FLASH VHEE Radiotherapy: Cell Survival and DNA Damage Experiments to Measure RBE at CLARA, ARES and CLEAR

  • Hannah Wanstall

Student thesis: Phd

Abstract

The main focus of this thesis is to explore the biological, chemical and physical effects of Very High Energy Electron (VHEE) radiotherapy through experimental studies. VHEEs are electrons in the 100 - 250 MeV energy range which are being considered as a novel radiotherapy modality. One major objective of this project was to firstly determine which biological method should, or could be used to define VHEE RBE. The next aim was to measure a value for VHEE RBE for cancer cells in vitro, to start to build a body of experimental work to guide future VHEE RBE studies. Due to electron RBE being defined reasonably well for clinical energies, another objective was to determine if electron RBE is energy dependant or independent by collating current studies, as well as producing additional data with experimental work across a range of electron energies. Measuring the biological effect of dose rate for VHEE experimentally was also considered an important focus for the project. To achieve these objectives, information was collected on VHEE accelerators (their physical parameters and biological capabilities), to plan a series of experimental plans that could achieve these goals. A meta-analysis of the cytokinesis block micronuclei (CBMN) was completed to determine the reliability of using this protocol to make comparisons between modalities. It was determined that the CBMN assay was not necessarily optimal for this context and combined with biological limitations at VHEE facilities, it was ultimately decided that cancer cell survival would be used as the biological endpoint for quantifying VHEE RBE. Cell survival experiments were completed with VHEE, resulting in the first in vitro quantification of VHEE RBE as well as the optimisation of scanning dosimetry to achieve uniform and repeatable sample irradiations. Initial cell survival experiments at ARES showed that VHEE RBE was between 0.74 and 0.99 in comparison to a photon reference (0.93 ± 0.05 (D0.5) and 0.99 ± 0.12 (D0.1) for A549 and 0.74 ± 0.14 (D0.5) and 0.93 ± 0.09 (D0.1) for PC3 cell lines respectively). This fit with data collated from other published studies, with the mean electron RBE calculated to be ~ 0.85 for studies using a photon reference < 1 MeV. The experiment at ARES showed that VHEE research machines can be used to successfully irradiate cell samples with dose repeatability and uniformity. Initial experiments measured the RBE of 35 MeV electrons at the CLARA facility, using DNA damage to plasmid DNA as a biological endpoint. Results indicated that 35 MeV electrons have an RBE of 1 - 1.18. A plasmid model was also used to test RBE across dose rates and energies and quantify DNA damage in response to VHEE at the CLEAR facility. The effect of dose rate was also measured to be significant for VHEE which is in line with the majority of in vivo studies across several radiation modalities. In this case, a plasmid DNA model was used, which showed 16 - 27% fewer DNA single-strand breaks (SSBs) for plasmid irradiated at ultra-high dose rates (UHDRs) in comparison to conventional dose rates. This study supplements current findings in the literature. To summarise, the current research into VHEE and its radiobiological effect on cells and DNA is extremely limited and needs to be expanded before clinical adoption. This work in this thesis acts as an extension to that small body of research and provides mechanistic insight as well as some truly novel quantification of VHEE RBE.
Date of Award31 Dec 2024
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorRoger Jones (Supervisor), Amy Chadwick (Supervisor), Elham Santina (Supervisor), Mike Merchant (Supervisor) & Nicholas Henthorn (Supervisor)

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