RESUMEN
Cardiotoxicity in children is a potentially fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT); therefore, early identification of risk factors can improve patient prognosis. However, there are few data on the clinical characteristics of early-stage cardiotoxicity in children after allo-HSCT. We conducted a retrospective single-center study of pediatric patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) between January 2016 and December 2022 at the Children's Hospital Affiliated with Chongqing Medical University to evaluate the clinical characteristics of early cardiac events (ECEs) after allo-HSCT and their impact on survival outcomes. We enrolled 444 patients who underwent allo-HSCT-304 males (68%) and 140 females (32%)-with a median age of 3.3 years (1.8-6.5 years) at transplantation. We found that 73 patients (16.4%) had ECEs after allo-HSCT. The ECEs included valvular disease (n = 46), pericardial effusion (n = 38), arrhythmia (n = 9), heart failure (n = 16), and dilated cardiomyopathy (n = 1). Female sex, age ≥ 6 years, body mass index (BMI) < 16 kg/m2 and HLA-type mismatches were risk factors for ECEs. We designed a stratified cardiac risk score that included these risk factors, and the higher the score was, the greater the cumulative incidence of ECEs. The occurrence of an ECE was closely associated with a lower overall survival (OS) rate and greater nonrelapse mortality (NRM). In addition, stratified analysis based on the number of combined ECEs showed that the greater the number of combined ECEs was, the more significant the negative impact on OS rates.
Asunto(s)
Cardiotoxicidad , Trasplante de Células Madre Hematopoyéticas , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Femenino , Masculino , Niño , Preescolar , Estudios Retrospectivos , Lactante , Cardiotoxicidad/etiología , Cardiotoxicidad/mortalidad , Factores de Riesgo , Tasa de Supervivencia , Trasplante Homólogo/efectos adversos , Cardiopatías/etiología , Cardiopatías/mortalidadRESUMEN
PURPOSE: Androgen deprivation therapy (ADT) includes bilateral orchiectomy or long-acting gonadotropin-releasing hormone (GnRH) agonists/antagonists. It remains controversial with respect to ADT associated cardiovascular outcomes. Hereby, we compared the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in patients with prostate cancer receiving either surgical castration or GnRH therapies. MATERIALS AND METHODS: Using the Taiwan Cancer Registry and Taiwan's National Health Insurance Research Database, we identified 8,413 patients receiving GnRH therapies compared with 694 receiving surgical castration from 2008 to 2017. The median followup duration was 3 years. RESULTS: The crude incidences of 3-year mortality and MACCEs were 19.90% vs 26.51% and 8.23% vs 8.65% in patients receiving GnRH therapies or surgical castration, respectively. After adjusting for age, cancer stage and comorbidities, despite no significant differences in MACCEs between groups there was a slight increase in the incidence of acute myocardial infarction (AMI) in patients receiving surgical castration compared with those receiving GnRH therapies. The mortality adjusted hazard ratios of MACCEs and AMI among patients receiving surgical castration were 1.11- and 1.8-fold higher than those receiving GnRH therapies. Notably, in subgroup analysis regarding cancer stage, patients with cancer stage IV showed the most significantly increasing risk of AMI in those receiving surgical castration compared with GnRH therapies. CONCLUSIONS: Collectively, we indicated an increased risk of AMI in patients with prostate cancer, especially in patients receiving surgical castration rather than those receiving GnRH therapies. Our findings highlight concerns regarding the cardiac safety of surgical castration compared with GnRH therapies.
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Antagonistas de Andrógenos/efectos adversos , Antineoplásicos Hormonales/efectos adversos , Cardiotoxicidad/etiología , Enfermedades Cardiovasculares/etiología , Orquiectomía/efectos adversos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/cirugía , Cardiotoxicidad/epidemiología , Cardiotoxicidad/mortalidad , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , Humanos , Masculino , Complicaciones Posoperatorias/etiología , Factores de Riesgo , Taiwán/epidemiologíaRESUMEN
Doxorubicin (DOX) is an effective anticancer drug. However, its use is hampered by the development of very mortal cardiomyopathy. Here, we investigate whether the co-administration of the antidepressant paroxetine (P), known to exert beneficial cardiovascular effects, would provide effective cardioprotection. Experiments were performed in male Wistar rats randomly assigned to control group (0.5 mL/kg 0.9% NaCl, i.v., n = 7), DOX group (DOX 5 mg /kg i.v., n = 23) and DOX+P group (DOX 5 mg/kg, i.v. plus P 10 mg/kg p.o. daily, beginning five days before DOX administration and during the follow-up period, n = 11). Rats' body weight and echocardiography parameters were monitored before and after drug/vehicle administration. Cardiac histology was performed post-mortem, as well as beta1-adrenergic receptor (ß1-AR), beta2-adrenergic receptor (ß2-AR), G protein-coupled receptor kinases type 2 (GRK2), type 3 (GRK3), beta-arrestin 1, and beta-arrestin 2 gene expression using RT-qPCR. DOX-treated rats exhibited bad general condition, adynamia, loss of body weight, and low survival. Echocardiography revealed two phenotypes: cardiomyopathy with left ventricular (LV) hypertrophy (DOX-HCM) and cardiomyopathy with LV dilation (DOX-DCM). In DOX-HCM rats only, there was an increased GRK2 and GRK3 gene expression and synthesis. DOX+P co-treated rats exhibited good general condition, normal spontaneous behaviour, gained weight over time, had increased survival, and preserved LV morphology and contractility. In these rats, gene expression and synthesis of GRK2 and GRK3 were decreased, while ß1-AR and ß2-AR were increased. Present results show for the first time that P effectively reduces DOX-induced cardiotoxicity and enhances survival.
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Cardiomiopatías/prevención & control , Cardiotoxicidad/prevención & control , Doxorrubicina/toxicidad , Paroxetina/farmacología , Animales , Antibióticos Antineoplásicos/toxicidad , Cardiomiopatías/inducido químicamente , Cardiomiopatías/mortalidad , Cardiotónicos/farmacología , Cardiotoxicidad/etiología , Cardiotoxicidad/mortalidad , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Remodelación Ventricular/efectos de los fármacosRESUMEN
Cancer treatment-related cardiotoxicity (ie, heart failure, coronary artery disease, vascular diseases, arrhythmia) is a growing cancer survivorship concern within oncology practice; heart disease is the leading cause of noncancer death in cancer survivors and surpasses cancer as the leading cause of death for some cancers with higher survival rates. The issue of cardiotoxicity introduces a critical tradeoff that must be acknowledged and reconciled in clinical oncology practice: treating cancer aggressively and effectively in the present vs preventing future cardiotoxicity. Although many cancers must be treated as aggressively as possible, for others, multiple treatment options are available. Yet even when effective and less cardiotoxic treatments are available, they are not always chosen. Wariness to choose equally effective but less cardiotoxic treatment options may result in part from providers' and patients' reliance on "cognitive heuristics," or mental shortcuts that people (including, research shows, medical professionals) use to simplify complex judgments. These heuristics include delay discounting, availability and affect heuristics, and default bias. In the current commentary, we describe relevant research that illuminates how use of heuristics leads to biased medical decision making and translate how this research may apply when the tradeoff between aggressive cancer treatment and preventing future cardiotoxicity is considered. We discuss the implications of these biases in oncology practice, offer potential solutions to reduce bias, and call for future research in this area.
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Cardiopatías/etiología , Heurística , Neoplasias/terapia , Enfermedades Vasculares/etiología , Antraciclinas/efectos adversos , Antibióticos Antineoplásicos/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Sesgo , Neoplasias de la Mama/tratamiento farmacológico , Supervivientes de Cáncer , Cardiotoxicidad/etiología , Cardiotoxicidad/mortalidad , Cardiotoxicidad/prevención & control , Causas de Muerte , Toma de Decisiones Clínicas , Adhesión a Directriz , Cardiopatías/mortalidad , Cardiopatías/prevención & control , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/radioterapia , Humanos , Neoplasias/mortalidad , Neoplasias/psicología , Radioterapia/efectos adversos , Trastuzumab/efectos adversos , Enfermedades Vasculares/mortalidad , Enfermedades Vasculares/prevención & controlRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) such as antibodies against programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1), have shown remarkable efficacies in many subtypes of cancers. However, ICIs may also cause severe immune-related adverse events in the recipient patients. Recently, ICI-associated myocarditis have been reported in hundreds of patients worldwide, with a mortality rate of approximately 50% in these cases. This study aims to recapitulate the cardiotoxicity and explore the detoxicifying approaches to attenuate mortality caused by PD-1/PD-L1 inhibitors in healthy mice. METHODS: Six to eight-week-old C57BL/6 mice were inoculated with anti-PD-1 antibody (12.5 µg/g every 5 days for 6 injections), anti-PD-L1 antibody (10 µg/g once a week for 6 weeks), anti-PD-L1 antibody (with the same dosage described above) in combination with levothyroxine (0.25 µg/g, intraperitoneally injected half an hour before anti-PD-L1 antibody injection), or isotype control immunoglobulin IgG (10 µg/g once a week for 6 weeks). The ejection function of the hearts was detected by echocardiography, body temperature and blood pressure were detected by Mouse MonitorTM and non-invassive blood pressure minotor, and serum free thyroxine concentration was detected by The enzyme linked immunosorbent assay (ELISA). RESULTS: PD-L1 was expressed at different levels by the cardiomyocytes of the mice. The isotype control immunoglobulin and anti-PD-1 antibody did not cause death of the mice. The 12 mice receiving 3-6 injections of anti-PD-L1 antibody showed a significant increase in the heart-to-tibial ratio and cardiomyoctye degeneration, hyalinization and extravascular inflammatory cell infiltration. In addition, the serum thyroxine was mardedly decreased to 1/3 of that in the control group mice, and the blood pressure and body temperature were abnormally decreased in mice upon treatment with PD-L1 blockade. Eight of the 12 (66.7%) mice died from multiple intravenous injection of anti-PD-L1 antibody.Intraperitoneal injection of levothyroxine 30 min before the injection of anti-PD-L1 antibody significantly attenuated the mortality rate of the anti-PD-L1 antibody-treated mice. CONCLUSIONS: The anti-PD-L1 antibody is cardiotoxic and lethal, and levothyroxine is able to rescue the mice from this immune checkpoint inhibitor-caused mortality.
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Cardiotoxicidad , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Tiroxina , Animales , Antígeno B7-H1/antagonistas & inhibidores , Cardiotoxicidad/etiología , Cardiotoxicidad/mortalidad , Cardiotoxicidad/prevención & control , Humanos , Ratones , Ratones Endogámicos C57BL , Miocarditis/inducido químicamente , Miocarditis/mortalidad , Miocarditis/prevención & control , Receptor de Muerte Celular Programada 1/metabolismo , Hormonas Tiroideas/farmacología , Hormonas Tiroideas/uso terapéutico , Tiroxina/farmacología , Tiroxina/uso terapéuticoRESUMEN
Although radiation-induced cardiotoxicity has been addressed, its prognostic relevance to modern radiotherapy (RT) techniques is unclear. This study assessed the impact of adjuvant RT on heart-related deaths in patients with ductal carcinoma in situ. Patients who underwent adjuvant RT after breast-conserving surgery between 1988 and 2008 were identified from the Surveillance, Epidemiology, and End Results database. KaplanâMeier and competing risks analyses were conducted after propensity score-matching according to tumor laterality. A total of 41,526 propensity-matched patients were identified (n = 20,763 for either left- or right-sided tumor). In the analysis of the cumulative incidence of heart-related mortality events, there was a greater risk increment in the left-sided group over the first to second decades after RT in patients aged ≤ 50 years (P = 0.048). Competing risks analysis of the young patients showed that left-sided RT was associated with higher heart-related mortality rates (Grey's test, P = 0.049). The statistical significance remained after adjusting for other covariates (subdistribution hazard ratio 2.35; 95% confidence interval 1.09â5.10). Regarding the intrinsic effect of modern RT techniques, further strategies to reduce heart-related risks are needed for young patients. Close surveillance within an earlier follow-up period should be considered for these patients in clinics.
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Neoplasias de la Mama/radioterapia , Carcinoma Intraductal no Infiltrante/radioterapia , Cardiotoxicidad , Radioterapia Adyuvante/efectos adversos , Anciano , Neoplasias de la Mama/cirugía , Carcinoma Intraductal no Infiltrante/cirugía , Cardiotoxicidad/etiología , Cardiotoxicidad/mortalidad , Femenino , Humanos , Mastectomía Segmentaria/métodos , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
INTRODUCTION: The cardiac radiation dose is an important predictor of cardiac toxicity and overall survival (OS) for patients with locally advanced non-small-cell lung cancer (NSCLC). However, radiation-induced cardiac toxicity among patients with early-stage NSCLC who have undergone stereotactic ablative radiotherapy (SABR) has been less well-characterized. Our objective was to assess the associations between cardiac radiation dosimetry and OS in patients with early-stage NSCLC undergoing SABR. MATERIALS AND METHODS: From 2009 to 2014, 153 patients with early-stage NSCLC had undergone SABR at a single institution. The maximum dose, mean dose, V10Gy, V25Gy, and V50Gy to 15 cardiac substructures and the whole heart were analyzed for their association with OS using the Kaplan-Meier method. An artificial neural network (ANN) analysis was performed to modulate confounding behaviors of dosimetric variables to predict for OS. RESULTS: A total of 112 patients were included in the present analysis. The right ventricle (RV) V10Gy most negatively predicted for OS, such that patients who had received a RV V10Gy dose < 4% had significantly longer OS than patients who had received a RV V10Gy does > 4% (5.3 years vs. 2.4 years). On ANN analysis, 74 input features, including cardiac dosimetry parameters, predicted for survival with a test accuracy of 64.7%. A repeat ANN analysis using dosimetry to dose neutral structure confirmed the predictive power of cardiac dosimetry. CONCLUSION: Cardiac dosimetry to subvolumes of the heart was associated with decreased OS in patients with early-stage NSCLC undergoing SABR. These data support the importance of minimizing the radiation dose to cardiac substructures. Further prioritizing the heart as an organ at risk might be warranted. Additionally, cardiac follow-up should be considered.
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Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Células Escamosas/mortalidad , Cardiotoxicidad/mortalidad , Neoplasias Pulmonares/mortalidad , Redes Neurales de la Computación , Radiocirugia/efectos adversos , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Cardiotoxicidad/diagnóstico , Cardiotoxicidad/etiología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Radiocirugia/mortalidad , Dosificación Radioterapéutica , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Limited information is available regarding the rate of long-term cardiovascular (CV) mortality in chronic myeloid leukaemia (CML) patients treated with second- and third-generation tyrosine kinase inhibitors (2ndG/3rdG TKIs) in the real-life practice. METHODS: We identified 656 consecutive CML patients treated with nilotinib, dasatinib, bosutinib and ponatinib. RESULTS: The 15-year CV-mortality free survival was 93⯱â¯2.8%. Age ≥65 years (pâ¯=â¯0.005) and a positive history of CV disease (pâ¯=â¯0.04) were significantly associated with a lower CV-mortality free survival. CV disease accounted for 16.5% and 5% of potential years of life lost (PYLL) in male and female patients, respectively. The standard mortality ratio (SMR) following ischemic heart disease (IHD) was 3.9 in males and 3.8 in female patients, meaning an excess of IHD deaths observed, in comparison with the population of control. CONCLUSION: Prevention strategies based on CV risk factors, in particular in those patients with a previous history of CV disease, should be considered.
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Compuestos de Anilina , Cardiotoxicidad , Enfermedades Cardiovasculares , Dasatinib , Imidazoles , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Nitrilos , Piridazinas , Pirimidinas , Quinolinas , Anciano , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Cardiotoxicidad/etiología , Cardiotoxicidad/mortalidad , Cardiotoxicidad/prevención & control , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/prevención & control , Dasatinib/administración & dosificación , Dasatinib/efectos adversos , Femenino , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Italia/epidemiología , Esperanza de Vida , Efectos Adversos a Largo Plazo/inducido químicamente , Efectos Adversos a Largo Plazo/mortalidad , Masculino , Mortalidad , Nitrilos/administración & dosificación , Nitrilos/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Piridazinas/administración & dosificación , Piridazinas/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Ajuste de Riesgo/métodosRESUMEN
AIMS: We sought to describe survival outcomes and toxicities of trastuzumab in real-world patients with HER2-positive, metastatic breast cancer (MBC) and compare these to a recent systematic review of clinical trials. METHODS: We searched the medical records of three Sydney cancer centers for patients with HER2-positive, MBC starting trastuzumab from January 2001 to March 2017. We recorded patient, tumor, and treatment characteristics; survival times from start of palliative trastuzumab; and rates of cardiac toxicity. Survival distribution was summarized using the following percentiles (represented scenario): 90th (worst-case), 75th (lower-typical), 25th (upper-typical), and 10th (best-case). Survival times were compared to recent review of HER2-positive MBC randomized trials. Factors associated with survival were assessed with Cox models. RESULTS: Characteristics of the 126 patients were: median age 53 years, ER positive cancer (50%), de-novo metastatic disease (23%), prior adjuvant trastuzumab (15%), liver metastases (37%), and brain metastases (23%). The median duration of first-line trastuzumab was 11 months (interquartile range, (IQR) 5-27). Survival times in months (vs the systematic review) were: 90th percentile 8 (9); 75th percentile 16 (19); and median 34 (33). Follow-up duration was insufficient to estimate the 25th and 10th percentiles, similar to the systematic review. Liver metastases were associated with shorter survival (HR = 1.74, 95% CI, 1.1-2.76, P = .02). Seventy percent of patients had a baseline cardiac assessment. Five patients (3.9%) developed symptomatic cardiac toxicity, similar to clinical trials. CONCLUSION: Survival and cardiac toxicity rates for women starting trastuzumab in routine practice were comparable to clinical trials. Oncologists can use clinical trial data as a reference point when explaining survival outcomes to women with HER2-positive MBC.
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Antineoplásicos Inmunológicos/efectos adversos , Neoplasias de la Mama/mortalidad , Cardiotoxicidad/mortalidad , Pautas de la Práctica en Medicina/estadística & datos numéricos , Receptor ErbB-2/metabolismo , Trastuzumab/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Cardiotoxicidad/etiología , Cardiotoxicidad/patología , Femenino , Humanos , Persona de Mediana Edad , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: We assessed long-term cardiac safety and efficacy in patients with human epidermal growth factor receptor 2-positive early breast cancer treated with a trastuzumab biosimilar (SB3) or its reference product, trastuzumab (TRZ), in a phase 3 study. METHODS: Patients who completed the phase 3 study could be enrolled in this extension study. The outcomes included the incidence of symptomatic congestive heart failure (CHF), asymptomatic significant left ventricular ejection fraction (LVEF) decrease, incidence of other cardiac events, event-free survival (EFS), and overall survival. In post hoc analysis, the Cox proportional hazards regression model was used to assess factors associated with EFS. RESULTS: A total of 367 patients were enrolled in the study (SB3, n = 186; TRZ, n = 181). The median follow-up duration from the main study enrolment was 40.8 and 40.5 months for SB3 and TRZ, respectively. During the two-year follow-up after adjuvant therapy, incidence of asymptomatic significant LVEF decrease was rare (SB3, n = 1; TRZ, n = 2), with all patients recovering with LVEF ≥ 50%, and no cases of symptomatic CHF or other cardiac events were reported. At 3 years, the EFS was 91.9% with SB3 and 85.2% with TRZ. The number of patients with events was 17 (9.1%) with SB3 and 31 (17.1%) with TRZ [hazard ratio: 0.47, 95% confidence interval: 0.26-0.87]. Antibody-dependent cell-mediated cytotoxicity (ADCC) activity and the breast pathologic complete response rate were the factors associated with EFS. CONCLUSION: Cardiotoxicity was rare in this extension study. EFS was higher with SB3 versus TRZ, with post hoc analysis suggesting that a downward drift in ADCC activity was a contributing factor. CLINICAL TRIAL REGISTRATION NUMBERS: NCT02771795 (EudraCT 2015-005663-17).
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Biosimilares Farmacéuticos/uso terapéutico , Neoplasias de la Mama/mortalidad , Carcinoma Ductal de Mama/mortalidad , Carcinoma Lobular/mortalidad , Terapia Neoadyuvante/mortalidad , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapéutico , Adulto , Anciano , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/tratamiento farmacológico , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patología , Cardiotoxicidad/mortalidad , Quimioterapia Adyuvante , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Volumen Sistólico , Tasa de Supervivencia , Función Ventricular IzquierdaRESUMEN
Anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. Genetic determinants contributing to this variation are difficult to study using current mouse models. Our objective was to determine whether a spectrum of anthracycline induced cardiac disease can be elicited across 10 Collaborative Cross mouse strains given the same dose of doxorubicin. Mice from ten distinct strains were given 5 mg/kg of doxorubicin intravenously once weekly for 5 weeks (total 25 mg/kg). Mice were killed at acute or chronic timepoints. Body weight was assessed weekly, followed by terminal complete blood count, pathology and a panel of biomarkers. Linear models were fit to assess effects of treatment, sex, and sex-by-treatment interactions for each timepoint. Impaired growth and cardiac pathology occurred across all strains. Severity of these varied by strain and sex, with greater severity in males. Cardiac troponin I and myosin light chain 3 demonstrated strain- and sex-specific elevations in the acute phase with subsequent decline despite ongoing progression of cardiac disease. Acute phase cardiac troponin I levels predicted the ultimate severity of cardiac pathology poorly, whereas myosin light chain 3 levels predicted the extent of chronic cardiac injury in males. Strain- and sex-dependent renal toxicity was evident. Regenerative anemia manifested during the acute period. We confirm that variable susceptibility to doxorubicin-induced cardiotoxicity observed in humans can be modeled in a panel of CC strains. In addition, we identified a potential predictive biomarker in males. CC strains provide reproducible models to explore mechanisms contributing to individual susceptibility in humans.
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Antibióticos Antineoplásicos/efectos adversos , Cardiotoxicidad/etiología , Doxorrubicina/efectos adversos , Animales , Antibióticos Antineoplásicos/uso terapéutico , Biomarcadores , Biopsia , Cardiotoxicidad/mortalidad , Cruzamientos Genéticos , Modelos Animales de Enfermedad , Doxorrubicina/uso terapéutico , Femenino , Fibrosis , Cardiopatías/diagnóstico , Cardiopatías/etiología , Humanos , Masculino , RatonesRESUMEN
Background: With antiprogrammed death receptor-1 (anti-PD-L1) therapy, a recent meta-analysis reported higher incidence of cutaneous, endocrine and gastrointestinal complications especially with dual anti-PD-L1 immunotherapy (IMM). Methods: Our primary outcome was assessment of all cardiotoxicity grades in IMM compared with different treatments, thus a systemic review and a meta-analysis on randomized clinical trials (RCTs) were done. Results: We included 11 RCTs with 6574 patients (3234 patients in IMM arm vs 3340 patients in the other arm). Three non-small-cell lung cancer RCTs, seven melanoma RCTs and only one prostatic cancer RCT met the inclusion criteria. There were five RCTs that compared monoimmunotherapy to chemotherapy "(n = 2631 patients)". No difference exists in all cardiotoxicity grades or high-grade cardiotoxicity (p > 0.05). Lung cancer exhibited a higher response rate and lower mortality in IMM. Conclusion: There was no reported statistically significant cardiotoxicity associated with anti-PD/PD-L1 use. Lung cancer subgroups showed better response and survival rates.
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Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas , Inmunoterapia , Neoplasias Pulmonares , Melanoma , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Cardiotoxicidad/inmunología , Cardiotoxicidad/mortalidad , Cardiotoxicidad/patología , Cardiotoxicidad/prevención & control , Femenino , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Masculino , Melanoma/inmunología , Melanoma/mortalidad , Melanoma/patología , Melanoma/terapia , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Background: There is an unmet need for markers predicting the outcome of patients with advanced soft tissue sarcoma (STS) treated with pazopanib. Since toxicity might be related to the anti-tumor activity of the drug, the aim of this study was to determine whether pazopanib-induced proteinuria, hypothyroidism and cardiotoxicity grade 3-4 were associated with outcome. Methods: The combined results of the EORTC 62043 and 62072 trials were retrospectively assessed and used in a landmark analysis to evaluate the effect of the toxicities on progression-free survival (PFS) and overall survival (OS), using the Kaplan-Meier method and Cox regression models. Results: Of the 333 eligible patients, 259 patients were included in the analyses, for which a landmark time point of 60 days after randomization/registration was selected. Proteinuria occurred in 25.1%, hypothyroidism in 22.0% and cardiotoxicity grade 3-4 in 5.8% of the patients (any grade in 41.7%). There was no effect of the occurrence of proteinuria (6-months PFS 35.4% for patients with vs. 38.3% for patients without proteinuria, HR 1.01, p = .953), hypothyroidism (41.2% vs. 36.5%, HR 0.82, p = .210) or cardiotoxicity grade 3-4 (26.7% vs. 38.2%, HR 0.97, p = .897) on PFS. Nor was there an effect of proteinuria (6-months OS 63.2% for patients with vs. 74.4% for patients without proteinuria, HR 1.22, p = .196), hypothyroidism (76.2% vs. 70.5%, HR 0.75, p = .093) or cardiotoxicity grade 3-4 (80.0% vs. 77.2%, HR 0.93, p = .801) on OS. Conclusion: There was no association between the occurrence of pazopanib-induced proteinuria, hypothyroidism and cardiotoxicity and outcome. Therefore, these toxicities cannot be used as predictors for pazopanib activity in patients with advanced STS.
Asunto(s)
Inhibidores de la Angiogénesis/efectos adversos , Cardiotoxicidad/mortalidad , Hipotiroidismo/mortalidad , Proteinuria/mortalidad , Pirimidinas/efectos adversos , Sarcoma/tratamiento farmacológico , Sulfonamidas/efectos adversos , Cardiotoxicidad/etiología , Cardiotoxicidad/patología , Femenino , Estudios de Seguimiento , Humanos , Hipotiroidismo/inducido químicamente , Hipotiroidismo/patología , Indazoles , Masculino , Persona de Mediana Edad , Pronóstico , Proteinuria/inducido químicamente , Proteinuria/patología , Estudios Retrospectivos , Sarcoma/patología , Tasa de SupervivenciaRESUMEN
PURPOSE: Some recent studies have suggested a relationship between cardiac dose and mortality in non-small cell lung cancer (NSCLC), but others have reported conflicting data. The goal of this study was to conduct a systematic review and meta-analysis to provide an evidence-based estimate of the relationship between cardiac dose and mortality in these patients. METHODS AND MATERIALS: A systematic review of MEDLINE (PubMed) and Embase databases (inception to January 2018) was performed according to PRISMA guidelines. Studies that evaluated cardiac dosimetric factors in patients with NSCLC and included outcomes of cardiac events, cardiac mortality, and/or overall survival were identified. RESULTS: From 5614 patients across 22 studies, a total of 214 cardiac dosimetric parameters (94 unique) were assessed as possible predictors of cardiac toxicity or death. Assessed predictors included general (eg, mean heart dose [MHD]), threshold-based (eg, heart V5), and anatomic-based (eg, atria, ventricles) dosimetric factors. The most commonly analyzed parameters were MHD, heart V5, and V30. Most studies did not make corrections for multiplicity of testing. For overall survival, V5 was found to be significant on multivariable analysis (MVA) in 1 of 11 studies and V30 in 2 of 12 studies; MHD was not significant in any of 8 studies. For cardiac events, V5 was found to be significant on multivariable analysis in 1 of 2 studies, V30 in 1 of 3 studies, and MHD in 2 of 4 studies. A meta-analysis of the data could not be performed because most negative studies did not report effect estimates. CONCLUSIONS: Consistent heart dose-volume parameters associated with overall survival of patients with NSCLC were not identified. Multiplicity of testing is a major issue and likely inflates the overall risk of type I errors in the literature. Future studies should specify predictors a priori, correct for multiplicity of testing, and report effect estimates for nonsignificant variables.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Corazón/efectos de la radiación , Neoplasias Pulmonares/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Cardiotoxicidad/mortalidad , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Dosis de Radiación , Exposición a la RadiaciónRESUMEN
Some randomized controlled trials (RCTs) have tested the efficacy of beta-blockers as prophylactic agents on cancer therapy-induced cardiotoxicity; however, the quality of this evidence remains undetermined. This systematic review and meta-analysis study aims to evaluate the prophylactic effects of beta-blockers, especially carvedilol, on chemotherapy-induced cardiotoxicity. RCTs were identified by searching the MEDLINE (PubMed), Embase (OvidSP), Cochrane CENTRAL (OvidSP), etc., until December 2017. Inclusion criteria were randomized clinical trial and adult cancer patients started beta-blockers before chemotherapy. We evaluated the mean differences (MD) by fixed- or random-effects model and the odds ratio by Peto's method. Primary outcome was the left ventricular ejection fraction (LVEF) of patients after chemotherapy, and secondary outcomes were all-cause mortality, clinically overt cardiotoxicity, and other echocardiographic measurements. In total, we included six RCTs that used carvedilol as a prophylactic agent in patients receiving chemotherapy. The LVEF was not significantly distinct between those using carvedilol and placebo after chemotherapy (MD, 1.74; 95% confidence interval (CI), - 0.18 to 3.66; P = 0.08). The incidence of clinically overt cardiotoxicity was lower in the carvedilol group compared with the control group (Peto OR, 0.42; 95% CI, 0.20-0.89; P = 0.02). Furthermore, after chemotherapy, the LV end-diastolic diameter did not increase in the carvedilol group compared with the placebo group (MD, - 1.41; 95% CI, - 2.32 to - 0.50; P = 0.002). The prophylactic use of carvedilol exerted no impact on the early asymptomatic LVEF decrease but seemed to attenuate the frequency of clinically overt cardiotoxicity and prevent ventricular remodeling.
Asunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Cardiotoxicidad/epidemiología , Cardiotoxicidad/prevención & control , Carvedilol/uso terapéutico , Sustancias Protectoras/uso terapéutico , Adulto , Anciano , Antineoplásicos/efectos adversos , Cardiotoxicidad/etiología , Cardiotoxicidad/mortalidad , Ecocardiografía , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Volumen Sistólico , Resultado del Tratamiento , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Adulto JovenRESUMEN
We aimed to investigate the drug-drug interaction (DDI) between doxorubicin (DOX) and Dioscorea bulbifera L. (DB) solution in mice, and to explore the effect of P-glycoprotein (P-gp) on this type of DDI. The toxicity of DOX in the liver, kidneys, and heart was assessed with alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cr), urea nitrogen (BUN), creatine kinase MB (CK-MB), creatine kinase (CK) and histopathology. High-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) was used to determine the concentrations of DOX in the serum, liver, kidneys and heart. Immunohistochemistry and western blots were used to determine the expression levels of P-gp in these tissues. Our results demonstrated that, after co-administration of DOX and DB, survival was significantly decreased compared with either administration of DOX or DB alone, or water. Co-administration of DOX and DB induced elevated levels of toxicity in the heart and kidneys, but not the liver, compared with DOX alone. We conclude that concurrent treatment with DOX and DB results in increased levels of toxicity due to the accumulation of DOX in the body. Delayed excretion of DOX is associated with inhibition of P-gp in liver and kidneys.
Asunto(s)
Cardiotoxicidad/etiología , Dioscorea/química , Doxorrubicina/efectos adversos , Doxorrubicina/farmacocinética , Riñón/efectos de los fármacos , Extractos Vegetales/efectos adversos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Cardiotoxicidad/metabolismo , Cardiotoxicidad/mortalidad , Interacciones de Hierba-Droga , Riñón/metabolismo , Riñón/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Mortalidad , Distribución TisularRESUMEN
Cardiotoxicity is a known risk of anthracycline treatment. However, the relative contribution of anthracyclines to the development of congestive heart failure (CHF), when included in a poly-chemotherapy regimen, is unclear. We examined cardiotoxicity in adult patients with diffuse large B-cell lymphoma and follicular lymphoma undergoing first-line immunochemotherapy from 2000-2012. In total, 2440 patients without previous heart disease were identified from the Danish Lymphoma Registry, of which 1994 (81·7%) were treated with anthracycline-containing chemotherapy [R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) or R-CHOEP (R-CHOP + etoposide)] and 446 (18·3%) were treated without anthracyclines (reference group). Compared to the reference group, the adjusted hazard ratio of CHF after 3-5 cycles of R-CHOP/CHOEP was 5·0 [95% confidence interval (CI) 1·4; 18·5], 6 cycles 6·8 (95% CI 2·0; 23·3) and >6 cycles 13·4 (95% CI 4·0; 45·0). The cumulative 5-year risk of CHF with all-cause mortality as competing risk was 4·6% after 3-5 cycles of R-CHOP/CHOEP, 4·5% after 6 and 7·9% after more than 6 cycles. Cumulative 5-year risk for patients treated without anthracyclines was 0·8%. Using anthracyclines in first-line lymphoma treatment increases risk of CHF in patients without previous history of heart disease. In particular, treatment with >6 cycles of R-CHOP/CHOEP is associated with a significant increase in CHF rate.
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Antraciclinas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Arritmias Cardíacas/inducido químicamente , Insuficiencia Cardíaca/inducido químicamente , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Arritmias Cardíacas/mortalidad , Cardiotoxicidad/etiología , Cardiotoxicidad/mortalidad , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Dinamarca/epidemiología , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Insuficiencia Cardíaca/mortalidad , Humanos , Inmunoterapia/efectos adversos , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/mortalidad , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Prednisona/efectos adversos , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo , Rituximab , Vincristina/administración & dosificación , Vincristina/efectos adversos , Adulto JovenRESUMEN
BACKGROUND: Cardiac damage caused by oncological therapy may manifest early or many years after the exposure. OBJECTIVES: To determine the differences between sub-acute and late-onset cardiotoxicity in left ventricular ejection fraction (LVEF) recovery as well as long-term prognosis. METHODS: We studied 91 patients diagnosed with impaired systolic function and previous exposure to oncological therapy. The study population was divided according to sub-acute (from 2 weeks to ≤ 1 year) and late-onset (> 1 year) presentation cardiotoxicity. Recovery of LVEF of at least 50% was defined as the primary end point and total mortality was the secondary end point. RESULTS: Fifty-three (58%) patients were classified as sub-acute, while 38 (42%) were defined as late-onset cardiotoxicity. Baseline clinical characteristics were similar in the two groups. The mean LVEF at presentation was significantly lower among patients in the late-onset vs. sub-acute group (28% vs. 37%, respectively, P < 0.001). Independent predictors of LVEF recovery were trastuzumab therapy and a higher baseline LVEF. Although long-term mortality rates were similar in the groups with sub-acute and late-onset cardiotoxicity, improvement of LVEF was independently associated with reduced mortality. CONCLUSIONS: Our findings suggest that early detection and treatment of oncological cardiotoxicity play an important role in LVEF recovery and long-term prognosis.
Asunto(s)
Antineoplásicos/efectos adversos , Cardiotoxicidad/epidemiología , Corazón/efectos de los fármacos , Trastuzumab/efectos adversos , Función Ventricular Izquierda/efectos de los fármacos , Cardiotoxicidad/etiología , Cardiotoxicidad/mortalidad , Femenino , Corazón/fisiopatología , Humanos , Israel/epidemiología , Masculino , Persona de Mediana Edad , Pronóstico , Recuperación de la Función/efectos de los fármacos , Factores de TiempoRESUMEN
This review summarizes the cardiovascular non-inferiority trials of novel antidiabetic drugs performed since 2008, when regulatory agencies started mandating thorough examination of their cardiovascular safety. So far, eight randomized trials on three different drug classes have been completed. Sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists may reduce cardiovascular risk and possibly mortality, while dipeptidyl dipeptidase-4 inhibitors may increase the risk of heart failure. A brief discussion of potential mechanisms and clinical implications is provided.
Asunto(s)
Enfermedades Cardiovasculares , Hipoglucemiantes , Cardiotoxicidad/etiología , Cardiotoxicidad/mortalidad , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/prevención & control , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Infarto del Miocardio/inducido químicamente , Infarto del Miocardio/mortalidad , Infarto del Miocardio/prevención & control , Factores de Riesgo , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacocinética , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Accidente Cerebrovascular/inducido químicamente , Accidente Cerebrovascular/mortalidad , Accidente Cerebrovascular/prevención & controlRESUMEN
Cardiotoxicity is a dose-limiting and potentially lethal complication of anthracycline administration. Previous studies failed to determine definitive toxic doses or cardioprotective factors. Current dosing strategies may utilize unnecessarily high anthracycline doses, such that survival benefit may not outweigh increased toxicity rates. A systematic review of randomized controlled trials and prospective/retrospective studies investigating anthracycline treatment in pediatric solid tumors was performed from PubMed/MEDLINE and Cochrane databases. Generalized linear models mapping survival, cardiotoxicity, and cardiotoxicity-free survival adjusted for male-to-female ratio, follow-up time, and concomitant chemotherapeutic drugs or cardioprotective agents (dexrazoxane) were generated using R. Survival rose linearly with increasing cumulative anthracycline dose whereas cardiotoxicity demonstrated exponential increases both without (dose, >200 mg/m) and with (dose, >400 mg/m) dexrazoxane. Maximum cardiotoxicity-free survival was 268.2 mg/m without and 431.8 mg/m with dexrazoxane. Despite increasing cardiotoxicity-free dose by >150 mg/m, dexrazoxane minimally improved projected survival (71.9% vs. 75.4%). Cardiotoxicity increased linearly as a function of follow-up time with rates doubling from 5 to 20 years, without evidence of plateau. On the basis of our model, current dosing regimens-doxorubicin doses >375 mg/m without dexrazoxane-overvalue increased anthracycline administration and may contribute to devastating cardiotoxicity. The linear increase of cardiotoxicity without evidence of plateau confirms the necessity for lifelong cardiac monitoring.