Radiotherapy Treatment Assessment using DCE-MRI

Abstract

The goal of modern radiotherapy is to precisely deliver a prescribed radiation dose to delineated target volumes that contain a significant amount of tumor cells while sparing the surrounding healthy tissues/organs. Precise delineation of treatment and avoidance volumes is the key for the precision radiation therapy. In recent years, considerable clinical and research efforts have been devoted to integrate MRI into radiotherapy workflow motivated by the superior soft tissue contrast and functional imaging possibility. Dynamic contrast-enhanced MRI (DCE-MRI) is a noninvasive technique that measures properties of tissue microvasculature. Its sensitivity to radiation-induced vascular pharmacokinetic (PK) changes has been preliminary demonstrated. In spite of its great potential, two major challenges have limited DCE-MRI’s clinical application in radiotherapy assessment: the technical limitations of accurate DCE-MRI imaging implementation and the need of novel DCE-MRI data analysis methods for richer functional heterogeneity information.

This study aims at improving current DCE-MRI techniques and developing new DCE-MRI analysis methods for particular radiotherapy assessment. Thus, the study is naturally divided into two parts. The first part focuses on DCE-MRI temporal resolution as one of the key DCE-MRI technical factors, and some improvements regarding DCE-MRI temporal resolution are proposed; the second part explores the potential value of image heterogeneity analysis and multiple PK model combination for therapeutic response assessment, and several novel DCE-MRI data analysis methods are developed.

I. Improvement of DCE-MRI temporal resolution. First, the feasibility of improving DCE-MRI temporal resolution via image undersampling was studied. Specifically, a novel MR image iterative reconstruction algorithm was studied for DCE-MRI reconstruction. This algorithm was built on the recently developed compress sensing (CS) theory. By utilizing a limited k-space acquisition with shorter imaging time, images can be reconstructed in an iterative fashion under the regularization of a newly proposed total generalized variation (TGV) penalty term. In the retrospective study of brain radiosurgery patient DCE-MRI scans under IRB-approval, the clinically obtained image data was selected as reference data, and the simulated accelerated k-space acquisition was generated via undersampling the reference image full k-space with designed sampling grids. Two undersampling strategies were proposed: 1) a radial multi-ray grid with a special angular distribution was adopted to sample each slice of the full k-space; 2) a Cartesian random sampling grid series with spatiotemporal constraints from adjacent frames was adopted to sample the dynamic k-space series at a slice location. Two sets of PK parameters’ maps were generated from the undersampled data and from the fully-sampled data, respectively. Multiple quantitative measurements and statistical studies were performed to evaluate the accuracy of PK maps generated from the undersampled data in reference to the PK maps generated from the fully-sampled data. Results showed that at a simulated acceleration factor of four, PK maps could be faithfully calculated from the DCE images that were reconstructed using undersampled data, and no statistically significant differences were found between the regional PK mean values from undersampled and fully-sampled data sets. DCE-MRI acceleration using the investigated image reconstruction method has been suggested as feasible and promising.

Second, for high temporal resolution DCE-MRI, a new PK model fitting method was developed to solve PK parameters for better calculation accuracy and efficiency. This method is based on a derivative-based deformation of the commonly used Tofts PK model, which is presented as an integrative expression. This method also includes an advanced Kolmogorov-Zurbenko (KZ) filter to remove the potential noise effect in data and solve the PK parameter as a linear problem in matrix format. In the computer simulation study, PK parameters representing typical intracranial values were selected as references to simulated DCE-MRI data for different temporal resolution and different data noise level. Results showed that at both high temporal resolutions (<1s) and clinically feasible temporal resolution (~5s), this new method was able to calculate PK parameters more accurate than the current calculation methods at clinically relevant noise levels; at high temporal resolutions, the calculation efficiency of this new method was superior to current methods in an order of 102. In a retrospective of clinical brain DCE-MRI scans, the PK maps derived from the proposed method were comparable with the results from current methods. Based on these results, it can be concluded that this new method can be used for accurate and efficient PK model fitting for high temporal resolution DCE-MRI.

II. Development of DCE-MRI analysis methods for therapeutic response assessment. This part aims at methodology developments in two approaches. The first one is to develop model-free analysis method for DCE-MRI functional heterogeneity evaluation. This approach is inspired by the rationale that radiotherapy-induced functional change could be heterogeneous across the treatment area. The first effort was spent on a translational investigation of classic fractal dimension theory for DCE-MRI therapeutic response assessment. In a small-animal anti-angiogenesis drug therapy experiment, the randomly assigned treatment/control groups received multiple fraction treatments with one pre-treatment and multiple post-treatment high spatiotemporal DCE-MRI scans. In the post-treatment scan two weeks after the start, the investigated Rényi dimensions of the classic PK rate constant map demonstrated significant differences between the treatment and the control groups; when Rényi dimensions were adopted for treatment/control group classification, the achieved accuracy was higher than the accuracy from using conventional PK parameter statistics. Following this pilot work, two novel texture analysis methods were proposed. First, a new technique called Gray Level Local Power Matrix (GLLPM) was developed. It intends to solve the lack of temporal information and poor calculation efficiency of the commonly used Gray Level Co-Occurrence Matrix (GLCOM) techniques. In the same small animal experiment, the dynamic curves of Haralick texture features derived from the GLLPM had an overall better performance than the corresponding curves derived from current GLCOM techniques in treatment/control separation and classification. The second developed method is dynamic Fractal Signature Dissimilarity (FSD) analysis. Inspired by the classic fractal dimension theory, this method measures the dynamics of tumor heterogeneity during the contrast agent uptake in a quantitative fashion on DCE images. In the small animal experiment mentioned before, the selected parameters from dynamic FSD analysis showed significant differences between treatment/control groups as early as after 1 treatment fraction; in contrast, metrics from conventional PK analysis showed significant differences only after 3 treatment fractions. When using dynamic FSD parameters, the treatment/control group classification after 1st treatment fraction was improved than using conventional PK statistics. These results suggest the promising application of this novel method for capturing early therapeutic response.

The second approach of developing novel DCE-MRI methods is to combine PK information from multiple PK models. Currently, the classic Tofts model or its alternative version has been widely adopted for DCE-MRI analysis as a gold-standard approach for therapeutic response assessment. Previously, a shutter-speed (SS) model was proposed to incorporate transcytolemmal water exchange effect into contrast agent concentration quantification. In spite of richer biological assumption, its application in therapeutic response assessment is limited. It might be intriguing to combine the information from the SS model and from the classic Tofts model to explore potential new biological information for treatment assessment. The feasibility of this idea was investigated in the same small animal experiment. The SS model was compared against the Tofts model for therapeutic response assessment using PK parameter regional mean value comparison. Based on the modeled transcytolemmal water exchange rate, a biological subvolume was proposed and was automatically identified using histogram analysis. Within the biological subvolume, the PK rate constant derived from the SS model were proved to be superior to the one from Tofts model in treatment/control separation and classification. Furthermore, novel biomarkers were designed to integrate PK rate constants from these two models. When being evaluated in the biological subvolume, this biomarker was able to reflect significant treatment/control difference in both post-treatment evaluation. These results confirm the potential value of SS model as well as its combination with Tofts model for therapeutic response assessment.

In summary, this study addressed two problems of DCE-MRI application in radiotherapy assessment. In the first part, a method of accelerating DCE-MRI acquisition for better temporal resolution was investigated, and a novel PK model fitting algorithm was proposed for high temporal resolution DCE-MRI. In the second part, two model-free texture analysis methods and a multiple-model analysis method were developed for DCE-MRI therapeutic response assessment. The presented works could benefit the future DCE-MRI routine clinical application in radiotherapy assessment.

Prospective Estimation of Radiation Dose and Image Quality for Optimized CT Performance

X-ray computed tomography (CT) is a non-invasive medical imaging technique that generates cross-sectional images by acquiring attenuation-based projection measurements at multiple angles. Since its first introduction in the 1970s, substantial technical improvements have led to the expanding use of CT in clinical examinations. CT has become an indispensable imaging modality for the diagnosis of a wide array of diseases in both pediatric and adult populations [1, 2]. Currently, approximately 272 million CT examinations are performed annually worldwide, with nearly 85 million of these in the United States alone [3]. Although this trend has decelerated in recent years, CT usage is still expected to increase mainly due to advanced technologies such as multi-energy [4], photon counting [5], and cone-beam CT [6].

Despite the significant clinical benefits, concerns have been raised regarding the population-based radiation dose associated with CT examinations [7]. From 1980 to 2006, the effective dose from medical diagnostic procedures rose six-fold, with CT contributing to almost half of the total dose from medical exposure [8]. For each patient, the risk associated with a single CT examination is likely to be minimal. However, the relatively large population-based radiation level has led to enormous efforts among the community to manage and optimize the CT dose.

As promoted by the international campaigns Image Gently and Image Wisely, exposure to CT radiation should be appropriate and safe [9, 10]. It is thus a responsibility to optimize the amount of radiation dose for CT examinations. The key for dose optimization is to determine the minimum amount of radiation dose that achieves the targeted image quality [11]. Based on such principle, dose optimization would significantly benefit from effective metrics to characterize radiation dose and image quality for a CT exam. Moreover, if accurate predictions of the radiation dose and image quality were possible before the initiation of the exam, it would be feasible to personalize it by adjusting the scanning parameters to achieve a desired level of image quality. The purpose of this thesis is to design and validate models to quantify patient-specific radiation dose prospectively and task-based image quality. The dual aim of the study is to implement the theoretical models into clinical practice by developing an organ-based dose monitoring system and an image-based noise addition software for protocol optimization.

More specifically, Chapter 3 aims to develop an organ dose-prediction method for CT examinations of the body under constant tube current condition. The study effectively modeled the anatomical diversity and complexity using a large number of patient models with representative age, size, and gender distribution. The dependence of organ dose coefficients on patient size and scanner models was further evaluated. Distinct from prior work, these studies use the largest number of patient models to date with representative age, weight percentile, and body mass index (BMI) range.

With effective quantification of organ dose under constant tube current condition, Chapter 4 aims to extend the organ dose prediction system to tube current modulated (TCM) CT examinations. The prediction, applied to chest and abdominopelvic exams, was achieved by combining a convolution-based estimation technique that quantifies the radiation field, a TCM scheme that emulates modulation profiles from major CT vendors, and a library of computational phantoms with representative sizes, ages, and genders. The prospective quantification model is validated by comparing the predicted organ dose with the dose estimated based on Monte Carlo simulations with TCM function explicitly modeled.

Chapter 5 aims to implement the organ dose-estimation framework in clinical practice to develop an organ dose-monitoring program based on a commercial software (Dose Watch, GE Healthcare, Waukesha, WI). In the first phase of the study we focused on body CT examinations, and so the patient’s major body landmark information was extracted from the patient scout image in order to match clinical patients against a computational phantom in the library. The organ dose coefficients were estimated based on CT protocol and patient size as reported in Chapter 3. The exam CTDIvol, DLP, and TCM profiles were extracted and used to quantify the radiation field using the convolution technique proposed in Chapter 4.

With effective methods to predict and monitor organ dose, Chapters 6 aims to develop and validate improved measurement techniques for image quality assessment. Chapter 6 outlines the method that was developed to assess and predict quantum noise in clinical body CT images. Compared with previous phantom-based studies, this study accurately assessed the quantum noise in clinical images and further validated the correspondence between phantom-based measurements and the expected clinical image quality as a function of patient size and scanner attributes.

Chapter 7 aims to develop a practical strategy to generate hybrid CT images and assess the impact of dose reduction on diagnostic confidence for the diagnosis of acute pancreatitis. The general strategy is (1) to simulate synthetic CT images at multiple reduced-dose levels from clinical datasets using an image-based noise addition technique; (2) to develop quantitative and observer-based methods to validate the realism of simulated low-dose images; (3) to perform multi-reader observer studies on the low-dose image series to assess the impact of dose reduction on the diagnostic confidence for multiple diagnostic tasks; and (4) to determine the dose operating point for clinical CT examinations based on the minimum diagnostic performance to achieve protocol optimization.

Chapter 8 concludes the thesis with a summary of accomplished work and a discussion about future research.

Application of Numerical Methods to Study Arrangement and Fracture of Lithium-Ion Microstructure

The focus of this work is to develop and employ numerical methods that provide characterization of granular microstructures, dynamic fragmentation of brittle materials, and dynamic fracture of three-dimensional bodies.

We first propose the fabric tensor formalism to describe the structure and evolution of lithium-ion electrode microstructure during the calendaring process. Fabric tensors are directional measures of particulate assemblies based on inter-particle connectivity, relating to the structural and transport properties of the electrode. Applying this technique to X-ray computed tomography of cathode microstructure, we show that fabric tensors capture the evolution of the inter-particle contact distribution and are therefore good measures for the internal state of and electronic transport within the electrode.

We then shift focus to the development and analysis of fracture models within finite element simulations. A difficult problem to characterize in the realm of fracture modeling is that of fragmentation, wherein brittle materials subjected to a uniform tensile loading break apart into a large number of smaller pieces. We explore the effect of numerical precision in the results of dynamic fragmentation simulations using the cohesive element approach on a one-dimensional domain. By introducing random and non-random field variations, we discern that round-off error plays a significant role in establishing a mesh-convergent solution for uniform fragmentation problems. Further, by using differing magnitudes of randomized material properties and mesh discretizations, we find that employing randomness can improve convergence behavior and provide a computational savings.

The Thick Level-Set model is implemented to describe brittle media undergoing dynamic fragmentation as an alternative to the cohesive element approach. This non-local damage model features a level-set function that defines the extent and severity of degradation and uses a length scale to limit the damage gradient. In terms of energy dissipated by fracture and mean fragment size, we find that the proposed model reproduces the rate-dependent observations of analytical approaches, cohesive element simulations, and experimental studies.

Lastly, the Thick Level-Set model is implemented in three dimensions to describe the dynamic failure of brittle media, such as the active material particles in the battery cathode during manufacturing. The proposed model matches expected behavior from physical experiments, analytical approaches, and numerical models, and mesh convergence is established. We find that the use of an asymmetrical damage model to represent tensile damage is important to producing the expected results for brittle fracture problems.

The impact of this work is that designers of lithium-ion battery components can employ the numerical methods presented herein to analyze the evolving electrode microstructure during manufacturing, operational, and extraordinary loadings. This allows for enhanced designs and manufacturing methods that advance the state of battery technology. Further, these numerical tools have applicability in a broad range of fields, from geotechnical analysis to ice-sheet modeling to armor design to hydraulic fracturing.