title: Time course of safety and efficacy of aflibercept in combination with FOLFIRI in patients with metastatic colorectal cancer who progressed on previous oxaliplatin-based therapy.
abstract: BACKGROUND
  Patients with metastatic colorectal cancer (mCRC) previously-treated with oxaliplatin benefit significantly from the addition of aflibercept to FOLFIRI in relation to overall survival, progression-free survival and response rate.
  
  
  METHODS
  The results for efficacy and safety over the time course of the VEGF Trap (aflibercept) with irinotecan in colorectal cancer after failure of oxaliplatin regimen trial were analysed based on data from 1226 patients randomised to receive FOLFIRI plus either aflibercept (n=612) or placebo (n=614). Hazard ratios (HR) by 6-month time period were estimated using a piecewise Cox proportional hazard model. Severity of adverse events (AEs) was graded using National Cancer Institute Common Terminology Criteria, version 3.0.
  
  
  RESULTS
  The estimated probabilities of survival were 38.5% versus 30.9% at 18 months, 28.0% versus 18.7% at 24 months and 22.3% versus 12.0% at 30 months, for the aflibercept- and placebo-treated arms, respectively. The proportional improvement in the HR over time was consistent with the survival probability results; survival at 24 months was improved by 50% and almost doubled at 30 months. The majority of worst-grade AEs occurred within the first four cycles of treatment and in a small percent of treatment cycles and were mostly reversible. Common chemotherapy- and anti-vascular epithelial growth factor (VEGF)-associated AEs occurred rarely and in a small proportion of cycles with the majority being of single occurrence.
  
  
  CONCLUSIONS
  The addition of aflibercept to FOLFIRI showed a continued and persistent improvement in overall survival over time in patients with mCRC. Although grade 3-4 AEs were more frequent in the aflibercept arm, they occurred in early treatment cycles and decreased sharply following initial presentation.
authors.affiliation: University of Witwatersrand, Faculty of Health Sciences, Johannesburg, South Africa. Electronic address: pruff@iafrica.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Ruff
authors.affiliation: Russells Hall Hospital, Dudley, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Ferry
authors.affiliation: Masaryk Memorial Cancer Institute, Brno, Czech Republic.
authors.forename: Radek
authors.initials: R
authors.lastname: Lakomỳ
authors.affiliation: Fakultni nemocnice v Motole, Praha, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Prausová
authors.affiliation: University of Western Australia, Western Australia, Australia.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Van Hazel
authors.affiliation: Centro De Oncologia/Hospital Sirio Libanes, São Paulo, Brazil.
authors.forename: Paulo M
authors.initials: PM
authors.lastname: Hoff
authors.affiliation: The Royal Marsden Hospital, Sutton, UK.
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.affiliation: Department of Medical Oncology, Tumor Biology Center, Freiburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Arnold
authors.affiliation: Martin Luther University Halle-Wittenberg, Germany.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Schmoll
authors.affiliation: Oncology Research Institute Na. NN. Petrov, St-Petersburg, Russian Federation.
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Moiseyenko
authors.affiliation: Monash University, Victoria, Australia.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: McKendrick
authors.affiliation: Amphia Hospital, Breda, The Netherlands.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Ten Tije
authors.affiliation: Sanofi Global Oncology Medical Affairs, Cambridge, MA, United States.
authors.forename: Raghu L
authors.initials: RL
authors.lastname: Vishwanath
authors.affiliation: Sanofi Global Oncology Research and Development, Cambridge, MA, United States.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Bhargava
authors.affiliation: Sanofi, Vitry-sur-Seine, France.
authors.forename: Soazig
authors.initials: S
authors.lastname: Chevalier
authors.affiliation: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Macarulla
authors.affiliation: University Hospitals Leuven and KU Leuven, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D016016:Proportional Hazards Models; D040262:Receptors, Vascular Endothelial Growth Factor / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D054316:Biomarkers, Pharmacological; D009944:Organoplatinum Compounds; D011993:Recombinant Fusion Proteins; D000077150:Oxaliplatin; C533178:aflibercept; D000077146:Irinotecan; D040262:Receptors, Vascular Endothelial Growth Factor; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: Aflibercept; Colorectal cancer; Efficacy; PlGF; Safety; VEGF-A; VEGF-B