February 2008, Volume 12, Number 1

 

Article

Putting Evidence Into Practice®: Evidence-Based Interventions for the Management of Oral Mucositis

Debra J. Harris, RN, MSN, OCN®, June Eilers, PhD, RN, BC, CS, Amber Harriman, RN, Barbara J. Cashavelly, MSN, RN, AOCN®, and Cathy Maxwell, RN, OCN®, CCRC

 

 

Mucositis, an inflammation of the mucous membranes, is a commonly occurring side effect of chemotherapy and radiation. Oral mucositis can cause significant clinical consequences, such as pain, malnutrition, and local and systemic infections. Nurses have a critical role in all aspects of managing mucositis, including assessing it, teaching oral care, administering pharmacologic interventions, and helping patients cope with symptom distress. Mucositis can have a negative impact on the overall treatment experience, especially when severe pain or infections occur. Many interventions for managing mucositis exist; however, some are based in tradition or expert opinion and have not been studied in large, randomized, controlled trials. In addition, a variety of assessment tools are available, which creates confusion and difficulties when comparing interventions across studies. This article reviews empirical evidence related to interventions for oral mucositis. Oral care and rinses, pharmacologic interventions, and other techniques are evaluated. Gaps in the literature and opportunities for research, education, and practice changes are discussed.

 

Nursing-sensitive patient outcomes are outcomes that are attained through or significantly impacted by nursing interventions. The interventions must be within the scope of nursing practice and integral to the process of nursing care.

 

Mucositis is a general term that describes the inflammatory response of mucosal epithelial cells to the cytotoxic effects of chemotherapy and radiation therapy. All mucous membrane–covered surfaces from the mouth to the rectum may be affected (Wojtaszek, 2000). Oral mucositis disrupts the function and integrity of the oral cavity, which, in turn, affects functional status and quality of life. It is associated with significant clinical morbidity, which may include pain, malnutrition, and local and systemic infections (Eilers, 2004). Treatment delays and dosage adjustments also can occur. The incidence and severity of mucositis vary among patient populations; however, mucositis can have a significant impact on treatment outcomes and quality of life in patients receiving mucotoxic therapy for cancer.

 

Although present throughout the gastrointestinal tract, mucositis in the oral cavity is studied more frequently and better characterized in the literature because of the ease of assessment. The mucositis Oncology Nursing Society Putting Evidence Into Practice® (PEP) group chose to examine interventions for the management of oral rather than gastrointestinal mucositis because of the greater breadth and more extensive literature in this area. Because mucositis is a systemic process, interventions with the greatest impact are those that exert their effects systemically.

 

Methods

 

The team searched MEDLINE®, the U.S. National Library of Medicine’s bibliographic database, CINAHL® (Cumulative Index to Nursing and Allied Health Literature) and CCRCT (Cochrane Central Register of Controlled Trials). Searches explored the terms neoplasms for nursing, prevention and control, diet therapy, drug therapy, radiotherapy, surgery, and therapy. Other search terms included mucositis, stomatitis, mucous membrane, radiotherapy, and antineoplastic agents. A health services librarian was consulted to review the search terms and strategy. The literature search included citations from 2000 to September 2006. Sources cited before 2000 were reviewed as appropriate.

 

Highlights of Reviewed Literature

 

Interventions have been applied to the appropriate level of evidence based the ONS PEP Weight-of-Evidence Classification Schema. See Table 1 for a description of this schema.

 

Recommended for Practice

 

Oral care is widely considered the foundation of mucosal health, integrity, and function; however, the specific components, methods, and frequency of oral care remain in dispute, partly because of the ethical considerations of withholding oral care in clinical trials. The literature does state that oral care protocols help to minimize the effects of oral mucositis in patients receiving treatment for cancer (Rubenstein et al., 2004). Oral care can reduce the amount of microbial flora, reduce pain and bleeding, and prevent infection. Good oral health also reduces the risk of dental complications (Cawley & Benson, 2005; Rubenstein et al.). Although oral care has not been demonstrated to prevent mucositis, adherence to a regimen can reduce the duration and severity of mucositis (McGuire, Correa, Johnson, & Wienandts, 2006; Rubenstein et al.). The review of the literature indicated that a systematic approach to oral care should be followed. The focus of oral care protocols is not on specific agents, but on feasibility, adherence, and patient education. The protocol also may be specific to patients’ diagnosis and treatment (Rubenstein et al.).

 

The basic components of an oral care protocol include assessment, patient education, tooth brushing, flossing, and oral rinses. A multidisciplinary, collaborative team approach is important for implementation of the protocol. Figure 1 includes a minimum of recommended oral care components. Oral assessment, using a validated tool, also should be conducted regularly to assess function, pain, and the oral mucosa. The participation of a dentist is recommended throughout treatment and follow-up (Multinational Association of Supportive Care in Cancer [MASCC], 2005). Bland rinses, recognized as an important part of oral hygiene, have not been studied adequately to meet the criteria for the Recommended for Practice category. They are included under Expert Opinion later in this article.

 

To date, few studies have addressed the superiority of different oral care regimens. As a result, the detailed components of oral care protocols currently meet the criteria for expert opinion. Two studies in the pediatric setting have demonstrated the superiority of using protocols over general oral care. One study (N =42) found a preventive oral care protocol consisting of patient education and instruction on tooth brushing and use of rinses effectively reduced oral mucositis in children with cancer. The control group consisted of children who did not receive the oral care protocol or information about oral care. The incidence of mucositis in the oral protocol group decreased by 38% compared to the children in the control group. The severity of pain and the severity of oral mucositis also were significantly reduced (Cheng, Molassiotis, Chang, Wai, & Cheung, 2001).

 

The second pediatric study (N = 40) compared three oral care protocols: tooth brushing, normal saline rinse, and chlorhexidine or benzydamine rinses. No significant differences in oral mucositis were found between protocols. The results of this study did not demonstrate superiority of a specific rinse, but rather, reinforced the importance of oral care (Cheng, Chang, & Yuen, 2004).

 

A third study compared salt and sodium bicarbonate (one teaspoon each of salt and sodium bicarbonate per pint of water) rinses, chlorhexadine and “magic” mouthwash (5 ml 0.5% lidocaine, 0.25 ml 0.0312% diphenhydramine, and l4.75 ml aluminum hydroxide/magnesium hydroxide) in adult patients receiving chemotherapy. The results of this randomized study (N = 142) did not show any significant difference for average number of days to mucositis resolution or pain scores. The similarity in the results for the three groups indicates the benefits of a systematic oral care protocol. These results also support the use of the inexpensive salt and sodium bicarbonate rinse (Dodd et al., 2000) as the other rinses are more expensive and may contain alcohol or other irritating ingredients.

 

Cryotherapy involves the use of ice chips or ice cold water for the prevention of oral mucositis. Patients suck on ice or hold ice cold water in their mouths prior to, during, and after rapid infusions of mucotoxic agents with a short half-life. Cryotherapy is based on the theory that vasoconstriction decreases exposure of the oral cavity mucous membranes to the mucotoxic agents (Lilleby et al., 2006, Mori et al., 2006, Nikoletti, Hyde, Shaw, Myers, & Kristjanson, 2005; Tartarone, Matera, Romano, Vigliotti, & Di Renzo, 2005).

 

Use of cryotherapy for bolus 5-fluorouracil (5-FU) is supported in the MASCC (2005) guidelines and a Cochrane Review of interventions for the prevention of oral mucositis (Worthington, Clarkson, & Eden, 2004). In addition, studies have provided support for the use of cryotherapy with high-dose melphalan (Lilleby et al., 2006, Mori et al., 2006). Reviews by Eilers (2004); Kwong (2004); Migliorati, Oberle-Edwards, and Schubert (2006); and Scully, Sonis, and Diz (2006) also recommended the use of cryotherapy, with those selected agents. Effectiveness is limited to chemotherapy agents with a short half-life and the majority of the evidence to date is for 5-FU and high-dose melphalan. Other agents that have been studied, but lack adequate evidence to make a recommendation regarding cryotherapy, include etoposide, platinol, mitomycin, edatrexate, and vinblastine (Karagozoglu & Ulusoy, 2005).

 

The optimum duration and intensity of cryotherapy requires further systematic investigation. Studies to date have been inconsistent as has documentation regarding patient adherence to the cooling protocol. Based on current knowledge, patients should hold ice or ice cold water in their mouths for at least five minutes prior to the infusion, during the infusion, and for 30 minutes after completion of the infusion. Individuals who do not tolerate cold in their oral cavity do not tolerate cryotherapy well. In addition, cryotherapy is not indicated with chemotherapy agents such as oxaliplatin, which are known to result in potential problems with exposure to cold. Oxaliplatin is associated with acute neurologic symptoms, including jaw tightness and laryngopharyngeal dysesthesia, which often occur after exposure to cold (Fischer, Knobf, Durivage, & Beaulieu, 2003).

 

Palifermin is a recombinant human keratinocyte growth factor that stimulates growth of epithelial cells. This drug has been shown to reduce severity and duration of mucositis in patients with hematologic malignancies receiving high-dose chemotherapy and total body irradiation with autologous stem cell transplantation (Spielberger et al., 2004). Palifermin is administered at a dose of 60 ug/kg per day via IV for three days prior to the beginning of the conditioning regimen and for three days after transplantation for the prevention of oral mucositis. Because of the high cost of this agent, it should be used for patients most likely to develop severe mucositis. The cost-effectiveness of palifermin and its use with specific conditioning regimens continue to be investigated. The most common side effects include mild rash and taste changes. Other adverse effects include pruritis, erythema, cough, edema, white coating of mouth or tongue, rhinitis, arthralgia, numbness, and paresthesia. These effects are mild to moderate, last approximately three days, and did not cause discontinuation of the drug in studies (MASCC, 2005; Scully et al., 2006; Spielberger et al.; von Bultzingslowen et al., 2006).

 

Effectiveness Not Established

 

Most of the agents examined in the review of literature were assigned to this category because of lack of clinical trials, inadequate sample size, methodological flaws, or conflicting evidence.

 

Antimicrobial agents: A wide variety of antimicrobial agents, including polymyxin, tobramycin, amphotericin B, fluconazole, and protegrin have been studied in several doses and combinations. No clear pattern of benefit has emerged, and little evidence exists to recommend the use of these agents (Donnelly, Bellm, Epstein, Sonis, & Symonds, 2003). One large (N =
275) placebo-controlled randomized trial has shown narrow-spectrum antibacterial lozenges to be effective for patients with head and neck cancer undergoing radiation (Scully et al., 2006). These agents may be costly, however, and the lack of effectiveness highlights the multifactorial pathophysiology of oral mucositis.

 

Benzydamine hydrogen chloride is a nonsteroidal drug with analgesic, anesthetic, anti-inflammatory, and antimicrobial properties that currently is used in Europe and Canada, but is not approved by the U.S. Food and Drug Administration. In one trial (N = 172), benzydamine produced a significant reduction (p = 0.009) in mucositis compared with placebo in patients receiving 0–5,000 cGy of radiation for head and neck cancer. Patients rinse with 15 ml of benzydamine for two minutes four to eight times daily before and during radiation therapy and for two weeks after completion of the course of radiation (Epstein et al. 2001). Those findings need to be replicated in additional large trials to determine benefit, dosage, and administration method (Scully et al., 2006; Worthington et al., 2004).

 

Growth factors and cytokines: Subcutaneous growth factors such as granulocyte–colony-stimulating factor and granulocyte macrophage–colony-stimulating factor (GM-CSF)
promote neutrophil development in the bone marrow and also may have effects in the submucosa (Kwong, 2004; Shih, Miaskowski,
Dodd, Stotts, & MacPhail, 2002). Studies with those agents have shown conflicting results, however, which may be because of inadequate sample sizes and variations in dose. Repifermin and velafermin are growth factors that are currently in clinical trials for mucositis (Freytes et al., 2004; Schuster et al., 2005).

 

Other Interventions 

 

Allopurinol is believed to inhibit enzymes involved in the formation of toxic 5-FU metabolites. Although initial small trials found some positive findings using allopurinol mouthwash, those results were not confirmed in controlled trials (Kwong, 2004; Rubenstein et al., 2004; Scully et al., 2006). Amifostine functions as a free radical scavenger. Although amifostine is effective for prevention of acute and late xerostomia in patients with head and neck during standard fractionated radiotherapy, it has not shown beneficial effects for management of mucositis. Multiple studies have failed to demonstrate significant effects for duration or severity of mucositis (Bensadoun, Schubert, Lalla, & Keefe, 2006; MASCC, 2005). Because of poor study design and inadequate sample size, anti-inflammatory rinses with ingredients such as kamillosan liquidum, hydrocortisone, prostaglandin E1, and oral corticosteroids are included in the Effectiveness Not Established category (Shih et al., 2002). L-alanyl-L-glutamine is a stable glutamine derivative that has been shown to decrease 5-FU–induced mucositis in animals and humans. Studies with the agent have produced weak results to date (Cerchietti et al., 2006; MASCC). Low-level laser therapy (LLLT) is a promising intervention that may prevent, treat, and provide pain control for mucositis with little or no toxicity (Genot & Klastersky, 2005; Migliorati et al., 2006; Nes & Posso, 2005). Laser therapy does require special equipment and training that is not widely available. Rubenstein et al. (2004) suggested using LLLT where available to reduce the incidence of oral mucositis and associated pain in patients receiving chemotherapy or chemoradiation before hematopoietic stem cell transplantation.

 

Multi-agent (“magic” or “miracle”) rinses include a variety of ingredients but typically contain lidocaine, diphenhydramine, and Maalox® (Novartis). As indicated previously, studies with these agents have not demonstrated their superiority over bland rinses to treat mucositis or alleviate pain. Concern that the numbing effect creates a potential for injury or difficulty swallowing exists. Formulations of those agents may contain alcohol, which should be avoided (Eilers, 2004). Zinc supplementation has been shown to delay the development and speed recovery of mucositis in one small trial (N = 30) and one larger trial (N = 97). The optimal dose has not been determined (Ertekin, Koc, Karslioglu, & Sezen, 2004; Lin, Que, Lin, & Lin, 2006). 

 

Effectiveness Unlikely

 

Iseganan is an oral antimicrobial agent provided as an oral rinse. Two multisite, randomized controlled trials were conducted with more than 500 subjects each. One trial enrolled individuals receiving high-dose chemotherapy and the other enrolled individuals receiving radiation therapy for head and neck cancers. The chemotherapy trial failed to demonstrate any benefit over standard oral care. In the radiation therapy study, no differences were found; however, the iseganan group did have fewer cases of ulcerative oral mucositis and experienced less severe oral mucositis than the group that received standard care only (Giles et al., 2004; Trotti et al., 2004).

 

Not Recommended for Practice

 

Although early studies appeared to demonstrate some benefit of the use of chlorhexidine for chemotherapy-induced mucositis, this benefit has not been repeated in subsequent studies, nor has it been shown for radiation-induced mucositis (Scully et al., 2006). Review of other studies indicates chlorhexidine is not effective in reducing the severity of mucositis. It was believed that chlorhexidine could impact mucositis by significantly suppressing oral flora; however, that claim also is not shown in the research literature (Scully et al.; Shih et al., 2002). The MASCC (2005) guidelines indicate that chlorhexidine should not be used to treat established oral mucositis because its superiority to bland rinses has not been established and it may contain alcohol (Rubenstein et al., 2004). Other reports indicate rinse-induced discomfort, taste alteration, and teeth staining (Cheng et al., 2001, 2004; Dodd et al., 2000; Eilers, 2004; Pitten, Kiefer, Buth, Dowlken, & Kramer, 2003).

 

GM-CSF is a hematopoietic growth factor that promotes neutrophil development and regulates functions of mature leukocytes and macrophages in the dermis and submucosa (Shih et al., 2002). Although three smaller studies (N = 31, 68, and 61, respectively) have demonstrated moderate benefits with GM-CSF mouthwashes (Henja et al., 2001; Mantovani et al., 2003; Nicolatou-Galitis et al., 2001), all of them had substantial methodologic flaws. One large (N = 90), well-controlled study failed to demonstrate a benefit (Dazzi et al., 2003), and another randomized control trial (N = 41) also demonstrated no benefit (Valcarcel et al., 2002). The updated MASCC (2005) guidelines indicate that GM-CSF mouthwashes should not be used for the prevention of oral mucositis in the transplantation setting (Rubenstein et al., 2004). That recommendation also is supported in systematic reviews that discuss this agent (Kwong, 2004; Shih et al.; von Bultzingslowen et al., 2006).

 

Sucralfate is a basic aluminum salt of sulphated sucrose that is used to treat gastric and duodenal ulcers. It is believed to protect the mucosa from local irritants. A number of smaller studies have produced conflicting results with this agent; however, double-blind studies have not demonstrated a benefit (Castagna et al., 2001; Dodd et al., 2003; Etiz et al., 2000; Nottage et al., 2003). Those studies used varying doses and frequencies, making comparison difficult. Sucralfate is not recommended because of the lack of tolerability related to nausea and other gastrointestinal effects, including rectal bleeding (Eilers, 2004; Kwong, 2004; MASCC, 2005; Rubenstein et al., 2004; Scully et al., 2006; Shih et al., 2002).

 

Expert Opinion

 

Bland Rinses

 

Rinses are used to remove loose debris and aid with oral hydration. Bland rinses include 0.9% saline (normal saline), sodium bicarbonate, and a saline and sodium bicarbonate mixture. Typical mixtures contain one teaspoon salt or sodium bicarbonate per pint of water. Any of those rinses can be administered at room temperature or refrigerated, and all are inexpensive. Patients should be instructed to take a tablespoon of the rinse, swish it in the oral cavity for at least 30 seconds, and expectorate. Sodium bicarbonate reduces the acidity of oral fluids, dilutes accumulating mucus, and discourages yeast colonization (Dodd et al., 2000; Eilers, 2004; Rubenstein et al., 2004; Scully et al., 2006; Shih et al., 2002).

 

Implications for Nursing Practice and Research

 

Measurement is essential to the establishment of sound evidence-based care. A major impediment to the advancement of care related to the prevention and treatment of mucositis in cancer care has been related to assessment and measurement of mucositis (Eilers & Epstein, 2004). Studies to date have not consistently used valid and reliable instruments to document changes in the oral cavity. In addition, many clinical settings do not use a valid and reliable assessment tool in daily practice. Mucositis assessment and grading scales have been reviewed for use by clinicians (Eilers & Epstein; Sonis et al., 2004). Eilers and Epstein identified questions to guide the selection of an instrument for mucositis assessment including: What information regarding the oral cavity is needed? How will the collected data be used? Does the instrument address the necessary area of concern? Does the instrument have established validity and reliability? Is the instrument able to provide the specificity needed? Who will be conducting the assessment? What skill or training is needed to complete the assessment?

 

Tools to consider include the Oral Assessment Guide (Eilers, Berger, & Petersen, 1988), Oral Mucosa Rating Scale (Kolbinson, Schubert, Flournoy, & Truelove, 1988), Oral Mucositis Index (McGuire et al., 2002; Schubert, Williams, Lloid, Donaldson, & Chapko, 1992), and Oral Mucositis Assessment Scale (Sonis et al., 1999). Grading scales to consider include the Western Consortium for Cancer Nursing Research (1998) stomatitis staging system, World Health Organization (1979) Cancer Treatment Toxicity, and National Cancer Institute (2006) Common Toxicity Criteria. See Table 2 for a summary of those tools and scales.

 

Nursing has an excellent opportunity to impact patient outcomes through diligent attention to evidence-based oral care. An organized approach for determining past history and practices related to oral care and oral health in general, coupled with routine use of a valid and reliable instrument for the assessment of the oral cavity, is foundational to professional nursing care of patients receiving mucotoxic antineoplastic therapies. Although the optimum oral care program is best accomplished through a well-organized, multidisciplinary effort with dental professionals, physicians, and nurses (MASCC, 2005), nursing must be willing to lead the effort when other disciplines are not available or attentive to this area of cancer care.

 

Awareness of the proposed pathophysiologic model by Sonis et al. (2004) can serve to guide interventions and future efforts to improve outcomes. The stages of mucositis proposed in this model are explained in Figure 2 and may be beneficial to guide decisions regarding interventions. Although research to date has not been able to identify a universally effective intervention for the prevention or treatment of mucositis, an integrated standard approach to oral care should be used (Rubenstein et al., 2004). Establishment of such a standard can serve as the first step toward improved oral care practices. Education of staff, patients, and family members should be incorporated in this approach.

 

Although standard plans should provide the basis for care, nurses must strive to develop individualized plans that are designed to provide the best results for each patient. This includes evaluating patients’ ability and willingness to perform the proposed oral care. Limited adherence to the best plan is less desirable than a compromise that addresses the patients’ preferences and abilities and avoids harmful products. Groups of patients such as those receiving high-dose therapies and those receiving treatment for head and neck cancer are at increased risk for severe oral mucositis and complications; thus, they should receive focused attention.

 

Unfortunately, a mucotoxicity rating scale for cancer treatments that could serve to aid clinicians in the prioritization of patients most likely to benefit from interventions is not yet available. Documentation of oral cavity changes based on assessment using a valid and reliable instrument will aid in the advancement of knowledge about mucotoxicity of various antineoplastic therapy protocols. Patients receiving less toxic regimens may not experience mucositis and so may not require the more intensive, often expensive, interventions.

 

Summary

 

Ongoing research related to preventing and treating oral mucositis shows some promising directions, including new growth factors, and novel therapies, such as LLLT. Further study is needed to determine the role for those therapies. At this time, oral care, cryotherapy, and palifermin are the only management strategies for which sufficient evidence for practice exists. Additional study is required to determine the frequency of the elements in an oral care protocol and the use of palifermin with additional populations. Oncology nurses are crucial to developing the evidence in those areas. Nurses must ensure that the assessment tools used are valid and reliable. Consistency of assessment in this area allows for better comparison of interventions. As new interventions become available, nurses will continue to directly impact patient outcomes. Evidence-based practice tools, such as the PEP cards, will allow nurses to access current information more easily and employ the appropriate interventions for specific patient needs.

 

The authors gratefully acknowledge the contributions of Oncology Nursing Society staff members, including Linda Eaton, MN, RN, AOCN®, and Kelly Egnotovich, as well as the outcomes project field reviewers.  

 

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Debra J. Harris, RN, MSN, OCN®, is the nursing practice and education coordinator for inpatient adult oncology at Oregon Health and Science University in Portland; June Eilers, PhD, RN, BC, CS, is a clinical nurse specialist at the Nebraska Medical Center in Omaha; Amber Harriman, RN, is a staff nurse at Oregon Health and Science University; Barbara J. Cashavelly, MSN, RN, AOCN®, is a nurse director of clinical practices at the Massachusetts General Hospital Cancer Center in Boston; and Cathy Maxwell, RN, OCN®, CCRC, is a director of clinical operations at Advanced Medical Specialties in Miami, FL. Eilers has served as a consultant, member of the nursing speakers bureau, and member of the advisory committee for Amgen Inc., Endo Cytogen, Merck and Company Inc., and Novartis Pharmaceuticals Corporation. Maxwell has received research grants from and worked as a nurse speaker and advisor for Amgen Inc. and MGI PHARMA Inc. Mention of specific products and opinions related to those products do not indicate or imply endorsement by the Clinical Journal of Oncology Nursing or the Oncology Nursing Society. (Submitted May 2007. Accepted for publication August 1, 2007.)

 

Author Contact: Debra J. Harris, RN, MSN, OCN®, can be reached at debrajean_harris@yahoo.com, with copy to editor at CJONEditor@ons.org.

 

Digital Object Identifier:10.1188/08.CJON.141-152