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Chemotherapy-Induced Oral Mucositis

  • Author: Nathaniel S Treister, DMD, DMSc; Chief Editor: William D James, MD  more...
 
Updated: Oct 09, 2015
 

Practice Essentials

Oral mucositis is a common complication of chemotherapy. It begins 5-10 days after the initiation of chemotherapy and lasts 7-14 days. Chemotherapy-induced oral mucositis causes the mucosal lining of the mouth to atrophy and break down forming ulcers. See the image below.

Erythematous oral mucositis lesion on the buccal m Erythematous oral mucositis lesion on the buccal mucosa.

See Cancer Chemotherapy: Keys to Diagnosing Common Toxicities, a Critical Images slideshow, to help recognize some of the more common complications of chemotherapy.

Signs and symptoms

Patients typically experience the following:

  • Oral pain
  • Erythema
  • Difficulty opening the mouth
  • Difficulty eating, drinking, and speaking
  • Difficulty with mouth care regimens

See Clinical Presentation for more detail.

Diagnosis

The diagnosis of chemotherapy-induced oral mucositis is based on clinical findings and the chronology of the development of lesions.

Cultures should be performed if erythema and ulcers are located on the hard palate, the attached gingiva, or the dorsum of the tongue. Biopsy may be indicated, but it is not routinely necessary for diagnosis.

The 2 most commonly used scales for grading oral mucositis are the following:

  • World Health Organization (WHO) Oral Toxicity Scale: Combines both objective and functional elements into a single score
  • National Cancer Institute Common Toxicity Criteria (NCI CTC): Scores functional elements only

See Workup for more detail.

Management

There are 5 main approaches to managing oral mucositis, as follows:

  • Oral debridement; mucolytic agents, such as Alkalol, help dislodge dried secretions
  • Oral decontamination, including antibacterial and antifungal rinses
  • Topical and systemic pain management, such as 2% viscous lidocaine, magic mouthwash preparations, and topical morphine solution; an oral rinse containing doxepin also appears to be effective against pain related to oral mucositis [1, 2]
  • Prophylaxis, such as ice-chip cryotherapy, Palifermin (keratinocyte growth factor), and antiviral medications
  • Control of bleeding by use of topical thrombin packs and antifibrinolytic agents

See Treatment and Medication for more detail.

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Background

Most patients receive chemotherapy on an outpatient basis and are admitted to the hospital if they develop fever and neutropenia, obvious infection, or some other complication. Most of the data cited in this article are from studies performed on patients in an inpatient setting. Nevertheless, oral complications, when they arise in either the inpatient setting or the outpatient setting, are similar.

Chemotherapy, either at conventional levels or in the higher-dosed myeloablative protocols used in conditioning regimens (with or without total body radiation in preparation for hematopoietic cell transplantation [HCT]), often results in erythema, edema, atrophy, and ulceration of the oral mucosa, a condition generally referred to as oral mucositis. Oral mucositis leads to pain and restriction of oral intake, and, in severe cases (eg, patients undergoing myeloablative therapy prior to HCT), necessitates total parenteral nutrition and increased use of narcotic analgesics.[3]

Prospective data on the incidence of severe mucositis during conventional cycled chemotherapy is lacking for various solid and hematologic malignancies; however Keefe et al reviewed the reported toxicity data from 99 published clinical trials including patients with non-Hodgkin lymphoma, breast, lung, or colorectal cancer.[4] They found that the incidence of severe mucositis (WHO grades 3 and 4) was no higher than 10% (and in most cases much lower) in any of the disease groups. It is generally accepted that mucositis is underreported when measured as a toxicity compared with studies in which mucositis is the endpoint being evaluated. In an interventional study by Rosen et al evaluating patients with colorectal cancer being treated with 5-fluorouracil and leucovorin, the incidence of ulcerative mucositis was approximately 50% in the placebo group.[5]

In patients undergoing HCT, oral mucositis is reported as the most debilitating aspect of their treatment. Ulcers may act as a site for local infection and a portal of entry for oral flora that, in some instances, may increase the risk of developing septicemia. In addition to direct morbidity, oral mucositis contributes indirectly to increased length of hospitalization and increased cost of treatment.

Mammalian target of rapamycin (mTOR) inhibitors in cancer therapy and oral mucositis

With the introduction of biologically targeted anticancer therapies, emerging oral toxicities have been identified in cancer patients that appear to be distinct from classic mucositis. These toxicities, for the most part, remain poorly described. The class of mTOR inhibitors, including sirolimus (rapamycin), temsirolimus, and everolimus, are increasingly being used as anticancer agents and have been associated with the development of oral aphthous-like ulcers, referred to as mTOR inhibitor–associated stomatitis, or mIAS.[6] These are characterized by discrete, ovoid ulcers with a characteristic erythematous halo, and they appear clinically identical to idiopathic aphthous stomatitis in otherwise healthy patients.

Because this toxicity clusters with dermatologic toxicities, rather than gastrointestinal (as is the case with conventional mucositis) toxicities, this suggests that the underlying pathophysiology is likely very different. Treatment approaches that are known to be effective for the management of aphthous stomatitis, such as high-potency topical steroids, may also be effective for mIAS.[7]

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Pathophysiology

Oral mucositis results from a complex interaction of local tissue damage, the local oral environment, the patient's level of myelosuppression, and the patient's intrinsic genetic predisposition (eg, single nucleotide polymorphisms) to develop oral mucositis.

The current working biological model for oral mucositis is based on 5 interrelated phases, including an initiation phase, a message generation phase, a signaling and amplification phase, an ulceration phase, and a healing phase.[8] In the initiation phase, the chemotherapeutic agents lead to the generation of free radicals and DNA damage. In the message generation phase, transcription factors such as nuclear factor kappaB (NFkB) are activated, which then up-regulate a number of proinflammatory cytokines such as interleukin (IL)–1beta and tumor necrosis factor-alpha (TNF-alpha). IL-1beta mediates inflammation and dilates vessels, potentially increasing the concentration of chemotherapeutic agents at the site. TNF-alpha causes tissue damage, perhaps in an escalating fashion.

During the signaling and amplification phase, positive feedback loops are activated. For example, TNF-alpha activates NFkB, mitogen-activated protein kinase (MAPK), and sphingomyelinase pathways while also contributing directly to cellular and tissue injury. The result is erythema from increased vascularity and epithelial atrophy 4-5 days after the initiation of chemotherapy. Microtrauma from day-to-day activities, such as speech, swallowing, and mastication, leads to ulceration.

During the ensuing ulcerative/bacteriologic phase (during which time neutropenia is common), putative bacterial colonization of ulcerations occurs, resulting in the flow of endotoxins into mucosal tissues and the subsequent release of more IL-1 and TNF-alpha. This is likely the phase most responsible for the clinical pain and morbidity associated with oral mucositis.

During the fifth and final healing phase, cell proliferation occurs with reepithelialization of ulcers. Signals from the extracellular matrix induce epithelial cells to migrate underneath the pseudomembrane (fibrin clot) of the ulcer. The epithelium then proliferates so that the thickness of the mucosa returns to normal. Reconstitution of the WBCs in neutropenic patients effects local control of bacteria, which also contributes to resolution of the ulcers. However, the direct relationship between the white blood cell count and oral mucositis is uncertain, and not all patients with mucositis demonstrate hematologic toxicity.

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Etiology

The underlying malignancy and the intensity and duration of the chemotherapy regimen are the two most important factors in determining the occurrence and the severity of oral mucositis. Hematologic malignancies and highly myelotoxic regimens are typically associated with more severe oral mucositis, but many factors can modify the occurrence and the degree of oral mucositis.

Other factors that modify the occurrence and the severity of oral mucositis include age, level of pretreatment oral health, oral care during treatment, and salivary flow. Young age, poor oral health before and during treatment, and hyposalivation all contribute to an increased risk and increased severity of mucositis. The use of methotrexate for GVHD prophylaxis is an additional significant risk factor for oral mucositis, and the use of non–methotrexate-containing regimens has been shown to reduce the overall severity of mucositis.[9] Nevertheless, as mentioned earlier, other factors, including underlying genetic predisposition, likely also play an important role in determining risk.

Generally, patients with hematologic malignancies have an increased rate of oral mucositis compared with those with solid tumors. This is to some extent related to the treatment regimens.

Great variability exists in the stomatotoxicity of different treatment regimens. Some of the most stomatotoxic agents include the antimetabolites 5-fluorouracil, methotrexate, and cytarabine.

Concomitant radiation therapy (to the head and neck region) increases the risk of oral mucositis because of synergistic effects with the chemotherapeutic agents.

Younger age is associated with more severe oral mucositis.

Chronic irritation from ill-fitting prostheses or faulty restorations predisposes patients to the development of oral mucositis due to local irritation and trauma.

Hyposalivation prior to and during treatment is associated with an increased risk of oral mucositis.

Oral mucositis occurs independently of oral mucosal infections of viral and fungal etiology, but it may be exacerbated by such concomitant infections.

Better pretreatment oral health is probably associated with a reduced incidence of and less severe oral mucositis; however, this has never been proven. Regardless, maintaining good oral hygiene with daily mouth care is important.

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Epidemiology

Frequency

Some degree of oral mucositis occurs in approximately 40% of patients who receive cancer chemotherapy. At least 75% of patients who receive myeloablative conditioning regimens (chemotherapy with or without total body irradiation) in preparation for HCT develop oral mucositis; the incidence may be even higher in children.[10] The incidence is also higher in patients who receive continuous infusion therapy for breast and colon cancer and in those who receive adjuvant therapy for head and neck tumors. However, in patients of the same age with similar diagnoses and treatment regimens and equivalent oral health status, the incidence of oral mucositis may vary considerably. This is most likely because of genetic differences and other factors that are not yet fully characterized or understood.

Race

No racial predilection is apparent for chemotherapy-induced oral mucositis.

Sex

No sexual predilection is reported for chemotherapy-induced oral mucositis.

Age

Younger patients tend to develop oral mucositis more often than older patients being treated for the same malignancy with the same regimen. This is apparently because of the more rapid rate of basal cell turnover noted in children, although this remains poorly characterized. However, the healing of oral mucositis also appears to occur more rapidly in the younger age group.

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Prognosis

Chemotherapy-induced oral mucositis is a self-limiting condition.

Mortality/morbidity

Oral mucositis causes pain, restricts oral intake, frequently contributes to interruption of therapy, may increase the use of antibiotics and narcotics, may increase the length of hospitalization, and may increase the overall cost of treatment. Patients with oral mucositis and neutropenia have a relative risk of septicemia more than 4 times that of patients with neutropenia without oral mucositis.

Patients with pulpal disease from dental caries or trauma, advanced periodontal disease, and low-grade soft tissue infections (especially those associated with partially erupted third molars) are at increased risk for developing septicemia of odontogenic origin when they are myelosuppressed. The incidence of alpha-hemolytic streptococcal infection increases in patients who undergo myeloablative conditioning regimens in preparation for HCT.7 Risk factors include prophylactic antibiotic therapy with quinolones, severe neutropenia, high-dose chemotherapy regimens, oral mucositis, strong colonization with viridans streptococci, and the use of Hickman and other long-term intravascular catheters. Viridans streptococci now account for more than 65% of bacteremic episodes in these patients and are associated with fever, hypotension, toxic shock–like syndrome, pneumonia, and adult respiratory distress syndrome.8

Oral mucositis lesions have been implicated as an important portal of entry for these organisms into the systemic circulation because many of these organisms are native to the oropharyngeal region. Combination prophylaxis, including the use of penicillin and other antibiotics effective against gram-positive streptococci, has been effective in reducing the incidence of septicemia.

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Patient Education

Patients should be informed about their risk for developing oral mucositis, as well as potential signs and symptoms, and should alert their provider at the earliest onset of oral discomfort. Patients should also be educated about the importance of maintaining good oral hygiene throughout the course of their cancer therapy.[11]

For patient education resources, see the Cancer and Tumors Center, as well as Cancer of the Mouth and Throat.

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Contributor Information and Disclosures
Author

Nathaniel S Treister, DMD, DMSc Assistant Professor of Oral Medicine, Harvard School of Dental Medicine; Associate Surgeon, Division of Oral Medicine and Dentistry, Brigham and Women's Hospital

Nathaniel S Treister, DMD, DMSc is a member of the following medical societies: American Academy of Oral Medicine, American Dental Association

Disclosure: Nothing to disclose.

Coauthor(s)

Sook-Bin Woo, DMD, MS Associate Professor, Chief, Division of Oral Medicine and Oral Pathology, Department of Oral Medicine and Diagnostic Services, Harvard School of Dental Medicine; Chief of Clinical Affairs, Brigham and Women's Hospital; Consultant, Dana Farber Cancer Institute, Beth Israel/Deaconess Medical Center

Sook-Bin Woo, DMD, MS is a member of the following medical societies: American Academy of Oral and Maxillofacial Pathology, American Academy of Oral Medicine, American Dental Association

Disclosure: Nothing to disclose.

Specialty Editor Board

David F Butler, MD Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: American Medical Association, Alpha Omega Alpha, Association of Military Dermatologists, American Academy of Dermatology, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Phi Beta Kappa

Disclosure: Nothing to disclose.

Drore Eisen, MD, DDS Consulting Staff, Department of Dermatology, Dermatology Research Associates of Cincinnati

Drore Eisen, MD, DDS is a member of the following medical societies: American Academy of Dermatology, American Academy of Oral Medicine, American Dental Association

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Ponciano D Cruz, Jr, MD Professor and Vice-Chair, Paul R Bergstresser Chair, Department of Dermatology, University of Texas Southwestern Medical Center

Ponciano D Cruz, Jr, MD is a member of the following medical societies: Texas Medical Association

Disclosure: Received consulting fee from RCTS for independent contractor; Received honoraria from Mary Kay Cosmetics for consulting; Received grant/research funds from Galderma for principal investigator.

References
  1. Mulcahy N. ‘New standard of care' for oral mucositis. Medscape Medical News. October 30, 2012. [Full Text].

  2. Mayo Clinic. Doxepin hydrochloride in treating oral mucositis pain in patients with head and neck cancer undergoing radiation therapy with or without chemotherapy. Available at http://tinyurl.com/ClinicalTrialDoxepin. Accessed: November 19, 2012.

  3. Scully C, Sonis S, Diz PD. Oral mucositis. Oral Dis. 2006 May. 12(3):229-41. [Medline].

  4. [Guideline] Lalla RV, Bowen J, Barasch A, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2014. 120:1453-61. [Medline].

  5. 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 Nov 20. 24(33):5194-200. [Medline].

  6. Sonis S, Treister N, Chawla S, Demetri G, Haluska F. Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients. Cancer. 2010 Jan 1. 116(1):210-5. [Medline].

  7. Pilotte AP, Hohos MB, Polson KM, Huftalen TM, Treister N. Managing stomatitis in patients treated with Mammalian target of rapamycin inhibitors. Clin J Oncol Nurs. 2011 Oct. 15(5):E83-9. [Medline].

  8. Sonis ST. Pathobiology of oral mucositis: novel insights and opportunities. J Support Oncol. 2007 Oct. 5(9 Suppl 4):3-11. [Medline].

  9. Cutler C, Li S, Kim HT, Laglenne P, Szeto KC, Hoffmeister L, et al. Mucositis after allogeneic hematopoietic stem cell transplantation: a cohort study of methotrexate- and non-methotrexate-containing graft-versus-host disease prophylaxis regimens. Biol Blood Marrow Transplant. 2005 May. 11 (5):383-8. [Medline].

  10. Vagliano L, Feraut C, Gobetto G, Trunfio A, Errico A, Campani V, et al. Incidence and severity of oral mucositis in patients undergoing haematopoietic SCT--results of a multicentre study. Bone Marrow Transplant. 2011 May. 46 (5):727-32. [Medline].

  11. Elad S, Raber-Durlacher JE, Brennan MT, 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 Jan. 23 (1):223-36. [Medline].

  12. Cutler C, Li S, Kim HT, et al. Mucositis after allogeneic hematopoietic stem cell transplantation: a cohort study of methotrexate- and non-methotrexate-containing graft-versus-host disease prophylaxis regimens. Biol Blood Marrow Transplant. 2005 May. 11(5):383-8. [Medline].

  13. Stiff PJ, Erder H, Bensinger WI, et al. Reliability and validity of a patient self-administered daily questionnaire to assess impact of oral mucositis (OM) on pain and daily functioning in patients undergoing autologous hematopoietic stem cell transplantation (HSCT). Bone Marrow Transplant. 2006 Feb. 37(4):393-401. [Medline].

  14. [Guideline] Lalla RV, Bowen J, Barasch A, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2014 May 15. 120 (10):1453-61. [Medline]. [Full Text].

  15. Vera-Llonch M, Oster G, Ford CM, Lu J, Sonis S. Oral mucositis and outcomes of autologous hematopoietic stem-cell transplantation following high-dose melphalan conditioning for multiple myeloma. J Support Oncol. 2007 May. 5 (5):231-5. [Medline].

  16. Brizel DM, Murphy BA, Rosenthal DI, et al. Phase II study of palifermin and concurrent chemoradiation in head and neck squamous cell carcinoma. J Clin Oncol. 2008 May 20. 26(15):2489-96. [Medline].

  17. 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 Sep 21. 153(6):358-67. [Medline].

  18. Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med. 2004 Dec 16. 351(25):2590-8. [Medline].

 
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Hairy tongue.
Multiple mucoceles on the hard palate.
Erythematous oral mucositis lesion on the buccal mucosa.
Ulcerative oral mucositis lesion on the buccal mucosa.
Ulcerative oral mucositis lesion on the lateral and ventral surfaces of the tongue.
Ulcerative oral mucositis lesions on the labial mucosa and the floor of the mouth.
Oral pseudomembranous candidiasis on the hard palate.
Herpes simplex virus ulceration on the dorsal surface of the tongue.
Herpes simplex virus ulceration on the hard and soft palate. Note lesions on the right upper lip and the dorsum of the tongue.
Acute graft versus host disease involving the dorsal surface of the tongue. This is a keratinized site that is usually not involved by oral mucositis.
 
 
 
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