Risk Factors For Cardiotoxicity Research Articles

Cardiovascular Complications of Novel Anti-Cancer Immunotherapy: Old Problems from New Agents?

Many novel anti-cancer therapies have dramatically improved outcomes of various cancer patients. However, it also poses a risk for cardiovascular complications as well. For the novel anti-cancer agent with which physicians does not have enough clinical experiences to determine the characteristics of cardiovascular complications, it is important to assess risk factors for cardiotoxicity before starting anti-cancer therapy. High-risk patient should be consulted to cardiologist before initiating anti-cancer therapy and pre-emptive cardiac function monitoring plan might be prepared in advance. The biomarkers, electrocardiography and echocardiography are useful tools for the detection of subclinical cardiotoxicity during anti-cancer therapy. This review article tried to suggest the cardiac function monitoring strategies for newly encountered potential cardiotoxic anti-cancer agents and to summarize the cardiovascular complications of novel anti-cancer immunotherapies including immune checkpoint inhibitor (ICI) and chimeric antigen receptor (CAR) T-cell therapy. ICIs can cause fatal myocarditis, which usually occurs early after initiation, and prompt treatment with high-dose corticosteroid is necessary. CAR T-cell therapy can cause cytokine release syndrome, which may result in circulatory collapse. Supportive treatment as well as tocilizumab, an anti-interleukin-6 receptor antibody are cornerstones of treatment.

Do excess weight and obesity increase the risk of cardiotoxicity in breast cancer Moroccan patients treated with Anthracyclines and Trastuzumab?

General population with metabolic syndrome are known to have an increased risk of cardiovascular disease and a greater risk of cardiotoxicity has recently been established in overweight and obese breast cancer patients treated with anthracyclines and/or trastuzumab, according to a meta-analysis reported in the Journal of Clinical Oncology by Guenancia et al. To assess the association between obesity and overweight and Trastuzumab induced cardiotoxicity (TIC) in Moroccan patients with breast cancer. A total of 971 patients treated with sequential anthracyclines and trastuzumab were followed in the Casablanca cardio-oncology unit from January 2017 to November 2018. Cardiac monitoring included physical examination and an assessment of LV function by echocardiography: it was evaluated before Trastuzumab initiation and every 12 weeks after. We then evaluated the risk for cardiotoxicity associated with being overweight defined by a body mass index BMI between 25 kg/m 2 and 29.9 kg/m 2 and obesity BMI ≥ 30 kg/m 2 . Among 971 patients, 186 (19.2%) were obese and 305 (31.4%) were considered overweight. Overall, the mean rate of cardiotoxicity was 9,3%. Multivariate analysis showed that obesity was significantly associated with a higher risk of cardiotoxicity ( P = 0, 042, 95% CI: 0.77–1.68) whereas overweight wasn’t ( P = 0.931, 95% CI: 0.53–0.89). Unlike Guenancia's meta-analysis, where a significantly increased risk was observed if obesity and overweight were combined (BMI > 25 kg/m 2 ) but not for obesity alone and overweight alone, our study shows a significant association between obesity alone and cartiotoxicity, but not with overweight. However, the specific TIC could not be assessed clearly, since all our patients also received anthracyclines. Moreover, we were unable to adjust for other classic risk factors of cardiotoxicity. Further studies are needed to determine the independent predictive value of obesity on cardiotoxicity.

Implementation of a Cardio Oncology Protocol in Uruguay

Introduction Survival of hemato oncologic patients has significantly improved in the last 50 years due to more intensive treatments and directed therapies. This has led to a paradigm shift focused not only in achieving cure but also addressing survivors' complications such as treatment toxicities and second malignancies. Cardiac toxicity is one of the most frequent long-term complications after cancer treatment leading to a significant burden in morbidity and mortality. Anthracyclines are type 1 cardiotoxic drugs. Risk of cardiotoxicity depends on patient characteristics and drug combinations as well as anthracyclines cumulative doses. Treatment of many hematologic malignancies often includes anthracyclines. Cardiac toxicity may limit oncologic treatment along with a negative impact on functional prognosis of survivors. Cardio oncology is an emerging field aimed at prophylaxis, early detection and proper treatment in order to improve quality of life in cancer survivors. This is the first Uruguayan experience in the implementation of a cardio oncology protocol. Methods This is a prospective interventional study conducted by a multidisciplinary team formed by hematologists and cardiologists. Inclusion criteria were patients older than 18 years old with hematologic malignancies who received anthracycline treatment between march 2017 and march 2019, treated at our institution. All patients gave their informed consent. This protocol was approved by our institution Ethical Committee. Patients who entered the protocol were followed at the Cardio Oncology Unit. Trans thoracic echocardiogram (TTE) were performed using the same equipment and by experimented operators. Left ventricular ejection fraction (LVEF) by Simpson and Global Longitudinal Strain (GLS) were measured. Figure 1 shows the algorithm used. We defined cardiotoxicity as the decrease of LVEF greater than 10% (relative to baseline LVEF) to a threshold inferior to 53%; or a relative reduction of GLS greater than 15%. Results We created a Cardio Oncology Unit (COU) at our institution with hematologists and cardiologists. Forty-four patients were included (table 1). Protocol compliance was 70%. Seven percent (3/44) of patients presented structural cardiopathy and 20% (9/44) were defined as high risk (figure 1). Cardiotoxicity was diagnosed in 16% (7/44) of patients. The diagnosis was made using LVEF decrease in every case, no patient was diagnosed based on GLS. Mean time of onset was 3 months (1-6). Mean doxorubicin dose was 115 mg/m2 (50-200). Four of the patients were asymptomatic and 3 presented with heart failure. Two patients required suspension of anthracyclines due to cardiotoxicity. Six of the 7 patients diagnosed with cardiotoxicity were treated with Beta blockers and ACE inhibitors and treatment was well tolerated. Of these patients, two died due to their oncologic disease, three improved their LVEF, one maintained the LVEF stable in spite of continuing on anthracyclines. Structural cardiopathy was associated with greater risk of cardiotoxicity (p=0.013). Conclusions We present the results of the implementation of a Cardio Oncology prospective protocol at our institution. The incidence of cardiotoxicity evidenced was greater than expected according to anthracycline used doses, with early onset during treatment. We identified structural cardiopathy as a risk factor for cardiotoxicity. Our results highlight the relevance of cardiologic follow up in patients receiving anthracyclines and makes us question whether prophylaxis would be beneficial for high risk patients. We strongly believe that cardiotoxicity is a major problem for hemato oncologic patients, and that a multidisciplinary approach with health care protocols is the best way to address it. Disclosures No relevant conflicts of interest to declare.

Cardiac safety of second-generation H1 -antihistamines when updosed in chronic spontaneous urticaria.

The symptoms of chronic urticaria, be it chronic spontaneous urticaria (CSU) or chronic inducible urticaria (CindU), are mediated primarily by the actions of histamine on H1 receptors located on endothelial cells (the weal) and on sensory nerves (neurogenic flare and pruritus). Thus, second-generation H1 antihistamines (sgAHs) are the primary treatment of these conditions. However, many patients are poorly responsive to licensed doses of antihistamines. In these patients, the current EAACI/GA2 LEN/EDF/WAO guideline for urticaria suggests updosing of sgAHs up to fourfold. However, such updosing is off-label and the responsibility resides with the prescribing physician. Therefore, the safety of the drug when used above its licensed dose is of paramount importance. An important aspect of safety is potential cardiotoxicity. This problem was initially identified some 20years ago with cardiotoxic deaths occurring with astemizole and terfenadine, two early sgAHs. In this review, we discuss the mechanisms and assessments of potential cardiotoxicity of H1 antihistamines when updosed to four times their licensed dose. In particular, we have focused on the potential of H1 antihistamines to block hERG (human Ether-a-go-go-Related Gene) voltage-gated K+ channels, also known as Kv11.1 channels according to the IUPHAR classification. Blockade of these channels causes QT prolongation leading to torsade de pointes that may possibly degenerate into ventricular fibrillation and sudden death. We considered in detail bilastine, cetirizine, levocetirizine, ebastine, fexofenadine, loratadine, desloratadine, mizolastine and rupatadine and concluded that all these drugs have an excellent safety profile with no evidence of cardiotoxicity even when updosed up to four times their standard licensed dose, provided that the prescribers carefully consider and rule out potential risk factors for cardiotoxicity, such as the presence of inherited long QT syndrome, older age, cardiovascular disorders, hypokalemia and hypomagnesemia, or the use of drugs that either have direct QT prolonging effects or inhibit sgAH metabolism.

Development of anthracycline-induced dilated cardiomyopathy due to mutation on LMNA gene in a breast cancer patient: a case report

BackgroundAnthracyclines are highly effective anticancer medication prescribed for the treatment of breast cancer. Nevertheless, the use of anthracyclines as chemotherapeutic agents involves a risk for development of cardiac toxicity which may cause restrictive and dilated cardiomyopathy. Currently, genetic predisposition is not considered as a risk factor for cardiotoxicity associated to the use of anthracyclines.Case presentationWe report the case of a 37-years old Panamanian female patient diagnosed with breast cancer who developed clinical signs of severe heart failure after treatment with doxorubicin. A diagnosis of anthracycline induced cardiomyopathy was made and treatment was initiated accordingly. A whole exome sequencing study performed to the patient showed the presence of a missense mutation in LMNA gene, which codifies for lamin A/C. Our results points to a correlation between the LMNA variant and the anthracycline cardiotoxicity developed by the woman. Improvement of the clinical symptoms and the left ventricle ejection fraction was observed after proper treatment.ConclusionsThis case report suggests for the first time a potential genetic predisposition for anthracyclines induced cardiomyopathy in patients with mutations in LMNA gene. Perhaps chemotherapies accelerate or deliver the “second-hit” in the development of DCM in patients with genetic mutations. More data is needed to understand the contribution of LMNA variants that predispose to DCM in patients receiving cardiotoxic therapies.

Cardiotoxicity of HER2-targeted therapies.

Cardiotoxicity is a well recognized adverse effect of human epidermal growth factor receptor 2 (HER2)-targeted therapies. The goal of this review is to highlight recent studies that have advanced our knowledge of the diagnosis, prevention, and management of cardiotoxicity associated with HER2-targeted agents. Several clinical risk factors for cardiotoxicity associated with HER2-targeted therapies have been identified including age, low-baseline left ventricular ejection fraction, and treatment with anthracyclines; however, these remain insufficient to identify all patients at risk for cardiotoxicity. Routine cardiac monitoring remains the standard for cardiotoxicity surveillance, although the optimal frequency and modality of monitoring remains uncertain. Global longitudinal strain, T1/T2 weighted CMR imaging protocols, and circulating biomarkers can detect early signs of cardiotoxicity, but studies are needed to investigate whether use of these markers in clinical practice improves patient outcomes. Cardioprotective medications (e.g. beta-blockers or ACE-inhibitors) may be of benefit to patients at increased risk for cardiotoxicity from HER2-taregeted therapies, particularly those who are treated with an anthracycline-containing regimen. Improved risk stratification of patients during HER2-targeted therapy and effective prevention and management strategies for cardiotoxicity are needed to enhance the value of longitudinal cardiac monitoring and increase cardiac safety so that optimal breast cancer treatment can be delivered.

Incidence of and risk factors for cardiotoxicity after fluorouracil-based chemotherapy in locally advanced or metastatic gastric cancer patients

Cardiotoxicity is an important side effect in patients receiving chemotherapy and the application of anthracycline drugs for gastric cancer treatment is uncommon. The purpose of this study was to determine the incidence rate of and risk factors for cardiotoxicity in gastric cancer patients treated with fluorouracil-based chemotherapy. We retrospectively enrolled patients with locally advanced or metastatic gastric cancer from 2011 to 2016. Patients were treated with multiple cycles of fluorouracil-based chemotherapy at Peking University First Hospital. The incidence of cardiotoxicity and patients' clinical data were obtained from hospital clinical databases and manually reviewed. A total of 129 patients were eligible for and were enrolled in this study. A median of 6 chemotherapy cycles were administered (range 1-18 cycles). Cardiotoxicity was observed in 38 of 129 patients (29.5%). Twelve patients (9.3%) exhibited toxicity greater than grade 2, and 2 (1.6%) patients died of cardiac toxicity. The only independent risk factor for serious cardiotoxicity identified by multivariable analysis was a history of cardiac disease (OR 4.108, 95% CI 2.778-6.074, P < 0.001). Chemotherapy-related cardiotoxicity may be underestimated in Chinese gastric cancer patients. Close monitoring for cardiotoxicity and enhanced cardiac management are recommended for patients who receive fluorouracil-based chemotherapy, especially for patients with high-risk factors for serious cardiotoxicity. New strategies, such as identifying the administration schedule of fluorouracil with minimal cardiotoxicity, and cardio-oncology, are necessary to prevent and treat chemotherapy-induced cardiotoxicity.

Carfilzomib Induces Acute Endothelial Dysfunction Which Correlates with the Occurrence of Cardiovascular Events

Carfilzomib Induces Acute Endothelial Dysfunction Which Correlates with the Occurrence of Cardiovascular Events

&lt;i&gt;ILE655VAL&lt;/i&gt; Genotyping Study of HER2 - Positive Breast Cancer of Patients from Padang - Indonesia With High Resolution Melting Technique

Transtuzumab has proven to be a great improvement in the treatment of HER2 + of breast cancer patients, but it is associated with relevant adverse cardiac events and with significantly elevated cost of treatment. One of the risk factors for cardiotoxicity due to transtuzumab is the I655V HER2 polymorphism (GTC&gt; ATC mutation) in which the allele mutant (Ile val or val / val) has a higher risk than the wild type (Ile/Ile). The detection of specific alleles is very important for therapeutic decision-making. In this study, our group have developed a HRM with EvaGreen dye method to discriminate specific allele of I655V HER2 (wild type, heterozygote mutant or homozygote mutant) in 66 frozen section samples of HER2+ of breast cancer patients. Our group reported the wild type is the most prevalent allele (77,27%), whereas heterozygous mutation is significantly present in this research (21,21%) and only 1,52% of sample detected as minor allele. It showed that only one sample detected as a minor allele (val/val) and may have relatively low abundance in the population. This method has been compared with sanger sequencing and giving 100% of validity.

ILE655VAL Genotyping Study of HER2 - Positive Breast Cancer of Patients from Padang - Indonesia With High Resolution Melting Technique

Transtuzumab has proven to be a great improvement in the treatment of HER2 + of breast cancer patients, but it is associated with relevant adverse cardiac events and with significantly elevated cost of treatment. One of the risk factors for cardiotoxicity due to transtuzumab is the I655V HER2 polymorphism (GTC&gt; ATC mutation) in which the allele mutant (Ile val or val / val) has a higher risk than the wild type (Ile/Ile). The detection of specific alleles is very important for therapeutic decision-making. In this study, our group have developed a HRM with EvaGreen dye method to discriminate specific allele of I655V HER2 (wild type, heterozygote mutant or homozygote mutant) in 66 frozen section samples of HER2+ of breast cancer patients. Our group reported the wild type is the most prevalent allele (77,27%), whereas heterozygous mutation is significantly present in this research (21,21%) and only 1,52% of sample detected as minor allele. It showed that only one sample detected as a minor allele (val/val) and may have relatively low abundance in the population. This method has been compared with sanger sequencing and giving 100% of validity.

Chemotherapy and echocardiographic indices in patients with non-Hodgkin lymphoma: the ONCO-ECHO study

The cardiotoxicity of chemotherapy (CTx) for non-Hodgkin’s lymphomas is not well recognized. In order to facilitate individual risk counseling for patients, we analyzed the effect of CTx on echocardiographic indices in regard to clinical data in patients treated for non-Hodgkin’s lymphoma (NHL). A prospective multicenter ONCO-ECHO trial included 67 patients with NHL (45 patients with DLBCL (diffuse large B cell lymphoma) and 22 with non-DLBCL). Patients received standard CTx, primarily R-CHOP, CHOP, R-COP and COP regimens. Clinical data and echocardiographic indices were obtained at baseline, 3-, 6- and 12-month follow-up. The primary end point representing CTx cardiotoxicity was defined as a ≥ 10% decrease in the left ventricular ejection fraction (LVEF) during 12-month observation. In a 12-month follow-up five (7.5%) deaths occurred, while no clinical manifestations of heart failure were reported. There was an increase in left ventricular end-systolic diameter (p = 0.002) and E/e′ index (p = 0.036) in 12-month observation. Preexisting coronary artery disease was associated with significant decrease in the ΔLVEF (p = 0.008), increase in ΔLVEDV (p = 0.03) and ΔLVESV (p = 0.02) and increase in the Δ left atrium diameter (p = 0.02); while history of arterial hypertension was related to significant decrease in the ΔLVEF (p = 0.039), diabetes mellitus was related to significant increase in the ΔE/e′ index (p = 0.002). The primary end point was reported in ten (14.9%) patients. There were no independent risk factors for cardiotoxicity in the study population. Chemotherapy administered to NHL patients may induce dilatation and impaired LV diastolic function. Standard cardiovascular risk factors may predispose patients to negative LV remodeling.

Anthracycline-induced cardiotoxicity in patients with paediatric bone sarcoma and soft tissue sarcoma.

Anthracycline cardiotoxicity is an important side-effect in long-term childhood cancer survivors. We evaluated the incidence of and factors associated with anthracycline cardiotoxicity in a population of patients diagnosed with bone or soft tissue sarcoma. Materials and methods We retrospectively enrolled patients diagnosed with bone or soft tissue sarcoma, from 1995 to 2011, treated with anthracycline chemotherapy at our Centre and with a follow-up echocardiography carried out ⩾3 years from cardiotoxic therapy completion. Cardiac toxicity was graded using Common Terminology Criteria for Adverse Events version 4.0. A total of 82 patients were eligible. The median age at treatment was 11.9 years (1.44-18). We evaluated the median cumulative anthracycline dose, age at treatment, sex, thoracic radiotherapy, hematopoietic stem cell transplantation, and high-dose cyclophosphamide treatment as possible risk factors for cardiotoxicity. The median cumulative anthracycline dose was 390.75 mg/m2 (80-580). Of the 82 patients, 12 (14.6%) developed cardiotoxicity with grade ⩾2 ejection fraction decline: four patients were asymptomatic and did not receive any treatment; six patients were treated with pharmacological heart failure therapy; one patient with severe cardiomyopathy underwent heart transplantation and did not need any further treatment; and one patient died while waiting for heart transplantation. The median time at cardiac toxicity, from the end of anthracycline frontline chemotherapy, was 4.2 years (0.05-9.6). Cumulative anthracycline dose ⩾300 mg/m2 (p 0.04) was the only risk factor for cardiotoxicity on statistical analyses. In our population, the cumulative incidence of cardiotoxicity is comparable to rates in the literature. This underlines the need for primary prevention and lifelong cardiac toxicity surveillance programmes in long-term childhood cancer survivors.

Abstract 987: Unanticipated cardiotoxicity due to targeted anti-cancer therapy in hematologic malignancies patients: Natural history and risk factors

Abstract INTRODUCTION: Unanticipated cardiotoxicity is now identified as a significant clinical problem associated with new anti-cancer targeted agents. Risk factors and natural history are still poorly understood. We aim to determine potential clinical risk factors for cardiotoxicity among patients with hematologic malignancies (HM) who were treated with targeted therapies over a 10-year period. METHODS: We used 114 diagnosis codes for HM and 17 codes for cardiac diseases in order to identify patients in our electronic medical records (EPIC) and identify patients with HM who met above criteria. Cardiotoxicity was defined mainly by left ventricular ejection fraction (LVEF) of &amp;lt; 50%, arrhythmias, or ischemic cardiovascular event that occurred after initiation of the drug of interest. The targeted agents of interest include tyrosine kinase inhibitors (TKIs), proteasome inhibitors, monoclonal antibodies, hypomethylating agents, and immunomodulatory agents. Multivariable logistic regression was performed to estimate the odds ratios (ORs) and 95% confidence intervals (95% CI) of the potential risk factors. Kaplan-Meier analysis and log-rank test were used to evaluate the effect of cardiotoxicity on the overall survival of the patients. RESULTS: Of 820 patients with both HM and cardiac diagnosis, 29 patients developed cardiotoxicity after initiation of targeted therapies. We selected 70 matched controls based on type of targeted therapy. In the study group, the median time from exposure to cardiac event was 120 days (range, 1-1176). Significantly higher number of patients had prior exposure to anthracyclines in study versus control group (65.5% vs 42.8%, P=0.04), however, this was not significant in multivariable analysis. Multiple other variables, including traditional risk factors for heart disease, were analyzed and did not differ significantly between the two groups. Only two variables remained significant in the multivariable analysis, including prior history of DVT/PE (OR 4.88, 95% CI: 1.44-16.54, P=0.011), and Karnofsky score of ≥80% (OR 3.99, 95% CI: 1.51-10.6, P= 0.005). With median follow-up of 27 months (range, 1-120), 17 patients in the study group died, but only 2 of cardiac causes. Repeat echocardiograms showed worsening of LVEF in 4 patients while stable/improved in 23 patients, and 21 patients were able to receive further chemotherapy. There was a trend towards worse overall survival in the study group (P= 0.071). CONCLUSIONS: About 3.5% of patients with HM experience unanticipated cardiotoxicity due to targeted anti-cancer agents with related mortality of 6.8 %. Most patients do well with stable compensated cardiac function and 35% have an objective improvement in LVEF. Risk of cardiotoxicity was significantly higher in patients with known history of DVT/PE. Future studies of possible underlying genetic predisposition will be of great importance. Citation Format: Chintan Shah, Yan Gong, Anita Szady, Qian Sun, carl J. Pepine, Taimour Langaee, Alexandra R. Lucas, Jan S. Moreb. Unanticipated cardiotoxicity due to targeted anti-cancer therapy in hematologic malignancies patients: Natural history and risk factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 987. doi:10.1158/1538-7445.AM2017-987

Cardiovascular complications of antineoplastic therapy in children

The improvement of long-term survival in children with malignant tumors is noted in the last five decades. Serious late consequences of the applied therapy including early death, the second tumors, different organ dysfunctions (heart, gonads, liver, lungs) began to come to light with increase in number of cured and follow-up. The article discusses the emergence of cardiotoxicity in children treated with cytostatic and radiation therapy for malignant tumors. Particular attention is paid to the influence of anthracycline antibiotics on the state of the heart muscle. Anthracycline and similar medicines - doxorubicin, rubomycin, idarubicin, mitoxantrone - are an important component of most regimen of chemotherapy in children. Briefly describes the history of the application of this group of drugs in oncology and the study of their effects on heart function. The attention to the pathogenesis of anthracycline cardiotoxicity risk factors for its development, display options, how to identify and mitigate. We describe the clinical manifestations of early and late cardiotoxicity arising after the application of antitumor antibiotics anthracyclines. The article defines the role of chemotherapeutic agents other groups in the development and worsening cardiotoxicity. No less important role in the development of long-term effects of the heart and blood vessels plays radiotherapy. The paper paid attention to cardiovascular dysfunctions that arise in different periods of observation after irradiation of the mediastinum. Finally, recommendations for practitioners on screening, monitoring and treatment of identified diseases of the cardiovascular system in patients cured of childhood malignancies are presented.

RISK FACTORS AND INCIDENCE OF MYOCARDIAL DAMAGE IN PATIENTS WITH HEMOBLASTOSIS RECEIVING ANTHRACYCLIN ANTIBIOTICS

Introduction . The anthracycline antibiotics cause clinically significant manifestations of cardiotoxicity (СТ) – myocardial injuries, reducing both quality and life expectancy of the oncological patients. The purpose of the study was to evaluate the incidence and risk factors anthracycline-induced СТ in patients with hemoblastosis. Materials and methods . The study included 131 case histories of patients with hemoblastosis, treated with anthracyclines. Patients were divided into two groups according to age – the 1st group involved 77 patients aged from 18 up to 50 years (average age of 25.6 ± 3.4 years), the 2nd – 54 patients aged from 51 up to 75 years (average age of 56.8 ± 4.6 years). At the first investigation phase we studied the incidence of anthracycline-induced СТ in various age groups patients. The second phase devoted to studying potential risk factors (a cumulative dose more than 240 mg/m 2 , a female, an age, the accompanying application of mediastinal radiation therapy or other cardiotoxic drugs, cardioprotection absence) influence on anthracycline-induced CD frequency. Results. The incidence of CT in young patients was 38.2% (95% confidence interval (CI) 25.6–51.6%), among the older age group – 14.3% (95% CI 5.3–26.7%). The incidence of CT is significantly higher among young people (χ 2 = 5.63, p = 0.018). According to the results of univariate regression analysis, significant risk factors for the development of myocardial damage in patients with CT signs were: age <50 years – the odds ratio (OR) 2.69; 95% CI 1.05–6.84; the cumulative anthracycline dose more than 240 mg/m 2 by doxorubicin (OR 5.17, 95% CI 1.38–27.55) and the absence of prophylactic cardioprotective therapy (OR 23.38, 95% CI 6.49–84.14 ). In multivariate regression analysis independent risk factors for myocardial damage development were only the cumulative anthracyclines dose more than 240 mg/m 2 (OR 6.17, 95% CI 1.32–28.71) and the absence of prophylactic cardioprotective therapy (OR 2.82, 95% CI 1.09–7.28). Conclusions . Statistically significant higher anthracycline-induced cardiotoxicity frequency appeared in young patients. Reliable (р <0.05) cardiotoxicity risk factors were cumulative dose more than 240 mg/m 2 and cardioprotection absence.

Is it possible to cure childhood acute myeloid leukaemia without significant cardiotoxicity?

Since cardiotoxicity is a life threatening late effect, a reduction of cardiotoxicity in the treatment of acute myeloid leukaemia (AML) is essential. This review is a compilation of the current knowledge about cardiotoxicity after AML treatment and of how future directions in treatment may affect its incidence. A total of six studies concerning AML and cardiotoxicity were identified. The incidence of late subclinical cardiotoxicity varied between 1·3 and 15·3%, and late clinical cardiotoxicity varied between 1·3 and 9·3%. Cumulative dose of anthracyclines (ACs) and history of relapse were the most common risk factors identified. No conclusions could be drawn about new, potentially less toxic ACs. Differences in treatment data and variations in study populations made comparisons uncertain. The echocardiographic techniques used in the majority of the studies are inferior to more modern echocardiographic methods. This decreases reproducibility and may increase the risk of overestimation of cardiotoxicity. In summary, AML cannot be cured today without ACs. However, some ACs may cause less cardiotoxicity than others. Furthermore there is currently no consensus on equipotent doses of ACs and risk factors for cardiotoxicity. Further research including randomized trials is needed to evaluate whether or not the potentially less cardiotoxic agents fulfil their promise.

Incidence and risk factors for capecitabine-induced symptomatic cardiotoxicity: a retrospective study of 452 consecutive patients with metastatic breast cancer

ObjectivesCase reports of capecitabine cardiotoxicity resemble those seen with intravenous 5-fluorouracil (5-FU) with chest pain as the predominant manifestation, but few studies of capecitabine cardiotoxicity are available. We aimed to...

Obesity As a Risk Factor for Anthracyclines and Trastuzumab Cardiotoxicity in Breast Cancer: A Systematic Review and Meta-Analysis.

Patients with metabolic syndrome have a greater risk of cardiovascular disease, although their susceptibility to chemotherapy-induced cardiac disease is not well documented. The aim of this meta-analysis was to assess associations between obesity or being overweight and cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab in patients with breast cancer. We performed a random-effects analysis and a network meta-analysis and assessed publication bias. We included 15 studies and 8,745 patients with breast cancers who were treated with anthracyclines and sequential anthracyclines and trastuzumab. Combination of obesity and being overweight was significantly associated with a greater risk of developing cardiotoxicity after anthracyclines and a sequential anthracyclines and trastuzumab regimen in patients with breast cancer. Pooled odds ratio for cardiotoxicity was 1.38 (95% CI, 1.06 to 1.80; I(2) = 43%; N = 8,745) for overweight or obesity (body mass index > 25 kg/m(2)), 1.47 (95% CI, 0.95 to 2.28; I(2) = 47%; n = 2,615) for obesity, and 1.15 (95% CI, 0.83 to 1.58; I(2) = 27%; n = 2,708) for overweight. Associations were independent of study design, year of publication, drug regimen (anthracyclines alone v sequential anthracyclines and trastuzumab), or definitions of cardiotoxicity and of overweight or obesity. There was no evidence of publication bias; however, we could not separate the contributions of obesity-related cardiovascular risk factors, such as diabetes and hypertension, from that of obesity itself in this largely unadjusted analysis. Our findings in a largely unadjusted analysis suggest that overweight and obesity are risk factors for cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab.

Evaluation and management of chemotherapy-induced cardiotoxicity in breast cancer: a Delphi study

PurposeWhile much progress has been made in the treatment of breast cancer, cardiac complications resulting from therapy remain a significant concern. Both anthracyclines and novel targeted agents can inflict cardiac damage. The present study aimed to evaluate the difference between what it is currently done and what standards of care should be used to minimizing and managing cardiac toxicity in breast cancer survivors.MethodsA two-round multicenter Delphi study was carried out. The panel consisted of 100 oncologists who were asked to define the elected therapies for breast cancer patients, the clinical definition and patterns of cancer drug-derived cardiac toxicity, and those protocols focused on early detection and monitoring of cardiovascular outcomes.ResultsExperts agreed a more recent definition of cardiotoxicity. Around 38 % of patients with early-stage disease, and 51.3 % cases with advanced metastatic breast cancer had preexisting risk factors for cardiotoxicity. Among risk factors, cumulative dose of anthracycline ≥450 mg/m2 and its combination with other anticancer drugs, and a preexisting cardiovascular disease were considered the best predictors of cardiotoxicity. Echocardiography and radionuclide ventriculography have been the proposed methods for monitoring changes in cardiac structure and function. Breast cancer is generally treated with anthracyclines (80 %), so that the panel strongly stated about the need to plan a strategy to managing cardiotoxicity. A decline of left ventricular ejection fraction (LVEF) >10 %, to an LVEF value <53 % was suggested as a criterion for changing the dose schedule of anthracyclines, or suspending the treatment of chemotherapy plus trastuzumab until the normalization of the left ventricular function. The use of liposomal anthracyclines was strongly suggested as a treatment option for breast cancer patients.ConclusionsThe present report is the first to produce a set of statements on the prevention, evaluation and monitoring of chemotherapy-induced cardiac toxicity in breast cancer patients.

Risk factors for anthracycline-associated cardiotoxicity.

Carbonyl reductase (CBR) catalyzes anthracycline metabolism, and single nucleotide polymorphisms (SNPs) in CBR impact metabolic efficiency. In pediatric patients, homozygosity for the major allele (G) in the CBR3 gene was associated with increased risk of anthracycline cardiotoxicity. We hypothesized that CBR SNPs contribute to cardiotoxicity in adults. We retrospectively identified female breast cancer patients in the Columbus Breast Tissue Bank Registry treated with adriamycin and cytoxan (AC) from 2003 to 2012. We selected patients who developed cardiomyopathy, defined as a drop in ejection fraction to <50 % or >15 % decrease from pre-therapy. Univariate and multivariate logistic regressions were performed to identify cardiotoxicity risk factors. SNPs were genotyped, and frequency of the major allele (G)/minor allele (A) of the CBR3 and CBR1 genes was calculated. We identified 52 cases of cardiotoxicity after AC and 110 controls. Multivariate analysis showed that trastuzumab (p = 0.009), diabetes (p = 0.05), and consumption of >8 alcoholic drinks/week (p = 0.024) were associated with higher cardiotoxicity risk. Moderate alcohol consumption (<8 drinks/week) was associated with lower risk (p = 0.009). No association was identified between CBR SNPs and cardiotoxicity (CBR1 p = 0.261; CBR3 p = 0.556). This is the first study to evaluate SNPs in the CBR pathway as predictors of AC cardiotoxicity in adults. We did not observe any significant correlation between cardiotoxicity and SNPs within the CBR pathway. Further investigation into CBR SNPs in a larger adult sample is needed. Additional exploration into genomic predictors of anthracycline cardiotoxicity may allow for the development of preventative and therapeutic strategies for those at risk.