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Prevention and Treatment of Oral Mucositis in Cancer Patients

Prevention and Treatment of Oral Mucositis in Cancer Patients

Volume 2, Issue 3, 1998 ISSN 1329 - 1874 BestPractice Evidence Based Practice Information Sheets for Health Professionals Prevention And Treatment Of Oral Mucositis In Patients

Introduction This Practice Information Sheet Levels of Evidence Oral mucositis, also called Covers The Following Concepts All studies were categorised according to the strength of the evidence based on the following , is a common, debilitating classification system. complication of cancer chemo- therapy and radiotherapy, occurring 1. Quality Of Research Level I Evidence obtained from a systematic in about 40% of patients. It results review of all relevant randomised from the systemic effects of controlled trials. Level II cytotoxic agents Evidence obtained from at least one and from the local effects of 2. Treatment Options properly designed randomised radiation to the . Oral controlled trial. Level III.1 mucositis is of the Evidence obtained from well mucosa of the mouth which ranges designed controlled trials without 3. What Is Effective randomisation. from redness to severe ulceration. Level III.2 Symptoms of mucositis vary from Evidence obtained from well designed cohort or case control pain and discomfort to an inability analytic studies preferably from more to tolerate food or fluids. Mucositis 4. Recommendations - than one centre or research group. may also limit the patient’s ability Level III.3 Oral Care Protocol Evidence obtained from multiple time to tolerate either chemotherapy or series with or without the radiotherapy. Mucositis may be so intervention. Dramatic results in uncontrolled experiments. severe as to delay treatment and Level IV so limit the effectiveness of cancer Opinion of respected authorities, therapy. Patients with damaged 5. Other Treatment Options based on clinical experience, descriptive studies, or reports of oral mucosa and reduced immunity expert committees. resulting from chemotherapy and radiotherapy are also prone to opportunistic in the whenever possible, or at least been developed to present the best mouth. The mucositis may affect treated to reduce its severity and available evidence related specifically patients' gum and dental condition, possible complications. to the prevention and treatment of oral speech and self esteem are mucositis induced by chemotherapy or reduced, further compromising Currently there is a bewildering radiotherapy in cancer patients. The patients’ response to treatment number of interventions to choose information presented in this document and/or palliative care. from, but no high quality synthesis is based on a systematic review of the best research evidence for undertaken by The Joanna Briggs It is therefore extremely important these interventions. This Best Institute for Evidence Based Nursing that mucositis be prevented Practice Information Sheet has and Midwifery.

volume 2, issue 3, page 1, 1998 Quality Of Research · immunomodulatory agents; 4 to 6 times per day The systematic review of the research · topical anaesthetics; have been evaluated as prophylaxis literature identified a vast number of · ; against mucositis resulting specifically from the action of 5- interventions that have been · antibacterial, and chemotherapy. Results of investigated to determine their antiviral agents the meta-analysis support the use of effectiveness in the prevention or · mucosal barriers and coating allopurinol to prevent treatment of oral mucositis in cancer agents; mucositis. patients. It is obvious that many · cytoprotectants; · mucosal cell ; interventions used in clinical practice Cryotherapy, or rapid cooling of the have never been rigorously evaluated. · psychotherapy; and oral cavity using ice, causes local Furthermore, many combinations of · . vasoconstriction and hence reduces agents are advocated by local experts flow to the oral mucosa. For without evidence to support their use. Oral Care Protocols cytotoxic and neoplastic such The quality of published papers was Much has been written about oral as 5-fluorouracil, which have a short variable, and although a large number care regimens and many discussion half life and are sometimes of experimental studies were papers have reported locally administered as a bolus , identified, some were rejected due to developed regimens. These cryotherapy may reduce the amount deficiencies in study design or in regimens typically include dental of reaching the oral mucous reporting. Combining results from work to eliminate caries and existing membranes, and may therefore different studies during the systematic gum disease before beginning reduce mucositis caused by local review and meta-analysis was limited cancer treatment, followed by cytotoxic activity of these drugs. mostly because of differences thorough and frequent cleaning of the Studies support the use of between the study participants', oral cavity with a variety of products, cryotherapy as a cheap and effective interventions, and the timing and some form of pain relief, anti- method of minimising mucositis induced by bolus 5-fluorouracil, but it method of measuring outcomes. inflammatory treatment as required and aggressive is not effective for continuous infusions. While many interventions used for the treatment for any new mouth treatment or prevention of mucositis infections. However there have been Mouthwashes With Mixed Actions very few experimental studies have some evidence supporting their A variety of mouthwashes with mixed use, no intervention has been designed to test the effectiveness of actions have been evaluated and conclusively validated by research. particular oral care protocols. It include benzydamine hydrochloride, Consequently, the recommendations should also be noted that most of the and chamomile. in this information sheet have been specific interventions for mucositis Benzydamine hydrochloride is a drug based on research findings and prevention and treatment reviewed which has anti-inflammatory, pain supplemented by expert clinical below were tested against a relieving, antipyretic and antimicrobial opinion. background of good oral care. There activities, and has been used as a appears to be broad support for gargle or mouthwash to prevent and Treatment Options some form of oral care protocol as a treat oral mucositis. There is good evidence that benzydamine Many different treatments are used to commonsense preventive measure, hydrochloride mouthwash is effective prevent or treat mucositis. To aid the but further research is required to in improving the symptoms of discussion of findings these optimise specific oral care regimens. radiation-induced mucositis in interventions have been categorised patients with . under the following headings; Interventions Which Reduce The However, further work is needed to · general oral care protocols; Mucosal Toxicity Of Chemotherapy evaluate the effectiveness of this · interventions to reduce the Drugs agent for chemotherapy-induced mucosal toxicity of chemotherapy The interventions used to minimise mucositis, and to compare drugs; mucosal toxicity include allopurinol benzydamine with other pre- · mouthwashes with mixed action; and cryotherapy. Allopurinol parations.

volume 2, issue 3, page 2, 1998 Chamomile is said to have anti- patients whose oral mucositis pain nystatin, clotrimazole and PTA inflammatory and spasmolytic effects is severe, but currently there is no lozenges. Nystatin is a broad spectrum and to promote mucosal healing, evidence to support their use. antifungal agent, and comparison however there is no evidence to Comparisons between dyclonine between nystatin mouthwash, support its use. Corticosteroids have HC1, viscous lignocaine with 1% or placebo failed to show any also been used in mouthwash and a containing significant difference in mucositis preparations as treatment for kaolin-pectin, diphenhydramine and severity or oral ulceration score. mucositis and there is limited saline, found dyclonine provided Clotrimazole alone, or in combination evidence in favour of better pain relief. with polymixin B and tobramycin has mouthwash. been evaluated, and while one study Antiseptics suggests it is more effective than Immunomodulatory Agents A range of have , issues of The effectiveness of colony been used including chlorhexidine, methodological quality of these studies stimulating factors and povidone iodine and hydrogen make it difficult to draw firm immunoglobulin have been peroxide. Chlorhexidine is perhaps conclusions. evaluated. Granulocyte- one of the most commonly used colony stimulating factor (GM-CSF) mouthwash solutions identified in lozenges designed to and granulocyte colony stimulating studies and has been used as dissolve in the mouth and factor (G-CSF) are cytokines which prophylaxis for both chemotherapy decontaminate the oral mucosa have stimulate haemopoiesis and and radiotherapy induced mucositis. been developed and have been widely modulate leukocyte functions. No However, the evidence does not recommended to reduce oral beneficial effect has been support its use, indeed it has been infections associated with mucositis. demonstrated with a mouthwash suggested that water mouthwashes The lozenges contain polymixin E, containing GM-CSF, but the results of are as effective as chlorhexidine. tobramycin and amphotericin B, which a small study suggest G-CSF together provide broad spectrum administered subcutaneously may be A single uncontrolled study was antibacterial and antifungal cover. effective in preventing and reducing identified which examined the use These are commonly known as PTA the duration of mucositis. It has been of a povidone iodine gargle for lozenges or PTA . There is suggested that administration of preventing mucositis in patients with some evidence supporting the use of human immunoglobulin might confer leukaemia. Two studies evaluating PTA lozenges in preventing infectious passive immunity to immuno- hydrogen peroxide mouth rinses in complications of mucositis in cancer compromised patients and so reduce cancer patients concluded that patients undergoing radiotherapy, but the severity of mucositis. While there systematic oral care may be more there is as yet no evidence relating to is some evidence to support its use important than the specific mouth their efficacy in chemotherapy treated for patients with head and neck rinsing agent used. There is patients. cancer undergoing chemo/ currently no evidence to support the radiotherapy it has not been shown use of either povidone iodine or Acyclovir is an antiviral agent which is to be effective in patients undergoing hydrogen peroxide mouthwash. active against the Herpes species that alone. commonly infect the oral mucous Antibacterial, Antifungal And membranes in immunosuppressed Topical Anaesthetics Antiviral Agents cancer patients. It appears that Topical anaesthetic agents have been Many oral care regimens include prophylactic acyclovir may have some included as part of some oral care prophylactic antibacterial and/or value in reducing oral lesions due to protocols, but their effectiveness has antifungal treatments to clear the Herpes in susceptible patients, but as rarely been evaluated. Viscous mouth of oral microflora before and the majority of mucositis lesions do not lignocaine and xylocaine in mouth during chemo/radiotherapy. result from a virus they are not affected rinses have been recommended for Antimicrobial agents used include by this agent.

volume 2, issue 3, page 3, 1998 Mucosal Barriers And Coating studies of the effectiveness of local significantly different. Relaxation and Agents application of prostaglandins were imagery training significantly reduced A variety of agents have been used promising, the evidence does not patient-assessed mucositis pain, but to act as a mucosal barrier, with support its use, and indeed, the reductions in pain were not subject to the most study. prostaglandin E may exacerbate matched by corresponding reductions Sucralfate is a sulfated disaccharide mucositis in these patients. in mucositis severity or intake of which is not absorbed, but binds opioids for oral pain relief. electrostatically to gastric ulcers, Mucosal Cell Stimulants Low energy laser treatment may acting as a barrier to irritants and Analgesics promote the proliferation of mucosal promoting healing. It has been Patients undergoing marrow suggested that sucralfate may also cells and wound healing, and has transplantation usually develop severe protect oral mucosal surfaces in been tried as a treatment for chemo/ mucositis requiring aggressive patients at risk of developing radiotherapy-induced mucositis. analgesia with intravenous opioids. A mucositis, but the available evidence The limited evidence available modification of patient controlled does not support its use. supports its use in transplant patients, but more analgesia, where individual pharmacokinetic profiles for morphine A number of other agents acting as research is required for non- mucosal barriers have been transplant cancer patients. Silver were used to tailor the infusion rates promoted as possible strategies for nitrate has also been used to for each patient, was compared to preventing or minimising chemo/ stimulate the mucosal epithelial traditional patient controlled bolus radiotherapy induced mucositis. cells to proliferate, but the available analgesia. The pharmacokinetically These include alginate, evidence suggests that silver nitrate based patient controlled analgesia kaolin-pectin, plastic wrap film, is of questionable value in was superior to conventional patient radiation guards and antacid. preventing radiation-induced controlled analgesia in terms of relief However none of these have been mucositis. , which is a of oral mucositis pain, and even rigorously tested in clinical trials, and major energy source for mucosal though more morphine was used by so no comments about their relative epithelial cells and stimulates the former group there were no efficacy can be made. mucosal growth and repair, has increases in the side effects of been evaluated and the limited morphine. A further trial was available evidence suggests that it Cytoprotectants conducted by the same research may decrease the duration of Beta-carotene (pro- A), vitamin group to compare the opioids mucositis, although further research E and oxpentifylline have morphine with alfentanil using this is required. cytoprotective properties and have system and morphine was significantly been used in cancer patients in an more potent than alfentanil for pain attempt to ameliorate the mucositis Psychotherapy relief. resulting from cytotoxic treatments, Psychological interventions for but currently there is no evidence to managing persistent Capsaicin, which is the active support their use. Azelastine have been advocated as adjuncts ingredient in chilli peppers and acts by hydrochloride has membrane to pharmacological techniques, but desensitising some neurones to stabilising and leukocyte suppressing little work has been done to activities and one study evaluating the evaluate these interventions. provide temporary pain relief, has also effectiveness of 2mg/day throughout Psychotherapy techniques tested been evaluated. Candies containing cytotoxic treatment suggests it include cognitive behaviour training, capsaicin have been promoted as an significantly reduces the duration and relaxation and imagery training, alternate treatment for severity of mucositis. Prostaglandins hypnosis and therapist support. chemotherapy-induced mucositis. E1 and E2 have many activities, Hypnosis reduced oral pain Currently, there is insufficient evidence including cytoprotective actions. experienced by patients, but intake to draw conclusions about the possible While early observational and pilot of opioid analgesics was not benefits of capsaicin candy.

volume 2, issue 3, page 4, 1998 Recommendations - Oral Care Protocol All patients at risk of developing mucositis should receive a standardised oral care regime as an ongoing component of their care. The aim of this regimen is to achieve and maintain a clean mouth and to limit opportunistic via the damaged mucosa. This information is based on Level IV evidence (expert opinion).

1) Mucositis Assessment Assess condition of the patient’s mouth daily. While there is no evidence to suggest any one assessment tool is better than others, below is the World Health Organisation of mucositis as an example of a typical tool.

Grade 0 No symptoms 1 Sore mouth, no ulcers 2 Sore mouth with ulcers, but able to eat normally 3 diet only 4 Unable to eat or drink

2) Before Commencement Of Therapy Interventions that may be beneficial prior to the commencement of treatment include: · treatment of caries and dental disease; and · education regarding the importance of orodental hygiene, how to maintain oral hygiene and to develop a daily routine of oral care.

3) Post Therapy Interventions that may be beneficial following treatment include: · clean teeth and gums after meals and before sleep with tooth brush or swab as tolerated; · rinse the mouth regularly; · if dentures are worn, remove and clean them daily and leave out while at rest; · avoid painful stimuli such as hot food and drinks, spicy food, and ; · regular inspection of mouth by the patient and health professionals; · report any redness, tenderness or sores on the or in mouth; · provide comfort measures such as lubrication of the lips, topical anaesthesia and analgesics; · prompt treatment of mucositis symptoms and oral infections.

Other Treatment Options In addition to the use of an oral care protocol, the following interventions may offer some benefits. It should be noted that the support for some of these interventions is based on limited Level II evidence, and with further research these findings may change. Some of these products are currently not available in Australia. 1) For patients with head and neck cancer and undergoing radiotherapy: a) Prevention of Mucositis b) Treatment of Mucositis Symptoms · benzydamine · benzydamine · PTA lozenges · dyclonine HCL 2) Patients receiving chemotherapy, with or without radiotherapy: a) Prevention of Mucositis b) Treatment of Mucositis Symptoms · allopurinol for patients treated with 5- · topical dyclonine or lignocaine fluorouracil · cryotherapy for patients treated with 5- fluorouracil boluses

3) For patients undergoing high dose chemotherapy for bone marrow transplantation: · patient controlled administration of opioids tailored to individual patient needs for .

volume 2, issue 3, page 5, 1998 What Is Effective? duration of mucositis? There is some mucositis. Hypnosis and relaxation and imagery therapy reduced the pain It is very difficult for the clinician to evidence to suggest that allopurinol choose from this bewildering array of and cryotherapy during boluses of 5- experienced by patients, but not the use treatment options. It appears many fluorouracil may reduce mucosal of analgesics or mucositis severity. interventions have little evidence toxicity. The evidence supports Morphine administered by patient supporting their effectiveness, while mouthwashes containing ben- controlled analgesia appears to be others have a small amount of zydamine for reducing the effects of effective for reducing mucositis pain evidence suggesting they may be radiation induced mucositis. There is What Interventions Do Not Have effective. No intervention has been also limited evidence to support the conclusively shown to be effective. use of mouthwashes containing Evidence To Support Their Use? Conversely, only prostaglandin E was corticosteroids. While subcutaneous While chlorhexidine is commonly shown to be potentially harmful in G-CSF appears to be effective, recommended and used, its terms of mucositis in this group of mouthwashes containing GM-CSF are effectiveness remains uncertain. patients. not. Intramuscular immunoglobulin Sucralfate has been the subject of many reduced the severity of mucositis in studies, however its effectiveness has This situation has arisen because of patients receiving chemo-radiotherapy, yet to be shown. There is no evidence the proliferation of small studies that but not in those receiving radiotherapy to support the use of beta-carotene or lack the power to adequately evaluate alone. In terms of topical anaesthetic vitamin E, and prostaglandin E may well interventions. Contributing to this agents, dyclonine appears to provide exacerbate mucositis, Silver nitrate is situation is the fact that few studies better pain relief than lignocaine or not supported and as a result of have been replicated, with each diphenhydramine. PTA lozenges insufficient evidence it is impossible to successive study utilising a different appear to minimise infectious evaluate the effectiveness of capsaicin. intervention, population or outcome complications in radiotherapy patients, measure. Finally, some studies failed but its usefulness in chemotherapy is As there are no interventions that have to provide sufficient information uncertain. Azelastine may reduce the conclusively been shown to be effective, regarding the research design, making duration and severity of mucositis. the following recommendations for the assessment of quality impossible. There is limited evidence to suggest prevention and management of oral low energy laser may be effective in mucositis are based on available So what interventions appear to bone marrow transplant patients. evidence and supplemented by the prevent or minimise the severity and Glutamine may reduce the duration of opinion of clinical experts.

This publication was produced based on a systematic review of the research literature Acknowledgment undertaken by The Joanna Briggs Institute under the guidance of a review panel of clinical experts. It has been subject to peer review by experts nominated by The Joanna Briggs Institute centres throughout Australia, New Zealand and Hong Kong and was led by Dr. Inge Kowanko The Joanna Briggs Institute Ð The Joanna Briggs Institute; Mr. Brent Hodgkinson - The Joanna Briggs Institute; Dr Lesley would like to acknowledge and Long - Royal Adelaide Hospital; Mr David Evans - The Joanna Briggs Institute. thank the review panel For further information contact: members whose expertise was ¥ The Joanna Briggs Institute for Evidence Based Nursing and Midwifery, Margaret Graham Building, Royal Adelaide Hospital, North Terrace, South Australia, 5000. invaluable during the conduct of http://www.joannabriggs.edu.au, ph: (08) 8303 4880, fax: (08) 8303 4881 ¥ NHS Centre for Reviews and Dissemination, Subscriptions Department, Pearson the systematic review and Professional, PO Box 77, Fourth Avenue, Harlow CM19 5BQ UK. developing this Best Practice ¥ AHCPR Publications Clearing House, PO Box 8547, Silver Spring, MD 20907 USA. Information Sheet. The review The information contained panel consisted of a Disseminated collaboratively by: within Best Practice is based on the best available information as multidisciplinary team that determined by an extensive included: review of the research literature and expert consensus. Great care is taken to ensure that the content accurately reflects the · Nursing Directors findings of the information · Specialist Cancer Nurses source, however the Joanna Briggs Institute for Evidence · Pharmacist Based Nursing and Midwifery and organisations from which · Dentist information may be derived, · Haematologist cannot be held liable for damages arising from the use of · Oncologist Best Practice.

volume 2, issue 3, page 6, 1998

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