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. 1998 May;77(10):1689–1695. doi: 10.1038/bjc.1998.279

Treatment-induced mucositis: an old problem with new remedies.

R P Symonds 1
PMCID: PMC2150071  PMID: 9635851

Abstract

Mucositis may be a painful, debilitating, dose-limiting side-effect of both chemotherapy and radiotherapy for which there is no widely accepted prophylaxis or effective treatment. The basis of management is pain relief, prevention of dehydration and adequate nutrition. When tested vigorously, most antiseptic mouthwashes and anti-ulcer agents are ineffective. Simple mechanical cleansing by saline is the most effective traditional measure. A variety of new agents are effective. Granulocyte macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) act outwith the haemopoeitic system and can reduce mucositis, but the best schedule, dosage and method of administration is not known or which is the best growth factor to prevent this side-effect. A placebo-controlled randomized trial of antibiotic pastilles has shown a significant reduction in mucositis and weight loss during radiotherapy for head and neck cancer. Another method to reduce radiation effects in normal tissue is to stimulate cells to divide before radiotherapy by silver nitrate or interleukin 1. These methods may be particularly effective when given along with hyperfractionated radiation treatment such as CHART.

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Selected References

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  1. Abouna G. M., Adnani M. S., Kumar M. S., Samhan S. A. Fate of transplanted kidneys with diabetic nephropathy. Lancet. 1986 Mar 15;1(8481):622–623. doi: 10.1016/s0140-6736(86)92849-7. [DOI] [PubMed] [Google Scholar]
  2. Allison R. R., Vongtama V., Vaughan J., Shin K. H. Symptomatic acute mucositis can be minimized or prophylaxed by the combination of sucralfate and fluconazole. Cancer Invest. 1995;13(1):16–22. doi: 10.3109/07357909509024890. [DOI] [PubMed] [Google Scholar]
  3. Amdur R. J., Parsons J. T., Mendenhall W. M., Million R. R., Cassisi N. J. Split-course versus continuous-course irradiation in the postoperative setting for squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 1989 Aug;17(2):279–285. doi: 10.1016/0360-3016(89)90440-9. [DOI] [PubMed] [Google Scholar]
  4. Atkinson K., Biggs J. C., Downs K., Juttner C., Bradstock K., Lowenthal R. M., Dale B., Szer J. GM-CSF after allogeneic bone marrow transplantation: accelerated recovery of neutrophils, monocytes and lymphocytes. Aust N Z J Med. 1991 Oct;21(5):686–692. doi: 10.1111/j.1445-5994.1991.tb01371.x. [DOI] [PubMed] [Google Scholar]
  5. Barker G., Loftus L., Cuddy P., Barker B. The effects of sucralfate suspension and diphenhydramine syrup plus kaolin-pectin on radiotherapy-induced mucositis. Oral Surg Oral Med Oral Pathol. 1991 Mar;71(3):288–293. doi: 10.1016/0030-4220(91)90301-r. [DOI] [PubMed] [Google Scholar]
  6. Barkvoll P., Attramadal A. Effect of nystatin and chlorhexidine digluconate on Candida albicans. Oral Surg Oral Med Oral Pathol. 1989 Mar;67(3):279–281. doi: 10.1016/0030-4220(89)90354-x. [DOI] [PubMed] [Google Scholar]
  7. Berger A., Henderson M., Nadoolman W., Duffy V., Cooper D., Saberski L., Bartoshuk L. Oral capsaicin provides temporary relief for oral mucositis pain secondary to chemotherapy/radiation therapy. J Pain Symptom Manage. 1995 Apr;10(3):243–248. doi: 10.1016/0885-3924(94)00130-D. [DOI] [PubMed] [Google Scholar]
  8. Berkowitz R. J., Crock J., Strickland R., Gordon E. M., Strandjord S., Coccia P. F. Oral complications associated with bone marrow transplantation in a pediatric population. Am J Pediatr Hematol Oncol. 1983 Spring;5(1):53–57. [PubMed] [Google Scholar]
  9. Bussolino F., Wang J. M., Defilippi P., Turrini F., Sanavio F., Edgell C. J., Aglietta M., Arese P., Mantovani A. Granulocyte- and granulocyte-macrophage-colony stimulating factors induce human endothelial cells to migrate and proliferate. Nature. 1989 Feb 2;337(6206):471–473. doi: 10.1038/337471a0. [DOI] [PubMed] [Google Scholar]
  10. Chi K. H., Chen C. H., Chan W. K., Chow K. C., Chen S. Y., Yen S. H., Chao J. Y., Chang C. Y., Chen K. Y. Effect of granulocyte-macrophage colony-stimulating factor on oral mucositis in head and neck cancer patients after cisplatin, fluorouracil, and leucovorin chemotherapy. J Clin Oncol. 1995 Oct;13(10):2620–2628. doi: 10.1200/JCO.1995.13.10.2620. [DOI] [PubMed] [Google Scholar]
  11. DeWalt E. M., Haines A. K. The effects of specified stressors on healthy oral mucosa. Nurs Res. 1969 Jan-Feb;18(1):22–27. [PubMed] [Google Scholar]
  12. Dinarello C. A. Interleukin-1 and interleukin-1 antagonism. Blood. 1991 Apr 15;77(8):1627–1652. [PubMed] [Google Scholar]
  13. Donnelly J. P., Muus P., Schattenberg A., De Witte T., Horrevorts A., DePauw B. E. A scheme for daily monitoring of oral mucositis in allogeneic BMT recipients. Bone Marrow Transplant. 1992 Jun;9(6):409–413. [PubMed] [Google Scholar]
  14. Epstein J. B., Stevenson-Moore P., Jackson S., Mohamed J. H., Spinelli J. J. Prevention of oral mucositis in radiation therapy: a controlled study with benzydamine hydrochloride rinse. Int J Radiat Oncol Biol Phys. 1989 Jun;16(6):1571–1575. doi: 10.1016/0360-3016(89)90964-4. [DOI] [PubMed] [Google Scholar]
  15. Epstein J. B., Vickars L., Spinelli J., Reece D. Efficacy of chlorhexidine and nystatin rinses in prevention of oral complications in leukemia and bone marrow transplantation. Oral Surg Oral Med Oral Pathol. 1992 Jun;73(6):682–689. doi: 10.1016/0030-4220(92)90009-f. [DOI] [PubMed] [Google Scholar]
  16. Epstein J. B., Wong F. L. The efficacy of sucralfate suspension in the prevention of oral mucositis due to radiation therapy. Int J Radiat Oncol Biol Phys. 1994 Feb 1;28(3):693–698. doi: 10.1016/0360-3016(94)90195-3. [DOI] [PubMed] [Google Scholar]
  17. Eriksson G., Johansson C., Aly A. Topical prostaglandin E2 for chronic leg ulcers. Lancet. 1986 Apr 19;1(8486):905–905. doi: 10.1016/s0140-6736(86)91002-0. [DOI] [PubMed] [Google Scholar]
  18. Feber T. Management of mucositis in oral irradiation. Clin Oncol (R Coll Radiol) 1996;8(2):106–111. doi: 10.1016/s0936-6555(96)80116-6. [DOI] [PubMed] [Google Scholar]
  19. Ferguson J. E., Dodwell D. J., Seymour A. M., Richards M. A., Howell A. High dose, dose-intensive chemotherapy with doxorubicin and cyclophosphamide for the treatment of advanced breast cancer. Br J Cancer. 1993 Apr;67(4):825–829. doi: 10.1038/bjc.1993.151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Foote R. L., Loprinzi C. L., Frank A. R., O'Fallon J. R., Gulavita S., Tewfik H. H., Ryan M. A., Earle J. M., Novotny P. Randomized trial of a chlorhexidine mouthwash for alleviation of radiation-induced mucositis. J Clin Oncol. 1994 Dec;12(12):2630–2633. doi: 10.1200/JCO.1994.12.12.2630. [DOI] [PubMed] [Google Scholar]
  21. Fox A. D., Kripke S. A., De Paula J., Berman J. M., Settle R. G., Rombeau J. L. Effect of a glutamine-supplemented enteral diet on methotrexate-induced enterocolitis. JPEN J Parenter Enteral Nutr. 1988 Jul-Aug;12(4):325–331. doi: 10.1177/0148607188012004325. [DOI] [PubMed] [Google Scholar]
  22. Fox P. C., Atkinson J. C., Macynski A. A., Wolff A., Kung D. S., Valdez I. H., Jackson W., Delapenha R. A., Shiroky J., Baum B. J. Pilocarpine treatment of salivary gland hypofunction and dry mouth (xerostomia). Arch Intern Med. 1991 Jun;151(6):1149–1152. [PubMed] [Google Scholar]
  23. Gabrilove J. L., Jakubowski A., Scher H., Sternberg C., Wong G., Grous J., Yagoda A., Fain K., Moore M. A., Clarkson B. Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium. N Engl J Med. 1988 Jun 2;318(22):1414–1422. doi: 10.1056/NEJM198806023182202. [DOI] [PubMed] [Google Scholar]
  24. Gordon B., Spadinger A., Hodges E., Ruby E., Stanley R., Coccia P. Effect of granulocyte-macrophage colony-stimulating factor on oral mucositis after hematopoietic stem-cell transplantation. J Clin Oncol. 1994 Sep;12(9):1917–1922. doi: 10.1200/JCO.1994.12.9.1917. [DOI] [PubMed] [Google Scholar]
  25. Hatton-Smith C. K. A last bastion of ritualised practice? A review of nurses' knowledge of oral healthcare. Prof Nurse. 1994 Feb;9(5):304, 306-8. [PubMed] [Google Scholar]
  26. Ho A. D., Del Valle F., Haas R., Engelhard M., Hiddemann W., Rückle H., Schlimok G., Thiel E., Andreesen R., Fiedler W. Sequential studies on the role of mitoxantrone, high-dose cytarabine, and recombinant human granulocyte-macrophage colony-stimulating factor in the treatment of refractory non-Hodgkin's lymphoma. Semin Oncol. 1990 Dec;17(6 Suppl 10):14–19. [PubMed] [Google Scholar]
  27. Holmes S. The oral complications of specific anticancer therapy. Int J Nurs Stud. 1991;28(4):343–360. doi: 10.1016/0020-7489(91)90061-7. [DOI] [PubMed] [Google Scholar]
  28. Horiot J. C., Bontemps P., van den Bogaert W., Le Fur R., van den Weijngaert D., Bolla M., Bernier J., Lusinchi A., Stuschke M., Lopez-Torrecilla J. Accelerated fractionation (AF) compared to conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced head and neck cancers: results of the EORTC 22851 randomized trial. Radiother Oncol. 1997 Aug;44(2):111–121. doi: 10.1016/s0167-8140(97)00079-0. [DOI] [PubMed] [Google Scholar]
  29. Jebb S. A., Osborne R. J., Maughan T. S., Mohideen N., Mack P., Mort D., Shelley M. D., Elia M. 5-fluorouracil and folinic acid-induced mucositis: no effect of oral glutamine supplementation. Br J Cancer. 1994 Oct;70(4):732–735. doi: 10.1038/bjc.1994.385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Johnson J. T., Ferretti G. A., Nethery W. J., Valdez I. H., Fox P. C., Ng D., Muscoplat C. C., Gallagher S. C. Oral pilocarpine for post-irradiation xerostomia in patients with head and neck cancer. N Engl J Med. 1993 Aug 5;329(6):390–395. doi: 10.1056/NEJM199308053290603. [DOI] [PubMed] [Google Scholar]
  31. LeVeque F. G., Montgomery M., Potter D., Zimmer M. B., Rieke J. W., Steiger B. W., Gallagher S. C., Muscoplat C. C. A multicenter, randomized, double-blind, placebo-controlled, dose-titration study of oral pilocarpine for treatment of radiation-induced xerostomia in head and neck cancer patients. J Clin Oncol. 1993 Jun;11(6):1124–1131. doi: 10.1200/JCO.1993.11.6.1124. [DOI] [PubMed] [Google Scholar]
  32. Ledingham I. M., Alcock S. R., Eastaway A. T., McDonald J. C., McKay I. C., Ramsay G. Triple regimen of selective decontamination of the digestive tract, systemic cefotaxime, and microbiological surveillance for prevention of acquired infection in intensive care. Lancet. 1988 Apr 9;1(8589):785–790. doi: 10.1016/s0140-6736(88)91656-x. [DOI] [PubMed] [Google Scholar]
  33. Loprinzi C. L., Wender D. B., Veeder M. H., O'Fallon J. R., Vaught N. L., Dose A. M., Ghosh C., Bartel J., Leitch J. M. Inhibition of 5-fluorouracil-induced ocular irritation by ocular ice packs. Cancer. 1994 Aug 1;74(3):945–948. doi: 10.1002/1097-0142(19940801)74:3<945::aid-cncr2820740324>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
  34. Mahood D. J., Dose A. M., Loprinzi C. L., Veeder M. H., Athmann L. M., Therneau T. M., Sorensen J. M., Gainey D. K., Mailliard J. A., Gusa N. L. Inhibition of fluorouracil-induced stomatitis by oral cryotherapy. J Clin Oncol. 1991 Mar;9(3):449–452. doi: 10.1200/JCO.1991.9.3.449. [DOI] [PubMed] [Google Scholar]
  35. Makkonen T. A., Boström P., Vilja P., Joensuu H. Sucralfate mouth washing in the prevention of radiation-induced mucositis: a placebo-controlled double-blind randomized study. Int J Radiat Oncol Biol Phys. 1994 Aug 30;30(1):177–182. doi: 10.1016/0360-3016(94)90533-9. [DOI] [PubMed] [Google Scholar]
  36. Matejka M., Nell A., Kment G., Schein A., Leukauf M., Porteder H., Mailath G., Sinzinger H. Local benefit of prostaglandin E2 in radiochemotherapy-induced oral mucositis. Br J Oral Maxillofac Surg. 1990 Apr;28(2):89–91. doi: 10.1016/0266-4356(90)90128-8. [DOI] [PubMed] [Google Scholar]
  37. McElroy T. H. Infection in the patient receiving chemotherapy for cancer: oral considerations. J Am Dent Assoc. 1984 Sep;109(3):454–456. doi: 10.14219/jada.archive.1984.0406. [DOI] [PubMed] [Google Scholar]
  38. Meisenberg B., Gollard R., Brehm T., McMillan R., Miller W. Prophylactic antibiotics eliminate bacteremia and allow safe outpatient management following high-dose chemotherapy and autologous stem cell rescue. Support Care Cancer. 1996 Sep;4(5):364–369. doi: 10.1007/BF01788843. [DOI] [PubMed] [Google Scholar]
  39. Meloni G., Capria S., Proia A., Trisolini S. M., Mandelli F. Ice pops to prevent melphalan-induced stomatitis. Lancet. 1996 Jun 15;347(9016):1691–1692. doi: 10.1016/s0140-6736(96)91518-4. [DOI] [PubMed] [Google Scholar]
  40. Meropol N. J., Miller L. L., Korn E. L., Braitman L. E., MacDermott M. L., Schuchter L. M. Severe myelosuppression resulting from concurrent administration of granulocyte colony-stimulating factor and cytotoxic chemotherapy. J Natl Cancer Inst. 1992 Aug 5;84(15):1201–1203. doi: 10.1093/jnci/84.15.1201. [DOI] [PubMed] [Google Scholar]
  41. Nemunaitis J., Rosenfeld C. S., Ash R., Freedman M. H., Deeg H. J., Appelbaum F., Singer J. W., Flomenberg N., Dalton W., Elfenbein G. J. Phase III randomized, double-blind placebo-controlled trial of rhGM-CSF following allogeneic bone marrow transplantation. Bone Marrow Transplant. 1995 Jun;15(6):949–954. [PubMed] [Google Scholar]
  42. Okuno S. H., Foote R. L., Loprinzi C. L., Gulavita S., Sloan J. A., Earle J., Novotny P. J., Burk M., Frank A. R. A randomized trial of a nonabsorbable antibiotic lozenge given to alleviate radiation-induced mucositis. Cancer. 1997 Jun 1;79(11):2193–2199. doi: 10.1002/(sici)1097-0142(19970601)79:11<2193::aid-cncr18>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
  43. Osaki T., Ueta E., Yoneda K., Hirota J., Yamamoto T. Prophylaxis of oral mucositis associated with chemoradiotherapy for oral carcinoma by Azelastine hydrochloride (Azelastine) with other antioxidants. Head Neck. 1994 Jul-Aug;16(4):331–339. doi: 10.1002/hed.2880160407. [DOI] [PubMed] [Google Scholar]
  44. Pettengell R., Gurney H., Radford J. A., Deakin D. P., James R., Wilkinson P. M., Kane K., Bentley J., Crowther D. Granulocyte colony-stimulating factor to prevent dose-limiting neutropenia in non-Hodgkin's lymphoma: a randomized controlled trial. Blood. 1992 Sep 15;80(6):1430–1436. [PubMed] [Google Scholar]
  45. Poon M. A., O'Connell M. J., Moertel C. G., Wieand H. S., Cullinan S. A., Everson L. K., Krook J. E., Mailliard J. A., Laurie J. A., Tschetter L. K. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol. 1989 Oct;7(10):1407–1418. doi: 10.1200/JCO.1989.7.10.1407. [DOI] [PubMed] [Google Scholar]
  46. Rocke L. K., Loprinzi C. L., Lee J. K., Kunselman S. J., Iverson R. K., Finck G., Lifsey D., Glaw K. C., Stevens B. A., Hatfield A. K. A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil-related stomatitis. Cancer. 1993 Oct 1;72(7):2234–2238. doi: 10.1002/1097-0142(19931001)72:7<2234::aid-cncr2820720728>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  47. Samaranayake L. P., Robertson A. G., MacFarlane T. W., Hunter I. P., MacFarlane G., Soutar D. S., Ferguson M. M. The effect of chlorhexidine and benzydamine mouthwashes on mucositis induced by therapeutic irradiation. Clin Radiol. 1988 May;39(3):291–294. doi: 10.1016/s0009-9260(88)80538-5. [DOI] [PubMed] [Google Scholar]
  48. Saunders M. I., Dische S., Barrett A., Parmar M. K., Harvey A., Gibson D. Randomised multicentre trials of CHART vs conventional radiotherapy in head and neck and non-small-cell lung cancer: an interim report. CHART Steering Committee. Br J Cancer. 1996 Jun;73(12):1455–1462. doi: 10.1038/bjc.1996.276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Sinzinger H., Porteder H., Matejka M., Peskar B. A. Prostaglandins in irradiation-induced mucositis. Lancet. 1989 Mar 11;1(8637):556–556. doi: 10.1016/s0140-6736(89)90097-4. [DOI] [PubMed] [Google Scholar]
  50. Spijkervet F. K., van Saene H. K., van Saene J. J., Panders A. K., Vermey A., Mehta D. M. Mucositis prevention by selective elimination of oral flora in irradiated head and neck cancer patients. J Oral Pathol Med. 1990 Nov;19(10):486–489. doi: 10.1111/j.1600-0714.1990.tb00792.x. [DOI] [PubMed] [Google Scholar]
  51. Stoutenbeek C. P., van Saene H. K., Miranda D. R., Zandstra D. F. The effect of selective decontamination of the digestive tract on colonisation and infection rate in multiple trauma patients. Intensive Care Med. 1984;10(4):185–192. doi: 10.1007/BF00259435. [DOI] [PubMed] [Google Scholar]
  52. Symonds R. P., McIlroy P., Khorrami J., Paul J., Pyper E., Alcock S. R., McCallum I., Speekenbrink A. B., McMurray A., Lindemann E. The reduction of radiation mucositis by selective decontamination antibiotic pastilles: a placebo-controlled double-blind trial. Br J Cancer. 1996 Jul;74(2):312–317. doi: 10.1038/bjc.1996.359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Taylor K. M., Jagannath S., Spitzer G., Spinolo J. A., Tucker S. L., Fogel B., Cabanillas F. F., Hagemeister F. B., Souza L. M. Recombinant human granulocyte colony-stimulating factor hastens granulocyte recovery after high-dose chemotherapy and autologous bone marrow transplantation in Hodgkin's disease. J Clin Oncol. 1989 Dec;7(12):1791–1799. doi: 10.1200/JCO.1989.7.12.1791. [DOI] [PubMed] [Google Scholar]
  54. Troussard X., Macro M., Vie B., Batho A., Peny A. M., Reman O., Tabah I., Leporrier M. Human recombinant granulocyte-macrophage colony stimulating factor (hrGM-CSF) improves double hemibody irradiation (DHBI) tolerance in patients with stage III multiple myeloma: a pilot study. Br J Haematol. 1995 Jan;89(1):191–195. doi: 10.1111/j.1365-2141.1995.tb08929.x. [DOI] [PubMed] [Google Scholar]
  55. Verdi C. J., Garewal H. S., Koenig L. M., Vaughn B., Burkhead T. A double-blind, randomized, placebo-controlled, crossover trial of pentoxifylline for the prevention of chemotherapy-induced oral mucositis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1995 Jul;80(1):36–42. doi: 10.1016/s1079-2104(95)80014-x. [DOI] [PubMed] [Google Scholar]
  56. Wardley A. M., Scarffe J. H. Role of granulocyte-macrophage colony-stimulating factor in chemotherapy-induced oral mucositis. J Clin Oncol. 1996 May;14(5):1741–1743. doi: 10.1200/JCO.1996.14.5.1741. [DOI] [PubMed] [Google Scholar]
  57. Warner S. J., Auger K. R., Libby P. Human interleukin 1 induces interleukin 1 gene expression in human vascular smooth muscle cells. J Exp Med. 1987 May 1;165(5):1316–1331. doi: 10.1084/jem.165.5.1316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Woo S. B., Sonis S. T., Monopoli M. M., Sonis A. L. A longitudinal study of oral ulcerative mucositis in bone marrow transplant recipients. Cancer. 1993 Sep 1;72(5):1612–1617. doi: 10.1002/1097-0142(19930901)72:5<1612::aid-cncr2820720520>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  59. Zaghloul M. S., Dorie M. J., Kallman R. F. Interleukin 1 increases thymidine labeling index of normal tissues of mice but not the tumor. Int J Radiat Oncol Biol Phys. 1994 Jul 1;29(4):805–811. doi: 10.1016/0360-3016(94)90569-x. [DOI] [PubMed] [Google Scholar]
  60. van Saene H. K., Martin M. V. Do microorganisms play a role in irradiation mucositis? Eur J Clin Microbiol Infect Dis. 1990 Dec;9(12):861–863. doi: 10.1007/BF01967499. [DOI] [PubMed] [Google Scholar]

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