Immune Checkpoint Inhibitors and Cardiotoxicity: A Comparative Meta-Analysis of Observational Studies and Randomized Controlled Trials.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have uncommon associations with cardiotoxicity, yet these cardiotoxic effects are associated with high mortality. An accurate assessment of risk for cardiotoxicity is essential for clinical decision-making, but data from randomized controlled trials often differ from real-world observational studies. METHODS AND RESULTS: A systematic search of PubMed, Embase, Cochrane Library, and Scopus was performed, including phase II and III randomized controlled trials (RCTs) and observational studies (OSs) reporting myocarditis or pericardial disease, myocardial infarction, or stroke with an immunotherapy. Odds ratios (ORs) were used to pool results between ICIs and other cancer therapy in RCTs and OSs. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline was followed. In total, 54 RCTs (N=38 264) and 24 OSs (N=12 561 455) were included. In RCTs, ICI use resulted in higher risk of myocarditis (OR, 3.55 [95% CI, 2.10-5.98]), pericardial disease (OR, 2.73 [95% CI, 1.57-4.77]), and myocardial infarction (OR, 1.83 [95% CI, 1.03-3.25]), compared with non-ICI (placebo or chemotherapy). In OSs, ICI use was not associated with myocarditis, pericardial disease, or myocardial infarction compared with controls; however, combination ICIs demonstrated higher risk of myocarditis compared with single ICI use (OR, 3.07 [95% CI, 1.28-7.39]). Stroke risk was not increased with use of ICIs in RCTs. CONCLUSIONS: We demonstrated increased risk of ICI myocarditis, pericardial disease, and myocardial infarction in RCTs but not OSs. Results of this study suggest there are differences between ICI cardiotoxicity risk, possibly suggesting differences in diagnoses and management, in clinical trials versus the OSs.

Androgen Deprivation Therapy/Androgen Receptor Signaling Inhibitor Treatments for Prostate Cancer: Pathophysiology and Review of Effects on Cardiovascular Disease.

Androgen deprivation therapy is the cornerstone of systemic management for prostate cancer but is associated with multiple adverse effects that must be considered during treatment. These effects occur because of the profound hypogonadism that is induced from lack of testosterone or due to the medications used in the treatment or in combination with androgen receptor signaling inhibitors. This article critically reviews the associations between androgen deprivation therapy, androgen receptor signaling inhibitors, and cardiovascular complications such as prolonged QT interval, atrial fibrillation, heart failure, atherosclerosis, coronary heart disease, venous thromboembolism, and peripheral arterial occlusive disease. These unfavorable outcomes reinforce the need for regular cardiovascular screening of patients undergoing androgen deprivation for the management of prostate cancer.

Soluble urokinase plasminogen activator receptor and cardiotoxicity in doxorubicin-treated breast cancer patients: a prospective exploratory study.

BACKGROUND: Soluble urokinase plasminogen activator receptor is an inflammatory biomarker that may prognosticate cardiovascular outcomes. We sought to determine the associations between soluble urokinase plasminogen activator receptor and established markers of cardiotoxicity in breast cancer patients receiving doxorubicin. METHODS: We conducted a prospective cohort study of women with newly diagnosed breast cancer receiving standard-dose doxorubicin (240 mg/m2) at Rush University Medical Center and Rush Oak Park Hospital (Chicago, IL) between January 2017 and May 2019. Left ventricular ejection fraction, global longitudinal strain, and cardiac biomarkers (N-terminal prohormone B-type natriuretic peptide, troponin-I, and high-sensitivity C-reactive protein) were measured at baseline and at intervals up to 12-month follow-up after end of treatment. The associations between soluble urokinase plasminogen activator receptor and these endpoints were evaluated using multivariable mixed effects linear regression. RESULTS: Our study included 37 women (mean age 47.0 ± 9.3 years, 60% white) with a median baseline soluble urokinase plasminogen activator receptor level of 2.83 ng/dL. No participant developed cardiomyopathy based on serial echocardiography by one-year follow-up. The median percent change in left ventricular strain was -4.3% at 6-month follow-up and absolute changes in cardiac biomarkers were clinically insignificant. There were no significant associations between soluble urokinase plasminogen activator receptor and these markers of cardiotoxicity (all p > 0.05). CONCLUSIONS: In this breast cancer cohort, doxorubicin treatment was associated with a very low risk for cardiotoxicity. Across this narrow range of clinical endpoints, soluble urokinase plasminogen activator receptor was not associated with markers of subclinical cardiotoxicity. Further studies are needed to clarify the prognostic utility of soluble urokinase plasminogen activator receptor in doxorubicin-associated cardiomyopathy and should include a larger cohort of leukemia and lymphoma patients who receive higher doses of doxorubicin.

Global Cardio Oncology Registry (G-COR): Registry Design, Primary Objectives, and Future Perspectives of a Multicenter Global Initiative.

BACKGROUND: Global collaboration in cardio-oncology is needed to understand the prevalence of cancer therapy-related cardiovascular toxicity in different risk groups, practice settings, and geographic locations. There are limited data on the socioeconomic and racial/ethnic disparities that may impact access to care and outcomes. To address these gaps, we established the Global Cardio-Oncology Registry, a multinational, multicenter prospective registry. METHODS: We assembled cardiologists and oncologists from academic and community settings to collaborate in the first Global Cardio-Oncology Registry. Subsequently, a survey for site resources, demographics, and intention to participate was conducted. We designed an online data platform to facilitate this global initiative. RESULTS: A total of 119 sites responded to an online questionnaire on their practices and main goals of the registry: 49 US sites from 23 states and 70 international sites from 5 continents indicated a willingness to participate in the Global Cardio-Oncology Registry. Sites were more commonly led by cardiologists (85/119; 72%) and were more often university/teaching (81/119; 68%) than community based (38/119; 32%). The average number of cardio-oncology patients treated per month was 80 per site. The top 3 Global Cardio-Oncology Registry priorities in cardio-oncology care were breast cancer, hematologic malignancies, and patients treated with immune checkpoint inhibitors. Executive and scientific committees and specific committees were established. A pilot phase for breast cancer using Research Electronic Data Capture Cloud platform recently started patient enrollment. CONCLUSIONS: We present the structure for a global collaboration. Information derived from the Global Cardio-Oncology Registry will help understand the risk factors impacting cancer therapy-related cardiovascular toxicity in different geographic locations and therefore contribute to reduce access gaps in cardio-oncology care. Risk calculators will be prospectively derived and validated.

Artificial intelligence modelling to assess the risk of cardiovascular disease in oncology patients.

Aims: There are no comprehensive machine learning (ML) tools used by oncologists to assist with risk identification and referrals to cardio-oncology. This study applies ML algorithms to identify oncology patients at risk for cardiovascular disease for referrals to cardio-oncology and to generate risk scores to support quality of care. Methods and results: De-identified patient data were obtained from Vanderbilt University Medical Center. Patients with breast, kidney, and B-cell lymphoma cancers were targeted. Additionally, the study included patients who received immunotherapy drugs for treatment of melanoma, lung cancer, or kidney cancer. Random forest (RF) and artificial neural network (ANN) ML models were applied to analyse each cohort: A total of 20 023 records were analysed (breast cancer, 6299; B-cell lymphoma, 9227; kidney cancer, 2047; and immunotherapy for three covered cancers, 2450). Data were divided randomly into training (80%) and test (20%) data sets. Random forest and ANN performed over 90% for accuracy and area under the curve (AUC). All ANN models performed better than RF models and produced accurate referrals. Conclusion: Predictive models are ready for translation into oncology practice to identify and care for patients who are at risk of cardiovascular disease. The models are being integrated with electronic health record application as a report of patients who should be referred to cardio-oncology for monitoring and/or tailored treatments. Models operationally support cardio-oncology practice. Limited validation identified 86% of the lymphoma and 58% of the kidney cancer patients with major risk for cardiotoxicity who were not referred to cardio-oncology.

Cancer Treatment-Related Cardiovascular Toxicity in Gynecologic Malignancies: JACC: CardioOncology State-of-the-Art Review.

Improvements in early detection and treatment of gynecologic malignancies have led to an increasing number of survivors who are at risk of long-term cardiac complications from cancer treatment. Multimodality therapies for gynecologic malignancies, including conventional chemotherapy, targeted therapeutics, and hormonal agents, place patients at risk of cancer therapy-related cardiovascular toxicity during and following treatment. Although the cardiotoxicity associated with some female predominant cancers (eg, breast cancer) have been well recognized, there has been less recognition of the potential adverse cardiovascular effects of anticancer therapies used to treat gynecologic malignancies. In this review, the authors provide a comprehensive overview of the cancer therapeutic agents used in gynecologic malignancies, associated cardiovascular toxicities, risk factors for cardiotoxicity, cardiac imaging, and prevention strategies.

Unusual vasovagal-type autonomic dysfunction secondary to immune checkpoint inhibitor therapy.

We present the case of a patient with oral squamous cell carcinoma treated with the programmed death ligand inhibitor, pembrolizumab, an immune checkpoint inhibitor. She subsequently developed vasovagal-type autonomic dysfunction thought to be secondary to the pembrolizumab. The patient's vasovagal symptoms resolved with the initiation of oral glucocorticoids.

Associations between sinus tachycardia and adverse cardiovascular outcomes and mortality in cancer patients.

BACKGROUND: Sinus tachycardia in cancer reflects a significant multi-system organ stressor and disease, with sparse literature describing its clinical significance. We assessed cardiovascular (CV) and mortality prognostic implications of sinus tachycardia in cancer patients. METHODS: We conducted a case-control study of 622 cancer patients at a U.S. urban medical center from 2008 to 2016. Cases had ECG-confirmed sinus tachycardia [heart rate (HR) ≥100 bpm] in ≥3 different clinic visits within 1 year of cancer diagnosis excluding a history of pulmonary embolism, thyroid dysfunction, left ventricular ejection fraction <50%, atrial fibrillation/flutter, HR >180 bpm. Adverse CV outcomes (ACVO) were heart failure with preserved ejection fraction (HFpEF), HF with reduced EF (HFrEF), hospital admissions for HF exacerbation (AHFE), acute coronary syndrome (ACS). Regression analyses were conducted to examine the effect of sinus tachycardia on overall ACVO and survival. RESULTS: There were 51 cases, age and sex-matched with 571 controls (mean age 70±10, 60.5% women, 76.4% Caucasian). In multivariate analysis over a 10-year follow-up period, sinus tachycardia (HR ≥100 vs. <100 bpm) was an independent predictor of overall ACVO (OR 2.8, 95% CI: 1.4-5.5; P=0.006). There was increased incidence of HFrEF (OR 3.3, 95% CI: 1.6-6.5; P=0.004) and AHFE (OR 6.3, 95% CI: 1.6-28; P=0.023), but not HFpEF or ACS (P>0.05) compared with controls. Sinus tachycardia was a significant predictor of overall mortality after adjusting for significant covariates (HR 2.9, 95% CI 1.8-5; P<0.001). CONCLUSIONS: Independent of typical factors that affect cardiovascular disease, sinus tachycardia around the time of cancer treatment is associated with increased ACVO and mortality in cancer patients at 10 years of follow-up.

Role of Physical Activity and Cardiac Rehabilitation in Patients Undergoing Hematopoietic Stem Cell Transplantation.

Hematopoietic stem cell transplantation (HSCT) is a standard treatment for several malignancies, and >50,000 HSCT are performed annually worldwide. As survival after HSCT improves, cardiovascular disease and associated risk factors have gained importance as a significant cause of morbidity and mortality in this cohort. In this article, we detail the risk factors for cardiovascular disease and their impact in patients undergoing HSCT. Additionally, we critically review the data on the impact of physical exercise in patients undergoing HSCT. Although limited by significant heterogeneity in methodologies, small sample sizes, attrition, and lack of long-term cardiovascular follow-up, most of these studies reinforce the beneficial effects of physical activity and exercise in this patient population. Cardiac rehabilitation (CR) is a structured exercise and lifestyle modification program that is typically instituted in patients who experience acute cardiovascular events. We review the data on CR in the oncologic and nononcologic populations with an aim of building a framework for use of CR in HSCT patients.

Soluble Urokinase Plasminogen Activator Receptor Is Associated With Subclinical Myocardial Impairment by Speckle Tracking Echocardiography in Lung Cancer Patients.

BACKGROUND: Plasma cardiac biomarkers have emerged as a cost-effective diagnostic tool aimed at early identification of cardiotoxicity. Soluble urokinase plasminogen activator receptor (suPAR) is a bone marrow cell derived signaling molecule that is associated with cardiovascular disease outcomes. OBJECTIVES: We investigated associations between suPAR and global longitudinal strain (GLS) as a marker of early myocardial impairment in lung cancer patients. METHODS: We retrospectively analyzed 52 patients with stage IV non-small cell lung cancer with normal left ventricular ejection fraction (LVEF >55%) and without known heart disease or end-stage renal disease (ESRD). We studied associations between cardiac biomarkers and echocardiographic measures of systolic and diastolic function. GLS was analyzed using 2D speckle-tracking echocardiography via vendor-independent software (TomTec). RESULTS: Median plasma suPAR was 7.0 ng/mL (interquartile range: 5.4-9.0). Mean LVEF was 61.9 ± 8.3% and mean GLS was-19.3 ± 2.1%. Inter-observer reproducibility was excellent for GLS as determined by Intraclass Correlation Coefficient analysis, ICC = 0.81 (0.68-0.89). After multivariate analysis, suPAR was the only biomarker associated with GLS (p = 0.009). suPAR was also associated with diastolic parameters E velocity (p = 0.018), A velocity (p = 0.017), and E/E' ratio (p = 0.033). Interestingly, suPAR was not associated with LVEF (p = 0.916). In addition, suPAR and GLS were found to be age-independent predictors of all-cause mortality, though only GLS remained significant after multivariate adjustment. CONCLUSIONS: In this cohort of stage IV non-small cell lung cancer patients with normal LVEF and without known heart disease or ESRD, suPAR was associated with GLS and diastolic impairment. suPAR is a readily available inexpensive biomarker; further research is required to evaluate the possible role of suPAR in screening for subclinical LV dysfunction in the high-risk oncological population.

Cardiometabolic risk factors and survival after cancer in the Women's Health Initiative.

BACKGROUND: Cardiometabolic abnormalities are a leading cause of death among women, including women with cancer. METHODS: This study examined the association between prediagnosis cardiovascular health and total and cause-specific mortality among 12,076 postmenopausal women who developed local- or regional-stage invasive cancer in the Women's Health Initiative (WHI). Cardiovascular risk factors included waist circumference, hypertension, high cholesterol, and type 2 diabetes. Obesity-related cancers included breast cancer, colorectal cancer, endometrial cancer, kidney cancer, pancreatic cancer, ovarian cancer, stomach cancer, liver cancer, and non-Hodgkin lymphoma. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for important predictors of survival. RESULTS: After a median follow-up of 10.0 years from the date of the cancer diagnosis, there were 3607 total deaths, with 1546 (43%) due to cancer. Most participants (62.9%) had 1 or 2 cardiometabolic risk factors, and 8.1% had 3 or 4. In adjusted models, women with 3 to 4 risk factors (vs none) had a higher risk of all-cause mortality (HR, 1.99; 95% CI, 1.73-2.30), death due to cardiovascular disease (CVD) (HR, 4.01; 95% CI, 2.88-5.57), cancer-specific mortality (HR, 1.37; 95% CI, 1.1-1.72), and other-cause mortality (HR, 2.14; 95% CI, 1.70-2.69). A higher waist circumference was associated with greater all-cause mortality (HR, 1.17; 95% CI, 1.06-1.30) and cancer-specific mortality (HR, 1.22; 95% CI, 1.04-1.42). CONCLUSIONS: Among postmenopausal women diagnosed with cancer in the WHI, cardiometabolic risk factors before the cancer diagnosis were associated with greater all-cause, CVD, cancer-specific, and other-cause mortality. These results raise hypotheses regarding potential clinical intervention strategies targeting cardiometabolic abnormalities that require future prospective studies for confirmation. LAY SUMMARY: This study uses information from the Women's Health Initiative (WHI) to find out whether cardiac risk factors are related to a greater risk of dying among older women with cancer. The WHI is the largest study of medical problems faced by older women in this country. The results show that women who have 3 or 4 risk factors are more likely to die of any cause, heart disease, or cancer in comparison with women with no risk factors. It is concluded that interventions to help to lower the burden of cardiac risk factors can have an important impact on survivorship among women with cancer.

Resistance to antihypertensive drugs targeting Renin-Angiotensin-Aldosterone-System in cancer patients: a case series.

Hypertension impacts overall prognosis in cancer patients. There are no specific recommendations for its management in these patients. We report a case series of 5 cancer patients with suboptimal BP lowering and even worsening BP with ACEi or ARBs that improved to normal upon discontinuation of these drugs.

Heart dose and coronary artery calcification in patients receiving thoracic irradiation for lung cancer.

BACKGROUND: Thoracic irradiation (TIR) is associated with an increased risk of coronary artery disease (CAD) and coronary-related death. Lung cancer patients receive considerable doses of TIR, making them a high-risk population that may benefit from post-therapy surveillance. Coronary artery calcium (CAC) is a known biomarker of CAD development and may serve as a useful indicator of disease progression in this population. We hypothesized greater CAC progression in lung cancer patients subjected to higher whole heart radiation doses. METHODS: CAC progression (pre- and >2 years post-TIR) from chest CT scans of lung cancer patients were evaluated. A 2:1 matched control population was established controlling for age, gender, race, and CT scan interval. Vessel-specific CAC presence, progression, and extension in pre- and post-interval CT studies was evaluated by two blinded reviewers using the ordinal method. Dosimetric treatment files were restored and contours of the whole heart and proximal left anterior descending artery (LAD) were created within existing plans to compute radiation doses (Pinnacle Treatment Planning Software). Binary logistic regression analysis identified factors predictive for CAC development. Multiple logistic regression analysis with hierarchal method was used to assess covariates. RESULTS: Thirty-five patients and 65 controls (50% female) were evaluated; mean age 57 years, mean follow-up post-radiation 4.9±2.2 years. Average mean and maximum left anterior descending coronary artery (LAD) radiation doses were 19.9 Gy (95% CI, 14.1-25.7) and 30.7 Gy (95% CI, 23.8-37.5), respectively; 91.6% inter-observer variability. There was greater incidence of coronary calcification in irradiated patients (48.6% vs. 24.6%; P=0.01). In interval CT scans, a greater proportion of radiated patients demonstrated new coronary calcification (P=0.007) and extension within the LAD (P=0.003). Radiation exposure was the only independent predictor of new calcification (OR 3.1; 95% CI: 1.09-9.2). CONCLUSIONS: We identified both an increase in the development and progression of CAC in lung cancer patients receiving TIR. Future studies utilizing alternative cancer populations and larger sample sizes are necessary to further correlate radiographic and dosimetric observations to cardiovascular events.

Successful Triplet Pregnancy Post-Allogeneic Stem Cell Transplant in a Patient With Doxorubicin-Induced Cardiomyopathy.

We report the unique case of a patient who recovered cardiac function despite a history of doxorubicin-induced cardiomyopathy, chest radiation therapy, high dose chemotherapy post-allogeneic stem cell transplant, and triplet pregnancy. Data are sparse on doxorubicin-induced cardiomyopathy in pregnant patients, calling for further studies to help formulate management or surveillance recommendations. (Level of Difficulty: Advanced.).

Triplet therapies - the new standard of care for multiple myeloma: how to manage common toxicities.

Introduction: Multiple three drug combination regimens have been approved for the treatment of multiple myeloma in the last few years. Triplets have become the new standard of care for transplant eligible and ineligible patients with newly diagnosed as well as relapsed multiple myeloma. Novel agents have a unique profile of side effects. The management of toxicities is important to maintain quality of life and maximize treatment duration and benefit. Areas covered: This article reviews efficacy data, incidence of key adverse events and provide recommendations and expert opinion regarding how to manage common toxicities in triplet therapies. Relevant publications and abstracts were searched in PubMed, ASH, ASCO and EHA meetings. Guidelines from IMWG, NCCN, ESMO and ASCO, published trial protocols and prescribing information were used to formulate recommendations for the management of toxicities. Expert commentary: Side effects are a critical factor guiding the selection of optimal chemotherapy regimens for multiple myeloma. The majority of toxicities encountered with triplet therapies are reversible and can be readily managed with supportive care and dose modifications.