Gut Microbiome-Dependent Metabolic Pathways and Risk of Lethal Prostate Cancer: Prospective Analysis of a PLCO Cancer Screening Trial Cohort.

BACKGROUND: Diet and the gut microbiome have a complex interaction that generates metabolites with an unclear effect on lethal prostate cancer risk. Identification of modifiable risk factors for lethal prostate cancer is challenging given the long natural history of this disease and difficulty of prospectively identifying lethal cancers. METHODS: Mass spectrometry was performed on baseline serum samples collected from 173 lethal prostate cancer cases and 519 controls enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening trial. Baseline serum levels of choline, carnitine, betaine, γ-butyrobetaine, crotonobetaine, phenylacetylglutamine, hippuric acid, and p-cresol sulfate were quantified and analyzed by quartile. Conditional multivariable logistic regression analysis associated analyte levels with lethal prostate cancer incidence after adjusting for body mass index and PSA. The Cochran-Armitage test evaluated analyte level trends across quartiles. RESULTS: Relative to those in the first quartile, cases with the highest baseline levels of choline (Q4 OR: 2.19; 95% CI, 1.23-3.90; P-trend: 0.005) and betaine (Q4 OR: 1.86; 95% CI, 1.05-3.30; P-trend: 0.11) exhibited increased odds of developing lethal prostate cancer. Higher baseline serum levels of phenylacetylglutamine (Q4 OR: 2.55; 95% CI, 1.40-4.64; P-trend: 0.003), a gut microbiome metabolite of phenylalanine with adrenergic activity, were also associated with lethal prostate cancer. CONCLUSIONS: Baseline serum levels of one-carbon methyl donors and adrenergic compounds resulting from human and gut microbiota-mediated metabolism are associated with increased lethal prostate cancer risk. IMPACT: Dietary composition, circulating metabolite levels, and downstream signaling pathways may represent modifiable risk factors associated with incident lethal prostate cancer. Beta-adrenergic blockade represents an additional target for oncologic risk reduction.

Oncologic outcomes among Black and White men with grade group 4 or 5 (Gleason score 8-10) prostate cancer treated primarily by radical prostatectomy.

BACKGROUND: The aim of this study was to describe pathologic and short-term oncologic outcomes among Black and White men with grade group 4 or 5 prostate cancer managed primarily by radical prostatectomy. METHODS: This was a multi-institutional, observational study (2005-2015) evaluating radical prostatectomy outcomes by self-identified race. Descriptive analysis was performed via nonparametric statistical testing to compare baseline clinicopathologic data. Univariable and multivariable time-to-event analyses were performed to assess biochemical recurrence (BCR), metastasis, cancer-specific mortality (CSM), and overall survival between Black and White men. RESULTS: In total, 1662 men were identified with grade group 4 or 5 prostate cancer initially managed by radical prostatectomy. Black men represented 11.3% of the cohort (n = 188). Black men were younger, demonstrated a longer time from diagnosis to surgery, and were at a lower clinical stage (all P < .05). Black men had lower rates of pT3/4 disease (49.5% vs 63.5%; P < .05) but higher rates of positive surgical margins (31.6% vs 26.5%; P = .14) on pathologic evaluation. There was no difference in BCR, CSM, or overall survival over a median follow-up of 40.7 months. Black men had a lower 5-year cumulative incidence of metastasis-free survival (93.6%; 95% confidence interval [CI], 86.5%-97.0%) in comparison with White men (85.8%; 95% CI, 83.1%-88.0%), which did not persist in an age-adjusted analysis. CONCLUSIONS: Black and White men with high-grade prostate cancer at diagnosis demonstrated similar oncologic outcomes when they were managed by primary radical prostatectomy. Our findings suggest that racial disparities in prostate cancer mortality are not related to differences in the efficacy of extirpative therapy.

Ductal Prostate Cancers Demonstrate Poor Outcomes with Conventional Therapies.

BACKGROUND: Ductal prostate adenocarcinoma (DAC) is a rare, aggressive, histologic variant of prostate cancer that is treated with conventional therapies, similar to high-risk prostate adenocarcinoma (PAC). OBJECTIVE: To assess the outcomes of men undergoing definitive therapy for DAC or high-risk PAC and to explore the effects of androgen deprivation therapy (ADT) in improving the outcomes of DAC. DESIGN, SETTING, AND PARTICIPANTS: A single-center retrospective review of all patients with cT1-4/N0-1 DAC from 2005 to 2018 was performed. Those undergoing radical prostatectomy (RP) or radiotherapy (RTx) for DAC were compared with cohorts of high-risk PAC patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Metastasis-free survival (MFS) and overall survival (OS) rates were analyzed using Kaplan-Meier and Cox regression models. RESULTS AND LIMITATIONS: A total of 228 men with DAC were identified; 163 underwent RP, 34 underwent RTx, and 31 had neoadjuvant therapy prior to RP. In this study, 163 DAC patients and 155 PAC patients undergoing RP were compared. Similarly, 34 DAC patients and 74 PAC patients undergoing RTx were compared. DAC patients undergoing RP or RTx had worse 5-yr MFS (75% vs 95% and 62% vs 93%, respectively, p < 0.001) and 5-yr OS (88% vs 97% and 82% vs 100%, respectively, p < 0.05) compared with PAC patients. In the 76 men who received adjuvant/salvage ADT after RP, DAC also had worse MFS and OS than PAC (p < 0.01). A genomic analysis revealed that 10/11 (91%) DACs treated with ADT had intrinsic upregulation of androgen-resistant pathways. Further, none of the DAC patients (0/15) who received only neoadjuvant ADT prior to RP had any pathologic downgrading. The retrospective nature was a limitation. CONCLUSIONS: Men undergoing RP or RTx for DAC had worse outcomes than PAC patients, regardless of the treatment modality. Upregulation of several intrinsic resistance pathways in DAC rendered ADT less effective. Further evaluation of the underlying biology of DAC with clinical trials is needed. PATIENT SUMMARY: This study demonstrated worse outcomes among patients with ductal adenocarcinoma of the prostate than among high-grade prostate adenocarcinoma patients, regardless of the treatment modality.

Urolithiasis in complicated inflammatory bowel disease: a comprehensive analysis of urine profile and stone composition.

PURPOSE: To evaluate the impact of extensive surgery on urine profile, serum exams and stone composition of complicated IBD patients. METHODS: Patients with IBD and a history of total proctocolectomy (TPC) with fecal diversion (end ileostomy or ileal pouch anal anastomosis-IPAA) were selected. Only patients with at least one complete 24-h urine profile were included. A case-control study was performed selecting patients with kidney stone disease in a random way who had also at least on complete 24-h urine profile. Case and controls were matched for age, gender, and body mass index (BMI). Groups were compared to urine profile, serum exams and stone composition. RESULTS: Sixty-eight patients were enrolled in this study, 34 patients with IBD who underwent TPC and had diagnosis of kidney stones and 34 matched patients with only kidney stones. IBD patients had a significantly lower urine volume, urine citrate and urine sodium. Regarding serum exams, only serum bicarbonate was statistically significant lower. In both groups, calcium oxalate stone was the most common. CONCLUSION: Patients with IBD with TPC and kidney stones have a low urine volume and low urine citrate as main risk factors for kidney stone formation. As seen in the general population, calcium oxalate is the most common stone composition.

Prediction of Organ-confined Disease in High- and Very-high-risk Prostate Cancer Patients Staged with Magnetic Resonance Imaging: Implications for Clinical Trial Design.

BACKGROUND: High-risk (HR) prostate cancer (PCa) is a heterogeneous disease leading to difficulties in designing appropriate inclusion criteria for clinical trials. OBJECTIVE: To describe clinical predictors of organ-confined disease in HR or very-high-risk (VHR) PCa patients staged with multiparametric magnetic resonance imaging with endorectal coil (mp-MRI-ER). DESIGN, SETTING, AND PARTICIPANTS: We reviewed 366 HR/VHR PCa patients who had preoperative mp-MRI-ER, and underwent radical prostatectomy and extended pelvic lymph node dissection between 2006 and 2015. INTERVENTION: Radical prostatectomy with preoperative mp-MRI-ER. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used multivariable logistic regression modeling to assess for associations with ≤ pT2N0 stage and multivariable cox modeling to assess for associations with biochemical failure. RESULTS AND LIMITATIONS: Of 366 patients, 132 had ≤ pT2N0 disease. For the entire cohort, negative staging mp-MRI-ER (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.06-2.83, p = 0.03), lower prostate-specific antigen (PSA; OR 0.98, 95% CI 0.97-1.00, p = 0.02), and fewer cores of Gleason ≥8 cancer (OR 0.86, 95% CI 0.79-0.93, p = 0.0002) were associated with ≤pT2N0 disease. In HR patients only, negative mp-MRI-ER (OR 3.41, 95% CI 1.73-6.72, p = 0.0004) and fewer than four cores of Gleason ≥8 disease (OR 3.38, 95% CI 1.20-9.56, p = 0.02) were still associated with ≤pT2N0 disease. Lack of non-organ-confined disease on MRI was associated with superior biochemical recurrence-free survival (p = 0.02). Limitations of this study include lack of a central review or quality control of the MRI reporting. CONCLUSIONS: In HR PCa, negative staging mp-MRI-ER, fewer positive cores of Gleason >8, and lower PSA were significant predictors of pathologic organ-confined disease. Improved prediction of organ-confined disease in HR patients may allow for their inclusion into studies evaluating treatments from which they would otherwise be excluded based solely on their HR status. PATIENT SUMMARY: In patients with high-risk prostate cancer, prostate magnetic resonance imaging along with other clinical parameters may help determine which patients are likely to have disease confined to the prostate and thus be eligible for clinical trials that they otherwise might be excluded from based on their high-risk status alone.

Downgrading from Biopsy Grade Group 4 Prostate Cancer in Patients Undergoing Radical Prostatectomy for High or Very High Risk Prostate Cancer.

PURPOSE: We examined rates of Grade Group 4 downgrading at radical prostatectomy among men diagnosed with high and very high risk prostate cancer at biopsy. MATERIALS AND METHODS: A pooled cohort of 1,776 patients from 3 tertiary referral centers who underwent radical prostatectomy for National Comprehensive Cancer Network® high risk (prostate specific antigen greater than 20 ng/ml, or Grade Group 4-5, or clinical stage T3 or greater) or very high risk (primary Gleason pattern 5, or more than 4 biopsy cores with Grade Group 4-5, or 2 or more high risk features) disease from 2005 to 2015 were reviewed. Overall 893 patients with Grade Group 4 disease at biopsy were identified and 726 patients were available for analysis. Multivariable logistic regression models were fit to determine factors associated with downgrading to Grade Group 3 or less at radical prostatectomy. RESULTS: Overall 333 (45%) cases were downgraded to Grade Group 3 or less at radical prostatectomy. Of these cases 198 (27%) had concordant Grade Group 4 biopsy and radical prostatectomy pathology and 195 (27%) were upgraded at radical prostatectomy to Grade Group 5. Of high risk cases with biopsy Grade Group 4 disease 49% had any downgrading vs 29% of very high risk cases (p <0.0001). Downgrading to Grade Group 2 or less occurred in 16% (98 of 604) of high risk and 7% (8 of 122) of very high risk cases (p <0.01). Downgraded cases had a lower prostate specific antigen, fewer positive biopsy cores and lower clinical stage (p <0.01). On multivariable analysis fewer positive biopsy cores were significantly associated with downgrading at radical prostatectomy (p <0.01). CONCLUSIONS: In this cohort of patients with high risk/very high risk prostate cancer, downgrading from biopsy Grade Group 4 at radical prostatectomy occurred less frequently than in other published reports. Any downgrading was significantly less common in very high risk compared to high risk patients, and downgrading to Grade Group 2 or less occurred in a minority of cases in high risk and very high risk patients.

HSD3B1 Genotype and Clinical Outcomes in Metastatic Castration-Sensitive Prostate Cancer.

Importance: The adrenal-restrictive HSD3B1(1245A) allele limits extragonadal dihydrotestosterone synthesis, whereas the adrenal-permissive HSD3B1(1245C) allele augments extragonadal dihydrotestosterone synthesis. Retrospective studies have suggested an association between the adrenal-permissive allele, the frequency of which is highest in white men, and early development of castration-resistant prostate cancer (CRPC). Objective: To examine the association between the adrenal-permissive HSD3B1(1245C) allele and early development of CRPC using prospective data. Design, Setting, and Participants: The E3805 Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) was a large, multicenter, phase 3 trial of castration with or without docetaxel treatment in men with newly diagnosed metastatic prostate cancer. From July 28, 2006, through December 31, 2012, 790 patients underwent randomization, of whom 527 had available DNA samples. In this study, the HSD3B1 germline genotype was retrospectively determined in 475 white men treated in E3805 CHAARTED, and clinical outcomes were analyzed by genotype. Data analysis was performed from July 28, 2006, to October 17, 2018. Interventions: Men were randomized to castration plus docetaxel, 75 mg/m2, every 3 weeks for 6 cycles or castration alone. Main Outcomes and Measures: Two-year freedom from CRPC and 5-year overall survival, with results stratified by disease volume. Patients were combined across study arms according to genotype to assess the overall outcome associated with genotype. Secondary analyses by treatment arm evaluated whether the docetaxel outcome varied with genotype. Results: Of 475 white men with DNA samples, 270 patients (56.8%) inherited the adrenal-permissive genotype (≥1 HSD3B1[1245C] allele). Mean (SD) age was 63 (8.7) years. Freedom from CRPC at 2 years was diminished in men with low-volume disease with the adrenal-permissive vs adrenal-restrictive genotype: 51.0% (95% CI, 40.9%-61.2%) vs 70.5% (95% CI, 60.0%-80.9%) (P = .01). Overall survival at 5 years was also worse in men with low-volume disease with the adrenal-permissive genotype: 57.5% (95% CI, 47.4%-67.7%) vs 70.8% (95% CI, 60.3%-81.3%) (P = .03). Hazard ratios were 1.89 (95% CI, 1.13-3.14; P = .02) for CRPC and 1.74 (95% CI, 1.01-3.00; P = .045) for death. There was no association between genotype and outcomes in men with high-volume disease. There was no interaction between genotype and benefit from docetaxel. Conclusions and Relevance: Inheritance of the adrenal-permissive HSD3B1 genotype is associated with earlier castration resistance and shorter overall survival in men with low-volume metastatic prostate cancer and may help identify men more likely to benefit from escalated androgen receptor axis inhibition beyond gonadal testosterone suppression.

Determining Clinically Based Factors Associated With Reclassification in the Pre-MRI Era using a Large Prospective Active Surveillance Cohort.

OBJECTIVE: To report biopsy-related and oncologic outcomes in a large prospective active surveillance cohort that was initiated in the premagnetic resonance imaging era and to additionally identify clinical factors associated with disease reclassification in order to inform future studies designed to improve enrollment and follow-up on active surveillance. METHODS: Patients were prospectively enrolled at a single institution from 2006 to 2014 and followed until 2016. Men with Gleason 6 or 7 disease were eligible, and those with >6 months follow-up were included in the analysis. Patients were risk stratified based on clinical/pathologic criteria, including based on a combination of baseline and confirmatory biopsy tumor characteristics. Reclassification-free survival, based on tumor volume increase or Gleason score increase, was analyzed using multivariable Cox proportional hazards models. RESULTS: Of 825 enrolled patients, 682 met inclusion criteria. Median follow-up was 40 months (range 6.6-126.8). Disease was reclassified in 249 (36.5%), and 157 (23.0%) underwent treatment. A single positive core with a negative confirmatory biopsy was significantly associated with time to reclassification (median not met vs 43 months, log rank test P <.001). Composite tumor length, defined as the combined tumor length between baseline and confirmatory biopsies, was associated with shorter Gleason upgrade-free survival (hazard ratio 1.24, 95% confidence interval 1.11-1.40, P <.001) in multivariable analysis. CONCLUSION: Baseline stratification using clinical factors including tumor length may refine risk stratification and offer the foundation on which new systems that incorporate modalities such as magnetic resonance imaging may be based.

Management of cT4 Prostate Cancer.

While radiotherapy with androgen deprivation therapy is the current standard of care for the treatment of stage cT4 prostate cancer (PC), surgery may also be an appropriate option in selected patients as part of a multimodal approach. The role and the sequence with which to optimize therapy combinations in this setting are still unknown. This mini review summarizes the current evidence for management of cT4 PC. PATIENT SUMMARY: This mini review examines current evidence for the treatment options for locally advanced prostate cancer. The role of surgery in these patients can be considered as part of a combination treatment strategy along with other modalities such as radiotherapy and hormone therapy.

Impact of preoperative prostate magnetic resonance imaging on the surgical management of high-risk prostate cancer.

OBJECTIVE: To evaluate the effect of adding multiparametric magnetic resonance imaging (mpMRI) to pre-surgical planning on surgical decision making for the management of high-risk prostate cancer (HRPC). PATIENTS AND METHODS: A survey was designed to query multiple centers on surgical decisions of 41 consecutive HRPC cases seen from 2012 to 2015. HRPC was defined by the National Comprehensive Cancer Center Network guidelines. Six fellowship-trained urologic oncologists were asked for their surgical plan in regards to the degree of planned nerve-sparing and lymph node dissection. Two rounds of surveys were administered to six external urologic oncologists. The first survey included the case description only and the second included case description with mpMRI images and report. The correct surgical plan was analyzed by correlation of the degree of planned surgical excision and consistency with the final pathologic evaluation. A priori, an effect size of 20% change was used to determine statistical significance, at p < 0.05. RESULTS: All cases had at least one change to surgical planning after mpMRI review. Forty (98%) patients had a change in the degree of planned nerve sparing: wider excision in 32% and increased nerve sparing in 24%. After mpMRI the correct surgical plan change was made in 49% for the right and left 51%, decreasing the potential for positive margins. Lymph node dissection was altered from standard to extended lymph node dissection in 17%. CONCLUSIONS: Although mpMRI is not integrated in guidelines for preoperative planning in HRPC, its use may impact surgical planning, cancer control, and quality of life.

Treatment of the Primary Tumor in Metastatic Hormone-sensitive Prostate Cancer: Not Yet Ready for Prime Time as the Standard of Care.

Retrospective studies in selected patients have demonstrated a survival benefit with prostatectomy or radiotherapy (RT) of the primary tumor in metastatic hormone-sensitive prostate cancer (mHSPC). However, there is currently not enough evidence to recommend RT to the primary tumor as the standard of care for patients treated with androgen deprivation therapy plus abiraterone or docetaxel for low-volume mHSPC.

Radical prostatectomy or radiotherapy for high- and very high-risk prostate cancer: a multidisciplinary prostate cancer clinic experience of patients eligible for either treatment.

OBJECTIVE: To compare radical prostatectomy (RP) vs radiotherapy (RT) with androgen-deprivation therapy (ADT) in the setting of patients with high-risk and very high-risk (VHR) prostate cancer who were deemed eligible for either therapy and made a treatment choice after consultation in a multidisciplinary prostate cancer clinic (MDPCC), and to compare the MDPCC patients' outcomes to a matched Surveillance, Epidemiology and End Results (SEER) cohort. PATIENTS AND METHODS: Prospectively collected, retrospective study comparing patients who underwent RP (231 patients) vs RT+ADT (73) from 2004 to 2013. Biochemical recurrence (BCR), local recurrence, distant metastasis failure, and overall survival (OS) were calculated for each treatment group overall and according to National Comprehensive Cancer Network risk strata. A propensity score matched comparison with a SEER cohort was performed for OS. RESULTS: There was no difference in local recurrence (hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.0-7.9; P = 0.06), distant metastasis failure (HR 2.5, 95% CI 0.8-7.8; P = 0.1) and OS (HR 1.35, 95% CI 0.4-4.8; P = 0.6) between patients undergoing RP vs RT+ADT. Patients treated via the MDPCC survived on average 16.9 months (95% CI 13.1-20.8) longer than those in the matched SEER cohort. CONCLUSIONS: Long-term outcomes appear similar amongst patients with high-risk and VHR prostate cancer deemed eligible for either RP or RT, and treated after consultation in a MDPCC. Outcomes of the MDPCC patients were superior to those of the matched SEER cohort.

Diet quality and Gleason grade progression among localised prostate cancer patients on active surveillance.

BACKGROUND: High diet quality may support a metabolic and anti-inflammatory state less conducive to tumour progression. We prospectively investigated diet quality in relation to Gleason grade progression among localised prostate cancer patients on active surveillance, a clinical management strategy of disease monitoring and delayed intervention. METHODS: Men with newly diagnosed Gleason score 6 or 7 prostate cancer enroled on a biennial monitoring regimen. Patients completed a food frequency questionnaire (FFQ) at baseline (n = 411) and first 6-month follow-up (n = 263). Cox proportional hazards models were fitted to evaluate multivariable-adjusted associations of diet quality [defined via the Healthy Eating Index (HEI)-2015] with Gleason grade progression. RESULTS: After a median follow-up of 36 months, 76 men progressed. Following adjustment for clinicopathologic factors, we observed a suggestive inverse association between baseline diet quality and Gleason grade progression [hazard ratio (HR) and 95% confidence interval (CI) for the highest vs. the lowest HEI-2015 tertile: 0.59 (0.32-1.08); Ptrend = 0.06]. We observed no associations with diet quality at 6-month follow-up, nor change in diet quality from baseline. CONCLUSIONS: In localised prostate cancer patients on surveillance, higher diet quality or conformance with United States dietary guidelines at enrolment may lower risk of Gleason grade progression, though additional confirmatory research is needed.

Does time from diagnosis to treatment of high- or very-high-risk prostate cancer affect outcome?

OBJECTIVE: To determine whether time from diagnosis to treatment impacted outcomes in a multicentre cohort of high- and very-high-risk (VHR) patients with prostate cancer undergoing radical prostatectomy (RP). PATIENTS AND METHODS: In all, 1392 patients from three tertiary centres who underwent RP for either high-risk or VHR disease, from 2005 to 2015, were identified. The cohort was divided into tertiles based on time from diagnostic biopsy to RP. Cumulative incidence of biochemical recurrence (BCR), metastasis, and prostate cancer-specific mortality (PCSM) were calculated for each tertile. The Kaplan-Meier method was used to evaluate for differences in all-cause mortality (ACM) amongst tertiles. Competing risks regression models, as well as Cox proportional hazards regression models, were fitted to assess the association between time-to-event outcomes and patient characteristics. RESULTS: The median (interquartile range [IQR]) time from biopsy to RP was 68 (50-94) days. The median (IQR) follow-up was 31 (12.1-55.7) months. The cumulative incidence of BCR (P = 0.14), metastasis (P = 0.15), and PCSM (P = 0.69) did not differ amongst time-to-treatment tertiles of VHR patients. Also, Kaplan-Meier estimates of ACM (P = 0.53) did not differ amongst time-to-treatment tertiles. Similarly, BCR, metastasis, PCSM, and ACM did not significantly differ amongst time-to-treatment tertiles in multivariable modelling. CONCLUSION: In this pooled meta-dataset of patients with high-risk or VHR prostate cancer, time from diagnosis to RP did not appear to significantly contribute to differences in clinical outcomes. This finding supports the safety of enrollment of such patients into neoadjuvant clinical trials.

Coffee, Caffeine Metabolism Genotype and Disease Progression in Patients with Localized Prostate Cancer Managed with Active Surveillance.

PURPOSE: Active surveillance is increasingly used as a management strategy for localized prostate cancer. Coffee intake has been associated with a lower prostate cancer incidence. We assessed whether coffee was associated with disease progression in men on active surveillance. MATERIALS AND METHODS: A total of 411 patients with newly diagnosed Gleason score 6 or 7 prostate cancer were enrolled on a prospective active surveillance protocol for at least 6 months and completed a baseline dietary assessment. The active surveillance protocol included a biennial monitoring regimen with disease progression defined as an increase in the Gleason score. Cox proportional hazards models were used to evaluate associations of coffee intake with progression-free survival. We also evaluated patient genotype in the caffeine metabolism related single nucleotide polymorphism rs762551. RESULTS: Median followup was 36 months (range 6 to 126) and the Gleason score progressed in 76 of the 411 patients (18.5%). Compared to 0 cups per day, in the multivariable model adjusting for prostate specific antigen, patient age and tumor length, less than 1 cup (HR 0.85, 95% CI 0.40-1.71), 1 to 1.9 cups (HR 0.64, 95% CI 0.29-1.43), 2 to 3.9 cups (HR 0.71, 95% CI 0.35-1.47) and 4 cups or more (HR 1.67, 95% CI 0.81-3.45) were not significantly associated with progression-free survival (p for nonlinearity = 0.01). Patients with low/moderate coffee intake and the AA fast caffeine metabolizer genotype were less likely to experience grade progression than nonconsumers (HR 0.36, 95% CI 0.15-0.88, p = 0.03). CONCLUSIONS: Low to moderate coffee intake appears safe in men on active surveillance of localized prostate cancer. Further work is needed to determine whether high consumption is associated with shorter progression-free survival in sensitive groups.

Trends and disparities in the use of neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) prior to radical or partial cystectomy is considered the standard of care for eligible patients with muscle-invasive urothelial carcinoma. Despite guideline recommendations, adoption of NAC has historically been low, although prior studies have suggested that use is increasing. In this contemporary study, we examine trends in the use of NAC and explore factors associated with its receipt. METHODS: We identified patients in the National Cancer Database who underwent radical or partial cystectomy for cT2-cT4N0M0 urothelial carcinoma from 2006-2014. The proportion of patients receiving NAC during each year was examined. Logistic regression models were used to evaluate clinical and socioeconomic factors associated with the receipt of NAC. RESULTS: A total of 18 188 patients were identified who underwent radical or partial cystectomy for muscle-invasive bladder cancer. Overall, 3940 (21.7%) received NAC. We noted a significant increase in the use of NAC over time, from 9.7% in 2006 to 32.2% in 2014. Factors associated with lower use of NAC include older age, higher comorbidity score, lower cT stage, lower hospital radical cystectomy volume, treatment at a non-academic facility, lower patient income, and receipt of partial cystectomy (all p<0.001). Interestingly, neither sex nor race were associated with receipt of NAC. CONCLUSIONS: Use of NAC has increased significantly over time to a modest rate of 32%. However, disparities still exist in the receipt of NAC, and future efforts aimed at mitigating these disparities are warranted.

Outcomes of very high-risk prostate cancer after radical prostatectomy: Validation study from 3 centers.

BACKGROUND: Among men with localized high-risk prostate cancer (PCa), patients who meet very high-risk (VHR) criteria have been shown to experience worse outcomes after radical prostatectomy (RP) in a previous study. Variations of VHR criteria have been suggested to be prognostic in other single-center cohorts, but multicenter outcomes validating VHR criteria have not been described. This study was designed to validate VHR criteria for identifying which PCa patients are at greatest risk for cancer progression. METHODS: Patients with high-risk PCa undergoing RP (2005-2015) at 3 tertiary centers were pooled. The outcomes of men with VHR PCa were compared with the outcomes of those who did not meet VHR criteria. The high-risk criteria were a clinical stage of T3 to T4, a prostate-specific antigen level > 20 ng/mL, or a biopsy Gleason grade sum of 8 to 10. The VHR criteria were multiple high-risk features, >4 biopsy cores with a Gleason grade sum of 8 to 10, or primary Gleason grade pattern 5. Biochemical recurrence, metastasis (METS), and cancer-specific mortality (CSM) were assessed with competing risks regressions. Overall mortality was assessed with Cox survival models. RESULTS: Among 1981 patients with high-risk PCa, men with VHR PCa (n = 602) had adverse pathologic outcomes: 37% versus 25% for positive margins and 37% versus 15% for positive lymph nodes (P < .001 for both comparisons). Patients with VHR PCa also had higher adjusted hazard ratios for METS (2.78; 95% confidence interval [CI], 2.08-3.72), CSM (6.77; 95% CI, 2.91-15.7), and overall mortality (2.44; 95% CI, 1.56-3.80; P < .001 for all comparisons). CONCLUSIONS: In a validation study of patients who underwent treatment for high-risk PCa, VHR criteria were strongly associated with adverse pathologic and oncologic outcomes.

Emerging role of cytoreductive prostatectomy in patients with metastatic disease.

Traditionally, systemic androgen deprivation therapy (ADT) has been the primary treatment modality in metastatic prostate cancer (mPCa) while treatment of the primary tumor has been reserved for patients with clinically localized disease. Emerging data suggests that treating the primary tumor in patients with metastatic disease may provide a survival benefit. However, these studies are fraught with selection bias towards patients with favorable disease characteristics. Despite these limitations, clinicians are becoming increasingly interested in consolidative treatment of the primary tumor in this setting. Many translational models and observational studies of cytoreduction in mPCa have yielded compelling results, suggesting a potential biological and clinical benefit. While there are no published randomized control trials on cytoreduction in mPCa, the literature regarding safety, feasibility, and potential symptomatic benefit of cytoreductive prostatectomy (CRP) in mPCa supports further investigation. Thus, MEDLINE and PubMed electronic databases were queried for English language articles related to patients with mPCa who underwent radical prostatectomy. Keywords used include: cytoreductive prostatectomy, radical prostatectomy, oligometastatic, mPCa, and oligometastasis. In this review we examine the literature regarding the feasibility of CRP as well as the reported oncologic outcomes, limitations of the literature, and future directions. Since there is currently no level one evidence to support its use, CRP should not be applied outside a clinical trial. A better understanding of the biology driving mPCa, in conjunction with standardization of clinical trials, will help expedite actionable data acquisition that may improve clinical outcomes.