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Management of Brain Metastases

Management of Brain Metastases

ABSTRACT: Brain metastases are the most common type of brain tumor in adults and are an increasingly important cause of morbidity and mortality in cancer patients. In recent years, important advances have been made in the diagnosis and management of brain metastases. These advances include the widespread use of magnetic resonance imaging (MRI), enabling small metastases to be detected; the introduction of stereotactic radiosurgery; and the performance of studies that have clarified the role of surgery and postoperative radiation therapy for single brain metastases. As a result, most patients receive effective palliation, and the majority do not die from their brain metastases. However, further studies are needed to define the optimal role of conventional treatments and to develop more effective novel therapies. [ONCOLOGY 13(7):941-961, 1999]

Introduction

Brain metastases are a common complication in
cancer patients and an important cause of morbidity and mortality.
They develop in approximately 10% to 30% of adults and 6% to 10% of
children with cancer.[1-6] Each year in the United States, an
estimated 97,800 to 170,000 new cases of brain metastasis are
diagnosed.[1,2,6] This number may be increasing as a result of the
increased ability of magnetic resonance imaging (MRI) to detect small
metastases and improvements in systemic therapy, leading to longer
patient survival.[1,6-9]

In adults, the primary tumors most often responsible for brain
metastases are lung cancer (50%), breast cancer (15% to 20%), unknown
primary tumor (10% to 15%), melanoma (10%), and colon cancer
(5%).[1-3,10] In children, the most common sources of brain
metastases are sarcomas, neuroblastoma, and germ cell tumors.[1,4,11]

Studies using MRI suggest that the proportion of single metastases is
lower than was previously believed, accounting for only one-third to
one-fourth of patients with cerebral metastases.[7,12] Metastases
from breast, colon, and renal cell carcinomas are often single, while
melanoma and lung cancer have a greater tendency to produce multiple metastases.[1,13]

Method of Spread and Distribution

The most common mechanism of metastasis to the brain is by
hematogenous spread.[1] These metastases are usually located directly
beneath the junction of the gray and white matter.[13] Brain
metastases tend to occur at this site because the blood vessels
decrease in size at this point and act as a trap for clumps of tumor
cells. Brain metastases also tend to be more common at the terminal
“watershed areas” of arterial circulation.[1,13]

The distribution of brain metastases roughly follows the relative
weight of (and blood flow to) each area. Approximately 80% of brain
metastases are located in the cerebral hemispheres, 15% in the
cerebellum, and 5% in the brainstem.[13] For unclear reasons, pelvic
(prostate and uterus) and gastrointestinal tumors have a predilection
to metastasize to the posterior fossa.[13]

Clinical Manifestations

It is estimated that more than two-thirds of patients with cerebral
metastases experience neurologic symptoms during the course of their
illness.[7] The clinical features of brain metastases are extremely
variable, and the presence of brain metastases should be suspected in
any cancer patient who develops new neurologic symptoms.

The majority of patients with brain metastases present with
progressive neurologic dysfunction resulting from a gradually
expanding tumor mass and the associated edema, or, rarely, from the
development of obstructive hydrocephalus. Approximately 10% to 20% of
patients present acutely with seizures, while another 5% to 10%
present acutely as a result of strokes caused by embolization of
tumor cells, invasion or compression of an artery by tumor, or
hemorrhage into a metastasis.[8,14,15] Melanoma, choriocarcinoma, and
thyroid and renal carcinomas have a particular propensity to bleed.[8]

The clinical presentation of brain metastases is similar to that of
other brain tumors and includes headaches, focal neurologic
dysfunction, cognitive dysfunction, and seizures. Headaches occur in
approximately 40% to 50% of patients with brain metastases. These are
usually dull, nonthrobbing, and often indistinguishable from tension
headaches.[16] The headaches are usually on the same side as the
tumor, although they can be diffuse. Headaches characteristic of
increased intracranial pressure, such as early morning headaches, or
headaches exacerbated by coughing, bending, and straining, are
present in less than half of patients with brain metastases. The
headaches may be associated with nausea, vomiting, and transient
visual obscurations. Patients with multiple metastases and posterior
fossa metastases have a higher frequency of headaches.[1]
(Papilledema is observed in fewer than 10% of patients at the time of presentation.)

Focal neurologic dysfunction is the presenting symptom in 20% to 40%
of patients. Hemiparesis is the most common complaint, but the
precise symptom varies depending on the location of the
metastases.[1] Cognitive dysfunction, including memory problems and
mood or personality changes, are the presenting symptoms in one-third
of patients, while seizures are the presenting symptom in another 10%
to 20%.[17-20]

Diagnosis

Brain metastases must be distinguished from primary brain tumors,
abscesses, demyelination, cerebral infarctions or hemorrhages,
progressive multifocal leukoencephalopathy, and the effects of
treatment, including radiation necrosis. In a study by Patchell et
al, 11% of patients who were initially felt to have a single brain
metastasis eventually were found to have a different diagnosis after
the lesion was biopsied.[21] Half of the nonmetastatic lesions were
primary brain tumors, while the other half were infections. The
false-positive rate for diagnosis of multiple metastases undoubtedly
is significantly lower than the 11% rate for single metastases.
Nonetheless, in any patient in whom the diagnosis of brain metastases
is in doubt, a biopsy should be performed since this is the only
reliable method of establishing the diagnosis.

Breast cancer patients with a single dural-based lesion pose a
particular diagnostic dilemma. Since the incidence of meningiomas is
increased in patients with breast cancer, it is important to
differentiate a dural-based metastasis from a meningioma.[22,23]
Frequently, imaging studies are inconclusive, and a biopsy or
surgical resection of the lesion is needed.

In addition to diagnosing brain metastases, it is also important to
differentiate patients with a single or solitary metastasis from
those with multiple brain metastases since their subsequent treatment
differs. The term “single brain metastasis” refers to a
single cerebral lesion, with no implication made regarding the extent
of extracranial disease. “Solitary brain metastasis”
describes the relatively rare occurrence of a single brain metastasis
that is the only known site of metastatic cancer in the body.[1]

Although computed tomographic (CT) scans detect the majority of brain
metastases, the best diagnostic test for brain metastases is
contrast-enhanced MRI. [12,24,25] This test is more sensitive than
enhanced CT scanning or nonenhanced MRI in detecting lesions in
patients suspected of having cerebral metastases, and in
differentiating these metastases from other central nervous system
(CNS) lesions.[ 24,25] Radiographic features that help differentiate
brain metastases from other CNS lesions include the presence of
multiple lesions (which helps distinguish metastases from gliomas or
other primary tumors), localization of the lesion at the gray-white
matter junction, more circumscribed margins, and relatively large
amounts of vasogenic edema compared to the size of the lesion.[7]

In the majority (80%) of patients, brain metastases develop after the
diagnosis of systemic cancer (metachronous presentation).[1,2]
However, in some patients, brain metastases may be diagnosed before
the primary tumor is found (precocious presentation) or at the same
time as the primary is detected (synchronous presentation).

For patients who present with brain metastases without a known
primary tumor, the lung should be the focus of the evaluation. Over
60% of these patients will have a lung primary or pulmonary
metastases from a primary tumor located elsewhere.[1,26,27] If the
chest radiograph is nondiagnostic, a chest CT scan should be
performed, as this significantly increases the likelihood of
detecting a lung tumor.[26] These patients also should have a CT scan
of the abdomen and pelvis and a bone scan to determine the extent of
metastatic disease. Breast cancer is an uncommon cause of brain
metastases without a known primary tumor, possibly due to its earlier
detection on physical examination, and its tendency to produce brain
metastases in the setting of widely disseminated disease. [27]

Management Goals

The management of patients with brain metastases can be divided into
symptomatic and definitive therapy. Symptomatic therapy includes the
use of corticosteroids for the treatment of peritumoral edema,
anticonvulsants for control of seizures, and anticoagulants or
inferior vena cava filters for the management of venous
thromboembolic disease.[8] Definitive therapy includes treatments
directed at eradicating the tumor itself, such as surgery,
radiotherapy, and chemotherapy.

Symptomatic Therapy

Corticosteroids

Corticosteroids were first used for treating peritumoral edema by
Kofman et al in 1957 in patients with breast cancer.[28] Galicich et
al introduced the use of dexamethasone in 1961,[29] and this has
remained the standard treatment for peritumoral edema ever since.
Corticosteroids produce their antiedema effect by reducing the
permeability of tumor capillaries, [30] and are indicated in any
patient with symptomatic edema.

Most patients are started on dexamethasone, which, compared with
other corticosteroids, has relatively little mineralocorticoid
activity, thus reducing the potential for fluid retention. In
addition, dexamethasone may be associated with a lower risk of
infection and cognitive impairment.[30]

Dexamethasone therapy is usually started as a 10-mg loading dose,
followed by 4 mg four times a day; however, there is some evidence
that lower doses may be as effective.[31] Although most patients
improve symptomatically within 24 to 72 hours, neuroimaging studies
may not show a decrease in the amount of edema for up to 1 week.[32]
In general, headaches tend to respond better than do focal deficits.
If 16 mg of dexamethasone is insufficient, the dose may be increased
up to 100 mg/d. Steroid dose is usually tapered following
irradiation, although the tapering process may begin earlier in
patients with minimal peritumoral edema.

Adverse Effects—Despite their usefulness, corticosteroids
are associated with a large number of well-known side effects,
including myopathy, weight gain, fluid retention, hyperglycemia,
insomnia, gastritis, acne, and immunosuppression.[33] The frequency
of these complications can be reduced by using the lowest possible dose.

There is increasing evidence that brain tumor patients who receive
corticosteroids are at increased risk of developing Pneumocystis
carinii pneumonia.[34] This complication can be prevented by treating
patients who are on prolonged courses of a corticosteroid, especially
those over the age of 50 years, with trimethoprim/sulfamethoxazole prophylaxis.[7]

Anticonvulsants

As mentioned previously, seizures are the presenting symptom in
approximately 10% to 20% of patients with brain metastases, and occur
at some stage of the illness in another 10% to 20% of
patients.[17-20] Patients with brain metastases who present with
seizures should be treated with standard anticonvulsants. In order to
minimize toxicity, the lowest effective anticonvulsant dose should be
used and polytherapy should be avoided whenever possible.
Electroencephalography may be useful if the diagnosis of seizures is
in doubt but is not routinely needed for patients who give a clear
history of seizures or, conversely, do not have symptoms suggestive
of seizures.

Adverse Effects and Drug Interactions—In addition to the
usual complications of anticonvulsants, brain tumor patients
experience an increased incidence of particular side effects,
especially drug rashes. Approximately 20% of brain tumor patients
treated with phenytoin and undergoing cranial irradiation develop a
morbilliform rash and a small percentage develop Stevens-Johnson
syndrome.[35,36] Stevens-Johnson syndrome also has been described in
brain tumor patients receiving carbamazepine,[37] while patients
receiving phenobarbital have an increased incidence of shoulder-hand syndrome.[38]

In addition to producing adverse effects, anticonvulsants also have
clinically significant interactions with other drugs commonly used in
patients with brain metastases. Phenytoin induces the hepatic
metabolism of dexamethasone and significantly reduces its half-life
and bioavailability.[39] Conversely, dexamethasone may also reduce
phenytoin levels.[40]

A number of chemotherapeutic agents commonly used in cancer patients
interact with phenytoin, causing serum drug levels to fall and
potentially leading to breakthrough seizures.[41] Also, hepatic
enzyme–inducing anticonvulsants, such as phenobarbital and
phenytoin, may interfere with chemotherapeutic agents, such as
paclitaxel (Taxol).[42]

Role in Patients With Supratentorial Metastases—Because
the risk of seizures in patients with infratentorial metastases is
very low, anticonvulsant therapy usually is not indicated. The role
of anticonconvulsant therapy in patients with supratentorial brain
metastases who have not had a seizure is controversial.

Cohen et al retrospectively reviewed 160 patients with brain
metastases who had not suffered a seizure. They found that patients
receiving prophylactic phenytoin had the same frequency of late
seizures (10%) as did patients receiving no antiseizure prophylaxis.[18]

Glantz et al conducted a prospective, placebo-controlled, randomized
study evaluating the efficacy of valproic acid in protecting 74
patients with newly diagnosed brain metastases from seizures.[19]
There was no significant difference in the incidence of seizures
between patients receiving valproic acid (35%) or placebo (24%),
suggesting that prophylactic anticonvulsants were not effective in
these patients.

Weaver et al conducted a prospective, randomized study of
prophylactic anticonvulsants in 100 brain tumor patients who had not
had seizures, including 60 with metastases.[20] Overall, 26% of
patients had seizures during the study. There was no difference in
the seizure rate between patients who did and did not receive anticonvulsants.

Recently, Glantz et al performed a meta-analysis of the randomized
clinical trials addressing this issue. They concluded that there is
no statistical evidence showing a significant benefit of prophylactic anticonvulsants.[43]

Recommendations—Because of the increased incidence of
allergic reactions in patients with brain metastases receiving
anticonvulsant therapy, and the lack of clear evidence that
anticonvulsant therapy reduces the incidence of seizures, routine
anticonvulsant therapy is probably unnecessary in patients with brain
metastases who have not experienced a seizure. Possible exceptions to
this are patients with brain metastases in areas of high
epileptogenicity (eg, the motor cortex), patients with multiple
metastases from melanoma, [44] and patients with both brain
metastases and leptomeningeal metastases.[8] These patients have a
higher incidence of seizures and may benefit from prophylactic
anticonvulsant therapy.

Treatment of Venous Thromboembolic Disease

Venous thromboembolic disease is common in patients with brain
metastases, occurring in approximately 20% of patients.[45] The
optimal therapy is unknown. These patients are often perceived to be
at increased risk of intracranial hemorrhage when treated with
anticoagulants because of the vascularity of the tumors and anecdotal
case reports of hemorrhage. As a result, the majority of brain
metastases patients with venous thromboembolic disease are managed
with inferior vena cava filtration devices rather than
anticoagulation. However, Levin et al found that complications occur
in up to 60% of brain tumor patients with venous thromboembolic
disease who are treated with inferior vena cava filters.[46]

Moreover, several retrospective studies have suggested that the risk
of intracranial hemorrhage may not be significantly increased in
patients with primary brain tumors who are anticoagulated after the
immediate postoperative period.[47] More recently, Schiff and
DeAngelis reviewed the Memorial Sloan-Kettering experience with
anticoagulation in patients with brain metastases who developed
venous thromboembolic disease.[48] Of the 42 patients who received
anticoagulation at some stage of their treatment, only 3 (7%)
experienced cerebral hemorrhage, 2 in the setting of overanticoagulation.

These studies suggest that anticoagulation may be more effective than
inferior vena cava filter placement, and is acceptably safe when the
prothrombin time is maintained within the normal range, especially in
patients with brain metastases that generally do not hemorrhage, such
as breast cancer.

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