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Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate
original article
Annals of Oncology 19: 1613–1618, 2008 doi:10.1093/annonc/mdn168 Published online 23 April 2008
Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate M. L. Telli1, R. M. Witteles2, G. A. Fisher1 & S. Srinivas1* 1
Division of Medical Oncology, Department of Medicine, 2Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, USA
Received 17 January 2008; revised 19 March 2008; accepted 20 March 2008
Background: In the pivotal phase III metastatic renal cell carcinoma trial, updated data indicates that 21% of
introduction Novel targeted cancer therapeutics are rapidly changing the way oncology is being practiced. An unexpected consequence of the use of some of these drugs, however, has been the development of cardiotoxicity as an ‘off-target’ side-effect. The initial signal of cardiotoxicity associated with the use of such agents came from the pivotal phase III trial of the anti-HER2 mAb trastuzumab in the treatment of metastatic HER2-positive breast cancer [1]. More recently, reports are beginning to emerge about the cardiotoxicity of small molecule tyrosine kinase inhibitors including lapatinib [2, 3] and imatinib [4, 5]. It has recently been suggested that a number of additional tyrosine kinase inhibitors are likely to be associated with cardiotoxicity on the basis of their mechanism of action [6]. Sunitinib malate (Sutent, Pfizer, New York, USA) is an oral small molecule tyrosine kinase inhibitor which inhibits multiple receptor tyrosine kinases including vascular endothelial growth factor receptor 1–3, platelet-derived growth factor receptor a and b, c-KIT, FLT3 kinase, colony-stimulating factor 1 receptor and RET kinase [6, 7]. Sunitinib is currently approved in the United States and European Union for the treatment of advanced renal cell carcinoma and the *Correspondence to: Dr S. Srinivas, Department of Medicine, Division of Medical, Oncology, Stanford University 875 Blake Wilbur Drive, Stanford, CA 94305, USA. Tel: +1-650-725-2078; Fax: +1-650-736-1640; E-mail: [email protected]
treatment of gastrointestinal stromal tumors after disease progression on or intolerance to imatinib mesylate [8]. This drug has shown clinical activity in numerous other solid tumors including breast, neuroendocrine, colorectal, thyroid, melanoma and non-small-cell lung cancers in addition to some sarcomas [7]. Studies exploring the efficacy of sunitinib in the adjuvant, neo-adjuvant and advanced/metastatic settings are currently ongoing in 33 different tumor types [9]. The initial publication from the pivotal phase III trial of sunitinib versus interferon alpha in patients with previously untreated metastatic renal cell carcinoma reported that the use of sunitinib was associated with a 10% incidence of decline in left ventricular ejection fraction (LVEF) to below normal [10]. Among sunitinib-treated patients, 2% had a grade 3 decline in LVEF compared with 1% of interferon-treated patients. This cardiac dysfunction was not associated with clinical sequelae and was reversible after discontinuation or dose modification. In February 2007, updated cardiotoxicity data indicated that 21% of patients treated with sunitinib versus 12% of patients treated with interferon alpha experienced a drop in LVEF to below normal [8]. This included 4% of patients treated with sunitinib versus 1% of patients treated with interferon alpha who developed severe drops in LVEF (LVEF decline >20% to an absolute level <50%). According to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0,
ª The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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sunitinib-treated patients experienced a decline in left ventricular ejection fraction to below normal. This cardiotoxicity was reported to be reversible and without clinical sequelae. We conducted a retrospective analysis of our institutional experience of cardiotoxicity with sunitinib after observing a high incidence of symptomatic heart failure. Patients and methods: Patients receiving sunitinib at Stanford University from 1 July 2004 to 1 July 2007 were identified. Medical records were reviewed and those patients experiencing symptomatic grade 3/4 left ventricular systolic dysfunction were identified. Potential cardiac risk factors were analyzed. Results: Forty-eight patients treated with sunitinib were assessable. Seven patients experienced symptomatic grade 3/4 left ventricular dysfunction 22–435 days after initiation of sunitinib. Three patients had persistent cardiac dysfunction after discontinuation of sunitinib and initiation of heart failure therapy. A history of congestive heart failure, coronary artery disease and lower body mass index were factors associated with increased risk. Conclusions: Among patients treated with sunitinib at our institution, 15% developed symptomatic grade 3/4 heart failure. Future studies of sunitinib-related cardiotoxicity are urgently needed, particularly as the oncologic indications for this drug continue to expand. Key words: cardiotoxicity, congestive heart failure, sunitinib, tyrosine kinase inhibitor
original article any drop in LVEF to below normal is indicative of at least grade 1 toxicity for left ventricular systolic dysfunction and any drop to below 50% represents at least grade 2 toxicity for left ventricular systolic dysfunction [11]. The updated prescribing information reports that only 1% of sunitinib-treated patients had left ventricular dysfunction and ‘<1% had congestive heart failure’ [8]. Failure to adhere to the CTCAE nomenclature has lead to a series of ambiguities regarding the exact nature of the cardiotoxicity. In our clinical experience, we observed symptomatic heart failure associated with the use of sunitinib. To further evaluate the incidence of and factors associated with the development of symptomatic heart failure, we carried out a retrospective analysis of our institutional experience with sunitinib.
patients and methods
inclusion in this analysis (Table 1). Sixteen (33%) of these patients were treated on clinical protocol. The mean age of all patients was 61 years (range 32–81), and 81% of the study cohort was male. Most patients (85%) treated with sunitinib had metastatic renal cell carcinoma. Eighty-one percent of patients were treated on the 4-week on/2-week off schedule (50 mg), with the remainder (19%) treated on the continuous daily dosing schedule (37.5 mg). Approximately two-thirds of the study cohort had a history of hypertension that was either preexisting (50%) or which developed during the course of treatment with sunitinib (17%). Few patients had a prior history of coronary artery disease, congestive heart failure/cardiomyopathy or diabetes. The mean BMI was 26.6 (64.6), with normal defined as <25. Thirty-eight percent of the study population was concomitantly receiving an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB); 25% of the patients were concomitantly receiving a beta blocker.
patients experiencing cardiotoxicity We identified seven patients in our cohort who developed symptomatic grade 3/4 left ventricular dysfunction while receiving sunitinib, for an incidence of 15% (95% confidence interval 6.1% to 27.8%) (Table 2). All patients presented with symptomatic heart failure and five patients required Table 1. Patient characteristics (n = 48)
results
Mean age, years (range) Gender Male Female Diagnosis Renal cell carcinoma GIST Cardiac risk factors Hypertension Preexisting On treatment Coronary artery disease CHF/cardiomyopathy Diabetes mellitus Hyperlipidemia Mean body mass index (SD) Prior therapy Anthracycline Imatinib Interferon Sorafenib Medications while on sunitinib ACE inhibitor/ARB Beta blocker Sunitinib dosing schedule 4 weeks on, 2 weeks off Continuous daily dosing
patient characteristics A total of 48 patients treated at our institution with sunitinib from 1 July 2004 to 1 July 2007 met eligibility criteria for
GIST, gastrointestinal stromal tumor; CHF, congestive heart failure; SD, standard deviation; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.
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61 (32–81) 39 (81%) 9 (19%) 41 (85%) 7 (15%) 32 24 8 3 3 4 12 26.6
(67%) (50%) (17%) (6%) (6%) (8%) (25%) (64.6)
1 7 6 8
(2%) (15%) (13%) (17%)
18 (38%) 12 (25%) 39 (81%) 9 (19%)
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Patients treated with sunitinib for renal cell carcinoma or gastrointestinal stromal tumor (GIST) at the Stanford University Comprehensive Cancer Center from 1 July 2004 to 1 July 2007 were identified. Patients treated on clinical protocol with sunitinib for GIST and renal cell carcinoma were identified using the Stanford Cancer Center Clinical Trials Database. Patients treated off clinical protocol with sunitinib for renal cell carcinoma were identified using the Genitourinary Oncology Database. The Stanford University Institutional Review Board approved this retrospective study. For patients treated on clinical protocol, informed consent was obtained in accordance with the Declaration of Helsinki. Patients were included in this analysis if they received all or part of their treatment with sunitinib at our institution and had at least one follow-up visit at Stanford Hospital and Clinics. For patients treated on clinical protocol, follow-up data regarding deaths were reviewed. Patients experiencing symptomatic grade 3/4 left ventricular dysfunction according to the CTCAE, Version 3.0 were identified following a comprehensive review of inpatient and outpatient medical records. In this system, criteria for grade 3 left ventricular systolic dysfunction are fulfilled if the patient experiences symptomatic congestive heart failure responsive to intervention or a decline in LVEF in the range of 20%–39%. Grade 4 left ventricular systolic dysfunction is defined as refractory congestive heart failure or LVEF <20%. Baseline age, medications and body mass index (BMI) were recorded for all patients. The presence or absence of baseline cardiac risk factors including hypertension, coronary artery disease, congestive heart failure/cardiomyopathy, hyperlipidemia and diabetes were also recorded for all patients. Potentially cardiotoxic prior therapies were noted including treatment with anthracyclines, imatinib, interferon alpha and sorafenib. For patients experiencing symptomatic cardiotoxicity, clinical evaluations and laboratory, radiographic and cardiac tests carried out at the time of diagnosis of cardiotoxicity were reviewed in detail. Baseline assessments of LVEF were recorded when available. When LVEF was reported as a range, the average was calculated and recorded. The time course of development of cardiotoxicity was evaluated with a focus on subsequent cardiac function following a diagnosis of symptomatic left ventricular dysfunction. Analyses of factors associated with the development of congestive heart failure were carried out using Fisher’s exact test (dichotomous variables), unpaired t-test (continuous variables) and exact Wilcoxon rank sum test (BMI data).
Annals of Oncology
original article
Annals of Oncology
Table 2. Patients experiencing grade 3/4 left ventricular dysfunction Patient
Gender
Presentation
PMH
Baseline EF
Nadir EF
1
Male
20%
Female
Hypertension; prior doxorubicin (450 mg/m2) Hypertension; prior interferon
63%
2
64%
20%–25%
3
Female
Left atrial myxoma in 2001
Normal, 2001
10%–15%
4
Male
Cardiogenic shock and multiorgan failure 22 days after starting sunitinib Fatigue and dyspnea with minimal exertion requiring hospitalization Fatigue and dyspnea with minimal exertion requiring hospitalization Fatigue and dyspnea on exertion not requiring hospitalization
58%
22%
5
Female
MI 1998; CHF 1999; cardiac arrest 1999; hypertension; hyperlipidemia; prior imatinib Prior imatinib
55%
38%
6
Male
Hypertension; CHF 2007
50%
35%
7
Male
CAD 1992; CHF 1998; aortic regurgitation; hypertension; hyperlipidemia
NA
NA
MI, myocardial infarction; CHF, congestive heart failure; CAD, coronary artery disease; NT-BNP, NT-pro-B-type natriuretic peptide; PMH, past medical history; EF, ejection fraction; NA, not available.
hospitalization. The most common presentation was fatigue and dyspnea with minimal exertion. One patient presented with cardiogenic shock 22 days after initiating sunitinib and required emergent intubation and vasopressor support. This patient had received prior doxorubicin at a dose of 450 mg/m2, but his LVEF was normal at the completion of his treatment with doxorubicin and was 63% at the time he started sunitinib. Three other patients had a history of prior congestive heart failure. One of these had mild heart failure symptoms at the time of initiation of sunitinib (LVEF 50%); the other two had compensated cardiac function and were asymptomatic at the time of initiation of sunitinib. LVEF assessed at the time of diagnosis of cardiotoxicity was <40% for six patients (range 12.5%–38%). One patient presented with severe dyspnea on exertion and did not have a LVEF assessed. He met criteria for Grade 3/4 left ventricular systolic dysfunction on clinical grounds, with profound pulmonary edema on admission chest X-ray and a markedly elevated NT-pro-B-type natriuretic peptide level (>30 000 pg/ml; normal <300 pg/ml). He had a computed tomography scan of the chest carried out that showed improvement in his pulmonary parenchymal disease and a decrease in size of his mediastinal lymphadenopathy, consistent with a positive response to treatment. He was transitioned to comfort care and died during that hospitalization. A second patient also was transitioned to hospice and died without further cardiac evaluation.
temporal trends in cardiac function Five patients had at least one LVEF assessment after being diagnosed with grade 3/4 left ventricular dysfunction at a follow-up of 30–197 days (Figure 1A). Three patients had persistent left ventricular dysfunction after discontinuation of sunitinib and initiation of standard heart failure therapy. One
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A
70% 60%
No HF Meds On HF Meds
50%
Deceased
40%
On HF Meds
30% On HF Meds
20% 1 2 3
10%
4 5 6
0% Baseline LVEF
LVEF at Diagnosis of Cardiotoxicity
Follow-up LVEF
B 0
50
100
150
200
250
300
350
400
450
500
Figure 1. (A) Temporal changes in left ventricular ejection fraction. Data for patient seven not available. LVEF, left ventricular ejection fraction; HF, heart failure; Meds, Medications. (B) Time to diagnosis of cardiotoxicity (days).
patient had recovery of her LVEF to normal after discontinuation of the drug and initiation of heart failure therapy. A second patient had recovery of her LVEF to normal after sunitinib was temporarily held and then dose reduced. The observed cardiotoxicity occurred 22–435 days after the initiation of sunitinib (Figure 1B).
factors associated with risk of cardiotoxicity Mean age of patients experiencing grade 3/4 left ventricular systolic dysfunction was 67 (range 57–81), with the mean age of those not experiencing cardiotoxicity being 60 (P = 0.09;
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Fatigue and dyspnea on exertion not requiring hospitalization Altered mental status, fatigue and dyspnea requiring hospitalization Profound dyspnea on exertion requiring hospitalization. Chest X-ray with pulmonary edema and decreased mediastinal adenopathy. NT-BNP >30 000 pg/ml. Transitioned to comfort care.
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Annals of Oncology
Table 3). A nonsignificant trend was observed with proportionally more women experiencing cardiotoxicity than men (P = 0.11). A prior history of congestive heart failure (P = 0.002) or coronary artery disease (P = 0.05) conferred increased risk. No association was noted with regard to hypertension or concomitant treatment with standard heart failure medications (ACE inhibitors, ARBs or beta blockers). Patients experiencing grade 3/4 left ventricular dysfunction had lower BMIs (mean 23.9) compared with those not experiencing cardiotoxicity (mean 27.1; P = 0.03).
discussion
Table 3. Factors associated with cardiotoxicity
Mean age, years (SD) Gender Male Female Diagnosis Renal cell carcinoma GIST Cardiac risk factors Hypertension Preexisting On treatment Coronary artery disease CHF/Cardiomyopathy Diabetes mellitus Hyperlipidemia Mean body mass index Normal (<25) Overweight/obese (>25) Prior therapy Anthracycline Imatinib Interferon Sorafenib Medications on sunitinib ACE inhibitor/ARB Beta blocker Sunitinib dosing schedule 4 weeks on, 2 weeks off Continuous daily dosing
CHF, n = 7
No CHF, n = 41
P
67 (69.1)
60 (69.8)
0.09
4 3
35 6
0.11
5 2
36 5
0.27
5 4 1 2 3 0 2 23.9 6 1
27 20 7 1 0 4 10 27.1 13 27
1.0
1a 2 1 0
0 5 5 8
0.14 0.27 1.0 0.58
4 2
14 10
0.40 1.00
6 1
33 8
1.0
0.05 0.002 1.0 1.0 0.03 0.01
a Doxorubicin 450 mg/m2. CHF, congestive heart failure; SD, standard deviation; GIST, gastrointestinal stromal tumor; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.
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Little information is known about the cardiotoxicity of the tyrosine kinase inhibitor sunitinib malate. Detailed cardiotoxicity data from the pivotal phase III trial of sunitinib versus interferon alpha in metastatic renal cell carcinoma has not been published. On the basis of the information detailed in the most recent version of the sunitinib prescribing information, it appears that the percentage of patients experiencing a decline in LVEF to less than the lower limit of
normal has increased from 10% in the initial report to 21% with longer follow-up [8]. Here we report seven patients who developed symptomatic grade 3/4 heart failure while taking sunitinib. The incidence of this cardiotoxicity in our cohort of 48 patients was 15%. Taking into account all of caveats of a retrospective analysis on a limited sample of patients, this report raises many questions regarding the cardiotoxicity of sunitinib including the impact of age, gender, dose, comorbid medical problems and other potentially cardiotoxic therapies. While it is not possible to definitively determine causality, all of patients had significant drops in LVEF in close temporal association with the initiation of sunitinib therapy. As a retrospective analysis without planned prospective cardiac monitoring, it is possible that the true incidence of cardiotoxicity was even higher than reported in this analysis. Our study is unique in that most of our patients were treated off clinical protocol and therefore are more representative of the general population of patients currently receiving sunitinib. As such, they represent a heterogeneous group in terms of disease type, treatment schedule and medical comorbidity. The high incidence of symptomatic congestive heart failure in our cohort was likely influenced by patient selection. Patients with uncontrolled hypertension or clinically significant cardiac events or disease in the preceding 12 months were ineligible for participation in the pivotal phase III renal cell carcinoma study. Three of the patients experiencing grade 3/4 left ventricular dysfunction in our study had a prior history of congestive heart failure (one symptomatic in the preceding 12 months) and two had a history of remote known coronary artery disease. In addition, a large proportion of patients in our cohort (67%) had a history of hypertension that was either preexisting or that developed during treatment with sunitinib, though this was not poorly controlled in any of the patients. The baseline cardiac comorbidity alone does not explain all of the discrepancy in our observed high incidence of cardiotoxicity compared with the clinical trials experience, however, since many of our patients experiencing cardiotoxicity would have been eligible for the phase III renal cell carcinoma trial. An important difference between our cohort and those patients treated in the phase III renal cell carcinoma trial exists and relates to the type of cardiac monitoring received. Among our group, only 15% of patients had routine prospective cardiac monitoring carried out as part of a clinical protocol. This is in contrast to the pivotal phase III renal cell carcinoma trial where all patients had prospective cardiac monitoring. As we have seen in the case of trastuzumab in breast cancer, initiation of algorithms to prospectively monitor patients for cardiotoxicity with prespecified guidelines for withholding or discontinuing treatment leads to decreases in the incidence of symptomatic heart failure and increases in the occurrence of asymptomatic left ventricular dysfunction [12]. Indeed, in the pivotal phase III renal cell trial where 21% of patients had declines in ejection fraction to below normal, sunitinib was held or dose reduced in response to these declines in ejection fraction which likely minimized the occurrence of symptomatic heart failure. Most of the patients in our cohort were treated during a time when there was less concern for cardiotoxicity from sunitinib
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Annals of Oncology
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risk:benefit ratio and highlights the critical importance of fully understanding the cardiac risks associated with this drug. Prospective cardiac monitoring using standardized methods of cardiotoxicity classification will be important in furthering our understanding of this problem. Recently, preliminary evidence has suggested that the preemptive use of ACE inhibitors or beta blockers in high-risk patients receiving chemotherapy may prevent cardiotoxicity [15, 16]. Trials investigating the use of ACE inhibitors and/or beta blockers for prevention of cardiotoxicity should be carried out since these strategies may hold promise for at-risk patients. Finally, this report—together with the most recent reports of cardiotoxicity from the sunitinib clinical trials—highlight the need for more rigorous and universal cardiac monitoring and reporting in chemotherapy trials. Until more data are available, we propose that routine monitoring of LVEF is appropriate in patients being treated with sunitinib. Our data indicate that monitoring in the early treatment period may be particularly important as the majority of our patients experienced symptomatic heart failure in the first 3 months of treatment. In the case of significant asymptomatic LVEF declines (>10% decline to below the lower limit of normal), consideration should be given to holding sunitinib until recovery. If an asymptomatic decline in ejection fraction is persistent after a short interval follow-up, treatment with standard heart failure therapy is appropriate. Treatment of asymptomatic left ventricular dysfunction has been given a class I recommendation by the American College of Cardiology and American Heart Association [17]. At the current time, there is a lack of data regarding whether sunitinib should be permanently discontinued or not in patients with asymptomatic declines in ejection fraction. For patients who develop symptomatic cardiac dysfunction, discontinuation of sunitinib and initiation of standard heart failure treatment is appropriate. For patients who develop sunitinib-induced hypertension, consideration should be given to initiating treatment with an ACE-I or beta blocker for blood pressure control, if there are no contraindications as these agents have been shown to favorably alter the progression of left ventricular dysfunction [15, 18, 19]. Future studies of sunitinib-related cardiotoxicity are urgently needed, particularly as the oncologic indications for this drug continue to expand.
funding Pfizer to GAF and SS.
acknowledgements Special thanks to Alex McMillan, PhD, Denise Haas, Ruth Lira and Anna Erispe. Conflict of interest statement: This retrospective study was designed by M.T. in collaboration with colleagues. No industry funding was provided for this study. GAF and SS have received honoraria from Pfizer. Selected for poster presentation and oral press program presentation at the 2008 American Society of Clinical Oncology Genitourinary Cancers Symposium (14–16 February 2008, San Francisco, CA, USA).
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and as such most patients did not have a baseline measurement of ejection fraction performed. It is therefore possible that the two patients without a baseline assessment of ejection fraction who experienced cardiotoxicity in our study may have had unknown asymptomatic left ventricular dysfunction at the time of initiation of sunitinib which could have placed them at increased risk for development of symptomatic heart failure. One additional patient had an ejection fraction at the time of initiation of sunitinib of 50%, which in our institution defines the lower limit of normal. We observed an increased risk of left ventricular dysfunction among patients with a prior history of coronary artery disease and congestive heart failure. This was true even among those patients who had well-compensated cardiac function and a normal ejection fraction at the time of initiation of sunitinib. There was a trend toward increased risk of cardiotoxicity among older patients and women. We also observed that patients with a lower BMI appeared to be at greater risk compared with those who had a higher BMI. The significance of this is not clear. One possibility is that the dose of sunitinib has an impact on the development of cardiotoxicity. Since all patients receive a standard dose of sunitinib not on the basis of weight or body surface area, it is possible that those patients with lower BMI have a higher effective serum level of drug with dose-related pharmacodynamic effects at the level of the cardiomyocyte. This may be related to the potential increased risk among women as women tend to have lower BMIs compared with men. Due on the limitations of sample size in this retrospective study, interpretation of subgroup analyses must be carried out with caution. As such, these associations are considered exploratory and require further prospective evaluation in a larger patient population. Among our patients who developed grade 3/4 left ventricular dysfunction on sunitinib, normalization of LVEF was seen in two patients, one of whom had the drug discontinued and received treatment for heart failure. The other patient had recovery of her LVEF after the medication was temporarily held and then dose reduced, suggesting some degree of reversibility. As we have learned through experience with trastuzumab in breast cancer, cardiac dysfunction initially labeled ‘reversible’ has been shown to be more persistent with longer follow-up [12–14]. Indeed, this follows a well-recognized model in which left ventricular dysfunction is the result of ‘multiple-hits’ in most cases: susceptibility (e.g. hypertension, prior myocardial infarction, prior anthracycline exposure) followed by an acute insult (e.g. sunitinib therapy). The remaining three patients for whom cardiac follow-up was available had persistent left ventricular dysfunction despite discontinuation of the drug and initiation of standard heart failure therapy. Two additional patients died shortly after being diagnosed with cardiotoxicity and did not have further cardiac evaluation. This report along with the reported 21% incidence of subclinical cardiotoxicity observed in the pivotal metastatic renal cell carcinoma trial provides compelling evidence that cardiac dysfunction is an important toxicity of sunitinib. For patients facing an incurable disease with limited treatment options, the risk:benefit ratio will favor treatment in many cases. The potential use of this drug in the adjuvant setting, however, may be associated with a markedly different
original article
Annals of Oncology
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Annals of Oncology 19: 1613–1618, 2008 doi:10.1093/annonc/mdn168 Published online 23 April 2008
Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate M. L. Telli1, R. M. Witteles2, G. A. Fisher1 & S. Srinivas1* 1
Division of Medical Oncology, Department of Medicine, 2Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, USA
Received 17 January 2008; revised 19 March 2008; accepted 20 March 2008
Background: In the pivotal phase III metastatic renal cell carcinoma trial, updated data indicates that 21% of
introduction Novel targeted cancer therapeutics are rapidly changing the way oncology is being practiced. An unexpected consequence of the use of some of these drugs, however, has been the development of cardiotoxicity as an ‘off-target’ side-effect. The initial signal of cardiotoxicity associated with the use of such agents came from the pivotal phase III trial of the anti-HER2 mAb trastuzumab in the treatment of metastatic HER2-positive breast cancer [1]. More recently, reports are beginning to emerge about the cardiotoxicity of small molecule tyrosine kinase inhibitors including lapatinib [2, 3] and imatinib [4, 5]. It has recently been suggested that a number of additional tyrosine kinase inhibitors are likely to be associated with cardiotoxicity on the basis of their mechanism of action [6]. Sunitinib malate (Sutent, Pfizer, New York, USA) is an oral small molecule tyrosine kinase inhibitor which inhibits multiple receptor tyrosine kinases including vascular endothelial growth factor receptor 1–3, platelet-derived growth factor receptor a and b, c-KIT, FLT3 kinase, colony-stimulating factor 1 receptor and RET kinase [6, 7]. Sunitinib is currently approved in the United States and European Union for the treatment of advanced renal cell carcinoma and the *Correspondence to: Dr S. Srinivas, Department of Medicine, Division of Medical, Oncology, Stanford University 875 Blake Wilbur Drive, Stanford, CA 94305, USA. Tel: +1-650-725-2078; Fax: +1-650-736-1640; E-mail: [email protected]
treatment of gastrointestinal stromal tumors after disease progression on or intolerance to imatinib mesylate [8]. This drug has shown clinical activity in numerous other solid tumors including breast, neuroendocrine, colorectal, thyroid, melanoma and non-small-cell lung cancers in addition to some sarcomas [7]. Studies exploring the efficacy of sunitinib in the adjuvant, neo-adjuvant and advanced/metastatic settings are currently ongoing in 33 different tumor types [9]. The initial publication from the pivotal phase III trial of sunitinib versus interferon alpha in patients with previously untreated metastatic renal cell carcinoma reported that the use of sunitinib was associated with a 10% incidence of decline in left ventricular ejection fraction (LVEF) to below normal [10]. Among sunitinib-treated patients, 2% had a grade 3 decline in LVEF compared with 1% of interferon-treated patients. This cardiac dysfunction was not associated with clinical sequelae and was reversible after discontinuation or dose modification. In February 2007, updated cardiotoxicity data indicated that 21% of patients treated with sunitinib versus 12% of patients treated with interferon alpha experienced a drop in LVEF to below normal [8]. This included 4% of patients treated with sunitinib versus 1% of patients treated with interferon alpha who developed severe drops in LVEF (LVEF decline >20% to an absolute level <50%). According to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0,
ª The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
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sunitinib-treated patients experienced a decline in left ventricular ejection fraction to below normal. This cardiotoxicity was reported to be reversible and without clinical sequelae. We conducted a retrospective analysis of our institutional experience of cardiotoxicity with sunitinib after observing a high incidence of symptomatic heart failure. Patients and methods: Patients receiving sunitinib at Stanford University from 1 July 2004 to 1 July 2007 were identified. Medical records were reviewed and those patients experiencing symptomatic grade 3/4 left ventricular systolic dysfunction were identified. Potential cardiac risk factors were analyzed. Results: Forty-eight patients treated with sunitinib were assessable. Seven patients experienced symptomatic grade 3/4 left ventricular dysfunction 22–435 days after initiation of sunitinib. Three patients had persistent cardiac dysfunction after discontinuation of sunitinib and initiation of heart failure therapy. A history of congestive heart failure, coronary artery disease and lower body mass index were factors associated with increased risk. Conclusions: Among patients treated with sunitinib at our institution, 15% developed symptomatic grade 3/4 heart failure. Future studies of sunitinib-related cardiotoxicity are urgently needed, particularly as the oncologic indications for this drug continue to expand. Key words: cardiotoxicity, congestive heart failure, sunitinib, tyrosine kinase inhibitor
original article any drop in LVEF to below normal is indicative of at least grade 1 toxicity for left ventricular systolic dysfunction and any drop to below 50% represents at least grade 2 toxicity for left ventricular systolic dysfunction [11]. The updated prescribing information reports that only 1% of sunitinib-treated patients had left ventricular dysfunction and ‘<1% had congestive heart failure’ [8]. Failure to adhere to the CTCAE nomenclature has lead to a series of ambiguities regarding the exact nature of the cardiotoxicity. In our clinical experience, we observed symptomatic heart failure associated with the use of sunitinib. To further evaluate the incidence of and factors associated with the development of symptomatic heart failure, we carried out a retrospective analysis of our institutional experience with sunitinib.
patients and methods
inclusion in this analysis (Table 1). Sixteen (33%) of these patients were treated on clinical protocol. The mean age of all patients was 61 years (range 32–81), and 81% of the study cohort was male. Most patients (85%) treated with sunitinib had metastatic renal cell carcinoma. Eighty-one percent of patients were treated on the 4-week on/2-week off schedule (50 mg), with the remainder (19%) treated on the continuous daily dosing schedule (37.5 mg). Approximately two-thirds of the study cohort had a history of hypertension that was either preexisting (50%) or which developed during the course of treatment with sunitinib (17%). Few patients had a prior history of coronary artery disease, congestive heart failure/cardiomyopathy or diabetes. The mean BMI was 26.6 (64.6), with normal defined as <25. Thirty-eight percent of the study population was concomitantly receiving an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB); 25% of the patients were concomitantly receiving a beta blocker.
patients experiencing cardiotoxicity We identified seven patients in our cohort who developed symptomatic grade 3/4 left ventricular dysfunction while receiving sunitinib, for an incidence of 15% (95% confidence interval 6.1% to 27.8%) (Table 2). All patients presented with symptomatic heart failure and five patients required Table 1. Patient characteristics (n = 48)
results
Mean age, years (range) Gender Male Female Diagnosis Renal cell carcinoma GIST Cardiac risk factors Hypertension Preexisting On treatment Coronary artery disease CHF/cardiomyopathy Diabetes mellitus Hyperlipidemia Mean body mass index (SD) Prior therapy Anthracycline Imatinib Interferon Sorafenib Medications while on sunitinib ACE inhibitor/ARB Beta blocker Sunitinib dosing schedule 4 weeks on, 2 weeks off Continuous daily dosing
patient characteristics A total of 48 patients treated at our institution with sunitinib from 1 July 2004 to 1 July 2007 met eligibility criteria for
GIST, gastrointestinal stromal tumor; CHF, congestive heart failure; SD, standard deviation; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.
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61 (32–81) 39 (81%) 9 (19%) 41 (85%) 7 (15%) 32 24 8 3 3 4 12 26.6
(67%) (50%) (17%) (6%) (6%) (8%) (25%) (64.6)
1 7 6 8
(2%) (15%) (13%) (17%)
18 (38%) 12 (25%) 39 (81%) 9 (19%)
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Patients treated with sunitinib for renal cell carcinoma or gastrointestinal stromal tumor (GIST) at the Stanford University Comprehensive Cancer Center from 1 July 2004 to 1 July 2007 were identified. Patients treated on clinical protocol with sunitinib for GIST and renal cell carcinoma were identified using the Stanford Cancer Center Clinical Trials Database. Patients treated off clinical protocol with sunitinib for renal cell carcinoma were identified using the Genitourinary Oncology Database. The Stanford University Institutional Review Board approved this retrospective study. For patients treated on clinical protocol, informed consent was obtained in accordance with the Declaration of Helsinki. Patients were included in this analysis if they received all or part of their treatment with sunitinib at our institution and had at least one follow-up visit at Stanford Hospital and Clinics. For patients treated on clinical protocol, follow-up data regarding deaths were reviewed. Patients experiencing symptomatic grade 3/4 left ventricular dysfunction according to the CTCAE, Version 3.0 were identified following a comprehensive review of inpatient and outpatient medical records. In this system, criteria for grade 3 left ventricular systolic dysfunction are fulfilled if the patient experiences symptomatic congestive heart failure responsive to intervention or a decline in LVEF in the range of 20%–39%. Grade 4 left ventricular systolic dysfunction is defined as refractory congestive heart failure or LVEF <20%. Baseline age, medications and body mass index (BMI) were recorded for all patients. The presence or absence of baseline cardiac risk factors including hypertension, coronary artery disease, congestive heart failure/cardiomyopathy, hyperlipidemia and diabetes were also recorded for all patients. Potentially cardiotoxic prior therapies were noted including treatment with anthracyclines, imatinib, interferon alpha and sorafenib. For patients experiencing symptomatic cardiotoxicity, clinical evaluations and laboratory, radiographic and cardiac tests carried out at the time of diagnosis of cardiotoxicity were reviewed in detail. Baseline assessments of LVEF were recorded when available. When LVEF was reported as a range, the average was calculated and recorded. The time course of development of cardiotoxicity was evaluated with a focus on subsequent cardiac function following a diagnosis of symptomatic left ventricular dysfunction. Analyses of factors associated with the development of congestive heart failure were carried out using Fisher’s exact test (dichotomous variables), unpaired t-test (continuous variables) and exact Wilcoxon rank sum test (BMI data).
Annals of Oncology
original article
Annals of Oncology
Table 2. Patients experiencing grade 3/4 left ventricular dysfunction Patient
Gender
Presentation
PMH
Baseline EF
Nadir EF
1
Male
20%
Female
Hypertension; prior doxorubicin (450 mg/m2) Hypertension; prior interferon
63%
2
64%
20%–25%
3
Female
Left atrial myxoma in 2001
Normal, 2001
10%–15%
4
Male
Cardiogenic shock and multiorgan failure 22 days after starting sunitinib Fatigue and dyspnea with minimal exertion requiring hospitalization Fatigue and dyspnea with minimal exertion requiring hospitalization Fatigue and dyspnea on exertion not requiring hospitalization
58%
22%
5
Female
MI 1998; CHF 1999; cardiac arrest 1999; hypertension; hyperlipidemia; prior imatinib Prior imatinib
55%
38%
6
Male
Hypertension; CHF 2007
50%
35%
7
Male
CAD 1992; CHF 1998; aortic regurgitation; hypertension; hyperlipidemia
NA
NA
MI, myocardial infarction; CHF, congestive heart failure; CAD, coronary artery disease; NT-BNP, NT-pro-B-type natriuretic peptide; PMH, past medical history; EF, ejection fraction; NA, not available.
hospitalization. The most common presentation was fatigue and dyspnea with minimal exertion. One patient presented with cardiogenic shock 22 days after initiating sunitinib and required emergent intubation and vasopressor support. This patient had received prior doxorubicin at a dose of 450 mg/m2, but his LVEF was normal at the completion of his treatment with doxorubicin and was 63% at the time he started sunitinib. Three other patients had a history of prior congestive heart failure. One of these had mild heart failure symptoms at the time of initiation of sunitinib (LVEF 50%); the other two had compensated cardiac function and were asymptomatic at the time of initiation of sunitinib. LVEF assessed at the time of diagnosis of cardiotoxicity was <40% for six patients (range 12.5%–38%). One patient presented with severe dyspnea on exertion and did not have a LVEF assessed. He met criteria for Grade 3/4 left ventricular systolic dysfunction on clinical grounds, with profound pulmonary edema on admission chest X-ray and a markedly elevated NT-pro-B-type natriuretic peptide level (>30 000 pg/ml; normal <300 pg/ml). He had a computed tomography scan of the chest carried out that showed improvement in his pulmonary parenchymal disease and a decrease in size of his mediastinal lymphadenopathy, consistent with a positive response to treatment. He was transitioned to comfort care and died during that hospitalization. A second patient also was transitioned to hospice and died without further cardiac evaluation.
temporal trends in cardiac function Five patients had at least one LVEF assessment after being diagnosed with grade 3/4 left ventricular dysfunction at a follow-up of 30–197 days (Figure 1A). Three patients had persistent left ventricular dysfunction after discontinuation of sunitinib and initiation of standard heart failure therapy. One
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A
70% 60%
No HF Meds On HF Meds
50%
Deceased
40%
On HF Meds
30% On HF Meds
20% 1 2 3
10%
4 5 6
0% Baseline LVEF
LVEF at Diagnosis of Cardiotoxicity
Follow-up LVEF
B 0
50
100
150
200
250
300
350
400
450
500
Figure 1. (A) Temporal changes in left ventricular ejection fraction. Data for patient seven not available. LVEF, left ventricular ejection fraction; HF, heart failure; Meds, Medications. (B) Time to diagnosis of cardiotoxicity (days).
patient had recovery of her LVEF to normal after discontinuation of the drug and initiation of heart failure therapy. A second patient had recovery of her LVEF to normal after sunitinib was temporarily held and then dose reduced. The observed cardiotoxicity occurred 22–435 days after the initiation of sunitinib (Figure 1B).
factors associated with risk of cardiotoxicity Mean age of patients experiencing grade 3/4 left ventricular systolic dysfunction was 67 (range 57–81), with the mean age of those not experiencing cardiotoxicity being 60 (P = 0.09;
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Fatigue and dyspnea on exertion not requiring hospitalization Altered mental status, fatigue and dyspnea requiring hospitalization Profound dyspnea on exertion requiring hospitalization. Chest X-ray with pulmonary edema and decreased mediastinal adenopathy. NT-BNP >30 000 pg/ml. Transitioned to comfort care.
original article
Annals of Oncology
Table 3). A nonsignificant trend was observed with proportionally more women experiencing cardiotoxicity than men (P = 0.11). A prior history of congestive heart failure (P = 0.002) or coronary artery disease (P = 0.05) conferred increased risk. No association was noted with regard to hypertension or concomitant treatment with standard heart failure medications (ACE inhibitors, ARBs or beta blockers). Patients experiencing grade 3/4 left ventricular dysfunction had lower BMIs (mean 23.9) compared with those not experiencing cardiotoxicity (mean 27.1; P = 0.03).
discussion
Table 3. Factors associated with cardiotoxicity
Mean age, years (SD) Gender Male Female Diagnosis Renal cell carcinoma GIST Cardiac risk factors Hypertension Preexisting On treatment Coronary artery disease CHF/Cardiomyopathy Diabetes mellitus Hyperlipidemia Mean body mass index Normal (<25) Overweight/obese (>25) Prior therapy Anthracycline Imatinib Interferon Sorafenib Medications on sunitinib ACE inhibitor/ARB Beta blocker Sunitinib dosing schedule 4 weeks on, 2 weeks off Continuous daily dosing
CHF, n = 7
No CHF, n = 41
P
67 (69.1)
60 (69.8)
0.09
4 3
35 6
0.11
5 2
36 5
0.27
5 4 1 2 3 0 2 23.9 6 1
27 20 7 1 0 4 10 27.1 13 27
1.0
1a 2 1 0
0 5 5 8
0.14 0.27 1.0 0.58
4 2
14 10
0.40 1.00
6 1
33 8
1.0
0.05 0.002 1.0 1.0 0.03 0.01
a Doxorubicin 450 mg/m2. CHF, congestive heart failure; SD, standard deviation; GIST, gastrointestinal stromal tumor; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.
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Little information is known about the cardiotoxicity of the tyrosine kinase inhibitor sunitinib malate. Detailed cardiotoxicity data from the pivotal phase III trial of sunitinib versus interferon alpha in metastatic renal cell carcinoma has not been published. On the basis of the information detailed in the most recent version of the sunitinib prescribing information, it appears that the percentage of patients experiencing a decline in LVEF to less than the lower limit of
normal has increased from 10% in the initial report to 21% with longer follow-up [8]. Here we report seven patients who developed symptomatic grade 3/4 heart failure while taking sunitinib. The incidence of this cardiotoxicity in our cohort of 48 patients was 15%. Taking into account all of caveats of a retrospective analysis on a limited sample of patients, this report raises many questions regarding the cardiotoxicity of sunitinib including the impact of age, gender, dose, comorbid medical problems and other potentially cardiotoxic therapies. While it is not possible to definitively determine causality, all of patients had significant drops in LVEF in close temporal association with the initiation of sunitinib therapy. As a retrospective analysis without planned prospective cardiac monitoring, it is possible that the true incidence of cardiotoxicity was even higher than reported in this analysis. Our study is unique in that most of our patients were treated off clinical protocol and therefore are more representative of the general population of patients currently receiving sunitinib. As such, they represent a heterogeneous group in terms of disease type, treatment schedule and medical comorbidity. The high incidence of symptomatic congestive heart failure in our cohort was likely influenced by patient selection. Patients with uncontrolled hypertension or clinically significant cardiac events or disease in the preceding 12 months were ineligible for participation in the pivotal phase III renal cell carcinoma study. Three of the patients experiencing grade 3/4 left ventricular dysfunction in our study had a prior history of congestive heart failure (one symptomatic in the preceding 12 months) and two had a history of remote known coronary artery disease. In addition, a large proportion of patients in our cohort (67%) had a history of hypertension that was either preexisting or that developed during treatment with sunitinib, though this was not poorly controlled in any of the patients. The baseline cardiac comorbidity alone does not explain all of the discrepancy in our observed high incidence of cardiotoxicity compared with the clinical trials experience, however, since many of our patients experiencing cardiotoxicity would have been eligible for the phase III renal cell carcinoma trial. An important difference between our cohort and those patients treated in the phase III renal cell carcinoma trial exists and relates to the type of cardiac monitoring received. Among our group, only 15% of patients had routine prospective cardiac monitoring carried out as part of a clinical protocol. This is in contrast to the pivotal phase III renal cell carcinoma trial where all patients had prospective cardiac monitoring. As we have seen in the case of trastuzumab in breast cancer, initiation of algorithms to prospectively monitor patients for cardiotoxicity with prespecified guidelines for withholding or discontinuing treatment leads to decreases in the incidence of symptomatic heart failure and increases in the occurrence of asymptomatic left ventricular dysfunction [12]. Indeed, in the pivotal phase III renal cell trial where 21% of patients had declines in ejection fraction to below normal, sunitinib was held or dose reduced in response to these declines in ejection fraction which likely minimized the occurrence of symptomatic heart failure. Most of the patients in our cohort were treated during a time when there was less concern for cardiotoxicity from sunitinib
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risk:benefit ratio and highlights the critical importance of fully understanding the cardiac risks associated with this drug. Prospective cardiac monitoring using standardized methods of cardiotoxicity classification will be important in furthering our understanding of this problem. Recently, preliminary evidence has suggested that the preemptive use of ACE inhibitors or beta blockers in high-risk patients receiving chemotherapy may prevent cardiotoxicity [15, 16]. Trials investigating the use of ACE inhibitors and/or beta blockers for prevention of cardiotoxicity should be carried out since these strategies may hold promise for at-risk patients. Finally, this report—together with the most recent reports of cardiotoxicity from the sunitinib clinical trials—highlight the need for more rigorous and universal cardiac monitoring and reporting in chemotherapy trials. Until more data are available, we propose that routine monitoring of LVEF is appropriate in patients being treated with sunitinib. Our data indicate that monitoring in the early treatment period may be particularly important as the majority of our patients experienced symptomatic heart failure in the first 3 months of treatment. In the case of significant asymptomatic LVEF declines (>10% decline to below the lower limit of normal), consideration should be given to holding sunitinib until recovery. If an asymptomatic decline in ejection fraction is persistent after a short interval follow-up, treatment with standard heart failure therapy is appropriate. Treatment of asymptomatic left ventricular dysfunction has been given a class I recommendation by the American College of Cardiology and American Heart Association [17]. At the current time, there is a lack of data regarding whether sunitinib should be permanently discontinued or not in patients with asymptomatic declines in ejection fraction. For patients who develop symptomatic cardiac dysfunction, discontinuation of sunitinib and initiation of standard heart failure treatment is appropriate. For patients who develop sunitinib-induced hypertension, consideration should be given to initiating treatment with an ACE-I or beta blocker for blood pressure control, if there are no contraindications as these agents have been shown to favorably alter the progression of left ventricular dysfunction [15, 18, 19]. Future studies of sunitinib-related cardiotoxicity are urgently needed, particularly as the oncologic indications for this drug continue to expand.
funding Pfizer to GAF and SS.
acknowledgements Special thanks to Alex McMillan, PhD, Denise Haas, Ruth Lira and Anna Erispe. Conflict of interest statement: This retrospective study was designed by M.T. in collaboration with colleagues. No industry funding was provided for this study. GAF and SS have received honoraria from Pfizer. Selected for poster presentation and oral press program presentation at the 2008 American Society of Clinical Oncology Genitourinary Cancers Symposium (14–16 February 2008, San Francisco, CA, USA).
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and as such most patients did not have a baseline measurement of ejection fraction performed. It is therefore possible that the two patients without a baseline assessment of ejection fraction who experienced cardiotoxicity in our study may have had unknown asymptomatic left ventricular dysfunction at the time of initiation of sunitinib which could have placed them at increased risk for development of symptomatic heart failure. One additional patient had an ejection fraction at the time of initiation of sunitinib of 50%, which in our institution defines the lower limit of normal. We observed an increased risk of left ventricular dysfunction among patients with a prior history of coronary artery disease and congestive heart failure. This was true even among those patients who had well-compensated cardiac function and a normal ejection fraction at the time of initiation of sunitinib. There was a trend toward increased risk of cardiotoxicity among older patients and women. We also observed that patients with a lower BMI appeared to be at greater risk compared with those who had a higher BMI. The significance of this is not clear. One possibility is that the dose of sunitinib has an impact on the development of cardiotoxicity. Since all patients receive a standard dose of sunitinib not on the basis of weight or body surface area, it is possible that those patients with lower BMI have a higher effective serum level of drug with dose-related pharmacodynamic effects at the level of the cardiomyocyte. This may be related to the potential increased risk among women as women tend to have lower BMIs compared with men. Due on the limitations of sample size in this retrospective study, interpretation of subgroup analyses must be carried out with caution. As such, these associations are considered exploratory and require further prospective evaluation in a larger patient population. Among our patients who developed grade 3/4 left ventricular dysfunction on sunitinib, normalization of LVEF was seen in two patients, one of whom had the drug discontinued and received treatment for heart failure. The other patient had recovery of her LVEF after the medication was temporarily held and then dose reduced, suggesting some degree of reversibility. As we have learned through experience with trastuzumab in breast cancer, cardiac dysfunction initially labeled ‘reversible’ has been shown to be more persistent with longer follow-up [12–14]. Indeed, this follows a well-recognized model in which left ventricular dysfunction is the result of ‘multiple-hits’ in most cases: susceptibility (e.g. hypertension, prior myocardial infarction, prior anthracycline exposure) followed by an acute insult (e.g. sunitinib therapy). The remaining three patients for whom cardiac follow-up was available had persistent left ventricular dysfunction despite discontinuation of the drug and initiation of standard heart failure therapy. Two additional patients died shortly after being diagnosed with cardiotoxicity and did not have further cardiac evaluation. This report along with the reported 21% incidence of subclinical cardiotoxicity observed in the pivotal metastatic renal cell carcinoma trial provides compelling evidence that cardiac dysfunction is an important toxicity of sunitinib. For patients facing an incurable disease with limited treatment options, the risk:benefit ratio will favor treatment in many cases. The potential use of this drug in the adjuvant setting, however, may be associated with a markedly different
original article
Annals of Oncology
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