Cumulative Dose Of Doxorubicin Research Articles

Early doxorubicin cardiotoxicity in Malawian children admitted to Queen Elizabeth Central Hospital, Malawi.

Doxorubicin is known to cause chemotherapy-induced cardiotoxicity. In resource-poor settings, monitoring for cardiotoxicity is not routinely done, and its incidence is unknown. The aim of this study was to determine the proportion of children who developed doxorubicin-induced cardiotoxicity within 1year of having received treatment at paediatric oncology ward. Children aged 3months to 18years with cancer were prospectively enrolled and followed up between January 2016 to June 2019. Transthoracic echocardiogram was done at baseline, 1month, 6months and a year after completion of therapy. Cardiotoxicity was defined as a decline in left ventricular ejection fraction (LVEF) of ≥10% to a final value of <50%. An overall incidence risk of developing cardiotoxicity was estimated. A one-way analysis of variance (ANOVA) was conducted to compare baseline LVEF with follow-up measurements. Ninety-one children were enrolled, 74% (68/91) were male, and 67% (62/91) were aged 5months to 14years. Most patients received a doxorubicin cumulative dose between 100 and 200mg/m2 and no cardiotoxicity was observed during the study period. However, of 77 children with at least one follow up, five children 6.54% (95% CI: 2.1-14.5) experienced LVEF reduction of >10%, though not to a final value of <50%. No deterioration of systolic function was found among 20 children who completed follow-up (F=2.43, p-value=.07). In this cohort of patients, most received a low cumulative doxorubicin dose and only 22% were available for evaluation at study end; no cardiotoxic events associated with doxorubicin administration were observed after 12months.

Coronary microcirculation damage in anthracycline cardiotoxicity.

AimsThe aim of this study was to study changes in coronary microcirculation status during and after several cycles of anthracycline treatment.Methods and resultsLarge-white male pigs (n=40) were included in different experimental protocols (ExPr.) according to anthracycline cumulative exposure [0.45 mg/kg intracoronary (IC) doxorubicin per injection] and follow-up: control (no doxorubicin); single injection and sacrifice either at 48 h (ExPr. 1) or 2 weeks (ExPr. 2); 3 injections 2 weeks apart (low cumulative dose) and sacrifice either 2 weeks (ExPr. 3) or 12 weeks (ExPr. 4) after third injection; five injections 2 weeks apart (high cumulative dose) and sacrifice 8 weeks after fifth injection (ExPr. 5). All groups were assessed by serial cardiac magnetic resonance (CMR) to quantify perfusion and invasive measurement of coronary flow reserve (CFR). At the end of each protocol, animals were sacrificed for ex vivo analyses. Vascular function was further evaluated by myography in explanted coronary arteries of pigs undergoing ExPr. 3 and controls. A single doxorubicin injection had no impact on microcirculation status, excluding a direct chemical toxicity. A series of five fortnightly doxorubicin injections (high cumulative dose) triggered a progressive decline in microcirculation status, evidenced by reduced CMR-based myocardial perfusion and CFR-measured impaired functional microcirculation. In the high cumulative dose regime (ExPr. 5), microcirculation changes appeared long before any contractile defect became apparent. Low cumulative doxorubicin dose (three bi-weekly injections) was not associated with any contractile defect across long-term follow-up, but provoked persistent microcirculation damage, evident soon after third dose injection. Histological and myograph evaluations confirmed structural damage to arteries of all calibres even in animals undergoing low cumulative dose regimes. Conversely, arteriole damage and capillary bed alteration occurred only after high cumulative dose regime.ConclusionSerial in vivo evaluations of microcirculation status using state-of-the-art CMR and invasive CFR show that anthracyclines treatment is associated with progressive and irreversible damage to the microcirculation. This long-persisting damage is present even in low cumulative dose regimes, which are not associated with cardiac contractile deficits. Microcirculation damage might explain some of the increased incidence of cardiovascular events in cancer survivors who received anthracyclines without showing cardiac contractile defects.

Electromechanical changes of the myocardium after anthracycline chemotherapy

Abstract Funding Acknowledgements Type of funding sources: None. Background and objectives The most common side effects of chemotherapeutics in breast cancer is on the cardiovascular system. Global longitudinal strain (GLS) is the only parameter recommended for follow-up in current guidelines with limited evidence. Other strain imaging parameters and electrical changes after chemotherapy is not well studied. It is not known whether electrical or mechanical changes occur initially. The aim of this study is to evaluate repolarization parameters on ECG and mechanical changes together after chemotherapy in breast cancer patients. Subjects and method Consecutive patients who received chemotherapy due to breast cancer were included. Strain echocardiography and ECGs were performed pre-treatment (T0) and 3rd month after chemotherapy (T2). Additionally, just in three hours of first dose of chemotherapy (T1) another ECG was performed. QT and QT correction for heart rate (QTc), QT dispersion (QT disp) and QTc dispersion (QTc disp), T wave peak to end time (Tpe) and Tpe corrected for QT-QTc measurements were performed (figüre 1 and 2). GLS, longitudinal strain for myocardial layers, circumferential strain (CS), radial strain (RS) and torsion measurements were performed. All mechanical and electrical parameters from different time intervals were compared. Results Thirty-five consecutive patients (35 females, mean age 48.9 ± 11.8 years) who received chemotherapy (mean doxorubicin cumulative dose 415 ± 32 mg/m2) due to breast cancer were included. There was no significant change in mean GLS values before and after treatment (T0 -%18.8 ± 6.82, T1 18.6 ± 3.5 p = 0,863 respectively). However, there was a significant decrease in CS, RS and torsion (T0 -%17,2 ± 3,5, T1-%13 ± 2,84 p &amp;lt;0,001, T0 %45,1 ± 8,3, T1 %35,6 ±10 p &amp;lt;0,001 and T0 %12,1 ± 3.5, T1 %7.7 ± 2.1 p &amp;lt;0,001, respectively). QT, QTc, QTc disp and Tpe, Tpe/QTc parameters were prolonged just after chemotherapy and were still prolonged 3 months after ((QTc: T1 440.01 ± 27.63, T2 468.00 ± 38.98, T3 467.86 ± 35.09), (QTc disp T1 55.48 ± 20.22, T2 78.59 ± 16.15, T3 66.16 ± 14.62), (Tpe (QTc) T1 104 ± 18.52, T2 148.62 ± 19.16, T3 139.77 ± 21.63), (Tpe/QTc T1 0.213 ± 0.05, T2 0.281 ± 0.08, T3 0.258 ± 0.06). Conclusion Electrical and mechanical functions of the heart could be impaired together acutely even three months after doxorubicin chemotherapy. Cardio toxicity should be evaluated in terms of both electrically and mechanically. Abstract Figure. ECG repolarization parameters

High cumulative doxorubicin dose for advanced soft tissue sarcoma

BackgroundThe recommended cumulative doxorubicin dose in soft tissue sarcoma (STS) treatment was based on cardiotoxicity data from retrospective studies of breast cancer patients. However, the treatment and prognosis of STS and breast cancer are quite different, and reference to breast cancer data alone may not reflect the efficacy of doxorubicin treatment in STS. This study, thus, aimed to review and analyze clinical data of STS patients treated with a high cumulative doxorubicin dose, to provide a reference for treatment selection and clinical trial design.MethodsWe retrospectively collected and analyzed clinical data of patients with advanced STS who received doxorubicin-based chemotherapy from January 2016 to January 2020. The patients were divided into a standard-dose group (who received ≤6 cycles of doxorubicin after the initial diagnosis) and an over-dose group (who were re-administered doxorubicin [doxorubicin-rechallenge] after receiving 6 cycles of doxorubicin therapy discontinuously). Patient characteristics, cumulative doxorubicin dose, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), cardiotoxicity incidence, and treatment effectiveness were evaluated in both groups.ResultsA total of 170 patients with advanced STS were recruited (146 in the standard-dose group and 24 in the over-dose group). The average cumulative doxorubicin dose was 364.04 ± 63.81 mg/m2 in the standard-dose group and 714.38 ± 210.09 mg/m2 in the over-dose group. The ORR, DCR, and median PFS were 15.07, 58.9%, and 6 (95% confidence interval [CI]: 5.8–6.5) months in the standard-dose group and 16.67, 66.67%, and 4 (95%CI: 2.0–5.8) months in the over-dose group, respectively. Symptomatic heart failure occurred in five patients (3.42%) of the standard-dose group and in one patient (4.17%) of the over-dose group. In these patients with cardiotoxicity, doxorubicin was discontinued, and all of them died of uncontrolled tumor growth. No drug-related deaths occurred.ConclusionsThe continuation of or rechallenge with doxorubicin beyond the recommended cumulative dose could be a promising therapeutic option in the treatment of chemotherapy-sensitive advanced sarcomas. Further evaluation is necessary in prospective trials.

Abstract 16119: Dexrazoxane Role in the Prevention of Anthracycline Cardiotoxicity in Sarcoma Patients - A Meta-analysis

Introduction: Cardiotoxic side effects limit anthracycline use. Dexrazoxane has been proved cardioprotective in the setting of low-dose exposure, but its value in young sarcoma patients, who are treated with higher doses, remains elusive. Purpose: To perform a meta-analysis in order to appraise the efficacy and safety of dexrazoxane in sarcoma patients managed with anthracyclines. Methods: We systematically searched Embase, MEDLINE, Web of Science, Cochrane CENTRAL and Google Scholar databases, using the terms “sarcoma”, “anthracycline” and “dexrazoxane”, from inception to June 1, 2020. Studies targeting cardiotoxicity, primary cancer outcome (suboptimal response to treatment, disease progression and oncologic death), secondary malignancy and mortality were selected. The primary endpoint was a composite of heart failure, ventricular arrhythmias and left ventricular systolic deterioration. Therapeutic arms were those of dexrazoxane and no drug or placebo. A random-effects model with Mantel-Haenszel method was used to calculate pooled odds ratios (OR) or mean differences (MD) and their 95% confidence interval (CI). Results: We encompassed 11 studies, of which 5 were prospective. 9 studies were conducted in children and doxorubicin was the most represented anthracycline. 1574 patients were included, of whom 679 were under dexrazoxane. There were 73 primary endpoint events, 21 secondary malignant neoplasms and 29 deaths. Cumulative doxorubicin dose was higher in the dexrazoxane arm (MD 70.66mg/m2, 95% CI 46.43-94.89, i 2 24%). Nevertheless, this agent reduced the odds of the primary endpoint (OR 0.37, 95% CI 0.20-0.71, i 2 11%), as well as numerically decreased acute heart failure events (OR 0.15, 95% CI 0.02-1.09, i 2 0%) and significantly halted left ventricular ejection fraction deterioration (MD 5.25%, 95% CI 1.98-8.53, i 2 26%). On the other hand, primary cancer outcome and risk of secondary malignancy did not differ between the two arms (OR 1, 95% CI 0.47-2.15, i 2 0% and OR 0.98, 95% CI 0.39-2.47, i 2 0%, respectively). Likewise, all-cause mortality was similar (OR 1.65, 95% CI 0.68-4.00, i 2 0%). Conclusion: Dexrazoxane seems to maintain its efficacy and safety in young sarcoma patients managed with high-dose anthracyclines.

Abstract 14613: Preclinical Animal Model of Doxorubicin-induced Left Ventricular Dysfunction: Echocardiography and Pressure-volume Analysis

Introduction: There is a need to implement a preclinical model in addition to the well established ischemic or volume-overload models that would mimic the clinical course of patients with chemotherapy-induced heart failure. Doxorubicin is an anthracycline chemotherapeutic that is widely used in oncology, although its cardiotoxicity. Hypothesis: Doxorubicin-induced left ventricular dysfunction in rats fulfills echocardiography and hemodynamic characteristics of chemotherapy-induced heart failure. Methods: We randomly assigned Ren-2 transgenic hypertensive (TGR, n = 17) and normotensive rats (HanSD, n = 22), at the age of 8 weeks to doxorubicin (2.5 mg/kg in 0.5 ml of normal saline) or placebo in 6 intraperitoneal doses within two weeks (cumulative doxorubicin dose 15 mg/kg). Two weeks later, we performed echocardiography study, pressure-volume analysis (PV), and we weighed the organs. Results: In doxorubicin groups, there was a decrease in the left ventricle weight (1,22 vs. 0,85 g in TGR), while an increase in wall stress (22036 vs. 29754 μL*mmHg/g in TGR). Echocardiography suggested heart remodeling with a decrease in relative wall thickness - RWT (1.02 vs. 0.65 mm in TGR), and together with PV analysis showed a decrease in systolic parameters - left ventricle ejection fraction - LVEF (71.41 vs. 59.96 % in TGR), end-systolic pressure-volume ratio - ESPVR (0.82 vs. 0.45 mmHg/uL in TGR) and preload recruitable stroke work - PRSW (75.71 vs. 60.98 mmHg in TGR). Ventricular-arterial coupling (VAC = Ea/Ees, a measure of cardiac efficiency) was worsened in the doxorubicin groups (1.69 vs. 2.52 in TGR). For all the above p &lt; 0.05, in HanSD, the results were similar (all p &lt; 0.05). Conclusions: Our results suggest that systolic dysfunction and decrease of cardiac efficiency in this model could be caused by heart atrophy, and such an animal model could potentially be an easily reproducible model of chemotherapy-induced heart failure in preclinical cardio-oncology studies.

Safety and Efficacy of Mitoxantrone Hydrochloride Liposome in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma and Extranodal NK/T-Cell Lymphoma: A Prospective, Single-Arm, Open-Label, Multi-Center, Phase II Clinical Trial

Background: Peripheral T cell lymphoma (PTCL) and Extranodal NK/T cell lymphoma (ENKTCL) are rare types of non-Hodgkin's lymphoma (NHL), with a higher incidence in Asian countries. Outcomes for patients with relapsed or refractory (R/R) PTCL and ENKTCL are very poor. There is still a lack of effective treatment for these patients. Mitoxantrone is a synthetic anthracenedione anti-cancer drug that is effective in lymphoma, leukemia, and other solid tumors. Liposome preparations have shown higher anti-tumor effect and lower toxicities due to modified drug release and particle shape. Mitoxantrone hydrochloride liposome (PLM60) was manufactured by Shijiazhuang Pharmaceutical Group Co., Ltd. (CSPC). High accumulation in tumor tissue was a key characteristic of PLM60 in our preclinical investigation. The pharmacokinetic parameters, especially half-life of PLM60 was prolonged significantly in phase Ⅰ trial. Phase II exploratory clinical trial showed promising results in R/R PTCL. Therefore, we conducted this pivotal registration phase II trial to evaluate the efficacy and safety of PLM60 in patients with R/R PTCL and ENKTCL. At the present time, this was the first clinical trial to assess PLM60 in treating R/R PTCL and ENKTCL worldwide. Methods : This was a prospective, single-arm, open-label, multi-center, phase II clinical trial. Adult patients with histologically confirmed PTCL (mainly peripheral T cell lymphoma, NOS, PTCL-NOS; angioimmunoblastic T-cell lymphoma, AITL; anaplastic large cell lymphoma, ALCL) after prior anthracyclines-based chemotherapy or ENKTCL failed from asparaginase-contained regimen, ECOG performance status ≤ 1, adequate organ function and bone marrow function, and at least one measurable or evaluable lesion were recruited in this trial. Main exclusion criteria were patients with a cumulative dose of doxorubicin &amp;gt;360 mg/m2, known history of a clinically significant cardiac malfunction or uncontrollable cardiovascular diseases. PLM60 20mg/m2 was administered intravenously every 4 weeks. Treatment may continue for up to 6 cycles or until disease progression, or intolerable toxicity. The primary endpoint was objective response rate (ORR) based on Independent Review Committee (IRC) assessments according to Revised Response Criteria for Malignant Lymphoma (version 2007). Secondary endpoints included ORR based on assessment between investigators, duration of response (DoR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Adverse events were rated according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 4.03. This trial is registered at ClinicalTrials.gov (NCT03776279). Results: One hundred and eight eligible patients were treated in 26 institutions in China between April 26, 2018 and May 19, 2020. Patient characteristics are summarized in Table 1. 98 patients were evaluable for response. 44 patients (40.7%, 95% CI, 31.4-50.6%) achieved an objective response including 22 (20.4%) patients achieved CR based on IRC assessment (Figure 1a). ORR were 34.4% (11/32), 50.0% (13/26), 52.4% (11/21), 12.5% (2/16) , 53.8% (7/13) and the CR rates were 18.8% (6/32), 23.1% (6/26), 28.6% (6/21), 6.3% (1/16), 23.1% (3/13) for PTCL-NOS, AITL, NKTCL, ALCL ALK+/-, and other subtypes , respectively (Figure 2). The ORR for patients who received at least 2 cycles of treatment (N=90) was 60.0% (95% CI, 49.1-70.2%). The investigator-evaluated ORR for the whole cohort was 43.5% (95% CI, 34.0-53.4%) (Figure 1b). Median DCR of all patients was 77.8% (95% CI, 68.8-85.2%). The median DoR of the whole group was 9.8 (95% CI, 5.1-not evaluated) months. 77.3% (34/44) of patients achieved response had a DoR ≥3 months (Figure 3). Median PFS of the whole cohort was 6.7 (95% CI, 5.5-10.4) months, with a 6-month PFS rate of 55.3% (95% CI, 44.5-64.8%). Median OS of the whole group was 16.3 (95% CI, 10.7-not evaluated) months, with a 6-month OS rate of 74.9% (95% CI, 64.9-82.4%) (Figure 4a, 4b). All-grade treatment-emergent adverse events (TEAEs, &amp;gt;5%) are listed in Table 2. The most common toxicities of PLM60 were hematological toxicities. The most common grade ≥3 toxicities were leukocytopenia (50.0%) and neutropenia (45.4%). Conclusion: PLM60 monotherapy yielded promising results for patients with R/R PTCL and ENKTCL with moderate toxicities. Further investigation of combination therapy is warranted. Disclosures Xia: CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.: Current Employment. Xue:CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.: Current Employment. Li:CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.: Current Employment.

A Multi-Center Analysis of the Impact of Dose Level of R-EPOCH on Outcomes of Patients with Double/Triple-Hit B-Cell Lymphoma

A Multi-Center Analysis of the Impact of Dose Level of R-EPOCH on Outcomes of Patients with Double/Triple-Hit B-Cell Lymphoma

Association between clinical risk factors and left ventricular function in patients with breast cancer following chemotherapy

Abstract Background The sequential or concurrent use of two different types of agents such as anthracyclines and trastuzumab may increase myocardial injury and cancer therapeutics-related cardiac dysfunction (CTRCD), which is often the result of the combined detrimental effect of the two therapies for breast cancer patients. For risk stratification to detect the development of CTRCD, the current position paper from the European Society of Cardiology (ESC) lists several factors associated with risk of cardiotoxicity following treatment with chemotherapy. However, the association between clinical risk factors and left ventricular (LV) function in breast cancer patients is currently unclear. Purpose Our purpose was to investigate the impact of baseline risk factors on LV function in patients with preserved LV ejection fraction (LVEF) who have undergone anthracycline or trastuzumab chemotherapy for breast cancer. Methods We studied 86 breast cancer patients treated with anthracyclines, trastuzumab, or both. Mean age was 59±13 years and LVEF was 67±5%. In accordance with the current definition, CTRCD was defined as a decline in LVEF of &amp;gt;10% to an absolute value of &amp;lt;53% after chemotherapy. Based on the 2016 ESC position paper, clinical risk factors for CTRCD were defined as: (1) a cumulative total doxorubicin dose of ≥240 mg/m2, (2) age ≥65-year-old, (3) body mass index ≥30 kg/m2, (4) a previous history of radiation therapy to chest or mediastinum, (5) B-type natriuretic peptide ≥100pg/mL, (6) a previous history of cardiovascular disease, (7) atrial fibrillation, (8) hypertension, (9) diabetes mellitus, (10) current or ex-smoker. Results The relative decrease in LVEF after chemotherapy for patients with more than four risk factors was significantly greater than that for patients without (−9.3±10.8% vs. −2.2±10.2%; p=0.02). However, this finding did not apply to patients with more than one, two or three risk factors. Patients with more than four risk factors also tended to show a higher prevalence of CTRCD than those without (14.3% vs. 2.8%, p=0.12). Moreover, patients with more than four risk factors were more likely to have higher LV mass index (109.3±29.0 g/m2 vs. 83.2±21.0g /m2, p&amp;lt;0.001), lower global longitudinal strain (18.4±2.8% vs. 20.0±2.6%, p=0.06) and higher E/e' (10.4 (8.9–13.0) vs. 9.0 (7.4–10.9), p=0.06) compared to those without. Conclusions Association between clinical risk factors and LV dysfunction following chemotherapy became stronger with an increase in the number of risk factors in breast cancer patients, and was especially strong for patients treated with chemotherapy who had more than four risk factors. Our findings can thus be expected to have clinical implications for better management of patients with breast cancer referred for chemotherapy. Funding Acknowledgement Type of funding source: None

Clinical features, risk factors, and prognosis of anthracycline-induced cardiotoxicity in patients with malignant lymphoma who received a CHOP like regimen

Abstract Background Anthracycline-induced cardiotoxicity is a serious complication in patients with malignant lymphoma (ML) who received chemotherapy, which threatens life prognosis and quality of life of patients. However, incidence and risk factors of cardiotoxicity in patients with ML who undergo intensive chemotherapy which aims complete remission is not clarified. Furthermore, prognosis after cardiotoxicity and that after recovery from cardiotoxicity have not been elucidated. Method We screened 443 ML patients who received either rituximab (R)-CHOP or CHOP regimen between January 2008 and December 2017 at Nagoya City University Hospital. Two handled forty-four patients who underwent echocardiography before and after chemotherapy were enrolled and data were analyzed retrospectively. Cardiotoxicity was defined as a decline in left ventricular ejection fraction (LVEF) of 10% or greater and an LVEF was below 50%. Partial recovery was defined as a 5% or more of increase in LVEF and an LVEF was ≥50% after cardiotoxicity. Complete recovery was defined as an increase in LVEF became more than 95% of the baseline value. Patient's basic characteristics, chemotherapeutic regimen, laboratory data, echocardiographic data, and prognosis were collected from the medical records by two cardiologists and two hematologists. Result At baseline, the median age was 71 years, the median cumulative dose of doxorubicin was 302 mg/m2 and the median LVEF was 69%. During the follow-up period, cardiotoxicity was observed in 52 out of 244 patients (21%), 30 patients (12%) had a symptomatic heart failure, and 5 patients died from cardiovascular cause. Thirty-five patients developed cardiotoxicity during the first year of chemotherapy. Multivariate analysis identified that only the baseline LVEF (HR 0.949, 95% CI 0.919–0.981, p=0.002) was an independent risk factor for cardiotoxicity. In our study, patients who received more than 200 mg/m2 of doxorubicin developed cardiotoxicity frequently. Among 52 patients who experienced cardiotoxicity, partial recovery and full recovery were observed in 18 (35%) and 4 (8%) patients, respectively. Four patients without recovery died due to heart failure and 1 patient with partial recovery died suddenly. Six out of 18 patients with partial recovery developed re-cardiotoxicity. Conclusion ML patients who undergo more than 200 mg/m2 of doxorubicin need a watchful follow-up. Only a baseline LVEF was an independent risk factor for cardiotoxicity. one third of patients with partial recovery developed re-cardiotoxicity. Funding Acknowledgement Type of funding source: None

Cardioprotective effect of Trimetazidine in patients with early breast cancer receiving anthracycline-based chemotherapy

Abstract Background Anthracyclines, alone or in combination with other drugs, are among the most effective chemotherapeutic agents to treat breast cancer both in the adjuvant and neoadjuvant settings. Unfortunately, anthracycline-associated dose-dependent cardiotoxicity is a limiting factor in clinical use. Extensive efforts have been devoted to identifying strategies to prevent anthracycline-induced cardiotoxicity. However, most cardioprotective agents have shown little efficacy in clinical trials. We hypothesized that myocardial damage by anthracyclines could be rationally prevented by using trimetazidine (TMZ), previously reported to interfere with anthracycline- and trastuzumab-induced cardiotoxicity. Therefore, we planned a randomized, controlled, open trial to determine whether TMZ may prevent the development of left ventricular (LV) dysfunction in patients receiving standard treatment for breast cancer. Methods The trial included 73 patients (41.2±8.1 years) undergoing surgery for breast cancer, who were scheduled for adjuvant epirubicin-containing chemotherapy and, if indicated, trastuzumab. Patients were randomly allocated in a 1:1 ratio to receive TMZ or baseline therapy only (control group). The main study endpoint was a reduction in the deterioration of left ventricular ejection fraction (LVEF), as evaluated by serial echocardiography performed at randomization and then every 3 months after the start of chemotherapy and for 1 year after its completion. Secondary outcome measures included echocardiographic indices of LV diastolic dysfunction, structural myocardial alterations, as assessed by speckle tracking echocardiography, and changes in cardiac biomarkers (troponin and brain natriuretic peptide). Results We found no significant differences between the two groups regarding baseline clinical and echocardiographic parameters. The two groups reached a similar cumulative dose of doxorubicin. No patient died during the study and no patients withdrew from chemotherapy. Three months after the start of chemotherapy, nonsignificant changes were observed in LVEF, shortening fraction, and LV diameters. No significant changes in cardiac biomarkers were observed in either group. Tissue Doppler imaging detected a significant decrease in myocardial velocities (P=0.001) in the control group, indicating LV diastolic dysfunction. In the same group, speckle tracking imaging revealed a statistically significant alteration in ventricular deformation (P=0.01), which means a decrease in LV systolic function. In the TMZ group, no significant alterations in LV diastolic function were observed. Conclusions Tissue Doppler imaging and speckle tracking imaging are more sensitive than conventional echocardiograms in the early diagnosis of cardiac dysfunction and TMZ seems to have an important role in the prevention of cardiotoxicity. Funding Acknowledgement Type of funding source: None

A PROSPECTIVE STUDY TO EVALUATE CARDIAC FUNCTIONS IN POSTMASTECTOMY LEFT-SIDED BREAST CANCER PATIENTS RECEIVING DOXORUBICIN BASED CHEMOTHERAPY AND CHEST WALL IRRADIATION

This prospective single institution study was carried out with 55 patients to evaluate the cardiac functions in left sided post mastectomy breast cancer patients who received Doxorubicin based chemotherapy with chest wall irradiation. Our study reported only 18% cardiotoxicity in contrast to about 30% in similar studies. There was a decline in the left ventricular ejection fraction after chemotherapy. Radiation did not affect left ventricular function much. The right ventricular systolic dysfunction observed in our study, as depicted by the value of TAPSE decreased after chemotherapy and then after radiation. Neither age nor the use of Taxanes following Doxorubicin administration factored much. The mean cumulative dose of Doxorubicin was confined to 360 mg/m2. Radiation induced cardiac dysfunction was mainly confined to the changes in the dimensions of the ventricles and left atrium volume. Decreased cardiotoxicity observed was probably due to short follow up of 6 months.

Predictors of new-onset heart failure and overall survival in metastatic breast cancer patients treated with liposomal doxorubicin

Cardiovascular diseases (CVDs) are the major cause of morbidity/mortality among breast cancer (BC) patients. Observation of the daily practice in eight experienced Polish oncology centers was conducted to find all possible predictors of new cases of heart failure (HF) and overall survival (OS) of metastatic BC patients treated with liposomal doxorubicin, taking into account the impact of pre-existing CVDs. HF was the cause of premature discontinuation of liposomal doxorubicin therapy in 13 (3.2%) of 402 patients. The probability of developing HF was higher in women with pre-existing CVDs (HR 4.61; 95%CI 1.38–15.38). Independent of CVDs history, a lower risk of HF was observed in those treated with a cumulative dose of liposomal doxorubicin > 300 mg/m2 (HR 0.14; 95% CI 0.04–0.54) and taxane-naive (HR 0.26; 95% CI 0.07–0.96). Multivariate analysis including the presence of pre-existing CVDs and occurrence of new HF, revealed a liposomal doxorubicin in cumulative doses of > 300 mg/m2 as a beneficial predictor for OS (HR 0.61; 95% CI 0.47–0.78) independently of subsequent chemotherapy (HR 0.72; 95% CI 0.57–0.92) or endocrine therapy (HR 0.65; 95% CI 0.49–0.87). Higher doses of liposomal doxorubicin can decrease mortality in metastatic BC without increasing the risk of HF. The clinical benefit is achieved regardless of pre-existing CVDs and subsequent anticancer therapy.

Association between clinical risk factors and left ventricular function in patients with breast cancer following chemotherapy.

The sequential or concurrent use of two different types of agents such as anthracyclines and trastuzumab may increase myocardial injury and cancer therapeutics-related cardiac dysfunction (CTRCD), which is often the result of the combined detrimental effect of the two therapies for breast cancer patients. However, the association between clinical risk factors and left ventricular (LV) function in such patients is currently unclear. We studied 86 breast cancer patients with preserved LV ejection fraction (LVEF) and treated with anthracyclines, trastuzumab, or both. Echocardiography was performed before and 16days after chemotherapy. In accordance with the current position paper, clinical risk factors for CTRCD were defined as: cumulative dose of doxorubicin > 240mg/m2, age > 65-year-old, body mass index > 30kg/m2, previous radiation therapy, B-type natriuretic peptide > 100pg/mL, previous history of cardiovascular disease, atrial fibrillation, hypertension, diabetes, and smoking. The relative decrease in LVEF after chemotherapy for patients with more than four risk factors was significantly greater than that for patients without (- 9.3 ± 10.8% vs. - 2.2 ± 10.2%; p = 0.02). However, this finding did not apply to patients with more than one, two or three risk factors. Patients with more than four risk factors also tended to show a higher prevalence of CTRCD than those without (14.3% vs. 2.8%; p = 0.12). Moreover, the relative decrease in LVEF became greater as the number of risk factors increased. This study found multiple risk factors were associated with LV dysfunction following chemotherapy. Our findings can thus be expected to have clinical implications for better management of patients with breast cancer referred for chemotherapy.

Analysis of the Doxorubicin and Doxorubicinol in the Plasma of Breast Cancer Patients for Monitoring the Toxicity of Doxorubicin.

IntroductionDoxorubicin is an anthracycline antibiotic used as an anticancer agent. Long-term use of this anticancer agent could accumulate its metabolite, doxorubicinol, and cause cardiomyopathy, due to its cardiotoxicity. This cardiotoxic effect depends on the amount of doxorubicin and doxorubicinol accumulated in the body. This study aimed to analyze doxorubicin and doxorubicinol levels in the blood plasma of breast cancer patients.MethodsParticipants of this study were 30 breast cancer patients who had received doxorubicin in their therapy regimen. The samples were analyzed using ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS), with the Acquity UPLC BEH C18 Waters chromatography column (2.1 x 100 mm : 1.7 μm). Plasma (250 μL) samples were prepared by protein precipitation, using methanol. The mobile phase consisted of 0.1% acetic acid (eluent A) and acetonitrile (eluent B), with gradient elution; the flow rate was 0.15 mL/min and runtime, 7 min.Results and DiscussionThis method was linear in the range of 1–1000 ng/mL for doxorubicin and 0.5–500 ng/mL for doxorubicinol. This method was successfully used to analyze doxorubicin and doxorubicinol, simultaneously, using hexamethylphosphoramide as the internal standard, in the plasma of breast cancer patients. Results showed that the measured concentrations of doxorubicin and doxorubicinol ranged between 12.54–620.01 ng/mL and 1.10–27.00 ng/mL, respectively. The measured cumulative doses of doxorubicin ranged between 48.76 and 319.01 mg/m2; thus, the risk of cardiomyopathy in the surveyed patients was under 4%, according to literature.

Prediction of doxorubicin cardiotoxicity by early detection of subclinical right ventricular dysfunction

BackgroundDoxorubicin remains one of the most common causes of cardiotoxicity in patients with lymphoma, leading to significant morbidity and mortality. Early decline in left ventricular (LV) ejection fraction predicts chemotherapy-induced cardiotoxicity and mortality, but limited data exist on doxorubicin-induced subclinical right ventricular (RV) dysfunction. We investigated dose-dependent subclinical doxorubicin-induced RV dysfunction in lymphoma patients.MethodsThirty-five patients with adult lymphoma treated with doxorubicin were studied. All patients had normal baseline LV ejection fraction (LVEF > 55%), and no known cardiopulmonary disease. We studied the dose-dependent effect of doxorubicin on RV strain by 2D speckle-tracking echocardiography (STE) using a vendor-independent software (TomTec). Images were analyzed offline by two independent observers blinded to the clinical characteristics of the study population. Baseline LVEF, RV fractional area change (RV FAC), RV free wall strain (RV FWS), and RV global longitudinal strain (RV GLS) were measured prior to chemotherapy initiation and compared with echo studies obtained at a 6-month follow-up interval. Patients served as their own controls. Comparisons between pre- and post-therapy were achieved using paired Student’s t-tests or Chi-Square test.ResultsThe Interobserver Intraclass Correlation Coefficient for RV GLS, RV FAC and RV FWS, was 0.87, 0.81 and 0.79, respectively. The mean age was 51 ± 13 years, 40% women, 60% white. The mean cumulative doxorubicin dose was 239 ± 104 mg m− 2. There was there was significant decline in RV FAC (47.3 ± 4.4% vs. 43.7 ± 3.9%), RV FWS (− 24.9 ± 3.3 vs. -22.2 ± 2.9), and RV GLS (− 22.4 ± 4.1 vs. -20.6 ± 3.4) (all p < 0.01); but no significant decline in LVEF during the 6-month follow up (63.3 ± 6.2% vs. 61.6 ± 11.1%, p = 0.374). At cumulative doxorubicin dose ≥200 mg m− 2 we found a significant decline in RV FAC (47.0 ± 4.7% vs. 42.2 ± 3.1%, p < 0.01), RV FWS (− 24.6 ± 3.6 vs. -21.5 ± 2.4, p < 0.01), and RV GLS (− 22.3 ± 4.5 vs. -20.1 ± 2.9, p = 0.03).ConclusionIn this cohort of adult lymphoma patients, doxorubicin-based therapy was associated with subclinical RV dysfunction, but not LV dysfunction, at a cumulative dose ≥200 mg m− 2. Additional studies evaluating the long-term prognostic implications of RV dysfunction in this population are essential.

Maximal cardiopulmonary exercise testing in childhood acute lymphoblastic leukemia survivors exposed to chemotherapy.

The purpose of this study was to demonstrate if childhood acute lymphoblastic leukemia (ALL) survivors exposed to chemotherapy (i.e., doxorubicin) are able to achieve a safe maximal cardiopulmonary exercise test (CPET). A total of 250 childhood ALL survivors were eligible to undergo a CPET on ergocycle. Analyses were performed in 216 survivors and stratified in regard to their prognostic risk groups: 99 survivors (55 males and 44 females) at standard risk and 117 survivors (56 males and 61 females) at high risk. Results showed that 100% (n = 216) of survivors completed a maximal CPET confirmed by the achievement of two out of three of the following criteria: 197 survivors (91.2%) reached a peak RER value of ≥ 1.15, 197 survivors (91.2%) reached a RPE score > 7, and 210 survivors (97.2%) reached a maximal heart rate ≥ 85% of the predicted value. Linear regression analysis showed a significant association between the survivors' cumulative dose of doxorubicin and their VO2 peak measured. Two non-fatal adverse events were observed and reported at the end of the maximal CPET, while non-fatal adverse events were reported in 5 survivors during the recovery period. None of these events resulted in a long-term complication. Childhood ALL survivors with prior exposure to chemotherapy can achieve a safe maximal CPET. They were able of achieving a maximal exercise test without being limited by symptoms, potential overprotection, or musculoskeletal issues. Thus, it should be the norm to realize a CPET prior a physical activity program to propose an optimal prescription. This study provides important information regarding the maximal physiological parameters that childhood ALL survivors are able to reach and have important clinical implications in the exercise and oncology field for this population of survivors.

Investigation of Association Between Cardiac Dose Distribution and Strain/Tissue Doppler Echocardiographic Indices During 1-Year Post-Mastectomy Radiation Therapy Follow-Up in Breast Cancer Patients

This study aimed to determine the association between cardiac dose distribution and strain and Tissue Imaging Doppler (TDI) echocardiographic indices during 1-year follow-up after Post-Mastectomy Radiotherapy (PMRT) in breast cancer patients. In this prospective cohort study, patients with left breast cancer candidate for PMRT were included. The patients treated radiation dose of 50 Gy in 25 fractions over 5 weeks. Before the radiotherapy, and 6 and 12 months after it, the patients underwent echocardiography using strain and TDI methods. The changes in echocardiographic indices and their association with cardiac radiation dose were evaluated. In this study, 31 patients with mean age of 36.6 ± 4.6 years old and the cumulative doses of doxorubicin to 237 ± 5 mg/m2 were participated. Correlation between cardiac dose during radiotherapy and changes in strain and TDI echocardiographic indices showed a significant inverse relation between minimum cardiac dose and 6-month TAPSE changes (p = 0.04, r = − 0.3), maximum cardiac dose and 6-month RV strain changes (p = 0.04, r = − 0.3) and 6 and 12-month S′ changes (p = 0.02, r = − 0.4 and p = 0.05, r = − 0.3), Cardiac V30 with 6 and 12-month E velocity changes (p = 0.05, r = − 0.3 and p = 0.02, r = − 0.4, respectively) and Heart V20 with 12-month E velocity changes (p = 0.04, r = − 0.3). Normal RV strain observed before starting the study in 12 patients (38.7%) was found to be abnormal after 6-month follow-up (p = 0.004). Results of this study showed that, PMRT was associated with left heart diastolic dysfunction and right heart systolic dysfunction especially in the first 6 months after radiotherapy.

Analysing the risk factors of doxorubicin-associated heart failure by a retrospective study of integrated, nation-wide databases

The incidence of dilated cardiomyopathy after anthracycline chemotherapy is mainly influenced by anthracycline cumulative dose. Previous researches showed doxorubicin treatment under cumulative dose of 450 mg/m2 associated with a low incidence of heart failure. Nowadays, doxorubicin is administered with a lower dose, the development of heart failure is largely determined by other factors. Our purpose was to identify the risk factors for heart failure due to doxorubicin therapy. With the use of the Hungarian financial healthcare databases merged with the National Cancer Registry, we performed a retrospective study. All the patients having confirmation for breast carcinoma between 2004 and 2015 were enrolled. The subjects with a preceding period characterized by any chemotherapy or diagnoses suggesting heart failure were excluded. Heart failure outcome event was defined by the assignment of I50 diagnosis code at hospital discharge or in autopsy reports. We used multivariate binary logistic regression to calculate odds ratios for heart failure. Besides the baseline characteristics, oncological state and cumulative doses of the chemotherapies were also taken into account. Among the analysed 3288, doxorubicin-treated patients, heart failure cumulative incidence was 6.2%. Doxorubicin cumulative dose over 400 mg/m2 increased the risk. The heart failure incidence was essentially influenced by age, even over 50 years the risk rose. Diabetes mellitus and the treatments with pyrimidine-analogues, carboplatin or bevacizumab were also associated with higher risk. By the integration of national financial and clinical databases, we could identify the risk factors for doxorubicin-associated heart failure. Orv Hetil. 2020; 161(26): 1094-1102.

Long-term cardiac outcomes of patients with HER2-positive breast cancer treated in the adjuvant lapatinib and/or trastuzumab Treatment Optimization Trial

BackgroundCardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting.MethodsThis is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T + L were eligible. Cardiac events (CEs) rates were compared according to treatment arm.ResultsWith 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T + L arm vs. 197 (9.3%) in T arm (OR = 0.85 [95% CI, 0.68–1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset = 6.6 months [IQR = 3.4–11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF < 55% (vs > 64%, OR 3.1 [95% CI 1.54–6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25–2.75]), BMI > 30 kg/m2 (vs < 25 mg/kg2, OR 2.21 [95% CI 1.40–3.49]), cumulative dose of doxorubicin ≥240 mg/m2 (OR 1.36 [95% CI 1.01–1.82]) and of epirubicin≥ 480 mg/m2 (OR 2.33 [95% CI 1.55–3.51]).ConclusionsDual HER2 blockade with T + L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial.Trial registration numberClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006–000562–36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2–06 /EGF106708/N063D.