title: Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial.
abstract: BACKGROUND
  For patients with initially unresectable liver metastases from colorectal cancer, chemotherapy can downsize metastases and facilitate secondary resection. We assessed the efficacy of bevacizumab plus modified FOLFOX-6 (5-fluorouracil/folinic acid, oxaliplatin) or FOLFOXIRI (5-fluorouracil/folinic acid, oxaliplatin, irinotecan) in this setting.
  
  
  METHODS
  OLIVIA was a multinational open-label phase II study conducted at 16 centres in Austria, France, Spain, and the UK. Patients with unresectable liver metastases were randomised to bevacizumab (5 mg/kg) plus mFOLFOX-6 [oxaliplatin 85 mg/m(2), folinic acid 400 mg/m(2), 5-fluorouracil 400 mg/m(2) (bolus) then 2400 mg/m(2) (46-h infusion)] or FOLFOXIRI [oxaliplatin 85 mg/m(2), irinotecan 165 mg/m(2), folinic acid 200 mg/m(2), 5-fluorouracil 3200 mg/m(2) (46-h infusion)] every 2 weeks. Unresectability was defined as ≥1 of the following criteria: no possibility of upfront R0/R1 resection of all lesions; <30% residual liver volume after resection; metastases in contact with major vessels of the remnant liver. Resectability was evaluated by multidisciplinary review. The primary end point was overall resection rate (R0/R1/R2). Efficacy end points were analysed by intention-to-treat analysis.
  
  
  RESULTS
  In patients assigned to bevacizumab-FOLFOXIRI (n = 41) or bevacizumab-mFOLFOX-6 (n = 39), the overall resection rate was 61% [95% confidence interval (CI) 45% to 76%] and 49% (95% CI 32% to 65%), respectively (difference 12%; 95% CI -11% to 36%). R0 resection rates were 49% and 23%, respectively. Overall tumour response rates were 81% (95% CI 65% to 91%) with bevacizumab-FOLFOXIRI and 62% (95% CI 45% to 77%) with bevacizumab-mFOLFOX-6. Median progression-free survival (PFS) was 18·6 (95% CI 12.9-22.3) months and 11·5 (95% CI 9.6-13.6) months, respectively. The most common grade 3-5 adverse events were neutropenia (bevacizumab-FOLFOXIRI, 50%; bevacizumab-mFOLFOX-6, 35%) and diarrhoea (30% and 14%, respectively).
  
  
  CONCLUSIONS
  Bevacizumab-FOLFOXIRI was associated with higher response and resection rates and prolonged PFS versus bevacizumab-mFOLFOX-6 in patients with initially unresectable liver metastases from colorectal cancer. Toxicity was increased but manageable with bevacizumab-FOLFOXIRI.
  
  
  BACKGROUND
  NCT00778102.
authors.affiliation: Department of Surgery I, Rudolfstiftung Hospital, Vienna, Austria. Electronic address: t.gruenberger@icloud.com.
authors.forename: T
authors.initials: T
authors.lastname: Gruenberger
authors.affiliation: Department of Oncology, University College London Cancer Institute, London.
authors.forename: J
authors.initials: J
authors.lastname: Bridgewater
authors.affiliation: Department of Medicine, The Royal Marsden Hospital, Sutton, UK.
authors.forename: I
authors.initials: I
authors.lastname: Chau
authors.affiliation: Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: García Alfonso
authors.affiliation: Department of Surgical Oncology, Léon Bérard Cancer Center, Université Claude Bernard Lyon I, Lyon, France.
authors.forename: M
authors.initials: M
authors.lastname: Rivoire
authors.affiliation: Department of Surgery, The Royal Marsden Hospital, Sutton, UK.
authors.forename: S
authors.initials: S
authors.lastname: Mudan
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Lasserre
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Hermann
authors.affiliation: Genentech, Inc., South San Francisco, USA.
authors.forename: D
authors.initials: D
authors.lastname: Waterkamp
authors.affiliation: Centre Hepato-Biliaire, AP-HP Hôpital Paul Brousse, UMR-S 776, Université Paris-Sud, Villejuif, France.
authors.forename: R
authors.initials: R
authors.lastname: Adam
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006498:Hepatectomy; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary / Q000601:surgery; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011379:Prognosis; D015996:Survival Rate
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000068258:Bevacizumab; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: bevacizumab; chemotherapy; colorectal cancer; liver metastases; secondary resection