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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 v.1 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 v.1 What is Quantitative Imaging? Which imaging parameters are quantitative? Morphology Volume, 3D techniques (vCT, vMR) Cellularity, density, composition of tissue Function Perfusion (DCE-MRI and DSC-MRI) Metabolic activity (PET) Molecule movement (DWI) MR Spectroscopy (MRS) MR: Quantitative Imaging in Clinical Trials v.1 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 MR: Quantitative Imaging in Clinical Trials v.1 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 MR: Quantitative Imaging in Clinical Trials v.1 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 MR: Quantitative Imaging in Clinical Trials v.1 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 v.1 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 v.1 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 v.1 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. MR: Quantitative Imaging in Clinical Trials v.1 MRI Imaging Protocols SERIES ACQUISITION Typical MRI Imaging Series Protocols Used in Clinical Trials MR: Quantitative Imaging in Clinical Trials v.1 MRI Imaging Protocols 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 MR: Quantitative Imaging in Clinical Trials v.1 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. MR: Quantitative Imaging in Clinical Trials v.1 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”. MR: Quantitative Imaging in Clinical Trials v.1 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. MR: Quantitative Imaging in Clinical Trials v.1 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 v.1 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 v.1 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. MR: Quantitative Imaging in Clinical Trials v.1 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. MR: Quantitative Imaging in Clinical Trials v.1 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? MR: Quantitative Imaging in Clinical Trials v.1 Morphologic Analysis Two Dimensional Measurement WHO: World Health Organization Standard for Bidimensional Measurement ca. 1979 6.4 x 3.6 = 23.0 MR: Quantitative Imaging in Clinical Trials v.1 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 MR: Quantitative Imaging in Clinical Trials v.1 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) MR: Quantitative Imaging in Clinical Trials v.1 Volumetric Analysis MR: Quantitative Imaging in Clinical Trials v.1 Volumetric Analysis Three Dimensional Measurement for Tumor Volume y x Axial Sagittal MR: Quantitative Imaging in Clinical Trials z Coronal v.1 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 MR: Quantitative Imaging in Clinical Trials v.1 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: MR: Quantitative Imaging in Clinical Trials Edge Detection Manual contouring Intensity based thresholding Seed-based region growing v.1 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. MR: Quantitative Imaging in Clinical Trials v.1 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 v.1 DSC-MRI Dynamic Susceptibility Contrast Enhanced MRI DCE-MRI Dynamic Contrast Enhanced Magnetic Resonance Imaging MR: Quantitative Imaging in Clinical Trials v.1 Standardization Requirements for Standardization: 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 MR: Quantitative Imaging in Clinical Trials v.1 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 MR: Quantitative Imaging in Clinical Trials v.1 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 v.1 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) MR: Quantitative Imaging in Clinical Trials v.1 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 MR: Quantitative Imaging in Clinical Trials v.1 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 v.1 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 MR: Quantitative Imaging in Clinical Trials v.1 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 MR: Quantitative Imaging in Clinical Trials v.1 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 MR: Quantitative Imaging in Clinical Trials v.1 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 MR: Quantitative Imaging in Clinical Trials v.1 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 v.1 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 v.1