Research progress on drugs for the prevention and treatment of radiotherapy-induced oral mucositis

doi:10.19438/j.cjoms.2025.02.015

Abstract

Abstract: Radiation oral mucositis is one of the most common complications of radiotherapy in patients with head and neck cancer. It can lead to mucosal ulceration, severe pain, eating and swallowing difficulties and other functional disorders, resulting in treatment interruption and poor curative effect. Radiation oral mucositis is currently believed to be a complex and dynamic process with multiple targets, and drug therapy targeting these targets can prevent and control the occurrence and development of mucositis. This review discussed the research progress of drugs for prevention and treatment of radiation mucositis, aiming at different targets of mucositis, including DNA damage, oxidative stress pathway, oral microbiota, epithelial proliferation, and analgesic management, which will provide references for the future research and clinical prevention and treatment of radiation oral mucositis.

Key words: Radiation therapy, Head and neck cancer, Radiotherapy-induced oral mucositis, Target

CLC Number:

R781.5

WANG Jia-min, AN Wei, CHEN Wen-ge. Research progress on drugs for the prevention and treatment of radiotherapy-induced oral mucositis[J]. China Journal of Oral and Maxillofacial Surgery, 2025, 23(2): 196-201.

References

[1] Pulito C, Cristaudo A, Porta C, et al.Oral mucositis: the hidden side of cancer therapy[J]. J Exp Clin Cancer Res, 2020, 39(1): 210-225.
[2] Iovoli AJ, Turecki L, Qiu ML, et al.Severe oral mucositis after intensity-modulated radiation therapy for head and neck cancer[J]. JAMA Netw Open, 2023, 6(10): e2337265.
[3] Sankar V, Xu Y.Oral complications from oropharyngeal cancer therapy[J]. Cancers (Basel), 2023, 15(18): 4548.
[4] Sonis ST.The pathobiology of mucositis[J]. Nat Rev Cancer, 2004, 4(4): 277-284.
[5] Hofer M, Falk M, Komurková D, et al.Two new faces of amifostine: protector from DNA damage in normal cells and inhibitor of DNA repair in cancer cells[J]. J Med Chem, 2016, 59(7): 3003-3017.
[6] Chang H, Yi W, Wang X, et al.Effectiveness and safety of different amifostine regimens: preliminary results of a phase Ⅱ multicenter randomized controlled trial[J]. Chin J Cancer Res, 2018, 30(3): 307-314.
[7] Gu J, Zhu S, Li X, et al.Effect of amifostine in head and neck cancer patients treated with radiotherapy: a systematic review and meta-analysis based on randomized controlled trials[J]. PLoS One, 2014, 9(5): e95968.
[8] Obrador E, Salvador R, Villaescusa JI, et al.Radioprotection and radiomitigation: from the bench to clinical practice[J]. Biomedicines, 2020, 8(11): 461.
[9] Zhang J, Li K, Zhang Q, et al.Polycysteine as a new type of radio-protector ameliorated tissue injury through inhibiting ferroptosis in mice[J]. Cell Death Dis, 2021, 12(2): 195.
[10] Clémenson C, Liu W, Bricout D, et al.Preventing radiation-induced injury by topical application of an amifostine metabolite-loaded thermogel[J]. Int J Radiat Oncol Biol Phys, 2019, 104(5): 1141-1152.
[11] Yang C, Tang H, Wang L, et al.Dimethyl sulfoxide prevents radiation-induced oral mucositis through facilitating DNA double-strand break repair in epithelial stem cells[J]. Int J Radiat Oncol Biol Phys, 2018, 102(5): 1577-1589.
[12] Amini P, Mirtavoos-Mahyari H, Motevaseli E, et al.Mechanisms for radioprotection by melatonin; can it be used as a radiation countermeasure?[J]. Curr Mol Pharmacol, 2019, 12(1): 2-11.
[13] Abdel Moneim AE, Guerra-Librero A, Florido J, et al.Oral mucositis: melatonin gel an effective new treatment[J]. Int J Mol Sci, 2017, 18(5): 1003.
[14] Onseng K, Johns NP, Khuayjarernpanishk T, et al.Beneficial effects of adjuvant melatonin in minimizing oral mucositis complications in head and neck cancer patients receiving concurrent chemoradiation[J]. J Altern Complement Med, 2017, 23(12): 957-963.
[15] Elsabagh HH, Moussa E, Mahmoud SA, et al.Efficacy of melatonin in prevention of radiation-induced oral mucositis: a randomized clinical trial[J]. Oral Dis, 2020, 26(3): 566-572.
[16] Lozano A, Marruecos J, Rubió J, et al.Randomized placebo-controlled phase Ⅱ trial of high-dose melatonin mucoadhesive oral gel for the prevention and treatment of oral mucositis in patients with head and neck cancer undergoing radiation therapy concurrent with systemic treatment[J]. Clin Transl Oncol, 2021, 23(9): 1801-1810.
[17] Abeesh P, Guruvayoorappan C.NF-κB as a potential target for the treatment and prevention of mucositis[J]. Curr Pharm Biotechnol, 2023, 24(13): 1613-1622.
[18] Liang L, Liu Z, Zhu H, et al.Efficacy and safety of thalidomide in preventing oral mucositis in patients with nasopharyngeal carcinoma undergoing concurrent chemoradiotherapy: a multicenter, open-label, randomized controlled trial[J]. Cancer, 2022, 128(7): 1467-1474.
[19] Ala M, Mohammad Jafari R, Ala M, et al.Sildenafil improves radiation-induced oral mucositis by attenuating oxidative stress, NF-κB, ERK and JNK signalling pathways[J]. J Cell Mol Med, 2022, 26(16): 4556-4565.
[20] Ala M, Mohammad Jafari R, Ala M, et al.Sumatriptan alleviates radiation-induced oral mucositis in rats by inhibition of NF-kB and ERK activation, prevention of TNF-α and ROS release[J]. Arch Oral Biol, 2020, 119: 104919.
[21] Luo J, Bian L, Blevins MA, et al.Smad7 promotes healing of radiotherapy-induced oral mucositis without compromising oral cancer therapy in a xenograft mouse model[J]. Clin Cancer Res, 2019, 25(2): 808-818.
[22] Ibrahim SS, Hassanein FEA, Zaky HW, et al.Clinical and biochemical assessment of the effect of glutamine in management of radiation induced oral mucositis in patients with head and neck cancer: randomized controlled clinical trial[J]. J Stomatol Oral Maxillofac Surg, 2024(3S): 101827.
[23] Boss MK, Ke Y, Bian L, et al.Therapeutic intervention using a Smad7-based tat protein to treat radiation-induced oral mucositis[J]. Int J Radiat Oncol Biol Phys, 2022, 112(3): 759-770.
[24] Zhu J, Zhang H, Li J, et al.LiCl promotes recovery of radiation-induced oral mucositis and dysgeusia[J]. J Dent Res, 2021, 100(7): 754-763.
[25] Braun S, Hanselmann C, Gassmann MG, et al.Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound[J]. Mol Cell Biol, 2002, 22(15): 5492-5505.
[26] Le QT, Kim HE, Schneider CJ, et al.Palifermin reduces severe mucositis in definitive chemoradiotherapy of locally advanced head and neck cancer: a randomized, placebo-controlled study[J]. J Clin Oncol, 2011, 29(20): 2808-2814.
[27] Henke M, Alfonsi M, Foa P, et al.Palifermin decreases severe oral mucositis of patients undergoing postoperative radiochemotherapy for head and neck cancer: a randomized, placebo-controlled trial[J]. J Clin Oncol, 2011, 29(20): 2815-2820.
[28] Bailly C.Potential use of edaravone to reduce specific side effects of chemo-, radio- and immuno-therapy of cancers[J]. Int Immunopharmacol, 2019, 77: 105967.
[29] Nakajima N, Watanabe S, Kiyoi T, et al.Evaluation of edaravone against radiation-induced oral mucositis in mice[J]. J Pharmacol Sci, 2015, 127(3): 339-343.
[30] Xu J, Yang G, An W, et al.Correlations between the severity of radiation-induced oral mucositis and salivary epidermal growth factor as well as inflammatory cytokines in patients with head and neck cancer[J]. Head Neck, 2023, 45(5): 1122-1129.
[31] Ariyawardana A, Cheng KKF, Kandwal A, et al.Systematic review of anti-inflammatory agents for the management of oral mucositis in cancer patients and clinical practice guidelines[J]. Support Care Cancer, 2019, 27(10): 3985-3995.
[32] Rastogi M, Khurana R, Revannasiddaiah S, et al.Role of benzydamine hydrochloride in the prevention of oral mucositis in head and neck cancer patients treated with radiotherapy (>50 Gy) with or without chemotherapy[J]. Support Care Cancer, 2017, 25(5): 1439-1443.
[33] Chaitanya B, Pai KM, Yathiraj PH, et al.Rebamipide gargle in preventive management of chemo-radiotherapy induced oral mucositis[J]. Oral Oncol, 2017, 72: 179-182.
[34] Aykin-Burns N, Pathak R, Boerma M, et al.Utilization of vitamin e analogs to protect normal tissues while enhancing antitumor effects[J]. Semin Radiat Oncol, 2019, 29(1): 55-61.
[35] Ucüncü H, Ertekin MV, Yörük O, et al.Vitamin E and L-carnitine, separately or in combination, in the prevention of radiation-induced oral mucositis and myelosuppression: a controlled study in a rat model[J]. J Radiat Res, 2006, 47(1): 91-102.
[36] Sayed R, El Wakeel L, Saad AS, et al.Pentoxifylline and vitamin E reduce the severity of radiotherapy-induced oral mucositis and dysphagia in head and neck cancer patients: a randomized, controlled study[J]. Med Oncol, 2019, 37(1): 8.
[37] Mokhtari Z, Hekmatdoost A, Nourian MJJoPD. Antioxidant efficacy of vitamin D[J]. J Parathyr Dis, 2016, 5(1): 11-16.
[38] Bakr IS, Zaki AM, El-Moslemany RM, et al.Vitamin D oral gel for prevention of radiation-induced oral mucositis: a randomized clinical trial[J]. Oral Dis, 2021, 27(5): 1197-1204.
[39] Giralt J, Tao Y, Kortmann RD, et al.Randomized phase 2 trial of a novel clonidine mucoadhesive buccal tablet for the amelioration of oral mucositis in patients treated with concomitant chemoradiation therapy for head and neck cancer[J]. Int J Radiat Oncol Biol Phys, 2020, 106(2): 320-328.
[40] Jiang C, Wang H, Xia C, et al.A randomized, double-blind, placebo-controlled trial of probiotics to reduce the severity of oral mucositis induced by chemoradiotherapy for patients with nasopharyngeal carcinoma[J]. Cancer, 2019, 125(7): 1081-1090.
[41] Mirza MA, Aruna D, Irukulla M.Efficacy of Bacillus clausii UBBC - 07 spores in the amelioration of oral mucositis in head and neck cancer patients undergoing radiation therapy[J]. Cancer Treat Res Commun, 2022, 31: 100523.
[42] Manifar S, Koopaie M, Jahromi ZM, et al.Effect of synbiotic mouthwash on oral mucositis induced by radiotherapy in oral cancer patients: a double-blind randomized clinical trial[J]. Support Care Cancer, 2022, 31(1): 31.
[43] Wang Y, Li J, Zhang H, et al.Probiotic Streptococcus salivarius K12 alleviates radiation-induced oral mucositis in mice[J]. Front Immunol, 2021, 12: 684824.
[44] Peng X, Li Z, Pei Y, et al.Streptococcus salivarius K12 alleviates oral mucositis in patients undergoing radiotherapy for malignant head and neck tumors: a randomized controlled trial[J]. J Clin Oncol, 2024, 42(12): 1426-1435.
[45] Lee RH, Oh JY, Choi H, et al.Therapeutic factors secreted by mesenchymal stromal cells and tissue repair[J]. J Cell Biochem, 2011, 112(11): 3073-3078.
[46] Shen Z, Wang J, Huang Q, et al.Genetic modification to induce CXCR2 overexpression in mesenchymal stem cells enhances treatment benefits in radiation-induced oral mucositis[J]. Cell Death Dis, 2018, 9(2): 229.
[47] 刘尚贤, 张瑜, 郑茁, 等. 人粒细胞巨噬细胞刺激因子含漱预防放射性口腔黏膜炎的疗效观察[J]. 中国医药科学, 2020, 10(14): 72-74, 108.
Liu SX, Zhang Y, Zheng Z, et al.Observation on the curative effect of hGM-CSF gargles in the prevention of radiation-induced oropharyngeal mucositis[J]. China Medicine and Pharmacy, 2020, 10(14): 72-74, 108.
[48] Xu J, Yang G, An W, et al.Correlations between the severity of radiation-induced oral mucositis and salivary epidermal growth factor as well as inflammatory cytokines in patients with head and neck cancer[J]. Head Neck, 2023, 45(5): 1122-1129.
[49] 刘静静. 重组人表皮生长因子外用溶液治疗放射性口腔黏膜炎的效果观察[J]. 中外医学研究, 2023, 21(3): 107-110.
Liu JJ.Observation on curative effect of recombinant human epidermal growth factor topical solution in the treatment of radiotherapy-induced oral mucositis[J]. Chinese and Foreign Medical Research, 2023, 21(3): 107-110.
[50] 余俊钦, 秦又发. 重组人表皮生长因子外用溶液(金因肽)雾化吸入对肿瘤放疗后咽喉黏膜损伤的疗效分析[J]. 北方药学, 2022, 19(4): 10-12.
Yu JQ, Qin YF.Therapeutic effect of atomized inhalation of recombinant human epidermal growth factor external solution (aurin peptide) on laryngeal mucosa injury after tumor radiotherapy[J]. Journal of North Pharmacy, 2022, 19(4): 10-12.
[51] Sarvizadeh M, Hemati S, Meidani M, et al.Morphine mouthwash for the management of oral mucositis in patients with head and neck cancer[J]. Adv Biomed Res, 2015, 4: 44.
[52] Schaller AKCS, Peterson A, Bäckryd E.Pain management in patients undergoing radiation therapy for head and neck cancer - a descriptive study[J]. Scand J Pain, 2021, 21(2): 256-265.
[53] 夏小龙, 张文平, 胡建兵, 等. 加巴喷丁联合奥施康定治疗放射性口腔黏膜炎疼痛的前瞻性Ⅱ期研究[J] .中国当代医药, 2021, 28(21):19-22, 28.
Xia XL, Zhang WP, Hu JB, et al.A prospective phaseⅡstudy of gabapentin combined with oxycontin in the treatment of pain in radiation oral mucositis[J]. China Modern Medicine, 2021, 28(21): 19-22, 28.
[54] Smith DK, Cmelak A, Niermann K, et al.Preventive use of gabapentin to decrease pain and systemic symptoms in patients with head and neck cancer undergoing chemoradiation[J]. Head Neck, 2020, 42(12): 3497-3505.
[55] Sio TT, Le-Rademacher JG, Leenstra JL, et al.Effect of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash vs placebo on radiotherapy-related oral mucositis pain: the alliance A221304 randomized clinical trial[J]. JAMA, 2019, 321(15): 1481-1490.
[56] Allison RR, Ambrad AA, Arshoun Y, et al.Multi-institutional, randomized, double-blind, placebo-controlled trial to assess the efficacy of a mucoadhesive hydrogel(MuGard) in mitigating oral mucositis symptoms in patients being treated with chemoradiation therapy for cancers of the head and neck[J]. Cancer, 2014, 120(9): 1433-1440.
[57] Ueno T, Yatsuoka W, Ishiki H, et al.Effects of an oral mucosa protective formulation on chemotherapy- and/or radiotherapy-induced oral mucositis: a prospective study[J]. BMC Cancer, 2022, 22(1): 90.
[58] Elad S, Cheng KKF, Lalla RV, et al.MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy[J]. Cancer, 2020, 126(19): 4423-4431.
[59] 陈传本, 陈晓钟, 何侠, 等. 头颈部肿瘤放射治疗相关急性黏膜炎的预防与治疗指南[J] 中华肿瘤防治杂志, 2022, 29(2):79-91.
Chen CB, Chen XZ, He X, et al.Guidelines for the prevention and treatment of acute mucositis associated with radiation therapy for head and neck tumors[J]. Chinese Journal of Cancer Prevention and Treatment, 2022, 29(2):79-91.
[60] Shu Z, Zeng Z, Yu B, et al.Nutritional status and its association with radiation-induced oral mucositis in patients with nasopharyngeal carcinoma during radiotherapy: a prospective study[J]. Front Oncol, 2020, 10: 594687.