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Steven E. Lipshultz - One of the best experts on this subject based on the ideXlab platform.
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Anthracycline-Induced Cardiotoxicity: A Review of Pathophysiology, Diagnosis, and Treatment
Current Treatment Options in Cardiovascular Medicine, 2014Co-Authors: Vivian I. Franco, Steven E. LipshultzAbstract:Anthracyclines have been widely used in children and adults to treat hematologic malignancies, soft-tissue sarcomas, and solid tumors. However, Anthracyclines come with both short- and long-term cardiotoxic effects, ranging from occult changes in myocardial structure and function to severe cardiomyopathy and heart failure that may result in cardiac transplantation or death. Here, we review the progress made over the past two decades in understanding the molecular and genetic basis of anthracycline-induced cardiotoxicity; detecting and monitoring myocardial dysfunction; using adjunct cardioprotectant therapies, such as dexrazoxane; and improving cardioprotection with agents such as liposomal and pegylated doxorubicin. Despite this increased understanding, preventing drug-induced cardiotoxicity while maintaining oncologic efficacy to achieve the highest quality of life over a lifespan remain cornerstones of successful anthracycline chemotherapy during childhood.
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Anthracycline Cardiotoxicity: From Bench to Bedside
Journal of Clinical Oncology, 2008Co-Authors: Luca Gianni, Steven E. Lipshultz, Giorgio Minotti, Eugene H Herman, Narine Sarvazyan, Douglas B SawyerAbstract:Anthracyclines remain among the most widely prescribed and effective anticancer agents. Unfortunately, life-threatening cardiotoxicity continues to compromise their usefulness. Despite more than four decades of investigation, the pathogenic mechanisms responsible for anthracycline cardiotoxicity have not been completely elucidated. In addition, new drugs and combination therapies often exacerbate the toxicity. The First International Workshop on Anthracycline Cardiotoxicity, held in fall 2006, in Como, Italy, focused on the state-of-the-art knowledge and discussed the research needed to address the cardiotoxicity of these drugs. Here, we incorporate these discussions into the framework of a broader review of preclinical and clinical issues.
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anthracycline induced cardiotoxicity course pathophysiology prevention and management
Expert Opinion on Pharmacotherapy, 2007Co-Authors: Elly Barry, Tracie L Miller, Jorge A Alvarez, Rebecca E Scully, Steven E. LipshultzAbstract:Although effective anti-neoplastic agents, Anthracyclines are limited by their well recognized and pervasive cardiotoxic effects. The incidence of late progressive cardiovascular disease in long-term survivors of cancer is established and may contribute to heart failure and death. To maximize the benefits of these drugs, a high-risk population has been identified and new strategies have been investigated to minimize toxic effects, including limiting the cumulative dose, controlling the rate of administration and using liposomal preparations and novel anthracycline analogues. Dexrazoxane also shows promise as a cardioprotectant during treatment. This paper reviews these strategies, as well as medications used to manage anthracycline-induced cardiotoxicity, and functional and biochemical means of monitoring cardiotoxicity, including echocardiography, radionuclide scans and biomarker analysis. The treatment of adult cancer survivors who have had anthracycline-related cardiotoxicity has not been systematically studied. Empirically, anthracycline-associated cardiac dysfunction is treated very similarly to other forms of heart failure. These treatments include avoiding additional cardiotoxic regimens, controlling hypertension, lifestyle changes, medications and heart transplantation.
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exposure to Anthracyclines during childhood causes cardiac injury
Seminars in Oncology, 2006Co-Authors: Steven E. LipshultzAbstract:The use of Anthracyclines in the treatment of acute lymphoblastic leukemia is limited by associated cardiotoxic effects, which can result in cardiomyopathy and congestive heart failure, and may be irreversible. Anthracycline-induced cardiotoxicity in long-term survivors of childhood cancer is characterized by reduced left ventricular wall thickness and mass, which is indicative of decreased cardiac muscle and depressed left ventricular contractility which is indicative of unhealthy heart muscle. Risk factors for anthracycline-induced cardiotoxicity include high cumulative anthracycline doses, high anthracycline dose intensity, and radiotherapy. Radiotherapy in patients with cancer treated with Anthracyclines can exacerbate anthracycline-induced cardiac tissue damage. Several studies have shown that cardiomyopathy disease progression can be delayed in adults by using angiotensin-converting enzyme inhibitors such as enalapril. Studies in long-term survivors of pediatric cancer showed that enalapril has significant benefits in preventing cardiac functional deterioration on a short-term basis, but this is not sustained. Anthracycline-associated cardiotoxic effects can be combated by preventing cardiac injury during chemotherapy administration. There is evidence that dexrazoxane significantly reduces the cardiotoxicity associated with Anthracyclines such as daunorubicin, doxorubicin, and epirubicin in adult patients with a wide range of tumor types. A study of the efficacy of dexrazoxane in reducing doxorubicin-induced cardiotoxicity in children and adolescents with high-risk acute lymphoblastic leukemia, showed that significantly fewer dexrazoxane-treated patients (21%) had elevated serum cardiac troponin (a biomarker of acute myocardial injury) levels than patients treated with chemotherapy alone (50%; P <.001). Dexrazoxane was also shown to have no effect on the event-free survival rate at 2.5 years, emphasizing that it does not detrimentally affect the efficacy of anthracycline therapy.
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protecting against anthracycline induced myocardial damage a review of the most promising strategies
British Journal of Haematology, 2005Co-Authors: Karlijn A Wouters, Leontien C M Kremer, Tracie L Miller, Eugene H Herman, Steven E. LipshultzAbstract:Over the last 40 years, great progress has been made in treating childhood and adult cancers. However, this progress has come at an unforeseen cost, in the form of emerging long-term effects of anthracycline treatment. A major complication of anthracycline therapy is its adverse cardiovascular effects. If these cardiac complications could be reduced or prevented, higher doses of Anthracyclines could potentially be used, thereby further increasing cancer cure rates. Moreover, as the incidence of cardiac toxicity resulting in congestive heart failure or even heart transplantation dropped, the quality and extent of life for cancer survivors would improve. We review the proposed mechanisms of action of Anthracyclines and the consequences associated with anthracycline treatment in children and adults. We summarise the most promising current strategies to limit or prevent anthracycline-induced cardiotoxicity, as well as possible strategies to prevent existing cardiomyopathy from worsening.
Tomas G. Neilan - One of the best experts on this subject based on the ideXlab platform.
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Upfront dexrazoxane for the reduction of anthracycline-induced cardiotoxicity in adults with preexisting cardiomyopathy and cancer: a consecutive case series
Cardio-Oncology, 2019Co-Authors: Sarju Ganatra, Anju Nohria, Sachin Shah, John D. Groarke, Ajay Sharma, David Venesy, Richard Patten, Krishna Gunturu, Corrine Zarwan, Tomas G. NeilanAbstract:Background Cardiotoxicity associated with anthracycline-based chemotherapies has limited their use in patients with preexisting cardiomyopathy or heart failure. Dexrazoxane protects against the cardiotoxic effects of Anthracyclines, but in the USA and some European countries, its use had been restricted to adults with advanced breast cancer receiving a cumulative doxorubicin (an anthracycline) dose > 300 mg/m^2. We evaluated the off-label use of dexrazoxane as a cardioprotectant in adult patients with preexisting cardiomyopathy, undergoing anthracycline chemotherapy. Methods Between July 2015 and June 2017, five consecutive patients, with preexisting, asymptomatic, systolic left ventricular (LV) dysfunction who required anthracycline-based chemotherapy, were concomitantly treated with off-label dexrazoxane, administered 30 min before each anthracycline dose, regardless of cancer type or stage. Demographic, cardiovascular, and cancer-related outcomes were compared to those of three consecutive patients with asymptomatic cardiomyopathy treated earlier at the same hospital without dexrazoxane. Results Mean age of the five dexrazoxane-treated patients and three patients treated without dexrazoxane was 70.6 and 72.6 years, respectively. All five dexrazoxane-treated patients successfully completed their planned chemotherapy (doxorubicin, 280 to 300 mg/m^2). With dexrazoxane therapy, changes in LV systolic function were minimal with mean left ventricular ejection fraction (LVEF) decreasing from 39% at baseline to 34% after chemotherapy. None of the dexrazoxane-treated patients experienced symptomatic heart failure or elevated biomarkers (cardiac troponin I or brain natriuretic peptide). Of the three patients treated without dexrazoxane, two received doxorubicin (mean dose, 210 mg/m^2), and one received daunorubicin (540 mg/m^2). Anthracycline therapy resulted in a marked reduction in LVEF from 42.5% at baseline to 18%. All three developed symptomatic heart failure requiring hospitalization and intravenous diuretic therapy. Two of them died from cardiogenic shock and multi-organ failure. Conclusion The concomitant administration of dexrazoxane in patients with preexisting cardiomyopathy permitted successful delivery of anthracycline-based chemotherapy without cardiac decompensation. Larger prospective trials are warranted to examine the use of dexrazoxane as a cardioprotectant in patients with preexisting cardiomyopathy who require Anthracyclines.
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Upfront dexrazoxane for the reduction of anthracycline-induced cardiotoxicity in adults with preexisting cardiomyopathy and cancer: a consecutive case series
Cardio-oncology (London England), 2019Co-Authors: Sarju Ganatra, Anju Nohria, John D. Groarke, David Venesy, Krishna Gunturu, Corrine Zarwan, Sachin P. Shah, Ajay K. Sharma, Richard D. Patten, Tomas G. NeilanAbstract:Cardiotoxicity associated with anthracycline-based chemotherapies has limited their use in patients with preexisting cardiomyopathy or heart failure. Dexrazoxane protects against the cardiotoxic effects of Anthracyclines, but in the USA and some European countries, its use had been restricted to adults with advanced breast cancer receiving a cumulative doxorubicin (an anthracycline) dose > 300 mg/m2. We evaluated the off-label use of dexrazoxane as a cardioprotectant in adult patients with preexisting cardiomyopathy, undergoing anthracycline chemotherapy. Between July 2015 and June 2017, five consecutive patients, with preexisting, asymptomatic, systolic left ventricular (LV) dysfunction who required anthracycline-based chemotherapy, were concomitantly treated with off-label dexrazoxane, administered 30 min before each anthracycline dose, regardless of cancer type or stage. Demographic, cardiovascular, and cancer-related outcomes were compared to those of three consecutive patients with asymptomatic cardiomyopathy treated earlier at the same hospital without dexrazoxane. Mean age of the five dexrazoxane-treated patients and three patients treated without dexrazoxane was 70.6 and 72.6 years, respectively. All five dexrazoxane-treated patients successfully completed their planned chemotherapy (doxorubicin, 280 to 300 mg/m2). With dexrazoxane therapy, changes in LV systolic function were minimal with mean left ventricular ejection fraction (LVEF) decreasing from 39% at baseline to 34% after chemotherapy. None of the dexrazoxane-treated patients experienced symptomatic heart failure or elevated biomarkers (cardiac troponin I or brain natriuretic peptide). Of the three patients treated without dexrazoxane, two received doxorubicin (mean dose, 210 mg/m2), and one received daunorubicin (540 mg/m2). Anthracycline therapy resulted in a marked reduction in LVEF from 42.5% at baseline to 18%. All three developed symptomatic heart failure requiring hospitalization and intravenous diuretic therapy. Two of them died from cardiogenic shock and multi-organ failure. The concomitant administration of dexrazoxane in patients with preexisting cardiomyopathy permitted successful delivery of anthracycline-based chemotherapy without cardiac decompensation. Larger prospective trials are warranted to examine the use of dexrazoxane as a cardioprotectant in patients with preexisting cardiomyopathy who require Anthracyclines.
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myocardial extracellular volume by cardiac magnetic resonance imaging in patients treated with anthracycline based chemotherapy
American Journal of Cardiology, 2013Co-Authors: Tomas G. Neilan, Otavio R Coelhofilho, Ravi V Shah, Jiazuo H Feng, Diego Penaherrera, Damien Mandry, Francois Pierremongeon, Bobak HeydariAbstract:We aimed to determine whether the myocardial extracellular volume (ECV), measured using T1 measurements obtained during cardiac magnetic resonance imaging were increased in patients treated with Anthracyclines. We performed cardiac magnetic resonance imaging and echocardiography and measured the ECV in 42 patients treated with Anthracyclines. The data from the cardiac magnetic resonance study were compared to those from healthy volunteers. The anthracycline-treated cohort consisted of 21 men and 21 women with a mean age of 55 ± 17 years, who presented a median of 84 months after chemotherapy with a cumulative anthracycline exposure of 282 ± 65 mg/m(2) and a mean left ventricular ejection fraction of 52 ± 12%. The ECV was elevated in the anthracycline-treated patients compared to the age- and gender-matched controls (0.36 ± 0.03 vs 0.28 ± 0.02, p <0.001). A positive association was found between the ECV and left atrial volume (ECV vs indexed left atrial volume, r = 0.65, p <0.001), and negative association was found between the ECV and diastolic function (E' lateral, r = -0.64, p <0.001). In conclusion, the myocardial ECV is elevated in patients with previous anthracycline treatment and is associated with the diastolic function and increased atrial volumes.
Bobak Heydari - One of the best experts on this subject based on the ideXlab platform.
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myocardial extracellular volume by cardiac magnetic resonance imaging in patients treated with anthracycline based chemotherapy
American Journal of Cardiology, 2013Co-Authors: Tomas G. Neilan, Otavio R Coelhofilho, Ravi V Shah, Jiazuo H Feng, Diego Penaherrera, Damien Mandry, Francois Pierremongeon, Bobak HeydariAbstract:We aimed to determine whether the myocardial extracellular volume (ECV), measured using T1 measurements obtained during cardiac magnetic resonance imaging were increased in patients treated with Anthracyclines. We performed cardiac magnetic resonance imaging and echocardiography and measured the ECV in 42 patients treated with Anthracyclines. The data from the cardiac magnetic resonance study were compared to those from healthy volunteers. The anthracycline-treated cohort consisted of 21 men and 21 women with a mean age of 55 ± 17 years, who presented a median of 84 months after chemotherapy with a cumulative anthracycline exposure of 282 ± 65 mg/m(2) and a mean left ventricular ejection fraction of 52 ± 12%. The ECV was elevated in the anthracycline-treated patients compared to the age- and gender-matched controls (0.36 ± 0.03 vs 0.28 ± 0.02, p <0.001). A positive association was found between the ECV and left atrial volume (ECV vs indexed left atrial volume, r = 0.65, p <0.001), and negative association was found between the ECV and diastolic function (E' lateral, r = -0.64, p <0.001). In conclusion, the myocardial ECV is elevated in patients with previous anthracycline treatment and is associated with the diastolic function and increased atrial volumes.
Giorgio Minotti - One of the best experts on this subject based on the ideXlab platform.
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anthracycline degradation in cardiomyocytes a journey to oxidative survival
Chemical Research in Toxicology, 2010Co-Authors: Pierantonio Menna, Emanuela Salvatorelli, Giorgio MinottiAbstract:The clinical use of doxorubicin (DOX) and other quinone-hydroquinone antitumor Anthracyclines is limited by dose-related cardiotoxicity. One-electron redox cycling of the quinone moiety has long been known to form reactive oxygen species (ROS) in excess of the limited antioxidant defenses of cardiomyocytes; therefore, anthracycline cardiotoxicity was perceived as a one-way process in which redox cycling of the quinone always primed cardiomyocytes to oxidant stress and death. The past few years witnessed a growing interest in an alternative process in which peroxidases and quinone-derived hydrogen peroxide were able to oxidize the hydroquinone moiety of Anthracyclines. Such a process was initially thought to amplify the cardiotoxicity induced by Anthracyclines. Here, we briefly review how oxyferrous myoglobin could be subsequently identified as the primary catalyst of anthracycline oxidation in cardiomyocytes and be shown to induce an anthracycline chemical degradation that diminished the cellular levels and toxicity of active parent compounds. Many aspects of anthracycline degradation remain obscure or only partially understood; nevertheless, it is not too naive to conclude that Anthracyclines are degraded and inactivated as a result of ROS production from their own redox cycling. Anthracycline redox reactions might therefore be viewed as two-way processes in which oxidative stress mediated both the death and survival of cardiomyocytes.
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Anthracycline Cardiotoxicity: From Bench to Bedside
Journal of Clinical Oncology, 2008Co-Authors: Luca Gianni, Steven E. Lipshultz, Giorgio Minotti, Eugene H Herman, Narine Sarvazyan, Douglas B SawyerAbstract:Anthracyclines remain among the most widely prescribed and effective anticancer agents. Unfortunately, life-threatening cardiotoxicity continues to compromise their usefulness. Despite more than four decades of investigation, the pathogenic mechanisms responsible for anthracycline cardiotoxicity have not been completely elucidated. In addition, new drugs and combination therapies often exacerbate the toxicity. The First International Workshop on Anthracycline Cardiotoxicity, held in fall 2006, in Como, Italy, focused on the state-of-the-art knowledge and discussed the research needed to address the cardiotoxicity of these drugs. Here, we incorporate these discussions into the framework of a broader review of preclinical and clinical issues.
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Anthracyclines molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity
Pharmacological Reviews, 2004Co-Authors: Giorgio Minotti, Pierantonio Menna, Emanuela Salvatorelli, Gaetano Cairo, Luca GianniAbstract:The clinical use of Anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, Anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of Anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-a-vis toxicity in cardiomyocytes) that Anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of Anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between Anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that Anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index.
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Anthracyclines : molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity
'American Society for Pharmacology & Experimental Therapeutics (ASPET)', 2004Co-Authors: Giorgio Minotti, Emanuela Salvatorelli, Gaetano Cairo, P. Menna, L. GianniAbstract:The clinical use of Anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, Anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of Anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-\ue0-vis toxicity in cardiomyocytes) that Anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of Anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between Anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that Anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index
Mark Verrill - One of the best experts on this subject based on the ideXlab platform.
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expert opinion on the use of Anthracyclines in patients with advanced breast cancer at cardiac risk
Annals of Oncology, 2009Co-Authors: Peter Barrettlee, J M Dixon, Carole Farrell, Andrew Jones, R C F Leonard, Noreen E Murray, Carlo Palmieri, C J Plummer, A Stanley, Mark VerrillAbstract: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.