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1.
Haematologica ; 2018 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-30076173

RESUMO

The randomized, phase 3 ALFA-0701 trial showed that a reduced and fractionated dose of gemtuzumab ozogamicin added to standard front-line chemotherapy significantly improves event-free survival in adults with de novo acute myeloid leukemia. Here we report an independent review of event-free survival, final overall survival, and additional safety results from ALFA-0701. Patients (N=271) aged 50-70 years with de novo acute myeloid leukemia were randomized to receive conventional front-line induction chemotherapy (3+7 daunorubicin+cytarabine) with/without gemtuzumab ozogamicin 3 mg/m2 on days 1, 4, and 7 during induction. Patients in remission following induction therapy received 2 courses of consolidation therapy (daunorubicin+cytarabine) with/without gemtuzumab ozogamicin (3 mg/2;/day on day 1) according to their initial randomization. The primary endpoint was investigator-assessed event-free survival. Secondary endpoints included overall survival and safety. A blinded independent review confirmed the investigator-assessed event-free survival results (August 1, 2011; hazard ratio, 0.66 [95% CI, 0.49-0.89]; 2-sided p=0.006), corresponding to a 34% reduction in risk of events in the gemtuzumab ozogamicin versus control arm. Final overall survival (April 30, 2013) favored gemtuzumab ozogamicin but was not significant. No differences were observed between arms in early death rate. The main toxicity associated with gemtuzumab ozogamicin was prolonged thrombocytopenia. Veno-occlusive disease (including after transplant) was observed in 6 patients in the gemtuzumab ozogamicin arm and 2 in the control arm. In conclusion, gemtuzumab ozogamicin added to standard intensive chemotherapy has a favorable benefit/risk ratio. These results expand front-line treatment options for adult patients with previously untreated acute myeloid leukemia. (ClinicalTrials.gov identifier: NCT00927498).

2.
N Engl J Med ; 372(1): 30-9, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25399551

RESUMO

BACKGROUND: The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients. METHODS: In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival. RESULTS: At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group. CONCLUSIONS: Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imidazóis/administração & dosagem , Indóis/uso terapêutico , Melanoma/tratamento farmacológico , Oximas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Humanos , Imidazóis/efeitos adversos , Indóis/efeitos adversos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mutação , Oximas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/efeitos adversos , Pirimidinonas/efeitos adversos , Neoplasias Cutâneas/patologia , Sulfonamidas/efeitos adversos , Análise de Sobrevida , Vemurafenib , Adulto Jovem
3.
Eur J Cancer ; 49(6): 1287-96, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23321547

RESUMO

BACKGROUND: In this randomised phase III study (VEG105192; NCT00334282), pazopanib previously demonstrated statistically and clinically meaningful improvement of progression-free survival versus placebo in patients with advanced/metastatic renal cell carcinoma (mRCC). Final overall survival (OS) and updated safety results are now reported. METHODS: Treatment-naive or cytokine-pretreated mRCC patients (n=435) stratified and randomised (2:1) to pazopanib 800 mg daily or placebo, were treated until disease progression, death or unacceptable toxicity. Upon progression, placebo patients could receive pazopanib through an open-label study. Final OS in the intent-to-treat population was analysed using a stratified log-rank test. Rank-preserving structural failure time (RPSFT) and inverse probability of censoring weighted (IPCW) analyses were performed post-hoc to adjust for crossover. FINDINGS: The difference in final OS between pazopanib- and placebo-treated patients was not statistically significant (22.9 versus 20.5 months, respectively; hazard ratio [HR]=0.91; 95% confidence interval [CI], 0.71-1.16; one-sided P=.224). Early and frequent crossover from placebo to pazopanib and prolonged duration of crossover treatment confounded the OS analysis. In IPCW analyses, pazopanib decreased mortality (HR=0.504; 95% CI, 0.315-0.762; two-sided P=.002). Similar, albeit non-significant, results were obtained in RPSFT analyses (HR=0.43; 95% CI, 0.215-1.388; two-sided P=.172). Since the last cutoff, cumulative exposure to pazopanib increased by 30%. The pazopanib safety profile showed no new safety signals or changes in the type, frequency and severity of adverse events. INTERPRETATION: Although no significant difference in OS was observed in this study, extensive crossover from placebo to pazopanib confounded final OS analysis. Post-hoc analyses adjusting for crossover suggest OS benefit with pazopanib treatment for mRCC patients.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Renais/patologia , Estudos Cross-Over , Diarreia/induzido quimicamente , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Hipertensão/induzido quimicamente , Estimativa de Kaplan-Meier , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Pirimidinas/efeitos adversos , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sulfonamidas/efeitos adversos , Resultado do Tratamento
4.
Breast Cancer Res Treat ; 137(2): 471-82, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23239151

RESUMO

This multi-center Phase II study evaluated lapatinib, pazopanib, and the combination in patients with relapsed HER2+ inflammatory breast cancer. In Cohort 1, 76 patients were randomized 1:1 to receive lapatinib 1,500 mg + placebo or lapatinib 1,500 mg + pazopanib 800 mg (double-blind) once daily until disease progression, unacceptable toxicity, or death. Due to high-grade diarrhea observed with this dose combination in another study (VEG20007), Cohort 1 was closed. The protocol was amended such that an additional 88 patients (Cohort 2) were randomized in a 5:5:2 ratio to receive daily monotherapy lapatinib 1,500 mg, lapatinib 1,000 mg + pazopanib 400 mg, or monotherapy pazopanib 800 mg, respectively. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival, and safety. In Cohort 1, ORR for the lapatinib (n = 38) and combination (n = 38) arms was 29 and 45 %, respectively; median PFS was 16.1 and 14.3 weeks, respectively. Grade ≥3 adverse events (AEs) were more frequent in the combination arm (71 %) than in the lapatinib arm (24 %). Dose reductions and interruptions due to AEs were also more frequent in the combination arm (45 and 53 %, respectively) than in the lapatinib monotherapy arm (0 and 11 %, respectively). In Cohort 2, ORR for patients treated with lapatinib (n = 36), lapatinib + pazopanib (n = 38), and pazopanib (n = 13) was 47, 58, and 31 %, respectively; median PFS was 16.0, 16.0, and 11.4 weeks, respectively. In the lapatinib, combination, and pazopanib therapy arms, grade ≥3 AEs were reported for 17, 50, and 46 % of patients, respectively, and the incidence of discontinuations due to AEs was 0, 24, and 23 %, respectively. The lapatinib-pazopanib combination was associated with a numerically higher ORR but no increase in PFS compared to lapatinib alone. The combination also had increased toxicity resulting in more dose reductions, modifications, and treatment delays. Activity with single-agent lapatinib was confirmed in this population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Quinazolinas/uso terapêutico , Receptor ErbB-2/metabolismo , Adulto , Diarreia/induzido quimicamente , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Inflamatórias Mamárias/metabolismo , Neoplasias Inflamatórias Mamárias/mortalidade , Lapatinib , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Resultado do Tratamento
5.
Pharm Res ; 29(3): 770-81, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22011930

RESUMO

PURPOSE: Lapatinib, a small molecule EGFR/HER2 inhibitor, partially inhibits the outgrowth of HER2+ brain metastases in preclinical models and in a subset of CNS lesions in clinical trials of HER2+ breast cancer. We investigated the ability of lapatinib to reach therapeutic concentrations in the CNS following (14)C-lapatinib administration (100 mg/kg p.o. or 10 mg/kg, i.v.) to mice with MDA-MD-231-BR-HER2 brain metastases of breast cancer. METHODS: Drug concentrations were determined at differing times after administration by quantitative autoradiography and chromatography. RESULTS: (14)C-Lapatinib concentration varied among brain metastases and correlated with altered blood-tumor barrier permeability. On average, brain metastasis concentration was 7-9-fold greater than surrounding brain tissue at 2 and 12 h after oral administration. However, average lapatinib concentration in brain metastases was still only 10-20% of those in peripheral metastases. Only in a subset of brain lesions (17%) did lapatinib concentration approach that of systemic metastases. No evidence was found of lapatinib resistance in tumor cells cultured ex vivo from treated brains. CONCLUSIONS: Results show that lapatinib distribution to brain metastases of breast cancer is partially restricted and blood-tumor barrier permeability is a key component of lapatinib therapeutic efficacy which varies between tumors.


Assuntos
Antineoplásicos/farmacocinética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Encéfalo/patologia , Neoplasias da Mama/patologia , Quinazolinas/farmacocinética , Receptor ErbB-2/genética , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Injeções Intravenosas , Lapatinib , Camundongos , Quinazolinas/administração & dosagem , Quinazolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Regulação para Cima
6.
J Neurooncol ; 105(3): 613-20, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21706359

RESUMO

Approximately one-third of patients with advanced, HER2-positive breast cancer develop brain metastases. A significant proportion of women experience central nervous system (CNS) progression after standard radiation therapy. The optimal treatment in the refractory setting is undefined. This study evaluated the toxicity and efficacy of lapatinib in combination with chemotherapy among patients with HER2-positive, progressive brain metastases. Patients with HER2-positive breast cancer with progressive brain metastases after trastuzumab and cranial radiotherapy were included. The primary endpoint was CNS objective response, defined as a ≥ 50% volumetric reduction of CNS lesion(s) in the absence of new or progressive CNS or non-CNS lesions, or increasing steroid requirements. The study was closed early after 22 of a planned 110 patients were enrolled due to excess toxicity and lack of efficacy in the lapatinib plus topotecan arm. The objective response rate (ORR) in the lapatinib plus capecitabine arm was 38% (exact 95% confidence interval [CI] 13.9-68.4). No responses were observed in the lapatinib plus topotecan arm. Although the study was stopped prior to full enrollment, some promising indications of CNS activity were noted for lapatinib plus capecitabine. The combination of lapatinib plus topotecan was not active and was associated with excess toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Quinazolinas/administração & dosagem , Adulto , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/análogos & derivados , Humanos , Lapatinib , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Quinazolinas/efeitos adversos , Receptor ErbB-2/biossíntese , Topotecan/administração & dosagem , Topotecan/efeitos adversos
7.
Clin Cancer Res ; 15(4): 1452-9, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19228746

RESUMO

PURPOSE: Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. EXPERIMENTAL DESIGN: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as >or=50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease. RESULTS: Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a >or=20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a >or=20% volumetric reduction in their CNS lesions. CONCLUSIONS: This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Receptor ErbB-2/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Lapatinib , Pessoa de Meia-Idade , Estudos Prospectivos , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Receptor ErbB-2/antagonistas & inibidores
8.
Clin Cancer Res ; 14(23): 7900-8, 2008 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-19047120

RESUMO

PURPOSE: Topotecan resistance can result from drug efflux by P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) as well as survival signals initiated by epidermal growth factor receptor family members. The present studies were done to determine the effect of combining topotecan and the dual epidermal growth factor receptor/HER2 inhibitor lapatinib in tissue culture, a murine xenograft model, and a phase I clinical trial. EXPERIMENTAL DESIGN: The effects of lapatinib on topotecan accumulation and cytotoxicity in vitro were examined in paired cell lines lacking or expressing Pgp or BCRP. Antiproliferative effects of the combination were assessed in mice bearing HER2+ BT474 breast cancer xenografts. Based on tolerability in this preclinical model, 37 patients with advanced-stage cancers received escalating doses of lapatinib and topotecan in a phase I trial. RESULTS: Lapatinib increased topotecan accumulation in BCRP- or Pgp-expressing cells in vitro, and the combination showed enhanced efficacy in HER2+ BT474 xenografts. In the phase I study, nausea, vomiting, diarrhea, and fatigue were dose limiting. The maximum tolerated doses were 1,250 mg/d lapatinib by mouth for 21 or 28 days with 3.2 mg/m2 topotecan i.v. on days 1, 8, and 15 of 28-day cycles. Pharmacokinetic analyses showed that combined drug administration resulted in decreased topotecan clearance consistent with transporter-mediated interactions. Seventeen (46%) patients had disease stabilization. CONCLUSIONS: The lapatinib/topotecan combination is well tolerated and warrants further study.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Feminino , Humanos , Técnicas In Vitro , Lapatinib , Masculino , Dose Máxima Tolerável , Camundongos , Pessoa de Meia-Idade , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Topotecan/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Natl Cancer Inst ; 100(15): 1092-103, 2008 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-18664652

RESUMO

BACKGROUND: The brain is increasingly being recognized as a sanctuary site for metastatic tumor cells in women with HER2-overexpressing breast cancer who receive trastuzumab therapy. There are no approved or widely accepted treatments for brain metastases other than steroids, cranial radiotherapy, and surgical resection. We examined the efficacy of lapatinib, an inhibitor of the epidermal growth factor receptor (EGFR) and HER2 kinases, for preventing the outgrowth of breast cancer cells in the brain in a mouse xenograft model of brain metastasis. METHODS: EGFR-overexpressing MDA-MB-231-BR (231-BR) brain-seeking breast cancer cells were transfected with an expression vector that contained or lacked the HER2 cDNA and used to examine the effect of lapatinib on the activation (ie, phosphorylation) of cell signaling proteins by immunoblotting, on cell growth by the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and on cell migration using a Boyden chamber assay. The outgrowth of large (ie, >50 microm(2)) and micrometastases was counted in brain sections from nude mice that had been injected into the left cardiac ventricle with 231-BR cells and, beginning 5 days later, treated by oral gavage with lapatinib or vehicle (n = 22-26 mice per treatment group). All statistical tests were two-sided. RESULTS: In vitro, lapatinib inhibited the phosphorylation of EGFR, HER2, and downstream signaling proteins; cell proliferation; and migration in 231-BR cells (both with and without HER2). Among mice injected with 231-BR-vector cells, those treated with 100 mg lapatinib/kg body weight had 54% fewer large metastases 24 days after starting treatment than those treated with vehicle (mean number of large metastases per brain section: 1.56 vs 3.36, difference = 1.80, 95% confidence interval [CI] = 0.92 to 2.68, P < .001), whereas treatment with 30 mg lapatinib/kg body weight had no effect. Among mice injected with 231-BR-HER2 cells, those treated with either dose of lapatinib had 50%-53% fewer large metastases than those treated with vehicle (mean number of large metastases per brain section, 30 mg/kg vs vehicle: 3.21 vs 6.83, difference = 3.62, 95% CI = 2.30 to 4.94, P < .001; 100 mg/kg vs vehicle: 3.44 vs 6.83, difference = 3.39, 95% CI = 2.08 to 4.70, P < .001). Immunohistochemical analysis revealed reduced phosphorylation of HER2 in 231-BR-HER2 cell-derived brain metastases from mice treated with the higher dose of lapatinib compared with 231-BR-HER2 cell-derived brain metastases from vehicle-treated mice (P < .001). CONCLUSIONS: Lapatinib is the first HER2-directed drug to be validated in a preclinical model for activity against brain metastases of breast cancer.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/prevenção & controle , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Receptores ErbB/análise , Quinazolinas/farmacologia , Receptor ErbB-2/análise , Análise de Variância , Animais , Neoplasias Encefálicas/secundário , Neoplasias da Mama/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Receptores ErbB/efeitos dos fármacos , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Immunoblotting , Imunoquímica , Lapatinib , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , RNA Interferente Pequeno , Receptor ErbB-2/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Projetos de Pesquisa , Transdução de Sinais/efeitos dos fármacos , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto
10.
N Engl J Med ; 355(26): 2733-43, 2006 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-17192538

RESUMO

BACKGROUND: Lapatinib, a tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu) and epidermal growth factor receptor (EGFR), is active in combination with capecitabine in women with HER2-positive metastatic breast cancer that has progressed after trastuzumab-based therapy. In this trial, we compared lapatinib plus capecitabine with capecitabine alone in such patients. METHODS: Women with HER2-positive, locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab were randomly assigned to receive either combination therapy (lapatinib at a dose of 1250 mg per day continuously plus capecitabine at a dose of 2000 mg per square meter of body-surface area on days 1 through 14 of a 21-day cycle) or monotherapy (capecitabine alone at a dose of 2500 mg per square meter on days 1 through 14 of a 21-day cycle). The primary end point was time to progression, based on an evaluation by independent reviewers under blinded conditions. RESULTS: The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The hazard ratio for the independently assessed time to progression was 0.49 (95% confidence interval, 0.34 to 0.71; P<0.001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events. CONCLUSIONS: Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. (ClinicalTrials.gov number, NCT00078572 [ClinicalTrials.gov].).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Capecitabina , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Progressão da Doença , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Cardiopatias/induzido quimicamente , Humanos , Lapatinib , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/efeitos adversos , Quinazolinas/efeitos adversos , Receptor ErbB-2/análise , Análise de Sobrevida
11.
Fertil Steril ; 84(2): 300-4, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16084868

RESUMO

OBJECTIVE: To establish the use of aromatase inhibitors as a therapeutic option for endometriosis. DESIGN: Prospective open-label Food and Drug Administration phase 2 trial with Institutional Review Board approval. SETTING: Outpatient tertiary care centers. PATIENT(S): Fifteen premenopausal patients with documented refractory endometriosis and chronic pelvic pain. INTERVENTION(S): After a 1-month washout of endometriosis hormone therapies, women took 1 mg anastrazole (Arimidex; AstraZeneca, Wilmington, DE) and one tablet of 20 microg ethinyl estradiol/0.1 mg levonorgestrel (Alesse; Wyeth, Madison, NJ) daily for 6 months. MAIN OUTCOME MEASURE(S): An analog pain scale recorded pelvic pain in daily diaries and surveys at baseline and after each treatment month. Side effects, blood counts, liver and renal function tests, cholesterol levels, and bone density were monitored. RESULT(S): Fourteen of 15 patients achieved significant pain reduction. Median pain scores decreased 55% after 6 months, while mean pain scores decreased 40%. Pain reduction comparing each treatment month to baseline achieved statistical significance. Average pain scores began dropping after only 1 treatment month and continued decreasing each additional month. No organ system experienced adverse effects. Estradiol levels were suppressed during treatment. Side effects were mild and improved over time. CONCLUSION(S): Fourteen of 15 patients with refractory endometriosis achieved significant pain relief using anastrazole and 20 microg ethinyl estradiol/0.1 mg levonorgestrel with minimal side effects. This treatment for endometriosis is a promising new modality that warrants further investigation.


Assuntos
Anticoncepcionais Orais/administração & dosagem , Endometriose/tratamento farmacológico , Nitrilos/administração & dosagem , Triazóis/administração & dosagem , Adulto , Anastrozol , Quimioterapia Combinada , Endometriose/fisiopatologia , Feminino , Humanos , Pessoa de Meia-Idade , Medição da Dor/efeitos dos fármacos , Medição da Dor/estatística & dados numéricos , Dor Pélvica/tratamento farmacológico , Dor Pélvica/fisiopatologia , Estudos Prospectivos
12.
Clin Endocrinol (Oxf) ; 62(2): 228-35, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15670201

RESUMO

OBJECTIVE: Although androgen replacement has been shown to have beneficial effects in hypogonadal men, there is concern that androgens may deleteriously affect cardiovascular risk in elderly men. DESIGN: Anastrozole is an oral aromatase inhibitor that normalizes serum testosterone levels and decreases oestradiol levels modestly in elderly men with mild hypogonadism. Thirty-seven elderly hypogonadal men were randomized to receive either anastrozole 1 mg daily (n = 12), anastrozole 1 mg twice weekly (n = 11), or daily placebo (n = 14) for 12 weeks in a double-blind fashion. PATIENTS: Men aged 62-74 years with mild hypogonadism defined by testosterone levels less than 350 ng/dl. MEASUREMENTS: Serum levels of fasting lipids, C-reactive protein (CRP), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and homeostatic model assessment (HOMA) scores were measured at 4-week intervals. RESULTS: Treatment with anastrozole did not significantly affect fasting lipids, inflammatory markers (IL-6, CRP), adhesion molecules (ICAM-1, VCAM-1) or insulin sensitivity (HOMA). There was, however, a positive correlation between changes in serum triglycerides and changes in serum oestradiol levels (P = 0.04). CONCLUSIONS: While short-term administration of anastrozole is an effective method of normalizing serum testosterone levels in elderly men with mild hypogonadism, it does not appear to adversely affect lipid profiles, inflammatory markers of cardiovascular risk or insulin resistance.


Assuntos
Inibidores da Aromatase/uso terapêutico , Doenças Cardiovasculares/sangue , Hipogonadismo/tratamento farmacológico , Lipídeos/sangue , Nitrilos/uso terapêutico , Testosterona/sangue , Triazóis/uso terapêutico , Idoso , Análise de Variância , Anastrozol , Biomarcadores/sangue , Proteína C-Reativa/análise , Distribuição de Qui-Quadrado , Homeostase , Humanos , Hipogonadismo/sangue , Molécula 1 de Adesão Intercelular/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Molécula 1 de Adesão de Célula Vascular/sangue
13.
J Clin Endocrinol Metab ; 89(9): 4428-33, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15356042

RESUMO

Pubertal gynecomastia is thought to result from transient imbalances between estrogen and androgen concentrations. Anastrozole (ARIMIDEX), a potent and selective aromatase inhibitor, decreases estrogen and increases testosterone concentrations in pubertal boys. The safety and efficacy of anastrozole for the treatment of pubertal gynecomastia were evaluated. In a randomized, double-blind, placebo-controlled study of 80 boys, aged 11-18 yr, with pubertal gynecomastia that had not reduced over a 3-month interval, subjects received either anastrozole (1 mg) or placebo once daily for 6 months. A response was defined as a 50% or greater reduction in the calculated volume of both breasts combined using ultrasonography measurements. A comparison of response rates was performed using logistic regression analysis. Secondary end points included changes in serum hormone concentrations. The percentage of patients with a response was 38.5% for the anastrozole group and 31.4% for the placebo group (odds ratio, 1.513; 95% confidence interval, 0.496-4.844; P = 0.47). At 6 months, the median percent change in the testosterone/estradiol ratio was 166% for the anastrozole group and 39% for the placebo group. Anastrozole treatment was well tolerated. In patients with pubertal gynecomastia, no significant difference in the percentage of patients with a 50% or greater reduction in total breast volume, as calculated from ultrasonography measurements, was demonstrated between the anastrozole and placebo groups.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Ginecomastia/tratamento farmacológico , Nitrilos/uso terapêutico , Triazóis/uso terapêutico , Adolescente , Anastrozol , Criança , Método Duplo-Cego , Estradiol/sangue , Ginecomastia/sangue , Humanos , Masculino , Nitrilos/efeitos adversos , Testosterona/sangue , Triazóis/efeitos adversos
14.
J Clin Endocrinol Metab ; 89(3): 1174-80, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15001605

RESUMO

As men age, serum testosterone levels decrease, a factor that may contribute to some aspects of age-related physiological deterioration. Although androgen replacement has been shown to have beneficial effects in frankly hypogonadal men, its use in elderly men with borderline hypogonadism is controversial. Furthermore, current testosterone replacement methods have important limitations. We investigated the ability of the orally administered aromatase inhibitor, anastrozole, to increase endogenous testosterone production in 37 elderly men (aged 62-74 yr) with screening serum testosterone levels less than 350 ng/dl. Subjects were randomized in a double-blind fashion to the following 12-wk oral regimens: group 1: anastrozole 1 mg daily (n = 12); group 2: anastrozole 1 mg twice weekly (n = 11); and group 3: placebo daily (n = 14). Hormone levels, quality of life (MOS Short-Form Health Survey), sexual function (International Index of Erectile Function), benign prostate hyperplasia severity (American Urological Association Symptom Index Score), prostate-specific antigen, and measures of safety were compared among groups. Mean +/- SD bioavailable testosterone increased from 99 +/- 31 to 207 +/- 65 ng/dl in group 1 and from 115 +/- 37 to 178 +/- 55 ng/dl in group 2 (P < 0.001 vs. placebo for both groups and P = 0.054 group 1 vs. group 2). Total testosterone levels increased from 343 +/- 61 to 572 +/- 139 ng/dl in group 1 and from 397 +/- 106 to 520 +/- 91 ng/dl in group 2 (P < 0.001 vs. placebo for both groups and P = 0.012 group 1 vs. group 2). Serum estradiol levels decreased from 26 +/- 8 to 17 +/- 6 pg/ml in group 1 and from 27 +/- 8 to 17 +/- 5 pg/ml in group 2 (P < 0.001 vs. placebo for both groups and P = NS group 1 vs. group 2). Serum LH levels increased from 5.1 +/- 4.8 to 7.9 +/- 6.5 U/liter and from 4.1 +/- 1.6 to 7.2 +/- 2.8 U/liter in groups 1 and 2, respectively (P = 0.007 group 1 vs. placebo, P = 0.003 group 2 vs. placebo, and P = NS group 1 vs. group 2). Scores for hematocrit, MOS Short-Form Health Survey, International Index of Erectile Function, and American Urological Association Symptom Index Score did not change. Serum prostate-specific antigen levels increased in group 2 only (1.7 +/- 1.0 to 2.2 +/- 1.5 ng/ml, P = 0.031, compared with placebo). These data demonstrate that aromatase inhibition increases serum bioavailable and total testosterone levels to the youthful normal range in older men with mild hypogonadism. Serum estradiol levels decrease modestly but remain within the normal male range. The physiological consequences of these changes remain to be determined.


Assuntos
Inibidores da Aromatase , Inibidores Enzimáticos/administração & dosagem , Hipogonadismo/tratamento farmacológico , Nitrilos/administração & dosagem , Testosterona/deficiência , Triazóis/administração & dosagem , Idoso , Envelhecimento/metabolismo , Anastrozol , Estrogênios/sangue , Humanos , Hipogonadismo/metabolismo , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Testosterona/sangue , Resultado do Tratamento
15.
J Pediatr ; 143(1): 60-6, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12915825

RESUMO

OBJECTIVE: We undertook a 1-year multicenter trial of tamoxifen treatment for precocious puberty in girls with McCune-Albright syndrome (MAS). STUDY DESIGN: Girls < or =10 years with classic or atypical MAS were recruited. Pretreatment history was collected for 6 months. Patients received 20 mg tamoxifen daily. Diaries were used to record bleeding. Evaluations included physical examination, bone age, pelvic ultrasound, hormone levels, and safety assessments. RESULTS: A total of 28 girls (2.9-10.9 years of age) were enrolled from 20 centers, of whom 25 completed 12 months of tamoxifen treatment. Compared with before the study, vaginal bleeding episodes decreased (3.42+/-3.36/year vs 1.17+/-1.41/year), growth velocity slowed (SDS 1.22+/-2.65 vs -0.59+/-3.06, P=.005), and rate of bone maturation decreased (1.21+/-0.78 vs 0.72+/-0.36, P=.02). Ovarian volumes were enlarged and asymmetric throughout the study, and uterine volumes were increased. No adverse events occurred. CONCLUSIONS: Tamoxifen treatment of precocious puberty in MAS results in a reduction of vaginal bleeding and significant improvements in growth velocity and rate of skeletal maturation.


Assuntos
Antagonistas de Estrogênios/uso terapêutico , Displasia Fibrosa Poliostótica/tratamento farmacológico , Puberdade Precoce/tratamento farmacológico , Tamoxifeno/uso terapêutico , Manchas Café com Leite/epidemiologia , Estradiol/sangue , Estrona/sangue , Feminino , Displasia Fibrosa Óssea/epidemiologia , Hormônio Foliculoestimulante/sangue , Humanos , Hipertireoidismo/epidemiologia , Fator de Crescimento Insulin-Like I/metabolismo , Hormônio Luteinizante/sangue , Estudos Prospectivos , Fatores de Tempo
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