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 efficacy [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 confirmed 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 significantly 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.
Table 4
Clinical research on Episil®
Table 1 Patient characteristics | |
Factor | | Number of patients / mean value |
Age | mean ± SD | 66.9 ± 10.9 |
Sex | male | 11 |
| female | 4 |
Primary site | oropharynx | 7 |
| oral cavity | 5 |
| nasal cavity | 1 |
| hypopharynx | 1 |
| nasopharynx | 1 |
Leukocytes | mean ± SD | 5727 ± 2142 |
Lymphocytes | mean ± SD | 1769 ± 1096 |
hemoglobin | mean ± SD | 12.4 ± 1.80 |
Albumin | mean ± SD | 3.60 ± 0.731 |
Method of RT | IMRT | 14 |
| 3D-CRT | 1 |
Conccurent chemotherapy* | RT alone | 4 |
| CDDP | 6 |
| CBCDA | 1 |
| DeVIC | 1 |
| Cet | 3 |
*RT: radiotherapy CDDP: cisplatin CBCDA: carboplatin DeVIC: dexamethasone, etoposide, ifosfamide, carboplatin |
Corticosteroids have excellent anti-inflammatory 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 efficacy 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 significant 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-inflammatory effects. Another reason for the reduced efficacy of Episil® may be that it was easily peeled off and was difficult 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 difficult 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 efficacy, 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 significant 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 difficult 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 confirm whether the material was applied correctly. However, this study is, to the best of our knowledge, the first to confirm the efficacy 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.