Issue: April 2020
Source/Disclosures
Disclosures: Collier, Sahni and Tamarappoo report no relevant financial disclosures. Barac reports she serves on advisory boards and safety monitoring boards for Bristol-Myers Squibb and Takeda. Fradley reports he received a research grant from Medtronic for the ARCHER trial and previously consulted for Novartis. Ky reports she received funding from the American Heart Association and NIH, has consulted for Bristol-Myers Squibb and is the editor-in-chief of JACC: CardioOncology. Moslehi reports he served on advisory boards for AstraZeneca, Audentes Pharmaceuticals, Bristol-Myers Squibb, Deciphera, GlaxoSmithKline, Intrexon, Ipsen, Myokardia, Nektar, Novartis, Pfizer, Regeneron and Takeda.
April 20, 2020
10 min read
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Cardio-oncology explosion: Increasing awareness, collaboration, research

Issue: April 2020
Source/Disclosures
Disclosures: Collier, Sahni and Tamarappoo report no relevant financial disclosures. Barac reports she serves on advisory boards and safety monitoring boards for Bristol-Myers Squibb and Takeda. Fradley reports he received a research grant from Medtronic for the ARCHER trial and previously consulted for Novartis. Ky reports she received funding from the American Heart Association and NIH, has consulted for Bristol-Myers Squibb and is the editor-in-chief of JACC: CardioOncology. Moslehi reports he served on advisory boards for AstraZeneca, Audentes Pharmaceuticals, Bristol-Myers Squibb, Deciphera, GlaxoSmithKline, Intrexon, Ipsen, Myokardia, Nektar, Novartis, Pfizer, Regeneron and Takeda.
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The cardio-oncology subspecialty has exploded in recent years, with the launch of dedicated cardio-oncology centers, entire conferences focusing on this area and new research, as awareness of cardiotoxicities associated with cancer treatment has increased.

The number of cancer survivors continues to grow. Today, there are more than 16.9 million cancer survivors in the U.S., and this number is expected to increase to 22.1 million by 2030, according to estimates from the American Cancer Society.

“Patients with cancer are living longer and, in many cases, surviving their disease,” Michael G. Fradley, MD, director of the cardio-oncology program and associate professor at University of South Florida College of Medicine and Moffitt Cancer Center in Tampa, who at press time was about to become medical director of cardio-oncology and associate professor of clinical medicine at University of Pennsylvania Perelman School of Medicine, told Cardiology Today. “We now have a large group of cancer survivors who had exposure to various cancer therapies, and we need to determine optimal long-term cardiovascular surveillance and management.”

The role of the cardiologist comes into play as patients who have undergone lifesaving treatment with cancer therapies such as anthracyclines, trastuzumab (Herceptin, Genentech) and immune checkpoint inhibitors often develop cardiotoxicity and other forms of CVD.

Bonnie Ky, MD, MSCE, from the University of Pennsylvania Perelman School of Medicine, said CV risk factors must be taken into account in patients with cancer.

Source: Penn Medicine. Reprinted with permission.

“An array of cancer therapeutics have emerged, from innumerable tyrosine kinase inhibitors to novel immunotherapy including immune checkpoint inhibitors and [chimeric antigen receptor] T-cell therapy, which have caused a paradigm shift in the treatment of previously untreatable malignancies,” Gagan Sahni, MD, FACC, FACP, director of cardio-oncology, director of cardiology consult services and associate professor of medicine at Mount Sinai Cardiovascular Institute, said in an interview. “However, the new promise comes with the old specter of potential cardiotoxicities — the mechanism of cardiotoxicity of each of these novel therapies being unique and still being studied. Hence, the so-called attempt at ‘cardioprotection’ against the cardiovascular effects of chemotherapeutics is a wide playing field with rules we are just beginning to understand.”

Increased awareness of cardiotoxicity related to cancer treatments has also resulted in change among professional cardiology societies. Guidelines and expert consensus statements have been published in collaboration with cancer societies. The American College of Cardiology launched JACC: CardioOncology — a new journal dedicated entirely to advancing the CV care of the growing cancer population — in September. Cardio-oncology tracks and sessions have been created at the major medical conferences.

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Key to cardio-oncology is cross-specialty collaboration.

“Communication and collaboration among physicians to better help patients is absolutely key,” Javid Moslehi, MD, director of the cardio-oncology program and associate professor of medicine in the division of cardiovascular medicine at Vanderbilt University Medical Center and Cardiology Today Editorial Board Member, said in an interview. “It is one of the reasons why this new field of cardio-oncology has come about. It would be a problem if cardiologists focused only on the heart, and completely ignore what happens to the cancer side.”

Broadened focus

Javid Moslehi

In recent years, cardiologists and oncologists alike have learned that while cardiotoxicity associated with cancer treatment was initially noticed as a cause of HF, its implications extend further. In addition, researchers have continued to identify therapies that may produce cardiotoxicity.

“A few years ago, the focus in cardio-oncology was predominately heart failure and imaging,” Fradley said. “While those still exist, the field of cardio-oncology has broadened substantially and now encompasses the entire range of cardiovascular diseases — from ischemic heart disease to arrhythmias to valvular heart disease — and these play an increasingly important role in both the clinical and research domains of cardio-oncology.”

Prevention and treatment of cardiotoxicity is another topic of increasing interest.

“A large part of the focus has always been to understand the cardiotoxicity occurring with anthracyclines and immune checkpoint inhibitors and how can we prevent it,” Balaji K. Tamarappoo, MD, PhD, assistant director of research of cardiac imaging and associate director and associate medical director of the Biomedical Imaging Research Institute at Cedars-Sinai, told Cardiology Today. “On the other hand, the preventive medications that we use in cardiology are relatively limited. We have ACE inhibitors, angiotensin receptor blockers, beta-blockers and then we have statins. Our armamentarium is still relatively limited.”

There is emerging evidence about how traditional risk factors can affect risk for poor CV outcomes in cancer survivors.

“We have learned a lot about the epidemiology of disease, and the role of modifiable cardiovascular risk factors in the development of subsequent cardiovascular disease in cancer patients and survivors,” Bonnie Ky, MD, MSCE, associate professor of medicine and epidemiology and director of the Penn Cardio-Oncology Center of Excellence at the University of Pennsylvania Perelman School of Medicine and editor-in-chief of JACC: CardioOncology, said in an interview. “A current emphasis in cardio-oncology clinical care and research is in understanding and preventing CVD and also in controlling common CV risk factors such as hypertension, hyperlipidemia and diabetes in survivors of cancer. This is in part because the relationship between CV risk factors and the development of CVD and the mortality associated with CVD is greater in cancer survivors than noncancer comparators.”

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Much of the current focus in cardio-oncology research programs across the country, including at Penn, is in developing models for risk prediction and in understanding how to mitigate that risk.

“We have realized that traditional CV risk prediction models such as the Framingham risk score are inadequate to identify CV risk in cancer patients and cancer survivors, as cancer therapeutics including chemotherapy, immunotherapy and radiation therapy all contribute additional CV risk factors,” Sahni said.

Genetic risk factors may predispose patients to both cancer and heart disease.

“If you have common causes for both cancer and heart disease, which are the No. 1 and No. 2 killers of all men and women, then it becomes an important issue to study better,” Moslehi said. “For example, one of these emerging concepts is CHIP, or clonal hematopoiesis of indeterminate potential, the recognition that acquired mutations in the genes in blood cells can cause both cancer and heart disease. This has implications for the patients we see in clinic, but if you understand the underlying biology better, this has public health implications.”

Trial design is also in the spotlight, particularly a call for including more CV events in the trials that support FDA approval of modern cancer therapies.

“The focus is going to be on how to bring knowledge to clinical care of a large population of patients with cancer with growing cardiovascular needs,” Ana Barac, MD, PhD, director of the cardio-oncology program at MedStar Heart and Vascular Institute and associate professor of medicine and oncology at Georgetown University, told Cardiology Today. “In the survivorship space, that will be screening interventions to improve outcomes. The cancer treatment space is an exploding area because of the rapidly growing number of novel cancer therapies with potential effect on cardiovascular homeostasis. The cardio-oncology focus will be to increase inclusion of cardiovascular endpoints in clinical trials.”

With increased focus and recognition of cardio-oncology as an important subspecialty, this may open the door for more opportunities to increase awareness and the knowledge base on potential cardiotoxicity of cancer treatments (Table).

“Maybe 10 years ago, there was a more limited understanding and a limited subset of questions,” Patrick Collier, MD, PhD, FACC, FASE, FESC, co-director of the Cardio-Oncology Center, associate director of the echo lab, and cardiologist at Cleveland Clinic and assistant professor at Clinic Lerner College of Medicine at Case Western Reserve University, told Cardiology Today. “Now, because of increased recognition and more people involved, we are beginning to see a trend toward more focused questions and, hopefully, more focused answers. That is a big change.”

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Awareness continues to increase

Increased awareness of the CV impact of cancer therapies has increased among patients and health care professionals.

Gagan Sahni

“Patients have made a major contribution in increasing awareness,” Barac said. “These are often the patients at the highest risk, having cardiovascular and cancer diagnoses, however, they also give us the opportunity to make a major difference in improving quantity and quality of care.”

Professional associations in both cardiology and oncology have made great strides to boost awareness. The ACC has designed and held a highly successful live course focused on cardio-oncology and also developed a cardio-oncology subcommittee that includes scientists and clinicians. The American Society of Clinical Oncology features an educational session during its annual meeting to inform attendees about CV needs in patients with cancer and has also sponsored guidelines in cardiac function. The American Heart Association has also organized a subcommittee on cardio-oncology and has increased funding for research in this area, experts told Cardiology Today.

A major milestone was the launch of JACC: CardioOncology in September.

“As a journal, we seek to be the ‘go to’ resource for cardio-oncology,” Ky said. “Our fundamental mission is to advance science and clinical care, and build our community. We want to accelerate the growth of the field globally by focusing on rigor, excellence and the community.”

Organizations including the American Society of Clinical Oncology, European Association of Echocardiography, European Society for Medical Oncology, American Society of Echocardiography, European Association of Cardiovascular Imaging and the Society for Cardiovascular Angiography and Interventions have published cardio-oncology guidelines and recommendations in recent years. In March of this year, the National Comprehensive Cancer Network released guidelines for patients with cancer and survivors. Even with an increase in these documents, more data are needed to help develop additional guidance, experts told Cardiology Today.

“For guidelines to be truly useful, they must be based more on data and less on expert opinion,” Fradley said. “Because the field is still in its infancy, we are still establishing our knowledge base and data related to cardio-oncology.”

Future research

Knowledge gaps remain on the basic mechanisms behind the association.

“We still do not understand why certain drugs cause toxicities,” Ky said. “It may be very well multifactorial, but we still do not have a full understanding.”

Ky’s ongoing research program at Penn focuses on “deep CV phenotyping”—understanding the cardiotoxic effects of cancer therapy through biomarkers, imaging measures and clinical tools, and also in developing prediction models to identify patients at increased risk for cardiotoxicity. Some examples of these ongoing studies include cohort studies in patients with breast cancer receiving anthracyclines and/or trastuzumab or patients with lung cancer receiving thoracic radiation therapy. She is also leading a trial in intensive BP control in patients with metastatic renal cell cancer through the National Cancer Institute-funded ECOG-ACRIN clinical trials network.

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Michael G. Fradley

Another study that is being executed by the National Cancer Institute cooperative groups is the UPBEAT trial, which focuses on understanding the CV basis of fatigue. This trial is assessing whether cancer therapy in patients with breast cancer affects the heart, exercise ability and fatigue compared with patients without cancer.

There is also a call for more cardioprotective therapies. For example, trials are currently underway to assess different cardioprotective medications, including statins, in patients receiving various cancer therapies to prevent cardiotoxicity associated with anthracyclines. Other medications that have been studied include angiotensin II receptor antagonists, beta-blockers and ACE inhibitors. There are also multiple ongoing studies in pediatrics evaluating the effects of cardioprotective strategies.

Several trials are ongoing to evaluate CV medications in patients undergoing cancer treatment, including the PRADA II trial, which will assess sacubitril/valsartan (Entresto, Novartis) vs. placebo in patients with breast cancer receiving anthracyclines; the PREVENT trial, which will assess statin therapy vs. placebo to prevent CV toxicity from anthracyclines; the TACTIC trial, which will assess carvedilol for cardiomyopathy from trastuzumab; and the PROACT trial, which will assess enalapril for cardiotoxicity from anthracycline treatment. Another trial, SUCCOUR, will examine the impact of global longitudinal strain surveillance via echocardiography in patients undergoing chemotherapy.

Tamarappoo and researchers at Cedars-Sinai recently submitted an application to the NIH to study the effect of chemotherapy on blood flow to the heart and skeletal muscle.

Fradley and colleagues are currently conducting the ARCHER study, which will assess the ability of an implantable cardiac monitoring system (Reveal LINQ, Medtronic) to evaluate long-term recurring atrial fibrillation in patients who underwent a stem cell transplant.

Although the cardio-oncology research area is ripe, trials need to reflect the patients we see in everyday clinical practice, Ky said.

“Oftentimes now, at least in the general cardiology world or even in the general oncology world, cancer patients or cardiovascular disease patients are excluded from trials, but understanding that these are the patients that will be receiving these drugs, expanding the clinical trials across both disease groups, hopefully, will be something in the future,” she said.

Working together

For many, the relationship between cardiologists and oncologists is an area that needs more improvement.

“Oncologists need to understand that their patients benefit from a cardiology consultation, especially if their patients have a lot of risk factors such as very high lipids, uncontrolled hypertension, uncontrolled diabetes, previous preexisting coronary artery disease that those patients are probably not even aware of. A consultation with a cardiologist is an important part of the workup of the patient,” Tamarappoo said.

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A major focus should be placed on communication itself, especially when the patient’s needs are at the forefront of the conversation.

“Cardiologists, oncologists and all members of the care team need to work together by picking up the phone and talking to each other — all in the best interest of the patient,” Ky said. “We can work best together if we remember that the patient is at the center of all this, doing everything we can to help make sure that patients receive the necessary cancer therapy that they need to get with the least toxicity possible. We need to work together to help ensure that survivors can live a life that is free of significant cardiovascular disease, and that we do everything we can to mitigate cardiovascular risk factors and decrease the development of subsequent cardiovascular disease.” – by Darlene Dobkowski

Disclosures: Collier, Sahni and Tamarappoo report no relevant financial disclosures. Barac reports she serves on advisory boards and safety monitoring boards for Bristol-Myers Squibb and Takeda. Fradley reports he received a research grant from Medtronic for the ARCHER trial and previously consulted for Novartis. Ky reports she received funding from the American Heart Association and NIH, has consulted for Bristol-Myers Squibb and is the editor-in-chief of JACC: CardioOncology. Moslehi reports he served on advisory boards for AstraZeneca, Audentes Pharmaceuticals, Bristol-Myers Squibb, Deciphera, GlaxoSmithKline, Intrexon, Ipsen, Myokardia, Nektar, Novartis, Pfizer, Regeneron and Takeda.