Managing Hypertension Associated With VEGF Inhibitors

Patients with cancer whose treatment includes any drug that inhibits signaling via the vascular endothelial growth factor (VEGF) pathway should receive regular blood pressure (BP) monitoring according to a panel of experts convened by the Angiogenesis Task Force of the National Cancer Institute Investigational Drug Steering Committee. Panel members, all experts in managing cardiovascular toxicities, determined that hypertension is a “mechanism-based toxic effect” of VEGF inhibitors. They outlined a set of 4 principles for managing elevated BP when using VEGF inhibitors to induce angiogenesis, a therapeutic approach the experts acknowledged is effective in patients with cancer (Table 1).

The panel reviewed studies in the literature that examined the relationship between BP, hypertension, and a specified VEGF inhibitor. The group also reviewed abstracts presented at major oncology meetings and assessed available data compiled during the development of these drugs. According to the investigators, “BP elevation is an effect common to all VEGF signaling pathway inhibitors, with hypertension reported as an adverse event in every trial of these drugs,” though they were not certain exactly how these inhibitors elevate BP. The researchers said VEGF inhibitors are also associated with hemorrhage, thrombosis, nephrotoxicity, and cardiac toxic effects, but the scope of their recommendations was limited to the more common and addressable concern of elevated BP.

In patients without cancer, chronic hypertension has been linked to congestive heart failure, myocardial infarction, stroke, and renal compromise, all conditions that increase rates of morbidity and mortality. According to the panel, managing chronic hypertension reduces the 10-year mortality rate by 9%. There are various algorithms and guidelines for long-term management of BP in general, but these may not be applicable to patients with metastatic cancer whose life expectancy is limited.

The researchers noted some might favor “minimalist approaches to hypertension for patients with incurable disease,” but they believe properly managing comorbidities such as hypertension might improve overall survival. In some cases, controlling hypertension might allow the patient to tolerate a higher dose of the VEGF inhibitor, contributing to improved survival outcomes.

Pretreatment Risk Assessment

The panel recommended conducting a “formal risk assessment for potential cardiovascular complications” before treating patients with a VEGF inhibitor. This should include at least 2 BP readings measured at different visits, obtaining a thorough patient history, and conducting a comprehensive examination to assess cardiovascular risk factors. Certain laboratory tests may also be required. Patients who have not been screened recently for cardiovascular disease will require an electrocardiogram and tests to measure serum cholesterol, triglycerides, and fasting plasma glucose before receiving VEGF inhibitors. Any pretreatment risk assessment should factor in subclinical organ damage and comorbidities. The panel suggested clinicians use the European Society of Hypertension/European Society of Cardiology system (Table 2) for assessing cardiovascular risk. Patients with no risk factors are considered low risk, those with 1 factor are high risk, and patients with ≥2 factors are higher risk.

The panel cautioned against dismissing high BP readings as a byproduct of “white coat hypertension” or uncontrolled pain. In cases where patients do have uncontrolled pain, the authors said the baseline measurement should be reassessed once the pain is better controlled. Clinicians should keep in mind that nonsteroidal anti-inflammatory drugs can increase BP, whereas narcotics and sufficient pain control are known to lower BP.

Currently approved inhibitors of VEGF signaling are bevacizumab (Avastin), a widely used monoclonal antibody administered alone or in combination with other agents to treat breast, colorectal, lung, and kidney cancer and glioblastoma; sorafenib (Nexavar), approved as monotherapy in liver and kidney cancer; sunitinib (Sutent), a single-agent treatment for kidney cancer and gastrointestinal stromal tumors; and pazopanib (Votrient), recently approved to treat kidney cancer. While these agents have different mechanisms of action, all block the kinase activity of VEGFR2. VEGF inhibitors in development include aflibercept, axitinib, cediranib, motesanib, and vandetanib (Zactima).

The purpose of conducting such an extensive evaluation, said the panel, “is not to exclude patients from potential life-extending VEGF signaling pathway inhibitor therapy.” Instead, it is meant to help clinicians assess and mitigate the risk of potential cardiac complications due to VEGF inhibitor therapy.

Blood Pressure Targets

Studies put the rate of hypertension in patients aged 56 to 59 years with solid tumors at ~28%, which is similar to the rate of hypertension in the general population. The Joint National Committee of the National Heart, Lung, and Blood Institute classifies BP <120/80 mm Hg as normal for typical adults aged ≥18 years; 120-139/80-89 mm Hg is considered prehypertension and warrants intervention. High-risk, stage I hypertension is considered to be 140-159/90-99 mm Hg, and stage II hypertension is identified as ≥60/110 mm Hg; both conditions warrant intervention.

BP goal for patients with diabetes or chronic kidney disease, for example, should be <130/80 mm Hg.

In patients treated with a VEGF inhibitor, the panel identified the primary target for BP as <140/90 mm Hg, with lower targets for patients at greater risk of cardiovascular complications. The For high-risk and higher-risk patients, BP should be <140/90 mm Hg before administering VEGF inhibitors.

In some patients with cancer, VEGF inhibitors cause a dramatic rise in BP compared with baseline measures; one clinical study found BP was as high as 29 mm Hg systolic and 27 mm Hg diastolic in the first week of treatment. It is not possible, said the investigators, to predetermine those

patients who will experience dramatic increases in BP.

Achieving Blood Pressure Control

Patients whose BP exceeds the recommended goal require antihypertensive therapy. The panel said shorter-acting agents can be used to bring BP to goal quickly, at which point a longer-acting agent can be used to maintain BP. “If the BP goal is not achieved, it may not be necessary to delay starting VEGF signaling pathway therapy until antihypertensive therapy is fully titrated as long as the BP is below the level that is likely to be associated with acute complications,” said the authors. For patients who do not show improving BP control before or after starting VEGF inhibitor therapy, the panel advised seeking consultation with a local hypertension specialist.

does not exceed 140/90 mm Hg.

Younger patients who are normotensive and at low risk for cardiac complications might need BP management if their BP shows a significant increase shortly after starting a VEGF inhibitor—even if BP

The panel advised “keeping the diastolic increase within 20 mm Hg of the baseline measurement.”

Based on National Cancer Institute (NCI) clinical trial protocol, the panel has recommended monitoring BP weekly during the first cycle of therapy with a VEGF and then every 2 to 3 weeks until therapy is completed. This can be done in the office or at home, after educating patients on the proper procedure for measuring BP. In patients with asymptomatic BP elevation, antihypertensive treatment can be initiated by telephone, said the authors, with appropriate follow-up in a few days’ time.

Patients who develop stage I hypertension or an increase in diastolic BP ≥20 mm Hg from baseline should receive antihypertensive therapy or titration of current antihypertensive therapy, if they are already taking medication. Patients fasting before in-office blood tests should be advised not to skip their BP medication.

The authors said they have used various agents to control hypertension in patients on VEGF inhibitors with success. These include thiazide diuretics, beta blockers, dihydropyridine and non-dihydropyridine calcium channel antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor antagonists. They did not identify any class of agents as superior to another.

In selecting an antihypertensive drug, they advised clinicians to consider the cancer, any compelling considerations, and time needed to titrate to reach goal. For example, oral ACE inhibitors tend to work more quickly than some dihydropyridine calcium channel antagonists. Some of the panel members said low doses of amlodipine combined with an ACE inhibitor or angiotensin II receptor blocker were effective.

VEGF inhibitor—associated BP elevation is reversible, and for some patients, discontinuation or dose reductions might be appropriate for controlling hypertension if antihypertensive medications fail to do so. “In NCI-sponsored trials, it is usually recommended that the bevacizumab dose be held for BP higher than 160 mm Hg systolic or 100 mm Hg

diastolic or any symptomatic hypertension at the time of treatment,” said the authors. If stopping bevacizumab for 4 weeks while continuing antihyper-

tensives fails to bring BP down, the panel advised clinicians to consider discontinuing bevacizumab.

The panel noted that physicians must be “mindful” of other agents known to intensify VEGF inhibitor—associated BP elevation. In addition to nonsteroidal anti-inflammatory drugs, excessive alcohol use, adrenal steroid hormones, erythropoietin, oral contraceptives, and sympathomimetics might increase BP.

Blood Pressure After VEGF Therapy Once VEGF therapy has been completed, any treatment-related increase in BP should diminish. Physicians might need to reassess BP and then reduce the dose of prescribed antihypertensives or discontinue them. The panel’s complete findings were published in the May issue of the Journal of the National Cancer Institute.