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Quick Facts
- Blood pressure is frequently increased during treatment with VEGF inhibitors
- Baseline blood pressure readings should be obtained and undiagnosed hypertension should be brought under control before beginning VEGF-inhibitor therapy
- JNC-7 guidelines for diagnosis and management of hypertension are appropriate for VEGF-induced hypertension
- Patients with refractory hypertension during or post-treatment should be referred to a cardiologist for management
Hypertension and Targeted Therapies for Cancer

Background


Bevacizumab, approved in 2004, was the first antiangiogenesis agent approved for clinical use in combination with fluorouracil-based chemotherapy for the treatment of metastatic colorectal cancer. It is a humanized monoclonal antibody targeted against the vascular endothelial growth factor (VEGF)-A ligand and exerts its effects primarily through prevention of VEGF-A binding to VEGF receptor (VEGFR), which in turn inhibits downstream signaling, preventing angiogenesis (the development of new blood vessels).


Sorafenib, sunitinib, dasatinib, nilotinib and pazopanib are all small molecule multityrosine kinase inhibitors (MKIs) that inhibit all of the VEGFRs (1, 2, and 3) in addition to other targets (e.g., CRAF, BRAF, KIT, FLT-3, RET, PDGFRs, and others). Each of these MKIs differs slightly in the other proteins they target. However, the biologic effects of inhibiting angiogenesis are paramount to clinical activity with this class of agents.


Hypertension (HTN) is one of the most common side effects of antiangiogenic and VEGF-inhibitor therapies. Targeted therapies that are associated with hypertension are shown in Table 1.



Based on information from Bayer HealthCare, 2011; Bristol-Myers Squibb, 2011; Genentech, 2011; GlaxoSmithKline, 2011; Novartis Oncology, 2011; Pfizer, 2011


Incidence


Hypertension is relatively common among the general population, especially among individuals over the age of 60 years. It is estimated that more than 50% of individuals over age 60 have elevated blood pressure (Chobanian et al., 2003).


The incidence of HTN among people with cancer who are receiving targeted therapy with angiogenesis-inhibiting agents varies according to the drug and dose. In the pivotal trial of patients with metastatic colorectal cancer, the incidence of HTN (> 150/100 mm Hg) in patients receiving bevacizumab with a 5-FU–based regimen ranged from 60% to 67%, compared with 43% in the control arm not receiving bevacizumab. The incidence of severe HTN, graded as 3 or 4 on the National Cancer Institute Common Terminology Criteria for Adverse Events [CTCAE]] v 4.03 (NCI, 2010) as  = 200/110 mm Hg, was 7% to 10%, compared with 2% in patients not receiving bevacizumab (Genentech, 2011). The incidence of severe HTN increased in patients receiving bevacizumab compared with controls. Across clinical studies, the incidence of NCI-CTC grade 3 or 4 HTN ranged from 8% to 18% (Genentech, 2011).


The incidence of HTN associated with oral multikinase inhibitors (MKIs) such as sunitinib and sorafenib is similar to bevacizumab (Hutson, Figlin, Kuhn & Motzer, 2008). Thirty-four percent of treatment-naive patients with renal cell carcinoma (RCC) receiving sunitinib developed HTN within the first 21 days of therapy with similar rates in patients with gastrointestinal stromal tumor (GIST) who were treated with first-line sunitinib (Pfizer, 2011). HTN among patients treated with sorafenib was reported in 9% of patients with RCC and 17% of patients with hepatocellular cancer (HCC) (Bayer, 2011). The hypertension associated with sorafenib appeared during the first four weeks of sorafenib therapy (Escudier et al, 2007). Pazopanib, a tyrosine kinase inhibitor (TKI) used to treat RCC, has a reported 40% incidence of HTN, primarily occurring early in the course of treatment (39% by treatment day 9 and 88% within the first 18 weeks of treatment (GlaxoSmithKline, 2011).


HTN associated with two TKIs that are used to treat chronic myelogenous leukemia (CML), dasatinib and nilotinib, have lower incidences of HTN, reported at less than 10% (Bristol-Myers Squibb, 2011; Novartis, 2011).


Patients with underlying hypertension appear to be more at risk for severe hypertension during cancer treatment than patients without a prior diagnosis of hypertension.

Pathophysiology


The mechanism of primary HTN is poorly understood. Secondary HTN – when HTN is the side effect of a medication, procedure or comorbid condition – may be explained by the mechanism of action of the implicated agent.  VEGF-inhibitor-associated HTN may be due to a cascade of events initiated by the inhibition of VEGF which then fails to stimulate the production of nitrous oxide, a vasodilator (Sane, Anton & Brosnihan, 2004). When less nitrous oxide is available, vasoconstriction may occur, causing a significant rise in blood pressure. Sane, Anton & Brosnihan (2004) also hypothesized that VEGF may have effects on the renin-angiotensin system, resulting in HTN.


Several mechanisms may induce VEGF inhibitor-related hypertension. Rarefaction, a decreased number of small arteries and arterioles, can result from treatment with VEGF kinase inhibitors. Microvascular rarefaction has also been shown in hypertensive adults in the general population. Steeghs et al (2008) first demonstrated capillary rarefaction in patients treated with telatinib (BAY 57–9352), an oral inhibitor of VEGF receptors-2 and -3 (VEGFR-2, -3).


A second mechanism that may contribute to hypertension is increased arterial stiffness in proximal or distal vessels. Veronese et al. (2006) found that patients treated with sorafenib for 3 to 6 weeks showed a significant increase in arterial stiffness, as indicated by the central aortic augmentation index and aortic pulse wave velocity. Plasma renin, aldosterone, and catecholamine levels were not affected in those patients, demonstrating that renovascular means and volume expansion were not considered major contributors to their development of hypertension.


A third proposed mechanism that may contribute to hypertension is increased vascular resistance due to decreased nitric oxide and prostacyclin production. A previous study demonstrated that VEGF plays a significant role in maintaining basal vascular tone by regulating nitric oxide synthesis [20]. Wheeler-Jones et al. demonstrated that another pathway may be involved in mediating the vasoactive effects of VEGF via prostacyclin release. Preliminary results suggested that inhibiting signaling through the VEGF pathway could lead to decreased nitric oxide and prostacyclin production, thus increasing vascular resistance and blood pressure (BP)(Escalante & Zalpour, 2011).

Assessment


Patient History


A careful history of all prescribed and over-the-counter medications should be obtained from all patients.  Some medications such as oral contraceptives, steroids, nonsteroidal anti-inflammatory drugs, decongestants and tricyclic antidepressants may raise blood pressure. These same drugs may interfere with the action of anti-hypertensive medications (National Blood Pressure Education Program, 2003).


A medical history should include

  • Family history of hypertension, diabetes, renal disease and cardiovascular disease (CVD)
  • Patient history of CVD, cerebrovascular disease, renal disease, and retinopathy
  • Known duration and levels of elevated blood pressure
  • Results and side effects of previous antihypertensive therapy
  • Use of drugs that may influence blood pressure
  • History of weight gain or loss, proteinuria, sodium intake, other dietary factors, exercise habits, and alcohol use
  • Symptoms suggesting secondary hypertension
  • Psychosocial and environmental factors (e.g., emotional stress, cultural food practices, economic status) that may influence blood pressure
  • Other cardiovascular risk factors including obesity, smoking, and hyperlipidemia

Physical Examination


Because blood pressure may rise in response to physical exertion or emotional stress and because some patients with diabetes have blood pressures that fall when they are in the standing position, it is recommended that blood pressure be measured in the supine, seated, and standing positions after patients have had time to relax. It is suggested that blood pressure be measured approximately 5 minutes after the patient has been seated. If the initial blood pressure is elevated, repeating the measurement later in the visit is recommended (National Blood Pressure Education Program, 2003).


Physical examination should include:

  • Two or more blood pressure determinations (a wide cuff should be used to measure the pressure of patients with obese arms)
  • Measurement of height and weight
  • Examination of the neck for carotid bruits, distended veins, and enlarged thyroid
  • Examination of the heart for a sustained point of maximal impulse (evidence of left ventricular hypertrophy), precordial heave, murmurs, arrhythmias, and S3 and S4 heart sounds

Assessment Tools





Case Study Exemplar, Part 1


Ted is a 70- year old male diagnosed with metastatic colorectal cancer (CRC). In good health before his diagnosis, Ted has no history of hypertension (HTN). He began a regimen that included bevacizumab 3 months ago. Per recommendations in the prescribing information, his oncology team has been monitoring his blood pressure at each visit, prior to ordering his bevacizumab infusion. His urine is also assessed for elevated protein as both HTN and proteinuria are common side effects of angiogenesis inhibitors, including bevacizumab. During the past 3 visits, a modest steady rise in Ted’s blood pressure was noted and a small amount of protein was found in the urine sample today. Neither finding was enough to hold the bevacizumab infusion, but enough to alert the nurse to more closely monitor Ted’s blood pressure.
As Ted’s bevacizumab therapy moved forward, his blood pressure readings continued to increase. At the last visit, his resting BP was 166/94 which indicated stage II HTN (CTCAE grade 2).Ted was having a good clinical response to his current chemotherapy regimen and was worried that HTN might be a dose-limiting toxicity and require discontinuation of bevacizumab. What would you do to manage Ted’s increasing HTN?


Case exemplar continues below.


Guidelines


Note: JNC8 Hypertension Guidelines are scheduled to be released for public comment in late 2011 and published in 2012


National Blood Pressure Education Program. JNC7 Express: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Bethesda MD: US Department of Health and Human Services, National Heart, Lung, and Blood Institute, NIH Publication 03-5233, 2003. http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf


National High Blood Pressure Education Program, National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health. JNC7 Reference Card for quick access to evaluation and treatment of hypertension is available as a PDF document at http://www.nhlbi.nih.gov/guidelines/hypertension/phycard.pdf

Management


In the presence of HTN, careful monitoring of blood pressure (BP) prior to each chemotherapy treatment or more frequently is warranted. Patients who develop HTN during therapy should be advised to purchase a home BP monitoring system. BP should be checked at home at least once daily, and patients should be advised to contact the clinic if they note either intermittent elevated BP levels or a trend toward an increase (Bourdeanu, Twardowski & Pal, 2011; Kurtin, 2009; Sharp, 2006; Viale & Sommers, 2007).


Bevacizumab-related HTN should be treated with standard oral antihypertensive therapy, titrated to effect. Published HTN management guidelines should be followed. If BP control is less than optimal, the patient should be referred to a cardiologist or to an internist specializing in HTN management. Standard oral antihypertensive agents used to manage bevacizumab-related HTN include: (Genentech, 2011; Miles, 2006)

  • Angiotensin-converting enzyme (ACE) inhibitors
  • Beta blockers
  • Calcium channel blockers
  • Diuretics

Treatment with bevacizumab should be temporarily suspended in patients with severe HTN that is not controlled with medical management and permanently discontinued in patients with hypertensive crisis. HTN can persist after discontinuation of bevacizumab (Genentech, 2011).

 JNC7 Hypertension Treatment Algorithm



Case Study Exemplar, Part 2


Ted is started on a loop diuretic (furosemide) 10 mg PO each morning and an angiotensin converting enzyme inhibitor (ACEI) (lisinopril) 2.5 mg PO each morning. This is a recommended combination for patients with stage 2, CTCAE grade 2 HTN (Chobanian et al. , 2003). In Ted’s case, the goal is to continue bevacizumab if his HTN can be brought under control. Because the presumed causative agent (bevacizumab) will be continued, the anti-HTN regimen should be aggressive enough to maintain BP control without causing undue side effects from the anti-HTN regimen. Drug escalation to effect is planned.


He is educated about the possible side effects from the anti-HTN drugs (dizziness, hypotension, frequent urination) and is instructed to purchase a home blood pressure monitor and take his blood pressure on arising and at bedtime, keeping a chart to bring to clinic each visit.
Are these drugs part of the JNC7 recommendations for stage 2 HTN? Would you make other drug or dose choices?


Case exemplar continues below.


Nursing Implications


Oncology nurses must be aware of side effects of agents commonly used in the treatment of patients with cancer. Unlike traditional cancer therapy side effects, HTN may be overlooked or incorrectly attributed to other medical conditions. A basic understanding of HTN assessment and treatment guidelines will help nurses intervene early and seek appropriate treatment on the patient’s behalf. Nurses can have a significant impact on prevention of worsening complications resulting from untreated HTN by assessing patients and reporting occurrences to physicians and nurse practitioners (Rosiak & Sadowski, 2005; Sharp, 2006; Viale & Sommers, 2007).

Case Study Exemplar, Part 3: Resolution


After 2 months on anti-HTN therapy, Ted has had two ACEI dose increases. Furosemide has remained at 10mg PO each morning and lisinopril is now 20mg PO each morning. His potassium levels have remained within normal limit; supplemental potassium has not been required. He had slight dizziness for 2 days after the most recent lisinopril increase, but no ongoing side effects to the regimen. His BP is consistently around 110/64 both morning and evening and in the clinic. He has continued on bevacizumab with clinical evaluation showing stable disease. Because HTN can continue after bevacizumab is discontinued, Ted has been advised that he will need to remain on anti-HTN therapy until directed by his oncology team. If Ted’s HTN control becomes unstable, he will be referred to a cardiologist who specializes in HTN management.

Multidisciplinary Team Care


As cancer screening methods and detection rates for common cancers such as breast and colorectal cancer continue to improve and the population affected by these cancers continues to age, many patients will be affected by primary or treatment-related hypertension. Because many of these patients will be cared for by primary care physicians as well as oncologists, it is important to communicate with patients’ primary care providers in order to improve patient outcomes.  These physicians and other healthcare providers may be asked to help manage their patients’ hypertension and other comorbidities. It is imperative that these clinicians be familiar with the fact that hypertension can be induced by VEGF inhibitors.

Summary


The currently recommended management of VEGF-induced hypertension is similar to the management of hypertension outlined in the JNC 7 guidelines. However, baseline BP measurement should be performed prior to administering any VEGF inhibitor, and elevated BP should be treated if it is not in the normotensive ranges recommended by the JNC 7 criteria. All patients should have careful BP monitoring during treatment, and aggressive BP treatment should be instituted when increases in BP are noted. Monitoring should be continued after treatment completion in those patients who have increased BP during treatment until the BP normalizes. Treatment selections include ACE inhibitors and calcium channel blockers, but that decision should be made on the basis of individual patients’ characteristics, the type of VEGF agent used, and other coexisting comorbidities. Those patients with undiagnosed hypertension at baseline should be diagnosed and treated appropriately before VEGF-inhibitor therapy is initiated.


References


Bayer HealthCare. (2011). Nexavar Prescribing Information. Retrieved from http://berlex.bayerhealthcare.com/html/products/pi/Nexavar_PI.pdf


Bourdeanu, L., Twardowski, P., & Pal, S. (2011). Nursing considerations with pazopanib therapy: Focus on metastatic renal cell carcinoma. Clinical Journal of Oncology Nursing, 15, 513-517. doi:10.1188/11.CJON.513-517


Bristol-Myers Squibb. (2011). Sprycel Prescribing Information. Retrieved from http://packageinserts.bms.com/pi/pi_sprycel.pdf


Chobanian AV, Bakris GL, Black HR, Cushman, W.C., Green, L.A., Izzo Jr., J.L.,…National High Blood Pressure Education Program Coordinating Committee. (2003).The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA, 289, 2560-2572. doi 10.1001/jama.289.19.2560


Escalante, C., & Zalpour, A. (2011). Vascular endothelial growth factor inhibitor-induced hypertension: Basics for primary care providers. Cardiology Research and Practice. Retrieved from http://www.hindawi.com/journals/crp/2011/816897/cta/   doi:10.4061/2011/816897


Escudier, B., Eisen, T., Stadler, W.M., Szczylik, C., Oudard, S., Siebels, M.,…Bukowski, R.M. (2007). Sorafenib in advanced clear-cell renal-cell carcinoma. New England Journal of Medicine, 356, 125-134.


Genentech, Inc. (2011). Avastin (bevacizumab) Prescribing Information. Retrieved from http://www.gene.com/gene/products/information/pdf/avastin-prescribing.pdf 


GlaxoSmithKline. (2011). Votrient Prescribing Information. Retrieved from http://us.gsk.com/products/assets/us_votrient.pdf


Hutson, T.E., Figlin, R.A., Kuhn, J.G., & Motzer, R.J. (2008). Targeted therapies for metastatic renal cell carcinoma: An overview of toxicity and dosing strategies. Oncologist, 13, 1084-1091. doi:10.1634/theoncologist.2008-0120


Kurtin, S. (2009). Hypertension management in the era of targeted therapies for cancer. Oncology Nurse Edition. Retrieved from http://www.cancernetwork.com/nurses/content/article/10165/1399609


Miles, J.S. (2006). Hypertension therapy for the oncology patient. Community Oncology, 3, 94-99.


National Blood Pressure Education Program. (2003). JNC7 Express: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Bethesda MD: US Department of Health and Human Services, National Heart, Lung, and Blood Institute, NIH Publication 03-5233. Retrieved from http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf


National Cancer Institute. (2010). Common Terminology Criteria for Adverse Events (CTCAE), v4.03, page 77. Retrieved from http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf


Novartis Oncology. (2011). Tasigna Prescribing Information. Retrieved from http://www.pharma.us.novartis.com/product/pi/pdf/tasigna.pdf


Pfizer, Inc. (2011). Sutent Prescribing Information. Retrieved from http://labeling.pfizer.com/ShowLabeling.aspx?id=607


Rosiak, J., & Sadowski, L. (2005). Hypertension associated with bevacizumab. Clinical Journal of Oncology Nursing, 9, 407-411.  doi:10.1188/05.CJON.407-411


Sane, D.C., Anton, L., & Brosnihan, K.B.(2004).  Angiogenic growth factors and hypertension. Angiogenesis, 7, 193–201. doi:10.1007/s10456-004-2699-3


Sharp, K. (2006). Hypertension: Just the facts. Clinical Journal of Oncology Nursing, 10, 737-729. doi:10.1188/06.CJON.727-729


Steeghs, N., Gelderblom, H., Roodt, J.O., Christensen, O., Rajagopalan, P., Hovens, M., Putter, H.,…de Koning, E. (2008). Hypertension and rarefaction during treatment with telatinib, a small molecule angiogenesis inhibitor. Clinical Cancer Research, 14, 3470–3476. doi:10.1158/1078-0432.CCR-07-5050


Veronese, M.L., Mosenkis, A., Flaherty, K.T., Gallagher, M., Stevenson, J.P., Townsend, R.R., & O’Dwyer, P.J. (2006). Mechanisms of hypertension associated with BAY 43-9006. Journal of Clinical Oncology, 24, 1363–1369. doi:10.1200/JCO.2005.02.0503


Viale, P.H., Sommers, R. (2007). Nursing Care of Patients Receiving Chemotherapy for Metastatic Colorectal Cancer: Implications of the Treatment Continuum Concept. Seminars in Oncology Nursing, 23 (suppl 1), 22-35. doi:10.1016/j.soncn.2006.08.003



Article Created On : 12/20/2011 10:20:38 AM             Article Updated On : 12/20/2011 10:20:38 AM