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JOURNAL OF CLINICAL ONCOLOGY

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chest discomfort with radiation to her left shoulder and arm, shortness of breath, diaphoresis, and tachycardia. She was transferred to the emergency department for further evaluation with a presumptive diagnosis of pneumothorax from a recent therapeutic thoracentesis. A chest x-ray demonstrated a large left pleural effusion without evidence of pneumothorax. An electrocardiogram was suggestive of an anterolateral ST elevation myocardial infarction (Fig 1) in association with elevated cardiac enzyme values, including a troponin I level of 6.95 ␮g/L, creatine kinase–myocardial band of 26.3 U/L, total creatine kinase of 179 U/L, and brain natriuretic peptide of 496 pg/mL. The patient was given 0.4 mg of sublingual nitroglycerin without improvement and consequently was admitted to the coronary care unit. A computed tomography scan of the chest confirmed the pleural effusion, and a chest tube was placed. Given the atypical presentation, persistent chest pain, and presence of elevated cardiac enzymes, a transthoracic echocardiogram (TTE) was performed, followed by cardiac angiography. A TTE in a four-chamber view mode (Figs 2A and 2B) demonstrated severe global hypokinesis of the left ventricle with anterior apical ballooning and evidence of a mildly dilated left ventricular chamber, with an estimated left ventricular ejection fraction of 20% to 25%. Angiographic studies were negative for any occlusive pattern. Right anterior oblique projection of end systolic frame (Fig 3A) compared with end diastolic frame (Fig 3B) showed a large anteroapical and inferoapical akinetic segment with inferobasal and anterobasal hyperkinesis, consistent with the diagnosis of TCM. The patient was managed medically with administration of carvedilol, lisinopril, aspirin, and termination of axitinib therapy. She remained in the intensive care unit for 1 week because of hypotension and was later transferred to the medical-oncology floor on normalization of her hemodynamic instability; she was subsequently discharged in stable condition. A TTE performed 3 weeks after her initial presentation demonstrated partial recovery with an ejection fraction of 50%

Association Between Takotsubo Cardiomyopathy and Axitinib: Case Report and Review of the Literature Introduction Axitinib, a small molecule tyrosine kinase inhibitor (TKI), has been approved as a second-line novel therapeutic agent in the treatment of advanced renal cell carcinoma (RCC). Axitinib blocks tumor angiogenesis by focusing specifically on the vascular endothelial growth factor receptor (VEGFR) pathway.1 Clinical trials have demonstrated improved progression-free and overall survival compared with other VEGF inhibitors and TKIs that are currently used as standard therapy. Commonly encountered cardiovascular adverse effects include hypertension, hypertensive crisis, and arterial-venous thrombotic events.1-5 Stress-induced cardiomyopathy, also known as takotsubo cardiomyopathy (TCM), has previously been reported in association with fluorouracil (FU), bevacizumab, and sunitinib,6-10 but to our knowledge, this relationship has never been described in patients undergoing chemotherapy with axitinib. TCM is a rare disorder that is characterized by acute transient left ventricular dysfunction without evidence of obstructive coronary artery disease.6 The clinical presentation of TCM cannot be distinguished from the symptoms of an acute myocardial infarction.7-9 We here describe a 71-year-old woman who developed TCM in the context of receiving adjuvant therapy with the recently US Food and Drug Administration–approved chemotherapeutic agent axitinib for RCC. Case Report A 71-year-old woman without known preexisting cardiovascular risk factors began receiving axitinib therapy for progressive metastatic RCC at the recommended dose of 5 mg orally twice per day. Within 24 hours of administration, the patient developed midsternal and lower

Fig 1. Journal of Clinical Oncology, Vol 33, No 1 (January 1), 2015: pp e1-e3

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angiographic examinations. As in the case of our postmenopausal patient, an electrocardiogram commonly shows ST segment elevation followed by T-wave inversion in precordial leads, which is suggestive of myocardial infarction. Cardiac enzymes are typically elevated and echocardiography demonstrates left ventricular apical hypokinesis with a compensatory basal hyperkinesis. Coronary angiographic examinations demonstrate the absence of an obstructive coronary artery pattern that distinguishes itself from the typical obstructive findings that are associated with myocardial infarction.6,8,9,11 QT prolongations as in torsade de pointes have also been observed.8,14 Cardiac magnetic resonance imaging is reported to be extremely useful in the diagnosis of TCM, and can contribute not only to judgment of the severity of the disease, but also to the differential diagnosis of TCM and acute myocardial infarction.15 In the case of our patient, cardiac magnetic resonance imaging was not performed, given that cardiac catheterization did not show evidence of coronary artery obstruction. TCM has previously been associated with the administration of FU, bevacizumab, and sunitinib,7-10,16-20 but a direct association between TCM and the novel VEGF inhibitor axitinib has never been reported. Because of its very recent introduction into oncology treatment options, only limited experience is currently available that would identify the precise mechanisms by which this VEGFR inhibitor induces cardiotoxicity and would assist in establishing a link with TCM. It is presumed that the method of chemotherapy delivery affects the incidence of cardiotoxicity. It has been found that a continuous infusion is more likely to cause a cardiac adverse effect compared with a bolus or an oral route.8,21 In most of the previously described cases of cardiomyopathy that have occurred with the administration of FU,

to 55% and moderate left ventricular and septal hypertrophy. The patient has remained asymptomatic and continues to have normal left ventricular ejection fraction as of her last follow-up, which was 6 months after her initial presentation. Discussion TCM was first encountered and described in 1991 by Dote et al9a in Japan.6 The syndrome is named after the Japanese tako-tsubo, a pod-shaped trap used to catch octopus; the shape of the tako-tsubo is descriptive of the ballooning of the left ventricle during systole in a TCM event.9,11 It is presumed that TCM is caused by an excessive release of catecholamines, specifically adrenaline/epinephrine, which overstimulates the adrenergic receptors on the surface of cardiomyocytes and consequently impairs the response of the cardiac tissue to further adrenergic stimuli.6,8,9,11 It is known that 2.1% to 21% of all adverse chemotherapy events are cardiotoxic in nature; ischemia, vasospasm, arrhythmia, hypertension, QT interval prolongation, and acute cardiomyopathy are the most frequently presumed pathogenetic mechanisms.3 It has been proposed that global reversible endothelial injury is the underlying pathogenetic mechanism in TCM.7-9 TCM most commonly affects postmenopausal women between age 58 and 77 years.6-9,11 The female predominance is not entirely understood, although some studies hypothesize that women and men have different adrenergic innervations, and that men may have higher adrenergic receptors in the membranes of cardiomyocytes.11-13 TCM presents with symptoms of myocardial ischemia and specific features in electrocardiographic, echocardiographic, and cardiac

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Diagnosis in Oncology

the symptom onset ensued soon after the first administration of the drug; other occurrences have been observed after serial exposures.8 In the two previously described cases of cardiomyopathy associated with bevacizumab, one of the patients developed symptom onset 48 hours after chemotherapy initiation, and the other patient 3 weeks later.9 In the case of our patient, the symptom onset 24 hours after oral initiation of axitinib is not surprising; despite the oral administration, this agent is rapidly absorbed and reaches peak concentrations within 2 to 6 hours.22 The management of TCM is supportive, and as with our patient, most patients are expected to undergo spontaneous and complete left ventricular dysfunction recovery within 3 to 4 weeks.8 Only 1.5% to 4% of lethal complications, such as cardiogenic shock or ventricular arrhythmias, have been reported in TCM, and recurrence has been observed in less than 10% of all patients.11 Our patient had no preexisting cardiovascular risk factors before the initiation of axitinib, and she was not taking any other chemotherapeutic agents. Her only other possible risk factor was her age, given that TCM is more common in postmenopausal women than in men, and estrogen deficiency may be a risk factor for this pathology, as in myocardial infarction.13 The presumed association between the initiation of axitinib therapy and TCM as described in this case report deserves further prospective clinical observation, but for many reasons, we believe strongly in a causal relationship between the administration of axitinib and the development of TCM in this patient. Two previous cases of TCM in patients receiving bevacizumab, a monoclonal antibody that inhibits VEGF, have been reported.9 Although axitinib is a TKI, it selectively inhibits VEGFR1, VEGFR2, and VEGFR3, and shares a common pathway with bevacizumab.1-3,5,9 Our patient’s cardiomyopathy resolved with supportive management and discontinuation of the medication. The absence of a convincing alternative explanation for our patient’s clinical signs and symptoms supports the assumption that axitinib was the responsible agent. Because of the widespread use of axitinib in the management of RCC and other malignancies,2-4 it is important for physicians to be aware of, recognize, and promptly treat this condition. The case presented here is, to our knowledge, the first observation of TCM that developed immediately after initiation of the second-generation VEGFR inhibitor axitinib.

Daniela Ovadia Cardiology Clinic of San Antonio, Methodist Hospital, San Antonio, TX

Yoshua Esquenazi University of Texas–Houston, Houston, TX

Moises Bucay Cardiology Clinic of San Antonio, Methodist Hospital, San Antonio, TX

Carlos R. Bachier Texas Transplant Institute, Methodist Hospital, San Antonio, TX

ACKNOWLEDGMENT

We thank Wilma Cain for her help in the preparation of this article.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest. REFERENCES 1. Rini BI, Escudier B, Tomczak P, et al: Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomised phase 3 trial. Lancet 378:1931-1939, 2011 2. Albiges L, Salem M, Rini B, et al: Vascular endothelial growth factortargeted therapies in advanced renal cell carcinoma. Hematol Oncol Clin North Am 25:813-833, 2011 3. Cohen RB, Oudard S: Antiangiogenic therapy for advanced renal cell carcinoma: Management of treatment-related toxicities. Invest New Drugs 30:2066-2079, 2012 4. Chowdhury S, Larkin JM, Gore ME: Recent advances in the treatment of renal cell carcinoma and the role of targeted therapies. Eur J Cancer 44:21522161, 2008 5. Gross-Goupil M, Massard C, Ravaud A: Targeted therapies in metastatic renal cell carcinoma: Overview of the past year. Curr Urol Rep 13:16-23, 2012 6. Lee YP, Poh KK, Lee CH, et al: Diverse clinical spectrum of stress-induced cardiomyopathy. Int J Cardiol 133:272-275, 2009 7. Gianni M, Dentali F, Lonn E: 5 flourouracil-induced apical ballooning syndrome: A case report. Blood Coagul Fibrinolysis 20:306-308, 2009 8. Grunwald MR, Howie L, Diaz LA Jr: Takotsubo cardiomyopathy and fluorouracil: Case report and review of the literature. J Clin Oncol 30:e11-e14, 2012 9. Franco TH, Khan A, Joshi V, et al: Takotsubo cardiomyopathy in two men receiving bevacizumab for metastatic cancer. Ther Clin Risk Manag 4:1367-1370, 2008 9a. Dote K, Sato H, Tateshi H, et al: Myocardial stunning due to simultaneous multivessel coronary spasms: A review of 5 cases. J Cardiol 21:203-214, 1991 10. Numico G, Sicuro M, Silvestris N, et al: Takotsubo syndrome in a patient treated with sunitinib for renal cancer. J Clin Oncol 30:e218 – e220, 2012 11. Banihashemi MR, Khan IA: Acute stress-induced cardiomyopathy: A brief observation. Int J Cardiol 134:273-277, 2009 12. Sto¨llberger C, Finsterer J: Why does takotsubo (“broken heart syndrome”) affect more females than males? Int J Cardiol 147:175-176, 2011 13. Schneider B, Athanasiadis A, Sto¨llberger C, et al: Gender differences in the manifestation of tako-tsubo cardiomyopathy. Int J Cardiol 166:584-588, 2013 14. Yamada Y, Tani T, Homma M, et al: Two cases of torsades de pointes associated with Takotsubo cardiomyopathy as the second insult. J Electrocardiol 44:806-809, 2011 15. Nakamori S, Matsuoka K, Onishi K, et al: Prevalence and signal characteristics of late gadolinium enhancement on contrast-enhanced magnetic resonance imaging in patients with takotsubo cardiomyopathy. Circ J 76:914-921, 2012 16. Cheriparambil KM, Vasireddy H, Kuruvilla A, et al: Acute reversible cardiomyopathy and thromboembolism after cisplatin and 5-fluorouracil chemotherapy: A case report. Angiology 51:873-878, 2000 17. Dalzell JR, Samuel LM: The spectrum of 5-fluorouracil cardiotoxicity. Anticancer Drugs 20:79-80, 2009 18. Stewart T, Pavlakis N, Ward M: Cardiotoxicity with 5-fluorouracil and capecitabine: More than just vasospastic angina. Intern Med J 40:303-307, 2010 19. Basselin C, Fontanges T, Descotes J, et al: 5-Fluorouracil-induced TakoTsubo-like syndrome. Pharmacotherapy 31:226-228, 2011 20. Radhakrishnan V, Bakhshi S: 5-Fluorouracil-induced acute dilated cardiomyopathy in a pediatric patient. J Pediatr Hematol Oncol 33:323-328, 2011 21. Kosmas C, Kallistratos MS, Kopterides P, et al: Cardiotoxicity of fluoropyrimidines in different schedules of administration: A prospective study. J Cancer Res Clin Oncol 134:75-82, 2008 22. Escudier B, Gore M: Axitinib for the management of metastatic renal cell carcinoma. Drugs R D 11:113-126, 2011

DOI: 10.1200/JCO.2013.48.7280; published online ahead of print at www.jco.org on February 24, 2014 ■ ■ ■

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Association between takotsubo cardiomyopathy and axitinib: case report and review of the literature.

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