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
T. Yokota,
T. Ogawa,
S. Takahashi,
K. Okami,
T. Fujii,
K. Tanaka,
S. Iwae,
I. Ota,
T. Ueda,
N. Monden,
K. Matsuura,
H. Kojima,
S. Ueda,
K. Sasaki,
Y. Fujimoto,
Y. Hasegawa,
T. Beppu,
H. Nishimori,
S. Hirano,
Y. Naka,
Y. Matsushima,
M. Fujii,
M. Tahara
Affiliations
T. Yokota
Division of Gastrointestinal Oncology, Shizuoka Cancer Center
T. Ogawa
Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine
S. Takahashi
Department of Medical Oncology, The Cancer Institute Hospital of JFCR
K. Okami
Department of Otolaryngology, Center of Head and Neck Surgery, Tokai University
T. Fujii
Department of Otolaryngology, Head and Neck Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases
K. Tanaka
Department of Medical Oncology, Kindai University Faculty of Medicine
S. Iwae
Department of Head and Neck Cancer, Hyogo Cancer Center
I. Ota
Department of Otolaryngology-Head and Neck Surgery, Nara Medical University
T. Ueda
Department of Otorhinolaryngology-Head and Neck Surgery, Hiroshima University Hospital
N. Monden
Department of Head and Neck Surgery, Shikoku Cancer Center
K. Matsuura
Department of Head and Neck Surgery, Miyagi Cancer Center
H. Kojima
Department of Otorhinolaryngology, Jikei University School of Medicine
S. Ueda
Medical Oncology, Nara Hospital, Kindai University School of Medicine
K. Sasaki
Head and Neck, Chiba Cancer Center
Y. Fujimoto
Department of Otorhinolaryngology, Nagoya University, Graduate School of Medicine
Y. Hasegawa
Department of Head and Neck Surgery, Aichi Cancer Center Hospital and Research Institute
T. Beppu
Division of Head and Neck Surgery, Saitama Cancer Center
H. Nishimori
Department of Hematology and Oncology, Okayama University Hospital
S. Hirano
Department of Otolaryngology-Head and Neck Surgery, Kyoto University Hospital
Y. Naka
Y. Matsushima
M. Fujii
Department of Otolaryngology, Eiju General Hospital
M. Tahara
Department of Head and Neck Medical Oncology, National Cancer Center Hospital East
Abstract Background 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). Methods 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. Results From April 2014 to August 2015, 97 patients with HNC were enrolled, of whom 94 received treatment. The incidence of grade ≥ 3 oral mucositis was 29% and 25% in the rebamipide 2% and 4% groups, respectively, compared with 39% in the placebo group. The proportion of patients who did not develop grade ≥ 3 oral mucositis by day 50 of treatment was 57.9% in the placebo group, whereas the proportion was 68.0% in the rebamipide 2% group and 71.3% in the rebamipide 4% group. The incidences of adverse events potentially related to the study drug were 16%, 26%, and 13% in the placebo, rebamipide 2%, and rebamipide 4% groups, respectively. There was no significant difference in treatment compliance among the groups. Conclusions The present phase II study suggests that mouth washing with rebamipide may be effective and safe for patients with HNC receiving chemoradiotherapy, and 4% liquid is the optimal dose of rebamipide. Trial registration ClinicalTrials.gov under the identifier NCT02085460 (the date of trial registration: March 11, 2014).
