Tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor (VEGFR) have proved to be effective drugs in the treatment of many solid tumors. However, their clinical benefit may come at the cost of cardiovascular toxicity if clinicians are not vigilant and proactive.
During a workshop at the 2021 American College of Cardiology (ACC) conference on Advancing the Cardiovascular Care of the Oncology Patient, Vivek Narayan, MD, MSCE, a genitourinary oncologist, discussed the risks, recognition, and management of the two most common cardiovascular problems related to the use of these agents: hypertension, which develops in up to 80% of patients, and left-ventricular systemic dysfunction, which is seen in up to 15%.1 Dr. Narayan is Assistant Professor of Medicine at the University of Pennsylvania Abramson Cancer Center, Philadelphia.
“VEGFR tyrosine kinase inhibitors are a standard systemic therapy for many patients with advanced clear cell kidney cancer, and they are increasingly being used in combination with immune checkpoint inhibitors. Since prolonged inhibition of VEGF signaling is a fundamental part of treatment, sequential use of these agents remains a standard practice,” explained Dr. Narayan.
It becomes a careful balance between trying to maximize the dose and oncologic outcomes and trying to heed concerns about toxicity and issues related to quality of life….— Vivek Narayan, MD, MSCE
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From an oncologic perspective, the optimal use of these agents depends on maintaining drug exposure and intensity throughout the treatment course. Thus, the aim is to minimize toxicity so patients can derive their full benefits.
VEGFR Tyrosine Kinase Inhibitor–Related Cardiovascular Effects
The clinical presentation of hypertension can be de novo or a worsening of preexisting hypertension, and it can manifest as an acute rise in blood pressure hours or days after initiation of treatment. This is a dose-dependent class effect that can be reversed with treatment holds or discontinuation. A variety of potential mechanisms are hypothesized to contribute to hypertension. Potential on-target effects, for example, include impaired balance between vasoconstrictors and vasodilators and capillary rarefaction, which may lead to increased systemic vascular resistance.
For left-ventricular dysfunction related to the use of tyrosine kinase inhibitors, the clinical presentation is broad, including asymptomatic disease, overt clinical heart failure, and even fulminant cardiogenic shock and death. These manifestations are likely mediated through both on-target and off-target effects, including direct myocardial toxicity amplified by hypertension, issues with mitochondrial dysfunction, inhibition of AMP-activated protein kinase, and effects on the myocardial hypertrophic response.
“The challenge is that accurate reporting of this toxicity has been limited by a lack of prospective data from echocardiograms, varying definitions of left-ventricular dysfunction, and nonspecific symptoms of heart failure that are common in patients with advanced cancer,” commented Dr. Narayan. The suggestion is that the real-world incidence of left-ventricular dysfunction in clinical settings is probably underestimated.
Incidence of Left-Ventricular Dysfunction
A multicenter prospective study led by Dr. Narayan followed 90 patients with advanced kidney cancer starting sunitinib who underwent serial comprehensive echocardiography and testing for cardiovascular biomarkers.2 The risk of left-ventricular dysfunction was found to be approximately 10%, with the majority of these events occurring during the first treatment cycle. All patients appeared to recover to baseline despite continuing on therapy but with the use of concurrent cardiovascular medications.
“Interestingly, about 20% of patients had elevations in cardiovascular biomarkers, but they did not correlate with changes in ejection fraction,” he noted. The findings were similar to those from a retrospective Stanford University study, showing a 10% incidence of left-ventricular ejection fraction decline, with 22% of patients demonstrating elevations in cardiovascular biomarkers.3
Clinical Cost to Patients
One way to quantify the clinical cost to patients is to look at fatal adverse events attributed to tyrosine kinase inhibitors. In a meta-analysis of 10 randomized controlled trials of VEGFR tyrosine kinase inhibitors involving 4,679 patients, the incidence of fatal adverse events related to these agents was 1.5% (many cardiovascular), correlating to a relative risk of 2.2.4 “However, beyond risk of fatal adverse events, other concerns can develop and contribute to this clinical cost,” Dr. Narayan said.
Dr. Narayan continued: “Treatment interruptions, dose reductions, and dose delays can lead to suboptimal dose intensity and ultimately to inferior oncologic outcomes. Like all things in oncologic management, it becomes a careful balance between trying to maximize the dose and oncologic outcomes and trying to heed concerns about toxicity and issues related to quality of life, especially in the palliative-intent setting.”
Management of Hypertension
The National Cancer Institute recommends the following steps in managing hypertension related to VEGFR tyrosine kinase inhibitors:5,6
- Early recognition and prompt initiation or escalation of antihypertensive treatment
- Weekly blood pressure monitoring during the first treatment cycle and every 2 to 3 weeks thereafter; use of home monitoring when feasible
- Consider treatment when blood pressure reaches 140/90 mm Hg
- When treatment is indicated, consider use of multiple agents if necessary; there is no clear evidence of a superior agent(s).
In one study of 228 patients, axitinib was associated with the greatest increase in blood pressure (12.6 mm Hg systolic and 10.3 mm Hg diastolic); calcium channel blockers and potassium-sparing diuretics were associated with the greatest reduction in blood pressure.7 Drug and dose adjustments in antihypertensive medication were required by 88% of patients on antihypertensives at baseline; 66% of patients not on an antihypertensive at baseline were started on one.
Practical Considerations in Managing Hypertension
Dr. Narayan outlined some practical considerations in managing hypertension in this patient population. The first, he said, is the “prognostic” value of hypertension related to tyrosine kinase inhibitors, based on data showing that the development of hypertension correlates with better survival, at least in advanced kidney cancer.
“Of note, antihypertensive treatment does not appear to attenuate the anticancer effects of tyrosine kinase inhibitors,” he added. “So, although it’s encouraging to patients from an oncologic standpoint, the development of hypertension is also a call to action that we need to manage blood pressure, and this will not affect outcomes.”
Antihypertensive treatment does not appear to attenuate the anticancer effects of tyrosine kinase inhibitors.— Vivek Narayan, MD, MSCE
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The second practical consideration is “rebound hypotension,” which may occur with intermittent dosing or when patients abruptly stop or hold tyrosine kinase inhibitors due to nonhypertension toxicities. “This is best exemplified by sunitinib, which in standard dosing is given for 4 weeks on, 2 weeks off. You see a steady rise in both systolic and diastolic blood pressure with this treatment, but blood pressure drops toward normotensive levels during the 2-week drug holiday,” explained Dr. Narayan.
The third consideration is whether the choice of VEGFR tyrosine kinase inhibitors influences blood pressure management. In the study previously noted, axitinib was associated with the greatest change in blood pressure6; however, from a practical standpoint, the choice of agent is often driven by other factors, such as how the drug synergizes with other therapies and potential concerns about nonhypertension toxicity, Dr. Narayan noted.
A fourth consideration is the increasing use of VEGFR tyrosine kinase inhibitors with checkpoint inhibitors, as there is the potential for immune-mediated toxicities, such as the rare but potentially serious myocarditis. It is reassuring to note that in published trials evaluating tyrosine kinase inhibitors alone and with checkpoint inhibitors, the incidence of hypertension does not appear to be increased with combination therapy, he indicated.
Management of Left-Ventricular Dysfunction
The American Society of Echocardiography has made the following recommendations for managing left-ventricular dysfunction related to the use of VEGFR tyrosine kinase inhibitors:
- Perform baseline echocardiography and consider a follow-up echocardiogram at 1 month and every 3 months while the patient is on tyrosine kinase inhibitor therapy.
- Prescribe conventional antihypertension agents for incident left-ventricular dysfunction.
- There is no clear role for prophylactic therapy with angiotensin-converting enzyme inhibitors or beta-blockers for patients starting VEGFR tyrosine kinase inhibitors.
“Note, these comments are just expert recommendations; we are still constrained by the lack of high-level supportive evidence,” according to Dr. Narayan. “The decision to hold or discontinue a tyrosine kinase inhibitor is certainly an individualized one. However, you could consider continuing or rechallenging with tyrosine kinase inhibitors, especially in patients with asymptomatic left-ventricular declines or those receiving concurrent cardiovascular medication. We need to have a low threshold for symptomatic evaluation in this population, given the nonspecific nature of heart failure symptoms in patients with advanced cancer, the fact that this toxicity may be reversible, and the existence of other potential oncology treatment options when VEGFR tyrosine kinase inhibitors are precluded.”
DISCLOSURE: Dr. Narayan has served as a consultant or advisor to AstraZeneca, Janssen Oncology, Merck, Modra Pharmaceuticals, Myovant Sciences, Pfizer/EMD Serono, and Regeneron; has received research funding from Bristol Myers Squibb, GlaxoSmithKline, Merck, and Pfizer; and has been reimbursed for travel, accommodations, or other expenses by Merck.
REFERENCES
1. Fradley M, Narayan V: Tyrosine kinase inhibitors: What are the most significant cardiovascular concerns? 2021 ACC conference on Advancing the Cardiovascular Care of the Oncology Patient. Workshop. Presented February 6, 2021.
2. Narayan V, Keefe S, Haas N, et al: Prospective evaluation of sunitinib-induced cardiotoxicity in patients with metastatic renal cell carcinoma. Clin Cancer Res 23:3601-3609, 2017.
3. Hall PS, Harshman LC, Srinivas S, et al: The frequency and severity of cardiovascular toxicity from targeted therapy in advanced renal cell carcinoma patients. JACC Heart Fail 1:72-78, 2013.
4. Schutz FAB, Je Y, Richards CJ, et al: Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors. J Clin Oncol 30:871-877, 2012.
5. Dobbin SJH, Cameron AC, Petrie MC, et al: Toxicity of cancer therapy: What the cardiologist needs to know about angiogenesis inhibitors. Heart 104:1995-2002, 2018.
6. Maitland ML, Bakris GL, Black HR, et al: Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. J Natl Cancer Inst 102:596-604, 2010.
7. Waliany S, Sainani KL, Park LS, et al: Increase in blood pressure associated with tyrosine kinase inhibitors targeting vascular endothelial growth factor. J Am Coll Cardiol CardioOnc 1:24-36, 2019.
