eMedicine Specialties > Dermatology > Diseases of the Oral Mucosa

Chemotherapy-Induced Oral Mucositis

Author: Nathaniel S Treister, DMD, DMSc, Assistant Professor, Harvard School of Dental Medicine; Consulting Staff, Division of Oral and Maxillofacial Surgery, Oral Medicine And Dentistry, Brigham and Women's Hospital and Dana Farber Cancer Institute
Coauthor(s): Sook-Bin Woo, DMD, MS, BDS, MMSc, Associate Professor, Chief, Division of Oral Medicine, Department of Oral Medicine and Diagnostic Services, Harvard School of Dental Medicine; Consulting Staff, Brigham and Women's Hospital, Dana Farber Cancer Institute, Beth Israel/Deaconess Medical Center
Contributor Information and Disclosures

Updated: Oct 31, 2008

Introduction

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 here 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 at the higher-dosed regimens 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 (OM). 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 (TPN) and increased use of narcotic analgesics.

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 cause septicemia. Approximately half of all patients who receive chemotherapy develop severe oral mucositis that is dose-limiting such that the patient's cancer treatment must be modified, compromising the prognosis. Durable disease remission and cure rates may be enhanced if more intensive therapies could be used without the untoward consequences of dose-limiting oral mucositis. In addition to direct morbidity, oral mucositis contributes indirectly to increased length of hospitalization and increased cost of treatment.

A related Medscape CME course is NCCN Task Force Report: Prevention and Management of Mucositis in Cancer Care (Slides With Transcript).

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 predisposition to develop this condition.

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. 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 NFkB are activated, which then up-regulate a number of proinflammatory cytokines such as interleukin (IL)–1 beta and tumor necrosis factor-alpha (TNF-alpha). IL-1 beta 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 has developed), 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.

Frequency

United States

Approximately 400,000 patients per year may develop acute or chronic oral complications during chemotherapy. Some degree of oral mucositis occurs in approximately 40% of patients who receive cancer chemotherapy. At least 75% of patients who receive conditioning regimens (chemotherapy with or without total body irradiation) in preparation for HCT develop oral mucositis. 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.

International

Figures are similar to those in the United States.

Mortality/Morbidity

Oral mucositis causes pain, restricts oral intake, may act as a portal of entry for organisms, 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 (eg, in preparation for HCT). The incidence of alpha-hemolytic streptococcal infection increases in patients who undergo conditioning regimens in preparation for HCT.¹ 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 (ARDS).²
• Mortality rates range from 6-30%. 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.

Race

No racial predilection is apparent.

Sex

No sexual predilection is reported.

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. However, the healing of oral mucositis is also more rapid in the younger age group.

Clinical

History

• Oral pain contributes to patient morbidity. Difficulty with eating, drinking, speaking, and maintenance of oral hygiene regimens typifies morbidity.
• A dry mouth from decreased salivary flow (hyposalivation) secondary to chemotherapy reduces natural lubrication and contributes to the accumulation of debris in the mouth, to the ease of trauma-induced ulceration, and to difficulty in eating and swallowing (dysphagia). A hairy tongue and superficial mucoceles may develop as a result (see Media Files 1-2).
• Dysgeusia, or altered taste sensation, may further reduce the patient's appetite contributing to poor oral intake, requiring parenteral nutrition.

Physical

The earliest changes are those of leukoedema, although these changes cannot always be appreciated. These changes present as diffuse, poorly defined areas of pallor or milky-white opalescence most noticeable on the buccal mucosa. These areas disappear if the mucosa is stretched.

Oral mucositis begins 5-10 days following the initiation of chemotherapy and lasts 7-14 days. Therefore, the whole process lasts 2-3 weeks in more than 90% of patients. Resolution (in the case of HCT) coincides with recovery of the WBC count, specifically when the absolute neutrophil count becomes greater than 500 cells/µL. In patients being treated for solid tumors, the duration of oral mucositis depends on the type, dose, and course of treatment.

Oral mucositis begins as areas of erythema (see Media File 3) and atrophy on the mucosa that may then break down to form ulcers that are covered by a yellowish white fibrin clot (the pseudomembrane). Peripheral erythema is usually present. Ulcers may range from 0.5 cm to greater than 4 cm in maximum dimension. At the height of oral mucositis, patients experience marked pain, difficulty opening the mouth, difficulty with any form of oral intake, and difficulty with mouth care regimens.

• Location
  • The mouth is a trauma-intense environment. When the oral mucosa becomes atrophic from chemotherapy and renewal of oral epithelium has been slowed by chemotherapy, local trauma leads to ulceration with nonkeratinized sites being the most vulnerable. Therefore, lesions occur bilaterally, mainly on the nonkeratinized sites in the mouth, namely the buccal mucosa, the ventral and lateral parts of the tongue, the labial mucosa, the floor of the mouth, the soft palate, and the oropharyngeal fauces (see Media Files 4-6).
  • Spontaneous healing (from the occurrence of erythema to resolution) without scar formation occurs within 2-3 weeks. Healing of ulcers usually takes 7-10 days.
  • Because many patients (especially those undergoing HCT) are profoundly thrombocytopenic, bleeding may occur from sites of ulcerative oral mucositis.
• In patients undergoing HCT, those who are conditioned with total body irradiation in preparation for allogenic transplantation are at a somewhat higher risk of experiencing more severe and prolonged oral mucositis.  Patients treated with methotrexate as part of their graft versus host disease (GVHD) prophylaxis are also at increased risk.
• With decreased salivary flow, debris that is normally washed away by saliva builds up in the oral cavity. One major manifestation of this is hairy tongue (see Media File 1). Hairy tongue is not a candidal infection; retention of keratin on the filiform papillae of the tongue from hyposalivation, alteration of constituents of the saliva, and eating a soft diet or not eating at all causes hairy tongue. The retention of keratin on other sites, such as the gingiva, may also be mistaken for oral candidiasis; however, hyposalivation changes the intraoral milieu and predisposes to candidiasis so that the conditions may coexist. Candidiasis is less likely when patients are on antifungal prophylaxis.

Causes

The underlying malignancy and chemotherapy regimens (that, in turn, determines the degree of neutropenia) are the 2 most important factors in determining the occurrence and the severity of oral mucositis. Hematologic malignancies and stomatotoxic regimens lead to 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 chronic GVHD prophylaxis may exacerbate lesions of oral mucositis, although this is less of a concern with newer prophylaxis regimens. Nevertheless, as mentioned earlier, other factors that as yet are poorly understood can affect oral mucositis so that patients who are controlled for these above factors may still experience different severities of oral mucositis.

• 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 (especially 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.

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