How We Monitor Cardiac Health in Breast Cancer Survivors.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.

Cardiovascular disease in thymic cancer patients.

Introduction: Cancer patients may have increased risk for adverse cardiac events, but our understanding of cardiovascular risk in thymic cancer patients is not clear. We sought to characterize baseline cardiometabolic risk factors before thymic cancer diagnosis and the potential association between cancer treatment and subsequent cardiac events. Methods: This was a retrospective cohort study evaluating patients with thymic cancer from 2003 to 2020 compared to age- and sex-matched controls without cancer. Baseline cardiovascular risk factors, cancer characteristics, and incidence of cardiac events were collected from the health information exchange. Multivariable regression was used to examine the impact of cardiovascular risk factors and cancer therapies. Results: We compared 296 patients with pathology-confirmed thymic cancer to 2,960 noncancer controls. Prior to cancer diagnosis, thymic cancer patients (TCPs) had lower prevalence of hypertension, dyslipidemia, and diabetes mellitus and similar rates of obesity, tobacco use, and pre-existing cardiovascular disease (CVD) compared to controls. After diagnosis, high-risk TCPs (>2 cardiovascular risk factors or pre-existing CVD) had higher risk for cardiac events (HR 3.73, 95% CI 2.88-4.83, p < 0.001). In the first 3 years after diagnosis, TCPs had higher incidence of cardiac events (HR 1.38, 95% CI 1.01-1.87, p = 0.042). High-risk TCPs who received radiotherapy or chemotherapy had higher risk of cardiac events (HR 4.99, 95% CI 2.30-10.81, p < 0.001; HR 6.24, 95% CI 2.84-13.72, p < 0.001). Discussion/conclusion: Compared to noncancer controls, TCPs experienced more cardiac events when adjusted for risk factors. Patients with multiple cardiovascular risk factors receiving radiotherapy or chemotherapy had higher incidence of cardiac events.

Cardiovascular Risks in Testicular Cancer: Assessment, Prevention, and Treatment.

PURPOSE OF REVIEW: Testicular cancer (TC) is the leading cancer in men between 18 and 39 years of age. Current treatment involves tumor resection followed by surveillance and/or one or more lines of cisplatin-based chemotherapy (CBCT) and/or bone marrow transplant (BMT). Ten years after treatment, CBCT has been associated with significant atherosclerotic cardiovascular disease (CVD) including myocardial infarction (MI), stroke, and heightened rates of hypertension, dyslipidemia, diabetes mellitus, and metabolic syndrome (MetS). Additionally, low testosterone levels and hypogonadism contribute to MetS and may further drive CVD. RECENT FINDINGS: CVD in TCS has been associated with worse physical functioning accompanied by role limitations, decreased energy, and decreased overall health. Exercise may play a role in ameliorating these effects. Systematic CVD screening practices are needed at TC diagnosis and in survivorship. We encourage a multidisciplinary partnership between primary care physicians, cardiologists, cardio-oncologists, medical oncologists, and survivorship providers to address these needs.

Fluoropyrimidine Cardiotoxicity: Incidence, Outcomes, and Safety of Rechallenge.

PURPOSE OF REVIEW: Fluoropyrimidine (FDP) chemotherapy regimens used in the treatment of solid tumors such as breast, gastrointestinal, and hepatobiliary malignancies have led to significant survival benefits. However, FDP cardiotoxicity can lead to premature termination of FDP-based chemotherapy treatments. Resuming these crucial therapies after initial FDP cardiotoxicity can be challenging for patients and healthcare providers. RECENT FINDINGS: Symptomatic cardiotoxicity occurs in up to 35% of patients treated with FDP-based chemotherapy. The most common symptom is chest pain, but palpitations, dyspnea, myocardial infarction, cardiogenic shock, and cardiac arrest can also occur. Several large studies have attempted to discern clinical and genetic risk factors in those who develop FDP cardiotoxicity. With cardiac risk factor optimization and aggressive pre-treatment with anti-anginal agents, rechallenging with FDP is possible and allows patients to resume optimal cancer-directed treatment. FDP cardiotoxicity remains a poorly understood identity. We highlight several recent publications attempting to define the risk factors associated with developing FDP cardiotoxicity. The management of FDP cardiotoxicity and consideration of rechallenge of FDP-based regimens highlights the importance of a multidisciplinary partnership between oncologists and cardiologists/cardio-oncologists.

Cisplatin, environmental metals, and cardiovascular disease: an urgent need to understand underlying mechanisms.

Significantly increased risks of cardiovascular disease occur in testicular cancer survivors given cisplatin-based chemotherapy. The postulated mechanism of platinum-based chemotherapy's vascular toxicity has been thought secondary to its different early- and late- effects on vascular injury, endothelial dysfunction, and induction of a hypercoagulable state. We highlight for the first time the similarities between platinum-associated vascular adverse events and the vascular toxicity associated with other xenobiotic-metal contaminants. The vascular toxicity seen in large epidemiologic studies of testicular cancer survivors may in part be similar and mechanistically linked to the risk seen in environmental heavy metal contaminants linked to cardiovascular disease. Future research should be directed to better understand the magnitude of the adverse cardiovascular effects of platinum and to elucidate the underlying mechanisms of action.

Early Cardiac Effects of Contemporary Radiation Therapy in Patients With Breast Cancer.

PURPOSE: To characterize the early changes in echocardiographically derived measures of cardiac function with contemporary radiation therapy (RT) in breast cancer and to determine the associations with radiation dose-volume metrics, including mean heart dose (MHD). METHODS AND MATERIALS: In a prospective longitudinal cohort study of 86 patients with breast cancer treated with photon or proton thoracic RT, clinical and echocardiographic data were assessed at 3 time points: within 4 weeks before RT initiation (T0), within 3 days before 6 weeks after the end of RT (T1), and 5 to 9 months after RT completion (T2). Associations between MHD and echocardiographically derived measures of cardiac function were assessed using generalized estimating equations to define the acute (T0 to T1) and subacute (T0 to T2) changes in cardiac function. RESULTS: The median estimates of MHD were 139 cGy (interquartile range, 99-249 cGy). In evaluating the acute changes in left ventricular ejection fraction (LVEF) from T0 to T1, and accounting for the time from RT, age, race, preexisting cardiovascular disease, and an interaction term with anthracycline or trastuzumab exposure and MHD, there was a modest decrease in LVEF of borderline significance (0.22%; 95% confidence interval [CI], -0.44% to 0.01%; P = .06) per 30-day interval for every 100 cGy increase of MHD. Similarly, there was a modest worsening in longitudinal strain (0.19%; 95% CI, -0.01% to 0.39%; P = .06) per 30-day interval for each 100 cGy increase in MHD. We did not find significant associations between MHD and changes in circumferential strain or diastolic function. CONCLUSIONS: With modern radiation planning techniques, there are modest subclinical changes in measures of cardiac function in the short-term. Longer-term follow-up studies are needed to determine whether these early changes are associated with the development of overt cardiac disease.

Cardioprotective strategies to prevent breast cancer therapy-induced cardiotoxicity.

Breast cancer is the most common malignancy affecting females, with over 260,000 new cases annually and over 3.1 million survivors in the United States alone. Exposure to potentially cardiotoxic therapies, including anthracyclines, trastuzumab, and radiation therapy, coupled with host factors, place patients at increased risk for the development of cardiovascular disease (CVD) compared to non-cancer controls. Overall survival outcomes are significantly worse in patients who develop CVD, and in certain breast cancer populations, cardiovascular death exceeds the risk of cancer death in the long-term. In order to mitigate the risk of CVD, there is a growing interest in the use of cardioprotective strategies at the time of cancer therapy initiation. In this review, we present a detailed evaluation of the evidence from recently completed as well as ongoing cardio-oncology clinical trials in pharmacologic cardioprotection in breast cancer patients. We focus primarily on the potential role of dexrazoxane, alterations in anthracycline dosing or formulation, neurohormonal antagonists, beta-blockers, and combination therapy. We also discuss ongoing studies in statin cardioprotection, radiation delivery strategies, use of risk-guided strategies and the study of specific cancer populations. We close with a discussion of the ongoing needs in the field of cardio-oncology in order to advance the clinical care of patients with rigorous, evidence-based medicine.

Applications of left ventricular strain measurements to patients undergoing chemotherapy.

PURPOSE OF REVIEW: We aim to summarize the utility of strain in monitoring the effects of cancer therapy-related cardiotoxicity (CTRC) on the development of left ventricular (LV) dysfunction. RECENT FINDINGS: Serial assessment of cardiac function at baseline and during treatment is recommended in patients undergoing cancer treatment. Historically, the use of left ventricular ejection fraction (LVEF) has been used to monitor for cardiac toxicity from cancer therapies but myocardial mechanic parameters, in particular global longitudinal strain (GLS), have emerged as powerful adjunctive tools. On the basis of longitudinal cohort studies in patients treated with anthracyclines and trastuzumab and retrospective studies of childhood survivors of cancers, strain has been used to detect subclinical LV dysfunction prior to changes in LVEF. Strain parameters decrease during both anthracycline and trastuzumab and these changes can persist after completion of therapy. Baseline GLS and changes in GLS during therapy can be independently prognostic for developing CTRC. Further, GLS has appeared to have an additive predictive value in addition to the traditional clinical parameters and baseline LVEF in the development of cardiotoxicity. The inclusion of strain parameters in clinical decision making and therapeutic planning is an area of intense research. SUMMARY: This review seeks to highlight the importance of echocardiographic strain measurements in early detection, treatment and prevention of LV dysfunction from CTRC.

Left Ventricular Dysfunction and Chemotherapeutic Agents.

PURPOSE OF REVIEW: We aim to summarize the effect of cancer therapy-related cardiotoxicity on the development of left ventricular (LV) dysfunction. RECENT FINDINGS: We discuss commonly used cancer therapeutics that have the potential for both acute and delayed cardiotoxicity. LV dysfunction from cancer therapies may be found by routine cardiac imaging prior to clinical manifestations of heart failure (HF) and we discuss the current multi-modality approaches for early detection of toxicity with the use of advanced echocardiographic parameters including strain techniques. Further, we discuss the role of biomarkers for detection of LV dysfunction from cancer therapies. Current approaches monitoring and treating LV dysfunction related to cancer therapy-related cardiotoxicity include addressing modifiable cardiovascular risk factors especially hypertension and early initiation of neurohormonal blockade (NHB) with disease-modifying beta-blockers and renin-angiotensin-aldosterone system (RAAS) inhibitors. Once LV dysfunction is identified, traditional ACC/AHA guideline-directed therapy is employed. Further, we highlight the use of advanced heart failure therapies including mechanical resynchronization devices, the use of durable ventricular assist devices, and cardiac transplantation as increasingly employed modalities for treatment of severe LV dysfunction and advanced heart failure in the cardio-oncology population. This review seeks to highlight the importance of early detection, treatment, and prevention of LV dysfunction from cancer therapy-related cardiotoxicity.

Carfilzomib-Associated Cardiovascular Adverse Events: A Systematic Review and Meta-analysis.

IMPORTANCE: Cardiovascular adverse events (CVAE) with carfilzomib in patients with multiple myeloma can be potentially life-threatening and remain incompletely characterized. We performed the first systematic review and meta-analysis of carfilzomib-associated CVAE. OBJECTIVE: To determine the incidence of carfilzomib-associated CVAE and to compare the rates of carfilzomib CVAE among different doses and companion therapies. DATA SOURCES: PubMed, EMBASE, Web of Science, and clinicaltrials.gov were queried for the keywords "carfilzomib," "Kyprolis," and "PX-171" through January 1, 2017. STUDY SELECTION: Phase 1 to 3 prospective clinical trials of carfilzomib in patients with multiple myeloma with evaluable toxic effects data were eligible for meta-analysis. DATA EXTRACTION AND SYNTHESIS: Data were independently extracted by 2 reviewers following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Pooled incidence rates and relative risks (for randomized trials) and 95% confidence intervals were calculated using a random effects model. Subgroup analyses were performed to assess study-level characteristics associated with CVAE. MAIN OUTCOMES AND MEASURES: Cardiovascular adverse events were defined as heart failure, hypertension, ischemia, and arrhythmia. All-grade and grades 3 or higher AEs and study characteristics were recorded. RESULTS: A total of 514 studies were assessed for eligibility. Of those, 24 studies were eligible, including a total of 2594 patients with multiple myeloma. All-grade and grades 3 and higher CVAE were seen in 617 (18.1%) and 274 (8.2%), respectively. Phase 2 or 3 studies and carfilzomib doses of 45 mg/m2 or higher were associated with high-grade CVAE. Median age older than 65 years, prior myeloma therapies, and concurrent myeloma therapies were not associated with CVAE. For the 3 randomized clinical trials, the summary relative risk of all-grade and grade 3 or higher CVAE for patients receiving carfilzomib compared with noncarfilzomib-receiving control patients were 1.8 and 2.2, respectively. CONCLUSIONS AND RELEVANCE: Carfilzomib was associated with a significant incidence of CVAE, with higher rates seen with higher doses of carfilzomib. Phase 1 studies may be underdetecting CVAE. Future studies are needed to identify patients at high risk for CVAE, develop optimal monitoring strategies, and explore strategies to mitigate these risks.

Left atrial abnormality (LAA) as a predictor of ibrutinib-associated atrial fibrillation in patients with chronic lymphocytic leukemia.

Results from several recent studies in chronic lymphocytic leukemia (CLL) have demonstrated an association between ibrutinib exposure and the development of atrial fibrillation, estimated incidence of 11% with long-term follow up. This is a common cause of ibrutinib discontinuation. Risk factors for atrial fibrillation include advanced age, hypertension (HTN), mitral valve disease (MVD), left atrial remodeling, coronary artery disease (CAD) and risk factors for cardiovascular dysfunction We conducted a retrospective case control study using the presence of left atrial abnormality identified on pre-ibrutinib EKGs, defined as either (1) Lead II-bifed p wave, with 40 mcsec between peaks for ≥ 2.5 mm wide ≥ 100 msec in duration, (2) Lead V1-biphasic P wave with terminal portion ≥ 40 msec in duration or terminal portion ≥ 1 mm deep or (3) PR interval ≥ 200 msec (intra-atrial conduction delay) as a predictor for development of atrial fibrillation. 183 consecutively CLL patients treated with ibrutinib were identified. 44 patients met inclusion criteria (20 cases, 24 controls). 20 (11.3%) of patients developed atrial fibrillation. Left atrial enlargement was identified as a significant predictor of development of atrial fibrillation (OR 9.1, 95% CI 2.2-37.3, p=0.02). Age, baseline HTN, CAD, diabetes, age and sex were not significant predictors. Area under the ROC curve for the model was estimated to be 75%. LAA identified by EKG is a moderately specific and sensitive finding that can identify patients at increased risk for this toxicity.

Fluoropyrimidine-induced cardiac toxicity: challenging the current paradigm.

BACKGROUND: Fluoropyrimidine chemotherapy [5-fluorouracil (5-FU) and capecitabine] are commonly used agents in the treatment of various solid malignancies. However, their use has been limited by cardiac toxicity, presenting as a wide spectrum of asymptomatic (e.g., EKG changes) and symptomatic (e.g., chest pain) manifestations related to coronary vasospasm leading to myocardial ischemia. Historically, patients with suspected coronary vasospasm have been treated with traditional acute ischemic workup and various combinations of anti-anginal therapies. In addition, most patients typically are not rechallenged with fluoropyrimidine after experiencing initial cardiovascular side-effects with resulting interruption of planned chemotherapy regimens. METHODS: We report a case series of 11 consecutive patients in a single-center with suspected fluoropyrimidine-induced coronary vasospasm who were successfully rechallenged with the culprit drug to allow for planned chemotherapy completion. Our protocol utilized rechallenge with bolus infusional regimen of intravenous fluoropyrimidine chemotherapy and oral capecitabine with cardioprotective pretreatment with two calcium blockers and long-acting oral nitrate therapy. RESULTS: We were successfully able to continue and complete the previously planned first-line chemotherapy regimen for all 11 patients with minimal therapeutic interruption. There have been no cardiac events or evidence of recurrent coronary spasm after completion of therapy with discontinuation of prophylactic medications upon therapy completion. CONCLUSIONS: We report a single-institution experience of successful rechallenge with fluoropyrimidines with careful cardiac monitoring and the combined use of calcium channel blockers and long-acting nitrates. With further study, this algorithm can be used to safely continue fluoropyrimidines, a potentially curative regimen in the treatment of many solid tumors.