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Proton FLASH radiotherapy
Huang Xin1, Zhang Guoliang1, Zhang Chunli2, Jin Jing3,4, Wang Lyuhua3,4, Peng Hao1
1Department of Medical Physics, Wuhan University, Wuhan 430072, China; 2CNNC High Energy Equipment (Tianjin) Co., Ltd, Tianjin 300300, China; 3National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; 4National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
Abstract FLASH radiotherapy (FLASH-RT) is a treatment modality that delivers ultra-high dose rate and ultra-fast radiation for cancer treatment. Compared to conventional dose rate radiotherapy, FLASH-RT can yield similar efficacy for tumors and achieve normal tissue protection, translating to an increased therapeutic window. Due to this unique feature, FLASH-RT is attracting increasing attention from the radiotherapy community, both academia and industry. Due to its unique Bragg peak as well as intrinsic high dose rate, application of FLASH has more value and profound significance in proton therapy while achieving highly conformal dose deposition simultaneously. This article reviews research progress on FLASH-RT, relevant cell and animal studies, experimental conditions and results. Moreover, this article also investigates the potential biological mechanisms, technical challenges for implementation and potential clinical applications of FLASH-RT.
[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] Al-Hallaq H, Cao M, Kruse J, et al.Cured in a FLASH:reducing normal tissue toxicities using ultra-high-dose rates[J]. Int J Radiat Oncol Biol Phys, 2019, 104(2):257-260.DOI:10.1016/j.ijrobp.2019.01.093. [3] Bourhis J, Sozzi WJ, Jorge PG, et al.Treatment of a first patient with FLASH-radiotherapy[J]. Radiother.Oncol, 2019, 139:18-22.DOI:10.1016/j.radonc.2019.06.019. [4] Hornsey S, Bewley DK.Hypoxia in mouse intestine induced by electron irradiation at high dose-rates[J]. Int J Radiat Biol Relat Stud Phys Chem Med, 1971, 19(5):479-483.DOI:10.1080/09553007114550611. [5] 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. [6] Montay-Gruel P, Bouchet A, Jaccard M, et al.X-rays can trigger the FLASH effect:Ultra-high dose-rate synchrotron light source prevents normal brain injury after whole brain irradiation in mice[J]. Radiother Oncol, 2018, 129(3):582-588.DOI:10.1016/j.radonc.2018.08.016. [7] Rao R, Ogurek S, Sertorio M, et al.Comparison of FLASH vs. conventional dose rate proton radiation in endogenous mouse brain tumor model[J]. Int J Radiat Oncol, 2020, 108(3):e742-e742.DOI:10.1016/j.ijrobp.2020.07.150. [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] 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, 2019, 105(1):S164-S165.DOI:10.1016/j.ijrobp.2019.06.187. [10] Girdhani S, Abel E, Katsis A, etAbstract B-280:FLASH:a novel paradigm changing tumor irradiation platform that enhances therapeutic ratio by reducing normal tissue toxicity and activating immune pathways[C]. Atlanta:AACR, 2019.DOI:10.1158/1538-7445.am2019-lb-280. [11] Abel E, Girdhani S, Jackson I, et al.Characterization of radiation-induced lung fibrosis and mode of cell death using single and multi-pulsed proton flash irradiation[J]. Int J Radiat Oncol, 2019, 105(1):E652-E653.DOI:10.1016/j.ijrobp.2019.06.1033. [12] Beyreuther E, Brand M, Hans S, et al.Feasibility of proton FLASH effect tested by zebrafish embryo irradiation[J]. Radiother Oncol, 2019, 139:46-50.DOI:10.1016/j.radonc.2019.06.024. [13] Iwata H, Toshito T, Omachi C, et al.Scanning proton FLASH irradiation using a synchrotron accelerator:effects on cultured cells and differences by irradiation positions[J]. Int J Radiat Oncol, 2020, 108(3):e522.DOI:10.1016/j.ijrobp.2020.07.1635. [14] Buonanno,M, Grilj V, Brenner DJ.Biological effects in normal cells exposed to FLASH dose rate protons[J]. Radiother Oncol, 2019, 139(1):51-55.DOI:10.1016/j.radonc.2019.02.009. [15] Bayart E, Flacco A, Delmas O, et al.Fast dose fractionation using ultra-short laser accelerated proton pulses can increase cancer cell mortality, which relies on functional PARP1 protein[J]. Sci Rep, 2019, 9(1):10132.DOI:10.1038/s41598-019-46512-1. [16] Pommarel L, Vauzour B, Mégnin-Chanet F, et al.Spectral and spatial shaping of a laser-produced ion beam for radiation-biology experiments[J]. Phys Rev Accel, 2017, 20(3):1-10.DOI:10.1103/PhysRevAccelBeams.20.032801. [17] Raschke S, Spickermann S, Toncian T, et al.Ultra-short laser-accelerated proton pulses have similar DNA-damaging effectiveness but produce less immediate nitroxidative stress than conventional proton beams[J]. Sci Rep, 2016, 6(1):32441.DOI:10.1038/srep32441. [18] Zeil K, Baumann M, Beyreuther E, et al.Dose-controlled irradiation of cancer cells with laser-accelerated proton pulses[J]. Appl Phys B Lasers Opt, 2013, 110:437-444.DOI:10.1007/s00340-012-5275-3. [19] Manti L, Perozziello FM, Borghesi M, et al.The radiobiology of laser-driven particle beams:focus on sub-lethal responses of normal human cells[J]. J Instrum, 2017, 12(3):C03084-C03084.DOI:10.1088/1748-0221/12/03/C03084. [20] Zlobinskaya O, Siebenwirth C, Greubel C, et al.The effects of ultra-high dose rate proton irradiation on growth delay in the treatment of human tumor xenografts in nude mice[J]. Radiat Res, 2014, 181(2):177-183.DOI:10.1667/RR13464.1. [21] Zlobinskaya O, Dollinger G, Michalski D, et al.Induction and repair of DNA double-strand breaks assessed by gamma-H2AX foci after irradiation with pulsed or continuous proton beams[J]. Radiat Environ Biophys, 2012, 51(1):23-32.DOI:10.1007/s00411-011-0398-1. [22] Auer S, Hable V, Greubel C, et al.Survival of tumor cells after proton irradiation with ultra-high dose rates[J]. Radiat Oncol, 2011, 6(1):139.DOI:10.1186/1748-717X-6-139. [23] Doria D, Kakolee KF, Kar S, et al.Biological effectiveness on live cells of laser driven protons at dose rates exceeding 109Gy/s[J]. AIP Adv, 2012, 2(1).DOI:10.1063/1.3699063. [24] Yogo A, Sato K, Nishikino M, et al.Application of laser-accelerated protons to the demonstration of DNA double-strand breaks in human cancer cells[J]. Appl Phys Lett, 2009, 94(18):181502.DOI:10.1063/1.3126452. [25] Hanton F, Chaudhary P, Doria D, et al.DNA DSB Repair Dynamics following Irradiation with Laser-Driven Protons at Ultra-High Dose Rates[J]. Sci Rep, 2019, 9(1):4471.DOI:10.1038/s41598-019-40339-6. [26] Dollinger G, Bergmaier A, Hable V, et al.Nanosecond pulsed proton microbeam[J]. Nucl Instru Meth Phys Res Sect B Beam Interact.with Mater, 2009, 267(12-13):2008-2012.DOI:10.1016/j.nimb.2009.03.006. [27] 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 USA, 2019, 116(22):10943-10951.DOI:10.1073/pnas.1901777116. [28] Doyen J, Sunyach MP, Almairac F, et al.Early toxicities after high dose rate proton therapy in cancer treatments[J]. Front Oncol, 2020, 10:613089.DOI:10.3389/fonc.2020.613089. [29] Fouillade C, Curras-Alonso S, Giuranno L, et al.FLASH irradiation spares lung progenitor cells and limits the incidence of radio-induced senescence[J]. Clin Cancer Res, 2020, 26(6):1497-1506.DOI:10.1158/1078-0432.CCR-19-1440. [30] Fournier C, Taucher-Scholz G.Radiation induced cell cycle arrest:an overview of specific effects following high-LET exposure[J]. Radiother Oncol, 2004, 73(2):S119-S122.DOI:10.1016/S0167-8140(04)80031-8. [31] Carter RJ, Nickson CM, Thompson JM, et al.Complex DNA damage induced by high linear energy transfer alpha-particles and protons triggers a specific cellular DNA damage response[J]. Int J Radiat Oncol Biol Phys, 2018, 100(3):776-784.DOI:10.1016/j.ijrobp.2017.11.012. [32] Hada M, Georgakilas AG.Formation of clustered DNA damage after high-LET irradiation:A review[J]. J Radiat Res, 2008, 49(3):203-210.DOI:10.1269/jrr.07123. [33] 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. [34] 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. [35] Kourkafas G, Bundesmann J, Fanselow T, et al.FLASH proton irradiation setup with a modulator wheel for a single mouse eye[J]. Med Phys, 2021, 48(4):1839-1845.DOI:10.1002/mp.14730. [36] van de Water S, Safai S, Schippers JM, et al.Towards FLASH proton therapy:the impact of treatment planning and machine characteristics on achievable dose rates[J]. Acta Oncol, 2019, 58(10):1463-1469.DOI:10.1080/0284186X.2019.1627416. [37] Jolly S, Owen H, Schippers M, et al.Technical challenges for FLASH proton therapy[J]. Phys Med, 2020, 78:71-82.DOI:10.1016/j.ejmp.2020.08.005. [38] van Goethem MJ, van der Meer R, Reist HW, et al.Geant4 simulations of proton beam transport through a carbon or beryllium degrader and following a beam line[J]. Phys Med Biol, 2009, 54(19):5831-5846.DOI:10.1088/0031-9155/54/19/011. [39] Macchi A, Borghesi M, Passoni M.Ion acceleration by superintense laser-plasma interaction[J]. Re Mol Phys, 2013, 85(2):751-793.DOI:10.1103/RevModPhys.85.751. [40] Zhang G, Wang J, Wang Y, et al.Proton FLASH:passive scattering or pencil beam scanning?[J]. Phys Med Biol, 2021, 66(3):03NT01.DOI:10.1088/1361-6560/abd22D. [41] Nesteruk KP, Togno M, Grossmann M, et al.Commissioning of a clinical pencil beam scanning proton therapy unit for ultra-high dose rates (FLASH)[J]. Med Phys, 2021, 48(7):4017-4026.DOI:10.1002/mp.14933. [42] Bourhis J, Montay-Gruel P, GonçalesJorge P, et al.Clinical translation of FLASH radiotherapy:why and how?[J]. Radiother Oncol, 2019, 139:11-17.DOI:10.1016/j.radonc.2019.04.008. [43] Baumann M, Krause M, Overgaard J, et al.Radiation oncology in the era of precision medicine[J]. Nat Rev Cancer, 2016, 16(4):234-249.DOI:10.1038/nrc.2016.18. [44] Feuvret L, Bracci S, Calugaru V, et al.Efficacy and safety of adjuvant proton therapy combined with surgery for chondrosarcoma of the skull base:a retrospective, population-based study[J]. Int J Radiat Oncol Biol Phys, 2016, 95(1):312-321.DOI:10.1016/j.ijrobp.2015.12.016. [45] SOURCE Varian.FlashForwardTM consortium[DB/OL][2021-03-10]. https://www.varian.com/about-varian/research/flashforward-consortium. [46] SOURCE IBA.Flash irradiation delivered in a Proteus®ONEtreatment room[DB/OL][2021-03-10]. https://iba-worldwide.com/content/flash-irradiation-delivered-proteus-one-treatment-room. [47] SOURCE Varian.Varian receives investigational device exemption (IDE) and prepares for first ever clinical trial of FLASH therapy[DB/OL][2021-03-10]. http://investors.varian.com/2020-10-12-Varian-Receives-Investigational-Device-Exemption-IDE-and-Prepares-for-First-Ever-Clinical-Trial-of-FLASH-Therapy.
2021, Vol. 30 
