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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.

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. / Science, Faculty of / Physics and Astronomy, Department of / Graduate

The effectiveness of cancer treatment is compromised by the need to reduce the uncertainties originating from a variety of factors including tumor volume delineation, patient setup, and irregular physiologic motion. In particular, effective yet practical tumor motion management remains a major challenge in current external beam radiation therapy. Many strategies such as motion encompassment, breath-hold techniques, and respiratory gating have been proposed in the literature and implemented clinically. These methods have shown success in certain situations with different limitations. With the advent of image guided radiation therapy, real-time tumor tracking methods have become popular in clinics to proactively address the challenge with on-board tumor localization. Nevertheless, such techniques rely on surrogate signals and have been reported vulnerable to errors. In this dissertation, EGRT is proposed as a new modality for effective and practical management strategy of cancer treatment uncertainties. One implementation of EGRT is to use PET emissions in real-time for direct tumor tracking during radiation delivery. Radiation beamlets are delivered along PET lines of response by a fast rotating ring therapy unit consisting of a linear accelerator and PET detectors. A complete treatment scheme with capabilities of accurate tumor tracking and dose planning is proposed to implement this EGRT concept. Simulation studies with physical phantom, 4D digital patient model, and clinical patient datasets are carefully designed to evaluate the feasibility and performance of EGRT. We show that with the capabilities of achieving both tumor tracking and sophisticated intensity modulation, EGRT has the potential to enable an effective implementation of 4D radiation therapy with true biological targeting and other advantages.

Abstract In New Zealand there are currently no regular external audits to verify the full treatment chain in radiotherapy. This thesis reports on a project to devise such an audit procedure suitable to assess the accuracy of the delivery of prescribed radiotherapy doses to patients over the full treatment process. The National Radiation Laboratory (NRL), regulatory authority, will use the method developed to conduct biennial audits of all radiotherapy centres. A commercial chest phantom with a MOSFET dosimetry system was provided for this project. The MOSFETs were commissioned and their characteristics determined, namely reproducibility, energy dependence and angular dependence. The MOSFETs were also tested in a clinical environment with the phantom. Measurements were carried out to test the MOSFET capabilities in both lung and soft tissue in the phantom. Two plans were devised for the audit process, a straightforward one with two parallel opposed beams and a more complex one involving lung tissue and wedges. These plans were designed to test the entire treatment planning and delivery process. It was found that each MOSFET detector needed to be individually calibrated. Reproducibility was found to have an average standard deviation of 2% on standard sensitivity and 1.2% on high sensitivity. The angular dependence of the detectors showed that when the MOSFET was rotated by 90 degrees to the beam axis a drop in response of 3% was observed with 6 MV. The energy dependence factor was constant within uncertainty for all MOSFETs. Overall, the MOSFET and phantom dosimetry system was determined to be suitable for the audit. The measurements with phantom showed that doses in high dose regions could be determined accurately. The greatest variation from the Treatment Planning system dose to the measured dose was 6%. The trial runs of the audit in two New Zealand radiotherapy centres showed that the procedure created is able to find discrepancies within the desired 5%, recommended by the ICRU, in the prescribed dose to the phantom.

Prognosis for lung cancer patients remains poor. For those receiving radiation therapy, local control and survival have been shown to improve with increased doses; however, deliverable dose is often limited by associated toxicity. Therefore, methods that reduce dose to normal tissues and allow isotoxic escalation are desirable. Adaptive radiation therapy seeks to improve treatment by modifying the initial plan throughout delivery, and has been shown to decrease normal tissue dose. Studies to date suggest a trend of increasing benefit with increases in replanning frequency; however, replanning is costly in terms of workload and past studies implement at most weekly adaptation. The purpose of this thesis is to quantify the benefit associated with daily replanning and characterize the tradeoff between replanning frequency and adaptive benefit. A software tool is developed to facilitate planning studies and to introduce complimentary methods for evaluating adaptive treatments. Synthetic images and contours are xii generated for each fraction of a typical fractionation schedule using principal component analysis and a novel method of sampling coefficients that preserves temporal trends in the data (e.g. tumor regression). Using the synthetic datasets, a series of adaptive schedules ranging from no adaption to daily replanning are simulated and compared to quantify adaptive benefits and characterize tradeoffs with frequency. Daily replanning resulted in significant reductions in all normal tissue planning metrics when compared to no adaptation, and incremental reductions were observed with each increase in replanning frequency while the magnitude of average reductions decreased with each step. Modest correlation between absolute change in planning target volume over the course of treatment and reductions in both mean lung dose and mean esophageal dose were observed.

M.Med., Faculty of Health Sciences, University of the Witwatersrand, 2009 / Objectives Cancer of the cervix is one of the commonest cancers in South African females. Up to 30% of patients are HIV positive. The addition of chemotherapy to radiotherapy has been shown to significantly improve local control and survival and concurrent chemoradiation is the standard treatment for locally advanced cancer of the cervix. There is very limited literature available concerning the tolerance and efficacy of this treatment in HIV positive patients. This study aims to assess the acute toxicity of combined modality treatment in these patients. This study is part of a multicenter International Atomic Energy Agency sponsored study. Materials and methods Patients with FIGO stage IB2 to IIIB (without hydronephrosis) cervical cancer and who are HIV positive, were randomized to receive radiotherapy alone or chemo-radiation. All patients received 46 Gy in 23 fractions external beam radiation and high-dose-ratei brachytherapy 8 Gy x 3 fractions. Chemotherapy consisted of bolus Cisplatin 30mg/m2 weekly given concurrently with the radiotherapy. Acute treatment toxicity was documented weekly during treatment. Results 64 patients were recruited to the study. 31 patients were randomized to the chemoradiation arm and 33 patients to the radiation alone arm. Of the 64 patients recruited to the study, 6 in the chemoradiation arm and 5 in the radiation only arm did not receive any treatment and were therefore not evaluated. Stage IIB was the most common stage. The mean CD4 count was 410 in the chemoradiation arm vs. 358.4 in the radiation only arm at randomization. Only 6 patients were on antiretroviral therapy at start of treatment, 3 in each arm. The number of chemotherapy cycles received by patients in the chemoradiation arm ranged between 0 and 5 cycles. A total of 96 chemotherapy cycles were administered, with a median of 4 cycles per patient. Overall, at least 76% of patients received at least 4 cycles of chemotherapy. The full five intended courses of cisplatin were administered in 10 (40%) patients. Chemotherapy was not administered most commonly due to toxicity (renal, leucopaenia), other reasons being logistical and non compliance. The principle major adverse effects observed were leucopaenia and cutaneous reactions.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Medicine in the branch of Radiation Oncology Johannesburg, 2016 / Purpose: To assess the improvement in swallowing status, overall survival and treatment related complications in patients with Carcinoma of the Oesophagus treated with palliative radiotherapy. Methods: A retrospective analysis of patients with advanced squamous cell carcinoma of the oesophagus who were treated for palliation from May 2007 to June 2012 at the Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) was done. Ninety- nine patients received palliative radiation therapy during this period, 63% were male and 37% female with a mean age of 60, 6 years. The predominant site of lesion was middle 3rd (56%) and 86, 9% of patients had lesions more than 5cm in length. Patients received palliative External beam irradiation (EBRT) with or without High dose rate brachytherapy (HDRBT) as per the CMJAH, Department of Radiation Oncology protocol. Results: There was an overall significant improvement in swallowing status (p<0,001). Eighty –four patients (85%) had an improvement in swallowing score after treatment. The effect of treatment was not significant in the relationship between the change in swallowing status and treatment group. Overall mean time to progression was 3, 7 months. The median overall survival was 7, 7 months. The type of treatment did not affect survival significantly, unadjusted (p=0, 31) or adjusted for prognostic parameters (age, sex, length of lesion, site of lesion, and pre-treatment swallowing status) (p=0.29). There were treatment related complications in 32% of cases, consisting of ulcerations (24%), tracheo- oesophageal fistula (5%) and strictures (3%). Conclusion: In patients with advanced squamous cell oesophageal carcinoma, palliative radiotherapy is an effective modality in improving a patient’s dysphagia and thus quality of life. / MT2016

There is a growing global need for proper access to radiation therapy. This need exists predominantly in low- and middle-income countries but exists in some high-income countries as well. The solution to this problem is complex and requires changes in government policy, education and technology. The objective of the work contained in this dissertation is the development of a novel external beam radiation therapy system capable of treating a variety of cancers. The intent of this system is to provide a cost-effective radiation therapy system, which can primarily be utilized in low- and middle-income countries. This new system uses kilovoltage rather than megavoltage x-rays and is therefore much more cost-effective. The ultimate purpose of this kilovoltage radiation therapy system is to improve access to radiation therapy worldwide by supplementing current radiation therapy technology. As a first step, the kilovoltage x-ray arc therapy or KVAT system was modeled using the EGSnrc BEAMnrc and DOSXYZnrc Monte Carlo software tools. For this initial study 200 kV arc-therapy was simulated on cylindrical water phantoms of two sizes, each of which contained a variety of planning target volume (PTV) sizes and locations. Additionally, prone and supine partial breast irradiation treatment plans were generated using KVAT. The objective of this work was to determine whether or not skin-sparing could be achieved using the KVAT system while also delivering a clinically relevant dose rate to the PTV. The results of the study indicated that skin-sparing is indeed achievable and that the quality of KVAT treatment plans improves for full 360-degree arcs and smaller PTV sizes. The second step of this project involved the Monte Carlo simulation of KVAT treatment plans for breast, lung and prostate cancer. Spherical PTVs of 3-cm diameter were used for the breast and lung treatment plans while a 4-cm diameter PTV was used for prostate. Additionally, inverse optimization was utilized to make full use of the non-conformal irradiation geometry of KVAT. As a means of comparison, megavoltage treatment plans that could be delivered by a clinical linear accelerator were generated for each patient as well. In order to evaluate the safety of KVAT treatment plans, dose constraints were taken from published Radiation Therapy Oncology Group (RTOG) reports. The results of this study indicated that the 200 kV breast and 225 kV lung KVAT treatment plans were within dose constraints and could be delivered in a reasonable length of time. The 225 kV prostate treatment plan, while technically within dose constraints, delivered a large dose to non-critical healthy tissues due to the limited number of beam angles that did not pass through boney anatomy. It was concluded that plans such as prostate with large volumes of bone present might not be feasible for KVAT treatment. The third step aimed to expand upon previous work and simulated more realistic KVAT treatment plans by using PTV volumes contoured by radiation oncologists. Additionally, this study used a completely redesigned KVAT geometry, which employed a stationary reflection anode and a new collimator design. The design modeled in this study was based upon the specifications of the prototype system under construction by PrecisionRT, a commercial partner. Three stereotactic ablative radiotherapy (SABR) lung patients were selected that had received treatment at the Vancouver Island Cancer Centre. In order to fully cover the PTVs of each patient, spherical sub-volumes were placed within the clinically contoured PTV of each patient. Dose constraints for at-risk organs were taken from an RTOG report on stereotactic body radiation therapy and were used to inversely optimize the 200 kV KVAT treatment plans. The calculated KVAT plans were compared with the clinical 6 MV SABR plans delivered to each patient. The results of this study indicated that KVAT lung plans were within dose constraints for all three patients with the exception of the ribs in the second patient who had a tumor directly adjacent to the rib cage. The fourth and last step of this project was the experimental validation of a simple, proof-of-principle KVAT system. Simple geometric methods were used to design a collimator consisting of two slabs of brass separated by ~6 cm, each with 5 apertures, which would create an array of 5 converging beamlets. The collimator was used with a tabletop x-ray tube system. A rectangular solid water phantom and cylindrical TIVAR 1000 phantom were placed on a rotation stage and irradiated using 360-degree arcs. EBT3 gafchromic film was placed in each phantom to measure two-dimensional dose distributions. Film dose distributions were analyzed and compared to Monte Carlo generated dose distributions. Both the rectangular solid water phantom and cylindrical TIVAR phantom showed skin-sparing effects in their dose distributions. The highest degree of skin-sparing was achieved in the larger, 20 cm diameter cylindrical phantom. Furthermore, the measured film data and calculated metrics of the rectangular phantom were within 10% of the MC calculated values for two out of three films. The discrepancy in the third film can be explained by errors in the experimental setup. In conclusion, the work contained in this dissertation has established the feasibility of a cost-effective kilovoltage arc-therapy system designed to treat deep-seated lesions by means of Monte Carlo simulations and experimental dosimetry. The studies performed so far suggest that KVAT is most suitable for smaller lesions in patient anatomy that does not involve large amounts of boney anatomy. Perhaps most importantly, an experimental study has demonstrated the skin-sparing ability of a simple KVAT prototype. / Graduate / 2020-07-10

To overcome the challenge in radiation therapy of delivering the prescribed dose to cancer cells while sparing normal tissue, preferential introduction of high Z material to tumour cells works as a method of radiation sensitization. Gold nanoparticles (GNPs) are very useful in this respect. It has been shown that the size, shape, and surface properties of GNPs affect their cellular uptake. Manipulation of the cell cycle to arrest cells at different stages offers a unique strategy to study the molecular and structural events as the cell cycle progresses. To optimize delivery of GNPs into tumour cells and enhance the effect of radiosensitization, nanoparticle (NP) uptake in synchronized populations of MDA-MB-231 breast cancer cells was investigated. Populations of MDA-MB-231 cells were first synchronized in S-phase using double-thymidine block, and allowed to progress through cell cycle in synchronization. Synchronized cells were incubated with 5 nm GNPs, 15 nm GNPs, 46 nm GNPs and two formulations of lipid NP encapsulated 5 nm GNPs. Uptake of NPs was visualized using hyperspectral optical imaging and quantified with inductively coupled plasma mass spectrometry (ICP-MS). Following internalization of GNPs, cells were irradiated with 6 MV photon beams from a linear accelerator, and the survival fraction and induced deoxyribonucleic acid (DNA) damage were studied. Cell cycle analysis after a double-thymidine block showed that the cell population was well synchronized. Uptake of NPs was 1.5-2 times higher in synchronized cell population compared to the control where cells were at different stages of the cell cycle. Clonogenic studies were used to evaluate the cell survival following radiation treatment. After a dose of 2 Gy, there was a decrease in cell survival fraction in synchronized cells treated with GNPs prior to radiation treatment compared to unsynchronized cells (control) indicating GNP-mediated dose-enhancement. The protein γ-H2AX, which is recruited to sites of DNA double strand breaks, was fluorescently labeled to evaluate damage due to the radiation treatment. Our results show more DNA double strand breaks in cells treated with GNPs prior to radiation. Interaction of ionization radiation with GNPs inside of cells produce secondary electrons. These secondary electrons can interact with water molecules and produce additional free radicals. These low energy electrons and free radicals interact with important cell structures and could cause cellular damage. Cell cycle synchronization has been shown to enhance GNP/PEG/RGD uptake in MDA-MB-231 cells resulting in greater cell radiosensitization and cellular damage. Cell synchronization is therefore an additional method available that can be employed to improve GNP uptake in cells. / Graduate