Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
1.
Neuro Oncol ; 2024 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-38963808

RESUMO

BACKGROUND: Brain metastases (BM) are a devastating complication of HER2-positive metastatic breast cancer (BC) and treatment strategies providing optimized local and systemic disease control are urgently required. The antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) and overall survival (OS) over trastuzumab emtansine but data regarding intracranial activity is limited. In the primary outcome analysis of TUXEDO-1, a high intracranial response rate (RR) was reported with T-DXd. Here, we report final PFS and OS results. PATIENTS AND METHODS: TUXEDO-1 accrued adult patients with HER2-positive BC and active BM (newly diagnosed or progressing) without indication for immediate local therapy. The primary endpoint was intracranial RR; secondary endpoints included PFS, OS, safety, quality-of-life (QoL), and neurocognitive function. PFS and OS were estimated with the Kaplan-Meier method and analysed in the per-protocol population. RESULTS: At 26.5 months median follow-up, median PFS was 21 months (95% CI 13.3-n.r.) and median OS was not reached (95% CI 22.2-n.r.). With longer follow-up, no new safety signals were observed. The most common grade 3 adverse event was fatigue (20%). Grade 2 interstitial lung disease and a grade 3 symptomatic drop of left-ventricular ejection fraction were observed in one patient each. QoL was maintained over the treatment period. DISCUSSION: T-DXd yielded prolonged intra- and extracranial disease control in patients with active HER2-positive BC BM in line with results from the pivotal trials. These results support the concept of ADCs as systemic therapy for active BM.

2.
Nat Med ; 28(9): 1840-1847, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35941372

RESUMO

Trastuzumab deruxtecan is an antibody-drug conjugate with high extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. We conducted the prospective, open-label, single-arm, phase 2 TUXEDO-1 trial. We enrolled patients aged ≥18 years with HER2-positive breast cancer and newly diagnosed untreated brain metastases or brain metastases progressing after previous local therapy, previous exposure to trastuzumab and pertuzumab and no indication for immediate local therapy. Patients received trastuzumab deruxtecan intravenously at the standard dose of 5.4 mg per kg bodyweight once every 3 weeks. The primary endpoint was intracranial response rate measured according to the response assessment in neuro-oncology brain metastases criteria. A Simon two-stage design was used to compare a null hypothesis of <26% response rate against an alternative of 61%. Fifteen patients were enrolled in the intention-to-treat population of patients who received at least one dose of study drug. Two patients (13.3%) had a complete intracranial response, nine (60%) had a partial intracranial response and three (20%) had stable disease as the best intracranial response, with a best overall intracranial response rate of 73.3% (95% confidential interval 48.1-89.1%), thus meeting the predefined primary outcome. No new safety signals were observed and global quality-of-life and cognitive functioning were maintained over the treatment duration. In the TUXEDO-1 trial (NCT04752059, EudraCT 2020-000981-41), trastuzumab deruxtecan showed a high intracranial response rate in patients with active brain metastases from HER2-positive breast cancer and should be considered as a treatment option in this setting.


Assuntos
Neoplasias Encefálicas , Neoplasias da Mama , Imunoconjugados , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Camptotecina/análogos & derivados , Feminino , Humanos , Imunoconjugados/efeitos adversos , Estudos Prospectivos , Receptor ErbB-2/genética , Trastuzumab/efeitos adversos
3.
Eur J Cancer ; 143: 101-112, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33296830

RESUMO

BACKGROUND: Pancreatic cancer (PC) ranks among the deadliest malignancies worldwide. In the MPACT study, first-line nab-paclitaxel plus gemcitabine (nab-P/G) demonstrated activity (median overall survival [OS], 8.7 months) and tolerability in patients with metastatic PC (mPC). However, the clinical evidence of nab-P/G in the elderly (>70 years), who account for the majority of patients with mPC, is limited. This is the first prospective, multicentre, non-interventional study evaluating the tolerability and effectiveness of nab-P/G in younger (≤70 years) versus elderly (>70 years) patients with mPC in the daily clinical routine. METHODS: Eligible patients with mPC were treated with nab-P/G and observed until disease progression or unacceptable toxicity. The primary objectives were safety and tolerability of nab-P/G, and the secondary objectives were efficacy and real-life dosing. RESULTS: A total of 317 patients with mPC (median age, 70 years) were recruited, of which 299, aged ≤70 (n = 162) and >70 (n = 137) years, were eligible for analysis. Baseline characteristics and the safety profile were comparable between the groups. However, fatigue (22.8% versus 13.0%) and decreased appetite (8.8% versus 1.2%) were more frequent in elderly patients. Younger versus elderly patients equally benefited in terms of objective response rate (36% versus 48%), median progression-free survival (5.6 versus 5.5 months; hazard ratio [HR] = 1.03; p = 0.81) and OS (10.6 versus 10.2 months; HR = 0.89; p = 0.4). In addition, the median treatment duration (5 versus 4 cycles), relative dose intensity (70% versus 74%) or reasons for treatment discontinuation were similar. Most patients (56.2% versus 47.4%) benefited from a second-line therapy. CONCLUSION: This prospective real-world analysis confirms the feasibility and tolerability of nab-P/G treatment and reveals OS data similar for younger patients and elderly patients aged >70 years. CLINICALTRIALS. GOV REGISTRATION: NCT02555813. AUSTRIAN NIS REGISTRY: NIS005071.


Assuntos
Albuminas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Albuminas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Feminino , Humanos , Masculino , Paclitaxel/farmacologia , Neoplasias Pancreáticas/patologia , Gencitabina
4.
Ther Adv Med Oncol ; 12: 1758835919900872, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32313566

RESUMO

BACKGROUND: The pretreatment De Ritis ratio [aspartate transaminase (AST)/alanine transaminase (ALT)] has been shown to be an adverse prognostic marker in various cancer entities. However, its relevance to advanced pancreatic ductal adenocarcinoma (PDAC) has not yet been studied. In the present study we investigated the AST/ALT ratio as a possible predictor of treatment response and disease outcome in patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel. METHODS: A post hoc analysis of a prospective, multicenter, noninterventional study was performed. A total of 202 patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel for whom the AST/ALT ratio was measured were included in this analysis. RESULTS: Median and 1-year progression-free survival estimates were 4.8 months and 5.1%, respectively in patients with an AST/ALT ratio above the 75th percentile of its distribution, and 6.0 months and 18.7%, respectively in patients with an AST/ALT ratio less than or equal to this cutoff, respectively (log-rank p = 0.004). In univariable Cox regression, a doubling of the AST/ALT ratio was associated with a 1.4-fold higher relative risk of progression or death [hazard ratio = 1.38, 95% confidence interval (CI): 1.06-1.80, p = 0.017]. The prognostic association was also found in multivariable analysis adjusting for Eastern Cooperative Oncology Group performance status and lung metastases (hazard ratio per AST/ALT ratio doubling = 1.32, 95% CI: 1.00-1.75, p = 0.047). In treatment response analysis, a doubling of the AST/ALT ratio was associated with a 0.5-fold lower odds of objective response (odds ratio = 0.54, 95% CI: 0.31-0.94, p = 0.020). CONCLUSIONS: The pretreatment serum AST/ALT ratio predicts poor disease outcome and response rate in patients with advanced PDAC treated with gemcitabine/nab-paclitaxel and might represent a novel and inexpensive marker for individual risk assessment in the treatment of pancreatic cancer.

5.
Cancer Lett ; 259(2): 231-9, 2008 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-18023527

RESUMO

PURPOSE: Pancreatic cancer still remains a treatment-refractory cancer. Standard therapy for metastatic cancer is gemcitabine (dFdC) chemotherapy. Since heavy water (deuterium oxide, D2O) was shown to be active in pancreatic cancer in vitro, we examined the simultaneous or sequential cytotoxic effects of D2O and dFdC in pancreatic cancer cell lines (AsPC-1, BxPC-3, and PANC-1). Moreover, we investigated the effect of D2O treatment on the colony formation of peripheral blood mononuclear cells (PBMNC) as well as the apoptosis inducing activity of D2O and dFdC and the regulation of tumor suppressor gene p21. RESULTS: Simultaneous incubation of human pancreatic carcinoma cells with D2O and dFdC led to a decrease of IC50 values of dFdC alone in all cell lines examined. Sequential application of D2O and dFdC caused synergistic effects. Treatment with 10-30% D2O did not show any significant inhibition effects on the colony formation of peripheral blood mononuclear cells (PBMNC), indicating limited adverse effects of D2O on bone marrow cells. Treatment with D2O in combination with dFdC significantly (p<0.05) increased the induction of apoptosis in PANC-1 and AsPC-1 cells and led to an overexpression of p21 tumor suppressor gene compared to incubation with dFdC alone. As the combination of D2O and dFdC might offer an additional option for the control of pancreatic cancer, this treatment should be investigated in a pancreas carcinoma animal model in order to scrutinize the in vitro data.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Óxido de Deutério/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Óxido de Deutério/uso terapêutico , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Pancreáticas/patologia , Ensaio Tumoral de Célula-Tronco , Gencitabina
6.
Clin Exp Metastasis ; 32(7): 729-37, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26303828

RESUMO

Brain metastases (BM) are frequently diagnosed in metastatic Her2-positive breast cancer. Local treatment remains the standard of care but lapatinib plus capecitabine was recently established as systemic therapy option. Due to a disruption of the blood-brain/tumour-barrier at metastatic sites, even large molecules may penetrate into the central nervous system (CNS). Here, we report on the activity of T-DM1 in Her2-positive breast cancer BM. T-DM1 was administered at a dose of 3.6 mg once every 3 weeks as primary systemic therapy for BM or upon documented CNS progression after initial local treatment. Thus, this study allowed for the appraisal of T-DM1 activity in BM. Restaging was conducted every 12 weeks with MRI or whenever symptoms of disease progression occurred. Ten patients were included; in two asymptomatic subjects, T-DM1 was administered as primary therapy, while eight had progressive BM. All patients had received prior treatment with trastuzumab, six had already received lapatinib, and three pertuzumab as well. Three patients had partial remission of BM, and two patient had stable disease lasting for ≥6 months; two further patients had stable disease for <6 months while three progressed despite treatment. At 8.5 months median follow-up, intracranial PFS was 5 months, and median OS from initiation of T-DM1 was not reached. Local treatment of BM remains the standard of care; lapatinib plus capecitabine is currently the best established systemic therapy option. Still, T-DM1 apparently offers relevant clinical activity in BM and further investigation is warranted.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Maitansina/análogos & derivados , Ado-Trastuzumab Emtansina , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Maitansina/uso terapêutico , Pessoa de Meia-Idade , Receptor ErbB-2/biossíntese , Receptor ErbB-2/genética , Estudos Retrospectivos , Trastuzumab
7.
Haematologica ; 88(11): 1204-12, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14607748

RESUMO

BACKGROUND AND OBJECTIVES: The levels of circulating hematopoietic progenitor cells are often increased in myelofibrosis with myeloid metaplasia (MMM). The prognostic relevance of this phenomenon is largely unknown. DESIGN AND METHODS: We determined the number of circulating myeloid (CFU-GM), erythroid (BFU-E), and pluripotent (CFU-GEMM) progenitors, in 110 patients with MMM at diagnosis using a semi-solid colony assay. Overall survival was investigated by plots of the Kaplan-Meier estimator; known risk factors and the number of circulating progenitor cells were tested by univariate and multiple Cox regression analysis. RESULTS: Univariate analysis showed that hemoglobin concentration (p=0.019), CFU-GM (p< 0.0001), BFU-E (p=0.002), and age (p=0.002) predicted survival. Numbers of circulating CFU-GM above the 75th percentile were associated with a significantly shorter survival than were CFU-GM levels at or below the 75th percentile (27 vs. 74 months, p=0.0007). Similarly, high numbers of BFU-E in peripheral blood (> 75th percentile) predicted a shorter survival (33 vs. 74 months; p=0.007). When myeloid and erythroid progenitor cells were calculated separately in the multiple Cox regression analysis, both CFU-GM (hazard ratio 2.8, 95% CI, 1.35 to 5.93) and BFU-E (hazard ratio 2.57, 95% CI, 1.26 to 5.21) numbers above the 75th percentile were independent adverse prognostic factors in our patients. INTERPRETATION AND CONCLUSIONS: High levels of circulating myeloid and erythroid progenitor cells are novel risks factors in patients with MMM. The assessment of hematopoietic progenitor cells may be useful to determine risk-adjusted treatment strategies.


Assuntos
Contagem de Células Sanguíneas , Células-Tronco Hematopoéticas , Mielofibrose Primária/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaio de Unidades Formadoras de Colônias , Células Precursoras Eritroides , Feminino , Seguimentos , Humanos , Tábuas de Vida , Masculino , Pessoa de Meia-Idade , Células Mieloides , Contagem de Plaquetas , Células-Tronco Pluripotentes , Mielofibrose Primária/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Contagem de Reticulócitos , Esplenomegalia/sangue , Análise de Sobrevida
8.
Anticancer Drugs ; 17(7): 865-8, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16926637

RESUMO

Among the several different combination chemotherapy regimens for the treatment of patients with metastatic colorectal cancer, oxaliplatin plus raltitrexed has shown encouraging therapeutic results and a fairly good toxicity profile. Here, we report on two patients with metastatic colorectal cancer receiving this combination therapy, which leads to severe enterocolitis and neutropenia resulting in death in one patient. One patient was a 67-year-old woman suffering from an adenocarcinoma of the sigmoid colon with multiple liver metastases. The other patient was a 74-year-old woman with colon cancer, and metachronous multiple pulmonal and hepatic metastases. In both patients, palliative chemotherapy consisted of oxaliplatin 130 mg/m2 in combination with raltitrexed 3 mg/m2 on day 1 every 21 days. Both patients developed neutropenia in combination with severe enterocolitis after the fourth and the second chemotherapy cycle, respectively. Despite antibiotic treatment, diarrhea persisted in both patients for weeks. One patient died 17 days after hospital admission because of enteric sepsis with bleeding of the colonic mucosa and multiorgan failure. The other patient recovered completely and was discharged from hospital after 8 weeks. Severe enterocolitis, a hitherto infrequently recognized adverse event, which has been described in association with 5-fluorouracil/leucovorin and oxaliplatin chemotherapy, may also occur with raltitrexed and oxaliplatin. Physicians should be aware of this rare, although potentially lethal, gastrointestinal toxicity.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Gastroenteropatias/induzido quimicamente , Compostos Organoplatínicos/efeitos adversos , Quinazolinas/efeitos adversos , Tiofenos/efeitos adversos , Adenocarcinoma/complicações , Adenocarcinoma/tratamento farmacológico , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Colonoscopia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Complicações do Diabetes , Diabetes Mellitus Tipo 1 , Quimioterapia Combinada , Enterocolite/induzido quimicamente , Enterocolite/patologia , Evolução Fatal , Feminino , Gastroenteropatias/complicações , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Quinazolinas/uso terapêutico , Tiofenos/uso terapêutico
9.
Blood ; 102(6): 2240-2, 2003 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-12763928

RESUMO

The overproduction of red blood cells in patients with polycythemia vera (PV) is reflected in vitro by the formation of erythroid burst-forming units (BFU-Es) in the absence of exogenous erythropoietin. In contrast to other myeloproliferative disorders, the molecular mechanism of PV is unknown and no specific chromosomal abnormality has been described. We speculated that imatinib mesylate may reverse the pathological overproduction of red cells by inhibition of autonomous erythropoiesis. In the present study, imatinib mesylate was found to either block or strongly inhibit autonomous BFU-E formation in vitro in all patients tested. Moreover, autonomous BFU-E growth was also markedly reduced by exposure of PV cells to imatinib mesylate prior to cultivation in semisolid medium. The profound effect of imatinib mesylate on autonomous erythropoiesis suggests the involvement of an as yet unidentified kinase in the pathogenesis of PV and should provide the rationale for a forthcoming clinical trial.


Assuntos
Antineoplásicos/administração & dosagem , Eritropoese/efeitos dos fármacos , Piperazinas/administração & dosagem , Policitemia Vera/tratamento farmacológico , Pirimidinas/administração & dosagem , Benzamidas , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Células Precursoras Eritroides/efeitos dos fármacos , Humanos , Mesilato de Imatinib , Técnicas In Vitro
10.
Blood ; 101(6): 2184-90, 2003 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-12424204

RESUMO

Myeloid lineage-derived dendritic cells (DCs) are considered the professional antigen-presenting cell type responsible for eliciting T-cell-mediated immune responses. Acute myelogenous leukemia (AML) is a disease in which tumor antigens are expressed by the malignant clone that also has the potential to differentiate into DC-like cells (leukemic DCs) with antigen-presenting capacity. This study investigated whether the constitutive expression of the cytokine interleukin-7 (IL-7) in primary AML cells during their differentiation toward leukemic DCs results in superior antigen-presenting cells. A bicistronic retroviral vector encoding the IL-7 cytokine and the surface immunoselectable low-affinity nerve growth factor receptor (LNGFr) gene was constructed and used for transduction experiments. A serum-free system was used to transduce and differentiate leukemic cells toward leukemic DCs. The study included 8 patients with AML. The transduction efficiency with the cytokine vector varied among patients, ranging from 5% to 30% as judged by LNGFr expression. The leukemic origin of the transduced cells was confirmed in a patient with a chromosomal translocation t(9:11) by fluorescence in situ hybridization analysis. Cytokine modified-cells consistently secreted IL-7 (mean, 415 pg +/- 190/10(6) cells/48 hours; n = 5). We demonstrate that IL-7-transduced cells are included in the differentiated leukemic DC subset, and, as shown in a particular case, that about half of the mature CD80(+) and CD83(+) populations coexpress the LNGFr transgene. In addition, IL-7-modified leukemic cells induce stronger allo-T-cell stimulation and higher amounts of IL-2 production in T cells compared with control groups. Finally, cytokine-transduced leukemic DCs can effectively prime and generate cytotoxic T lymphocytes against autologous leukemic blasts.


Assuntos
Células Dendríticas/metabolismo , Expressão Gênica , Interleucina-7/genética , Leucemia Mieloide Aguda/patologia , Retroviridae/genética , Células Apresentadoras de Antígenos/imunologia , Antígenos CD , Antígeno B7-1/análise , Diferenciação Celular , Células Dendríticas/patologia , Genes , Vetores Genéticos , Humanos , Imunoglobulinas/análise , Hibridização in Situ Fluorescente , Interleucina-2/análise , Interleucina-7/imunologia , Interleucina-7/metabolismo , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/metabolismo , Teste de Cultura Mista de Linfócitos , Glicoproteínas de Membrana/análise , Fator de Crescimento Neural/genética , Proteínas Recombinantes de Fusão , Linfócitos T/química , Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Antígeno CD83
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA