Yokota, T., Ogawa, T., Takahashi, S., Okami, K., Fujii, T., Tanaka, K., . . . Naka, Y. (2017). Efficacy and safety of rebamipide liquid for chemoradiotherapy-induced oral mucositis in patients with head and neck cancer: A multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II study. BMC Cancer, 17, 314.

Recent preclinical and phase I studies have reported that rebamipide decreased the severity of chemoradiotherapy-induced oral mucositis in patients with oral cancer. This placebo-controlled randomized phase II study assessed the clinical benefit of rebamipide in reducing the incidence of severe chemoradiotherapy-induced oral mucositis in patients with head and neck cancer (HNC).

Patients aged 20–75 years with HNC who were scheduled to receive chemoradiotherapy were enrolled. Patients were randomized to receive rebamipide 2% liquid, rebamipide 4% liquid, or placebo. The primary endpoint was the incidence of grade ≥ 3 oral mucositis determined by clinical examination and assessed by central review according to the Common Terminology Criteria of Adverse Events, version 3.0. Secondary endpoints were the time to onset of grade ≥ 3 oral mucositis and the incidence of functional impairment (grade ≥ 3) based on the evaluation by the Oral Mucositis Evaluation Committee.

• N: 97
• AGE: 20–75 years with HNC 
• MALES: 100% 
• CURRENT TREATMENT: Chemotherapy, radiation
• KEY DISEASE CHARACTERISTICS: HNC, oral cavity, nasopharynx, oropharynx, hypopharynx, and larynx

• SITE: Multi-site
• SETTING TYPE: Outpatient
• LOCATION: Japan

• PHASE OF CARE: Active anti-tumor treatment
• APPLICATIONS: Elder care, palliative care

Patients aged 20–75 years with HNC who were scheduled to receive chemoradiotherapy were enrolled. Patients were randomized to receive rebamipide 2% liquid, rebamipide 4% liquid, or placebo.

The incidence of oral mucositis in each group was compared using the chi-square test. A step-down strategy was used for the between-group comparison, adjusting for multiplicity. Comparisons were made first between the rebamipide 4% and the placebo groups, and then between the rebamipide 2% and placebo groups. The Cochran-Armitage test was used as a trend test. All statistical analyses were performed using SAS, version 9.2.

In a trend test, a decrease in the incidence of grade ≥ 3 oral mucositis was observed with an increasing concentration of rebamipide liquid; however, this decrease was not statistically significant (p = 0.2399).

The rebamipide 2% and 4% groups showed a trend of delaying the time to onset of grade ≥ 3 oral mucositis as compared with the placebo group, although the difference between the groups was not statistically significant

A decrease in incidence of grade ≥ 3 oral mucositis in patients treated with rebamipide 2% and 4% compared with those treated with placebo, these differences were not statistically significant.

There was a prolongation in the time to onset of grade ≥ 3 oral mucositis and a decrease in functional impairment in patients treated with rebamipide 4% compared to those treated with placebo; these results may suggest a clinical benefit of rebamipide in reducing the incidence of severe oral mucositis induced by CRT.

• Small sample (< 100)
• Other limitations/explanation: Differenced in oral retention and swallowing compliance for the study drugs between treatment groups.

Systemic oral care alone is insufficient to decrease the incidence of severe oral mucositis. Therefore, there is a strong demand for the development of prophylactic and therapeutic agents against oral mucositis. There is efficacy and safety profiles that suggest rebamipide 4% is safe and effective, although not statistically significant. Further studies are needed using rebamipide 4% for treatment of CRT-induced oral mucositis.