Classification
Systolic BP (mmHg)
Diastolic BP (mmHg)
Normal
<120
<80
Prehypertension
120–139
80–89
Stage 1
140–159
90–99
Stage 2
>160
>100
Within oncology, the Common Terminology Criteria for Adverse Events is a set of toxicity assessments during cancer research published by the National Cancer Institute that defines a number of complications of antineoplastic therapy , including hypertension. The most recent criteria published in 2009 define five grades of hypertension, ranging from 1 through 5 (Table 5.2) [13]. Grade 1 hypertension corresponds with prehypertension, as defined by JNC7 (SBP 120–139 mmHg and DBP 80–89); Grade 2 and Grade 3 hypertension correspond with Stage 1 and Stage 2 hypertension, respectively. Grade 4 is defined as hypertension that results in a life-threatening condition, including malignant hypertension, transient or permanent neurologic deficit, and hypertensive crisis. Finally, Grade 5 hypertension includes blood pressure elevation leading to death. These standards are commonly used for reporting adverse events during clinical trials and thus will serve as a common reference point in this chapter.
Table 5.2
Common terminology criteria for adverse events for hypertension
Grade | ||||
|---|---|---|---|---|
1 | 2 | 3 | 4 | 5 |
Prehypertension (systolic BP 120–139 mmHg or diastolic BP 80–89 mmHg) | Stage 1 hypertension (systolic BP 140–159 mmHg or diastolic BP 90–99 mmHg); medical intervention indicated; recurrent or persistent (>=24 h); symptomatic increase by >20 mmHg (diastolic) or to >140/90 mmHg if previously WNL; monotherapy indicated | Stage 2 hypertension (systolic BP >=160 mmHg or diastolic BP >=100 mmHg); medical intervention indicated; more than one drug or more intensive therapy than previously used indicated | Life-threatening consequences (e.g., malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis); urgent intervention indicated | Death |
Treatment
The benefits of treating hypertension are clear. Often described as the “silent killer ,” the immediate effects may not be apparent, but the long-term consequences are well known. The goal of hypertension therapy is to reduce end-organ damage associated with long-term high blood pressure. Clinical trials have shown that antihypertensive therapy is associated with marked reductions in stroke, myocardial infarction, heart failure, and renal failure [14]. Treating just 11 patients with Stage 1 hypertension over 10 years prevents one death [15].
The first line of therapy recommended for all levels of hypertension, whether prehypertension, Stage 1, or Stage 2, is lifestyle modification [11]. These modifications include weight reduction, adoption of the Dietary Approaches to Stop Hypertension (DASH) diet, dietary sodium reduction, physical activity, and moderate alcohol consumption [16–22]. Despite universal recommendation, these approaches commonly lead to a modest improvement, with the average reduction in systolic blood pressure between 2 and 20 mmHg [11].
For those who continue to have Stage 1 or Stage 2 high blood pressure despite lifestyle modification, the initiation of pharmacological therapy is indicated (Table 5.3). The most recent recommendations advise the use of either a thiazide-type diuretic, calcium channel blocker (CCB) , angiotensin-converting enzyme inhibitor (ACEI) , or angiotensin receptor blocker (ARB) [23]. Each of these medications has similar effects on mortality and cardiovascular outcomes, so none is preferred. However, there are certain populations in which specific therapy is recommended.
Table 5.3
Oral antihypertension therapy
Drug class | Name | Dose range (mg/d) |
|---|---|---|
Thiazide-type diuretics | Chlorothiazide | 125–500 |
Chlorthalidone | 12.5–25 | |
Hydrochlorothiazide | 12.5–50 | |
Metolazone | 2.5–5 | |
Calcium channel blockers | Amlodipine | 2.5–10 |
Dihydropyridines | Nicardipine sustained release | 60–120 |
Nifedipine long-acting | 30–60 | |
Non-dihydropyridines | Diltiazem extended release | 180–540 |
Verapamil immediate release | 80–320 | |
Verapamil long-acting | 120–360 | |
ACE inhibitors | Benazepril | 10–40 |
Captopril | 25–100 | |
Enalapril | 2.5–40 | |
Fosinopril | 10–40 | |
Lisinopril | 10–40 | |
Quinapril | 10–40 | |
Ramipril | 2.5–20 | |
Aldosterone receptor blockers | Eplerenone | 50–100 |
Spironolactone | 25–50 |
In the black population, thiazide-type diuretics and CCBs are preferred. These agents have been shown to have better outcomes than inhibition of the angiotensin-renin system in this population [23]. Furthermore, patients with chronic kidney disease, defined as a GFR of less than 30, should include an ACEI or ARB as part of their medication regimen. The combination of ACEI and ARB, however, should be avoided as this may lead to adverse effects on kidney function and a dangerous elevation in potassium.
When initiating pharmacological therapy, the clinician should begin with one of the classes of medications reviewed above. Blood pressure should continue to be assessed, and, if elevated after 1 month despite maximum therapy, a second agent should be added from a different class of medications. An additional agent should not be added, however, until the highest tolerated dose of the first agent is used. For instance, if an otherwise healthy patient is started on lisinopril and remains hypertensive even on 40 mg daily, then a thiazide-type diuretic or CCB may be considered. As with any new medication, drug-drug interactions should be evaluated, especially with concurrent chemotherapy .
If treatment remains insufficient with two medications at maximum tolerated doses, then a third agent should be added from the remaining classes of medications. Blood pressure that remains elevated despite three medications is defined as resistant and may require additional assessment by a specialist. Patients with cardiovascular comorbidities, including heart failure, coronary artery disease, chronic kidney disease, and diabetes, should be targeted to a lower systolic blood pressure.
Hypertension Associated with Antineoplastic Therapy
As discussed previously, hypertension is increasingly recognized as an important comorbidity in oncology. While some patients will have a history of hypertension at the time of their cancer diagnosis, others will develop hypertension over the course of antineoplastic therapy. An important subset of new cases of hypertension will be the direct result of the therapies they receive for cancer treatment.
Advances in cancer therapy have produced a number of new strategies for treating malignancy, some with serious cardiovascular side effects. One group of new chemotherapy agents in particular, agents that inhibit the vascular endothelial growth factor (VEGF) signaling pathway, is highly associated with hypertension. However other broad categories of chemotherapy may contribute to high blood pressure as well, including immunosuppressant agents used during the course of stem cell transplant. There are also several sporadic reports of other antineoplastic medications and alternative non-pharmacological therapies associated with hypertension that will be reviewed here.
Angiogenesis Inhibitors
The classic group of medications associated with hypertension is the angiogenesis (VEGF) inhibitors. This class of agents can include tyrosine kinase inhibitors (TKI) as well as monoclonal antibodies. Angiogenesis is a biological prerequisite for benign tumors to become malignant. Within the last two decades, highly specific agents, which encompass both small molecule TKIs and monoclonal antibodies, have proven to be important inhibitors of angiogenesis. These pharmacological agents function by inhibiting the steps of the signaling pathways necessary for vascular growth, which may include vascular endothelial growth factor and/or its receptor (VEGFR), epidermal growth factor receptor (EGFR) , basic fibroblast growth factor (bFGF) , and platelet-derived growth factor receptor (PDGFR) [24].
Bevacizumab is a monoclonal antibody that binds to and inhibits the activity of VEGF. It has approval for treatment of multiple solid tumors and is one of the more widely used antiangiogenic therapies [25]. Bevacizumab is prototypical in this class as a medication shown to cause hypertension. Several retrospective studies have estimated a prevalence of all-grade hypertension between 4 and 35 % with its use [26–33] and a rate of CTCAE Grade 3 hypertension in 11–18 % of patients [26–29, 34]. Rarely, hypertension associated with bevacizumab can be severe enough to require hospitalization or discontinuation of therapy. There may be a dose-dependent relationship with the degree of hypertension [29]
Tyrosine kinase inhibitors were first introduced as inhibitors of highly specific signal transduction in the 1980s and 1990s [35]. Imatinib, released in 2000, was the first TKI introduced to clinical practice. Antiangiogenic TKIs may target VEGFR, EGFR, and PDGFR and have been strongly associated with hypertension. Multiple TKIs targeting angiogenesis have been developed; examples of hypertensive effects are described below.
Sunitinib is a small molecule TKI used to treat renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor (GIST) . It is a potent inhibitor of VEGFR-1, VEGFR-2, and PDGFR. In the initial Phase I and II clinical trials, it was associated with an overall rate of hypertension of 17 %, and at least one patient developed Grade 4 hypertension [36, 37]. Other rarely observed cardiovascular complications included myocardial infarction and impaired systolic function . In larger Phase III clinical trials of sunitinib, a lower risk of hypertension was observed, with Grade 3 hypertension in 2–8 % of patients [37–41]. Hypertension was typically diagnosed within the first 4 weeks of therapy in this group of patients [42].
Sorafenib is a small molecule TKI also used to treat advanced renal cell carcinoma [6]. Like sunitinib, it inhibits VEGFR-2 as well as PDGFR. Initial Phase I and II clinical trials showed comparable rates of hypertension as sunitinib. The overall rate of all-grade hypertension was 17 %, with a very low rate of Grade 4 hypertension, at 1 % [6]. Across all clinical trials, the rates of all-grade hypertension observed in patients receiving sorafenib were moderate, occurring in 17–43 % of patients [6, 43–46]. Rates of Grade 3/Grade 4 hypertension were variable, occurring in 1.4–38 % of patients. A meta-analysis showed the incidence of Stage 3 or higher hypertension with sorafenib to be 2.1–30.7 % [47].
Pazopanib , a recently approved oral TKI for advanced renal cell cancer, is also associated with hypertension. One meta-analysis showed an incidence of all-grade hypertension of 35.9 %, with a rate of severe hypertension of 6.5 % [48]. Like the other VEGFR inhibitors, close monitoring is recommended for any patients initiating pazopanib therapy.
Significant work has investigated the mechanisms for hypertension when the VEGF pathway is inhibited [49]. The most likely explanation for TKI-associated hypertension is the impact on nitric oxide bioavailability. VEGF stimulates endothelial nitric oxide synthase (eNOS) , increasing NO production and arterial vasodilation. Inhibition of VEGF signaling reduces eNOS activity and decreases NO levels, leading to vasoconstriction and hypertension (Fig. 5.1) [49]. Nitric oxide is a potent vasodilator, so any inhibition of its production will lead to an increase in vascular tone [50]. Increases in blood pressure have been shown to correlate with VEGFR-2 inhibition [51].
Fig. 5.1
Vandetanib reduced plasma nitrite levels (Adapted from Mayer et al. 2011)
Other downstream effects of VEGF inhibition include stimulation of plasminogen activator inhibitor-1 expression and increased vascular and renal endothelin production [50, 52]. Vascular rarefaction is an additional proposed mechanism by which these angiogenesis inhibitors can cause hypertension through the loss of peripheral microvessels [53].
VEGF may also have a role within the renin-angiotensin system, which is a well-known regulator of blood pressure, although the evidence for this is conflicting [54, 55]. Finally, inhibition of VEGF may lead to damage of the glomerulus through cholesterol emboli syndrome or renal thrombotic microangiopathy [56, 57]. In reality, a combination of all of the above mechanisms likely contributes to hypertension in patients receiving this class of antineoplastic therapy .
Alkylating Agents
Alkylating agents were among the first antineoplastic medications associated with hypertension. One retrospective study studied the rates of cardiovascular disease in testicular cancer patients at least 10 years after receiving ifosfamide-containing chemotherapy. Their analysis showed a higher rate of hypertension (39 %) and hypercholesterolemia (79 %) compared with similar stage I controls [7]. These patients also had higher rates of coronary artery disease and diastolic dysfunction.
Another study looked at patients receiving multiple alkylating agents following bone marrow transplant and showed hypertension developing in 15 of 18 patients [58]. Busulfan, an alkylating agent used in chronic myelogenous leukemia (CML) prior to bone marrow transplant , has a reported frequency of hypertension of 36 % [3].
Taxanes
The taxane family of chemotherapy agents , including paclitaxel and docetaxel, derives from the Taxus genus of plants [59]. They are effective through inhibition of microtubule function and have been used since the 1990s to treat a number of solid tumors, including breast cancer, ovarian cancer, and non-small cell lung cancer [59].
When co-administered with doxorubicin, docetaxel has been shown to have a number of cardiovascular complications, including arrhythmias and hypertension, although the incidence of these findings is still rare [60]. Up to 3 % of patients receiving paclitaxel have been shown to have severe cardiovascular complications, including chest pain, cardiac arrest, supraventricular arrhythmias, and hypertension [2, 61]. The package insert for paclitaxel lists a frequency of hypertension of 1–10 % [3]. Notably, some patients have been shown to exhibit orthostatic hypotension, likely due to autonomic dysfunction [62]. These effects appear to be related to administration of the drug and typically resolve with cessation of therapy [59].
Neuroendocrine Agents
Certain types of cancers can be targeted through blockage of specific neuroendocrine pathways. Since many of these same hormones participate in blood pressure regulation, there is an association with hypertension with some of these agents.
Men receiving androgen deprivation therapy for prostate cancer are occasionally found to have worsening high blood pressure. For instance, nilutamide, an antiandrogen agent, has a reported frequency of hypertension of 1–10 % [3]. Another example is octreotide, a somatostatin inhibitor used in carcinoid disease, has a reported frequency of hypertension of 5–15 % [3]. Most of the hypertension associated with these agents is transitory and resolves with cessation of therapy.
Immunosuppression Agents
Hypertension is a well-known complication of bone marrow transplantation, especially with the introduction of cyclosporine for graft-versus-host prophylaxis [63–66].
Early clinical trials comparing cyclosporine versus methotrexate showed rates of high blood pressure of 57 % versus 4 %, respectively [63]. These rates were in stark contrast to the relatively normotensive state of most patients prior to transplant. The effect was compounded by the addition of glucocorticoids, which are commonly used during and posttransplant [63, 66].
Hypertension occurs in at least 20 % of patients receiving glucocorticoids, and the degree of high blood pressure is typically dose dependent. A dose of 80–200 mg of cortisol a day can increase systolic blood pressure by 15 mmHg [67]. The combination of steroids with natural licorice candy or even certain topical agents, include hemorrhoid creams , can potentiate this effect and lead to further hypertension [68].
Other Chemotherapy Agents
There are a number of additional chemotherapeutic agents that have been associated with observational reports of hypertension but do not fit into a single category. One review identified several drugs whose package inserts included hypertension as a known side effect [3]. These included alemtuzumab, arsenic, clofarabine, daunorubicin, gemtuzumab, goserelin, interferon, pentostatin, tretinoin, vinblastine, and vincristine [3]. The use of these agents should prompt close monitoring for rises in blood pressure.
Symptomatic Agents
While the adverse effects of antineoplastic agents are well known, one area in which toxicities may be underappreciated is those medications used to treat the complications of chemotherapy.
Several commonly used antiemetics, including metoclopramide, alizapride, and prochlorperazine, are all associated with a transient rise in blood pressure [67]. There may be a synergistic relationship between metoclopramide and cisplatin as the elevation in blood pressure was particularly profound in patients receiving both these medications [68].
Recombinant erythropoietin is an agent commonly used to treat profound anemia secondary to malignancy and antineoplastic therapy [69]. While effective at stimulating hematopoiesis, it has the side effect of hypertension. Up to 20–30 % of patients receiving erythropoietin will develop or have a worsening of high blood pressure [70]. This effect may be dose dependent and can be seen as early as 2 weeks or as late as 4 months following therapy [67]. Hypertension due to erythropoietin is not often serious, although hypertensive urgency has been reported [71].
Surgery and Irradiation
Although beyond the scope of this chapter, surgery and radiation therapy can also contribute to hypertension in the oncology patient who may receive a full range of treatment modalities in addition to pharmacotherapy.
Disruption of the patient’s native baroreflex system can lead to refractory hypertension that is often difficult to manage. This can be due to direct tumor invasion of regions within the baroreflex arc, including the carotid sinus, glossopharyngeal nerve, and vagus nerve [72]. Also, surgical resection and radiation therapy to these regions can lead to refractory hypertension, especially in the setting of head and neck cancers [72, 73].
Patients with baroreflex failure often present dramatically, typically with profound hypertensive crisis with systolic blood pressures exceeding 250 mmHg or particularly volatile hypertension with wide variations in blood pressure [72]. Orthostatic tachycardia, while a common problem, is not typically due to baroreflex failure but rather neuropathic postural tachycardia syndrome [74]. Management of high blood pressure in patients with baroreflex dysfunction often requires multiple antihypertensive medications and consultation with a specialist.
A Focused Strategy for Treatment
Today’s oncologist will increasingly encounter hypertension , regardless of his or her practice setting, whether ambulatory or inpatient. With the increasing ability of antineoplastic therapies to manage malignancy, the burden of cardiovascular disease, including hypertension, may continue to rise, both in patients undergoing active treatment and in cancer survivors. The mechanism by which blood pressure rises varies based on the type of antineoplastic therapy. Thus, a focused approach to the treatment of hypertension must be utilized. We will introduce a basic framework with which to approach newly diagnosed hypertension. In some cases, however, hypertension may be multifactorial, a result of prior risk factors, genetic predisposition, and the initiation of cancer therapy.
In 2010, the Cardiovascular Toxicities Panel, convened by the Angiogenesis Task Force of the National Cancer Institute Investigational Drug Steering Committee, issued a set of recommendations for the approach to patients with hypertension secondary to VEGF signaling pathway inhibitors [5]. They stopped short of making guidelines, as the quantity of evidence was limited; however, these recommendations are a useful start for the management of hypertension related to cancer therapy. While specifically written for VEGF inhibitors, these recommendations can be broadened to any oncology patient presenting with hypertension.
Before any antineoplastic therapy is initiated, a comprehensive risk assessment should be made which includes measurement of blood pressure, review of known cardiovascular risk factors, and targeted laboratory studies. While not every patient requires electrocardiographic or echocardiographic evaluation, when indicated, these studies should be performed prior to initiating therapy. Careful consideration should be made for the use of known cardiotoxic therapies in patients who already have cardiovascular disease.
Blood pressure should be actively monitored following the initiation of VEGF inhibitors, as well as other chemotherapy agents associated with hypertension. There are no established guidelines; however, biweekly blood pressure checks while receiving potentially toxic agents would be reasonable. A rise in blood pressure is typically seen within the first cycle of therapy, and the risk may be highest in those with preexisting hypertension or known risk factors. The presentation of high blood pressure can be delayed, however, so monitoring should be ongoing throughout therapy. Routine screening every 2 to 3 weeks is appropriate.
The goals for hypertension control are based on the most recent recommendations from JNC 7 [11]. Most adults should have a treatment goal of less than 140 mmHg of systolic blood pressure and 90 mmHg of diastolic blood pressure. Patients with coronary disease and/or heart failure should be targeted to a lower blood pressure and may require the assistance of a specialist [75].
When the decision to begin pharmacotherapy is made, careful consideration regarding drug choice should be made based on a number of factors. The mechanism by which chemotherapy increases blood pressure may be directly related to the mechanism of action against malignancy. Thus, when an oncologist is treating a patient with hypertension, it is important to first determine what agents may be contributing to the patient’s high blood pressure.
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