Summary
Background
Episil is a type of barrier-forming gel. This study was to observe the effects of Episil on oral mucositis (OM) and nutritional status in patients with head and neck cancer (HNC) receiving radiotherapy.
Methods
A multicenter and randomized controlled trial included 200 intention-to-treat patients across 7 medical centers in China from February 2022 to June 2024. HNC patients eligible for enrollment were randomly divided into control group and Episil group by 1:1. When the patients developed OM, the control group was gargled with oral gargle solution and the Episil group were sprayed with Episil after using the same gargle intervention. The primary endpoint was incidence of advanced OM, and secondary endpoints were pain relief, nutritional status, overall survival (OS), progression-free survival (PFS), immune function, quality of life (QOL), psychology status and other adverse effects. This trial was registered with Chinese Clinical Trials Registry (URL: https://www.chictr.org.cn/bin/project/edit?pid=136241); accession no: ChiCTR2100055088.
Findings
A total of 200 patients were enrolled from 2022 to 2024, including 100 in the control group and 100 in the Episil group. The incidence of Grade III/IV OM in the Episil group was lower than that in the control group (4/100, 4% vs. 14/100, 14%, P = 0.024). The intensity decline of oral pain at 2 h (P < 0.0001) and 4 h (P < 0.0001) after first drug therapy of Episil group was better than control group. After 4 weeks of radiotherapy (Week 4), the weight loss, the loss of body mass index (BMI) and the loss of pre-albumin in the Episil group were lower than those in the control group (P = 0.036, P = 0.040, P = 0.0040). The EORTC QLQ-C30 global health status score of QOL at Week 4 was better in the Episil group than in the control group (65.00 (5.17) vs. 60.02 (5.38), P < 0.0001). No significant difference in the incidence of other adverse reactions was detected between the control group and Episil group (all P > 0.05).
Interpretation
Episil was shown to delay advanced OM and oral pain in HNC patients undergoing radiotherapy, while improving nutritional status and QOL. Larger prospective multi-national studies are required for further investigation.
Funding
This study was funded by the Jilin Province Health Science And Technology ability improvement program (grant numbers: 2024A021), The First Hospital of Jilin University Talent Reserve Program (grant numbers: JDYY-TRP-2024012) and Jilin Province Medical and Health Talents Special Foundation (grant numbers: JLSWSRCZX2023-68 and JLSRCZX2025-042).
Keywords: Episil, Head and neck cancer, Radiotherapy, Oral mucositis, Nutritional status
Research in context.
Evidence before this study
Radiation-induced oral mucositis (OM) is very common in head and neck cancer (HNC) patients. We searched PubMed for clinical trials published from database inception until April 17, 2025, using search terms of “head and neck cancer” and “radiation-induced oral mucositis”. Current drugs for radiation-induced OM have limited effectiveness and are prone to side effects.
Added value of this study
This study is a randomized, controlled, multicenter clinical trial that investigated the role of bioadhesive barrier-forming gel called Episil in HNC patients undergoing radiotherapy. Our results show that Episil can improved OM and oral pain symptoms in HNC patients undergoing radiotherapy, while improving nutritional status and QOL.
Implications of all the available evidence
If confirmed in larger trials, these results could provide the basis and reference for the treatment of mucositis induced by radiotherapy in patients with HNC.
Introduction
Radiation-induced oral mucositis (OM) refers to the damage of oral mucosa after radiotherapy, which is characterized by hyperemia, erosion and ulceration.1, 2, 3 OM can often cause unbearable oral pain in patients, which not only significantly affects nutritional status and rest, but also reduces tolerance and compliance to anti-tumor therapy, affecting quality of life (QOL) and treatment effect.4, 5, 6 The prevalence of malnutrition in head and neck cancer (HNC) patients is between 50% and 70%.7, 8, 9 In addition to the symptomatic factors of dysphagia caused by the primary tumor, radiation-induced OM may be the main cause of malnutrition.10, 11, 12
Episil is a type of bioadhesive barrier-forming gel. After spraying into the oral mucosal wound, a protective film is formed to cover the ulcer surface and play a role in pain relief and wound healing.13,14 The effect of Episil on radiation-induced OM has been reported. A multicenter, randomized, single-use, position-controlled clinical trial demonstrated that patients with radiation-induced OM who received Episil had significantly better local analgesia within 6 h than those who received other oral ulcer gargles.15 The results of our single-center retrospective clinical study show that Episil can effectively improve OM and malnutrition in HNC patients undergoing radiotherapy.16 However, there is a lack of large sample multicenter randomized controlled trials to further confirm the effect of Episil.
Therefore, we conducted a randomized, controlled, multicenter clinical trial, to evaluate the effectiveness of Episil in improving OM and nutritional status in HNC patients undergoing radiotherapy.
Methods
Ethics
This multicenter, prospective, randomized controlled trial was approved by the Ethics Committee of the First Hospital of Jilin University (ethical approval number: 21K111-002) and was conducted in accordance with the Declaration of Helsinki. The study protocol was registered at the Chinese Clinical Trials Registry (https://www.chictr.org.cn/bin/project/edit?pid=136241; ChiCTR-ID: ChiCTR2100055088) and was explained to all patients; a written informed consent was obtained. We used eCRF to record the trial data of the patients. At the same time, all confidential information related to the trial shall be kept confidential. If the patient suffers any injury due to participating in the trial, the Department of Radiotherapy of the First Hospital of Jilin University will be responsible for the compensation. The specific compensation will cover the expenses related to adverse reactions.
Participants
Between February 2022 and July 2024, patients with HNC admitted to seven centers were screened and enrolled. The inclusion criteria were as follows: (1) HNC diagnosed via histopathology requiring radiotherapy; (2) Age must be over 18 years old; (3) Eastern Cooperative Oncology Group (ECOG) score ≤3. The exclusion criteria were as follows: (1) The patient had serious endocrine or metabolic diseases; (2) Have underlying diseases associated with oral infections; (3) A treatment that may cause an oral infection is being used. When selecting the subjects, we comprehensively considered factors such as the disease, economy and family environment, in order to ensure that subjects with good compliance were selected. Meanwhile, during the informed consent process, we provided detailed explanations to the subjects and their families in order to enhance their trust in the treatment plan. After participating in the clinical trial, the subjects were required to strictly follow the trial procedures and promptly informed the doctor of any physical discomfort they experience (Fig. S3). Furthermore, the subjects helped to promote and publicize the trial through WeChat groups and forums.
Sample size
This experiment employed a difference test method to compare whether Episil could reduce the incidence rate of advanced OM (Grade III/IV). Based on previous research results, the incidence rate of advanced OM (Grade III/IV) during radiotherapy among those receiving conventional treatment for HNC patients was 50.0%. It was hypothesized that the incidence rate of advanced OM (Grade III/IV) among those receiving Episil could be reduced to 27.0%. Specific parameters include: α = 0.05 (two-tailed), power = 0.9. This data was calculated by the PASS software. The required sample size for each group between the control group and the Episil group is 92 cases. Considering 8% loss rate, the sample size for each group should be 100 cases, and the final sample size is 200 cases.
Randomization method
This was a randomized controlled trial. After the subjects signed the informed consent form and were formally enrolled, the randomization grouping began. The specific randomization time was two weeks before the start of radiotherapy treatment. Subjects who met inclusion criteria were randomly assigned to two groups including control group and Episil group by 1:1. The allocation method of the experiment adopted a hidden allocation mechanism, and the random sequence is generated on the computer by a third party who does not participate in the experiment. The random sequence was generated by SPSS software and randomly permuted blocks. The size of the block was four. After the randomization began, the doctors sent the subject's information to a third-party researcher. The third-party researcher then allocated the next treatment on the list and notified doctors.
Intervention for OM
There was no difference in the initial intervention period between the two groups of patients. When the patients developed OM about 2 weeks after radiotherapy, the control group was gargled with 10 ml oral gargle called Kangfuxin solution for 10 min each time, 3 times/day. Kangfuxin is an extract from the dried body of the American cockroach. Its main components include polyols and small molecule peptide active substances. It plays an important role in anti-inflammation, pain relief, and antibacterial activities. After using the same gargle, the patients in the Episil group were then sprayed with Episil oral gel to form a gel protective film in the mouth, 3 times/day. The duration of treatment intervention was from the onset of OM to the disappearance of OM after radiotherapy. During the treatment period, both groups of patients were prohibited from using any other oral gargle or oral gel medications. When adverse reactions occur in either of the two groups of patients due to the use of the intervention drugs, the medication will be stopped immediately without the need to reduce the dosage first. When both groups of patients present with Grade III or higher OM and infection symptoms, antibiotic or antifungal intervention may be considered based on the pharyngeal swab culture and drug sensitivity results of patients. Meanwhile, the dosage of the Episil oral gel in the Episil group and the oral gargle in the control group did not require any additional adjustment.
Endpoints
Incidence of advanced OM
The primary endpoint was incidence of advanced OM (Grade III/IV). OM was evaluated every week by the wound care team during radiotherapy. We eventually conducted a statistical analysis of the most severe OM condition experienced by the patients during their treatment. We did not use blindness in the evaluation of OM. Despite being an open label condition, our evaluation of OM was fair. In addition, the wound-care team was composed of multiple senior professors and nurses. We tried to avoid bias caused by personal subjective factors. According to the Radiation Therapy Oncology Group criteria,17 The rating for radiation-induced OM scoring are as follows: (1) Grade 0: No change; (2) Grade I: Congestion or mild pain. No need for analgesic; (3) Grade II: Lamellar mucositis, inflammatory secretion. Moderate pain that requires analgesic intervention; (4) Grade III: Confluent mucositis. Severe pain; (5) Grade IV: Ulcer, bleeding, or necrosis. We defined OM of Grades 0, I and II as lower OM, while Grades III and IV were defined as advanced mucositis. In addition, we did not conduct subgroup analysis or sensitivity analysis settings in this trial.
Pain relief
We evaluated the pain relief of the control group and Episil group after the initial medication intervention. All patients were evaluated for oral mucosal pain at different time points including baseline, 30 min, 1 h, 2 h, 4 h, 1 day, 2 days and 3 days after medication. Oral mucosal pain was assessed using Likert scale scores. These represent the range of pain intensity using numbers from 0 to 10. 0 indicates no pain, 1–3 represents mild pain, 4–6 indicates moderate pain, 7–10 indicates severe pain, and 10 represents the most intense imaginable pain.
Nutritional status
Nutritional status was assessed based on nutrition-related hematological indicators, body mass index (BMI) score, body weight change, and patient-generated subjective global assessment (PG-SGA) scores. Hematological markers associated with nutrition include hemoglobin, pre-albumin, and total lymphocyte count. The nutritional status of patients was assessed three times during the trial: before radiotherapy, four weeks after the start of radiotherapy (Week 4), and seven weeks after the start of radiotherapy (Week 7).
Survival assessment
Survival measures included overall survival (OS) and progression-free survival (PFS).
Immune function
Immune function was evaluated based on lymphocyte subsets (T cell CD3+, B cell CD19+ and CD4+/CD8+) and total lymphocyte count.
QOL and psychology assessment
The European Organization for Research in Treatment of Cancer QOL (EORTC QLQ-C30) scale was used to assess the score of QOL mainly considering global health status, with higher scores indicating better QOL. We used the distress thermometer (DT) and Hospital Anxiety and Depression Scale (HADS) to conduct psychological assessment of the patients. The higher the score, the worse the psychological state of the patients.
Other adverse reactions
Other adverse reactions were also recorded during the trial, including xerostomia, radiation-induced caries, osteoradionecrosis, vomiting, nausea, ototoxicity and neurotoxicity.
Statistics
All trial data were statistically analyzed using IBM SPSS Statistics version 24.0 software. Categorical variables data were expressed as numbers and percentages (%). Continuous variables data were expressed as mean (standard deviation) and methodology based on Student t-tests were applied to calculate mean differences between the groups, 95% confidence intervals and tests of significance. We compared the data of categorical variables between groups by the Cochran–Armitage test and Fisher's exact test. Kaplan–Meier curves described OS and PFS outcomes over time in the treatment, differences were tested by log-rank test and the interarm hazard ratio (HR) was estimated using Cox proportional hazards model.
Trial oversight and monitoring
This trial had a dedicated data monitor. The data monitor followed the standard operating procedures to supervise the conduct of the clinical trial and verified that all data were recorded and reported accurately and completely. All electronic case report forms were entered promptly and correctly, and were consistent with the original data, ensuring that the trial was carried out in accordance with the clinical research protocol. Meanwhile, the Ethics Committee of the First Hospital of Jilin University, acting as the coordinating center and the data monitoring committee (DMC), was responsible for the coordination of the trial and the continuous review of all data tracking. Annual submission of trial data and progress reports was required.
Role of the funding source
The funder of the study had no role in the study design, patient recruitment, data collection, data analysis, data interpretation, manuscript writing or the decision to submit the study for publication.
Results
Subject characteristics
Of the 210 HNC patients screened during the study, 200 patients met the inclusion criteria (Fig. 1). No patients dropped out during the study, and no data was missing for any reported variables. The characteristics of the patients in control group and Episil group at the baseline of the study were shown in Table 1.
Fig. 1.
Flowchart of patient eligibility. Reasons for exclusion included exceeding the age limit; underlying severe diseases associated with oral infections.
Table 1.
Baseline characteristics of control group and Episil group.
| Characteristics | Control group (n = 100) | Episil group (n = 100) |
|---|---|---|
| Age (years) | 60.3 (8.5) | 58.4 (9.1) |
| Sex ratio (M/F) | 79/21 | 80/20 |
| Weight (kg) | 66.2 (13.7) | 65.6 (11.2) |
| Body mass index (kg/m2) | 22.9 (4.1) | 23.2 (4.2) |
| PG-SGA (score) | 1.81 (1.09) | 1.63 (0.76) |
| Albumin (g/L) | 41.06 (4.88) | 40.74 (5.57) |
| Pre-albumin (g/L) | 0.258 (0.050) | 0.254 (0.052) |
| Hemoglobin (g/L) | 134.8 (17.3) | 133.6 (16.7) |
| Total lymphocyte count | 1.60 (0.75) | 1.53 (0.53) |
| T cell CD3+ (%) | 72.7 (9.0) | 71.5 (11.9) |
| CD4+/CD8+ | 1.53 (0.82) | 1.59 (0.86) |
| B cell CD19+ (%) | 9.49 (3.83) | 9.80 (4.05) |
| Cancer type | ||
| Nasopharyngeal carcinoma (%) | 27 (27%) | 29 (29%) |
| Oropharyngeal cancer (%) | 8 (8%) | 15 (15%) |
| Oral cavity cancer (%) | 17 (17%) | 13 (13%) |
| Hypopharyngeal cancer (%) | 17 (17%) | 19 (19%) |
| Laryngeal cancer (%) | 23 (23%) | 17 (17%) |
| Other cancer (%) | 8 (8%) | 7 (7%) |
| T-stage | ||
| T0–T2 (%) | 35 (35%) | 28 (28%) |
| T3–T4 (%) | 65 (65%) | 72 (72%) |
| N-stage | ||
| N0–N2 (%) | 85 (85%) | 82 (82%) |
| N3 (%) | 15 (15%) | 18 (18%) |
| M-stage | ||
| M0 (%) | 95 (95%) | 93 (93%) |
| M1 (%) | 5 (5%) | 7 (7%) |
| Therapy | ||
| Radiotherapy (%) | 54 (54%) | 50 (50%) |
| Radiotherapy + chemotherapy (%) | 46 (46%) | 50 (50%) |
Categorical variables are presented as counts (%).
Continuous variables presented as mean (SD).
OM
The incidence of advanced OM (III/IV) in the Episil group was lower than that in the control group (4/100, 4% vs. 14/100, 14%, P = 0.024) (Table 2). There was no difference in the treatment initiation time for OM between the control group and Episil group (2.05 (0.22) weeks after radiotherapy vs. 2.07 (0.26) weeks after radiotherapy, P = 0.55). There was no difference in the onset time of advanced OM (Grade III/IV) between the control group and Episil group (3.23 (0.44) weeks after radiotherapy vs. 3.75 (0.50) weeks after radiotherapy, P = 0.063). There was no difference in the duration of advanced OM (Grade III/IV) between the control group and Episil group (2.23 (0.60) weeks vs. 1.75 (0.50) weeks, P = 0.17). Among the patients with advanced OM (III/IV) in the control group, one case showed fungal infection in the throat swab test. After receiving antifungal treatment, the condition improved. The patients with advanced OM (III/IV) in the Episil group did not have bacterial or fungal infections.
Table 2.
Result of radiation-induced oral mucositis in control group and Episil group.
| Lower oral mucositis (0, I, II) | Advanced oral mucositis (III, IV) | P valuea | |
|---|---|---|---|
| Control group (n = 100) | 86 (86%) | 14 (14%) | |
| Episil group (n = 100) | 96 (96%) | 4 (4%) | 0.024 |
Categorical variables are presented as counts (%).
Bolded P values indicate statistical significance (P < 0.05).
Fisher exact test.
Pain relief
Oral pain relief was more significant in Episil group at 2 h (2.71 (1.12) vs. 1.78 (1.28), P < 0.0001) and 4 h (2.70 (1.05) vs. 2.09 (1.09), P < 0.0001) after first drug therapy than in control group (Fig. 2A). After 1 day, 2 days and 3 days of first drug therapy, the pain relief of patients in the Episil group was better than that of the control group (Fig. 2B).
Fig. 2.
Result of pain score after the initial drug intervention in control group and Episil group. A: Pain relief after 30 min, 1 h, 2 h, 4 h of initial drug intervention; B: Pain relief after 1 day, 2 days and 3 days of initial drug intervention. The points represent mean pain scores and bars represent SDs.
Nutritional status
By Week 4 weight loss was significantly lower in the Episil group than in the control group (0.40 (6.83) kg vs. 2.67 (8.24) kg, P = 0.036) and loss of BMI was significantly lower in the Episil group than in the control group (0.29 (1.90) kg/m2 vs. 0.83 (1.77) kg/m2, P = 0.040). At Week 4, the decrease of pre-albumin in the Episil group was lower than that in the control group (0.021 (0.063) g/L vs. 0.049 (0.070) g/L, P = 0.0040) (Table 3). The PG-SGA score at Week 7 showed that there were more well-nourished patients in the Episil group than in the control group (P = 0.017) (Table S1).
Table 3.
Nutritional status of control group and Episil group.
| Outcome | Control group (n = 100) | Episil group (n = 100) | P value |
|---|---|---|---|
| Weight (kg) | |||
| Baseline | 66.2 (13.7) | 65.6 (11.2) | |
| Week 4 | 63.6 (12.4) | 65.2 (11.9) | |
| Week 7 | 63.2 (13.2) | 64.1 (11.8) | |
| Weight loss (kg) | |||
| Week 4 | 2.67 (8.24) | 0.40 (6.83) | 0.036a |
| Week 7 | 3.06 (7.88) | 1.43 (8.32) | 0.16 |
| Body mass index (kg/m2) | |||
| Baseline | 22.9 (4.3) | 23.2 (4.2) | |
| Week 4 | 22.1 (4.3) | 22.9 (4.3) | |
| Week 7 | 22.3 (4.6) | 22.7 (4.3) | |
| Loss of body mass index (kg/m2) | |||
| Week 4 | 0.83 (1.77) | 0.29 (1.90) | 0.040a |
| Week 7 | 0.59 (2.71) | 0.46 (2.52) | 0.74 |
| Albumin (g/L) | |||
| Baseline | 41.06 (4.88) | 40.74 (5.57) | |
| Week 4 | 38.72 (3.93) | 39.40 (3.51) | |
| Week 7 | 36.29 (7.17) | 36.61 (4.93) | |
| Loss of albumin (g/L) | |||
| Week 4 | 2.35 (5.54) | 1.35 (6.27) | 0.24 |
| Week 7 | 4.78 (7.68) | 4.14 (7.15) | 0.54 |
| Pre-albumin (g/L) | |||
| Baseline | 0.258 (0.050) | 0.254 (0.052) | |
| Week 4 | 0.209 (0.053) | 0.233 (0.049) | |
| Week 7 | 0.212 (0.231) | 0.207 (0.059) | |
| Loss of pre-albumin (g/L) | |||
| Week 4 | 0.049 (0.070) | 0.021 (0.063) | 0.0040a |
| Week 7 | 0.046 (0.231) | 0.047 (0.075) | 0.96 |
| Hemoglobin (g/L) | |||
| Baseline | 134.8 (17.3) | 133.6 (16.8) | |
| Week 4 | 131.9 (21.2) | 132.2 (22.3) | |
| Week 7 | 127.7 (17.5) | 129.6 (17.1) | |
| Loss of hemoglobin (g/L) | |||
| Week 4 | 2.83 (24.81) | 1.38 (23.51) | 0.67 |
| Week 7 | 7.01 (21.9) | 4.02 (22.38) | 0.33 |
Continuous variables presented as mean (SD).
The data loss shown in the Table were all compared with the baseline data.
Statistical significance is reported at P < 0.05.
Survival assessment
The PFS of the control group and Episil group was shown in Fig. S1A. The estimated HR was 0.630 (95% confidence interval [CI]: 0.339–1.173), with a two-sided log-rank P = 0.15. The OS of the control group and Episil group was shown in Fig. S1B. The estimated HR was 0.508 (95% CI: 0.259–0.995), with a two-sided log-rank P = 0.052.
Immune function
There was no significant difference in total lymphocyte count and lymphocyte subsets between the two groups (all P > 0.05) (Table S2).
QOL and psychology assessment
The EORTC QLQ-C30 global health status score at Week 4 was better in the Episil group than in the control group (65.00 (5.17) vs. 60.02 (5.38), P < 0.0001). The DT score of the Episil group at Week 4 was lower than that of the control group (3.63 (2.09) vs. 4.56 (2.20), P = 0.0030). The HADS-Anxiety score of the Episil group at Week 4 was lower than that of the control group (4.27 (3.18) vs. 5.27 (3.37), P = 0.032). The HADS-depression score of the Episil group at Week 4 was lower than that of the control group (4.17 (3.02) vs. 5.07 (3.08), P = 0.039) (Fig. S2).
Other adverse reactions
No significant difference in the incidence of other adverse reactions was detected between the control group and Episil group (all P > 0.05) (Table S3).
Discussion
Radiation-induced OM is very common in HNC patients.18,19 Current drugs for radiation-induced OM have limited effectiveness and are prone to side effects.20, 21, 22 Our previous retrospective study has shown that Episil can relieve OM caused by radiotherapy.16 This study conducted a randomized controlled clinical trial with a large sample. Our results showed that the incidence of advanced OM was significantly reduced after treatment with Episil (4/100, 4% vs. 14/100, 14%, P = 0.024). After Episil treatment, mucosal damage caused by radiation was better repaired and the oral environment was significantly improved. As a result, the OM did not get any worse.
Radiation-induced OM may lead to severe oral mucosal pain that requires long-term use of opioid analgesics during treatment.23, 24, 25 The analgesic effect is poor, and painkillers can also cause related adverse reactions.26, 27, 28 Hadjieva et al. demonstrated that Episil was effective in relieving the pain of radiation-induce OM in HNC patients.29 Qin et al. reported a multicenter, randomized, single-use, position-controlled registered study in China that demonstrated that Episil provided significantly better local analgesia than other oral gargles within 6 h of use.15 Our results showed that Episil group patients had better oral pain relief at 2 h and 4 h than the control group. At the same time, the analgesic effect was better than that of the control group within three days after medication. Episil had a good analgesic effect in relieving the pain caused by OM.
The probability of malnutrition caused by head and neck radiotherapy is high.30, 31, 32 The main factors were related to eating difficulty and swallowing pain caused by radiation-induced OM.33,34 Alleviating OM and oral pain may be an important way to improve the nutritional status of HNC patients. Our results have confirmed the effect of Episil on OM and oral pain. In the results of nutritional status assessment, we found that the weight loss, BMI decline and loss of pre-albumin in the Episil group after 4 weeks of radiotherapy were better than those in the control group. In addition, after 7 weeks of radiotherapy, the PG-SGA in the Episil group was better than that in the control group. Therefore, we believe that Episil can further improve the nutritional status of patients on the basis of alleviating OM and oral pain.
The 5-year OS rate of locally advanced HNC patients was less than 50%.35, 36, 37 Malnutrition is an important factor affecting the prognosis and survival of HNC patients.38,39 The randomized controlled trial of Lu et al. confirmed that early nutrition supportive care can improve survival in patients treated with radiotherapy for esophageal cancer.40 Our results confirmed that Episil improved nutritional status in HNC patients. Therefore, our trial also focused on patient survival. The PFS and OS were slightly better in the Episil group than in the control group, but the difference was not statistically significant. In addition, we conducted periodic assessment of the immune function indicators between the two groups and found no significant differences.
The QOL of HNC patients is affected significantly due to oral pain and difficulty in eating.41, 42, 43 Karlsson et al. found that quality of life scores decreased significantly after severe oral mucositis reactions.44 Our results found that global health status score at Week 4 was better in the Episil group than in the control group. The treatment of Episil can alleviate OM and oral pain, which may be the main factor to improve the QOL of HNC patients. In addition, psychological state is also important for HNC patients.45, 46, 47 Research has found that depression and anxiety are associated with a significant increase in cancer mortality.48, 49, 50 Our results showed that the DT, HADS-Anxiety and HADS-depression scores of Episil group at Week 4 were lower than those of the control group. After the treatment of Episil alleviated the OM and oral pain, the psychological state of patients was also significantly improved.
A limitation of this study is that the trial included only Chinese patients, which may limit the generality of our results to other races. In addition, we did not use blind method to evaluate OM, which may cause a certain degree of bias, but we formed a professional team composed of several experts and nurses to prevent evaluation bias as far as possible. Furthermore, we lack detailed data collection and statistics on various levels of OM. We considered to evaluate the efficacy of Episil in controlling all levels of OM in subsequent trials and focused more on details. Another crucial limitation was that we did not conduct multivariate analysis for the incidence of advanced OM (Grade III/IV). We have several important considerations. First, at the beginning of the design, we did not pre-determine any subgroups. Randomly dividing the subgroups after the experiment might lead to incorrect conclusions due to data mining. Secondly, further subgroup division may result in insufficient sample sizes for each subgroup, reducing the test's efficacy and increasing the risk of false negative results. Finally, multivariate analysis requires prior evaluation and design. We will conduct further research in future trials.
In conclusion, this study suggests that Episil can relieve OM and oral pain during radiotherapy in HNC patients and improve their nutritional status and QOL. Our study will provide the basis and reference for future research into the treatment of adverse effects of radiotherapy for HNC.
Contributors
Conceptualization, X.J.; methodology, JL.W.; software, ST.C.; validation, X.J.; formal analysis, JL.W.; investigation, Q.Z.; resources, X.J.; data curation, YL.C. and J.W.; writing-original draft preparation, JL.W. and Q.Z.; writing-review and editing, X.J.; visualization, X.J.; supervision, CC.H., WX.Z., X.L., HJ.L., XJ.J., B.W., Y.M., AF.W. and X.J.; project administration, X.J.; funding acquisition, X.J. X.J. had access to the dataset and held the final responsibility for the decision to submit the manuscript for publication. All authors read and approved the final version of the manuscript. X.J. and JL.W. have verified the underlying data.
Data sharing statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This study was funded by the Jilin Province Health Science And Technology ability improvement program (grant numbers: 2024A021), The First Hospital of Jilin University Talent Reserve Program (grant numbers: JDYY-TRP-2024012) and Jilin Province Medical and Health Talents Special Foundation (grant numbers: JLSWSRCZX2023-68 and JLSRCZX2025-042). We would like to express our gratitude to all the researchers at each research site and to all the staff who participated in this study.
Footnotes
Supplementary data related to this article can be found at https://doi.org/10.1016/j.eclinm.2025.103631.
Appendix A. Supplementary data
Fig. S1.
Kaplan-Meier graph for PFS and OS of control group and Episil group patients.
Fig. S2.
EORTC QLQ-C30 global health status scores, DT, HADS-anxiety and HADS-depression at Week 0 and Week 4 in control group and Episil group.
Fig. S3.
Participant Timeline.
References
- 1.Lee C.T., Galloway T.J. Pathogenesis and amelioration of radiation-induced oral mucositis. Curr Treat Options Oncol. 2022;23(3):311–324. doi: 10.1007/s11864-022-00959-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Liu S., Zhao Q., Zheng Z., et al. Status of treatment and prophylaxis for radiation-induced oral mucositis in patients with head and neck cancer. Front Oncol. 2021;11 doi: 10.3389/fonc.2021.642575. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Zheng Z., Zhao X., Zhao Q., et al. The effects of early nutritional intervention on oral mucositis and nutritional status of patients with head and neck cancer treated with radiotherapy. Front Oncol. 2020;10 doi: 10.3389/fonc.2020.595632. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Wardill H.R., Bossi P., Sonis S.T. Understanding protective mechanisms of an oral probiotic in reducing radiation-induced oral mucositis. J Clin Oncol. 2024;42(12):1436–1438. doi: 10.1200/JCO.23.02706. [DOI] [PubMed] [Google Scholar]
- 5.Ibrahim S.S., Hassanein F.E.A., Zaky H.W., Gamal H. Clinical and biochemical assessment of the effect of glutamine in management of radiation induced oral mucositis in patients with head and neck cancer: randomized controlled clinical trial. J Stomatol Oral Maxillofac Surg. 2024;125(3s) doi: 10.1016/j.jormas.2024.101827. [DOI] [PubMed] [Google Scholar]
- 6.Xu J., Yang G., An W., et al. Correlations between the severity of radiation-induced oral mucositis and salivary epidermal growth factor as well as inflammatory cytokines in patients with head and neck cancer. Head Neck. 2023;45(5):1122–1129. doi: 10.1002/hed.27313. [DOI] [PubMed] [Google Scholar]
- 7.Kubrak C., Martin L., Gramlich L., et al. Prevalence and prognostic significance of malnutrition in patients with cancers of the head and neck. Clin Nutr. 2020;39(3):901–909. doi: 10.1016/j.clnu.2019.03.030. [DOI] [PubMed] [Google Scholar]
- 8.Reed W.T., Jiang R., Ohnuma T., et al. Malnutrition and adverse outcomes after surgery for head and neck cancer. JAMA Otolaryngol Head Neck Surg. 2024;150(1):14–21. doi: 10.1001/jamaoto.2023.3486. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Findlay M., White K., Brown C., Bauer J.D. Nutritional status and skeletal muscle status in patients with head and neck cancer: impact on outcomes. J Cachexia Sarcopenia Muscle. 2021;12(6):2187–2198. doi: 10.1002/jcsm.12829. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Wei J., Chen Y., Su J., et al. Effects of early nutritional intervention on oral mucositis and basic conditions in patients receiving radiotherapy for head and neck cancer: randomized controlled trial (ChiCTR2000031418) Clin Nutr. 2024;43(7):1717–1723. doi: 10.1016/j.clnu.2024.05.029. [DOI] [PubMed] [Google Scholar]
- 11.Wei J., Wu J., Meng L., et al. Effects of early nutritional intervention on oral mucositis in patients with radiotherapy for head and neck cancer. QJM. 2020;113(1):37–42. doi: 10.1093/qjmed/hcz222. [DOI] [PubMed] [Google Scholar]
- 12.Shu Z., Zeng Z., Yu B., et al. Nutritional status and its association with radiation-induced oral mucositis in patients with nasopharyngeal carcinoma during radiotherapy: a prospective study. Front Oncol. 2020;10 doi: 10.3389/fonc.2020.594687. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Fukutani T., Yoshioka Y., Imori S., et al. Efficacy of Episil in patients with hematologic malignancies: a comparative study. BMC Oral Health. 2024;24(1):522. doi: 10.1186/s12903-024-04233-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Ueno T., Yatsuoka W., Ishiki H., Miyano K., Uezono Y. Effects of an oral mucosa protective formulation on chemotherapy- and/or radiotherapy-induced oral mucositis: a prospective study. BMC Cancer. 2022;22(1):90. doi: 10.1186/s12885-021-09107-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Cheng Y., Qin S.K., Chen Y.P., et al. Local analgesic effect of a bioadhesive barrier-forming oral liquid in cancer patients with oral mucositis caused by chemotherapy and/or radiotherapy: a randomized multicenter, single-use, positive-controlled, open-label study. OncoTargets Ther. 2018;11:8555–8564. doi: 10.2147/OTT.S185915. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Wei J., Wu J., Wang H., et al. 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. Front Oncol. 2021;11 doi: 10.3389/fonc.2021.617392. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Villa A., Vollemans M., De Moraes A., Sonis S. Concordance of the WHO, RTOG, and CTCAE v4.0 grading scales for the evaluation of oral mucositis associated with chemoradiation therapy for the treatment of oral and oropharyngeal cancers. Support Care Cancer. 2021;29(10):6061–6068. doi: 10.1007/s00520-021-06177-x. [DOI] [PubMed] [Google Scholar]
- 18.Lin P., Zhuang J., Lai J., Cui J., Jiang D., Huang J. Efficacy of probiotics in the treatment of oral mucositis in head and neck cancer patients: a systematic review and meta-analysis. Microb Pathog. 2024;193 doi: 10.1016/j.micpath.2024.106785. [DOI] [PubMed] [Google Scholar]
- 19.Bergamaschi L., Vincini M.G., Zaffaroni M., et al. Management of radiation-induced oral mucositis in head and neck cancer patients: a real-life survey among 25 Italian radiation oncology centers. Support Care Cancer. 2023;32(1):38. doi: 10.1007/s00520-023-08185-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Zhang S., Li J., Zhang Y., et al. Efficacy of nonpharmacological interventions for severe radiation-induced oral mucositis among head and neck cancer patients: a network meta-analysis of randomised controlled trials. J Clin Nurs. 2024;33(6):2030–2049. doi: 10.1111/jocn.17087. [DOI] [PubMed] [Google Scholar]
- 21.Guan Z., Zhang J., Jiang N., Tian M., Wang H., Liang B. Efficacy of mesenchymal stem cell therapy in rodent models of radiation-induced xerostomia and oral mucositis: a systematic review. Stem Cell Res Ther. 2023;14(1):82. doi: 10.1186/s13287-023-03301-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Shuai T., Tian X., Xu L.L., et al. Oral glutamine may have no clinical benefits to prevent radiation-induced oral mucositis in adult patients with head and neck cancer: a meta-analysis of randomized controlled trials. Front Nutr. 2020;7:49. doi: 10.3389/fnut.2020.00049. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Steinmann D., Eilers V., Beynenson D., Buhck H., Fink M. Effect of Traumeel S on pain and discomfort in radiation-induced oral mucositis: a preliminary observational study. Altern Ther Health Med. 2012;18(4):12–18. [PubMed] [Google Scholar]
- 24.Baig V., Hashmi S.F., Altuhafy M., Khan J. Efficacy of prophylactic gabapentin in managing oral mucositis pain in patients undergoing non-surgical management of head and neck tumors. Support Care Cancer. 2025;33(3):236. doi: 10.1007/s00520-025-09298-9. [DOI] [PubMed] [Google Scholar]
- 25.Saunders D.P., Rouleau T., Cheng K., et al. Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the management of oral mucositis in cancer patients and clinical practice guidelines. Support Care Cancer. 2020;28(5):2473–2484. doi: 10.1007/s00520-019-05181-6. [DOI] [PubMed] [Google Scholar]
- 26.Christoforou J., Karasneh J., Manfredi M., et al. World workshop on oral medicine VII: non-opioid pain management of head and neck chemo/radiation-induced mucositis: a systematic review. Oral Dis. 2019;25(Suppl 1):182–192. doi: 10.1111/odi.13074. [DOI] [PubMed] [Google Scholar]
- 27.Ju J., Li Z., Liu J., Peng X., Gao F. Biased opioid receptor agonists: balancing analgesic efficacy and side-effect profiles. Int J Mol Sci. 2025;26(5) doi: 10.3390/ijms26051862. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Britch S.C., Walsh S.L. Treatment of opioid overdose: current approaches and recent advances. Psychopharmacology (Berl) 2022;239(7):2063–2081. doi: 10.1007/s00213-022-06125-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Hadjieva T., Cavallin-Ståhl E., Linden M., Tiberg F. Treatment of oral mucositis pain following radiation therapy for head-and-neck cancer using a bioadhesive barrier-forming lipid solution. Support Care Cancer. 2014;22(6):1557–1562. doi: 10.1007/s00520-014-2117-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Homa-Mlak I., Mlak R., Brzozowska A., et al. High level of irisin as a marker of malnutrition in head and neck cancer patients subjected to radiotherapy. Med Sci Monit. 2022;28 doi: 10.12659/MSM.936857. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Vergauwen A., Baudelet M., Van den Steen L., et al. Exploratory research: patient-reported factors contributing to decreased oral intake during radiotherapy in head and neck cancer. Head Neck. 2025;47:1717–1725. doi: 10.1002/hed.28089. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Brewczyński A., Jabłońska B., Mrowiec S., Składowski K., Rutkowski T. Nutritional support in head and neck radiotherapy patients considering HPV status. Nutrients. 2020;13(1) doi: 10.3390/nu13010057. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Anderson C., Saunders D. Oral mucositis in head and neck cancer patients. Semin Radiat Oncol. 2025;35(2):271–277. doi: 10.1016/j.semradonc.2025.02.011. [DOI] [PubMed] [Google Scholar]
- 34.Su L., Lin Q.J., Ma S.Q., et al. The effect of early oral nutritional supplements on improving nutritional outcomes and radiation-induced oral mucositis for nasopharyngeal carcinoma patients undergoing concurrent chemoradiotherapy. Head Neck. 2023;45(11):2798–2808. doi: 10.1002/hed.27503. [DOI] [PubMed] [Google Scholar]
- 35.Lydiatt W., O'Sullivan B., Patel S. Major changes in head and neck staging for 2018. Am Soc Clin Oncol Educ Book. 2018;38:505–514. doi: 10.1200/EDBK_199697. [DOI] [PubMed] [Google Scholar]
- 36.Petit C., Lacas B., Pignon J.P., et al. Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis. Lancet Oncol. 2021;22(5):727–736. doi: 10.1016/S1470-2045(21)00076-0. [DOI] [PubMed] [Google Scholar]
- 37.Tsujimoto T., Wasa M., Inohara H., Ito T. L-Glutamine and survival of patients with locally advanced head and neck cancer receiving chemoradiotherapy. Nutrients. 2023;15(19) doi: 10.3390/nu15194117. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Büntzel J., Micke O., Kisters K., Büntzel J., Mücke R. Malnutrition and survival - bioimpedance data in head neck cancer patients. In Vivo. 2019;33(3):979–982. doi: 10.21873/invivo.11567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Bastien A.J., Amin L., Vasquez M., et al. Baseline weight recovery and mortality risk in head and neck cancer. Head Neck. 2025;47(1):139–149. doi: 10.1002/hed.27898. [DOI] [PubMed] [Google Scholar]
- 40.Lu Z., Fang Y., Liu C., et al. Early interdisciplinary supportive care in patients with previously untreated metastatic Esophagogastric Cancer: a phase III randomized controlled trial. J Clin Oncol. 2021;39(7):748–756. doi: 10.1200/JCO.20.01254. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Evangelista L., Nativ-Zeltzer N., Bewley A., et al. Functional laryngectomy and quality of life in survivors of head and neck cancer with intractable aspiration. JAMA Otolaryngol Head Neck Surg. 2024;150(4):335–341. doi: 10.1001/jamaoto.2024.0049. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Balogun Z., Gardiner L.A., Li J., Moroni E.A., Rosenzweig M., Nilsen M.L. Neighborhood deprivation and symptoms, psychological distress, and quality of life among head and neck cancer survivors. JAMA Otolaryngol Head Neck Surg. 2024;150(4):295–302. doi: 10.1001/jamaoto.2023.4672. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Hajdú S.F., Wessel I., Dalton S.O., Eskildsen S.J., Johansen C. Swallowing exercise during head and neck cancer treatment: results of a randomized trial. Dysphagia. 2022;37(4):749–762. doi: 10.1007/s00455-021-10320-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Karlsson C., Bohm N., Andersson J.S., Finizia C., Almståhl A. Prospective study on health-related quality of life, oral mucositis and oral health on during treatment of head and neck cancer. BMC Oral Health. 2024;24(1):697. doi: 10.1186/s12903-024-04466-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Gosak M., Gradišar K., Rotovnik Kozjek N., Strojan P. Psychological distress and nutritional status in head and neck cancer patients: a pilot study. Eur Arch Otorhinolaryngol. 2020;277(4):1211–1217. doi: 10.1007/s00405-020-05798-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Peng H.L., Chen Y.H., Lee H.Y., et al. Factors associated with shame and stigma among head and neck cancer patients: a cross-sectional study. Support Care Cancer. 2024;32(6):357. doi: 10.1007/s00520-024-08568-2. [DOI] [PubMed] [Google Scholar]
- 47.Kar A., M R.A., Bhaumik U., Rao V.U.S. Psychological issues in head and neck cancer survivors: need for addressal in rehabilitation. Oral Oncol. 2020;110 doi: 10.1016/j.oraloncology.2020.104859. [DOI] [PubMed] [Google Scholar]
- 48.Wang Y.H., Li J.Q., Shi J.F., et al. Depression and anxiety in relation to cancer incidence and mortality: a systematic review and meta-analysis of cohort studies. Mol Psychiatry. 2020;25(7):1487–1499. doi: 10.1038/s41380-019-0595-x. [DOI] [PubMed] [Google Scholar]
- 49.Xia S., Zhu Y., Luo L., et al. Prognostic value of depression and anxiety on colorectal cancer-related mortality: a systematic review and meta-analysis based on univariate and multivariate data. Int J Colorectal Dis. 2024;39(1):45. doi: 10.1007/s00384-024-04619-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.McCabe-White L., Moghaddam N., Tickle A., Biswas S. Factors associated with psychological distress for couples facing head and neck cancer: a systematic literature review. Psychooncology. 2021;30(8):1209–1219. doi: 10.1002/pon.5686. [DOI] [PubMed] [Google Scholar]
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