Effects of bio-adhesive barrier-forming oral liquid (Episil®) on pain due to radiation-induced oral mucositis in patients with head and neck cancer: A randomized crossover trial

Background Bio-adhesive barrier-forming oral liquid (Episil®) is a recently developed medical device for the management of pain caused by oral mucositis associated with cancer radiotherapy or chemotherapy. The purpose of this study was to evaluate the effectiveness of this material for the relief of pain resulting from radiation-induced oral mucositis in patients with head and neck cancer who are undergoing radiotherapy. Methods This was a randomized, open-labeled, crossover trial investigating the pain relief effects of Episil® using dexamethasone ointment as a control. Fifteen patients who had mild or moderate pain due to radiation induced oral mucositis were randomly assigned to two groups: group A applied dexamethasone ointment once on the rst day, had a wash-out period on the second day, and used Episil® once on the third day. Conversely, group B used Episil® on day 1, followed by a wash-out period on day 2 and dexamethasone ointment on day 3. The effectiveness of the test drug/materials on the relief of pain was compared. Results One patient reported nausea immediately after application of Episil® and was therefore excluded from the analysis of pain relief. Dexamethasone ointment relieved pain in 85.7% of patients compared to 71.4% with Episil® (p = 0.682). Nine patients wished to continue dexamethasone ointment after the study while only ve wished to continue Episil®. Conclusions Our ndings suggest that the pain relief effect of Episil® is comparable to or less than that of dexamethasone ointment. Larger follow-up studies are needed to verify these ndings.

on day 2 and dexamethasone ointment on day 3. The effectiveness of the test drug/materials on the relief of pain was compared.
Results One patient reported nausea immediately after application of Episil® and was therefore excluded from the analysis of pain relief. Dexamethasone ointment relieved pain in 85.7% of patients compared to 71.4% with Episil® (p = 0.682). Nine patients wished to continue dexamethasone ointment after the study while only ve wished to continue Episil®.
Conclusions Our ndings suggest that the pain relief effect of Episil® is comparable to or less than that of dexamethasone ointment. Larger follow-up studies are needed to verify these ndings.
Trial registration: The study protocol was registered in the Japan Registry of Clinical Trials (jRCT) on March 3rd, 2019 (jRCTs072180039).

Background
Although widely used for the treatment of head and neck cancer, radiotherapy (RT) causes a range of adverse events, including xerostomia, oral mucositis, taste disturbance, oral candidiasis, radiationinduced dental caries, and osteoradionecrosis. Oral mucositis is a serious early complication that can cause severe pain leading to di culties in eating, which decreases the patients' quality of life and in some cases hinders the continuation of RT. However, effective methods for preventing radiation-induced oral mucositis have not yet been established [1][2][3].
We previously conducted a randomized controlled trial to determine whether the application of a spacer, accompanied by administration of pilocarpine and topical dexamethasone ointment, were effective in preventing severe oral mucositis during RT for oral cancer [4]. Our results revealed that these measures were able to signi cantly prevent severe oral mucositis during RT alone; however, no e cacy was observed during RT combined with cisplatin or cetuximab therapy, demonstrating a continued need for an effective pain management treatment for use with combined RT and bio-or chemotherapy.
Bio-adhesive barrier-forming oral liquid (Episil®) was a recently developed medical device for the management of pain in oral mucositis associated with cancer chemotherapy or RT [5]. After application of the material to the oral mucosa, phospholipid and triglyceride lipid components spread and selfassemble with a trace volume of aqueous uid at the mucosal surface to form a bio-adhesive liquid crystalline lining protecting the sore and in amed mucosa. However, since Episil® is not a drug but a medical material, no phase 3 clinical trials have been conducted and therefore e cacy has not been established. The purpose of this study is to examine the pain relief effects of Episil® using a randomized crossover trial with dexamethasone ointment as control.

Study design
This is a randomized, open-labeled, crossover trial investigating the pain relief effects of Episil® (Solasia Pharma Inc., Tokyo, Japan), using dexamethasone ointment (Dexaltin® Oral Ointment 1 mg/g; Nihon Kayaku Co., Ltd, Tokyo Japan) as a control. This study was conducted as a speci c clinical study in

Patients
The study subjects were drawn from patients diagnosed with head and neck cancer who received RT in Nagasaki University Hospital or Kansai Medical University Hospital between March 2019 and March 2020, and whose oral cavity was contained in the radiation eld. Patients judged to be lacking cognitive ability and those with hypersensitivity to the test drug/material were excluded.

Intervention
Patients who had mild or moderate pain due to radiation induced oral mucositis were enrolled and randomly assigned to two groups: Group A applied dexamethasone ointment once on the rst day, had a second day as a wash out period, and used Episil® once on the third day. Group B conversely used Episil® on day 1, followed by a wash-out on day 2 and dexamethasone ointment on day 3. The treatment assignment was performed using computer software, and the assignment factor was the presence or absence of combination with chemotherapy.
Pain relief effects were classi ed according to the patients' subjective symptoms into one of four categories: 1) marked improvement, 2) improvement, 3) unchanged, and 4) worsening.

Endpoints
The primary endpoint of the study was a comparison of the pain relief effects of Episil® and dexamethasone ointment. Where pain relief was achieved, the duration was recorded. The secondary endpoint was the drug/material that the patient wished to continue after the study, and the incidence of adverse events of the test drug/material.

Statistical analysis
All statistical analyses were performed using SPSS software (version 24.0; Japan IBM Co., Tokyo, Japan).
The difference in pain relief between Episil® and dexamethasone ointment was analyzed by Fisher's exact test. The difference in pain relief duration between the test drug/materials was analyzed by Mann-Whitney U test. In all analyses, two-tailed p values < 0.05 were considered statistically signi cant.

Patient characteristics
A total of fteen patients were enrolled, with 8 assigned to group A and 7 to group B ( Table 1). The primary site in 7 patients was the oropharynx, while the oral cavity was the primary site in 5 patients, and nasal cavity, hypopharynx, and nasopharynx in one each. All but one of the 15 patients underwent intensity modulated radiation therapy (IMRT), and 11 patients had concurrent chemo-or biotherapy. On average, Episil® or the control substance was applied 3.8 days (range, 0-13 days) after the onset of grade 2 oral mucositis.

Comparison of pain relief effect of Episil® and dexamethasone ointment
The effects of Episil® versus the control ointment on pain relief are summarized in Table 2. Application of dexamethasone ointment was associated with marked improvement in 4 patients, while an additional 8 described some improvement. Pain levels were unchanged in 2 patients, and no patient experienced worsening pain following treatment. In comparison, a marked improvement of pain levels was reported in 4 patients following application of Episil®, while an additional 6 patients reported some improvement. No change was reported in 3 patients, and 1 patient reported worsening pain. The improvement ratio (marked improvement plus improvement / total patients) of dexamethasone ointment was 85.7%, while that of Episil® was 71.4%, although the difference was not statistically signi cant (p = 0.682). Test drug/material that patients wished to continue after the study In 14 patients, excluding one who could not use Episil® due to nausea, 9 wished to continue dexamethasone ointment after the study and 5 wished to continue Episil® (Table 3).

Adverse events
One patient was nauseated immediately after application of Episil® and the material was immediately removed. Nausea disappeared shortly after removal, with no subsequent side effects. This case was excluded from the analysis of pain relief effect. No other drug/material-related adverse events were found.

Discussion
Oral mucositis develops almost 100% when the head and neck cancer is treated with RT. Thus far, none of the preventative measures that have been tried has demonstrated any e cacy [1,2]. The Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) clinical practice guidelines recommends several prophylactic and therapeutic measures during head and neck RT such as the use of mouthwashes containing benzydamine, 2% morphine, or 0.5% doxepin, the use of low-level laser therapy, and administration of systemic zinc supplements [3]. However, these treatments are not covered by public medical insurance in Japan, and therefore are not widely administered.
In Japan, dexamethasone ointment or triamcinolone ointment have been widely used since the 1980s for the treatment of oral mucositis including radiation-induced oral mucositis. In a phase 2 trial, Rugo et al reported that prophylactic use of dexamethasone oral solution substantially reduced the incidence and severity of stomatitis in patients receiving everolimus and exemestane therapy [6]. A 'prophylactic care bundle' that includes topical administration of dexamethasone ointment has been advocated for radiation induced oral mucositis [7]. However, a subsequent randomized controlled trial con rmed that although dexamethasone ointment had a preventive effect on oral mucositis in patients with RT alone, there was no effect when administered to patients undergoing CRT or BRT [4].
Episil® is a bio-adhesive barrier-forming oral liquid developed for the management of pain in oral mucositis. Previous studies that investigated the pain relief effect of this material reported that Episil® demonstrated effectiveness as a pain reliever in patients undergoing RT or chemotherapy [5,8] (Table 4). Hadjieva et al tested the pain relief effects of Episil® and Episil®-benzydamine in patients showing moderate radiation-induced oral mucositis, and the effects did not differ between the two materials [5], while Chen et al compared the pain relief effects of Episil® and Kangsu™ (Luye Pharmaceutical Co. Ltd, Nanjing, China), which is an oral rinse approved in China as a class II medical device for the treatment of various oral mucositis including RT-or chemotherapy-induced mucositis. They found that the local analgesic effect of Episil® was signi cantly better than that of Kangsu™. In Japan, medical insurance is applicable to spacers, pilocarpine, dexamethasone ointment, and various gargles in radiation-related oral adverse events, but neither Episil®-benzydamine or Kangsu™ are covered under this system.  Corticosteroids have excellent anti-in ammatory properties, and steroid ointments are widely used for various stomatitis. However, it has also been established that inadvertent use of steroids can result in infection, and there is a concern that the use of steroid ointment in cancer patients with reduced overall health could increase the risk of oral candidiasis. In an observational study of 326 patients with oral or oropharyngeal cancer, we recently reported that the risk factors for oral candidiasis were leukopenia and exacerbation of stomatitis, and that steroid ointment was not a risk factor [9]. For these reasons, we conducted a preliminary study to determine the e cacy of Episil® using dexamethasone ointment as a control treatment.
We conducted a randomized crossover study to determine whether Episil® is more effective than dexamethasone ointment in relieving pain associated with RT induced oral mucositis using a small number of patients for preliminary investigation. The results suggested that Episil® was less effective as an analgesic than dexamethasone ointment, however there was no statistically signi cant differences between the two test-drug/materials, likely due to the small number of cases examined here. It is possible that Episil® only adheres to the mucosal surface and has no anti-in ammatory effects. Another reason for the reduced e cacy of Episil® may be that it was easily peeled off and was di cult to accurately apply to the site of mucositis for a longer duration. Our study focused on the use of Episil® for RT induced oral mucositis, a condition that occurs rapidly and spreads widely. Under these circumstances it is therefore di cult to apply Episil® accurately; however, it is expected to be effective for oral mucositis that occurs in a small area such as everolimus-related oral mucositis.
In addition to e cacy, we also investigated the duration of pain relief. Hadjieva et al. [5] reported that the analgesic effects of Episil® persisted for up to 8 hours. In this study, the effect of Episil® lasted for 103 minutes, which was slightly longer than that of dexamethasone ointment (63 minutes), although there was no signi cant difference. In order to clarify the duration of the effect of this material, additional investigations are required involving a larger number of cases.
This study has some limitations and therefore may be di cult to generalize to a larger population. First, this is a preliminary study, so the number of cases was small and adequate statistical analysis could not be performed. Second, since the Episil® treatment was applied directly by the patient, it was not possible to con rm whether the material was applied correctly. However, this study is, to the best of our knowledge, the rst to con rm the e cacy of this material using a steroid ointment as a control group. In the future, we recommend consideration of this material for treatment of oral mucositis caused by anticancer drugs or molecular targeted drugs for solid cancer.

Conclusions
Our ndings suggest that the pain relief effect of Episil ® is comparable to or less than that of dexamethasone ointment. Larger follow-up studies are needed to verify these ndings.