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This study determined the effects of doxorubicin and/or trastuzumab on diastolic function and the relationship between diastolic function and systolic dysfunction. Doxorubicin and trastuzumab can result in left ventricular ejection fraction (LVEF) declines. However, the effects of these therapies on diastolic function remain incompletely defined. In a rigorously phenotyped, longitudinal cohort study of 362 breast cancer participants treated with doxorubicin, doxorubicin followed by trastuzumab, or trastuzumab alone, changes in diastolic function were evaluated using linear models estimated via generalized estimating equations. Associations between baseline and changes in diastolic function with LVEF and longitudinal strain were also determined using generalized estimating equations. The Kaplan-Meier estimator derived the proportion of participants who experienced incident diastolic dysfunction. Cox proportional hazards models estimated the associations between participant characteristics and diastolic dysfunction risk, and between diastolic function and cancer therapy−related cardiac dysfunction risk, defined by an LVEF decline of ≥10% to <50%. Over a median of 2.1 years (interquartile range [IQR]: 1.3 to 4.2 years), participants treated with doxorubicin or doxorubicin followed by trastuzumab demonstrated a persistent worsening in diastolic function, with reductions in the E/A ratio, lateral and septal e′ velocities, and increases in E/e′ (p < 0.01). These changes were not observed with trastuzumab alone. Incident abnormal diastolic function grade occurred in 60% at 1 year, 70% by 2 years, and 80% by 3 years. Abnormal diastolic function grade was associated with a subsequent decrease in LVEF (−2.1%; 95% confidence intervals [CI]: −3.1 to −1.2; p < 0.001) and worsening in longitudinal strain (0.6%; 95% CI: 0.1 to 1.1; p = 0.013) over time. Changes in E/e′ ratio were modestly associated with worsening longitudinal strain (0.1%; 95% CI: 0.0 to 0.2; p = 0.022). A modest, persistent worsening of diastolic function is observed with contemporary breast cancer therapy. Abnormal and worsening diastolic dysfunction is associated with a small risk of subsequent systolic dysfunction. (Cardiotoxicity of Cancer Therapy [CCT]; NCT01173341) [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy has significantly advanced the treatment of patients with relapsed and refractory hematologic malignancies and is increasingly investigated as a therapeutic option of other malignancies. The main adverse effect of CAR T-cell therapy is potentially life-threatening cytokine release syndrome (CRS). Clinical cardiovascular (CV) manifestations of CRS include tachycardia, hypotension, troponin elevation, reduced left ventricular ejection fraction, pulmonary edema, and cardiogenic shock. Although insults related to CRS toxicity might be transient and reversible in most instances in patients with adequate CV reserve, they can be particularly challenging in higher-risk, often elderly patients with pre-existing CV disease. As the use of CAR T-cell therapy expands to include a wider patient population, careful patient selection, pre-treatment cardiac evaluation, and CV risk stratification should be considered within the CAR T-cell treatment protocol. Early diagnosis and management of CV complications in patients with CRS require awareness and multidisciplinary collaboration. [ABSTRACT FROM AUTHOR]

Objectives This study sought to determine the relationships between echocardiography-derived measures of myocardial mechanics and cancer therapeutics–related cardiac dysfunction (CTRCD). Background Doxorubicin and trastuzumab are highly effective breast cancer therapies, but have a substantial risk of CTRCD. There is a critical need for the early detection of patients at increased risk of toxicity. Methods We performed a prospective, longitudinal cohort study of breast cancer participants undergoing doxorubicin and/or trastuzumab therapy. Echocardiography was performed prior to therapy initiation (baseline) and at standardized follow-up intervals during and after completion of therapy. Ejection fraction (EF), strain, strain rate, and ventricular-arterial coupling (effective arterial elastance [Ea]/end-systolic elastance [Ees sb ]) were quantitated. CTRCD was defined as a ≥10% reduction in EF from baseline to <50%. Multivariable logistic regression models were used to determine the associations between baseline levels and changes from baseline in echocardiographic measures and CTRCD. Receiver-operating characteristic curves were used to evaluate the predictive ability of these measures. Results In total, 135 participants contributed 517 echocardiograms to the analysis. Over a median follow-up time of 1.9 years (interquartile range: 0.9 to 2.4 years), 21 participants (15%) developed CTRCD. In adjusted models, baseline levels and changes in Ea/Ees sb , circumferential strain, and circumferential strain rate were associated with 21% to 38% increased odds of CTRCD (p < 0.001). Changes in longitudinal strain (p = 0.037), radial strain (p = 0.015), and radial strain rate (p = 0.006) were also associated with CTRCD. Ea/Ees sb (area under the curve: 0.703; 95% confidence interval: 0.583 to 0.807) and circumferential strain (area under the curve: 0.655; 95% confidence interval: 0.517 to 0.767) demonstrated the greatest predictive utility. Sensitivity analyses using an alternative CTRCD definition did not impact our results. Conclusions Over an extended follow-up time, ventricular-arterial coupling and circumferential strain were strongly predictive of CTRCD. Our findings suggest a noninvasive strategy to identify high-risk patients prior to, during, and after cardiotoxic cancer therapy. [ABSTRACT FROM AUTHOR]

The world population is aging and 60% of all cancer diagnoses and 70% of all cancer mortality occur in patients greater than 65 years of age. The elderly have multiple medical and non-medical comorbidities that accompany changes in pharmacokinetics and pharmacodynamics and poly-pharmacy that all impact their treatment. The elderly derive benefit from cancer treatment but are often denied chemotherapy or are undertreated based on age. Treatment decision should be based on physiologic rather than chronological age and there is a need for inclusion of more elderly patients in cancer clinical trials. [ABSTRACT FROM AUTHOR]

Abstract: Trastuzumab is the standard of care for the treatment of patients with ERB2-positive breast cancer. In a minority of patients, trastuzumab is associated with an increased incidence of cardiac dysfunction that ranges from asymptomatic decreases in left ventricular ejection fraction to symptomatic heart failure. In trials in the adjuvant setting, the difference in the incidence of cardiac events between the control and trastuzumab-containing arms was less than 4%. The baseline evaluation and oncologic setting (adjuvant versus metastatic disease) drive algorithms for the cardiac monitoring and management of these patients. When a patient develops documented left ventricular dysfunction, standard treatments for the management of heart failure should be prescribed. Trastuzumab cardiac dysfunction is an important clinical entity that can be managed effectively and individualized to maximize the cancer treatment benefit and minimize the risk and consequences of cardiac dysfunction. [ABSTRACT FROM AUTHOR]

Many existing and emerging cancer therapies have a significant effect on the cardiovascular health of patients with cancer and cancer survivors. This paper examines current aspects of interdisciplinary cardio-oncology clinical care delivery and education in the United States and outlines how these data provide a platform for future development of the field. We present the results of the nationwide survey on cardio-oncology services, practices, and opinions, conducted among chiefs of cardiology and program directors, which demonstrate ranges of clinical activities and identify significant interest for increased educational opportunities and expert training of cardiovascular physicians in this field. The survey respondents recognized clinical relevance but emphasized lack of national guidelines, lack of funds, and limited awareness and infrastructure as the main challenges for development and growth of cardio-oncology. We discuss potential solutions to unmet needs through interdisciplinary collaboration and the active roles of professional societies and other stakeholders. [ABSTRACT FROM AUTHOR]

Purpose: We characterized the early changes in cardiovascular biomarkers with contemporary thoracic radiation therapy (RT) and evaluated their associations with radiation dose-volume metrics including mean heart dose (MHD), V5, and V30.Methods and Materials: In a prospective longitudinal study of 87 patients with breast cancer, lung cancer, or mediastinal lymphoma treated with photon or proton thoracic RT, blood samples were obtained pre-RT and after completion of RT (median, 20 days; interquartile range [IQR], 1-35). High-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, placental growth factor (PIGF), and growth differentiation factor 15 (GDF-15) were measured. Associations between MHD, V5 and V30, and biomarker levels and associations between echocardiography-derived measures of cardiac function and biomarker levels were assessed in multivariable linear regression models. Analyses were performed according to the following subgroups: (1) breast cancer alone and (2) lung cancer and lymphoma combined.Results: The median (IQR) estimates of MHD ranged from 1.3 Gy (0.9-2.4) in breast cancer (n = 60) to 6.8 Gy (5.4-10.2) in mediastinal lymphoma (n = 14) and 8.4 Gy (6.7-16.1) in lung cancer (n = 13) patients (P < .001). There were no significant increases in biomarker levels from pre-RT to post-RT in breast cancer. In lung cancer/lymphoma, PIGF increased from a median (IQR) of 20 ng/L (16-26) to 22 ng/L (16-30) (P = .005), and GDF-15 increased from 1171 ng/L (755-2493) to 1887 ng/L (903-3763) (P = .006). MHD, V5, and V30 were significantly associated with post-RT PIGF and GDF-15 levels in multivariable models. Changes in biomarkers were not significantly associated with changes in echocardiography-derived measures of cardiac function.Conclusion: Contemporary thoracic RT induces acute abnormalities in vascular and inflammatory biomarkers that are associated with radiation dose-volume metrics, particularly in lung cancer and mediastinal lymphoma. Long-term follow-up studies are needed to determine the impact of these changes on the development of overt cardiac disease. [ABSTRACT FROM AUTHOR]

Background: Oxidative/nitrosative stress and endothelial dysfunction are hypothesized to be central to cancer therapeutics-related cardiac dysfunction (CTRCD). However, the relationship between circulating arginine-nitric oxide (NO) metabolites and CTRCD remains unstudied.Objectives: This study sought to examine the relationship between arginine-NO metabolites and CTRCD in a prospective cohort of 170 breast cancer patients treated with doxorubicin with or without trastuzumab.Methods: Plasma levels of arginine, citrulline, ornithine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and N-monomethylarginine (MMA) were quantified at baseline, 1 month, and 2 months after doxorubicin initiation. Determinants of baseline biomarker levels were identified using multivariable linear regression, and Cox regression defined the association between baseline levels and 1- or 2-month biomarker changes and CTRCD rate in 139 participants with quantitated echocardiograms at all time points.Results: Age, hypertension, body mass index, and African-American race were independently associated with ≥1 of baseline citrulline, ADMA, SDMA, and MMA levels. Decreases in arginine and citrulline and increases in ADMA were observed at 1 and 2 months (all p < 0.05). Overall, 32 participants experienced CTRCD over a maximum follow-up of 5.4 years. Hazard ratios for ADMA and MMA at 2 months were 3.33 (95% confidence interval [CI]: 1.12 to 9.96) and 2.70 (95% CI: 1.35 to 5.41), respectively, and 0.78 (95% CI: 0.64 to 0.97) for arginine at 1 month.Conclusions: In breast cancer patients undergoing doxorubicin therapy, early alterations in arginine-NO metabolite levels occurred, and early biomarker changes were associated with a greater CTRCD rate. Our findings highlight the potential mechanistic and translational relevance of this pathway to CTRCD. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to determine if individual or multiple biomarkers are associated with cardiotoxicity in patients with breast cancer undergoing cancer therapy. Background: Current methods to identify patients at risk for cardiotoxicity from cancer therapy are inadequate. Methods: We measured 8 biomarkers in a multicenter cohort of 78 patients with breast cancer undergoing doxorubicin and trastuzumab therapy: ultrasensitive troponin I (TnI), high-sensitivity C-reactive protein (CRP), N-terminal pro–B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor (sFlt)-1, and galectin (gal)-3. Cardiotoxicity, defined by the Cardiac Review and Evaluation Committee criteria, was assessed every 3 months for up to 15 months. Hazard ratios (HRs) of cardiotoxicity risk were assessed for each biomarker at baseline, at visit 2 (3 months), and as a function of the difference between visit 2 and baseline. Joint models were assessed for the most promising biomarkers. Results: TnI, CRP, GDF-15, MPO, PlGF, and sFlt-1 levels increased from baseline to visit 2 (p < 0.05). A greater risk of cardiotoxicity was associated with interval changes in TnI (HR: 1.38 per SD; 95% confidence interval: 1.05 to 1.81; p = 0.02) and MPO (HR: 1.34 per SD; 95% confidence interval: 1.00 to 1.80; p = 0.048) and in models combining both markers (p = 0.007 and p = 0.03, respectively). The risk of cardiotoxicity was 46.5% in patients with the largest changes in both markers (ΔTnI >121.8 μg/l; ΔMPO >422.6 pmol/l). Conclusions: Early increases in TnI and MPO levels offer additive information about the risk of cardiotoxicity in patients undergoing doxorubicin and trastuzumab therapy. Independent validation of these findings is necessary before application to clinical practice. [Copyright &y& Elsevier]

As breast cancer survival increases, cardiotoxicity associated with chemotherapeutic regimens such as anthracyclines and trastuzumab becomes a more significant issue. Assessment of the left ventricular (LV) ejection fraction fails to detect subtle alterations in LV function. The objective of this study was to evaluate whether more sensitive echocardiographic measurements and biomarkers could predict future cardiac dysfunction in chemotherapy-treated patients. Forty-three patients diagnosed with breast cancer who received anthracyclines and trastuzumab therapy underwent echocardiography and blood sampling at 3 time points (baseline and 3 and 6 months during the course of chemotherapy). The LV ejection fraction; peak systolic myocardial longitudinal, radial, and circumferential strain; echocardiographic markers of diastolic function; N-terminal pro–B-type natriuretic peptide; and high-sensitivity cardiac troponin I were measured. Nine patients (21%) developed cardiotoxicity (1 at 3 months and 8 at 6 months) as defined by the Cardiac Review and Evaluation Committee reviewing trastuzumab. A decrease in longitudinal strain from baseline to 3 months and detectable high-sensitivity cardiac troponin I at 3 months were independent predictors of the development of cardiotoxicity at 6 months. The LV ejection fraction, parameters of diastolic function, and N-terminal pro–B-type natriuretic peptide did not predict cardiotoxicity. In conclusion, cardiac troponin plasma concentrations and longitudinal strain predict the development of cardiotoxicity in patients treated with anthracyclines and trastuzumab. The 2 parameters may be useful to detect chemotherapy-treated patients who may benefit from alternative therapies, potentially decreasing the incidence of cardiotoxicity and its associated morbidity and mortality. [Copyright &y& Elsevier]

Evidence supporting the role of hematopoietic stem cell transplantation (SCT) in the therapy of multiple myeloma (MM) is presented and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published medical literature and for grading the quality of the evidence, the strength of the evidence, and the strength of the treatment recommendations. Treatment recommendations based on the evidence presented in the review were made unanimously by a panel of MM experts. Recommendations for SCT as an effective therapy for MM include the following: SCT is preferred to standard chemotherapy as de novo therapy; SCT is preferred as de novo rather than salvage therapy; autologous peripheral blood stem cell transplantation (PBSCT) is preferred to bone marrow transplantation (BMT); and melphalan is preferred to melphalan plus total body irradiation as the conditioning regimen for autologous SCT. Recommendations that SCT is not effective include the following: current purging techniques of bone marrow. Recommendations of equivalence include the following: PBSCT using CD34+ selected or unselected stem cells. No recommendation is made for indications or transplantation techniques that have not been adequately studied, including the following: SCT versus standard chemotherapy as salvage therapy, tandem autologous SCT, autologous or allogeneic SCT as a high-dose sequential regimen, allogeneic BMT versus PBSCT, a preferred allogeneic myeloablative or non-myeloablative conditioning regimen, and maintenance therapy post–autologous SCT with interferon alpha post-SCT. The priority area of needed future research is maintenance therapy posttransplantation with nothing versus interferon alpha versus other agents such as corticosteroids or thalidomide or its derivatives. © 2003 American Society for Blood and Marrow TransplantationBiology of Blood and Marrow Transplantation 9:4-37 (2003) [Copyright &y& Elsevier]