RESUMO
BACKGROUND: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. METHODS: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. INTERPRETATION: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.
Assuntos
Antagonistas de Androgênios , Anilidas , Nitrilas , Prostatectomia , Neoplasias da Próstata , Compostos de Tosil , Humanos , Masculino , Neoplasias da Próstata/patologia , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/terapia , Neoplasias da Próstata/tratamento farmacológico , Antagonistas de Androgênios/uso terapêutico , Antagonistas de Androgênios/administração & dosagem , Idoso , Compostos de Tosil/uso terapêutico , Compostos de Tosil/administração & dosagem , Anilidas/uso terapêutico , Anilidas/administração & dosagem , Pessoa de Meia-Idade , Nitrilas/uso terapêutico , Nitrilas/administração & dosagem , Oligopeptídeos/uso terapêutico , Oligopeptídeos/administração & dosagem , Hormônio Liberador de Gonadotropina/agonistas , Terapia Combinada , Antígeno Prostático Específico/sangueRESUMO
BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.
Assuntos
Antagonistas de Androgênios , Anilidas , Nitrilas , Prostatectomia , Neoplasias da Próstata , Compostos de Tosil , Humanos , Masculino , Neoplasias da Próstata/patologia , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/terapia , Neoplasias da Próstata/cirurgia , Antagonistas de Androgênios/uso terapêutico , Antagonistas de Androgênios/administração & dosagem , Idoso , Compostos de Tosil/uso terapêutico , Compostos de Tosil/administração & dosagem , Pessoa de Meia-Idade , Anilidas/uso terapêutico , Anilidas/administração & dosagem , Nitrilas/uso terapêutico , Nitrilas/administração & dosagem , Oligopeptídeos/administração & dosagem , Oligopeptídeos/uso terapêutico , Hormônio Liberador de Gonadotropina/agonistas , Antígeno Prostático Específico/sangue , Terapia Combinada , Esquema de MedicaçãoRESUMO
BACKGROUND: Female-pattern hair loss (FPHL) is characterized by decreased scalp hair density, thinning of hair shafts, and progressive miniaturization of hair follicles. OBJECTIVE: To compare the safety and efficacy of spironolactone versus bicalutamide in female pattern hair loss [FPHL]. METHODS: The study design was retrospective, and all eligible females aged between 18 years and 50 years with FPHL were included. We identified 120 patients from our database who fulfilled the inclusion and exclusion criteria, and patients were then categorized into two groups, Group A comprising patients who were taking 100 mg of spironolactone once daily and Group B comprising patients who were taking 50 mg of bicalutamide once daily along with topical minoxidil 2% in both groups. Patient were analysed at approximately at 24 weeks from the commencement of the treatment. RESULTS: Mean reduction in hair loss severity score on Sinclair scale was 19.51% in spironolactone group compared to 28.20% in bicalutamide group at 24 weeks, which was statistically significant. On global photographic assessment, marked improvement was seen in bicalutamide group compared to spironolactone group (p = 0.139). CONCLUSIONS: Our study, though limited by its retrospective design and small sample size, showed that bicalutamide has greater efficacy and better safety profile in comparison to spironolactone in the treatment of FPHL.
Assuntos
Alopecia , Anilidas , Nitrilas , Espironolactona , Compostos de Tosil , Humanos , Feminino , Espironolactona/uso terapêutico , Espironolactona/efeitos adversos , Anilidas/efeitos adversos , Anilidas/uso terapêutico , Estudos Retrospectivos , Alopecia/tratamento farmacológico , Adulto , Pessoa de Meia-Idade , Compostos de Tosil/efeitos adversos , Compostos de Tosil/uso terapêutico , Nitrilas/efeitos adversos , Nitrilas/uso terapêutico , Nitrilas/administração & dosagem , Adulto Jovem , Minoxidil/uso terapêutico , Minoxidil/efeitos adversos , Resultado do Tratamento , Adolescente , Índice de Gravidade de DoençaRESUMO
Myoepithelial tumor is a rare form of cancer, mainly arising from the salivary glands and extremities. Due to its rarity, no formal treatment guidelines exist. Here we report a case of a male patient diagnosed with metastatic myoepithelial tumor which was successfully treated with an androgen-receptor (AR) antagonist (bicalutamide), based on the results of molecular testing. Six years after the initiation of bicalutamide, patient was diagnosed with metastatic prostate cancer. To our knowledge, this is the first case described in literature that demonstrate the effectiveness of anti-androgens in treating myoepithelial tumor. Vigilance should be maintained when screening these patients for prostate cancer as their 'true' prostate specific antigen levels might be masked by the ongoing endocrine therapy.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Anilidas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Mioepitelioma/tratamento farmacológico , Nitrilas/uso terapêutico , Antígeno Prostático Específico/efeitos dos fármacos , Neoplasias da Próstata/patologia , Compostos de Tosil/uso terapêutico , Idoso , Humanos , Masculino , Metástase NeoplásicaRESUMO
PURPOSE: Long-term androgen deprivation therapy has been associated with decreased bone mineral density in men with prostate cancer. Some evidence suggests that there is no impact on fracture risk despite this bone mineral density loss. Our study aimed to quantify changes in bone mineral density in men with high risk prostate cancer on long-term androgen deprivation therapy and calcium and vitamin D supplementation. MATERIALS AND METHODS: Bone mineral density analysis was conducted for localized high risk prostate cancer patients enrolled in the phase III randomized trial PCS-V (Prostate Cancer Study 5), comparing conventional and hypofractionated radiation therapy. Patients received 28 months of luteinizing hormone-releasing hormone agonist and calcium and vitamin D supplementation (500 mg calcium BID+400 IU vitamin D3 BID). The areal density and T-scores (spine, femoral neck and total femur) at baseline and 30 months of followup were extracted, and the absolute change was calculated. Clinical bone density status (normal, osteopenia, osteoporosis) was monitored. RESULTS: The lumbar spine, femoral neck and total femoral bone mineral density were measured for 226, 231, and 173 patients, respectively. The mean percent change in bone mineral density was -2.65%, -2.76% and -4.27% for these respective sites (p <0.001 for all). The average decrease in bone mineral density across all sites was -3.2%, with no decline in bone mineral density category in most patients (83%). Eight patients (4%) became osteoporotic. CONCLUSIONS: Despite a mild decline in bone mineral density, the change in clinical bone mineral density category remained low with long-term androgen deprivation therapy. Consequently, calcium and vitamin D supplementation alone may suffice for most localized prostate cancer patients on long-term androgen deprivation therapy.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Anilidas/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Densidade Óssea , Hormônio Liberador de Gonadotropina/agonistas , Nitrilas/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/fisiopatologia , Compostos de Tosil/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Humanos , Leuprolida , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de TempoRESUMO
LESSONS LEARNED: Studies targeting the androgen receptor (AR) signaling pathway in aromatase inhibitor (AI)-resistant breast cancer are limited. Bicalutamide, one of the commonly used AR inhibitors in prostate cancer, in combination with AI, did not show synergistic activity in patients with estrogen receptor-positive and AI-resistant disease in this phase II, single-arm study. The clinical benefit rate and objective response rate at 6 months were 16.7% and 0%, respectively, and the study was terminated after the first stage. BACKGROUND: Endocrine resistance is a major problem in clinical practice. Studies have shown that androgen receptor (AR) signaling activation may be one of the mechanisms, and targeting AR showed some promising results in AR-positive triple-negative breast cancer. The aim of this study was to assess the efficacy and safety of bicalutamide plus another aromatase inhibitor in patients with nonsteroidal aromatase inhibitor (AI) or steroidal AI resistance and estrogen receptor (ER)-positive and AR-positive advanced breast cancer. METHODS: A Simon's two-stage, phase II, single-arm study was conducted. We assumed the clinical benefit rate (CBR) of 40% would be significant in clinical practice. In this case, if ≥4 patients of the 19 patients in the first stage benefited from treatment, the CBR would achieve the assumed endpoint. If fewer than four patients benefited from treatment in the first stage, the trial would be terminated. All patients received bicalutamide 50 mg per day orally plus another aromatase inhibitor. The primary outcome was CBR; secondary outcomes included objective response rate (ORR), progression-free survival (PFS), and tolerability. RESULTS: A total of 19 patients enrolled in the first stage, and 18 patients met all criteria for analysis. The trial terminated according to protocol after the first stage. After a median follow-up of 14 months, the CBR at 6 months was 16.7% (3/18); no patients with partial or complete response were observed. The median PFS was 2.7 months. Bicalutamide in combination with AI was well tolerated. CONCLUSION: Bicalutamide in combination with another AI did not show synergistic activity in patients with ER-positive breast cancer and AI resistance. Results suggest that no more large-sample clinical trials should be conducted in this population for overcoming endocrine resistance.
Assuntos
Anilidas/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Nitrilas/uso terapêutico , Compostos de Tosil/uso terapêutico , Adulto , Idoso , Anilidas/farmacologia , Feminino , Humanos , Pessoa de Meia-Idade , Nitrilas/farmacologia , Compostos de Tosil/farmacologiaRESUMO
BACKGROUND: Salvage radiation therapy is often necessary in men who have undergone radical prostatectomy and have evidence of prostate-cancer recurrence signaled by a persistently or recurrently elevated prostate-specific antigen (PSA) level. Whether antiandrogen therapy with radiation therapy will further improve cancer control and prolong overall survival is unknown. METHODS: In a double-blind, placebo-controlled trial conducted from 1998 through 2003, we assigned 760 eligible patients who had undergone prostatectomy with a lymphadenectomy and had disease, as assessed on pathological testing, with a tumor stage of T2 (confined to the prostate but with a positive surgical margin) or T3 (with histologic extension beyond the prostatic capsule), no nodal involvement, and a detectable PSA level of 0.2 to 4.0 ng per milliliter to undergo radiation therapy and receive either antiandrogen therapy (24 months of bicalutamide at a dose of 150 mg daily) or daily placebo tablets during and after radiation therapy. The primary end point was the rate of overall survival. RESULTS: The median follow-up among the surviving patients was 13 years. The actuarial rate of overall survival at 12 years was 76.3% in the bicalutamide group, as compared with 71.3% in the placebo group (hazard ratio for death, 0.77; 95% confidence interval, 0.59 to 0.99; P=0.04). The 12-year incidence of death from prostate cancer, as assessed by means of central review, was 5.8% in the bicalutamide group, as compared with 13.4% in the placebo group (P<0.001). The cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, as compared with 23.0% in the placebo group (P=0.005). The incidence of late adverse events associated with radiation therapy was similar in the two groups. Gynecomastia was recorded in 69.7% of the patients in the bicalutamide group, as compared with 10.9% of those in the placebo group (P<0.001). CONCLUSIONS: The addition of 24 months of antiandrogen therapy with daily bicalutamide to salvage radiation therapy resulted in significantly higher rates of long-term overall survival and lower incidences of metastatic prostate cancer and death from prostate cancer than radiation therapy plus placebo. (Funded by the National Cancer Institute and AstraZeneca; RTOG 9601 ClinicalTrials.gov number, NCT00002874 .).
Assuntos
Antagonistas de Androgênios/uso terapêutico , Anilidas/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/radioterapia , Nitrilas/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Compostos de Tosil/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/efeitos adversos , Anilidas/efeitos adversos , Terapia Combinada , Método Duplo-Cego , Seguimentos , Ginecomastia/induzido quimicamente , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/mortalidade , Estadiamento de Neoplasias , Nitrilas/efeitos adversos , Prostatectomia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/cirurgia , Radioterapia/efeitos adversos , Taxa de Sobrevida , Compostos de Tosil/efeitos adversosRESUMO
BACKGROUND: There is no consensus on the association between the use of androgen deprivation therapy (ADT) and the risk of developing depression. This study investigated the association between ADT use and the development of depression, outpatient psychiatric services, inpatient psychiatric services, and suicide in a homogeneous group of men with prostate cancer (PC) treated with definitive radiation therapy (RT) after controlling for multiple sources of selection bias. METHODS: This was a retrospective, observational cohort study of 39,965 veterans with PC who were treated with definitive RT and were diagnosed by the US Department of Veterans Affairs health care system between January 1, 2001, and October 31, 2015. Exposure was ADT initiation within 1 year of the PC diagnosis. The primary outcome was new development of depression. Secondary outcomes were outpatient psychiatric use, inpatient psychiatric use, and suicide. RESULTS: During follow-up, 934 patients were newly diagnosed with depression, 7825 patients used outpatient psychiatric services, 358 patients used inpatient psychiatric services, and 54 patients committed suicide. In the multivariable competing risks regression model, ADT was associated with the development of depression (subdistribution hazard ratio [SHR], 1.50; 95% confidence interval [CI], 1.32-1.71; P < .001). ADT was also associated with outpatient psychiatric utilization (SHR, 1.21; 95% CI, 1.16-1.27; P < .001). Finally, ADT was not associated with inpatient psychiatric utilization or suicide. CONCLUSIONS: An increase in the risk of depression and the use of outpatient psychiatric services was observed in a large cohort of men with PC who received ADT with definitive RT. These results may provide further evidence for the long-term risks of ADT for psychiatric health in the treatment of PC.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Transtorno Depressivo/epidemiologia , Neoplasias da Próstata/terapia , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial/estatística & dados numéricos , Anilidas/uso terapêutico , Depressão/epidemiologia , Flutamida/uso terapêutico , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/uso terapêutico , Gosserrelina/uso terapêutico , Hospitalização/estatística & dados numéricos , Humanos , Imidazolidinas/uso terapêutico , Leuprolida/uso terapêutico , Masculino , Serviços de Saúde Mental/estatística & dados numéricos , Pessoa de Meia-Idade , Nitrilas/uso terapêutico , Oligopeptídeos/uso terapêutico , Neoplasias da Próstata/psicologia , Radioterapia , Estudos Retrospectivos , Suicídio/estatística & dados numéricos , Compostos de Tosil/uso terapêuticoRESUMO
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwideand haslimited treatment options. In view of this, zafirlukast (ZAF) was administered orally to DEN-induced HCC rats to evaluate its antineoplastic properties. ELISA, qRT-PCR and Western blot were used to determine the molecular mechanism associated with ZAF therapy for HCC. We found that HCC developed as a result of lower expression of caspases 3 and 9, but their levels returned to normal when the expression of eNOS, BAX, BAD, and Cyt C was decreased and when the expression of iNOS, Bcl-xl, and Bcl-2 was increased. Again, ZAF (80â¯mg/kg dose) treatment normalized the expression of caspase-mediated apoptotic factors, i.e. BAX and Bcl-2 proteins, as established through Western blot analysis. Later, 1H NMR-based serum metabolomics study revealed that levels of perturbed metabolites in DEN-induced rat serum returned to normal after ZAF administration. Altogether, the antineoplastic potential of ZAF was found to be comparable, and to some degree better, than the marketed chemotherapeutic 5-flurouracil, which may be beneficial for anti-HCC treatment from a future drug design perspective.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Compostos de Tosil/farmacologia , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/sangue , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Dietilnitrosamina/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Indóis , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas Experimentais/sangue , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/metabolismo , Masculino , Metabolômica , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fenilcarbamatos , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Sulfonamidas , Compostos de Tosil/uso terapêuticoRESUMO
Background: There is no standard first-line chemotherapy for recurrent/metastatic (RM) or unresectable locally advanced (LA) salivary gland carcinoma (SGC). Patients and methods: We conducted a single institution, open-label, single arm, phase II trial of combined androgen blockade (CAB) for androgen receptor (AR)-positive SGC. Leuprorelin acetate was administered subcutaneously at a dose of 3.75 mg every 4 weeks. Bicalutamide was administered orally at a daily dose of 80 mg. Patients were treated until progressive disease or unacceptable toxicities. Results: Thirty-six eligible patients were enrolled. Thirty-three patients had RM disease and three patients had LA disease. The pathological diagnoses were salivary duct carcinoma (34 patients, 94%) and adenocarcinoma, NOS (two patients, 6%). The best overall response rate was 41.7% [n = 15, 95% confidence interval (CI), 25.5%-59.2%], the clinical benefit rate was 75.0% (n = 27, 95% CI, 57.8%-87.9%). The median progression-free survival was 8.8 months (95% CI, 6.3-12.3 months) and the median overall survival was 30.5 months (95% CI, 16.8 months to not reached). Additional analyses between treatment outcomes and clinicopathological factors or biomarkers including AR positivity, human epidermal growth factor receptor 2 status, and its complex downstream signaling pathway gene mutations showed no statistically significant differences. Elevated grade 3 liver transaminases and increased serum creatinine were reported in two patients, respectively. Discontinuation of leuprorelin acetate or bicalutamide due to adverse event occurred in one patient. Conclusion: This study suggests that CAB has equivalent efficacy and less toxicity for patients with AR-positive RM or unresectable LA SGC compared with conventional chemotherapy, which warrants further study. Clinical Trial Registration: UMIN-CTR (http://www.umin.ac.jp/ctr/index-j.htm), identification number: UMIN000005703.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Leuprolida/uso terapêutico , Metástase Neoplásica , Receptores Androgênicos/metabolismo , Neoplasias das Glândulas Salivares/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/administração & dosagem , Anilidas/administração & dosagem , Anilidas/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Leuprolida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Nitrilas/uso terapêutico , Estudos Prospectivos , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/patologia , Compostos de Tosil/administração & dosagem , Compostos de Tosil/uso terapêutico , Resultado do TratamentoRESUMO
PURPOSE: Enzalutamide significantly prolonged median progression-free survival vs bicalutamide in chemotherapy naïve men with metastatic castration resistant prostate cancer in the TERRAIN (Enzalutamide versus Bicalutamide in Castrate Men with Metastatic Prostate Cancer) trial. In this post hoc analysis we investigated the influence of age on the efficacy and safety of enzalutamide vs bicalutamide in this population. MATERIALS AND METHODS: Patients were randomized 1:1 to enzalutamide 160 mg per day or bicalutamide 50 mg per day. Progression-free survival, time to prostate specific antigen progression and safety were analyzed post hoc in younger (age less than 75 years) and older (age 75 years or greater) subgroups. RESULTS: Enzalutamide significantly reduced the risk of disease progression or death vs bicalutamide in patients younger than 75 years (HR 0.38, 95% CI 0.27-0.52, p <0.0001) and 75 years old or older (HR 0.59, 95% CI 0.37-0.92, p = 0.018). Time to prostate specific antigen progression was also significantly prolonged with enzalutamide vs bicalutamide in each subgroup. The adverse event distribution between treatments was similar in each subgroup except for more (5% or greater difference between subgroups) atrial fibrillation, urinary tract infections, falls and decreased appetite as well as less extremity pain and hot flushing in enzalutamide treated patients 75 years old or older, and less back pain and hot flushing in bicalutamide treated patients 75 years old or older. Grade 3 or greater cardiac events were more frequent in enzalutamide treated and bicalutamide treated patients who were 75 years old or older vs younger than 75 years. Fatigue was more frequent in enzalutamide treated patients with a similar distribution in each age subgroup. CONCLUSIONS: Enzalutamide improved clinical outcomes vs bicalutamide irrespective of age. Increased falls and cardiac events suggest caution when prescribing to older patients (age 75 years or greater) with significant comorbidity.
Assuntos
Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Nitrilas/uso terapêutico , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Compostos de Tosil/uso terapêutico , Fatores Etários , Idoso , Anilidas/efeitos adversos , Antineoplásicos/efeitos adversos , Benzamidas , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Feniltioidantoína/efeitos adversos , Feniltioidantoína/uso terapêutico , Intervalo Livre de Progressão , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/patologia , Compostos de Tosil/efeitos adversos , Resultado do TratamentoRESUMO
Apalutamide (ARN-509) is an antiandrogen that binds selectively to androgen receptors (AR) and does not show antagonist-to-agonist switch like bicalutamide. We compared the activity of ARN versus bicalutamide on prostate cancer cell lines. The 22Rv1, PC3, and DU145 cell lines were used to study the effect of ARN and bicalutamide on the expression cytoplasmic/nuclear kinetics of AR, AR-V7 variant, phosphorylated AR, as well as the levels of the AR downstream proteins prostate-specific antigen and TMPRSS2, under exposure to testosterone and/or hypoxia. The effects on autophagic flux (LC3A, p62, TFEB, LAMP2a, cathepsin D) and cell metabolism-related enzymes (hypoxia-inducible factor 1α/2α, BNIP3, carbonic anhydrase 9, LDHA, PDH, PDH-kinase) were also studied. The 22Rv1 cell line responded to testosterone by increasing the nuclear entry of AR, AR-V7, and phosphorylated AR and by increasing the levels of prostate-specific antigen and TMPRSS2. This effect was strongly abrogated by ARN and to a clearly lower extent by bicalutamide at 10 µmol/l, both in normoxia and in hypoxia. ARN had a stronger antiproliferative effect than bicalutamide, which was prominent in the 22Rv1 hormone-responsive cell line, and completely repressed cell proliferation at a concentration of 100 µmol/l. No effect of testosterone or of antiandrogens on autophagy flux, hypoxia-related proteins, or metabolism enzyme levels was noted. The PC3 and DU145 cell lines showed poor expression of the proteins and were not responsive to testosterone. On the basis of in-vitro studies, evidence has been reported that ARN is more potent than bicalutamide in blocking the AR pathway in normoxia and in hypoxia. This reflects a more robust, dose-dependent, repressive effect on cell proliferation.
Assuntos
Antagonistas de Androgênios/farmacologia , Anilidas/farmacologia , Nitrilas/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/efeitos dos fármacos , Tioidantoínas/farmacologia , Compostos de Tosil/farmacologia , Antagonistas de Androgênios/uso terapêutico , Anilidas/uso terapêutico , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Hipóxia/tratamento farmacológico , Hipóxia/metabolismo , Masculino , Nitrilas/uso terapêutico , Antígeno Prostático Específico/biossíntese , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Testosterona/farmacologia , Testosterona/uso terapêutico , Tioidantoínas/uso terapêutico , Compostos de Tosil/uso terapêuticoRESUMO
BACKGROUND: Salvage treatments for biochemical relapse (BCR) after radical prostatectomy (RP) have several problems in terms of indications or adverse events. We studied the possibility of 2 years of bicalutamide monotherapy for BCR after RP. METHODS: Patients who showed BCR (prostate-specific antigen (PSA) ≥ 0.2 ng/ml) after RP were recruited. Protocol treatment was planned as 2 years of bicalutamide (80 mg/day) followed by observation. Protocol treatment failure was defined as PSA re-elevation of ≥0.2 ng/ml, clinical progression, any other treatments, or discontinuation or restart of bicalutamide. Primary endpoint of this study is time to protocol treatment failure from initiation of bicalutamide. RESULTS: A total of 91 patients were registered between 2003 and 2009. Median age and PSA at initiating bicalutamide were 68 (range, 55-78) years and 0.32 (range, 0.19-7.91) ng/ml. Twenty-four (26.4%) patients could not complete 2 years of bicalutamide mainly due to progression of disease. Of the 91 patients, 2- and 5-year protocol treatment failure-free survivals were 74.6% and 33.0%, with a median follow-up of 76 (range, 11-118) months. Median time from initiating bicalutamide to treatment failure was 43 (95% confidence interval, 33-47) months. High-risk status at RP and time to BCR after RP < 6 months were significant predictors of second BCR. CONCLUSIONS: Two years of bicalutamide monotherapy should not be recommended as standard management for BCR after RP, but might be feasible for selected patients who do not have high-risk status at RP and short time to BCR.
Assuntos
Anilidas/uso terapêutico , Recidiva Local de Neoplasia/patologia , Nitrilas/uso terapêutico , Prostatectomia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/cirurgia , Compostos de Tosil/uso terapêutico , Idoso , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Antígeno Prostático Específico/metabolismo , Terapia de Salvação , Falha de TratamentoRESUMO
BACKGROUND: This analysis estimated the number needed to treat with enzalutamide versus bicalutamide to achieve one additional patient with chemotherapy-naïve metastatic castration-resistant prostate cancer who would obtain clinical benefit regarding progression-free survival, radiographic progression-free survival, or no prostate-specific antigen progression at 1 and 2 years following treatment initiation. METHODS: Clinical event rates were obtained from the STRIVE (NCT01664923) and TERRAIN (NCT01288911) trials, and the number needed to treat was the inverse of the absolute rate difference between the event rates of enzalutamide and bicalutamide. The 95% Confidence Interval of the number needed to treat was derived from the 95% Confidence Interval of the event rate difference. RESULTS: Using STRIVE data (patients with metastatic disease: n = 128 enzalutamide; n = 129 bicalutamide) comparing enzalutamide with bicalutamide at 1 and 2 years, the numbers needed to treat to achieve one additional patient with chemotherapy-naïve metastatic castration-resistant prostate cancer with progression-free survival were 2.0 and 2.8, respectively; with radiographic progression-free survival, 2.6 and 3.0, respectively; and without prostate-specific antigen progression, 1.8 and 2.4, respectively. Using TERRAIN data (n = 184 enzalutamide; n = 191 bicalutamide) comparing enzalutamide with bicalutamide at 1 and 2 years, the numbers needed to treat to achieve one additional patient with progression-free survival were 4.3 and 3.7, respectively; with radiographic progression-free survival, 10.0 and 2.8, respectively; and without prostate-specific antigen progression, 2.1 and 3.2, respectively. CONCLUSIONS: The combined data from TERRAIN and STRIVE demonstrated that treating chemotherapy-naïve metastatic castration-resistant prostate cancer with enzalutamide leads to more patients without clinical progression at 1 and 2 years than with bicalutamide. TRIAL REGISTRATION: STRIVE (NCT01664923; registration date: August 10, 2012) and TERRAIN (NCT01288911; registration date: February 1, 2011).
Assuntos
Antagonistas de Androgênios/uso terapêutico , Anilidas/uso terapêutico , Nitrilas/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Compostos de Tosil/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de PesquisaRESUMO
BACKGROUND: Phase 3 trials have demonstrated a benefit from adjuvant radiation therapy (ART) for men who have adverse factors at radical prostatectomy (RP). However, some patients have a high risk of progression despite ART. The role of systemic therapy with ART in this high-risk group remains to be defined. METHODS: Patients who had either a post-RP prostate-specific antigen (PSA) nadir > 0.2 ng/mL and a Gleason score ≥7 or a PSA nadir ≤0.2 ng/mL, a Gleason score ≥8, and a pathologic tumor (pT) classification ≥ pT3 received 6 months of androgen-deprivation therapy (ADT) plus radiotherapy and 6 cycles of docetaxel. The primary objective was to assess whether the addition of ADT and docetaxel to ART resulted in a freedom from progression (FFP) rate ≥ 70% compared with an expected rate of 50%. Multivariate logistic and Cox regression analyses were used to model associations between factors and outcomes. RESULTS: In total, 74 patients were enrolled. The median follow-up was 4.4 years. The pathologic tumor classification was pT2 in 4% of patients, pT3 in 95%, and pT4 in 1%. The Gleason score was 7 in 18% of patients and ≥8 in 82%. Post-RP PSA levels were ≤0.2 ng/mL in 53% of patients and >0.2 ng/mL in 47%. The 3-year FFP rate was 73% (95% confidence interval, 61%-83%), and the 3-year cumulative incidence of biochemical, distant, and local failure was 26%, 7%, and 0%, respectively. In multivariate models, postprostatectomy PSA nadir was associated with 3-year FFP, Gleason score, and PSA with biochemical failure. Grade 3 and 4 neutropenia was common; however, only 3 episodes of febrile neutropenia occurred. Late toxicities were not impacted by the addition of systemic therapy. CONCLUSIONS: Combined ADT, docetaxel, and ART for men with high-risk prostate cancer after prostatectomy exceeded the prespecified study endpoint of 70% 3-year FFP. Phase 3 trials assessing combined local and systemic therapies for these high-risk patients are warranted. Cancer 2017;123:2489-96. © 2017 American Cancer Society.
Assuntos
Adenocarcinoma/terapia , Antagonistas de Androgênios/uso terapêutico , Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Quimiorradioterapia Adjuvante/métodos , Nitrilas/uso terapêutico , Prostatectomia , Neoplasias da Próstata/terapia , Taxoides/uso terapêutico , Compostos de Tosil/uso terapêutico , Adenocarcinoma/sangue , Adenocarcinoma/patologia , Adulto , Idoso , Intervalo Livre de Doença , Docetaxel , Hormônio Liberador de Gonadotropina/agonistas , Humanos , Calicreínas/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Radioterapia Conformacional , Radioterapia de Intensidade ModuladaRESUMO
BACKGROUND: As androgen deprivation therapy (ADT) is increasingly being used in men with localised prostate cancer, our goal was to examine the association between ADT and the risk of cardiovascular disease (CVD). METHODS: We conducted a prospective cohort study using records of a large health-care system in California. The study included men with newly diagnosed localised prostate cancer (1998-2008) who initially underwent active surveillance (N=7637) and were followed through 2010. We examined 10 individual CVD outcomes. Cox proportional hazard models incorporated time-varying treatment variables and controlled for race/ethnicity, age, and tumour characteristics, recurrence risk, CVD medication use, and CVD risk factors. RESULTS: Of the 7637 subjects, nearly 30% were exposed to ADT. In the multivariable analyses, ADT was associated with an increased risk of heart failure (adjusted HR=1.81, 95% CI 1.40-2.32) in men without preexisting CVD. Elevated risks of arrhythmia (adjusted HR=1.44, 95% CI 1.02-2.01), and conduction disorder (adjusted HR=3.11, 95% CI 1.22, 7.91) were only observed among patients with preexisting CVD. CONCLUSIONS: In men with clinically localised prostate cancer who were initially under active surveillance, ADT was associated with a greater risk of heart failure in men without any preexisting CVD. We also found an increased risk of arrhythmia and conduction disorder in men with preexisting CVD. This study provides the basis for identifying high-risk men treated with ADT who might benefit from regular cardiac monitoring and lifestyle modification recommendations.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Arritmias Cardíacas/epidemiologia , Insuficiência Cardíaca/epidemiologia , Neoplasias da Próstata/tratamento farmacológico , Idoso , Anilidas/uso terapêutico , California/epidemiologia , Doenças Cardiovasculares/epidemiologia , Estudos de Coortes , Flutamida/uso terapêutico , Hormônio Liberador de Gonadotropina/agonistas , Gosserrelina/uso terapêutico , Humanos , Imidazolidinas/uso terapêutico , Leuprolida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Nitrilas/uso terapêutico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Fatores de Risco , Compostos de Tosil/uso terapêuticoRESUMO
BACKGROUND/AIMS: Little is known about the potential mechanism of action for androgen receptor (AR) targeting treatment in estrogen receptor (ER)-negative breast cancer. This study aimed to evaluate AR status and its prognosis in four breast cancer subtypes. Bicalutamide has been identified as an AR antagonist and used for treating AR+/ER- breast cancer in a phase II trial. Our studies will clarify its mechanism in breast cancer treatment. METHODS: A total of 510 consecutive cases of invasive ductal cancer (IDC) were evaluated in this study. The expression of AR was analyzed by immunohistochemistry and compared with patient survival, and its implications were evaluated in four subtypes of IDC. We examined bicalutamide as an AR antagonist to inhibit proliferation and increased apoptosis in AR+/ER- breast cancer cell lines. We explored the tumor suppressive functions of bicalutamide in vitro and vivo and its related mechanisms in AR+/ER- breast cancer. RESULTS: AR expression was related to that of ER (P<0.001), PR (P<0.001), Her2 (P=0.017), Ki-67(P=0.020) and to four subtypes (P<0.001). AR retained independent prognostic signifcance (P=0.007, ER- cases; P=0.001, ER+ cases; P=0.001, total cases). We found that bicalutamide significantly decreased viability and increased apoptosis in vitro and vivo. The mechanistic analysis revealed that bicalutamide blocked androgen-stimulated oncogenic AR and Wnt/ß-catenin signaling and inhibited the growth of AR+/ER- breast cancer. CONCLUSION: Our studies provide novel insights into bicalutamide as an antagonist of AR function in AR+/ER- breast cancer and reveal the mechanistic basis for targeting AR as a therapeutic opportunity for patients with AR+/ER- breast cancer.
Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Anilidas/farmacologia , Neoplasias da Mama/patologia , Nitrilas/farmacologia , Receptores Androgênicos/genética , Receptores de Estrogênio/genética , Compostos de Tosil/farmacologia , Transcrição Gênica/efeitos dos fármacos , beta Catenina/metabolismo , Antagonistas de Receptores de Andrógenos/uso terapêutico , Anilidas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Nitrilas/uso terapêutico , Prognóstico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores Androgênicos/química , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Compostos de Tosil/uso terapêutico , Transplante Heterólogo , beta Catenina/genéticaRESUMO
PURPOSE: To determine whether setup errors during external beam radiation therapy (RT) for prostate cancer are influenced by the combination of androgen deprivation treatment (ADT) and RT. MATERIALS AND METHODS: Data from 175 patients treated for prostate cancer were retrospectively analyzed. Treatment was as follows: concurrent ADT plus RT, 33 patients (19%); neoadjuvant and concurrent ADT plus RT, 91 patients (52%); RT only, 51 patients (29%). Required couch shifts without rotations were recorded for each megavoltage (MV) cone beam computed tomography (CBCT) scan, and corresponding alignment shifts were recorded as left-right (x), superior-inferior (y), and anterior-posterior (z). The nonparametric Mann-Whitney test was used to compare shifts by group. Pearson's correlation coefficient was used to measure the correlation of couch shifts between groups. Mean prostate shifts and standard deviations (SD) were calculated and pooled to obtain mean or group systematic error (M), SD of systematic error (Σ), and SD of random error (σ). RESULTS: No significant differences were observed in prostate shifts in any direction between the groups. Shifts on CBCT were all less than setup margins. A significant positive correlation was observed between prostate volume and the zdirection prostate shift (r = 0.19, p = 0.04), regardless of ADT group, but not between volume and x or ydirection shifts (r = 0.04, p = 0.7; r = 0.03, p = 0.7). Random and systematic errors for all patient cohorts and ADT groups were similar. CONCLUSION: Hormone therapy given concurrently with RT was not found to significantly impact setup errors. Prostate volume was significantly correlated with shifts in the anterior-posterior direction only.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Artefatos , Marcadores Fiduciais , Posicionamento do Paciente , Neoplasias da Próstata/radioterapia , Idoso , Idoso de 80 Anos ou mais , Anilidas/uso terapêutico , Quimiorradioterapia , Terapia Combinada , Tomografia Computadorizada de Feixe Cônico , Hormônio Liberador de Gonadotropina/agonistas , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Nitrilas/uso terapêutico , Tamanho do Órgão , Próstata/efeitos da radiação , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/tratamento farmacológico , Estudos Retrospectivos , Compostos de Tosil/uso terapêuticoRESUMO
PURPOSE: The study aimed to evaluate the effects of metformin on insulin, C-peptide and body weight in Chinese men undergoing androgen deprivation therapy (ADT). METHODS: Between March 2013 and June 2014, 62 newly diagnosed patients of prostate cancer (PCa) due to receive ADT were recruited from 7 hospitals in Shanghai. Patients were randomized to respectively receive ADT (n = 31) and ADT + metformin (n = 31) for 6 months. Fasting and postprandial serum levels of insulin and C-peptide, blood glucose, prostate specific antigen, body mass index (BMI) and waist circumference (WC) were measured at the beginning and end of 6-month treatment. RESULTS: Baseline characteristics were comparable between the 2 groups. Controlling for baseline levels, the ADT group had significantly higher levels of fasting glucose (p = 0.01) and higher WC (p = 0.04) than the ADT + metformin group. The levels of insulin, C-peptide and BMI did not differ significantly. CONCLUSIONS: Metformin may be potentially efficient as a concomitant therapy on patients with PCa undergoing androgen deprivation treatment.