Epidemiology

Oral mucositis is a significant problem in patients receiving chemotherapy for solid tumors. In one study, 303 of 599 (51%) patients receiving chemotherapy for solid tumors or lymphoma developed oral or gastrointestinal (GI) mucositis, or both.¹⁷ Oral mucositis developed in 22% of 1236 cycles of chemotherapy, GI mucositis developed in 7% of cycles, and oral and GI mucositis developed in 8% of cycles. Among patients who receive high-dose chemotherapy before HCT, an even higher percentage (approximately 75% to 80%) developed clinically significant oral mucositis.⁸³

Morbidity

Oral mucositis can be very painful and can significantly affect nutritional intake, mouth care, and quality of life.^16,42 For patients receiving high-dose chemotherapy before HCT, oral mucositis has been reported to be the most debilitating complication of transplantation.^4,80 In patients immunosuppressed because of chemotherapy, increased severity of oral mucositis was found to be significantly associated with an increased number of days requiring total parenteral nutrition and parenteral narcotic therapy, increased number of days with fever, incidence of significant infection, increased time in the hospital, and increased total inpatient charges.⁸³ A reduction in the next dose of chemotherapy was twice as common after cycles with mucositis than after cycles without mucositis.¹⁷ Mucositis is not only a concern for pain and suffering, but can also cause dose-limiting toxicity of cancer chemotherapy with direct effects on patient survival.

Pathogenesis and clinical presentation

The mucosal surfaces throughout the oral cavity have different cellular turnover rates, which can vary from 4 to 5 days for nonkeratinized buccal and labial mucosa to 14 days for the orthokeratinized hard palate. The more rapid the cell division rate of the progenitor epithelial cells, the higher the susceptibility to damage from chemotherapy and radiation therapy. The mechanisms involved are more complex, however, than simply direct damage to oral epithelial cells from chemotherapy or radiation therapy. The currently accepted model for the pathogenesis of mucositis postulates five stages associated with tissue damage and healing. Initiation of direct tissue injury is thought to be mediated by production of reactive oxygen species resulting in cell death. This stage is followed by activation of second messengers that upregulate the production of proinflammatory cytokines in mucosal epithelium and submucosal tissues and lead to widespread tissue injury. Through feedback mechanisms, these cytokines can amplify the cascade of tissue injury further, leading to ulceration and secondary infection. The final stage is characterized by the stimulation of epithelial proliferation and differentiation, leading to mucosal healing.⁷⁷

Histologically, the mucosal damage is characterized by mucosal atrophy, inflammatory cell infiltrates, collagen degradation, and edema.⁴⁹ Clinically, these changes are initially evident as mucosal redness. As the damage increases to basal epithelial cells, ulceration can manifest as isolated lesions. The process progresses to confluent ulcers, often covered by a white pseudomembranous fibrin exudate (Figure 50-1).

FIGURE 50-1 Oral mucositis ulcer involving the right lateral and ventral tongue.

Because of the complex cascade of events that occur, lesions may arise 1 to 2 weeks after stomatotoxic chemotherapy. Lesions are usually limited to nonkeratinized areas such as the buccal and labial mucosa, lateral tongue, and soft palate. Keratinized tissues, such as the attached gingiva, dorsal tongue, and hard palate, are less commonly affected. Mucositis typically heals 2 to 4 weeks after the last dose of stomatotoxic therapy has been delivered.⁴³ Oral infections caused by organisms acquired during hospitalization and the reactivation of latent viruses (e.g., herpes simplex virus [HSV], cytomegalovirus [CMV], varicella-zoster virus [VZV]) can also influence the clinical presentation of mucositis and may prolong the duration of ulcerative lesions.

The presence of oral dryness resulting from direct toxic effects of chemotherapeutic agents on the salivary glands concomitant nonchemotherapeutic agents with xerostomic side effects, or dehydration leads to decreased hydration and lubrication of the mucosa. This oral dryness may exacerbate mucositis lesions by traumatizing existing lesions or cause sufficient trauma that may initiate a new oral lesion.

Management

Management of mucositis currently is focused on palliation of pain and efforts to reduce the influence of secondary factors on mucositis. Based on an extensive systematic review of the literature, the Mucositis Study Group of the Multinational Association for Supportive Care in Cancer and the International Society of Oral Oncology (MASCC/ISOO) has developed clinical practice guidelines for the management of mucositis.³⁷ These guidelines are discussed subsequently and addressed in Table 50-1.

TABLE 50-1 Agents Studied for Oral Mucositis

FDA, Food and Drug Administration; RT, Radiation therapy.

* Multinational Association for Supportive Care in Cancer and the International Society of Oral Oncology.

Pain control

Pain control is provided through various strategies, including topical anesthetics, mucosal coating agents, and systemic pain medications. Focal application of topical anesthetic agents is preferred over widespread oral administration for many reasons. Generalized oral mucosal anesthesia carries the risk of accidental mucosal trauma. Generalized rinsing with anesthetics also may reduce or eliminate the gag reflex, which may increase the risk of aspiration pneumonia. Systemic absorption or swallowing of anesthetics from ulcerated mucosa can result in systemic toxicity, depending on the agent and the dose that is swallowed. However, when mucositis becomes extensive, intentional generalized topical applications of anesthetics are often used to reduce pain.

A common approach to managing oral mucositis is to use a combination solution that includes many different agents, such as topical anesthetics, coating agents, and antifungal drugs. When using these rinses, the clinician faces numerous considerations, as follows:

When topical pain control strategies become inadequate for controlling pain, systemic analgesics are necessary. Opioids are usually the drugs of choice. Various delivery systems such as time-release oral tablets, dermal patches, and suppositories can also be used to provide adequate pain relief.

The combination of long-term indwelling venous catheters and computerized drug administration pumps to provide patient-controlled analgesia has significantly increased the ability to control severe mucositis pain while reducing the dose and side effects of opioid analgesics. The MASCC/ISOO guidelines recommend patient-controlled analgesia with morphine for patients undergoing HCT.³

Maintenance of oral hygiene

Multiple studies have shown that good oral hygiene plays an important role in the management of oral mucositis.^8,10,47 The MASCC/ISOO guidelines recommend use of a standardized oral care protocol including brushing with a soft toothbrush, flossing, and use of nonmedicated rinses (e.g., saline or sodium bicarbonate rinses). Patients and caregivers should be educated regarding the importance of effective oral hygiene.⁵³

Therapeutic interventions

Various agents have been studied to prevent oral mucositis or to reduce its severity, including cryotherapy, growth factors, anti-inflammatory agents, antibacterial agents, promoters of healing, and mucosal coating agents. Table 50-1 lists selected agents studied more recently for oral mucositis. The MASCC/ISOO recommendations are also provided for agents where a guideline exists.

Fungal infections

Superficial colonization by Candida species, especially Candida albicans, is a common finding in cancer patients receiving chemotherapy. As the degree and duration of immunosuppression increase in patients receiving myelosuppressive/immunosuppressive therapy, there is a distinct increase in the risk for invasive oral fungal infections such as aspergillosis and mucormycosis and numerous other invasive fungal organisms. Yeast and fungal organisms generally have low infectivity, but with changes in the local or systemic immunity, they can pose a significant infectious risk.

Factors affecting oral colonization and infection risk include alterations in competing oral bacterial flora (most commonly associated with the use of systemic antimicrobials), decreased salivary gland flow rates, and immunosuppression. The latter is especially related to neutropenia. Alteration in host oral bacterial flora in cancer patients with myelosuppression supports increased candidal colonization. With the development of new strategies to prevent and treat fungal infections, however, the fungal organisms associated with oral infections are changing. The widespread use of fluconazole prophylaxis has been associated with increasing numbers of Candida glabrata (Torulopsis glabrata) and Candida krusei infections that may have decreased sensitivity to fluconazole and other antifungal agents.⁸⁴

Oral candidal infections can have various clinical presentations—pseudomembranous, erythematous, atrophic, hyperplastic, and invasive. The most common form is pseudomembranous candidiasis, in which mild to heavy surface colonization occurs with raised, white, debris-like masses of organisms. With hyphal invasion of the upper cellular layers of the mucosal epithelium, the mucosal surface can become atrophic, often with little or no evidence of pseudomembranous masses. Atrophic or erythematous candidiasis is particularly common on the dorsal tongue, where the only clinical evidence of infection may be a patchy loss of filiform papillae. Candidal infections of the lip commissures usually manifest with cracking, pain, and varying degrees of erythema. With deeper mucosal invasion, a hyperplastic or ulcerative lesion can be noted. Invasive candidiasis is usually characterized by discrete, firm, almost leathery, white-yellow lesions with marginal erythema. These lesions are primarily noted in patients who are significantly immunocompromised and are at high risk of systemic dissemination. Although oral candidal infections are classically reported to be associated with symptoms of “metallic taste” and “increased sensitivity to spices,” this is not frequently noted in infections associated with cancer therapy.

The diagnosis of Candida infection often requires correlation of the clinical presentation of lesions with laboratory tests. Clinical lesions are often nonspecific, and because Candida can be a normal inhabitant, reliance only on fungal cultures may lead to false-positive results. Using direct microscopic examination (with Gram stain or potassium hydroxide to identify pseudobranching hyphae) followed by culture to determine the species of the fungus can be helpful. Increasing numbers of Candida organisms on culture (1+ to 4+) generally correlate with increasing significance of infection. Because different species of Candida can have different sensitivities to different antifungals, speciation becomes particularly important in cases in which the patient has not responded to therapy or when there is frequent recurrence of oral candidiasis. For hyperplastic and invasive candidiasis, cultures from surface swabs and scrapings can produce false-negative results, and biopsy with culture from tissue samples along with specific stains for Candida may be required to establish a definitive diagnosis.

More recent Cochrane reviews addressed the efficacy of various antifungal drugs in prevention and treatment of oral candidiasis in cancer patients.^11,87 Nystatin, although commonly used, was found to be ineffective, possibly because it is not absorbed in the GI tract. Drugs partially absorbed from the GI tract, such as topical clotrimazole or miconazole, were found to be effective and can be useful for superficial oral infection. Persistent or locally invasive infection (including atrophic and erythematous candidiasis), especially when a risk exists for systemic spread, should be treated with appropriate systemic agents. Systemic azoles (e.g., fluconazole, itraconazole, ketoconazole) that are fully absorbed in the GI tract are very effective against the organisms and generally considered the most effective way to prevent or reduce fungal colonization and subsequent infection. These drugs are secreted in saliva; salivary concentrations of fluconazole are directly proportional to plasma concentrations.³⁸ It has been suggested that systemic antifungals may be less effective for oral candidiasis in patients with decreased salivary production because of reduced oral delivery of the drug through saliva. In one study, salivary concentrations of fluconazole were not found to correlate to response to therapy,²⁷ however; this area requires further research.

The treatment of disseminated candidal infections remains difficult and can be complicated by the presence of azole-resistant organisms. Amphotericin B and the newer agent caspofungin are the systemic antifungals of choice for severe deep mycoses, especially in immunocompromised patients. Organisms that can cause serious oral infections in immunocompromised cancer patients include Aspergillus, Mucor, and Rhizopus. These infections often have a nonspecific appearance and can be confused with other oral toxic effects. Diagnosis depends on laboratory tests, and systemic therapy must be instituted immediately because these infections can spread systemically and lead to fatal outcomes.

Viral infections

Herpes group viruses can cause significant oral disease in patients receiving cancer chemotherapy.^70,72,73 HSV, VZV, CMV, and Epstein-Barr virus (EBV) are recognized causes of oral lesions in cancer patients. Most infections with HSV, VZV, and EBV represent reactivation of latent virus, whereas CMV infections can result from either reactivation of latent virus or newly acquired virus. Other viruses causing oral lesions in cancer chemotherapy and HCT patients are adenovirus, coxsackieviruses, and human herpesvirus. The diagnosis of viral lesions in the mouth can be made through direct immunofluorescent examination of scrapings from lesions, />