RESUMO
Mantle cell lymphoma is an aggressive B-cell malignancy. Current frontline chemoimmunotherapies produce high response rates but relapse is inevitable. Furthermore, the elderly and those with comorbidities are precluded from standard regimens and stem cell transplant, leaving them with limited options. Targeted therapies, including Bruton tyrosine kinase inhibitors, are an effective treatment strategy in mantle cell lymphoma. Zanubrutinib is a potent next-generation Bruton tyrosine kinase inhibitor that has demonstrated complete and sustained Bruton tyrosine kinase occupancy, minimal off-target effects and favorable pharmacokinetic/pharmacodynamic properties. Described herein is an ongoing Phase III study comparing the efficacy and safety of zanubrutinib plus rituximab followed by zanubrutinib monotherapy versus bendamustine plus rituximab followed by observation in transplant-ineligible patients with previously untreated mantle cell lymphoma. Clinical Trial Registration: NCT04002297 (ClinicalTrials.gov).
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Cloridrato de Bendamustina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/patologia , Intervalo Livre de Progressão , Recidiva , Rituximab/uso terapêutico , Segurança , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: This exploratory analysis evaluated second-line (2L) therapy for metastatic pancreatic cancer in a large phase 3 trial (MPACT). METHODS: Patients who received first-line (1L) nab-paclitaxel+gemcitabine (nab-P+Gem) or Gem were assessed for survival based on 2L treatment received. Multivariate analyses tested influence of treatment effect and prognostic factors on survival. RESULTS: The majority of 2L treatments (267 out of 347, 77%) contained a fluoropyrimidine (5-fluorouracil or capecitabine). Median total survival (1L randomisation to death) for patients who received 2L treatment after 1L nab-P+Gem vs Gem alone was 12.8 vs 9.9 months (P=0.015). Median total survival for patients with a fluoropyrimidine-containing 2L therapy after nab-P+Gem vs Gem was 13.5 vs 9.5 months (P=0.012). Median 2L survival (duration from start of 2L therapy to death) was 5.3 vs 4.5 months for nab-P+Gem vs Gem, respectively (P=0.886). Factors significantly associated with longer post-1L survival by multivariate analyses included 1L nab-P+Gem, receiving 2L treatment, longer 1L progression-free survival, and Karnofsky performance status⩾70 and neutrophil-to-lymphocyte ratio⩽5 at the end of 1L treatment. CONCLUSIONS: These findings support the use of 2L therapy for patients with metastatic pancreatic cancer. Fluoropyrimidine-containing treatment after 1L nab-P+Gem is an active regimen with significant clinical effect.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Albuminas/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/patologia , GencitabinaRESUMO
BACKGROUND: The phase 3 MPACT trial in patients with metastatic pancreatic cancer demonstrated superior efficacy of nab-paclitaxel (nab-P) + gemcitabine (Gem) vs Gem monotherapy for all endpoints examined including overall survival, the primary endpoint. In the MPACT trial, patients were treated until progressive disease (PD) or unacceptable toxicity. The current exploratory analysis investigated outcomes of patients from the MPACT trial who were treated until PD, in order to understand how to maximize treatment benefit from nab-P + Gem. METHODS: The trial design has been described in detail previously. Progressive disease was determined by the investigator on the basis of radiological imaging. RESULTS: Among patients who were treated until PD, overall survival was significantly longer for those who received nab-P + Gem vs Gem (median, 9.8 vs 7.5 months; P < 0.001). Independently assessed progression-free survival and overall response rate were significantly greater among patients in the treatment-to-PD cohort who received nab-P + Gem compared with Gem (P < 0.001 for each). Although not compared statistically, patients who were treated until PD received greater treatment exposure and experienced more favourable efficacy than the intent-to-treat population of the MPACT trial. Among patients who were treated with nab-P + Gem until PD, > 50 % went on to receive a subsequent therapy. The safety profile for patients treated until PD was similar to what was reported in the overall MPACT trial. CONCLUSION: The nab-P + Gem regimen is an active first-line treatment option; most patients were treated until PD, and this exposure was associated with improved efficacy outcomes. Prolonged first-line treatment exposure and ability to receive subsequent therapies likely contributed to the improved survival among these patients. Our data highlight the importance of managing adverse events and indicate that patients should be treated until PD when possible. TRIAL REGISTRATION: ClinicalTrials.gov NCT00844649 (MPACT trial); Registration date of this prospective phase III trial: February 13, 2009; current exploratory subanalysis was conducted retrospectively.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Idoso , Idoso de 80 Anos ou mais , Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/mortalidade , Modelos de Riscos Proporcionais , Retratamento , Análise de Sobrevida , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: nab-Paclitaxel in combination with gemcitabine has emerged as a new treatment option for patients with metastatic pancreatic cancer (MPC), based on superiority over gemcitabine demonstrated in the phase III MPACT trial. Previously, Karnofsky performance status (KPS) score and the presence of liver metastases were shown to be predictive of survival with nab-paclitaxel plus gemcitabine treatment. This analysis sought to further explore the relationship between clinical characteristics and survival in the MPACT trial and to identify potential predictors of overall survival and progression-free survival in patients with MPC. MATERIALS AND METHODS: Cox regression models adjusted for stratification factors and a stepwise multivariate analysis of prespecified baseline prognostic factors were performed. RESULTS: Treatment effect was significantly associated with survival, with a similar magnitude of reduction in risk of death compared with the previously reported primary analysis. Treatment effect consistently favored nab-paclitaxel plus gemcitabine across the majority of the prespecified factors. In addition to KPS score and presence of liver metastases, age and number of metastatic sites were independent prognostic factors of overall and progression-free survival. Baseline carbohydrate antigen 19-9 was not found to be an independent prognostic factor of survival in this analysis. CONCLUSION: The results of this analysis confirm broad utility of nab-paclitaxel plus gemcitabine for the treatment of MPC. In addition, these findings suggest that KPS score, presence of liver metastases, age, and number of metastatic sites are important predictors of survival that may be useful when making treatment decisions and designing future clinical trials.
Assuntos
Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/análogos & derivados , Neoplasias Hepáticas/tratamento farmacológico , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Desoxicitidina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Prognóstico , GencitabinaRESUMO
AIM: The phase III MPACT trial (N = 861) demonstrated superior overall survival (OS) with first-line nab-paclitaxel plus gemcitabine versus gemcitabine alone (median, 8.7 months vs 6.6 months; hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.62-0.83; P < 0.001) in patients with metastatic pancreatic cancer. The efficacy benefit of the combination over gemcitabine alone was observed across patient subgroups, including those based on region. This subset analysis was designed to examine the safety and efficacy of nab-paclitaxel plus gemcitabine in patients treated in Australia to understand whether differences in patient population or regional variations in patient care had any impact on clinical outcomes. METHODS: Patients with metastatic pancreatic cancer received first-line nab-paclitaxel plus gemcitabine or gemcitabine alone in the MPACT study; this analysis focused on those treated in Australia. RESULTS: In the Australian cohort, 120 patients were randomized to receive nab-paclitaxel plus gemcitabine (n = 61) or gemcitabine alone (n = 59). Median OS was 9.4 months with nab-paclitaxel plus gemcitabine versus 6.7 months with gemcitabine alone (HR, 0.64; 95% CI, 0.44-0.94; P = 0.022). Progression-free survival (median, 5.5 months vs 3.6 months; HR, 0.65; 95% CI, 0.42-1.00; P = 0.049) and the overall response rate (23% vs 2%; P < 0.001) were significantly improved with the combination. No new safety signals were observed. CONCLUSIONS: The results of this subset analysis confirm the efficacy and manageable safety profile of nab-paclitaxel plus gemcitabine in patients with metastatic pancreatic cancer treated in Australia.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/administração & dosagem , Austrália , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/patologia , Resultado do Tratamento , GencitabinaRESUMO
PURPOSE: This single-arm, phase II trial evaluated nab-paclitaxel monotherapy in pretreated patients with metastatic colorectal cancer (mCRC). METHODS: Patients with mCRC (RAS wild-type and RAS mutant cohorts) received nab-paclitaxel 125 mg/m2 days 1, 8, and 15 (28-day cycle). The primary endpoint was investigator-assessed progression-free survival (PFS) rate at week 8; secondary endpoints included overall survival, overall response rate, and safety. Stage 1 planned enrollment was 15 patients per cohort per Simon 2-stage design. Stage 2 enrollment was to continue unless ≤8 of the first 15 patients per cohort achieved PFS at 8 weeks. RESULTS: Stage 1 enrolled 41 patients (RAS wild type: n = 18; RAS mutant: n = 23). In both RAS cohorts, 3 of 15 patients initially enrolled were progression-free at week 8 (20%; 95% CI 4.0-48.0). Median PFS was 8.1 weeks (95% CI 7.7-8.6) and 7.9 weeks (95% CI 7.6-8.0) for RAS wild-type and RAS mutant cohorts, respectively. There were no complete or partial responses. The overall disease control rate was 16% (95% CI 6.0-32.0), and rates were similar in the RAS wild-type and RAS mutant cohorts (18 and 15%, respectively). No new safety signals were reported; the most common grade ≥3 adverse events included neutropenia, asthenia, and peripheral neuropathy. This study did not progress to stage 2 per the preplanned statistical stopping rule. CONCLUSIONS: In patients with heavily pretreated mCRC, nab-paclitaxel did not demonstrate promising antitumor activity; further assessment of nab-paclitaxel monotherapy in this population of patients is not supported. TRIAL REGISTRATION: NCT02103062.
Assuntos
Albuminas/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Paclitaxel/uso terapêutico , Albuminas/efeitos adversos , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Genes ras , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Paclitaxel/efeitos adversosRESUMO
INTRODUCTION: The phase III MPACT trial in patients with metastatic pancreatic cancer (MPC) demonstrated superior efficacy of nab-paclitaxel (nab-P) plus gemcitabine (Gem) compared with Gem monotherapy, including the primary endpoint of overall survival (OS; median 8.7 vs. 6.6 months; hazard ratio [HR] 0.72; P < 0.001). A significant treatment difference favoring nab-P + Gem over Gem was observed for OS in patients treated in North America. The majority of patients were from the US (88%) with only 12% from Canada. Healthcare systems and treatment patterns are different between the 2 countries, and there is limited published information on outcomes of Canadian patients treated with first-line nab-P + Gem. This analysis evaluated efficacy and safety outcomes in Canadian patients in the MPACT trial. METHODS: Treatment-naive patients with MPC (N = 861) received either nab-P 125 mg/m(2) + Gem 1000 mg/m(2) on days 1, 8, and 15 every 4 weeks or Gem 1000 mg/m(2) weekly for the first 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle ≥2). RESULTS: The MPACT trial enrolled 63 patients in Canada. Baseline characteristics were well balanced and comparable with those of the intent-to-treat population. Both OS (median 11.9 vs. 7.1 months; HR 0.76; P = 0.373) and progression-free survival (median 7.2 vs. 5.2 months; HR 0.65; P = 0.224) were numerically longer and overall response rate (27% vs. 17%; P = 0.312) was numerically higher with nab-P + Gem vs. Gem. The most common grade ≥3 adverse events with nab-P + Gem vs. Gem were neutropenia (22% vs. 10%), fatigue (34% vs. 33%), and neuropathy (25% vs. 0%). CONCLUSION: This subanalysis confirmed that nab-P + Gem is an efficacious treatment option and has a manageable safety profile in patients with MPC treated in Canada. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00844649. FUNDING: Celgene Corporation, Summit, NJ, USA.
Assuntos
Adenocarcinoma , Albuminas , Desoxicitidina/análogos & derivados , Paclitaxel , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Canadá , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/prevenção & controle , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Resultado do Tratamento , Gencitabina , Neoplasias PancreáticasRESUMO
BACKGROUND: Dose modifications following adverse events (AEs) are an important part of the management of patients with pancreatic cancer treated with chemotherapy. While dose modifications are utilized to ensure patient safety, the subsequent influence of dose adjustments on treatment exposure and efficacy have not been reported in detail. This exploratory analysis examined the influence of dose modifications on treatment exposure and efficacy in the phase III MPACT trial, which demonstrated superior efficacy of nab-paclitaxel (nab-P) plus gemcitabine (Gem) to Gem alone for the treatment of metastatic pancreatic cancer. METHODS: Patients received either nab-P 125 mg/m(2) + Gem 1,000 mg/m(2) on days 1, 8, and 15 every 4 weeks or Gem 1,000 mg/m(2) weekly for the first 7 of 8 weeks (cycle 1) and then days 1, 8, and 15 every 4 weeks (cycle ≥2). The protocol allowed up to 2 dose reductions per agent. Dose delays were also used to manage toxicities. RESULTS: Toxicities that most commonly led to dose modifications were neutropenia, peripheral neuropathy, thrombocytopenia, and fatigue for nab-P and neutropenia, thrombocytopenia, and fatigue for Gem alone. Baseline characteristics were similar in patients with dose modifications and the intent-to-treat (ITT) population. Among the 421 treated patients in the nab-P + Gem arm, all patients initiated treatment at the per-protocol nab-P starting dose of 125 mg/m(2); 172 (41%) had a nab-P dose reduction, and 300 (71%) had a nab-P dose delay during the study. Most dose modifications occurred after the first 3 months (2 cycles) of treatment. The majority of patients (104/172, 60%) required only 1 nab-P dose reduction, and over half of patients (163/300) had either 1 or 2 dose delays. Patients who underwent dose modifications of nab-P had greater treatment exposure than those who did not in terms of treatment duration, number of cycles administered, and cumulative dose of nab-P delivered. Overall survival (OS) was shorter in the nab-P + Gem arm for patients who did not vs. did undergo dose reduction [median, 6.9 vs. 11.4 months; hazard ratio (HR), 1.93; 95% CI, 1.53-2.44; P<0.0001] and for those who did not vs. did undergo a dose delay (median, 6.2 vs. 10.1, HR, 2.05; 95% CI, 1.60-2.63; P<0.0001). Progression-free survival (PFS) and overall response rate (ORR) were also improved in patients with dose modifications. Similar trends were observed in the Gem-alone arm. Multivariate analyses confirmed that both dose delay and dose reduction were significantly associated with OS. CONCLUSIONS: This analysis suggests that although most doses of nab-P were given at the starting dose of 125 mg/m(2) the first 3 of 4 weeks, dose reductions and delays were effective when necessary to ameliorate toxicity allowing greater treatment exposure without compromising efficacy.
RESUMO
PURPOSE: nab-Paclitaxel plus gemcitabine was superior to gemcitabine alone for patients with metastatic pancreatic cancer (MPC) in the phase III MPACT trial. This study evaluated the association of secreted protein acidic and rich in cysteine (SPARC) levels with efficacy as an exploratory endpoint. EXPERIMENTAL DESIGN: Patients with previously untreated MPC (N = 861) received nab-paclitaxel plus gemcitabine or gemcitabine alone. Baseline SPARC level was measured in the tumor stroma and epithelia (archival biopsies) and plasma. Experiments were performed in pancreatic cancer mouse models in which SPARC was intact or deleted. RESULTS: SPARC was measured in the tumor stroma of 256 patients (30%), the tumor epithelia of 301 patients (35%), and plasma of 343 patients (40%). Stroma-evaluable samples were from metastases (71%), from the pancreas (11%), or of unidentifiable origin (insufficient tissue to determine; 17%). For all patients, stromal SPARC level [high (n = 71) vs. low (n = 185)] was not associated with overall survival (OS; HR, 1.019; P = 0.903); multivariate analysis confirmed this lack of association. There was no association between stromal SPARC level and OS in either treatment arm. Neither tumor epithelial SPARC nor plasma SPARC was associated with OS. Results from a SPARC knockout mouse model treated with nab-paclitaxel plus gemcitabine revealed no correlation between SPARC expression and tumor progression or treatment efficacy. CONCLUSIONS: SPARC levels were not associated with efficacy in patients with MPC. This exploratory analysis does not support making treatment decisions regarding nab-paclitaxel plus gemcitabine or gemcitabine alone in MPC based on SPARC expression.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Expressão Gênica , Osteonectina/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Albuminas/administração & dosagem , Animais , Biomarcadores , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Modelos Animais de Doenças , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Camundongos Knockout , Metástase Neoplásica , Osteonectina/sangue , Osteonectina/metabolismo , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Células Estromais/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto , GencitabinaRESUMO
BACKGROUND: Positive findings from the phase III MPACT trial led to the regulatory approval of nab-paclitaxel plus gemcitabine as a treatment option for patients with metastatic pancreatic cancer. This report is an update of overall survival (OS) based on longer follow-up. METHODS: Patients (n = 861) with metastatic pancreatic cancer and a Karnofsky performance status of 70 or greater were randomly assigned one to one to receive nab-paclitaxel + gemcitabine or gemcitabine alone. Efficacy data for this post hoc analysis were collected through May 9, 2013. Exploratory analyses of carbohydrate antigen 19-9 (CA19-9) and neutrophil-to-lymphocyte ratio (NLR) were conducted. The primary efficacy endpoint was OS, which was analyzed for all randomly assigned patients by the Kaplan-Meier method. All statistical tests were two-sided. RESULTS: The median OS was statistically significantly longer for nab-paclitaxel plus gemcitabine vs gemcitabine alone (8.7 vs 6.6 months, hazard ratio [HR] = 0.72, 95% confidence interval [CI] = 0.62 to 0.83, P < .001). Long-term (>three-year) survivors were identified in the nab-paclitaxel plus gemcitabine arm only (4%). In pooled treatment arm analyses, higher CA19-9 level and NLR at baseline were statistically significantly associated with worse OS. There appeared to be a treatment effect for OS favoring nab-paclitaxel plus gemcitabine over gemcitabine alone in poor-prognosis subgroups defined by these factors (HR = 0.612, P < .001 for CA19-9 level ≥ median and HR = 0.81, P = .079 for NLR > 5). CONCLUSIONS: These data confirm and extend the primary report of OS, supporting the superior efficacy of nab-paclitaxel plus gemcitabine over gemcitabine alone. Subgroup analyses support the relevance of CA 19-9 and NLR as prognostic markers in metastatic pancreatic cancer.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Antígenos Glicosídicos Associados a Tumores/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/sangue , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Seguimentos , Humanos , Cooperação Internacional , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/secundário , Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Neoplasias Pancreáticas/patologia , Prognóstico , Resultado do Tratamento , GencitabinaRESUMO
Metastasis, also called secondary neoplastic disease, is a tumour newly formed in a site different from that of origin, as a consequence of cancer progression and dissemination largely through blood and lymphatic vessels. The ability to form metastases is the main property that distinguishes malignant from benign tumours. Treatments for metastatic cancer are similar in practice to those for primary tumours, but such treatments are mostly palliative; indeed, almost all deaths caused by solid tumours occur in the metastatic phase. Increasing evidence supports the concept that therapies for primary tumours are inadequate to treat metastasis and can even promote formation of metastases, while exerting local growth control. Furthermore, recurrent tumours, which are denoted by increased aggressiveness and therapy resistance in comparison with the primary tumour, have an increased metastatic potential. Genetic modifications occurring during tumour progression lead to substantial differences between the primary and metastatic tumours. This emphasises the importance of designing novel therapies for metastasis. In the last decade, a number of studies have contributed to the understanding of the genetic rearrangements underlying the conversion of cancer cells into the metastasis founder cells. The present article aims at reviewing recent advances in metastasis research and attempts to discuss the reasons for which the therapeutic strategies against primary tumours may not satisfactorily address their metastatic counterparts.
Assuntos
Neoplasias/metabolismo , Animais , Linhagem da Célula , Movimento Celular , Progressão da Doença , Humanos , Metástase Neoplásica , Neoplasias/patologia , Neoplasias/terapia , Células-Tronco Neoplásicas/metabolismoAssuntos
Formação de Anticorpos/efeitos dos fármacos , Desenho de Fármacos , Animais , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Produtos Biológicos , Vacinas Anticâncer/uso terapêutico , Genômica , Humanos , Toxinas Marinhas/farmacologia , Toxinas Marinhas/uso terapêutico , Preparações Farmacêuticas/química , Polietilenoglicóis/química , Poríferos/química , Interferência de RNA , Receptor IGF Tipo 1/efeitos dos fármacos , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Talassemia/tratamento farmacológicoRESUMO
UNLABELLED: This study assessed the immunomodulatory effects in previously treated KRAS-mutant metastatic colorectal cancer patients participating in a phase II multicenter, open-label clinical trial receiving lenalidomide alone or lenalidomide plus cetuximab. The main findings show the T cell immunostimulatory properties of lenalidomide as the drug induced a decrease in the percentage CD45RA(+) naïve T cells 3-fold while increasing the percentage HLA-DR(+) activated T helper cells and percentage total CD45RO(+) CD8(+) memory T cytotoxic cells, 2.6- and 2.1-fold respectively (p<0.0001). In addition, lenalidomide decreased the percentage of circulating CD19(+) B cells 2.6-fold (p<0.0001). Lenalidomide increased a modest, yet significant, 1.4-fold change in the percentage of circulating natural killer cells. Our findings indicate that lenalidomide significantly activates T cells, suggestive of an immunotherapeutic role for this drug in settings of maintenance therapy and tumor immunity. Furthermore, reported for the first time is the effect of lenalidomide in combination with cetuximab on T cell function, including increases in circulating naïve and central memory T cells. In summary, lenalidomide and cetuximab have significant effects on circulating immune cells in patients with colorectal carcinoma. TRIAL REGISTRATION: ClinicalTrials.gov NCT01032291.
Assuntos
Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/imunologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/imunologia , Proteínas Proto-Oncogênicas/genética , Talidomida/análogos & derivados , Proteínas ras/genética , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab , Neoplasias Colorretais/genética , Humanos , Lenalidomida , Mutação , Proteínas Proto-Oncogênicas p21(ras) , Talidomida/administração & dosagem , Talidomida/imunologia , Talidomida/uso terapêuticoRESUMO
UNLABELLED: This study aimed to assess the efficacy and safety of combination treatment with lenalidomide and cetuximab in KRAS-mutant metastatic colorectal cancer patients. This was a phase II multicenter, open-label trial comprising a safety lead-in phase (phase IIa) to determine the maximum tolerated dose, and a randomized proof of concept phase (phase IIb) to determine the response rate of lenalidomide plus cetuximab combination therapy. Phase IIa treatment comprised oral lenalidomide (starting dose 25 mg/day) and intravenous cetuximab (400 mg/m(2) followed by weekly 250 mg/m(2)) in 28-day cycles. In phase IIb patients were randomized to either the phase IIa treatment schedule of lenalidomide plus cetuximab combination therapy or lenalidomide 25 mg/day monotherapy. Eight patients were enrolled into phase IIa. One patient developed a dose-limiting toxicity and the maximum tolerated dose of lenalidomide was determined at 25 mg/day. Forty-three patients were enrolled into phase IIb proof of concept. Best response was stable disease in 9 patients and study enrollment was terminated prematurely due to lack of efficacy in both treatment arms and failure to achieve the planned response objective. The majority of adverse events were grade 1 and 2. In both phases, the adverse events most commonly attributed to any study drugs were fatigue, rash and other skin disorders, diarrhea, nausea, and stomatitis. Thirty-nine deaths occurred; none was related to study drug. The combination of lenalidomide and cetuximab appeared to be well tolerated but did not have clinically meaningful activity in KRAS-mutant metastatic colorectal cancer patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT01032291.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cetuximab , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Humanos , Lenalidomida , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas Proto-Oncogênicas p21(ras) , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/análogos & derivados , Fatores de TempoRESUMO
The current management of the stenosis of the coronary arteries relies on the insertion of a metal mesh tube, namely stent, into the obstructed vessel. Coronary stents have been envisaged to reduce the restenosis after balloon angioplasty. Nonetheless, one of the major complications after successful revascularization is the late in-stent restenosis. Such lesion consists mainly of inflammatory reaction and neointima formation as a consequence of the mechanical injury of the vessel. In this review, we examine the molecular players underlying the in-stent restenosis, with particular reference to the role of the mTOR pathway and the intracellular receptor immunophilins. The 'limus' based drugs, which are developed or are under development in drug-eluting stent technology, will be also discussed.
Assuntos
Reestenose Coronária/prevenção & controle , Estenose Coronária/cirurgia , Stents , Angioplastia com Balão/métodos , Reestenose Coronária/patologia , Desenho de Fármacos , Stents Farmacológicos , Humanos , Imunofilinas/metabolismo , Inflamação/etiologia , Inflamação/fisiopatologia , Neointima/etiologia , Neointima/patologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
Coronary artery disease consists of obstruction (stenosis) of the coronary arteries by the deposition of atherosclerotic plaques, resulting in an insufficient supply of oxygen to the heart muscle. Treatment options include the insertion of a stent - a metal mesh tube - into the obstructed vessel to keep the artery open, thus preventing acute occlusion and restenosis. The occlusion of vessels resulting from subacute stent thrombosis and late in-stent restenosis are potential complications after successful revascularization. However, the rate of stent thrombosis has been reduced dramatically by means of adequate antiplatelet therapy, and in-stent restenosis has been addressed successfully with drug-eluting stents. These drug-eluting stents are engineered to release bioactive agents into the affected blood vessels, plaques or tissues adjacent to the stent. Various antimitotic, anti-inflammatory, and anticoagulant immunosuppressive agents have been attached to stents, including sirolimus and tacrolimus. Future opportunities include the use of gene therapies released from gene-eluting stents. These advances highlight some of the opportunities for optimizing stent-based treatment for coronary artery disease.