Not Recommended for Practice

Chlorhexidine (Not Prophylactic)

for Mucositis

Chlorhexidine is an antiseptic that has a broad spectrum effect against both gram-positive and -negative bacteria. Chlorhexidine gluconate oral rinse, which contains glycerol, coloring, flavoring and other compounds, has been studied in patients with cancer for the prevention and treatment of mucositis. (Note: prophylactic use before development of mucositis has a different PEP category than the use of chlorhexidine in patients who already have mucositis symptoms.)

Systematic Review/Meta-Analysis

Nashwan, A. J. (2011). Use of chlorhexidine mouthwash in children receiving chemotherapy: A review of literature. Journal of Pediatric Oncology Nursing, 28, 295–299.

Purpose

To evaluate the effectiveness of chlorhexidine mouthwash in children receiving chemotherapy

Search Strategy

Databases searched were PubMed and ScienceDirect.

Search keywords were oral chlorhexidine, chemotherapy-induced mucositis/stomatitis, and pediatrics/children.

Studies were included in the review if they

  • Were published between 1980 and January 1, 2010, in English.
  • Involved human clinical trials in children between 0–18 years of age.
  • Were prospective trials published in peer-reviewed journals.
  • Used any antimicrobial agent for management of oral mucositis (OM).

Studies were excluded if they

  • Included adults.
  • Were meeting abstracts, letters, comments, case reports, or review articles.
  • Were animal or in vitro, pharmacokinetic or pharmacodynamic, or retrospective and meta-analysis studies.

Literature Evaluated

  • A total of 13 references were retrieved, and five met the inclusion criteria. 
  • All five studies assess chlorhexidine using a scale to assess OM. Three of them used the Modified Oral Assessment Guide 1–3 scale, one used the World Health Organization (WHO) 10-cm visual analog scale (VAS), and one study did not report the method of oral assessment (both groups were measured by presence of OM, bacteremia, and length of hospital stay).
  • Antimicrobial treatment began before the start of OM in four studies and after the start of OM in one study.
  • The duration of treatment for OM ranged from 6 weeks to 6 months.
  • The five studies differed regarding types of patient, age groups, types of cancer treatment, concentrations of chlorhexidine rinse, how OM was assessed, and outcomes measured.

Sample Characteristics

  • A total of 175 patients were involved in the fix studies, with samples across studies ranging from 14–47.
  • Two of the studies involved patients undergoing bone marrow transplant. All studies involved patients undergoing chemotherapy.
  • All five studies used a control, usually a placebo mouthwash or sterile water.

Phase of Care and Clinical Applications

  • Patients were undergoing the active treatment phase of care.
  • This study has clinical applicability for pediatrics.

Results

  • Three studies reported on the benefit of using chlorhexidine over benzydamine (Cheng & Chang, 2003; Cheng et al., 2004).
  • One study showed benefit over placebo (Costa et al., 2003).
  • One study showed no benefit using chlorhexidine over placebo (Raether et al., 1989).
  • One study reported acceptance and tolerability of chlorhexidine (Cheng, 2004).

Conclusions

  • Chlorhexidine may play a part in reducing OM during chemotherapy in pediatric patients.
  • Further clinical trials are needed to examine more effective methods to prevent and manage OM.

Limitations

  • Most studies involved a small number of patients.
  • The different scoring systems were not validated and were subjective.
  • Studies were not blinded
  • Studies differed in type of patient, age groups, type of cancer treatment, concentration of chlorhexidine rinse, how OM was assessed, and what outcomes were measured
  • Literature evaluated was published over a 20-year period.

Nursing Implications

  • Oral rinses for prevention or treatment of OM are a usually a good vehicle for treatment as long as they are easy to use, well tolerated, provide some quick relief of discomfort from OM, and are cost effective and accessible.
  • The Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology recommends nonmedicated oral rinses for prevention of oral mucositis in adult patients with solid tumors of the head and neck and who are undergoing radiation therapy. 
  • Oncology nurses are well positioned to educate children and their caregivers on proper use of oral rinses.
Print

Potting, C.M., Uitterhoeve, R., Scholte Op Reimer, W., & Van Achterberg, T. (2006). The effectiveness of commonly used mouthwashes for the prevention of chemotherapy-induced oral mucositis: A systematic review. European Journal of Cancer Care, 15, 431–439.

Search Strategy

Databases searched were MEDLINE and CINAHL (1992 to fall 2004).

Search keywords were mucositis, stomatitis, and chemotherapy in combination with prevention, mouthwashes, antiseptic, oral infection, chlorhexidine, chamomile, povidone-iodine, and sodium bicarbonate.

Studies were included in the review if they

  • Were randomized studies of the effect of mouthwashes for the prevention and amelioration of oral mucositis in adult patients undergoing chemotherapy.
  • Involved mouthwashes for oral mucositis, had a controlled study design, and included an outcome measure of the severity of mucositis.

Literature Evaluated

Seven studies met the criteria. Five investigated chlorhexidine, one investigated iodine mouthwash, and one investigated chamomile solution. All studies randomly allocated participants to either an intervention or a comparison group. One study assigned patients by stratified block randomization. Most studies used a placebo mouthwash or sterile water as a control.

Sample Characteristics

  • Patients were adults with a mean age of 53.6 years.
  • Among the patients included across all studies, 72% of the patients received chemotherapy, 6% of the patient received hematopoietic stem cell transplantation, and 22% had unknown treatments.

Results

  • The five studies investigating chlorhexidine mouthwash showed no significant effect (weighted mean difference = 0.22; 95% CI = –0.20, 0.63). I
  • n the chamomile study, no differences were found between the chamomile group and the control group in either incidence or severity of mucositis.
  • In the povidone-iodine study, the iodine group had significantly less severe mucositis and shorter duration compared with the control group; however, the sample size (n = 40; power ≤ 80) was too small to be confident in the findings.

Conclusions

Povidone-iodine was the only agent to show activity for preventing mucositis. Because of the effects of chlorhexidine (e.g., teeth discoloration, bitter taste, unpleasant sensations), the authors concluded that sterile water, 0.9% saline solution, or sodium bicarbonate all are better alternatives.

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Shih, A., Miaskowski, C., Dodd, M. J., Stotts, N.A., & MacPhail, L. (2002). A research review of the current treatments for radiation-induced oral mucositis in patients with head and neck cancer. Oncology Nursing Forum, 29, 1063–1078.

Search Strategy

Database searched was MEDLINE (1966–2001). Additional papers were found from reference lists.

Studies were included in the review if they were aimed at prevention, palliation, or reduction of radiation-induced oral mucositis in patients with head and neck cancer.

Studies were excluded if they were not in English.

Literature Evaluated

More than 50 studies were included. Most were randomized, controlled trials; some were pilot or descriptive studies. 

Sample Characteristics

Sample sizes ranged from 10 to more than 200.

Conclusions

Based on the findings of studies conducted to date, no conclusions regarding the agents and their ability to decrease the severity of radiation-induced oral mucositis were possible. Results were inconsistent. The most effective measure to treat radiation-induced mucositis was frequent oral rinsing with a bland mouthwash such as saline or sodium bicarbonate. Consistent oral care, dental care, oral assessment, and standardized oral hygiene were the suggested approaches to managing oral mucositis. Sodium bicarbonate reduces the acidity of the oral fluids immediately; it also dilutes accumulating mucus and discourages yeast colonization.

Findings related to benzydamine were inconsistent. In a trial of chlorhexidine versus benzydamine, patients reported more discomfort with benzydamine and were more likely to discontinue participation in the trial. Chlorhexidine was not effective in reducing the severity of mucositis in three double-blind, placebo-controlled trials. Two trials that examined antimicrobial activity failed to show any significant effects on the suppression of any type of oral flora using chlorhexidine.

Dose variations in granulocyte macrophage colony-stimulating factor (subcutaneous) trials make it impossible to determine whether this agent has a role in the radiation setting.

Four studies investigated the effectiveness of using topical antibiotics with a more specific spectrum for gram-negative bacteria and yeast. Two placebo-controlled, randomized clinical trials, both with fewer than 100 patients, and one case-controlled study investigated the efficacy of amphotericin B (polymyxis E, tobramycin, and amphotericin B [PTA] lozenge) to reduce the severity of radiation-induced mucositis. One study examined tetracaine and antibiotics. Additional work is warranted to determine the effects of the PTA lozenge on mucositis severity, pain severity, and dysphagia. Results for the trial were promising; however, conclusions cannot be drawn because only one study examined tetracaine.

Nursing Implications

Additional investigation of immunoglobulin and povidone-iodine are recommended.

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Worthington, H.V., Clarkson, J.E., Bryan, G., Furness, S., Glenny, A.M., Littlewood, A., … Khalid, T. (2011). Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database of Systematic Reviews (Online), 4(4), CD000978.

Purpose

To evaluate the evidence for prophylactic agents in management of oral mucositis in patients with cancer receiving treatment

Search Strategy

Databases searched were MEDLINE, CANCERLIT, Embase, CINAHL, Latin American and Caribbean Health Sciences Literature (LILACS), System for Information on Grey Literature in Europe (SIGLE), and the Cochrane Database.

An extensive list of search terms and strategies used per database was provided in the article.

Studies were included in the review if they

  • Were randomized controlled trials (RCTs).
  • Compared an intervention to a placebo or no treatment.

Literature Evaluated

A total of 383 references were retrieved. Risk of bias was evaluated according to the Cochrane Handbook for Systematic Reviews of Interventions. Studies were categorized as low, unclear, or high risk of bias. Studies were labeled using the GRADES system for evaluating quality of evidence.

Sample Characteristics

  • The final number of studies included in the review was 131.
  • The total sample size across all studies was 10,514 with an across-study sample range of 12–301. 
  • Studies involved a variety of cancers and patients receiving chemotherapy, radiation therapy, or both.

Phase of Care and Clinical Applications

  • Patients were in the active antitumor treatment phase of care.
  • This study has clinical applicability to pediatrics.

Results

  • Only 8% of studies included were seen to have a low risk of bias. 
  • Studies included a variety of treatments such as acyclovir, allopurinol rinse, aloe vera, amifostine, antibiotic paste, systemic antibiotics, axulene, benzydamine, beta carotene, chamomile, chewing gum, Chinese herbs, chlorhezidine, cryotherapy, epidermal growth factor, glutamine, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), histamine gel, honey, hydrolytic enymes, indigo wood root, intestinal trefoil factor, keratinocyte growth factor, laser, anti-inflammatory drugs, oral care, pentoxifylline, pilocarpine, polymixin/tobramycin/amphotericin (PTA), traumeel, sucralfate, zinc sulphate, and povidone iodine. 
  • From all analyses, at least moderately strong evidence of benefit was found for cryotherapy (RR = 0.74, 95% confidence interval [CI] 0.57–0.95, p = 0.02) for any mucositis and for keratinocyte growth factor (RR = 0.82, 95% CI 0.71–0.94, p = .0005) for any mucositis. 
  • Weak and unreliable evidence for potential benefit was found with aloe vera, amifostine, glutamine, G-CSF, honey, laser, polymixin/tobramycin, amphotericin lozenges, and sucralfate.
  • A substantial body of evidence showed no benefit of chlorhexidine.

Conclusions

Findings support the benefits of cryotherapy and keratinocyte growth factor. The low quality of evidence in most of the other interventions points to the need for ongoing, well-designed research in this area. The presentation of findings in many publications made meta-analysis impossible.

Limitations

The rationale for the authors' summaries of findings was not entirely clear. Similar RR ratio results with similar evidence quality levels were identified differently in terms of potential benefit. Although the review was inclusive and extensive, interpretation of results was inconsistent. High heterogeneity existed in most interventions, and most studies were either at high or unclear risk of bias with low GRADES scoring. Studies did not always differentiate between mucositis and candidiasis, which would affect recommendations.

Nursing Implications

This article suggests strong support for use of cryotherapy and keratinocyte growth factor for mucositis prevention. It suggests possible benefit from aloe vera, amifostine, IV glutamine, G-CSF, honey, laser, and antibiotic lozenges. Sucralfate may reduce the severity of mucositis. These findings should be interpreted with caution, given the relatively low quality of overall evidence and high heterogeneity across studies included in meta-analysis, as well as the fact that treatments and sample characteristics were highly varied.

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Guideline / Expert Opinion

Niscola, P., Scaramucci, L., Giovannini, M., Ales, M., Bondanini, F., Cupelli, L., et al. (2009). Palifermin in the management of mucositis in hematological malignancies: Current evidences and future perspectives. Cardiovascular & Hematological Agents in Medicinal Chemistry, 7, 305–312. 

Purpose & Patient Population

To review the role of palifermin and other current and potential treatments for chemotherapy-induced mucositis in the context of pathobiology in hematologic malignancies

Type of Resource/Evidence-Based Process

Database searched was MEDLINE. Abstracts and published proceedings reporting the role of palifermin in the management of mucositis were reviewed. 

Search keywords were MeSH headings for chemotherapy, cyclophosphamide, etoposide, GI mucositis, GVHD, hematology, hematological malignancies, hematopoeietic stem cell transplantation, hemorrhagic  cystitis, HSCT, keratinocyte growth factor, KGF, leukemia, lymphoma, melphalan, methotrexate, mucositis, multiple myeloma, oncohematology, oral mucositis, pain, palifermin, radiation, radiotherapy, soreness, and total parenteral nutrition.

Studies were included in the review if they involved patients with hematologic malignancies or undergoing stem cell transplantation.
 
Volumes of literature and processes for review, inclusion, and any analysis of quality were not discussed.

Results Provided in the Reference

Palifermin in standard and high dose chemotherapy

  • Only case reports and one small study were included.  It was concluded that insufficient evidence exists to support palifermin use in patients without transplantation.

Palifermin in autologous stem cell transplantation

  • One study in 212 patients showed that among those who developed grade 3 or 4 mucositis, the duration was shorter in those who received palifermin (p < 0.001).
  • No randomized controlled trials and only a few additional small studies and case series were included.
  • Insufficient evidence was found to make any recommendation regarding palifermin in these cases.

Palfiermin in graft-versus-host disease

  • Two studies using palifermin were cited, but no appraisal of findings was provided. It was noted that palifermin is used in this setting, and the biological rationale and brief findings in animal models are stated.

Other interventions for management of mucositis

  • Findings from meta analyses indicate that, while some interventions have some benefit, the strength of the evidence was variable, and findings in one meta-analysis reported that no single intervention was capable of completely preventing oral mucositis.
  • A number of cytokines and growth factors other than palifermin were indicated that have been or are currently being investigated to treat or prevent mucositis. The mechanism of potential activity and effects seen were provided.
  • Other agents outlined included chlorhexidine, povidone iodine, pilocarpine, histamine gel, benzydamine oral rinse, amifostine, systemic glutamine, nonsteroidal anti-inflammatory drugs, and oral doxepin. Evidence was deemed insufficient to determine the efficacy and role of these agents.

Guidelines & Recommendations

Control of oral mucositis pain and provision of supportive therapy and regular assessment are critical management components.

Limitations

This article provided information about various approaches in the management and prevention of oral mucositis in patients with hematologic malignancies and outlined the biologic mechanism of action and observed effects from review of the literature. However, it provided little information about the actual strength of evidence and is based on a limited literature search. No clear description of rationale for article inclusion was included.

The authors concluded that evidence supports the use of palifermin, but the article stated elsewhere that evidence in this area is insufficient in some patient groups, and only one nonrandomized study is cited where the duration of high-grade mucositis was shorter in patients who received palifermin, suggesting a biased view of the role of palifermin.

Nursing Implications

This article can provide useful information regarding the mechanism of action of various treatments, but it is not helpful in determining relative effectiveness of various interventions.

Print

Peterson, D.E., Bensadoun, R.J., Roila, F., & ESMO Guidelines Working Group. (2010). Management of oral and gastrointestinal mucositis: ESMO Clinical Practice Guidelines. Annals of Oncology, 21(Suppl. 5), v261–v265.

Purpose & Patient Population

To summarize the evidence around the use of radiotherapy, standard-dose chemotherapy, and high-dose chemotherapy with or without total body irradiation plus hematopoietic stem cell transplantation (HSCT) for the management of mucositis

Type of Resource/Evidence-Based Process

  • Databases searched were the Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO).
  • Evidence was evaluated based on the American Society of Clinical Oncology (ASCO) Levels of Evidence (I-V) and Grades of Recommendation (A-D). Statements without grading were considered justified standard clinical practice by the expert authors and the European Society for Medical Oncology (ESMO) faculty.

Guidelines & Recommendations

  • Institutions should develop oral care protocols based on clinical practice and interdisciplinary involvement. Staff and patient education are essential. Basic oral care should include saline mouth rinses 4–6 times per day and use of a soft toothbrush replaced on a regular basis. 
  • Patient-controlled analgesic (PCA) with morphine is recommended for the treatment of pain in patients with oral mucositis undergoing HSCT.
  • Regular oral pain assessment and topical anesthetics can provide short-term pain relief. 
  • Chlorhexidine rinses are not recommended to treat established mucositis but may be an option to enhance treatment of oral infection.
  • Benzydamine oral rinse is recommended for prevention of mucositis in patients with head and neck cancer receiving radiotherapy.
  • For prevention of mucositis in patients receiving standard-dose chemotherapy,
    • Oral cryotherapy for 30 minutes is recommended in patients receiving fluorouracil (5-FU).
    • Keratinocyte growth factor-1 (palifermin) 40 mcg/kg per day for three days may be useful in patients receiving bolus 5-FU plus leucovorin.
  • For prevention of mucositis in patients receiving high-dose chemotherapy with or without total body irradiation plus HSCT, the following are recommended.
    • Palifermin 60 mcg/kg per day for three days prior to transplant and three days post-transplant
    • Cryotherapy in high-dose melphalan
    • Low-level laser therapy (LLLT) before HSCT

Limitations

The primary author was the principal investigator on the National Institutes of Health (NIH) R13 Conference Grant that provided partial support for the symposium “Oral Complications of Emerging Cancer Therapies,” 14-15 April 2009, Bethesda, MD, USA. Production of a Journal of the National Cancer Institute (JNCI) Monograph for conference publications was supported by an unrestricted educational grant form Biovirum, which owned palifermin at the time of the publication. Peterson also is a member of the Scientific Advisory Board and a paid consultant for the GI Co., Inc, which is responsible for the development of recombinant intestinal trefoil factor, for which the phase II study is cited in the references.

Nursing Implications

The mucositis guidelines reported contain few changes from the previous two versions of the ESMO Clinical Practice Guidelines. With the 2009 MASCC/ISCO Mucositis Study Group in June 2009, it was decided that no new guidelines were warranted based on the current published literature. Progress has been made in the understanding of molecular basis of mucositis. Evidence-based, cancer-specific identification of risk factors and management of mucositis depend on clinical research so that approval of new drugs and devices will be possible.

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