Vascular Endothelial Growth Factor Inhibitor-Induced Hypertension: Basics for Primary Care Providers

Abstract

Frequently, primary care providers continue to manage the overall medical care of cancer patients. With newer and often more potent antitumor agents, patients may present to their local physicians with drug-induced toxicities such as hypertension induced by vascular endothelial growth factor (VEGF) inhibitors. It is imperative that these healthcare providers are aware of basic aspects of this drug class, as its use has increased significantly in the last several years. Uncontrolled or malignant hypertension due to these agents should be recognized readily and treated early to prevent more severe outcomes. This overview provides a brief background on the role of VEGF and angiogenesis in tumor metabolism as well as theories of the mechanism of VEGF inhibitors and hypertension. Helpful clinical practice aspects including the types of inhibitors used in the United States and their pharmacologic characteristics will be discussed. Also, diagnosis and treatment of hypertension induced by vascular endothelial growth factors are reviewed. A summary of key aspects of this drug class and hypertension is included.

A Phase Ib Study of the VEGF Receptor Tyrosine Kinase Inhibitor Tivozanib and Modified FOLFOX-6 in Patients With Advanced Gastrointestinal Malignancies

“…5,10 Frequencies of hypertension for other VEGFR TKIs vary from 1% to 40%. 16,17 Hypertension has been shown to be associated with improved clinical outcome in patients with renal cell carcinoma treated with VEGFR TKIs and probably, therefore, indicates on-target biological activity rather than a side effect. 18,19 Serum tivozanib levels in this combination study were comparable with those observed in single-agent studies.…”

“…16,17 Hypertension developed in 53% of patients, was easily manageable, and only 2 patients required dose reduction. Hypertension did not result in interruption or termination of treatment in this study.…”

Cardioprotective effect of valsartan in mice with short-term high-salt diet by regulating cardiac aquaporin 1 and angiogenic factor expression

“…VEGF is expressed in virtually every tissue and is required for development-related angiogenesis and adult vascular homeostasis [26]. VEGF signaling is closely correlated with hypertension and use of VEGF inhibitors in cancer treatment causes pathological hypertension, probably due to decreased number of small arteries and increased arterial stiffness in proximal or distal vessels [27]. Transforming growth factor β1 (TGF-β1) is a multifunctional peptide produced by many cell types and affecting angiogenesis, immune regulations, and wound healing [28].…”

Anti-VEGF-induced hypertension and cancer outcomes: translating research into clinical practice

“…Clinical trials and observational studies have also reported an increased incidence of hypertension during systemic, but not intra-ocular, treatment with all commercially available anti-VEGF drugs [3]. Differences in patient characteristics, type of cancer, anti-VEGF treatment regimens and methods for assessing blood pressure notwithstanding, the reported incidence of hypertension ranges between 9% and 67%, and the incidence of severe hypertension (Grade 3 or Grade 4) ranges between 3% and 18% [9]. The available evidence suggests that both the incidence and the severity of anti-VEGF-induced hypertension are dosedependent [10].…”