ABSTRACT Objective The use of conformal radiation therapy in the treatment of carcinoma of the prostate has allowed for dose escalation and improved local control. The dose to the rectum is an important consideration in determining complication rates. This study aims to evaluate the effect of a Foleys rectal catheter balloon on the dose volume histograms to the rectum and to assess the effect of the balloon catheter on prostate gland immobilization during treatment of intermediate risk cancer of the prostate. Design and methods Ten patients with intermediate risk prostate cancer, each acting as his own control, were recruited in the study; eight patients had complete data for analysis. CT scans were done at intervals during treatment, with and without a rectal balloon filled with 30 ml of contrast. 3 pairs of CT scans for each patient were performed and were available for analysis. All patients were treated with 6-field conformal radiotherapy up to 66 Gy followed by a boost of 12 Gy in 3 fractions to the prostate using a rectal balloon and a 3- field plan. Dose volume histograms were calculated for the boost plan with and without the rectal balloon. Movements of the prostate in the superior-inferior and the anteriorposterior directions were measured with and without the balloon for each treatment. There was a slight reduction in the dose received by 1% and 2 % of the rectal volume with the balloon (55% and 52% respectively), compared to without a balloon (57% and 54.3% respectively) (p> 0.05). Results There was a non significant increase in the dose received by 50% of the rectum (p>0.05) with the use of the rectal balloon due to the rectum being pushed towards the symphysis pubis by the balloon. With the use of rectal balloon, the superior / inferior displacement of the prostate was reduced (p=0.04) and a displacement of more than 5 mm was observed in one out of eight patients. The anterior / posterior displacement of the prostate was decreased with the rectal balloon with a mean of 4 mm compared to 5 mm with no rectal balloon. This was not statistically significantly (p>0.05). However, displacement of more than 5 mm was observed in 2 patients with the rectal balloon. No grade 3 acute rectal toxicity was recorded in the 8 patients. Conclusion There was no significant change in the percentage dose received by the rectum with the use of the rectal balloon in this study. The study showed however that the rectal balloon significantly reduced prostate movement during treatment.

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A previous approach to robust intensity-modulated radiation therapy (IMRT) treatment planning for moving tumours in the lung involves solving a single planning problem before treatment and using the resulting solution in all of the subsequent treatment sessions. In this thesis, we develop two adaptive robust IMRT optimization approaches for lung cancer, which involve using information gathered in prior treatment sessions to guide the reoptimization of the treatment for the next session. The first method is based on updating an estimate of the uncertain effect, while the second is based on additionally updating the dose requirements to account for prior errors in dose. We present computational results using real patient data for both methods and an asymptotic analysis for the first method. Through these results, we show that both methods lead to improvements in the final dose distribution over the traditional robust approach, but differ greatly in their daily dose performance.

A previous approach to robust intensity-modulated radiation therapy (IMRT) treatment planning for moving tumours in the lung involves solving a single planning problem before treatment and using the resulting solution in all of the subsequent treatment sessions. In this thesis, we develop two adaptive robust IMRT optimization approaches for lung cancer, which involve using information gathered in prior treatment sessions to guide the reoptimization of the treatment for the next session. The first method is based on updating an estimate of the uncertain effect, while the second is based on additionally updating the dose requirements to account for prior errors in dose. We present computational results using real patient data for both methods and an asymptotic analysis for the first method. Through these results, we show that both methods lead to improvements in the final dose distribution over the traditional robust approach, but differ greatly in their daily dose performance.

Intensity-modulated radiation therapy (IMRT) is an advanced mode of high- precision radiation therapy that utilizes computer-controlled x-ray accelerators to deliver precise radiation doses to malignant tumors. The radiation dose is designed to conform to the three-dimensional (3-D) shape of a tumor by modulating the intensity of the radiation beam to focus a higher radiation dose to the tumor while minimizing radiation exposure to surrounding normal tissue. One form of IMRT is known as tomotherapy. Tomotherapy achieves dose conformity to a tumor by modulating the intensity of a fan beam of radiation as the source revolves about a patient. Current available tomotherapy machines use x-ray linear accelerators (linacs) as a source of radiation. However, since linacs are technologically complex, the world- wide use of linac-based tomotherapy is limited. This thesis involves an investigation of Cobalt 60 (Co-60) based tomotherapy. The inherent simplicity of Co-60 has the potential to extend the availability of this technique to clinics throughout the world. The goal of this thesis is to generate two-dimensional (2-D) Co-60 tomotherapy con- formal dose distributions with a computer program and experimentally validate them on ¯lm using a ¯rst generation bench-top tomotherapy apparatus. The bench-top apparatus consists of a rotation-translation stage that can mimic a 2-D tomotherapy delivery by translating the phantom across a thin, "pencil- like" photon beam from various beam orientations. In this thesis, several random and clinical patterns are planned using an in-house inverse treatment planning system and are delivered on ¯lm using the tomotherapy technique. The delivered dose plans are compared with the simulated plans using the gamma dose comparison method. The results show a reasonably good agreement between the plans and the measurements, suggesting that Co-60 tomotherapy is indeed capable of providing state-of-the-art conformal dose delivery. / Thesis (Master, Physics, Engineering Physics and Astronomy) -- Queen's University, 2008-04-25 02:20:56.102 / Canadian Institutes of Health Research (CIHR) and the ORDCF’s Ontario Consortium for Image-guided Therapy and Surgery.

External beam radiation therapy (EBRT) is the most common form of radiation therapy (RT) that uses controlled energy sources to eradicate a predefined tumour volume, known as the planning target volume (PTV), whilst at the same time attempting to minimise the dose delivered to the surrounding healthy tissues. Tumours in the thoracic and abdomen regions are susceptible to motion caused mainly by the patient respiration and movement that may occur during the treatment preparation and delivery. Usually, an adaptive approach termed adaptive radiation therapy (ART), which involves feedback from imaging devices to detect organ/surrogate motion, is considered. The feasibility of such techniques is subject to two main problems. First, the exact position of the tumour has to be estimated/detected in real-time and second, the delay that can arise from the tumour position acquisition and the motion tracking compensation. The research work described in this thesis is part of the European project entitled ‘Methods and advanced equipment for simulation and treatment in radiation oncology’ (MAESTRO), see Appendix A. The thesis presents both theoretical and experimental work to model and predict the respiratory surrogate motion. Based on a widely investigated clinical internal and external respiratory surrogate motion data, two new approaches to model respiratory surrogate motion were developed. The first considers the lung as a bilinear model that replicates the motion in response to a virtual input signal that can be seen as a signal generated by the nervous system. This model and a statistical model of the respiratory period and duty cycle were used to generate a set of realistic respiratory data of varying difficulties. The aim of the latter was to overcome the lack of test data for a researcher to evaluate their algorithms. The second approach was based on an online polynomial function that was found to adequately replicate the breathing cycles of regular and irregular data, using the same number of parameters as a benchmark sinusoidal model.

This study aimed to apply human factors methods to identify potentially unsafe aspects of a radiation therapy delivery system at Princess Margaret Hospital, and to provide recommendations accordingly. Analyses were conducted to examine the workflow, work environment and user interfaces involved in the treatment process. Based on findings from these analyses, components of the user interface were redesigned to address some of the issues found. Sixteen radiation therapy students were then used to experimentally evaluate the redesigned interface through a usability test. Compared to the current interface, the error rates of two common errors were significantly lower, and the average task completion time was significantly shorter when the redesigned interface was used. Results from a post-test questionnaire also indicated a high degree of satisfaction with the redesigned interface. Therefore, human factors methods can be applied to evaluate and design radiation therapy systems for improved error rates, efficiency and user satisfaction.

This study aimed to apply human factors methods to identify potentially unsafe aspects of a radiation therapy delivery system at Princess Margaret Hospital, and to provide recommendations accordingly. Analyses were conducted to examine the workflow, work environment and user interfaces involved in the treatment process. Based on findings from these analyses, components of the user interface were redesigned to address some of the issues found. Sixteen radiation therapy students were then used to experimentally evaluate the redesigned interface through a usability test. Compared to the current interface, the error rates of two common errors were significantly lower, and the average task completion time was significantly shorter when the redesigned interface was used. Results from a post-test questionnaire also indicated a high degree of satisfaction with the redesigned interface. Therefore, human factors methods can be applied to evaluate and design radiation therapy systems for improved error rates, efficiency and user satisfaction.

The primary objective of this research was to develop and implement a new approach to on-line adaptive radiation therapy (ART) in which daily imaging, plan adaptation and radiation delivery are temporally integrated and performed concurrently. The advantages of this approach are: reduction of treatment time compared to conventional on-line ART; ability to perform a complete plan re-optimization with minimal extension of treatment time; ability to detect and correct for intra-fractional patient motion. This work was motivated by an initial study which compared four radiosurgery techniques. This study was the first quantitative analysis of the correlation between patient anatomy and the quality of treatment plans produced by different radiosurgery techniques. A number of different relationships, both qualitative and quantitative, were discovered between patient anatomy and dosimetric parameters for different techniques. The results were used to successfully predetermine the optimal radiosurgery technique based on patient anatomy. The first step in developing a new approach to on-line ART involved accelerating plan adaptation (re-optimization) using direct aperture optimization (DAO). A series of techniques for adapting the original treatment plan to correct for the deterioration of dose distribution quality caused by the anatomical deformations were investigated. Through modification of the DAO algorithm the optimization search space was reduced and the plan adaptation was significantly accelerated. Next, a new approach to on-line ART was proposed and investigated, in which accelerated plan adaptation and radiation delivery were integrated together and performed concurrently. A fundamental advantage of this approach is that most of the plan re-optimization was performed during radiation delivery, so the time spent adapting the original plan did not significantly increase the overall treatment time. Finally, daily imaging, accelerated plan adaptation and radiation delivery were all temporally integrated using an integrated Linac/Cone Beam CT system. Intra-fractional patient images were used to successfully re-optimize the original treatment plan in near real-time to account for anatomy deformations. This thesis concludes that integration of daily imaging, plan adaptation and radiation delivery for near real-time ART is both feasible and advantageous. With further advances in related technologies, it promises to become a part of clinical practice in the near future.

Gliomblastoma is a highly malignant tumor of the central nervous system that is resistant to radiation and chemotherapy. Evidences accumulated over recent years have indicated the phosphoinositide 3-kinase/Akt signal transduction pathway as one of the major factors implicated in cancer resistance to conventional therapies. In this study we determined whether inhibition of PI3K/Akt signal pathway through pharmacological and/or genetic manipulation could enhance radiation sensitivity in glioma cells. Our results showed 6 of 12 glioma cell lines with activated Akt mostly due to reciprocal down-regulation of PTEN activity (loss-of-function mutations) but not by PIK3CA gain-of-function mutations. U87 and U373 glioma cell lines with PTEN mutation showing strong Akt Ser473 phopshorylation were treated with PI3K inhibitor LY294002 and irradiated with 0, 2.5, 5 and 7.5 Gy of radiation dosages. The results showed LY294002 inhibited Akt actvation in the glioma cells and decreased clonogenic survival in a radiation dose-dependent manner. Expression of dominant-negative Akt and PTEN through adenovirus mediated gene delivery in U87 and U373 glioma cells sensitized tumor cells to radiation treatment. Furthermore, PDK1 and mTOR inhibitors were also used on radiation sensitivity test. But both inhibitors had no radiosensitization in glioma cells. Glioma invasion was linked to advanced tumor stages. Recently, Type 1 insulin-like growth factor regulates tumor invasion have been showed to be mediated through the PI3K/Akt signaling pathway. In this study, we treated glioma cells with LY294002 to analyze its effects on invasion and migration potentials of the tumor cells. The results showed LY294002 inhibited both abilities in most glioma cell lines in vitro. In addition we used adv-PTEN and adv-dnAkt to confirm these results. Adv-PTEN performed dramatic decrease in glioma cell invasion potentials. Furthermore, we investigated whehter PI3K downstream PDK1, and mTOR involved in tumor cell invasion. We used PDK1 and mTOR inhibitors in glioma and determined their effects on invasion by Boyden chamber assay. Unfortunately, both of inhibitors had only limited inhibition on glioma invasion. Take together, our results indicate the feasibility of using PI3K/Akt inhibiting genetic and pharmacological agents to induce glioma cells to become more sensitive to radiation treatment and reduced invasion potentials. However, glioma radiosensitization and invasion may also be regulated by other signaling pathway.