Risk of rash and stomatitis with everolimus, a mammalian target of rapamycin (mTOR) inhibitor: A meta-analysis.

Abstract

e19556 Background: Everolimus, an mTOR inhibitor, is indicated for the treatment of patients with subependymal giant cell astrocytoma associated with tuberous sclerosis and advanced renal cell carcinoma. Mucocutaneous toxicities are the most commonly reported, and are assessed in oncology clinical trials as an adverse event based on the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTC AE) grading system for dermatologic toxicities. We systematically investigated the overall incidence and risk of rash and stomatitis in patients receiving everolimus. Methods: Relevant publications were identified from PubMed database (2001 to 2011). Eligible studies for analysis were limited to prospective Phase II-III clinical trials with 10mg per day dosing and the use of the NCI-CTC AE grading system, version 3.0. Incidence, relative risk (RR), and 95% confidence intervals were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies. Results: A total of 1,592 patients from 11 clinical trials were available for analysis. The overall incidences of all-grade and high-grade (grade ≥3) rash were 35.8% (95% CI: 28.4-43.9) and 1.3% (95% CI: 0.7-2.2), respectively. The overall incidences of all-grade and high-grade stomatitis were 55.7 % (CI: 48.0-63.2) and 5.5% (95% CI: 4.1-7.4). Everolimus was associated with significantly increased risk of all-grade rash and all-grade stomatitis (RR=2.74, 95% CI: 1.29-5.80; P<0.01 and RR=4.81, 95% CI: 2.87-8.05; P<0.001) in comparison with controls. The risk of high-grade rash was increased (RR=2.93, 95% CI: 0.50-17.14; p=0.23). The risk of high-grade stomatitis was significantly increased (RR=4.67, 95% CI: 1.38-15.81; P=0.013). Conclusions: Cancer patients treated with everolimus are at significant risk for developing mucocutaneous toxicities. Although the newest NCI-CTC AE version, 3.0, has made improvements by categorizing rash using more descriptive terms, these terms were rarely used in the studies analyzed. A more accurate grading system is urgently needed, in addition to further studies for prevention and treatment of these untoward toxicities.