Modeling the impact of tissue oxygen profiles and oxygen depletion parameter uncertainties on biological response and therapeutic benefit of FLASH.
Modeling the impact of tissue oxygen profiles and oxygen depletion parameter uncertainties on biological response and therapeutic benefit of FLASH.
复制标题
DOI：
10.1002/mp.16366
复制
发表时间：
2023-03
期刊：
影响因子：
3.8
通讯作者：
Hongyu Zhu;J. Schuemann;Qixian Zhang;L. Gerweck
中科院分区：
文献类型：
--
作者：
Hongyu Zhu;J. Schuemann;Qixian Zhang;L. Gerweck
背景据报道，超高剂量率（FLASH）辐射可以有效抑制肿瘤生长，同时保护正常组织，然而，不同组织保护效应的机制仍不清楚。长期以来，人们都知道氧气会对放射生物学反应产生深远的影响，并且放射解氧耗竭被认为是 FLASH 现象的可能原因或促成因素。目的 这项工作研究肿瘤和正常组织中组织 pO2 分布、每单位剂量的氧消耗 (g) 以及产生半最大放射增敏作用的氧浓度（其最大值和 1 的平均值）(k) 的影响。方法我们开发了一个模型，该模型考虑了氧气消耗与闪光照射引起的放射敏感性变化之间的依赖关系。该模型假设 FLASH 照射消耗细胞内氧气的速度比从细胞外环境扩散到细胞内的速度更快。基于线性二次线性模型计算细胞存活率，并以施用剂量的1Gy增量调整放射敏感性相关参数。该模型重现了用不同细胞系和氧气浓度获得的已发表的实验数据，并用于分析参数不确定性对放射生物学响应的影响。这项研究根据临床确定的总体和个体患者 pO2 曲线，将 FLASH 的氧消耗分析扩展到正常人体组织和肿瘤。结果 结果表明，pO2 曲线是影响生物反应的最重要因素，基于中位 pO2 而非完整 pO2 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存在一小部分细胞会显着改变由于 FLASH 氧耗尽而引起的生物反应。我们发现，由于肿瘤中较低 pO2 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。如果肿瘤和正常组织中的 g 值相同，g 值的变化会影响氧消耗影响反应的剂量，但不会改变剂量依赖性反应趋势。结论 FLASH 氧耗竭的治疗效果可能取决于患者和组织。对于乳腺癌，FLASH 在少数情况下是有益的，然而，在氧合良好的肿瘤中，由于诱导正常组织缺氧，可能会实现治疗效果。本文受版权保护。版权所有。
BACKGROUND Ultra-high dose rate (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. PURPOSE This work investigates the impact of tissue pO2 profiles, oxygen depletion per unit dose (g), and the oxygen concentration yielding half-maximum radiosensitization (the average of its maximum value and one) (k) in tumor and normal tissue. METHODS We developed a model that considers the dependent relationship between oxygen depletion and change of radiosensitivity by FLASH irradiation. The model assumed that FLASH irradiation depletes intracellular oxygen more rapidly than it diffuses into the cell from the extracellular environment. Cell survival was calculated based on the linear quadratic-linear model and the radiosensitivity related parameters were adjusted in 1 Gy increments of the administered dose. The model reproduced published experimental data that were obtained with different cell lines and oxygen concentrations, 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. RESULTS 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 due to FLASH oxygen depletion. 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. CONCLUSIONS The therapeutic efficacy of FLASH oxygen depletion is likely patient and tissue dependent. For breast cancer, FLASH is beneficial in a minority of cases, however, in a subset of well oxygenated tumors, a therapeutic gain may be realized due to induced normal tissue hypoxia. This article is protected by copyright. All rights reserved.