组织氧分布和氧消耗参数不确定性对FLASH生物学反应和治疗获益的影响建模
Modeling the impact of tissue oxygen profiles and oxygen depletion parameter uncertainties on biological response and therapeutic benefit of FLASH
摘要：
据报道，闪光辐射可以有效地抑制肿瘤生长，同时保留正常组织，然而，差异组织保留效应的机制仍不清楚。氧长期以来一直被认为是深刻影响放射生物学反应，和辐解氧耗尽已被认为是一个可能的原因或贡献者的闪光现象。这项工作研究了肿瘤和正常组织中组织pO 2分布、每单位剂量氧耗（g）以及产生半数最大放射增敏作用的氧浓度（k）的影响。我们开发了一个模型，认为在闪光灯照射过程中的氧耗和辐射敏感性的变化之间的依赖关系。基于LQ-L模型计算细胞存活率，并调整分次照射时的辐射敏感性相关参数。该模型再现了已发表的实验数据，并用于分析参数不确定性对放射生物学效应的影响。本研究基于临床确定的总体和个体患者pO 2曲线，将FLASH的氧消耗分析扩展至正常人体组织和肿瘤。结果表明，pO 2曲线是影响生物反应的最重要因素，基于中位pO 2而非完整pO 2曲线的分析可能不可靠且具有误导性。此外，在放射生物学缺氧阈值上的一小部分细胞的存在实质上改变了对FLASH照射的生物学反应。我们发现，由于肿瘤中较低pO 2值的频率较高，k值的增加通常比正常组织对肿瘤更具保护作用。g值的变化会影响氧消耗影响反应的剂量，但如果肿瘤和正常组织中的g值相同，则不会改变剂量依赖性反应趋势。
英文摘要：
FLASH radiation has been reported to efficiently suppress tumor growth while sparing normal tissue, however, the mechanism of the differential tissue sparing effect is still not known. Oxygen has long been known to profoundly impact radiobiological responses, and radiolytic oxygen depletion has been considered to be a possible cause or contributor to the FLASH phenomenon. This work investigates the impact of tissue pO2 profiles, oxygen depletion per unit dose (g), and the oxygen concentration yielding half-maximal radiosensitization (k) in tumor and normal tissue. We developed a model that considers the dependent relationship between oxygen depletion and change of radiosensitivity during FLASH irradiation. Cell survival was calculated based on the LQ-L model and the radiosensitivity related parameters were adjusted while delivering fractional doses of FLASH irradiation The model reproduced published experimental data and was used to analyze the impact of parameter uncertainties on the radiobiological responses. This study expands the oxygen depletion analysis of FLASH to normal human tissue and tumor based on clinically determined aggregate and individual patient pO2 profiles. The results show that the pO2 profile is the most essential factor that affects biological response and analyses based on the median pO2 rather than the full pO2 profile can be unreliable and misleading. Additionally, the presence of a small fraction of cells on the threshold of radiobiologic hypoxia substantially alters biological response to FLASH irradiation. We found that an increment in the k value is generally more protective of tumor than normal tissue due to a higher frequency of lower pO2 values in tumors. Variation in the g value affects the dose at which oxygen depletion impacts response, but does not alter the dose dependent response trends, if the g value is identical in both tumor and normal tissue.
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