RESUMO
BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is a disease that primarily affects older men. Abiraterone acetate (AA), a selective androgen biosynthesis inhibitor, in combination with low-dose prednisone (P) improved overall survival (OS) in a randomised trial in mCRPC progressing after docetaxel versus placebo (PL) plus P. OBJECTIVE: To examine the efficacy and safety of AA plus P versus PL plus P in subgroups of elderly (aged ≥ 75 yr) (n=331) and younger patients (<75 yr) (n=863). DESIGN, SETTING, AND PARTICIPANTS: We conducted a post hoc analysis of a randomised double-blind PL-controlled study in mCRPC patients progressing after docetaxel chemotherapy. INTERVENTION: Patients were randomised 2:1 to AA (1000 mg) plus low-dose P (5mg twice daily) (n=797) or PL plus P (n=398). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary end point was OS. Secondary end points were time to prostate-specific antigen (PSA) progression (TTPP), radiographic progression-free survival (rPFS), and PSA response rate. Treatment differences were compared using the stratified log-rank test. The Cox proportional hazards model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI). The key limitation was the post hoc analysis. RESULTS AND LIMITATIONS: Elderly patients treated with AA plus P showed improved OS (HR: 0.64; 95% CI, 0.478-0.853; p=0.0022), TTPP (HR: 0.76; 95% CI, 0.503-1.155; p=0.1995), and rPFS (HR: 0.66; 95% CI, 0.506-0.859; p=0.0019), and higher PSA response rate with relative risk (HR: 4.15; 95% CI, 2.2-8.0]; p ≤ 0.0001) compared with patients treated with PL plus P. Grade 3/4 adverse events occurred in 62% of elderly patients and in 60% of patients aged <75 yr treated with AA plus P. Incidences of hypertension and hypokalaemia, although increased in the AA plus P arm, were similar in both age subgroups and readily managed. CONCLUSIONS: AA improves OS and is well tolerated in both elderly patients and younger patients with mCRPC following docetaxel, hence providing an important treatment option for elderly patients who may not tolerate alternative therapies with greater toxicity. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT00638690.
Assuntos
Androstadienos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Acetato de Abiraterona , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Androstadienos/efeitos adversos , Intervalo Livre de Doença , Docetaxel , Método Duplo-Cego , Fadiga/induzido quimicamente , Humanos , Hipertensão/induzido quimicamente , Hipopotassemia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Taxa de Sobrevida , Taxoides/uso terapêuticoRESUMO
PURPOSE: The objective of this trial was to evaluate the clinical effects of sorafenib, a multi-targeted kinase inhibitor, in combination with androgen receptor blockade in patients with castration-resistant prostate cancer. METHODS: This was a multicenter, two-stage, phase 2 trial. Eligible patients had rising PSA, minimal symptoms and were chemotherapy-naïve. Sorafenib 400 mg twice daily was administered with bicalutamide 50 mg once daily on a 28-day cycle. The primary endpoint was PSA response (≥ 50% decline) or stable disease ≥ 6 months. RESULTS: 39 patients were enrolled including eight without clinical evidence of metastases. Eighteen (47%) patients have had either a PSA response or stable disease ≥ 6 months. PSA declines of ≥ 50% occurred in 12 (32%) of 38 assessable patients, including seven of 27 patients (26%) with prior anti-androgen use. Median time to treatment failure was 5.5 months (95%CI = 4.8.1-8.3). Grade ≥ 3 adverse events included fatigue, skin rash, and hand-foot syndrome. CONCLUSIONS: PSA declines and stable disease were observed with a combination of sorafenib and bicalutamide including in patients previously progressing on bicalutamide. Strategies to combine multi-targeted kinase inhibitors with hormonal therapies warrant further study in patients with CRPC.
Assuntos
Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzenossulfonatos/uso terapêutico , Nitrilas/uso terapêutico , Orquiectomia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/cirurgia , Piridinas/uso terapêutico , Compostos de Tosil/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anilidas/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzenossulfonatos/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Nitrilas/efeitos adversos , Compostos de Fenilureia , Antígeno Prostático Específico/metabolismo , Piridinas/efeitos adversos , Sorafenibe , Fatores de Tempo , Compostos de Tosil/efeitos adversos , Falha de TratamentoRESUMO
An understanding of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways has greatly changed the way metastatic renal cell carcinoma (RCC) is treated. Based on available phase III randomized trials, anti-VEGF agents such as sunitinib, sorafenib, bevacizumab-based therapy, and mTOR-targeted agents such as temsirolimus and everolimus have been used in the treatment armamentarium for this disease. Now that agents directed against these pathways have largely replaced immunotherapy as the standard of care, new questions have emerged and are the subject of ongoing clinical trials. The development of new targeted therapies including axitinib, pazopanib, cediranib, volociximab, tivozanib (AV-951), BAY 73-4506, and c-met inhibitors such as GSK1363089 and ARQ197 may potentially expand the list of treatment options. Sequential and combination targeted therapies are currently under investigation in advanced disease as are adjuvant and neo-adjuvant approaches around nephrectomy.
RESUMO
PURPOSE: There are no robust data on prognostic factors for overall survival (OS) in patients with metastatic renal cell carcinoma (RCC) treated with vascular endothelial growth factor (VEGF) -targeted therapy. METHODS: Baseline characteristics and outcomes on 645 patients with anti-VEGF therapy-naïve metastatic RCC were collected from three US and four Canadian cancer centers. Cox proportional hazards regression, followed by bootstrap validation, was used to identify independent prognostic factors for OS. RESULTS: The median OS for the whole cohort was 22 months (95% CI, 20.2 to 26.5 months), and the median follow-up was 24.5 months. Overall, 396, 200, and 49 patients were treated with sunitinib, sorafenib, and bevacizumab, respectively. Four of the five adverse prognostic factors according to the Memorial Sloan-Kettering Cancer Center (MSKCC) were independent predictors of short survival: hemoglobin less than the lower limit of normal (P < .0001), corrected calcium greater than the upper limit of normal (ULN; P = .0006), Karnofsky performance status less than 80% (P < .0001), and time from diagnosis to treatment of less than 1 year (P = .01). In addition, neutrophils greater than the ULN (P < .0001) and platelets greater than the ULN (P = .01) were independent adverse prognostic factors. Patients were segregated into three risk categories: the favorable-risk group (no prognostic factors; n = 133), in which median OS (mOS) was not reached and 2-year OS (2y OS) was 75%; the intermediate-risk group (one or two prognostic factors; n = 301), in which mOS was 27 months and 2y OS was 53%; and the poor-risk group (three to six prognostic factors; n = 152), in which mOS was 8.8 months and 2y OS was 7% (log-rank P < .0001). The C-index was 0.73. CONCLUSION: This model validates components of the MSKCC model with the addition of platelet and neutrophil counts and can be incorporated into patient care and into clinical trials that use VEGF-targeted agents.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Neoplasias Renais/mortalidade , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Benzenossulfonatos/uso terapêutico , Bevacizumab , Feminino , Humanos , Indóis/uso terapêutico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Prognóstico , Piridinas/uso terapêutico , Pirróis/uso terapêutico , Sorafenibe , Sunitinibe , Taxa de SobrevidaRESUMO
BACKGROUND: Studies of cancer risk and molecular carcinogenesis suggest a role for inflammation in cancer development and progression. The authors sought to determine whether specific blood proteins associated with inflammation predict for outcomes in men with metastatic androgen-independent prostate cancer (AIPC) who are initiating docetaxel-based chemotherapy. METHODS: Baseline plasma samples were stored (-80 degrees C) from 160 of 250 patients enrolled in the AIPC Study of Calcitriol ENhancing Taxotere (ASCENT) trial, a randomized, placebo-controlled trial comparing weekly docetaxel plus high-dose calcitriol with weekly docetaxel. Multiplex immunoassays measured 16 cytokine, chemokine, cardiovascular, or inflammatory markers. The Cox proportional hazards model was used to assess associations between baseline biomarkers, clinical characteristics, and survival. Logistic regression was used for analyses of associations with prostate-specific antigen (PSA) decline. RESULTS: C-reactive protein (CRP) was found to be significantly predictive of a shorter overall survival (hazards ratio [HR] of 1.41 for each natural logarithm [ln] [CRP] increase; 95% confidence interval [95% CI], 1.20-1.65 [P < .0001]). When CRP (continuous) was entered into a multivariate model using 13 baseline clinical variables, only elevated CRP remained a significant predictor (P < .0001) of shorter overall survival. When categorized as normal (
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Proteína C-Reativa/metabolismo , Calcitriol/uso terapêutico , Agonistas dos Canais de Cálcio/uso terapêutico , Neoplasias Hormônio-Dependentes/sangue , Neoplasias da Próstata/sangue , Taxoides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Docetaxel , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias Hormônio-Dependentes/patologia , Placebos , Prognóstico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Taxa de SobrevidaRESUMO
BACKGROUND: Survival in patients with metastatic, chemotherapy-naive, androgen-independent prostate cancer (AIPC) is improved with 10 to 12 cycles of docetaxel-containing chemotherapy but further management is undefined. In the current study, the authors examined retreatment with the same regimen after a treatment holiday. METHODS: Patients treated with docetaxel at a dose of 36 mg/m(2) plus either high-dose calcitriol (DN-101; 45 mug) or placebo administered weekly for 3 of every 4 weeks could suspend treatment if their serum prostate-specific antigen (PSA) level was reduced >or=50% and reached a level
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Calcitriol/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Taxoides/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Docetaxel , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangueRESUMO
PURPOSE: To compare the safety and activity of DN-101, a new high-dose oral formulation of calcitriol designed for cancer therapy, and docetaxel with placebo and docetaxel. PATIENTS AND METHODS: Patients with progressive metastatic androgen-independent prostate cancer and adequate organ function received weekly docetaxel 36 mg/m2 intravenously for 3 weeks of a 4-week cycle combined with either 45 microg DN-101 or placebo taken orally 1 day before docetaxel. The primary end point was prostate-specific antigen (PSA) response within 6 months of enrollment, defined as a 50% reduction confirmed at least 4 weeks later. RESULTS: Two hundred fifty patients were randomly assigned. Baseline characteristics were similar in both arms. Within 6 months, PSA responses were seen in 58% in DN-101 patients and 49% in placebo patients (P = .16). Overall, PSA response rates were 63% (DN-101) and 52% (placebo), P = .07. Patients in the DN-101 group had a hazard ratio for death of 0.67 (P = .04) in a multivariate analysis that included baseline hemoglobin and performance status. Median survival has not been reached for the DN-101 arm and is estimated to be 24.5 months using the hazard ratio, compared with 16.4 months for placebo. Grade 3/4 adverse events occurred in 58% of DN-101 patients and in 70% of placebo-treated patients (P = .07). Most common grade 3/4 toxicities for DN-101 versus placebo were neutropenia (10% v 8%), fatigue (8% v 16%), infection (8% v 13%), and hyperglycemia (6% v 12%). CONCLUSION: This study suggests that DN-101 treatment was associated with improved survival, but this will require confirmation because survival was not a primary end point. The addition of weekly DN-101 did not increase the toxicity of weekly docetaxel.
Assuntos
Androgênios/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Calcitriol/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/mortalidade , Taxoides/administração & dosagem , Fatores Etários , Idoso , Biópsia por Agulha , Calcitriol/efeitos adversos , Docetaxel , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Placebos/administração & dosagem , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia , Medição de Risco , Taxa de Sobrevida , Taxoides/efeitos adversos , Resultado do TratamentoRESUMO
The incidence of venous and arterial thrombosis in a placebo-controlled randomised trial of DN-101 (high dose calcitriol) with docetaxel versus docetaxel was compared. Of the 13 thrombotic events observed in the 250 patients enroled in this study, two occurred in DN-101 and 11 in placebo-treated patients (P = 0.01). This difference remained significant after adjustment for baseline history of thrombosis, atrial fibrillation and use of anti-thrombotic agents. In vitro and vitamin D receptor (VDR) knockout mouse studies predict that nanomolar concentrations of calcitriol may act as an antithrombotic agent. We report the first clinical observation that supports this hypothesis in humans.