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Meeting ID: 885 816 1765

Abstract: Radiotherapy (RT) is a cornerstone method used to treat over 50% of the nearly 2 million new cancer diagnoses each year in the US. The success of RT directly relies on an optimal balance between maximizing the dose to the tumor while minimizing dose to surrounding normal tissues. Achieving this balance is often challenging due to underlying radiation transport and the presence of anatomical constraints that limit the beam delivery geometry. In turn, healthy tissue toxicity prevents use of a more aggressive tumor killing approach, and even in curative cases may decrease the patient’s quality of life due to induced physical complications. Minimizing healthy tissue damage is the main topic of radiotherapy research, with current research strategies including novel beam modalities, real time tissue visualization to improve dose conformality, and the use of an adjuvant therapy. Recently, ultra-high dose rate (UHDR) particle beams were found to induce drastically less toxicity to healthy tissue, termed the FLASH effect. However, the exact underlying mechanisms of FLASH are not currently known, and the preclinical results show large variability of treatment outcomes depending on beam parameters, tissue type, and physiological condition of tissues. Further, the future clinical use of UHDR beams requires a paradigm change in dosimetry and calibration methods to ensure safe patient treatments.  

This thesis aims to improve some of the major factors inducing variability in UHDR radiotherapy outcomes, including tissue oxygenation and beam delivery parameters, such as dose and dose rate. The thesis is divided into three parts to accomplish this. First, quantification of tissue oxygen levels and other physiological factors were investigated to address their negative impact on the reproducibility of the FLASH effect, namely the impact of anesthesia used in pre-clinical studies. Second, the long-standing challenge of accurate dosimetry of UHDR beams is addressed via development of a scintillation-based imaging system capable of multi-kilohertz, sub-millimeter beam monitoring. This system is deployed and validated in all UHDR modalities, including proton and electron accelerators. Lastly, the knowledge and technology further developed in Part II is translated into a clinical product to facilitate routine use, most specifically for UHDR clinical trials. 

Thesis Committee: David Gladstone (chair), Petr Bruza, Brian Pogue, Lesley Jarvis, Jan Scheumann (external, MGH)