Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice

Abstract

In recent years oral mucosal injury has been increasingly recognized as an important toxicity associated with mammalian target of rapamycin (mTOR) inhibitors, including in patients with breast cancer who are receiving everolimus. This review addresses the state‐of‐the‐science regarding mTOR inhibitor‐associated stomatitis (mIAS), and delineates its clinical characteristics and management. Given the clinically impactful pain associated with mIAS, this review also specifically highlights new research focusing on the study of the molecular basis of pain. The incidence of mIAS varies widely (2–78%). As reported across multiple mTOR inhibitor clinical trials, grade 3/4 toxicity occurs in up to 9% of patients. Managing mTOR‐associated oral lesions with topical oral, intralesional, and/or systemic steroids can be beneficial, in contrast to the lack of evidence supporting steroid treatment of oral mucositis caused by high‐dose chemotherapy or radiation. However, steroid management is not uniformly efficacious in all patients receiving mTOR inhibitors. Furthermore, technology does not presently exist to permit clinicians to predict a priori which of their patients will develop these lesions. There thus remains a strategic need to define the pathobiology of mIAS, the molecular basis of pain, and risk prediction relative to development of the clinical lesion. This knowledge could lead to novel future interventions designed to more effectively prevent mIAS and improve pain management if clinically significant mIAS lesions develop.

On the pathogenesis of mTOR inhibitor‐associated stomatitis (mIAS)—studies using an organotypic model of the oral mucosa

“…It is the latter that seems to have been an effective therapeutic target, although it is still unclear why an immunosuppressive agent (steroids) would be effective when mTORi are not. As recently proposed by Peterson and his colleagues, differences in mIAS risk among patients may well be associated with variations in individuals’ genomic response to everolimus (Peterson et al , ).…”

Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218

“…Significant oral mucositis and hypertriglyceridemia, accounting for four DLTS, occurred in a pediatric study of temsirolimus (15 mg/m 2 weekly) with vinorelbine and cyclophosphamide for rhabdomyosarcoma . mTOR inhibitor–associated stomatitis (mIAS) is recognized as a distinct entity with underlying pathobiology that is likely multifactorial, but may relate to dysregulation of cellular pathways leading to mucosal injury . We show that the combination of weekly vinblastine (4 mg/m 2 ) and temsirolimus (15 mg/m 2 ) is associated with significant toxicity and exceeds the MTD in pediatrics.…”

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

“…and detect preexisting mucosal disease [106]. Good oral health also relies on basic oral care interventions [33, [106][107][108][109][110] (Table 3). In a recent phase 2 prevention trial (SWISH trial), Rugo et al [111] reported on the prophylactic use of 10 mL of alcohol-free dexamethasone (0.5 mg/5 mL, four times daily for 8 weeks) mouthwash to prevent mIAS in patients receiving everolimus 10 mg/exemestane 25 mg for HR+, HER2− advanced or metastatic breast cancer.…”

“…Dose reduction, interruption, or discontinuation (see Table 4) mIAS may also be managed by dose adjustments. The severity and/or the recurrence of the lesions as well as the time needed to recover will determine whether full dosing can be resumed or whether dose reduction or discontinuation is required [101,102,110,114,115].…”