Topical Treatment of Oral Mucositis in Cancer Patients: A Systematic Review of Randomized Clinical Trials

Background and Purpose: Evidence-based protocols of topical therapy for oral mucositis (OM) induced by chemoradiotherapy (CRT) are continuously established and updated. Thus, the present systematic review aims to evaluate the scientific literature in terms of effectiveness of topical treatment of OM in cancer patients undergoing CRT. Materials and Methods: This systematic review was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Checklist. Randomized clinical trials were identified through electronic database searches on CINAHL, Cochrane Library, LILACS, Livivo, PubMed, SCOPUS, and Web of Science. Grey literature was also assessed on Google Scholar, Open Grey, and ProQuest. The risk of bias in the included studies was assessed by the Cochrane Collaboration Risk of Bias Tool. Results: Twenty-three randomized clinical trials (n=1169 patients) met the inclusion criteria. Twenty-three different topical agents were examined and categorized into five groups: analgesics (30.4%), natural agents (21.7%), other topical agents (21.7%), antimicrobial agents (17.4%), and growth factors (8.8%). Of the included studies, 50% presented a resolution of OM within 14 days. Topical natural agents yielded good results with average resolution time of 3–7 days. The included studies generally demonstrated that patients treated with mouthwashes presented superior benefits compared to the control, depending on OM severity. Conclusion: Topical agents effectively reduced the severity of OM lesions and pain intensity in patients receiving chemoradiotherapy, although the effects varied by agent type. However, the heterogeneity in the results of these topical intervention studies underscores the need for standardized clinical trial methodologies. Clinical Relevance: Topical agents were effective in patients with severe OM lesions receiving chemoradiotherapy and are a good alternative of home care in relation to pain control, reduction of inflammation and consequent improvement in quality of life.


Introduction
Oral mucositis (OM) is one of the most prevalent adverse effect of head and neck radiotherapy (RT) and chemotherapy (CT) that is characterized by an inflammatory response of the oral cavity and oropharynx. OM affects 20-40% of patients receiving conventional CT, up to 80% of patients undergoing hematopoietic stem cell transplantation and receiving high doses of CT and almost all patients undergoing head and neck RT (Dodd et al., 2003;Miranzadeh et al., 2015;Sheibani et al., 2015;Lalla et al., 2014). Generally, patients undergoing CT experience some degree of oral discomfort within 5-10 days after treatment initiation (Nagarajan, 2015), while those undergoing RT usually develop OM within 1-2 weeks of treatment. Generally, OM causes great discomfort during eating, drinking, and speaking consequently resulting in weight loss and a decline in general health condition (Sahebjamee et al., 2015;Mogensen et al., 2017).
Taking into account that in many health services, patients do not have access to strategies for the prevention of OM, it is necessary that they have an alternative of home care in relation to pain control, reduction of inflammation and consequent improvement in quality of life. Given that topical agents are more easily applied, relatively inexpensive and have fewer side effects when compared to systemic therapies, the present systematic review aimed to summarize the scientific evidence available in the literature regarding the clinical practice of using topical agents as a therapeutic alternative for OM in patients undergoing cancer treatment.

Protocol and registration
This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Checklist (Moher et al., 2009;Shamseer et al., 2015). The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database under registration number CRD42017073116 (Prospero, 2017).

Study Design and terminology definition
The present study is a systematic review of randomized controlled trials that assessed topical agents for OM treatment in cancer patients undergoing CT and/or RT. Topical intervention was defined as any treatment applied to the oral mucosa with local effects, including mouthwashes, creams, ointments, and jellies.

Eligibility criteria Inclusion criteria
This systematic review followed the PICOS (population, intervention, comparison, outcome, and study design) approach in order to define the inclusion criteria. Only randomized clinical studies (S) assessing the effects of topical agents (I) for OM treatment (O) in cancer patients aged ≥18 years who underwent CT and/or RT (P). Any comparisons were considered for inclusion and only full-text articles were considered.

Information sources and search strategy
To identify literature published until April 17, 2019, individual search strategies were applied to the following electronic databases: CINAHL EBSCO, Cochrane Library, LILACS, Livivo, PubMed, SCOPUS, and Web of Science (Appendix 1). A gray literature search on Google Scholar, Open Grey, and ProQuest Dissertations and Theses Global was also performed. The references of included studies were manually screened for potential studies that could have been missed on database search. Duplicate references were removed using Rayyan, a reference manager software (Ouzzani et al., 2016).

Study selection
During a two-phase study selection process, two authors (GSA and AGCN) independently reviewed the titles and abstracts of identified articles in Phase 1 and selected those appearing to meet the inclusion criteria. In Phase 2, these authors independently read the full texts of all selected articles and excluded those that did not meet the inclusion criteria (Appendix 2). Disagreements between evaluators were resolved by consensus, with final decisions by a third reviewer (IPT) if needed.

Data collection process
One author (GSA) collected key data from each selected article, which were crosschecked for accuracy by a second reviewer (AGCN). Disagreements were resolved by discussion and mutual agreement among GSA, AGCN, and IPT. The following information was recorded for all included studies: author(s), publication year, country, patients' ages (years), cancer type, cancer treatment, intervention type, control type, sample size (cases and controls), follow-up period, and main conclusions (Tables  1 and 2).

Risk of bias in individual studies
The risk of bias of included trials was assessed by the Cochrane Risk of Bias (RoB) tool. "High," "low," or "unclear" risk scores were based on the randomization method; allocation concealment; blinding of participants, personnel, and outcome assessors; completeness of outcome data; and selective reporting (Higgins and Green, 2011). The reviewers compared evaluations, resolved disagreements and reported their RoB assessments using Review Manager software (RevMan 5.3, The Nordic Cochrane Centre, Copenhagen, Denmark).

Summary measures
The primary outcome of this systematic review was a reduction in the OM severity grade based on the World Health Organization assessment scale. The secondary CT exclusively. Table 2 summarizes the descriptive characteristics of studies assessing patients undergoing chemoradiotherapy and RT.

Results of individual studies
All 23 articles described different types of topical agents for OM treatment. Despite heterogeneity in the evaluated topical interventions, most patients receiving CT and/or RT exhibited reduced OM severity (i.e., grade) and/or pain intensity.

Treatment characteristics
The treatment characteristics are shown in Tables 1 and 2. More than half (n=63,2%) of the included patients received CT alone (Table 1), while almost 46% (n=537) received RT and/or CT (Table 2). Most studies of different cancer treatments identified the incidence of mucositis as a secondary outcome. Twelve studies evaluated the treatment of head and neck cancer, while 11 included several types of cancer (Tables 1 and 2). Of the 23 topical agents evaluated in this descriptive analysis, natural agents, analgesics, antimicrobial agents, growth factors, and others were applied to 209, 148, 98, 32, and outcomes were the scores for erythema, wound healing, pain intensity, and eating and drinking ability. Any type of outcome measurement was considered in this review (categorical and continuous variables).

Risk of bias across studies
Individuals using novel topical interventions for OM management were compared with individuals using placebo and/or routine mouthwashes. Clinical heterogeneity (by comparing variability among the participant´s characteristics and outcomes assessed), methodological (by comparing the variability in study design and risk of bias), and statistical heterogeneity were considered in order to critically analyze the results.

Study selection
In phase 1, 994 citations were identified in seven electronic databases, and 480 remained after removing duplicates. Any references were included from gray literature. After screening the titles and abstracts, 376 references were excluded as irrelevant to the research question. One more reference was included after an updated search. A manual search of the reference lists yielded no additional studies. The full texts of 105 articles were screened (phase 2), and 81 were excluded (Appendix 2). Finally, 23 were selected for the descriptive analysis. A flow chart of the study identification, inclusion, and exclusion process is shown in Figure 1.
Topical analgesics are essential for pain control, and consequently for an appropriate food and fluid intake, communication, and sleep (Quinn et al., 2017). Studied  DOI:10.31557/APJCP.2020.21.7.1851  Two weeks after study initiation, mucositis severity was significantly lower in the treatment group than in the control group. Lesions persisted for 4.5 days in the treatment group and 3-7 days in the control group. The minimum duration of lesion healing in the intervention group was 6 days, and 2 subjects required >14 days. The mucositis grade was determined using the WHO scale, and pain intensity was measured using an NRS. There was a statistical difference in the moment of transition to oral nutrition for patients in the experimental groups. The time of oral nutrition time in the first experimental group that applied chlorhexidine was lower than in the group that applied cryotherapy and the control group (P<0.01). Chlorhexidine mouthwash is recommended for the treatment of OM. The mucositis grade was determined using the WHO scale. The study was limited by the lack of description of the pain measurement scale.  topical analgesics included 0.5% or 1% phenytoin (Baharvand et al., 2010;Baharvand et al., 2015), 1% or 2% morphine (Cerchietti et al., 2003;Sarvizadeh et al., 2015;Vayne-Bossert et al., 2010), doxepin (Leenstra et al., 2014), and sucralfate (Dodd et al., 2003). Phenytoin mouthwash significantly improved patients' pain and quality of life (Baharvand et al., 2010;Baharvand et al., 2015). Only one study on topical morphine described pain relief 28 minutes after the first use of mouthwash, with an average duration of relief of 216 minutes (Cerchietti et al., 2003). Doxepin rinse significantly reduced mouth and throat pain due to OM caused by RT and CT for HNC (P<0.001), however no significant correlation was found between this topical intervention and OM severity (Leenstra et al., 2014). Similarly, the use of topical sucralfate had no significant impact on OM severity (P=0.85) or pain reduction (P=0.54) (Dodd et al., 2003), suggesting the need for further randomized clinical trials with these agents. The studied topical antimicrobials included chlorhexidine gluconate (Dodd et al., 2000;Erden and Ipekcoban, 2017), nystatin + diphenhydramine + tetracycline + hydrocortisone (Rothwell and Spektor,1990), and triclosan (Satheeshkumar et al., 2010). Erden (2017) evaluated the efficacy of chlorhexidine on oral nutrition transition times in patients with CT-induced OM and observed a significant difference in days for OM resolution between the chlorhexidine (8.53±1.04) and control groups (13.53±1.69). In contrast, Dodd (2000) found no significant differences in the time of OM resolution (P=0.59) or in patients' pain ratings over time among chlorhexidine and control mouthwashes groups. The use of oral rinse containing nystatin, diphenhydramine, tetracycline and hydrocortisone resulted in reduced OM severity compared to control group (Rothwell and Spektor,1990), as well as the use of triclosan was also capable of reducing the severity and duration of OM (Satheeshkumar et al., 2010).

Cabrera
Regarding growth factors, two studies on human granulocyte and macrophage colony-stimulating factor (GM-CSF) (Sprinzl et al., 2001;Hejna et al., 2001) yielded conflicting results. Hejna et al., (2001) recommended the topical use of GM-CSF for the treatment of CT-induced OM in patients with head and neck cancer since this topical treatment was effective on reducing the time of resolution of OM (P=0.0008) when compared to control. On the other hand, Sprinzl et al., (2001) did not recommend this application since there was no statistical difference between GM-CSF and conventional mouthwash in terms of OM severity. This difference may have probably occurred because in the study by Hejna et al., (2001) the patients were submitted to CT only, while in the study by Sprinzl et al., (2001) the patients were submitted to an association of CT and head and neck RT, causing a more severe mucositis.
Other topical agents included vitamin E oil (Wadleigh  (32) 3-14 The 2 groups differed significantly in terms of stomatitis intensity and pain between days 3 and 14 (P<0.05 and P=0.013, respectively), thus confirming the study hypothesis and demonstrating that Aloe vera could effectively reduce stomatitis intensity and pain. The mucositis grade was measured using the WHO scale. Pain intensity was measured using a VAS.  (9) Placebo oil (coconut and soybean oils) (9) 5

Miranzadeh
Six of 9 patients in the vitamin E group achieved a complete resolution of their lesions within 4 days of initiating therapy (median: 3 days), whereas 8 of 9 patients receiving placebo did not achieve a complete resolution during the 5-day study period (P=0.025). The topical administration of vitamin E may be effective for the treatment of chemotherapy-induced mucositis. The mucositis grade was measured using WHO scale. Pain intensity was measured using a VAS.
7 On day 7 of the trial, 65% of patients in the propolis group were completely healed. There were significant differences in the incidence of OM, wound, and erythema between the propolis and placebo groups, but no significant differences in eating and drinking abilities. Propolis-based mouth rinse is safe and effective for the treatment of RT-induced mucositis. The mucositis grade was determined using the WHO scale. The study was limited by a lack of description of the pain measurement scale.
Cherry syrup containing sorbitol, magnesia and alumina suspension, and vitamins 42 The topical application of nystatin, diphenhydramine, tetracycline, and hydrocortisone may reduce the incidence of RT-associated mucositis. Although the experimental group of patients developed mucositis, their symptoms were less severe and were not exacerbated beyond the third week of therapy. Pain intensity was measured on a scale of 0-5. The study was limited by a lack of description of the scale used to determine the mucositis grade. In a statistical analysis, GM-CSF was not superior to conventional mouthwash in terms of OM, pain perception, incidence of secondary infection, and abnormal hematological parameters. Therefore, topical GM-CSF is not recommended for the treatment of OM induced by chemoradiotherapy in patients with HNC. The mucositis grade was determined using the WHO scale. Pain intensity was measured using a VAS.  (Porta et al., 1994), AG013 (ActoBiotic) (Limaye et al., 2013), and 5% phenylbutyrate (Yen et al., 2012). Topical vitamin E oil, which has antioxidant effects, was reported by Wadleigh et al.,

Vayne-Bossert
This study analyzed the effectiveness of three mouthwashes used to treat chemotherapyinduced mucositis.
Clinical studies of chemotherapyinduced mucositis in patients with breast and colon cancer and non-Hodgkin lymphoma 64% 12 The three groups had similar times to the cessation of mucositis signs and symptoms (mean: 6.6-7.17 days).

Most significant result
Proposed mechanism Ref.
Chlorhexidine mouthwash (30) This study aimed to compare the effects of chlorhexidine vs. a control on oral nutrition transition times in patients with chemotherapy-induced oral mucositis.
Clinical studies of chemotherapyinduced mucositis in patients with gastric, colon, pancreatic, rectal, and metastatic cancer (unknown cause) 50%

7-14
The mean transition time for oral nutrition differed significantly between the chlorhexidine group (8.53 ± 1.04 days) and the control groups (13.53 ± 1.69 days). This finding was statistically significant (P <0.05).
Antimicrobial, antiinflammatory Erden et al. 2016 Nystatin, diphenhydramine, tetracycline, and hydrocortisone mouthwash (5) This study aimed to analyze the effectiveness of an oral rinse comprising hydrocortisone, nystatin, tetracycline, and diphenhydramine for controlling radiation-related mucositis.
Clinical studies of radiotherapy-induced mucositis in patients with head and neck cancer 33% 42 As expected, the control group exhibited increasingly severe mucositis with increasing exposure to irradiation throughout the course of therapy. Mucositis severity increased in the experimental group during the first 3 weeks, but then decreased during the last 3 weeks of therapy.
Antimicrobial, antiinflammatory Rothwell et al. 1990 Triclosan mouthwash (12) This study aimed to determine the effectiveness of triclosan for the management of radiation-induced oral mucositis and to compare the effectiveness of a triclosan mouth rinse with that of a conventional sodium bicarbonate mouth rinse. Mucositis grade, body weight, food intake, and pain were assessed during weekly follow-ups throughout and after radiation treatment.
Clinical studies of radiotherapy-induced mucositis in patients with oral carcinoma even distribution between men and women.

24
A triclosan mouth rinse was superior to a sodium bicarbonate mouth rinse for reducing the severity and duration of oral mucositis. The groups differed in terms of the recovery of mucositis from grade 3 to grade 0, which required a mean of 23.6 days in the intervention group vs. 36.5 days in the control group.    oxidase (Porta et al., 1994;Fields et al., 1996). Porta et al., (1994) reported that all patients receiving CT developed grade 2-3 stomatitis, which resolved completely or partially by allopurinol mouthwash in 40.9% and 86.3% of patients, respectively. AG013 is an oral rinse containing the recombinant L. lactis strain engineered to secrete the mucosal protectant hTFF1. Limaye et al., (2013) reported that treatment with AG013 led to a 35% reduction in the mean duration of ulcerative OM (UOM) vs. placebo and reduced the numbers of unplanned office and emergency room visits. Furthermore, 29% of individuals receiving AG013 had none or 1 day of UOM; all other participants had ≥2 days of UOM. Yen et al., (2012) demonstrated that patients receiving a mouthwash containing phenylbutyrate and histone deacetylase inhibitor had significantly lower intensity of OM ulceration than those receiving a placebo (p=0.0485); suggesting that phenylbutyrate enhanced oral nutrition intake compared to the control (P=0.0085). Twenty-one of 23 topical agents were administered as mouthwashes while one study used as a cream vehicle (Lin et al., 2015). Treatment with mouthwashes containing the following 15 agents were effective on reducing the duration of severe OM (functional impairment): propolis (Akhavankarbassi et al., 2016), royal jelly (Erdem and Güngörmüş, 2014), Aloe vera gel (Mansouri et al., 2016); Achillea millefolium distillate (Miranzadeh et al., 2015), 0.5% phenytoin (Baharvand et al., 2015), chlorhexidine gluconate (Dodd et al., 2000), chlorhexidine (Erden and Ipekcoban, 2017), nystatin+diphenhydramine+tetracycli ne and hydrocortisone, triclosan (Satheeshkumar et al., 2010), GM-CSF (Hejna et al., 2001), allopurinol (Porta et al., 1994), AG013 (Limaye et al., 2013), and 5% phenylbutyrate (Yen et al., 2012).

Risk of bias across studies
The use of similar and robust methodologies in the included studies reduced the potential for misinterpretation. All included studies were randomized controlled trials and the majority were considered to be of moderate risk of bias, for these reasons, were considered to be relatively homogeneous in terms of methodological characteristics. When it comes to clinical aspects, the studies were considered similar in terms of participant characteristics and outcomes, but considerably heterogeneous in relation to topical interventions, consequently impacting the unfeasibility of a meta-analysis. Nevertheless, the results of our review could be considered consistent and trustworthy.

Summary of evidence
Cancer is one of the most common causes of death worldwide and its incidence has been gradually increasing, mainly due to both aging and growth of the population, as well as changes in the prevalence and distribution of the main risk factors for cancer (Bray et al., 2018). Its treatment depends on several factors that include the type of the tumor, the location, the clinical and pathological staging as well as the patient's health status. Currently, there are several types of CT and RT that can be used alone or in combination to manage the disease. Both therapies are extremely effective in destroying tumor cells but as a result they end up causing side effects so damaging that treatment often needs to be interrupted. One of the most prevalent side effects is oral mucositis, which affects around 40% of patients undergoing chemotherapy, such as Methotrexate, Cisplatine and 5-Fluorouracil, and almost 100% of patients undergoing head and neck RT (Sonis, 2009;Scully et al., 2003).
The pathobiology of oral mucositis is divided into 5 phases: initiation, signaling, amplification, ulceration and healing. Once the chemotherapeutic drug or radiotherapy contacts the mucosa, several chemical changes occur in the tissue, resulting in the release of reactive oxygen species that in turn activate transcription factors capable of amplifying the production and release of inflammatory cytokines. This amplification causes a cycle of constant production of cytokines that result in clinically evident and painful ulceration susceptible to bacterial colonization and secondary infection (Sonis, 2009). Thus, the need of early intervention is fundamental in order to reduce the severity of the injury. Although many therapeutic agents have been investigated, no effective prevention or treatment standard protocol has been completely successful to handle OM (Dos Santos Filho et al., 2018).
It is not uncommon in clinical dentistry practice for patients to ask for medications that they can apply at home in order to reduce pain and control inflammation. Prevention with photobiomodulation has been widely accepted and applied, but, unfortunately, in many health services such therapy is still inaccessible to many patients (Zadik et al., 2019). Thus, topical therapeutic alternatives for OM are necessary, which are cost-effective, easily applicable and cause less additional side effects in patients who are already systemically compromised.
For the best of our knowledge, this is the first systematic review of randomized clinical trials that compiled the highest level of scientific evidence available in the literature in terms of efficacy of topical agents for OM in patients with cancer. The included studies generally demonstrated that patients treated with mouthwash presented superior benefits when compared to the control, depending on mucositis severity.
In the case of natural agents, royal jelly treatment was effective during the initial but not final stages of OM, and the corresponding control group benefited from benzydamine hydrochloride and nystatin mouthwash (Erdem and Güngörmüş, 2014). Moreover, propolis mouthwash improved oral health in patients undergoing CT (Akhavankarbassi et al., 2016), thus reinforcing the recommendations for therapeutic mouthwashes to promote oral hygiene, prevent/treat infections, moisten the oral cavity, and provide pain relief (Quinn et al., 2017). Both honey and propolis exert various anti-inflammatory effects, antioxidant activity, prostaglandin synthesis-inhibiting activity in mucosal tissue, pro-immune effects via the stimulation of phagocytic activity and cellular immunity, and healing effects in epithelial tissues. Propolis is rich in iron and zinc, which are important elements in collagen synthesis (Akhavankarbassi et al., 2016;Erdem and Güngörmüş, 2014;Zakaria, 2017). The anti-inflammatory agents Achillea millefolium distillate (Miranzadeh et al., 2015) and Plantago major extract (Cabrera-Jaime et al., 2018) yielded different responses. Achillea millefolium mouthwash improved the mean healing time of grade 3-4 OM to 14 days, whereas Plantago major extract was not superior to control treatment (sodium bicarbonate or chlorhexidine). However, Plantago major extract reduced the healing time from 7 to 5 days when combined with sodium bicarbonate in a mouthwash. Accordingly, strategies involving oral hygiene products are evidence-based therapeutic approaches to mucositis prevention and treatment (Cabrera-Jaime et al., 2018). The antioxidant activity of topical Aloe vera gel is mediated by polysaccharides, anthraquinone, lectin, superoxide dismutase, glycoproteins, amino acids, vitamins C and E, and minerals. Mansouri et al., (2016) reported significantly reduced pain and OM intensity between 3 and 14 days after the use of Aloe vera mouthwash (p<0.05 and 0.013, respectively).
Among topical analgesics, phenytoin mouthwash yielded significant improvements in pain and quality of life (Baharvand et al., 2010;Baharvand et al., 2015). The topical antimicrobial chlorhexidine exhibited activity against gram-positive and gram-negative bacteria and fungi and had minimal systemic adverse reactions when used at a low concentration, which reduced absorption in the gastrointestinal tract (Dodd et al., 2000;Erden and Ipekcoban, 2017).
GM-CSF is a hematopoietic growth factor that promotes neutrophil proliferation and differentiation. Previously, Liang et al., (2017) reported that GM-CSF could prevent and treat CT-and RT-induced OM in patients with head and neck cancer. In our review, two studies reported conflicting results regarding the efficacy of topical GM-CSF for OM (Sprinzl et al., 2001;Hejna et al., 2001), although this discrepancy might have been related to the use of RT. Specifically, RT-induced OM begins with inflammation of the oral mucosa, tongue, and pharynx, followed by a normal tissue lesion for 7-98 days (Limaye et al., 2013;Maria et al., 2017;Sonis, 2010).
In addition to the primary outcome of the present review, which was to assess the effect of topical therapies currently available on OM control, some studies have contemplated other secondary outcomes. Nine included studies discussed the importance of oral hygiene, monitoring and controlling of opportunistic infections via antimicrobial treatments and preventive dental protocols, including selective extractions, restorations, and fluoride programs. These randomized controlled trials addressed the reduction of the incidence of sepsis in patients with OM, a considerable risk factor reported in most studies (Dodd et al., 2003;Akhavankarbassi et al., 2016;Sprinzl et al., 2001;Erden and Ipekcoban,2017;Mansouri et al., 2016;Sarvizadeh et al., 2015;Satheeshkumar et al., 2010;Rothwell and Spektor, 1990;Hejna et al., 2001).

Limitations
This review had some limitations that should be considered. First, the methodological quality was overall moderate, mainly due to heterogeneity of the studies as a consequence of the large number of topical interventions. Second, there was also heterogeneity in terms of presentation of results among the studies, as some analyzed treatment evolution according to OM severity while others presented results with medians. Moreover, there was a wide variation on duration of the interventions, ranging from 1 day to 4 weeks. Due to all this considerable heterogeneity among reviewed studies, a meta-analysis could not be conducted. The absence of pain measurement scales was also a limitation.
In conclusion, in this review, the efficacy of topical agents for OM in cancer patients undergoing CT and/or RT was evaluated. Particularly, topical natural agents yielded good results and significant improvements in the patients' quality of life. Generally, topical agents reduced the OM severity and pain intensity in patients receiving CT and RT, although the effects varied among interventions. However, the heterogeneity of the studies' results demonstrates the need to standardize the validated assessment instruments and similar interventions that would enable comparisons and analyses of treatment effects based on well-designed randomized clinical trials.