Hypertension Due to Antiangiogenic Cancer Therapy With Vascular Endothelial Growth Factor Inhibitors: Understanding and Managing a New Syndrome

Novel antiangiogenic cancer therapies, particularly agents that block vascular endothelial growth factor (VEGF) signalling, have improved outcomes in patients with cancers and are now used as first-line therapies for some tumours. However, with VEGF inhibitors (VEGFIs) are new complications, particularly hypertension. VEGFI-induced hypertension is a dose-dependent phenomenon due to on-target effects rather than off-target effects. Increased blood pressure occurs in almost 100% of patients who take VEGFIs, with a subset who develop severe hypertension. Molecular mechanisms underlying VEGFI-induced hypertension are unclear, but endothelial dysfunction and increased vascular resistance, due to impaired nitric oxide signalling, reduced prostacyclin production, endothelin-1 (ET-1) upregulation, oxidative stress, and rarefaction have been implicated. Treatment of hypertension should be aimed at reducing the risk of short-term morbidity associated with hypertension while maintaining effective dosing of antiangiogenic therapy for optimal cancer treatment. Although specific guidelines are not yet available for the management of VEGFI-induced hypertension, angiotensin-converting enzyme inhibitors and dihydropyridine calcium channel blockers are commonly used. Severe hypertension might require reduction of VEGFI dosing, or in some cases, interruption of treatment. As more potent VEGFIs are developed and as more cancer patients are treated with VEGFIs, the burden of hypertension toxicity will increase. This will be further compounded as the use of antiangiogenic drugs broadens to include older patients and those with pre-existing cardiovascular disease. Here we focus on VEGF as a target for antiangiogenesis and how this affects increased blood pressure. Putative mechanisms underlying VEGFI-induced hypertension are highlighted and therapeutic strategies to manage such hypertension are discussed.