Incidence and risk of rash to mTOR inhibitors in cancer patients – a meta-analysis of randomized controlled trials

Abstract

Background. Inhibitors of the mammalian target of rapamycin (mTOR) are currently approved for the treatment of several cancers, and their use is associated with serious rash, which affects patient ' s quality of life and leads to undesirable dose reductions or interruptions. A meta-analysis of randomized controlled trials (RCTs) was performed to determine the overall risk of developing high-grade rash with mTOR inhibitors in cancer patients. Methods. We searched the PubMed database and abstracts presented at the American Society of Clinical Oncology (ASCO) meetings up to December 2013 for relevant studies. Eligible studies included RCTs in which everolimus or temsirolimus was compared to controls in cancer patients. The summary incidence, relative risk (RR), and 95% confidence intervals (CI) were calculated using a random-or fi xed-effects model depending on the heterogeneity of the included trials. Results. A total of 11 RCTs with 4752 patients (mTORs: 2725, controls: 2027) with a variety of solid tumors were included in the analysis. The incidences of all-grade (grade 1 -4) and high-grade rash (grade 3 -4) were 27.3% (95% CI 21.0 -34.7%) and 1.0% (95% CI 0.6 -1.4%), respectively. In comparison with controls, mTOR inhibitors signifi cantly increased the risk for developing all-grade rash (RR ϭ 3.55, 95% CI 3.0 -4.20, p Ͻ 0.001) and high-grade rash (RR ϭ 4.25, 95% CI 1.63 -11.10, p ϭ 0.003). The increased risk of high-grade rash did not vary signifi cantly among different tumors (p ϭ 0.91). There was no signifi cant difference between everolimus and temsirolimus (p ϭ 0.60). There was also no signifi cant difference between mTOR inhibitors alone and in combination with other agents (p ϭ 0.57). Conclusions. Everolimus and temsirolimus signifi cantly increased the risk of high-grade rash in cancer patients. Early recognition and appropriate treatment is recommended.

Risk of hyperglycemia attributable to everolimus in cancer patients: A meta-analysis

“…Points are given for studies that specify randomization, denote the specific method of randomization, mention double-blind trial design, explain appropriateness of double blinding, and describe the study's dropouts and withdrawals [14]. Our interpretation of study quality using the Jadad score is consistent with meta-analyses in the literature [15,16].…”

Everolimus in the treatment of neuroendocrine tumors: efficacy, side-effects, resistance, and factors affecting its place in the treatment sequence

“…According to meta-analyses including patients with NETs, treatment with everolimus as well as other mTOR inhibitors, is most commonly associated with an increased risk of stomatitis [150–153], rash[151,154], fatigue[155], infection[156], pulmonary toxicities [152,157,158], hyperglycemia[155,159], anemia[160,161], and thrombocytopenia[160]. The pharmacokinetic analysis of RADIANT-2 trial also revealed that an increased everolimus minimum concentration was associated with higher risk for pulmonary and metabolic events[64].…”