Signal Amplifi cation Pathophysiology of Oral Mucositis

11.2.2.4 Ulceration Ulceration is the phase with the most clinical sig-

nifi cance. Ulceration develops as a consequence of the direct and indirect mechanisms noted in the previous phases that cause damage and apop- totic changes to mucosal epithelium Sonis 2009 . Mucosal integrity is lost, resulting in pain- ful ulcers. The ulcers are covered by a pseudo- membrane and are a desirable environment for secondary bacterial colonization. Neutropenic patients are at greater risk of sepsis due to the Gram-positive and Gram-negative organisms that thrive in the pseudomembrane Sonis 2007 .

11.2.2.5 Healing

In the absence of infection, healing is usually complete within 2–3 weeks. The healing phase is the least understood of the phases of mucositis but is thought to be controlled by signaling from the submucosal mesenchyme to the epithelium. Signaling controls migration, differentiation and proliferation of new tissue across the base of the ulcer Treister and Sonis 2007 .

11.2.3 Clinical Course of Oral Mucositis

On initial presentation of OM, the oral mucosa fi rst shows erythema which then progresses to erosion and ultimately ulceration. Ulcerations are typically covered by a white fi brinous pseudomembrane. Lesions will heal approximately 2–4 weeks after the last dose of the offending chemotherapy or radiation therapy. In the case of immunosuppressed patients, resolution of OM usually coincides with granulocyte recovery Lalla et al. 2008 . Chemotherapy-induced OM is limited to nonkeratinized surfaces such as the lateral and ventral tongue, buccal mucosa, and soft palate Lalla et al. 2008 . Radiation-induced OM occurs in the radiation fi eld with nonkeratinized tis- sue affected more often. Patients receiving increas- ing cumulative doses beyond 30 Gy will be more severely affected Sonis 2007 ; Lalla et al. 2008 . The clinical course of mucositis can be complicated by infection, particularly in the immunocompromised patient.

11.3 Assessment

and Measurement of Oral Mucositis Historically, mucositis measurement and assess- ment in pediatrics have relied on tools developed for adults Tomlinson et al. 2009 . Reliable oral assessment is essential to facilitate management strategies or implement clinical trials in mucosi- tis prevention and treatment Tomlinson et al. 2007 , 2009 . The scales currently utilized to assess pediatric OM do not address practical issues such as mechanisms for optimal visualiza- tion of the oral cavity and approaching an unco- operative child. There are also limitations to reporting subjective and functional domains in the child Tomlinson et al. 2007 . Simple instruments such as the World Health Organization WHO grading system and the National Cancer Institute NCI Common Terminology Criteria for Adverse Events are scales that range from 0 with no symptoms to 4 or 5 worst symptoms possible Fig. 11.2 . Generally these scales are based on the ability to eat and drink combined with objective signs of mucositis. These instruments are utilized by pediatric oncology groups as part of toxicity criteria measurement. They are seen to be the most relevant scales for clinical management as a global score is achieved readily Sonis et al. 2004 . However, these simple scales may underreport mucositis if effective anal- gesia is administered to the patient Sonis 2009 . The Oral Mucositis Assessment Scale OMAS was developed by a panel of experts to be an objective, simple, and reproducible assessment tool to be applied to multicenter clinical trials of mucositis Sonis et al. 1999 . The OMAS mea- sures degree of ulceration, pseudomembrane for- mation, and mucosal erythema in specifi c mouth sites Sonis et al. 1999 Fig. 11.2 . Testing has demonstrated that the OMAS is reliable and valid in adults with the only reported limitation being that patients with severe mucositis had diffi culty undergoing repeated examinations Sonis et al. 1999 . Sung et al. 2007 demonstrated that the OMAS is valid in the measurement of mucositis in children ≥6 years of age. Fig. 11.2 Oral Mucositis Grading Scales. a World Health Organization scoring criteria. b National Cancer Institute Common Terminology Criteria for Adverse Events CTCAE version 4.0. c Oral Mucositis Assessment Scale. d Oral Assessment Guide a World Health Organization WHO Scoring Criteria for Oral Mucositis Grade 1 2 3 4 Description Normal Soreness with or without erythema Ulceration and erythema; patient can swallow a solid diet Ulceration and erythema; patient cannot swallow a solid diet Ulceration and pseudomembrane formation of such severity that alimentation is not possible Adapted from Sonis et al. 2004a With permission from Sonis et al. 1999 b National Cancer Institute Common Terminology Criteria for Adverse Events CTCAE version 4.0 Adverse event Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Oral mucositis definition: a disorder characterized by inflammation of the oral mucosa Asymptomatic or mild symptoms; intervention not indicated Moderate pain; not interfering with oral intake; modified diet indicated Severe pain; interfering with oral intake Life-threatening consequences; urgent intervention indicated Death http:www.acrin.orgPortalsoAdministrationRegulatoryCTACE_4.02_2009-09-15_QuickReference_5x7.pdf c Oral Mucositis Assessment Scale Location UlcerationPseudomembrane circle Erythema circle Upper lip Lower lip Right cheek Left cheek Right ventral and lateral tongue Left ventral and lateral tongue Floor of mouth Soft palatefauces Hard palate 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 Ulcerationpseudomembrane: 0 = no lesion 1 = 1 cm 2 2 = 1 cm 2 –3 cm 2 3 = 3 cm 2 Erythema: 0 = none 1 = not severe 2 = severe d Oral Assessment Guide Numerical and Descriptive Ratings Category Tools for Assessment Methods of Measurement 1 2 3 Swallow Observation Ask patient to swallow. To test gag reflex, gently place blade on back of tongue and depress Normal swallow Some pain on swallow Unable to swallow Voice Auditory Converse with patient Normal Deeper or raspy Difficulty talking or painful Lip Visualpalpation Observe and feel tissue Smooth and pink and moist Dry or cracked Ulcerated or bleeding Tongue Visualpalpation Feel and observe appearance of tissue Pink and moist and papillae present Coated or loss of papillae with a shiny appearance with or without redness Blistered or cracked Saliva Tongue blade Insert blade into mouth, touching the center of the tongue and the floor of the mouth Watery Thick or ropy Absent Mucous membrane Visual Observe appearance of tissue Pink and moist Reddened or coated increased whiteness without ulcerations Ulcerations with or without bleeding Gingiva Tongue blade and visual Gently press tissue with tip of blade Pink and stippled Edematous with or without redness Spontaneous bleeding or bleeding with pressure Teeth Visual Observe appearance of teeth Clean and no debris Plaque or debris in localized area between teeth if present Plaque or debris generalized along gum line Adapted from Eilers et al. 1988