title: Safety, tolerability and biological effects of long-term metronomic administration of non-cytotoxic anti-angiogenic agents.
abstract: BACKGROUND
  alpha-Interferon, thalidomide and celecoxib inhibit tumour angiogenesis by differing mechanisms.
  
  
  METHODS
  In a randomized phase II trial to assess tolerability and safety, we assigned patients with advanced slow-growing solid tumours to 1 of 6 two- or three-drug combinations: alpha-interferon 0.5 million IU b.i.d., thalidomide (100 mg b.i.d. reduced to 100 mg daily), or celecoxib (400 mg daily reduced to 200 mg). Circulating endothelial cells and progenitors (CECs, CEPs) and vascular endothelial growth factor were also studied.
  
  
  RESULTS
  From January 2002 to September 2005, 62 patients were enrolled. Four months after initiating treatment, 3 (4%) had partial response, 40 (64%) had stable disease and 19 (30%) had disease progression. Median duration of clinical benefit (partial response/stable disease) was 11.3 months. Patients receiving a third drug had significantly less stable disease plus partial response (chi(2) test, p = 0.002) than those receiving two drugs. The treatments were generally well tolerated, but neurotoxicity (G3 lethargy) occurred in 6 patients. Baseline CEPs were lower (p = 0.004) in patients with clinical benefit at 6 months than those without benefit. After 2 months of treatment CECs were lower than at baseline (p = 0.018) in patients without clinical benefit, and CEPs were higher than at baseline (p = 0.003) in patients with benefit.
  
  
  CONCLUSIONS
  In pretreated patients with advanced slow-growing solid tumours, long-term metronomic administration of two-drug combinations of alpha-interferon, thalidomide or celecoxib was well tolerated and had antitumour activity. Low baseline CEPs in patients with subsequent clinical benefit suggest that CEC count may identify patients likely to benefit from long-term metronomic anti-angiogenic treatment.
authors.affiliation: Clinical Pharmacology and New Drugs Development Unit, Department of Medicine, European Institute of Oncology, Milan, Italy. cristina.noberasco@ieo.it
authors.forename: Cristina
authors.initials: C
authors.lastname: Noberasco
authors.forename: Gianluca
authors.initials: G
authors.lastname: Spitaleri
authors.forename: Patrizia
authors.initials: P
authors.lastname: Mancuso
authors.forename: Laura
authors.initials: L
authors.lastname: Zorzino
authors.forename: Davide
authors.initials: D
authors.lastname: Radice
authors.forename: Alessandra
authors.initials: A
authors.lastname: Milani
authors.forename: Andrea
authors.initials: A
authors.lastname: Rocca
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertolini
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Sandri
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Curigliano
authors.forename: Tommaso
authors.initials: T
authors.lastname: de Pas
authors.forename: Costantino
authors.initials: C
authors.lastname: Jemos
authors.forename: Emanuela
authors.initials: E
authors.lastname: Omodeo Salè
authors.forename: Sabrina
authors.initials: S
authors.lastname: Boselli
authors.forename: Filippo
authors.initials: F
authors.lastname: de Braud
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A