in size are at greater risk for radionecrosis and due to this, the dose of radiation that can be safely administered is reduced. This keeps the risk of radionecrosis at approximately 3-5% in most series.

IV. Prognosis

In general, brain metastases are associated with poor prognosis. Despite major advances in oncologic diagnosis and treatment, the survival time for patients treated with radiation therapy still remains at 3-6 months. Overall survival is often determined by extent and activity of the primary tumor. Consideration towards discussions of goals of care should be initiated upon diagnosis of brain metastases.

Poor prognosis patients should be steered towards hospice care alone. Survival is worse in those with poor performance status, extensive extracranial disease and aged more than 65. Those with a Karnofsky performance status less than 70 (e.g., unable to perform activities of daily living alone) have the worst prognosis (slightly over 2 months) and as such are unlikely to gain benefit from radiotherapy.

Steroid therapy alone confers a survival of 1-2 months, whereas whole brain radiotherapy lengthens lifespan to 4 months. Survival is also dictated by the primary tumor, with the best survival observed in breast cancer patients (6-22 months median, depending on treatment) and the worst survival in metastatic gastrointestinal tumors (2-10 months median, depending on treatment).

V. What's the evidence?

Modi, M, Mochan, A, Modi, G. “Management of HIV-associated focal brain lesions in developing countries”. QJM. vol. 97. 2004 Jul. pp. 413-21.

Knisely, JP, Yamamoto, M, Gross, CP, Castrucci, WA, Jokura, H, Chiang, VL. “Radiosurgery alone for 5 or more brain metastases: expert opinion survey”. J Neurosurg. vol. 113. 2010 Dec. pp. 84-9.

Aoyama, H, Shirato, H, Tago, M, Nakagawa, K, Toyoda, T, Hatano, K. “Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial”. JAMA. vol. 295. 2006 Jun 7. pp. 2483-91.

Chang, EL, Wefel, JS, Hess, KR, Allen, PK, Lang, FF, Kornguth, DG. ““Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial.””. Lancet Oncol. vol. 10. 2009 Nov. pp. 1037-44.

Langer, CJ, Mehta, MP. ““Current management of brain metastases, with a focus on systemic options.””. J Clin Oncol. vol. 23. 2005 Sep 1. pp. 6207-19.

Sperduto, PW, Chao, ST, Sneed, PK, Luo, X, Suh, J, Roberge, D. ““Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients.””. Int J Radiat Oncol Biol Phys. vol. 77. 2010 Jul 1. pp. 655-61.

Reijneveld, JC, Sitskoorn, MM, Klein, M, Nuyen, J, Taphoorn, MJ. ““Cognitive status and quality of life in patients with suspected versus proven low-grade gliomas.””. Neurology. vol. 56. 2001 Mar 13. pp. 618-23.

Mikkelsen, T, Paleologos, NA, Robinson, PD, Ammirati, M, Andrews, DW, Asher, AL. ““The role of prophylactic anticonvulsants in the management of brain metastases: a systematic review and evidence-based clinical practice guideline.””. J Neurooncol. vol. 96. 2010 Jan. pp. 97-102.

Chang, EL, Wefel, JS, Hess, KR, Allen, PK, Lang, FF, Kornguth, DG, Arbuckle, RB, Swint, JM, Shiu, AS, Maor, MH, Meyers, CA. ““Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial.””. Lancet Oncol. vol. 10. 2009 Nov. pp. 1037-44.

Andrews, DW, Scott, CB, Sperduto, PW, Flanders, AE, Gaspar, LE, Schell, MC. ““Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial.””. Lancet. vol. 363. 2004 May 22. pp. 1665-72.

Eichler, A, Loeffler, J. “Multidisciplinary Management of Brain Metastases”. The Oncologist. vol. 12. 2007. pp. 884-898.