Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors

Development of biological targeted therapies and immune checkpoint inhibitors has redefined the treatment for many cancers; however, the increasing use of new protocols has led to physicians observing a new spectrum of toxicities. To date, oral adverse events induced by these new anticancer therapies have been mainly reported using nonspecific terminology ("stomatitis," "mucosal inflammation," "mucositis") and remain poorly characterized, with the exception of mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis. Oral toxicities of targeted therapies often display very characteristic features which clearly differ from classic oral injuries observed with cytotoxic chemotherapy and/or radiotherapy. In addition, they frequently affect more than 20% of treated patients and can lead to a significant morbidity or permanent treatment discontinuation. Oral mucosal toxicities described in this review include mTOR inhibitor-associated stomatitis (mIAS); stomatitis, benign migratory glossitis, and osteonecrosis of the jaw associated with multi-targeted kinase inhibitors of the VEGF and PDGF receptors; mucositis induced by EGFR inhibitors (in monotherapy or in combination with head and neck radiotherapy and/or chemotherapy); hyperkeratotic lesions with BRAF inhibitors; pigmentary changes and lichenoid reactions secondary to imatinib; and more recent data on the "Osler-Weber-Rendu-like syndrome" described with the antibody-drug conjugate, TDM-1. Finally, we provide, to our knowledge, the first available structured data on oral toxicities induced by the new recently FDA- and EMA-approved monoclonal antibodies targeting PD-1. Clinical management of these targeted therapy-related oral changes is also discussed.