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Otorhinolaryngological Toxicities of New Drugs in Oncology


Many new or relatively new cancer drugs—personalized anticancer agents—have been approved for use in various clinical settings in oncology or are still under evaluation in clinical trials. Targeted therapies as well as new immune checkpoint blockers have toxicity profiles that differ from conventional cytotoxic chemotherapy, and many can cause adverse effects that affect the mouth and pharynx, the nasal cavities, and the larynx. This review aims to provide an overview of current knowledge concerning these side effects and contemporary management. Adverse effects of the mouth/pharynx, nasal cavities, larynx, and cochlear-vestibular system are generally low grade (according to the Common Terminology Criteria for Adverse Events) and generally present non-life-threatening symptoms. However, the impact on patients’ quality of life could be important. The incidence and severity vary according to the drug, its target(s), and dose, but there are currently no known predictive factors, and each patient has an individual toxicity profile. Management guidelines are based on expert opinion. These ear, nose, and throat adverse effects are not frequently mentioned in the literature because of the often non-specific nature of the symptoms and their mildness, but also the absence of specific treatment. These symptoms can contribute to decreased quality of life and lead to drug compliance issues if not diagnosed and managed appropriately.

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Anaplastic Lymphoma Kinase


AXL receptor tyrosine kinase


B-raf proto-oncogene, serine/threonine kinase


RAF proto-oncogene serine/threonine-protein kinase


Common Terminology Criteria for Adverse Events


Cytotoxic T-lymphocyte associated protein 4


Epidermal growth factor


Epidermal growth gactor receptor


Ear, nose and throat


Fms Related tyrosine kinase 3


Fibroblast growth factor receptor


Human epidermal growth factor receptor


Immune checkpoint blockade


KIT Proto-oncogene receptor tyrosine kinase


Mitogen-Activated Protein Kinases


MET proto-oncogene, receptor tyrosine kinase


mTOR inhibitor-associated stomatitis


Medication–related osteonecrosis of the jaw


Mammalian target of rapamycin


Protein kinase inhibitor


Poly (ADP-ribose) polymerase


Platelet-derived growth factor


Platelet-derived growth factor receptor


Programmed cell death 1


Programmed cell death ligand 1


Phosphatidylinositol-4,5-bisphosphate 3-kinase


Phosphatidylinositol glycan anchor biosynthesis class F


REarranged during transfection


Tyrosine kinase inhibitor


Vascular endothelial growth factor


Vascular endothelial growth factor receptor


  1. Rosti G, Castagnetti F, Gugliotta G, Baccarani M. Tyrosine kinase inhibitors in chronic myeloid leukaemia: which, when, for whom? Nat Rev Clin Oncol. 2017;14(3):141–4.

  2. U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0. Available at Accessed Dec 2016.

  3. European Medicines Agency. Accessed 15 Dec 2016.

  4. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6.

    CAS  Article  PubMed  Google Scholar 

  5. Weis SM, Cheresh DA. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med. 2011;17(11):1359–70.

    CAS  Article  PubMed  Google Scholar 

  6. Albiges L, Izzedine H, Ederhy S, et al. Axitinib in metastatic renal carcinomas: update of knowledge about side effects. Bull Cancer. 2014;101(10):976–88.

    PubMed  Google Scholar 

  7. Alasker A, Meskawi M, Sun M, et al. A contemporary update on rates and management of toxicities of targeted therapies for metastatic renal cell carcinoma. Cancer Treat Rev. 2013;39(4):388–401.

    CAS  Article  PubMed  Google Scholar 

  8. Peterson DE, Boers-Doets CB, Bensadoun RJ, Herrstedt J, Committee EG. Management of oral and gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Ann Oncol. 2015;26(Suppl 5):v139–51.

    Article  PubMed  Google Scholar 

  9. Peterson DE, O’Shaughnessy JA, Rugo HS, et al. Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice. Cancer Med. 2016;5(8):1897–907.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Melosky B, Hirsh V. Management of common toxicities in metastatic NSCLC related to anti-lung cancer therapies with EGFR-TKIs. Front Oncol. 2014;4:238.

    PubMed  PubMed Central  Google Scholar 

  11. Melosky B, Leighl NB, Rothenstein J, Sangha R, Stewart D, Papp K. Management of EGFR TKI-induced dermatologic adverse events. Curr Oncol. 2015;22(2):123–32.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Kwitkowski VE, Prowell TM, Ibrahim A, et al. FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma. Oncologist. 2010;15(4):428–35.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Yuan A, Kurtz SL, Barysauskas CM, Pilotte AP, Wagner AJ, Treister NS. Oral adverse events in cancer patients treated with VEGFR-directed multitargeted tyrosine kinase inhibitors. Oral Oncol. 2015;51(11):1026–33.

    CAS  Article  PubMed  Google Scholar 

  14. LeVeque FG, Montgomery M, Potter D, et al. A multicenter, randomized, double-blind, placebo-controlled, dose-titration study of oral pilocarpine for treatment of radiation-induced xerostomia in head and neck cancer patients. J Clin Oncol. 1993;11(6):1124–31.

    CAS  Article  PubMed  Google Scholar 

  15. National Comprehensive Cancer Network Clinical Practice Guidelines for Head and Neck Cancer. NCCN head-and-neck Version 2.2014 NCCN, Inc. 701 2014.

  16. Simcock R, Fallowfield L, Monson K, et al. ARIX: a randomised trial of acupuncture v oral care sessions in patients with chronic xerostomia following treatment of head and neck cancer. Ann Oncol. 2013;24(3):776–83.

    CAS  Article  PubMed  Google Scholar 

  17. Blom M, Lundeberg T. Long-term follow-up of patients treated with acupuncture for xerostomia and the influence of additional treatment. Oral Dis. 2000;6(1):15–24.

    CAS  Article  PubMed  Google Scholar 

  18. Kaymakcalan MD, Xie W, Albiges L, et al. Risk factors and model for predicting toxicity-related treatment discontinuation in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy: results from the international metastatic renal cell carcinoma database consortium. Cancer. 2016;122(3):411–9.

    CAS  Article  PubMed  Google Scholar 

  19. Dodson TB. The frequency of medication-related osteonecrosis of the jaw and its associated risk factors. Oral Maxillofac Surg Clin North Am. 2015;27(4):509–16.

    Article  PubMed  Google Scholar 

  20. Patel V, Kelleher M, Sproat C, Kwok J, McGurk M. New cancer therapies and jaw necrosis. Br Dent J. 2015;219(5):203–7.

    CAS  Article  PubMed  Google Scholar 

  21. Khan AA, Morrison A, Hanley DA, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. 2015;30(1):3–23.

    Article  PubMed  Google Scholar 

  22. Guarneri V, Miles D, Robert N, et al. Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer. Breast Cancer Res Treat. 2010;122(1):181–8.

    CAS  Article  PubMed  Google Scholar 

  23. Garuti F, Camelli V, Spinardi L, Bucci L, Trevisani F. Osteonecrosis of the jaw during sorafenib therapy for hepatocellular carcinoma. Tumori. 2016;102(Suppl 2):69–70.

  24. Ruggiero SL, Dodson TB, Fantasia J, et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw–2014 update. J Oral Maxillofac Surg. 2014;72(10):1938–56.

    Article  PubMed  Google Scholar 

  25. Rosella D, Papi P, Giardino R, Cicalini E, Piccoli L, Pompa G. Medication-related osteonecrosis of the jaw: clinical and practical guidelines. J Int Soc Prev Commun Dent. 2016;6(2):97–104.

    Article  Google Scholar 

  26. Kim KM, Rhee Y, Kwon YD, Kwon TG, Lee JK, Kim DY. Medication related osteonecrosis of the jaw: 2015 position statement of the Korean Society for Bone and Mineral Research and the Korean Association of Oral and Maxillofacial Surgeons. J Bone Metab. 2015;22(4):151–65.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Saad F, Brown JE, Van Poznak C, et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol. 2012;23(5):1341–7.

    CAS  Article  PubMed  Google Scholar 

  28. Advisory Committee for Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committee. September 9. Accessed 15 Dec 2016.

  29. Pruliere-Escabasse V, Gomez-Roca C, Escudier E, et al. Rhinitis in patients treated with a combination of an mTOR inhibitor and an EGFR inhibitor. Onkologie. 2010;33(7):401–2.

    Article  PubMed  Google Scholar 

  30. Ruiz JN, Belum VR, Boers-Doets CB, et al. Nasal vestibulitis due to targeted therapies in cancer patients. Support Care Cancer. 2015;23(8):2391–8.

    Article  PubMed  PubMed Central  Google Scholar 

  31. D’Amico M, Pagano M, Pasa A, et al. An observational study of nasal cavity toxicity in cancer patients treated with bevacizumab. Expert Opin Drug Saf. 2014;13(11):1437–42.

    Article  PubMed  Google Scholar 

  32. Ramiscal JA, Jatoi A. Nasal septal perforation from bevacizumab: a discussion of outcomes, management, and pharmacovigilance. Curr Oncol Rep. 2012;14(4):307–10.

    CAS  Article  PubMed  Google Scholar 

  33. Mailliez A, Baldini C, Van JT, Servent V, Mallet Y, Bonneterre J. Nasal septum perforation: a side effect of bevacizumab chemotherapy in breast cancer patients. Br J Cancer. 2010;103(6):772–5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Saavedra E, Hollebecque A, Soria JC, Hartl DM. Dysphonia induced by anti-angiogenic compounds. Invest New Drugs. 2014;32(4):774–82.

    CAS  Article  PubMed  Google Scholar 

  35. Ovnat Tamir S, Gershnabel Milk D, Roth Y, et al. Laryngeal side effects of tyrosine kinase inhibitors. J Voice. 2016;30(5):606–10.

    Article  PubMed  Google Scholar 

  36. Hartl DM, Bahleda R, Hollebecque A, Bosq J, Massard C, Soria JC. Bevacizumab-induced laryngeal necrosis. Ann Oncol. 2012;23(1):276–8.

    CAS  Article  PubMed  Google Scholar 

  37. Hartl DM, Ferte C, Loriot Y, et al. Dysphonia induced by vascular endothelium growth factor/vascular endothelium growth factor receptor inhibitors. Invest New Drugs. 2010;28(6):884–6.

    CAS  Article  PubMed  Google Scholar 

  38. Naidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26(12):2375–91.

    CAS  PubMed  Google Scholar 

  39. Abdel-Wahab N, Shah M, Suarez-Almazor ME. Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports. PLoS One. 2016;11(7):e0160221.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Morita S, Nakamaru Y, Obara N, Masuya M, Fukuda S. Characteristics and prognosis of hearing loss associated with Vogt-Koyanagi-Harada disease. Audiol Neuro-otol. 2014;19(1):49–56.

    Google Scholar 

  41. Villadolid J, Amin A. Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. Transl Lung Cancer Res. 2015;4(5):560–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016;27(4):559–74.

    CAS  Article  PubMed  Google Scholar 

  43. European Organisation for Research and Treatment of Cancer. Accessed 15 Dec 2016.

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This article was written by members and invitees of the International Head and Neck Scientific Group (

No funding or sponsorship was received for this study or publication of this article. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.


Dana M. Hartl, Daphné Morel, Erika Saavedra, Christophe Massard, Alessandra Rinaldo, Nabil F. Saba, Alfio Ferlito, and J.C. Soria have nothing to disclose.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

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Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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Correspondence to Dana M. Hartl.

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Hartl, D.M., Morel, D., Saavedra, E. et al. Otorhinolaryngological Toxicities of New Drugs in Oncology. Adv Ther 34, 866–894 (2017).

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  • Mucositis
  • Oncology
  • Protein kinase inhibitors
  • Small molecule inhibitors