Click here to read an expert perspective from Roohi Ismail-Khan, MD, MSc.
The treatment of cancer patients with vascular endothelial growth factor (VEGF) therapy is sometimes associated with cardiotoxicity. Therefore, it is important that clinicians understand the predictors of these adverse effects and learn how best to monitor for them. In this interview, ONCOLOGY spoke with Joerg Herrmann, MD, Director of the Cardio-Oncology Clinic at the Mayo Clinic in Rochester Minnesota, who evaluates and treats patients with cancer and heart disease.
Q: How do VEGF inhibitors work? What are the associated cardiotoxicities that have been documented with these agents in clinical trials?
DR. HERRMANN: VEGF inhibitors go back to Dr. Judah Folkman’s great vision of antagonizing angiogenesis, including the critical role that angiogenesis plays in cancer growth and metastasis. VEGF is one of the cardinal angiogenesis factors that tumors use to develop their vasculature, thereby aiding in the growth and development of cancer. Therefore, antagonizing VEGF with VEGF inhibitors was a conceptual breakthrough that also translated into clinical improvement.
Bevacizumab is one such VEGF inhibitor used to treat a number of cancers. Despite the fact that it is one of the best-selling drugs of all time, it has been associated with several toxicities—some that were expected and some that were not. These include hypertension, ischemic events, thrombotic events, both arterial and venous events, bleeding events, cardiac dysfunction, and heart failure.
Q: Some of these cardiotoxicities are part of the mechanism of the VEGF agents. However, do VEGF inhibitors also cause off-target effects?
DR. HERRMANN: Yes, indeed. VEGF is critical for the development of new vessels, a process called neovascularization. However, it has been debated how important VEGF is to adults with developed vasculature. Research has shown that it does still play a role in these individuals, especially in the endocrine organs and for those with fenestrated capillaries (ie, the thyroid and other endocrine glands). These vessels regress quite rapidly following VEGF inhibitor therapy, but they also regrow following the end of therapy.
Since the heart is not subjected to as much growth inhibition and regrowth as endocrine organs, we don’t see the same regression there. However, it is critically important that the VEGF-driven compensatory angiogenesis response occurs when the heart is subjected to increased afterload. Most of the time, the cause of an increased afterload is increased blood pressure or uncontrolled hypertension, but aortic stenosis or inhibiting VEGF in this setting can also be detrimental. There are several other conditions that may predispose patients to this phenomenon that occurs as part of the mechanism of these VEGF agents.
Q: How, specifically, should patients taking VEGF inhibitors be monitored for cardiac toxicities?
DR. HERRMANN: All patients taking VEGF inhibitors should be monitored for cardiotoxicities. According to the 2014 American Society of Echocardiography and the European Association of Cardiovascular Imaging consensus recommendations, patients undergoing VEGF inhibitor therapy should undergo an echocardiogram after the first month of therapy and then every 3 months thereafter. This is because any drop in ejection fraction can sometimes be seen early after initiating anti-VEGF therapy. It also supports the idea that the myocardium plays a compensatory role that evolves very early on, and, while it may not be directly cardiotoxic, it can evolve along the vascular concept of cardiomyopathy. We also have to be cognizant that cardiovascular effects can occur later on, which is why screening every 3 months is recommended. Another important component observed from clinical practice is that about 50% to 60% of patients will have reversibility of the drop in ejection fraction. This provides more impetus to conduct these surveillance echocardiograms, since we can truly alter the course and prevent heart failure.
Of note, several of the tyrosine kinase inhibitors can cause QTc prolongation. It is recommended that an electrocardiogram be obtained regularly, maybe after 2, 4, and 8 weeks. This can be done at longer intervals after patients have been on therapy for a while with no events. In addition, blood pressure should be monitored very closely in these patients, particularly in the first few weeks when most changes are seen following the first cycles of treatment. There has been some thought about whether ambulatory blood pressure monitoring should be utilized in this population. However, it can also be done with whole blood pressure measurements and office measurements. These are the cardinal elements for serial surveillance: echocardiography, electrocardiography, and blood pressure measurements.
Q: Do certain comorbidities preclude patients from receiving anti-VEGF therapy? In addition, do certain cardiac conditions increase the risk of cardiotoxicity from VEGF inhibitors?
DR. HERRMANN: Studies have shown that the predictors of cardiotoxicity are coronary heart disease and hypertension. When encountering patients with these conditions in the clinic, you should carefully discuss the risks and benefits of VEGF inhibitors. It is worth noting that a bit of debate surrounds the actual risk, as in how many patients a clinician needs to actually treat before seeing that kind of harm. A meta-analysis published in 2017 found that about 140 patients need to be treated before seeing one with cardiac dysfunction, and 410 patients need to be treated before seeing one with clinical heart failure. I think it is important to mention these numbers and to put the benefits vs risks of these therapies into perspective. They can have huge benefits and we don’t want to overstate the risks, but we should be realistic. More than 1,200 patients need to be treated before a fatal event occurs. This, too, puts the risk-benefit conversation in perspective.
In the clinic, we need to counsel patients about these risks and ensure that their blood pressure is well-controlled. High blood pressure may cause sub-endocardial ischemia, which can evolve with increased pressure in the heart chamber alone. Myocardial ischemia can also be triggered by a significant stenosis in the coronary artery. Therefore, a stress test and treatment of such conditions should be completed before initiating VEGF inhibitor therapy. Since no randomized clinical trials or other evidence are currently available to support these recommendations, they are more of a consensus by the experts in the field.
Financial Disclosure: Dr. Herrmann received unrelated research support from Amgen.
The Benefit of Cardio- Oncology Programs for Cancer Patients
Roohi Ismail-Khan, MD, MSc
Cardio-oncology is a cutting-edge, multidisciplinary field focusing on the management and prevention of cardiovascular complications in cancer patients and survivors. Although survival rates for cardiovascular disease and cancer have improved dramatically, these conditions are still the two biggest killers of patients today. Cardiac toxicity is the second most common cause of morbidity and mortality in cancer survivors. Despite advances in both fields, many cancer patients experience cardiovascular complications as a result of cancer therapy. In addition, a large proportion of patients with pre-existing cardiovascular disease require cardiotoxic therapy for cancer.
In this interview, Dr. Herrmann perfectly describes the cardiotoxicity associated with vascular endothelial growth factor (VEGF) inhibitors. Although VEGF inhibitors pose a risk of cardiovascular toxicity, they may significantly improve progression-free survival (PFS). Simply put, new blood vessel formation (angiogenesis) is critical for the growth of tumors, and anti-angiogenic therapy assists in tumor regression. Bevacizumab, a humanized monoclonal antibody directed against VEGF, was the first targeted angiogenesis inhibitor to be developed. Since its approval in 2004, it has become one of the top ten best-selling drugs of all time. In patients with colorectal cancer and non–squamous-cell lung cancer, the addition of the angiogenesis inhibitor bevacizumab doubled PFS. Similarly, in patients with metastatic renal cell carcinoma, sunitinib (another VEGF inhibitor) more than doubled overall survival.
Interestingly, in breast cancer, bevacizumab was granted accelerated approval in 2008 based on the E2100 trial, which showed that treatment with bevacizumab led to a 5.5-month improvement in PFS. However, the drug was associated with serious cardiotoxicity. Two subsequent studies, AVADO and RIBBON-1, showed only a slight effect on tumor growth with no benefit in OS compared with standard chemotherapy. Therefore, on November 18, 2011, the US Food and Drug Administration (FDA) withdrew bevacizumab’s breast cancer indication after concluding that it had not been shown to be safe and effective for the treatment of breast cancer. The FDA’s decision was met with mixed emotions among patients and healthcare professionals, including many breast oncologists like myself who had seen solid success stories in the clinic. Could it be that if we proactively monitored, managed, and controlled the cardiovascular side effects during treatment of our patients on bevacizumab, as Dr. Herrmann suggests, that we would still be using this drug in breast cancer patients today?
The cardiovascular toxicities associated with bevacizumab include both vascular and cardiac side effects, which are based on the role VEGF plays in the development and functional integrity of the vasculature, as well as the importance of the vasculature to heart function. The spectrum of toxicity of bevacizumab in the literature spans from hypertension to atherosclerosis, arterial and venous thrombotic events, and heart failure.
Various other novel drugs and targeted therapies used to treat cancer also have cardiovascular side effects. Many of these drugs may cause newly diagnosed cardiovascular problems, or can exacerbate previously identified cardiovascular disease. The rate of cardiotoxicity from cancer-related therapeutics has been reported to be greater than 30%, with some events occurring many years after therapy completion.
All of these facts necessitate the existence of a cardio-oncology program, in which oncologists and cardio-oncologists work together to manage patients. The initial focus of cardio-oncology was on heart failure associated with anthracycline use. However, increasingly utilized novel anticancer agents—such as VEGF inhibitors, tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, and various immunotherapy treatments—are associated with many other cardiotoxicities beyond heart failure, including hypertension, arrhythmias, thromboembolic disease, vascular disease, and coronary disease.
Given these complexities, it is important that patients have access to providers who possess knowledge of both cardiovascular disease and cancer therapeutics. This multidisciplinary approach to treating patients is why the field of cardio-oncology is growing by leaps and bounds; it is also why a number of academic and community programs have embraced this approach. Going forward, smart management and treatment of cancer therapy–related cardiac dysfunction can have a profound impact on improving morbidity and mortality in cancer patients.
FINANCIAL DISCLOSURE: Dr. Ismail-Khan has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
1. Fradley MG, Brown AC, Shields B, et al. Developing a comprehensive cardio-oncology program at a cancer institute: the Moffitt Cancer Center experience. Oncol Rev. 2017;11:340.
Dr. Ismail-Khan is a Medical Oncologist and Co-Director of the Cardio-Oncology Program at H. Lee Moffitt Cancer Center in Tampa, Florida, where she works with the University of South Florida Director of the program, Michael Fradley, MD.
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