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Case Report
Pazopanib- and bevacizumab-induced reversible heart failure in a patient with metastatic renal cell carcinoma: A case report
J Oncol Pharm Practice 0(0) 1–5 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155215585189 opp.sagepub.com
Al-Ola Abdallah1,2, Srikanth Vallurupalli3,4 and Anuradha Kunthur1,2
Introduction Vascular endothelial growth factor receptor (VEGFR) antagonists are used in the treatment of metastatic renal cell carcinoma (mRCC) and other tumors. They are known to cause cardiovascular toxicities such as hypertension, left ventricular systolic dysfunction (LVSD), heart failure, thromboembolism, myocardial ischemia and infarction.1–4 Pazopanib is a tyrosine kinase inhibitor targeting (VEGFR)-1-2-3, plateletderived growth factor receptor (PDGFR)–a/-b and stem cell growth factor receptor, tyrosine protein kinase (c-kit). It is approved for the treatment of mRCC and soft tissue sarcoma.5 Severe LVSD is a rare but serious adverse effect of pazopanib with an incidence of less than 0.6% in patients with mRCC and 1% in patients with soft tissue sarcoma.6,7 We report a case of symptomatic reversible heart failure induced by pazopanib in a patient with mRCC, which recurred with subsequent bevacizumab treatment. To date, only five patients enrolled in various clinical trials developed severe LVSD after receiving pazopanib, and only two cases of pazopanib-associated heart failure are published.8,9 To our knowledge, this is the first case of recurrent heart failure caused from different vascular endothelial growth factor (VEGF) inhibitors which resolved after discontinuation of both agents.
started on sunitinib 50 mg) daily four weeks on and two weeks off, though treatment was discontinued after two weeks due to neutropenic fever, severe weakness and hepatic dysfunction. A multi-gated acquisition (MUGA) scan was done to rule out sunitinib-induced heart failure showed a normal left ventricular ejection fraction (LVEF) of 60%, with normal ventricular wall motion. Treatment was changed to pazopanib 800 mg daily. On day 18 of starting the treatment, he was hospitalized for shortness of breath and back pain. His physical examination was unremarkable except for a heart rate (HR) of 106 beats/min, and his SPO2 was 96% on room air. His blood pressure was normal at 120/60 mmHg. Brain natriuretic peptide (BNP) was 13 pg/ml and troponin was not obtained. Echocardiogram was not obtained since he had a normal BNP without signs of fluid over load. Complete blood count and electrolytes were normal. Serum creatinine was 1.6 mg/dL at baseline. A CT of the chest was negative for pulmonary embolism (PE). Pazopanib was withheld during hospitalization, and his symptoms improved in two days; he was discharged on the same dose of pazopanib.
1
Case report A 67-year-old man was diagnosed with left localized renal cell carcinoma (RCC) in 2011. His medical history included chronic kidney disease (CKD), hyperlipidemia and renal calculi. Patient was on atorvastatin. He subsequently underwent left nephrectomy, and the pathology confirmed a stage IIIA clear cell carcinoma. A computed tomography (CT) scan of the chest in June 2013 showed multiple lung nodules, and the fine needle aspiration cytology confirmed mRCC. The patient was
Department of Internal Medicine, Division of Hematology and Oncology, University of Arkansas for Medical Sciences (UAMS), Little Rock, Arkansas, USA 2 Department of Internal Medicine, Division of Hematology and Oncology, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA 3 Department of Internal Medicine, Division of Cardiology, University of Arkansas for Medical Sciences (UAMS), Little Rock, Arkansas, USA 4 Department of Internal Medicine, Division of Cardiology, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA Corresponding author: Anuradha Kunthur, Department of Hematology/Oncology, 4300 W 7th Street, Little rock, Arkansas 72205, USA. Email: [email protected]
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Figure 1. Echocardiogram shows the left ventricle with basal hypecontractility and apical dyskinesis.
On day 34, the patient was readmitted for worsening exertional shortness of breath, loss of appetite and an eight pound weight loss. His physical examination was unremarkable except for an oxygen saturation of 96%, pulse rate of 116 beats/min. His chest X-ray did not reveal cardiomegaly or pulmonary vascular congestion. PE was ruled out by a CT chest scan, and an electrocardiogram (EKG) showed no evidence of acute ischemia. Pazopanib was discontinued on admission. The patient’s lab work was unremarkable with normal levels of troponin and BNP. An echocardiogram showed severe left ventricular dysfunction with an EF of 30%, grade I diastolic dysfunction, and severe global hypokinesia with dyskinetic apex and basal hypercontractility mimicking apical ballooning syndrome (ABS) (Figure 1). Cardiology was consulted, and the patient was started on a low dose of metoprolol and lisinopril. His symptoms improved within a week after discontinuing pazopanib. MUGA was not repeated since the patient improved clinically. He was started on intravenous bevacizumab 10 mg/kg every two weeks and Interferon alfa-2B at 9 million units subcutaneously three times a week, one month after discontinuation of pazopanib. The patient started having dyspnea with exertion and fatigue after one month of starting bevacizumab and interferon. His symptoms worsened gradually, and the patient was admitted four months after starting bevacizumab. His physical examination was unremarkable except for a pulse SPO2 of 80% on room air and an HR of 104 beats/min. His work up included a CT of the
chest which was again negative for PE. He underwent a myocardial perfusion stress test that did not show any evidence of ischemia and echocardiogram which showed decreased LVEF of 45% with no wall motion abnormalities. His symptoms resolved after two weeks of discontinuing bevacizumab and interferon and he was started on 10 mg daily of everolimus, an inhibitor of mTOR. Patient did not have recurrence of exertional shortness of breath. Patient was monitored with MUGA, which showed stable EF off VEGF inhibitor therapy. A graph demonstrates the correlation of EF during the course of treatment (Figure 2). Six months after discontinuation of bevacizumab, a cardiac magnetic resonance imaging was performed to rule out intrinsic myocardial disease. It showed a normal EF of 58% with no evidence of myocardial infiltrative disease based on morphology and a normal late gadolinium enhancement pattern (Figure 3).
Discussion Congestive heart failure (CHF) is a rare but serious adverse side effect of pazopanib. A review of published clinical trials and case reports revealed symptomatic cardiac dysfunction in only six patients treated with pazopanib. In the overall safety population for RCC, cardiac dysfunction was only observed in 0.6% (4/586) patients, out of which only two patients had grade 3 myocardial dysfunction.9,18 In a randomized soft tissue sarcoma trial, 16/240 patients had a decline in their cardiac EF of less than 10% of their baseline, and
Downloaded from opp.sagepub.com at UNIV OF PENNSYLVANIA on May 14, 2015
XML Template (2015) [5.5.2015–12:24pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/OPPJ/Vol00000/150029/APPFile/SG-OPPJ150029.3d
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Abdallah et al.
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EF
70% A
G
60% E
50%
F
D 40% B
C
30% 20% EF 10% 0% 1
3
7
8
11
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Figure 2. (a) Baseline EF of 60%, before starting pazopinib, (b) EF ¼ 30%, pazopinib discontinued, (c) CHF symptoms clinically improved, he was started on bevacizumab, (d) EF ¼ 40%, bevacizumab discontinued, (e) EF 45% after bevacizumab discontinuation, (f) clinical symptoms improved, stable EF, started on everlimous, (g) normal LVEF while on everlimous.
Figure 3. Cardiac MRI that shows normal end diastolic wall thickness, wall motion and contractile thickening.
only 1% (3/240) of patients had symptomatic CHF.6 The incidence of cardiac dysfunction was likely higher in patients treated with soft tissue sarcoma compared to RCC because of prior anthracycline exposure and these patients were monitored by serial echocardiograms during the study.
Heart failure is a very rare complication of bevacizumab in patients with mRCC. A meta-analysis assessing five clinical trials involving 3784 patients with breast cancer showed the incidence of high-grade CHF to be 1.6% in patients treated with bevacizumab compared to 0.4% in the control or placebo groups,
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resulting in an overall relative risk of developing high-grade CHF of 4.74.10 To our knowledge, this is also the first case of reversible heart failure due to two different VEGF inhibitors in a same patient which improved with cessation of this class of drugs. Our case is unique, because his presentation was atypical with fatigue, exertional shortness of breath without evidence of vascular congestion on chest X-ray, normal BNP and normal blood pressure. Hence, he was worked up extensively to rule out other causes. His symptoms improved within days after discontinuation of pazopanib therapy and with the initiation of beta blocker therapy. MUGA scan was not repeated since his symptoms improved dramatically and he was started on bevacizumab with recurrence of heart failure. His EF normalized six months after discontinuation of bevacizumab. This case suggests that close cardiac monitoring should be considered in patients on VEGF inhibitor therapy, even when the patient presents with atypical symptoms, to allow for early detection of cardiac dysfunction and to consider starting on mTOR therapy instead of different VEGF inhibitor. The exact mechanism of cardiomyopathy in this patient is not clear. This could be an atypical case of apical ballooning syndrome (ABS), since he had complete resolution of symptoms within days of discontinuing pazopanib. He had all the features of ABS including apical hypokinesis with basal hypercontractility on EKG. He did not have evidence of ischemia by myocardial perfusion stress test. His EF did not normalize after pazopanib was discontinued, perhaps because he was placed on a different VEGF inhibitor bevacizumab. ABS is a distinctive reversible cardiomyopathy that mimics an acute coronary syndrome. For a clinical diagnosis of ABS to be made all four criteria must be present: (1) transient hypokinesis akinesis, or dyskinesia of the left ventricle mid segments with or without apical involvement and with the abnormalities extending beyond a single epicardial vascular distribution, (2) absence of obstructive coronary artery or angiographic evidence of acute plaque rupture, (3) new EKG abnormalities (ST-segment elevation and/or T-wave inversion) or elevated cardiac troponin and (4) absence of recent significant head trauma, intracranial bleeding, pheochromocytoma, myocarditis and hypertrophic cardiomyopathy.11 Patients with ABS generally have a good prognosis, with most cases resolving within several days regardless of the type of medical treatment given; therefore, definitive therapy is unclear at this time.12,13 The pathophysiology of ABS is not completely understood, and several mechanisms have been proposed such as multi-vessel epicardial spasm, microvascular spasm, catecholamine-induced myocardial
stunning and direct myocyte injury.11 It has been proposed that the unique contractile abnormalities associated with ABS may be caused by an augmented responsiveness of the apex of the heart to sympathetic stimulation, including abrupt changes in levels of catecholamines, resulting in hypertension (HTN), acute coronary syndrome and CHF.14 One hypothesis for the mechanism of cardiac dysfunction via the VEGF signaling is by inhibition of 50 monophosphate-activated protein kinase signaling that causes reversible mitochondrial injury15 and PDGFR inhibition that may impair stress-induced paracrine angiogenic capacity.16 VEGF inhibition could lead to reduced myocardial capillary density and hypoxic signaling induction in the myocardium, through the stabilization of hypoxia-inducible factor, and cardiac hibernation as recently shown in transgenic mice.17 The investigation of the molecular pathogenesis associated with VEGF inhibitors could assist in developing therapies that spare cardiac signaling pathways. In summary, this patient developed reversible cardiomyopathy mimicking ABS while receiving pazopanib; he improved clinically after discontinuation of pazopanib but developed recurrent heart failure after changing therapy to bevacizumab, a different VEGF inhibitor, but finally returned to normal after discontinuation of all VEGF inhibition therapies. Cardiomyopathy from VEGF inhibitors may be a class effect in some patients. Alternate therapies with mTOR inhibitors may be useful in such patients. Consent Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
References: 1. Maitland ML, Bakris GL, Black HR, et al. Initial assessment, surveillance and management of blood pressure in patients receiving vascular endothelial growth factor pathway inhibitors. J Natl Cancer Inst 2010; 102: 596–604. 2. Telli ML, Witteles RM, Fisher GA, et al. Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate. Ann Oncol 2008; 19: 1613–1618. 3. Hutson TE, Figlin RA, Kuhn JG, et al. Targeted therapies for metastatic renal cell carcinoma: an overview of toxicity and dosing strategies. Oncologist 2008; 13: 1084–1096.
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4. Force T, Krause DS and Van Etten RA. Molecular mechanism of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 2007; 7: 332–344. 5. Sonpavde G and Hutson TE. Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep 2007; 9: 115–119. 6. Van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012; 379: 1879–1886. 7. Votrient (Glaxo Smithkline LLC) FDA package insert. http://medlibrary.org/lib/rx/meds/votrient. 8. White AJ, LaGerche A, Toner GC, et al. Apical ballooning syndrome during treatment with a vascular endothelial growth factor receptor antagonist. Int J Cardiol 2009; 131: e92–4. 9. Lucarini V, Madrigali S, et al. Pazopanib-induced heart failure in a metastatic sarcoma patient: between reversible side effect and efficacy. AJCC Rep 2014; 2: 2. 10. Choueiri TK, Mayer EL, Je Y, et al. Congestive heart failure risk in patients with breast cancer treated with bevacizumab. J Clin Oncol 2011; 29: 632–638. 11. Prasad A. Apical ballooning syndrome: an important differential diagnosis of acute myocardial infarction. Circulation 2007; 115: e56–e59. 12. Akashi YJ, Nakazawa K, Sakakibara M, et al. The clinical features of Takotsubo cardiomyopathy. QJM 2003; 96: 563–573.
13. Virani SS, Khan AN, Mendoza CE, et al. Takotsubo cardiomyopathy, or broken heart syndrome. Tex Heart Inst J 2007; 34: 76–79. 14. Kawai S, Suzuki H, Yamaguchi H, et al. Ampulla cardiomyopathy (‘‘takotsubo’’cardiomyopathy) — reversible left ventricular dysfunction with ST segment elevation. Jpn Circ J 2000; 64: 156–159. 15. Kerkela R, Woulfe KC, Durand JB, et al. Sunitinibinduced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase. Clin Transl Sci 2009; 2: 15–25. 16. Chintalgattu V, Ai D, Langley RR, et al. Cardiomyocyte PDGFR-beta signaling is an essential component of the mouse cardiac response to load-induced stress. J Clin Invest 2010; 120: 472–484. 17. May D, Gilon D, Djonov V, et al. Transgenic system for conditional induction and rescue of chronic myocardial hibernation provides insights into genomic programs of hibernation. Proc Natl Acad Sci USA 2008; 105: 282–287. 18. Sternberg CN1, Hawkins RE, Wagstaff J, et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer 2013; 49: 1287–1296.
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(OPP)
[1–5] [INVALID Stage]
Case Report
Pazopanib- and bevacizumab-induced reversible heart failure in a patient with metastatic renal cell carcinoma: A case report
J Oncol Pharm Practice 0(0) 1–5 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155215585189 opp.sagepub.com
Al-Ola Abdallah1,2, Srikanth Vallurupalli3,4 and Anuradha Kunthur1,2
Introduction Vascular endothelial growth factor receptor (VEGFR) antagonists are used in the treatment of metastatic renal cell carcinoma (mRCC) and other tumors. They are known to cause cardiovascular toxicities such as hypertension, left ventricular systolic dysfunction (LVSD), heart failure, thromboembolism, myocardial ischemia and infarction.1–4 Pazopanib is a tyrosine kinase inhibitor targeting (VEGFR)-1-2-3, plateletderived growth factor receptor (PDGFR)–a/-b and stem cell growth factor receptor, tyrosine protein kinase (c-kit). It is approved for the treatment of mRCC and soft tissue sarcoma.5 Severe LVSD is a rare but serious adverse effect of pazopanib with an incidence of less than 0.6% in patients with mRCC and 1% in patients with soft tissue sarcoma.6,7 We report a case of symptomatic reversible heart failure induced by pazopanib in a patient with mRCC, which recurred with subsequent bevacizumab treatment. To date, only five patients enrolled in various clinical trials developed severe LVSD after receiving pazopanib, and only two cases of pazopanib-associated heart failure are published.8,9 To our knowledge, this is the first case of recurrent heart failure caused from different vascular endothelial growth factor (VEGF) inhibitors which resolved after discontinuation of both agents.
started on sunitinib 50 mg) daily four weeks on and two weeks off, though treatment was discontinued after two weeks due to neutropenic fever, severe weakness and hepatic dysfunction. A multi-gated acquisition (MUGA) scan was done to rule out sunitinib-induced heart failure showed a normal left ventricular ejection fraction (LVEF) of 60%, with normal ventricular wall motion. Treatment was changed to pazopanib 800 mg daily. On day 18 of starting the treatment, he was hospitalized for shortness of breath and back pain. His physical examination was unremarkable except for a heart rate (HR) of 106 beats/min, and his SPO2 was 96% on room air. His blood pressure was normal at 120/60 mmHg. Brain natriuretic peptide (BNP) was 13 pg/ml and troponin was not obtained. Echocardiogram was not obtained since he had a normal BNP without signs of fluid over load. Complete blood count and electrolytes were normal. Serum creatinine was 1.6 mg/dL at baseline. A CT of the chest was negative for pulmonary embolism (PE). Pazopanib was withheld during hospitalization, and his symptoms improved in two days; he was discharged on the same dose of pazopanib.
1
Case report A 67-year-old man was diagnosed with left localized renal cell carcinoma (RCC) in 2011. His medical history included chronic kidney disease (CKD), hyperlipidemia and renal calculi. Patient was on atorvastatin. He subsequently underwent left nephrectomy, and the pathology confirmed a stage IIIA clear cell carcinoma. A computed tomography (CT) scan of the chest in June 2013 showed multiple lung nodules, and the fine needle aspiration cytology confirmed mRCC. The patient was
Department of Internal Medicine, Division of Hematology and Oncology, University of Arkansas for Medical Sciences (UAMS), Little Rock, Arkansas, USA 2 Department of Internal Medicine, Division of Hematology and Oncology, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA 3 Department of Internal Medicine, Division of Cardiology, University of Arkansas for Medical Sciences (UAMS), Little Rock, Arkansas, USA 4 Department of Internal Medicine, Division of Cardiology, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA Corresponding author: Anuradha Kunthur, Department of Hematology/Oncology, 4300 W 7th Street, Little rock, Arkansas 72205, USA. Email: [email protected]
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Figure 1. Echocardiogram shows the left ventricle with basal hypecontractility and apical dyskinesis.
On day 34, the patient was readmitted for worsening exertional shortness of breath, loss of appetite and an eight pound weight loss. His physical examination was unremarkable except for an oxygen saturation of 96%, pulse rate of 116 beats/min. His chest X-ray did not reveal cardiomegaly or pulmonary vascular congestion. PE was ruled out by a CT chest scan, and an electrocardiogram (EKG) showed no evidence of acute ischemia. Pazopanib was discontinued on admission. The patient’s lab work was unremarkable with normal levels of troponin and BNP. An echocardiogram showed severe left ventricular dysfunction with an EF of 30%, grade I diastolic dysfunction, and severe global hypokinesia with dyskinetic apex and basal hypercontractility mimicking apical ballooning syndrome (ABS) (Figure 1). Cardiology was consulted, and the patient was started on a low dose of metoprolol and lisinopril. His symptoms improved within a week after discontinuing pazopanib. MUGA was not repeated since the patient improved clinically. He was started on intravenous bevacizumab 10 mg/kg every two weeks and Interferon alfa-2B at 9 million units subcutaneously three times a week, one month after discontinuation of pazopanib. The patient started having dyspnea with exertion and fatigue after one month of starting bevacizumab and interferon. His symptoms worsened gradually, and the patient was admitted four months after starting bevacizumab. His physical examination was unremarkable except for a pulse SPO2 of 80% on room air and an HR of 104 beats/min. His work up included a CT of the
chest which was again negative for PE. He underwent a myocardial perfusion stress test that did not show any evidence of ischemia and echocardiogram which showed decreased LVEF of 45% with no wall motion abnormalities. His symptoms resolved after two weeks of discontinuing bevacizumab and interferon and he was started on 10 mg daily of everolimus, an inhibitor of mTOR. Patient did not have recurrence of exertional shortness of breath. Patient was monitored with MUGA, which showed stable EF off VEGF inhibitor therapy. A graph demonstrates the correlation of EF during the course of treatment (Figure 2). Six months after discontinuation of bevacizumab, a cardiac magnetic resonance imaging was performed to rule out intrinsic myocardial disease. It showed a normal EF of 58% with no evidence of myocardial infiltrative disease based on morphology and a normal late gadolinium enhancement pattern (Figure 3).
Discussion Congestive heart failure (CHF) is a rare but serious adverse side effect of pazopanib. A review of published clinical trials and case reports revealed symptomatic cardiac dysfunction in only six patients treated with pazopanib. In the overall safety population for RCC, cardiac dysfunction was only observed in 0.6% (4/586) patients, out of which only two patients had grade 3 myocardial dysfunction.9,18 In a randomized soft tissue sarcoma trial, 16/240 patients had a decline in their cardiac EF of less than 10% of their baseline, and
Downloaded from opp.sagepub.com at UNIV OF PENNSYLVANIA on May 14, 2015
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EF
70% A
G
60% E
50%
F
D 40% B
C
30% 20% EF 10% 0% 1
3
7
8
11
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Months
Figure 2. (a) Baseline EF of 60%, before starting pazopinib, (b) EF ¼ 30%, pazopinib discontinued, (c) CHF symptoms clinically improved, he was started on bevacizumab, (d) EF ¼ 40%, bevacizumab discontinued, (e) EF 45% after bevacizumab discontinuation, (f) clinical symptoms improved, stable EF, started on everlimous, (g) normal LVEF while on everlimous.
Figure 3. Cardiac MRI that shows normal end diastolic wall thickness, wall motion and contractile thickening.
only 1% (3/240) of patients had symptomatic CHF.6 The incidence of cardiac dysfunction was likely higher in patients treated with soft tissue sarcoma compared to RCC because of prior anthracycline exposure and these patients were monitored by serial echocardiograms during the study.
Heart failure is a very rare complication of bevacizumab in patients with mRCC. A meta-analysis assessing five clinical trials involving 3784 patients with breast cancer showed the incidence of high-grade CHF to be 1.6% in patients treated with bevacizumab compared to 0.4% in the control or placebo groups,
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resulting in an overall relative risk of developing high-grade CHF of 4.74.10 To our knowledge, this is also the first case of reversible heart failure due to two different VEGF inhibitors in a same patient which improved with cessation of this class of drugs. Our case is unique, because his presentation was atypical with fatigue, exertional shortness of breath without evidence of vascular congestion on chest X-ray, normal BNP and normal blood pressure. Hence, he was worked up extensively to rule out other causes. His symptoms improved within days after discontinuation of pazopanib therapy and with the initiation of beta blocker therapy. MUGA scan was not repeated since his symptoms improved dramatically and he was started on bevacizumab with recurrence of heart failure. His EF normalized six months after discontinuation of bevacizumab. This case suggests that close cardiac monitoring should be considered in patients on VEGF inhibitor therapy, even when the patient presents with atypical symptoms, to allow for early detection of cardiac dysfunction and to consider starting on mTOR therapy instead of different VEGF inhibitor. The exact mechanism of cardiomyopathy in this patient is not clear. This could be an atypical case of apical ballooning syndrome (ABS), since he had complete resolution of symptoms within days of discontinuing pazopanib. He had all the features of ABS including apical hypokinesis with basal hypercontractility on EKG. He did not have evidence of ischemia by myocardial perfusion stress test. His EF did not normalize after pazopanib was discontinued, perhaps because he was placed on a different VEGF inhibitor bevacizumab. ABS is a distinctive reversible cardiomyopathy that mimics an acute coronary syndrome. For a clinical diagnosis of ABS to be made all four criteria must be present: (1) transient hypokinesis akinesis, or dyskinesia of the left ventricle mid segments with or without apical involvement and with the abnormalities extending beyond a single epicardial vascular distribution, (2) absence of obstructive coronary artery or angiographic evidence of acute plaque rupture, (3) new EKG abnormalities (ST-segment elevation and/or T-wave inversion) or elevated cardiac troponin and (4) absence of recent significant head trauma, intracranial bleeding, pheochromocytoma, myocarditis and hypertrophic cardiomyopathy.11 Patients with ABS generally have a good prognosis, with most cases resolving within several days regardless of the type of medical treatment given; therefore, definitive therapy is unclear at this time.12,13 The pathophysiology of ABS is not completely understood, and several mechanisms have been proposed such as multi-vessel epicardial spasm, microvascular spasm, catecholamine-induced myocardial
stunning and direct myocyte injury.11 It has been proposed that the unique contractile abnormalities associated with ABS may be caused by an augmented responsiveness of the apex of the heart to sympathetic stimulation, including abrupt changes in levels of catecholamines, resulting in hypertension (HTN), acute coronary syndrome and CHF.14 One hypothesis for the mechanism of cardiac dysfunction via the VEGF signaling is by inhibition of 50 monophosphate-activated protein kinase signaling that causes reversible mitochondrial injury15 and PDGFR inhibition that may impair stress-induced paracrine angiogenic capacity.16 VEGF inhibition could lead to reduced myocardial capillary density and hypoxic signaling induction in the myocardium, through the stabilization of hypoxia-inducible factor, and cardiac hibernation as recently shown in transgenic mice.17 The investigation of the molecular pathogenesis associated with VEGF inhibitors could assist in developing therapies that spare cardiac signaling pathways. In summary, this patient developed reversible cardiomyopathy mimicking ABS while receiving pazopanib; he improved clinically after discontinuation of pazopanib but developed recurrent heart failure after changing therapy to bevacizumab, a different VEGF inhibitor, but finally returned to normal after discontinuation of all VEGF inhibition therapies. Cardiomyopathy from VEGF inhibitors may be a class effect in some patients. Alternate therapies with mTOR inhibitors may be useful in such patients. Consent Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
References: 1. Maitland ML, Bakris GL, Black HR, et al. Initial assessment, surveillance and management of blood pressure in patients receiving vascular endothelial growth factor pathway inhibitors. J Natl Cancer Inst 2010; 102: 596–604. 2. Telli ML, Witteles RM, Fisher GA, et al. Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate. Ann Oncol 2008; 19: 1613–1618. 3. Hutson TE, Figlin RA, Kuhn JG, et al. Targeted therapies for metastatic renal cell carcinoma: an overview of toxicity and dosing strategies. Oncologist 2008; 13: 1084–1096.
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Abdallah et al.
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4. Force T, Krause DS and Van Etten RA. Molecular mechanism of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 2007; 7: 332–344. 5. Sonpavde G and Hutson TE. Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep 2007; 9: 115–119. 6. Van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012; 379: 1879–1886. 7. Votrient (Glaxo Smithkline LLC) FDA package insert. http://medlibrary.org/lib/rx/meds/votrient. 8. White AJ, LaGerche A, Toner GC, et al. Apical ballooning syndrome during treatment with a vascular endothelial growth factor receptor antagonist. Int J Cardiol 2009; 131: e92–4. 9. Lucarini V, Madrigali S, et al. Pazopanib-induced heart failure in a metastatic sarcoma patient: between reversible side effect and efficacy. AJCC Rep 2014; 2: 2. 10. Choueiri TK, Mayer EL, Je Y, et al. Congestive heart failure risk in patients with breast cancer treated with bevacizumab. J Clin Oncol 2011; 29: 632–638. 11. Prasad A. Apical ballooning syndrome: an important differential diagnosis of acute myocardial infarction. Circulation 2007; 115: e56–e59. 12. Akashi YJ, Nakazawa K, Sakakibara M, et al. The clinical features of Takotsubo cardiomyopathy. QJM 2003; 96: 563–573.
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