RESUMO
Approximately 75% of patients with breast cancer present hormone receptor-positive tumors. This subtype of breast cancer initially shows a high overall response rate to hormonal treatments. However, resistance eventually develops, resulting in tumor progression. The PI3K/Akt/mTOR pathway regulates several cellular functions in cancer such as cell growth, survival, and proliferation. In addition, a high activation level of the PI3K/Akt/mTOR pathway is related to resistance to conventional chemotherapy and hormone therapy. The mTOR inhibitor everolimus, in combination with hormonal treatments, has led to excellent results in progression-free survival in patients with metastatic breast cancer resistant to hormone therapies. Therefore, everolimus has entered the National Comprehensive Cancer Network (NCCN) guidelines 2012 and its combination with exemestane was approved recently by the US Food and Drug Administration and the European Medicines Agency. This is the first time that a drug will have been approved for the restoration of hormone sensitivity in breast cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Androstadienos/administração & dosagem , Animais , Inibidores da Aromatase/administração & dosagem , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Everolimo , Feminino , Humanos , Transdução de Sinais/efeitos dos fármacos , Sirolimo/administração & dosagem , Serina-Treonina Quinases TOR/metabolismo , Resultado do TratamentoRESUMO
The diagnosis of bone metastases is an event with certain consequences for the patient. They often mean pain and can also mean pathological fractures, hypercalcemia, and spinal cord compression, all synonymous with a diminished quality of life and often also hospitalization. Since the advent of the intravenous bisphosphonates, things began to look a bit brighter for patients with bone metastases-bone destruction was kept at bay a little longer. The next generation of bone metastasis treatments is well on its way in clinical development, and among them, the most advanced drug is denosumab. Denosumab is a fully human monoclonal antibody that inhibits osteoclast maturation, activation, and function by binding to receptor activator of nuclear factor kappa B ligand, with the final result being a reduced rate of bone resorption. In this review, we give an overview of relevant preclinical and clinical data regarding the use of denosumab in patients with solid tumors in general and prostate cancer in particular.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Ligante RANK/antagonistas & inibidores , Anticorpos Monoclonais Humanizados , Remodelação Óssea/efeitos dos fármacos , Neoplasias da Mama/patologia , Ensaios Clínicos como Assunto , Denosumab , Humanos , Masculino , Mieloma Múltiplo/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Neoplasias da Próstata/patologia , Ligante RANK/metabolismo , Ligante RANK/uso terapêutico , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Resultado do TratamentoRESUMO
The importance of angiogenesis in tumour growth and development is well known. Overexpression of vascular endothelial growth factor (VEGF), the key mediator of angiogenesis, is associated with poor prognosis in cancer. As a result, several therapeutic agents that inhibit the actions of VEGF or its receptors are currently in development for use in advanced solid tumours, such breast, colorectal, lung and renal cancer. Clinical data from trials of anti-VEGF agents in this group of tumours are discussed, with a particular focus on the efficacy and safety of bevacizumab, the anti-VEGF agent at the most advanced stage of development in those tumour types. Future potential uses of bevacizumab in cancer therapy will be discussed.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzenossulfonatos/farmacologia , Benzenossulfonatos/uso terapêutico , Bevacizumab , Ensaios Clínicos como Assunto , Terapia Combinada , Sistemas de Liberação de Medicamentos , Previsões , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Terapia Neoadjuvante , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Niacinamida/análogos & derivados , Compostos de Fenilureia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Sorafenibe , Sunitinibe , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
No disponible
Assuntos
Masculino , Feminino , Humanos , Ética Médica/educação , Oncologia/ética , Anticorpos Monoclonais , Eutanásia/ética , Cuidados Paliativos/métodos , Cuidados Paliativos/organização & administração , Atitude do Pessoal de Saúde , Atitude Frente a Morte , Relações Médico-Paciente/ética , Papel do Médico/psicologia , Papel (figurativo) , Formação de Conceito/ética , Pacientes Incuráveis/normas , Cuidados Paliativos/ética , Cuidados Paliativos/tendências , Neoplasias/epidemiologiaRESUMO
PURPOSE: To study the prognostic significance of the presence of breast cancer-specific mRNA transcripts in peripheral blood (PB), defined by serial analysis of gene expression, in high-risk breast cancer (HRBC) patients undergoing high-dose chemotherapy after receiving adjuvant chemotherapy. METHODS: From 1994 to 2000, 84 HRBC patients (median age, 44 years; > 10 nodes; 74%) received adjuvant chemotherapy (fluorouracil, epirubicin, and cyclophosphamide for six cycles [83%] or doxorubicin and cyclophosphamide followed by paclitaxel) before undergoing one course of cyclophosphamide plus thiotepa plus carboplatin (STAMP V). Radiotherapy or hormone therapy was administered whenever indicated. Aliquots of apheresis-mononuclear blood cells were frozen from each patient. mRNA was isolated using an automatic nucleic acid extractor based on the magnetic beads technology; reverse transcription was performed using random hexamers. Cytokeratin 19, HER-2, P1B, PS2, and EGP2 transcripts were quantified to B-glucuronidase by real-time polymerase chain reaction (RT-PCR) using a linear DNA probe marked with a quencher and reporter fluorophores used in RT-PCR. Presence of PB micrometastases, estrogen receptor and progesterone receptor status, tumor size, age, tumor grade, number of nodes affected, and treatment with paclitaxel were included in the statistical analysis. RESULTS: Median follow-up was 68.3 months (range, 6 months to 103 months). Forty-seven relapses (56%) and 35 deaths (41.7%) were registered. Both tumor size and presence of micrometastases reached statistical significance according to the Cox multivariate model. Relapse hazard ratio (HR) for those patients with PB micrometastases was 269% (P = .006); death HR, 300% (P = .011). Time relapse was 53 months longer for patients without micrometastases: 31.3 v 84.2 months (P = .021). CONCLUSION: PB micrometastases presence after adjuvant chemotherapy predicts both relapse and death more powerful than classical factors in HRBC patients undergoing high-dose chemotherapy. Micrometastases search using a gene panel appears to be a more accurate procedure than classical approaches involving only one or two genes.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Transplante de Células-Tronco de Sangue Periférico , Precursores de RNA/sangue , Adulto , Idoso , Antígenos de Superfície/genética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/sangue , Neoplasias da Mama/química , Neoplasias da Mama/terapia , Proteínas de Ligação ao Cálcio/genética , Carboplatina/administração & dosagem , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Epirubicina/administração & dosagem , Molécula de Adesão da Célula Epitelial , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Queratinas/genética , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Paclitaxel/administração & dosagem , Valor Preditivo dos Testes , Presenilina-2 , Prognóstico , RNA Mensageiro , RNA Neoplásico , Receptor ErbB-2/genética , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medição de Risco , Fatores de Risco , Análise de Sobrevida , Tiotepa/administração & dosagem , Resultado do TratamentoRESUMO
PURPOSE: To compare the antitumor activity and toxicity of the two induction chemotherapy treatments of paclitaxel, cisplatin, and fluorouracil (FU; PCF) versus standard cisplatin and FU (CF), both followed by chemoradiotherapy (CRT), in locally advanced head and neck cancer (HNC). PATIENTS AND METHODS: Eligibility criteria included biopsy-proven, previously untreated, stage III or IV locally advanced HNC. Patients received either CF (cisplatin 100 mg/m2 on day 1 plus FU 1000 [corrected] mg/m2 continuous infusion on days 1 through 5) or PCF (paclitaxel 175 mg/m2 on day 1, cisplatin 100 mg/m2 on day 2, and FU 500 mg/m2 continuous infusion on days 2 through 6); both regimens were administered for three cycles every 21 days. Patients with complete response (CR) or partial response of greater than 80% in primary tumor received additional CRT (cisplatin 100 mg/m2 on days 1, 22, and 43 plus 70 Gy). RESULTS: A total of 382 eligible patients were randomly assigned to CF (n = 193) or PCF (n = 189). The CR rate was 14% in the CF arm v 33% in the PCF arm (P < .001). Median time to treatment failure was 12 months in the CF arm compared with 20 months in the PCF arm (log-rank test, P = .006; Tarone-Ware, P = .003). PCF patients had a trend to longer overall survival (OS; 37 months in CF arm v 43 months in PCF arm; log-rank test, P = .06; Tarone-Ware, P = .03). This difference was more evident in patients with unresectable disease (OS: 26 months in CF arm v 36 months in PCF arm; log-rank test, P = .04; Tarone-Ware, P = .03). CF patients had a higher occurrence of grade 2 to 4 mucositis than PCF patients (53% v 16%, respectively; P < .001). CONCLUSION: Induction chemotherapy with PCF was better tolerated and resulted in a higher CR rate than CF. However, new trials that compare induction chemotherapy plus CRT versus CRT alone are needed to better define the role of neoadjuvant treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Adulto , Idoso , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Terapia Combinada , Relação Dose-Resposta a Droga , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mucosite/induzido quimicamente , Análise Multivariada , Recidiva Local de Neoplasia/terapia , Neutropenia/induzido quimicamente , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Cooperação do Paciente , Estudos Prospectivos , Radioterapia Adjuvante , Indução de Remissão , Espanha , Análise de Sobrevida , Resultado do TratamentoRESUMO
Pemetrexed is a novel multitargeted antifolate analog. The drug has shown encouraging activity in a wide range of solid tumors, including cervix, head and neck, and bladder carcinomas, which are the focus of this review. Toxicity, particularly hematologic, is higher in patients with these tumor types than in other populations exposed to pemetrexed. Supplementation with folic acid and vitamin B(12) appears to effectively reduce the incidence of severe toxicity and may optimize the therapeutic index of pemetrexed in patient subsets with poor nutritional status. The role of this agent in the management of these and other tumor types, as a single agent or in combination, shall be determined by randomized phase III studies.