Prevention and treatment options for mTOR inhibitor-associated stomatitis

Mammalian target of rapamycin (mTOR), a serine–threonine protein kinase, operates in the phosphoinositide 3-kinase (PI3K)–protein kinase B (AKT)–mTOR signal transduction pathway regulating both normal and cancer cellular processes, including cell growth, proliferation, motility, survival, and protein and lipid synthesis.1 Genetic alterations affecting this pathway, including mutations in receptor tyrosine kinases PI3K and AKT, occur frequently in human cancers,2 supporting the rationale to develop drugs that target pathway components, such as mTOR inhibitors. Two mTOR inhibitors are currently approved by the US Food and Drug Administration for cancer treatment: temsirolimus, for advanced renal cell carcinoma (RCC; approved 2007)3 and everolimus, for advanced RCC (approved 2009), advanced pancreatic neuroendocrine tumors (pNET; approved 2011), and hormone receptor-positive (HR-positive), human epidermal growth factor receptor-2 (HER2)-negative advanced breast cancer (approved 2012).4 Another mTOR inhibitor, sirolimus, is approved for use as an immunosuppressive agent and prophylactic against organ rejection after kidney transplant.5 Stomatitis, inflammation of the oral mucosa with contributing factors of genetic predisposition, nutritional deficiencies, infections, and immunological or hematologic dysfunction,6 occurs frequently as a side effect associated with mTOR inhibitor treatment.7-9 Left untreated or managed unsatisfactorily, mTOR inhibitor-associated stomatitis (mIAS) may cause patients discomfort and trouble with maintaining adequate nutritional intake and proper oral hygiene, as well as strict adherence to cancer treatment. It is therefore important for health care providers of cancer patients receiving mTOR inhibitor treatment to be knowledgeable about this side effect. The purpose of the present systematic review of published literature is to provide a better understanding of the differential diagnosis of mIAS, the pathophysiology of mIAS, preventive strategies for patients initiating mTOR inhibitor treatment, and treatment options available to manage mIAS.