Chemotherapy-Induced Oral Mucositis 

Updated: Jun 22, 2017
Author: Nathaniel S Treister, DMD, DMSc; Chief Editor: Jeff Burgess, DDS, MSD 

Overview

Practice Essentials

Oral mucositis is a common complication of cancer 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 and burning

  • Erythema and ulcerations

  • 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, attached gingiva, or dorsum of the tongue. Biopsy may be indicated, but it is not routinely necessary for diagnosis.

The two 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

The five main approaches to managing oral mucositis are as follows:

  • Oral debridement (eg, brushing, toothettes); 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 may be considered[1, 2]

  • Prophylaxis, such as ice-chip cryotherapy or Palifermin (keratinocyte growth factor, FDA approved for mucositis prevention in hematopoietic cell transplantation)

  • Low-level laser therapy (photobiomodulation)

See Treatment and Medication for more detail.

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 are lacking for various solid and hematologic malignancies; however, Lalla et al, while reviewing published trials for the 2014 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) guidelines, found that mucositis occurs in approximately 20-40% of patients receiving conventional chemotherapy and in 80% of patients receiving high-dose chemotherapy.[4] 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. Once present, 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.

Targeted therapies

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 mammalian target of rapamycin (mTOR) inhibitors, including sirolimus (rapamycin), temsirolimus, and everolimus, are increasingly being used as anticancer agents for neuroendocrine tumors of the GI tract, lung, and pancreas and breast and renal cancers, and have been associated with the development of oral aphthous–like ulcers, referred to as mTOR inhibitor–associated stomatitis, or mIAS.[6] They occur in 35-52.9% of patients and are characterized by discrete, ovoid ulcers with a characteristic erythematous halo, and they appear clinically identical to idiopathic aphthous stomatitis in otherwise healthy patients. Like aphthous ulcers, these are confined to the nonkeratinized tissues and have a quicker onset compared with classic mucositis.

Because this toxicity clusters with dermatologic toxicities, rather than GI (as is the case with conventional mucositis) toxicities, this suggests that the underlying pathophysiology is likely very different. Investigations from 2017 suggest the following three-stage sequence[7, 8] :

  1. Direct mTOR inhibitor–initiated epithelial injury
  2. Release of proinflammatory cytokines
  3. Activation of the innate immune response with influx of inflammatory cells

Treatment approaches known to be effective for the management of aphthous stomatitis, such as high-potency topical steroids, also may be effective for mIAS.[7, 8]

Dysgeusia and xerostomia have been reported adverse effects in these targeted therapies. They tend to have a greater impact on quality of life; however, these adverse effects may also affect the patients ability to maintain adequate nutritional intake, leading to weight loss.

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 five interrelated phases, including an initiation phase, a message-generation phase, a message-activation and up-regulation phase, a signaling and amplification phase, and an ulceration/microbiological phase, and a healing phase.[9] In the initiation phase, cellular damage causes direct DNA breaks with the generation of reactive oxygen species, which damage lipids, DNA, and connective tissue, leading to cell death and the release of inflammatory substances. In the up-regulation/activation phase, transcription factors such as nuclear factor (NF)–κβ and distinct pathogen-associated molecular patterns such as toll-like receptor signaling emerge.

During the signaling and amplification phase, positive feedback loops are activated. For example, tumor necrosis factor (TNF)–α activates NF-κβ, 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 interleukin (IL)–1 and TNF-α. 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 WBC count and oral mucositis is uncertain, and not all patients with mucositis demonstrate hematologic toxicity.

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 graft versus host disease (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.[10] Stomatitis occurs more frequently in patients with breast cancer treated with a 5-flurouracil, doxorubicin, and cyclophosphamide regimen versus a doxorubicin and paclitaxel regimen.[11] Nevertheless, 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.

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.[12] 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.

Prognosis

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

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 four times that of patients with neutropenia without oral mucositis.

Patients with pulpal disease from dental caries or trauma, periodontal disease, and low-grade soft-tissue infections (especially those associated with partially erupted third molars) are at increased risk for bacteremia due to oral viridans streptococci (Streptococcus mitis, Streptococcus oralis, Streptococcus acidominimus); the rate was reported to be as high as 28% in subjects undergoing HCT. All of these patients had either gingivitis or periodontitis.[13]

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.

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.[14]

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

 

Presentation

History

Patients may initially describe generalized burning or sensitivity of the oral mucosa about 1 week after starting chemotherapy. With onset of frank ulcerations, patients typically report pain, which can be quite severe. Oral pain contributes to patient morbidity. Difficulty with eating, drinking, speaking, and maintenance of oral hygiene regimens typifies morbidity. Additionally, oropharyngeal and esophageal involvement is common and may precede the onset of oral ulcers. Some patients with severe mucositis may require parenteral nutrition until they are better able to swallow adequately. Dysgeusia, or altered taste sensation, may further reduce the patient's appetite.

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 hematopoietic cell transplantation [HCT]) coincides with recovery of the WBC count, specifically when the absolute neutrophil count becomes greater than 500 cells/µL (see the Absolute Neutrophil Count Calculator). In patients being treated for solid tumors, the duration of oral mucositis depends on the type, dose, and course of treatment. Patients undergoing HCT conditioned with total body irradiation are at somewhat higher risk of experiencing more severe and prolonged oral mucositis.

Physical Examination

The oral cavity should be examined, using an adequate light source, on a daily basis for inpatients and at every clinic visit for outpatients. All oral mucosal sites should be assessed; therefore, it is important to have the patient move his or her tongue and to retract the buccal mucosa to visualize the posterior aspects and buccal vestibules.

The earliest changes in chemotherapy-induced oral mucositis 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. This is followed by erythema (see images below) and atrophy on the mucosa that may then break down to form ulcers that are covered by a yellowish-white fibrin clot (the pseudomembrane). 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.

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

The mouth is a trauma-intense environment. When the oral mucosa becomes atrophic from chemotherapy and renewal of oral epithelium has been slowed, 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 below). Because many patients (especially those undergoing HCT) are profoundly thrombocytopenic, bleeding may occur from sites of ulcerative oral mucositis.

Ulcerative oral mucositis lesion on the buccal muc Ulcerative oral mucositis lesion on the buccal mucosa.
Ulcerative oral mucositis lesion on the lateral an Ulcerative oral mucositis lesion on the lateral and ventral surfaces of the tongue.
Ulcerative oral mucositis lesions on the labial mu Ulcerative oral mucositis lesions on the labial mucosa and the floor of the mouth.

Patients treated with methotrexate as part of their graft versus host disease (GVHD) prophylaxis are also at increased risk; non–methotrexate-containing regimens have been associated with lower rates of mucositis.[15]

A dry mouth (xerostomia) from decreased salivary flow (hyposalivation) secondary to chemotherapy reduces natural lubrication and contributes to the ease of trauma-induced ulceration, difficulty in eating and swallowing (dysphagia), and the accumulation of debris in the mouth. In general, this is of much greater concern in patients undergoing radiation therapy to the head and neck, which, in addition to causing significant salivary gland hypofunction, is also associated with significant rates and severity of oral mucositis. A hairy tongue and superficial mucoceles may develop as a result of decreased salivary flow and limited oral intake (see the images below). 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 contribute to the development of hairy tongue. While retention of keratin on other sites, such as the gingiva and hard palate, may also be mistaken for oral candidiasis, 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.

Hairy tongue. Hairy tongue.
Multiple mucoceles on the hard palate. Multiple mucoceles on the hard palate.

Complications

A wide range of complications are associated with oral mucositis, including, but not limited to, the following:

  • Inadequate pain control
  • Poor nutrition
  • Dehydration
  • Interruption of cytoreductive therapy
  • Increased length of hospitalization
  • Increased cost of treatment
  • Increased risk of local and systemic infection

Oral mucositis is a painful condition, which, when severe, may require intensive pain control and nutritional support. In the context of HCT, severe oral mucositis has been associated with increased overall hospital costs and hospital length of stay.[16] If oral intake is severely limited, patients may become dehydrated and require intravenous support. Patients with severe and prolonged oral mucositis, for example in the context of HCT, may require total parenteral nutritional support.

 

DDx

Diagnostic Considerations

Overall, candidiasis is the most frequent oral infection in patients who are myelosuppressed (see image below); recurrent herpes simplex virus (HSV)–1 infection is the most frequent oral viral infection in these patients (see images below).

Oral pseudomembranous candidiasis on the hard pala Oral pseudomembranous candidiasis on the hard palate.
Herpes simplex virus ulceration on the dorsal surf Herpes simplex virus ulceration on the dorsal surface of the tongue.
Herpes simplex virus ulceration on the hard and so Herpes simplex virus ulceration on the hard and soft palate. Note lesions on the right upper lip and the dorsum of the tongue.

HSV infection should be suspected when ulcers are noted extraorally on the lips and intraorally on keratinized sites (ie, tongue dorsum, gingiva, and hard palate); in immunocompromised patients, HSV may reactivate in nonkeratinized sites, and, in some cases, this can occur despite antiviral prophylaxis. Consider other viral infections, including human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), and cytomegalovirus (CMV).

Acute graft versus host disease (GVHD) occurs typically within the first 100 days after allogeneic hematopoietic cell transplantation (HCT) and involves the skin; the liver; and the mucosae of the eye, mouth, and GI tract. Acute GVHD lesions in the oral cavity occur following engraftment and restoration of the WBC count and well after the resolution of oral mucositis lesions, although in some cases, they may manifest as a continuation or exacerbation of oral mucositis. An important difference is that lesions of acute GVHD may affect the keratinized mucosa, which is not a feature of oral mucositis (see image below).

Acute graft versus host disease involving the dors 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.

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. Chronic GVHD develops in most cases at least 3 months after HCT and should never be mistaken for mucositis.

A high index of suspicion of secondary or concomitant infection in lesions of oral mucositis is imperative. Cultures should be obtained to rule out such infections. Effective antimicrobial treatments are available for herpetic, fungal, and 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.

Differential Diagnoses

 

Workup

Approach Considerations

Diagnosis is primarily based on the clinical findings and the chronology of the development of lesions.

There are no routine hematologic or blood chemistry laboratory investigations needed in the workup of a patient with chemotherapy-induced oral mucositis.

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.

Particularly in hematopoietic cell transplantation (HCT) patients, biopsy is indicated 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. Biopsy should also be considered when oral ulcerations are exacerbated with engraftment and restoration of the WBC count, especially when skin changes are absent, because this is suggestive of emerging acute graft versus host disease (GVHD). However, biopsy is not routinely necessary for oral mucositis.

There is no indication for ordering imaging studies in a patient with suspected chemotherapy-induced oral mucositis.

Oral mucositis should be assessed routinely using a validated instrument. The two 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 previously had separate scores for objective (erythema and ulceration) and functional (pain and ability to eat solids, liquids, or nothing by mouth) components, version 4.0 is based entirely on function (what a patient is able to eat). The WHO score combines both objective and functional 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, is a validated instrument that correlates with oral mucositis severity based on the WHO score.[17]

Of note, symptoms may precede objective findings by 1-3 days and therefore can serve as an important prognostic indicator.

Histologic Findings

In banal oral mucositis, 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. Staining for fungi and viruses may be necessary to identify organisms.

 

Treatment

Approach Considerations

Treatment of chemotherapy-induced oral mucositis begins with patient education and reinforcing the importance of good oral care throughout cancer treatment. Mucositis is self-limiting, and the goal of treatment is to make the patient as comfortable as possible and to maintain adequate nutrition and hydration. In both inpatient and outpatient settings, patients should be assessed routinely to ensure good symptom control.

Medical Care

Because oral mucositis is self-limited, management of lesions is divided into five main approaches, described below.

Basic oral care

Basic oral care is divided into two sections: debridement and decontamination.[4] General debridement with a soft or ultra-soft toothbrush or toothettes is recommended. Because patients with oral mucositis lesions are frequently neutropenic and thrombocytopenic, perform oral debridement with caution because tooth brushing can cause gingival bleeding and, more importantly, result in transient bacteremia. Dried secretions may become caked on the mucosal surfaces, particularly the palate (and often misdiagnosed as candidiasis). Mucolytic agents, such as Alkalol, help to soften and dislodge them. The decontamination regimen consists of antifungal and antibacterial rinses. Antibacterial rinses with chlorhexidine are effective in reducing the overall bacterial load in the oral cavity and are used at some hematopoietic cell transplantation (HCT) centers. Candidal prophylaxis usually includes nystatin rinses or 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. None of these treatments has been shown to specifically reduce the risk of developing oral mucositis.

Topical and systemic pain management

Pain in patients with oral mucositis may be severe and not just limited to the oral mucosa. Local rinses (eg, 2% viscous lidocaine, magic mouthwash preparations, topical morphine solution) and systemic analgesics are used together to control pain. Topical solutions should be kept in the mouth for 2-5 minutes, as tolerated. Frequent rinsing with sodium chloride solution helps to keep the mucosa moist, reduces caking of secretions, and soothes inflamed/ulcerated mucosa. An oral rinse containing the antidepressant doxepin appears to be effective for easing the pain of acute oral mucositis caused by radiation therapy, with or without chemotherapy.[1, 2] Topical devices, such as Gelclair (EKR Therapeutics, Inc.) and Caphosol (EUSA Pharma) have also been approved by the US Food and Drug Administration (FDA) for mucositis symptom management.

Prophylaxis/prevention

Cryotherapy with ice chips has been shown to effectively attenuate the onset and severity of mucositis in patients undergoing bolus chemotherapy with 5-fluorouracil and melphalan. Patients should suck on ice chips for 30 minutes prior to and during the chemotherapy infusion. Palifermin (keratinocyte growth factor) is FDA approved for the prevention of oral mucositis in patients undergoing HCT with myeloablative conditioning (see below). Antimicrobial prophylaxis is generally limited to antivirals to prevent herpes simplex virus (HSV) reactivation; however, some centers use fluconazole as prophylaxis against candidiasis. Neither antiviral nor antifungal prophylaxis prevents mucositis. Increasing evidence supports the effectiveness of photobiomodulation therapy (low-level laser therapy) for the prevention and management of oral mucositis, but its use remains limited. Regimens, including laser wavelength and intensity, have varied considerably from study to study, and specialized equipment is required.

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

Patients with poorly controlled symptoms and difficulty eating may benefit from consultation with the following services:

  • Oral medicine specialist
  • Pain and palliative care specialist
  • Nutritionist

Diet

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

Activity

Patients with chemotherapy-induced oral mucositis have no specific activity restrictions but typically eat a modified diet, owing to the pain from oral mucositis.

Prevention

See above under Medical Care.

Long-Term Monitoring

Patients with chemotherapy-induced oral mucositis should be followed for signs and symptoms until complete healing and recovery. Chemotherapy-induced oral mucositis is an acute self-limiting condition. There are no long-term implications.

 

Guidelines

Guidelines Summary

Comprehensive, evidence-based guidelines for the prevention and treatment of oral mucositis are available. See the following:

 

Medication

Medication Summary

Oral mucositis is a self-limited condition. Currently, no approved preventive or therapeutic agent consistently prevents oral mucositis in all clinical settings.

Palifermin, or human recombinant keratinocyte growth factor (KGF), given intravenously significantly reduces the incidence, duration, and severity of oral mucositis in patients undergoing autologous hematopoietic cell transplantation (HCT) and has been approved for use in patients with hematologic malignancies undergoing high-dose chemotherapy with or without concomitant total body irradiation, with autologous or allogeneic stem cell transplantation.[5, 18, 19] Human KGF may be considered for hematologic malignancies.[20]

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.

Palliation

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 used alone or is mixed in equal volumes with diphenhydramine hydrochloride and bismuth subsalicylate (Kaopectate) or even aluminum hydroxide/magnesium hydroxide (Maalox) as a soothing mouth rinse. Topically applied morphine solution has demonstrated efficacy in controlling symptoms. With increasing severity of mucositis, and especially when involving the esophagus, systemic opioids may be indicated.

Antifungals

Class Summary

These agents are used prophylactically against candidal infections in all patients. Reevaluate the diagnosis if no clinical response is detected.

Nystatin (Nystex, Mycostatin, Nilstat)

Nystatin is a fungicidal and fungistatic antibiotic obtained from Streptomyces noursei. It is effective against various yeasts and yeastlike fungi. It changes the permeability of the fungal cell membrane after binding to cell membrane sterols, causing cellular contents to leak. Nystatin is not absorbed significantly from the GI tract.

Clotrimazole (Lotrimin, Mycelex, Femazole)

Clotrimazole is a broad-spectrum antifungal agent that inhibits yeast growth by altering cell membrane permeability, causing death of fungal cells. Reevaluate the diagnosis if no clinical improvement is seen after 4 weeks.

Fluconazole (Diflucan)

Fluconazole has fungistatic activity. It is a synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents the conversion of lanosterol to ergosterol, thereby disrupting cellular membranes.

Antibacterials

Class Summary

Rinses are the basis of the oral decontamination regimen.

Chlorhexidine oral (Peridex, PerioChip, PerioGard)

Chlorhexidine oral is an effective, safe, and reliable antiseptic mouthwash. It is a polybiguanide with bactericidal activity; it is usually supplied as gluconate salt. At physiologic pH, salt dissociates to a cation that binds to bacterial cell walls. Chlorhexidine is active against gram-positive and gram-negative organisms, facultative anaerobes, aerobes, and yeast. Precede use of the solution by flossing and brushing teeth, if possible. Completely rinse toothpaste from mouth.

Anesthetics

Class Summary

Oral rinses are used to reduce pain and discomfort.

Viscous lidocaine 2% (Xylocaine, Dilocaine, Anestacon)

Viscous lidocaine 2% decreases permeability to sodium ions in neuronal membranes. This results in inhibition of depolarization, blocking the transmission of nerve impulses.

Antivirals

Class Summary

Nucleoside analogs are initially phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate. Once phosphorylated, it causes DNA chain termination when acted on by DNA polymerase. These molecules inhibit herpes simplex virus (HSV) polymerase with 30-50 times the potency of human alpha-DNA polymerase.

Acyclovir (Zovirax)

Use acyclovir for patients who have been exposed to HSV or varicella-zoster virus (VZV) infection. Reactivation of such infections occurs in 70-90% of patients who have antibodies to these agents and can aggravate preexisting oral mucositis and result in systemic infection. It inhibits the activity of HSV-1 and HSV-2. Patients experience less pain and faster resolution of cutaneous lesions when used within 48 hours of rash onset. Acyclovir may prevent recurrent outbreaks. Early initiation of therapy is imperative.

Valacyclovir (Valtrex)

Valacyclovir is a prodrug and is rapidly converted to the active drug acyclovir. It is more expensive but has better bioavailability and a more convenient dosing regimen than acyclovir.

Famciclovir (Famvir)

Famciclovir is for prophylactic use to prevent recurrent HSV infections. It is a prodrug, which, when biotransformed into its active metabolite, penciclovir, may inhibit viral DNA synthesis/replication. It inhibits viral DNA polymerase.

Oral Rinses

Class Summary

Mucoadhesive action reduces pain by adhering to the mucosal surface of the mouth.

Magic Mouthwash

Magic mouthwashes in general form a viscous adhesive substance that protects the oral lining.

Artificial saliva (Caphosol, Aquoral, Oasis)

These preparations typically contain methylcellulose, sorbitol, and salts to moisten and lubricate the mouth.

Bioadherent oral (Gelclair)

This agent adheres to the mucosal surface of the mouth and forms a protective coating that shields exposed and overstimulated nerve endings. Ingredients include water, maltodextrin, propylene glycol, polyvinylpyrrolidone (PVP), sodium hyaluronate, potassium sorbate, sodium benzoate, hydroxy ethylcellulose, polyethylene glycol (PEG)–40, hydrogenated castor oil, disodium edetate, benzalkonium chloride, flavoring, saccharin sodium, and glycyrrhetinic acid.

Growth factors

Class Summary

Human KGF may be considered for hematologic malignancies.

Palifermin (Kepivance)

Palifermin is a human KGF that enhances epithelial cell proliferation, differentiation, and migration. The KGF receptor is not present on hematopoietic cells, but has enhanced growth of human epithelial tumor cell lines in vitro. It is indicated to decrease severe oral mucositis incidence and duration in patients with hematologic malignancies.