With rare exceptions, current radiation therapy facilities deliver dose-rates around 0.1 Gy.s-1 and most clinical protocols involve daily fractions of 2 Gy cumulated to reach the tolerance limit of normal tissues located in the radiation field. Another methodology, named "FLASH-RT", has emerged recently [1]. It consists in delivering large doses (10-15 Gy) in a single microsecond pulse, or else in a limited number of 1-2 Gy pulses given at 4-10 ms interval in such a way that the total beam-on time is ≤ 100 ms. A linear electron accelerator with a thermoionic cathode and a triode electron gun, was used for these studies.
Relative to conventional dose-rate irradiation (CONV), FLASH-RT reportedly elicits in mice a dramatic decrease of the incidence of lung fibrosis [1] and of memory loss subsequent to brain irradiation [2] whilst keeping the anti-tumor efficiency unchanged. Such specific normal tissue sparing has been confirmed in cats and pigs [3] and a patient with cutaneous lymphoma has already been treated with FLASH-RT [4]. FLASH-RT has recendy been shown to minimize DNA damage in normal fibroblasts, spare lung stem cells from radio-induced death, and reduce the risk of replicative senescence altogether [5]. Physicists are investigating the feasibility of FLASH-RT with proton beams [6,7] and promising results with fibrogenesis of small intestine as an endpoint have been reported in mice exposed to 230 MeV protons at high dose-rate [8]. The construction of LINACs for intra-operative treatment of tumors, is currently in progress.
In our presentation we shall focus on the temporal and dose requirements these facilities should provide for maximizing optimal protection of healthy tissues in the prospect of anticancer radiotherapy.
1. Favaudon V, Caplier L, Monceau V, Pouzoulet F, Sayarath M, Fouillade C et al. (2014). Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Sci. Transl. Med. 6, 245ra293.
2. Montay-Gruel P, Petersson K, Jaccard M, Boivin G, Germond JF, Petit B et al. (2017). Irradiation in a flash: Unique sparing of memory in mice after whole brain irradiation with dose rates above 100Gy/s. Radiother Oncol 124, 365-369.
3. Vozenin MC, De Fornel P, Petersson K, Favaudon V, Jaccard M, Germond JF et al. (2019). The advantage of FLASH radiotherapy confirmed in mini-pig and cat-cancer patients. Clin. Cancer Res. 25, 35-42.
4. Bourhis J, Sozzi WJ, Jorge PG, Gaide O, Bailat C, Duclos F et al. (2019). Treatment of a first patient with FLASH-radiotherapy. Radiother Oncol 139, 18-22.
5. Fouillade C, Curras-Alonso S, Giuranno L, Quelennec E, Heinrich S, Bonnet-Boissinot S et al. (2020). FLASH Irradiation Spares Lung Progenitor Cells and Limits the Incidence of Radio-induced Senescence. Clin Cancer Res 26, 1497-1506.
6. Patriarca A, Fouillade C, Auger M, Martin F, Pouzoulet F, Nauraye C et al. (2018). Experimental Set-up for FLASH Proton Irradiation of Small Animals Using a Clinical System. Int J Radiat Oncol Biol Phys 102, 619-626.
7. Buonanno M, Grilj V, Brenner DJ (2019). Biological effects in normal cells exposed to FLASH dose rate protons. Radiother Oncol 139, 51-55.
8. Diffenderfer ES, Verginadis, II, Kim MM, Shoniyozov K, Velalopoulou A, Goia D et al. (2020). Design, Implementation, and in Vivo Validation of a Novel Proton FLASH Radiation Therapy System. Int J Radiat Oncol Biol Phys 106, 440-448.
