Closing the loop: understanding the parameter space for FLASH proton therapy

Abstract

FLASH radiotherapy is a novel cancer treatment technique that uses radiation delivered at ultra-high dose rates to achieve enhanced sparing of healthy tissue and equivalent tumour control compared to conventional radiotherapy. Protons have been shown to be a promising modality to deliver FLASH radiation. Their dosimetric advantages over other radiation types, ability to reach deep-seated tumours, and current clinical availability in many areas make protons an attractive modality for FLASH research and the most likely route for its translation towards widespread clinical use. However, the mechanism behind the FLASH sparing effect remains unknown. To make full use of the clinical advantages of protons, and general radiotherapy treatment strategies developed over many decades, there needs to be an increased understanding of the bounds within which the FLASH effect operates. In this thesis, an in silico approach is used to explore the parameter space for FLASH radiotherapy. A computational model is presented that is built around the most long-standing, and perhaps most disputed, explanation behind the observed sparing effect: the oxygen depletion hypothesis. This theory is based on the radiation-induced consumption of oxygen in cells, at a sufficiently high rate to overcome replenishment from the blood supply, inducing a transient hypoxic response in healthy tissue. The model is used to identify the key parameters involved in this process and evaluate their plausibility in facilitating an observable sparing effect using literature-reported values. A parameter space for effective oxygen depletion is shown, and the model is used to guide experimental work to hone in on the parameters driving the feasibility of the effect. Model developments to investigate additional mechanisms proposed for FLASH are also included. Looking to more clinically relevant treatments using proton FLASH, the model is applied to investigate how oxygen levels are affected by the spatio-temporal nature of radiation delivery from pencil-beam scanning. Clinical parameters are incorporated into simulations and example case studies are used to show how methods of inducing FLASH sparing in treatment plans can be explored using a mechanistic approach. Empirical approaches of exploring FLASH-augmented treatment planning in the absence of an established mechanism are also discussed, and used to highlight how research into both the underlying FLASH biology and the clinical translation of FLASH radiotherapy can exist in parallel, provided that both tracks remain flexible and open to convergence. The model developed provides a prime example of this required flexibility. It is only through a full understanding of why FLASH sparing happens that we can optimise the effect for patient benefit.

Date of Award	1 Aug 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Amy Chadwick (Supervisor), Karen Kirkby (Supervisor), Mike Merchant (Supervisor) & Norman Kirkby (Supervisor)