Oral Mucositis in Head and Neck Cancer: Risk, Biology, and Management Stephen T. Sonis, DMD, DMSc OVERVIEW Of the toxicities associated with conventional forms of treatment for head and neck cancers, probably none has such a consistent legacy as oral mucositis. 1 Despite the fact that mucosal injury was noted as far back as Marie Curie’s first forays into therapeutic radiation, an effective intervention has yet to be developed. In addition to its historic link to radiation, new therapeutic strategies including induction chemotherapy often produce mucositis, and targeted therapies appear to alter mucositis risk and its severity and course. 2 The symptomatic effect of oral mucositis is profound. Disabling oral and oropharyngeal pain prevents patients from eating normally, requires opiate analgesics, and in some cases results in alteration or discontinuation of anticancer therapy. 3 Furthermore, the health and economic consequences of oral mucositis are far from trivial. The incremental cost of oral mucositis in patients with head and neck cancer exceeds $17,000 (USD). 4 A lthough the incidence of mucositis has been described as almost ubiquitous among patients with head and neck cancer treated with conventional chemoradiation regimens, there are clearly differences in the frequency and severity of its manifestations. The lack of uniform scoring criteria, vari- ability of reporting thresholds (some studies only report grades 3 or 4), differences in the biologic challenge as a con- sequence of variations in chemoradiation treatment regi- mens, radiation fıelds, and tumor location have resulted in inconsistent incidence reporting. Furthermore, there contin- ues to be a disconnect between health care professionals and patients relative to their assessments of the presence, severity, and effect of mucositis. The rate, symptom severity, and in- fluence of mucositis on quality of life is routinely perceived as being greater among patients than the medical literature would suggest. 3 This might reflect the common and under- standable attitude among those charged with treating the cancer that a marginally tolerable level of collateral damage to normal tissue is an acceptable price for tumor eradication. It is unclear what the acceptable level is from a patient’s per- spective, and it probably varies from patient to patient. Cou- ple all of this with the realization that not all patients are at equal risk for mucositis, and it becomes easier to understand the reported range of mucositis frequency from as low as 30% to 40% to almost 100% when all severities of mucositis are evaluated. 5,6 Mucositis incidence data surrounding intensity-modulated radiation therapy (IMRT) is illustrative of the lack of consis- tent reporting. 7-9 Many studies report mucositis incidence in patients being treated for head and neck cancers. While some reports are limited to cancers of the mouth, others are less restrictive in their inclusion criteria and include patients with cancers of the nasopharynx, sinuses, hypopharynx, and lar- ynx as well as the mouth and oropharynx. Interpretation of results must account for this variation because it appears that the risk of signifıcant (this defınition varies from including all ulcerative mucositis to only grades 3 and 4) mucositis is markedly influenced by tumor location, as it affects the vol- ume of oral mucosa that is exposed to radiation. The use of concomitant chemotherapy, now the standard of care, en- hances mucositis risk and apparently, so does the concomi- tant use of targeted agents. Regardless of the criteria used to assess the presence of mu- cositis in patients with head and neck cancers, it is clear there is a cohort of patients who go through treatment relatively unscathed by the toxicity. This observation has fueled spec- ulation and studies on the topic of mucositis risk determi- nants. Approximately 30% of radiation therapy-induced side effects are attributable to therapy-related or patient-specifıc factors. A radiation dose–response analysis recently de- scribed by Bhide et al demonstrated the effect of different dose-response schedules on the development of mucositis. 10 In general, the volume of oral mucosa that receives weekly cumulative doses of 9.5Gy to 10Gy is likely to determine overall mucositis risk among susceptible patients. But even at this dose, about one-third of patients will not develop the condition. Likewise, among patients receiving cycled in- duction chemotherapy, almost one-half develop ulcerative From the Biomodels, LLC, Brigham and Women’s Hospital, and the Dana-Farber Cancer Institute, Boston, MA. Author’s disclosures of potential conflicts of interest are found at the end of this article. Corresponding author: Stephen T. Sonis, DMD, DMSc, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115; email: ssonis@partners.org. © 2013 by American Society of Clinical Oncology. STEPHEN T. 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