Targeting and inhibiting the vascular endothelial growth factor (VEGF)-signaling pathway has become an integral modality in the treatment of a variety of malignancies, including renal-cell carcinoma (RCC); glioblastoma; hepatocellular carcinoma; gastrointestinal stromal tumors; and colorectal, lung, gastric, and ovarian cancers. Monoclonal antibodies and tyrosine kinase inhibitors (TKIs) that make up these types of drugs include bevacizumab, ramucirumab, cabozantinib, regorafenib, sorafenib, sunitinib, ponatinib, and axitinib. A classwide adverse event associated with the VEGF-signaling pathway inhibitors is cardiovascular toxicity, which can manifest as hypertension, thromboembolic disease, proteinuria, and heart failure.1
Hypertension is the most common cardiovascular event that may occur with VEGF-signaling pathway inhibitors.1 For example, the overall incidence of hypertension with bevacizumab has been described as being up to 24%, with up to 16% of patients experiencing grade 3 to 4 hypertension (Table 1).2-5 With sorafenib, all-grade hypertension may occur in 23.4% of patients, with 5.7% having severe, grade 3 to 4 hypertension.6 Although untreated hypertension can lead to severe medical events, such as myocardial infarction or stroke, some evidence suggests that hypertension secondary to anti–VEGF-signaling pathway therapy can be a biomarker for clinical efficacy of this class of drugs in the treatment of various malignancies.7
VEGF represents a family of proteins that are involved in the regulation of vascular and lymphatic endothelium.1 VEGF binds to the tyrosine kinase receptors VEGFR1, VEGFR2, and VEGFR3, which comprise the VEGF-signaling pathway. The VEGF-signaling pathway is a critical component in the formation and maintenance of blood vessels, a process known as angiogenesis.8 In the context of cancer, angiogenesis is a factor in tumor growth and metastasis formation. When the VEGF-signaling pathway is inhibited in tumor cells, it can prevent tumor angiogenesis.
VEGF is highly expressed in endothelial cells.8 The activation of VEGF can lead to the phosphorylation of endothelial nitric oxide synthase, which increases the production of nitric oxide.7 Through this mechanism, VEGF plays a role in nitric oxide production and vasodilation. It has been proposed that when the VEGF-signaling pathway is inhibited, hypertension may occur secondary to the subsequent decrease in nitric oxide production.7 Another proposed mechanism by which VEGF-signaling pathway inhibition leads to hypertension is that inhibition of the VEGF-signaling pathway may increase the production of endothelin-1, a potent vasoconstrictor.1
Several risk factors have been identified that may predispose patients to VEGF-signaling pathway inhibitor–induced hypertension. Specifically, preexisting hypertension, obesity, and older age were predictive risk factors for VEGF-signaling pathway inhibitor–induced hypertension with the use of sorafenib, pazopanib, and sunitinib.7 In addition, the risk for hypertension may be associated with the tumor type being treated, as well as the dose of the VEGF inhibitor. It has been suggested that patients with RCC who receive high doses of bevacizumab may be at an increased risk for hypertension.2 In addition, patients who receive sunitinib or sorafenib for metastatic RCC have been shown to be at an increased risk for treatment-related hypertension compared with patients who receive these drugs for other indications.9
Before the initiation of anti–VEGF-signaling pathway therapy, patients should be evaluated for preexisting hypertension and for risk factors for cardiovascular disease.10 For patients who have hypertension as a result of anti–VEGF-signaling pathway therapy, hypertension should be promptly managed to prevent further complications. An important reason to control blood pressure (BP) in this setting is that management of comorbidities has a demonstrated positive effect on survival in patients with cancer.11
Hypertension secondary to VEGF-signaling pathway inhibitors should be managed similarly to hypertension in the general population: there is no evidence to suggest otherwise. Although no formal guidelines exist for managing VEGF-signaling pathway inhibitor–induced hypertension, the National Cancer Institute (NCI) recommends following the Joint National Committee hypertension guidelines in this setting.12,13 Therefore, a common BP goal is <140/90 mm Hg. The NCI recommends monitoring BP weekly during the first cycle of anti–VEGF-signaling pathway therapy, and then at least every 2 to 3 weeks for the duration of treatment.12
In general, patients whose BPs increase to ≥140/90 mm Hg after initiation of anti–VEGF-signaling pathway therapy should initiate antihypertensive therapy, titrate any BP medication, or add another antihypertensive medication to the regimen if they are already receiving a BP-lowering medication without room to titrate.12 Although lifestyle modifications, such as diet, exercise, and weight loss, are often suggested for the general hypertensive population, these strategies may not be suitable for patients with cancer and hypertension secondary to anti–VEGF-signaling pathway therapy.14 Many of these patients may have unintentional weight loss or fatigue related to their cancer or its treatment, rendering lifestyle modifications difficult to implement. Aside from medical management, in cases of severe hypertension, some anti–VEGF-signaling pathway therapies may need to be temporarily interrupted until poorly controlled BP or hypertensive crises can be managed.12
Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and calcium channel blockers (CCBs) are 3 antihypertensive drug classes that should be considered for most patients who need to initiate therapy for hypertension secondary to anti–VEGF-signaling pathway therapy (Table 2).5,12,13 Thiazide diuretics and beta-blockers may also be considered. The superiority of one class of antihypertensive over another has not been demonstrated.12
The choice of the antihypertensive drug in this setting should consider several patient-specific factors, including the potential for drug interactions, preexisting antihypertensive medications, and comorbidities. For example, as was demonstrated in a retrospective study, patients with RCC whose VEGF-signaling pathway inhibitor–induced hypertension was treated with an ACE inhibitor or an ARB had improved overall survival compared with patients who received other types of antihypertensive medications.9 In addition, many anti–VEGF-signaling pathway TKIs undergo metabolism by the cytochrome (CY) P450 3A4 isoenzyme; nondihydropyridine CCBs, such as verapamil and diltiazem, are inhibitors of CYP3A4 and therefore may not be preferred choices for the treatment of hypertension secondary to some anti–VEGF-signaling pathway TKIs. Furthermore, some regimens that include bevacizumab may include cytotoxic chemotherapy that is dependent on renal clearance, such as cisplatin and pemetrexed; therefore, caution with concomitant use of ACE inhibitors and ARBs should be exercised.12
VEGF-signaling pathway inhibitors is a common treatment modality for several types of cancer; therefore, hypertension secondary to such therapy can pose a challenge to clinicians. Hypertension should be managed to prevent additional and more severe complications, such as myocardial infarction or stroke. Antihypertensive therapy selection should be based on patient-specific factors, such as previous use of antihypertensive treatment, and the potential for drug interactions, adverse events of the antihypertensive drug, and comorbidities.
In some cases, anti–VEGF-signaling pathway therapy may require temporary discontinuation or dose reductions to manage the presence of severe, treatment-related hypertension, or hypertension refractory to medical management.
Author Disclosure Statement
Dr Moore, Dr Kientzel, and Ms Fasan have no conflicts of interest to report.
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