Annals of Oncology Advance Access originally published online on January 15, 2009
Annals of Oncology 2009 20(5):807-815; doi:10.1093/annonc/mdn713
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Management of hypertension in angiogenesis inhibitor-treated patients
1 Department of Nephrology, La Pitie-Salpetriere Hospital
2 Department of Cardiology, Saint Antoine Hospital
3 Department of Medical Oncology, Cochin Hospital, Paris
4 Department of Medical Oncology, Institut Gustave Roussy, Villejuif
5 Oncopharmacology Unit, Centre Antoine Lacassagne, Nice
6 Department of Medical Oncology, Pitie-Salpetriere Hospital, Paris, France
* Correspondence to: Dr H. Izzedine, Department of Nephrology, La Pitié-Salpêtrière Hospital, 47-80 Boulevard de l'Hôpital, Assistance Publique-Hopitaux de Paris, Pierre et Marie Curie University, 75013 Paris, France. Tel: +331-42177226; Fax: +331-42177232; E-mail: hassan.izzedine{at}psl.aphp.fr
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abstract |
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 Top abstract introductionclassification of HTNprevalence of HTN induced...management of HTNrecommendationsconclusionsreferences |
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Background: Hypertension (HTN) is one of the most frequent side-effects of systemic inhibition of vascular endothelial growth factor (VEGF) signaling. Its incidence and severity are dependent on the type of drugs, dose, and schedule used. The recognition of this side-effect is an important issue because poorly controlled HTN could lead to serious cardiovascular events. On another hand, HTN induced by anti-VEGF agents maybe a predictive factor of oncologic response. Knowledge of this clinical toxicity and/or therapeutic target or novel biomarker of drug activity can aid clinicians choosing the optimal and least toxic regimen suitable for an individual patient.
Methods: A Medline search was carried out using the following criteria: (i) all Medline listings as of 1 January 2000 with abstracts, (ii) English language, and (iii) Humans. The following phrases were used to query the database: (‘hypertension’, OR ‘blood pressure’) AND (‘anti-VEGF’ OR ‘VEGF inhibition’ OR ‘bevacizumab’ OR ‘sunitinib’ OR ‘sorafenib’ OR ‘VEGF Trap’). The references of each article identified were carefully reviewed for additional reference.
Results: Lifestyle modification should be encouraged. However, these nonpharmacologic strategies are not always suitable to patients with altered performance status related to metastatic cancer necessitating early drug intervention. Only one randomized study showed a beneficial effect of a calcium channel blocker use to prevent or minimize HTN secondary to antiangiogenic therapy. Nitrates looks as effective in controlling such side-effect.
Conclusions: No clear recommendation for an antihypertensive agent can be made in this context because there is a lack of controlled studies addressing the subject. Blood pressure-lowering drugs should be individualized to the patient's clinical circumstances and angiogenic inhibitors should be withheld only from patients who experienced hypertensive crisis.
Key words: angiogenesis inhibitors, anti-VEGF agents, drug, hypertension management
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introduction |
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Topabstractintroductionclassification of HTNprevalence of HTN induced...management of HTNrecommendationsconclusionsreferences |
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Hypertension (HTN) is one of the most frequent comorbid conditions found in cancer registry patients [1] and observed side-effects of systemic inhibition of vascular endothelial growth factor (VEGF) signaling. It is an established risk factor for coronary heart disease, stroke, heart failure, and end-stage renal disease [2]. On another hand, a higher incidence of intracerebral hemorrhage has been recently reported in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor (VEGFR) [3] probably related to uncontrolled HTN at diagnosis [4].
The incidence and severity of HTN in cancer patients are dependent on the type of drugs, dose, and schedule used (Table 1) [5–19], age of patients, as well as the presence of coexisting cardiac diseases. The advent of angiogenesis inhibition in the treatment of oncology has revolutionized the care of cancer-affected patients. With the reductions in cancer-related morbidity and mortality brought on by the inhibition of angiogenesis, patients with cancer are expected to live longer. These prolonged survivals indicate that oncologists, who follow middle-aged and elderly cancer patients, should be alert to preventing HTN. Indeed, the adverse event in which angiogenic inhibitors are most likely to be implicated on the basis of earlier studies and known antiangiogenic class effects is HTN. This was one of the most common grade 3 events reported with the majority of the affected patients having preexisting HTN. The recognition and management of HTN is an important issue in these patients because poorly controlled HTN could lead to serious cardiovascular events. However, the toxicity was readily managed and did not necessitate drug discontinuation as a result. Indeed, cardiac ischemia or infarction was more common in patients receiving anti-VEGF agents than in those receiving placebo [17]. Also, the use of these drugs maybe associated with reversible posterior leukoencephalopathy syndrome, a significant event likely secondary to HTN [20–22]. On another hand, HTN maybe a predictive factor of angiogenic inhibition [23]. Knowledge of this clinical toxicity and/or therapeutic target or novel biomarker of drug activity can aid clinicians to choose the optimal and least toxic regimen suitable for an individual patient.
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classification of HTN |
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HTN was recorded according to versions II or III of the Common Terminology Criteria for Adverse Events of National Cancer Institute (http://ctep.cancer.gov/reporting/ctc_archive.html) [24] (Table 2).
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However, this definition of HTN was different from those proposed by the 2003 Joint National Committee on Prevention, Detection, Evaluation, and the Treatment of High Blood Pressure (JNC7) guidelines who classify blood pressure (BP) by stage and provide recommendations for treatment and follow-up [25]. The JNC7 classification system consists of three main BP categories: normal, prehypertension, and HTN, which are shown in Table 2. In general, normal BP for adults consists of a systolic blood pressure (SBP) reading of <120 mmHg and a diastolic blood pressure (DBP) reading of <80 or 120/80 mmHg. Prehypertension is a new category derived from the previous guidelines that includes patients with ranges of SBP from 120 to 139 mmHg and/or of DBP from 80 to 89 mmHg. Note that prehypertension is not a disease category; rather, it is a guideline for identifying individuals at high risk of developing HTN such as cancer-affected patients on antiangiogenesis agents to alert both patients and clinicians of this risk so that they can consider appropriate interventions for preventing or delaying development of the disease. Careful attention to patients in the prehypertension category is important because several studies indicate that mortality rates for myocardial infarctions, strokes, and other vascular diseases increase progressively with a rise in BP and can begin at levels as low as 115/75 mmHg [26].
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prevalence of HTN induced by angiogenic inhibitor agents |
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The prevalence of HTN in the cancer-affected population remains unclear. Estimates suggest that HTN prevalence before the introduction of angiogenesis inhibition agents was similar to that of the general population (between 32% and 48%) [27]. Table 1 summarizes the findings of the available phase III studies concerning the HTN induced by anti-VEGF agents. In patients on bevacizumab, HTN had an overall incidence of up to 32% [5]; 11%–16% of patients required intensive therapy with multiple drugs (grade 3), but only 1% had grade 4 life-threatening hypertensive crisis. According to the Avastin package insert (2004, Genentech, Inc., South San Francisco, CA), the incidence of HTN using bevacizumab with 5-fluorouracil (5-FU) regimes ranges from 60% to 67%, compared with 43% in control groups receiving 5-FU regimes without bevacinimab [28]. The data collecting from meta-analysis revealed a 22.5%–57.7% incidence of HTN under angiogenic inhibitors associated with a 7.5, 6.1, and 3.9 relative risks for developing HTN with bevacizumab, sorafenib, and sunitinib, respectively [29]. This incidence could be even higher if we followed a more strict definition and classification of HTN like that of JNC7 rather than the actually National Cancer Institute one used. Furthermore, the incidence of HTN was dose related (Table 1) and half of the patients developing HTN on bevacizumab had a history of elevated BP [3]. At 5 mg/kg per dose of bevacizumab, HTN occurred in 11% of patients, increasing to 28% at a dose of 10 mg/kg [3].
The emerging toxicity profile was further supported by the First BEAT, BRiTE, and TREE trials. The First BEAT trial was initiated to evaluate the safety profile of bevacizumab in a broader patient population with metastatic colorectal cancer (mCRC) using bevacizumab in combination with a variety of chemotherapy regimens. Up to 2000 patients from 41 different countries in Europe, Canada, and Australia were enrolled from June 2004 to February 2006. Eligible patients received first-line, 5-FU-based chemotherapy. Bevacizumab was administered in a dose of either 5 mg/kg every 2 weeks with 5-FU regimens or 7.5 mg/kg every 3 weeks with capecitabine-based regimens. In March 2006, data from 1789 patients were evaluated, with a median follow-up of 8.7 months. Bevacizumab-related HTN was reported in 5.1% [30]. The BRiTE study is a large, community-based observational USA registry of patients with mCRC receiving bevacizumab plus first-line chemotherapy. One thousand nine hundred fifty-three patients were followed for up to 3 years with data reporting every 3 months that 18.4% of patients with no history of HTN developed HTN requiring medication and 18.7% of patients who had HTN requiring medication at baseline experienced worsening of their HTN while on study treatment [31]. The TREE randomized, multicenter trial was designed to assess the safety, tolerability, and efficacy of each of three oxaliplatin plus bolus, infusional, or oral fluoropyrimidine regimens without (TREE1 cohort) or with (TREE2 cohort) bevacizumab for first-line treatment of mCRC patients. The addition of bevacizumab in TREE2 caused more grade 3–4 HTN [32].
Both sorafenib and sunitinib are associated with a significant and sustained increase in BP.
In patients on sunitinib, HTN had an incidence of 28% (6% had grade 3) in phase II trials in metastatic renal cell carcinoma [15, 33] and an incidence of 15% (4% had grade 3) in a phase III trial in gastrointestinal stromal tumors [15]. In patients on sorafenib, HTN had an overall incidence of 17% (3% had grade 3 or 4) [34].
The grades 3–4 HTN adverse event attributable to vatalanib in the CONFIRM-1 and 2 trials was 21% for vatalanib versus 5% for placebo [35].
In phase I study of Cediranib (Recentin; AZD2171), one-third of patients developed grade 3 or 4 HTN [36] which was dose limiting in 7 of 47 patients. This toxicity occurred at AZD2171 doses of 20 mg and higher [37]. Clinicians should always remember that concomitant infusional 5-FU could have contributed to the development of HTN in some patients due to its effects on the vascular endothelium.
Drug-related HTN can occur with drug initiation and within the first year of treatment. Yang et al. [8] reported that the median interval from the first dose of bevacizumab to the onset of HTN was 131 days, with a range of 7–316 days. Johnson et al. [38] reported that the greatest increases in systolic pressure ranged 7–14 mmHg on day 42 and that 7 of 12 patients who had a significant systolic pressure increase had preexisting HTN. Azizi et al. [39] showed that sunitinib-treated patient experienced increase in BP levels during the second cycle of treatment, and Veronese et al. [40] reported usually an increase by 20% and 10%, in systolic and DBP, respectively, after 3 weeks of treatment with sorafenib, reaching a plateau thereafter. Tighter grading and closer surveillance of blood pressure is hence highly recommended. This would permit earlier detection of this common side effect.
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management of HTN |
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HTN de novo or worsening control of a preexisting one after the introduction of antiangiogenic treatment may indicate many possible underlying mechanisms: renal thrombotic microangiopathy [41], glomerular lesions, but more commonly it is isolated HTN secondary to treatment itself. In the first two cases, the glomerular or vascular affection explain the HTN and hence the importance of evaluating renal abnormalities (serum creatinine, calculating the clearance by Modification of Diet in Renal Disease formula, searching for proteinuria, microscopic hematuria) and markers of hemolytic anemia or thrombocytopenia. Referral to a nephrologist is recommended for the evaluation of abnormal, declining kidney function, or proteinuria [42]. Indications for renal biopsy in patients with cancer should be the same as in patients without cancer, including significant proteinuria, evidence of progressive kidney disease, unexplained acute/subacute renal failure, or nephritic syndrome [43].
Because clinical diagnosis on the basis of cancer or angiogenic inhibitor types and degree of proteinuria may not predict histological diagnosis in those patients and because treatment options and prognosis maybe influenced by the renal pathological diagnosis, and there is no evidence of higher risk related to biopsy in cancer patients compared with general population, renal biopsy maybe recommended whenever feasible.
The mechanism of action by which angiogenic inhibitors causes ‘isolated HTN’ is uncertain. Measured BP is the product of the cardiac output by systemic vascular resistance (SVR). Drugs which increase either one as in case of β1+ or 
+ inotropic drugs are known to increase BP. In the case of angiogenic inhibitors, heart failure with marked decrease of ejection fraction have been reported [44]. Intracoronary VEGF infusions in VIVA trial induced vasodilatation thus decreasing BP level [45]. So the HTN induced by antiangiogenic drugs is probably related to an increase in SVR.
Mechanisms inducing high SVR include neurohormonal factors (such as renin, and aldosterone, catecholamines, epinephrine, norepinephrine, endothelin I), vascular rarefaction (decrease in the density of microvessels), and endothelial dysfunction associated with a decrease in nitric oxide (NO) production and an increase in oxidative stress. There were no significant changes in humoral factors in sorafenib-treated patients experiencing HTN [40], implies that impaired angiogenesis or endothelial dysfunction maybe the cornerstone mechanism of elevated BP. An important part of the mechanism of HTN associated with VEGF inhibition is thought to involve decreased production of NO in the wall of arterioles and other resistance vessels. VEGF increases NO synthesis through upregulation of endothelial NO synthase, and VEGF inhibition diminishes NO synthesis [46, 47]. Indeed, the inhibition of VEGF may cause increased SVR [48, 49] and vascular rarefaction [50] leading to HTN. Furthermore, VEGF inhibition may induce renal thrombotic microangiopathy [41] leading to BP disequilibrium (Figure 1).
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The medical literature gives no indication that cancer-affected patients with HTN or prehypertension should be managed in a way other than that recommended in the JNC7 guidelines. For patients with stage 1 or 2 uncomplicated HTN, the target BP level is <140/90 mmHg. Current guidelines from the National Kidney Foundation, which have not been specifically validated in patients with cancer-related kidney diseases, recommend a target BP of 125/75 mmHg or less, as tolerated, for patients with diabetes mellitus, proteinuria, or reduced kidney function; alternatively, the recommended BP goal is 130/80 mmHg [42]. Indeed, in cancer patients with comorbidities such as chronic kidney disease, a target BP level of <135/85 mmHg should be recommended [25]. Clinicians should consider individual patients’ comorbid conditions when selecting classes of antihypertensive drugs for treatment and blockade of the renin–angiotensin system may have specific benefits in those hypertensive patients with proteinuria.
Lifestyle modification including adoption of the Dietary Approaches to Stop Hypertension eating plan [51] which limits intake of both saturated and unsaturated fats and increases that of fruits, legumes, and vegetables without changing total caloric input and above all insisting on salt restriction (4 g/day maximum) maybe encouraged.
However, these nonpharmacologic strategies are not always suitable to patients with altered performance status related to metastatic cancer necessitating early drug intervention.
No clear recommendation for an antihypertensive agent can be made in this context because there is a lack of controlled studies addressing the subject. Different types of monitoring for BP have been proposed in the literature: the rule of three ambulatory measures (the mean of three morning measurements at 5-min interval, also three night measurements for 3 days/week) [39]. Another method is one measure weekly during the first 6 weeks of treatment for Wu et al. [29] and thereafter HTN should be monitored and treated according to the standard medical practice. HTN, which can occur anytime after the initiation of treatment, usually can be managed with oral antihypertensive agents, and treatment can be continued without reduction in dose.
In cases of severe or persistent HTN despite the initiation of antihypertensive treatment, temporary, or permanent discontinuation of angiogenic inhibitor should be considered. In most patients, HTN can be controlled with standard antihypertensive medications [29].
In BRiTE study, patients on three or more classes of antihypertensive drugs at baseline showed the lowest incidence of increased HTN associated with bevacizumab use compared with patients who were on one or two classes of medication [31]. The majority of patients who developed de novo HTN with bevacizumab use were treated with one class of antihypertensive medication. Subsequent addition of antihypertensive medication classes was required in 27% of those who developed de novo HTN. Angiotensin-converting enzyme (ACE) inhibitors (33.3%) and beta blockers (29%) were most commonly used to manage HTN in de novo hypertensive patients. Other antihypertensive classes included diuretics (26.6%), calcium channel blockers (CCBs) (22.7%), angiotensin 2 receptor antagonist (ARA) (15%), and others (9.7%) [52].
Hurwitz et al. [5] reported that all the HTN occurring in the phases I and II bevacizumab trials in mCRC patients was readily responsive to standard oral antihypertensive agents including diuretics, ACE inhibitors, and CCBs. There were no hypertensive crises, deaths, or bevacizumab discontinuations. Another angiogenesis inhibitor drug study reported successful HTN treatment using diuretics and/or β-blockers [53].
Because angiogenic inhibitor adverse events are also characterized by proteinuria, patients may need to be screened for proteinuria. Glomerular nephrin underexpression is one of the mechanisms of the proteinuria induced by angiogenic inhibitors [54]. It has been demonstrated that ACE inhibitors induced reexpression of nephrin in diabetic nephropathy [55] and improved endothelial function and microcirculatory density [56]. Furthermore, there is significant evidence that both ACE inhibitors and ARA may induced cytostatic effects on the cultures of several lines of both normal and neoplastic cells and also delayed the growth of different types of tumors in a variety of experimental animals. Moreover, incidence and growth of different neoplasms was delayed in hypertensive subjects treated with ACE inhibitors or ARA when compared with hypertensive patients receiving alternate medications in retrospective studies. This antineoplastic effect maybe exerted by reduction or inhibition of angiotensin 2 synthesis. Angiotensin 2 is a powerful mitogen and facilitates cellular growth through transforming growth factor beta, epidermal growth factor, and tyrosine kinase. Angiotensin 2 also regulates apoptotic mechanisms and angiogenesis [57] and both ACE inhibitors and ARA can inhibit myocardial angiogenesis induced by VEGF [58]. However, it has been reported that ACE inhibitors may promote angiogenesis in cardiac infarction, but its mechanism is irrelative to the expression of VEGF [59]. Given the efficacy of ACE inhibitors and ARA, clinicians may consider using one as a first-line agent when a patient's plasma creatinine is <2 mg/dl or there is no evidence of hyperkalemia or renal artery stenosis.
The nondihydropyridine CCBs, such as verapamil and diltiazem, are CYP3A4 inhibitors and nifedipine a dihydropyridine CCB has been shown to induce VEGF secretion [60]. In the absence of available data from clinical studies, CCB dihydropyridines, such as amlodipine and felodipine, are the preferred class of CCB and the nondihydropyridine CCB should be contraindicated or used cautiously in conjunction with angiogenic inhibitors metabolized by CYP3A4 (Figure 2). Langenberg et al. [61] prospectively investigated the optimal hypertensive management approach to minimize dose interruptions and reductions in order to maximize the dose intensity of cediranib (AZD2171) an oral, highly potent, and selective inhibitor of VEGF signaling, with activity against VEGFR-1, -2, and -3. Patients with advanced solid tumors (n = 126) were randomized to one of four treatment groups: cediranib 30 or 45 mg/day ± antihypertensive prophylaxis. The prophylaxis groups received a low dose of CCB 3–7 days before starting cediranib. All patients received standardized, predefined HTN management commencing with a CCB followed, when needed, by a beta blocker and/or an ACE inhibitor. Only one patient developed severe hypertension in the groups receiving prophylaxis compared with 18 patients in the nonprophylaxis groups. Prophylaxis did not result in less dose reductions or interruptions. In all arms, the adverse event profile and steady-state pharmacokinetic parameters were similar to other single-agent studies with cediranib. Prophylactic treatment with antihypertensives did not reduce dose interruptions.
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Because the pathogenesis of this type of HTN clearly is a class effect of compounds targeting the VEGF signaling pathway and that VEGF is known to increase endothelial nitric oxygen, it might be supported that the hypertensive effect of anti-VEGF compounds is considered to be mediated by the drop in endothelial nitric oxide synthetase. In healthy subjects, a positive correlation between serum nitrate and VEGF levels has been reported [62]. The classes acting to increase NO (e.g. nitrates, phosphodiesterase inhibitors, or Nébivolol) might be of particular relevance, at least theoretically, and evaluated in prospective clinical trials [63]. Indeed, Dixirt et al. [64] recently reported exquisite responses to long-acting oral nitrates with prompt return of pretreatment BP in spite of continuous anti-VEGF treatment in several hypertensive refractory patients under adequate dosing of a ACE inhibitor and CCB-association. From a randomized, double-blind, two-way crossover study, Oliver et al. [65] reported that regular sildenafil, a phosphodiesterase type 5 inhibitor agent, constitutes effective antihypertensive therapy. Nebivolol is a β-blocker with a vasodilating effect mediated by the endothelial L-arginine NO pathway. As the BP-lowering effect of Nebivolol is mainly related to a reduction in peripheral resistance, this drug should be a good option for treating antiangiogenic agent-induced HTN [66]. Whether the addition of these drugs to the angiogenic inhibitor agents might affect its antitumor effect and induce BP control deserves further studies in clinical practice.
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Globally, several messages could be proposed:
- (i) Patients suitable to angiogenic inhibitor therapy must be assessed at baseline for existing kidney disease with a screening BP, urine analysis for proteinuria, and a calculated estimate of renal function [creatinine clearance or glomerular filtration rate (GFR)]. Repeat screening should be carried out every week for the eight first weeks and before any infusion (for anti-VEGF humanized antibodies and VEGF-Trap) or cycle (for oral tyrosine kinase inhibitors). BP measurement maybe carried out either with home BP or office monitoring.
- (ii) HTN definition level should be adapted according to JNC7 recommendations for earlier management.
- (iii) Elevated BP under angiogenic inhibitors maybe secondary to renal thrombotic microangiopathy, glomerular damage, or more frequently related to the VEGF vascular effect. Indeed, patients who under angiogenic inhibitors developed proteinuria of grade
1+ by dipstick analysis, mechanic hemolytic anemia, or reduced renal function (GFR, <60 ml/min per 1.73 m2) should be referred to a nephrologist for additional evaluation.
- (iv) BP-lowering drugs should be individualized to the patient's clinical circumstances; ACE inhibitors or ARA should be preferred for those patients with proteinuria, chronic kidney disease risks, or metabolic syndrome; nondihydropyridine CCB should be avoided in treating patients receiving CYP450 inhibitors. Dihydropyridine CCB should be preferred in elderly or black patients. Angiogenic inhibitors should be withheld only from patients who experienced hypertensive crisis.
- (v) One test dose of 5–10 mg isosorbide dinitrate maybe administered in case of de novo HTN or added to previous antihypertensive treatment in case of disequilibrium of previously controlled BP. Prompt return of pretreatment BP in spite of continuous anti-VEGF treatment may justify long-acting oral nitrates prescription (Algorithm 1). On the same idea, antihypertensive properties of phosphodiesterase inhibitors or Nebivolol should be evaluated in prospective clinical trials.
- (ii) HTN definition level should be adapted according to JNC7 recommendations for earlier management.
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conclusions |
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The relationship between angiogenic inhibitors and BP has now been established, and clinicians must recognize the growing consensus that these drugs used to treat cancer may exacerbate cardiac risk factors. Proactive introduction or even prophylactic use of antihypertensive drugs can allow maintenance of therapy despite the onset of HTN.
Clinicians who assume responsibility for the primary care of their angiogenic inhibitor cancer-treated patients must now address issues related to the reduction of HTN risk factors, in addition to managing the patient's cancer disease.
Received for publication August 22, 2008. Revision received October 13, 2008. Accepted for publication October 20, 2008.
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