Cardinale, T. Suter, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO clinical practice guidelines. Ann Oncol, 23 , pp. Swain, F. Whaley, M. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer, 97 , pp. Yeh, A. Tong, D. Lenihan, et al. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. B9 Medline. Leite-Moreira, et al. Cardiotoxicity associated with cancer therapy: pathophysiology and prevention strategies.
Rev Port Cardiol, 32 , pp. Legha, R. Benjamin, B. Mackay, et al. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med, 96 , pp. Lipshultz, T. Miller, S. Lipsitz, et al. Continuous versus bolus infusion of doxorubicin in children with ALL: long-term cardiac outcomes. Pediatrics, , pp. Valdivieso, M. Burgess, M. Ewer, et al. Increased therapeutic index of weekly doxorubicin in the therapy of non-small cell lung cancer: a prospective, randomized study.
J Clin Oncol, 2 , pp. Pacciarini, B. Barbieri, T. Colombo, et al. Distribution and antitumor activity of adriamycin given in a high-dose and a repeated low-dose schedule to mice. Cancer Treat Rep, 62 , pp. Caron, H. Dickinson, et al. Cardioprotective interventions for cancer patients receiving anthracyclines. Hamed, I. Barshack, G. Luboshits, et al. Erythropoietin improves myocardial performance in doxorubicin-induced cardiomyopathy. Eur Heart J, 27 , pp.
Clinical efficacy and prospects for use of pegylated liposomal doxorubicin in the treatment of ovarian and breast cancers. Drugs, 54 , pp. Michiels, H. Caron, et al. Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Food and Drug Administration. Drug safety and availability. Hensley, L. Schuchter, C. Lindley, et al.
American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. J Clin Oncol, 17 , pp. Martin, A. Thougaard, M. Grauslund, et al. Evaluation of the topoisomerase II-inactive bisdioxopiperazine ICRF as a protectant against doxorubicin-induced cardiomyopathy. Toxicology, , pp. Hasinoff, D. Patel, X. The oral iron chelator ICLA deferasirox does not protect myocytes against doxorubicin. Free Radic Biol Med, 35 , pp. Lyu, J. Kerrigan, C. Lin, et al. Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane.
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Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol, 11 , pp. Salzer, M. Devidas, W. Carroll, et al. Long-term results of the pediatric oncology group studies for childhood acute lymphoblastic leukemia a report from the children's oncology group. Leukemia, 24 , pp. Vrooman, D. Neuberg, K. Stevenson, et al.
The low incidence of secondary acute myelogenous leukaemia in children and adolescents treated with dexrazoxane for acute lymphoblastic leukaemia: a report from the Dana-Farber Cancer Institute ALL Consortium. Eur J Cancer, 47 , pp. Spallarossa, S. Garibaldi, P. Altieri, et al. Carvedilol prevents doxorubicin-induced free radical release and apoptosis in cardiomyocytes in vitro.
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Seidman, C. Hudis, M. Pierri, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol, 20 , pp. Kongbundansuk, W. Noninvasive imaging of cardiovascular injury related to the treatment of cancer. J Am Coll Cardiol Imaging, 7 , pp. Takigiku, M. Takeuchi, C. Izumi, et al. Circ J, 76 , pp. Subscribe to our newsletter. Organization and implementation of a cardio-oncology New prospects for the management of cardiovascular effects Global and regional patterns of longitudinal strain in Instructions for authors Submit an article Ethics in publishing.
Article options. Are you a health professional able to prescribe or dispense drugs? To improve our services and products, we use "cookies" own or third parties authorized to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here. Se continuar a navegar, consideramos que aceita o seu uso. They cause redox reactions through formation of cytotoxic free radicals.. Disruption of the dynamic regulation of cardiac function, altering adrenergic and adenylyl cyclase activity and calcium homeostasis..
Acute lymphoblastic leukemia Acute myeloid leukemia. Advanced ovarian cancer Stomach cancer Breast cancer Lung cancer. Acute lymphocytic leukemia Acute myeloid leukemia. Acute: Arrhythmias Atrial fibrillation Myocardial infarction Thromboembolism Chronic: Dilated cardiomyopathy Contractile dysfunction Congestive heart failure. Advanced breast cancer Acute myeloid leukemia in adults Non-Hodgkin lymphoma. Cardiomyopathy characterized by a decrease in cardiac LVEF that is either global or more severe in the septum. Symptoms of CHF. Detection of S3 gallop, tachycardia, or both;.
Using human pluripotent stem cell-derived cardiomyocytes to test drug cardiac toxicity
Standard transthoracic echocardiography. LV systolic function. Diastolic function. Non-invasive Low cost Measures QT interval, prolongation of which is a known marker of cardiotoxicity. Doppler echocardiography. Intra- and inter-observer variability Measurement of LVEF subject to variability and dependent on image quality Doubtful predictive value for early detection of subclinical lesions. Tissue Doppler imaging. Superior to LVEF for predicting cardiovascular mortality in the general population Better risk stratification in HF patients Able to recognize early LV dysfunction in patients undergoing cardiotoxic therapy Reproducible when performed by an experienced operator.
Stress echocardiography. Assessment of myocardial contractile reserve. Semi-invasive Controversial and limited data on early detection of cardiotoxicity. Radionuclide angiography. Ionizing radiation Low spatial and temporal resolution Underestimates ventricular volumes Underestimates LVEF in small ventricles women and children Does not assess valve function Little information on diastolic function Limited predictive value for early detection of subclinical lesions and changes in LVEF.
Magnetic resonance imaging. Reproducible No ionizing radiation Assessment of myocardial perfusion and function and pericardium, and detection of myocardial masses Useful in patients with poor echocardiographic image quality Gold standard for calculation of LV volumes and of LVEF T2 sequences: detects segmental or global changes in myocardial water content resulting from inflammation or microvascular or myocyte damage T1 sequences: provides information on myocardial lesions and fibrosis; with gadolinium contrast, detects histopathological alterations including intracellular vacuolization, enabling prediction of subsequent decrease in LVEF Late enhancement: detection of myocardial fibrosis associated with poor prognosis in patients with CAD, hypertrophic cardiomyopathy and infiltrative disease.
Computed tomography. High-resolution image Identifies pericardial calcification or thickening in patients undergoing radiotherapy or surgery Visualizes and assesses calcification of the coronary arteries. Ionizing radiation Documented coronary calcification prior to anticancer therapy is not predictive of CV risk in patients undergoing anthracycline chemotherapy Little used for detection and monitoring of subclinical changes in cardiac function.
Non-invasive Functional and structural assessment. Ionizing radiation Limited availability Low temporal resolution Limited data. Non-invasive Low inter-observer variability Assessment of CV function and potential signs of cardiac damage Promising for early detection of myocardial injury. Endomyocardial biopsy. Detects histological evidence of cardiac damage, including loss of myofibrils, vacuolization of cytoplasm, dilatation of the sarcoplasmic reticulum, increased numbers of lysosomes and mitochondrial swelling.
Invasive Histological interpretation requires specialist knowledge No functional information Results limited by quantity and quality of biopsy sample. Assessment of endothelial damage. Alternate parameters of cardiotoxicity such as cytokines, adhesion molecules and carotid artery intima-media thickness. Genetic analysis. Minimally invasive Assesses individual susceptibility to cardiotoxicity. Undetermined predictive value. Cumulative doses exceeding:.
The lead electrocardiogram can be used routinely to screen for arrhythmias due to anthracycline-related cardiotoxicity, while hour Holter monitoring or an event recorder can be useful to investigate the etiology of syncope presumed to result from arrhythmia or advanced atrioventricular block. These parameters, being dependent on pre- and afterload, are less sensitive for early detection of preclinical cardiac disease. Various studies have suggested that assessment of diastolic function by Doppler echocardiography may enable early detection of anthracycline-induced cardiomyopathy.
CMRI can detect subtle changes in the myocardium and increases in extracellular volume, which suggest edema or diffuse fibrosis. Although it is highly sensitive and reproducible for assessment of cardiac function and characterization of myocardial tissue, CMRI has the disadvantages of limited availability and high cost. Biomarkers have been validated in various studies; they are specific not only in detecting cardiovascular injury but also in determining its extent and reversibility.
Advantages and disadvantages of diagnostic exams in the assessment of anthracycline-induced cardiotoxicity.. Adapted from 5,12, Normal values of global longitudinal strain by vendor of scanner, gender, and age.. Initiation of a regimen potentially associated with anthracycline-induced cardiotoxicity. Cardiovascular risk factors should be identified and treated appropriately as soon as cancer is diagnosed. Patients should be encouraged to adopt a healthy lifestyle, including a diet low in saturated fat and a maximum of 2.
Exercise, whether of low or high intensity, during anthracycline therapy increases cardiovascular reserve 15 and studies in animal models have indicated that it may reduce the cardiotoxic effects of these agents. Another measure is to reduce or avoid the use of drugs that prolong QT interval, particularly 5-hydroxytryptamine 3 antagonists frequently used to prevent adverse effects of chemotherapy including nausea and vomiting and antihistamines.
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Risk factors for anthracycline-induced cardiotoxicity.. Patients aged over 65 and children may develop cardiotoxicity with lower cumulative doses.. Adapted from 12, The only case in which continuous infusion of doxorubicin appears to have no cardioprotective effect compared to rapid infusion is in children with acute lymphoblastic leukemia ALL.
Although animal studies demonstrated that anthracycline levels in tumor tissue were the same however the drugs were administered continuous or rapid infusion , this was not true of cardiac tissue, in which rapid infusion led to higher concentrations and thus greater toxicity. Although antioxidants neutralize free radicals formed by anthracycline therapy and thus theoretically reduce or prevent cardiotoxicity, clinical trials of N-acetylcysteine, coenzyme Q, L-carnitine, phenethylamines, amifostine and a combination of vitamins E and C and N-acetylcysteine did not show a cardioprotective effect.
One way to combat the adverse cardiac effects of anthracyclines is to change the formulation of the drugs such as encapsulating them in liposomes. Administration of dexrazoxane concomitantly with anticancer regimens can have a cardioprotective effect, preventing elevation of troponins and reducing the incidence of HF. However, two studies comparing dexrazoxane with placebo in children with ALL followed for five and 10 years showed no difference in the incidence of secondary malignancy.
The cardioprotection afforded by beta-blockers BBs appears to derive from their antioxidant and anti-apoptotic properties. One BB, carvedilol, has shown particular promise in reducing the incidence of anthracycline-induced cardiomyopathy and preserving systolic and diastolic function. ACE inhibitors and angiotensin receptor blockers ARBs show cardioprotective properties, possibly by reducing oxidative stress, left ventricular remodeling, and apoptosis.
Statins have antioxidant and anti-inflammatory properties. Finally, it should be emphasized that there is as yet no solid evidence for the effectiveness of pharmacological prevention of anthracycline-induced cardiomyopathy, and so the main preventive strategy remains thorough prior cardiovascular assessment of patients and appropriate monitoring, selection and adjustment of chemotherapy dosages..
After the development of signs or symptoms of HF or a reduction in LVEF due to chemotherapy-related cardiotoxicity, treatment should be based on the current guidelines. Several clinical trials are currently under way aiming to assess various therapeutic strategies, pharmacological and non-pharmacological, for the prevention of anthracycline-induced cardiomyopathy Table 8.
It will be some years before the results are known, and there is still a pressing need for evidence-based guidelines for the assessment and clinical monitoring of these patients.. Clinical trials on prevention of anthracycline-induced cardiomyopathy.. The longer survival of patients undergoing anticancer therapy and the consequent increase in the incidence of anthracycline-induced cardiomyopathy mean that it is necessary to investigate and determine the precise mechanisms leading to adverse cardiac effects, in order to prevent them.
Further research will enable specific and validated prevention plans to be established.. The authors have no conflicts of interest to declare.. Rev Port Cardiol. Revista Portuguesa de Cardiologia English edition. ISSN: Open Access Option. Previous article Next article. Issue 6. Pages June Cardiotoxicity in anthracycline therapy: Prevention strategies. Download PDF. Corresponding author. This item has received.
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No short-term cardiac toxicity of novel biological therapies for advanced non-sm
Table 8. Show more Show less. In this review the authors discuss the state of the art of the assessment, monitoring, and, above all, the prevention of anthracycline-induced cardiotoxicity. Introduction According to the World Health Organization, cancer is the second leading cause of death worldwide. Diagnosis of cardiac dysfunction induced by cancer therapy has been the subject of various studies, 3,5 one of which 5 is considered the reference publication on the subject, and is based on HF symptoms, physical examination and parameters of left ventricular function.
Cardiotoxicity, pharmacokinetics and therapeutic use of anthracyclines. Anthracyclines inhibit helicase, preventing enzymatic cleavage of the DNA double strand and thus interfering with replication and transcription. They cause redox reactions through formation of cytotoxic free radicals. Main mechanisms: - topoisomerase II beta-mediated DNA damage - lipid peroxidation - oxidative stress - apoptosis and necrosis of cardiac cells Impaired synthesis of DNA, RNA and proteins and of transcription factors involved in regulation of genes specific to the heart.
Negative balance of sarcomeric proteins in cardiac cells caused by reduced protein expression and increased myofilament degradation. Combination therapy exacerbates myofilament loss. Mitochondrial DNA damage and changes in mitochondrial bioenergetics. Disruption of the dynamic regulation of cardiac function, altering adrenergic and adenylyl cyclase activity and calcium homeostasis.
AV: atrioventricular. Criteria to confirm or revise a preliminary diagnosis of chemotherapy-induced cardiac dysfunction, according to the Cardiac Review and Evaluation Committee. Any one of the criteria is sufficient to confirm a diagnosis of cardiac dysfunction. Table 3. Recommended cardio-oncology echocardiogram protocol. Adapted from 5. Echocardiographical assessment of systolic and diastolic function in the cancer patient. Advantages and disadvantages of diagnostic exams in the assessment of anthracycline-induced cardiotoxicity. Normal values of global longitudinal strain by vendor of scanner, gender, and age.
Figure 1. Table 7. Risk factors for anthracycline-induced cardiotoxicity. CV: cardiovascular. Patients aged over 65 and children may develop cardiotoxicity with lower cumulative doses. Clinical trials on prevention of anthracycline-induced cardiomyopathy. Lead author and ClinicalTrials. Mathers, D. Projections of global mortality and burden of disease from to PLoS Med, 3 , pp.
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J Clin Oncol, 17 , pp. Martin, A. Thougaard, M.