RESUMO
Human epidermal growth factor receptor (HER)2 imaging with radiolabeled trastuzumab might support HER2-targeted therapy. It is, however, frequently questioned whether HER2 imaging is also possible during trastuzumab treatment as the receptor might be saturated. We studied the effect of trastuzumab treatment on 111In-trastuzumab uptake. Patients received trastuzumab weekly and paclitaxel once every 3 weeks. 111In-trastuzumab was injected on day 1 of cycle 1 and day 15 of cycle 4. Whole-body planar scintigraphy was acquired at different time points postinjection. Tumor uptake and organ distribution between the first and repeated scan series were calculated via residence times. Twenty-five tumor lesions in 12 patients were visualized on both scintigraphy series. Tumor uptake decreased (19.6%; p â=â .03). The residence times of normal organs remained similar except for the cardiac blood pool (+ 16.3%; p â=â .014). Trastuzumab treatment decreases tumor 111In-trastuzumab uptake around 20%. HER2 imaging is feasible during trastuzumab treatment.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Radioisótopos de Índio , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Esquema de Medicação , Feminino , Humanos , Metástase Neoplásica/diagnóstico por imagem , Metástase Neoplásica/tratamento farmacológico , Paclitaxel/administração & dosagem , Cintilografia , Receptor ErbB-2/metabolismo , TrastuzumabRESUMO
Cardiovascular toxicity is one of the most devastating complications of cancer treatment and can arise during or shortly after treatment, or even several years later. Identification of the left ventricular ejection fraction (LVEF) is the most common method to screen for toxic effects on the heart; however, this approach underestimates cardiac damage and additional strategies for the monitoring of treatment-induced cardiotoxicity are being explored. Guidelines for monitoring have been formulated for several cancer treatments; however, appropriate underlying evidence is still largely absent. In this Review, we summarise conventional and contemporary methods for early detection of cardiotoxicity and designate a level of evidence for the basis of each method.
Assuntos
Antineoplásicos/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/diagnóstico , Coração/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Diagnóstico Precoce , HumanosRESUMO
BACKGROUND: The use of trastuzumab, an antibody against the human epidermal growth factor receptor 2 (HER2), in patients with HER2 positive metastatic breast cancer, is related to cardiotoxicity. AIMS: To investigate whether serum HER2 is increased in heart failure patients and related to disease severity. METHODS: Serum HER2, plasma tumor necrosis factor (TNF)-alpha and its soluble (s) receptors (sTNF-R1 and 2) were determined with ELISA in chronic heart failure patients and age and gender-matched healthy controls. RESULTS: Serum HER2 was higher (P=0.013) in 50 heart failure patients (18 female; median age 57 (range 33-77) years), mean 12.1+/-S.D. 2.3 ng/mL, than in 15 controls, 10.4+/-2.6 ng/mL. Serum HER2 levels correlated inversely with left ventricular ejection fraction (P=0.037) and were highest among NYHA class III patients, followed by NYHA class II patients and controls (P=0.029, Kruskal-Wallis test). STNF-R1 (P<.001) and sTNF-R2 (P=0.015) were higher in patients than controls, and correlated positively with HER2 (P=0.027 and P=0.036, respectively). CONCLUSIONS: Serum HER2 levels are increased in chronic heart failure patients. Further research is necessary to determine whether HER2 plays a role in the pathophysiology of heart failure.
Assuntos
Genes erbB-2/fisiologia , Insuficiência Cardíaca/sangue , Adulto , Idoso , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença , Perfil de Impacto da Doença , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: Circulating apoptotic proteins are increased in heart failure patients. We evaluated whether circulating soluble apoptosis-related protein levels change after anthracycline-containing chemotherapy and radiotherapy in relation to cardiac dysfunction or the applied treatment. PATIENTS AND METHODS: Circulating apoptotic proteins were measured with immunoassay in 40 breast cancer patients following surgery (TO), one month (T1) and one year (T2) after epirubicin-based chemotherapy. Standard-dose (n=21) or high-dose (n=19) myeloablative chemotherapy, preceded irradiation and tamoxifen. Circulating apoptotic proteins were compared with previous cardiac evaluations. RESULTS: Soluble tumor necrosis factor receptor 1 (+30%), 2 (+43%) and Fas (+40%) were transiently increased at T1 compared to T0, whereas Fas ligand (-64%) was transiently decreased, especially in the high-dose group. Apoptosis markers were not associated with cardiac dysfunction. CONCLUSION: Significant, but transient changes in soluble apoptotic protein levels were observed, particularly after high-dose chemotherapy. No relation was found between apoptosis-related proteins and cardiotoxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose , Proteínas Sanguíneas/análise , Neoplasias da Mama/tratamento farmacológico , Coração/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/sangue , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Tamoxifeno/administração & dosagemRESUMO
In recent years, apoptosis has increasingly drawn the attention of both oncologists and cardiologists alike. Anticancer treatment is possible by induction of apoptosis in cancer cells, and targeted anticancer drugs are being developed to promote this. However, since these drugs usually are not selective for malignant cells, side effects on non-cancerous tissue, such as the myocardium must be anticipated. Since apoptosis is a pathophysiological mechanism in cardiac diseases leading to heart failure, cardiologists in contrast to oncologists, aim at preventing apoptosis in the heart. The purpose of this review is to describe new insights in mechanisms of cardiomyocyte apoptosis. In addition to the mitochondrial and death receptor apoptotic pathways, apoptosis through lack or inhibition of growth factor receptor-mediated signalling is discussed. Exploration of the apoptotic pathways in the heart can contribute to the safer use of new anticancer drugs and to the development of new therapies for heart failure.
Assuntos
Antineoplásicos/efeitos adversos , Apoptose/fisiologia , Miócitos Cardíacos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Transdução de Sinais/fisiologia , Coração/efeitos dos fármacos , HumanosRESUMO
Trastuzumab (Herceptin) is a recombinant humanised IgG1 monoclonal antibody against the human epidermal growth factor receptor 2 (HER2), used for metastatic breast cancer treatment. Radiolabelled trastuzumab may have several future applications for diagnostic use. The aim of the present study was to develop clinical grade (111)Indium ((111)In) radiolabelled trastuzumab, to evaluate the stability and immunoreactivity of the tracer and to perform a biodistribution study in human tumour-bearing mice. Trastuzumab was radiolabelled with (111)In using DTPA as a chelator. (111)In-DTPA-trastuzumab (labelling yield 92.3+/-2.3%, radiochemical purity 97.0+/-1.5%) is stable in PBS when stored at 4 degrees C for more than 14 days. The immunoreactive fraction determined by cell-binding assays, using the HER2-overexpressing human ovarian SK-OV-3 tumour cell line, was 0.87+/-0.06. Biodistribution and tumour targeting were studied in HER2 receptor-positive and -negative tumour-bearing athymic mice. The HER2-positive tumour showed (9.77+/-1.14% injected dose per gram (ID g(-1))) substantial uptake of the labelled antibody already after 5 h. The difference in uptake between HER2-positive versus -negative tumours was even more pronounced 3 days after injection (16.30+/-0.64% ID g(-1)), and was visualised by radioimmunoscintigraphy. Liver, spleen and kidney showed marked tracer uptake. In summary, trastuzumab can be efficiently radiolabelled with (111)In with high labelling yields and high stability. (111)In-DTPA-trastuzumab selectively binds to the human HER2 receptor both in vitro and in vivo in animals. Therefore, (111)In-DTPA-trastuzumab appears suitable for clinical use.
Assuntos
Neoplasias da Mama/radioterapia , Ácido Pentético/análogos & derivados , Ácido Pentético/farmacocinética , Compostos Radiofarmacêuticos/uso terapêutico , Animais , Neoplasias da Mama/terapia , Estabilidade de Medicamentos , Imuno-Histoquímica , Índio/farmacocinética , Marcação por Isótopo , Camundongos , Camundongos Nus , Transplante de Neoplasias , Controle de Qualidade , Compostos Radiofarmacêuticos/farmacocinética , Distribuição TecidualAssuntos
Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Fator Natriurético Atrial/sangue , Peptídeo Natriurético Encefálico/sangue , Precursores de Proteínas/sangue , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Humanos , Neoplasias/sangue , Neoplasias/epidemiologia , Neoplasias/fisiopatologia , Valor Preditivo dos TestesAssuntos
Antraciclinas/efeitos adversos , Fármacos Cardiovasculares/uso terapêutico , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/prevenção & controle , Animais , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Modelos Cardiovasculares , Razoxano/uso terapêutico , Volume Sistólico/efeitos dos fármacosRESUMO
We determined the efficiency of a screening protocol based on coronary calcium scores (CCS) compared with exercise testing in patients with suspected coronary artery disease (CAD), a normal ECG and troponin levels. Three-hundred-and-four patients were enrolled in a screening protocol including CCS by electron beam computed tomography (Agatston score), and exercise testing. Decision-making was based on CCS. When CCS>or=400, coronary angiography (CAG) was recommended. When CCS<10, patients were discharged. Exercise tests were graded as positive, negative or nondiagnostic. The combined endpoint was defined as coronary event or obstructive CAD at CAG. During 12+/-4 months, CCS>or=400, 10-399 and <10 were found in 42, 103 and 159 patients and the combined endpoint occurred in 24 (57%), 14 (14%) and 0 patients (0%), respectively. In 22 patients (7%), myocardial perfusion scintigraphy was performed instead of exercise testing due to the inability to perform an exercise test. A positive, nondiagnostic and negative exercise test result was found in 37, 76 and 191 patients, and the combined endpoint occurred in 11 (30%), 15 (20%) and 12 patients (6%), respectively. Receiver-operator characteristics analysis showed that the area under the curve of 0.89 (95% CI: 0.85-0.93) for CCS was superior to 0.69 (95% CI: 0.61-0.78) for exercise testing (P<0.0001). In conclusion, measurement of CCS is an appropriate initial screening test in a well-defined low-risk population with suspected CAD.
Assuntos
Calcinose/diagnóstico , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico , Teste de Esforço/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Eletrocardiografia , Feminino , Coração/diagnóstico por imagem , Humanos , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Cintilografia , Fatores de Risco , Sensibilidade e Especificidade , Troponina/sangueRESUMO
The monoclonal antibody against HER2, trastuzumab (Herceptin), has become an important player in the treatment of patients with HER2-positive breast cancer. Both in the metastatic and adjuvant setting, the addition of trastuzumab to other systemic treatments has led to a striking increase in tumor response and survival. The downside with the use of this agent, however, is its inherent cardiotoxicity, which is particularly common when anthracyclines are used concurrently. This review will focus on all aspects of the cardiac side-effects of trastuzumab, ranging from epidemiology and pathophysiology to cardiac monitoring, and treatment and prevention.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Cardiopatias/induzido quimicamente , Anticorpos Monoclonais Humanizados , Feminino , Cardiopatias/epidemiologia , Cardiopatias/fisiopatologia , Humanos , Incidência , Monitorização Fisiológica , Fatores de Risco , TrastuzumabRESUMO
Circulating apoptotic proteins are increased in patients with heart failure. We evaluated whether circulating soluble (s) apoptosis-related proteins and inflammation markers are increased in long-term disease free breast cancer survivors and associated with cardiotoxicity, and if subgroups could be identified based on the applied treatments. Circulating tumour necrosis factor (TNF) alpha, sTNF-receptor (sTNF-R) 1 and 2, sFas, sFas ligand, sTNF-related apoptosis inducing ligand (sTRAIL) and serum HER2 were measured with immunoassay. High-sensitivity C-reactive protein (HS-CRP), fibrinogen, plasma B-type and N-terminal atrial natriuretic peptide (NT-ANP and BNP) were also determined. Thirty-four patients with median 6.0 years follow-up and 12 healthy age-matched women were enrolled. Chemotherapy, consisting of five cycles fluorouracil, epirubicin (90 mg/m(2)), cyclophosphamide (FEC) (n=14) or four cycles FEC followed by myeloablation with high-dose carboplatin, cyclophosphamide, thiotepa (n=20), preceded irradiation and tamoxifen. Circulating apoptosis markers were higher in patients than in controls. No associations with cardiac dysfunction were observed. sFas ligand and sTRAIL were higher in the high-dose than in the standard-dose group. In conclusion, we observed increased circulating apoptotic protein levels in long-term disease-free breast cancer survivors, treated with adjuvant chemoradiotherapy, particularly after myeloablative chemotherapy. The potential relation with late cardiotoxicity of antineoplastic therapy deserves further study.
Assuntos
Apoptose , Neoplasias da Mama/sangue , Neoplasias da Mama/terapia , Insuficiência Cardíaca/etiologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteínas Reguladoras de Apoptose/sangue , Fator Natriurético Atrial/sangue , Neoplasias da Mama/complicações , Proteína C-Reativa/análise , Estudos Transversais , Intervalo Livre de Doença , Feminino , Humanos , Glicoproteínas de Membrana/sangue , Pessoa de Meia-Idade , Miocárdio/patologia , Peptídeo Natriurético Encefálico/sangue , Radioterapia/efeitos adversos , Receptor ErbB-2/sangue , Ligante Indutor de Apoptose Relacionado a TNF , Tamoxifeno/uso terapêutico , Fator de Necrose Tumoral alfa/análise , Receptor fas/sangueRESUMO
PURPOSE: The cardiac and antineoplastic effects of trastuzumab may be related to specific uptake of trastuzumab in myocardium and tumor tissue, respectively. We evaluated whether indium-111 (111In)-labeled trastuzumab scintigraphy can predict cardiotoxicity and identify tumor lesions. In addition, we evaluated whether plasma markers for cardiac dysfunction can be used to predict cardiotoxicity. PATIENTS AND METHODS: Patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer underwent gamma camera imaging from 15 minutes to 7 days after injection of 150 MBq 111In-diethylenetriamine penta-acetic acid anhydride (DTPA) -trastuzumab, after loading-dose trastuzumab, and after once-a-week trastuzumab doses for 11 weeks, and concomitant paclitaxel once every 3 weeks. Cardiac assessments were performed before treatment, and after four and six cycles. Plasma N-terminal probrain natriuretic peptide (NT-proBNP) and serum troponin I were measured with immunoassay. RESULTS: Fifteen of the 17 patients were available for cardiac and tumor uptake analysis. On the first scan, myocardial 111In-DTPA-trastuzumab uptake was observed in one patient with pre-existing cardiac arrhythmias, who did not develop heart failure during treatment. Severe cardiotoxicity occurred in three patients, without initial myocardial uptake, whereas one showed weak myocardial uptake after four cycles. The detection rate of single tumor lesions was 45%. New tumor lesions were discovered in 13 of 15 patients. Pretreatment plasma NT-proBNP levels were higher in patients with than without heart failure (mean, 534 [standard deviation, 236] v 105 [standard deviation, 79] ng/L; P = .009). CONCLUSION: Radiolabeled trastuzumab scintigraphy was not valuable in predicting trastuzumab-related cardiotoxicity in metastatic breast cancer patients, but can identify HER2-positive tumors. Measurement of plasma NT-proBNP is promising regarding prediction of trastuzumab-related cardiotoxicity.