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Centers for Quantitative Imaging Excellence (CQIE)
LEARNING MODULE
QUANTITATIVE IMAGING IIN
MULTICENTER CLINICAL TRIALS: MRI
American College of Radiology
Clinical Research Center
v.1
Centers for Quantitative Imaging Excellence (CQIE)
LEARNING MODULE
This module is intended to provide a brief overview
of general and MRI-specific issues relevant to
quantitative imaging for clinical trials. For additional
information related to quantitative imaging for
clinical trials, please see USEFUL LINKS on the CQIE
web page (address provided below). For additional
CQIE program information and qualification
materials (MOP, forms, etc.), please refer to the CQIE
web page.
CQIE MOP and program information:
www.acrin.org/NCI-CQIE.aspx
After you have reviewed this module please let us know by submitting the
learning module attestation. The link is provided at the end of this module.
MR: Quantitative Imaging in Clinical Trials
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What is Quantitative Imaging?
As defined by the Toward Quantitative Imaging (TQI) task force of the
Radiological Society of North America (RSNA):
“Quantitative imaging is the extraction of quantifiable features from
medical images for the assessment of normal or the severity, degree of
change, or status of a disease, injury, or chronic condition relative to
normal. Quantitative imaging includes the development, standardization,
and optimization of anatomical, functional, and molecular imaging
acquisition protocols, data analysis, display methods, and reporting
structures. These features permit the validation of accurately and
precisely obtained image-derived metrics with anatomically and
physiologically relevant parameters, including treatment response and
outcome, and the use of such metrics in research and patient care.”
Buckler, et al., A Collaborative Enterprise for Multi-Stakeholder Participation in the Advancement of
Quantitative Imaging, Radiology; Volume 258: Number 3, March 2011
MR: Quantitative Imaging in Clinical Trials
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What is Quantitative Imaging?
Which imaging parameters are quantitative?
Morphology
 Volume, 3D techniques (vCT, vMR)
 Cellularity, density, composition of tissue
Function
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Perfusion (DCE-MRI and DSC-MRI)
Metabolic activity (PET)
Molecule movement (DWI)
MR Spectroscopy (MRS)
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Quantitative Imaging as Biomarker
What is an imaging biomarker?
“…any anatomic, physiologic, biochemical, or
molecular parameter detectable with one or more
imaging methods used to help establish the presence
and/or severity of disease.” Ideally, a biomarker is an
objectively measurable characteristic (versus a
qualitative observation).
Why use biomarkers?
To speed the development of safe and effective
medical therapies and procedures.
Smith, et al., Biomarkers in Imaging: Realizing Radiology’s Future, Radiology; Volume 227, Number 3,
June 2003
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Imaging Biomarkers in Clinical Trials
Uses:
Buckler, et al., A Collaborative Enterprise for Multi-Stakeholder Participation in the Advancement of
Quantitative Imaging, Radiology; Volume 258: Number 3, March 2011
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Imaging Biomarkers in Clinical Trials
Needs:
 Standardization - the consistent performance
of imaging, and adherence to protocols, for
every research study performed at a given
clinical site.
 Harmonization - the identification and
implementation of mechanisms to control for
inconsistencies of data between the different
sites, particularly to ensure that imaging data
generated with different systems are
comparable.
Facilitating the Use of Imaging Biomarkers in Therapeutic Clinical Trials, M.Graham, RSNA/SNM/FDA
Two Topic Imaging Workshop, 2010
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Imaging Standardization/Harmonization
Why? Good Science
Reliable decision making based on medical imaging
requires comprehensive standards and tools to
maintain integrity and ensure quality of results. For
results to be of benefit to researchers and patients, the
results must be accurate, comparable and reproducible
(across patients, time-points, and institutions).
 Standardize imaging equipment (when possible)
 Standardize image/data acquisition
 Standardize image/data reconstruction
 Standardize image/data processing
 Standardize image interpretation
MR: Quantitative Imaging in Clinical Trials
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General Challenges in MR Quantification
Arbitrary signal intensity units
 Magnitude and homogeneity of the main magnetic field (Bo)
 Higher Bo better signal-to-noise; homogeneity impacts image uniformity and
spatial accuracy
 Magnetic field gradient/nonlinearity and/or miscalibration
 Spatial accuracy depends strongly on gradient subsystem characteristics
 Radiofrequency (RF) coil dependency: RF coil type, sensitivity
profiles, subject positioning within the coil
 Image signal uniformity; impact on longitudinal signal intensity measures
 Slice profile variations (with RF pulse shape, flip angle, etc.)
 Slice thickness depends on pulse sequence and RF pulse shape;
prescribed thickness and measured thickness differ, especially for fast
imaging techniques
 System stability issues
 Quality control programs are critical for reproducible measures!
Standards for Imaging Endpoints in Clinical Trials: Standardization and Optimization of Image Acquisitions:
MR, E.F. Jackson, FDA Workshop, April 13, 2010
MR: Quantitative Imaging in Clinical Trials
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Multi-Center Clinical Trials
Major Challenges
 Acquisition protocols
 Harmonization across centers and vendors
 Distribution and activation of acquisition protocols
 Site compliance with acquisition protocols
 Widely varying quality control
 Ranging from specific QC for a given imaging biomarker,
to ACR accreditation, to none
 Even if QC program is in place, it may not test
parameters relevant to the study
 Scanner upgrades over course of trial
Standards for Imaging Endpoints in Clinical Trials: Standardization and Optimization of Image Acquisitions:
MR, E.F. Jackson, FDA Workshop, April 13, 2010
MR: Quantitative Imaging in Clinical Trials
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CQIE MR Qualification - Rationale
 Qualify NCI cancer centers in quantitative
imaging methodologies:
 Volumetric MRI (brain), DCE-MRI (body and brain)
 Standardized qualification process and
assessment, across 58 NCI-designation
Cancer Centers
 Promote imaging standardization and
harmonization within multi-center clinical
trials.
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MRI Imaging Protocols
SERIES ACQUISITION
Typical MRI Imaging Series
Protocols Used in Clinical Trials
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MRI Imaging Protocols
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High Resolution 3D T1w Gradient Echo
T1 Spin Echo 2D
FLAIR
T2 / T2*
DWI – Diffusion Weighted Imaging
DTI – Diffusion Tensor Imaging
PWI – Perfusion Weighted Imaging
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MRI Imaging Protocols
 High Resolution 3D T1w Gradient Echo
Performed post-contrast to visualize
enhancing disease on T1 weighted imaging,
T1-weighted “Spoiled” Gradient Echo imaging
is often used to quantify tumor volume over
time.
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MRI Imaging Protocols
 T1 Spin Echo 2D
In evaluating disease in the brain such as
glioblastoma multiforme (GBM), conventional
two-dimensional spin echo imaging will
demonstrate gadolinium enhancement in
areas of disease where the blood-brain barrier
is compromised. Ordinary linear markup
permits fundamental analysis of the tumor
area “in-plane”.
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MRI Imaging Protocols
 FLAIR (T2)
Fluid Attenuated Inversion Recovery is a T2
weighted series, wherein fluid (particularly
CSF in the brain) is suppressed (i.e. appears
dark). Among other advantages, this
technique allows for better delineation of CSF
from T2 abnormalities.
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MRI Imaging Protocols
 T2/T2*
Whether performed as a fast-spin echo or a
gradient echo, T2 weighted imaging will show
areas of disease with special note to areas of
edema and other abnormalities not seen on
T1 or T1 enhanced imaging. T2* imaging also
allows further delineation for assessment of
hemorrhagic areas by demonstrating blood as
dark (or “hypo-intense”).
MR: Quantitative Imaging in Clinical Trials
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MRI Imaging Protocols
 DWI/DTI
Diffusion-Weighted and Diffusion-Tensor
Imaging is sensitive to directional perfusion of
intra-cellular water. Ischemic areas (such as
areas of acute stroke) appear bright.
Composite “ADC maps” (Apparent Diffusion
Coefficient) allow for compositing and
delineation T2 weighted regions in the brain.
DTI allows for more comprehensive
directional analysis of diffusion and better
microstructural assessment of brain tissue.
MR: Quantitative Imaging in Clinical Trials
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MRI Imaging Protocols
 PWI
Perfusion weighted imaging affords an
analysis of blood flow over time. Areas of the
brain deemed “normal” are compared to
“abnormal” areas by measuring the rate of
enhancement as gadolinium is injected.
Overall assessments of cerebral blood
volume may be calculated, and the rates of
enhancement are compared over the course
of a patient’s therapy.
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MRI Imaging Protocols
 PWI
Dynamic Susceptibility Contrast-enhanced
imaging (DSC) and Dynamic Contrast
Enhanced MRI (DCE-MRI) are two such
methods of perfusion imaging.
• DSC uses T2* gradient echo weighted imaging to
leverage the inherent magnetic susceptibility effects of
gadolinium.
• DCE uses a T1w spoiled gradient echo approach of Gd
enhancement analysis provided the inherent T1 value
of the tissues are understood.
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Quantifying Disease
Morphologic analysis
 “What type of tumor is this?”
 “Just how big is it?”
Functional Analysis
 “What type of tumor is this?”
 “What is this tumor doing?”
• How is it growing?
• Will it continue to grow/spread?
– How fast?
– What will stop it?
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Morphologic Analysis
Two Dimensional Measurement
WHO:
World Health
Organization
Standard for Bidimensional
Measurement
ca. 1979
6.4 x 3.6 = 23.0
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Morphologic Analysis
Uni-Dimensional Measurement
RECIST: Response
Criteria in Solid Tumors
Unidimensional
measurement
for sufficient
evaluation of
“tumor burden”
response to
therapies for
NSCLC.
Cortes, et al. Br J Cancer. 2002
July 15; 87(2): 158–160
6.4 + 3.9 = 10.3
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Morphologic Analysis
Uni-Dimensional Measurement
RECIST: Response Criteria in Solid Tumors
Complete Response (=0)
Partial Response (>30%)
“Stable” Disease
Progressive Disease (>20%)
T0: 6.4 + 3.9 = 10.3
Status
% Change
CR
100%
PR
>30%
SD
Neither PD nor Response
PD
>20%
Non- Evaluable
T1: 4.4 + 2.6 = 7.0 (>30%)
T2: 4.4 + 2.4 = 6.8 (PR confirmed)
T3: 6.2 + 4.6 = 10.8 (>20% from lowest)
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Volumetric Analysis
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Volumetric Analysis
Three Dimensional Measurement
for Tumor Volume
y
x
Axial
Sagittal
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Coronal
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Volumetric Analysis
The significance of geometry:
256 x 256 (1:1)
256x192 (1 : 0.75)
Isometric voxels (i.e. voxel
dimensions that are the same on all
sides) are essential to
demonstrating pathology accurately
in all 3 planes using multi-planar
reconstruction of the 3D dataset
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Volumetric Analysis
Semi- Automated 3D Segmentation of Glioma
Boundaries of enhancing
disease on 3D T1 can be
identified with specialized
software to determine tumor
volume
Methods:
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Edge Detection
Manual contouring
Intensity based thresholding
Seed-based region growing
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Functional Analysis
Measurements of tumor dimensions such
as area and volume of gadolinium
enhancement alone, may not necessarily
be a totally reliable indicator of active
tumor, particularly in regions blood-brain
barrier breakdown has not occurred.
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Angiogenesis & Vascular Endothelial Cells
Tumor physiology:
How “vascular” is
the tumor?
Source: NCI
Measuring:
•Blood flow
•Blood volume
•Permeability
Assessing response to
anti-angiogenics and
VEGF inhibitors
(Drugs which target the proteins for
vascular endothelial cell growth)
(e.g.Avastin®/Bevacizumab)
MR: Quantitative Imaging in Clinical Trials
Blood vessel
Vascular
endothelial
cells
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DSC-MRI
Dynamic Susceptibility Contrast Enhanced MRI
DCE-MRI
Dynamic Contrast Enhanced Magnetic Resonance Imaging
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Standardization
Requirements for Standardization:
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Patient preparation and positioning
Gadolinium contrast (dose, rate, timing)
Field strength
Receiver coils
Acquisition pulse sequence
Distortion correction
Reconstruction parameters
Input function (normalized versus measured)
Kinetic modeling and analysis
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Data Acquistion Challenges
 Pulse Sequence
 Contrast response must be well characterized and
maintained for duration of study (or a process for
compensation for changes must be developed)
 Temporal Resolution
 Must match choice of pharmacokinetic model and
parameters of interest
• Must be rapid (< 4-6 seconds) for generalized kinetic model
• Recommended to be < 15 seconds for any pharmacokinetic model
 T1 Measurements
 Required if contrast agent concentration is used in
modeling
 Must be obtained in reasonable scan time
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Data Acquisition Challenges (con’t)
 Spatial Resolution
 Must be adequate for target lesion size and application
 Anatomic Coverage
 Should fully cover target lesion(s) & include appropriate
vascular structure
 Motion
 Effects should be mitigated prospectively during
acquisition and/or retrospective (e.g. rigid body or
deformable registration)
Standards for Imaging Endpoints in Clinical Trials: Standardization and Optimization of Image
Acquisitions: MR, E.F. Jackson, FDA Workshop, April 13, 2010
MR: Quantitative Imaging in Clinical Trials
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DSC Perfusion Imaging
DSC-MRI in the Brain
Measuring Signal Intensity vs. time
Semi-quantitative measurements:
 Slope, AUC, CER
Quantitative measurement:
 Cerebral Blood Volume (CBV)
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DCE-MRI
DCE-MRI in the Brain
Measuring Concentration vs. time
 Quantitative analysis of kinetics between extra-cellular/extra-vascular
space and tumor
 T1 mapping using multiple flip angles prior to the dynamic series can
be used to estimate the T1 of tissue pre-gad
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DCE-MRI
DCE-MRI in the Body
Porosity of
vessels &
Permeability
Arterial Input Function (AIF)
→
Gd
Small pores in artery (low permeability)
Ktrans
Kep
Large pores in vein (hi permeability)
DCE-MRI can provide data regarding kinetics of blood flow: the
distribution of Gd from the Intravascular space to the EES (Ktrans)
and ‘back’ (Kep)
MR: Quantitative Imaging in Clinical Trials
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Sorafenib (BAY 43-9006) in RCC
0.3
Pre-BAY
0.25
0.2
AIF
[gadolinium]
Tumor
Rate of
enhancement
for tumor
decreases
post therapy
0.15
0.1
0.05
0
-100
-50
0
50
100
150
200
250
300
-0.05
time(seconds)
Post-BAY (d21)
4.5
4
3.5
AIF
3
[gadolinium]
Tumor
While arterial
input function
(AIF)
remained
constant
2.5
2
1.5
1
0.5
0
-100
-50
0
50
100
150
200
250
300
-0.5
Rosen, Schnall Innovations and Challenges in Renal Cancer
time(seconds)
Clinical Cancer Research 13, 770s-776s, January 15, 2007 Slide courtesy M.Rosen
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DCE-MRI Parameters
Target lesion is chosen at the ‘baseline’
timepoint prior to the start of therapy
3D anatomical volume is obtained
within a standardized spatial resolution
Contrast is injected at a relatively rapid
rate
The same lesion is imaged the exact
same way on the same system, using
the same injection rate, at each time
point throughout their therapy
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DCE-MRI
Brain DCE MRI Sample Protocol
 Five T1 Mapping Series, Pre Gd
 Multi-phase 3D T1w GRE
 Temporal Resolution goal:
<8 seconds/phase,
~6 minute series
 Inject after 10 phases
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DCE-MRI
Body DCE MRI Sample Protocol
 Oblique Coronal Plane
 Three T1 Mapping Series
 Temporal Resolution goal:
<10 seconds/phase, 6 minute series
 Inject after 10 phases
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References
1.
WHO Handbook, WHO handbook for reporting results of cancer
treatment. Offset Publication No. 48. Geneva (Switzerland): World
Health Organization; 1979.
2.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS,
Rubinstein L, Verweij J, van Glabbeke M, van Oosterom AT,
Christian MC, Gwyther SG: New guidelines to evaluate the
response to treatment in solid tumors. J Natl Cancer Inst.
2000;3:205–216.
3.
Holodny, A. I., Nusbaum, A. O., Festa, S. et al. Correlation Between
the Degree of Contrast Enhancement and the Volume of
Peritumoral Edema in Meningiomas and Malignant Gliomas.
Neuroradiology 41, 820-825 (1999)
4.
Rosen M, Schnall M: Innovations and Challenges in Renal Cancer;
Clinical Cancer Research 13, 770s-776s, January 15, 2007
MR: Quantitative Imaging in Clinical Trials
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Please follow the link below to report
your review of this module
https://www.surveymonkey.com/s/CQIE_QuantitativeImaging_MRI
CQIE PET questions should be directed to
[email protected]
American College of Radiology
Clinical Research Center
1818 Market Street - Suite 1600
Philadelphia, PA 19103
Thank you!
MR: Quantitative Imaging in Clinical Trials
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