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.

Keywords: FLASH; effectiveness model; scanned proton therapy.

FIGURE 1

Illustration of the procedure of determining whether the dose delivered at time t (red marker) is delivered in FLASH mode (top panel). If the average dose rate and the total dose delivered between any t ₀ ≤ t and t ₁ ≥ t (black markers) are above the respective thresholds, FLASH is triggered at time t. Bottom panel: spot‐wise dose rate that defines the given cumulative dose

FIGURE 2

Illustration of the three delivery techniques considered in this study

FIGURE 3

Example dose distributions showing all planning strategies for the pancreas case PA1. The considered parameters were 22.29 Gy fraction dose, 5 Gy dose threshold, 40 Gy/s dose rate threshold, and 200 ms persistence time. (a) Physical dose distributions, given in percent of the prescribed dose. (b) Voxel‐wise FLASH effect given as the effective dose reduction relative to the respective voxel dose. Note that no reduction is shown within the GTV, because it mainly consists of tumor cells, which are assumed not to be subject to FLASH. (c) FEF‐weighted dose, given in percent of the prescribed dose. (d) Plan descriptions. S, single‐field plan; M, multi‐field plan; U, upstream energy modulation; D, downstream energy modulation; T, transmission (no energy modulation). FEF, FLASH effectiveness factor

FIGURE 4

Comparison of the magnitude of the FLASH effect for the different planning approaches for the pancreas case PA1. The considered parameters were 22.29 Gy fraction dose, 5 Gy dose threshold, 40 Gy/s dose rate threshold, and 200 ms persistence time. Note that the clinical reference plan is a multifield, upstream‐modulated plan, that is, it corresponds to the red solid plots when considering the FLASH‐weighted dose. (a) DVHs of the GTV‐to‐PTV margin for all planning scenarios. The red and blue curves indicate the FEF‐weighted doses, whereas the black curve shows the physical (non‐FEF‐weighted) dose of the clinical reference plan as a comparison. (b) Legend of the colors and of the different line styles (for [a]) and face textures (for [c] and [d]). (c) Reduction of the integral dose induced by the FLASH effect for every plan separately. Bars close to zero indicate little FLASH, whereas bars close to 33% present near‐maximum FLASH. (d) Clinical benefit of each FEF‐weighted plan compared to the clinical physical reference plan. Positive values indicate less FEF‐weighted integral dose for the respective plan than for the non‐FLASH‐weighted clinical plan. DVH, dose volume histogram; FEF, FLASH effectiveness factor

FIGURE 5

Comparison of the magnitude of the FLASH effect for five different treatment sites with two patients each and the two selected planning strategies. (a) FLASH effect in terms of integral dose reduction for each plan separately. (b) FLASH effect in terms of mean dose reduction within the GTV–PTV margin. (c) Clinical benefit of each FEF‐weighted plan compared to the clinical physical reference plan. Positive values indicate a lower FEF‐weighted integral dose for the respective plan than for the non‐FEF‐weighted clinical plan. (d) Legend for subfigures (a) to (c). FEF, FLASH effectiveness factor

FIGURE 6

Sensitivity analysis of the FLASH effect for varying parameter values. The shaded bands include all 10 patients for the single‐field transmission plan (dotted) and the single‐field, downstream‐modulated Bragg peak plan (ruled). The solid line describes the median. The dashed‐dotted line indicates the reference value of each parameter. The dotted lines in the upper right plots additionally indicate the fraction dose as a reference. (a) Reduction in integral dose within one plan due to FLASH. Low values indicate little FLASH, whereas 33% (dotted line) describes a maximally possible FLASH effect. (b) Clinical benefit of each plan compared to the clinical reference plan (MU). Positive values indicate a lower integral dose of the respective FEF‐weighted plan compared to the non‐FEF‐weighted clinical reference plan, thus showing a potential clinical benefit. (c) Legend for both (a) and (b). FEF, FLASH effectiveness factor