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

Management of Motion and Anatomical Variations in Charged Particle Therapy:Past, Present, and Into the Future

The major aim of radiation therapy is to provide curative or palliative treatment to cancerous malignancies while minimizing damage to healthy tissues. Charged particle radiotherapy utilizing carbon ions or protons is uniquely suited for this task due to its ability to achieve highly conformal dose distributions around the tumor volume. For these treatment modalities, uncertainties in the localization of patient anatomy due to inter- and intra-fractional motion present a heightened risk of undesired dose delivery. A diverse range of mitigation strategies have been developed and clinically implemented in various disease sites to monitor and correct for patient motion, but much work remains. This review provides an overview of current clinical practices for inter and intra-fractional motion management in charged particle therapy, including motion control, current imaging and motion tracking modalities, as well as treatment planning and delivery techniques. We also cover progress to date on emerging technologies including particle-based radiography imaging, novel treatment delivery methods such as tumor tracking and FLASH, and artificial intelligence and discuss their potential impact towards improving or increasing the challenge of motion mitigation in charged particle therapy

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

The Impact of Lateral Electron Disequilibrium on Stereotactic Body Radiation Therapy of Lung Cancer

Stereotactic Body Radiation Therapy (SBRT) is an effective treatment option for patients with inoperable early-stage lung cancer. SBRT uses online image-guidance technology [e.g. cone-beam CT (CBCT)] to focus small-fields of high energy x-rays onto a tumour to deliver ablative levels of radiation dose (e.g. 54 Gy) in a few treatment fractions (e.g. 3). For the combination of these treatment parameters and a low density lung, lateral electron disequilibrium (LED) can potentially occur, reducing lung and tumour doses. The goal of this thesis was to determine the impact of LED on stereotactic body radiation therapy for lung cancer. The effect of LED on lung dose distribution was studied using Monte Carlo simulations of a lung slab phantom. The magnitude of lung dose reduction due to LED, and the specific conditions (beam energy, field size, and lung density) that cause the phenomenon, were quantified and could be predicted using a relative depth dose factor (RDDF). The RDDF concept was then used to develop a novel SBRT technique, called LED-optimized SBRT (LED-SBRT), which creates steep dose gradients, caused by intentional LED, to elevate tumour dose, while reducing/maintaining dose levels in healthy lung. Further, the RDDF aided in assessing the accuracy required in CBCT-derived lung density, when applied to adaptive SBRT dose calculations. In this regard, we determined that CBCT image artefacts produced erroneously low lung density, artificially triggering LED, and incorrectly predicting lower lung/tumour dose levels. As a result, CBCT number corrective techniques were developed in order to improve dose calculation accuracy. The results of this thesis provide physicians and physicists with a much better prediction of the radiation dosimetry under disequilibrium conditions, and allow exploration of irradiation conditions that can cause LED. With this knowledge in-mind, competent decisions can be made regarding the choice of dose calculation algorithm, and aid in the design and interpretation of SBRT clinical trials. Furthermore, the outcomes of this work can help launch a new generation of SBRT techniques that exploit LED effects that may offer a dosimetric benefits for selected patients

Developments in PET-MRI for Radiotherapy Planning Applications

The hybridization of magnetic resonance imaging (MRI) and positron emission tomography (PET) provides the benefit of soft-tissue contrast and specific molecular information in a simultaneous acquisition. The applications of PET-MRI in radiotherapy are only starting to be realised. However, quantitative accuracy of PET relies on accurate attenuation correction (AC) of, not only the patient anatomy but also MRI hardware and current methods, which are prone to artefacts caused by dense materials. Quantitative accuracy of PET also relies on full characterization of patient motion during the scan. The simultaneity of PET-MRI makes it especially suited for motion correction. However, quality assurance (QA) procedures for such corrections are lacking. Therefore, a dynamic phantom that is PET and MR compatible is required. Additionally, respiratory motion characterization is needed for conformal radiotherapy of lung. 4D-CT can provide 3D motion characterization but suffers from poor soft-tissue contrast. In this thesis, I examine these problems, and present solutions in the form of improved MR-hardware AC techniques, a PET/MRI/CT-compatible tumour respiratory motion phantom for QA measurements, and a retrospective 4D-PET-MRI technique to characterise respiratory motion. Chapter 2 presents two techniques to improve upon current AC methods that use a standard helical CT scan for MRI hardware in PET-MRI. One technique uses a dual-energy computed tomography (DECT) scan to construct virtual monoenergetic image volumes and the other uses a tomotherapy linear accelerator to create CT images at megavoltage energies (1.0 MV) of the RF coil. The DECT-based technique reduced artefacts in the images translating to improved μ-maps. The MVCT-based technique provided further improvements in artefact reduction, resulting in artefact free μ-maps. This led to more AC of the breast coil. In chapter 3, I present a PET-MR-CT motion phantom for QA of motion-correction protocols. This phantom is used to evaluate a clinically available real-time dynamic MR images and a respiratory-triggered PET-MRI protocol. The results show the protocol to perform well under motion conditions. Additionally, the phantom provided a good model for performing QA of respiratory-triggered PET-MRI. Chapter 4 presents a 4D-PET/MRI technique, using MR sequences and PET acquisition methods currently available on hybrid PET/MRI systems. This technique is validated using the motion phantom presented in chapter 3 with three motion profiles. I conclude that our 4D-PET-MRI technique provides information to characterise tumour respiratory motion while using a clinically available pulse sequence and PET acquisition method

Technical Feasibility of MR-Integrated Proton Therapy: Beam Deflection and Image Quality

Es wird erwartet, dass die Integration der Magnetresonanztomografie (MRT) in die Protonentherapie die Treffgenauigkeit bei der Strahlentherapie für Krebserkrankungen deutlich verbessern wird. Besonders für Tumoren in beweglichen Organen des Thorax oder des Abdomens könnte die MRT-integrierte Protonentherapie (MRiPT) eine Synchronisierung der Bestrahlung mit der Tumorposition ermöglichen, was zu einer verminderten Normalgewebsdosis und weniger Nebenwirkungen führen könnte. Bis heute ist solch eine Integration jedoch aufgrund fehlender Studien zu potenziellen gegenseitigen Störeinflüssen dieser beiden Systeme nicht vollzogen worden. Diese Arbeit widmete sich zwei solcher Störeinflüsse, und zwar der Ablenkung des Protonenstrahls im Magnetfeld des MRT- Scanners, und umgekehrt, dem Einfluss der elekromagnetischen Felder der Protonentherapieanlage und des Protonenstrahls selbst auf die MRT-Bilder. Obwohl vorangegangene Studien den derzeitigen Konsens aufgezeigt haben, dass die Trajektorie eines abgebremsten Protonenstrahls im homogenen Phantom in einem transversalen Magnetfeld vorhersagbar ist, zeigte sich im quantitativen Vergleich der publizierten Modelle, der im ersten Teil dieser Arbeit vorgestellt wurde, dass die Vorhersagen dieser Modelle nur für eine begrenzte Anzahl von Kombinationen aus Magnetfeldstärke und Protonenenergie übereinstimmen. Die Schwächen bestehender analytischer Modelle wurden deshalb analysiert und quantifiziert. Kritische Annahmen und die mangelnde Anwendbarkeit auf realistische, d.h. inhomogene Magnetfeldstärken und Patientengeometrien wurden als Hauptprobleme identifiziert. Um diese zu überwinden, wurde ein neues semianalytisches Modell namens RAMDIM entwickelt. Es wurde gezeigt, dass dieses auf realistischere Fälle anwendbar und genauer ist als existierende analytische Modelle und dabei schneller als Monte-Carlo-basierte Teilchenspursimulationen. Es wird erwartet, dass dieses Modell in der MRiPT Anwendung findet zur schnellen und genauen Ablenkungsberechnung, zur Betrahlungsplanoptimierung und bei der MRT-geführten Strahlnachführung. In einem zweiten Schritt wurde die magnetfeldinduzierte Protonenstrahlablenkung in einem gewebeähnlichen Material durch Filmdosimetrie erstmalig gemessen und mit Monte-Carlo-Simulationen verglichen. In einem transversalen Magnetfeld einer Flussdichte von 0,95 T wurde experimentell gezeigt, dass die laterale Versetzung des Bragg-Peaks für Protonenenergien zwischen 80 und 180 MeV in PMMA zwischen 1 und 10 mm liegt. Die Retraktion des Bragg-Peaks war ≤ 0,5 mm. Es wurde gezeigt, dass die gemessene Versetzung des Bragg-Peaks innerhalb von 0,8 mm mit Monte-Carlo-basierten Vorhersagen übereinstimmt. Diese Ergebnisse weisen darauf hin, dass die Protonenstrahlablenkung durch Monte-Carlo-Simulationen genau vorhersagbar ist und damit der Realisierbarkeit der MRiPT nicht im Wege steht. Im zweiten Teil dieser Arbeit wurde erstmalig ein MRT-Scanner in eine Protonenstrahlführung integriert. Hierfür wurde ein offener Niederfeld-MRT-Scanner am Ende einer statischen Forschungsstrahlführung einer Protonentherapieanlage platziert. Die durch das statische Magnetfeld des MRT-Scanners hervorgerufene Strahlablenkung wurde bei der Ausrichtung des MRT-Scanners berücksichtigt. Die sequenzabhängigen, veränderlichen Gradientenfelder hatten keinen messbaren Einfluss auf das transversale Strahlprofil hinter dem MRT-Scanner. Die Magnetfeldhomogenität des Scanners lag innerhalb der Herstellervorgaben und zeigte keinen relevanten Einfluss von Rotationen der Protonengantry im benachbarten Bestrahlungsraum. Eine magnetische Abschirmung war zum gleichzeitigen Betrieb des MRT-Scanners und der Protonentherapieanlage nicht notwendig. Dies beweist die Machbarkeit gleichzeitiger Bestrahlung und Bildgebung in einem ersten MRiPT Aufbau. Die MRT-Bildqualität des Aufbaus wurde darauffolgend anhand eines angepassten Standardprotokolls aus Spin-Echo- und Gradienten-Echo-Sequenzen quantifiziert und es wurde gezeigt, dass die Bildqualität sowohl ohne als auch mit gleichzeitiger Bestrahlung hinreichend ist. Alle bestimmten geometrischen Parameter stimmten mit den physikalischen Abmessungen des verwendeten Phantoms innerhalb eines Bildpixels überein. Wie es für Niederfeld-MRT-Scanner üblich ist, war das Signal-Rausch-Verhältnis (SNR) der MRT-Bilder gering, was im Vergleich zu den Standardkriterien zu einer geringen Bildhomogenität und zu einem hohen Geisterbildanteil im Bild führte. Außerdem wurde aufgrund von Unsicherheiten in der Hochfrequenzkalibrierung des MRT-Scanners eine starke Schwankung der vertikalen Phantomposition mit einem Interquartilabstand von bis zu 1,5 mm beobachtet. T2*-gewichtete Gradientenechosequenzen zeigten zudem aufgrund von Magnetfeldinho- mogenitäten relevante ortsabhängige Bildverzerrungen. Es wurde gezeigt, dass die meisten Bildqualitätsparameter mit und ohne gleichzeitige Betrahlung äquivalent sind. Es wurde jedoch ein signifikanter Betrahlungseinfluss in Form von einer vertikalen Bildverschiebung und einer Verminderung des SNR beobachtet, die durch eine Änderung im Magnetfeld des MRT-Scanners erklärt werden können, welche durch zu diesem Feld parallel ausgerichtete Komponenten im Fernfeld der Strahlführungsmagneten hervorgerufen wird. Während das verminderte SNR vermutlich irrelevant ist (Dif- ferenz im Median ≤ 1,5), ist die sequenzabhängige Bildverschiebung (Differenz im Median bis zu 0,7 mm) nicht immer vernachlässigbar. Diese Ergebisse zeigen, dass die MRT-Bilder durch gleichzeitige Bildgebung nicht schwerwiegend verfälscht werden, dass aber eine dedizierte Optimierung der Hochfrequenzkalibrierung und der MRT-Bildsequenzen notwendig ist. Im letzten Teil der Arbeit wurde gezeigt, dass ein stromabhängiger Einfluss des Protonenstrahls auf MRT-Bilder eines Wasserphantoms durch zwei verschiedene MRT-Sequenzen messbar gemacht und zur Reichweiteverifikation genutzt werden kann. Der Effekt war in verschiedenen Flüssigkeiten, jedoch nicht in viskosen und festen Materialen, nachweisbar und wurde auf Hitzekonvektion zurückgeführt. Es wird erwartet, dass diese Methode in der MRiPT für Konstanztests der Protonenreichweite bei der Maschinenqualitätssicherung nützlich sein wird. Zusammenfassend hat diese Arbeit die Genauigkeit der Vorhersage der Strahlablenkung quantifiziert und verbessert, sowie Potenzial und Realisierbarkeit einer gleichzeitigen MRT-Bildgebung und Protonenbestrahlung gezeigt. Die weitere Entwicklung eines ersten MRiPT-Prototyps ist demnach gerechtfertigt.:List of Figures v List of Tables vii 1 General Introduction 1 2 State of the Art: Proton Therapy and Magnetic Resonance Imaging 3 2.1 Proton Therapy 4 2.1.1 Physical Principle 4 2.1.2 Beam Delivery 7 2.1.3 Motion Management and the Role of Image Guidance 10 2.2 Magnetic Resonance Imaging 14 2.2.1 Physical Principle 14 2.2.2 Image Generation by Pulse Sequences 18 2.2.3 Image Quality 21 2.3 MR-Guided Radiotherapy 24 2.3.1 Offline MR Guidance 24 2.3.2 On-line MR Guidance 25 2.4 MR-Integrated Proton Therapy 28 2.4.1 Aims of this Thesis 32 3 Magnetic Field-Induced Beam Deflection and Bragg Peak Displacement 35 3.1 Analytical Description 36 3.1.1 Review of Analytical Models 36 3.1.2 New Model Formulation 41 3.1.3 Evaluation of Analytical and Numerical Models 44 3.1.4 Discussion 51 3.2 Monte Carlo Simulation and Experimental Verification 54 3.2.1 Verification Setup 54 3.2.2 Monte Carlo Simulation 56 3.2.3 Experimental Verification 60 3.2.4 Discussion 61 3.3 Summary 63 4 Integrated In-Beam MR System: Proof of Concept 65 4.1 Integration of a Low-Field MR Scanner and a Static Research Beamline 65 4.1.1 Proton Therapy System 66 4.1.2 MR Scanner 66 4.1.3 Potential Sources of Interference 67 4.1.4 Integration of Both Systems 68 4.2 Beam and Image Quality in the Integrated Setup 70 4.2.1 Beam Profile 70 4.2.2 MR Magnetic Field Homogeneity 72 4.2.3 MR Image Quality - Qualitative In Vivo and Ex Vivo Test 74 4.2.4 MR Image Quality - Quantitative Phantom Tests 77 4.3 Feasibility of MRI-based Range Verification 86 4.3.1 MR Sequences 86 4.3.2 Proton Beam Parameters 88 4.3.3 Target Material Dependence 91 4.3.4 Discussion 92 4.4 Summary 96 5 Discussion and Future Perspectives 99 6 Summary/Zusammenfassung 105 6.1 Summary 105 6.2 Zusammenfassung 108 Bibliography I Supplementary Information XXIX A Beam Deflection: Experimental Measurements XXIX A.1 Setup XXIX A.2 Film Handling and Evaluation XXX A.3 Uncertainty Estimation XXX B Beam Deflection: Monte Carlo Simulations XXXIII B.1 Magnetic Field Model XXXIII B.2 Uncertainty Estimation XXXIV C Integrated MRiPT Setup XXXVI C.1 Magnetic Field Map XXXVI C.2 Sequence Parameters XXXVI C.3 Image Quality Parameters XLII C.4 Range Verification Sequences XLIIThe integration of magnetic resonance imaging (MRI) into proton therapy is expected to strongly increase the targeting accuracy in radiation therapy for cancerous diseases. Especially for tumours situated in mobile organs in the thorax and abdomen, MR-integrated proton therapy (MRiPT) could enable the synchronisation of irradiation to the tumour position, resulting in less dose to normal tissue and reduced side effects. However, such an integration has been hindered so far by a lack of scientific studies on the potential mutual interference between the two components. This thesis was dedicated to two of these sources of interference, namely the deflection of the proton beam by the magnetic field of the MR scanner and, vice versa, alterations of the MR image induced by the electromagnetic fields of the proton therapy facility and by the beam itself. Although previous work has indicated that there is general consensus that the trajectory of a slowing down proton beam in a homogeneous phantom inside a transverse magnetic field is predictable, a quantitative comparison of the published methods, as presented in the first part of this thesis, has shown that predictions of different models only agree for certain proton beam energies and magnetic flux densities. Therefore, shortcomings of previously published analytical methods have been analysed and quantified. The inclusion of critical assumptions and the lack of applicability to realistic, i.e. non-uniform, magnetic flux densities and patient anatomies have been identified as main problems. To overcome these deficiencies, a new semi-analytical model called RAMDIM has been developed. It was shown that this model is both applicable to more realistic setups and less assumptive than existing analytical approaches, and faster than Monte Carlo based particle tracking simulations. This model is expected to be useful in MRiPT for fast and accurate deflection estimations, treatment plan optimisation, and MR-guided beam tracking. In a second step, the magnetic field-induced proton beam deflection has been measured for the first time in a tissue-mimicking medium by film dosimetry and has been compared against Monte Carlo simulations. In a transverse magnetic field of 0.95 T, it was experimentally shown that the lateral Bragg peak displacement ranges between 1 mm and 10 mm for proton energies between 80 and 180 MeV in PMMA. Range retraction was found to be ≤ 0.5 mm. The measured Bragg peak displacement was shown to agree within 0.8 mm with Monte Carlo simulations. These results indicate that proton beam deflection in a homogeneous medium is accurately predictable for intermediate proton beam energies and magnetic flux densities by Monte Carlo simulations and therefore not impeding the feasibility of MRiPT. In the second part of this thesis, an MR scanner has been integrated into a proton beam line for the first time. For this purpose, an open low-field MR scanner has been placed at the end of a fixed horizontal proton research beam line in a proton therapy facility. The beam deflection induced by the static magnetic field of the scanner was taken into account for alignment of the beam and the FOV of the scanner. The pulse sequence-dependent dynamic gradient fields did not measurably affect the transverse beam profile behind the MR scanner. The MR magnetic field homogeneity was within the vendor’s specifications and not relevantly influenced by the rotation of the proton gantry in the neighbouring treatment room. No magnetic field compensation system was required for simultaneous operation of the MR scanner and the proton therapy system. These results proof that simultaneous irradiation and imaging is feasible in an in-beam MR setup. The MR image quality of the in-beam MR scanner was then quantified by an adapted standard protocol comprising spin and gradient echo imaging and shown to be acceptable both with and without simultaneous proton beam irradiation. All geometrical parameters agreed with the mechanical dimensions of the used phantom within one pixel width. As common for low-field MR scanners, the signal-to-noise ratio (SNR) of the MR images was low, which resulted in a low image uniformity and a high ghosting ratio in comparison to the standardised test criteria. Furthermore, a strong fluctuation of the vertical phantom position due to uncertainties in the pre-scan frequency calibration was observed, with an interquartile range of up to 1.5 mm. T2*-weighted gradient echo images showed relevant nonuniform deformations due to magnetic field inhomogeneities. Most image quality parameters were shown to be equivalent with and without simultaneous proton beam irradiation. However, a significant influence of simultaneous irradiation was observed as a shift of the vertical phantom position and a decrease in the SNR, both of which can be explained by a change in the B0 field of the MR scanner induced by components of the fringe field of the beam line magnets directed parallel to B0 . While the decrease in SNR is not expected to be relevant (median differences were within 1.5 ), the sequence-dependent phantom shift (median differences of up to 0.7 mm) can become non-negligible. These results show that the MR images are not severely distorted by simultaneous irradiation, but a dedicated optimisation of the pre-scan RF calibration and the MR sequences is required for MRiPT. Lastly, a current-dependent influence of the proton beam on the MR image was shown to be measurable in water in two different MR sequences, which allowed for range verification measurements. The effect was observed in different liquids but not in highly viscose and solid materials, and most probably induced by heat convection. This method is expected to be useful in MRiPT for consistency tests of the proton range during machine-specific quality assurance. In conclusion, this work has improved and quantified the accuracy of beam deflection predictions and shown the feasibility and potential of in-beam MR imaging, justifying further research towards a first MRiPT prototype.:List of Figures v List of Tables vii 1 General Introduction 1 2 State of the Art: Proton Therapy and Magnetic Resonance Imaging 3 2.1 Proton Therapy 4 2.1.1 Physical Principle 4 2.1.2 Beam Delivery 7 2.1.3 Motion Management and the Role of Image Guidance 10 2.2 Magnetic Resonance Imaging 14 2.2.1 Physical Principle 14 2.2.2 Image Generation by Pulse Sequences 18 2.2.3 Image Quality 21 2.3 MR-Guided Radiotherapy 24 2.3.1 Offline MR Guidance 24 2.3.2 On-line MR Guidance 25 2.4 MR-Integrated Proton Therapy 28 2.4.1 Aims of this Thesis 32 3 Magnetic Field-Induced Beam Deflection and Bragg Peak Displacement 35 3.1 Analytical Description 36 3.1.1 Review of Analytical Models 36 3.1.2 New Model Formulation 41 3.1.3 Evaluation of Analytical and Numerical Models 44 3.1.4 Discussion 51 3.2 Monte Carlo Simulation and Experimental Verification 54 3.2.1 Verification Setup 54 3.2.2 Monte Carlo Simulation 56 3.2.3 Experimental Verification 60 3.2.4 Discussion 61 3.3 Summary 63 4 Integrated In-Beam MR System: Proof of Concept 65 4.1 Integration of a Low-Field MR Scanner and a Static Research Beamline 65 4.1.1 Proton Therapy System 66 4.1.2 MR Scanner 66 4.1.3 Potential Sources of Interference 67 4.1.4 Integration of Both Systems 68 4.2 Beam and Image Quality in the Integrated Setup 70 4.2.1 Beam Profile 70 4.2.2 MR Magnetic Field Homogeneity 72 4.2.3 MR Image Quality - Qualitative In Vivo and Ex Vivo Test 74 4.2.4 MR Image Quality - Quantitative Phantom Tests 77 4.3 Feasibility of MRI-based Range Verification 86 4.3.1 MR Sequences 86 4.3.2 Proton Beam Parameters 88 4.3.3 Target Material Dependence 91 4.3.4 Discussion 92 4.4 Summary 96 5 Discussion and Future Perspectives 99 6 Summary/Zusammenfassung 105 6.1 Summary 105 6.2 Zusammenfassung 108 Bibliography I Supplementary Information XXIX A Beam Deflection: Experimental Measurements XXIX A.1 Setup XXIX A.2 Film Handling and Evaluation XXX A.3 Uncertainty Estimation XXX B Beam Deflection: Monte Carlo Simulations XXXIII B.1 Magnetic Field Model XXXIII B.2 Uncertainty Estimation XXXIV C Integrated MRiPT Setup XXXVI C.1 Magnetic Field Map XXXVI C.2 Sequence Parameters XXXVI C.3 Image Quality Parameters XLII C.4 Range Verification Sequences XLI

Modelling the effect of geometric uncertainties, clonogen distribution and IMRT interplay effect on tumour control probability

Geometric uncertainties are inevitable in radiotherapy. These uncertainties in tumour position are classi�fied as systematic (�) and random (�) errors. To account for these uncertainties, a margin is added to the clinical target volume (CTV) to create the planning target volume (PTV). The size of the PTV is critical for obtaining an optimal treatment plan. Dose-based (i.e., physical) margin recipes as a function of systematic and random errors based on coverage probability of a certain level of dose (90% or 95% of the prescription dose) have been published and widely used. However, with a TCP-based margin it is possible to consider fractionation and the radiobiological characteristics, especially the dose-response slope (50) of the tumour. Studies have shown that the density of the clonogens decrease from the boundary of the gross tumour volume (GTV). In such a scenario, dose that is lower than in the GTV should be suffi�cient to eradicate these clonogens. Thus a smaller PTV margin with a gradual dose fall off� can be used if the clonogen density in the GTV-CTV region is found to be lower than in GTV. Studies have reported tiny tumour islets outside the CTV region. These tiny tumour islets can be eradicated in some cases by the incidental dose outside the PTV due to the nature of the photon beam irradiation, but if they are not in the beam path the treatment outcome is compromised. In this thesis, a Monte Carlo approach is used to simulate the e�ect of geometric uncertainties, number of fractions and dose-response slope (gamma50) using the `enhanced Marsden' TCP model on the treatment outcome. Systematic and random errors were drawn from a pseudo-random number generator.The dose variations caused by tumour displacements due to geometric uncertainties in the CTV are accumulated each fraction on a voxel-by-voxel basis. Required margins for � 1% mean population TCP (TCPpop) for four-�field (4F) brick and a highly conformal spherical dose distribution for varying number of fractions, di�fferent 50 and di�fferent combinations of � and � are investigated. It is found that TCP-based margins are considerably smaller than dose-based recipes in most cases except for tumours with a steep dose-response slope (high 50) and a small number of fractions for both 4F and spherical dose distributions. For smaller geometric uncertainties (systematic,random� = �=1 mm) margins can be close to zero for the 4F technique due to high incidental dose outside the PTV. It is evident from the analyses that margins depend on the number of fractions, 50, the degree of dose conformality in addition to � and �. Ideally margins should be anisotropic and individualized, taking into account 50, number of fractions, and the dose distribution, as well as estimates of � and �. No single \recipe" can adequately account for all these variables.Using an exponential clonogen distribution in the GTV-CTV region, possible PTV margin reduction is demonstrated. Moreover, the e�ect of extra-CTV tumour islets is studied using a prostate IMRT plan. The islets were randomly distributed around the CTV with in a radius of 3 cm to represent di�erent patients. The doses were rescaled up to 102 Gy to obtain the dose-response curve (DRC). Interestingly, the obtained DRC showed a biphasic response where 100% TCP could not be achieved just by escalating the dose. Another potential problem encountered in intensity-modulated radiotherapy (IMRT) is the problems caused by the `interplay' e�ect between the respiration-induced tumour motion and the multileaf collimator (MLC) leaves movement during treatment. Several dosimetric studies in the literature have shown that `interplay' eff�ects blur the dose distribution by producing `hot' and `cold' dose inside the tumour. Most of these studies were done in a phantom with ion chambers or �lms, which provide only 1D or 2D dose information. If 3D dose information is available, a TCP based analysis would provide a direct estimate of interplay on the clinical outcome. In this thesis, an in-house developed dose model enabled us to calculate the 3D time-resolved dose contribution to each voxel in the target volume considering the change in segment shapes and position of the target volume. Using the model, delivered dose is accumulated in a voxel-by-voxel basis inclusive of tumour motion over the course of treatment. The eff�ect of interplay on dose and TCP is studied for conventionally and hypofractionated treatments using DICOM datasets. Moreover, the e�ect of dose rate on interplay is also studied for single-fraction treatments. Simulations were repeated several times to obtain mean population TCP (TCPpop) for each plan. The average variation observed in mean dose to the target volumes wer

Performance and Methodological Aspects in Positron Emission Tomography

Performance standards for Positron emission tomography (PET) were developed to be able to compare systems from different generations and manufacturers. This resulted in the NEMA methodology in North America and the IEC in Europe. In practices, the NEMA NU 2- 2001 is the method of choice today. These standardized methods allow assessment of the physical performance of new commercial dedicated PET/CT tomographs. The point spread in image formation is one of the factors that blur the image. The phenomenon is often called the partial volume effect. Several methods for correcting for partial volume are under research but no real agreement exists on how to solve it. The influence of the effect varies in different clinical settings and it is likely that new methods are needed to solve this problem. Most of the clinical PET work is done in the field of oncology. The whole body PET combined with a CT is the standard investigation today in oncology. Despite the progress in PET imaging technique visualization, especially quantification of small lesions is a challenge. In addition to partial volume, the movement of the object is a significant source of error. The main causes of movement are respiratory and cardiac motions. Most of the new commercial scanners are in addition to cardiac gating, also capable of respiratory gating and this technique has been used in patients with cancer of the thoracic region and patients being studied for the planning of radiation therapy. For routine cardiac applications such as assessment of viability and perfusion only cardiac gating has been used. However, the new targets such as plaque or molecular imaging of new therapies require better control of the cardiac motion also caused by respiratory motion. To overcome these problems in cardiac work, a dual gating approach has been proposed. In this study we investigated the physical performance of a new whole body PET/CT scanner with NEMA standard, compared methods for partial volume correction in PET studies of the brain and developed and tested a new robust method for dual cardiac-respiratory gated PET with phantom, animal and human data. Results from performance measurements showed the feasibility of the new scanner design in 2D and 3D whole body studies. Partial volume was corrected, but there is no best method among those tested as the correction also depends on the radiotracer and its distribution. New methods need to be developed for proper correction. The dual gating algorithm generated is shown to handle dual-gated data, preserving quantification and clearly eliminating the majority of contraction and respiration movementSiirretty Doriast

Optical Methods in Sensing and Imaging for Medical and Biological Applications

The recent advances in optical sources and detectors have opened up new opportunities for sensing and imaging techniques which can be successfully used in biomedical and healthcare applications. This book, entitled ‘Optical Methods in Sensing and Imaging for Medical and Biological Applications’, focuses on various aspects of the research and development related to these areas. The book will be a valuable source of information presenting the recent advances in optical methods and novel techniques, as well as their applications in the fields of biomedicine and healthcare, to anyone interested in this subject