Drug Safety

, Volume 42, Issue 2, pp 159–179 | Cite as

Safety and Tolerability of Anti-Angiogenic Protein Kinase Inhibitors and Vascular-Disrupting Agents in Cancer: Focus on Gastrointestinal Malignancies

  • Letizia Procaccio
  • Vera Damuzzo
  • Francesca Di Sarra
  • Alberto Russi
  • Federica Todino
  • Vincenzo Dadduzio
  • Francesca Bergamo
  • Alessandra Anna Prete
  • Sara Lonardi
  • Hans Prenen
  • Angelo Claudio Palozzo
  • Fotios LoupakisEmail author
Review Article


Angiogenesis is an essential process for tumor growth and metastasis. Inhibition of angiogenesis as an anticancer strategy has shown significant results in a plethora of tumors. Anti-angiogenic agents are currently part of many standard-of-care options for several metastatic gastrointestinal cancers. Bevacizumab, aflibercept, ramucirumab, and regorafenib have significantly improved both progression-free and overall survival in different lines of treatment in metastatic colorectal cancer. Second-line ramucirumab and third-line apatinib are effective anti-angiogenic treatments for patients with metastatic gastric cancer. Unfortunately, the anti-angiogenic strategy has major practical limitations: resistance inevitably develops through redundancy of signaling pathways and selection for subclonal populations adapted for hypoxic conditions. Anti-angiogenic agents may be more effective in combination therapies, with not only cytotoxics but also other emerging compounds in the anti-angiogenic class or in the separate class of the so-called vascular-disrupting agents. This review aims to provide an overview of the approved and “under development” anti-angiogenic compounds as well as the vascular-disrupting agents in the treatment of gastrointestinal cancers, focusing on the actual body of knowledge available on therapy challenges, pharmacodynamic and pharmacokinetic mechanisms, safety profiles, promising predictive biomarkers, and future perspectives.


Compliance with Ethical Standards

Conflict of interest

Letizia Procaccio, Vera Damuzzo, Francesca Di Sarra, Alberto Russi, Federica Todino, Vincenzo Dadduzio, Francesca Bergamo, Alessandra Anna Prete, Sara Lonardi, Hans Prenen, Angelo Claudio Palozzo and Fotios Loupakis have no conflicts of interest that are directly relevant to the content of this study.


No sources of funding were used to conduct this study or prepare this manuscript.


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Letizia Procaccio
    • 1
    • 2
  • Vera Damuzzo
    • 3
  • Francesca Di Sarra
    • 4
  • Alberto Russi
    • 3
  • Federica Todino
    • 4
  • Vincenzo Dadduzio
    • 1
  • Francesca Bergamo
    • 1
  • Alessandra Anna Prete
    • 1
  • Sara Lonardi
    • 1
  • Hans Prenen
    • 5
    • 6
  • Angelo Claudio Palozzo
    • 4
  • Fotios Loupakis
    • 1
    Email author
  1. 1.Unit of Medical Oncology 1Veneto Institute of Oncology IOV—IRCCSPaduaItaly
  2. 2.Department of Surgery, Oncology and GastroenterologyUniversity of PaduaPaduaItaly
  3. 3.Department of Pharmaceutical and Pharmacological Sciences, School of Hospital PharmacyUniversity of PaduaPaduaItaly
  4. 4.PharmacyVeneto Institute of Oncology IOV—IRCCSPaduaItaly
  5. 5.Oncology DepartmentUniversity Hospital AntwerpEdegemBelgium
  6. 6.Center for Oncological Research, Antwerp UniversityEdegemBelgium

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