Hypertension is a common adverse effect of chemotherapy agents that
inhibit the vascular endothelial growth factor signaling pathway.
These agents include bevacizumab (Avastin, Genentech), sorafenib
(Nexavar, Bayer HealthCare), sunitinib (Sutent, Pfizer), pazopanib (Votrient,
GlaxoSmithKline) and axitinib (Inlyta, Pfizer).
Lisa K. Lohr
It is important to detect and treat hypertension in patients receiving
this therapy, as uncontrolled blood pressure could lead to serious
Hypertension is one of the most common nononcologic medication
conditions seen in patients with cancer. The reported prevalence of
hypertension in the general population of adults in the United States ranges
from 28% to 48%. The prevalence of pre-existing hypertension in patients with
cancer is probably in the same range. The classification of hypertension by the
Joint National Committee on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure (JNC 7) is noted in Table 1.
The NCI–Common Terminology Criteria for Adverse Events describes
hypertension as an adverse effect of cancer treatment somewhat differently,
although these criteria have been revised to correspond more closely to the JNC
7 criteria than before.
Hypertension induced by VEGF pathway inhibitors can be seen in patients
without a history of hypertension, as well as worsening BP control in those
with pre-existing hypertension. It can be seen soon after starting therapy or
may be delayed. The RR for hypertension is higher with certain VEGF agents, and
it is at least partly dose-related.
VEGF signaling has vasodilation and hypotensive effects on the vascular
endothelial cells. Likewise, inhibition of the VEGF pathway can lead to
hypertension, likely due to an increase in the peripheral vascular resistance.
The precise mechanism of this hypertension is not known, but it might be due to
neurohormonal factors or a reduction in the number of microvessels (vascular
However, the leading proposed mechanism for VEGF inhibitor hypertension
is the reduction of nitric oxide and prostacylin production seen in the
vascular endothelium. This can lead to an increased systemic vascular
resistance and hypertension. In addition, it has been proposed that the
renin-angiotensin system is down-regulated because of the VEGF
inhibitor-induced hypertension. Hypertension associated with VEGF inhibitors
may be predictive of antineoplastic effect, as a sign of substantial VEGF
Patients should be monitored carefully for the development or worsening
of hypertension when therapy with a VEGF pathway inhibitor is started. Many
patients have access to a home BP monitor, whereas those without access can
have their BP monitored at a local clinic, pharmacy or other sites.
Patients can be advised to monitor their BP two to three times per week
at the beginning of therapy. The BP goal for most patients is less than 140 mm
Hg/90 mm Hg.
The JNC 7 recommends a lower goal of less than 130 mm Hg/80 mm Hg for
patients with diabetes or chronic kidney disease. Patients with uncontrolled
pre-existing hypertension who are not meeting goal BPs should have their
antihypertensive medications adjusted before starting VEGF inhibitor therapy.
In the absence of literature-based guidelines, hypertension caused by
VEGF inhibitor therapy probably should be treated in the same manner as
hypertension in patients without cancer. Lifestyle modifications in diet and
exercise probably should be encouraged but may not be appropriate for some
patients with cancer.
The recommendations in the JNC 7 report suggest starting with a thiazide
diuretic for patients with stage I hypertension, although in the context of
VEGF inhibitor chemotherapy, it is unlikely to be effective as monotherapy.
Patients with stage II hypertension (systolic BP >160 mm Hg or diastolic BP
>100 mm Hg) usually should be started on two antihypertensive agents. Loop
diuretics usually are not recommended in these situations because the efficacy
is lowered by inhibitors of nitric oxide.
Vasodilating agents such as nitrates might be very effective in treating
hypertension caused by VEGF inhibitors, but nitrates possibly could reduce the
antineoplastic effects. The choice of antihypertensive agents also should be
guided by preferred medications for concomitant medical conditions (see Table 4).
Calcium channel blockers with more cardiac tissue activity, such as
verapamil and diltiazem, are less likely to be as effective as the
dihydropyridine calcium channel blockers, which have more of an effect on the
peripheral vessels. In addition, verapamil and diltiazem are CYP3A4 inhibitors
and are likely to inhibit the hepatic metabolism of the anti-VEGF tyrosine
Nifedipine would not be a good choice, as it can induce VEGF secretion.
The dihydropyridine calcium channel blockers amlodipine and felodipine are the
preferred agents and can be effective in controlling hypertension caused by
A new antihypertensive medication, nebivolol (Bystolic, Forest Labs), is
a beta-blocker that reduces peripheral resistance by the nitric oxide pathway.
This mechanism makes this agent an attractive choice for treating VEGF
M. Sitki Copur, MD, FACP, and Angela Obermiller, PharmD,
both of Saint Francis Cancer Treatment Center in Grand Island, Neb., recently
published their experiences with their algorithm for treating hypertension
caused by inhibitors of the VEGF pathway. Besides incorporating the JNC 7
guidelines for medication choice based on comorbid conditions, they recommend
secondary antihypertensive choices as shown in Table 3.
Development or worsening of hypertension is commonly seen in patients
treated with chemotherapy agents that inhibit the VEGF signaling pathway.
Patients should have careful monitoring throughout therapy because it can
develop early on or later.
The hypertension usually can be controlled with standard
antihypertensive agents, although dose modification and dual therapy is often
needed. The anti-VEGF therapy usually can be continued with careful management.
- Chobanian AV. Hypertension. 2003;42:1206-1252.
- Copur MS. Clin Colorectal Cancer. 2011;10:151-156.
- Izzedine H. Ann Oncol. 2009;20:807-815.
For more information:
- Lisa K. Lohr, PharmD, BCPS, BCOP, is a clinical pharmacy specialist
and oncology medication therapy management provider at Masonic Cancer Center at
the University of Minnesota/Fairview in Minneapolis. She also is a HemOnc
Today Editorial Board member. Dr. Lohr reports no relevant financial