title: Sorafenib in advanced clear-cell renal-cell carcinoma.
abstract: BACKGROUND
  We conducted a phase 3, randomized, double-blind, placebo-controlled trial of sorafenib, a multikinase inhibitor of tumor-cell proliferation and angiogenesis, in patients with advanced clear-cell renal-cell carcinoma.
  
  
  METHODS
  From November 2003 to March 2005, we randomly assigned 903 patients with renal-cell carcinoma that was resistant to standard therapy to receive either continuous treatment with oral sorafenib (at a dose of 400 mg twice daily) or placebo; 451 patients received sorafenib and 452 received placebo. The primary end point was overall survival. A single planned analysis of progression-free survival in January 2005 showed a statistically significant benefit of sorafenib over placebo. Consequently, crossover was permitted from placebo to sorafenib, beginning in May 2005.
  
  
  RESULTS
  At the January 2005 cutoff, the median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio for disease progression in the sorafenib group, 0.44; 95% confidence interval [CI], 0.35 to 0.55; P<0.01). The first interim analysis of overall survival in May 2005 showed that sorafenib reduced the risk of death, as compared with placebo (hazard ratio, 0.72; 95% CI, 0.54 to 0.94; P=0.02), although this benefit was not statistically significant according to the O'Brien-Fleming threshold. Partial responses were reported as the best response in 10% of patients receiving sorafenib and in 2% of those receiving placebo (P<0.001). Diarrhea, rash, fatigue, and hand-foot skin reactions were the most common adverse events associated with sorafenib. Hypertension and cardiac ischemia were rare serious adverse events that were more common in patients receiving sorafenib than in those receiving placebo.
  
  
  CONCLUSIONS
  As compared with placebo, treatment with sorafenib prolongs progression-free survival in patients with advanced clear-cell renal-cell carcinoma in whom previous therapy has failed; however, treatment is associated with increased toxic effects. (ClinicalTrials.gov number, NCT00073307 [ClinicalTrials.gov].).
authors.affiliation: Department of Medicine, Institut Gustave Roussy, Villejuif, France. escudier@igr.fr
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.forename: Tim
authors.initials: T
authors.lastname: Eisen
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.forename: Cezary
authors.initials: C
authors.lastname: Szczylik
authors.forename: Stéphane
authors.initials: S
authors.lastname: Oudard
authors.forename: Michael
authors.initials: M
authors.lastname: Siebels
authors.forename: Sylvie
authors.initials: S
authors.lastname: Negrier
authors.forename: Christine
authors.initials: C
authors.lastname: Chevreau
authors.forename: Ewa
authors.initials: E
authors.lastname: Solska
authors.forename: Apurva A
authors.initials: AA
authors.lastname: Desai
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rolland
authors.forename: Tomasz
authors.initials: T
authors.lastname: Demkow
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hutson
authors.forename: Martin
authors.initials: M
authors.lastname: Gore
authors.forename: Scott
authors.initials: S
authors.lastname: Freeman
authors.forename: Brian
authors.initials: B
authors.lastname: Schwartz
authors.forename: Minghua
authors.initials: M
authors.lastname: Shan
authors.forename: Ronit
authors.initials: R
authors.lastname: Simantov
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Bukowski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000009:adverse effects / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib