Anti-vascular endothelial growth factor therapies and cardiovascular toxicity: what are the important clinical markers to target?

Abstract

Background: Therapies targeting vascular endothelial growth factor (VEGF) are associated with hypertension, cardiotoxicity, and thromboembolic events.

Methods: All prospective phase I-III clinical trials published up to December 2008 of approved anti-VEGF therapies (bevacizumab, sunitinib, sorafenib) and relevant literature were reviewed.

Results: The rates of Common Toxicity Criteria (version 3) grade 3-4 hypertension with bevacizumab, sunitinib, and sorafenib were 9.2%, 6.9%, and 7.2%, respectively. Grade 3-4 left ventricular systolic dysfunction was noted in 0.3%, 1.4%, and 0.05% of patients, respectively, whereas the rates of grade 3-4 thromboembolism were 9.6%, 1.2%, and 3.8%, respectively. The renin-angiotensin-aldosterone system (RAAS) may play a key role in vasoconstriction and capillary rarefaction, which are unleashed when VEGF signaling is targeted. Inhibiting RAAS may be the optimal approach for managing these toxicities.

Conclusions: In anticipation of cardiovascular complications with anti-VEGF therapies, early detection and personalized management may improve clinical outcomes and tolerance.

Figure 1.

VEGF inhibition by the approved anti-VEGF therapies has differential effects on the VEGF–VEGFR axis in tumor cells and normal tissues. In noncancer tissues, endothelial dysfunction and microvascular rarefaction set the stage for the development of hypertension, cardiomyopathy, and thrombotic microangiopathy and proteinuria in the kidney (histologic pictures courtesy of Dr. Elsa Sotelo, University of Texas at Houston). Abbreviations: VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.