title: Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II).
abstract: OBJECTIVE
  Cediranib is a highly potent inhibitor of vascular endothelial growth factor (VEGF) signaling with activity against all three VEGF receptors. HORIZON II [Cediranib (AZD2171, RECENTIN) in Addition to Chemotherapy Versus Placebo Plus Chemotherapy in Patients With Untreated Metastatic Colorectal Cancer] assessed infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (FOLFOX/CAPOX) with or without cediranib in patients with previously untreated metastatic colorectal cancer (mCRC).
  
  
  METHODS
  Eligible patients were initially randomly assigned 1:1:1 to receive cediranib (20 or 30 mg per day) or placebo plus FOLFOX/CAPOX. In an early analysis of this and two other cediranib studies (HORIZON I [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Previously Treated Metastatic Colorectal Cancer] and HORIZON III [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Untreated Metastatic Colorectal Cancer]), the 20-mg dose met the predefined criteria for continuation. Subsequent patients were randomly assigned 2:1 to the cediranib 20 mg or placebo arms. Progression-free survival (PFS) and overall survival (OS) were coprimary end points.
  
  
  RESULTS
  In all, 860 patients received cediranib 20 mg (n = 502) or placebo (n = 358). The addition of cediranib to FOLFOX/CAPOX resulted in PFS prolongation (hazard ratio [HR], 0.84; 95% CI, 0.73 to 0.98; P = .0121; median PFS, 8.6 months for cediranib v 8.3 months for placebo) but had no impact on OS (HR, 0.94; 95% CI, 0.79 to 1.12; P = .5707; median OS, 19.7 months for cediranib v 18.9 months for placebo). There were no significant differences in the secondary end points of objective response rate, duration of response, or liver resection rate. Median chemotherapy dose-intensity was decreased by approximately 10% in patients treated with cediranib. Adverse events (AEs) associated with cediranib were manageable. CONCLUSION Addition of cediranib 20 mg to FOLFOX/CAPOX resulted in a modest PFS prolongation, but no significant difference in OS. The cediranib AE profile was consistent with those from previous studies. Because of the lack of improvement in OS, cediranib plus an oxaliplatin-based regimen cannot be recommended as a treatment for patients with mCRC.
authors.affiliation: FACP, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo 251, São Paulo, Brazil. paulo.hoff@icesp.org.br
authors.forename: Paulo M
authors.initials: PM
authors.lastname: Hoff
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Bernhard C
authors.initials: BC
authors.lastname: Pestalozzi
authors.forename: Niall C
authors.initials: NC
authors.lastname: Tebbutt
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Tae Won
authors.initials: TW
authors.lastname: Kim
authors.forename: Krassimir D
authors.initials: KD
authors.lastname: Koynov
authors.forename: Galina
authors.initials: G
authors.lastname: Kurteva
authors.forename: Tamás
authors.initials: T
authors.lastname: Pintér
authors.forename: Ying
authors.initials: Y
authors.lastname: Cheng
authors.forename: Brigitte
authors.initials: B
authors.lastname: van Eyll
authors.forename: Laura
authors.initials: L
authors.lastname: Pike
authors.forename: Anitra
authors.initials: A
authors.lastname: Fielding
authors.forename: Jane D
authors.initials: JD
authors.lastname: Robertson
authors.forename: Mark P
authors.initials: MP
authors.lastname: Saunders
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001938:Brazil; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D011379:Prognosis; D016016:Proportional Hazards Models; D011725:Pyridines / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use*; D016019:Survival Analysis; D007211:Indoles
chemical_list: D000069287:Capecitabine; D003841:Deoxycytidine; D005472:Fluorouracil; D002955:Leucovorin; D009944:Organoplatinum Compounds; D011725:Pyridines; D011799:Quinazolines; C431073:oxiplatin; C500926:cediranib; D007211:Indoles