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

3-D lung deformation and function from respiratory-gated 4-D x-ray CT images : application to radiation treatment planning.

Many lung diseases or injuries can cause biomechanical or material property changes that can alter lung function. While the mechanical changes associated with the change of the material properties originate at a regional level, they remain largely asymptomatic and are invisible to global measures of lung function until they have advanced significantly and have aggregated. In the realm of external beam radiation therapy of patients suffering from lung cancer, determination of patterns of pre- and post-treatment motion, and measures of regional and global lung elasticity and function are clinically relevant. In this dissertation, we demonstrate that 4-D CT derived ventilation images, including mechanical strain, provide an accurate and physiologically relevant assessment of regional pulmonary function which may be incorporated into the treatment planning process. Our contributions are as follows: (i) A new volumetric deformable image registration technique based on 3-D optical flow (MOFID) has been designed and implemented which permits the possibility of enforcing physical constraints on the numerical solutions for computing motion field from respiratory-gated 4-D CT thoracic images. The proposed optical flow framework is an accurate motion model for the thoracic CT registration problem. (ii) A large displacement landmark-base elastic registration method has been devised for thoracic CT volumetric image sets containing large deformations or changes, as encountered for example in registration of pre-treatment and post-treatment images or multi-modality registration. (iii) Based on deformation maps from MOFIO, a novel framework for regional quantification of mechanical strain as an index of lung functionality has been formulated for measurement of regional pulmonary function. (iv) In a cohort consisting of seven patients with non-small cell lung cancer, validation of physiologic accuracy of the 4-0 CT derived quantitative images including Jacobian metric of ventilation, Vjac, and principal strains, (V?1, V?2, V?3, has been performed through correlation of the derived measures with SPECT ventilation and perfusion scans. The statistical correlations with SPECT have shown that the maximum principal strain pulmonary function map derived from MOFIO, outperforms all previously established ventilation metrics from 40-CT. It is hypothesized that use of CT -derived ventilation images in the treatment planning process will help predict and prevent pulmonary toxicity due to radiation treatment. It is also hypothesized that measures of regional and global lung elasticity and function obtained during the course of treatment may be used to adapt radiation treatment. Having objective methods with which to assess pre-treatment global and regional lung function and biomechanical properties, the radiation treatment dose can potentially be escalated to improve tumor response and local control

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

Quantifying the reproducibility of lung ventilation images between 4-Dimensional Cone Beam CT and 4-Dimensional CT.

PURPOSE: Computed tomography ventilation imaging derived from four-dimensional cone beam CT (CTVI4DCBCT ) can complement existing 4DCT-based methods (CTVI4DCT ) to track lung function changes over a course of lung cancer radiation therapy. However, the accuracy of CTVI4DCBCT needs to be assessed since anatomic 4DCBCT has demonstrably poor image quality and small field of view (FOV) compared to treatment planning 4DCT. We perform a direct comparison between short interval CTVI4DCBCT and CTVI4DCT pairs to understand the patient specific image quality factors affecting the intermodality CTVI reproducibility in the clinic. METHODS AND MATERIALS: We analysed 51 pairs of 4DCBCT and 4DCT scans acquired within 1 day of each other for nine lung cancer patients. To assess the impact of image quality, CTVIs were derived from 4DCBCT scans reconstructed using both standard Feldkamp-Davis-Kress backprojection (CTVIFDK4DCBCT) and an iterative McKinnon-Bates Simultaneous Algebraic Reconstruction Technique (CTVIMKBSART4DCBCT). Also, the influence of FOV was assessed by deriving CTVIs from 4DCT scans that were cropped to a similar FOV as the 4DCBCT scans (CTVIcrop4DCT), or uncropped (CTVIuncrop4DCT). All CTVIs were derived by performing deformable image registration (DIR) between the exhale and inhale phases and evaluating the Jacobian determinant of deformation. Reproducibility between corresponding CTVI4DCBCT and CTVI4DCT pairs was quantified using the voxel-wise Spearman rank correlation and the Dice similarity coefficient (DSC) for ventilation defect regions (identified as the lower quartile of ventilation values). Mann-Whitney U-tests were applied to determine statistical significance of each reconstruction and cropping condition. RESULTS: The (mean ± SD) Spearman correlation between CTVIFDK4DCBCT and CTVIuncrop4DCT was 0.60 ± 0.23 (range -0.03-0.88) and the DSC was 0.64 ± 0.12 (0.34-0.83). By comparison, correlations between CTVIMKBSART4DCBCT and CTVIuncrop4DCT showed a small but statistically significant improvement with = 0.64 ± 0.20 (range 0.06-0.90, P = 0.03) and DSC = 0.66 ± 0.13 (0.31-0.87, P = 0.02). Intermodal correlations were noted to decrease with an increasing fraction of lung truncation in 4DCBCT relative to 4DCT, albeit not significantly (Pearson correlation R = 0.58, P = 0.002). CONCLUSIONS: This study demonstrates that DIR based CTVIs derived from 4DCBCT can exhibit reasonable to good voxel-level agreement with CTVIs derived from 4DCT. These correlations outperform previous cross-modality comparisons between 4DCT-based ventilation and nuclear medicine. The use of 4DCBCT scans with iterative reconstruction and minimal lung truncation is recommended to ensure better reproducibility between 4DCBCT- and 4DCT-based CTVIs

Evaluating the accuracy of 4D-CT ventilation imaging: First comparison with Technegas SPECT ventilation.

PURPOSE: Computed tomography ventilation imaging (CTVI) is a highly accessible functional lung imaging modality that can unlock the potential for functional avoidance in lung cancer radiation therapy. Previous attempts to validate CTVI against clinical ventilation single-photon emission computed tomography (V-SPECT) have been hindered by radioaerosol clumping artifacts. This work builds on those studies by performing the first comparison of CTVI with 99m Tc-carbon ('Technegas'), a clinical V-SPECT modality featuring smaller radioaerosol particles with less clumping. METHODS: Eleven lung cancer radiotherapy patients with early stage (T1/T2N0) disease received treatment planning four-dimensional CT (4DCT) scans paired with Technegas V/Q-SPECT/CT. For each patient, we applied three different CTVI methods. Two of these used deformable image registration (DIR) to quantify breathing-induced lung density changes (CTVIDIR-HU ), or breathing-induced lung volume changes (CTVIDIR-Jac ) between the 4DCT exhale/inhale phases. A third method calculated the regional product of air-tissue densities (CTVIHU ) and did not involve DIR. Corresponding CTVI and V-SPECT scans were compared using the Dice similarity coefficient (DSC) for functional defect and nondefect regions, as well as the Spearman's correlation r computed over the whole lung. The DIR target registration error (TRE) was quantified using both manual and computer-selected anatomic landmarks. RESULTS: Interestingly, the overall best performing method (CTVIHU ) did not involve DIR. For nondefect regions, the CTVIHU , CTVIDIR-HU , and CTVIDIR-Jac methods achieved mean DSC values of 0.69, 0.68, and 0.54, respectively. For defect regions, the respective DSC values were moderate: 0.39, 0.33, and 0.44. The Spearman r-values were generally weak: 0.26 for CTVIHU , 0.18 for CTVIDIR-HU , and -0.02 for CTVIDIR-Jac . The spatial accuracy of CTVI was not significantly correlated with TRE, however the DIR accuracy itself was poor with TRE > 3.6 mm on average, potentially indicative of poor quality 4DCT. Q-SPECT scans achieved good correlations with V-SPECT (mean r > 0.6), suggesting that the image quality of Technegas V-SPECT was not a limiting factor in this study. CONCLUSIONS: We performed a validation of CTVI using clinically available 4DCT and Technegas V/Q-SPECT for 11 lung cancer patients. The results reinforce earlier findings that the spatial accuracy of CTVI exhibits significant interpatient and intermethod variability. We propose that the most likely factor affecting CTVI accuracy was poor image quality of clinical 4DCT

Optimization of Decision Making in Personalized Radiation Therapy using Deformable Image Registration

Cancer has become one of the dominant diseases worldwide, especially in western countries, and radiation therapy is one of the primary treatment options for 50% of all patients diagnosed. Radiation therapy involves the radiation delivery and planning based on radiobiological models derived primarily from clinical trials. Since 2015 improvements in information technologies and data storage allowed new models to be created using the large volumes of treatment data already available and correlate the actually delivered treatment with outcomes. The goals of this thesis are to 1) construct models of patient outcomes after receiving radiation therapy using available treatment and patient parameters and 2) provide a method to determine real accumulated radiation dose including the impact of registration uncertainties. In Chapter 2, a model was developed predicting overall survival for patients with hepatocellular carcinoma or liver metastasis receiving radiation therapy. These models show which patients benefit from curative radiation therapy based on liver function, and the survival benefit of increased radiation dose on survival. In Chapter 3, a method was developed to routinely evaluate deformable image registration (DIR) with computer-generated landmark pairs using the scale-invariant feature transform. The method presented in this chapter created landmark sets for comparing lung 4DCT images and provided the same evaluation of DIR as manual landmark sets. In Chapter 4, an investigation was performed on the impact of DIR error on dose accumulation using landmarked 4DCT images as the ground truth. The study demonstrated the relationship between dose gradient, DIR error and dose accumulation error, and presented a method to determine error bars on the dose accumulation process. In Chapter 5, a method was presented to determine quantitatively when to update a treatment plan during the course of a multi-fraction radiation treatment of head and neck cancer. This method investigated the ability to use only the planned dose with deformable image registration to predict dose changes caused by anatomical deformations. This thesis presents the fundamental elements of a decision support system including patient pre-treatment parameters and the actual delivered dose using DIR while considering registration uncertainties

Inverse-Consistent Determination of Young\u27s Modulus of Human Lung

Human lung undergoes respiration-induced deformation due to sequential inhalation and exhalation. Accurate determination of lung deformation is crucial for tumor localization and targeted radiotherapy in patients with lung cancer. Numerical modeling of human lung dynamics based on underlying physics and physiology enables simulation and virtual visualization of lung deformation. Dynamical modeling is numerically complicated by the lack of information on lung elastic behavior, structural heterogeneity as well as boundary constrains. This study integrates physics-based modeling and image-based data acquisition to develop the patient-specific biomechanical model and consequently establish the first consistent Young\u27s modulus (YM) of human lung. This dissertation has four major components: (i) develop biomechanical model for computation of the flow and deformation characteristics that can utilize subject-specific, spatially-dependent lung material property; (ii) develop a fusion algorithm to integrate deformation results from a deformable image registration (DIR) and physics-based modeling using the theory of Tikhonov regularization; (iii) utilize fusion algorithm to establish unique and consistent patient specific Young\u27s modulus and; (iv) validate biomechanical model utilizing established patient-specific elastic property with imaging data. The simulation is performed on three dimensional lung geometry reconstructed from four-dimensional computed tomography (4DCT) dataset of human subjects. The heterogeneous Young\u27s modulus is estimated from a linear elastic deformation model with the same lung geometry and 4D lung DIR. The biomechanical model adequately predicts the spatio-temporal lung deformation, consistent with data obtained from imaging. The accuracy of the numerical solution is enhanced through fusion with the imaging data beyond the classical comparison of the two sets of data. Finally, the fused displacement results are used to establish unique and consistent patient-specific elastic property of the lung

SUBJECT-SPECIFIC 4D ULTRASOUND LIVER MODEL AND DYNAMIC PHANTOM FOR ROBOTIC-ASSISTED LIVER BIOPSY STUDY

Ph.DDOCTOR OF PHILOSOPH