Abstract： Proton is formed after hydrogen atom loses an electron with a positive charge of particle (H+).After the proton is accelerated,it possesses significant advantages in terms of the distribution of physical dose compared with the photon. Currently,proton radiation has captivated extensive attention and has been actively applied in clinical practice. Nevertheless,due to the small amount of proton facilities and lack of clinical trials,the proton therapy,especially the radiobiological characteristics and biological effect of photon radiotherapy has been poorly understood. In this article,these issues were summarized as below.
[1] Sakurai H,Ishikawa H,Okumura T.Proton beam therapy in Japan:current and future status[J].Jpn J Clin Oncol,2016,46(10):885-892.DOI:10.1093/jjco/hyw102. [2] Romesser PB,Cahlon O,Scher E,et al. Proton beam radiation therapy results in significantly reduced toxicity compared with intensity-modulated radiation therapy for head and neck tumors that require ipsilateral radiation[J].Radiother Oncol,2016,118(2):286.DOI:10.1016/j.radonc.2015.12.008. [3] Mizumoto M,Oshiro Y,Yamamoto T,et al. Proton beam therapy for pediatric brain tumor[J].Neurol Med Chir (Tokyo),2017,57(7):343-355.DOI:10.2176/nmc.ra.2017-0003. [4] Girdhani S,Sachs R,Hlatky L.Biological effects of proton radiation:what we know and don′t know[J].Radiat Res,2013,179(3):257-272.DOI:10.1667/RR2839.1. [5] Tommasino F,Durante M.Protonradiobiology[J].Cancers (Basel),2015,7(1):353-381.DOI:10.3390/cancers7010353. [6] Mcnamara AL,Schuemann J,Paganetti H.A phenomenological relative biological effectiveness (RBE) model for proton therapy based on all published in vitro cell survival data[J].Phys Med Biol,2015,60(21):8399-8416.DOI:10.1088/0031-9155/60/21/8399. [7] Mohan R,Grosshans D.Proton therapy-present and future[J].Adv Drug Deliv Rev,2017,109:26-44.DOI:10.1016/j.addr.2016.11.006. [8] Giovannini G,Bohlen T,Cabal G,et al. Variable RBE in proton therapy:comparison of different model predictions and their influence on clinical-like scenarios[J].Radiat Oncol,2016,11:68.DOI:10.1186/s13014-016-0642-6. [9] Sorensen BS,Overgaard J,Bassler N.In vitro RBE-LET dependence for multiple particle types[J].Acta Oncol,2011,50(6):757-762.DOI:10.3109/0284186X.2011.582518. [10] Paganetti H.Relative biological effectiveness (RBE) values for proton beam therapy. Variations as a function of biological endpoint,dose,and linear energy transfer[J].Phys Med Biol,2014,59(22):R419-R472.DOI:10.1088/0031-9155/59/22/R419. [11] Paganetti H,Niemierko A,Ancukiewicz M,et al. Relative biological effectiveness (RBE) values for proton beam therapy[J].Int J Radiat Oncol Biol Phys,2002,53(2):407-421.DOI:10.1016/S0360-3016(02)02754-2. [12] Kanemoto A,Hirayama R,Moritake T,et al. RBE and OER within the spread-out Bragg peak for proton beam therapy:in vitro study at the Proton Medical Research Center at the University of Tsukuba[J].J Radiat Res,2014,55(5):1028-1032.DOI:10.1093/jrr/rru043. [13] Zhang X,Lin SH,Fang B,et al. Therapy-resistant cancer stem cells have differing sensitivity to photon versus proton beam radiation[J].J Thorac Oncol,2013,8(12):1484-1491.DOI:10.1097/JTO.0b013e3182a5fdcb. [14] Giedzinski E,Rola R,Fike JR,et al. Efficient production of reactive oxygen species in neural precursor cells after exposure to 250 MeV protons[J].Radiat Res,2005,164(4 Pt 2):540-544.DOI:10.1667/RR3369.1. [15] Alan MR,Wang Y,Shah J,et al. Proton beam radiation induces DNA damage and cell apoptosis in glioma stem cells through reactive oxygen species[J].Sci Rep,2015,5:13961.DOI:10.1038/srep13961. [16] Czapla-Masztafiak J,Szlachetko J,Milne CJ,et al. Investigating DNA Radiation Damage Using X-Ray Absorption Spectroscopy[J].Biophys J,2016,110(6):1304-1311.DOI:10.1016/j.bpj.2016.01.031. [17] Vysin L,Pachnerova BK,Stepan V,et al. Proton-induced direct and indirect damage of plasmid DNA[J].Radiat Environ Biophys,2015,54(3):343-352.DOI:10.1007/s00411-015-0605-6. [18] Padellec AL,Moretto-Capelle P,Richard-Viard M,et al. Ionization and fragmentation of DNA,RNA bases induced by proton impact[J].J Phys Conf Ser,2008,101:12007.DOI:10.1088/1742-6596/101/1/012007. [19] Calugaru V,Nauraye C,Noel G,et al. Radiobiological characterization of two therapeutic proton beams with different initial energy spectra used at the Institut Curie Proton Therapy Center in Orsay[J].Int J Radiat Oncol Biol Phys,2011,81(4):1136-1143.DOI:10.1016/j.ijrobp.2010.09.003. [20] Grosse N,Fontana AO,Hug EB,et al. Deficiency in homologous recombination renders Mammalian cells more sensitive to proton versus photon irradiation[J].Int J Radiat Oncol Biol Phys,2014,88(1):175-181.DOI:10.1016/j.ijrobp.2013.09.041. [21] Fontana AO,Augsburger MA,Grosse N,et al. Differential DNA repair pathway choice in cancer cells after proton-and photon-irradiation[J].Radiother Oncol,2015,116(3):374-380.DOI:10.1016/j.radonc.2015.08.014. [22] Kim B,Bae H,Lee H,et al. Proton beams inhibit proliferation of breast cancer cells by altering DNA methylation status[J].J Cancer,2016,7(3):344-352.DOI:10.7150/jca.13396. [23] Goetz W,Morgan MN,Baulch JE.The effect of radiation quality on genomic DNA methylation profiles in irradiated human cell lines[J].Radiat Res,2011,175(5):575-587.DOI:10.1667/RR2390.1. [24] Kumar A,Rai PS,Upadhya R,et al.γ-radiation induces cellular sensitivity and aberrant methylation in human tumor cell lines[J].Int J Radiat Biol,2011,87(11):1086.DOI:10.3109/09553002.2011.605417. [25] Esteller M.Cancer epigenomics:DNA methylomes and histone-modification maps[J].Nat Rev Genet,2007,8(4):286-298.DOI:10.1038/nrg2005. [26] Hojo H,Dohmae T,Hotta K,et al. Difference in the relative biological effectiveness and DNA damage repair processes in response to proton beam therapy according to the positions of the spread out Bragg peak[J].Radiat Oncol,2017,12(1):111.DOI:10.1186/s13014-017-0849-1. [27] Markova E,Schultz N,Belyaev IY.Kinetics and dose-response of residual 53BP1/gamma-H2AX foci:co-localization,relationship with DSB repair and clonogenic survival[J].Int J Radiat Biol,2007,83(5):319-329.DOI:10.1080/09553000601170469. [28] Bracalente C,Ibaez IL,Molinari B,et al. Induction and persistence of large γh2ax foci by high linear energy transfer radiation in DNA-dependent protein kinase-deficient cells[J].Int J Radiat Oncol Biol Phys,2013,87(4):785-794.DOI:10.1016/j.ijrobp.2013.07.014. [29] Finnberg N,Wambi C,Ware JH,et al. Gamma-radiation (GR) triggers a unique gene expression profile associated with cell death compared to proton radiation (PR) in mice in vivo[J].Cancer Biol Ther,2008,7(12):2023-2033.DOI:10.4161/cbt.7.12.7417. [30] Gerelchuluun A,Hong Z,Sun L,et al. Induction of in situ DNA double-strand breaks and apoptosis by 200 MeV protons and 10 MV X-rays in human tumour cell lines[J].Int J Radiat Biol,2011,87(1):57-70.DOI:10.3109/09553002.2010.518201. [31] Pietro CD,Piro S,Tabbi G,et al. Cellular and molecular effects of protons:apoptosis induction and potential implications for cancer therapy[J].Apoptosis,2006,11(1):57-66.DOI:10.1007/s10495-005-3346-1. [32] Narang H,Bhat N,Gupta SK,et al. Differential activation of mitogen-activated protein kinases following high and low LET radiation in murine macrophage cell line[J].Mol Cell Biochem,2009,324(1-2):85-91.DOI:10.1007/s11010-008-9987-y. [33] Lee KB,Lee JS,Park JW,et al. Low energy proton beam induces tumor cell apoptosis through reactive oxygen species and activation of caspases[J].Exp Mol Med,2008,40(1):118-129.DOI:10.3858/emm.2008.40.1.118. [34] Narang H,Kumar A,Bhat N,et al. Effect of proton and gamma irradiation on human lung carcinoma cells:gene expression,cell cycle,cell death,epithelial-mesenchymal transition and cancer-stem cell trait as biological end points[J].Mutat Res,2015,780:35-46.DOI:10.1016/j.mrfmmm.2015.07.006. [35] Moeller BJ,Cao Y,Li CY,et al. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors:role of reoxygenation,free radicals,and stress granules[J].Cancer Cell,2004,5(5):429-441.DOI:10.1016/S1535-6108(04)00115-1. [36] Ogata T,Teshima T,Kagawa K,et al. Particle irradiation suppresses metastatic potential of cancer cells[J].Cancer Res,2005,65(1):113-120. [37] Girdhani S,Lamont C,Hahnfeldt P,et al. Proton irradiation suppresses angiogenic genes and impairs cell invasion and tumor growth[J].Radiat Res,2012,178(1):33-45.DOI:10.1667/RR2724.1. [38] Sofia VI,Martins LR,Imaizumi N,et al. Low doses of ionizing radiation promote tumor growth and metastasis by enhancing angiogenesis[J/OL].PLoS One,2010,5(6):e11222.DOI:10.1371/journal.pone.0011222. [39] Chang PY,Bjornstad KA,Rosen CJ,et al. Particle radiation alters expression of matrix metalloproteases resulting in ECM remodeling in human lens cells[J].Radiat Environ Biophys,2007,46(2):187-194.DOI:10.1007/s00411-006-0087-7. [40] Wang M,Hada M,Saha J,et al. Protons sensitize epithelial cells to mesenchymal transition[J/OL].PLoS One,2012,7(7):e41249.DOI:10.1371/journal.pone.0041249. [41] Stick LB,Yu J,Maraldo MV,et al. Joint estimation of cardiac toxicity and recurrence risks after comprehensive nodal photon versus proton therapy for breast cancer[J].Int J Radiat Oncol Biol Phys,2017,97(4):754-761.DOI:10.1016/j.ijrobp.2016.12.008. [42] Caujolle JP,Paoli V,Chamorey E,et al. Local recurrence after uveal melanoma proton beam therapy:recurrence types and prognostic consequences[J].Int J Radiat Oncol Biol Phys,2013,85(5):1218-1224.DOI:10.1016/j.ijrobp.2012.10.005. [43] Shah DJ,Sachs RK,Wilson DJ.Radiation-induced cancer:a modern view[J].Br J Radiol,2012,85(1020):1166-73.DOI:10.1259/bjr/25026140. [44] Chung CS,Yock TI,Nelson K,et al. Incidence of second malignancies among patients treated with proton versus photon radiation[J].Int J Radiat Oncol Biol Phys,2013,87(1):46-52.DOI:10.1016/j.ijrobp.2013.04.030. [45] Stokkevag CH,Engeseth GM,Ytre-Hauge KS,et al. Estimated risk of radiation-induced cancer following paediatric cranio-spinal irradiation with electron,photon and proton therapy[J].Acta Oncol,2014,53(8):1048-1057.DOI:10.3109/0284186X.2014.928420. [46] Wilson RR.Radiological use of fast protons[J].Radiology,1946,47(5):487-491.DOI:10.1148/47.5.487. [47] Lawrence JH,Tobias CA,Born JL,et al. Pituitary irradiation with high-energy proton beams:a preliminary report[J].Cancer Res,1958,18(2):121-134. [48] Particle therapy patient statistics (per end of 2015)[2017-08-10].https://ptcogch/archive/patient_statistics/Patientstatistics-updateDec2015pdf. [49] Seibel I,Cordini D,Rehak M,et al. Local recurrence after primary proton beam therapy in uveal melanoma:risk factors,retreatment approaches,and outcome[J].Am J Ophthalmol,2015,160(4):628-636.DOI:10.1016/j.ajo.2015.06.017. [50] Greenfield BJ,Jaramillo S,Abboud M,et al. Outcomes for pediatric patients with central nervous system germ cell tumors treated with proton therapy[J].Clin Transl Radiat Oncol,2016(1):9-14.DOI:10.1016/j.ctro.2016.08.002. [51] Delaney TF,Liebsch NJ,Pedlow FX,et al. Long-term results of Phase Ⅱ study of high dose photon/proton radiotherapy in the management of spine chordomas,chondrosarcomas,and other sarcomas[J].J Surg Oncol,2014,110(2):115-122.DOI:10.1002/jso.23617. [52] Chang JY,Zhang W,Komaki R,et al. Long-term outcome of phase Ⅰ/Ⅱ prospective study of dose-escalated proton therapy for early-stage non-small cell lung cancer[J].Radiother Oncol,2017,122(2):274-280.DOI:10.1016/j.radonc.2016.10.022. [53] Lee SU,Park JW,Kim TH,et al. Effectiveness and safety of proton beam therapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis[J].Strahlenther Onkol,2014,190(9):806-814.DOI:10.1007/s00066-014-0604-6. [54] Amini A,Raben D,Crawford ED,et al. Patient characterization and usage trends of proton beam therapy for localized prostate cancer in the United States:a study of the national cancer database[J].Urol Oncol,2017,35(6):438-446.DOI:10.1016/j.urolonc.2017.01.013. [55] Bensoussan E,Thariat J,Maschi C,et al. Outcomes after proton beam therapy for large choroidal melanomas in 492 patients[J].Am J Ophthalmol,2016,165:78-87.DOI:10.1016/j.ajo.2016.02.027. [56] Vogel J,Berman AT,Lin L,et al. Prospective study of proton beam radiation therapy for adjuvant and definitive treatment of thymoma and thymic carcinoma:Early response and toxicity assessment[J].Radiother Oncol,2016,118(3):504-509.DOI:10.1016/j.radonc.2016.02.003. [57] Zenda S,Akimoto T,Mizumoto M,et al. Phase Ⅱ study of proton beam therapy as a nonsurgical approach for mucosal melanoma of the nasal cavity or para-nasal sinuses[J].Radiother Oncol,2016,118(2):267-271.DOI:10.1016/j.radonc.2015.10.025. [58] Scaringi C,Minniti G,Bozzao A,et al. Radiation-induced malignant meningioma following proton beam therapy for a choroidal melanoma[J].J Clin Neurosci,2015,22(6):1036-1037.DOI:10.1016/j.jocn.2014.12.021.
2018, Vol. 27 
