Cumulative Anthracycline Dose Research Articles

Assessment of brachial artery reactivity, carotid intima-media thickness, and adhesion molecules in pediatric solid tumor patients treated with anthracyclines

ABSTRACTThe aim of this study was to determine subclinical atherosclerosis and endothelial functional disturbance with measurement of carotid intima-media thickness (IMT), brachial artery reactivity (BAR), and levels of serum adhesion molecules in children with solid tumors who were treated with anthracyclines and are actually in complete remission. Fifty patients who were in remission and 30 healthy children were included in the study. Mean ages of patient and control groups were 13.5 ± 4.7 years (range: 3–23 years) and 12.00 ± 4.3 years (range: 4–21 years), respectively. The patients were divided into 3 groups according to cumulative doxorubicin dose: Group 1, ≤100 mg/m2; Group 2, 101–299 mg/m2; Group 3, ≥300 mg/m2. The BAR and carotid IMT were measured in order to determine the endothelial function. The serum adhesion molecule levels in our patients and controls were also measured. The BAR of the patients with cumulative anthracycline dose ≥300 mg/m2 was significantly lower than the patients with cumulative anthracycline dose ≤100 mg/m2 and healthy controls (P =.005 and P =.003, respectively). Also, there was a negative correlation between brachial artery reactivity and increasing cumulative anthracycline dose (r = −.287, P =.044). We also found significant difference between the mean carotid IMT of the patients and the healthy children (P =.041). No statistically significant difference was detected between the serum levels of sICAM-1 (soluble intercellular adhesion molecule-1), sVCAM-1 (soluble vascular cell adhesion molecule-1), sE-selectin of the patients and controls. The use of anthracyclines in pediatric patients with cancer could result in increase of the carotid IMT and endothelial dysfunction.

Echocardiographic evaluation of the early cardiotoxic effect of hematopoietic stem cell transplantation in patients with hematologic malignancies

The purpose was to evaluate the early cardiotoxic effects of the treatment in the course of hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies. The studies were conducted on 47 patients qualified for the HSCT. Echocardiography was carried out prior to the HSCT and after the HSCT. It was shown that higher age, administration of cyclophosphamide and higher glucose concentrations represented independent risk factors for the worsening of left ventricular diastolic function. Higher cumulative dose of anthracyclines in the previous cytostatic treatment, higher age and administration of cyclophosphamide represented independent risk factors for worsening of left ventricular systolic function. Peri-transplant therapy in the course of HSCT in patients with hematologic malignancies gives the negative effect on the diastolic and systolic left ventricular function, however, previous treatment is of importance, as higher cumulative dose of anthracyclines represents an independent risk factor for the worsening of left ventricular systolic function.

0534: Utility of research of the QT/QT-c intervals dispersion and cardiac biomarkers for early diagnosis of anthracycline induced cardiotoxicity in children

To establish the usefulness of research of dispersion QT / QTc intervals and values of cardiac biomarkers- B natriuretic peptide (BNP) and troponin (cTnI) for early detection of cardiotoxicity in children with malignancies. Patients: 46 children (2 months-18 years), treated with anthracyclines for malignancies. Control group: 20 healthy children without cardiovascular history. Patients and controls were evaluated by clinical exam, surface 12 lead ECG (3 consecutive cycles of measuring the QT/QTc intervals and QT/QTc intervals dispersion), Doppler echocardiography(echo), determining plasma levels of cardiac biomarkers BNP and cTnI. Significant changes of the parameters in patients compared with controls: – increasing the dispersion of the QT / QTc intervals (73% of cases, especially those with a cumulative dose of anthracyclines >250mg/m 2 and in patients with echo changes induced by anthracycline cardiotoxicity, even only with LV diastolic dysfunction: • the mean of QT dispersion: 80 miliseconds in patients-40 millisec in controls; • the mean QTc dispersion: 87,103 millisec. in patients-55.47 millisec in controls; – increased plasma levels of BNP in 45.7% of patients, to value 240 ng/ml increasing cTnI values plasma at 4.34% of cases. Biological changes were correlated in most cases with clinical manifestations, echo changes induced cardiotoxicity and increase of dispersion QT/QTc intervals. Increased levels of cardiac biomarkers: BNP and cTnI and of the dispersion of QT/QTc intervals in children treated with anthracyclines±other drugs with cardiotoxic efects positively correlates with installation of the cardiotoxicity with clinical or infraclinical manifestations, constituing an useful indicator for the.cardiotoxicity. Changes in this parameters appeared early than echo changes anthracicline induced cardiotoxicity and is necessary to systematic monitoring these parameters during and after cyto-static treatment.

0560: New parameters for early diagnosis of anthracycline induced cardiotoxicity in children

To establish the usefulness of research of dispersion QT / QTc intervals and values of cardiac biomarkers-B natriuretic peptide (BNP) for early detection of cardiotoxicity in children with malignant diseases. Patients: 46 children (2 months-18 years), treated with anthracyclines for malignancies. Control group: 20 healthy children without cardiovascular history. Patients and controls were evaluated by clinical exam, surface 12 lead ECG (3 consecutive cycles of measuring the QT/QTc intervals and QT/QTc intervals dispersion), Doppler echocardiography (Echo), determining plasma levels of cardiac biomarkers BNP and cTnI. Were found some significant changes in patients comparativ with controls: *increasing the dispersion of the QT / QTc intervals (73% cases especially those with a cumulative dose of anthracyclines>250mg/m 2 and in patients with echo changes induced by anthracycline cardiotoxicity, even only with diastolic dysfunction of LV:- the mean of QT dispersion: 80 miliseconds in patients -40 millisec. in controls; - the mean QTc dispersion: 87,103 millisec. in patients-55.47 millisec in controls; ** Increased plasma levels of BNP in 45.7% of patients, from a mean baseline of 89 ng/ml to value 240 ng/ml. Biological changes were correlated with the presence of clinical manifestations, echo changes induced cardiotoxicity and increase of dispersion QT / QTc intervals. Conclusions. Increased levels of cardiac biomarkers: BNP and cTnI and of the dispersion of QT/QTc intervals in children treated with anthracyclines±other drugs with cardiotoxic efects positively correlates with installation of the cardiotoxicity with clinical or infraclinical manifestations, constituing an useful indicator for the cardiotoxicity. Changes in this parameters appeared early than echo changes anthracicline induced cardiotoxicity and is necessary to systematic monitoring these parameters during and after cyto-static treatment.

The Role of Biomarkers in Decreasing Risk of Cardiac Toxicity after Cancer Therapy.

With the improvement of cancer therapy, survival related to malignancy has improved, but the prevalence of long-term cardiotoxicity has also increased. Cancer therapies with known cardiac toxicity include anthracyclines, biologic agents (trastuzumab), and multikinase inhibitors (sunitinib). The most frequent presentation of cardiac toxicity is dilated cardiomyopathy associated with poorest prognosis. Monitoring of cardiac toxicity is commonly performed by assessment of left ventricular (LV) ejection fraction, which requires a significant amount of myocardial damage to allow detection of cardiac toxicity. Accordingly, this creates the impetus to search for more sensitive and reproducible biomarkers of cardiac toxicity after cancer therapy. Different biomarkers have been proposed to that end, the most studied ones included troponin release resulting from cardiomyocyte damage and natriuretic peptides reflecting elevation in LV filling pressure and wall stress. Increase in the levels of troponin and natriuretic peptides have been correlated with cumulative dose of anthracycline and the degree of LV dysfunction. Troponin is recognized as a highly efficient predictor of early and chronic cardiac toxicity, but there remains some debate regarding the clinical usefulness of the measurement of natriuretic peptides because of divergent results. Preliminary data are available for other biomarkers targeting inflammation, endothelial dysfunction, myocardial ischemia, and neuregulin-1. The purpose of this article is to review the available data to determine the role of biomarkers in decreasing the risk of cardiac toxicity after cancer therapy.

Two-Dimensional Speckle Tracking Echocardiography Detects Subclinical Left Ventricular Systolic Dysfunction among Adult Survivors of Childhood, Adolescent, and Young Adult Cancer.

Two-dimensional speckle tracking echocardiography (2DSTE) provides a sensitive measure of left ventricular (LV) systolic function and may aid in the diagnosis of cardiotoxicity. 2DSTE was performed in a cross-sectional study of 134 patients (mean age: 31.4 ± 8.8 years; 55% male; mean time since diagnosis: 15.4 ± 9.4 years) previously treated with anthracyclines (mean cumulative dose: 320 ± 124 mg/m2), with (n = 52) or without (n = 82) mediastinal radiotherapy. The prevalence of LV systolic dysfunction, defined as fractional shortening < 27%, LV ejection fraction (LVEF) < 55%, and global longitudinal strain (GLS) ≤ 16%, was 5.2%, 6.0%, and 23.1%, respectively. Abnormal GLS was observed in 24 (18%) patients despite a normal LVEF. Indices of LV systolic function were similar regardless of anthracycline dose. However, GLS was worse (18.0 versus 19.0, p = 0.003) and prevalence of abnormal GLS was higher (36.5% versus 14.6%, p = 0.004) in patients treated with mediastinal radiotherapy. Mediastinal radiotherapy was associated with reduced GLS (p = 0.040) after adjusting for sex, age, and cumulative anthracycline dose. In adult survivors of childhood, adolescent, and young adult cancer, 2DSTE frequently detects LV systolic dysfunction despite a normal LVEF and may be useful for the long-term cardiac surveillance of adult cancer survivors.

Feasibility of Echocardiographic Techniques to Detect Subclinical Cancer Therapeutics–Related Cardiac Dysfunction among High-Dose Patients When Compared with Cardiac Magnetic Resonance Imaging

Cardiac magnetic resonance imaging (CMR) is the gold standard for the quantification of global and regional myocardial function and can detect subclinical myocardial dysfunction in anthracycline-induced cardiomyopathy. The aim of this study was to ascertain reliable echocardiographic parameters that can be used for the early identification of cancer therapeutics-related cardiac dysfunction, compared with CMR. Fifty-seven pediatric cancer survivors, 10 to 42years of age, with cumulative anthracycline doses≥200mg/m(2), were studied with transthoracic echocardiography and CMR 2.4 to 26.9years after chemotherapy. Three-dimensional echocardiography had the highest sensitivity in identifying subjects with CMR-derived ejection fractions<55%. Subjects with end-systolic volume index values>29mL/m(2) were more likely to have CMR-derived ejection fractions<55%. Three-dimensional speckle-tracking echocardiographic peak global longitudinal strain magnitude<-17.5% best identified subjects with abnormal peak midwall longitudinal strain magnitude by CMR. A decrease in early atrial myocardial velocity of <10cm/sec at the interventricular septum also identified subjects with lower average peak midwall longitudinal strain and peak midwall circumferential strain magnitudes by CMR. Three-dimensional echocardiographic ejection fraction<55%, end-systolic volume index>29mL/m(2), three-dimensional speckle-tracking echocardiographic peak global longitudinal strain magnitude<-17.5%, and a decrease in early atrial myocardial velocity at the interventricular septum of <10cm/sec by Doppler tissue imaging are the most sensitive transthoracic echocardiographic parameters to identify subjects with subclinical myocardial dysfunction by CMR.

Excellent Outcome in Pediatric AML with Response Guided Chemotherapy without Allogeneic HSCT in First Complete Remission: Results from Protocol DB-AML01

Background: Contemporary treatment schedules for pediatric acute myeloid leukemia (AML) have improved 5 year-overall survival rates up to 70% . These schedules usually consist of 4 to 5 intensive courses mainly based on cytarabine (AraC) and anthracyclines, with allo-HSCT upfront in a subset of patients . Long-term side effects such as late cardiotoxicity caused by high cumulative anthracycline dosages are a major concern. Therefore, the DCOG/BSPHO collaboration adapted the NOPHO 2004 protocol to DB-AML01 to reduce cumulative anthracyclines from 420-450 mg/m² to 300-330 mg/m² and to omit HSCT in CR1.Material: The treatment consisted of 5 chemotherapy courses: first induction course AIET (AraC conventional dose and Idarubicin (Ida) 36 mg/m2); second induction course AM (AraC conventional dose and Mitoxantrone (Mitox) 30 mg/m2) when blasts at day 15 < 5% or FLA-DNX (high dose AraC and Daunoxome (DNX) 180 mg/m2) when blasts > 5% at day 15 or t(8;21) AML; 3 consolidation courses (high dose AraC with Etoposide as course 3 and 5 and in between high dose AraC alone). Cumulative dose of AraC is 43,4 gr/m2 and of anthracyclines 300 mg/m² for patients receiving AIET+AM or 330 mg/m² for patients receiving AIET/FLA-DNX.Results: From 2010 to 2014 a total of 113 children with AML, median age 6.0 yrs (range 0-16), gender 56 males, were included. Second induction course was AM in n=75 and FLA-DNX in n= 33. Death in induction occurred in 4 patients, CR rate was 102/113 (90.3%) and 7 patients were refractory after induction. The later events were death in CR (n=2), relapse in CR (n=40), and secondary malignancies (n=0). HSCT was given to 3 patients in CR1 (physician's decision). Median follow up time is 2.6 years (range (range 1-5). Probability of EFS at 2 years was 60% (95% CI 49-69%) and 2-yr OS was 76 (95% CI 66-83%)77.9%. Especially inv 16 (n=10) and t(8;21) AML (n=16) had an excellent outcome (inv 16:2-yr EFS: 70% (95% CI 32-89%) and 2-yr OS 91% (95% CI 51-99%) resp t(8;21):2-yr EFS: 87% (95% CI 57-97%) and OS: 94% (95% CI 63-99%)), EFS nor OS in other genetic subgroups such as FLT3-ITD and MLL rearrangements were significantly different from the total group. Children with an older age (> 10 years) (n=34) or high WBC count (>50.109/l) (n=41) had the poorest 2-yr EFS: 51 (95% CI 33-67%) resp EFS: 40% (95% CI 24-56%), whereas OS was not significantly worse. For the patients with a relapse, 32 achieved a second CR and 4 a partial remission (90%) . In second CR 34 patients received an allo-HSCT. Until now 26 of the 40 patients are still in second CR.Conclusion: The DB-AML01 outcome data suggest that the choice of high cumulative doses of AraC with moderate cumulative doses of anthracyclines up to 300-330 mgr/m² results in a favorable overall survival for particularly those children with t(8;21), inv (16) AML, young age or lower WBC counts. Children with relapsed AML could be rescued with second line treatment and allo-HSCT. These results underscore the relevance of identification of subgroups of pediatric AML patients, based on age, WBC count and t(8;21) or inv 16, curable with "lower risk" treatment arms without allo-HSCT in CR1. DisclosuresKaspers:Janssen-Cilag: Research Funding.

Risk-Group Stratified and Minimal Residual Disease (MRD)-Guided Treatment with Extended ATRA and Reduced-Anthracycline Chemotherapy in Childhood Acute Promyelocytic Leukemia (APL): Results from ICC APL Study 01 (NCT01226303; EudraCT 2008-002311-40)

The combined treatment of all-trans retinoic acid (ATRA) and anthracyclines at high cumulative doses (>500-600 mg/m2) is associated with good outcomes in adults and children with acute promyelocytic leukemia (APL). However, high cumulative anthracyclines doses carry a significant risk of late cardiotoxicity, especially in children. In addition, children are more susceptible to ATRA-related side effects (particularly pseudo-tumor cerebri). This suggests that children should receive a lower dose of ATRA. We therefore established an international consortium on childhood APL, ICC APL, and developed the first multinational, multicenter childhood APL study, ICC APL Study 01, with the aim of investigating the safety and efficacy of a regimen with reduced anthracycline cumulative doses and modified ATRA. In some countries the protocol treatment was delivered out as a treatment guideline. Eligible patients had either typical cytogenetics (t(15;17)) or ATRA-sensitive molecular aberration (predominantly PML-RARα). Treatment was stratified by risk group (standard-SR or high-HR, based on white blood cell (WBC) count at diagnosis < or > 10x109/L) and minimal residual disease (MRD) level during post-remissional treatment. SR patients received induction (ATRA plus idarubicin on days 3-5-7) followed by two consolidation courses (I: ATRA, intermediate-dose cytarabine, mitoxantrone; II: ATRA plus idarubicin). HR patients received ATRA plus idarubicin (days 1-3-5) in induction, followed by 3 consolidation courses (I and II identical to SR patients, III: ATRA, intermediate-dose cytarabine, idarubicin). This therapy was followed by 2 years of maintenance in all patients with ATRA given every 3 months, methotrexate weekly and mercaptopurine daily. The daunorubicin-equivalent dose of anthracyclines was 355 mg/m2 and 405 mg/m2 for SR and HR patients, respectively. The cytarabine dose was 6,000 mg/m2 and 12,000 mg/m2 for SR and HR patients, respectively. ATRA was given at a dose of 25mg/m2. Treatment was guided by MRD bone marrow monitoring at the end of consolidation and 3 monthly during and for one year after maintenance completion. SR patients with persistent molecular disease after consolidation received a third course of treatment identical to that given to HR patients. Children with persistent molecular disease after 3 courses, and those with molecular or frank relapse during or after treatment, were eligible for salvage arsenic-trioxide (ATO) treatment. A total of 227 patients were enrolled into the study between January 2008 and May 2015; median age was 10,7 years (range, 0 - 19,9) and 53% of patients were female. FAB type was M3 in 81% and M3 variant in 16% (data N/A for 3% of patients). One hundred and twenty-nine (57%) and 98 (43%) were assigned to the SR and HR groups, respectively. Median WBC and platelet count at diagnosis were 6.1x109/L (range, 0.59-454) and 26x109/L (range, 2-262), respectively. PML/RARα fusion transcript was bcr 1 in 100, 2 in 6, 3 in 88 and not known in 33 patients. Clinical response and MRD data are available for 179/227 patients (79%). Early death rate was 3.1%. MRD positivity decreased over time; 80% of patients MRD were positive after induction, 31% after consolidation course I, 11% after consolidation course II and 4% after consolidation course III. A frank or molecular relapse occurred in 6 (all HR) and 8 (4 HR; 4 SR) patients, respectively; salvage ATO treatment was effective in 12 of these patients. One patient died of therapy-related leukemia. The 3-year probability of overall survival was 95% in the whole cohort of patients (96.5% and 93% in SR and HR patients, respectively; p 0.17). The 3-year probability of event-free survival was 83% for all patients (87% and 79% in SR and HR patients, respectively; p 0.09). In summary, the ICC APL study 01 produced an outcome comparable to that of children treated with AIDA 2000 protocol, which employed higher anthracyclines doses (650 mg/m2 daunorubicin-equivalent) (Testi et al. ASH 2010). These results confirm those reported by Creutzig et al. (BrJHaematol 2010), delivering reduced anthracyclines (cumulative dose 350 mg/m2) with extended ATRA and cytarabine. Data from a randomised study published by Lo Coco et al. (NEJM 2013) urged our consortium to develop ICC APL Study 02, in which SR patients will be treated with ATRA plus ATO and HR patients with ATRA, ATO and gemtuzumab ozogamicin; a front-line treatment without conventional chemotherapy. DisclosuresKaspers:Janssen-Cilag: Research Funding.

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

BackgroundSubacute 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.MethodsFive 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.ResultsNinety 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/m2. 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.ConclusionsThis 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 %.

Cardiovascular disease after treatment for Hodgkin's lymphoma: an analysis of nine collaborative EORTC-LYSA trials

Cardiovascular disease after treatment is an important concern in cancer survivors. However, knowledge of cardiotoxicity is limited by the retrospective nature of data, which often does not contain details of treatment exposure. To facilitate individual risk counselling of patients, we aimed to quantify the effect of anthracyclines, vinca-alkaloids, and radiotherapy on the risk of cardiovascular disease in patients treated for Hodgkin's lymphoma. In 2009-10, a Life Situation Questionnaire (LSQ) was distributed to patients by mail to assess late-onset effects of Hodgkin's lymphoma treatment in patients who were included in nine successive European Organisation for Research and Treatment of Cancer (EORTC) and the Groupe d'Etude des Lymphomes de l'Adulte (GELA, now renamed LYSA) randomised trials between 1964 and 2004. We reconstructed the mean radiation doses to the heart and carotid arteries and the cumulative doses of anthracyclines and vinca-alkaloids for all patients. Incidence of cardiovascular disease was reported during follow-up and updated through the LSQ. We applied Cox proportional hazards regression analyses to quantify the effect of chemotherapy and radiation on the risk of a first cardiovascular disease event. Information of primary treatment was complete for 6039 patients (median age at diagnosis 30 years [IQR 23-40]; median length of follow-up 9 years [6-14]). 1919 patients responded to the LSQ. 1238 first cardiovascular events were recorded in 703 patients, most were ischaemic heart disease (132 [19%]), congestive heart failure (85 [12%]), arrhythmia (110 [16%]), and valvular disease (77 [11%]). The mean heart radiation dose per 1 Gy increase (HR 1·015 [95% CI 1·006-1·024], p=0·0014) and the dose of anthracyclines per 50 mg/m(2) increase in cumulative dose (1·077 [1·021-1·137], p=0·0064) were significant predictors of cardiovascular disease. Cumulative dose of vinblastine (unadjusted model p=0·77), vincristine (p=0·36), and mean radiation dose to the left (p=0·41) or right (p=0·70) internal carotid artery did not predict for cardiovascular events. Quantification of the increased cardiovascular risk with specific doses of radiation and anthracycline exposure will enable a quantitative assessment of the optimum combination of systemic therapy and radiation, which will help clinicians to balance the risks and benefits of different regimens for individual patients. Rigshospitalet Research Committee, the EORTC Cancer Research Fund, and the Sally Snowman Survivorship Fellowship.

Dental abnormalities after chemotherapy in long-term survivors of childhood acute lymphoblastic leukemia 7-40 years after diagnosis.

Factors associated with the long-term dental effects after chemotherapy for childhood malignancies have not been well described. The primary aims of this study were as follows: (1) to assess whether age at diagnosis and treatment-related factors are associated with dental defects in survivors of childhood acute lymphoblastic leukemia (ALL) and (2) to assess the survivors' annual expenses for dental treatment compared to reference data. This cross-sectional study enrolled 111 Norwegian survivors of ALL diagnosed before the age of 16. All of the subjects completed a questionnaire and underwent medical and oral examinations. Dental defects were registered according to the individual defect index, with 0 = no defects and 140 = anodontia, and the caries experience was registered according to the decayed-missing-filled teeth index (DMFT). Age-matched reference data were drawn from a national general population survey (n = 555). The mean age at examination was 29.1 years (SD 7.2), and mean follow-up period was 22.9 years (SD 7.3). In a regression model, diagnoses occurring at ≤5 years of age (B = -9.6, p < 0.001) and a cumulative dose of anthracyclines >120 mg/m(2) (B = 11.5, p < 0.001) were strongly associated with more severe dental defects. Survivors treated after the age of 5 had experienced more caries than those treated at a younger age [DMFT 9.6 (SD 6.1) vs. 6.0 (SD 4.6), respectively; p = 0.001]. High annual expenses for dental treatment were reported by a larger percentage of the reference population compared to the survivor group (18 vs. 9 %, respectively; p = 0.02). The age at diagnosis and the dose of anthracyclines appear to be strongly associated with the severity of dental defects, although few survivors reported high annual expenses for dental treatment. The increased risk of dental defects during adulthood should be communicated to ALL survivors.

Significance of Echocardiography in the Assessment of Left Ventricular Function in Patients Receiving Combined Adjuvant Treatment with Anthracyclines and Trastuzumab / Značaj ehokardiografije u proceni funkcije leve komore kod bolesnica na adjuvantnoj terapji (kombinovana terapija antraciklinima i trastuzumabom)

Abstract The application of anthracycline and trastuzumab in adjuvant breast cancer treatment approach has significantly improved the survival of patients, but also carries the risk of cardiotoxicity that is manifested by reducing the ejection fraction of the heart. The aim of the study was to investigate the effect of cumulative anthracycline dose in combination therapy with trastuzumab on the left ventricular ejection fraction, and the influence of the time interval for starting the treatment with trastuzumab. The study included a group of 80 breast cancer patients (aged 28 to 75 years) who underwent the therapy with anthracyclines (IV-VI cycles) with the continuation of trastuzumab therapy for a period of one year. Ejection fraction at the end of completing the treatment period (VI anthracycline cycles and trastuzumab) was significantly lower in 68 (93%) patients compared to the value at the beginning of the study (68.2% ± 6.06 to 62.1 ± 6.1%; p &lt;0.0001; difference 6.1%). In five patients (anthracyclines and trastuzumab IV cycles) a decrease of 7.1% EF; p = 0.0043 was registered compared to the baseline values. The reduction in the ejection fraction was highest in patients in whom the trastuzumab therapy was initiated one month after the last anthracycline therapy (7.33%), and lowest in the subgroup who started receiving the therapy after three months (5.31%). In patients on cytostatic therapy, echocardiography proves the reduction in the left ventricular ejection fraction, which is cumulative and dose-dependent, and it also proves that the shorter time interval between the last cycle of anthracycline and the initial trastuzumab treatment the more it is associated with a marked decrease in the left ventricular ejection fraction.

Cardiac assessment of early breast cancer patients 18 years after treatment with cyclophosphamide-, methotrexate-, fluorouracil- or epirubicin-based chemotherapy

BackgroundEpirubicin-based chemotherapy improves the outcome of early breast cancer (BC) patients. However, cardiotoxicity remains an important side effect. MethodsWe re-consented node-positive BC patients enrolled in a phase III trial between 1988 and 1996 which compared six cycles of oral cyclophosphamide, methotrexate, fluorouracil (CMF) versus two epirubicin–cyclophosphamide regimens differing by the anthracycline cumulative dose [standard-dose epirubicin and cyclophosphamide (SDE) (8×60mg/m2) and higher-dose epirubicin and cyclophosphamide (HDE) (8×100mg/m2)]. Eligible patients were those who were alive and free of disease and had no contra-indications to the proposed tests (cardiac evaluation). Cardiotoxicity was defined as asymptomatic systolic dysfunction (left ventricular ejection fraction (LVEF)<50%, New York Heart Association (NYHA) Class I) or symptomatic heart failure (NYHA Class II–IV).Differences in cardiotoxicity between CMF and SDE/HDE were assessed using chi-square and Fisher Exact tests for binary variables and t-test and Wilcoxon test for continuous variables. ResultsAmong the 777 patients, 20 cases of CHF were reported (CMF=1, SDE=5, HDE=14; p<0.001). Between September 2010 and June 2013, 82 patients (30%) out of 269 eligible patients accepted to participate in this substudy. Median follow-up was 18years (range 15–24). Epirubicin-treated patients had significantly higher heart rate, more abnormal echocardiograms and LVEF by magnetic resonance imaging (MRI) compared to CMF-treated ones. A trend towards higher BNP was also observed in the SDE/HDE group (P=0.08). No differences were observed in LVEF assessed by echocardiogram or troponin T levels. ConclusionsParticipation rate in this substudy was lower than expected highlighting the complexity of re-calling patients several years after the initial BC diagnosis. After 18years, epirubicin-treated patients had a lower LVEF by MRI, more abnormal echocardiograms, higher heart rates compared to patients treated with CMF. However, no major delayed cardiotoxicity was observed.

Non-Hodgkin Lymphoma in Children and Adolescents: Progress Through Effective Collaboration, Current Knowledge, and Challenges Ahead.

Non-Hodgkin lymphoma is the fourth most common malignancy in children, has an even higher incidence in adolescents, and is primarily represented by only a few histologic subtypes. Dramatic progress has been achieved, with survival rates exceeding 80%, in large part because of a better understanding of the biology of the different subtypes and national and international collaborations. Most patients with Burkitt lymphoma and diffuse large B-cell lymphoma are cured with short intensive pulse chemotherapy containing cyclophosphamide, cytarabine, and high-dose methotrexate. The benefit of the addition of rituximab has not been established except in the case of primary mediastinal B-cell lymphoma. Lymphoblastic lymphoma is treated with intensive, semi-continuous, longer leukemia-derived protocols. Relapses in B-cell and lymphoblastic lymphomas are rare and infrequently curable, even with intensive approaches. Event-free survival rates of approximately 75% have been achieved in anaplastic large-cell lymphomas with various regimens that generally include a short intensive B-like regimen. Immunity seems to play an important role in prognosis and needs further exploration to determine its therapeutic application. ALK inhibitor therapeutic approaches are currently under investigation. For all pediatric lymphomas, the intensity of induction/consolidation therapy correlates with acute toxicities, but because of low cumulative doses of anthracyclines and alkylating agents, minimal or no long-term toxicity is expected. Challenges that remain include defining the value of prognostic factors, such as early response on positron emission tomography/computed tomography and minimal disseminated and residual disease, using new biologic technologies to improve risk stratification, and developing innovative therapies, both in the first-line setting and for relapse.

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.

Continued value of adjuvant anthracyclines as treatment for early breast cancer

Anthracyclines are frequently used in the adjuvant treatment of early-stage breast cancer. However, with the increasing use of other active drugs--mainly taxanes and trastuzumab in HER2-positive disease--coupled with concerns about anthracycline-associated toxic effects, there is debate about whether anthracyclines are still needed. Three major factors should be taken into consideration with the investigation of the role of anthracyclines in management of early breast cancer; specifically, the proven efficacy of anthracyclines in breast cancer, the absence of superiority of non-anthracycline-based chemotherapy over anthracycline-taxane regimens, and the low risk of toxic effects associated with the cumulative doses of anthracyclines used in contemporary regimens. The risks remain substantially outweighed by the benefits of treatment with anthracyclines, and thus, they maintain an important role in adjuvant treatment of breast cancer, particularly in women with high-risk disease.

Treatment, behavioral, and psychosocial components of cardiovascular disease risk among survivors of childhood and young adult cancer.

The incidence of childhood, adolescent, and young adult (AYA) cancers have been increasing since 1975.[1][1] In 2014, an estimated 10 450 and 5330 new cancers will be diagnosed among children aged birth–14 and adolescents aged 15 to 19 years old, respectively.[2][2] For young adults aged 20 to 34

Prospective cardiac MRI for the analysis of biventricular function in children undergoing cancer treatments.

Cardiotoxicity is one of the most serious long-term complications in childhood cancer survivors. Measurement of the left ventricular ejection and shortening fraction remains the most common screening tool for cardiac systolic dysfunction. However, M-mode echocardiography can be viewed as a crude approach as refined strategies are now available. The aim of this prospective study was to determine the role of cardiac MRI in the detection of subclinical left or right ventricular dysfunction as well as the prevalence of myocardial scaring in patients undergoing cancer treatments. Eighty-one children were enrolled in a pre-chemotherapy and then in a yearly protocol including a: (i) clinical evaluation; (ii) laboratory evaluation; (iii) electrocardiogram; (iv) echocardiogram; and (v) a cardiac magnetic resonance imaging (cMRI). Early left ventricular systolic dysfunction was only detected in two patients. The entire cohort presented a significant increase of the left atrial volume as measured by cMRI. This finding correlated with the total cumulative dose of anthracyclines (r = 0.34; P < 0.05) and the mean left ventricular radiation dose (r = 0.86; P < 0.05). We also observed a mild increase of myocardial scaring, similarly correlated to the radiation dose (r = 0.85; P < 0.05). Screening tools for late-onset cardiomyopathy secondary to cancer treatment are lacking. Our findings support the use of cMRI for the evaluation of the left atrial volume, as an early marker of diastolic dysfunction, and myocardial delayed enhancement, as a marker of myocardial fibrosis and scaring. Longer follow-up and larger studies are still needed to better define the role of cMRI in the evaluation of childhood cancer survivors.

Early left ventricular dysfunction in children after hematopoietic stem cell transplantation for acute leukemia: a case control study using speckle tracking echocardiography.

Background and ObjectivesCardiovascular complications are the leading cause of morbidity and mortality in childhood cancer survivors. Hematopoietic stem cell transplantation (HSCT) is a curable therapy for pediatric cancer. However, changes in cardiac function in children after HSCT are not well known. We assessed left ventricular (LV) function in children after HSCT using speckle tracking echocardiography (STE).Subjects and MethodsForty consecutive patients with median age of 11.9 years (range, 1.5-16 years) who received HSCT for acute leukemia and had comprehensive echocardiography before and after (median 9.2 month) HSCT were included in this study. The LV function parameters including conventional tissue Doppler imaging (TDI) and STE data were collected from pre- and post-HSCT echocardiography. These data were compared to those of 39 age-matched normal controls.ResultsCompared to normal controls, post HSCT patients had similar (p=0.06) LV ejection fraction. However, the following three LV function parameters were significantly decreased in post HSCT patients: rate-corrected velocity of circumferential fiber shortening (p=0.04), mitral inflow E velocity (p<0.001), and mitral septal annular E' velocity (p=0.03). The following four STE parameters were also significantly decreased in post HSCT patients: LV global circumferential systolic strain (p<0.01), strain rate (SR, p=0.01), circumferential diastolic SR (p<0.01), and longitudinal diastolic SR (p<0.001). There was no significant change in TDI or STE parameters after HSCT compared to pre-HSCT. Patients with anthracycline cumulative dose >400 mg/m2 showed significantly (p<0.05) lower circumferential systolic strain and circumferential diastolic SR.ConclusionSubclinical cardiac dysfunction is evident in children after HSCT. It might be associated with pre-HSCT anthracycline exposure with little effect of conditioning regimens. Serial monitoring of cardiac function is mandatory for all children following HSCT.