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December 2014, Supplement to Volume 18, Number 6
Evidence-Based Interventions for Cancer Treatment–Related Mucositis: Putting Evidence Into Practice
June Eilers, PhD, APRN-CNS, BC, Debra Harris, RN, MSN, OCN®, Karen Henry, MSN, ARNP, FNP-BC, AOCNP®, and Lee Ann Johnson, MSN, RN
Mucositis is an inflammatory process that can involve the mucosal epithelial cells from the mouth to the rectum. Historically, mucositis and stomatitis were used interchangeably, but momentum has increased toward more specific terminology since the 2000s. Stomatitis refers to inflammatory diseases of the mouth, including the mucosa, dentition, periapices, and periodontium, whereas mucositis refers more globally to an inflammatory process involving the mucous membranes of the oral cavity and the gastrointestinal tract. In addition, differentiation is needed regarding mucositis involving the oral cavity and the remainder of the gastrointestinal tract that require use of a scope-type device for close examination. As a result, oral cavity mucositis has been the focus of the majority of the studies reported to date. The mucous membranes beyond the oral cavity are more challenging to view, so the mouth has been presented as revealing potential changes in the gastrointestinal tract. However, because of the variation in morphology, function of different locations, and risks associated with procedures to validate that speculation, evidence is limited. The purpose of this article is to review evidence-based interventions for mucositis, particularly in the oral cavity, and provide clinicians with guidelines for nursing interventions.
Advances in the pharmacologic and supportive therapy management of cancer treatment–related bone marrow suppression, nausea and vomiting, and neutropenia-related infections have enabled dose escalation of many treatment protocols. However, mucositis is now seen with increased frequency and has evolved into a dose-limiting side effect of treatment. As a result, prevention and management of this side effect have become more relevant for cancer treatment success.
Once believed to involve a simple linear process, mucositis is now seen as a complex process involving many different factors, including the inflammatory process, cellular apoptosis, cytokines, cytotoxicity of treatments, and micro-organisms in the oral cavity. Sonis (2004) developed a proposed theoretical model to facilitate understanding of the complex process. When the inflammation progresses to a breakdown in the protective mucosal barrier, the micro-organisms normally present in the oral cavity and throughout the gastrointestinal tract are able to enter the bloodstream and cause potentially life-threatening infections that require strategic intervention. In addition to the risk of infections, mucositis causes pain, restricts oral intake, and contributes to malnutrition, interruption of treatment, and increased hospitalizations. The incremental costs of mucositis are usually associated with hospital stays, but the costs more than double when mucositis is severe (Carlotto, Hogsett, Maiorini, Razulis, & Sonis, 2013).
Patients receiving chemotherapy, epidermal growth factor receptor inhibitors, tyrosine kinase inhibitors, and/or radiation to the head and neck are susceptible to the development of oral mucositis. Mucositis occurs in about 40% of patients after standard doses of chemotherapy, and in as many as 100% of patients receiving high-dose chemotherapy or combination chemotherapy and radiation for head and neck cancer (Gibson et al., 2013). Risks for mucositis include patient- and treatment-related factors (Barasch & Peterson, 2003). Patient-focused factors include poor nutrition, age (children and older adults), neutropenia, poor oral hygiene, genetic factors, impaired salivary function, and use of alcohol and tobacco. Treatment-focused risk factors include specific chemotherapy agents, chemotherapy dose and administration schedule (high doses and stem cell transplantation), combination radiation and chemotherapy, radiation for head and neck cancer, and concomitant medications.
One of the reasons for the wide variation in documented incidence of mucositis is inconsistent use of valid and reliable instruments for the assessment of oral cavity changes. In addition, the severity of mucositis can range from mild erythema to severe ulcerations and bleeding. Visible changes associated with mucositis include erythema, ulceration, and pseudomembrane formation. Patients with membrane changes experience varying degrees of pain and changes in function including difficulty speaking and swallowing. As a result, patients focus on the symptoms that affect quality of life rather than the risk of life-threatening infection that is of concern to healthcare professionals. The increased length of hospitalization and costs attributed to mucositis are primarily related to pharmacologic management of the infections associated with mucositis and altered ability to maintain oral nutrition. To improve patient outcomes, the goals of nursing care are to prevent membrane breakdown, maintain the ability to eat, and treat or prevent pain.
This article builds on the earlier work by Oncology Nursing Society (ONS) Putting Evidence Into Practice (PEP®) mucositis teams (Eaton & Tipton, 2009; Harris, Eilers, Harriman, Cashavelly, & Maxwell, 2008; Johnson, Henry, Saca-Hazboun, & Samuel-Blalock, 2014). The span of the work attests to the commitment of oncology nurses to make a difference in patient outcomes through evidence-based practice and the ongoing challenge of mucositis in cancer care.
The literature search for relevant articles indexed in PubMed and CINAHL® was conducted by a research librarian at ONS. Search terms selected were consistent with prior searches for earlier PEP mucositis teams. PubMed was searched for Mucositis[ti] OR Mucositis[majr] OR “oral complication*” and CINAHL was searched for (MM “Mucositis” OR MM “Stomatitis” OR TI Mucositis OR TI stomatitis OR “oral complication*”) AND (cancer OR neoplasms OR oncolog* OR chemotherap*). The articles had to include patients with cancer and be published in English from May 1, 2008 to December 31, 2013. The search yielded 635 PubMed citations and 338 CINAHL citations. The abstracts were reviewed based on the following inclusion criteria: (a) studies were full research reports, systematic reviews, guidelines, or meta-analyses; (b) studies had to report on the results of measurement of oral mucositis; (c) studies examined an intervention aimed at affecting the problem of oral mucositis; and (d) the study samples included patients with cancer. Studies were excluded if they included grey literature, were descriptive, or reported intervention effects on the pain of mucositis but not the actual incidence or severity of the symptom mucositis itself. The screening of abstracts identified 138 articles for full article review. After removal of duplicates and studies that did not meet inclusion criteria and the addition of manuscripts retrieved in other topics meeting topic specific criteria, 100 publications were identified for team member review. Four additional studies were identified through an ongoing alert from the ONS research librarian. As a result, 104 publications were added to the prior ONS PEP mucositis work. Because the methods used for the PEP reviews presented in this supplement were consistent across the evidence-based practice teams, the detail of that content is available in Johnson (2014).
New research in mucositis is plentiful, particularly related to novel agents with many derived from natural sources. The bulk of those agents are classified as effectiveness not established because of inadequate research, study design flaws, and conflicting or unconfirmed results. The evidence was challenging to categorize because clinical measurement of mucositis was inconsistent across trials and the validity and reliability of the measurement was not always addressed by the study authors.
Recommended for practice: This category includes interventions for which effectiveness has been demonstrated by strong evidence from rigorously designed studies, meta-analyses, or systematic reviews and for which expectation of harm is small compared with the benefits. In previous reviews, only oral care protocols were recommended. However, additional therapies now included in this category are cryotherapy, low-level laser therapy, oral care protocols, palifermin, and sodium bicarbonate mouth rinses (see Table 1).
Likely to be effective: These interventions include evidence from a single rigorously conducted controlled trial, consistent evidence from well-designed controlled trials using small samples, evidence from meta-analyses or systematic reviews using small samples, or evidence from guidelines developed from evidence and supported by expert opinion. New recommendations in this category include prophylactic chlorhexidine, benzydamine, and lactobacillus lozenges (see Table 2).
Effectiveness not established: This category includes interventions for which data are insufficient or lack adequate quality. Numerous topical and systemic pharmacologic and nonpharmacologic interventions have been studied for efficacy in the prevention and management of oral mucositis or management of associated pain. Evidence for the interventions is limited because of inconsistent research results, small studies, and study designs. As a result, this category includes the greatest number of agents (see Table 3 page 1 and page 2).
Effectiveness unlikely: These are interventions for which lack of effectiveness has been demonstrated by negative evidence from a single rigorously conducted controlled trial, consistent negative evidence from well-designed controlled trials using small samples, small samples within meta-analysis or systematic reviews, or ineffective guidelines developed by consensus or expert opinion. Three agents are in this classification. One of these agents, Traumeel S, consists of multiple homeopathic substances that are expected to have effects on wound healing and inflammation. This compound was studied for its effect on oral mucositis. Other agents previously included and remaining in this category are iseganan and Wobe-Mugos E. Studies with the agents failed to produce statistically significant results (see Table 4). Misoprostol, an agent previously classified in this category, has been moved to effectiveness not established.
Not recommended for practice: Interventions in this category are those for which lack of effectiveness or harmfulness has been demonstrated by strong evidence from rigorously conducted studies, meta-analyses, or systematic reviews or interventions for which the costs, burdens, or harms associated with the intervention exceed anticipated benefit. Two agents remain in this category: chlorhexidine (nonprophylactic) and sucralfate. The concerns with both agents for treatment of mucositis is related to rinse-induced discomfort and taste. The recommendation is supported by other systematic reviews (Kwong, 2004; Shih, Miaskowski, Dodd, Stotts, & MacPhail, 2002; von Bültzingslöwen et al., 2006) (see Table 5).
The extensive volume of literature available regarding treatment and prevention of mucositis presents a challenge for systemic reviews of evidence. In addition to interventions categorized for this article, many others have been trialed and reported in various journals and venues. When systematic reviews are included in a process such as is reported here, multiple agents may have been involved. For the most part, the agents are not included if the researchers concluded that they were not able to make a recommendation. The numerous nonpharmacologic agents used in different settings throughout the world also present a challenge because reviewers were not always able to ascertain the details of the mixtures used. In addition, nonpharmacologic interventions have not always received the same scrutiny prior to use.
Agents that provide a protective barrier are an example of another type of intervention (e.g., Episil®, Gelclair, MuGard™). Typically, that type of agent is regarded as a device, which undergoes a different review process prior to approval for use. As a result, the studies reported may not have the same scientific rigor required for randomized clinical trials. In addition, the literature is not always clear regarding whether the primary outcome for a given study is pain management or mucositis management.
Implications for Practice
This comprehensive review of mucositis literature examined pharmacologic and nonpharmacologic interventions. Although only a limited number of interventions met the criteria for recommended for practice, they can provide clinicians with a basis for improved outcomes. Nurses are frequently acknowledged as the professionals spending the greatest amount of time with patients. The reality is that nurses in the clinical setting are facing an ever-increasing number of challenges and are expected to do more with less; therefore, nursing interventions such as basic oral care once seen as routine in acute care settings are becoming much less routine. That change in practice and the shift of the majority of cancer care to the outpatient setting have contributed to inconsistency in the promotion of oral care protocols that may be seen as too basic. This review adds support to the use of oral care protocols as the foundation for mucositis prevention and treatment. Nurses have a primary role to relay that importance to patients and families and to provide instruction regarding agents to avoid, particularly those containing alcohol, which has long been stated in the literature. In addition, nurses should recommend the use of sodium bicarbonate mouth rinses as an essential component of the routine oral care protocol.
Although indications for cryotherapy are restricted to potentially mucotoxic agents with a short half-life being administered over a relatively short time period, the intervention is low cost and evidence-based nursing practice. Individuals with cancerous lesions in their oral cavity would not be candidates for the intervention because the vasoconstriction induced by the cooling has the potential to limit exposure of the cancer cells to effective antineoplastic doses. In addition, cryotherapy is not indicated for individuals receiving oxaliplatin because of problems with exposure to cold, including pain, sensitivity, chest tightness, and laryngospasm.
The two remaining recommended interventions fall within interprofessional care. Low-level laser therapy requires the necessary equipment and trained personnel, so it is not available in all treatment centers. Variations in terminology and dose related to the use of lasers and other forms of light therapy for mucositis must be considered. The second intervention, palifermin, has been approved by the U.S. Food and Drug Administration for patients with hematologic malignancies who receive high doses of chemotherapy and radiation therapy followed by stem cell rescue. Palifermin requires a prescription, and, because of its expense, has not been universally adopted. As a result, further work is needed to identify those to treat with palifermin.
Nurses regularly involved in direct patient care have difficulty staying adequately abreast of the literature on a topic such as mucositis, particularly when their practice is not restricted to the management of one symptom. Therefore, ongoing reviews are at the core to advancing evidence-based practice. Nurses would benefit from ready availability of a simplified version of the tables in the current article to guide practice. With current advances in technology, this could be available electronically and updated regularly. Such a table would also facilitate knowledge regarding the current status of agents that have been identified as unlikely to be effective and/or not recommended for practice. At this time, the number of agents in the categories remains limited, which would facilitate easy review.
Knowledge of resources for accessing the available reports of evidence summaries and how to evaluate new publications will assist nurses in remaining up-to-date regarding changes in the literature. Participation in professional organizations such as ONS and the Multinational Association of Supportive Care in Cancer (MASCC) also provides nurses with support to improve patient outcomes. Initial review of the recommendations from these two organizations may trigger questions regarding inconsistencies. The important component to consider when comparing any other guidelines is to be aware of the criteria used when evaluating individual references and for classification of the levels of evidence once the review content is synthesized. Some of the difference is because ONS is focused on nursing and primarily addresses care in North America, whereas MASCC is multinational and more multidisciplinary in approach. That further explains the stronger focus on dental interventions in the MASCC guidelines as compared to ONS clinical teams, which do not incorporate dental services.
Nurses can contribute to the evidence guiding future practice by participating in research studies. When the resources and opportunities to participate are not available, nurses still can play a key role in improving patient outcomes through performance improvement activities at the local level or perhaps with other institutions. Participation will necessitate the use of valid and reliable assessment tools.
Assessment is the essential initial step for nurses to truly make a difference. Unfortunately, this process is inconsistent at best and often uses instruments that lack essential validity and reliability (see Harris et al., 2008). The more common assessment instruments, such as the Common Terminology Criteria for Adverse Events, version 4.0 (U.S. Department of Health and Human Services, 2010), and the World Health Organization’s (1979) scale, focus on grading mucositis and are used in clinical trials, whereas some instruments, such as the Oral Mucositis Assessment Scale (Sonis et al., 1999), focus on mucous membranes with quantifiable function and objective or subjective measures, and other instruments, such as the Oral Assessment Guide (Eilers, Berger, & Petersen, 1988), address overall changes in the oral cavity but do not grade the mucositis. Awareness of the divergent basis has implications for nursing. Although pain is a common component of the mucositis experience, retaining the pain assessment as a separate element is rational because the rating is dependent on adequacy of treatment, not just the severity of mucositis. Regardless of the mucositis assessment method chosen, the critical aspect involved is that all healthcare providers in an institution should be trained to rate the characteristics in a similar manner and cross-checked to ensure accuracy between assessors.
A baseline assessment is needed to focus on risk factors and the initial status of the oral cavity. Given that one of the identified risk factors for mucositis is cancer treatment, increased understanding is needed about the severity of the risk with a given treatment. Knowing the emetogenecity of cancer treatments, including combination protocols, guides treatment plans, but practice would also benefit from increased awareness of the mucotoxicity of therapies. That information could then enable nursing to establish electronic flags to accompany cancer treatment order sets. The flags could include the need to conduct assessments, which would be followed by evidence-based interventions. Such practice is dependent on adequate evidence that tends to be available, but that will need to be updated regularly.
As is commonly seen in research reports and reviews of evidence, research on mucositis remains limited. The bulk of the literature consists of small studies, nonrandomized designs, and a lack of valid and reliable instruments. Another concern is lack of clarity if the intent of the intervention was prevention or treatment of mucositis. Each concern needs to be addressed with a higher level of science in future work. Although not included in the results section of this review, the population treated and details of the intervention protocol are important to note. Readers are encouraged to refer to the original studies to determine the level of detail available for the studies reported in the current article.
The work reported has strengths, particularly in the volume reviewed and the number of nurses involved in the ONS PEP review for mucositis. However, improvement is needed. Evidence-based practice encourages nurses to evaluate their processes, which can also guide the PEP process. How can nurses build on past reviews and continue to refine the process used? How should nurses decide when to include miscellaneous agents individually to allow building on the information with future work? How do nurses decide when an intervention that was not found to have adequate evidence should move into an archive rather than remain on an evidence table with an outdated reference? Clinicians need to become critical consumers of attempts to promote the use of specific interventions or new products. Requiring a review of the evidence would serve clinicians and patients. As quality-improvement advocates, clinicians have a responsibility to identify areas of concern and question why established evidence is not being followed. In addition, researchers need to create well-designed studies with valid and reliable instruments, a clear purpose, intervention rigor, and an adequate sample. Finally, those results must be published and shared to pursue excellence as a profession.
Mucositis is a complex process involving the mucosal membranes of the oral cavity. Further knowledge regarding the process will continue to drive the identification of new potential treatments and the reevaluation of others. This update of the evidence for the prevention and management of mucositis provides essential information to guide nursing care of individuals experiencing this potentially life-threatening side effect. The guidelines are not intended to be static in nature, and they should not be blindly followed for every patient. Evidence-based practice must be seen as a process requiring ongoing diligence and review of the literature as well as the appropriateness for application with specific patients. Evidence-based interventions are critical for optimal prevention and management of mucositis. Similarly, the process used for PEP should continually be refined to allow for the provision of meaningful information to clinicians.
Implications for Practice
Ø Assess for oral mucositis with a valid and reliable instrument as an initial step for prevention and management.
Ø Develop evidence-based oral care protocols as the foundation for cancer-related mucositis care.
Ø Teach oral cavity self-management techniques for mucositis to patients and family members.
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June Eilers, PhD, APRN-CNS, BC, is a research associate professor in the College of Nursing at the University of Nebraska Medical Center College of Nursing in Omaha; Debra Harris, RN, MSN, OCN®, is a nurse manager at Oregon Health and Science University in Portland; Karen Henry, MSN, ARNP, FNP-BC, AOCNP®, is a nurse practitioner at the University of Miami Sylvester Comprehensive Cancer Center in Florida; and Lee Ann Johnson, MSN, RN, is a research associate at the Oncology Nursing Society in Pittsburgh, PA. The authors take full responsibility for the content of the article. The authors did not receive honoraria for this work. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or editorial staff. 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. Eilers can be reached at firstname.lastname@example.org, with copy to editor at CJONEditor@ons.org. (Submitted May 2014. Revision submitted July 2014. Accepted for publication July 25, 2014.)
Key words: mucositis; oral cavity; nursing management; evidence-based practice; cancer-related treatment