RESUMO
BACKGROUND: We have shown previously in multivariable analysis that black men had 19% lower risk of death than white men with metastatic castration-resistant prostate cancer (mCRPC) treated with a docetaxel and prednisone (DP)-based regimen. The primary goal of this analysis was to compare progression-free survival (PFS), biochemical PFS, ≥50% decline in prostate-specific antigen (PSA) from baseline and objective response rate (ORR) in white, black and Asian men with mCRPC treated with a DP-based regimen. PATIENTS AND METHODS: Individual patient data from 8820 mCRPC men randomized on nine phase III trials to a DP-containing regimen were combined. Race used in the analysis was based on self-report. End points were PFS, biochemical PSA, ≥50% decline in PSA from baseline and ORR. The proportional hazards and the logistic regression models were employed to assess the prognostic importance of race in predicting outcomes adjusting for established prognostic factors. RESULTS: Of 8820 patients, 7528 (85%) were white, 500 (6%) were black, 424 were Asian (5%) and 368 (4%) had race unspecified. Median PFS were 8.3 [95% confidence interval (CI) 8.2-8.5], 8.2 (95% CI 7.4-8.8) and 8.3 (95% CI 7.6-8.8) months in white, black and Asian men, respectively. Median PSA PFS were 9.9 (95% CI 9.7-10.4), 8.5 (95% CI 8.0-10.3) and 11.1 (95% CI 9.9-12.5) months in white, black and Asian men, respectively. CONCLUSIONS: We observed no differences in clinical outcomes by race and ethnic groups in men with mCRPC enrolled on these phase III clinical trials with DP.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Docetaxel/uso terapêutico , Etnicidade , Humanos , Masculino , Prednisona/uso terapêutico , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE: Prostate specific antigen has limited performance in detecting prostate cancer. The transcription factor GATA2 is expressed in aggressive prostate cancer. We analyzed the predictive value of urine extracellular vesicle GATA2 mRNA alone and in combination with a multigene panel to improve detection of prostate cancer and high risk disease. MATERIALS AND METHODS: GATA2 mRNA was analyzed in matched extracellular vesicles isolated from urines before and after prostatectomy (16) and paired urine and tissue prostatectomy samples (19). Extracellular vesicle GATA2 mRNA performance to distinguish prostate cancer and high grade disease was tested in training (52) and validation (165) cohorts. The predictive value of a multigene score including GATA2, PCA3 and TMPRSS2-ERG (GAPT-E) was tested in both cohorts. RESULTS: Confirming its prostate origin, urine extracellular vesicle GATA2 mRNA levels decreased significantly after prostatectomy and correlated with prostate cancer tissue GATA2 mRNA levels. In the training and validation cohort GATA2 discriminated prostate cancer (AUC 0.74 and 0.66) and high grade disease (AUC 0.78 and 0.65), respectively. Notably, the GAPT-E score improved discrimination of prostate cancer (AUC 0.84 and 0.72) and high grade cancer (AUC 0.85 and 0.71) in both cohorts when compared with each biomarker alone and PT-E (PCA3 and TMPRSS2-ERG). A GAPT-E score for high grade prostate cancer would avoid 92.1% of unnecessary prostate biopsies, compared to 61.9% when a PT-E score is used. CONCLUSIONS: Urine extracellular vesicle GATA2 mRNA analysis improves the detection of high risk prostate cancer and may reduce the number of unnecessary biopsies.
Assuntos
Vesículas Extracelulares/química , Fator de Transcrição GATA2/genética , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , RNA Mensageiro/análise , Idoso , Idoso de 80 Anos ou mais , Biópsia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Whole virion inactivated vaccine CoronaVac (C) and Spike (S) mRNA BNT162b2 (B) vaccines differ greatly in their ability to elicit neutralizing antibodies but have somewhat comparable effectiveness in protecting from severe COVID-19. We conducted further analyses for a randomized trial (Cobovax study, NCT05057169) of third dose homologous and heterologous booster vaccination, i.e. four interventions CC-C, CC-B, BB-C and BB-B. Here, we assess vaccine immunogenicity beyond neutralizing function, including S and non-S antibodies with Fc receptor (FcR) binding, antibody avidity and T cell specificity to 6 months post-vaccination. Ancestral and Omicron S-specific IgG and FcR binding are significantly higher by BNT162b2 booster than CoronaVac, regardless of first doses. Nucleocapsid (N) antibodies are only increased in homologous boosted CoronaVac participants (CC-C). CoronaVac primed participants have lower baseline S-specific CD4+ IFNγ+ cells, but are significantly increased by either CoronaVac or BNT162b2 boosters. Priming vaccine content defined T cell peptide specificity preference, with S-specific T cells dominating B primed groups and non-S structural peptides contributing more in C primed groups, regardless of booster type. S-specific CD4+ T cell responses, N-specific antibodies, and antibody effector functions via Fc receptor binding may contribute to protection and compensate for less potent neutralizing responses in CoronaVac recipients.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Vacina BNT162 , Vacinas contra COVID-19 , COVID-19 , Receptores Fc , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Vacinas de Produtos Inativados , Vacinas de mRNA , Humanos , SARS-CoV-2/imunologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , COVID-19/imunologia , Receptores Fc/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Neutralizantes/imunologia , Vacina BNT162/imunologia , Vacina BNT162/administração & dosagem , Vacinas de Produtos Inativados/imunologia , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de mRNA/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Feminino , Imunização Secundária , Imunogenicidade da Vacina , Adulto , Linfócitos T/imunologia , Masculino , Imunoglobulina G/imunologia , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Activation of the c-Met pathway occurs in a range of malignancies, including papillary renal cell carcinoma (RCC). Its activity in clear cell RCC is less clear. We investigated c-Met expression and inhibition in a large cohort of RCC tumors and cell lines. METHODS: c-Met protein expression was determined by automated quantitative analysis (AQUA) on a tissue microarray (TMA) constructed from 330 RCC tumors paired with adjacent normal renal tissue. c-Met expression and selective inhibition with SU11274 and ARQ 197 were studied in clear cell RCC cell lines. RESULTS: Higher c-Met expression was detected in all RCC subtypes than in the adjacent normal renal tissue (P < 0.0001). Expression was highest in papillary and sarcomatoid subtypes, and high-grade and stage tumors. Higher c-Met expression correlated with worse disease-specific survival [risk ratio = 1.36; 95% confidence interval (CI) 1.08-1.74; P = 0.0091] and was an independent predictor of survival, maintained in clear cell subset analyses. c-Met protein was activated in all cell lines, and proliferation (and colony formation) was blocked by SU11274 and ARQ 197. CONCLUSIONS: c-Met is associated with poor pathologic features and prognosis in RCC. c-Met inhibition demonstrates in vitro activity against clear cell RCC. Further study of ARQ 197 with appropriate biomarker studies in RCC is warranted.
Assuntos
Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Fator de Crescimento de Hepatócito/antagonistas & inibidores , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Indóis/farmacologia , Neoplasias Renais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Piperazinas/farmacologia , Prognóstico , Pirrolidinonas/farmacologia , Pirrolidinonas/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Sulfonamidas/farmacologia , Análise Serial de TecidosRESUMO
Together, histone acetyltransferases and histone deacetylases (HDACs) determine the acetylation status of histones. This acetylation affects the regulation of gene expression, and inhibitors of HDACs have been found to cause growth arrest, differentiation and/or apoptosis of many tumours cells by altering the transcription of a small number of genes. HDAC inhibitors are proving to be an exciting therapeutic approach to cancer, but how do they exert this effect?
Assuntos
Histona Desacetilases/fisiologia , Proteínas de Neoplasias/fisiologia , Neoplasias/enzimologia , Acetilação/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Cromatina/enzimologia , Cromatina/ultraestrutura , Ensaios Clínicos como Assunto , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/classificação , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Previsões , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Inativação Gênica/efeitos dos fármacos , Inativação Gênica/fisiologia , Inibidores de Histona Desacetilases , Histonas/metabolismo , Humanos , Masculino , Modelos Moleculares , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/enzimologia , Nucleossomos/enzimologia , Nucleossomos/ultraestrutura , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/fisiologia , Saccharomyces cerevisiae/enzimologia , Proteínas de Saccharomyces cerevisiae/fisiologia , Especificidade da Espécie , Fatores de Transcrição/fisiologia , Ativação Transcricional/efeitos dos fármacosRESUMO
BACKGROUND: Docetaxel is associated with prolonged survival in castration-resistant prostate cancer (CRPC). Platinum compounds have modest but distinct single-agent activity. Carboplatin may have greatest potential for benefit when combined with taxanes. We investigated whether there is a subset of patients with CRPC for whom the efficacy of combination taxane-estramustine-carboplatin (TEC) chemotherapy may be greatest. PATIENTS AND METHODS: Individual patient data (n = 310) were obtained from seven trials using TEC chemotherapy. Prostate-specific antigen (PSA) response was defined as > or = 50% post-therapy decline from baseline. Overall survival was defined from baseline to death from any cause. Logistic and Cox regression were used to investigate heterogeneity in outcome to TEC by patient and disease characteristics. Predicted survival probabilities were calculated from the Halabi Cancer and Leukemia Group B (CALGB) nomogram. RESULTS: The pooled PSA response proportion was 69% [95% confidence interval (CI) 56% to 80%]. There was no evidence of differential PSA response by disease characteristics. Established prognostic factors were associated with survival. The pooled 12-month survival estimate of 79% (95% CI 71% to 84%) was higher than the median 59% 12-month nomogram-predicted survival. CONCLUSIONS: TEC chemotherapy has significant clinical activity in CRPC. A randomized, controlled trial evaluating the addition of carboplatin to taxane-based chemotherapy is needed to elucidate the value of carboplatin in CRPC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Carboplatina/administração & dosagem , Castração , Neoplasias da Próstata/tratamento farmacológico , Taxoides/administração & dosagem , Idoso , Ensaios Clínicos como Assunto/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/cirurgia , Falha de Tratamento , Resultado do TratamentoRESUMO
A re-examination of the methods of developing new treatments for patients with prostate cancer whose disease has progressed during hormone therapy is necessitated by the following: 1) the impact of prostate-specific antigen (PSA) testing on patient selection, 2) the increasing number of studies using noncytotoxic approaches, and 3) the lack of validated methods to report outcomes. PSA monitoring after primary therapy has increased the number of patients referred for therapy with a rising value in this marker or an asymptomatic change in a radionuclide bone scan as the only manifestation(s) of relapse. The development of drugs for this population of patients presents a unique challenge because the classical criterion used to assess efficacy in the phase II setting, i.e., the presence of objective changes in measurable disease sites, frequently does not apply. Since no approach has been proven to prolong survival, the highest priority must be placed on developing new therapies. Standardizing the methods for evaluating treatments is also essential so that promising strategies are pursued and inactive therapies are not developed further.
Assuntos
Ensaios Clínicos como Assunto , Recidiva Local de Neoplasia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Biomarcadores Tumorais/sangue , Humanos , Masculino , Neoplasias Hormônio-Dependentes/patologia , Neoplasias Hormônio-Dependentes/terapia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/imunologia , Qualidade de Vida , Resultado do TratamentoRESUMO
PURPOSE: To evaluate the effect of discontinuation of the antiandrogen, flutamide, in patients with metastatic prostate cancer who are progressing on hormonal therapy. PATIENTS AND METHODS: Thirty-six patients with progressive disease on hormonal treatment that included flutamide had discontinuation of the antiandrogen. Thirty-five (95%) had progressive increases in prostate-specific antigen (PSA) levels, despite castrate levels of testosterone. Twenty-five patients (69%) were treated with combined androgen blockade (orchiectomy or gonadotropin-releasing hormone [GnRH] analog plus flutamide) as initial therapy and 11 (31%) were started on monotherapy alone. Patients who had not undergone a previous orchiectomy were continued on the GnRH analog. Patients were monitored clinically and with serial PSA measurements, radionuclide scans, and radiographs as indicated to assess response. RESULTS: Considering the 35 patients with increasing PSA values, 10 (29%) showed a significant decline (> or = 80% in seven, and > or = 50% in three) in PSA from baseline. All 10 had received combined androgen blockade as initial therapy. The duration of decline was short (median, 5+ months; range, 2 to 10+), but was associated with improvement in clinical symptoms, while one patient had a partial response in an epidural mass with parallel decline in PSA. None of the patients started on single hormone therapies responded. CONCLUSION: Discontinuation of flutamide was associated with a significant decrease in PSA values in 10 of 25 patients (40%; 95% confidence interval, 21% to 59%) and clinical improvement in a subset of patients who had an initial response, but later progressive disease on combined androgen blockade. A trial of flutamide withdrawal should be considered in patients progressing on total androgen blockade before the initiation of more toxic therapies. It is likely that flutamide withdrawal has contributed to the observed responses in phase II trials of both second-line hormonal therapies and new cytotoxic agents. Future phase II trials in hormone-refractory prostatic cancer must control for this observation, and insure that progression off flutamide is documented before initiation of alternative treatment.
Assuntos
Flutamida/efeitos adversos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/tratamento farmacológico , Síndrome de Abstinência a Substâncias/sangue , Idoso , Terapia Combinada , Flutamida/administração & dosagem , Flutamida/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Síndrome de Abstinência a Substâncias/etiologiaRESUMO
PURPOSE: To evaluate the prognostic significance of pretreatment parameters and posttherapy declines in prostate-specific antigen (PSA) in relation to the survival of patients with hormone-refractory prostate cancer. PATIENTS AND METHODS: One hundred ten assessable patients treated on seven sequential protocols at Memorial Sloan-Kettering Cancer Center (MSKCC) for hormone-refractory prostate cancer were evaluated for 29 different pretherapy and posttherapy parameters, including a posttherapy decline in PSA of 50% and 80% from baseline. RESULTS: In the univariate analysis, initial Karnofsky performance status (KPS) > or = 80% was associated with a favorable outcome (P = .005), while age, extent of disease on bone scan, and individual sites of metastatic disease were not significant. No difference in survival was observed between patients with measurable or assessable (bone only) disease. Initial hemoglobin (HGB; P = .0012), alkaline phosphatase (ALK; P = .0015), and lactate dehydrogenase (LDH; P = .0002) levels were significant discriminators, while the initial PSA was not. Using a landmark analysis, a significantly longer median survival rate was observed for patients with a > or = 50% decline in PSA (median not reached) versus patients with a less than 50% decline in PSA (median, 8.6 months; P = .0001). Multivariate analysis using the Cox proportional hazards model showed that a > or = 50% decline in PSA (P = .0004) and the natural log of LDH (P = .0001) were the two most significant variables predicting survival. The model was confirmed on an independent data set from the Norwegian Radium Hospital (NRH) in Oslo, Norway. CONCLUSION: The results suggest that posttherapy PSA declines can be used as a surrogate end point to evaluate new agents in hormone-refractory prostate cancer. The criteria for response need prospective validation in phase III trials.
Assuntos
Antígeno Prostático Específico/análise , Neoplasias da Próstata/terapia , Idoso , Idoso de 80 Anos ou mais , Dietilestilbestrol/uso terapêutico , Flutamida/uso terapêutico , Hormônios/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Orquiectomia , Prognóstico , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Taxa de SobrevidaRESUMO
PURPOSE: To assess efficacy of intermittent infusion of suramin in patients with androgen-independent prostate cancer who have had disease progression on hydrocortisone. PATIENTS AND METHODS: Chemotherapy-naive patients with progressive androgen-independent prostate cancer were given hydrocortisone 40 mg/d and monitored for treatment effect. At the time of disease progression, suramin was administered on a pharmacokinetically derived, 2-week dosing schedule. RESULTS: Thirty patients with a median Karnofsky performance status (KPS) of 90% were treated with hydrocortisone. No responses were seen in 12 patients with measurable disease or 29 patients with abnormal bone scans. Thirty patients had an increasing prostate-specific antigen (PSA) level before treatment and six (20%) had a more than 50% decline in PSA from the baseline value for a median of 16 weeks (range, 12 to 52+). Twenty-eight patients had disease progression after a median of 7 weeks (range, 3 to 23), and two patients have continued to receive hydrocortisone for 44 and 52 weeks. Twenty-eight patients received hydrocortisone and suramin, with median suramin concentrations of 97 to 170 micrograms/mL for 4 weeks. No responses in measurable disease and no improvements in bone scans were seen. Five patients (18%) showed a more than 50% decline in PSA levels from baseline, of whom three had previously responded to hydrocortisone. Only two of 24 patients who did not show a posttherapy decline in PSA levels after hydrocortisone had a reduction in PSA levels with the addition of suramin. Toxicity profiles were acceptable with each agent, although a higher proportion of subjects showed hematologic, cardiac, and neurologic events when suramin was added. CONCLUSION: Suramin has limited efficacy in patients with androgen-independent prostate cancer who have had disease progression after hydrocortisone.
Assuntos
Hidrocortisona/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Suramina/administração & dosagem , Testosterona/metabolismo , Idoso , Esquema de Medicação , Quimioterapia Combinada , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , Indução de Remissão , Suramina/farmacocinéticaRESUMO
PURPOSE: PC-SPES is an herbal supplement for which there are anecdotal reports of anti-prostate cancer activity. This phase II study was undertaken to assess the efficacy and toxicity of PC-SPES in prostate cancer patients. PATIENTS AND METHODS: Thirty-three patients with androgen-dependent prostate cancer (ADPCa) and 37 patients with androgen-independent prostate cancer (AIPCa) were treated with PC-SPES at a dose of nine capsules daily. Clinical outcome was assessed with serial serum prostate-specific androgen (PSA) level measurement and imaging studies. RESULTS: One hundred percent of ADPCa patients experienced a PSA decline of >/= 80%, with a median duration of 57+ weeks. No patient has developed PSA progression. Thirty-one patients (97%) had declines of testosterone to the anorchid range. Two ADPCa patients had positive bone scans; both improved. One patient with a bladder mass measurable on computed tomography scan experienced disappearance of this mass. Nineteen (54%) of 35 AIPCa patients had a PSA decline of >/= 50%, including eight (50%) of 16 patients who had received prior ketoconazole therapy. Median time to PSA progression was 16 weeks (range, 2 to 69+ weeks). Of 25 patients with positive bone scans, two had improvement, seven had stable disease, 11 had progressive disease, and five did not have a repeat bone scan because of PSA progression. Severe toxicities included thromboembolic events (n = 3) and allergic reactions (n = 3). Other frequent toxicities included gynecomastia/gynecodynia, leg cramps, and grade 1 or 2 diarrhea. CONCLUSION: PC-SPES seems to have activity in the treatment of both ADPCa and AIPCa and has acceptable toxicity. Further study is required to determine whether its effects exceed those expected with estrogen therapy.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Extratos Vegetais/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Adenocarcinoma/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Androgênios/fisiologia , Antineoplásicos Fitogênicos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Hormônio-Dependentes/sangue , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Extratos Vegetais/efeitos adversos , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Testosterona/sangueRESUMO
PURPOSE: To determine the therapeutic effects of bicalutamide 200 mg in patients with prostate cancers of different hormone sensitivities. METHODS: Patients with progressive prostate cancer were treated with bicalutamide 200 mg daily. Before treatment, patients' tumors were classified on the basis of prior hormone exposure and by serum testosterone levels into androgen-dependent and androgen-independent groups. Prior exposure to flutamide and response to flutamide withdrawal was also considered. Outcomes were reported independently on the basis of posttherapy changes in prostate-specific antigen (PSA), measurable disease, and radionuclide bone scans. RESULTS: Outcomes varied by prior hormone exposure as a higher proportion of patients with progression of androgen-dependent tumors showed posttherapy PSA decreases of more than 50% or more than 80%, measurable disease regression, and improvement on radionuclide bone scans than did patients with androgen-independent progression. Within the category of androgen-independent progression, clinical benefit was observed in patients who had previously progressed on flutamide, independent of the response to flutamide withdrawal. Patients who had progressed on a gonadotropin-releasing hormone (GnRH) analog alone had a low response proportion, whereas those who progressed after two or more hormone therapies did not respond. Overall, the drug was well tolerated. After progression on bicalutamide monotherapy, one third of patients with androgen-dependent progression responded to medical castration with a GnRH analog. CONCLUSION: Classifying patient tumors on the basis of prior hormone exposure permits a more precise estimate of the potential benefit of a specific hormone therapy for the individual patient. The precision is further increased by reporting the effects of a drug on each parameter of disease independently. The difference in outcomes for patients with androgen-independent progression suggests that the specific hormone therapy administered and the response to that therapy can influence the biology of the relapsing tumor and the sensitivity to subsequent therapies. The sensitivity to bicalutamide after progression on flutamide deserves further study.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Androgênios , Anilidas/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/efeitos adversos , Anilidas/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Neoplasias Ósseas/secundário , Osso e Ossos/diagnóstico por imagem , Progressão da Doença , Flutamida/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas , Antígeno Prostático Específico/análise , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Cintilografia , Compostos de TosilRESUMO
PURPOSE: A phase II randomized trial of gallium nitrate/fluorouracil (5-FU) versus dose-intense methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) was performed in poor-risk patients with advanced urothelial tract tumors. The efficacy and toxicity of these regimens were compared. Assessment of dose-intense M-VAC as salvage treatment in patients who failed to respond to the gallium nitrate/5-FU regimen was also performed. PATIENTS AND METHODS: Thirty-four patients who had not received prior systemic chemotherapy were randomized to either arm of the study. All patients had one or more clinical features predicting a low likelihood of durable complete response to standard chemotherapy, ie, weight loss, visceral metastases, and low performance status. Gallium nitrate and 5-FU were each administered by continuous 5-day infusions every 28 days. M-VAC was recycled every 21 days, with prophylactic recombinant human granulocyte colony-stimulating factor (rh-G-CSF). RESULTS: Two of 17 patients (12%; 95% confidence interval [CI], 1.4% to 36.4%) had a major response to gallium nitrate/5-FU. Sixteen of 17 patients treated with M-VAC (94%; 95% CI, 71.3% to 99.8%) demonstrated a major response. Five of 12 patients who failed to respond to the gallium nitrate/5-FU combination responded to M-VAC as second-line therapy (42%; 95% CI, 15.2% to 72.3%). Median survival for the gallium nitrate and 5-FU arm was 19 versus 17 months for the M-VAC arm, with a median follow-up duration of 35 months (range, 2 to 51) for all patients. Dose-intense M-VAC was associated with a greater incidence of neutropenia and thrombocytopenia. CONCLUSION: Dose-intense M-VAC is superior to gallium nitrate/5-FU in poor-risk patients (P < .0001). Despite the overall high response rate, the median survival for patients with M-VAC remained unsatisfactory. Similar survival distributions were observed for patients who received investigational therapy followed by cisplatin-based therapy and patients treated with initial cisplatin-based therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Fluoruracila/administração & dosagem , Gálio/administração & dosagem , Neoplasias Urológicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Fluoruracila/efeitos adversos , Gálio/efeitos adversos , Humanos , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/efeitos adversosRESUMO
PURPOSE: A phase II trial of docetaxel was conducted to assess its efficacy and toxicity in patients with advanced transitional-cell carcinoma (TCC) who had failed to respond to prior cisplatin-based therapy. PATIENTS AND METHODS: Thirty assessable patients who had failed to respond to or relapsed after one prior cisplatin-containing regimen were treated with docetaxel 100 mg/m2 over 1 hour, every 21 days. All patients were premedicated with dexamethasone and diphenhydramine to reduce allergic reactions. Reductions of subsequent doses were made for severe hematologic toxicity. Prophylactic hematopoietic growth factors were not used. RESULTS: Four of 30 patients (13.3%; 95% confidence interval [CI], 3.8% to 30.7%) demonstrated a partial response (PR), with durations of response ranging from 3 to 8 months. The estimated median survival duration for all patients is 9 months (95% CI, 6 to 12 months) with a median follow-up time of 14 months (range, 1 to 27). Hematologic toxicity included anemia, thrombocytopenia, neutropenia, and febrile neutropenia. Nonhematologic toxicity included alopecia and mucositis. Fluid retention was not observed and cutaneous toxicity was mild and infrequent. Dose reductions were necessary for adverse events in 18 patients (60%). CONCLUSION: Docetaxel is an active single agent in previously treated patients with TCC of the urothelial tract. Therapy was well tolerated in this patient population but myelosuppression was frequent. Further study in previously untreated patients, both alone and in combination, is warranted.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Paclitaxel/análogos & derivados , Taxoides , Neoplasias Urológicas/tratamento farmacológico , Adulto , Idoso , Antineoplásicos Fitogênicos/efeitos adversos , Docetaxel , Hipersensibilidade a Drogas/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Indução de Remissão , Análise de SobrevidaRESUMO
PURPOSE: This phase I trial sought to evaluate the toxicity of and determine the maximum-tolerated dose (MTD) for the two-drug regimen doxorubicin and gemcitabine (AG) followed by the three-drug regimen of ifosfamide, paclitaxel, and cisplatin (ITP) in patients with unresectable or metastatic transitional-cell carcinoma. PATIENTS AND METHODS: Patients received AG every other week for six cycles followed by ITP every 3 weeks for four cycles. Five AG dose levels were investigated, up to doxorubicin 50 mg/m(2) and gemcitabine 2, 000 mg/m(2), to determine the MTD of the regimen. The dose and schedule of ITP were constant: ifosfamide 1,500 mg/m(2) (days 1 to 3); paclitaxel 200 mg/m(2) (day 1); and cisplatin 70 mg/m(2) (day 1). Granulocyte colony-stimulating factor was given between all cycles of therapy. RESULTS: Fifteen patients enrolled onto this phase I trial. AG was well tolerated at all dose levels, with no grade 3 or 4 myelosuppression. Toxicity experienced with ITP included grade 3 and 4 granulocytopenia in four patients and grade 3 nausea/vomiting in three patients. No grade 3 and 4 neurotoxicity was observed. Eight of 14 assessable patients experienced a major response to AG, including five of six patients treated at the two highest AG dose levels. After completion of AG-ITP, nine of 14 assessable patients had a major response (three complete responses and six partial responses). CONCLUSION: AG is a well-tolerated and active regimen. Sequential chemotherapy with AG-ITP is also well tolerated, and phase II investigation at the highest dose level is ongoing.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Cisplatino/administração & dosagem , Desoxicitidina/análogos & derivados , Doxorrubicina/administração & dosagem , Ifosfamida/administração & dosagem , Paclitaxel/administração & dosagem , Neoplasias Urológicas/tratamento farmacológico , Idoso , Agranulocitose/induzido quimicamente , Antibióticos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Fitogênicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Células da Medula Óssea/efeitos dos fármacos , Carcinoma de Células de Transição/secundário , Cisplatino/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Doxorrubicina/efeitos adversos , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Ifosfamida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Paclitaxel/efeitos adversos , Indução de Remissão , Vômito/induzido quimicamente , GencitabinaRESUMO
PURPOSE: To assess the feasibility and tolerance of neoadjuvant and concomitant estramustine phosphate and vinblastine (EV) with high-dose three-dimensional conformal radiotherapy (3D-CRT) for patients with unfavorable-risk prostate cancer. PATIENTS AND METHODS: Twenty-seven patients with unfavorable-risk prostate cancer were enrolled onto a prospective study to determine the feasibility of combining EV with 3D-CRT. Patients were eligible if any of the following requirements were satisfied: (1) Gleason score > or =8 and prostate-specific antigen (PSA) > 10 ng/mL; (2) Gleason score of 7 and PSA > 20 ng/mL; (3) clinical stage T3N0M0 disease with PSA > 20 ng/mL; (4) any patient with T4N0M0 disease; or (5) patients with TXN1MO disease. Therapy consisted of three 8-week cycles of EV and 8 weeks of 3D-CRT. Estramustine phosphate was given orally beginning on week 1 and continued until the completion of 3D-CRT. Each 8-week cycle of vinblastine consisted of 6 weekly intravenous injections followed by a 2-week rest period. Radiation therapy was administered using a three-dimensional conformal approach to a prescription dose of 75.6 Gy. The median follow-up was 26 months (range, 6 to 40 months). RESULTS: Twenty-three (85%) of 27 patients completed the entire course of therapy and were assessable for toxicities and biochemical outcome. Two patients (7%) developed grade 3 hematologic toxicity that resolved, and two patients (7%) developed grade 3 hepatoxicity, manifesting as persistent elevation of serum transaminase levels, necessitating discontinuation of the chemotherapy and withdrawal from the treatment program. The most prominent adverse effects from this regimen were mild to moderate (grade 1 to 2) nausea and fatigue related to estramustine. Mild peripheral edema was seen in 15% of patients and was treated with diuresis. 3D-CRT was tolerated well in these patients. Medications were required for relief of acute grade 2 rectal (gastrointestinal [GI]) and urinary (genitourinary [GU]) symptoms in 35% and 48% of patients, respectively. Three patients developed acute grade 3 GU toxicities. The 2-year actuarial likelihood of late grade 2 GI toxicity was 20%. No late grade 3 or 4 GI toxicities were observed. The 2-year actuarial likelihoods of late grade 2 and 3 GU toxicities were 25% and 12%, respectively. No grade 4 GU toxicity was observed. CONCLUSION: Neoadjuvant and concomitant EV with high-dose 3D-CRT is well tolerated in patients with unfavorable-risk prostate cancer. Although the incidence of modest (grade 2) late GI and GU toxicities seem to be increased compared with 3D-CRT alone or in combination with androgen ablation therapy, no severe toxicities were encountered with this regimen.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Radioterapia Conformacional , Administração Oral , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Estramustina/administração & dosagem , Etoposídeo/administração & dosagem , Gastroenteropatias/induzido quimicamente , Humanos , Injeções Intravenosas , Masculino , Doenças Urogenitais Masculinas/induzido quimicamente , Terapia Neoadjuvante , Estudos Prospectivos , Antígeno Prostático Específico/análise , Neoplasias da Próstata/patologia , Dosagem Radioterapêutica , Radioterapia Conformacional/efeitos adversos , Fatores de Risco , Resultado do Tratamento , Vimblastina/administração & dosagem , Vindesina/administração & dosagemRESUMO
PURPOSE: To determine the frequency with which prostate-specific antigen (PSA)-positive cells can be detected in the peripheral blood of patients with prostatic cancer in different stages and with different sensitivities to hormonal therapy. PATIENTS AND METHODS: Peripheral blood from 107 men with prostatic cancer and 27 non-prostate cancer controls was analyzed for PSA mRNA using reverse-transcriptase polymerase chain reaction (RT-PCR) and Southern blotting. RESULTS: The lower limit of detection was one PSA-producing cell diluted into 1 x 10(6) blood mononuclear cells. The test detected PSA mRNA in four of 25 patients (16%) with clinically organ-confined (T1-2) disease, three of 10 (30%) with T3-4 or N+ tumors, and 25 of 72 (35%) with distant metastases. None of the control samples were positive. An increase in positivity was observed with increasing PSA levels. Within the subgroup of patients with distant metastases, positivity was observed in six of 16 patients (38%) with normal or undetectable PSA levels after hormonal therapy and, overall, in 37% of patients (21 of 57) with androgen-independent disease. CONCLUSION: An RT-PCR-based assay for PSA mRNA can detect circulating cells in the peripheral blood of patients with prostatic cancer. The frequency of positivity increases with tumor stage. A unique observation was the detection of cells in patients with no measurable PSA on hormonal therapy. This suggests that continued seeding of distant sites may still be occurring in these patients, despite seemingly successful therapy. The relationship between continued seeding, disease progression, and survival will require further study.
Assuntos
Metástase Neoplásica , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico , Sequência de Bases , Southern Blotting , Estudos de Avaliação como Assunto , Humanos , Masculino , Dados de Sequência Molecular , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Antígeno Prostático Específico/genética , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , RNA Mensageiro/análise , RNA Neoplásico/análise , Sensibilidade e EspecificidadeRESUMO
PURPOSE: The combination of suramin and hydrocortisone has shown clinical benefit in patients with androgen-independent prostate cancer. Widespread use was limited by the complex dose schedules and the need for pharmacologic monitoring. This study reports three sequential pharmacokinetically derived treatment regimens that simplified the administration of suramin and hydrocortisone with reduced toxicity. PATIENTS AND METHODS: Three cohorts of patients with advanced prostate cancer that progressed despite castrate levels of testosterone received oral hydrocortisone plus suramin administered in the following manners: (1) a loading dose of suramin followed by a continuous infusion using an adaptive control program (cohort A); (2) an intermittent schedule using a simplified adaptive control schedule (cohort B); and (3) an empiric dosing regimen (cohort C). Drug concentrations were monitored along with the toxicities associated with each regimen. Efficacy was assessed using measurable-disease criteria, radionuclide scans, and posttherapy changes in prostate-specific antigen (PSA) levels. RESULTS: Fifty-six patients were treated and plasma suramin concentrations were similar for each regimen. A partial response was observed in 4% (one of 28; 95% confidence interval, 0% to 18.4%) of patients with measurable disease, while 12% (six of 50; 95% confidence interval, 4.5% to 24.3%) had a greater than 80% decline in the baseline PSA level. The median duration of response was 12 months. No responses on radionuclide scans were seen. Anemia and lymphocytopenia were the most common toxicities, while 7% of patients developed a sensory or motor neurotoxicity. In the sequential regimens, the frequency of renal insufficiency (P = .04) and coagulopathy (P < .0001) decreased, while transaminase elevations (P = .05) were more common using intermittent infusions (cohorts B and C) versus continuous infusion schedules (cohort A). CONCLUSION: The administration of suramin was simplified and the drug concentrations were maintained. In this cohort of patients with advanced prostate cancer, the clinical activity of suramin using these dosing schedules was limited. Pharmacodynamic issues, patients selection, and criteria to assess efficacy could have effected the clinical outcome.
Assuntos
Hidrocortisona/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Suramina/administração & dosagem , Testosterona/metabolismo , Adaptação Fisiológica , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Estudos de Coortes , Esquema de Medicação , Monitoramento de Medicamentos , Quimioterapia Combinada , Humanos , Infusões Intravenosas , Linfopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/sangue , Neoplasias da Próstata/metabolismo , Indução de Remissão , Suramina/efeitos adversos , Suramina/farmacocinéticaRESUMO
PURPOSE: A phase II trial of ifosfamide, paclitaxel, and cisplatin (ITP) was conducted in previously untreated patients with advanced transitional-cell carcinoma (TCC) to assess its efficacy and toxicity. PATIENTS AND METHODS: Thirty patients with metastatic or unresectable TCC were treated with ifosfamide 1.5 g/m2/d for 3 days with paclitaxel 200 mg/m2 over 3 hours and cisplatin 70 mg/m2 on day 1 of each 28-day treatment cycle. Therapy was continued for a maximum of six cycles. Prophylactic hematopoietic growth factor (recombinant human granulocyte colony-stimulating factor [rhG-CSF]) was given on days 6 to 17 of each cycle. RESULTS: Twenty-three of 29 assessable patients (79%; 95% confidence interval [CI], 60% to 92%) demonstrated a major response (six complete [CR] and 17 partial [PR]) with response durations that ranged from 5 to 24+ months. Five patients with T4 bladder primary tumors had a major response, two with pathologic CR. At a median follow-up duration of 17.9 months, nine (31%) patients remain disease-free (range, 10+ to 24+). Hematologic toxicity included anemia, thrombocytopenia, and neutropenia; febrile neutropenia was observed in 17% of patients and 4% of cycles. No grade 4 nonhematologic toxicity was observed. Grade 3 nonhematologic toxicity included alopecia, allergy (3%), renal insufficiency (13%), and neuropathy (10%). Dose reductions or drug omissions were necessary for adverse events in seven (23%) patients. CONCLUSION: ITP is an active, well-tolerated regimen in previously untreated patients with TCC of the urothelial tract. Further study of this regimen in patients with both TCC and non-transitional-cell urothelial tumors is ongoing.