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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
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