The FLASH effect-an evaluation of preclinical studies of ultra-high dose rate radiotherapy

Abstract

FLASH radiotherapy (FLASH-RT) is a novel radiotherapy approach based on the use of ultra-high dose radiation to treat malignant cells. Although tumours can be reduced or eradicated using radiotherapy, toxicities induced by radiation can compromise healthy tissues. The FLASH effect is the observation that treatment delivered at an ultra-high dose rate is able to reduce adverse toxicities present at conventional dose rates. While this novel technique may provide a turning point for clinical practice, the exact mechanisms underlying the causes or influences of the FLASH effect are not fully understood. The study presented here uses data collected from 41 experimental investigations (published before March 2024) of the FLASH effect. Searchable databases were constructed to contain the outcomes of the various experiments in addition to values of beam parameters that may have a bearing on the FLASH effect. An in-depth review of the impact of the key beam parameters on the results of the experiments was carried out. Correlations between parameter values and experimental outcomes were studied. Pulse Dose Rate had positive correlations with almost all end points, suggesting viability of FLASH-RT as a new modality of radiotherapy. The collective results of this systematic review study suggest that beam parameter qualities from both FLASH and conventional radiotherapy can be valuable for tissue sparing and effective tumour treatment.

Keywords: FLASH; FLASH-RT; normal-tissue sparing; radiation - adverse effects; radiotherapy; therapeutic index; ultra-high dose rate; ultra-high dose rate irradiation.

Figure 1

TIS plotted against the most significant and strongest beam parameter, Pulse Dose Rate. A positive correlation between the parameters suggests that an increase in dose rate will increase the chance of observing a higher therapeutic index, as predicted in section 2.

Figure 2

TCS plotted against the most significant and strongest beam parameter, Total Dose. A positive correlation between the parameters suggests that an increase in irradiation dose increases tumour control.

Figure 3

NTSS plotted against the most statistically significant beam parameter, Mean Dose Rate. A positive correlation between the parameters suggests that a decrease in pulse rate may increase the chance of observing a sparing effect in normal tissue.

Figure 4

ILS plotted against the most significant and strongest beam parameter, Total Dose. A strong positive correlation between the parameters implies that an increase in dose can increase the lifespan of small animals.

Figure 5

S₃ percentage plotted against the most significant and strongest beam parameter, Number of Pulses. A strong positive correlation between the parameters implies that an increase in the Number of Pulses can increase the survival time of small animals.

Figure 6

Pearson’s correlation coefficients in heat map form to show the correlations between the log of each beam parameter and the corresponding endpoint. The values range between -1 and 1, where the extremities (closest to -1 and 1) have the deepest colour and the weakest correlations (closer to 0) have a weak colour. Statistically significant correlations are identifiable by an asterisk at the top right of the corresponding correlation coefficient. TIS, Therapeutic Index Score; TCS, Tumour Control Score; NTSS, Normal-tissue Sparing Score; ILS, Increased Lifespan; S ₁, Survival % at 1 month; S ₂, Survival % at 2 month; S ₃, Survival % at 3 month.