Treatment of metastatic osteosarcoma with the somatostatin analog OncoLar: Significant reduction of insulin-like growth factor-1 serum levels

Patrick J. Mansky, David J. Liewehr, Seth M. Steinberg, George P. Chrousos, Nilo A. Avila, Lauren Long, Donna Bernstein, Crystal L. Mackall, Douglas S. Hawkins, Lee J. Helman

Research output: Contribution to journalArticlepeer-review

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. Study Purpose: 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. Design/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% (P < 0.0001, n = 21) and 53% (P = 0.003, n = 10). The difference of the area under the curve (AUC) minus baseline AUC (ΔAUC) for arginine-stimulated GH serum levels at week two was lower than baseline (P < 0.01). At weeks two and eight, GH peak values were lower than baseline (P < 0.0001 and P = 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.

Original languageEnglish (US)
Pages (from-to)440-446
Number of pages7
JournalJournal of Pediatric Hematology/Oncology
Volume24
Issue number6
DOIs
StatePublished - Aug 2002

Keywords

  • Growth hormone-IGF-1 axis
  • IGF-1
  • OncoLar
  • Osteosarcoma
  • Phase 1 study

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

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