title: Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study.
abstract: OBJECTIVE
  Evaluate the activity of everolimus (RAD001) in combination with octreotide long-acting repeatable (LAR) in patients with advanced low- to intermediate-grade neuroendocrine tumors.
  
  
  METHODS
  Treatment consisted of RAD001 5 mg/d (30 patients) or 10 mg/d (30 patients) and octreotide LAR 30 mg every 28 days. Thirty carcinoid and 30 islet cell patients were enrolled.
  
  
  RESULTS
  Intent-to-treat response rate was 20%. Per protocol, there were 13 with partial responses (22%), 42 with stable disease (SD; 70%), and five patients with progressive disease (8%). Overall median progression-free survival (PFS) was 60 weeks. Median PFS for patients with known SD at entry was longer than for those who had progressive disease (74 v 50 weeks; P < .01). Median overall survival has not been reached. One-, 2-, and 3-year survival rates were 83%, 81%, and 78%, respectively. Among 37 patients with elevated chromogranin A, 26 (70%) achieved normalization or more than 50% reduction. Most common toxicity was mild aphthous ulceration. Grade 3/4 toxicities occurring in >or= 10% of patients included hypophosphatemia (11%), fatigue (11%), and diarrhea (11%). Treatment was associated with a dose-dependent rise in lactate dehydrogenase (LDH). Those with lower than 109 U/L rise in LDH at week 4 had shorter PFS (38 v 69 weeks; P = .01). Treatment was also associated with a decrease in proliferation marker Ki-67 among patients who underwent optional paired pre- and post-treatment biopsy (P = .04).
  
  
  CONCLUSIONS
  RAD001 at 5 or 10 mg/d was well tolerated in combination with octreotide LAR, with promising antitumor activity. Confirmatory studies are ongoing.
authors.affiliation: Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. jyao@mdanderson.org
authors.forename: James C
authors.initials: JC
authors.lastname: Yao
authors.forename: Alexandria T
authors.initials: AT
authors.lastname: Phan
authors.forename: David Z
authors.initials: DZ
authors.lastname: Chang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wolff
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hess
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gupta
authors.forename: Carmen
authors.initials: C
authors.lastname: Jacobs
authors.forename: Jeannette E
authors.initials: JE
authors.lastname: Mares
authors.forename: Andrea N
authors.initials: AN
authors.lastname: Landgraf
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002276:Carcinoid Tumor / Q000188:drug therapy; D018273:Carcinoma, Islet Cell / Q000188:drug therapy; D003692:Delayed-Action Preparations; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy*; D015282:Octreotide / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D003692:Delayed-Action Preparations; D000068338:Everolimus; D015282:Octreotide; D020123:Sirolimus
references.citation: Eur J Surg Oncol. 1996 Jun;22(3):298-301
references.pmid: 8654616
references.citation: Acta Pathol Jpn. 1991 Nov;41(11):847-56
references.pmid: 1686137
references.citation: Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8573-8
references.pmid: 15937108
references.citation: Urol Res. 2003 Feb;30(6):380-6
references.pmid: 12599018
references.citation: J Clin Oncol. 2006 Jan 20;24(3):401-6
references.pmid: 16421420
references.citation: Clin Cancer Res. 2007 Jan 1;13(1):234-40
references.pmid: 17200360
references.citation: Acta Oncol. 2003;42(7):672-92
references.pmid: 14690153
references.citation: J Clin Oncol. 2004 Dec 1;22(23):4762-71
references.pmid: 15570077
references.citation: Cancer Res. 2006 Feb 1;66(3):1500-8
references.pmid: 16452206
references.citation: Cancer Res. 2006 Jun 1;66(11):5549-54
references.pmid: 16740688
references.citation: Endocr Relat Cancer. 2008 Mar;15(1):257-66
references.pmid: 18310292
references.citation: Genes Chromosomes Cancer. 2008 Jan;47(1):84-92
references.pmid: 17943967
references.citation: J Clin Oncol. 2008 Mar 10;26(8):1316-23
references.pmid: 18323556
references.citation: Mod Pathol. 2007 Jul;20(7):802-10
references.pmid: 17483816
references.citation: Anticancer Res. 1989 Jul-Aug;9(4):889-91
references.pmid: 2817814
references.citation: Ann Oncol. 1997 Jul;8(7):685-90
references.pmid: 9296223
references.citation: Cancer. 2003 Feb 15;97(4):934-59
references.pmid: 12569593
references.citation: Clin Cancer Res. 2004 Sep 15;10(18 Pt 1):6111-8
references.pmid: 15447997
references.citation: Neth J Med. 1994 Jun;44(6):202-6
references.pmid: 8052343
references.citation: Ann Surg Oncol. 2007 Feb;14(2):780-5
references.pmid: 17146740
references.citation: Virchows Arch. 2007 Oct;451(4):757-62
references.pmid: 17674042
references.citation: Mod Pathol. 1999 May;12(5):539-45
references.pmid: 10349994
references.citation: J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
references.pmid: 10655437
references.citation: Endocr Pract. 2002 Mar-Apr;8(2):109-12
references.pmid: 11942775
references.citation: Pharmacogenomics. 2007 Dec;8(12):1705-13
references.pmid: 18086000
references.citation: Cancer Res. 2000 Aug 15;60(16):4573-81
references.pmid: 10969809
references.citation: Acta Oncol. 2008;47(5):941-7
references.pmid: 17906983
references.citation: Mod Pathol. 2005 Aug;18(8):1079-87
references.pmid: 15920555
references.citation: Eur J Pediatr. 1999 Apr;158(4):284-7
references.pmid: 10206124