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Simple Summary Cardiac biomarkers have proved increasingly useful in the various branches of cardiology, not sparing the field of cardio-oncology. With specific reference to the latter subject, they have been investigated as predictors and/or diagnostic and monitoring tools, as well as prognostic factors, with the purpose of allowing the early prevention of many cardiovascular complications related to the direct action of some cancer types or related to the toxicity of its treatments. However, despite this great potential and excellent cost-effectiveness, their usefulness in some areas still seems to be limited due to lack of sufficient specificity or sensitivity. In fact, in clinical practice, while their use is nowadays standard in some circumstances, evidence does not yet support their routine use in other cases. Abstract In patients with cancer—and especially some specific subtypes—the heart can be pathologically affected due to the direct action of the tumor or its secretion products or due to the toxicity of some oncological treatments. Cardiac biomarkers have been investigated as inexpensive and easily accessible tools for prediction, early diagnosis, monitoring, or prognosis of various forms of cancer-related cardiac diseases. However, their clinical usefulness was not always clearly demonstrated in every area of cardioncology. For the identification of anthracycline related cardiotoxicity in the very early stages troponins proved to be more efficient detectors than imaging methods. Nevertheless, the lack of a standardized dosage methodology and of cardiotoxicity specific thresholds, do not yet allow to outline the precise way to employ them in clinical routine and to incorporate them into appropriate diagnostic or managing algorithms. Cardiac biomarkers proved also effective in patients with primary cardiac amyloidosis, in which both troponins and natriuretic peptides were able to predict adverse outcome, and carcinoid heart disease, where a precise diagnostic cut-off for N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was identified to screen patients with valvular involvement. Likewise, NT-proBNP proved to be an excellent predictor of postoperative atrial fibrillation (POAF). On the contrary, evidence is still not sufficient to promote the routine use of cardiac biomarkers to early diagnose myocarditis due to immune check points inhibitors (ICIs), radiotherapy induced cardiotoxicity and cardiac complications related to androgenetic deprivation. In this review we present all the evidence gathered so far regarding the usefulness and limitations of these relatively inexpensive diagnostic tools in the field of cardio-oncology.

Cardiac monitoring is becoming an important part of breast cancer care. Breast cancer and cardiovascular disease (CVD) share many common risk factors, and it is estimated that by the median age of diagnosis, many patients with breast cancer will have established or subclinical CVD. In addition, a number of treatments for metastatic breast cancer are known to have cardiac effects. As such, there is a clear need to prevent, identify, and effectively manage cardiovascular events in patients with breast cancer. Current clinical practice for patients with metastatic breast cancer involves a comprehensive set of assessments to ensure efficacy and safety of treatment. Adding cardiac monitoring to the assessments already required for patients with breast cancer may improve survival and quality of life. Currently, cardiac monitoring is recommended for several breast cancer treatments, and guidelines related to cardiac monitoring are available. Here, we review the risk of CVD in patients with breast cancer, providing an overview of the cardiac events associated with standard therapies for metastatic breast cancer. We also assess the current clinical recommendations relating to cardiac monitoring, and practical management strategies for oncologists. Cardio-oncology is a growing medical subspecialty that promotes the need for effective cancer therapy while minimizing cardiac effects. Integrating cardiac monitoring into routine clinical practice may safeguard patients with metastatic breast cancer against adverse cardiac effects. Implications for Practice This review details the common risk factors associated with cardiovascular disease that are frequently observed in patients with metastatic breast cancer, as well as the adverse cardiac effects of many therapies that are commonly prescribed. The review also provides a rationale for routine and comprehensive cardiovascular assessment of all patients at baseline, and during and after therapy depending on the treatment and presence of risk factors for cardiovascular disease. The medical discipline of cardio-oncology is increasingly being recognized as an important part of clinical practice to ensure effective cancer therapy while maintaining cardiac health.

Discovered in the 1960s, anthracyclines are still among the most widely used chemotherapy drugs, but are associated with cardiotoxicity. To date, the main strategies that seem to be effective in reducing its incidence and severity include screening and treating preexisting cardiovascular risk factors, limiting the cumulative anthracycline dose with a preference for less toxic analogues, and administering cardioprotective drugs as early as possible after its diagnosis. A better understanding of the underlying mechanisms and greater refinement of the diagnostic tools at our disposal has led to considerable progresses in the detection of this serious side effect at a preclinical stage, allowing for prompt intervention. However, despite increasing efforts to identify early predictors of cardiotoxicity and growing evidence of the importance of cardiac biomarkers for this purpose, large randomized multicenter clinical trials are still lacking and so there is still no scientific agreement on the best approach for early diagnosis. Nonetheless, dosing troponin at each chemotherapy cycle and initiating, when it increases above the threshold, a therapy with renin-angiotensin-aldosterone system inhibitors and/ or β-blockers has proved to be an effective strategy in reducing the progression of microscopic myocardial damage into left ventricular remodelling and clinically evident cardiotoxicity.

Anthracyclines are anti-neoplastic drugs presenting cardiotoxicity as a side effect. Cardiac troponins (cTn) and echocardiography are currently used to assess cardiac damage and dysfunction, but early biomarkers identifying patients in need of preventive treatments remain a partially met need. Circulating microRNAs (miRNAs) represent good candidates, so we investigated their possible roles as predictors of troponin elevation upon anthracycline treatment. Eighty-eight female breast cancer patients administered with doxorubicin (DOX) or epirubicin (EPI) were divided into four groups basing on drug type and cTn positive (cTn+) or negative (cTn&minus, ) levels: DOX cTn&minus, DOX cTn+, EPI cTn&minus, and EPI cTn+. Blood was collected at baseline, during treatment, and at follow-up. We identified plasma miRNAs of interest by OpenArray screening and single assay validation. Our results showed miR-122-5p, miR-499a-5p and miR-885-5p dysregulation in DOX patients at T0, identifying a signature separating, with good accuracy, DOX cTn&minus, from DOX cTn+. No miRNAs showed differential expression in EPI subjects. Conversely, an anthracycline-mediated modulation (regardless of cTn) was observed for miR-34a-5p, -122-5p and -885-5p. Our study indicates specific circulating miRNAs as possible prediction markers for cardiac troponin perturbation upon anthracycline treatment. Indeed, our findings hint at the possible future use of plasma miRNAs to predict the cardiac responsiveness of patients to different anticancer agents.

The breakthroughs of breast cancer management have led to a significant improvement in patient survival. However, to obtain this outcome a considerable price has been paid regarding cardiovascular side effects. Indeed, cardiovascular disease is the main cause of mortality in patients with breast cancer over fifty years of age, contributing more than cancer mortality in older cancer survivors. Thus, the identification and the management of patients with breast cancer at risk for cardiovascular events has become critical in order to reduce morbidity and mortality from cardiovascular toxicity due to cancer therapy, which may blunt its effectiveness. Today, cardioncology is a novel and recognized medical discipline, which aims to encourage a close interaction between cardiology and oncology, explore new strategies, collect evidence-based indications, and develop interdisciplinary expertise with the ultimate goal of minimize the risk of developing cardiovascular disease during and after anticancer therapy, prevent the breast cancer patient cured today from becoming the heart patient of tomorrow, and avoiding the possibility that pre-existent cardiac disease be a barrier leading to a reduction of a patient's therapeutic opportunities. In this review we discussed the advantages of a cardioncology approach in terms of risk stratification, monitoring for early diagnosis, prevention, and early treatment of cardiotoxicity.

Background Acute kidney injury (AKI) frequently occurs in several medical and surgical settings, and it is associated with increased morbidity and mortality. In patients undergoing lung cancer surgery, AKI has not been fully investigated. We prospectively evaluated the incidence, clinical relevance, and risk factors of AKI in patients undergoing lung cancer surgery. Moreover, we estimated the accuracy of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the prediction of AKI. Methods Patients undergoing lung cancer surgery were included in the study. Plasma NT-proBNP was measured before and soon after surgery. Postoperative AKI was defined according to the Acute Kidney Injury Network (AKIN) classification. Results A total of 2179 patients were enrolled. Of them, 222 (10%) developed AKI and had a more complicated in-hospital clinical course (overall complication rate: 35% vs. 16%; P Conclusions Acute kidney injury occurs in 10% of patients undergoing lung cancer surgery, and it is associated with a high incidence of postoperative complications. The risk of AKI can be accurately predicted by the combined evaluation of preoperative serum creatinine and NT-proBNP.

Cardiotoxicity is a feared side effect that may limit the clinical use of anthracyclines. It may indeed affect the quality of life and survival of patients with cancer, regardless of oncological prognosis. This paper provides an overview of anthracycline-induced cardiotoxicity in terms of definition, classification, incidence, risk factors, possible mechanisms, diagnosis, and treatment. We also report effective strategies for preventing cardiotoxicity. In addition, we discuss limiting current approaches, the need for a new classification, and early cardiotoxicity detection and treatment. Probably, anthracycline-induced cardiotoxicity is a continuous phenomenon that starts from myocardial cell injury; it is followed by left ventricular ejection fraction (LVEF) and, if not diagnosed and cured early, progressively leads to symptomatic heart failure. Anthracycline-induced cardiotoxicity can be detected at a preclinical phase. The role of biomarkers, in particular troponins, in identifying subclinical cardiotoxicity and its therapy with angiotensin-converting enzyme inhibitors (mainly enalapril) to prevent LVEF reduction is a recognized and effective strategy. If cardiac dysfunction has already occurred, partial or complete LVEF recovery may still be obtained in case of early detection of cardiotoxicity and prompt heart failure treatment.

Drug-induced cardiotoxicity is a major clinical problem; cardiotoxic drugs may induce both cardiac dysfunction and myocardial injury. Several recent studies reported that cardiac troponins measured with high-sensitivity methods (hs-cTn) can enable the early detection of myocardial injury related to chemotherapy or abuse of drugs that are potentially cardiotoxic. Several authors have some concerns about the standard definition of cardiotoxicity, in particular, regarding the early evaluation of chemotherapy cardiotoxicity in cancer patients. Several recent studies using the hs-cTn assay indicate that myocardial injury may precede by some months or years the diagnosis of heart failure (HF) based on the evaluation of left ventricular ejection fraction (LVEF). Accordingly, hs-cTn assay should considered to be a reliable laboratory test for the early detection of asymptomatic or subclinical cardiotoxic damage in patients undergoing cancer chemotherapy. In accordance with the Fourth Universal Definition of Myocardial Infarction and also taking into account the recent experimental and clinical evidences, the definition of drug-cardiotoxicity should be updated considering the early evaluation of myocardial injury by means of hs-cTn assay. It is conceivable that the combined use of hs-cTn assay and cardiac imaging techniques for the evaluation of cardiotoxicity will significantly increase both diagnostic sensitivity and specificity, and also better prevent chemotherapy-related left ventricular (LV) dysfunction and other adverse cardiac events. However, large randomized clinical trials are needed to evaluate the cost/benefit ratio of standardized protocols for the early detection of cardiotoxicity using hs-cTn assay in patients receiving chemotherapy for malignant diseases.

Aims: A multicentre trial, ICOS-ONE, showed increases above the upper limit of normality of cardiac troponin (cTn) in 27% of patients within 12months after the end of cancer chemotherapy (CT) with anthracyclines, whether cardiac protection with enalapril was started at study entry in all (prevention arm) or only upon first occurrence on supra-normal cTn (troponin-triggered arm). The aims of the present post hoc analysis were (i) to assess whether anthracycline-based treatment could induce cardiotoxicity over 36month follow-up and (ii) to describe the time course of three cardiovascular biomarkers (i.e. troponin I cTnI-Ultra, B-type natriuretic peptide BNP, and pentraxin 3 PTX3) and of left ventricular (LV) function up to 36months. Methods and results: Eligible patients were those prescribed first-in-life CT, without evidence of cardiovascular disease, normal cTn, LV ejection fraction (EF) >50%, not on renin-angiotensin aldosterone system antagonists. Patients underwent echocardiography and blood sampling at 24 and 36months. No differences were observed in biomarker concentration between the two study arms, ‘prevention' vs. ‘troponin-triggered'. During additional follow-up 13 more deaths occurred, leading to a total of 23 (9.5%), all due to a non-cardiovascular cause. No new occurrences of LV-dysfunction were reported. Two additional patients were admitted to the hospital for cardiovascular causes, both for acute pulmonary embolism. No first onset of raised cTnI-Ultra was reported in the extended follow-up. BNP remained within normal range: at 36months was 23.4ng/L, higher (N.S.) than at baseline, 17.6ng/L. PTX3 peaked at 5.2ng/mL 1month after CT and returned to baseline values thereafter. cTnI-Ultra peaked at 26ng/L 1month after CT and returned to 3ng/L until the last measurement at 36months. All echocardiographic variables remained stable during follow-up with a median LVEF of 63% and left atrial volume index about 24mL/m2. Conclusions: First-in-life CT with median cumulative dose of anthracyclines of 180mg/m2 does not seem to cause clinically significant cardiac injury, as assessed by circulating biomarkers and echocardiography, in patients aged 51years (median), without pre-existing cardiac disease. This may suggest either a 100% efficacy of enalapril (given as preventive or troponin-triggered) or a reassuringly low absolute cardiovascular risk in this cohort of patients, which may not require intensive cardiologic follow-up.

Atrial fibrillation (AF) is a common supraventricular arrhythmia, a recognized risk factor for ischemic stroke, as a potential driver for heart failure (HF). Cancer patients have an increased risk for AF, even not including any cancer-specific treatment, as surgery or chemotherapy. The mechanism is multifactorial, with inflammation and changes in autonomic tone as critical actors. Commonly, AF is a recurrent complication of the post-operative period in cancer surgery (especially thoracic). Recent papers confirmed a significant incidence of post-operative (non-cardiac surgery) AF (PAF), partially mitigated by the use of prophylactic (rate o rhythm control) treatments. A relevant difference, in terms of mean hospitalization time, emerges between patients developing PAF and those who do not, while long term impact remains a matter of debate, due to several potential confounding factors. Besides clinical predictors, structural (i.e., echocardiographic) and bio-humoral findings may help in risk prediction tasks. In this respect, pre-operative natriuretic peptides (NPs) concentrations are nowadays recognized as significant independent predictors of perioperative cardiovascular complications (including PAF), while elevated post-operative levels may further enhance risk stratification. The aim of the present paper is to trace the state of the art in terms of incidence, management, prevention, and outcome of PAF in the field of thoracic surgical oncology.

Cancer and cardiovascular (CV) disease are the most prevalent diseases in the developed world. Evidence increasingly shows that these conditions are interlinked through common risk factors, coincident in an ageing population, and are connected biologically through some deleterious effects of anticancer treatment on CV health. Anticancer therapies can cause a wide spectrum of short- and long-term cardiotoxic effects. An explosion of novel cancer therapies has revolutionised this field and dramatically altered cancer prognosis. Nevertheless, these new therapies have introduced unexpected CV complications beyond heart failure. Common CV toxicities related to cancer therapy are defined, along with suggested strategies for prevention, detection and treatment. This ESMO consensus article proposes to define CV toxicities related to cancer or its therapies and provide guidance regarding prevention, screening, monitoring and treatment of CV toxicity. The majority of anticancer therapies are associated with some CV toxicity, ranging from asymptomatic and transient to more clinically significant and long-lasting cardiac events. It is critical however, that concerns about potential CV damage resulting from anticancer therapies should be weighed against the potential benefits of cancer therapy, including benefits in overall survival. CV disease in patients with cancer is complex and treatment needs to be individualised. The scope of cardio-oncology is wide and includes prevention, detection, monitoring and treatment of CV toxicity related to cancer therapy, and also ensuring the safe development of future novel cancer treatments that minimise the impact on CV health. It is anticipated that the management strategies discussed herein will be suitable for the majority of patients. Nonetheless, the clinical judgment of physicians remains extremely important; hence, when using these best clinical practices to inform treatment options and decisions, practitioners should also consider the individual circumstances of their patients on a case-by-case basis.

Acute kidney injury (AKI) is a serious complication after cardiac surgery, occurring between 5% to 30% of patients, according to the used definition (1-16). In 6% to 20% of patients experiencing AKI, dialysis is required (11,12). Development of AKI leads to an increase in mortality, both at short- and long-term follow-up (1-18). In particular, it has been showed that 12% to 64% of patients experiencing AKI die, as compared to 1% to 5% of patients not developing AKI (11-15). This mortality risk increases also with minor serum creatinine elevations, exceeding 50% in cases requiring hemodialysis (15). Moreover, AKI has a critical impact on non-renal morbidity, as it is associated after cardiac surgery with a higher rate of respiratory insufficiency, infections, sepsis, and gastrointestinal bleeding (1-12).

Simple Summary Atrial fibrillation that occurs after surgery raises further questions with respect to spontaneous atrial fibrillation, being an event unquestionably related to the surgical act itself and always quite self-limiting. The purpose of this review is to present the knowledge gained so far, including the most recent findings, regarding this peculiar form of arrhythmia. Its prognostic impact and the possibility of predicting and preventing it were the subject of our analysis, as well as the similarities and differences with spontaneous atrial fibrillation in relation to anticoagulation. Where possible, the search for evidence has focused on studies involving lung cancer patients undergoing thoracic surgery, highlighting any differences with cardiac surgery. Abstract Atrial fibrillation (AF) is a common complication of the early postoperative period of various types of surgery, including that for lung cancer. Although induced by the homeostatic alterations related to surgery, there is evidence that it is not a mere stand-alone transitory event, but it represents a relevant complication of surgery, bearing considerable prognostic consequences. Different methods have therefore been explored to predict the occurrence of postoperative atrial fibrillation (POAF) and prevent it. In particular, the age among clinical factors, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), as a marker, have proven to be good predictors, and the use of beta-blockers or amiodarone in primary prevention seems to reduce its incidence significantly. There is growing evidence that POAF significantly increases the risk of stroke and global mortality in the long term; therefore, it should be managed in the same way as spontaneous atrial fibrillation. In this review, we will present the strongest evidence found so far and the most recent findings regarding the management of POAF, with a special focus on patients undergoing thoracic surgery for lung cancer.

Supplemental Digital Content is available in the text., Rationale: In contrast to cardiomyocyte necrosis, which can be quantified by cardiac troponin, functional cardiomyocyte impairment, including mitochondrial dysfunction, has escaped clinical recognition in acute myocardial infarction (AMI) patients. Objective: To investigate the diagnostic accuracy for AMI and prognostic prediction of in-hospital mortality of cytochrome c. Methods and Results: We prospectively assessed cytochrome c serum levels at hospital presentation in 2 cohorts: a diagnostic cohort of patients presenting with suspected AMI and a prognostic cohort of definite AMI patients. Diagnostic accuracy for AMI was the primary diagnostic end point, and prognostic prediction of in-hospital mortality was the primary prognostic end point. Serum cytochrome c had no diagnostic utility for AMI (area under the receiver-operating characteristics curve 0.51; 95% confidence intervals 0.44–0.58; P=0.76). Among 753 AMI patients in the prognostic cohort, cytochrome c was detectable in 280 (37%) patients. These patients had higher in-hospital mortality than patients with nondetectable cytochrome c (6% versus 1%; P

Patients with cancer are at increased risk of cardiovascular disease, with a reported prevalence of acute coronary syndrome (ACS) ranging from 3% to 17%. The increased risk of ACS in these patients seems to be due to the complex interaction of shared cardiovascular risk factors, cancer type and stage, and chemotherapeutic and radiotherapy regimens. The management of ACS in patients with cancer is a clinical challenge, particularly due to cancer’s unique pathophysiology, which makes it difficult to balance thrombotic and bleeding risks in this specific patient population. In addition, patients with cancer have largely been excluded from ACS trials. Hence, an evidence-based treatment for ACS in this group of patients is unknown and only a limited proportion of them is treated with antiplatelets or invasive revascularization, despite initial reports suggesting their beneficial prognostic effects in cancer patients. Finally, cancer patients experiencing ACS are also at higher risk of in-hospital and long-term mortality as compared to non-cancer patients. In this review, we will provide an overview on the available evidence of the relationship between ACS and cancer, in terms of clinical manifestations, possible underlying mechanisms, and therapeutic and prognostic implications.

Recent breakthroughs in cancer treatment has improved the prospects and life expectancy of cancer patients. Therefore, risk of cardiotoxicity induced by oncologic therapies has become an important determinant of patient's survival and quality of life, independently of the oncologic prognosis. Areas covered: This paper provides an overview of the proposed strategies to mitigate the risk of cardiotoxicity. Limitation of current approaches, the need for early detection and the treatment of cardiotoxicity are also discussed. Possible future research directions are also described. Expert opinion: The most effective approach to minimize cardiotoxicity is early identification and early onset of a prophylactic treatment. However, the current standard of cardiac monitor identifies cardiotoxicity only when a functional impairment has already occurred, precluding any chance of effective prevention. The use of troponins to identify subclinical cardiotoxicity, and early treatment with ACE-inhibitors to prevent cardiac dysfunction and cardiac events have recently emerged, and appear to be an effective tool against this complication.

Anthracycline-induced cardiotoxicity is of considerable concern, as it may compromise the clinical effectiveness of treatment, affecting both quality of life and overall survival in cancer patients, independently of the oncological prognosis. It is probable that anthracycline-induced cardiotoxicity is a unique and continuous phenomenon starting with myocardial cell injury, followed by progressive left ventricular ejection fraction (LVEF) decline that, if disregarded and not treated progressively leads to overt heart failure. The main strategy for minimizing anthracycline-induced cardiotoxicity is early detection of high-risk patients and prompt prophylactic treatment. According to the current standard for monitoring cardiac function, cardiotoxicity is usually detected only when a functional impairment has already occurred, precluding any chance of its prevention. At present, anthracycline-induced cardiotoxicity can be detected at a preclinical phase, very much before the occurrence of heart failure symptoms, and before the LVEF drops by measurement of cardiospecific biochemical markers or by Doppler myocardial and deformation imaging. The role of troponins in identifying subclinical cardiotoxicity and treatment with angiotensin-converting enzyme inhibitors, in order to prevent LVEF reduction is an effective strategy that has emerged in the last 15 years. If cardiac dysfunction has already occurred, partial or complete LVEF recovery may still be achieved if cardiac dysfunction is detected early after the end of chemotherapy and heart failure treatment is promptly initiated.

Acute kidney injury (AKI) frequently occurs in several medical and surgical settings, and it is associated with increased morbidity and mortality. In patients undergoing lung cancer surgery, AKI has not been fully investigated. We prospectively evaluated the incidence, clinical relevance, and risk factors of AKI in patients undergoing lung cancer surgery. Moreover, we estimated the accuracy of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the prediction of AKI.Patients undergoing lung cancer surgery were included in the study. Plasma NT-proBNP was measured before and soon after surgery. Postoperative AKI was defined according to the Acute Kidney Injury Network (AKIN) classification.A total of 2179 patients were enrolled. Of them, 222 (10%) developed AKI and had a more complicated in-hospital clinical course (overall complication rate: 35% vs. 16%; P 0.0001), and a longer hospital stay (10 ± 7 vs. 7 ± 4 days; P 0.0001). The incidence of AKI increased in parallel with the extent of lung resection. Among the independent predictors of AKI, serum creatinine (area under the curve [AUC] 0.70 [95% CI 0.67-0.74]) and NT-proBNP (AUC 0.71 [95% CI 0.67-0.74]) provided the highest predictive accuracy, and their combination further significantly improved AKI prediction (AUC 0.74 [95% CI 0.71-0.77]). No difference in AKI prediction was observed between preoperative and postoperative NT-proBNP (P = 0.84).Acute kidney injury occurs in 10% of patients undergoing lung cancer surgery, and it is associated with a high incidence of postoperative complications. The risk of AKI can be accurately predicted by the combined evaluation of preoperative serum creatinine and NT-proBNP.

Breast cancer (BC) is the second leading cause of cancer death among women in Western Countries. Beta-blocker (BB) drugs, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) were suggested to have a favorable role in the development and progression of BC. We have performed a meta-analysis to clarify the potential benefits of these drugs on BC survival. A total number of 46 265 BC patients from eleven papers were included, ten independent studies on BB use and seven on ACEi/ARB use. The summary hazard ratio (SHR) was estimated by pooling the study-specific estimates with random effects models and maximum likelihood estimation. We assessed the homogeneity of the effects across studies and evaluated between-study heterogeneity by meta-regression and sensitivity analyses. We found a significant improvement in BC specific survival for patients treated with BB drugs at the time of BC diagnosis (SHR: 0.44; 95%CI: 0.26-0.73 with I(2) = 78%). We also observed a borderline significant improvement in disease free survival for subjects treated with BB (SHR: 0.71, 95%CI: 0.19-1.03). No association of ACEi/ARB use with disease free and overall survival was found. In conclusion, we report epidemiological evidence that BB improve BC-specific survival. Clinical trials addressing this hypothesis are warranted.

Answer questions and earn CME/CNE Cancer and heart disease are the leading causes of morbidity and mortality in the industrialized world. Modern treatment strategies have led to an improvement in the chances of surviving a diagnosis of cancer; however, these gains can come at a cost. Patients may experience adverse cardiovascular events related to their cancer treatment or as a result of an exacerbation of underlying cardiovascular disease. With longer periods of survival, late effects of cancer treatment may become clinically evident years or decades after completion of therapy. Current cancer therapy incorporates multiple agents whose deleterious cardiac effects may be additive or synergistic. Cardiac dysfunction may result from agents that can result in myocyte destruction, such as with anthracycline use, or from agents that appear to transiently affect left ventricular contractility. In addition, cancer treatment may be associated with other cardiac events, such as severe treatment-induced hypertension and vasospastic and thromboembolic ischemia, as well as rhythm disturbances, including QTc prolongation, that may be rarely life-threatening. Early and late effects of chest radiation can lead to radiation-induced heart disease, including pericardial disease, myocardial fibrosis, cardiomyopathy, coronary artery disease, valvular disease, and arrhythmias, in the setting of myocardial fibrosis. The discipline of cardio-oncology has developed in response to the combined decision making necessary to optimize the care of cancer patients, whether they are receiving active treatment or are long-term survivors. Strategies to prevent or mitigate cardiovascular damage from cancer treatment are needed to provide the best cancer care. This review will focus on the common cardiovascular issues that may arise during or after cancer therapy, the detection and monitoring of cardiovascular injury, and the best management principles to protect against or minimize cardiotoxicity during the spectrum of cancer treatment strategies. CA Cancer J Clin 2016;66:309-325. © 2016 American Cancer Society.

Background— Three types of anthracycline-induced cardiotoxicities are currently recognized: acute, early-onset chronic, and late-onset chronic. However, data supporting this classification are lacking. We prospectively evaluated incidence, time of occurrence, clinical correlates, and response to heart failure therapy of cardiotoxicity. Methods and Results— We assessed left ventricular ejection fraction (LVEF), at baseline, every 3 months during chemotherapy and for the following year, every 6 months over the following 4 years, and yearly afterward in a heterogeneous cohort of 2625 patients receiving anthracycline-containing therapy. In case of cardiotoxicity (LVEF decrease >10 absolute points, and 5 absolute points and >50%) or full (LVEF increase to the baseline value). The median follow-up was 5.2 (quartile 1 to quartile 3, 2.6–8.0) years. The overall incidence of cardiotoxicity was 9% (n=226). The median time elapsed between the end of chemotherapy and cardiotoxicity development was 3.5 (quartile 1 to quartile 3, 3–6) months. In 98% of cases (n=221), cardiotoxicity occurred within the first year. Twenty-five (11%) patients had full recovery, and 160 (71%) patients had partial recovery. At multivariable analysis, end-chemotherapy LVEF (hazard ratio, 1.37; 95% confidence interval, 1.33–1.42 for each percent unit decrement) and cumulative doxorubicin dose (hazard ratio, 1.09; 95% confidence interval, 1.04–1.15 for each 50 mg/m 2 increment) were independent correlates of cardiotoxicity. Conclusions— Most cardiotoxicity after anthracycline-containing therapy occurs within the first year and is associated with anthracycline dose and LVEF at the end of treatment. Early detection and prompt therapy of cardiotoxicity appear crucial for substantial recovery of cardiac function.

As a result of aging, the number of patients with cardiac implantable electronic device (CIED) requiring radiotherapy (RT) continues to rise. The aim of this work was to evaluate RT-related malfunctions of CIED in a cohort of patients who underwent RT in our clinic from June 2010 to December 2016. We retrospectively analyzed 93 RT treatments in 63 patients with CIEDs. Patients were treated with 3D conformal RT, intensity-modulated RT and stereotactic RT. We collected clinical characteristics of cancer, models of CIEDs, total RT dose to tumor and radiation energy. Radiation dose delivered to CIED and its dysfunctions after RT was evaluated. Subgroup analysis of 48 RT treatments (32 patients) on chest and neck plus on 13 RT treatments (12 patients) with 18 MV neutron-producing photon energy considered as high risk was performed. The number of treatments of patients with CIEDs increased from 0.3% in 2011 to 1.2% in 2016. Two patients, treated with 18 MV photon beam, with implantable cardioverter–defibrillators (ICDs) that received a maximum dose of around 2.1 Gy, experienced adverse events: a reprogramming of ICD when the patient reached a delivered dose to the tumor of 32 Gy, and an altered sensing function requiring replacement after 11 months from the end of RT. Nearly 2% of patients with CIEDs from high-risk patients subgroup had experienced a damage of the device. Close cooperation between radiation oncologists, cardiologists, medical physicists and radiation technologists is needed to achieve the best practice management in these patients.

Purpose To evaluate the tolerance of concomitant administration of anthracycline-based chemotherapy (CHT) and 3-dimensional conformal radiotherapy (RT) after breast-conserving surgery. Methods and Materials Sixty-seven patients, treated with conservative surgery followed by 3-dimensional whole breast RT and concomitant CHT regimens including “Canadian modified” CEF (5-fluorouracil, epirubicin, cyclophosphamide) or AC (doxorubicin, cyclophosphamide) were evaluated for toxicity. They were compared in terms in compliance and acute toxicity with 67 patients irradiated sequentially after having received anthracyclines. Results Acute grade ≥2 skin toxicity was significantly higher in the concomitant group compared to the sequential group, although the incidence of Grade 3 desquamation showed no statistical difference (9% vs. 3%, p = 0.14). Haematological toxicity represented the main cause of treatment discontinuation, reporting higher rate of grade 3-4 leuco-neutropenia in the concomitant group (20.9% vs. 6%, p = 0.01). Mean RT duration was longer in the concomitant group (51 days vs. 45 days) owing to RT breaks. Late toxicity was acceptable. No symptomatic lung and heart events were reported. Radiological lung hyperdensity was detected in 27.7% of the patients in the concomitant group. Post-treatment left ventricular ejection fraction significantly decreased compared with baseline, but cardiac function remained within the normal range, without any difference between left or right-sided RT. Conclusions Although there was more acute grade ≥2 skin toxicity in the concomitant group, the rate of grade 3 dermatitis was lower than expected, suggesting some advantages of 3-D CRT over older techniques. Haematological toxicity exerted a significant impact on both RT and CHT delivery.

Over the past 20 years, cancer treatments have become more effective, leading to significant improvements in survival rates. However, anticancer drugs can have several possible cardiovascular side effects; in particular, the development of left ventricular dysfunction with chemoradiation therapy can negatively affect patients’ cardiac outcome, and can limit anticancer treatments. This is an ongoing issue that will continue to persist, due to the ongoing development of new antitumor agents with potential cardiotoxic effects, and the prolonged life expectancy of long-term cancer survivors. Thus, the need for cooperation between oncologists and cardiologists in the management of cancer patients has led to the development of a new medical discipline-cardio-oncology—where the issue of cardiotoxicity is a topic of intense interest and research. However, several issues remain—the proper definition and diagnosis of cardiotoxicity, as well as monitoring and treatment strategies. In this review, the current advances in cardio-oncology, limitations of current approaches, and future research fields will be discussed.

In anticancer drug development, there has been increasing consideration for the potential of a compound to cause adverse electrocardiographic changes, especially QT interval prolongation, which can be associated with risk of torsades de pointes and sudden death. Irrespective of overt clinical toxicities, QTc assessment can influence decision making during the conduct of clinical studies, including eligibility for protocol therapy, dose delivery or discontinuation, and analyses of optimal dose for subsequent development. Efforts are needed to refine strategies for risk management, avoiding unintended consequences that negatively affect patient access and clinical development of promising new cancer treatments. In this comprehensive review, we will analyze potential effects on QTc prolongations of targeted agents approved by regulatory agencies and under investigation. A thoughtful risk management plan was generated by an organized collaboration between oncologists, cardiologists, and regulatory agencies to support a development program essential for oncology agents with cardiac safety concerns.

Beta-blockers (BB) drugs have been used for decades worldwide, mainly to treat hypertension. However, in recent epidemiological studies, BBs were suggested to improve cancer prognosis. In the wake of this evidence, we evaluated the possible therapeutic effect of BBs in triple-negative breast cancer (TNBC) patients. We identified 800 postmenopausal women operated between 1997 and 2008 for early primary TNBC. The effect of BB intake on the risk of breast cancer (BC) recurrence and death was evaluated through competing risk and Cox regression survival models. At cancer diagnosis, 74 (9.3 %) women out of 800 were BBs users. Median age was 62 years in BB users and 59 years in non-users (P = 0.02). BB users and non-users were similarly distributed by all tumor characteristics. The 5-year cumulative incidence of BC-related events was 13.6 % in BB users and 27.9 % in non-users (P = 0.02). The beneficial impact of BBs remained statistically significant at multivariable analysis (HR, 0.52; 95 % CI 0.28-0.97), after the adjustment for age, tumor stage, and treatment, peritumoral vascular invasion and use of other antihypertensive drugs, antithrombotics, and statins. Adjusted HRs for metastases and for BC deaths were 0.32 (95 % CI 0.12-0.90) and 0.42 (95 % CI 0.18-0.97), respectively, in favor of BBs. Hypertension, other antihypertensive drugs, antithrombotics, and statins did not impact prognosis. In this series of postmenopausal TNBC patients, BB intake was associated with a significantly decreased risk of BC-related recurrence, metastasis, and BC death. Innovative therapeutic strategies including BBs should be urgently explored in cancer patients.

The increase in survivorship of cancer patients makes the understanding of the available options for prevention and treatment of cardiotoxicity induced by antineoplastic agents a crucial topic both for cardiologists and oncologists. The most frequent and typical clinical manifestation of cardiotoxicity is asymptomatic or symptomatic left ventricular dysfunction, which may progress to overt heart failure. It may be induced not only by conventional cancer therapy, like anthracyclines, but also by new antitumoral targeted therapy such as trastuzumab. The current standard for monitoring cardiac damage during antineoplastic treatment, mainly based on the quantification of left ventricular ejection fraction, detects cardiac toxicity only when a functional impairment has already occurred. Evaluation of cardiac biomarkers such as troponin, however, has shown excellent sensitivity in the early detection of cardiotoxicity by the identification of patients with subclinical cardiac injury that precedes the development of cardiac dysfunction. The use of angiotensin-converting enzyme inhibitors in patients with troponin elevation during chemotherapy may be an effective tool to prevent left ventricular ejection fraction reduction and late cardiac events. There are no well established recommendations for treatment of cancer patients who develop cardiac dysfunction. Angiotensin-converting enzyme inhibitors and beta-blockers have proven to be effective in this setting. However, there are concerns in using these medications in cancer patients, and therefore the tendency is to treat patients only if symptomatic. However, the clinical benefit of these medications may be more evident in asymptomatic patients, and the recovery of cardiac function strongly depends on the amount of time elapsed from the end of chemotherapy to the start of heart failure therapy. This observation suggests that the early detection of cardiac damage is crucial and early use of angiotensin-converting enzyme inhibitors and beta-blockers should be considered in patients with left ventricular dysfunction induced by antineoplastic agents.

Cardiotoxicity is a common complication that may compromise the clinical effectiveness of anticancer therapy. The current standard for monitoring cardiac function detects cardiotoxicity only when a functional impairment has already occurred, not allowing for any early preventive strategy. Areas covered: A novel approach, based on the use of biomarkers has recently emerged, resulting in a very effective tool for early, real-time identification, and monitoring of cardiotoxicity. In particular, cardiac troponin elevation during chemotherapy allows to identify patients more prone to develop myocardial dysfunction and cardiac events. In these patients, use of angiotensin-converting enzyme inhibitors, such as enalapril, has shown to be effective in improving clinical outcomes, giving the chance for cardioprotective strategies in a selected population. The authors reviewed the currently available data about the role of biomarkers in this setting. Expert commentary: Early identification of patients at high risk of cardiotoxicity by cardiac biomarkers - in particular troponin - provides a rationale for targeted preventive strategies against cancer therapy-induced left ventricular dysfunction and its associated clinical complications, with the advantage of limiting prophylactic therapy only to a restricted number of patients. Although the major international oncologic societies encourage this approach, some limitations to a routinely use of biomarkers still exist.

Advances in oncologic therapies have led to considerable improvements in prognosis and survival. However, these improvements may ultimately be diminished by the increase of cardiovascular side effects. Typically, both conventional and new antitumoral therapies may induce asymptomatic or symptomatic left ventricular dysfunction. Its development still remains a major deterrent that may compromise clinical effectiveness of cancer treatment, independently of the oncologic prognosis, having a serious impact on the patient's survival and quality of life. Hence, prevention of cardiotoxicity remains a crucial topic both for cardiologists and oncologists. Many strategies to mitigate the risk of cardiotoxicity have been developed, including cardiac function monitoring, limitation of chemotherapy doses, use of anthracycline analogues and cardioprotectants, and early detection of cardiotoxicity by biomarkers, followed by prophylactic intervention in selected high risk patients. We reviewed the currently available approaches which have been demonstrated to be effective in preventing or limiting cancer drug-induced cardiotoxicity.

Cardiotoxicity remains a major limitation of chemotherapy, strongly affecting the quality of life and the overall survival of cancer patients, regardless of their oncologic prognosis. The time elapsed from the end of cancer therapy to the beginning of heart failure therapy for chemotherapy-induced cardiac dysfunction is an important determinant of the extent of recovery. This highlights the need for a real-time diagnosis of cardiac injury. The current standard for monitoring cardiac function detects cardiotoxicity only when a functional impairment has already occurred, precluding any chance of preventing its development. In the last decade, early identification, assessment, and monitoring of cardiotoxicity, by measurement of serum cardiospecific biomarkers, have been proposed as an effective alternative. In particular, the role of troponin I in identifying patients at risk for cardiotoxicity and of angiotensin-converting enzyme inhibitors in preventing left ventricular ejection fraction reduction and cardiac events has clearly proved to be an effective strategy for this complication. In addition, novel biomarkers for the identification of cardiotoxicity are emerging. The use of a multimarker approach may provide a unique opportunity for advancement in this field, allowing for better stratification of the cardiac risk in cancer patients treated with anticancer drugs.

Cardiac disease in patients with cancer is common and influences the longevity and quality of life both of patients in active treatment and of survivors of cancer. The disciplines of cardiology and oncology have increasingly recognized the benefits to patients of collaborating in the care of cancer patients with cardiac disease. This increased recognition arises from several factors: the aging population in which both cardiac and cancer diagnoses are common; the cellular and molecular therapeutic targets of newer medical treatments, and, in particular, the specific patient treatment choices and decisions that require careful, effective clinical interactions between these 2 disciplines. Responding to this need for an effective partnership between cardiology and oncology, the International CardiOncology Society was created and has set goals to develop and enhance our understanding and management of these clinical difficulties.

Objectives The purpose of this study was to evaluate the clinical relevance of anthracycline-induced cardiomyopathy (AC-CMP) and its response to heart failure (HF) therapy. Background The natural history of AC-CMP, as well as its response to modern HF therapy, remains poorly defined. Hence, evidence-based recommendations for management of this form of cardiomyopathy are still lacking. Methods We included in the study 201 consecutive patients with a left ventricular ejection fraction (LVEF) ≤45% due to AC-CMP. Enalapril and, when possible, carvedilol were promptly initiated after detection of LVEF impairment. LVEF was measured at enrollment, every month for the first 3 months, every 3 months during the first 2 following years, and every 6 months afterward (mean follow-up 36 ± 27 months). Patients were considered responders, partial responders, or nonresponders according to complete, partial, or no recovery in LVEF, respectively. Major adverse cardiac events during follow-up were also evaluated. Results Eighty-five patients (42%) were responders; 26 patients (13%) were partial responders, and 90 patients (45%) were nonresponders. The percentage of responders progressively decreased as the time from the end of chemotherapy to the start of HF treatment increased; no complete recovery of LVEF was observed after 6 months. Responders showed a lower rate of cumulative cardiac events than partial and nonresponders (5%, 31%, and 29%, respectively; p Conclusions In cancer patients developing AC-CMP, LVEF recovery and cardiac event reduction may be achieved when cardiac dysfunction is detected early and a modern HF treatment is promptly initiated.

Chemotherapy (CT)-induced cardiotoxicity remains an unresolved problem that strongly affects the quality of life and overall survival of cancer patients. The most typical form of cardiotoxicity, a dilated cardiomyopathy (CMP), usually becomes manifest late in the course of the disease and is classically considered to be refractory to therapy. Preventing cardiotoxicity remains the most important strategy, and several measures have been proposed, including cardiac function monitoring, limitation of CT dose, use of anthracycline analogues and cardioprotectants, and early detection of cardiotoxicity by biomarkers. The response to modern heart failure therapy of CT-induced CMP has never been evaluated in clinical trials, and no definite guidelines have been adopted. Although it is likely that medications used for other forms of CMP, particularly angiotensin-converting enzyme inhibitors and beta-blockers, may be highly effective, there is still some unjustified concern regarding their use in cancer patients.

The goal of drug development is to define potential risks and benefits of new therapies. Assessment of new drugs for their potential to alter cardiac repolarisation, prolong QTc interval and induce potentially fatal proarrhythmias such as 'torsade de pointes' is now one of the major goals during phase I-II studies. The results from these early phase clinical studies can profoundly influence 'go, no-go' decisions as well as decisions on the selection of optimal dose regimen for subsequent development, its delivery and conduct of pivotal clinical studies, including eligibility of patients. Increasingly, anticancer drugs are now also attracting attention with regard to their proarrhythmic safety. Unfortunately, regulatory guidelines focus essentially on non-cytotoxic drugs and there is no clear guidance available for evaluation of the potential of cytotoxic drugs to alter cardiac repolarisation during their development. We propose a strategy to assess the QT-liability of a cytotoxic agent in early phase I-II studies without compromising the objectives of these studies or patient access to potentially beneficial novel agents. A pragmatic and thoughtful strategy for the assessment of this proarrhythmic risk and its management, involving close collaboration between drug developers, regulatory agencies, oncologists and cardiologists, is essential for the development of these oncology agents.

We appreciate the thoughtful comments of Patane, Gallucci, and coworkers regarding our study.1 The aim of our clinical study was to prospectively evaluate the incidence, timing of occurrence, clinical correlation, and response to heart failure therapy in a large population of anthracycline-treated patients, followed up for many (up to 19) years. Because of its clinical slant, the investigation of possible mechanisms underlying anthracycline-induced cardiomyopathy was beyond the scope of our study. Regardless of the possible mechanisms involved in the development of this form of cardiomyopathy, the clinically relevant result of our study is that anthracycline-induced cardiotoxicity is a dose-dependent condition, and it occurs mostly during the first year after the end of chemotherapy. Notably, the latter aspect is in contrast …

OBJECTIVE We performed a prospective, randomized clinical study to assess whether prophylactic treatment with metoprolol or losartan, initiated soon after lung cancer surgery in patients with elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, reduces the incidence of postoperative atrial fibrillation. BACKGROUND Postoperative atrial fibrillation is a well recognized complication after lung cancer surgery, with an incidence as high as 30%. Perioperative increase of NT-proBNP has been demonstrated to be a strong independent predictor of postoperative atrial fibrillation in this setting. METHODS NT-proBNP concentration was measured 24 hours before surgery and soon after surgery in 1116 patients. Three hundred twenty (29%) patients showed a high NT-proBNP value and were enrolled: 108 were assigned to the metoprolol group, 102 to the losartan group, and 110 to the control group. RESULTS Overall, the incidence of postoperative atrial fibrillation was 20% (n = 64); it was significantly lower in the metoprolol and losartan groups compared with the control group [6%, 12%, and 40%, respectively; relative risk 0.19, 95% confidence intervals (CIs), 0.09-0.37; P < 0.001 in the metoprolol group; and 0.29, 95% CI, 0.16-0.52; P < 0.001 in the losartan group). No significant difference was found when the metoprolol and losartan groups were directly compared (P = 0.21). CONCLUSIONS A prophylactic treatment with metoprolol or losartan, initiated soon after lung cancer surgery in patients with high NT-proBNP levels, significantly reduced the occurrence of postoperative atrial fibrillation.

Background— Postoperative atrial fibrillation (AF) is a complication of thoracic surgery for lung cancer, with a reported incidence that can run as high as 42%. Recently, it has been observed retrospectively that B-type natriuretic peptide predicts AF after cardiac surgery. We performed a prospective study to evaluate the role of N-terminal pro–B-type natriuretic peptide (NT-proBNP) as a marker for risk stratification of postoperative AF in patients undergoing thoracic surgery for lung cancer. Methods and Results— We measured NT-proBNP levels in 400 patients (mean age, 62±10 years; 271 men) 24 hours before and 1 hour after surgery. The primary end point of the study was the incidence of postoperative AF. Overall, postoperative AF occurred in 72 patients (18%). Eighty-eight patients (22%) showed an elevated perioperative NT-proBNP value. When patients with either preoperatively or postoperatively elevated NT-proBNP were pooled, a greater incidence of AF was observed compared with patients with normal values (64% versus 5%; P P P Conclusions— Elevation of perioperative NT-proBNP is a strong independent predictor of postoperative AF in patients undergoing thoracic surgery for lung cancer. This finding should facilitate studies of therapies to reduce AF in selected high-risk patients.

Objective: Pericardial involvement is a common feature in different neoplastic diseases, having a strong influence on the natural history of the disease and on the quality of life of the patients. This study was performed in order to investigate the long-term effects of intracavitary treatment with thiotepa in the reduction of pericardial effusion (PE) recurrences. Design: Prospective controlled intervention study. Setting: European Institute of Oncology, Milan, Italy. Patients: We studied 33 patients, 15 men and 18 women, with malignant PE, who were affected by breast cancer (11 patients), lung cancer (16 patients), microcytoma (4 patients), endometrial cancer (1 patients), and melanoma (1 patient). Intervention: All patients with large PE, with or without cardiac tamponade, underwent percutaneous pericardiocentesis (PC) under echocardiographic monitoring. Patients with neoplastic cells in drained fluid were considered to be eligible for treatment. After drainage, the catheter was maintained in the pericardial sac for the instillation of a sclerosing, alkylating antiblastic agent (thiotepa) on days 1, 3, and 5 after the PC (15 mg at each step). Results: No procedure-related complications or side effects were observed. Two patients died because of disease progression, without PE evidence. No PE occurred in the remaining patients during the first month. Three recurrences occurred (9.1%), requiring additional PC and intrapericardial treatment. The median survival time was 115 days (range, 22 to 1,108 days) in the overall population, and 272 days in patients with breast cancer. Conclusions: Intrapericardial treatment with thiotepa carries a minimal risk and is a repeatable procedure that can dramatically increase quality of life, or even can improve survival and the natural history of disease in cancer patients.

Background— In patients with aggressive malignancies who are undergoing high-dose chemotherapy, even minimal elevation of troponin I (TnI) is associated with late left ventricular dysfunction. The time course of the subclinical myocardial damage and its impact on the clinical outcome have never been investigated previously. Methods and Results— In 703 cancer patients, we measured TnI soon after chemotherapy (early TnI) and 1 month later (late TnI). Troponin was considered positive for values ≥0.08 ng/mL. Clinical and left ventricular ejection fraction evaluation (echocardiography) were performed before chemotherapy, 1, 3, 6, and 12 months after the end of the treatment, and again every 6 months afterward. Three different TnI patterns were identified, and patients were grouped accordingly. In 495 patients, both early and late TnI values were −/− group); in 145, there was only an early increase (TnI +/− group); and in 63 patients, both values increased (TnI +/+ group). In the TnI −/− group, no significant reduction in ejection fraction was observed during the follow-up, and there was a very low incidence of cardiac events (1%). In contrast, a greater incidence of cardiac events occurred in TnI-positive patients, particularly in the TnI +/+ group (84% versus 37% in the TnI +/− group; P Conclusions— TnI release pattern after high-dose chemotherapy identifies patients at different risks of cardiac events in the 3 years thereafter. This stratification allows us to differentiate the monitoring program and to plan, in selected patients, preventive strategies aimed at improving clinical outcome.