Cumulative Anthracycline Dose Research Articles

Intensified induction therapy with reduced total anthracycline exposure in pediatric low-risk acute myeloid leukemia.

10533 Background: Despite advances in risk stratification and therapy, the post-induction disease free survival (DFS) and overall survival (OS) for children with low-risk acute myeloid leukemia (LR-AML) remain low with DFS and OS of 50% and 68%, respectively, on the standard arm of the recent Children’s Oncology Group (COG) trial, AAML1031. Additionally, current therapy for pediatric LR-AML contains anthracycline doses exceeding thresholds known to increase the risk of adverse cardiac effects. In an effort to decrease exposure to cardiotoxic therapy, the Aflac Cancer and Blood Disorders Center adopted an institutional practice to treat LR-AML patients with a regimen of intensified induction therapy with decreased anthracycline exposure (Aflac-AML consisting of ADE10, Mitox/HiDAC, HiDAC/VP, Capizzi II). The aim of this study is to describe the associated toxicities and outcomes of this regimen in pediatric LR-AML. Methods: We retrospectively reviewed medical records of patients diagnosed with de novo LR-AML and treated per the Aflac-AML regimen from 2011-2014. Charts were reviewed for cardiac outcomes, ICU admissions, and the rate of infectious toxicities. DFS and OS were determined using Kaplan-Meier survival analysis. Results: We identified 11 LR-AML patients treated with Aflac-AML therapy. Patients received a planned 317 mg/m2 cumulative anthracycline dose vs 442 mg/m2for those treated on AAML1031. There was no decrease in LVEF with a mean change of +2.17% for Aflac-AML patients from the time of diagnosis to therapy completion (p = 0.23). The primary infectious toxicities observed were febrile neutropenia and bacterial infections with a median of 36.4±6% documented bacterial infections per cycle. Fungal and viral infections were rare as were ICU admissions – median 4.5±4% per cycle – and there were no toxic mortalities. The 3-year DFS and OS from end of induction I for Aflac-AML patients were 72.7% and 90.9%, respectively. Conclusions: The Aflac-AML regimen resulted in short-term toxicities and outcomes comparable to current chemotherapy regimens for pediatric LR-AML but with reduced anthracycline exposure. These data support use of this regimen for pediatric LR-AML patients.

Comparison of myocardial strain in cancer patients undergoing chemotherapy with and without anthracycline.

e21600 Background: Cardiotoxicity has been reported in cancer patients treated with anthracycline- and non-anthracycline-based chemotherapy. Myocardial strain assessed by speckle-tracking echocardiography enables early detection of subclinical chemotherapy-induced cardiotoxicity. However, comparisons of strain indices in patients undergoing chemotherapy with and without anthracyclines have not been reported. The prupose of this study was to compare myocardial strain in patients treated with these two chemotherapy regimens. Methods: This study was approved by the institutional review board at Saint Francis Hospital. 43 adult cancer patients (30 with solid tumors, 6 with lymphomas, 6 with leukemias and 1 with multiple myeloma) treated with anthracyline-based or non-anthracycline-based chemotherapy, were studied with conventional 2D and 3D echocardiography, 2D speckle-tracking imaging, and cardiac biomarkers. Results: Of the 43 patients, 22 received anthracycline-based chemotherapy, with an average cumulative anthracycline dose of 235 mg/m2. The other 21 patients received non-anthracycline-based chemotherapy including VEGF inhibitors and HER-2 receptor antagonists. There was no difference in 2D or 3D left ventricular ejection fraction (LVEF) (60.9 ± 4.5% vs 62.0 ± 4.9% by 2D; 60.5 ± 5.4 % vs 62.1± 5.2% by 3D, p = 0.35 for both 2D and 3D), troponin or NT-proBNP between anthracyline-treated patients and non-anthracycline treated patients. However, global longitudinal strain (GLS) and global circumferential strain (GCS) were decreased in patients treated with anthracycline-based chemotherapy compared with patients treated with non-anthracycline-based chemotherapy (-17.8 ± 2.8 vs 19.9 ± 2.9, p = 0.018 for GLS; -21.6 ± 4.8 vs 24.8 ± 4.8, p = 0.041 for GCS). Conclusions: In contrast with patients treated with non-anthracyline-based chemotherapy, patients treated with anthracyclines had reduced myocardial systolic strain even at low cumulative doses. This occurred in the absence of detectable reductions in LVEF. Thus early assessement of myocardial strain abnormality and early intervention with cardioprotective agents may be considered for these patients.

7 Sex differences in late chemotherapy-induced cardiomyopathy in adult cancer survivors: a cardiovascular magnetic resonance study

Introduction Chemotherapy induced cardiomyopathy (CIC) carries significant morbidity and mortality in cancer survivors. Female sex is a recognised risk factor for CIC in paediatric populations but the effect of sex in adult patients has not been established. We investigated sex differences in CIC using cardiovascular magnetic resonance (CMR). Method 76 patients without abnormal left ventricular function prior to chemotherapy (30 male [59±15 years], and 46 female [58±13 years, p=0.86]) were included. Cumulative anthracycline dose (193±165 vs. 189±119 mg/m 2 , p=0.91) and follow-up interval (8.75±8.75 years vs. 8.75±9 years, p=0.99) were similar. All patients underwent contrast-enhanced CMR at 1.5T, including long and short axis cine imaging, mitral and tricuspid annular peak systolic excursion (MAPSE and TAPSE, respectively), and late gadolinium enhancement (LGE). Multivariate regression analysis was undertaken. Results Left (39±13 vs 46±10%; p=0.027) and right ventricular ejection fraction (50±10 vs. 55±8%; p=0.042) were significantly lower in males, largely driven by differences in LV (208±83 vs. 167±42, p=0.02) and RV end diastolic volume (150±44 vs. 120±31, p=0.002). MAPSE and LAVi correlated significantly with LVEF (p Conclusions Adult male cancer survivors developed comparably worse late biventricular CIC than their female counterparts despite receiving similar doses of cancer treatment. These findings need confirmation in larger cohort studies, and if confirmed, could inform bespoke monitoring strategies taking sex differences into account.

Assessment of late cardiomyopathy by magnetic resonance imaging in patients with acute promyelocytic leukaemia treated with all-trans retinoic acid and idarubicin.

Late cardiomyopathy CMP is regarded as a potential severe long-term complication after anthracycline-based regimens for acute promyelocitic leukaemia (APL). We assess by MRI the incidence and severity of clinical and subclinical long-term CMP in a cohort of adult APL patients in first complete remission with PETHEMA trials. Adult patients diagnosed with APL in first complete remission lasting ≥2years underwent anamnesis and physical examination and were asked to perform a cardiac MRI. Clinical CMP was defined as radiographic and physical signs of heart failure accompanied by symptoms or by left ventricle ejection fraction (LVEF) <45% by MRI with or without symptoms. Subclinical CMP was defined as the following MRI abnormalities: LVEF 45-50% or late gadolinium enhancement or two or more of LVEF ≤55%, left ventricle end-diastolic volume index ≥98ml/m2, left ventricle end-systolic volume index ≥38ml/m2, right ventricle end-diastolic volume index ≥106ml/m2 and regional wall motion abnormalities. Of the 82 patients enrolled in the study, median cumulative dose of anthracyclines (doxorubicin equivalence) was 650mg/m2, and median time from APL diagnosis to the study was 87months (range, 24-195). Seven out of 57 patients with available MRI (12%) had subclinical CMP (all of them showed late gadolinium enhancement in MRI), and none had clinical CMP. Among the 25 patients without MRI, none had CMP by chest X-ray and physical assessment. In summary, we found 12% of subclinical and no clinical late CMP assessed by MRI in APL patients treated with PETHEMA protocols. Due to the low number of patients, we must interpret our results cautiously.

The utility of routine pre-chemotherapy screening with cardiac gated blood pool scan for patients at low risk of anthracycline toxicity

Background Anthracycline-based chemotherapy is used in many malignancies. Current recommendations by several groups suggest cardiac monitoring prior to and during anthracycline therapy. We aim to review the usefulness of baseline cardiac screening for left ventricular ejection fraction to assess if it had any impact on chemotherapy decisions in patients to be treated with anthracycline-based regimens or any beneficial effect upon outcomes. Methods We conducted a retrospective three-year audit of cancer patients who underwent GBPS prior to anthracycline (doxorubicin) chemotherapy. Subjects were identified via records from the Department of Nuclear Medicine. Pharmacy dispensing records identified those who received doxorubicin. Patient demographics, cancer type, cardiac risk factors, GBPS ejection fraction (EF), and cumulative anthracycline dose were collected. Results From 1 August 2009 to 31 July 2012, 179 patients underwent GBPS pre-doxorubicin chemotherapy. The mean age was 59 years (range 21-89 years), with 51% being males. Only two patients (1.1%) had an abnormal EF < 50%, while 33 patients (18%) had an EF 51-59% and 144 patients (80%) had EF ≥ 60%. The two patients with reduced baseline EF still received anthracycline-based chemotherapy. All 135 patients without any known cardiovascular risk factors had normal EFs. The total number of patients who received anthracycline chemotherapy during the same period was 207. Thus 28 patients (13%) commenced anthracycline without a prior GBPS. Conclusion Only 1.1% of the screened patients had EF < 50%. These two patients still received doxorubicin chemotherapy despite a compromised EF, as their treating clinicians believed that the benefits of chemotherapy outweighed the risk of potential cardiac toxicity. Our audit questions the practice of routine cardiac evaluation pre-anthracycline screening with GBPS. We propose that routine screening only be requested if cardiac risk factors are present.

Evaluation of the cardiac function in patients with breast cancer before and after receiving anthracycline by three-dimensional speckle tracking imaging

Objective To probe the clinical value of three-dimensional speckle tracking echocardiography in evaluating the early ventricular myocardial dysfunction in breast cancer patients treated with anthracycline. Methods A group of 40 breast cancer postoperative patients were received a epirubicin-based chemotherapy. Conventional and 3D dynamic echocardiography were measured before chemotherapy and 2 cycles and 4 cycles after chemotherapy during 24 hours, and to compare the change of the parameters before and after the chemotherapy. Results Left ventricular global area strain(LVGAS), left ventricular global longitudinal strain(LVGLS), right ventricular global longitudinal strain(RVGLS), right ventricular global circular strain(RVGCS) and right ventricular global radial strain(RVGRS) were significantly lower after the chemotherapy than those before the chemotherapy, and negatively correlated to cumulative anthracycline dose, in which the area under the ROC curve of LVGAS was 0.897(P=0.000). If -30.55% was selected as the diagnosis cut-off point, the sensitivity was 0.857, and the specificity was 0.917; some of right ventricular strain parameters were earlier than those of the left. Conclusions 3D-STI is useful to find the early left and right ventricular myocardial dysfunction in breast cancer patients treated with anthracycline and early access the subclinical cardiactoxicity, and right ventricular dysfunction may emerge earlier than the left, which can provide diagnosis basis to intervene timely for the clinical. Key words: Echocardiography, three-dimensional; Anthracycline; Breast neoplasms; Ventricular function; Speckle tracking image

RISK FACTORS AND INCIDENCE OF MYOCARDIAL DAMAGE IN PATIENTS WITH HEMOBLASTOSIS RECEIVING ANTHRACYCLIN ANTIBIOTICS

Introduction . The anthracycline antibiotics cause clinically significant manifestations of cardiotoxicity (СТ) – myocardial injuries, reducing both quality and life expectancy of the oncological patients. The purpose of the study was to evaluate the incidence and risk factors anthracycline-induced СТ in patients with hemoblastosis. Materials and methods . The study included 131 case histories of patients with hemoblastosis, treated with anthracyclines. Patients were divided into two groups according to age – the 1st group involved 77 patients aged from 18 up to 50 years (average age of 25.6 ± 3.4 years), the 2nd – 54 patients aged from 51 up to 75 years (average age of 56.8 ± 4.6 years). At the first investigation phase we studied the incidence of anthracycline-induced СТ in various age groups patients. The second phase devoted to studying potential risk factors (a cumulative dose more than 240 mg/m 2 , a female, an age, the accompanying application of mediastinal radiation therapy or other cardiotoxic drugs, cardioprotection absence) influence on anthracycline-induced CD frequency. Results. The incidence of CT in young patients was 38.2% (95% confidence interval (CI) 25.6–51.6%), among the older age group – 14.3% (95% CI 5.3–26.7%). The incidence of CT is significantly higher among young people (χ 2 = 5.63, p = 0.018). According to the results of univariate regression analysis, significant risk factors for the development of myocardial damage in patients with CT signs were: age <50 years – the odds ratio (OR) 2.69; 95% CI 1.05–6.84; the cumulative anthracycline dose more than 240 mg/m 2 by doxorubicin (OR 5.17, 95% CI 1.38–27.55) and the absence of prophylactic cardioprotective therapy (OR 23.38, 95% CI 6.49–84.14 ). In multivariate regression analysis independent risk factors for myocardial damage development were only the cumulative anthracyclines dose more than 240 mg/m 2 (OR 6.17, 95% CI 1.32–28.71) and the absence of prophylactic cardioprotective therapy (OR 2.82, 95% CI 1.09–7.28). Conclusions . Statistically significant higher anthracycline-induced cardiotoxicity frequency appeared in young patients. Reliable (р <0.05) cardiotoxicity risk factors were cumulative dose more than 240 mg/m 2 and cardioprotection absence.

Incidence, time of occurrence and response to heart failure therapy in patients with anthracycline cardiotoxicity.

Anthracyclines are commonly used chemotherapeutic medications. In the current analysis, we evaluated all-cause mortality and incidence, timing and response to medical therapy of anthracycline cardiotoxicity. Left ventricular ejection fraction (LVEF) was serially assessed using gated heart pool scan/echocardiography in patients receiving anthracycline-based chemotherapy from January 2009 to December 2014. A total of 1204 patients was administered anthracyclines during the study period. During a median follow up of 32 (interquartile range: 15-58) months, all-cause mortality was 38% (n = 463), with the incidence of cardiotoxicity 10.2% (n = 123). Only 15.4% (n = 19) patients required heart failure hospitalisation, with 48% (n = 59) of patients commenced on beta blockade therapy and/or angiotensin-converting enzyme inhibitors. The majority of patients (73.2%, n = 90) experienced cardiotoxicity within 1 year of anthracycline initiation. The proportion of patients with complete, partial and no LVEF recovery were 16.3% (n = 20), 29.3% (n = 36) and 54.4% (n = 67) respectively. Mortality was higher in the cardiotoxicity group (49% vs 37%, P < 0.01). History of coronary artery disease, leukaemia, idarubicin use and high cumulative anthracycline dose were predictors of cardiotoxicity. Cardiotoxicity after anthracycline use predictably occurs within the first year of therapy and is dose-related, with variable degrees of recovery. While the need for hospitalisation for heart failure was uncommon, medical therapy appears underutilised, suggesting there may be a role for improved surveillance and early initiation of treatment.

Early Detection of Chemotherapy- Induced Cardiotoxicity in Hematological Patients: A Prospective Study

Introduction: Chemotherapy-induced cardiotoxicity is an important concern in the long-term survivors era, especially in those younger patients who may suffer excess cardiovascular morbidity and worse outcomes. There is no consensus on monitoring criteria for this phenomenon and prompt therapy has not been yet properly established. We aim to evaluate prospectively early detection of cardiotoxicity, incidence, timing of occurrence and pre-existing factors during two years.Methods: This prospective study is being conducted at La Paz University Hospital in the period 2012-2013 (n=80) (age 18-84) based on anthracycline chemotherapy. A second phase of the study is ongoing, pending completion of the two year follow-up. Patients’ levels of analytical biomarkers cardiac troponin (cTnl) and B type natriuretic peptid (NT pro BNP), echocardiogram parameters left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were measured before starting chemotherapy, 3 weeks and 3 months afterwards, and then every six months during 2 years. In the first visit different clinical variables were also measured, including age, sex, body mass index, cardiovascular risk factors and previous treatments with chemotherapy and radiotherapy. Cardiotoxicity was defined as a reduction in LVEF <50% or >10% with basal >50%. Another cardiotoxicity conditions such as ischemic cardiomyopathy, arrhythmia, pericarditis and valvular heart disease were also considered. The cumulative dose of chemotherapy was measured in every visit.Results: Eighty patients were included; 49% women; 53.75% non-Hodgkin lymphoma, 22.5% Hodgkin lymphoma and 23.75% acute myeloid leukemia. Fifteen patients died (18.75%), 100% due to tumour related causes. Nine patients did not attend follow-up (11.25%). A total of 14 cardiotoxicity events occurred (17.5%): the most frequent event was reduction in LVEF (78,5%). Ischemic events and valvular disease were also observed. No hospitalization was needed in any of the events. Two of them recovered LVEF-levels spontaneously in the next visit. The other 9 were treated with heart failure therapy: 8 with ACE (angiotensin converting enzyme) inhibitors and beta- blockers and 1 with ACE inhibitors. Six (66.6%) of those who received specific treatment recovered basal LVEF-levels, 2 maintained LVEF dysfunction, and 1 died during follow-up due to tumour-related causes. In 85.7% of patients, cardiotoxicity occurred within the first year of follow-up. Basal LVEF and previous treatment with chemotherapy were significant predictors of subsequent cardiotoxicity (Cox regression model).Conclusions: early detection of cardiotoxic events provides an opportunity to start heart failure therapy on time to prevent progression to established heart failure. Previous chemotherapy treatment points to an increased risk of cardiotoxicity, so more intensive surveillance is necessary. Extended analysis of patients being included in the ongoing study will extend the information about cumulative anthracycline dose and cardiotoxicity induced by non-anthracycline chemotherapy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Is it possible to cure childhood acute myeloid leukaemia without significant cardiotoxicity?

Since cardiotoxicity is a life threatening late effect, a reduction of cardiotoxicity in the treatment of acute myeloid leukaemia (AML) is essential. This review is a compilation of the current knowledge about cardiotoxicity after AML treatment and of how future directions in treatment may affect its incidence. A total of six studies concerning AML and cardiotoxicity were identified. The incidence of late subclinical cardiotoxicity varied between 1·3 and 15·3%, and late clinical cardiotoxicity varied between 1·3 and 9·3%. Cumulative dose of anthracyclines (ACs) and history of relapse were the most common risk factors identified. No conclusions could be drawn about new, potentially less toxic ACs. Differences in treatment data and variations in study populations made comparisons uncertain. The echocardiographic techniques used in the majority of the studies are inferior to more modern echocardiographic methods. This decreases reproducibility and may increase the risk of overestimation of cardiotoxicity. In summary, AML cannot be cured today without ACs. However, some ACs may cause less cardiotoxicity than others. Furthermore there is currently no consensus on equipotent doses of ACs and risk factors for cardiotoxicity. Further research including randomized trials is needed to evaluate whether or not the potentially less cardiotoxic agents fulfil their promise.

SUBCLINICAL CARDIAC DAMAGE IN SURVIVORS OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA

Long-term cardiac health of survivors of childhood acute lymphoblastic leukemia (ALL) is often compromised by a wide spectrum of cardiac abnormalities directly related to anthracycline cumulative dose. In this study, we assessed the late-occurring side effects of ALL treatment on the heart performance of young adult survivors from the PETALE cohort. We aimed to evaluate the impact of the ALL treatment with or without cardioprotection on survivors’ cardiac function according to their baseline susceptibility.

Is screening for abnormal ECG patterns justified in long-term follow-up of childhood cancer survivors treated with anthracyclines?

ECG and echocardiography are noninvasive screening tools to detect subclinical cardiotoxicity in childhood cancer survivors (CCSs). Our aims were as follows: (1) assess the prevalence of abnormal ECG patterns, (2) determine the agreement between abnormal ECG patterns and echocardiographic abnormalities; and (3) determine whether ECG screening for subclinical cardiotoxicity in CCSs is justified. We retrospectively studied ECG and echocardiography in asymptomatic CCSs more than 5 years after anthracycline treatment. Exclusion criteria were abnormal ECG and/or echocardiogram at the start of therapy, incomplete follow-up data, clinical heart failure, cardiac medication, and congenital heart disease. ECG abnormalities were classified using the Minnesota Code. Level of agreement between ECG and echocardiography was calculated with Cohen kappa. We included 340 survivors with a mean follow-up of 14.5 years (range 5-32). ECG was abnormal in 73 survivors (21.5%), with ventricular conduction disorders, sinus bradycardia, and high-amplitude R waves being most common. Prolonged QTc (>0.45 msec) was found in two survivors, both with a cumulative anthracycline dose of 300 mg/m2 or higher. Echocardiography showed abnormalities in 44 survivors (12.9%), mostly mild valvular abnormalities. The level of agreement between ECG and echocardiography was low (kappa 0.09). Male survivors more often had an abnormal ECG (corrected odds ratio: 3.00, 95% confidence interval: 1.68-5.37). Abnormal ECG patterns were present in 21% of asymptomatic long-term CCSs. Lack of agreement between abnormal ECG patterns and echocardiographic abnormalities may suggest that ECG is valuable in long-term follow-up of CCSs. However, it is not clear whether these abnormal ECG patterns will be clinically relevant.

Facteurs de risque et surveillance à long terme des complications cardiaques après traitement pour un cancer pendant l’enfance

Anthracycline-induced cardiotoxicity (ACT) is a severe complication in children and young adults that may lead to congestive heart failure. Some risk factors have been identified: high anthracycline cumulative dose, high radiation dose delivered on the cardiac area, or young age during the treatment. Primary prevention is not clearly defined in children. The dexrazoxane iron chelator seems to be interesting based on its short-term cardioprotective property in patients receiving doxorubicin-containing regimens. However, its long-term benefits remain to be determined, as well as the risk of secondary cancer. Childhood cancer survivors treated with anthracyclines are annually followed in the long-term. Trans-thoracic echocardiography is classically performed every 2 to 5 years for assessing the ventricular hemodynamics and function. Recent modern techniques including echocardiography with strain assessment and cardiac MRI seems to be promising for an early detection of myocardial impairment. Further studies are mandatory for validating their usefulness in the setting of anthracycline-induced cardiomyopathy. Recently, ACT predisposing variants in genes involved in oxydative stress and in metabolism and transport of anthracyclines have been identified. Their use in clinical practice could improve ACT risk stratification of children treated with anthracyclines-containing regimens. Predictive models combining replicated genetic variants and clinical factors need to be validated with the challenge to identify patients at high risk of cardiomyopathy. The objective is to personalize treatment strategy according to individual genetic background.

Prognostic Significance of New-Onset Atrial Fibrillation in Patients With Non-Hodgkin's Lymphoma Treated With Anthracyclines

Cancer therapeutics-related cardiac dysfunction induced by anthracycline is highly problematic, and its early recognition is of importance. Atrial fibrillation (AF) is sometimes seen after anthracycline chemotherapy. We aimed to test whether new-onset AF predicts anthracycline-induced heart failure. We prospectively studied 249 lymphoma patients who received anthracyclines. The patients were followed up with a frequent electrocardiographic examination. Fifteen patients (6%) newly developed AF after the chemotherapy, and during a mean follow-up of 34months, they had a higher incidence of acute heart failure (40% vs 3.8%; p <0.001) and greater all-cause mortality (60% vs 14.1%; p <0.001) than those without AF. The onset of AF preceded the development of heart failure by a mean of 2.4months. New-onset AF was independently associated with both acute heart failure (hazard ratio 12.78; p <0.001) and all-cause mortality (hazard ratio 4.77; p <0.001). The cumulative anthracycline dose did not differ between the patients with and without heart failure, yet it was another independent predictor of the mortality. In conclusion, new-onset AF may predict unfavorable outcomes after anthracycline chemotherapy in patients with malignant lymphoma.

Efficacy and safety of Dexrazoxane (DRZ) in sarcoma patients receiving high cumulative doses of anthracycline therapy - a retrospective study including 32 patients.

BackgroundAnthracyclines, as the most effective therapy, are the cornerstone of advanced stage sarcoma treatment. However, anthracyclines can also contribute to myocardial dysfunction and congestive heart failure, ultimately limiting the therapeutic potential of the drug. Coadministration of Dexrazoxane has been shown to effectively reduce cardiotoxicity, however primarily in patients suffering in diseases other than sarcoma.MethodsThe aim of this retrospective analysis was to evaluate safety and efficacy of chemotherapy with high cumulative doses of anthracyclines in combination with Dexrazoxane. The medical charts of 32 patients treated in four institutions were analyzed. Reasons for coadministration were rechallenge, reaching the cumulative anthracycline dose and preexisting heart failure.ResultsThe median age was 54 years [18–68 years]. The median cumulative anthracycline dose before adding DRZ was 450 mg/m2 and after administration of last anthracycline containing therapy 750 mg/m2. Either during treatment or follow up, 2/27 patients (7 %) without preexisting major cardiac findings developed anthracycline-induced cardiotoxicity. The median overall survival (OS) from start of the first anthracycline containing chemotherapy was 46 months and 17 months from the initial coadministration of DRZ. At rechallenge, the median progression free survival (PFS) with DRZ was 7 months. In continuous therapy, the median PFS was 13 months from beginning of chemotherapy and 9 months from the addition of DRZ.ConclusionChemotherapy with high cumulative doses of anthracyclines in addition with DRZ demonstrated a remarkable OS in these advanced disease patients. Cardiac side-effects due to high cumulative doses of anthracyclines requiring discontinuation of anthracycline treatment were rare. A PFS of 9 months from the beginning of the coadministration of DRZ indicates that continuing anthracycline therapy beyond established cumulative doses is a promising therapeutic option.

Noninvasive early detection of anthracycline-induced cardiotoxicity in patients with hematologic malignancies using the phased tracking method.

Anthracyclines are among the most effective and widely used anticancer drugs; however, their use is limited by serious cardiotoxicity. Early detection is necessary to prevent the high mortality rate associated with heart failure (HF). We evaluated cardiac function in 142 patients using conventional echocardiography and the phased tracking method (PTM), which was measured using the minute vibration and the rapid motion components, neither of which is recognized in standard M‐mode nor in tissue Doppler imaging. For systolic function comparison, we compared left ventricular ejection fraction (LVEF) in conventional echocardiography with the average velocity of ventricular septum myocytes (Vave) in the PTM. The Vave of 12 healthy volunteers was 1.5 (m/s)/m or more. At baseline of 99 patients, there was a positive correlation between LVEF and Vave in all patients. There were no significant differences in baseline cardiac function between patients with and without HF. There was a negative correlation between the cumulative anthracycline dose and LVEF or Vave among all patients. We determined that Vave 1.5 (m/s)/m was equivalent to LVEF 60%, 1.25 (m/s)/m to 55%, and 1.0 (m/s)/m to 50%. During the follow‐up period, there was a pathological decrease in LVEF (<55%) and Vave (<1.25 m/s/m) in patients with HF; decreases in Vave were detected significantly earlier than those in LVEF (P < 0.001). When Vave declined to 1.5 (m/s)/m or less, careful continuous observation and cardiac examination was required. When Vave further declined to 1.0 (m/s)/m or lower, chemotherapy was postponed or discontinued; thus, serious drug‐induced cardiomyopathy was avoided in patients who did not relapse. The PTM was superior to echocardiography for early, noninvasive detection and intermediate‐term monitoring of left ventricle systolic function associated with anthracycline chemotherapy, among patients with hematologic malignancies. The PTM was an effective laboratory procedure to avoid the progression to serious cardiomyopathy.

Utility of Global Longitudinal Strain by Echocardiography to Detect Left Ventricular Dysfunction in Long-Term Adult Survivors of Childhood Lymphoma and Acute Lymphoblastic Leukemia

Measuring left ventricular (LV) global longitudinal strain (GLS) is recommended in screening of long-term cancer survivors for cardiotoxicity. However, there are limited data on GLS in this setting, in particular in survivors with apparently normal LV function without risk factors of impaired GLS. In the present study, we measured GLS in 191 adult survivors of childhood lymphoma or acute lymphoblastic leukemia, with normal LV ejection fraction and fractional shortening (FS) and without known hypertension, diabetes mellitus, myocardial infarction, or stroke. We compared GLS in the survivors with 180 controls. Mean GLS was-19.0 ± 2.2% in the survivor group and-21.4 ± 2.0% in the controls (p <0.001). Impaired GLS, defined as mean - 1.96 SDs in the control group, occurred in 53 of 191 survivors (28%). We included survivors with impaired LV ejection fraction and/or FS or traditional risk factors (n= 231 in all) in multiple regression analyses to explore associations with previous cancer treatment. Survivors treated with mediastinal radiotherapy had an odds ratio of impaired GLS of 5.2 (95% confidence interval 2.2 to 12) compared with other survivors. Survivors treated with cumulative anthracycline doses>300mg/m(2) had an odds ratio of 4.8 (95% confidence interval 1.7 to 14) of impaired GLS. In conclusion, this study demonstrates a high proportion of LV dysfunction assessed by GLS in apparently healthy adult survivors of childhood cancer. Impaired GLS wasassociated with previous exposure to mediastinal radiotherapy and high doses of anthracyclines. The prognostic role of measuring GLS in this specific patient population should be examined in prospective studies.

Evaluation and management of chemotherapy-induced cardiotoxicity in breast cancer: a Delphi study

PurposeWhile much progress has been made in the treatment of breast cancer, cardiac complications resulting from therapy remain a significant concern. Both anthracyclines and novel targeted agents can inflict cardiac damage. The present study aimed to evaluate the difference between what it is currently done and what standards of care should be used to minimizing and managing cardiac toxicity in breast cancer survivors.MethodsA two-round multicenter Delphi study was carried out. The panel consisted of 100 oncologists who were asked to define the elected therapies for breast cancer patients, the clinical definition and patterns of cancer drug-derived cardiac toxicity, and those protocols focused on early detection and monitoring of cardiovascular outcomes.ResultsExperts agreed a more recent definition of cardiotoxicity. Around 38 % of patients with early-stage disease, and 51.3 % cases with advanced metastatic breast cancer had preexisting risk factors for cardiotoxicity. Among risk factors, cumulative dose of anthracycline ≥450 mg/m2 and its combination with other anticancer drugs, and a preexisting cardiovascular disease were considered the best predictors of cardiotoxicity. Echocardiography and radionuclide ventriculography have been the proposed methods for monitoring changes in cardiac structure and function. Breast cancer is generally treated with anthracyclines (80 %), so that the panel strongly stated about the need to plan a strategy to managing cardiotoxicity. A decline of left ventricular ejection fraction (LVEF) >10 %, to an LVEF value <53 % was suggested as a criterion for changing the dose schedule of anthracyclines, or suspending the treatment of chemotherapy plus trastuzumab until the normalization of the left ventricular function. The use of liposomal anthracyclines was strongly suggested as a treatment option for breast cancer patients.ConclusionsThe present report is the first to produce a set of statements on the prevention, evaluation and monitoring of chemotherapy-induced cardiac toxicity in breast cancer patients.

Growth-differentiation Factor-15 and Tissue Doppler Imaging in Detection of Anthracycline-induced Cardiomyopathy During Therapy of Childhood Cancers.

The aim of this study was to evaluate the importance of growth-differentiation factor-15 (GDF-15) levels and tissue Doppler imaging (TDI) in the early detection of anthracycline-induced cardiomyopathy during the treatment of childhood cancers. Twenty patients (13 males and 7 females) newly diagnosed with childhood cancer whose treatment protocol included anthracycline were included in the study. Echocardiography, including M-mode, pulse Doppler, and TDI, was performed after the first anthracycline treatment at cumulative doses of 100, 200, and 300 mg/m and at least 6 months after the last treatment. GDF-15 and troponin-I were also measured at these time points. The median age of the patients was 14 years (range, 3 to 18 y). The median cumulative anthracycline dose was 220 mg/m (range, 60 to 400 mg/m). Conventional pulse wave and pulse wave tissue Doppler methods revealed significant differences in the right ventricular myocardial performance indices of the patients who received cumulative anthracycline doses of 300 mg/m compared with their indices at least 6 months after the last treatment. The serum GDF-15 levels after the cumulative anthracycline dose of 200 mg/m were also higher than the patients' pretreatment levels. Doppler/TDI and GDF-15 levels may be used in the early determination of anthracycline-induced cardiomyopathy during the treatment of childhood cancers.

Cardioprotection in women with neoplastic disease

Cardiotoxicity (CTX) is a serious adverse effect of anticancer drugs that impacts on quality of life and overall survival of cancer patients. Hypokinetic cardiomyopathy is the most typical form of CTX, and it is traditionally considered refractory to therapy. Prevention of CTX remains of paramount importance, and several measures, including serial cardiac function monitoring, reduction of cumulative anthracycline dose, use of anthracycline analogues and cardioprotective agents, have been proposed. Over the last decade, however, a new approach based on cardiac biomarkers has emerged as an effective alternative strategy for the early detection of subclinical cardiac injury. In particular, the role of troponin I in identifying patients at risk of CTX as well as of angiotensin-converting enzyme inhibitors in preventing left ventricular dysfunction and late cardiac events in high-risk patients, namely those with raised troponin I levels after chemotherapy, has been consistently demonstrated as an effective tool for CTX prevention.