Michael G. Fradley, MD
In patients with cancer, improvements in survival have opened the door to broader consideration of the long-term effects of treatment and how best to manage them. Cardiotoxicity is 1 such adverse event (AE) that is getting more attention among oncologists, as evidenced by a sudden rise in meetings and educational events devoted to this aspect of care. Statistics help explain this growing attention to downstream effects of treatment. An estimated 15.5 million cancer survivors are in the United States, and more than 60% of cancer survivors are alive 5 years after diagnosis. Even at 10 years, survivorship is about 40% overall.1-3
As patients live longer following cancer diagnosis and treatment, quality of life concerns and moderation of AEs related to treatment have grown in importance. Simply put, cardiotoxicity has become a facet of cancer survivorship that oncologists must learn to manage and, ideally, prevent (Tables 14,25-8
Fortunately, physicians do not have to do it alone, thanks to the emerging subspecialty of cardio-oncology. Cardiologists who focus on the cardiotoxic effects of anticancer agents can provide guidance on cardiac-related toxicities, diagnoses, AEs and treatment strategies; this dovetails with oncologists’ core expertise. Now an integral part of academic medical centers, cardio-oncologists are finding their way into the community practice setting. “We really want to change the care paradigm to be more collaborative, to emphasize that oncologists and cardiologists need to be interacting together to provide good care,” said Michael G. Fradley, MD, an attending cardiologist and electrophysiologist at Moffitt Cancer Center in Tampa, Florida. “Because so many patients are living longer and surviving their disease, we don’t want them to have major cardiac issues down the road.”
The National Cancer Institute defines cardiotoxicity very broadly as “toxicity that affects the heart,” which various organizations refine as a host of diseases and conditions that result from treatment with a variety of oncologic drugs. Major medical associations including the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology, the National Comprehensive Cancer Network (NCCN), the International Society for Geriatric Oncology, and the American Heart Association have begun to formulate recommendations and guidelines that address various aspects of cardiotoxicity.
In a June report on guidelines for cardiovascular toxicity in cancer survivors, Carlyn Tan, MD, and Crystal S. Denlinger, MD, noted that each guideline has a different focus and intended usership. Some focus on pre- and on-treatment care, and others address posttreatment surveillance and management.9
Although these guidelines offer helpful recommendations for specific populations and circumstances, their limited scope makes it challenging for oncologists to apply recommendations across the broad spectrum of clinical practice.
Fradley, who also directs the joint University of South Florida–Moffitt Cancer Center Cardio- Oncology Program, believes the lack of consensus on cardiotoxicity stems from the profession’s extensive experience with anthracycline-induced cardiomyopathy and heart failure among patients with breast cancer. “But the field has become much broader as different treatments have evolved,” he told OncologyLive®
. “As we’ve moved away from chemotherapeutics [alone] toward targeted therapies and immunotherapies and CAR [chimeric antigen receptor] T-cell therapies, we’re starting to learn that those different treatments come with many types of cardiovascular problems, including arrhythmias, vascular disease, and heart attacks.”
Table 2. Agents Responsible for Cardiotoxicity in Cancer Treatments5-8
Kalyan Banda, MD, a medical oncologist specializing in breast cancer at Seattle Cancer Care Alliance in Washington, finds the lack of a universally accepted definition of cardiotoxicity frustrating. “If there is no universally accepted definition, how are we going to identify who has cardiotoxicity, who we should be following, and who we should be treating? Whose therapy should we be stopping or changing?” he said. “Right now, every oncologist seems to have their own definition of what cardiotoxicity is. Is it a drop in the ejection fraction, some sort of dysfunction seen on echocardiogram, or a combination of symptoms?”
As the debate continues and the desire for clarity on recognizing and managing cardiotoxicity grows, it is helpful to review what is known thus far. The following summarizes details regarding the cardiotoxic effects of different agents and treatment modalities, as well as how cardio-oncology can be incorporated into practice to improve both medical and quality-of-life outcomes for patients with cancer and survivors alike.
Much of what is known about cardiotoxicity stems from clinicians’ experiences with anthracyclines, which for 50 years have been used to treat various malignancies, especially breast and pediatric cancers. Doxorubicin, daunorubicin, epirubicin (Pharmorubicin), and idarubicin (Idamycin) have all been implicated in anthracycline- induced cardiomyopathy. Writing in Heart, Peter Henriksen, MBChB, PhD, FRCP, of the Centre for Cardiovascular Science in Edinburgh, Scotland, describes anthracycline-induced cardiomyopathy as a disease spectrum ranging from asymptomatic decline in left ventricular ejection fraction (LVEF) to development of heart failure with symptoms and clinical signs. He also notes that up to 5% of highrisk patients develop clinical heart failure.10
Researchers believe that anthracyclines’ cardiotoxic effects are dose dependent and irreversible. However, in a recent review article in Frontiers in Cardiovascular Medicine, Jerry Dong, PhD, and Hong Chen, PhD, of Boston Children’s Hospital in Massachusetts, stated that evidence is mounting that verified late-onset complications are occurring, regardless of dose: “The immediate cardiotoxic effects can range from a few weeks to years after treatment, even after treatment has been discontinued. Therefore, there is no dosage regimen of doxorubicin that is completely safe.”11
Another cornerstone of breast cancer therapy, the monoclonal antibody trastuzumab (Herceptin), can also cause cardiotoxicity. Used as a first-line adjuvant to chemotherapy, trastuzumab inhibits the HER2 signaling pathway. HER2 receptors are overexpressed in 25% to 30% of patients.12,13
Trastuzumab increases the risk of asymptomatic decreased LVEF, leading to complications such as heart failure. The damaging effects appear shortly after treatment has begun and do not appear to be dose dependent. Importantly, these effects are reversible, allowing oncologists to discontinue and restart trastuzumab as needed.
Although targeted therapies are making significant progress in changing both the treatment paradigms and patient prognoses in a number of malignancies, they bring a host of cardiotoxic AEs. These include left ventricular dysfunction, hypertension, ischemic events, severe atherosclerosis, and more.
According to Fradley, hypertension is the most common cardiac AE associated with tyrosine kinase inhibitors (TKIs), such as imatinib (Gleevec), gefitinib (Iressa), erlotinib (Tarceva), sorafenib (Nexavar), sunitinib (Sutent), and dasatinib (Sprycel). Even though many oncologists feel comfortable treating and managing hypertension, Fradley suggests that patients who receive TKIs should be seen by a cardio-oncologist. “These patients can have extremely refractory blood pressure measurements, so it’s essential that they be evaluated by a cardio-oncologist to avoid complications from accelerated hypertension if they will be on the TKI for any length of time,” he said. “If we’re talking about potentially years on the drug, letting a 70-year-old patient live with [systolic] blood pressures of 160 or 170, for example, is not feasible.”
The BCR-ABL TKIs that treat chronic myelogenous leukemia also have notable cardiotoxicities, apart from the first-generation therapy imatinib. “The second- and the third-generation TKIs all have quite a bit of cardiovascular toxicities,” Fradley said. “Those are primarily vascular events, so we are seeing increased rates of heart attack, strokes, and peripheral arterial disease.”
The kinase inhibitors such as ibrutinib (Imbruvica), which are used to treat B-cell malignancies like chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström macroglobulinemia, are also associated with atrial fibrillation (AFib). “When these patients develop AFib, we often put them on blood thinners, so it becomes a complex dance between the oncologist and the cardiologist to find a balance that allows the patient to continue on therapy, while also making sure their cardiac issues are treated effectively,” Fradley said.
TKIs are also associated with QT prolongation, which predisposes patients to life-threatening heart rhythm disorders, he added.
Among cardio-oncologists, there is a growing belief that the incidence of immunotherapy-associated cardiotoxicity is likely underestimated and may increase as immune checkpoint inhibitors and adoptive T-cell therapies are used in larger populations and for longer durations of therapy.14
Immune checkpoint inhibitors are generally well tolerated but have the potential to cause myocarditis, for example. “We think myocarditis is a new clinical phenomenon that is a rare but clinically significant complication of cancer immunotherapy,” said Javid J. Moslehi, MD, director of the cardiooncology program at Vanderbilt University School of Medicine in Nashville, Tennessee. “There’s variable presentation, at least in some of the early cases, where we may see concomitant myositis and rhabdomyolysis.”
According to Moslehi, a small percentage of patients with immunotherapy-driven myocarditis will experience sudden death as a result. “The very severe cases can have up to 50% mortality,” he said, “but we’re also seeing more subacute cases of myocarditis as colleagues become more cognizant of the complication.”
Moslehi uses this as an example of the need for more precise diagnoses. “One thing we don’t want to have happen is for the heightened awareness of myocarditis to lead to overdiagnosis and the withholding of lifesaving cancer therapies,” he said. “Because if you think somebody has myocarditis, you’re going to withhold cancer treatment while you try to figure things out. That’s really an important challenge for both oncologists and cardiologists right now.”
Achieving balance among competing medical priorities calls for the burgeoning discipline of cardio-oncology. These specialists emphasize both the importance and the potential difficulty of preventing cardiotoxic adverse events in cancer patients. “Before starting a patient on any of these potentially toxic drugs, you’ll want to do a very thorough cardiovascular risk factor evaluation,” Fradley said.
He gives the example of a newly diagnosed patient with cancer who has uncontrolled hypertension and diabetes and is continuing to smoke. “A patient with all of these conditions is going to have an increased likelihood of developing cardiovascular dysfunction from [his or her] treatment,” Fradley said, noting that cardiotoxicity is additive. “By focusing on all of those risk factors up front, you may be able to prevent downstream effects from the different cancer treatments.”
Moslehi and collaborators have created several ABCDE guidelines to help both physicians and patients focus on cardiovascular health after cancer treatment. The first, “ABCDE Steps to Prevent Heart Disease in Breast Cancer Survivors,” appeared in Circulation in 2014.15
The following year, the journal published the collaborators’ “ABCDE Steps for Heart and Vascular Wellness Following a Prostate Cancer Diagnosis.”16
The algorithm for breast cancer survivors is as follows:
A = Awareness of risks of heart disease, aspirin
B = Blood pressure
C = Cholesterol and tobacco cessation D = Diet, weight management; chemotherapy or radiation; diabetes mellitus prevention/treatment
E = Exercise, echocardiogram
The team also created a general ABCDE plan for cardiovascular health among all cancer survivors. These are being considered as part of several national guidelines, including NCCN guidance. “The ABCDE concepts apply to all cancers, so we want to provide oncologists with an easy-to-use, generalizable tool,” Moslehi said.
He is also behind CardioOnc.org, another emerging cardiotoxicity resource. Aimed at oncologists, cardiologists, and primary care physicians, the site contains a searchable database of oncology drugs that lists the class, cancer indication, and known cardiotoxic AEs of each agent.
Physicians can also use the site to report cardiotoxic events and request consultative assistance in managing specific patients. “Many oncologists may be unaware of the cardiac complications associated with cancer therapies, [whereas] cardiologists may be unaware of new cancer treatments and how they work,” Moslehi said. “The website acts as a platform for physicians to collaborate with one other and learn about managing cardiotoxicity. It’s becoming a novel way to advance both the science and practice of an important new area of medicine.”
Other educational resources abound. Circulation recently published a theme issue entirely devoted to cardio-oncology, as sessions devoted to cardiotoxicity are proliferating at both cardiology and oncology conferences.17
For example, at the 2018 ASCO Annual Meeting, Moslehi’s education session on novel cardiac toxicities in the era of precision medicine filled one of the largest halls to capacity.18
“That never would have happened even a few years ago,” he said. “Similarly, the cardio-oncology sessions at cardiology meetings are becoming the biggest draws.”
Cardio-oncology-specific conferences now exist, as well. Fradley chaired this year’s Global Cardio- Oncology Summit, held in Tampa, Florida, which brought together some 300 practitioners from both disciplines. He said organizers sought to achieve a 50/50 mixture of cardiologists and oncologists to enable the highest exchange of ideas and perspectives.
Having access to an in-house cardio-oncology service can be a huge advantage, according to Banda. “The in-house service is incredibly valuable and saves me a lot of worry and time,” he said. “I know that the cardio-oncologists are up-todate on our cancer treatments and will make good recommendations.”
For oncologists who don’t yet have the luxury of in-house cardio-oncology colleagues, Banda recommends developing close working relationships with trusted cardiologists and giving them relevant background information. “When you refer a patient, provide the cardiologist with some context along the lines of the names of the cancer therapies and what we know about their performance,” he said. “This kind of close collaboration is good for everybody—the oncologist, the cardiologist, and, most importantly, the patient.”
Fradley agrees: “At its core, cardio-oncology is a collaborative discipline, meant to bring together the perspectives of the cardiologist so that patients can continue to receive the optimal treatments for their cancer while minimizing potential toxicities to the cardiovascular system,” he said. “The system works best when both specialties communicate and collaborate with a holistic view of the patient.”
- Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016;66(4):271-289. doi: 10.3322/caac.21349.
- de Moor JS, Mariotto AB, Parry C, et al. Cancer survivors in the United States: prevalence across the survivorship trajectory and implications for care. Cancer Epidemiol Biomarkers Prev. 2013;22(4):561-570. doi: 10.1158/1055-9965.EPI-12-1356.
- DeSantis CE, Lin CC, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin. 2014;64(4):252-271. doi: 10.3322/caac.21235.
- Armenian SH, Lacchetti C, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2017;35(8):893-911. doi: 10.1200/JCO.2016.70.5400.
- Aapro M. SIOG (International Society of Geriatric Oncology) recommendations for anthracycline use in the elderly. Hematol Rep. 2011;3(suppl 3):e6. doi: 10.4081/hr.2011.s3.e6.
- Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2012;23(suppl 7):vii155-vii166. doi: 10.1093/annonc/mds293.
- NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Survivorship. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/survivorship.pdf. Updated July 30, 2018. Accessed September 9, 2018.
- Plana JC, Galderisi M, Barac A, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2014;27(9):911-939. doi: 10.1016/j.echo.2014.07.012.
- Tan C, Denlinger C. Cardiovascular toxicity in cancer survivors: current guidelines and future directions. American College of Cardiology website. acc.org/latest-in-cardiology/articles/2018/06/29/12/57/cv-toxicity-in-cancer-survivors. Published June 29, 2018. Accessed September 10, 2018.
- Henricksen PA. Anthracycline cardiotoxicity: an update on mechanisms, monitoring and prevention. Heart. 2017;104(12):971-977. doi: 10.1136/heartjnl-2017-312103.
- Dong J, Chen H. Cardiotoxicity of anticancer therapeutics. Front Cardiovasc Med. 2018;5:9. doi: 10.3389/fcvm.2018.00009.
- Jain D, Russell RR, Schwartz RG, Panjrath GS, Aronow W. Cardiac complications of cancer therapy: pathophysiology, identification, prevention, treatment, and future directions. Curr Cardiol Rep. 2017;19(5):36. doi: 10.1007/s11886-017-0846-x.
- Chen ZI, Ai DI. Cardiotoxicity associated with targeted cancer therapies. Mol Clin Oncol. 2016;4(5):675-681. doi: 10.3892/mco.2016.800.
- Asnani, A. Cardiotoxicity of immunotherapy: incidence, diagnosis, and management. Curr Oncol Rep. 2018;20(6):44. doi: 10.1007/s11912-018-0690-1.
- Montazeri K, Unitt C, Foody JA, Harris JR, Partridge AH, Moslehi J. ABCDE steps to prevent heart disease in breast cancer survivors. Circulation. 2014;130(18):e157-e159. doi: 10.1161/CIRCULATIONAHA.114.008820.
- Guan J, Khambhati J, Jones LW, et al. Cardiology patient page. ABCDE steps for heart and vascular wellness following a prostate cancer diagnosis. Circulation. 2015;132(18):e218-e220. doi: 10.1161/CIRCULATIONAHA.115.012521.
- Zaha VG, Hundley WG, Hill JA. Cardio-oncology: Circulation themed issue. Circulation. 2018;138(7):663-665. ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.036869.
- Blaes AH, Thavendiranathan P, Moslehi J. Cardiac toxicities in the era of precision medicine: underlying risk factors, targeted therapies, and cardiac biomarkers. ASCO Educational Book. 2018;38:764-774. doi: 10.1200/EDBK_208509.