metas brain tumors

METASTATIC BRAIN TUMORS 601
CHAPTER 28
Metastatic
brain tumors
Lisa M. DeAngelis, MD, Jay S. Loeffler, MD, and Adam N. Mamelak, MD
Brain metastases occur in ~15% of cancer patients as a result of hematogenous
dissemination of systemic cancer, and the incidence may be rising with better
control of systemic disease. Lung and breast cancers are the most common
solid tumors that metastasize to the CNS. Melanoma and testicular and renal
carcinoma have the greatest propensity to metastasize to the brain, but their
relative rarity explains the low incidence of these neoplasms in large series of
patients with brain metastases.
Patients with brain metastases from nonpulmonary primaries have a 70%
incidence of lung metastases. Although many physicians presume that all brain
metastases are multiple, in fact, half are single and many are potentially amenable
to focal therapies.
Signs and symptoms
Lateralizing signs and symptoms of brain metastasis depend on the location of
the lesion(s) and are similar to the signs and symptoms of other space-occupying
masses. However, a few features unique to brain metastases deserve emphasis.
Seizures Focal or generalized seizures are the presenting symptom in 15%-20%
of patients with brain metastasis. Metastases from melanoma have a 50% inci-
dence of seizures, perhaps due to their hemorrhagic nature.
Lateralizing signs More than half of patients with brain metastases have later-
alizing signs, including hemiparesis, aphasia, or visual field deficits.
Headaches are seen in about half of patients but are rarely an isolated finding
of metastatic disease.
Altered mental status Approximately 75% of patients with brain metastases
have impairment of consciousness or cognitive function. Some patients with
multiple bilateral brain metastases may present with an altered sensorium as
the only manifestation of metastatic disease; this finding can be easily confused

with a metabolic encephalopathy.
METASTATIC BRAIN
METASTATIC BRAIN TUMORS 603
the superior test and should be performed whenever feasible in any patient
being evaluated for metastatic brain disease (Figure 1). A high-quality, con-
trast-enhanced MR scan should be obtained to define the number of meta-
static nodules and to look for evidence of leptomeningeal disease. If MRI is
unavailable, CT is adequate to exclude brain metastases in most patients, but it
can miss small lesions or tumors located in the posterior fossa.
Radiographic appearance of lesions On CT or MRI, most brain metastases
are enhancing lesions surrounded by edema, which extends into the white
matter (Figure 1). Unlike primary brain tumors, metastatic lesions rarely in-
volve the corpus callosum or cross the midline.
The radiographic appearance of brain metastases is nonspecific and may mimic
other processes, such as infection. Therefore, the CT or MR scan must always
be interpreted within the context of the clini-
cal picture of the individual patient, par-
ticularly since cancer patients are vulnerable
to opportunistic CNS infections or may de-
velop second primaries, which can include
primary brain tumors.
Pathology
The pathology of metastatic brain lesions re-
capitulates the pathology of the underlying
primary neoplasm. This feature often enables
the pathologist to suggest the primary source in patients whose systemic can-
cer presents as a brain metastasis. However, even after a complete systemic
evaluation, the site of the primary tumor remains unknown in 5%-13% of pa-
tients with brain metastases.

Staging and prognosis
Any patient with brain metastasis has disseminated systemic cancer, and stag-
ing usually is not employed, unless the patient is being considered for surgical
resection and the extent of systemic disease is unknown.
For a large proportion of patients with brain metastases, median survival is
only 4-6 months after whole-brain radiotherapy. However, some patients (ie,
those who are < 60 years old, have a single lesion, and have controlled or
controllable systemic disease) can achieve prolonged survival, and these
individuals warrant a more aggressive therapeutic approach. Furthermore, most
of these patients qualify for vigorous local therapy for their brain metastases,
such as surgical resection or, possibly, stereotactic radiosurgery. These ap-
proaches can achieve a median survival of 40 weeks or longer.
Thyroid transcription factor-1
(TTF-1) is expressed in lung
adenocarcinomas and thyroid
carcinomas but not in adenocarci-
nomas from other sites. TTF-1
immunohistochemical staining can
identify whether a brain metastasis
from an unknown primary is
coming from a pulmonary or
nonpulmonary source (Srodon M,
Westra WH: Hum Pathol 33:642-645,
2002).
604 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH
Treatment
Treatment for brain metastases is both supportive (see chapter 27) and defini-
tive. Definitive treatment includes surgery, radiotherapy, and chemotherapy.
DEFINITIVE THERAPY
Surgery

Resection followed by whole-brain irradiation significantly prolongs survival
compared with whole-brain irradiation alone in patients with a solitary brain
metastasis, and some patients achieve long-term disease-free survival. Most
patients with brain metastases have a life expectancy of < 9 months, but the
majority who undergo resection of a solitary metastatic lesion followed by
irradiation will die of systemic rather than intracranial disease.
If brain metastases are the presenting sign of systemic cancer and no clear
primary source can be identified with routine staging, surgery may also be
required to establish a tissue diagnosis and plan further therapy.
In addition, surgical removal of a brain metastasis often reverses the neurologic
deficits caused by compression of local structures by tumor and reduces
intracranial hypertension.
Excision of metastases is rarely curative, however, as microscopic cells may be
left behind. Nevertheless, the reduced tumor burden becomes more amenable
to adjuvant irradiation and/or chemotherapy.
Criteria for surgery The decision whether to recommend surgery should be
based on the following factors:
Extracranial oncologic status A comprehensive work-up of the patient’s extra-
cranial oncologic status is necessary. Extensive critical organ metastases pre-
clude surgery in favor of palliative irradiation as the sole therapy. Brain sur-
gery should not be performed in patients with limited expected survival (3-6
weeks) based on extracranial disease.
Number of metastases In general, only patients harboring a single metastasis are
considered for resection. Occasionally, a large tumor will be removed in the
presence of multiple smaller nodules if the edema and mass effect of this lesion
are causing a substantial neurologic deficit that could be improved by tumor
removal.
Three recent studies concluded that when multiple (up to three distinct locations)
metastases are resected, either with or without radiotherapy, survival times are
identical to those in patients with surgically resected solitary metastases and

almost twice as long as those in patients treated by radiation therapy or radio-
surgery alone. These studies suggest that a more aggressive surgical approach
may be justified in patients with multiple brain metastases who have stable
systemic disease.
Recurrence of solitary metastases Up to 20% of solitary metastases may
recur in long-term survivors. In these cases, a second operation may be war-
METASTATIC BRAIN TUMORS 605
ranted to remove the recurrent lesion and confirm the histologic diagnosis (ie,
exclude radionecrosis).
Radiation therapy
For symptomatic patients with brain metastases, median survival is about
1 month if untreated and 3-6 months if
whole-brain radiation therapy is delivered,
with no significant differences among various
conventional radiotherapy fractionation
schemes (20 Gy in 5 fractions, 30 Gy in 10
fractions, 40 Gy in 20 fractions). A more pro-
tracted schedule is used for patients who have
limited or no evidence of systemic disease or
for those who have undergone resection of a
single brain metastasis, since these patients
have the potential for long-term survival or
even cure. The use of hypofractionated regi-
mens is associated with an increased risk of
late neurologic toxicity.
Relief of neurologic symptoms The major
result of whole-brain radiation therapy is an
improvement in neurologic symptoms, such
as headache, motor loss, and impaired mentation. The overall response rate
ranges from 70% to 90%. Unfortunately, symptomatic relief is not permanent,

and symptoms recur with intracranial tumor progression.
Solitary lesion Postoperative whole-brain radiation therapy significantly im-
proves control of CNS disease after resection of a single brain metastasis but
has no impact on overall survival. Postoperative whole-brain radiation therapy
may be withheld, therefore, in selected patients, such as elderly individuals or
those with highly radioresistant primaries (eg, renal cancer), because these pa-
tients are vulnerable to the toxic effects of cranial irradiation without reaping
the potential benefits.
Multiple lesions Patients with multiple le-
sions are generally treated with whole-brain
radiation therapy alone. Retreatment with a
second course of whole-brain radiation
therapy can provide further palliation for
patients with progressive brain metastases
(who have at least a 6-month or longer re-
mission of symptoms after the initial course
of cranial irradiation).
Concomitant steroid therapy Since the radio-
graphic and clinical responses to whole-brain
irradiation take several weeks, patients with
significant mass effect should be treated with
Temozolomide (Temodar) given
concurrently with whole-brain
radiotherapy in patients treated
for brain metastates from lung or
breast cancer have a higher
response rate (complete plus
partial responses)—96%, compared
with a 66% intracranial response in
those receiving whole-brain

radiotherapy alone (P = .017).
Overall survival was not affected,
but temozolomide may function as
an effective radiation sensitizer in
this situation (Antonadou D,
Paraskevaides M, Coliarakis N, et al:
Proc Am Soc Clin Oncol [abstract]
20:57a , 2001).
A recent phase III trial was
completed evaluating the role of
motexafingadolinium (MGd) as a
radiation enhancer in patients with
brain metastases. A total of 401
patients were randomized to
receive either whole-brain
radiotherapy alone or whole-brain
radiotherapy plus MGd. There was
no difference in median overall
survival (5.2 months MGd and 4.9
months control) or median time to
neurologic disease progression
(9.5 months MGd and 8.3 months
control) between the two
treatment arms (Mehta MP,
Rodrigus P, Terhaard C,et al: Proc Am
Soc Clin Oncol [abstract] 21:286a,
2002).
606 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH
steroids during whole-brain radiation therapy. Dexamethasone (16 mg/d) is
started prior to therapy, and the dose may be tapered as tolerated during treat-

ment. Occasionally, higher doses are necessary to ameliorate neurologic symp-
toms. However, most patients can be safely tapered off corticosteroids at the
completion of whole-brain radiotherapy.
Radiosurgery
Radiosurgery has been used as sole therapy, as a boost to whole-brain radia-
tion therapy, or for recurrent lesions in patients with brain metastases. Radio-
surgery has the advantage of delivering effective focal treatment, usually in a
single dose, without irradiating all of the normal brain. It is particularly useful
for patients who have 1-3 lesions, each < 4 cm in diameter. Patients with nu-
merous lesions are not good candidates for radiosurgery because some of the
ports may overlap, and, more importantly, these patients likely harbor other
microscopic lesions in the brain that are not being effectively treated with such
focal therapy.
Brain metastases are particularly amenable to treatment with radiosurgery.
Metastatic tumors do not infiltrate the brain and tend to have well-circum-
scribed borders; therefore, they can be targeted effectively with highly focused
irradiation techniques that maintain a sharp delineation between the enhanc-
ing tumor seen on neuroimaging and normal brain. Furthermore, radiosur-
gery does not have the operative morbidity that may be associated with resec-
tion of a brain metastasis. Consequently, it can be used safely in many patients
who are not surgical candidates, and it can even treat lesions in surgically un-
approachable locations such as the brainstem.
Radiosurgery can achieve crude focal control rates of 73%-98% over a median
follow-up of 5-26 months. Radiosurgery was initially used primarily as a boost
after treatment with whole-brain radiotherapy. Three randomized trials have
reported on the value of radiosurgery in addition to whole-brain radiotherapy
for patients with multiple brain metastases. Although all three studies show a
local control advantage and an improvement in quality-of-life end points with
the addition of a radiosurgery boost, none shows a statistical advantage in sur-
vival. For patients with multiple brain metastases, adding radiosurgery to whole-

brain radiotherapy only offers an improved neurologic quality of life with no
impact on survival.
Radiosurgery is often considered an alternative to standard surgical resection,
but it is unclear whether they are equivalent. Some retrospective studies sug-
gest that the two techniques produce identical results, but a case-control study
demonstrated that surgery is superior to radiosurgery in the treatment of a
single brain metastasis. An ongoing prospective study being conducted by the
Radiation Therapy Oncology Group (RTOG) is comparing the efficacy of ra-
diosurgery vs that of surgery plus whole-brain radiotherapy in the treatment of
brain metastases.
Increasingly, radiosurgery is being used as sole therapy for one to three brain
metastases. A prospective randomized trial is currently underway to deter-
METASTATIC BRAIN TUMORS 607
mine outcome with radiosurgery ± whole-brain radiotherapy, but most inves-
tigators expect the results to be similar to those observed in the phase III trial
of surgical resection of a single brain metastasis ± radiotherapy: improved lo-
cal control but no survival benefit. There is growing evidence from large retro-
spective series that radiosurgery alone may be as effective as radiosurgery plus
whole-brain irradiation for the control of CNS disease; however, some series
point to a 4% incidence of brain recurrence if whole-brain radiotherapy is with-
held. Radiosurgery alone substantially shortens treatment time and eliminates
the risk of cognitive impairment associated with whole-brain irradiation, par-
ticularly in elderly patients.
Median survival from the time of radiosurgery is 6-15 months, and some pa-
tients can live for years without recurrence. Most patients exhibit clinical im-
provement and decreased steroid requirements after radiosurgery, and only
11%-25% of patients eventually die of neuro-
logic causes.
Treatment recommendations
In patients with one to three brain metastases,

aggressive local therapy (surgical resection or
radiosurgery) produces superior survival and quality of life than does whole-
brain radiation therapy alone. Radiosurgery may be the optimal choice for
elderly patients at greater risk for surgical morbidity. Whole-brain radiotherapy
does not contribute to survival after surgical resection and probably not after
radiosurgery. Increasingly, we are reserving it for use at CNS recurrence and
not following a complete resection or radiosurgery with routine whole-brain
irradiation.
Chemotherapy
Chemotherapy usually has a limited role in the treatment of brain metastases
and has not proven to be effective as an adjuvant therapy after irradiation or
surgery. However, it may have some efficacy in patients with recurrent brain
metastases who are not eligible for further whole-brain radiation therapy or
stereotactic radiosurgery (see box above). In addition, a recent phase III trial
of chemotherapy with early vs delayed whole-brain radiotherapy in NSCLC
patients with brain metastases showed an identical intracranial response rate
and survival. Thus, systemic chemotherapy had some efficacy against brain
metastases.
Brain metastases from chemosensitive primary tumors Brain metastases
from primary tumors that are chemosensitive, such as SCLC, choriocarcinoma,
and breast cancer, may be responsive to systemic therapy. Single drugs or drug
combinations should be selected based on their expected activity against the
primary tumor.
Temozolomide has some activity
against recurrent brain metastases,
especially from non–small-cell lung
cancer (Abrey LE, Christodoulou C:
Semin Oncol 13:34-42, 2001).
608 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH
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