title: Incidence and risk of treatment-related mortality with mTOR inhibitors everolimus and temsirolimus in cancer patients: a meta-analysis.
abstract: BACKGROUND
  Two novel mammalian targets of rapamycin (mTOR) inhibitors everolimus and temsirolimus are now approved by regulatory agencies and have been widely investigated among various types of solid tumors, but the risk of fatal adverse events (FAEs) with these drugs is not well defined.
  
  
  METHODS
  We searched PubMed, EMBASE, and Cochrane library databases for relevant trials. Eligible studies included prospective phase II and III trials evaluating everolimus and temsirolimus in patients with all malignancies and data on FAEs were available. Statistical analyses were conducted to calculate the summary incidence, RRs and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of the included studies.
  
  
  RESULTS
  A total of 3322 patients with various advanced solid tumors from 12 trials were included. The overall incidence of mTOR inhibitors associated FAEs was 1.8% (95%CI: 1.3-2.5%), and the incidences of everolimus related FAEs were comparable to that of temsirolimus (1.7% versus 1.8%). Compared with the controls, the use of mTOR inhibitors was associated with an increased risk of FAEs, with a RR of 3.24 (95%CI: 1.21-8.67, p = 0.019). On subgroup analysis, a non-statistically significant increase in the risk of FAEs was found according to different mTOR inhibitors, tumor types or controlled therapy. No evidence of publication bias was observed.
  
  
  CONCLUSIONS
  With the present evidence, the use of mTOR inhibitors seems to increase the risk of FAEs in patients with advanced solid tumors. More high quality trials are still needed to investigate this association.
authors.affiliation: Department of Oncology, the Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Wei-Xiang
authors.initials: WX
authors.lastname: Qi
authors.forename: Yu-Jing
authors.initials: YJ
authors.lastname: Huang
authors.forename: Yang
authors.initials: Y
authors.lastname: Yao
authors.forename: Zan
authors.initials: Z
authors.lastname: Shen
authors.forename: Da-Liu
authors.initials: DL
authors.lastname: Min
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002423:Cause of Death; D000068338:Everolimus; D006801:Humans; D015994:Incidence; D009369:Neoplasms / Q000188:drug therapy / Q000453:epidemiology / Q000401:mortality*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D012306:Risk; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C401859:temsirolimus; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus