Oral Mucositis in Head and Neck Cancer

8/6/2019 Oral Mucositis in Head and Neck Cancer

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Oral mucositis in head and neck cancer

Introduction

Significant advancements have been made in the management of patients undergoing cancer chemotherapy (CT) and radiotherapy (RT).Mounting evidence indicates that more aggressiveregimens improve loco-regional tumour control and survival in patients of head and neck cancer (HNC). The better treatment outcome, however, have come at the expense of increased patientmorbidity in the form of many debilitating side effects such as nausea, vomiting, diarrhoea, andmucositis. Such critical issues often delay or restrict the therapy and impede recovery.

Mucositis is the inflammation of the mucous membrane lining of the digestive tract from themouth on down to the anus and when such inflammation involves the mucous membrane of oraland oropharyngeal region, termed as oral mucositis (OM). Oral mucositis is a major problem for cancer patients receiving head and neck radiotherapy, stem cell transplantation and

myelosuppressive chemotherapy for solid tumours.

So, OM if not detected or treated adequately, can lead to pain, discomfort and inability totolerate food or fluids with increased propensity for opportunistic infections in the mouth andworsens the patients quality of life. Poorly managed OM is one of the leading causes for unplanned treatment interruptions and therefore increasing overall treatment time. Prolongationof overall treatment time adversely affects the tumour control probability. It also increases theoverall cost of the treatment.

The main aim of this module is to provide you with the knowledge and understanding of the riskfactors, pathogenesis and development of oral mucositis. It will guide the reader for the earlydiagnosis and accurate management of oral mucositis in head and cancer patients undergoingtreatment.

This module should take approximately 4-5 hours to complete, comprising the learning activitiesand time for reading, thinking and reflection.

Learning objectives

The activities and content of this module are built around the following learning objectives:

Understanding the magnitude of the problem;

Understanding the risk factors;

Understanding the pathogenesis and its development;

Developing skills for early and exact diagnosis;

Learning the accurate management.

The incidence of oral mucositis

Mucositis is defined as inflammatory and/or ulcerative lesions of the oral cavity usually causedby cancer therapy.


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Oral mucositis (OM) is a common complication of treatment in head and neck cancer patients.The nature and degree of mucositis varies according to the treatment regimen applied, whether radiotherapy or chemotherapy as an independent modality or in combination. Trotti (2003)studied more than 6,000 patients with squamous cell carcinoma of the head and neck (SCCHN)who received radiotherapy (RT) with or without chemotherapy (CT). The overall incidence of mucositis in this patient population was 80 to 100%, with 25-45 % of cases being grade 3/4,(Table 1) which limited or prevented alimentation and significantly decreases a patient's quality

of life.Table 1: Incidence of oral mucositis among cancer patients (Trotti et al, 2003)

Incidence (%) Grade 3/4 (%)

Radiotherapy for head and neck cancer 85100 2545

Stem-cell transplantation 75100 2560

Solid tumors with myelosuppression 540 515

Significant proportions (approximately 40%) of patients who receive standard-dose CT alsodevelop mucositis (Sonis, 1993). Degree of OM may vary according to the drugs being used like5-fluorouracil (5-FU) and cisplatin causes aggressive OM compared to gemcitabine.

Higher rates of mucositis, 60%, are seen in the stem cell transplantation (SCT) setting. This isas a result of high dose CT or total-body irradiation (TBI) (Woo, 1993).

Risk factors for oral mucositis

A systematic review of the research literature identified a vast number of patient and treatmentrelated risk factors (Table 2) (Dodd, 1999).

Table 2: Risk factors for oral mucositis

Patient-related Gender Age older than 65 years or younger than 20

years Inadequate oral health and hygiene practices Periodontal diseases Microbial flora Chronic low-grade mouth infections Salivary gland secretory dysfunction Herpes simplex virus infection Inborn inability to metabolize

chemotherapeutic agents effectively Inadequate nutritional status

Treatment-related Radiation therapy: dose, schedule Chemotherapy: agent; dose, schedule Myelosuppression Neutropenia Immunosuppression Reduced secretory immunoglobulin A Inadequate oral care during treatment Infections of bacterial, viral, fungal origin Use of antidepressants, opiates,

antihypertensives, antihistamines, diuretics,and sedatives

Impairment of renal and/or hepatic function


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Exposure to oral stressors including alcoholand smoking

Ill-fitting dental prostheses

Protein or calorie malnutrition, anddehydration

Xerostomia

The development of OM is predominantly influenced by the type of malignancy and thecytotoxic therapy administered, but patient factors also play a role. Several patient related

factors like poor oral health at baseline, existing mucosal damage, impaired immune status, anddecreased salivary production are among the risk factors. Younger patients are moresusceptible for OM due to more rapid epithelial mitotic rate or the presence of more epidermalgrowth factor receptors in the epithelium at the early age. On the other hand, the physiologicdecline in renal function associated with aging may result in higher incidence of OM in older patients.

Any decrease in neutrophil count before therapy may result in an impaired ability to mount anadequate inflammatory response on the oral mucosa thus causing more OM.

Factors that are treatment-related include specific chemotherapeutic drug, dose, schedule, anduse of radiation therapy (Borowski, 1994). All of these will affect the subsequent development(severity and duration) of mucositis. Certain chemotherapeutic agents such as methotrexateand etoposide may also be secreted in the saliva, thus the patients being treated by theseagents have higher chances of developing OM.

Pathogenesis of oral mucositis

Molecular and cell biology and translational research suggest OM a complex, multistep process.Healthy oropharyngeal mucosa has a rapid cell turn over with a renewal period of 7 14 daysand it serves as a barrier to infections. It has been analyzed that shortly after CT or RT

administration acute inflammatory/vascular changes occur which leads to the development of OM. Sonis (2004) has described a five phase model to characterize the major steps indevelopment and resolution of OM. (Figure 1, Table 3).

Figure 1. The 5 phases of mucositis(Adapted from Sonis (2004) Nature Reviews Cancer. 4:277-284)


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Table 3: The phases of the biologic process of mucositis

The phases of oral mucositis

Initiation Cell exposure to chemo- and radiotherapy causes DNA damage andgenerates reactive oxygen species (ROS), which are able to injure cells,tissues and blood vessels

Signalling ROS cause further DNA damage and stimulate expression of transcriptionfactors that lead to tissue injury and apoptosis

Amplification Release of pro-inflammatory cytokines result in further tissue damage, whichamplifies the signalling cascade

Ulceration Painful ulcers form that provide an entry point for bacteria, viruses and fungi.Bacterial cell wall components can further induce inflammation

Healing A signal from submucosal tissue allows renewed cellular proliferation anddifferentiation restoring the lining of the oral cavity

1. Initiation: reactive oxygen species (ROS) generated by exposure to chemotherapy or radiation therapy result in DNA strand breaks and damage to cells, tissues, and bloodvessels, which ultimately cause apoptosis.

2. Message generation: Such damage triggers activation of transcription factors such asnuclear factor kappa B (NF- B), which in turn causes increased production of pro-inflammatory cytokines like interleukin (IL)-1 and IL-6. These increased levels of cytokines thus trigger the initiation of various pathways that damage epithelial cells andsurrounding fibroblasts causing tissue injury and apoptosis.

3. Signaling and amplification: Proinflammatory cytokines, such as tumor necrosis factor alpha (TNF- ) activates ceramide and caspase pathways and these signals further increase production of TNF- , IL1 and IL-6 and thus causing amplification effect.

4. Ulceration and inflammation: Inflammatory infiltrate composed of polymorphoneuclear and round inflammatory cells are found in the mucosa. As there is a breach in the mucosalbarrier, penetration of the epithelium into the submucosa can occur and mucosa getsprone for bacterial infection which further lead to increase in the production of TNF- , IL1 and IL-6. This further enhances the mucosal injury thus causing more severe mucositis inform of ulceration allowing colonization by oral bacteria and increasing the risk of sepsis. It

is likely that each of these stages of mucositis pathogenesis occurs in a continuous,overlapping manner.

5. Healing: Healing of oral lesions starts with a signal from the extracellular matrix in thenonmyelosuppressed patient within 2 to 3 weeks following cancer treatment. Mechanismsof healing include renewal of epithelial proliferation and differentiation in parallel with whiteblood cell recovery, and re-establishment of normal local microbial flora.

This pathogenesis model has suggested a variety of potential therapeutic targets which can acton various steps. Hence it has led to the development of agents that can prevent or amelioratethe process of OM and associated symptoms e.g. some agents down regulate NF- B activationwhich is a trigger for activation of various pathways leading to the oral mucosal damage.


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Activity 1 (allow approximately 60 minutes)

Task 1: Consider the different treatment and patient related risk factors causing oral mucositisin cancer patients. How does the severity of oral mucositis vary with age?

Allow 30 minutes

Task 2: Follow the five stage of pathogenesis given by Sonis and try to locate the possiblesites where intervention can help in the management of oral mucositis.

Allow 30 minutes

Resources required to complete this activity

Useful websites

Cancer Consultants

http://www.cancerconsultants.com/mouth-sores-mucositis/

National Institute of Dental and Craniofacial Research (Oral Complications of Cancer Treatment: What the Oncology Team Can Do)http://www.nidcr.nih.gov/oralhealth/topics/cancertreatment/oralcomplicationscanceroncology.htm

From CancerCare, a downloadable patient guide to mucositis:http://cancercare.org/pdf/booklets/ccc_mouth_pain.pdf

Background reading

Borowski B, Benhamou E, Pico JL , Laplanche A, Margainaud JP & Hayat M. (1994)Prevention of oral mucositis in patients treated with high-dose chemotherapy and bone marrowtransplantation: a randomized controlled trial comparing two protocols of dental care. EuropeanJournal of Cancer. Part B: Oral Oncology. 30B:93-97.

Dodd M J, Miaskowski C, Shiba G H, Dibble S L, Greenspan D, MacPhail L, Paul S M & LarsonP. (1999) Dodd MJ, Miaskowski C, Shiba GH, et al. Risk factors for CT-induced oral: dentalappliances, oral hygiene, previous oral lesion, and a history of smoking. Cancer Investigation.17:278.

Sonis ST. (1993) Oral complications of cancer therapy. In: DeVita VT, Hellman S, RosenbergSA, eds. Cancer: Principles and Practice of Oncology, 4th ed. Philadelphia: JB Lippincott Co.pp2385.

Sonis ST. (2004) The pathobiology of mucositis. Nature Reviews Cancer. 4:277284.

Trotti A, Bellm LA, Epstein JB, Frame D, Fuchs HJ, Gwede CK, Komaroff E, Nalysnyk L &Zilberberg MD. (2003) Mucositis incidence, severity and associated outcomes in patients withhead and neck cancer receiving radiotherapy with or without chemotherapy: a systematicliterature review. Radiotherapy & Oncology. 66:253262.

Woo S-B, Sonis ST, Monopoli MM, & Sonis AL. (1993) A longitudinal study of oral ulcerative inbone marrow transplant recipients. Cancer. 72:1612.


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How to diagnose oral mucositis

Diagnosis is based on the clinical appearance, location, timing of oral lesions and use of certaintypes of therapy known to be associated with OM. It is characterized by erythema, inflammation,pain and ulceration.

Symptoms can include: Ulcers or sores on the mouth, gums, or tongue A burning sensation in the mouth Loss of taste Sensitivity to hot or cold foods Dry mouth

All assessors should have thorough familiarity with the normal anatomy of oral cavity, clinicalsigns and symptoms of oral complications. Consistent and frequent oral cavity assessmentunder intense white light is needed to visualize all soft and hard tissues and dentition before,

during, and after the treatment time course.

OM, if not diagnosed and managed, may interfere with daily activities such as talking andeating, increases the risk for systemic infections and possibly hospitalization. Systemic effectsof OM results in the symptom complex, characterized by fatigue, taste alterations, anaemia,anorexia, cachexia, neurocognitive alterations, and depression which may often be termed assickness syndrome (Hickok, 2005).

Thus a systematic and routine assessment of the oral cavity should be performed in all patientsvulnerable to be at risk for developing oral mucositis. This permits early identification of thelesion and makes timely intervention possible.

A number of scoring systems have been defined to assess the severity of OM (Table 4), but noone scale is uniformly employed. The major hurdle has been a lack of a definitive technique toappropriately measure OM. Some established guidelines are those proposed by the WorldHealth Organization (WHO) in 1979 and the National Cancer Institutes Common Toxicity Cri-teria (NCI CTC version 3 and 4). Both objective mucosal changes like redness, ulceration withfunctional outcomes like ability to eat has been integrated in WHO scale. In contrast, NCI CTChas been developed to classify OM in patients receiving radiation therapy, chemotherapy, andconditioning regimens for bone marrow transplantation. Based upon clinical examination four distinct stages/grades can be identified which have been given 0 to 4 mucositis scores. Oralintake is maintained in grade 1 and 2 however compromised thereafter in higher grades.

Sonis et al (1999 ) have devised an Oral Mucositis Assessment Scale (OMAS). This scaleseparates objective and subjective findings. Degrees of ulceration and redness measured inspecific sites in the mouth were primary indicators of OM while oral pain, difficulty in swallowing,and the ability to eat were taken as secondary indicators. A single score is not produced fromthis scale, rather a score for ulceration and redness based on different locations in the mouthare used. This scale is more quantitative for clinical research but may be difficult to use inroutine clinical care.

Other scoring systems by RTOG have been proposed (Cox, 1995), but the lack of standardization has hampered their acceptance.


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Because of large variation among these scales, making comparisons between the scales isdifficult.

Table 4: Oral mucositis assessment scales

Grade 0 Grade 1 Grade 2 Grade 3 Grade 4

WHO None Soreness witherythema

Erythema, ulcers, caneat solids

Ulcers, liquid dietonly

Alimentation notpossible

RTOG No changeover baseline

Injection/ mayexperiencemild pain notrequiringanalgesic

Patchy mucositis whichmay produce aninflammatoryserosanguinitisdischarge/ mayexperience moderatepain requiring analgesia

Confluent fibrinousmucositis/ mayinclude severe painrequiring narcotic

Ulceration,haemorrhage or necrosis

OMASUlceration/ erythema

NormalNormal

Not severe< 1 sq cm

Severe1 3 sq cm

NA>3 sq cm

NANA

None erythema of the mucosa

patchy ulcerations or pseudomembranes

confluentulcerations or pseudomembrane;bleeding with minor trauma

tissue necrosis:significantspontaneousbleeding: life-threateningconsequences

NCI -CTCAEv3.0

ClinicalCriteria

FunctionalCriteria

None Minimalsymptoms,normal diet

Symptomatic but caneat and swallowmodified diet;

Symptomatic andunable toadequately alimentor hydrate orally

Symptomsassociated withlife-threateningconsequences

NCI -CTCAEv4.0

None Asymptomaticor mildsymptoms;interventionnot indicated

Moderate pain; notinterfering with oralintake; modified dietindicated

Severe pain;interfering with oralintake

Life-threateningconsequences;urgentinterventionindicated.

WHO: World Health Organization, RTOG: Radiation therapy oncology group, OMAS: Oral mucositis assessmentscale, NCI-CTCAE: National Cancer Institute Common Toxicity Criteria for Adverse Events

Differential diagnosis of OM may include Oral candidiasis (thrush) Herpes simplex virus (HSV) Graft-versus-host disease (GVHD) in transplant patients

Candidal overgrowth (candidiasis), which occurs in response to RT or CT, usually responds wellto systemic antifungal medication. HSV is frequently seen in immunocompromised cancer

patients receiving chemotherapy, with lesions appearing on the lips (cold sores) or intraoralmucosa.


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Initiation of antiviral therapy may ameliorate HSV-associated OM and reduce symptoms. OMcan also occur in patients receiving myeloablative conditioning regimens for allogeneichematopoietic SCT and in those with GVHD, affecting the oral mucosa.

Economic impact

Mucositis and its treatment can have a significant economic impact. Patients incur increasedcosts for treatment, including in some cases hospitalization or emergency room visits for complications or life-threatening situations.


Task 1: Select a patient receiving radiotherapy. Observe the changes in oral mucosa develop during the course of radiotherapy. What symptoms does the patient describe? How do these oral problems affect the treatment plan and quality of life of the

patient?

Allow 45 minutes

Task 2: Compare the severity of oral mucositis in different schedules of radiotherapy. What are the differences in grades of oral mucositis in patients receiving

concurrent chemo-radiotherapy?

Allow 45 minutes

Resources required to complete this activity

Useful websites

For a review article published in the Journal of Supportive Oncology, New Strategies for Management of Oral Mucositis in Cancer Patients:www.supportiveoncology.net/journal/0402s1.html

For information from the National Cancer Institute:www.cancer.gov/CancerTopics/pdq/supportivecare/oralcomplications/HealthProfessional/page5

Cancer Therapy Evaluation Program (CTEP) website athttp://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm Updated January12, 2010.

Background reading

Cox JD, Stetz J, Pajak TF. (1995) Toxicity criteria of the Radiation Therapy Oncology Group(RTOG) and the European Organization for Research and Treatment of Cancer (EORTC).International Journal of Radiation Oncology*Biology*Physics. 31:1341-1346.

Hickok JT, Morrow GR, Roscoe JA, Mustian K, Okunieff P. (2005) Occurrence, severity, andlongitudinal course of twelve common symptoms in 1129 consecutive patients duringradiotherapy for cancer. Journal of Pain Symptom Management. 30: 433442.


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National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE) Version4.0 Published: May 28, 2009 (v4.03: June 14, 2010) U.S. Department of health and humanservices National Institutes of Health (NIH) Publication No. 09-5410http://evs.nci.nih.gov/ftp1/CTCAE/About.html

Sonis ST, Eilers JP, Epstein JB, LeVeque FG, Liggett WH Jr, Mulagha MT, Peterson DE, RoseAH, Schubert MM, Spijkervet FKL, Wittes JP. (1999) Validation of a new scoring system for the

assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy.Mucositis Study Group. Cancer. 85(10): 2103-13.

Trotti A, Dimitrios CA, Setser A, Rusch V, Jaques D, Budach V, Langer C, Murphy B, CumberlinR, Norman CC & Rubin P. (2003) CTCAE v3.0: development of a comprehensive gradingsystem for the adverse effects of cancer treatment. Seminars in Radiation Oncology. 13( 3):176-181

World Health Organization. (1979) WHO Handbook For Reporting Results Of Cancer Treatment. Geneva, Switzerland: World Health Organization. 15-22.

Sonis 2003

Management guidelines

Several management protocols have been developed for prevention and treatment of OM butthe widely accepted one is given by Multinational Association of Supportive Care in Cancer andInternational Society for Oral Oncology (MASCC/ISOO). These guidelines were first publishedafter the work of Rubenstein in 2004. These were later updated by the Multinational Associationof Supportive Care in Cancer and International Society for Oral Oncology (MASCC/ISOO)

(McGuire, 2006). Discussions by the panel resulted in the development of a set of recommen-dations for the prevention and treatment of OM and guidelines that are relevant to the care of patients with head and neck cancer. In 2007, Keefe et al and the MASCC/ISOO Mucositis StudyGroup updated clinical practice guidelines for the prevention and treatment of mucositis. Theseguidelines are most widely employed in our clinical practice [Table 5].

These guidelines suggest a multi-professional intervention for early diagnosis and managementof OM. Foundation of care includes oral care, routine assessment of oral cavity, pain manage-ment using validated instruments, and regular dental assessment and dental care prior to thestart of cancer therapy. It clearly suggests avoidance of any irritants to the oral mucosa (e.g.,

spicy foods or alcohol). This recommendation also stressed the need for education of staff aswell as patients and their families. They should be properly told about the proper oral care andthe importance of outcome.


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Table 5: Management guidelines for OM

Summary of Evidence-based Clinical Practice Guidelines for Care ofPatients with Oral and Gastrointestinal Mucositis (2005 Update)

Oral Mucositis

Foundations of Care Multidisciplinary development and evaluation of oral care protocols that include frequent

use of non-medicated oral rinses (e.g. saline mouth rinses 46 times/day) isrecommended.

Patient and staff education in the use of such protocols to reduce the severity of oralmucositis from chemotherapy and/or radiation therapy.

As part of the protocols, the use of a soft toothbrush that is replaced on a regular basis. Elements of good clinical practice should include the use of validated tools to regularly

assess oral pain and oral cavity health. The inclusion of dental professionals is vitalthroughout the treatment and follow-up phases.

Patient-controlled analgesia with morphine as the treatment of choice for oral mucositispain in patients undergoing hematopoietic stem cell transplantation (HSCT).

Regular oral pain assessment using validated instruments for self-reporting is essential.

Radiation Therapy Prevention

Recommended Use of midline radiation blocks and three-dimensional radiationtreatment to reduce mucosal injury.

Benzydamine oral rinse for prevention of radiation-induced mucositis inpatients with head and neck cancer receiving moderate-dose radiationtherapy.

Not

Recommended

Sucralfate

Antimicrobial lozenges Chlorhexidine

Standard-Dose ChemotherapyPrevention

Recommended Oral cryotherapy (30 min) in patients receiving bolus 5-FU Oral cryotherapy (2030 min) is suggested to decrease mucositis in

patients treated with bolus doses of edatrexate

NotRecommended

Acyclovir and its analogues.

Standard-Dose ChemotherapyTreatment

Chlorhexidine not to be used to treat established oral mucositis.

Resources

Background reading

Rubenstein EB, Peterson DE, Schubert M, Keefe D, McGuire D, Epstein J, Elting LS, Fox PC,Cooksley C, Sonis ST. (2004) Mucositis Study Section of the Multinational Association for Supportive Care in Cancer; International Society for Oral Oncology. Clinical practice guidelinesfor the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis.Cancer. 100(suppl):20262046.


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Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, Migliorati CA,McGuire DB, Hutchins RD, Peterson DE. (2007) Mucositis Study Section of the MultinationalAssociation of Supportive Care in Cancer, International Society for Oral Oncology. Updatedclinical practice guidelines for the prevention and treatment of mucositis. Cancer. Mar.1;109(5):820-31.

Treatment options

Given that hundreds of thousands of cancer patients worldwide are affected by OM, asignificant need for effective therapy exists. A single efficacious intervention or agent for theprophylaxis or management of RT or CT induced OM has not yet been identified. Many differenttreatments are used to prevent or treat OM. Few interventions used in clinical practice havenever been rigorously evaluated. Furthermore, many combinations of agents are advocated bylocal experts without evidence to support their use. Several new approaches to OM have beentaken, but in the absence of double-blind and placebo controlled clinical trials many of themanagement recommendations are subjective.

Basic oral care

Poor oral hygiene along with associated dental and periodontal pathology, such as dentalcaries, ill-fitting prostheses, orthodontic appliances, leads to a greater risk for OM in the courseof RT or CT. Hence MASCC/ISOO recommends basic oral care as a standard practice toprevent and alleviate mucosal symptoms .

The basic oral care (McGuire, 2006 ) typically includes: Pretreatment careful inspection of the oral cavity

Evaluation by dental specialists Dental work to eliminate caries and existing gum disease before beginning cancer

treatment Examination of oral cavity should be repeated in the course of treatment

This pre-treatment assessment not only helps in the differentiation of OM from preexistingchanges, such as pemphigoid, lichen planus, leukoplakia, and GVHD, but also permits theidentification and elimination of pre-existing potential sources of infection which may affect theseverity of the OM. Meticulous pretreatment assessment will reduce the incidence and durationof OM thus further reducing the risk for dental complications, including infections, caries,

gingivitis, and osteoradionecrosis (Shieh, 1997).The basic oral care protocols during radiation involve:

Brushing in a non-traumatic fashion, 2-3 times in a day with a soft-bristle toothbrush. Replacing the toothbrush on a regular basis. Using o ral rinses with regular frequency. Avoiding irritation like hot, spicy, and coarse foods, fruits and beverages with a high acid

content, and alcohol (including alcohol-containing elixirs). Abstaining from smoking.

Dental fluoride prophylaxis as (brushing) gels, rinses, and vacuum-formed vinyl splints loadedwith fluoride gel are frequently used to prevent caries and mucositis in the course of RT or CT. It


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has been seen that fluoride incorporates into tooth enamel and dentin and they also reduce oralbacterial load. But their role has not been confirmed in different studies.

Oral rinsesTo maintain oral moistness patients should do frequent rinsing with bland solutions such asnormal saline. This saline solution is made by adding tablespoon salt to 1 litre water and thesolution can be administered at room or refrigerated temperatures, depending on patient

preference. The patient should rinse several times as often as necessary to maintain oralcomfort. Sodium bicarbonate (baking soda) tablespoons can be added, if viscous saliva ispresent. Saline solution can increase oral lubrication by acting directly as well as by stimulatingsalivary glands to increase salivary flow.

saline solution is made by adding

tablespoon salt to 1 litre water

Oral care protocols not routinely recommended include: Daily use hydrogen peroxide rinses. Chlorhexidine, antiseptic mouthwash. Magic mouthwash or mouthwash cocktail.

The daily use hydrogen peroxide rinses is not recommended, especially if mucositis is presentbecause of the potential for damage to fibroblasts and keratinocytes, which can cause delayedwound healing (Tombes, 1993). Using 3% hydrogen peroxide diluted 1:1 with water or normalsaline to remove hemorrhagic debris may be helpful; however, this approach should only beused for 1 to 2 days since more extended use may impair timely healing of mucosal lesionsassociated with bleeding.

Chlorhexidine is an oral broad spectrum antibiotic rinse, known to reduce the colonization of microorganism in the oral cavity. Randomized controlled trial of Cheng et al (2004) concludedthat the use of chlorhexidine, antiseptic mouthwash was associated with increase in oralmucosal inflammation, general mouth discomfort, taste alteration and staining of teeth. Basedon these trials and updated recommendations of MASCC/ISOO, use is not recommended.

The so called magic mouthwash or mouthwash cocktail is used by different institutionsacross the world. Such mouthwash usually have a variety of ingredients like lidocaine,diphenhydramine, topical antifungal nystatin and an antacid containing aluminum/magnesiumhydroxide in equal parts. These formulae are popular for OM treatment owing to its pain-relieving properties and its coating of the mucosa. However diphenhydramine is sedating, maycarry unpleasant anticholinergic properties and on the other hand oral ketoconazole andfluconazole are more efficient in controlling oral candidiasis compare to nystatin. MASCC/ISOOguidelines do not recommends use of such cocktail mouth wash for the prevention andtreatment of oral mucositis.

It is also recommended that patients should be advised to avoid factors that cause irritation likehot, spicy, and coarse foods, fruits and beverages with a high acid content, and alcohol(including alcohol-containing elixirs) and should abstain from smoking (Rugg,1990).


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Conformal radiotherapy & intensity-modulated radiation therapy (IMRT)

Mucositis is a common complication of radiotherapy to the head and neck region that occurs inup to 100% of patients. Many factors like field size, radiation dose and fractionation scheduledetermines the severity of mucositis. Combined use of CT and RT has resulted in better tumour control and overall survival in locally advanced head and cancer patients. Now-a-daysmonoclonal antibody, cetuximab have also been tried as concurrent chemo radiotherapy(Bonner, 2010) with promising results. But this intensification in treatment modalities is at thecost of increased toxicity in the form of OM. Trotti et al (2003), in his literature review articleconcluded more incidences of grade 3 mucositis in patients treated by concurrentchemotherapy plus radiation in comparison to radiation alone.

Course/ pattern of Oral Mucositis (Wong, 2006)

Chemotherapy Radiotherapy

Usually begins 3 to 5 days after

the start of therapy and peaksat 7 to 10 days.

Typically appears toward the end of the second week

of treatment, plateaus during the fourth week of radiation, and may persist for 2 to 3 weeks after treatment is over.

Pathogenesis of radiation induced oral mucositis:

RT directly damages the basal epithelial cell layer of the oral mucosa leading to the loss of therenewal capacity of the epithelium. Erythema of the involved mucosa in the second week of therapy will result due to subepithelial edema aggravating to an epithelial breakdown. Astreatment continues, the epithelial surface cells shed, but their replacement by cells from the

basal level does not occur. The mucosa becomes thin and superficially ulcerated, appearing aswhite patches, commonly mistaken for a yeast infection. As radiation progresses, the patchescoalesce, forming large fields of superficial ulceration, referred to as confluent mucositis.Infrequently, radiation-induced mucositis can form deep ulceration with necrosis andhemorrhage. By the end of treatment, diffuse erythema, ulceration, spontaneous bleeding, andwhite or yellow pseudomembrane formation may be present.

Among the various radiotherapy techniques available like IMRT, 3-Dimensional or 2-Dimensional Radiotherapy technique only IMRT has the advantage of generating the sharpdose fall off near the targets and thus limiting the radiation dose to critical structures. Althoughall the radiotherapy techniques results in the varying grades of mucositis but with the help of

IMRT we can spare the mucosa and thus limit the acute and long term morbidity associated withgrade 3 and 4 mucositis (Sanguineti, 2006). In conventional radiotherapy, midline blocks help toreduce the incidence of mucositis (Perch, 1995). MASCC guidelines suggest use of midlineradiation blocks and three dimensional radiation treatments to reduce the mucositis.

Cryotherapy

In this method, patient is advised to chew popsicles or ice chips during or after cancer treatment. This results in local vasoconstriction thus reducing the blood flow to the oral mucosa.Reduced blood flow will also reduce the amount of drug reaching to the oral mucous

membranes, and may therefore will reduce mucositis caused by CT drugs such as 5-fluorouracil(5-FU).


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Sucking ice chips for half an hour during intravenous infusion of 5-FU significantly reduces theseverity and incidence of OM, successfully studied in the randomized trials (Cascinu, 1994;Mahood, 1991) The use of cryotherapy is a readily available, cheap and effective method of minimizing mucositis induced by bolus 5-FU, but this measure is not effective for continuousinfusions (Rocke, 1993). Use of ice chips in patients receiving melphalan and edatrexate basedCT regimens as a prophylactic measure also indicate reduced incidence of OM. CurrentMASCC/ISOO guidelines recommend cryotherapy for the prevention of oral mucositis with

standard dose chemotherapy.

Pain management

Pain is the single most important distressing symptom in cancer patient having some degree of OM. If not properly addressed, it can also lead to decreased oral intake leading to malnutritionand the need for total parenteral nutrition (TPN). The inability to control mucositis-related paincan be frustrating for both the patient and the treating physician. Most patients require bothsystemic and topical analgesics.

Recommendation is:

Systemic analgesics, including patient-controlled analgesia, should beimplemented as needed to reduce the pain associated with severe mucositis.

So many local anesthetics agents, such as diphenhydramine, viscous xylocaine, lidocaine asoral solutions, are frequently used for the temporary relief of OM related pain. But all theseagents interfere with taste perception, thus possibly contributing to hypo alimentation. Thusthese topical anesthetic agents are not recommended. So the frequent and prophylactic useshould be discouraged. Few studies suggest combinations of local anesthetics and mouth

coating agents like sucralfate can also be used ([Barker, 1991). However the use of sucralfate iscontroversial as most of the randomized trials (Carter, 1999) failed to demonstrate beneficialeffects. MASCC/ISOO guidelines do not support the use of sucralfate.

One may have to use systemic analgesics and opioids to control the pain. A randomized trial of morphine versus tricyclic antidepressants for treatment of RT induced OM pain in HNC, showedthat morphine produces greater pain relief than do tricyclic antidepressants (Ehrnrooth, 2001)Such patients should be given narcotic analgesics in the form of morphine, transdermal fentanylpatches along with laxatives to avoid constipation. Irritant laxative are preferred compared tobulk forming because of compromised oral intake. The dose of narcotic analgesic, their frequency, and duration should be regularly adjusted to meet the intensity level of pain. Despite

the recommendations from MASCC/ISOO a recent symptom review study shows that very fewpatients are being given adequate narcotic analgesia.


Task 1: Select a patient who is receiving cancer treatment either by radiotherapy or chemotherapy and consider the following:

How can you help the patient maintain oral hygiene and proper oral care? How can the patient make an ideal oral rinse from salt and water? How many times should the patient use an oral rinse?

Allow 40 minutes


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McGuire DB, Correa ME, Johnson J, Wienandts P. (2006) The role of basic oral care and goodclinical practice principles in the management of oral mucositis. Support Care Cancer. 14:541547.

Perch SJ, Machtay M, Markiewicz DA, Kligerman MM. (1995) Decreased acute toxicity by usingmidline mucosa-sparing blocks during radiation therapy for carcinoma of the oral cavity,oropharynx, and nasopharynx. Radiology;197:863-866.

Rocke LK, Loprinzi CL, Lee JK, Kunselman SJ, Iverson RK, Finck G, Lifsey D, Glaw KC,Stevens BA, Hatfield AK, Vaught NL, Bartel J, Pierson N (1993) A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil- related stomatitis.Cancer. 72(7): 2234- 2238.

Rugg T, Saunders MI, Dische S. (1990) Smoking and mucosal reactions to radiotherapy. BritishJournal of Radiology. 63: 554-556.

Sanguineti G, Endres EJ, Gunn BG, Parker B. (2006) Is there a mucosa-sparing benefit of IMRT for head-and-neck cancer? International Journal of Radiation Oncology*Biology*Physics.66: 931938.

Shieh SH, Wang ST, Tsai ST, Tseng CC. (1997) Mouth care for nasopharyngeal cancer patients undergoing radiotherapy. Oral Oncology. 33: 36-41.

Tombes MB & Gallucci B. (1993) The effects of hydrogen peroxide rinses on the normal oralmucosa. Nursing Research. 42(6): 332-337.

Trotti A, Bellm LA, Epstein JB, Frame D, Fuchs HJ, Gwede CK, Komaroff E, Nalysnyk L,Zilberberg MD. (2003) Mucositis incidence, severity and associated outcomes in patients withhead and neck cancer receiving radiotherapy with or without chemotherapy: a systematicliterature review. Radiotherapy Oncology. 66: 253262.

Wong PC, Dodd MJ, Miaskowski C, Paul SM, Bank KA, Shiba GH, Facione N. (2006) Mucositispain induced by radiation therapy: prevalence, severity, and use of self-care behaviors. Journalof Pain Symptom Management. 32: 2737.

Targeting infection

It is well known that oral cavity of normal individual harbours a variety of potentially pathogenicmicroorganisms. But due to maintained mucosal integrity and normal immunity, healthyindividual are not susceptible to infection in oral cavity. But due to decreased immunity, cancer patients are more vulnerable to get infections from viral, fungal, and bacterial sources. Normally,the mucous membranes are a barrier to these agents, but the loss of mucosal integrity canpermit systemic entry of organisms that leads to infection (Costa, 2004). It is important thatpatients be monitored closely for any acute exacerbation of sign and symptoms which willsuggest oral/pharyngeal infection that may commonly include candidiasis, bacterial, or herpessimplex. Keeping a high index of suspicion, culture and sensitivity should be done. A number of systemic and topical antimicrobial agents have been evaluated for OM. Many authors haveemphasized the necessity of a variety of disinfectant, antibacterial, antiviral, and antifungalagents for the prophylaxis and treatment of OM (Makkonen, 1989), but due to variable resultsthere are no uniform consensus and therefore, routine use is not recommended (Symonds,1996).


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Targeting inflammation

Various preclinical and clinical researches have evaluated the role of anti inflammatory agents,steroidal and nonsteroidal like betamethasone, prednisolone, and prostaglandins E1 (PGE1).None have shown positive impact on OM prevention (Lalla, 2006). The prophylactic use of theprostaglandin E2 (PGE2) derivate, misoprostol have produced controversial results (Labar,1993).

Benzydamine hydrochloride is a nonsteroidal agent, frequently used in Canada and theEuropean Union exhibits, antimicrobial, anti-inflammatory, anesthetic, and analgesic effects(Kim, 1986). Its action may be mediated by the prostaglandin system. It has been evaluated inphase III trials and found to be effective in low doses of radiation up to 50 Gy (Epstein, 1989).Thus this study provided preliminary evidence that benzydamine might be beneficial in patientsundergoing radiation therapy to the oral cavity. Patients were instructed to rinse withbenzydamine hydrochloride for 2 minutes, four to eight times daily, before and during radiationtherapy and for 2 weeks after completion of radiation therapy.

Benzydamine hydrochloride

Associated with significantly reduced erythema and ulceration and delayed use of systemic analgesics.

Effective in patients receiving lowdose radiotherapy

Not effective for patients receivingaccelerated or high dose radiation therapy.

MASCC guidelines do recommend the use of benzydamine for the prevention of radiation induced mucositis in patients with HN cancer receiving moderate-doseradiation therapy.

Useful resources

Background reading

Costa SF, Miceli MH, Anaissie EJ. (2004) Mucosa or skin as a source of coagulase-negativestaphylococcal bacteraemia? Lancet Infectious Diseases. 4: 278286.

Epstein JB, Stevenson-Moore P, Jackson S, Mohamed JH, Spinelli JJ. (1989) Prevention of

oral mucositis in radiation therapy: a controlled study with benzydamine hydrochloride rinse.International Journal of Radiation Oncology*Biology*Physics. 16(6): 1571-1575

Kim JH, Chu FC, Lakshmi V, Houde R. Benzydamine HCl. (1986) A new agent for the treatmentof radiation mucositis of the oropharynx. American Journal of Clinical Oncology. 9: 132-134.

Labar B, Mrsic M, Pavletic Z, Bogdani V, Nemet D, Aurer I, Radman I, Filipovi -Grci N, Serti D, Kaleni S. (1993) Prostaglandin E2 for prophylaxis of oral mucositis following BMT. BoneMarrow Transplant. 11(5): 379-382.

Lalla RV, Schubert MM, Bensadoun RJ, Keefe D. (2006) Anti-inflammatory agents in themanagement of alimentary mucositis. Support Care Cancer. 14(6): 558-565.


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Makkonen TA, Borthen L, Heimdahl A, Joensuu H, Lehtonen OP, Nord CE . (1989)Oropharyngeal colonisation with fungi and gram-negative rods in patients treated withradiotherapy of the head and neck . British Journal of Oral and Maxillofacial Surgery. 27: 334-340.

Symonds RP, McIlroy P, Khorrami J, Paul J, Pyper E, Alcock SR, McCallum I, SpeekenbrinkAB, McMurray A, Lindemann E,Thomas M. (1996) The reduction of radiation mucositis by

selective decontamination antibiotic pastilles: A placebo controlled double-blind trial. BritishJournal of Cancer. 74(2): 312-317.

Future directions

A number of targeted therapies have recently been evaluated for prevention and/or treatment of oral mucositis, including amifostine and other antioxidants, growth factors, cytokines, andglutamine

Amifostine Amifostine is a cytoprotective pro-drug which is selectively taken up by non malignant cells andgets activated to the free thiol metabolite at the tissue site. These thiol metabolites areresponsible for most of the cytoprotective and radioprotective properties of amifostine. It ispreferentially taken up by healthy cells where it binds to and detoxifies reactive metabolites of platinum and alkylating agents as well as scavenges free radicals. It has unique antioxidantproperty acting against ROS produced by RT and responsible for mucositis (Grdina, 2000). Itsrole for prevention of oral mucositis induced by CT or RT has been widely studied. A meta-analysis (Sasse, 2006) of 1,451 has demonstrated statistically significant role in reducing theseverity of oral mucositis in patients receiving RT with amifostine. However this reduction was atthe cost of increased adverse effects associated with amifostine like nausea, vomiting, hypo-

tension, and allergic reactions. Because of inconsistent results it has not been approved for OM.Till now amifostine has been approved for reducing the incidence of severe xerostomia inpatients with head and neck cancer associated with radiation therapy.

PaliferminPalifermin is a human recombinant keratinocyte growth factor (KGF) produced in Escherichiacoli. It reduces the OM due to RT and CT by stimulating the growth of the cells that line thesurface of the oral cavity. Palifermin selectively binds to the epithelial cell-surface receptors andstimulates epithelial cell proliferation, differentiation, and upregulation of cytoprotectivemechanisms (Blijlevens, 2007). It reduces the incidence and duration of severe oral mucositis(Spielberger, 2004) by protecting those cells and stimulating the growth of new epithelial cells tobuild up the mucosal barrier.

Clinical trials have demonstrated that palifermin can exert a mucoprotective effect in patientswho were treated with chemotherapy or radiation therapy (Rosen, 2006).

Further studies are ongoing to further evaluate and confirm the ability of epithelial growth factor reduce oral mucositis in patients receiving chemoradiotherapy for head and neck cancer.

GlutamineGlutamine is a nonessential amino acid which reduces mucosal injury by reducing theproduction of pro-inflammatory cytokines and cytokines related apoptosis (Klimberg, 1990).


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Many malignancies are characterized by decreased glutamine levels, which can be further exacerbated by cell damage caused by cancer therapy. Glutamine supplementation can reversethis effect and may help to protect mucosal tissues from damage by RT or CT and thusaccelerate recovery (Savarese, 2003). Glutamine has been used in different trials as oral,systemic and as mouth washes. Data suggest that this agent may be useful in preventing or reducing the incidence and severity of oral mucositis in patients undergoing cancer therapy(Anderson, 1998). However due to inconsistent results, MASCC/ISOO do not recommends its

routine use in present guidelines. Further studies on this approach are warranted.

G-CSF and GM-CSFThese granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are used extensively with high dose chemotherapy as systemicadministration. Research data have clearly shown the local accumulation of activatedneutrophils following to systemic administration of G-CSF and GM-CSF. This local accumulationthus enhances the defense mechanisms of the oral mucosa (Lieschke, 1992). Both thesystemic (Schneider, 1999) and local use as topical mouth wash of G-CSF and GM-CSF,respectively, has been evaluated in different trials for the prevention and treatment of oralmucositis. But the results of these trials favor the systemic intervention group however nopreventive effect was found for the topical administration group. In view of inconsistent resultsMASCC/ISOO guidelines do not recommend the routine use of GM-CSF and G-CSF in anyform for the prevention or treatment of oral mucositis.

Low-level laser therapy (LLLT)LLLT or soft laser has been thought to have analgesic, anti-inflammatory, and wound healingeffects by speeding up the oral re-epithelialization. Different trials have evaluated LLLT duringRT for head and neck cancer and in the transplant setting (Bensadoun, 1999). There is noknown clinical toxicity or side effects of the application of low-energy helium-neon lasers (softlasers) and it favorably influence the outcome of oral mucositis. However there is no specificguideline regarding type of light source, wavelength, and dose schedule which has to be usedand it requires special training and necessary technology. MASCC guidelines suggest LLLT usein the transplant setting but do not offer any specific recommendation during RT for HNC for which there are less available data.

Alternative therapyMany supportive drugs have been suggested like:

Vitamin A Vitamin E Vitamin B12 Folic acid Aloe Vera PV701 Milk-Derived Protein Extract

Conflicting and insufficient evidence are available hence no guidelines are possible.

Useful resources

Background reading

Anderson PM, Schroeder G, Skubitz KM. (1998) Oral glutamine reduces the duration and

severity of stomatitis after cytotoxic cancer chemotherapy. Cancer. 83:1433-1439.


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Bensadoun RJ, Franquin JC, Ciais G, Darcourt V, Schubert MM, Viot M, Dejou J, Tardieu C,Benezery K, Nguyen TD, Laudoyer Y, Dassonville O, Poissonnet G, Vallicioni J, Thyss A,Hamdi M, Chauvel P, Demard F. (1999) Low-energy He/Ne laser in the prevention of radiationinduced mucositis. A multicenter phase III randomized study in patients with head and neckcancer. Support Care Cancer. 7: 244-252

Blijlevens N, Sonis S. (2007) Palifermin (recombinant keratinocyte growth factor-1): a pleiotropic

growth factor with multiple biological activities in preventing chemotherapy- and radiotherapy-induced mucositis. Annals of Oncology. 18(5): 817-826.http://annonc.oxfordjournals.org/content/18/5/817.full.pdf

Grdina DJ, Kataoka Y, Murley JS. (2000) Amifostine: mechanisms of action underlyingcytoprotection and chemoprevention . Drug Metabolism and Drug Interactions . 16: 237279.

Klimberg VS, Souba WW, Dolson DJ, Salloum RM, Hautamaki RD, Plumley DA, MendenhallWM, Bova FJ, Khan SR, Hackett RL. (1990) Prophylactic glutamine protects the intestinalmucosa from radiation injury. Cancer. 66:62-68.

Lieschke GJ, Ramenghi U, OConnor MP, Sheridan W, Szer J, Morstyn G. (1992) Studies of oral neutrophil levels in patients receiving G-CSF after autologous marrow transplantation.British Journal of Haematology. 82: 589-595.

Rosen LS, Abdi E, Davis ID, Gutheil J, Schnell FM, Zalcberg J, Cesano A, Gayko U, Chen MG,Clarke S. (2006) Palifermin reduces the incidence of oral mucositis in patients with metastaticcolorectal cancer treated with fluorouracil-based chemotherapy. Journal of Clinical Oncology.24: 51945200.

Sasse AD, Clark LG, Sasse EC, Clark OA. (2006) Amifostine reduces side effects and improvescomplete response rate during radiotherapy: results of a meta-analysis. International Journal of Radiation Oncology*Biology*Physics. 64: 784791.

Savarese DM, Savy G, Vahdat L, Wischmeyer PE, Corey B. (2003) Prevention of chemotherapyand radiation toxicity with glutamine. Cancer Treatment Reviews. 29: 501513.

Schneider SB, Nishimura RD, Zimmerman RP, Tran L, Shiplacoff J, Tormey M, Contreras R,Juillard GF. (1999). Filgrastim (r-metHuG-CSF) and its potential use in the reduction of radiation-induced oropharyngeal mucositis: an interim look at a randomized, double-blind,placebo-controlled trial. Cytokines, Cellular & Molecular Therapy. 5: 175-180.

Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T, Shea T, YanovichS, Hansen K, Noga S, McCarty J, LeMaistre CF, Sung EC, Blazar BR, Elhardt D, Chen MG,Emmanouilides C. (2004) Palifermin for oral mucositis after intensive therapy for hematologiccancers. New England Journal of Medicine. 351:25902598.

Discussion Board

The discussion board is a forum in which you can exchange ideas with other participants. Thisactivity relates to the work you will have completed in earlier tasks and provides an opportunityfor you to explore the difference in perspectives between the participants.


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Discussion Board

When will it take place

For a 3 month period from date of publication of this article.

Which discussion thread

Oral mucositis in head and neck cancer

What is expected of you as a participant

This module has only touched on some of the issues oral mucositis in head and neck cancer.By sharing your experiences of the issues that affect your practice, we can build on the currentbody of knowledge.

Summary of this module

By completing this module you should have a broad overview of oral mucositis and its diagnosisas well as management.

On completion of this module you will have had the opportunity to:

Consider oral mucositis is a serious side effect of cancer therapy. Consider how accurate diagnosis of oral mucositis is critical to ensure selection and

timely initiation of optimal therapy. Gain a knowledge of the scales in order to accurately diagnose the grade of OM.

Understand the guidelines that are most widely employed in our clinical practice. Understand how basic oral care and good oral hygiene remains the cornerstone of care

for these patients . Consider that despite the availability of variety of bland and/ or medicated oral rinses in

the market, no rinse appears to be more effective and well tolerated than normal salinesolution.

Understand how mucositis-related pain should be carefully managed through the use of topical analgesics and nonsteroidal agents and patient controlled analgesia (opioids) for severe pain when necessary.

Dr Madhup Rastogi Assistant Professor Department of Radiotherapy & OncologyIndira Gandhi Medical CollegeShimla 171001 Indiaemail: [email protected]

Dr Rehan A KaziHonorary Lecturer and Research Team Leader Head and Neck UnitRoyal Marsden HospitalFulham Road, London SW3 6JJ, UK.E-mail: [email protected]

Dr Raghav C DwivediClinical FellowHead and Neck UnitRoyal Marsden HospitalFulham Road, London SW3 6JJ, UK.email: [email protected]

Documents

Oral Mucositis in Head and Neck Cancer