A biomechanical approach for real-time tracking of lung tumors during External Beam Radiation Therapy (EBRT)

Lung cancer is the most common cause of cancer related death in both men and women. Radiation therapy is widely used for lung cancer treatment. However, this method can be challenging due to respiratory motion. Motion modeling is a popular method for respiratory motion compensation, while biomechanics-based motion models are believed to be more robust and accurate as they are based on the physics of motion. In this study, we aim to develop a biomechanics-based lung tumor tracking algorithm which can be used during External Beam Radiation Therapy (EBRT). An accelerated lung biomechanical model can be used during EBRT only if its boundary conditions (BCs) are defined in a way that they can be updated in real-time. As such, we have developed a lung finite element (FE) model in conjunction with a Neural Networks (NNs) based method for predicting the BCs of the lung model from chest surface motion data. To develop the lung FE model for tumor motion prediction, thoracic 4D CT images of lung cancer patients were processed to capture the lung and diaphragm geometry, trans-pulmonary pressure, and diaphragm motion. Next, the chest surface motion was obtained through tracking the motion of the ribcage in 4D CT images. This was performed to simulate surface motion data that can be acquired using optical tracking systems. Finally, two feedforward NNs were developed, one for estimating the trans-pulmonary pressure and another for estimating the diaphragm motion from chest surface motion data. The algorithm development consists of four steps of: 1) Automatic segmentation of the lungs and diaphragm, 2) diaphragm motion modelling using Principal Component Analysis (PCA), 3) Developing the lung FE model, and 4) Using two NNs to estimate the trans-pulmonary pressure values and diaphragm motion from chest surface motion data. The results indicate that the Dice similarity coefficient between actual and simulated tumor volumes ranges from 0.76±0.04 to 0.91±0.01, which is favorable. As such, real-time lung tumor tracking during EBRT using the proposed algorithm is feasible. Hence, further clinical studies involving lung cancer patients to assess the algorithm performance are justified

A Composite Material-based Computational Model for Diaphragm Muscle Biomechanical Simulation

Lung cancer is the most common cause of cancer related death among both men and women. Radiation therapy is the most widely used treatment for this disease. Motion compensation for tumor movement is often clinically important and biomechanics-based motion models may provide the most robust method as they are based on the physics of motion. In this study, we aim to develop a patient specific biomechanical model that predicts the deformation field of the diaphragm muscle during respiration. The first part of the project involved developing an accurate and adaptable micro-to-macro mechanical approach for skeletal muscle tissue modelling for application in a FE solver. The next objective was to develop the FE-based mechanical model of the diaphragm muscle based on patient specific 4D-CT data. The model shows adaptability to pathologies and may have the potential to be incorporated into respiratory models for the aid in treatment and diagnosis of diseases

Evaluation of deformable image registration for improved 4D CT-derived ventilation for image guided radiotherapy

Recent treatment planning studies have demonstrated the use of physiologic images in radiation therapy treatment planning to identify regions for functional avoidance. This image-guided radiotherapy (IGRT) strategy may reduce the injury and/or functional loss following thoracic radiotherapy. 4D computed tomography (CT), developed for radiotherapy treatment planning, is a relatively new imaging technique that allows the acquisition of a time-varying sequence of 3D CT images of the patient\u27s lungs through the respiratory cycle. Guerrero et al. developed a method to calculate ventilation imaging from 4D CT, which is potentially better suited and more broadly available for IGRT than the current standard imaging methods. The key to extracting function information from 4D CT is the construction of a volumetric deformation field that accurately tracks the motion of the patient\u27s lungs during the respiratory cycle. The spatial accuracy of the displacement field directly impacts the ventilation images; higher spatial registration accuracy will result in less ventilation image artifacts and physiologic inaccuracies. Presently, a consistent methodology for spatial accuracy evaluation of the DIR transformation is lacking. Evaluation of the 4D CT-derived ventilation images will be performed to assess correlation with global measurements of lung ventilation, as well as regional correlation of the distribution of ventilation with the current clinical standard SPECT. This requires a novel framework for both the detailed assessment of an image registration algorithm\u27s performance characteristics as well as quality assurance for spatial accuracy assessment in routine application. Finally, we hypothesize that hypo-ventilated regions, identified on 4D CT ventilation images, will correlate with hypo-perfused regions in lung cancer patients who have obstructive lesions. A prospective imaging trial of patients with locally advanced non-small-cell lung cancer will allow this hypothesis to be tested. These advances are intended to contribute to the validation and clinical implementation of CT-based ventilation imaging in prospective clinical trials, in which the impact of this imaging method on patient outcomes may be tested

A Heterogeneous Patient-Specific Biomechanical Model of the Lung for Tumor Motion Compensation and Effective Lung Radiation Therapy Planning

Radiation therapy is a main component of treatment for many lung cancer patients. However, the respiratory motion can cause inaccuracies in radiation delivery that can lead to treatment complications. In addition, the radiation-induced damage to healthy tissue limits the effectiveness of radiation treatment. Motion management methods have been developed to increase the accuracy of radiation delivery, and functional avoidance treatment planning has emerged to help reduce the chances of radiation-induced toxicity. In this work, we have developed biomechanical model-based techniques for tumor motion estimation, as well as lung functional imaging. The proposed biomechanical model accurately estimates lung and tumor motion/deformation by mimicking the physiology of respiration, while accounting for heterogeneous changes in the lung mechanics caused by COPD, a common lung cancer comorbidity. A biomechanics-based image registration algorithm is developed and is combined with an air segmentation algorithm to develop a 4DCT-based ventilation imaging technique, with potential applications in functional avoidance therapies

Evaluating and Improving 4D-CT Image Segmentation for Lung Cancer Radiotherapy

Lung cancer is a high-incidence disease with low survival despite surgical advances and concurrent chemo-radiotherapy strategies. Image-guided radiotherapy provides for treatment measures, however, significant challenges exist for imaging, treatment planning, and delivery of radiation due to the influence of respiratory motion. 4D-CT imaging is capable of improving image quality of thoracic target volumes influenced by respiratory motion. 4D-CT-based treatment planning strategies requires highly accurate anatomical segmentation of tumour volumes for radiotherapy treatment plan optimization. Variable segmentation of tumour volumes significantly contributes to uncertainty in radiotherapy planning due to a lack of knowledge regarding the exact shape of the lesion and difficulty in quantifying variability. As image-segmentation is one of the earliest tasks in the radiotherapy process, inherent geometric uncertainties affect subsequent stages, potentially jeopardizing patient outcomes. Thus, this work assesses and suggests strategies for mitigation of segmentation-related geometric uncertainties in 4D-CT-based lung cancer radiotherapy at pre- and post-treatment planning stages

Magnetic resonance imaging of lung cancer in the presence of respiratory motion: Dynamic keyhole and audio visual biofeedback

Breath-to-breath variations in breathing can cause image artefacts. Day-to-day variations can cause a disagreement of position and volume between planning and treatment throughout radiotherapy procedures, requiring a larger treatment margin and longer treatment time. An advanced radiotherapy system requires: (1) a fast imaging technique for the compensation of breathing variations and/or (2) a respiratory motion management technique for the control of breathing variations. A novel MRI reconstruction method called “Dynamic keyhole” was proposed as a fast imaging technique. This thesis investigated (1) the concept of this method in terms of the improvement in temporal resolution with healthy volunteer MRI datasets and (2) the applicability of real-time lung tumour localization in terms of the accuracy of tumour motion and shape with lung cancer patient MRI datasets. The dynamic keyhole method achieved an increase in imaging frequency by up to a factor of five when compared with full k-space methods whilst achieving sub-millimetre tumour motion accuracy and preserving tumour shape within 98%. AV biofeedback respiratory guidance was used for healthy volunteers and lung cancer patients. This thesis investigated the impact of AV biofeedback on (1) intra- and inter-fraction lung tumour motion using cine-MRI, (2) inter-fraction lung tumour position and intra-fraction tumour volume using breath-hold MRI and (3) the improvement in image quality and the reduction in scan time using respiratory-gated MRI. AV biofeedback respiratory guidance improved intra- and inter-fraction tumour motion and position reproducibility, and intra-fraction tumour volume consistency. In addition, it was found to improve image quality and reduce scan time. The performance of the dynamic keyhole method and AV biofeedback respiratory guidance shown in this thesis illustrates potential advantages of real-time tumour imaging and tumour motion management in the course of lung cancer radiotherapy

Development of a Carbon Nanotube-Based Micro-CT and its Applications in Preclinical Research

Due to the dependence of researchers on mouse models for the study of human disease, diagnostic tools available in the clinic must be modified for use on these much smaller subjects. In addition to high spatial resolution, cardiac and lung imaging of mice presents extreme temporal challenges, and physiological gating methods must be developed in order to image these organs without motion blur. Commercially available micro-CT imaging devices are equipped with conventional thermionic x-ray sources and have a limited temporal response and are not ideal for in vivo small animal studies. Recent development of a field-emission x-ray source with carbon nanotube (CNT) cathode in our lab presented the opportunity to create a micro-CT device well-suited for in vivo lung and cardiac imaging of murine models for human disease. The goal of this thesis work was to present such a device, to develop and refine protocols which allow high resolution in vivo imaging of free-breathing mice, and to demonstrate the use of this new imaging tool for the study many different disease models. In Chapter 1, I provide background information about x-rays, CT imaging, and small animal micro-CT. In Chapter 2, CNT-based x-ray sources are explained, and details of a micro-focus x-ray tube specialized for micro-CT imaging are presented. In Chapter 3, the first and second generation CNT micro-CT devices are characterized, and successful respiratory- and cardiac-gated live animal imaging on normal, wild-type mice is achieved. In Chapter 4, respiratory-gated imaging of mouse disease models is demonstrated, limitations to the method are discussed, and a new contactless respiration sensor is presented which addresses many of these limitations. In Chapter 5, cardiac-gated imaging of disease models is demonstrated, including studies of aortic calcification, left ventricular hypertrophy, and myocardial infarction. In Chapter 6, several methods for image and system improvement are explored, and radiation therapy-related micro-CT imaging is present. Finally, in Chapter 7 I discuss future directions for this research and for the CNT micro-CT.Doctor of Philosoph

Incorporating Cardiac Substructures Into Radiation Therapy For Improved Cardiac Sparing

Growing evidence suggests that radiation therapy (RT) doses to the heart and cardiac substructures (CS) are strongly linked to cardiac toxicities, though only the heart is considered clinically. This work aimed to utilize the superior soft-tissue contrast of magnetic resonance (MR) to segment CS, quantify uncertainties in their position, assess their effect on treatment planning and an MR-guided environment. Automatic substructure segmentation of 12 CS was completed using a novel hybrid MR/computed tomography (CT) atlas method and was improved upon using a 3-dimensional neural network (U-Net) from deep learning. Intra-fraction motion due to respiration was then quantified. The inter-fraction setup uncertainties utilizing a novel MR-linear accelerator were also quantified. Treatment planning comparisons were performed with and without substructure inclusions and methods to reduce radiation dose to sensitive CS were evaluated. Lastly, these described technologies (deep learning U-Net) were translated to an MR-linear accelerator and a segmentation pipeline was created. Automatic segmentations from the hybrid MR/CT atlas was able to generate accurate segmentations for the chambers and great vessels (Dice similarity coefficient (DSC) \u3e 0.75) but coronary artery segmentations were unsuccessful (DSC\u3c0.3). After implementing deep learning, DSC for the chambers and great vessels was ≥0.85 along with an improvement in the coronary arteries (DSC\u3e0.5). Similar accuracy was achieved when implementing deep learning for MR-guided RT. On average, automatic segmentations required ~10 minutes to generate per patient and deep learning only required 14 seconds. The inclusion of CS in the treatment planning process did not yield statistically significant changes in plan complexity, PTV, or OAR dose. Automatic segmentation results from deep learning pose major efficiency and accuracy gains for CS segmentation offering high potential for rapid implementation into radiation therapy planning for improved cardiac sparing. Introducing CS into RT planning for MR-guided RT presented an opportunity for more effective sparing with limited increase in plan complexity

Incorporating Cardiac Substructures Into Radiation Therapy For Improved Cardiac Sparing

Growing evidence suggests that radiation therapy (RT) doses to the heart and cardiac substructures (CS) are strongly linked to cardiac toxicities, though only the heart is considered clinically. This work aimed to utilize the superior soft-tissue contrast of magnetic resonance (MR) to segment CS, quantify uncertainties in their position, assess their effect on treatment planning and an MR-guided environment. Automatic substructure segmentation of 12 CS was completed using a novel hybrid MR/computed tomography (CT) atlas method and was improved upon using a 3-dimensional neural network (U-Net) from deep learning. Intra-fraction motion due to respiration was then quantified. The inter-fraction setup uncertainties utilizing a novel MR-linear accelerator were also quantified. Treatment planning comparisons were performed with and without substructure inclusions and methods to reduce radiation dose to sensitive CS were evaluated. Lastly, these described technologies (deep learning U-Net) were translated to an MR-linear accelerator and a segmentation pipeline was created. Automatic segmentations from the hybrid MR/CT atlas was able to generate accurate segmentations for the chambers and great vessels (Dice similarity coefficient (DSC) \u3e 0.75) but coronary artery segmentations were unsuccessful (DSC\u3c0.3). After implementing deep learning, DSC for the chambers and great vessels was ≥0.85 along with an improvement in the coronary arteries (DSC\u3e0.5). Similar accuracy was achieved when implementing deep learning for MR-guided RT. On average, automatic segmentations required ~10 minutes to generate per patient and deep learning only required 14 seconds. The inclusion of CS in the treatment planning process did not yield statistically significant changes in plan complexity, PTV, or OAR dose. Automatic segmentation results from deep learning pose major efficiency and accuracy gains for CS segmentation offering high potential for rapid implementation into radiation therapy planning for improved cardiac sparing. Introducing CS into RT planning for MR-guided RT presented an opportunity for more effective sparing with limited increase in plan complexity

Improving Dose-Response Correlations for Locally Advanced NSCLC Patients Treated with IMRT or PSPT

The standard of care for locally advanced non-small cell lung cancer (NSCLC) is concurrent chemo-radiotherapy. Despite recent advancements in radiation delivery methods, the median survival time of NSCLC patients remains below 28 months. Higher tumor dose has been found to increase survival but also a higher rate of radiation pneumonitis (RP) that affects breathing capability. In fear of such toxicity, less-aggressive treatment plans are often clinically preferred, leading to metastasis and recurrence. Therefore, accurate RP prediction is crucial to ensure tumor coverage to improve treatment outcome. Current models have associated RP with increased dose but with limited accuracy as they lack spatial correlation between accurate dose representation and quantitative RP representation. These models represent lung tissue damage with radiation dose distribution planned pre-treatment, which assumes a fixed patient geometry and inevitably renders imprecise dose delivery due to intra-fractional breathing motion and inter-fractional anatomy response. Additionally, current models employ whole-lung dose metrics as the contributing factor to RP as a qualitative, binary outcome but these global dose metrics discard microscopic, voxel-(3D pixel)-level information and prevent spatial correlations with quantitative RP representation. To tackle these limitations, we developed advanced deformable image registration (DIR) techniques that registered corresponding anatomical voxels between images for tracking and accumulating dose throughout treatment. DIR also enabled voxel-level dose-response correlation when CT image density change (IDC) was used to quantify RP. We hypothesized that more accurate estimates of biologically effective dose distributions actually delivered, achieved through (a) dose accumulation using deformable registration of weekly 4DCT images acquired over the course or radiotherapy and (b) the incorporation of variable relative biological effectiveness (RBE), would lead to statistically and clinically significant improvement in the correlation of RP with biologically effective dose distributions. Our work resulted in a robust intra-4DCT and inter-4DCT DIR workflow, with the accuracy meeting AAPM TG-132 recommendations for clinical implementation of DIR. The automated DIR workflow allowed us to develop a fully automated 4DCT-based dose accumulation pipeline in RayStation (RaySearch Laboratories, Stockholm, Sweden). With a sample of 67 IMRT patients, our results showed that the accumulated dose was statistically different than the planned dose across the entire cohort with an average MLD increase of ~1 Gy and clinically different for individual patients where 16% resulted in difference in the score of the normal tissue complication probability (NTCP) using an established, clinically used model, which could qualify the patients for treatment planning re-evaluation. Lastly, we associated dose difference with accuracy difference by establishing and comparing voxel-level dose-IDC correlations and concluded that the accumulated dose better described the localized damage, thereby a closer representation of the delivered dose. Using the same dose-response correlation strategy, we plotted the dose-IDC relationships for both photon patients (N = 51) and proton patients (N = 67), we measured the variable proton RBE values to be 3.07–1.27 from 9–52 Gy proton voxels. With the measured RBE values, we fitted an established variable proton RBE model with pseudo-R2 of 0.98. Therefore, our results led to statistically and clinically significant improvement in the correlation of RP with accumulated and biologically effective dose distributions and demonstrated the potential of incorporating the effect of anatomical change and biological damage in RP prediction models