February
2008, Volume 12, Number 1
Article
Putting Evidence Into
Practiceฎ: Evidence-Based Interventions for the Management of Oral Mucositis
Debra J. Harris, RN, MSN, OCNฎ, June Eilers,
PhD, RN, BC, CS, Amber Harriman, RN, Barbara J. Cashavelly,
MSN, RN, AOCNฎ, and Cathy Maxwell, RN, OCNฎ, 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 membranecovered 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 Practiceฎ (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 MEDLINEฎ, the U.S.
National Library of Medicines bibliographic database, CINAHLฎ
(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 05,000 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 granulocytecolony-stimulating factor and granulocyte
macrophagecolony-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-FUinduced 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 Maaloxฎ (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, AOCNฎ,
and Kelly Egnotovich, as well as the outcomes project field reviewers.
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Debra J. Harris, RN, MSN, OCNฎ, 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, AOCNฎ, is a nurse
director of clinical practices at the Massachusetts General Hospital Cancer
Center in Boston; and Cathy Maxwell, RN, OCNฎ, 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, OCNฎ, 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
