Corrigendum to "Androgen Deprivation and Radiotherapy with or Without Docetaxel for Localized High-risk Prostat Cancer: Long-term Follow-up from the Randomized NRG Oncology RTOG 0521 Trial" [Eur. Eurol. 84(2) (2023) 156-163].

BACKGROUND: Intensification of therapy may improve outcomes for patients with high-risk localized prostate cancer. OBJECTIVE: To provide long-term follow-up data from phase III RTOG 0521, which compared a combination of androgen deprivation therapy (ADT) + external beam radiation therapy (EBRT) + docetaxel with ADT + EBRT. DESIGN, SETTING, AND PARTICIPANTS: High-risk localized prostate cancer patients (>50% of patients had Gleason 9-10 disease) were prospectively randomized to 2 yr of ADT + EBRT or ADT + EBRT + six cycles of docetaxel. A total of 612 patients were accrued, and 563 were eligible and included in the modified intent-to-treat analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was overall survival (OS). Analyses with Cox proportional hazards were performed as prespecified in the protocol; however, there was evidence of nonproportional hazards. Thus, a post hoc analysis was performed using the restricted mean survival time (RMST). The secondary endpoints included biochemical failure, distant metastasis (DM) as detected by conventional imaging, and disease-free survival (DFS). RESULTS AND LIMITATIONS: After 10.4 yr of median follow-up among survivors, the hazard ratio (HR) for OS was 0.89 (90% confidence interval [CI] 0.70-1.14; one-sided log-rank p = 0.22). Survival at 10 yr was 64% for ADT + EBRT and 69% for ADT + EBRT + docetaxel. The RMST at 12 yr was 0.45 yr and not statistically significant (one-sided p = 0.053). No differences were detected in the incidence of DFS (HR = 0.92, 95% CI 0.73-1.14), DM (HR = 0.84, 95% CI 0.73-1.14), or prostate-specific antigen recurrence risk (HR = 0.97, 95% CI 0.74-1.29). Two patients had grade 5 toxicity in the chemotherapy arm and zero patients in the control arm. CONCLUSIONS: After a median follow-up of 10.4 yr among surviving patients, no significant differences are observed in clinical outcomes between the experimental and control arms. These data suggest that docetaxel should not be used for high-risk localized prostate cancer. Additional research may be warranted using novel predictive biomarkers. PATIENT SUMMARY: No significant differences in survival were noted after long-term follow-up for high-risk localized prostate cancer patients in a large prospective trial where patients were treated with androgen deprivation therapy + radiation to the prostate ± docetaxel.

Androgen Deprivation and Radiotherapy with or Without Docetaxel for Localized High-risk Prostate Cancer: Long-term Follow-up from the Randomized NRG Oncology RTOG 0521 Trial.

BACKGROUND: Intensification of therapy may improve outcomes for patients with high-risk localized prostate cancer. OBJECTIVE: To provide long-term follow-up data from phase III RTOG 0521, which compared a combination of androgen deprivation therapy (ADT) + external beam radiation therapy (EBRT) + docetaxel with ADT + EBRT. DESIGN, SETTING, AND PARTICIPANTS: High-risk localized prostate cancer patients (>50% of patients had Gleason 9-10 disease) were prospectively randomized to 2 yr of ADT + EBRT or ADT + EBRT + six cycles of docetaxel. A total of 612 patients were accrued, and 563 were eligible and included in the modified intent-to-treat analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was overall survival (OS). Analyses with Cox proportional hazards were performed as prespecified in the protocol; however, there was evidence of nonproportional hazards. Thus, a post hoc analysis was performed using the restricted mean survival time (RMST). The secondary endpoints included biochemical failure, distant metastasis (DM) as detected by conventional imaging, and disease-free survival (DFS). RESULTS AND LIMITATIONS: After 10.4 yr of median follow-up among survivors, the hazard ratio (HR) for OS was 0.89 (90% confidence interval [CI] 0.70-1.14; one-sided log-rank p = 0.22). Survival at 10 yr was 64% for ADT + EBRT and 69% for ADT + EBRT + docetaxel. The RMST at 12 yr was 0.45 yr and not statistically significant (one-sided p = 0.053). No differences were detected in the incidence of DFS (HR = 0.92, 95% CI 0.73-1.14), DM (HR = 0.84, 95% CI 0.73-1.14), or prostate-specific antigen recurrence risk (HR = 0.97, 95% CI 0.74-1.29). Two patients had grade 5 toxicity in the chemotherapy arm and zero patients in the control arm. CONCLUSIONS: After a median follow-up of 10.4 yr among surviving patients, no significant differences are observed in clinical outcomes between the experimental and control arms. These data suggest that docetaxel should not be used for high-risk localized prostate cancer. Additional research may be warranted using novel predictive biomarkers. PATIENT SUMMARY: No significant differences in survival were noted after long-term follow-up for high-risk localized prostate cancer patients in a large prospective trial where patients were treated with androgen deprivation therapy + radiation to the prostate ± docetaxel.

Metabolic activity diffusion imaging (MADI): II. Noninvasive, high-resolution human brain mapping of sodium pump flux and cell metrics.

We introduce a new 1 H2 O magnetic resonance approach: metabolic activity diffusion imaging (MADI). Numerical diffusion-weighted imaging decay simulations characterized by the mean cellular water efflux (unidirectional) rate constant (kio ), mean cell volume (V), and cell number density (ρ) are produced from Monte Carlo random walks in virtual stochastically sized/shaped cell ensembles. Because of active steady-state trans-membrane water cycling (AWC), kio reflects the cytolemmal Na+ , K+ ATPase (NKA) homeostatic cellular metabolic rate (c MRNKA ). A digital 3D "library" contains thousands of simulated single diffusion-encoded (SDE) decays. Library entries match well with disparate, animal, and human experimental SDE decays. The V and ρ values are consistent with estimates from pertinent in vitro cytometric and ex vivo histopathological literature: in vivo V and ρ values were previously unavailable. The library allows noniterative pixel-by-pixel experimental SDE decay library matchings that can be used to advantage. They yield proof-of-concept MADI parametric mappings of the awake, resting human brain. These reflect the tissue morphology seen in conventional MRI. While V is larger in gray matter (GM) than in white matter (WM), the reverse is true for ρ. Many brain structures have kio values too large for current, invasive methods. For example, the median WM kio is 22s-1 ; likely reflecting mostly exchange within myelin. The kio •V product map displays brain tissue c MRNKA variation. The GM activity correlates, quantitatively and qualitatively, with the analogous resting-state brain 18 FDG-PET tissue glucose consumption rate (t MRglucose ) map; but noninvasively, with higher spatial resolution, and no pharmacokinetic requirement. The cortex, thalamus, putamen, and caudate exhibit elevated metabolic activity. MADI accuracy and precision are assessed. The results are contextualized with literature overall homeostatic brain glucose consumption and ATP production/consumption measures. The MADI/PET results suggest different GM and WM metabolic pathways. Preliminary human prostate results are also presented.

BMI and BPH correlate with urinary microbiome diversity and lower urinary tract symptoms in men.

Several studies have identified bacteria and other microbes in the bladder and lower urinary tract in the absence of infection. In women, the urinary microbiome has been associated with lower urinary tract symptoms (LUTS), however, similar studies have not been undertaken in large cohorts of men. Here we examine the urinary microbiome and its association with LUTS in a subset of 500 men aged 65 to 90 years from the Osteoporotic Fractures in Men (MrOS) study. We identified significant associations between benign prostatic hyperplasia (BPH), age, and body mass index (BMI) with several diversity metrics. Our analysis revealed complex relationships between BMI, BPH, LUTS, and alpha diversity which give insight into the intricate dynamics of the urinary microbiome. By beginning to uncover the interrelationships of BPH, BMI, LUTS, and the urinary microbiome, these results can inform future study design to better understand the heterogeneity of the male urinary microbiome.

Calibrated Regression Models Based on the Risk of Clinical Nodal Metastasis Should be Used as Decision Aids for Prostate Cancer Staging to Reduce Unnecessary Imaging.

INTRODUCTION: Radionuclide imaging will change the role of computed tomography and magnetic resonance imaging (CT/MRI) for prostate cancer (CaP) staging. Current guidelines recommend abdominopelvic imaging for new cases of CaP categorized as unfavorable intermediate risk (UIR) or higher. We assessed the performance characteristics of CT/MRI based on the National Comprehensive Cancer Network (NCCN) guidelines and developed a model that predicts cN1 disease using conventional imaging. PATIENTS AND METHODS: We selected patients in the National Cancer Database diagnosed with CaP from 2010 to 2016 with available age, prostate specific antigen, clinical locoregional staging, biopsy Gleason grading, and core information. Multivariate logistic regression (MLR) was used on a undersampled training dataset using cN1 as the outcome. Performance characteristics were compared to those of the three most recent versions of the NCCN guidelines. RESULTS: A total of 443,640 men were included, and 2.5% had cN1 disease. Using CT/MRI only, the current NCCN guidelines have a sensitivity of 99%, and the number needed to image (NNI) is 24. At the same sensitivity, the cN1 risk was 1.6% using the MLR. The NNI for UIR alone is 341. Using the MLR model and a threshold of 10%, the PPV is 10.3% and 64% of CTs/MRIs could be saved at a cost of missing 6% of cN1 patients (or 0.15% of all patients). CONCLUSION: The NCCN guidelines are sensitive for detecting cN1 with CT/MRI, however, the number needed to image is 24. Obtaining CT/MRI for nodal staging when patients have a cN1 risk of 10% would reduce total imaging while still remaining sensitive. As novel PET tracers becomes increasingly used for initial CaP staging, well calibrated prediction models trained on the outcome of interest should be developed as decision aids for obtaining imaging.

The Influence of the Pretreatment Immune State on Response to Radiation Therapy in High-Risk Prostate Cancer: A Validation Study From NRG/RTOG 0521.

PURPOSE: The immunoinflammatory state has been shown to be associated with poor outcomes after radiation therapy (RT). We conducted an a priori designed validation study using serum specimens from Radiation Therapy Oncology Group (RTOG) 0521. It was hypothesized the pretreatment inflammatory state would correlate with clinical outcomes. METHODS AND MATERIALS: Patients on RTOG 0521 had serum banked for biomarker validation. This study was designed to validate previous findings showing an association between elevations in C-reactive protein (CRP) and shorter biochemical disease free survival (bDFS). CRP levels were measured in pretreatment samples. An exploratory panel of related cytokines was also measured including: monocyte chemotactic protein-1, granulocyte-macrophage colony-stimulating factor, interferon-γ, interleukin (IL)-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17A, IL-23, and tumor necrosis factor. The primary endpoint examined was bDFS. Additional exploratory endpoints included overall survival, distant metastases, and toxicity events attributed to RT. RESULTS: Two hundred and two patients in RTOG/NRG 0521 had serum samples available. Median age was 66 years (48-83), and 90% of patients were White. There was not an association between CRP and bDFS (adjusted hazard ratio [HR], 1.07 per 1 log increase in CRP; 95% confidence interval, 0.83-1.38; P = .60). In the exploratory, unplanned analysis, pretreatment IL-10 was significantly associated with worse bDFS (adjusted HR, 1.61 per log increase; P = .0027) and distant metastases (HR, 1.55 per log increase; P = .028). The association of IL-10 with bDFS was maintained on a multiplicity adjustment. The exploratory analyses of pretreatment levels of interferon-γ, IL-1b, IL-2, IL-13, IL-23 were negatively associated with grade 2 or higher pollakiuria (adjusted odds ratio, 0.64, 0.65, 0.71, 0.72, and 0.74, respectively, all P < .05), and IL-6 was negatively associated with grade 2 or higher erectile dysfunction (odds ratio, 0.62; P = .027). CONCLUSIONS: Pretreatment CRP was not associated with a poorer bDFS after RT. In a hypothesis- generating analysis, higher baseline levels of IL-10 were associated with lower rates of bDFS. These findings require additional prospective evaluation.

Survival outcomes and practice trends for off-label use of adjuvant targeted therapy in high-risk locoregional renal cell carcinoma.

IMPORTANCE: The appropriate use of adjuvant targeted therapy (TT) for high-risk locoregional renal cell carcinoma (RCC) after nephrectomy is currently unclear due to mixed results from the relevant randomized controlled trials. National-level survival outcomes and practice trends for the use of adjuvant TT in the United States have not been reported. OBJECTIVE: To compare overall survival for patients who did and did not receive adjuvant TT after nephrectomy for high-risk locoregional RCC. DESIGN, SETTING, AND PARTICIPANTS: This cohort study reviewed the National Cancer Database from 2006 to 2015. Patients with nonmetastatic clear cell RCC who underwent nephrectomy with either stage pT3a or greater or pN+ were included. MAIN OUTCOMES AND MEASURES: Adjuvant TT was defined as receipt of TT within 3 months of nephrectomy. The primary end point was overall survival from initial diagnosis to date of death or censored at last follow-up. Baseline characteristics were described, and a multivariable analysis identified associations for receipt of adjuvant TT. Nearest-neighbor propensity matching was performed to create similar groups for comparison. A survival analysis was performed using Kaplan-Meier analysis and log-rank test. RESULTS: The final study population included 41,127 patients. Two thousand seventy-one patients (5.04%) received off-label adjuvant TT. Younger age, white race, private insurance, positive margins, pT4, and pN+ were associated with receipt of adjuvant TT. After nearest-neighbor propensity matching for clinically and statistically relevant covariates, 1,604 patients remained in the matched cohort, with statistically nonsignificant differences between the groups for all baseline characteristics. Median overall survival was 52 months for patients in the Adjuvant TT group versus 79 months for those who did not receive adjuvant TT (P < 0.001). Decreased overall survival for patients receiving adjuvant therapy was also seen in pathologic subgroups with and without lymph node involvement. CONCLUSIONS: The propensity matched survival analysis revealed significantly decreased overall survival in patients who received off-label adjuvant TT for high-risk locoregional RCC.

Veterans Affairs Cooperative Studies Program Study #553: Chemotherapy After Prostatectomy for High-risk Prostate Carcinoma: A Phase III Randomized Study.

BACKGROUND: The Veterans Affairs Cooperative Studies Program study #553 was designed to evaluate the efficacy of adjuvant chemotherapy added to the standard of care (SOC) for patients who are at high risk for relapse after prostatectomy. OBJECTIVE: To test whether addition of chemotherapy to surgery for high-risk prostate cancer improves progression-free survival (PFS). DESIGN, SETTING, AND PARTICIPANTS: Eligible patients after prostatectomy were randomized to the SOC group with observation or to the chemotherapy group with docetaxel and prednisone administered every 3 wk for six cycles. Randomization was stratified for prostate-specific antigen, Gleason, tumor stage, and surgical margin status. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was PFS. Secondary endpoints included overall, prostate cancer-specific, and metastasis-free survival, and time to androgen deprivation therapy. RESULTS AND LIMITATIONS: A total of 298 of the planned 636 patients were randomized. The median follow-up was 59.1 mo (0.2-103.7 mo). For the primary endpoint, the two groups did not statistically differ in PFS (median 55.5 mo in the chemotherapy group and 42.2 mo in the SOC group; test adjusted for site via gamma frailty p=0.21; adjusted hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.58-1.11; p=0.18). Prespecified subgroup analyses showed benefit in PFS for patients with tumor stage ≥T3b (HR 0.54, 95% CI 0.32-0.92; p=0.022) and patients with Gleason score ≤7 (HR 0.65, 95% CI 0.43-0.99; p=0.046). Secondary endpoint analyses are hampered by low event rates. The most common adverse events (≥grade 3 related or possibly related to chemotherapy) included neutropenia (43%), hyperglycemia (20%), and fatigue (5%), with febrile neutropenia in 2%. CONCLUSIONS: Adjuvant chemotherapy in high-risk prostate cancer using docetaxel and prednisone did not lead to statistically significant improvement in PFS for the intention-to-treat population as a whole. The analysis was challenged by lower power due to accrual limitation. Subgroup analyses suggest potential benefit for patients with Gleason grade ≤7 and stage≥pT3b (ClinicalTrials.gov number NCT00132301). PATIENT SUMMARY: In this randomized trial, we tested whether addition of chemotherapy to surgery for high-risk prostate cancer decreased the risk of prostate-specific antigen rise after surgery. We found no benefit from docetaxel given after radical prostatectomy, although some subgroups of patients may benefit.

Sulforaphane Bioavailability and Chemopreventive Activity in Men Presenting for Biopsy of the Prostate Gland: A Randomized Controlled Trial.

Previous studies suggest compounds such as sulforaphane (SFN) derived from cruciferous vegetables may prevent prostate cancer development and progression. This study evaluated the effect of broccoli sprout extract (BSE) supplementation on blood histone deacetylase (HDAC) activity, prostate RNA gene expression, and tissue biomarkers (histone H3 lysine 18 acetylation (H3K18ac), HDAC3, HDAC6, Ki67, and p21). A total of 98 men scheduled for prostate biopsy were allocated into either BSE (200 µmol daily) or a placebo in our double-blind, randomized controlled trial. We used nonparametric tests to evaluate the differences of blood HDAC activity and prostate tissue immunohistochemistry biomarkers between treatment groups. Further, we performed RNA-Seq analysis on the prostate biopsies and identified 40 differentially expressed genes correlated with BSE treatment, including downregulation of two genes previously implicated in prostate cancer development, AMACR and ARLNC1. Although urine and plasma SFN isothiocyanates and individual SFN metabolites were statistically higher in the treatment group, our results did not show a significant difference in HDAC activity or prostate tissue biomarkers. This study indicates BSE supplementation correlates with changes in gene expression but not with several other prostate cancer biomarkers. More research is required to fully understand the chemopreventive effects of BSE supplementation on prostate cancer.

Phytol and its metabolites phytanic and pristanic acids for risk of cancer: current evidence and future directions.

This review summarizes the current evidence on the potential role of phytol, a microbial metabolite of chlorophyl A, and its metabolites, phytanic and pristanic acids, in carcinogenesis. Primary food sources in Western diets are the nut skin for phytol and lipids in dairy, beef and fish for its metabolites. Phytol and its metabolites gained interest as dietary compounds for cancer prevention because, as natural ligands of peroxisome proliferator-activated receptor-α and -γ and retinoid X receptor, phytol and its metabolites have provided some evidence in cell culture studies and limited evidence in animal models of anti-carcinogenic, anti-inflammatory and anti-metabolic-syndrome properties at physiological concentrations. However, there may be a narrow range of efficacy, because phytol and its metabolites at supra-physiological concentrations can cause in vitro cytotoxicity in non-cancer cells and can cause morbidity and mortality in animal models. In human studies, evidence for a role of phytol and its metabolites in cancer prevention is currently limited and inconclusive. In short, phytol and its metabolites are potential dietary compounds for cancer prevention, assuming the challenges in preventing cytotoxicity in non-cancer cells and animal models and understanding phytol metabolism can be mitigated.

Polymorphisms in oxidative stress pathway genes and prostate cancer risk.

PURPOSE: Age-related factors including oxidative stress play an important role in prostate carcinogenesis. We hypothesize that germline single-nucleotide polymorphisms (SNPs) in oxidative stress pathway are associated with prostate cancer (PCa) risk. In this study, we aim to examine which of these SNPs is associated with PCa. METHODS: Participants included in this analyses came from the "Genetic Susceptibility, Environment and Prostate Cancer Risk Study" conducted at the Veterans Affairs Portland Health Care System. After applying exclusion criteria, 231 PCa cases and 382 prostate biopsy-negative controls who had genotyping data on twenty-two single-nucleotide polymorphisms (SNPs) in six genes (MAPK14, NRF2, CAT, GPX1, GSTP1, SOD2, and XDH) associated with oxidative stress pathway were included in the analyses. The genotyping of SNPs was conducted by the Illumina BeadXpress VeraCode platform. We investigated these SNPs in relation to overall and aggressive PCa risk using logistic regression models controlling for relevant covariates. RESULTS: One SNP in the MAPK14 (rs851023) was significantly associated with incident PCa risk. Compared to men carrying two copies of allele A, the presence of one or two copies of the G allele was associated with decreased risk of PCa [OR (95% CI) 0.19 (0.06-0.51)]. There was no statistically significant association between other SNPs in the NRF2, CAT, GPX1, GSTP1, SOD2, and XDH genes and PCa risk. CONCLUSIONS: The MAPK14 gene SNP rs851023 was associated with PCa and aggressive PCa risk after multiple comparison adjustment. Further studies in other populations or functional studies are needed to validate the finding.

Dairy Product Consumption and Prostate Cancer Risk in the United States.

An ongoing controversy exists regarding the effect of dairy products on prostate cancer risk in observational studies. We prospectively investigated the associations between dairy product consumption and prostate cancer risk among men in the United States. After calculating pre-diagnostic intake of individual or subgroups of dairy products using a validated food frequency questionnaire, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for pathologically-verified cases of incident prostate cancer among men, overall, or stratified by severity. Among 49,472 men, 4134 were diagnosed with prostate cancer during an average follow-up period of 11.2 years. The median total dairy intake was 101 g/1000 kcal. Consumption of total, individual, or subgroups of dairy products was not statistically significantly associated with prostate cancer risk overall (HR = 1.05, 95% CI = 0.96-1.15 comparing the highest with lowest quartile) or stratified by severity, except for regular-fat dairy product intake with late-stage prostate cancer risk (HR = 1.37, 95% CI = 1.04-1.82 comparing the highest with lowest quartile) and 2%-fat milk intake with advanced prostate cancer risk (HR = 1.14, 95% CI = 1.02-1.28 comparing the higher than median intake with no intake group). Our findings do not support the previously reported harmful impact of dairy consumption on overall prostate cancer risk among men in the United States.

The estimated prevalence of missed positive lymph nodes based on extent of lymphadenectomy at radical prostatectomy.

PURPOSE: To determine practice patterns for the extent of lymphadenectomy at radical prostatectomy and associations with detection of pN1 prostate cancer, as well as the impact of lymphadenectomy extent on underdetection of pN1 disease and overall survival. MATERIALS AND METHODS: Prostatectomy cases in the NCDB from 2004 to 2013 were included. Lymphadenectomy extent was defined by the number of nodes examined. Logistic regression was used to identify risk factors for the top quartile of lymph node count and pN1 disease. This model was created to estimate the expected prevalence of pN1, and generated observed over expected ratios. A Cox regression model was used to evaluate the effect of lymph node count on overall survival. RESULTS: Lymphadenectomy was performed in 209,789 (60%) of 358,522 surgeries, with pN1 in 6,428 (3.08%). Increasing quartiles for lymph node count was associated with pN1 (3-5 nodes OR 2.11; 6-8 nodes OR 3.12; ≥9 nodes OR 5.91, all P< 0.001). The logistic regression model suggested that 59% of pN1 cases are missed due to low lymph node count. Increased lymph node count was associated with increasing pN1 detection (O/E: 1-2 nodes = 0.18; 3-5 nodes = 0.37; 6-8 nodes = 0.56; ≥9 nodes = 1.01). Cox proportional hazards modeling demonstrated that the top quartile for lymph node count had improved overall survival (HR 0.93, CI 0.87-0.99, P= 0.03). CONCLUSIONS: Increasing lymphadenectomy extent was associated with pN1 disease on multivariate analysis, and logistic regression modeling suggested a substantial proportion of pN1 were missed due to low lymphadenectomy extent across all risk groups.

Effect of Chemotherapy With Docetaxel With Androgen Suppression and Radiotherapy for Localized High-Risk Prostate Cancer: The Randomized Phase III NRG Oncology RTOG 0521 Trial.

PURPOSE: Radiotherapy (RT) plus long-term androgen suppression (AS) are a standard treatment option for patients with high-risk localized prostate cancer. We hypothesized that docetaxel chemotherapy (CT) could improve overall survival (OS) and clinical outcomes among patients with high-risk prostate cancer. PATIENTS AND METHODS: The multicenter randomized NRG Oncology RTOG 0521 study enrolled patients with high-risk nonmetastatic disease between 2005 and 2009. Patients were randomly assigned to receive standard long-term AS plus RT with or without adjuvant CT. RESULTS: A total of 612 patients were enrolled; 563 were evaluable. Median prostate-specific antigen was 15.1 ng/mL; 53% had a Gleason score 9 to 10 cancer; 27% had cT3 to cT4 disease. Median follow-up was 5.7 years. Treatment was well tolerated in both arms. Four-year OS rate was 89% (95% CI, 84% to 92%) for AS + RT and 93% (95% CI, 90% to 96%) for AS + RT + CT (hazard ratio [HR], 0.69; 90% CI, 0.49 to 0.97; one-sided P = .034). There were 59 deaths in the AS + RT arm and 43 in the AS + RT + CT arm, with fewer deaths resulting from prostate cancer in the AS + RT + CT arm versus AS + RT (23 v 16 deaths, respectively). Six-year rate of distant metastasis was 14% for AS + RT and 9.1% for AS + RT + CT, (HR, 0.60; 95% CI, 0.37 to 0.99; two-sided P = .044). Six-year disease-free survival rate was 55% for AS + RT and 65% for AS + RT + CT (HR, 0.76; 95% CI, 0.58 to 0.99; two-sided P = .043). CONCLUSION: For patients with high-risk nonmetastatic prostate cancer, CT with docetaxel improved OS from 89% to 93% at 4 years, with improved disease-free survival and reduction in the rate of distant metastasis. The trial suggests that docetaxel CT may be an option to be discussed with selected men with high-risk prostate cancer.

Optimizing the Sequence of Chemotherapy for Upper Tract Urothelial Carcinoma with Clinically Positive Regional Lymph Nodes.

PURPOSE: Upper tract urothelial carcinoma with clinically positive regional lymph nodes is an aggressive disease state with a high propensity for metastasis and death. The current literature is limited regarding national practice patterns and outcomes in this patient population. MATERIALS AND METHODS: We identified 1,658 patients in the NCDB (National Cancer Database) who had cN+M0 upper tract urothelial carcinoma. Patients were stratified into treatment groups. We compared baseline patient and tumor characteristics between the groups, and completed survival analysis using a multivariate Cox regression model. RESULTS: There were 1,658 patients in the final study population. Preoperative chemotherapy was the least performed treatment. That group comprised 6.8% of the overall population and was associated with the highest median overall survival of 36 months compared to 21 months for adjuvant chemotherapy, 14 for chemotherapy only, 10 for surgery without perioperative chemotherapy and 5 for no treatment. On multivariate analysis preoperative chemotherapy was associated with improved median overall survival compared to that in the adjuvant chemotherapy group (HR 0.58, 95% CI 0.38-0.87). There was no statistically significant difference in survival between the chemotherapy only and the surgery only groups. Of patients in the preoperative chemotherapy group 34.6% achieved pN0 status compared to 10.3% of those who underwent surgery as initial therapy. CONCLUSIONS: Preoperative chemotherapy was the least performed treatment strategy in the management of cN+M0 upper tract urothelial carcinoma but it was associated with the highest median overall survival. There was no difference in survival between the chemotherapy only and the surgery only groups. Overall these results suggest that initial chemotherapy is appropriate in this population when feasible.

Endorectal MR imaging of prostate cancer: Evaluation of tumor capsular contact length as a sign of extracapsular extension.

OBJECTIVE: To evaluate the length of contact between dominant tumor foci and the prostatic capsule as a sign of extracapsular extension at endorectal multiparametric MR imaging. MATERIALS AND METHODS: We retrospectively identified 101 patients over a three-year interval who underwent endorectal multiparametric prostate MR imaging prior to radical prostatectomy for prostate cancer. Two readers identified the presence of dominant tumor focus (largest lesion with PI-RADS version 2 score of 4 or 5), and measured the length of tumor capsular contact and likelihood of extracapsular extension by standard criteria (1-5 Likert scale). Results were analyzed using histopathological review as reference standard. RESULTS: Extracapsular extension was found at histopathological review in 27 patients. Reader 1 (2) identified dominant tumor in 79 (73) patients, with mean tumor capsular contact length of 18.2 (14.0) mm. The area under the receiver operating characteristic curve for identification of extracapsular extension by tumor capsular contact length was 0.76 for reader 1 and 0.77 for reader 2, with optimal discrimination at values of 18 mm and 21 mm, respectively. In the subset of patients without obvious extracapsular extension by standard criteria (Likert scores 1-3), corresponding values were 0.74 and 0.66 with optimal thresholds of 24 and 21 mm. CONCLUSION: Length of contact between the dominant tumor focus and the capsule is a moderately useful sign of extracapsular extension at endorectal multiparametric prostate MR imaging, including the subset of patients without obvious extracapsular extension by standard criteria, with optimal discrimination at threshold values of 18 to 24 mm.

Unconventional Bladder Preservation: Factors Predicting Failure to Receive Definitive Surgery following Chemotherapy for Nonmetastatic Muscle Invasive Bladder Cancer in the National Cancer Database.

PURPOSE: Neoadjuvant chemotherapy is an important adjunct to cystectomy for managing muscle invasive bladder cancer. Using the National Cancer Database we investigated factors that predict failure to undergo surgery following multi-agent chemotherapy for nonmetastatic muscle invasive bladder cancer. MATERIALS AND METHODS: We performed a cohort study in patients diagnosed with cT2-4aN0M0 urothelial cell carcinoma of the bladder between 2004 and 2013 who underwent multi-agent chemotherapy. We excluded those with surgery prior to chemotherapy, clinical T4b disease and those who received radiotherapy. Socioeconomic and clinical predictors, including time from diagnosis to treatment, were analyzed using logistic regression for the receipt of surgery after chemotherapy. Cox proportional hazards modeling was applied to perform time dependent analysis. RESULTS: Of the 4,640 patients who met our study inclusion and exclusion criteria 4,244 (91%) proceeded to surgery. Negative predictors of surgery included African American or Hispanic race (OR 0.58, p = 0.007 and 0.48, p = 0.002, respectively), increasing age (OR 0.44, p <0.001) and greater time between diagnosis and chemotherapy initiation (fourth quartile greater than 59 days, OR 0.51, p <0.001). African American race (HR 0.79, p <0.001), Medicare (HR 0.86, p <0.001) and other government insurance (HR 0.73, p <0.001) were associated with delayed chemotherapy. CONCLUSIONS: Increasing age, African American or Hispanic race and longer time to chemotherapy predicted failure to undergo surgery. Furthermore, African American race was associated with delayed chemotherapy. Chemotherapy was also delayed in patients on Medicare or other government insurance. Longer time to neoadjuvant chemotherapy is a modifiable risk factor that should be closely observed in multimodal cancer treatment.