Does FLASH deplete Oxygen? Experimental Evaluation for Photons, Protons and Carbon Ions
Jeannette Jansen, Jan Knoll, Elke Beyreuther, Jörg Pawelke, Raphael Skuza, Rachel Hanley, Stephan Brons, Francesca Pagliari, Joao Seco
DDoes FLASH deplete Oxygen? Experimental Evaluation forPhotons, Protons and Carbon Ions.
Jeannette Jansen , , Jan Knoll , , Elke Beyreuther , , J¨orgPawelke , , Raphael Skuza , , Rachel Hanley , , Stephan Brons ,Francesca Pagliari , Joao Seco , Division of Biomedical Physics in Radiation Oncology, German Cancer Research Center(DKFZ), Heidelberg, Germany Faculty of Physics and Astronomy, Ruprecht-Karls-University Heidelberg, Germany OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine andUniversity, Hospital Carl Gustav Carus, Technische Universit¨at Dresden, Helmholtz-ZentrumDresden – Rossendorf, Dresden, Germany Helmholtz-Zentrum Dresden – Rossendorf (HZDR), Institute of Radiation Physics, Dresden,Germany Helmholtz-Zentrum Dresden – Rossendorf (HZDR), Institute of Radiooncology - OncoRay,Dresden, Germany Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, GermanyVersion typeset March 2, 2021
Author to whom correspondence should be addressed: Joao Seco. email: [email protected]
AbstractPurpose:
To investigate experimentally, if FLASH irradiation depletes oxygen withinwater for different radiation types such as photons, protons and carbon ions.
Methods:
This study presents measurements of the oxygen consumption in sealed,3D printed water phantoms during irradiation with X-rays, protons and carbon ionsat varying dose rates up to 340 Gy/s. The oxygen measurement was performed usingan optical sensor allowing for non-invasive measurements.
Results:
Oxygen consumption in water only depends on dose, dose rate and linear en-ergy transfer (LET) of the irradiation. The total amount of oxygen depleted per 10 Gywas found to be 0.04 % atm - 0.18 % atm for 225 kV photons, 0.04 % atm - 0.25 % atmfor 224 MeV protons and 0.09 % atm - 0.17 % atm for carbon ions. Consumption de-pends on dose rate by an inverse power law and saturates for higher dose rates becauseof self-interactions of radicals. Higher dose rates yield lower oxygen consumption. Nototal depletion of oxygen was found for clinical doses.
Conclusions:
FLASH irradiation does consume oxygen, but not enough to deplete allthe oxygen present. For higher dose rates, less oxygen was consumed than at standardradiotherapy dose rates. No total depletion was found for any of the analyzed radiationtypes for 10 Gy dose delivery using FLASH. i a r X i v : . [ phy s i c s . m e d - ph ] M a r he table of contents is for drafting and refereeing purposes only. Note that all links toreferences, tables and figures can be clicked on and returned to calling point using cmd[ ona Mac using Preview or some equivalent on PCs (see View - go to on whatever reader). Contents I . Introduction 1 I . A . Radiolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 II . Materials and Methods 3 II . A . Preparation of Oxygen Meter for Measuring Dissolved Oxygen . . . . . . . . 3 II . B . Photons, Protons and Carbon Ion Beams . . . . . . . . . . . . . . . . . . . . 4 II . C . Measurement Setup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 II . D . Beam Microstructure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 II . E . Dosimetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 III . Results 7
III . A . Oxygen Consumption for Varying Water Phantom Volumes . . . . . . . . . . 7 III . B . Oxygen Consumption in Photons, Protons and Carbon Ion Beams . . . . . . 7 IV . Discussion 12 V . Conclusion 14 VI . Acknowledgments 15 VII .Conflict of Interest 15References 18 ii consumption in water with X-ray, p and C ions. Printed March 2, 2021 page 1 I . Introduction Over the last years, research on the irradiation with high dose rates (i.e. FLASH irradiation)became increasingly important.
In vivo , studies showed a radio-protective effect in healthytissue when irradiated with electrons at high dose rates ( >
40 Gy/s) whereas the tumorcontrol probability remained comparable to usual (clinical) dose rates of around 2 Gy/min .Applied to a clinical setup, FLASH dose rate irradiation could therefore enlarge the thera-peutic window, i.e. healthy tissue is protected and irradiation with higher doses in the tumoris made possible.Although this differential effect of radio-protection of the normal tissue has been studied andconfirmed already in vivo , the mechanism behind the FLASH effect still remains unknown .It is believed that dissolved oxygen in the cellular cytoplasm plays a major role: Early find-ings in the 1960s and 1970s showed a hypoxic-like cell survival behavior when Escherichiacoli bacteria were irradiated with ultra-high dose rates of X-rays . Oxygen measurements forthe same experimental setup showed a decrease of oxygen during irradiation. Similar resultswere obtained in HeLa cells and chinese hamster cells . One of the possible mechanismsto explain the FLASH effect nowadays is that oxygen is depleted during irradiation whichcauses a hypoxic environment in the irradiated volume. Hypoxic tissues are known to be 2-3times more radio-resistant than normoxic tissues . As tumors are mostly hypoxic (i.e. theO concentration is lower than 0.5 % atm) and healthy tissue (with an O concentration of1 % - 11 % ) is not, the oxygen depletion theory is of current interest as it could explain theobserved radio-protective effect.In this case, the consumption of oxygen, which can lead to complete depletion, is due toradiolysis. This process creates various radicals which then react with oxygen and result ina decrease in molecular oxygen. I . A . Radiolysis Ionizing radiation causes radiolysis of water molecules producing a range of reactive species(see Table 1). On short timescales after irradiation (until 10 − s), a high production ofe –aq and H is observable. In presence of molecular oxygen dissolved in water, these species Last edited
Date : March 2, 2021 age 2 Jansen et al. can interact with O which leads to the production of superoxide (O ) and HO . Theseproducts react further with each other on time scales until up to 10 − s. After 10 − seconds,the production of most radicals is in a stable regime and will not cause further reactions .For the studies presented, those reactions, which have O as direct product or educt, are ofmain interest, i.e. reactions in which O is directly consumed or produced (see Table 2 + 3).Photons (1.2 MeV) Protons CG value of: 1 keV/ µ m 10 keV/ µ m 15 keV/ µ m 20 keV/ µ mOH 2.7 2.5 1.7 1.5 1.3e –aq O and for ionradiation in water at 25 ◦ C and pH 7.Reaction Reaction rate k (cid:2) dm mol − s − (cid:3) e –aq + O O –2 HO k (cid:2) dm mol − s − (cid:3) OH + HO O + H O 1.0OH + O –2 O + OH – + HO H O + O + O –2 O + HO –2 , , ), but there is a lack ofmeasurement data and systems that not only measure oxygen consumption before and afterirradiation, but can also be used in-vitro (i.e. together with cell culture) and online. Theaim of this work is therefore to investigate experimentally the oxygen consumption in purewater as a potential mechanism of FLASH using an online oxygen meter. Thereby, the study I. INTRODUCTION I.A. Radiolysis consumption in water with X-ray, p and C ions. Printed March 2, 2021 page 3 is designed to cover a broad range of radiation types (X-ray, p and C radiation) and doserates (2 Gy/min - 340 Gy/s). II . Materials and Methods II . A . Preparation of Oxygen Meter for Measuring Dissolved Oxy-gen For the experimental part of the study, radiolysis of water and the resulting oxygen consump-tion were investigated using the solid optical sensors TROXSP5 from PyroScience GmbH ina 3D-printed water phantom.The water phantoms suitable for this study had to be airtight, preparable in differentgeometries to adapt to different irradiation beam set ups and transparent to read the sen-sor optically. To fulfill these requirements, phantoms were 3D-printed out of the materialVeroClear (Stratasys Ltd., Israel), a rigid, colourless and transparent material. The opticalsensor was glued with silicone into the phantom and the phantom was filled with de-ionizedwater. The oxygen dissolved in water was measured via a fluorescent layer in the sensor,which was read-out with the purchased system FireStingO2 (FSO2-4, PyroScience GmbH).With the FireStingO2, the sensor is excited at 650 nm wavelength and emits light in the nearinfrared regime. This signal is then further processed in the FireStingO2. Time resolutionof around 400 ms can be achieved.Since the read-out is performed optically, it was possible to measure the changes in oxygenconcentration inside a water phantom non-invasively. This is the main advantage over stud-ies with other commonly used oxygen probes where measurements are usually an invasiveprocess.The phantom itself was 20 mm long, of cylindrical shape and produced for multiple beamdiameters, to achieve a uniform dose distribution within the phantom. Hence, the phantom’sdiameter was constructed significantly smaller than the FWHM of the respective beam usedfor irradiation. For the present study, phantoms of 5 mm (Fig. 1) in diameter were appliedfor photon radiation, and phantoms of 2 mm in diameter were applied for proton and Cradiation.
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Date : March 2, 2021 age 4 Jansen et al. p, 12C X -r a y Figure 1: 3D-printed water phantom of 5 mm inner diameter. O sensor (black) is placed onthe inside on the left end, facing away from the beam. At this side, the optical fiber can becoupled to the phantom. On the right, facing the beam, two openings for filling the phantomare visible, which can be closed with plastic screws. O-rings were used between the screwsand the phantom for additional air tightness. The white arrows show the beam’s directionfor the respective beam types. II . B . Photons, Protons and Carbon Ion Beams To investigate the oxygen consumption as a function of dose and dose rate (i.e. the amountof dose deposited per time interval), the water phantom with the sensor was irradiated atdifferent dose rates with vertical beams of 225 kV photons (Faxitron MultiRad225, FaxitronBioptics, LLC). Irradiations with carbon ions were performed at Heidelberg Ion beam Ther-apy facility HIT, Germany at up to 9.5 Gy/s peak dose rate using the horizontal beam linein the QS room of HIT. Irradiations with protons were performed at OncoRay, Dresden,Germany at dose rates up to 340 Gy/s using the horizontal beam line in the experimentalroom of the University Proton Therapy facility. The applied beam parameters can be foundin Table 4. For both proton and carbon ion setups, the phantom was irradiated with highenergy particles, i.e. in the plateau region of the depth-dose-curve of the beam. II . C . Measurement Setup For measuring oxygen consumption, the phantom was filled entirely with pure, double-deionized water, without air bubbles, and closed with plastic screws. The oxygen content ofthe water was changed using a Sci-Tive hypoxic chamber (Baker Ruskinn), in which N is II. MATERIALS AND METHODS II.B. Photons, Protons and Carbon Ion Beams consumption in water with X-ray, p and C ions. Printed March 2, 2021 page 5
Energy LET H O [keV/ µ m] Av. DR [Gy/s] Spill DR [Gy/s] Beam StructureX-ray 225 kV ∼ C 400 MeV/u 10.89 0.06 - 2.4 0.12 - 5.1 1.5 s - 4.9 s on+ 4 s - 5 s off C 150 MeV/u 19.47 0.04 - 1.8 0.06 - 9.5 1.5 s - 4.9 s on+ 4 s - 5 s offTable 4: Beam parameters used for irradiation. Linear energy transfer (LET) was calculatedusing ICRU49 and ICRU73 . Photon LET was estimated .Figure 2: Experimental set up at OncoRay, Dresden for irradiation with 224 MeV protons.The beam passed a Bragg peak chamber (model T34070-2.5 from PTW) for dose monitoringand was shaped with a scatterer of 24 mm PMMA equivalent thickness and a 20 mm thickbrass collimator to deliver a homogenous beam spot. The phantom was held in place witha sample holder.used as air substitute. The pure water was placed in the hypoxic chamber for 2 days untilthe desired O level was reached and the phantoms were then filled with hypoxic water insidethe chamber. Then, the phantom was placed at the beam’s central beam axis. For protonand carbon ion measurements, the phantom’s cylinder axis was placed on the beam axis.For photon measurements, the phantom was placed perpendicular to the beam instead.By that, the phantoms were always positioned horizontally to ensure homogeneous watercomposition. On the sensor’s side of the phantom, a fiber holder was placed to connect the Last edited
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II.C. Measurement Setupage 6 Jansen et al. phantom’s sensor to the FireStingO2 meter with a 2 m long optical fiber of 2.2 mm diameter.The FireStingO2 meter was then connected to the laptop for data acquisition. The obtainedvalues for O concentration are in a range of 0 % - 20.95 % (air saturated). Figure 2 showsa photograph of the experimental setup for proton radiation. II . D . Beam Microstructure For defining the dose rate, recent studies have raised the importance to distinguish continuouswave (CW) and spilled (pulsed) beams . In order to achieve the same average dose ratein a spilled beam compared to a CW beam, a much higher dose rate would be required ineach pulse of a spilled beam to compensate for the beam pauses. Hence, for spilled beams,it is crucial to take both the pulse dose rate (i.e. the dose rate obtained in one spill) and theaverage dose rate into account .In this study, clear CW structure was obtained in X-rays. Protons at OncoRay showa quasi-continuous structure: 2 ns beam-on time is followed by 8 ns beam-off. At HIT, thebeam shows a spill-like structure: A continuous beam during spill duration of 1.5-4.9 s and atime between two spills of around 4-5 s in which no particles and hence no dose is delivered.The study presented here shows both the oxygen consumption in pulsed beams and in CWbeams. II . E . Dosimetry The dosimetry at phantom site for photon irradiation was carried out using a Semiflex ion-ization chamber (IC, type number TM31010, PTW, Germany). For carbon ion irradiation, aPinPoint chamber (type number TM31015, PTW, Germany) was used and both respectivelycoupled to a Unidos electrometer (PTW, Germany). Proton dosimetry was achieved usingan Advanced Markus IC (type number: 34045, PTW), coupled to an Unidos electrometer aswell. For the maximum dose rate of 340 Gy/s applied, a small saturation correction k sat of1.01 was determined for the Markus IC . Therefore, recombination effects can be neglectedand no dose rate dependent saturation correction was applied.In the experiments with photons presented in this study, it was possible to take addi- II. MATERIALS AND METHODS II.D. Beam Microstructure consumption in water with X-ray, p and C ions. Printed March 2, 2021 page 7 tional advantage of the beam’s geometry: The beam is conically shaped (as schematicallyshown in Figure 7a) and the dose is hence inversely proportional to the squared distancefrom the source, i.e. D ∼ /r . Accordingly, the same must apply to the dose rate, i.e.˙ D ∼ /r . Therefore, irradiating the phantom at different distances from the source auto-matically leads to a 1 /r -dependent dose rate (see Figure 7b) that can be used for furthermeasurements. In the experiments with protons and carbon ions, dose rate and dose waschanged by setting the beam current and irradiation time in the beam control system. III . Results
III . A . Oxygen Consumption for Varying Water Phantom Volumes At first, different phantoms with 80 µ l, 583 µ l, 6.138 ml and 6.876 ml water volume were irra-diated at a constant dose rate of 0.0799 Gy/s with 225 kV photons and the concentration ofO was measured during irradiation until the concentration of O reached zero. The resultsof this study are displayed in Figure 3a. It was observed that the rate of oxygen removal (i.e.dO/dt) was mostly constant and especially independent on the irradiated volume, as long asthe phantoms were irradiated homogeneously. Therefore, due to the observed independenceon volume, the phantom’s diameter was selected according to the beam’s geometries for thefollowing experiments. The stability of O over time in the phantom was tested withoutradiation for different oxygen levels. Even for low O levels, no diffusion was visible (see Fig.3b). III . B . Oxygen Consumption in Photons, Protons and Carbon IonBeams At all radiation sources, the oxygen consumption in dependence on irradiation time wasstudied for different dose rates (Fig. 4a, 4c, 4e). For photons and protons, the dose dependentoxygen consumption can be achieved by multiplying the time axis with the dose rate presentduring irradiation (Fig. 4b, 4d). For carbon ions, beam delivery in spills results in a step-wise oxygen consumption (Fig. 4e, 4f). For transferring the time axis into a dose axis, theaverage dose rate was used. For better comparison, curves were shifted in time to match
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Date : March 2, 2021 age 8 Jansen et al. O xy g e n C o n c e n t r a t i o n [ % a i r ] Photons 225 kV, DR = 0.0799 Gy/s
583 µl6.876 ml6.138 ml80 µl (a) O xy g e n C o n c e n t r a t i o n [ % a i r ] Stability of oxygen over time (b)
Figure 3: (a) Oxygen consumption for phantoms with different volumes, irradiated with adose rate (DR) of 0.0799 Gy/s. For better visibility, the curves are separated with a time-offset. (b) Oxygen stability was checked in phantom prior to irradiation.the same oxygen start level, i.e. irradiation also happened at t <
0. This was a reasonablesimplification as the depletion behavior was mostly linear.All measurements showed that dose rate had an impact on how fast oxygen got consumedand how much dose was needed for total depletion. Furthermore, the curves showed an almostlinear behavior, i.e. the average consumption per unit dose ( d O d D ) was extracted via a linearfit. III. RESULTS III.B. Oxygen Consumption in Photons, Protons and Carbon Ion Beams consumption in water with X-ray, p and C ions. Printed March 2, 2021 page 9 O xy g e n C o n c e n t r a t i o n [ % a i r ] Photons 225 kV, Oxygen Concentration vs Time
52 Gy/s8.1 Gy/s2.4 Gy/s1.0 Gy/s (a) O xy g e n C o n c e n t r a t i o n [ % a i r ] Photons 225 kV, Oxygen Concentration vs Dose
52 Gy/s8.1 Gy/s2.4 Gy/s1.0 Gy/s (b) O xy g e n C o n c e n t r a t i o n [ % a i r ] Protons 224 MeV, Oxygen Concentration vs Time
20 Gy/s5 Gy/s2 Gy/s (c) O xy g e n C o n c e n t r a t i o n [ % a i r ] Protons 224 MeV, Oxygen Concentration vs Dose
20 Gy/s5 Gy/s2 Gy/s (d) O xy g e n C o n c e n t r a t i o n [ % a i r ] Carbon 400 MeV/u, Oxygen Concentration vs Time av.: 1.19 Gy/s; spill: 2.55 Gy/sav.: 2.43 Gy/s; spill: 5.01 Gy/s (e) O xy g e n C o n c e n t r a t i o n [ % a i r ] Carbon 400 MeV/u, Oxygen Concentration vs Dose av.: 1.19 Gy/s; spill: 2.55 Gy/sav.: 2.43 Gy/s; spill: 5.01 Gy/s (f)
Figure 4: Oxygen concentration over irradiation time and dose for photon, proton andcarbon irradiation. For better comparison, some curves were shifted in time to match thesame initial O2 level.
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III.B. Oxygen Consumption in Photons, Protons and Carbon Ion Beamsage 10 Jansen et al.
Subsequently, a broader analysis over multiple measurements was carried out to extractthe average amount of depleted oxygen per unit dose ( d O d D ) as a function of dose rate. Toobtain the average consumption d O d D , the curves from data like exemplarily shown in Figures4b, 4d and 4f were linearly fitted, beginning from the start of irradiation, and the slope fitparameters ( d O d D ) were used for further analysis in Figure 5. The resulting average consump-tion d O d D was plotted against the respective dose rate for all radiation types in Figure 5. Forcarbon ion data, d O d D was plotted against the dose rate within one spill and not the averagedose rate. - d O / d D [ % a i r / G y ]
225 kV Photons
Photon 225 kV fitPhoton 225 kV (a) - d O / d D [ % a i r / G y ]
224 MeV Protons
Proton, 224 MeV fitProton, 224 MeV (b) - d O / d D [ % a i r / G y ]
150 MeV/u and 400 MeV/u 12C
Carbon, 400 MeV/u fitCarbon, 150 MeV/u fitCarbon, 400 MeV/uCarbon, 150 MeV/u (c)
Figure 5: Average oxygen consumption per 10 Gy ( d O d D ) as a dependence on dose rate ( d D d t )depicted for all measurements in the respective beams types III. RESULTS III.B. Oxygen Consumption in Photons, Protons and Carbon Ion Beams consumption in water with X-ray, p and C ions. Printed March 2, 2021 page 11
The fit function used in Figure 5 to describe the amount of consumed oxygen per dosewas chosen according to Labarbe et al. and Mihaljevic et al. and is given by a powerlaw, with the parameters a ≤ b > O d D = a + b · (cid:18) d D d t (cid:19) − . (1)Eq. 1 was used for C data, with d O d D being the average consumption per measurement,derived from average dose rate in the measurement. d D d t described the peak dose rate. Forproton and X-ray measurements, peak dose rate and average dose rate were identical, so itwas more convenient to work with d O d t data directly from measurement. For this purpose,Eq. 1 was multiplied by d D d t to obtain Eq. 2. In a second step, fit parameters from Eq. 2were used to generate Fig. 5a and Fig. 5b using Eq. 1.d O d t = a · d D d t + b · (cid:18) d D d t (cid:19) +0 . (2)It is evident that all depicted curves in Fig. 5 show a similar curvature, meaning thathigher dose rates lead to less oxygen consumption. Furthermore, different beam types havean impact on the oxygen consumption. Figures 6a - 6c show the fit results per irradiationtype applied to a starting oxygen concentration O initial of 2 % atm and extrapolated todifferent dose rates, assuming a linear depletion (which is in reasonable agreement to themeasured data). It was used: O ( D ) = O initial − d O d D · D with d O d D as parametrized in Equation1 with fit parameters a and b obtained from fits shown in Figure 5.Considering Figure 6, it is evident that 2 % atm O cannot be depleted within 10 Gy byany of the used beams. Last edited
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III.B. Oxygen Consumption in Photons, Protons and Carbon Ion Beamsage 12 Jansen et al. O xy g e n C o n c e n t r a t i o n [ % a i r ]
50 Gy/s
Protons 224 MeVPhotons 225 kVCarbon ions 400 MeV/uCarbon ions 150 MeV/u (a) O xy g e n C o n c e n t r a t i o n [ % a i r ] Protons 224 MeVPhotons 225 kVCarbon ions 400 MeV/uCarbon ions 150 MeV/u (b) O xy g e n C o n c e n t r a t i o n [ % a i r ] Protons 224 MeVPhotons 225 kVCarbon ions 400 MeV/uCarbon ions 150 MeV/u (c)
Figure 6: Linearly extrapolated oxygen consumption starting from 2 % atm O for variousdose rates. For all settings, large doses (more than 10 Gy) would be needed to deplete allO . IV . Discussion The aim of the study was to investigate if oxygen depletion occurs during (FLASH-) irradia-tion, by measuring the oxygen concentration in-vitro during irradiation of water by photons,protons and carbon ions. For all experiments, TROXSP5 sensors were used to measure theoxygen concentration during irradiation, with the sensors not being affected by the radiation.The oxygen consumed during irradiation was found to be linear in time and dose and inde-pendent of the initial oxygen concentration (Fig. 4a-4f). Oxygen consumption was evaluatedper total dose delivered, where we defined d O d D to represent the total oxygen removed per unitdose (Fig. 4b, 4d, 4f). The d O d D represents also the total amount of radicals produced pertotal dose delivered, which have reacted with the diluted oxygen to create a reactive oxygen IV. DISCUSSION consumption in water with X-ray, p and C ions. Printed March 2, 2021 page 13 species (ROS). The d O d D as a function of dose rate (Fig. 5a-5c) follows the same non-linearbehavior as described by Labarbe et al. in organic environments, and given by the expres-sion a + b · (cid:0) d D d t (cid:1) − . . The nonlinearity was described in Labarbe et al. as the self-interactionof ROO molecules, part of the termination reaction. In the present study, experimentswere carried out with only pure water and therefore without the presence of any RH orR molecules. However, in pure water, self-interactions of the radicals play a major role inremoving the radicals that could potentially react with oxygen. This applies especially toe –aq and H as described in the following:e –aq + e –aq + 2 H O H + 2 OH – (3)e –aq + O O –2 (4)H + H H (5)H + O HO (6)The presence or absence of e –aq yields directly a change in O as described in the reac-tion (4). Therefore one would expect that an increased dose rate should yield a higher O consumption because of the higher production of e –aq per second. However, because of thecompeting reaction (3), e –aq is removed faster with increased dose rate yielding a lower steadystate of e –aq . The lower steady state of e –aq means there is less of e –aq available to react withO via reaction (4). The same process applies to H , as described in reactions (5) and (6).The amount of radicals produced is given by G · C · d D d t · t with G being the G -value, C is aconstant (1 . × − s × [ G ] − ( Gys ) − ) , d D d t is the dose rate and t the irradiation time. Inorder to understand if radicals can self-interact we need to check the mean free path length ofthe radicals. The radicals will diffuse for an average path length R rms of 2 . · (cid:113) D diff · t ( )with t being the half-life and D diff being the diffusion constant. Typical values for e –aq are D diff = 4 . × − , and t = 47 µ s ( , , ). From these values, a mean free path lengthof ∼ µ m can be estimated. Hence, it becomes clear that the solvated electrons e –aq diffusefar enough to interact with each other, ultimately reducing the steady state’s concentration. Therefore, O consumption is reduced with increasing dose rate as observed inour experiments. Last edited
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The study presented here showed that for FLASH dose rates, radical recombinations,via reaction (3) and (5), reduce the oxygen consumption within the medium. In addition,we observed experimentally that the amount of oxygen consumed by radiation depends alsoon the particle type and its LET but further investigation would be needed. For the caseof 10 Gy dose delivery, the amount of oxygen consumed was 0.04 % atm - 0.18 % atm for225 kV photons, 0.04 % atm - 0.25 % atm for 224 MeV protons and 0.09 % atm - 0.17 %atm for carbon ions, dependent on the dose rate (Fig. 5a-5c). The obtained experimentalvalues are in good agreement with other published results of experiments in water, whereoxygen consumption was between 0.26 % atm to 0.42 % atm for photon radiation.Recent modeling studies also yielded oxygen consumption between 0.05 % atm up to 0.27 %atm for photon, proton and carbon ion beams. In addition, a theoretical prediction byPetersson et al. yields an oxygen consumption in the range of 0.1 % atm to 2 % atm for totaldelivered dose of 10 Gy with FLASH. Applying the experimental findings and curves of Fig.5a-5c onto an exemplary case of a water phantom with 2 % atm O content, it is evident that10 Gy radiation of any analyzed radiation type cannot deplete oxygen completely in water(Fig. 6a-6c). It can be concluded, that for higher FLASH dose rates, less oxygen depletionper dose was observed. V . Conclusion This study showed that TROXSP5 sensors are a suitable sensor type to measure oxygenconsumption during radiation non-invasively in water phantoms. No total depletion of oxy-gen was observed for 10 Gy delivery by FLASH irradiation for photons, protons and carbonions. Hence, oxygen depletion is not a suitable mechanism to explain the FLASH effectalone but rather a reduction of oxygen consumption was found for higher dose rates whichwas related to the lower steady state values of e –aq radicals. The results presented here arein good agreement with previous data and recent radio-chemical models but the outcomestresses non-linear dose rate dependence of the oxygen consumption, even without thepresence of organic molecules, which is to date not implemented in current models.
V. CONCLUSION consumption in water with X-ray, p and C ions. Printed March 2, 2021 page 15 VI . Acknowledgments This work was supported by the Deutsche Forschungsgemeinschaft (GSC129). Furthermore,this project has received funding from the European Union’s Horizon 2020 research andinnovation program under grant agreement No. 730983 (INSPIRE).This work was also supported by grants of the German-Israeli Helmholtz Research Schoolin Cancer Biology – Cancer Transitional and Research Exchange Program (Cancer-TRAX).The authors would like to thank Dr. Peter H¨aring and Mona Lifferth from the departmentof Physical Quality Assurance in Radiation Therapy, DKFZ for help with the dosimetry.
VII . Conflict of Interest
The authors declare no conflict of interest.
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Appendix
VII. CONFLICT OF INTEREST consumption in water with X-ray, p and C ions. Printed March 2, 2021 page 17 (a) (b)
Figure 7: (a) Schematic of the conically shaped beam in Faxitron225. (b) Dose rate dependsproportionally on 1 /r , r being the distance to the beam source. Fit curve in (b) was usedto determine dose rates close to source. Last edited
Date : March 2, 2021 age 18 Jansen et al.
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List of Figures sensor (black) is placedon the inside on the left end, facing away from the beam. At this side, theoptical fiber can be coupled to the phantom. On the right, facing the beam,two openings for filling the phantom are visible, which can be closed withplastic screws. O-rings were used between the screws and the phantom foradditional air tightness. The white arrows show the beam’s direction for therespective beam types. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 LIST OF FIGURES LIST OF FIGURES consumption in water with X-ray, p and C ions. Printed March 2, 2021 page 21 d O d D ) as a dependence on dose rate( d D d t ) depicted for all measurements in the respective beams types . . . . . . 106 Linearly extrapolated oxygen consumption starting from 2 % atm O for var-ious dose rates. For all settings, large doses (more than 10 Gy) would beneeded to deplete all O . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 (a) Schematic of the conically shaped beam in Faxitron225. (b) Dose ratedepends proportionally on 1 /r , r being the distance to the beam source. Fitcurve in (b) was used to determine dose rates close to source. . . . . . . . . . 17 Last edited