Papel de PCA3 y SelectMDx en la optimización de la vigilancia activa en el cáncer de próstata

Introduction and objectivesA not negligible percentage of patients included in active surveillance (AS) for low and very low risk prostate cancer (PCa) are reclassified in the confirmatory biopsy or have disease progression during follow-up. Our aim is to evaluate the role of PCA3 and SelectMDx, in an individual and combined way, in the prediction of pathological progression (PP) in a standard AS program.Materials and methodsProspective and observational study comprised of 86 patients enrolled in an AS program from 2009 to 2019, with results for PCA3 and SelectMDx previous to PCa diagnosis or during their confirmatory period. Univariate and multivariate analysis were performed to correlate PCA3 and SelectMDx scores as well as clinical and pathological variables with PP-free survival (PPFS). The most reliable cut-offs for both biomarkers in the context of AS were defined.ResultsSelectMDx showed statistically significant differences related to PPFS (HR: 1.035; 95% CI: 1.012-1.057) (P = .002) with a C-index of 0.670 (95% CI: 0.529-0.810) and AUC of 0.714 (95% CI: 0.603-0.825) at 5 years. In our series, the most reliable cut-off point for SelectMDx was 5, with a sensitivity and specificity for PP of 69.8% and 67.4%, respectively. Same figure for PCA3 was 65, with a sensitivity and specificity for PP of 51.16% and 74.42%, respectively. The combination of both biomarkers did not improve the prediction of PP, C-index 0.630 (95% CI: 0.455-0.805).ConclusionsIn the context of low or very low risk PCa, SelectMDx > 5 predicted 5 years PP free survival with a moderate discrimination ability outperforming PCA3. The combination of both tests did not improved outcomes.     

Factores que predicen el desarrollo de metástasis óseas por cáncer de próstata: recomendaciones de seguimiento y opciones terapéuticas

ContextProstate cancer is a public health problem in Spain and in the Western world. Bone involvement, associated to significant morbidity, is practically constant in the advanced stages of the disease. This work aims to review the prognostic factors used in the usual clinical practice that predict the development of bone metastases and to analyze the follow-up and treatment option in these patient profiles.Acquiring of evidenceWe performed a review of the literature on the useful factors in the context of therapy with intention to cure. We included the classical clinical values in the diagnosis (PSA, clinical stage, Gleason score on the biopsy) pathological factors (pT stage, margins, bladder invasion, tumor volume, lymph node involvement) and PSA kinetics in their different contexts and the histological and molecular parameters.Synthesis of evidenceThe tumor differentiation «Gleason» score and PSA are the most important predictive factors in the prediction of bone metastases in patients with intention to cure. Kinetic factors such as PSA doubling time (TDPSA) < 8 months or PSA > 10 ng/ml in the case of castration-resistant prostate cancer (CPRC), are predictive factors for the development of metastasis. Zoledronic acid and denosumab have demonstrated their effectiveness for the treatment of bone disease in randomized studies.ConclusionsThere are predictive factors within the usual clinical practice that make it possible to recognize the «patient at risk» to develop bone metastatic disease. The currently available treatments, zoledronic acid or denosumab, can help us in the management of the patient at risk of developing metastasis or metastatic patient, increasing the quality of life and decreasing skeletal events.     

Terapia focal en cáncer de próstata. Alternativas de tratamiento

ContextThe great controversy surrounding the treatment of localized prostate cancer is related with its possibilities of radical treatment or active surveillance. The objective of this paper is to analyze the rationale selection among current focal therapy modalities regarding tumor and patient selection.Evidence acquisitionCurrent articles about advantages and disadvantages on the treatment of localized prostate cancer as well as information about focal therapy regarding tumour selection, characteristics and indications cited in MEDLINE search were reviewed.Summary of evidenceFocal therapy standardized criteria must be: low risk tumors, PSA < 10-15, Gleason score ≤ 6, and unilateral presentation all supported by image-guided biopsy and nuclear magnetic resonance (NMR). There are doubts about the suitability of focal therapy in cases of bilateralism or in those with Gleason score 3 + 4 or PSA > 15.ConclusionsFocal therapy is an alternative for localized prostate cancer treatment. However, some aspects of their diagnosis and selection criteria should be defined by prospective studies which should provide knowledge about the indication for focal therapy.     

Actualización y optimización de la vigilancia activa en cáncer de próstata en 2021

Introduction and objectivesWithin the paradigm shift of the last decade in the management of prostate cancer (PCa), perhaps the most relevant event has been the emergence of active surveillance (AS) as a mandatory strategy in low-risk disease. We carry out a critical review of the clinical, pathological and radiological improvements that allow optimizing AS in 2021.Material and methodsCritical narrative review of the literature on improvement issues and controversial aspects of AS.ResultsAdequate use of traditional criteria, optimized by enhanced biopsy and calculation of the prostate volume technique thanks to multiparametric magnetic resonance imaging (mpMRI) allow a better selection of patients for AS. This management should not be limited to patients under 60 years of age, and patients with intermediate-risk PCa should be carefully selected to be included. Biopsies are still required in the follow-up, which can be personalized according to risk patterns. The pathologist must identify the cribriform or intraductal histology on biopsies in order to exclude these patients from AS, in the same way as with patients with alterations in DNA repair genes.ConclusionsControversial indications such as the inclusion of patients from intermediate-risk groups, or the transition to active treatment due to exclusive progression in tumor volume, should be further optimized. It is possible that the future competition of tissue biomarkers, the refinement of objective parameters of mpMRI and the validation of PSA kinetics calculators may sub-stratify risk groups.     

Papel de la activación adicional del gen RA en el desarrollo del fenotipo resistente a la castración en el cáncer de próstata

IntroductionSeveral studies have already shown that changes in the AR gene may be associated with a more aggressive disease phenotype and even castration-resistant prostate cancer. Thus, we investigated cytogenetic and molecular alterations linked to AR.Materials and methodsTo evaluate AR methylation, we performed a cytogenetic-molecular analysis using fluorescence in situ hybridization that uses specific probes for the AR gene (Xq11.12) and the X chromosome centromere. For AR activity, we performed a qualitative analysis of human androgen receptor activity. To analyze the expression of AR in PC3 and LNCaP cell lines, we used qPCR assays.ResultsIn the qPCR assay, we found downregulation of AR in the PC3 cell line compared with the LNCaP. We found the presence of X chromosome polysomy in PC-3 and LNCaP cell lines by FISH assay. In the HUMARA-Q assay, we found two X chromosomes/cell and the activity of both AR in the PC-3 cell line. In LNCaP cells, we found two X chromosomes/cell and methylation of only one AR.ConclusionCastration-resistant prostate cancer phenotype represents a significant challenge in the setting of urological management. The X chromosomes and AR-linked alterations may contribute to a better understanding of the disease. However, further studies should be performed in an attempt to elucidate as much as possible the role of AR in the castration-resistant prostate cancer phenotype.     

Salud ósea en pacientes con cáncer de próstata

ContextIn patients with prostate cancer, bone health is compromised by advanced age at diagnosis, androgen suppression treatments and the developmentofbone metastases. In this paper the medical literature is reviewed in order to update the state of the art on their incidence, prevention and management.Evidence acquisitionA literature review about bone involvement in patients with prostate cancer in different clinical settings is performed.Synthesis of the evidenceDecreased bone mineral density is higher in patients diagnosed of prostate cancer before starting treatment than in healthy men with the same age. During the first year of treatment, a severe loss bone density is reported due to androgen suppression therapy. From then on, loss bone density seems to slow down, persisting at long-term. It is important to know the starting point and the dynamics of loss bone in order to prevent its progression. The skeletal events have an important impact on quality of life in patients with prostate cancer. Both Denosumab and Zoledronic Acid have proven effective in reducing loss bone.ConclusionsThe prevention and management of bone involvement in patients with prostate cancer is critical to quality of life in these patients and requires an individualized approach. Before starting a prolonged androgen deprivation, baseline risk of fracture should be evaluated in order to adopt the proper protective measures. In patients with metastases, early treatments reducing the risk of bone events should be taken into account.     

Hipogonadismo prolongado tras la suspensión de tratamiento hormonal en pacientes con cáncer de próstata

ObjectivesTo study the levels of LH, testosterone and PSA after suspending prolonged treatment with LH-RH analogs.Materials and MethodHormonal evolution was studied in 29 patients from whom treatment had been withdrawn. The patients had previously been receiving treatment with LH-RH analog for more than one year, and with LH< 2 mUI/mL and testosterone <2.8 ng/mL. LH, testosterone and PSA were determined monthly, together with clinical assessment. The treatment was re-initiated and the period of monitoring ended before the presence of clinical progression and/or PSA ? 10 ng/mL. The cohort was described and survival was calculated using Kaplan-Meier and Cox regression.ResultsThe mean period of time without treatment for the series was 35 months (CI 95%, 15.7-54.2 months). Prolonged hypogonadism (> 24 months) was presented by 17% of the patients. The recovery of the LH-T-PSA axis, when it occurred, followed the expected sequence. The variables that influenced the period of recovery of the PSA were the PSA pretreatment and the association of an antiandrogen.ConclusionsAfter withdrawing the prolonged treatment with LH-RH analogs, most of the patients recovered the levels of LH-T-PSA, although a subgroup remained hypogonadic for more than 24 months.     

Enzalutamida y apalutamida en el tratamiento del cáncer de próstata no metastásico resistente a la castración: comparación indirecta de la eficacia

ObjectivesTo perform an adjusted indirect comparison of the efficacy of enzalutamide and apalutamide in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) with a high risk of progression to metastatic disease.Material and methodsAfter carrying out a literature search, we performed an adjusted indirect comparison (Bucher et al.) of the relative efficacy of enzalutamide and apalutamide in patients with nmCRPC with a high risk of progression to metastatic disease. The outcomes included were metastasis-free survival (MFS) and PSA response rate (PSARR).ResultsThere were no statistically significant differences between enzalutamide and apalutamide regarding the analysed outcomes. For the comparison enzalutamide + ADT vs. apalutamide + ADT: MFS a HR (95% CI) = 1,036 (0.781-1.373) was obtained. For PSARR, a RR (95% CI) = 0.81 (0.339-1.938) was obtained.ConclusionsThe adjusted indirect comparison performed in this study shows that there are no statistically significant differences in terms of efficacy regarding MFS and PSARR between enzalutamide + ADT and apalutamide + ADT in patients with nmCRPC with a high risk of progression to metastatic disease. However, in order to confirm these results, an independent trial with direct comparison between both drugs would be required.     

Vigilancia activa en cáncer de próstata de bajo riesgo. Aceptación por el paciente y resultados

ObjectivesTo evaluate the acceptance of active monitoring by patients treated in our healthcare community and to report the clinical results of an active surveillance program in patients with low-risk prostate cancer.Material and methodsProspective study of patients enrolled in an active surveillance programme at our centre between 2004 and 2012. The inclusion criteria were PSA <10 ng/ml, Gleason score ≤ 6, clinical stage T1c/T2a, ≤ 2 positive cores, and no more than 50% of the core being affected. Curative treatment was proposed when faced with pathological progression over the course of the monitoring.ResultsIn 2011, only 17% of the total number of potential candidate patients rejected their inclusion in a surveillance programme and were treated actively. We analysed a series of 144 patients included in our active surveillance protocol. The mean follow-up time was 3.22 years (SD 2.08). A total of 110 patients (76.3%) remained under active monitoring, with an estimated median treatment-free survival after diagnosis of 6.9 years (95% CI: 6.2-7.6). The percentage of patients who remained free of treatment at 2 and 5 years was 96.3% (95% CI: 92.8%-99.8%) and 70.9% (95% CI: 59.3%-85.5%), respectively. Thirty four patients (23.6%) required curative treatment. The mean time to treatment was 4.6 years (SD 2.3).ConclusionsActive surveillance of highly selected patients with low-risk prostate cancer is a valid alternative therapy that is accepted by patients in our community.     

Factores relacionados con la resistencia a la castración precoz en el cáncer de próstata metastásico. Resultados del Registro nacional de cáncer de próstata en España

IntroductionThe objective of the study was to determine the factors independently related with the development of castration resistance (CR) in prostate cancer (PC) in the medium term.Material and methods155 patients diagnosed with metastatic PC with a follow-up of up to 39 months. Data taken from the National PC Registry.The evaluated variables were age, PSA, nadir PSA, Gleason, perineural invasion, TNM stages, and ADT type (intermittent/continuous).ResultsMean follow-up 26,2 ± 13,4 months. 47.1% developed early CR, with mean time until onset of 12,2 ± 8,7 months.Univariate analysis the mean PSA was correlated with CR (290 ± 905,1 ng/mL in non CR, 519,1 ± 1437,2 ng/mL in CR, P < .001), mean age (73,3 ± 8,3 years in non CR, 69,1 ± 9,3 in CR P = .01), mean PSA nadir (15,5 ± 57,3 ng/mL in non CR, 15,9 ± 23,7 ng/mL in CR, p < 0,001), Gleason (in ≥8, HR:2,11. 95% CI: 1.22-3.65, p = 0.006), and T stage (in T3-T4, HR: 2.85. 95% CI: 1.57-5.19, P < .001).Multivariate analysis the independent variables associated to CR are age (HR: 0.96. 95% CI: 0.94-0.99, P = .01), PSA nadir (HR: 1.65. 95% CI: 1,43-1,91, P < .001), and T3-T4 stage (HR: 2.11. 95% CI: 1.10-4.04, P = .02).ConclusionsPSA nadir and T3-T4 tumor stage at diagnosis are associated to an increased risk of developing CR. In addition, age at diagnosis is shown as a variable that decreases risk. Therefore, an older age would be associated with lower risk probability of CR in the medium term.     

Una actualización en el protocolo en cáncer de próstata metastásico hormonosensible

To review and update last protocols in hormone sensitive metastatic prostate cancer for improving clinical management in routine. Evidence analysis available about recent updates protocols in hormone sensitive metastatic prostate cancer according to expert panel of clinicians about this field. A nominal consensus group for unify and improve the recommendations to the management of sensitive metastatic prostate cancer patients is currently needed. This document unifies and improve the management of patients with hormone sensitive metastatic prostate cancer, with a methodology that combines data quantitative and qualitative and based on the participation of a broad scientific committee appointed by the Spanish Association of Urology.     

Terapia focal en cáncer de próstata. Racionalidad,indicaciones y selección

ContextThe great controversy surrounding the treatment of localized prostate cancer is related with its possibilities of radical treatment or active surveillance. The objective of this paper is to analyze the rationale selection among current focal therapy modalities regarding tumor and patient selection.Evidence acquisitionCurrent articles about advantages and disadvantages on the treatment of localized prostate cancer as well as information about focal therapy regarding tumour selection, characteristics and indications cited in MEDLINE search were reviewed.Summary of evidenceFocal therapy standardized criteria must be: low risk tumors, PSA < 10-15, Gleason score ≤ 6, and unilateral presentation all supported by image-guided biopsy and nuclear magnetic resonance (NMR). There are doubts about the suitability of focal therapy in cases of bilateralism or in those with Gleason score 3 + 4 or PSA > 15.ConclusionsFocal therapy is an alternative for localized prostate cancer treatment. However, some aspects of their diagnosis and selection criteria should be defined by prospective studies which should provide knowledge about the indication for focal therapy.     

Impacto en la calidad de vida del tratamiento del cáncer de próstata organoconfinado

IntroductionProstate cancer (PCa) is the second most common male cancer in the world. Its incidence is estimated to grow to 1.7 million new cases and 499,000 new deaths by 2030. Treatment of OCPC can affect patients physically and mentally, as well as their close relationships and their job or career, which conditions health-related quality of life (QoL).ObjectiveEvaluate the impact on QoL attributable to the treatment for Organ Confined Prostate Cancer (OCPC).Materials and methodsProspective multicenter observational study of 406 patients with OCPC treated from January 2015 to June 2018. The sample was divided into four study groups, according to the type of treatment: radical prostatectomy (RP) (GA), external radiotherapy (ERT) (GB), brachytherapy (BT) (GC) and other treatments different from monotherapy with RP, ERT or BT (GD).ResultsThe age in GC was lower, the mean Prostate Specific Antigen (PSA) of all patients was 8.13 ng/ml, the group with the highest mean PSA was GB with a mean of 10.43 ng/dL, the mean Tumor Stage (TNM) was 3.82, and GD had the lowest post treatment quality of life.ConclusionOCPC treatment affects QoL. Curative monotherapies, specifically RP and BT, have less effect on QoL than external radiotherapy or other therapeutic alternatives. Urinary incontinence and fistulas secondary to OCPC have the highest impact on QOL impairment. The internationally validated SF 36 questionnaire is a useful cross-sectional measure of QOL to compare the impact of OCPC treatment modalities.     

Terapia de privación de andrógenos en el cáncer de próstata localizado. Situación actual y tendencias futuras

IntroductionProstate cancer (PCa) has been recognized as an androgen-sensitive disease since the investigations from Huggins and Hodges in 1941. Thanks to these findings, they received the Nobel Prize in 1966. This was the beginning of the development of androgen deprivation therapy (ADT) as treatment for patients with PCa.ObjectiveTo summarize the current indications of ADT in localized PCa.Evidence acquisitionWe conducted a comprehensive English and Spanish language literature research, focused on the main indications for ADT in localized PCa.Evidence synthesisNowadays, the indications for ADT as monotherapy in localized PCa have been limited to specific situations, to patients unwilling or unable to receive any form of local treatment if they have a PSA-DT < 12 months, and either a PSA > 50 ng/mL, a poorly differentiated tumor, or troublesome local disease-related symptoms. ADT can be used in combination with local treatment in different scenarios. Although neoadjuvant treatment with ADT prior to surgery with curative intent has no clear oncological impact, as a future sight, PCa is a heterogeneous disease, and there could be a group of patients with high-risk localized disease that could benefit.ConclusionsWe need to optimize the treatment with ADT in localized PCa, selecting the patients accordingly to their disease characteristics. Given that the therapeutic armamentarium evolves day by day, there is a need for the development of new clinical trials, as well as a molecular studies of patients to identify those who might benefit from an early multimodal treatment.     

Recomendaciones sobre el manejo de controversias en cáncer de próstata avanzado resistente a la castración

ContextControversies and uncertainties among integral management of advanced castration resistant prostate cancer continue to exist despite the number of evidence based clinical practice guidelines published with high international consensus.ObjectiveTo develop a document that reviews the management of controversies in advanced castration resistant prostate cancer, with recommendations from the definition, to the management in hormonal maneuvers, first-line treatment and second-line with new treatments as cabazitaxel or abirarerone and the multidisciplinary approach of the pathology with the goal of finding the most efficient, best time to act and safety.Evidence AcquisitionTwo meetings of a multidisciplinary group of experts involved in the management of this disease (Oncologist and Urologist) where pooled analysis of original literature and reached consensus document of recommendations on castration resistant prostate cancer, reviewing and attempting to address the current controversies of the disease.Evidence SynthesisThis document is endorsed by the corresponding Scientific Associations and Working Groups involved in the current management of Genitourinary Tumours: the Spanish Association of Urology (AEU) with the Uro-Oncoloy Group (GUO) and the Spanish Oncology of Genitourinary Group (SOGUG).ConclusionsWith the adaptation and implementation of this Document of Recommendations for clinical practice are available for the first time, a real road map for quality, efficiency and safety in the management of patients with CRPC.     

Manejo de la ginecomastia en pacientes con cáncer de próstata y deprivación androgénica

ContextGynecomastia, defined as benign proliferation of glandular breast tissue has a prevalence of 32% to 72% in the male. In the urology setting, it is associated to patients with prostate cancer and hormone treatment with a prevalence of 15% in the case of complete hormone blockage and 75% in monotherapy. The different options of treatment in prostate cancer have changed in recent decades. Thus, we have focused on this subject to evaluate the different therapy options of hormone manipulation induced gynecomastia in prostate cancer patients.ObjectiveTo synthesize the available evidence on the different therapeutic options in prostate cancer patients who develop gynecomastia due to the use of nonsteroidal antiandrogens and to generate a diagnostic algorithm and treatment.Acquisition of evidenceUsing the PICO type structured search strategy (Patient or problem, Intervention, Comparison, Outcome or result) in the data bases of PubMed-Medline and Cochrane, identification was made of the relevant studies related to the treatment of gynecomastia in Prostate Cancer patients treated with nonsteroidal antiandrogens.Synthesis of evidenceWe have found 3 possible therapeutic options for the treatment of gynecomastia and mastodynia in patients with hormone deprivation therapy for prostate cancer. The 10 Gy radiotherapy would be an option for the treatment of gynecomastia, although not all the patients need prophylactic treatment since only 50% report moderate-severe discomfort. Another option is the use of drugs such as tamoxifen 20 mg/day that lead to a significant decrease in the mammary effects.ConclusionsGynecomastia and mastodynia, given their high incidence, make the physical examination a fundamental tool for all patients before initiating treatment with antiandrogens. The use of tamoxifen 20 mg/day is the best treatment and prevention option against gynecomastia and mastodynia, while in the case of long-course established gynecomastia, surgery is the gold standard.     

Radio-223 en el tratamiento del cáncer de próstata resistente a la castración metastásico: una ventana de oportunidad

Context

The elimination of bone metastases, restoration and/or preservation of bone morphology and prevention and/or delay of skeletal events are a fundamental objective in the management of metastatic castration-resistant prostate cancer (mCRPC). Radium-223 is the first targeted alpha therapy with effects on bone that has been shown to increase survival in these patients, besides providing other bone-related benefits.

Protocolo de vigilancia activa para el cáncer de próstata en Portugal

ObjectiveTo examine clinical practice patterns in locally managing patients under an active surveillance protocol among Portuguese urologists.IntroductionProstate cancer (PCa) is a heterogeneous disease with many prostate adenocarcinomas being indolent and a low probability of ever causing symptoms or death. Active surveillance (AS) is a form of conservative management aimed to reduce over-treatment for low-risk PCa patients. Over the years, experience with AS has grown considerably and is now standard in some countries, however a universal protocol still does not exist.MethodsNationwide anonymous e-survey concerning habits and practices on AS among Portuguese urologists, that consisted of 12 questions and was sent electronically to all 368 current members of the Portuguese Urological Association.Results56 urologists were surveyed (15.21% answer rate), evenly distributed geographically and allocated according to years of experience as well as number of PCa patients managed monthly. The vast majority of respondents recommends AS to their patients, particularly ISUP grade 1 patients, whose PSA serum level is bellow 20ng/mL. Observance of AS programs by patients was not in question but concerns exist over psychological morbidity while harboring disease. Majority believed that international guidelines surveillance protocols were adequate and sufficient, but there are some constraints concerning availability of periodic MRIs and re-biopsy needs.ConclusionsAS seems to be sustained in urologist clinical practice, although patients still lag to adhere and choose for active treatment. AS may not be an easy choice for patients and clinicians due to uncertainty of disease progression, risk of loss to follow-up and repeated biopsies but is also a cause for anxiety, depression, uncertainty and a perception of danger.