Management of cardiac toxicity in patients receiving vascular endothelial growth factor signaling pathway inhibitors

Progress in Cardiology

Management of cardiac toxicity in patients receiving vascular endothelial growth factor signaling pathway inhibitors Richard M. Steingart, MD, a George L. Bakris, MD, b Helen X. Chen, MD, c Ming-Hui Chen, MD, MMSc, d Thomas Force, MD, e S. Percy Ivy, MD, c Carl V. Leier, MD, f Glenn Liu, MD, g Daniel Lenihan, MD, h JoAnn Lindenfeld, MD, i Michael L. Maitland, MD, PhD, b Scot C. Remick, MD, j and W. H. Wilson Tang, MD k New York, NY; Chicago, IL; Bethesda, MD; Boston, MA; Philadelphia, PA; Columbus, and Cleveland, OH; Madison, WI; Nashville, TN; Denver, CO; Morgantown, WV

Background Interfering with angiogenesis is an effective, widely used approach to cancer therapy, but antiangiogenic therapies have been associated with important systemic cardiovascular toxicities such as hypertension, left ventricular dysfunction, heart failure, and myocardial ischemia and infarction. As the use of vascular endothelial growth factor signaling pathway (VSP) inhibitors broadens to include older patients and those with existing cardiovascular disease, the adverse effects are likely to be more frequent, and cardiologists will increasingly be enlisted to help oncologists manage patients who develop adverse cardiovascular effects. Methods The Cardiovascular Toxicities Panel of the National Cancer Institute reviewed the published literature and abstracts from major meetings, shared experience gained during clinical development of VSP inhibitors, and contributed extensive clinical experience in evaluating and treating patients with cancer with cardiovascular disease. This report was edited and approved by the National Cancer Institute Investigational Drug Steering Committee. It presents the panel's expert opinion on the current clinical use and future investigation for safer, more expansive use of these drugs. Results and Conclusions The panel recommends that physicians (1) conduct and document a formal risk assessment for existing cardiovascular disease and potential cardiovascular complications before VSP inhibitor treatment recognizing that preexisting hypertension and cardiovascular disease are common in patients with cancer, (2) actively monitor for blood pressure elevations and cardiac toxicity with more frequent assessments during the first treatment cycle, and (3) aggressively manage blood pressure elevations and early symptoms and signs of cardiac toxicity to prevent clinically limiting complications of VSP inhibitor therapy. (Am Heart J 2012;163:156-63.)

Interfering with angiogenesis is an effective, widely used approach to cancer therapy, but antiangiogenic therapies have been associated with important systemic cardiovascular toxicities such as hypertension, left ventricular systolic dysfunction (LVSD), heart failure

From the aMemorial Sloan-Kettering Cancer Center, New York, NY, bUniversity of Chicago, Chicago, IL, cNational Cancer Institute, Bethesda, MD, dChildren's Hospital of Boston and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, eThomas Jefferson University, Philadelphia, PA, fThe Ohio State University, Columbus, OH, g

University of Wisconsin Carbone Cancer Center, Madison, WI, hVanderbilt University, Nashville, TN, iUniversity of Colorado Denver, Denver, CO, jMary Babb Randolph Cancer Center West Virginia University School of Medicine, Morgantown, WV, and kCleveland Clinic, Cardiovascular Toxicities Panel, Convened by the Angiogenesis Task Force of the National Cancer Institute Investigational Drug Steering Committee, Cleveland, OH. Submitted August 14, 2011; accepted October 20, 2011. Reprint requests: Richard M. Steingart, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065. E-mail: [email protected] 0002-8703/$ - see front matter © 2012, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2011.10.018

(HF), and myocardial ischemia and infarction. 1-4 QT interval prolongation has also been reported. 5-7 Vascular endothelial growth factor (VEGF) signaling pathway (VSP) inhibitors constitute a subclass of angiogenesis inhibitors, with 5 agents currently approved by the US Food and Drug Administration (FDA): bevacizumab, sunitinib, sorafenib, pazopanib, and vandetanib. As the use of VSP inhibitors increases and is expanded to older patients and to other populations with more comorbidity, the adverse effects are likely to be more frequent, and cardiologists will increasingly be enlisted to help oncologists manage patients who develop adverse cardiovascular effects. This Cardiovascular Toxicities Panel, assembled by the National Cancer Institute, included cardiologists, oncologists, pharmacologists, and hypertension experts. The first report of the panel was on blood pressure (BP) management in patients receiving VSP inhibitors. 1 The current article extends those principles to the issue of cardiac toxicity (LVSD, HF, myocardial ischemia and infarction, and QT prolongation) based on

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the framework provided by the recommendations for hypertension assessment and management. This is not a guidelines document but rather a collection of “points to consider” about cardiac toxicity based on expert opinion when prescribing VSP inhibitors, assembled after a comprehensive literature review by the multispecialty panel whose members have extensive research and clinical experience with the use of VSP inhibitors in patients with cancer. No extramural funding was used to support this work. This report focuses on drugs that block angiogenesis (the formation of new branches from existing blood vessels to support tumor growth). The term VSP inhibitor is used to describe agents that, within their typical therapeutic range, block the downstream signaling of the soluble ligand, VEGF, and its primary cognate receptor on endothelial cells, VEGF receptor 2 (VEGFR2).

Vascular endothelial growth factor signaling pathway inhibitors Mechanisms of action and current indications Bevacizumab (Avastin) 8 is a monoclonal antibody that binds the ligand VEGFA that activates signaling within endothelial cells. Binding of VEGFR2 by VEGF activates the receptor's kinase function, triggering multiple downstream signaling cascades associated with different VEGF effects, including increased capillary permeability, enhanced survival of endothelial cells under stress, migration and proliferation of endothelial cells, and release of nitric oxide leading to vascular smooth muscle relaxation. 1 Bevacizumab blocks these effects. Currently, bevacizumab is approved in combination regimens for the treatment of advanced colorectal, lung cancer, and renal cell carcinoma and as monotherapy for glioblastoma. The FDA has also approved 4 small-molecule inhibitors that block the kinase activity of VEGFR2 and several other kinases (see section B below) that have effects on cellular function and survival in a variety of tissues including the myocardium: sunitinib (Sutent), pazopanib (Votrient), vandetanib (Caprelsa), and sorafenib (Nexavar). 5-7,9 Sorafenib has been approved as a single agent in the treatment of hepatocellular and renal cancer; sunitinib, as single-agent therapy for renal, gastrointestinal stromal, and progressive well-differentiated pancreatic neuroendocrine tumors; pazopanib, for treatment of advanced renal cell cancer; and vandetanib, for treatment of medullary thyroid cancer. Although the small-molecule kinase inhibitors disrupt VEGF signaling by different mechanisms from bevacizumab, we collectively refer to these drugs as VSP inhibitors. These kinase inhibitors and bevacizumab were developed to disrupt VEGF signaling at typically achieved plasma and tissue concentrations. Some drugs disrupt VEGF signaling at multiple tiers in the pathway (eg, sorafenib inhibits VEGFR2 and

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c-Raf kinase), and most disrupt multiple signaling pathways (eg, sunitinib, in addition to inhibiting VEGFRs, inhibits platelet derived growth factor receptors (PDGFRs), stem cell factor receptor (c-Kit), receptortype tyrosine-protein kinase 3, colony stimulating factor-1 receptor, rearranged during transfection, etc). This classification of the VSP inhibitors distinguishes these 5 drugs from other kinase inhibitors (such as imatinib and erlotinib) and monoclonal antibodies (such as trastuzumab and cetuximab). Blood pressure elevation is a class effect of VSP inhibitors, with hypertension reported in every trial of these drugs. 1 Available data also strongly associate cardiac toxicity with these VSP inhibitors, but the exact nature, incidence, and significance of the cardiac toxicity are not completely characterized at present.

What causes cardiotoxicity with these agents? Vascular endothelial growth factor signaling response creates a cardiac stressor. All of the VSP inhibitors, through inhibition of endothelial cell function and production of microvasculature dilator nitric oxide (NO), cause BP elevation (Figure 1). In an animal model, targeted inhibition of VEGF receptors in the heart lead to a net reduction in capillary density, a reduction in cardiac hypertrophy, and left ventricular dilatation and loss in contractile function when the hearts were subjected to pressure overload. 10 Inhibiting other kinases such as platelet-derived growth factor (PDGF) in animal models in the setting of elevated systemic pressure has demonstrated deleterious effects on the heart, leading to HF. 11 Among the FDA-approved VSP inhibitors, sunitinib has the most potent concomitant inhibition of PDGF and is associated with the highest reported incidence of treatment-related LVSD and HF. Survival signals. The same targets that transduce proliferative and/or “survival signals” in cancer cells may also transduce survival signals in cardiomyocytes (PDGF, Raf kinases). By blocking these survival signals in the heart, treatment with VSP inhibitors can lead to HF. 12 Energy stress. The myocardium is a metabolically active organ and, thus, is very susceptible to metabolic pertubations. Some kinase inhibitors can impair energy generation, in part, via poorly understood effects on mitochondria. Any disturbance in energy generation could have greater effects on the heart than other organs, particularly in the setting of hypertension or other stresses. Drugs (eg, sunitinib) that inhibit kinases that respond to energy stress (eg, 5' adenosine monophosphateactivated protein kinase [AMPK], mammalian target of rapamycin [mTOR], eukaryotic initiation factor 2K [eIF2K], etc) are especially likely to be associated with adverse cardiovascular effects. 13

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Figure 1

Kinase inhibition leads to adenosine triphosphate depletion in the mitochondrion-rich myocyte. In addition, myocardial proapoptotic kinases are activated by kinase inhibition. These effects, coupled with hypertension due to systemic microvascular dysfunction, have been mechanistically linked to myocyte dysfunction and cell death. Myocardial ischemia, infarction, and HF have been associated with the clinical use of kinase inhibition in susceptible populations. ATP indicates adenosine triphosphate.

Guidance for current and future cancer therapy Hypertension is a common, important, but not exclusive mechanism by which VSP inhibitor therapy can cause LVSD, HF, ischemia, and/or infarction. Therefore, the evaluation and treatment of hypertension is a practical starting point for intervention in cardiac toxicity. 1 Per the European Society of Hypertension guidelines, 14 the degree of BP elevation coupled with other cardiac risk factors can be used to classify patients as low, moderate, high, and very high risk for a fatal or nonfatal event relative to the average population risk (Table I). The European Society of Hypertension guidelines recognize that not all the variables contained in Table I will or should be available for every patient, but more detailed knowledge of individual organ system damage is useful in assessing the risk of hypertension and in gauging the aggressiveness of therapy. 14

Pretreatment risk assessment for cardiovascular complications This panel recommends that the treating oncologist— or any other members of the patient's care team (primary caregivers and/or cardiovascular medicine specialists)— systematically identify and address risk factors for potential complications of VSP inhibitor therapy for each patient to permit the most complete and uninterrupted cancer therapy.

Pretreatment assessment should entail • repeated BP measurements and • a thorough history and examination

Directed laboratory or instrument investigations as clinically indicated A baseline 12-lead electrocardiogram (ECG) should be strongly considered for all persons scheduled for VSP inhibitor therapy. A baseline ECG will likely prove useful even for some patients with cancer with none of the risk factors cited in Table I, as they can still experience acute, high-magnitude elevations in BP and present with symptoms consistent with myocardial ischemia. Vandetanib, sunitinib, and pazopanib have been reported to cause QT interval prolongation and Torsades de pointes, the risk considerably higher with vandetanib than with the other agents. Therefore, in addition to a baseline ECG, serial ECGs are recommended when these agents are used, the frequency and timing of these ECGs depending on the drug administered and the clinical circumstances (see below). Vascular endothelial growth factor signaling pathway inhibitor therapy should not be administered in patients with • unstable or poorly controlled angina/myocardial ischemia or after recent myocardial infarction or other arterial thrombotic event;

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Table I. Individuals at high risk of adverse consequences of hypertension and cardiac toxicity 14 ∗

Systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg Diabetes mellitus ∗ Established cardiovascular disease including any history of Ischemic stroke, cerebral hemorrhage, or transient ischemic attack Myocardial infarction, angina, coronary revascularization, or HF Peripheral artery disease Retinal hemorrhages or exudates, papilledema ∗ Established or subclinical renal disease including Microalbuminuria or proteinuria (N30 mg/24 h) Serum creatinine in men N1.5 mg/dL and in women N1.4 mg/dL Calculated/estimated glomerular filtration rate b60 mL/min/1.73 m 2 ∗ Subclinical organ damage previously documented by ECG or echocardiogram revealing left ventricular hypertrophy Carotid ultrasound study revealing wall thickening or plaque ∗ ≥3 of the following cardiovascular risk factors Age (men N55 y, women N65 y) Cigarette smoking Dyslipidemia as measured by Total cholesterol N190 mg/dL Low-density lipoprotein cholesterol N130 mg/dL, or High-density lipoprotein cholesterol (men b40 mg/dL, women b46 mg/dL) Or Triglycerides N150 mg/dL Fasting plasma glucose N100 mg/dL Family history of premature cardiovascular disease (first degree male relative age b55 y old or first degree female relative b65 y old) Abdominal obesity—male waist circumference N40 in, † female N35 in † ∗

* Criteria marked with * indicate high risk of adverse consequences of hypertension. Patients meeting >1 of these criteria are at even higher risk. † In persons of East Asian ancestry, male waist circumference N35 in and women N31 in.

Table II. Panel's recommendations for responding to cardiac ischemia associated with VSP inhibitor therapy Nonspecific T-wave flattening or changes: continue VSP inhibitor with frequent monitoring. Asymptomatic ST and T-wave changes suggesting ischemia: hold VSP inhibitor and conduct cardiac evaluation. Based on this evaluation, continue VSP inhibitor only at the discretion of the investigator. Angina without evidence of infarction (eg, dynamic ischemic ECG changes, abnormal stress test, or cardiac angiography): discontinue VSP inhibitor. Acute myocardial infarction: discontinue VSP inhibitor.

• uncontrolled HF; • uncontrolled arrhythmia; • uncontrolled hypertension (the goal is a baseline BP b140/90 mm Hg 1); and • significant QT interval prolongation.

Drug interactions Strong inhibitors of cytochrome P450 3A4 (CYP3A4) (eg, ketoconazole) can increase pazopanib and sunitinib plasma concentrations. 5-7,9 A dose reduction of these agents should be considered when they must be administered with strong

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inhibitors of CYP3A4. No clinically significant interaction has been shown between vandetanib and the potent CYP3A4 inhibitor itraconazole. CYP3A4 inducers such as rifampin may decrease the plasma concentrations of pazopanib, sunitinib, sorafenib, and vandetanib. The package inserts state that pazopanib should not be administered if strong inducers of CYP3A4 cannot be avoided, and dose increases of sunitinib and sorafenib should be considered if they must be administered along with strong inducers of CYP3A4. The concomitant use of strong inducers of CYP3A4 should be avoided while receiving vandetanib therapy. Drug interactions with sorafenib are complex and include uridine diphosphate glucuronosyltransferase 1A1, uridine diphosphate glucuronosyltransferase 1A9, cytochrome P450 2B6, and cytochrome P450 2C8 substrates.

Risk for cardiovascular events may increase during VSP inhibitor therapy in patients with 1. ≥2 bolded categories of risk factors for cardiovascular disease (Table I). It is likely, but not proven, that these risk factors for patients with high BP in the general population are relevant for patients with hypertension associated with VSP inhibitor therapy. 2. Known cardiovascular disease consistent with elevated risk for myocardial ischemia (history of myocardial infarction, abnormal cardiac catheterization [including coronary disease and any coronary intervention], abnormal exercise/perfusion stress test results, or history of signs/symptoms consistent with angina). 3. Known ventricular dysfunction. The safety of VSP inhibitor therapy in New York Heart Association class I or II (symptom controlled) patients with reduced ejection fraction or valvular heart disease has not been established and warrants attentive management if VSP inhibitor therapy is planned. 4. Known cerebrovascular disease (history of transient ischemic attacks or cerebrovascular occlusion/hemorrhage). 5. Known peripheral vascular disease (history of claudication and any history of intervention including arterial bypass or stent and graft procedures). 6. An abnormal baseline ECG consistent with possible ischemia, ventricular hypertrophy, or uncontrolled rhythm or conduction abnormality. 7. History of cancer-specific risk of adverse cardiac events such as prior or current exposure to anthracyclines or chest radiation that included the heart in the irradiated field. 8. Baseline QT interval prolongation, genetic predisposition to QT prolongation, or concomitant drug therapy or electrolyte disturbances known to prolong the QT interval.

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Monitoring for QT interval prolongation Vandetanib, sunitinib, and pazopanib can prolong the QT interval and Torsades de pointes, and sudden death has been reported with these drugs. 5-7 The highest incidence of these abnormalities has been seen with vandetanib. The package insert cautions that it should not be administered in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Drugs known to prolong the QT interval should be avoided. Electrocardiograms should be obtained at baseline, at 2 to 4 weeks, and 8 to 12 weeks after starting treatment and every 3 months thereafter. After any dose reduction for QT prolongation or interruption for N2 weeks, QT assessment should be conducted as above. Only prescribers and pharmacies certified with the restricted distribution program are able to prescribe and dispense vandetanib. 7 Sunitinib and pazopanib can also prolong the QT interval in a dose-dependent fashion, but the incidence of QT interval prolongation and Torsades de pointes is lower than that with vandetanib. The package inserts for these drugs recommend that they should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant cardiovascular disease, bradycardia, or electrolyte disturbances. Periodic monitoring with on-treatment ECGs and electrolytes should be considered. 5,6 Monitoring BP and for the development of HF and LVSD during treatment Because VSP inhibitors can cause dramatic and somewhat unpredictable increases in BP early in treatment, National Cancer Institute clinical trial protocols recommend monitoring BP weekly during the first cycle of VSP inhibitor therapy and then at least every 2 to 3 weeks for the duration of treatment. 1 In a recent study of pazopanib for the treatment of soft tissue sarcoma, hypertension was seen during treatment in 40% of patients, and the first documented occurrence of hypertension was during the first 4 weeks of therapy. Only a few patients developed hypertension thereafter. 15 The panel recommends that patients developing stage 1 hypertension (N140/90) or increases in diastolic BP of 20 mm Hg and higher from baseline should initiate antihypertensive therapy, have current therapy titrated to better control, or have another agent added. 1 Because most BP elevations are seen early in VSP inhibitor therapy, after the first cycle is completed, and a stable BP is achieved, the evaluation schedule might be more conveniently aligned with routine clinical evaluations. During the course of VSP inhibitor therapy, patients may develop dyspnea, orthopnea, paroxysmal nocturnal dyspnea, cough, pleural effusions, ascites, peripheral edema, unexplained weight gain, or sinus tachycardia. Vascular endothelial growth factor signaling pathway–

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related HF should be in the differential diagnosis, and if the patient is to continue VSP inhibition therapy, HF should be ruled out in a timely fashion. Early satiety, fatigue, nausea and vomiting, abdominal discomfort (especially in the right upper quadrant suggesting hepatic distension), wheezing, and confusion are other nonspecific symptoms of HF. These nonspecific findings, although common in patients with cancer without HF, should stimulate a search for more specific symptoms or clinical signs of cardiac toxicity before proceeding to more advanced confirmatory testing. The small molecule VSP inhibitors can cause hypothyroidism (more rarely hyperthyroidism) that can contribute to and further confuse the presentation of HF and LVSD. Proactive monitoring of thyroid function tests is recommended. 5-7 For the oncologist, urgent consultation with a cardiovascular specialist might expedite evaluation, including further testing as needed and effective management if ventricular dysfunction or another cardiac abnormality is identified. Vascular endothelial growth factor signaling pathway inhibitors should be held in patients with symptomatic HF. The safety of resuming VSP inhibition upon recovery from HF has not been established, and the risk-benefit should be carefully assessed on an individual basis.

Monitoring for myocardial ischemia during treatment Table II describes the panel's recommendations for management of cardiac ischemia during therapy with VSP inhibitors. 1. Cardiology consultation should be conducted in patients with asymptomatic ECG changes and in those with symptoms suggesting myocardial ischemia. 2. If there is documented myocardial ischemia, suspend VSP inhibitor therapy. a. A collaborative decision should then be made as to whether more advanced cardiac testing (eg, stress testing and coronary angiography) is needed and whether the benefits of resuming therapy with aggressive supportive care outweigh the risk. 3. The panel believes that documented myocardial infarction during receipt of VSP inhibitor therapy could indicate the need for permanent discontinuation of that therapy. Risks and benefits must be weighed on an individual patient basis.

Recommendations for imaging studies: baseline and follow-up 1. Baseline imaging studies (either multiple-gated acquisition scan [MUGA] or echocardiography) are not mandatory in all patients receiving VSP

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inhibitors but should be considered in accord with local standards of care for patients with history or clinical findings of HF or LVSD or those at high risk for a cardiac event. When available, echocardiography may be preferred. Echocardiography provides the opportunity to serially (if necessary) evaluate left ventricular wall motion, valve function, right side of the heart structure and function, and left atrial and pulmonary artery pressures concurrent with left ventricular ejection fraction assessment but without radiation exposure. 2. There is no evidence-based guideline for follow-up echocardiograms or MUGA scans in asymptomatic patients receiving VSP inhibitors. Although some LVEF-based dose modification algorithms have been used in clinical trials that called for periodic echocardiogram/MUGA assessments, at the time of this writing, there are no data on which to base general recommendations for VSP inhibitor dose adjustment. This is an area worthy of investigation in future trials of VSP inhibitor therapy. If serial imaging studies are performed, consistent use of the same monitoring technique is recommended.

Literature review: reported cardiac toxicities of the FDA-approved VSP inhibitors Bevacizumab In patients with metastatic colorectal cancer randomized to chemotherapy with or without bevacizumab, grade 3 hypertension (11% vs 2.3%) was more common with bevacizumab than control therapy (P b .01). 16 In patients with non–small cell lung cancer randomized to chemotherapy with or without bevacizumab, grade 3 hypertension was more commonly seen (7%) in bevacizumab-treated patients than in control (b1%, P b .001), but the hypertension did not require discontinuation of therapy. 17 Heart failure was not reported as a complication of bevacizumab therapy. For HF, results from randomized trials with bevacizumab do suggest increased clinically significant HF in patients with prior exposure to anthracycline. 18 In patients with metastatic breast cancer refractory to prior anthracycline and taxane therapy, symptomatic cardiomyopathy was reported in 3% of patients treated with bevacizumab and capecitabine compared with 1% in the chemotherapy control arm. In another trial of patients with metastatic breast cancer randomized to paclitaxel alone or with bevacizumab, LVSD was reported in 0.8% and 0.3% of bevacizumab vs control patients (P = not significant). 19 An increase in the risk of arterial ischemic events was identified in a pooled analysis of 5 trials encompassing 1,745 patients randomized to chemotherapy vs chemo-

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therapy plus bevacizumab for metastatic colorectal cancer, breast cancer, and non–small cell lung cancer. 20 Compared with chemotherapy alone, the addition of bevacizumab was associated with a 2-fold increase in arterial thromboembolic events (3.8% vs 1.7%), including cerebral vascular events (1.7%) and myocardial infarction (1.5%). The relative increase of arterial thromboembolic events with VSP inhibitor therapy was further increased in older patients or those with a history of arterial thromboembolism. The panel considered the potential risk of coronary thrombosis in patients with drug-eluting coronary stents, but the lack of data specific to this subject precluded recommendations on the use of antiplatelet therapies beyond standard indications.

Sunitinib In a pivotal study of sunitinib in metastatic renal cell cancer, grade 3 or 4 hypertension was seen in 8% of sunitinib vs 1% of interferon α–treated patients (P b .05). Updated data indicated that 21% of patients treated with sunitinib and 12% of patients treated with interferon α experienced a drop in LVEF to below normal in this same study. 21 A thorough retrospective review of all cardiovascular events in 75 patients with imatinib-resistant metastatic gastrointestinal stromal tumors who had been enrolled in a trial of sunitinib indicated a greater risk for cardiac toxicity and hypertension with sunitinib than what was seen in the above-referenced pivotal trial. 22 For the group as a whole, a steady reduction in LVEF was observed during the first 4 cycles of approved dose of sunitinib. Eight patients (11%) had a cardiovascular event while receiving sunitinib (1 death, 1 myocardial infarction, and 6 HF), and almost half the patients developed hypertension. Multivariable regression analysis suggested that history of cardiovascular disease was the only independent predictor of a cardiovascular event. Observations of cardiac toxicities in patients treated with sunitinib have also been reported outside the clinical trial setting. A single-center report of patients with primarily renal cell carcinoma described 48 patients treated with sunitinib. 2 Fifty percent had existing hypertension, and an additional 17% of patients developed severe hypertension with sunitinib therapy. A total of 7 patients developed symptomatic grade 3 or 4 left ventricular dysfunction during treatment. A prior history of CVD or HF conferred an increased risk. A third report of cardiac toxicity while using sunitinib described 6 patients who developed HF early in the course of therapy. 23 All had hypertension during therapy, whereas most had hypertension at baseline. Heart failure developed as early as 4 days after the start of therapy. Left ventricular systolic dysfunction was not completely reversed with institution of HF therapy after discontinuation of sunitinib in most patients. A fourth report indicated 14 of 75 patients with renal cell carcinoma

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treated with sunitinib developed a cardiac event that included LVSD or serious arrhythmia. 24 These adverse effects improved with cardiac therapy. Sunitinib has been shown to prolong the QT interval in a dose-dependent manor. Torsades de pointes has been observed in b0.1% of sunitinib-exposed patients. 5

Sorafenib In the pivotal trial of sorafenib in patients with advanced clear cell renal carcinoma, cardiac ischemia or infarction occurred in 3% of the sorafenib group and b1% of the placebo group (P = .01). 25 In the pivotal trial of sorafenib in subjects with advanced hepatocellular carcinoma, 26 cardiac ischemia and infarction were statistically similar in the sorafenib and control groups (3% and 1%). Heart failure was not noted as a significant toxicity. However, in an observational single-center report of cardiac toxicity among patients treated with VSP inhibitors in a nonclinical trial setting, 14 of 25 patients treated with sorafenib were considered to have a cardiac event defined as increased cardiac enzymes, symptomatic arrhythmia requiring treatment, new LVSD, or acute coronary syndrome. 24 The cardiac events in all 14 treated patients were associated with abnormal cardiac enzymes; 3 had an abnormal LVEF at the time of the event. Pazopanib In a study of patients with locally advanced or metastatic renal cell cancer screened to exclude significant CVD at baseline, arterial thromboembolic events occurred in 3%, including myocardial infarction and cerebrovascular events. 27 The package insert states that pazopanib should not be used in patients who have had such an event within the last 6 months. 6 In another study of 225 patients with renal cell carcinoma, peripheral edema was noted in 10%. 28 Pazopanib has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive HF) in patients with various cancer types. In the overall safety population for renal cell cancer, cardiac dysfunction was observed in 4 (b1%) of 586 patients. 8 In controlled trials of pazopanib, QT prolongation N500 ms was identified in routine ECG monitoring in b2% of patients. Torsades de pointes occurred in b1% of patients who received pazopanib in the monotherapy studies. 6 Vandetanib The clinical experience with the cardiovascular toxicity of vandetanib is limited, and safety monitoring has focused on QT prolongation. 7 In 231 patients with medullary thyroid cancer, vandetanib 300 mg once daily was associated with plasma concentration–dependent QT prolongation, and 4.3% of patients had a corrected QT N500 ms. Torsades de pointes and sudden death have been reported.

Hypertension was seen in 33%, and there are known instances of ischemic cerebrovascular events and HF in treated patients. Because of concerns over QTc prolongation and resultant Torsades de pointes, the drug is available on a limited distribution basis to prescribers who have completed a drug safety training program and who agree to follow those precepts during the course of treatment.

Summary The panel recommends, based on expert opinion, the following ways to reduce cardiovascular toxicity because of VSP inhibitor therapy: 1. Conduct and document a formal risk assessment for existing CVD and potential cardiovascular complications before VSP inhibitor treatment. 2. Recognize that preexisting hypertension and CVD are common in patients with cancer. These should be addressed in a timely manner that allows for the prompt institution of VSP inhibitor therapy. 3. Actively monitor BP and for cardiac toxicity throughout treatment, with more frequent assessments during the first treatment cycle. 4. Aggressively manage BP elevations and early symptoms and signs of cardiac toxicity to prevent clinically limiting complications.

Acknowledgements The panel would like to thank John Finkle, MD, for his review of this manuscript and Amy Gravel for her invaluable management of the project. The authors are solely responsible for the drafting and editing of the manuscript and its final contents.

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