Considerations in the Diagnosis and Management of Brain Metastases

Considerations in the Diagnosis and Management of Brain Metastases

ABSTRACT: Brain metastases are a common complication of systemic cancer and a significant cause of morbidity. For patients whose brain metastases remain untreated, the prognosis is poor. The advent of contrast-enhanced magnetic resonance imaging has made accurate diagnosis of brain metastases among symptomatic patients a much more manageable task. However, approximately one-third of patients with intracranial metastases are asymptomatic, and therefore, greater awareness of the risk factors for developing brain metastases may permit better targeting of "at risk" patients for further evaluation. Advances in technology and surgical techniques have created more options for the management of brain metastases via the use of various combinations of surgery, irradiation, and stereotactic radiosurgery. However, successful application of these therapies has redefined the potential for long-term morbidity associated with radiation therapy. Thus, considerable effort is now being directed toward finding a balance between the use of whole-brain radiotherapy, surgery, and radiosurgery, and tailoring those treatment modalities to the unique needs of the patient. Although more prospective, randomized studies are needed before an informed consensus regarding the optimal means for managing brain metastases can be established, this article provides an overview of some of the advantages and disadvantages of therapeutic approaches recently under study. [ONCOLOGY 15:1144-1165, 2001]

A common complication of systemic cancer is the development of brain metastases—the predominant type of intracranial neoplasm found
in adults. Brain metastases are a significant cause of morbidity, typically due
to some combination of peritumoral edema, the effect of the tumor mass itself,
or the presence of an obstructive hydrocephalus. Any of these conditions can
cause an increase in intracranial pressure. Brain lesions may also directly
compress adjacent neurons, resulting in focal irritation or neuron
destruction.[1] Not surprisingly, they are an important contributing factor to
patient mortality.[1-4] While statistical projections have put the number of
patient deaths due to brain and other central nervous system neoplasms at
approximately 2.4% (13,300 of 564,800) of all cancer deaths,[5] the actual
number is likely to be higher because the death of patients with intracranial
metastases is often attributed to underlying systemic disease.[1,2,6-8]

The incidence of brain metastases appears to be increasing,[1,6] possibly as
a result of earlier and more accurate methods of detection. Other factors that
may contribute to this increase are the success of aggressive treatment
modalities that prolong survival, the increasing incidence of primary cancers
with a propensity to metastasize to the brain (eg, lung and breast cancer), and
the overall aging of the population.[1,8-10]

In 1998, it was projected that more than 1.2 million patients in the United
States would be newly diagnosed with cancer.[5] Based on projections regarding
the frequency of brain metastases stemming from various types of cancer, and
using the high end of the projected ranges—48%, 32%, and 21% for patients with
skin, lung, and breast cancer, respectively—we calculated that the yearly
incidence of new brain metastases would reach more than 107,000 cases in

The prognosis for untreated brain metastases is poor, with median survival
projected to be 2 months or less.[3,11] While techniques for confirming
diagnoses have improved substantially in the past decade or so, a review of the
literature suggests that up to one-third of patients are asymptomatic, and
consequently many of these metastases go undetected. Autopsy studies show that
24% to 31% of patients with cancer develop intracranial metastases,[9,12-14] and
the results of several studies suggest that substantially higher percentages of
patients have been diagnosed with intracranial metastases postmortem than during
their lifetime. Hirsch et al reported that 21% of patients were clinically
diagnosed based on signs and symptoms vs 50% at autopsy,[15] and Amer et al
reported that 46% were diagnosed clinically vs 75% at autopsy.[16] Although
clinical disease progression is expected to continue up to the time of death,
making the development of more tumors likely, these findings still serve to
underscore the challenge of diagnosing asymptomatic patients.

Once brain metastases have been successfully diagnosed, there are numerous
treatment options to be considered, depending on the patient’s profile and
underlying disease. Recent advances in technology and therapeutic techniques
have expanded the possibilities for the management of brain metastases through
the use of chemotherapy, radiation, surgery, and stereotactic radiosurgery,
either alone or in combination.

This review addresses the array of considerations the clinician must weigh in
the diagnosis and treatment of patients presenting with brain metastases.
Emphasis is placed on the need to identify asymptomatic patients at greatest
risk for developing brain metastases. In addition, an overview is provided of
the advantages and disadvantages of the primary treatment options, with a focus
on some of the current, prospective therapeutic approaches and the indications
for their use.

Clinical Presentation

Presenting Signs and Symptoms

For cancer patients, the signs and symptoms of neurologic dysfunction are
usually the initial indication that underlying disease has metastasized to the
brain. Metastases are believed to be primarily disseminated hematogenously,
particularly through the arteries.[1,17,18] Typically, tumoral microemboli are
distributed in proportion to the relative blood flow to each area of the
brain.[18-20] Consequently, 80% to 85% of metastatic tumors are located in the
cerebral hemispheres, 10% to 15% in the cerebellum, and 3% to 5% in the brain

The clinical manifestations of intracranial lesions are generally dictated by
the location of the metastases. Increased intracranial pressure and mental
changes are symptomatic of a frontal metastatic lesion, visual field defects and
cortical blindness are indicative of an occipital metastasis, motor weakness
suggests a frontoparietal lesion, and a cerebellar metastasis may manifest
itself as ataxia or symptoms related to hydrocephalus.[23]

Most neurologic symptoms can be ascribed to increased intracranial pressure
(headache, nausea, vomiting, confusion, and lethargy), focal irritation, or
destruction of adjacent brain tissue (aphasia, ataxia, visual field defects,
hemiparesis, and focal seizures).[1,22,24] A review of six representative
studies of patients with brain metastases secondary to a cross section of cancer
types showed that the most common presenting symptoms were headache, focal
weakness, mental and behavioral disturbances, seizure, ataxia, aphasia, visual
field defect, and sensory change.[1]

Headache is the predominant presenting symptom, reported by approximately 50%
of all patients with a single intracranial metastasis (40% reporting early
morning headaches) and by a larger percentage of patients with multiple
metastases.[17] Hemorrhage is also a serious complication, especially with
metastases secondary to malignant melanoma, choriocarcinoma, and gestational and
testicular cancers.[19] Patients have been reported to present with acute
symptoms of stroke secondary to bleeding into a metastatic lesion, embolization
of tumor cells, or tumor invasion or compression of an adjacent artery.[9,20]

Leptomeningeal Metastases—Leptomeningeal metastases are a somewhat
unique subset of brain metastases. Between 30% and 50% of leptomeningeal
metastases are secondary to leukemia, and 8% to 15% are secondary to solid
tumors, primarily melanoma, lung cancer, and breast cancer. As with other brain
metastases, leptomeningeal metastases typically develop following hematogenous
dissemination involving the superficial arachnoid veins, but they may also
result from the extension of intracranial metastases into the subarachnoid space
or the ventricles. The primary symptoms of leptomeningeal metastases include
headache, back pain, nausea/vomiting, paresthesias, and diplopia.[19]

Cancers Associated With Brain Metastases—The three types of cancers with
the greatest predisposition for brain metastases are lung cancer (particularly
adenocarcinoma and small-cell cancers), breast cancer, and melanoma.[1] Lung
cancer is the leading cause of cancer death among men and women in the United
States and is the primary site of cancer for 24% to 60% of all patients with
metastases.[3,11,14,25-30] Breast cancer, the second most common cause of cancer
death among US women and the leading cause of death for US women aged 15 to
54,[5] may be the site of primary disease for 10% to 30% of all brain metastases among

Melanoma is particularly prone to the formation of brain metastases and may
account for between 5% and 21% of all patients with brain
metastases.[3,11,25,26,31] Table 1 summarizes the most frequently reported
symptoms of brain metastases from representative studies in patients with
melanoma, lung cancer, and breast cancer.[13,15,16,32-35] The most commonly
reported adverse events for this subset of patients are headache, cognitive
dysfunction, seizure, motor symptoms, cranial nerve paralysis, cerebellar
symptoms, and aphasia.

Treatment Considerations

Corticosteroids, notably dexamethasone and methylprednisolone, and
anticonvulsants have become standard treatment for the control of peritumoral
edema and seizures, respectively.[1,20,21,36] In particular, corticosteroids
provide effective palliative therapy for acute symptoms of brain metastases, but
they should only be used for symptomatic lesions. Patients should receive the
lowest possible effective doses of corticosteroids and anticonvulsants to
minimize toxicity, particularly corticosteroids, due to the severity and
frequency of associated adverse events such as Cushing’s disease,
hypertension, hyperglycemia, and peripheral myopathies.[1,20] Notably, response
to acute corticosteroid therapy should be monitored carefully, because it is a
useful indicator of a patient’s potential for neurologic recovery following
surgical treatment of brain metastases.[37]

Good clinical practice dictates that any patient known to have cancer and
presenting with one or more neurologic symptoms should be further evaluated for
the presence of brain metastases. However, only about two-thirds of patients
with brain metastases are thought to be symptomatic. The majority of patients
with no history of cancer and a single brain lesion are symptomatic[21]; thus,
most asymptomatic patients are likely to have underlying disease. Many of the
newer antineoplastic agents approved for the treatment of melanoma, lung cancer,
and breast neoplasms have much better safety profiles and show less
neurotoxicity than some of their older counterparts, yet they are still
associated with adverse events that could mask common signs and symptoms of
brain metastases (Table 2).

For example, paclitaxel (Taxol) is associated with mild-to-moderate
dysfunction of the peripheral nervous system in most patients treated on a
weekly basis (severe reactions are reported for patients taking doses over
100 mg/m²). Symptoms of neuropathy usually begin 1 to 3 days after
treatment and may last for 3 to 6 months.[38] Although routine diagnostic
evaluation of all asymptomatic patients may not be feasible, magnetic resonance
imaging (MRI) is being ordered more liberally for patients at risk of developing
brain metastases. This at-risk group should include "asymptomatic"
patients with primary melanoma, breast cancer, or lung cancer who are currently
receiving or have recently been treated with chemotherapeutic agents that may
mask the clinical signs and symptoms of brain metastases.

Constrast-Enhanced MRI—Once intracranial metastases are suspected,
contrast-enhanced MRI is the best tool for determining whether a brain or leptomeningeal metastasis is
present.[24] Compared with computed tomography (CT) and other radiographic
techniques, contrast-enhanced MRI is associated with superior sensitivity and
specificity in determining the presence of brain metastases and their location
and number.[19,21,24] When used with T2-weighted spin-echo sequences, MRI is
better equipped to detect even slight edema and to image regions of the brain
such as the brain stem, temporal lobe, and cerebellum (which CT scans are unable
to depict clearly).[24]

At present, single-dose gadolinium (gadolinium diethylenetriamine pentaacetic
acid) is the most commonly used contrast agent,[1] although new agents (eg,
gadolinium texaphyrin) and new techniques (eg, pulse sequence software, coil
design, and postprocessing capabilities) are under investigation.[39] Despite
the tremendous advantages of contrast-enhanced MRI, biopsy remains the most
definitive test for differentiating brain metastases from cerebral abscess or a
primary brain tumor.[1] It should also be noted that whereas contrast-enhanced
MRI has great sensitivity, it does not have comparably high specificity in
diagnosing leptomeningeal metastases. Consequently, definitive diagnosis of
leptomeningeal metastases requires careful examination of the cerebrospinal
fluid, collected ideally from one or more lumbar punctures.[19]


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