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Patients who have or are at high risk for developing cardiovascular disease and who are taking tyrosine kinase inhibitors for renal cell carcinoma should receive routine cardiovascular event monitoring during the first 4 months of therapy.
Targeted therapies have transformed the treatment of many malignant diseases by inhibiting molecular pathways involved in tumor growth and oncogenesis. Although these therapies can prevent disease progression, toxicities often result. Renal cell carcinoma (RCC) is one of many cancers that responds well to these therapies.
RCC accounts for 2% to 3% of all malignancies in adults worldwide. About 30% of patients with RCC present with metastatic or advanced disease.1 Cytokine therapy was the standard of care until multitargeted tyrosine kinase inhibitors (TKIs) were developed. Over the past 12 years, the US Food and Drug Administration (FDA) has approved 6 TKIs for the treatment of RCC: axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib, and sunitinib. Vascular endothelial growth factor receptor (VEGFR) is one of many tyrosine kinase receptors targeted by these medications. This mechanism prevents angiogenesis and consequently increases the risk for hypertension, bleeding, and clot formation.
Given these risks, many patients were excluded from the initial clinical trials of these medications if they had a history of uncontrolled hypertension, advanced heart failure (HF), or a significant cardiovascular (CV) event within 6 months prior to study enrollment. Many of these studies did not report the incidence of CV events (other than hypertension) that occurred during the early trials.2 The recommended monitoring for TKI therapies is focused mainly on blood pressure. For patients on pazopanib and sunitinib therapy, baseline and periodic electrocardiograms (ECGs) are recommended; echocardiograms are recommended only for patients with a history of cardiac disease.3,4 In patients on sorafenib therapy, ECG is recommended for those at risk for corrected QT (QTc) intervalprolongation.5
According to a meta-analysis of the literature published between 1966 and 2013,many studies reported a CV toxicity risk associated with the TKIs used in RCC treatment.6 However, some studies have found modest, not clinically significant changes in cardiac function in patients with advanced disease. In 2013, Hall and colleagues found 73% of patients they studied experienced some type of CV toxicity, whereas only 33% of patients had CV toxicity when hypertension was excluded.7 Interestingly, Rini and colleagues found that RCC patients receiving sunitinib had better response rates and progression-free survival when they developed hypertension compared with those who did not develop hypertension.8
A review of several studies revealed similar numbers in patients on TKI therapy presenting with symptomatic HF, but Hall and colleagues found that 27% of patients developed asymptomatic left ventricular dysfunction.7,9,10 These results suggest routine monitoring may allow for appropriate preventive interventions. In patients receiving TKI therapy, CV events, including QTc prolongation, left ventricular HF, myocardial infarction (MI), hypertension, pulmonary hypertension, and stroke, were commonly reported by investigators.7,9,10 Currently, there are no studies of the incidence of CV events for the 5 TKIs (axitinib, cabozantinib, pazopanib, sorafenib, sunitinib) in this patient population.
TKI therapy may require cardiac monitoring of all patients, as studies have associated TKIs with CV toxicity in varying degrees. Therefore, the authors set out to determine the incidence of CV events as well as time to first CV event in patients with and without a history of CV disease (CVD) who received a TKI for advanced RCC. More frequent monitoring for CV toxicity may present opportunities for clinical interventions for all patients on TKI therapy—especially for those with HF or other diseases in which the goal of therapy is to prevent disease progression. As TKIs have emerged as the standard treatment option for advanced RCC, many patients will continue therapy until disease progression or intolerable toxicity. Identifying and using appropriate monitoring parameters can lead to preventive interventions that allow patients to benefit from TKI therapy longer. At the US Department of Veterans Affairs (VA) San Diego Healthcare System (VASDHS), patients undergo routine cardiac monitoring at the discretion of the provider.
In this retrospective study, the authors wanted to determine the incidence of CV events in patients with and without a history of CVD who were receiving TKIs for advanced RCC. The authors also wanted to evaluate time to CV event from start of therapy in order to determine how often monitoring may be needed. The outcomes of this study may lead to a change in practice and development of monitoring parameters to ensure appropriate and adequate management of TKI therapy in RCC.
Methods
Each year, the VASDHS oncology team diagnose 5 to 10 patients with RCC who begin TKI therapy. When sorafenib was approved by the FDA in 2005, VASDHS estimated that about 100 of its patients had an RCC diagnosis and would be treated with a TKI between December 2005 and July 2017.
The authors identified VASDHS patients with a diagnosis of advanced RCC who received axitinib, cabozantinib, pazopanib, sorafenib, or sunitinib between December 1, 2005 and July 31, 2017. Patients were included if they had been on therapy for at least 30 days. The VASDHS pharmacy informatics team assisted in extracting a list of patients with an ICD-9 or ICD-10 diagnosis of RCC and using prescription fills for any of the 5 TKIs previously noted. Medical records were reviewed for frequency of prescription fills, age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, TKI treatment duration, previous history of CVD, ethnicity, and smoking status. If documented, the incidence of CV events was reviewed for each patient at 0, 1, 3, 6, and 12 months. Patients who received medications (Appendix) for their CVD were assessed for adherence based on history of prescription refills from their medical records. Adherence was evaluated for the duration that patients were concurrently taking an oral TKI. The institutional review board at VASDHS approved the study design.
All patients included in this study started TKI therapy since the December 2005 FDA approval of sorafenib, the first oral TKI for treatment of RCC. Each new start was recorded as a separate event, regardless of previous oral TKI therapy. Albiges and colleagues found that the approximate median time from starting TKI therapy to complete response was 12.6 months, and the median duration of TKI therapy after complete response was 10.3 months.11 Based on these results, the follow-up period for patients in this study was 2 years after the start of each TKI therapy. For data analysis, patients were stratified by CVD history (yes or no). In addition, composite outcomes were evaluated to identify a potential cumulative increased risk for CV events for patients who had been on multiple TKI therapies.
For this study, CV toxicities were characterized using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03; severity of adverse events (AEs) was graded 1 to 5. CTCAE commonly has been used to assess AEs in oncology clinical trials. The CV AEs selected for this study included QTc prolongation, hypertension, left ventricular dysfunction, stroke, myocardial infarction (MI), and pulmonary arterial hypertension.
Primary outcomes included incidence of CV events and time to first CV event after initiation of TKI therapy. Secondary outcomes included changes in ECG or echocardiogram results at 0, 1, 3, 6, and 12 months. Secondary outcomes at scheduled time points were not readily available for every patient, but any available time points were gathered to aid in identifying an optimal period for cardiac monitoring. In addition, patients with a history of CVD were evaluated for adherence to common first-line therapies for each disease.
A Fischer exact test was used to compare the incidence of CV events in patients with and without a history of CVD (significance level, α = 0.05). A subgroup analysis was used to compare the incidence of CV events in patients who experienced a CV event (significance level, α = 0.05). A Kaplan-Meier survival curve was used to determine time to first CV event. A log-rank test with significance level set at α = 0.05 also was used.
Results
An initial database search identified 134 patients who received TKI therapy at VASDHS between December 1, 2005 and July 31, 2017. According to retrospective chart review, 54 patients met the inclusion criteria for the study (Table 1). 
Patients without a history of CVD (17%) did not experience any CV events while on TKI therapy. Of the patients with a history of CVD, 9 (20%) experienced ≥ 1 CV event. Fifty-five percent of the events experienced were hypertension. One patient experienced QTc prolongation, and 2 patients experienced MI. As already noted, each new start of TKI was recorded as a separate event, regardless of previous TKI therapy. Among patients with a history of CVD, 2 experienced 2 CV events. Overall, 11 CV events occurred among patients who received ≥ 1 TKI, corresponding to an overall incidence of 24% (Table 2). 
Of the 13 patients who were exposed to ≥ 2 TKI therapies, 2 experienced a CV event. Both patients were started on sunitinib and were switched to sorafenib. One of these used sunitinib for 7 months, experienced a partial response and was switched to sorafenib (with a 3-month break between therapies). The second patient was on sunitinib for 24 months, with multiple doses held because of low blood counts and diarrhea. While on sunitinib, this patient experienced a HF exacerbation, determined to be caused by the underlying disease. This event occurred 17 months after sunitinib was started, and therapy was continued for another 7 months. The patient was switched to sorafenib because of poor tolerability and disease progression. While on sorafenib, this patient experienced grade 1 QTc prolongation.
Discussion
Of the available oral TKI therapies for RCC, sunitinib and sorafenib have the most data associated with nonhypertensive CV toxicity.2,7-10,12 Instudies, the percentage of patients who experienced CV toxicity while on sunitinib or sorafenib has ranged widely, from 2.7% to 33.8%; the variance may be attributable to differences in how institutions report CV toxicities.7-9
According to the prescribing information for TKIs, hypertension is frequently reported as an AE for all 5 TKIs, and BP monitoring is recommended.3,4 However, the development of hypertension with these TKIs has been associated with response to therapy.7 With pazopanib, sorafenib, and sunitinib, there is a higher incidence of other AEs: edema, HF, MI, and QTc prolongation. Baseline ECG is recommended for all patients started on pazopanib and sunitinib and for patients with a history of CVD who are started on sorafenib. An ECG is recommended for patients with a history of CVD who are started on pazopanib and sunitinib.
Even with the medication prescribing information recommendations, it is unclear how frequently patients should be monitored. At VASDHS, CV monitoring for any patient started on a TKI remains at the discretion of the oncologist. There are concerns that ordering cardiac monitoring tests, which might be unnecessary, will change or guide therapy. In this study, data evaluation revealed 1 patient who experienced a CV event had a CVD history that was not documented in the patient’s medical history. It is important that providers obtain a detailed clinical assessment of patients CV history during each visit to determine whether CV monitoring should be considered. Patients also may benefit from additional counseling to emphasize the importance of adherence to CV medication therapy to reduce the incidence of these events.
Data from this study indicate that routine CV monitoring should be considered in patients with CVD, in keeping with current medication prescribing information recommendations. Of the patients who had a CV event, 54% experienced hypertension, 18% MI, and 28% stroke, QTc prolongation, or congestive HF. 
Limitations
This retrospective study had several limitations. Many patients did not have a baseline cardiac monitoring test or any monitoring during therapy. Often, a cardiac test was performed only when the patient was symptomatic or experiencing a CV event. In addition, because of intolerance or nonadherence to therapy, many patients discontinued treatment early, before completing 30 days. That axitinib and cabozantinib are newer therapies and not first-line at VASDHS during the data collection period accounts for the small number of patients on these therapies. Therapy was shorter for patients started on pazopanib, axitinib, and cabozantinib than it was for patients on sunitinib and sorafenib. Duration of therapy may affect treatment-related events, but the majority of patients in this study experienced an event within 4 months of therapy. About half of the patients who experienced an event were nonadherent to their CV medication regimen. Another potential limitation is that this study was conducted at VASDHS, where most patients are male (RCC incidence is 2:1 male:female).
Conclusion
In this study, CV events occurred in 24% of patients with a history of CVD; 11% of these events were nonhypertensive. Baseline cardiac monitoring was not performed for most patients started on TKI therapy, but tests were performed once patients became symptomatic. The study results suggest that high-risk patients should undergo routine cardiac monitoring during the first 4 months of TKI therapy, in keeping with medication package insert monitoring recommendations. Cardiac monitoring of high-risk patients will allow for earlier identification of cardiac decline and offer opportunities for interventions, such as pharmacist-driven protocols to start CV medications. Implementation of this study’s recommendations should be evaluated to determine whether outcomes improve with routine cardiac monitoring in these high-risk patients.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, FrontlineMedical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects— before administering pharmacologic therapy to patients.
1. Rini, BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939.
2. Tolcher AW, Appleman LJ, Shapiro GI, et al. A phase I open-label study evaluating the cardiovascular safety of sorafenib in patients with advanced cancer. Cancer Chemother Pharmacol. 2011;67(4):751-764.
3. Votrient [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2017.
4. Sutent [package insert]. New York, NY: Pfizer Labs; 2018.
5. Nexavar [package insert]. Wayne, NJ; Bayer HealthCare Pharmaceuticals Inc; 2018.
6. Ghatalia P, Morgan CJ, Je Y, et al. Congestive heart failure with vascular endothelial growth factor receptor tyrosine kinase inhibitors. Crit Rev Oncol Hematol 2015;94:228–237.
7. Hall PS, Harshman LC, Srinivas S, Witteles RM. The frequency and severity of cardiovascular toxicity from targeted therapy in advanced renal cell carcinoma patients. JACC Heart Fail. 2013;1(1):72-78.
8. Rini BI, Cohen DP, Lu DR, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst. 2011;103(9):763-773.
9. Richards CJ, Je Y, Schutz FA, et al. Incidence and risk of congestive heart failure in patients with renal and nonrenal cell carcinoma treated with sunitinib. J Clin Oncol. 2011;29(25):3450-3456.
10. Schmidinger M, Zielinski CC, Vogl UM, et al. Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2008;26(32):5204-5212.
11. Albiges L, Oudard S, Negrier S, et al. Complete remission with tyrosine kinase inhibitors in renal cell carcinoma. J Clin Oncol. 2012;30(5):482-487.
12. Jang S, Zheng C, Tsai HT, et al. Cardiovascular toxicity after antiangiogenic therapy in persons older than 65 years with advanced renal cell carcinoma. Cancer. 2016;122(1):124-130
13. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520.
14. Yancy CW, Jessup M, Bozkurt B, et al. ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. JACC. 2017;70(6):776-803.
15. Kernan WN, Ovbiagele B, Black HR, et al; American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(7):2160-2236.
16. O’Gara PT, Kushner FG, Ascheim DD, et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. JACC. 2013;61(4):e78-e140.
17. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64(24):e139-e228.
18. Galiè N, Humbert M, Vachiery JL, et al; ESC Scientific Document Group. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-119.
Patients who have or are at high risk for developing cardiovascular disease and who are taking tyrosine kinase inhibitors for renal cell carcinoma should receive routine cardiovascular event monitoring during the first 4 months of therapy.
Patients who have or are at high risk for developing cardiovascular disease and who are taking tyrosine kinase inhibitors for renal cell carcinoma should receive routine cardiovascular event monitoring during the first 4 months of therapy.
Targeted therapies have transformed the treatment of many malignant diseases by inhibiting molecular pathways involved in tumor growth and oncogenesis. Although these therapies can prevent disease progression, toxicities often result. Renal cell carcinoma (RCC) is one of many cancers that responds well to these therapies.
RCC accounts for 2% to 3% of all malignancies in adults worldwide. About 30% of patients with RCC present with metastatic or advanced disease.1 Cytokine therapy was the standard of care until multitargeted tyrosine kinase inhibitors (TKIs) were developed. Over the past 12 years, the US Food and Drug Administration (FDA) has approved 6 TKIs for the treatment of RCC: axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib, and sunitinib. Vascular endothelial growth factor receptor (VEGFR) is one of many tyrosine kinase receptors targeted by these medications. This mechanism prevents angiogenesis and consequently increases the risk for hypertension, bleeding, and clot formation.
Given these risks, many patients were excluded from the initial clinical trials of these medications if they had a history of uncontrolled hypertension, advanced heart failure (HF), or a significant cardiovascular (CV) event within 6 months prior to study enrollment. Many of these studies did not report the incidence of CV events (other than hypertension) that occurred during the early trials.2 The recommended monitoring for TKI therapies is focused mainly on blood pressure. For patients on pazopanib and sunitinib therapy, baseline and periodic electrocardiograms (ECGs) are recommended; echocardiograms are recommended only for patients with a history of cardiac disease.3,4 In patients on sorafenib therapy, ECG is recommended for those at risk for corrected QT (QTc) intervalprolongation.5
According to a meta-analysis of the literature published between 1966 and 2013,many studies reported a CV toxicity risk associated with the TKIs used in RCC treatment.6 However, some studies have found modest, not clinically significant changes in cardiac function in patients with advanced disease. In 2013, Hall and colleagues found 73% of patients they studied experienced some type of CV toxicity, whereas only 33% of patients had CV toxicity when hypertension was excluded.7 Interestingly, Rini and colleagues found that RCC patients receiving sunitinib had better response rates and progression-free survival when they developed hypertension compared with those who did not develop hypertension.8
A review of several studies revealed similar numbers in patients on TKI therapy presenting with symptomatic HF, but Hall and colleagues found that 27% of patients developed asymptomatic left ventricular dysfunction.7,9,10 These results suggest routine monitoring may allow for appropriate preventive interventions. In patients receiving TKI therapy, CV events, including QTc prolongation, left ventricular HF, myocardial infarction (MI), hypertension, pulmonary hypertension, and stroke, were commonly reported by investigators.7,9,10 Currently, there are no studies of the incidence of CV events for the 5 TKIs (axitinib, cabozantinib, pazopanib, sorafenib, sunitinib) in this patient population.
TKI therapy may require cardiac monitoring of all patients, as studies have associated TKIs with CV toxicity in varying degrees. Therefore, the authors set out to determine the incidence of CV events as well as time to first CV event in patients with and without a history of CV disease (CVD) who received a TKI for advanced RCC. More frequent monitoring for CV toxicity may present opportunities for clinical interventions for all patients on TKI therapy—especially for those with HF or other diseases in which the goal of therapy is to prevent disease progression. As TKIs have emerged as the standard treatment option for advanced RCC, many patients will continue therapy until disease progression or intolerable toxicity. Identifying and using appropriate monitoring parameters can lead to preventive interventions that allow patients to benefit from TKI therapy longer. At the US Department of Veterans Affairs (VA) San Diego Healthcare System (VASDHS), patients undergo routine cardiac monitoring at the discretion of the provider.
In this retrospective study, the authors wanted to determine the incidence of CV events in patients with and without a history of CVD who were receiving TKIs for advanced RCC. The authors also wanted to evaluate time to CV event from start of therapy in order to determine how often monitoring may be needed. The outcomes of this study may lead to a change in practice and development of monitoring parameters to ensure appropriate and adequate management of TKI therapy in RCC.
Methods
Each year, the VASDHS oncology team diagnose 5 to 10 patients with RCC who begin TKI therapy. When sorafenib was approved by the FDA in 2005, VASDHS estimated that about 100 of its patients had an RCC diagnosis and would be treated with a TKI between December 2005 and July 2017.
The authors identified VASDHS patients with a diagnosis of advanced RCC who received axitinib, cabozantinib, pazopanib, sorafenib, or sunitinib between December 1, 2005 and July 31, 2017. Patients were included if they had been on therapy for at least 30 days. The VASDHS pharmacy informatics team assisted in extracting a list of patients with an ICD-9 or ICD-10 diagnosis of RCC and using prescription fills for any of the 5 TKIs previously noted. Medical records were reviewed for frequency of prescription fills, age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, TKI treatment duration, previous history of CVD, ethnicity, and smoking status. If documented, the incidence of CV events was reviewed for each patient at 0, 1, 3, 6, and 12 months. Patients who received medications (Appendix) for their CVD were assessed for adherence based on history of prescription refills from their medical records. Adherence was evaluated for the duration that patients were concurrently taking an oral TKI. The institutional review board at VASDHS approved the study design.
All patients included in this study started TKI therapy since the December 2005 FDA approval of sorafenib, the first oral TKI for treatment of RCC. Each new start was recorded as a separate event, regardless of previous oral TKI therapy. Albiges and colleagues found that the approximate median time from starting TKI therapy to complete response was 12.6 months, and the median duration of TKI therapy after complete response was 10.3 months.11 Based on these results, the follow-up period for patients in this study was 2 years after the start of each TKI therapy. For data analysis, patients were stratified by CVD history (yes or no). In addition, composite outcomes were evaluated to identify a potential cumulative increased risk for CV events for patients who had been on multiple TKI therapies.
For this study, CV toxicities were characterized using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03; severity of adverse events (AEs) was graded 1 to 5. CTCAE commonly has been used to assess AEs in oncology clinical trials. The CV AEs selected for this study included QTc prolongation, hypertension, left ventricular dysfunction, stroke, myocardial infarction (MI), and pulmonary arterial hypertension.
Primary outcomes included incidence of CV events and time to first CV event after initiation of TKI therapy. Secondary outcomes included changes in ECG or echocardiogram results at 0, 1, 3, 6, and 12 months. Secondary outcomes at scheduled time points were not readily available for every patient, but any available time points were gathered to aid in identifying an optimal period for cardiac monitoring. In addition, patients with a history of CVD were evaluated for adherence to common first-line therapies for each disease.
A Fischer exact test was used to compare the incidence of CV events in patients with and without a history of CVD (significance level, α = 0.05). A subgroup analysis was used to compare the incidence of CV events in patients who experienced a CV event (significance level, α = 0.05). A Kaplan-Meier survival curve was used to determine time to first CV event. A log-rank test with significance level set at α = 0.05 also was used.
Results
An initial database search identified 134 patients who received TKI therapy at VASDHS between December 1, 2005 and July 31, 2017. According to retrospective chart review, 54 patients met the inclusion criteria for the study (Table 1).
Patients without a history of CVD (17%) did not experience any CV events while on TKI therapy. Of the patients with a history of CVD, 9 (20%) experienced ≥ 1 CV event. Fifty-five percent of the events experienced were hypertension. One patient experienced QTc prolongation, and 2 patients experienced MI. As already noted, each new start of TKI was recorded as a separate event, regardless of previous TKI therapy. Among patients with a history of CVD, 2 experienced 2 CV events. Overall, 11 CV events occurred among patients who received ≥ 1 TKI, corresponding to an overall incidence of 24% (Table 2).
Of the 13 patients who were exposed to ≥ 2 TKI therapies, 2 experienced a CV event. Both patients were started on sunitinib and were switched to sorafenib. One of these used sunitinib for 7 months, experienced a partial response and was switched to sorafenib (with a 3-month break between therapies). The second patient was on sunitinib for 24 months, with multiple doses held because of low blood counts and diarrhea. While on sunitinib, this patient experienced a HF exacerbation, determined to be caused by the underlying disease. This event occurred 17 months after sunitinib was started, and therapy was continued for another 7 months. The patient was switched to sorafenib because of poor tolerability and disease progression. While on sorafenib, this patient experienced grade 1 QTc prolongation.
Discussion
Of the available oral TKI therapies for RCC, sunitinib and sorafenib have the most data associated with nonhypertensive CV toxicity.2,7-10,12 Instudies, the percentage of patients who experienced CV toxicity while on sunitinib or sorafenib has ranged widely, from 2.7% to 33.8%; the variance may be attributable to differences in how institutions report CV toxicities.7-9
According to the prescribing information for TKIs, hypertension is frequently reported as an AE for all 5 TKIs, and BP monitoring is recommended.3,4 However, the development of hypertension with these TKIs has been associated with response to therapy.7 With pazopanib, sorafenib, and sunitinib, there is a higher incidence of other AEs: edema, HF, MI, and QTc prolongation. Baseline ECG is recommended for all patients started on pazopanib and sunitinib and for patients with a history of CVD who are started on sorafenib. An ECG is recommended for patients with a history of CVD who are started on pazopanib and sunitinib.
Even with the medication prescribing information recommendations, it is unclear how frequently patients should be monitored. At VASDHS, CV monitoring for any patient started on a TKI remains at the discretion of the oncologist. There are concerns that ordering cardiac monitoring tests, which might be unnecessary, will change or guide therapy. In this study, data evaluation revealed 1 patient who experienced a CV event had a CVD history that was not documented in the patient’s medical history. It is important that providers obtain a detailed clinical assessment of patients CV history during each visit to determine whether CV monitoring should be considered. Patients also may benefit from additional counseling to emphasize the importance of adherence to CV medication therapy to reduce the incidence of these events.
Data from this study indicate that routine CV monitoring should be considered in patients with CVD, in keeping with current medication prescribing information recommendations. Of the patients who had a CV event, 54% experienced hypertension, 18% MI, and 28% stroke, QTc prolongation, or congestive HF.
Limitations
This retrospective study had several limitations. Many patients did not have a baseline cardiac monitoring test or any monitoring during therapy. Often, a cardiac test was performed only when the patient was symptomatic or experiencing a CV event. In addition, because of intolerance or nonadherence to therapy, many patients discontinued treatment early, before completing 30 days. That axitinib and cabozantinib are newer therapies and not first-line at VASDHS during the data collection period accounts for the small number of patients on these therapies. Therapy was shorter for patients started on pazopanib, axitinib, and cabozantinib than it was for patients on sunitinib and sorafenib. Duration of therapy may affect treatment-related events, but the majority of patients in this study experienced an event within 4 months of therapy. About half of the patients who experienced an event were nonadherent to their CV medication regimen. Another potential limitation is that this study was conducted at VASDHS, where most patients are male (RCC incidence is 2:1 male:female).
Conclusion
In this study, CV events occurred in 24% of patients with a history of CVD; 11% of these events were nonhypertensive. Baseline cardiac monitoring was not performed for most patients started on TKI therapy, but tests were performed once patients became symptomatic. The study results suggest that high-risk patients should undergo routine cardiac monitoring during the first 4 months of TKI therapy, in keeping with medication package insert monitoring recommendations. Cardiac monitoring of high-risk patients will allow for earlier identification of cardiac decline and offer opportunities for interventions, such as pharmacist-driven protocols to start CV medications. Implementation of this study’s recommendations should be evaluated to determine whether outcomes improve with routine cardiac monitoring in these high-risk patients.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, FrontlineMedical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects— before administering pharmacologic therapy to patients.
Targeted therapies have transformed the treatment of many malignant diseases by inhibiting molecular pathways involved in tumor growth and oncogenesis. Although these therapies can prevent disease progression, toxicities often result. Renal cell carcinoma (RCC) is one of many cancers that responds well to these therapies.
RCC accounts for 2% to 3% of all malignancies in adults worldwide. About 30% of patients with RCC present with metastatic or advanced disease.1 Cytokine therapy was the standard of care until multitargeted tyrosine kinase inhibitors (TKIs) were developed. Over the past 12 years, the US Food and Drug Administration (FDA) has approved 6 TKIs for the treatment of RCC: axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib, and sunitinib. Vascular endothelial growth factor receptor (VEGFR) is one of many tyrosine kinase receptors targeted by these medications. This mechanism prevents angiogenesis and consequently increases the risk for hypertension, bleeding, and clot formation.
Given these risks, many patients were excluded from the initial clinical trials of these medications if they had a history of uncontrolled hypertension, advanced heart failure (HF), or a significant cardiovascular (CV) event within 6 months prior to study enrollment. Many of these studies did not report the incidence of CV events (other than hypertension) that occurred during the early trials.2 The recommended monitoring for TKI therapies is focused mainly on blood pressure. For patients on pazopanib and sunitinib therapy, baseline and periodic electrocardiograms (ECGs) are recommended; echocardiograms are recommended only for patients with a history of cardiac disease.3,4 In patients on sorafenib therapy, ECG is recommended for those at risk for corrected QT (QTc) intervalprolongation.5
According to a meta-analysis of the literature published between 1966 and 2013,many studies reported a CV toxicity risk associated with the TKIs used in RCC treatment.6 However, some studies have found modest, not clinically significant changes in cardiac function in patients with advanced disease. In 2013, Hall and colleagues found 73% of patients they studied experienced some type of CV toxicity, whereas only 33% of patients had CV toxicity when hypertension was excluded.7 Interestingly, Rini and colleagues found that RCC patients receiving sunitinib had better response rates and progression-free survival when they developed hypertension compared with those who did not develop hypertension.8
A review of several studies revealed similar numbers in patients on TKI therapy presenting with symptomatic HF, but Hall and colleagues found that 27% of patients developed asymptomatic left ventricular dysfunction.7,9,10 These results suggest routine monitoring may allow for appropriate preventive interventions. In patients receiving TKI therapy, CV events, including QTc prolongation, left ventricular HF, myocardial infarction (MI), hypertension, pulmonary hypertension, and stroke, were commonly reported by investigators.7,9,10 Currently, there are no studies of the incidence of CV events for the 5 TKIs (axitinib, cabozantinib, pazopanib, sorafenib, sunitinib) in this patient population.
TKI therapy may require cardiac monitoring of all patients, as studies have associated TKIs with CV toxicity in varying degrees. Therefore, the authors set out to determine the incidence of CV events as well as time to first CV event in patients with and without a history of CV disease (CVD) who received a TKI for advanced RCC. More frequent monitoring for CV toxicity may present opportunities for clinical interventions for all patients on TKI therapy—especially for those with HF or other diseases in which the goal of therapy is to prevent disease progression. As TKIs have emerged as the standard treatment option for advanced RCC, many patients will continue therapy until disease progression or intolerable toxicity. Identifying and using appropriate monitoring parameters can lead to preventive interventions that allow patients to benefit from TKI therapy longer. At the US Department of Veterans Affairs (VA) San Diego Healthcare System (VASDHS), patients undergo routine cardiac monitoring at the discretion of the provider.
In this retrospective study, the authors wanted to determine the incidence of CV events in patients with and without a history of CVD who were receiving TKIs for advanced RCC. The authors also wanted to evaluate time to CV event from start of therapy in order to determine how often monitoring may be needed. The outcomes of this study may lead to a change in practice and development of monitoring parameters to ensure appropriate and adequate management of TKI therapy in RCC.
Methods
Each year, the VASDHS oncology team diagnose 5 to 10 patients with RCC who begin TKI therapy. When sorafenib was approved by the FDA in 2005, VASDHS estimated that about 100 of its patients had an RCC diagnosis and would be treated with a TKI between December 2005 and July 2017.
The authors identified VASDHS patients with a diagnosis of advanced RCC who received axitinib, cabozantinib, pazopanib, sorafenib, or sunitinib between December 1, 2005 and July 31, 2017. Patients were included if they had been on therapy for at least 30 days. The VASDHS pharmacy informatics team assisted in extracting a list of patients with an ICD-9 or ICD-10 diagnosis of RCC and using prescription fills for any of the 5 TKIs previously noted. Medical records were reviewed for frequency of prescription fills, age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, TKI treatment duration, previous history of CVD, ethnicity, and smoking status. If documented, the incidence of CV events was reviewed for each patient at 0, 1, 3, 6, and 12 months. Patients who received medications (Appendix) for their CVD were assessed for adherence based on history of prescription refills from their medical records. Adherence was evaluated for the duration that patients were concurrently taking an oral TKI. The institutional review board at VASDHS approved the study design.
All patients included in this study started TKI therapy since the December 2005 FDA approval of sorafenib, the first oral TKI for treatment of RCC. Each new start was recorded as a separate event, regardless of previous oral TKI therapy. Albiges and colleagues found that the approximate median time from starting TKI therapy to complete response was 12.6 months, and the median duration of TKI therapy after complete response was 10.3 months.11 Based on these results, the follow-up period for patients in this study was 2 years after the start of each TKI therapy. For data analysis, patients were stratified by CVD history (yes or no). In addition, composite outcomes were evaluated to identify a potential cumulative increased risk for CV events for patients who had been on multiple TKI therapies.
For this study, CV toxicities were characterized using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03; severity of adverse events (AEs) was graded 1 to 5. CTCAE commonly has been used to assess AEs in oncology clinical trials. The CV AEs selected for this study included QTc prolongation, hypertension, left ventricular dysfunction, stroke, myocardial infarction (MI), and pulmonary arterial hypertension.
Primary outcomes included incidence of CV events and time to first CV event after initiation of TKI therapy. Secondary outcomes included changes in ECG or echocardiogram results at 0, 1, 3, 6, and 12 months. Secondary outcomes at scheduled time points were not readily available for every patient, but any available time points were gathered to aid in identifying an optimal period for cardiac monitoring. In addition, patients with a history of CVD were evaluated for adherence to common first-line therapies for each disease.
A Fischer exact test was used to compare the incidence of CV events in patients with and without a history of CVD (significance level, α = 0.05). A subgroup analysis was used to compare the incidence of CV events in patients who experienced a CV event (significance level, α = 0.05). A Kaplan-Meier survival curve was used to determine time to first CV event. A log-rank test with significance level set at α = 0.05 also was used.
Results
An initial database search identified 134 patients who received TKI therapy at VASDHS between December 1, 2005 and July 31, 2017. According to retrospective chart review, 54 patients met the inclusion criteria for the study (Table 1).
Patients without a history of CVD (17%) did not experience any CV events while on TKI therapy. Of the patients with a history of CVD, 9 (20%) experienced ≥ 1 CV event. Fifty-five percent of the events experienced were hypertension. One patient experienced QTc prolongation, and 2 patients experienced MI. As already noted, each new start of TKI was recorded as a separate event, regardless of previous TKI therapy. Among patients with a history of CVD, 2 experienced 2 CV events. Overall, 11 CV events occurred among patients who received ≥ 1 TKI, corresponding to an overall incidence of 24% (Table 2).
Of the 13 patients who were exposed to ≥ 2 TKI therapies, 2 experienced a CV event. Both patients were started on sunitinib and were switched to sorafenib. One of these used sunitinib for 7 months, experienced a partial response and was switched to sorafenib (with a 3-month break between therapies). The second patient was on sunitinib for 24 months, with multiple doses held because of low blood counts and diarrhea. While on sunitinib, this patient experienced a HF exacerbation, determined to be caused by the underlying disease. This event occurred 17 months after sunitinib was started, and therapy was continued for another 7 months. The patient was switched to sorafenib because of poor tolerability and disease progression. While on sorafenib, this patient experienced grade 1 QTc prolongation.
Discussion
Of the available oral TKI therapies for RCC, sunitinib and sorafenib have the most data associated with nonhypertensive CV toxicity.2,7-10,12 Instudies, the percentage of patients who experienced CV toxicity while on sunitinib or sorafenib has ranged widely, from 2.7% to 33.8%; the variance may be attributable to differences in how institutions report CV toxicities.7-9
According to the prescribing information for TKIs, hypertension is frequently reported as an AE for all 5 TKIs, and BP monitoring is recommended.3,4 However, the development of hypertension with these TKIs has been associated with response to therapy.7 With pazopanib, sorafenib, and sunitinib, there is a higher incidence of other AEs: edema, HF, MI, and QTc prolongation. Baseline ECG is recommended for all patients started on pazopanib and sunitinib and for patients with a history of CVD who are started on sorafenib. An ECG is recommended for patients with a history of CVD who are started on pazopanib and sunitinib.
Even with the medication prescribing information recommendations, it is unclear how frequently patients should be monitored. At VASDHS, CV monitoring for any patient started on a TKI remains at the discretion of the oncologist. There are concerns that ordering cardiac monitoring tests, which might be unnecessary, will change or guide therapy. In this study, data evaluation revealed 1 patient who experienced a CV event had a CVD history that was not documented in the patient’s medical history. It is important that providers obtain a detailed clinical assessment of patients CV history during each visit to determine whether CV monitoring should be considered. Patients also may benefit from additional counseling to emphasize the importance of adherence to CV medication therapy to reduce the incidence of these events.
Data from this study indicate that routine CV monitoring should be considered in patients with CVD, in keeping with current medication prescribing information recommendations. Of the patients who had a CV event, 54% experienced hypertension, 18% MI, and 28% stroke, QTc prolongation, or congestive HF.
Limitations
This retrospective study had several limitations. Many patients did not have a baseline cardiac monitoring test or any monitoring during therapy. Often, a cardiac test was performed only when the patient was symptomatic or experiencing a CV event. In addition, because of intolerance or nonadherence to therapy, many patients discontinued treatment early, before completing 30 days. That axitinib and cabozantinib are newer therapies and not first-line at VASDHS during the data collection period accounts for the small number of patients on these therapies. Therapy was shorter for patients started on pazopanib, axitinib, and cabozantinib than it was for patients on sunitinib and sorafenib. Duration of therapy may affect treatment-related events, but the majority of patients in this study experienced an event within 4 months of therapy. About half of the patients who experienced an event were nonadherent to their CV medication regimen. Another potential limitation is that this study was conducted at VASDHS, where most patients are male (RCC incidence is 2:1 male:female).
Conclusion
In this study, CV events occurred in 24% of patients with a history of CVD; 11% of these events were nonhypertensive. Baseline cardiac monitoring was not performed for most patients started on TKI therapy, but tests were performed once patients became symptomatic. The study results suggest that high-risk patients should undergo routine cardiac monitoring during the first 4 months of TKI therapy, in keeping with medication package insert monitoring recommendations. Cardiac monitoring of high-risk patients will allow for earlier identification of cardiac decline and offer opportunities for interventions, such as pharmacist-driven protocols to start CV medications. Implementation of this study’s recommendations should be evaluated to determine whether outcomes improve with routine cardiac monitoring in these high-risk patients.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, FrontlineMedical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects— before administering pharmacologic therapy to patients.
1. Rini, BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939.
2. Tolcher AW, Appleman LJ, Shapiro GI, et al. A phase I open-label study evaluating the cardiovascular safety of sorafenib in patients with advanced cancer. Cancer Chemother Pharmacol. 2011;67(4):751-764.
3. Votrient [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2017.
4. Sutent [package insert]. New York, NY: Pfizer Labs; 2018.
5. Nexavar [package insert]. Wayne, NJ; Bayer HealthCare Pharmaceuticals Inc; 2018.
6. Ghatalia P, Morgan CJ, Je Y, et al. Congestive heart failure with vascular endothelial growth factor receptor tyrosine kinase inhibitors. Crit Rev Oncol Hematol 2015;94:228–237.
7. Hall PS, Harshman LC, Srinivas S, Witteles RM. The frequency and severity of cardiovascular toxicity from targeted therapy in advanced renal cell carcinoma patients. JACC Heart Fail. 2013;1(1):72-78.
8. Rini BI, Cohen DP, Lu DR, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst. 2011;103(9):763-773.
9. Richards CJ, Je Y, Schutz FA, et al. Incidence and risk of congestive heart failure in patients with renal and nonrenal cell carcinoma treated with sunitinib. J Clin Oncol. 2011;29(25):3450-3456.
10. Schmidinger M, Zielinski CC, Vogl UM, et al. Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2008;26(32):5204-5212.
11. Albiges L, Oudard S, Negrier S, et al. Complete remission with tyrosine kinase inhibitors in renal cell carcinoma. J Clin Oncol. 2012;30(5):482-487.
12. Jang S, Zheng C, Tsai HT, et al. Cardiovascular toxicity after antiangiogenic therapy in persons older than 65 years with advanced renal cell carcinoma. Cancer. 2016;122(1):124-130
13. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520.
14. Yancy CW, Jessup M, Bozkurt B, et al. ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. JACC. 2017;70(6):776-803.
15. Kernan WN, Ovbiagele B, Black HR, et al; American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(7):2160-2236.
16. O’Gara PT, Kushner FG, Ascheim DD, et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. JACC. 2013;61(4):e78-e140.
17. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64(24):e139-e228.
18. Galiè N, Humbert M, Vachiery JL, et al; ESC Scientific Document Group. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-119.
1. Rini, BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939.
2. Tolcher AW, Appleman LJ, Shapiro GI, et al. A phase I open-label study evaluating the cardiovascular safety of sorafenib in patients with advanced cancer. Cancer Chemother Pharmacol. 2011;67(4):751-764.
3. Votrient [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2017.
4. Sutent [package insert]. New York, NY: Pfizer Labs; 2018.
5. Nexavar [package insert]. Wayne, NJ; Bayer HealthCare Pharmaceuticals Inc; 2018.
6. Ghatalia P, Morgan CJ, Je Y, et al. Congestive heart failure with vascular endothelial growth factor receptor tyrosine kinase inhibitors. Crit Rev Oncol Hematol 2015;94:228–237.
7. Hall PS, Harshman LC, Srinivas S, Witteles RM. The frequency and severity of cardiovascular toxicity from targeted therapy in advanced renal cell carcinoma patients. JACC Heart Fail. 2013;1(1):72-78.
8. Rini BI, Cohen DP, Lu DR, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst. 2011;103(9):763-773.
9. Richards CJ, Je Y, Schutz FA, et al. Incidence and risk of congestive heart failure in patients with renal and nonrenal cell carcinoma treated with sunitinib. J Clin Oncol. 2011;29(25):3450-3456.
10. Schmidinger M, Zielinski CC, Vogl UM, et al. Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2008;26(32):5204-5212.
11. Albiges L, Oudard S, Negrier S, et al. Complete remission with tyrosine kinase inhibitors in renal cell carcinoma. J Clin Oncol. 2012;30(5):482-487.
12. Jang S, Zheng C, Tsai HT, et al. Cardiovascular toxicity after antiangiogenic therapy in persons older than 65 years with advanced renal cell carcinoma. Cancer. 2016;122(1):124-130
13. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520.
14. Yancy CW, Jessup M, Bozkurt B, et al. ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. JACC. 2017;70(6):776-803.
15. Kernan WN, Ovbiagele B, Black HR, et al; American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(7):2160-2236.
16. O’Gara PT, Kushner FG, Ascheim DD, et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. JACC. 2013;61(4):e78-e140.
17. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64(24):e139-e228.
18. Galiè N, Humbert M, Vachiery JL, et al; ESC Scientific Document Group. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-119.