Cancer is the second most common cause of
mortality in the United States, accounting for approximately
one-quarter of all deaths. Although primary central nervous system
(CNS) cancers are relatively rare, the annual estimated incidence of
brain metastases in the United States exceeds 100,000 cases. The vast
majority of patients with metastatic brain cancer die within a few
months of diagnosis, making this one of the most common immediate
causes of death in the United States.
The most frequent primary cause of brain metastases is lung cancer,
which is responsible for almost half of all secondary tumors of the
brain. Other major primary tumors that contribute significantly to
the occurrence of brain metastases include breast cancer, melanoma,
and colorectal cancer. Less commonly, primary tumors of the kidney,
other gastrointestinal neoplasms, lymphomas, sarcomas, gynecologic
tumors, and, rarely, prostate cancer also metastasize to the brain.
Recent therapeutic advances have led to longer disease-free survival
for patients with several types of cancer, thereby increasing the
overall population of cancer survivors. Unfortunately, these patients
are not truly cured, and their longer disease-free interval places
them at higher risk of developing metastatic disease at sanctuary
sites, such as the brain, where penetration of traditional cytotoxic
therapeutic agents is impaired by the blood-brain barrier. These
clinical observations, combined with enhanced utilization of cranial
imaging, explain the apparent perception of an increase in the
overall incidence of brain metastases.
In 1954, Chao et al first reported on the value of external-beam
radiation in the treatment of brain metastases. Because of its
simplicity and ease of delivery as an outpatient modality, with
little morbidity, low cost, and minimal disruption of quality of
life, external-beam radiation rapidly became the most commonly used
strategy in the management of patients with brain metastases.
The Radiation Therapy Oncology Group (RTOG) has conducted several
sequential studies exploring a variety of different fractionation
schedules.[3,4] Four major conclusions were drawn from these studies:
(1) Median survival improves to 15 to 21 weeks, a slight improvement
over steroids only. (2) A radiation dose of 30 Gy in 10 fractions is
as efficacious as more prolonged regimens or higher doses. (3) No
significant survival advantage is afforded by prolonged fractionation
or higher doses (up to 50 Gy), implying the lack of a dose-response
relationship in this range. (4) Prognostic criteria that predict for
slightly improved survival include age < 60 years, Karnofsky
performance score (KPS) > 70, control of the primary tumor, and
the brain as the sole site of metastasis. Subsequent reanalysis of
these data by Swift et al showed the presence of three or fewer
lesions to be an additional favorable prognostic factor.
Based on the RTOG trials, the standard treatment for most patients
with brain metastases for the last 2 decades has been conventional
external-beam radiation (30 Gy in 10 fractions) delivered to the
whole brain. The fact that this is, indeed, the most widely practiced
community standard was confirmed in the Patterns of Care palliation
survey conducted in the 1980s.
Accelerated Hyperfrationated Schedules
In the older RTOG studies, one-third to one-half of the patients died
from neurologic deterioration. One might logically assume that if
such deterioration could be controlled, survival might be enhanced.
In order to test this hypothesis, a recent RTOG study evaluated the
role of dose-escalation using accelerated hyperfractionation (1.6 Gy
twice daily to total doses ranging from 48 to70.4 Gy). This study
demonstrated that higher doses significantly improve survival and
neurologic function, suggesting that control of intracranial disease
may be related to dose and that such control may translate into a
neurologic improvement and survival advantage.
Although this phase I/II RTOG report suggested a potential benefit
from an altered fractionation regimen in patients with limited
metastatic disease and good KPS or neurologic function, a randomized
trial failed to conclusively demonstrate any improvement in survival
with accelerated hyperfractionated radiotherapy (1.6 Gy twice daily
to a total dose of 54.4 Gy), as compared to a conventional regimen of
30 Gy in 10 fractions. The results of this phase III trial
notwithstanding, the fact remains that relatively low doses, on the
order of 30 Gy, cannot successfully diminish tumor growth or control
it for a sustained period. The need for a higher dose to improve
tumor control is one of the central reasons for considering
The role of surgery in the treatment of brain metastasis remains
controversial. Clear indications for resection include craniotomy or
stereotactic biopsy to establish the diagnosis, when it is in doubt,
and removal of the tumor mass when such therapy is likely to provide
immediate palliation. Such indications lead to a very high level of
selectivity in surgical series. It is common practice in some
institutions to select patients with a single brain metastasis who
are otherwise clinically stable for surgical resection.
Resection Plus Whole-Brain Radiation
Retrospective data suggest that, in patients undergoing craniotomy
without external-beam radiation, the relapse rate approaches 85%.
In a recent prospective, randomized trial, the addition of
whole-brain radiation therapy to surgical resection improved
intracranial progression-free survival. Several retrospective
series suggest that, in highly selected patients, surgical resection
followed by whole-brain radiotherapy may prolong survival from a
median of 16 to 26 months.
To establish whether improved intracranial control would reduce
morbidity, improve quality of life, prolong survival, and alter
mortality patterns, three, small, randomized trials have compared
surgery plus whole-brain external-beam radiotherapy to radiotherapy
alone in patients with single brain metastases. Two of the trials
showed an improvement in median survival, to 43 and 40 weeks,
respectively, with the addition of surgery.[12,13] These two trials
also demonstrated that functional independence, as defined by
maintenance of KPS at or above a level of 70 following therapy, was
sustained for a longer duration in patients undergoing surgery. These
findings therefore established resection as a new standard for
selected patients with single brain metastases.
These results lend credence to the notion that aggressive management
strategies directed at improving local control are beneficial for
selected patients with brain metastases. However, a more recent and
slightly larger randomized trial addressing this issue failed to
identify a survival benefit from the addition of surgery: Median
survival was 6.3 months in the radiation-alone group, as compared
with 5.6 months in the resection group.
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