蒽环类药物普通制剂及脂质体制剂的心脏毒性研究进展

蒽环类药物属于抗肿瘤抗生素,为细胞周期靶向非特异性药物,具有广谱、强效的特点,临床上广泛用于实体肿瘤和恶性血液系统肿瘤的治疗.但是,因为容易引起心脏毒性事件而使其临床应用受到了一定程度的限制.经多年研究表明,与蒽环类药物普通制剂相比,脂质体制剂不但疗效相当,而且能减轻心脏毒性.本文就蒽环类药物普通制剂和脂质体制剂心脏毒...     

Evaluating the role of dexrazoxane as a cardioprotectant in cancer patients receiving anthracyclines

Anthracyclines remain an important group of chemotherapeutic agents, despite their inherent cardiotoxicity. This cardiotoxicity may be even more of a concern in the future, as combination therapies of anthracyclines with newer agents become routine. Such combinations may be highly effective, but cardiotoxicity may also be increased. Dexrazoxane reduces the incidence of cardiotoxicity, as demonstrated in numerous clinical trials in both adults and children. Evidence from the literature suggests no effect of dexrazoxane on the antitumour efficacy of anthracyclines, and there is no adverse effect on survival. Dexrazoxane is therefore a valuable tool for oncologists using anthracycline-based regimens.     

Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk

Anthracyclines are considered to be among the most active agents for the treatment of breast cancer. However, their use is limited by cumulative, dose-related cardiotoxicity. Such cardiotoxicity results in a permanent loss of cardiac myocytes and a progressive reduction in cardiac function following each subsequent dose of anthracycline. Initially, damage to the heart is subclinical; however, increasingly impaired cardiac function can result in cardiovascular symptoms, with serious cardiac injury resulting in chronic heart failure. Since the early detection and treatment of cardiotoxicity can reduce its clinical effects, it is important that oncologists are aware of these adverse effects and manage them appropriately. This review examines the risk factors for anthracycline-associated cardiotoxicity and offers recommendations on strategies to reduce the cardiotoxicity of anthracyclines in the management of patients with advanced breast cancer.     

miRNA在肿瘤治疗相关心脏毒性中的研究进展

因心脏毒性的发生使抗肿瘤药物的临床使用受限。化疗、放疗、靶向治疗和免疫治疗均表现出不同频度和程度的心脏毒性,严重者可发生心力衰竭,危及患者生命。不同抗肿瘤治疗导致的心脏毒性作用机制复杂,氧化应激、DNA损伤、细胞凋亡等均可能参与。miRNA（microRNA）是细胞增殖、死亡、凋亡和分化的关键调控因子,其失调还与心脏重塑和心脏毒性密切相关。本文将对miRNAs可能参与不同肿瘤治疗所致心脏毒性发生的作用机制,及其在监测和治疗中的作用进行综述。      

Therapy Insight: anthracyclines and trastuzumab--the optimal management of cardiotoxic side effects

Anthracyclines and trastuzumab are key agents in the management of patients with breast cancer, and have revolutionized the management of both early-stage and advanced-stage disease. The use of anthracyclines, however, can be compromised by the potential for cardiotoxicity; trastuzumab also has the potential for causing cardiotoxicity in patients receiving concurrent or prior anthracyclines. Although its development is treatment limiting, cardiotoxicity can be minimized with appropriate clinical care and drug scheduling. We discuss the efficacy of trastuzumab, its potential for cardiac compromise, and its interaction with anthracyclines. We highlight biological mechanisms that might be responsible for cardiotoxicity, describe the established and trial schedules of both agents, and discuss clinical strategies used to minimize the risk of developing cardiac failure through appropriate scheduling of trastuzumab with anthracyclines.     

Personalized Decision Making in Early Stage Breast Cancer: Applying Clinical Prediction Models for Anthracycline Cardiotoxicity and Breast Cancer Mortality Demonstrates Substantial Heterogeneity of Benefit-Harm Trade-off

BackgroundAnthracycline agents can cause cardiotoxicity. We used multivariable risk prediction models to identify a subset of patients with breast cancer at high risk of cardiotoxicity, for whom the harms of anthracycline chemotherapy may balance or exceed the benefits.Patients and MethodsA clinical prediction model for anthracycline cardiotoxicity was created in 967 patients with human epidermal growth factor receptor-negative breast cancer treated with doxorubicin in the ECOG-ACRIN study E5103. Cardiotoxicity was defined as left ventricular ejection fraction (LVEF) decline of ≥ 10% to < 50% and/or a centrally adjudicated clinical heart failure diagnosis. Patient-specific incremental absolute benefit of anthracyclines (compared with non-anthracycline taxane chemotherapy) was estimated using the PREDICT model to assess breast cancer mortality risk.ResultsOf the 967 women who initiated therapy, 51 (5.3%) developed cardiotoxicity (12 with clinical heart failure). In a multivariate model, increasing age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01-1.08), higher body mass index (OR, 1.06; 95% CI, 1.02-1.10), and lower baseline LVEF (OR, 0.93; 95% CI, 0.89-0.98) at baseline were significantly associated with cardiotoxicity. The concordance statistic of the risk model was 0.70 (95% CI, 0.63-0.77). In patients with low anticipated treatment benefit (n = 176) from the addition of anthracycline (< 2% absolute risk difference of breast cancer mortality at 10 years), 16 (9%) of 176 had a > 10% risk of cardiotoxicity and 61 (35%) of 176 had a 5% to 10% risk of cardiotoxicity at 1 year.ConclusionOlder age, higher body mass index, and lower baseline LVEF were associated with increased risk of cardiotoxicity. We identified a subgroup with low predicted absolute benefit of anthracyclines but with high predicted risk of cardiotoxicity. Additional studies are needed incorporating long-term cardiac outcomes and cardiotoxicity model external validation prior to implementation in routine clinical practice.     

Fluoropyrimidine-Induced Cardiotoxicity: Manifestations,Mechanisms, and Management

Fluoropyrimidines—5-fluorouracil (5-FU) and capecitabine—have been implicated as cardiotoxic chemotherapy agents. This rare, albeit potentially serious toxicity has been described in nearly four decades of case reports, case series, and in vitro modeling; however, there is a paucity in clinical trials and prospective analyses focused on cardioprotective strategies and cardiotoxic surveillance of these agents. While much attention has focused on the well-known cardiac toxicity of anthracyclines and monoclonal antibody agents such as trastuzumab, fluoropyrimidines remain one of the most common causes of chemotherapy-associated cardiotoxicity. The introduction of capecitabine, an oral prodrug of 5-FU, has made the treatment of solid tumors more convenient along with a subsequent rise in documented cardiotoxic cases. This review discusses the symptomatology, clinical manifestations, and proposed molecular mechanisms that attempt to describe the heterogeneous spectrum of fluoropyrimidine-induced cardiotoxicity. Four case examples showcasing the varied manifestations of cardiotoxicity are presented. Finally, several proposed management strategies for cardiotoxicity and post-hospital course precautions are discussed.     

Anthracycline–trastuzumab regimens for HER2/neu-overexpressing breast cancer: current experience and future strategies

Anthracycline–trastuzumab-containing regimens demonstrate significant clinical activity in human epidermal growth factor receptor 2 (HER2)-positive breast cancer; however, the utility of this strategy is limited by unacceptably high rates of significant cardiotoxicity, particularly with concurrent administration. Anthracycline-induced cardiotoxicity is thought to be mediated primarily through increased myocardial oxidative stress, modified partly by the activity of neuregulins. Trastuzumab-induced cardiotoxicity is thought to be mediated by the ErbB/neuregulin system, with exposure to trastuzumab partly blocking the protective effect of neuregulins on the myocardium. As a result, trastuzumab increases the risk of anthracycline-induced cardiotoxicity. Several strategies have been adopted in attempts to minimize cardiotoxicity, including patient selection on the basis of preexisting cardiac risk, monitoring of cardiac function during treatment, and early management of cardiac dysfunction. The use of less cardiotoxic anthracyclines may be one strategy to lessen the risk of cardiotoxicity. Liposomal doxorubicin products offer similar efficacy compared with conventional doxorubicin, with significantly less cardiotoxicity, and have been successfully used in combination with trastuzumab in the metastatic and neo-adjuvant setting. Clinical trials are currently underway to assess the safety of pegylated liposomal doxorubicin during concurrent administration with trastuzumab compared with standard sequential treatment using conventional doxorubicin in the adjuvant setting.     

Prediction of Anthracycline Induced Cardiotoxicity: Study of thirty-one Iraqi adult patients

Objective: To look for a nearly ideal tool for prediction of anthracycline-induced cardiotoxicity. Method: Thirty-one patients with various hematological malignancies were included in the study which was conducted from Sept. 2005 to Sept. 2006 in Baghdad Teaching Hospital - Hematology Unit. Initial cardiovascular assessment including cardiac troponin I, electrocardiography and echocardiography were done and repeated one month after the commencement of anthracycline-based regimen. Cardiotoxicity was considered present if the patient has clinical and electrocardiographic evidences, troponin positivity, echocardiographic evidence, or any combination of these. Results: The mean age for the study sample was 34.1±17.2 years comprising of 17 male and 14 female patients. Increasing age, body surface area, anthracycline dose as well as the concomitant use of cyclophosphomide/All Trans Retinoic Acid were associated with increased risk of cardiotoxicity. The cut-off point of body surface area above which the risk of anthracycline-induced cardiotoxicity is increased was 1.88 m2 while the cut-off point for anthracyclines dose was 145.5 mg/m2. The constellation of clinical data, ECG, and cTnI was 92% predictive of early evidence of anthracycline-induced cardiotoxicity. More weight is added when echocardiography is used as a diagnostic tool. The incidence of cardiotoxicity attributed to treatment was 38.7%. The predictive power of cardiac troponin I alone was 58.3%, whereas it increases to 91% when combined with electrocardiography and to 95% when combined with echocardiographic study. Conclusion: The age, anthracyclines dose and the use of other chemotherapeutics increase the risk of anthracycline-induced cardiotoxicity. Cardiac troponin I is a simple non-invasive indicator for the presence of anthracycline-induced cardiotoxicity especially when used in combination with other parameters. Keywords: Anthracycline, Cardiotoxicity, Troponin.     

Cardiac safety of liposomal anthracyclines

Anthracyclines have demonstrated antitumor activity in a variety of cancers; however, irreversible cardiac damage is a major dose-limiting toxicity, restricting lifetime cumulative dose. The most successful strategy to improve the cardiac safety of anthracyclines to date involves liposomal encapsulation, which alters the tissue distribution and pharmacokinetics of these agents. The cardiac safeties of liposomal daunorubicin, liposomal doxorubicin (D-99), and pegylated liposomal doxorubicin have been studied in several clinical trials. The lack of published data comparing liposomal daunorubicin with conventional daunorubicin makes it difficult to draw meaningful conclusions regarding the relative cardiac safeties of these formulations. Studies indicate that the risk of anthracycline-induced cardiotoxicity is considerably lower with liposomal doxorubicin formulations than with conventional doxorubicin. Pegylated liposomal doxorubicin has been studied most extensively and has demonstrated the most significant reductions in risk for cardiotoxicity. Compared with conventional doxorubicin, pegylated liposomal doxorubicin has shown similar efficacy with a significantly lower incidence of cardiotoxicity and significantly fewer cardiac events. Although the long-term cardiac safety of these agents is unknown, data suggest that liposomal anthracyclines, particularly pegylated liposomal doxorubicin, may offer a significant clinical benefit for patients with higher risks for anthracycline-induced cardiotoxicity.     

Detection of anthracycline-induced cardiotoxicity.

The use of anthracyclines, a group of potent anti-cancer agents incorporated into the treatment of a wide variety of solid and haematological tumours, is limited by its cardiotoxicity that can result in congestive heart failure (CHF). The best method to detect cardiotoxicity at an early stage in order to prevent severe deterioration, is still an unsolved problem. Although endomyocardial biopsy is considered to be the most sensitive and specific test for this purpose, its use is limited by its invasiveness. In daily practice, oncologists make use of parameters of systolic function (left ventricular ejection fraction, or fractional shortening) to detect cardiotoxicity, but these methods are not able to identify cardiotoxicity at an early stage.Based on increasing knowledge into the pathophysiology of anthracycline-induced cardiotoxicity and heart failure in general, new methods including the determination of diastolic function parameters, anti-myosin scintigraphy, assessment of heart rate variability, and the determination of biochemical markers have been proposed to identify patients at risk of the development of CHF in an early stage. However, most of these newer methods have not yet been adequately evaluated to allow them to be recommended for use in routine clinical practice.     

Advanced imaging modalities to detect cardiotoxicity

Recent advances in cancer treatments have significantly improved survival rates, reemphasizing the focus on reducing the potential complications associated with some therapies. Cardiovascular disease associated with chemotherapies is a major cause of morbidity and mortality in cancer survivors. Early detection of cardiotoxicity improves cardiac outcomes among cancer patients. The review will focus on imaging modalities used to assess cardiotoxicity - the cardiovascular consequences of chemotherapies. The review will discuss the benefits and limitations associated with each technique, as well as the guidelines available to help identify at risk patients. We will discuss novel techniques that may help detect earlier signs of cardiotoxicity, directing management that may improve clinical outcomes.     

参芎对改善化疗引起的心脏毒性的疗效观察

目的探讨参芎葡萄糖注射液对化疗引起的心肌损伤的疗效。方法选择乳腺癌患者及淋巴瘤患者共126人,随机分为治疗组(62例)和对照组(64例),治疗组在化疗基础上加用参芎注射液,观察治疗组和对照组患者的心电图、动态心电图及临床症状。结果治疗组患者的心电图、动态心电图及临床症状均好于对照组,差异有统计学意义(P<0.05)。结论参芎葡萄糖能改善由化疗引起的心肌损伤。     

蒽环类药物心脏毒性防治药物研究进展

蒽环类药物包括阿霉素、表阿霉素、柔红霉素和阿克拉霉素等,广泛地用于治疗血液系统恶性肿瘤和实体肿瘤,如急性白血病、淋巴瘤、乳腺癌、胃癌、软组织肉瘤和卵巢癌等。蒽环类药物可以与其他化疗药物及分子靶向药物联合应用,以蒽环类药物为基础的联合治疗通常是一线治疗的标准方案。蒽环类药物的抗瘤谱广,抗瘤作用强,疗效确切,但是可以引起脱发、骨髓抑制和心脏毒性等毒副反应。针对骨髓抑制可采用造血刺激因子(G-CSF、EPO、TPO等)进行防治,而心脏毒性是蒽环类药物最严重的毒副反应。临床研究和实践观察均显示蒽环类药物导致的心脏毒性呈进展性和不可逆性,特别是初次使用蒽环类药物就可能造成心脏损伤,因此早期监测和积极预防蒽环类药物引起的心脏毒性显得尤为重要,已经引起临床上的高度重视,制定了蒽环类药物心脏毒性防治指南。本研究对目前蒽环类药物心脏毒性的防治药物进行综述。      

Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review.

BACKGROUND: The aim of this systematic review was to summarise and appraise the published evidence with regard to the frequency and risk factors of subclinical cardiotoxicity in apparently healthy survivors of childhood cancer after anthracycline therapy. PATIENTS AND METHODS: A search was made in Medline for studies published between 1966 and May 2001 that included >50 children and reported on the frequency of measures of subclinical cardiotoxicity. Information about the studies was abstracted by two reviewers and a validity score was calculated for each study. RESULTS: The reported frequency of subclinical cardiotoxicity varied between 0% and 57% in the 25 studies included. Differences in outcome definitions of subclinical cardiotoxicity and differences in study patients with respect to the dose of anthracycline seemed to explain part of the wide variance of the frequency of subclinical cardiotoxicity. Fourteen of the 25 studies showed serious methodological limitations. CONCLUSIONS: The reported frequency of subclinical cardiotoxicity shows a wide variation. Well designed studies with accurate and precise outcome measurements in well described groups of patients, after a sufficiently long follow-up period, are needed to obtain more insight into the frequency and importance of risk factors, and the clinical consequences of anthracycline-related subclinical cardiotoxicity.     

Attenuation of doxorubicin chronic toxicity in metallothionein-overexpressing transgenic mouse heart

Previous studies have shown that cardiac-specific metallothionein (MT)-overexpressing transgenic mice are highly resistant to acute cardiotoxicity induced by doxorubicin (DOX), a most effective anticancer agent. However, cumulative dose-dependent chronic cardiotoxicity attributable to long-term administration of DOX is a significant clinical problem. Because MT is a potent antioxidant and oxidative stress is critically involved in DOX-induced heart injury, the present study was undertaken to test the hypothesis that MT also provides protection against DOX chronic cardiotoxicity. Transgenic mice containing high levels of cardiac MT and nontransgenic controls were treated with a cumulative dose of 40 mg/kg of DOX in 10 equal i.v. injections over a period of 7 weeks. Three weeks after the last injection, the mice were killed for an analysis of cardiotoxicity. As compared with nontransgenic controls, DOX-induced cardiac hypertrophy was significantly inhibited in the transgenic mice. Light microscopic examination revealed that DOX-induced myocardial morphological changes were markedly suppressed or almost eliminated in the transgenic mice. Under electron microscopy, extensive sarcoplasmic vacuolization and severe disruption of mitochondrial fine structure were observed in nontransgenic cardiomyocytes, but almost no sarcoplasmic vacuolization was observed, and the mitochondrial structural changes were almost completely prevented in the transgenic cardiomyocytes. The results thus indicate that MT elevation is a highly effective approach to prevent chronic cardiomyopathy attributable to DOX. This study also suggests that oxidative stress is critically involved in the DOX-induced chronic cardiotoxicity.     

The iron chelator Dp44mT inhibits the proliferation of cancer cells but fails to protect from doxorubicin-induced cardiotoxicity in spontaneously hypertensive rats

Purpose  

The iron chelator Dp44mT is a potent topoisomerase IIα inhibitor with novel anticancer activity. Doxorubicin (Dox), the current front-line therapy for breast cancer, induces a dose-limiting cardiotoxicity, in part through an iron-mediated pathway. We tested the hypothesis that Dp44mT can improve clinical outcomes of treatment with Dox by alleviating cardiotoxicity.     

7-monohydroxyethylrutoside protects against chronic doxorubicin-induced cardiotoxicity when administered only once per week.

Doxorubicin is a very effective antitumor agent, but its clinical use is limited by the occurrence of a cumulative dose-related cardiotoxicity, resulting in congestive heart failure. 7-Monohydroxyethylrutoside (monoHER), a flavonoid belonging to the semisynthetic hydroxyethylrutoside family, has been shown to protect against doxorubicin-induced cardiotoxicity when administered i.p. at a dose of 500 mg/kg five times/week in combination with a weekly i.v. dose of doxorubicin. Such a dosing schedule would be very inconvenient in clinical practice. We therefore investigated a dosing schedule of one administration of monoHER just before doxorubicin. The electrocardiogram was measured telemetrically in mice after the combined treatment of doxorubicin (4 mg/kg, i.v.) with one dose of monoHER (500 mg/kg, i.p., administered 1 h before doxorubicin) for 6 weeks. These data were compared with the five times/week schedule (500 mg/kg, i.p., administered 1 h before doxorubicin and every 24 h for 4 days). The increase of the ST interval was used as a measure for cardiotoxicity. It was shown that 500 mg/kg monoHER administered only 1 h before doxorubicin provided complete protection against the cardiotoxicity. This protection was present for at least 10 weeks after the last treatment. Because of the short half-life of monoHER, these results suggest that the presence of monoHER is only necessary during the highest plasma levels of doxorubicin.     

Dysregulated miR1254 and miR579 for cardiotoxicity in patients treated with bevacizumab in colorectal cancer

Methods for detecting circulating microRNAs (miRNAs), small RNAs that control gene expression, at high sensitivity and specificity in the blood have been reported in recent studies. The goal of this study was to determine if detectable levels of specific miRNAs are released into the circulation for bevacizumab-induced cardiotoxicity. A miRNA array analysis was performed using RNA isolated from 10 control patients in bevacizumab treatment, and n?=?10 patients have been confirmed to have bevacizumab-induced cardiotoxicity. From the array, we selected 19 candidate miRNA for a second validation study in 90 controls and 88 patients with bevacizumab-induced cardiotoxicity. Consistent with the data obtained from the microRNA array, circulating levels of five miRNAs were significantly increased in patients with bevacizumab-induced cardiotoxicity compared with controls. To confirm these data, we compared selected miRNAs in the plasma of patients with bevacizumab-induced cardiotoxicity with those of 66 patients with acute myocardial infarction (AMI). Moreover, we went on to analyze what factors may influence the levels of potential biomarker miRNAs. Consistent with the data obtained from the microRNA array, circulating levels of five miRNAs were significantly increased in patients with bevacizumab-induced cardiotoxicity compared with those of healthy bevacizumab treatment controls. However, only miRNA1254 and miRNA579 showed high specificity in the validation experiments. Moreover, we went on to analyze what factors may influence the levels of potential biomarker miRNAs. We identify two miRNAs that are specifically elevated in patients with bevacizumab-induced cardiotoxicity, miR1254 and miRNA579, and miRNA1254 shows the strongest correlation to the clinical diagnosis of bevacizumab-induced cardiotoxicity.     

Trastuzumab-related cardiotoxicity in the elderly: a role for cardiovascular risk factors

BackgroundElderly breast cancer patients are usually excluded from clinical trials. Nevertheless, with the increasing use of trastuzumab, there is a need to address trastuzumab-related cardiotoxicity in this population.Patients and methodsRecords for patients ≥70 years treated with trastuzumab since 2005 were reviewed. New York Heart Association classification was used to document symptomatic cardiotoxicity. Asymptomatic cardiotoxicity was defined as an absolute drop ≥10% with a final left ventricular ejection fraction <50% or an absolute drop >20%.ResultsForty-five patients, median age 75.9 years (range 70–92), were identified. Three of 24 (12.5%) early breast cancer patients and 5 of 21 (23.8%) with advanced disease experienced asymptomatic cardiotoxicity. Four of 45 patients (8.9%), all with advanced breast cancer, developed symptomatic congestive heart failure. All but one of them recovered in a median time of 5 weeks (range 3–21). Patients with trastuzumab-related cardiotoxicity presented more often with cardiovascular risk factors, such as history of cardiac disease (33% versus 9.1%, P = 0.017) and diabetes (33.3% versus 6.1%, P = 0.010), compared with those without.ConclusionsElderly breast cancer patients with a history of cardiac disease and/or diabetes treated with trastuzumab have an increased incidence of cardiotoxicity. Continuous cardiac monitoring is especially advised in this population.