Chemotherapy-Induced Oral Mucositis
- Author: Nathaniel S Treister, DMD, DMSc; Chief Editor: Dirk M Elston, MD more...
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.[1]
Prospective data on the incidence of severe mucositis during conventional cycled chemotherapy is lacking for various solid and hematologic malignancies; however Keefe et al reviewed the reported toxicity data from 99 recently published clinical trials including patients with non-Hodgkin lymphoma, breast, lung, or colorectal cancer.[2] They found that the incidence of severe mucositis (WHO grades 3 and 4) was no higher than 10% (and in most cases much lower) in any of the disease groups. It is generally accepted that mucositis is underreported when measured as a toxicity compared with studies in which mucositis is the endpoint. 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.[3]
In patients undergoing HCT, oral mucositis is reported as the most debilitating aspect of their treatment. Ulcers may act as a site for local infection and a portal of entry for oral flora that, in some instances, may 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.
Mammalian target of rapamycin ( mTOR) inhibitors in cancer therapy and oral mucositis [4]
With the introduction of numerous new targeted anticancer therapies, emerging oral toxicities have been noted that appear to be distinct from classic mucositis. These toxicities, for the most part, remain poorly described. The class of mTOR inhibitors, including sirolimus (rapamycin), temsirolimus, and everolimus, are increasingly being used as anticancer agents and have been associated with the development of oral aphthouslike ulcers, referred to as mTOR inhibitor–associated stomatitis, or mIAS. These are characterized by discrete, ovoid ulcers with a characteristic erythematous halo, and they appear clinically identical to idiopathic aphthous stomatitis in otherwise healthy patients.
Because this toxicity clusters with dermatologic toxicities, rather than gastrointestinal (as is the case with conventional mucositis) toxicities, this suggests that the underlying pathophysiology is likely very different. However, to date, no specific preventive or management strategies have been developed for mIAS that are any different from those used for conventional chemotherapy-induced oral mucositis. Treatment approaches that are known to be effective for the management of aphthous stomatitis, such as high-potency topical steroids, may also be effective for mIAS.
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 5 interrelated phases, including an initiation phase, a message generation phase, a signaling and amplification phase, an ulceration phase, and a healing phase.[5] 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 nuclear factor kappaB (NFkB) are activated, which then up-regulate a number of proinflammatory cytokines such as interleukin (IL)–1beta and tumor necrosis factor-alpha (TNF-alpha). IL-1beta 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 is common), putative bacterial colonization of ulcerations occurs, resulting in the flow of endotoxins into mucosal tissues and the subsequent release of more IL-1 and TNF-alpha. This is likely the phase most responsible for the clinical pain and morbidity associated with oral mucositis.
During the fifth and final healing phase, cell proliferation occurs with reepithelialization of ulcers. Signals from the extracellular matrix induce epithelial cells to migrate underneath the pseudomembrane (fibrin clot) of the ulcer. The epithelium then proliferates so that the thickness of the mucosa returns to normal. Reconstitution of the WBCs in neutropenic patients effects local control of bacteria, which also contributes to resolution of the ulcers. However, the direct relationship between the white blood cell count and oral mucositis is uncertain, and clearly not all patients with mucositis demonstrate hematologic toxicity.
Epidemiology
Frequency
United States
Approximately 400,000 patients per year may develop acute or chronic oral complications during chemotherapy. Some degree of oral mucositis occurs in approximately 40% of patients who receive cancer chemotherapy. At least 75% of patients who receive myeloablative conditioning regimens (chemotherapy with or without total body irradiation) in preparation for HCT develop oral mucositis. The incidence is also higher in patients who receive continuous infusion therapy for breast and colon cancer and in those who receive adjuvant therapy for head and neck tumors. However, in patients of the same age with similar diagnoses and treatment regimens and equivalent oral health status, the incidence of oral mucositis may vary considerably. This is most likely because of genetic differences and other factors that are not yet fully characterized or understood.
International
Oral mucositis figures are similar to those in the United States.
Mortality/Morbidity
Oral mucositis causes pain, restricts oral intake, may act as a portal of entry for organisms, frequently contributes to interruption of therapy, may increase the use of antibiotics and narcotics, may increase the length of hospitalization, and may increase the overall cost of treatment. Patients with oral mucositis and neutropenia have a relative risk of septicemia more than 4 times that of patients with neutropenia without oral mucositis.
Patients with pulpal disease from dental caries or trauma, advanced periodontal disease, and low-grade soft tissue infections (especially those associated with partially erupted third molars) are at increased risk for developing septicemia of odontogenic origin when they are myelosuppressed (eg, in preparation for HCT). The incidence of alpha-hemolytic streptococcal infection increases in patients who undergo myeloablative conditioning regimens in preparation for HCT.[6] Risk factors include prophylactic antibiotic therapy with quinolones, severe neutropenia, high-dose chemotherapy regimens, oral mucositis, strong colonization with viridans streptococci, and the use of Hickman and other long-term intravascular catheters. Viridans streptococci now account for more than 65% of bacteremic episodes in these patients and are associated with fever, hypotension, toxic shock–like syndrome, pneumonia, and adult respiratory distress syndrome (ARDS).[7]
Mortality rates range from 6-30%. Oral mucositis lesions have been implicated as an important portal of entry for these organisms into the systemic circulation because many of these organisms are native to the oropharyngeal region. Combination prophylaxis, including the use of penicillin and other antibiotics effective against gram-positive streptococci, has been effective in reducing the incidence of septicemia.
Race
No racial predilection is apparent 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. However, the healing of oral mucositis is also more rapid in the younger age group.
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