Biological Benefits of Ultra-high Dose Rate FLASH Radiotherapy: Sleeping Beauty Awoken

Abstract

FLASH radiotherapy (FLASH-RT) is a technology that could modify the way radiotherapy is delivered in the future. This technique involves the ultra-fast delivery of radiotherapy at dose rates several orders of magnitude higher than those currently used in routine clinical practice. This very short time of exposure leads to the striking observation of relative protection of normal tissues that are exposed to FLASH-RT as compared with conventional dose rate radiotherapy. Here we summarise the current knowledge about the FLASH effect and provide a synthesis of the observations that have been reported on various experimental animal models (mice, zebrafish, pig, cats), various organs (lung, gut, brain, skin) and by various groups across 40 years of research. We also propose possible mechanisms for the FLASH effect, as well as possible paths for clinical application.

Keywords: Differential effect; FLASH radiotherapy; normal tissue protection; oxygen.

Fig 1.

Dose-escalation study. Irradiation was 4 hours post-fertilization (4hpf). Eggs were given 5–12 Gy delivered with FLASH or conventional dose rate irradiation. Radiation-induced alteration of zebrafish morphology was assessed 5 days post-fertilization (5dpf) by body length measurement. FLASH radiotherapy induced lower morphological alterations than conventional radiotherapy at doses above 10 Gy. Mean ± standard deviation and Mann–Whitney’s-test: *P < 0.05; **P < 0.01; ***P < 0.001 (n = 9–19 embryos/group).

Fig 2.

Chronology of physical, physicochemical, chemical, biochemical and biological events occuring after irradiation in the biological tissue. The difference between FLASH radiotherapy and radiotherapy delivered at the conventional dose rate is the duration of the exposure to the ionising radiation during the chemical step of the cascade. The chemical steps are highly dependent on dioxygen concentration within tissues.

Fig 3.

(a) Effect of FLASH in vitro. Representation of isoeffective cell survival to FLASH irradiation in air versus in 0.35% oxygen (~2 mm Hg). The slope in the latter condition becomes parallel to that in nitrogen, i.e. the cells in 0.35% oxygen are depleted to zero oxygen by FLASH irradiation to result in a radioresistant anoxic response. The ratio of the slopes (0.35% oxygen versus air) in this example is ~2.6 and the ratio of isoeffective doses is ~ 30/15 = 2. The difference in these ratios is because of the presence of the breakpoint dose of ~7 Gy needed to deplete the oxygen from 0.35% to zero. The breakpoint dose is higher for higher initial levels of oxygen. Figure based on the results of Nias et al. [22] using Hela cells and 10 MeV linac electrons delivered in a single 1 μs pulse. Very similar results were reported by Berry and Stedeford [6], using P-388 murine leukaemia cell survival assayed in vivo after a single 3 ns pulse from a Febetron-706 400 keV electron generator (see inset graph). 3000 rads = 30 Gy. (b) Effect of FLASH delivery times at 50 (1 μs) pulses per second in vivo. Data taken from [5]. ND₅₀ = dose to produce necrosis in 50% of murine tails by 6 weeks after irradiation. Each data point was derived from two to four experiments; standard errors are ~ ±3% of the mean values plotted. Numbers in circles: tail temperature at the time of irradiation, showing loss of the FLASH effect, presumably due to improved blood flow and higher oxygen tension in the tissue. Numbers in squares: number of (1 μs) pulses per second using the same intrapulse dose rate of 0.4 × 10⁶ Gy/s, showing loss of the FLASH effect with protraction of overall dose delivery.

Fig 4.

Average lung reaction scores per dose group = sum of percentage of animals × 1, 2, 3, 4 unitised scores of ±, +, ++, +++, read from [9, figure 1]. C,D, conventional dose rate, assay at 24 and 36 weeks; F,G, FLASH dose rate, assay at 24 and 36 weeks. Dashed lines are drawn for visual trend, no strict linear model is implied.