Natural history, management and pharmacokinetics of Everolimus-induced-oral ulcers: Insights into compliance issues

Background: Oral Ulcers is a well-recognised adverse event (AE) of mTOR inhibitors. Paradoxically, little is known about its natural history, risk factors, and basic management. Patients and methods: AEs of 79 patients prospectively enrolled in 6 phase I-II studies testing Everolimus were reviewed. The following parameters were analysed: incidence, severity, duration and associated AE. The association between OU and Everolimus dose, pharmacokinetics and the effectiveness of empiric treatments were explored. Results: OU, grade 3-4 OU, prolonged time under OU and RCOU (recurrent and chronic oral ulcer) were observed in 72% 11%, 30% and 25% patients, respectively. Patients with antecedent of prior chemotherapy, with PS 1, or receiving Everolimus in combination tended to present higher rates of prolonged time under OU and of grade 3-4 OU. As Everolimus daily dose increased, the median time to OU was shorter, the median duration was longer and OU incidence tended to increase. Simultaneously, OU tended to be associated with higher Everolimus exposure. None of the empiric treatments appeared effective against OU (preventive or curative intent). Conclusion: Everolimus-induced OU is a frequent, recurrent and sometimes harmful complication. A dose effect relationship is displayed. Its daily management remains challenging. OU represents a key issue in the compliance of mTOR inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.