Manuela Schmidinger M.D., Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Email: email@example.com
Targeted agents have significantly improved outcomes in patients with metastatic renal cell carcinoma, and are changing long-term expectations in these patients. Experience with these agents highlights a distinct safety and tolerability profile, differing from that observed with conventional chemotherapy and radiotherapy. Cardiovascular adverse events have been observed when treating with targeted agents. This is of particular importance for patients with metastatic renal cell carcinoma who are elderly and present with significant comorbidities. A multidisciplinary approach and close collaboration between oncologists and cardiologists is essential for optimal management of cardiovascular adverse events. Strategies for the management of these adverse events include assessment of cardiovascular status at baseline and at regular intervals, patient education, and the use of supportive medication. Effective therapy management allows patients with cardiovascular adverse events to receive and continue targeted therapy with careful monitoring. Implementation of therapy management measures contributes towards maximizing treatment outcomes with targeted agents in patients with metastatic renal cell carcinoma.
RCC, the most common form of kidney cancer, is associated with a 5-year survival rate of just 10–20% with stage IV disease, and a recurrence rate of approximately 40% in patients treated for localized disease.1,2 The majority of RCC cases are of clear-cell histology and this is often associated with mutations of the VHL tumor suppressor gene. Inactivation of VHL impacts on the expression of several genes including VEGF, which is implicated in tumor angiogenesis and growth.3–6
Until recently, the standard of care for systemic treatment for mRCC was cytokine therapy with high-dose interleukin-2 and/or interferon.7–9 Cytokine treatment was associated with substantial toxicity and with efficacy in only a small subset of patients.8 Targeted therapies are now the standard of care for advanced RCC and offer a significantly improved prognosis.7–9 Based on the efficacy observed in clinical studies, six targeted agents are currently approved for first- and second-line treatment of mRCC.7–9 These include TKI, sunitinib, sorafenib and pazopanib; the anti-VEGF antibody, bevacizumab (in combination with interferon-α); and the mTOR kinase inhibitors, temsirolimus and everolimus.10–16
In view of the efficacy achievable with targeted agents, treatment expectations for mRCC are focusing towards long-term outcomes for patients. As such, it is increasingly important to manage the side-effects associated with these treatments in order to maintain patients on therapy for as long as possible.17–19 Experience with targeted agents has highlighted distinctive safety and tolerability profiles, differing from those observed with conventional chemotherapy or immunotherapy. Some important similarities, as well as differences, related in part to their mechanisms of action, have been observed between the targeted agents.
In the present review, we briefly discuss the impact of the mechanisms of action of the targeted agents, primarily the VEGF-targeted inhibitors, on the cardiovascular system. We then discuss the management of cardiovascular toxicities associated with targeted agents, focusing on practical strategies that might be implemented to maintain patients on treatment and maximize clinical benefit.
Mechanism of action and impact on the cardiovascular system
Sunitinib is a multikinase inhibitor, targeting PDGFR-α and -β; VEGFR-1, -2 and -3; stem cell factor receptor (c-KIT); Flt3; CSF-1R and RET.20 Sorafenib targets VEGFR-1, -2 and -3; PDGFR-β, Flt3, c-KIT; and the intracellular serine/threonine kinases c-raf and b-raf;21 whereas pazopanib inhibits VEGFR-1, -2 and -3; PDGFR-α and -β; and c-KIT.22 Bevacizumab is a humanized recombinant monoclonal antibody that targets VEGF.21 Temsirolimus and everolimus are both mTOR inhibitors.21 Axitinib and tivozanib, both currently in late-stage development, are selective inhibitors of VEGFR-1, -2 and -3.23,24
Not all TKI exert the same toxicities on the heart muscle, and differences also exist with regard to the intensity of the AE observed; sunitinib has been associated with CHF and LVEF decline in some patients; for example, while acute coronary syndromes have been reported with sorafenib.25 This might show that, despite targeting common tyrosine kinases or growth factors, the differences in cardiotoxicity profiles between the various targeted agents cannot be attributed solely to mechanisms of action. However, the inhibition of one or more of these receptors appears to impact on cardiovascular function, leading to the occurrence of cardiovascular side-effects. While the underlying mechanisms remain under investigation, several explanations have been proposed.
Cardiomyocytes express PDGFR, and overexpression of these receptors can promote survival.25 In turn, the inhibition of PDGFR might result in the apoptosis of cardiomyocytes and cardiotoxicity.25 Normal RAF1 function includes protecting the heart from pressure overload stress and inhibiting the activity of the proapoptotic kinases, ASK1 and MST-2.25,26 Disruption of RAF1 activity leads to increased cardiomyocyte apoptosis.25 In addition, inhibition of the VEGF receptor might be responsible for the occurrence of hypertension. An increase in vascular resistance, caused by decreased nitric oxide and prostacyclin production, vascular rarefaction and increased arterial stiffness, might result in hypertension in patients treated with targeted agents.27–32
Cardiovascular adverse events associated with targeted agents
The occurrence of cardiovascular AE is of particular importance for mRCC where the majority of patients are aged over 60 years,8 and often present with cardiovascular risk factors and other underlying comorbidities.13 This might lead to dose reductions and discontinuations, thus impacting on the clinical benefit of treatment.18 In mRCC patients in particular, therefore, an oncologist's awareness of the AE profile is essential for formulating the most favorable therapy management strategy in order to maintain patients on treatment at the optimal dose for as long as possible.
Data suggest that the risk for hypertension and other cardiovascular events is dose-related,31,33 as shown in a meta-analysis of randomized controlled trials of bevacizumab in advanced cancers, which documented increased relative risks of both hypertension and proteinuria in patients receiving high-dose (10–15 mg/kg) versus low-dose (2.5–7.5 mg/kg) treatment.29 Interestingly, it has been proposed that the presence of hypertension and other cardiovascular AE observed with targeted agents, particularly with the VEGF inhibitors, might serve as an indicator of clinical efficacy.31,33 A retrospective analysis of data from four efficacy and safety studies of sunitinib in patients with mRCC suggested improved clinical outcomes in patients with sunitinib-associated hypertension, showing its potential as a marker of treatment efficacy.34 A similar correlation between hypertension and treatment outcomes has been suggested with bevacizumab,35 axitinib36 and tivozanib.37
Hypertension is the most commonly reported cardiovascular AE documented with targeted agents.33,38 In a phase III study of sunitinib, all-grade and grade 3/4 hypertension occurred in 30% and 12% of patients treated with sunitinib, respectively,13 whereas in an expanded-access study, the incidence of all-grade hypertension was 22% and grade 3/4 hypertension was 5% among sunitinib recipients.39 Overall, the incidence of grade 3/4 hypertension with targeted agents in clinical studies in mRCC has ranged between 1% and 13%.13,16,39–42 Furthermore, meta-analyses of sorafenib, sunitinib and bevacizumab studies have shown that treatment with these agents is associated with a significantly increased risk of hypertension.29,43,44 However, the incidence of hypertension has not been documented in a substantial proportion of studies of targeted therapies, whereas the reported incidence of all-grade hypertension has varied considerably between studies.33,38
As shown in clinical trials of axitinib,45 the management of hypertension remains important in light of its role as an independent risk factor for both cardiac and renal AE.44 In addition, hypertension might cause or exacerbate other cardiovascular side-effects, such as left ventricular dysfunction, and might also necessitate dose adjustments, thus impacting on clinical benefit.25,44 Therefore, although elevated blood pressure has been proposed to reflect the clinical efficacy of VEGF signal inhibition with targeted treatment,31 control of hypertension is essential to avoid serious cardiac side-effects.
Cardiac dysfunction and other cardiovascular AE
Although less common, other cardiovascular AE observed with targeted treatments include reduced LVEF, CHF, conduction disturbances and changes in the ST-segment or T-wave. A review of treatment-related AE in phase III trials of targeted therapies in mRCC (sunitinib, sorafenib, bevacizumab, everolimus, temsirolimus and pazopanib) reported incidences of all-grade and grade 3–4 LVEF decline of 13% and 3%, respectively, with sunitinib; and 0% and <1%, respectively, with bevacizumab.38 It is of note that no LVEF data were available for sorafenib, everolimus, temsirolimus or pazopanib. A phase I/II study of sunitinib in patients with advanced imatinib-resistant gastrointestinal stromal tumors showed evidence of LVEF <50% (20% of patients), sunitinib-associated New York Heart Association class III–IV heart failure (8%) and non-fatal myocardial infarction (1%).46 The trial investigators reported that cardiovascular AE were manageable with standard medical therapies in most cases, and recommended close monitoring and prompt treatment for hypertension and left ventricular dysfunction. Elevation of cardiac serum markers, such as troponin-T, might also occur and clinical symptoms, such as angina and dyspnoea, or onset of myocardial infarction have been observed in patients treated with anti-VEGF agents.32,42,47,48
Treatment with the VEGFR inhibitors, sunitinib and sorafenib, has been associated with significant increases in the risks of arterial thromboembolic events and hemorrhage. However, no clear guidelines are available at present on treatments or prophylaxis for the management of such complications in this setting. Low-molecular-weight heparins and/or low-dose aspirin might be considered, as in other malignancies; however, clinicians must take into account the potential increased risk for hemorrhage in severely hypertensive patients when selecting these therapies.49,50
Clinical experience has identified key therapy management strategies that can be implemented in practice with targeted agents for advanced RCC, focusing on the three interlinked areas of dosing optimization, treatment duration and side-effect management.18 Management of side-effects with appropriate prophylactic and supportive therapy management measures allows patient well-being to be improved during treatment such that patients are able to remain on treatment at the most optimal dose with few treatment interruptions, discontinuations or dose reductions, and achieve optimal benefit from treatment.18
Management of cardiovascular adverse events
Given the possible variations in the type, onset and severity of cardiovascular AE between targeted agents,51,52 no general recommendation for their management can be made. Instead, management of cardiovascular AE requires a multidisciplinary approach or close collaboration between oncologists and cardiologists, and the risk for cardiovascular complications should be assessed on an individual patient basis.
Sunitinib is known to be associated with cardiotoxicity, and physicians should monitor patients receiving the drug closely, particularly those with pre-existing risk factors or a history of cardiac disease.25 Rates of cardiotoxicities associated with sorafenib appear to be low, but when these toxicities occur they can be severe and potentially life-threatening; studies are ongoing to identify at-risk patient populations.25 Treatment with sunitinib or sorafenib should be interrupted in cases of severe therapy-resistant hypertension.17 Bevacizumab is associated with low-to-moderate rates of arterial thrombosis, hypertension and proteinuria.26 Early detection and management of hypertension and proteinuria are essential to promote the optimal use of this agent; treatment should be suspended in patients with moderate-to-severe proteinuria and discontinued in patients with nephritic syndrome.51 Pazopanib has been associated with hypertension and low incidences of myocardial infarction/ischemia, cerebrovascular accident and transient ischemic attack.16 Patients should be monitored for hypertension and treated with antihypertensive therapy as required; dose reduction should be considered in cases of persistent hypertension with subsequent treatment discontinuation if severe hypertension persists. Baseline and periodic electrocardiography should also be carried out to monitor patients for QT prolongation.53 In clinical trials, hypertension was one of the most frequently-reported AE with axitinib and tivozanib;24,54 hypertension associated with these therapies is generally easily managed with standard antihypertensive treatment.55 Where two antihypertensive agents do not allow sufficient control or where signs of organ damage have occurred, tivozanib treatment should be interrupted or dose reduced.24 Cardiovascular AE have not been reported with temsirolimus and everolimus.26
To avoid cardiac complications, patients with mRCC receiving targeted therapies should be evaluated for cardiovascular risk at baseline. As shown in Figure 1, individual assessments of cardiovascular status, including medical history, assessment of risk factors for cardiac diseases, clinical symptoms, ECG and echocardiography, should be carried out at baseline and after the initial two treatment cycles, followed by repetition of the ECG every 2–3 months. Where baseline evaluations are acceptable, treatment might be initiated. In the event of clinically relevant findings, the cardiologist should initiate further investigations and/or interventions (e.g. thallium stress test or coronary angiography). A discussion regarding treatment initiation, after achieving cardiac optimization, should be held with the oncologist and the cardiologist before proceeding with treatment. The patient should be informed about the early signs and symptoms of cardiovascular AE, so as to know what to look for,18 and any pre-existing hypertension should be stabilized according to standard medical practice.18,19
It should be noted that the treatment algorithm for the management of cardiovascular AE in patients receiving targeted therapies described here and presented in Figure 1 has not been proven in terms of its clinical or cost-effectiveness benefit, but is based on our experience in managing patients in this setting. As a result of the lack of clinical data, specific, evidence-based guidance for hypertension management in the mRCC setting is not available.38
Management of hypertension
Before the initiation of targeted therapy, patients should be assessed for prehypertension, defined as SBP 120–139 mmHg and DBP 80–89 mmHg, a new risk category in the Joint National Committee on Prevention, Detection, Evaluation, and the Treatment of High Blood Pressure (JNC7) classification system.56 Those patients showing prehypertension should receive antihypertensive treatment for 3–7 days before the commencement of targeted therapy.33
During treatment, regular monitoring, patient support and prophylactic management minimize the impact of AE, and allow the continuation of targeted treatment.38
Blood pressure should be monitored on a regular basis during the initial treatment cycles based on clinical assessment of patient risk.18 During the first treatment cycle, weekly blood pressure monitoring is recommended, either in the clinic or at home, with additional assessments every 2 weeks using 24-h ambulatory blood pressure monitoring. Thereafter, blood pressure should be monitored during clinic visits before the start of each subsequent treatment cycle, with additional weekly blood pressure checks either in the clinic or through self-assessment at home. It is advisable to use the same monitoring equipment throughout to avoid any discrepancies between different devices.18 The patient should use a blood pressure protocol where levels are indicated along with the current antihypertensive medication and a description of clinical symptoms. The selection of antihypertensive medication should be based on the general cardiovascular status of the patient, as assessed at baseline, as well as drug interactions and contraindications.38
No clear recommendations for specific antihypertensive therapies in hypertensive patients receiving specific targeted therapies can be made as a result of the lack of controlled studies in this setting. However, there is some evidence supporting the selection of particular antihypertensive drugs in preference to others based on the patient's status, as described by guidelines published by the ESC (Table 1).57,58 In addition, the vasocontrictive activity of the VEGFR inhibitors might favor antihypertensive treatment with vasodilative drugs, such as ACEI, angiotensin II receptor blockers or calcium channel antagonists, in preference to diuretics or beta-blockers.24 Selection should also consider potential advantages of selecting one antihypertensive drug versus another. For example, carvedilol might protect cardiac mitochondria from TKI-induced cardiac toxicity.59 The potential impact of CYP3A4 induction or inhibition on TKI metabolism – such as with sunitinib – should be considered when initiating antihypertensive medication.18 Accordingly, non-dihydropyridine calcium channel blockers, such as verapamil or diltiazem, should be avoided because of CYP3A4 inhibition, particularly for long-term antihypertensive therapy. During treatment, repeating ECG and echocardiography every 2–3 months is also recommended.18
Table 1. Selection of antihypertensive medications based on patient status
Preferred class of drug(s)
Reproduced from Mancia et al.58 with permission from the European Society of Cardiology.
Where appropriate, dose interruption and/or reduction might be sufficient to allow treatment to be continued with careful monitoring if management according to standard medical practice is insufficient. Temporary treatment suspension might also be useful based on the grade of toxicity experienced by the patient. The decision on when and how treatment can be resumed after recovery should be evaluated by both the cardiologist and the oncologist. In some patients, however, it might be appropriate to discontinue treatment altogether. Assessment of LVEF through baseline and periodic evaluation should be used to monitor patients who have experienced cardiac events, such as CHF or myocardial infarction, within 12 months before receiving treatment, or who have a history of coronary artery disease, hypertension, diabetes or vascular disease. Data from studies of sunitinib in mRCC suggest that echocardiography of LVEF should be carried out during every treatment cycle for the first four cycles, and every three cycles subsequently, in patients at high cardiovascular risk receiving targeted therapies, and every three cycles in patients with no cardiovascular history.38 Evaluation of cardiac biomarkers, such as BNP, should also be considered in this setting. Although their utility in predicting cardiotoxicity is not yet established and they should not be used as a substitute for echocardiographic evaluation, an increase in BNP levels should prompt cardiological evaluation.60 However, an increase in plasma BNP or its coreleased prohormone, NT-proBNP, is a frequent occurrence that might not necessarily reflect cardiac damage in terms of overt CHF.
Where LVEF is <50% and has decreased >20% below baseline, dose interruption and/or reduction should be considered. Importantly, a study by Cardinale et al. suggested that early detection of cardiac dysfunction, and treatment initiation with a combination of the ACEI enalapril and the beta-blocker carvedilol might allow complete recovery of LVEF and reduce associated cardiac events in patients treated with anthracyclines.61 As such, prompt treatment of patients with a decrease in LVEF, ideally within 6 months of occurrence of heart failure, might not only allow complete recovery of LVEF and reversal of myocardial injury resulting from treatment with a targeted agent,61 but also ensure that the associated impact on clinical benefit from the current and subsequent treatments is minimized. However, it must be acknowledged that the pathogenesis of anthracycline- and TKI-related LVEF dysfunction might differ, and the efficacy of combination therapy with an ACEI and a beta-blocker in the management of TKI-related LVEF dysfunction has not been proven. Figure 2 and Table 2 summarize the guidelines provided by the ESC for the management of patients with symptomatic heart failure, as well as guidance on selecting treatment based on patient characteristics.62
Table 2. Guidance for the selection of medications based on patient characteristics for the treatment of heart failure and associated symptoms
Management of acute myocardial ischemia and rhythm disturbances
In addition to the measures outlined above, supportive measures should be implemented for the treatment of more infrequently observed cardiovascular complications. Where risk factors for cardiovascular disease are present or where myocardial ischemia is suspected, cardiac enzymes and markers, such as troponins (cTNT) and myocardial muscle creatine kinase (CK-MB), should be monitored. Patients experiencing acute myocardial infarction must be treated with the indicated therapy according to the current and local guidelines, including coronary intervention, anticoagulation and antiplatelet therapy as standardized, or lysis as appropriate. The combination of ACEI, aspirin, beta-blocker and statin should be given as usual in coronary artery syndromes. Cardiac ischemia can result in serious arrhythmia, and patients should be monitored closely. Treatment of cardiac ischemia and rhythm disturbances can include administration of anti-ischemic and anti-arrhythmic medications, such as beta-blockers, to increase blood flow to the heart and promote a regular heart beat. Patients with signs of ischemia or rhythm disturbances should be referred immediately to the cardiologist and treatment initiated. Further investigation with coronary angiography, coronary computed tomography angiography or nuclide stress tests might also be appropriate. Risk factors for the occurrence of arterial thromboembolic events should be assessed and treated appropriately before starting treatment in order to minimize the risk of arterial thromboembolism. Finally, treatment should be discontinued in patients with reduced LVEF and symptoms of CHF.
Agents that target VEGF-mediated angiogenesis are now the therapy of choice for the treatment of mRCC; targeted agents approved in Europe and/or the USA include sunitinib, sorafenib, temsirolimus, everolimus, bevacizumab in combination with IFN-α, and pazopanib; whereas axitinib and tivozanib are in late-stage development. Sunitinib, sorafenib, pazopanib, axitinib and tivozanib all target the VEGF receptor, as well as other tyrosine kinase target; whereas bevacizumab targets the VEGF protein, and both temsirolimus and everolimus are mTOR inhibitors. In comparison with cytokines, the previous standard of care for mRCC, targeted agents have shown significant improvements in progression-free and overall survival in randomized trials, and in the clinical setting. As a result, oncologists' expectations with respect to long-term outcomes have changed substantially, and safety and quality of life have become important considerations when selecting targeted agents for treatment.
Effective therapy management can allow patients with a history of cardiovascular events to receive treatment with targeted agents provided they are monitored carefully in order to minimize the potential impact of AE on clinical benefit. In this context, close collaboration between oncologists and cardiologists remains essential. Long-term studies examining the precise incidence, severity and impact of cardiovascular AE on treatment with targeted agents are required. However, in the short-term, the implementation of practical strategies to maximize clinical benefit remains key for optimal treatment with targeted agents.
Editorial assistance was provided by Minal Kotecha and Caroline Patrick at ACUMED (Tytherington, UK), and funded by Pfizer Inc.
Conflict of interest
Manuela Schmidinger is a consultant for and has received honoraria from Astellas, GSK, Novartis, Pfizer and Roche. Jutta Bergler-Klein has no potential conflicts of interests to declare.