The

Oncologist
This material is protected by U.S. Copyright law.
Unauthorized reproduction is prohibited.
For reprints contact: Reprints@AlphaMedPress.com

Diagnosis and Management of Central Nervous System

Metastases from Breast Cancer
ERIC L. CHANG,a SIMON LOb
a
The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA; bLoyola University
Medical Center, Maywood, Illinois, USA

Key Words. Breast cancer Brain metastases Leptomeningeal metastasis Spinal metastasis Choroidal metastasis

L EARNING O BJECTIVES
After completing this course, the reader will be able to:
1. Select appropriate diagnostic tests for brain, spinal, leptomeningeal, and ocular metastases from breast cancer.
2. Select appropriate therapy for brain, spinal, leptomeningeal, and ocular metastases from breast cancer.
3. Discuss the efficacy and toxicities of therapy for brain, spinal, leptomeningeal, and ocular metastases from breast
cancer.

CME Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

A BSTRACT
The brain, cranial nerves, leptomeninges, spinal cord,
and eye compose the central nervous system (CNS) and
are at risk for the development of metastases from breast
cancer. Such metastases are diagnosed on the basis of
clinical suspicion and substantiated by neuroimaging,
resection when indicated, and sampling of cerebrospinal
fluid when leptomeningeal metastasis (LM) is suspected.
Treatment is aimed at palliation of symptoms and preser-
vation of neurologic function. Historically, conventional
radiation therapy has been the mainstay of palliative
treatment for brain, cranial nerve, spinal cord, and ocu-
lar metastases. However, additional treatment options
for brain metastases have been brought about by techno-
logical advances in surgery to resect brain metastases,
and stereotactic radiosurgery (SRS) to focally irradiate
metastases, both of which have been substantiated by
data from randomized trials. Ongoing research is aimed
at refining criteria to select which patients with brain
metastases should undergo surgery and SRS and how
these focal therapies should be optimally integrated
with whole-brain radiotherapy. Therapy for LM must
carefully balance the potential risks and perceived ben-
efits associated with CNS-directed therapies. Despite
advances in neuroimaging, surgery, and radiation ther-
apy, novel treatments are needed to improve the effec-
tiveness of treatments for CNS metastases, especially LM,
while reducing attendant neurotoxicity. The Oncologist
2003;8:398-410

INTRODUCTION risk for developing metastases from breast cancer. Metastasis

The brain, cranial nerves, spinal cord, leptomeninges, and to the brain is diagnosed in patients with breast cancer at a rate
eyes compose the central nervous system (CNS) and can be at of 10%-20%, making breast cancer the second most common

Correspondence: Eric L. Chang, M.D., The University of Texas M.D. Anderson Cancer Center, Division of Radiation
Oncology, 1515 Holcombe Boulevard, Unit 97, Houston, Texas 77030, USA. Telephone: 713-563-2336; Fax: 713-563-
2331; e-mail: echang@mdanderson.org Received April 2, 2003; accepted for publication May 28, 2003. AlphaMed Press
1083-7159/2003/$12.00/0

The Oncologist 2003;8:398-410 www.TheOncologist.com

399 CNS Metastases from Breast Cancer

source of brain metastases [1-3]; the true prevalence, however, In the case of solitary metastases, surgical resection should be
as determined on the basis of autopsy data, could be as high as performed if possible to firmly establish the diagnosis of brain
30% [4]. Patients with breast cancer rarely present with mani- metastasis because this is the first manifestation of metastatic
festations of brain metastasis before detection of the primary disease. A brain lesion could represent an abscess, glioma, or
breast cancer [5]. The median interval between the diagnoses even meningioma, since patients with breast cancer have a
of breast cancer and brain metastasis is 34 months [2]. Brain slightly higher incidence of meningioma than does the general
metastasis is usually associated with aggressive tumor behav- population [11, 12]. It should be noted that a biopsy-proven
ior, a negative hormone-receptor status, relatively young age false-positive rate of 11% for presumed single brain metas-
(premenopausal), and the presence of lung and liver metas- tases was reported in patients undergoing screening for a ran-
tases. In most series, no relationship has been found between domized brain metastasis trial [13]. The management of single
the primary tumor size and number of positive lymph nodes brain metastases, which constitute up to 50% of all brain
and the development of brain metastases [6, 7]. metastases presentations, deserves special consideration.
The estimated frequencies of leptomeningeal metastasis While surgical resection remains the gold standard for the
(LM) in clinical and autopsy series of patients with breast can- treatment of single brain metastases, it is important to ade-
cer are 2%-5% and 3%-6%, respectively [8]. The incidence of quately stage the extent of metastatic brain disease preopera-
epidural spinal cord compression in patients with breast can- tively with MRI because occult metastases undetected on CT
cer is reported to be 4% [9]. Breast cancer metastasizes to the may render surgery inappropriate if multiple metastases are
eye at a higher rate than do other primary cancers [10]. present [14]. For ambiguous single brain lesions suspected to
be brain metastases but too small to resect, observation with
DIAGNOSTIC CONSIDERATIONS serial MRI studies until tumor growth can be confirmed may
The diagnosis of brain metastasis is made on the basis of be prudent [15, 16]. A treatment algorithm for the primary
clinical suspicion that must be confirmed by contrast- treatment of brain metastases is presented in Figure 1.
enhanced computed tomography (CT) or, preferably, mag-
netic resonance imaging (MRI) of the brain. According to MANAGEMENT OF CNS BRAIN METASTASES
one series, patients with brain metastases from breast cancer
presented with motor symptoms including deficit and gait Medical Treatment
disturbances (24%), seizures (23%), headaches (16%), cog- Symptomatic therapy involving medical treatment is
nitive dysfunction (14%), nausea and vomiting (11%), cra- aimed at stabilizing the acute neurologic symptoms caused
nial nerve dysfunction (10%), cerebellar symptoms (2%), by peritumoral edema and controlling seizures. Headache,
and speech disturbances (2%) [4].
MRI is the most sensitive
method of detecting brain metas- Primary therapy for metastatic brain disease
tases. For brain metastases, the term Surgery
solitary indicates the absence of Lesion number Diagnostic uncertainty
and asymptomatic
or
If grows, surgery
extracranial metastatic disease, <1 cm observation
or SRS WBRT
whereas the term single merely Convincing metastasis
indicates the presence of one brain 1
KPS 70 and *Surgery or SRS
metastasis with no implication as to Single controlled primary (<3 cm) WBRT
>1 cm
the status of extracranial disease [5].
KPS < 70 and WBRT (surgery if tumor
uncontrolled primary causes mass effect)
Figure 1. Treatment algorithm detail- Solitary Surgery WBRT
ing treatment for newly diagnosed or
brain metastases. *Whether surgery or SRS (<3 cm) WBRT
SRS is offered depends on the size and for non-surgical candidate
location of the tumor and the presence (if >3 cm, WBRT only)
or absence of pressure effects. Lesions 2-3 WBRT SRS for KPS 70 and controlled primary
>3 cm are, in general, not suitable for or
SRS. Lesions causing significant pres- Surgery (if highly symptomatic or mass effect) + WBRT
sure effects are best treated with or
surgery, if feasible. Lesions located in WBRT for KPS <70 or uncontrolled primary
eloquent areas, such as the motor or
speech cortex, may not be considered >3 WBRT (surgery to lesions causing mass effect)
suitable for surgery.
Chang, Lo
nausea, vomiting, and mental status changes are the most
common signs and symptoms of elevated intracranial pres-
sure. Dexamethasone should be given immediately to
patients with these symptoms, typically with a loading dose
of 10-20 mg followed by doses of 4 mg four times a day. An
H2-receptor antagonist, such as famotidine, should be given
concurrently to protect against gastritis [17], and trimetho-
prim-sulfamethoxazole may help prevent Pneumocystis
carinii pneumonitis [5]. The treatment of patients presenting
with seizures is straightforward and involves the use of stan-
dard anticonvulsants, such as phenytoin, carbamazepine,
and sodium valproate [18].
Patients with brain metastases who receive anticonvul-
sant therapy have a greater incidence of allergic reactions,
and clear evidence that anticonvulsant therapy reduces the
incidence of seizures in patients who have never had a
seizure is lacking. Therefore, routine prophylactic anticon-
vulsant therapy is probably unnecessary, except in cases of
brain metastases located in the motor cortex and cases
involving synchronous brain metastases and LM [5].
Whole-Brain Radiotherapy for Brain Metastases
Whole-brain radiotherapy (WBRT) is considered stan-
dard treatment for patients with brain metastases and may
prevent or delay progression of neurologic deficits, restore
Figure 2. Treatment response to WBRT in a patient with multiple brain metastases from breast cancer.
400
function, and decrease steroid dependency [19-22]. On
occasion, a robust radiographic response of multiple brain
metastases from breast cancer also can be observed (Fig. 2).
A frequently prescribed WBRT regimen used in the
U.S. to treat brain metastases is 30 Gy in 10 fractions, but
the fractionation schedule should be tailored to patient prog-
nosis so that late toxicity of WBRT can be minimized in
long-term breast cancer survivors. The results of WBRT
alone for brain metastases from breast cancer are shown in
Table 1. Data from the Cleveland Clinic [23], Humboldt
University in Berlin [24], and Karolinska Hospital in
Stockholm [25] showed a median survival ranging from 4.2
to 6.5 months (26 weeks). The prognostic factors implicated
are also shown in Table 1.
Dural-based metastases from breast cancer can be palli-
ated with radiation therapy. If a dural lesion is isolated and
less than 3 cm in diameter, it can be treated with stereotactic
radiosurgery (SRS), otherwise focal techniques using conven-
tional radiation may be used. If a dural lesion is accompanied
by parenchymal metastases, WBRT can be used to treat both
the dural and parenchymal brain metastases simultaneously.
Similarly, isolated skull base lesions that are frequently asso-
ciated with cranial nerve deficits are appropriately treated
with limited-field irradiation encompassing the entire base of
the skull. Care should be taken to allow for cranial irradiation
401 CNS Metastases from Breast Cancer

Table 1. Brain metastases series representing breast cancer patients

Institution n of patients Treatment Survival duration Prognostic factors Remarks
Surgery
M.D. Anderson 63 Surgery + WBRT 16 months Menopause, WBRT, systemic 54 patients (86%)
Cancer Center [33] disease, neurologic status, age received WBRT
Memorial Sloan- 70 Surgery + WBRT 16.2 months Estrogen-receptor status, WBRT, Surgery only in nine
Kettering Cancer leptomeningeal disease patients
Center [32]
SRS
Miami Neuroscience 68 Gamma knife 7.8 months Survival independent of 38 patients previously
Center [101] radiosurgery number of lesions treated received WBRT; average
+/- WBRT of eight lesions treated
per patient
University of 30 Gamma knife 13 months Solitary metastasis Tumor control 93%
Pittsburgh [102] radiosurgery
+ WBRT
WBRT
Cleveland Clinic [23] 116 WBRT 4.2 months KPS Patients treated with
WBRT alone
Humboldt University, 162 WBRT 26 weeks KPS, primary tumor WBRT, 30 Gy in
Berlin [24] size, dose, solitary 15 fractions
Karolinska Hospital, 99 WBRT 5 months Extracranial disease Median time from breast
Stockholm [25] cancer diagnosis to brain
metastasis was 33 months
Chemotherapy
Italian Oncology 56 Front-line 31 weeks Post-chemotherapy
Group [103] chemotherapy: WBRT may have
platinum, etoposide, confounded results
median 3 cycles,
(range 1-8)

to be given at a future date in case brain metastases develop.
This can be accomplished by giving 10 2.5-Gy fractions of
radiation to the base of skull, allowing for a subsequent course
of 10 3-Gy fractions of cranial irradiation to be given. The
optic chiasm should be appropriately blocked to avoid optic
neuropathy.
radiation (3-6 Gy) may have contributed to a greater inci-
dence of late toxicities. On the basis of results from that
study, fractionation schemes with smaller fraction sizes,
such as 30 Gy in 12 fractions of 2.5 Gy/day or even 30 Gy
in 15 fractions of 2 Gy/day, may need to be considered for
patients with favorable prognostic factors.

Toxicity of WBRT Surgery for Brain Metastases

The acute toxicities of WBRT include headache, nau-
sea, possible vomiting, blockage of ears, mild-to-moderate
fatigue, hair loss, and mild scalp erythema leading to skin
hyperpigmentation. Hair usually returns after 3-6 months,
but occasionally hair loss may be permanent and may be due
to dose hot spots created by tangential radiation beams
over the vertex of the head. Long-term survivors may be at
risk for developing progressive dementia, ataxia, and even
urinary incontinence. CT identified cortical atrophy and
hypodense white-matter changes in one study [26]. Those
changes were most likely due to demyelination secondary to
irradiation of the brain [27]. Unusually large fractions of
The goals of surgery in the management of brain metas-
tases are to obtain immediate symptom relief, gain local con-
trol of the metastasis, and confirm the diagnosis histologically
[28]. Most lesions are surgically accessible due to improve-
ments in stereotactic techniques, cortical mapping, and the
use of ultrasonography [29]. For the general population of
patients with brain metastases, a landmark randomized trial
demonstrated that selected patients with resectable single
brain metastases randomized to undergo resection and WBRT
survived longer than did those who received biopsies and
WBRT alone [30]. This randomized trial and a confirmatory
trial have established surgery and postoperative irradiation as
Chang, Lo
the standard approach for such patients [31]. Retrospective
data from the Memorial Sloan-Kettering Cancer Center [32]
and the M.D. Anderson Cancer Center [33] on the surgical
treatment of brain metastases from breast cancer showed
median survival times of approximately 16 months (Table 1).
Stereotactic Radiosurgery for Brain Metastases
The hallmark of SRS is the rapid dose fall-off at the tar-
get edges, permitting a clinically significant dose to be given
to the target while a clinically insignificant dose is delivered
to the surrounding brain [28]. The combined experience from
multiple institutions using SRS for single brain metastases
considered eligible for resection showed that SRS and
WBRT for a single brain metastasis produced a median sur-
vival of 56 weeks [34]. The advantages of SRS include lower
risks for hemorrhage, infection, and tumor seeding, as well as
lower costs from not requiring hospitalization. On the other
hand, surgery immediately relieves the mass effects, pro-
vides a pathologic diagnosis, and has no risk of radiation
necrosis [35]. In the Radiation Therapy Oncology Group
(RTOG) 95-08 trial, patients with one to three brain metas-
tases were randomized to receive WBRT either alone or with
SRS. The results showed a survival benefit associated with
SRS for patients with single metastases [36, 37]. It was also
noted that patients in the WBRT plus SRS group were more
likely to have stable or improved performance statuses than
were members of the WBRT alone group.
Adjuvant WBRT
The role of postoperative radiation therapy for brain
metastases not exclusive to breast cancer has been examined
by several retrospective studies, most of which did not
demonstrate any survival benefit associated with postopera-
tive WBRT [26, 38-42]. The only prospective randomized
study included mostly patients with lung cancer but also
included nine patients with single brain metastases from
breast cancer who were treated with complete surgical resec-
tion and then randomized to undergo either postoperative
WBRT or observation. Recurrence was significantly less fre-
quent in the WBRT group (18%) than in the observation
group (70%) (p < 0.001). The incidence of neurologic death
was also lower in the postoperative WBRT group (14% ver-
sus 44%, p = 0.003). Overall survival did not differ signifi-
cantly between the two groups. The investigators in that trial
concluded, on the basis of a demonstrable lower number of
neurologic deaths, that postoperative WBRT should be given
routinely [43], but this point is highly controversial in the
neurooncology community.
The role of adjuvant WBRT in the setting of radiosurgery
has been retrospectively investigated, and the outcomes were
reported from 106 patients with single or multiple brain
402
metastases who were managed initially with SRS or with
SRS followed by WBRT [44]. In both treatment groups, the
median survival was on the order of 11 months. The group
treated with SRS alone had a significantly higher rate of
tumor progression in the brain at 1 year (69%) than the
group receiving SRS plus WBRT (28%). A multi-institu-
tional study retrospectively analyzing 569 evaluable
patients treated with SRS either alone or with WBRT for
brain metastases resulted in a conclusion that the omission
of up-front WBRT did not seem to compromise length of
survival in patients treated with SRS for newly diagnosed
brain metastases [45].
Intracavitary and Interstitial Brain Irradiation
The GliaSite Radiation Therapy System (RTS)
(Proxima Therapeutics; Alpharetta, GA; http://www.glia
site.com) has been approved by the U.S. Food and Drug
Administration for delivering intracavitary radiation for the
treatment of brain tumors. Evaluation of the GliaSite RTS
for the treatment of resected solitary brain metastases is
ongoing in a multicenter prospective phase II study. It is a
single-applicator system that is used to deliver a conformal
dose of 60 Gy of radiation to a depth 10 mm beyond the
resection cavity at risk for recurrence. The radiation source
consists of Iotrex (125I radiotherapy solution) infused
through the GliaSite RTS catheter, which has a dual silicone
balloon configuration at the distal end. The inner balloon acts
as a reservoir for the Iotrex, while the outer balloon acts as
a backup reservoir in case the integrity of the inner balloon is
compromised. The primary end point of that study is the 1-
year local control rate of a resected solitary metastasis treated
with GliaSite RTS.
Cosgrove et al. reported the use of a novel SRS device
for interstitial irradiation of malignant brain tumors.
Fourteen patients with cerebral lesions less than 3.5 cm in
greatest diameter were treated with 12.5 Gy of radiation.
Local control was obtained in 10 of the 13 patients with
tumors, with a mean follow-up of 12 months. However, the
use of this system has not been popularized [46].
Repeat Cranial Irradiation
Of the two types of repeat irradiation (SRS and WBRT),
SRS is preferable if it can be done, because it can spare nor-
mal brain from being irradiated. Repeat WBRT should be
reserved for patients with greater than three recurrent lesions
who have limited systemic disease, good performance status,
and a controlled primary. Not infrequently, the radiation
oncologist may be called upon to consider reirradiation in
cases in which patients who have already received WBRT
develop new or progressive brain metastases. The results of
a study examining reirradiation with SRS in the context of
403
prior WBRT were reported [47]. That study involved 18
patients with 21 recurrent or persistent brain metastases
treated with SRS. Patient eligibility requirements for treat-
ment were Karnofsky Performance Score (KPS) 70 and sta-
ble systemic disease. With a reported median follow-up of 9
months, all tumors treated were controlled and no cases of
symptomatic radiation necrosis occurred. Breneman et al.
reported a series of 84 patients (79 of whom had recurrent
brain metastases and prior WBRT) with brain metastases
treated with SRS [48]. The median survival time and median
time to failure were 43 weeks and 35 weeks, respectively.
Noel et al. reported a 2-year local control rate of 84%, a 2-
year brain control rate of 57%, and a 2-year overall survival
of 28% for 54 patients treated with SRS for recurrent brain
metastases [49].
The RTOG 90-05 study was initiated to study the maxi-
mum tolerable dose of single-fraction SRS in patients with
previously irradiated primary brain tumors or brain metas-
tases [50]. Multivariate analysis showed that maximum
tumor diameter was associated with a significantly greater
risk of grade 3, 4, or 5 neurotoxicity. The following dose rec-
ommendations were made: 24 Gy for tumors 2 cm, 18 Gy
for tumors 2-3 cm, and 15 Gy for tumors 3-4 cm in maximum
diameter [51].
When recurrences following WBRT are too numerous to
treat with SRS, carefully evaluated reirradiation with WBRT
can be considered. The largest published series on external
beam reirradiation of brain metastases involved 86 patients
from the Mayo Clinic [52]. The median survival following
reirradiation was 4 months. There was complete symptom
resolution in 27%, partial resolution in 43%, and no change or
worsening of neurologic symptoms in 29% of patients. No
significant toxicity related to reirra-
diation in the majority of patients
was reported. The absence of
extracranial disease was associ-
ated with greater survival on mul-
tivariate analysis. A treatment
algorithm for recurrent metastatic
brain disease based on our own
practice is presented in Figure 3.
Recurrent
metastatic
Radiation Sensitization for Brain brain
disease
Metastases
RSR13 (efaproxiral; Allos
Therapeutics; Westminster, CO;
http://www.allos.com) is an allo-
Systemic disease
steric modifier of hemoglobin that progression and
limited systemic
therapy options
Figure 3. Treatment algorithm for
recurrent brain metastases.
CNS Metastases from Breast Cancer
decreases the affinity of hemoglobin binding to oxygen, per-
mitting greater oxygenation of hypoxic tumor cells to theo-
retically enhance radiation cell killing. A multicenter,
randomized, open-label phase III study was completed,
involving 538 patients, 107 of whom were prestratified breast
cancer patients, demonstrating a doubling in median survival
time among eligible patients with metastatic breast cancer
who received WBRT plus RSR13 versus WBRT alone
(9 months versus 4.47 months, p = 0.002). Preliminary results
will be reported at a scientific meeting and are available
online [53]. A confirmatory trial focused on brain metastases
from breast cancer is currently planned.
Chemotherapy for Brain Metastases
The role of chemotherapy for the treatment of brain
metastases has not been defined [5]. Because of the blood-
brain barrier, chemotherapy is rarely used as part of the
treatment plan for brain metastases. A study was conducted
by Rosner et al., who treated 100 patients with brain metas-
tases from breast cancer [54]. Fifty percent of patients had
an objective response (10% complete response and 40%
partial response), whereas 9% had stable disease. The
median duration of remission was 10 months for those who
had a complete response and 7 months for those who had a
partial response. The most common regimens used were
CFP (cyclophosphamide, 5-fluorouracil, and prednisone)
and CFPMV (CFP plus methotrexate and vincristine).
Rosner et al. used the same regimens and added cyclophos-
phamide and doxorubicin for an additional 26 patients with
progressive brain metastases from breast cancer. The
median survival time in that study was 12 months for
responders but only 2.4 months for nonresponders [55].
Salvage therapy
SRS to eligible lesions
1-3 Surgery for mass effect
Recurrent or
metastases WBRT if not previously
Absent or
stable systemic given
disease
WBRT if not previously
>3
given
Recurrent
WBRT if good prior
metastases
response to WBRT
(>4 months interval)
Limited field radiotherapy
Chemotherapy
Rapid course WBRT
(4 Gy 5 or 3 Gy 10)
if no previous WBRT
or
Supportive care
or
Chemotherapy
Chang, Lo 404

More recently, temozolamide has been investigated. It is an

agent with a good safety profile that crosses the blood-brain
barrier and has shown activity against many solid tumors.
Early data showed that the drug was safe and well tolerated
and demonstrated antitumor activity [56]. A phase II trial
showed partial response and disease stabilization rates of
4% and 17%, respectively, in heavily pretreated patients
with brain metastases from solid tumors (four of 27 patients
had breast cancer) [57]. Another phase II trial showed 6%
and 44% partial response and disease stabilization rates for
patients with recurrent or progressive brain metastases [58].
The median survival was 6.6 months. Clinical activity
against brain metastases from breast cancer was shown for
capecitabine in one case report [59].

MANIFESTATIONS OF CNS METASTASES OTHER

THANBRAIN

LM
LM is an increasingly common complication of breast
cancer [8, 60], and breast cancer accounts for the largest
number of patients in most large series evaluating LM [61].
Both clinical and autopsy series confirm the propensity of
lobular carcinoma to spread to the leptomeninges, although
the reason for this propensity is not known [62-64]. The
occurrence of LM can range from weeks to more than 15
years from the initial breast cancer diagnosis [65, 66].
Although patients with cancers other than breast tend to
have widespread metastatic disease when LM is diagnosed,
patients with breast cancer may develop LM even when
systemic disease is under control or absent [67]. A diag-
nostic MRI showing LM enhancement of the brain can be
seen in Figure 4.
Spinal symptoms, particularly leg weakness, constitute
the most frequent presentation of LM and are often accom-
panied by paresthesia. The simultaneous occurrence of
multifocal abnormalities at more than one level of the neu-
raxis, from cerebrum, cranial nerve, or spine, is highly sug-
gestive of LM [68]. The obstruction of cerebrospinal fluid
(CSF) flow can lead to headache, changes in mentation
manifested as lethargy, confusion, and memory loss, nau-
sea, vomiting, and ataxia. Seizures are rarely the presenting
symptom. Mental status changes are the most common
finding of cerebral dysfunction. Diplopia, facial weakness,
and diminished hearing are the most frequent cranial nerve
findings [65, 66].
The demonstration of malignant cells in the CSF by lum-
bar puncture is the definitive method for diagnosing LM. The
success of obtaining malignant cells depends on the amount
of CSF available for analysis and increases with additional
spinal taps. An elevated CSF protein level and a mononuclear
Figure 4. Axial T1-weighted contrast-enhanced MRI of the brain in
a breast cancer patient with LM. Enhancement of the cerebellar folia
and pial enhancement around the pons can be seen (arrows).
pleocytosis are commonly present. Less frequently, a patho-
logically abnormal CSF glucose level <70% of the serum glu-
cose level is discovered. The CSF carcinoembryonic antigen
(CEA) level is elevated in some cases of breast carcinoma
metastatic to the leptomeninges, but must be compared with
the serum CEA level because CEA can cross the blood-brain
barrier. Elevated CEA levels in CSF may be a result of ele-
vated serum CEA levels [69]. Neuroimaging is necessary to
help diagnose and define the extent of disease, which may be
as low as the cauda equina (Fig. 5), and to determine whether
parenchymal brain metastases exist. Patients with LM require
MRI of the entire brain and spine to identify bulk disease.
Radiation therapy is focally directed to bulky or symptomatic
sites of disease along the craniospinal neuraxis. Intrathecal
chemotherapy administration follows radiation therapy.
Cerebrospinal fluid flow studies are needed for patients with
normal imaging to show flow abnormalities that may interfere
with the delivery of intrathecal chemotherapy and that may be
relieved with focal irradiation [70]. The preferred route of
administration of chemotherapy is intraventricular, to assure
steady therapeutic levels into the CSF. The standard agents
administered intrathecally are limited to methotrexate, thiotepa
to a lesser extent, and rarely cytarabine, except in the form of
a DepoCyt (SkyePharma; London, UK; http://www.skye
pharma.com), a recently available slow-release preparation
 405
Figure 5. Sagittal contrast-enhanced MRI of the spine. LM and bone metastasis
are present in this breast cancer patient. Enhancement is seen along the dorsal
aspect of the thoracic cord (arrows). In the lumbosacral spine, there is a lep-
tomeningeal tumor nodule posterior to the L2 vertebral body (arrow). A bony
metastatic lesion is seen in the L5 vertebral body (dashed arrow).
that can be administered once every 2 weeks. A randomized
trial comparing DepoCyt with intrathecal methotrexate in
patients with neoplastic meningitis showed similar response
rates and a significantly greater time to neurological progres-
sion (58 days versus 30 days) [71]. Although a number of
agents, including mafosfamide (a derivative of cyclophos-
phamide), busulfan, topotecan, diaziquinone, interferon,
monoclonal antibodies, and interleukin-2, as well as gene
therapy, are under active investigation, these are limited to use
in the setting of experimental protocols and are not widely
available [72]. There is no agreed upon standard regarding the
best therapy. Therefore, expected complications may be the
overriding factor in deciding whether or not to give treatment
that may have a profoundly negative effect on the quality of
life of patients with short-term life expectancies [70].
Neurotoxicity from Treatment of LM
All CNS-directed therapies designed to treat LM are
associated with high rates of complications [70]. The most
serious potential delayed toxicity that can occur from cranial
irradiation is leukoencephalopathy, which is diagnosed by
CNS Metastases from Breast Cancer
MRI. Typical findings of leukoencephalopathy include
periventricular white-matter hyperintensity on T2-weighted
and fluid attenuated inversion recovery (FLAIR) images,
brain atrophy, and ventricular dilatation. Symptoms include
cognitive decline, behavioral changes, gait abnormalities,
and seizures. The use of radiotherapy with chemotherapy,
especially methotrexate, may enhance the likelihood of
developing leukoencephalopathy but may not be clinically
significant because of the very limited prognosis of patients
with LM [73].
While the Ommaya reservoir provides a consistent
means of achieving therapeutic drug levels, surgical compli-
cations from the Ommaya reservoir may arise in up to 10%
of cases. A very high complication rate of about 70%, rang-
ing from 37% to 84% in 14 series, has been reported on
intra-CSF chemotherapy [70]. Severe and life-threatening
complications account for 20%-45% of all complications,
including neutropenia, sepsis, meningitis, decline in con-
sciousness, and ascending myelopathy. Treatment-related
deaths are reported to occur at a rate of about 5%. Aseptic
meningitis is a frequently encountered complication directly
related to intra-CSF injection and occurs at a rate of about
20%. Unrelated to any specific agent injected into the CSF,
aseptic meningitis is marked by an abrupt onset of headache,
stiff neck, nausea, vomiting, lethargy, and fever several hours
after the injection and may last for 12 to 72 hours.
Focal radiation therapy is used to palliate symptomatic
cranial neuropathies and bulky tumor deposits that may
impair CSF flow and delivery of intrathecal drugs. Chemo-
therapy is used to treat the entire CSF compartment. Cranio-
spinal irradiation is not indicated as a first-line therapy in the
treatment of LM because it can cause severe myleosuppres-
sion, precluding subsequent chemotherapy. In our experience,
craniospinal irradiation may be occasionally offered as palli-
ation for increased symptoms related to LM as a last measure
in the setting of intrathecal chemotherapy failure [74].
Spinal Metastases
Epidural metastases arise most commonly from the ver-
tebral column (85% of cases) and less commonly from the
paravertebral space, invading the epidural space through
bone or the neuroforamen [75]. The vertebral column is the
most common site for bone metastases, with incidences of
60% in patients with breast cancer [76] and up to 84% in
those with advanced breast cancer (Fig. 5) [3]. Epidural
spinal cord compression occurs with an incidence of 4% in
patients with breast cancer [9]. Spinal cord damage results
from direct compression of the spinal cord by the tumor
rather than from compression of radicular arteries [3]. The
median time from diagnosis of breast cancer to epidural
spinal cord compression is 42 months [9]. The thoracic
Chang, Lo
spine is most commonly involved in cases of spinal metas-
tasis. The principal symptom of spinal metastasis is pain,
which may be local, radicular, or referred, and precedes
other symptoms by a mean of 6 weeks [77]. Isolated back
pain without neurologic symptoms should be evaluated first
with plain spine radiographs. If an abnormality is found,
then further evaluation should be performed with spinal
MRI. If the diagnosis still remains uncertain, bone scan and
high-resolution CT of the vertebrae may also be performed
to distinguish benign lesions, such as hemangioma, from
bone metastases.
Pain is usually worsened by lying supine, coughing,
sneezing, or straining. Myelopathy can occur in the form of
limb weakness, numbness, paresthesia, and alterations in
bladder and bowel functions. Signs of myelopathy may
include increased tone, clonus, hyperreflexia, bladder dis-
tension, or an abnormal sensory level. In the setting of
myelopathy, the entire spinal cord should be imaged with
MRI. Left untreated, epidural spinal cord compression will
inexorably lead to paraplegia or quadriplegia, depending
upon the level of compression along the spine. Therefore,
prompt evaluation is of the utmost importance when
epidural spinal cord compression is suspected. Once
epidural spinal cord compression is diagnosed, steroids
should be instituted immediately, along with emergent radi-
ation therapy. A randomized study showed that high-dose
(100 mg loading dose) dexamethasone preceding radiother-
apy resulted in a greater proportion of patients who were
able to ambulate after treatment [78]. Patients whose MRI
demonstrates epidural disease without cord compression
can be given a lower loading dose of 10 mg dexametha-
sone. Maintenance dosing consists of 4 mg of dexametha-
sone every 6 hours and should be slowly tapered once
radiation therapy has begun and symptoms have stabilized.
Radiation therapy to the involved region is the treatment of
choice for most patients with epidural spinal cord compres-
sion. For progressive or recurrent spinal cord progression in
the previously irradiated spine, surgery is recommended
because of the risk of radiation myelopathy from reirradia-
tion. Laminectomy is not highly effective, because most
epidural metastases are located in the anterolateral location,
which is difficult to decompress using a posterior approach,
and may further weaken the spine. Vertebral body resection
and stabilization with methylmethacrylate cement has been
used to overcome problems with laminectomy. Results
from nonrandomized studies suggest that vertebral body
resection restores ambulatory function better than does
radiation therapy [79-82]. However, the highly selected
patient population in those studies and the use of historical
controls may limit the generalizability and validity of such
results. For patients who are ambulatory prior to treatment,
406
ambulation is preserved on the order of 80% of patients.
However, in those who are paraplegic or quadriplegic, the
rate is less than 10% [9, 83-85]. The median survival time
in patients with breast cancer who develop spinal cord com-
pression ranges from 4 to 13 months in those studies, yet
ambulatory status following treatment is the most important
prognostic factor for survival [9, 85].
Current research in the treatment of metastatic spinal dis-
ease is aimed at developing image-guided SRS procedures
that may be used to safely treat paraspinal metastases [86,
87]. It is hoped that the metastasis control rates achieved with
spinal SRS will be comparable with those achieved with
intracranial SRS.
Ocular Metastases
The choroid is the most common site for ocular metas-
tasis; among all cancers, breast cancer has the highest inci-
dence (40%-70%) of ocular metastatic involvement
[88-93]. Diagnosis should be made by indirect fundoscopic
examination. After a diagnosis of ocular metastasis has
been established, it is important to image the brain for
metastatic involvement, because simultaneous metastatic
involvement to the brain is common. The median time from
diagnosis of breast cancer to development of choroidal
metastasis is 4 years [94]. Presenting symptoms include
worsened visual acuity, blind spot, diplopia, and image dis-
tortion. Fundoscopic examination may reveal retinal
detachment and hemorrhage [95]. For progressive visual
symptoms, patients should be referred for palliative radia-
tion therapy. The target volume to be irradiated is the entire
choroid posterior to the equator. For bilateral disease, both
eyes should be treated. For patients with synchronous brain
metastases, the field includes the entire cranial contents and
the posterior halves of the globes. Fractionation schemes of
20 Gy in 2 weeks, 25 Gy in 1-2 weeks, 30 Gy in 2 weeks,
and 50 Gy in 5 weeks have been described, with the major-
ity demonstrating a response rate of greater than about 60%
[96-99]. Reported complications include retinopathy, ker-
atopathy, optic neuropathy, and glaucoma [100]. In a series
of 42 breast cancer patients with choroid metastases treated
with radiation therapy, the median survival time was 10
months [99].
CONCLUSION
The CNS remains a sanctuary site for metastases from
breast cancer. The need for more effective CNS-directed
treatments may become more pressing because improve-
ments in systemic treatment for breast cancer could lead to
a greater incidence of CNS metastases. Radiation therapy
remains the mainstay of treatment for CNS metastases.
Technological advances have enabled focal treatment,
407
such as surgery and SRS, to benefit patients with limited
metastatic brain disease and good performance statuses.
Similarly, it is hoped that focused treatments to the spine
using spinal SRS, which are currently under active investi-
gation, may be beneficial as well. The treatment of LM
R EFERENCES
1 Lee YT. Breast carcinoma: pattern of metastasis at autopsy.
J Surg Oncol 1983;23:175-180.
2 DiStefano A, Yong Yap Y, Hortobagyi GN et al. The natural
history of breast cancer patients with brain metastases.
Cancer 1979;44:1913-1918.
3 Posner JB. Back pain and epidural spinal cord compression.
Med Clin North Am 1987;71:185-205.
4 Tsukada Y, Fouad A, Pickren JW et al. Central nervous sys-
tem metastasis from breast carcinoma. Autopsy study.
Cancer 1983;52:2349-2354.
5 Wen PY, Shafman TD. Site-specific therapy of metastatic
breast cancer. In: Harris JR, ed. Disease of the Breast.
Philadelphia: Lippincott Williams & Wilkins, 2000:841-853.
6 Stewart JF, King RJ, Sexton SA et al. Oestrogen receptors,
sites of metastatic disease and survival in recurrent breast
cancer. Eur J Cancer 1981;17:449-453.
7 Sparrow GE, Rubens RD. Brain metastases from breast can-
cer: clinical course, prognosis and influence of treatment.
Clin Oncol 1981;7:291-301.
8 DeAngelis L, Rogers L, Foley KM. Leptomeningeal metas-
tasis. In: Harris JR, ed. Diseases of the Breast. Philadelphia:
Lippincott Williams & Wilkins, 2000:867-874.
9 Hill ME, Richards MA, Gregory WM et al. Spinal cord com-
pression in breast cancer: a review of 70 cases. Br J Cancer
1993;68:969-973.
10 McCormick B, Abramson DH. Ocular metastases. In: Harris
JR, ed. Diseases of the Breast. Philadelphia: Lippincott
Williams & Wilkins, 2000:889-891.
11 Rubinstein AB, Schein M, Reichenthal E. The association of
carcinoma of the breast with meningioma. Surg Gynecol
Obstet 1989;169:334-336.
12 Schoenberg BS, Christine BW, Whisnant JP. Nervous sys-
tem neoplasms and primary malignancies of other sites. The
unique association between meningiomas and breast cancer.
Neurology 1975;25:705-712.
13 Patchell RA, Cirrincione C, Thaler HT et al. Single brain metas-
tases: surgery plus radiation or radiation alone. Neurology
1986;36:447-453.
14 Peretti-Viton P, Margain D, Murayama N et al. Brain metas-
tases. J Neuroradiol 1991;18:161-172.
15 Chang E, Hassenbusch SJ, Lang F et al. What is the opti-
mum timing of radiosurgery for sub-centimeter brain metas-
tases? Neuro-oncol 2002;4:352a.
16 Chang EL, Hassenbusch SJ, Shiu A et al. The role of tumor size
in the radiosurgical management of patients with ambiguous
brain metastases. Neurosurgery 2003;53:272-281.
CNS Metastases from Breast Cancer
remains a significant challenge because of difficulties with
neurotoxicity from combined intrathecal chemotherapy
and radiotherapy. Future research should be directed at
developing more effective agents for LM that have less
neurotoxicity.
17 Levin VA, Prados MR, Wara WM et al. Radiation therapy and
bromodeoxyuridine chemotherapy followed by procarbazine,
lomustine, and vincristine for the treatment of anaplastic
gliomas. Int J Radiat Oncol Biol Phys 1995;32:75-83.
18 Yung W, Kunschner L, Sawaya R et al. Intracranial metas-
tases. In: Levin V, ed. Cancer in the Nervous System,
Second Edition. New York: Oxford University Press,
2002:321-340.
19 Order SE, Hellman S, Von Essen CF et al. Improvement in
quality of survival following whole-brain irradiation for
brain metastasis. Radiology 1968;91:149-153.
20 Borgelt B, Gelber R, Kramer S et al. The palliation of brain
metastases: final results of the first two studies by the
Radiation Therapy Oncology Group. Int J Radiat Oncol Biol
Phys 1980;6:1-9.
21 Kurtz JM, Gelber R, Brady LW et al. The palliation of brain
metastases in a favorable patient population: a randomized
clinical trial by the Radiation Therapy Oncology Group. Int
J Radiat Oncol Biol Phys 1981;7:891-895.
22 West J, Maor M. Intracranial metastases: behavioral patterns
related to primary site and results of treatment by whole
brain irradiation. Int J Radiat Oncol Biol Phys 1980;6:11-15.
23 Mahmoud-Ahmed AS, Suh JH, Lee SY et al. Results of
whole brain radiotherapy in patients with brain metastases
from breast cancer: a retrospective study. Int J Radiat Oncol
Biol Phys 2002;54:810-817.
24 Lentzsch S, Reichardt P, Weber F et al. Brain metastases in
breast cancer: prognostic factors and management. Eur J
Cancer 1999;35:580-585.
25 Fokstuen T, Wilking N, Rutqvist LE et al. Radiation therapy
in the management of brain metastases from breast cancer.
Breast Cancer Res Treat 2000;62:211-216.
26 DeAngelis LM, Mandell LR, Thaler HT et al. The role of
postoperative radiotherapy after resection of single brain
metastases. Neurosurgery 1989;24:798-805.
27 Asai A, Matsutani M, Kohno T et al. Subacute brain atrophy
after radiation therapy for malignant brain tumor. Cancer
1989;63:1962-1974.
28 Wen PY, Loeffler JS. Management of brain metastases.
Oncology (Huntingt) 1999;12:941-954, 957-961; discussion
961-962, 969.
29 Lang FF, Sawaya R. Surgical management of cerebral
metastases. Neurosurg Clin N Am 1996;7:459-484.
30 Patchell RA, Tibbs PA, Walsh JW et al. A randomized trial
of surgery in the treatment of single metastases to the brain.
N Engl J Med 1990;322:494-500.
Chang, Lo
31 Noordijk EM, Vecht CJ, Haaxma-Reiche H et al. The choice
of treatment of single brain metastasis should be based on
extracranial tumor activity and age. Int J Radiat Oncol Biol
Phys 1994;29:711-717.
32 Wronski M, Arbit E, McCormick B et al. Surgical treatment
of 70 patients with brain metastases from breast carcinoma.
Cancer 1997;80:1746-1754.
33 Pieper DR, Hess KR, Sawaya RE. Role of surgery in the
treatment of brain metastases in patients with breast cancer.
Ann Surg Oncol 1997;4:481-490.
34 Auchter RM, Lamond JP, Alexander E et al. A multiinstitu-
tional outcome and prognostic factor analysis of radiosurgery
for resectable single brain metastasis. Int J Radiat Oncol Biol
Phys 1996;35:27-35.
35 Loeffler J, Alexander E. Radiosurgery for the treatment of
intracranial metastases. In: Loeffler JS, ed. Stereotactic
Radiosurgery. New York: McGraw-Hill, 1993:197-206.
36 Sperduto PW, Scott C, Andrews D et al. Preliminary report
of RTOG 9508: a phase III trial comparing whole brain
irradiation alone versus whole brain irradiation plus stereo-
tactic radiosurgery for patients with two or three unre-
sected brain metastases. Int J Radiat Oncol Biol Phys
2000;48(suppl):133a.
37 Sperduto PW, Scott C, Andrews D et al. Stereotactic radio-
surgery with whole brain radiation therapy improves sur-
vival in patients with brain metastases: report of radiation
therapy oncology group phase III study 95-08. Int J Radiat
Oncol Biol Phys 2002;54:3a.
38 Dosoretz DE, Blitzer PH, Russell AH et al. Management
of solitary metastasis to the brain: the role of elective brain
irradiation following complete surgical resection. Int J
Radiat Oncol Biol Phys 1980;6:1727-1730.
39 Hagen NA, Cirrincione C, Thaler HT et al. The role of radi-
ation therapy following resection of single brain metastasis
from melanoma. Neurology 1990;40:158-160.
40 Smalley SR, Schray MF, Laws ER Jr et al. Adjuvant radia-
tion therapy after surgical resection of solitary brain metas-
tasis: association with pattern of failure and survival. Int J
Radiat Oncol Biol Phys 1987;13:1611-1616.
41 Skibber JM, Soong SJ, Austin L et al. Cranial irradiation
after surgical excision of brain metastases in melanoma
patients. Ann Surg Oncol 1996;3:118-123.
42 Armstrong JG, Wronski M, Galicich J et al. Postoperative
radiation for lung cancer metastatic to the brain. J Clin Oncol
1994;12:2340-2344.
43 Patchell RE, Tibbs PA, Regine WF et al. Postoperative
radiotherapy in the treatment of single metastases to the
brain: a randomized trial. JAMA 1998;280:1485-1489.
44 Sneed PK, Lamborn KR, Forstner JM et al. Radiosurgery for
brain metastases: is whole brain radiotherapy necessary? Int
J Radiat Oncol Biol Phys 1999;43:549-558.
45 Sneed PK, Suh JH, Goetsch SJ et al. A multi-institutional
review of radiosurgery alone vs. radiosurgery with whole
brain radiotherapy as the initial management of brain metas-
tases. Int J Radiat Oncol Biol Phys 2002;53:519-526.
408
46 Cosgrove GR, Hochberg FH, Zervas NT et al. Interstitial
irradiation of brain tumors, using a miniature radiosurgery
device: initial experience. Neurosurgery 1997;40:518-523;
discussion 523-525.
47 Loeffler JS, Kooy HM, Wen PY et al. The treatment of
recurrent brain metastases with stereotactic radiosurgery.
J Clin Oncol 1990;8:576-582.
48 Breneman JC, Warnick RE, Albright RE Jr et al. Stereotactic
radiosurgery for the treatment of brain metastases. Results of
a single institution series. Cancer 1997;79:551-557.
49 Noel G, Proudhom MA, Valery CA et al. Radiosurgery for
re-irradiation of brain metastasis: results in 54 patients.
Radiother Oncol 2001;60:61-67.
50 Shaw E, Scott C, Souhami L et al. Radiosurgery for the treat-
ment of previously irradiated recurrent primary brain tumors
and brain metastases: initial report of radiation therapy
oncology group protocol (90-05). Int J Radiat Oncol Biol
Phys 1996;34:647-654.
51 Shaw E, Scott C, Souhami L et al. Single dose radiosurgical
treatment of recurrent previously irradiated primary brain
tumors and brain metastases: final report of RTOG protocol
90-05. Int J Radiat Oncol Biol Phys 2000;47:291-298.
52 Wong WW, Schild SE, Sawyer TE et al. Analysis of out-
come in patients reirradiated for brain metastases. Int J
Radiat Oncol Biol Phys 1996;34:585-590.
53 Allos Therapeutics, Inc. Allos reports preliminary results of
pivotal phase 3 clinical trial of RSR13 in brain metastases.
Press release April 3, 2003. Available at www.allos.com/
press_release.cfm?&id=59. Accessed June 16, 2003.
54 Rosner D, Nemoto T, Lane WW. Chemotherapy induces
regression of brain metastases in breast carcinoma. Cancer
1986;58:832-839.
55 Rosner D, Flower A, Lane W. Chemotherapy induces
regression of brain metastases in breast carcinoma patients:
update study. Proc Am Soc Clin Oncol 1993;12:508a.
56 Antonadou D, Paraskevaidis M, Sarris G et al. Phase II ran-
domized trial of temozolomide and concurrent radiotherapy in
patients with brain metastases. J Clin Oncol 2002;20:3644-
3650.
57 Christodoulou C, Bafaloukos D, Kosmidis P et al. Phase II
study of temozolomide in heavily pretreated cancer patients
with brain metastases. Ann Oncol 2001;12:249-254.
58 Abrey LE, Olson JD, Raizer JJ et al. A phase II trial of temo-
zolomide for patients with recurrent or progressive brain
metastases. J Neurooncol 2001;53:259-265.
59 Wang ML, Yung WK, Royce ME et al. Capecitabine for 5-
fluorouracil-resistant brain metastases from breast cancer.
Am J Clin Oncol 2001;24:421-424.
60 Chamberlain MC, Kormanik PR. Carcinomatous meningitis
secondary to breast cancer: predictors of response to com-
bined modality therapy. J Neurooncol 1997;35:55-64.
61 Grossman SA. Advances in the treatment of central nervous
system metastases: treatment of neoplastic meningitis. In:
Perry M, ed. American Society of Clinical Oncology 2001
409
Educational Book. Alexandria: American Society of Clinical
Oncology, 2001:598-603.
62 Harris M, Howell A, Chrissohou M et al. A comparison of
the metastatic pattern of infiltrating lobular carcinoma and
infiltrating duct carcinoma of the breast. Br J Cancer
1984;50:23-30.
63 Lamovec J, Zidar A. Association of leptomeningeal carcino-
matosis in carcinoma of the breast with infiltrating lobular
carcinoma. An autopsy study. Arch Pathol Lab Med
1991;115:507-510.
64 Smith DB, Howell A, Harris M et al. Carcinomatous menin-
gitis associated with infiltrating lobular carcinoma of the
breast. Eur J Surg Oncol 1985;11:33-36.
65 Ongerboer de Visser BW, Somers R, Nooyen WH et al.
Intraventricular methotrexate therapy of leptomeningeal metas-
tasis from breast carcinoma. Neurology 1983;33:1565-1572.
66 Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treat-
ment of leptomeningeal metastases from solid tumors: expe-
rience with 90 patients. Cancer 1982;49:759-772.
67 Yap HY, Yap BS, Rasmussen S et al. Treatment for meningeal
carcinomatosis in breast cancer. Cancer 1982;50:219-222.
68 Jayson GC, Howell A. Carcinomatous meningitis in solid
tumours. Ann Oncol 1996;7:773-786.
69 Twijnstra A, van Zanten AP, Hart AA et al. Serial lumbar
and ventricle cerebrospinal fluid lactate dehydrogenase
activities in patients with leptomeningeal metastases from
solid and haematological tumours. J Neurol Neurosurg
Psychiatry 1987;50:313-320.
70 Siegal T. Toxicity of treatment for neoplastic meningitis.
Curr Oncol Rep 2003;5:41-49.
71 Glantz MJ, Jaeckle KA, Chamberlain MC et al. A random-
ized controlled trial comparing intrathecal sustained-release
cytarabine (DepoCyt) to intrathecal methotrexate in patients
with neoplastic meningitis from solid tumors. Clin Cancer
Res 1999;5:3394-3402.
72 Berg SL, Chamberlain MC. Systemic chemotherapy,
intrathecal chemotherapy, and symptom management in the
treatment of leptomeningeal metastasis. Curr Oncol Rep
2003;5:29-40.
73 Brecher ML, Berger P, Freeman AI et al. Computerized tomog-
raphy scan findings in children with acute lymphocytic
leukemia treated with three different methods of central nervous
system prophylaxis. Cancer 1985;56:2430-2433.
74 Chang EL, Maor MH. Standard and novel radiotherapeutic
approaches to neoplastic meningitis. Curr Oncol Rep
2003;5:24-28.
75 McColl CD, Freilich RJ. Epidural metastases. In: Harris JR,
ed. Disease of the Breast. Philadelphia: Lippincott Williams
& Wilkins, 2000:855-865.
76 Fornasier VL, Horne JG. Metastases to the vertebral column.
Cancer 1975;36:590-594.
77 Kim RY, Spencer SA, Meredith RF et al. Extradural spinal
cord compression: analysis of factors determining functional
CNS Metastases from Breast Cancer
prognosisprospective study. Radiology 1990;176:279-
282.
78 Sorensen S, Helweg-Larsen S, Mouridsen H et al. Effect of
high-dose dexamethasone in carcinomatous metastatic spinal
cord compression treated with radiotherapy: a randomised
trial. Eur J Cancer 1994;32A:22-27.
79 Harrington KD. Anterior cord decompression and spinal sta-
bilization for patients with metastatic lesions of the spine.
J Neurosurg 1984;61:107-117.
80 Siegal T, Siegal T. Surgical decompression of anterior and
posterior malignant epidural tumors compressing the spinal
cord: a prospective study. Neurosurgery 1985;17:424-432.
81 Sundaresan N, Galicich JH, Lane JM et al. Treatment of neo-
plastic epidural cord compression by vertebral body resection
and stabilization. J Neurosurg 1985;63:676-684.
82 Sundaresan N, Digiacinto GV, Hughes JE et al. Treatment of
neoplastic spinal cord compression: results of a prospective
study. Neurosurgery 1991;29:645-650.
83 Gilbert RW, Kim JH, Posner JB. Epidural spinal cord com-
pression from metastatic tumor: diagnosis and treatment.
Ann Neurol 1978;3:40-51.
84 Sorensen PS, Borgesen SE, Rohde K et al. Metastatic
epidural spinal cord compression. Results of treatment and
survival. Cancer 1990;65:1502-1508.
85 Maranzano E, Latini P, Checcaglini F et al. Radiation ther-
apy of spinal cord compression caused by breast cancer:
report of a prospective trial. Int J Radiat Oncol Biol Phys
1992;24:301-306.
86 Ryu SI, Chang SD, Kim DH et al. Image-guided hypo-fraction-
ated stereotactic radiosurgery to spinal lesions. Neurosurgery
2001;49:838-846.
87 Yenice KM, Lovelock DM, Hunt MA et al. CT image-
guided intensity-modulated therapy for paraspinal tumors
using stereotactic immobilization. Int J Radiat Oncol Biol
Phys 2003;55:583-593.
88 Albert DM, Rubenstein RA, Scheie HG. Tumor metastasis
to the eye. Incidence in 213 adult patients with generalized
malignancy. Am J Ophthalmol 1967;63:723-726.
89 Bloch RS, Gartner S. The incidence of ocular metastatic
carcinoma. Arch Ophthalmol 1971;85:673-675.
90 Ferry AP. The biological behavior and pathological features
of carcinoma metastatic to the eye and orbit. Trans Am
Ophthalmol Soc 1973;71:373-425.
91 Freedman MI, Folk JC. Metastatic tumors to the eye and
orbit. Patient survival and clinical characteristics. Arch
Ophthalmol 1987;105:1215-1219.
92 Glassburn JR, Klionsky M, Brady LW. Radiation therapy for
metastatic disease involving the orbit. Am J Clin Oncol
1984;7:145-148.
93 Stephens RF, Shields JA. Diagnosis and management of can-
cer metastatic to the uvea: a study of 70 cases. Ophthalmology
1979;86:1336-1349.
Chang, Lo
94 Ratanatharathorn V, Powers WE, Grimm J et al. Eye metasta-
sis from carcinoma of the breast: diagnosis, radiation treatment
and results. Cancer Treat Rev 1991;18:261-276.
95 Reese A. Neoplastic metastasis to the eye and orbit. In:
Tumors of the Eye. New York: Harper and Row, 1963:496.
96 Rottinger EM, Heckemann R, Scherer E et al. Radiation
therapy of choroidal metastases from breast cancer. Albrecht
Von Graefes Arch Klin Exp Ophthalmol 1976;200:243-250.
97 Chu FC, Huh SH, Nisce LZ et al. Radiation therapy of choroid
metastasis from breast cancer. Int J Radiat Oncol Biol Phys
1977;2:273-279.
98 Thatcher N, Thomas PR. Choroidal metastases from breast
carcinoma: a survey of 42 patients and the use of radiation
therapy. Clin Radiol 1975;26:549-553.
99 Maor M, Chan RC, Young SE. Radiotherapy of choroidal
metastases: breast cancer as primary site. Cancer
1977;40:2081-2086.
410
100 Rudoler SB, Shields CL, Corn BW et al. Functional vision
is improved in the majority of patients treated with exter-
nal-beam radiotherapy for choroid metastases: a multi-
variate analysis of 188 patients. J Clin Oncol
1997;15:1244-1251.
101 Amendola BE, Wolf AL, Coy SR et al., Gamma knife radio-
surgery in the treatment of patients with single and multiple
brain metastases from carcinoma of the breast. The Cancer
Journal, 2000;6:88-92.
102 Firlik KS, Kondziolka D, Flickinger JC et al., Stereotactic
radiosurgery for brain metastases from breast cancer. Ann
Surg Oncol, 2000;7:333-338.
103 Franciosi V, Cocconi G, Michiara M et al., Front-line
chemotherapy with cisplatin and etoposide for patients with
brain metastases from breast carcinoma, nonsmall cell lung
carcinoma, or malignant melanoma: a prospective study.
Cancer 1999;85:1599-1605.