title: Risk of anemia attributable to everolimus in patients with cancer: a meta-analysis of randomized controlled trials.
abstract: BACKGROUND
  Everolimus, an inhibitor of mammalian target of rapamycin (mTOR) used for the treatment of various solid tumors, is associated with anemia, which can lead to morbidity and treatment interruption or discontinuation. Because the underlying causes of anemia can be multifactorial, we performed a meta-analysis of randomized controlled trials (RCTs) to determine the overall risk of anemia specifically attributable to everolimus in cancer patients.
  
  
  METHODS
  We searched the PubMed database and abstracts presented at the American Society of Clinical Oncology annual meetings up to May 2014 for relevant studies. Eligible studies included RCTs in which everolimus alone or in combination with other agents was compared to placebo alone or with other agents in patients with cancer. Summary incidences, relative risks (RR), and 95% confidence intervals (CI) were calculated using a random- or fixed-effects model depending on the heterogeneity of the included trials. The attributable risk was determined by the incidence with everolimus minus that without everolimus in controls.
  
  
  RESULTS
  A total of nine RCTs with 3,678 patients (everolimus, n=2,162; controls, n=1,516) were included in our analysis. In comparison with controls, everolimus significantly increased the risk of all-grade (RR=2.18, 95% CI=1.56-3.04, p<0.001) and high-grade anemia (RR=2.63, 95% CI=1.35-5.15, p<0.001). The summary incidences of all-grade (grades 1-4) and high-grade (grades 3-4) anemia in patients treated with everolimus were 32.1% (95% CI=17.5-51.3%) and 6.9% (95% CI=4.1-11.3%) respectively, with 13.3% (95% CI=10.0-17.5%) and 4.7% (95% CI=2.8-7.7%) specifically attributable to everolimus. Risk factors of high-grade anemia attributable to everolimus included tumor type (p=0.012), with the highest seen in renal cell carcinoma (8.0%, 95% CI=5.3-11.9%), and chemotherapy (p<0.001).
  
  
  CONCLUSIONS
  There is a substantial risk of all-grade and high-grade anemia attributable to everolimus therapy for cancer.
authors: Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, U.S.A.
authors: Raji
authors: R
authors: Shameem
authors: Department of Internal Medicine, Wayne State University/Detroit Medical Center, Detroit, MI, U.S.A.
authors: Muhammad Saad
authors: MS
authors: Hamid
authors: Division of Hematology/Oncology, Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY, U.S.A. Northport VA Medical Center, Northport, NY, U.S.A. shenhong.wu@stonybrook.edu.
authors: Shenhong
authors: S
authors: Wu
mesh_terms: D000740:Anemia / Q000139:chemically induced / Q000473:pathology*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000068338:Everolimus; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D039781:PubMed; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: everolimus; mTOR inhibitor; mTOR inhibitor-associated anemia