Oral mucositis: the hidden side of cancer therapy

Claudio Pulito, Antonio Cristaudo, Caterina La Porta, Stefano Zapperi, Giovanni Blandino, Aldo Morrone, Sabrina Strano, Claudio Pulito, Antonio Cristaudo, Caterina La Porta, Stefano Zapperi, Giovanni Blandino, Aldo Morrone, Sabrina Strano

Abstract

Inflammation response of epithelial mucosa to chemo- radiotherapy cytotoxic effects leads to mucositis, a painful side effect of antineoplastic treatments. About 40% of the patients treated with chemotherapy develop mucositis; this percentage rises to about 90% for head and neck cancer patients (HNC) treated with both chemo- and radiotherapy. 19% of the latter will be hospitalized and will experience a delay in antineoplastic treatment for high-grade mucositis management, resulting in a reduction of the quality of life, a worse prognosis and an increase in patient management costs. Currently, several interventions and prevention guidelines are available, but their effectiveness is uncertain. This review comprehensively describes mucositis, debating the impact of standard chemo-radiotherapy and targeted therapy on mucositis development and pointing out the limits and the benefits of current mucositis treatment strategies and assessment guidelines. Moreover, the review critically examines the feasibility of the existing biomarkers to predict patient risk of developing oral mucositis and their role in early diagnosis. Despite the expression levels of some proteins involved in the inflammation response, such as TNF-α or IL-1β, partially correlate with mucositis process, their presence does not exclude others mucositis-independent inflammation events. This strongly suggests the need to discover biomarkers that specifically feature mucositis process development. Non-coding RNAs might hold this potential.

Keywords: Biomarker; Cytokine; HNC; Non-coding RNA; Oral mucositis; Quality of life.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Mucositis pathobiology: (a) normal tissue; (b) initiation phase and primary injury response. Radio and chemotherapy-induced damages lead to an increase in DNA double strand brakes and ROS production with a consequent induction of cell apoptosis and DAMPS release. DAMPs and ROS signaling promote the NF-κB-mediated transcription of cytokines; (c) amplification of the injury signal. The effectors produced during the previous phase lead to an amplification of the injury signal. The released TNF-α initiates the activation of MAPK that sustains NF-κB activity. During this stage, the primary damage signaling is amplified through positive-feedback loop mechanisms. (d) ulceration. Breaks in the submucosa allows to microorganisms to invade this tissue district leading to mononuclear-infiltrating cells-mediated inflammation response; (e) tissue re-epithelialization. Stimuli from the submucosa extracellular matrix and mesenchyme promote the healing process
Fig. 2
Fig. 2
Representative images of mucositis induced by target therapies. (a-b) patchy ulcerations (aphtous ulcerations) induced by cetuximab, (c) erythema of the mucosa induced by temsirolimus and (d) ulcerations bleeding with minor trauma induced by everolimus

References

    1. Villa A, Sonis ST. Pharmacotherapy for the management of cancer regimen-related oral mucositis. Expert Opin Pharmacother. 2016;17:1801–7. doi: 10.1080/14656566.2016.1217993.
    1. Chansky K, Benedetti J, Macdonald JS. Differences in toxicity between men and women treated with 5-fluorouracil therapy for colorectal carcinoma. Cancer. 2005;103:1165–71. doi: 10.1002/cncr.20878.
    1. Sloan JA, Goldberg RM, Sargent DJ, Vargas-Chanes D, Nair S, Cha SS, et al. Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer. J Clin Oncol. 2002;20:1491–8. doi: 10.1200/JCO.2002.20.6.1491.
    1. Lalla RV, Sonis ST, Peterson DE. Management of oral mucositis in patients who have cancer. Dent Clin North Am 2008, 52:61–77, viii.
    1. Sonis ST. The pathobiology of mucositis. Nat Rev Cancer. 2004;4:277–84. doi: 10.1038/nrc1318.
    1. Manakova S, Puttonen KA, Raasmaja A, Mannisto PT. Ara-C induces apoptosis in monkey fibroblast cells. Toxicol In Vitro. 2003;17:367–73. doi: 10.1016/S0887-2333(03)00024-9.
    1. Logan RM, Stringer AM, Bowen JM, Gibson RJ, Sonis ST, Keefe DM. Serum levels of NFkappaB and pro-inflammatory cytokines following administration of mucotoxic drugs. Cancer Biol Ther. 2008;7:1139–45. doi: 10.4161/cbt.7.7.6207.
    1. Logan RM, Stringer AM, Bowen JM, Yeoh AS, Gibson RJ, Sonis ST, et al. The role of pro-inflammatory cytokines in cancer treatment-induced alimentary tract mucositis: pathobiology, animal models and cytotoxic drugs. Cancer Treat Rev. 2007;33:448–60. doi: 10.1016/j.ctrv.2007.03.001.
    1. Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell. 2000;103:239–52. doi: 10.1016/S0092-8674(00)00116-1.
    1. Braun S, Hanselmann C, Gassmann MG, auf dem Keller U, Born-Berclaz C, Chan K, et al. Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound. Mol Cell Biol. 2002;22:5492–505. doi: 10.1128/MCB.22.15.5492-5505.2002.
    1. Bamba S, Andoh A, Yasui H, Araki Y, Bamba T, Fujiyama Y. Matrix metalloproteinase-3 secretion from human colonic subepithelial myofibroblasts: role of interleukin-17. J Gastroenterol. 2003;38:548–54. doi: 10.1007/s00535-002-1101-8.
    1. Sasaki M, Kashima M, Ito T, Watanabe A, Izumiyama N, Sano M, et al. Differential regulation of metalloproteinase production, proliferation and chemotaxis of human lung fibroblasts by PDGF, interleukin-1beta and TNF-alpha. Mediators Inflamm. 2000;9:155–60. doi: 10.1080/09629350020002895.
    1. Bian L, Han G, Zhao CW, Garl PJ, Wang XJ. The role of Smad7 in oral mucositis. Protein Cell. 2015;6:160–9. doi: 10.1007/s13238-014-0130-4.
    1. Alikhani M, Alikhani Z, He H, Liu R, Popek BI, Graves DT. Lipopolysaccharides indirectly stimulate apoptosis and global induction of apoptotic genes in fibroblasts. J Biol Chem. 2003;278:52901–8. doi: 10.1074/jbc.M307638200.
    1. Engels-Deutsch M, Pini A, Yamashita Y, Shibata Y, Haikel Y, Scholler-Guinard M, et al. Insertional inactivation of pac and rmlB genes reduces the release of tumor necrosis factor alpha, interleukin-6, and interleukin-8 induced by Streptococcus mutans in monocytic, dental pulp, and periodontal ligament cells. Infect Immun. 2003;71:5169–77. doi: 10.1128/IAI.71.9.5169-5177.2003.
    1. Mougeot JC, Stevens CB, Morton DS, Brennan MT, Mougeot FB. Oral Microbiome and Cancer Therapy-Induced Oral Mucositis. J Natl Cancer Inst Monogr. 2019;53:lgz002.
    1. Sonis ST. Pathobiology of mucositis. Semin Oncol Nurs. 2004;20:11–5. doi: 10.1053/j.soncn.2003.10.003.
    1. Abdel-Rahman O, ElHalawani H, Essam-Eldin S. S-1-based regimens and the risk of oral and gastrointestinal mucosal injury: a meta-analysis with comparison to other fluoropyrimidines. Expert Opin Drug Saf. 2016;15:5–20. doi: 10.1517/14740338.2016.1105959.
    1. Keefe DM, Elting LS, Nguyen HT, Grunberg SM, Aprile G, Bonaventura A, et al. Risk and outcomes of chemotherapy-induced diarrhea (CID) among patients with colorectal cancer receiving multi-cycle chemotherapy. Cancer Chemother Pharmacol. 2014;74:675–80. doi: 10.1007/s00280-014-2526-5.
    1. Ribeiro RA, Wanderley CW, Wong DV, Mota JM, Leite CA, Souza MH, et al. Irinotecan- and 5-fluorouracil-induced intestinal mucositis: insights into pathogenesis and therapeutic perspectives. Cancer Chemother Pharmacol. 2016;78:881–93. doi: 10.1007/s00280-016-3139-y.
    1. Yamamoto H, Ishihara K, Takeda Y, Koizumi W, Ichikawa T. Changes in the mucus barrier during cisplatin-induced intestinal mucositis in rats. Biomed Res Int. 2013;2013:276186.
    1. Hartmann JT, Lipp HP. Toxicity of platinum compounds. Expert Opin Pharmacother. 2003;4:889–901. doi: 10.1517/14656566.4.6.889.
    1. Pico JL, Avila-Garavito A, Naccache P, Mucositis Its Occurrence, Consequences, and Treatment in the Oncology Setting. Oncologist. 1998;3:446–51. doi: 10.1634/theoncologist.3-6-446.
    1. Trotti A, Bellm LA, Epstein JB, Frame D, Fuchs HJ, Gwede CK, et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol. 2003;66:253–62. doi: 10.1016/S0167-8140(02)00404-8.
    1. Sanguineti G, Sormani MP, Marur S, Gunn GB, Rao N, Cianchetti M, et al. Effect of radiotherapy and chemotherapy on the risk of mucositis during intensity-modulated radiation therapy for oropharyngeal cancer. Int J Radiat Oncol Biol Phys. 2012;83:235–42. doi: 10.1016/j.ijrobp.2011.06.2000.
    1. Bonner JA, Giralt J, Harari PM, Baselga J, Spencer S, Bell D, et al. Association of human papillomavirus and p16 status with mucositis and dysphagia for head and neck cancer patients treated with radiotherapy with or without cetuximab: Assessment from a phase 3 registration trial. Eur J Cancer. 2016;64:1–11. doi: 10.1016/j.ejca.2016.05.008.
    1. Bossi P, Bergamini C, Miceli R, Cova A, Orlandi E, Resteghini C, et al. Salivary Cytokine Levels and Oral Mucositis in Head and Neck Cancer Patients Treated With Chemotherapy and Radiation Therapy. Int J Radiat Oncol Biol Phys. 2016;96:959–66. doi: 10.1016/j.ijrobp.2016.08.047.
    1. Villa A, Sonis ST. Mucositis: pathobiology and management. Curr Opin Oncol. 2015;27:159–64. doi: 10.1097/CCO.0000000000000180.
    1. Bossi P, Lucchesi M, Antonuzzo A. Gastrointestinal toxicities from targeted therapies: measurement, duration and impact. Curr Opin Support Palliat Care. 2015;9:163–7. doi: 10.1097/SPC.0000000000000128.
    1. Elting LS, Chang YC, Parelkar P, Boers-Doets CB, Michelet M, Hita G, et al. Risk of oral and gastrointestinal mucosal injury among patients receiving selected targeted agents: a meta-analysis. Support Care Cancer. 2013;21:3243–54. doi: 10.1007/s00520-013-1821-8.
    1. Sonis ST. Regimen-related gastrointestinal toxicities in cancer patients. Curr Opin Support Palliat Care. 2010;4:26–30. doi: 10.1097/SPC.0b013e328335fb76.
    1. Vigarios E, Epstein JB, Sibaud V. Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors. Support Care Cancer. 2017;25:1713–39. doi: 10.1007/s00520-017-3629-4.
    1. Shameem R, Lacouture M, Wu S. Incidence and risk of high-grade stomatitis with mTOR inhibitors in cancer patients. Cancer Invest. 2015;33:70–7. doi: 10.3109/07357907.2014.1001893.
    1. Abdel-Rahman O, Fouad M. Risk of oral and gastrointestinal mucosal injury in patients with solid tumors treated with everolimus, temsirolimus or ridaforolimus: a comparative systematic review and meta-analysis. Expert Rev Anticancer Ther. 2015;15:847–58. doi: 10.1586/14737140.2015.1047350.
    1. Basile D, Di Nardo P, Corvaja C, Garattini SK, Pelizzari G, Lisanti C, et al. Mucosal Injury during Anti-Cancer Treatment: From Pathobiology to Bedside. Cancers (Basel). 2019;11:857.
    1. Lacouture ME, Anadkat MJ, Bensadoun RJ, Bryce J, Chan A, Epstein JB, et al. Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer. 2011;19:1079–95. doi: 10.1007/s00520-011-1197-6.
    1. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–45. doi: 10.1056/NEJMoa033025.
    1. Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014;15:569–79. doi: 10.1016/S1470-2045(14)70118-4.
    1. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123–32. doi: 10.1056/NEJMoa050753.
    1. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733–43. doi: 10.1056/NEJMoa064320.
    1. Park K, Tan EH, O’Byrne K, Zhang L, Boyer M, Mok T, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17:577–89. doi: 10.1016/S1470-2045(16)30033-X.
    1. Ramalingam SS, Janne PA, Mok T, O’Byrne K, Boyer MJ, Von Pawel J, et al. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:1369–78. doi: 10.1016/S1470-2045(14)70452-8.
    1. Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015;16:897–907. doi: 10.1016/S1470-2045(15)00006-6.
    1. Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010;11:21–8. doi: 10.1016/S1470-2045(09)70311-0.
    1. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567–78. doi: 10.1056/NEJMoa053422.
    1. Maddalo M, Borghetti P, Tomasini D, Corvo R, Bonomo P, Petrucci A, et al. Cetuximab and Radiotherapy Versus Cisplatin and Radiotherapy for Locally Advanced Head and Neck Cancer: Long Term Survival and Toxicity Outcomes of a Randomized Phase Ii Trial. Int J Radiat Oncol Biol Phys. 2020;107:469-77.
    1. Magrini SM, Buglione M, Corvo R, Pirtoli L, Paiar F, Ponticelli P, et al. Cetuximab and Radiotherapy Versus Cisplatin and Radiotherapy for Locally Advanced Head and Neck Cancer: A Randomized Phase II Trial. J Clin Oncol. 2016;34:427–35. doi: 10.1200/JCO.2015.63.1671.
    1. Sibaud V, Niec RE, Schindler K, Busam KJ, Roche H, Modi S, et al. Ado-trastuzumab emtansine-associated telangiectasias in metastatic breast cancer: a case series. Breast Cancer Res Treat. 2014;146:451–6. doi: 10.1007/s10549-014-3001-z.
    1. Sibaud V, Vigarios E, Combemale P, Lamant L, Lacouture ME, Lacaze JL, et al. T-DM1-related telangiectasias: a potential role in secondary bleeding events. Ann Oncol. 2015;26:436–7. doi: 10.1093/annonc/mdu533.
    1. Lasheen S, Shohdy KS, Kassem L, Abdel-Rahman O. Fatigue, alopecia and stomatitis among patients with breast cancer receiving cyclin-dependent kinase 4 and 6 inhibitors: a systematic review and meta-analysis. Expert Rev Anticancer Ther. 2017;17:851–6. doi: 10.1080/14737140.2017.1355242.
    1. Sledge GW, Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol. 2017;35:2875–84. doi: 10.1200/JCO.2017.73.7585.
    1. Dickler MN, Tolaney SM, Rugo HS, Cortes J, Dieras V, Patt D, et al. MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR(+)/HER2(-) Metastatic Breast Cancer. Clin Cancer Res. 2017;23:5218–24. doi: 10.1158/1078-0432.CCR-17-0754.
    1. Xu H, Yu S, Liu Q, Yuan X, Mani S, Pestell RG, et al. Recent advances of highly selective CDK4/6 inhibitors in breast cancer. J Hematol Oncol. 2017;10:97. doi: 10.1186/s13045-017-0467-2.
    1. Boussemart L, Routier E, Mateus C, Opletalova K, Sebille G, Kamsu-Kom N, et al. Prospective study of cutaneous side-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients. Ann Oncol. 2013;24:1691–7. doi: 10.1093/annonc/mdt015.
    1. Gencler B, Gonul M. Cutaneous Side Effects of BRAF Inhibitors in Advanced Melanoma: Review of the Literature. Dermatol Res Pract. 2016;2016:5361569. doi: 10.1155/2016/5361569.
    1. Lacouture ME, Duvic M, Hauschild A, Prieto VG, Robert C, Schadendorf D, et al. Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist. 2013;18:314–22. doi: 10.1634/theoncologist.2012-0333.
    1. Yuan A, Kurtz SL, Barysauskas CM, Pilotte AP, Wagner AJ, Treister NS. Oral adverse events in cancer patients treated with VEGFR-directed multitargeted tyrosine kinase inhibitors. Oral Oncol. 2015;51:1026–33. doi: 10.1016/j.oraloncology.2015.09.003.
    1. Collins LK, Chapman MS, Carter JB, Samie FH. Cutaneous adverse effects of the immune checkpoint inhibitors. Curr Probl Cancer. 2017;41:125–8. doi: 10.1016/j.currproblcancer.2016.12.001.
    1. Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Ugurel S, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer. 2016;60:190–209. doi: 10.1016/j.ejca.2016.02.025.
    1. Marthey L, Mateus C, Mussini C, Nachury M, Nancey S, Grange F, et al. Cancer Immunotherapy with Anti-CTLA-4 Monoclonal Antibodies Induces an Inflammatory Bowel Disease. J Crohns Colitis. 2016;10:395–401. doi: 10.1093/ecco-jcc/jjv227.
    1. Gupta A, De Felice KM, Loftus EV, Jr, Khanna S. Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment Pharmacol Ther. 2015;42:406–17. doi: 10.1111/apt.13281.
    1. Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med. 2004;351:2590–8. doi: 10.1056/NEJMoa040125.
    1. Henke M, Alfonsi M, Foa P, Giralt J, Bardet E, Cerezo L, et al. Palifermin decreases severe oral mucositis of patients undergoing postoperative radiochemotherapy for head and neck cancer: a randomized, placebo-controlled trial. J Clin Oncol. 2011;29:2815–20. doi: 10.1200/JCO.2010.32.4103.
    1. Le QT, Kim HE, Schneider CJ, Murakozy G, Skladowski K, Reinisch S, et al. Palifermin reduces severe mucositis in definitive chemoradiotherapy of locally advanced head and neck cancer: a randomized, placebo-controlled study. J Clin Oncol. 2011;29:2808–14. doi: 10.1200/JCO.2010.32.4095.
    1. Koukourakis MI. Amifostine in clinical oncology: current use and future applications. Anticancer Drugs. 2002;13:181–209. doi: 10.1097/00001813-200203000-00001.
    1. Mell LK, Movsas B. Pharmacologic normal tissue protection in clinical radiation oncology: focus on amifostine. Expert Opin Drug Metab Toxicol. 2008;4:1341–50. doi: 10.1517/17425255.4.10.1341.
    1. Blijlevens NM, Donnelly JP, Naber AH, Schattenberg AV, DePauw BE. A randomised, double-blinded, placebo-controlled, pilot study of parenteral glutamine for allogeneic stem cell transplant patients. Support Care Cancer. 2005;13:790–6. doi: 10.1007/s00520-005-0790-y.
    1. Cerchietti LC, Navigante AH, Lutteral MA, Castro MA, Kirchuk R, Bonomi M, et al. Double-blinded, placebo-controlled trial on intravenous L-alanyl-L-glutamine in the incidence of oral mucositis following chemoradiotherapy in patients with head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2006;65:1330–7. doi: 10.1016/j.ijrobp.2006.03.042.
    1. Peterson DE. New strategies for management of oral mucositis in cancer patients. J Support Oncol. 2006;4:9–13.
    1. Vidal-Casariego A, Calleja-Fernandez A, Ballesteros-Pomar MD, Cano-Rodriguez I. Efficacy of glutamine in the prevention of oral mucositis and acute radiation-induced esophagitis: a retrospective study. Nutr Cancer. 2013;65:424–9. doi: 10.1080/01635581.2013.765017.
    1. Ward E, Smith M, Henderson M, Reid U, Lewis I, Kinsey S, et al. The effect of high-dose enteral glutamine on the incidence and severity of mucositis in paediatric oncology patients. Eur J Clin Nutr. 2009;63:134–40. doi: 10.1038/sj.ejcn.1602894.
    1. Arbabi-kalati F, Deghatipour M, Ansari Moghadam A. Evaluation of the efficacy of zinc sulfate in the prevention of chemotherapy-induced mucositis: a double-blind randomized clinical trial. Arch Iran Med. 2012;15:413–7.
    1. Eilers J, Harris D, Henry K, Johnson LA. Evidence-based interventions for cancer treatment-related mucositis: putting evidence into practice. Clin J Oncol Nurs. 2014;18 Suppl:80–96.
    1. Ertekin MV, Koc M, Karslioglu I, Sezen O. Zinc sulfate in the prevention of radiation-induced oropharyngeal mucositis: a prospective, placebo-controlled, randomized study. Int J Radiat Oncol Biol Phys. 2004;58:167–74. doi: 10.1016/S0360-3016(03)01562-1.
    1. Lin LC, Que J, Lin LK, Lin FC. Zinc supplementation to improve mucositis and dermatitis in patients after radiotherapy for head-and-neck cancers: a double-blind, randomized study. Int J Radiat Oncol Biol Phys. 2006;65:745–50. doi: 10.1016/j.ijrobp.2006.01.015.
    1. Rostan EF, DeBuys HV, Madey DL, Pinnell SR. Evidence supporting zinc as an important antioxidant for skin. Int J Dermatol. 2002;41:606–11. doi: 10.1046/j.1365-4362.2002.01567.x.
    1. Sangthawan D, Phungrassami T, Sinkitjarurnchai W. A randomized double-blind, placebo-controlled trial of zinc sulfate supplementation for alleviation of radiation-induced oral mucositis and pharyngitis in head and neck cancer patients. J Med Assoc Thai. 2013;96:69–76.
    1. Clarkson JE, Worthington HV, Furness S, McCabe M, Khalid T, Meyer S. Interventions for treating oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 2010:CD001973.
    1. Khurana H, Pandey RK, Saksena AK, Kumar A. An evaluation of Vitamin E and Pycnogenol in children suffering from oral mucositis during cancer chemotherapy. Oral Dis. 2013;19:456–64. doi: 10.1111/odi.12024.
    1. Sung L, Tomlinson GA, Greenberg ML, Koren G, Judd P, Ota S, et al. Serial controlled N-of-1 trials of topical vitamin E as prophylaxis for chemotherapy-induced oral mucositis in paediatric patients. Eur J Cancer. 2007;43:1269–75. doi: 10.1016/j.ejca.2007.02.001.
    1. Cinausero M, Aprile G, Ermacora P, Basile D, Vitale MG, Fanotto V, et al. New Frontiers in the Pathobiology and Treatment of Cancer Regimen-Related Mucosal Injury. Front Pharmacol. 2017;8:354. doi: 10.3389/fphar.2017.00354.
    1. Moslehi A, Taghizadeh-Ghehi M, Gholami K, Hadjibabaie M, Jahangard-Rafsanjani Z, Sarayani A, et al. N-acetyl cysteine for prevention of oral mucositis in hematopoietic SCT: a double-blind, randomized, placebo-controlled trial. Bone Marrow Transplant. 2014;49:818–23. doi: 10.1038/bmt.2014.34.
    1. Blakaj A, Bonomi M, Gamez ME, Blakaj DM. Oral mucositis in head and neck cancer: Evidence-based management and review of clinical trial data. Oral Oncol. 2019;95:29–34. doi: 10.1016/j.oraloncology.2019.05.013.
    1. Rao S, Dinkar C, Vaishnav LK, Rao P, Rai MP, Fayad R, et al. The Indian Spice Turmeric Delays and Mitigates Radiation-Induced Oral Mucositis in Patients Undergoing Treatment for Head and Neck Cancer: An Investigational Study. Integr Cancer Ther. 2014;13:201–10. doi: 10.1177/1534735413503549.
    1. Giralt J, Tao Y, Kortmann RD, Zasadny X, Contreras-Martinez J, Ceruse P, 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. Int J Radiat Oncol Biol Phys. 2020;106:320–8. doi: 10.1016/j.ijrobp.2019.10.023.
    1. Han G, Bian L, Li F, Cotrim A, Wang D, Lu J, et al. Preventive and therapeutic effects of Smad7 on radiation-induced oral mucositis. Nat Med. 2013;19:421–8. doi: 10.1038/nm.3118.
    1. Epstein JB, Silverman S, Jr, Paggiarino DA, Crockett S, Schubert MM, Senzer NN, et al. Benzydamine HCl for prophylaxis of radiation-induced oral mucositis: results from a multicenter, randomized, double-blind, placebo-controlled clinical trial. Cancer. 2001;92:875–85. doi: 10.1002/1097-0142(20010815)92:4<875::AID-CNCR1396>;2-1.
    1. Kazemian A, Kamian S, Aghili M, Hashemi FA, Haddad P. Benzydamine for prophylaxis of radiation-induced oral mucositis in head and neck cancers: a double-blind placebo-controlled randomized clinical trial. Eur J Cancer Care (Engl) 2009;18:174–8. doi: 10.1111/j.1365-2354.2008.00943.x.
    1. Gruber S, Schmidt M, Bozsaky E, Wolfram K, Haagen J, Habelt B, et al. Modulation of radiation-induced oral mucositis by pentoxifylline: preclinical studies. Strahlenther Onkol. 2015;191:242–7. doi: 10.1007/s00066-014-0775-1.
    1. Sayed R, El Wakeel L, Saad AS, Kelany M, El-Hamamsy M. Pentoxifylline and vitamin E reduce the severity of radiotherapy-induced oral mucositis and dysphagia in head and neck cancer patients: a randomized, controlled study. Med Oncol. 2019;37:8. doi: 10.1007/s12032-019-1334-5.
    1. Kudrimoti M, Curtis A, Azawi S, Worden F, Katz S, Adkins D, et al. Dusquetide: A novel innate defense regulator demonstrating a significant and consistent reduction in the duration of oral mucositis in preclinical data and a randomized, placebo-controlled phase 2a clinical study. J Biotechnol. 2016;239:115–25. doi: 10.1016/j.jbiotec.2016.10.010.
    1. Biswal BM, Zakaria A, Ahmad NM. Topical application of honey in the management of radiation mucositis: a preliminary study. Support Care Cancer. 2003;11:242–8. doi: 10.1007/s00520-003-0443-y.
    1. Khanal B, Baliga M, Uppal N. Effect of topical honey on limitation of radiation-induced oral mucositis: an intervention study. Int J Oral Maxillofac Surg. 2010;39:1181–5. doi: 10.1016/j.ijom.2010.05.014.
    1. Motallebnejad M, Akram S, Moghadamnia A, Moulana Z, Omidi S. The effect of topical application of pure honey on radiation-induced mucositis: a randomized clinical trial. J Contemp Dent Pract. 2008;9:40–7. doi: 10.5005/jcdp-9-3-40.
    1. Rashad UM, Al-Gezawy SM, El-Gezawy E, Azzaz AN. Honey as topical prophylaxis against radiochemotherapy-induced mucositis in head and neck cancer. J Laryngol Otol. 2009;123:223–8. doi: 10.1017/S0022215108002478.
    1. Maddocks-Jennings W, Wilkinson JM, Cavanagh HM, Shillington D. Evaluating the effects of the essential oils Leptospermum scoparium (manuka) and Kunzea ericoides (kanuka) on radiotherapy induced mucositis: a randomized, placebo controlled feasibility study. Eur J Oncol Nurs. 2009;13:87–93. doi: 10.1016/j.ejon.2009.01.002.
    1. You WC, Hsieh CC, Huang JT. Effect of extracts from indigowood root (Isatis indigotica Fort.) on immune responses in radiation-induced mucositis. J Altern Complement Med. 2009;15:771–8. doi: 10.1089/acm.2008.0322.
    1. Loo WT, Jin LJ, Chow LW, Cheung MN, Wang M. Rhodiola algida improves chemotherapy-induced oral mucositis in breast cancer patients. Expert Opin Investig Drugs. 2010;19(Suppl 1):91–100. doi: 10.1517/13543781003727057.
    1. Carl W, Emrich LS. Management of oral mucositis during local radiation and systemic chemotherapy: a study of 98 patients. J Prosthet Dent. 1991;66:361–9. doi: 10.1016/0022-3913(91)90264-W.
    1. Fidler P, Loprinzi CL, O’Fallon JR, Leitch JM, Lee JK, Hayes DL, et al. Prospective evaluation of a chamomile mouthwash for prevention of 5-FU-induced oral mucositis. Cancer. 1996;77:522–5. doi: 10.1002/(SICI)1097-0142(19960201)77:3<522::AID-CNCR14>;2-6.
    1. Su CK, Mehta V, Ravikumar L, Shah R, Pinto H, Halpern J, et al. Phase II double-blind randomized study comparing oral aloe vera versus placebo to prevent radiation-related mucositis in patients with head-and-neck neoplasms. Int J Radiat Oncol Biol Phys. 2004;60:171–7. doi: 10.1016/j.ijrobp.2004.02.012.
    1. Naidu MU, Ramana GV, Ratnam SV, Sudhavani T, Naidu KJ, Roy P, et al. A randomised, double-blind, parallel, placebo-controlled study to evaluate the efficacy of MF 5232 (Mucotrol), a concentrated oral gel wafer, in the treatment of oral mucositis. Drugs R D. 2005;6:291–8. doi: 10.2165/00126839-200506050-00005.
    1. Oberbaum M, Yaniv I, Ben-Gal Y, Stein J, Ben-Zvi N, Freedman LS, et al. A randomized, controlled clinical trial of the homeopathic medication TRAUMEEL S in the treatment of chemotherapy-induced stomatitis in children undergoing stem cell transplantation. Cancer. 2001;92:684–90. doi: 10.1002/1097-0142(20010801)92:3<684::AID-CNCR1371>;2-#.
    1. Chaveli-Lopez B, Bagan-Sebastian JV. Treatment of oral mucositis due to chemotherapy. J Clin Exp Dent. 2016;8:e201–9.
    1. Peterson DE, Boers-Doets CB, Bensadoun RJ, Herrstedt J. Management of oral and gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Ann Oncol. 2015;26(Suppl 5):v139–151. doi: 10.1093/annonc/mdv202.
    1. Mego M, Chovanec J, Vochyanova-Andrezalova I, Konkolovsky P, Mikulova M, Reckova M, et al. Prevention of irinotecan induced diarrhea by probiotics: A randomized double blind, placebo controlled pilot study. Complement Ther Med. 2015;23:356–62. doi: 10.1016/j.ctim.2015.03.008.
    1. Prisciandaro LD, Geier MS, Butler RN, Cummins AG, Howarth GS. Probiotic factors partially improve parameters of 5-fluorouracil-induced intestinal mucositis in rats. Cancer Biol Ther. 2011;11:671–7. doi: 10.4161/cbt.11.7.14896.
    1. Elad S, Cheng KKF, Lalla RV, Yarom N, Hong C, Logan RM, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2020;126:4423-31.
    1. Ferraiuolo M, Pulito C, Finch-Edmondson M, Korita E, Maidecchi A, Donzelli S, et al. Agave negatively regulates YAP and TAZ transcriptionally and post-translationally in osteosarcoma cell lines. Cancer Lett. 2018;433:18–32. doi: 10.1016/j.canlet.2018.06.021.
    1. Godwin P, Baird AM, Heavey S, Barr MP, O’Byrne KJ, Gately K. Targeting nuclear factor-kappa B to overcome resistance to chemotherapy. Front Oncol. 2013;3:120. doi: 10.3389/fonc.2013.00120.
    1. Pulito C, Korita E, Sacconi A, Valerio M, Casadei L, Lo Sardo F, et al. Dropwort-induced metabolic reprogramming restrains YAP/TAZ/TEAD oncogenic axis in mesothelioma. J Exp Clin Cancer Res. 2019;38:349. doi: 10.1186/s13046-019-1352-3.
    1. Pulito C, Mori F, Sacconi A, Casadei L, Ferraiuolo M, Valerio MC, et al. Cynara scolymus affects malignant pleural mesothelioma by promoting apoptosis and restraining invasion. Oncotarget. 2015;6:18134–50. doi: 10.18632/oncotarget.4017.
    1. Yarom N, Ariyawardana A, Hovan A, Barasch A, Jarvis V, Jensen SB, et al. Systematic review of natural agents for the management of oral mucositis in cancer patients. Support Care Cancer. 2013;21:3209–21. doi: 10.1007/s00520-013-1869-5.
    1. Lopes NN, Plapler H, Chavantes MC, Lalla RV, Yoshimura EM, Alves MT. Cyclooxygenase-2 and vascular endothelial growth factor expression in 5-fluorouracil-induced oral mucositis in hamsters: evaluation of two low-intensity laser protocols. Support Care Cancer. 2009;17:1409–15. doi: 10.1007/s00520-009-0603-9.
    1. Lopes NN, Plapler H, Lalla RV, Chavantes MC, Yoshimura EM, da Silva MA, et al. Effects of low-level laser therapy on collagen expression and neutrophil infiltrate in 5-fluorouracil-induced oral mucositis in hamsters. Lasers Surg Med. 2010;42:546–52. doi: 10.1002/lsm.20920.
    1. Basso FG, Oliveira CF, Kurachi C, Hebling J, Costa CA. Biostimulatory effect of low-level laser therapy on keratinocytes in vitro. Lasers Med Sci. 2013;28:367–74. doi: 10.1007/s10103-012-1057-8.
    1. Kujawa J, Zavodnik L, Zavodnik I, Buko V, Lapshyna A, Bryszewska M. Effect of low-intensity (3.75-25 J/cm2) near-infrared (810 nm) laser radiation on red blood cell ATPase activities and membrane structure. J Clin Laser Med Surg. 2004;22:111–7. doi: 10.1089/104454704774076163.
    1. Sonis ST, Hashemi S, Epstein JB, Nair RG, Raber-Durlacher JE. Could the biological robustness of low level laser therapy (Photobiomodulation) impact its use in the management of mucositis in head and neck cancer patients. Oral Oncol. 2016;54:7–14. doi: 10.1016/j.oraloncology.2016.01.005.
    1. Lalla RV, Bowen J, Barasch A, Elting L, Epstein J, Keefe DM, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2014;120:1453–61. doi: 10.1002/cncr.28592.
    1. Cerchietti LC, Navigante AH, Korte MW, Cohen AM, Quiroga PN, Villaamil EC, et al. Potential utility of the peripheral analgesic properties of morphine in stomatitis-related pain: a pilot study. Pain. 2003;105:265–73. doi: 10.1016/S0304-3959(03)00227-6.
    1. Allison RR, Ambrad AA, Arshoun Y, Carmel RJ, Ciuba DF, Feldman E, 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. Cancer. 2014;120:1433–40. doi: 10.1002/cncr.28553.
    1. Elting LS, Cooksley CD, Chambers MS, Garden AS. Risk, outcomes, and costs of radiation-induced oral mucositis among patients with head-and-neck malignancies. Int J Radiat Oncol Biol Phys. 2007;68:1110–20. doi: 10.1016/j.ijrobp.2007.01.053.
    1. Citrin DE, Hitchcock YJ, Chung EJ, Frandsen J, Urick ME, Shield W, et al. Determination of cytokine protein levels in oral secretions in patients undergoing radiotherapy for head and neck malignancies. Radiat Oncol. 2012;7:64. doi: 10.1186/1748-717X-7-64.
    1. Xanthinaki A, Nicolatou-Galitis O, Athanassiadou P, Gonidi M, Kouloulias V, Sotiropoulou-Lontou A, et al. Apoptotic and inflammation markers in oral mucositis in head and neck cancer patients receiving radiotherapy: preliminary report. Support Care Cancer. 2008;16:1025–33. doi: 10.1007/s00520-007-0379-8.
    1. Meirovitz A, Kuten M, Billan S, Abdah-Bortnyak R, Sharon A, Peretz T, et al. Cytokines levels, severity of acute mucositis and the need of PEG tube installation during chemo-radiation for head and neck cancer–a prospective pilot study. Radiat Oncol. 2010;5:16. doi: 10.1186/1748-717X-5-16.
    1. Seyyednejad F, Rezaee A, Haghi S, Goldust M. Survey of pre-inflammation cytokines levels in radiotherapy-induced-mucositis. Pak J Biol Sci. 2012;15:1098–101. doi: 10.3923/pjbs.2012.1098.1101.
    1. Chen HW, Chang YC, Lai YL, Chen YJ, Huang MJ, Leu YS, et al. Change of plasma transforming growth factor-beta1 levels in nasopharyngeal carcinoma patients treated with concurrent chemo-radiotherapy. Jpn J Clin Oncol. 2005;35:427–32. doi: 10.1093/jjco/hyi126.
    1. Chen HW, Yang SF, Chang YC, Wang TY, Chen YJ, Hwang JJ. Epstein-Barr virus infection and plasma transforming growth factor-beta1 levels in head and neck cancers. Acta Otolaryngol. 2008;128:1145–51. doi: 10.1080/00016480701714293.
    1. Epstein JB, Emerton S, Guglietta A, Le N. Assessment of epidermal growth factor in oral secretions of patients receiving radiation therapy for cancer. Oral Oncol. 1997;33:359–63. doi: 10.1016/S1368-8375(97)00009-2.
    1. Epstein JB, Gorsky M, Guglietta A, Le N, Sonis ST. The correlation between epidermal growth factor levels in saliva and the severity of oral mucositis during oropharyngeal radiation therapy. Cancer. 2000;89:2258–65. doi: 10.1002/1097-0142(20001201)89:11<2258::AID-CNCR14>;2-Z.
    1. Dumbrigue HB, Sandow PL, Nguyen KH, Humphreys-Beher MG. Salivary epidermal growth factor levels decrease in patients receiving radiation therapy to the head and neck. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;89:710–6. doi: 10.1067/moe.2000.106343.
    1. Ki Y, Kim W, Nam J, Kim D, Park D. C-reactive protein levels and radiation-induced mucositis in patients with head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2009;75:393–8. doi: 10.1016/j.ijrobp.2008.11.012.
    1. Ehrsson YT, Hellstrom PM, Brismar K, Sharp L, Langius-Eklof A, Laurell G. Explorative study on the predictive value of systematic inflammatory and metabolic markers on weight loss in head and neck cancer patients undergoing radiotherapy. Support Care Cancer. 2010;18:1385–91. doi: 10.1007/s00520-009-0758-4.
    1. Mohammed FF, Poon I, Zhang L, Elliott L, Hodson ID, Sagar SM, et al. Acute-phase response reactants as objective biomarkers of radiation-induced mucositis in head and neck cancer. Head Neck. 2012;34:985–93. doi: 10.1002/hed.21848.
    1. Chethana, Rao PS, Madathil LP, Rao S, Shetty P, Patidar M. Quantitative Analysis of Acute Phase Proteins in Post Chemo-Radiation Mucositis. J Clin Diagn Res. 2015;9:ZC28–31.
    1. Bhattathiri VN, Sreelekha TT, Sebastian P, Remani P, Chandini R, Vijayakumar T, et al. Influence of plasma GSH level on acute radiation mucositis of the oral cavity. Int J Radiat Oncol Biol Phys. 1994;29:383–6. doi: 10.1016/0360-3016(94)90294-1.
    1. Wardman P, Folkes LK, Bentzen SM, Stratford MR, Hoskin PJ, Phillips H, et al. Influence of plasma glutathione levels on radiation mucositis. Int J Radiat Oncol Biol Phys. 2001;51:460–4. doi: 10.1016/S0360-3016(01)01612-1.
    1. Li P, Du CR, Xu WC, Shi ZL, Zhang Q, Li ZB, et al. Correlation of dynamic changes in gamma-H2AX expression in peripheral blood lymphocytes from head and neck cancer patients with radiation-induced oral mucositis. Radiat Oncol. 2013;8:155. doi: 10.1186/1748-717X-8-155.
    1. Fleckenstein J, Kuhne M, Seegmuller K, Derschang S, Melchior P, Graber S, et al. The impact of individual in vivo repair of DNA double-strand breaks on oral mucositis in adjuvant radiotherapy of head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2011;81:1465–72. doi: 10.1016/j.ijrobp.2010.08.004.
    1. Gonzalez-Arriagada WA, Ramos LM, Silva AA, Vargas PA, Coletta RD, Bingle L, et al. Salivary BPIFA1 (SPLUNC1) and BPIFA2 (SPLUNC2 A) are modified by head and neck cancer radiotherapy. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015;119:48–58. doi: 10.1016/j.oooo.2014.09.026.
    1. Handschel J, Prott FJ, Sunderkotter C, Metze D, Meyer U, Joos U. Irradiation induces increase of adhesion molecules and accumulation of beta2-integrin-expressing cells in humans. Int J Radiat Oncol Biol Phys. 1999;45:475–81. doi: 10.1016/S0360-3016(99)00202-3.
    1. Normando AGC, Rocha CL, de Toledo IP, de Souza Figueiredo PT, Dos Reis PED, De Luca Canto G, et al. Biomarkers in the assessment of oral mucositis in head and neck cancer patients: a systematic review and meta-analysis. Support Care Cancer. 2017;25:2969–88. doi: 10.1007/s00520-017-3783-8.
    1. Pulito C, Terrenato I, Di Benedetto A, Korita E, Goeman F, Sacconi A, et al. Cdx2 polymorphism affects the activities of vitamin D receptor in human breast cancer cell lines and human breast carcinomas. PLoS One. 2015;10:e0124894. doi: 10.1371/journal.pone.0124894.
    1. Pratesi N, Mangoni M, Mancini I, Paiar F, Simi L, Livi L, et al. Association between single nucleotide polymorphisms in the XRCC1 and RAD51 genes and clinical radiosensitivity in head and neck cancer. Radiother Oncol. 2011;99:356–61. doi: 10.1016/j.radonc.2011.05.062.
    1. Venkatesh GH, Manjunath VB, Mumbrekar KD, Negi H, Fernandes DJ, Sharan K, et al. Polymorphisms in radio-responsive genes and its association with acute toxicity among head and neck cancer patients. PLoS One. 2014;9:e89079. doi: 10.1371/journal.pone.0089079.
    1. Werbrouck J, De Ruyck K, Duprez F, Veldeman L, Claes K, Van Eijkeren M, et al. Acute normal tissue reactions in head-and-neck cancer patients treated with IMRT: influence of dose and association with genetic polymorphisms in DNA DSB repair genes. Int J Radiat Oncol Biol Phys. 2009;73:1187–95. doi: 10.1016/j.ijrobp.2008.08.073.
    1. Gutierrez-Camino A, Oosterom N, den Hoed MAH, Lopez-Lopez E, Martin-Guerrero I, Pluijm SMF, et al. The miR-1206 microRNA variant is associated with methotrexate-induced oral mucositis in pediatric acute lymphoblastic leukemia. Pharmacogenet Genomics. 2017;27:303–6. doi: 10.1097/FPC.0000000000000291.
    1. Laheij A, Raber-Durlacher JE, Koppelmans RGA, Huysmans M, Potting C, van Leeuwen SJM, et al. Microbial changes in relation to oral mucositis in autologous hematopoietic stem cell transplantation recipients. Sci Rep. 2019;9:16929. doi: 10.1038/s41598-019-53073-w.
    1. Gawronski KAB, Kim J. Single cell transcriptomics of noncoding RNAs and their cell-specificity. Wiley Interdiscip Rev RNA. 2017;8. 10.1002/wrna.1433.
    1. Grillone K, Riillo C, Scionti F, Rocca R, Tradigo G, Guzzi PH, et al. Non-coding RNAs in cancer: platforms and strategies for investigating the genomic “dark matter”. J Exp Clin Cancer Res. 2020;39:117.
    1. Zhang Y, Liang W, Zhang P, Chen J, Qian H, Zhang X, et al. Circular RNAs: emerging cancer biomarkers and targets. J Exp Clin Cancer Res. 2017;36:152. doi: 10.1186/s13046-017-0624-z.

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