Treatment patterns in hormone-sensitive metastatic prostate cancer: data from a referral hospital in Bogota, real-world evidence study / Patrones de tratamiento en cáncer de próstata metastásico hormonosensible: datos de un hospital de referencia de Bogotá, estudio de evidencia del mundo real

Objective: The objective of the study is to determine through a historical cohort, the characteristics, treatment patterns, and outcomes of a population with hormone-sensitive metastatic cancer at a referral center in Bogota. Method: This was a historical cohort observational study. All patients with metastatic hormone-sensitive prostate cancer from 2018 to May 2022 who received androgen deprivation therapy with or without treatment intensification were included through convenience sampling. The distribution of the epidemiological variables of interest, treatment of choice, and survival analysis was performed, as well as the distribution by years of the therapies of choice. Statistical significance was set at p < 0.05. Results: We included 125 hormone-sensitive metastatic prostate cancer (mHSPC) patients with a median age of 73.5 years (confidence interval: 71.48-75.31), a median PSA of 209 ng/mL, and 90% of patients with synchronous mHSPC. The distribution of high-volume mHSPC was 92% and M1b was 91%. The distribution of castration methods over time revealed that 21% of the patients underwent surgical castration and 79% received pharmacological castration. Since 2018, 40% of patients received androgen deprivation therapies (ADT) exclusively, 30% received treatment with taxanes, and 30% received androgen receptor axis-directed therapies. Trends in treatment distribution from 2018 to 2022 indicated a decline in exclusive ADT use from 41% in 2019 to 16% in 2022. 9% of the patients abandoned treatment. Conclusion: A description of the population of a national reference center for the treatment of hormone-sensitive prostate cancer with demographic characteristics according to global trends was provided

Objetivo: Caracterizar a la población y el tratamiento recibido de pacientes con cáncer metastásico hormonosensible (mHSPC) en un centro de referencia en Bogotá. Método: Cohorte histórica, observacional. Se incluyeron todos los pacientes con mHSPC que recibieron terapia de supresión androgénica, con o sin intensificación, desde el 2018 hasta mayo del 2022. Muestreo por conveniencia. Se describe la distribución de las variables epidemiológicas de interés, el tratamiento de elección, se realiza un análisis de supervivencia, así como de distribución por años de las terapias de elección. Se consideró significación estadística con un grado de significación (p) < 0,05. Resultados: Se incluyeron 125 pacientes con mHSPC, con una mediana de edad de 73,5 años (IC: 71,48-75,31), con una mediana de antigeno porstático específico (PSA) de 209 ng/mL, el 90% de los pacientes con mHSPC sincrónicos. La distribución de mHSPC de alto volumen fue del 92%, M1b 91%. La distribución global en el tiempo de castración quirúrgica fue del 21% y farmacológica del 79%. El 40% de los pacientes recibieron desde el 2018 terapia de deprivación de andrógenos (ADT) exclusiva, tratamiento con taxanos el 30% y terapias dirigidas al eje del receptor de andrógenos el 30% de los pacientes. Se describen las tendencias de distribución por años desde 2018 hasta 2022, pasando de ADT exclusiva en un 41% para el 2019 a un 16% para el 2022. El 9% de los pacientes abandonaron el tratamiento. Conclusión: Se realiza una descripción de la población de un centro de referencia nacional en el tratamiento de cáncer de próstata hormonosensible con características demográficas acorde a las tendencias globales

The androgen receptor-targeted proteolysis targeting chimera and other alternative therapeutic choices in overcoming the resistance to androgen deprivation treatment in prostate cancer.

Androgen receptor (AR) plays a vital role in prostate cancer (PCa), including castration-resistant PCa, by retaining AR signalling. Androgen deprivation treatment (ADT) has been the standard treatment in the past decades. A great number of AR antagonists initially had been found effective in tumour remission; however, most PCa relapsed that caused by pre-translational resistance such as AR mutations to turn antagonist into agonist, and AR variants to bypass the androgen binding. Recently, several alternative therapeutic choices have been proposed. Among them, proteolysis targeting chimera (PROTAC) acts different from traditional drugs that usually function as inhibitors or antagonists, and it degrades oncogenic protein and does not disrupt the transcription of an oncogene. This review first discussed some essential mechanisms of ADT resistance, and then introduced the application of AR-targeted PROTAC in PCa cells, as well as other AR-targeted therapeutic choices.

Androgens, brain and androgen deprivation therapy in paraphilic disorders: A narrative review.

Sexual delinquency is a global problem where those with paraphilic disorders, such as paedophiles, are more likely to commit and reoffend. Androgen deprivation therapy (ADT) has been suggested as a solution. The objective of this narrative review is to present current information on its risks, benefits and limitations as a treatment for paraphilias. The importance of testosterone in sexual function, the effect of its deficiency by age or by pharmacological treatment (anti-androgens, GnRH agonists and GnRH antagonists) and the effect of testosterone replacement therapy will be reviewed. The relationship between androgens, brain, sexual behaviour and pathophysiology of paraphilic disorders will also be explored. ADT reduces sexual urges, but has adverse effects and, because its reversible nature, it does not ensure less recidivism. Likewise, the research quality of ADT drugs is limited and not enough to support their use. Child sex offenders, and not paraphilic subjects who have not committed assaults, show signs of elevated prenatal exposure to androgens and a higher methylation state of the androgen receptor gene. Sexual behaviour is regulated by subcortical (hypothalamus, brainstem and spinal cord) and cortical structures of the brain, in addition to brain circuits (dopaminergic, serotonergic). Those with paraphilic disorders show abnormalities at these levels that could relate to the risk of sexual offences. In conclusion, androgens represent a significant part of the pathophysiology of paraphilias and therefore, ADT seems promising. Nonetheless, more studies are needed to make definite conclusions about the efficacy of long-term ADT in paraphilic patients.

Evaluation of maintenance of the common androgen deprivation therapy with the new antiandrogen therapy in patients with castration-resistant prostate cancer: a systematic review.

PURPOSE: Advanced prostate cancer does not respond to traditional androgen deprivation therapy (ADT) at some point in the treatment. The development of new hormonal agents demonstrated clear efficacy and changed the treatment scenario. OBJECTIVES: To evaluate the use of new antiandrogens alone versus their use in combination with maintenance ADT in patients with advanced castration-resistant prostate cancer. METHODS: A literature systematic review of randomized clinical trials, cohorts, and real-life studies including patients who received the new antiandrogens with or without ADT due to histologic confirmed advanced castration-resistant prostate adenocarcinoma was carried out. RESULTS: 2181 articles were identified and three studies were included with a total of 246 patients. Two studies were randomized clinical trials, and the third was a retrospective study, which showed similar results for both arms, in relation to PSA response, radiological progression-free survival, and testosterone levels, in addition to cost analysis with savings avoided in the ADT maintenance-free arm. Despite the positive data, it is still not possible to categorically state whether there is a statistical benefit in suspending the ADT during the use of new antiandrogens, due to the heterogeneity of the studies. CONCLUSION: The literature is limited on the issue. Available data are still immature with no clear benefit of the use of newer antiandrogens alone in the setting of advanced castration-resistant prostate cancer.

Experience of bipolar androgen therapy (BAT) in Argentinian oncology centres.

Background: Previous studies with bipolar androgen therapy (BAT) have shown clinical activity in metastatic Castration Resistant Prostate Cancer (mCRPC) as well as the potential to re-sensitise prostate cancer cells to prior androgen receptor-targeted agents. None of these studies had tested BAT after chemotherapy. In this study, we gathered real-world evidence from three centres in Argentina where BAT is being used in castration-resistant prostate cancer (CRPC), not only prior to chemotherapy but also after several lines of treatment. Materials and methods: This retro-prospective nonrandomised multicentre cohort study included patients with mCRPC, who received BAT in different scenarios defined by the treating physician at three centres in Argentina. Results: A total of 21 asymptomatic patients with mCRPC were included. There was a median of two lines before BAT, with nine patients (42.8%) receiving three or more lines, and 13 patients (61.9%) receiving chemotherapy previously. Previous lines included next-generation hormonal agents (NHA) in 100% (abiraterone 33.3% and enzalutamide 71.4%), chemotherapy in 61.9%, Radium-223 in 47.6% and others in 4.8%. The progression free survival (PFS) after BAT was 3.5 months (95% CI: 3.06-7.97). PSA50 response rate (RR) was 28.5% and the overall RR was 14.3%. Of the 17 patients who had disease progression, 9 had a rechallenge to NHA, achieving a 55% RR, 6 received other treatment (chemotherapy in 5 and 177Lu-PSMA in 1) with a 66% RR and 2 best supportive care. The PFS2, calculated after the initiation of BAT in the 15 patients who received further therapy, was 7.93 months (95% CI: 6.73-NR). Treatment was overall well tolerated, with only two patients requiring hospitalisation and treatment interruption due to worsening pain. Conclusion: To the authors' knowledge, this is the first publication of BAT in later lines of therapy in mCRPC. BAT showed clinical activity in this scenario. Our data supports that BAT may play a role in CRPC re-sensitisation after multiple treatment lines.

Prostate cancer treatment and the relationship of androgen deprivation therapy to cognitive function.

Prostate cancer is the second most common form of cancer in men. For advanced, high risk prostate cancer, androgen deprivation therapy (ADT) is the preferred treatment and can induce remission, but resistance to ADT brings biochemical recurrence and progression of cancer. ADT brings adverse effects such as erectile dysfunction, decreased libido, and diminished physical strength. It is estimated that between 25 and 50% of men on ADT manifest some form of cognitive dysfunction that may be self-reported or reported by a family member. There is concern that impaired cognitive function with ADT is due to loss of testosterone support. Testosterone and its metabolites are known to possess neuroprotective properties. While a direct causal relationship between ADT and cognitive decline in prostate cancer patients has not been established, this review describes the controversy surrounding the possible connection between ADT and neurocognitive deterioration. The cellular and molecular mechanisms believed to underlie the protection of neuronal integrity by androgens are discussed. Results from animal models and human clinical studies are presented. Finally, we call attention to lifestyle modifications that may minimize cognitive issues in prostate cancer patients.

Characteristics and progression-free survival of Afro-Caribbean men with metastatic hormone-sensitive prostate cancer at the time of diagnosis.

INTRODUCTION AND OBJECTIVES: Metastatic hormone-sensitive prostate cancer (mHSPC) accounts for 12% of prostate cancers diagnosed in Guadeloupe according to the Guadeloupean cancer registry. Most published studies have been conducted on the Caucasian population, whereas data concerning mHSPC in the Afro-Caribbean population are lacking. We aimed to describe the patient characteristics and estimate the progression-free survival of men with mHSPC in an Afro-Caribbean population according to the available treatment. PATIENTS AND METHODS: This was a monocentric retrospective study that consecutively included 133 men with mHSPC between January 1, 2015 and December 31, 2019 at the University Hospital of Guadeloupe. The primary endpoint was a description of the patients' characteristics with a description of complications at diagnosis. The secondary endpoint was progression-free survival. Kaplan-Meier survival and Cox proportional hazard analyses were performed. RESULTS: The median age at diagnosis was 71 years. The median prostate-specific antigen (PSA) was 147 ng/ml and 37% of patients presented with a disease-related complication at diagnosis. The survival analysis according to treatment showed median survival of 15 months for the androgen deprivation therapy (ADT) + chemotherapy group, 20 months for the ADT + new hormone therapy group, and 21.5 months for the ADT alone group, with no significant difference between the three therapeutic options (log-rank test: 0.27). In univariate analysis, none of the patient characteristics at diagnosis (i.e., age, PSA, bone lesions, visceral lesions) were significantly associated with the risk of progression, regardless of the treatment. CONCLUSION: There was no significant difference in terms of progression-free survival between currently validated treatments administered in the first line, regardless of the tumor volume or risk group. Future studies with larger numbers of patients and involving molecular factors are required to confirm or invalidate these results and understand the evolution of prostate cancer in our population and thus better prevent complications related to the disease.

Syncope due to non-sustained episodes of Torsade de Pointes associated to androgen-deprivation therapy use: a case presentation.

BACKGROUND: Abiraterone is a medication frequently used for metastatic castrate-resistant prostate cancer. We report a case of non-sustained episodes of TdP associated with severe hypokalemia due to androgen-deprivation therapy. Few case presentations describe this association; the novelty lies in the potentially lethal cardiovascular events among cancer patients receiving hormonal therapy. CASE PRESENTATION: A 70-year-old male presented with recurrent syncope without prodrome. ECG revealed frequent ventricular ectopy, non-sustained episodes of TdP, and severe hypomagnesemia and hypokalemia. During potassium and magnesium infusion for repletion, the patient underwent temporary transvenous atrial pacing. As part of the work-up, coronary angiography revealed a mild coronary artery disease, and transthoracic echocardiogram showed a moderately depressed ejection fraction. After electrolyte disturbances were corrected, the QT interval normalized, and transvenous pacing was no longer necessary. Abiraterone was discontinued during the admission, and the patient returned to baseline. CONCLUSIONS: Cancer treatment is complex and requires a multidisciplinary approach. We presented a case of non-sustained TdP associated with androgen-deprivation therapy in an elderly patient with mild coronary artery disease and moderately reduced ejection fraction. Close follow-up and increased awareness are required in patients with hormonal treatment, especially in the setting of other cardiovascular risk factors.

Distribution and Effects of Estrogen Receptors in Prostate Cancer: Associated Molecular Mechanisms.

Estrogens are hormones that have been extensively presented in many types of cancer such as breast, uterus, colorectal, prostate, and others, due to dynamically integrated signaling cascades that coordinate cellular growth, differentiation, and death which can be potentially new therapeutic targets. Despite the historical use of estrogens in the pathogenesis of prostate cancer (PCa), their biological effect is not well known, nor their role in carcinogenesis or the mechanisms used to carry their therapeutic effects of neoplastic in prostate transformation. The expression and regulation of the estrogen receptors (ERs) ERα, ERß, and GPER stimulated by agonists and antagonists, and related to prostate cancer cells are herein reviewed. Subsequently, the structures of the ERs and their splice variants, the binding of ligands to ERs, and the effect on PCa are provided. Finally, we also assessed the contribution of molecular simulation which can help us to search and predict potential estrogenic activities.

Transitioning from conformal radiotherapy to intensity-modulated radiotherapy after radical prostatectomy: Clinical benefit, oncologic outcomes and incidence of gastrointestinal and urinary toxicities.

AIM: The purpose of this study was to review genitourinary (GU) and gastrointestinal (GI) toxicity associated with high-dose radiotherapy (RT) delivered with 3-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) or volumetric arc therapy (VMAT) following radical prostatectomy (RP). BACKGROUND: RP is a therapeutic option for the management of prostate cancer (PrCa). When assessing postoperative RT techniques for PrCa, the published literature focuses on patients treated with 2-dimensional conventional methods without reflecting the implementation of 3D-CRT, IMRT, or VMAT. MATERIALS AND METHODS: A total of 83 patients were included in this analysis; 30 patients received 3D-CRT, and 53 patients received IMRT/VMAT. Acute and late symptoms of the GU and lower GI tract were retrospectively graded according to the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer radiation toxicity grading systems. The relapse failure-free rate and overall survival were also evaluated. RESULTS: The rate of acute GU toxicity was 9.4% vs. 13.3% for the IMRT/VMAT and 3D-CRT groups (p = 0.583). The 5-year actuarial rates of late GI toxicity for IMRT/VMAT and 3D-CRT treatments were 1.9% and 6.7%, respectively. The rate of late GU toxicity for the IMRT/VMAT and 3D-CRT treatment groups was 7.5% and 16.6%, respectively (p = 0.199). We found no association between acute or late toxicity and the RT technique in univariate and multivariate analyses. CONCLUSION: Postprostatectomy IMRT/VMAT and 3D-CRT achieved similar morbidity and cancer control outcomes. The clinical benefit of highly conformal techniques in this setting is unclear although formal analysis is needed.

Androgen deprivation therapy improves the in vitro capacity of high-density lipoprotein (HDL) to receive cholesterol and other lipids in patients with prostate carcinoma.

BACKGROUND: Androgen deprivation therapy (ADT) is widely used in the treatment of testosterone-dependent prostate carcinomas. ADT often increases plasma LDL and HDL cholesterol and triglycerides. The aim was to test whether ADT changes the transfer of lipids to HDL, an important aspect of this metabolism and HDL protective functions, and related parameters. METHODS: Sixteen volunteers with advanced prostate carcinoma submitted to pharmacological ADT or orchiectomy had plasma collected shortly before and after 6 months of ADT. In vitro transfer of lipids to HDL was performed by incubating plasma with donor emulsion containing radioactive lipids by 1 h at 37 °C. After chemical precipitation of apolipoprotein B-containing lipoprotein, the radioactivity of HDL fraction was counted. RESULTS: ADT reduced testosterone to nearly undetectable levels and markedly diminished PSA. ADT increased the body weight but glycemia, triglycerides, LDL and HDL cholesterol, HDL lipid composition and CETP concentration were unchanged. However, ADT increased the plasma unesterified cholesterol concentration (48 ± 12 vs 56 ± 12 mg/dL, p = 0.019) and LCAT concentration (7.15 ± 1.81 vs 8.01 ± 1.55µg/mL, p = 0.020). Transfer of unesterified (7.32 ± 1.09 vs 8.18 ± 1.52%, p < 0.05) and esterified cholesterol (6.15 ± 0.69 vs 6.94 ± 1.29%, p < 0.01) and of triglycerides (6.37 ± 0.43 vs 7.18 ± 0.91%, p < 0.001) to HDL were increased after ADT. Phospholipid transfer was unchanged. CONCLUSION: Increase in transfer of unesterified and esterified cholesterol protects against cardiovascular disease, as shown previously, and increased LCAT favors cholesterol esterification and facilitates the reverse cholesterol transport. Thus, our results suggest that ADT may offer anti-atherosclerosis protection by improving HDL functional properties. This could counteract, at least partially, the eventual worse effects on plasma lipids.

Age, Gleason Score, and PSA are important prognostic factors for survival in metastatic castration-resistant prostate cancer. Results of The Uroncor Group (Uro-Oncological Tumors) of the Spanish Society of Radiation Oncology (SEOR).

INTRODUCTION: The treatment of metastatic castration-resistant prostate cancer (mCRPC) has changed significantly in recent years. Inhibitors of androgen receptors have shown especially significant benefits in overall (OS) and progression-free survival (PFS), with a good toxicity profile. Treatment selection depends on the patient's individual clinical, radiological, and biological characteristics. OBJECTIVE: To describe treatment outcomes (efficacy, toxicity) in a cohort of patients with mCRPC in Spain. MATERIALS AND METHODS: Multicenter, retrospective study of patients with mCRPC included in a database of the Urological Tumour Working Group (URONCOR) of the Spanish Society of Radiation Oncology (SEOR). Metastatic CRPC was defined according to the prostate cancer working group 3 (PCWG3) criteria. The Kaplan-Meier technique was used to evaluate OS and the Common Terminology Criteria for Adverse Events (CTCAE, v.4.0) were used to assess toxicity. Univariate and multivariate Cox regression analyses were performed to identify the factors significantly associated with OS. RESULTS: A total of 314 patients from 17 hospitals in Spain diagnosed with mCRPC between June 2010 and September 2017 were included in this study. Mean age at diagnosis was 68 years (range 45-89). At a median follow-up of 35 months, OS at 1, 3, and 5 years were 92%, 38%, and 28%, respectively. Grades 1-2 and grade 3 toxicity rates were, respectively, 68% and 19%. No grade 4 toxicities were observed. On the multivariate analysis, the following factors were significantly associated with OS: age (hazard ratio [HR] 0.42, p = 0.010), PSA value at diagnosis of mCRPC (HR 0.55, p = 0.008), and Gleason score (HR 0.61, p = 0.009). CONCLUSIONS: Age, Gleason score, and PSA at diagnosis of mCRPC are independently associated with overall survival in patients with mCRPC. The efficacy and toxicity outcomes in this patient cohort treated in radiation oncology departments in Spain are consistent with previous reports.

The LACOG-0415 phase II trial: abiraterone acetate and ADT versus apalutamide versus abiraterone acetate and apalutamide in patients with advanced prostate cancer with non-castration testosterone levels.

BACKGROUND: Testosterone suppression is the standard treatment for advanced prostate cancer, and it is associated with side-effects that impair patients' quality of life, like sexual dysfunction, osteoporosis, weight gain, and increased cardiovascular risk. We hypothesized that abiraterone acetate with prednisone (AAP) and apalutamide, alone or in combination, can be an effective hormonal therapy also possibly decreasing castration-associated side effects. METHODS: Phase II, open-label, randomized, efficacy trial of abiraterone acetate plus prednisone (AAP) and Androgen Deprivation Therapy (ADT) versus apalutamide versus the combination of AAP (without ADT) and apalutamide. Key eligibility criteria are confirmed prostate adenocarcinoma; biochemical relapse after definitive treatment (PSA ≥ 4 ng/ml and doubling time less than 10 months, or PSA ≥ 20 ng/ml); newly diagnosed locally advanced or metastatic prostate cancer; asymptomatic to moderately symptomatic regarding bone symptoms. Patients with other histology besides adenocarcinoma or previous use of hormonal therapy or chemotherapy were excluded. DISCUSSION: There is an urgent need to study and validate regimens such as new hormonal agents that may add benefit to castration with an acceptable safety profile. We aim to evaluate if apalutamide in monotherapy or in combination with AAP is an effective and safety hormonal treatment that can spare patients of androgen deprivation therapy. TRIAL REGISTRATION: This trial was registered in ClinicalTrials.gov on October 16, 2017, under Identifier: NCT02867020.

Testosterone Recovery Profiles After Cessation of Androgen Deprivation Therapy for Prostate Cancer.

INTRODUCTION: Androgen deprivation therapy (ADT) is frequently used in the treatment of prostate cancer worldwide. Variable testosterone (T) recovery profiles after ADT cessation have been cited. AIM: To evaluate T recovery after cessation of ADT. METHODS: We reviewed our institutional prospectively maintained database of patients with prostate cancer who received ADT. Serum early morning total T (TT) levels, collected at baseline and periodically after ADT cessation, were analyzed. Patient age, baseline T level, duration of ADT, and presence of diabetes and sleep apnea were selected as potential predictors of T recovery. 3 metrics of T recovery after 24 months of ADT cessation were analyzed: return to non-castrate level (TT > 50 ng/dL), return to normal (T > 300 ng/dL), and return back to baseline level (BTB). Multivariable time-to-event analysis (Cox proportional hazards), χ2 test, logistic regression model, and Kaplan-Meier curve were performed to define impact of the above predictors on time and chance of T recovery. MAIN OUTCOME MEASURES: Time and chance of T recovery to non-castrate level (TT > 50 ng/dL), return to normal (T > 300 ng/dL), and return BTB. RESULTS: 307 men with a mean age of 65 ± 8 years were included. Mean duration of ADT was 17 ± 25 months, and median follow-up was 31 ± 35 months. Mean TT values were 379 ng/dL at baseline and 321 ng/dL at >24 months. At 24 months after cessation of ADT, 8% of men remained at castrate level, 76% returned to TT >300 ng/dL, and 51% had returned BTB. Lower baseline T levels (TT < 400 ng/dL) and ADT duration >6 months were associated with a lower likelihood of recovery to normal TT at 24 months. Age >65 years and receiving ADT for >6 months were significantly associated with a slower T recovery. CLINICAL IMPLICATIONS: T recovery after ADT is not certain and may take longer than expected. Considering the range of side effects of low T, we believe that these findings must be discussed with patients before initiating such therapies. STRENGTHS & LIMITATIONS: Our strengths consisted of a relatively large database, long follow-up, and clinically meaningful endpoints. Limitations included the retrospective design of the study. CONCLUSION: T recovery rates after ADT cessation vary according to patient age, ADT duration, and baseline T levels. Approximately one-quarter of patients failed to normalize their TT level, and one-tenth of men remained at castrate levels 24 months after ADT cessation. Nascimento B, Miranda EP, Jenkins LC, et al. Testosterone Recovery Profiles After Cessation of Androgen Deprivation Therapy for Prostate Cancer. J Sex Med 2019;16:872-879.

Outcomes and prognostic factors in intermediate-risk prostate cancer: multi-institutional analysis of the Spanish RECAP database.

PURPOSE: To retrospectively assess outcomes and to identify prognostic factors in patients diagnosed with intermediate-risk (IR) prostate cancer (PCa) treated with primary external beam radiotherapy (EBRT). MATERIALS AND METHODS: Data were obtained from the multi-institutional Spanish RECAP database, a population-based prostate cancer registry in Spain. All IR patients (NCCN criteria) who underwent primary EBRT were included. The following variables were assessed: age; prostate-specific antigen (PSA); Gleason score; clinical T stage; percentage of positive biopsy cores (PPBC); androgen deprivation therapy (ADT); and radiotherapy dose. The patients were stratified into one of three risk subcategories: (1) favourable IR (FIR; GS 6, ≤ T2b or GS 3 + 4, ≤ T1c), (2) marginal IR (MIR; GS 3 + 4, T2a-b), and (3) unfavourable IR (UIR; GS 4 + 3 or T2c). Biochemical relapse-free survival (BRFS), disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) were assessed. RESULTS: A total of 1754 patients from the RECAP database were included and stratified by risk group: FIR, n = 781 (44.5%); MIR, n = 252 (14.4%); and UIR, n = 721 (41.1%). Mean age was 71 years (range 47-86). Mean PSA was 10.4 ng/ml (range 6-20). The median radiotherapy dose was 74 Gy, with mean doses of 72.5 Gy (FIR), 73.4 Gy (MIR), and 72.8 Gy (UIR). Most patients (88%) received ADT for a median of 7.1 months. By risk group (FIR, MIR, UIR), ADT rates were, respectively, 88.9, 86.5, and 86.9%. Only patients with ≥ 24 months of follow-up post-EBRT were included in the survival analysis (n = 1294). At a median follow-up of 52 months (range 24-173), respective 5- and 10-year outcomes were: OS 93.6% and 79%; BRFS 88.9% and 71.4%; DFS 96.1% and 89%; CSS 98.9% and 94.6%. Complication rates (≥ grade 3) were: acute genitourinary (GU) 2%; late GU 1%; acute gastrointestinal (GI) 2%; late GI 1%. There was no significant association between risk group and BRFS or OS. However, patients with favourable-risk disease had significantly better 5- and 10-year DFS than patients with UIR: 98.7% vs. 92.4% and 92% vs. 85.8% (p = 0.0005). CSS was significantly higher (p = 0.0057) in the FIR group at 5 (99.7% vs. 97.3%) and 10 years (96.1% vs. 93.4%). On the multivariate analyses, the following were significant predictors of survival: ADT (BRFS and DFS); dose ≥ 74 Gy (BRFS); age (OS). CONCLUSIONS: This is the first nationwide study in Spain to report long-term outcomes of patients with intermediate-risk PCa treated with EBRT. Survival outcomes were good, with a low incidence of both acute and late toxicity. Patients with unfavourable risk characteristics had significantly lower 5- and 10-year disease-free survival rates. ADT and radiotherapy dose ≥ 74 Gy were both significant predictors of treatment outcomes.

Nur77 suppression facilitates androgen deprivation-induced cell invasion of prostate cancer cells mediated by TGF-ß signaling.

BACKGROUND: Androgen deprivation therapy (ADT) remains a standard treatment for advanced prostate cancers. However, recent studies revealed that while inhibiting the growth of certain types of prostate cancer cells, ADT promotes invasion. In the current study, we explored the effects of Nur77, an orphan nuclear receptor, on prostate cancer cell invasion following ADT. METHODS: Androgen receptor (AR) and Nur77 protein expression in patient tissues and cell lines were quantified via ELISA and western blot. The effects of AR-signaling on Nur77 expression were examined. The effects of Nur77 over-expression and knockdown on ADT-induced prostate cancer cell invasion were characterized. RESULTS: The results showed that AR and Nur77 are both highly expressed in prostate cancers of patients. Nur77 is positively regulated by AR-signaling at transcriptional level in NCI-H660, a widely used prostate cancer cell line. AR antagonists, Casodex and MDV3100 treatment resulted in significant inhibition of prostate cancer cell growth but enhanced cancer cell invasion. Nur77 over-expression blocked invasion-promoting effect of ADT, which is consistent with the down-regulation of MMP9 and Snail protein expression. Further mechanistic investigations showed that Nur77 inhibited transcription of TGF-ß target genes (Snail and MMP9), and thereby inhibits TGF-ß-mediated prostate cancer cell invasion following androgen antagonism. In addition, our data suggested the nature of this inhibitory effect of Nur77 on TGF-ß-signaling is selective, for Smad3-signaling, the classical effector of TGF-ß-signaling, was not interrupted by Nur77 over-expression. CONCLUSION: Considering the limited success of management of prostate cancer metastasis following ADT, our data strongly suggest that Nur77 regulation could be a promising direction for search of complementary therapeutic strategy on top of classic ADT therapy.

Exercise and prostate cancer: From basic science to clinical applications.

Prostate cancer (PCa) is a disease of increasing medical significance worldwide. In developed countries, PCa is the most common non-skin cancer in men, and one of the leading causes of cancer-related deaths. Exercise is one of the environmental factors that have been shown to influence cancer risk. Moreover, systemic reviews and meta-analysis have suggested that total physical activity is related to a decrease in the risk of developing PCa. In addition, epidemiological studies have shown that exercise, after diagnosis, has benefits regarding PCa development, and positive outcome in patients under treatment. The standard treatment for locally advanced or metastatic PCa is Androgen deprivation therapy (ADT). ADT produces diverse side effects, including loss of libido, changes in body composition (increase abdominal fat), and reduced muscle mass, and muscle tone. Analysis of numerous research publications showed that aerobic and/or resistance training improve patient's physical condition, such us, cardiorespiratory fitness, muscle strength, physical function, body composition, and fatigue. Therefore, exercise might counteract several ADT treatment-induced side effects. In addition of the aforementioned benefits, epidemiological, and in vitro studies have shown that exercise might decrease PCa development. Thus, physical activity might attenuate the risk of PCa and supervised exercise intervention might improve deleterious effects of cancer treatment, such as ADT side effects. This review article provides evidence indicating that exercise could complement, and potentiate, the current standard treatments for advanced PCa, probably by creating an unfavorable microenvironment that can negatively affect tumor development, and progression.

SEOM clinical guidelines for the treatment of metastatic prostate cancer (2017).

Androgen deprivation treatment was the only treatment available for metastatic prostate cancer until recently, with docetaxel as the only treatment with a proven survival benefit in castration-resistant prostate cancer (CRPC). Several drugs have been approved in the castration-resistant disease (sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, radium-223). More recently, docetaxel and abiraterone have been moved to the hormone-sensitive disease setting, achieving better patient survival. The purpose of this article is to define the state of the art in the treatment of prostate carcinoma.

Experiencia inicial en seguridad, tolerancia y adherencia al uso de docetaxel en pacientes con cáncer de próstata castración sensibles en un centro oncológico nacional / Initial experience in safety, tolerance and adherence to the use of docetaxel in patients with sensitive castration prostate cancer in a national cancer center

INTRODUCCIÓN: El cáncer de próstata (PC) es una enfermedad de alta incidencia y prevalencia (90/100.00 habitantes) y constituye la segunda causa por muerte oncológica en hombres, fenómeno que acontece en su fase metastásica (mPC). El tratamiento estándar en esta etapa corresponde a la terapia de deprivación androgénica (TDA) que produce una respuesta oncológica favorable en términos de descenso del PSA y estabilización y/o regresión de las metástasis. Ésta primera etapa (castración sensible) dura en promedio 2 a 3 años, tras lo cual ocurre una independización tumoral del estímulo androgénico, fenómeno conocido como castración-resistencia (mCRPC). En esta etapa la quimioterapia (QMT) con docetaxel prolonga la sobrevida aproximadamente 4 meses, lo cual en conjunto con otros tratamientos de segunda línea (abiraterona, enzalutamida, etc.) logra alcanzar una sobrevida media desde el diagnostico de mCRPC de 24 meses. Diversos estudios (CHAARTED y STAMPEDE) han demostrado que el inicio de docetaxel junto con TDA en pacientes con mPC castración-sensible (mCSPC) prolongan sobrevida global hasta 17 meses, especialmente si hay alto volumen de enfermedad. El objetivo del estudio es describir las características clínicas, la respuesta oncológica inicial y el perfil de efectos adversos de pacientes con mCSPC sometidos a docetaxel. MATERIALES Y MÉTODOS: Estudio retrospectivo descriptivo entre mayo 2014 a Julio 2017. Se incluyeron pacientes ng/ml (rango 10,8 - 5550) y mediana de seguimiento 6 meses (rango 3 ­ 20). Catorce pacientes tenían Gleason > 8, 18 eran M+ de los cuales 9 eran viscerales. Solo uno recibió tratamiento local previo. La mediana de inicio de QMT fue 3,1 (0 ­ 6,1) meses post inicio TDA.Dieciséis pacientes completaron docetaxel y 4 siguen en curso. No hubo suspensión de QMT por efectos adversos. Los más frecuentes fueron diarrea (8/20), neuropatía (5/20) y vómitos (2/20). La mayoría fue grado 1 y solo tres presentaron complicaciones grado 3 (diarrea, leucopenia y trombocitopenia). No hubo complicaciones grado 4 -5. Diez pacientes alcanzaron un antígeno < 2 ng/ml a las 12 semanas post tratamiento y 7 presentaron recidiva bioquímica durante el seguimiento. Uno tuvo respuesta imagenológica completa, 10 respuesta parcial, 7 estabilidad y 2 mostraron progresión. CONCLUSIONES: El uso de Docetaxel en mCSPC es seguro, presenta escasos efectos adversos (la mayoría de intensidad leve) que no motivan suspensión. El tratamiento con docetaxel exhibe una respuesta prometedora en términos de control de PSA, sin embargo se requiere mayor seguimiento de esta cohorte para evaluar impacto en sobrevida. con mCSPC con enfermedad de alto volumen (metástasis óseas extra-axiales, viscerales o Gleason 9-10) y ECOG 0-1. Los pacientes recibieron TDA y seis ciclos de Docetaxel. Se registraron datos demográficos, clínicos, histopatológicos, PSA, imagenológicos (RECIST V1.1) y toxicidad (NCI CAE 4.0) RESULTADOS: Se incluyeron 20 pacientes, mediana de edad 63 años (rango 49 ­ 75). Mediana PSA de ingreso 267,5 ng/ml (rango 10,8 - 5550) y mediana de seguimiento 6 meses (rango 3 ­ 20). Catorce pacientes tenían Gleason > 8, 18 eran M+ de los cuales 9 eran viscerales. Solo uno recibió tratamiento local previo. La mediana de inicio de QMT fue 3,1 (0 ­ 6,1) meses post inicio TDA.Dieciséis pacientes completaron docetaxel y 4 siguen en curso. No hubo suspensión de QMT por efectos adversos. Los más frecuentes fueron diarrea (8/20), neuropatía (5/20) y vómitos (2/20). La mayoría fue grado 1 y solo tres presentaron complicaciones grado 3 (diarrea, leucopenia y trombocitopenia). No hubo complicaciones grado 4 -5. Diez pacientes alcanzaron un antígeno < 2 ng/ml a las 12 semanas post tratamiento y 7 presentaron recidiva bioquímica durante el seguimiento. Uno tuvo respuesta imagenológica completa, 10 respuesta parcial, 7 estabilidad y 2 mostraron progresión. CONCLUSIONES: El uso de Docetaxel en mCSPC es seguro, presenta escasos efectos adversos (la mayoría de intensidad leve) que no motivan suspensión. El tratamiento con docetaxel exhibe una respuesta prometedora en términos de control de PSA, sin embargo se requiere mayor seguimiento de esta cohorte para evaluar impacto en sobrevida.(AU)

INTRODUCTION: Prostate cancer is a disease with high incidence and prevalence (90/100.000 habitants) and the second cause of cancer related death in men. Standard treatment in this setting is androgen-deprivation therapy (TDA), which causes decrease in PSA levels and stabilization or regression of metastatic lesions. Responses in castration sensitive phase last in average 3 years, after which tumor is described to become independent from the androgenic stimuli, reaching a castration-resistance (mCRPC) state. At this point chemotherapy with docetaxel as well as second line treatments (abiraterone, enzalutamide, among others)have shown to improve survival in 4 months with mean survival from diagnosis of mCRPC of 24 months. Studies including CHAARTED and STAMPEDE have demonstrated that early treatment with docetaxel with ADT in patients with mCSPC prolongs overall survival, especially if high volume disease exists. This study describes the clinical characteristics, initial oncologic response and side effects profile of mCSPC treated with Docetaxel plus ADT. MATERIALS AND METHODS: Descriptive Retrospective study from May 2014 to July 2017. mCSPC patients with high volume disease (extra axial bone metastasis, visceral metastasis or Gleason 9-10) and ECOG 0-1 were included. Patients received ADT and 6 cycles of Docetaxel. Demographic, clinical and histopathological characteristicswere registered, together with PSA, radiologic data (RECIST V1.1) and toxicity (NCI CAE 4.0). RESULTS: 20 patients were included, median age 63 years (49-75 range). Median initial PSA 267,5 ng/ml (10,8-5550 range), and median follow up 6 months (3-20 range). Fourteen patients had Gleason > 8, 18presented bone metastasis and 9/14 viscerametastasis. Only 1 patient received previous local treatment. Median initialtime to initiation of Docetaxel post ADT was 3,1 (0-6,1) months.Sixteen patients completed docetaxel and 4 are still receiving treatment. There was no chemotherapy suspension due side effects. Most frequent side effects were diarrhea (8/20), neuropathy (5/20) and vomiting (2/20). Most were grade 1 and three patients presented grade 3 side effects (diarrhea, leukopenia and thrombocytopenia). No grade 4-5 side effects were reported.Ten patients reached PSA< 2 ng/m after 12 weeks of treatment, and 7 had biochemical relapse during follow up. One had complete radiologic response, 10 partial response, 7 remained stable and 2 showed progression of disease. CONCLUSION: The use of docetaxel in mCSPC isassociated to few side effects and none requiredsuspension of treatment. Treatment with Docetaxel exhibits promising results in terms of decrease in PSA, however longer follow up and greater number of patients are required to report benefits in overall survival.(AU)

Intermittent versus continuous androgen deprivation therapy to biochemical recurrence after external beam radiotherapy: a phase 3 GICOR study.

PURPOSE: We compared biochemical control and quality of life with intermittent (6 months) versus continuous (36 months) androgen deprivation therapy (ADT) in a non-inferiority randomized phase 3 trial in patients with biochemical failure (BF) after external beam radical radiotherapy (EBRT). MATERIALS AND METHODS: Patients were stratified according to the Gleason score (GS) and were classified as low risk with a GS < 6 and 7 (3 + 4) and high risk with a GS of 7 (4 + 3) and >7. Patients were followed with PSA determinations and quality-of-life assessments (QLQ C-30 and QLQ PR-25) every 6 months for a period of 3 years. BF after radiation was defined as a PSA level of nadir +2 ng/ml. Disease progression (DP) after ADT was defined as PSA ≥4 ng/ml (BF) and/or metastases. RESULTS: Seventy-seven patients were included in this multicenter phase 3 trial from 2005 to 2009. Thirty-eight and 39 patients were included in the intermittent and continuous groups, respectively. The median follow-up for both groups was 48 months (40-68). DP after ADT in the intermittent group was seen in three patients (distant metastases in one patient) versus 0 in the continuous group. The QLQ-C30 and QLQ PR-25 scores did not show any statistically difference between the two ADT groups. CONCLUSIONS: No significant differences were seen in DP and QLQ between intermittent (6 months) and continuous (36 months) ADT in patients with BF after EBRT.