The majority of patients undergoing radiation therapy for head and neck (HN) cancer will develop oral mucositis, which is a clinical syndrome characterized by erythema, ulcerations, and odynophagia (see Table 1<\/i>). It is almost universal and more severe among patients with oral cavity, oropharynx, and nasopharynx primaries.^{1\u20133<\/sup> Although therapeutic ratio and outcomes are improved by concominant chemotherapy4,5<\/sup> or altered fractionation,6<\/sup> both are related to dose-limiting mucositis and increase the risk for consequential dysphagia. Finally, mucositis is associated with unplanned breaks in radiation therapy, hospital admissions for pain management or insertion of enteral feeding tube,3 and is associated with increased costs.7<\/sup> Reducing mucositis could be achieved by different means. This editorial will describe the available data and future perspectives in mucositis management.<\/p>\n}

Mouth Hygiene and Preventive Dental Care <\/b>
\nBasic oral care protocols including daily topical fluoride, flossing, and frequent mouth rinses can be helpful for preventing and alleviating of mucositis.^{8,9<\/sup> The evidence to support this approach is not strong, yet maintaining oral hygiene is supported by the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology(MASCC\/ISOO) Clinical Practice Guidelines.10<\/sup> Although different mouthwash preparations are available (normal saline, sodium bicarbonate, calcium phosphate), none of them had been consistently recommended by the gathered evidence-based data, but the panel suggested that they might beconsidered for oral care. The only rinse that the MASCC\/ISOO recommended against was chlorhexidine mouthwash.10<\/sup><\/p>\n}

Pretreatment dental care reduces risk for osteoradionecrosis.^{11<\/sup> In addition, designing dental protective stents to prevent electron back-scatter off metal caps\/bridges into the neighboring soft tissue could be beneficial for mucositis risk reduction.12\u201314<\/sup><\/p>\n}

Reducing Mucositis by Antiviral\/Antibacterial\/ Mucosal Coating Agents <\/b>
\nDifferent preparations including acyclovir, nystatin, fluconazole, sucralfate, and aluminum salt of sulfated sucrose were evaluated by multiple (mostly conflicting) studies. None of the above can be recommended to reduce chemoraditherapy mucositis.^{15<\/sup><\/p>\n}

Newer mucosal protectants are available for HN cancer patients. Keratinocyte growth factor (palifermin) stimulates differentiation of mucosal cells. Two randomized studies have shown reduction of likelihood and median duration of severe mucositis, but narcotic use, patient-reported pain, and chemoradiotherapy compliance were not different from placebo.^{16,17<\/sup> Marketed mucoadhesive hydrogel has been reported to significantly reduce patient-reported oral soreness and mucositis World Health Organization (WHO) score on the last day of radiation therapy compared with placebo,18<\/sup> but it was not evaluated versus other preparations.<\/p>\n}

Pain Management <\/b>
\nPain is the main debilitating symptom of mucositis. Topical anesthetics, narcotics, and antidepressants could control it. While the former could not be advocated based on the available data,^{15<\/sup> both topical morphine19,20<\/sup> and transdermal fentanyl15,21 <\/sup>had been shown as highly effective in producing pain relief. In addition, long-acting opioid patches reduce the need for immediate-release opiates and provide lengthier freedom from pain.<\/p>\n}

Tricyclic antidepressants reduce patient-reported symptoms without affecting the severity of mucositis. A randomized, double-blind, crossover study^{22<\/sup> of oral solution containing doxepin had shown significantly reduced mucositis pain compared with placebo, it was associated with more burning, unpleasant taste, and greater drowsiness, but most patients elected to continue doxepin during radiotherapy (RT) after the double-blind part of the study was completed.<\/p>\n}

Different recipes for solutions (so-called magic mouthwash solutions) containing a mix of different antibiotics, antihistamines, local anesthetics, an antifungal (e.g. nystatin), a corticosteroid, and antacids are in use; unfortunately, there are no data to show any benefit in alleviation of mucositis.^{10<\/sup><\/p>\n}

Pharmacologic Prevention and Treatmentof Mucositis <\/b>
\nAmifostine is an organic thiophosphate that competes with oxygen binding to the free radicals, which is essential to their activity in damaging the DNA, exerting a protective effect. The pro-drug is activated by membrane alkaline phosphatase, the concentration of which is lower in the acidic environment of cancer, potentially resulting in preferential protection of normal tissues. Unfortunately, besides the side effects (hypotension, nausea if administered parenterally, and skin reaction; local pain and nausea if injected subcutaneously), three randomized studies^{23\u201325<\/sup> failed to show a definitive benefit of amifostine over placebo.<\/p>\n}

Better Radiosensitizers? <\/b>
\nEpidermal growth factor receptor (EGFR) is overexpressed in the majority of HN tumors, suggesting a potential benefit of EGFR signaling pathway inhibition. Indeed, in the randomized phase III study^{26<\/sup> RT concurrent with cetuximab (a monoclonal antibody to EGFR) resulted in improved tumorcontrol rates compared with RT alone with no difference in mucositis rates between the arms. Still, others27<\/sup> report that cetuximab can induce enhanced mucosal injury. This finding could be potentially explained by heterogeneity in EGFR expression found in mucosal cells in different patients.28<\/sup><\/p>\n}

Reduced Treatment Intensity <\/b>
\nHuman papillomavirus (HPV)-positive oropharyngeal cancer has a better prognosis, especially in patients without or with minimal smoking history.^{29<\/sup> Overall survival in this favorable cohort exceeds 80 %. This yielded the following hypothesis: can we keep high tumor control-rates in these patients while reducing treatment intensity and toxicity? The phase II Eastern Cooperative Oncology Group (ECOG) 1308 study30<\/sup> was designed to answer this question. If complete remission (CR) was achieved in the primary tumor following induction chemotherapy, the dose to the primary tumor bed was reduced to 54 Gy (instead of the standard dose of 70 Gy), concurrent with cerituximab. Local-regional control rate in these patients was 95 %. The ongoing phase III Quarterback trial will provide us with definite answers on this topic.<\/p>\n}

Mucositis-related Toxicity <\/b>
\nAlterations in taste are dose dependent, and radiation to the anterior tongue and oral cavity seems to have the biggest effect.^{31<\/sup> Preliminary data suggest zinc sulfate may alleviate these symptoms. Unfortunately this hypothesis was refuted by findings of the negative phase III study.32<\/sup><\/p>\n}

N-acetyl cystein is a mucolytic that breaks disulfide bonds in mucus.^{33<\/sup> We prescribe it after the completion of RT to patients who still suffer thick secretions, although data to support this recommendation are lacking.<\/p>\n}

Finally, to address complications related to significant weight loss caused by malnutrition, prophylactic insertion of percutaneous endoscopic gastrostomy (PEG) feeding tubes in all patients prior to RT start was compared with reactive feeding tubes in two randomized trials.^{34,35<\/sup> Both found that prophylactic PEG resulted in less weight loss, improved patientreported quality of life (QOL), and lower long-term dysphagia. However, the benefit of prophylactic PEGs may come at the expense of longer dependence on PEG and increased late esophageal strictures requiring dilatation (30 % versus 6 %).36,37<\/sup><\/p>\n}

Conclusions <\/b>
\nHN patients following RT are affected in different ways, many of them related to mucositis. Proper management of mucosal damage by prophylactic (maintaining of mouth hygiene and dental care) and active (pain management, dose reduction when possible, and nutritional care) steps can substantially improve treatment-related QOL.<\/p>\n","protected":false},"excerpt":{"rendered":"

The majority of patients undergoing radiation therapy for head and neck (HN) cancer will develop oral mucositis, which is a clinical syndrome characterized by erythema, ulcerations, and odynophagia (see Table 1). It is almost universal and more severe among patients with oral cavity, oropharynx, and nasopharynx primaries.1\u20133 Although therapeutic ratio and outcomes are improved by […]<\/p>\n","protected":false},"author":53489,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_relevanssi_hide_post":"","_relevanssi_hide_content":"","_relevanssi_pin_for_all":"","_relevanssi_pin_keywords":"","_relevanssi_unpin_keywords":"","_relevanssi_related_keywords":"","_relevanssi_related_include_ids":"","_relevanssi_related_exclude_ids":"","_relevanssi_related_no_append":"","_relevanssi_related_not_related":"","_relevanssi_related_posts":"","_relevanssi_noindex_reason":"","rank_math_lock_modified_date":false,"footnotes":""},"categories":[1],"tags":[],"class_list":["post-2192","post","type-post","status-publish","format-standard","hentry","category-uncategorized","vocabulary_1-head-and-neck-cancer","vocabulary_1-supportive-cancer-care"],"acf":{"wpcf-article_introduction":"","wpcf-article_abstract":"Painful ulcers and sores and related dysphagia, thick saliva, taste impairment, and weight loss significantly affect the quality of life of head and neck cancer patients undergoing radiation treatment with or without concomitant chemotherapy. The available data for mucositis prophylaxis and treatment could be heterogeneous for clinical interpretation. In this editorial, we will describe what is already known and to outline the most important aspects of mucositis care.","wpcf-article_keywords":"Chemoradiotherapy, head and neck cancer, mucositis, radiotherapy, supportive care","wpcf-article_citation_override":"Oncology & Hematology Review,<\/i> 2015;11(1):50\u20132 DOI: https:\/\/doi.org\/10.17925\/OHR.2015.11.01.50<\/a>","wpcf-compliance-with-ethics":"","wpcf-article_disclosure":"Eli Sapir, MD, and Avraham Eisbruch, MD, have no conflicts of interest to declare. No funding was received in the publication of this article.","wpcf-review_process":"","wpcf-authorship":"","wpcf-article_correspondence":"Avraham Eisbruch, MD, Department of Radiation Oncology, University of Michigan Hospital, Ann Arbor, MI 48109, US. E: Eisbruch@umich.edu\r\n\r\nOpen Access:<\/b> This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.","wpcf-article_support":"","wpcf-open_access":"","wpcf-article_pdf":"https:\/\/touchoncology.com\/wp-content\/uploads\/sites\/2\/2015\/07\/private_articles_21951_pdf_AvrahamEisbruch.pdf","wpcf-article_pdf-gated":true,"wpcf-article_doi":"","wpcf-old_nid":"","wpcf-article_image":"https:\/\/touchoncology.com\/wp-content\/uploads\/sites\/2\/2018\/08\/Onc-28_T.png","wpcf-editor_choice":true,"wpcf-old_author_ids":"","wpcf-article_references":"

\r\n \t
1. Trotti A, Bellm LA, Epstein JB, et al., Mucositis incidence, severity\r\nand associated outcomes in patients with head and neck\r\ncancer receiving radiotherapy with or without chemotherapy: a\r\nsystematic literature review, Radiother Oncol, 2003;66:253\u201362.<\/li>\r\n \t
2. Vera-Llonch M, Oster G, Hagiwara M, Sonis S, Oral mucositis\r\nin patients undergoing radiation treatment for head and neck\r\ncarcinoma, Cancer, 2006;106:329\u201336.<\/li>\r\n \t
3. Elting LS, Cooksley CD, Chambers MS, Garden AS, Risk,\r\noutcomes, and costs of radiation-induced oral mucositis among\r\npatients with head-and-neck malignancies, Int J Radiat Oncol\r\nBiol Phys, 2007;68:1110\u201320.<\/li>\r\n \t
4. Pignon JP, Bourhis J, Domenge C, et al., Chemotherapy added\r\nto locoregional treatment for head and neck squamous-cell\r\ncarcinoma: Three meta-analyses of updated individual data.\r\nMACH-NC collaborative group. Meta-analysis of chemotherapy\r\non head and neck cancer, Lancet, 2000;355:949\u201355.<\/li>\r\n \t
5. Lee IH, Eisbruch A, Mucositis versus tumor control: the\r\ntherapeutic index of adding chemotherapy to irradiation of head\r\nand neck cancer, Int J Radiat Oncol Biol Phys, 2009;75:1060\u20133.<\/li>\r\n \t
6. Bourhis J, Overgaard J, Audry H, Ang KK, et al., Hyperfractionated\r\nor accelerated radiotherapy in head and neck cancer: a metaanalysis,\r\nLancet, 2006;368:843\u201354.<\/li>\r\n \t
7. Elting LS, Cooksley CD, Chambers MS, Garden AS, Risk,\r\noutcomes, and costs of radiation-induced oral mucositis among\r\npatients with head-and-neck malignancies, Int J Radiat Oncol\r\nBiol Phys, 2007;68:1110\u201320.<\/li>\r\n \t
8. McGuire DB, Correa ME, Johnson J, Wienandts P, The role\r\nof basic oral care and good clinical practice principles in\r\nthe management of oral mucositis, Support Care Cancer,\r\n2006;14:541\u20137.<\/li>\r\n \t
9. McGuire DB, Fulton JS, Park J, et al., Systematic review of basic\r\noral care for the management of oral mucositis in cancer\r\npatients, Support Care Cancer, 2013;21:3165\u201377.<\/li>\r\n \t
10. Lalla RV, Bowen J, Barasch A, et al., MASCC\/ISOO clinical\r\npractice guidelines for the management of mucositis secondary\r\nto cancer therapy, Cancer, 2014;120:1453\u201361.<\/li>\r\n \t
11. Ben-David MA, Diamante M, Radawski JD, et al., Lack of\r\nosteoradionecrosis of the mandible after intensity-modulated\r\nradiotherapy for head and neck cancer: likely contributions of\r\nboth dental care and improved dose distributions, Int J Radiat\r\nOncol Biol Phys, 2007;68:396\u2013402.<\/li>\r\n \t
12. Thilmann C, Adamietz IA, Ramm U, et al., In vivo dose increase in\r\nthe presence of dental alloys during 60Co-gamma-ray therapy\r\nof the oral cavity, Med Dosim, 1996;21:149\u201354.<\/li>\r\n \t
13. Chin DW, Treister N, Friedland B, et al., Effect of dental\r\nrestorations and prostheses on radiotherapy dose distribution:\r\na Monte Carlo study, J Appl Clin Med Phys, 2009;10:2853.<\/li>\r\n \t
14. Reitemeier B, Reitemeier G, Schmidt A, et al., Evaluation of a device\r\nfor attenuation of electron release from dental restorations in a\r\ntherapeutic radiation field, J Prosthet Dent, 2002;87:323\u20137.<\/li>\r\n \t
15. Saunders DP, Epstein JB, Elad S, et al., Systematic review of\r\nantimicrobials, mucosal coating agents, anesthetics, and\r\nanalgesics for the management of oral mucositis in cancer\r\npatients, Support Care Cancer, 2013;21:3191\u2013207.<\/li>\r\n \t
16. Le QT, Kim HE, Schneider CJ, et al., Palifermin reduces severe\r\nmucositis in definitive chemoradiotherapy of locally advanced\r\nhead and neck cancer: a randomized, placebo-controlled study,\r\nJ Clin Oncol, 2011;29:2808\u201314.<\/li>\r\n \t
17. Henke M, Alfonsi M, Foa P, et al., Palifermin decreases\r\nsevere oral mucositis of patients undergoing postoperative\r\nradiochemotherapy for head and neck cancer: a randomized,\r\nplacebo-controlled trial, J Clin Oncol, 2011;29:2815\u201320.<\/li>\r\n \t
18. Allison RR, Ambrad AA, Arshoun Y, et al., Multi-institutional,\r\nrandomized, double-blind, placebo-controlled trial to assess\r\nthe efficacy of a mucoadhesive hydrogel (MuGard) in mitigating\r\noral mucositis symptoms in patients being treated with\r\nchemoradiation therapy for cancers of the head and neck,\r\nCancer, 2014;120:1433\u201340.<\/li>\r\n \t
19. Cerchietti LC, Navigante AH, Bonomi MR, et al., Effect of topical\r\nmorphine for mucositis-associated pain following concomitant\r\nchemoradiotherapy for head and neck carcinoma, Cancer,\r\n2002;95:2230\u20136.<\/li>\r\n \t
20. Cerchietti LC, Navigante AH, K\u00f6rte MW, et al., Potential utility of\r\nthe peripheral analgesic properties of morphine in stomatitisrelated\r\npain: a pilot study, Pain, 2003;105:265\u201373.<\/li>\r\n \t
21. Chang JT, Lin CY, Lin JC, et al., Transdermal fentanyl for pain\r\ncaused by radiotherapy in head and neck cancer patients\r\ntreated in an outpatient setting: a multicenter trial in Taiwan,\r\nJpn J Clin Oncol, 2010;40:307\u201312.<\/li>\r\n \t
22. Leenstra JL, Miller RC, Qin R, et al., Doxepin rinse versus\r\nplacebo in the treatment of acute oral mucositis pain in\r\npatients receiving head and neck radiotherapy with or without\r\nchemotherapy: a phase III, randomized, double-blind trial,\r\nJ Clin Oncol, 2014;32:1571\u20137.<\/li>\r\n \t
23. Buentzel J, Micke O, Adamietz IA, et al., Intravenous amifostine\r\nduring chemoradiotherapy for head-and-neck cancer: a\r\nrandomized placebo-controlled phase III study, Int J Radiat\r\nOncol Biol Phys, 2006;64:684\u201391.<\/li>\r\n \t
24. Vacha P, Fehlauer F, Mahlmann B, et al., Randomized phase\r\nIII trial of postoperative radiochemotherapy +\/- amifostine in\r\nhead and neck cancer. Is there evidence for radioprotection?,\r\nStrahlenther Onkol, 2003;179:385\u20139.<\/li>\r\n \t
25. Haddad R, Sonis S, Posner M, et al., Randomized phase 2 study\r\nof concomitant chemoradiotherapy using weekly carboplatin\/\r\npaclitaxel with or without daily subcutaneous amifostine in\r\npatients with locally advanced head and neck cancer, Cancer,\r\n2009;115:4514\u201323.<\/li>\r\n \t
26. Bonner JA, Harari PM, Giralt J, et al., Radiotherapy plus\r\ncetuximab for squamous-cell carcinoma of the head and neck,\r\nN Engl J Med, 2006;354:567\u201378.<\/li>\r\n \t
27. Pryor DI, Porceddu SV, Burmeister BH, et al., Enhanced toxicity\r\nwith concurrent cetuximab and radiotherapy in head and neck\r\ncancer, Radiother Oncol, 2009;90:172\u20136.<\/li>\r\n \t
28. Tsien CI, Nyati MK, Ahsan A, et al., Effect of erlotinib on epidermal\r\ngrowth factor receptor and downstream signaling in oral cavity\r\nsquamous cell carcinoma, Head Neck, 2013;35:1323\u201330.<\/li>\r\n \t
29. Ang KK, Harris J, Wheeler R, et al., Human papillomavirus and\r\nsurvival of patients with oropharyngeal cancer, N Engl J Med,\r\n2010;363:24\u201335.<\/li>\r\n \t
30. Marur S, Lee J, Cmelak A, et al., Reduced-dose IMRT in human\r\npapilloma virus (HPV)-associated resectable oropharyngeal\r\nsquamous carcinomas (OPSCC) after clinical complete response\r\n(cCR) to induction chemotherapy (IC), J Clin Oncol, 2014;32:5s\r\n(suppl; abstr LBA6006).<\/li>\r\n \t
31. Vernia N, Feng FY, Braun T, et al., Dosimetric predictors\r\nof taste impairment in patients treated with\r\nchemoradiation for head and neck cancer, IJROBP,\r\n2009;75(Suppl):S179.<\/li>\r\n \t
32. Halyard MY, Jatoi A, Sloan JA, et al., Does zinc sulfate\r\nprevent therapy-induced taste alterations in head and\r\nneck cancer patients? Results of phase III double-blind,\r\nplacebo-controlled trial from the North Central Cancer\r\nTreatment Group (N01C4), Int J Radiat Oncol Biol Phys,\r\n2007;67:1318\u201322.<\/li>\r\n \t
33. Sheffner AL, The reduction in vitro in viscosity of\r\nmucoprotein solutions by a new mucolytic agent, N-acetyl-Lcysteine,\r\nAnn N Y Acad Sci, 1963;106:298\u2013310.<\/li>\r\n \t
34. Salas S, Baumstarck-Barrau K, Alfonsi M, et al., Impact of\r\nthe prophylactic gastrostomy for unresectable squamous cell\r\nhead and neck carcinomas treated with radio-chemotherapy\r\non quality of life: Prospective randomized trial, Radiother Oncol,\r\n2009;93:503\u20139.<\/li>\r\n \t
35. Silander E, Nyman J, Bove M, et al., Impact of prophylactic\r\npercutaneous endoscopic gastrostomy on malnutrition and\r\nquality of life in patients with head and neck cancer:\r\na randomized study, Head Neck, 2012;34:1\u20139.<\/li>\r\n \t
36. Chen AM, Li BQ, Lau DH, et al., Evaluating the role of\r\nprophylactic gastrostomy tube placement prior to definitive\r\nchemoradiotherapy for head and neck cancer, Int J Radiat\r\nOncol Biol Phys, 2010;78:1026\u201332.<\/li>\r\n \t
37. Koyfman SA, Adelstein DJ, Enteral feeding tubes in patients\r\nundergoing definitive chemoradiation therapy for head-andneck\r\ncancer: a critical review, Int J Radiat Oncol Biol Phys,\r\n2012;84:581\u20139.<\/li>\r\n<\/ol>","wpcf-article_received_date":"2015-02-04T00:00:00","wpcf-article_accepted_date":"2015-02-04T00:00:00","wpcf-article_published_online":null,"wpcf-podcast":"","wpcf-ogg":"","wpcf-article_end_page":"","wpcf-article_start_page":"","wpcf-acknowledgements":"","wpcf-errata_pdf":"","wpcf-article_flipper_image":"https:\/\/touchoncology.com\/wp-content\/uploads\/sites\/2\/2018\/08\/article_flipper_images_Onc-28_F.jpg","wpcf-corrected_online":null,"wpcf-supplementary_information":"","wpcf-article_highlight_pdf":"","data_availability":"","digital_features":""},"_links":{"self":[{"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/posts\/2192","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/users\/53489"}],"replies":[{"embeddable":true,"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/comments?post=2192"}],"version-history":[{"count":1,"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/posts\/2192\/revisions"}],"predecessor-version":[{"id":27982,"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/posts\/2192\/revisions\/27982"}],"wp:attachment":[{"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/media?parent=2192"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/categories?post=2192"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/tags?post=2192"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}