Introduction: Some past breast cancer radiotherapy regimens led to an increased risk of death from heart disease. Although heart dose from breast cancer radiotherapy has generally reduced over the past few decades, there may still be some cardiac risk. Estimation of future risk for women irradiated today requires both measurement of their cardiac dose and dose-response relationships, which depend on cardiac dosimetry of past regimens, in conjunction with long-term follow-up data. Methods: Virtual simulation and computed tomography 3-dimensional treatment planning on a representative patient were used to estimate mean heart and coronary artery doses for women irradiated since 1950 in 71 randomised trials in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overview. Patient-to-patient variability in cardiac dose was assessed. Heart and coronary artery doses were also calculated for breast cancer radiotherapy regimens used since the 1950s in Sweden. Cardiac doses from contemporary (year 2006) radiotherapy were assessed for 55 patients who received tangential breast cancer irradiation at a large UK radiotherapy centre. The maximum heart distance (i.e. the maximum distance between the anterior cardiac contour and the posterior tangential field edges) was measured for the left-sided patients, and its value as a predictor of cardiac doses assessed. Results: Mean heart dose for women irradiated in the EBCTCG trials varied from <1 to 18 Gray, and mean coronary artery dose from <1 to 57 Gray. Patient-to-patient variability was moderate. Mean heart dose for women irradiated in Sweden since the 1950s varied from <1 to 24 Gray, and mean coronary artery dose from <1 to 46 Gray. Heart dose from tangential irradiation has reduced over the past four decades. However, mean heart dose for left-sided patients irradiated in 2006 was 2 Gray and around half of them still received >20 Gray to parts of the heart and left anterior descending coronary artery. For these patients, maximum heart distance was a reliable predictor of cardiac doses. For the other patients, mean heart dose varied little and was usually less than 2 Gray. Conclusions: Cardiac doses from breast cancer radiotherapy can be estimated reliably and are now available for use in deriving dose-response relationships in the EBCTCG data and in a Scandinavian case-control study. Cardiac dose has reduced over the past four decades. Therefore the cardiac risk is also likely to have reduced. Nevertheless, for some patients, parts of the heart still receive >20 Gray in the year 2006.

No description available.

Hintergrund Die strahlentherapeutische Behandlung von Krebserkrankungen erfolgt zurzeit hauptsächlich durch eine Bestrahlung mit hochenergetischen Photonen und Elektronen aus kompakten Therapie-Linearbeschleunigern. Seltener werden auch Protonenstrahlen eingesetzt. Diese besitzen gegenüber Photonen und Elektronen vorteilhaftere physikalische und strahlenbiologische Eigenschaften, die besonders bei der Bestrahlung von tiefliegenden Tumoren in der Nähe von lebenswichtigen, strahlenempfindlichen Organen von Bedeutung sind. Die Behandlung mit Protonen erfordert jedoch sehr große und teure Bestrahlungsanlagen, weshalb es weltweit bisher nur ca. 50 solcher Anlagen an großen Zentren gibt. In den letzten Jahren wurde das völlig neuartige Prinzip der Teilchenbeschleunigung durch Hochleistungslaser soweit entwickelt, dass eine medizinische Anwendung zur Krebstherapie vorstellbar ist. Die laserbasierte Teilchenbeschleunigung verspricht deutlich kompaktere und kostengünstigere Protonenbeschleuniger, erzeugt jedoch im Unterschied zu herkömmlichen Beschleunigern sehr kurze (~ps) hochintensive Protonenpulse mit großer Strahldivergenz und breitem Energiespektrum. Im Rahmen des Verbundprojektes onCOOPtics wird die klinische Anwendbarkeit derartiger laserbeschleunigter Protonenstrahlen untersucht, was nicht nur die Entwicklung des notwendigen Laser-Teilchen-Beschleunigers, sondern auch die Entwicklung eines geeigneten Strahlführungssystems beinhaltet.

Radiotherapy has been shown to increase the subsequent risk of heart disease among survivors of breast cancer, but little is known about factors, other than the dose of radiation delivered to the heart, which determine the magnitude of the risk. In addition, survivors of teenage and young adult cancer are internationally acknowledged as an understudied population, and limited information is available on their late health risks. This thesis sought to utilise the largest observational datasets available to date for these populations: the Collaborative Group on Observational Studies of Breast Cancer Survivors and the Teenage and Young Adult Cancer Survivor Study. These were used to firstly characterise the radiation-related risks of heart disease and lung cancer, and secondly to provide an overview of the long-term risk of heart disease for the entire spectrum of cancers diagnosed in teenagers and young adults aged 15 to 39. Initially, a methodology study and systematic review demonstrated that selection effects and other biases can be very problematic during analyses of observational cohorts, particularly when using a radiotherapy comparison. However, in the case of heart disease and lung cancer, one can take advantage of the breast being a paired organ and use a laterality comparison, particularly when laterality played little effect in treatment selection. This comparison was used throughout the analyses of breast cancer patients. This thesis demonstrated that adjuvant radiotherapy for breast cancer significantly increased the risk of heart disease among women with left-sided breast cancer and those patients with ipsilateral lung cancer. Interestingly, younger women were at the highest risk of heart disease, and a progressive proportional decrease in risk with increasing age at diagnosis was found, which has not been shown before. It also suggested that radiotherapy and chemotherapy combined may further increase the risk of heart disease among breast cancer patients. Survivors of teenage and young adult cancer, particularly Hodgkin lymphoma, were at a significantly raised cardiac mortality risk compared to the matched general population. The findings of this thesis provide evidence to support continued follow-up for cancer patients, as survivors were found to be at a substantial risk into the second or third decade after treatment. It has permitted the detection of groups of individuals at particularly increased risks, for example younger patients and survivors of Hodgkin lymphoma diagnosed in teenagers and young adults, for whom closer monitoring for late effects or measures to reduce the risk, such as adaptations to treatment, may be appropriate. Finally, evidence was also presented to support the development of clinical follow-up guidelines specifically for survivors of teenage and young adult cancer.

Delta-like ligand 4 (DLL4) is a ligand for the Notch family of receptors. DLL4 is an important regulator of angiogenesis and DLL4 blockade promotes non-productive angiogenesis and delays tumour growth. The aim of this thesis was to investigate the effects of anti-DLL4 therapy in solid tumours in combination with a clinically relevant dose of ionising radiation (5 Gy; IR) and to analyse alterations in the Notch pathway induced by the treatments. Combining both treatments resulted in a greater than additive tumour growth delay in LS174T tumours, compared to either treatment alone. DLL4 blockade dysregulated vasculature and increased necrosis in LS174T and HCT-15 (DLL4-expressing and negative cell lines respectively) tumours within 3 days after treatment, but no changes were observed with IR alone. Additionally, combined IR and anti-DLL4 treatment of FaDu tumours (another DLL4-negative cell line) by our colleagues, also resulted in a supra-additive growth delay. These results show that combining IR with DLL4 blockade is an effective strategy for prolonging tumour growth delay and suggest that the stroma/vasculature provide the main therapeutic target for the anti-DLL4 therapy. Analysis of Notch pathway shows that IR upregulated Jag1 in tumour cells, and may inhibit Notch and downregulate DLL4 in the stroma. These changes may potentially affect tumour vessels and response to anti-DLL4 therapy. In vitro, anti-DLL4 therapy induced proliferation in quiescent contact-inhibited endothelial cells and also appeared to abrogate IR-induced inhibition of migration. These results suggest that DLL4 may be important in maintaining vessel quiescence and that IR may in part decrease migration through Notch signalling. Combining IR and DLL4 blockade to target tumour growth is an effective and well tolerated strategy and warrants further validation and refinement to be translated into clinical practice.

Objectives. The goal in radiotherapy is to deliver adequate radiation to the tumor volume while limiting damage to the surrounding healthy tissue. However, this goal is challenged by respiratory-induced motion. The objective of this work was to identify whether motion in electronic portal images can be tracked with an optical flow algorithm and whether a neural network can predict tumor motion. Methods. A multi-resolution optical flow algorithm that incorporates weighting based on the differences between image frames was used to automatically sample the vectors corresponding to the motion. The global motion was obtained by computing the average weighted mean from the set of vectors. The algorithm was evaluated using tumor trajectories taken from seven lung cancer patients, a 3D printed patient tumor and a virtual dynamic multi-leaf collimator (DMLC) system. The feasibility of detecting and tracking motion at the field edge was examined with a proof-of-concept implementation that included (1) an algorithm that detected local motion, and (2) a control algorithm that adapted the virtual MLC. To compensate for system latency, a generalized neural network, using both offline (treatment planning data) and online (during treatment delivery) learning, was implemented for tumor motion prediction. Results and Conclusions. The algorithm tracked the global motion of the target with an accuracy of around 0.5 mm. While the accuracy is similar to other methods, this approach does not require manual delineation of the target and can, therefore, provide real-time autonomous motion estimation during treatment. Motion at the treatment field edge was tracked with an accuracy of -0.4 ± 0.3 mm. This proof-of-concept simulation demonstrated that it is possible to adapt MLC leaves based on the motion detected at the field edges. Unplanned intrusions of external organs-at-risk could be shielded. A generalized network with a prediction error of 0.59 mm, and a shorter initial learning period (compared to previous studies) was achieved. This network may be used as a plug-and-play predictor in which tumor position could be predicted at the start of treatment and the need for pretreatment data and optimization for individual patients may be avoided. / February 2017

Respiratory motion poses significant problems in the radiotherapy of tumors located at sites (lung, liver, pancreas, breast) that are affected by such motion. Effects of respiratory motion on the different stages of the radiotherapy process (imaging, treatment planning and treatment delivery), has formed the focus of significant research over the last decade. Results from such research have revealed that respiratory motion affects the instantaneous position of almost all structures in the thorax and abdomen to different degrees based on their corresponding anatomic location and muscular attachments. As an example, diaphragm motion was found to be of the order of 1.5 cm, predominantly in the superior-inferior (SI) direction during normal breathing. This indicates a similar magnitude of motion for tumors located in the lower lobes of the lung and in the abdomen.The conventional method of accounting for such motion is to add a margin (based on an estimate of the expected range of organ motion) around the clinical target volume (CTV) that is delineated from the image data. This margin also includes errors due beam-bony anatomy alignment during radiation delivery and errors in patient position between simulation and subsequent treatment delivery sessions. Such a margin estimate may or may not encompass the "current" extent of motion exhibited by the tumor, resulting in either a higher dose to the surrounding normal tissue or a potential cold spot in the tumor volume. Several clinical studies have reported the existence of a direct relationship between the reduction in mean dose to the lung and the incidence of radiation induced pneumonitis. Therefore, subjecting additional normal lung tissue to high dose radiation by adding large margins based on organ motion estimates may result in an increased risk of radiation induced lung injury.Monitoring and accounting for respiratory motion can however potentate a reduction in the amount of normal tissue that receives high dose radiation, thereby decreasing the probability of normal tissue complication and also increasing the possibility for dose escalation to the actual tumor volume. The management (monitoring and accounting) of respiratory motion during radiation oncology forms the primary theme of this dissertation.Specific aims of this thesis dissertation include (a) identifying the deleterious effects of respiratory motion on conventional radiation therapy techniques (b) examining the different solutions that have been proposed to counter the deleterious effects of respiratory motion during radiotherapy (c) summarizing the relevant work conducted at our institution as part of this thesis in addressing the issue of respiratory motion and (d) visualizing the future direction of research in the management of respiratory motion in radiation oncology.Among the various techniques available to manage respiratory motion in radiation oncology such as respiratory gated and breath hold based radiotherapy, our research initially focused on respiratory gated radiotherapy, employing a commercially available external marker based real time position monitoring system. Multiple session recordings of simultaneous diaphragm motion and external marker motion revealed a consistent linear relationship between the two signals indicating that the external marker motion (along the anterior-posterior (AP) direction) could be used as a "surrogate" for motion of internal anatomy (along the SI direction). The predictability of diaphragm motion based on such external marker motion both within and between treatment sessions was also determined to be of the order of 0.1 cm.Analysis of the parameters that affected the accuracy and efficacy of respiratory gated radiotherapy revealed a direct relationship between the amount of residual motion and the width of the "gate" window. It also followed therefore that a trade-off existed between the width of the "gate" and the accuracy of gated treatments and also the overall "Beam ON" time. Further, gating during exhale was found to be more reproducible than gating during inhale. Although, it was evident that a reduction in the width of the "gate" implied a reduction in the margins added around the clinical target volume (CTV), such a reduction was limited by setup error.A study of the potential gains that could be derived from respiratory gating (based on motion phantom experimental set up) indicated a potential CTV-PTV margin reduction of 0.2-1.1 cm while employing gating alone in combination with an electronic portal imaging device, thus decreasing the amount of healthy tissue receiving radiation. In addition, gating also improved the quality of images obtained during simulation by reducing the amount of motion artifacts that are typically seen during conventional spiral CT imaging.Imparting some form of training was hypothesized to better enable patients to breathe in a reproducible fashion, which was further thought to increase the accuracy and efficacy of gated radiotherapy, especially when the "gate" was set close to the inhale portion of the breathing cycle. An analysis of breathing patterns recorded from five patients over several sessions under conditions of normal quiet breathing, breathing with audio instructions and breathing with visual feedback indicated that training improved the reproducibility of amplitude or frequency of patient breathing cycles.An initial exploration into respiration synchronized radiotherapy was thought to facilitate realization of reduced margins without having to hold the radiation beam delivery during a breathing cycle (as is the case with gating). A feasibility study based on superimposition of respiratory motion of a tumor (simulated by a sinusoidal motion oscillator) onto the initial beam aperture as formed by the multileaf collimator (MLC) revealed that tumor dose measurements obtained with such a set up were equivalent to those delivered to a static tumor by a static beam.Finally, a feasibility study for a method to acquire respiration synchronized images of a motion phantom and a patient (in order to perform respiration synchronized treatment planning and delivery) yielded success in the form of a 4D CT data set with reduced motion artifacts.In summary, respiratory gated radiotherapy and respiration synchronized are both viable approaches to account for respiratory motion during radiotherapy. While respiratory gated radiotherapy has been successfully implemented in some centers, several technical advances are required to enable similar success in the implementation of respiration synchronized radiotherapy. However, the potential clinical gains that can be obtained from either of the above approaches and their relative contributions to margin reduction will determine their future applicability as routine treatment procedures.

Accelerated tumor cell repopulation during radiation therapy is one of the leading causes for low survival rates of head-and-neck cancer patients. The therapeutic effectiveness of radiotherapy could be improved by selectively targeting proliferating tumor subvolumes with higher doses of radiation. Positron emission tomography (PET) imaging with 3´-deoxy-3´-[18F]-fluorothymidine (FLT) has shown great potential as a non-invasive approach to characterizing the proliferation status of tumors. This thesis focuses on histopathological validation of FLT PET imaging specifically for image-guidance applications in biologically adaptive radiotherapy. The lack of experimental data supporting the use of FLT PET imaging for radiotherapy guidance is addressed by developing a novel methodology for histopathological validation of PET imaging. Using this new approach, the spatial concordance between the intratumoral pattern of FLT uptake and the spatial distribution of cell proliferation is demonstrated in animal tumors. First, a two-dimensional analysis is conducted comparing the microscopic FLT uptake as imaged with autoradiography and the distribution of active cell proliferation markers imaged with immunofluorescent microscopy. It was observed that when tumors present a pattern of cell proliferation that is highly dispersed throughout the tumor, even high-resolution imaging modalities such as autoradiography could not accurately determine the extent and spatial distribution of proliferative tumor subvolumes. While microscopic spatial coincidence between high FLT uptake regions and actively proliferative subvolumes was demonstrated in tumors with highly compartmentalized/aggregated features of cell proliferation, there were no conclusive results across the entire set of utilized tumor specimens. This emphasized the need for addressing the limited resolution of FLT PET when imaging microscopic patterns of cell proliferation. This issue was emphasized in the second part of the thesis where the spatial concordance between volumes segmented on FLT simulated FLT PET images and the three dimensional spatial distribution of cell proliferation markers was analyzed.

Les patients atteints de cancers reçoivent différents traitement, tels que la radiothérapie ou la chimiothérapie. Actuellement, environ 60% des enfants survivants du cancer développent des effets secondaires cognitifs, consécutifs aux traitements énoncés précédemment. Compte tenu de la perspective du développement psychomoteur de l’enfant et de l’immaturité du système nerveux central (SNC) chez ces patients, il s’avère particulièrement pertinent d’étudier les effets secondaires que provoquent les traitements anticancéreux sur le développement cognitif de cette population de malades. Des études ont démontrées l’existence de liens étroits entre ces effets secondaires et l’abolition de la neurogénèse provoquée principalement par l’irradiation. Ce projet de maîtrise porte sur les effets du facteur de croissance épidermique, l’EGF (un facteur de croissance impliqué dans la prolifération cellulaire) sur la neurogénèse de la souris. Nous avons également cherché un vecteur de sécrétion efficace pour permettre une diffusion continue d’EGF à long terme (2 à 4 semaines). Notre hypothèse est que l’EGF serait capable de stimuler la neurogénèse et protéger les cellules de l’apoptose dans le cerveau de la souris, suite à une irradiation. Nous avons montré un effet positif de l’EGF sur la formation et la prolifération des neuroblastes Dcx(+) dans la zone sous ventriculaire (ZSV) et non dans l’hippocampe (Hi), suite à l’injection de l’EGF, directement dans le cerveau à l’aide d’une pompe osmotique. Nous avons observé que cette augmentation de la quantité de jeunes neurones est indépendante de la capacité de l’EGF à les protéger de l’apoptose. L’EGF ne protège pas non plus les blastes leucémiques, issus de lignées de cellules humaines, des effets secondaires d’une irradiation. Les cellules souches mésenchymateuses (CSM) modifiées génétiquement et générées pour sécréter l’EGF ne montrent aucun effet sur la stimulation de la neurogénèse quand elles sont directement injectées dans le cerveau. Finalement, nos résultats indiquent que l’EGF pourrait être un bon candidat pour le développement de nouvelles thérapies pour traiter les effets secondaires que provoque une irradiation du cerveau. L’utilisation de pompes pour permettre l’administration d’EGF dans le cerveau devient alors très intéressante pour améliorer la qualité de vie des patients. / Patients with cancer receive different treatments such as radiotherapy (ionizing radiation) or chemotherapy. Currently about 60% of children surviving cancer are prone to the development of treatment-related delayed side effects, such as neurocognitive impairments. Given the prospect of psychomotor development of children and central nervous system (CNS) immaturity in these patients, it is especially relevant to study the adverse effects related to cognitive impairment caused by cancer treatments on this population of patients. Studies have shown the existence of close links between this delayed side effects and the abolition of neurogenesis caused mainly by irradiation. This masters degree project concerns the effects of epidermal growth factor, EGF (a growth factor involved in cell proliferation), on neurogenesis in the C57BL/6 mice, which drastically decrease after exposure to ionizing radiation. We also sought a vector of efficient secretion to allow continuous long-term secretion of EGF (2-4 weeks). Our hypothesis is that EGF will stimulate neurogenesis and protect cells from apoptosis in the brain of mice following radiation. We have shown a positive effect of EGF on the formation and proliferation of young neurons Dcx (+) in the subventricular zone (SVZ) but not in the hippocampus (Hi) following EGF injection directly in the brain using an osmotic pump. We also observed that the increase of young neurons is independent of the ability of EGF to protect them from apoptosis. Moreover, EGF doesn’t protect leukemic human blasts after irradiation. Mesenchymal stem cells (MSC) genetically engineered to secrete EGF did not stimulate neurogenesis when injected directly in the brain. Finally our results indicate that EGF could be a good candidate for the development of new therapies to treat the side effects that irradiation causes in the brain. The use of pumps to allow the administration of recombinant EGF in specific brain regions becomes very interesting. Indeed this delivery system is increasingly used and effective to help improve the quality of life of patients.

In the thesis, we developed and studied a novel polymer delivery system for the DNA-intercalator bearing radioisotope iodine-125. Auger electrons emitting radioisotopes (such as iodine-125 or indium-111) are a potentially effective cancer treatment. Their use as an effective cancer therapy requires that they will be transported within close proximity of DNA, where they induce double-strand breaks leading to the cell death. This type of therapy may be even more beneficial when associated with drug delivery systems. The DNA intercalators proved to be effective carriers for the delivery of Auger electron emitters into DNA. Therefore, the new radioiodinated DNA-intercalating ellipticinium derivatives were synthesized and characterized. These compounds were linked to N-(2-hydroxypropyl) methacrylamide copolymer with narrow molecular weight distribution via acid-sensitive hydrazone linker. The structure of the linker plays a crucial role in the biological effectivity of the delivery system, so it was optimized to be stable at pH 7.4 (representing the pH of blood plasma), whereas in slightly acidic pH in endosomes after the cell internalization, the radioiodine-containing biologically active intercalator is rapidly released from its polymer carrier. The intercalating ability of the active compound was...