Prevention Of Anthracycline Cardiotoxicity Research Articles

Renin-angiotensin System Antagonists and Beta-blockers in Prevention of Anthracycline Cardiotoxicity: a Systematic Review and Meta-analysis.

The evidence supporting the use of renin-angiotensin-aldosterone system (RAAS) inhibitors and beta-blockers for the prevention of anthracycline-induced cardiomyopathy is controversial. We performed a meta-analysis to assess the effectiveness of these drugs in preventing cardiotoxicity. The meta-analysis included prospective, randomized studies in adults receiving anthracycline chemotherapy and compared the use of RAAS inhibitors or beta-blockers versus placebo with a follow-up of 6 to 18 months. The primary outcome was change in left ventricular ejection fraction (LVEF) during chemotherapy. Secondary outcomes were the incidence of heart failure, all-cause mortality, and changes in end-diastolic measurement. Heterogeneity was assessed by stratification and meta-regression. A significance level of p < 0.05 was adopted. The search resulted in 17 studies, totaling 1,530 patients. The variation (delta) in LVEF was evaluated in 14 studies. Neurohormonal therapy was associated with a lower delta in pre- versus post-therapy LVEF (weighted mean difference 4.42 [95% confidence interval 2.3 to 6.6]) and higher final LVEF (p < 0.001). Treatment resulted in a lower incidence of heart failure (risk ratio 0.45 [95% confidence interval 0.3 to 0.7]). There was no effect on mortality (p = 0.3). For analysis of LVEF, substantial heterogeneity was documented, which was not explained by the variables explored in the study. The use of RAAS inhibitors and beta-blockers to prevent anthracycline-induced cardiotoxicity was associated with less pronounced reduction in LVEF, higher final LVEF, and lower incidence of heart failure. No changes in mortality were observed. (CRD PROSPERO 42019133615).

Primary Mediastinal Large B-cell Lymphoma Treatment and Prevention of Anthracycline Cardiotoxicity: A Case Report

Primary mediastinal B-cell lymphoma (PMBCL) is a relatively rare lymphoma subtype affecting mainly young adults. Its molecular signature and clinical features resemble classical Hodgkin lymphoma. The optimal chemotherapy for this lymphoma subtype has not been established. The addition of rituximab to anthracycline based chemotherapy improved response rates and survival. Many centers use R-CHOP as standard treatment, but the role of the intensified regimens and consolidation radiotherapy has to be clarified. Recent data coming from retrospective analyses and an ongoing prospective study addressing the problem of consolidation radiotherapy will help to better identify risk groups and apply risk-adapted and effective treatment strategies. The latest research has helped to understand molecular mechanisms of PMBCL pathogenesis and indicated targets of directed therapy for the future.

Primary Mediastinal Large B-cell Lymphoma Treatment and Prevention of Anthracycline Cardiotoxicity: A Case Report

Primary Mediastinal Large B-cell Lymphoma Treatment and Prevention of Anthracycline Cardiotoxicity: A Case Report

Evaluation of the cost-effectiveness of dexrazoxane for the prevention of anthracycline-related cardiotoxicity in children with sarcoma and haematologic malignancies: a European perspective

BackgroundAnthracycline-treated childhood cancer survivors are at higher risk of cardiotoxicity, especially with cumulative doses received above 250 mg/m2. Dexrazoxane is the only option recommended for cardiotoxicity prevention in high-risk patients supported by randomised trials but its cost-effectiveness in paediatric cancer patients has not been established.MethodsA cost-effectiveness model applicable to different national healthcare system perspectives, which simulates 10,000 patients with either sarcoma or haematologic malignancies, based upon baseline characteristics including gender, age at diagnosis, cumulative anthracycline dose and exposure to chest irradiation. Risk equations for developing congestive heart failure and death from recurrence of the original cancer, secondary malignant neoplasms, cardiac death, pulmonary death, and death from other causes were derived from published literature. These are applied to the individual simulated patients and time until development of these events was determined. The treatment effect of dexrazoxane on the risk of CHF or death was based upon a meta-analysis of randomised and non-randomised dexrazoxane studies in each tumour type. The model includes country specific data for drug and administration costs, all aspects of heart failure diagnosis and management, and death due to different causes for each of the five countries considered; France, Germany, the UK, Italy, and Spain.ResultsDexrazoxane treatment resulted in a mean QALY benefit across the five countries ranging from 0.530 to 0.683 per dexrazoxane-treated patient. Dexrazoxane was cost-effective for paediatric patients receiving anthracycline treatment for sarcoma and for haematologic malignancies, irrespective of the cumulative anthracycline dose received. The Incremental Cost Effectiveness Ratio (ICER) was favourable in all countries irrespective of anthracycline dose for both sarcoma and haematological malignancies (range: dominant to €2196). Individual ICER varied considerably according to country with dominance demonstrated for dexrazoxane in Spain and Italy and ratios approximately double the European average in the UK and Germany.ConclusionsDexrazoxane is a highly cost-effective therapy for the prevention of anthracycline cardiotoxicity in paediatric patients with sarcoma or haematological malignancies in Europe, irrespective of the healthcare system in which they receive treatment. These benefits persist when patients who receive doses of anthracycline > 250 mg/m2 are included in the model.

P375 To evaluate the effectiveness of primary prevention of anthracycline cardiotoxicity using modern STE technologies

Abstract Funding Acknowledgements without financial supports Introduction Despite the high efficiency, the use of chemotherapeutic drugs involves to the development of cardiomyopathy and heart failure. Correction of myocardial damage is most effective before the appearance of clinical manifestations of cardiomyopathy. Aim of study. To evaluate the effectiveness of primary prevention of anthracycline cardiotoxicity using modern STE technologies. Material and methods.The study included 65 patients with breast cancer. All patients had a collection of anamnesis, echocardiography with STE , were performed before the study. All patients were prescribed chemotherapy with anthracycline, after which the patients included in the study were randomly randomized into two groups. Patients of the first group, in which 27 patients were included, were additionally assigned ivabradine in a daily dose of 10 mg, followed by titration of the dose to achieve a heart rate of less than 70 beats per minute. The comparison group consisted of 38 patients who received only chemotherapy. Results A six-month treatment with ivabradine was accompanied by a significant decrease in heart rate by the first month (from 83.6 ± 9.5 to 67.1 ± 7.5 bpm, p &amp;lt;0.001) and persisted until the sixth month (from 83.6 ± 9.5 Up to 74.2 ± 14.9 beats per minute, p &amp;lt;0.001). The analysis of echocardiographic indices did not reveal significant differences between the groups.The reliable dynamics of the LV ejection fraction was not detected in both groups.To assess the effect of ivabradine on the development of subclinical systolic dysfunction of the left ventricle during chemotherapy, a global longitudinal systolic deformation was also evaluated. The groups did not differ in terms of global longitudinal strain (-20.4 ± 1.8% in the ivabradine group and -19.9 ± 2.0% in the control group). In the control group, there was a tendency to decrease global deformation (from -19.9 ± 2.0% to -19.0 ± 1.8% by 3 months to -18.9 ± 1.7% by the 6th month of observation), and in Group of ivabradine, the deformation parameters were at a stable level (from -20.4 ± 1.8% to-20.6 ± 2.4% by 3 months and -20.4 ± 1.9% by the 6th month of observation), which led to significant differences between groups at the first and third and sixth month of observation (-21.1 ± 1.8% to 1 month and -20.6 ± 2.4% to 3 months and -20.4 ± 1.9% to 6 months in the ivabradine group compared to -19.6 ± 2.1% to 1 Month and -19.0 ± 1.8% by 3 months and -18.9 ± 1.7 by the 6th month of observation p &amp;lt;0.05 in the control group). Conclusions.Therapy with ivabradine in patients with breast cancer with heart rate&amp;gt; 70 beats per minute is safe. The appointment of ivabradine is accompanied by a significant decrease in the number of patients with complaints of heart beat, contributes to the preservation of normal global longitudinal deformation of the left ventricle against chemotherapy, while in the control group has a negative dynamics with a maximum at the 6th month of follow-up

How to improve quality of life in patients with acute leukemia and comorbid ischemic heart disease treated with anthracycline-based induction chemotherapy.

To evaluate the quality of life (QoL) parameters in patients with acute leukemia (AL) during standard induction chemotherapy, depending on the presence of concomitant ischemic heart disease and to improve them by the prevention of anthracycline cardiotoxicity with L-arginine. A total of 147adult AL patients (72males and 75females with the mean age 54.7 ± 9.3years) were enrolled in the study. QoL assessment was performed at baseline and after induction chemotherapy using SF-36questionnaire. Both physical and mental parameters were evaluated. The QoL analysis of patients with AL at the time of initial diagnosis showed extremely low QoL level in all subgroups compared with healthy individuals. It should be noted that the level of patients' QoL after achieving remission remained significantly lower than those of practically healthy, which is primarily due to the need for further long-term treatment and, probably, the fear of the disease relapse development. It was found that the administration of L-arginine during induction chemotherapy in order to reduce the risk of anthracycline cardiotoxicity development has allowed improving the QoL in patients with concomitant ischemic heart disease. L-arginine decreases the risk of anthracycline-induced myocardial injury and improves QoL in AL patients.

Association of Anthracycline-Related Cardiac Histological Lesions With NADPH Oxidase Functional Polymorphisms

Treatment with anthracyclines may cause cardiac dysfunction, but the sequence of anthracycline-induced heart lesions has been incompletely characterized. NADPH oxidase, a key mediator of oxidative cardiac damage and remodeling, modulates anthracycline clinical cardiotoxicity. Our aim was to determine which cardiac histological lesions are specifically induced by anthracycline treatment and to investigate the role of NADPH functional genetic polymorphisms in their development. Using a retrospective case-control design, we evaluated cardiac histological lesions and NADPH genotype (polymorphisms rs1883112, rs4673, and rs13058338) in 97 consecutive decedents with a cancer diagnosis (48 treated with anthracyclines). Myocytolysis (60%), patched myocardial necrosis (19%), and myocardial fibrosis (diffuse and patched; 62% and 23%, respectively) were associated with anthracycline treatment. In patients receiving anthracyclines, NADPH oxidase polymorphism rs4673 protected against focal myocardial necrosis (odds ratio [OR], 0.11; 95% confidence interval [CI], 0.20-0.63) whereas rs1883112 was strongly associated with cardiac fibrosis (OR, 5.11; 95% CI, 1.59-16.43), which was present in all homozygotes. Anthracyclines induce a cardiac remodeling pattern characterized by interstitial or patched fibrosis. The contribution of the functionally relevant NADPH polymorphisms rs1883112 and rs4673 to anthracycline-related heart lesions provides a plausible explanation for their modulation of cardiotoxicity. If confirmed, these findings may lead to better individualized strategies for early detection and prevention of anthracycline cardiotoxicity.

Prevention of chronic anthracycline cardiotoxicity in the adult Fischer 344 rat by dexrazoxane and effects on iron metabolism

Anthracyclines, such as doxorubicin and daunorubicin, continue to be widely used in the treatment of cancer, although they share the adverse effect of chronic, cumulative dose-related cardiotoxicity. The only approved treatment in prevention of anthracycline cardiotoxicity is dexrazoxane, a putative iron chelator. Previous in vitro studies have shown that disorders of iron metabolism, including altered IRP1-IRE binding, may be an important mechanism of anthracycline cardiotoxicity. This study examined the role of IRP1-IRE binding ex vivo in a chronic model of daunorubicin cardiotoxicity in the Fischer 344 rat and whether dexrazoxane could prevent any daunorubicin-induced changes in IRP1 binding. Young adult (5-6 months) Fischer 344 rats received daunorubicin (2.5 mg/kg iv once per week for 6 weeks) with and without pretreatment with dexrazoxane (50 mg/kg ip). Other groups received saline (controls) or dexrazoxane alone. Rats were killed either 4 h or 2 weeks after the last dose of daunorubicin to assess IRP1-IRE binding. Contractility (dF/dt) of atrial tissue, obtained from rats 2 weeks after the last dose of daunorubicin, was significantly reduced in daunorubicin-treated compared to control rats. Dexrazoxane pretreatment protected against the daunorubicin-induced decrease in atrial dF/dt. However, left ventricular IRP1/IRE binding was not affected by daunorubicin treatment either 4 h or 2 weeks after the last dose of daunorubicin. IRP1 binding may not be altered in the rat model of chronic anthracycline cardiotoxicity.

Recent advances in the prevention of anthracycline cardiotoxicity in childhood.

The prevention of anthracycline cardiotoxicity is particularly important in children who can be expected to survive for decades after cancer chemotherapy with these agents. The rapid increase in clinical toxicity at doses greater than 550 mg/m(2) of doxorubicin (DOX) has made this dose the limiting one in order to avoid DOX-induced cardiac failure. However, arbitrary dose limitation is inadequate because of variability of individual tolerance. Decreasing myocardial concentrations of anthracyclines (ANT) and their metabolites and schedule modification of administration can reduce anthracycline cardiotoxicity. Anthracycline structural analogues such as epirubicin, idarubicin and mitoxantrone have been used in clinical practice. In addition, the liposomal ANT, which can be incorporated into a variety of liposomal preparations, are a new class of agents that may permit more specific organ targeting of ANT, thereby producing less cardiac toxicity. Much interest has focused on the administration of ANT in conjunction with another agent that will selectively attenuate the cardiotoxicity. As is known, the ANT chelate iron and the DOX-iron complex catalyzes the formation of extremely reactive hydroxyl radicals. Many agents, such as dexrazoxane (DEX), able to remove iron from DOX, have been investigated as anthracycline cardioprotectors. Clinical trials of DEX have been conducted in children and significant short-term cardioprotection with no evidence of interference with antitumor activity has been demonstrated. Whether long-term cardiac toxicity will also be avoided in surviving patients has not yet been determined.

Use of ICRF-187 for Prevention of Anthracycline Cardiotoxicity in Children: Preliminary Results

The objective of this study is to assess the efficacy of ICRF-187 as a protective agent against anthracycline cardiotoxicity. Cardiac function was evaluated by echocardiography before and after each cycle of anthracycline chemotherapy associated with ICRF-187 and compared with that of a second group receiving anthracycline chemotherapy without ICRF-187. The patients were a group of 15 consecutive children affected with various types of solid tumors who were treated with either doxorubicin-daunomycin or epirubicin (average doses 340 and 280 mg/m2, respectively), and treatment was associated with ICRF-187. A second group of 15 consecutive children affected with different malignancies werre simultaneously treated with either doxorubicin-daunomycin or epirubicin (average doses 309 and 270 mg/m2, respectively), but without ICRF-187 association. None of the patients treated with anthracydines and ICRF-187 association showed abnormalities on echocardiography examination. In the second group of patients treated with anthracyclines but without ICRF-187 association, we observed a decrease in the left ventricular ejection fraction to <55% and a decrease in the. left ventricular fractional shortening to <28% in two patients (13.3%). One of these (6.6%) showed a dilatative cardiomyopathy. Both groups of patients were treated with low doses of anthracyclines. Although this study was not randomized, in patients without ICRF-87 cardioprotection, there was a trend for a worse evolution with one case of clinical cardiomyopathy as well as subclinical cardiac abnormalities.

Anthracycline-induced cardiotoxicity.

To review the current understanding of the clinical significance, detection, pathogenesis, and prevention of anthracycline-induced cardiotoxicity. A MEDLINE search of the English-language medical literature and a manual search of the bibliographies of relevant articles, including abstracts from national cardiology meetings. Pertinent clinical and experimental studies addressing the clinical relevance, pathogenesis, detection, and prevention of anthracycline cardiotoxicity were selected from peer-reviewed journals without judgments about study design. A total of 137 original studies and 9 other articles were chosen. Data quality and validity were assessed by each author independently. Statistical analysis of combined data was inappropriate given the differences in patient selection, testing, and follow-up in the available studies. Anthracycline-induced cardiotoxicity limits effective cancer chemotherapy by causing early cardiomyopathy, and it can produce late-onset ventricular dysfunction years after treatment has ceased. Detection of subclinical anthracycline-induced cardiomyopathy through resting left ventricular ejection fraction or echocardiographic fractional shortening is suboptimal. Conventional doses of anthracycline often lead to permanent myocardial damage and reduced functional reserve. Underlying pathogenetic mechanisms may include free-radical-mediated myocyte damage, adrenergic dysfunction, intracellular calcium overload, and the release of cardiotoxic cytokines. Dexrazoxane is the only cardioprotectant clinically approved for use against anthracyclines, and it was only recently introduced for selected patients with breast cancer who are receiving anthracycline therapy. A rapidly growing number of persons, including an alarming fraction of the 150 000 or more adults in the United States who have survived childhood cancer, will have substantial morbidity and mortality because of anthracycline-related cardiac disease. The development of effective protection against anthracycline-induced cardiotoxicity will probably have a significant effect on the overall survival of these patients.

Prevention of Anthracycline Cardiotoxicity by Iron Chelation

The use of anthracycline antineoplastic drugs is limited by a cumulative, dose-dependent toxicity to the heart. Of the cellular organelles proposed as possible primary sites of anthracycline toxicity, the mitochondrial membrane appears to be most likely target. Cardiolipin, a major phospholipid component of the inner mitochondrial membrane is rich in polyunsaturated fatty acids and is particularly susceptible to peroxidative injury by harmful radicals produced by redox cycling of anthracyclines. This, in turn, leads to the inactivation of key enzymes in the mitochondrial respiratory chain. Since the formation of free radicals is catalyzed by iron through the Haber-Weiss reaction, it was hypothesized that iron depletion by deferoxamine (DFO) may limit anthracycline cardiotoxicity. Recent studies indicate that iron-loading aggravates doxorubicin cardiotoxicity by enhancing mitochondrial damage, and this can be prevented by prior DFO treatment. Although these observations are intriguing, further studies are required to show that the cardioprotective effects of DFO do not interfere with the therapeutic, antitumoral action of anthracyclines.