The FLASH effect depends on oxygen concentration

Abstract

Objective: Recent in vivo results have shown prominent tissue sparing effect of radiotherapy with ultra-high dose rates (FLASH) compared to conventional dose rates (CONV). Oxygen depletion has been proposed as the underlying mechanism, but in vitro data to support this have been lacking. The aim of the current study was to compare FLASH to CONV irradiation under different oxygen concentrations in vitro. Methods: Prostate cancer cells were irradiated at different oxygen concentrations (relative partial pressure ranging between 1.6 and 20%) with a 10 MeV electron beam at a dose rate of either 600 Gy/s (FLASH) or 14 Gy/min (CONV), using a modified clinical linear accelerator. We evaluated the surviving fraction of cells using clonogenic assays after irradiation with doses ranging from 0 to 25 Gy. Results: Under normoxic conditions, no differences between FLASH and CONV irradiation were found. For hypoxic cells (1.6%), the radiation response was similar up to a dose of about 5–10 Gy, above which increased survival was shown for FLASH compared to CONV irradiation. The increased survival was shown to be significant at 18 Gy, and the effect was shown to depend on oxygen concentration. Conclusion: The in vitro FLASH effect depends on oxygen concentration. Further studies to characterize and optimize the use of FLASH in order to widen the therapeutic window are indicated. Advances in knowledge: This paper shows in vitro evidence for the role of oxygen concentration underlying the difference between FLASH and CONV irradiation.

Hypofractionated FLASH-RT as an Effective Treatment against Glioblastoma that Reduces Neurocognitive Side Effects in Mice

“…Nevertheless, differences between tumor, normal cell metabolism and the microenvironment might provide some explanation for the FLASH effect. A recent report investigating FLASH and conventional dose rate irradiation has indicated the importance of oxygen tension in clonogenic survival assays (31), corroborating several past results (14,32). Increased oxygen tension afforded by carbogen breathing was also found to negate the neurocognitive benefits of FLASH, again suggesting a role for oxygen and ROS in the FLASH effect (14).…”

Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool's Gold?

“…The range of oxygen concentrations used in this study was relatively narrow (0.44-0.7% O 2 ) and therefore the phenomenon could have been limited to cells already in hypoxic environments. However, the recent in vitro study by Adrian et al used physiologically relevant oxygen concentrations (1.6-8.3% O 2 ) and showed that the sparing effect of FLASH irradiation is dependent on oxygen concentration (48). An in vivo mouse model has also shown that irradiation of mouse tails at ultra-high dose rates induced radioresistance indicative of oxygen depletion (49).…”

Significant changes in yields of 7-hydroxy-coumarin-3-carboxylic acid produced under FLASH radiotherapy conditions

“…12 Adrian et al reported that FLASH effect highly depends on the intracellular oxygen concentration, indicating the importance of the depletion and rediffusion of oxygen and/or radical-radical interaction for the FLASH effect. 13 This view was also pointed out over 60 years ago. 14,15 Under ionizing radiations, cells have been affected by the depletion of an oxygen-containing solute by radiation-chemical reactions, when replenishment by diffusion is insufficient.…”

“…In addition, the sparing effect observed under the FLASH condition. 13 The sparing effect was seen when the relative partial oxygen pressure was 4.4, 2.7 and 1.6%, namely under the hypoxia condition. In comparison to this, the sparing effect was not conrmed at the relative partial oxygen pressure of 8.8 and 20%.…”

“…This view agrees with the sparing effect is seen under the FLASH condition. 13 From the reduction behavior of G values of 7OH-C3CA with dose rate, there would be two plausible interpretations to understand the mechanism of the FLASH effect;…”