May oxygen depletion explain the FLASH effect? A chemical track structure analysis

Boscolo, Daria; Scifoni, E.; Durante, Marco; Krämer, M.; Fuß, Martina

doi:10.1016/j.radonc.2021.06.031

Cited by 68 publications

(44 citation statements)

References 60 publications

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“…However, it may not account for the results of in vitro studies carried out with normal cells in equilibrium with air ([O 2 ] ≈ 220 μM; Table 1) or apply to normoxic organs such as lung and brain. It has been challenged by recent Monte Carlo track structure analysis 136–138 and further by time‐resolved measurement of oxygen consumption following UHDR pulses in pure water, bovine serum albumin solutions, normal tissue, and tumors by means of 3 O 2 ‐induced quenching of the emission of fluorescent or phosphorescent microprobes 87,88 An alternative model, based on termination of peroxidative chain reactions through bimolecular self‐annihilation of peroxyl radicals, has been proposed to explain the FLASH effect 21,56 .…”

Section: Discussionmentioning

confidence: 99%

Radiobiology of the FLASH effect

et al. 2021

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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

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Section: Discussionmentioning

confidence: 99%

Radiobiology of the FLASH effect

et al. 2021

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“…In addition to this clinical need, there is still a lot of ambiguity regarding the manifestation of the FLASH effect and its underlying radiobiology from oxygen depletion to immune modulation. The oxygen depletion theory, which traces its roots to the hockey stick phenomenon of the 1950s and 1960s seems to be the more discussed interpretation to date 20,21 . For instance, Petersson et al 21 .…”

Section: Introductionmentioning

confidence: 99%

“…The oxygen depletion theory, which traces its roots to the hockey stick phenomenon of the 1950s and 1960s seems to be the more discussed interpretation to date. 20,21 For instance, Petersson et al 21 investigated models of oxygen kinetics during irradiation and developed a time-dependent model of the oxygen enhancement ratio in mammalian cells with oxygen depletion. The model was evaluated in terms of dose and dose rate dependency and was fit to experimental in vitro and in vivo datasets.…”

Section: Introductionmentioning

confidence: 99%

Image guidance for FLASH radiotherapy

et al. 2022

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FLASH radiotherapy (FLASH-RT) is an emerging ultra-high dose (>40 Gy/s) delivery that promises to improve the therapeutic potential by limiting toxicities compared to conventional RT while maintaining similar tumor eradication efficacy. Image guidance is an essential component of modern RT that should be harnessed to meet the special emerging needs of FLASH-RT and its associated high risks in planning and delivering of such ultra-high doses in short period of times. Hence, this contribution will elaborate on the imaging requirements and possible solutions in the entire chain of FLASH-RT treatment, from the planning, through the setup and delivery with online in vivo imaging and dosimetry, up to the assessment of biological mechanisms and treatment response. In patient setup and delivery, higher temporal sampling than in conventional RT should ensure that the short treatment is delivered precisely to the targeted region. Additionally, conventional imaging tools such as cone-beam computed tomography will continue to play an important role in improving patient setup prior to delivery, while techniques based on magnetic resonance imaging or positron emission tomography may be extremely valuable for either linear accelerator (Linac) or particle FLASH therapy, to monitor and track anatomical changes during delivery. In either planning or assessing outcomes, quantitative functional imaging could supplement conventional imaging for more accurate utilization of the biological window of the FLASH effect, selecting for or verifying things such as tissue oxygen and existing or transient hypoxia on the relevant timescales of FLASH-RT delivery. Perhaps most importantly at this time, these tools might help improve the understanding of the biological mechanisms of FLASH-RT response in tumor and normal tissues. The high dose deposition of FLASH provides an opportunity to utilize pulse-to-pulse imaging tools such as Cherenkov or radiation acoustic emission imaging. These could provide individual pulse mapping or assessing the 3D dose delivery superficially or at tissue depth, respectively. In summary, the most promising components of modern RT should be used for safer application of FLASH-RT, and new promising developments could be advanced to cope with its novel demands but also exploit new opportunities in connection with the unique nature of pulsed delivery at unprecedented dose rates, opening a new era of biological image guidance and ultrafast, pulsebased in vivo dosimetry.

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“…Recent modelling studies have tested the role of FLASH irradiation-induced oxygen depletion [ 23 , 24 , 66 – 68 ] and suggest that the radiation doses required to induce radiobiological hypoxia are several magnitudes higher than the dose used for in vivo and in vitro FLASH experiments. However, the model of radiation induced transient oxygen depletion, as suggested by Favaudon et al, seems to be a reasonable explanation for the FLASH effects alongside the differential nature and variations in the bimolecular composition, metabolism, free radicals generation and free radicals clearance mechanisms of the normal and cancer cells [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

Development of a portable hypoxia chamber for ultra-high dose rate laser-driven proton radiobiology applications

et al. 2022

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Background There is currently significant interest in assessing the role of oxygen in the radiobiological effects at ultra-high dose rates. Oxygen modulation is postulated to play a role in the enhanced sparing effect observed in FLASH radiotherapy, where particles are delivered at 40–1000 Gy/s. Furthermore, the development of laser-driven accelerators now enables radiobiology experiments in extreme regimes where dose rates can exceed 109 Gy/s, and predicted oxygen depletion effects on cellular response can be tested. Access to appropriate experimental enviroments, allowing measurements under controlled oxygenation conditions, is a key requirement for these studies. We report on the development and application of a bespoke portable hypoxia chamber specifically designed for experiments employing laser-driven sources, but also suitable for comparator studies under FLASH and conventional irradiation conditions. Materials and methods We used oxygen concentration measurements to test the induction of hypoxia and the maintenance capacity of the chambers. Cellular hypoxia induction was verified using hypoxia inducible factor-1α immunostaining. Calibrated radiochromic films and GEANT-4 simulations verified the dosimetry variations inside and outside the chambers. We irradiated hypoxic human skin fibroblasts (AG01522B) cells with laser-driven protons, conventional protons and reference 225 kVp X-rays to quantify DNA DSB damage and repair under hypoxia. We further measured the oxygen enhancement ratio for cell survival after X-ray exposure in normal fibroblast and radioresistant patient- derived GBM stem cells. Results Oxygen measurements showed that our chambers maintained a radiobiological hypoxic environment for at least 45 min and pathological hypoxia for up to 24 h after disconnecting the chambers from the gas supply. We observed a significant reduction in the 53BP1 foci induced by laser-driven protons, conventional protons and X-rays in the hypoxic cells compared to normoxic cells at 30 min post-irradiation. Under hypoxic irradiations, the Laser-driven protons induced significant residual DNA DSB damage in hypoxic AG01522B cells compared to the conventional dose rate protons suggesting an important impact of these extremely high dose-rate exposures. We obtained an oxygen enhancement ratio (OER) of 2.1 ± 0.1 and 2.5 ± 0.1 respectively for the AG01522B and patient-derived GBM stem cells for X-ray irradiation using our hypoxia chambers. Conclusion We demonstrated the design and application of portable hypoxia chambers for studying cellular radiobiological endpoints after exposure to laser-driven protons at ultra-high dose, conventional protons and X-rays. Suitable levels of reduced oxygen concentration could be maintained in the absence of external gassing to quantify hypoxic effects. The data obtained provided indication of an enhanced residual DNA DSB damage under hypoxic conditions at ultra-high dose rate compared to the conventional protons or X-rays.

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May oxygen depletion explain the FLASH effect? A chemical track structure analysis

Cited by 68 publications

References 60 publications

Radiobiology of the FLASH effect

Radiobiology of the FLASH effect

Image guidance for FLASH radiotherapy

Development of a portable hypoxia chamber for ultra-high dose rate laser-driven proton radiobiology applications

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