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Oral Complications of Chemotherapy and Head/Neck Radiation (PDQ®)

Health Professional Version
Last Modified: 04/23/2014

Oral Mucositis

Chemoradiotherapy and Hematopoietic Stem Cell Transplantation Patients
        Management of mucositis
Current Clinical Trials

The terms oral mucositis and stomatitis are often used interchangeably at the clinical level, but they do not reflect identical processes.

Oral Mucositis:

  • Describes inflammation of oral mucosa resulting from chemotherapeutic agents or ionizing radiation.[1-3]
  • Typically manifests as erythema or ulcerations.
  • May be exacerbated by local factors.

Stomatitis:

  • Refers to any inflammatory condition of oral tissue, including mucosa, dentition/periapices, and periodontium.
  • Includes infections of oral tissues as well as mucositis.

Risk of oral mucositis has historically been characterized by treatment-based and patient-based variables.[4] The current model of oral mucositis involves a complex trajectory of molecular, cellular, and tissue-based changes. There is increasing evidence of genetic governance of this injury,[5-8] characterized in part by upregulation of nuclear factor kappa beta and inflammatory cytokines (e.g., tumor necrosis factor-alpha) and interleukin-1 in addition to epithelial basal cell injury. Comprehensive knowledge of the molecular-based causation of the lesion has contributed to targeted drug development for clinical use.[9] The pipeline of new drugs in development (e.g., recombinant human intestinal trefoil factor [10] may lead to strategic new advances in the ability of clinicians to customize the prevention and treatment of oral mucositis in the future.[11]

Erythematous mucositis typically appears 7 to 10 days after initiation of high-dose cancer therapy. Clinicians should be alert to the potential for increased toxicity with escalating dose or treatment duration in clinical trials that demonstrate gastrointestinal mucosal toxicity. High-dose chemotherapy, such as that used in the treatment of leukemia and hematopoietic stem cell transplant regimens, may produce severe mucositis. Mucositis is self-limited when uncomplicated by infection and typically heals within 2 to 4 weeks after cessation of cytotoxic chemotherapy.

Systematic assessment of the oral cavity following treatment permits early identification of lesions.[12-16] Oral hygiene and other supportive care measures are important to minimizing the severity of the lesion.

In an effort to standardize measurements of mucosal integrity, oral assessment scales have been developed to grade the level of stomatitis by characterizing alterations in lips, tongue, mucous membranes, gingiva, teeth, pharynx, quality of saliva, and voice.[12-14] Specific instruments of assessment have been developed to evaluate the observable and functional dimensions of mucositis. These evaluative tools vary in complexity.

Chemoradiotherapy and Hematopoietic Stem Cell Transplantation Patients

Management of mucositis

Prophylactic measures and treatment options should be employed by practitioners for patients in the appropriate clinical settings. Specific recommendations for minimizing oral mucositis include the following:

  • Good oral hygiene.
  • Avoidance of spicy, acidic, hard, and hot foods and beverages.
  • Use of mild-flavored toothpastes.
  • Use of saline-peroxide mouthwashes 3 or 4 times per day.

Updated guidelines from the American Society of Clinical Oncology for the prevention and treatment of mucositis were published in 2007 [17] and include the following:

  • Palifermin for oral mucositis associated with stem cell transplantation.
  • Amifostine for radiation proctitis.
  • Cryotherapy for high-dose-melphalan–induced mucositis.

Specific recommendations against specific practices include the following:

  • No systemic glutamine for the prevention of gastrointestinal mucositis.
  • No sucralfate or antibiotic lozenges for radiation-induced mucositis.
  • No granulocyte-macrophage colony-stimulating factor mouthwashes.

Oral mucositis in hematopoietic stem cell transplantation patients produces clinically significant toxicities that require multiprofessional interventions.[18-25] The lesion can increase risk of systemic infection,[1] produce clinically significant pain,[26][Level of evidence: II] and promote oral hemorrhage. It can also compromise the upper airway such that endotracheal intubation is required. Use of total parenteral nutrition is often necessary because of the patient’s inability to receive enteral nutrition.

Once mucositis has developed, its severity and the patient’s hematologic status govern appropriate oral management. Meticulous oral hygiene and palliation of symptoms are essential. Some established guidelines for oral care include oral assessments twice daily for hospitalized patients and frequent oral care (minimum of every 4 hours and at bedtime) that increases in frequency as the severity of mucositis increases.

Oral care protocols generally include atraumatically cleansing the oral mucosa, maintaining lubrication of the lips and oral tissues, and relieving pain and inflammation. Several health professional organizations have produced evidence-based oral mucositis guidelines. These organizations include but are not limited to the following:

  • Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology [17]

  • National Comprehensive Cancer Network [27]

  • European Society of Medical Oncology [11]

  • European Oncology Nursing Society

  • The Cochrane Collaboration [28,29]

In many cases, there is similarity in recommendations across the organizations. The Cochrane Collaboration, however, uses a meta-analysis approach and thus provides a unique context for purposes of guideline construction.

Palifermin (Kepivance), also known as keratinocyte growth factor-1, has been approved to decrease the incidence and duration of severe oral mucositis in patients with hematologic cancers undergoing conditioning with high-dose chemotherapy, with or without radiation therapy, followed by hematopoietic stem cell rescue.[9][Level of evidence: I] The standard dosing regimen is three daily doses before conditioning and three additional daily doses starting on day 0 (day of transplant). Palifermin has also been shown in a randomized, placebo-controlled trial to reduce the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy.[30][Level of evidence: I] In addition, a single dose of palifermin prevented severe oral mucositis in patients who had sarcoma and were receiving doxorubicin-based chemotherapy.[31][Level of evidence: I]

In two randomized, placebo-controlled trials conducted in head/neck cancer patients undergoing postoperative chemoradiotherapy and in patients receiving definitive chemoradiotherapy for locally advanced head/neck cancer, intravenous palifermin administered weekly for 8 weeks decreased severe oral mucositis,[32,33][Level of evidence: I] as graded by providers using standard toxicity assessments and during multicycle chemotherapy.[31] Patient-reported outcomes related to mouth and throat soreness and to treatment breaks or compliance were not significantly different between arms in either trial. In one study, opioid analgesic use was also not significantly different between arms.[33]

Evidence from several studies has supported the potential efficacy of low-level laser therapy in addition to oral care to decrease the duration of chemotherapy-induced oral mucositis in children.[34][Level of evidence: I][35][Level of evidence: I]

Mucositis Management

  • Bland rinses:
    • 0.9% saline solution.

    • Sodium bicarbonate solution.

    • 0.9% saline/sodium bicarbonate solution.

  • Topical anesthetics:
    • Lidocaine: viscous, ointments, sprays.

    • Benzocaine: sprays, gels.

    • 0.5% or 1.0% dyclonine hydrochloride (HCl).

    • Diphenhydramine solution.

  • Mucosal coating agents:
    • Amphojel.

    • Kaopectate.

    • Hydroxypropyl methylcellulose film-forming agents (e.g., Zilactin).

    • Gelclair (approved by the U.S. Food and Drug Administration [FDA] as a device).

  • Analgesics:
    • Benzydamine HCl topical rinse (not approved in the United States).

    • Opioid drugs: oral, intravenous (e.g., bolus, continuous infusion, patient-controlled analgesia [PCA]), patches, transmucosal.

  • Growth factor (keratinocyte growth factor-1):
    • Palifermin (approved by the FDA in December 2004 to decrease the incidence and duration of severe oral mucositis in patients undergoing high-dose chemotherapy with or without radiation therapy followed by bone marrow transplant for hematologic cancers).

Management of oral mucositis via topical approaches should address efficacy, patient acceptance, and appropriate dosing. A stepped approach is typically used, with progression from one level to the next as follows:

  • Bland rinses (e.g., 0.9% normal saline and/or sodium bicarbonate solutions).

  • Mucosal coating agents (e.g., antacid solutions, kaolin solutions).

  • Water-soluble lubricating agents, including artificial saliva for xerostomia.

  • Topical anesthetics (e.g., viscous lidocaine, benzocaine sprays/gels, dyclonine rinses, diphenhydramine solutions).

  • Cellulose film-forming agents for covering localized ulcerative lesions (e.g., hydroxypropyl cellulose).

Normal saline solution is prepared by adding approximately 1 tsp of table salt to 32 oz of water. The solution can be administered at room or refrigerated temperatures, depending on patient preference. The patient should rinse and swish approximately 1 tbsp, followed by expectoration; this can be repeated as often as necessary to maintain oral comfort. Sodium bicarbonate (1–2 tbsp/qt) can be added, if viscous saliva is present. Saline solution can enhance oral lubrication directly as well as by stimulating salivary glands to increase salivary flow.

A soft toothbrush that is replaced regularly should be used to maintain oral hygiene.[17] Foam-swab brushes do not effectively clean teeth and should not be considered a routine substitute for a soft nylon-bristled toothbrush; additionally, the rough sponge surface may irritate and damage the mucosal surfaces opposite the tooth surfaces being brushed.

On the basis of nonoral mucosa wound-healing studies, the repeated use of hydrogen peroxide rinses for daily preventive oral hygiene is not recommended, especially if mucositis is present, because of the potential for damage to fibroblasts and keratinocytes, which can cause delayed wound healing.[36-39] Using 3% hydrogen peroxide diluted 1:1 with water or normal saline to remove hemorrhagic debris may be helpful; however, this approach should only be used for 1 or 2 days because more extended use may impair timely healing of mucosal lesions associated with bleeding.[40]

Focal topical application of anesthetic agents is preferred over widespread oral topical administration, unless the patient requires more extensive pain relief. Products such as the following may provide relief:

  • 2% viscous lidocaine
  • Diphenhydramine solution
  • One of the many extemporaneously prepared mixtures combining the following coating agents with topical anesthetics:
    • Milk of magnesia.
    • Kaolin with pectin suspension.
    • Mixtures of aluminum.
    • Magnesium hydroxide suspensions (many antacids).

The use of compounded topical anesthetic rinses should be considered carefully relative to the cost of compounding these products versus their actual efficacy.

Irrigation should be performed before topical medication is applied because removal of debris and saliva allows for better coating of oral tissues and prevents material from accumulating. Frequent rinsing cleans and lubricates tissues, prevents crusting, and palliates painful gingiva and mucosa.

Systemic analgesics should be administered when topical anesthetic strategies are not sufficient for clinical relief. Opiates are typically used;[26][Level of evidence: II] the combination of chronic indwelling venous catheters and computerized drug administration pumps to provide PCA has significantly increased the effectiveness of controlling severe mucositis pain while lowering the dose and side effects of narcotic analgesics. Nonsteroidal anti-inflammatory drugs that affect platelet adhesion and damage gastric mucosa are contraindicated, especially if thrombocytopenia is present.

Although mucositis continues to be one of the dose-limiting toxicities of fluorouracil (5-FU), cryotherapy may be an option for preventing oral mucositis. Because 5-FU has a short half-life (5–20 minutes), patients are instructed to swish ice chips in their mouths for 30 minutes, beginning 5 minutes before 5-FU is administered.[41][Level of evidence: I] Oral cryotherapy has been studied in patients receiving high-dose melphalan conditioning regimens used with transplantation;[42,43] further research is needed.

Many agents and protocols have been promoted for management or prevention of mucositis.[44-46] Although not adequately supported by controlled clinical trials, allopurinol mouthwash and vitamin E have been cited as agents that decrease the severity of mucositis. Prostaglandin E2 was not effective as a prophylaxis of oral mucositis following bone marrow transplant, although studies indicate possible efficacy when prostaglandin E2 is administered via a different dosing protocol.

Current Clinical Trials

Check NCI’s list of cancer clinical trials for U.S. supportive and palliative care trials about mucositis that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References
  1. Sonis ST: Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 34 (1): 39-43, 1998.  [PUBMED Abstract]

  2. Lalla RV, Brennan MT, Schubert MM: Oral complications of cancer therapy. In: Yagiela JA, Dowd FJ, Johnson BS, et al., eds.: Pharmacology and Therapeutics for Dentistry. 6th ed. St. Louis, Mo: Mosby Elsevier, 2011, pp 782-98. 

  3. Sonis ST, Elting LS, Keefe D, et al.: Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 100 (9 Suppl): 1995-2025, 2004.  [PUBMED Abstract]

  4. Barasch A, Peterson DE: Risk factors for ulcerative oral mucositis in cancer patients: unanswered questions. Oral Oncol 39 (2): 91-100, 2003.  [PUBMED Abstract]

  5. Ezzeldin HH, Diasio RB: Predicting fluorouracil toxicity: can we finally do it? J Clin Oncol 26 (13): 2080-2, 2008.  [PUBMED Abstract]

  6. Schwab M, Zanger UM, Marx C, et al.: Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol 26 (13): 2131-8, 2008.  [PUBMED Abstract]

  7. Werbrouck J, De Ruyck K, Duprez F, 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 73 (4): 1187-95, 2009.  [PUBMED Abstract]

  8. Hahn T, Zhelnova E, Sucheston L, et al.: A deletion polymorphism in glutathione-S-transferase mu (GSTM1) and/or theta (GSTT1) is associated with an increased risk of toxicity after autologous blood and marrow transplantation. Biol Blood Marrow Transplant 16 (6): 801-8, 2010.  [PUBMED Abstract]

  9. Spielberger R, Stiff P, Bensinger W, et al.: Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 351 (25): 2590-8, 2004.  [PUBMED Abstract]

  10. Peterson DE, Barker NP, Akhmadullina LI, et al.: Phase II, randomized, double-blind, placebo-controlled study of recombinant human intestinal trefoil factor oral spray for prevention of oral mucositis in patients with colorectal cancer who are receiving fluorouracil-based chemotherapy. J Clin Oncol 27 (26): 4333-8, 2009.  [PUBMED Abstract]

  11. Peterson DE, Bensadoun RJ, Roila F, et al.: Management of oral and gastrointestinal mucositis: ESMO clinical recommendations. Ann Oncol 20 (Suppl 4): 174-7, 2009.  [PUBMED Abstract]

  12. Schubert MM, Williams BE, Lloid ME, et al.: Clinical assessment scale for the rating of oral mucosal changes associated with bone marrow transplantation. Development of an oral mucositis index. Cancer 69 (10): 2469-77, 1992.  [PUBMED Abstract]

  13. Sonis ST, Eilers JP, Epstein JB, et al.: Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Mucositis Study Group. Cancer 85 (10): 2103-13, 1999.  [PUBMED Abstract]

  14. McGuire DB, Peterson DE, Muller S, et al.: The 20 item oral mucositis index: reliability and validity in bone marrow and stem cell transplant patients. Cancer Invest 20 (7-8): 893-903, 2002.  [PUBMED Abstract]

  15. Larson PJ, Miaskowski C, MacPhail L, et al.: The PRO-SELF Mouth Aware program: an effective approach for reducing chemotherapy-induced mucositis. Cancer Nurs 21 (4): 263-8, 1998.  [PUBMED Abstract]

  16. Schubert MM: Oro-pharyngeal mucositis. In: Atkinson K, ed.: Clinical Bone Marrow and Blood Stem Cell Transplantation. 2nd ed. Cambridge, UK: Cambridge University Press, 2000, pp 812-20. 

  17. Keefe DM, Schubert MM, Elting LS, et al.: Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 109 (5): 820-31, 2007.  [PUBMED Abstract]

  18. Elting LS, Cooksley C, Chambers M, et al.: The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer 98 (7): 1531-9, 2003.  [PUBMED Abstract]

  19. Elting LS, Cooksley CD, Chambers MS, et al.: Risk, outcomes, and costs of radiation-induced oral mucositis among patients with head-and-neck malignancies. Int J Radiat Oncol Biol Phys 68 (4): 1110-20, 2007.  [PUBMED Abstract]

  20. Lalla RV, Sonis ST, Peterson DE: Management of oral mucositis in patients who have cancer. Dent Clin North Am 52 (1): 61-77, viii, 2008.  [PUBMED Abstract]

  21. Peterson DE, Lalla RV: Oral mucositis: the new paradigms. Curr Opin Oncol 22 (4): 318-22, 2010.  [PUBMED Abstract]

  22. Rosenthal DI: Consequences of mucositis-induced treatment breaks and dose reductions on head and neck cancer treatment outcomes. J Support Oncol 5 (9 Suppl 4): 23-31, 2007.  [PUBMED Abstract]

  23. Sonis ST, Oster G, Fuchs H, et al.: Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol 19 (8): 2201-5, 2001.  [PUBMED Abstract]

  24. Sonis ST: Regimen-related gastrointestinal toxicities in cancer patients. Curr Opin Support Palliat Care 4 (1): 26-30, 2010.  [PUBMED Abstract]

  25. Trotti A, Bellm LA, Epstein JB, 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 66 (3): 253-62, 2003.  [PUBMED Abstract]

  26. Pillitteri LC, Clark RE: Comparison of a patient-controlled analgesia system with continuous infusion for administration of diamorphine for mucositis. Bone Marrow Transplant 22 (5): 495-8, 1998.  [PUBMED Abstract]

  27. Bensinger W, Schubert M, Ang KK, et al.: NCCN Task Force Report. prevention and management of mucositis in cancer care. J Natl Compr Canc Netw 6 (Suppl 1): S1-21; quiz S22-4, 2008.  [PUBMED Abstract]

  28. Clarkson JE, Worthington HV, Furness S, et al.: Interventions for treating oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev (8): CD001973, 2010.  [PUBMED Abstract]

  29. Worthington HV, Clarkson JE, Bryan G, et al.: Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 12: CD000978, 2010.  [PUBMED Abstract]

  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 24 (33): 5194-200, 2006.  [PUBMED Abstract]

  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 153 (6): 358-67, 2010.  [PUBMED Abstract]

  32. Henke M, Alfonsi M, Foa P, 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 29 (20): 2815-20, 2011.  [PUBMED Abstract]

  33. Le QT, Kim HE, Schneider CJ, et al.: Palifermin reduces severe mucositis in definitive chemoradiotherapy of locally advanced head and neck cancer: a randomized, placebo-controlled study. J Clin Oncol 29 (20): 2808-14, 2011.  [PUBMED Abstract]

  34. Kuhn A, Porto FA, Miraglia P, et al.: Low-level infrared laser therapy in chemotherapy-induced oral mucositis: a randomized placebo-controlled trial in children. J Pediatr Hematol Oncol 31 (1): 33-7, 2009.  [PUBMED Abstract]

  35. Schubert MM, Eduardo FP, Guthrie KA, et al.: A phase III randomized double-blind placebo-controlled clinical trial to determine the efficacy of low level laser therapy for the prevention of oral mucositis in patients undergoing hematopoietic cell transplantation. Support Care Cancer 15 (10): 1145-54, 2007.  [PUBMED Abstract]

  36. National Institutes of Health Consensus Development Conference on Oral Complications of Cancer Therapies: Diagnosis, Prevention, and Treatment. Bethesda, Maryland, April 17-19, 1989. NCI Monogr (9): 1-184, 1990.  [PUBMED Abstract]

  37. Bavier AR: Nursing management of acute oral complications of cancer. NCI Monogr (9): 123-8, 1990.  [PUBMED Abstract]

  38. Takahashi A, Aoshiba K, Nagai A: Apoptosis of wound fibroblasts induced by oxidative stress. Exp Lung Res 28 (4): 275-84, 2002.  [PUBMED Abstract]

  39. Bennett LL, Rosenblum RS, Perlov C, et al.: An in vivo comparison of topical agents on wound repair. Plast Reconstr Surg 108 (3): 675-87, 2001.  [PUBMED Abstract]

  40. Schubert MM, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Oxford, UK: Wiley-Blackwell, 2009, pp 1589-1607. 

  41. Rocke LK, Loprinzi CL, Lee JK, et al.: A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil-related stomatitis. Cancer 72 (7): 2234-8, 1993.  [PUBMED Abstract]

  42. Mori T, Yamazaki R, Aisa Y, et al.: Brief oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients. Support Care Cancer 14 (4): 392-5, 2006.  [PUBMED Abstract]

  43. Ohbayashi Y, Imataki O, Ohnishi H, et al.: Multivariate analysis of factors influencing oral mucositis in allogeneic hematopoietic stem cell transplantation. Ann Hematol 87 (10): 837-45, 2008.  [PUBMED Abstract]

  44. Lugliè PF, Mura G, Mura A, et al.: [Prevention of periodontopathy and oral mucositis during antineoplastic chemotherapy. Clinical study] Minerva Stomatol 51 (6): 231-9, 2002.  [PUBMED Abstract]

  45. Cheng KK, Molassiotis A, Chang AM, et al.: Evaluation of an oral care protocol intervention in the prevention of chemotherapy-induced oral mucositis in paediatric cancer patients. Eur J Cancer 37 (16): 2056-63, 2001.  [PUBMED Abstract]

  46. Wardley AM, Jayson GC, Swindell R, et al.: Prospective evaluation of oral mucositis in patients receiving myeloablative conditioning regimens and haemopoietic progenitor rescue. Br J Haematol 110 (2): 292-9, 2000.  [PUBMED Abstract]