Radiotherapy-associated Sensorineural Hearing Loss in Pediatric
Oncology Patients

Muhammad   Ammar   Aslam; Hassaan      Ahmad; Hamza   Sultan   Malik; Herlina      Uinarni; Yasir   Salam   Karim; Yusuf   Makhmudovich   Akhmedov; Walid   Kamal   Abdelbasset; Sura   A.   Awadh; Mohammed   Kadhem   Abid; Yasser   Fakri   Mustafa; Bagher      Farhood; Amirhosein      Sahebkar
Abstract

During the radiotherapeutic treatment of pediatric oncology patients, they would be at a latent risk of developing ionizing radiation-induced ototoxicity when the cochlea or auditory nerve is located within the radiation field. Sensorineural hearing loss (SNHL) is an irreversible late complication of radiotherapy, and its incidence depends on various factors such as the patient’s hearing sensitivity, total radiation dose to the cochlea, radiotherapy fractionation regimen, age and chemoradiation. Importantly, this complication exhibits serious challenges to adult survivors of childhood cancer, as it has been linked to impairments in academic achievement, psychosocial development, independent living skills, and employment in the survivor population. Therefore, early detection and proper management can alleviate academic, speech, language, social, and psychological morbidity arising from hearing deficits. In the present review, we have addressed issues such as underlying mechanisms of radiation-induced SNHL, audiometric findings of pediatric cancer patients treated with radiotherapy, and management and protection measures against radiation-induced ototoxicity.
Keywords: Pediatric cancer, radiotherapy, sensorineural hearing loss, ototoxicity, chemoradiation, childhood cancer.
[1]
Mortezaee, K.; Narmani, A.; Salehi, M.; Bagheri, H.; Farhood, B.; Haghi-Aminjan, H.; Najafi, M. Synergic effects of nanoparticles-mediated hyperthermia in radiotherapy/chemotherapy of cancer. Life Sci.,  2021, 269, 119020.
 [http://dx.doi.org/10.1016/j.lfs.2021.119020] [PMID: 33450258]

[2]
Abdi Goushbolagh, N.; Farhood, B.; Astani, A.; Nikfarjam, A.; Kalantari, M.; Zare, M.H. Quantitative cytotoxicity, cellular uptake and radioprotection effect of cerium oxide nanoparticles in MRC-5 normal cells and MCF-7 cancerous cells. Bionanoscience,  2018, 8(3), 769-777.
 [http://dx.doi.org/10.1007/s12668-018-0538-z]

[3]
Abdi Goushbolagh, N.; Keshavarz, M.; Zare, M.H.; Bahreyni-Toosi, M.H.; Kargar, M.; Farhood, B. Photosensitizer effects of MWCNTs-COOH particles on CT26 fibroblastic cells exposed to laser irradiation. Artif. Cells Nanomed. Biotechnol.,  2019, 47(1), 1326-1334.
 [http://dx.doi.org/10.1080/21691401.2019.1593997] [PMID: 30964347]

[4]
Ford, E.C.; Terezakis, S. How safe is safe? Risk in radiotherapy. Int. J. Radiat. Oncol. Biol. Phys.,  2010, 78(2), 321-322.
 [http://dx.doi.org/10.1016/j.ijrobp.2010.04.047] [PMID: 20832662]

[5]
Baskar, R.; Lee, K.A.; Yeo, R.; Yeoh, K.W. Cancer and radiation therapy: Current advances and future directions. Int. J. Med. Sci.,  2012, 9(3), 193-199.
 [http://dx.doi.org/10.7150/ijms.3635] [PMID: 22408567]

[6]
Mortezaee, K.; Parwaie, W.; Motevaseli, E.; Mirtavoos-Mahyari, H.; Musa, A.E.; Shabeeb, D.; Esmaely, F.; Najafi, M.; Farhood, B. Targets for improving tumor response to radiotherapy. Int. Immunopharmacol.,  2019, 76, 105847.
 [http://dx.doi.org/10.1016/j.intimp.2019.105847] [PMID: 31466051]

[7]
Farhood, B; Geraily, G; Abtahi, SMM A systematic review of clinical applications of polymer gel dosimeters in radiotherapy. Appl Radiat Isot.,  2019, 143, 47-59.
 [http://dx.doi.org/10.1016/j.apradiso.2018.08.018]

[8]
Farhood, B.; Mortezaee, K.; Haghi-Aminjan, H.; Khanlarkhani, N.; Salehi, E.; Nashtaei, M.S.; Najafi, M.; Sahebkar, A. A systematic review of radiation-induced testicular toxicities following radiotherapy for prostate cancer. J. Cell. Physiol.,  2019, 234(9), 14828-14837.
 [http://dx.doi.org/10.1002/jcp.28283] [PMID: 30740683]

[9]
Bagheri, H.; Rabie Mahdavi, S.; Shekarchi, B.; Manouchehri, F.; Farhood, B. Measurement of the contralateral breast photon and thermal neutron doses in breast cancer radiotherapy: A comparison between physical and dynamic wedges. Radiat. Prot. Dosimetry,  2018, 178(1), 73-81.
 [http://dx.doi.org/10.1093/rpd/ncx076] [PMID: 28591863]

[10]
Mauch, P.; Constine, L.; Greenberger, J.; Knospe, W.; Sullivan, J.; Liesveld, J.L.; Deeg, H.J. Hematopoietic stem cell compartment: Acute and late effects of radiation therapy and chemotherapy. Int. J. Radiat. Oncol. Biol. Phys.,  1995, 31(5), 1319-1339.
 [http://dx.doi.org/10.1016/0360-3016(94)00430-S] [PMID: 7713791]

[11]
Motallebzadeh, E.; Tameh, A.A.; Zavareh, S.A.T.; Farhood, B.; Aliasgharzedeh, A.; Mohseni, M. Neuroprotective effect of melatonin on radiation-induced oxidative stress and apoptosis in the brainstem of rats. J. Cell. Physiol.,  2020, 235(11), 8791-8798.
 [http://dx.doi.org/10.1002/jcp.29722] [PMID: 32324264]

[12]
Straub, J.M.; New, J.; Hamilton, C.D.; Lominska, C.; Shnayder, Y.; Thomas, S.M. Radiation-induced fibrosis: Mechanisms and implications for therapy. J. Cancer Res. Clin. Oncol.,  2015, 141(11), 1985-1994.
 [http://dx.doi.org/10.1007/s00432-015-1974-6] [PMID: 25910988]

[13]
Pan, C.C.; Eisbruch, A.; Lee, J.S.; Snorrason, R.M.; Ten Haken, R.K.; Kileny, P.R. Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients. Int. J. Radiat. Oncol. Biol. Phys.,  2005, 61(5), 1393-1402.
 [http://dx.doi.org/10.1016/j.ijrobp.2004.08.019] [PMID: 15817342]

[14]
Hua, C.; Bass, J.K.; Khan, R.; Kun, L.E.; Merchant, T.E. Hearing loss after radiotherapy for pediatric brain tumors: effect of cochlear dose. Int. J. Radiat. Oncol. Biol. Phys.,  2008, 72(3), 892-899.
 [http://dx.doi.org/10.1016/j.ijrobp.2008.01.050] [PMID: 18395355]

[15]
Mujica-Mota, M.; Waissbluth, S.; Daniel, S.J. Characteristics of radiation-induced sensorineural hearing loss in head and neck cancer: A systematic review. Head Neck,  2013, 35(11), 1662-1668.
 [http://dx.doi.org/10.1002/hed.23201] [PMID: 23280686]

[16]
Bohne, B.A.; Marks, J.; Glasgow, G.P. Delayed effects of ionizing radiation on the ear. Laryngoscope,  1985, 95(7), 818-828.
 [http://dx.doi.org/10.1288/00005537-198507000-00014] [PMID: 4010422]

[17]
Gurney, J.G.; Tersak, J.M.; Ness, K.K.; Landier, W.; Matthay, K.K.; Schmidt, M.L. Hearing loss, quality of life, and academic problems in long-term neuroblastoma survivors: A report from the Children’s Oncology Group. Pediatrics,  2007, 120(5), e1229-e1236.
 [http://dx.doi.org/10.1542/peds.2007-0178] [PMID: 17974716]

[18]
Brinkman, T.M.; Bass, J.K.; Li, Z.; Ness, K.K.; Gajjar, A.; Pappo, A.S.; Armstrong, G.T.; Merchant, T.E.; Srivastava, D.K.; Robison, L.L.; Hudson, M.M.; Gurney, J.G. Treatment-induced hearing loss and adult social outcomes in survivors of childhood CNS and non-CNS solid tumors: Results from the St. Jude Lifetime Cohort Study. Cancer,  2015, 121(22), 4053-4061.
 [http://dx.doi.org/10.1002/cncr.29604] [PMID: 26287566]

[19]
Contrera, K.J.; Sung, Y.K.; Betz, J.; Li, L.; Lin, F.R. Change in loneliness after intervention with cochlear implants or hearing aids. Laryngoscope,  2017, 127(8), 1885-1889.
 [http://dx.doi.org/10.1002/lary.26424] [PMID: 28059448]

[20]
Stelmachowicz, P.G.; Pittman, A.L.; Hoover, B.M.; Lewis, D.E.; Moeller, M.P. The importance of high-frequency audibility in the speech and language development of children with hearing loss. Arch. Otolaryngol. Head Neck Surg.,  2004, 130(5), 556-562.
 [http://dx.doi.org/10.1001/archotol.130.5.556] [PMID: 15148176]

[21]
Bass, J.K.; Hua, C.H.; Huang, J.; Onar-Thomas, A.; Ness, K.K.; Jones, S.; White, S.; Bhagat, S.P.; Chang, K.W.; Merchant, T.E. Hearing loss in patients who received cranial radiation therapy for childhood cancer. J. Clin. Oncol.,  2016, 34(11), 1248-1255.
 [http://dx.doi.org/10.1200/JCO.2015.63.6738] [PMID: 26811531]

[22]
Pollom, EL; Deng, L; Pai, RK; Brown, JM; Giaccia, A; Loo, BW, Jr Gastrointestinal toxicities with combined antiangiogenic and stereotactic body radiation therapy. Int. J. Radiat. Oncol. Biol. Phys.,  2015, 92(3), 568-576.
 [http://dx.doi.org/10.1016/j.ijrobp.2015.02.016]

[23]
Farhood, B.; Aliasgharzadeh, A.; Amini, P.; Saffar, H.; Motevaseli, E.; Rezapoor, S.; Nouruzi, F.; Shabeeb, D.; Eleojo Musa, A.; Ashabi, G.; Mohseni, M.; Moradi, H.; Najafi, M. Radiation-induced dual oxidase upregulation in rat heart tissues: Protective effect of melatonin. Medicina,  2019, 55(7), 317.
 [http://dx.doi.org/10.3390/medicina55070317] [PMID: 31252673]

[24]
Yahyapour, R.; Amini, P.; Saffar, H.; Rezapoor, S.; Motevaseli, E.; Cheki, M.; Farhood, B.; Nouruzi, F.; Shabeeb, D.; Eleojo Musa, A.; Najafi, M. Metformin Protects against radiation-induced heart injury and attenuates the upregulation of dual oxidase genes following rat’s chest irradiation. Int. J. Mol. Cell. Med.,  2018, 7(3), 193-202.
 [PMID: 31565651]

[25]
Aliasgharzadeh, A.; Farhood, B.; Amini, P.; Saffar, H.; Motevaseli, E.; Rezapoor, S.; Nouruzi, F.; Shabeeb, D.H.; Eleojo Musa, A.; Mohseni, M.; Moradi, H.; Najafi, M. Melatonin attenuates upregulation of Duox1 and Duox2 and protects against lung injury following chest irradiation in rats. Cell J.,  2019, 21(3), 236-242.
 [PMID: 31210428]

[26]
Sheikhzadeh, P.D.; Khezerloo, D.; Mortezazadeh, T.; Farhood, B.; Seyfizadeh, N.; Pezhman, L. The effect of date palm seed extract as a new potential radioprotector in gamma-irradiated mice. J. Cancer Res. Ther.,  2019, 15(3), 517-521.
 [http://dx.doi.org/10.4103/jcrt.JCRT_1341_16] [PMID: 31169213]

[27]
Farhood, B.; Aliasgharzadeh, A.; Amini, P.; Rezaeyan, A.; Tavassoli, A.; Motevaseli, E.; Shabeeb, D.; Eleojo Musa, A.; Najafi, M. Mitigation of radiation-induced lung pneumonitis and fibrosis using metformin and melatonin: A histopathological study. Medicina,  2019, 55(8), 417.
 [http://dx.doi.org/10.3390/medicina55080417] [PMID: 31366142]

[28]
Amini, P.; Nodooshan, S.J.; Ashrafizadeh, M.; Eftekhari, S.M.; Aryafar, T.; Khalafi, L.; Musa, A.E.; Mahdavi, S.R.; Najafi, M.; Farhood, B. Resveratrol induces apoptosis and attenuates proliferation of MCF-7 cells in combination with radiation and hyperthermia. Curr. Mol. Med.,  2021, 21(2), 142-150.
 [http://dx.doi.org/10.2174/18755666MTA2pODE0z] [PMID: 32436827]

[29]
Farhood, B.; Hassanzadeh, G.; Amini, P.; Shabeeb, D.; Musa, A.E.; Khodamoradi, E.; Mohseni, M.; Aliasgharzadeh, A.; Moradi, H.; Najafi, M. Mitigation of radiation-induced gastrointestinal system injury using resveratrol or alpha-lipoic acid: A pilot histopathological study. Antiinflamm. Antiallergy Agents Med. Chem.,  2020, 19(4), 413-424.
 [http://dx.doi.org/10.2174/1871523018666191111124028] [PMID: 31713500]

[30]
Nodooshan, S.J.; Amini, P.; Ashrafizadeh, M.; Tavakoli, S.; Aryafar, T.; Khalafi, L.; Musa, A.E.; Mahdavi, S.R.; Najafi, M.; Ahmadi, A.; Farhood, B. Suberosin attenuates the proliferation of MCF-7 breast cancer cells in combination with radiotherapy or hyperthermia. Curr. Drug Res. Rev.,  2021, 13(2), 148-153.
 [http://dx.doi.org/10.2174/2589977512666201228104528] [PMID: 33371865]

[31]
Jamesdaniel, S. Oxidative Stress and Hearing Loss. In: Inflammatory Mechanisms in Mediating Hearing Loss; Springer, 2018; pp. 15-30.
 [http://dx.doi.org/10.1007/978-3-319-92507-3_2]

[32]
Hu, L.F.; Lan, H.R.; Li, X.M.; Jin, K.T. A systematic review of the potential chemoprotective effects of resveratrol on doxorubicin-induced cardiotoxicity: Focus on the antioxidant, antiapoptotic, and anti-inflammatory activities. Oxid. Med. Cell. Longev.,  2021, 2021, 1-19.
 [http://dx.doi.org/10.1155/2021/2951697] [PMID: 34471463]

[33]
Xavier, J; Farias, CP; Soares, MSP Ayahuasca prevents oxidative stress in a rat model of depression elicited by unpredictable chronic mild stress. Arch. Clin. Psychiatry,  2021, 48, 90-98.

[34]
Barjaktarovic, Z.; Schmaltz, D.; Shyla, A.; Azimzadeh, O.; Schulz, S.; Haagen, J.; Dörr, W.; Sarioglu, H.; Schäfer, A.; Atkinson, M.J.; Zischka, H.; Tapio, S. Radiation-induced signaling results in mitochondrial impairment in mouse heart at 4 weeks after exposure to X-rays. PLoS One,  2011, 6(12), e27811.
 [http://dx.doi.org/10.1371/journal.pone.0027811] [PMID: 22174747]

[35]
Kim, G.J.; Fiskum, G.M.; Morgan, W.F. A role for mitochondrial dysfunction in perpetuating radiation-induced genomic instability. Cancer Res.,  2006, 66(21), 10377-10383.
 [http://dx.doi.org/10.1158/0008-5472.CAN-05-3036] [PMID: 17079457]

[36]
Vaiserman, A.M.; Lushchak, O.V.; Koliada, A.K. Anti-aging pharmacology: Promises and pitfalls. Ageing Res. Rev.,  2016, 31, 9-35.
 [http://dx.doi.org/10.1016/j.arr.2016.08.004] [PMID: 27524412]

[37]
Sharma, R.; Vallis, K. Basics of Radiation Therapy. , 2008. 

[38]
Pyun, J.H.; Kang, S.U.; Hwang, H.S.; Oh, Y.T.; Kang, S.H.; Lim, Y.A.; Choo, O.S.; Kim, C.H. Epicatechin inhibits radiation-induced auditory cell death by suppression of reactive oxygen species generation. Neuroscience,  2011, 199, 410-420.
 [http://dx.doi.org/10.1016/j.neuroscience.2011.09.012] [PMID: 21946009]

[39]
Low, WK; Tan, MG; Sun, L; Chua, AW; Goh, LK; Wang, DY Dose-dependant radiation-induced apoptosis in a cochlear cell-line.  Apoptosis.,  2006, 11(12), 2127-2136.
 [http://dx.doi.org/10.1007/s10495-006-0285-4]

[40]
Yahyapour, R; Motevaseli, E; Rezaeyan, A; Abdollahi, H; Farhood, B; Cheki, M Reduction-oxidation (redox) system in radiation-induced normal tissue injury: Molecular mechanisms and implications in radiation therapeutics. Clin Transl Oncol,  2018, 20(8), 975-988.

[41]
Said, R.S.; Mohamed, H.A.; Kassem, D.H. Alpha-lipoic acid effectively attenuates ionizing radiation-mediated testicular dysfunction in rats: Crosstalk of NF-ĸB, TGF-β, and PPAR-ϒ pathways. Toxicology,  2020, 442, 152536.
 [http://dx.doi.org/10.1016/j.tox.2020.152536] [PMID: 32649955]

[42]
El-Dein, E.; Anees, L.M.; Aly, S.M.E. Effects of α-lipoic acid on γ-radiation and lindane-induced heart toxicity in rats. Pak. J. Zool.,  2016, 48(5)

[43]
Sheikholeslami, S.; Khodaverdian, S.; Dorri-Giv, M.; Mohammad Hosseini, S.; Souri, S.; Abedi-Firouzjah, R.; Zamani, H.; Dastranj, L.; Farhood, B. The radioprotective effects of alpha-lipoic acid on radiotherapy-induced toxicities: A systematic review. Int. Immunopharmacol.,  2021, 96, 107741.
 [http://dx.doi.org/10.1016/j.intimp.2021.107741] [PMID: 33989970]

[44]
Sha, S.H.; Taylor, R.; Forge, A.; Schacht, J. Differential vulnerability of basal and apical hair cells is based on intrinsic susceptibility to free radicals. Hear. Res.,  2001, 155(1-2), 1-8.
 [http://dx.doi.org/10.1016/S0378-5955(01)00224-6] [PMID: 11335071]

[45]
Winther, F.Ø. X-ray irradiation of the inner ear of the guinea pig. An electron microscopic study of the degenerating outer hair cells of the organ of Corti. Acta Otolaryngol.,  1970, 69(1-6), 61-76.
 [http://dx.doi.org/10.3109/00016487009123336] [PMID: 5446609]

[46]
Choi, K.M.; Kang, C.M.; Cho, E.; Kang, S.; Lee, S.; Um, H.D. Ionizing radiation-induced micronucleus formation is mediated by reactive oxygen species that are produced in a manner dependent on mitochondria, Nox1, and JNK. Oncol. Rep.,  2007, 17(5), 1183-1188.
 [http://dx.doi.org/10.3892/or.17.5.1183] [PMID: 17390063]

[47]
Yamamori, T.; Yasui, H.; Yamazumi, M.; Wada, Y.; Nakamura, Y.; Nakamura, H.; Inanami, O. Ionizing radiation induces mitochondrial reactive oxygen species production accompanied by upregulation of mitochondrial electron transport chain function and mitochondrial content under control of the cell cycle checkpoint. Free Radic. Biol. Med.,  2012, 53(2), 260-270.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2012.04.033] [PMID: 22580337]

[48]
Hajnóczky, G.; Csordás, G.; Das, S.; Garcia-Perez, C.; Saotome, M.; Sinha Roy, S.; Yi, M. Mitochondrial calcium signalling and cell death: Approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosis. Cell Calcium,  2006, 40(5-6), 553-560.
 [http://dx.doi.org/10.1016/j.ceca.2006.08.016] [PMID: 17074387]

[49]
Murphy, M.P. Mitochondrial dysfunction indirectly elevates ROS production by the endoplasmic reticulum. Cell Metab.,  2013, 18(2), 145-146.
 [http://dx.doi.org/10.1016/j.cmet.2013.07.006] [PMID: 23931748]

[50]
Lee, I.T.; Yang, C.M. Role of NADPH oxidase/ROS in pro-inflammatory mediators-induced airway and pulmonary diseases. Biochem. Pharmacol.,  2012, 84(5), 581-590.
 [http://dx.doi.org/10.1016/j.bcp.2012.05.005] [PMID: 22587816]

[51]
Ushio-Fukai, M. Compartmentalization of redox signaling through NADPH oxidase-derived ROS. Antioxid. Redox Signal.,  2009, 11(6), 1289-1299.
 [http://dx.doi.org/10.1089/ars.2008.2333] [PMID: 18999986]

[52]
Mortezaee, K.; Goradel, N.H.; Amini, P.; Shabeeb, D.; Musa, A.E.; Najafi, M.; Farhood, B. NADPH oxidase as a target for modulation of radiation response; implications to carcinogenesis and radiotherapy. Curr. Mol. Pharmacol.,  2019, 12(1), 50-60.
 [http://dx.doi.org/10.2174/1874467211666181010154709] [PMID: 30318012]

[53]
Azmoonfar, R.; Amini, P.; Saffar, H.; Rezapoor, S.; Motevaseli, E.; Cheki, M.; Yahyapour, R.; farhood, B.; Nouruzi, F.; Khodamoradi, E.; Shabeeb, D.; Eleojo Musa, A.; Najafi, M. Metformin protects against radiation-induced pneumonitis and fibrosis and attenuates upregulation of dual oxidase genes expression. Adv. Pharm. Bull.,  2018, 8(4), 697-704.
 [http://dx.doi.org/10.15171/apb.2018.078] [PMID: 30607342]

[54]
Bánfi, B.; Malgrange, B.; Knisz, J.; Steger, K.; Dubois-Dauphin, M.; Krause, K.H. NOX3, a superoxide-generating NADPH oxidase of the inner ear. J. Biol. Chem.,  2004, 279(44), 46065-46072.
 [http://dx.doi.org/10.1074/jbc.M403046200] [PMID: 15326186]

[55]
Juarez, J.C.; Manuia, M.; Burnett, M.E.; Betancourt, O.; Boivin, B.; Shaw, D.E.; Tonks, N.K.; Mazar, A.P.; Doñate, F. Superoxide dismutase 1 (SOD1) is essential for H2O2 -mediated oxidation and inactivation of phosphatases in growth factor signaling. Proc. Natl. Acad. Sci.,  2008, 105(20), 7147-7152.
 [http://dx.doi.org/10.1073/pnas.0709451105] [PMID: 18480265]

[56]
Najafi, M.; Hooshangi Shayesteh, M.R.; Mortezaee, K.; Farhood, B.; Haghi-Aminjan, H. The role of melatonin on doxorubicin-induced cardiotoxicity: A systematic review. Life Sci.,  2020, 241, 117173.
 [http://dx.doi.org/10.1016/j.lfs.2019.117173] [PMID: 31843530]

[57]
Najafi, M.; Mortezaee, K.; Rahimifard, M.; Farhood, B.; Haghi-Aminjan, H. The role of curcumin/curcuminoids during gastric cancer chemotherapy: A systematic review of non-clinical study. Life Sci.,  2020, 257, 118051.
 [http://dx.doi.org/10.1016/j.lfs.2020.118051] [PMID: 32634426]

[58]
Gondo, H.K. The effect of spirulina on apoptosis through the caspase-3 pathway in a Preeclamptic Wistar rat model. J. Nat. Sci. Biol. Med.,  2021, 12(3), 280-284.

[59]
Mortezaee, K.; Najafi, M.; Farhood, B.; Ahmadi, A.; Potes, Y.; Shabeeb, D.; Musa, A.E. Modulation of apoptosis by melatonin for improving cancer treatment efficiency: An updated review. Life Sci.,  2019, 228, 228-241.
 [http://dx.doi.org/10.1016/j.lfs.2019.05.009] [PMID: 31077716]

[60]
Tan, P.X.; Du, S.S.; Ren, C.; Yao, Q.W.; Yuan, Y.W. Radiation-induced Cochlea hair cell death: mechanisms and protection. APJCP,  2013, 14(10), 5631-5635.
 [PMID: 24289554]

[61]
Chao, C.; Saito, S.; Anderson, C.W.; Appella, E.; Xu, Y. Phosphorylation of murine p53 at Ser-18 regulates the p53 responses to DNA damage. Proc. Natl. Acad. Sci.,  2000, 97(22), 11936-11941.
 [http://dx.doi.org/10.1073/pnas.220252297] [PMID: 11035798]

[62]
Hu, B.H.; Henderson, D.; Nicotera, T.M. Extremely rapid induction of outer hair cell apoptosis in the chinchilla cochlea following exposure to impulse noise. Hear. Res.,  2006, 211(1-2), 16-25.
 [http://dx.doi.org/10.1016/j.heares.2005.08.006] [PMID: 16219436]

[63]
Cheng, A.G.; Cunningham, L.L.; Rubel, E.W. Mechanisms of hair cell death and protection. Curr. Opin. Otolaryngol. Head Neck Surg.,  2005, 13(6), 343-348.
 [http://dx.doi.org/10.1097/01.moo.0000186799.45377.63] [PMID: 16282762]

[64]
Marchenko, N.D.; Zaika, A.; Moll, U.M. Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling. J. Biol. Chem.,  2000, 275(21), 16202-16212.
 [http://dx.doi.org/10.1074/jbc.275.21.16202] [PMID: 10821866]

[65]
Devarajan, P.; Savoca, M.; Castaneda, M.P.; Park, M.S.; Esteban-Cruciani, N.; Kalinec, G.; Kalinec, F. Cisplatin-induced apoptosis in auditory cells: role of death receptor and mitochondrial pathways. Hear. Res.,  2002, 174(1-2), 45-54.
 [http://dx.doi.org/10.1016/S0378-5955(02)00634-2] [PMID: 12433395]

[66]
Tabuchi, K.; Nishimura, B.; Nakamagoe, M.; Hayashi, K.; Nakayama, M.; Hara, A. Ototoxicity: Mechanisms of cochlear impairment and its prevention. Curr. Med. Chem.,  2011, 18(31), 4866-4871.
 [http://dx.doi.org/10.2174/092986711797535254] [PMID: 21919841]

[67]
Khan, S.; Adhikari, J.S.; Rizvi, M.A.; Chaudhury, N.K. Radioprotective potential of melatonin against 60Co γ-ray-induced testicular injury in male C57BL/6 mice. J. Biomed. Sci.,  2015, 22(1), 61.
 [http://dx.doi.org/10.1186/s12929-015-0156-9] [PMID: 26205951]

[68]
Herceg, Z.; Wang, Z.Q. Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat. Res.,  2001, 477(1-2), 97-110.
 [http://dx.doi.org/10.1016/S0027-5107(01)00111-7] [PMID: 11376691]

[69]
Haimovitz-Friedman, A.; Kolesnick, R.N.; Fuks, Z. Ceramide signaling in apoptosis. Br. Med. Bull.,  1997, 53(3), 539-553.
 [http://dx.doi.org/10.1093/oxfordjournals.bmb.a011629] [PMID: 9374036]

[70]
Peña, L.A.; Fuks, Z.; Koksnick, R. Stress-induced apoptosis and the sphingomyelin pathway. Biochem. Pharmacol.,  1997, 53(5), 615-621.
 [http://dx.doi.org/10.1016/S0006-2952(96)00834-9] [PMID: 9113079]

[71]
Yabu, T.; Shiba, H.; Shibasaki, Y.; Nakanishi, T.; Imamura, S.; Touhata, K.; Yamashita, M. Stress-induced ceramide generation and apoptosis via the phosphorylation and activation of nSMase1 by JNK signaling. Cell Death Differ.,  2015, 22(2), 258-273.
 [http://dx.doi.org/10.1038/cdd.2014.128] [PMID: 25168245]

[72]
Hadi, L.A.; Di Vito, C.; Marfia, G.; Navone, S.E.; Campanella, R.; Riboni, L. The role and function of sphingolipids in glioblastoma multiforme. Bioactive Sphingolipids in Cancer Biology and Therapy; Springer, 2015, pp. 259-293.
 [http://dx.doi.org/10.1007/978-3-319-20750-6_12]

[73]
Ueda, N. Ceramide-induced apoptosis in renal tubular cells: a role of mitochondria and sphingosine-1-phoshate. Int. J. Mol. Sci.,  2015, 16(12), 5076-5124.
 [http://dx.doi.org/10.3390/ijms16035076] [PMID: 25751724]

[74]
Lin, X.; Fuks, Z.; Kolesnick, R. Ceramide mediates radiation-induced death of endothelium. Crit. Care Med.,  2000, 28(S4), N87-N93.
 [http://dx.doi.org/10.1097/00003246-200004001-00010] [PMID: 10807320]

[75]
Kolesnick, R.; Fuks, Z. Radiation and ceramide-induced apoptosis. Oncogene,  2003, 22(37), 5897-5906.
 [http://dx.doi.org/10.1038/sj.onc.1206702] [PMID: 12947396]

[76]
Mujica-Mota, M.A.; Lehnert, S.; Devic, S.; Gasbarrino, K.; Daniel, S.J. Mechanisms of radiation-induced sensorineural hearing loss and radioprotection. Hear. Res.,  2014, 312, 60-68.
 [http://dx.doi.org/10.1016/j.heares.2014.03.003] [PMID: 24650954]

[77]
Schwartz, I.; Kim, C-S.; Shin, S-O. Ultrastructural changes in the cochlea of the guinea pig after fast neutron irradiation. Otolaryngol. Head Neck Surg.,  1994, 110(4), 419-427.
 [http://dx.doi.org/10.1177/019459989411000412] [PMID: 8170687]

[78]
Shi, W.; Hou, X.; Bao, X.; Hou, W.; Jiang, X.; Ma, L.; Jiang, X.; Dong, L. Mechanism and protection of radiotherapy induced sensorineural hearing loss for head and neck cancer. BioMed Res. Int.,  2021, 2021, 1-10.
 [http://dx.doi.org/10.1155/2021/3548706] [PMID: 34970625]

[79]
Burotto, M.; Chiou, V.L.; Lee, J.M.; Kohn, E.C. The MAPK pathway across different malignancies: A new perspective. Cancer,  2014, 120(22), 3446-3456.
 [http://dx.doi.org/10.1002/cncr.28864] [PMID: 24948110]

[80]
Johnson, G.L.; Stuhlmiller, T.J.; Angus, S.P.; Zawistowski, J.S.; Graves, L.M. Molecular pathways: adaptive kinome reprogramming in response to targeted inhibition of the BRAF-MEK-ERK pathway in cancer. Clin. Cancer Res.,  2014, 20(10), 2516-2522.
 [http://dx.doi.org/10.1158/1078-0432.CCR-13-1081] [PMID: 24664307]

[81]
Brown, L.; Benchimol, S. The involvement of MAPK signaling pathways in determining the cellular response to p53 activation: Cell cycle arrest or apoptosis. J. Biol. Chem.,  2006, 281(7), 3832-3840.
 [http://dx.doi.org/10.1074/jbc.M507951200] [PMID: 16330547]

[82]
Murai, N.; Kirkegaard, M.; Järlebark, L.; Risling, M.; Suneson, A.; Ulfendahl, M. Activation of JNK in the inner ear following impulse noise exposure. J. Neurotrauma,  2008, 25(1), 72-77.
 [http://dx.doi.org/10.1089/neu.2007.0346] [PMID: 18355160]

[83]
Sabapathy, K. Role of the JNK pathway in human diseases. Prog. Mol. Biol. Transl. Sci.,  2012, 106, 145-169.
 [http://dx.doi.org/10.1016/B978-0-12-396456-4.00013-4] [PMID: 22340717]

[84]
Wang, J.; Ruel, J.; Ladrech, S.; Bonny, C.; van de Water, T.R.; Puel, J.L. Inhibition of the c-Jun N-terminal kinase-mediated mitochondrial cell death pathway restores auditory function in sound-exposed animals. Mol. Pharmacol.,  2007, 71(3), 654-666.
 [http://dx.doi.org/10.1124/mol.106.028936] [PMID: 17132689]

[85]
Chauhan, D.; Li, G.; Hideshima, T.; Podar, K.; Mitsiades, C.; Mitsiades, N.; Munshi, N.; Kharbanda, S.; Anderson, K.C. JNK-dependent release of mitochondrial protein, Smac, during apoptosis in multiple myeloma (MM) cells. J. Biol. Chem.,  2003, 278(20), 17593-17596.
 [http://dx.doi.org/10.1074/jbc.C300076200] [PMID: 12665525]

[86]
Shin, Y.S.; Hwang, H.S.; Kang, S.U.; Chang, J.W.; Oh, Y.T.; Kim, C.H. Inhibition of p38 mitogen-activated protein kinase ameliorates radiation-induced ototoxicity in zebrafish and cochlea-derived cell lines. Neurotoxicology,  2014, 40, 111-122.
 [http://dx.doi.org/10.1016/j.neuro.2013.12.006] [PMID: 24374476]

[87]
Redza-Dutordoir, M.; Averill-Bates, D.A. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim. Biophys. Acta Mol. Cell Res.,  2016, 1863(12), 2977-2992.
 [http://dx.doi.org/10.1016/j.bbamcr.2016.09.012] [PMID: 27646922]

[88]
Haghi-Aminjan, H.; Farhood, B.; Rahimifard, M.; Didari, T.; Baeeri, M.; Hassani, S.; Hosseini, R.; Abdollahi, M. The protective role of melatonin in chemotherapy-induced nephrotoxicity: a systematic review of non-clinical studies. Expert Opin. Drug Metab. Toxicol.,  2018, 14(9), 937-950.
 [http://dx.doi.org/10.1080/17425255.2018.1513492] [PMID: 30118646]

[89]
Al-Saikhan, F.I. Anti-inflammatory potentials of Fibraurea tinctoria leaves extract in experimental rats or animals. J. Pharm. Res. Int.,  2020, 32(8), 79-83.
 [http://dx.doi.org/10.9734/jpri/2020/v32i830474]

[90]
Farhood, B.; Mortezaee, K.; Goradel, N.H.; Khanlarkhani, N.; Salehi, E.; Nashtaei, M.S.; Najafi, M.; Sahebkar, A. Curcumin as an anti-inflammatory agent: Implications to radiotherapy and chemotherapy. J. Cell. Physiol.,  2019, 234(5), 5728-5740.
 [http://dx.doi.org/10.1002/jcp.27442] [PMID: 30317564]

[91]
Jeong, B.K.; Song, J.H.; Jeong, H.; Choi, H.S.; Jung, J.H.; Hahm, J.R.; Woo, S.H.; Jung, M.H.; Choi, B.H.; Kim, J.H.; Kang, K.M. Effect of alpha-lipoic acid on radiation-induced small intestine injury in mice. Oncotarget,  2016, 7(12), 15105-15117.
 [http://dx.doi.org/10.18632/oncotarget.7874] [PMID: 26943777]

[92]
Yahyapour, R.; Amini, P.; Rezapour, S.; Cheki, M.; Rezaeyan, A.; Farhood, B.; Shabeeb, D.; Musa, A.E.; Fallah, H.; Najafi, M. Radiation-induced inflammation and autoimmune diseases. Mil. Med. Res.,  2018, 5(1), 9.
 [http://dx.doi.org/10.1186/s40779-018-0156-7] [PMID: 29554942]

[93]
Multhoff, G.; Molls, M.; Radons, J. Chronic inflammation in cancer development. Front. Immunol.,  2012, 2, 98.
 [http://dx.doi.org/10.3389/fimmu.2011.00098] [PMID: 22566887]

[94]
Waetzig, V.; Czeloth, K.; Hidding, U.; Mielke, K.; Kanzow, M.; Brecht, S.; Goetz, M.; Lucius, R.; Herdegen, T.; Hanisch, U.K. c-Jun N-terminal kinases (JNKs) mediate pro-inflammatory actions of microglia. Glia,  2005, 50(3), 235-246.
 [http://dx.doi.org/10.1002/glia.20173] [PMID: 15739188]

[95]
Lee, Y.B.; Schrader, J.W.; Kim, S.U. p38 map kinase regulates tnf-α production in human astrocytes and microglia by multiple mechanisms. Cytokine,  2000, 12(7), 874-880.
 [http://dx.doi.org/10.1006/cyto.2000.0688] [PMID: 10880231]

[96]
Zhang, W.; Dai, M.; Fridberger, A.; Hassan, A.; DeGagne, J.; Neng, L.; Zhang, F.; He, W.; Ren, T.; Trune, D.; Auer, M.; Shi, X. Perivascular-resident macrophage-like melanocytes in the inner ear are essential for the integrity of the intrastrial fluid–blood barrier. Proc. Natl. Acad. Sci.,  2012, 109(26), 10388-10393.
 [http://dx.doi.org/10.1073/pnas.1205210109] [PMID: 22689949]

[97]
Shi, X. Resident macrophages in the cochlear blood-labyrinth barrier and their renewal via migration of bone-marrow-derived cells. Cell Tissue Res.,  2010, 342(1), 21-30.
 [http://dx.doi.org/10.1007/s00441-010-1040-2] [PMID: 20838812]

[98]
Wright, H.L.; Moots, R.J.; Bucknall, R.C.; Edwards, S.W. Neutrophil function in inflammation and inflammatory diseases. Rheumatology,  2010, 49(9), 1618-1631.
 [http://dx.doi.org/10.1093/rheumatology/keq045] [PMID: 20338884]

[99]
Vanhoutte, P.M.; Shimokawa, H.; Feletou, M.; Tang, E.H.C. Endothelial dysfunction and vascular disease - a 30th anniversary update. Acta Physiol.,  2017, 219(1), 22-96.
 [http://dx.doi.org/10.1111/apha.12646] [PMID: 26706498]

[100]
Tousoulis, D.; Kampoli, A.M.; Tentolouris Nikolaos Papageorgiou, C.; Stefanadis, C.; Stefanadis, C. The role of nitric oxide on endothelial function. Curr. Vasc. Pharmacol.,  2012, 10(1), 4-18.
 [http://dx.doi.org/10.2174/157016112798829760] [PMID: 22112350]

[101]
Kerr, R.; Stirling, D.; Ludlam, C.A. Interleukin 6 and Haemostasis. Br. J. Haematol.,  2001, 115(1), 3-12.
 [http://dx.doi.org/10.1046/j.1365-2141.2001.03061.x] [PMID: 11722403]

[102]
Hellweg, C.E. The Nuclear Factor κB pathway: A link to the immune system in the radiation response. Cancer Lett.,  2015, 368(2), 275-289.
 [http://dx.doi.org/10.1016/j.canlet.2015.02.019] [PMID: 25688671]

[103]
Min, A.K.; Kim, M.K.; Seo, H.Y.; Kim, H.S.; Jang, B.K.; Hwang, J.S.; Choi, H.S.; Lee, K.U.; Park, K.G.; Lee, I.K. Alpha-lipoic acid inhibits hepatic PAI-1 expression and fibrosis by inhibiting the TGF-β signaling pathway. Biochem. Biophys. Res. Commun.,  2010, 393(3), 536-541.
 [http://dx.doi.org/10.1016/j.bbrc.2010.02.050] [PMID: 20153726]

[104]
Shih, R.H.; Wang, C.Y.; Yang, C.M. NF-kappaB signaling pathways in neurological inflammation: A mini review. Front. Mol. Neurosci.,  2015, 8, 77.
 [http://dx.doi.org/10.3389/fnmol.2015.00077] [PMID: 26733801]

[105]
Smith, D.I.; lawrence, M.; Hawkins, J.E., Jr Effects of noise and quinine on the vessels of the stria vascularis: An image analysis study. Am. J. Otolaryngol.,  1985, 6(4), 280-289.
 [http://dx.doi.org/10.1016/S0196-0709(85)80056-9] [PMID: 3898894]

[106]
Jereczek-Fossa, B.A.; Zarowski, A.; Milani, F.; Orecchia, R. Radiotherapy-induced ear toxicity. Cancer Treat. Rev.,  2003, 29(5), 417-430.
 [http://dx.doi.org/10.1016/S0305-7372(03)00066-5] [PMID: 12972360]

[107]
Gamble, J.E.; Peterson, E.A.; Chandler, J.R. Radiation effects on the inner ear. Arch Otolaryngol,  1968, 88(2), 156-161.
 [http://dx.doi.org/10.1001/archotol.1968.00770010158008]

[108]
Landier, W. Ototoxicity and cancer therapy. Cancer,  2016, 122(11), 1647-1658.
 [http://dx.doi.org/10.1002/cncr.29779] [PMID: 26859792]

[109]
 Common Terminology Criteria for Adverse Events (CTCAE). Available from: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm

[110]
Brock, P.R.; Bellman, S.C.; Yeomans, E.C.; Pinkerton, C.R.; Pritchard, J. Cisplatin ototoxicity in children: A practical grading system. Med. Pediatr. Oncol.,  1991, 19(4), 295-300.
 [http://dx.doi.org/10.1002/mpo.2950190415] [PMID: 2056973]

[111]

Audiologic management of individuals receiving cochleotoxic drug therapy; American Speech-Language-Hearing Association, 1994. 

[112]
Chang, K.W.; Chinosornvatana, N. Practical grading system for evaluating cisplatin ototoxicity in children. J. Clin. Oncol.,  2010, 28(10), 1788-1795.
 [http://dx.doi.org/10.1200/JCO.2009.24.4228] [PMID: 20194861]

[113]
Brock, P.R.; Knight, K.R.; Freyer, D.R.; Campbell, K.C.M.; Steyger, P.S.; Blakley, B.W.; Rassekh, S.R.; Chang, K.W.; Fligor, B.J.; Rajput, K.; Sullivan, M.; Neuwelt, E.A. Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale. J. Clin. Oncol.,  2012, 30(19), 2408-2417.
 [http://dx.doi.org/10.1200/JCO.2011.39.1110] [PMID: 22547603]

[114]
Huang, E.; Teh, B.S.; Strother, D.R.; Davis, Q.G.; Chiu, J.K.; Lu, H.H.; Carpenter, L.S.; Mai, W.Y.; Chintagumpala, M.M.; South, M.; Grant, W.H., III; Butler, E.B.; Woo, S.Y. Intensity-modulated radiation therapy for pediatric medulloblastoma: early report on the reduction of ototoxicity. Int. J. Radiat. Oncol. Biol. Phys.,  2002, 52(3), 599-605.
 [http://dx.doi.org/10.1016/S0360-3016(01)02641-4] [PMID: 11849779]

[115]

BIAP recommendation No. 02/1 bis: Audiometric classification of hearing impairments, 1996. Available from: http://www.biap.org/biapanglais/rec021eng.htm

[116]
Bhandare, N.; Antonelli, P.J.; Morris, C.G.; Malayapa, R.S.; Mendenhall, W.M. Ototoxicity after radiotherapy for head and neck tumors. Int. J. Radiat. Oncol. Biol. Phys.,  2007, 67(2), 469-479.
 [http://dx.doi.org/10.1016/j.ijrobp.2006.09.017] [PMID: 17236969]

[117]
Merchant, T.E.; Gould, C.J.; Xiong, X.; Robbins, N.; Zhu, J.; Pritchard, D.L.; Khan, R.; Heideman, R.L.; Krasin, M.J.; Kun, L.E. Early neuro-otologic effects of three-dimensional irradiation in children with primary brain tumors. Int. J. Radiat. Oncol. Biol. Phys.,  2004, 58(4), 1194-1207.
 [http://dx.doi.org/10.1016/j.ijrobp.2003.07.008] [PMID: 15001264]

[118]
Emami, B.; Lyman, J.; Brown, A.; Cola, L.; Goitein, M.; Munzenrider, J.E.; Shank, B.; Solin, L.J.; Wesson, M. Tolerance of normal tissue to therapeutic irradiation. Int. J. Radiat. Oncol. Biol. Phys.,  1991, 21(1), 109-122.
 [http://dx.doi.org/10.1016/0360-3016(91)90171-Y] [PMID: 2032882]

[119]
Marks, L.B.; Yorke, E.D.; Jackson, A.; Ten Haken, R.K.; Constine, L.S.; Eisbruch, A.; Bentzen, S.M.; Nam, J.; Deasy, J.O. Use of normal tissue complication probability models in the clinic. Int. J. Radiat. Oncol. Biol. Phys.,  2010, 76(S3), S10-S19.
 [http://dx.doi.org/10.1016/j.ijrobp.2009.07.1754] [PMID: 20171502]

[120]
Honoré, H.B.; Bentzen, S.M.; Møller, K.; Grau, C. Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: individualized risk estimation. Radiother. Oncol.,  2002, 65(1), 9-16.
 [http://dx.doi.org/10.1016/S0167-8140(02)00173-1] [PMID: 12413669]

[121]
Cacciotti, C.; Fleming, A.; Ramaswamy, V. Advances in the molecular classification of pediatric brain tumors: a guide to the galaxy. J. Pathol.,  2020, 251(3), 249-261.
 [http://dx.doi.org/10.1002/path.5457] [PMID: 32391583]

[122]
Gondi, V.; Yock, T.I.; Mehta, M.P. Proton therapy for paediatric CNS tumours — improving treatment-related outcomes. Nat. Rev. Neurol.,  2016, 12(6), 334-345.
 [http://dx.doi.org/10.1038/nrneurol.2016.70] [PMID: 27197578]

[123]
Bouffet, E.; Bernard, J.L.; Frappaz, D.; Gentet, J.C.; Roche, H.; Tron, P.; Carrie, C.; Raybaud, C.; Joannard, A.; Lapras, C.; Choux, M.; Carton, M.; Aimard, L.; Philip, T.; Brunat-Mentigny, M. M4 protocol for cerebellar medulloblastoma: Supratentorial radiotherapy may not be avoided. Int. J. Radiat. Oncol. Biol. Phys.,  1992, 24(1), 79-85.
 [http://dx.doi.org/10.1016/0360-3016(92)91025-I] [PMID: 1512166]

[124]
Fossati, P.; Ricardi, U.; Orecchia, R. Pediatric medulloblastoma: Toxicity of current treatment and potential role of protontherapy. Cancer Treat. Rev.,  2009, 35(1), 79-96.
 [http://dx.doi.org/10.1016/j.ctrv.2008.09.002] [PMID: 18976866]

[125]
Breen, S.L.; Kehagioglou, P.; Usher, C.; Plowman, P.N. A comparison of conventional, conformal and intensity-modulated coplanar radiotherapy plans for posterior fossa treatment. Br. J. Radiol.,  2004, 77(921), 768-774.
 [http://dx.doi.org/10.1259/bjr/67922606] [PMID: 15447964]

[126]
Gupta, T.; Mohanty, S.; Kannan, S.; Jalali, R. Prospective longitudinal assessment of sensorineural hearing loss with hyperfractionated radiation therapy alone in patients with average-risk medulloblastoma. Neurooncol. Pract.,  2014, 1(3), 86-93.
 [http://dx.doi.org/10.1093/nop/npu017] [PMID: 31386031]

[127]
Paulino, A.C.; Lobo, M.; Teh, B.S.; Okcu, M.F.; South, M.; Butler, E.B.; Su, J.; Chintagumpala, M. Ototoxicity after intensity-modulated radiation therapy and cisplatin-based chemotherapy in children with medulloblastoma. Int. J. Radiat. Oncol. Biol. Phys.,  2010, 78(5), 1445-1450.
 [http://dx.doi.org/10.1016/j.ijrobp.2009.09.031] [PMID: 20231075]

[128]
Vieira, W.A.; Weltman, E.; Chen, M.J.; da Silva, N.S.; Cappellano, A.M.; Pereira, L.D.; Gonçalves, M.I.R.; Ferrigno, R.; Hanriot, R.M.; Nadalin, W.; Odone Filho, V.; Petrilli, A.S. Ototoxicity evaluation in medulloblastoma patients treated with involved field boost using intensity-modulated radiation therapy (IMRT): a retrospective review. Radiat. Oncol.,  2014, 9(1), 158.
 [http://dx.doi.org/10.1186/1748-717X-9-158] [PMID: 25041714]

[129]
Scobioala, S.; Parfitt, R.; Matulat, P.; Kittel, C.; Ebrahimi, F.; Wolters, H.; am Zehnhoff-Dinnesen, A.; Eich, H.T. Impact of radiation technique, radiation fraction dose, and total cisplatin dose on hearing. Strahlenther. Onkol.,  2017, 193(11), 910-920.
 [http://dx.doi.org/10.1007/s00066-017-1205-y] [PMID: 28887665]

[130]
Paulino, A.C.; Mahajan, A.; Ye, R.; Grosshans, D.R.; Fatih Okcu, M.; Su, J.; McAleer, M.F.; McGovern, S.; Mangona, V.A.; Chintagumpala, M. Ototoxicity and cochlear sparing in children with medulloblastoma: Proton vs. photon radiotherapy. Radiother. Oncol.,  2018, 128(1), 128-132.
 [http://dx.doi.org/10.1016/j.radonc.2018.01.002] [PMID: 29373195]

[131]
Polkinghorn, W.R.; Dunkel, I.J.; Souweidane, M.M.; Khakoo, Y.; Lyden, D.C.; Gilheeney, S.W.; Becher, O.J.; Budnick, A.S.; Wolden, S.L. Disease control and ototoxicity using intensity-modulated radiation therapy tumor-bed boost for medulloblastoma. Int. J. Radiat. Oncol. Biol. Phys.,  2011, 81(3), e15-e20.
 [http://dx.doi.org/10.1016/j.ijrobp.2010.11.081] [PMID: 21481547]

[132]
Merchant, T.E.; Hua, C.; Shukla, H.; Ying, X.; Nill, S.; Oelfke, U. Proton versus photon radiotherapy for common pediatric brain tumors: Comparison of models of dose characteristics and their relationship to cognitive function. Pediatr. Blood Cancer,  2008, 51(1), 110-117.
 [http://dx.doi.org/10.1002/pbc.21530] [PMID: 18306274]

[133]
Lee, C.T.; Bilton, S.D.; Famiglietti, R.M.; Riley, B.A.; Mahajan, A.; Chang, E.L.; Maor, M.H.; Woo, S.Y.; Cox, J.D.; Smith, A.R. Treatment planning with protons for pediatric retinoblastoma, medulloblastoma, and pelvic sarcoma: How do protons compare with other conformal techniques? Int. J. Radiat. Oncol. Biol. Phys.,  2005, 63(2), 362-372.
 [http://dx.doi.org/10.1016/j.ijrobp.2005.01.060] [PMID: 16168831]

[134]
St Clair, W.H.; Adams, J.A.; Bues, M.; Fullerton, B.C.; La Shell, S.; Kooy, H.M.; Loeffler, J.S.; Tarbell, N.J. Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. Int. J. Radiat. Oncol. Biol. Phys.,  2004, 58(3), 727-734.
 [http://dx.doi.org/10.1016/S0360-3016(03)01574-8] [PMID: 14967427]

[135]
Eaton, B.R.; Esiashvili, N.; Kim, S.; Weyman, E.A.; Thornton, L.T.; Mazewski, C.; MacDonald, T.; Ebb, D.; MacDonald, S.M.; Tarbell, N.J.; Yock, T.I. Clinical outcomes among children with standard-risk medulloblastoma treated with proton and photon radiation therapy: A comparison of disease control and overall survival. Int. J. Radiat. Oncol. Biol. Phys.,  2016, 94(1), 133-138.
 [http://dx.doi.org/10.1016/j.ijrobp.2015.09.014] [PMID: 26700707]

[136]
Moeller, B.J.; Chintagumpala, M.; Philip, J.J.; Grosshans, D.R.; McAleer, M.F.; Woo, S.Y.; Gidley, P.W.; Vats, T.S.; Mahajan, A. Low early ototoxicity rates for pediatric medulloblastoma patients treated with proton radiotherapy. Radiat. Oncol.,  2011, 6(1), 58.
 [http://dx.doi.org/10.1186/1748-717X-6-58] [PMID: 21635776]

[137]
Jimenez, R.B.; Sethi, R.; Depauw, N.; Pulsifer, M.B.; Adams, J.; McBride, S.M.; Ebb, D.; Fullerton, B.C.; Tarbell, N.J.; Yock, T.I.; MacDonald, S.M. Proton radiation therapy for pediatric medulloblastoma and supratentorial primitive neuroectodermal tumors: outcomes for very young children treated with upfront chemotherapy. Int. J. Radiat. Oncol. Biol. Phys.,  2013, 87(1), 120-126.
 [http://dx.doi.org/10.1016/j.ijrobp.2013.05.017] [PMID: 23790826]

[138]
Yock, T.I.; Yeap, B.Y.; Ebb, D.H.; Weyman, E.; Eaton, B.R.; Sherry, N.A.; Jones, R.M.; MacDonald, S.M.; Pulsifer, M.B.; Lavally, B.; Abrams, A.N.; Huang, M.S.; Marcus, K.J.; Tarbell, N.J. Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: A phase 2 single-arm study. Lancet Oncol.,  2016, 17(3), 287-298.
 [http://dx.doi.org/10.1016/S1470-2045(15)00167-9] [PMID: 26830377]

[139]
Fortin, D.; Tsang, D.; Ng, A.; Laperriere, N.; Hodgson, D.C. Monte Carlo-driven predictions of neurocognitive and hearing impairments following proton and photon radiotherapy for pediatric brain-tumor patients. J. Neurooncol.,  2017, 135(3), 521-528.
 [http://dx.doi.org/10.1007/s11060-017-2597-3] [PMID: 28825228]

[140]
Jazmati, D.; Steinmeier, T.; Ahamd Khalil, D.; Frisch, S.; Peters, S.; Schulze, S.S. Feasibility of proton beam therapy for infants with brain tumours: Experiences from the prospective kiproreg registry study. J Clin Oncol,  2021, 33(7), e295-e304.

[141]
Bass, J.K.; Huang, J.; Hua, C.H.; Bhagat, S.P.; Mendel, L.L.; Onar-Thomas, A.; Indelicato, D.J.; Merchant, T.E. Auditory outcomes in patients who received proton radiotherapy for craniopharyngioma. Am. J. Audiol.,  2018, 27(3), 306-315.
 [http://dx.doi.org/10.1044/2018_AJA-18-0026] [PMID: 30073327]

[142]
MacDonald, S.M.; Sethi, R.; Lavally, B.; Yeap, B.Y.; Marcus, K.J.; Caruso, P.; Pulsifer, M.; Huang, M.; Ebb, D.; Tarbell, N.J.; Yock, T.I. Proton radiotherapy for pediatric central nervous system ependymoma: Clinical outcomes for 70 patients. Neuro-oncol.,  2013, 15(11), 1552-1559.
 [http://dx.doi.org/10.1093/neuonc/not121] [PMID: 24101739]

[143]
Indelicato, D.J.; Bradley, J.A.; Rotondo, R.L.; Nanda, R.H.; Logie, N.; Sandler, E.S.; Aldana, P.R.; Ranalli, N.J.; Beier, A.D.; Morris, C.G.; Mendenhall, N.P. Outcomes following proton therapy for pediatric ependymoma. Acta Oncol.,  2018, 57(5), 644-648.
 [http://dx.doi.org/10.1080/0284186X.2017.1413248] [PMID: 29239262]

[144]
Indelicato, D.J.; Ioakeim-Ioannidou, M.; Bradley, J.A.; Mailhot-Vega, R.B.; Morris, C.G.; Tarbell, N.J.; Yock, T.; MacDonald, S.M. Proton therapy for pediatric ependymoma: Mature results from a bicentric study. Int. J. Radiat. Oncol. Biol. Phys.,  2021, 110(3), 815-820.
 [http://dx.doi.org/10.1016/j.ijrobp.2021.01.027] [PMID: 33508372]

[145]
Borsanyi, S.J.; Blanchard, C.L. Ionizing radiation and the ear. JAMA,  1962, 181(11), 958-961.
 [http://dx.doi.org/10.1001/jama.1962.03050370026006] [PMID: 13871468]

[146]
Qiu, W.Z.; Peng, X.S.; Xia, H.Q.; Huang, P.Y.; Guo, X.; Cao, K.J. A retrospective study comparing the outcomes and toxicities of intensity-modulated radiotherapy versus two-dimensional conventional radiotherapy for the treatment of children and adolescent nasopharyngeal carcinoma. J. Cancer Res. Clin. Oncol.,  2017, 143(8), 1563-1572.
 [http://dx.doi.org/10.1007/s00432-017-2401-y] [PMID: 28342002]

[147]
Lu, S.; Wei, J.; Sun, F.; Xiao, W.; Cai, R.; Zhen, Z.; Zhu, J.; Wang, J.; Huang, J.; Lu, L.; Sun, X.; Gao, Y. Late sequelae of childhood and adolescent nasopharyngeal carcinoma survivors after radiation therapy. Int. J. Radiat. Oncol. Biol. Phys.,  2019, 103(1), 45-51.
 [http://dx.doi.org/10.1016/j.ijrobp.2018.09.015] [PMID: 30244159]

[148]
Uezono, H.; Indelicato, D.J.; Rotondo, R.L.; Sandler, E.S.; Katzenstein, H.M.; Dagan, R.; Mendenhall, W.M.; Mailhot Vega, R.; Brennan, B.M.; Bradley, J.A. Proton therapy following induction chemotherapy for pediatric and adolescent nasopharyngeal carcinoma. Pediatr. Blood Cancer,  2019, 66(12), e27990.
 [http://dx.doi.org/10.1002/pbc.27990] [PMID: 31524334]

[149]
Lockney, N.A.; Friedman, D.N.; Wexler, L.H.; Sklar, C.A.; Casey, D.L.; Wolden, S.L. Late toxicities of intensity-modulated radiation therapy for head and neck rhabdomyosarcoma. Pediatr. Blood Cancer,  2016, 63(9), 1608-1614.
 [http://dx.doi.org/10.1002/pbc.26061] [PMID: 27195454]

[150]
Schoot, RA; Theunissen, EA; Slater, O; Lopez-Yurda, M; Zuur, CL; Gaze, MN Hearing loss in survivors of childhood head and neck rhabdomyosarcoma: A long-term follow-up study. Clin Otolaryngol.,  2016, 41(3), 276-283.
 [http://dx.doi.org/10.1111/coa.12527]

[151]
Jacob, J.T.; Carlson, M.L.; Schiefer, T.K.; Pollock, B.E.; Driscoll, C.L.; Link, M.J. Significance of cochlear dose in the radiosurgical treatment of vestibular schwannoma: Controversies and unanswered questions. Neurosurgery,  2014, 74(5), 466-474.
 [http://dx.doi.org/10.1227/NEU.0000000000000299] [PMID: 24476904]

[152]
Nader, M.E.; Gidley, P. Challenges of hearing rehabilitation after radiation and chemotherapy. J. Neurol. Surg. B Skull Base,  2019, 80(2), 214-224.
 [http://dx.doi.org/10.1055/s-0039-1677865] [PMID: 30931231]

[153]
Lamaj, E.; Vu, E.; van Timmeren, J.E.; Leonardi, C.; Marc, L.; Pytko, I.; Guckenberger, M.; Balermpas, P. Cochlea sparing optimized radiotherapy for nasopharyngeal carcinoma. Radiat. Oncol.,  2021, 16(1), 64.
 [http://dx.doi.org/10.1186/s13014-021-01796-4] [PMID: 33794949]

[154]
Cheraghi, S.; Mahdavi, S.R.; Rezaeyan, A.; Nikoofar, A.; Bakhshandeh, M.; Farahani, S. Comparison of radiation and chemoradiation-induced sensorineural hearing loss in head and neck cancer patients. J. Cancer Res. Ther.,  2020, 16(3), 539-545.
 [http://dx.doi.org/10.4103/jcrt.JCRT_891_16] [PMID: 32719264]

[155]
Yang, Q; Cao, SM; Guo, L; Hua, YJ; Huang, PY; Zhang, XL Induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: Long-term results of a phase III multicentre randomised controlled trial. Eur. J. Cancer,  2019, 119, 87-96.
 [http://dx.doi.org/10.1016/j.ejca.2019.07.007]

[156]
Kortmann, R.D.; Kühl, J.; Timmermann, B.; Mittler, U.; Urban, C.; Budach, V.; Richter, E.; Willich, N.; Flentje, M.; Berthold, F.; Slavc, I.; Wolff, J.; Meisner, C.; Wiestler, O.; Sörensen, N.; Warmuth-Metz, M.; Bamberg, M. Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: Results of the German prospective randomized trial hit ’91. Int. J. Radiat. Oncol. Biol. Phys.,  2000, 46(2), 269-279.
 [http://dx.doi.org/10.1016/S0360-3016(99)00369-7] [PMID: 10661332]

[157]
Petsuksiri, J.; Sermsree, A.; Thephamongkhol, K.; Keskool, P.; Thongyai, K.; Chansilpa, Y.; Pattaranutaporn, P. Sensorineural hearing loss after concurrent chemoradiotherapy in nasopharyngeal cancer patients. Radiat. Oncol.,  2011, 6(1), 19.
 [http://dx.doi.org/10.1186/1748-717X-6-19] [PMID: 21333025]

[158]
Altas, E.; Ertekin, M.V.; Kuduban, O.; Gundogdu, C.; Demirci, E.; Sutbeyaz, Y. Effects of piracetam supplementation on cochlear damage occurring in guinea pigs exposed to irradiation. Biol. Pharm. Bull.,  2006, 29(7), 1460-1465.
 [http://dx.doi.org/10.1248/bpb.29.1460] [PMID: 16819189]

[159]
Altas, E.; Ertekin, M.V.; Gundogdu, C.; Demirci, E. L-carnitine reduces cochlear damage induced by gamma irradiation in Guinea pigs. Ann. Clin. Lab. Sci.,  2006, 36(3), 312-318.
 [PMID: 16951273]

[160]
Low, W.K.; Sun, L.; Tan, M.G.K.; Chua, A.W.C.; Wang, D.Y. L-N-Acetylcysteine protects against radiation-induced apoptosis in a cochlear cell line. Acta Otolaryngol.,  2008, 128(4), 440-445.
 [http://dx.doi.org/10.1080/00016480701762490] [PMID: 18368580]

[161]
Lessa, R.M.; Oliveira, J.A.A.; Rossato, M.; Ghilardi Netto, T. Analysis of the cytoprotective effect of amifostine on the irradiated inner ear of guinea pigs: An experimental study. Rev. Bras. Otorrinolaringol.,  2009, 75(5), 694-700.
 [http://dx.doi.org/10.1590/S1808-86942009000500014] [PMID: 19893938]

[162]
Karaer, I.; Simsek, G.; Gul, M.; Bahar, L.; Gürocak, S.; Parlakpinar, H.; Nuransoy, A. Melatonin protects inner ear against radiation damage in rats. Laryngoscope,  2015, 125(10), E345-E349.
 [http://dx.doi.org/10.1002/lary.25376] [PMID: 25994110]

[163]
Chen, T.; Luo, Y.; Li, Q.; Yang, C.; Yuan, Y.; Peng, J.; Ban, M.; Liang, Y.; Zhang, W. Melatonin reduces radiation damage in inner ear. J. Radiat. Res.,  2021, 62(2), 217-225.
 [http://dx.doi.org/10.1093/jrr/rraa137] [PMID: 33454767]

[164]
Crowson, M.G.; Hertzano, R.; Tucci, D.L. Emerging therapies for sensorineural hearing loss. Otol. Neurotol.,  2017, 38(6), 792-803.
 [http://dx.doi.org/10.1097/MAO.0000000000001427]

[165]
Chang, W.W.T.; Yeung, K.N.K.; Luk, B.P.K.; Leung, K.K.Y.; Sung, J.K.K.; Tong, M.C.F. Cochlear implantation in postirradiated ears: A case-control comparative study. Laryngoscope Investig. Otolaryngol.,  2020, 5(6), 1163-1167.
 [http://dx.doi.org/10.1002/lio2.486] [PMID: 33364408]

[166]
Dinh, C.T.; Chen, S.; Dinh, J.; Goncalves, S.; Bas, E.; Padgett, K.; Johnson, P.; Elsayyad, N.; Telischi, F.; Van De Water, T. Effects of intratympanic dexamethasone on high-dose radiation ototoxicity in vivo. Otol. Neurotol.,  2017, 38(2), 180-186.
 [http://dx.doi.org/10.1097/MAO.0000000000001289]
Cite As
Current Medicinal Chemistry

Radiotherapy-associated Sensorineural Hearing Loss in Pediatric Oncology Patients

Abstract
