Strain longitudinal global como preditor de cardiotoxicidade induzida por quimioterapia / Global longitudinal strain as predictor of chemotherapy-induced cardiotoxicity

Fundamento: A cardiotoxicidade induzida por quimioterapia (CiC) é uma complicação importante entre os pacientes que recebem antraciclinas. Biomarcadores e parâmetros de imagem têm sido estudados por sua capacidade de identificar pacientes com risco de desenvolver essa complicação. O strain longitudinal global do ventrículo esquerdo (SLG-VE) tem sido descrito como um parâmetro sensível para detectar disfunção sistólica, mesmo na presença de fração de ejeção do ventrículo esquerdo (FEVE) preservada. Objetivo: avaliar o papel do SLG-VE como preditor de CiC. Métodos: O presente estudo consiste em uma análise post-hoc do estudo CECCY (Carvedilol for Prevention of ChemotherapyRelated Cardiotoxicity [Carvedilol para Prevenção da Cardiotoxicidade Relacionada à Quimioterapia]), que avaliou a prevenção primária de cardiotoxicidade com carvedilol durante quimioterapia com doxorrubicina em uma população com câncer de mama. Definiu-se cardiotoxicidade como uma redução >10% na FEVE. O SLG-VE foi obtido antes da quimioterapia em pacientes sem doença cardiovascular prévia ou anormalidades no ecocardiograma. Resultados: Trinta e um pacientes submetidos a estudo ecocardiográfico completo incluindo avaliação de SLG-VE antes da quimioterapia foram incluídos nesta análise. Um SLG-VE absoluto <16,9% antes da quimioterapia mostrou 100% de sensibilidade e 73% de especificidade para predizer cardiotoxicidade (AUC=0,85; IC 95% 0,680­0,959, p<0,001). Nesta população, os valores de FEVE antes da quimioterapia não foram preditores de CiC (IC 95% 0,478 a -0,842, p=0,17). A associação de baixos níveis séricos de SLG-VE (<17%) e BNP (>17 pg/mL) dois meses após a quimioterapia aumentou a precisão para detectar CiC de início precoce (100% de sensibilidade, 88% de especificidade, AUC=0,94; IC 95% 0,7810,995, p<0,0001). Conclusões: Nossos dados sugerem que o SLG-VE é um possível preditor de cardiotoxicidade induzida por quimioterapia. São necessários estudos maiores para confirmar a relevância clínica desse parâmetro ecocardiográfico nesse cenário clínico. (AU)

Background: Chemotherapy-induced cardiotoxicity (ChC) is an important complication among patients receiving anthracyclines. Biomarkers and imaging parameters have been studied for their ability to identify patients at risk of developing ChC. Left ventricular global longitudinal strain (LV-GLS) is a sensitive parameter for detecting systolic dysfunction despite the presence of preserved left ventricular ejection fraction (LVEF). Objective: To evaluate the role of the LV-GLS as a predictor of ChC. Methods: This was a post-hoc analysis of the Carvedilol for Prevention of Chemotherapy-Related Cardiotoxicity trial, which evaluated the primary prevention of cardiotoxicity with carvedilol during doxorubicin chemotherapy in a population of patients with breast cancer. Cardiotoxicity was defined as a reduction ≥10% in LVEF. LV-GLS was determined before chemotherapy in patients with no prior cardiovascular disease or echocardiogram abnormalities. Results: Thirty-one patients for whom a complete echocardiography study including measurement of LV-GLS was performed before chemotherapy were included in this analysis. An absolute LV-GLS<16.9% before chemotherapy showed 100% sensitivity and 73% specificity for predicting cardiotoxicity (area under the curve [AUC], 0.85; 95% confidence interval [CI], 0.680­0.959; p<0.001). In this population, LVEF values before chemotherapy did not predict ChC (95% CI, 0.478 to -0.842; p=0.17). The association of low LV-GLS (<17%) and brain-type natriuretic peptide serum levels (>17 pg/mL) at 2 months after chemotherapy increased the accuracy for detecting early-onset ChC (100% sensitivity, 88% specificity; AUC, 0.94; 95% CI, 0.781­0.995; p<0.0001). Conclusions: Our data suggest that LV-GLS is a potential predictor of ChC. Larger studies are needed to confirm its clinical relevance in this clinical setting. (AU)

Disfunção diastólica precoce em pacientes com câncer de mama submetidas à quimioterapia / Early diastolic dysfunction in breast cancer patients undergoing chemotherapy

Fundamento: A quimioterapia para o câncer de mama está associada a complicações cardiovasculares graves, como a insuficiência cardíaca. A fração de ejeção do ventrículo esquerdo é o principal parâmetro para avaliar a função sistólica nessas pacientes. Todavia, a ocorrência de disfunção diastólica pode preceder à disfunção sistólica. Objetivos: Avaliar as funções diastólica e sistólica do ventrículo esquerdo de portadoras de câncer de mama em tratamento quimioterápico com antraciclinas. Métodos: Trata-se de estudo observacional, longitudinal, analítico e prospectivo. Estudaram-se 62 mulheres com câncer de mama, com idades de 21 a 75 anos, que realizaram ecocardiogramas basais e após 3 meses de tratamento. Avaliaram-se parâmetros de função diastólica, e as pacientes foram classificadas em disfunção diastólica tipos:1, 2 ou 3. Definiu-se a disfunção sistólica como fração de ejeção do ventrículo esquerdo ≤ 53%. Resultados: Decorridos 3 meses de tratamento, 35 pacientes (56,4%) apresentavam disfunção diastólica tipo 1, e apenas uma (1,6%) do tipo 2. A disfunção diastólica ocorreu em 26 pacientes já na etapa basal e surgiu em dez indivíduos no decurso do tratamento. Os parâmetros de função diastólica velocidade de onda E e relação E/A diminuíram significativamente (p < 0,05) com a quimioterapia, todavia, os demais não tiveram variação significativa. Apenas três pacientes apresentaram disfunção sistólica, porém verificou-se maior redução da fração de ejeção do ventrículo esquerdo no grupo que desenvolveu disfunção diastólica durante o tratamento comparativamente ao grupo que apresentava já disfunção diastólica no período basal (p = 0,04). Conclusão: A disfunção diastólica ocorre precocemente em portadoras de câncer de mama submetidas à quimioterapia. O surgimento de disfunção diastólica no decurso do tratamento se associa à redução significativa da fração de ejeção do ventrículo esquerdo. (AU)

Background: Chemotherapy for breast cancer is associated with serious cardiovascular complications such as heart failure. The left ventricular ejection fraction is the main parameter used to assess systolic function in these patients. However, the occurrence of diastolic dysfunction may precede that of systolic dysfunction. Objectives: To evaluate left ventricle diastolic and systolic functions in women with breast cancer undergoing chemotherapy using anthracyclines. Methods: This observational, longitudinal, analytical, and prospective study included 62 women with breast cancer aged 21­75 years old who underwent echocardiography at baseline and after three months of treatment. Diastolic function parameters were evaluated, and the patients were classified as diastolic dysfunction type 1, 2, or 3. Systolic dysfunction was defined as a left ventricular ejection fraction ≤ 53%. Results: After three months of treatment, 35 patients (56.4%) had type 1 diastolic dysfunction, while one (1.6%) had type 2. Diastolic dysfunction was identified in 26 patients at baseline and developed in 10 patients during treatment. Diastolic function parameters, E wave velocity, and E/A ratio decreased significantly (p < 0.05) with chemotherapy; however, the others showed no significant variations. Only three patients had systolic dysfunction, but there was a greater reduction in left ventricular ejection fraction in the group that developed diastolic dysfunction during treatment versus the group with diastolic dysfunction at baseline (p = 0.04). Conclusion: Diastolic dysfunction occurs early in women with breast cancer undergoing chemotherapy. Its onset during the course of treatment is associated with a significantly reduced left ventricular ejection fraction. (AU)

Factores predictivos de cardiotoxicidad inducida por antraciclinas en una cohorte retroprolectiva de niños supervivientes de cáncer / Predictors of anthracycline-induced cardiotoxicity in a retro-prolective cohort of children surviving cancer

Resumen Introducción: La cardiotoxicidad es una reacción adversa asociada al uso de antraciclinas. Objetivo: Estimar los factores asociados al desarrollo de cardiotoxicidad por antraciclinas en pacientes pediátricos supervivientes de cáncer. Método: Cohorte retroprolectiva de niños con diagnóstico de cáncer tratados con antraciclinas. Se realizó determinación ecocardiográfica basal de la fracción de expulsión (FEVi0) antes del inicio del tratamiento y a los 12 meses (FEVi1). Del expediente se obtuvieron las características demográficas y el tratamiento. Se realizó un modelo de regresión logística múltiple (RLM); la FEVi1 < 50 % fue la variable dependiente, que se ajustó por las principales variables confusoras. Resultados: Se incluyeron 65 pacientes, 36.9 % fue del sexo femenino y 56.8 % presentó un tumor sólido. La FEVi0 fue de 74.79 ± 7.3 % y la FEVi1, de 67.96 ± 6.7 % (p = 0.001); 60 % desarrolló cardiotoxicidad. En la RLM solo la dosis acumulada > 430 mg se asoció a cardiotoxicidad (p = 0.001). Conclusiones: En los niños mexicanos se debe evitar una dosis acumulada > 430 mg de antraciclinas para evitar la cardiotoxicidad.

Abstract Introduction Cardiotoxicity is an adverse reaction associated with the use of anthracyclines. Objective: To estimate the factors associated with the development of anthracycline cardiotoxicity in pediatric patients surviving cancer. Method: Retro-prolective cohort of children diagnosed with cancer and treated with anthracyclines. Baseline echocardiographic determination of ejection fraction (LVEF0) was carried out before the start of treatment and again at 12 months (LVEF1). Demographic characteristics and treatment were obtained from the medical record. A multiple logistic regression (MLR) model was constructed; LVEF1 < 50 % was the dependent variable, which was adjusted for the main confounding variables. Results: Sixty-five patients were included, out of which 36.9 % were females and 56.8 % had a solid tumor. LVEF0 was 74.79 ± 7.3 % and LVEF1, 67.96 ± 6.7 % (p = 0.001); 60 % developed cardiotoxicity. In the MLR, only a cumulative dose > 430 mg was associated with cardiotoxicity (p = 0.001). Conclusions: In Mexican children, an anthracycline cumulative dose > 430 mg should be avoided in order to prevent cardiotoxicity.

High-dose tamoxifen plus ifosfamide and anthracycline in a patient with angiosarcoma of the breast / Tamoxifen en dosis alta con ifosfamida y antraciclina en un paciente con angiosarcoma de mama

Although breast cancer is, unfortunately, not uncommon in women, a mere 0.04% of malignant breast tumours are primary angiosarcomas. Chemotherapy is advocated for treatment of breast angiosarcomas; however, no guidelines exist regarding optimal chemotherapeutics or protocols. Presently, the prognosis for breast angiosarcomas is poor. This case report describes a 24-year old woman diagnosed with primary breast angiosarcoma. She initially refused to receive treatment, but later returned to the hospital four years later with a haemopneumothorax. She was treated with rescue chemotherapy using a combination of high-dose tamoxifen plus ifosfamide and epirubicin (an anthracycline). She achieved a partial response, but died 16 months after therapy was initiated. More research is needed to devise novel chemotherapeutics and protocols to improve outcomes in women diagnosed with primary angiosarcomas ofthe breast.

Aunque el cáncer de mama, desafortunadamente, no es poco común en las mujeres, apenas 0.04% de los tumores malignos de mama son angiosarcomas primarios. La quimioterapia es el tratamiento de preferencia en los casos de angiosarcomas de mama. Sin embargo, no existen guías en relación con los protocolos o la quimioterapia óptima. En la actualidad, el pronóstico para los angiosarcomas de mama es pobre. Este informe del caso describe a una mujer de 24 años diagnosticada con angiosarcoma primario de mama. Inicialmente la paciente se negó a recibir tratamiento, pero volvió al hospital cuatro años más tarde con un hemoneumotórax. Fue tratada entonces con quimioterapia de rescate usando una combinación de alta dosis de tamoxifen con ifosfamida y epirrubicina (antraciclina). Llegó a responder parcialmente al tratamiento, pero falleció 16 meses después del inicio de la terapia. Se necesitan más investigaciones para elaborar nuevos quimioterápeuticos y protocolos que mejoren los resultados en los casos de mujeres diagnosticadas con angiosarcomas primarios de mama.

Effect of neoadjuvant chemotherapy on stromal CD10 antigens in breast cancer - A preliminary study.

Introduction: CD10 is a zinc-dependent peptidase (metalloproteinase). Stromal CD10 expression in breast cancer correlates with poor prognosis, oestrogen receptor negativity and higher grade. CD10 may be a potential target of new cancer therapies as it is involved in cleavage of doxorubicin. Aim: To evaluate the effect of neo-adjuvant anthracycline-based chemotherapy on status of stromal CD10 antigens in breast cancer. Materials and Methods: Patients with invasive breast cancer scheduled for anthracycline-based neo-adjuvant chemotherapy were included in the study. Tumor stromal CD10 expression was estimated before and after 3 cycles of chemotherapy, and change in its status was correlated with clinical response to chemotherapy. Results: 16 out of the 29 patients had strong CD10 expression; in these 16 patients, 14 (87.5%) were hormone receptor negative, and 14 (87.5%) had HER-2/neu overexpression. Stromal CD10 expression remained same in 13 out of 29 cases (44.83%) after chemotherapy. There was a change in CD10 expression in the remaining 16 cases (55.17%); in 13 cases (44.83%) it decreased from its pre-chemotherapy status, while its expression increased in 3 cases (10.34%). In cases of complete and partial clinical response, there was no increase in CD10 expression. Where CD10 expression had increased after chemotherapy, there was either a minor response or no response to chemotherapy. In 13 cases where CD10 expression had decreased, 12 cases had a clinical response to chemotherapy. Conclusions: Strong CD10 expression correlates with hormone receptor negativity and HER-2/neu overexpression. Stromal CD10 expression in breast cancer is not static and changes with neo-adjuvant anthracycline-based chemotherapy. A stable or decrease in CD10 expression correlates with complete or partial clinical response, while an increase in CD10 expression appears to correlate with poor clinical response. A larger series is required to determine the clinical significance of these changes. As stromal CD10 expression and its change with chemotherapy may have a prognostic significance, they should be documented in breast cancer patients before and after chemotherapy.

Adjuvant chemotherapy with six cycles of AC regimen versus three cycles of AC regimen followed by three cycles of Paclitaxel in node-positive breast cancer.

Context: Antracycline-Cyclophosphamide (AC) along with Paclitaxel/Docetaxel, either in combination or sequential regimens, is showing superior results than Anthracycline-containing regimens. Aims: This study was designed to determine whether adding Paclitaxel to a standard adjuvant chemotherapy regimen AC for breast cancer patients would prolong the time to recurrence and survival. Settings and Design: Randomized, prospective, open-labeled, single-institutional study. Materials and Methods: Fifty stage II breast cancer patients accruing 25 patients in each arm, treated between July 2007 and January 2010, were included in the study. Initial surgical treatment was Modified Radical Mastectomy. Systemic therapy was to have begun within 4-6 weeks of the patient's surgery. In the control arm, all the patients were treated with six cycles of adjuvant chemotherapy with AC regimen repeated at an interval of 3 weeks. For the study arm, the patients received adjuvant chemotherapy with three cycles of AC regimen followed by three cycles of Paclitaxel, repeated at an interval of 3 weeks. All the patients of both the arms received locoregional external beam radiotherapy (EBRT) after the entire course of chemotherapy. All the hormone receptor-positive patients received Tamoxifen. Statistical Analysis Used: Statistical analysis was performed using the chi-square test and the Kaplan Meier survival analysis with the log-rank (Mantel-Cox) test. Results: Adding Paclitaxel to AC resulted in a statistically significant disease-free survival. The overall survival was also improved significantly. The toxicity profile in both the arms was comparable. Conclusions: In early and node-positive breast cancer, the addition of three cycles of Paclitaxel after completion of three cycles of AC improves the disease-free and overall survival.

Clinical and pathological response rates of docetaxel-based neoadjuvant chemotherapy in locally advanced breast cancer and comparison with anthracycline-based chemotherapies: Eight-year experience from single centre.

Introduction: The administration of neoadjuvant chemotherapy (NACT) prior to local therapy is advantageous for women with locally advanced breast cancer (LABC), since it can render inoperable tumors resectable and can increase rates of breast conservative surgeries. Materials and Methods: We retrospectively analyzed LABC patients who received NACT from January 2000 to December 2007. Out of 3000 case records screened, 570 (19%) were LABC and 110/570 (19%) treatment-naïve patients started on NACT were analyzed. Ninety-one (37 docetaxel [D], 54 anthracycline [A]) patients were eligible for response and survival analysis. Pathological complete remission (pCR) was defined as no evidence of malignancy in both breast and axilla. Results: Median age of the whole cohort was 45 years (range 25-68 years). Premenopausal were 42% and estrogen receptor + 49.5%. Most (90%) were T4 tumors and 70% were Stage IIIB. Median numbers of preoperative cycles were six and three in the D and A group respectively. Overall clinical response rates for breast primary were 74.3% and 53.7% (CR 28.6% vs. 16.7%, P=0.58) while for axilla ORR were 75.7% vs. 54.8% (51.4% vs. 40.4% CR, P=0.77) respectively for D and A. Corresponding pCR rates were 19% vs. 13% respectively. There was no significant difference in disease-free (three-year 56.84% vs. 61.16%, P=0.80) and overall survival (three-year 70% vs. 78.5%, P=0.86) between the two groups. Conclusions: Although pCR rates were higher with docetaxel-based NACT, it did not translate into superior disease-free survival / overall survival compared to anthracycline-based chemotherapies.

Insuficiência cardíaca induzida pela quimioterapia: mecanismos e tratamentos / Chemotherapy-induced heart failure: mechanisms and treatments

Nas últimas décadas, o advento de estratégias de tratamento para diversos tipos de tumores permitiu aos pacientes oncológicos longa sobrevida, possibilitando o desenvolvimento de complicações cardiovasculares em grande número de pacientes. A incidência e a gravidade das lesões dependem do quimioterápico administrado, da dose cumulativa empregada, da presença prévia ou não de cardiomiopatias, da existência de comorbidades e da utilização de outros tratamentos utilizados, tais como a radioterapia. A quimioterapia pode levar a toxicidade cardiovascular, manisfestada pela ocorrência de miocardiopatia com ou sem insuficiência cardíaca, disfunção endotelial e arritmias. Apesar de os efeitos dos quimioterápicos e de a incidência de cardiomiopatia estarem bem documentados, ainda não existem estudos específicos direcionados para o tratamento dessa população de pacientes. A base do tratamento proposto tem sido a mesma utilizada para outras formas de agressões miocárdicas, ou seja, fundamentada no uso de inibidor da enzima de conversão. betabloqueador e diuréticos.

Over the last decades, the advent of new and effective treatments for different tumor types has enabled oncologic patients to live longer, however, a large number of these patients develop cardiovascular complications. The incidence and severity of the lesions depend on the type of chemotherapy drug used, cumulative dose, presence of coexisting cardiac disease, others co- morbidities and the association with other treatments such as radiotherapy. Chemotherapy may lead to cardiovascular toxicity, which is manifested by cardiomyopathy with or without heart failure, endothelial lesion and arrhythmias. Although the potential cardiac effects of chemotherapy and cardiomyopathy have been well documented, there is a lack of specific studies focusing on the treatment of this population of patients. The proposed therapy has been the same as that used in other types of myocardial lesions, i.e., the use of angiotensin converting enzyme, betablockers and diuretics.