Hypertension in Cancer Patients

Interest in hypertension in patients who have underlying malignancy has surged recently due to the increased prevalence of hypertension caused by the use of angiogenesis inhibitors in targeted cancer therapy. This topic, however, is not new, and hypertension has been well studied and reported in the setting of other cancer therapies. The importance of adequately diagnosing and managing hypertension in this patient population arises from the facts that hypertension is well established as a risk factor for chemotherapy-induced cardiotoxicity and that poorly controlled hypertension can significantly influence cancer management and even lead to the discontinuation of certain therapies.

Hypertension has been reported to be the most common comorbidity encountered in patients with malignancy (37%).¹ Its prevalence before chemotherapy is similar to that in the general population (29%).² The much higher rate is observed after the initiation of certain chemotherapeutic agents (angiogenesis inhibitors, 17%–80%; alkylating agents, 36%–39%; and immunosuppressants after stem-cell transplantation, 30%–80%).^3–5 The most common chemotherapeutic agents known to cause hypertension include several of the angiogenesis inhibitors commonly known as vascular signaling pathway (VSP) inhibitors. Hypertension is emerging as one of the most common side effects of these agents. These drugs include the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab and certain tyrosine kinase inhibitors (sunitinib, sorafenib, and pazopanib). The incidence of de novo or worsening hypertension in association with these drugs varies between 17% and 80%. The mechanism is not well understood and continues to be investigated. Several theories have been suggested, including endothelial dysfunction associated with reduced nitric oxide bioavailability and with increased vascular and renal endothelin production; increase in vascular tone; vascular rarefaction (decrease in density of microvessels); and renal thrombotic microangiopathy with secondary glomerular structural and functional changes that lead to proteinuria and hypertension.^6–8 In the absence of a proven single dominant mechanism, it is likely that the real cause is a combination of several of these suggested mechanisms.

Other classes of chemotherapeutic agents are known to induce hypertension by several mechanisms: alkylating agents and calcineurin can cause endothelial dysfunction and arterial vasoconstriction, calcineurin can activate the renin-angiotensin system, and steroids can increase patients' sensitivity to vasoactive substances and contribute to salt and fluid retention. Moreover, surgery or radiation therapy that involves the head or neck can lead to baroreflex failure and to associated difficult-to-treat labile hypertension and hypertensive crisis.⁹

Several limited observations have raised the interesting concept of using hypertension as a marker of cancer's response to VSP inhibitors. Rini and colleagues¹⁰ recently presented data in support of this concept. In their retrospective review of more than 4,500 patients with renal cell carcinoma, sunitinib-associated hypertension was significantly and independently associated with improved clinical outcome (median survival, 30.9 vs 7.2 mo, P <0.0001). Management and adequate control of hypertension did not alter cancer's response to therapy. More data are needed in order to clarify the clinical significance of such observational studies.

Historically, there have been significant discrepancies between specialists in reporting the prevalence of cancer-therapy–related hypertension, and also in managing it. This is partly related to the fact that internists and cardiologists typically follow the Joint National Committee (JNC) classification and guidelines for the evaluation and treatment of high blood pressure,¹¹ while oncologists are more familiar with the common terminology criteria for adverse events (CTCAE).¹² The CTCAE was intended for reporting trial-based side effects and are not meant to guide hypertension management.

In order to confront the increasingly recognized problem of hypertension during cancer-targeted therapy with VSP inhibitors, a panel of experts was established by the Investigational Drug Steering Committee of the National Cancer Institute. In 2010, the panel published its recommendations in regard to the evaluation, surveillance, and management of blood pressure problems in patients receiving VSP inhibitors.² The aim of this document was to establish principles of hypertension care on the basis of the available published literature, in addition to expert opinion. The summary of their recommendations includes the following:

1. There is a need for patient risk stratification at baseline: pre-existing hypertension is common in cancer patients and should be identified and treated before initiation of VSP inhibitors.

2. Active monitoring of blood pressure throughout the period of cancer management is recommended, especially during the 1st cycle of therapy when most patients experience a secondary elevation in blood pressure.

3. The target of blood pressure management should match the JNC 7 classification and guidelines¹¹ with the target blood pressure below 140/90 mmHg in general and below 130/80 mmHg in patients who have diabetes mellitus or kidney disease.

4. Aggressive blood pressure control is advised in order to minimize the risk of end-organ damage.

5. Attention to the choice of antihypertensive medication is also recommended. The panel encouraged the referral of patients to hypertension specialists whenever oncologists face difficulties in achieving adequate blood pressure control.

In the absence of clinical data to suggest otherwise, the management of other causes of cancer-treatment–related hypertension should also follow the JNC 7 guidelines. The choice of an antihypertensive medication should take into consideration 3 main factors: the mechanism and pathophysiology of the blood pressure elevation (for example, calcium-channel blockers for calcineurin-induced hypertension, diuretic agents for steroid-related hypertension, and clonidine for baroreflex failure); the possibility of drug–drug interaction that can cause potentiated toxicity of the chemotherapeutic and antihypertensive medications; and any compelling indication to use or avoid specific antihypertensive agents (for example, β-blockers and angiotensin-converting enzyme inhibitors should be considered for use in patients with prior myocardial infarction or congestive heart failure).

New or worsening hypertension is commonly encountered in cancer patients. Causes include many of the therapeutic agents used to care for these patients. Diagnosis and treatment should follow the JNC 7 guidelines. The aim is to minimize the risk of end-organ damage and to enable the continuation of needed cancer therapy. A team approach involving collaborative efforts between oncologists and other specialists (internists, cardiologists, and nephrologists) is encouraged for optimal management of this comorbidity. Future studies need to determine how the management of hypertension can influence, positively or negatively, cancer therapy and outcomes.