The role of glutamine metabolism in castration-resistant prostate cancer / 亚洲男科学杂志(英文版)

Reprogramming of metabolism is a hallmark of tumors, which has been explored for therapeutic purposes. Prostate cancer (PCa), particularly advanced and therapy-resistant PCa, displays unique metabolic properties. Targeting metabolic vulnerabilities in PCa may benefit patients who have exhausted currently available treatment options and improve clinical outcomes. Among the many nutrients, glutamine has been shown to play a central role in the metabolic reprogramming of advanced PCa. In addition to amino acid metabolism, glutamine is also widely involved in the synthesis of other macromolecules and biomasses. Targeting glutamine metabolic network by maximally inhibiting glutamine utilization in tumor cells may significantly add to treatment options for many patients. This review summarizes the metabolic landscape of PCa, with a particular focus on recent studies of how glutamine metabolism alterations affect therapeutic resistance and disease progression of PCa, and suggests novel therapeutic strategies.

PD-1 inhibitor plus anlotinib for metastatic castration-resistant prostate cancer: a real-world study / 亚洲男科学杂志(英文版)

Management and treatment of terminal metastatic castration-resistant prostate cancer (mCRPC) remains heavily debated. We sought to investigate the efficacy of programmed cell death 1 (PD-1) inhibitor plus anlotinib as a potential solution for terminal mCRPC and further evaluate the association of genomic characteristics with efficacy outcomes. We conducted a retrospective real-world study of 25 mCRPC patients who received PD-1 inhibitor plus anlotinib after the progression to standard treatments. The clinical information was extracted from the electronic medical records and 22 patients had targeted circulating tumor DNA (ctDNA) next-generation sequencing. Statistical analysis showed that 6 (24.0%) patients experienced prostate-specific antigen (PSA) response and 11 (44.0%) patients experienced PSA reduction. The relationship between ctDNA findings and outcomes was also analyzed. DNA-damage repair (DDR) pathways and homologous recombination repair (HRR) pathway defects indicated a comparatively longer PSA-progression-free survival (PSA-PFS; 2.5 months vs 1.2 months, P = 0.027; 3.3 months vs 1.2 months, P = 0.017; respectively). This study introduces the PD-1 inhibitor plus anlotinib as a late-line therapeutic strategy for terminal mCRPC. PD-1 inhibitor plus anlotinib may be a new treatment choice for terminal mCRPC patients with DDR or HRR pathway defects and requires further investigation.

Scaffold protein MAPK8IP2 expression is a robust prognostic factor in prostate cancer associated with AR signaling activity / 亚洲男科学杂志(英文版)

Mitogen-activated protein kinase-8-interacting protein 2 (MAPK8IP2) is a scaffold protein that modulates MAPK signal cascades. Although MAPK pathways were heavily implicated in prostate cancer progression, the regulation of MAPK8IP2 expression in prostate cancer is not yet reported. We assessed MAPK8IP2 gene expression in prostate cancer related to disease progression and patient survival outcomes. MAPK8IP2 expression was analyzed using multiple genome-wide gene expression datasets derived from The Cancer Genome Atlas (TCGA) RNA-sequence project and complementary DNA (cDNA) microarrays. Multivariable Cox regressions and log-rank tests were used to analyze the overall survival outcome and progression-free interval. MAPK8IP2 protein expression was evaluated using the immunohistochemistry approach. The quantitative PCR and Western blot methods analyzed androgen-stimulated MAPK8IP2 expression in LNCaP cells. In primary prostate cancer tissues, MAPK8IP2 mRNA expression levels were significantly higher than those in the case-matched benign prostatic tissues. Increased MAPK8IP2 expression was strongly correlated with late tumor stages, lymph node invasion, residual tumors after surgery, higher Gleason scores, and preoperational serum prostate-specific antigen (PSA) levels. MAPK8IP2 upregulation was significantly associated with worse overall survival outcomes and progression-free intervals. In castration-resistant prostate cancers, MAPK8IP2 expression strongly correlated with androgen receptor (AR) signaling activity. In cell culture-based experiments, MAPK8IP2 expression was stimulated by androgens in AR-positive prostate cancer cells. However, MAPK8IP2 expression was blocked by AR antagonists only in androgen-sensitive LNCaP but not castration-resistant C4-2B and 22RV1 cells. These results indicate that MAPK8IP2 is a robust prognostic factor and therapeutic biomarker for prostate cancer. The potential role of MAPK8IP2 in the castration-resistant progression is under further investigation.

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.

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.

Consensus on diagnosis and management of non-metastatic castration resistant prostate cancer in Brazil: focus on patient, selection, treatment efficacy, side effects and physician's perception according to patient comorbidities

ABSTRACT Background: Non-metastatic castration resistant prostate cancer (M0 CRPC) has seen important developments in drugs and diagnostic tools in the last two years. New hormonal agents have demonstrated improvement in metastasis free survival in M0 CRPC patients and have been approved by regulatory agencies in Brazil. Additionally, newer and more sensitive imaging tools are able to detect metastasis earlier than before, which will impact the percentage of patients staged as M0 CRPC. Based on the available international guidelines, a group of Brazilian urology and medical oncology experts developed and completed a survey on the diagnosis and treatment of M0 CRPC in Brazil. These results are reviewed and summarized and associated recommendations are provided. Objective: To present survey results on management of M0 CRPC in Brazil. Design, setting, and participants: A panel of six Brazilian prostate cancer experts determined 64 questions concerning the main areas of interest: 1) staging tools, 2) treatments, 3) side effects of systemic treatment/s, and 4) osteoclast-targeted therapy. A larger panel of 28 Brazilian prostate cancer experts answered these questions in order to create country-specific recommendations discussed in this manuscript. Outcome measurements and statistical analysis: The panel voted publicly but anonymously on the predefined questions. These answers are the panelists' opinions, not a literature review or meta-analysis. Therapies not yet approved in Brazil were excluded from answer options. Each question had five to seven relevant answers including two non-answers. Results were tabulated in real time. Conclusions: The results and recommendations presented can be used by Brazilian physicians to support the management of M0 CRPC patients. Individual clinical decision making should be supported by available data, however, for Brazil, guidelines for diagnosis and management of M0 CRPC patients have not been developed. This document will serve as a point of reference when confronting this disease stage.

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.

Eficacia y seguridad de acetato de abiraterona o enzalutamida en pacientes con cáncer de próstata metastásico visceral resistente a la castración con progresión a quimioterapia previa / Efficacy and safety of abiraterone acetate or enzalutamide in patients with castration-resistant visceral metastatic prostate cancer with progression to prior chemotherapy

INTRODUCCIÓN: El cáncer de próstata es el segundo cáncer más frecuente entre hombres a nivel mundial. El estadiaje clínico de la enfermedad se basa en la clasificación TNM (T: tumor, N: compromiso ganglionar, y M: metástasis), que en estadios avanzados, pueden invadir estructuras adyacentes o tener metástasis a distancia a nivel óseo o visceral como pulmón, hígado, pleura o glándula suprarrenal. El tratamiento sistémico se basa en la terapia de deprivación de andrógenos. Sin embargo, cuando la enfermedad progresa se conoce como cáncer de próstata resistente a la castración (CPRC) y puede presentar metástasis al esqueleto óseo y a estructuras viscerales.  El Petitorio Farmacológico de EsSalud cuenta con docetaxel y mitoxantrona que pueden ser usados como agentes quimioterapéuticos en pacientes con CPRC metastásico. Además, se dispone de acetato de abiraterona que fue aprobado para uso en EsSalud en pacientes con CPRC metastásico excluyendo a aquellos con metástasis viscerales, por lo cual es necesario evaluar si existen otras opciones que puedan ser utilizadas en el tratamiento de estos pacientes. OBJETIVO: Evaluar la mejor evidencia disponible sobre la eficacia y seguridad de acetato de abiraterona o enzalutamida, en pacientes con cáncer de próstata metastásico visceral resistente a la castración con progresión a quimioterapia previa. TECNOLOGÍAS SANITARIAS DE INTERÉS: Acetato de Abiraterona o Enzalutamida: Los aspectos generales de acetato de abiraterona se describen con mayor detalle en el Dictamen Preliminar de Evaluación de Tecnología Sanitaria N° 036-SDEPFyOTSDETS-IETSI-2016. Se describen las características más relevantes de la tecnología sanitaria de interés. Acetato de abiraterona es un inhibidor selectivo de la enzima 17α-hidroxilasa/C17,20- liasa (CYP17) que interviene en la síntesis de andrógenos en los tejidos testiculares, suprarrenales y tejidos prostáticos tumorales reduciendo la concentración sérica de testosterona y otros andrógenos hasta niveles inferiores a los obtenidos con agonistas de la hormona liberadora de hormona luteinizante (LHRH) o con orquiectomía (European Medicines Agency 2016). METODOLOGÍA: Se llevó a cabo una búsqueda bibliográfica exhaustiva y jerárquica de la literatura biomédica para evaluar la eficacia y seguridad de acetato de abiraterona o enzalutamida en pacientes con cáncer de próstata metastásico visceral resistente a la castración con progresión a quimioterapia previa. Previamente, para describir la tecnología sanitaria de interés, se revisó la información de etiqueta disponible por entes reguladores y normativos de autorización comercial como la FDA en Estados Unidos, EMA en Europa, y DIGEMID en Perú. RESULTADOS: Se llevó a cabo una búsqueda de evidencia científica, sin restricción temporal ni de idioma, relacionada al uso de enzalutamida o acetato de abiraterona comparados con la mejor terapia de soporte en pacientes adultos con diagnóstico de cáncer de próstata metastásico visceral resistente a la castración con progresión a quimioterapia previa. En la presente sinopsis se reporta la evidencia disponible según el tipo de publicación priorizada en los criterios de inclusión; no obstante, a la fecha no se ha publicado un ECA acerca de las tecnologías evaluadas que incluya a la población de interés. CONCLUSIONES: A la fecha no se dispone de evidencia que compare directamente a abiraterona y enzalutamida, por lo que, no se puede establecer la superioridad a favor de unas de las dos tecnologías. Tres GPC identificadas (EAU-EANM-ESTRO-ESUR-SIOG 2019, ESMO 2015, ASCO 2014) consideran a abiraterona o enzalutamida como alternativas de tratamiento en pacientes con cáncer de próstata metastásico resistente a la castración con progresión a quimioterapia previa. La guía de la NCCN brinda recomendaciones a favor de ambas tecnologías evaluadas para la población de la pregunta PICO de interés. Ninguna de las GPC pone por encima a alguna de las tecnologías evaluadas. Por su parte, las ETS identificadas concuerdan en considerar que tanto abiraterona como enzalutamida son una alternativa de tratamiento en pacientes con CPRC metastásico que han progresado a la quimioterapia. Así la ETS de CADTH menciona que abiraterona es el estándar de tratamiento en este grupo de pacientes, además que tanto abiraterona como enzalutamida tienen el mismo precio y similar eficacia, por lo que existiría una diferencia mínima en la costoefectividad incremental a favor de enzalutamida que puede ser modificada hacia una u otra por cambios en el precio de la tecnología. Lo anterior es importante, debido a la diferencia de precios que tienen las tecnologías en el Perú y que favorecería a abiraterona (aun sumando el precio mínimo que tiene prednisona) cuyo precio es diez veces menor que enzalutamia. Por su parte el NICE recomienda a abiraterona y enzalutamida en pacientes con CPRC metastásico que han progresado durante o después de un régimen de quimioterapia a base de docetaxel solo si el fabricante aplica un descuento al precio del medicamento. Ninguna de las ETS descrita establece recomendaciones específicas para los pacientes con CPRC metastásico visceral que han progresado a la quimioterapia. La evidencia más cercana sobre el uso de abiraterona en la población incluida en la pregunta PICO del presente dictamen, es el ECA COU-AA-301, el cual incluyó un subgrupo de pacientes con cáncer de próstata metastásico visceral resistente a la castración con progresión a quimioterapia previa. El análisis por subgrupos dentro de un análisis interino que se realizó en el estudio COU-AA-301 y AFFIRM, reporta que solo abiraterona (COU-AA-301) obtuvo una reducción significativa en la tasa de riesgo instantánea para muerte en pacientes portadores de metástasis visceral desde el reclutamiento. Ninguno de los estudios reportó resultados de otros desenlaces para el subgrupo de pacientes que forman parte de la pregunta PICO de interés. En consecuencia, la evidencia proveniente del análisis por subgrupos (que puede ser considerado como exploratorio ya que el estudio no fue diseñado para evaluar diferencias en esta subpoblación) del estudio COU-AA-301, sugiere que existiría un beneficio neto por parte de abiraterona, en nuestra población de interés. Asimismo, se debe tener la información presentada en la RS de De Nunzio et al. donde a partir de las notificaciones europeas de eventos adversos se encontró un mayor porcentaje de eventos adversos que fueron fatales en el grupo de pacientes que recibió enzalutamida (18 %) vs. abiraterona (14 %), lo cual genera incertidumbre acerca del balance riesgo-beneficio de enzalutamida. Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación-IETSI aprueba el uso fuera del petitorio de acetato de abiraterona, en pacientes con cáncer de próstata metastásico visceral resistente a la castración con progresión a quimioterapia previa, según lo establecido en el Anexo N° 1. No se aprueba el uso de enzalutamida para la condición clínica en mención. La vigencia del presente dictamen preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de nueva evidencia que pueda surgir en el tiempo.

Seguridad y eficacia de acetato de abiraterona en pacientes con cáncer de próstata metastásico resistente a castración sin quimioterapia previa / Safety and efficacy of abiraterone acetate in patients with castration-resistant metastatic prostate cancer without prior chemotherapy

A nivel mundial el cáncer de próstata es el segundo más común entre las personas de sexo masculino. En el año 2012, se estimó una prevalencia de los últimos cinco años de cerca de cuatro millones de pacientes diagnosticados con cáncer de próstata entre el total de la población mundial de hombres. En el Perú, la Dirección General de Epidemiología a través del Sistema Nacional de Vigilancia Epidemiológica reportó que el cáncer de próstata representa alrededor del 5.8% del total de cáncer en el Perú. -\tEl cáncer de próstata metastásico resistente a castración representa una forma letal de esta enfermedad, teniendo opciones limitadas de tratamiento y un tiempo medio de sobrevida menor a dos años. El Petitorio Farmacológico de EsSalud cuenta en la actualidad con prednisona y docetaxel como alternativas de tratamiento. Sin embargo, existen algunos pacientes, como los considerados en la presente pregunta PICO, en quienes la quimioterapia aún no se encuentra clínicamente indicada. El acetato de abiraterona es un inhibidor selectivo de la biosíntesis de andrógeno, bloquea irreversiblemente el citocromo P17 (enzima comprometida en la producción de la testosterona) por ello se suspende la síntesis de andrógenos por la glándula adrenal, tejido prostático y tumor prostático. En el presente dictamen se incluye la búsqueda realizada, sintetizada y evaluada con respecto al uso de acetato de abiraterona en combinación con prednisona para el tratamiento de cáncer de próstata metastásico resistente a castración, en pacientes sin quimioterapia previa. Así, se incluyeron cuatro guías de práctica clínica, dos evaluaciones de tecnologías sanitarias y un ensayo clínico de fase III.\tToda la evidencia incluida se basa en el ensayo clínico de fase III (i.e., COU-AA-302) el cual ha demostrado beneficio en relación a la sobrevida global, la sobrevida libre de progresión, el retraso de inicio de quimioterapia, la calidad de vida y eventos adversos tolerables para el grupo de acetato de abiraterona en combinación con prednisona en relación al grupo placebo. Por lo tanto, la evidencia encontrada es homogénea y consistente al recomendar el uso de acetato de abiraterona en combinación con prednisona como una alternativa de tratamiento para pacientes asintomáticos o con síntomas leves, sin quimioterapia previa, con dicha condición. Sin embargo, el efecto en el aumento de la mediana de la sobrevida es pequeño, inclusive superponiéndose ligeramente sus rangos intercuartiles. Asimismo, se evidencia un aumento en la proporción de los eventos adversos de grado de severidad 3-4. Por lo tanto, la relación riesgo-beneficio no se precisa de forma clara y esa falta de precisión en conjunto con el elevado costo del tratamiento, hacen que sea necesario realizar una evaluación. de costo efectividad contextualizada al nivel local que permita en un futuro, complementar la decisión del presente dictamen. Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) aprueba por el periodo de dos años, el uso de acetato de abiraterona en combinación con prednisona para el tratamiento de cáncer de próstata metastásico resistente a castración en pacientes sin quimioterapia previa; entendiendo la necesidad de una evaluación de costo-efectividad que permita complementar la decisión de este dictamen preliminar.(AU)

Informe de adopción de ETS: abiraterona para cáncer de próstata / ETS adoption report: abiraterone for prostate cancer

El uso de acetato de abiraterona en combinación con prednisona para el tratamiento de cáncer de próstata metastásico resistente a castración, en pacientes sin quimioterapia previa, es un tratamiento alternativo a la quimioterapia que ha probado beneficio en la sobrevida global, la sobrevida libre de progresión, el retraso de uso de quimioterapia, la calidad de vida y eventos adversos similares a los obtenidos con el tratamiento a base de prednisona sola. El uso de acetato de abiraterona en combinación con prednisona para el tratamiento de cáncer de próstata metastásico resistente a castración, en pacientes que han progresado a un solo régimen de quimioterapia a base de docetaxel., es un tratamiento que, en comparación con prednisona sola, ha probado tener beneficio en la sobrevida global, mejora en la calidad de vida y eventos adversos tolerables. Se recomienda la cobertura del medicamento acetato de abiraterona en combinación con prednisona para el tratamiento de cáncer de próstata metastásico resistente a castración, en pacientes sin quimioterapia previa, bajo la modalidad de cobertura con restricciones y cobertura con generación de evidencia. Se recomienda la cobertura del medicamento acetato de abiraterona en combinación con prednisona para el tratamiento de cáncer de próstata metastásico resistente a castración, en pacientes que han progresado a un solo régimen de quimioterapia a base de docetaxel, bajo la modalidad de cobertura con restricciones y cobertura con generación de evidencia.(AU)

Protocolo de evaluación rápida de tecnología sobre seguridad y efectividad del uso de Acetato de Abiraterona en el tratamiento de cáncer de próstata metastásico resistente a la castración sin quimioterapia previa / Protocol of rapid evaluation of technology on safety and effectiveness of the use of Abiraterone Acetate in the treatment of metastatic prostate cancer resistant to castration without prior chemotherapy

El cáncer constituye un problema de salud pública a nivel mundial, en la región de las Américas y en nuestro país, por su alta mortalidad como por la discapacidad que produce. El Estado Peruano ha declarado de interés nacional la atención integral del cáncer y el mejoramiento del acceso a los servicios oncológicos poniendo en marcha en Noviembre del año 2012 el Plan Nacional para la Atención Integral del Cáncer y Mejoramiento del Acceso a los Servicios Oncológicos del Perú denominado Plan Esperanza (D.S. N° 009-2012-SA). El Fondo Intangible Solidario de Salud solicita la evaluación de la tecnología sanitaria acetato de abiraterona como tratamiento en hombres adultos con cáncer de próstata metastásico resistente a la castración en los cuales la quimioterapia no está aún clínicamente indicada, la cual a su vez fue solicitada Hospital Nacional Hipólito Unánue, a raíz de un caso. Luego de una primera revisión, se determina que la tecnología acetato de abiraterona, comercializada en el Perú como Zytiga 250 mg, supera la tolerancia al riesgo para evaluación de tecnologías sanitarias en el Seguro Integral de Salud, por lo se consideró sea evaluada por el área de Evaluación de Tecnologías Sanitarias en el SIS Central.(AU)

Histological changes caused by meclofenamic acid in androgen independent prostate cancer tumors: evaluation in a mouse model

ABSTRACT Meclofenamic acid is a nonsteroidal anti-inflammatory drug that has shown therapeutic potential for different types of cancers, including androgen-independent prostate neoplasms. The antitumor effect of diverse nonsteroidal anti-inflammatory drugs has been shown to be accompanied by histological and molecular changes that are responsible for this beneficial effect. The objective of the present work was to analyze the histological changes caused by meclofenamic acid in androgen-independent prostate cancer. Tumors were created in a nude mouse model using PC3 cancerous human cells. Meclofenamic acid (10 mg/kg/day; experimental group, n=5) or saline solution (control group, n=5) was administered intraperitoneally for twenty days. Histological analysis was then carried out on the tumors, describing changes in the cellular architecture, fibrosis, and quantification of cellular proliferation and tumor vasculature. Meclofenamic acid causes histological changes that indicate less tumor aggression (less hypercellularity, fewer atypical mitoses, and fewer nuclear polymorphisms), an increase in fibrosis, and reduced cellular proliferation and tumor vascularity. Further studies are needed to evaluate the molecular changes that cause the beneficial and therapeutic effects of meclofenamic acid in androgen-independent prostate cancer.

Effects of statin use on the response duration to androgen deprivation therapy in metastatic prostate cancer

PURPOSE: To determine whether statin use delays the development of castration-resistant prostate cancer (CRPC) in patients with metastatic prostate cancer treated with androgen deprivation therapy (ADT). MATERIALS AND METHODS: A total of 171 patients with metastatic prostate cancer at the time of diagnosis who were treated with ADT between January 1997 and December 2013 were retrospectively analyzed. The patients were classified into two groups: the nonstatin use group (A group) and the statin use group (B group). Multivariate analysis was performed on statin use and other factors considered likely to have an effect on the time to progression to CRPC. RESULTS: The mean patient age was 67.1+/-9.1 years, and the mean follow-up period was 52 months. The mean initial prostate-specific antigen (PSA) level was 537 ng/mL. Of the 171 patients, 125 (73%) were in group A and 46 (27%) were in group B. The time to progression to CRPC was 22.7 months in group A and 30.5 months in group B, and this difference was significant (p=0.032). Blood cholesterol and initial PSA levels did not differ significantly according to the time to progression to CRPC (p=0.288, p=0.198). Multivariate analysis using the Cox regression method showed that not having diabetes (p=0.037) and using a statin (p=0.045) significantly increased the odds ratio of a longer progression to CRPC. CONCLUSIONS: Statin use in metastatic prostate cancer patients appears to delay the progression to CRPC. Large-scale, long-term follow-up studies are needed to validate this finding.

Clinical effect of abiraterone acetate in Korean patients with metastatic castration-resistant prostate cancer according to duration of androgen deprivation therapy

PURPOSE: Few data are available concerning the clinical outcome of abiraterone acetate treatment in patients with metastatic castration-resistant prostate cancer (mCRPC) in terms of the duration of androgen deprivation therapy (ADT) before diagnosis of CRPC. We investigated the clinical efficacy of abiraterone acetate according to the duration of ADT. MATERIALS AND METHODS: We reviewed the medical records of 20 patients with mCRPC who received abiraterone acetate after failure of docetaxel chemotherapy from May 2012 to March 2014 at Seoul National University Bundang Hospital. Clinical factors including prostate-specific antigen (PSA) nadir level, time to PSA nadir, PSA doubling time, PSA response, and modes of progression (PSA, radiologic, clinical) were analyzed. Disease progression was classified according to the Prostate Cancer Working Group 2 criteria. RESULTS: The mean age and PSA value of the entire cohort were 76.0+/-7.2 years and 158.8+/-237.9 ng/mL, respectively. The median follow-up duration was 13.4+/-6.7 months. There were no statistically significant differences in clinical characteristics between patients who received abiraterone acetate with ADT duration or =35 months. There were also no significant differences in terms of PSA progression-free survival, radiologic progression-free survival, and clinical progression-free survival between patients with ADT duration or =35 months. CONCLUSIONS: Although this was a retrospective study with a small sample size, we did not observe any statistically significant differences in the clinical response to abiraterone acetate between mCRPC patients with long ADT duration and those with short ADT duration in terms of disease progression-free survival.

The effect of continuous androgen deprivation treatment on prostate cancer patients as compared with intermittent androgen deprivation treatment

PURPOSE: To investigate the efficacy of androgen deprivation treatment (ADT) between continuous and intermittent ADT. MATERIALS AND METHODS: Between January 2006 and May 2015, 603 patients were selected and divided into continuous ADT (CADT) (n=175) and intermittent ADT (IADT) (n=428) groups. The median follow-up in this study was 48.19 (1.0-114.0) months. The primary end point was time to castration resistant prostate cancer (CRPC). The types of ADT were monotherapy and maximal androgen blockade (i.e., luteinizing hormone-releasing hormone agonist and antiandrogen). RESULTS: The characteristics of patients showed no significant differences between the CADT and IADT groups, except for the Gleason score (p<0.001). The median time to CRPC of all enrolled patients with ADT was 20.60±1.60 months. The median time to CRPC was 11.20±1.31 months in the CADT group as compared with 22.60±2.08 months in the IADT group. In multivariate analysis, percentage of positive core (p=0.047; hazard ratio [HR], 0.976; 95% confidence interval [CI], 0.953-1.000), Gleason score (p=0.007; HR, 1.977; 95% CI, 1.206-3.240), lymph node metastasis (p=0.030; HR, 0.498; 95% CI, 0.265-0.936), bone metastasis (p=0.028; HR, 1.921; 95% CI, 1.072-3.445), and CADT vs. IADT (p=0.003; HR, 0.254; 95% CI. 0.102-0.633) were correlated with the duration of progression to CRPC. The IADT group presented a significantly longer median time to CRPC compared with the CADT group. Additionally, patients in the IADT group showed a longer duration in median time to CRPC in subgroup analysis according to the Gleason score. CONCLUSIONS: This study found that IADT produces a longer duration in median time to CRPC than does CADT.

Beyond ten cycles of cabazitaxel for castrate-resistant prostate cancer.

Background: There are limited data regarding cabazitaxel use beyond 10 cycles. Patients and Methods: Retrospective analysis of prospectively collected data of patients with metastatic castrate-resistant prostate cancer who received over 10 cycles of cabazitaxel after docetaxel failure. Results: Four patients received between 14 and 27 cycles. Reasons for stopping cabazitaxel were toxicity (2), progression (1) and logistics (1). Two of the three patients with measurable disease attained a partial remission (PR). Three patients continued to have a PSA response after 10 cycles; PSA nadir occurred between 17 and 23 cycles. Other than peripheral neuropathy (PN), all the cabazitaxel-related toxicities occurred after the initial cycles and did not increase cumulatively. Clinically significant neuropathy occurred after 15-17 cycles. The cabazitaxel-induced PN was partially reversible, with improvement from grade 3 to grade 2 after a 3-5-month long drug holiday. Conclusion: Cautiously continuing cabazitaxel until progression or intolerable toxicity may maximize efficacy.

Inmunoterapia con células presentadoras de antígenos en el tratamiento del cáncer de próstata resistente a la castración / Antigen presenting cells immunotherapy in the treatment of castration resistant prostate cancer

El cáncer de próstata es el tumor más frecuentemente diagnosticado en hombres en países industrializados y es segunda causa de muerte por cáncer en hombres en Norteamérica y Europa. En Chile, según las estadísticas del año 2009, el cáncer de próstata es también la segunda causa de muerte por cáncer en hombres, y se espera que la mortalidad aumente un 30 por ciento en los próximos 10 años. Esta elevada mortalidad se explica por la presencia de pacientes con enfermedad avanzada, tanto por compromiso extraprostático o por diseminación a distancia, así como pacientes que presentan recurrencia de la enfermedad después de tratados como cáncer órgano-confinado. En estos casos, la principal medida terapéutica es el uso de la terapia de deprivación androgénica (TDA). La TDA tiene una efectividad de un 80 a 85 por ciento en el control de la enfermedad. Sin embargo, no es una terapia curativa y su efecto tiene una mediana de duración de 14 a 30 meses, debido al desarrollo de células neoplásicas cuya proliferación es independiente del estímulo androgénico, por lo que prácticamente todos los pacientes se vuelven resistentes al tratamiento. El cáncer de próstata resistente a la castración (CPRC) comprende un grupo heterogéneo de pacientes con cáncer de próstata avanzado, que sometidos a TDA presentan una enfermedad progresiva, tanto bioquímica como aumento o aparición de nuevas lesiones metastásicas. Múltiples denominaciones se han utilizado para categorizar a estos pacientes, además de CPRC, como andrógeno-independiente, hormono-refractario u hormono-independiente, aunque sutiles diferencias existen entre los diferentes términos. El pronóstico de los pacientes con CPRC es poco alentador, ya que presentan una progresión progresiva, con una mediana de sobrevida general entre 12 y 24 meses...

Prostate cancer is the most frequently diagnosed tumor in men in industrialized countries and is second leading cause of cancer death in men in North America and Europe. In Chile, according to the statistics of 2009, prostate cancer is the second leading cause of cancer death in men, and mortality is expected to increase by 30 percent in the next 10 years. This high mortality is explained by the presence of patients with advanced disease, both with extraprostatic or distant spread and patients with recurrent disease after been treated as organ-confined cancer.In these cases, the primary therapeutic measure is the use of androgen deprivation therapy (TDA). TDA has an effectiveness of 80 to 85 percent control of the disease. However, it is not a curative therapy and its effect has a median duration of 14 to 30 months, due to the development of neoplasic cells whose proliferation is independent of androgen stimulus, so that virtually all patients become resistant to treatment. Cancer castration-resistant prostate cancer (CRPC) comprises a heterogeneous group of patients with advanced prostate cancer who alter undergoing TDA exhibit both an increase or appearance of biochemical failure as of new or progressive metastatic lesions. Multiple names have been used to categorize these patients, one is CPRC, other examples are androgen-independent, hormone-refractory or hormone independent, although there are subtle differences between different names. The prognosis of patients with CRPC is poor, as they have a gradual progression, with a median overall survival between 12 and 24 months. Therapeutic options are limited in the CPRC and include different hormonal measures and act as rescue treatment...

Tratamiento con dietilestilbestrol en pacientes refractarios a la castración por análogos LH- RH / Treatment with diethylstilbestrol in patients who had failed to androgen deprivation by lhrh agonists

Introducción: El objeto de este trabajo clínico es estudiar la eficacia de la administración de Dietilestilbestrol (DES) oral en pacientes con cáncer de próstata avanzado y que han presentado refractariedad al tratamiento con análogos LH-RH y además evaluar los efectos colaterales atribuibles a su uso. Material y métodos: Entre Noviembre de 2010 y Mayo de 2012 se ingresaron en forma consecutiva al estudio 15 pacientes con cáncer prostático avanzado, refractarios a manejo con análogos LH-RH. Edad promedio de los pacientes 69,4 años .Rango 57-80. Se registró el tipo de tratamiento realizado, detallando el manejo hormonal previo al que fueron sometidos. Se consideró refractariedad a los análogos, la detección de 2 alzas consecutivas del APE durante la administración de éstos. Se indicó a los pacientes 1mg. de DES al día. La evaluación del tratamiento se hizo cada 30 días con determinación de APE y registro de efectos colaterales. Resultados: De los 15 pacientes, 8 (53,3 por ciento) disminuyeron su APE inicial, 6 de ellos (40 por ciento) lo hicieron en más de un 50 por ciento de su valor y 2 (13,3 por ciento) disminuyeron el APE pero en menos de un 50 por ciento. 7 pacientes (46,6 por ciento) no disminuyeron su valor de APE y fueron considerados como fracasos. Como efectos colaterales del tratamiento tuvimos 13 pacientes (86,6 por ciento) que presentaron hipersensibilidad de los pezones, pero solo 2 requirieron tratamiento sintomático. 4 pacientes (26,6 por ciento) desarrollaron ginecomastia leve a moderada y no tuvimos ninguna complicación cardiovascular en los 15 pacientes estudiados. Conclusión: Consideramos de acuerdo a nuestros resultados que el DES oral es efectivo como tratamiento en los pacientes que han fallado o son refractarios a la deprivación androgénica por análogos LH-RH, con una baja morbilidad, buena aceptación de los pacientes y de muy bajo costo.

Introduction: The object of this clinical trial is to study the effectiveness of the administration of Diethylstilbestrol (DES) oral in patients with advanced cancer of prostate and that has presented resistance to the treatment with analogs LH-RH and in addition to evaluate the collateral effects attributable to its use. Material and methods: Between November of 2010 and May of 2012 15 patients with advanced prostate cancer, refractory to handling with analogs LH-RH entered themselves in consecutive form the study. Age average of the patients 69, 4 years, Rank 57-80. The type of made treatment was registered, detailing previous the hormonal handling which they were put under. Resistance to the analogs, the detection of 2 consecutive rises of the PSA was considered during the administration of this one. 1 mg. was indicated to the patients of DES to the day. The evaluation of the treatment was made every 30 days with determination of PSA and registry of collateral effects. Results: Of the 15 patients, 8 (53,3 percent) diminished their initial PSA, 5 of them (40 percent)did in more of a 50 percent of their value and 2 (13,3 percent) diminished the PSA but in less of a 50 percent. 7 patients (46,6 percent) did not diminished their value of PSA and were considered like failures. As collateral effects of the treatment we had 13 patients (86,6 percent) who presented hypersensitivity of the nipples, but single 2 required symptomatic treatment, 4 patients (26,6 percent) developed ginecomastia weighs moderate and we did not have any cardiovascular complication in the 15 studied patients. Conclusion: We considered according to our results that the oral DES is effective like treatment in the patients who have failed or ar refractory to the androgenic deprivation by analogs LH-RH, with a low morbidity, good acceptance of the patients and very low cost.