Transcriptomic and clinical heterogeneity of metastatic disease timing within metastatic castration-sensitive prostate cancer.

BACKGROUND: Metastatic castration-sensitive prostate cancer (mCSPC) is commonly classified into high- and low-volume subgroups which have demonstrated differential biology, prognosis, and response to therapy. Timing of metastasis has similarly demonstrated differences in clinical outcomes; however, less is known about any underlying biologic differences between these disease states. Herein, we aim to compare transcriptomic differences between synchronous and metachronous mCSPC and identify any differential responses to therapy. PATIENTS AND METHODS: We performed an international multi-institutional retrospective review of men with mCSPC who completed RNA expression profiling evaluation of their primary tumor. Patients were stratified according to disease timing (synchronous versus metachronous). The primary endpoint was to identify differences in transcriptomic profiles between disease timing. The median transcriptomic scores between groups were compared with the Mann-Whitney U test. Secondary analyses included determining clinical and transcriptomic variables associated with overall survival (OS) from the time of metastasis. Survival analysis was carried out with the Kaplan-Meier method and multivariable Cox regression. RESULTS: A total of 252 patients were included with a median follow-up of 39.6 months. Patients with synchronous disease experienced worse 5-year OS (39% versus 79%; P < 0.01) and demonstrated lower median androgen receptor (AR) activity (11.78 versus 12.64; P < 0.01) and hallmark androgen response (HAR; 3.15 versus 3.32; P < 0.01). Multivariable Cox regression identified only high-volume disease [hazard ratio (HR) = 4.97, 95% confidence interval (CI) 2.71-9.10; P < 0.01] and HAR score (HR = 0.51, 95% CI 0.28-0.88; P = 0.02) significantly associated with OS. Finally, patients with synchronous (HR = 0.47, 95% CI 0.30-0.72; P < 0.01) but not metachronous (HR = 1.37, 95% CI 0.50-3.92; P = 0.56) disease were found to have better OS with AR and non-AR combination therapy as compared with monotherapy (P value for interaction = 0.05). CONCLUSIONS: We have demonstrated a potential biologic difference between metastatic timing of mCSPC. Specifically, for patients with low-volume disease, those with metachronous low-volume disease have a more hormone-dependent transcriptional profile and exhibit a better prognosis than synchronous low-volume disease.

Benefits of early salvage therapy on oncological outcomes in high-risk prostate cancer with persistent PSA after radical prostatectomy

BackgroundPatients with prostate-specific antigen (PSA) persistence are at the increased risk of disease progression. The aim of our study was to evaluate the impact of early salvage therapy on oncological outcomes in patients with persistent PSA after radical prostatectomy (RP).MethodsWithin a single tertiary centre database, we identified men with persistent (≥ 0.1 ng/ml) versus undetectable (< 0.1 ng/ml) PSA 4–8 weeks after RP for high-risk prostate cancer (HRPCa). The cumulative incidence function was used to estimate cancer-specific survival (CSS) and clinical progression-free survival (CPFS). The Kaplan–Meier method was used to estimate overall survival (OS). The effects on oncological outcomes of salvage radiotherapy (SRT) ± androgen deprivation therapy (ADT) vs. ADT monotherapy were tested in the subgroup of patients with persistent PSA.ResultsOf 414 consecutive patients who underwent RP for HRPC, 125 (30.2%) had persistent PSA. Estimated 10-year CPFS, CSS and OS for men with persistent vs. undetectable PSA were 63.8% vs. 93.5%, 78.5% vs. 98.3% and 54% vs. 83.2% (all p < 0.0001), respectively. In men with persistent PSA, ADT alone was associated with higher risk (hazard ratio (HR) for worse CSS (HR 3.9, p = 0.005) and OS (HR 4.7, p < 0.0001) but not for CP (HR 1.6, p = 0.2) when compared with SRT ± ADT.ConclusionIn patients who underwent RP for HRPCa, persistent PSA was associated with poor oncological outcomes. Early SRT ± ADT resulted in significantly improved CSS and OS in men with persistent PSA comparing with early androgen deprivation monotherapy.

Benefits of early salvage therapy on oncological outcomes in high-risk prostate cancer with persistent PSA after radical prostatectomy.

BACKGROUND: Patients with prostate-specific antigen (PSA) persistence are at the increased risk of disease progression. The aim of our study was to evaluate the impact of early salvage therapy on oncological outcomes in patients with persistent PSA after radical prostatectomy (RP). METHODS: Within a single tertiary centre database, we identified men with persistent (≥ 0.1 ng/ml) versus undetectable (< 0.1 ng/ml) PSA 4-8 weeks after RP for high-risk prostate cancer (HRPCa). The cumulative incidence function was used to estimate cancer-specific survival (CSS) and clinical progression-free survival (CPFS). The Kaplan-Meier method was used to estimate overall survival (OS). The effects on oncological outcomes of salvage radiotherapy (SRT) ± androgen deprivation therapy (ADT) vs. ADT monotherapy were tested in the subgroup of patients with persistent PSA. RESULTS: Of 414 consecutive patients who underwent RP for HRPC, 125 (30.2%) had persistent PSA. Estimated 10-year CPFS, CSS and OS for men with persistent vs. undetectable PSA were 63.8% vs. 93.5%, 78.5% vs. 98.3% and 54% vs. 83.2% (all p < 0.0001), respectively. In men with persistent PSA, ADT alone was associated with higher risk (hazard ratio (HR) for worse CSS (HR 3.9, p = 0.005) and OS (HR 4.7, p < 0.0001) but not for CP (HR 1.6, p = 0.2) when compared with SRT ± ADT. CONCLUSION: In patients who underwent RP for HRPCa, persistent PSA was associated with poor oncological outcomes. Early SRT ± ADT resulted in significantly improved CSS and OS in men with persistent PSA comparing with early androgen deprivation monotherapy.

Treatment of patients with newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) in Belgium: a real world data analysis.

INTRODUCTION: Abiraterone acetate + prednisone (AAP) and docetaxel have proven their efficacy in the treatment of patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) in clinical trials. However, real-world data are scarce. The goal of this study is to evaluate real-world data on the efficacy and safety of these therapies in mHSPC patients. PATIENTS AND METHODS: Records of 93 patients from 21 different centres were retrospectively reviewed. Primary and secondary endpoints were radiographic and PSA progression-free survival (RPFS - PSA-PFS) and cancer specific and overall survival (CSS - OS), respectively. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. Differences in oncological outcome and AEs were evaluated between three treatment groups: ADT only (N=26) - ADT + AAP (N=48) - ADT + docetaxel (N=19). Survival analysis was performed using Kaplan-Meier statistics. RESULTS: Median RPFS was 13 months (95% confidence interval [CI]: 9-17) for ADT only, 21 months (95% CI: 19-23) for ADT + AAP and 12 months (95% CI: 11-14) for ADT + docetaxel (p = 0.004). The 1-year PSA-PFS, CSS and OS were 73.5%, 90.7% and 88.7%, respectively, with no significant differences between the three groups. Adverse events of grade 3 or higher were not observed more frequently. CONCLUSION: Retrospective real-world data show a significantly longer RPFS for mHSPC patients treated with ADT + AAP compared to ADT only or ADT + docetaxel at short-term follow-up. This can aid in counselling of mHSPC patients in daily clinical practice.

Factores de riesgo de enfermedad residual en la re-RTU en una gran cohorte de pacientes con enfermedad T1G3 / Risk factors for residual disease at re-TUR in a large cohort of T1G3 patients

Introducción y objetivos: Los objetivos de la resección transuretral (RTU) del tumor vesical son la resección completa de las lesiones y la realización de un diagnóstico correcto con el objetivo de estadificar adecuadamente al paciente. Es bien sabido que la presencia de músculo detrusor en el espécimen es un requisito previo para minimizar el riesgo de infraestadificación.La persistencia de enfermedad tras la resección de los tumores vesicales no es infrecuente, y es la razón por la que las guías europeas recomiendan una re-resección transuretral (re-RTU) para todos los tumores T1. Recientemente se ha publicado que, en los casos con inclusión de músculo en el espécimen, la re-RTU no afecta la progresión ni la supervivencia específica del cáncer.Presentamos aquí los factores relacionados con el paciente y el tumor que pueden influir en la presencia de enfermedad residual en la re-RTU.Material y métodosDe nuestra cohorte retrospectiva de 2.451 pacientes con tumores T1G3 primarios tratados inicialmente con bacilo de Calnette-Guérin (BCG), están disponibles los resultados patológicos de 934 pacientes (38,1%) que se sometieron a una re-RTU. El 74% tenía tumores multifocales, el 20% de los tumores tenía más de 3 cm de diámetro y el 26% tenía carcinoma in situ (CIS) concomitante. En este subgrupo de pacientes que se sometieron a una segunda RTU, no hubo enfermedad residual en 267 pacientes (29%) y se presentó enfermedad residual en 667 pacientes (71%): Ta en 378 (40%) y T1 en 289 (31%) pacientes. Se analizaron la edad, el sexo, el estado del tumor (primario/recurrente), la terapia intravesical previa, el tamaño del tumor, la multifocalidad del tumor, la presencia de CIS concomitante y la inclusión de músculo en el espécimen para evaluar los factores de riesgo de enfermedad residual en la re-RTU, tanto en los análisis univariantes, como en las regresiones logísticas multivariantes. (AU)

Introduction and objectives: The goals of transurethral resection of a bladder tumor (TUR) are to completely resect the lesions and to make a correct diagnosis in order to adequately stage the patient. It is well known that the presence of detrusor muscle in the specimen is a prerequisite to minimize the risk of under staging.Persistent disease after resection of bladder tumors is not uncommon and is the reason why the European Guidelines recommended a re-TUR for all T1 tumors. It was recently published that when there is muscle in the specimen, re-TUR does not influence progression or cancer specific survival.We present here the patient and tumor factors that may influence the presence of residual disease at re-TUR.Material and methodsIn our retrospective cohort of 2451 primary T1G3 patients initially treated with BCG, pathology results for 934 patients (38.1%) who underwent re-TUR are available. 74% had multifocal tumors, 20% of tumors were more than 3 cm in diameter and 26% had concomitant CIS.In this subgroup of patients who underwent re-TUR, there was no residual disease in 267 patients (29%) and residual disease in 667 patients (71%): Ta in 378 (40%) and T1 in 289 (31%) patients. Age, gender, tumor status (primary/recurrent), previous intravesical therapy, tumor size, tumor multi-focality, presence of concomitant CIS, and muscle in the specimen were analyzed in order to evaluate risk factors of residual disease at re-TUR, both in univariate analyses and multivariate logistic regressions. (AU)

Risk factors for residual disease at re-TUR in a large cohort of T1G3 patients.

INTRODUCTION AND OBJECTIVES: The goals of transurethral resection of a bladder tumor (TUR) are to completely resect the lesions and to make a correct diagnosis in order to adequately stage the patient. It is well known that the presence of detrusor muscle in the specimen is a prerequisite to minimize the risk of under staging. Persistent disease after resection of bladder tumors is not uncommon and is the reason why the European Guidelines recommended a re-TUR for all T1 tumors. It was recently published that when there is muscle in the specimen, re-TUR does not influence progression or cancer specific survival. We present here the patient and tumor factors that may influence the presence of residual disease at re-TUR. MATERIAL AND METHODS: In our retrospective cohort of 2451 primary T1G3 patients initially treated with BCG, pathology results for 934 patients (38.1%) who underwent re-TUR are available. 74% had multifocal tumors, 20% of tumors were more than 3 cm in diameter and 26% had concomitant CIS. In this subgroup of patients who underwent re-TUR, there was no residual disease in 267 patients (29%) and residual disease in 667 patients (71%): Ta in 378 (40%) and T1 in 289 (31%) patients. Age, gender, tumor status (primary/recurrent), previous intravesical therapy, tumor size, tumor multi-focality, presence of concomitant CIS, and muscle in the specimen were analyzed in order to evaluate risk factors of residual disease at re-TUR, both in univariate analyses and multivariate logistic regressions. RESULTS: The following were not risk factors for residual disease: age, gender, tumor status and previous intravesical chemotherapy. The following were univariate risk factors for presence of residual disease: no muscle in TUR, multiple tumors, tumors > 3 cm, and presence of concomitant CIS. Due to the correlation between tumor multi-focality and tumor size, the multivariate model retained either the number of tumors or the tumor diameter (but not both), p < 0.001. The presence of muscle in the specimen was no longer significant, while the presence of CIS only remained significant in the model with tumor size, p < 0.001. CONCLUSIONS: The most significant factors for a higher risk of residual disease at re-TUR in T1G3 patients are multifocal tumors and tumors more than 3 cm. Patients with concomitant CIS and those without muscle in the specimen also have a higher risk of residual disease.

Concordance Between Biopsy and Radical Prostatectomy Gleason Scores: Evaluation of Determinants in a Large-Scale Study of Patients Undergoing RARP in Belgium.

To determine whether Gleason scores were concordant between prostate biopsies (bGS) and the definitive resection specimen (pGS) excised with robot-assisted radical prostatectomy (RARP); to identify clinical and pathological factors that might predict upgrading; and to evaluate how upgrading affected outcome. Between 2009 and 2016, 25 Belgian centers participated in collecting prospective data for patients that underwent RARP. We analyzed the concordance rate between the bGS and the pGS in 8021 patients with kappa statistics, and we compared concordance rates from different centers. We assessed the effect of several clinical and pathological factors on the concordance rate with logistic regression analysis. The concordance rate for the entire population was 62.9%. Upgrading from bGS to pGS occurred in 27.3% of patients. The number of biopsies was significantly associated with concordance. Older age (>60 y), a higher clinical T stage (≥cT2), a higher PSA value at the time of biopsy (>10 ng/ml), and more time between the biopsy and the radical prostatectomy were significantly associated with a higher risk of upgrading. Positive margins and PSA relapse occurred more frequently in upgraded patients. Center size did not significantly affect the concordance rate (p = 0.40).This prospective, nationwide analysis demonstrated a Gleason score concordance rate of 62.9%. Upgrading was most frequently observed in the non-concordant group. We identified clinical and pathological factors associated with (non)-concordance. Upgrading was associated with a worse oncological outcome. Center volume was not associated with pathological accuracy.

Surgical management of acquired rectourethral fistula: a retrospective analysis of 52 consecutive patients.

BACKGROUND: Acquired rectourethral fistula (RUF) is an uncommon complication mostly resulting from surgery or radiation. Standardization of the surgical management is lacking. The aim of this study was to report our experience with surgery for RUF. METHODS: This was a retrospective study of a prospectively maintained clinical database. The surgical strategy was tailored to complexity of RUF, presence of sepsis, history of radiation and residual urinary/fecal functionality. Outcomes measured were RUF closure and permanent fecal/urinary diversion. Impact of radiotherapy was also assessed. RESULTS: Between November 2002 and January 2019, 52 patients were identified (100% males). Median follow-up was 10.5 (0.5-16.8) years. Three patients had RUF closure after conservative management. The remaining 49 patients had a total of 76 procedures. The cumulative closure rate after the first, second and third attempt was 55.1%, 85.7% and 95.9%, respectively. Fistula closure together with preservation of the fecal and urinary function was achieved in 49%, 65.3% and 67.3% after the first, second and third repair, respectively. The overall success rate for transanal, transperineal, restorative transabdominal and non-restorative transabdominal procedures was 35.7%, 64.3%, 57.1% and 94.1%, respectively. A significantly higher rate of urinary/intestinal stomas was observed in the irradiated vs non-irradiated patients (84.2% vs 42.4%; p = 0.004). CONCLUSIONS: Surgery ensured healing in 96% of the patients. Radiotherapy led to higher rate of permanent urinary/fecal diversion. Nearly all irradiated patients who had transabdominal repair end up with a definitive stoma. When transperineal repair with gracilis flap interposition was used, the rate of fistula closure approached 90%. A treatment algorithm is proposed.

Salvage Radiotherapy for Prostate Cancer.

For patients experiencing biochemical recurrence in the absence of distant metastasis, salvage radiotherapy (SRT) with or without androgen deprivation therapy (ADT) is currently the only possible curative treatment option. Prostate-specific antigen (PSA) monitoring and the selected use of SRT has some advantages when compared with adjuvant radiotherapy. The most important one is avoidance of a potential overtreatment of patients who would never have disease progression, even in the presence of high-risk pathological features. The identification of a specific PSA cut-off seems to be incorrect. In patients with more adverse pathological features, early SRT administered at the very first sign of a PSA rise granted better disease control. Dose-intensified SRT is feasible and well tolerated with no significant difference in grade 2 or more acute and late toxicity. At least 66 Gy must be given in the salvage setting. ADT has a radio-sensitising effect on the radiotherapy by inhibiting the repair of DNA double-strand breaks. The use of ADT in the salvage setting results in a better oncological outcome. Hormonal therapy is associated with a decrease in quality of life and side-effects depending on the duration of hormone therapy. The oncological benefit of hormone therapy duration depends on their clinical and pathological characteristics. 68-Ga-prostate-specific membrane antigen positron emission tomography-computed tomography is the gold standard in staging prostate cancer patients with biochemical persistence or recurrence after radical prostatectomy. The implementation of 18F-labelled PSMA tracers can provide a further improvement.

Molecular underpinnings of enzalutamide resistance

Prostate cancer (PCa) is among the most common adult malignancies, and the second leading cause of cancer-related death in men. As PCa is hormone dependent, blockade of the androgen receptor (AR) signaling is an effective therapeutic strategy for men with advanced metastatic disease. The discovery of enzalutamide, a compound that effectively blocks the AR axis and its clinical application has led to a significant improvement in survival time. However, the effect of enzalutamide is not permanent, and resistance to treatment ultimately leads to development of lethal disease, for which there currently is no cure. This review will focus on the molecular underpinnings of enzalutamide resistance, bridging the gap between the preclinical and clinical research on novel therapeutic strategies for combating this lethal stage of prostate cancer.

Predictors of oncological outcomes in T1G3 patients treated with BCG who undergo radical cystectomy.

PURPOSE: To evaluate the oncological impact of postponing radical cystectomy (RC) to allow further conservative therapies prior to progression in a large multicentre retrospective cohort of T1-HG/G3 patients initially treated with BCG. METHODS: According to the time of RC, the population was divided into 3 groups: patients who did not progress to muscle-invasive disease, patients who progressed before radical cystectomy and patients who experienced progression at the time of radical cystectomy. Clinical and pathological outcomes were compared across the three groups. RESULTS: Of 2451 patients, 509 (20.8%) underwent RC. Patients with tumors > 3 cm or with CIS had earlier cystectomies (HR = 1.79, p = 0.001 and HR = 1.53, p = 0.02, respectively). Patients with tumors > 3 cm, multiple tumors or CIS had earlier T3/T4 or N + cystectomies. In patients who progressed, the timing of cystectomy did not affect the risk of T3/T4 or N + disease at RC. Patients with T3/T4 or N + disease at RC had a shorter disease-specific survival (HR = 4.38, p < 0.001), as did patients with CIS at cystectomy (HR = 2.39, p < 0.001). Patients who progressed prior to cystectomy had a shorter disease-specific survival than patients for whom progression was only detected at cystectomy (HR = 0.58, p = 0.024) CONCLUSIONS: Patients treated with RC before experiencing progression to muscle-invasive disease harbor better oncological and survival outcomes compared to those who progressed before RC and to those upstaged at surgery. Tumor size and concomitant CIS at diagnosis are the main predictors of surgical treatment while tumor size, CIS and tumor multiplicity are associated with extravesical disease at surgery.

Recurrence, progression and cancer-specific mortality according to stage at re-TUR in T1G3 bladder cancer patients treated with BCG: not as bad as previously thought.

PURPOSE: The goals of transurethral resection of a bladder tumor (TUR) are to completely resect the lesions and to make a correct diagnosis to adequately stage and treat the patient. Persistent disease after TUR is not uncommon and is why re-TUR is recommended in T1G3 patients. When there is T1 tumor in the re-TUR specimen, very high risks of progression (82%) have been reported. We analyze the risks of recurrence, progression to muscle-invasive disease and cancer-specific mortality (CSM) according to tumor stage at re-TUR in T1G3 patients treated with BCG. METHODS: In our retrospective cohort of 2451 T1G3 patients, 934 patients (38.1%) underwent re-TUR. 667 patients had residual disease (71.4%): Ta in 378 (40.5%), T1 in 289 (30.9%) patients. Times to recurrence, progression and CSM in the three groups were estimated using cumulative incidence functions and compared using the Cox regression model. RESULTS: During a median follow-up of 5.2 years, 512 patients recurred. The recurrence rate was significantly higher in patients with a T1 at re-TUR (P < 0.001). Progression rates differed according to the pathology at re-TUR, 25.3% in T1, 14.6% in Ta and 14.2% in case of no residual tumor (P < 0.001). Similar trends were seen in both patients with and without muscle in the original TUR specimen. CONCLUSIONS: Patients with T1G3 tumors and no residual disease or Ta at re-TUR have better recurrence, progression and CSM rates than previously reported, with a CSM rate of 13.1 and a 25.3% progression rate in re-TUR T1 disease.

The role of TET-mediated DNA hydroxymethylation in prostate cancer.

Ten-eleven translocation (TET) proteins are recently characterized dioxygenases that regulate demethylation by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine and further derivatives. The recent finding that 5hmC is also a stable and independent epigenetic modification indicates that these proteins play an important role in diverse physiological and pathological processes such as neural and tumor development. Both the genomic distribution of (hydroxy)methylation and the expression and activity of TET proteins are dysregulated in a wide range of cancers including prostate cancer. Up to now it is still unknown how changes in TET and 5(h)mC profiles are related to the pathogenesis of prostate cancer. In this review, we explore recent advances in the current understanding of how TET expression and function are regulated in development and cancer. Furthermore, we look at the impact on 5hmC in prostate cancer and the potential underlying mechanisms. Finally, we tried to summarize the latest techniques for detecting and quantifying global and locus-specific 5hmC levels of genomic DNA.

Treatment-induced changes in the androgen receptor axis: Liquid biopsies as diagnostic/prognostic tools for prostate cancer.

Prostate cancer progression and treatment relapse is associated with changes in the androgen receptor axis, and analysis of alternations of androgen receptor signaling is valuable for prognostics and treatment optimization. The profile of androgen receptor axis is currently obtained from biopsy specimens, which are not always easy to obtain. Moreover, the information acquired only provides a snapshot of the tumor biology, with strict spatial and temporal limitations. On the other hand, circulation is easily accessible source of both circulating tumor cells and circulating tumor DNA, which can be sampled at numerous time points. This Review will explore the potential use of androgen receptor axis alternations detectable in the blood in therapeutic decision-making and precision medicine for advancing metastatic castration-resistant prostate cancer.

The survival impact of neoadjuvant hormonal therapy before radical prostatectomy for treatment of high-risk prostate cancer.

BACKGROUND: Several randomized controlled trials assessed the outcomes of patients treated with neoadjuvant hormonal therapy (NHT) before radical prostatectomy (RP). The majority of them included mainly low and intermediate risk prostate cancer (PCa) without specifically assessing PCa-related death (PCRD). Thus, there is a lack of knowledge regarding a possible effect of NHT on PCRD in the high-risk PCa population. We aimed to analyze the effect of NHT on PCRD in a multicenter high-risk PCa population treated with RP, using a propensity-score adjustment. METHODS: This is a retrospective multi-institutional study including patients with high-risk PCa defined as: clinical stage T3-4, PSA >20 ng ml-1 or biopsy Gleason score 8-10. We compared PCRD between RP and NHT+RP using competing risks analysis. Correction for group differences was performed by propensity-score adjustment. RESULTS: After application of the inclusion/exclusion criteria, 1573 patients remained for analysis; 1170 patients received RP and 403 NHT+RP. Median follow-up was 56 months (interquartile range 29-88). Eighty-six patients died of PCa and 106 of other causes. NHT decreased the risk of PCRD (hazard ratio (HR) 0.5; 95% confidence interval (CI) 0.32-0.80; P=0.0014). An interaction effect between NHT and radiotherapy (RT) was observed (HR 0.3; 95% CI 0.21-0.43; P<0.0008). More specifically, of patients who received adjuvant RT, those who underwent NHT+RP had decreased PCRD rates (2.3% at 5 year) compared to RP (7.5% at 5 year). The retrospective design and lack of specific information about NHT are possible limitations. CONCLUSIONS: In this propensity-score adjusted analysis from a large high-risk PCa population, NHT before surgery significantly decreased PCRD. This effect appeared to be mainly driven by the early addition of RT post-surgery. The specific sequence of NHT+RP and adjuvant RT merits further study in the high-risk PCa population.

Older patients with low Charlson score and high-risk prostate cancer benefit from radical prostatectomy.

INTRODUCTION: The aim of the study was to identify the appropriate level of Charlson comorbidity index (CCI) in older patients (>70 years) with high-risk prostate cancer (PCa) to achieve survival benefit following radical prostatectomy (RP). METHODS: We retrospectively analyzed 1008 older patients (>70 years) who underwent RP with pelvic lymph node dissection for high-risk prostate cancer (preoperative prostate-specific antigen >20 ng/mL or clinical stage ≥T2c or Gleason ≥8) from 14 tertiary institutions between 1988 and 2014. The study population was further grouped into CCI < 2 and ≥2 for analysis. Survival rate for each group was estimated with Kaplan-Meier method and competitive risk Fine-Gray regression to estimate the best explanatory multivariable model. Area under the curve (AUC) and Akaike information criterion were used to identify ideal 'Cut off' for CCI. RESULTS: The clinical and cancer characteristics were similar between the two groups. Comparison of the survival analysis using the Kaplan-Meier curve between two groups for non-cancer death and survival estimations for 5 and 10 years shows significant worst outcomes for patients with CCI ≥ 2. In multivariate model to decide the appropriate CCI cut-off point, we found CCI 2 has better AUC and p value in log rank test. CONCLUSION: Older patients with fewer comorbidities harboring high-risk PCa appears to benefit from RP. Sicker patients are more likely to die due to non-prostate cancer-related causes and are less likely to benefit from RP.

RANK/OPG ratio of expression in primary clear-cell renal cell carcinoma is associated with bone metastasis and prognosis in patients treated with anti-VEGFR-TKIs.

BACKGROUND: Bone metastases (BMs) are associated with poor outcome in metastatic clear-cell renal carcinoma (m-ccRCC) treated with anti-vascular endothelial growth factor tyrosine kinase inhibitors (anti-VEGFR-TKIs). We aimed to investigate whether expression in the primary tumour of genes involved in the development of BM is associated with outcome in m-ccRCC patients treated with anti-VEGFR-TKIs. METHODS: Metastatic clear-cell renal cell carcinoma patients with available fresh-frozen tumour and treated with anti-VEGFR-TKIs. Quantitative real-time PCR (qRT-PCR) for receptor activator of NF-kB (RANK), RANK-ligand (RANKL), osteoprotegerin (OPG), the proto-oncogene SRC and DKK1 (Dickkopf WNT signalling pathway inhibitor-1). Time-to-event analysis by Kaplan-Meier estimates and Cox regression. RESULTS: We included 129 m-ccRCC patients treated between 2005 and 2013. An elevated RANK/OPG ratio was associated with shorter median time to metastasis (HR 0.50 (95% CI 0.29-0.87); P=0.014), shorter time to BM (HR 0.54 (95% CI 0.31-0.97); P=0.037), shorter median overall survival (mOS) since initial diagnosis (HR 2.27 (95% CI 1.44-3.60); P=0.0001), shorter median progression-free survival (HR 0.44 (95% CI 0.28-0.71); P=0.001) and mOS (HR 0.31 (95% CI 0.19-0.52); P<0.0001) on first-line anti-VEGFR-TKIs in the metastatic setting. Higher RANK expression was associated with shorter mOS on first-line anti-VEGFR-TKIs (HR 0.46 (95% CI 0.29-0.73); P=0.001). CONCLUSIONS: RANK/OPG ratio of expression in primary ccRCC is associated with BM and prognosis in patients treated with anti-VEGFR-TKIs. Prospective validation is warranted.

Guidelines for the definition of time-to-event end points in renal cell cancer clinical trials: results of the DATECAN project†.

BACKGROUND: In clinical trials, the use of intermediate time-to-event end points (TEEs) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for end point definitions. MATERIALS AND METHODS: A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the nonmetastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each end point. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent end points and the associated events. RESULTS: Thirty-four experts scored 121 events for 9 end points. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds, respectively. The expert recommend the use of three and two endpoints in NM and MA setting, respectively. In the NM setting: disease-free survival (contralateral RCC, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), metastasis-free survival (appearance of metastases, regional recurrence, death from RCC); and local-regional-free survival (local or regional recurrence, death from RCC). In the MA setting: kidney cancer-specific survival (death from RCC or protocol treatment) and progression-free survival (death from RCC, local, regional, or metastatic progression). CONCLUSIONS: The consensus method revealed that intermediate end points have not been well defined, because all of the selected end points had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons.

Predicting prostate cancer-specific outcome after radical prostatectomy among men with very high-risk cT3b/4 PCa: a multi-institutional outcome study of 266 patients.

BACKGROUND: The value of radical prostatectomy (RP) as an approach for very high-risk prostate cancer (PCa) patients is controversial. To examine the risk of 10-year cancer-specific mortality (CSM) and other-cause mortality (OCM) according to clinical and pathological characteristics of very high-risk cT3b/4 PCa patients treated with RP as the primary treatment option. METHODS: In a multi-institutional cohort, 266 patients with very high-risk cT3b/4 PCa treated with RP were identified. All patients underwent RP and pelvic lymph-node dissection. Competing-risk analyses assessed 10-year CSM and OCM before and after stratification for age and Charlson comorbidity index (CCI). RESULTS: Overall, 34 (13%) patients died from PCa and 73 (28%) from OCM. Ten-year CSM and OCM rates ranged from 5.6% to 12.9% and from 10% to 38%, respectively. OCM was the leading cause of death in all subgroups. Age and comorbidities were the main determinants of OCM. In healthy men, CSM rate did not differ among age groups (10-year CSM rate for ⩽64, 65-69 and ⩾70 years: 16.2%, 11.5% and 17.1%, respectively). Men with a CCI ⩾1 showed a very low risk of CSM irrespective of age (10-year CSM: 5.6-6.1%), whereas the 10-year OCM rates increased with age up to 38% in men ⩾70 years. CONCLUSION: Very high-risk cT3b/4 PCa represents a heterogeneous group. We revealed overall low CSM rates despite the highly unfavorable clinical disease. For healthy men, CSM was independent of age, supporting RP even for older men. Conversely, less healthy patients had the highest risk of dying from OCM while sharing very low risk of CSM, indicating that this group might not benefit from an aggressive surgical treatment. Outcome after RP as the primary treatment option in cT3b/4 PCa patients is related to age and comorbidity status.

[Postoperative prognosis of chromophobic renal cell carcinoma: comparative analysis of the multinational CORONA database]. / Die postoperative Prognose des chromophoben Nierenzellkarzinoms : Eine vergleichende Analyse anhand der multinationalen CORONA-Datenbank.

BACKGROUND: The chromophobe subtype represents the third most common histological subtype of renal cell carcinoma (chRCC). Due to the rarity of this subtype only one publication regarding the specific analysis of clinical and histopathological criteria as well as survival analysis of more than 200 patients with chRCC is known to date. MATERIALS AND METHODS: A total of 6,234 RCC patients from 11 centres who were treated by (partial) nephrectomy are contained in the database of this multinational study. Of the patients 259 were diagnosed with chRCC (4.2 %) and thus formed the study group for this retrospective investigation. These subjects were compared to 4,994 patients with a clear cell subtype (80.1 %) with respect to clinical and histopathological criteria. The independent influence of the chromophobe subtype regarding tumor-specific survival and overall survival was determined using analysis by Cox proportional hazards regression models. The median follow-up was 59 months (interquartile range 29-106 months). RESULTS: The chRCC patients were significantly younger (60 vs. 63.2 years, p < 0.001), more often female (50 vs. 41 %, p = 0.005) and showed simultaneous distant metastases to a lesser extent (3.5 vs. 7.1 %, p = 0.023) compared to patients with a clear cell subtype. Despite a comparable median tumor size a ≥ pT3 tumor stage was diagnosed in only 24.7 % of the patients compared to of 30.5 % in patients with a clear cell subtype (p = 0.047). In addition to the clinical criteria of age, sex and distant metastases, the histological variables pTN stage, grade and tumor size showed a significant influence on tumor-specific and overall survival. However, in the multivariable Cox regression analysis no independent effect on tumor-specific mortality (HR 0.88, p = 0.515) and overall mortality (HR 1.00, p = 0.998) due to the histological subtype was found (c-index 0.86 and 0.77, respectively). CONCLUSIONS: Patients with chRCC and clear cell RCC differ significantly concerning the distribution of clinical and histopathological criteria. Patients with chRCC present with less advanced tumors which leads to better tumor-specific survival rates in general; however, this advantage could not be verified after adjustment for the established risk factors.