Original Research

Cardiovascular Effects of Tyrosine Kinase Inhibitors in Patients With Advanced Renal Cell Carcinoma at the VA San Diego Healthcare System

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.

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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.


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