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

Dosimetry and 4D Modelling for Advanced Radiotherapy Treatments: Towards MRI-Guided Lung SBRT

A major problem for radiation therapy of lung cancer is respiration-induced motion, which causes both the tumour and surrounding normal tissue to move during treatment. This motion often results in inadequate target coverage and increases the likelihood of additional healthy tissue exposure; therefore detracting from the therapeutic benefits and increasing the risk of radiation induced toxicity. Some motion-management techniques include additional treatment margins to encompass the range of tumour motion, monitoring the respiratory cycle and treating only when in a particular phase i.e. respiratory gating, or imaging the tumour during treatment and adapting the radiation beam aperture to follow the tumour i.e. image guidance and tracking. Magnetic-Resonance-Imaging (MRI)-linacs are a form of image guided radiotherapy, these systems offer high soft-tissue contrast imaging (with MRI) while simultaneously treating with a therapeutic radiation beam (linear accelerator or linac). The effects of the magnetic field on dose deposition and detector response should be well understood to safely translate this technology to clinical treatments. For MRI-linacs where the magnetic field is inline with respect to the beam, the effects of the magnetic field on electron trajectories in lung can be significant and therefore it is important to study the impacts of this on dose distribution in order to treat lung SBRT on these systems. In this thesis, a 4D Monte Carlo dose calculation tool is developed and implemented for assessing current radiotherapy techniques for lung Stereotactic Body Radiotherapy (SBRT). In recent years there has been an increasing interest in MRI-guided radiotherapy and its potential to be used for lung SBRT. With the higher doses per fraction used for SBRT there is an increased need for highly accurate dose calculations and localised delivery; particularly for MRI-linac lung treatments, where the magnetic field strongly influences lung tissue and tumour dose distributions. This thesis also presents work towards translating the 4D Monte Carlo method for inline MRI-linacs

Translational Research of Audiovisual Biofeedback: An investigation of respiratory-guidance in lung and liver cancer patient radiation therapy

Through the act of breathing, thoracic and abdominal anatomy is in constant motion and is typically irregular. This irregular motion can exacerbate errors in radiation therapy, breathing guidance interventions operate to minimise these errors. However, much of the breathing guidance investigations have not directly quantified the impact of regular breathing on radiation therapy accuracy. The first aim of this thesis was to critically appraise the literature in terms of the use of breathing guidance interventions via systematic review. This review found that 21 of the 27 identified studies yielded significant improvements from the use of breathing guidance. None of the studies were randomised and no studies quantified the impact on 4DCT image quality. The second aim of this thesis was to quantify the impact of audiovisual biofeedback breathing guidance on 4DCT. This study utilised data from an MRI study to program the motion of a digital phantom prior to then simulating 4DCT imaging. Audiovisual biofeedback demonstrated to significantly improved 4DCT image quality over free breathing. The third aim of this thesis was to assess the impact of audiovisual biofeedback on liver cancer patient breathing over a course of stereotactic body radiation therapy (SBRT). The findings of this study demonstrated the effectiveness of audiovisual biofeedback in producing consistent interfraction respiratory motion over a course of SBRT. The fourth aim of this thesis was to design and implement a phase II clinical trial investigating the use and impact of audiovisual biofeedback in lung cancer radiation therapy. The findings of a retrospective analysis were utilised to design and determine the statistics of the most comprehensive breathing guidance study to date: a randomised, stratified, multi-site, phase II clinical trial.. The fifth aim of this thesis was to explore the next stages of audiovisual biofeedback in terms of translating evidence into broader clinical use through commercialisation. This aim was achieved by investigating the the product-market fit of the audiovisual biofeedback technology. The culmination of these findings demonstrates the clinical benefit of the audiovisual biofeedback respiratory guidance system and the possibility to make breathing guidance systems more widely available to patients

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 Deep Learning U-Net for Detecting and Segmenting Liver Tumors

Visualization of liver tumors on simulation CT scans is challenging even with contrast-enhancement, due to the sensitivity of the contrast enhancement to the timing of the CT acquisition. Image registration to magnetic resonance imaging (MRI) can be helpful for delineation, but differences in patient position, liver shape and volume, and the lack of anatomical landmarks between the two image sets makes the task difficult. This study develops a U-Net based neural network for automated liver and tumor segmentation for purposes of radiotherapy treatment planning. Non-contrast simulation based abdominal CT axial scans of 52 patients with primary liver tumors were utilized. Preprocessing steps included HU windowing to isolate livers from the scan and creating masks for liver and tumor using the radiotherapy structure set (RTSTRUCT) DICOM file, and converting the images to a PNG format. The RTSTRUCT file contained the ground truth contours that were manually labelled by the physician for both liver and tumor. The image slices were split into 1400 for training and 600 for validation. Two fully convolutional neural networks with a U-Net architecture were used in this study. The first U-Net segments the livers. The second U-Net segments the tumor from the liver segments produced from the first network. The dice coefficient for liver segmentation was 89.5% and the dice coefficient for liver tumor segmentation was 44.4%. The results showed that the proposed algorithm had good performance in liver segmentation and shows areas for improvement for liver tumor segmentation

Quantification of heterogeneity in lung disease with image-based pulmonary function testing

Published: 27 July 2016Computed tomography (CT) and spirometry are the mainstays of clinical pulmonary assessment. Spirometry is effort dependent and only provides a single global measure that is insensitive for regional disease, and as such, poor for capturing the early onset of lung disease, especially patchy disease such as cystic fibrosis lung disease. CT sensitively measures change in structure associated with advanced lung disease. However, obstructions in the peripheral airways and early onset of lung stiffening are often difficult to detect. Furthermore, CT imaging poses a radiation risk, particularly for young children, and dose reduction tends to result in reduced resolution. Here, we apply a series of lung tissue motion analyses, to achieve regional pulmonary function assessment in β-ENaC-overexpressing mice, a well-established model of lung disease. The expiratory time constants of regional airflows in the segmented airway tree were quantified as a measure of regional lung function. Our results showed marked heterogeneous lung function in β-ENaC-Tg mice compared to wild-type littermate controls; identified locations of airway obstruction, and quantified regions of bimodal airway resistance demonstrating lung compensation. These results demonstrate the applicability of regional lung function derived from lung motion as an effective alternative respiratory diagnostic tool.Charlene S. Stahr, Chaminda R. Samarage, Martin Donnelley, Nigel Farrow, Kaye S. Morgan, Graeme Zosky, Richard C. Boucher, Karen K. W. Siu, Marcus A. Mall, David W. Parsons, Stephen Dubsky and Andreas Foura

Segmentation Of Intracranial Structures From Noncontrast Ct Images With Deep Learning

Presented in this work is an investigation of the application of artificially intelligent algorithms, namely deep learning, to generate segmentations for the application in functional avoidance radiotherapy treatment planning. Specific applications of deep learning for functional avoidance include generating hippocampus segmentations from computed tomography (CT) images and generating synthetic pulmonary perfusion images from four-dimensional CT (4DCT).A single institution dataset of 390 patients treated with Gamma Knife stereotactic radiosurgery was created. From these patients, the hippocampus was manually segmented on the high-resolution MR image and used for the development of the data processing methodology and model testing. It was determined that an attention-gated 3D residual network performed the best, with 80.2% of contours meeting the clinical trial acceptability criteria. After having determined the highest performing model architecture, the model was tested on data from the RTOG-0933 Phase II multi-institutional clinical trial for hippocampal avoidance whole brain radiotherapy. From the RTOG-0933 data, an institutional observer (IO) generated contours to compare the deep learning style and the style of the physicians participating in the phase II trial. The deep learning model performance was compared with contour comparison and radiotherapy treatment planning. Results showed that the deep learning contours generated plans comparable to the IO style, but differed significantly from the phase II contours, indicating further investigation is required before this technology can be apply clinically. Additionally, motivated by the observed deviation in contouring styles of the trial’s participating treating physicians, the utility of applying deep learning as a first-pass quality assurance measure was investigated. To simulate a central review, the IO contours were compared to the treating physician contours in attempt to identify unacceptable deviations. The deep learning model was found to have an AUC of 0.80 for left, 0.79 for right hippocampus, thus indicating the potential applications of deep learning as a first-pass quality assurance tool. The methods developed during the hippocampal segmentation task were then translated to the generation of synthetic pulmonary perfusion imaging for use in functional lung avoidance radiotherapy. A clinical data set of 58 pre- and post-radiotherapy SPECT perfusion studies (32 patients) with contemporaneous 4DCT studies were collected. From the data set, 50 studies were used to train a 3D-residual network, with a five-fold validation used to select the highest performing model instances (N=5). The highest performing instances were tested on a 5 patient (8 study) hold-out test set. From these predictions, 50th percentile contours of well-perfused lung were generated and compared to contours from the clinical SPECT perfusion images. On the test set the Spearman correlation coefficient was strong (0.70, IQR: 0.61-0.76) and the functional avoidance contours agreed well Dice of 0.803 (IQR: 0.750-0.810), average surface distance of 5.92 mm (IQR: 5.68-7.55) mm. This study indicates the potential applications of deep learning for the generation of synthetic pulmonary perfusion images but requires an expanded dataset for additional model testing