Radiobiology of high dose-rate particle beams

In the past few years, the normal tissue protecting effect of Flash electron irradiation was shown for several endpoints and in different species [1], [2]. Contrary to conventional, clinical beam delivery over minutes, the therapeutic dose is administered within less than 0.5 s by Flash irradiation. Hence, this treatment regime is linked to high mean dose rates of ~100 Gy/s and high pulse dose rates of ≥105 Gy/s, clearly exceeding the parameters of a few Gy/min on time average and of ~ 102 Gy/s within one pulse of conventional, clinical Linacs. Of note, tumors were cured by electron Flash as efficient as by conventional electron beam treatment over minutes [1]. Moreover, the protecting Flash effect was recently validated for photons [3], which promises a general validity of this effect also for other types of clinically used radiation.
First attempts testing the feasibility of proton Flash were conducted at clinical proton beam facilities in France [4] and at the University Proton Therapy Dresden (UPTD), Germany. At UPTD, a setup was established that allows for the irradiation of zebrafish embryo either with dose rates of 100 Gy/s for Flash or of 5 Gy/min for conventional reference. The zebrafish embryo were treated with graded doses up to 40 Gy and embryonic survival as well as the manifestation of morphological abnormalities were followed for up to four days. However, analysing the different endpoints, a clear dependency on dose but no significant dependence on proton dose rate was revealed.
This unexpected result implies, that more studies are needed to resolve the influence on beam time structure for the induction of a protective Flash effect. Here, research facilities like FAIR with a broader parameter space regarding ion species, particle fluence, LET, pulsing and beam time structure provide the possibility to study the physical limits of Flash in more detail. Therewith also questions on a potential influence or interaction of high dose-rate particle beam, high LET and oxygen level of the irradiated tissue could be investigated systematically. The results obtained therein could help to further develop dedicated clinical accelerators, like superconducting or heavy ion synchrotrons, to make clinical use of the Flash effect.

[1] V. Favaudon et al., “Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice,” Sci. Transl. Med., vol. 6, no. 245, p. 245ra93, Jul. 2014.
[2] P. Montay-Gruel et al., “Irradiation in a flash: Unique sparing of memory in mice after whole brain irradiation with dose rates above 100Gy/s,” Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol., vol. 124, no. 3, pp. 365–369, 2017.
[3] P. Montay-Gruel et al., “X-rays can trigger the FLASH effect: Ultra-high dose-rate synchrotron light source prevents normal brain injury after whole brain irradiation in mice,” Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol., vol. 129, no. 3, pp. 582–588, Dec. 2018.
[4] A. Patriarca et al., “Experimental Set-up for FLASH Proton Irradiation of Small Animals Using a Clinical System,” Int. J. Radiat. Oncol. Biol. Phys., vol. 102, no. 3, pp. 619–626, Nov. 2018.