Abstract
Background:
Oral mucositis (OM) is a common and severe side effect of radiotherapy in head and neck cancer (HNC). The study aimed to investigate the longitudinal changes in OM and its influencing factors in patients with HNC during radiotherapy.
Methods:
This was a retrospective longitudinal observational study. From July 2022 to March 2023, patients with HNC undergoing radiation therapy were enrolled. OM, oral hygiene, oral infections, oral pain, feeding route, and laboratory indicators were measured at 7 times. The influencing factors of OM were analyzed using generalized estimation equations (GEEs).
Results:
A total of 160 patients were included in this study. The prevalence of severe OM at T0, T1, T2, T3, T4, T5, and T6 was 0, 0, 2.5%, 9.4%, 26.9%, 24.4%, and 26.9%, respectively. The prevalence of grade 1-2 OM at T0, T1, T2, T3, T4, T5, and T6 was 0, 16.3%, 53.1%, 65.1%, 61.9%, 70.7%, and 71.3%, respectively. Duration of diagnosis, clinical stage, N stage, M stage, surgery, diabetes, radiotherapy dose, oral hygiene, oral infection, oral pain, feeding route, and lymphocyte impacted OM significantly in the GEEs multivariate model.
Conclusions:
OM occurs in almost all patients with HNC who undergo radiotherapy. Changes in the severity of OM are a dynamic process, with the severity increasing with the cumulative radiotherapy dose. Specialist oral evaluation and oral care are needed to alleviate the severity of OM in HNC patients.
Introduction
Head and neck cancer (HNC) is a broad term encompassing epithelial malignancies from the paranasal sinuses, nasal cavity, oral cavity, pharynx, larynx, and salivary glands. 1 Radiotherapy is the most essential treatment for HNC. However, radiation kills neoplastic tissues and destroys surrounding normal tissues, causing damage to the mucous membrane of the mouth and pharynx, which in turn leads to oral mucositis (OM). OM is a common and severe side effect in HNC patients undergoing radiotherapy, with an incidence of 85%-100%.2,3 A retrospective multicenter study of 326 patients 4 showed that the incidence of grade 1, 2, and 3 OM was 5.8%, 51.5%, and 41.7%, respectively. Clinically, sequelae of OM include significant pain, dysphagia, dehydration, dysgeusia, anorexia, considerable weight loss, increased susceptibility to secondary and systemic infections, interruptions of radiotherapy, and compromised treatment efficacy and outcomes. 5 Reducing the incidence and alleviating the severity of OM is an urgent issue to be addressed.
Historically, risk factors for OM have been attributed to patient, disease, and treatment-related characteristics. 6 Previously known risk factors, such as: age, gender, smoking status, nutritional status, diabetes, and concurrent chemoradiotherapy, remain controversial.4,7-16 Furthermore, inflammatory cells and associated hematological indicators were also significantly associated with OM.4,7,8,17 Therefore, it is incomplete to explore only the impact of patient, disease, and treatment-related factors on OM. Furthermore, most of those studies were cross-sectional studies7,8,18 that could not reflect the trend of OM over time and provide direct evidence of causality. Longitudinal studies can compensate for the shortcomings of cross-sectional studies and demonstrate the trajectory of OM during radiotherapy. Chen et al. 9 and Thomas et al. 19 investigated longitudinal changes in the prevalence of OM, but sample sizes were limited in their studies. The objectives of the study were to investigate the OM trajectory and to identify factors that contribute to predicting the development of OM in patients with HNC during radiotherapy.
Methods
Data Source and Patient Selection
This was a retrospective longitudinal observational study. The study was approved by the ethics committee of the Xiangya Hospital Central South University (No. 2022060874). All data were obtained from the medical records of HNC patients who had undergone radiotherapy from July 2022 to March 2023 in the Xiangya Hospital Central South University. The inclusion criteria were as follows: (1) diagnosed as HNC through pathological reports; (2) age ≥18 years; (3) agreed to radiotherapy and signed informed consent; and (4) no mental or intellectual impairment. Patients were excluded if they had other malignant tumors, incomplete clinical data, or OM existed before radiotherapy.
The researchers assessed the oral-related characteristics, the laboratory test results and the severity of OM at 7 time points: baseline (before radiotherapy) and 1, 2, 3, 4, 5, and 6 weeks after starting radiotherapy (T0, T1, T2, T3, T4, T5, and T6, respectively).
Sampling
The sample size was calculated by referring to the table provided by Barcikowski and Robey 20 in the single-group repeated measures analysis. This study required 7 repeated measures: if the mean correlation coefficient was 0.50, the effect size was 0.14, the significance level was 0.05, and finally, the sample size was 106 cases. Considering 10%-20% missed visits and invalid questionnaires, a sample size of 117-127 cases was required for this study.
Survey Instruments
Demographic and Clinical Characteristics
The following demographic and clinical characteristics were collected from medical records: demographic characteristics [gender, ethnicity, age, body mass index (BMI), education level, years of smoking, years of drinking, years of betel nut chewing, occupational status, marital status, sleep status, and place of residence]; disease-related factors (cancer type, duration of diagnosis, degree of differentiation, clinical stage, T stage, N stage, M stage, number of comorbidities, diabetes, dental caries, length of hospitalization); and treatment-related factors (surgery, concurrent chemoradiotherapy, targeted therapy, and radiotherapy dose). The duration of diagnosis refers to the time it takes for a patient from being diagnosed with HNC to receiving radiotherapy. The clinical stage followed the recent 8th edition of American Joint Committee on Cancer TNM staging system (AJCC TNM) staging.
Oral-Related Characteristics
Oral-related characteristics included oral hygiene, oral pain, oral infection, and feeding route. Oral hygiene was classified into 3 grades: clean, without materia alba visible with the naked eye; general, with food debris or materia alba visible in ≤3 tooth positions; and poor, with food debris, materia alba visible in >3 tooth positions or with gingivitis. 21 Diagnostic criteria for oral infection 22 : (1) histopathological examination or surgical confirmation; (2) purulent secretions in the oral cavity; (3) diagnosed by a physician and treated with oral antifungal therapy. Oral infection can be diagnosed if any of the above criteria are met. The Numerical Rating Scale was used to evaluate patients’ pain on a scale from 0 to 10 where 0 indicates no pain and 10 reflects the worst possible pain. Pain scores are interpreted as: 0, no pain; 1-3, mild pain; 4-6, moderate pain; 7-10, severe pain. 23
Laboratory Tests
Laboratory test results include leukocyte, erythrocyte, hemoglobin, platelet, neutrophil, lymphocyte, monocyte, neutrophil percentage, total protein, albumin, globulin, and creatinine.
OM Assessment
The patient’s OM grade was assessed according to the World Health Organization OM grading criteria: grade 0, no change; grade 1, soreness/erythema; grade 2, erythema, ulcers, can eat solids; grade 3, ulcers with liquid diet only; and grade 4, alimentation not possible.
Treatment Plan
All HNC patients received radical intensity-modulated radiotherapy (IMRT) with a 6 MV X-ray. Patients underwent radiotherapy 5 times a week from Monday to Friday for 6-7 weeks. Some patients were treated with platinum-based agents for concurrent chemotherapy or nimotuzumab for concurrent targeted therapy.
Oral Management Associated with Radiotherapy
All patients received professional oral administration during radiotherapy. Oral assessment was performed regularly for HNC patients undergoing radiotherapy. According to the results of the evaluation, the charge nurse provided professional oral care to patients with poor oral condition, such as wiping the teeth with water-drenched cotton balls to keep the oral cavity as clean as possible, choosing an appropriate mouthwash, and instructing patients to rinse their mouth correctly, including clean water, physiological saline, lidocaine, nystatin, Kangfuxin lipid, compound chlorhexidine, sodium bicarbonate, etc. Professional oral management was continued until the end of the radiotherapy treatment or hospital discharge.
Statistical Analysis
All data were analyzed using IBM SPSS version 25.0 (IBM Corporation, Chicago, IL, USA). Continuous variables were described as mean (M) and standard deviation (SD). Categorical variables were described as frequency or percentage. Repeated-measures analysis of variance was used to describe changes in laboratory indicators over time. The influencing factors of OM were analyzed by generalized estimation equations (GEE). The significant level was established at α = .05 (two-sided).
Results
Demographic and Clinical Characteristics
A total of 160 patients were included in this study. The mean age of the patients was 51.73 years (SD = 11.63), and the majority were men (81.9%). Most of the patients had a BMI between 18.5 and 23.9 (62.5%). Of these patients, 57.5% were smoking, 40.7% were drinking, and 25.5% were betel nut chewing. Most of the patients were diagnosed with oral cancer (40.0%) and nasopharyngeal cancer (39.4%). About 87.5% of the patients were in the advanced stage (stages III and IV). 55.6% of the patients received surgery, 61.3% received concurrent chemoradiotherapy, and 28.8% received targeted therapy. The mean total dose of radiotherapy was 65.15 Gy (SD = 7.95). Other information is shown in Table 1.
Demographic and Clinical Characteristics.
Changes in OM and Oral-Related Characteristics
Table 2 shows the changes in the OM and oral-related characteristics of patients over time. A grade of 3 or 4 indicates severe OM. The prevalence of severe OM at T0, T1, T2, T3, T4, T5, and T6 was 0, 0, 2.5%, 9.4%, 26.9%, 24.4%, and 26.9%, respectively. The prevalence of severe OM increased from T0 to T4, peaked at T4, decreased at T5, and again peaked at T6. The prevalence of grade 1-2 OM at T0, T1, T2, T3, T4, T5, and T6 was 0, 16.3%, 53.1%, 65.1%, 61.9%, 70.7%, and 71.3%, respectively. The prevalence of grade 1-2 OM increased from T0 to T3, decreased at T4, increased again at T5 and T6, and reached its peak at T6. With increasing doses of radiotherapy, oral hygiene gradually changed from clean to general; the oral pain gradually changed from painless to mild pain; a few patients changed from oral feeding to tube feeding.
Changes in OM and Oral-Related Characteristics.
Abbreviation: PN, parenteral nutrition.
Changes in Laboratory Test Results Over Time
Table 3 shows the changes in different laboratory indicators over time. Repeated measures analysis of variance showed statistically significant differences in leukocytes, erythrocytes, hemoglobin, platelets, lymphocytes, neutrophil percentage, total protein, albumin, and globulin within each period.
Changes in Laboratory Test Results at 7 Time Points.
Statistically significant (P < 0.05).
GEE Modeling to Estimate Factors Influencing OM
GEE was used to estimate the impact of each variable on OM. The univariate results indicated that years of betel nut chewing, occupational status, cancer type, duration of diagnosis, degree of differentiation, clinical stage, N stage, M stage, diabetes, surgery, radiotherapy dose, oral hygiene, oral infection, oral pain, feeding route, platelet, lymphocyte, neutrophil percentage, total protein, albumin, and globulin affected OM, as shown in Table 4. The variables that were statistically significant in the univariate analysis were entered into the multivariate model, and we revealed the essential factors that influenced OM, including duration of diagnosis, clinical stage, N stage, M stage, surgery, diabetes, radiotherapy dose, oral hygiene, oral infection, oral pain, feeding route, and lymphocyte, as shown in Table 5.
Generalized Estimation Equation (GEE) Univariate Analysis.
Abbreviations: SE, standard error; OR, odds ratio; CI, confidence interval.
Reference group.
Statistically significant (P < .05).
Generalized Estimation Equation (GEE) Multifactorial Analysis.
Abbreviations: SE, standard error; OR, odds ratio; CI, confidence interval.
Reference group.
Statistically significant (P < .05).
Discussion
Mucositis is a biologically complex process that involves a dynamic and interactive sequence of pan-mucosal events that ultimately target epithelial stem cells. Chemotherapy-induced mucositis usually develops within 4–7 days after initiation of treatment and peaks within 2 weeks; radiation-induced mucositis usually begins at cumulative doses of approximately 15 Gy (after around 10 days) and reaches full severity at 30 Gy, lasts for weeks or even months. 24 An increase in the dose of radiotherapy affects the prevalence of OM. Our study found that the prevalence of severe OM at T0, T1, T2, T3, T4, T5, and T6 was 0, 0, 2.5%, 9.4%, 26.9%, 24.4%, and 26.9%, respectively, which were similar to those of Costa et al. 25 On the contrast, some studies are not entirely consistent with our findings. Chen et al. 9 found that the prevalence of severe OM at T0, T1, T2, T3, T4, T5, T6, T7, and T8 was 1.3%, 3.9%, 20.8%, 61.0%, 77.9%, 88.3%, 87.0%, 62.3%, and 33.8%, respectively. These differences may be related to cumulative radiotherapy doses, heterogeneity of the sample, and oral management practices during radiotherapy. In summary, the findings will be useful for healthcare professionals in providing interventions during acute radiation care based on the optimal timing of mucositis management.
The severity of OM was strongly associated with the duration of diagnosis, clinical stage, N stage, M stage, diabetes, surgery, radiotherapy dose, oral hygiene, oral infection, oral pain, feeding route, and lymphocytes.
The risk of OM was significantly higher in patients with a duration of diagnosis ≥4 years and a clinical stage of II, III, or IV. This reason may be related to the fact that the number of people in the advanced stage increases with the duration of the diagnosis and thus requires a higher dose of irradiation. It has been reported that a higher single dose in a short period tends to initiate early irradiation damage that causes more sensitivity to further exposure to irradiation, more significant early reactions, and tissue damage.15,26 Also, N stage and M stage of cancer were equally used as risk factors for OM, possibly because cancers with lymph node involvement or metastases usually require a higher dose of radiation.
Diabetes has been recognized as an essential risk factor for acute radiation oral mucosal reaction due to microvascular changes in the gingiva and alveolar mucosa. Microvascular changes include the capillary basement membrane’s thickening, the lumen’s narrowing, and peri-endothelial thickening and stasis in the microcirculation. 10 Besides modifying the vascular wall, defective leukocyte chemotaxis and abnormal collagen synthesis in diabetic patients may contribute to oral infection and impaired mucosal wound healing during radiotherapy.27,28 Furthermore, hyposalivation due to glycosuria may also worsen OM. 29 Therefore, patients with HNC combined with diabetes should be careful to control their blood glucose during radiotherapy to prevent or alleviate the severity of OM.
Surgical treatment remains essential for modern cancer therapy, including HNC. However, surgical patients are at greater risk of developing OM, which is possible because postoperative vascular function is insufficient, and surgical treatment of advanced-stage lesions can produce numerous oral functional sequelae, including difficulty tasting, speaking, chewing, and swallowing.8,30 Radical radiotherapy is the core of HNC treatment and is closely related to the occurrence of OM. Several radiotherapy factors related to OM include radiotherapy fractionation, radiotherapy dose, and radiotherapy technique. The effect of higher single radiotherapy doses on OM has already been discussed. IMRT, an upgrade of three-dimensional conformal radiotherapy, rapidly replaces conventional radiotherapy as the primary radiotherapy technique for the treatment of HNC due to its better dose distribution and better protection of surrounding tissues. 31 However, numerous studies have shown that the prevalence of OM remains high in patients with HNC treated with IMRT, with more than 50% of patients experiencing severe OM. 32 Sonis et al. 33 demonstrated that approximately 11% of patients suspended radiotherapy due to severe OM. The 1-day interruption of radiotherapy reduced tumor control by at least 1%. 34 Therefore, it is crucial to understand the trajectory of OM in HNC patients undergoing radiotherapy so that healthcare professionals take timely interventions to alleviate the severity of OM and improve the prognosis of the patient.
Oral microbial communities are crucial to maintain oral homeostasis, protecting the oral cavity, and preventing disease development. 35 Reyes-Gibby et al. 36 noted that oral microbial features were associated with the time to the onset of severe OM in patients with HNC. Poor oral hygiene can lead to dysbiosis of the oral microbiota, making it more susceptible to changes in resident oral bacteria and concurrent infections, thus aggravating OM. Our study considered poor oral hygiene as a risk factor for OM, consistent with the findings of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology Clinical Practice Guidelines. 37 The presence of infectious pathogenic microorganisms in the oral cavity increases the severity of mucositis, and prevention of OM requires a reduction in the bacterial load in the oral cavity, which can be achieved with antiseptic mouthwash.
Painful OM frequently occurs, leading to inadequate oral food intake and thus requiring excessive enteral nutrition or PN. Our study found a higher risk of OM in patients receiving tube feeding or PN compared to oral feeding. The incidence of significant mucositis was reported to be 76% in the 91 patients with feeding tubes at 1 month of treatment. 38 Inpatients receiving nasogastric tubes for nutritional support are prone to several complications, including nasal, pharyngeal, and laryngeal irritation, mucosal ulceration, and aspiration. 38 PN is considered complementary to enteral nutrition. However, metabolic complications associated with PN include hyperglycemia, hypoglycemia, hyperlipidemia, hypercapnia, acid-base disorders, and liver complications, which may lead to a higher prevalence of OM. 39 Therefore, clinical staff need to enhance oral management of patients with tube feeding or PN.
Total peripheral blood lymphocytes reflect the nutritional status and inflammatory response in the body and are correlated with tumor immune surveillance. It often decreases to varying degrees after stressful events such as surgery, trauma, and radiotherapy. Lower lymphocyte counts before radiotherapy predict severe OM. 8 In addition, the high neutrophil-to-lymphocyte ratio, which may be caused by lower lymphocyte counts, is an important predictor of death in patients with HNC and is strongly associated with severe radiation mucositis.7,17,40,41
There are several limitations to this study. First, all participants were enrolled before radiotherapy and followed up until the end of the radiotherapy. However, most of them continued to suffer from OM after completing radiotherapy. Future studies should extend the follow-up period. Second, this is a retrospective longitudinal study, and there may be information bias in data recording. In the future, prospective longitudinal studies could be conducted to investigate risk factors for OM. Finally, the results may not generalize nationally, since our samples come from a single hospital in China. Multicenter studies should be conducted to explore the trajectory of OM in the future.
Conclusion
OM occurs in almost all HNC patients undergoing radiotherapy. Changes in the severity of OM are a dynamic process, with the severity increasing with cumulative radiotherapy dose. Duration of diagnosis, clinical stage, N stage, M stage, surgery, diabetes, oral hygiene, oral infection, oral pain, feeding route, radiotherapy dose, and lymphocytes are crucial factors affecting the OM of patients with HNC. A supportive care plan, including patient-specific oral assessment, oral care, patient education, nutrition, and food choice to prevent malnutrition, may be the means to be better manage OM.
Footnotes
Author Contributions
Meizi Liu: Conceptualization, Methodology, Formal analysis, Investigation, Writing—Original draft preparation. Ran An: Conceptualization, Methodology, Investigation, Writing—Review and Editing. Zitong Wu: Investigation. Leping Dai: Investigation. Qiaomiao Zeng: Investigation. Wenfeng Chen: Conceptualization, Methodology, Writing—Review and Editing, Supervision, Funding acquisition.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Hunan Provincial Health Commission (grant number D202309038051).
Data Availability
The data, which support the findings of this study, are available from the corresponding author on a reasonable request.