Safety, tolerability and biological effects of long-term metronomic administration of non-cytotoxic anti-angiogenic agents

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Abstract

Background: α-Interferon, thalidomide and celecoxib inhibit tumour angiogenesis by differing mechanisms. Patients and 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: α-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 (χ 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 α-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.

Original languageEnglish
Pages (from-to)358-365
Number of pages8
JournalOncology
Volume77
Issue number6
DOIs
Publication statusPublished - Feb 2010

Fingerprint

Metronomic Administration
Celecoxib
Safety
Thalidomide
Interferons
Drug Combinations
Pharmaceutical Preparations
Neoplasms
Lethargy
Therapeutics
Patient Safety

Keywords

  • Anti-angiogenic treatment
  • Celecoxib
  • Circulating endothelial cells
  • Interferon
  • Solid tumours
  • Thalidomide
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

@article{e39e9ed650f64e2e9961b07754782bc0,
title = "Safety, tolerability and biological effects of long-term metronomic administration of non-cytotoxic anti-angiogenic agents",
abstract = "Background: α-Interferon, thalidomide and celecoxib inhibit tumour angiogenesis by differing mechanisms. Patients and 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: α-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 (χ 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 α-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.",
keywords = "Anti-angiogenic treatment, Celecoxib, Circulating endothelial cells, Interferon, Solid tumours, Thalidomide, Vascular endothelial growth factor",
author = "Cristina Noberasco and Gianluca Spitaleri and Patrizia Mancuso and Laura Zorzino and Davide Radice and Alessandra Milani and Andrea Rocca and Francesco Bertolini and Sandri, {Maria Teresa} and Giuseppe Curigliano and {De Pas}, Tommaso and Costantino Jemos and {Omodeo Sal{\`e}}, Emanuela and Sabrina Boselli and {De Braud}, Filippo",
year = "2010",
month = "2",
doi = "10.1159/000275830",
language = "English",
volume = "77",
pages = "358--365",
journal = "Oncology",
issn = "0030-2414",
publisher = "UBM Medica Healthcare Publications",
number = "6",

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TY - JOUR

T1 - Safety, tolerability and biological effects of long-term metronomic administration of non-cytotoxic anti-angiogenic agents

AU - Noberasco, Cristina

AU - Spitaleri, Gianluca

AU - Mancuso, Patrizia

AU - Zorzino, Laura

AU - Radice, Davide

AU - Milani, Alessandra

AU - Rocca, Andrea

AU - Bertolini, Francesco

AU - Sandri, Maria Teresa

AU - Curigliano, Giuseppe

AU - De Pas, Tommaso

AU - Jemos, Costantino

AU - Omodeo Salè, Emanuela

AU - Boselli, Sabrina

AU - De Braud, Filippo

PY - 2010/2

Y1 - 2010/2

N2 - Background: α-Interferon, thalidomide and celecoxib inhibit tumour angiogenesis by differing mechanisms. Patients and 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: α-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 (χ 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 α-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.

AB - Background: α-Interferon, thalidomide and celecoxib inhibit tumour angiogenesis by differing mechanisms. Patients and 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: α-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 (χ 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 α-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.

KW - Anti-angiogenic treatment

KW - Celecoxib

KW - Circulating endothelial cells

KW - Interferon

KW - Solid tumours

KW - Thalidomide

KW - Vascular endothelial growth factor

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U2 - 10.1159/000275830

DO - 10.1159/000275830

M3 - Article

VL - 77

SP - 358

EP - 365

JO - Oncology

JF - Oncology

SN - 0030-2414

IS - 6

ER -