Oxygen Depletion in Proton Spot Scanning: A Tool for Exploring the Conditions Needed for FLASH

FLASH radiotherapy is a rapidly developing field which promises improved normal tissue protection compared to conventional irradiation and no compromise on tumour control. The transient hypoxic state induced by the depletion of oxygen at high dose rates provides one possible explanation. However, studies have mostly focused on uniform fields of dose and there is a lack of investigation into the spatial and temporal variation of dose from proton pencil-beam scanning (PBS). A model of oxygen reaction and diffusion in tissue has been extended to simulate proton PBS delivery and its impact on oxygen levels. This provides a tool to predict oxygen effects from various PBS treatments, and explore potential delivery strategies. Here we present a number of case applications to demonstrate the use of this tool for FLASH-related investigations. We show that levels of oxygen depletion could vary significantly across a large parameter space for PBS treatments, and highlight the need for in silico models such as this to aid in the development and optimisation of FLASH radiotherapy.

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The FLASH effect depends on oxygen concentration

British Journal of Radiology ◽

10.1259/bjr.20190702 ◽

2020 ◽

Vol 93 (1106) ◽

pp. 20190702 ◽

Cited By ~ 12

Author(s):

Gabriel Adrian ◽

Elise Konradsson ◽

Michael Lempart ◽

Sven Bäck ◽

Crister Ceberg ◽

...

Keyword(s):

Oxygen Concentration ◽

Underlying Mechanism ◽

Oxygen Depletion ◽

Therapeutic Window ◽

High Dose ◽

Dose Rates ◽

Conventional Dose ◽

Oxygen Concentrations

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.

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Transient hypoxia in water irradiated by swift carbon ions at ultra-high dose rates: implication for FLASH carbon-ion therapy

Canadian Journal of Chemistry ◽

10.1139/cjc-2021-0110 ◽

2021 ◽

Author(s):

Abdullah Muhammad Zakaria ◽

Nicholas W. Colangelo ◽

Jintana Meesungnoen ◽

Jean-Paul Jay-Gerin

Keyword(s):

Normal Tissue ◽

Molecular Mechanisms ◽

Oxygen Depletion ◽

Radiation Chemistry ◽

High Dose ◽

Carbon Ions ◽

Human Patient ◽

Dose Rates ◽

Depth Dose ◽

Ion Therapy

Large doses of ionizing radiation delivered to tumors at ultra-high dose rates (i.e., in a few milliseconds) paradoxically spare the surrounding healthy tissue while preserving anti-tumor activity (compared to conventional radiotherapy delivered at much lower dose rates). This new modality is known as “FLASH radiotherapy” (FLASH-RT). Although the molecular mechanisms underlying FLASH-RT are not yet fully understood, it has been suggested that radiation delivered at high dose rates spares normal tissue via oxygen depletion followed by subsequent radioresistance of the irradiated tissue. To date, FLASH-RT has been studied using electrons, photons and protons in various basic biological experiments, pre-clinical studies, and recently in a human patient. However, the efficacy of heavy ions, such as swift carbon ions, under FLASH conditions remains unclear. Given that living cells and tissues consist mainly of water, we set out to study, from a pure radiation chemistry perspective, the effects of ultra-high dose rates on the transient yields and concentrations of radiolytic species formed in water irradiated by 300-MeV per nucleon carbon ions (LET ~ 11.6 keV/μm). This mimics irradiation in the “plateau” region of the depth-dose distribution of ions, i.e., in the “normal” tissue region in which the LET is rather low. We used Monte Carlo simulations of multiple, simultaneously interacting radiation tracks together with an “instantaneous pulse” irradiation model. Our calculations show a pronounced oxygen depletion around 0.2 μs, strongly suggesting, as with electrons, photons and protons, that irradiation with energetic carbon ions at ultra-high dose rates is suitable for FLASH-RT.

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Oxygen Depletion in Cells Irradiated at Ultra-high Dose-rates and at Conventional Dose-rates

International Journal of Radiation Biology and Related Studies in Physics Chemistry and Medicine ◽

10.1080/09553007414550901 ◽

1974 ◽

Vol 26 (1) ◽

pp. 17-29 ◽

Cited By ~ 17

Author(s):

H. Weiss ◽

E.R. Epp ◽

J.M. Heslin ◽

C.C. Ling ◽

A. Santomasso

Keyword(s):

Oxygen Depletion ◽

High Dose ◽

Dose Rates ◽

Conventional Dose ◽

In Cells

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THE EFFECT OF ELECTRIC FIELDS, AND A RELATED DEPENDENCE ON DOSE RATE, IN THE γ-RADIOLYSIS OF HYDROCARBON GASES

Canadian Journal of Chemistry ◽

10.1139/v63-198 ◽

1963 ◽

Vol 41 (6) ◽

pp. 1463-1468 ◽

Cited By ~ 14

Author(s):

T. W. Woodward ◽

R. A. Back

Keyword(s):

Dose Rate ◽

Gas Phase ◽

Electric Fields ◽

Low Dose ◽

High Dose ◽

Hydrogen Yield ◽

Hydrocarbon Gases ◽

Saturation Field ◽

Dose Rates ◽

And Diffusion

The effect of electric fields on the γ-radiolysis of ethane, propane, and the butanes has been investigated briefly at 800 mm pressure, with dose rates between 2 × 1010 and 400 × 1010 ev/cc sec. Yields of hydrogen were reduced when a saturation field was applied, except with ethane at low dose rate, where a slight increase in hydrogen yield was observed. With propane and n-butane, the yield of hydrogen in the presence of a saturation field was independent of dose rate, while with ethane, it decreased with decreasing dose rate. At the same time, a dose rate dependence was discovered in the simple radiolysis, in the absence of any field, of ethane, propane, and n-butane, a decrease in the yield of hydrogen at low dose rates being observed. An explanation of these observations is suggested in terms of a competition between neutralization of ions in the gas phase and diffusion of ions to the wall. High dose rates should favor the former process, and low dose rates the latter. At sufficiently high dose rates, all ions should be neutralized in the gas phase. At sufficiently low dose rates, all ions should diffuse to the wall before neutralization, and it is suggested that the radiolysis under these conditions should closely resemble that in the presence of a saturation field at higher dose rates.

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Electron Beam Damage of Biomolecules Assessed by Energy Loss Spectroscopy

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100069855 ◽

1978 ◽

Vol 36 (3) ◽

pp. 61-69

Author(s):

M. Isaacson ◽

M.L. Collins ◽

M. Listvan

Keyword(s):

Electron Microscopy ◽

Radiation Damage ◽

Structural Integrity ◽

Analytical Electron Microscopy ◽

High Dose ◽

Dose Rates ◽

Special Cases ◽

Analytical Electron ◽

Atom Migration ◽

Beam Damage

Over the past five years it has become evident that radiation damage provides the fundamental limit to the study of blomolecular structure by electron microscopy. In some special cases structural determinations at very low doses can be achieved through superposition techniques to study periodic (Unwin & Henderson, 1975) and nonperiodic (Saxton & Frank, 1977) specimens. In addition, protection methods such as glucose embedding (Unwin & Henderson, 1975) and maintenance of specimen hydration at low temperatures (Taylor & Glaeser, 1976) have also shown promise. Despite these successes, the basic nature of radiation damage in the electron microscope is far from clear. In general we cannot predict exactly how different structures will behave during electron Irradiation at high dose rates. Moreover, with the rapid rise of analytical electron microscopy over the last few years, nvicroscopists are becoming concerned with questions of compositional as well as structural integrity. It is important to measure changes in elemental composition arising from atom migration in or loss from the specimen as a result of electron bombardment.

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Electron-diffraction studies in synthetic polymer materials

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100075579 ◽

1983 ◽

Vol 41 ◽

pp. 362-365

Author(s):

D.T. Grubb

Keyword(s):

Electron Diffraction ◽

Synthetic Polymer ◽

Polymer Materials ◽

Crystallographic Structure ◽

High Dose ◽

Electron Dose ◽

Dose Rates ◽

First Case ◽

Diffraction Patterns ◽

The Many

Diffraction studies in polymeric and other beam sensitive materials may bring to mind the many experiments where diffracted intensity has been used as a measure of the electron dose required to destroy fine structure in the TEM. But this paper is concerned with a range of cases where the diffraction pattern itself contains the important information.In the first case, electron diffraction from paraffins, degraded polyethylene and polyethylene single crystals, all the samples are highly ordered, and their crystallographic structure is well known. The diffraction patterns fade on irradiation and may also change considerably in a-spacing, increasing the unit cell volume on irradiation. The effect is large and continuous far C94H190 paraffin and for PE, while for shorter chains to C 28H58 the change is less, levelling off at high dose, Fig.l. It is also found that the change in a-spacing increases at higher dose rates and at higher irradiation temperatures.

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