Vol.:(0123456789) Drug Safety https://doi.org/10.1007/s40264-018-0776-6 REVIEW ARTICLE Safety and Tolerability of Anti‑Angiogenic Protein Kinase Inhibitors and Vascular‑Disrupting Agents in Cancer: Focus on Gastrointestinal Malignancies 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 © Springer Nature Switzerland AG 2019 Abstract Angiogenesis is an essential process for tumor growth and metastasis. Inhibition of angiogenesis as an anticancer strategy has shown signifcant results in a plethora of tumors. Anti-angiogenic agents are currently part of many standard-of-care options for several metastatic gastrointestinal cancers. Bevacizumab, afibercept, ramucirumab, and regorafenib have sig- nifcantly improved both progression-free and overall survival in diferent lines of treatment in metastatic colorectal cancer. Second-line ramucirumab and third-line apatinib are efective 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 efective 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, phar- macodynamic and pharmacokinetic mechanisms, safety profles, promising predictive biomarkers, and future perspectives. Hans Prenen, Angelo Claudio Palozzo, and Fotios Loupakis are co-senior authors. Part of a theme issue on “Safety of Novel Anticancer Therapies: Future Perspectives”. Guest Editors: Rashmi R. Shah, Giuseppe Curigliano. * Fotios Loupakis fotios.loupakis@iov.veneto.it 1 Unit of Medical Oncology 1, Veneto Institute of Oncology IOV—IRCCS, Padua, Italy 2 Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy 3 Department of Pharmaceutical and Pharmacological Sciences, School of Hospital Pharmacy, University of Padua, Padua, Italy 4 Pharmacy, Veneto Institute of Oncology IOV—IRCCS, Padua, Italy 5 Oncology Department, University Hospital Antwerp, Edegem, Belgium 6 Center for Oncological Research, Antwerp University, Edegem, Belgium Key Points An anti-angiogenic treatment strategy produced sig- nifcant benefts with diferent compounds in diferent settings and diseases among gastrointestinal cancers. Despite initial expectations, their results have been rather disappointing. Perspectives are reinvigorated by newer possible com- bination strategies with vascular-disrupting agents and immunotherapy. 1 Introduction In 1971, Judah Folkman frst highlighted the role of neo- angiogenesis as a crucial determinant for tumor development and progression, providing the basis for a new antitumoral strategy [1]. Since then, an increasing number of new anti- angiogenic agents have been developed.