Total body irradiation is the irradiation of the entire patient as a conditioning for bone marrow transplants. The conditioning process involves destroying the bone marrow allowing for repopulation of the donor bone marrow cells, suppression of the immune system to allow stop graft rejection, and to eliminate the cancer cell population within the patient. Studies have been done demonstrating the importance of TBI conditioning for BMT5. A range of TBI treatment techniques exist, this department uses a bi-lateral technique which requires bolus packed around the patient to simplify the geometry of the treatment. This investigation will focus on one technique which involves using a translating bed. This technique effectively scans a radiation beam over the patient as the bed moves through the beam. Other investigations on translating beds concentrated on varying the scan speed to achieve a dose uniformity to within ±5%. The recommendations quote a dose uniformity of +5% and -10% as acceptable⁹. The dose uniformity in these investigations was along the midline in the longitudinal direction only. This investigation varied field size to achieve dose uniformity to within ±2.5% along the midline of an anthropomorphic phantom. The goal was to determine if a dynamic multi-leaf collimator could be used to give a uniform in the transverse direction as well as the longitudinal direction. An advantage of utilizing the DMLC for this treatment is the ability to shield organs at risk, i.e. lungs and kidneys, without requiring resources to produce shielding blocks14. Gafchromic-EBT film18 was used as a dosimeter but gave unreliable results due to the lack of film scanning equipment with an appropriate sensitivity for reading the dose to the film. Scans were simulated using Xio treatment planning software. The results from the simulations gave a more reliable indication of the absorbed dose to the midline of the phantom. The disadvantage of this varying field size technique was the time and complexity involved in creating a treatment plan. Within the Xio software exists a limit on the number of beams allowed to be applied in a single plan. There is a maximum of 99 beams allowed which is not enough for complete coverage of a patient. A way around this is to increase the field sizes and decrease the scan speed. This option was not investigated. The advantage of this technique was the increased dose uniformity (±2.5%) in comparison to the varying scan speed techniques (±5%). This technique also allows the patient to be unencumbered during the treatment making the process more comfortable for them.

Cobalt-60 (Co-60) units played an integral role in radiation therapy from the mid-1950s to the 1970s. Although they continue to be used to treat cancer in some parts of the world, their role has been significantly reduced due to the invention of medical linear accelerators. A number of groups have indicated a strong potential for Co-60 units in modern radiation therapy. The Medical Physics group at the Cancer Center of the Southeastern Ontario and Queen’s University has shown the feasibility of Intensity Modulated Radiation Therapy (IMRT) via simple conformal treatment planning and dose delivery using a Co-60 unit. In this thesis, initial Co-60 tomotherapy planning investigations on simple uniform phantoms are extended to actual clinical cases based on patient CT data. The planning is based on radiation dose data from a clinical Co-60 unit fitted with a multileaf collimator (MLC) and modeled in the EGSnrc Monte Carlo system. An in house treatment planning program is used to calculate IMRT dose distributions. Conformal delivery in a single slice on a uniform phantom based on sequentially delivered pencil beams is verified by Gafchromic film. Volumetric dose distributions for Co-60 serial tomotherapy are then generated for typical clinical sites that had been treated at our clinic by conventional 6MV IMRT using Varian Eclipse treatment plans. The Co-60 treatment plans are compared with the clinical IMRT plans using conventional matrices such as dose volume histograms (DVH). Dose delivery based on simultaneously opened MLC leaves is also explored and a novel MLC segmentation method is proposed. In order to increase efficiency of dose calculations, a novel convolution based fluence model for treatment planning is also proposed. The ion chamber measurements showed that the Monte Carlo modeling of the beam data under the MIMiC MLC is accurate. The film measurements from the uniform phantom irradiations confirm that IMRT plans from our in-house treatment planning system are deliverable. Comparing the Co-60 dose distributions and DVHs to the IMRT plans from the clinic indicates that Co-60 is able to provide similar dose conformality to targets and dose sparing to critical organs. The results of the novel MLC segmentation algorithm and the photon fluence model proposed in this work compared well with the Monte Carlo calculations. In summary, the investigations presented in this thesis confirm that Co-60 tomotherapy is indeed capable of providing state-of-the-art conformal dose delivery. We have shown that the perceived beam limitations often identified with Co 60 (e.g., lower penetration, source size artifacts under small field collimation, and larger penumbra) are negligible when using intensity modulated techniques. / Thesis (Ph.D, Physics, Engineering Physics and Astronomy) -- Queen's University, 2013-08-22 11:34:14.861

Cobalt-60 (Co-60) units played an integral role in radiation therapy from the mid-1950s to the 1970s. Although they continue to be used to treat cancer in some parts of the world, their role has been significantly reduced due to the invention of medical linear accelerators. A number of groups have indicated a strong potential for Co-60 units in modern radiation therapy. The Medical Physics group at the Cancer Center of the Southeastern Ontario and Queen’s University has shown the feasibility of Intensity Modulated Radiation Therapy (IMRT) via simple conformal treatment planning and dose delivery using a Co-60 unit. In this thesis, initial Co-60 tomotherapy planning investigations on simple uniform phantoms are extended to actual clinical cases based on patient CT data. The planning is based on radiation dose data from a clinical Co-60 unit fitted with a multileaf collimator (MLC) and modeled in the EGSnrc Monte Carlo system. An in house treatment planning program is used to calculate IMRT dose distributions. Conformal delivery in a single slice on a uniform phantom based on sequentially delivered pencil beams is verified by Gafchromic film. Volumetric dose distributions for Co-60 serial tomotherapy are then generated for typical clinical sites that had been treated at our clinic by conventional 6MV IMRT using Varian Eclipse treatment plans. The Co-60 treatment plans are compared with the clinical IMRT plans using conventional matrices such as dose volume histograms (DVH). Dose delivery based on simultaneously opened MLC leaves is also explored and a novel MLC segmentation method is proposed. In order to increase efficiency of dose calculations, a novel convolution based fluence model for treatment planning is also proposed. The ion chamber measurements showed that the Monte Carlo modeling of the beam data under the MIMiC MLC is accurate. The film measurements from the uniform phantom irradiations confirm that IMRT plans from our in-house treatment planning system are deliverable. Comparing the Co-60 dose distributions and DVHs to the IMRT plans from the clinic indicates that Co-60 is able to provide similar dose conformality to targets and dose sparing to critical organs. The results of the novel MLC segmentation algorithm and the photon fluence model proposed in this work compared well with the Monte Carlo calculations. In summary, the investigations presented in this thesis confirm that Co-60 tomotherapy is indeed capable of providing state-of-the-art conformal dose delivery. We have shown that the perceived beam limitations often identified with Co 60 (e.g., lower penetration, source size artifacts under small field collimation, and larger penumbra) are negligible when using intensity modulated techniques. / Thesis (Ph.D, Physics, Engineering Physics and Astronomy) -- Queen's University, 2013-08-22 11:34:14.861

<p>A tenet of modern radiotherapy (RT) is to identify the treatment target accurately, following which the high-dose treatment volume may be expanded into the surrounding tissues in order to create the clinical and planning target volumes. Respiratory motion can induce errors in target volume delineation and dose delivery in radiation therapy for thoracic and abdominal cancers. Historically, radiotherapy treatment planning in the thoracic and abdominal regions has used 2D or 3D images acquired under uncoached free-breathing conditions, irrespective of whether the target tumor is moving or not. Once the gross target volume has been delineated, standard margins are commonly added in order to account for motion. However, the generic margins do not usually take the target motion trajectory into consideration. That may lead to under- or over-estimate motion with subsequent risk of missing the target during treatment or irradiating excessive normal tissue. That introduces systematic errors into treatment planning and delivery. In clinical practice, four-dimensional (4D) imaging has been popular in For RT motion management. It provides temporal information about tumor and organ at risk motion, and it permits patient-specific treatment planning. The most common contemporary imaging technique for identifying tumor motion is 4D computed tomography (4D-CT). However, CT has poor soft tissue contrast and it induce ionizing radiation hazard. In the last decade, 4D magnetic resonance imaging (4D-MRI) has become an emerging tool to image respiratory motion, especially in the abdomen, because of the superior soft-tissue contrast. Recently, several 4D-MRI techniques have been proposed, including prospective and retrospective approaches. Nevertheless, 4D-MRI techniques are faced with several challenges: 1) suboptimal and inconsistent tumor contrast with large inter-patient variation; 2) relatively low temporal-spatial resolution; 3) it lacks a reliable respiratory surrogate. In this research work, novel 4D-MRI techniques applying MRI weightings that was not used in existing 4D-MRI techniques, including T2/T1-weighted, T2-weighted and Diffusion-weighted MRI were investigated. A result-driven phase retrospective sorting method was proposed, and it was applied to image space as well as k-space of MR imaging. Novel image-based respiratory surrogates were developed, improved and evaluated.</p> / Dissertation

<p>Approximately 50% of all patients with cancer receive radiation therapy at some point during the course of their illness. Despite advances in radiation delivery and treatment planning, normal tissue toxicity often limits the ability of radiation to eradicate tumors. The tumor microenvironment consists of tumor cells and stromal cells such as endothelial cells that contribute to tumor initiation, progression and response to therapy. Although endothelial cells can contribute to normal tissue injury following radiation, the contribution of stromal cells to tumor response to radiation therapy remains controversial. To investigate the contribution of endothelial cells to the radiation response of primary tumors, we have developed the technology to contemporaneously mutate different genes in the tumor cells and stromal cells of a genetically engineered mouse model of soft tissue sarcoma. Using this dual recombinase technology, we deleted the DNA damage response gene <italic>Atm</italic> in sarcoma and heart endothelial cells. Although deletion of <italic>Atm</italic> increased cell death of proliferating tumor endothelial cells, <italic>Atm</italic> deletion in quiescent endothelial cells of the heart did not sensitize mice to radiation-induced myocardial necrosis. In addition, the ATM inhibitor NVP-BEZ235 selectively radiosensitized primary sarcomas, demonstrating a therapeutic window for inhibiting ATM during radiation therapy. Sensitizing tumor endothelial cells to radiation by deleting <italic>Atm</italic> prolonged tumor growth delay following a non-curative dose of radiation, but failed to increase local control. In contrast, deletion of <italic>Atm</italic> in tumor parenchymal cells increased the probability of tumor eradication. These results demonstrate that tumor parenchymal cells rather than endothelial cells are the critical targets that regulate tumor eradicaiton by radiation therapy.</p> / Dissertation

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.

Bakgrund: Prostatacancer är den vanligaste cancerformen i Sverige där det finns olika behandlingsalternativ. Behandlingarna medför olika biverkningar och effekter för männen. Under behandlingen är det oftast en sjuksköterska männen träffar innan, under och efter behandlingen. Syfte: Syftet var att beskriva mäns upplevelser av livskvalitet under behandling av prostatacancer. Metod: En litteraturöversikt av aktuell forskning med kvalitativ och kvantitativ ansats där 12 artiklar har analyserats. Resultat: Många män upplevde en förändrad livsrytm och att det var viktigt att försöka leva så normalt och hälsosamt som möjligt. Männen upplevde förändringar av kroppen vilket ledde till att en del män kände skam och upplevde sig mindre manliga. Männen upplevde en förändrad syn på livet. Flera av männen upplevde att relationen till deras partner kunde bli påverkad både positivt och negativt. För att kunna hantera sjukdomen upplevde männen att det var viktigt med stöd och information från sjukvården för att behålla sin livskvalitet. Konklusion: Studien visar att män under behandling av prostatacancer upplever flera olika förändringar som påverkar deras livskvalitet. Män upplever en förändrad livsrytm, en förändring av kroppen, en förändrad syn på livet, ett förändrat samliv och ett behov av information och stöd från sjukvården. Som sjuksköterska är det därför viktigt att ha kunskap om förändringarna för att kunna vara ett stöd för patienten och därmed minska lidande.

The objective of this dissertation is to develop treatment planning techniques that have the potential to improve radiation therapy of time-dependent (4D) anatomy. Specifically, this study examines dose estimation, dose evaluation, and decision making in the context of optimizing lung cancer radiation therapy. Two methods of dose estimation are compared in patients with locally advanced and early stage lung cancer: dose computed on a single image (3D-dose) and deformably registered, accumulated dose (or 4D-dose). The results indicate that differences between 3D- and 4D- dose are not significant in organs at risk (OARs), however, 4D-dose to a moving lung cancer target can deviate from 3D-dose. These differences imply that optimization of the 4D-dose through multiple-anatomy optimization (MAO) can improve radiation therapy in 4D-anatomy. MAO incorporates time-dependent target and OAR geometry while enabling a simple, clinically realizable delivery. MAO has the potential to enhance the therapeutic ratio in terms of target coverage and OAR sparing in 4D-anatomy. In dose evaluation within 4D-anatomy; dose-to-mass is a more intuitive and precise metric in estimating the effects of radiation in tissues. Assuming physical density is proportional to functional tissue density, dose-to-mass has a 1-1 correspondence with radiation damage. Dose-to-mass optimization boosts dose in massive regions of lung cancer targets and can reduce integral dose to lung by preferentially treating through regions of low-density lung tissue. Finally, multi-criteria optimization (MCO) is implemented in order to clarify decision making during plan design for lung cancer treatment. An MCO basis set establishes a patient-specific decision space which reveals trade-offs in OAR-dose at a fixed, constrained target dose. By interpolating the MCO basis set and evaluating the plan on 4D-anatomy, patient- and organ- specific conservatism in plan design can be expressed in real time. Through improved methods of dose estimation, dose evaluation, and decision making, this dissertation will positively impact radiation therapy of time-dependent anatomy.

When breast tumor cells encounter stress due to cancer therapies, they may enter a dormant state, escaping from treatment-induced apoptosis. Dormant cells may eventually regain proliferative capabilities and cause recurrent metastatic disease, which is the leading cause of mortality in breast cancer patients. We sought to determine if a high dose of radiation therapy (RT) or combined chemo-immunotherapy, with and without the blockade of autophagy by chloroquine (CQ), could overcome treatment-induced tumor dormancy or relapse. We found that autophagy contributes in part to treatment-induced tumor dormancy. We also found that three therapeutic strategies were successful in inhibiting or preventing tumor relapse. These include: 18Gy/day RT, chemotherapy combined with the blockade of autophagy, and combined chemo-immunotherapy. Follow-up studies are needed to determine the feasibility of preventing tumor relapse by prolonging tumor dormancy versus eliminating dormant tumor cells.

In radiation therapy, interfraction organ motion introduces a level of geometric uncertainty into the planning process. Plans, which are typically based upon a single instance of anatomy, must be robust against daily anatomical variations. For this problem, a model of the magnitude, direction, and likelihood of deformation is useful. In this thesis, principal component analysis (PCA) is used to statistically model the 3D organ motion for 19 prostate cancer patients, each with 8-13 fractional computed tomography (CT) images. Deformable image registration and the resultant displacement vector fields (DVFs) are used to quantify the interfraction systematic and random motion. By applying the PCA technique to the random DVFs, principal modes of random tissue deformation were determined for each patient, and a method for sampling synthetic random DVFs was developed. The PCA model was then extended to describe the principal modes of systematic and random organ motion for the population of patients. A leave-one-out study tested both the systematic and random motion model’s ability to represent PCA training set DVFs. The random and systematic DVF PCA models allowed the reconstruction of these data with absolute mean errors between 0.5-0.9 mm and 1-2 mm, respectively. To the best of the author’s knowledge, this study is the first successful effort to build a fully 3D statistical PCA model of systematic tissue deformation in a population of patients. By sampling synthetic systematic and random errors, organ occupancy maps were created for bony and prostate-centroid patient setup processes. By thresholding these maps, PCA-based planning target volume (PTV) was created and tested against conventional margin recipes (van Herk for bony alignment and 5 mm fixed [3 mm posterior] margin for centroid alignment) in a virtual clinical trial for low-risk prostate cancer. Deformably accumulated delivered dose served as a surrogate for clinical outcome. For the bony landmark setup subtrial, the PCA PTV significantly (p30, D20, and D5 to bladder and D50 to rectum, while increasing rectal D20 and D5. For the centroid-aligned setup, the PCA PTV significantly reduced all bladder DVH metrics and trended to lower rectal toxicity metrics. All PTVs covered the prostate with the prescription dose.