Contour-Driven Atlas-Based Segmentation

We propose new methods for automatic segmentation of images based on an atlas of manually labeled scans and contours in the image. First, we introduce a Bayesian framework for creating initial label maps from manually annotated training images. Within this framework, we model various registration- and patch-based segmentation techniques by changing the deformation field prior. Second, we perform contour-driven regression on the created label maps to refine the segmentation. Image contours and image parcellations give rise to non-stationary kernel functions that model the relationship between image locations. Setting the kernel to the covariance function in a Gaussian process establishes a distribution over label maps supported by image structures. Maximum a posteriori estimation of the distribution over label maps conditioned on the outcome of the atlas-based segmentation yields the refined segmentation. We evaluate the segmentation in two clinical applications: the segmentation of parotid glands in head and neck CT scans and the segmentation of the left atrium in cardiac MR angiography images

Biomechanically-Regularized Deformable Image Registration for Head and Neck Adaptive Radiation Therapy

Radiation treatment (RT), one of the best treatments available for head and neck (HN) cancer, may fail to accurately target tumors and spare surrounding healthy tissue that change in shape and location during 5-7 weeks of RT. This anatomical change can be monitored by calculating deformation maps from planning computed tomography (CT) image (taken prior to the start of RT) to treatment CT images (taken at every treatment fractions for patient setup) via deformable image registration (DIR). In response to the deformations estimated by DIR, initial radiation treatment plan established on the planning CT can be adjusted to deliver sufficient radiation dose to the tumors while sparing healthy tissue. However, since DIR is formulated as an optimization problem to find a deformation map that simply maximizes a similarity metric between two images, it may result in physically unreasonable deformations, such as bone warping. Moreover, DIR accuracy of HN soft tissue region is limited and parameter-dependent as reported in previous studies. Finally, previous studies have evaluated DIR accuracy with a limited number of landmarks, with which accuracy of volumetric deformation cannot be rigorously evaluated. The objective of this dissertation is 1) to improve registration accuracy of HN CT images by introducing penalty terms (from biomechanical principles) into B-spline DIR, in which deformation is represented using a linear combinations of B-spline functions, and 2) to develop an improved evaluation method for DIR accuracy based on finite element model (FE) model of HN region. First, a penalty for prevent the bone warping was developed to preserve inter-voxel distances within each of rigid regions. Second, a penalty that prevents resultant deformations from violating the static equilibrium equations of linear elastic material was used for the B-spline DIR of muscle in HN region. Third, a FE HN model was developed to generate deformation maps similar to those seen in patients that can be used as ground-truth for the evaluation of registration accuracy. The outcome of the dissertation would support research/development in RT of HN cancer by enabling the accurate estimation of deformations of healthy tissue surrounding tumor and the rigorous assessment of registration accuracy.PhDMechanical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113532/1/jihun_1.pd

Quantifying, Understanding and Predicting Differences Between Planned and Delivered Dose to Organs at Risk in Head & Neck Cancer Patients Undergoing Radical Radiotherapy to Promote Intelligently Targeted Adaptive Radiotherapy

Introduction: Radical radiotherapy (RT) is an effective but toxic treatment for head and neck cancer (HNC). Contemporary radiotherapy techniques sculpt dose to target disease and avoid organs at risk (OARs), but anatomical change during treatment mean that the radiation dose delivered to the patient – delivered dose (DA), is different to that anticipated at planning – planned dose (DP). Modifying the RT plan during treatment – Adaptive Radiotherapy (ART) – could mitigate these risks by reducing dose to OARs. However, clinical data to guide patient selection for, and timing of ART, are for lacking. Methods: 337 patients with HNC were recruited to the Cancer Research UK VoxTox study. Demographic, disease and treatment data were collated, and both DP and DA to organs at risk (OARs) were computed from daily megavoltage CT image guidance scans, using an open-source deformable image registration package (Elastix). Toxicity data were prospectively collected. Relationships between DP, DA and late toxicities were investigated with univariate, and logistic regression normal tissue complication probability (NTCP) modelling approaches. A sub-study of VoxTox recruited 18 patients who had MRI scans before RT fractions 1, 6, 16, and 26. Changes in salivary gland volumes and relative apparent diffusion coefficient (ADC) values were measured and related to toxicity events. Results: Spinal cord dose differences were small, and not predicted by weight loss or shape change. Mean DA to all other OARs was higher than DP; factors predicting higher DA included primary disease site, concomitant therapy, shape change and advanced neck disease. Nine patients (3.7%) saw DA>DP by 2Gy to more than half of the OARs assessed. These patients all had received bilateral neck RT for N-stage 2b oropharyngeal cancer. Strong uni- and multivariate relationships between OAR dose and toxicity were seen. Differences between DA and DP-based dose-toxicity models were minimal, and not statistically significant. On MRI, both parotid and submandibular glands shrank during treatment, whilst relative ADC rose. Relationships with toxicity were inconclusive. Conclusions: Small differences between OAR DP and DA mean that DA-based toxicity prediction models confer negligible additional benefit at the population level. Factors such as primary disease sub-site, concomitant systemic therapy, staging and shape change may help to select the patients that do develop clinically significant dose differences, and would benefit most from ART for toxicity reduction

INTEGRATION OF BIOMEDICAL IMAGING AND TRANSLATIONAL APPROACHES FOR MANAGEMENT OF HEAD AND NECK CANCER

The aim of the clinical component of this work was to determine whether the currently available clinical imaging tools can be integrated with radiotherapy (RT) platforms for monitoring and adaptation of radiation dose, prediction of tumor response and disease outcomes, and characterization of patterns of failure and normal tissue toxicity in head and neck cancer (HNC) patients with potentially curable tumors. In Aim 1, we showed that the currently available clinical imaging modalities can be successfully used to adapt RT dose based-on dynamic tumor response, predict oncologic disease outcomes, characterize RT-induced toxicity, and identify the patterns of disease failure. We used anatomical MRIs for the RT dose adaptation purpose. Our findings showed that after proper standardization of the immobilization and image acquisition techniques, we can achieve high geometric accuracy. These images can then be used to monitor the shrinkage of tumors during RT and optimize the clinical target volumes accordingly. Our results also showed that this MR-guided dose adaptation technique has a dosimetric advantage over the standard of care and was associated with a reduction in normal tissue doses that translated into a reduction of the odds of long-term RT-induced toxicity. In the second aim, we used quantitative MRIs to determine its benefit for prediction of oncologic outcomes and characterization of RT-induced normal tissue toxicity. Our findings showed that delta changes of apparent diffusion coefficient parameters derived from diffusion-weighted images at mid-RT can be used to predict local recurrence and recurrence free-survival. We also showed that Ktrans and Ve vascular parameters derived from dynamic contrast-enhanced MRIs can characterize the mandibular areas of osteoradionecrosis. In the final clinical aim, we used CT images of recurrence and baseline CT planning images to develop a methodology and workflow that involves the application of deformable image registration software as a tool to standardize image co-registration in addition to granular combined geometric- and dosimetric-based failure characterization to correctly attribute sites and causes of locoregional failure. We then successfully applied this methodology to identify the patterns of failure following postoperative and definitive IMRT in HNC patients. Using this methodology, we showed that most recurrences occurred in the central high dose regions for patients treated with definitive IMRT compared with mainly non-central high dose recurrences after postoperative IMRT. We also correlated recurrences with pretreatment FDG-PET and identified that most of the central high dose recurrences originated in an area that would be covered by a 10-mm margin on the volume of 50% of the maximum FDG uptake. In the translational component of this work, we integrated radiomic features derived from pre-RT CT images with whole-genome measurements using TCGA and TCIA data. Our results demonstrated a statistically significant associations between radiomic features characterizing different tumor phenotypes and different genomic features. These findings represent a promising potential towards non-invasively tract genomic changes in the tumor during treatment and use this information to adapt treatment accordingly. In the final project of this dissertation, we developed a high-throughput approach to identify effective systemic agents against aggressive head and neck tumors with poor prognosis like anaplastic thyroid cancer. We successfully identified three candidate drugs and performed extensive in vitro and in vivo validation using orthotopic and PDX models. Among these drugs, HDAC inhibitor and LBH-589 showed the most effective tumor growth inhibition that can be used in future clinical trials

Intensity modulated radiation therapy and arc therapy: validation and evolution as applied to tumours of the head and neck, abdominal and pelvic regions

Intensiteitsgemoduleerde radiotherapie (IMRT) laat een betere controle over de dosisdistributie (DD) toe dan meer conventionele bestralingstechnieken. Zo is het met IMRT mogelijk om concave DDs te bereiken en om de risico-organen conformeel uit te sparen. IMRT werd in het UZG klinisch toegepast voor een hele waaier van tumorlocalisaties. De toepassing van IMRT voor de bestraling van hoofd- en halstumoren (HHT) vormt het onderwerp van het eerste deel van deze thesis. De planningsstrategie voor herbestralingen en bestraling van HHT, uitgaande van de keel en de mondholte wordt beschreven, evenals de eerste klinische resultaten hiervan. IMRT voor tumoren van de neus(bij)holten leidt tot minstens even goede lokale controle (LC) en overleving als conventionele bestralingstechnieken, en dit zonder stralingsgeïnduceerde blindheid. IMRT leidt dus tot een gunstiger toxiciteitprofiel maar heeft nog geen bewijs kunnen leveren van een gunstig effect op LC of overleving. De meeste hervallen van HHT worden gezien in het gebied dat tot een hoge dosis bestraald werd, wat erop wijst dat deze “hoge dosis” niet volstaat om alle clonogene tumorcellen uit te schakelen. We startten een studie op, om de mogelijkheid van dosisescalatie op geleide van biologische beeldvorming uit te testen. Naast de toepassing en klinische validatie van IMRT bestond het werk in het kader van deze thesis ook uit de ontwikkeling en het klinisch opstarten van intensiteitgemoduleerde arc therapie (IMAT). IMAT is een rotationele vorm van IMRT (d.w.z. de gantry draait rond tijdens de bestraling), waarbij de modulatie van de intensiteit bereikt wordt door overlappende arcs. IMAT heeft enkele duidelijke voordelen ten opzichte van IMRT in bepaalde situaties. Als het doelvolume concaaf rond een risico-orgaan ligt met een grote diameter, biedt IMAT eigenlijk een oneindig aantal bundelrichtingen aan. Een planningsstrategie voor IMAT werd ontwikkeld, en type-oplossingen voor totaal abdominale bestraling en rectumbestraling werden onderzocht en klinisch toegepast

A Method for Predicting Dose Changes for HN Treatment Using Surface Imaging

Head and neck cancer is commonly treated with a six- to seven-week course of radiotherapy, during which a patient’s anatomy may change substantially, due to target reduction or weight loss. Anatomical changes lead to reduction in treatment quality due to decreased setup reproducibility and altered dose deposition compared to the original plan. Few clinics have developed a standard method for triggering resimulation and replan due to anatomic changes. This work investigates a new method for determining when to resimulate and replan HNC patients by utilizing their topographic anatomical changes to predict differences in planned versus delivered dose distributions. The first part of the work presents a method for deformable image registration of CT to CBCT which addresses the challenges of inaccurate Hounsfield units and truncated field of view present in CBCT. The registration method was validated on 10 HN patients using contour comparison, with average DSC of 0.82, 0.74, 0.72, and 0.69 for mandible, cord, and left and right parotid. The registration method was then used to generate dose maps and surface contours for 47 patients for the second part of this work, the development of a U-Net which takes the original dose distribution, the original surface, and the treatment day surface as input and predicts the treatment day dose distribution as output. The average RMSE and MAE between the true and predicted dose distributions for a test set of 6 patients was 4.25 and 2.15. This work proves feasibility of a dose prediction neural network using surface imaging

Toward adaptive radiotherapy

Intensity Modulated Radiotherapy (IMRT) and proton therapy are the state-of-art external radiotherapy modalities. To make the most of such precise delivery, accurate knowledge of the patient anatomy and biology during treatment is necessary, as unaccounted variations can compromise the outcome of the treatment. Treatment modification to account for deviations from the planning stage is a framework known as adaptive radiotherapy (ART). To fully utilise the information extracted from different modalities and/or at different time-points it is required to accurately align the imaging data. In this work the feasibility of cone-beam computed tomography (CBCT) and deformable image registration (DIR) for ART was evaluated in the context of head and neck (HN) and lung malignancies, and for IMRT and proton therapy applications. This included the geometric validation of deformations for multiple DIR algorithms, estimating the uncertainty in dose recalculation of a CBCT-based deformed CT (dCT), and the uncertainty in dose summation resulting from the properties of the underlying deformations. The dCT method was shown to be a good interim solution to repeat CT and a superior alternative to simpler direct usage of CBCT for dose calculation; proton therapy treatments were more sensitive to registration errors than IMRT. The ability to co-register multimodal and multitemporal data of the HN was also explored; the results found were promising and the limitations of current algorithms and data acquisition protocols were identified. The use of novel artificial cancer masses as a novel platform for the study of imaging during radiotherapy was explored in this study. The artificial cancer mass model was extended to generate magnetic resonance imaging (MRI)-friendly samples. The tumoroids were imageable in standard T1 and T2 MRI acquisitions, and the relaxometric properties were measured. The main limitation of the current tumour model was the poor reproducibility and controllability of the properties of the samples