Metastasic Prostate Cancer: Predictive Factors of Earlier Progression to Castration-Resistance

Introduction: Prostate cancer (PCa) can progress to the lethal phenotype of metastatic castration resistance (mCRPC), either from initially localized disease or de novo metastatic cancer. New drugs improving overall survival are now the cornerstone of treatment. Nevertheless, there are no defined sequences or established timing to initiate or discontinue treatments; besides, not all patients end in CRPC or reach this stage at the same time. Objective: To evaluate characteristics of patients who progress to mCRPC and establish an association with time to mCRPC diagnosis. Material and Methods: Retrospective, descriptive and observational study of 35 mCRPC patients, performed from 2013 to 2017. Variables analyzed were age, Gleason score and prostate-specific antigen (PSA) at diagnosis, initial stage, response time to androgen deprivation therapy (ADT), PSA nadir on ADT and time until mCRPC progression. Statistical analysis comparing variables with time to mCRPC diagnosis was performed. Results: Average age at diagnosis was 68.9 years; PSA values were classified into 3 categories: <20 ng/ml, 20-50 and >50. Gleason score was 7 in 50%, and 8-9 in the rest. Tumor was initially localized in 46% of the patients and metastatic in the rest. PSA nadir on ADT was <1 ng/ml in 67%. Average time to androgen deprivation: 5.5 years, time to mCRPC diagnosis: 6.9 years. Significant associations between time to mCRPC and time of androgen deprivation, PSA nadir during ADT and stage at diagnosis were found. Conclusion: Response time to ADT <1 year, PSA nadir value >5 ng/ml during treatment and metastatic stage at diagnosis were associated with earlier progression to mCRPC (AU)

Introducción: El cáncer de próstata (CaP) puedeprogresar al fenotipo letal de resistencia a la castraciónmetastásica (CPRCm), ya sea por enfermedad inicialmentelocalizada o por cáncer metastásico de novo. Los nuevosmedicamentos que mejoran la supervivencia general sonahora la piedra angular del tratamiento. Sin embargo, nohay secuencias definidas ni tiempos establecidos para iniciar o suspender los tratamientos; además, no todos los pacientes terminan en CPRC o llegan a esta etapa al mismotiempo.Objetivo: Evaluar las características de los pacientesque progresan a CPRCm y establecer una asociación entreéstas y el tiempo hasta el diagnóstico de CPRCm.Material y Métodos: Estudio retrospectivo, descriptivo y observacional de 35 pacientes con CPRCm, realizado entre 2013 y 2017. Las variables analizadas fueronedad, puntaje de Gleason y antígeno prostático específico(PSA, por sus siglas en inglés) al diagnóstico, estadio inicial, tiempo de respuesta a la terapia de deprivación androgénica (TDA), Nadir de PSA en TDA y tiempo hastala progresión a CPRCm. Se realizó un análisis estadísticocomparando las variables con el tiempo hasta el diagnósticode CPRCm.Resultados: La edad promedio al diagnóstico fue de68,9 años; Los valores de PSA<20: 15% de los pacientes,PSA 20-50: 63% de los pacientes, y PSA>50 20%. La puntuación de Gleason fue de 7 en el 50% y de 8-9 en el resto.El tumor fue inicialmente localizado en el 46% de los pacientes y metastásico en el resto. El nadir de PSA en TDAfue <1 ng / ml en 67%. Tiempo medio de respuesta a TDA:5,5 años, tiempo hasta el diagnóstico de CPRCm: 6,9 años.Se encontraron asociaciones significativas entre el tiempohasta CPRCm y el tiempo de deprivación de andrógenos, elnadir de PSA durante el TDA y el estadio al momento deldiagnóstico.Conclusión: el tiempo de respuesta a TDA <1 año... (AU)

Enzalutamide as monotherapy for advanced prostate cancer: why not? / Enzalutamida como monoterapia para cáncer de próstata avanzado: ¿por qué no?

OBJECTIVES: Prostate cancer (PCa) is an androgen-dependent disease. In some cases, the tumor progresses despite castration levels of serum testosterone, turning into the lethal phenotype of castration-resistant prostate cancer (CRPC), still driven by androgens and requiring the androgen receptor as a driver and responsible for progression. Enzalutamide, an androgen receptor inhibitor, is indicated for the treatment of metastatic CRPC, asymptomatic or mildly symptomatic, after failure of androgen deprivation. In both clinical trials that led to its approval, Enzalutamide was administered with an LHRH analog, setting the "standard of care" for its use. In this article we evaluate the available evidence and theory on the use of Enzalutamide as monotherapy. METHODS: Androgen deprivation well-known adverse events, together with the fact that its clinical benefit is moderate and the evidence strength is weak, and the direct negative impact on the common chronic conditions affecting this age-group led to investigation of Enzalutamide without LHRH analogs. RESULTS: There are clinical trials on Enzalutamide monotherapy for hormone-sensitive prostate cancer with favourable outcomes, and there are also two ongoing studies in different advanced PCa scenarios, the PROSPER and EMBARK trials. It would be up to now a safe alternative, with less toxicity and lower costs. CONCLUSION: It is mandatory to validate these early results on the use on Enzalutamide monotherapy for advanced prostate cancer, hormone-sensitive or castration resistant, metastatic or not, but in the meantime, we wonder, why not?

Prostatic specific antigen. From its early days until becoming a prostate cancer biomarker. / Antígeno prostático específico. Desde sus inicios hasta su reconocimiento como biomarcador de cáncer de próstata.

Prostate-specific antigen (PSA) has been since the mid 80's the most commonly used biomarker for measuring current and future risk of prostate cancer, for its early detection and to measure response to treatments and detecting recurrence in all stages of the disease. PSA's early development came along with progress in the field of immunology, which allowed detection and study of antigens from different tissues and fluids when injecting them into rabbits to promote immune response. Rubin Flocks in 1960 was the first to investigate and discover prostate-specific antigens in benign and malignant tissue. Some years later, Hara, a Japanese forensic investigator, found 'gamma seminoprotein', that he used to detect human semen in rape cases. However, his work published in Japanese did not reach the Englishspeaking scientific community. In 1970 Ablin discovered both in prostatic fluid and tissue what he called "prostate-specific antigen", but he didn't characterize or describe it. Investigators Li and Beling, and Sensabaugh, approached the current PSA, but they were limited by available technology at that time. Dr T Ming Chu led a research team on prostate cancer in New York, USA and published their results in 1979. He finally received the patent for the discovery of "human purified prostate antigen" in 1984. Due to this work, the Food and Drug Administration (FDA), in USA, approved the use of PSA for monitoring recurrence after treatment. It was later known that PSA was not prostate-specific since it was produced in other tissues and fluids, but it was recognized that it was human species-specific. Works by Papsidero and Stamey showed new indications and utilities for PSA, but it was Catalona who first used it as a marker for prostate cancer in 1991. Thanks to these advances FDA authorized in 1994 the clinical use of PSA for early detection of prostate cancer.

Outcome of radical prostatectomy in patients meeting criteria for active surveillance.

OBJECTIVES: Advances in diagnosis of prostate cancer (PCa)have led to an increased detection of these tumors, some of them with low-risk of progression, with the consequent risk of overdiagnosis and overt treatment. In consequence, there is a tendency to offer alternatives to active therapy, like active surveillance (AS)however, some patients under AS need definitive therapy and after surgery it becomes evident that they are not "low-risk" patients. We retrospectively reviewed the data of patients who met criteria for low-risk tumors treated with radical prostatectomy. METHODS: We selected 21 out of 190 patients treated with radical prostatectomy from January 2004 to December 2008 who met Epstein's criteria for low-risk tumors. We analyzed the number of organ-confined tumors,Gleason undergrading and understaging by biopsy, surgical margins and postoperative PSA. RESULTS: Mean age was 58.6 years; mean PSA was 6.6 ng/ml, predominant Gleason score was 6 (3+3), 76%were unilateral tumors and 90%were organ-confined, 10% had extracapsular extension, none had involvement of the seminal % vesicles, 15% of the patients had Gleason score >6 and surgical margins were positive in 30% of the specimens. Eighty five percent had their first postoperative PSA <0.10 ng/ml and 75% remain free of biochemical recurrence. According to the Johns Hopkins criteria for "incurable tumors ", our cohort had 28%. CONCLUSION: Patients with low-risk prostate cancer include cases that may have greater risk than estimated. In our series, we had 10% extracapsular disease, 15% understaging for Gleason score and 25% biochemical recurrence, which demonstrates that current criteria do not warrant good oncological results. Active surveillance offers good quality of life and acceptable oncological results, it can be proposed until definitive therapy, without seriously endangering the patient. Anyway, as a therapeutic tool, it still requires improvements. Technical advances are awaited so as to properly assess each patient's risk and to define the best therapeutic option for every case.

Resultados de prostatectomía radical en pacientes con criterios para vigilancia activa. (Active Surveillance) / Outcome of radical prostatectomy in patients meeting criteria for active surveillance

OBJETIVO: Los avances en el diagnóstico del cáncer de próstata (CaP) permiten detectar cada vez más neoplasias, muchas de ellas con bajo riesgo de progresión. Esto conlleva la posibilidad de “sobrediagnóstico” y consecuente “sobretratamiento”. En consecuencia, existe una tendencia a ofrecer alternativas al tratamiento activo, entre éstas la vigilancia activa (VA) o active surveillance. Sin embargo, hay pacientes en VA que requieren tratamiento definitivo y que, tras operarlos, no corresponden a casos de “bajo riesgo”. Examinamos retrospectivamente pacientes tratados con prostatectomía radical que cumplían criterios para tumores de bajo riesgo y analizamos los resultados. MÉTODO: De 190 pacientes prostatectomizados entre enero de 2004 y diciembre de 2008, seleccionamos 21 con criterios de Epstein para tumores de bajo riesgo. Analizamos número de tumores localizados, subestadificación por biopsia, subestimación del score de Gleason, márgenes quirúrgicos y PSA postoperatorio. RESULTADOS: Media de edad: 58.6 años, media de PSA: 6.6 ng/ml; score de Gleason predominante: 6 (3+3); 76%: tumores unilaterales, 90%: localizados, 10% tenía extensión extracapsular, no hubo compromiso de vesículas seminales; 15% de los pacientes tuvo score de Gleason >6 y 30% márgenes quirúrgicos positivos; 85% tuvo su primer PSA postoperatorio <0.10 ng/ml y 75% permanece libre de recidiva bioquímica. Según los criterios del Johns Hopkins de “tumor incurable”, nuestra serie tuvo 28% (AU)

CONCLUSIONES: El CaP de bajo riesgo incluye pacientes que pueden tener mayor riesgo que el estimado. En nuestra serie tuvimos 10% de enfermedad extracapsular, 15% de subestadificación del score de Gleason y 25% de recidiva bioquímica, lo que prueba que los criterios actuales no garantizan buenos resultados oncológicos. La VA ofrece buena calidad de vida y margen de seguridad aceptable, se puede proponer hasta realizar el tratamiento definitivo. Es necesario redefinir los criterios de inclusión mientras se esperan aportes en imágenes y nuevos marcadores para evaluar el riesgo de cada paciente y así poder ofrecerle la mejor opción (AU)

OBJECTIVES: Advances in diagnosis of prostate cancer (PCa) have led to an increased detection of these tumors, some of them with low-risk of progression, with the consequent risk of overdiagnosis and overt treatment. In consequence, there is a tendency to offer alternatives to active therapy, like active surveillance (AS); however, some patients under AS need definitive therapy and after surgery it becomes evident that they are not “low-risk” patients. We retrospectively reviewed the data of patients who met criteria for low-risk tumors treated with radical prostatectomy. METHODS: We selected 21 out of 190 patients treated with radical prostatectomy from January 2004 to December 2008 who met Epstein´s criteria for low-risk tumors. We analyzed the number of organ-confined tumors, Gleason undergrading and understaging by biopsy, surgical margins and postoperative PSA. RESULTS: Mean age was 58.6 years; mean PSA was 6.6 ng/ml, predominant Gleason score was 6 (3+3), 76% were unilateral tumors and 90% were organ-confined, 10% had extracapsular extension, none had involvement of the seminal vesicles, 15% of the patients had Gleason score >6 and surgical margins were positive in 30% of the specimens. Eighty five percent had their first postoperative PSA <0.10 ng/ml and 75% remain free of biochemical recurrence. According to the Johns Hopkins criteria for “incurable tumors”, our cohort had 28% (AU)

CONCLUSION: Patients with low-risk prostate cancer include cases that may have greater risk than estimated. In our series, we had 10% extracapsular disease, 15% understaging for Gleason score and 25% biochemical recurrence, which demonstrates that current criteria do not warrant good oncological results. Active surveillance offers good quality of life and acceptable oncological results, it can be proposed until definitive therapy, without seriously endangering the patient. Anyway, as a therapeutic tool, it still requires improvements. Technical advances are awaited so as to properly assess each patient´s risk and to define the best therapeutic option for every case (AU)