Progress in the prevention and treatment of chemotherapy-induced mucositis_West China Medical Journal

Authors：

SHU Xinyao ¹ , HAO Yating ² , ZHOU Yuwen ¹ ,  QIU Meng ¹

1. Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, P. R. China;

Corresponding author：

QIU Meng, Email: qiumeng@wchscu.cn

Keywords：

Gastrointestinal mucositis; oral mucositis; adverse events; toxicity; chemotherapy

DOI：

10.7507/1002-0179.202107112

Video：

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Abstract Full text Figures/Tables Video References Cited by

Chemotherapy-induced mucositis, one of the most common complications of chemotherapy, can be subdivided in oral and gastrointestinal mucositis. The patients always suffer from oral pain and ulcers, nausea, vomiting, abdominal pain and diarrhea. 5-Fluorouracil- and irinotecan-based regimens are frequently associated with a higher risk and more severe grade of mucositis. The onset of mucositis is also influenced by the patient’s characteristics including age, sex, genetic polymorphisms, systemic comorbidities. At present, the diagnosis of chemotherapy-induced mucositis is mainly based on medical history, physical examination and gastroenteroscopy, lack of reliable biomarkers for early diagnosis. The principles of diagnosis and treatment mainly refer to the clinical practice guidelines issued. Therefore, this article will review the mechanism, diagnosis, latest preventive and treatment strategies of chemotherapy-induced mucositis for helping clinicians to further correctly understand and deal with the adverse reactions.

Citation： SHU Xinyao, HAO Yating, ZHOU Yuwen, QIU Meng. Progress in the prevention and treatment of chemotherapy-induced mucositis. West China Medical Journal, 2023, 38(5): 765-769. doi: 10.7507/1002-0179.202107112 Copy

1.	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2.	Zhang QY, Wang FX, Jia KK, et al. Natural product interventions for chemotherapy and radiotherapy-induced side effects. Front Pharmacol, 2018, 9: 1253.
3.	Kuchay RA. A review of complementary therapies for chemotherapy induced gastrointestinal mucositis. Drug Discov Ther, 2017, 10(6): 292-299.
4.	Keefe DM, Sonis ST, Bowen JM. Emerging drugs for chemotherapy-induced mucositis. Expert Opin Emerg Drugs, 2008, 13(3): 511-522.
5.	Grabenbauer GG, Holger G. Management of radiation and chemotherapy related acute toxicity in gastrointestinal cancer. Best Pract Res Clin Gastroenterol, 2016, 30(4): 655-664.
6.	Krishna SG, Zhao W, Grazziutti ML, et al. Incidence and risk factors for lower alimentary tract mucositis after 1529 courses of chemotherapy in a homogenous population of oncology patients: clinical and research implications. Cancer, 2011, 117(3): 648-655.
7.	Elting LS, Cooksley C, Chambers M, et al. The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer, 2003, 98(7): 1531-1539.
8.	Cinausero M, Aprile G, Ermacora P, et al. New frontiers in the pathobiology and treatment of cancer regimen-related mucosal injury. Front Pharmacol, 2017, 8: 354.
9.	Kuiken NSS, Rings EHHM, Blijlevens NMA, et al. Biomarkers and non-invasive tests for gastrointestinal mucositis. Support Care Cancer, 2017, 25(9): 2933-2941.
10.	石薇, 俞晓立. 乳腺癌脊柱寡转移的体部立体定向放射治疗. 中国癌症杂志, 2019, 29(9): 739-745.
11.	傅琤琤, 王如菊, 吴德沛. 嵌合抗原受体 T 细胞疗法 CRS/ICANS 反应的 ASTCT 共识解读. 中国实验血液学杂志, 2021, 29(6): 1982-1986.
12.	Sonis ST, Elting LS, Keefe D, et al. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer, 2004, 100(Suppl 9): 1995-2025.
13.	Stringer AM, Logan RM. The role of oral flora in the development of chemotherapy-induced oral mucositis. J Oral Pathol Med, 2015, 44(2): 81-87.
14.	Ciorba MA. A gastroenterologist’s guide to probiotics. Clin Gastroenterol Hepatol, 2012, 10(9): 960-968.
15.	Abdel Moneim AE, Guerra-Librero A, Florido J, et al. Oral mucositis: melatonin gel an effective new treatment. Int J Mol Sci, 2017, 18(5): 1003.
16.	van Vliet MJ, Tissing WJ, Rings EH, et al. Citrulline as a marker for chemotherapy induced mucosal barrier injury in pediatric patients. Pediatr Blood Cancer, 2009, 53(7): 1188-1194.
17.	Blijlevens NM, Lutgens LC, Schattenberg AV, et al. Citrulline: a potentially simple quantitative marker of intestinal epithelial damage following myeloablative therapy. Bone Marrow Transplant, 2004, 34(3): 193-196.
18.	Elad S, Cheng KKF, Lalla RV, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer, 2020, 126(19): 4423-4431.
19.	Peterson DE, Boers-Doets CB, Bensadoun RJ, et al. Management of oral and gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Ann Oncol, 2015, 26(Suppl 5): v139-v151.
20.	Correa MEP, Cheng KKF, Chiang K, et al. Systematic review of oral cryotherapy for the management of oral mucositis in cancer patients and clinical practice guidelines. Support Care Cancer, 2020, 28(5): 2449-2456.
21.	Zadik Y, Arany PR, Fregnani ER, et al. Systematic review of photobiomodulation for the management of oral mucositis in cancer patients and clinical practice guidelines. Support Care Cancer, 2019, 27(10): 3969-3983.
22.	Silva GB, Mendonça EF, Bariani C, et al. The prevention of induced oral mucositis with low-level laser therapy in bone marrow transplantation patients: a randomized clinical trial. Photomed Laser Surg, 2011, 29(1): 27-31.
23.	Antunes HS, Herchenhorn D, Small IA, et al. Phase Ⅲ trial of low-level laser therapy to prevent oral mucositis in head and neck cancer patients treated with concurrent chemoradiation. Radiother Oncol, 2013, 109(2): 297-302.
24.	Epstein JB, Silverman S Jr, Paggiarino DA, 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(4): 875-885.
25.	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. Support Care Cancer, 2019, 27(10): 3985-3995.
26.	Orvain C, Moles-Moreau MP, François S, et al. Miconazole mucoadhesive buccal tablet in high-dose therapy with autologous stem cell transplantation (HDT/ASCT)-induced mucositis. Support Care Cancer, 2015, 23(2): 359-364.
27.	Saunders DP, Rouleau T, Cheng K, et al. Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the management of oral mucositis in cancer patients and clinical practice guidelines. Support Care Cancer, 2020, 28(5): 2473-2484.
28.	Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med, 2004, 351(25): 2590-2598.
29.	Stiff PJ, Emmanouilides C, Bensinger WI, et al. Palifermin reduces patient-reported mouth and throat soreness and improves patient functioning in the hematopoietic stem-cell transplantation setting. J Clin Oncol, 2006, 24(33): 5186-5193.
30.	Rosen LS, Abdi E, Davis ID, et al. Palifermin reduces the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy. J Clin Oncol, 2006, 24(33): 5194-5200.
31.	Vadhan-Raj S, Trent J, Patel S, et al. Single-dose palifermin prevents severe oral mucositis during multicycle chemotherapy in patients with cancer: a randomized trial. Ann Intern Med, 2010, 153(6): 358-367.
32.	Cerchietti LC, Navigante AH, Bonomi MR, et al. Effect of topical morphine for mucositis-associated pain following concomitant chemoradiotherapy for head and neck carcinoma. Cancer, 2002, 95(10): 2230-2236.
33.	Loprinzi CL, Ghosh C, Camoriano J, et al. Phase Ⅲ controlled evaluation of sucralfate to alleviate stomatitis in patients receiving fluorouracil-based chemotherapy. J Clin Oncol, 1997, 15(3): 1235-1238.
34.	McCullough RW. Practice insights on patient care-management overview for chemoradiation toxic mucositis-guidelines, guideline-supported therapies and high potency polymerized cross-linked sucralfate (ProThelial). J Oncol Pharm Pract, 2019, 25(2): 409-422.
35.	Osterlund P, Ruotsalainen T, Korpela R, et al. Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study. Br J Cancer, 2007, 97(8): 1028-1034.
36.	Stringer AM, Al-Dasooqi N, Bowen JM, et al. Biomarkers of chemotherapy-induced diarrhoea: a clinical study of intestinal microbiome alterations, inflammation and circulating matrix metalloproteinases. Support Care Cancer, 2013, 21(7): 1843-1852.
37.	Delia P, Sansotta G, Donato V, et al. Prevention of radiation-induced diarrhea with the use of VSL#3, a new high-potency probiotic preparation. Am J Gastroenterol, 2002, 97(8): 2150-2152.
38.	Mego M, Chovanec J, Vochyanova-Andrezalova I, et al. Prevention of irinotecan induced diarrhea by probiotics: a randomized double blind, placebo controlled pilot study. Complement Ther Med, 2015, 23(3): 356-362.
39.	Topkan E, Parlak C, Topuk S, et al. Influence of oral glutamine supplementation on survival outcomes of patients treated with concurrent chemoradiotherapy for locally advanced non-small cell lung cancer. BMC cancer, 2012, 12: 502.
40.	Rotovnik Kozjek N, Kompan L, Soeters P, et al. Oral glutamine supplementation during preoperative radiochemotherapy in patients with rectal cancer: a randomised double blinded, placebo controlled pilot study. Clin Nutr, 2011, 30(5): 567-570.
41.	Topkan E, Karaoglu A. Octreotide in the management of chemoradiotherapy-induced diarrhea refractory to loperamide in patients with rectal carcinoma. Oncology, 2006, 71(5/6): 354-360.
42.	Hoff PM, Saragiotto DF, Barrios CH, et al. Randomized phase Ⅲ trial exploring the use of long-acting release octreotide in the prevention of chemotherapy-induced diarrhea in patients with colorectal cancer: the LARCID trial. J Clin Oncol, 2014, 32(10): 1006-1011.
43.	Zachariah B, Gwede CK, James J, et al. Octreotide acetate in prevention of chemoradiation-induced diarrhea in anorectal cancer: randomized RTOG trial 0315. J Natl Cancer Inst, 2010, 102(8): 547-556.

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2. Zhang QY, Wang FX, Jia KK, et al. Natural product interventions for chemotherapy and radiotherapy-induced side effects. Front Pharmacol, 2018, 9: 1253.
3. Kuchay RA. A review of complementary therapies for chemotherapy induced gastrointestinal mucositis. Drug Discov Ther, 2017, 10(6): 292-299.
4. Keefe DM, Sonis ST, Bowen JM. Emerging drugs for chemotherapy-induced mucositis. Expert Opin Emerg Drugs, 2008, 13(3): 511-522.
5. Grabenbauer GG, Holger G. Management of radiation and chemotherapy related acute toxicity in gastrointestinal cancer. Best Pract Res Clin Gastroenterol, 2016, 30(4): 655-664.
6. Krishna SG, Zhao W, Grazziutti ML, et al. Incidence and risk factors for lower alimentary tract mucositis after 1529 courses of chemotherapy in a homogenous population of oncology patients: clinical and research implications. Cancer, 2011, 117(3): 648-655.
7. Elting LS, Cooksley C, Chambers M, et al. The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer, 2003, 98(7): 1531-1539.
8. Cinausero M, Aprile G, Ermacora P, et al. New frontiers in the pathobiology and treatment of cancer regimen-related mucosal injury. Front Pharmacol, 2017, 8: 354.
9. Kuiken NSS, Rings EHHM, Blijlevens NMA, et al. Biomarkers and non-invasive tests for gastrointestinal mucositis. Support Care Cancer, 2017, 25(9): 2933-2941.
10. 石薇, 俞晓立. 乳腺癌脊柱寡转移的体部立体定向放射治疗. 中国癌症杂志, 2019, 29(9): 739-745.
11. 傅琤琤, 王如菊, 吴德沛. 嵌合抗原受体 T 细胞疗法 CRS/ICANS 反应的 ASTCT 共识解读. 中国实验血液学杂志, 2021, 29(6): 1982-1986.
12. Sonis ST, Elting LS, Keefe D, et al. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer, 2004, 100(Suppl 9): 1995-2025.
13. Stringer AM, Logan RM. The role of oral flora in the development of chemotherapy-induced oral mucositis. J Oral Pathol Med, 2015, 44(2): 81-87.
14. Ciorba MA. A gastroenterologist’s guide to probiotics. Clin Gastroenterol Hepatol, 2012, 10(9): 960-968.
15. Abdel Moneim AE, Guerra-Librero A, Florido J, et al. Oral mucositis: melatonin gel an effective new treatment. Int J Mol Sci, 2017, 18(5): 1003.
16. van Vliet MJ, Tissing WJ, Rings EH, et al. Citrulline as a marker for chemotherapy induced mucosal barrier injury in pediatric patients. Pediatr Blood Cancer, 2009, 53(7): 1188-1194.
17. Blijlevens NM, Lutgens LC, Schattenberg AV, et al. Citrulline: a potentially simple quantitative marker of intestinal epithelial damage following myeloablative therapy. Bone Marrow Transplant, 2004, 34(3): 193-196.
18. Elad S, Cheng KKF, Lalla RV, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer, 2020, 126(19): 4423-4431.
19. Peterson DE, Boers-Doets CB, Bensadoun RJ, et al. Management of oral and gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Ann Oncol, 2015, 26(Suppl 5): v139-v151.
20. Correa MEP, Cheng KKF, Chiang K, et al. Systematic review of oral cryotherapy for the management of oral mucositis in cancer patients and clinical practice guidelines. Support Care Cancer, 2020, 28(5): 2449-2456.
21. Zadik Y, Arany PR, Fregnani ER, et al. Systematic review of photobiomodulation for the management of oral mucositis in cancer patients and clinical practice guidelines. Support Care Cancer, 2019, 27(10): 3969-3983.
22. Silva GB, Mendonça EF, Bariani C, et al. The prevention of induced oral mucositis with low-level laser therapy in bone marrow transplantation patients: a randomized clinical trial. Photomed Laser Surg, 2011, 29(1): 27-31.
23. Antunes HS, Herchenhorn D, Small IA, et al. Phase Ⅲ trial of low-level laser therapy to prevent oral mucositis in head and neck cancer patients treated with concurrent chemoradiation. Radiother Oncol, 2013, 109(2): 297-302.
24. Epstein JB, Silverman S Jr, Paggiarino DA, 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(4): 875-885.
25. 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. Support Care Cancer, 2019, 27(10): 3985-3995.
26. Orvain C, Moles-Moreau MP, François S, et al. Miconazole mucoadhesive buccal tablet in high-dose therapy with autologous stem cell transplantation (HDT/ASCT)-induced mucositis. Support Care Cancer, 2015, 23(2): 359-364.
27. Saunders DP, Rouleau T, Cheng K, et al. Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the management of oral mucositis in cancer patients and clinical practice guidelines. Support Care Cancer, 2020, 28(5): 2473-2484.
28. Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med, 2004, 351(25): 2590-2598.
29. Stiff PJ, Emmanouilides C, Bensinger WI, et al. Palifermin reduces patient-reported mouth and throat soreness and improves patient functioning in the hematopoietic stem-cell transplantation setting. J Clin Oncol, 2006, 24(33): 5186-5193.
30. Rosen LS, Abdi E, Davis ID, et al. Palifermin reduces the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy. J Clin Oncol, 2006, 24(33): 5194-5200.
31. Vadhan-Raj S, Trent J, Patel S, et al. Single-dose palifermin prevents severe oral mucositis during multicycle chemotherapy in patients with cancer: a randomized trial. Ann Intern Med, 2010, 153(6): 358-367.
32. Cerchietti LC, Navigante AH, Bonomi MR, et al. Effect of topical morphine for mucositis-associated pain following concomitant chemoradiotherapy for head and neck carcinoma. Cancer, 2002, 95(10): 2230-2236.
33. Loprinzi CL, Ghosh C, Camoriano J, et al. Phase Ⅲ controlled evaluation of sucralfate to alleviate stomatitis in patients receiving fluorouracil-based chemotherapy. J Clin Oncol, 1997, 15(3): 1235-1238.
34. McCullough RW. Practice insights on patient care-management overview for chemoradiation toxic mucositis-guidelines, guideline-supported therapies and high potency polymerized cross-linked sucralfate (ProThelial). J Oncol Pharm Pract, 2019, 25(2): 409-422.
35. Osterlund P, Ruotsalainen T, Korpela R, et al. Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study. Br J Cancer, 2007, 97(8): 1028-1034.
36. Stringer AM, Al-Dasooqi N, Bowen JM, et al. Biomarkers of chemotherapy-induced diarrhoea: a clinical study of intestinal microbiome alterations, inflammation and circulating matrix metalloproteinases. Support Care Cancer, 2013, 21(7): 1843-1852.
37. Delia P, Sansotta G, Donato V, et al. Prevention of radiation-induced diarrhea with the use of VSL#3, a new high-potency probiotic preparation. Am J Gastroenterol, 2002, 97(8): 2150-2152.
38. Mego M, Chovanec J, Vochyanova-Andrezalova I, et al. Prevention of irinotecan induced diarrhea by probiotics: a randomized double blind, placebo controlled pilot study. Complement Ther Med, 2015, 23(3): 356-362.
39. Topkan E, Parlak C, Topuk S, et al. Influence of oral glutamine supplementation on survival outcomes of patients treated with concurrent chemoradiotherapy for locally advanced non-small cell lung cancer. BMC cancer, 2012, 12: 502.
40. Rotovnik Kozjek N, Kompan L, Soeters P, et al. Oral glutamine supplementation during preoperative radiochemotherapy in patients with rectal cancer: a randomised double blinded, placebo controlled pilot study. Clin Nutr, 2011, 30(5): 567-570.
41. Topkan E, Karaoglu A. Octreotide in the management of chemoradiotherapy-induced diarrhea refractory to loperamide in patients with rectal carcinoma. Oncology, 2006, 71(5/6): 354-360.
42. Hoff PM, Saragiotto DF, Barrios CH, et al. Randomized phase Ⅲ trial exploring the use of long-acting release octreotide in the prevention of chemotherapy-induced diarrhea in patients with colorectal cancer: the LARCID trial. J Clin Oncol, 2014, 32(10): 1006-1011.
43. Zachariah B, Gwede CK, James J, et al. Octreotide acetate in prevention of chemoradiation-induced diarrhea in anorectal cancer: randomized RTOG trial 0315. J Natl Cancer Inst, 2010, 102(8): 547-556.

West China Medical Journal

Progress in the prevention and treatment of chemotherapy-induced mucositis

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