Cardiovascular toxicity induced by anti-VEGF/VEGFR agents: a special focus on definitions, diagnoses, mechanisms and management

ABSTRACT

Introduction

Vascular endothelial growth factor (VEGF) is a key target in cancer therapy. However, cardiovascular safety has been one of the most challenging aspects of anti-VEGF/VEGF receptor (VEGFR) agent development and therapy. While accurate diagnostic modalities for assessment of cardiac function have been developed over the past few decades, a lack of an optimal definition and precise mechanism still places a significant limit on the effective management of cardiovascular toxicity.

Areas covered

Here, we report the cardiovascular toxicity profile associated with anti-VEGF/VEGFR agents and summarize the clinical diagnoses as well as management that are already performed in clinical practice or are currently being investigated. Furthermore, the review discusses the potential molecular toxicological mechanisms, which may provide strategies to prevent toxicity and drive drug discovery.

Expert opinion

Cardiovascular toxicity associated with anti-VEGF/VEGFR agents has been a substantial risk for cancer treatment. To improve its management, the development of guidelines for prevention, monitoring and treatment of cardiovascular toxicity has become a hot topic. The summary of cardiovascular toxicity profile, mechanisms and management given in this review is not only significant for the optimal use of existing anti-VEGF/VEGFR agents to protect patients predisposed to cardiovascular toxicity but is also beneficial for drug development.

KEYWORDS:

• Cardiomyopathy
• cardiovascular toxicity
• hypertension
• management
• molecular mechanism
• VEGF/VEGFR inhibitors

Article highlights

• VEGF/VEGFR inhibitors are potent agents used by oncologists for the management of malignancy. However, cardiovascular safety has been one of the most challenging aspects of therapy and new drug development.

• Further large-scale, prospective randomized trials are needed to generate an optimal definition of cardiovascular toxicity and for the comprehensive recognition of its prevalence.

• Appropriate prevention and periodic evaluation of cardiac function with advanced diagnostic modalities are essential for clinicians to make diagnoses. Subsequent intervention during surveillance should be performed so that the patients can continue to undergo potential lifesaving treatment.

• VEGF signaling suppression, through changes in both NO suppression and ET-1 stimulation, determines endothelial dysfunction and vasoconstriction, which are the major reasons for hypertension. The mechanisms of other adverse effects remain unclear.

• Future research should concentrate on the mechanisms underlying cardiovascular toxicity, which may help to determine the overlapping mechanisms between cardiovascular disease and the toxicity of existing or future drugs.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [Nos. 81673522 and 81872936] and the Science Technology Plan Project of Zhejiang Province [No. 2017C33139].