Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 31
Filtrar
1.
Curr Oncol ; 26(2): e175-e179, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31043824

RESUMO

Objectives: In the present study, we explored the real-world efficacy of the immuno-oncology checkpoint inhibitor nivolumab and the tyrosine kinase inhibitor cabozantinib in the second-line setting. Methods: Using the International Metastatic Renal Cell Carcinoma Database Consortium (imdc) dataset, a retrospective analysis of patients with metastatic renal cell carcinoma (mrcc) treated with nivolumab or cabozantinib in the second line after prior therapy targeted to the vascular endothelial growth factor receptor (vegfr) was performed. Baseline characteristics and imdc risk factors were collected. Overall survival (os) and time to treatment failure (ttf) were calculated using Kaplan-Meier curves. Overall response rates (orrs) were determined for each therapy. Multivariable Cox regression analysis was performed to determine survival differences between cabozantinib and nivolumab treatment. Results: The analysis included 225 patients treated with nivolumab and 53 treated with cabozantinib. No significant difference in median os was observed: 22.10 months [95% confidence interval (ci): 17.18 months to not reached] with nivolumab and 23.70 months (95% ci: 15.52 months to not reached) with cabozantinib (p = 0.61). The ttf was also similar at 6.90 months (95% ci: 4.60 months to 9.20 months) with nivolumab and 7.39 months (95% ci: 5.52 months to 12.85 months) with cabozantinib (p = 0.20). The adjusted hazard ratio (hr) for nivolumab compared with cabozantinib was 1.30 (95% ci: 0.73 to 2.3), p = 0.38. When adjusted by imdc criteria and age, the hr was 1.32 (95% ci: 0.74 to 2.38), p = 0.35. Conclusions: Real-world imdc data indicate comparable os and ttf for nivolumab and cabozantinib. Both agents are reasonable therapeutic options for patients progressing after initial first-line vegfr-targeted therapy.


Assuntos
Anilidas/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Nivolumabe/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Idoso , Carcinoma de Células Renais/mortalidade , Bases de Dados Factuais , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Masculino , Resultado do Tratamento
2.
Clin Drug Investig ; 38(12): 1155-1165, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30267257

RESUMO

BACKGROUND AND OBJECTIVE: The development of new targeted therapies in kidney cancer has shaped disease management in the metastatic phase. Our study aims to conduct a cost-utility analysis of sunitinib versus pazopanib in first-line setting in Canada for metastatic renal cell carcinoma (mRCC) patients using real-world data. METHODS: A Markov model with Monte-Carlo microsimulations was developed to estimate the clinical and economic outcomes of patients treated in first-line with sunitinib versus pazopanib. Transition probabilities were estimated using observational data from a Canadian database where real-life clinical practice was captured. The costs of therapies, disease progression, and management of adverse events were included in the model in Canadian dollars ($Can). Utility and disutility values were included for each health state. Incremental cost-utility ratio (ICUR) and incremental cost-effectiveness ratios (ICER) were calculated for a time horizon of 5 years, from the Canadian Healthcare System perspective. RESULTS: The cost difference was $36,303 and the difference in quality-adjusted life year (QALY) was 0.54 in favour of sunitinib with an ICUR of $67,227/QALY for sunitinib versus pazopanib. The major cost component (56%) is related to best supportive care (BSC) where patients tend to stay for a longer period of time compared to other states. The difference in life years gained (LYG) between sunitinib and pazopanib was 1.21 LYG (33.51 vs 19.03 months) and the ICER was $30,002/LYG. Sensitivity analysis demonstrated the robustness of the model with a high probability of sunitinib being a cost-effective option when compared to pazopanib. CONCLUSION: When using real-world evidence, sunitinib is found to be a cost-effective treatment compared to pazopanib in mRCC patients in Canada.


Assuntos
Antineoplásicos/economia , Carcinoma de Células Renais/economia , Análise Custo-Benefício , Neoplasias Renais/economia , Pirimidinas/economia , Sulfonamidas/economia , Sunitinibe/economia , Inibidores da Angiogênese/economia , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Canadá/epidemiologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/epidemiologia , Análise Custo-Benefício/tendências , Feminino , Custos de Cuidados de Saúde/tendências , Humanos , Indazóis , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/epidemiologia , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Pirimidinas/uso terapêutico , Anos de Vida Ajustados por Qualidade de Vida , Sulfonamidas/uso terapêutico , Sunitinibe/uso terapêutico , Resultado do Tratamento
4.
Clin Oncol (R Coll Radiol) ; 29(4): 231-238, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28034487

RESUMO

Circadian rhythm-dependent cell cycle progression produces daily variations in radiosensitivity. This literature review aims to summarise the data on whether radiotherapy outcomes differ depending on administration time. A literature search was conducted on Ovid Medline, Embase, Cochrane Central Register of Controlled Trials and PubMed using key words such as 'radiotherapy', 'circadian rhythm', 'treatment outcome' and 'survival'. Articles evaluating the correlation between radiotherapy time and outcomes in cancer patients were included and relevant information was extracted. Nine studies met the inclusion criteria. Four investigated lung cancer patients undergoing stereotactic radiosurgery for brain metastases, with one study observing improved local control and survival in patients treated in the morning. Another two studies with breast and cervical cancer patients observed that the prevalence of toxicities was higher in afternoon and morning cohorts, respectively. Two studies in head and neck cancer patients found trends indicating morning patients experienced less oral mucositis. Increased toxicities and biochemical failure rates were associated with evening treatment in prostate cancer patients. As inconsistencies in the literature exist regarding the time dependency of radiotherapy outcomes, further investigation is warranted.


Assuntos
Ritmo Circadiano/efeitos da radiação , Neoplasias/radioterapia , Radioterapia/métodos , Humanos , Radioterapia/efeitos adversos , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento
5.
Br J Cancer ; 113(1): 12-9, 2015 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-26086878

RESUMO

BACKGROUND: We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for registration-directed trials. METHODS: Patients ⩾18 years received oral sunitinib 50 mg per day on a 4-weeks-on-2-weeks-off schedule. Safety was assessed regularly. Tumour measurements were scheduled per local practice. RESULTS: A total of 4543 patients received sunitinib. Median treatment duration and follow-up were 7.5 and 13.6 months. Objective response rate was 16% (95% confidence interval (CI): 15-17). Median progression-free survival (PFS) and overall survival (OS) were 9.4 months (95% CI: 8.8-10.0) and 18.7 months (95% CI: 17.5-19.5). Median PFS in subgroups of interest: aged ⩾65 years (33%), 10.1 months; Eastern Cooperative Oncology Group performance status ⩾2 (14%), 3.5 months; non-clear cell histology (12%), 6.0 months; and brain metastases (7%), 5.3 months. OS was strongly associated with the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (n=4065). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (10%), fatigue (9%), and asthenia, neutropenia, and hand-foot syndrome (each 7%). CONCLUSION: Final analysis of the sunitinib expanded-access trial provided a good opportunity to evaluate the long-term side effects of a tyrosine kinase inhibitor used worldwide in mRCC. Efficacy and safety findings were consistent with previous results.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Metástase Neoplásica , Pirróis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/patologia , Feminino , Humanos , Indóis/efeitos adversos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Pirróis/efeitos adversos , Sunitinibe , Adulto Jovem
6.
Br J Cancer ; 110(8): 1917-22, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24691425

RESUMO

BACKGROUND: Limited data exist on outcomes for metastatic renal cell carcinoma (mRCC) patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counselling and clinical trial design. METHODS: Outcomes of mRCC patients from the International mRCC Database Consortium database treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) were calculated using different population inclusion criteria. RESULTS: In total, 2705 patients were treated with TT of which 57% received only first-line TT, 27% received two lines of TT, and 16% received 3+ lines of TT. Overall survival of patients who received 1, 2, or 3+ lines of TT were 14.9, 21.0, and 39.2 months, respectively, from first-line TT (P<0.0001). On multivariable analysis, 2 lines and 3+ lines of therapy were each associated with better OS (HR=0.738 and 0.626, P<0.0001). Survival outcomes for the subgroups were as follows: for all patients, OS 20.9 months and PFS 7.2 months; for those similar to eligible patients in the first-line ADAPT trial, OS 14.7 months and PFS 5.6 months; for those similar to patients in first-line TIVO-1 trial, OS 24.8 months and PFS 8.2 months; for those similar to patients in second-line INTORSECT trial, OS 13.0 months and PFS 3.9 months; and for those similar to patients in the third-line GOLD trial, OS 18.0 months and PFS 4.4 months. CONCLUSIONS: Patients who are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing clinical trials.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Terapia de Alvo Molecular , Serina-Treonina Quinases TOR/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/patologia , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Modelos de Riscos Proporcionais , Análise de Sobrevida , Resultado do Tratamento
7.
Br J Cancer ; 110(5): 1250-9, 2014 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-24496460

RESUMO

BACKGROUND: Metastatic clear cell renal cell carcinoma (ccRCC) patients have <9% 5-year survival rate, do not respond well to targeted therapy and eventually develop resistance. A better understanding of molecular pathways of RCC metastasis is the basis for the discovery of novel prognostic markers and targeted therapies. METHODS: We investigated the biological impact of galectin-1 (Gal-1) in RCC cell lines by migration and invasion assays. Effect of Gal-1 expression on the mitogen-activated protein kinase pathway was assessed by proteome array. RESULTS: Increased expression of Gal-1 increased cell migration while knocking down Gal-1 expression by siRNA resulted in reduced cellular migration (P<0.001) and invasion (P<0.05). Gal-1 overexpression increased phosphorylation of Akt, mTOR and p70 kinase. Upon hypoxia and increased HIF-1α, Gal-1 increased in a dose-dependent manner. We also found miR-22 overexpression resulted in decreased Gal-1 and HIF-1α. Immunohistochemistry analysis showed that high Gal-1 protein expression was associated with larger size tumor (P=0.034), grades III/IV tumors (P<0.001) and shorter disease-free survival (P=0.0013). Using the Cancer Genome Atlas data set, we found that high Gal-1 mRNA expression was associated with shorter overall survival (41 vs 78 months; P<0.01). CONCLUSIONS: Our data suggest Gal-1 mediates migration and invasion through the HIF-1α-mTOR signaling axis and is a potential prognostic marker and therapeutic target.


Assuntos
Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Galectina 1/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Serina-Treonina Quinases TOR/metabolismo , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Progressão da Doença , Intervalo Livre de Doença , Galectina 1/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Renais/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Prognóstico , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética
8.
Ann Oncol ; 25(1): 149-54, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24356626

RESUMO

BACKGROUND: Targeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown. PATIENTS AND METHODS: mRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 10(3)/uL, or neutrophil count <1500/mm(3). RESULTS: Overall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378-1.751, P < 0.0001). CONCLUSIONS: The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Definição da Elegibilidade , Humanos , Indazóis , Indóis/administração & dosagem , Estimativa de Kaplan-Meier , Avaliação de Estado de Karnofsky , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Sorafenibe , Sulfonamidas/administração & dosagem , Sunitinibe , Resultado do Tratamento
9.
Carcinogenesis ; 34(10): 2231-9, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23715501

RESUMO

MicroRNAs (miRNAs) play a crucial role in tumor progression and metastasis. We, and others, recently identified a number of miRNAs that are dysregulated in metastatic renal cell carcinoma compared with primary renal cell carcinoma. Here, we investigated three miRNAs that are significantly downregulated in metastatic tumors: miR-192, miR-194 and miR-215. Gain-of-function analyses showed that restoration of their expression decreases cell migration and invasion in renal cell carcinoma cell line models, whereas knockdown of these miRNAs resulted in enhancing cellular migration and invasion abilities. We identified three targets of these miRNAs with potential role in tumor aggressiveness: murine double minute 2, thymidylate synthase, and Smad Interacting protein 1/zinc finger E-box binding homeobox 2. We observed a convergent effect (the same molecule can be targeted by all three miRNAs) and a divergent effect (the same miRNA can control multiple targets) for these miRNAs. We experimentally validated these miRNA-target interactions using three independent approaches. First, we observed that miRNA overexpression significantly reduces the mRNA and protein levels of their targets. In the second, we observed significant reduction of the luciferase signal of a vector containing the 3'UTR of the target upon miRNA overexpression. Finally, we show the presence of inverse correlation between miRNA changes and the expression levels of their targets in patient specimens. We also examined the prognostic significance of miR-215 in renal cell carcinoma. Lower expression of miR-215 is associated with significantly reduced disease-free survival time. These findings were validated on an independent data set from The Cancer Genome Atlas. These results can pave the way to the clinical use of miRNAs as prognostic markers and therapeutic targets.


Assuntos
Carcinoma de Células Renais/genética , Redes Reguladoras de Genes , Neoplasias Renais/genética , MicroRNAs/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Progressão da Doença , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Invasividade Neoplásica , Prognóstico , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Interferência de RNA , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco
10.
Ann Oncol ; 23(12): 3110-3116, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22745214

RESUMO

BACKGROUND: Molecular circadian clocks can modify cancer chemotherapy effects, with a possible moderation according to sex differences. We investigated whether sex determine the optimal delivery schedule of chemotherapy for metastatic colorectal cancer. PATIENTS AND METHODS: A meta-analysis was performed using individual data from three international Phase III trials comparing 5-fluorouracil, leucovorin and oxaliplatin administered in chronomodulated (chronoFLO) or conventional (CONV) infusions. The data from 345 females and 497 males were updated at 9 years. The main end point was survival. RESULTS: Overall survival was improved in males on chronoFLO when compared with CONV (P = 0.009), with respective median values of 20.8 (95% CL, 18.7 to 22.9) and 17.5 months (16.1 to 18.8). Conversely, median survival was 16.6 months (13.9 to 19.3) on chronoFLO and 18.4 months (16.6 to 20.2) on CONV in females (P = 0.012). The sex versus schedule interaction was a strong predictive factor of optimal treatment schedule, with a hazard ratio of 1.59 (1.30 to 1.75) for overall survival (P = 0.002) in multivariate analysis. CONCLUSIONS: Males lived significantly longer on chronomodulated chemotherapy rather than on conventional chemotherapy. The current chronoFLO schedule deserves prospective assessment as a safe and more effective first-line treatment option than conventional delivery for male patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Relógios Circadianos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Idoso , Cronoterapia , Esquema de Medicação , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Compostos Organoplatínicos/uso terapêutico , Fatores Sexuais , Taxa de Sobrevida , Resultado do Tratamento
11.
Ann Oncol ; 23(6): 1549-55, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22056973

RESUMO

BACKGROUND: A subset of patients treated with initial anti-vascular endothelial growth factor (VEGF) therapy exhibit progressive disease (PD) as the best response per RECIST criteria. METHODS: Data from patients with metastatic renal cell carcinoma (mRCC) treated with anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. RESULTS: One thousand and fifty-six assessable patients received initial VEGF inhibitors and 272 (26%) of these patients had PD as best response. Initial treatment included sunitinib (n = 203), sorafenib (n = 51), or bevacizumab (n = 18). Six percent of patients were at favorable risk, 55% at intermediate risk, and 39% at poor risk. On multivariable analysis, predictors of PD were Karnofsky performance status < 80% [odds ratio (OR) = 2.3, P < 0.0001], diagnosis to treatment < 1 year (OR = 2.1, P < 0.0001), neutrophilia (OR = 1.9, P = 0.0021), thrombocytosis (OR = 1.7, P = 0.0068), and anemia (OR = 1.6, P = 0.0058). Median progression-free survival (PFS) in patients with PD versus without PD was 2.4 versus 11 months (P < 0.0001) and overall survival (OS) was 6.8 versus 29 months (P < 0.0001), respectively. One hundred and eight (40%) VEGF-refractory patients proceeded to receive further systemic therapies. Response rate, PFS, and OS for subsequent therapy were 9%, 2.5 months, and 7.4 months, respectively, with no statistical differences between patients who received VEGF versus mammalian target of rapamycin (mTOR) inhibitors. CONCLUSIONS: Primary anti-VEGF-refractory mRCC patients have a dismal prognosis. Second-line anti-mTOR and anti-VEGF agents produce similar outcomes.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Renais/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Benzenossulfonatos/farmacologia , Benzenossulfonatos/uso terapêutico , Bevacizumab , Carcinoma de Células Renais/mortalidade , Intervalo Livre de Doença , Everolimo , Feminino , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Fatores de Risco , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Sorafenibe , Sunitinibe , Resultado do Tratamento
12.
Br J Cancer ; 105(11): 1741-9, 2011 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-22033272

RESUMO

BACKGROUND: Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney. Metastatic RCC is difficult to treat. The 5-year survival rate for metastatic RCC is ≤10%. Recently, microRNAs (miRNAs) have been shown to have a role in cancer metastasis and potential as prognostic biomarkers in cancer. METHOD: We performed a miRNA microarray to identify a miRNA signature characteristic of metastatic compared with primary RCCs. We validated our results by quantitative real-time PCR. We performed experimental and bioinformatic analyses to explore the involvement of miR-215 in RCC progression and metastasis. RESULTS: We identified 65 miRNAs that were significantly altered in metastatic compared with primary RCCs. We validated our results by examining the expression of miR-10b, miR-126, miR-196a, miR-204 and miR-215, in two independent cohorts of patients. We showed that overexpression of miR-215 decreased cellular migration and invasion in an RCC cell line model. In addition, through gene expression profiling, we identified direct and indirect targets of miR-215 that can contribute to tumour metastasis. CONCLUSION: Our analysis showed that miRNAs are altered in metastatic RCCs and can contribute to kidney cancer metastasis through different biological processes. Dysregulated miRNAs represent potential prognostic biomarkers and may have therapeutic applications in kidney cancer.


Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Genes Supressores de Tumor , Neoplasias Renais/genética , Neoplasias Renais/patologia , MicroRNAs/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/metabolismo , Processos de Crescimento Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Progressão da Doença , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Testes Genéticos/métodos , Proteínas de Homeodomínio/metabolismo , Humanos , Neoplasias Renais/metabolismo , Análise em Microsséries/métodos , Invasividade Neoplásica , Metástase Neoplásica , Proteínas do Tecido Nervoso/metabolismo , Prognóstico , Proteínas de Ligação a RNA/metabolismo , Reação em Cadeia da Polimerase em Tempo Real/métodos , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Taxa de Sobrevida , Homeobox 2 de Ligação a E-box com Dedos de Zinco
13.
Curr Oncol ; 18 Suppl 2: S11-9, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21969807

RESUMO

Traditionally, overall survival (os) has been considered the "gold standard" for evaluating new systemic oncologic therapies, because death is easy to define, is easily compared across disease sites, and is not subject to investigator bias. However, as the available options for continuing therapy increase, the use of os as a clinical trial endpoint has become problematic because of the increasing crossover and contamination of trials. As a result, the approval of promising new therapies may be delayed.Many clinicians believe that progression-free survival (pfs) is a more viable option for evaluating new therapies in metastatic and advanced renal cell carcinoma. As with all endpoints, pfs has inherent biases, and those biases must be addressed to ensure that trial results are not compromised and that they will be accepted by regulatory authorities. In this paper, we examine the issues surrounding the use of pfs as a clinical trial endpoint, and we suggest solutions to ensure that data integrity is maintained.

14.
J Clin Oncol ; 21(8): 1524-9, 2003 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-12697876

RESUMO

PURPOSE: A multi-institution phase II study was undertaken by National Cancer Institute of Canada-Clinical Trials Group to evaluate the efficacy and toxicity of intravenous troxacitabine (Troxatyl; Shire Pharmaceuticals Plc, Laval, Quebec, Canada), in patients with renal cell carcinoma. PATIENTS AND METHODS: Between June 1999 and March 2000, 35 patients (24 male) with a mean age of 60 years who had advanced and/or metastatic disease were treated with troxacitabine given as an intravenous infusion over 30 minutes at a dose of 10 mg/m2 intravenously, once every 3 weeks. RESULTS: Of the 33 of 35 patients evaluable for response, there were two confirmed partial responses, 21 patients had stable disease (median duration, 4.4 months), and 10 patients had progressive disease. Eight patients remained stable for more than 6 months, of whom six remain free of progression. The most common drug-related nonhematologic toxicities observed were skin rash (77.1%), hand-foot syndrome (68.6%), alopecia (51.4%), fatigue (51.4%), and nausea (57.1%). Out of a total of 145 cycles of treatment, 98 were given without steroid premedication, whereas 47 cycles were given with steroid premedication. Without premedication, skin rash occurred in 37% of cycles compared with 26% when steroids were given prophylactically. CONCLUSION: Troxacitabine given at a dose of 10 mg/m2 once every 3 weeks was well tolerated in patients with metastatic renal cell cancer, with common toxicities being a moderate to severe granulocytopenia and skin rash. Steroid premedication may reduce the frequency and severity of the skin rash. Our current study suggests that the nucleoside analog troxacitabine may have modest activity against renal cell carcinoma; however, larger studies are required to confirm this.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/secundário , Citosina/uso terapêutico , Dioxolanos/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Canadá , Citosina/administração & dosagem , Citosina/efeitos adversos , Citosina/análogos & derivados , Dioxolanos/administração & dosagem , Dioxolanos/efeitos adversos , Progressão da Doença , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
15.
Int J Gynecol Cancer ; 11(5): 418-21, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11737476

RESUMO

Primary squamous cell carcinoma (SCC) of the ovary arising from mature cystic teratoma (MCT) is rare. Survival is very poor. Although different postoperative treatments have been tried, none appears to have influenced outcomes. A 44-year-old patient with FIGO stage IIB SCC of the ovary arising in MCT had exploratory laparotomy and left salpingo-oophorectomy, leaving macroscopic residual pelvic disease. Postoperative treatment consisted of a continuous concurrent chronomodulated infusion of 5-fluorouracil 150 mg/m2/day and leucovorin 10 mg/m2/day with 5 weeks of pelvic radiotherapy. Three years after initial surgery, she remains disease and complication free. Given this patient's unusually long disease-free survival and the efficacy of concurrent chemotherapy and radiotherapy in other SCCs, the concurrent circadian treatment approach used for this patient should be explored in other cases of SCC of the ovary.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Pélvicas/tratamento farmacológico , Teratoma/tratamento farmacológico , Adulto , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/secundário , Carcinoma de Células Escamosas/cirurgia , Terapia Combinada , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/radioterapia , Neoplasias Ovarianas/cirurgia , Ovariectomia , Neoplasias Pélvicas/radioterapia , Neoplasias Pélvicas/secundário , Neoplasias Pélvicas/cirurgia , Cuidados Pós-Operatórios , Teratoma/patologia , Teratoma/radioterapia , Teratoma/cirurgia
16.
Breast Cancer Res Treat ; 66(2): 123-33, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11437098

RESUMO

PURPOSE: Obesity and breast cancer are common conditions that often coexist. Concerns of relative overdosing of chemotherapy in the large cancer patient have led clinicians to apply empiric dose reductions, 'cap' the body surface area (BSA) at 2 m2, or use ideal rather than actual body weight to calculate BSA. There are no data supporting or refuting these practices and their prevalence is unknown. We sought to determine the distribution of body size and prevalence of obesity in the breast cancer population of our cancer centre, and to determine clinician chemotherapy dosing practices in the era of modern adjuvant chemotherapy. PATIENTS AND METHODS: Women with invasive breast cancer receiving systemic therapy at our institution between 1980 and 1998 were identified and their recorded height and weight were used to calculate BSA and body mass index (BMI). We reviewed the first cycle adjuvant chemotherapy dosing practices from 1990-1998. The ideal dose of chemotherapy was calculated based on calculated BSA, and then contrasted with the actual dose received at cycle one. Discrepancies were recorded and categorized, using the largest single drug reduction if more than one drug was reduced. RESULTS: Mean BMI in the systemic therapy population was 26.4 +/- 5.3 kg/m2, 54% were overweight, 2% severely obese and 18% moderately so. Their mean BSA was 1.7 +/- 0.2 m2 and only 5% had a BSA > or = 2 m2. In the adjuvant chemotherapy subgroup, most patients received > or = 85% of their ideal dose. The mean dose reduction was 5.3 +/- 11.3% versus 9.9 +/- 11.3% in the BSA < 2 and > or = 2 m2 groups, respectively (p = 0.02), and 4.3 +/- 8.2% versus 6.7 +/- 13.1% in the BMI < 25 and > or = 25 kg/m2 groups, respectively (p = 0.008). While only 24% of chemotherapy dose reductions of > or = 15% were in the BSA > or = 2 m2 group, 76% were in the BMI > or = 25 kg/m2 group. CONCLUSIONS: Obesity is prevalent in this breast cancer population. BSA is not a sensitive index of large body size. We consistently detected more frequent empiric dose reductions at cycle one of adjuvant chemotherapy, with reductions of greater magnitude in the largest women (BSA > or = 2 m2) and those who were overweight (BMI > or = 25 kg/m2).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Atitude do Pessoal de Saúde , Neoplasias da Mama/tratamento farmacológico , Oncologia/normas , Obesidade , Padrões de Prática Médica , Preconceito , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Doxorrubicina/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Humanos , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Ontário , Estudos Retrospectivos
17.
Am J Pathol ; 158(5): 1793-801, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11337377

RESUMO

We studied the relative RNA expression of clock genes throughout one 24-hour period in biopsies obtained from the oral mucosa and skin from eight healthy diurnally active male study participants. We found that the human clock genes hClock, hTim, hPer1, hCry1, and hBmal1 are expressed in oral mucosa and skin, with a circadian profile consistent with that found in the suprachiasmatic nuclei and the peripheral tissues of rodents. hPer1, hCry1, and hBmal1 have a rhythmic expression, peaking early in the morning, in late afternoon, and at night, respectively, whereas hClock and hTim are not rhythmic. This is the first human study to show a circadian profile of expression for all five clock genes as documented in rodents, suggesting their functional importance in man. In concurrent oral mucosa biopsies, thymidylate synthase enzyme activity, a marker for DNA synthesis, had a circadian variation with peak activity in early afternoon, coinciding with the timing of S phase in our previous study on cell-cycle timing in human oral mucosa. The major peak in hPer1 expression occurs at the same time of day as the peak in G(1) phase in oral mucosa, suggesting a possible link between the circadian clock and the mammalian cell cycle.


Assuntos
Ritmo Circadiano/fisiologia , Proteínas de Drosophila , Proteínas do Olho , Mucosa Bucal/metabolismo , Células Fotorreceptoras de Invertebrados , Pele/metabolismo , Transativadores/genética , Fatores de Transcrição ARNTL , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Proteínas CLOCK , Ciclo Celular/fisiologia , Proteínas de Ciclo Celular , Ritmo Circadiano/genética , Criptocromos , Flavoproteínas/genética , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular , Mucosa Bucal/enzimologia , Proteínas Nucleares/genética , Proteínas Circadianas Period , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Acoplados a Proteínas G , Timidilato Sintase/genética , Timidilato Sintase/metabolismo , Fatores de Transcrição/genética
18.
Anticancer Drugs ; 11(9): 709-13, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11129733

RESUMO

We present the circumstances surrounding a 57-year-old Caucasian man with advanced colorectal cancer who developed relapsing interstitial lung disease following a single exposure to irinotecan (CPT-11). Progressive pulmonary insufficiency and death were reported in the initial Japanese studies, despite institution of empiric steroid therapy for a syndrome similar to that which our patient experienced. As a result, patients with compromised pulmonary function were generally excluded from US clinical trials. Notwithstanding this, cough and dyspnea were reported in approximately 20% of patients in the US studies. As the clinical indications for the use of this agent expand, we describe irinotecan-associated interstitial pneumonitis as a serious potential adverse effect. Patients with pre-existing pulmonary disease may be at higher risk for this complication and clinicians should be alert to this possibility.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Camptotecina/análogos & derivados , Camptotecina/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade
19.
Prog Cell Cycle Res ; 4: 193-206, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10740826

RESUMO

Most physiological, biochemical and behavioural processes have been shown to vary in a regular and predictable periodic manner with respect to time. This review focuses on the circadian rhythm in cell proliferation in bone marrow and gut and how this is associated with a circadian expression of cell cycle proteins in human oral mucosa. The control of circadian rhythms by the suprachiasmatic nuclei and the evolving understanding of the genetic and molecular biology of the circadian clock is outlined. Finally, the potential clinical impact of chronobiology in cancer medicine is discussed.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Ritmo Circadiano/fisiologia , Animais , Divisão Celular/fisiologia , Humanos , Mucosa Bucal/citologia
20.
Acta Oncol ; 38(2): 255-9, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10227449

RESUMO

In a multicenter phase II study, 30 patients with unresectable, locally advanced or metastatic squamous cell or adenocarcinoma of the esophagus were treated with folinic acid 200 mg/m2/d, 5-FU 300 mg/m2/d, and cisplatin 20 mg/m2/d intravenously for 5 days every 4 weeks. Two of 13 patients with squamous cell carcinoma (SCC) had a complete response (CR), but one died of pneumonia after 9 months while still in CR, and the other still in CR after more than 5 years. Six other patients (3 SCC, 2 of 16 with adenocarcinoma, 1 mixed histology) had a partial response with a median duration of 9 months (range 5 to 57 + months) for an overall response rate of 27%. A further 6 patients (20%) had stable disease. Grade 4 neutropenia occurred in 6 patients (20%), with 5 requiring antibiotics for associated fever. Other grade 4 toxicities were nausea and vomiting (1), anemia (1), and thrombocytopenia (1); there were three early deaths (emphysema, cardiac arrest, pulmonary embolism). This combination appears to be an active, convenient regimen for advanced esophageal cancer, resulting in prolonged remission and survival in some patients.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/secundário , Cisplatino/administração & dosagem , Progressão da Doença , Esquema de Medicação , Neoplasias Esofágicas/mortalidade , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Ontário , Índice de Gravidade de Doença , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...