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Originally published as JCO Early Release 10.1200/JCO.2007.15.6331 on October 6 2008 © 2008 American Society of Clinical Oncology. Cardiac Toxicity of Sunitinib and Sorafenib in Patients With Metastatic Renal Cell Carcinoma
From the Clinical Division of Oncology, Department of Medicine I and Cancer Center and Department of Cardiology, Medical University Vienna, Vienna, Austria Corresponding author: Manuela Schmidinger, MD, Clinical Division of Oncology, Department of Medicine I and Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria; e-mail: manuela.schmidinger{at}meduniwien.ac.at
Purpose Sunitinib and sorafenib are tyrosine kinase inhibitors (TKIs) that have considerable efficacy in metastatic renal cell carcinoma. TKI-associated cardiotoxicity was reported in approximately 10% of the patients. Detailed cardiovascular monitoring during TKI treatment may reveal early signs of myocardial damage. Patients and Methods In this observational, single-center study, all patients intended for TKI treatment were analyzed for coronary artery disease (CAD) risk factors, history or evidence of CAD, hypertension, rhythm disturbances, and heart failure. Monitoring included assessment of symptoms, ECGs, and biochemical markers (ie, creatine kinase-MB, troponin T). Echocardiography was performed at baseline in selected patients and in all patients who experienced a cardiac event. A cardiac event was defined as the occurrence of increased enzymes if normal at baseline, symptomatic arrhythmia that required treatment, new left ventricular dysfunction, or acute coronary syndrome. Results A total of 86 patients were treated with either sunitinib or sorafenib. Among 74 eligible patients, 33.8% experienced a cardiac event, 40.5% had ECG changes, and 18% were symptomatic. Seven patients (9.4%) were seriously compromised and required intermediate care and/or intensive care admission. All patients recovered after cardiovascular management (ie, medication, coronary angiography, pacemaker implantation, heart surgery) and were considered eligible for TKI continuation. Statistically, there was no significant survival difference between patients who experienced a cardiac event and those who did not experience a cardiac event. Conclusion Our observations indicate that cardiac damage from TKI treatment is a largely underestimated phenomenon but is manageable if patients have careful cardiovascular monitoring and cardiac treatment at the first signs of myocardial damage.
Sunitinib and sorafenib are tyrosine kinase inhibitors (TKIs) of growth factor receptors—the most important of which are the vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor (PDGF) receptor, and stem cell factor KIT receptor.1-3 By inhibiting the intracellular kinases RAF and BRAF, sorafenib also affects the RAS-RAF-MEK-ERK signaling pathway.1 Both agents target the Von-Hippel-Lindau hypoxia-inducible (HIF) gene pathway, which leads to inhibition of one or more HIF-induced gene products.4,5 This inhibition significantly affects tumor angiogenesis and/or tumor cell proliferation. Both agents have considerable efficacy in patients with metastatic renal cell carcinoma (mRCC).6-8 A recently published phase III trial reported the superiority of sunitinib compared with interferon-alfa (IFN-  ) in terms of progression-free survival (PFS).7 Thus, sunitinib is presently considered the reference standard first-line treatment for these patients.7 Sorafenib improved PFS in pretreated patients compared with placebo6 and, therefore, is recommended as a second-line treatment option. Both agents have been approved for the treatment of advanced renal cell carcinoma. The most common adverse effects of sunitinib and sorafenib treatment are fatigue, diarrhea, hand-foot syndrome, hypertension, stomatitis, hypothyroidism, and myelotoxicity.6,7,9 Cardiac adverse effects seem to appear far less frequently, although some TKIs have induced cardiotoxicity to a certain degree. Thus, the use of sunitinib resulted in a decline of ejection fraction by 10%,7,10,11 and the use of sorafenib led to cardiac ischemia in 3% of patients.6 Finally, imatinib, which is widely used for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors, had deleterious effects on cardiomyocytes in culture and in vivo.12,13 The precise rate of cardiotoxicity associated with TKIs and its reversibility is unknown. Phase III trials have not pursued cardiac end points, and the identification of cardiac adverse effects was predominantly based on the occurrence of clinical symptoms. However, symptoms for cardiac dysfunction, such as dyspnea, chest pain, and dizziness, may be unreliable indicators in patients who have tumors. It is particularly remarkable in this context that HIF-1–related gene products, which represent targets for both sunitinib and sorafenib, are physiologic mediators of myocardial response to acute or chronic ischemia, myocardial remodelling, peri-infarct vascularization, and vascular permeability.14-16 Moreover, inhibition of VEGF-VEGF receptor signaling was important in poorly controlled hypertension, in that the disruption of this signaling cascade reduced capillary density, contractile dysfunction, fibrosis, and heart failure.17,18 The first aim of this observational study was to investigate clinical and biochemical signs of myocardial damage in a real-world setting (ie, in patients with mRCC who were not included in clinical trials). These patients may either be healthy or have typical age- and lifestyle-related comorbidities, such as coronary artery disease (CAD), hypertension, rhythm disturbances, and heart failure. Second, the reversibility of cardiac adverse effects and the efficacy of classical cardiovascular treatments were studied. Third, the question of continuation of TKI treatment despite the occurrence of cardiac events was analyzed.
Eighty-six consecutive patients referred to our department were included in this analysis. Patients either had progressed on cytokines or other treatment or had no prior treatment. As no clinical trials were available, the choice to use sorafenib or sunitinib was based on the availability of each drug first and, later, on the results of phase III trials.6,7 After elevated cardiac enzymes and changes in ECGs were observed in the first 10 patients, data on cardiotoxicity were assessed prospectively for the rest of the patient population. Sunitinib and sorafenib were administered at a daily dose of 50 mg/d (on a schedule of 4 weeks on/2 weeks off) and 800 mg/d (continuously), respectively. For both drugs, a 25% dose reduction was made at the occurrence of grade 3 toxicity. Staging investigations were performed every 12 weeks. Before treatment started, all patients were analyzed for CAD risk factors, history or evidence of hypertension, CAD, rhythm disturbances, and heart failure. Cardiovascular monitoring included the following assessments.
Biochemical markers for cardiac damage (eg, creatine kinase, creatine-kinase MB, cardiac troponin T) were assessed at baseline, bimonthly, and at the occurrence of clinical symptoms. CK-MB and TNT were considered normal when they were less than 24 units/L (or less than 6% of total CK level) and ECGs were assessed at baseline, once monthly in asymptomatic patients, and immediately at the occurrence of clinical symptoms or elevated serum markers. ECG recordings were made at a paper speed of 25 mm/sec. The QT interval was measured in lead II and was corrected for heart rate by using the Bazett formula.19 Cardiac symptoms were assessed at baseline and twice monthly during the entire treatment period. A cardiac symptom was defined as the occurrence of dyspnea at exertion, typical angina, and dizziness if it was unlikely that these symptoms were related to specific metastatic locations. Blood pressure (BP) measurements were assessed at baseline in the outpatient ward and then three times daily by using self measurements. Uncontrolled hypertension at baseline or during treatment was defined as documented episodes of hypertension despite already initiated antihypertensive medication. Echocardiography was performed at baseline in selected patients, notably in those suspected of having cardiac diseases (ie, patients who had evidence or history of chest pain or dyspnea at exertion, edema, pleural effusions, myocardial infarction, overt heart failure, or rhythm disturbances). In the other patients, echocardiograms were performed only at the occurrence of symptoms or abnormal biochemistry. Left ventricular fraction (LVEF) was defined as normal, slightly reduced, moderately reduced, and severely reduced at an ejection fraction of greater than 56%, less than 56%, less than 40%, and less than 30%, respectively. An informed consent was not required, because cardiac enzymes are part of the routine test battery for serum chemistry at our department and because neither the volume of blood taken nor the frequency of venous punction was different from a general patient population. The same is true for ECG assessments and echocardiography, which both are routinely performed, noninvasive investigations in a department of internal medicine.
Definition of Cardiac Events and Clinical Approach at Occurrence of Cardiac Events
Statistics
Patients Baseline Characteristics and Demographics Between March 2006 and June 2007, a total of 86 patients with mRCC who had a median age of 66 years (range, 46 to 86 years) were treated with either sunitinib, sorafenib, or both by sequential administration (Table 1). Most of the patients (67.4%) had good Eastern Cooperative Oncology Group performance score (ECOG PS; score of 0).
Cardiovascular assessment before the start of treatment revealed a history of CAD, myocardial infarction, heart failure, rhythm disturbances, and uncontrolled hypertension in 9.3%, 5.8%, 7%, 3.5%, and 3.5% of patients, respectively. Assessment of cardiovascular risk factors revealed that the following were most common: hypertension (48.8%), hypercholesterolemia (defined as fasting cholesterol > the upper limit normal; 26.7%), non–insulin-dependent diabetes mellitus (22%), hypertriglyceridemia (defined as fasting triglycerides > the upper limit normal; 12.8%). At the start of treatment, two patients had cardiac symptoms and were diagnosed with therapeutically controlled heart failure class II according to the New York Heart Association (NYHA) functional classification system. All patients had normal CK-MB/TNT levels at baseline. Twelve of 86 patients were lost to follow-up of cardiovascular monitoring for various reasons (which included treatment interruption for unknown reasons before toxicity assessment, noncompliance to treatment, or noncompliance to follow-up visits). Thus, 74 patients were finally eligible for assessment of cardiotoxicity during TKI treatment. Patients who experienced a cardiac event (event patients) and those who did not experience a cardiac event (nonevent patients) were comparable in terms of age, ECOG PS, and history of cardiovascular diseases. Among all variables expected to be associated with an increased risk for cardiac event, only hypercholesterolemia and hypertriglyceridemia were significantly more pronounced in the group of event patients compared with nonevent patients (P = .05 and .022, respectively). Pretreatment with targeted agents (bevacizumab, n = 8; sorafenib, n = 1) was not associated with an increased risk of event.
Event Patients: Clinical and Cardiovascular Findings
Thirteen of 25 event patients had typical clinical symptoms, which included angina, dyspnea, and dizziness. Among these, seven were seriously compromised and required treatment in the intermediate (n = 4) or intensive care (n = 3) units. ECG changes were found in 12 of 25 event patients and included changes in rhythm, conduction disturbances, change in axis, change in QRS amplitude, ST segment depression and elevation, T wave changes, and QT prolongation (Table 3; Figs 1A through 1D).
CK-MB and TNT were elevated above the normal limit in 17 and nine patients, respectively. Echocardiograms at event that were obtained in 22 patients were abnormal in 10 patients; abnormalities included reduced LVEF (n = 9), regional contractile dysfunctions (n = 7), relaxation disturbances greater than grade 1 (n = 1), and pericardial effusion (n = 1). No statistically significant differences were found in terms of patient characteristics, occurrence of events, cardiac symptoms, ECG changes, enzymes, and LVEF decline when patients on sunitinib and sorafenib were compared (Table 4). Noncardiac vascular events were observed in another two patients (event group, n = 1; nonevent group, n = 1): one patient experienced an acute ischemic optical neuropathy, and the other experienced an acute occlusion of the posterior tibial artery.
Symptomatic Event Patients: Cardiovascular Management and Course of TKI Treatment After Event All symptomatic patients (n = 13) interrupted TKI treatment and underwent cardiovascular treatment, depending on clinical findings (Table 2). Cardiovascular management consisted of medical intervention (n = 12), coronary angiography (n = 7), and surgical procedures (device surgery, n = 1; open-heart surgery, n = 1). All angiographies were inconspicuous. On initiation of cardiovascular treatment, all symptomatic patients recovered without additional symptoms; however, three patients had persisting abnormal biochemistry (CK-MB, n = 3; TNT, n = 1) throughout the entire TKI treatment period. All patients were considered eligible for TKI continuation after recovery. In patients who were seriously compromised at event, TKI treatment was reinitiated with permanent cardiovascular inpatient monitoring for 2 weeks. Three patients discontinued treatment after recovery, one patient discontinued with diagnosis of progressive disease shortly after the event, and two discontinued because of noncardiac toxicities. There was no statistically significant survival difference in patients who experienced an event compared with those who did not (Fig 2).
Asymptomatic Event Patients: Cardiovascular Management and Course of TKI Treatment After Event Twelve event patients had no clinical symptoms but had elevated enzymes (CK-MB, n = 11; TNT, n = 2) or elevated enzymes and ECG changes (n = 3). Two patients interrupted treatment. Three of 12 asymptomatic patients had TKI dose reduction after the event, and the others continued with the identical dose. In five of 12 asymptomatic patients, cardiac enzymes dropped to normal ranges when TKI treatment was interrupted because of diarrhea or disease progression. Another patient had normal enzymes only after the dose of low–molecular weight heparin was increased because of immobilization. In three patients, cardiac enzymes returned to normal ranges without treatment interruption or any therapeutic intervention. In two patients, enzymes alternated depending on treatment on and off periods and on the TKI dose. One patient continued to have elevated enzyme levels throughout 15 months of observation.
Non-Event Patients: Clinical and Cardiovascular Findings
This observational study investigated the occurrence of cardiotoxicity in patients with mRCC who were treated with sunitinib or sorafenib. The principal finding was that cardiac events of varying degrees and severity occur with both agents and more often (in this series, in 33.8% of patients) than they are reported in clinical trials.6,7 Some patients were asymptomatic (16.2%) and had biochemical signs and ECG changes only, whereas others (17.6%) had mild to life-threatening clinical symptoms. All symptomatic patients and some asymptomatic patients underwent cardiovascular treatment, recovered, and were considered eligible to resume TKI treatment. The high rate of cardiotoxicity in our analysis is related to our definition of a cardiac event. This definition was based on the intention to detect overt as well as early or minor signs of myocardial damage, which may, however, increase with longer treatment periods. Others have defined a cardiac event as the occurrence of heart failure, edema or conduction disturbances.22 However, these variables often don’t reflect the true situation; for example, in myocardial infarction, nearly half of the patients present with an LVEF within normal limits.23 In the case of ischemia, myocardial damage is well defined,20 and TNT is acknowledged to be the most important biochemical marker for ischemic injury. The nature of myocardial damage from TKI treatment has not been extensively investigated, and the significance of biochemical signs, ECG changes, clinical symptoms, and abnormal echocardiograms in this situation is still unknown. The variability of our findings, which include different ECG changes, variable enzyme patterns, and variable symptoms, also may be explained by the fact that tests were performed at prespecified intervals and not only at the occurrence of clinical symptoms, as is the case with myocardial ischemia. Thus, we might have detected a snapshot of a cardiac event, a subclinical aspect, or an early sign of a pending event. Myocardial damage caused by ongoing TKI treatment may have different underlying pathologic mechanisms than ischemic injuries. Therefore, enzyme patterns, the appearance of clinical symptoms, and the type of ECG change may vary. Moreover, the type of cell death caused by TKI treatment does not appear to follow a pattern, because it is the result of necrosis and apoptosis and depends on the amount of ATP depletion.12 Recently, a hypothesis on the underlying pathologic mechanisms of cardiotoxicity caused by sunitinib and sorafenib was published.24 Sunitinib-induced inhibition of ribosomal S6 kinase may trigger an intracellular signaling cascade that releases the pro apoptotic factor BCL2, an antagonist of cell death, and consequently releases cytochrome c. This could induce the activation of the intrinsic apoptotic pathway and ATP depletion, whereas myocyte loss and ATP depletion would lead to left ventricular dysfunction. In addition, sunitinib mediates inactivation of AMP-activated protein kinase, which is crucial in the response of cells to hypoxia and which may affect the survival of cardiomyocytes. Finally, sunitinib-mediated inactivation of AMP-activated protein kinase could promote hypertrophy through increased activity of the eukaryotic elongation factor-2 and mammalian target of rapamycin.24 Similarly, among the kinases targeted by sorafenib, RAF and BRAF may be relevant for cardiomyocyte survival. Deletion of RAF1 in the heart caused dilation and hypocontractility with increased cardiomyocyte apoptosis and fibrosis.25 Sorafenib-mediated inhibition of RAF1 and BRAF kinase activity may disrupt signaling through the ERK kinase cascade, which plays an important role for myocyte survival during conditions of stress.24 The high rate of cardiac events in our patients also may be related to the high frequency of hypertension. Although hypertension appeared to be therapeutically controlled, patients may have had undocumented episodes of high blood pressure. Permanent TKI-mediated inhibition of VEGF-VEGFR signaling may have been relevant in these patients, because a normal angiogenic response is necessary to maintain an adequate response of cardiomyocytes to pressure load.17,26 If this does not occur, the heart transitions rapidly from compensated hypertrophy to heart failure. An important issue is the reversibility of cardiac events and the effect of a cardiac event on the course of the oncologic treatment. We considered all patients eligible for TKI treatment after recovery, independent of the severity of their event. Whether recovery was achieved through treatment interruption or through cardiovascular management was unclear in some patients. However, there were no more clinically relevant cardiac events in those who resumed TKI treatment in combination with cardiovascular medication. We believe that individualized cardiovascular management is essential for reversibility and additional safety. An a priori initiation of angiotensin-converting enzyme inhibitor treatment may ensure consistently normal blood pressure. In addition, drugs that protect myocyte mitochondria appear important, as mitochondria may be the chief targets for TKIs. However, the importance of the latter has only been demonstrated for imatinib-induced cardiotoxicity.12 In the case of TKI-induced cardiotoxicity, comedication with beta blockers, particularly with carvedilol, appears reasonable. Carvedilol, a β-adrenergic receptor antagonist that has antioxidant properties, has a positive impact on cardiac mitochondria and protects cells against mitochondrial cardiomyopathy.27,28 Similarly, simvastatin is a protector of cardiomyocytes via activation of nitric oxide synthase and mitochondrial ATP-sensitive potassium channels29 and may be considered. Finally, the development of microembolism as an additional cause of cardiac damage cannot be entirely excluded, so concomitant antithrombotic treatment may be reasonable. This is supported by the findings of myocardial necrosis with normal coronary arteries; conduction disturbances, which possibly arise from embolism of the atrioventricular nodal artery; and the occurrence of noncardiac vascular events in two patients. In conclusion, our observations indicate that cardiac damage from TKI treatment may be a largely underestimated phenomenon. Integration of cardiology (ie, a careful cardiovascular monitoring as well as prophylactic cardiovascular treatment) is essential and may allow continuation of aggressive therapy for the underlying cancer. Finally, it is important to point out that cardiotoxicity may mimic oncologic disease progression by causing symptoms such as a decline in ECOG PS, dyspnea, and pleural/pericardial effusion. These symptoms should be put into context with the patient's cardiac status and should not result in the deprivation of oncologic treatment with efficacious drugs. Our findings add evidence to the series of untargeted adverse effects that result from the use of targeted agents in malignant disease and warrant additional investigation in a large patient population.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Manuela Schmidinger, Pfizer Inc, Bayer (C) Stock Ownership: None Honoraria: Manuela Schmidinger, Pfizer Inc, Bayer Research Funding: Manuela Schmidinger, Pfizer Inc; Herwig Schmidinger, Pfizer Inc Expert Testimony: None Other Remuneration: None
Conception and design: Manuela Schmidinger, Herwig Schmidinger Administrative support: Manuela Schmidinger, Christoph C. Zielinski, Ursula M. Vogl, Andja Bojic, Marija Bojic, Marquerite Ruhsam, Herwig Schmidinger Provision of study materials or patients: Manuela Schmidinger, Christoph C. Zielinski, Ursula M. Vogl, Andja Bojic, Marija Bojic, Christoph Schukro, Marquerite Ruhsam, Michael Hejna, Herwig Schmidinger Collection and assembly of data: Manuela Schmidinger, Ursula M. Vogl, Andja Bojic, Marija Bojic, Christoph Schukro, Marquerite Ruhsam, Michael Hejna, Herwig Schmidinger Data analysis and interpretation: Manuela Schmidinger, Herwig Schmidinger Manuscript writing: Manuela Schmidinger Final approval of manuscript: Manuela Schmidinger, Christoph C. Zielinski, Herwig Schmidinger
published online ahead of print at www.jco.org on October 6, 2008. Supported by the Medical University of Vienna, Vienna, Austria. Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Shiojima I, Sato K, Izumiya Y, et al: Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest 115:2108-2118, 2005[CrossRef][Medline] 18. Hubner N, Yagil C, Yagil Y: Novel integrative approaches to the identification of candidate genes in hypertension. Hypertension 47:1-5, 2006 19. Adler FH: Memoir of H.C. Bazett (1885-1950). Trans Stud Coll Physicians Phila 19:121, 1952[Medline] 20. Motzer JR, Bacik J, Murphy BA, et al: Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 20:289-296, 2002 21. Bassand JP, Hamm CW, Ardissino D, et al: Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. Eur Heart J 28:1598-1660, 2007 22. Cardinale D, Sandri MT, Colombo A, et al: Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation 109:2749-2754, 2004 23. Sanderson JE: Heart failure with a normal ejection fraction. Heart 93:155-158, 2007 24. Force T, Krause DS, Van Etten RA: Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 7:332-344, 2007[CrossRef][Medline] 25. Yamaguchi O, Watanabe T, Nishida K, et al: Cardiac-specific disruption of the c-RAF-1 gene induces cardiac dysfunction and apoptosis. J Clin Invest 114:937-943, 2004[CrossRef][Medline] 26. Izumiya Y, Shiojima I, Sato K, et al: Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload. Hypertension 47:887-893, 2006 27. Oliveira PJ, Goncalves L, Monteiro P, et al: Are the antioxidant properties of carvedilol important for the protection of cardiac mitochondria? Curr Vasc Pharmacol 3:147-158, 2005[CrossRef][Medline] 28. Carreira RS, Monteiro P, Gon Alves LM, et al: Carvedilol: Just another beta-blocker or a powerful cardioprotector? Cardiovasc Hematol Disord Drug Targets 6:257-266, 2006[Medline] 29. Jones SP, Teshima Y, Akao M, et al: Simvastatin attenuates oxidant-induced mitochondrial dysfunction in cardiac myocytes. Circ Res 93:697-699, 2003 Submitted December 5, 2007; accepted July 17, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
0.03 ng/mL, respectively. 
2 test was used to compare the variables among groups. Survival was calculated from start of TKI treatment to death on an intention-to-treat basis. Survival time was evaluated by using Kaplan-Meier survival curves. Differences between groups were tested by using the log-rank test. 
