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METASTATIC BRAIN TUMORS
Brain metastases are the most common type of brain tumors, with the
total number diagnosed annually outnumbering all other intracranial
tumors combined (22, 30). With the increasing survival of patients
with systemic (extracranial) disease, the incidence of the most common
cancers (lung, breast, melanoma, renal and colon) is thought to be
rising. Autopsy data show that the frequency of brain metastases in
patients dying from cancer varies from 20 to 50%, and may be higher if
dural, leptomeningeal, or spinal metastases are taken into account.
As the incidence of brain metastases rises due to improved cancer
therapy for systemic disease (18), it is imperative that improved
intracranial therapy be developed as well.
The most common source of brain metastases in males is lung cancer
and in females is breast cancer (29), but with the increasing frequency
of lung cancer in females, it is expected that for females this too
will be the primary cause of metastatic brain tumors (22).
How Do Tumors Metastasize?
The mechanisms by which primary tumors produce brain metastases is
thought to be hematogenous spread from primary or secondary sites in
the lung. Since the brain has no lymphatic system, all tumors
metastasizing to the brain do so by spreading through the bloodstream.
Arterial blood passes through the lungs before entering the brain,
and collects tumor cells filtered out in capillaries, which
subsequently embolize to the brain. This is correlated with sites
of localization: the cerebrum is involved in 80 to 85% of all brain
metastases, the cerebellum in 10 to 15% and the brainstem in 3 to 5%
(6, 10, 29). The overall distribution corresponds roughly to the
relative size of blood flow regions in the brain.
Different types of primary tumors have different relative
frequencies of single versus multiple metastases. Melanoma has the
highest tendency to produce multiple lesions, followed by lung and
breast cancers (19, 22). Though many studies have indicated that 37
to 50% of patients present with a single metastasis (6, 29), recent
studies have shown that patients with one lesion detected by CT may
demonstrate multiple lesions detected by MRI (4, 28). These findings
clearly agree with our data in which the majority of patients
presented with multiple lesions upon contrast dye with MRI. (1).
Common Symptoms
Metastatic brain tumors present with the usual signs and symptoms of
any expanding intracranial mass lesion. These include increased
intracranial pressure and focal neurological deficits with focal
irritations. Such symptoms include headaches, focal weakness, mental
status changes, seizures, ataxia [inability to coordinate voluntary
muscular movements] and sensory and visual changes. Though most of
these symptoms are of gradual onset, acute episodes may occur due to
hemorrhages into a metastasis (15). When such an event occurs, either
choroid carcinoma or melanoma must be considered, because these have
the greatest tendency to hemorrhage (15). Because of the greater
incidence of bronchogenic metastasis, these lesions represent the most
common source of a hemorrhagic lesion (15, 21).
Whole Brain Radiation Therapy (WBRT)
Brain metastases carry an ominous prognosis regardless of primary
status or treatment given. The median survival of untreated patients,
or those treated with corticosteroids alone to reduce brain edema, is
about one month (32). Whole brain radiation therapy (WBRT) is the most
widely used method of treating brain metastasis, despite the fact that
patients treated this way have an expected survival of only three to
four months. Death from recurrent or persistent tumors occurs in
about 50% of the patients (12, 29).
The radiosensitivity of the tumor itself is not taken into account
when these patients are being treated. Most tumors that metastasize
to the brain, such as non-small cell lung, renal, colon, and melanoma
are radioresistant [resistant to radiation therapy]. Worse yet, many
treating facilities continue to use prophylactic cranial radiation
despite the fact that only one study has ever demonstrated a
statistically significant increase in life span (20). (Prophylactic
radiation therapy is treatment given before lesions have appeared
within the brain.)
Significant neurotoxicity has been reported with the use of WBRT.
Acute effects include hair loss (alopecia), nausea, vomiting,
lethargy, otitis media and severe cerebral edema. Though some of these
effects can be transient, dermatitis, alopecia, and otitis media can
persist for months after irradiation (23). Chronic effects are even
more serious, and these include atrophy, leukoencephalopathy,
radiation necrosis, neurological deterioration and dementia (5).
Reports of development of severe radiation induced dementia have
varied between 11% in one-year survivors (23, 24, 27) to 50% in those
surviving two years (7, 23). The time involved in this therapeutic
intervention frequently is over two weeks, in itself a burden to many
patients (5, 8).
Surgery and WBRT
Surgical removal of solitary and occasionally multiple lesions has
been reported to enhance survival (2, 6, 7, 10, 16, 26), with several
reports indicating improvement of neurological function. Recently,
the concept of multiple craniotomies for multiple lesions has been
promoted (2), though only in those patients with "accessible
locations" and "good clinical condition." The risks of postoperative
morbidity in "eloquent" areas must also be considered when
contemplating surgical intervention. The complications of the surgery
itself include hemorrhages and wound infection.
Pseudomeningoceles form in 8 to 9% of patients, and an estimated
10% of patients develop clinically evident thromboembolic
complications such as deep vein thrombosis or pulmonary embolisms
(3, 9). Recent reports have also indicated an operative mortality of
approximately 3%. Though adjunct WBRT has been prescribed in the past
, and Patchell et al (16) showed that a subset of patients with
favorable prognosis and a single brain metastasis that had surgery
followed by adjunct WBRT had a median survival of 10 months, other
subsequent randomized trials failed to show a benefit to surgical
resection (14).
Radiosurgery
Radiosurgery is a technique which allows the delivery of a single
high dose of radiation in a highly accurate manner (24, 25). The
Gamma Knife (a dedicated neuro-surgical instrument) allows numerous
beams of radiation to converge on a target site, resulting in a high
dose of radiation delivered to the target site with a sharp dose
gradient at the target edge. A recent report by Somaza et al (25)
revealed that even in patients with radioresistant tumors (such as
melanoma), local tumor control was achieved in 97% of patients and
neurological improvement occurred in 53% of affected patients.
Median survival with radiosurgery alone improved from two to three
months to nine months in patients with single or multiple metastatic
melanoma lesions to the brain (25). Despite such results,
radiosurgery has not been considered a primary therapy. In the recent
past most treatment centers treat only unresectable tumors or
recurrent tumors with this modality (17, 31, 32).
Multiple Metastases
The issue of multiple metastases has become important, as has the
issue of lesion size. From our perspective, neither number of lesions
nor the size of the lesions has been shown scientifically to be a
limiting factor in single session Gamma Knife treatment. Multiple
metastases may be more of an issue in terms of the equipment itself
not allowing multiple lesions to be treated in a single sitting. At
The Miami Neuroscience Center, at Health South Doctor's Hospital in
Coral Gables, Florida, we have treated 460 patients (261 females and
199 males) with a mean of four lesions per treatment. The patients
had the following types of cancers: 111 males and 111 females had lung
cancer, 32 males and 16 females had melanoma, 7 males and 20 females
had colon cancer, and 8 males and 16 females had renal cancer.
When we looked specifically at the outcome of metastatic breast
carcinoma (1), we found the following results: 68 women were treated,
ranging in age from 25 to 83 years, and the median age was 52.
Thirty-eight patients had previously received conventional modalities,
including WBRT. A total of 110 treatments were given to the 68 women
with an average of eight tumor sites per patient. Twenty-seven (40%)
of 68 survived one year, seven (10%) survived two years, and two (3%)
survived more than three years. Twenty-six patients with one to three
lesions were treated, 18 with four to seven lesions, and 24 with more
than eight lesions. Their overall local control rate was 94%, with 39
(91%) of the 43 patients expiring, dying of causes unrelated to their
brain metastases. There was no significant difference in survival and
local control based on the number of lesions treated. Survival was
clearly found to be independent of the number of lesions treated.
Similarly, when we looked at our renal cell carcinoma patients, we
found similar results. Twenty-two patients were treated: 8 females
and 14 males. The range of lesions was between 1 and 21, with a median
of 3.4 per patient. Twelve of 22 (55%) had WBRT. Age ranged from 38
to 80, with a median age of 60. The median survival was 8.7 months
(3 to 55 months), with local control in 20 of 22 patients (91%).
Eight patients (36%) required re-treatment for new lesions. Survival
at one year was 24% in patients older than 60, but 54% in those
younger than 60. Once again, the number of sites or prior WBRT did not
have statistically significant effects on survival.
In our study, Gamma Knife radiosurgery shifted the question of
survival to that of systemic control. Previous whole brain radiation
therapy results have yielded no survival advantage to the treatment.
The overall complication rate with one-session Gamma Knife has been
1.2%, in which patients having biopsy proven radiation necrosis
required treatment with stereotactic aspiration and corticosteroids.
This is a very low rate of complications.
Conclusion
In conclusion, we believe that one-session Gamma Knife radiosurgery
for brain metastases is a superior mode of treatment for either single
or multiple metastases. Survival rates match or exceed those
previously reported for surgery with whole brain radiation or whole
brain radiation alone. Radiosurgery yields added advantages:
outpatient treatment, lower morbidity, greater flexibility in terms of
local and number of tumors treated, and the ability to treat the
patient over multiple periods of time for the development of new
lesions.
We have not found that WBRT leads to a survival benefit nor that it
prevents later onset of remote metastases in other brain locations.
In our opinion, radiosurgery alone is the primary mode of therapy for
brain metastases, unless the patient presents with neurological
deficits resulting from mass effect, thus requiring surgical
intervention. Radiosurgery clearly provides a very high rate of
local control and preservation of neurological function with minimum
effort and morbidity to the patient.
Dr. Aizik Wolf is a practicing neurosurgeon at The
Miami Neuroscience Center located at The Health South Doctor's Hospital
in Coral Gables, Florida. He can be reached at +305-669-3427.
Corresponding references to numbered items can be requested through
Dr. Wolf.
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