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

Development of a tool for automatic segmentation of the cerebellum in MR images of children

The human cerebellar cortex is a highly foliated structure that supports both motor and complex cognitive functions in humans. Magnetic Resonance Imaging (MRI) is commonly used to explore structural alterations in patients with psychiatric and neurological diseases. The ability to detect regional structural differences in cerebellar lobules may provide valuable insights into disease biology, progression and response to treatment, but has been hampered by the lack of appropriate tools for performing automated structural cerebellar segmentation and morphometry. In this thesis, time intensive manual tracings by an expert neuroanatomist of 16 cerebellar regions on high-resolution T1-weighted MR images of 18 children aged 9-13 years were used to generate the Cape Town Pediatric Cerebellar Atlas (CAPCA18) in the age-appropriate National Institute of Health Pediatric Database (NIHPD) asymmetric template space. An automated pipeline was developed to process the MR images and generate lobule-wise segmentations, as well as a measure of the uncertainty of the label assignments. Validation in an independent group of children with ages similar to those of the children used in the construction of the atlas, yielded spatial overlaps with manual segmentations greater than 70% in all lobules, except lobules VIIb and X. Average spatial overlap of the whole cerebellar cortex was 86%, compared to 78% using the alternative Spatially Unbiased Infra-tentorial Template (SUIT), which was developed using adult images

Applicability and usage of dose mapping/accumulation in radiotherapy

Dose mapping/accumulation (DMA) is a topic in radiotherapy (RT) for years, but has not yet found its widespread way into clinical RT routine. During the ESTRO Physics workshop 2021 on "commissioning and quality assurance of deformable image registration (DIR) for current and future RT applications", we built a working group on DMA from which we present the results of our discussions in this article. Our aim in this manuscript is to shed light on the current situation of DMA in RT and to highlight the issues that hinder consciously integrating it into clinical RT routine. As a first outcome of our discussions, we present a scheme where representative RT use cases are positioned, considering expected anatomical variations and the impact of dose mapping uncertainties on patient safety, which we have named the DMA landscape (DMAL). This tool is useful for future reference when DMA applications get closer to clinical day-to-day use. Secondly, we discussed current challenges, lightly touching on first-order effects (related to the impact of DIR uncertainties in dose mapping), and focusing in detail on second-order effects often dismissed in the current literature (as resampling and interpolation, quality assurance considerations, and radiobiological issues). Finally, we developed recommendations, and guidelines for vendors and users. Our main point include: Strive for context-driven DIR (by considering their impact on clinical decisions/judgements) rather than perfect DIR; be conscious of the limitations of the implemented DIR algorithm; and consider when dose mapping (with properly quantified uncertainties) is a better alternative than no mapping

Atlas construction and spatial normalisation to facilitate radiation-induced late effects research in childhood cancer

Reducing radiation-induced side effects is one of the most important challenges in paediatric cancer treatment. Recently, there has been growing interest in using spatial normalisation to enable voxel-based analysis of radiation-induced toxicities in a variety of patient groups. The need to consider three-dimensional distribution of doses, rather than dose-volume histograms, is desirable but not yet explored in paediatric populations. In this paper, we investigate the feasibility of atlas construction and spatial normalisation in paediatric radiotherapy. We used planning computed tomography (CT) scans from twenty paediatric patients historically treated with craniospinal irradiation to generate a template CT that is suitable for spatial normalisation. This childhood cancer population representative template was constructed using groupwise image registration. An independent set of 53 subjects from a variety of childhood malignancies was then used to assess the quality of the propagation of new subjects to this common reference space using deformable image registration (i.e., spatial normalisation). The method was evaluated in terms of overall image similarity metrics, contour similarity and preservation of dose-volume properties. After spatial normalisation, we report a dice similarity coefficient of 0.95±0.05, 0.85±0.04, 0.96±0.01, 0.91±0.03, 0.83±0.06 and 0.65±0.16 for brain and spinal canal, ocular globes, lungs, liver, kidneys and bladder. We then demonstrated the potential advantages of an atlas-based approach to study the risk of second malignant neoplasms after radiotherapy. Our findings indicate satisfactory mapping between a heterogeneous group of patients and the template CT. The poorest performance was for organs in the abdominal and pelvic region, likely due to respiratory and physiological motion and to the highly deformable nature of abdominal organs. More specialised algorithms should be explored in the future to improve mapping in these regions. This study is the first step toward voxel-based analysis in radiation-induced toxicities following paediatric radiotherapy

Improvements in the registration of multimodal medical imaging : application to intensity inhomogeneity and partial volume corrections

Alignment or registration of medical images has a relevant role on clinical diagnostic and treatment decisions as well as in research settings. With the advent of new technologies for multimodal imaging, robust registration of functional and anatomical information is still a challenge, particular in small-animal imaging given the lesser structural content of certain anatomical parts, such as the brain, than in humans. Besides, patient-dependent and acquisition artefacts affecting the images information content further complicate registration, as is the case of intensity inhomogeneities (IIH) showing in MRI and the partial volume effect (PVE) attached to PET imaging. Reference methods exist for accurate image registration but their performance is severely deteriorated in situations involving little images Overlap. While several approaches to IIH and PVE correction exist these methods still do not guarantee or rely on robust registration. This Thesis focuses on overcoming current limitations af registration to enable novel IIH and PVE correction methods.El registre d'imatges mèdiques té un paper rellevant en les decisions de diagnòstic i tractament clíniques així com en la recerca. Amb el desenvolupament de noves tecnologies d'imatge multimodal, el registre robust d'informació funcional i anatòmica és encara avui un repte, en particular, en imatge de petit animal amb un menor contingut estructural que en humans de certes parts anatòmiques com el cervell. A més, els artefactes induïts pel propi pacient i per la tècnica d'adquisició que afecten el contingut d'informació de les imatges complica encara més el procés de registre. És el cas de les inhomogeneïtats d'intensitat (IIH) que apareixen a les RM i de l'efecte de volum parcial (PVE) característic en PET. Tot i que existeixen mètodes de referència pel registre acurat d'imatges la seva eficàcia es veu greument minvada en casos de poc solapament entre les imatges. De la mateixa manera, també existeixen mètodes per la correcció d'IIH i de PVE però que no garanteixen o que requereixen un registre robust. Aquesta tesi es centra en superar aquestes limitacions sobre el registre per habilitar nous mètodes per la correcció d'IIH i de PVE