Cumulative Anthracycline Dose Research Articles

Current Possibilities of Early Detection of Cardiotoxicity of Cytostatic Treatment.

Due to growing long-term survival rate of oncologic patients, there is increased interest in cardiotoxicity of oncologic treatment among medical professionals. It is concerning both paediatric and adult patients. When prescribing oncologic treatment, there should be focus on the efficacy and safety of the used drugs. Nowadays, the main problem is early dia-gnosis of cardiotoxicity. In our work we wanted to investigate whether the increase in bio-markers after the cytostatic therapy with anthracyclines can predict further increase in the left ventricular volume and decrease of the left ventricular ejection fraction. We were monitoring 36 patients with the dia-gnosis of non-Hodgkins lymphoma who received therapy with anthracyclines. After the therapy we were measuring the cardiac bio-markers NT-proBNP and high-sensitivity troponin I and performed echocardiography. In our group of patients there is a statistically significant correlation between increased levels of troponin I, NT-proBNP and increment of the left ventricular volume measured before the treatment and 3 months after the treatment. There is also a significant inverse correlation between the left ventricular volume and left ventricular ejection fraction. There was no relationship between higher cumulative doses of anthracyclines and the increment of the left ventricular volume. There is a significant correlation between higher cumulative doses of anthracyclines and higher levels of troponin I. The measurement of bio-markers troponin I and NT-proBNP should be considered for an early dia-gnosis of cardiotoxicity in oncologic patients. Echocardiography is also beneficial for the dia-gnosis in these patients. All efforts after the dia-gnosis should be focused on the therapy with cardioprotective drugs, which can prevent the development of severe heart failure.

P1781 Cardio-protective role of dexrazoxane co-administered with anthracyclines: long-term echocardiographic follow-up in adult survivors of pediatric cancer

Abstract Background Cardiovascular disease is a well-recognized cause of increased late morbidity and mortality among survivors of childhood cancer treated with anthracyclines. A decrease in left ventricular (LV) ejection fraction (LVEF) and fractional shortening may be observed during follow-up. Previous studies reported non-negligible prevalence of subclinical systolic dysfunction assessed with deformation imaging at short-, mid- and long-term follow up. Co-administration of Dexrazoxane has been shown to significantly reduce short-term and mid-term cardiotoxicity. The usefulness of dexrazoxane in preventing late (>10 years) anthracycline cardiotoxicity remains under discussion. Purpose Aim of this study was to assess cardiac function in long-term (>10 years) survivors of childhood tumors treated with dexrazoxane/anthracycline association. Methods Twenty cancer survivors previously treated with co-administration of anthracyclines and dexrazoxane for childhood renal tumors or sarcoma and a control group of 20 healthy non-athletic subjects matched for age, sex and body surface area were enrolled in the study. Echocardiographic measurements included 3D LVEF and LV and right ventricular (RV) global longitudinal strain (GLS). Cancer survivors were evaluated at median follow-up time of 21.5 years (range 10-26). Results No evidence of cardiac toxicity, as defined by current guidelines, was reported in all survivors. None of survivors presented LVEF < 50% or abnormal longitudinal strain, defined as a value >2 SDs below the mean using sex-specific and age-specific strain values. No significant differences in standard and deformation imaging parameters were observed between survivors and controls (3D LVEF 58 ± 3 % vs 60 ± 5 % p = NS; LV GLS -21 ± 1 % vs - 21 ± 2 % p= NS; RV GLS - 23 ± 2 % vs - 23 ± 5 % p= NS). Moreover, considering subjects who received a cumulative dose of anthracyclines above the median (doxorubicin-equivalent dose ≥208 mg/m2) no significant differences were found as compared to the group receiving a lower dose. Conclusions No evidence of cardiac toxicity was detected in all survivors. Our findings support the cardio-protective role of dexrazoxane in children undergoing anthracycline-based treatment. Parameters Cancer survivors (n= 20) Controls (n= 20) P 3D LVEF (%) 58 ± 3 60 ± 5 NS LV GLS (%) -21 ± 1 -21 ± 2 NS RV GLS (%) -23 ± 2 -23 ± 5 NS 3 D LVEF: Three-Dimensional Left Ventricular Ejection Fraction, LV GLS: Left Ventricular Global Longitudinal Strain; LV; RV GLS: Right Ventricular Global Longitudinal Strain. Abstract P1781 Figure. LV strain analysis in a survivor

Diagnostic echocardiographic parameters of early cardiotoxicity of anthracyclines in pediatric population

Hematological malignancies are the most common tumors in pediatrics. Anthracyclines represent the molecule of choice in their treatments, and are responsible for improving survival. Their cardiovascular complications, increased the morbidity. Evaluate diagnostic echocardiographic parameters of early cardiotoxicity of anthracyclines in children. Prospective observational study (18 months) including 43 patients followed in onco-hematology for hematological malignancy, on anthracycline, who had a cardiovascular assessment and follow-up. The average age is 7.4 years (range 6 months to 16 years), with male predominance (sex ratio = 2.07). All patients were followed for hematologic malignancy: 14 cases of LH, 12 cases of NHL, 12 cases of ALL, and 5 cases of AML. 21 patients were in treatment, 12 patients in remission, and 10 patients scheduled for bone marrow transplantation. All patients were on anthracyclines, with an average cumulative dose of 223 mg/m 2 . A complete cardiovascular assessment was performed in all patients with a control before each treatment in patients in treatment and every 3 months in patients in remission. Echocardiographic parameters that varied significantly in post chemotherapy were: Ea, Sa, and SGL. Tissue Doppler parameters decreased in 14% of cases after an average cumulative dose of 160 mg/m 2 . SGL decreased significantly in 7% of cases after an average cumulative anthracycline dose of 290 mg/m 2 . The tissue doppler and the global longitudinal strain have an interest in both the child and the adult in the early detection of anthracycline cardiotoxicity, allowing better management.

Symptomatic Heart Failure in Acute Leukemia Patients Treated With Anthracyclines

ObjectivesThe purpose of this study was to investigate the occurrence and develop a risk score for heart failure (HF) in acute leukemia. BackgroundKnowledge is scarce regarding the incidence and risk factors of symptomatic HF in patients with acute leukemia. MethodsBaseline clinical and echocardiographic parameters, including indices of cardiac function (left ventricular ejection fraction and myocardial strain [global longitudinal strain; GLS]), were obtained in 450 patients with acute leukemia treated with anthracyclines, before chemotherapy initiation. Potential risk factors for HF were evaluated using Fine and Gray’s regression analysis, and from this, a 21-point risk score was generated. ResultsForty patients (8.9%) developed HF. The HF risk score included a baseline GLS >−15% (indicative of greater impairment) (6 points), baseline left ventricular ejection fraction <50%, pre-existing cardiovascular disease, acute myeloid leukemia (4 points each), cumulative anthracycline dose ≥250 mg/m2 (2 points), and age >60 years (1 point). Patients were stratified into low (score 0 to 6), moderate (score 7 to 13), and high risk (score 14 to 21). The estimated 1-year cumulative incidence of HF for low-, moderate-, and high-risk groups was 1.0%, 13.6%, and 35.0%, respectively (p < 0.001). The HF risk score was also predictive of all-cause mortality (p < 0.001). After adjustment for age and leukemia type, however, only GLS was significantly associated with all-cause mortality (hazard ratio: 1.73; 95% confidence interval: 1.30 to 2.31; p < 0.001). ConclusionsWe developed a baseline risk score to determine risk of HF in patients with acute leukemia. Additional studies are needed to determine the external validity of these findings.

Echocardiographic Assessment of Cardiac Function in Pediatric Survivors of Anthracycline-Treated Childhood Cancer.

Anthracycline-induced cardiotoxicity is a major cause of morbidity and mortality in childhood cancer survivors (CCSs). Echocardiographic myocardial strain imaging is recommended in adult patients with cancer, but its role in pediatric CCSs has not been well established. Aims of this study were to determine the prevalence of abnormalities in left ventricular strain in pediatric CCSs, to compare strain with other echocardiographic measurements and blood biomarkers, and to explore risk factors for reduced strain. CCSs ≥3 years from their last anthracycline treatment were enrolled in this multicenter study and underwent a standardized functional echocardiogram and biomarker collection. Regression analysis was used to identify factors associated with longitudinal strain (LS). Five hundred forty-six pediatric CCSs were compared with 134 healthy controls. Abnormal left ventricular ejection fraction (<50%) and mean LS (Z score, <-2) was found in 0.8% and 7.7% of the CCSs, respectively. LS was significantly lower in CCSs than in controls, but the absolute difference was small (0.7%). Lower LS in CCSs was associated with older current age and higher body surface area. Sex, cumulative anthracycline dose, radiotherapy, and biomarkers were not independently associated with LS. Circumferential strain, diastolic parameters, and biomarkers were not significantly different in pediatric CCSs. Global systolic function and LS are only mildly reduced in pediatric CCSs, and most LS values are within normal range. This makes single LS measurements of limited added value in identifying CCSs at risk for cardiac dysfunction. The utility of strain imaging in the long-term follow-up of CCS remains to be demonstrated.

Impact of Arterial Hypertension on Doxorubicin-Based Chemotherapy-Induced Subclinical Cardiac Damage in Breast Cancer Patients.

Advances in oncologic therapies have allowed to achieve better outcomes and longer survival in many patients with breast cancer. Anthracyclines are cytotoxic antibiotics widely used in daily oncology practice. However, anthracyclines cause cardiotoxicity which is a limiting factor of its use. Cumulative dose of anthracyclines is the major cause of induced cardiotoxicity. According to previous clinical trials, the major predisposing high-risk factors for anthracycline-based chemotherapy-induced cardiotoxicity are age, body weight, female gender, radiotherapy, and other diseases such as diabetes and hypertension. Experimental studies in animals confirm that hypertension may be a significant factor predisposing anthracycline-based chemotherapy cardiotoxicity. The main objective of our study was to identify the effect of pre-existing arterial hypertension on the development of subclinical cardiac damage during or after doxorubicin-based chemotherapy in breast cancer patients. The study was performed prospectively between March 2016 and January 2017 in the Hospital of Lithuanian University of Health Sciences Kaunas Clinics Department of Oncology and Department of Cardiology. Data of 73 women with breast cancer treated with doxorubicin-based chemotherapy in outpatient clinic were analyzed. Statistically significant association between pre-existing arterial hypertension and left ventricular systolic dysfunction after completion of chemotherapy was observed (P < 0.004). Our study demonstrated that pre-existing arterial hypertension has a very important role in the development of anthracycline-based chemotherapy-induced cardiotoxicity, despite arterial hypertension control quality. Consequently, further studies evaluating impact of other risk factors and how early and sufficient management of arterial hypertension could influence the development of cardiotoxicity are needed to avoid permanent cardiac damage.

Left ventricle segmental function in childhood cancer survivors using speckle-tracking echocardiography.

Anthracycline-associated cardiotoxicity in childhood cancer survivors may relate to global or segmental left ventricular abnormalities from associated thromboembolic events and myocardial microinfarcts. We characterized left ventricular segmental changes by two-dimensional speckle-tracking echocardiography in anthracycline-treated asymptomatic childhood cancer survivors. Childhood cancer survivors' echocardiograms with normal left ventricular fractional shortening >1 year after anthracycline chemotherapy were studied. Cancer-free control children had normal echocardiograms. Apical two-, three-, and four-chamber peak systolic left ventricular longitudinal and global longitudinal strain, and peak systolic left ventricular radial and circumferential strain at papillary muscle levels were analyzed. The mean (standard deviation) age was 12.7 (3.8) years in 41 childhood cancer survivors. The median (interquartile range) follow-up after anthracycline chemotherapy was 4.73 (2.15-8) years. The median (range) cumulative anthracycline dose was 160.2 (60-396.9) mg/m2. In childhood cancer survivors, the mean (standard deviation) left ventricular longitudinal strain was lower in two- (-18.6 [3.2] versus -21.3 [2.5], p < 0.001), three- (-16.3 [6.0] versus -21.7 [3.0], p < 0.001), and four- (-17.6 [2.7] versus -20.8 [2.0], p < 0.001) chamber views compared to controls. The left ventricular global longitudinal strain (-17.6 [2.7] versus -21.3 [2.0]) and circumferential strain (-20.8 [4.3] versus -23.5 [2.6], p < 0.001) were lower in childhood cancer survivors. Among childhood cancer survivors, 12 out of 16 left ventricular segments had significantly lower longitudinal strain than controls. Asymptomatic anthracycline-treated childhood cancer survivors with normal left ventricular fractional shortening had lower global longitudinal and circumferential strain. The left ventricular longitudinal strain was lower in majority of the segments, suggesting that anthracycline cardiotoxicity is more global than regional.

Right ventricular 2D speckle-tracking echocardiography in children with osteosarcoma under chemotherapy

BackgroundCardiotoxicity from anthracyclin chemotherapy is a leading cause of death in patients with cancer. Therefore, left ventricular (LV) function is routinely assessed during protocol to detect cardiotoxicity; however, animal studies suggest that right ventricular (RV) function may be also impaired. So, our objective was to investigate the incidence of RV dysfunction in children with osteosarcoma receiving anthracyclines and to highlight the role of 2D STE in early detection of RV dysfunction.ResultsRV function was affected by anthacyclines through direct cardiotoxic effect on RV myocardium without simultaneous derangement of LV function. Furthermore, there is a direct proportion between the incidence of RV dysfunction and the cumulative dose of anthracyclines. At the first echo follow-up at 10th week, 7 patients had impaired RV GLS in comparison to baseline study. At 20th week, the number of patients with impaired RV strain increased to 10. At 29th week, it reaches 12 patients. This effect was early detected by RV 2DSTE before adversely affecting TAPSE and FAC. The incidence of RV dysfunction from anthracyclines was around 12%, and the recovery rate was around 8% in 3 months after completion of chemotherapy.ConclusionRV 2DSTE is the best modality to detect early affection of RV function in comparison with other modalities. RV function decreases early even before derangement of LV function. Accordingly, it should be assessed separately in all patients who received anthracyclines even without evident LV affection.

Occurrence and Resolution of Anthracycline Cardiotoxicity and Impact on Treatment Outcomes Among Children Treated on the AAML1031 Clinical Trial: A Report from the Children's Oncology Group

Background: Children treated for acute myeloid leukemia (AML) receive high doses of anthracyclines. Anthracycline cardiotoxicity causes significant short and long term morbidity and mortality, thus it is crucial to understand its risk factors, natural history, and impact on treatment outcome. Methods: Between June 2011 and September 2018, AAML1031 enrolled patients aged &amp;lt;30 years for treatment of de novo AML. Echocardiographic evaluations (echo) were required before each treatment course, at the end of protocol therapy, and at yearly intervals during off-protocol follow-up. The lowest shortening fraction (SF) and ejection fraction (EF) in each reporting period were prospectively collected. Cardiotoxicity was defined as SF &amp;lt;28% or EF &amp;lt;55% which represent the protocol-mandated thresholds at which anthracyclines were to be withheld. Higher-grade toxicity (SF &amp;lt;24%, EF &amp;lt;50%) consistent with grade 2 or higher left ventricular systolic dysfunction (grade 2+ LVSD) per CTCAE v3 definitions, and its resolution were also assessed. Resolution was defined as SF returning to baseline or &amp;gt;30% and EF returning to baseline or &amp;gt;60%. Resource utilization (RU) data for patients enrolled at hospitals contributing to the Pediatric Health Information Systems database (PHIS) were merged with AAML1031 study data. Cox regressions were used to assess risk factors for incident cardiotoxicity and recovery among cases, as well as to compare event-free (EFS) and overall survival (OS) in patients with and without cardiotoxicity. Poisson regressions were used to compare on-protocol RU. Cardiotoxicity was treated as a time-varying exposure introduced at time of documented onset in comparisons of EFS, OS and RU. Patients with high allelic ratio FLT3/ITD+ AML were excluded from analyses. Results: 1092 patients were treated on AAML1031 and included in the primary analyses. Echo compliance was high overall (mean ±sd: 74.5% ±19.6), but lower and more variable during off-protocol (mean ±sd: 58.1%, ±31.0) than on-protocol (mean ±sd: 90.6% ±19.5) reporting periods. Over a median follow-up of 3.5 years, 39% (n=428) of patients experienced protocol-defined cardiotoxicity, of whom 54% (n=232) suffered grade 2+ LVSD. Cumulative incidence was higher among patients randomized to receive bortezomib, non-infants, females, and patients with low risk disease who receive more cumulative anthracycline during frontline therapy (Table 1). Patients treated with dexrazoxane were less likely to develop cardiotoxicity. Among patients with grade 2+ LVSD, 49% experienced recovery of cardiac function within a median of 14 months (IQR: 9-20) from initial detection. High risk disease classification and dexrazoxane exposure were associated with LVSD recovery (Table 1). Both EFS (HR 1.23, 95% CI: 1.01-1.50) and OS (HR 1.45, 95% CI 1.15-1.84) were significantly worse in patients with cardiotoxicity meeting per-protocol thresholds for treatment modification. The magnitude of the association with EFS (HR 1.24, 95% CI: 0.98, 1.58) was similar when restricting to grade 2+ LVSD, but more pronounced for OS (HR 1.80, 95% CI 1.38, 2.34). A subset of 389 patients (23% suffered grade 2+ LVSD) were treated at PHIS hospitals and contributed to RU analyses. Cardiotoxicity was associated with greater cardiac ICU requirements, increased use of cardiac-directed interventions including antihypertensives, vasopressors, and heart failure medications, and reduced cardioprotection (Table 2). Conclusions: Echo compliance and cardiotoxicity rates were higher than previously described due in part to more frequent echoes and required reporting of raw echo results. Approximately 20% of pediatric AML patients on AAML1031 developed grade 2+ LVSD, only half of whom had documented resolution of LVSD. Dexrazoxane was strongly associated with reduced LVSD risk and potentially superior recovery. Our results offer further evidence that early cardiotoxicity decreases EFS/OS and that cumulative anthracycline dose is the principal predictor of LVSD. These data argue for comparative effectiveness studies of cardiac-directed interventions after LVSD, and identification of clinical and genetic risk factors for anthracycline cardiotoxicity and its recovery. Such studies may allow for anthracycline de-escalation in select patient populations. Work is ongoing to inform optimal supportive care practices for patients with LVSD using clinical data merged with PHIS. Disclosures Leger: Abbott: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BTG Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Impact of Competing Treatment Scenarios on Lifetime Disease Burden and Quality Adjusted Life Expectancy (QALE) Among Survivors of High-Risk Childhood Hodgkin Lymphoma (HR-HL): A Modeling Study Based on the St. Jude Lifetime (SJLIFE) Cohort

Background: Children and young adults diagnosed with HR-HL have a 5-year survival rate of &amp;gt;95%. Yet, as compared to the general population, survivors remain at elevated risk for therapy-related early mortality and excess long-term morbidity. Second malignancies (SMNs), cardiac disease, and pulmonary complications are major contributors to excess mortality/morbidity experienced by survivors of HL. Since several treatment regimens used for younger HR-HL all offer excellent overall survival and tolerable short-term morbidity profiles, it is not clear which is best. The objective of this study was to compare the life-long impact of treatment-related toxicity and early mortality associated with 4 common treatment scenarios used to treat HR-HL. Outcomes measured included overall life expectancy (LE), 10-year post-diagnosis QALE and cause of death. Methods: A microsimulation model was developed using the lifetime horizon for a cohort of 10-year survivors of HR-HL treated with 4 common treatment scenarios utilized by pediatric and adult oncology groups. The data from 5522 adult 10-year survivors of childhood cancers in the SJLIFE cohort (56% males; mean age at last follow-up=35.3 years [y], range 18.9-67.9; ≥18y at study enrollment) was used to estimate the mortality risk and incidence of cardiac and pulmonary complications and SMNs as functions of age at primary cancer diagnosis, attained age, sex, race, and treatment exposures including cumulative doses of anthracyclines, alkylating agents, and bleomycin plus radiation dose to the heart and chest. Prospective and retrospective clinical assessments were used to obtain and grade late-effect outcomes using a modified Common Terminology Criteria for Adverse Events. Rates from population-based registries and published systematic analyses were used for background mortality, mortality risk from the complications and for extrapolation. Calibration was performed against SJLIFE data to ensure model consistency. Quality of life utility weights (ranging from 1 for perfect health to 0 for dead) associated with complications were estimated from the SJLIFE cohort. The mortality and incidence functions and utility weights were applied to the lifetime of 10,000 simulated HL survivors (same demographic distribution as in the 667 SJLIFE HL participants: 58% males; mean age at HL diagnosis=13.9y, range 3-25) starting at 10y after HL diagnosis to death to calculate the average LE and QALE associated with the 4 treatment scenarios. Results: The figure shows the results for 4 scenarios based on OEPA [vincristine, etoposide, prednisone, doxorubicin] (2 cycles) plus COPDac [cyclophosphamide, vincristine, prednisone, dacarbazine] (4 cycles) and ABVD [doxorubicin, bleomycin, vincristine, dacarbazine] (6 cycles), both with and without heart and chest radiation. The average LE for the cohort assuming general population mortality risk is 80.8y (dashed line). Average LEs associated with the 4 scenarios are represented by the asterix above each bar. The average 10-year post-diagnosis QALE and the proportion of time spent living with cardiac, pulmonary and/or SMN are depicted in the colored stacked bar-chart. The decrement in average LE due to treatment for HR-HL ranged from 12.8y for OEPA/COPDac alone to 25.8y for ABVD with radiation. OEPA/COPDac based regimens without and with radiation had higher average LE (68.1y and 64.1y, respectively) and QALE (29.9y and 27.4y, respectively) compared to the ABVD regimens (LE: 60.9y and 55.0y; QALE: 25.0y and 22.7y). The addition of radiation reduced average LE and QALE in both the OEPA/COPDac (4.0y and 2.5y) and ABVD (5.8y and 2.3y) regimens and increased the proportion of the cohort who developed pulmonary disease and SMNs for all scenarios. The cohort receiving OEPA/COPDac with radiation had similar average post-10 year QALE compared to those treated with ABVD without radiation. Increased proportional mortality due to SMN was observed among the cohort exposed to ABVD. Conclusion: Using a lifetime horizon simulation approach, we demonstrate that the OEPA/COPDac regimen results in greater average LE and QALE when compared against ABVD for HR-HL. This approach highlights a yet untapped opportunity to leverage data from survivorship cohorts by evaluating late-effect trade-offs to inform clinical trial design and aid patient decision-making when choosing between different treatment options that have similar efficacy. Disclosures No relevant conflicts of interest to declare.

Heart failure after treatment for breast cancer.

BackgroundWe aimed to develop dose–response relationships for heart failure (HF) following radiation and anthracyclines in breast cancer treatment, and to assess HF associations with trastuzumab and endocrine therapies.Methods and resultsA case–control study was performed within a cohort of breast cancer survivors treated during 1980–2009. Cases (n = 102) had HF as first cardiovascular diagnosis and were matched 1:3 on age and date of diagnosis. Individual cardiac radiation doses were estimated, and anthracycline doses and use of trastuzumab and endocrine therapy were abstracted from oncology notes. For HF cases who received radiotherapy, the estimated median mean heart dose (MHD) was 6.8 Gy [interquartile range (IQR) 0.9–13.7]. MHD was not associated with HF risk overall [excess rate ratio (ERR) = 1%/Gy, 95% confidence interval (CI) −2 to 10]. In patients treated with anthracyclines, exposure of ≥20% of the heart to ≥20 Gy was associated with a rate ratio of 5.7 (95% CI 1.7–21.7) compared to <10% exposed to ≥20 Gy. For cases who received radiotherapy, median cumulative anthracycline dose was 247 mg/m2 (IQR 240–319). A dose‐dependent increase was observed after anthracycline without trastuzumab (ERR = 1.5% per mg/m2, 95% CI 0.5–4.1). After anthracycline and trastuzumab, the rate ratio was 34.9 (95% CI 11.1–110.1) compared to no chemotherapy.ConclusionsIn absence of anthracyclines, breast cancer radiotherapy was not associated with increased HF risk. Strongly elevated HF risks were observed after treatment with anthracyclines and also after treatment with trastuzumab. The benefits of these systemic treatments usually exceed the risks of HF, but our results emphasize the need to support ongoing efforts to evaluate preventative strategies.

Myocardial dysfunction in long-term breast cancer survivors treated at ages 40-50 years.

AimsAnthracyclines increase heart failure (HF) risk, but the long‐term prevalence of myocardial dysfunction in young breast cancer (BC) survivors is unknown. Early measures of left ventricular myocardial dysfunction are needed to identify BC patients at risk of symptomatic HF.Methods and resultsWithin an established cohort, we studied markers for myocardial dysfunction among 569 women, who were 5–7 years (n = 277) or 10–12 years (n = 292) after BC treatment at ages 40–50 years. Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were assessed by echocardiography. N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) was measured in serum. Associations between patient‐related and treatment‐related risk factors and myocardial dysfunction were evaluated using linear and logistic regression. Median ages at BC diagnosis and cardiac assessment were 46.7 and 55.5 years, respectively. Anthracycline‐treated patients (n = 313), compared to the no‐anthracycline group (n = 256), more often had decreased LVEF (10% vs. 4%), impaired GLS (34% vs. 27%) and elevated NT‐proBNP (23% vs. 8%). GLS and LVEF declined in a linear fashion with increasing cumulative anthracycline dose (GLS: +0.23 and LVEF: −0.40 per cycle of 60 mg/m2; P < 0.001) and GLS was worse for patients with left breast irradiation. The risk of NT‐proBNP >125 ng/L was highest for patients who received 241–300 mg/m2 anthracycline dose compared to the no‐anthracycline group (odds ratio: 3.30, 95% confidence interval: 1.83–5.96).ConclusionImpaired GLS and increased NT‐proBNP levels are present in a substantial proportion of young BC survivors treated with anthracyclines. Whether this will lead to future cardiac disease needs to be evaluated by longitudinal assessment.

Association of Breast Cancer Risk After Childhood Cancer With Radiation Dose to the Breast and Anthracycline Use

Chest irradiation for childhood cancer is associated with increases in breast cancer risk. Growing evidence suggests that anthracyclines increase this risk, but the outcome of combined anthracycline use and radiotherapy has not been studied. To evaluate breast cancer risk in childhood cancer survivors following radiotherapy and chemotherapy and assess whether risks varied by estrogen receptor (ER) status. In a North American hospital-based nested case-control study, a retrospective cohort of 14 358 five-year survivors of childhood cancer, diagnosed from 1970 to 1986 and followed up through December 31, 2016, was analyzed. Cases (n = 271) were defined as women with subsequent breast cancer. Controls (n = 1044) were matched 4:1 to cases by age at first cancer and duration of follow-up (± 2 years). Data analysis was conducted from September 2017 to July 2018. Radiation dose to breast tumor site and ovaries and cumulative chemotherapy doses, including anthracyclines and alkylating agents. Odds ratios (ORs) for subsequent breast cancer by ER status. A total of 271 women served as breast cancer cases (median age at first cancer diagnosis, 15 years [range, 3-20]; median age at breast cancer diagnosis, 39 years [range, 20-57]): 201 invasive (113 ER positive [ER+], 41 ER negative [ER-], and 47 unknown) and 70 in situ breast cancers. The OR for breast cancer increased with increasing radiation dose to the breast (OR per 10 Gy, 3.9; 95% CI, 2.5-6.5) and was similar for ER+ (OR per 10 Gy, 5.5; 95% CI, 2.8-12.6) and ER- (OR per 10 Gy, 4.8; 95% CI, 1.7-22.3) cancers. For women who received ovarian doses less than 1 Gy, the OR per 10 Gy to the breast was higher (OR, 6.8; 95% CI, 3.9-12.5) than for women who received ovarian doses greater than or equal to 15 Gy (OR, 1.4; 95% CI, 1.0-6.4). The OR for breast cancer increased with cumulative anthracycline dose (OR per 100 mg/m2, 1.23; 95% CI, 1.09-1.39; P < .01 for trend), and was 1.49 (95% CI, 1.21-1.83) for ER+ cancer vs 1.10 (95% CI, 0.84-1.45) for ER- cancers (P value for heterogeneity = .47). There was an additive interaction between radiotherapy and anthracycline treatment (P = .04) with the OR for the combined association between anthracycline therapy and breast radiation dose of 10 Gy or more (compared with 0 to less than 1 Gy) of 19.1 (95% CI, 7.6-48.0) vs 9.6 (95% CI, 4.4-20.7) without anthracycline use. This study provides the first evidence to date that the combination of anthracyclines and radiotherapy may increase breast cancer risks compared with use of neither treatment with a similar radiation dose response for ER+ and ER- cancers and possibly higher anthracycline risks for ER+ cancers. These results might help inform surveillance guidelines for childhood cancer survivors.

P674Behavior of 2D and 3D derived ejection fraction and strain in patients with Hodgkin and non-Hodgkin lymphoma undergoing anthracycline-based chemotherapy, a prospective study

Abstract Background Anthracyclines are one of the most effective chemotherapeutic agents but can lead to a decline in cardiac function. Two-dimensional (2D) speckle tracking echocardiography derived strain can predict cancer therapeutics-related cardiac dysfunction (CTRCD). However, little is known about the role of three-dimensional (3D) strain imaging in this setting. Purpose To evaluate different methods of Left Ventricular Ejection Fraction (LVEF) and strain, and to identify the best strain parameter for the prediction of CTRCD in this group of patients during treatment with anthracycline based chemotherapy. Methods Patients with Hodgkin's or non-Hodgkin's lymphoma receiving anthracycline based chemotherapy were enrolled. 2D-and 3D echocardiography was performed at 3 time points: baseline, at the completion of chemotherapy and at 1 year. 2D- and 3D LVEF (2D Modified Quinones, M-mode, 2D Biplane, 3D Philips, 3D GE and 3D TomTec), peak systolic left and right ventricular longitudinal, radial and circumferential strain and strain rate were measured. CTRCD was defined as a decrease in LVEF &gt;10% to an absolute value of &lt;53%. Lin's Concordance Correlation Coefficient (CCC) was calculated to compare LVEF methods. ANOVA, uni and multivariate analysis was performed. Results A total of 130 patients (79 males, mean age 57±16 years) were enrolled; 104 non-Hodgkin.3D Philips and GE (CCC 0.88 [0.84, 0.92]), 3D Philips and biplane (CCC 0.84 [0.79, 0.89]), 3D Philips and Modified Quinones (CCC 0.86 [0.82, 091]) as well as 3D Philips and M-mode (CCC 0.77 [0.70, 0.85]) showed strong correlation for LVEF. 15 patients (12%) developed CTRCD. Mean cumulative anthracycline dose was 263±65 mg/m2. 2D and 3D global longitudinal and circumferential peak systolic strain, 2D global longitudinal systolic and early diastolic strain rate, 2D global early diastolic strain rate, 2D right ventricular longitudinal peak systolic strain and systolic strain rate, 2D global radial peak systolic strain and systolic strain rate measured at the completion of chemotherapy were independent predictors of the development of CTRCD at 1 year post-chemotherapy. The strongest predictors of CTRCD were 3D global longitudinal and circumferential strain either individually (area under the curve, 0.90 and 0.95 respectively) or combined (area under the curve, 0.95) at the completion of chemotherapy; a cutoff value of &lt;-18% in 3D global longitudinal strain had a sensitivity of 82% and specificity of 99%, while for 3D global circumferential peak systolic strain of &lt;-24% had a sensitivity of 82% and specificity of 95%. Conclusions To our knowledge this is the first prospective trial that shows that 3D EF correlates well with other EF methods and 3D strain predicts cardiac toxicity in this group of patients with a very good sensitivity and specificity. Acknowledgement/Funding Department of Cardiovascular Medicine-Mayo Clinic Rochester MN

Evaluation of cardiomyopathy in acute myeloid leukemia patients treated with anthracyclines

Acute myeloid leukemia patients receive anthracycline-containing induction chemotherapy. Anthracyclines cause cardiotoxicity; however, there is a paucity of data reflecting the risk of cardiotoxicity in the acute myeloid leukemia population, and risk factors for development of reduced left ventricular ejection fraction are not well established in this population. A retrospective cohort study of adult acute myeloid leukemia patients receiving anthracycline-containing induction chemotherapy between March 2011 and August 2017 was performed. Baseline and all additional cardiac monitoring within one year of induction were collected. Home medications and new medication initiation were determined via the electronic health record and new outpatient prescriptions. Of 97 evaluable patients, 25 (25.8%) developed reduced left ventricular ejection fraction and 18 (18.6%) experienced clinical heart failure within one year of induction. The median difference from baseline to lowest left ventricular ejection fraction was -5.0 percentage points, with a range of +10.0 to -52.5. The median time to onset of reduced left ventricular ejection fraction was 27 days, at a median cumulative anthracycline dose of 270 mg/m2. No patient-specific or medication-specific factors were significantly associated with the risk of developing reduced left ventricular ejection fraction. Of 14 patients started on medical management for reduced left ventricular ejection fraction, 10 (71%) responded to therapy. In this retrospective analysis, we observed that acute myeloid leukemia patients experienced reduced left ventricular ejection fraction more quickly and at lower doses than previously reported in the solid tumor population. Reduced left ventricular ejection fraction was at least partially reversible in most patients started on medical management. Although no factors were significantly associated with decreased cardiomyopathy risk, future assessment of cardioprotective medications may be warranted.

Critical Illness and Cardiac Dysfunction in Anthracycline-Exposed Pediatric Oncology Patients.

To determine if the presence of cardiac dysfunction in anthracycline-exposed pediatric oncology patients is associated with an increased frequency of PICU admission or mortality. Retrospective parallel cohort study. PICU at an academic freestanding children's hospital. Children with oncologic diagnoses who received anthracyclines between January 2006 and December 2014 and were admitted to the hospital within 1 year of completion of therapy. None. Charts of 734 patients were reviewed and 545 were included in analysis. Anthracycline-exposed pediatric oncology patients with cardiac dysfunction were more likely to be admitted to the PICU than those without cardiac dysfunction (87% vs 37% rate of PICU admission). PICU admission was also associated with identified infection and higher cumulative anthracycline dose. Once admitted to the PICU, those anthracycline-exposed patients with cardiac dysfunction had significantly higher mortality (26% vs 6%) and longer length of stay (7 vs 2 d) than children without cardiac dysfunction. Patients with cardiac dysfunction were more likely to require mechanical ventilation (59% vs 18%), required more vasoactive medications for longer, and were more likely to develop fluid overload. Death within 1 year of ICU admission was associated with higher cumulative anthracycline dose. Children with cancer who received anthracyclines, especially at higher doses, and who develop cardiac dysfunction are at higher risk of critical illness, have higher rates of multiple organ dysfunction and higher rates of mortality than anthracycline-exposed patients without cardiac dysfunction.

Combined effect of radiotherapy and anthracyclines on risk of breast cancer among female childhood cancer survivors: A report from the Childhood Cancer Survivor Study (CCSS).

10053 Background: Breast cancer is a common late-effect for female childhood cancer survivors and chest radiotherapy is an established risk factor. Recent findings showed that treatment with anthracyclines also increases breast cancer risk. However, the risk from the combined effect of radiotherapy and anthracyclines is unknown. Methods: We conducted a matched case-control study of 271 subsequent breast cancer and 1044 controls nested within the CCSS - a North-American cohort of five-year survivors of childhood cancer, diagnosed from 1970-1986 and followed-up through 2016. Detailed treatment records were abstracted to estimate radiation dose (Gy) to the breast cancer location and ovaries and calculate cumulative chemotherapy doses (mg/m2). Multivariable conditional logistic regression was used to estimate Odds ratios (OR) and 95% confidence intervals (CI). Results: Breast cancer risk increased linearly with radiation dose to the breast (OR per 10Gy = 3.9, 95%CI:2.5-6.5) and decreased with increasing ovarian dose (p &lt; 0.01). Adjusted for radiation dose, the highest quartile of dose (455+mg/m2) of anthracyclines was associated with a 3.8-fold increased risk of breast cancer (95%CI:1.8-8.2) compared to no anthracyclines. This risk increased with cumulative anthracycline dose (p-trend &lt; 0.01) and was non-significantly higher for ER+ than ER- breast cancers. For a breast dose of 10+Gy, the OR was 19.1 (95%CI:7.6-48.0) with anthracyclines versus 9.6 (95%CI:4.4-20.7) without anthracyclines, compared to 0- &lt; 1Gy breast dose and no anthracyclines (p-additive interaction = 0.04). Conclusions: The combination of anthracyclines and radiotherapy doses to the breast can markedly increase breast cancer risk compared to those who receive neither treatment. Our results can be used to inform risk management for childhood cancer patients treated in the past, as well as project potential breast cancer risk from current treatment protocols.

Risk prediction model for long-term heart failure incidence after epirubicin chemotherapy for breast cancer – A real-world data-based, nationwide classification analysis

BackgroundDilated cardiomyopathy (DCM) incidence during and after anthracycline therapy is highly dependent on anthracycline cumulative dose (CD), but its detailed risk factors remained unexplored. Our aim was to assess heart failure (HF) incidence after epirubicin therapy and construct a HF risk-prediction score. Methods and resultsA retrospective study was conducted by anonymized integration of nationwide healthcare databases. All the analysed patients were diagnosed with breast carcinoma confirmed by histology from 2007 to 2016. Participants did not undergo chemo- or radiotherapy or suffer HF/DCM during the preceding 3 years. The HF endpoint was established by assignment of I50 International Classification of Diseases (ICD) codes upon discharge from hospital or issuance of an autopsy report. 8068 patients treated with epirubicin were analysed. The 3–10-year HF cumulative incidence was 6.9%. Using binomial logistic regression the independent predictors were identified. A CD-dependent and significant effect on HF was revealed for epirubicin (threshold dose: 709 mg/m2, odds ratio (OR): 1.76) and docetaxel (CD: >510 mg/m2, OR: 1.59; CD ≤510 mg/m2, OR: 1.28, respectively). HF risk increased with age, even over 40. A risk-prediction score derived from regression coefficients consisting of age, diabetes mellitus, hypertension, coronary artery disease, stroke, epirubicin CD, docetaxel CD, capecitabine, gemcitabine, bevacizumab and cancer stage was able to classify HF risk over a wide range (2–30%). ConclusionLong-term HF risk for patients treated with epirubicin was stratified by our risk-prediction score with a nearly 15-fold difference between the lowest and highest groups.

Cardioprotective effect of renin-angiotensin inhibitors and β-blockers in trastuzumab-related cardiotoxicity.

Trastuzumab-related cardiotoxicity (TRC) has been considered as reversible. However, recent studies have raised concern against reversibility of left ventricular (LV) systolic dysfunction in breast cancer patients treated with trastuzumab. In addition, the efficacy of medical treatment for heart failure (HF) including renin-angiotensin inhibitors and β-blockers has not been defined in TRC. We retrospectively studied 160 patients with breast cancer receiving trastuzumab in the adjuvant (n = 129) as well as metastatic (n = 31) settings in our institution from 2006 to 2015. During the median follow-up of 3.5years, 20 patients (15.5%) receiving adjuvant trastuzumab and 7 patients (22.6%) with metastatic breast cancer developed TRC with a mean decrease in LV ejection fraction (EF) of 19.8%. By the multivariate analysis, lower LVEF before trastuzumab (OR 1.30; 95% CI 1.16-1.48; P = 0.0001) independently predicted subsequent development of TRC. LV systolic dysfunction was reversible in 20 patients (74.1%) with a median time to recovery of 7months, which was independently associated with lower dose of anthracyclines (OR 1.03; 95% CI 1.01-1.07, P = 0.020) and an introduction of renin-angiotensin inhibitors and β-blockers (OR 19.0; 95% CI 1.00-592.2, P = 0.034). Irreversible decline in LVEF occurred in patients who underwent trastuzumab in combination with anthracyclines with a relatively high frequency. The lower cumulative dose of anthracyclines and HF treatment including renin-angiotensin inhibitors and β-blockers were both independent predictors to enhance LV functional reversibility in patients with TRC.

Attenuation of doxorubicin-induced cardiotoxicity in a human in vitro cardiac model by the induction of the NRF-2 pathway

Dose-dependent cardiotoxicity is the leading adverse reaction seen in cancer patients treated with doxorubicin. Currently, dexrazoxane is the only approved drug that can partially protect against this toxicity in patients, however, its administration is restricted to those patients receiving a high cumulative dose of anthracyclines. Investigations into the mechanisms of cardiotoxicity and efforts to improve cardioprotective strategies have been hindered by the limited availability of a phenotypically relevant in vitro adult human cardiac model system. Here, we adapted a readily reproducible, functional 3D human multi-cell type cardiac system to emulate patient responses seen with doxorubicin and dexrazoxane. We show that administration of two NRF2 gene inducers namely the semi-synthetic triterpenoid Bardoxolone methyl, and the isothiocyanate sulfurophane, result in cardioprotection against doxorubicin toxicity comparable to dexrazoxane as evidenced by an increase in cell viability and a decrease in the production of reactive oxygen species. We further show a synergistic attenuation of cardiotoxicity when the NRF2 inducers and dexrazoxane are used in tandem. Taken together, our data indicate that the 3D spheroid is a suitable model to investigate drug induced cardiotoxicity and we reveal an essential role of the NRF2 pathway in cardioprotection providing a novel pharmacological mechanism and intervention route towards the alleviation of doxorubicin-induced toxicity.