Avances en la prevención y el tratamiento de las metástasis óseas en cáncer de próstata. Papel de la inhibición de RANK/RANKL / Advances in Prevention and Treatment of Bone Metastases in Prostate Cancer. Role of RANK/RANKL Inhibition

Contexto: Las metástasis óseas son una complicación frecuente en el cáncer de próstata, por lo que su tratamiento y prevención son fundamentales para disminuir la progresión de la enfermedad y la aparición de eventos relacionados con el esqueleto (ERE), los cuales tienen devastadoras consecuencias en la calidad de vida de los pacientes. Adquisición de evidencia: Realizamos una revisión de la literatura basada en el análisis de los ensayos clínicos, desarrollados en la prevención y tratamiento de las metástasis óseas, y de las nuevas estrategias en marcha con asociación de nuevas dianas terapéuticas. Síntesis de evidencia: Las metástasis óseas se caracterizan por un aumento del recambio óseo yalteración del equilibrio entre osteogénesis y osteólisis, con activación del sistema del RANK y su ligando (RANKL). En pacientes con cáncer de próstata metastásico los bifosfonatos han sido los agentes dirigidos al hueso más utilizados hasta la fecha. El ácido zoledrónico ha demostrado su eficacia en la disminución y retraso de ERE en pacientes con metastásis óseas. Denosumab, inhibidor selectivo de RANKL, ha demostrado un efecto superior frente al ácido zoledrónico en la prevención de ERE en cáncer de próstata resistente a la castración (CPRC). Ambos agentes están siendo considerados, junto con otros nuevos agentes dirigidos al hueso, en la prevención de metástasis óseas en pacientes con CPRC no metastásico, donde denosumab ha demostrado ya superioridad frente a placebo. Conclusiones: Denosumab y el ácido zoledrónico previenen los ERE en pacientes con cáncer de próstata y metástasis óseas. Denosumab también podría tener un papel en el retraso de las metástasis óseas en pacientes no metastásicos. Los avances en el tratamiento del CPRC incluyen un enfoque creciente hacia la prevención de la progresión ósea de la enfermedad (AU)

Background: Bone metastases are a common complication of prostate cancer, so treatment and prevention are essential to slow the progression of the disease and the occurrence of skeletal related events (SREs), which have devastating consequences for the quality of life of patients. Evidence acquisition: We reviewed the literature based on analysis of clinical trials developed in the prevention and treatment of bone metastases and in the new strategies in place with association of new therapeutic targets. Summary of evidence: Bone metastases are characterized by increased bone turnover and altered balance between osteogenesis and osteolysis, with activation of the RANK and its ligand (RANKL). In patients with metastatic prostate cancer, bisphosphonates have been the bonetargeted agents most commonly used to date. Zoledronic acid has demonstrated efficacy in the reduction and delay of SREs in patients with bone metastases. Denosumab, a RANKL inhibitor, has been demonstrated to be superior to zoledronic acid in the prevention of SREs in castration-resistant prostate cancer (CRPC). Both agents are being considered, along with other new bone-targeted agents, for the prevention of bone metastases in patients with non metastatic CRPC, where denosumab has already demonstrated superiority over placebo. Conclusions: Denosumab and zoledronic acid prevent SREs in patients with prostate cancer and bone metastases. Denosumab also has a potential role in delaying bone metastases in nonmetastatic patients. Advances in the treatment of CRPC include an increasing focus on prevention of the progression of bone disease (AU)

Advances in prevention and treatment of bone metastases in prostate cancer. Role of RANK/RANKL inhibition.

BACKGROUND: Bone metastases are a common complication of prostate cancer, so treatment and prevention are essential to slow the progression of the disease and the occurrence of skeletal related events (SREs), which have devastating consequences for the quality of life of patients. SUMMARY OF EVIDENCE: Bone metastases are characterized by increased bone turnover and altered balance between osteogenesis and osteolysis, with activation of the RANK and its ligand (RANKL). In patients with metastatic prostate cancer, bisphosphonates have been the bone-targeted agents most commonly used to date. Zoledronic acid has demonstrated efficacy in the reduction and delay of SREs in patients with bone metastases. Denosumab, a RANKL inhibitor, has been demonstrated to be superior to zoledronic acid in the prevention of SREs in castration-resistant prostate cancer (CRPC). Both agents are being considered, along with other new bone-targeted agents, for the prevention of bone metastases in patients with nonmetastatic CRPC, where denosumab has already demonstrated superiority over placebo. CONCLUSIONS: Denosumab and zoledronic acid prevent SREs in patients with prostate cancer and bone metastases. Denosumab also has a potential role in delaying bone metastases in nonmetastatic patients. Advances in the treatment of CRPC include an increasing focus on prevention of the progression of bone disease.

Papel actual del antígeno prostático específico y otros marcadores en el diagnóstico del cáncer de próstata / Current role of PSA and other markers in the diagnosis of prostate cancer

OBJETIVOS: Valorar el papel actual del PSA como método de diagnóstico en el cáncer de próstatay analizar los avances con nuevos marcadores relacionadoscon dicho tumor.MÉTODOS: Revisamos en la literatura el valor del PSA como marcador para definir la presencia de cáncer de próstata, así como sus fórmulas moleculares. Las factores relacionados con sus modificaciones, modelos predictivoso las diferentes discrepancias en la utilidad sobre el nivel de corte para definir riesgo o como marcador en si mismo. Analizamos los posibles nuevos marcadores o líneas más interesantes de trabajo en el desarrollo de nuevos test. Utilizamos como vía de trabajo fundamental para la búsqueda bibliografica el Medline.RESULTADOS: Los datos disponibles confirman que el PSA mantiene un nivel alto de sensibilidad aunque la especificidad es baja especialmente en rango de PSA≤10 ngr/ml, se puede ver aumentada con sus diferentesisoformas moleculares, ratios o modelos predictivos.Si bien es verdad que a pesar de dichos estudios persiste la dificultad para aumentar la especificidad y por lo tanto obviar biopsias. En la actualidad se disponede nuevos marcadores, algunos comercializados y otros en vía de desarrollo como las nuevas isoformas o con biología molecular, que parecen mejorar la especificidaddel PSA.CONCLUSIONES: El PSA sigue siendo el marcador patrón para el diagnóstico del cáncer de próstata. Es importante mejorar la especificidad para lo que necesitamosnuevos modelos predictivos o nuevas isoformas que puedan ayudarnos a seleccionar mejor los pacientescandidatos a biopsia. Existen en este momento diferenteslíneas de investigación prometedoras con nuevos marcadores, si bien aún no existe sustituto ideal para el PSA que sigue siendo el patron estándar

OBJECTIVES: To evaluate the current role of PSA as a diagnostic method for prostate cancer, as well as to analyze possible new markers.METHODS: We perform a bibliographic review for PSA, and its molecular forms, as a marker to define the presence of prostate cancer. We review the factorsrelated to PSA modifications, predictive models, or the current controversies about the usefulness of its cutpoint to define the risk of prostate cancer or the marker itself. We analyze possible new markers and the most interesting work lines in the development of new markers. We used MEDLINE for the bibliographic search.RESULTS: Available data confirm that PSA has a high sensitivity; although specificity is low, mainly in the ≤ 10ng/ml range, it may be increased with the use of variousmolecular isoforms, ratios or predictive models.Nevertheless, it is true that despite such studies it isdifficult to increase specificity, so biopsies are reduced. Currently we have new markers, some of them already marketed, others in development, which seem to improve the specificity of PSA (isoforms, use of molecular biology).CONCLUSIONS: PSA is still the standard marker for the diagnosis of prostate cancer. It is important to improve the specificity; therefore we need new predictive models or new isoforms that help us to do a better selection of candidates for biopsy. There are various promising research lines with new markers, but there is not ideal substitute for PSA yet

[Current role of PSA and other markers in the diagnosis of prostate cancer]. / Papel actual del antígeno prostático específico y otros marcadores en el diagnóstico del cáncer de próstata.

OBJECTIVES: To evaluate the current role of PSA as a diagnostic method for prostate cancer, as well as to analyze possible new markers. METHODS: We perform a bibliographic review for PSA, and its molecular forms, as a marker to define the presence of prostate cancer. We review the factors related to PSA modifications, predictive models, or the current controversies about the usefulness of its cutpoint to define the risk of prostate cancer or the marker itself. We analyze possible new markers and the most interesting work lines in the development of new markers. We used MEDLINE for the bibliographic search. RESULTS: Available data confirm that PSA has a high sensitivity; although specificity is low, mainly in the < 10 ng/ml range, it may be increased with the use of various molecular isoforms, ratios or predictive models. Nevertheless, it is true that despite such studies it is difficult to increase specificity, so biopsies are reduced. Currently we have new markers, some of them already marketed, others in development, which seem to improve the specificity of PSA (isoforms, use of molecular biology). CONCLUSIONS: PSA is still the standard marker for the diagnosis of prostate cancer. It is important to improve the specificity; therefore we need new predictive models or new isoforms that help us to do a better selection of candidates for biopsy. There are various promising research lines with new markers, but there is not ideal substitute for PSA yet.