Ultrafast Tracking of Oxygen Dynamics During Proton FLASH

Khatib, Mirna El; Slyke, Alexander L. Van; Velalopoulou, Anastasia; Kim, Michele M.; Shoniyozov, Khayrullo; Allu, Srinivasa Rao; Diffenderfer, Eric; Busch, Theresa M.; Wiersma, R; Koch, Cameron J.; Vinogradov, Sergei A.

doi:10.1016/j.ijrobp.2022.03.016

Cited by 30 publications

(42 citation statements)

References 43 publications

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“…The measured depletion yields are consistent with the values reported previously [13][14][15]29,30]. Depletion yields of 0.5-0.6 l M/Gy were achieved in the plateau region of the curve, with a significant drop in the yield of oxygen depletion for lower oxygen concentrations.…”

Section: Discussionsupporting

confidence: 91%

“…While the exact mechanism of FLASH-RT remains to be more fully elucidated, oxygen has emerged as an important and relevant factor. First, oxygen is known to be depleted from the irradiated medium during the application of large doses of radiation [12][13][14][15][16][17]. For CDR radiation, this depletion occurs slowly, and the loss of oxygen is counteracted by replenishment through diffusion from the vasculature.…”

mentioning

confidence: 99%

“…For CDR radiation, this depletion occurs slowly, and the loss of oxygen is counteracted by replenishment through diffusion from the vasculature. In contrast, UHDR radiation is rapid enough to induce a transient and measurable drop in the local concentration of oxygen in the irradiated tissues [14,15], which has the potential to alter radiobiological responses [18][19][20][21]. In addition, a second reason is that changes in oxygen levels within the irradiated tis-sues have been shown to modulate the ability of UHDR radiation to spare normal tissues, a clear indication that oxygen is involved in mediating the FLASH effect [8][9][10][22][23][24].…”

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confidence: 99%

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Real-time optical oximetry during FLASH radiotherapy using a phosphorescent nanoprobe

Liang

Liu

et al. 2022

Radiotherapy and Oncology

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

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confidence: 99%

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Real-time optical oximetry during FLASH radiotherapy using a phosphorescent nanoprobe

Liang

Liu

et al. 2022

Radiotherapy and Oncology

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“…Nevertheless, the results obtained in our study using FLASH-RT reverses this paradigm completely. For rigor, tumor oxygenation was measured directly and non-invasively, where severe hypoxia (1-2 mmHg O 2 , < 0.5% O 2 ) was confirmed within minutes after clamping (15,21–24). The same methodology confirmed that carbogen breathing resulted in a modest increase in tumor pO 2 consistent with the literature (25,26).…”

Section: Discussionmentioning

confidence: 99%

Hypoxic tumors are sensitive to FLASH radiotherapy

Leavitt

Almeida

Grilj

et al. 2022

Preprint

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Tumor hypoxia is a major cause of resistance to cancer treatments and especially to radiotherapy. To address this specifically, we investigated whether ultra-high dose rate FLASH radiotherapy could overcome this resistance. Tumor cells from various origins were engrafted subcutaneously in mice to provide a reliable and rigorous way to modulate oxygen supply by vascular clamping or carbogen breathing. Tumors were irradiated using a single 20 Gy fraction at both conventional (CONV) and FLASH dose-rates using the Oriatron/eRT6 (PMB-Alcen, FR). Interestingly, and unlike radiotherapy at conventional dose rate, FLASH maintains its anti-tumor efficacy under extreme hypoxia. These findings demonstrate that in addition to normal tissue sparing, FLASH overcomes hypoxia-mediated tumor resistance. Follow-up molecular analysis using RNA-seq profiling uncovered specific metabolic shifts that discriminated FLASH from conventional dose rate irradiation, data that provides specific insights into the mechanism of action and identifies new targets for interventions.

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“…The term

reflects the reduced oxygen depletion rate at lower oxygen level with small l (0.29 μM from Lai et al.). Recently, measurements of proton radiation oxygen depletion in bovine serum albumin (BSA) solutions or Buffer 3G solution were made using phosphorescence quenching method ( 63 ) in addition to a similar measurement under electron beams ( 64 ). The G-value varies from 0.37 to 0.72 μM/Gy depending on the solution and dose rate.…”

Section: Methodsmentioning

confidence: 99%

A phenomenological model of proton FLASH oxygen depletion effects depending on tissue vasculature and oxygen supply

Zou

Kim²,

Diffenderfer³

et al. 2022

Front. Oncol.

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IntroductionRadiation-induced oxygen depletion in tissue is assumed as a contributor to the FLASH sparing effects. In this study, we simulated the heterogeneous oxygen depletion in the tissue surrounding the vessels and calculated the proton FLASH effective-dose-modifying factor (FEDMF), which could be used for biology-based treatment planning.MethodsThe dose and dose-weighted linear energy transfer (LET) of a small animal proton irradiator was simulated with Monte Carlo simulation. We deployed a parabolic partial differential equation to account for the generalized radiation oxygen depletion, tissue oxygen diffusion, and metabolic processes to investigate oxygen distribution in 1D, 2D, and 3D solution space. Dose and dose rates, particle LET, vasculature spacing, and blood oxygen supplies were considered. Using a similar framework for the hypoxic reduction factor (HRF) developed previously, the FEDMF was derived as the ratio of the cumulative normoxic-equivalent dose (CNED) between CONV and UHDR deliveries.ResultsDynamic equilibrium between oxygen diffusion and tissue metabolism can result in tissue hypoxia. The hypoxic region displayed enhanced radio-resistance and resulted in lower CNED under UHDR deliveries. In 1D solution, comparing 15 Gy proton dose delivered at CONV 0.5 and UHDR 125 Gy/s, 61.5% of the tissue exhibited ≥20% FEDMF at 175 μm vasculature spacing and 18.9 μM boundary condition. This percentage reduced to 34.5% and 0% for 8 and 2 Gy deliveries, respectively. Similar trends were observed in the 3D solution space. The FLASH versus CONV differential effect remained at larger vasculature spacings. A higher FLASH dose rate showed an increased region with ≥20% FEDMF. A higher LET near the proton Bragg peak region did not appear to alter the FLASH effect.ConclusionWe developed 1D, 2D, and 3D oxygen depletion simulation process to obtain the dynamic HRF and derive the proton FEDMF related to the dose delivery parameters and the local tissue vasculature information. The phenomenological model can be used to simulate or predict FLASH effects based on tissue vasculature and oxygen concentration data obtained from other experiments.

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Ultrafast Tracking of Oxygen Dynamics During Proton FLASH

Cited by 30 publications

References 43 publications

Real-time optical oximetry during FLASH radiotherapy using a phosphorescent nanoprobe

Real-time optical oximetry during FLASH radiotherapy using a phosphorescent nanoprobe

Hypoxic tumors are sensitive to FLASH radiotherapy

A phenomenological model of proton FLASH oxygen depletion effects depending on tissue vasculature and oxygen supply

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