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Heart Failure Associated With Sunitinib Malate
A Multitargeted Receptor Tyrosine Kinase Inhibitor
Aarif Y. Khakoo, MD1
Christos M. Kassiotis, MD2
Nizar Tannir, MD3
Juan Carlos Plana, MD1
Marc Halushka, MD, PhD4
Courtney Bickford, PharmD5
Jon Trent 2nd, MD6
J. Chris Champion, MD1
Jean-Bernard Durand, MD1
Daniel J. Lenihan, MD1
BACKGROUND. Sunitinib malate is a novel multitargeted receptor tyrosine kinase
inhibitor with established efficacy in the treatment of metastatic renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor. This report describes
the development of heart failure in cancer patients who received this novel agent.
METHODS. A retrospective study was conducted at M. D. Anderson Cancer Center
during a 1-year period on patients who received sunitinib and developed heart
failure.
RESULTS. During 2006, 6 of 224 (2.7%) patients who received sunitinib developed
heart failure (HF) that resulted in substantial morbidity and, in some cases, mortality. Symptomatic heart failure occurred soon after initiation of sunitinib (mean
onset 22 days after initiation), was associated with decline in cardiac function
1
Department of Cardiology, The University of
Texas M. D. Anderson Cancer Center, Houston,
Texas.
and elevations in blood pressure, and was not completely reversible in most
2
Division of Cardiology, The University of Texas
Medical School at Houston, Houston, Texas.
ure may represent a potentially serious toxicity and underscore the need for care-
3
these patients. Studies to elucidate potential mechanisms of heart failure and left
Genitourinary Medical Oncology, The University
of Texas M. D. Anderson Cancer Center, Houston,
Texas.
patients, even after termination of sunitinib therapy.
CONCLUSIONS. These observations suggested that sunitinib-associated heart failful monitoring of cardiac function and aggressive control of hypertension in
ventricular dysfunction resulting from treatment with sunitinib are necessary to
develop strategies for prevention and treatment of this complication. Cancer
4
2008;112:2500–8. 2008 American Cancer Society.
5
Division of Pharmacy, The University of Texas
M. D. Anderson Cancer Center, Houston, Texas.
KEYWORDS: sunitinib, cardiotoxicity, heart failure, angiogenesis inhibitors, hypertension.
Department of Pathology at Johns Hopkins University School of Medicine, Baltimore, Maryland.
6
Department of Sarcoma Medical Oncology, The
University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Jean-Bernard Durand is on the speakers bureau
of GST, Novartis, and Sanofi.
Address for reprints: Daniel J. Lenihan, MD, and
Aarif Y. Khakoo, MD, Department of Cardiology449, University of Texas M. D. Anderson Cancer
Center, 1515 Holcombe Blvd, Houston, TX 77030.
Fax: (713) 745-1942; E-mail: dlenihan@mdanderson.
org, aykhakoo@ mdanderson.org
Received October 2, 2007; revision received
November 9, 2007; accepted November 26,
2007.
ª 2008 American Cancer Society
S
unitinib malate (Sutent, SU11248; Pfizer, New York, NY) is a
multitargeted tyrosine kinase inhibitor with profound antiangiogenic activity and whose targets include the stem cell factor receptor CD117 (c-kit), the platelet-derived growth factor receptor
(PDGFR), and the vascular endothelial growth factor receptor
(VEGFR).1 In early 2006, sunitinib received US Food and Drug
Administration approval for the treatment of advanced renal cell
carcinoma (RCC) based, in large part, on data from 2 phase 2 clinical trials that demonstrated its safety and efficacy in the treatment
of patients with cytokine refractory, metastatic RCC,2,3 a tumor for
which treatment options are limited. Recently, a large phase 3 randomized trial demonstrated a doubling of median progression-free
survival with sunitinib compared with interferon-alpha in patients
with previously untreated metastatic RCC.4 Sunitinib has also been
shown to substantially increase time to tumor progression compared with placebo in patients with imatinib-resistant gastrointestinal stromal tumor (GIST) in a phase 3, randomized, placebocontrolled clinical trial,5 a study which led to its FDA approval for
this indication in early 2006.3
DOI 10.1002/cncr.23460
Published online 3 April 2008 in Wiley InterScience (www.interscience.wiley.com).
HF in Patients Treated with Sunitinib/Khakoo et al.
Questions about the cardiac safety of sunitinib
emerged from early clinical trials of the drug. In 1
study of patients with gastrointestinal stromal tumor,
11% of patients experienced treatment-related left
ventricular dysfunction (LVD) compared with 3%
treated with placebo.3 Similarly, a study in patients
with metastatic renal cell carcinoma identified new
LVD in 4% of patients.6 In addition, 4.6% of patients
treated with sunitinib monotherapy for renal cell
carcinoma have been reported to have LVD, as
defined by a reduction in left ventricular ejection
fraction (LVEF) >20%.2 Despite the suggestion of
LVD associated with sunitinib malate, the development of clinically significant heart failure associated
with this drug has not yet been described in the
literature.
Thus, we present 6 cases in which the development of heart failure (HF) in patients who were
receiving sunitinib resulted in serious morbidity and/
or mortality. The unifying features of the cardiotoxicity in these 6 patients included 1) development of
HF early after administration of the drug, 2) profound morbidity and/or mortality in these patients
in part due to cardiac dysfunction, 3) incomplete reversibility of cardiac function after termination of the
drug in many cases, and 4) significant hypertension
associated with sunitinib in these patients.
MATERIALS AND METHODS
Patients reported here were referred to the University
of Texas M. D. Anderson Cancer Center Cardiology
Department for evaluation and management of HF
associated with cancer therapy between January 1
and December 31, 2006. Patients’ records were
reviewed, and a detailed assessment of cardiac risk
factors and prior history of heart disease was performed. Demographic data from the group, not
including those who developed HF, are summarized
in Table 1. Relevant laboratory and radiologic examinations, including all specialized cardiac testing,
were individually reviewed. Finally, the temporal
relation between initiation of sunitinib treatment and
development of HF was explored. HF was diagnosed
by standard combined symptoms by using criteria
determined by Framingham Heart Study investigators7 coupled with either LVD and/or elevation of Btype natriuretic peptide (BNP), a marker highly sensitive and specific for diagnosis of HF.8 To determine
the number of patients who were receiving sunitinib
at M. D. Anderson Cancer Center during this time,
inpatient and outpatient department of pharmacy
database records were interrogated. Echocardiograms
were interpreted by a single cardiologist (J.C.P.) who
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TABLE 1
Baseline Demographics for Patients Receiving Sunitinib Who Did Not
Develop Heart Failure (n 5 218)
Characteristic
Sex
Men
Women
Cancer
Renal cell
Prostate
VHL
Lung
Myelofibrosis
Sarcoma
GI stromal
Carcinoid
Adenocarcinoma
GE junction
Established coronary artery disease
Cardiac risk factors
Hypertension
Hyperlipidemia
Diabetes
Tobacco use
Prior cancer treatment
Surgery
Anthracyclines
Interferon
Bevacizumab
Sorafenib
Erlotinib
Imatinib
Gefitinib
Tipifarnib
Bortezomib
Mean ECOG score (SD)
No. of patients (%)
158 (72)
60 (28)
167 (77)
26 (12)
6 (2.8)
8 (3.7)
5 (2.3)
1 (0.5)
2 (1)
1 (0.5)
1 (0.5)
1 (0.5)
27 (12)
116 (53)
32 (15)
32 (15)
14 (6)
35 (16)
11 (5)
24 (11)
56 (26)
72 (33)
23 (11)
3 (1.4)
2 (1)
2 (1)
1 (0.5)
1.115 (0.885)
ECOG indicates Eastern Cooperative Oncology Group; VHL, Von Hippel-Lindau disease; SD, standard
deviation.
was unaware of the clinical details of the patients,
including timing of sunitinib treatment.
RESULTS
During a 1-year period, 6 patients who developed
symptomatic cardiac dysfunction without any other
obvious cause (eg, valvular heart disease or myocardial infarction) while receiving sunitinib were identified. Their mean age was 65 years. Four patients had
metastatic renal cell carcinoma, 1 had a metastatic
neuroendocrine tumor, and 1 had metastatic prostate
cancer. All patients were New York Heart Association
(NYHA) class I at baseline. Patient characteristics and
baseline functional status before initiation of sunitinib of all patients are shown in Table 2. The nature
of the cardiotoxicity and severity of HF as well as the
short-term outcome are detailed in Table 3. A brief
description of each case is described below.
73
64
65
61
69
61
1
2
3
4
5
6
W
M
M
M
M
W
Sex
1
1
3
1
1
1
ECOG score
at baseline
DM, HTN
HTN
HTN
HTN
HTN, CAD
Chol
CAD
RF
R-CHOP, IFN bevacizumab, erlotinib,
gemcitabine, capecitabine
IFN, IL-2, 5-FU, cis-retinoic acid,
bevacizumab
None
Interferon, IL-2, thalidomide, gemcitabine,
capecitabine
None
None
Prior
therapies
55–60%
65–70%
61%
55–60%
Unknown
55–60%
Predrug
LVEF
I
I
I
I
I
I
NYHA class
baseline
Renal cell
Prostate
Neuroendocrine
Renal cell
Renal cell
Renal cell
Cancer
11.9
16.3
9.1
8.9
11.5
10.1
Hgb,
gm/dL
0.7
1.2
0.9
0.9
2.3
1.0
Cr,
mg/dL
150/72
150/80
140/94
142/67
162/92
146/75
1
2
3
4*
5
6
50
50
50
50
25
25
Dose
20
29
44
4
4
29
Duration
of drug, d
4
3
4
3
4
2
Worst NYHA
class
409
356
558
3338
2110
409
BNP, pg/mL
(normal £100)
ACE-I, B-blocker
Nitrates, B-blocker
Increased ACE-I
Increased ACE-I
Added ACE-I, B-blocker
B-blocker
<20%
50–55%
HF
therapy
25–30%
30–35%
25–30%
40–45%
LVEF
postdrug
—
—
25–30%
45–50%
30%
60–65%
LVEF post-treatment
with HF therapy
195/97
160/80
155/85
184/110
210/110
174/85
Max BP
on drug
Died in 6 mo
Died in 4 mo
Died in 1 mo
LVEF improved then worsened to 35–
40% on sunitinib. Subsequently
tolerated reduced dose.
Died in 1 mo
HF symptoms improved after sunitinib
was discontinued. Died 7 mo later.
Outcome
Pt no. indicates patient number; BP, blood pressure; NYHA, New York Heart Association; BNP, B-type natriuretic peptide; LVEF, left ventricular ejection fraction; HF, heart failure; ACE-I, angiotension-converting enzyme inhibitor; B-blocker, beta-blocker; —, not done.
* Drug continued.
BP at
baseline
Pt no.
TABLE 3
Nature of Cardiotoxicity, Severity of Heart Failure, and Short Term Outcomes
CANCER
Pt no. indicates patient number; ECOG, Eastern Cooperative Oncology Group; CAD RF, coronary artery disease risk factors; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association Class for heart failure; Hgb, hemoglobin; Cr, serum creatinine; W, women; M,
men; Chol, cholesterol; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; IFN, interferon-alpha; HTN, hypertension; CAD, coronary artery disease; IL-2, interleukin-2; 5-FU, 5 fluorouracil; DM, diabetes mellitus.
Age
Pt no.
TABLE 2
Clinical Characteristics and Baseline Functional Status Prior to Sunitinib of Patients Who Developed Heart Failure
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HF in Patients Treated with Sunitinib/Khakoo et al.
Patient 1
A 73-year-old female developed renal cell carcinoma
for which she underwent right nephrectomy in 2000.
She also developed follicular cell lymphoma and was
treated with 8 cycles of R-CHOP (rituxan, cyclophosphamide, doxorubicin, vincristine, and prednisone)
in 2001, achieving a sustained complete remission.
She developed metastatic renal cell carcinoma in
2004 and was treated with interferon-alpha, followed
by treatment with bevacizumab and erlotinib.
Because of her disease progression, she received a
combination of gemcitabine and capecitabine in late
2005. In January 2006, she was started on treatment
with sunitinib. Eastern Cooperative Oncology Group
(ECOG) performance status was 1 as was her NYHA
HF class. Six weeks after initiation of sunitinib, she
presented with dyspnea on exertion, fatigue, and
lower extremity edema. An echocardiogram (Echo)
performed in February 2006 revealed an LVEF of 20–
25% with restrictive physiology on Doppler hemodynamic assessment. A previous Echo study several
years earlier was normal. A coronary angiogram
revealed no evidence of flow-limiting coronary artery
disease. She was started on therapy with carvedilol
3.125 mg twice daily. Sunitinib was discontinued
without improvement in the LVEF, although with
medical therapy, her HF symptoms did not worsen.
She died 4 months later of progressive metastatic
RCC.
Patient 2
A 64-year-old male was diagnosed with metastatic
renal cell carcinoma during a preoperative evaluation
for coronary artery bypass surgery that was performed in 1996. He subsequently had multiple therapies for his renal cell cancer which included 1)
surgical removal of his left kidney and adrenal gland
in December 1996, 2) interferon, interleukin-2, and
5-fluorouracil treatment in 1998 after disease progression, and 3) interferon, cis-retinoic acid treatment followed by pegylated interferon in 2005, and
4) bevacizumab. Due to progression of disease, bevacizumab was discontinued. His performance status
was ECOG 1, and his NYHA HF class was 1. In May
2006, he was started on treatment with sunitinib at
50 mg daily. His blood pressure was 150/80 mm Hg.
He presented 4 days later with weakness and cough.
His blood pressure was 184/110 mm Hg, and he had
marked lower extremity edema and significant jugular venous distension on physical examination. An
Echo revealed an LVEF of 20% to 25% with severe
global hypokinesis of the left ventricle and Doppler
evidence of elevated left atrial pressure. There was
no biochemical or electrocardiographic evidence of
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myocardial infarction. He was treated with diuretics,
hydralazine, nitrates, and carvedilol. Sunitinib was
discontinued. An Echo repeated 6 days later demonstrated improvement of the LVEF up to 40% to 45%,
at which time his blood pressure had decreased to
144/73. Because of the progressive nature of his disease, he was treated with sorafenib 400 mg twice
daily. He tolerated this reasonably well for several
weeks but ultimately died of progressive disease
6 months later.
Patient 3
A 65-year-old male was referred to our institution for
treatment of presumed metastatic clear cell renal
cancer, which was diagnosed during evaluation of
fever of unknown origin. His baseline performance
status was ECOG 3, but his NYHA class was 1, and
he had normal LVEF and a normal stress test less
than 1 month before initiation of sunitinib. He was
started on treatment with sunitinib 25 mg daily. His
initial blood pressure was 140/94. Four days later, he
was noted to be in respiratory distress, his blood
pressure was severely elevated to 226/120 mm Hg,
he was hypoxic, and chest x-ray revealed changes
consistent with pulmonary edema. An Echo revealed
an LVEF of 25% to 30% (Fig. 1). Despite maximal
supportive care, he had progressive clinical deterioration over the next 2 weeks, and he ultimately died of
multiple organ failure. Findings at postmortem were
notable for cardiomegaly (His heart weight was 480 g,
and a normal heart weight is 400 68 g).9 with no
evidence of epicardial coronary artery disease. Hematoxylin and eosin staining of his heart revealed
mild myocyte hypertrophy but no other structural
abnormalities (Fig. 2), including no evidence of myocardial infarction, myocyte necrosis, or myocarditis.
A malignant neuroendocrine tumor with widespread
metastasis to several organs was identified.
Patient 4
A 61-year-old male with metastatic renal cell cancer
was started on therapy with sunitinib after several
regimens were attempted, including interferon-alpha,
interleukin-2, thalidomide, and gemcitabine plus
capecitabine chemotherapy. His performance status
was ECOG 1. His baseline ejection fraction was 55%
to 60%. He received sunitinib for 8 days before it was
temporarily stopped because of an episode of gastrointestinal bleeding. No source of active bleeding was
identified, and he was discharged to home after
receiving transfusions. Twenty days later, after presenting as an outpatient with mild fatigue and dyspnea, an Echo revealed an LVEF of 40% to 45%. He
was treated with an angiotensin-converting enzyme
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June 1, 2008 / Volume 112 / Number 11
FIGURE 1. An echocardiogram in Patient 3 with left ventricular dysfunction is shown. Two-dimensional images reveal severe LV dysfunction with no substantial change between systole (left) and diastole (right) in the cardiac cycle. Arrows indicate the closed mitral valve (systolic) and open mitral valve (diastolic) but
no significant change in LV chamber sizes.
for 7 months with excellent radiographic tumor response. The patient then reported increased fatigue
with activity (NYHA class II) after receiving sunitinib
50 mg daily for 5 28-day cycles. A repeat echocardiogram at this time revealed moderate, global, cardiac
dysfunction with an LVEF of 35% to 40%. At this
time, his blood pressure was 174/85, and his BNP
level was 409 pg/mL (normal, <100 pg/mL). His
sunitinib dosage was subsequently reduced with no
worsening of his heart failure symptoms.
FIGURE 2. Photomicrograph of stained section from Patient 3 shows cardiomyopathy after exposure to sunitinib (original magnification, 3100; H & E
stain). This specimen reveals mild myocyte hypertrophy without evidence of
vacuolization or myocyte necrosis. There was no evidence of substantial
myocardial fibrosis or inflammatory myocardial infiltrate.
inhibitor (ACE-I), and his fatigue improved. Sunitinib
therapy was resumed at 50 mg daily. Repeat LVEF
was 60% to 65% 3 months later, and blood pressure
at that time was 137/67. Sunitinib was continued
Patient 5
A 69-year-old female was started on sunitinib for
newly diagnosed metastatic renal cell carcinoma
involving the bone, lungs, and liver. Her performance
status was ECOG 1. Her initial blood pressure was
160/92 mm Hg, but she was asymptomatic from a
cardiac standpoint. Twenty days later, she suffered a
cardiac arrest due to ventricular fibrillation while
undergoing imaging studies. She was successfully
resuscitated. Her blood pressure was 195/97 before
the event. Initial LVEF before sunitinib was 50% to
60% but dropped to less than 20% when measured
24 hours after onset of ventricular arrhythmia. There
was no biochemical evidence of acute myocardial infarction or significant electrolyte abnormality to
which to attribute her ventricular arrhythmia. She
was ultimately stabilized, discharged to home hospice, and died soon thereafter.
HF in Patients Treated with Sunitinib/Khakoo et al.
Patient 6
A 61-year-old male with advanced, castration-resistant, prostate cancer metastatic to the bone was
started on an investigational protocol using sunitinib.
His baseline performance status was ECOG 1. His
baseline LVEF was 65% to 70%, and his baseline
blood pressure was 146/75. Twenty-nine days after
initiation of sunitinib, he presented with symptoms
of HF with an elevated BNP of 356 pg/mL. A repeat
echocardiogram revealed mild global ventricular
hypokinesis with a calculated LVEF of 50% to 55%.
He was also found to have atrial fibrillation with
rapid ventricular response. Sunitinib was discontinued. He was cardioverted after pharmacological
intervention failed to restore normal sinus rhythm.
His HF symptoms improved significantly after sinus
rhythm was restored. His blood pressure was 160/80
after cardioversion but was ultimately controlled. A
computed tomography angiography scan of the chest
revealed bilateral small pulmonary emboli. Anticoagulation with enoxaparin was initiated. The patient
died due to disease progression 7 months later.
DISCUSSION
The patients described in this report all developed
symptomatic HF shortly after receiving sunitinib.
None of these patients had a history of HF before
initiation of sunitinib, and objective measurement of
LVEF before initiation of sunitinib in 5 of the 6
patients revealed normal left ventricular systolic
function (Table 2). The LVEF of Patient 2 before
initiation of sunitinib was unknown, but he had no
history of LVD before initiation of drug and had been
without symptoms of angina or HF for several years.
Five of the 6 patients developed severe HF while on
sunitinib (NYHA class III or IV), necessitating discontinuation of this therapy. One patient was able to tolerate dose reduction of sunitinib and simultaneous
treatment of hypertension with an ACE-I, although
he subsequently developed left ventricular dysfunction months later.
During the identification of HF and investigation
into potential causes, none of these patients had evidence of myocardial infarction by symptom assessment, troponin elevation, or electrocardiographic
analysis. Patient 1 had a cardiac catheterization upon
initial presentation with HF, and this revealed no evidence of significant coronary artery disease. Patients
3 and 5 had normal myocardial perfusion studies
during the month preceding initiation of sunitinib,
making existing coronary artery disease and myocardial infarction an unlikely cause of HF in these
selected patients. Patient 3 actually had no epicardial
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coronary disease at autopsy, but he had a malignant
neuroendocrine tumor, which could have contributed to elevation of his blood pressure and development of HF, although serum catecholamine levels
were not significantly elevated during his illness. In
addition, 5 of these patients had no significant valvular heart disease or arrhythmia identified that could
contribute to their HF while they were receiving
sunitinib. The initial sign of cardiotoxicity in Patient
5 was a ventricular arrhythmia. This patient had no
evidence of an acute myocardial infarction or electrolyte disturbances to account for her arrhythmia,
suggesting that the arrhythmia was more likely a
manifestation of a new-onset cardiomyopathy. This
is very consistent with the observation that patients
with nonischemic cardiomyopathies are at high risk
for sudden death due to ventricular arrhythmias.10
Patient 6, on the other hand, developed atrial flutter
in addition to HF. Whether or not atrial flutter in this
patient was caused by or led to the decline in LV
function in this patient is unclear. Atrial arrhythmias,
such as atrial fibrillation or atrial flutter, often
unmask a new-onset cardiomyopathy. Large, epidemiologic studies reveal that LV dysfunction is the
most potent risk factor for development of atrial fibrillation.11 However, atrial arrhythmias can contribute to a reduction in ventricular function and, thus,
precipitate or aggravate HF symptoms.12
In addition, none of the patients had evidence of
hypothyroidism, a frequent complication of sunitinib
treatment13 and a rare cause of cardiomyopathy.14
Only Patient 2 did not have an assessment of thyroid
function and lacked clinical symptoms of hypothyroidism. Patient 3 may have had an uncontrolled
infection that could have contributed to development
of HF. Finally, although 4 of the 6 patients had been
extensively treated with other agents for metastatic
RCC before being started on sunitinib (Table 2),
none of these agents carry a substantial risk for development of nonreversible left ventricular dysfunction with the exception of anthracyclines, which only
Patient 1 received. Notably, Patient 1 had a normal
echocardiogram and no symptoms of heart failure
before being started on sunitinib. It is possible that
her anthracycline exposure predisposed her to development of HF while she was on sunitinib.
HF after initiation of sunitinib occurred as early
as 4 days after onset of therapy and as late as 44
days after the drug was started (Table 3). Notably,
the short amount of time between onset of heart failure after initiation of sunitinib suggests that this toxicity is mechanistically distinct from anthracyclinemediated cardiotoxicity, which is dose dependent
and typically occurs after prolonged drug exposure.15
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June 1, 2008 / Volume 112 / Number 11
In fact, sunitinib-associated left ventricular dysfunction may bear more similarity to cardiotoxicity seen
in breast cancer patients treated with trastuzumab,
in which there is no known association between
dose or duration of drug and subsequent cardiotoxicity.16 Of note, all of the patients had hypertension
(HTN) associated with taking sunitinib, although
each had either a history of HTN or elevated BP at
baseline. HTN is a known side effect of sunitinib6,17,18 and other angiogenesis inhibitors,19
although the mechanism by which these agents produce HTN is poorly understood. Uncontrolled hypertension is a major contributor to cardiac dysfunction
and symptomatic HF.20 In fact, when one considers
that no other major causative factor was identified in
5 of 6 patients, hypertension remains the most likely
major contributor leading to decompensated HF.
Sunitinib was discontinued in 5 of the 6 patients
after they developed HF associated with LVD, and
none of these patients were rechallenged with the
drug. Typical HF therapy was initiated including
ACE-I and/or beta blockers in all of the patients as
well as diuretics, as appropriate, after their diagnosis
of HF. In the majority of patients, LVD was not completely reversed after termination of sunitinib despite
appropriate HF therapy, suggesting that this toxicity
may represent a nonreversible injury. Alternatively,
the follow-up period may not have been long enough
to allow for improvement. Patient 1 had persistent LV
dysfunction 1 month after stopping sunitinib and
had symptomatic HF until she died several months
later. Patient 2 had marked improvement in left ventricular function after sunitinib was stopped, and his
blood pressure was controlled, but his left ventricular
function never completely returned to normal.
Patient 3 had no improvement in left ventricular
ejection fraction 2 weeks after termination of sunitinib and then died. Patient 4 was continued on sunitinib, and left ventricular function normalized with
improved blood pressure control but subsequently
worsened as sunitinib was continued. In Patient 5,
there was no LVEF reassessment before death, and in
Patient 6, the LVEF was reduced but remained within
the normal range.
The incidence of HF associated with sunitinib is
difficult to determine, especially when one considers
different patient populations. Review of outpatient
and inpatient pharmacy records during the year
2006, when these patients were identified, revealed
223 patients treated with sunitinib at our institution,
suggesting that the incidence of HF associated with
sunitinib is approximately 3%. Whether this number
is actually higher will require a prospective analysis
in which patients are objectively screened for HF
before initiation of drug and are monitored closely
for the development of HF. The use of BNP during
therapy appears to be an important parameter to follow during chemotherapy and predicts the subsequent development of cardiotoxicity, particularly in
anthracycline-containing regimens. It is likely that
this biomarker may also be useful for other systemic
therapies, but this remains to be fully investigated.
In this population, all 6 patients had a substantially
elevated BNP when they became symptomatic with
HF. Furthermore, BNP is more specific for the diagnosis of HF than LVEF alone, which is especially relevant because nearly 50% of all patients with HF have
a normal ejection fraction.21 In addition, the outcomes of patients with symptomatic HF and a normal ejection fraction is not much different from
those patients with a low LVEF, thus suggesting that
LVEF is not the most important predictor of outcomes. In light of this knowledge, biomarker testing
may be an effective means to identify cardiotoxicity
due to sunitinib, a hypothesis which we are currently
testing prospectively.
The mechanism of HF associated with sunitinib
treatment is unknown. Our findings do suggest that
hypertension may be exerting an important effect. It
is noteworthy that other antiangiogenic agents, such
as bevacizumab, have been associated with severe
hypertension22 and have been reported to be associated with HF.15 Other potential mechanisms include
inhibition of a receptor tyrosine kinase that is responsible for the appropriate cardiac response to hypertensive stress, and the combination of hypertension
and inhibition of this receptor tyrosine kinase leads
to a maladaptive vicious cycle resulting in HF subacutely after initiation of sunitinib. For instance,
PDGF-receptor is known to be expressed on cardiac
myocytes23 and is a potent stimulus in vitro and in
vivo of cardiomyocyte growth,24 which represents the
normal myocyte response to hypertensive stress.
Recent animal studies have shown that administration of PDGF prevents development of cardiac dysfunction after myocardial infarction, seemingly acting
directly to protect cardiac myocytes from ischemic
stress.25 More generally, preclinical studies have
demonstrated that intact receptor tyrosine kinase signaling within the heart is essential to preserve the
normal response to hypertensive stress. It is known
that mice with cardiomyocyte-specific knockout of
the receptor tyrosine kinase ErbB2, the target of the
known cardiotoxic anticancer agent trastuzumab
(Herceptin), exhibit a phenotype of dilated cardiomyopathy but have preserved physiologic response to
the proinotropic agent dobutamine.26 However, 70%
of these mice die in response to pressure-overload
HF in Patients Treated with Sunitinib/Khakoo et al.
stress compared with <10% of wild-type animals.
Thus, the combination of substantial hypertension
and inhibition of receptor tyrosine kinase function in
the heart may a play key role in the cardiotoxicity
associated with sunitinib described in this report.
Other mechanisms are certainly possible, including a
structural effect on the myocardial cell, resulting in
apoptosis. However, the 1 pathologic specimen in this
series did not confirm ultrastructural changes. It is
likely that HF and LVD in our population of patients
has a multifactorial origin.
In summary, we report the development of
symptomatic HF in selected patients exposed to
sunitinib. The clinical syndrome of HF may be
related to the hypertensive response seen in these
patients, but other factors are likely contributory. The
rapid onset after initiation of this drug and the lack
of reversibility in some of these patients make direct
cardiac toxicity potentially a great concern. On the
basis of these findings, patients being treated with
sunitinib should be carefully evaluated and treated
for hypertension before initiation of therapy. Furthermore, given the presence of substantial increases
in blood pressure in these patients, aggressive antihypertensive therapy, preferably with ACE-I, betablockers and/or angiotensin-receptor blockers,27 in
patients who are receiving sunitinib may be necessary at initiation or early in the course of sunitinib
therapy. In addition, our findings underscore the
manufacturer’s recommendation that patients should
be carefully evaluated for signs and symptoms of
heart failure before and while being treated with
sunitinib.6 Biomarker evaluation and echocardiography may be useful when patients report new symptoms on sunitinib therapy that may be attributable
to cardiac dysfunction such as fatigue, dyspnea, or
lower extremity edema. Most importantly, our findings demonstrate the need for careful, prospective
evaluation to clearly elucidate the incidence of congestive heart failure due to sunitinib, which is currently being undertaken at multiple centers. Finally,
the mechanism of sunitinib-associated heart failure
is as yet unknown, and our findings highlight the importance of more detailed preclinical studies to
determine the mechanism of cardiotoxicity associated with sunitinib and to guide the development
of strategies to prevent the development of heart failure resulting from this promising cancer therapeutic.
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