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Perspective

Current management of mTOR inhibitor-associated stomatitis

    Nikita C Shah

    *Author for correspondence:

    E-mail Address: nikita.shah@orlandohealth.com

    Breast Cancer Specialty Section, University of Florida Health Cancer Center – Orlando Health, 1400 South Orange Avenue, MP 760, Orlando, FL 32806, USA

    Search for more papers by this author

    Published Online:20 Oct 2015https://doi.org/10.2217/bmt.15.19

    Abstract

    mTOR inhibitor-associated stomatitis (mIAS) is an adverse event associated with mTOR inhibitor treatment for advanced cancers. mIAS tends to occur within 2 weeks of treatment start and resolve within weeks of symptom onset. mIAS is usually mild in severity and often self-limiting. Nevertheless, inadequately controlled mIAS can negatively affect patient function and treatment adherence. This review summarizes efficacy and mIAS safety data of mTOR inhibitors, and discusses prevention and treatment of mIAS. Patient cases are used to illustrate important practice points. Although mIAS has been recognized as a cancer treatment-related adverse event only in the last decade, several clinical studies are ongoing. This raises the expectation that management of mIAS in the future will be guided by strong evidence.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Lauring J, Park BH, Wolff AC. The phosphoinositide-3-kinase-Akt-mTOR pathway as a therapeutic target in breast cancer. J. Natl Compr. Canc. Netw. 11(6), 670–678 (2013).
      Medline CASGoogle Scholar
    • 2 Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat. Rev. Drug Discov. 13(2), 140–156 (2014).
      Medline CASGoogle Scholar
    • 3 Chia S, Gandhi S, Joy AA et al. Novel agents and associated toxicities of inhibitors of the pi3k/Akt/mtor pathway for the treatment of breast cancer. Curr. Oncol. 22(1), 33–48 (2015).
      Medline CASGoogle Scholar
    • 4 Yamnik RL, Digilova A, Davis DC, Brodt ZN, Murphy CJ, Holz MK. S6 kinase 1 rulates estrogen receptor alpha in control of breast cancer cell proliferation. J. Biol. Chem. 284(10), 6361–6369 (2009).
      Medline CASGoogle Scholar
    • 5 Afinitor®, prescribing information. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA (2015).
      Google Scholar
    • 6 Torisel®, prescribing information. Pfizer, Inc., Philadelphia, PA, USA (2014).
      Google Scholar
    • 7 Baselga J, Campone M, Piccart M et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366(6), 520–529 (2012).
      Medline CASGoogle Scholar
    • 8 Hudes G, Carducci M, Tomczak P et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356(22), 2271–2281 (2007).
      Medline CASGoogle Scholar
    • 9 Motzer RJ, Escudier B, Oudard S et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled Phase III trial. Lancet 372(9637), 449–456 (2008).
      Medline CASGoogle Scholar
    • 10 Yao JC, Shah MH, Ito T et al. Everolimus for advanced pancreatic neuroendocrine tumors. N. Engl. J. Med. 364(6), 514–523 (2011).
      Medline CASGoogle Scholar
    • 11 Demetri GD, Chawla SP, Ray-Coquard I et al. Results of an international randomized Phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J. Clin. Oncol. 31(19), 2485–2492 (2013).
      Medline CASGoogle Scholar
    • 12 Yardley DA, Noguchi S, Pritchard KI et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv. Ther. 30(10), 870–884 (2013).•• Reports final results of the BOLERO-2 study (median 18 months of follow-up), including final progression-free survival analysis.
      Medline CASGoogle Scholar
    • 13 Piccart M, Hortobagyi GN, Campone M et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-native advanced breast cancer: overall survival results from BOLERO-2. Ann. Oncol. 25(12), 2357–2362 (2014).
      Medline CASGoogle Scholar
    • 14 Rugo HS, Pritchard KI, Gnant M et al. Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2. Ann. Oncol. 25(4), 808–815 (2014).•• Reports the kinetics of everolimus-related adverse events, including mIAS, occurring in the BOLERO-2 study.
      Medline CASGoogle Scholar
    • 15 Afshar M, Pascoe J, Whitmarsh S, James N, Porfiri E. Temsirolimus for patients with metastatic renal cell carcinoma: outcomes in patients receiving temsirolimus within a compassionate use program in a tertiary referral center. Drug Des. Devel. Ther. 9, 13–19 (2015).
      Medline CASGoogle Scholar
    • 16 Panzuto F, Rinzivillo M, Fazio N et al. Real-world study of everolimus in advanced progressive neuroendocrine tumors. Oncologist 19(9), 966–974 (2014).
      Medline CASGoogle Scholar
    • 17 Jerusalem G, Mariani G, Ciruelos Gil EM et al. Everolimus in combination with exemestane in hormone receptor-positive, locally advanced or metastatic breast cancer patients progressing on prior non-steroidal aromatase inhibitors (NSAIs): BALLET study (CRAD001YIC04). Presented at: San Antonio Breast Cancer Symposium (SABCS). San Antonio, TX, USA, 9–13 December 014.
      Google Scholar
    • 18 Jackisch C, Grischke E-M, Schneeweiss A et al. Subgroup analysis of efficacy in routine treatment – results of the 2nd interim analysis of BRAWO, the non-interventional trial ‘Breast Cancer Treatment With Everolimus and Exemestane for HR+ Women’. Presented at: San Antonio Breast Cancer Symposium (SABCS). San Antonio, TX, USA, 9–13 December 2014.
      Google Scholar
    • 19 Tesch H, Stoetzer O, Decker T et al. 4EVER – final efficacy analysis of the Phase IIIb, multi-center, open-label study for postmenopausal women with estrogen receptor-positive locally advanced or metastatic breast cancer treated with everolimus in combination with exemestane. Presented at: San Antonio Breast Cancer Symposium (SABCS). San Antonio, TX, USA, 9–13 December 2014.
      Google Scholar
    • 20 National Cancer Insititute. Common Terminology Criteria for Adverse Events v3.0 (CTCAE).http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf
      Google Scholar
    • 21 National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v4.03. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
      Google Scholar
    • 22 Lueftner D, Schuetz F, Grischke EM et al. Breast cancer treatment with everolimus and exemestane for ER+ women: results of the first interim analysis of the noninterventional trial BRAWO. J. Clin. Oncol. 32(Suppl. 5), abstract 578 (2014).
      Google Scholar
    • 23 Boers-Doets CB, Epstein JB, Raber-Durlacher JE et al. 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 (2012).
      Medline CASGoogle Scholar
    • 24 Keefe DM, Schubert MM, Elting LS et al. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 109(5), 820–831 (2007).• Practice guidelines for chemotherapy- and/or radiation therapy-related oral mucositis.
      Medline CASGoogle Scholar
    • 25 Sonis S, Treister N, Chawla S, Demetri G, Haluska F. Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients. Cancer 116(1), 210–215 (2010).•• Represents the earliest clinical description of mTOR inhibitor-associated stomatitis (mIAS).
      Medline CASGoogle Scholar
    • 26 Epstein JB, Thariat J, Bensadoun RJ et al. Oral complications of cancer and cancer therapy: from cancer treatment to survivorship. CA Cancer J. Clin. 62(6), 400–422 (2012).
      MedlineGoogle Scholar
    • 27 Scully C. Clinical practice. Aphthous ulceration. N. Engl. J. Med. 355(2), 165–172 (2006).• Comprehensive overview of the management of aphthous ulcers.
      Medline CASGoogle Scholar
    • 28 de Oliveira MA, Martins EMF, Wang Q et al. Clinical presentation and management of mTOR inhibitor-associated stomatitis. Oral Oncol. 47(10), 998–1003 (2011).
      MedlineGoogle Scholar
    • 29 Rubenstein EB, Peterson DE, Schubert M et al. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 100(Suppl. 9), 2026–2046 (2004).
      MedlineGoogle Scholar
    • 30 ClinicalTrials Database: NCT01265810. https://clinicaltrials.gov/ct2/show/NCT01265810?term=NCT01265810&rank=1
      Google Scholar
    • 31 ClinicalTrials Database: NCT02376985. https://clinicaltrials.gov/ct2/show/NCT02376985?term=NCT02376985&rank=1
      Google Scholar
    • 32 ClinicalTrials Database: NCT02015559. https://clinicaltrials.gov/ct2/show/NCT02015559?term=NCT02015559&rank=1
      Google Scholar
    • 33 ClinicalTrials Database: NCT01952847. https://clinicaltrials.gov/ct2/show/NCT01952847?term=NCT01952847&rank=1
      Google Scholar
    • 34 ClinicalTrials Database: NCT02069093. https://clinicaltrials.gov/ct2/show/NCT02069093?term=NCT02069093&rank=1
      Google Scholar
    • 35 ClinicalTrials Database: NCT02229136. https://clinicaltrials.gov/ct2/show/NCT02229136?term=NCT02229136&rank=1
      Google Scholar
    • 36 Chelf JH, Deshler AM, Thiemann KM, Dose AM, Quella SK, Hillman S. Learning and support preferences of adult patients with cancer at a comprehensive cancer center. Oncol. Nurs. Forum 29(5), 863–867 (2002).
      MedlineGoogle Scholar
    • 37 Borowski B, Benhamou E, Pico JL, Laplanche A, Margainaud JP, Hayat M. Prevention of oral mucositis in patients treated with high-dose chemotherapy and bone marrow transplantation: a randomised controlled trial comparing two protocols of dental care. Eur. J. Cancer B Oral Oncol. 30B(2), 93–97 (1994).
      Medline CASGoogle Scholar
    • 38 Cheng KK, Molassiotis A, Chang AM, Wai WC, Cheung SS. Evaluation of an oral care protocol intervention in the prevention of chemotherapy-induced oral mucositis in paediatric cancer patients. Eur. J. Cancer 37(16), 2056–2063 (2001).
      Medline CASGoogle Scholar
    • 39 Dudjak LA. Mouth care for mucositis due to radiation therapy. Cancer Nurs. 10(3), 131–140 (1987).
      Medline CASGoogle Scholar
    • 40 Graham KM, Pecoraro DA, Ventura M, Meyer CC. Reducing the incidence of stomatitis using a quality assessment and improvement approach. Cancer Nurs. 16(2), 117–122 (1993).
      Medline CASGoogle Scholar
    • 41 Kenny SA. Effect of two oral care protocols on the incidence of stomatitis in hematology patients. Cancer Nurs. 13(6), 345–353 (1990).
      Medline CASGoogle Scholar
    • 42 Larson PJ, Miaskowski C, MacPhail L et al. The PRO-SELF Mouth Aware program: an effective approach for reducing chemotherapy-induced mucositis. Cancer Nurs. 21(4), 263–268 (1998).
      Medline CASGoogle Scholar
    • 43 Levy-Polack MP, Sebelli P, Polack NL. Incidence of oral complications and application of a preventive protocol in children with acute leukemia. Spec. Care Dentist 18(5), 189–193 (1998).
      Medline CASGoogle Scholar
    • 44 Yeager KA, Webster J, Crain M, Kasow J, McGuire DB. Implementation of an oral care standard for leukemia and transplantation patients. Cancer Nurs. 23(1), 40–47; quiz 47–48 (2000).
      Medline CASGoogle Scholar
    • 45 Pilotte AP, Hohos MB, Polson KM, Huftalen TM, Treister N. Managing stomatitis in patients treated with mammalian target of rapamycin inhibitors. Clin. J. Oncol. Nurs. 15(5), e83–e89 (2011).
      MedlineGoogle Scholar
    • 46 Bonnaure-Mallet M, Bunetel L, Tricot-Doleux S, Guerin J, Bergeron C, LeGall E. Oral complications during treatment of malignant diseases in childhood: effects of tooth brushing. Eur. J. Cancer 34(10), 1588–1591 (1998).
      Medline CASGoogle Scholar
    • 47 Martins F, de Oliveira MA, Wang Q et al. A review of oral toxicity associated with mTOR inhibitor therapy in cancer patients. Oral Oncol. 49(4), 293–298 (2013).
      Medline CASGoogle Scholar
    • 48 Rugo HS, Chambers MS, Litton JK et al. Prevention of stomatitis in patients with hormone receptor-positive advanced breast cancer treated with everolimus plus exemestane: a Phase II study of a steroid-based mouthwash. J. Clin. Oncol. 32(Suppl. 5), abstract TPS661 (2014).
      Google Scholar
    • 49 ResearchGate. Boers-Doets CB, Nicolatou-Galitis O, Lalla RV. The mIAS scale: a scale to measure mTOR inhibitor-associated stomatitis. www.researchgate.net/publication/259802622_The_mIAS_scale_a_scale_to_measure_mTOR_inhibitor-associated_stomatitis• A proposed, although thus far unvalidated, set of criteria to grade the severity of mIAS.
      Google Scholar
    • 50 Chuang P, Langone AJ. Clobetasol ameliorates aphthous ulceration in renal transplant patients on sirolimus. Am. J. Transplant. 7(3), 714–717 (2007).
      Medline CASGoogle Scholar
    • 51 Tom WC. Magic mouthwash recipes. Pharm. Lett. Prescrib. Lett. 25(11), 251103 (2009).• A collection of commonly used magic mouthwash formulations.
      Google Scholar
    • 52 Aapro M, Andre F, Blackwell K et al. Adverse event management in patients with advanced cancer receiving oral everolimus: focus on breast cancer. Ann. Oncol. 25(4), 763–773 (2014).
      Medline CASGoogle Scholar