title: Bevacizumab efficacy in metastatic colorectal cancer is dependent on primary tumor resection.
abstract: OBJECTIVE
  Bevacizumab plus fluoropyrimidine-based chemotherapy is standard treatment for first-line and second-line metastatic colorectal cancer (mCRC). However, to date, there is no current biomarker predictive for the benefit of bevacizumab use for these patients. Preclinical data suggest that the presence of the primary tumor could be involved in less efficient antitumor activity of antiangiogenic agents, but no clinical data currently support this hypothesis.
  
  
  METHODS
  We performed a retrospective analysis of factors associated with overall survival (OS) in a study cohort of 409 mCRC patients. Univariate and multivariate Cox proportional hazard regression models were used to assess the influence of primary tumor resection and bevacizumab use on OS. We evaluated associations linking bevacizumab use and OS among patients who previously underwent or did not undergo primary tumor resection. Results were externally validated in a second independent cohort of 328 mCRC patients.
  
  
  RESULTS
  In the study cohort, bevacizumab use and resection of the primary tumor were associated with improved OS. However, subgroup analyses indicate that bevacizumab did not influence survival of patients bearing a primary colorectal tumor (hazard ratio (HR) 0.98, 95 % confidence interval (CI) 0.60-1.61, log-rank test P = 0.6). By contrast, the survival benefit of bevacizumab was restricted to patients who previously underwent primary tumor resection (HR 0.71, 95 % CI 0.55-0.92, P = 0.009). Similar results were observed in the validation cohort.
  
  
  CONCLUSIONS
  Addition of bevacizumab to chemotherapy is associated with improvement of OS only in patients with primary tumor resection. These data support the rationale to validate prospectively the influence of primary tumor resection on bevacizumab antitumor effect in synchronous mCRC.
authors.affiliation: Department of Medical Oncology, Centre Georges-François Leclerc, INSERM Avenir 866, Dijon, France, francois.ghiringhelli@yahoo.fr.
authors.forename: Francois
authors.initials: F
authors.lastname: Ghiringhelli
authors.forename: Damien
authors.initials: D
authors.lastname: Bichard
authors.forename: Samuel
authors.initials: S
authors.lastname: Limat
authors.forename: Veronique
authors.initials: V
authors.lastname: Lorgis
authors.forename: Julie
authors.initials: J
authors.lastname: Vincent
authors.forename: Christophe
authors.initials: C
authors.lastname: Borg
authors.forename: Julie
authors.initials: J
authors.lastname: Berthou
authors.forename: David
authors.initials: D
authors.lastname: Orry
authors.forename: Pablo
authors.initials: P
authors.lastname: Ortega-Deballon
authors.forename: Zaher
authors.initials: Z
authors.lastname: Lakkis
authors.forename: Olivier
authors.initials: O
authors.lastname: Facy
authors.forename: Bruno
authors.initials: B
authors.lastname: Heyd
authors.forename: Patrick
authors.initials: P
authors.lastname: Rat
authors.forename: Virginie
authors.initials: V
authors.lastname: Nerich
authors.forename: Sylvain
authors.initials: S
authors.lastname: Ladoire
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D005500:Follow-Up Studies; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011379:Prognosis; D011446:Prospective Studies; D012189:Retrospective Studies; D015996:Survival Rate
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000068258:Bevacizumab; D000069287:Capecitabine; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin