[an error occurred while processing this directive] | [an error occurred while processing this directive]
Research progress on the oxygen depletion hypothesis of ultra-high dose rate radiotherapy
Zhu Hongyu1, Zhang Qixian2, Deng Xiaowu1
1Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China; 2Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200030, China
Abstract In recent years, ultra-high dose rate (FLASH) radiotherapy has become one of the most advanced research topics in the field of radiotherapy. Experimental data indicate that FLASH radiotherapy can significantly reduce the irradiation damage in normal tissues while being as effective as clinical conventional dose rate radiotherapy in tumor control. The oxygen depletion hypothesis is considered as one of the key mechanisms underlying the FLASH effect. In this article, research progress on the discovery, experimental evidence and reaction principle of oxygen depletion was reviewed, the measurement methods and biological effect modeling methods of the oxygen depletion hypothesis were summarized, and the oxygen depletion difference between normal tissue and tumor was also discussed.
Fund:National Key R&D Program of China (2022YFC2402300); National Natural Science Foundation of China (12005316); Science and Technology Program of Guangzhou, China (202201011076)
Corresponding Authors:
Deng Xiaowu, Email: dengxw@sysucc.org.cn
Cite this article:
Zhu Hongyu,Zhang Qixian,Deng Xiaowu. Research progress on the oxygen depletion hypothesis of ultra-high dose rate radiotherapy[J]. Chinese Journal of Radiation Oncology, 2023, 32(4): 379-383.
Zhu Hongyu,Zhang Qixian,Deng Xiaowu. Research progress on the oxygen depletion hypothesis of ultra-high dose rate radiotherapy[J]. Chinese Journal of Radiation Oncology, 2023, 32(4): 379-383.
[1] Favaudon V, Caplier L, Monceau V, et al. Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice[J]. Sci Transl Med, 2014,6(245):245ra93. DOI: 10.1126/scitranslmed.3008973. [2] Montay-Gruel P, Petersson K, Jaccard M, et al.Irradiation in a flash: unique sparing of memory in mice after whole brain irradiation with dose rates above 100Gy/s[J]. Radiother Oncol, 2017,124(3):365-369. DOI: 10.1016/j.radonc.2017.05.003. [3] Vozenin MC, De Fornel P, Petersson K, et al.The advantage of FLASH radiotherapy confirmed in mini-pig and cat-cancer patients[J]. Clin Cancer Res, 2019,25(1):35-42. DOI: 10.1158/1078-0432.CCR-17-3375. [4] 张樱子, 姚升宇, 陈佳艺, 等. FLASH放疗技术相关热点分析[J].辐射研究与辐射工艺学报,2020,38(6):21-29. DOI: 10.11889/j.1000-3436.2020.rrj.38.060103. Zhang YZ, Yao SY, Chen JY, et al.Hot spot analysis on FLASH radiotherapy technology[J]. J Radiat Res Radiat Process,2020,38(6):21-29. DOI: 10.11889/j.1000-3436. 2020.rrj.38.060103. [5] Zhou GM. Mechanisms underlying FLASH radiotherapy, a novel way to enlarge the differential responses to ionizing radiation between normal and tumor tissues[J]. Radiat Med Prot, 2020,1(1):35-40. DOI: 10.1016/j.radmp.2020. 02.002. [6] Wilson JD, Hammond EM, Higgins GS, et al.Ultra-high dose rate (FLASH) radiotherapy: silver bullet or fool's gold?[J]. Front Oncol, 2019,9:1563. DOI: 10.3389/fonc. 2019.01563. [7] 赵维, 田源, 彭浩. Flash放疗[J]. 中华放射肿瘤学杂志, 2019,28(11):862-866. DOI: 10.3760/cma.j.issn.1004- 4221.2019.11.014. Zhao W, Tian Y, Peng H.Flash radiotherapy[J]. Chin J Radiat Oncol, 2019,28(11):862-866. DOI: 10.3760/cma.j.issn.1004-4221.2019.11.014. [8] Diffenderfer ES, Verginadis II, Kim MM, et al.Design, implementation, and in vivo validation of a novel proton FLASH radiation therapy system[J]. Int J Radiat Oncol Biol Phys, 2020,106(2):440-448. DOI: 10.1016/j.ijrobp.2019. 10.049. [9] Montay-Gruel P, Acharya MM, Petersson K, et al.Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species[J]. Proc Natl Acad Sci U S A, 2019,116(22):10943-10951. DOI: 10.1073/pnas.1901777116. [10] Labarbe R, Hotoiu L, Barbier J, et al.A physicochemical model of reaction kinetics supports peroxyl radical recombination as the main determinant of the FLASH effect[J]. Radiother Oncol, 2020,153:303-310. DOI: 10.1016/j.radonc.2020.06.001. [11] Spitz DR, Buettner GR, Petronek MS, et al.An integrated physico-chemical approach for explaining the differential impact of FLASH versus conventional dose rate irradiation on cancer and normal tissue responses[J]. Radiother Oncol, 2019,139:23-27. DOI: 10.1016/j.radonc. 2019.03.028. [12] Jin JY, Gu A, Wang W, et al.Ultra-high dose rate effect on circulating immune cells: a potential mechanism for FLASH effect?[J]. Radiother Oncol, 2020,149:55-62. DOI: 10.1016/j.radonc.2020.04.054. [13] Eggold JT, Chow S, Melemenidis S, et al.Abdominopelvic FLASH irradiation improves PD-1 immune checkpoint inhibition in preclinical models of ovarian cancer[J]. Mol Cancer Ther, 2022,21(2):371-381. DOI: 10.1158/1535- 7163.MCT-21-0358. [14] Dewey DL, Boag JW.Modification of the oxygen effect when bacteria are given large pulses of radiation[J]. Nature, 1959,183(4673):1450-1451. DOI: 10.1038/1831 450a0. [15] Rama N, Saha T, Shukla S, et al. Improved tumor control through t-cell infiltration modulated by ultra-high dose rate proton FLASH using a clinical pencil beam scanning proton system[J]. Int J Radiat Oncol Biol Phys, 2019,105(1):S164-S165. DOI:10.1016/j.ijrobp.2019.06.187 [16] Friedl AA, Prise KM, Butterworth KT, et al.Radiobiology of the FLASH effect[J]. Med Phys, 2022,49(3):1993-2013. DOI: 10.1002/mp.15184. [17] Cooper CR, Jones D, Jones GD, et al.FLASH irradiation induces lower levels of DNA damage ex vivo, an effect modulated by oxygen tension, dose, and dose rate[J]. Br J Radiol, 2022,95(1133):20211150. DOI: 10.1259/bjr.2021 1150. [18] Adrian G, Konradsson E, Lempart M, et al.The FLASH effect depends on oxygen concentration[J]. Br J Radiol, 2020,93(1106):20190702. DOI: 10.1259/bjr.20190702. [19] Ling CC, Michaels HB, Epp ER, et al.Oxygen diffusion into mammalian cells following ultrahigh dose rate irradiation and lifetime estimates of oxygen-sensitive species[J]. Radiat Res, 1978,76(3):522-532. [20] Epp ER, Weiss H, Djordjevic B, et al.The radiosensitivity of cultured mammalian cells exposed to single high intensity pulses of electrons in various concentrations of oxygen[J]. Radiat Res, 1972,52(2):324-332. [21] Zhu HY, Li JL, Deng XW, et al. Modeling of cellular response after FLASH irradiation: a quantitative analysis based on the radiolytic oxygen depletion hypothesis[J]. Phys Med Biol, 2021,66(18)DOI: 10.1088/1361-6560/ac226d. [22] Hall EJ, Giaccia AJ.Radiobiology for the Radiologist[M]. 8th ed. Philadelphia, PA: Lippincottt Williams & Wilkins, 2018. [23] Weiss H, Epp ER, Heslin JM, et al.Oxygen depletion in cells irradiated at ultra-high dose-rates and at conventional dose-rates[J]. Int J Radiat Biol Relat Stud Phys Chem Med, 1974,26(1):17-29. DOI: 10.1080/09553007414550901. [24] Cao X, Zhang RX, Esipova TV, et al.Quantification of oxygen depletion during FLASH irradiation in vitro and in vivo[J]. Int J Radiat Oncol Biol Phys, 2021,111(1):240-248. DOI: 10.1016/j.ijrobp.2021.03.056. [25] Cao X, Allu SR, Jiang SD, et al.High-resolution pO2 imaging improves quantification of the hypoxic fraction in tumors during radiation therapy[J]. Int J Radiat Oncol Biol Phys, 2021,109(2):603-613. DOI: 10.1016/j.ijrobp.2020.09.046. [26] Boscolo D, Scifoni E, Durante M, et al. May oxygen depletion explain the FLASH effect? A chemical track structure analysis[J]. Radiother Oncol, 2021,162: 68-75. DOI: 10.1016/j.radonc.2021.06.031. [27] Lai YF, Jia X, Chi YJ.Modeling the effect of oxygen on the chemical stage of water radiolysis using GPU-based microscopic Monte Carlo simulations, with an application in FLASH radiotherapy[J]. Phys Med Biol, 2021,66(2):025004. DOI: 10.1088/1361-6560/abc93b. [28] Petersson K, Adrian G, Butterworth K, et al.A quantitative analysis of the role of oxygen tension in FLASH radiation therapy[J]. Int J Radiat Oncol Biol Phys, 2020,107(3):539-547. DOI: 10.1016/j.ijrobp.2020.02.634. [29] Zhu HY, Schuemann J, Zhang QX, et al. FLASH depletion of oxygen in tumor and normal tissue,its likely consequences[J/OL]. (2022-01-06)[2022-02-01].https://arxiv.org/vc/arxiv/papers/2201/2201.02278v1.pdf. [30] Pratx G, Kapp DS.A computational model of radiolytic oxygen depletion during FLASH irradiation and its effect on the oxygen enhancement ratio[J]. Phys Med Biol, 2019,64(18):185005. DOI: 10.1088/1361-6560/ab3769. [31] Pratx G, Kapp DS.Ultra-high-dose-rate FLASH irradiation may spare hypoxic stem cell niches in normal tissues[J]. Int J Radiat Oncol Biol Phys, 2019,105(1):190-192. DOI: 10.1016/j.ijrobp.2019.05.030. [32] Hu AK, Qiu R, Wu Z, et al.A computational model for oxygen depletion hypothesis in FLASH effect[J]. Radiat Res, 2022,197(2):175-183. DOI: 10.1667/RADE-20- 00260.1. [33] Carlson DJ, Stewart RD, Semenenko VA.Effects of oxygen on intrinsic radiation sensitivity: a test of the relationship between aerobic and hypoxic linear-quadratic (LQ) model parameters[J]. Med Phys, 2006,33(9):3105-3115. DOI: 10.1118/1.2229427. [34] Grimes DR, Partridge M.A mechanistic investigation of the oxygen fixation hypothesis and oxygen enhancement ratio[J]. Biomed Phys Eng Express, 2015,1(4):045209. DOI: 10.1088/2057-1976/1/4/045209. [35] Gao F, Yang YW, Zhu HY, et al.First demonstration of the FLASH effect with ultrahigh dose rate high-energy X-rays[J]. Radiother Oncol, 2022,166:44-50. DOI: 10.1016/j.radonc.2021.11.004. [36] Spencer JA, Ferraro F, Roussakis E, et al.Direct measurement of local oxygen concentration in the bone marrow of live animals[J]. Nature, 2014,508(7495):269-273. DOI: 10.1038/nature13034. [37] Mohyeldin A, Garzón-Muvdi T, Quiñones-Hinojosa A.Oxygen in stem cell biology: a critical component of the stem cell niche[J]. Cell Stem Cell, 2010,7(2):150-161. DOI: 10.1016/j.stem.2010.07.007. [38] Vaupel P, Kallinowski F, Okunieff P.Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review[J]. Cancer Res, 1989,49(23):6449-6465. [39] Vaupel P, Schlenger K, Knoop C, et al.Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements[J]. Cancer Res, 1991,51(12):3316-3322. [40] Hall EJ, Giaccia AJ.Radiobiology for the Radiologist[M]. Philadelphia: Lippincott Williams & Wilkins, 2011.