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Correspondence to: Xiaolin Hu, West China School of Nursing, West China Hospital/Department of Nursing, Sichuan University, No 37 Guo-xue-xiang Lane, Wuhou District, Chengdu, Sichuan, PR China.
To evaluate the incidence and identify the risk factors for radiotherapy-induced oral mucositis among patients with nasopharyngeal carcinoma.
Methods
A meta-analysis was conducted. Eight electronic databases (Medline, Embase, Cochrane Library, CINAHL Plus with Full Text, Web of Science, China National Knowledge Infrastructure, Wanfang Database, and Chinese Scientific Journals Database) were systematically searched from inception to 4 March 2023 for relevant studies. Study selection and data extraction were conducted by two independent authors. The Newcastle‒Ottawa scale was used for quality assessment among the included studies. Data synthesis and analyses were performed in R software package version 4.1.3 and Review Manager Software 5.4. The pooled incidence was calculated using proportions with 95% confidence intervals (CIs), and the risk factors were evaluated using the odds ratio (OR) with 95% CIs. Sensitivity analysis and predesigned subgroup analyses were also conducted.
Results
A total of 22 studies published from 2005 to 2023 were included. The results of the meta-analysis showed that the incidence of radiotherapy-induced oral mucositis was 99.0% among nasopharyngeal carcinoma patients, and the incidence of severe radiotherapy-induced oral mucositis was 52.0%. Poor oral hygiene, overweight before radiotherapy, oral pH < 7.0, the use of oral mucosal protective agents, smoking, drinking, combined chemotherapy, and the use of antibiotics at early treatment stage are risk factors for severe radiotherapy-induced oral mucositis. Sensitivity analysis and subgroup analyses also revealed that our results are stable and reliable.
Conclusions
Almost all patients with nasopharyngeal carcinoma have suffered from radiotherapy-induced oral mucositis, and more than half of patients have experienced severe oral mucositis. Facilitating oral health might be the key focus of reducing the incidence and severity of radiotherapy-induced oral mucositis among nasopharyngeal carcinoma patients.
]. Due to the deep-seated anatomic location and high sensitivity to ionizing radiation, radiotherapy is the mainstay treatment modality for patients with nasopharyngeal carcinoma. The radiotherapy techniques have progressed from conventional two-dimensional radiotherapy to 3D conformal radiotherapy and then to intensity-modulated radiotherapy over time. The locoregional control and survival have been enhanced by the parallel improved dosimetric properties [
]. Despite improvements in the radiotherapy techniques, the ongoing and intensive irradiation that is required might still cause the normal tissues around the tumor to suffer from a series of acute and chronic radiation toxicities, which lead patients to experience various treatment-related problems and poor quality of life [
]. Radiotherapy-induced oral mucositis is the most frequent and distressing radiation complication, with an incidence ranging from 85.0% to 100.0% among patients with head and neck cancer during therapy [
A randomized, controlled phase II trial of maxillofacial and oral massage in attenuating severe radiotherapy-induced oral mucositis and lipid metabolite changes in nasopharyngeal carcinoma.
Randomized, double-blind, placebo-controlled trial of shuanghua baihe tablets to prevent oral mucositis in patients with nasopharyngeal cancer undergoing chemoradiation therapy.
]. Great attention to this unpleasant complication is needed.
Radiotherapy-induced oral mucositis refers to erythematous and painful ulcerative lesions of the oral mucosa and is observed in patients who are treated with radiotherapy combined with or without chemotherapy [
]. The presence of severe radiotherapy-induced oral mucositis can have detrimental effects on patients’ daily functioning and quality of life: unable to eat, drink, and talk due to painful ulceration, ultimately leading to weight loss, nutritional deficiencies, secondary infections, extended length of hospital stay, and increased associated economic costs [
]. What is worse, severe radiotherapy-induced oral mucositis might lead to dose reduction and treatment interruption, which could adversely affect the treatment effects and disease prognosis [
A network meta-analysis in comparing prophylactic treatments of radiotherapy-induced oral mucositis for patients with head and neck cancers receiving radiotherapy.
]. Although a range of treatments have been used for oral mucositis, such as palifermin, growth factor, cryotherapy, and low-level laser treatment, no treatment is fully effective [
]. Active precaution for a complication beforehand is much easier and cheaper than treating it, and preventive strategies directed towards the risk factors for oral mucositis might effectively decrease the incidence of these complications [
]. Therefore, it is urgent and necessary to determine the risk factors and accordingly develop targeted preventive measures of radiotherapy-induced oral mucositis among patients with nasopharyngeal carcinoma.
Currently, studies on radiotherapy-induced oral mucositis are mainly interventional studies that focus on symptom treatment and the effectiveness of these treatment measures [
]. There are only a small number of studies exploring the risk factors for radiotherapy-induced oral mucositis, and the limited studies are mostly focused on patients with head and neck cancer (such as oral cancer and oropharyngeal cancer) [
Factors associated with severe oral mucositis and candidiasis in patients undergoing radiotherapy for oral and oropharyngeal carcinomas: a retrospective multicenter study of 326 patients.
]. Although originating from similar cell or tissue lineages, nasopharyngeal carcinoma is distinctly different from other epithelial head and neck cancers [
] included 166 patients with nasopharyngeal carcinoma and found that smoking, poor oral hygiene, oral pH less than 7.0, and chemotherapy were risk factors for radiotherapy-induced oral mucositis. Dong et al. [
] explored the risk factors among 116 patients and found that smoking, oral pH less than 6.5, concurrent chemotherapy, and oral irradiation dose more than 32 Gy might contribute to the development of radiotherapy-induced oral mucositis. In addition, the incidence of severe radiotherapy-induced oral mucositis has varied in different studies, with a range from 30% to 100% [
Analysis of main associated factors of radiation therapy-induced oral mucositis during intensity-modulated radiotherapy among patients with nasopharyngeal carcinoma.
]. To the best of our knowledge, no study has systematically explored the incidence and risk factors for radiotherapy-induced oral mucositis and its incidence among patients with nasopharyngeal carcinoma. Therefore, the objectives of our study are to (1) identify the incidence of radiotherapy-induced oral mucositis among patients with nasopharyngeal carcinoma, (2) explore the possible risk factors for severe radiotherapy-induced oral mucositis in nasopharyngeal carcinoma patients, and (3) provide evidence-based references for developing targeted preventive measures of radiotherapy-induced oral mucositis.
Methods
This meta-analysis was registered with International Prospective Register of Systematic Reviews (http://www.crd.york.ac.uk/PROSPERO), and it was performed and reported according to the updated Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA2020) guidelines [
Two authors independently screened and selected all literature. Studies were included if they met the following inclusion criteria: (1) participants were patients diagnosed with nasopharyngeal carcinoma, aged over 18 years, and received radiotherapy; (2) the exact diagnostic criteria for radiotherapy-induced oral mucositis were available; (3) the incidence or risk factors for radiotherapy-induced oral mucositis were reported; (4) the research types were observational including cross-sectional studies, case-control studies, and cohort studies; and (5) the study language was English or Chinese. The exclusion criteria were as follows: (1) studies did not provide complete data; (2) the full-text of the study was unavailable; and (3) studies were conference abstracts, dissertations, study protocols, and duplicate reports.
Data sources and search strategies
Eight electronic databases, including Medline, Embase, Cochrane Library, CINAHL Plus with Full Text, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Database, and Chinese Scientific Journals Database (VIP), were searched from inception to 4 March 2023 for all possible literature. The search strategies were established by using medical subject headings (MeSH) terms, text word searches, and Boolean calculation searches (see supplemental material Table 1). For instance, in Medline of Ovid, the search terms were as follows: Nasopharyngeal neoplasms [Mesh] or “nasopharyngeal neoplasms” or “nasopharynx cancer” or “nasopharyngeal cancer” or “nasopharynx neoplasms” or “nasopharyngeal carcinoma” or NPC OR (nasopharynx [Mesh] or nasopharynx or nasopharyngeal or nasopharyngitis ∗ or rhinopharyngitis ∗ or choanae) and (neoplasms [Mesh] or carcinoma∗ or cancer∗ or neoplasm∗ or tumor∗ or tumour∗ or malignancy∗ or onco∗)), and “radiation-induced oral mucositis” or “radiotherapy oral mucositis” or RTOM or ((radiotherapy [Mesh] or radiotherapy∗ or irradiation∗ or “radiation therapy”) and (Stomatitis [Mesh] or “oral mucositis” or stomatitis or stomatitides or oromucositis or oromucositides or (oral and (mucositis [Mesh] or mucositis or mucositides or mucosa inflammation). Additionally, the searches were limited to human adults, published in English or Chinese. The reference lists of the relevant studies were also screened for potentially relevant articles.
Study selection and data extraction
The reference management software EndNote X9 was used for data management. After removing duplicates, two authors independently screened the titles and abstracts of all citations in accordance with the inclusion and exclusion criteria. Then, the full-texts of citations were retrieved when considered potentially relevant by either investigator. Each article was evaluated by two independent authors for final study inclusion based on the eligibility criteria. The reference lists of the included studies were also screened for additional possible studies. Disagreements during the selection process were resolved by discussion or consultation with the third author.
Two independent authors extracted relevant data from the included studies using predesigned data collection forms. The following data were collected: the study author, date of publication, study site, study design, sample size, number of female and male patients, mean age, cancer stage, treatment regimen, diagnostic criteria, incidence of radiotherapy-induced oral mucositis, and assessed risk factors.
Quality assessment
Quality assessment was conducted by two independent authors. No cross-sectional studies were included in this study, and the quality of case‒control studies and cohort studies was assessed using the Newcastle‒Ottawa scale [
]. The scale evaluated the quality of the study from three domains: selection of subjects, comparability of study groups, and ascertainment of the exposure or outcome. The total score of the scale ranges from 0 to 9, with scores of 0‒3, 4‒6, and 7‒9 indicating low, moderate, and high quality of each study, respectively.
Data synthesis and analysis
We used R software package version 4.1.3 and Review Manager Software 5.4 for the heterogeneity test and quantitative data synthesis. Heterogeneity among the included studies was evaluated using Cochrane's Q statistic, and the I2 statistic and p value were used to assess the degree of heterogeneity. I2 ≤ 50% and a p value > .050 were regarded as indicating low heterogeneity and a fixed effect model was used to pool the results; otherwise, a random effect model was used to obtain more conservative pooled results. The incidence of radiotherapy-induced oral mucositis was presented as the proportion with 95% confidence intervals (CIs) and analysed using the Freeman-Turkey double-arcsine transformation random-effects model [
] in R software package version 4.1.3. The risk factors of severe radiotherapy-induced oral mucositis were determined by odds ratio (ORs) with 95% CIs in Review Manager Software 5.4. A two-sided p value less than .050 was used to indicate a statistically significant difference. In addition, predesigned subgroup analyses were performed according to the study characteristics and the different severities of oral mucositis. A sensitivity analysis was also conducted to test the stability and reliability of the pooled results of incidence and risk factors. Finally, a funnel plot and Egger's linear regression (p < .100 was considered as significant) method were used to evaluate the publication bias.
Results
Study selection
Our study selection process is presented in Fig. 1. A total of 1453 records were retrieved from eight electronic databases. After removing the duplicates (n = 392), another 1020 records were excluded according to the titles and abstracts because the participants were not patients with nasopharyngeal carcinoma (n = 148), the studies were not related to radiotherapy-induced oral mucositis (n = 536) nor to its risk factors (n = 49), and the studies were non‒observational studies (n = 284), protocol (n = 1), and conference abstracts (n = 2). Next, the full-texts of 41 citations were retrieved and evaluated based on the eligibility criteria, and 21 studies were excluded for the reasons presented in Fig. 1. Finally, another two records were identified from citation searching were included, a total of 22 studies [
Analysis of main associated factors of radiation therapy-induced oral mucositis during intensity-modulated radiotherapy among patients with nasopharyngeal carcinoma.
Clinical observation of acute skin and oral mucous membrane reactions in patients with nasopharyngeal carcinoma treated with concurrent radiochemotherapy and correlated factors.
Impact of dose volume parameters and clinical factors on acute radiation oral mucositis for locally advanced nasopharyngeal carcinoma patients treated with concurrent intensity-modulated radiation therapy and chemoradiotherapy.
Predicting nomogram for severe oral mucositis in patients with nasopharyngeal carcinoma during intensity-modulated radiation therapy: a retrospective cohort study.
Associated risk factors of acute mucosa reaction in patients with nasopharyngeal carcinoma after radiotherapy and chemotherapy and application of OREM self-protection theory.
Correlation analysis between prognostic nutritional index before radiotherapy and severity of acute oral mucositis in patients with nasopharyngeal carcinoma.
Table 1 presents the characteristics of the included studies. The 22 included studies all were observational studies, 12 of which were prospective cohort studies, five was a retrospective cohort study, and another five studies were case‒control studies. All these studies were published between 2005 and 2023, and they were from China (n = 20), Italy (n = 1), and Japan (n = 1). The sample size of the included studies ranged from 22 to 1674, and the total sample size was 4507. The mean ages of all the participants ranged from 46.3 to 64.3 years old. Most studies (n = 17) included all stages of patients with nasopharyngeal carcinoma, one study included patients at stage, one study included patients at stage T3-4NxM0 or TxN2-3M0 following the Union for International Cancer Control (2010), and three studies included only locally advanced patients (stage). All participants were treated with radiotherapy alone or combined with chemotherapy. The diagnostic criteria of radiotherapy-induced oral mucositis varied in these included studies, grade 2 or above was defined as severe radiotherapy-induced oral mucositis. Specifically, 10 studies [
Clinical observation of acute skin and oral mucous membrane reactions in patients with nasopharyngeal carcinoma treated with concurrent radiochemotherapy and correlated factors.
Impact of dose volume parameters and clinical factors on acute radiation oral mucositis for locally advanced nasopharyngeal carcinoma patients treated with concurrent intensity-modulated radiation therapy and chemoradiotherapy.
Associated risk factors of acute mucosa reaction in patients with nasopharyngeal carcinoma after radiotherapy and chemotherapy and application of OREM self-protection theory.
Correlation analysis between prognostic nutritional index before radiotherapy and severity of acute oral mucositis in patients with nasopharyngeal carcinoma.
Analysis of main associated factors of radiation therapy-induced oral mucositis during intensity-modulated radiotherapy among patients with nasopharyngeal carcinoma.
Predicting nomogram for severe oral mucositis in patients with nasopharyngeal carcinoma during intensity-modulated radiation therapy: a retrospective cohort study.
Abbreviations: BMI = Body Mass Index, CTCAE = Common Terminology Criteria for Adverse Events, EUD = Equivalent Uniform Dose, NA = Not Accessible, , NOS = Newcastle-Ottawa scale, RTOG = Radiation Therapy Oncology Group, RTOM = Radiotherapy-Induced Oral Mucositis WHO = World Health Organization, OM = Oral Mucositis, ,.
Analysis of main associated factors of radiation therapy-induced oral mucositis during intensity-modulated radiotherapy among patients with nasopharyngeal carcinoma.
Clinical observation of acute skin and oral mucous membrane reactions in patients with nasopharyngeal carcinoma treated with concurrent radiochemotherapy and correlated factors.
Impact of dose volume parameters and clinical factors on acute radiation oral mucositis for locally advanced nasopharyngeal carcinoma patients treated with concurrent intensity-modulated radiation therapy and chemoradiotherapy.
Predicting nomogram for severe oral mucositis in patients with nasopharyngeal carcinoma during intensity-modulated radiation therapy: a retrospective cohort study.
Associated risk factors of acute mucosa reaction in patients with nasopharyngeal carcinoma after radiotherapy and chemotherapy and application of OREM self-protection theory.
Correlation analysis between prognostic nutritional index before radiotherapy and severity of acute oral mucositis in patients with nasopharyngeal carcinoma.
] were rated as having moderate quality and moderate risk of bias. In addition, the funnel plots and Egger's linear regression indicated that there was no significant publication bias (p = .224) in these included studies (see supplemental material Fig. 1).
Meta-analysis
Incidence of radiotherapy-induced oral mucositis
A total of 20 studies with 4135 participants were included in the quantitative meta-analysis, and the incidence of radiotherapy-induced oral mucositis ranged from 50% to 100%. In detail, 16 studies reported that all the participants experienced radiotherapy-induced oral mucositis with an incidence of 100%. In addition, four studies [
Clinical observation of acute skin and oral mucous membrane reactions in patients with nasopharyngeal carcinoma treated with concurrent radiochemotherapy and correlated factors.
Associated risk factors of acute mucosa reaction in patients with nasopharyngeal carcinoma after radiotherapy and chemotherapy and application of OREM self-protection theory.
] reported that the incidences of oral mucositis were 98%, 90%, 84%, and 50%, respectively. As a high level of heterogeneity (I2 = 97%, p < .01) existed among these studies, a random-effect model was used to obtain more conservative results, and the pooled results (Fig. 2) showed that the incidence of radiotherapy-induced oral mucositis was 99% (95% CI: 96% to 100%).
Figure 2Forest Plot of Incidence of Radiotherapy-Induced Oral Mucositis. CI = Confidence Interval.
A sensitivity analysis was performed using a one-study-out method to test the stability and reliability of the pooled results. The pooled estimated incidence of radiotherapy-induced oral mucositis did not change significantly, ranging from 99% (95% CI: 96‒100%) to 100% (95% CI: 99‒100%) (see supplemental material Fig. 2).
Subgroup analysis
The results of the subgroup analysis showed that the incidences of mild and severe radiotherapy-induced oral mucositis were 46% (95% CI: 36‒55%, I2% = 97%) and 52% (95% CI: 43‒61%, I2% = 98%), respectively (Fig. 3). In addition, the subgroup analyses conducted based on the participant characteristics (gender, cancer stage, and treatment regimen) and study characteristics (study design, study language, sample size, and diagnostic criteria) showed that there were no significant differences no matter the participant and study characteristics (see supplemental material Table 2).
Figure 3(A) Forest Plot of Incidence of Mild Radiotherapy-Induced Oral Mucositis. (B) Forest Plot of Incidence of Severe Radiotherapy-Induced Oral Mucositis. CI = Confidence Interval.
Clinical observation of acute skin and oral mucous membrane reactions in patients with nasopharyngeal carcinoma treated with concurrent radiochemotherapy and correlated factors.
Impact of dose volume parameters and clinical factors on acute radiation oral mucositis for locally advanced nasopharyngeal carcinoma patients treated with concurrent intensity-modulated radiation therapy and chemoradiotherapy.
Associated risk factors of acute mucosa reaction in patients with nasopharyngeal carcinoma after radiotherapy and chemotherapy and application of OREM self-protection theory.
Correlation analysis between prognostic nutritional index before radiotherapy and severity of acute oral mucositis in patients with nasopharyngeal carcinoma.
Analysis of main associated factors of radiation therapy-induced oral mucositis during intensity-modulated radiotherapy among patients with nasopharyngeal carcinoma.
Predicting nomogram for severe oral mucositis in patients with nasopharyngeal carcinoma during intensity-modulated radiation therapy: a retrospective cohort study.
] did not report relevant data for meta-analysis. The potential risk factors from the included studies were categorized into demographic factors (gender and age), health-related factors (such as BMI, weight loss, oral pH, diabetes, cancer stage, and oral hygiene), and lifestyle-related factors (such as smoking and drinking). Among these factors, nine factors (oral hygiene, oral pH, the use of oral mucosal protective agents, smoking, drinking, overweight before radiotherapy, combined chemotherapy, and the use of antibiotics at early treatment stage, and diabetes) from 14 studies had data that could be used for quantitative meta-analysis. The pooled results showed that poor oral hygiene (OR = 4.78, 95% CI: 2.56‒8.91), oral pH < 7.0 (OR = 3.56, 95% CI: 2.58‒4.91), smoking (OR = 3.60, 95% CI: 2.59‒5.01), drinking (OR = 3.24, 95% CI: 1.92‒5.46), overweight before radiotherapy (OR = 4.72, 95% CI: 2.45‒9.09), and combined chemotherapy (OR = 7.89, 95% CI: 3.66‒16.99) were significant risk factors, while the use of oral mucosal protective agents (OR = .26, 95% CI: .14‒.48) and the use of antibiotics at early treatment stage (OR = .30, 95% CI: .13‒.68) were protective factors of radiotherapy-induced oral mucositis among patients with nasopharyngeal carcinoma. In addition, results showed that patient with diabetes (OR = 1.33, 95% CI: .45‒3.91) was a risk factor but with no statistical significance (Fig. 4).
Figure 4(A) Forest Plot of Odds Ratio of Poor Oral Hygiene. (B) Forest Plot of Odds Ratio of Oral pH < 7.0. (C) Forest Plot of Odds Ratio of the Use of Oral Mucosal Protective Agents. (D) Forest Plot of Odds Ratio of Smoking. (E) Forest Plot of Odds Ratio of Drinking. (F) Forest Plot of Odds Ratio of Overweight Before Radiotherapy. (G) Forest Plot of Odds Ratio of Combined Chemotherapy. (H) Forest Plot of Odds Ratio of the Use of Antibiotics. (I) Forest Plot of Odds Ratio of the Use of Diabetes. CI = Confidence Interval, BMI = Body Mass Index.
Figure 4(A) Forest Plot of Odds Ratio of Poor Oral Hygiene. (B) Forest Plot of Odds Ratio of Oral pH < 7.0. (C) Forest Plot of Odds Ratio of the Use of Oral Mucosal Protective Agents. (D) Forest Plot of Odds Ratio of Smoking. (E) Forest Plot of Odds Ratio of Drinking. (F) Forest Plot of Odds Ratio of Overweight Before Radiotherapy. (G) Forest Plot of Odds Ratio of Combined Chemotherapy. (H) Forest Plot of Odds Ratio of the Use of Antibiotics. (I) Forest Plot of Odds Ratio of the Use of Diabetes. CI = Confidence Interval, BMI = Body Mass Index.
Figure 4(A) Forest Plot of Odds Ratio of Poor Oral Hygiene. (B) Forest Plot of Odds Ratio of Oral pH < 7.0. (C) Forest Plot of Odds Ratio of the Use of Oral Mucosal Protective Agents. (D) Forest Plot of Odds Ratio of Smoking. (E) Forest Plot of Odds Ratio of Drinking. (F) Forest Plot of Odds Ratio of Overweight Before Radiotherapy. (G) Forest Plot of Odds Ratio of Combined Chemotherapy. (H) Forest Plot of Odds Ratio of the Use of Antibiotics. (I) Forest Plot of Odds Ratio of the Use of Diabetes. CI = Confidence Interval, BMI = Body Mass Index.
To our knowledge, this is the first meta-analysis to estimate the incidence and to explore risk factors for radiotherapy-induced oral mucositis among patients with nasopharyngeal carcinoma. Most of the included studies in our review were from China, which resulted from the extremely uneven geographical global distribution, with more than 70.0% new cases per year are in East and Southeast Asia [
]. High rates of nasopharyngeal carcinoma have long been observed in the population of Southern China, with an age-standardized rate (world) of 3.0/100000 [
Hepatitis B virus infection: an insight into the clinical connection and molecular interaction between hepatitis B virus and host extrahepatic cancer risk.
]. Although nasopharyngeal carcinoma is relatively uncommon compared with other cancers, it remains a significant public health problem in East and Southeast Asia [
]. Based on the comprehensive search strategy from eight electronic databases and systematic review of relevant studies, our study results provided evidence-based references for developing targeted preventive measures of radiotherapy-induced oral mucositis among patients with nasopharyngeal carcinoma.
Incidence of radiotherapy-induced oral mucositis
The pooled results of the meta-analysis revealed that almost all patients with nasopharyngeal carcinoma have experienced oral mucositis during the radiotherapy process, with a pooled incidence of 99.0%, and more than half (52.0%) of patients suffered from severe oral mucositis, which is as high as that among patients with head and neck cancers [
]. On the one hand, the persistent and concentrated high-dose irradiation can inevitably induce acute and chronic toxicity reactions including radiotherapy-induced oral mucositis [
] in spite of the modern advances in radiotherapy technology. On the other hand, currently, the consistent and targeted assessment tools for oral mucositis are insufficient [
], nurses are unable to evaluate radiotherapy-induced oral mucositis comprehensively during clinical practice, which might cause inadequate attention and underestimation of the severity of oral mucositis among patients with nasopharyngeal carcinoma. In addition, consistent with other countries in the world, patients with nasopharyngeal carcinoma in China usually are treated with outpatient radiotherapy, which means they were inaccessible to systemic and structured professional care and support compared to the inpatient setting [
A qualitative comparison of the nutrition care experiences of carers supporting patients with head and neck cancer throughout surgery and radiation treatment and survivorship.
], such as basic oral care, oral health education, and coping skills for oral mucositis. Thus, patients with nasopharyngeal carcinoma often suffer from high incidence of radiotherapy-induced oral mucositis, and it is urgent and necessary to pay more attention to nasopharyngeal carcinoma patients and take effective measures for the early identification and prevention of oral mucositis during their treatment process.
To test the reliability and stability of pooled results and explore the potential sources of heterogeneity, we also conducted subgroup analyses on the basis of participant characteristics (gender, cancer stage, and treatment regime) and study characteristics (study design, study language, sample size, and diagnostic criteria). The results showed that the incidence of radiotherapy-induced oral mucositis was similar within subgroups, which suggested that the results were stable and reliable, but there might be other possible sources of heterogeneity among these included studies. For example, the sample sources and age groups varied among the different studies, which might contribute to the high heterogeneity of our study.
Risk factors for severe radiotherapy-induced oral mucositis
This study identified eight significant risk factors for severe radiotherapy-induced oral mucositis among patients with nasopharyngeal carcinoma, including poor oral hygiene, oral pH less than 7.0, the use of oral mucosal protective agents, overweight before radiotherapy, smoking, drinking, combined chemotherapy, and the use of antibiotics.
Poor oral hygiene, oral pH less than 7.0, and the use of oral mucosal protective agents are three oral health-related risk factors for severe radiotherapy-induced oral mucositis, among which poor oral hygiene is the most significant risk factor. Previous studies also showed that the status of oral health and hygiene is a risk factor for radiotherapy-induced oral mucositis [
Relationship between oral mucositis and the oral bacterial count in patients with head and neck cancer undergoing carbon ion radiotherapy: a prospective study.
]. However, it was reported that 64.4% of patients who received radiotherapy had poor oral hygiene, and the proportion of poor oral hygiene was much higher among patients with oral mucositis (69.1%) than among patients without oral mucositis (42.9%) [
]. Oral health, starting with good oral hygiene, is essential for patient wellness, and providing oral health education and prevention interventions to promote good oral hygiene can prevent infection by oral bacteria and consequently could reduce the risk and severity of oral mucositis [
The effectiveness of an oral health education and prevention program on the incidence and severity of oral mucositis in pediatric cancer patients: a non-randomized controlled study.
]. In addition, previous studies have already identified that the use of oral mucosal protective agents and interventions promoting the oral pH to shift from an acidic to alkaline could enhance oral protection against mucositis and decrease the susceptibility to oral mucositis among patients [
The effect of cryotherapy on the prevention of oral mucositis and on the oral pH value in multiple myeloma patients undergoing autologous stem cell transplantation.
A bioadhesive barrier-forming oral liquid gel improved oral mucositis and nutritional status in patients with head and neck cancers undergoing radiotherapy: a retrospective single center study.
]. Thus, preventive strategies are needed to target facilitating oral health during and even prior to radiation treatment to decrease the risk and severity of oral mucositis among patients with nasopharyngeal carcinoma [
Factors associated with acute oral mucosal reaction induced by radiotherapy in head and neck squamous cell carcinoma: a retrospective single-center experience.
] conducted among patients with head and neck carcinoma also revealed that smoking was a risk factor for radiotherapy-induced oral mucositis. Although drinking was not identified as a risk factor in previous studies, alcohol use is one of the leading risk factors for a range of diseases and injury conditions, and there is even a causal relationship between them [
]. As common lifestyle-related risk factors, further targeted strategies and interventions are needed to reduce the utilization of tobacco and alcohol among patients.
This meta-analysis showed that overweight before radiotherapy was a risk factor for radiotherapy-induced oral mucositis, which was inconsistent with Saito et al. [
] who reported significant association between low BMI and oral mucositis. However, as oral mucositis might lead to anorexia, dysphagia, and low BMI during radiotherapy, it is difficult to confirm whether low BMI caused oral mucositis, or the oral mucositis resulted in low BMI. For our result, a previous study [
] has identified the significant correlation between overweight and poor oral conditions, and the possible mechanism is that adipose tissue could cause increased levels of IL-6, IL-8, and TNF- α, resulting in raised leukocytes, which might activate systemic inflammation. Therefore, overweight status before radiotherapy also might be the focus for preventing severe oral mucositis.
Our study showed that concomitant chemotherapy and the use of antibiotics at early treatment stage were treatment-related risk factors for radiotherapy-induced oral mucositis. Although identified as a potential protective factor of oral mucositis, the use of antibiotics at early treatment stage for prevention oral mucositis was not recommended by any guidelines to be used in the prevention of oral mucositis, and caution is needed for antibiotic utilization among patients [
]. Moreover, due to the toxicity of chemotherapeutics, patients who receive radiotherapy combined with chemotherapy can be definitely more prone to experiencing severe oral mucositis [
], and more attention is needed to patients who receive chemoradiotherapy when providing preventive measures of oral mucositis.
Limitations
Some limitations should be considered when interpreting the results: (1) due to the inconsistent characteristics among the included studies, high heterogeneity existed in our study; (2) some potential risk factors were not available for meta-analysis because they were reported in less than three studies, or reported with incomplete data; and (3) due to the geographical features of nasopharyngeal carcinoma, most of the studies included in our study were published in China. Wider researches with larger sample sizes are needed to further identify the incidence and risk factors for radiotherapy-induced oral mucositis.
Implications for further research and nursing practice
The results of this study showed that almost all nasopharyngeal carcinoma patients inevitably experienced radiotherapy-induced oral mucositis, and more than half of patients even suffered from severe oral mucositis during radiotherapy. Radiotherapy-induced oral mucositis poses negative effects on patients’ physical, emotional, and social dimensions and quality of life [
], which should be highly valued as an interdisciplinary problem during clinical practice. Therefore, interventions for effective management of oral mucositis should cover interdisciplinary professionals, including oncology, stomatology, psychology, and nutritional science. For instance, in addition to the symptom management of oral mucositis, it is also essential for regular clinical screening the risk of nutritional and psychological problems [
]. In addition, most risk factors for oral mucositis in our study were modifiable, including oral hygiene, oral pH, the use of oral mucosal protective agents, smoking, drinking, and overweight. Further studies and clinical practitioners should focus on the controllable risk factors and should accordingly develop targeted preventive measures for radiotherapy-induced oral mucositis among patients with nasopharyngeal carcinoma.
Conclusions
This study found that almost all patients with nasopharyngeal carcinoma have experienced radiotherapy-induced oral mucositis, and more than half of patients have suffered from severe oral mucositis during radiation therapy. Poor oral hygiene, oral pH less than 7.0, use of protective agents, smoking, drinking, overweight before radiotherapy, combined chemotherapy, and the use of antibiotics at early treatment stage are risk factors for severe radiotherapy-induced oral mucositis. Wider and larger well-designed studies are needed to explore the risk factors for radiotherapy-induced oral mucositis, and promoting oral health, especially good oral hygiene, might be the key focus of decreasing the risk and severity of radiotherapy-induced oral mucositis among patients with nasopharyngeal carcinoma.
Contributions
Study Design and writing: JJL, XLH and CMZ.
Data Collection: JJL, YZ, CG and QW.
Data Analysis and Interpretation: JJL, CMZ, YXD and XLH.
Manuscript Writing: JJL and XLH.
Funding
The study is supported by the National Natural Sciences Foundation of China (82172842 and 81803104), Sichuan Science and Technology Program and TianFu Laboratory (2022YFSY0012 and 2021ZYCD011), the National Key Research and Development Program of China (2021YFE0206600), the Post-Doctor Research Project, West China Hospital, Sichuan University (2020HXBH119), West China Nursing Discipline Development Special Fund Project, Sichuan University (HXHL21008), and the China Medical Board (Grant #22-482).
Ethical statement
Informed consent and ethical approval were unnecessary, as the data used in this study came from already published studies.
Data availability statement
The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.
Conflict of interest
No conflict of interest exists in the submission of this manuscript.
Acknowledgments
We would like to thank the Professor Mary for her support and guidance.
Appendix A. Supplementary data
The following is the Supplementary data to this article.
A randomized, controlled phase II trial of maxillofacial and oral massage in attenuating severe radiotherapy-induced oral mucositis and lipid metabolite changes in nasopharyngeal carcinoma.
Randomized, double-blind, placebo-controlled trial of shuanghua baihe tablets to prevent oral mucositis in patients with nasopharyngeal cancer undergoing chemoradiation therapy.
A network meta-analysis in comparing prophylactic treatments of radiotherapy-induced oral mucositis for patients with head and neck cancers receiving radiotherapy.
Factors associated with severe oral mucositis and candidiasis in patients undergoing radiotherapy for oral and oropharyngeal carcinomas: a retrospective multicenter study of 326 patients.
Analysis of main associated factors of radiation therapy-induced oral mucositis during intensity-modulated radiotherapy among patients with nasopharyngeal carcinoma.
Clinical observation of acute skin and oral mucous membrane reactions in patients with nasopharyngeal carcinoma treated with concurrent radiochemotherapy and correlated factors.
Impact of dose volume parameters and clinical factors on acute radiation oral mucositis for locally advanced nasopharyngeal carcinoma patients treated with concurrent intensity-modulated radiation therapy and chemoradiotherapy.
Predicting nomogram for severe oral mucositis in patients with nasopharyngeal carcinoma during intensity-modulated radiation therapy: a retrospective cohort study.
Associated risk factors of acute mucosa reaction in patients with nasopharyngeal carcinoma after radiotherapy and chemotherapy and application of OREM self-protection theory.
Correlation analysis between prognostic nutritional index before radiotherapy and severity of acute oral mucositis in patients with nasopharyngeal carcinoma.
Hepatitis B virus infection: an insight into the clinical connection and molecular interaction between hepatitis B virus and host extrahepatic cancer risk.
A qualitative comparison of the nutrition care experiences of carers supporting patients with head and neck cancer throughout surgery and radiation treatment and survivorship.
Relationship between oral mucositis and the oral bacterial count in patients with head and neck cancer undergoing carbon ion radiotherapy: a prospective study.
The effectiveness of an oral health education and prevention program on the incidence and severity of oral mucositis in pediatric cancer patients: a non-randomized controlled study.
The effect of cryotherapy on the prevention of oral mucositis and on the oral pH value in multiple myeloma patients undergoing autologous stem cell transplantation.
A bioadhesive barrier-forming oral liquid gel improved oral mucositis and nutritional status in patients with head and neck cancers undergoing radiotherapy: a retrospective single center study.
Factors associated with acute oral mucosal reaction induced by radiotherapy in head and neck squamous cell carcinoma: a retrospective single-center experience.
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