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Mucositis

  • Emma Bateman
  • Richard Logan
  • Rachel Gibson
  • Dorothy KeefeEmail author
Reference work entry

Abstract

Mucositis is an inflammatory reaction of the mucosa of the alimentary tract (AT) caused by chemotherapy, radiotherapy, and targeted therapy for cancer. It presents a significant burden not only to patient quality of life but also may result in diminished tumor control (through dose reductions) and increased treatment costs (due to extended hospital stays and supportive care). Mucositis symptoms may vary not only due to the treatment modality but also according to genetic predispositions of the patient toward developing toxicity (toxicogenomics). Management of mucositis is at present supportive only, with treatments that reduce incidence, severity, and duration of clinical symptoms, but do not prevent or cure mucositis altogether. A great deal of current research into the mechanisms involved in development and progression of mucositis is also being carried out; it is hoped that a clear understanding of mucositis pathophysiology, along with comprehensive toxicogenomics, will enable more preventative treatments to be developed.

Abbreviations

5-FU

5-fluorouracil

AT

alimentary tract

BF

Bayes factor

CAM

complementary and alternative medicine

CT

chemotherapy

GI

gastrointestinal

GLP

glucagon-like peptide

H2BT

hydrogen breath test

HSCT

hematopoietic stem cell transplantation

IL

interleukin

LIL

low-intensity laser

LLLT

low-level laser therapy

MASCC/ISOO

Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology

mAb

monoclonal antibody

MMPs

matrix metalloproteases

mTOR

mechanistic target of rapamycin

NCI-CTCAE

National Cancer Institute Common Terminology Criteria for Adverse Events

NF-κB

nuclear factor kappa B

OM

oral mucositis

PRO

patient-reported outcome

QOL

quality of life

RCT

randomized controlled trial

RT

radiotherapy

SBS

short bowel syndrome

SBT

13C-sucrose breath test

TAT

targeted anticancer therapy

TBI

total body irradiation

TKI

tyrosine kinase inhibitor

TLR

toll-like receptor

TNF

tumour necrosis factor

WHO

World Health Organization

References

  1. Abimosleh SM, Tran CD, Howarth GS. Emu oil: a novel therapeutic for disorders of the gastrointestinal tract? J Gastroenterol Hepatol. 2012;27:857–61.PubMedCrossRefPubMedCentralGoogle Scholar
  2. Abraham C, Cho JH. Inducing intestinal growth. N Engl J Med. 2005;353:2297–9.PubMedCrossRefPubMedCentralGoogle Scholar
  3. Al-Dasooqi N, et al. Matrix metalloproteinases and their inhibitors are altered in a time-course model of irinotecan-induced mucositis. J Gastroenterol Hepatol. 2010;25(3):A2.Google Scholar
  4. Al-Dasooqi N, et al. Emerging evidence on the pathobiology of mucositis. Support Care Cancer. 2013;21:3233–41.PubMedCrossRefPubMedCentralGoogle Scholar
  5. Al-Dasooqi N, Wardill HR, Gibson RJ. Gastrointestinal mucositis: the role of MMP-tight junction interactions in tissue injury. Pathol Oncol Res. 2014;20:485–91.PubMedCrossRefPubMedCentralGoogle Scholar
  6. Allen S, Kilian C, Phelps J, Whelan HT. The use of hyperbaric oxygen for treating delayed radiation injuries in gynecologic malignancies: a review of literature and report of radiation injury incidence. Support Care Cancer. 2012;20:2467–72.PubMedCrossRefPubMedCentralGoogle Scholar
  7. Al-Mamgani A, et al. The impact of treatment modality and radiation technique on outcomes and toxicity of patients with locally advanced oropharyngeal cancer. Laryngoscope. 2013;123:386–93.PubMedCrossRefPubMedCentralGoogle Scholar
  8. Al-Waili N, Salom K, Al-Ghamdi AA. Honey for wound healing, ulcers, and burns; data supporting its use in clinical practice. ScientificWorldJournal. 2011;11:766–87.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Aprile G, Ramoni M, Keefe D, Sonis S. Application of distance matrices to define associations between acute toxicities in colorectal cancer patients receiving chemotherapy. Cancer. 2008;112:284–92.PubMedCrossRefPubMedCentralGoogle Scholar
  10. Aprile G, Ramoni M, Keefe D, Sonis S. Links between regimen-related toxicities in patients being treated for colorectal cancer. Curr Opin Support Palliat Care. 2009;3:50–4.PubMedCrossRefPubMedCentralGoogle Scholar
  11. Arbabi-kalati F, 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.PubMedPubMedCentralGoogle Scholar
  12. Bateman E, Keefe D. Patient-reported outcomes in supportive care. Semin Oncol. 2011;38:358–61.PubMedCrossRefPubMedCentralGoogle Scholar
  13. Bateman EH, Bowen JM, Wignall A, Keefe DMK. Development of a fractionated radiotherapy model to investigate acute and chronic radiation-induced gastrointestinal injury in a Dark Agouti rat model. Supportive Care Cancer. 2012;20:1–283.Google Scholar
  14. Bhanja P, et al. Protective role of R-spondin1, an intestinal stem cell growth factor, against radiation-induced gastrointestinal syndrome in mice. PLoS One. 2009;4:e8014.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Blijlevens N, et al. In a high-dose melphalan setting, palifermin compared with placebo had no effect on oral mucositis or related patient’s burden. Bone Marrow Transplant. 2013;48:966–71.PubMedCrossRefPubMedCentralGoogle Scholar
  16. Boushey RP, Yusta B, Drucker DJ. Glucagon-like peptide (GLP)-2 reduces chemotherapy-associated mortality and enhances cell survival in cells expressing a transfected GLP-2 receptor. Cancer Res. 2001;61:687–93.PubMedPubMedCentralGoogle Scholar
  17. Bowen JM. Development of the rat model of lapatinib-induced diarrhoea. Scientifica (Cairo). 2014;2014:194185.Google Scholar
  18. Bowen J, Gibson R, Cummins A, Tyskin A, Keefe D. Irinotecan changes gene expression in the small intestine of the rat with breast cancer. Support Care Cancer. 2006;14:629.CrossRefGoogle Scholar
  19. Bowen JM, et al. VSL#3 probiotic treatment reduces chemotherapy-induced diarrhea and weight loss. Cancer Biol Ther. 2007;6:1449–54.PubMedCrossRefPubMedCentralGoogle Scholar
  20. Bowen JM, et al. Determining the mechanisms of lapatinib-induced diarrhoea using a rat model. Cancer Chemother Pharmacol. 2014;74:617–27.PubMedCrossRefPubMedCentralGoogle Scholar
  21. Carlotto A, Hogsett VL, Maiorini EM, Razulis JG, Sonis ST. The economic burden of toxicities associated with cancer treatment: review of the literature and analysis of nausea and vomiting, diarrhoea, oral mucositis and fatigue. PharmacoEconomics. 2013;31:753–66.PubMedCrossRefPubMedCentralGoogle Scholar
  22. Cheah KY, Howarth GS, Bastian SE. Grape seed extract dose-responsively decreases disease severity in a rat model of mucositis; concomitantly enhancing chemotherapeutic effectiveness in colon cancer cells. PLoS One. 2014;9:e85184.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Cho HK, Jeong YM, Lee HS, Lee YJ, Hwang SH. Effects of honey on oral mucositis in patients with head and neck cancer: a meta-analysis. Laryngoscope. 2015;125:2085–92.PubMedCrossRefPubMedCentralGoogle Scholar
  24. Elad S, et al. Basic oral care for hematology-oncology patients and hematopoietic stem cell transplantation recipients: a position paper from the joint task force of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and the European Society for Blood and Marrow Transplantation (EBMT). Support Care Cancer. 2015;23:223–36.PubMedCrossRefPubMedCentralGoogle Scholar
  25. Flichy-Fernandez AJ, et al. The effect of orally administered probiotic Lactobacillus reuteri-containing tablets in peri-implant mucositis: a double-blind randomized controlled trial. J Periodontal Res. 2015;50:775–85.PubMedCrossRefPubMedCentralGoogle Scholar
  26. Gibson RJ, Bowen JM. Biomarkers of regimen-related mucosal injury. Cancer Treat Rev. 2011;37:487–93.PubMedCrossRefPubMedCentralGoogle Scholar
  27. Gibson RJ, Stringer AM. Chemotherapy-induced diarrhoea. Curr Opin Support Palliat Care. 2009;3:31–5.PubMedCrossRefPubMedCentralGoogle Scholar
  28. Gibson RJ, et al. Effect of interleukin-11 on ameliorating intestinal damage after methotrexate treatment of breast cancer in rats. Dig Dis Sci. 2002;47:2751–7.PubMedCrossRefPubMedCentralGoogle Scholar
  29. Gibson RJ, Bowen JM, Inglis MR, Cummins AG, Keefe DM. Irinotecan causes severe small intestinal damage, as well as colonic damage, in the rat with implanted breast cancer. J Gastroenterol Hepatol. 2003;18:1095–100.PubMedCrossRefPubMedCentralGoogle Scholar
  30. Gibson R, Bowen J, Alvarez E, Keefe D. Detailed investigation and comparison of single dose irinotecan-induced diarrhoea in Dark Agouti rats with and without tumours. Support Care Cancer. 2005;13:401–83.CrossRefGoogle Scholar
  31. Gibson RJ, et al. Systematic review of agents for the management of gastrointestinal mucositis in cancer patients. Support Care Cancer. 2013;21:313–26.PubMedCrossRefPubMedCentralGoogle Scholar
  32. Gibson RJ, et al. Chemotherapy-induced gut toxicity and pain: involvement of TLRs. Support Care Cancer. 2016;24:2251–8.PubMedCrossRefPubMedCentralGoogle Scholar
  33. Goldberg JD, et al. Palifermin is efficacious in recipients of TBI-based but not chemotherapy-based allogeneic hematopoietic stem cell transplants. Bone Marrow Transplant. 2013;48:99–104.PubMedCrossRefPubMedCentralGoogle Scholar
  34. Hallstrom H, Lindgren S, Widen C, Renvert S, Twetman S. Probiotic supplements and debridement of peri-implant mucositis: a randomized controlled trial. Acta Odontol Scand. 2016;74:60–6.PubMedCrossRefPubMedCentralGoogle Scholar
  35. Hawley P, Hovan A, McGahan CE, Saunders D. A randomized placebo-controlled trial of manuka honey for radiation-induced oral mucositis. Support Care Cancer. 2014;22:751–61.PubMedCrossRefPubMedCentralGoogle Scholar
  36. Herbers AH, Feuth T, Donnelly JP, Blijlevens NM. Citrulline-based assessment score: first choice for measuring and monitoring intestinal failure after high-dose chemotherapy. Ann Oncol. 2010;21:1706–11.PubMedCrossRefPubMedCentralGoogle Scholar
  37. Hoffmann M, et al. Long term results of postoperative Intensity-Modulated Radiation Therapy (IMRT) in the treatment of Squamous Cell Carcinoma (SCC) located in the oropharynx or oral cavity. Radiat Oncol. 2015;10:251.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Howarth GS, Tooley KL, Davidson GP, Butler RN. A non-invasive method for detection of intestinal mucositis induced by different classes of chemotherapy drugs in the rat. Cancer Biol Ther. 2006;5:1189–95.PubMedCrossRefPubMedCentralGoogle Scholar
  39. Keefe DMK. Gastrointestinal mucositis: a new biological model. Support Care Cancer. 2004;12:6–9.PubMedCrossRefPubMedCentralGoogle Scholar
  40. Keefe DM. Mucositis management in patients with cancer. Support Cancer Ther. 2006;3:154–7.PubMedCrossRefPubMedCentralGoogle Scholar
  41. Keefe DM, Bateman EH. Tumor control versus adverse events with targeted anticancer therapies. Nat Rev Clin Oncol. 2012;9:98–109.CrossRefGoogle Scholar
  42. Keefe DMK, Bateman EH. Potential successes and challenges of targeted cancer therapies. J Natl Cancer Inst Monogr. In press.Google Scholar
  43. Kelly N, et al. The role of the glutathione antioxidant system in gut barrier failure in a rodent model of experimental necrotizing enterocolitis. Surgery. 2004;136:557–66.PubMedCrossRefPubMedCentralGoogle Scholar
  44. Kim KA, et al. Mitogenic influence of human R-spondin1 on the intestinal epithelium. Science. 2005;309:1256–9.PubMedCrossRefPubMedCentralGoogle Scholar
  45. Kissow H, et al. Exogenous glucagon-like peptide-2 (GLP-2) prevents chemotherapy-induced mucositis in rat small intestine. Cancer Chemother Pharmacol. 2012;70:39–48.PubMedCrossRefPubMedCentralGoogle Scholar
  46. Kissow H, Hartmann B, Holst JJ, Poulsen SS. Glucagon-like peptide-1 as a treatment for chemotherapy-induced mucositis. Gut. 2013;62:1724–33.PubMedCrossRefPubMedCentralGoogle Scholar
  47. Kuchay RA. A review of complementary therapies for chemotherapy induced gastrointestinal mucositis. Drug Discov Ther. 2017;10(6):292–99.CrossRefGoogle Scholar
  48. Lalla RV, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2014;120:1453–61.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Lee J, et al. Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nat Cell Biol. 2006;8:1327–36.PubMedCrossRefPubMedCentralGoogle Scholar
  50. Logan RM, et al. The role of pro-inflammatory cytokines in cancer treatment-induced alimentary tract mucositis: pathobiology, animal models and cytotoxic drugs. Cancer Treat Rev. 2007a;33:448–60.PubMedCrossRefPubMedCentralGoogle Scholar
  51. Logan RM, Gibson RJ, Sonis ST, Keefe DM. Nuclear factor-kappaB (NF-kappaB) and cyclooxygenase-2 (COX-2) expression in the oral mucosa following cancer chemotherapy. Oral Oncol. 2007b;43:395–401.PubMedCrossRefPubMedCentralGoogle Scholar
  52. Logan RM, et al. Serum levels of NFkappaB and pro-inflammatory cytokines following administration of mucotoxic drugs. Cancer Biol Ther. 2008;7:1139–45.PubMedCrossRefPubMedCentralGoogle Scholar
  53. Lotfi-Jam K, et al. Nonpharmacologic strategies for managing common chemotherapy adverse effects: a systematic review. J Clin Oncol. 2008;26:5618–29.PubMedCrossRefPubMedCentralGoogle Scholar
  54. Lutgens L, Lambin P. Biomarkers for radiation-induced small bowel epithelial damage: an emerging role for plasma Citrulline. World J Gastroenterol. 2007;13:3033–42.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Lutgens LC, et al. Citrulline: a physiologic marker enabling quantitation and monitoring of epithelial radiation-induced small bowel damage. Int J Radiat Oncol Biol Phys. 2003;57:1067–74.PubMedCrossRefPubMedCentralGoogle Scholar
  56. Lutgens LC, et al. Plasma citrulline concentration: a surrogate end point for radiation-induced mucosal atrophy of the small bowel. A feasibility study in 23 patients. Int J Radiat Oncol Biol Phys. 2004;60:275–85.PubMedCrossRefPubMedCentralGoogle Scholar
  57. Lutgens LC, et al. Monitoring myeloablative therapy-induced small bowel toxicity by serum citrulline concentration: a comparison with sugar permeability tests. Cancer. 2005;103:191–9.PubMedCrossRefPubMedCentralGoogle Scholar
  58. Mahood DJ, et al. Inhibition of fluorouracil-induced stomatitis by oral cryotherapy. J Clin Oncol. 1991;9:449–52.PubMedCrossRefPubMedCentralGoogle Scholar
  59. Mashtoub S, et al. Emu oil combined with Lyprinol reduces small intestinal damage in a rat model of chemotherapy-induced mucositis. Nutr Cancer. 2016;68:1171–80.PubMedCrossRefPubMedCentralGoogle Scholar
  60. McGuire DB, Correa ME, Johnson J, Wienandts P. The role of basic oral care and good clinical practice principles in the management of oral mucositis. Support Care Cancer. 2006;14:541–7.PubMedCrossRefPubMedCentralGoogle Scholar
  61. McGuire DB, et al. Systematic review of basic oral care for the management of oral mucositis in cancer patients. Support Care Cancer. 2013;21:3165–77.PubMedCrossRefPubMedCentralGoogle Scholar
  62. Mehdipour M, Zenoz AT, Kermani IA, Hosseinpour A. A comparison between zinc sulfate and chlorhexidine gluconate mouthwashes in the prevention of chemotherapy-induced oral mucositis. Daru. 2011;19:71.PubMedPubMedCentralGoogle Scholar
  63. Metri K, Bhargav H, Chowdhury P, Koka PS. Ayurveda for chemo-radiotherapy induced side effects in cancer patients. J Stem Cells. 2013;8:115–29.PubMedPubMedCentralGoogle Scholar
  64. Migliorati C, et al. Systematic review of laser and other light therapy for the management of oral mucositis in cancer patients. Support Care Cancer. 2013;21:333–41.PubMedCrossRefPubMedCentralGoogle Scholar
  65. Pan CX, Morrison RS, Ness J, Fugh-Berman A, Leipzig RM. Complementary and alternative medicine in the management of pain, dyspnea, and nausea and vomiting near the end of life. A systematic review. J Pain Symptom Manag. 2000;20:374–87.CrossRefGoogle Scholar
  66. Pelton NS, Tivey DR, Howarth GS, Davidson GP, Butler RN. A novel breath test for the non-invasive assessment of small intestinal mucosal injury following methotrexate administration in the rat. Scand J Gastroenterol. 2004;39:1015–6.PubMedCrossRefPubMedCentralGoogle Scholar
  67. Peterson DE, et al. Systematic review of oral cryotherapy for management of oral mucositis caused by cancer therapy. Support Care Cancer. 2013;21:327–32.PubMedCrossRefPubMedCentralGoogle Scholar
  68. Peterson DE, et al. Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice. Cancer Med. 2016;5:1897–907.PubMedPubMedCentralCrossRefGoogle Scholar
  69. Prisciandaro LD, Geier MS, Butler RN, Cummins AG, Howarth GS. Evidence supporting the use of probiotics for the prevention and treatment of chemotherapy-induced intestinal mucositis. Crit Rev Food Sci Nutr. 2011;51:239–47.PubMedCrossRefPubMedCentralGoogle Scholar
  70. Raber-Durlacher JE, et al. Systematic review of cytokines and growth factors for the management of oral mucositis in cancer patients. Support Care Cancer. 2013;21:343–55.PubMedCrossRefPubMedCentralGoogle Scholar
  71. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004;118:229–41.PubMedCrossRefPubMedCentralGoogle Scholar
  72. Rangwala F, Zafar SY, Abernethy AP. Gastrointestinal symptoms in cancer patients with advanced disease: new methodologies, insights, and a proposed approach. Curr Opin Support Palliat Care. 2012;6:69–76.PubMedCrossRefPubMedCentralGoogle Scholar
  73. Rasmussen AR, et al. The intestinotrophic peptide, GLP-2, counteracts the gastrointestinal atrophy in mice induced by the epidermal growth factor receptor inhibitor, erlotinib, and cisplatin. Dig Dis Sci. 2010;55:2785–96.PubMedCrossRefPubMedCentralGoogle Scholar
  74. Rubenstein EB, et al. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer. 2004;100:2026–46.PubMedCrossRefPubMedCentralGoogle Scholar
  75. Samdariya S, Lewis S, Kauser H, Ahmed I, Kumar D. A randomized controlled trial evaluating the role of honey in reducing pain due to radiation induced mucositis in head and neck cancer patients. Indian J Palliat Care. 2015;21:268–73.PubMedPubMedCentralCrossRefGoogle Scholar
  76. Schwartz LK, et al. Long-term teduglutide for the treatment of patients with intestinal failure associated with short bowel syndrome. Clin Transl Gastroenterol. 2016;7:e142.PubMedPubMedCentralCrossRefGoogle Scholar
  77. Smith K. The photobiological basis of low level laser radiation therapy. Laser Ther. 1991;3:19–24.CrossRefGoogle Scholar
  78. Song JJ, Twumasi-Ankrah P, Salcido R. Systematic review and meta-analysis on the use of honey to protect from the effects of radiation-induced oral mucositis. Adv Skin Wound Care. 2012;25:23–8.PubMedCrossRefPubMedCentralGoogle Scholar
  79. Sonis ST. A biological approach to mucositis. J Support Oncol. 2004;2:21–32; discussion 35–6.PubMedPubMedCentralGoogle Scholar
  80. Sonis ST. Oral mucositis. Anti-Cancer Drugs. 2011;22:607–12.PubMedCrossRefPubMedCentralGoogle Scholar
  81. Spielberger R, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med. 2004;351:2590–8.PubMedCrossRefPubMedCentralGoogle Scholar
  82. Stringer AM. Interaction between host cells and microbes in chemotherapy-induced mucositis. Forum Nutr. 2013;5:1488–99.Google Scholar
  83. Stringer A, et al. Mucositis, microflora and mucins: the effect of fluorouracil. Support Care Cancer. 2008;15:651–797.Google Scholar
  84. Stringer AM, et al. Irinotecan-induced mucositis manifesting as diarrhoea corresponds with an amended intestinal flora and mucin profile. Int J Exp Pathol. 2009a;90:489–99.PubMedPubMedCentralCrossRefGoogle Scholar
  85. Stringer AM, Gibson RJ, Bowen JM, Keefe DM. Chemotherapy-induced modifications to gastrointestinal microflora: evidence and implications of change. Curr Drug Metab. 2009b;10:79–83.PubMedCrossRefPubMedCentralGoogle Scholar
  86. Stubbe CE, Valero M. Complementary strategies for the management of radiation therapy side effects. J Adv Pract Oncol. 2013;4:219–31.PubMedPubMedCentralGoogle Scholar
  87. Tooley KL, Howarth GS, Butler RN. Mucositis and non-invasive markers of small intestinal function. Cancer Biol Ther. 2009;8:753–8.PubMedCrossRefPubMedCentralGoogle Scholar
  88. Van Sebille YZ, Gibson RJ, Wardill HR, Bowen JM. ErbB small molecule tyrosine kinase inhibitor (TKI) induced diarrhoea: chloride secretion as a mechanistic hypothesis. Cancer Treat Rev. 2015;41:646–52.PubMedCrossRefPubMedCentralGoogle Scholar
  89. van Vliet MJ, et al. Citrulline as a marker for chemotherapy induced mucosal barrier injury in pediatric patients. Pediatr Blood Cancer. 2009;53:1188–94.PubMedCrossRefPubMedCentralGoogle Scholar
  90. Walsh D, Rybicki L. Symptom clustering in advanced cancer. Support Care Cancer. 2006;14:831–6.PubMedCrossRefPubMedCentralGoogle Scholar
  91. Wardill HR, et al. Irinotecan disrupts tight junction proteins within the gut: implications for chemotherapy-induced gut toxicity. Cancer Biol Ther. 2014a;15:236–44.PubMedCrossRefPubMedCentralGoogle Scholar
  92. Wardill HR, Gibson RJ, Logan RM, Bowen JM. TLR4/PKC-mediated tight junction modulation: a clinical marker of chemotherapy-induced gut toxicity? Int J Cancer. 2014b;135:2483–92.PubMedCrossRefPubMedCentralGoogle Scholar
  93. Wardill HR, Gibson RJ, Logan RM, Bowen JM. Does TLR4/PKC signalling drive chemotherapy induced barrier dysfunction and mucositis? Support Care Cancer. 2014c;22:S96.Google Scholar
  94. Wardill H, et al. TLR4 deletion attenuates irinotecan-induced gut toxicity and barrier dysfunction in the Balb/C mouse offering a new therapeutic target. Support Care Cancer. 2015a;23(Suppl 1):1–388.Google Scholar
  95. Wardill HR, et al. Toll-like receptor 4 signaling: a common biological mechanism of regimen-related toxicities: an emerging hypothesis for neuropathy and gastrointestinal toxicity. Cancer Treat Rev. 2015b;41:122–8.PubMedCrossRefPubMedCentralGoogle Scholar
  96. Wardill HR, et al. Irinotecan-induced gastrointestinal dysfunction and pain are mediated by common TLR4-dependent mechanisms. Mol Cancer Ther. 2016a;15:1376–86.PubMedCrossRefPubMedCentralGoogle Scholar
  97. Wardill HR, et al. TLR4-dependent claudin-1 internalization and secretagogue-mediated chloride secretion regulate irinotecan-induced diarrhea. Mol Cancer Ther. 2016b.Google Scholar
  98. Xu JL, et al. Effects of honey use on the management of radio/chemotherapy-induced mucositis: a meta-analysis of randomized controlled trials. Int J Oral Maxillofac Surg. 2016.Google Scholar
  99. Yao Q, et al. Protective effect of curcumin on chemotherapy-induced intestinal dysfunction. Int J Clin Exp Pathol. 2013;6:2342–9.PubMedPubMedCentralGoogle Scholar
  100. Yarom N, et al. Systematic review of natural agents for the management of oral mucositis in cancer patients. Support Care Cancer. 2013;21:3209–21.PubMedCrossRefPubMedCentralGoogle Scholar
  101. Yeoh AS, et al. A novel animal model to investigate fractionated radiotherapy-induced alimentary mucositis: the role of apoptosis, p53, nuclear factor-kappaB, COX-1, and COX-2. Mol Cancer Ther. 2007;6:2319–27.PubMedCrossRefPubMedCentralGoogle Scholar
  102. Yokomizo H, et al. Prophylactic efficacy of allopurinol ice ball for leucovorin/5-fluorouracil therapy-induced stomatitis. Anticancer Res. 2004;24:1131–4.PubMedPubMedCentralGoogle Scholar
  103. Zhao J, et al. R-Spondin1 protects mice from chemotherapy or radiation-induced oral mucositis through the canonical Wnt/beta-catenin pathway. Proc Natl Acad Sci U S A. 2009;106:2331–6.PubMedPubMedCentralCrossRefGoogle Scholar
  104. Zhou WJ, Geng ZH, Spence JR, Geng JG. Induction of intestinal stem cells by R-spondin 1 and Slit2 augments chemoradioprotection. Nature. 2013;501:107–11.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Emma Bateman
    • 1
  • Richard Logan
    • 1
    • 2
  • Rachel Gibson
    • 1
    • 3
  • Dorothy Keefe
    • 1
    Email author
  1. 1.Cancer Treatment Toxicities Group, School of MedicineUniversity of AdelaideAdelaideAustralia
  2. 2.School of DentistryUniversity of AdelaideAdelaideAustralia
  3. 3.Division of Health SciencesUniversity of South AustraliaAdelaideAustralia

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