title: Bevacizumab plus octreotide and metronomic capecitabine in patients with metastatic well-to-moderately differentiated neuroendocrine tumors: the XELBEVOCT study.
abstract: BACKGROUND
  We assessed the activity and toxicity of the XELBEVOCT regimen in patients with metastatic well-to-moderately differentiated neuroendocrine neoplasms (WMD-NEN). Ancillary studies evaluated hypertension, proteinuria, and vascular endothelial growth factor (VEGF) polymorphisms in predicting progression-free survival (PFS) and the predictive role of serum vitamin D in progression-free survival and proteinuria onset.
  
  
  METHODS
  This prospective phase 2 study included 45 patients with WMD-NEN arising from various primary sites. The treatment regimen was octreotide long-acting release (LAR), 20 mg monthly, metronomic capecitabine, 2000 mg/daily, and intravenous bevacizumab, 5 mg/kg every 2 weeks, without interruption for 9 months. Bevacizumab was continued until disease progression.
  
  
  RESULTS
  Partial response was obtained in 8 patients (17.8%, 95% confidence interval [CI], 6.4%-28.2%); tumor response was more frequent in pancreatic than in non-pancreatic malignancies. The median PFS was 14.9 months; median overall survival was not attained. Biochemical and symptomatic responses were observed in 52.9% and 82.3% of cases, respectively. The treatment was well tolerated. Grade 3 toxicities included hand and foot syndrome (11.1%), proteinuria (4.4%), and renal toxicity (2.2%). Proteinuria (all grades) was correlated with longer PFS (p = 0.017). There was an inverse relationship between proteinuria and vitamin D levels. VEGF polymorphisms were not associated with patient outcome.
  
  
  CONCLUSIONS
  The XELBEVOCT regimen is active and well tolerated in patients with metastatic WMD-NEN. Proteinuria correlated with hypovitaminosis D status and was the best predictive factor of treatment efficacy.
  
  
  BACKGROUND
  Trial registration number NCT01203306.
authors.affiliation: Oncologia Medica, Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica, Università degli Studi di Brescia, Azienda Ospedaliera Spedali Civili Piazzale Spedali Civili 1, 25123 Brescia, Italy. alfredo.berruti@gmail.com.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Berruti
authors.forename: Nicola
authors.initials: N
authors.lastname: Fazio
authors.forename: Anna
authors.initials: A
authors.lastname: Ferrero
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Brizzi
authors.forename: Marco
authors.initials: M
authors.lastname: Volante
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Nobili
authors.forename: Lucia
authors.initials: L
authors.lastname: Tozzi
authors.forename: Lisa
authors.initials: L
authors.lastname: Bodei
authors.forename: Mirella
authors.initials: M
authors.lastname: Torta
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Avolio
authors.forename: Adriano Massimiliano
authors.initials: AM
authors.lastname: Priola
authors.forename: Nadia
authors.initials: N
authors.lastname: Birocco
authors.forename: Vito
authors.initials: V
authors.lastname: Amoroso
authors.forename: Guido
authors.initials: G
authors.lastname: Biasco
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.forename: Luigi
authors.initials: L
authors.lastname: Dogliotti
mesh_terms: D059250:Administration, Metronomic; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D000068258:Bevacizumab; D000069287:Capecitabine; D003841:Deoxycytidine / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000473:pathology; D015282:Octreotide / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D003841:Deoxycytidine; D000068258:Bevacizumab; D000069287:Capecitabine; D015282:Octreotide; D005472:Fluorouracil