May 19, 2020
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Managing CV toxicities of targeted antiangiogenesis therapies

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Clinical outcomes for patients with malignancies have improved in the past decade, in part due to the emergence of VEGF inhibitors, which are anticancer drugs that are commonly used to treat patients diagnosed with metastatic malignancies who have limited treatment options. However, clinicians must be aware that these agents present risk for cardiotoxicities.

The efficacy of these agents is due to their ability to suppress tumor growth by inhibiting VEGF, a proangiogenic growth factor that is overexpressed in a wide range of solid tumors. Given that angiogenesis is essential for tumor growth and survival, it is no surprise that VEGF inhibitors have been an integral addition to the treatment of several cancers.

Sally Arif
Niree Kalfayan

The introduction of VEGF inhibitor therapy has also transformed outcomes for patients with neovascular age-related macular degeneration (AMD), which occurs in 15 of 1,000 adults older than 75 years. The dosage for intravitreal injection of these agents is significantly less than doses used in oncology, but can still result in detectable serum drug concentrations. The extent of VEGF inhibition these agents provide could potentially lead to systemic CV adverse events common to VEGF inhibitors such as proteinuria and hypertension.

Risk for cardiotoxicities

Despite being commonly used to treat various cancers successfully, inhibition of VEGF can also have negative effects on the CV system. Angiogenesis plays a critical role in cardiac repair after CV events such as MI. Inhibiting angiogenesis impairs the body’s ability to recover or compensate after a cardiac event. Binding of VEGF prevents interaction with its receptors, therefore inhibiting formation of new blood vessels in primary and metastatic tumors.

VEGF inhibitors have been associated with an increased risk for CV events such as hypertension, myocardial ischemia, left ventricular dysfunction, HF, QT interval prolongation and thromboembolic events in oncology trials. A recent meta-analysis of 77 studies by Husam Abdel-Qadir, MD, PhD, cardiologist at Women’s College Hospital and Peter Munk Cardiac Centre in the University of Toronto Health Network, and colleagues found that 139 patients need to be treated to see one case of cardiac dysfunction, and 410 patients need to be treated before seeing one case of clinical HF (Table). Although these may seem like rare events, VEGF inhibitor therapy should still be considered as a contributor to cardiac dysfunction. In the same meta-analysis, hypertension was most commonly reported as grade 3 or higher and one case of severe hypertension occurred for every 17 patients treated with VEGF inhibitor therapy. Statistically significant risk for fatal CV events and congestive HF were not observed in patients taking VEGF inhibitors. Additionally, there was no clinically significant difference in the risk for CV events between the two classes of angiogenesis inhibitors.

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In the setting of using lower doses of anti-VEGF agents to treat AMD, patients at highest risk for experiencing systemic adverse effects include those with diabetes, a recent MI or a recent stroke. Data surrounding CV and cerebrovascular events with intravitreal therapy remain controversial. Most clinical trials do not show a significant increase in the incidence of CV events, cerebrovascular accidents (CVA), MI and death with the use of intravitreal VEGF administration.

Proteinuria resulting from intravitreal administration of VEGF inhibitor therapy is not well documented and is limited to case reports. One diabetic macular edema trial reported more arterial thrombotic events with ranibizumab (Lucentis, Genentech) compared with aflibercept (Eylea, Regeneron). Neil M. Bressler, MD, James P. Gills Professor of Ophthalmology at Johns Hopkins Medicine, and colleagues evaluated the risk for stroke in five randomized controlled ranibizumab AMD trials and found that patients with an elevated baseline risk for stroke had a sevenfold increased risk for stroke during the trials with use of ranibizumab compared with the control group. There was no increased risk for CVA. According to the Pan-American Collaborative Retina Study Group, some patients receiving intravitreal bevacizumab (Avastin, Genentech) experienced an acute BP elevation (0.59%), MI (0.4%), CVA (0.5%) and death (0.42%). In a meta-analysis by Takashi Ueta, MD, PhD, professor of ophthalmology at Harvard Medical School and Tokyo University, and colleagues, there was a 2.2% incidence of all CVAs, including transient ischemic attack, stroke and other ischemic cerebral events, vs. 0.7% in the control group, although this analysis was underpowered.

Monitoring and management of cardiotoxicities

Key management points in the setting of VEGF inhibitor-induced cardiotoxicity include identifying risk factors, obtaining baseline risk assessments and providing close monitoring. Reversal of most cardiotoxic effects of anticancer agents can be accomplished if recognized early and medication is discontinued. Fortunately, unlike the irreversible cardiotoxicities seen with anthracyclines, VEGF inhibitor-related cardiotoxicity is not known to be dose-dependent. The challenge is the potential for cancer disease progression with the cessation of VEGF inhibitor therapy once adverse effects are noted.

Currently there is no standard best practice on how to manage patients with preexisting or developing cardiac dysfunction who require treatment with VEGF inhibitors for cancer treatment. Certain treatments warrant stress echocardiography before starting therapy to evaluate myocardial perfusion and probability for CAD (Figure).

Monitoring for cardiotoxicities during treatment with antiangiogenesis agents in cancer treatment. Note: graphic provided by authors. Sources: Plana JC, et al. J Am Soc Echocardiogr. 2014;doi:10.1016/j.echo.2014.07.012. Touyz RM, et al. NPJ Precis Oncol. 2018;doi:10.1038/s41698-018-0056-z.
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Based on recommendations from the 2014 American Society of Echocardiography and the European Association of Cardiovascular Imaging consensus, any patient receiving VEGF inhibitor therapy should undergo an echocardiogram after completing 1 month of treatment, then every 3 months thereafter. Hypertension, including new cases and worsening of previously controlled hypertension, is the most common adverse effect of VEGF inhibitor therapy and presents within 3 to 4 weeks of initiation. Hypertension should be managed with routine antihypertensive therapy. It has been noted that CAD and hypertension are the most important predictors for the development of HF with a tyrosine kinase inhibitor such as sunitinib (Sutent, Pfizer).

Patients who develop HF can be treated with conventional therapy; however, the role of prophylactic treatment for patients with existing risk factors has not been defined. In some cases, it is recommended to discontinue treatment with a tyrosine kinase inhibitor (ie, sunitinib) if a patient develops LV dysfunction while on therapy. The incidence of QT prolongation with tyrosine kinase inhibitors is 4.4%, but should still be monitored at baseline and 2 to 4 weeks after starting treatment, especially in patients taking other QT-prolonging agents.

There are no clear guidelines on when to initiate or continue treatment with VEGF inhibitors after ACS or MI, since angiogenesis is required for the healing process. Generally, myocyte degeneration declines after 4 weeks and the risk for hemorrhage declines after 2 weeks when angiogenesis stabilizes. Ensuring patients are optimized on appropriate treatment after a cardiac event is crucial in managing cardiotoxicity in patients treated with VEGF inhibitors. The risks and the need to manage closely predictors of cardiotoxicity — such as hypertension and CAD — from VEGF inhibitors should be discussed with the patient before the start of cancer treatment.

More awareness is also required to monitor and evaluate CV symptoms with patients receiving intravitreal anti-VEGF therapies. For now, it is important to consider that the association of systemic CV events with intravitreal VEGF injections is not negligible, especially in high-risk populations. As the use for anti-VEGF therapies increases, investigators are looking for treatments with prolonged duration and different routes of delivery. This will ultimately lead to increased risk for systemic toxicities due to an extended period of VEGF inhibition. More trials specifically powered to evaluate systemic events are necessary to determine the true risk to the general population as well as to patients with preexisting conditions such as diabetes, stroke and diabetic macular edema.

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Cardio-oncology services

The emergence of novel targeted cancer therapies like VEGF inhibitors has led to patients using these agents for longer periods of time because of their increased tolerability and improved survival rates compared with traditional chemotherapy. With the emergence of CV adverse effects from these agents, it becomes imperative to have an integrative multidisciplinary approach to monitor patients and reduce risk for morbidity and mortality. Latent CV toxicities from oncology treatments are likely underreported or unknown. Establishing cardio-oncology programs where oncologists and cardiologists collaborate to minimize CV complications without reducing effectiveness of treatment plans for patients with cancer is an important first step.

Disclosures: The authors report no relevant financial disclosures.