2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Functional Imaging in Neuro-Oncology
Magnetic Resonance Perfusion
Given the antiangiogenic effects of bevacizumab, perfusion
imaging is intuitively an appealing technique for assessing
the effect of drug treatment. Several methods of
obtaining perfusion data have been developed, the two most
common of which are dynamic susceptibility contrast
(DSC) imaging and dynamic contrast enhanced (DCE)
imaging. DSC is used to generate maps of relative cerebral
(or tumor) blood volume (rCBV), and relative cerebral blood
flow (rCBF), among other metrics. DCE is generally used to
measure the permeability constant Ktrans, which is a metric
of capillary leakiness. Many groups have investigated the
role of perfusion imaging in the evaluation of gliomas. For
instance, maximal rCBV has prognostic value in astrocytoma,
even when controlling for tumor grade. 11 A number of
studies have shown that high rCBV or increasing rCBV is
associated with a worse prognosis across tumor grades. 12
Perfusion imaging has been used to assess response to
standard (radiation and cytotoxic chemotherapy) as well as
antiangiogenic treatment. For patients with GBM who receive
standard therapy, the percentage change in rCBV from
pre- to post-treatment measurements is predictive of 1-year
survival. 13 In patients with recurrent GBM who are treated
with antiangiogenic therapy, a “vascular normalization index”
that is generated by combining Ktrans, microvessel
KEY POINTS
● Magnetic resonance imaging (MRI) is the imaging
modality of choice to evaluate brain tumor location,
size and extent, mass effect, involvement of critical
structures such as adjacent blood vessels, and compromise
of the blood-brain barrier.
● Perfusion and diffusion magnetic resonance imaging
tools are examples of physiologic imaging modalities
that may provide quantitative data on tumor burden,
although further investigation is required to define
their roles in routine care and clinical trials.
● In approximately 20% to 30% of glioblastoma cases,
the first MRI obtained after radiation therapy and
concurrent temozolomide meets the criteria for progressive
disease, but subsequent follow-up scans
show lesion shrinkage or stability. This has been
termed pseudoprogression and is among the most
common causes of misdiagnosed tumor recurrence.
● Because of its antipermeability effect, antiangiogenic
therapy with bevacizumab results in marked reduction
of tumor enhancement, which reduces the sensitivity
of magnetic resonance imaging for diagnosing
tumor recurrence.
● Response critieria for high-grade gliomas have recently
been updated by the Response Assessment in
Neuro-Oncology working group. The new criteria account
for nonenhancing tumor in addition to the
contrast-enhancing abnormalities on which older criteria
relied.
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volume, and circulating collagen IV is predictive of survival,
even though it is acquired only 1 day after treatment
initiation. 14 Yet many studies that assess treatment response
to bevacizumab therapy have not been particularly
successful in relating changes in CBV or CBF to outcomes.
15,16 Thus challenges continue in the application of
perfusion indices as a biomarker of treatment response in
this setting. The use of perfusion as an early response (1-day
posttreatment initiation marker 14 ) could have a clinical
effect, however.
Perfusion imaging has also been applied to the issue of
differentiating true from pseudoprogression. In general,
true progression has higher perfusion than radiationinduced
changes, although there can be overlap in
values. 17-20 Standardized protocols may help improve the
use of perfusion imaging in multicenter trials, but overall
accuracy also must be increased to have the desired clinical
affect.
Magnetic Resonance Diffusion
Diffusion-weighting imaging (DWI) is another potential
physiology-based magnetic resonance biomarker for the
evaluation of gliomas. Based on the movement of water
molecules, diffusion data are typically reported as the
apparent diffusion coefficient (ADC); decreased water motion
corresponds to lower ADC values. Since water molecules
are generally more motion-restricted intracellularly
compared to extracellularly, necrosis and cell death or
lysis can result in increased ADC. Similarly, edema increases
ADC by expanding the interstitial, extracellular
fluid volume, which also allows for freer movement of
water molecules. Conversely, lower ADC is associated
with increased cell density. 23 Because of these properties,
DWI has the potential to indicate treatment response in
gliomas.
Functional diffusion maps (fDMs) are used to assess
the voxel-wise changes in ADC measured in the same
patient over time. 21-24 This can increase the sensitivity in
detecting subtle changes in tumor cell density. Initially
fDMs were used to predict response to cytotoxic chemotherapy
and radiotherapy within the contrast-enhancing tumor
bed, 22-24 but recent studies have demonstrated their effective
use outside regions of contrast enhancement 21,25,26 and
as tools for studying the effects of antiangiogenic treatment.
27,28
Another approach to using diffusion imaging data is to
construct histograms of ADC values. ADC histogram analysis
has been investigated as a predictive biomarker of
bevacizumab treatment response in the setting of recurrent
GBM. 29 For this application, tumors with low ADC values
before initiation of bevacizumab were more likely to progress
by 6 months compared with tumors with high ADC
values. These results have since been confirmed in a retrospective
analysis of a large multicenter trial. 30 However,
prospectively validated biomarkers for response to antiangiogenesis
treatment are not currently available for clinical
use.
Imaging of Recurrent Gliomas
NORDEN, POPE, AND CHANG
The Macdonald criteria defined progressive disease, or
recurrence, as “. . . � 25% increase in size of enhancing