AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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• Clinical
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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 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). OM 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, OM 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 OM 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 OM. In addition to direct morbidity, OM contributes indirectly to increased length of hospitalization and increased cost of treatment.

Pathophysiology

OM 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 OM 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 OM.

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 OM 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 OM. 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 OM 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

OM 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 OM and neutropenia have a relative risk of septicemia more than 4 times that of patients with neutropenia without OM.

• 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. Risk factors include prophylactic antibiotic therapy with quinolones, severe neutropenia, high-dose chemotherapy regimens, OM, 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).
• Mortality rates range from 6-30%. OM 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 OM 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 OM is also more rapid in the younger age group.

CLINICAL

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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 Images 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.

OM 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 OM depends on the type, dose, and course of treatment.

OM begins as areas of erythema (see Image 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 OM, 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 Images 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 OM.
• 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 OM.
• 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 Image 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 OM. Hematologic malignancies and stomatotoxic regimens lead to more severe OM, but many factors can modify the occurrence and the degree of OM.

Other factors that modify the occurrence and the severity of OM 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 graft versus host disease (GVHD) prophylaxis may exacerbate lesions of OM, 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 OM so that patients who are controlled for these above factors may still experience different severities of OM.

• Generally, patients with hematologic malignancies have an increased rate of OM compared to 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 OM because of synergistic effects with the chemotherapeutic agents.
• Younger age is associated with more severe OM.
• Chronic irritation from ill-fitting prostheses or faulty restorations predisposes patients to the development of OM due to local irritation and trauma.
• Hyposalivation prior to and during treatment is associated with an increased risk of OM.
• OM 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 OM.

DIFFERENTIALS

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Other Problems to be Considered

Chemotherapy and bone marrow transplantation–induced mucositis

Overall, candidiasis is the most frequent oral infection in patients who are myelosuppressed (see Image 7), whereas recurrent herpes simplex virus 1 (HSV-1) is the most frequent oral viral infection in these patients (see Images 8-9). Consider other viral infections, including human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), and cytomegalovirus (CMV).

Acute GVHD occurs within the first 100 days after transplantation and involves the skin; the liver; and the mucosa of the eye, the mouth, and the GI tract. Acute GVHD lesions in the oral cavity occur 3-4 weeks after HCT, typically after the resolution of OM lesions, although in some cases, they may manifest as a continuation or exacerbation of OM. An important difference is that lesions of acute GVHD may affect the keratinized mucosa, which is not a feature of OM (see Image 10). Risk factors include HLA disparity, sex mismatching, multiple donor pregnancies, and advanced age. Management includes controlling systemic acute GVHD with systemic immunosuppressive therapy, controlling pain, and providing local palliative measures.

WORKUP

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Lab Studies

• Diagnosis is primarily based on the clinical findings and the chronology of the development of lesions.
• WBC count with differential (absolute neutrophil count in particular) is a helpful test. OM usually occurs when the absolute neutrophil count is less than 500 cells/µL.
• Cultures (particularly for herpetic infection) should be performed if erythema and ulcers (or vesicles) are located on the keratinized tissues of the hard palate, the attached gingiva, or the dorsum of the tongue or if lesions persist after the period of profound neutropenia has passed. If the patient is on prophylactic antiviral agents, the possibility of breakthrough infection or the development of resistant strains must be considered.
• Biopsy is indicated, especially if a deep fungal infection is suspected. Infection may present as a rapidly growing discrete ulcer on either the keratinized mucosa or the nonkeratinized mucosa (see Procedures). However, biopsy is not routinely necessary for OM.

Other Tests

• The severity of OM can be evaluated using several different instruments. The 2 most commonly used are the World Health Organization (WHO) Oral Toxicity score and the National Cancer Institute (NCI) Common Toxicity Criteria for oral mucositis. While the NCI system has separate scores for objective (erythema and ulceration) and functional (pain and ability to eat solids, liquids, or nothing by mouth) components, the WHO score combines both elements into a single score that is useful for measuring severity over time. The Oral Mucositis Daily Questionnaire (OMDQ), which evaluates mouth and throat soreness and its impact on daily activities, has been recently validated and shown to correlate with OM severity based on the WHO score. Of note, symptoms have been found to precede objective findings by 1-3 days.

Procedures

• A biopsy may be necessary, particularly to rule out a deep fungal infection or CMV infection (although CMV infection usually occurs as a later event).
• • The patient should have a minimum of 50,000-80,000 platelets/µL. Antibiotic coverage may be necessary if the patient has less than 1000 neutrophils/µL. The antibiotics should be administered 30 minutes to 1 hour prior to the biopsy to reduce bacteremia and the possibility of a central venous line infection, if such a line is present, and should continue for 5-7 days after the biopsy. Infectious disease physicians should be consulted for their recommendation for the most appropriate antibiotic if the patient is already on a variety of antimicrobial agents.
  • The biopsy is performed under local anesthesia. If indicated, a portion of the tissue should be submitted fresh for fungal culture (for speciation) and viral culture. The wound should be primarily closed with sutures.

Histologic Findings

Routine biopsies are not performed on OM lesions unless other pathology is suspected, such as a deep fungal infection. In banal OM, the oral mucosa exhibits ulceration that unlike other ulcerative conditions shows a paucity of neutrophils in the fibrin clot. Granulation tissue is present at the base of the ulcer with chronic inflammatory cells. Stains for fungi and viruses may be necessary to identify organisms.

TREATMENT

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Medical Care

Because OM is self-limited, management of lesions is divided into 5 main approaches, including the following:

• Oral debridement: Because patients with OM lesions are neutropenic and thrombocytopenic, perform oral debridement with caution because toothbrushing can cause gingival bleeding and, more importantly, result in transient bacteremia. In some centers, sponge-tipped applicators and gauze soaked in sodium chloride solution are used for oral debridement because of these concerns. Dried secretions may become caked on the mucosal surfaces, particularly the palate. Mucolytic agents, such as Alkalol, help to soften and dislodge them.
• Oral decontamination (mouth care): This regimen consists of antifungal and antibacterial rinses. The fluoride rinses and gels used in some oral care regimens are used primarily for antibacterial activity against gingival plaque; they are not used expressly for the prevention of dental caries. Candidal prophylaxis usually includes nystatin rinses and clotrimazole troches. If patients have a very dry mouth, troches are not as effective because they do not dissolve well in a dry environment. Amphotericin rinses also are occasionally used in place of nystatin. Fluconazole may be used for candidal prophylaxis or for treatment of suspected candidiasis.
• Topical and systemic pain management: Pain in patients with OM may be severe and not just limited to the oral mucosa. Local rinses (eg, 2% viscous lidocaine) and systemic analgesics are used together to control pain. Frequent rinsing with sodium chloride solution helps to keep the mucosa moist, reduces caking of secretions, and soothes inflamed/ulcerated mucosa.
• Prophylaxis: Systemic prophylaxis for OM is generally limited to antivirals; however, some centers use fluconazole as prophylaxis against candidiasis.
• Control of bleeding: Maintaining platelets at 20,000 cells/µL and using topical thrombin packs and topical antifibrinolytic agents, such as tranexamic acid, may control bleeding from ulcers.

Consultations

Involving dentists and oral medicine specialists in the care of a patient with OM is important because oral hygiene modifies the occurrence and the severity of OM and alpha-hemolytic streptococcal sepsis has become increasingly prevalent (in patients undergoing HCT).

• In the outpatient setting, a dentist or an oral medicine specialist should see patients several weeks or months prior to the initiation of chemotherapy, especially in the case of HCT. If this is not possible, the patient should be seen for an evaluation during his or her hospitalization for a baseline dental evaluation, even if intervention may not be possible at that visit.
• • The role of the dentist/oral medicine specialist is to identify and remove dental/oral sources of infection prior to myelosuppression and HCT.
  • Procedures may include but are not limited to comprehensive oral and head and neck examination, full mouth series of dental radiographs, and pulp-vitality testing.
  • Appropriate therapy includes identification and management of soft tissue lesions, restoration of carious teeth, extraction of nonsalvageable teeth, extraction of third molars as necessary (particularly those that are not full bony impacted and not fully erupted), and scaling and root planing. Treatment should be completed at least 1 week before initiation of conditioning therapy for HCT.
• After the patient has been admitted to the hospital, the dentist/oral medicine specialist should follow up with these patients to monitor OM, identify signs and symptoms of secondary infection, evaluate slow healing of OM, identify non-OM oral mucosal pathology, and adjust the oral care regimen as needed.

Diet

A bland, soft diet is recommended. Patients should keep the mouth moist with frequent sips of water, ice chips, or popsicles. Patients with severe OM may require total parenteral nutrition. Patients should avoid acidic, spicy, salty, coarse, and dry foods.

Activity

Patients with chemotherapy-induced OM are generally seen in the hospital. Activities are prescribed for them as part of the daily physical therapy regimen.

MEDICATION

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OM is a self-limited condition. Currently, no approved preventive or therapeutic agent consistently prevents OM in all clinical settings. Human recombinant keratinocyte growth factor (KGF) given intravenously was recently demonstrated to significantly reduce the incidence, duration, and severity of OM in patients undergoing autologous HCT and has been approved for use in patients with hematologic malignancies undergoing high-dose chemotherapy with or without concomitant total body irradiation. More studies of KGF in other patient populations are ongoing to evaluate safety and efficacy, especially in patients with solid cancers that are known to express growth factor receptors because tumor growth promotion is a concern. Other biological-based treatments are currently in clinical trials, and it is not unreasonable to expect a number of these agents to be approved for treatment of OM in the future.

Medications are used for prophylaxis against viral and fungal infections, decontamination of the oral cavity, and palliation for pain. This section discusses common medications used for prophylaxis, decontamination, and topical palliation only. Topical palliation for pain may be as simple as frequent sodium chloride solution or salt/bicarbonate of soda rinses and ice chips. Often, 2% viscous lidocaine is mixed in equal volumes with diphenhydramine hydrochloride and bismuth subsalicylate (Kaopectate) or even aluminum hydroxide/magnesium hydroxide (Maalox) as a soothing mouth rinse. In general, most patients require systemic pain control using centrally acting narcotic agents.

Experimental therapies that have been reported include the use of topically applied agents, such as misoprostol (a cytoprotectant), cytokines, and other modifiers of inflammation (eg, IL-1, IL-11, TGF-beta3), amino acid supplementation (eg, glutamine), vitamins, topical morphine, colony-stimulating factors, cryotherapy, and laser therapy.

Drug Category: Antifungals

These agents are used prophylactically against candidal infections in all patients.

Drug Category: Antibacterials

Rinses are the basis of the oral decontamination regimen.

Drug Category: Anesthetics

Oral rinses are used to reduce pain and discomfort.

Drug Category: Antivirals

Nucleoside analogs are initially phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate. These molecules inhibit HSV polymerase with 30-50 times the potency of human alpha-DNA polymerase.

Drug Category: Gastrointestinal agents

These agents are used to protect the GI tract from irritants.

Drug Category: Growth factors

Human KGF may be considered for hematologic malignancies.

FOLLOW-UP

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Further Inpatient Care

• OM is self-limiting in most patients. If lesions persist or secondary complications occur, consider other etiologies and treatments as discussed above.

Deterrence/Prevention

• Although OM cannot be effectively prevented, measures discussed in Treatment may help to reduce the severity of lesions and the risk of developing septicemia.

Complications

• A wide range of complications are associated with OM, including, but not limited to, the following:
• • Increased risk of local and systemic infection
  • Poor nutrition
  • Dehydration
  • Interruption of cytoreductive therapy
  • Increased length of hospitalization
  • Increased cost of treatment

Prognosis

• OM is self-limiting.

Patient Education

• The patient should understand the predisposing factors and the natural course of OM. Adherence to an oral hygiene regimen during hospitalization helps to minimize the risk of infection or the exacerbation of lesions.
• For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Cancer of the Mouth and Throat.

MISCELLANEOUS

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Medical/Legal Pitfalls

• A high index of suspicion of secondary or concomitant infection in lesions of OM is imperative. Cultures should be obtained to rule out such infections. Effective antimicrobial treatments are available for herpetic infections or secondary bacterial infections. The failure to make the diagnosis and, therefore, to treat such conditions may lead to dissemination of infection or unnecessary and prolonged pain and suffering.

MULTIMEDIA

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Media file 1:  Hairy tongue.
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Media file 2:  Multiple mucoceles on the hard palate.
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Media file 3:  Erythematous oral mucositis lesion on the buccal mucosa.
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Media file 4:  Ulcerative oral mucositis lesion on the buccal mucosa.
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Media file 5:  Ulcerative oral mucositis lesion on the lateral and ventral surfaces of the tongue.
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Media file 6:  Ulcerative oral mucositis lesions on the labial mucosa and the floor of the mouth.
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Media file 7:  Oral pseudomembranous candidiasis on the hard palate.
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Media file 8:  Herpes simplex virus ulceration on the dorsal surface of the tongue.
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Media file 9:  Herpes simplex virus ulceration on the hard and soft palate. Note lesions on the right upper lip and the dorsum of the tongue.
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Media file 10:  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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REFERENCES

Section 11 of 11

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• Barasch A, Peterson DE. Risk factors for ulcerative oral mucositis in cancer patients: unanswered questions. Oral Oncol. Feb 2003;39(2):91-100. [Medline].
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• Rapoport AP, Miller Watelet LF, Linder T, et al. Analysis of factors that correlate with mucositis in recipients of autologous and allogeneic stem-cell transplants. J Clin Oncol. Aug 1999;17(8):2446-53. [Medline].
• Ruescher TJ, Sodeifi A, Scrivani SJ, et al. The impact of mucositis on alpha-hemolytic streptococcal infection in patients undergoing autologous bone marrow transplantation for hematologic malignancies. Cancer. Jun 1 1998;82(11):2275-81. [Medline].
• Sonis ST. Oral complications. Cancer Med. 2000;5:2371-9.
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• Sonis ST. Oral mucositis in cancer therapy. J Support Oncol. Nov-Dec 2004;2(6 Suppl 3):3-8. [Medline].
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• Spijkervet FK, Sonis ST. New frontiers in the management of chemotherapy-induced mucositis. Curr Opin Oncol. Aug 1998;10 Suppl 1:S23-7. [Medline].
• 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. Feb 2006;37(4):393-401. [Medline].
• Wilkes JD. Prevention and treatment of oral mucositis following cancer chemotherapy. Semin Oncol. Oct 1998;25(5):538-51. [Medline].
• Woo SB, Sonis ST, Monopoli MM, Sonis AL. A longitudinal study of oral ulcerative mucositis in bone marrow transplant recipients. Cancer. Sep 1 1993;72(5):1612-7. [Medline].
• Woo SB, Lee SJ, Schubert MM. Graft-vs.-host disease. Crit Rev Oral Biol Med. 1997;8(2):201-16. [Medline].

Article Last Updated: Oct 2, 2006