Anthracycline-induced cardiotoxicity in children and young adults

Giantris, Amy; Abdurrahman, Luby; Hinkle, Andrea S.; Asselin, Barbara L.; Lipshultz, Steven E.

doi:10.1016/s1040-8428(97)10007-5

Cited by 188 publications

(149 citation statements)

References 93 publications

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“…Consistent with previous studies, preexisting heart disease, age at diagnosis, cumulative anthracycline dose, and bone marrow transplant were significant risk factors associated with myocardial dysfunction [33,34]. Persistent cardiomyopathy occurred in 22 % of subjects with previous myocardial dysfunction, and in agreement to previous reports, was associated with a survival of < 50 % at 5 years [35].…”

Section: Discussionsupporting

confidence: 90%

Effect of myocardial dysfunction in cardiac morbidity and all cause mortality in childhood cancer subjects treated with anthracycline therapy

et al. 2015

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Background: Subacute cardiotoxicity, consisting of acute myocyte damage and associated left ventricular dysfunction, occurs early during anthracycline therapy. We investigated the impact of myocardial dysfunction, defined herein by a shortening fraction (SF) < 29 % at any time during or after anthracycline therapy, on late onset cardiomyopathy and all-cause mortality, among childhood cancer survivors exposed to anthracyclines. In addition, we sought to identify subpopulations of subjects at highest risk for cardiomyopathy and death from all causes. Methods: Five hundred thirty-one childhood cancer survivors exposed to anthracyclines were enrolled and studied on average 10 (1.4-27.3) years following their initial exposure. The medical records were reviewed to identify known risk factors associated with cardiotoxicity, including cumulative anthracycline dose, length of post-therapy interval, administration of other cardiotoxic medications (vinca alkaloids), previous heart disease, radiation dose to the heart, history of bone marrow transplantation, age at treatment, gender, systolic dysfunction, and history of congestive heart failure during anthracycline therapy. Results: Ninety subjects (16.9 %) developed SF < 29 % and 71 patients (13.4 %) died on average 10 years after initial exposure (range 1.4-27.3 years). Total cumulative dose (OR 3.27, 95 % CI 1.94, 5.49, p < 0.001) and bone marrow transplantation (OR 2.57, 95 % CI 1.24, 5.30, p = 0.01) were found to be statistically significant risk factors for development of myocardial dysfunction. There was a 3-fold increase in the odds of having a SF < 29 % at any point during or following cancer therapy if a subject underwent bone marrow transplantation or had a total cumulative dose anthracycline therapy ≥ 240 mg/m 2 . The all-cause mortality ratio was almost seven-fold higher (95 % CI, 2.40-fold to 17.81-fold higher) if a subject developed systolic dysfunction, defined by a previous SF < 29 % anytime during or after anthracycline therapy. Nine deaths (12.7 %) were attributed to cardiovascular disease. The risk of dying as a result of cardiac disease also was significantly higher in individuals who had a SF < 29 % at any time during or after therapy. Conclusions: This study demonstrates an almost seven-fold increase in all cause mortality in pediatric cancer survivors with a history of anthracycline induced myocardial dysfunction defined as SF < 29 %.

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Section: Discussionsupporting

confidence: 90%

Effect of myocardial dysfunction in cardiac morbidity and all cause mortality in childhood cancer subjects treated with anthracycline therapy

et al. 2015

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“…Furthermore, it has been demonstrated that doxorubicin causes myocyte injury early in the course of treatment with the first changes occurring as early as the second cycle of chemotherapy (Elbl, Hrstkova 2003). Thus, even with use of cumulative doses of less than 450 mg/m2, delayed cardiotoxicity manifesting more than a year following termination of treatment is important, especially in the pediatric and young adult population (Elbl, Hrstkova 2003, Giantris, Abdurrahman 1998, Lipshultz, Lipsitz 2005, Steinherz, Steinherz 1991. Subclinical impairment of left ventricular function has been reported in more than 50% of patients in the first decade following chemotherapy with clinical symptoms occurring in 5−19% of patients (Elbl, Hrstkova 2003, Grenier and Lipshultz 1998, Kremer, van der Pal 2002, Nysom, Holm 1998.…”

Section: Discussion and Summarymentioning

confidence: 99%

Early Detection of Doxorubicin Cardiomyopathy Using Two-Dimensional Strain Echocardiography

Migrino

Aggarwal

Konorev

et al. 2008

Ultrasound in Medicine & Biology

111

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Doxorubicin is one of the most effective chemotherapeutic agents; however, it causes dose-dependent cardiomyopathy that may lead to heart failure. Conventional measures of ventricular function, such as fractional shortening, are insensitive in detecting early doxorubicin cardiomyopathy. We tested whether novel 2-dimensional radial strain echocardiography (2DSE) can detect early doxorubicin injury following chronic administration in a rat model. 14 male Sprague Dawley rats (240−260 g) received doxorubicin 2.5 mg/k IV per week for 10 (n=4) or 12 weeks (n=10); 17 controls received saline (10 weeks, n=7 and 12 weeks, n=10). Serial 2DSE from 0−12 weeks was done at the mid left ventricle using Vivid 7 echo (General Electric, Waukesha, WI, USA). With Q analysis software, radial strain was obtained. From the 2D image, anatomical M-mode through the anterior/inferior walls was used to measure fractional shortening. Fibrosis (Masson's trichrome) and caspase-3 activity were measured from excised hearts. Radial strain was lower in the doxorubicin group (12 week: 26.7 ±3 vs. 38.3±2.6%, p=0.006), with significant difference by 8 weeks whereas fractional shortening was lower with doxorubicin only after 12 weeks (30.2±1.7 vs. 37.6±1.4%, p=0.02). Doxorubicin group had lower cardiac mass (0.85±0.09 vs. 1.14±0.04 g, p=0.001), higher caspase-3 activity (1.95 ±0.2 fold increase over control, p<0.0001) and fibrosis (3.9±0.7 vs. 0.7±0.1%, p=0.005). Radial strain was related directly to cardiac mass (R=0.61, p=0.0007) and inversely to caspase-3 activity (R=−0.5, p=0.005). 2-dimensional radial strain echocardiography is useful in the early detection of doxorubicin cardiac injury and the reduction in radial strain is associated with histologic markers of doxorubicin cardiomyopathy.

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“…Although effective, anthracyclines are also cardiotoxic and can induce acute, subacute, or delayed cardiac side effects (Steinherz and Yahalom, 1997). Irreversible subacute or early-onset chronic progressive cardiotoxicity (Giantris et al, 1998) are the most common forms of cardiotoxicity resulting from anthracycline administration and depend on both the cumulative dose and the administration rate (Von Hoff et al, 1979). Manifestation of these types of cardiotoxicity usually occur within a year of completing anthracycline therapy and produce mortality rates of up to 60% (Shan et al, 1996;Steinherz and Yahalom, 1997;Giantris et al, 1998).…”

mentioning

confidence: 99%

“…Irreversible subacute or early-onset chronic progressive cardiotoxicity (Giantris et al, 1998) are the most common forms of cardiotoxicity resulting from anthracycline administration and depend on both the cumulative dose and the administration rate (Von Hoff et al, 1979). Manifestation of these types of cardiotoxicity usually occur within a year of completing anthracycline therapy and produce mortality rates of up to 60% (Shan et al, 1996;Steinherz and Yahalom, 1997;Giantris et al, 1998). If the risk of anthracycline-induced cardiotoxicity could be accurately predicted, high-risk populations might be spared anthracycline exposure and low-risk patients might accrue maximum benefit from adequate doses of anthracyclines.…”

mentioning

confidence: 99%

Clinical and economic impact of multiple gated acquisition scan monitoring during anthracycline therapy

et al. 2002

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The clinical and economic impacts of monitoring cardiac function in patients given doxorubicin have yet to be determined, especially in relation to patient age, cumulative doxorubicin dose, and the relative efficacies of doxorubicin-based vs alternative regimens. We developed a decision analysis model that includes these factors to estimate the incremental survival benefit and cost-effectiveness of using multiple gated acquisition scans to measure left-ventricular ejection fraction before and during doxorubicin chemotherapy. Probability distributions for the incidences of abnormal left-ventricular ejection fraction findings and congestive heart failure were derived from a retrospective review of 227 consecutive cases at The University of Michigan Medical Center and published findings. Multiple gated acquisition-scan monitoring minimally improved the probability of 5-year survival (51.5% in the base -case scenario). For patients who received up to 350 mg m 72 of doxorubicin, multiple gated acquisition-scan screening had an incremental cost of $425 402 per life saved for patients between the ages of 15 -39. This incremental cost markedly decreased to $138 191, for patients between the ages of 40 -59, and to $86 829 for patients older than 60 years. The small gain in 5-year survival probability secondary to multiple gated acquisition scan monitoring doubled for all age groups when the average cumulative dose for doxorubicin reached 500 mg m 72. Variations in the cure rate differences between the doxorubicin and alternative regimens had insignificant effects on the improvement in 5-year survival rates from multiple gated acquisition-scan screening. The use of multiple gated acquisition scans for pretreatment screening appears to be more cost-effective for patients who are 40 years or older, when cumulative doxorubicin dose is 350 mg m 72 or less.

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Anthracycline-induced cardiotoxicity in children and young adults

Cited by 188 publications

References 93 publications

Effect of myocardial dysfunction in cardiac morbidity and all cause mortality in childhood cancer subjects treated with anthracycline therapy

Effect of myocardial dysfunction in cardiac morbidity and all cause mortality in childhood cancer subjects treated with anthracycline therapy

Early Detection of Doxorubicin Cardiomyopathy Using Two-Dimensional Strain Echocardiography

Clinical and economic impact of multiple gated acquisition scan monitoring during anthracycline therapy

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