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REVIEW ARTICLE
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Effectiveness of mouthrinses in prevention and treatment of radiation induced mucositis: A systematic review


 Department of Public Health Dentistry, K. V. G. Dental College and Hospital, Sullia, Karnataka, India

Correspondence Address:
Varsha Manoharan,
Department of Public Health Dentistry, K. V. G. Dental College and Hospital, Sullia, Karnataka
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_176_18

 > Abstract 


Mucositis is a frequent, severe consequence of radiation therapy among patients undergoing radiotherapy for the head-and-neck cancer, often requiring hospitalization and even breaks or discontinuity in treatment. Mouth rinsing with various agents has demonstrated effectiveness in the prevention and treatment of radiation-induced mucositis (OM), but evidence for the same is lacking. This systematic review is therefore conducted with the aim of assessing the evidence for the effectiveness of mouthrinses in prevention and treatment of OM. Joanna Briggs Institute guidelines were followed to conduct this review. Six databases were searched and a total of 25 randomized clinical trials published over a period of the past 31 years were included for qualitative synthesis. Analysis of 25 studies revealed that 1299 participants, aged 46–69 years were assigned to the test groups and control groups. A total of 16 different formulations were studied among patients over a duration of 6 days to 1 year in varying dosages. The overall preventive fraction ranged from 1.9% to 77.8% for a reduction in clinical grades of mucositis, 7.6%–83.3% for a reduction in pain and 20%–50% for a reduction in bacterial counts. Adverse effects such as mouth burning, altered taste, sore throat, have been reported, especially with chlorhexidine and benzydamine hydrochloride. Evidence for the included studies is IC and ID. Studies using herbal based products and tissue regenerating agents revealed comparatively better effectiveness with lesser side effects. However, the number of studies to support such a claim is very limited.

Keywords: Head-and-neck cancer, mouthrinses, palliative care, radiation mucositis



How to cite this URL:
Manoharan V, Fareed N, Battur H, Khanagar S, Praveena J. Effectiveness of mouthrinses in prevention and treatment of radiation induced mucositis: A systematic review. J Can Res Ther [Epub ahead of print] [cited 2019 Dec 11]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=263525




 > Introduction Top


Head-and-neck cancer (HNC) encompasses a heterogeneous group of upper aerodigestive tract malignancies that together comprise to be the 7th most common cancer worldwide.[1] Radiation therapy (RT) is the most common treatment modality for cancer of the nasopharynx, larynx, and oropharynx.[2] RT confined to a person's head and/or neck region, often leads to complications such as mucositis, xerostomia, bacterial, fungal, or viral infection, dental caries, loss of taste, and osteoradionecrosis.[3] The current head-and-neck radiotherapy protocols have a mucositis incidence of 85%–100%.[4] Oral mucositis is a painful inflammation of the mucous membrane with clinical signs of erythema, pseudomembrane formation and ulceration of the oral mucosa. It is estimated that approximately one-half of the patients who develop severe ulcerative oropharyngeal mucositis will require modification of their cancer treatment regimen.[5] Thus, management of mucositis remains a crucial issue in RT of HNC. Various treatment modalities for the management of radiation-induced mucositis (OM) include basic oral care and oral care protocols.[6] Mouth rinsing, because of its convenience has been considered as the most common intervention to prevent or treat OM. Mouthrinses of different formulations have been studied among patients, each claiming to be effective in reducing OM but evidence on the effectiveness of these are critically lacking. A Cochrane review published in 2011 has focused on general management of oral mucositis.[7] There is a need for evidence-based approach focussing specifically upon the use of mouth rinsing as a preventive and treatment strategy for OM. This systematic review was thus undertaken to qualitatively analyze the effectiveness of mouthrinses in prevention and treatment of mucositis specifically due to RT.


 > Methodology Top


This systematic review is conducted as per the Joanna Briggs Institute (JBI) guidelines [8] and reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis.

Types of studies

Randomised controlled trials published over a period of 31 years (1986-2017) were included in this review. Studies wherein radiotherapy with or without adjunct chemotherapy were provided for the head-and-neck malignancies irrespective of their duration and dose were included in this review.

Types of interventions

Active agents: different formulations of mouth rinses prescribed for oral mucositis.

Control: placebo, or another active intervention.

Types of outcome measures

Reduction in mucositis was assessed through

  1. Reduction in clinical grades of mucositis (World Health Organization [WHO] Oral Mucositis Assessment Scale)
  2. Reduction in pain assessed through Visual Analog Scale, Numerical Rating Scale, Visual Rating Scale and HICKEY scale
  3. Reduction in bacterial counts (colony forming units).


Literature search and screening strategy

An initial electronic search of six databases including COCHRANE LIBRARY EMBASE, EBSCOHOST GOOGLE SCHOLAR, MEDLINE, and WHO IRIS using the search terms (alone or in combination) head-and-neck cancer, RT, chemoradiotherapy, mucositis, mouthrinses, radiation mucositis, prevention, chlorhexidine and radiation mucositis, benzydamine and radiation mucositis, herbal mouthrinses, and radiation mucositis was carried out. All relevant titles, abstracts published in English over the past 31 years (1986-2017) were identified and retrieved by the first two authors. A total of 285 relevant full-text articles were obtained. Potentially, relevant reports identified from the reference lists of relevant studies, review articles and chapters were hand searched, which yielded an additional 10 abstracts. Request letters were mailed to the authors of the included studies seeking relevant information regarding unpublished studies. The University websites were accessed to obtain relevant unpublished dissertations. Companies that manufacture mouthrinses were contacted for the identification of unpublished trials. Thus, a total of 295 titles and abstracts were retrieved.

At the 2nd level, since multiple databases were searched, a total of 175 abstracts were identified as duplicates and were excluded and 120 records were further assessed for eligibility. An additional 23 abstracts were excluded as they were clinical case reports or literature reviews. As the main objective of our investigation was a reduction in OM following mouth rinsing, further 69 records were eliminated as their focus was general management OM and the effects of mouth rinses on chemotherapy-induced mucositis.

At the 3rd level, a total of 28 records were considered potentially eligible and sought for further assessment and full-length articles were retrieved. These full reports were assessed independently by three authors with expertise in the content area, to establish whether the studies met the inclusion criteria and three records were excluded through unanimous decision of the group. Disagreements were resolved by discussion and wherever resolution was not possible, a third review author, Professor, and Head of the Department of Oral medicine and radiology were consulted and his decision was considered as final. Eventually, 25 records were selected to be included in this review and sought for qualitative synthesis in this systematic review. The title of the article, name of the journal, and authors with respective affiliation were masked and circulated among a panel of five reviewers. Each manuscript was analyzed for methodological quality according to a prepared checklist containing 15 main items as recommended by the JBI critical appraisal checklist for systematic reviews. Details of the search steps and the reasons for exclusion from the review were documented and are presented in [Figure 1].
Figure 1: Screening of manuscripts

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 > Results Top


A total of 25 studies published during 1986-2017 were included in this review. Analysis of the studies revealed that 16 different formulations of mouthrinses over a period of 6 days to 1 year, either before initiation of radiotherapy or during radiotherapy have been studied on 1299 participants with an age ranging from 46 to 69 years who underwent RT for HNC. Higher number of studies were reported from Iran (6 [24%]) and India (5 [20%]). Twenty-two out of the 25 studies were considered adequately powered (level of Evidence IC). Details of the formulations, dosage, duration, and their respective preventive fractions are depicted in [Table 1].
Table 1: Qualitative synthesis of included studies

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Blinding methodology was reported to have been employed in 14 (56%) studies, detailed analysis revealed a preventive fraction with a narrow range of 13.7% to 66.6% for reduction in clinical grades of mucositis, 32.3% to 66.5% for reduction in pain, and 20% to 50% for reduction in bacterial counts among double blind studies (12 [48%]) compared to nonblind studies (11 [44%]) which yielded a preventive fraction of 1.9% to 77.8% for reduction in clinical grades of mucositis and 7.6% to 83.3% for reduction in pain.

Analysis in relation to the outcome variable measures revealed a preventive fraction ranging from 1.9% to 77.8% for studies (22 [80%]) which considered reduction in clinical grades of mucositis as an outcome measure, 7.6% to 83.3% for studies (14 [56%]) which considered reduction in pain as an outcome measure and 20% to 50% (2 [8%]) for studies which considered reduction in bacterial counts as an outcome measure.

Adverse effects were reported among (8 [32%]) studies, the common adverse effects were burning sensation, altered taste, staining, excessive numbness, and sore throat. Chlorhexidine mouthrinse followed by benzydamine mouthrinse was reported to be commonly associated with adverse effects.

Studies with company funding yielded a preventive fraction of 33.3% for reduction in clinical grades of mucositis and 33.1% for reduction in pain compared to self-funded studies with a preventive fraction ranging from 1.9% to 77.8% for reduction in clinical grades of mucositis, and 7.6% to 83.3% for reduction in pain whereas studies with university grants or funding by philanthropic organizations reported a preventive fraction of 1.9% to 50% for reduction in clinical grades of mucositis, 11.3% to 32.3% for reduction in pain, and 20% to 50% or reduction in bacterial counts.

Details of the qualitative synthesis of included articles are shown in [Table 1].


 > Discussion Top


Globally, more than half a million patients are annually diagnosed with squamous-cell carcinoma of the head and neck.[34] Radiotherapy is the single most widely accepted form of treatment for patients with unressectable and/or inoperable locally advanced HNCs, the rationale being organ preservation and eradication of systemic micrometastasis.[35] A plethora of adverse effects of radiation has been reported, the effects result from epithelial, connective tissue, and vascular reactions within the radiation field and include mucositis, xerostomia (hyposalivation), taste changes, dysphagia, and dysphonia, as well as negative effect on dentition and quality of life.[2] The term oral mucositis emerged in the late 1980s to describe the radiotherapy and chemotherapy-induced inflammation of the oral mucosa, which represents a separate entity distinct from all other oral lesions.[36] Radiation-induced oral OM is common among patients with HNC, and is considered as the single most debilitating side effect of RT. Acute severe OM is associated with significant discomfort and impairment of the patient's ability to eat and swallow, the placement of feeding tubes, hospitalization and even temporary cessation in treatment.[37]

Many interventions are used to prevent or treat OM. These interventions have been categorised under the following headings such as general oral care protocols, interventions to reduce the mucosal toxicity, immunomodulatory agents, topical anesthetics and analgesics, antiseptics, antibacterial, antifungal and antiviral agents, mucosal barriers and coating agents, cytoprotectants, mucosal cell stimulants, and psychotherapy. It is very difficult for the clinician to choose from this bewildering array of treatment options.[38]

The present systematic review based on 25 studies reported over a period of 31 years, (1986-2017) is aimed to provide a qualitative analysis of the effectiveness of mouthrinses in the prevention and treatment of OM. Most of the studies were reported in Iran [6] and India [5] probably because of the reported higher prevalence of oral cancer in these countries. From our analysis, we have categorized the mouthrinses for the prevention and management of OM as (1) antimicrobial agents, (2) topical analgesics/anti-inflammatory, (3) tissue regenerating agents, (4) tissue coating agents, (5) herbal agents, and (6) miscellaneous. These formulations have been studied in comparison with either a placebo or gold standard.

Anti-microbial agents

Chlorhexidine gluconate (0.1%) is a cationic bisbiguanide was found to have been used in five studies (both as a treatment and control) yielding a preventive fraction of 13.7%–36. About 5% for a reduction in clinical grades of mucositis, 40% for a reduction in pain, and 20%–50% for a reduction in bacterial counts. Various side effects such as alteration in taste, stinging, staining, and stomatitis have been clearly reported in four studies.

Povidone-iodine (1:8), an antimicrobial agent used in three studies has yielded a preventive fraction ranging from 36.5%–66.6% for a reduction in clinical grades of mucositis with reported adverse effects such as irritation swelling and erythema in one study. Povidone-iodine yielded a better preventive fraction compared to chlorhexidine in reducing mucositis.[20]

Topical analgesics/anti-inflammatory

Benzydamine hydrochloride (0.15%) a nonsteroidal anti-inflammatory drug which affects the formation of thromboxane and alter the rate of prostaglandin produced, as reported by Epstein et al. The use of benzydamine was reported in six studies yielding a preventive fraction ranging from 19%–44.4% for reduction in pain and 15%–38% for reduction in clinical grades of mucositis. Side effects such as burning sensation, stinging, taste alteration, and excessive numbness were reported in two studies.[9]

Morphine (2%), an opioid analgesic which activates the opioid receptors that are expressed on peripheral sensory neurons and results in pain relief, were reported in two studies yielded a preventive fraction of 60% for a reduction in clinical grades of mucositis and 32.3% for reduction in pain. Side effects such as oral burning, itching, and intolerable taste were reported by Sarvizadeh et al. in one study.[24]

Prophylactic effect of allopurinol (a free radical scavenger) mouthrinse against OM is not reported in the literature; however, one study conducted by Abbasi et al. has shown alleviation of OM but the data were insufficient to calculate the preventive fraction.[22]

Phenytoin (1%) and diphenyhydramine plus kaolin-pectin were singularly reported. Phenytoin shortens the healing time of dermal and mucosal ulcers. It improves regional blood circulation and produces anti-inflammatory effects. It yielded a preventive fraction of 33.1% for reduction in pain. It was well tolerated and no side effects were reported.[30]

Diphenhydramine plus kaolin-pectin (50:50) is an antihistamine which provides symptomatic relief from the pain due to mucositis. Its use reported to have a preventive fraction of 33.3% for reduction in pain and reduction in clinical grades of mucositis, respectively, and causing mucosal erythema as an adverse effect.[17]

Tissue regenerating agents

Granulocyte-macrophage colony-stimulating factor (GM-CSF 37.5 μg) is a potent growth factor for the myeloid lineage of hematopoietic cells. GM-CSF enhances colony formation of granulocyte, macrophage, and eosinophil and also regulates several functions of mature leukocytes, macrophages, and dendritic cells in the dermis and submucosa. Their use may be associated with mucosal healing during RT and less frequent interruptions during the RT course. GM-CSF mouthwashes were well tolerated with a preventive fraction of 83.3% for reduction in pain which was the highest.[21]

Tissue coating agents

Three studies have reported the use of sucralfate (1 g/5 ml), a nonabsorbable aluminium salt of sulphated disaccharide which binds to positively charged proteins in mucosal erosions and ulcers forming a protective barrier and induces prostaglandin synthesis enhancing mucus production and blood flow to the mucosa and thus yielding a preventive fraction ranging from 40%–66.5% for reduction in pain and 16.1%–66.6% for reduction in clinical grades of mucositis. There were two studies reporting side effects such as erythema and mouth burning.[19]

Herbal mouthrinses

Natural honey, calendula flower extract, curcumin, Kangfuxin and clove-based mouth rinses were reported in single studies each, with the highest preventive fraction for honey-based mouth rinse (77.8%) and the least for clove-based mouth rinse (16%). The mechanism of action of these formulations was not clearly mentioned, and none of the studies reported side effects.

Miscellaneous (Salts)

Salts of calcium phosphate (CP) (1:1) and sodium carbonate (1 vial) were employed in three and two studies, respectively. CP mouth rinse is intended to moisten, lubricate and clean the oral mucosa, tongue, and throat. Stokman et al. vehave indicated the use of CP for the treatment of dryness of the mouth and as an adjunct to standard oral care in the prevention and treatment of mucositis caused by radiation or high-dose chemotherapy. There were no significant effects found on the frequency, duration, and severity of oral mucositis in any of the three studies. However, it yielded a lesser range of preventive fraction of 1.9%–33.3% for reduction in clinical grades of mucositis and 7.6%–11.3% for reduction in pain with no reported adverse effects.[25]

Sodium bicarbonate neutralizes the acid produced in the mouth and act as an antiseptic to help prevent infections from occurring. It aids in preventing progression of infection or inhibiting some inflammatory triggers in the oral cavity and can effectively act as the main material for preventing mucositis in patients undergoing radiotherapy. It was reported to have a preventive fraction of 13.7% for reduction in clinical grades of mucositis with no reported adverse effects.[29]

Even though sample size estimation is a fundamental procedural step in randomized control trials, only a few studies have reported it. Studies with sample size as less as six seriously limit the internal validity of the study. Detailed analysis of the possible strength and weaknesses of the included studies are reported in [Table 2] systematic reviews and qualitative synthesis of multiple studies are presently being used to overcome these limitations and to have a better understanding of research question.
Table 2: Analysis of the strengths and weaknesses of the included studies (chronological order)

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Our analysis of literature revealed that mouthrinses had been used both as a preventive and treatment measure for OM. Both yielding a wide range in preventive fraction. The possible reasons for these wide variations are inherent in the strengths and weaknesses of these studies as shown in [Table 2], further reasons if any needs a thorough analysis.

Many interventions have little evidence supporting their effectiveness, while others have a small amount of evidence suggesting that they may be effective. The situation has arisen because of the proliferation of small studies that lack the power to adequately evaluate interventions. Contributing to this situation is the fact that few studies have been replicated, with each successive study utilizing a different intervention, population or outcome measure. Finally, some studies failed to provide sufficient information regarding the research design, making assessment of quality impossible.[38] So what interventions appear to prevent or minimize the severity and duration of mucositis is still an unclarified question.

It is also important to note that the number of studies directed at comparing the relative efficacy of mouth rinse agent to complement oral care protocol were very limited. As yet, the optimal oral rinse agent for complementing the oral care protocols to alleviate OM has not been determined, and thus, remains a controversial issue. The literature on oral rinse agents in OM is at best inconclusive. The cancer treatment should be more emphasised on providing therapeutic and preventive care for oral mucositis.

The initial expert panels' evidence-based guidelines for managing mucositis in cancer patients was published in 2004 and revised in 2005. The recommendations included regular assessment of oral pain, regular and systematic oral hygiene care using a standardized protocol, dental examinations and treatment.[39]

There is no single strategy or specific approaches shown to be uniformly efficacious and can be widely accepted as an evidence-based standard therapy for oropharyngeal mucositis even though it has been studied for many years. Hence, it still remains as an unsettled diversified clinical issue for oncological teams in treating patients undergoing head and neck radiotherapy. The institution of good and consistent oral hygiene measures is critical and one of the most important factors in the prevention of oropharyngeal mucositis. Oral hygiene status at base line has not been reported in most of the studies though it is one of the most important confounders to determine the effectiveness of a mouthrinse. A study conducted by Kumar et al. has reported the oral hygiene index in terms of plaque and gingival index at base line. The data reported in that study were insufficient to calculate the preventive fraction. Thus the possible beneficial effects of mouthrinses on OM should be interpreted with caution Oral hygiene protocols of low cost, the simplicity of oral care and patient acceptance should be a priority in the prevention and treatment of mucositis. We should follow the concrete guidelines or protocols developed from well-designed clinical trials to support standardized preventive and treatment methodologies for the management OM.

As with any systematic review, conclusions from this dataset may be subject to change based on additional published evidence and also the confounding effects of chemotherapy-induced mucositis have not been accounted for. Despite these limitations, we believe that this is the best possible summary of evidence pertaining to the topic. Thus, we recommend conducting well-designed trials with sufficient numbers of participants to perform subgroup analyses by type of mouthrinses and its effectiveness on OM.


 > Conclusion Top


The results of this systematic review revealed that use of mouthrinses showed marginal reduction in radiation mucositis, with limited evidence. Studies using herbal-based products and tissue regenerating agents revealed comparatively better effectiveness with lesser side effects. However, the number of studies to support such a claim is very limited.

Acknowledgment

The authors sincerely express their gratitude to Dr. Jayaprasad Anekar for his complete support for conducting this review.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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