Petersson Kristoffer, Adrian Gabriel, Butterworth Karl, McMahon Stephen J
Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom; Department of Haematology, Oncology and Radiation Physics, Radiation Physics, Skåne University Hospital, Lund, Sweden.
Department of Clinical Sciences Lund, Oncology, Skåne University Hospital, Lund University, Lund, Sweden.
Int J Radiat Oncol Biol Phys. 2020 Jul 1;107(3):539-547. doi: 10.1016/j.ijrobp.2020.02.634. Epub 2020 Mar 5.
Recent demonstrations of normal tissue sparing by high-dose, high-dose-rate FLASH radiation therapy have driven considerable interest in its application to improve clinical outcomes. However, significant uncertainty remains about the underlying mechanisms of FLASH sparing and how deliveries can be optimized to maximize benefit from this effect. Rapid oxygen depletion has been suggested as a potential mechanism by which these effects occur, but this has yet to be quantitatively tested against experimental data.
Models of oxygen kinetics during irradiation were used to develop a time-dependent model of the oxygen enhancement ratio in mammalian cells that incorporates oxygen depletion. The characteristics of this model were then explored in terms of the dose and dose-rate dependence of the oxygen enhancement ratio. This model was also fit to experimental data from both in vitro and in vivo data sets.
In cases of FLASH radiation therapy, this model suggests that oxygen levels can be depleted by amounts that are sufficient to affect radiosensitivity only in conditions of intermediate oxygen tension, with no effect seen at high or very low initial oxygen levels. The model also effectively reproduced the dose, dose rate, and oxygen tension dependence of responses to FLASH radiation therapy in a range of systems, with model parameters compatible with published data.
Oxygen depletion provides a credible quantitative model to understand the biological effects of FLASH radiation therapy and is compatible with a range of experimental observations of FLASH sparing. These results highlight the need for more detailed quantification of oxygen depletion under high-dose-rate radiation exposures in relevant systems and the importance of oxygen tension in target tissues for FLASH sparing to be observed.
近期高剂量、高剂量率的FLASH放射治疗对正常组织的保护作用已引发了人们对其改善临床疗效应用的浓厚兴趣。然而，关于FLASH保护的潜在机制以及如何优化放疗方案以最大化这种效应带来的益处，仍存在重大不确定性。快速氧耗竭被认为是产生这些效应的一种潜在机制，但这尚未根据实验数据进行定量测试。
利用辐照期间的氧动力学模型，建立了一个包含氧耗竭的哺乳动物细胞氧增强比随时间变化的模型。然后从氧增强比的剂量和剂量率依赖性方面探讨了该模型的特性。该模型还与体外和体内数据集的实验数据进行了拟合。
在FLASH放射治疗的情况下，该模型表明，仅在中等氧张力条件下，氧水平可被耗竭到足以影响放射敏感性的程度，而在高初始氧水平或极低初始氧水平下则未观察到影响。该模型还有效地再现了一系列系统中FLASH放射治疗反应的剂量、剂量率和氧张力依赖性，模型参数与已发表的数据相符。
氧耗竭为理解FLASH放射治疗的生物学效应提供了一个可靠的定量模型，并且与一系列FLASH保护的实验观察结果相符。这些结果凸显了在相关系统中对高剂量率辐射暴露下的氧耗竭进行更详细定量分析的必要性，以及靶组织中的氧张力对于观察到FLASH保护的重要性。
