New syndrome of hypertension related to new cancer therapies emerges

The mechanisms underlying vascular endothelial growth factor (VEGF)-inhibitor-induced hypertension need to be better understood and clear guidelines and improved management are needed, according to a recent review.

New cancer therapies, particularly agents that block VEGF signaling, have improved the outlook for patients with some cancers and are now used as a first line therapy for some tumors. However, almost 100% of patients who take VEGF inhibitors (VEGFIs) develop high blood pressure, and a subset develops severe hypertension.

"Exactly how VEGFIs cause hypertension is unknown. However, what is clear is that inhibition of VEGF in the vasculature directly increases blood pressure because hypertension develops acutely in response to VEGFIs and blood pressure returns to normal once the treatment is stopped," said senior investigator Rhian M. Touyz, MD, PhD, of the Institute of Cardiovascular and Medical Sciences, University of Glasgow, Scotland. He was corresponding author of the review article, published in the Canadian Journal of Cardiology (2014; doi:10.1016/j.cjca.2014.02.011).

Angiogenesis inhibitors are a new class of cancer drugs that are designed to prevent the formation of new blood vessels, thereby stopping or slowing the growth or spread of tumors. Angiogenesis requires the binding of signaling molecules, such as VEGF, to receptors on the surface of normal endothelial cells.

When VEGF and other endothelial growth factors bind to their receptors on endothelial cells, signals within these cells are initiated that promote the growth and survival of new blood vessels, which are necessary for tumor growth. Angiogenesis inhibitors interfere with various steps in this process.

Increased blood pressure has been observed in every trial involving VEGFIs and is the most common cardiovascular complication; it has an associated increased risk of fatal adverse cardiovascular events.

Some studies have suggested that VEGFI-induced hypertension is toxicity that is mechanism-dependent and on-target. This has led to the concept that hypertension might be indicative of effective VEGF inhibition and a positive antiangiogenic response, and as such could be a biomarker of a favorable outcome from VEGFI treatment.

"This further adds to the challenges, because improved cancer responsiveness might thus be associated with potentially greater cardiovascular risk," noted Touyz.

The exact factors that predispose to VEGFI-induced hypertension still remain to be established, the investigators stated. However, risk factors that have been associated with VEGFI-induced hypertension include a previous history of hypertension, combination therapy with more than one anti-VEGFI, older than 65 years, smoking, and possibly high cholesterol. Body mass index, renal function, race, a family history of hypertension, and cardiovascular disease do not seem to predict development of hypertension with VEGFI treatment.

The investigators recommend that management of hypertension in patients being treated with VEGFIs 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. Expert opinion recommends that patients be fully assessed for hypertension and cardiovascular disease before VEGFI treatment, monitor blood pressure frequently, and aggressively treat hypertension to target (less than 140/90 mm Hg).

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