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1.
Breast Cancer Res Treat ; 158(3): 485-95, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27393622

RESUMO

SWOG S0800, a randomized open-label Phase II clinical trial, compared the combination of weekly nab-paclitaxel and bevacizumab followed by dose-dense doxorubicin and cyclophosphamide (AC) with nab-paclitaxel followed or preceded by AC as neoadjuvant treatment for HER2-negative locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). Patients were randomly allocated (2:1:1) to three neoadjuvant chemotherapy arms: (1) nab-paclitaxel with concurrent bevacizumab followed by AC; (2) nab-paclitaxel followed by AC; or (3) AC followed by nab-paclitaxel. The primary endpoint was pathologic complete response (pCR) with stratification by disease type (non-IBC LABC vs. IBC) and hormone receptor status (positive vs. negative). Overall survival (OS), event-free survival (EFS), and toxicity were secondary endpoints. Analyses were intent-to-treat comparing bevacizumab to the combined control arms. A total of 215 patients were accrued including 11 % with IBC and 32 % with triple-negative breast cancer (TNBC). The addition of bevacizumab significantly increased the pCR rate overall (36 vs. 21 %; p = 0.019) and in TNBC (59 vs. 29 %; p = 0.014), but not in hormone receptor-positive disease (24 vs. 18 %; p = 0.41). Sequence of administration of nab-paclitaxel and AC did not affect the pCR rate. While no significant differences in OS or EFS were seen, a trend favored the addition of bevacizumab for EFS (p = 0.06) in TNBC. Overall, Grade 3-4 adverse events did not differ substantially by treatment arm. The addition of bevacizumab to nab-paclitaxel prior to dose-dense AC neoadjuvant chemotherapy significantly improved the pCR rate compared to chemotherapy alone in patients with triple-negative LABC/IBC and was accompanied by a trend for improved EFS. This suggests reconsideration of the role of bevacizumab in high-risk triple-negative locally advanced breast cancer.


Assuntos
Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Paclitaxel/administração & dosagem , Adulto , Idoso , Albuminas/uso terapêutico , Bevacizumab/uso terapêutico , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/uso terapêutico , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
2.
Ann Oncol ; 26(2): 259-71, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25214542

RESUMO

BACKGROUND: The morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is gaining momentum as evidence strengthens for the clinical relevance of this immunological biomarker. Accumulating evidence suggests that the extent of lymphocytic infiltration in tumor tissue can be assessed as a major parameter by evaluation of hematoxylin and eosin (H&E)-stained tumor sections. TILs have been shown to provide prognostic and potentially predictive value, particularly in triple-negative and human epidermal growth factor receptor 2-overexpressing BC. DESIGN: A standardized methodology for evaluating TILs is now needed as a prerequisite for integrating this parameter in standard histopathological practice, in a research setting as well as in clinical trials. This article reviews current data on the clinical validity and utility of TILs in BC in an effort to foster better knowledge and insight in this rapidly evolving field, and to develop a standardized methodology for visual assessment on H&E sections, acknowledging the future potential of molecular/multiplexed approaches. CONCLUSIONS: The methodology provided is sufficiently detailed to offer a uniformly applied, pragmatic starting point and improve consistency and reproducibility in the measurement of TILs for future studies.


Assuntos
Neoplasias da Mama/imunologia , Linfócitos do Interstício Tumoral , Feminino , Humanos
3.
Osteoporos Int ; 26(7): 1971-7, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25749740

RESUMO

UNLABELLED: Bone mineral density (BMD) measurement can vary depending upon anatomical site, machine, and normative values used. This analysis compared different BMD endpoints in two clinical trials. Trial results differed across endpoints. Future clinical trials should consider inclusion of multiple endpoints in sensitivity analysis to ensure sound overall study conclusions. INTRODUCTION: Methodological issues hamper efficacy assessment of osteoporosis prevention agents in cancer survivors. Osteoporosis diagnosis can vary depending upon which bone mineral density (BMD) anatomical site and machine is used and which set of normative values are applied. This analysis compared different endpoints for osteoporosis treatment efficacy assessment in two clinical studies. METHODS: Data from North Central Cancer Treatment Group phase III clinical trials N02C1 and N03CC (Alliance) were employed involving 774 patients each comparing two treatments for osteoporosis prevention. Endpoints for three anatomical sites included raw BMD score (RawBMD); raw machine-based, sample-standardized, and reference population-standardized T scores (RawT, TSamp, TRef); and standard normal percentile corresponding to the reference population-standardized T score (TPerc). For each, treatment arm comparison was carried out using three statistical tests using change and percentage change from baseline (CB, %CB) at 1 year. RESULTS: Baseline correlations among endpoints ranged from 0.79 to 1.00. RawBMD and TPerc produced more statistically significant results (14 and 19 each out of 36 tests) compared to RawT (11/36), TSamp (8/36), and TRef (7/36). Spine produced the most statistically significant results (26/60) relative to femoral neck (20/60) and total hip (13/60). Lastly, CB resulted in 44 statistically significant results out of 90 tests, whereas %CB resulted in only 15 significant results. CONCLUSIONS: Treatment comparisons and interpretations were different across endpoints and anatomical sites. Transforming via sample statistics provided similar results as transforming via reference or machine-based norms. However, RawBMD and TPerc may be more sensitive to change as clinical trial endpoints.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Osteoporose Pós-Menopausa/prevenção & controle , Absorciometria de Fóton/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Difosfonatos/uso terapêutico , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Colo do Fêmur/fisiopatologia , Humanos , Imidazóis/uso terapêutico , Vértebras Lombares/fisiopatologia , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/diagnóstico , Osteoporose Pós-Menopausa/fisiopatologia , Reprodutibilidade dos Testes , Ácido Risedrônico/uso terapêutico , Resultado do Tratamento , Ácido Zoledrônico
4.
Br J Cancer ; 111(6): 1065-71, 2014 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-25117817

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR) has been hypothesised to modulate the effectiveness of anti-HER2 therapy. We used a standardised, quantitative immunofluorescence assay and a novel EGFR antibody to evaluate the correlation between EGFR expression and clinical outcome in the North Central Cancer Treatment Group (NCCTG) N9831 trial. METHODS: Tissue microarrays were constructed that allowed analysis of 1365 patients randomly assigned to receive chemotherapy alone (Arm A), sequential trastuzumab after chemotherapy (Arm B) and chemotherapy with concurrent trastuzumab (Arm C). Measurement of EGFR was performed using the EGFR antibody, D38B1, on the fluorescence-based AQUA platform. The result was validated using an independent retrospective metastatic breast cancer cohort (n=130). RESULTS: Epidermal growth factor receptor assessed as a continuous (logarithmic transformed) variable shows an association with disease-free survival in Arm C (P=0.009) but not in Arm A or B. High EGFR expression was associated with worse outcome (Hazard ratio (HR)=2.15; 95% CI 1.28-3.60, P=0.004). Validation in a Greek metastatic breast cancer cohort showed an HR associated with high EGFR expression of 1.92 (P=0.0073). CONCLUSIONS: High expression of EGFR appears to be associated with decreased benefit from adjuvant concurrent trastuzumab. Since other treatment options exist for HER2-driven tumours, further validation of these data may select patients for alternative or additive therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Neoplasias da Mama/tratamento farmacológico , Receptores ErbB/análise , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/análise , Taxa de Sobrevida , Análise Serial de Tecidos , Trastuzumab
5.
Br J Cancer ; 111(6): 1241-8, 2014 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-25117820

RESUMO

BACKGROUND: Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No reliable markers are available for predicting bevacizumab-induced hypertension. METHODS: A genome-wide association study (GWAS) was performed in the phase III bevacizumab-based adjuvant breast cancer trial, ECOG-5103, to evaluate for an association between genotypes and hypertension. GWAS was conducted in those who had experienced systolic blood pressure (SBP) >160 mm Hg during therapy using binary analysis and a cumulative dose model for the total exposure of bevacizumab. Common toxicity criteria (CTC) grade 3-5 hypertension was also assessed. Candidate SNP validation was performed in the randomised phase III trial, ECOG-2100. RESULTS: When using the phenotype of SBP>160 mm Hg, the most significant association in SV2C (rs6453204) approached and met genome-wide significance in the binary model (P=6.0 × 10(-8); OR=3.3) and in the cumulative dose model (P=4.7 × 10(-8); HR=2.2), respectively. Similar associations with rs6453204 were seen for CTC grade 3-5 hypertension but did not meet genome-wide significance. Validation study from ECOG-2100 demonstrated a statistically significant association between this SNP and grade 3/4 hypertension using the binary model (P-value=0.037; OR=2.4). CONCLUSIONS: A genetic variant in SV2C predicted clinically relevant bevacizumab-induced hypertension in two independent, randomised phase III trials.


Assuntos
Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Hipertensão/induzido quimicamente , Hipertensão/genética , Glicoproteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Bevacizumab , Biomarcadores , Pressão Sanguínea , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
6.
Ann Oncol ; 24(10): 2548-2554, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23798616

RESUMO

BACKGROUND: Based on preclinical studies, the vascular endothelial pathway is an important mechanism for estrogen receptor resistance. We conducted a phase II study of fulvestrant and bevacizumab in patients with aromatase inhibitor pretreated metastatic breast cancer. PATIENTS AND METHODS: A single-stage phase II study was conducted with these objectives: 6-month progression-free survival (PFS), tumor response, toxic effect, and overall survival. Regimen: 250 mg fulvestrant days 1 and 15 (cycle 1) then day 1 (cycle 2 and beyond) and 10 mg/kg bevacizumab days 1 and 15 of each 4-week cycle. RESULTS: At interim analysis, 20 eligible patients initiated treatment, 11 were progression free and on treatment at 3 months, not meeting the protocol-specified efficacy requirements (at least 12 of 20). Accrual remained open during interim analysis with 36 patients enrolling before final study closure. Among the 33 eligible patients, the median PFS was 6.2 months [95% confidence interval (CI) 3.6-10.1 months]. Of the 18 with measurable disease, 4 (22%) patients (95% CI 6% to 48%) had a confirmed tumor response (1 complete, 3 partial). The most common grade 3/4 adverse events were hypertension 3 (9%) and headache 3 (9%). CONCLUSIONS: The fulvestrant/bevacizumab combination is safe and tolerable; however, it did not meet its statistical end point.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Estradiol/análogos & derivados , Receptores de Estrogênio/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Bevacizumab , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Estradiol/efeitos adversos , Estradiol/uso terapêutico , Feminino , Fulvestranto , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Qualidade de Vida
8.
Ann Oncol ; 24(2): 355-361, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23028039

RESUMO

BACKGROUND: MA17 showed improved outcomes in postmenopausal women given extended letrozole (LET) after completing 5 years of adjuvant tamoxifen. PATIENTS AND METHODS: Exploratory subgroup analyses of disease-free survival (DFS), distant DFS (DDFS), overall survival (OS), toxic effects and quality of life (QOL) in MA17 were performed based on menopausal status at breast cancer diagnosis. RESULTS: At diagnosis, 877 women were premenopausal and 4289 were postmenopausal. Extended LET was significantly better than placebo (PLAC) in DFS for premenopausal [hazard ratio (HR) = 0.26, 95% confidence interval (CI) 0.13-0.55; P = 0.0003] and postmenopausal women (HR = 0.67; 95% CI 0.51-0.89; P = 0.006), with greater DFS benefit in those premenopausal (interaction P = 0.03). In adjusted post-unblinding analysis, those who switched from PLAC to LET improved DDFS in premenopausal (HR = 0.15; 95% CI 0.03-0.79; P = 0.02) and postmenopausal women (HR = 0.45; 95% CI 0.22-0.94; P = 0.03). CONCLUSIONS: Extended LET after 5 years of tamoxifen was effective in pre- and postmenopausal women at diagnosis, and significantly better in those premenopausal. Women premenopausal at diagnosis should be considered for extended adjuvant therapy with LET if menopausal after completing tamoxifen.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Nitrilas/uso terapêutico , Pré-Menopausa , Triazóis/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Inibidores da Aromatase/efeitos adversos , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/diagnóstico , Quimioterapia Adjuvante , Intervalo Livre de Doença , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Letrozol , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Placebos , Pós-Menopausa , Qualidade de Vida , Sobrevida , Tamoxifeno/uso terapêutico , Resultado do Tratamento , Triazóis/efeitos adversos
9.
Spinal Cord ; 51(12): 898-903, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23999111

RESUMO

STUDY DESIGN: Cross-sectional validation study. OBJECTIVES: The goals of this study were to validate the use of accelerometers by means of multiple linear models (MLMs) to estimate the O2 consumption (VO2) in paraplegic persons and to determine the best placement for accelerometers on the human body. SETTING: Non-hospitalized paraplegics' community. METHODS: Twenty participants (age=40.03 years, weight=75.8 kg and height=1.76 m) completed sedentary, propulsion and housework activities for 10 min each. A portable gas analyzer was used to record VO2. Additionally, four accelerometers (placed on the non-dominant chest, non-dominant waist and both wrists) were used to collect second-by-second acceleration signals. Minute-by-minute VO2 (ml kg(-1) min(-1)) collected from minutes 4 to 7 was used as the dependent variable. Thirty-six features extracted from the acceleration signals were used as independent variables. These variables were, for each axis including the resultant vector, the percentiles 10th, 25th, 50th, 75th and 90th; the autocorrelation with lag of 1 s and three variables extracted from wavelet analysis. The independent variables that were determined to be statistically significant using the forward stepwise method were subsequently analyzed using MLMs. RESULTS: The model obtained for the non-dominant wrist was the most accurate (VO2=4.0558-0.0318Y25+0.0107Y90+0.0051YND2-0.0061ZND2+0.0357VR50) with an r-value of 0.86 and a root mean square error of 2.23 ml kg(-1) min(-1). CONCLUSIONS: The use of MLMs is appropriate to estimate VO2 by accelerometer data in paraplegic persons. The model obtained to the non-dominant wrist accelerometer (best placement) data improves the previous models for this population.


Assuntos
Acelerometria/instrumentação , Acelerometria/normas , Metabolismo Energético/fisiologia , Monitorização Ambulatorial/instrumentação , Paraplegia/etiologia , Traumatismos da Medula Espinal/complicações , Cadeiras de Rodas , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Consumo de Oxigênio/fisiologia , Paraplegia/metabolismo , Paraplegia/reabilitação , Traumatismos da Medula Espinal/reabilitação
10.
Ann Oncol ; 23(2): 331-7, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21821545

RESUMO

BACKGROUND: E2104 was designed to evaluate the safety of two different strategies incorporating bevacizumab into anthracycline-containing adjuvant therapy as a precursor to a definitive randomized phase III trial. PATIENTS AND METHODS: Patients were sequentially assigned to one of two treatment arms. In addition to dose-dense doxorubicin and cyclophosphamide followed by paclitaxel (Taxol) (ddAC→T), all patients received bevacizumab (10 mg/kg every 2 weeks × 26) initiated either concurrently with AC (Arm A: ddBAC→BT→B) or with paclitaxel (Arm B: ddAC→BT→B). The primary end point was incidence of clinically apparent cardiac dysfunction (CHF). RESULTS: Patients enrolled were 226 in number (Arm A 104, Arm B 122). Grade 3 hypertension, thrombosis, proteinuria and hemorrhage were reported for 12, 2, 2 and <1% of patients, respectively. Two patients developed grade 3 or more cerebrovascular ischemia. Three patients in each arm developed CHF. There was no significant difference between arms in the proportion of patients with an absolute decrease in left ventricular ejection fraction of >15% or >10% to below the lower limit of normal post AC or post bevacizumab. CONCLUSIONS: Incorporation of bevacizumab into anthracycline-containing adjuvant therapy does not result in prohibitive cardiac toxicity. The definitive phase III trial (E5103) was activated with systematic and extensive cardiac monitoring to define the true impact of bevacizumab on cardiac function.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Cardiopatias/induzido quimicamente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Projetos Piloto
11.
Front Public Health ; 9: 646863, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34760856

RESUMO

Countries are recording health information on the global spread of COVID-19 using different methods, sometimes changing the rules after a few days. All of them are publishing the number of new individuals infected, recovered and dead individuals, along with some supplementary material. These data are often recorded in a non-uniform manner and do not conform the standard definitions of these variables. In this paper we show that, using data from the first wave of the epidemic (February-June), Kaplan-Meier curves calculated with them could provide useful information on the dynamics of the disease in different countries. We developed our scheme based on the cumulative total number of infected, recovered and dead individuals provided by the countries. We present a robust and simple model to show certain characteristics of the evolution of the dynamic process, showing that the differences in evolution between countries are reflected in the corresponding Kaplan-Meier-type curves. We compare the curves obtained for the most affected countries at that time, with the corresponding interpretation of the properties that distinguish them. The model is revealed as a practical tool for countries in the management of the Healthcare System.


Assuntos
COVID-19 , Epidemias , Humanos , Estimativa de Kaplan-Meier , SARS-CoV-2
12.
Ann Oncol ; 21(3): 493-497, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19625343

RESUMO

BACKGROUND: Because of the single-agent activity of irinotecan hydrochloride, combination of irinotecan and docetaxel treatment against metastatic breast cancer (MBC) should be evaluated. PATIENTS AND METHODS: Single-stage phase 2 study of irinotecan and docetaxel to evaluate tumor response, toxicity, time to progression, and overall survival was carried out. Regimen of docetaxel (25 mg/m(2)) and irinotecan (70 mg/m(2)) was administered on days 1 and 8 of each 3-week cycle. Patients had histologically confirmed breast adenocarcinoma and metastatic cancer measurable with RECIST. RESULTS: Of 70 patients enrolled, 64 were assessable. Prior treatment with an anthracycline and a taxane was required. Eighteen (28%) patients [95% confidence interval (CI) 15% to 31%] had tumor response, plus four patients had stable disease (less than 30% decrease in sum of longest diameter and less than 20% increase) for >6 months. The clinical benefit rate was 34% overall. Median duration of tumor response was 6.7 months (95% CI 4.2-37.7 months); median follow-up was 18.6 months (range 8.5-37.7 months). The most common severe adverse events included fatigue [n = 16 (25%)] and neutropenia [n = 13 (20%)]. CONCLUSIONS: Weekly dosing of combination of irinotecan and docetaxel is active against MBC. However, the response rate to our regimen was not significantly better than single-agent docetaxel. Other schedules of irinotecan plus docetaxel should be considered for future studies.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Recidiva Local de Neoplasia/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Docetaxel , Feminino , Seguimentos , Humanos , Irinotecano , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Terapia de Salvação , Taxa de Sobrevida , Taxoides/administração & dosagem , Resultado do Tratamento
13.
Ann Oncol ; 21(2): 269-274, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19901014

RESUMO

BACKGROUND: Docetaxel (T; Taxotere) with capecitabine (X) is active against metastatic breast cancer (MBC); bevacizumab (BV) has demonstrated efficacy with taxanes in the first-line setting. This study was conducted to assess the safety and efficacy of TX-BV in patients with MBC. PATIENTS AND METHODS: In this single-arm, multicenter phase II study, patients received first-line bevacizumab 15 mg/kg and docetaxel 75 mg/m(2) on day 1 and capecitabine 825 mg/m(2) twice per day on days 1-14 every 21 days. Primary and secondary end points were tumor response rate (RR), overall survival (OS), progression-free survival (PFS), and toxicity. RESULTS: A total of 45 assessable patients received TX-BV for a median of seven cycles. Two complete and 20 partial responses were observed (overall RR 49%); nine patients had stable disease >6 months, for a clinical benefit rate of 69%. Median response duration was 11.8 months. Median OS and PFS were 28.4 and 11.1 months, respectively. Grade 3/4 adverse events included hand-foot syndrome (29%), fatigue (20%), febrile neutropenia (18%), and diarrhea (18%). In cycles 3-10, median dose levels of docetaxel and capecitabine were 60 mg/m(2) and 660 mg/m(2), respectively. CONCLUSION: TX-BV demonstrated significant activity; dose modifications were required to manage drug-related toxic effects.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Taxoides/administração & dosagem , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Neoplasias da Mama/patologia , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Intervalo Livre de Doença , Docetaxel , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Metástase Neoplásica , Taxoides/efeitos adversos , Resultado do Tratamento , Estados Unidos
15.
Ann Oncol ; 19(9): 1561-5, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18534964

RESUMO

BACKGROUND: Women with triple-negative (TN) breast cancer are at increased risk of distant metastases and have reduced survival versus other breast cancer patients. Relative survival of women with TN breast cancer who develop brain metastases is unknown. METHODS: Patients with breast cancer who developed brain metastases at our institution from 1993 to 2006 were reviewed. Four survival time intervals were compared in patients with TN disease and those with non-TN disease: initial diagnosis to distant metastases, distant metastases to brain metastases, brain metastases to death, and overall diagnosis to death. RESULTS: One hundred and eighteen patients were identified. Fifty-one (50%) of 103 were estrogen receptor positive, 26 (39%) of 67 were human epidermal growth factor receptor 2 positive, and 20 (22%) of 91 were TN. Survival times were shorter for TN patients, with overall survival of 26 months in TN patients versus 49 months for non-TN patients. In TN patients, time to development of distant metastases, brain metastases, and death after brain metastases was shorter than in non-TN patients. CONCLUSION: Patients with TN disease were more likely to develop distant metastases earlier than non-TN patients, developed brain metastases sooner, and had shorter overall survival.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/secundário , Linfonodos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha , Neoplasias Encefálicas/diagnóstico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/terapia , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Probabilidade , Prognóstico , Modelos de Riscos Proporcionais , Receptor ErbB-2/análise , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/análise , Receptores de Estrogênio/metabolismo , Medição de Risco , Análise de Sobrevida
16.
Ann Oncol ; 19(7): 1231-1241, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18325918

RESUMO

BACKGROUND: The role of chemotherapy in addition to combined endocrine therapy for premenopausal women with endocrine-responsive early breast cancer remains an open question, yet trials designed to answer it have repeatedly failed to adequately accrue. The International Breast Cancer Study Group initiated two concurrent trials in this population: in Premenopausal Endocrine Responsive Chemotherapy (PERCHE), chemotherapy use is determined by randomization and in Tamoxifen and Exemestane Trial (TEXT) by physician choice. PERCHE closed with inadequate accrual; TEXT accrued rapidly. METHODS: From 2003 to 2006, 1317 patients (890 with baseline data) were randomly assigned to receive ovarian function suppression (OFS) plus tamoxifen or OFS plus exemestane for 5 years in TEXT. We explore patient-related factors according to whether or not chemotherapy was given using descriptive statistics and classification and regression trees. RESULTS: Adjuvant chemotherapy was chosen for 64% of patients. Lymph node status was the predominant determinant of chemotherapy use (88% of node positive treated versus 46% of node negative). Geography, patient age, tumor size and grade were also determinants, but degree of receptor positivity and human epidermal growth factor receptor 2 status were not. CONCLUSIONS: The perceived estimation of increased risk of relapse is the primary determinant for using chemotherapy despite uncertainties regarding the degree of benefit it offers when added to combined endocrine therapy in this population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Tomada de Decisões , Androstadienos/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Feminino , Gosserrelina/administração & dosagem , Humanos , Pré-Menopausa , Ensaios Clínicos Controlados Aleatórios como Assunto , Tamoxifeno/administração & dosagem
17.
Ann Oncol ; 19(5): 877-82, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18332043

RESUMO

BACKGROUND: MA.17 evaluated letrozole or placebo after 5 years of tamoxifen and showed significant improvement in disease-free survival (DFS) for letrozole [hazard ratio (HR) 0.57, P = 0.00008]. The trial was unblinded and placebo patients were offered letrozole. PATIENTS AND METHODS: An intent-to-treat analysis of all outcomes, before and after unblinding, on the basis of the original randomization was carried out. RESULTS: In all, 5187 patients were randomly allocated to the study at baseline and, at unblinding, 1579 (66%) of 2383 placebo patients accepted letrozole. At median follow-up of 64 months (range 16-95), 399 recurrences or contralateral breast cancers (CLBCs) (164 letrozole and 235 placebo) occurred. Four-year DFS was 94.3% (letrozole) and 91.4% (placebo) [HR 0.68, 95% confidence interval (CI) 0.55-0.83, P = 0.0001] and showed superiority for letrozole in both node-positive and -negative patients. Corresponding 4-year distant DFS was 96.3% and 94.9% (HR 0.80, 95% CI 0.62-1.03, P = 0.082). Four-year overall survival was 95.1% for both groups. The annual rate of CLBC was 0.28% for letrozole and 0.46% for placebo patients (HR 0.61, 95% CI 0.39-0.97, P = 0.033). CONCLUSIONS: Patients originally randomly assigned to receive letrozole within 3 months of stopping tamoxifen did better than placebo patients in DFS and CLBC, despite 66% of placebo patients taking letrozole after unblinding.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Estrogênios , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Nitrilas/uso terapêutico , Progesterona , Triazóis/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/administração & dosagem , Intervalo Livre de Doença , Método Duplo-Cego , Humanos , Estimativa de Kaplan-Meier , Letrozol , Metástase Linfática , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/epidemiologia , Nitrilas/administração & dosagem , Aceitação pelo Paciente de Cuidados de Saúde , Placebos , Pós-Menopausa , Modelos de Riscos Proporcionais , Recidiva , Tamoxifeno/uso terapêutico , Triazóis/administração & dosagem
18.
Ann Oncol ; 18 Suppl 8: viii26-35, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17890211

RESUMO

Adjuvant endocrine therapy plays an important role in the management of hormone-receptor-positive early breast cancer, and has increased life expectancy for millions of women. Many patients receive adjuvant treatment for at least 5 years following tumor resection, hence good long-term safety is important for endocrine agents to gain widespread acceptance. Tamoxifen has been used as adjuvant therapy for early breast cancer for many years, and safety data have been well documented, but a poor risk:benefit profile limits treatment duration to 5 years. Increased efficacy over tamoxifen and good tolerability have recently made the third-generation aromatase inhibitors (AIs) the first-choice agents for adjuvant endocrine therapy; however, it is currently not known whether AI therapy, like tamoxifen, will be limited to 5 years. Many side effects of endocrine therapy, such as hot flushes and mood disturbances, are related to estrogen deprivation and are common to tamoxifen and AIs, reflecting the mechanism of action of these drugs. In addition, tamoxifen has estrogenic effects that are beneficial in some tissues: tamoxifen lowers serum cholesterol levels and protects against bone loss and cardiovascular disease, but is also associated with potentially life-threatening side effects, such as endometrial cancer and thromboembolic disease. As AIs lack estrogenic activity, they are not associated with these serious adverse events. Clinical trials comparing AIs with tamoxifen in the adjuvant setting have shown that AIs are well tolerated and are associated with a lower incidence of gynecological symptoms and hot flushes than tamoxifen. However, AIs are associated with musculoskeletal side effects, such as arthralgia, myalgia and bone loss, but these events are preventable or manageable. The effects of AIs on lipid metabolism and the cardiovascular system are still debatable, but placebo-controlled trials provide no evidence to suggest that AIs adversely affect these systems. Furthermore, the AIs allow women to maintain a good quality of life, comparable with women receiving tamoxifen or placebo, and are a cost-effective therapeutic option. Ongoing trials will provide more information regarding the long-term effects of AI therapy and will provide comparative data on the efficacy and safety of the different AIs, thereby helping to determine the optimal treatment strategy for these highly effective and well-tolerated drugs.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Tamoxifeno/uso terapêutico , Antineoplásicos Hormonais/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Neoplasias Hormônio-Dependentes/patologia , Neoplasias Hormônio-Dependentes/cirurgia , Tamoxifeno/efeitos adversos
19.
J Natl Cancer Inst ; 81(10): 790-4, 1989 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-2541260

RESUMO

Between October 1985 and March 1987, 92 patients were registered on a phase II study of the Northern California Oncology Group investigating the importance of dose intensity in the treatment of advanced non-small cell lung cancer (NSCLC). Treatment consisted of high-dose cisplatin in hypertonic saline (200 mg/m2 on a 28-day cycle) given in a divided day 1 and day 8 schedule. The response rate among 76 assessable patients was 36% (27/76), with complete response (CR) in 8% (6/76) and partial response (PR) in 28% (21/76). If all patients receiving any drug therapy were considered, the overall response rate was 31% (27/87), with CR in 7% (6/87) and PR in 24% (21/87). Median survival times for all assessable patients and all patients receiving any therapy were 37 and 35 weeks, respectively. With the use of a protocol design specifying dose delays rather than dose reduction for toxicity, the mean dose intensity delivered was 47.2 mg/m2 per week, or 94% of projected. Compared with other dose-intensive regimens of cisplatin, this day 1 and day 8 schedule was relatively well tolerated, with peripheral neuropathy as the dose-limiting toxicity. The data on response and median survival times among patients receiving this single-agent therapy are encouraging. They support the potential importance of cisplatin dose intensity in the treatment of NSCLC. Whether these results represent a positive dose-response effect in NSCLC will be tested in a randomized comparative trial of high-dose versus standard-dose cisplatin therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/efeitos adversos , Esquema de Medicação , Avaliação de Medicamentos , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia
20.
J Clin Oncol ; 13(4): 1036-43, 1995 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-7707101

RESUMO

PURPOSE: This analysis was undertaken to review published reports of the comparative efficacy and safety of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists in the prophylaxis of acute chemotherapy-induced emesis. METHODS: Comparison data used are the preclinical pharmacology as well as the design and results of clinical trials. Seven comparative studies that used granisetron, ondansetron, or tropisetron in patients who received either moderately or highly emetogenic chemotherapy are reviewed. As the study designs, patient population, chemotherapy, antiemetic doses and schedule, and methods of assessment were slightly different, the results of each study are analyzed independently. Effectiveness is assessed by emetic episodes, nausea, and patient preference. RESULTS: The preclinical pharmacologic profile is different among the 5-HT3 antagonists in terms of potency, selectivity, dose response, and duration of action. The comparative clinical trials show that a single intravenous (i.v.) dose of granisetron 3 mg is as effective as multiple (8 mg x 3) or single (32 mg) i.v. doses of ondansetron for the prevention of acute nausea and emesis due to cisplatin. In the two moderately emetogenic clinical trials, granisetron 3 mg i.v. was at least as effective as ondansetron 8 mg i.v. +/- 24 mg orally and tropisetron 5 mg i.v. Patient preference was evaluated in three of the four crossover trials: granisetron was preferred in three of four, and no preference was reported in the fourth. The one trial to compare ondansetron 0.15 mg/kg x 3 versus granisetron 10 micrograms/kg x 1 or granisetron 40 micrograms/kg i.v. demonstrated equivalent control of nausea and vomiting in patients who received cisplatin-based chemotherapy. CONCLUSION: The 5-HT3 receptor antagonists compared are highly effective antiemetic agents that have now become the standard of care for preventing chemotherapy-induced emesis. Whether the described preclinical differences among these agents are also clinically significant remains to be seen. In the comparative trials analyzed, the 5-HT3 receptor antagonists demonstrated relatively equivalent clinical efficacy. Cost analysis may favor the use of one agent over another depending on the emetogenic challenge, dose of the 5-HT3 antagonists, and number of doses recommended. Patient preference may be an important factor to be considered in future antiemetic trials.


Assuntos
Antieméticos/uso terapêutico , Antineoplásicos/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Vômito/tratamento farmacológico , Antieméticos/economia , Cisplatino/efeitos adversos , Granisetron/uso terapêutico , Humanos , Indóis/uso terapêutico , Ondansetron/uso terapêutico , Prognóstico , Inibidores Seletivos de Recaptação de Serotonina/economia , Tropizetrona , Vômito/induzido quimicamente
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