Radical Production with Pulsed Beams: Understanding the Transition to FLASH

Abstract

Ultra-high dose rate (UHDR) irradiation regimes have the potential to spare normal tissue while keeping equivalent tumoricidal capacity than conventional dose rate radiotherapy (CONV-RT). This has been called the FLASH effect. In this work, we present a new simulation framework aiming to study the production of radical species in water and biological media under different irradiation patterns. The chemical stage (heterogeneous phase) is based on a nonlinear reaction-diffusion model, implemented in GPU. After the first 1 μs, no further radical diffusion is assumed, and radical evolution may be simulated over long periods of hundreds of seconds. Our approach was first validated against previous results in the literature and then employed to assess the influence of different temporal microstructures of dose deposition in the expected biological damage. The variation of the Normal Tissue Complication Probability (NTCP), assuming the model of Labarbe et al., where the integral of the peroxyl radical concentration over time (AUC-ROO) is taken as surrogate for biological damage, is presented for different intra-pulse dose rate and pulse frequency configurations, relevant in the clinical scenario. These simulations yield that overall, mean dose rate and the dose per pulse are the best predictors of biological effects at UHDR.

Phenomenological toy model for flash effect in proton therapy

“…However, increasing the duration of the pulse relative to the pulse repetition period increases the fraction of the total treatment time where the system stays at saturation. This feature of the model gives rise to different predictions from those of other modeling efforts which do not incorporate saturation, such as [17]. This is an important prediction which could eventually be validated or refuted based on future experimental work.…”

“…Since a value of 40 Gy/s is often given as a threshold for FLASH effect reproduced in in vivo experiments, we have chosen this same value for our parameter D 0 /τ . To select individual values for D 0 and τ, we consider the characteristic time τ 1 μs, similar to the kinetic constant of many relevant reactions and often used as a threshold for the homogeneous phase of the reaction process [17,7]. Therefore, to maintain a dose rate threshold D 0 /τ 40 Gy/s, we select a value of D 0 4 10 -5 Gy.…”

“…Finally, in a field as applied as radiation oncology, some models are designed to guide future clinical implementation, particularly in proton therapy facilities, some have investigated on the minimal FLASH sparing effect needed to compensate the increase in radiobiological damage due to hypofractionation for late-reacting tissues [13], while other have focused on the treatment-planning side of potential patient FLASH facilities based on pencil-beam scanning [14,15]. Models investigate different physical, chemical and biological mechanisms of radiation damage such as quantification of oxygen depletion [6], inter-track effects [16] or the effect of pulsation schemes at equivalent dose rates [17] during FLASH irradiation. Different in vivo and in-vitro endpoints are modeled; defining for example different RBE quantities for survival and/or mutation induction [10].…”

Technical note: Measurement of the bunch structure of a clinical proton beam using a SiPM coupled to a plastic scintillator with an optical fiber

“…2 Furthermore, it has been shown that the onset of the FLASH effect is deeply influenced by the beam pulse structure (instantaneous dose-rate, dose-per-pulse or the number of pulses) as it modifies the cell's exposure to free radicals. [2][3][4][5] Therefore, fast and accurate monitoring of the time structure of the beam is vital for FLASH treatments, which challenges existing solutions. Bunch monitors are also crucial for some range verification techniques in particle therapy that rely on the prompt-gamma ray production within the patient.…”

Definition of dose rate for FLASH pencil‐beam scanning proton therapy: A comparative study

“…It is often assumed that the time scale related to the FLASH effect is larger than the duration of a pulse so that the dose rate may be considered constant during the delivery of a spot [15][16][17] (∼1-10 ms) hence unchanged between pulsed or continuous delivery, 18 although this remains to be further demonstrated. 9 Nevertheless, in PBS, the total dose received by a voxel is generally the sum of the contributions of several spots.…”