title: Lanreotide in metastatic enteropancreatic neuroendocrine tumors.
abstract: BACKGROUND
  Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited.
  
  
  METHODS
  We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety.
  
  
  RESULTS
  Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group).
  
  
  CONCLUSIONS
  Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).
authors.affiliation: From Royal Free Hospital, London (M.E.C.); Charité University Medicine Berlin, Berlin (M.P.); University of Warmia and Mazury, Olsztyn, Poland (J.B.Ć.); University of Texas M.D. Anderson Cancer Center, Houston (A.T.P.); University Hospital, Vienna (M.R.); Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic (E.S.); Robert-Debré Hospital, Reims (G.C.), Ipsen, Les Ulis, (A.L., S.M., J.B.), Beaujon Hospital, Clichy (P.R.), and Paris Diderot University, Paris (P.R.) - all in France; Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles (E.M.W.); Vall d'Hebron University Hospital, Barcelona (J.C.); Western General Hospital, Edinburgh (L.W.); and Università Cattolica del Sacro Cuore, Rome (G.R.).
authors.forename: Martyn E
authors.initials: ME
authors.lastname: Caplin
authors.forename: Marianne
authors.initials: M
authors.lastname: Pavel
authors.forename: Jarosław B
authors.initials: JB
authors.lastname: Ćwikła
authors.forename: Alexandria T
authors.initials: AT
authors.lastname: Phan
authors.forename: Markus
authors.initials: M
authors.lastname: Raderer
authors.forename: Eva
authors.initials: E
authors.lastname: Sedláčková
authors.forename: Guillaume
authors.initials: G
authors.lastname: Cadiot
authors.forename: Edward M
authors.initials: EM
authors.lastname: Wolin
authors.forename: Jaume
authors.initials: J
authors.lastname: Capdevila
authors.forename: Lucy
authors.initials: L
authors.lastname: Wall
authors.forename: Guido
authors.initials: G
authors.lastname: Rindi
authors.forename: Alison
authors.initials: A
authors.lastname: Langley
authors.forename: Séverine
authors.initials: S
authors.lastname: Martinez
authors.forename: Joëlle
authors.initials: J
authors.lastname: Blumberg
authors.forename: Philippe
authors.initials: P
authors.lastname: Ruszniewski
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003692:Delayed-Action Preparations; D003967:Diarrhea / Q000209:etiology; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010456:Peptides, Cyclic / Q000009:adverse effects / Q000627:therapeutic use*; D013004:Somatostatin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D010456:Peptides, Cyclic; C060347:lanreotide; D013004:Somatostatin