International Journal of Clinical Oncology

, Volume 24, Issue 10, pp 1320–1327 | Cite as

A single-arm, phase 2 study of steroid-containing mouthwash for the prevention of everolimus-associated stomatitis in multiple tumor types

  • Masaya HattoriEmail author
  • Sumitaka Hagiwara
  • Haruru Kotani
  • Michiko Tatematsu
  • Masahiko Tachi
  • Susumu Hijioka
  • Junichi Shimizu
  • Masashi Andoh
  • Yasunari Mizuno
  • Masataka Sawaki
  • Akiyo Yoshimura
  • Naomi Gondo
  • Yayoi Adachi
  • Kenichi Yoshimura
  • Hiroji Iwata
Original Article



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.


Steroid-containing mouthwash Breast cancer Neuroendocrine tumors Everolimus Prophylaxis Stomatitis 



We thank Edanz Group for English editing a draft of this manuscript.

Author contributions

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.

Supplementary material

10147_2019_1476_MOESM1_ESM.docx (371 kb)
Supplementary material 1 (DOCX 371 kb)


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Copyright information

© Japan Society of Clinical Oncology 2019

Authors and Affiliations

  • Masaya Hattori
    • 1
    Email author
  • Sumitaka Hagiwara
    • 2
  • Haruru Kotani
    • 1
  • Michiko Tatematsu
    • 3
  • Masahiko Tachi
    • 4
  • Susumu Hijioka
    • 5
  • Junichi Shimizu
    • 6
  • Masashi Andoh
    • 7
  • Yasunari Mizuno
    • 3
  • Masataka Sawaki
    • 1
  • Akiyo Yoshimura
    • 1
  • Naomi Gondo
    • 1
  • Yayoi Adachi
    • 1
  • Kenichi Yoshimura
    • 8
  • Hiroji Iwata
    • 1
  1. 1.Department of Breast OncologyAichi Cancer CenterNagoyaJapan
  2. 2.Department of Head and Neck SurgeryAichi Cancer CenterNagoyaJapan
  3. 3.Department of PharmacyAichi Cancer CenterNagoyaJapan
  4. 4.Aichi Prefectural Institute of Public HealthNagoyaJapan
  5. 5.Department of Hepatobiliary and Pancreatic OncologyNational Cancer CenterTokyoJapan
  6. 6.Department of Thoracic OncologyAichi Cancer CenterNagoyaJapan
  7. 7.Department of Clinical OncologyAichi Cancer CenterNagoyaJapan
  8. 8.Innovative Clinical Research CenterKanazawa UniversityKanazawaJapan

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