title: Gastrointestinal perforation associated with bevacizumab use in metastatic colorectal cancer: results from a large treatment observational cohort study.
abstract: BACKGROUND
  Bevacizumab prolongs overall and progression-free survival when added to fluorouracil-based chemotherapy in patients with metastatic colorectal cancer in randomised controlled trials (RCTs). However, gastrointestinal perforation (GIP) occurs in 1-2% of treated patients. We sought to describe the incidence, temporal pattern, outcomes and potential risk factors for GIP in a large, community-based observational cohort study of patients treated with bevacizumab.
  
  
  METHODS
  Baseline patient and tumour characteristics, including potential GIP risk factors, were collected at study entry. Treatment, targeted adverse events, progression events and survival data were recorded every 3 months. Detailed clinical information was collected for all patients experiencing a GIP event. Effects of baseline risk factors on GIP risk were investigated using Cox proportional hazards regression.
  
  
  RESULTS
  Of 1953 evaluable patients followed for a median of 20.1 months, 37 (1.9%) experienced GIP. Most GIP events were surgically managed with successful outcomes; four events were fatal. The majority of GIP events (26/37) occurred ≤6 months after starting bevacizumab (median, 3.35 months). Univariate and multivariate analyses showed that age ≥65 years was significantly associated with lower GIP risk. In multivariate analyses, intact primary tumour and prior adjuvant radiotherapy were significantly associated with increased risk of GIP within 6 months after starting bevacizumab. A regression analysis that assessed the risk of GIP over time showed no cumulative risk associated with bevacizumab exposure.
  
  
  CONCLUSIONS
  The observed rate of GIP in this large, community-based experience was consistent with rates reported in RCTs. Most events were successfully managed with surgical intervention.
authors.affiliation: Department of Medicine, Division of Hematology & Oncology, University of California at Los Angeles, 924 Westwood Blvd, Los Angeles, CA 90095-7207, USA.
authors.forename: Fairooz F
authors.initials: FF
authors.lastname: Kabbinavar
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Flynn
authors.forename: Mark
authors.initials: M
authors.lastname: Kozloff
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ashby
authors.forename: Amy
authors.initials: A
authors.lastname: Sing
authors.forename: Charles E
authors.initials: CE
authors.lastname: Barr
authors.forename: Axel
authors.initials: A
authors.lastname: Grothey
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects* / Q000627:therapeutic use; D000068258:Bevacizumab; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007416:Intestinal Perforation / Q000139:chemically induced*; D008875:Middle Aged; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab