OncoLog, Volume 57, Number 10, October 2012 Page: 2
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Alleviating Central Nervous System Radiation Necrosis
[Continued from page 1]have only recently been discovered.
It has been shown that CNS radiation
necrosis is associated with increased
cytokine production. According to this
model, radiation therapy causes vascu-
lar abnormalities in the brain that re-
duce blood vessel density, ultimately
restricting the blood supply to brain
tissue (chronic ischemia). Ischemia,
in turn, causes infiltrative tumor cells
and adjacent astrocytes to respond by
producing cytokines, such as vascular
endothelial growth factor (VEGF), to
help the tumor cells or astrocytes sur-
vive. In addition to irradiation, some
chemotherapy drugs also cause ischemia
and may exacerbate necrosis.
Irradiation of the CNS can also pro-
duce damage to the myelin sheath of
neurons (demyelination). This appears
to be caused by the effect of radiation
on the oligodendrocytes that make and
repair the myelin covering neuronal
axons. This effect is seen early on mag-
netic resonance images of most patients
treated with radiation therapy, with or
without chemotherapy.
Diagnosis
CNS radiation necrosis is difficult
to diagnose accurately because it often
appears the same as a progressive tumor
on diagnostic imaging. Radiation necro-
sis usually occurs at the treatment site
but can also be distant, usually near
a cerebral ventricle; necrosis can also
be diffuse or multifocal and resemble
tumor metastasis.
Ashok J. Kumar, M.D., a professor
in the Department of Diagnostic Ra-
diology at MD Anderson, was the first
author of a seminal study published
in 2000 of imaging patterns that differ-
entiate radiation necrosis from brain
tumors. According to Dr. Kumar, diag-
nosing radiation necrosis remains diffi-
cult, but experienced physicians can
recognize the patterns of necrosis and
treat it early. Dr. Kumar said radiation
necrosis lesions have a "Swiss cheese"
or "soap bubble" enhancement pattern
on magnetic resonance imaging (MRI).
However, this pattern does not provide
a definitive diagnosis.
On diffusion-weighted MRI, which"[Tihe fact
that even short treat-
ment with bevacizum-
ab seems to turn off
the cycle of radiation
damage further con-
firms the central role of
VEGF in the process."
- Dr. Victor Levin
measures the magnitude and direction
of free water movement, tumors tend
to restrict water movement, whereas
necrosis tends to increase water mobility.
On magnetic resonance spectroscopy,
necrotic lesions tend to exhibit reduced
levels of N-acetyl aspartate and crea-
tine, whereas tumors tend to exhibit
high levels of choline. Magnetic reso-
nance perfusion, which measures the
relative cerebral blood volume, can
indicate necrotic lesions, but this
modality also detects fast-growing
tumors that exceed their blood supply.
None of these imaging modalities
can differentiate necrosis from tumor
progression (or necrotic lesions mixed
with a recurrent tumor) definitively.
Even invasive tests such as biopsy can-
not definitively distinguish between
necrosis and recurrent cancer owing to
sampling error. Experienced physicians
and radiologists can learn to recognize
signs that indicate a high probability
of necrosis versus tumor progression.
A diagnosis of CNS radiation necrosis
instead of cancer is not cause for relief,
however. Necrosis can have the same
debilitating effects as a tumor and can
even be fatal if unchecked.
Treatment
Until just a few years ago, treatment
for CNS radiation necrosis was restricted
to alleviating its symptoms. Physicians
have long prescribed corticosteroids to
control swelling and psychostimulants
to address psychomotor slowing andfatigue in patients with CNS necrosis.
Corticosteroids also help counteract
the radiation-induced vascular damage
that can disrupt the blood-brain barri-
er. Sometimes symptoms return if
patients stop using the steroids, so
problems arising from chronic steroid
use must also be treated. Anticoag-
ulants, such as warfarin or heparin,
can slow the progression of necrosis
in some patients. Hyperbaric oxygen
treatment can help restore oxygen con-
centrations to a normal level in order
to encourage angiogenesis. Patients can
also undergo brain surgery to remove
necrotic tissue.
In 2009, a group at MD Anderson
revolutionized treatment options for
radiation necrosis. They found that
bevacizumab, a monoclonal antibody
that prevents blood vessel growth in
tumors by blocking VEGF, also causes
necrotic lesions in the brain to regress,
reversing radiation damage. This obser-
vation spurred the design of a double-
blind, placebo-controlled phase II trial
of bevacizumab as a therapy for CNS
radiation necrosis. Treatment involved
four cycles of bevacizumab (7.5 mg/kg
intravenously every 3 weeks). At a
median 10 months' follow-up, 9 of the
12 patients treated with the drug had
necrotic lesion shrinkage on MRI. This
trial provided class I evidence of the
efficacy of bevacizumab as a treatment
for CNS radiation necrosis.
"Just the fact that bevacizumab
works has helped us understand much
more about what happens in radiation
necrosis," said Victor A. Levin, M.D.,
a professor emeritus in the Department
of Neuro-Oncology at MD Anderson
and the senior researcher on these stud-
ies. "We presume necrosis is related
to the release of cytokines like VEGF,
since bevacizumab is very specific and
only reduces VEGF levels. We think
aberrant production of VEGF is in-
volved with radiation necrosis of the
brain, and the fact that even short
treatment with bevacizumab seems to
turn off the cycle of radiation damage
further confirms the central role of
VEGF in the process." Astrocytes try
to protect neurons by expressing VEGF,2 OncoLog October 2012
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University of Texas M.D. Anderson Cancer Center. OncoLog, Volume 57, Number 10, October 2012, periodical, October 2012; Houston, Texas. (https://texashistory.unt.edu/ark:/67531/metapth639634/m1/2/: accessed March 19, 2024), University of North Texas Libraries, The Portal to Texas History, https://texashistory.unt.edu; crediting UNT Libraries Government Documents Department.