|
The Neuro Center's physician newsletter. Click here to go to Neurogram's
home page or the University of Virginia Health System's Neuro-Oncology
pages.
Management of Brain Metastases
Brain metastases are by far the most common malignant brain tumor;
roughly 75,000 patients receive this diagnosis each year in the
United States, four times the number diagnosed with malignant primary
brain tumors. Lung cancer accounts for 40-50% of patients with brain
metastases, breast cancer 20%, and melanoma and renal cell carcinoma
5-10% each. Melanoma and lung cancer are the two tumors most likely
to metastasize to the brain; ovarian and prostate cancer rarely
do so.
In at least 10% of patients brain metastases are the first indication
of cancer. Most of these patients lack symptoms or physical findings
pointing to the systemic origin of their metastases. Two-thirds
of these patients have lung cancer, and many of the remaining patients
have lung metastases. Thus, initial work-up for a systemic primary
tumor is best focused on the chest with chest x-ray or chest CT.
However, it is important to remember that only 15% of solitary intracranial
tumors in patients without a history of systemic cancer will turn
out to be metastases; most will turn out to be high-grade gliomas
and other malignant primary brain tumors. One of the explanations
for this is that 75% of patients with brain metastases have multiple
brain metastases.
The symptoms and physical findings with brain metastases are quite
variable. Headache is common but not ubiquitous, and focal weakness,
gait unsteadiness, and mental status changes are also frequent complaints.
Only 20% of patients with brain metastases have had seizures by
the time of diagnosis. Papilledema is now a distinctly uncommon
physical finding.
Neuroimaging of Brain Metastases
MRI long ago supplanted CT scanning in the radiographic diagnosis
of brain metastases. MR scanning without intravenous contrast is
as good as contrast-enhanced CT scanning for lesion detection, and
the addition of post-gadolinium contrast images renders MRI markedly
superior to the best contrast-enhanced CT scan. Metastases as small
as 0.5-1.0 cm are usually seen with standard gadolinium-enhanced
MRI; for metastases < 0.5 cm in diameter, triple doses of gadolinium
increase sensitivity dramatically.
Symptomatic Management
Corticosteroids have been used in the management of brain metastases
since the late 1950s, and have provided tremendous symptomatic benefit.
They decrease vasogenic cerebral edema, presumably through their
effects on capillary permeability. Whatever the mechanism, they
improve symptoms in two-thirds of patients. Dexamethasone is usually
prescribed because of its long biological half-life (36-54 hours)
that allows b.i.d.-t.i.d. dosing as well as its minimal mineralocorticoid
activity. Although physicians have traditionally prescribed daily
doses in the range of 16-24 mg, a recent controlled study demonstrated
that patients not imminently at risk of herniation did just as well
on 2-4 mg b.i.d. as they did on 4 mg q.i.d. with significantly less
steroid-related toxicity.
Another pragmatic question that arises is whether the 80% of patients
who have not had seizures by the time they present should receive
prophylactic anti-epileptic drugs (AEDs). Two prospective randomized
clinical trials examining this issue have shown no benefit to the
use of prophylactic AEDs, leading to a recent practice parameter
from the American Academy of Neurology advising against their use.
Deep venous thrombosis and pulmonary emboli are common problems
in this population, and their management poses a dilemma in patients
with brain metastases. Although there is a small risk of precipitating
or aggravating intratumoral hemorrhage with anticoagulants, the
alternative - use of inferior vena cava filters - is ineffective
in this population. It is not uncommon for patients to suffer pulmonary
emboli despite IVC filter, or to clot off their IVC filter. Consequently,
if a non-contrast head CT shows no intratumoral bleeding, anticoagulation
appears to be a safer and more effective strategy.
Definitive Treatment of Brain Metastases
Standard Radiotherapy
The median survival of patients with brain metastases receiving
supportive care and corticosteroids is less than two months. The
addition of fractionated whole brain radiotherapy doubles this endpoint
to four months. Whole brain radiotherapy (WBRT) is generally painless
and well-tolerated, although it produces fatigue and temporary alopecia.
Different dose-fractionation schemes have not yielded superior results,
and 10 treatments of 300 centigray each over two weeks is a common,
convenient schedule. Fifty to 70% of patients improve symptomatically
with WBRT, though most patients do not achieve a radiographic complete
response and 40% still die from intracranial tumor. Age < 60,
good performance status, having no extracranial sites of metastasis,
and having a resected or locally controlled primary tumor site are
all beneficial prognostic factors; patients with all four factors
live a median of 7 months. Radiation sensitizers thus far have not
improved upon these results, although a recent phase III trial suggested
that Xcytrin (gadolinium texaphyrin), an agent with selective uptake
into tumors that increases oxidative stress on tumor cells, significantly
prolongs time to neurologic progression in patients with brain metastases
from lung cancer. Further studies of Xcytrin are planned at UVa
and other medical centers.
One drawback of WBRT is the risk of delayed side-effects in long-term
survivors. Ten to 30% of one-year survivors of WBRT develop cognitive
deficits, particularly in the areas of attention and memory. CT
and MRI commonly demonstrate atrophy and periventricular white matter
changes. Elderly patients are particularly prone to this outcome.
Surgery
In 1990 a phase III trial confirmed the belief of many neurosurgeons
that selected patients with a single brain metastasis (25% of all
patients) benefited from resection of that tumor. In this trial,
patients (most of whom had metastases from non-small cell lung cancer)
were randomized to surgery plus standard WBRT versus WBRT alone.
The addition of surgery reduced the risk of local brain tumor recurrence
from 52% to 20% and increased median survival from 15 to 40 weeks.
Disseminated systemic cancer was a negative prognostic factor, confirmed
in a similarly designed Dutch study that found a benefit to resection
so long as there was no active systemic tumor. These studies highlighted
the potential of local strategies to improve prognosis with brain
metastases.
Given the dramatic impact of surgery on patients with single brain
metastases, and the potentially deleterious consequences of WBRT
on long-term survivors, one might wonder whether resection of a
single brain metastasis would suffice and whether patients might
be spared WBRT. A randomized controlled trial explored this issue,
although the results are open to multiple interpretations. Patients
with a single brain metastasis on MRI were randomized to surgical
resection plus or minus WBRT. They were then followed clinically
and radiographically. Relapsed patients who had been randomized
to the surgery-only group were allowed to get WBRT. The addition
of WBRT to surgery significantly decreased the rate of relapse both
at the surgical site and elsewhere in the brain. Deaths attributed
to neurologic progression occurred significantly more frequently
in the surgery-only group, although this is a subjective endpoint
and clinicians were not blinded to treatment assignment. In contrast,
there was no difference in survival or time during which patients
were independent in activities of daily living in the two groups.
Thus, proponents of WBRT could argue this was a positive study,
while critics of WBRT could claim that WBRT could be safely deferred
without worsening the outcome. Resolution of this issue will require
further studies and more attention to neurocognitive and quality-of-life
outcome measures.
Although surgery is occasionally performed to resect more than
one brain metastasis, the presence of multiple lesions complicates
surgery substantially. The advent of stereotactic radiosurgery has
diminished the potential role of surgery in management of patients
with multiple brain metastases.
Stereotactic Radiosurgery
Stereotactic radiosurgery (RS) refers to the use of specialized
equipment to deliver high doses of radiation to localized targets
in the brain in a single treatment session. The precision of the
radiation beams ensures a very rapid fall-off in radiation in surrounding
normal brain tissue in contrast to conventional radiation equipment.
The two most common radiosurgical technologies are the Gamma
Knife machine and modified linear accelerators. The Gamma Knife
is essentially a large helmet with 201 radioactive cobalt sources
all focused at the center of the helmet. The patient's head is attached
to a stereotactic frame, and the targeted lesion aligned in the
center of the helmet where the beams converge. Modified linear accelerators
utilize a rotating gantry to deliver multiple coplanar arcs, which
summate on the desired target. Thus, despite the use of the word
"surgery", RS involves no cutting.
RS offers the advantage of being able to treat deep-seated brain
lesions (e.g., in the basal ganglia, thalamus, and brainstem) without
having to cut through normal tissue to reach them. It is essentially
painless, apart from the discomfort of a stereotactic head frame.
It can be performed with an overnight hospitalization or even as
an outpatient procedure. A crucial limitation of RS is that the
maximum diameter of effectively treated lesions is £ 3.5 cm.
RS has been extensively studied both as the initial treatment of
brain metastases and as an effective therapy in patients failing
WBRT. Numerous reports attest to a local control rate of 80-90%
and to its effectiveness in shrinking metastases from melanoma and
renal cell carcinoma which are typically highly resistant to fractionated
radiotherapy. The median survival in patients undergoing RS is 9-10
months, similar to the outcome of patients undergoing resection
of a single metastasis. RS can be utilized for multiple (usually
£ 4) metastases with results similar to treatment of a single
lesion. The major complication is radionecrosis, which results in
development of a local contrast-enhancing mass with surrounding
edema simulating recurrent tumor. Fortunately, this complication
arises in fewer than 10% of cases.
The noninvasive nature of RS with results seemingly comparable
to surgical resection naturally raise the question of whether RS
has been validated in a phase III trial akin to those proving the
benefit of surgery for a single brain metastasis. Recently, the
Radiation Therapy Oncology Group (RTOG) completed accrual to a randomized
trial of WBRT plus RS versus WBRT in patients with two or three
brain metastases. Preliminary results suggest no difference in survival
between the two groups (median 6 months), and a slight but insignificant
advantage in one-year local control in the group receiving adjuvant
radiosurgery. A much smaller completed trial evaluating the same
question in patients with two to four brain metastases found that
the addition of radiosurgery markedly improved local control with
a trend towards improved survival. Thus, until final results of
the RTOG trial are presented, the benefits of adjuvant RS for patients
with multiple brain metastases are uncertain. Accrual to the RTOG
study for patients with a single brain metastasis is ongoing.
Assuming that RS proves to be beneficial when added to WBRT for
single brain metastases, as most people presume, the obvious follow-up
question, as with surgical resection, is whether patients with a
single brain metastasis treated radiosurgically can safely defer
WBRT. Unfortunately, as yet no prospective randomized trial has
addressed this issue. Three retrospective, unrandomized studies
suggest that the addition of WBRT to RS improves either local brain
metastasis control or intracranial control. However, that none of
these found a significant survival benefit suggests that patients
who eventually relapse intracranially following RS may be treated
effectively with WBRT.
The formation of a new clinical trials cooperative group promises
to shed light on several of these important unanswered questions
with respect to brain metastasis management. The American College
of Surgical Oncology (ACOSOG) has formed a Brain Organ Site subcommittee,
initially chaired by Edward Laws, M.D. and currently vice chaired
by Mark Shaffrey, M.D. (UVa neurosurgeons). ACOSOG has recently
opened a trial randomizing patients with one to three newly diagnosed
brain metastases to receive RS alone or RS plus WBRT. Patients will
be followed not only for survival and time to local failure, but
for quality of life, cognitive function with neuropsychological
testing, and functional independence. These latter endpoints may
be as or more important than the former in helping to determine
the pros and cons of adjuvant WBRT.
Another key question is how RS compares to surgical resection for
patients with a single brain metastasis. Although single-institution
case series of RS yield results comparable to surgery, this has
never been confirmed in a clinical trial. The ACOSOG is planning
a randomized phase III trial to address this issue.
Therapies for Multiple Brain Metastases
Despite progress with surgical and radiosurgical interventions,
many patients have too many brain metastases to benefit from these
local strategies. Such patients typically undergo WBRT but often
relapse in the brain several months later. Two approaches have occasionally
proven helpful in this situation:
1. Chemotherapy: Systemic (oral or intravenous) chemotherapy has
the theoretical advantages of going everywhere in the brain, as
well as potentially being able to treat the active systemic tumor
that such patients often harbor. Although the blood-brain barrier
is a theoretical impediment, some chemotherapies are lipid-soluble
and thus cross the barrier. Moreover, the fact that virtually
all brain metastases enhance with intravenous contrast is a demonstration
that the blood-brain barrier is defective around the tumor. Modest
results, more often tumor stabilization than tumor shrinkage,
have been achieved with chemotherapy in this setting. As new chemotherapies
are developed, this strategy will deserve further evaluation.
2. Re-irradiation: Patients who clearly derived some benefit from
an initial course of WBRT, particularly when that first course
was ³ a year earlier, are candidates for a 2nd course of
WBRT. In one large series, 27% of re-irradiated patients had a
complete response of neurologic symptoms and 42% a partial response;
median response duration was three months. When long-term survival
is unlikely, the palliative benefit may outweigh the relatively
small risk of radiation-associated cognitive decline.
Summary
In the last decade, clinical trials have improved the care and
outcome of patients with brain metastases by defining the role of
surgery and adjuvant radiotherapy. Ongoing clinical trials promise
to address the corresponding role of radiosurgery. Further studies
assessing radiation sensitizers and systemic chemotherapy for brain
metastases may help improve the outcome for patients with multiple
lesions akin to the progress we have witnessed for patients with
single brain metastases.
David Schiff, M.D., ds4jd@virginia.edu
Click here to go to the University of Virginia Health
System's Neuro-Oncology pages.
|