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1.
Can Urol Assoc J ; 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31702551

RESUMO

INTRODUCTION: Although radical cystectomy is considered the standard of care for muscle-invasive bladder cancer (MIBC), recent data has suggested comparable survival outcomes for bladder-sparing trimodality therapy (TMT). We conducted a retrospective, single-institution analysis of MIBC patients to evaluate the efficacy of TMT as an alternative, curative approach to surgical intervention. METHODS: We conducted a retrospective analysis of MIBC patients assessed by a multidisciplinary team at the Juravinski Cancer Centre from 2010-2016. Patients underwent transurethral resection of bladder tumor (TURBT) followed by radiotherapy with or without concurrent chemotherapy. Patients could receive neoadjuvant treatment. Clinical data and response rates were summarized, and overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. RESULTS: Our analytic cohort included 115 patients, of whom 53 underwent TMT and 62 who underwent radiotherapy alone following TURBT. Median age at diagnosis was 79 years and median followup was 21 months. Complete response rates in those receiving TMT and radiation without chemotherapy were 84.4% and 66.7%, respectively. For TMT patients, three-year OS and DFS were 68.5% and 49.6%, respectively. Patients who received TMT had reduction in risk of mortality (hazard ratio [HR] 0.49; p=0.026) and disease recurrence (HR 0.55; p=0.017) compared to those who had radiation without chemotherapy. Overall, four patients had grade 3 or higher late toxicity. CONCLUSIONS: In this single-institution analysis, TMT appears to be a safe and effective approach in the short-term management of MIBC in appropriately selected patients. Extended followup and analysis are necessary to validate these results.

2.
Oncologist ; 24(11): 1405-1409, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31315962

RESUMO

Trastuzumab is an effective treatment for HER2-positive breast cancer. Current guidelines recommend withholding trastuzumab in patients experiencing a significant asymptomatic decline in left ventricular function. In this commentary, we discuss the survival benefits afforded by trastuzumab juxtaposed against the risk of trastuzumab-mediated cardiotoxicity. It is not known whether the net benefit of continuing trastuzumab in the setting of mild cardiotoxicity outweighs the associated risks. We describe a potential approach undertaken by our group, and others, and call for a randomized trial.

5.
PLoS One ; 13(12): e0209486, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30571754

RESUMO

BACKGROUND: Preclinical evidence suggests statins may have anti-tumor properties. Large observational studies are also consistent with improved survival and cancer-specific outcomes among cancer patients on statins. We sought to evaluate the randomized controlled trials of statins in addition to usual anti-cancer therapy. METHODS: A systematic search of MEDLINE, Embase, CINAHL, Cochrane Library, Web of Science, Papers First and Clinicaltrials.gov was performed from inception through to July 4, 2017 to identify randomized clinical trials that investigated statin therapy in cancer patients. Our primary outcome was overall survival and our secondary outcome was progression-free survival. We calculated summary hazard ratio's (HR) and 95% confidence intervals (CI) based on random-effects models using aggregate data. PROSPERO (CRD42017065503). RESULTS: Ten studies with 1,881 individuals were included with 1,572 deaths and a median follow-up of 23 months. All trials included patients with advanced (stage 3 or higher) disease. There was minimal between-study statistical heterogeneity (I2 = 1.8%, for OS; I2 = 0%, for PFS). The pooled HR for overall survival in patients randomized to statins plus standard anti-cancer therapy versus standard therapy alone was 0.94 (95% CI, 0.85 to 1.04). In the 9 studies that reported progression-free survival (1,798 participants), the pooled HR for statin plus standard therapy versus standard therapy alone was 0.97 (95% CI, 0.87 to 1.07). CONCLUSIONS: In patients with advanced cancer and a prognosis <2 years, the addition of statins to standard anti-cancer therapy does not appear to improve overall survival or progression-free survival. Future research should assess if cancer patients with better prognosis benefit from longer-term statin therapy.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo
6.
Can J Cardiol ; 34(8): 1059-1068, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29980467

RESUMO

BACKGROUND: Immune checkpoint inhibitors, including programmed cell death-1, programmed cell death ligand-1 and cytotoxic lymphocyte antigen-4 inhibitors, have emerged as important therapeutic alternatives for advanced malignancies. This drug class upregulates T-cell activity, leading to an immune response against cancer cells. However, the increased activity of T cells can lead to autoimmune reactions. METHODS: We conducted a systematic review of all published articles and grey literature in PubMed, Medline, and Embase on cardiac complications associated with checkpoint inhibitor use from September 1, 1996 to November 10, 2017. RESULTS: The search strategy yielded 908 unique articles. Of these, 835 were excluded on the basis of abstract and full-text review. A total of 73 studies met eligibility criteria and were included. We found a total of 99 cases of cardiotoxicity with the use of checkpoint inhibitors. Myocarditis (45%) was the most common cardiotoxicity. The overall case fatality rate was 35%. This was notably higher in patients with myocarditis, complete heart block, or conduction abnormalities, and ventricular arrhythmias. There was no difference in outcomes for patients treated with or without steroids. Immunosuppressive therapies such as infliximab, mycophenolate, intravenous immunoglobulin, antithymocyte globulin, and/or plasmapheresis were used in 12 patients leading to survival in 9 of these patients (75%). CONCLUSIONS: Immune checkpoint inhibitors are associated with cardiotoxicity. Because of the high case fatality rate, close surveillance and prompt empiric therapy for cardiovascular complications of checkpoint inhibitors should be considered. Aggressive treatment with immunosuppressive agents and/or plasmapheresis might lead to clinical improvement and increased survival.


Assuntos
Cardiopatias/induzido quimicamente , Imunossupressores/efeitos adversos , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Linfócitos T/microbiologia , Cardiotoxicidade , Humanos , Imunossupressores/uso terapêutico
7.
Breast Cancer Res Treat ; 164(2): 371-378, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28447237

RESUMO

BACKGROUND: Metformin is associated with low levels of vitamin B12 (VitB12) in patients with diabetes. The CCTG/MA.32 trial investigates the effects of metformin vs placebo on breast cancer (BC) outcomes in non-diabetic high-risk BC patients. We analyzed VitB12 at baseline and after 6 months of metformin (versus placebo) in the first 492 patients with paired blood samples. METHODS: VitB12 was analyzed centrally in baseline and 6-month fasting plasma. Levels <181 pmol/L were considered deficient, 181-221 pmol/L borderline, and ≥222 pmol/L sufficient. Methylmalonic acid (MMA) and homocysteine (HC) were assayed in those with VitB12 levels <222 pmol/L. Statistical analyses used Spearman's rank correlation coefficients and Wilcoxon signed-rank test for continuous variables and Chi-square test for categorical variables. RESULTS: 237 patients received metformin and 255 received placebo; median (inter quartile range) baseline VitB12 levels were 390 (290, 552) and 370 (290, 552) pmol/L in the metformin and placebo arms, respectively (p = 0.97). At 6 months, the median levels were 320 (244, 419) in the metformin versus 380 (286, 546) pmol/L in the placebo arm (p = 0.0001). At baseline, 15 patients (11 metformin and 4 placebo) had VitB12 <181 pmol/L, and at 6 months, 18 patients (15 metformin and 3 placebo) (p = 0.004). Median hemoglobin was similar at baseline, metformin, 130 g/L (124-137), and placebo arms, 131 g/L (124-137) (p = 0.38), and at 6 months, metformin, 131 g/L (91-162), and 131 g/L (106-169) in placebo group (p = 0.11). Of the 74 subjects with vitamin B12 <222 pmol/L at either time point (45 metformin, 29 placebo), at baseline MMA was normal in all patients and two had elevated HC (>15µmol/L). At 6 months, one patient (metformin) had MMA >0.4µmol/L and 3 (2 metformin, 1 placebo) had HC > 15µmol/L. CONCLUSIONS: There was an increased rate of biochemical VitB12 deficiency after 6 months of metformin; this was not associated with anemia. Further research will investigate VitB12 levels in all subjects at baseline and at 6 and 60 months.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Metformina/administração & dosagem , Vitamina B 12/sangue , Adulto , Antineoplásicos/uso terapêutico , Neoplasias da Mama/sangue , Neoplasias da Mama/metabolismo , Feminino , Homocisteína/sangue , Humanos , Metformina/uso terapêutico , Ácido Metilmalônico/sangue , Pessoa de Meia-Idade , Resultado do Tratamento
8.
Lancet Oncol ; 18(4): 473-485, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28283282

RESUMO

BACKGROUND: Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a second-generation antisense oligonucleotide that inhibits clusterin production. The aim of the SYNERGY trial was to investigate the effect of custirsen in combination with docetaxel and prednisone on overall survival in patients with metastatic castration-resistant prostate cancer. METHODS: SYNERGY was a phase 3, multicentre, open-label, randomised trial set at 134 study centres in 12 countries. Patients were eligible for participation if they had: metastatic castration-resistant prostate cancer and had received no previous chemotherapy; prostate-specific antigen greater than 5 ng/mL; and a Karnofsky performance score of 70% or higher. Patients were randomly assigned 1:1 centrally to either the docetaxel, prednisone, and custirsen combination or docetaxel and prednisone alone. Patients were not masked to treatment allocation. Randomisation was stratified by opioid use for cancer-related pain and radiographic evidence of progression. All patients received docetaxel 75 mg/m2 intravenously with 5 mg of prednisone orally twice daily. Patients assigned docetaxel, prednisone, and custirsen received weekly doses of custirsen 640 mg intravenously after three loading doses of 640 mg. The primary endpoint was overall survival analysed in the intention-to-treat population. Patients who received at least one study dose were included in the safety analysis set. This trial is registered with ClinicalTrials.gov, number NCT01188187. The trial is completed and final analyses are reported here. FINDINGS: Between Dec 10, 2010, and Nov 7, 2012, 1022 patients were enrolled to the trial, of whom 510 were assigned docetaxel, prednisone, and custirsen and 512 were allocated docetaxel and prednisone. No difference in overall survival was recorded between the two groups (median survival 23·4 months [95% CI 20·9-24·8] with docetaxel, prednisone, and custirsen vs 22·0 months [19·5-24·0] with docetaxel and prednisone; hazard ratio [HR] 0·93, 95% CI 0·79-1·10; p=0·415). The most common adverse events of grade 3 or worse in the docetaxel, prednisone and custirsen group (n=501) compared with the docetaxel and prednisone alone group (n=499) were neutropenia (grade 3, 63 [13%] vs 28 [6%]; grade 4, 98 [20%] vs 77 [15%]), febrile neutropenia (grade 3, 52 [10%] vs 31 [6%]; grade 4, four [1%] vs two [<1%]), and fatigue (grade 3, 53 [11%] vs 41 [8%]; grade 4, three [1%] vs one [<1%]). One or more serious adverse events were reported for 214 (43%) of 501 patients treated with docetaxel, prednisone, and custirsen and 181 (36%) of 499 receiving docetaxel and prednisone alone. Adverse events were attributable to 23 (5%) deaths in the docetaxel, prednisone, and custirsen group and 24 (5%) deaths in the docetaxel and prednisone alone group. INTERPRETATION: Addition of custirsen to first-line docetaxel and prednisone was reasonably well tolerated, but overall survival was not significantly longer for patients with metastatic castration-resistant prostate cancer treated with this combination, compared with patients treated with docetaxel and prednisone alone. FUNDING: OncoGenex Technologies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Progressão da Doença , Docetaxel , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prednisona/administração & dosagem , Prognóstico , Neoplasias de Próstata Resistentes à Castração/patologia , Taxa de Sobrevida , Taxoides/administração & dosagem , Tionucleotídeos/administração & dosagem
9.
Cancer Immunol Res ; 4(10): 881-892, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27604597

RESUMO

MUC1 is a glycoprotein expressed on the apical surface of ductal epithelial cells. Malignant transformation results in loss of polarization and overexpression of hypoglycosylated MUC1 carrying truncated carbohydrates known as T or Tn tumor antigens. Tumor MUC1 bearing Tn carbohydrates (Tn-MUC1) represent a potential target for immunotherapy. We evaluated the Tn-MUC1 glycopeptide in a human phase I/II clinical trial for safety that followed a preclinical study of different glycosylation forms of MUC1 in rhesus macaques, whose MUC1 is highly homologous to human MUC1. Either unglycosylated rhesus macaque MUC1 peptide (rmMUC1) or Tn-rmMUC1 glycopeptide was mixed with an adjuvant or loaded on autologous dendritic cells (DC), and responses were compared. Unglycosylated rmMUC1 peptide induced negligible humoral or cellular responses compared with the Tn-rmMUC1 glycopeptide. Tn-rmMUC1 loaded on DCs induced the highest anti-rmMUC1 T-cell responses and no clinical toxicity. In the phase I/II clinical study, 17 patients with nonmetastatic castrate-resistant prostate cancer (nmCRPC) were tested with a Tn-MUC1 glycopeptide-DC vaccine. Patients were treated with multiple intradermal and intranodal doses of autologous DCs, which were loaded with the Tn-MUC1 glycopeptide (and KLH as a positive control for immune reactivity). PSA doubling time (PSADT) improved significantly in 11 of 16 evaluable patients (P = 0.037). Immune response analyses detected significant Tn-MUC1-specific CD4+ and/or CD8+ T-cell intracellular cytokine responses in 5 out of 7 patients evaluated. In conclusion, vaccination with Tn-MUC1-loaded DCs in nmCRPC patients appears to be safe, able to induce significant T-cell responses, and have biological activity as measured by the increase in PSADT following vaccination. Cancer Immunol Res; 4(10); 881-92. ©2016 AACR.


Assuntos
Vacinas Anticâncer/uso terapêutico , Células Dendríticas/transplante , Mucina-1/imunologia , Neoplasias de Próstata Resistentes à Castração/terapia , Idoso , Idoso de 80 Anos ou mais , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Estudos de Viabilidade , Humanos , Macaca mulatta , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/imunologia , Vacinação
10.
Breast ; 29: 126-31, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27484016

RESUMO

BACKGROUND: Recently the impact of completion axillary lymph node dissection (cALND) after positive sentinel lymph node biopsy on significant outcomes has been questioned, leading to variation in surgical practice. To address this variation, a multidisciplinary working group created a regional guideline for cALND. We explored the views and experiences of surgeons, medical oncologists (MOs), radiation oncologists (ROs) in a qualitative study that examined guideline implementation in practice. METHODS: The Pathman framework (awareness, agreement, adoption and adherence) informed the interview guide design and analysis. Semi-structured interviews were conducted with MOs, ROs and surgeons and transcribed. Transcripts were coded independently by 2 members of the study team and analyzed. Disagreements were resolved through consensus. RESULTS: Twenty-eight physicians (5 MO; 6RO; 17S) of 41 (68% of those approached) were interviewed. Ten of 11 (91%) hospital sites (54% community; 46% academic) and all 4 cancer clinics within the region were represented. Twenty-seven physicians (96%) were aware of the guideline, with all physicians reporting agreement and general adherence to the guideline. Most physicians indicated nodal factors, age and patient preference were key components of cALND decision-making. Physicians from all disciplines perceived that the guideline helped reduce variation in practice across the region. There were concerns that the guideline could be applied rigidly and not permit individual decision-making. CONCLUSIONS: Physicians identified breast cancer as an increasingly complex and multidisciplinary issue. Facilitators to guideline implementation included perceived flexibility and buy-in from all disciplines, while individual patient factors and controversial supporting evidence may hinder its implementation.


Assuntos
Neoplasias da Mama/cirurgia , Excisão de Linfonodo/normas , Oncologia , Guias de Prática Clínica como Assunto , Radioterapia (Especialidade) , Cirurgiões , Adulto , Atitude do Pessoal de Saúde , Axila , Neoplasias da Mama/patologia , Feminino , Fidelidade a Diretrizes , Humanos , Excisão de Linfonodo/psicologia , Linfonodos/patologia , Linfonodos/cirurgia , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Biópsia de Linfonodo Sentinela
11.
Ann Surg Oncol ; 23(10): 3354-64, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27342830

RESUMO

INTRODUCTION: Evidence from the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial suggests completion axillary lymph node dissection (cALND) after positive sentinel lymph node biopsy (+SLNB) does not improve outcomes in select patients, leading to practice variation. A multidisciplinary group of surgeons, oncologists, and pathologists developed a regional guideline for cALND which was disseminated in August 2012. We assessed the impact of Z0011 and the regional guideline on cALND rates. METHODS: Consecutive invasive breast cancer cases undergoing SLNB were reviewed at 12 hospitals. Patient, tumor, and process measures were collected for three time periods: TP1, before publication of Z0011 (May 2009-August 2010); TP2, after publication of Z0011 (March 2011-June 2012); and TP3, after guideline dissemination (January 2013-April 2014). Cases were categorized by whether they met the guideline criteria for cALND (i.e. ≤50 years, mastectomy, T3 tumor, three or more positive sentinel lymph nodes [SLNs]) or not (e.g. age > 50 years, breast-conserving surgery, T1/T2 tumor, and one to two positive SLNs). RESULTS: The SLNB rate increased from 56 % (n = 620), to 70 % (n = 774), to 78 % (n = 844) in TP1, TP2, and TP3, respectively. Among cases not recommended for cALND using the guideline criteria, cALND rates decreased significantly over time (TP1, 71 %; TP2, 43 %; TP3, 17 %) [p < 0.001]. The cALND rate also decreased over time among cases recommended to have cALND using the guideline criteria (TP1, 92 %; TP2, 69 %; TP3, 58 %) [p < 0.001]. Based on multivariable analysis, age and nodal factors appeared to be significant factors for cALND decision making. CONCLUSION: Publication of ACOSOG Z0011 and regional guideline dissemination were associated with a marked decrease in cALND after +SLNB, even among several cases in which the guideline recommended cALND.


Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Excisão de Linfonodo/estatística & dados numéricos , Linfonodos/cirurgia , Guias de Prática Clínica como Assunto , Biópsia de Linfonodo Sentinela/estatística & dados numéricos , Fatores Etários , Idoso , Área Sob a Curva , Axila , Feminino , Humanos , Análise de Séries Temporais Interrompida , Linfonodos/patologia , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Curva ROC , Carga Tumoral
12.
Breast Cancer (Auckl) ; 10: 53-60, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27226720

RESUMO

INTRODUCTION: Breast magnetic resonance imaging (MRI) is considered a more sensitive diagnostic test for detecting invasive breast cancer than mammography or breast ultrasound. Breast MRI may be particularly useful in younger premenopausal women with higher density breast tissue for differentiating between dense fibroglandular breast tissue and breast malignancies. The main objective of this study was to determine the impact of preoperative breast MRI on surgical decision-making in young women with breast cancer. METHODS: A retrospective review of patients with newly diagnosed invasive breast cancer and age of ≤50 years was performed. All patients underwent physical examination, preoperative mammogram, breast ultrasound, and bilateral breast MRI. Two breast cancer surgeons reviewed the preoperative mammogram report, breast ultrasound report, and physical examination summary and were asked if they would recommend a lumpectomy, a quandrantectomy, or a mastectomy. A few weeks later, the two surgeons were shown the same information with the breast MRI report and were asked what type of surgery they would now recommend. In each case, MRI was classified by two adjudicators as having affected the surgical outcome in a positive, negative, or neutral fashion. A positive impact was defined as the situation where breast MRI detected additional disease that was not found on physical examination, mammogram, or breast ultrasound and led to an appropriate change in surgical management. A negative impact was defined as the situation where breast MRI led the surgeon to recommend more extensive surgery, with less extensive disease actually found at pathology. No impact was defined as the situation where MRI findings did not alter surgical recommendations or outcomes. RESULTS: Of 37 patients whose charts were reviewed, five patients were deemed to be ineligible due to having received neoadjuvant chemotherapy, having previous breast implants, or having had their tumor fully excised during biopsy. In total, 32 patients met the inclusion criteria of this study and were appropriate for analysis. The median age of our study patient population was 42 years. The pathologic diagnosis was invasive ductal carcinoma in 91% (29/32) of patients and invasive lobular carcinoma in 9% (3/32) of patients. For surgeon A, clinical management was altered in 21/32 (66%) patients, and for surgeon B, management was altered in 13/32 (41%) patients. The most common change in surgical decision-making after breast MRI was from breast-conserving surgery to a mastectomy. Mastectomy rates were similar between both surgeons after breast MRI. After reviewing the pathology results and comparing them with the breast MRI results, it was determined that breast MRI led to a positive outcome in 13/32 (41%) patients. Breast MRI led to no change in surgical management in 15/32 (47%) patients and resulted in a negative change in surgical management in 4/32 (13%) patients. Bilateral breast MRI detected a contralateral breast cancer in 2/32 (6%) patients. CONCLUSIONS: Preoperative breast MRI alters surgical management in a significant proportion of younger women diagnosed with breast cancer. Prospective studies are needed to confirm these findings and to help determine if this change in surgical decision-making will result in improved local control.

13.
J Natl Cancer Inst ; 107(3)2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25740979

RESUMO

BACKGROUND: Metformin may improve metabolic factors (insulin, glucose, leptin, highly sensitive C-reactive protein [hs-CRP]) associated with poor breast cancer outcomes. The NCIC Clinical Trials Group (NCIC CTG) MA.32 investigates effects of metformin vs placebo on invasive disease-free survival and other outcomes in early breast cancer. Maintaining blinding of investigators to outcomes, we conducted a planned, Data Safety Monitoring Committee-approved, analysis of the effect of metformin vs placebo on weight and metabolic factors at six months, including examination of interactions with baseline body mass index (BMI) and insulin, in the first 492 patients with paired blood samples. METHODS: Eligible nondiabetic subjects with T1-3, N0-3, M0 breast cancer who had completed surgery and (neo)adjuvant chemotherapy (if given) provided fasting plasma samples at random assignment and at six months. Glucose was measured locally; blood was aliquoted, frozen, and stored at -80°C. Paired plasma aliquots were analyzed for insulin, hs-CRP, and leptin. Spearman correlation coefficients were calculated and comparisons analyzed using Wilcoxon signed rank test. All statistical tests were two-sided. RESULTS: Mean age was 52.1±9.5 years in the metformin group and 52.6 ± 9.8 years in the placebo group. Arms were balanced for estrogen/progesterone receptor, BMI, prior (neo)adjuvant chemotherapy, and stage. At six months, decreases in weight and blood variables were statistically significantly greater in the metformin arm (vs placebo) in univariate analyses: weight -3.0%, glucose -3.8%, insulin -11.1%, homeostasis model assessment -17.1%, leptin -20.2%, hs-CRP -6.7%; all P values were less than or equal to .03. There was no statistically significant interaction of change in these variables with baseline BMI or insulin. CONCLUSIONS: Metformin statistically significantly improved weight, insulin, glucose, leptin, and CRP at six months. Effects did not vary by baseline BMI or fasting insulin.


Assuntos
Glicemia/metabolismo , Neoplasias da Mama/sangue , Neoplasias da Mama/terapia , Hipoglicemiantes/farmacologia , Insulina/sangue , Leptina/sangue , Metformina/farmacologia , Adulto , Idoso , Glicemia/efeitos dos fármacos , Índice de Massa Corporal , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Proteína C-Reativa/efeitos dos fármacos , Proteína C-Reativa/metabolismo , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , América do Norte/epidemiologia , Projetos de Pesquisa , Estatísticas não Paramétricas , Suíça/epidemiologia , Reino Unido/epidemiologia
14.
Prostate ; 75(8): 836-44, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25683285

RESUMO

BACKGROUND: The open-label, single-arm enzalutamide expanded access program (EAP) in the United States and Canada evaluated the safety of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received docetaxel. METHODS: Patients (n = 507) received enzalutamide 160 mg/day until disease progression, intolerable adverse events (AEs), or commercial availability occurred. AEs and other safety variables were assessed on day 1, weeks 4 and 12, and every 12 weeks thereafter. Data following transition to commercial drug were not collected. RESULTS: Median age was 71 years (range 43-97); 426 patients (83.9%) had a baseline ECOG score of ≤1. In addition to docetaxel, the majority of patients had received prior prostate cancer treatments such as abiraterone (76.1%) or cabazitaxel (28.6%). Median study treatment duration was 2.6 months (range 0.03-9.07). The most frequently reported reasons for discontinuation were commercial availability of enzalutamide (46.7%) and progressive disease (33.7%). A total of 88.2% of patients experienced AEs; 45.4% experienced AEs with a maximum grade of 1 or 2. Fatigue (39.1%), nausea (22.7%), and anorexia (14.8%) were the most commonly reported AEs. Seizure was reported in four patients (0.8%). The most commonly reported event leading to death was progression of metastatic prostate cancer (7.7%). CONCLUSION: In this heavily pretreated EAP population with progressive mCRPC, enzalutamide was well tolerated and the safety profile was consistent with that of the AFFIRM trial.


Assuntos
Antineoplásicos/uso terapêutico , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/epidemiologia , Taxoides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Docetaxel , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fadiga/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , América do Norte/epidemiologia , Feniltioidantoína/efeitos adversos , Feniltioidantoína/uso terapêutico , Taxoides/efeitos adversos , Resultado do Tratamento
15.
Clin Cancer Res ; 21(7): 1621-7, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25593303

RESUMO

PURPOSE: Gene fusions leading to androgen receptor-modulated ERG overexpression occur in up to 70% of metastatic castration-resistant prostate cancers (mCRPC). We assessed the association between ERG rearrangement status and clinical benefit from abiraterone acetate. EXPERIMENTAL DESIGN: COU-AA-302 is a phase III trial comparing abiraterone acetate and prednisone versus prednisone in chemotherapy-naïve mCRPC. ERG status was evaluated by FISH on archival tumors. End points included radiographic progression-free survival (rPFS), time to PSA progression (TTPP), rate of ≥50% PSA decline from baseline, and overall survival (OS). Cox regression was used to evaluate association with time-to-event measures and Cochran-Mantel-Haenszel for PSA response. RESULTS: ERG status was defined for 348 of 1,088 intention-to-treat patients. ERG was rearranged in 121 of 348 patients with confirmed ERG status (35%). Cancers with an ERG fusion secondary to deletion of 21q22 and increased copy number of fusion sequences (class 2+ Edel) had a greater improvement in rPFS after abiraterone acetate and prednisone [22 vs. 5.4 months; HR (95% confidence interval, CI), 0.31 (0.15-0.68); P = 0.0033] than cancers with no ERG fusion [16.7 vs. 8.3 months; 0.53 (0.38-0.74); P = 0.0002] or other classes of ERG rearrangement. There was also greater benefit in this subgroup for TTPP. CONCLUSIONS: Both ERG-rearranged and wild-type cancers had a significant improvement in rPFS with abiraterone acetate and prednisone in the COU-AA-302 trial. However, our data suggest that 2+ Edel cancers, accounting for 15% of all mCRPC patients and previously associated with a worse outcome, derived the greatest benefit.


Assuntos
Acetato de Abiraterona/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/genética , Transativadores/genética , Idoso , Intervalo Livre de Doença , Método Duplo-Cego , Humanos , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Modelos de Riscos Proporcionais , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Regulador Transcricional ERG
16.
Urol Oncol ; 32(7): 975-80, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25027682

RESUMO

OBJECTIVES: Patients receiving cisplatin are at high risk of thromboembolic events (TEEs). The objective of this study was to assess the effect of cisplatin-based neoadjuvant chemotherapy (NCT) on the incidence of perioperative TEEs in patients undergoing radical cystectomy. METHODS AND MATERIALS: We analyzed a consecutive sample of 202 patients with urothelial carcinoma treated with radical cystectomy between 2005 and 2013. Data were collected retrospectively by reviewing medical records. Median follow-up was 16.9 months. Events of interest were defined as venous or arterial TEEs occurring from the date of diagnosis to 30 days after surgery. TEE incidence among patients treated with NCT and cystectomy was compared with that among patients treated with cystectomy alone using Fisher exact test and Cox proportional hazards regression. Proportional hazards regression was also used to assess whether TEE is a predictor of cancer progression and survival. RESULTS: Of 202 patients, 17 (8.4%) developed a TEE, including 8 of 42 (19.1%) treated with NCT and cystectomy and 9 of 160 (5.6%) treated with cystectomy alone (risk ratio = 3.39, 95% CI: 1.39-8.24). After adjustment for observation time, there remained an association between treatment with NCT and risk of TEE (hazard ratio = 2.40; 95% CI: 0.92-6.27; P = 0.07). Overall, 7 events occurred before cystectomy and 10 occurred postoperatively. Among patients treated with NCT, 6 of 8 events occurred before cystectomy. Detection of TEE was clinically significant as preoperative TEE was found to be an independent predictor of progression and cancer-specific mortality (adjusted hazard ratio = 3.91, 95% CI: 1.34-11.45). The main limitations of our study are its retrospective data collection and small absolute number of events. CONCLUSIONS: TEE occurs commonly in patients with urothelial carcinoma undergoing NCT. Preoperative TEE is an independent predictor of progression and cancer-specific mortality.


Assuntos
Antineoplásicos/efeitos adversos , Carcinoma de Células de Transição/tratamento farmacológico , Cisplatino/efeitos adversos , Tromboembolia/epidemiologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Idoso , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/cirurgia , Quimioterapia Adjuvante/efeitos adversos , Terapia Combinada , Cistectomia , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Tromboembolia/etiologia , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/cirurgia
17.
Invest New Drugs ; 32(4): 746-52, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24671507

RESUMO

PURPOSE: To investigate the efficacy and safety of combining vandetanib, an orally available multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR), with bicalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: This was an open-label, randomized phase II multi-center study. Eligible patients had rising PSA on androgen deprivation therapy, minimal symptoms and were chemotherapy-naïve. Protocol therapy was either vandetanib 300 mg oral daily plus bicalutamide 50 mg oral daily (Arm A) or bicalutamide 50 mg oral daily alone (Arm B) with cross-over to vandetanib monotherapy at progression. The primary endpoint was PSA response (≥ 50 % decline from baseline). RESULTS: Thirty-nine patients were recruited, 19 in Arm A and 20 in Arm B. PSA response was comparable in Arm A and Arm B (18 vs. 19 %). Time to PSA progression was 3.16 months (95 % confidence interval (CI): 1.09, not reached (NR)) for Arm A and 3.09 months (95 % CI: 1.22, NR) for Arm B. Treatment discontinuation due to adverse events was more common in Arm A compared to Arm B (42 vs. 5 %; p = 0.019). Treatment with vandetanib was associated with a reduction in soluble VEGFR-2 levels after two cycles but an increase in plasma VEGF levels. CONCLUSION: The combination of vandetanib and bicalutamide was associated with considerable toxicity and did not have superior efficacy over bicalutamide alone. Further evaluation of this combination is not warranted in mCRPC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Anilidas/administração & dosagem , Anilidas/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Humanos , Masculino , Nitrilos/administração & dosagem , Nitrilos/efeitos adversos , Piperidinas/administração & dosagem , Antígeno Prostático Específico/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Quinazolinas/administração & dosagem , Compostos de Tosil/administração & dosagem , Compostos de Tosil/efeitos adversos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
18.
Can Urol Assoc J ; 8(11-12): 398-402, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25553152

RESUMO

INTRODUCTION: Pivotal phase III trials have positioned angiogenesis inhibitors as first-line therapy for the management of most advanced or metastatic renal cell carcinomas (mRCC). Approaches to second-line therapy, however, remain more controversial with respect to drug selection and drug sequencing. METHODS: In this study we evaluated mRCC patients who were initially treated on the first-line National Cancer Institute (NCI) trial with the highly potent vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI), cediranib, to determine the efficacy and tolerability of subsequent therapies. RESULTS: Twenty-eight (65.1%) of the 43 patients enrolled on the first-line cediranib trial were known to receive second-line therapy, most commonly sunitinib (n = 21), with 4 (14%), 2 (7%) and 1 (3%) patients receiving temsirolimus, sorafenib, and interleukin, respectively. Of these, 14 (50%) went on to have 3 or more lines of therapy. The progression-free survival (PFS) proportion (PFS) at 1 year from starting second line was 30% (14.5%-47.9%). Longer duration of first-line cediranib treatment was modestly associated with longer duration of second-line treatment (Spearman rho 0.26). Patients who discontinued cediranib for toxicity were less likely to receive second-line sunitinib. CONCLUSION: In this real world evaluation, sequential use of TKIs for the management of mRCC was common. PFS with sequential TKIs was similar to observed and published results for any second-line therapy. Prior toxicity affected treatment patterns and the frequent use of at least 3 lines of therapy underscores the need for prospective sequencing trials in this disease.

19.
Lancet Oncol ; 14(8): 769-76, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23706985

RESUMO

BACKGROUND: No standard treatment exists for patients with platinum-refractory urothelial cancer. Taxanes and vinflunine are commonly used, but response is less than 20% with no survival benefit. In this phase 2 study, we assessed efficacy and tolerability of nanoparticle albumin-bound (nab) paclitaxel in platinum-refractory urothelial cancer. METHODS: We did an open-label, single-group, two-stage study at five centres in Canada. We enrolled patients aged at least 18 years with histologically confirmed, locally advanced, or metastatic measurable urothelial cancer, with documented progression on or within 12 months of treatment with one previous platinum-containing regimen. Patients received nab-paclitaxel at 260 mg/m(2) intravenously every 3 weeks. Treatment continued until disease progression or occurrence of unacceptable toxic effects. The primary endpoint was objective tumour response, defined by a complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (version 1.0) criteria. Tumour response and safety were assessed in all patients who received at least one cycle of nab-paclitaxel. This study is registered with ClinicalTrials.gov, number NCT00683059. FINDINGS: We enrolled 48 patients between Oct 16, 2008, and June 23, 2010. Patients received a median of six cycles (range one to 15). 47 patients were evaluable; one (2·1%) had a CR and 12 (25·5%) had PRs, resulting in an overall response of 27·7% (95% CI 17·3-44·4). The most frequently recorded adverse events of any grade were fatigue (38 of 48; 79%), pain (37 of 48; 77%), alopecia (34 of 48; 71%), and neuropathy (30 of 48; 77%). The most frequently recorded adverse events of grade 3 or higher were pain (11 of 48; 23%), fatigue (five of 48; 23%), hypertension (three of 48; 6%), neuropathy (three of 48, 6%), and joint stiffness or pain (two of 48; 4%). INTERPRETATION: Nab-paclitaxel was well tolerated in this population of patients with pretreated advanced urothelial cancer with an encouraging tumour response. These results warrant further study of nab-paclitaxel in second-line treatment of urothelial cancer. FUNDING: Abraxis Bioscience, Celgene.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Carcinoma/tratamento farmacológico , Portadores de Fármacos/química , Neoplasias Renais/tratamento farmacológico , Nanopartículas , Paclitaxel/administração & dosagem , Neoplasias Ureterais/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Urotélio/efeitos dos fármacos , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Paclitaxel Ligado a Albumina , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Albuminas/química , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/química , Canadá , Carcinoma/secundário , Química Farmacêutica , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Paclitaxel/química , Modelos de Riscos Proporcionais , Fatores de Tempo , Resultado do Tratamento , Neoplasias Ureterais/patologia , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia
20.
Invest New Drugs ; 31(4): 1008-15, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23354849

RESUMO

BACKGROUND: Inhibition of angiogenesis has emerged as an effective therapeutic strategy in metastatic renal cell cancer (mRCC). In this single arm phase 2 study, we evaluated the efficacy and tolerability of cediranib (AZD2171) a potent angiogenesis inhibitor in first line mRCC. METHODS: Eligible patients who had no prior systemic therapy received cediranib 45 mg orally once daily continuously. The primary endpoint was objective response rate (ORR). Secondary endpoints were clinical benefit rate (ORR plus stable disease (SD) ≥ 4 months), duration of response, progression free survival (PFS), median overall survival (OS), safety and tolerability. RESULTS: Between January 2006 and April 2008, 44 patients were accrued. The median age was 62 (range 44-83) and performance status was either 0 (22 patients) or 1 (22 patients). Of the 39 evaluable patients there were 15 (38 %) partial responses (95 % CI: 23-55 %); 18 stable disease (SD) for a clinical benefit rate of 33/39 = 85 % (95 % CI: 69-94 %) and 6 progressive disease. Median PFS was 8.9 months (95 % CI: 5.1-12.9); and median OS was 28.6 months (95 % CI: 18.2-37.3 months). The most frequent grade 3 or higher AEs included hypertension, fatigue, hand-foot syndrome and diarrhea. CONCLUSIONS: Cediranib demonstrated significant anti-tumour activity in first line, treatment-naive mRCC, with efficacy parameters comparable to the other approved agents (sunitinib and pazopanib) in this setting. The main toxicities were fatigue, diarrhea and hypertension. Based on these encouraging results, further evaluation of cediranib in mRCC at a more tolerable dose of 30 mg daily appears warranted.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Progressão da Doença , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Quinazolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Carcinoma de Células Renais/patologia , Meios de Contraste , Demografia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento
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