Author ORCID Identifier

https://orcid.org/0000-0002-0942-6513

Date of Graduation

8-2025

Document Type

Dissertation (PhD)

Program Affiliation

Medical Physics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Emil Schüler

Committee Member

Sam Beddar

Committee Member

Tze Yee Lim

Committee Member

Devarati Mitra

Committee Member

Ethan Ludmir

Abstract

Advisory Professor: Emil Schüler, PhD

Radiation therapy (RT) is a crucial component of curative cancer therapy, with a majority of cancer patients in the United States receiving RT as part of treatment. The goal of RT is to maximize the therapeutic index in curing disease while minimizing any associated normal-tissue complications1. Recently, ultra-high dose-rate (UHDR) RT (mean dose rates ≥40 Gy/s for a total duration of ≤200 ms) has been reported to selectively spare normal tissues and organs while maintaining an isoeffective tumoricidal effect compared to conventional (CONV) dose rate RT in a variety of in vivo preclinical models2. This phenomenon has been termed the “FLASH effect.” FLASH RT represents a fundamentally new paradigm for increasing the therapeutic index of RT relative to the same doses given at CONV dose rates (0.01–0.1 Gy/s), spurring accelerated efforts to bring it to clinical application3-6.

Although the FLASH effect has been documented in multiple preclinical studies between different institutions, the original definition involving only mean dose rate and total irradiation time to invoke or magnify the FLASH effect may be insufficient—with variable results in the induction and magnitude of normal tissue sparing in a variety of published studies from different institutions3,7. A likely cause of this discrepancy is due to marked differences in the beam parameter settings that are used but are not often reported which complicates retrospective studies evaluating the FLASH effect. Additionally, limitations in existing dosimetry systems in accurately capturing these beam parameters may also be one of the key factors limiting their robust documentation in preclinical studies.

In light of these shortcomings, we will demonstrate the limitations and modifications required in existing radiation dosimeters and their respective protocols to accurately measure the beam parameters used to document UHDR beamlines. With these established detectors and protocols in place, we propose a series of systematic and rigorous preclinical in vivo experiments to compare quantitively the magnitude of FLASH effects based on radiation beam type and beam delivery parameters to optimize the FLASH therapeutic index. The information produced by this work will have high translational relevance as it would inform the design of emerging FLASH human clinical trials and accelerate the development of a new RT treatment paradigm while simultaneously providing direction to future mechanistic studies. The three specific aims of this project are as follows:

Aim 1: Establish real-time beam monitoring in electron UHDR beamlines using beam current transformers (BCTs) calibrated to dose-rate independent dosimeters. We will characterize BCTs in their response to monitor different relevant beam parameters in real-time such as beam energy, dose, dose per pulse, mean and instantaneous dose-rate by modifying machine parameters such as pulse width, pulse amplitude, pulse number, and pulse repetition frequency. BCTs will be used in conjunction with dose-rate independent passive dosimeters, such as Gafchromic film and OSLDs/TLDs, capable of accurate dose measurements in UHDR beamlines. We hypothesize that concurrent use of BCTs with passive dose-rate independent detectors will be suitable for accurate real-time dose and beam monitoring, within a dose uncertainty of < 5%.

Aim 2: Develop the next generation of ionization (ion) chambers for UHDR reference dosimetry towards clinical translation. We will evaluate existing ion chambers to pinpoint specific features in their design that can be altered to provide more accurate readings in UHDR beamlines through the development of these next generation ion chambers. Confirmation and evaluation of ion chamber characteristics in FLASH will be obtained from beam measurements and design modifications of current ion chamber technology in collaboration with Standard Imaging Inc. to minimize ion recombination and polarity effects. We hypothesize that parallel-plate ion chambers with sub-mm electrode spacings at sufficiently high electric field gradients (≥ 1000 V/mm) will be able to in accurately measuring dose delivered from electron FLASH beamlines, and bring dosimetric calibration and reporting up to the standards necessary for clinical translation and subsequent clinical implementation of FLASH RT.

Aim 3: Optimize the physical beam parameters to maximally reduce normal tissue toxicity while maintaining therapeutic efficacy against tumors. We will perform an unprecedented, systematic, and comprehensive comparison of the physical beam parameters (e.g., total dose, mean dose rate, dose per pulse, radiation type) required to maximize the FLASH effect on normal tissue sparing of irradiated mice while investigating their therapeutic efficacy against tumors. We hypothesize that modifying beam parameters such as dose, dose per pulse, pulse width, radiation type, and mean dose-rate will yield differential tissue sparing effects and that the efficacy of FLASH RT is isoeffective with CONV RT in treating tumors. We expect to have determined the optimal set of beam parameters for maximally reduced GI toxicity using regenerating crypt and survival assays to validate our findings.

Impact: Completion of the proposed project will lay the foundation for our understanding of the physical beam parameters that are needed to achieve the FLASH effect with the infrastructure necessary for accurate real-time dose monitoring and measurement. These answers are critical for the successful implementation of FLASH RT in the clinical setting.

Keywords

FLASH, Ultra-high dose rate, UHDR, Radiation biology, ion chamber, beam current transformers, FLASH radiotherapy

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