Cardiotoxic Cancer Therapy Research Articles

CHANGES IN CARDIOVASCULAR BIOMARKERS WITH BREAST CANCER THERAPY AND ASSOCIATIONS WITH CARDIAC DYSFUNCTION

There is a critical need to understand the role of biomarkers in the surveillance of cardiac dysfunction in patients treated with cardiotoxic cancer therapy. We aimed to determine the longitudinal associations between changes in biomarkers and left ventricular ejection fraction (LVEF) and cancer

Evolution of Asymptomatic Left Ventricular Dysfunction in 380 Long-term Survivors of Childhood Cancer

Introduction Long-term childhood cancer survivors (CCS) treated with cardiotoxic cancer therapies (CTCT) are screened for LV dysfunction (LVD). The intervals of 2 to 5 years in the Dutch Childhood Oncology Group guideline (Annals of Oncology 2012) depend on anthracycline (300 mg/m2) and radiotherapy dose (30 Gy). There is a gap between detection of LVD, defined as an ejection fraction (EF) Methods Patient and treatment characteristics were collected from a CCS cohort diagnosed with cancer between 1966 and 1997 who received anthracyclines and/or chest radiotherapy. Patients with congenital heart disease and heart failure before baseline echocardiogram were excluded. The first available echocardiogram at >5 years since cancer diagnosis was the baseline echocardiogram. All subsequent echocardiograms were collected. FS was measured by M-mode echocardiography. EF was calculated from two apical chamber views by the Simpson formula. If no EF was available, EF was calculated using the Teicholz formula. Patients with an available baseline echocardiogram were stratified into three subgroups: Reduced (EF Results Of 671 CCS eligible, 448 had a baseline echocardiogram at a median of 17years since cancer diagnosis and 381 had at least one follow-up echocardiogram. At baseline, 6, 41, and 334 CCS were in the reduced, grey zone and preserved EF group respectively. CCS in the grey zone received higher anthracycline dose (median 350 mg/m2) compared to the preserved group (median 200 mg/m2), and more CCS with anthracycline dose >300 mg/m2 were present in the grey zone (51.2% vs 26.6%). In the grey zone group 4.9% and 7.3% developed an EF Conclusion Long-term CCS treated with CTCT with an EF in the grey zone are at an increased risk of developing an EF

Pregnancy and Cardiomyopathy After Anthracyclines in Childhood.

With advances in cancer therapy, there has been a remarkable increase in survival in children diagnosed with malignancies. Many of these children are treated with anthracyclines which are well known to cause cardiotoxicity. As more childhood cancer survivors reach childbearing age, many will choose to become pregnant. At this time, the factors associated with development of cardiomyopathy after anthracycline treatment are not clearly identified. It is possible that cardiac stress could predispose to cardiac deterioration in a patient with reduced functional reserve from prior anthracycline exposure. Pregnancy is one form of cardiovascular stress. The cardiac outcomes of pregnancy in childhood cancer survivors must be considered. In view of limited data, guidelines for pregnancy planning, management, and monitoring after cardiotoxic cancer therapy have not been established. This review summarizes the limited data available on the topic of pregnancy after anthracyclines in childhood.

Clinical manual for diagnosis, prevention and treatment of cardiovascular complications of cancer therapy. Parts VI-VII

Advances in treatment have led to improved survival of patients with cancer but have also resulted in untoward side effects associated with treatment. Cardiovascular diseases are one of the most frequent of these side effects. Myocardial dysfunction and heart failure, myocardial ischaemia, arrhythmias, arterial hypertension, thromboembolic disease and other cardiovascular complications can interfere with the efficacy of treatment, decrease quality of life, or impact the actual survival of the patient with cancer. This manual discusses concepts for timely diagnosis, intervention, and surveillance of patients treated with cardiotoxic cancer therapies. In this part оf manual we discuss the diagnostic, prevention and treatment aspects of cancer therapy-related thromboembolism and complications of radiotherapy.

Clinical Manual for Diagnosis, Prevention and Treatment of Cardiovascular Complications of Cancer Therapy. Part I

Advances in treatment have led to improved survival of patients with cancer but have also resulted in untoward side effects associated with treatment. Cardiovascular diseases are one of the most frequent of these side effects. Myocardial dysfunction and heart failure, myocardial ischaemia, arrhythmias, arterial hypertension, thromboembolic disease and other cardiovascular complications can interfere with the efficacy of treatment, decrease quality of life, or impact the actual survival of the patient with cancer. This manual discusses concepts for timely diagnosis, intervention, and surveillance of patients treated with cardiotoxic cancer therapies. In this first part оf manual we discuss the diagnostic, prevention and treatment aspects of cancer therapy-related cardiac dysfunction and heart failure.

Clinical Manual for Diagnosis, Prevention and Treatment of Cardiovascular Complications of Cancer Therapy. Parts II-V

Advances in treatment have led to improved survival of patients with cancer but have also resulted in untoward side effects associated with treatment. Cardiovascular diseases are one of the most frequent of these side effects. Myocardial dysfunction and heart failure, myocardial ischaemia, arrhythmias, arterial hypertension, thromboembolic disease and other cardiovascular complications can interfere with the efficacy of treatment, decrease quality of life, or impact the actual survival of the patient with cancer. This manual discusses concepts for timely diagnosis, intervention, and surveillance of patients treated with cardiotoxic cancer therapies. In this second part оf manual we discuss the diagnostic, prevention and treatment aspects of cancer therapy-related coronary artery disease, arterial hypertension, arrhythmias and pulmonary hypertension.

Cardiotoxicity of cancer chemotherapy: identification, prevention and treatment.

Cardiotoxicity is an important complication of several cancer therapeutic agents. Several well established and newer anticancer therapies such as anthracyclines, trastuzumab and other HER2 receptor blockers, antimetabolites, alkylating agents, tyrosine kinase inhibitors (TKIs), angiogenesis inhibitors, and checkpoint inhibitors are associated with significant cardiotoxicity. Cardiovascular imaging employing radionuclide imaging, echocardiography and magnetic resonance imaging are helpful in early detection and prevention of overt heart failure secondary to cardiotoxicity of cancer therapy. An understanding of the mechanism of the cardiotoxicity of cancer therapies can help prevent and treat their adverse cardiovascular consequences. Clinical implementation of algorithms based upon cardiac imaging and several non-imaging biomarkers can prevent cardiac morbidity and mortality associated with the use of cardiotoxic cancer therapies.

Prevention of Cardiovascular Disease Among Cancer Survivors: the Role of Pre-existing Risk Factors and Cancer Treatments

Purpose of Review The two leading causes of death in North America are cardiovascular disease (CVD) and cancer. As a result of necessary cancer treatments, survivors are at an increased risk of CVD. The contribution of cardio-toxic chemotherapy, targeted therapy, and radiation therapy to CVD is discussed. This paper addresses shared CVD and cancer risk factors (smoking tobacco, diet, obesity, sedentary lifestyle, hypertension, alcohol consumption, and hyperlipidemia) and the influence on cardiovascular outcomes in those treated with cardio-toxic cancer therapies.

Winning the battle, but losing the war: mechanisms and morphology of cancer-therapy-associated cardiovascular toxicity.

In the United States, the lifetime risk of a cancer diagnosis is nearly 40%; in 2016, that represents almost 1.6 million new patients, and despite advances in early diagnosis and treatment, roughly 35% will ultimately die of their malignancy. Fortunately, the number of patients living with a cancer diagnosis also continues to expand, anticipated to be more than 19 million in less than a decade. In calculating the relative risks and benefits of therapy, it is therefore important to consider the morbidity and mortality associated with antitumor therapy itself. Significantly, excluding demise due to the malignancy itself, treatment-induced adverse cardiovascular events are the leading cause of death in cancer patients. Chemotherapy, targeted therapies, immune checkpoint inhibition, and radiation therapy can all adversely impact cardiac function, and their effects can be synergistic. Consequently, it is important that possible side effects of therapy be recognized and effectively controlled. This review highlights the mechanisms and histopathologic findings associated with common forms of potentially cardiotoxic cancer therapy including anthracyclines, tyrosine kinase inhibitors, and most recently immune checkpoint (PD-1) inhibitors. Although for many cases the histologic findings are nonspecific, in the appropriate clinical context, therapeutic cardiotoxicity can be inferred and the treatment approach refined appropriately.

Cardio-oncology: a multidisciplinary approach for detection, prevention and management of cardiac dysfunction in cancer patients.

Cardiac dysfunction that develops during or after completion of cancer therapy is a growing health concern that should be addressed in a multidisciplinary setting. Cardio-oncology is a new discipline that focuses on screening, monitoring and treating cardiovascular disease during and after cancer treatment. A baseline cardiovascular risk assessment is essential. For high-risk patients, a tailored and detailed plan for cardiovascular management throughout treatment and beyond should also be established. Anthracycline and/or trastuzumab-containing chemotherapy and chest-directed radiation therapy are well known cardiotoxic cancer therapies. Monitoring for the development of subclinical cardiotoxicity is crucial for the prevention of clinical heart failure. Detecting a decreased left ventricular ejection fraction after cancer therapy might be a late finding; therefore, earlier markers of cardiac injury are being actively explored. Abnormal myocardial strain and increased serum cardiac biomarkers (e.g. troponins and natriuretic peptides) are possible candidates for this purpose. An important method for preventing heart failure is the avoidance or minimization of the use of cardiotoxic therapies. Decisions must balance the anti-tumor efficacy of the treatment with its potential cardiotoxicity. If patients develop cardiac dysfunction or heart failure, they should be treated in accordance with established guidelines for heart failure. Cancer survivors who have been exposed to cardiotoxic cancer therapies are at high risk of developing heart failure. The management of cardiovascular risk factors and periodic screening with cardiac imaging and biomarkers should be considered in high-risk survivors.

ANMCO/AIOM/AICO Consensus Document on clinical and management pathways of cardio-oncology: executive summary.

Cardiovascular disease and cancer are leading causes of death. Both diseases share the same risk factors and, having the highest incidence and prevalence in the elderly, they often coexist in the same individual. Furthermore, the enhanced survival of cancer patients registered in the last decades and linked to early diagnosis and improvement of care, not infrequently exposes them to the appearance of ominous cardiovascular complications due to the deleterious effects of cancer treatment on the heart and circulatory system. The above considerations have led to the development of a new branch of clinical cardiology based on the principles of multidisciplinary collaboration between cardiologists and oncologists: Cardio-oncology, which aims to find solutions to the prevention, monitoring, diagnosis and treatment of heart damage induced by cancer care in order to pursue, in the individual patient, the best possible care for cancer while minimizing the risk of cardiac toxicity. In this consensus document we provide practical recommendations on how to assess, monitor, treat and supervise the candidate or patient treated with potentially cardiotoxic cancer therapy in order to treat cancer and protect the heart at all stages of the oncological disease. Cardiovascular diseases and cancer often share the same risk factors and can coexist in the same individual. Such possibility is amplified by the deleterious effects of cancer treatment on the heart. The above considerations have led to the development of a new branch of clinical cardiology, based on multidisciplinary collaboration between cardiologist and oncologist: the cardio-oncology. It aims to prevent, monitor, and treat heart damages induced by cancer therapies in order to achieve the most effective cancer treatment, while minimizing the risk of cardiac toxicity. In this paper, we provide practical recommendations on how to assess, monitor, treat and supervise patients treated with potential cardiotoxic cancer therapies.

Cardiac Complications of Cancer Therapy: Pathophysiology, Identification, Prevention, Treatment, and Future Directions.

Cardiotoxicity is an important complication of cancer therapy. With a significant improvement in the overall survival and prognosis of patients undergoing cancer therapy, cardiovascular toxicity of cancer therapy has become an important public health issue. Several well-established as well as newer anticancer therapies such as anthracyclines, trastuzumab, and other HER2 receptor blockers, antimetabolites, alkylating agents, tyrosine kinase inhibitors, angiogenesis inhibitors, checkpoint inhibitors, and thoracic irradiation are associated with significant cardiotoxicity. Cardiovascular imaging employing radionuclide imaging, echocardiography, and magnetic resonance imaging is helpful in early detection of the cardiotoxicity and prevention of overt heart failure. These techniques also provide important tools for understanding the mechanism of cardiotoxicity of these modalities, which would help develop strategies for the prevention of cardiac morbidity and mortality related to the use of these agents. An understanding of the mechanism of the cardiotoxicity of cancer therapies can help prevent and treat their adverse cardiovascular consequences. Clinical implementation of algorithms based upon cardiac imaging and several non-imaging biomarkers can prevent cardiac morbidity and mortality associated with the use of cardiotoxic cancer therapies.

Developing a cardiac monitoring plan in at-risk cancer survivors.

133 Background: Improvements in early detection, screening, and treatment of cancer translate into survivors living longer, highlighting the need for guidelines to address the late and long-term effects of cancer treatment. A particularly concerning effect is Cancer Therapeutics-Related Cardiac Dysfunction (CTRCD). Cancer treatments can result in a range of cardiovascular toxicity including left ventricular dysfunction, heart failure and radiation-induced heart disease (RIHD). Various consensus statements related to cardiovascular care for adult cancer survivors exist; however there are no globally accepted follow-up guidelines. Our purpose is to create a protocol to stratify a survivor’s cardiac risk and provide a basis for follow-up recommendations. Methods: We first evaluated existing resources within our institution and identified key stakeholders who were recruited to form a multidisciplinary workgroup (2 survivorship advanced practice providers, an oncologist, a radiation oncologist, and 2 cardio-oncologists). We then reviewed current research and literature on cardiotoxic cancer therapies and identified two consensus statements from the American Society of Echocardiography and the European Association of Cardiovascular Imaging which helped inform our protocol. Finally, we created a cardiac assessment that could be applied in the pre-treatment phase and extend into the post-treatment phase. Results: Two assessment tools were developed. The first is an algorithm initiated in the pre-treatment setting by an oncologist when a Type I or Type II cardiotoxic agent is planned. The second is a risk assessment tool that is initiated in the post-treatment setting to stratify cardiac risk and provide follow-up recommendations. Conclusions: Development of standardized guidelines for assessment and treatment of late and long-term effects of treatment is critical. This protocol has been developed to account for the many factors that contribute to overall cardiac risk after various anti-cancer therapies. Further data is needed to evaluate long-term cardiac and survival outcomes based on this protocol.

Cardiovascular risk and communication among early stage breast cancer survivors

ObjectiveAfrican American (AA) women have disproportionately high rates of cardiovascular (CV) risk factors that, coupled with potentially cardiotoxic breast cancer (BC) therapies, place them at risk of adverse CV outcomes. The purpose of this study was to assess CV risk factors among white and AA BC survivors and perceptions of patient-provider CV-related communication and post-treatment information needs. MethodsEarly-stage, English-speaking BC survivors were recruited through community-based survivorship organizations/clinics in New Jersey. Qualitative, semi-structured interviews and a brief survey of socio-demographics and comorbidities were conducted. ResultsBC survivors reported high rates of CV risk factors. Most reported their health as good/excellent despite their cancer history and CV risk profile. Approximately half of overweight/obese BC survivors reported no weight-related conversation with their health care team and, among those who reported discussion, 36% indicated it was self-initiated and dismissed. More than half of BC survivors’ reported a desire for lifestyle-related information and guidance. ConclusionBC survivors may not understand how their separate, yet cumulative, health issues can impact their CV risk. Practice implicationsPatient-provider communication on behavioral risk factor modification and CV risk is needed, particularly among at-risk subgroups such as AA and obese BC survivors, to improve BC and CV outcomes.

ANMCO/AICO/AIOM Consensus document: Clinical and management pathways in cardio-oncology

In Italy, cardiovascular diseases and cancer are the leading causes of death. Both diseases share the same risk factors and, having the highest incidence and prevalence in the elderly, they often coexist in the same individual. Furthermore, the enhanced survival of cancer patients registered in the last decades and linked to early diagnosis and improvement of care, not infrequently exposes them to the appearance of ominous cardiovascular complications due to the deleterious effects of cancer treatment on the heart and circulatory system. The above considerations have led to the development of a new branch of clinical cardiology based on the principles of multidisciplinary collaboration between cardiologists and oncologists: Cardio-oncology, which aims to find solutions to the prevention, monitoring, diagnosis and treatment of heart damage induced by cancer care in order to pursue, in the individual patient, the best possible care for cancer while minimizing the risk of cardiac toxicity. In this consensus document we provide practical recommendations on how to assess, monitor, treat and supervise the candidate or patient treated with potentially cardiotoxic cancer therapy in order to treat cancer and protect the heart at all stages of the oncological disease.

Noninvasive Measures of Ventricular-Arterial Coupling and Circumferential Strain Predict Cancer Therapeutics–Related Cardiac Dysfunction

ObjectivesThis study sought to determine the relationships between echocardiography-derived measures of myocardial mechanics and cancer therapeutics–related cardiac dysfunction (CTRCD). BackgroundDoxorubicin and trastuzumab are highly effective breast cancer therapies, but have a substantial risk of CTRCD. There is a critical need for the early detection of patients at increased risk of toxicity. MethodsWe performed a prospective, longitudinal cohort study of breast cancer participants undergoing doxorubicin and/or trastuzumab therapy. Echocardiography was performed prior to therapy initiation (baseline) and at standardized follow-up intervals during and after completion of therapy. Ejection fraction (EF), strain, strain rate, and ventricular-arterial coupling (effective arterial elastance [Ea]/end-systolic elastance [Eessb]) were quantitated. CTRCD was defined as a ≥10% reduction in EF from baseline to <50%. Multivariable logistic regression models were used to determine the associations between baseline levels and changes from baseline in echocardiographic measures and CTRCD. Receiver-operating characteristic curves were used to evaluate the predictive ability of these measures. ResultsIn total, 135 participants contributed 517 echocardiograms to the analysis. Over a median follow-up time of 1.9 years (interquartile range: 0.9 to 2.4 years), 21 participants (15%) developed CTRCD. In adjusted models, baseline levels and changes in Ea/Eessb, circumferential strain, and circumferential strain rate were associated with 21% to 38% increased odds of CTRCD (p < 0.001). Changes in longitudinal strain (p = 0.037), radial strain (p = 0.015), and radial strain rate (p = 0.006) were also associated with CTRCD. Ea/Eessb (area under the curve: 0.703; 95% confidence interval: 0.583 to 0.807) and circumferential strain (area under the curve: 0.655; 95% confidence interval: 0.517 to 0.767) demonstrated the greatest predictive utility. Sensitivity analyses using an alternative CTRCD definition did not impact our results. ConclusionsOver an extended follow-up time, ventricular-arterial coupling and circumferential strain were strongly predictive of CTRCD. Our findings suggest a noninvasive strategy to identify high-risk patients prior to, during, and after cardiotoxic cancer therapy.

Long-Term Outcomes After Cardiotoxic Cancer Therapy in Children

What are the long-term consequences of having received cardiotoxic therapy for childhood cancer? To answer this question, researchers enrolled 1800 adults (age, ≥18; median age, 31) who had received anthracycline chemotherapy or cardiac-directed radiation for childhood cancer at least 10 years earlier. Most participants had received treatment …

Abstract 13501: Measures of Three-dimensional Left Ventricular Mechanics Deteriorate Acutely After Cardiotoxic Cancer Therapy

Background: Doxorubicin and trastuzumab are commonly used breast cancer therapies with established cardiotoxic effects. However, the changes in myocardial mechanics with cancer therapy cardiotoxicity remain poorly defined, and noninvasive measures are needed to identify patients at increased risk. Our objective was to define the acute changes in three-dimensional (3D) echocardiography-derived indices of cardiac mechanics in patients receiving these therapies. Methods: In a prospective, longitudinal cohort of women with breast cancer receiving doxorubicin and/or trastuzumab, we obtained 3D echocardiography images before therapy (baseline) and during therapy at 3 months and 1 year of follow-up. Images were acquired at a minimum of 22 frames per second and analyzed by two readers using a vendor-independent analysis platform (TomTec Cardiac Performance Analyses, Unterschleissheim, Germany). Left ventricular twist, torsion, and principal strain were quantitated semi-automatically using 3D speckle tracking imaging. Standard descriptive statistics were used to summarize these measures over time. Results: Eighty-seven patients (mean age at baseline 49 years, 65% Caucasian) contributed at least 1 observation to the analysis. At baseline, median twist was 10.96° (interquartile range [IQR] 6.64, 13.59), torsion was 1.41°/cm (IQR 0.86, 1.70), and principal strain was -30.40% (-33.64, -28.55). At 3 months and 1 year, there were consistent declines in twist, torsion, and principal strain as displayed in Table I. Conclusions: In a prospective cohort of women with breast cancer receiving doxorubicin and/or trastuzumab, left ventricular twist, torsion, and principal strain declined over the first year of therapy. Ongoing research is focused on determining the clinical significance of these changes over time. Table 1. Longitudinal changes in 3D twist, torsion, and principal strain; summaries presented as median (interquartile range).

Cardiovascular prevention in the cancer survivor.

Cancer survivorship should be defined starting not from completion of treatment, but from the time of diagnosis. Assessing and controlling the cancer patient's cardiovascular risk before, during, and after treatment is crucial to improving their overall outcome. There are many cancer therapies, including but not limited to anthracyclines, radiation, and vascular signaling pathway inhibitors which should be considered nontraditional cardiovascular risk factors with significant morbidity. Monitoring novel populations, such as a younger age group, for ischemic coronary disease or congestive heart failure (CHF) is not intuitive to many clinicians. Symptoms of CHF and coronary artery disease overlap with common side effects of cancer and cancer treatment. Cancer survivors may also have fewer typical symptoms of cardiovascular disease. Increased surveillance and aggressive control of cardiovascular disease is important in cancer patients both while undergoing active treatment and in the long term. Despite the increasing interest in cardio-oncology, data-driven guidelines are lacking due to small study sizes and low event rates over a short period of time. Most practice guidelines have been based on clinical practice and expert opinion. The list of cardiotoxic cancer therapies continues to grow each year. This review is not intended to be a comprehensive review of all cancer therapy toxicity, but will focus on recent literature regarding prevention of CHF and coronary artery disease (CAD) during active cancer therapy as well as current screening guidelines for long-term survivors.

Left Ventricular Dysfunction in Patients Receiving Cardiotoxic Cancer Therapies: Are Clinicians Responding Optimally?

The purpose of this study was to examine treatment practices for cancer therapy-associated decreased left ventricular ejection fraction (LVEF) detected on echocardiography and whether management was consistent with American College of Cardiology/American Heart Association guidelines. Patients treated with anthracyclines or trastuzumab are at risk of cardiotoxicity. Decreased LVEF represents a Class I indication for drug intervention according to American College of Cardiology/American Heart Association guidelines. Patients receiving anthracycline or trastuzumab at Stanford University from October 2005 to October 2007 and who had undergone echocardiography before and after receiving an anthracycline or trastuzumab were identified. Chart review examined chemotherapy regimens, cardiac risk factors, imaging results, concomitant medications, and cardiology consultations. Eighty-eight patients received therapy with an anthracycline or trastuzumab and had a pre-treatment and follow-up echocardiogram. Ninety-two percent were treated with anthracyclines, 17% with trastuzumab after an anthracycline, and 8% with trastuzumab without previous treatment with anthracycline. Mean baseline LVEF was 60%, with 14% having a baseline <55%. Forty percent had decreased LVEF (<55%) after anthracycline and/or trastuzumab treatment. Of these patients, 40% received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, 51% beta-blocker therapy, and 54% cardiology consultation. Of patients with asymptomatic decreased LVEF, 31% received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, 35% beta-blocker therapy, and 42% cardiology consultation. Of those with symptomatic decreased LVEF, 67% received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, 100% beta-blocker therapy, and 89% cardiology consultation. Many cancer survivors are not receiving treatment consistent with heart failure guidelines. There is substantial opportunity for collaboration between oncologists and cardiologists to improve the care of oncology patients receiving cardiotoxic therapy.