title: Treatment of metastatic osteosarcoma with the somatostatin analog OncoLar: significant reduction of insulin-like growth factor-1 serum levels.
abstract: BACKGROUND
  Insulin-like growth factor-1 (IGF-1) has been implicated in the growth and/or metastasis of osteosarcoma (OS) and chondrosarcoma based on in vitro and experimental animal studies.
  
  
  OBJECTIVE
  To determine the degree of growth hormone (GH), IGF-1 axis blockade, toxicities, and antitumor effect of OncoLar (ONC) (Novartis, East Hanover, NJ, U.S.A.) in OS.
  
  
  METHODS
  A phase 1 study with ONC enrolled 21 OS patients (median age 19 y) in four cohorts: ONC 60 mg or 90 mg intramuscularly every 4 weeks with/without tamoxifen (TAM) 20 mg oral daily.
  
  
  RESULTS
  There were no dose-limiting toxicities. Nineteen percent of patients had grade III drug-related toxicities including: 62% of patients showed progressive disease after two courses (8 wk). Nineteen percent received four courses. No clinical responses were observed. At weeks two and eight of therapy, IGF-1 serum levels dropped 46% ( < 0.0001, n = 21) and 53% ( = 0.003, n = 10). The difference of the area under the curve (AUC) minus baseline AUC (DeltaAUC) for arginine-stimulated GH serum levels at week two was lower than baseline ( < 0.01). At weeks two and eight, GH peak values were lower than baseline ( < 0.0001 and = 0.002, respectively).
  
  
  CONCLUSIONS
  A long-acting somatostatin analog was able to lower IGF-1 levels of OS patients. IGF-BP-3 and GH were only transiently reduced. Although ONC was well tolerated, no sustained clinical responses were observed. The pathophysiology of serum versus tissue concentrations of IGF-1 as well as the interplay of IGFs, IGF-binding proteins, and other growth factors and cytokines in osteosarcoma warrants further investigation. A better understanding of these processes should lead to a more effective exploitation of these pathways for the targeted therapy of OS.
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-2669, USA. Mansky@mail.nih.gov
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Mansky
authors.forename: David J
authors.initials: DJ
authors.lastname: Liewehr
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: George P
authors.initials: GP
authors.lastname: Chrousos
authors.forename: Nilo A
authors.initials: NA
authors.lastname: Avila
authors.forename: Lauren
authors.initials: L
authors.lastname: Long
authors.forename: Donna
authors.initials: D
authors.lastname: Bernstein
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Mackall
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Hawkins
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Helman
mesh_terms: D000293:Adolescent; D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D002648:Child; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D013006:Growth Hormone / Q000097:blood; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008297:Male; D015282:Octreotide / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use*; D012516:Osteosarcoma / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D011098:Polyglactin 910 / Q000627:therapeutic use; D013629:Tamoxifen / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D018969:Insulin-Like Growth Factor Binding Proteins; D013629:Tamoxifen; D011098:Polyglactin 910; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D013006:Growth Hormone; D015282:Octreotide