RESUMO
BACKGROUND: The GeparQuattro study showed that adding capecitabine or prolonging the duration of anthracycline-taxane-based neoadjuvant chemotherapy from 24 to 36 weeks did not increase pathological complete response (pCR) rates. Trastuzumab-treated patients with HER2-positive disease showed a higher pCR rate than patients with HER2-negative disease treated with chemotherapy alone. We here present disease-free (DFS) and overall survival (OS) analyses. PATIENTS AND METHODS: Patients (n = 1495) with cT ≥ 3 tumors, or negative hormone-receptor status, or positive hormone-receptor and clinically node-positive disease received four times epirubicin/cyclophosphamide and were thereafter randomly assigned to four times docetaxel (Taxotere), or four times docetaxel/capecitabine over 24 weeks, or four times docetaxel followed by capecitabine over 36 weeks. Patients with HER2-positive tumors received 1 year of trastuzumab, starting with the first chemotherapy cycle. Follow-up was available for a median of 5.4 years. RESULTS: Outcome was not improved for patients receiving capecitabine (HR 0.92; P = 0.463 for DFS and HR 93; P = 0.618 for OS) as well as for patients receiving 36 weeks of chemotherapy (HR 0.97; P = 0.818 for DFS and HR 0.97; P = 0.825 for OS). Trastuzumab-treated patients with HER2-positive disease showed similar DFS (P = 0.305) but a significantly better adjusted OS (P = 0.040) when compared with patients with HER2-negative disease treated with chemotherapy alone. Recorded long-term cardiac toxicity was low. CONCLUSIONS: Long-term results, similar to the results of pCR, do not support the use of capecitabine in the neoadjuvant setting in addition to an anthracycline-taxane-based chemotherapy. However, the results support previous data showing a benefit of trastuzumab as predicted by higher pCR rates.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/mortalidade , Capecitabina , Carcinoma Ductal de Mama/mortalidade , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Docetaxel , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Terapia Neoadjuvante , Modelos de Riscos Proporcionais , Taxoides/administração & dosagem , Trastuzumab , Resultado do TratamentoRESUMO
AIM: Final 10-year analysis of the prospective randomised Chemo-N0 trial is presented. Based on the Chemo-N0 interim results and an European Organisation for Research and Treatment of Cancer (EORTC) pooled analysis (n=8377), American Society of Clinical Oncology (ASCO) and Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) guidelines recommend invasion and metastasis markers urokinase-type plasminogen activator (uPA)/plasminogen activator inhibitor-1 (PAI-1) for risk assessment and treatment decision in node-negative (N0) breast cancer (BC). METHODS: The final Chemo-N0 trial analysis (recruitment 1993-1998; n=647; 12 centres) comprises 113 (5-167) months of median follow-up. Patients with low-uPA and PAI-1 tumour tissue levels (n=283) were observed. External quality assurance guaranteed uPA/PAI-1 enzyme-linked immunosorbent assay (ELISA) standardisation. Of 364 high uPA and/or PAI-1 patients, 242 agreed to randomisation for CMF chemotherapy (n=117) versus observation (n=125). RESULTS: Actuarial 10-year recurrence rate (without any adjuvant systemic therapy) for high-uPA/PAI-1 observation group patients (randomised and non-randomised) was 23.0%, in contrast to only 12.9% for low-uPA/PAI-1 patients (plog-rank=0.011). High-risk patients randomised to cyclophosphamide-methotrexate-5-fluorouracil (CMF) therapy had a 26.0% lower estimated probability of disease recurrence than those randomised for observation (intention-to-treat (ITT)-analysis: hazard ratio (HR) 0.74 (0.44-1.27); plog-rank=0.28). Per-protocol analysis demonstrated significant treatment benefit: HR 0.48 (0.26-0.88), p=0.019, disease-free survival (DFS) Cox regression, adjusted for tumour stage and grade. CONCLUSIONS: Chemo-N0 is the first prospective biomarker-based therapy trial in early BC defining patients reaching good long-term DFS without adjuvant systemic therapy. Using a standardised uPA/PAI-1 ELISA, almost half of N0-patients could be spared chemotherapy, while high-risk patients benefit from adjuvant chemotherapy. These 10-year results validate the long-term prognostic impact of uPA/PAI-1 and the benefit from adjuvant chemotherapy in the high-uPA/PAI-1 group at highest level of evidence. They thus support the guideline-based routine use of uPA/PAI-1 for risk-adapted individualised therapy decisions in N0 breast cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Tomada de Decisões , Intervalo Livre de Doença , Tratamento Farmacológico/métodos , Tratamento Farmacológico/psicologia , Ensaio de Imunoadsorção Enzimática , Feminino , Fluoruracila/administração & dosagem , Humanos , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Prognóstico , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Ativador de Plasminogênio Tipo Uroquinase/metabolismoRESUMO
BACKGROUND: The objective of this study was to compare the effect of dose-intensified neoadjuvant chemotherapy with that of standard epirubicin plus cyclophosphamide followed by paclitaxel in combination with or without darbepoetin on survival in primary breast cancer. PATIENTS AND METHODS: A total of 733 patients received either four cycles of neoadjuvant epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks followed by four cycles of paclitaxel 175 mg/m(2) every 3 weeks (ECâT), or three cycles of epirubicin 150 mg/m(2) every 2 weeks followed by three cycles of paclitaxel 225 mg/m(2) every 2 weeks followed by three cycles of combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (E(dd)âT(dd)âCMF). The patients were randomly assigned to receive darbepoetin or none. The primary objective was to demonstrate a superior disease-free survival (DFS) of E(dd)âT(dd)âCMF compared with ECâT. RESULTS: Estimated 3-year DFS was 75.8% with ECâT versus 78.8% with E(dd)âT(dd)âCMF [hazard ratio (HR) 1.14; P = 0.37] and overall survival (OS) 88.4% versus 91.5% (HR 1.26; P = 0.237). Three-year DFS was 74.3% with darbepoetin versus 80.0% without (HR 1.31; P = 0.061) and OS 88.0% versus 91.8% (HR 1.33; P = 0.139). Patients with a pathologically documented complete response [pathological complete response (pCR)] had a significantly better DFS compared with those without achieving a pCR (estimated 3-year DFS: 89.2% versus 74.9%; HR 2.27; P = 0.001). CONCLUSION: Neoadjuvant dose-intensified chemotherapy compared with standard chemotherapy did not improve DFS, whereas the addition of darbepoetin might have detrimental effects on DFS.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Anemia/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/sangue , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Darbepoetina alfa , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Epirubicina/administração & dosagem , Epirubicina/efeitos adversos , Eritropoetina/administração & dosagem , Eritropoetina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Análise Multivariada , Terapia Neoadjuvante , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Cooperação do Paciente , Cuidados Pré-Operatórios , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Preoperative chemotherapy is a recommended treatment of both primary operable and locally advanced breast cancer. Strategies to improve efficacy include the use of anthracyclines, taxanes, and intensified dose with bone marrow support. PATIENTS AND METHODS: Patients received neoadjuvant epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) followed by paclitaxel 175 mg/m(2) (ECâT), each 3-weekly for four cycles (n = 370), or epirubicin 150 mg/m(2) followed by paclitaxel 225 mg/m(2) with pegfilgrastim followed by CMF (cyclophosphamide 500 mg/m(2), methotrexate 40 mg/m(2), fluorouracil 600 mg/m(2)) on days 1 and 8 (E(dd)âT(dd)âCMF), each 2-weekly and for three cycles (n = 363). Patients were randomly allocated to either simultaneous darbepoetin alfa (DA) (n = 356) or none (n = 377). RESULTS: Pathological complete response (pCR) rate (breast) was higher with E(dd)âT(dd)âCMF, 18.7% versus 13.2% with ECâT; P = 0.043, ypT0/Tis; ypN0 was reported in 20.9% versus 14.3% respectively; P = 0.019. Patients with grade 3 tumors and negative hormone receptor status had a significantly higher pCR rate. Mean hemoglobin values maintained higher with DA (13.6 versus 12.6 g/dl). E(dd)âT(dd)âCMF regimen showed more grade 3-4 mucositis, sensory neuropathy, and neurological complaints. Thromboembolic events were more frequent on DA (3% versus 6%; P = 0.055). CONCLUSION: Dose-dense and -intensified neoadjuvant chemotherapy with E(dd)âT(dd)âCMF was potentially superior to ECâT in terms of pCR. Primary use of DA did not affect pCR.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Darbepoetina alfa , Relação Dose-Resposta a Droga , Epirubicina/administração & dosagem , Epirubicina/efeitos adversos , Eritropoetina/administração & dosagem , Eritropoetina/análogos & derivados , Feminino , Filgrastim , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Hemoglobinas/metabolismo , Humanos , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Cooperação do Paciente , Polietilenoglicóis , Cuidados Pré-Operatórios , Proteínas Recombinantes/administração & dosagem , Adulto JovemRESUMO
Trastuzumab (Herceptin; Genentech, Inc., CA, USA) is a humanized monoclonal antibody developed to target the HER-2/neu receptor, which is overexpressed in 20 - 25% of breast carcinomas. Clinical studies showed that trastuzumab is effective as single-agent therapy and that it has greater antitumour activity in combination with chemotherapy than chemotherapy alone in metastatic breast cancer. The indication for trastuzumab monotherapy and the combination with various chemotherapy agents is country-specific and is largely based on trials of efficacy and safety. Patients with a HER-2/neu overexpression level of 3+, determined by immunohistochemical assay or amplification using fluorescence in situ hybridisation, derive most clinical benefit from trastuzumab. Trastuzumab is generally well-tolerated. Cardiotoxicity is the main concern; thus, monitoring of cardiac function is recommended. Ongoing trials investigate the role of trastuzumab in the adjuvant and neoadjuvant settings.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/terapia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Capecitabina , Quimioterapia Adjuvante , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/análogos & derivados , Cardiopatias/etiologia , Humanos , Terapia Neoadjuvante , Metástase Neoplásica , Seleção de Pacientes , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Taxoides/uso terapêutico , Trastuzumab , Vimblastina/análogos & derivados , Vimblastina/uso terapêutico , VinorelbinaRESUMO
The emerging evidence gained from randomized controlled trials accelerated the widespread use of adjuvant endocrine and cytotoxic regimens and their combinations for most breast cancer patients. Even for the earliest cancer stages with low-risk tumour profiles, endocrine treatment can be recommended as adjuvant therapy if the tumour is endocrine responsive. The 8th consensus conference on early breast cancer in St. Gallen in 2003 opened a plethora of treatment options to nearly all breast cancer patients. Key issues were the introduction of adjuvant therapy with anastrozole for those postmenopausal patients with contra-indications or intolerability of tamoxifen and the definition of a group of 'more potent' regimens like the FEC- and the taxane-based regimens for high-risk patients. Unfortunately the expert panel did not clearly define any recommendations either for choosing optimal candidates for purely endocrine treatments (which are a valid option for all patients with optimal endocrine responsive disease or arguments against chemotherapy) or for the proper high-risk patients scheduled for more aggressive regimens. In the meantime, new or updated studies have provided additional information helpful for the shared decision-making with our patients. The Canadian MA.17 study revealed a significant benefit from adding a sequential therapy with letrozole after 5 years of tamoxifen compared to tamoxifen alone. Together with the updated evaluation from the ATAC trial and the Italian ITA study, the role of adjuvant treatment with aromatase inhibitors is steadily strengthened. Several studies comparing taxane-based and taxane-free regimens showed significant survival and/or recurrence benefits for the former. These data should be communicated to the patients. In the complex process of decision-making, a profound knowledge of the study results and the early and complete involvement of the woman and her personal beliefs are mandatory.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Terapia Combinada , Procedimentos Clínicos , Feminino , Humanos , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
BACKGROUND: Most patients with lymph node-negative breast cancer are cured by locoregional treatment; however, about 30% relapse. Because traditional histomorphologic and clinical factors fail to identify the high-risk patients who may benefit from adjuvant chemotherapy, other prognostic factors are needed. In a unicenter study, we have found that levels of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) in the primary tumor are predictive of disease recurrence. Thus, we designed the Chemo N(0) prospective randomized multicenter therapy trial to investigate further whether uPA and PAI-1 are such prognostic factors and whether high-risk patients identified by these factors benefit from adjuvant chemotherapy. After 4.5 years, we present results of the first interim analysis. METHODS: We studied 556 patients with lymph node-negative breast cancer. The median follow-up was 32 months. All patients with low tumor levels of uPA (< or = 3 ng/mg of protein) and of PAI-1 (< or = 14 ng/mg of protein) were observed. Patients with high tumor levels of uPA (> 3 ng/mg of protein) and/or of PAI-1 (> 14 ng/mg of protein) were randomly assigned to combination chemotherapy or subjected to observation only. All statistical tests were two-sided. RESULTS: A total of 241 patients had low levels of uPA and PAI-1, and 315 had elevated levels of uPA and/or PAI-1. The estimated 3-year recurrence rate for patients with low tumor levels of uPA and PAI-1 (low-risk group) was 6.7% (95% confidence interval [CI] = 2.5% to 10.8%). This rate for patients with high tumor levels of uPA and/or PAI-1 (high-risk group) was 14.7% (95% CI = 8.5% to 20.9%) (P = 0.006). First interim analysis suggests that high-risk patients in the chemotherapy group benefit, with a 43.8% lower estimated probability of disease recurrence at 3 years than high-risk patients in the observation group (intention-to-treat analysis: relative risk = 0.56; 95% CI = 0.25 to 1.28), but further follow-up is needed for confirmation. CONCLUSIONS: Using uPA and PAI-1, we have been able to classify about half of the patients with lymph node-negative breast cancer as low risk, for whom adjuvant chemotherapy may be avoided, and half as high risk, who appear to benefit from adjuvant chemotherapy.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Inibidor 1 de Ativador de Plasminogênio/uso terapêutico , Ativadores de Plasminogênio/uso terapêutico , Ativador de Plasminogênio Tipo Uroquinase/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Linfonodos/patologia , Menopausa , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Inibidor 1 de Ativador de Plasminogênio/efeitos adversos , Inibidor 1 de Ativador de Plasminogênio/sangue , Ativadores de Plasminogênio/efeitos adversos , Ativadores de Plasminogênio/sangue , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Ativador de Plasminogênio Tipo Uroquinase/efeitos adversos , Ativador de Plasminogênio Tipo Uroquinase/sangueRESUMO
PURPOSE: To optimize detection and diagnosis of breast lesions with contrast-enhanced magnetic resonance (MR) imaging. MATERIALS AND METHODS: A three-dimensional fast low-angle shot pulse sequence was used for a group comparison consisting of 76 high-dose (0.16 mmol gadopentetate dimeglumine per kilogram of body weight) and 76 low-dose (0.1 mmol/kg) examinations. Intraindividual comparisons were possible in a subgroup of 20 patients. RESULTS: Enhancement with the high dose was about 1.5 times higher for benign and malignant tissues. With the lower dose, no false-positive findings could be avoided and definition of a threshold that excluded false-negative findings was problematic. Conspicuity of malignant lesions was much improved with the higher dose (a good to excellent rating in 81% vs 26% with the lower dose). Three small foci were visible only with the higher dose. CONCLUSION: The higher dose of contrast material allowed much better results. Dose comparison studies are also recommended for other techniques.
Assuntos
Mama/patologia , Meios de Contraste/administração & dosagem , Imageamento por Ressonância Magnética , Meglumina , Compostos Organometálicos , Ácido Pentético/análogos & derivados , Doenças Mamárias/diagnóstico , Neoplasias da Mama/diagnóstico , Carcinoma/diagnóstico , Combinação de Medicamentos , Feminino , Fibroadenoma/diagnóstico , Doença da Mama Fibrocística/diagnóstico , Gadolínio DTPA , Humanos , Aumento da Imagem , Meglumina/administração & dosagem , Compostos Organometálicos/administração & dosagem , Ácido Pentético/administração & dosagemRESUMO
We examined bone marrow aspirates from 100 metastasis-free primary breast cancer patients. In 38/100 patients (38%), tumour cells were detected in the marrow using an immunocytochemical technique with a cocktail of two monoclonal antibodies: anti-EMA and anti-cytokeratin. Median follow-up was 34 months: 15/38 (39%) tumour cell-positive patients have since relapsed, but only 9/62 (15%) tumour cell-negative patients. The median interval between tumour cell detection and relapse was 11.4 months. No statistically significant correlation existed between tumour cell presence and 'established' prognostic factors. However, relapse-free survival was significantly shorter in tumour cell-positive patients. Multivariate analysis showed tumour cell presence as a strong, significant prognostic factor for relapse-free as well as overall survival. We conclude that screening for tumour cells in bone marrow of primary breast cancer patients identifies high-risk patients for early relapse. In particular, patients with node-negative tumours who have tumour cells in their bone marrow may require subsequent systemic therapy.