FOXA1 in prostate cancer / 亚洲男科学杂志(英文版)

Most prostate cancers initially respond to androgen deprivation therapy (ADT). With the long-term application of ADT, localized prostate cancer will progress to castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), and neuroendocrine prostate cancer (NEPC), and the transcriptional network shifted. Forkhead box protein A1 (FOXA1) may play a key role in this process through multiple mechanisms. To better understand the role of FOXA1 in prostate cancer, we review the interplay among FOXA1-targeted genes, modulators of FOXA1, and FOXA1 with a particular emphasis on androgen receptor (AR) function. Furthermore, we discuss the distinct role of FOXA1 mutations in prostate cancer and clinical significance of FOXA1. We summarize possible regulation pathways of FOXA1 in different stages of prostate cancer. We focus on links between FOXA1 and AR, which may play different roles in various types of prostate cancer. Finally, we discuss FOXA1 mutation and its clinical significance in prostate cancer. FOXA1 regulates the development of prostate cancer through various pathways, and it could be a biomarker for mCRPC and NEPC. Future efforts need to focus on mechanisms underlying mutation of FOXA1 in advanced prostate cancer. We believe that FOXA1 would be a prognostic marker and therapeutic target in prostate cancer.

Radiomics based on biparametric MRI for the detection of significant residual prostate cancer after androgen deprivation therapy: using whole-mount histopathology as reference standard / 亚洲男科学杂志(英文版)

We aimed to study radiomics approach based on biparametric magnetic resonance imaging (MRI) for determining significant residual cancer after androgen deprivation therapy (ADT). Ninety-two post-ADT prostate cancer patients underwent MRI before prostatectomy (62 with significant residual disease and 30 with complete response or minimum residual disease [CR/MRD]). Totally, 100 significant residual, 52 CR/MRD lesions, and 70 benign tissues were selected according to pathology. First, 381 radiomics features were extracted from T2-weighted imaging, diffusion-weighted imaging, and apparent diffusion coefficient (ADC) maps. Optimal features were selected using a support vector machine with a recursive feature elimination algorithm (SVM-RFE). Then, ADC values of significant residual, CR/MRD lesions, and benign tissues were compared by one-way analysis of variance. Logistic regression was used to construct models with SVM features to differentiate between each pair of tissues. Third, the efficiencies of ADC value and radiomics models for differentiating the three tissues were assessed by area under receiver operating characteristic curve (AUC). The ADC value (mean ± standard deviation [s.d.]) of significant residual lesions ([1.10 ± 0.02] × 10-3 mm2 s-1) was significantly lower than that of CR/MRD ([1.17 ± 0.02] × 10-3 mm2 s-1), which was significantly lower than that of benign tissues ([1.30 ± 0.02] × 10-3 mm2 s-1; both P < 0.05). The SVM feature models were comparable to ADC value in distinguishing CR/MRD from benign tissue (AUC: 0.766 vs 0.792) and distinguishing residual from benign tissue (AUC: 0.825 vs 0.835) (both P > 0.05), but superior to ADC value in differentiating significant residual from CR/MRD (AUC: 0.748 vs 0.558; P = 0.041). Radiomics approach with biparametric MRI could promote the detection of significant residual prostate cancer after ADT.

Apalutamide for metastatic castration-sensitive prostate cancer: final analysis of the Asian subpopulation in the TITAN trial / 亚洲男科学杂志(英文版)

The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial showed improvement in overall survival (OS) and other efficacy endpoints with apalutamide plus androgen deprivation therapy (ADT) versus ADT alone in patients with metastatic castration-sensitive prostate cancer (mCSPC). As ethnicity and regional differences may affect treatment outcomes in advanced prostate cancer, a post hoc final analysis was conducted to assess the efficacy and safety of apalutamide in the Asian subpopulation. Event-driven endpoints were OS, and time from randomization to initiation of castration resistance, prostate-specific antigen (PSA) progression, and second progression-free survival (PFS2) on first subsequent therapy or death. Efficacy endpoints were assessed using the Kaplan-Meier method and Cox proportional-hazards models without formal statistical testing and adjustment for multiplicity. Participating Asian patients received once-daily apalutamide 240 mg ( n = 111) or placebo ( n = 110) plus ADT. After a median follow-up of 42.5 months and despite crossover of 47 placebo recipients to open-label apalutamide, apalutamide reduced the risk of death by 32% (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.42-1.13), risk of castration resistance by 69% (HR: 0.31; 95% CI: 0.21-0.46), PSA progression by 79% (HR: 0.21; 95% CI: 0.13-0.35) and PFS2 by 24% (HR: 0.76; 95% CI: 0.44-1.29) relative to placebo. The outcomes were comparable between subgroups with low- and high-volume disease at baseline. No new safety issues were identified. Apalutamide provides valuable clinical benefits to Asian patients with mCSPC, with an efficacy and safety profile consistent with that in the overall patient population.

Neoadjuvant radiohormonal therapy for oligo-metastatic prostate cancer: safety and efficacy outcomes from an open-label, dose-escalation, single-center, phase I/II clinical trial / 医学前沿

To evaluate the safety and efficacy of neoadjuvant radiohormonal therapy for oligometastatic prostate cancer (OMPC), we conducted a 3 + 3 dose escalation, prospective, phase I/II, single-arm clinical trial (CHiCTR1900025743), in which long-term neoadjuvant androgen deprivation was adopted 1 month before radiotherapy, comprising intensity modulated radiotherapy to the pelvis, and stereotactic body radiation therapy to all extra-pelvic bone metastases for 4-7 weeks, at 39.6, 45, 50.4, and 54 Gy. Robotic-assisted radical prostatectomy was performed after 5-14 weeks. The primary outcome was treatment-related toxicities and adverse events; secondary outcomes were radiological treatment response, positive surgical margin (pSM), postoperative prostate-specific antigen (PSA), pathological down-grading and tumor regression grade, and survival parameters. Twelve patients were recruited from March 2019 to February 2020, aging 66.2 years in average (range, 52-80). Median baseline PSA was 62.0 ng/mL. All underwent RARP successfully without open conversions. Ten patients recorded pathological tumor down-staging (83.3%), and 5 (41.7%) with cN1 recorded negative regional lymph nodes on final pathology. 66.7% (8/12) recorded tumor regression grading (TRG) -I and 25% (3/12) recorded TRG-II. Median follow-up was 16.5 months. Mean radiological progression-free survival (RPFS) was 21.3 months, with 2-year RPFS of 83.3%. In all, neoadjuvant radiohormonal therapy is well tolerated for oligometastatic prostate cancer.

Tratamiento hormonal de la pedofilia: ¿puede curar la pedofilia con la castración química? / Pedophilia hormonal therapy: can pedophilia be cured with chemical castration

Históricamente la sociedad ha rechazado el abuso sexual de menores de 13 años, dictándose leyes al respecto. La justicia luego de un debido proceso condenaba al victimario con reclusión incluso hasta la década del 70-80, con orquiectomía. Los adelantos en neurobiología, endocrinología, sicofarmacología y sicología se consideraron las bases para tratar al pedófilo y someterlo a libertad condicional, ahorrándose el costo financiero de la reclusión de por vida. Diversos países dictaron leyes contra la conducta pedófila. En dicha legislación ejerció gran influencia la promulgación en EE.UU. (estado de Washington "sobre el ofensor sexual" y el dictamen de la Corte Suprema en 1997 en el juicio de Kansas vs Hendricks). En Chile en los 90 el caso del pedófilo apodado "Zacarach" sacó a la luz pública el tema que no se quería ver. En esa fecha se presentó al parlamento un proyecto de Ley para "curar" la pedofilia con acetato de Medroxiprogesterona imitando legislación de EE.UU. Causó sorpresa en el medio endocrinológico que se usara terapia hormonal como "cura" de la pedofilia. Se ha utilizado en varios países la castración química producida por gestágenos o agonístas del GnRH más antiandrógenos (acetato de Ciproterona), para inhibir la secreción y acción de la testosterona disminuyendo líbido y erección. No se ha demostrado que exista curación de la orientación pedófila y existen dudas de la prevención primaria y secundaria de la pedofilia. Pese al adelanto tecnológico en neurociencias para estudio de las zonas vinculadas a la sexualidad, aún no existen marcadores que permitan diagnosticar o pronosticar futuros resultados de la terapia. El tratamiento médico de la pedofilia no garantiza curación ni prevención del delito pedofílico.

Historically, society has rejected sexual abuse of children under 13, with there having been laws enacted in this regard. The judicial system, after a due process, condemned the perpetrator with reclusion and even up until the decades of the 70s and 80s with orchiectomy. Advances in neurobiology, endocrinology, psychopharmacology and psychology were considered the basis for treating the pedophile and putting them on probation, saving the financial cost of imprisonment for life. Multiple countries have enacted laws against pedophilic behaviour. Such legislation was greatly influenced by the enactment in the USA (state of Washington "on the sex offender" and the ruling of the Supreme Court in 1997 in the trial of Kansas against Hendricks). In Chile in the 90s, the case of a pedophile nicknamed "Zacarach" brought to light an issue that nobody wanted to see. Around that time, a bill was presented to Parliament to try and "cure" pedophilia with Medroxyprogesterone acetate, imitating US legislation. It was a surprise in the endocrinological world that hormonal therapy would be used as a "cure" for pedophilia. Chemical castration produced by gestagens or GnRH agonists plus antiandrogens (Cyproterone acetate) has been used in several countries to inhibit the secretion and action of testosterone, reducing libido and erection. It has not been proven that there is a cure for pedophile orientation and there are doubts about the primary and secondary prevention of pedophilia. Despite technological advances in neurosciences for the study of the zones pertaining to sexuality, there are still no indicators that allow for diagnosis or prediction of future results of therapy. The medical treatment of pedophilia does not guarantee cure or prevention of pedophilic crime.

Influence of statins in metastatic castration-resistant prostate cancer patients treated with new antiandrogen therapies: a systematic review and meta-analysis

ABSTRACT Objective To evaluate whether the addition of statins to the new antiandrogens (enzalutamide or abiraterone) affects overall survival in patients with metastatic castration-resistant prostate cancer. Methods We searched studies in English language including the keywords statins, overall survival, and metastatic castration-resistant prostate cancer, at PubMed® (MEDLINE®), Embase and Cochrane databases. Results A total of 195 articles were initially identified, but only four met the inclusion criteria and were selected for the meta-analysis. A total of 955 patients, 632 on the new antiandrogens only group, and 323 on the new antiandrogens + statins group, were analyzed. In all four studies the combination therapy (new antiandrogens + statin) was well tolerated, regardless of which new antiandrogens were used. Neither the type of statin nor the doses and duration of use were well specified in the studies. The combination therapy in metastatic castration-resistant prostate cancer was associated with an overall survival improvement, and a 46% reduction in death (hazard ratio of 0.54; 95%CI 0.34-0.87; p<0.01) in multivariate analysis. Conclusion There seems to be a clinical benefit with the association of statins to the new antiandrogens in patients with metastatic castration-resistant prostate cancer, suggesting longer overall survival with no important collateral effect. However, due to fragility of the studies available in the literature, we are not yet capable of recommending this combination of drugs in the clinical practice. Further randomized prospective studies are warranted to confirm these beneficial outcomes.

Complete androgen blockade vs. medical castration alone as adjuvant androgen deprivation therapy for prostate cancer patients following radical prostatectomy: a retrospective cohort study / 中华医学杂志(英文版)

BACKGROUND@#Till date, the optimal treatment strategy for delivering adjuvant androgen deprivation therapy (ADT) in localized and locally advanced prostate cancer (PCa), as a lower stage in PCa progression compared with metastatic PCa, is still unclear. This study compares the efficacy of castration alone with complete androgen blockade (CAB) as adjuvant ADT in patients with localized and locally advanced PCa undergoing radical prostatectomy (RP).@*METHODS@#Patients diagnosed with PCa, without lymph node or distant metastasis, who received RP in West China Hospital between January 2009 and April 2019, were enrolled in this study. We performed survival, multivariable Cox proportional hazard regression, and subgroup analyses.@*RESULTS@#A total of 262 patients were enrolled, including 107 patients who received castration alone and 155 patients who received CAB. The survival analysis revealed that there was no significant difference between the two groups (hazard ratios [HR] = 1.07, 95% confidence intervals [95% CI] = 0.60-1.90, P = 0.8195). Moreover, the multivariable Cox model provided similarly negative results before and after adjustment for potential covariant. Similarly, there was no significant difference in the clinical recurrence between the two groups in both non-adjusted and adjusted models. Furthermore, our subgroup analysis showed that CAB achieved better biochemical recurrence (BCR) outcomes than medical castration alone as adjuvant ADT for locally advanced PCa (P for interaction = 0.0247, HR = 0.37, 95% CI = 0.14-1.00, P = 0.0497).@*CONCLUSION@#Combined androgen blockade achieved better BCR outcomes compared with medical castration alone as adjuvant ADT for locally advanced PCa without lymph node metastasis.

Clinical efficacy of docetaxel combined with carboplatin in patients with metastatic castration-resistant prostate cancer / 北京大学学报(医学版)

OBJECTIVE@#To observe the early efficacy and toxicity of docetaxel combined with carboplatin in patients with metastatic castration-resistant prostate cancer (mCRPC).@*METHODS@#From May 2017 to July 2019, fifteen patients with mCRPC treated in Peking University First Hospital were collected. The median age was 70 years (43-77 years), and the pathological types were all adenocarcinoma, which was confirmed as distant metastasis by imaging examination. They were given the chemotherapy of docetaxel combined with carboplatin. The specific method was as follows: each cycle was 28 days. Androgen deprivation therapy was administered routinely throughout the treatment period. Blood routine, liver and kidney function, blood clotting function and prostate-specific antigen (PSA) tests were performed before each cycle. Docetaxel was administered intravenously on the first day of each cycle at a dose of 75 mg/m2, and carboplatin was administered intravenously on the second day at the dose calculated by Calvert formula. The main outcome measures including PSA decline range, pain remission rate and occurrence of adverse reactions were observed and analyzed.@*RESULTS@#Among the 15 patients, 12 had completed at least 4 cycles of chemotherapy and had short-term efficacy evaluation. PSA decline range > 50% was observed in 8 patients (66.7%). Among the 9 patients with bone pain, remarkable pain relief was observed in 4 patients (44.4%). Among the 4 patients with measurable metastatic lesions, 2 achieved partial response, 1 was evaluated as stable disease, and 1 was evaluated as progressive disease. The main adverse reactions of chemotherapy included bone marrow suppression, gastrointestinal reactions, fatigue and neurological disorders, and most of them were within the tolerable range.@*CONCLUSION@#This report is a case series study of docetaxel combined with carboplatin in the treatment of mCRPC reported in China and the conclusions are representative. The chemotherapy of docetaxel combined with carboplatin has positive short-term efficacy and high safety in patients with mCRPC, which is worthy of further promotion and exploration in clinical practice.

Clinical and surgical assistance in prostate cancer during the COVID-19 Pandemic: implementation of assistance protocols

ABSTRACT Purpose: Propose an approach of prostate cancer (PCa) patients during COVID-19 pandemic. Material and Methods: We conducted a review of current literature related to surgical and clinical management of patients during COVID-19 crisis paying special attention to oncological ones and especially those suffering from PCa. Based on these publications and current urological guidelines, a manual to manage PCa patients is suggested. Results: Patients suffering from cancer are likely to develop serious complications from COVID-19 disease together with an increased risk of postoperative morbidity and mortality. Therefore, the management of oncological patients should be taken into special consideration and most of the treatments postponed. In case the procedure is not deferrable, it should be adapted to the current situation. While the shortest radiotherapy (RT) regimens should be applied, surgical procedures must undergo the following recommendations proposed by main surgical associations. PCa prognosis is generally favourable and therefore one can safely delay most of the biopsies up to 6 months without interfering with survival outcomes in the vast majority of cases. In the same way, most of the localised PCa patients are suitable for active surveillance (AS) or hormonal therapy until local definitive treatment could be reconsidered. In metastatic as well as castration resistant PCa stages, adding androgen receptor targeted agents (abiraterone, apalutamide, darolutamide or enzalutamide) to androgen-deprivation therapy (ADT) could be considered in high risk patients. On the contrary, chemotherapy, immunotherapy and Radium-223 must be avoided with regard to the consequence of hematologic toxicity and risk of COVID-19 infection because of immunodepression. Conclusions: Most of the biopsies should be delayed while AS is advised in those patients with low risk PCa. ADT allows us to defer definitive local treatment in many cases of intermediate and high risk PCa. In regard to metastatic and castration resistant PCa, combination therapies with abiraterone, apalutamide, darolutamide or enzalutamide could be considered. Chemotherapy, Radium-223 and immunotherapy are discouraged.

Salud ósea en personas transgénero / Bone health in transgender subjects

Una persona transgénero es aquella en la cual el género autopercibido difiere del asignado al nacer, mientras que el término cisgénero es utilizado en aquellos individuos no trans. El tratamiento hormonal cruzado (THC) constituye una opción para lograr caracteres sexuales secundarios deseados. Es conocido que los esteroides sexuales desempeñan un rol fundamental en la adquisición de la densidad mineral ósea (DMO) durante la pubertad. Por lo tanto, el impacto del THC sobre la masa ósea se ha convertido en materia de estudio. En estadios puberales tempranos, los análogos de la hormona liberadora de gonadotrofinas (GnRH) son utilizados con un efecto reversible. Si bien la DMO parece mantenerse estable, cuando se compara con una población de referencia del mismo sexo biológico y edad, el Z-score se encuentra por debajo de lo esperado. En adultos, durante el THC no se informaron disminuciones en la DMO. Está reportado que las mujeres trans antes del inicio del TH presentan características densitométricas diferentes de los hombres cisgénero. Hasta el momento, la carga de datos para los calculadores del riesgo de fractura y el software del equipo DXA se basan en el sexo biológico y no en identidad de género. Recientemente, la International Society for Clinical Densitometry (ISCD) emitió sus recomendaciones para la evaluación de la masa ósea en personas transgénero y en aquellos individuos no conformes con el género. Si bien la ISCD sugiere realizar la evaluación únicamente en aquellos pacientes con factores de riesgo, es de importancia realizar DXA basal, sobre todo en mujeres transgénero, para determinar el riesgo inicial de dicha población. En este artículo se revisa la evidencia disponible sobre el impacto del THC en la salud ósea de personas transgénero. (AU)

Cross sex hormone therapy (CSHT) in transgender women (TW) it is an option to achieve desired secondary sexual characteristics. It is known that sex steroids play a fundamental role in the acquisition of bone mineral density during puberty, in addition to determining a different characteristic bone pattern between both biological sexes. So the impact of affirming HT on bone is it has become in subject of study. In early pubertal stages, GnRH analogs are used with a reversible effect. Although bone mineral density (BMD) seems to remain stable, when compared with a reference population of the same biological sex and age, the Z-score is lower than expected. In adults, during CSHT no decreases in BMD were reported. However, it was reported that TW prior to starting CSHT present different densitometric characteristics than cisgender men. So far, the data load for the fracture risk calculators and DXA software is based on biological sex and not gender identity. Recently the ISCD issued its recommendations for the evaluation of bone mass in transgender subjects and in those non-conforming to gender. Although the ISCD suggests performing the evaluation only in those patients with risk factors, our group recognizes that baseline DXA, especially in TW, constitutes a useful tool to determine the initial risk of this population. Our proposal arises from our own experience and from that compiled in the international literature, where it is observed that even without starting CSHT, transgender women have lower BMD. DXA. This article reviews the available evidence regarding the effect of CSHT on health bone in transgender people. (AU)

Síndrome de Insensibilidad Completa a Andrógenos (SICA): reporte de un caso clínico / Complete Androgen Insensitivity Syndrome (CAIS): report of a clinical case

INTRODUCTION: Complete Androgen Insensitivity Syndrome (CAIS) is a X-linked recessive disorder characterized by a complete resistance of the Androgen Receptor (AR) to androgens. As a result, affected individuals present complete female external genitalia, but are genetically male with a 46, XY karyotype. The typical presentation for this syndrome is either inguinal swellings in a new born or infant, or primary amenorrhoea in an adolescent. CAIS is commonly diagnosed in one of these clinical scenarios, although recently prenatal diagnosis has been reported. We present a case of a phenotypically female infant with an inguinal swelling, which was biopsied and exposed as testicular tissue, doing the diagnosis of CAIS. A review of the literature on this disorder is made.

Síndrome dos ovários policísticos: tratamento das manifestações androgênicas / Polycystic ovary syndrome: treatment of androgenic manifestations

A síndrome dos ovários policísticos (SOP) é um distúrbio endócrino-metabólico muito frequente no período reprodutivo. Quando associado ao distúrbio metabólico, as mulheres com SOP podem ter ainda risco acrescido para doença cardiovascular. O objetivo deste manuscrito é descrever as repercussões metabólicas, incluindo quais as principais, como investigar e as consequências desse distúrbio sobre a saúde da mulher. É uma revisão narrativa mostrando a implicação da resistência insulínica, das dislipidemias e da síndrome metabólica sobre o sistema reprodutor e sobre o risco cardiovascular da mulher com SOP, bem como do uso de sensibilizadores de insulina no seu tratamento. Conclui-se que a correção dos distúrbios metabólicos na SOP é benéfica tanto para o sistema reprodutor quanto para o cardiovascular. A primeira linha de tratamento é a mudança de estilo de vida e a perda de peso. Na resposta inadequada, o tratamento medicamentoso está recomendado. Nas mulheres com obesidade mórbida que não tiveram bons resultados com o tratamento clínico, a cirurgia bariátrica é uma opção.(AU)

Enhancing PSMA-uptake with androgen deprivation therapy - a new way to detect prostate cancer metastases?

ABSTRACT Purpose: 68Ga-PSMA PET/CT imaging is a promising modality for the staging of recurrent prostate cancer (PCa). Current evidence suggests limited diagnostic value of the 68Ga-PSMA PET/CT in PSA-levels ≤0.3ng/mL. Experimental data have demonstrated an increase in PSMA-expression in PCa metastases by androgen deprivation in vitro. The aim of the current study was to investigate a possible enhancing effect of PSMA with low-dose androgen deprivation in patients with BCR and low PSA-levels. Materials and Methods: Five patients with PCa and BCR, following radical prostatectomy, underwent 68Ga-PSMA PET/CT. A consecutive 68Ga-PSMA PET/CT was performed 6 to 11 days after injection of 80mg of Degarelix (Firmagon®). We recorded PSA and testosterone serum-levels and changes of PSMA-uptake in 68Ga-PSMA PET/CT images. Results: Median PSA prior 68Ga-PSMA PET/CT was 0.27ng/mL. All patients had a decrease in testosterone serum levels from median 2.95μg/l to 0.16μg/l following Degarelix injection. We observed an increase in the standardized uptake value (SUV) in PSMA-positive lymphogenous and osseous lesions in two patients following androgen deprivation. In another two patients, no PSMA positive signals were detected in either the first or the second scan. Conclusion: Our preliminary results of this feasibility assessment indicate a possible enhancing effect of PSMA-imaging induced by low-dose ADT. Despite several limitations and the small number of patients, this could be a new approach to improve staging by 68Ga-PSMA PET/CT in PCa patients with BCR after primary therapy. Further prospective studies with larger number of patients are needed to validate our findings.

Cost-effectiveness analysis of abiraterone, docetaxel or placebo plus androgen deprivation therapy for hormone-sensitive advanced prostate cancer / Análise de custo-efetividade da adição de abiraterona ou quimioterapia ao tratamento do câncer de próstata metastático hormônio-sensível

ABSTRACT Objective To evaluate the cost-effectiveness of the addition of chemotherapy or abiraterone to androgen deprivation. Methods We developed an analytical model to determine the cost-effectiveness of the addition of docetaxel or abiraterone versus androgen deprivation therapy alone. Direct and indirect costs were included in the model. The effects were expressed in Quality-Adjusted Life Years adjusted for side effects. Results Compared to androgen deprivation therapy alone, the addition of chemotherapy and of abiraterone generated 0.492 and 0.999, respectively, in Quality-Adjusted Life Years. Abiraterone led to a Quality-Adjusted Life Years gain of 0.506 compared to docetaxel. The incremental costs per Quality-Adjusted Life Years were R$ 133.649,22 for docetaxel, R$ 330.828,70 for abiraterone and R$ 571.379,42 for abiraterone compared to docetaxel, respectively. Conclusion The addition of chemotherapy to androgen deprivation therapy is more cost-effective than the addition of abiraterone to androgen deprivation therapy. However, discounts on abiraterone cost might improve cost-effectiveness.

RESUMO Objetivo Avaliar a relação custo-efetividade da adição de quimioterapia ou abiraterona à terapia de privação hormonal. Métodos Um modelo analítico foi desenvolvido para determinar a relação custo-efetividade da adição de docetaxel ou abiraterona comparada à terapia de privação hormonal isolada. Custos diretos e indiretos foram incluídos no modelo. Os efeitos foram expressos em Anos de Vida Ajustados para Qualidade corrigidos pelos efeitos colaterais de cada terapia. Resultados A adição de quimioterapia e de abiraterona à terapia de privação hormonal aumentou os Anos de Vida Ajustados para Qualidade em 0,492 e 0,999, respectivamente, em comparação à terapia de privação hormonal isolada. A abiraterona promoveu ganho de Anos de Vida Ajustados para Qualidade de 0,506 em relação ao docetaxel. O custo incremental por Anos de Vida Ajustados para Qualidade foi R$ 133.649,22 para o docetaxel, R$ 330.828,70 para a abiraterona e R$ 571.379,42 para a abiraterona comparada ao docetaxel. Conclusão A adição de quimioterapia à terapia de privação hormonal é mais custo-efetiva que a adição de abiraterona à terapia de privação hormonal. Contudo, descontos no custo da abiraterona poderiam tornar esse tratamento mais custo-efetivo.

Current opinion and mechanistic interpretation of combination therapy for castration-resistant prostate cancer / 亚洲男科学杂志(英文版)

Recent advances in genomics technology have led to the massive discovery of new drug targets for prostate cancer; however, none of the currently available therapeutics is curative. One of the greatest challenges is drug resistance. Combinations of therapies with distinct mechanisms of action represent a promising strategy that has received renewed attention in recent years. Combination therapies exert cancer killing functions through either concomitant targeting of multiple pro-cancer factors or more effective inhibition of a single pathway. Theoretically, the combination therapy can improve efficacy and efficiency compared with monotherapy. Although increasing numbers of drug combinations are currently being tested in clinical trials, the mechanisms by which these combinations can overcome drug resistance have yet to be fully understood. The purpose of this review is to summarize recent work on therapeutic combinations in the treatment of castration-resistant prostate cancer and discuss emerging mechanisms underlying drug resistance. In addition, we provide an overview of the current preclinical mechanistic studies on potential therapeutic combinations to overcome drug resistance.

The current status of hormone treatment for prostate cancer patients in Korean real-world practice: a multi-institutional observational study / 亚洲男科学杂志(英文版)

We aimed to evaluate the current nationwide trend, efficacy, safety, and quality of life (QoL) profiles of hormone treatment in real-world practice settings for prostate cancer (PCa) patients in Korea. A total of 292 men with any biopsy-proven PCa (TanyNanyMany) from 12 institutions in Korea were included in this multi-institutional, observational study of prospectively collected data. All luteinizing hormone-releasing hormone (LHRH) agonists were allowed to be investigational drugs. Efficacy was defined as (1) the rate of castration (serum testosterone ≤50 ng dl-1) at 4-week visit and (2) breakthrough (serum testosterone >50 ng dl-1 after castration). Safety assessments included routine examinations for potential adverse events, laboratory tests, blood pressure, body weight, and bone mineral density (BMD, at baseline and at the last follow-up visit). QoL was assessed using the Expanded Prostate Cancer Index Composite-26 (EPIC-26). The most common initial therapeutic regimen was LHRH agonist with anti-androgen (78.0%), and the most commonly used LHRH agonist for combination and monotherapy was leuprolide (64.0% for combination and 58.0% for monotherapy). The castration and breakthrough rates were 78.4% and 6.6%, respectively. The laboratory results related to dyslipidemia worsened after 4 weeks of hormone treatment. In addition, the mean BMD T-score was significantly lower at the last follow-up (mean: -1.950) compared to baseline (mean: -0.195). The mean total EPIC-26 score decreased from 84.8 (standard deviation [s.d.]: 12.2) to 78.3 (s.d.: 8.1), with significant deterioration only in the urinary domain (mean: 23.5 at baseline and 21.9 at the 4-week visit). These findings demonstrate the nationwide trend of current practice settings in hormone treatment for PCa in Korea.

Enzalutamide: a new indication for nonmetastatic castration-resistant prostate cancer / 亚洲男科学杂志(英文版)

PROSPER is an international Phase III trial demonstrating the beneficial role of enzalutamide, an androgen receptor antagonist, in prolonging metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer. The trial showed that the median metastasis-free survival was 21.9 months longer for those treated with enzalutamide (36.6 months) compared to those treated with placebo (14.7 months). Enzalutamide also showed prolonged time to PSA progression, PSA response, and time to initiating additional antineoplastic therapy although overall survival is not yet reached. Enzalutamide is the second antiandrogen (next to apalutamide) that has gained the United States Food and Drug Administration (US FDA) label indication for use in the setting of nonmetastatic castration-resistant prostate cancer.

The regulatory pathways leading to stem-like cells underlie prostate cancer progression / 亚洲男科学杂志(英文版)

Prostate cancer (PCa) is the most common cause of malignancy in males and the third leading cause of cancer mortality in the United States. The standard care for primary PCa with local invasive disease mainly is surgery and radiation. For patients with distant metastases, androgen deprivation therapy (ADT) is a gold standard. Regardless of a favorable outcome of ADT, patients inevitably relapse to an end-stage castration-resistant prostate cancer (CRPC) leading to mortality. Therefore, revealing the mechanism and identifying cellular components driving aggressive PCa is critical for prognosis and therapeutic intervention. Cancer stem cell (CSC) phenotypes characterized as poor differentiation, cancer initiation with self-renewal capabilities, and therapeutic resistance are proposed to contribute to the onset of CRPC. In this review, we discuss the role of CSC in CRPC with the evidence of CSC phenotypes and the possible underlying mechanisms.

Lineage plasticity-mediated therapy resistance in prostate cancer / 亚洲男科学杂志(英文版)

Therapy resistance is a significant challenge for prostate cancer treatment in clinic. Although targeted therapies such as androgen deprivation and androgen receptor (AR) inhibition are effective initially, tumor cells eventually evade these strategies through multiple mechanisms. Lineage reprogramming in response to hormone therapy represents a key mechanism that is increasingly observed. The studies in this area have revealed specific combinations of alterations present in adenocarcinomas that provide cells with the ability to transdifferentiate and perpetuate AR-independent tumor growth after androgen-based therapies. Interestingly, several master regulators have been identified that drive plasticity, some of which also play key roles during development and differentiation of the cell lineages in the normal prostate. Thus, further study of each AR-independent tumor type and understanding underlying mechanisms are warranted to develop combinational therapies that combat lineage plasticity in prostate cancer.