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Objectives

The following module was designed to supplement medical students' learning in the clinic. Please take the time to read through each module by clicking the headings below.

By the end of the module, the following objectives should be addressed:

  1. Understand the epidemiology of brain metastases and know the five cancers that most commonly metastasize to the brain
  2. Understand the presentation of brain metastases and features suggestive of an intracranial mass
  3. Understand what imaging modalities should be used in the investigation of brain metastases, and when a biopsy is indicated
  4. Recognize that symptomatic brain metastases warrant urgent treatment to improve symptoms and prevent neurological deterioration, particularly complications of increased intracranial pressure and brain herniation.
  5. Understand the initial management of symptomatic brain metastases
  6. Know the general therapeutic options for brain metastases
  7. Appreciate the patient, tumour and treatment factors that guide selection of therapy for brain metastases

Please also refer to the module on increased intracranial pressure and brain herniation (under construction) to learn about the presentation and emergency management of increased intracranial pressure and its sequelae in cancer.

Introduction

Brain metastases occur in between 10-30% of cancer patients, and are the most common intracranial tumours in adults. They can be asymptomatic or present with symptoms such as headaches, or sequelae such as seizures, altered mental status and increased intracranial pressure. Symptomatic brain metastases warrant urgent treatment to improve neurological deficits and quality of life and prevent further neurological deterioration, particularly sequelae of increased intracranial pressure, with brain herniation being the most serious.

In this module, we will discuss issues relating to brain metastases. The pathophysiology, clinical manifestations and emergency management of increased ICP and brain herniation in cancer patients is reviewed in more detail in our module on increased intracranial pressure and brain herniation (under construction).

Epidemiology

Incidence

Brain metastases affect between 10% and 30% of adult patients with cancer (1), and 6% to 10% of children (2). The 5-year cumulative incidence of brain metastasis in the cancers that most commonly metastasize to the brain is as follows (2):

  • 16-20% in lung cancer
  • 7-10% in renal cell carcinoma
  • 7% in melanoma
  • 5% in breast cancer
  • 1-2% in colorectal cancer

Causes

Cancers that commonly metastasize to brain in adults are usually carcinomas, including those of the lung, breast, kidney, and colorectal carcinoma, as well as melanoma (2). In children, sarcomas, neuroblastomas, germ cell tumours commonly metastasize to the brain (2). Carcinomas of esophagus, oropharynx and prostate, and non-melanoma skin cancers, rarely metastasize to the brain (2).

Pathophysiology

In order to metastasize, cancer cells must get into the circulation, survive circulation, and arrest in a capillary bed (3). Finally, once in a capillary bed in the brain, cancer cells must extravasate into the brain parenchyma and grow in order to form a metastasis (3). In some cases, cancer cells can lie dormant in the brain before growing into tumours years or decades after the primary cancer has been cured (3).

Distribution of Brain Metastases

The distribution of brain metastases is approximately 80% to the cerebral hemispheres, 15% to the cerebellum and 5% to the brainstem (e.g. 5, 6). The distribution of brain metastases to each part of the brain roughly correlates with the relative amount of blood supply it receives. Brain metastases most commonly occur in the vascular border zones between the regions supplied by the cerebral arteries and cerebellar arteries (62% of lesions in a 1995 study of 100 patients), and at the grey matter/white matter junction (64% of lesions), where the diameter of blood vessels abruptly decreases and tumour emboli are therefore more likely to be lodged (6).

Signs and Symptoms

The presentation of brain metastases is widely variable. It can be asymptomatic in one-third of patients, while two-thirds of patients with brain metastases experience neurologic symptoms from the metastases (1). Symptoms from brain metastases are usually secondary to the tumour mass and associated edema, but symptoms can less commonly be caused by intratumoral hemorrhage, obstructive hydrocephalus, or tumour embolism (2). Brain tumours can cause increased intracranial pressure leading to sequelae such as impaired cerebral perfusion and brain herniation (4). For more information, please see our module on increased intracranial pressure and brain herniation (under construction).

Brain metastases may present synchronously in up to one-third of patients, either as the presenting complaint leading to diagnosis of cancer, or within 1 month of the primary cancer diagnosis, or asynchronously later on in the course of disease (1).  It is possible that  fewer patients present symptomatically now with increasing use of brain imaging at time of diagnosis for staging (1).

The most common symptoms are listed as follows (1):

  • headache (25% to 50%)
  • focal weakness (15% to 40%) - most commonly hemiparesis (2)
  • altered mental status (25% to 30%)
  • seizures (15%)
  • ataxia (10% to 20%)
  • stroke (5% to 10%) (2) - due to hemorrhage into a metastasis, hypercoagulability, invasion or compression of an artery by tumour, or embolization of tumour cells (2). Melanoma, choriocarcinoma, thyroid and renal carcinomas have a particular propensity to bleed (2).

In a cancer patient complaining of headaches, an important feature that possibly suggests a brain metastasis is a change from the patient's previous headache pattern. Features that may suggest increased intracranial pressure (and possible brain metastases) can include nausea and vomiting and positional worsening of the headache. The classic "morning headache" is uncommon, but highly suggestive of increased intracranial pressure when present (2). It can be worse with bending over in 32% of patients, and may also be worse with coughing, sneezing or Valsalva manoeuvres (2).

Diagnostic Approach

Differential Diagnosis

The differential diagnosis of neurological symptoms in a cancer patient is broad. With respect to malignant causes this can include brain metastases, primary CNS tumours, paraneoplastic phenomena, and if they have received prior radiation to their brain, effects of treatment such as radiation necrosis (2). Benign causes can include infectious processes or cerebral infarction/bleeding (stroke) amongst others.

History

In a cancer patient in whom brain metastasis is suspected, the history should include exploration of the following:

History of the presenting illness
  • Neurological symptoms such as headache, focal neurological deficits, altered mental status, confusion
  • Any associated nausea, vomiting, bowel or bladder dysfunction
  • Presence of fever or chills (to rule out possible infections)
  • Recent trauma or falls (to rule out cerebral hemorrhage)
History of the cancer
  • Presenting complaints
  • Diagnosis, stage, other metastases
  • Treatments so far (e.g. past WBRT or SRS to brain -> increased risk of radiation necrosis)
Past medical history
  • Immunosuppression (for infectious processes) - HIV, immunosuppressive medications, etc.
  • History of stroke or other vascular disease
  • History of neurological disorders e.g. MS
  • Anticoagulation or head trauma (cerebral bleeding)

Physical

Physical examination should always begin with an assessment of the patient's airway, breathing, circulation and vital signs. Additionally, in the evaluation of brain metastases, one should perform a full physical examination, including a complete neurological examination for any focal neurological deficits, and examination of the fundi for papilloedema.

Certain physical findings may give clues as to the location of the tumour, but there may be no focal deficits, or signs may be falsely localizing (4). For example, impaired lateral gaze and diplopia may be a result of cranial nerve VI compression or displacement at the base of the brain (4).

  • Frontal lobe tumours may produce anosmia (4)
  • Temporal and occipital lobe tumours may produce visual field deficits (7), such as homonymous hemianopia in the setting of occipital lobe tumours (4)
  • Pineal tumours or metastases may produce impairment of upward gaze (4, 7)
  • Brainstem and cerebellar tumours may produce ataxia and incoordination, nystagmus, upper motor neuron signs, and sensory deficits or cranial nerve palsies (4)

While a complete discussion of the neurological exam is not provided here, it may be useful to review your knowledge of the neurological exam and the relevant neuroanatomy for your clinical practice.

Imaging

In a patient with suspected brain metastases, contrast-enhanced MRI the preferred imaging modality (2). Contrast-enhanced MRI is more sensitive than CT or non-enhanced MRI in detecting brain metastases and differentiating them from other CNS lesions (2), as well as for the number, distribution and size of lesions (1). Up to 20% of MRI-detected lesions are not seen on CT (8). Having said that, in many centers, a CT scan is still much easier to obtain. As such, it is reasonable to do a contrast CT scan as a preliminary step.

Imaging findings suggesting brain metastases include the following (2):

  • The presence of multiple lesions
  • Localization at the junction of the grey and white matter
  • Circumscribed margins
  • Large amounts of vasogenic edema compared with the size of the lesion

Other features include: hypointensity on T1 and hyperintensity on T2 (8), and marked ring-enhancement with gadolinium contrast (2, 8)

Biopsy

If the diagnosis remains in doubt with imaging, a biopsy should be obtained (1, 2).  For most patients the clinical history will help to determine the need for a biopsy.  For instance in a patient with disseminated metastases from an established malignancy (e.g. lung cancer) a biopsy may not be needed.  However for a patient with no other evidence of metastases or a very long disease free interval, a discussion with a neurosurgeon on the suitability for biopsy or resection may be useful.

Management

Symptomatic brain metastases warrant urgent treatment to improve symptoms and prevent further neurological deterioration. Though brain metastases are not emergencies themselves, they can result in sequelae requiring emergency medical treatment, such as seizures, altered mental status, stroke, intracranial hemorrhage, or increased intracranial pressure resulting in sequelae such as impaired cerebral perfusion and brain herniation. Increased intracranial pressure and emergency management of its sequelae are reviewed in the module on increased intracranial pressure and brain herniation (under construction).

Initial management

Initial management should focus on ensuring the stability of the patient's airway, breathing and circulation, followed by management of symptoms.

Corticosteroids are used to treat symptomatic edema from brain metastases (1). Dexamethasone is usually used for its low mineralocorticoid effect and long half-life (9). Corticosteroids are thought to reduce edema by reducing the permeability of abnormal tumour capillaries (1). Most guidelines recommend an initial dose of 4 to 8 mg/day in two divided doses, while higher doses (for example, 16 mg/day) should be used in patients with severe symptoms, significant mass effect, or those who do not respond within 48 hours (9). Patients often show improvement within hours of the first dose, with maximum effect after 3 to 7 days (1). Common short-term side effects of steroids include insomnia, increase in appetite, fluid retention, mood symptoms, acne, and exacerbation of diabetes (1). Chronic side effects include weight gain, steroid myopathy, immunosuppression, and aseptic necrosis of the femoral head (1).

Patients who present with or develop seizures should be treated with antiseizure medications (1, 9). Prophylactic antiseizure are generally not given in patients who have not experienced seizures (1, 9).

Venous thromboembolism treatment and prophylaxis

Patients with cancer are at an increased risk of venous thromboembolism (1). However, patients with brain metastases are also thought to be at a higher risk for intracranial hemorrhage if given anticoagulation (1). Recommendations vary, and the decision to give anticoagulation should be individualized for each patient (10).

Limited data suggests that it is safe to use anticoagulation in the setting of brain metastases in tumours that are less prone to hemorrhage (e.g. 1, Easaw article, ASCO guidelines), and that anticoagulation is safer and more effective than IVC filters in patients with brain metastases who had had venous thromboembolism (9). However, some sources recommend against routine prophylactic anticoagulation (10).

Some sources recommend avoiding anticoagulation in the setting of tumours with a propensity to bleed, such as melanoma, choriocarcinoma, thyroid carcinoma, and renal cell carcinoma (1, 10). However, some studies including patients with brain metastases from melanoma and renal cell carcinoma have not found a statistically significant increase in the risk of intracranial hemorrhage with anticoagulation (e.g. 11, 12).

Treatment of brain metastases

Treatment of brain metastases depends on a number of factors. In general, the options for brain metastases include whole-brain radiation therapy (WBRT), or focal therapy using surgery or stereotactic radiosurgery (SRS). For certain histologies, advances are also being made in the use of systemic therapies for brain metastases. In the management of any oncological condition, it is important to consider patient, tumour and treatment factors.

Patient factors

Prognosis and performance status

In planning treatment for brain metastases, it is useful to consider the performance status and the prognostic indices developed for brain metastasis (see Prognosis). In patients with a poor prognosis or performance status, aggressive surgery is generally not pursued. Whole-brain radiation therapy is usually used, but stereotactic radiosurgery may also be considered (13).

Quality of life

It is important to consider the impact of each possible course of management on the patient's quality of life, from both disease and treatment.

Patient preference

Similarly, it is also important to consider the patient's preference in weighing the various treatment options. The clinician and patient should work together to decide on a treatment plan.

Tumour factors

Extent of disease (both intra- and extracranial), and resectability of tumour

  • For a single metastasis with a large tumour or significant mass effect and edema, surgery provides rapid symptom relief, and in carefully selected patients, has been shown to improve survival over radiation alone (13).
  • For small tumours that are not surgically accessible, with diameter less than 3 cm, stereotactic radiosurgery may be considered, rather than surgery or whole-brain radiation therapy (13).
  • For multiple large tumours or a high tumour burden, whole-brain radiation therapy  is the mainstay of therapy, but surgery may also be considered for removing a large, dominant mass prior to radiation therapy (13).

Type of cancer

  • Certain primary tumours such as breast and lung cancer, particularly small cell lung cancer, are more sensitive to radiation therapy than others (9). Importantly, however, the radiosensitivity of the tumours does not appear to influence the efficacy of stereotactic radiosurgery (13).
  • Brain metastases from certain highly chemotherapy-sensitive primary tumours may benefit from chemotherapy (9). Additionally, for certain histologies, advances are being made in systemic therapies for brain metastases (e.g. melanoma, breast cancer, and NSCLC with ALK fusion oncogenes or activating EGFR mutations) (13).

Symptoms associated with tumour

In some cases, asymptomatic brain metastases may not require treatment. For example, in a patient with poor prognosis or poor performance status who had brain metastases not amenable to surgery or SRS, the goal of offering radiation therapy would be for symptom relief. As such, no treatment may be offered or only possibly when symptoms develop.

Treatment factors

Whole brain radiation therapy (WBRT)

Whole brain radiation therapy (WBRT) is frequently used in the setting of multiple brain metastases, and improves neurological symptoms and survival (9). WBRT can also be considered in the setting of large brain metastases not amenable to stereotactic radiosurgery, in recurrent brain metastases, or patients with poor performance status (9). The recommended dose of WBRT is 20 Gy in 5 fractions, or 30 Gy in 10 fractions of 3 Gy per day (9).

Efficacy of WBRT

The response rates are variable and depend on the primary malignancy amongst other factors. The response rate to WBRT is 40-60%, while the rate of neurologic improvement or preservation is about 25-40% (13).

Acute adverse effects of WBRT

WBRT may cause worsening of cerebral edema initially (13). In patients with large tumours and evidence of mass effect, corticosteroids should be given 48 hours prior to and over the course of radiation, and slowly tapered down (13). Other short-term adverse effects include loss of hair, a mild skin reaction on the scalp, and fatigue, which usually improve after weeks to months (1). Some patients may experience ototoxicity, and occasionally patients may need myringotomy to relieve pressure from radiation-induced fluid buildup behind the tympanic membrane (1).

Delayed adverse effects of WBRT

Long-term adverse effects from WBRT include the following (1, 13):

  • White matter changes, neurocognitive decline and dementia
  • Ataxia and urinary dysfunction from normal pressure hydrocephalus
  • Neuroendocrine dysfunction, most commonly hypothyroidism
  • Radiation necrosis
  • Cerebrovascular disease

These adverse effects may be dependent on the dose and fractionation scheme used, and modern fractionation schemes are lower-risk (1). The risk of these complications is also related to the patient's age, extent of disease, and their degree of neurological impairment at presentation (13). Investigations of neuroprotective strategies such as hippocampal-avoidance radiation and the use of other neuroprotective agents are ongoing (9, 13)

Stereotactic radiosurgery (SRS):

Stereotactic radiosurgery can be very helpful for the treatment of a limited number of small tumours that are not surgically accessible (9, 13). The risk of neurotoxicity and local failure increase with larger lesions, and therefore SRS should generally be limited to lesions of 3 cm in diameter or less (13).

Efficacy of SRS

In suitable patients with tumours up to 3 cm in diameter, SRS provides a local control rate of 70% at 1 year, which is improved to 90% with WBRT. Its efficacy is similar with both radiosensitive and radioresistant tumour types. (13)

Acute complications of SRS

Neurological symptoms can occur, and may be a consequence of transient edema. Patients may experience mild nausea, dizziness, vertigo, or a new headache. The risk of SRS-related toxicity can be reduced using corticosteroids (13).

Delayed complications of SRS

Radiation necrosis may occur in up to 10% of patients, from 6 months to several years after treatment (13). The risk of radiation necrosis is increased in patients who have previously received SRS or WBRT, or those with a large tumour size. Radiation necrosis may be asymptomatic, or may present with neurologic signs and symptoms from cerebral edema (13). Management of radiation necrosis is largely symptomatic using corticosteroids to reduce edema and improve neurological function, but some patients may require surgical resection of the necrosis (13, 9). Bevacizumab has also been investigated for the management of radiation necrosis (13, 9).

Recurrence after SRS

Recurrence rates are very variable. In some series with SRS alone, the recurrence rate is approximately 25-50% within 6-12 months. Risk factors for this include progressive or widespread systemic disease, large number of brain metastases, and certain tumour histologies and subtypes (triple negative breast cancer, melanoma). (13)

Role of adjunctive WBRT

Studies comparing SRS alone to SRS with WBRT have shown that while WBRT decreases the rate of both local and distant recurrence of brain metastases, there is no improvement in overall survival (9, 13). In light of the lack of survival benefit, risk of radiation necrosis and potential concerns raised by some studies about impairment in cognition with the addition of WBRT, the decision to use adjunctive WBRT should be individualized (9, 13).

Surgery

Surgery allows rapid reduction of mass effect, and allows pathological analysis when the diagnosis is uncertain. It should be considered in the setting of a single brain metastasis, especially when associated with extensive cerebral edema (9).

Efficacy of surgery

Of three randomized trials in the 1990s of surgery plus WBRT versus WBRT alone in the setting of single brain metastases, two trials showed improved outcomes with surgery (improved survival of 40 weeks vs. 15 weeks in one trial, and 10 months vs. 6 months in another) (9, 13). This improvement in survival appeared to be most pronounced in patients without active extracranial disease, or those with stable extracranial disease (13). Although a third trial did not show increased survival, this is attributed to the worse performance status and a higher proportion of patients with extracranial disease in this cohort (13), and 22% of patients in the WBRT-alone group went on to have surgery for recurrence (9). Therefore, surgery is generally regarded as an effective treatment for single brain metastases that may improve survival and outcomes (9).

Risks and complications of surgery

Risks associated with surgery include worsening of neurologic function postoperatively, infection, intracranial hemorrhage, and stroke. One-month neurologic outcomes are either stable or improved in approximately 90 percent of patients. The risk of permanent paresis is estimated to be about 8 to 9 percent. One study showed increased risk for post-operative weakness with preoperative chemotherapy or radiation therapy, or with RPA class III (i.e. Karnofsky performance score < 70) (see Prognosis).

Recurrence after surgery

Recurrence is very variable and depends on the type of tumour, response to other therapies (chemotherapy) and patient factors. In some series, with surgery alone, the recurrence rate is approximately 50% within 6-12 months (13).

Role of post-operative radiation

Recent evidence suggests that while post-operative WBRT reduces the risk of local and distant recurrence, it confers no survival benefit (9, 13). Given this and the risk of side effects associated with WBRT, some authors suggest focal radiation of the surgical site with close radiologic follow-up instead (13). Investigations into post-operative SRS following surgery have yielded favourable results, with a 2013 systematic review showing overall survival of 14 months and 1-year local control of 85%, comparable to post-operative WBRT (9, 14). Distant recurrence occurred in 49% of patients, with 29% requiring WBRT (14). The decision for post-operative WBRT should be made by the radiation oncologist and surgeon on a patient-by-patient basis.

Systemic therapy:

There is an evolving role for systemic therapy in the management of brain metastases, depending on the primary tumour and its sensitivity to chemotherapy. Particularly, brain metastases from highly chemotherapy-sensitive primary tumours such as germ cell tumours and in some instances small cell lung cancer may be initially treated with chemotherapy (9). Systemic therapy may also be used for asymptomatic brain metastases with monitoring of the response if systemic therapy is planned for extracranial disease (9). Additionally, advances have been made with targeted agents for certain specific histologies, including melanoma, breast cancer, and non-small cell lung cancer with activating EGFR mutations or ALK fusion oncogenes (13). Finally, systemic therapy may be considered when other therapeutic options have been exhausted and a reasonable systemic agent is available (9).

Summary of treatment of brain metastases

The treatment options for brain metastases and the various patient, tumour and treatment factors that guide their selection are summarized below.

Table 1. Summary of treatment of brain metastases.

Follow-up

Patients treated for brain metastases should undergo surveillance using MRI or CT in order to detect recurrence early, particularly if they did not receive WBRT and are well enough to tolerate additional treatments (13).

Prognosis

While survival is variable, depending on the primary tumour, untreated across all malignancies, median survival in the setting of brain metastases is 1-2 months (13). This is improved with treatment - randomized trials of WBRT for brain metastases from NSCLC and breast cancer showed median survival of 4-6 months (13), and this is increasing all the time with improved systemic treatments.

Adverse prognostic factors in the setting of brain metastases include increasing age, poor performance status (such as poor overall health or a fixed neurological deficit), squamous histology, multiple metastases, or large metastasis (8). Favourable prognostic factors include adenocarcinoma or germ cell histology, a single metastasis or small metastases, and the resectability of the tumour (8).

A number of prognostic indices have been developed to guide management of patients with brain metastases. These indices generally incorporate some measure of performance status (usually the Karnofsky performance score [KPS] - see table below), the presence of extracranial metastases, and other factors such as age or whether the primary tumour has been controlled (15).

One prognostic index that is widely used is the recursive partitioning analysis (RPA), which was published by the Radiation Therapy Oncology Group in 1997 and divides patients into three prognostic classes (13):

Table 2. Recursive partitioning analysis.

In light of the fact that survival following treatment for brain metastases varies depending on the primary tumour, the diagnosis-specific graded prognostic assessment (DS-GPA) was created as another prognostic index (13, 16). The DS-GPA gives a score of 0 to 4 based on certain factors, with a different scoring system for each of lung cancer (SCLC and NSCLC), melanoma, renal cell carcinoma, breast cancer, and gastrointestinal cancer, based on these factors (13, 16):

  • Lung cancer: age, Karnofsky performance score, presence of extracranial metastases, and number of brain metastases
  • Melanoma and renal cell carcinoma: Karnofsky performance score and number of brain metastases
  • Breast cancer: Karnofsky performance score, subtype (based upon estrogen receptor/progesterone receptor, HER2 status), and age
  • Gastrointestinal cancers: Karnofsky performance score
Table 3. Karnofsky performance score.

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References

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