Purpose: To assess (1) the potential benefit that MRI may bring to prostate radiotherapy planning and delivery; (2) a method of improving registration of MRI and CT imaging to aid the RT planning workflow; (3) the role of in-bore MRI guided biopsy in informing management; (4) dosimetric outcome and toxicity of an integrated High Dose Rate (HDR-B) or Volumetric Modulated Arc Therapy (VMAT-IB) boost to the area of dominant disease within the prostate; (5) whether a predictive response can be identified measuring changes in Diffusion Weighted Imaging (DWI) and Dynamic Contrast Enhancement (DCE) during prostate RT after neo-adjuvant HT (NA-HT); (6) the necessity of hormone therapy (HT) with dose escalated radiotherapy (DE-RT) for intermediate risk prostate cancer. Methods: (1) Perform a systematic review of literature pertaining to MRI and image guided radiotherapy; (2) compare registration accuracy, based on displacement of fiducial markers or degree of overlap of segmented prostate measured by Dice Similarity Coefficient (DSC), of MRI and CT for 14 patients after conventional operator driven visual matching and then an additional registration step using interstitial points identified on high quality volumetric CT (HQVCT); (3) assess the predictive power of in-bore MRI guided biopsy of areas with suspicious appearance on multi-parametric MRI by comparing biopsy accuracy to histological findings and repeat biopsy results for 42 PIRADS 4-5 lesions in 31 men; (4) analyse patients treated in a prospective study receiving standard radiotherapy to the prostate plus a HDR-B (20 patients) or VMAT-IB (26) to a total dose of 250 Gy BED to assess acute and late toxicity and dosimetric variation between the two methods; (5) prospectively recruit 15 patient who have received NA-HT and perform DWI and DCE before, during and after completion of radiotherapy to look for significant changes in values in normal and malignant tissue which may predict for ultimate outcome; (6) Assess clinical outcome for patients receiving 75.6 – 78 Gy +/- bicalutamide. Results: (1) The review has quantified uncertainties in treatment delivery and the degree that the addition of MRI may mitigate this; (2) point based registration of CT and MRI imaging after visual registration achieved a significant reduction in fiducial marker displacement and a significant increase in DSC; (3) seven lesions targeted by in-bore MR guided biopsy had non-significant or negative results, most with biopsy needle deflected to the target periphery with four confirmed false negative on repeat biopsy; (4) with a median follow up of 12 months acute and late toxicity was similar after either treatment with HDR-B delivering a significantly higher dose to a proportion of the gross tumour volume (GTV) but with significantly lower minimum dose to the planned target volume (PTV); (5) tumour DWI values during RT after NA-HT were not found to significantly alter, DCE was found to vary significantly during treatment and initial changes correlated with changes in DWI; (6) the addition of bicalutamide did not significantly improve biochemical control or overall survival. Conclusions: (1) Routine use of MRI will to improve radiotherapy planning and delivery; (2) repeat point based registration using interstitial points has the potential to improve visual CT and MRI registration; (3) an in-bore MRI guided biopsy has little value in informing a decision to offer focal therapy to an MRI identified PIRADS 4-5 lesion due to its high false negative rate; (4) with limited follow up HDR-B and VMAT-IB appear safe methods of focal dose escalation although with significant dosimetric variations;(5) early changes in DWI and DCE during RT after NA-HT appear to correlate, longer follow up will assess their prognostic value; (6) A benefit of HT combined with DE-RT was not shown in this study.

L'imagerie est maintenant partie intégrante des traitements de radiothérapie. Avec la technologie CBCT embarquée sur les appareils de traitement, l'imagerie tomographique permet non seulement de repositionner fidèlement le patient tout au long de son traitement mais aussi d'adapter la planification initiale aux modifications quotidiennes de volume. C'est la radiothérapie adaptative, objet des travaux de cette thèse. Nous avons établi les limites techniques de précision de repositionnement des équipements utilisé. Ensuite, à partir des acquisitions CBCT quotidiennes de patients traités pour la prostate, nous avons élaboré une stratégie de traitement basée sur une banque de plans personnalisés. Nous avons mis au point une méthode semi-automatique de sélection du plan de traitement du jour qui a montré une efficacité supérieure à la sélection par des opérateurs expérimentés. Enfin, nous avons quantifié les doses additionnelles à la dose thérapeutique associées à l'utilisation quotidienne de l'imagerie CBCT. En conclusion, on peut dire qu'avec l'imagerie CBCT embarquée, on peut voir ce que l'on veut traiter, irradier ce que l'on a vu et contrôler ce qu'on a traité. / Imaging is now fully integrated in the radiation therapy process. With on-board CBCT systems, tomography imaging allows not only patient positioning but also treatment planning adaptation with patient anatomy modifications, throughout the entire treatment. This is called adaptive radiation therapy, and is the main subject of this PhD thesis. During this work, we measured the repositioning accuracy of the system used. We also developed a treatment strategy using daily CBCT images and a personalized plan database to adapt treatment plan to patient anatomy. We found a way to select the daily treatment plan that shows superiority over operator selection. Then we also quantified the additional dose delivered while using this technique and the impact with regards to the risks added to patients. As a conclusion, with CBCT imaging, radiation therapy has entered an era where one can see what need to be treated, can treat what has been seen and can control what has been treated.

BACKGROUND:The aim of the study is to assess the effectiveness of intensity-modulated radiotherapy (IMRT) or image-guided radiotherapy (IGRT) for the prevention of retropharyngeal nodal recurrences in locally advanced head and neck cancer.METHODS:A retrospective review of 76 patients with head and neck cancer undergoing concurrent chemoradiation or postoperative radiotherapy with IMRT or IGRT who were at risk for retropharyngeal nodal recurrences because of anatomic site (hypopharynx, nasopharynx, oropharynx) and/or the presence of nodal metastases was undertaken.The prevalence of retropharyngeal nodal recurrences was assessed on follow-up positron emission tomography (PET)-CT scans.RESULTS:At a median follow-up of 22months (4-53months), no patient developed retropharyngeal nodal recurrences.CONCLUSION:Prophylactic irradiation of retropharyngeal lymph nodes with IMRT or IGRT provides effective regional control for individuals at risk for recurrence in these nodes.

<p>The daily uncertainty concerning tumor localization is one of the major problems during the course of radiation therapy. Image guided-radiation therapy (IGRT) can be used to improve the localization and adjustment of the planning target volume. The aim of this work was to evaluate both the IGRT technique used for prostate cancer patients at the department of the Karolinska University Hospital and an alternative on-line adaptive radiation therapy (ART) method with an On-Board Imager (OBI).</p><p>In the first part of the thesis 2D and 3D image registration with an OBI were compared. Ten prostate cancer patients were involved in the analyses. Two different statistical tests were used to determine significant systematic deviations between the two methods. The second part concerns daily dose verifications and dose plan reoptimization of one intensity modulated radiation therapy (IMRT) prostate cancer patient treated with IGRT. The study was based on cone-beam computed tomography (CBCT) images acquired at 6 different treatment fractions. The risk of developing late rectal and bladder toxicity was quantified using normal tissue complication probability (NTCP) calculations. Additional measurements on an Alderson phantom were performed to verify the accuracy of using the CBCT images for dose calculations.</p><p>A statistically significant difference between the 2D-2D and the 3D-3D match applications could be observed in lateral and longitudinal direction. However, the effect differed among the patients. The phantom measurements showed small dose deviations between the CT and CBCT image, with a mean dose increase to the prostate and seminal vesicles (SV) of 2.5 %. The daily dose to the prostate and SV of the IMRT patient showed to be satisfactory. The daily dose to the rectum did not exceed the prescribed rectal dose except at one treatment fraction and the highest risk of developing late rectal toxicity was about 10.4 %. Large daily bladder dose variations were observed and at two treatment fractions the bladder dose restrictions were exceeded. With a reoptimization process of the dose plan, the dose to the bladder could be reduced while conserving the dose to the target.</p><p>This work shows that for these specific patient cases appropriate doses to the prostate and SV can be delivered with IGRT. However, introducing a suitable ART method could lead to a reduction of inter-fractional rectal and bladder dose variations.</p>

The daily uncertainty concerning tumor localization is one of the major problems during the course of radiation therapy. Image guided-radiation therapy (IGRT) can be used to improve the localization and adjustment of the planning target volume. The aim of this work was to evaluate both the IGRT technique used for prostate cancer patients at the department of the Karolinska University Hospital and an alternative on-line adaptive radiation therapy (ART) method with an On-Board Imager (OBI). In the first part of the thesis 2D and 3D image registration with an OBI were compared. Ten prostate cancer patients were involved in the analyses. Two different statistical tests were used to determine significant systematic deviations between the two methods. The second part concerns daily dose verifications and dose plan reoptimization of one intensity modulated radiation therapy (IMRT) prostate cancer patient treated with IGRT. The study was based on cone-beam computed tomography (CBCT) images acquired at 6 different treatment fractions. The risk of developing late rectal and bladder toxicity was quantified using normal tissue complication probability (NTCP) calculations. Additional measurements on an Alderson phantom were performed to verify the accuracy of using the CBCT images for dose calculations. A statistically significant difference between the 2D-2D and the 3D-3D match applications could be observed in lateral and longitudinal direction. However, the effect differed among the patients. The phantom measurements showed small dose deviations between the CT and CBCT image, with a mean dose increase to the prostate and seminal vesicles (SV) of 2.5 %. The daily dose to the prostate and SV of the IMRT patient showed to be satisfactory. The daily dose to the rectum did not exceed the prescribed rectal dose except at one treatment fraction and the highest risk of developing late rectal toxicity was about 10.4 %. Large daily bladder dose variations were observed and at two treatment fractions the bladder dose restrictions were exceeded. With a reoptimization process of the dose plan, the dose to the bladder could be reduced while conserving the dose to the target. This work shows that for these specific patient cases appropriate doses to the prostate and SV can be delivered with IGRT. However, introducing a suitable ART method could lead to a reduction of inter-fractional rectal and bladder dose variations.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21653号 / 医博第4459号 / 新制||医||1035(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 鈴木 実, 教授 富樫 かおり, 教授 森田 智視 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Les changements anatomiques des patients au cours du traitement de radiothérapie peuvent engendrer des conséquences dosimétriques significatives sur les volumes cibles (VC) ou les organes à risques (OARs). Le processus de radiothérapie adaptative peut compenser ces variations, cependant son déploiement en clinique est ralentit par une charge de travail supplémentaire considérable pour les équipes médicales et aucun logiciel n'est disponible pour une utilisation en clinique. Nous avons développé un outil d'alerte dosimétrique in vivo simple permettant d'identifier rapidement les situations où une adaptation de traitement est requise pour un patient. L'évaluation dosimétrique des traitements délivrés a été réalisée sur l'imagerie embarquée 3D (CBCT) dont la précision des calculs de dose a dû être évaluée. L'outil d'alerte permet de s'affranchir d'une nouvelle délinéation de volumes d'intérêt et est basé sur des critères objectifs et quantifiables constitués par le dépassement des limites dosimétriques définies pour chacun des volumes considérés. La précision et la détectabilité de l'outil ont été validées puis il a été appliqué dans une étude rétrospective de 10 patients ORL afin de surveiller l'administration du traitement et d'identifier les patients pour lesquels une adaptation du traitement aurait pu être envisagée. Dans son implémentation clinique, le processus de radiothérapie adaptative requiert des algorithmes de recalage déformable capable de suivre les déformations locales d'un patient se produisant au cours du traitement, seulement leur utilisation n'est pas encore validée. Nous avons procédé à l'évaluation de la précision d'un algorithme de recalage déformable, de type Block Matching présentant l'avantage d'être adapté à l'imagerie multimodale CT/CBCT, en comparaison par rapport à un algorithme de recalage rigide. Une étude a été menée pour 10 patients ORL en se basant sur la comparaison de contours de volumes d'intérêt pour 76 CBCT. Les paramètres de similarité utilisés consistaient en l'Indice de Similarité Dice, la distance de Hausdorff robuste (en mm) et la différence de volume absolu (en cm3) / Changing anatomy during radiotherapy can lead to significant dosimetric consequences for organs at risk (OARs) and/or target volumes. Adaptive radiotherapy can compensate for these variations however its deployment for clinical work is hampered by the increased workload for the medical staff and there is still no commercialized software available for clinical use. We developed a simple in vivo dosimetric alert tool allowing rapid identification of patients who might benefit from an adaptive radiotherapy. Dosimetric evaluation of delivered treatment has been conducted onto 3D on board imaging (CBCT) whose dose calculation accuracy has been evaluated. The tool does not require a new volume of interest delineation. Tool alert is based on objectives and quantifiable criteria defined by the exceeding volumes of interest dose thresholds. Tool precision and detectability have been validated and applied in a retrospective study on 10 head and neck patients. The tool allows detecting patients where an adaptive treatment could have been considered. In its clinical implementation, adaptive radiotherapy process requires deformable matching algorithms to follow patient local's deformations occurring during treatment. Nevertheless, their use has not been validated. We conducted an evaluation of the Block Matching deformable algorithm, suitable for multimodality imaging (CT/CBCT), in comparison to rigid algorithm. A study has been conducted for 10 head and neck patients based on volume of interest contours comparison for 76 CBCT. Similarity parameters used consisted on Dice Similarity Index, Robust Hausdorff Distance (in mm) and the absolute volume difference (in cc)

Accurate tumor tracking remains as a major challenge in radiation therapy. Large margins are added to the clinical target volume (CTV) to ensure the treatment of tumor in presence of patient setup uncertainty and that caused by intra-motion. Fiducial seeds and calypso markers are commonly implanted into the disease sites to further reduce the dose delivery error due to tumor motion. For more accurate dose delivery and improved patient comfort, the use of radioactive tracers in positron emission tomography (PET) as non-invasive tumor markers has been proposed - a concept called emission-guided radiation therapy (EGRT). Instead of using images obtained from a stand-alone PET scanner for treatment guidance, we mount a positron imaging system on a radiation therapy machine. Such an EGRT system is able to track the tumor in real time based on the lines of response (LOR) of the tumor positron events, and perform radiation therapy simultaneously. In this work, we illustrate the EGRT concept using computer simulations and propose a typical treatment scheme. EGRT's advantage on increased dose delivery accuracy is demonstrated using a pancreas tumor case and a lung tumor case without the setup margin and motion margin. The emission process is simulated by Geant4 Application for Tomographic Emission package and Linac dose delivery is simulated using a voxel-based Monte Carlo algorithm. The tumor tracking error can be controlled within 2 mm which indicates margins can be significantly reduced. The dose distributions show that the proposed EGRT can accurately deliver the prescribed dose to the CTV with much less margins. Although still in a preliminary research stage, EGRT has the potential to substantially reduce tumor location uncertainties and to greatly increase the performance of current radiation therapy.

Cobalt 60 (Co-60) radiation therapy is a simple and reliable method of treating cancer by irradiating treatment volumes within the patient with high energy gamma rays. Medical linear accelerators (linacs) began to replace Co-60 units during the 1960’s in more developed countries, but Co 60 has remained the main source of radiotherapy treatment in less developed countries around the world. As a result, technological advancements made in more developed countries to deliver more precise radiation treatment that improves patient outcome have not been clinically applied to Co-60 machines. The medical physics group at the Cancer Centre of Southeastern Ontario has shown that these same technological advancements can be applied to Co-60 machines which would increase the accessibility of these modern improvements in radiotherapy treatment. However, for these modern treatments to improve patient outcome they require more precise localization of the patient prior to therapy. In more developed countries, this is currently provided by comparing computed tomography (CT) used for treatment planning with images acquired on the linac immediately before treatment. In the past decade, cone-beam CT (CBCT) has been developed to provide 3D CT images of the patient immediately prior to treatment on a linac. This imaging modality would also be ideal for patient localization when conducting modern Co-60 treatments since it would only require the addition of an imaging panel to produce CBCT images using the Co-60 source. A prototype Co-60 CBCT imaging system was implemented and characterized. Image noise, contrast, spatial resolution, and artifacts were studied. Algorithms to reduce the image artifacts were implemented and found to improve perceived image quality. The imaging system was found to have a ~1.8 mm high-contrast spatial resolution and the ability to detect 3 cm low-contrast soft-tissue structures in water. Anthropomorphic phantoms were also imaged and the observed anatomy in Co-60 CBCT images was comparable to kilovoltage CT. These results are comparable to clinically relevant linac-based CBCT using high energy X rays of similar energies to Co-60 gamma rays. This suggests that Co-60 CBCT should be able to provide the necessary images to localize patients for modern Co-60 radiation treatments. / Thesis (Master, Physics, Engineering Physics and Astronomy) -- Queen's University, 2010-11-30 13:40:07.61

<p>To date, image localization of mobile tumors prior to radiation delivery has primarily been confined to 2D and 3D technologies, such as fluoroscopy and 3D cone-beam CT (3D-CBCT). Due to the limited information from these images, larger volumes of healthy tissue are often irradiated in order to ensure the radiation field encompasses the entirety of the target motion. Since the overarching goal of radiation therapy is to deliver maximum dose to cancerous cells and simultaneously minimize the radiation delivered to healthy surrounding tissues, it would be ideal to use 4D imaging to obtain time-resolved volume images of the tumor motion during respiration. </p><p>4D-CBCT imaging has been previously investigated, but has not yet seen large clinical translation due to the obstacles of long acquisition time and large image radiation dose. Furthermore, 4D-CBCT currently requires the use of external surrogates to correlate the patient's respiration with the image acquisition process. This correlation has been under question by a multitude of studies demonstrating the uncertainties that exist between the surrogate and the actual motion of the internal anatomy. Errors in the correlation process may result in image artifacts, which could potentially lead to reconstructions with inaccurate target volumes, thereby defeating the purpose of even using 4D-CBCT. </p><p>It is therefore the aim of this dissertation to initially highlight an additional limitation of using 3D-CBCT for imaging respiratory motion and thereby reiterate the need for 4D-CBCT imaging in the treatment room, develop a simple and efficient technique to achieve markerless, self-sorted 4D-CBCT and finally to comprehensively evaluate its robustness across a variety of potential clinical scenarios with a digital human phantom. </p><p>People often spend a longer period of time exhaling as compared with inhaling, and some do so in an extremely disproportionate manner. To demonstrate the disadvantage of using 3D-CBCT in such instances, a dynamic thorax phantom was imaged with a large variety of simulated and patient-derived respiratory traces of ratios of time spent in the inspiration phase versus time spent in the expiration phase (I/E ratio). Canny edge detection and contrast measures were employed to compare the internal target volumes (ITVs) generated per profile. The results revealed that an I/E ratio of less than one can lead to potential underestimation of the ITV with the severity increasing as the inspiration becomes more disproportionate to the expiration. This occurs because of the loss of contrast in the inspiration phase, due to the fewer number of projections acquired there. The measured contrast reduction was as high as 94% for small targets (0.5 cm) moving large amplitudes (2.0 cm) and still as much as 22.3% for large targets (3.0 cm) moving small amplitudes (0.5 cm). This is alarming because the degraded visibility of the target in the inspiration phase may inaccurately impact the alignment of the planning ITV with that of the FB-CBCT and thereby affect the accuracy of the localization and consequent radiation delivery. These potential errors can be avoided with the use of 4D-CBCT instead, to form the composite volume and serve as the verification ITV for alignment.</p><p>In order to delineate accurate target volumes from 4D-CBCT phase images, it is crucial that the projections be properly associated with the patient's respiration. Thus, in order to improve previously developed 4D-CBCT techniques, the basics of Fourier Transform (FT) theory were utilized to extract the respiratory signal directly from the acquired projection data. Markerless, self-sorted 4D-CBCT reconstruction was achieved by developing methods based on the phase and magnitude information of the Fourier Transform. Their performance was subsequently compared to the gold standard of visual identification of peak-inspiration projections. Slow-gantry acquired projections of two sets of physical phantom data with sinusoidal respiratory cycles of 3 and 6 seconds as well as three patients were used as initial evaluation of the feasibility of the Fourier technique. Quantitative criteria consisted of average difference in respiratory phase (ADRP) and percentage of projections assigned within 10% respiratory phase of the gold standard (PP10). For all five projection datasets, the results supported feasibility of both FT-Phase and FT-Magnitude methods with ADRP values less than 5.3% and PP10 values of 87.3% and above. </p><p>Because the technique proved to be promising in the initial feasibility study, a more comprehensive evaluation was necessary in order to assess the robustness of the technique across a larger set of possibilities that may be encountered in the clinic. A 4D digital XCAT phantom was used to generate an array of respiratory and anatomical variables that affect the performance of the technique. The respiratory variables studied included: inspiration to expiration ratio, respiratory cycle length, diaphragmatic motion amplitude, AP chest wall expansion amplitude, breathing irregularities such as baseline shift and inconsistent peak-inspiration amplitude, as well as six breathing profiles derived from cine-MRI images of three healthy volunteers and three lung cancer patients. The anatomical variables studied included: male and female patient size (physical dimension and adipose content), body-mass-index (BMI) category, tumor location, and percentage of the lung in the field-of-view (FOV) of the projection data. CBCT projections of each XCAT phantom were then generated. Additional external imaging factors such as image noise and detector wobble were added to select cases with different percentages of lung in the projection FOV to investigate any effects on the robustness. FT-Phase and FT-Magnitude were each applied and quantitatively compared to the gold standard. Both methods proved to be robust across the studied scenarios with ADRP<10% and PP10>90%, when incorporating minor modifications to region-of-interest (ROI) selection and/or low-frequency location to certain cases of diaphragm amplitude and lung percentage in the FOV of the projection (for which a method may have previously struggled). Nevertheless, in the instance where one method initially faltered, the other method prevailed and successfully identified peak-inspiration projections. This is promising because it suggests that the two methods provide complementary information to each other. To ensure appropriate clinical adaptation of markerless, self-sorted 4D-CBCT, perhaps an optimal integration of the two methods can be developed.</p> / Dissertation