title: Bevacizumab plus capecitabine in patients with progressive advanced well-differentiated neuroendocrine tumors of the gastro-intestinal (GI-NETs) tract (BETTER trial)--a phase II non-randomised trial.
abstract: OBJECTIVE
  Gastro-intestinal neuroendocrine tumours (GI-NETs) are chemotherapy-resistant tumours. Bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF), has shown promising results in several phase II trials of gastro-entero-pancreatic-NETs. We assessed bevacizumab combined with capecitabine, specifically in GI-NET patients.
  
  
  METHODS
  BEvacizumab in The Treament of neuroEndocrine tumoRs (BETTER) was a multicentre, open-label, non-randomised, two-group phase II trial. Here we present the group of patients with progressive, metastatic, well-differentiated GI-NETs. Patients Eastern Cooperative Oncology Group-performance status (ECOG-PS)⩽2, Ki-67 proliferation rate <15% and no prior systemic chemotherapy were treated with bevacizumab (7.5 mg/kg/q3w) and capecitabine (1000 mg/m2 twice daily, orally d1-14, resumed on d22) for 6-24 months. The primary end-point was progression-free survival (PFS); secondary end-points included overall survival (OS), response rate, safety and quality of life.
  
  
  RESULTS
  Of the 49 patients included, 53% were men, median age was 60 years (41-82), primary tumour site was ileal in 82% patients and Ki-67 was <15% in 48 patients and not available for one patient. After a maximum of 24 month follow-up per patient, the median PFS by investigator assessment was 23.4 months [95% confidence interval (CI): 13.2; not reached] and the overall disease control rate was 88% (18% partial response, 70% stable disease). The 2-year survival rate was 85%. Median OS was not reached. The most frequent grade 3-4 adverse events were hypertension (31%), diarrhoea (14%) and hand-foot syndrome (10%).
  
  
  CONCLUSIONS
  The combination of bevacizumab and capecitabine showed clinical activity and a manageable safety profile in the treatment of GI-NETs that warrant confirmation in a randomised phase III trial.
authors.affiliation: Medical Oncology Department, Curie Institute, Paris, France. Electronic address: emmanuel.mitry@curie.net.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mitry
authors.affiliation: Medical Oncology Department, Edouard Herriot Hospital, Lyon, France. Electronic address: thomas.walter@chu-lyon.fr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walter
authors.affiliation: Nuclear Medicine and Endocrine Oncology Department, Gustave Roussy Institute, Villejuif, France. Electronic address: Eric.BAUDIN@igr.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Baudin
authors.affiliation: Hematology and Oncology Department, University Hospital, Strasbourg, France. Electronic address: J-Emmanuel.KURTZ@chru-strasbourg.fr.
authors.forename: Jean-Emmanuel
authors.initials: JE
authors.lastname: Kurtz
authors.affiliation: Gastroenterology and Pancreatology Department, Beaujon Hospital, Clichy, France. Electronic address: philippe.ruszniewski@bjn.aphp.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Ruszniewski
authors.affiliation: Hematology and Oncology Department, Oscar Lambret Center, Lille, France. Electronic address: Dominguez.Sophie@ghicl.net.
authors.forename: Sophie
authors.initials: S
authors.lastname: Dominguez-Tinajero
authors.affiliation: Medical Oncology Department, Saint-Antoine Hospital, Bordeaux, France. Electronic address: leila.bengrine-lefevre@sat.aphp.fr.
authors.forename: Leïla
authors.initials: L
authors.lastname: Bengrine-Lefevre
authors.affiliation: Hepato-Gastroenterology and Digestive Oncology Department, Robert Debré Hospital, Reims, France. Electronic address: gcadiot@chu-reims.fr.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Cadiot
authors.affiliation: Radio Diagnostic Department, Gustave Roussy Institute, Villejuif, France. Electronic address: dromain@igr.fr.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Dromain
authors.affiliation: Laboratory of Translational Research, Gustave Roussy Institute, Villejuif, France. Electronic address: francoise.farace@igr.fr.
authors.forename: Françoise
authors.initials: F
authors.lastname: Farace
authors.affiliation: Hepato-Gastroenterology and Digestive Oncology Department, Georges Pompidou European Hospital, Université Paris V, Paris, France. Electronic address: philippe.rougier@egp.aphp.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Rougier
authors.affiliation: Gastrointestinal Oncology Department, Gustave Roussy Institute, Villejuif, France. Electronic address: Michel.DUCREUX@igr.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Ducreux
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000401:mortality; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D003841:Deoxycytidine; D000068258:Bevacizumab; D000069287:Capecitabine; D005472:Fluorouracil
keywords: Bevacizumab; Capecitabine; Gastro-intestinal neuroendocrine tumours; Metastatic