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, β-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.

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.

Advances in cancer treatment have greatly improved survival rates of children with cancer. However, these same chemotherapeutic or radiologic treatments may result in long-term health consequences. Anthracyclines, chemotherapeutic drugs commonly used to treat children with cancer, are known to be cardiotoxic, but the mechanism by which they induce cardiac damage is still not fully understood. A higher cumulative anthracycline dose and a younger age of diagnosis are only a few of the many risk factors that identify the children at increased risk of developing cardiotoxicity. While cardiotoxicity can develop at anytime, starting from treatment initiation and well into adulthood, identifying the best cardioprotective measures to minimize the long-term damage caused by anthracyclines in children is imperative. Dexrazoxane is the only known agent to date, that is associated with less cardiac dysfunction, without reducing the oncologic efficacy of the anthracycline doxorubicin in children. Given the serious long-term health consequences of cancer treatments on survivors of childhood cancers, it is essential to investigate new approaches to improving the safety of cancer treatments.

Objective-To assess parental health literacy and numeracy skills in understanding instructions for caring for young children, and to develop and validate a new parental health literacy scale, the Parental Health Literacy Activities Test (PHLAT).Methods-Caregivers of infants (age <13 months) were recruited in a cross-sectional study at pediatric clinics at three academic medical centers. Literacy and numeracy skills were assessed with previously validated instruments. Parental health literacy was assessed with the new 20-item PHLAT. Psychometric analyses were performed to assess item characteristics and to generate a shortened, 10-item version (PHLAT-10).Results-182 caregivers were recruited. While 99% had adequate literacy skills, only 17% had >9 th -grade numeracy skills. Mean score on the PHLAT was 68% (SD 18); for example, only 47% of caregivers could correctly describe how to mix infant formula from concentrate, and only 69% could interpret a digital thermometer to determine if an infant had a fever. Higher performance on the PHLAT was significantly correlated (p<0.001) with education, literacy skill, and numeracy level (r=0.29, 0.38, and 0.55 respectively). Caregivers with higher PHLAT scores were also more likely to interpret age recommendations for cold medications correctly (OR 1.6, 95% CI 1.02, 2.6). Internal reliability on the PHLAT was good (KR-20=0.76). The PHLAT-10 also demonstrated good validity and reliability. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conclusions-Many parents do not understand common health information required to care for their infants. The PHLAT, and PHLAT-10 have good reliability and validity and may be useful tools for identifying parents who need better communication of health-related instructions. NIH Public Access

OBJECTIVE Concerns about the safety and efficacy of over-the-counter cold medications have led to a recent US Food and Drug Administration public health advisory against their use in children <2 years of age. Our goal was to examine caregiver understanding of the age indication of over-the-counter cold medication labels and identify factors, associated with caregiver understanding. METHODS Caregivers of infant children (≤1 year old) were recruited from clinics at 3 institutions. Questions were administered regarding the use of 4 previously common “infant” over-the-counter cold and cough medicines labeled to consult a physician if used in children <2 years of age. Literacy and numeracy skills were assessed with validated instruments. RESULTS A total of 182 caregivers were recruited; 87% were the infants’ mothers. Mean education level was 12.5 years, and 99% had adequate literacy skills, but only 17% had >9th-grade numeracy skills. When examining the front of the product label, 86% of the time parents thought these products were appropriate for use in children <2 years of age. More than 50% of the time, parents stated they would give these over-the-counter products to a 13-month-old child with cold symptoms. Common factors that influenced parental decisions included label saying “infant,” graphics (eg, infants, teddy bears, droppers), and dosing directions. Caregivers were influenced by the dosing directions only 47% of the time. Caregivers with lower numeracy skills were more likely to provide inappropriate reasons for giving an over-the-counter medication. CONCLUSIONS Misunderstanding of over-the-counter cold products is common and could result in harm if medications are given inappropriately. Label language and graphics seem to influence inappropriate interpretation of over-the-counter product age indications. Poorer parental numeracy skills may increase the misinterpretation of these products. Opportunities exist for the Food and Drug Administration and manufacturers to revise existing labels to improve parental comprehension and enhance child safety.

Background Doxorubicin is associated with progressive cardiac dysfunction, possibly by forming doxorubicin-iron complexes leading to free-radical injury. We 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 two common HFE allelic variants: C282Y and H63D. Serum cardiac troponin-T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP), biomarkers of cardiac injury and cardiomyopathy, respectively, were assayed during therapy. Left ventricular (LV) structure and function were assessed with echocardiography. Results 184 patients had DNA results for at least one variant, and 167 had both: 24% carried H63D and 10% carried C282Y. Heterozygous C282Y genotype was associated with multiple elevations in cTnT concentrations (p=0.039), but not NT-proBNP. At a median of 2.2 years (1.0–3.6) after diagnosis, mean [SE] Z-scores for LV fractional shortening (−0.71 [0.25], p=0.008), mass (−0.84 [0.17], p<0.001), and end-systolic (−4.36 [0.26], p<0.001) and end-diastolic posterior wall thickness (−0.68 [0.25], p=0.01) were abnormal in children with either allele (n=32). Non-carriers (n=63) also had below-normal LV mass (−0.45 [0.15], p=0.006) and end-systolic posterior wall thickness (−4.06 [0.17], p<0.001). Later follow-up showed similar results. Conclusions Doxorubicin-associated myocardial injury was associated with C282Y HFE carriers. Although LV mass and wall thickness were 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.

Purpose To determine the oncologic efficacy, cardioprotective effectiveness, and safety of dexrazoxane added to chemotherapy that included a cumulative doxorubicin dose of 360 mg/m2 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 = 79-84 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.

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.