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Treatment advances have increased survival in children with cancer, but subclinical, progressive, irreversible, and sometimes fatal treatment-related cardiovascular effects may appear years later. Cardio-oncologists have identified promising preventive and treatment strategies. Dexrazoxane provides long-term cardioprotection from doxorubicin-associated cardiotoxicity without compromising the efficacy of anticancer treatment. Continuous infusion of doxorubicin is as effective as bolus administration in leukemia treatment, but no evidence has indicated that it provides long-term cardioprotection; continuous infusions should be eliminated from pediatric cancer treatment. Angiotensin-converting enzyme inhibitors can delay the progression of subclinical and clinical cardiotoxicity. All survivors, regardless of whether they were treated with anthracyclines or radiation, should be monitored for systemic inflammation and the risk of premature cardiovascular disease. Echocardiographic screening must be supplemented with screening for biomarkers of cardiotoxicity and perhaps by identification of genetic susceptibilities to cardiovascular diseases; optimal strategies need to be identified. The health burden related to cancer treatment will increase as this population expands and ages.

In the US, children diagnosed with cancer are living longer, but not without consequences from the same drugs that cured their cancer. In these patients, cardiovascular disease is the leading cause of non-cancer-related morbidity and mortality. Although this review focuses on anthracycline-related cardiomyopathy in childhood cancer survivors, the global lifetime risk of other cardiovascular diseases such as atherosclerosis, arrhythmias and intracardiac conduction abnormalities, hypertension, and stroke also are increased. Besides anthracyclines, newer molecularly targeted agents, such as vascular endothelial growth factor receptor and tyrosine kinase inhibitors, also have been associated with acute hypertension, cardiomyopathy, and increased risk of ischemic cardiac events and arrhythmias, and are summarized here. This review also covers other risk factors for chemotherapy-related cardiotoxicity (including both modifiable and non-modifiable factors), monitoring strategies (including both blood and imaging-based biomarkers) during and following cancer treatment, and discusses the management of cardiotoxicity (including prevention strategies such as cardioprotection by use of dexrazoxane).

BACKGROUND Doxorubicin is associated with progressive cardiac dysfunction, possibly through the formation of doxorubicin-iron complexes leading to free-radical injury. The authors determined the frequency of hemochromatosis (HFE) gene mutations associated with hereditary hemochromatosis and their relationship with doxorubicin-associated cardiotoxicity in survivors of childhood high-risk acute lymphoblastic leukemia. METHODS Peripheral blood was tested for 2 common HFE allelic variants: C282Y and H63D. Serum cardiac troponin-T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP), which are biomarkers of cardiac injury and cardiomyopathy, respectively, were assayed during therapy. Left ventricular (LV) structure and function were assessed with echocardiography. RESULTS A total of 184 patients had DNA results for at least 1 variant, and 167 had DNA results for both: 24% carried H63D and 10% carried C282Y. Heterozygous C282Y genotype was associated with multiple elevations in cTnT concentrations ( P = .039), but not NT-proBNP. At a median of 2.2 years (range, 1.0 years-3.6 years) after diagnosis, the mean Z-scores for LV fractional shortening (−0.71 [standard error (SE), 0.25]; P = .008), mass (−0.84 [SE, 0.17]; P < .001), and end-systolic (−4.36 [SE, 0.26], P < .001) and end-diastolic (−0.68 [SE, 0.25]; P = .01) posterior wall thickness were found to be abnormal in children with either allele (n = 32). Noncarriers (n = 63) also were found to have below-normal LV mass (−0.45 [SE, 0.15]; P = .006) and end-systolic posterior wall thickness (−4.06 [SE, 0.17]; P < .001). Later follow-up demonstrated similar results. CONCLUSIONS Doxorubicin-associated myocardial injury was associated with C282Y HFE carriers. Although LV mass and wall thickness were found to be abnormally low overall, they were even lower in HFE carriers, who also had reduced LV function. Screening newly diagnosed cancer patients for HFE mutations may identify those at risk for doxorubicin-induced cardiotoxicity. Cancer 2013;119:3555-3562.. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Advances in treating childhood cancers over the past 40 years have more than doubled 5-year survival rates. More effective use of chemotherapeutic agents has been key to this success. However, the increase has come at a price: chronic conditions are significantly more prevalent in long-term survivors of childhood cancer than they are in the general population, and managing these survivors can be challenging. In patients receiving anthracyclines, cardiotoxicity is the leading cause of morbidity and mortality after relapse and second malignancies. More than 50% of patients exposed to anthracyclines exhibit some form of cardiac dysfunction within 20 years after completing chemotherapy, and about 5% develop heart failure. These conditions greatly reduce the quality of life of the individual and also consume substantial amounts of healthcare resources. Dexrazoxane has been used to reduce anthracycline-related cardiotoxicity in children with cancer, but in 2011, the European Medicines Agency determined, on what it acknowledged were limited data, that dexrazoxane was contraindicated in children. Here, we review the evidence for the clinical effects of dexrazoxane in children. Studies published since 2011 have confirmed the efficacy of dexrazoxane in preventing or reducing anthracycline-related cardiotoxicity in children with cancer, and no new evidence of increased risks for recurrence of primary or second malignancies, or reductions in antitumor efficacy has been reported. As a result, we believe that dexrazoxane should be available to children with high-risk cancers to reduce the risk of cardiotoxicity associated with high-dose anthracycline treatment. [ABSTRACT FROM AUTHOR]

With growing numbers of childhood cancer survivors, it becomes increasingly important to understand the long-term toxicities associated with cure from malignancy. Many survivors were exposed to cardiotoxic chemotherapeutic agents at young ages. Indeed, cardiotoxicity is a leading cause of treatment-related morbidity and mortality in survivors of childhood cancer, and anthracycline exposure is a leading cause of these late cardiac effects. Nonetheless, anthracyclines remain critical agents in treating many pediatric cancers. Strategies to prevent anthracycline-associated cardiotoxicity include limiting lifetime cumulative anthracycline doses and adding cardioprotectant agents, such as dexrazoxane, to anthracycline-based regimens. However, attempts to reduce the cardiotoxicity of anthracyclines must also consider their effect on anti-cancer efficacy as well as new potential toxicities. In survivors of childhood acute lymphoblastic leukemia, the data suggest that including dexrazoxane in anthracycline-based regimens can prevent heart damage, does not reduce anti-leukemic efficacy, and can be safely administered. The controversies associated with dexrazoxane exemplify the challenges of changing therapy in cancers with a relatively good chance of event-free survival in efforts to prevent long-term sequelae. Studies of very-long-term survivor cohorts will continue to inform current practices. Continued efforts are needed to minimize cardiotoxic exposures during cancer treatment, to deliver safe and effective cardioprotectant measures when cardiotoxic agents cannot be avoided, to identify patients at greatest risk of serious cardiac toxicity, and to educate providers in the optimal care of survivors. [ABSTRACT FROM AUTHOR]

One of the most complex issues in cancer treatment is the unavoidable conflict between administering cytotoxic agents with variable tumor selectivity and the resulting dose-dependent short- and long-term damage to normal tissues. Further, there is great uncertainty as to whether late outcomes from prior treatment protocols are relevant to the anticipated late outcomes from current protocols. Virtually all recipients of anthracycline therapy should be considered to have some degree of cardiotoxicity. However, the severity of cardiotoxicity, not its presence, should determine what actions are appropriate. Currently, changes in ejection fraction and other imaging or serologic biomarkers (singly or in combination) during therapy have weak predictive value for chronic cardiomyopathy after the end of therapy, and their clinical utility requires further verification. Cardiotoxicity justifying individual dose modification during therapy requires evidence that it improves survival. The low prior probability of congestive heart failure during anthracycline therapy with the current monitoring protocols means that the ejection fraction has an unacceptably low predictive value. As a result, continued reliance on published recommendations for withholding chemotherapy based on asymptomatic changes in ejection fraction increases the risk of treatment failure more than it decreases the likelihood of irreversible cardiac injury. However, abnormalities in ventricular size and function after the end of therapy do predict chronic, progressive cardiomyopathy and justify longitudinal monitoring. Here, we discuss the cardiotoxicity of some of these chemotherapeutic agents and provide a framework for deciding when the evidence of cardiotoxicity is strong enough to justify a change in management. [ABSTRACT FROM AUTHOR]

Cardiotoxicity related to doxorubicin chemotherapy is a major late effect in childhood cancer survivors. Serum cardiac troponin concentrations (cTnT) can be elevated during doxorubicin therapy but the cellular associations with this myocardial injury are not well understood. We evaluate a novel nanotechnology-based biomarker discovery approach on a pilot set of serial serum samples from 11 children with acute lymphoblastic leukemia receiving doxorubicin therapy to determine if a proteomic signature of myocardial injury could be identified. This nanoparticle-based biomarker capture technology was utilized to analyze 40 serial serum samples from these children, 3 of whom seroconverted, 2 from cTnT-negative to cTnT-positive and 1 from cTnT-positive to cTnT-negative. High-resolution mass spectrometry analysis of the captured material identified 13 differentially expressed candidate proteins, whose spectral count values reflected changes in cTnT concentrations, which were verified in the serum samples from the 3 consistently cTnT-negative and 5 consistently cTnT-positive children. Of the 13 candidate proteins, 5 were significantly elevated (p < 0.1) in the independent validation set of cTnT-positive samples (serum amyloid A, cardiac muscle actin proprotein, a gamma globulin, HIV-enhancer-element binding protein, and C-reactive protein). These results demonstrate the potential for novel nanoparticle-capture biomarker discovery workflow to be applied to the doxorubicin cardiotoxicity-based setting. The identified candidate biomarkers require further validation in larger cohorts to evaluate clinical impact. Significance Identification of new biomarkers for early detection of chemotherapy-induced cardiotoxicity is of critical importance so that administration of cardioprotectants can be utilized before substantial heart damage has occurred. We developed and utilized a unique biomarker workflow based on a novel nanotechnology method in order to demonstrate the potential for such an approach to uncover low abundance markers that could be useful in a clinical setting once extensively validated. [ABSTRACT FROM AUTHOR]

A scientific statement from the American Heart Association on long-term cardiovascular toxicity in children, adolescents and young adults receiving cancer therapy is presented. It describes cardiovascular changes induced by chemotherapeutic agents, including paclitaxel and thalidomide. It also cites challenges in developing targeted therapies for decreasing lifelong cardiovascular risk in cancer survivors.

BACKGROUND AND OBJECTIVES: Doxorubicin, effective against many malignancies, is limited by cardiotoxicity. Continuous-infusion doxorubicin, compared with bolus-infusion, reduces early cardiotoxicity in adults. Its effectiveness in reducing late cardiotoxicity in children remains uncertain. We determined continuous-infusion doxorubicin cardioprotective efficacy in long-term survivors of childhood acute lymphoblastic leukemia (ALL). METHODS: The Dana-Farber Cancer Institute ALL Consortium Protocol 91-01 enrolled pediatric patients between 1991 and 1995. Newly diagnosed high-risk patients were randomly assigned to receive a total of 360 mg/m2 of doxorubicin in 30 mg/m2 doses every 3 weeks, by either continuous (over 48 hours) or bolus-infusion (within 15 minutes). Echocardiograms at baseline, during, and after doxorubicin therapy were blindly remeasured centrally. Primary outcomes were late left ventricular (LV) structure and function. RESULTS: A total of 102 children were randomized to each treatment group. We analyzed 484 serial echocardiograms from 92 patients (n = 49 continuous; n = 43 bolus) with ≥1 echocardiogram ≥3 years after assignment. Both groups had similar demographics and normal baseline LV characteristics. Cardiac follow-up after randomization (median, 8 years) showed changes from baseline within the randomized groups (depressed systolic function, systolic dilation, reduced wall thickness, and reduced mass) at 3, 6, and 8 years; there were no statistically significant differences between randomized groups. Ten-year ALL event- free survival rates did not differ between the 2 groups (continuous- infusion, 83% versus bolus-infusion, 78%; P = .24). CONCLUSIONS: In survivors of childhood high-risk ALL, continuous- infusion doxorubicin, compared with bolus-infusion, provided no long- term cardioprotection or improvement in ALL event-free survival, hence provided no benefit over bolus-infusion. [ABSTRACT FROM AUTHOR]