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

Abstract

Purpose In ultrahigh dose rate radiotherapy, the FLASH effect can lead to substantially reduced healthy tissue damage without affecting tumor control. Although 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 optimized to maximally exploit this protective FLASH effect. Materials and Methods To investigate the potential of pencil beam scanned 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 multifield 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 multifield 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, whereas 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.

Single-fraction 34 Gy Lung Stereotactic Body Radiation Therapy Using Proton Transmission Beams: FLASH-dose Calculations and the Influence of Different Dose-rate Methods and Dose/Dose-rate Thresholds

“…It might make more sense to use a method that considers the time necessary to deliver a certain minimum dose, which has been described earlier. 49 …”

Treatment planning for Flash radiotherapy: General aspects and applications to proton beams

“…We assumed that Flash occurs whenever the dose delivered within the time window is larger than the dose threshold; in that case, all dose within the time window is considered as “Flash dose” (i.e., no gradual build‐up of Flash effect is hypothesized). As such, this metric is very similar to the “Flash effectiveness model” proposed by Krieger et al 41 . The sliding window metric does not provide 3D dose rate distributions as the DADR metric does, but directly gives the 3D Flash dose distribution as output instead.…”

“…Identifying Flash dose using a sliding window slided over the dose delivery time trace per voxel for each field, and the combination of Flash dose rate and dose thresholds determines the time window width (e.g., 40 Gy/s and 4 Gy thresholds imply a 100 ms time window). We assumed that Flash occurs whenever the dose delivered within the time window is larger than the dose threshold; in that case, all dose within the time window is considered as "Flash dose" (i.e., no gradual buildup of Flash effect is hypothesized).As such,this metric is very similar to the "Flash effectiveness model" proposed by Krieger et al 41 The sliding window metric does not provide 3D dose rate distributions as the DADR metric does, but directly gives the 3D Flash dose distribution as output instead.…”

FLASH radiotherapy treatment planning and models for electron beams

“…• Various dose delivery parameter-based metrics that aim to quantify the 'FLASH potential' of a dose distribution have been proposed. They include simple parameter thresholds, such as dose, dose rate and dose rate volume histogram thresholds and aim typically to quantify voxels or a dose fraction per voxel that fulfil these criteria, assuming a binary FLASH effect [115,[118][119][120][121]. Furthermore, more complex metrics, such as dose-averaged dose rate and '95% of the dose in a voxel delivered within a certain time', have been proposed for UHDR treatments with a more complex delivery time structure, such as scanned beams delivered via multiple portals [75,115,119,[122][123][124].…”