Radiobiology of the FLASH effect

Abstract

Radiation exposures at ultra-high dose rates (UHDR) at several orders of magnitude greater than in current clinical radiotherapy have been shown to manifest differential radiobiological responses compared to conventional dose rates (CONV). This has led to studies investigating the application of UHDR for therapeutic advantage (FLASH-RT) which have gained significant interest since the initial discovery in 2014 that demonstrated reduced lung toxicity with equivalent levels of tumour control compared with conventional dose-rate radiotherapy. Many subsequent studies have demonstrated the potential protective role of FLASH-RT in normal tissues, yet the underlying molecular and cellular mechanisms of the FLASH effect remain to be fully elucidated. Here, we summarise the current evidence of the FLASH effect and review FLASH-RT studies performed in preclinical models of normal tissue response. To critically examine the underlying biological mechanisms of responses to UHDR radiation exposures, we evaluate in vitro studies performed with normal and tumour cells. Differential responses to UHDR vs CONV irradiation recurrently involve reduced inflammatory processes and differential expression of pro-and anti-inflammatory genes. In addition, frequently reduced levels of DNA damage or misrepair products are seen after UHDR irradiation. So far, it is not clear what signal elicits these differential responses, but there are indications for involvement of reactive species. Different susceptibility to FLASH effects observed between normal and tumour cells may result from altered metabolic and detoxification pathways and/or repair pathways used by tumour cells. We summarize the current theories that may explain the FLASH effect and highlight This article is protected by copyright. All rights reserved.3 important research questions which are key to a better mechanistic understanding and, thus, the future implementation of FLASH-RT in the clinic. -INTRODUCTIONRadiation therapy (RT) remains a critical part of clinical cancer care prescribed to > 50% of patients in high-income countries and contributes to more than 30% of all long-term cancer survivors 1,2 . Technological advances in imaging and RT delivery techniques have resulted in major improvements in patient survival through improved precision and ability to conform dose to the tumour targets whilst minimising dose to surrounding organs at risk (OARs). In addition to improvements in technical radiotherapy, major research efforts have been made to exploit the unique radiobiological responses that occur at ultra-high dose rates (UHDR). In comparison to conventional clinical dose rates (CONV) in the region of 0.01-0.40 Gy/s, UHDR radiotherapy was originally established using microsecond pulses of 5 MeV electrons with intra-pulse dose rate in the range 10 6 -10 7 Gy/s, time-averaged dose rate > 40 Gy/s and

The Therapeutic Potential of FLASH-RT for Pancreatic Cancer

“…Under the transient hypoxia hypothesis, this heterogeneity should then introduce a sparing effect also on tumors, which is not supported by the literature [ 9 ]. Second, in vitro studies of normal, non-immortalized cells have shown a sparing effect when irradiated in ambient air conditions (pO2 ≈ 159 mmHg) [ 23 , 24 , 25 , 26 ]. Third, simulation studies and oxygen consumption studies in pure water and cell buffer solutions have also challenged this hypothesis by showing that total oxygen depletion did not occur with the use of FLASH radiation [ 27 , 28 , 29 ].…”

Online Charge Measurement for Petawatt Laser-Driven Ion Acceleration

“…Laser-driven proton and heavier ion pulses can deliver several orders of magnitude higher instantaneous dose rates (IDR) than typical conventional (radiofrequency) accelerators, potentially further increasing the differential sparing effect on normal tissue and consequently broadening the therapeutic window for radiotherapy. Access to conventional experimental and medical machines has been rather limited for this type of research [9] while the steady increase in available compact LD particle sources has already started to open up new experimental options for systematic radiobiological studies [10].…”

Non-Targeted Effects of Synchrotron Radiation: Lessons from Experiments at the Australian and European Synchrotrons

“…Ultra-high doses of MRT beams are likely to induce high DNA damage-generated 'immunogenic cell death', as has been suggested for FLASH irradiation [36].…”

“…Similar to the activation of the immune system after heterogenous dose delivery with conventional-source SFRT [37], immune cells in the valleys are spared following MRT and can activate an anti-tumor immune response (manuscript under review). In addition, short-pulse FLASH mode is capable of protecting the majority of local and circulating immune cells [36], thus further contributing to the active recruitment of immune cells to the microbeam paths.…”

“…Ultra-high doses of MRT beams are likely to induce high DNA damage-generated 'immunogenic cell death', as has been suggested for FLASH irradiation [36]. • Similar to the activation of the immune system after heterogenous dose delivery with conventional-source SFRT [37], immune cells in the valleys are spared following MRT and can activate an anti-tumor immune response (manuscript under review).…”