Abstract 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.

Cardiac signaling proteins regulate the intrinsic cardioprotective and repair response to doxorubicin cardiotoxicity. We estimated the relationship between these proteins, serum biomarkers of cardiac status and imaging in doxorubicin-treated children with ALL. Concentrations of the proteins

In cancer treatment, the pervasive late effects of radiation and chemotherapy limit their utility, especially in children, in whom treatment often leads to lifelong morbidity and excess mortality. Advances in understanding the molecular pathways related to tumorigenesis have led to the development of targeted therapies, but recurrent late effects, as in the case of trastuzumab, and unexpectedly high rates of cardiotoxicity highlight gaps in our understanding of drug pathways and the mechanisms of treatment toxicity. Here, we review the mechanisms of anthracycline activity in tumor and cardiac cells, as well as the clinical manifestations and their associated cardiotoxicity, prevention strategies, and monitoring recommendations. We also describe the cardiac effects of trastuzumab with specific attention to its interaction with anthracyclines.

Within the first 30 years after cancer diagnosis, survivors of childhood cancers have an estimated 75% cumulative incidence of treatment-related chronic health problems. In the United States, where 1 in 680 people between 20 and 50 years old are survivors of childhood cancer, the impact of long-term health consequences is concerning, particularly because this population is growing. Cancer treatment-related cardiotoxicity is the leading noncancer cause of morbidity, and after 30 years, exceeds the mortality rates of cancer recurrence. Cumulative anthracycline chemotherapy dose received is one of the major risk factors. Others include female sex, younger age at diagnosis, and now emerging genetic mutations. However, evidence-based guidelines to identify and monitor cardiotoxicity are lacking. Dexrazoxane provides cardioprotective benefits in children with high-risk cancers, but additional preventive strategies are still needed. An improved understanding of the lifetime cardiovascular risk associated with these factors in long-term childhood cancer survivors may help guide treatment and predict any potential additional cardiovascular risk of specific cancer therapies, such as anthracyclines.

Linked ArticlesThis 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)1476‐5381The 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.

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.

BACKGROUNDImpaired 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.METHODSThis 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.RESULTSAt 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.CONCLUSIONSDoxorubicin‐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. Cancer 2016;122:946–53. © 2016 American Cancer Society.

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.

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. (C) 2015 Published by Elsevier Ireland Ltd.

Advances in cancer treatments have brought hope to patients with these diseases once thought to be incurable. However, these same treatments can inadvertently harm healthy cells and affect systems unrelated to the cancer, especially the cardiovascular system [1]. A precise definition of cardiotoxicity is still lacking [2]. However, an overwhelming body of evidence has established that patients exposed to antitumor therapies have several laboratory or clinical indices of cardiovascular dysfunction and that become more evident as patients live longer. As a result, patients with cancer who have or who are at risk of cardiovascular toxicity are now being treated collaboratively by oncologists-hematologists, radiotherapists, and cardiologists, which has led to a new interdisciplinary field, cardio-oncology. The journal Cardio-Oncology is a dedicated forum for oncologists, cardiologists, researchers, and other health providers who care for patients who have survived or who are being treated for cancer. It also provides the opportunity for the latest and highest quality evidence in this emerging field to be widely shared in the medical community. The mission of Cardio-Oncology is to publish research that addresses the balance between curing cancer and limiting the adverse cardiovascular effects of cancer treatment. To achieve this mission, we welcome a broad range of original research and review articles addressing many questions in this complex field from a multidisciplinary approach. Cardio-oncology has many areas of research. Here, we highlight some of the more pressing issues in the field and invite authors to submit for publication their work on these and other issues. First, we have to better understand the risks of cardiovascular toxicity to establish effective prevention and surveillance protocols. A lack of awareness or underestimating the cardiovascular risks of cancer treatment

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.

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.

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 β-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.

Purpose of reviewAnthracyclines 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 findingsSome 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, -blockers, and growth hormone replacement therapy. Cardiac transplantation remains the treatment of last resort.SummaryDespite 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.

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.

Improvements in long-term childhood cancer survival are attributed to therapies with known cardiotoxic effects. Cardiovascular-related disease is the leading non-cancer-related cause of morbidity and mortality in these survivors. Many of these long-term survivors will develop traditional, modifiable risk factors related to aging, hereditary predisposition, or unhealthy lifestyle behaviors, which further increase their risk of having a cardiac event later in life. Evidence from several long-term, prospective, clinical trials have shown the persistent and progressive nature of anthracycline-induced cardiotoxicity in childhood cancer survivors. However, efforts to find effective primary prevention strategies in children are still ongoing, such as the promising use of the cardioprotectant dexrazoxane. Here we introduce the works presented in the second session of the International Colloquium on Cardio-oncology (Rome, March 12–14, 2014) entitled ‘Cardiotoxicity in children, adolescents, and young adults’. Here, presenters addressed the advances and challenges in identifying, preventing, and treating the cardiac late-effects in childhood cancer survivors, and highlighted the long-term cardiovascular complications faced by adult survivors of childhood cancer. Validated cardiac monitoring and screening are now needed to identify early signs of cardiac dysfunction in high-risk childhood cancer patients who would benefit most from tailored,combined preventive measures. Ultimately, the goal is to prevent anthracycline-induced cardiotoxicity altogether without reducing oncologic efficacy.