title: Multikinase inhibitors in metastatic renal cell carcinoma: indirect comparison meta-analysis.
abstract: BACKGROUND
  Randomized controlled trials (RCTs) of multikinase inhibitors sunitinib, sorafenib, and pazopanib have reported efficacy compared with results from placebo and interferon-α (INF-α). To date, these drugs have not been compared in head-to-head trials.
  
  
  OBJECTIVE
  To review systematically the evidence of clinical effectiveness of multikinase inhibitors in the treatment of metastatic renal cell carcinoma (mRCC) and, via an indirect meta-analysis, to determine an optimal treatment among these agents.
  
  
  METHODS
  A systematic literature search of MEDLINE, EMBASE, CANCERLIT, and Cochrane controlled trials register databases was performed. All RCTs of multikinase inhibitors (sorafenib, sunitinib, and pazopanib) used to treat mRCC were included. The study selection, data extraction, and quality assessment were performed independently by 2 reviewers, with all disagreements being resolved by consensus. The effects of multikinase inhibitors on progression-free survival (PFS) were compared using an indirect treatment comparison method with INF-α or placebo as a comparator.
  
  
  RESULTS
  Four studies were included. Two studies examined sunitinib or sorafenib versus IFN-α, and the other 2 studies investigated sorafenib or pazopanib versus placebo. Compared with placebo, 2 interventions reported improvement for PFS (sorafenib: hazard ratio [HR] = 0.44, P = 0.01; pazopanib: HR = 0.46, P = 0.0001), whereas only sunitinib improved PFS over IFN-α (HR = 0.539, P = 0.001). An indirect comparison suggests that sunitinib is likely to demonstrate greater clinical benefit than sorafenib in terms of PFS (HR = 0.47; 95% CI, 0.316-0.713; P < 0.001), using IFN-α as the comparator. Sorafenib was not statistically different from pazopanib using placebo as the comparator in the indirect comparison (HR = 0.957; 95% CI, 0.657-1.39; P = 0.24).
  
  
  CONCLUSIONS
  Some multikinase inhibitors have a favorably reported PFS for patients with mRCC compared with results using IFN-α or placebo. Our findings suggest that sunitinib might offer some clinical benefit over sorafenib in terms of PFS. No statistical difference was found between sorafenib and pazopanib treatments. However, these conclusions are based on 2 indirect comparisons of single RCTs. More RCTs are required to confirm these findings and investigate the clinical effectiveness of multikinase inhibitors in the treatment of mRCC.
authors.affiliation: Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taiwan.
authors.forename: Henry W C
authors.initials: HW
authors.lastname: Leung
authors.forename: Agnes L F
authors.initials: AL
authors.lastname: Chan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000494:pharmacology / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007191:Indazoles; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D000077157:Sorafenib; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D007191:Indazoles; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D009536:Niacinamide; C516667:pazopanib; D000077157:Sorafenib; D000077210:Sunitinib