Diffusion Weighted MRI and Magnetic Resonance Spectroscopy
to Differentiate Radiation Necrosis and Recurrent Disease in
Gliomas
Lars Ewell, Russell Hamilton 11/27/05
Outline
I)
Introduction
II)
Radiation Therapy
III)
Imaging Modalities
A) Diffusion Weighted MRI
B) Magnetic Resonance Spectroscopy
C) Time/Resolution
IV)
Apoptosis/Mitosis
V)
Flow Determination
VI)
Discussion
VII) Conclusion
VIII) References
Introduction
When using a typical T2 weighted Magnetic Resonance Image (MRI) to assist in
the diagnosis of a glioma patient, a difficulty often encountered is differentiating
between Radiation Induced Necrosis (RIN) and recurrent disease. Both frequently appear
as ‘enhancing lesions’. Diffusion Weighted MRI (DWMRI) and Magnetic Resonance
Spectroscopy (MRS) have the potential to aid in this differentiation.
DWMRI has been linked via an Apparent Diffusion Coefficient (ADC) of water
to effective cancer therapy. It is hypothesized that as effective tumor therapy progresses,
cellular breakdown of cancer cells lead to increased water mobility which in turns leads
to an increase of the ADC. Since RIN also involves cellular breakdown, it is possible
that DWMRI can in the same manner assist in elucidating this malady.
MRS has the ability to measure the concentration of brain metabolites, such as
Choline, Creatin and N-Acetyl Aspartate, the ratios of which have been shown to
discriminate between RIN and recurrent disease. There are two problems associated with
MRS: 1) Limited resolution. 2) Increased scan time required. These problems, and
others, will be addressed.
We plan on initiating an imaging protocol for patients that have been treated with
hypo-fractionated Intensity Modulated Radiation Therapy (IMRT) from our recently
purchased Novalis Brainlab linear accelerator, as described below. We will study how
best to implement these two complimentary non-invasive imaging modalities, so as to
obtain the most useful information in the least amount of scan time.
Radiation Therapy
Hypo-fractionated IMRT for glioblastoma has been shown to be an effective
means to deliver an acceptable dose in a shorter amount of time (1). We plan on
administering a dose of between 50 and 80 Gy via IMRT in five equal fractions on our
recently acquired Novalis Brainlab linear accelerator1. After surgical resection, but prior
to receiving any radiation therapy, all of the patients enrolled in the imaging protocol will
receive an initial CT scan used to plan the radiation therapy. In addition to the CT, a
baseline set of MRI scans, including DWMRI and MRS will be taken prior to therapy.
The MRI scans will be registered with the CT scans using the Brainscan planning
software, which uses mutual information as a similarity measure to fuse the two different
sets of images(2).
Once these images are fused, the radiation oncologist and neurosurgeon will
contour the region to be treated and radiation therapy will commence. After five
fractions (one Fx/day), the initial round of radiotherapy will be done.
An advantage of using this system is that the radiation isodose distributions can
be superimposed upon the fused CT-MRI images. By doing this, it may be possible to
correlate radiation induced changes with individual isodose curves. In addition to this,
the thin (3mm) W leaves in the Multi-Leaf Collimator (MLC) of this machine allow for a
very high degree of dose conformality (3). This high conformality could prove useful if,
e.g., it is shown that patients may benefit if an area, e.g. the periphery, of a tumor is given
a higher radiation dose.
1
Note: Hypo-fractionated radiotherapy has been used for some time here in the
department of Radiation Oncology at the University of Arizona. This imaging proposal
is not intended to effect in any way, the decision of what type of radiation therapy is
prescribed for an individual patient.
The neural cells in the brain are generally thought of as a ‘late-responding’ tissue
with respect to radiation (4). In this regards, we do not expect to see any evidence of RIN
for some months after the cessation of radiotherapy.
Imaging Modalities
Diffusion Weighted MRI
As indicated above, DWMRI has been linked via a rise in the ADC of water with
effective therapy, and visa versa (5,6). While this is certainly a useful application of this
new imaging modality, it is not specifically what we propose to do.
Since necrotic tissue, cancerous or otherwise, is thought to undergo cellular
breakdown leading to increased water mobility, it has been suggested that DWMRI could
also be useful in discriminating between RIN and recurrent disease.
In the laboratory, melanoma xenografts were imaged using DWMRI in an attempt
to delineate necrotic tumor fraction. While the results were promising, the limited
resolution of the DWMRI images used at that time prevented smaller lesions from being
measured (7).
In the clinic, DWMRI has been used in an attempt to differentiate RIN from
recurrent disease with mixed results. Some investigators have indicated it has provided
no additional information above MRS in discrimination (8,9), while others have reported
that DWMRI can aid (10,11). One of the main goals of this study is to settle the question
of whether or not DWMRI can assist in discrimination of RIN and recurrent disease.
In both the laboratory and the clinic, the limited resolution of DWMRI was
mentioned as a potential reason why this imaging modality had restricted usefulness in
differentiating RIN from recurrent disease. With this in mind, and for the isotropic
diffusion that we are interested in, we plan on implementing a new method of DWMRI,
Radial Fast Spin Echo (RFSE), that promises higher resolution and reduced imaging time
(12). In this method, the diffusion weighting direction is varied during acquisition of a
full radial k-space data set such that images reconstructed from the data have effectively
isotropic weighting. This allows for reduction in artifacts due to susceptibility gradients,
as well as motion. In Figure 1, two diffusion weighted images are displayed (12). As can
be seen, the RFSE image has better resolution than the more typical Single Shot Echo
Planar Image (SSEPI).
Magnetic Resonance Spectroscopy
MRS, also known as Chemical Shift Imaging (CSI), has proven useful in
discriminating between RIN and recurrent disease. It can determine metabolite levels,
the ratios of which have the ability to differentiate. MRS obtains its signal from the shift
Figure 1: Two diffusion weighted images of a stroke victim: a) A trace image using
Single Shot Echo Planar Imaging (SSEPI). b) An isotropic Radial Fast Spin Echo
(RFSE) image of the same patient(12).
a)
b)
Figure 2: a) T1 weighted MRI scan of a healthy volunteer. b) Corresponding MRS (CSI)
scan of red inset showing Cho, Cr and NAA peaks. The vertical axis is the strength of the
MR signal, and the horizontal axis is the shift in frequency in parts per million (ppm).
in the MR signal due to the surrounding chemical environment (13). Regarding the brain,
three of the main metabolites of interest are: 1) Choline (Cho) a neurotransmitter that is
increased in tumors. 2) N-Acetyl Aspartate (NAA) a neuronal metabolite that is
decreased in tumors (13). 3) Creatin (Cr), a brain metabolite. In Figure 2, a T1 weighted
MRI along with an MRS spectra of a healthy volunteer is displayed.
Ratio
Metabolite Ratios for Different Tissue
5
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
Cho/Cr
Cho/NAA
NAA/Cr
1
Recurrent
Tumor
2
Radiation
Induced Necrosis
3
White
Matter
Figure 3: Metabolite ratios for different tissue types (15).
It has been revealed that the Cho to Cr and Cho to NAA ratios are generally
highest in recurrent tumor, followed by RIN and finally normal appearing white matter
(15). This is depicted graphically in Figure 3.
Time/Resolution
As indicated above, two of the disadvantages of MRS are the limited resolution
and the long scan time required. In past studies using MRS, scans have taken on average
1.5 hours (14). A goal of this study is to quantify, and attempt to minimize, the amount
of time necessary to obtain a useful set of images. While the method of using RFSE for
the DWMRI should save an amount of time, the majority of time spent in imaging these
patients will be for the MRS. Another area where these two different imaging modalities
differ is in resolution.
As indicated in the Experimental Methodology section, 3D multivoxel data
acquisition will be used for the MRS. We expect that the 3D resolution of these scans
will be on the order of 1cc. In contrast, the resolution for the DWMRI scans will be
approximately 1mm2 in the non-scan direction, and a slice thickness of 3mm.
Consequently, there will be approximately 3x10x10 or 300 DWMRI voxels for each
MRS voxel. We will combine the DWMRI voxels to get an average ADC for each of the
larger MRS voxels, but will also examine the smaller detail that the DRMWI images
afford, as well as the normal MRI images.
Apoptosis/Mitosis
The two primary mechanisms of clonogenic cell death following irradiation are
mitotic death and apoptosis (4). Mitotic death, which occurs when cells fail to divide
because of damaged or lost chromosomal material or the failure of spindle formation
during cytokinesis, is the most common mechanism. One or more cell divisions may
occur prior to cell death. Apoptosis prevalence depends strongly on the tumor type and
occurs without cell division.
The expected ADC signal is significantly different for mitotic and apoptotic
death. Cells undergoing mitotic death increase their size, for example when giant cells
with multiple nuclei form. The ADC is expected to decrease during this process since the
intercellular spacing and fluid are reduced. Then these cells become necrotic and their
membranes are compromised, resulting in excess intercellular fluid and expected
increases in water mobility and the ADC. The duration of this process depends on the
cell cycle time since cells undergo one or more cell divisions before dying. This would
be considered a delayed response to radiation as it would occur days after exposure. In
apoptotic death, the cell detaches from its neighbors, chromatin condenses at the nuclear
membrane, cytoplasmic condensation causes the cell to shrink, and water is lost. An
increase in ADC is expected to occur (16). Next, these cells become necrotic and are
then phagocytized. During these processes, the ADC is expected to be larger than prior to
irradiation. Apoptosis occurs within 4 to 24 hours following exposure. Finally, for either
mechanism, the tissue in the irradiated volume must reorganize. The ADC in this region
may be larger or smaller than in the pretreatment scan, depending on whether tumor or
normal cells occupy this volume and their density within it.
Flow Determination
While DWMRI is sensitive to the amount of water mobility, Cerebral Blow Flow
(CBF) has also been investigated as it relates to gliomas, mostly through perfusion
studies (17,18). While we have no current plans to include perfusion related
measurements in this study, we are cognizant of the of the fact that blood flow can make
definitive diagnosis more difficult. By using a small amount of diffusion weighting in
RFSE imaging, it has been shown that blood flow can be suppressed, thereby making
lesion detection more reliable (19). In Figure 4, this technique is shown on a patient with
a liver hemangioma. We intend on using similar techniques in the brains, as needed.
Fig. 4. Axial images of a patient with a liver hemangioma. (a) Radial MR image acquired
with conventional spatial saturation MRI pulses for flow suppression. (b) Radial MR
image acquired with a small amount of diffusion weighting (b=1.2 s/mm2) in addition to
the spatial saturation pulses to better suppress flow. The bright signal from vessels in (a),
as those indicated by the arrows, is better suppressed throughout the slice in (b)(19).
Discussion
It appears likely that a lack of resolution is a major reason why the potential of
DWMRI has not yet been realized with regards to differentiation of RIN and recurrent
disease. In this regards, we are hopeful that the RFSE method of acquiring DWMRI
images will be helpful.
Conclusion
To realize the full potential of these two complimentary non-invasive imaging
modalities will take some time and effort. By initiating our protocol as soon as possible,
we expect to be able to answer some very important questions about how best to obtain
the ideal imaging sequence to achieve the best clinical outcome.
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