Advances in real-time thoracic guidance systems

Substantial tissue motion: \u3e1cm) arises in the thoracic/abdominal cavity due to respiration. There are many clinical applications in which localizing tissue with high accuracy: \u3c1mm) is important. Potential applications include radiation therapy, radio frequency ablation, lung/liver biopsies, and brachytherapy seed placement. Recent efforts have made highly accurate sub-mm 3D localization of discrete points available via electromagnetic: EM) position monitoring. Technology from Calypso Medical allows for simultaneous tracking of up to three implanted wireless transponders. Additionally, Medtronic Navigation uses wired electromagnetic tracking to guide surgical tools for image guided surgery: IGS). Utilizing real-time EM position monitoring, a prototype system was developed to guide a therapeutic linear accelerator to follow a moving target: tumor) within the lung/abdomen. In a clinical setting, electromagnetic transponders would be bronchoscopically implanted into the lung of the patient in or near the tumor. These transponders would ax to the lung tissue in a stable manner and allow real-time position knowledge throughout a course of radiation therapy. During each dose of radiation, the beam is either halted when the target is outside of a given threshold, or in a later study the beam follows the target in real-time based on the EM position monitoring. We present quantitative analysis of the accuracy and efficiency of the radiation therapy tumor tracking system. EM tracking shows promise for IGS applications. Tracking the position of the instrument tip allows for minimally invasive intervention and alleviates the trauma associated with conventional surgery. Current clinical IGS implementations are limited to static targets: e.g. craniospinal, neurological, and orthopedic intervention. We present work on the development of a respiratory correlated image guided surgery: RCIGS) system. In the RCIGS system, target positions are modeled via respiratory correlated imaging: 4DCT) coupled with a breathing surrogate representative of the patient\u27s respiratory phase/amplitude. Once the target position is known with respect to the surrogate, intervention can be performed when the target is in the correct location. The RCIGS system consists of imaging techniques and custom developed software to give visual and auditory feedback to the surgeon indicating both the proper location and time for intervention. Presented here are the details of the IGS lung system along with quantitative results of the system accuracy in motion phantom, ex-vivo porcine lung, and human cadaver environments

In-house Implementation and Validation of the Mid-Position CT approach for the Treatment Planning of Respiration-induced Moving Tumours in Radiotherapy for Lung and Upper abdomen cancer

Tese mestrado integrado, Engenharia Biomédica e Biofísica (Engenharia Clínica e Instrumentação Médica) Universidade de Lisboa, Faculdade de Ciências, 2022A Radioterapia é uma das modalidades principais para tratamentos de foro oncológico que visa destruir a ação proliferativa das células cancerígenas e reduzir o volume tumoral. A sua ação terapêutica através do uso de radiação ionizante tem, subjacente, a máxima de irradiar o tumor com uma elevada dose, ao mesmo tempo que os órgãos de risco (OARs) adjacentes, são tanto quanto possível protegidos. Quando um tumor se localiza no pulmão ou abdómen superior, como no fígado ou pâncreas, o seu movimento devido à respiração pode alcançar até 4 cm, especialmente na direção crânio-caudal, aumentando as incertezas relativas à posição do tumor. No Centro Clínico Champalimaud (CCC), o planeamento convencional dos tratamentos de radioterapia faz uso de uma tomografia computadorizada (CT) que é adquirida aquando da respiração livre do doente e que, por isso, apresenta geralmente artefactos que podem ser uma fonte de erro durante o planeamento. Nos casos em que o movimento do tumor é considerável, é ainda adquirida uma tomografia computadorizada quadrimensional (4DCT) que consiste entre 8 e 10 CTs que representam fases do ciclo respiratório. Posteriormente, a 4DCT é utilizada para delinear o volume interno do alvo (ITV) que engloba toda a extensão do movimento do tumor. Apesar da estratégia do ITV garantir uma adequada cobertura do volume-alvo, os OARs ficam expostos a doses de radiação desnecessárias e a um maior risco de toxicidade. Este efeito é ainda mais preocupante em tratamentos hipofracionados, onde doses mais elevadas são administradas num número reduzido de frações. Nos últimos anos têm sido desenvolvidas estratégias que visam tornar os tratamentos de radioterapia mais eficazes. Uma delas é a reconstrução de uma CT que representa a posição média do doente ao longo do ciclo respiratório (Mid-P CT). Esta estratégia resulta em volumes de tratamento menores do que a estratégia do ITV, possibilitando o aumento da dose e maior controlo tumoral local. O primeiro passo para a reconstrução do Mid-P CT é o registo deformável de imagens (DIR) entre uma das fases da respiração (uma CT da 4DCT), definida como a fase de referência, e as restantes fases. Deste processo resultam campos vetoriais deformáveis (DVF) que contém informação do deslocamento dos tecidos. Os DVFs são subsequentemente utilizados para transformar cada uma das fases da respiração para a posição média. O método do Mid-P foi implementado com sucesso no Instituto do Cancro Holandês (NKI) em 2008. Apesar dos bons resultados clínicos, o número de centros de radioterapia que utiliza esta técnica é muito reduzido. Tal deve-se, por um lado, à inexistência de soluções comerciais com esta funcionalidade e, por outro, ao esforço necessário alocar para implementar e validar soluções desenvolvidas internamente. O presente projeto teve como principal objetivo implementar a estratégia do Mid-P no CCC (Portugal). Para tal, foi otimizado um módulo – RunMidP – desenvolvido para o software 3D Slicer, que calcula o Mid-P CT e estima a amplitude do movimento do tumor e OARs com base nos DVFs. Considerando que a precisão do módulo e a qualidade de imagem do Mid-P CT devem atender os requisitos para o planeamento em radioterapia, foram realizados testes para validar o módulo. Sempre que possível, a sua performance foi comparada com outras aplicações desenvolvidas para a implementação da técnica do Mid-P, nomeadamente com um protótipo desenvolvido pela empresa Mirada Medical Ltd. (Reino Unido) – Mirada – e com o software desenvolvido no NKI (Holanda) – Wimp. Os testes foram divididos em três estudos diferentes, cada um com um conjunto de dados diferente. No primeiro estudo (estudo A), foram utilizadas 4DCT de 2 fantomas digitais, cuja função respiratória e cardíaca foi modelada de forma simplificada, e de 18 doentes com tumores localizados no pulmão (N = 8), no fígado (N = 6) e no pâncreas (N = 4). Neste estudo, foram comparados dois algoritmos DIR disponíveis no software 3D Slicer, o Plastimatch e o Elastix, em termos da precisão do registo e da qualidade de imagem do Mid-P CT reconstruído. Foi ainda avaliado a capacidade dos softwares RunMidP e Mirada representarem corretamente a posição média do doente e as diferenças das amplitudes do movimento do tumor estimadas pelos dois softwares. No estudo B, foram realizados testes de verificação semelhantes aos supre mencionados, em imagens sintéticas provenientes de 16 doentes, desta vez com a vantagem de se conhecer o “verdadeiro” Mid-P CT e as “verdadeiras” amplitudes do movimento do tumor. Estes foram comparados com os resultados obtidos com os softwares RunMidP e Mirada. Ainda, as unidades de Hounsfield (HU) no Mid-P CT reconstruído por RunMidP e Mirada foram comparadas com as HU na fase de referência, de modo a verificar se os Mid P CTs produziriam diferenças dosimétricas relevantes. No último estudo (estudo C), a qualidade de imagem do Mid-P CT foi avaliada quantitativamente e qualitativamente. Durante a análise qualitativa, foi pedido a dois médicos especialistas que avaliassem a viabilidade dos Mid-P CTs, reconstruídos pelos três softwares (RunMidP, Mirada e Wimp), para o planeamento dos tratamentos. O tempo da reconstrução do Mid-P CT a partir da 4DCT foi de cerca de 1h. Ambos os algoritmos, Plastimach e Elastix, demonstraram ser adequados para DIR de imagens do pulmão e abdómen superior, com diferenças estatisticamente não significativas (p > 0.05) em termos da precisão do registo. Contudo, o Mid-P CT reconstruído com Elastix apresentou uma melhoria na qualidade de imagem, sendo assim o algoritmo DIR escolhido para ser implementado no RunMidP. Em termos de métricas aplicadas a contornos definidos manualmente, tais como a distância de Hausdorf (HD) e coeficiente de Dice (DSC), o erro do registo de imagem foi menor que 1 mm, dentro do contorno do tumor, e 2 mm no pulmão. Os Mid-P CTs reconstruídos com o RunMidP e Mirada apresentaram maiores diferenças, relativamente ao “verdadeiro” Mid-P CT, na região do diafragma e zonas de maior homogeneidade como, por exemplo, no ar presente no intestino. Contudo, para a maioria dos doentes do estudo B, o Mid-P CT reconstruído com o software Mirada apresentou maior índice de similaridade estrutural (SSIM) relativamente ao “verdadeiro” Mid-P CT. Estes resultados podem estar na origem do uso de diferentes algoritmos DIR, mas deveram-se principalmente a uma falha na aplicação das transformações deformáveis pelo módulo RunMiP que foi corrigida posteriormente. Ainda, as diferenças entre as amplitudes estimadas e previstas foram menores que 1 mm para 37 tumores (78,9%), que resultam em diferenças menores que 0.3mm quando convertidas em margens de planeamento. Para além disso, as diferenças nos valores de HU dos Mid-P CTs comparativamente à fase de referência foram, em média, de 1 HU no tumor e OARs. Foram também observadas melhorias na qualidade de imagem do Mid-P CT, nomeadamente um aumento da relação sinal-ruído (SNR) e diminuição dos artefactos. Estes resultados estão de acordo com a avaliação dos médicos que, em geral, consideraram que os Mid-P CTs reconstruídos pelos três softwares são adequados para o planeamento dos tratamentos. No entanto, os Mid-P CTs reconstruídos com dados 4DCT provenientes do CCC apresentaram classificações inferiores aos reconstruídos com dados 4DCT do NKI. Em suma, as modificações do algoritmo DIR Plastimach para Elastix e a correção do método para aplicar as transformações deformáveis, permitiram uma melhoria na qualidade de imagem do Mid P CT e melhor performance do algoritmo, respetivamente. O módulo RunMidP, neste projeto otimizado e validado, apresenta um forte potencial para a reconstrução e implementação da estratégia do Mid-P na clínica, com performance comparável a outras aplicações existentes (Mirada e Wimp). Atenção especial deve ser dada aos dados 4DCT de input que parecem afetar a qualidade de imagem final do Mid-P CT. No futuro, valerá a pena otimizar os parâmetros de aquisição e reconstrução da 4DCT de modo a melhorar a qualidade de imagem e, ainda, o módulo RunMidP pode potencialmente ser otimizado no que respeita ao tempo de reconstrução do Mid-P CT e à precisão do DIR.Radiotherapy for tumours in the thorax and upper abdomen is challenging since they move notably with breathing. To cover the whole extent of tumour motion, relatively large margins are added to treatment volumes, posing a higher risk of toxicity for surrounding organs-at-risk (OARs). The Mid Position (Mid-P) method accounts for breathing motion by using deformable image registration (DIR) to transform all phases of a 4DCT scan to a time-weighted average 3DCT scan (Mid-P CT). The Mid-P strategy results in smaller treatment volumes, potentially boosting the delivery of hypofractionated treatments. To bring the Mid-P approach to the Champalimaud Clinical Centre (CCC), an in-house Mid position software module – RunMidP – was optimized. The module reconstructs the Mid-P CT and estimates breathing motion amplitudes of tumours and relevant OARs. In addition, this project presents a set of experiments to evaluate the performance of the Mid-P method and its feasibility for clinical implementation. The experiments were conducted throughout three different studies using 4DCT data from 18 phantoms and 23 patients. In Study A, the accuracy and image quality of two DIR algorithms (Plastimatch and Elastix) were assessed using quantitative metrics applied on either warped images or manually delineated contours. The reproduction of the patient’s mean position by the Mid-P CT and the estimation of motion amplitudes were compared to a soon-to-be Mid-P commercial software developed by Mirada Medical Ltd. In Study B,similar experiments were performed, this time using a more rigorous reference – “true” Mid-P CT scans and “true” motion estimations. In Study C, the image quality of Mid P CT scans was assessed quantitatively and qualitatively. Both Plastimatch and Elastix registration showed comparable registration accuracy, although Elastix showed superior image quality of reconstructed Mid-P CTs. Based on contour metrics, the registration error was less than 2 mm. In-house Mid-P CTs showed a slightly lower match to ground truth Mid-P CTs than the ones reconstructed by the Mirada prototype due to differences in DIR methods and small shifts to the original image geometry. Higher image differences were found in the diaphragm lung interface, where the patient's anatomy moves faster due to breathing, and in homogeneous regions such as the air regions in the bowel. On the other hand, differences (estimated-predicted) in motion amplitudes smaller than 1 mm were observed in 37 moving tumours (78.7%), showing a good performance of the Mid-P algorithm. Regarding the image quality, improvements in the signal-to-noise ratio and removal of image artefacts in Mid-P CTs are great advantages for using them as the planning CT. Clinicians also gave a good assessment of the suitability of Mid-P CT scans for treatment planning. No significant differences were found in the performance of the RunMidP compared to other Mid-Position packages, although worse scores were given to the CCC dataset than the dataset from another hospital. The in-house Mid-position algorithm shows promising results regarding the use of the software module in radiotherapy for lung and upper abdomen cancer. Further exploration must be given to improve the registration accuracy, image quality of the input data, and speed up the reconstruction of the Mid-P CT scan

A Free-Breathing Lung Motion Model

Lung cancer has been the leading cause of cancer deaths for decades in the United States. Although radiotherapy is one of the most effective treatments, side effects from error in delivery of radiation due to organ motion during breathing remain a significant issue. To compensate the breathing motion during the treatment, a free breathing lung motion model, x= x0+αv+βf, was developed and discussed, where x is the position of a piece of tissue located at reference position x0. α is a parameter which characterizes the motion due to local air filling: motion as a function of tidal volume) and β is the parameter that accounts for the motion due to the imbalance of dynamical stress distributions during inspiration and exhalation which cause lung motion hysteresis: motion as a function of airflow). The parameters α and β together provide a quantitative characterization of breathing motion that inherently includes the complex hysteresis interplay. The theoretical foundation of the model was built by investigating the stress distribution inside of a lung and the biomechanical properties of the lung tissues. Accuracy of the model was investigated by using 49 free-breathing patient data sets. Applications of the model in localizing lung cancer, monitoring radiation damage and suppressing artifacts in free-breathing PET images were also discussed. This work supported in part by NIHR01CA096679 and NIHR01CA11671

Clinical implementation of 4-dimensional radiotherapy for treatment of lung cancer

Senan, S. [Promotor]Slotman, B.J. [Promotor]Lagerwaard, F.J. [Copromotor

Estimating current and future demands for stereotactic ablative body radiotherapy (SABR) in the Australian lung cancer population

Stereotactic ablative body radiotherapy (SABR) is the current standard of care for inoperable early-stage non-small cell lung carcinoma (NSCLC). It is a curative treatment option that offers excellent survival rates through non-invasive out-patient visits. SABR can be offered to frail, elderly patients and those with comorbidities or poor performance status, who may be ineligible for surgery or radical radiotherapy and would otherwise be referred to palliative treatments or (sometimes) left untreated. While strong evidence from randomised trials have supported SABR use for peripherally located tumours (>2cm from the proximal bronchial tree (PBT), treatment of central tumours with SABR remains controversial due to increased risks of severe toxicities. Determining the total demand for lung SABR, also known as the optimal rate of utilisation, is an important step in ensuring adequate and efficient provision of radiotherapy services. Once established, it can used as a benchmark against which actual SABR utilisation rates can be compared and any shortfalls in service provision identified. This optimal SABR utilisation rate can be calculated using an evidence-based approach involving first identifying all indications/clinical situations for which lung SABR is a guideline-recommended treatment, then obtaining data on the proportion of each indication within the lung cancer population. This, however, has so far been hindered by lack of published data on the proportions of peripheral versus centrally located lung tumours. The difficulty in determining the distribution of central and peripheral tumours is related to how these tumours are distinguished in clinical practice; based on clinicians’ manual delineations (i.e. contours) of the PBT. Manual contouring is a well-known source of uncertainty caused by inter- and intra-observer variabilities. Such uncertainties preclude relying on retrospective records of patients (assessed by multiple clinicians) to establish reliable estimates of the proportions of central and peripheral tumours. To overcome this, a novel, fully automatic tool for PBT contouring and measuring distance to the tumour was developed as part of this thesis. The tool relies on an intensity-based algorithm that detects bronchus airways based on pre-determined Hounsfield Unit thresholds. Manual PBT contours generated by different clinicians were used to assess inter-observer variabilities11 and to assess the accuracy of automatically generated contours. Results from this investigation have validated the tool’s ability to generate contours within the accuracy experts-generated ones without the need for manual intervention. Subsequently, this tool was applied on a retrospective dataset (N=234) of Stage I and II NSCLC patients treated with radiotherapy at Liverpool and Macarthur Cancer Therapy Centre in Sydney, Australia. This allowed for patients’ tumour centrality to be assessed efficiently and, more importantly, with less influence from observer variabilities. The tool successfully generated PBT contours and measured the minimum distance to the tumour for all patients within the obtained dataset. Patients were then stratified based on the tumour proximity to the PBT, allowing the distribution of peripheral and central tumours to be determined. Previous studies reporting this distribution have relied on manual PBT contours, which are largely affected by observer variabilities as shown in this work. To calculate the total demand for lung SABR, epidemiological data on the proportions of all clinical attributes where SABR is recommended (including the proportion of peripheral versus central tumours) were incorporated into an evidence-based optimal utilisation model developed as part of this work. Based on most recent evidence and guidelines, it was estimated that a total of 6% of all new patients diagnosed with lung cancer in Australia will require SABR at least once during the course of their illness. In those with early-stage NSCLC, this rate was estimated to be at 24%. This is the first report of evidence-based optimal rates of lung SABR utilisation. The utilisation model can be easily modified and updated with new data to ensure accurate and up-to-date estimates of lung SABR demands within the population. Finally, this work also provided an investigation into the potential impact of upcoming technologies on future demands for lung SABR. Magnetic resonance imaging (MRI) guidance, for example, promises to significantly improve treatment accuracy and transform how radiotherapy is delivered. A planning study was conducted to simulate the dosimetric gains expected by such technologies, in particular, the potential reductions in planning safety margins. Results from this study indicated the potential for such technologies to extend SABR treatments to a substantial proportion of patients currently deemed too high-risk to receive it. As such, it is expected that the demand for lung SABR may increase in the near future as such technologies become more widely availabl

Quantitative Analysis of Radiation-Associated Parenchymal Lung Change

Radiation-induced lung damage (RILD) is a common consequence of thoracic radiotherapy (RT). We present here a novel classification of the parenchymal features of RILD. We developed a deep learning algorithm (DLA) to automate the delineation of 5 classes of parenchymal texture of increasing density. 200 scans were used to train and validate the network and the remaining 30 scans were used as a hold-out test set. The DLA automatically labelled the data with Dice Scores of 0.98, 0.43, 0.26, 0.47 and 0.92 for the 5 respective classes. Qualitative evaluation showed that the automated labels were acceptable in over 80% of cases for all tissue classes, and achieved similar ratings to the manual labels. Lung registration was performed and the effect of radiation dose on each tissue class and correlation with respiratory outcomes was assessed. The change in volume of each tissue class over time generated by manual and automated segmentation was calculated. The 5 parenchymal classes showed distinct temporal patterns We quantified the volumetric change in textures after radiotherapy and correlate these with radiotherapy dose and respiratory outcomes. The effect of local dose on tissue class revealed a strong dose-dependent relationship We have developed a novel classification of parenchymal changes associated with RILD that show a convincing dose relationship. The tissue classes are related to both global and local dose metrics, and have a distinct evolution over time. Although less strong, there is a relationship between the radiological texture changes we can measure and respiratory outcomes, particularly the MRC score which directly represents a patient’s functional status. We have demonstrated the potential of using our approach to analyse and understand the morphological and functional evolution of RILD in greater detail than previously possible

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

Ph.DDOCTOR OF PHILOSOPH

Intensity modulated radiotherapy for inoperable, locally-advanced non-small cell lung cancer : development and clinical outcomes at a cancer centre in Eastern India

Background The submitted publications outline the sequential steps taken for clinical implementation of intensity modulated radiotherapy (IMRT) for lung cancer at a cancer centre in Eastern India. A literature review combined with a detailed risk assessment for IMRT in lung cancer guided the careful implementation for cases where three-dimensional conformal radiotherapy (3D-CRT) did not generate a safe radiotherapy (RT) plan with acceptable tumour coverage. With growing experience, IMRT was expanded to patients receiving concurrent chemoradiation (CCRT) and accelerated RT, including continuous hyperfractionated accelerated radiotherapy (CHART) as well as moderately hypofractionated accelerated radiotherapy. Survival outcomes from radical radiotherapy and chemoradiation (both sequential and concurrent) were audited and found to be comparable to contemporary published literature. In patients with large volume (>500ml) disease, IMRT resulted in non-inferior outcomes despite treating larger volumes and more advanced stage disease. A predictive model that estimates the probability that IMRT would be necessary to produce an acceptable and safe RT plan, was developed from the planning data of 202 patients. Methods An external prospective study was designed to validate this data-driven, decision aid in cohort of patients from multiple hospitals. Apart from assessing the accuracy of the developed predictive model, we are hoping to quantify the planning time saved by opting for IMRT without attempting a 3D-CRT plan. Updated systematic review of prospective studies was carried out to assess the efficacy and safety of IMRT for locally-advanced NSCLC. 9 Results and conclusion No direct impact of IMRT or volumetric modulated arc therapy (VMAT) was seen on local control and survival for these patients, on updated systematic review. IMRT and VMAT was shown to be feasible and safe in the treated patient population. IMRT makes curative treatment possible for large-volume or complex-shaped, locally-advanced NSCLC, resulting non-inferior survival outcomes