title: Bifractionated CPT-11 with LV5FU2 infusion (FOLFIRI-3) in combination with bevacizumab: clinical outcomes in first-line metastatic colorectal cancers according to plasma angiopoietin-2 levels.
abstract: BACKGROUND
  Optimization of chemotherapy effectiveness in metastatic colorectal cancers (mCRC) is a major endpoint to enhance the possibility of curative intent surgery. FOLFIRI3 has shown promising results as second-line chemotherapy for mCRC patients previously exposed to oxaliplatin. The clinical efficacy of FOLFIRI3 was never determined in association with bevacizumab in non-previously treated mCRC patients.
  
  
  METHODS
  We conducted a phase II clinical trial to characterize the response rate and toxicity profile of FOLFIRI3-bevacizumab as initial treatment for mCRC. Sixty-one patients enrolled in 3 investigation centers were treated with FOLFIRI3-bevacizumab (median of 10 cycles) followed by a maintenance therapy combining bevacizumab and capecitabine. Levels of plasma angiopoietin-2 (Ang-2) were measured by enzyme-linked immunosorbent assay at baseline.
  
  
  RESULTS
  Overall response rate (ORR) was 66.7% (8% of complete and 58% of partial responses). The disease control rate was 91.7%. After a median time of follow-up of 46.7 months, 56 patients (92%) had progressed or died. The median progression free survival (PFS) was 12.7 months (95% confidence interval (CI) 9.7-15.8 months). The median overall survival (OS) was 24.5 months (95% CI: 10.6-38.3 months). Twenty-one patients underwent curative intent-surgery including 4 patients with disease initially classified as unresectable. Most common grade III-IV toxicities were diarrhea (15%), neutropenia (13%), asthenia (10%), and infections (4%). Hypertension-related medications needed to be increased in 3 patients. In multivariate analysis, surgery of metastases and Ang-2 levels were the only independent prognostic factors for PFS and OS. Indeed, baseline level of Ang-2 above 5 ng/mL was confirmed as an independent prognostic factor for progression free survival (HR = 0.357; 95% CI: 0.168-0.76, p = 0.005) and overall survival (HR = 0.226; 95% CI: 0.098-0.53, p = 0.0002).
  
  
  CONCLUSIONS
  As front-line therapy, FOLFIRI-3-bevacizumab is associated with an acceptable toxicity and induced promising objective response rates. However, unfavorable clinical outcomes were observed in patients with high levels of angiopoietin-2.
authors.forename: Stefano
authors.initials: S
authors.lastname: Kim
authors.forename: Erion
authors.initials: E
authors.lastname: Dobi
authors.forename: Marine
authors.initials: M
authors.lastname: Jary
authors.forename: Franck
authors.initials: F
authors.lastname: Monnien
authors.forename: Elsa
authors.initials: E
authors.lastname: Curtit
authors.forename: Thierry
authors.initials: T
authors.lastname: Nguyen
authors.forename: Zaher
authors.initials: Z
authors.lastname: Lakkis
authors.forename: Bruno
authors.initials: B
authors.lastname: Heyd
authors.forename: Serge
authors.initials: S
authors.lastname: Fratte
authors.forename: Denis
authors.initials: D
authors.lastname: Cléau
authors.forename: Najib
authors.initials: N
authors.lastname: Lamfichekh
authors.forename: Virginie
authors.initials: V
authors.lastname: Nerich
authors.forename: Boris
authors.initials: B
authors.lastname: Guiu
authors.forename: Martin
authors.initials: M
authors.lastname: Demarchi
authors.affiliation: Department of medical oncology, University Hospital of Besançon, Besançon, France. christophe.borg@efs.sante.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Borg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042702:Angiopoietin-2 / Q000097:blood*; 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 / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: C586513:ANGPT2 protein, human; D042702:Angiopoietin-2; D061067:Antibodies, Monoclonal, Humanized; D003841:Deoxycytidine; D000068258:Bevacizumab; D000069287:Capecitabine; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin