para>Severe oral mucositis can cause airway compromise in children that can be life-threatening. �
Epidemiology
Incidence
Mucositis can affect up to 100% of patients undergoing high-dose chemotherapy prior to hematopoietic/stem cell transplantation, up to 85% of patients receiving radiation therapy for head/neck cancers, and up to 40% of patients undergoing chemotherapy alone. �
Prevalence
- The type(s) and dose of chemotherapeutic agents as well as possible underlying genetic factors determine the frequency and severity of mucositis.
- Many chemotherapeutic agents can cause mucositis. Cytotoxic agents such as 5-fluorouracil, capecitabine, and cisplatin appear to have the highest incidence.
- Other agents commonly associated with mucositis include, but are not limited to, methotrexate and related antimetabolites, doxorubicin, receptor tyrosine kinase inhibitors (sunitinib, sorafenib), epidermal growth factor receptor (EGFR) inhibitors (cetuximab, erlotinib), and mammalian target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus).
- Head/neck and total body irradiation are also high risk for developing mucositis.
Etiology and Pathophysiology
Mucositis progresses through five stages. �
- Initiation: Direct cellular damage from radiation and/or chemotherapy leading to epithelial cell destruction and free radical creation.
- Upregulation: Free radicals activate second messengers to upregulate proinflammatory cytokines.
- Amplification: Proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) produce further damage to mucosal cells and activate immune cellular response.
- Inflammation/ulceration: Inflammatory cell infiltrates cause mucosal ulceration and are further stimulated by colonizing flora.
- Healing: Inflammation diminishes to allow epithelial hypertrophy and restoration of the mucosal barrier (1).
Genetics
Genetic polymorphisms have been identified that may predispose individuals to methotrexate-induced mucositis, and research is ongoing into other theorized genetic factors. �
Risk Factors
- Type of chemotherapeutic agent used as well as dosing and frequency
- Frequency, dosing, and location of radiation therapy
- Genetic predispositions which are not fully understood at this time
General Prevention
- Pretreatment oral assessment 2-3 weeks prior to initiation of therapy to address asymptomatic oral infections, dental caries, and periodontal disease (1,2)
- Use of oral care protocols including frequent use of nonmedicated oral rinses, flossing, and brushing with soft toothbrushes (1,3,4)[B]
- Aggressive treatment of xerostomia with saliva replacements or saliva stimulants to promote healthy oral mucosa (2)
- Prevention of GI mucositis includes basic bowel care with strategies to achieve adequate hydration and avoid exacerbation by transient lactase deficiency.
Commonly Associated Conditions
- Pain, odynophagia, dehydration, impaired nutrition
- Superinfections with fungi, bacteria, or viruses. See "Complications."�
Diagnosis
History
- Clinical diagnosis is made based on the appearance of oral mucosal changes and pain or GI symptoms within 7 days of initiation of chemotherapy or radiation treatment.
- Mucositis is usually self-limited with resolution 10-14 days after onset.
Physical Exam
- Oral mucositis ranges from erythema to ulceration with possible pseudomembrane formation of white exudative material.
- Commonly found on buccal mucosa, soft palate, ventral tongue, and floor of mouth.
- Radiation-induced mucositis will primarily affect the tissues in the field of radiation.
- Multiple scales are used to grade the degree and severity of oral mucositis but few exist for GI mucositis. The most common scales for oral mucositis are from the World Health Organization (0-4 scale based on subjective and objective findings) and the National Cancer Institute Common Terminology Criteria (1-5 scale based on subjective and objective findings).
Differential Diagnosis
- Fungal infection: primarily caused by Candida albicans with formation of adherent white plaques on erythematous mucosa.
- Viral infections: Croppy lesions in keratinized mucosal areas, sometimes associated with fever and other symptoms. Consider herpes simplex virus type 1 (HSV-1) reactivation, as patients undergoing chemotherapy are immunocompromised.
- Graft-versus-host disease: Look for dramatic lichenoid lesions in patients who have undergone transplant.
Diagnostic Tests & Interpretation
Initial Tests (lab, imaging)
- Indicated only if diagnosis is in question
- Consider culture or exfoliative cytologic studies to distinguish mucositis from viral or fungal infections.
- Stool studies, particularly Clostridium difficile toxin assays
Test Interpretation
- Mucositis will show inflammation, cellular necrosis, and debris, whereas cytologic studies and cultures will identify viruses or fungi.
- Distinguish between mucositis-related GI symptoms and bacterial infection or malabsorptive cause.
Treatment
General Measures
- Mucositis will most likely be prophylaxed or treated by the oncologist, but primary care providers need to be aware of various treatments in case they are called upon to initiate evaluation and treatment or to direct the patient toward definitive therapy.
- Pain control
- Nutritional support during periods of decreased oral intake
- Prevention of and monitoring for secondary infection
- Reduction in dose or frequency of chemotherapy or radiation, if necessary
Medication
First Line
- Oral mucositis
- Use of keratinocyte growth factor-1 (KGF-1/palifermin) for 3 days prior to high-dose initiation chemotherapy and 3 days posthematopoietic cell transplant (3)[A].
- Gelclair bioadherent oral rinse-combination of polyvinylpyrrolidone, sodium hyaluronate, and glycyrrhetinic acid with other ingredients-diluted then rinsed for at least 1 minute, 1 hour prior to meals and prn. Adheres to mucosa (4)[B].
- Cryotherapy with oral ice chips for 30 minutes prior to infusion of 5-fluorouracil and melphalan(3)[A].
- Benzydamine mouthwash prior to receiving moderate dose radiation therapy (up to 50 Gy) for head/neck cancers(1,3)[A]
- Systemic oral zinc supplementation for patients undergoing radiation or chemoradiation
- Mouthwash preparations using lidocaine, magnesium aluminum hydroxide, and diphenhydramine to treat oral pain (1,4)[B]
- Doxepin 0.5% mouthwash to treat oral cavity pain
- Morphine 2% mouthwash to treat oral cavity pain. It is less effective if the patient is already taking oral opioids.
- Chlorhexidine is not recommended for established oral mucositis (3)[A].
- Avoidhydrogen peroxide.
- GI mucositis
- Use of ranitidine or omeprazole to prevents esophagitis and/or gastritis (3)[A].
- Amifostine given intravenously (IV) to prevent radiation proctitis from abdominal/pelvic radiotherapy and esophagitis from combined chemoradiation therapy (3)[B]
- Sulfasalazine 500 mg oral twice daily to prevent radiation-induced enteropathy (3)[B]
- Lactobacillus-containing probiotics to prevent diarrheal symptoms
- Oral loperamide for diarrheal symptoms (3)[C]
- Sucralfate enemas for chronic radiation proctitis with rectal bleeding (3)[B]
Second Line
- Oral mucositis
- Patient-controlled analgesia with IV morphine shown to be effective for oral pain not controlled with topical therapy and proven to decrease total opioid dose compared to continuous infusion (5)[A].
- GI mucositis
- Octreotide subcutaneously at least 100 mcg twice daily for diarrhea not responding to oral loperamide(3)[A]
- Interventions
- Oral hygiene protocols (1,3)
- Counsel regarding diet, oral care, and treatment options (3,4)[B].
- Use of midline radiation blocks during radiotherapy (3)[B]
- For centers offering low-level laser treatment (LLLT), treatment of the oral cavity in patients prior to receiving high-dose chemotherapy followed by hematopoietic cell transplant and potentially in those receiving head/neck radiotherapy alone (3,5)[B]
Potential New Therapies
- Small studies have shown some benefit from ketamine mouthwash for topical treatment of refractory oral mucositis pain (6)[C].
- Research into upregulation of anti-inflammatory cytokines such as IL-4, IL-10, and IL-11 to treat mucositis(7)[C].
Complementary & Alternative Therapies
Currently, only Traumeel S (a proprietary complex) has shown promise as better than placebo for the treatment of oral mucositis (8)[B]. �
Aloe vera and honey show some weak but statistically significant evidence for prevention or decreasing severity of mucositis compared to no treatment or placebo (9)[C]. �
Inpatient Considerations
Admission Criteria/Initial Stabilization
Dehydration, uncontrolled pain, superinfection, and/or GI hemorrhage �
IV Fluids
- Indicated for dehydration resulting from odynophagia, dysphagia, and/or diarrhea due to mucositis
- Antibiotics, especially if neutropenic, for superinfection
Ongoing Care
Follow-up Recommendations
Patient Monitoring
Pain, hydration, and nutrition status �
Diet
- Avoid foods that require significant chewing.
- Bland-avoid foods that are dry, acidic, spicy, or salty.
- Avoid alcohol and tobacco products.
Patient Education
Encourage daily monitoring for development and/or extent of mucositis as well as amount of oral intake and adequacy of symptom control. �
Prognosis
Mucositis follows a self-limited, episodic course with resolution generally occurring spontaneously 10-14 days after onset. Likelihood of future recurrence is based on future dosing and frequency of chemotherapy and/or radiation. �
Complications
- Pain and odynophagia leading to dehydration, impaired nutrition, and/or difficulty following regimens for dental hygiene and oral medications. Dehydration and malnutrition are common given the associated decreased oral intake and/or malabsorption.
- Most serious side effect is development of systemic infection producing septicemia as disrupted mucosal barrier is a source for both bacteria and fungi to gain access to bloodstream.
- Oral candidiasis is the most common superinfection in patients with mucositis and in rare cases can lead to systemic fungemia. Topical treatment with nystatin suspension or clotrimazole troches is recommended. The use of oral fluconazole is not needed.
- HSV-1 reactivation in the oral cavity occurs in 65-90% of seropositive patients receiving high-dose chemotherapy. Due to this high rate, screening for HSV-1 and prophylaxis with acyclovir may be considered in patients at high risk for mucositis.
- Gram -: Pseudomonas, Klebsiella, Serratia, and Escherichia coli
- Gram +: staph and strep, especially Streptococcus viridans(4)
References
1.Lalla �RV, Sonis �ST, Peterson �DE. Management of oral mucositis in patients with cancer. Dent Clin North Am. 2008;52(1):61-77, viii. �
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2.O'Brien �CP. Management of stomatitis. Can Fam Physician. 2009;55(9):891-892. �
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3.Peterson �DE, Bensadoun �RJ, Roila �F; ESMO Guidelines Working Group. Management of oral and gastrointestinal mucositis: ESMO Clinical Practice Guidelines. Ann Oncol. 2010;21(Suppl. 5):v261-v265. �
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4.Cawley �MM, Benson �LM. Current trends in managing oral mucositis. Clin J Oncol Nurs. 2005;9(5):584-592. �
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5.Clarkson �JE, Worthington �HV, Furness �S, et al. Interventions for treating oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev. 2010;(8):CD001973. �
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6.Ryan �AJ, Lin �F, Atayee �RS. Ketamine mouthwash for mucositis pain. J Palliat Med. 2009;12(11):989-991. �
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7.Sultani �M, Stringer �AM, Bowen �JM, et al. Anti-inflammatory cytokines: important immunoregulatory factors contributing to chemotherapy-induced gastrointestinal mucositis. Chemother Res Pract. 2012;2012:490804. �
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8.Kassab �S, Cummings �M, Berkovitz �S, et al. Homeopathic medicines for adverse effects of cancer treatments. Cochrane Database Syst Rev. 2009;(2):CD004845. �
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9.Worthington �HV, Clarkson �JE, Furness �S, et al. Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev. 2011;(4):CD000978. �
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Codes
ICD09
- 528.01 Mucositis (ulcerative) due to antineoplastic therapy
ICD10
- K12.31 Oral mucositis (ulcerative) due to antineoplastic therapy
SNOMED
- 109256003 Mucositis following chemotherapy (disorder)
Clinical Pearls
- Mucositis often occurs in patients receiving chemotherapy and usually involves the mouth, but it can affect any part of the GI tract.
- Monitor for pain, dehydration, and malnutrition.
- Sepsis is the most serious complication.