Cardiovascular disease in adult survivors of childhood cancer.

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.

Prevention of cardiotoxicity among survivors of childhood cancer.

LINKED ARTICLES: This article is part of a joint Themed section with the British Journal of Pharmacology on Cardiotoxicity. The rest of the Themed section will appear in a future issue of BJP and will be available at http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1476-5381 The number of survivors of childhood cancers has increased exponentially over the past few decades. However, these survivors are also at substantially increased long-term risk of morbidity and mortality, especially from treatment-related cardiotoxicity. Preventing these risks is now a priority when treating children and adolescents with cancer. Dexrazoxane reduces the risk of anthracycline-induced cardiotoxicity among adults and children with cancer without reducing its antineoplastic effects or event-free survival. Thus, it should be strongly considered as a part of therapy for children and adolescents treated with anthracyclines.

Impaired mitochondrial function is abrogated by dexrazoxane in doxorubicin-treated childhood acute lymphoblastic leukemia survivors.

BACKGROUND: Impaired cardiac function in doxorubicin-treated childhood cancer survivors is partly mediated by the disruption of mitochondrial energy production. Doxorubicin intercalates into mitochondrial DNA (mtDNA) and disrupts genes encoding for polypeptides that make adenosine triphosphate. METHODS: This cross-sectional study examined mtDNA copy numbers per cell and oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) in 64 childhood survivors of high-risk acute lymphoblastic leukemia (ALL) who had been treated on Dana-Farber Cancer Institute childhood ALL protocols and had received doxorubicin alone (42%) or doxorubicin with the cardioprotectant dexrazoxane (58%). The number of mtDNA copies per cell and the OXPHOS enzyme activity of nicotinamide adenine dinucleotide dehydrogenase (complex I [CI]) and cytochrome c oxidase (complex IV [CIV]) were measured with quantitative real-time polymerase chain reaction immunoassays and thin-layer chromatography, respectively. RESULTS: At a median follow-up of 7.8 years after treatment, the median number of mtDNA copies per cell for patients treated with doxorubicin alone (1106.3) was significantly higher than the median number for those who had also received dexrazoxane (310.5; P = .001). No significant differences were detected between the groups for CI or CIV activity. CONCLUSIONS: Doxorubicin-treated survivors had an increased number of PBMC mtDNA copies per cell, and concomitant use of dexrazoxane was associated with a lower number of mtDNA copies per cell. Because of a possible compensatory increase in mtDNA copies per cell to maintain mitochondrial function in the setting of mitochondrial dysfunction, overall OXPHOS activity was not different between the groups. The long-term sustainability of this compensatory response in these survivors at risk for cardiac dysfunction over their lifespan is concerning.

Cardiac complications in childhood cancer survivors treated with anthracyclines.

Cardiovascular complications are among the leading causes of morbidity and mortality among survivors of childhood cancer, after cancer relapse and secondary malignancies. Although advances in cancer treatment have improved the 5-year survival rates, the same treatments, such as anthracyclines, that cure cancer also increase the risk for adverse cardiovascular effects. Anthracycline-related cardiotoxicity in survivors of childhood cancer is progressive and can take years to develop, initially presenting as sub-clinical cardiac abnormalities that, if left undetected or untreated, can lead to heart failure, myocardial infarction, or other clinical cardiac dysfunction. A higher cumulative dose of anthracycline is associated with cardiotoxicity in children; however, sub-clinical cardiac abnormalities are evident at lower doses with longer follow-up, suggesting that there is no "safe" dose of anthracycline. Other risk factors include female sex, younger age at diagnosis, black race, trisomy 21, longer time since treatment, and the presence of pre-existing cardiovascular disease and co-morbidities. Cardioprotective strategies during treatment are limited in children. Enalapril provides only temporary cardioprotection, whereas continuous anthracycline infusion extends none. On the other hand, dexrazoxane successfully prevents or reduces anthracycline-related cardiotoxicity in children with cancer, without increased risks for recurrence of primary or second malignancies or reductions in anti-tumour efficacy. With more childhood cancer survivors now reaching adulthood, it is vital to understand the adverse effects of cancer treatment on the cardiovascular system and their long-term consequences to identify and establish optimal prevention and management strategies that balance oncologic efficacy with long-term safety.

Anthracycline-related cardiotoxicity in childhood cancer survivors.

PURPOSE OF REVIEW: Anthracyclines have markedly improved the survival rates of children with cancer. However, anthracycline-related cardiotoxicity is also well recognized and can compromise the long-term outcome in some patients. The challenge remains of how to balance the chemotherapeutic effects of anthracycline treatment with its potentially serious cardiovascular complications. Here, we review the pathophysiology, risk factors, clinical manifestations, prevention, and treatment of anthracycline-related cardiotoxicity. RECENT FINDINGS: Some risk factors and biomarkers associated with an increased probability of anthracycline-related cardiotoxicity have been identified. Modifying the structural forms and dosages of anthracyclines and coadministering cardioprotective agents may prevent some of these cardiotoxic effects. Cardiovascular complications have also been treated with angiotensin-converting enzyme inhibitors, ß-blockers, and growth hormone replacement therapy. Cardiac transplantation remains the treatment of last resort. SUMMARY: Despite major advances in cancer treatment, anthracycline-related cardiotoxicity remains a major cause of morbidity and mortality in survivors of childhood cancer. Promising areas of research include: use of biomarkers for early recognition of cardiac injury in children receiving chemotherapy, development and application of cardioprotective agents for prevention of cardiotoxicity, and advancements in therapies for cardiac dysfunction in children after anthracycline treatment.

Combined genetic and nutritional risk models of triple negative breast cancer.

Triple negative breast cancer (TNBC) presents clinical challenges due to unknown etiology, lack of treatment targets, and poor prognosis. We examined combined genetic and nutritional risk models of TNBC in 354 breast cancer cases. We evaluated 18 DNA-repair nonsynonymous single nucleotide polymorphisms (nsSNPs) and dietary/nutritional intakes. Multivariate Adaptive Regression Splines models were used to select nutrients of interest and define cut-off values for logistic regression models. Our results suggest that TNBC was associated with 6 DNA-repair nsSNPs, ERCC4 R415Q (rs1800067), MSH3 R940Q (rs184967), MSH6 G39E (rs1042821), POLD1 R119H (rs1726801), XRCC1 R194W (rs1799782), and XPC A499V (rs2228000) and/or deficiencies in 3 micronutrients (zinc, folate, and ß-carotene). Combined analyses of these 6 nsSNPs and 3 micronutrients showed significant association with TNBC: odds ratios = 2.77 (95% confidence interval = 1.01-7.64) and 10.89 (95% confidence interval = 3.50-33.89) for 2 and at least 3 risk factors, respectively. To the best of our knowledge, this is the first study to suggest that multiple genetic and nutritional factors are associated with TNBC, particularly in combination. Our findings, if validated in larger studies, will have important clinical implication that dietary modulations and/or micronutrient supplementations may prevent or reverse TNBC phenotype, so tumors can be treated with less toxic therapeutic strategies, particularly in genetically susceptible women.

Cardiotoxicity and cardioprotection in childhood cancer.

Children diagnosed with cancer are now living longer as a result of advances in treatment. However, some commonly used anticancer drugs, although effective in curing cancer, can also cause adverse late effects. The cardiotoxic effects of anthracycline chemotherapy, such as doxorubicin, and radiation can cause persistent and progressive cardiovascular damage, emphasizing a need for effective prevention and treatment to reduce or avoid cardiotoxicity. Examples of risk factors for cardiotoxicity in children include higher anthracycline cumulative dose, higher dose of radiation, younger age at diagnosis, female sex, trisomy 21 and black race. However, not all who are exposed to toxic treatments experience cardiotoxicity, suggesting the possibility of a genetic predisposition. Cardioprotective strategies under investigation include the use of dexrazoxane, which provides short- and long-term cardioprotection in children treated with doxorubicin without interfering with oncological efficacy, the use of less toxic anthracycline derivatives and nutritional supplements. Evidence-based monitoring and screening are needed to identify early signs of cardiotoxicity that have been validated as surrogates of subsequent clinically significant cardiovascular disease before the occurrence of cardiac damage, in patients who may be at higher risk.

Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia.

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.

A high school-based voluntary cardiovascular risk screening program: issues of feasibility and correlates of electrocardiographic outcomes.

Risk factors for adult cardiovascular events can be identified from the prenatal period through childhood. We performed a cardiovascular risk-screening program in students from grades 9-12 in 7 high schools in Hillsborough County, FL. We obtained blood pressure (BP) measurements and calculated body mass index (BMI) as risk factors for future cardiovascular events as well as obtained an electrocardiogram (ECG) for the purposes of detecting possible life-threatening arrhythmias. Of ~14,000 students contacted, 600 (4 %) participated in the screening. Of these, 517 (86 %) were diagnosed with normal, 71 (12 %) with borderline, and 12 (1 %) with abnormal ECGs. Although no participant had any cardiac history, two of the abnormal ECGs indicated a cardiac diagnosis associated with the potential for sudden cardiac death. Both systolic and diastolic BP increased as the ECG diagnosis moved from normal (115.6/73.8) through borderline (121.0/75.9) to an abnormal (125.0/80.7) diagnosis (all P ≤ .0016). An increase in BMI was only observed when an ECG diagnosis was abnormal (P = .0180). Boys had a greater prevalence (18.97 %) of borderline or abnormal ECGs compared with girls (6.75 %), whereas no discernible differences were seen in ECG diagnosis between white and nonwhite individuals (15.09 and 12.26 %, respectively). Although participation rates were low, a high school-based cardiovascular risk-screening program including ECG is feasible. Although ECG diagnosis tended to be related to other known cardiovascular risk factors (BP, BMI), the utility of an abnormal ECG in adolescence as a predictor of future cardiovascular risk will require further evaluation in more controlled settings.

The prognostic role of cancer-specific beliefs among prostate cancer survivors.

OBJECTIVE: The objective of this study is to evaluate the association between cancer-specific beliefs and survival among men newly diagnosed with prostate cancer. METHODS: Based on data from a biracial cohort monitored for mortality for up to 15 years, we investigated the association between beliefs and survival among 251 men newly diagnosed with prostate cancer between 1987 and 1990. We examined patients' beliefs related to efficacy of regular checkups for detection, potential negative treatment effects, and perceived curability of cancer. Cox proportional hazards models were adjusted for sociodemographic variables, medical care measures, clinical factors, and lifestyle. RESULTS: In a fully adjusted model, not believing that most cancers can be cured was associated with an increased risk of death from any cause (Hazard Ratio = 1.62; 95% confidence interval = 1.11, 2.38). Beliefs regarding the efficacy of checkups or potential negative treatment effects were not associated with survival. CONCLUSIONS: Prostate cancer patients who reported not believing that most cancers are curable experienced poorer survival after adjusting for a wide array of prognostic factors and potential confounders. Future research to identify underlying behavioral (medical protocol adherence, lifestyle) and physiological (immune and endocrine regulation) mechanisms of this association would translate into improved intervention strategies for cancer survivors.

Anthracycline-associated cardiotoxicity in survivors of childhood cancer.

Anthracycline chemotherapeutic agents are widely used to treat childhood cancers, helping to create an increasing population of childhood cancer survivors. Cardiac complications can occur years after exposure to anthracyclines and are a leading cause of noncancerous morbidity and mortality in this population. The mechanism of its cardiotoxicity is not completely known, although oxidative stress is believed to play a significant role. This pathway and other nonoxidative mechanisms are reviewed. Several risk factors such as age, dose, female gender, and concomitant radiation therapy are known, but the relative risks of many comorbidities such as diabetes and hypertension are not well studied. No standard, evidence-based guidelines for appropriate screening methods to detect cardiotoxicity exist. Periodic imaging with echocardiography or radionuclide angiography is appropriately recommended for long-term survivors but is of limited use during therapy. Biomarkers such as cardiac troponins and brain natriuretic peptides may aid in detecting cardiotoxicity. Studies investigating the use of agents such as angiotensin-converting enzyme (ACE)-inhibitors and beta-blockers to treat anthracycline cardiotoxicity have shown promise, but more data are needed. Structural analogs such as epirubicin were developed to minimize cardiotoxicity but have not sufficiently reduced it. Liposome-encapsulated anthracyclines have shown a considerable decrease of cardiotoxicity in adults without sacrificing efficacy, but the data related to children are sparse. The only agent proven to be cardioprotective is the iron chelator, dexrazoxane. Studies have shown that dexrazoxane is safe and significantly reduces the incidence of cardiotoxicity. Dexrazoxane should be considered for pediatric oncology protocols using anthracyclines that include longitudinal assessment.

Effects of dexrazoxane on doxorubicin-related cardiotoxicity and second malignant neoplasms in children with osteosarcoma: a report from the Children's Oncology Group.

BACKGROUND: Dexrazoxane protects from lower-cumulative-dose doxorubicin cardiotoxicity, but the effect of dexrazoxane in children with sarcoma treated with higher-cumulative-dose doxorubicin is unknown. METHODS: We evaluated children with osteosarcoma (OS) on two Children's Oncology Group trials with higher dose doxorubicin (375-600 mg/m2) preceded by dexrazoxane (10:1 dexrazoxane:doxorubicin dosing). They were evaluated after the minimum expected treatment time (METT), defined as 28 weeks. Cardiotoxicity was identified by echocardiography and serum N-terminal pro-brain natriuretic peptide (NT-proBNP). Second malignant neoplasm (SMN) data was collected. RESULTS: All children had normal left ventricular (LV) systolic function as measured by LV fractional shortening and no heart failure. The end-diastolic septal thickness Z-scores (P < 0.01) and LV mass Z-scores (P < 0.01) were significantly smaller than normal for body-surface area in both sexes. The average LV mass Z-scores were significantly smaller for girls (P < 0.01) and marginally smaller for boys (P = 0.06). Girls had significantly smaller LV end-diastolic dimension Z-scores normalized to BSA (P < 0.01) compared to healthy controls and had significant increases in NT-proBNP. Four children developed SMNs as first events, a rate similar to historical controls. CONCLUSIONS: Dexrazoxane prevented LV dysfunction and heart failure in children with OS receiving higher dose doxorubicin. However, LV structural changes were not fully prevented, especially in girls. As a result, hearts become abnormally small for body size, resulting in higher LV stress. Dexrazoxane did not increase the risk of SMN. Dexrazoxane should be used in this population, particularly for girls, to mitigate anthracycline-induced cardiotoxicity. TRIAL REGISTRATIONS: ClinicalTrials.gov: NCT00003937 (P9754) registered 1 Nov 1999, and NCT00023998 (AOST0121) registered 13 Sept 2001.

Late Cardiotoxicity: Issues for Childhood Cancer Survivors.

OPINION STATEMENT: Cardiovascular-related morbidity is a substantial health burden in survivors of childhood cancers. This burden is gaining importance as this population increases through advancements in therapy. Anthracyclines are commonly used agents that are known to cause late cardiotoxicity. Cardiotoxicity is also increased by other risk factors, such as concurrent radio- or chemotherapy, younger age at diagnosis, female sex, comorbidities, lifestyle factors, and genetic factors, such as hemochromatosis gene mutations. Treatment of late cardiotoxicity depends on the type of cardiac abnormalities and consists of pharmacotherapy, mechanical support, or heart transplantation. Because cardiotoxicity is progressive and often irreversible, prevention, risk reduction, and early detection are of utmost importance. The cardioprotectant dexrazoxane decreases anthracycline cardiotoxicity. Screening for other risk factors at the time of diagnosis may identify risk that when present, if used to tailor therapy, may reduce the severity of cardiac damage. The effects of exercise and other lifestyle changes in reducing the cardiovascular diseases in cancer survivors are unclear. However, it may be beneficial to encourage survivors to engage in physical activity tailored to survivor medical status, but with close monitoring.

Cardioprotection and Safety of Dexrazoxane in Patients Treated for Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or Advanced-Stage Lymphoblastic Non-Hodgkin Lymphoma: A Report of the Children's Oncology Group Randomized Trial Pediatric Oncology Group 9404.

PURPOSE: To determine the oncologic efficacy, cardioprotective effectiveness, and safety of dexrazoxane added to chemotherapy that included a cumulative doxorubicin dose of 360 mg/m(2) to treat children and adolescents with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic non-Hodgkin lymphoma (L-NHL). PATIENTS AND METHODS: Patients were treated on Pediatric Oncology Group Protocol POG 9404, which included random assignment to treatment with or without dexrazoxane given as a bolus infusion immediately before every dose of doxorubicin. Cardiac effects were assessed by echocardiographic measurements of left ventricular function and structure. RESULTS: Of 573 enrolled patients, 537 were eligible, evaluable, and randomly assigned to an arm with or without dexrazoxane. The 5-year event-free survival (with standard error) did not differ between groups: 77.2% (2.7%) for the dexrazoxane group versus 76.0% (2.7%) for the doxorubicin-only group (P = .9). The frequencies of severe grade 3 or 4 hematologic toxicity, infection, CNS events, and toxic deaths were similar in both groups (P ranged from .26 to .64). Of 11 second malignancies, eight occurred in patients who received dexrazoxane (P = .17). The mean left ventricular fractional shortening, wall thickness, and thickness-to-dimension ratio z scores measured 3 years after diagnosis were worse in the doxorubicin-alone group (n = 55 per group; P ≤ .01 for all comparisons). Mean fractional shortening z scores measured 3.5 to 6.4 years after diagnosis remained diminished and were lower in the 21 patients who received doxorubicin alone than in the 31 patients who received dexrazoxane (-2.03 v -0.24; P ≤ .001). CONCLUSION: Dexrazoxane was cardioprotective and did not compromise antitumor efficacy, did not increase the frequencies of toxicities, and was not associated with a significant increase in second malignancies with this doxorubicin-containing chemotherapy regimen. We recommend dexrazoxane as a cardioprotectant for children and adolescents who have malignancies treated with anthracyclines.

Anthracycline-induced cardiotoxicity: a review of pathophysiology, diagnosis, and treatment.

OPINION STATEMENT: 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.

Managing chemotherapy-related cardiotoxicity in survivors of childhood cancers.

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).

An expert opinion on pharmacologic approaches to reducing the cardiotoxicity of childhood acute lymphoblastic leukemia therapies.

INTRODUCTION: Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children. Treatment-related cardiac damage is progressive and often difficult to reverse. Strategies to minimize cardiotoxicity during treatment are crucial to prevent severe lasting effects on health and quality of life. AREAS COVERED: This comprehensive review covers the pathophysiology and various presentations, both clinical and subclinical, of treatment-induced cardiotoxicity and characteristics associated with increased risk of cardiac dysfunction in childhood ALL survivors. Additionally, contemporary prevention strategies such as limiting cumulative anthracycline dose, altering drug administration schedule, the use of anthracycline structural analogs, liposomal encapsulated anthracyclines, cardioprotective agents and nutritional supplements are critically analyzed. Finally, this review covers the management options of chemotherapy-induced damage and other treatment-related cardiotoxicity. EXPERT OPINION: Higher lifetime cumulative doses of anthracyclines, younger age at diagnosis, longer follow-up, female sex, higher dose rates and cranial irradiation are associated with more severe cardiotoxic effects. Long-term adverse effects of both anthracycline and non-anthracycline chemotherapeutic agents are becoming an increasing focus during treatment of childhood malignancies. There must be a careful balance between achieving remission of childhood ALL while avoiding the development of another often-fatal illness, heart failure.

Treatment-related cardiotoxicity in survivors of childhood cancer.

Treatment advances and higher participation rates in clinical trials have rapidly increased the number of survivors of childhood cancer. However, chemotherapy and radiation treatments are cardiotoxic and can cause cardiomyopathy, conduction defects, myocardial infarction, hypertension, stroke, pulmonary oedema, dyspnoea and exercise intolerance later in life. These cardiotoxic effects are often progressive and irreversible, emphasizing a need for effective prevention and treatment to reduce or avoid cardiotoxicity. Medical interventions, such as angiotensin-converting enzyme inhibitors, ß-blockers, and growth hormone therapy, might be used to treat cardiotoxicity in childhood cancer survivors. Preventative strategies should include the use of dexrazoxane, which provides cardioprotection without reducing the oncological efficacy of doxorubicin chemotherapy; less-toxic anthracycline derivatives and the use of antioxidant nutritional supplements might also be beneficial. Continuous-infusion doxorubicin provides no benefit over bolus infusion in children. Identifying patient-related (for example, obesity and hypertension) and drug-related (for example, cumulative dose) risk factors for cardiotoxicity could help tailor treatments to individual patients. However, all survivors of childhood cancer are at increased risk of cardiotoxicity, suggesting that survivor screening recommendations for assessment of global risk of premature cardiovascular disease should apply to all survivors. Optimal, evidence-based monitoring strategies and multiagent preventative treatments still need to be identified.

An analysis of energy-drink toxicity in the National Poison Data System.

CONTEXT: Small studies have associated energy drinks-beverages that typically contain high concentrations of caffeine and other stimulants-with serious adverse health events. OBJECTIVE: To assess the incidence and outcomes of toxic exposures to caffeine-containing energy drinks, including caffeinated alcoholic energy drinks, and to evaluate the effect of regulatory actions and educational initiatives on the rates of energy drink exposures. METHODS: We analyzed all unique cases of energy drink exposures reported to the US National Poison Data System (NPDS) between October 1, 2010 and September 30, 2011. We analyzed only exposures to caffeine-containing energy drinks consumed as a single product ingestion and categorized them as caffeine-containing non-alcoholic, alcoholic, or "unknown" for those with unknown formulations. Non-alcoholic energy drinks were further classified as those containing caffeine from a single source and those containing multiple stimulant additives, such as guarana or yerba mate. The data were analyzed for the demographics and outcomes of exposures (unknown data were not included in the denominator for percentages). The rates of change of energy drink-related calls to poison centers were analyzed before and after major regulatory events. RESULTS: Of 2.3 million calls to the NPDS, 4854 (0.2%) were energy drink-related. The 3192 (65.8%) cases involving energy drinks with unknown additives were excluded. Of 1480 non-alcoholic energy drink cases, 50.7% were children < 6 years old; 76.7% were unintentional; and 60.8% were males. The incidence of moderate to major adverse effects of energy drink-related toxicity was 15.2% and 39.3% for non-alcoholic and alcoholic energy drinks, respectively. Major adverse effects consisted of three cases of seizure, two of non-ventricular dysrhythmia, one ventricular dysrhythmia, and one tachypnea. Of the 182 caffeinated alcoholic energy drink cases, 68.2% were < 20 years old; 76.7% were referred to a health care facility. Educational and legislative initiatives to enhance understanding of the health consequences of energy drink consumption were significantly associated with a decreased rate of energy drink-related cases (p = 0.036). CONCLUSIONS: About half the cases of energy drink-related toxicity involved unintentional exposures by children < 6 years old. Educational campaigns and legal restrictions on the sale of energy drinks were associated with decreasing calls to poison centers for energy drink toxicity and are encouraged.