Review Article

Brain Metastases
Address correspondence to
Dr April Eichler, Massachusetts
General Hospital, 55 Fruit Street,
Yawkey Building 9E, Boston, MA
Christine Lu-Emerson, MD; April F. Eichler, MD, MPH 02114, aeichler@partners.org.
Relationship Disclosure:
Dr Lu-Emerson reports no
disclosure. Dr Eichler holds
ABSTRACT more than $10,000 in stock
Purpose of Review: Brain metastases are the most common neurologic com- in Johnson & Johnson
Services, Inc.
plication related to systemic cancer. With continued improvements in systemic Unlabeled Use of
treatment, the incidence is expected to increase. This article reviews the clinical pre- Products/Investigational
sentation, pathophysiology, prognostic factors, and treatment of metastatic brain Use Disclosure:
Drs Lu-Emerson and Eichler
tumors. report no disclosure.
Recent Findings: Brain metastases from systemic cancer are up to 10 times more * 2012, American Academy
common than primary malignant brain tumors and are a significant burden in the of Neurology.
management of patients with advanced cancer. Common presenting symptoms in-
clude headache, focal weakness or numbness, mental status change, and seizure.
Management and treatment of metastatic brain tumors is complex and dependent
on several factors, including age, performance status, number of metastases at
presentation, and status of systemic disease. At the time of diagnosis, most patients
have more than one brain metastasis, and treatment has traditionally consisted of
whole-brain radiation therapy (WBRT). For those patients with single brain metastases,
aggressive local treatment with surgery or stereotactic radiosurgery (SRS) combined
with WBRT has been shown to improve survival and neurologic outcomes compared
with WBRT alone. In patients with a limited number of brain metastases, SRS alone is
being increasingly explored as a treatment option that spares the upfront toxicity of
WBRT. Currently, the role of chemotherapy is limited to experimental settings and
salvage after radiation therapy.
Summary: Patients with brain metastases have complex needs and require a multi-
disciplinary approach in order to optimize intracranial disease control while maximizing
neurologic function and quality of life. Patients with multiple metastases, uncontrolled
systemic disease, and poor functional status are typically treated with WBRT alone,
whereas surgery and SRS may be used for additional local control in a subset of patients
with fewer tumors and good functional status. The incorporation of neuropsycho-
logical outcomes, neurologic function, and quality of life as end points in future stud-
ies will offer further guidance for providing comprehensive care to patients with
metastatic brain tumors.

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INTRODUCTION to longer survival resulting from more

Brain metastases are the most common
intracranial neoplasm in adults and are a
significant cause of morbidity and mor-
tality in patients with advanced cancer.
The exact incidence of metastatic brain
tumors in the United States is unknown
but is estimated to range between
150,000 and 200,000 cases per year,
affecting 10% to 30% of patients with
cancer.1 The frequency of diagnosis
appears to be increasing over time due
effective systemic treatment, the aging
population, and improved imaging
modalities. Most brain metastases orig-
inate from lung cancer, breast cancer,
or melanoma, but renal cell carcinoma,
colon cancer, and gynecologic malig-
nancies also make up a significant
fraction. While lung cancer accounts
for the majority of brain metastases,
melanoma has the highest propensity
to disseminate to the brain; 50% of

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 Brain Metastases
KEY POINTS
h Brain metastases are patients with advanced melanoma
the most common eventually develop metastatic brain
intracranial neoplasm disease.2 About 10% of metastatic le-
in adults and are a sions will present as an intraparenchy-
significant cause of mal hemorrhage; this is most com-
morbidity and mortality mon in patients with melanoma, renal
in patients with cell carcinoma, thyroid carcinoma, and
advanced cancer. choriocarcinoma.
h Upon entry into the The distribution of metastatic lesions
cranial circulation, reflects cerebral blood flow and volume.
metastatic cells tend Approximately 80% of metastases occur
to arrest at the in the cerebral hemispheres, 15% in the
gray-white junction cerebellum, and 5% in the brainstem.3
and ‘‘watershed’’ Hemispheric lesions tend to occur in
zones where the brain
‘‘watershed’’ areas, sites of slow capil-
vasculature narrows
lary flow at vascular branch points. Clin-
substantially.
ical signs and symptoms result from
destruction or displacement of normal
brain tissue by the growing lesion and
its associated edema. Increased intra-
cranial pressure and vascular injury may
also ensue.
Management of brain metastases has
improved over the past decades with
advances in surgical and radiation tech-
niques, a better understanding of the
underlying biology, and an awareness of
prognostic factors leading to better pa-
tient selection for invasive treatments.
Both symptomatic and therapeutic strat-
egies are crucial for optimal treatment
of the patient with brain metastases.
Historically, research on metastatic
brain tumors has lagged behind that of
primary brain tumors, but with the
projected increase in the incidence of
brain metastases and improvements in
the treatment of systemic disease there
has been renewed interest in this area
of research.
This article provides a general over-
view of brain metastases. It explores the
underlying pathophysiology, clinical
presentations, prognostic factors, and
management, including the role of sur-
gery, radiation therapy, and chemo-
therapy. The article concludes with a
discussion of new areas of treatment
under active investigation.
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PATHOPHYSIOLOGY
Metastatic spread involves a series of
sequential steps, beginning with the
escape of cancer cells from the primary
tumor site, followed by invasion of sur-
rounding tissue into the bloodstream
or lymphatics, and finally extravasation,
survival, and proliferation in a secondary
site. It is believed that only a subpopu-
lation of cells have the necessary genetic
and epigenetic alterations necessary
for invasion and dissemination.4,5 Upon
entry into the cranial circulation, meta-
static cells tend to arrest at the gray-
white junction and ‘‘watershed’’ zones
where the brain vasculature narrows
substantially. Arrest is dependent not
only on tumor cell size but also on
tumor cell recognition of specific endo-
thelial surface receptors in the target
organ. To complete the metastatic proc-
ess, tumor cells must leave the capillary
beds and enter the brain parenchyma in
a process called extravasation.
Growth of the tumor at both the
primary and secondary site is depen-
dent on the establishment of an ade-
quate blood supply. Blood vessels can
be recruited via multiple mechanisms,
including angiogenesis, which is the
formation of new blood vessels from
sprouts of existing vessels. Morphologic
examination of these new vessels re-
veals them to be significantly larger with
thicker basement membranes, resulting
in an inefficient vascular network.6 This
results in areas of hypoxia and hypo-
perfusion, which could be a barrier to
effective drug delivery.
Several theories have been postu-
lated to explain the propensity of tumor
types to disseminate to specific organs,
such as the brain. The classic ‘‘seed and
soil’’ hypothesis, originated by Paget in
1889, states that a tumor’s organ-specific
spread is dependent on protumorigenic
interactions between the tumor cell
and its microenvironment.7 Alterna-
tively, the pathologist Ewing believed
April 2012

that circulatory patterns between the
primary tumor and targeted secondary
organs were sufficient to explain the
specific pattern of metastatic spread.
Today, attention has been directed to
the role of cancer stem cells as the
‘‘seed’’ and the effects of specific stro-
mal components, or the ‘‘soil,’’ on ma-
lignant progression and resistance to
therapy.8 Most recently, researchers
have hypothesized that cancer cells pos-
sess the ability to bring their own
stromal components from the primary
site to secondary sites in order to es-
tablish a favorable microenvironment
for further growth.9 Thus, it appears
that the successful dissemination of
cancer cells to the brain relies on a
symbiotic relationship between the
tumor cell and its host.
KEY POINTS
deficits (Table 2-1, Case 2-1). Charac- h Most patients present
terization of brain tumor headaches with brain metastasis
is nonspecific; they often resemble after a diagnosis of a
other headache types and are not primary cancer has been
necessarily accompanied by papille- established, often
dema. Therefore, a high index of within the previous
suspicion is required in patients with 2 years but occasionally
cancer presenting with new headaches. many years before.
Focal weakness is another common h Any patient with a
symptom, typically caused by a lesion history of cancer who
in the contralateral hemisphere. Cog- develops new
nitive impairment and behavioral neurologic symptoms
changes are frequent, and detailed neu- warrants careful
ropsychological testing reveals deficits examination.
across multiple domains in about 65%
of patients with brain metastases.11,12
These cognitive changes may be sub-
tle and detected only with formal eval-
uation. Common affective changes
include depression and apathy, which

CLINICAL PRESENTATION
Most patients present with brain meta- TABLE 2-1 Common Presenting
Signs and Symptoms
stasis after a diagnosis of a primary of Brain Metastases
cancer has been established, often
within the previous 2 years but occa- b Presenting Signs
sionally many years before. About 5% to
Cognitive impairment
10% of patients present simultaneously
with both systemic and intracranial dis- Hemiparesis
ease at the time of initial diagnosis, a Hemisensory loss
so-called synchronous presentation. This Gait ataxia
is particularly common in patients with
nonYsmall cell lung cancer (NSCLC). Aphasia
Metastatic brain disease can present as Visual changes
a solitary lesion or as multiple lesions. Papilledema
About half of all patients have three
b Presenting Symptoms
or fewer lesions. Brain metastases may
present with overt symptoms or remain Headache
clinically silent and be found incidentally Focal weakness
during cranial imaging for unrelated
Mental and behavioral
reasons. Up to one-third of patients with disturbance
brain metastases remain undiagnosed
during their lifetime as shown in autopsy Gait disturbance
studies.10 Seizures
Any patient with a history of cancer Modified from DeAngelis L, Posner J. Neuro-
who develops new neurologic symp- logical complications of cancer. 2nd ed.
New York, NY: Oxford University Press, 2008.
toms warrants careful examination. B 2008, with permission from Oxford Univer-
sity Press.
Common clinical presentations include
headache, seizures, and focal neurologic
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 Brain Metastases

Case 2-1
A 57-year-old right-handed woman presented to the emergency department with a 1-week history of
progressive mild right-sided weakness and confusion. On the day of presentation, she developed a
severe headache with vomiting. One year ago she was diagnosed with stage IB nonYsmall cell lung
cancer that was treated with left lower lobectomy and four cycles of adjuvant chemotherapy. On
examination in the emergency department she was alert and oriented. She had a partial right
homonymous hemianopsia, right-sided sensory neglect, and a mild right hemiparesis. A brain MRI
(Figure 2-1 ) demonstrated a large enhancing mass in the left parieto-occipital lobe (A) with significant
surrounding edema (B). Body CT scan revealed no evidence of systemic cancer recurrence. She underwent
a left parietal craniotomy
for resection of the mass.
Pathology showed
metastatic carcinoma with
extensive necrosis,
consistent with a lung
primary. Postoperatively,
she had improved right-sided
strength and resolution of
the partial field cut.
Comment. This case
demonstrates the typical
presenting features of a
metastatic brain tumor,
namely subacute
progressive focal
weakness and new
headaches in a patient
FIGURE 2-1 MRI demonstrating a large enhancing mass in the left parieto-occipital with a known cancer
lobe (A) with significant surrounding edema (B).
diagnosis.

KEY POINT may confuse the diagnostic picture PROGNOSTIC FACTORS

h Important prognostic and delay diagnosis. Seizures can occur
factors include age, at presentation or later in the course,
functional status,
with an incidence ranging from 20% to
number of brain
25% of patients with brain metastases.
metastases, primary
tumor type, time
The likelihood of seizure increases
elapsed between the with the number of metastatic lesions
primary cancer and with involvement of the leptome-
diagnosis and ninges. In general, neurologic signs
development of brain and symptoms are progressive, reflect-
disease, and extent of ing the local expansion and growth of
active systemic disease. the tumor, which results in displace-
ment or destruction of normal brain
tissue. Occasionally, neurologic deficits
may have an acute onset secondary to
vascular compromise. This may be due
to general hypercoagulability, disturb-
ance of arterial flow, tumor emboliza-
tion, or hemorrhage into the lesion.
298 www.aan.com/continuum
Brain metastases are typically associated
with a poor prognosis; most studies
show a median survival of less than
6 months. Clinical variables associated
with survival have been well studied
over the years. Important prognostic
factors include age, functional status
(designated by Karnofsky Performance
Scale [KPS], Table 2-2), number of
brain metastases, primary tumor type,
time elapsed between the primary can-
cer diagnosis and development of
brain disease, and extent of active
systemic disease. The most well-known
prognostic scoring system is called the
recursive partitioning analysis (RPA)
classification, which was developed
from 1200 patients who received
April 2012

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TABLE 2-2 Karnofsky Performance Scale

Score Clinical Characteristics

100 Normal, no complaints, no evidence of disease
90 Able to carry on normal activity; minor symptoms of disease
80 Normal activity with effort; some signs and symptoms of disease
70 Cares for self; unable to carry on normal activity or work
60 Requires occasional assistance but is able to care for needs
50 Requires considerable assistance and requires frequent medical care
40 Disabled; requires special care and assistance
30 Severely disabled; hospitalization is indicated, death is not imminent
20 Very sick with hospitalization necessary; active treatment necessary
10 Moribund, fatal processes progressing rapidly
0 Death
Reprinted from Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In:
MacLeod CM, ed. Evaluation of chemotherapeutic agents. New York, NY: Columbia University Press, 1949:199Y208.

whole-brain radiation therapy (WBRT)
for treatment of brain metastases in the
Radiation Therapy Oncology Group
(RTOG) database (Table 2-3).13 Patients
were categorized into one of three
classes on the basis of their age, KPS
score, status of primary tumor, and ex-
tent of extracranial disease. In the orig-
inal study, those patients who were
younger than 65 and had a KPS score
greater than 70, a controlled primary
tumor, and no extracranial disease (des-
ignated RPA Class I) had a median sur-
vival of 7.1 months. This was in contrast
to patients with a KPS score less than or
equal to 70 (designated RPA Class III)
who had a median survival of only
2.3 months. In addition to these four
factors, the number of brain metasta-
ses also appears to be important in
determining survival; across multiple
studies, patients with single metastases
consistently survive longer than those
with multiple metastases, even after

TABLE 2-3 Recursive Partitioning Analysis Classification System

Recursive Partitioning Median Survival

Analysis Class Clinical Characteristics (months)
I Karnofsky Performance Scale 7.1
(KPS) score Q 70
Age G 65 years
Controlled primary tumor
No extracranial metastasis
II All other patients 4.2
III KPS score G 70 2.3

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 Brain Metastases

KEY POINT
h Occasionally a biopsy is
needed to confirm the
diagnosis of brain
metastases, particularly
in patients without
systemic metastatic
disease, those with a
long interval between
the primary cancer
diagnosis and the new
brain mass, or those
with atypical imaging
features.
adjusting for other prognostic factors.14
More recently, the Graded Prognostic
Assessment scale was developed on the
basis of an analysis of 1960 patients in
the RTOG database. Unlike the RPA,
this scale incorporates the number of
metastatic lesions and also simplifies
the assessment of extracranial disease
status (Table 2-4).15,16 At this time, it is
unclear whether one prognostication
system is superior to another, and
physicians must be cautious of relying
too heavily on these indices, as patients
with brain metastases represent a very
heterogenous population. Finally, retro-
spective data suggest that certain sub-
populations of patients, such as those
with ERBB2-positive breast cancer (for-
merly known as HER2) or those with
NSCLC caused by mutations in the epi-
dermal growth factor receptor gene,
EGFR, survive longer than comparable
patients with wild-type tumors.17,18
TREATMENT
Upon suspicion of brain metastases, an
MRI with and without contrast should
be obtained. MRI has superior sensitivity
to CT with contrast for the detection of
small tumors and has greater specificity
to exclude alternative diagnoses. One or
more contrast-enhancing lesions may
be seen, and in the appropriate clinical
setting, the diagnosis may be estab-
lished. Occasionally a biopsy is needed
to confirm the diagnosis of brain meta-
stases, particularly in patients without
systemic metastatic disease, those with a
long interval between the primary can-
cer diagnosis and the new brain mass, or
those with atypical imaging features
(Case 2-2). Brain lesions smaller than
1 cm that are indeterminate for meta-
stasis can be closely monitored without
affecting the success of subsequent
therapy.19 Larger lesions require imme-
diate attention.
The management and treatment of
brain metastasis is complex and depen-
dent on several factors, including the
number and size of the metastatic le-
sions, the age of the patient, the func-
tional status, the extent of systemic dis-
ease, the histopathology, and the site of
metastasis. The goal is to maximize sur-
vival while providing good neurologic
quality of life. Supportive care includes

TABLE 2-4 Graded Prognostic Assessment Scoring System

Clinical Characteristics
Karnofsky Presence of Number Total Graded Median
Performance Age Extracranial of Brain Prognostic Survival
Scoring Scale (years) Disease Metastases Assessment Score (months)a
1 point 90 to 100 G 50 No 1 3.5 to 4 11.0/21.7
0.5 point 70 to 80 51 to 59 Not available 2 to 3 3 8.9/17.5
0 points G 70 9 60 Yes 93 1.5 to 2.5 3.8/5.9
0 to 1 2.6/3.0
a
Median survival is given for analyzed patients from the Radiation Therapy Oncology Group database and the Minnesota database,
respectively.
Data from Sperduto PW, Berkey B, Gaspar LE, et al. A new prognostic index and comparison to three other indices for patients with brain metastases: an
analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 2008;70(2):510Y514.
Data from Sperduto CM, Watanabe Y, Mullan J, et al. A validation study of a new prognostic index for patients with brain metastases: the Graded
Prognostic Assessment. J Neurosurg 2008;109(suppl):87Y89.

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 Case 2-2
A 47-year-old right-handed man was being treated with
interferon for a stage IIIB acral melanoma when he had a
witnessed 90-second episode of slurred speech and
versive head movements to the left. He was taken to a
local emergency department, where he was noted to
have a normal neurologic examination except for
mild upper motor neuron weakness in the left face. A
head CT and later MRI demonstrated a single large
ring-enhancing mass lesion in the right frontal lobe with
surrounding edema (Figure 2-2). The differential
diagnosis included metastatic melanoma; high-grade
glioma and abscess were less likely. A PET/CT scan
performed 1 week earlier had shown two new
metabolically active subcutaneous nodules in the right
neck that were suggestive of metastatic disease,
although they were too small to fully characterize. Given FIGURE 2-2 Ring-enhancing mass lesion in
the right frontal lobe with
the large size of the new brain mass, the patient’s young surrounding edema.
age and excellent functional status, and the presence of
minimal systemic disease, he was felt to be a good
candidate for surgical resection. Pathology showed a tumor with high cell density, pleomorphism,
mitoses, microvascular proliferation, and extensive necrosis, consistent with a diagnosis of
glioblastoma.
Comment. This case illustrates the importance of considering biopsy in patients who present with
a single brain mass, particularly if there are atypical imaging features (in this case, the large amount
of central necrosis may have been a clue) or an absence of clear systemic metastatic disease.

symptomatic therapies such as cortico-
steroids to decrease peritumoral edema
and the initiation of anticonvulsants for
seizure control. Medications such as
antidepressants may help with mood,
and there is evidence that methylphe-
nidate and donepezil can improve cog-
nition, mood, function, and overall
quality of life.20,21 The remainder of
this article focuses on definitive treat-
ment strategies, including radiation,
surgery, and chemotherapy.
Whole-Brain Radiation Therapy
Traditionally, radiation therapy has con-
stituted the backbone of treatment for
brain metastases. WBRT is administered
to address both visible disease and
presumed microdeposits of tumor cells
in the brain. A total dose of 30 Gy to
40 Gy is typically delivered to the patient
in daily fractions of 2 Gy to 3 Gy. In-
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crease of either total dose or daily frac- KEY POINT
tion size raises the risk of neurotoxicity.22 h Traditionally, radiation
therapy has constituted
WBRT can be given alone or as adjunc-
the backbone of
tive therapy, although monotherapy is
treatment for brain
usually reserved for patients with multi- metastases.
ple brain metastases not amenable to
surgery or SRS, poor performance sta-
tus, or active systemic disease.
Nonrandomized studies have found
that WBRT impacts survival only mod-
estly, increasing median survival from 1
to 2 months to 3 to 6 months.23 About
60% of patients experience a complete
response or partial response on follow-
up imaging. Reports of symptom stabi-
lization or improvement occur in a
similar proportion, although improve-
ments are often only transient. Tumor
histology also plays a role in the ef-
fectiveness of WBRT: some tumors,
such as small cell lung cancer, breast
cancer, and germ cell tumors, tend to
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 Brain Metastases
KEY POINT
h One of the greatest
concerns about
whole-brain radiation
therapy is the risk of late
neurocognitive effects,
which can range from
mild cognitive
impairment to overt
dementia.
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be highly sensitive to fractionated ra-
diation, whereas melanoma, sarcoma,
and renal cell carcinoma are relatively
unresponsive.
There have been multiple attempts
over the years to identify drugs that may
act as radiosensitizers, improving upon
the therapeutic potency of radiation
while sparing toxicity to normal brain
tissue. A variety of agents, including
lonidamine, metronidazole, misonida-
zole, motexafin gadolinium, efaproxiral,
and bromodeoxyuridine, have been
studied in patients with brain metasta-
ses, but the results have been disap-
pointing, showing no difference in local
tumor control, tumor progression, or
overall survival, and an increase in severe
adverse effects in those patients receiv-
ing radiosensitizers. However, it appears
that specific tumor subtypes might
benefit preferentially. For example, a
recently completed phase III trial dem-
onstrated an increased time to neuro-
logic progression in patients with NSCLC
treated with motexafin gadolinium, and
another study reported improved sur-
vival and quality of life in patients with
breast cancer who received efaproxi-
ral.24,25 It remains to be seen whether
these study results will translate into
formal approval of either agent for
clinical use in the United States.
In addition to radiosensitizers, there
has also been interest in combining
chemotherapy with WBRT as a way to
improve CNS control and to target
concurrent systemic disease. Several
agents, including fotemustine, tenipo-
side, chloroethylnitrosourea, tegafur,
and topotecan, have been studied, and
while some studies found an increase
in time to progression in the combina-
tion arm, there was also greater toxicity
with combined therapy and no apparent
effect on overall survival. More recently,
temozolomide has shown promising
response rates and an acceptable tox-
icity profile when combined with WBRT,
particularly in patients with metastatic
melanoma, although the overall effect
on survival remains unclear.26Y28
One of the greatest concerns about
WBRT is the risk of late neurocognitive
effects, which can range from mild
cognitive impairment to overt demen-
tia. Unfortunately, the actual neurocog-
nitive impact of WBRT in patients with
brain metastases is not well studied.
A retrospective study published by
DeAngelis and colleagues in 1989 was
one of the first to raise concern about
major neurotoxicity from WBRT in pa-
tients with brain metastases.22 They
described 12 patients who developed
disabling and progressive dementia a
median of 14 months after receipt of
WBRT given in daily fractions of 3 Gy
to 6 Gy. Notably, patients who re-
ceived daily fractions lower than 3 Gy
had a greatly reduced risk of significant
neurotoxicity. Thus, the current prac-
tice is to limit daily WBRT fractions to
3 Gy or less. Even with these schedules,
however, it is clear that some patients
develop significant problems with
short-term memory and cognition that
cannot be explained by tumor pro-
gression or other insults and that neg-
atively impact quality of life. Future
research should focus on identifying
risk factors that predict vulnerability to
delayed radiation toxicity as well as
integrating neurocognitive end points
into prospective clinical trials. In ad-
dition, hippocampal-sparing WBRT is
a technique under active investigation
in a large multicenter clinical trial and
could prove to be useful in decreasing
the neurotoxicity of WBRT (clinicaltrials.
gov identifier: NCT01227954).
Stereotactic Radiosurgery
Because of the concerns of late neuro-
toxicity associated with WBRT, atten-
tion has been directed toward more
focal treatments, including stereotactic
April 2012

radiosurgery (SRS). SRS uses multiple
convergent beams to deliver a single
high dose of radiation to a discrete target
volume. The three most common deliv-
ery systems are the linear accelerator
(high energy x-rays), gamma knife
(gamma radiation), and cyclotron (pro-
tons). All three systems have a rapid fall-
off dose at the margin of the tumor
volume, resulting in delivery of a clin-
ically insignificant radiation dose to the
surrounding normal tissue. Because
brain metastases are distinct lesions with
discrete pathologic and radiographic
margins, they are attractive targets for
SRS. In general, SRS is reserved for
lesions whose maximum diameter is
3 cm or less, with better tumor control
rates seen in smaller lesions. A distinct
advantage of SRS is its ability to treat
locations that have traditionally been
surgically inaccessible, such as the brain-
stem or basal ganglia. Local tumor con-
trol with SRS ranges from 70% to 90% at
1 year in various studies and tends to be
higher when combined with WBRT.
Data regarding the response rates of
traditionally ‘‘radioresistant tumors’’ (eg,
renal cell carcinoma, sarcoma, and mel-
anoma) are mixed; some studies report
comparable response rates and others
report response rates of less than 50%.
Complications of SRS include edema,
seizures, and radiation necrosis.
The index study supporting the uti-
lity of SRS as an add-on treatment to
WBRT in patients with brain metastases
was RTOG 95-08.29 In this study, 333
RPA Class I and II patients with one to
three brain metastases were random-
ized to receive either WBRT with SRS
to all tumors or WBRT alone. Overall,
no significant difference was seen in
median overall survival (5.7 months for
WBRT plus SRS versus 6.5 months for
WBRT alone, P=.14). However, in pa-
tients with a single metastasis, median
survival was increased in the WBRT
plus SRS group (6.9 months versus 4.9
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KEY POINTS
months, P=.04). Patients with one to h Stereotactic
three lesions experienced superior radiosurgery uses
local control (P=.001) and improved multiple convergent
KPS score in the combination arm. A beams to deliver a
smaller randomized controlled trial single high dose of
evaluated patients with two to four radiation to a discrete
metastases, each less than 2.5 cm, who target volume.
received either WBRT with SRS or h For patients with a
WBRT alone.30 This study was stopped single brain metastasis
early because of the overwhelming and good performance
benefit of combination therapy in status, a stereotactic
terms of local control rate and median radiosurgery boost after
time to recurrence. Because the study whole-brain radiation
was stopped at 60% accrual, its ability therapy improves
neurologic outcomes
to detect a statistical difference in
and survival, and for
median survival was limited, although
patients with multiple
there was a trend toward increased tumors, a stereotactic
survival in the WBRT plus SRS group radiosurgery boost may
(11 months versus 7.5 months). Taken improve local control
together, these trials suggest that for but does not clearly
patients with a single brain metastasis prolong survival.
and good performance status, an SRS h Although uncommon
boost after WBRT improves neurologic prior to the 1980s,
outcomes and survival, and for patients resection of brain
with multiple tumors, an SRS boost metastases has now
may improve local control but does not become a standard
clearly prolong survival. treatment option in
patients with surgically
accessible single lesions,
Surgery good performance
status, and controlled
Surgical resection of brain metastases is
or absent extracranial
a treatment option considered primarily
disease.
in patients with single large tumors.
Unlike SRS, surgery allows for a definite
diagnosis while providing immediate
relief of neurologic symptoms due to
mass effect. Although uncommon prior
to the 1980s, resection of brain meta-
stases has now become a standard treat-
ment option in patients with surgically
accessible single lesions, good perfor-
mance status, and controlled or absent
extracranial disease. Improvements in
surgical techniques have decreased sur-
gical morbidity and mortality substan-
tially; data from a large series suggest
that lower mortality is significantly asso-
ciated with high-volume surgical centers
(1.8% versus 4.4%).31
www.aan.com/continuum 303
 Brain Metastases
KEY POINT
h Given the success of Support for surgical resection of a
focal techniques such as single brain metastasis followed by
stereotactic radiosurgery WBRT comes from two landmark ran-
and surgery at achieving domized studies reporting a survival
durable local control benefit with the addition of surgical
and the concern about resection to WBRT in patients with a
neurocognitive single brain metastasis and favorable
consequences of prognostic factors.32,33 Patchell and col-
whole-brain radiation leagues randomized patients to receive
therapy (WBRT), in either biopsy plus WBRT or complete
recent years attention
surgical resection plus WBRT.32 The
has turned to
arm treated with complete surgical
determining whether
WBRT can be avoided in
resection followed by WBRT had a
certain patients without statistically significant increase in sur-
sacrificing disease vival (40 weeks versus 15 weeks), lon-
control or survival. ger time to recurrence, and longer
duration of functional independence.
The second study randomized patients
with reasonable quality of life (defined
as spending less than 50% of time in
bed and not requiring hospitalization)
to receive either complete surgical
resection plus WBRT or WBRT alone.33
Again, increased survival was seen in
the combination arm (10 months ver-
sus 6 months), with a nonsignificant
trend toward longer duration of func-
tional independence.
Focal Therapies With or
Without Whole-Brain
Radiation Therapy
Given the success of focal techniques
such as SRS and surgery at achieving
durable local control and the concern
about neurocognitive consequences of
WBRT, in recent years attention has
turned to determining whether WBRT
can be avoided in certain patients with-
out sacrificing disease control or sur-
vival. In practice, as SRS has become
more widely available, many more
patients have been receiving SRS ini-
tially, with WBRT being reserved for
relapse if used at all. The evidence base
for this practice comes from a variety of
studies looking at various combinations
of SRS, surgery, and WBRT. Some of the
important studies are discussed below.
304 www.aan.com/continuum
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Stereotactic radiosurgery plus
whole-brain radiation therapy ver-
sus stereotactic radiosurgery alone.
Aoyama and colleagues conducted a pro-
spective randomized trial of 132 patients
with one to four metastases and a KPS
score greater than or equal to 70 who
were treated with SRS alone or SRS plus
WBRT.34 In this study, patients receiving
SRS plus WBRT had a significant im-
provement in local and distant control
rates in brain as well as decreased need
for salvage therapy compared with pa-
tients who received SRS alone. However,
there was no significant difference
between the two groups with regards
to overall survival. Analysis of Folstein
Mini-Mental State Examination scores
before and after treatment indicated no
clear detriment in the patients receiving
WBRT. Similar findings were reported
from the European Organization for
Research and Treatment of Cancer
(EORTC) Protocol 22952-26001, a study
in which patients with up to three brain
metastases were treated with either
surgery or SRS at the discretion of treat-
ing physicians and then randomized to
receive either WBRT or observation.
This study also found no difference in
overall survival or duration of functional
independence between the two arms
but, similar to the Aoyama study, showed
an increase in progression-free survival
and in rates of intracranial control in the
combination arm.35 A third randomized
study was stopped early when interim
analysis of the primary end point of neu-
rocognitive outcome, as assessed by the
Hopkins Verbal Learning TestYRevised
(HVLT-R) at 4 months, showed that more
patients in the combined treatment arm
(SRS plus WBRT) experienced a 5-point
drop in HVLT-R scores than patients
receiving SRS alone (52% versus 24%).36
The neurocognitive deficits were accom-
panied by worse survival in the com-
bined treatment arm but improved local
and distant control rates in brain.
April 2012

Taken together, these studies indi-
cate that withholding WBRT at diagnosis
and treating with SRS alone in patients
with a limited number of brain meta-
stases does not sacrifice overall survival
and may be associated with improved
neurocognitive outcomes, at least in the
first few months after treatment. In this
respect, it is an attractive approach for
many patients. However, the trade-off is
that use of SRS alone is associated with
worsened brain control rates and in-
creased need for salvage therapy com-
pared with a combined SRS plus WBRT
approach. This emphasizes the need
for close serial monitoring and imaging
of patients in whom WBRT has been de-
ferred in order to recognize relapse
early and minimize neurologic decline
associated with intracranial progression.
Surgery plus whole-brain radia-
tion therapy versus surgery alone.
This treatment question has obvious
parallels to the debate over SRS plus
WBRT versus SRS alone presented
above. In another seminal randomized
trial by Patchell and colleagues, patients
with a single brain metastasis under-
going resection had superior local (90%
versus 54%, PG.001), distant (86% ver-
sus 63%, PG.01), and overall (82%
versus 30%, PG.001) intracranial control
rates when they received postoperative
WBRT compared with patients receiving
surgical resection alone.37 However,
akin to the SRS T WBRT trials, no
survival benefit was found for postop-
erative WBRT. Neurocognitive mea-
sures were not included in this study.
An older retrospective study of 98 pa-
tients found that postoperative WBRT
significantly prolonged the time to neu-
rologic relapse at 1 year (postoperative
WBRT 22%, surgical resection alone
46%, P=.034), with no statistical differ-
ence in overall survival (postoperative
WBRT 20.6 months, surgical resection
alone 14.4 months, P=NS).38 These re-
sults are consistent with the findings of
Continuum Lifelong Learning Neurol 2012;18(2):295–311
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
EORTC 22952-26001, which did not h Studies indicate that
demonstrate increased survival or pro- withholding whole-brain
longed functional independence with radiation therapy at
the addition of WBRT to surgery but did diagnosis and treating
show an increase in intracranial control with stereotactic
of disease.35 More recently, treating the radiosurgery alone in
postoperative surgical bed with SRS has patients with a limited
come into practice, with the goal of number of brain
decreasing the risk of local recurrence metastases does not
compared with surgery alone while sacrifice overall survival
and may be associated
sparing patients the toxicity of WBRT.
with improved
Similar to SRS alone, this approach re-
neurocognitive outcomes,
quires close follow-up over time be- at least in the first few
cause of a higher risk of developing months after treatment.
new metastases elsewhere in the brain.
h More recently, treating
Multiple retrospective studies have sug-
the postoperative
gested that this approach leads to high surgical bed with
rates of local control, and several large stereotactic radiosurgery
prospective studies examining this has come into practice,
approach are currently underway. with the goal of
decreasing the risk of
Stereotactic Radiosurgery local recurrence
Versus Surgery compared with surgery
No randomized control trials comparing alone while sparing
surgery to SRS have been reported, and patients the toxicity of
many patients with single brain meta- whole-brain radiation
therapy.
stases would be eligible to receive either
treatment. One retrospective study of h If a tumor is large with
75 patients reported increased survival extensive edema and
with surgical resection.39 However, mass effect, surgery is
preferable to
three other retrospective studies were
stereotactic radiosurgery
unable to duplicate these results and
because it provides
essentially showed no difference be- more rapid relief of
tween the two modalities.40Y42 Need- edema and quicker
less to say, it is apparent that aggressive neurologic recovery.
management of a single metastatic le-
sion, either through SRS or surgery,
followed by WBRT, results in better
outcomes in patients with good prog-
nostic factors. It is therefore recom-
mended that the decision between the
two modalities be based on the indi-
vidual patient and his or her circum-
stances. For instance, if a tumor is large
with extensive edema and mass effect,
surgery is preferable to SRS because it
provides more rapid relief of edema
and quicker neurologic recovery. This
is especially true in the posterior fossa,
www.aan.com/continuum 305
 Brain Metastases
KEY POINTS
h Traditionally, several which can be quite unforgiving in
factors have limited the terms of mass effect. Surgery is also
role of chemotherapy in indicated if there is diagnostic uncer-
the treatment of brain tainty, as a way of confirming the di-
metastases. agnosis and excluding other entities,
h As with systemic such as primary brain tumor or abscess.
disease, the response of On the other hand, SRS may be prefer-
brain metastases to able to surgery in cases of very small
epidermal growth factor metastases, tumors in deep locations, or
receptor inhibitors tumors embedded in eloquent cortex.
correlates with the
presence of EGFR Chemotherapy
mutations, and these Several factors have traditionally limited
drugs offer little hope of the role of chemotherapy in the treat-
activity in patients
ment of brain metastases. Classically,
without mutations.
the brain has been regarded as a
‘‘sanctuary’’ site for metastases because
of chemotherapy’s decreased access to
the brain due to the blood-brain barrier
(BBB). However, this is likely not the
only factor, since studies have found
that intracranial and extracranial re-
sponse rates in patients treated with
first-line chemotherapeutic agents are
roughly equivalent. Another barrier
regarding the efficacy of chemotherapy
for brain metastases is the chemosensi-
tivity of the original solid tumor. Since
brain metastases often occur in the
setting of advanced metastatic disease,
patients have already been exposed to
chemotherapy, and clones that form in
brain may be more resistant to drugs
than the original primary tumor. Cur-
rently, data regarding the use of chemo-
therapy for brain metastases stem
mostly from small phase II studies,
which often include patients who have
been heavily pretreated. Nonetheless,
some newer small molecule and tar-
geted drugs show promise for patients
with brain metastases from specific tu-
mor subtypes.
NonYsmall cell lung cancer. A
variety of agents with activity against
NSCLC, primarily the platinums, have
been studied for patients with brain
metastases, and response rates tend to
be highest in patients who have not
306 www.aan.com/continuum
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
received prior systemic chemotherapy.
Platinum agents such as cisplatin and
carboplatin alone or in combination
with other chemotherapeutic agents
like paclitaxel, vinorelbine, gemcitabine,
etoposide, fotemustine, and teniposide
have response rates of 20% to 40%
in chemotherapy-naBve patients.23 The
data for temozolomide (TMZ), an oral
alkylating agent with good BBB pene-
tration that is approved for treatment
of glioblastoma, have been disappoint-
ing, likely because TMZ does not have
much activity against NSCLC itself.
Objective responses in several studies
have ranged from 0% to 10%. In fact,
the EORTC phase II study of TMZ in
NSCLC patients with brain metastases
was prematurely closed because of the
lack of intracranial responses in the
treated patients.43
Small molecule targeted agents, such
as the epidermal growth factor receptor
(EGFR) inhibitors erlotinib and gefitinib,
show more promise, at least in patients
whose tumors carry activating mutations
in the EGFR gene, perhaps because
these drugs have better BBB pene-
tration than traditional chemotherapy.
A prospective series of 41 patients
with brain metastases found an overall
disease control rate of 27% (10% with
partial response and 17% with stable
disease).44 As with systemic disease,
the response of brain metastases to
EGFR inhibitors correlates with the pres-
ence of EGFR mutations, and these
drugs offer little hope of activity in
patients without mutations. The like-
lihood of response is particularly high
in patients with synchronous brain
and systemic presentations of EGFR-
mutated NSCLC, and in patients with
small asymptomatic brain metastases
it may be reasonable to start with an
EGFR inhibitor and defer brain radia-
tion therapy, provided there is close
follow-up. Other targeted agents, in-
cluding angiogenesis inhibitors such
April 2012

as bevacizumab (a monoclonal antibody
against vascular endothelial growth
factor) and receptor tyrosine kinase in-
hibitors such as sorafenib and suniti-
nib, are currently being evaluated for
safety and efficacy in patients with brain
metastases.
Breast cancer. Risk factors for devel-
oping brain metastases from breast
cancer include young age, hormone
receptorYnegative tumors, increased lac-
tate dehydrogenase levels, positive
lymph nodes, lymphovascular invasion,
and ERBB2 overexpression. Breast can-
cer is generally more chemosensitive
than NSCLC, and consequently many of
the traditional drugs with activity in
breast cancer and reasonable BBB pen-
etration have a track record of utility in
patients with brain metastases. Objective
response rates of 43% to 59% have been
documented in patients with newly
diagnosed brain metastases treated
with cyclophosphamide/5-fluorouracil
(5-FU)/prednisone; 5-FU/prednisone/
methotrexate/vincristine; and 5-FU/
methotrexate.45,46 A phase II study of
56 patients with new brain metastases
from breast cancer treated with cisplatin
and etoposide documented a complete
response in seven patients, a partial re-
sponse in 14 patients, and stable dis-
ease in 12 patients.47 Many case reports
and case series have reported that
capecitabine, an oral prodrug that is
metabolized to 5-FU intracellularly, has
activity against progressive brain metas-
tases after radiation therapy.
Oral targeted agents have also been
studied in breast cancer. Brain metasta-
ses are especially common in patients
with ERBB2-positive tumors treated
with trastuzumab, a monoclonal anti-
body against ERBB2 (Case 2-3). This
increased risk stems from a combi-
nation of the propensity of ERBB2-
positive tumors to metastasize to the brain
and other visceral sites and improved
systemic disease control and survival
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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINT
with trastuzumab, which has poor BBB h Brain metastases are
penetration.48 A multicenter phase II especially common in
trial evaluated the efficacy of lapatinib, patients with
a small molecule tyrosine kinase inhib- ERBB2Ypositive
itor of EGFR and ERBB2, in 242 pa- tumors treated with
tients with new or progressive intracra- trastuzumab, a
nial metastatic ERBB2-positive breast monoclonal antibody
cancer who were previously treated with against ERBB2.
trastuzumab and cranial radiation ther-
apy. The study demonstrated modest
activity of lapatinib; objective response
rates were seen in 6% of patients and
tumor reduction was seen in 21% of
patients.49 Lapatinib combined with
capecitabine is associated with higher
response rates in this same population,
and this combination is a good option
for patients with ERBB2-positive disease
who have progressive brain metastases
after radiation therapy.49,50
Melanoma. Metastatic melanoma
typically has a poor response rate to sys-
temic chemotherapy both intracranially
and extracranially. Few trials have eval-
uated the role of chemotherapy in mel-
anoma patients with brain metastases,
and most have focused on fotemustine
(in Europe) and TMZ. Fotemustine is a
nitrosourea with good BBB penetration
that has been evaluated as a single agent
and in combination with WBRT and
appears to have modest activity against
metastatic lesions in the brain.51Y53 TMZ
has systemic activity against advanced
melanoma and has been investigated as
a possible therapy for brain metastases.
A phase II study of 151 patients treated
with TMZ reported an objective re-
sponse rate of 7% and stable disease in
29%.54 Another study combining TMZ
with radiation therapy reported an ob-
jective response rate of 9%, with sta-
ble disease in 26%.55
More recently, antibodies that en-
hance antitumor immune responses by
blocking the interaction of cytotoxic
T lymphocyteYassociated antigen 4
(CTLA-4) with its ligands B7.1 and B7.2
have shown clinical benefit in patients
www.aan.com/continuum 307
 Brain Metastases

Case 2-3
A 50-year-old right-handed woman palpated a lump in her left breast and a mammogram
demonstrated a 1.5-cm spiculated mass. She underwent lumpectomy with lymph node dissection, and
pathology revealed an estrogen receptorYpositive, ERBB2/positive infiltrating ductal carcinoma. She
was treated with adjuvant radiation and chemotherapy. Five years later, she developed back pain and
was found to have a lytic lesion at T8 as well as multiple pulmonary nodules. A needle biopsy of the
T8 lesion confirmed metastatic breast cancer. She was treated with chemotherapy and trastuzumab,
an anti-ERBB2 monoclonal antibody, and achieved a partial response. Nine months later, she presented
with the sudden onset of speech arrest, which lasted for about 1 minute and then resolved. Her
neurologic examination at
the time of presentation
to an emergency
department was normal.
A brain MRI demonstrated
multiple solid and cystic
enhancing masses
throughout the brain,
including the cerebellum,
consistent with brain
metastases (Figure 2-3 ).
Body CT scans showed
stable disease in the spine
and lungs. She was
treated with whole-brain
radiation therapy.
Comment. Patients
with ERBB2-positive
breast cancer often FIGURE 2-3 MRI demonstrating multiple solid and cystic enhancing masses
throughout the brain.
present with new brain
metastases in the setting
of controlled systemic disease. This is likely due to the poor blood-brain barrier penetration of drugs
such as trastuzumab.

KEY POINT with metastatic melanoma. Ipilimumab,
h Ipilimumab, an an anti-CTLA-4 monoclonal antibody
anti/CTLA-4 monoclonal
recently approved by the US Food and
antibody recently
Drug Administration, has been associ-
approved by the US Food
and Drug Administration,
ated with objective responses in brain and
has been associated with durable disease control in patients with
objective responses in brain metastases from melanoma.56,57
brain and durable disease Larger studies are needed to better un-
control in patients with derstand what role ipilimumab should
brain metastases from play in relation to radiation therapy for
melanoma. patients with CNS melanoma.
FUTURE DIRECTIONS
The treatment of brain metastases
requires a multimodal approach that
includes radiation therapy, surgery, and
308 www.aan.com/continuum
sometimes chemotherapy. Studies have
shown that there is a clear survival ben-
efit in a subset of patients with single
metastatic lesions and well-controlled
extracranial disease treated with surgery
or SRS in combination with WBRT com-
pared to WBRT alone. In general, WBRT
remains the standard of care in patients
with multiple metastases, widespread
metastatic disease, or poor functional
status. The role of chemotherapy is still
limited to clinical trial settings given the
paucity of large randomized phase III
studies. Investigations are now beginning
to incorporate end points such as neu-
ropsychological outcomes, neurologic
April 2012

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


function, time to progression, and
quality of life in addition to the tradi-
tional outcome measures of survival.
These outcome measures may be
especially relevant in patients whose
survival after diagnosis of brain meta-
stases is expected to be longer than
historical estimates, such as those
patients with ERBB2-positive breast
cancer or EGFR-mutated NSCLC, since
these patients may have well-con-
trolled systemic disease and live long
enough to experience the late toxic-
ities of therapy.
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