title: Risk of serious adverse events and fatal adverse events with sorafenib in patients with solid cancer: a meta-analysis of phase 3 randomized controlled trials†.
abstract: Sorafenib is a multikinase-tyrosine kinase inhibitor commonly used in a variety of cancers. There are concerns about the increased risk of serious adverse events (SAEs) and fatal adverse events (FAEs) with sorafenib. We performed an up-to-date meta-analysis of all phase 3 randomized controlled trials (RCTs) of sorafenib to quantify the increased risk of SAEs and FAEs.
  
  
  
  We carried out a systematic search of electronic databases for studies published from inception to February 2016 without any restrictions. Eligibility criteria included phase 3 RCTs of solid tumors comparing sorafenib, alone or in combination with nontargeted chemotherapy (Sorafenib arm) versus placebo or nontargeted chemotherapy (control arm). Data on SAEs and FAEs for both the arms were extracted from each study and pooled to determine the overall incidence, relative risks (RRs) and 95% Confidence Intervals (CIs).
  
  
  
  Of 471 studies identified, a total of 12 phase 3 RCTs involving 6797 solid cancer patients comparing sorafenib with control met the eligibility criteria and were included. The overall incidence of SAEs and FAEs with sorafenib were 26.4% (95% CI, 18.0-36.9%) and 1.3% (95% CI: 0.8-2.2%), respectively. Compared with control, sorafenib use significantly increased the risk of both SAEs (RR: 1.49, 95% CI: 1.18-1.89, P = 0.001) and FAEs (RR: 1.82, 95% CI: 1.05-3.14, P = 0.033). This association varied significantly with cancer types (P < 0.001) and approval status (P = 0.012) for SAEs but no evidence of heterogeneity was found for FAEs.
  
  
  
  This meta-analysis of phase 3 RCTs demonstrates an increased risk of both SAEs and FAEs with sorafenib use in adult patients with solid cancers. This quantification of increased risks of SAEs and FAEs will be important in considering the trade-off of sorafenib treatment during shared decision-making.
authors: Department of Clinical Oncology and Chemotherapy, Nagoya University Graduate School of Medicine, Nagoya.
authors: B
authors: B
authors: Gyawali
authors: Department of Clinical Oncology and Chemotherapy, Nagoya University Graduate School of Medicine, Nagoya.
authors: T
authors: T
authors: Shimokata
authors: Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
authors: M
authors: M
authors: Ando
authors: Department of Clinical Oncology and Chemotherapy, Nagoya University Graduate School of Medicine, Nagoya.
authors: K
authors: K
authors: Honda
authors: Department of Clinical Oncology and Chemotherapy, Nagoya University Graduate School of Medicine, Nagoya.
authors: Y
authors: Y
authors: Ando
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D017326:Clinical Trials, Phase III as Topic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000009:adverse effects*; D016016:Proportional Hazards Models; D012306:Risk; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib
keywords: fatal adverse events; meta-analysis; serious adverse events; sorafenib