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VOLUME
30
䡠
NUMBER
24
䡠
AUGUST
20
2012
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
I N
O N C O L O G Y
Takotsubo Syndrome in a Patient Treated
With Sunitinib for Renal Cancer
mia. Treatment is essentially supportive.1-3 The disease is largely
prevalent in women and has been related with stressful situations or
drug exposure. We report a case of Takotsubo syndrome that occurred in a patient with renal cell cancer who was taking sunitinib.
Introduction
Left ventricular apical ballooning syndrome is a potentially severe, sudden myocardial dysfunction that can mimic myocardial infarction but is not sustained by coronary artery obstruction. The
clinical presentation of this syndrome, which is also recognized as
Takotsubo syndrome, is thoracic pain and dyspnea that occur mostly
in postmenopausal women. The most common electrocardiographic
features are ST-segment elevation in the precordial leads followed by
inversions of T waves and pathologic Q waves. Troponin and creatinine-kinase–myocardial band (CK-MB) levels are increased in the
majority of the cases. Left ventricular function is usually depressed and
the left ventricular ejection fraction is usually severely impaired and
ranges between 20% and 40%. At echocardiography, midventricular
wall-motion abnormalities, apical akinesia, or dyskinesia with preserved or hyperkinetic contractile function of basal left ventricular
segments are characteristic features. The clinical picture seems in
agreement with a myocardial infarction; the two major differences are
the coronary artery angiography, which is usually normal or demonstrates mild obstruction, and the clinical evolution that is benign and
leads to spontaneous improvement. Possible complications of Takotsubo syndrome are heart failure, ventricular thrombosis, and arrhyth-
Case Report
The patient was a 57-year-old woman with clear-cell renal cancer. After renal surgery in 2005, the tumor recurred in mediastinal
nodes in 2007. The patient had been treated with sunitinib at a dose of
50 mg per day for 4 weeks every 6 weeks since January 2007, which
achieved a partial response. Subjective toxicities (palmoplantar disesthesia, fatigue, and skin rash) caused a progressive dose reduction to
12.5 mg per day without impairment of the response. During treatment, the patient developed subclinical hypothyroidism, which was
treated with tyroxine supplementation, and grade 2 hypertension,
which was well controlled with carvedilole.
The patient presented on December 2010 to the medical oncology unit complaining chest pain and severe dyspnea. These
symptoms occurred suddenly the day before the visit. At physical
examination, the following two features were noticed by the oncologist: a jugular vein distention and a strong ejective systolic murmur. The initial ECG showed ST-segment increase (Fig 1A).
Troponin T blood levels were 1,247 ng/L (normal values, 0 to 14
ng/L) at admission. A transthoracic echocardiogram revealed severe global hypokinesis of the left ventricle with apical ballooning
in systole and diastole (Figs 2A and 2B, arrows) and severe mitral
A
B
Fig 1.
e218
© 2012 by American Society of Clinical Oncology
Journal of Clinical Oncology, Vol 30, No 24 (August 20), 2012: pp e218-e220
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Diagnosis in Oncology
A
B
Fig 2.
regurgitation. The ejection fraction was estimated at 15% to 20%.
A coronarographic study did not reveal any coronary obstruction.
The patient was treated with angiotensin-converting enzyme inhibitor, ␤ blocker, and prophylactic low-molecular weight heparin
and followed up in the intensive care unit. Troponin levels progressively decreased in the next 2 days as did the symptoms of heart failure.
The ECG performed on day 4 showed marked T-wave inversion in the
anterolateral precordial leads (Fig 1B) but normalized in the following
days. A control echocardiogram performed 2 days after the event
showed a left ventricular ejection fraction of 35% and of 42% 1 week
after. The mitral insufficiency completely resolved, as did the objective
finding of the murmur. Unfortunately, the patient developed a left
ventricular apical thrombus, and thus, an anticoagulant dose of dalteparin was given. A computed tomography scan of the chest revealed
progressive disease. The patient was discharged from the hospital 7
days after the critical episode with mild dyspnea. A second-line treatment with everolimus was initiated. At the 3-month evaluation, no
other sign or symptom of heart failure recurred, and the dyspnea
gradually improved. The echocardiographic control showed complete
disappearance of the ventricular thrombus and a left ventricular ejection fraction of 68%.
Discussion
Several reports have described Takotsubo syndrome in association with fluorouracil administration.4-10 Fluorouracil is a wellknown cardiotoxic agent, although the exact mechanism of action is
not clearly established. To the best of our knowledge, Takotsubo
syndrome has been recognized in association of sunitinib in only one
case by Korean clinicians. In that case, a 48-year old woman developed
sudden congestive heart failure after a few weeks of sunitinib treatment, with echocardiographic features that were suggestive of Takotsubo syndrome. The clinical and imaging picture completely resolved
at the 6-month control. Unfortunately, no angiographic study was
performed, and thus, an ischemic event was not formally excluded.11
Sunitinib has a recognized cardiovascular toxicity potential.12
Typical effects are hypertension and reduction of the left ventricular
ejection fraction. Moreover, thyroid dysfunction may add some other
toxicity on the cardiovascular system. Toxicity does not seem to be
related to the duration of drug exposure because it has been described
after a few weeks of administration. In the series conducted by researchers of the Harvard Medical School in patients with imatinibwww.jco.org
resistant GIST, sunitinib induced cardiac events in 11% of treated
patients, the majority of which were congestive heart failures. The
decrease of the left ventricular ejection fraction was gradual and occurred mostly in the first 24 weeks of treatment. Two cases of myocardial infarction were described but with no coronarographic or
echocardiographic study. Moreover, 18% of patients had a moderate
increase of troponine I blood levels (mean, 0.74 ng/mL).13 Telli et al14
of Stanford University reported seven cases of symptomatic cardiac
dysfunction among 48 patients treated with sunitinib. However, no
case presented with the features of ischemic heart disease or Takotsubo syndrome.
Khakoo et al15of the MD Anderson Cancer Center described six
cases of symptomatic cardiac dysfunction without any obvious cause
that occurred from 4 to 44 days after sunitinib exposure. Although
none of these cases was related to ischemic changes, several of them
were associated with severe hypertension or had a progressive evolution. Furthermore, three of these patients had been previously treated
with potentially cardiotoxic agents, and all of them had pretreatment
known risk factors for cardiovascular disease. None of them appeared
to have the echocardiographic findings of Takotsubo syndrome.15
The clinically evidenced cardiac toxicity has a preclinical basis.
Studies conducted on mouse models showed that sunitinib exposure
induced cardiomyocyte injury, with mitochondrial swelling and damage at electron microscopy.16 At the molecular level, it was shown that
inhibition by sunitinib of adenosine monophosphate–activated protein kinase, which is a kinase that plays key roles in maintaining
metabolic homeostasis in the heart, especially in the setting of energy
stress, accounts, at least in part, for sunitinib-induced toxicity seen
in cardiomyocytes.17
The patient described in our report had developed both lowgrade hypertension and subclinical hypothyroidism. However, Takotsubo syndrome developed suddenly after 4 years of sunitinib
exposure. The following possible pathophysiologic mechanisms have
been suggested to be at the base of Takotsubo syndrome: epicardial
artery spasm, microvessel myocardial ischemia, increased cathecolamine plasma levels, or myocarditis.18 Although a possible alternative
cause such as a stressful personal condition cannot be excluded, we
suggest that this clinical picture should be kept in mind when using
sunitinib because of possible severe consequences and the frequent
resolution with medical supportive treatment.
© 2012 by American Society of Clinical Oncology
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e219
Numico et al
Gianmauro Numico and Marco Sicuro
Ospedale U. Parini, Aosta, Italy
Nicola Silvestris
Cancer Institute “Giovanni Paolo II,” Bari, Italy
Alessandro Mozzicafreddo, Antonio Trogu,
Alessandra Malossi, Antonella Cristofano,
and Benedetta Thiebat
Ospedale U. Parini, Aosta, Italy
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
REFERENCES
1. Gianni M, Dentali F, Grandi AM, et al: Apical ballooning syndrome or
takotsubo cardiomyopathy: A systematic review. Eur Heart J 27:1523-1529, 2006
2. Golabchi A, Sarrafzadegan N: Takotsubo cardiomyopathy or broken heart
syndrome: A review article. J Res Med Sci 16:340-345, 2011
3. Pernicova I, Garg S, Bourantas CV, et al: Takotsubo cardiomyopathy: A
review of the literature. Angiology 61:166-173, 2010
4. 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
5. Radhakrishnan V, Bakhshi S: 5-Fluorouracil-induced acute dilated cardiomyopathy in a pediatric patient. J Pediatr Hematol Oncol 33:323, 2011
6. Basselin C, Fontanges T, Descotes J, et al: 5-Fluorouracil-induced TakoTsubo-like syndrome. Pharmacotherapy 31:226, 2011
7. 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
8. Stewart T, Pavlakis N, Ward M: Cardiotoxicity with 5-fluorouracil and
capecitabine: More than just vasospastic angina. Intern Med J 40:303-307, 2010
9. Gianni M, Dentali F, Lonn E: 5 flourouracil-induced apical ballooning
syndrome: A case report. Blood Coagul Fibrinolysis 20:306-308, 2009
10. Kobayashi N, Hata N, Yokoyama S, et al: A case of Takotsubo cardiomyopathy during 5-fluorouracil treatment for rectal adenocarcinoma. J Nihon Med
Sch 76:27-33, 2009
11. Lim TJ, Lee JH, Chang SG, et al: Life-threatening complications associated
with the tyrosine kinase inhibitor sunitinib malate. Urol Int 85:475-478, 2010
12. Schutz FA, Je Y, Richards CJ, et al: Meta-analysis of randomized controlled
trials for the incidence and risk of treatment-related mortality in patients with
cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors.
J Clin Oncol 30:871-877, 2012
13. Chu TF, Rupnick MA, Kerkela R, et al: Cardiotoxicity associated with the
tyrosine kinase inhibitor sunitinib. Lancet 370:2011-2019, 2007
14. Telli ML, Witteles RM, Fisher GA, et al: Cardiotoxicity associated with the
cancer therapeutic agent sunitinib malate. Ann Oncol 19:1613-1618, 2008
15. Khakoo AY, Kassiotis CM, Tannir N, et al: Heart failure associated with
sunitinib malate: A multitargeted receptor tyrosine kinase inhibitor. Cancer
112:2500-2508, 2008
16. Di Lorenzo G, Autorino R, Bruni G, et al: Cardiovascular toxicity following
sunitinib therapy in metastatic renal cell carcinoma: A multicenter analysis. Ann
Oncol 20:1535-1542, 2009
17. Cheng H, Force T: Why do kinase inhibitors cause cardiotoxicity and what
can be done about it? Prog Cardiovasc Dis 53:114-120, 2010
18. Vaklavas C, Lenihan D, Kurzrock R, et al: Anti-vascular endothelial growth
factor therapies and cardiovascular toxicity: What are the important clinical
markers to target? The Oncologist 15:130-141, 2010
DOI: 10.1200/JCO.2012.42.4911; published online ahead of print at
www.jco.org on July 16, 2012
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© 2012 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
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Copyright © 2012 American Society of Clinical Oncology. All rights reserved.