The effectiveness of rebamipide mouthwash therapy for radiotherapy and chemoradiotherapy-induced oral mucositis in patients with head and neck cancer: a systematic review and meta-analysis

Shinsuke Akagi, Takashi Fujiwara, Mai Nishida, Akiko Okuda, Yuka Nagao, Toshikatsu Okuda, Hidenori Tokuda, Kazunobu Takayanagi, Shinsuke Akagi, Takashi Fujiwara, Mai Nishida, Akiko Okuda, Yuka Nagao, Toshikatsu Okuda, Hidenori Tokuda, Kazunobu Takayanagi

Abstract

Background: Oral mucositis is a frequent and severe adverse event in patients undergoing chemoradiotherapy for head and neck cancers, especially grade 3 or 4 mucositis. Occurrence may result in drop-out from treatment, thereby reducing survival. We aimed to clarify the effectiveness and safety of rebamipide mouthwash for oral mucositis in patients with head and neck cancer receiving treatment.

Methods: We carried out a systematic review and meta-analysis of patients with head and neck cancer who were treated with rebamipide mouthwash. We searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL), and the World Health Organization (WHO) International Clinical Trial Registry Platform. The primary outcome was the incidence of severe oral mucositis, and secondary outcomes were time from treatment start to onset of oral mucositis, the response rate of radiotherapy, and any adverse events.

Results: We included three studies comparing rebamipide versus placebo, all of which evaluating chemoradiotherapy induced oral mucositis. The chemotherapeutic agent was docetaxel in one study and cisplatin in the remaining two. Radiotherapy in each study consisted of 3D-conformal radiation therapy, intensity modulated radiation therapy and conventional radiation therapy, respectively. The calculated odds ratio was 0.29 [95% confidence interval (CI): 0.15 to 0.55], showing a positive association in the three studies between the incidence of grade 3-4 oral mucositis and chemotherapy for head and neck cancer. One study reported an onset of oral mucositis and the time to onset was 14.6 ± 6.4 days for the rebamipide group and 11.2 ± 4.4 days for placebo. One study reported a complete response of 8.3% for placebo and 16.7% for the rebamipide the group, and the partial response was 91.7 and 75.0%, respectively. Adverse events were reported in two studies to be 6.1 and 11.6% for placebo, and 19.4 and 26.0% in the rebamipide group, respectively.

Conclusions: Rebamipide mouthwash is effective in the prevention of severe mucositis and stomatitis. However, evaluation of adverse events in observational studies are needed.

Keywords: Adverse event; Chemoradiotherapy; Chemotherapy; Head and neck cancer; Meta-analysis; Mouthwash; Mucositis; Rebamipide.

Conflict of interest statement

Competing interestsThe authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Process of study selection
Fig. 2
Fig. 2
Risk of bias graph: review authors’ judgement about each risk of bias item presented as percentages across all included trials
Fig. 3
Fig. 3
A forest plot of meta-analysis of a comparison of incidence of grade 3–4 mucositis between rebamipide and placebo

References

    1. Nutting C. Radiotherapy in head and neck cancer management: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol. 2016;130(S2):S66–S67. doi: 10.1017/S0022215116000463.
    1. Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007;357:1705–1715. doi: 10.1056/NEJMoa070956.
    1. Nguyen-Tan PF, Zhang Q, Ang KK, Weber RS, Rosenthal DI, Soulieres D, et al. Randomized phase III trial to test accelerated versus standard fractionation in combination with concurrent cisplatin for head and neck carcinomas in the radiation therapy oncology group 0129 trial: long-term report of efficacy and toxicity. J Clin Oncol. 2014;32:3858–3866. doi: 10.1200/JCO.2014.55.3925.
    1. Trotti A, Bellm LA, Epstein JB, Frame D, Fuchs HJ, Gwede CK, et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol. 2003;66:253–262. doi: 10.1016/S0167-8140(02)00404-8.
    1. Prescribing information: Mucosta® tablets 100mg, Ohtsuka Japan Inc, 2017 (In Japanese). Available from: .
    1. Matsuda T, Yamada H, Hoshi K, Ichikawa Y, Sakane T, Mizushima Y. The beneficial effect of rebamipide on recurrent oral aphthous ulcers in Behcet’s disease. J Clin Exp Med. 1994;170:773–774.
    1. Matsuda T, Ohno S, Hirohata S, Miyanaga Y, Ujihara H, Inaba G, et al. Efficacy of rebamipide as adjunctive therapy in the treatment of recurrent oral aphthous ulcers in patients with Behçet’s disease: a randomized, double-blind, placebo-controlled study. Drugs R D. 2003;4:19–28. doi: 10.2165/00126839-200304010-00002.
    1. Nabeta I, Nakamura K, Kimura M, Kaya M, Tsuneizumi M, Nakagami K, et al. The effect of rebamipide fir prevention of mucositis associated with anthracycline chemotherapy for breast cancer. J Jpn Soc Hosp Pharm. 2010;46:1629–1634.
    1. Yasuda T, Chiba H, Satomi T, Matsuo A, Kaneko T, Chikazu D, et al. Preventive effect of rebamipide gargle on chemoradiotherpy-induced oral mucositis in patients with oral cancer: a pilot study. J Oral Maxillofac Res. 2011;2(4):e3.
    1. Yokota T, Ogawa T, Takahashi S, Okami K, Fujii T, Tanaka K, et al. 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. 2017;17:314. doi: 10.1186/s12885-017-3295-4.
    1. Chaitanya B, Pai KM, Yathiraj PH, Fernandes D, Chhaparwal Y. Rebamipide gargle in preventive management of chemo-radiotherapy induced oral mucositis. Oral Oncol. 2017;72:179–182. doi: 10.1016/j.oraloncology.2017.07.024.
    1. Worthington HV, Clarkson JE, Bryan G, Furness S, Glenny A-M, Littlewood A, et al. Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev. 2011;4:CD000978.
    1. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6:e1000100. doi: 10.1371/journal.pmed.1000100.
    1. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981;47:207–214. doi: 10.1002/1097-0142(19810101)47:1<207::AID-CNCR2820470134>;2-6.
    1. RTOG: RTOG/EORTC Late Radiaton Morbidity Scoring Scheme. . Accessed 4 Mar 2019.
    1. Mazumdar M, Smith A, Schwartz LH. A statistical simulation study finds discordance between WHO criteria and RECIST guideline. J Clin Epidemiol. 2004;57:358–365. doi: 10.1016/j.jclinepi.2003.07.015.
    1. Higgins JPT, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0 [updated March 2011]: The Cochrane Collaboration; 2011. . Accessed 4 Mar 2019.
    1. Kishimoto S, Fujimura J, Machino H, Shimamoto T, Kobayashi H, Shimizu S, et al. Therapeutic effects of oral rebamipide and in combination with cimetidine on experimental gastritis in rats. Res Commun Chem Pathol Pharmacol. 1992;78:259–277.
    1. Yamasaki K, Sakurai K. Role of lipid peroxidation in protection of rats by rebamipide against gastric mucosal lesions induced by stress plus indomethacin. Pathophysiology. 1994;1:251–257. doi: 10.1016/0928-4680(94)90006-X.
    1. Ishihara K, Komuro Y, Nishiyama N, Yamasaki K, Hotta K. Effect of rebamipide on mucus secretion by endogenous prostaglandin-independent mechanism in rat gastric mucosa. Arzneimittelforschung. 1992;42:1462–1466.
    1. Ogino K, Hobara T, Ishiyama H, Yamasaki K, Kobayashi H, Izumi Y, Oka S. Antiulcer mechanism of action of rebamipide, a novel antiulcer compound, on diethyldithiocarbamate-induced antral gastric ulcers in rats. Eur J Pharmacol. 1992;212:9–13. doi: 10.1016/0014-2999(92)90065-C.
    1. Yoshikawa T, Naito Y, Nakamura S, Nishimura S, Kaneko T, Iinuma S, et al. Effect of rebamipide on lipid peroxidation and gastric mucosal injury induced by indometacin in rats. Arzneimittelforschung. 1993;43:1327–1330.
    1. Naito Y, Yoshikawa T, Tanigawa T, Sakurai K, Yamasaki K, Uchida M, et al. Hydroxyl radical scavenging by rebamipide and related compounds: electron paramagnetic resonance study. Free Radic Biol Med. 1995;18:117–123. doi: 10.1016/0891-5849(94)00110-6.
    1. Suzuki M, Miura S, Mori M, Kai A, Suzuki H, Fukumura D, et al. Rebamipide, a novel antiulcer agent, attenuates helicobacter pyloni induced gastric mucosal cell injury associated with neutrophil derived oxidants. Gut. 1994;35:1375–1378. doi: 10.1136/gut.35.10.1375.
    1. Pignon JP, Bourhis J, Domenge C, Designé L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet. 2000;355:949–955. doi: 10.1016/S0140-6736(00)90011-4.
    1. Wendt TG, Grabenbauer GG, Rödel CM, Thiel HJ, Aydin H, Rohloff R, et al. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol. 1998;16:1318–1324. doi: 10.1200/JCO.1998.16.4.1318.
    1. Kim CD, Hong KW. Preventive effect of rebamipide on gastric lesions induced by ischemia-reperfusion in the rat. J Pharmacol Exp Ther. 1995;275:340–344.
    1. Masamune A, Yoshida M, Sakai Y, Shimosegawa T. Rebamipide inhibits ceramide-induced Interleukin-8 production in Kato III human gastric Cancer cells. J Pharmacol Exp Thr. 2001;298:485–492.
    1. Baharvand M, Hamian M, Moosavizadeh MA, Mortazavi A, Ameri A. Phenytoin mouthwash to treat cancer therapy-induced oral mucositis: a pilot studyPrimaryneuroendocrine carcinoma of breast: a rare tumor. Indian J Cancer. 2015;52:81–85. doi: 10.4103/0019-509X.175597.

Source: PubMed

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