A quantitative FLASH effectiveness model to reveal potentials and pitfalls of high dose rate proton therapy.

PURPOSE In ultra-high dose rate radiotherapy, the FLASH effect can lead to substantially reduced healthy tissue damage without affecting tumour control. While many studies show promising results, the underlying biological mechanisms and the relevant delivery parameters are still largely unknown. It is unclear, particularly for scanned proton therapy, how treatment plans could be optimised to maximally exploit this protective FLASH effect. MATERIALS & METHODS To investigate the potential of PBS proton therapy for FLASH treatments, we present a phenomenological model, which is purely based on experimentally observed phenomena such as potential dose rate and dose thresholds, and which estimates the biologically effective dose during FLASH radiotherapy based on several parameters. We applied this model to a wide variety of patient geometries and proton treatment planning scenarios, including transmission and Bragg peak plans as well as single- and multi-field plans. Moreover, we performed a sensitivity analysis to estimate the importance of each model parameter. RESULTS Our results showed an increased plan-specific FLASH effect for transmission compared with Bragg peak plans (19.7% vs 4.0%) and for single-field compared with multi-field plans (14.7% vs 3.7%), typically at the cost of increased integral dose compared to the clinical reference plan. Similar FLASH magnitudes were found across the different treatment sites, while the clinical benefits with respect to the clinical reference plan varied strongly. The sensitivity analysis revealed that the threshold dose as well as the dose per fraction strongly impacted the FLASH effect, whereas the persistence time only marginally affected FLASH. An intermediate dependence of the FLASH effect on the dose rate threshold was found. CONCLUSIONS Our model provided a quantitative measure of the FLASH effect for various delivery and patient scenarios, supporting previous assumptions about potentially promising planning approaches for FLASH proton therapy. Positive clinical benefits compared to clinical plans were achieved using hypofractionated, single-field transmission plans. The dose threshold was found to be an important factor, which may require more investigation. This article is protected by copyright. All rights reserved