A single-arm, phase 2 study of steroid-containing mouthwash for the prevention of everolimus-associated stomatitis in multiple tumor types
- 127 Downloads
Everolimus is a mammalian target of rapamycin inhibitor used in the treatment of multiple tumor types, and its most common toxicity, stomatitis, can affect patient quality of life. Recent studies in breast cancer have supported the efficacy of steroid mouthwash for the prevention of everolimus-associated stomatitis. However, a few studies have been reported to date, and none have examined this effect in other tumor types.
This single-arm phase 2 study was designed to evaluate the efficacy of steroid-containing mouthwash for the prevention of stomatitis in patients with multiple tumor types receiving everolimus. The primary outcome was incidence of grade ≥ 2 stomatitis at 8 weeks of everolimus with steroid-containing mouthwash prophylaxis. We also assessed the stability of steroid-containing mouthwash components.
Twenty-nine patients were evaluated, of which 76% had breast cancer and 24% had neuroendocrine tumors originating in the lung, gastrointestinal tract, pancreas, or of unknown primary origin. Grade ≥ 2 stomatitis incidence at 8 weeks was 28.1% (90% CI 16.2–46.1); the higher confidence limit exceeded the prespecified threshold of 30%. No patients developed grade ≥ 3 stomatitis. Most stomatitis occurred behind the oral cavity, with no lesions observed on the lips or floor of the mouth.
Our findings did not support a prophylactic effect of steroid-containing mouthwash on everolimus-associated stomatitis. Given the needs of prevention of everolimus-associated stomatitis in various tumor types, further studies in a larger population using a randomized controlled trial design are, therefore, required to confirm the efficacy of steroid-containing mouthwash.
KeywordsSteroid-containing mouthwash Breast cancer Neuroendocrine tumors Everolimus Prophylaxis Stomatitis
We thank Edanz Group for English editing a draft of this manuscript.
M.H.: conceptualization, data curation, formal analysis, investigation, resources and writing—original draft, and writing—review and editing. S.H.: formal analysis, data curation, investigation, methodology, and writing—review and editing. H.K.: project administration, investigation, resources, and methodology. M.T.: investigation, methodology, and resources. M.T.: data curation, formal analysis, methodology, investigation, writing—original draft, and writing—review and editing. S.H.: investigation, resources, supervision, and writing—review and editing. J.S.: investigation, resources, supervision, and writing—review and editing. M.A.: resources, supervision, and writing—review and editing. Y.M.: investigation, methodology, and resources. M.S.: investigation and resources. A.Y.: investigation and resources. N.G.: investigation and resources. Y.A.: investigation and resources. K.Y.: formal analysis, methodology, and supervision. H.I.: conceptualization, supervision, and writing—review and editing.
No specific funding has been provided for this study.
Compliance with ethical standards
Conflict of interest
Masaya Hattori received honoraria from Chugai Pharmaceutical, Eli Lilly Japan, Novartis Pharma, AstraZeneca, Pfizer Japan, and Eisai for work performed outside of the current study. Susumu Hijioka received honoraria from Novel Pharma, Novartis Pharma, and Tenjin Pharma for work performed outside of the current study. Hiroji Iwata received research funding from Chugai Pharmaceutical, MSD K.K, Eli Lilly Japan, and Novartis Pharma for work performed outside of the current study; received honoraria from Chugai Pharmaceutical, Daiichi Sankyo, and AstraZeneca for work performed outside of the current study; and is a member of scientific advisory board of Daiichi Sankyo, Chugai Pharmaceutical, Eli Lilly Japan, Kyowa Hakko Kirin, Pfizer Japan, Novartis Pharma, and AstraZeneca for work performed outside of the current study. The other authors have no conflicts of interest to declare.
- 4.Yao JC, Fazio N, Singh S et al (2016) Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 387(10022):968–977. https://doi.org/10.1016/S0140-6736(15)00817-X CrossRefGoogle Scholar
- 5.Martins F, de Oliveira MA, Wang Q et al (2013) A review of oral toxicity associated with mTOR inhibitor therapy in cancer patients. Oral Oncol 49(4):293–298. https://doi.org/10.1016/j.oraloncology.2012.11.008 CrossRefGoogle Scholar
- 7.Rugo HS, Seneviratne L, Beck JT et al (2017) Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial. Lancet Oncol. https://doi.org/10.1016/s1470-2045(17)30109-2 Google Scholar
- 13.Toi M, Masuda N, Andre F et al (2013) Everolimus plus trastuzumab and vinorelbine in Asian patients with HER2-positive metastatic breast cancer. In: Thirty-sixth annual CTRC-AACR San Antonio Breast Cancer Symposium, San Antonio. https://doi.org/10.1158/0008-5472.sabcs13-p4-12-19. Published December 2013
- 14.Toyama T, Jeong J, Srimuninnimit V et al (2017) Everolimus (EVE)+ letrozole (LET) in Asian patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC): results of a subgroup analysis from the BOLERO-4 study. In: ESMO Asia, Singapore. https://doi.org/10.1093/annonc/mdx654
- 15.Niikura N, Nakatukasa K, Amamiya T, Watanabe K-i, Hata H, Kikawa Y, Taniike N, Yamanaka T, Mitsunaga S, Nakagami K, Adachi M, Kondo N, Horii K, Hayashi N, Naito M, Kashiwabara K, Yamashita T, Umeda M, Mukai H, Ota Y (2019) Abstract P1–11-01: oral care evaluation to prevent oral mucositis in estrogen receptor positive metastatic breast cancer patients treated with everolimus (Oral Care-BC): a randomized controlled phase III trial. Cancer Res 79(4):P1-11-01-P11-11-01. https://doi.org/10.1158/1538-7445.sabcs18-p1-11-01 Google Scholar
- 18.Steven KH (1997) Adrenal cortical steroids. Drug facts and comparisons, 5th edn. Facts and Comparisons, Inc., St. LouisGoogle Scholar
- 20.Boers-Doets CB, Epstein JB, Raber-Durlacher JE et al (2012) Oral adverse events associated with tyrosine kinase and mammalian target of rapamycin inhibitors in renal cell carcinoma: a structured literature review. Oncologist 17(1):135–144. https://doi.org/10.1634/theoncologist.2011-0111 CrossRefGoogle Scholar