title: Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial.
abstract: BACKGROUND
  Bevacizumab plus fluoropyrimidine-based chemotherapy is standard treatment for first-line and bevacizumab-naive second-line metastatic colorectal cancer. We assessed continued use of bevacizumab plus standard second-line chemotherapy in patients with metastatic colorectal cancer progressing after standard first-line bevacizumab-based treatment.
  
  
  METHODS
  In an open-label, phase 3 study in 220 centres in Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, the Netherlands, Norway, Portugal, Saudi Arabia, Spain, Sweden, and Switzerland, patients (aged ≥18 years) with unresectable, histologically confirmed metastatic colorectal cancer progressing up to 3 months after discontinuing first-line bevacizumab plus chemotherapy were randomly assigned in a 1:1 ratio to second-line chemotherapy with or without bevacizumab 2·5 mg/kg per week equivalent (either 5 mg/kg every 2 weeks or 7·5 mg/kg every 3 weeks, intravenously). The choice between oxaliplatin-based or irinotecan-based second-line chemotherapy depended on the first-line regimen (switch of chemotherapy). A combination of a permuted block design and the Pocock and Simon minimisation algorithm was used for the randomisation. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00700102.
  
  
  RESULTS
  Between Feb 1, 2006, and June 9, 2010, 409 (50%) patients were assigned to bevacizumab plus chemotherapy and 411 (50%) to chemotherapy alone. Median follow-up was 11·1 months (IQR 6·4-15·6) in the bevacizumab plus chemotherapy group and 9·6 months (5·4-13·9) in the chemotherapy alone group. Median overall survival was 11·2 months (95% CI 10·4-12·2) for bevacizumab plus chemotherapy and 9·8 months (8·9-10·7) for chemotherapy alone (hazard ratio 0·81, 95% CI 0·69-0·94; unstratified log-rank test p=0·0062). Grade 3-5 bleeding or haemorrhage (eight [2%] vs one [<1%]), gastrointestinal perforation (seven [2%] vs three [<1%]), and venous thromboembolisms (19 [5%] vs 12 [3%]) were more common in the bevacizumab plus chemotherapy group than in the chemotherapy alone group. The most frequently reported grade 3-5 adverse events were neutropenia (65 [16%] in the bevacizumab and chemotherapy group vs 52 [13%] in the chemotherapy alone group), diarrhoea (40 [10%] vs 34 [8%], respectively), and asthenia (23 [6%] vs 17 [4%], respectively). Treatment-related deaths were reported for four patients in the bevacizumab plus chemotherapy group and three in the chemotherapy alone group.
  
  
  CONCLUSIONS
  Maintenance of VEGF inhibition with bevacizumab plus standard second-line chemotherapy beyond disease progression has clinical benefits in patients with metastatic colorectal cancer. This approach is also being investigated in other tumour types, including metastatic breast and non-small cell lung cancers.
  
  
  BACKGROUND
  F Hoffmann-La Roche.
authors.affiliation: Institut de Cancérologie de l'Ouest, Nantes, France.
authors.forename: Jaafar
authors.initials: J
authors.lastname: Bennouna
authors.forename: Javier
authors.initials: J
authors.lastname: Sastre
authors.forename: Dirk
authors.initials: D
authors.lastname: Arnold
authors.forename: Pia
authors.initials: P
authors.lastname: Österlund
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Roger
authors.initials: R
authors.lastname: von Moos
authors.forename: Jose Maria
authors.initials: JM
authors.lastname: Viéitez
authors.forename: Olivier
authors.initials: O
authors.lastname: Bouché
authors.forename: Christophe
authors.initials: C
authors.lastname: Borg
authors.forename: Claus-Christoph
authors.initials: CC
authors.lastname: Steffens
authors.forename: Vicente
authors.initials: V
authors.lastname: Alonso-Orduña
authors.forename: Christoph
authors.initials: C
authors.lastname: Schlichting
authors.forename: Irmarie
authors.initials: I
authors.lastname: Reyes-Rivera
authors.forename: Belguendouz
authors.initials: B
authors.lastname: Bendahmane
authors.forename: Thierry
authors.initials: T
authors.lastname: André
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicka
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D000068258:Bevacizumab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab