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1.
Eur J Nucl Med Mol Imaging ; 44(8): 1319-1327, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28421240

RESUMO

BACKGROUND: Rhenium-188-HEDP is a beta-emitting radiopharmaceutical used for palliation of metastatic bone pain. We investigated whether the addition of rhenium-188-HEDP to docetaxel/prednisone improved efficacy of chemotherapy in patients with CRPC. METHODS: Patients with progressive CRPC and osteoblastic bone metastases were randomised for first-line docetaxel 75 mg/m2 3-weekly plus prednisone with or without 2 injections of rhenium-188-HEDP after the third (40 MBq/kg) and after the sixth (20 MBq/kg) cycle of docetaxel. Primary endpoint was progression-free survival (PFS), defined as either PSA, radiographic or clinical progression. Patients were stratified by extent of bone metastases and hospital. RESULTS: Forty-two patients were randomised for standard treatment and 46 patients for combination therapy. Median number of cycles of docetaxel was 9 in the control group and 8 in the experimental group. Median follow-up was 18.4 months. Two patients from the experimental group did not start treatment after randomisation. In the intention to treat analysis no differences in PFS, survival and PSA became apparent between the two groups. In an exploratory per-protocol analysis median overall survival was significantly longer in the experimental group (33.8 months (95%CI 31.75-35.85)) than in the control group (21.0 months (95%CI 13.61-28.39); p 0.012). Also median PFS in patients with a baseline phosphatase >220U/L was significantly better with combination treatment (9.0 months (95%CI 3.92-14.08) versus 6.2 months (95%CI 3.08-9.32); log rank p 0.005). As expected, thrombocytopenia (grade I/II) was reported more frequently in the experimental group (25% versus 0%). CONCLUSION: Combined treatment with rhenium-188-HEDP and docetaxel did not prolong PFS in patients with CRPC. The observed survival benefit in the per-protocol analysis warrants further studies in the combined treatment of chemotherapy and radiopharmaceuticals.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/secundário , Ácido Etidrônico/uso terapêutico , Compostos Organometálicos/uso terapêutico , Prednisona/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Taxoides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Docetaxel , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade
2.
Oncology ; 91(5): 267-273, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27544669

RESUMO

OBJECTIVE: To evaluate the efficacy of enzalutamide (Enz) as fourth- or fifth-line treatment in men with metastasized castration-resistant prostate cancer (mCRPC), by analyzing a retrospective cohort of heavily pretreated patients. METHODS: We evaluated toxicity, overall survival (OS), progression-free survival (PFS) and time to prostate-specific antigen (PSA) progression data from 47 CRPC patients treated with fourth- or fifth-line Enz. RESULTS: All patients were treated with docetaxel and abiraterone acetate and 42 patients (89%) with cabazitaxel. The median age of the patients was 69 years (IQR, 63-73.5), 79% had bone metastases, 55% had lymph node metastases, and 17% had visceral metastases. The median duration of Enz treatment was 12.0 weeks (IQR, 8.3-20.4), and 11 patients (23%) responded to Enz (maximum PSA decline ≥50%). In general, Enz was well tolerated, with the most frequently reported adverse events being fatigue and nausea. The median OS was 40.1 weeks (95% CI, 25.4-61.4), the median PFS was 12.1 weeks (95% CI, 9.9-14.0) and the median time to PSA progression was 15.7 weeks (95% CI, 14.0-28.7). CONCLUSIONS: Analysis of this retrospective cohort suggests that Enz is well tolerated and that there is a 23% response rate in heavily pretreated CRPC patients, which is comparable with third-line treatment outcomes.


Assuntos
Neoplasias Abdominais/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias Abdominais/secundário , Acetato de Abiraterona/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Benzamidas , Neoplasias Ósseas/secundário , Progressão da Doença , Intervalo Livre de Doença , Docetaxel , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Nitrilas , Feniltioidantoína/efeitos adversos , Feniltioidantoína/uso terapêutico , Radioisótopos/uso terapêutico , Rádio (Elemento)/uso terapêutico , Retratamento , Estudos Retrospectivos , Taxa de Sobrevida , Taxoides/uso terapêutico
3.
Cancer ; 120(7): 968-75, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24382803

RESUMO

BACKGROUND: Enzalutamide (Enz) and abiraterone acetate (AA) are hormone treatments that have a proven survival advantage in patients with metastatic, castration-resistant prostate cancer who previously received docetaxel (Doc). Recently, limited activity of AA after Enz and of Enz after AA was demonstrated in small cohort studies. Here, the authors present the activity and tolerability of Enz in patients who previously received AA and Doc in the largest cohort to date. METHODS: The efficacy and tolerability of Enz were investigated in men with progressive, metastatic, castrate-resistant prostate cancer who previously received Doc and AA. Toxicity, progression-free survival, time to prostate-specific antigen (PSA) progression, and overall survival were retrospectively evaluated. RESULTS: Sixty-one patients were included in the analysis. The median age was 69 years (interquartile range [IQR], 64-74 years), 57 patients (93%) had an Eastern Cooperative Oncology Group performance status from 0 to 2, 48 patients (79%) had bone metastases, 33 patients (54%) had lymph node metastases, and 13 patients (21%) had visceral metastases. The median duration of Enz treatment was 14.9 weeks (IQR, 11.1-20.0 weeks), and 13 patients (21%) had a maximum PSA decline ≥50%. The median progression-free survival was 12.0 weeks (95% confidence interval [CI], 11.1-16.0 weeks), the median time to PSA progression was 17.4 weeks (95% CI, >16.0 weeks), and the median overall survival was 31.6 weeks (95% CI, >28.7 weeks). Enz was well tolerated, and fatigue and musculoskeletal pain were the most frequent grade ≥2 adverse events. The PSA response to Doc and AA did not predict the PSA response to Enz. CONCLUSIONS: Enz has modest clinical activity in patients with metastatic, castrate-resistant prostate cancer who previously received Doc and AA. PSA response to Doc and AA does not predict for PSA response to ENz.


Assuntos
Antineoplásicos/uso terapêutico , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Androstenos , Androstenóis/uso terapêutico , Antineoplásicos/efeitos adversos , Benzamidas , Docetaxel , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas , Feniltioidantoína/efeitos adversos , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/patologia , Análise de Sobrevida , Taxoides/uso terapêutico , Resultado do Tratamento
4.
Lancet Oncol ; 13(5): 509-17, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22326922

RESUMO

BACKGROUND: The granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against prostate cancer; preclinical studies have shown potent synergy when combined with ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4. We aimed to assess the safety of combined treatment with GVAX and ipilimumab in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: We did an open-labelled, single-centre, dose-escalation study of ipilimumab concurrent with a fixed dose of GVAX, with a subsequent expansion phase, both at the VU University Medical Centre (Amsterdam, Netherlands). Eligible patients had documented mCRPC and had not been previously treated with chemotherapy. All patients received a 5×10(8) cell priming dose of GVAX intradermally on day 1 with subsequent intradermal injections of 3×10(8) cells every 2 weeks for 24 weeks. The vaccinations were combined with intravenous ipilimumab every 4 weeks. We enrolled patients in cohorts of three; each cohort received an escalating dose of ipilimumab at 0·3, 1·0, 3·0, or 5·0 mg/kg. Our primary endpoint was safety. This study is registered with ClinicalTrials.gov, number NCT01510288. FINDINGS: We enrolled 12 patients into our dose-escalation cohort. We did not record any severe immune-related adverse events at the first two dose levels. At the 3·0 mg/kg dose level, one patient had grade 2 and two patients grade 3 hypophysitis; at the 5·0 mg/kg dose level, two patients had grade 3 hypophysitis and one patient developed grade 4 sarcoid alveolitis (a dose-limiting toxic effect). Due to observed clinical activity and toxic events, we decided to expand the 3·0 mg/kg dose level, rather than enrol a further three patients at the 5·0 mg/kg level. 16 patients were enrolled in the expansion cohort, two of whom developed grade 2 hypophysitis, three colitis (one grade 1 and two grade 2), and one grade 3 hepatitis--all immune-related adverse events. The most common adverse events noted in all 28 patients were injection-site reactions (grade 1-2 events seen in all patients), fatigue (grade 1-2 in 20 patients, grade 3 in two), and pyrexia (grade 1-2 in 15 patients, grade 3 in one). 50% or greater declines in prostate-specific antigen from baseline was recorded in seven patients (25%); all had received 3·0 mg/kg or 5·0 mg/kg ipilimumab. INTERPRETATION: GVAX combined with 3·0 mg/kg ipilimumab is tolerable and safe for patients with mCRPC. Further research on the combined treatment of patients with mCRPC with vaccination and ipilimumab is warranted. FUNDING: Cell Genesys Inc, Prostate Cancer Foundation, Dutch Cancer Society (KWF-VU 2006-3697), and Foundation Stichting VUmc Cancer Center Amsterdam.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Neoplasias da Próstata/terapia , Adulto , Idoso , Terapia Combinada , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Imunoterapia , Ipilimumab , Masculino , Pessoa de Meia-Idade , Orquiectomia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/secundário , Transplante Homólogo , Células Tumorais Cultivadas
5.
Eur J Cancer ; 90: 1-9, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29268139

RESUMO

BACKGROUND: Docetaxel is standard first-line chemotherapy for patients with metastatic castration-resistant prostate carcinoma (mCRPC). Docetaxel re-challenge has never been tested in a prospective randomised controlled study. As some studies support the addition of carboplatin to docetaxel, we performed a phase II trial investigating the combination of docetaxel plus carboplatin versus docetaxel re-treatment in docetaxel pre-treated mCRPC patients. METHODS: Patients with mCRPC with a progression-free interval of ≥3 months after initial docetaxel treatment were randomised between docetaxel 75 mg/m2 or docetaxel 60 mg/m2 plus carboplatin AUC4. The primary end-point was progression-free survival (PFS; PSA/RECIST). RESULTS: Owing to insufficient recruitment, the study was discontinued early after inclusion of 75 patients (targeted 150) PFS and overall survival (OS) were comparable between both groups (median PFS 12.7 months (95% CI 9.9-17.5 months) with docetaxel monotherapy and 11.7 months (95% CI 8.5-21.0 months) with combination therapy (p = 0.98); OS 18.5 months (95% CI 11.8-24.5 months) versus 18.9 months (95% CI 16.0-23.7 months) (p = 0.79). An interim analysis (SEQTEST) showed that the null hypothesis could already be excepted, and no significant difference between both study arms was expected if inclusion would be completed. The incidence of grade 3-4 infections and gastrointestinal side-effects was numerical higher in the carboplatin arm (p = 0.056). CONCLUSION: This early terminated study suggests no benefit from the addition of carboplatin to docetaxel re-treatment in patients with mCRPC, whereas the combination resulted in more toxicity. Re-treatment with docetaxel monotherapy appears to be feasible, save and effective for patients with mCRPC and an initial good response to docetaxel. TRIAL REGISTRATION: NTR3070.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Carboplatina/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Taxoides/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/efeitos adversos , Intervalo Livre de Doença , Docetaxel , Término Precoce de Ensaios Clínicos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Taxoides/efeitos adversos
6.
Med Oncol ; 28(4): 1136-9, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20567941

RESUMO

Colorectal carcinomas are among the most common tumor types and are generally treated with palliative chemotherapy in case of metastatic disease. Here, we describe the case of a 58 year old woman with metastatic rectal carcinoma who developed severe gastrointestinal toxicity when the thus far well-tolerated intravenous 5-fluorouracil (5-FU)/leucovorin containing chemotherapeutic regimen was replaced by the same chemotherapeutic regimen in combination with the oral 5-FU prodrug capecitabine. This increased toxicity is probably due to the intracellular retention of polyglutamated folates induced by prior leucovorin therapy which, upon subsequent administration of capecitabine, will result in an enhanced and prolonged inhibition of the, for DNA synthesis important, enzyme thymidylate synthase, essentially creating a situation equivalent to overdosing.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antimetabólitos Antineoplásicos/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Íleus/induzido quimicamente , Adenocarcinoma/complicações , Adenocarcinoma/secundário , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Atorvastatina , Bisoprolol/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Capecitabina , Cólica/induzido quimicamente , Neoplasias Colorretais/complicações , Neoplasias Colorretais/patologia , Desoxicitidina/efeitos adversos , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Humanos , Hipercolesterolemia/complicações , Leucovorina/uso terapêutico , Metástase Linfática/patologia , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Pirróis/uso terapêutico , Complexos Ventriculares Prematuros/complicações , Complexos Ventriculares Prematuros/tratamento farmacológico , Vômito/induzido quimicamente
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