The Clinical Cell-Cycle Risk (CCR) Score Is Associated With Metastasis After Radiation Therapy and Provides Guidance on When to Forgo Combined Androgen Deprivation Therapy With Dose-Escalated Radiation.

PURPOSE: The clinical cell-cycle risk (CCR) score, which combines the University of California, San Francisco's Cancer of the Prostate Risk Assessment (CAPRA) and the cell cycle progression (CCP) molecular score, has been validated to be prognostic of disease progression for men with prostate cancer. This study evaluated the ability of the CCR score to prognosticate the risk of metastasis in men receiving dose-escalated radiation therapy (RT) with or without androgen deprivation therapy (ADT). METHODS AND MATERIALS: This retrospective, multi-institutional cohort study included men with localized National Comprehensive Cancer Network (NCCN) intermediate-, high-, and very high-risk prostate cancer (N = 741). Patients were treated with dose-escalated RT with or without ADT. The primary outcome was time to metastasis. RESULTS: The CCR score prognosticated metastasis with a hazard ratio (HR) per unit score of 2.22 (95% confidence interval [CI], 1.71-2.89; P < .001). The CCR score better prognosticated metastasis than NCCN risk group (CCR, P < .001; NCCN, P = .46), CAPRA score (CCR, P = .002; CAPRA, P = .59), or CCP score (CCR, P < .001; CCP, P = .59) alone. In bivariable analyses, CCR score remained highly prognostic when accounting for ADT versus no ADT (HR, 2.18; 95% CI, 1.61-2.96; P < .001), ADT duration as a continuous variable (HR, 2.11; 95% CI, 1.59-2.79; P < .001), or ADT given at or below the recommended duration for each NCCN risk group (HR, 2.19; 95% CI, 1.69-2.86; P < .001). Men with CCR scores below or above the multimodality threshold (CCR score, 2.112) had a 10-year risk of metastasis of 3.7% and 21.24%, respectively. Men with below-threshold scores receiving RT alone had a 10-year risk of metastasis of 3.7%, and for men receiving RT plus ADT, the 10-year risk of metastasis was also 3.7%. CONCLUSIONS: The CCR score accurately and precisely prognosticates metastasis and adds clinically actionable information relative to guideline-recommended therapies based on NCCN risk in men undergoing dose-escalated RT with or without ADT. For men with scores below the multimodality threshold, adding ADT may not significantly reduce their 10-year risk of metastasis.

Development and Validation of a Clinical Prognostic Stage Group System for Nonmetastatic Prostate Cancer Using Disease-Specific Mortality Results From the International Staging Collaboration for Cancer of the Prostate.

Importance: In 2016, the American Joint Committee on Cancer (AJCC) established criteria to evaluate prediction models for staging. No localized prostate cancer models were endorsed by the Precision Medicine Core committee, and 8th edition staging was based on expert consensus. Objective: To develop and validate a pretreatment clinical prognostic stage group system for nonmetastatic prostate cancer. Design, Setting, and Participants: This multinational cohort study included 7 centers from the United States, Canada, and Europe, the Shared Equal Access Regional Cancer Hospital (SEARCH) Veterans Affairs Medical Centers collaborative (5 centers), and the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry (43 centers) (the STAR-CAP cohort). Patients with cT1-4N0-1M0 prostate adenocarcinoma treated from January 1, 1992, to December 31, 2013 (follow-up completed December 31, 2017). The STAR-CAP cohort was randomly divided into training and validation data sets; statisticians were blinded to the validation data until the model was locked. A Surveillance, Epidemiology, and End Results (SEER) cohort was used as a second validation set. Analysis was performed from January 1, 2018, to November 30, 2019. Exposures: Curative intent radical prostatectomy (RP) or radiotherapy with or without androgen deprivation therapy. Main Outcomes and Measures: Prostate cancer-specific mortality (PCSM). Based on a competing-risk regression model, a points-based Score staging system was developed. Model discrimination (C index), calibration, and overall performance were assessed in the validation cohorts. Results: Of 19 684 patients included in the analysis (median age, 64.0 [interquartile range (IQR), 59.0-70.0] years), 12 421 were treated with RP and 7263 with radiotherapy. Median follow-up was 71.8 (IQR, 34.3-124.3) months; 4078 (20.7%) were followed up for at least 10 years. Age, T category, N category, Gleason grade, pretreatment serum prostate-specific antigen level, and the percentage of positive core biopsy results among biopsies performed were included as variables. In the validation set, predicted 10-year PCSM for the 9 Score groups ranged from 0.3% to 40.0%. The 10-year C index (0.796; 95% CI, 0.760-0.828) exceeded that of the AJCC 8th edition (0.757; 95% CI, 0.719-0.792), which was improved across age, race, and treatment modality and within the SEER validation cohort. The Score system performed similarly to individualized random survival forest and interaction models and outperformed National Comprehensive Cancer Network (NCCN) and Cancer of the Prostate Risk Assessment (CAPRA) risk grouping 3- and 4-tier classification systems (10-year C index for NCCN 3-tier, 0.729; for NCCN 4-tier, 0.746; for Score, 0.794) as well as CAPRA (10-year C index for CAPRA, 0.760; for Score, 0.782). Conclusions and Relevance: Using a large, diverse international cohort treated with standard curative treatment options, a proposed AJCC-compliant clinical prognostic stage group system for prostate cancer has been developed. This system may allow consistency of reporting and interpretation of results and clinical trial design.

Performance of clinicopathologic models in men with high risk localized prostate cancer: impact of a 22-gene genomic classifier.

BACKGROUND: Prostate cancer exhibits biological and clinical heterogeneity even within established clinico-pathologic risk groups. The Decipher genomic classifier (GC) is a validated method to further risk-stratify disease in patients with prostate cancer, but its performance solely within National Comprehensive Cancer Network (NCCN) high-risk disease has not been undertaken to date. METHODS: A multi-institutional retrospective study of 405 men with high-risk prostate cancer who underwent primary treatment with radical prostatectomy (RP) or radiation therapy (RT) with androgen-deprivation therapy (ADT) at 11 centers from 1995 to 2005 was performed. Cox proportional hazards models were used to determine the hazard ratios (HR) for the development of metastatic disease based on clinico-pathologic variables, risk groups, and GC score. The area under the receiver operating characteristic curve (AUC) was determined for regression models without and with the GC score. RESULTS: Over a median follow-up of 82 months, 104 patients (26%) developed metastatic disease. On univariable analysis, increasing GC score was significantly associated with metastatic disease ([HR]: 1.34 per 0.1 unit increase, 95% confidence interval [CI]: 1.19-1.50, p < 0.001), while age, serum PSA, biopsy GG, and clinical T-stage were not (all p > 0.05). On multivariable analysis, GC score (HR: 1.33 per 0.1 unit increase, 95% CI: 1.19-1.48, p < 0.001) and GC high-risk (vs low-risk, HR: 2.95, 95% CI: 1.79-4.87, p < 0.001) were significantly associated with metastasis. The addition of GC score to regression models based on NCCN risk group improved model AUC from 0.46 to 0.67, and CAPRA from 0.59 to 0.71. CONCLUSIONS: Among men with high-risk prostate cancer, conventional clinico-pathologic data had poor discrimination to risk stratify development of metastatic disease. GC score was a significant and independent predictor of metastasis and may help identify men best suited for treatment intensification/de-escalation.

Prostate cancer incidence across stage, NCCN risk groups, and age before and after USPSTF Grade D recommendations against prostate-specific antigen screening in 2012.

BACKGROUND: We sought to determine the extent to which US Preventive Services Task Force (USPSTF) 2012 Grade D recommendations against prostate-specific antigen screening may have impacted recent prostate cancer disease incidence patterns in the United States across stage, National Comprehensive Cancer Network (NCCN) risk groups, and age groups. METHODS: SEER*Stat version 8.3.4 was used to calculate annual prostate cancer incidence rates from 2010 to 2015 for men aged ≥50 years according to American Joint Committee on Cancer stage at diagnosis (localized vs metastatic), NCCN risk group (low vs unfavorable [intermediate or high-risk]), and age group (50-74 years vs ≥75 years). Age-adjusted incidences per 100,000 persons with corresponding year-by-year incidence ratios (IRs) were calculated using the 2000 US Census population. RESULTS: From 2010 to 2015, the incidence (per 100,000 persons) of localized prostate cancer decreased from 195.4 to 131.9 (Ptrend  < .001) and from 189.0 to 123.4 (Ptrend  < .001) among men aged 50-74 and ≥75 years, respectively. The largest relative year-by-year decline occurred between 2011 and 2012 in NCCN low-risk disease (IR, 0.77 [0.75-0.79, P < .0001] and IR 0.68 [0.62-0.74, P < .0001] for men aged 50-74 and ≥75 years, respectively). From 2010-2015, the incidence of metastatic disease increased from 6.2 to 7.1 (Ptrend  < .001) and from 16.8 to 22.6 (Ptrend  < .001) among men aged 50-74 and ≥75 years, respectively. CONCLUSIONS: This report illustrates recent prostate cancer "reverse migration" away from indolent disease and toward more aggressive disease beginning in 2012. The incidence of localized disease declined across age groups from 2012 to 2015, with the greatest relative declines occurring in low-risk disease. Additionally, the incidence of distant metastatic disease increased gradually throughout the study period.

Genomic Validation of 3-Tiered Clinical Subclassification of High-Risk Prostate Cancer.

PURPOSE: Recent data and National Comprehensive Cancer Network (NCCN) guidelines suggest that high-risk prostate cancer (cT3-4, Gleason score ≥8, or prostate-specific antigen [PSA] >20 ng/mL) is a heterogenous group in terms of long-term patient outcomes. We sought to determine whether subclassification of high-risk prostate cancer based on clinical factors correlates with genomic markers of risk. METHODS AND MATERIALS: We identified 3220 patients with NCCN unfavorable intermediate-risk (n = 2000) or high-risk (n = 1220) prostate cancer from a prospective multi-institutional registry cohort. We defined the following subclassification of high-risk prostate cancer based on previously published data: favorable high risk (cT1c, Gleason 6, and PSA >20 ng/mL or cT1c, Gleason 4 + 4 = 8, PSA <10 ng/mL); very high risk (cT3b-T4 or primary Gleason pattern 5); and standard high risk (all others with cT3a, Gleason score ≥8, or PSA >20 ng/mL). We used a set of 33 previously developed genomic classifiers, including Decipher, to determine whether high-risk genomic features correlate with clinical subclasses of high-risk prostate cancer. RESULTS: Among those with favorable high-risk, standard high-risk, and very high-risk prostate cancer, 50.4%, 64.2%, and 81.6% had a high-risk Decipher score, respectively (P < .001). Among 32 other genomic signatures, 29 had a similar trend of increasing risk scores across the 3 subclasses of high-risk disease (P < .05 after correction for multiple hypothesis testing). Patients in the 3 subclasses of high-risk disease had a median of 4, 6, and 13 high-risk signatures, respectively. In comparison, among those with unfavorable intermediate-risk prostate cancer, 38.2% had a high-risk Decipher score, and the median number of high-risk signatures was 3. CONCLUSIONS: Although NCCN guidelines currently use a 2-tiered system for high-risk prostate cancer, genomic markers of risk correlate with the clinically validated subclassification of high-risk prostate cancer into favorable high-risk, standard high-risk, and very high-risk disease, further confirming the prognostic utility of this 3-tiered stratification.

Use and early mortality outcomes of active surveillance in patients with intermediate-risk prostate cancer.

BACKGROUND: Certain patients with intermediate-risk prostate cancer (PCa) may be appropriate candidates for active surveillance (AS). In the current study, the authors sought to characterize AS use and early mortality outcomes for patients with intermediate-risk PCa in the United States. METHODS: The novel Surveillance, Epidemiology, and End Results Active Surveillance/Watchful Waiting database identified 52,940 men diagnosed with National Comprehensive Cancer Network intermediate-risk PCa (cT2b-c, Gleason score of 7, or a prostate-specific antigen level of 10-20 ng/mL) and actively managed (AS, radiotherapy, or radical prostatectomy) from 2010 through 2015. The Cuzick test assessed AS time trends, and logistic multivariable regression characterized features associated with AS. Fine-Gray and Cox modeling determined PCa-specific mortality (PCSM) and overall survival, respectively. RESULTS: The rate of AS increased from 3.7% in 2010 to 7.3% in 2015, and from 7.2% to 11.7% among men aged ≥70 years. Among men with favorable and unfavorable intermediate-risk disease, the use of AS increased from 7.2% to 14.9% and from 2.2% to 3.8%, respectively (all P value for trend, <.001). The mean age of those patients managed with AS decreased from 69.9 years to 67.9 years (P = .0004). Factors found to be associated with AS included favorable risk disease; black race; higher socioeconomic status; older age; and diagnosis in the West, Northwest, or Midwest regions of the United States. The 5-year PCSM rate was comparable to AS versus treatment among patients with low-risk and favorable intermediate-risk disease, but was worse with AS among those with unfavorable intermediate-risk disease (PCSM, 1.3% vs 0.5%; adjusted hazard ratio, 2.48 [95% CI, 1.11-5.50; P = .026]) and intermediate-risk disease overall (PCSM, 1.1% vs 0.4%; adjusted hazard ratio, 2.34 [95% CI, 1.25-4.37; P = .008]). CONCLUSIONS: The use of AS for patients with intermediate-risk PCa is increasing across the United States, particularly for older men and those with favorable intermediate-risk disease. Early estimates of cancer-specific and overall mortality rates are low with AS, although significantly higher compared with treatment.

A comparative analysis of overall survival between high-dose-rate and low-dose-rate brachytherapy boosts for unfavorable-risk prostate cancer.

PURPOSE: External beam radiation therapy (EBRT) with low-dose-rate (LDR) brachytherapy boost has been associated with improved biochemical progression-free survival and overall survival (OS) compared with dose-escalated EBRT (DE-EBRT) alone for unfavorable-risk prostate cancer. However, it is not known whether high-dose-rate (HDR) boost provides a similar benefit. We compare HDR boost against LDR boost and DE-EBRT with respect to OS. METHODS: Using the National Cancer Database, we identified 122,896 patients who were diagnosed with National Comprehensive Cancer Network intermediate- or high-risk prostate cancer between 2004 and 2014 and treated with DE-EBRT (75.6-86.4 Gy), LDR boost, or HDR boost. We compared the OS among the three groups using multivariable Cox proportional hazards regression. Inverse probability treatment weighting was used to adjust for covariate imbalance. RESULTS: On multivariable Cox proportional hazards regression, HDR boost was associated with a similar OS to LDR boost (adjusted hazard ratio [AHR] 1.03 [0.96, 1.11]; p = 0.38) but significantly better OS than DE-EBRT (AHR 1.36 [1.29, 1.44]; p < 0.001). Inverse probability treatment weighting analysis yielded similar results. There was no significant difference between LDR and HDR boosts for National Comprehensive Cancer Network intermediate-risk (AHR 1.05 [0.96, 1.15]; p = 0.32) and high-risk (AHR 1.00 [0.89, 1.12]; p = 0.98) subgroups (p-interaction = 0.55). CONCLUSIONS: Our results suggest that HDR brachytherapy boost yields similar OS benefits compared with LDR brachytherapy boost for unfavorable-risk prostate cancer. HDR boost may be a suitable alternative to LDR boost.

Long-term outcomes of partial prostate treatment with magnetic resonance imaging-guided brachytherapy for patients with favorable-risk prostate cancer.

BACKGROUND: Partial prostate treatment has emerged as a potential method for treating patients with favorable-risk prostate cancer while minimizing toxicity. The authors previously demonstrated poor rates of biochemical disease control for patients with National Comprehensive Cancer Network (NCCN) intermediate-risk disease using partial gland treatment with brachytherapy. The objective of the current study was to estimate the rates of distant metastasis and prostate cancer-specific mortality (PCSM) for this cohort. METHODS: Between 1997 and 2007, a total of 354 men with clinical T1c disease, a prostate-specific antigen (PSA) level < 15 ng/mL, and Gleason grade ≤3 + 4 prostate cancer underwent partial prostate treatment with brachytherapy to the peripheral zone under 0.5-Tesla magnetic resonance guidance. The cumulative incidences of metastasis and PCSM for the NCCN very low-risk, low-risk, and intermediate-risk groups were estimated. Fine and Gray competing risk regression was used to evaluate clinical factors associated with time to metastasis. RESULTS: A total of 22 patients developed metastases at a median of 11.0 years (interquartile range, 6.9-13.9 years). The 12-year metastasis rates for patients with very low-risk, low-risk, and intermediate-risk disease were 0.8% (95% confidence interval [95% CI], 0.1%-4.4%), 8.7% (95% CI, 3.4%-17.2%), and 15.7% (95% CI, 5.7%-30.2%), respectively, and the 12-year PCSM estimates were 1.6% (95% CI, 0.1%-7.6%), 1.4% (95% CI, 0.1%-6.8%), and 8.2% (95% CI, 1.9%-20.7%), respectively. On multivariate analysis, NCCN risk category (low risk: hazard ratio, 6.34 [95% CI, 1.18-34.06; P = .03] and intermediate risk: hazard ratio, 6.98 [95% CI, 1.23-39.73; P = .03]) was found to be significantly associated with the time to metastasis. CONCLUSIONS: Partial prostate treatment with brachytherapy may be associated with higher rates of distant metastasis and PCSM for patients with intermediate-risk disease after long-term follow-up. Treatment of less than the full gland may not be appropriate for this cohort.

Patient-Reported Sexual Aid Utilization and Efficacy After Radiation Therapy for Localized Prostate Cancer.

PURPOSE: To report sexual health-related quality of life outcomes and utilization and efficacy of sexual aids in a contemporary cohort of patients treated for localized prostate cancer. PATIENTS AND METHODS: Between 2008 and 2013, 471 consecutive men with localized prostate cancer were treated on 2 institutional protocols (NCT01766492, NCT01618851) or on a prospective institutional registry with patient-reported health-related quality of life. All patients were treated with ultra-hypofractionated radiation therapy. Erectile function (EF) was defined as "firm enough for intercourse" with or without aids per Expanded Prostate Cancer Index Composite-26 (n = 222 at baseline); results apply to this cohort unless specifically noted. Sexual aid utilization and efficacy were patient reported. Multivariable analysis of EF was performed. RESULTS: Median follow-up was 60 months, median age was 67 years, and 70% had intermediate- or high-risk disease per National Comprehensive Cancer Network guidelines. At 24 and 60 months, questionnaire response rates were 86% and 67%, and EF was retained in 53% and 41%, respectively. Baseline sexual aid utilization was 37% (n = 82) and was associated with lower 24-month EF preservation on multivariable analysis (adjusted odds ratio 0.49, 95% confidence interval 0.26-0.92). By 60 months, 70% of men had tried aids. Of those who found aids helpful at baseline, 84% to 89% reported continued benefit at 24 to 60 months. Among aid-naïve patients, efficacy was 80% with first-time use within 12 months and 70% more than 12 months after radiation therapy (P = .02). Among men who developed erectile dysfunction but found sexual aids helpful, 25% were not current users at 60 months. CONCLUSIONS: One-third of men used sexual aids at baseline, which doubled by 5 years after radiation therapy. Self-reported efficacy was high and sustained. Despite significant declines in EF, a number of men reported helpfulness of aids but were not active users. Future study is required to understand drivers of aid utilization to optimize posttreatment sexual function.

Development and Validation of a Novel Integrated Clinical-Genomic Risk Group Classification for Localized Prostate Cancer.

Purpose It is clinically challenging to integrate genomic-classifier results that report a numeric risk of recurrence into treatment recommendations for localized prostate cancer, which are founded in the framework of risk groups. We aimed to develop a novel clinical-genomic risk grouping system that can readily be incorporated into treatment guidelines for localized prostate cancer. Materials and Methods Two multicenter cohorts (n = 991) were used for training and validation of the clinical-genomic risk groups, and two additional cohorts (n = 5,937) were used for reclassification analyses. Competing risks analysis was used to estimate the risk of distant metastasis. Time-dependent c-indices were constructed to compare clinicopathologic risk models with the clinical-genomic risk groups. Results With a median follow-up of 8 years for patients in the training cohort, 10-year distant metastasis rates for National Comprehensive Cancer Network (NCCN) low, favorable-intermediate, unfavorable-intermediate, and high-risk were 7.3%, 9.2%, 38.0%, and 39.5%, respectively. In contrast, the three-tier clinical-genomic risk groups had 10-year distant metastasis rates of 3.5%, 29.4%, and 54.6%, for low-, intermediate-, and high-risk, respectively, which were consistent in the validation cohort (0%, 25.9%, and 55.2%, respectively). C-indices for the clinical-genomic risk grouping system (0.84; 95% CI, 0.61 to 0.93) were improved over NCCN (0.73; 95% CI, 0.60 to 0.86) and Cancer of the Prostate Risk Assessment (0.74; 95% CI, 0.65 to 0.84), and 30% of patients using NCCN low/intermediate/high would be reclassified by the new three-tier system and 67% of patients would be reclassified from NCCN six-tier (very-low- to very-high-risk) by the new six-tier system. Conclusion A commercially available genomic classifier in combination with standard clinicopathologic variables can generate a simple-to-use clinical-genomic risk grouping that more accurately identifies patients at low, intermediate, and high risk for metastasis and can be easily incorporated into current guidelines to better risk-stratify patients.

Lack of Benefit From the Addition of External Beam Radiation Therapy to Brachytherapy for Intermediate- and High-risk Prostate Cancer.

PURPOSE: A recent randomized controlled trial demonstrated that the addition of external beam radiation therapy (EBRT) to brachytherapy did not improve progression-free survival in select patients with intermediate-risk prostate cancer. We evaluated whether the addition of EBRT to brachytherapy improves prostate cancer-specific mortality (PCSM) for intermediate- and high-risk disease using a large national database. METHODS AND MATERIALS: We identified 5836 patients in the Surveillance, Epidemiology, and End Results-Medicare linked database with a diagnosis of National Comprehensive Cancer Network intermediate-risk (Gleason score 7, prostate-specific antigen 10-20 ng/mL, or stage cT2b-T2c) or high-risk (Gleason score 8-10 or prostate-specific antigen >20 ng/mL and stage ≤cT3a) prostate cancer who had undergone brachytherapy, with or without EBRT and androgen deprivation therapy (ADT). Patients were diagnosed from 2004 through 2009. Intermediate-risk patients with Gleason score ≤3+4 and 1 intermediate-risk factor were considered favorable and all others unfavorable. We used multivariable Fine-Gray competing risks regression to study PCSM while adjusting for sociodemographic and clinical factors and ADT use. RESULTS: Overall, 50.3% of intermediate- and high-risk patients who received brachytherapy and EBRT did not have significantly improved PCSM compared with that of the patients who received brachytherapy alone (adjusted hazard ratio [AHR] 1.46, 95% confidence interval [CI] 0.69-3.11; P=.322; 5-year PCSM 2.4% vs 1.0%). This lack of benefit was seen among favorable intermediate-risk (AHR 2.66, 95% CI 0.93-7.62, P=.069; 5-year PCSM 1.3% vs 0.6%), unfavorable intermediate-risk (AHR 0.68, 95% CI 0.16-2.96, P=.612; 5-year PCSM 1.0% vs 1.2%), and high-risk (AHR 1.82, 95% CI 0.67-4.98, P=.242; 5-year PCSM 5.3% vs 2.1%) subgroups. CONCLUSIONS: These results suggest that certain patients with intermediate- or high-risk prostate cancer treated with brachytherapy might not benefit from the addition of EBRT. A randomized controlled trial of brachytherapy plus ADT with or without EBRT for unfavorable intermediate- and favorable high-risk organ-confined prostate cancer should be undertaken.

Ability of a Genomic Classifier to Predict Metastasis and Prostate Cancer-specific Mortality after Radiation or Surgery based on Needle Biopsy Specimens.

BACKGROUND: Decipher is a validated genomic classifier developed to determine the biological potential for metastasis after radical prostatectomy (RP). OBJECTIVE: To evaluate the ability of biopsy Decipher to predict metastasis and Prostate cancer-specific mortality (PCSM) in primarily intermediate- to high-risk patients treated with RP or radiation therapy (RT). DESIGN, SETTING, AND PARTICIPANTS: Two hundred and thirty-five patients treated with either RP (n=105) or RT±androgen deprivation therapy (n=130) with available genomic expression profiles generated from diagnostic biopsy specimens from seven tertiary referral centers. The highest-grade core was sampled and Decipher was calculated based on a locked random forest model. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Metastasis and PCSM were the primary and secondary outcomes of the study, respectively. Cox analysis and c-index were used to evaluate the performance of Decipher. RESULTS AND LIMITATIONS: With a median follow-up of 6 yr among censored patients, 34 patients developed metastases and 11 died of prostate cancer. On multivariable analysis, biopsy Decipher remained a significant predictor of metastasis (hazard ratio: 1.37 per 10% increase in score, 95% confidence interval [CI]: 1.06-1.78, p=0.018) after adjusting for clinical variables. For predicting metastasis 5-yr post-biopsy, Cancer of the Prostate Risk Assessment score had a c-index of 0.60 (95% CI: 0.50-0.69), while Cancer of the Prostate Risk Assessment plus biopsy Decipher had a c-index of 0.71 (95% CI: 0.60-0.82). National Comprehensive Cancer Network risk group had a c-index of 0.66 (95% CI: 0.53-0.77), while National Comprehensive Cancer Network plus biopsy Decipher had a c-index of 0.74 (95% CI: 0.66-0.82). Biopsy Decipher was a significant predictor of PCSM (hazard ratio: 1.57 per 10% increase in score, 95% CI: 1.03-2.48, p=0.037), with a 5-yr PCSM rate of 0%, 0%, and 9.4% for Decipher low, intermediate, and high, respectively. CONCLUSIONS: Biopsy Decipher predicted metastasis and PCSM from diagnostic biopsy specimens of primarily intermediate- and high-risk men treated with first-line RT or RP. PATIENT SUMMARY: Biopsy Decipher predicted metastasis and prostate cancer-specific mortality risk from diagnostic biopsy specimens.

Focal MRI-Guided Salvage High-Dose-Rate Brachytherapy in Patients With Radiorecurrent Prostate Cancer.

INTRODUCTION: Whole-gland salvage treatment of radiorecurrent prostate cancer has a high rate of severe toxicity. The standard of care in case of a biochemical recurrence is androgen deprivation treatment, which is associated with morbidity and negative effects on quality of life. A salvage treatment with acceptable toxicity might postpone the start of androgen deprivation treatment, might have a positive influence on the patients' quality of life, and might even be curative. Here, toxicity and biochemical outcome are described after magnetic resonance imaging-guided focal salvage high-dose-rate brachytherapy in patients with radiorecurrent prostate cancer. MATERIALS AND METHODS: Seventeen patients with pathologically proven locally recurrent prostate cancer were treated with focal high-dose-rate brachytherapy in a single 19-Gy fraction using magnetic resonance imaging for treatment guidance. Primary radiotherapy consisted of external beam radiotherapy or low-dose-rate brachytherapy. Tumors were delineated with Ga-68-prostate-specific membrane antigen or F18-choline positron emission tomography in combination with multiparametric magnetic resonance imaging. All patients had a prostate-specific antigen level of less than 10 ng/mL at the time of recurrence and a prostate-specific antigen doubling time of ≥12 months. Toxicity was measured by using the Common Terminology Criteria for Adverse Events version 4. RESULTS: Eight of 17 patients had follow-up interval of at least 1 year. At a median follow-up interval of 10 months (range 3-40 months), 1 patient experienced a biochemical recurrence according to the Phoenix criteria, and prostate-specific membrane antigen testing revealed that this was due to a distant nodal metastasis. One patient had a grade 3 urethral stricture at 2 years after treatment. CONCLUSION: Focal salvage high-dose-rate brachytherapy in patients with radiorecurrent prostate cancer showed grade 3 toxicity in 1 of 17 patients and a distant nodal metastasis in another patient. Whether this treatment option leads to cure in a subset of patients or whether it can successfully postpone androgen deprivation treatment needs further investigation.

Association Between Travel Distance and Choice of Treatment for Prostate Cancer: Does Geography Reduce Patient Choice?

OBJECTIVE: To determine whether the distance between a prostate cancer patient's home and treatment facility was related to the choice of treatment received among those opting for surgery or radiation. METHODS AND MATERIALS: We identified 222,804 patients diagnosed with National Comprehensive Cancer Network low-, intermediate-, or high-risk N0M0 prostate cancer and treated with local therapy (surgery or radiation alone, with or without hormone therapy) using the National Cancer Database. We used multivariable logistic regression to determine whether the choice of radiation therapy vs radical prostatectomy varied by distance among patients living in rural and urban areas. Analyses were adjusted for geographic location within the United States, age, race, Charlson/Deyo comorbidity score, year of diagnosis, income quartile, education quartile, Gleason score, prostate-specific antigen level, and T stage. RESULTS: Patients living in urban or rural areas were less likely to receive radiation compared with surgery if they lived farther from the treatment facility. Among urban patients living ≤5 miles from the treatment facility, 53.3% received radiation, compared with 47.0%, 43.6%, and 33.8% of those living 5 to 10, 10 to 15, or >15 miles away, respectively (P<.001 in all cases). Similarly, rural patients were less likely to receive radiation the farther they lived from the treatment facility (≤25 miles: 62.3%; 25-50 miles: 55.5%; 50-75 miles: 38.4%; >75 miles: 23.8%; P<.05 in all cases). These trends were also present when each risk group was analyzed separately. CONCLUSION: Patients with prostate cancer in both urban and rural settings were less likely to receive radiation therapy rather than surgery the farther away they lived from a treatment center. These findings raise the possibility that the geographic availability of radiation treatment centers may be an important determinant of whether patients are able to choose radiation rather than surgery for localized prostate cancer.

Factors associated with the omission of androgen deprivation therapy in radiation-managed high-risk prostate cancer.

PURPOSE: Androgen deprivation therapy (ADT) has been shown to improve survival for men with unfavorable-risk prostate cancer (PCa). We investigated the utilization and factors associated with the omission of ADT in radiation-managed high-risk PCa. METHODS AND MATERIALS: We used the National Cancer Database to identify men with National Comprehensive Cancer Network high-risk PCa treated with external beam radiation therapy (EBRT) with or without brachytherapy boost from 2004 to 2012. Multivariable logistic regression adjusting for clinical and sociodemographic factors was used to identify independent predictors for ADT use. RESULTS: A total of 57,968 radiation-treated high-risk PCa men were included in our analysis. There were 49,363 patients (85.2%) treated with EBRT alone and 8605 patients (14.8%) treated with EBRT plus brachytherapy boost. Overall, 77% of men received ADT. In multivariable regression analysis, the use of brachytherapy boost was associated with a significantly lower utilization of ADT (70% vs. 78%; adjusted odds ratio [AOR]: 0.65; 95% CI: 0.62-0.69; p-Value <0.0001), as was treatment at an academic vs. nonacademic center (AOR: 0.90; 95% CI: 0.86-0.95; p-Value <0.0001) and treatment in 2010-2012 compared to 2004-2006 (AOR: 0.85; 95% CI: 0.81-0.90; p-Value <0.0001). Conversely, greater ADT use was seen with higher Gleason scores, PSA, and T-category (all p-Values <0.001). CONCLUSIONS: Approximately one in four men with radiation-managed high-risk PCa do not receive ADT, which may reflect concerns about its toxicity profile despite known improvements in overall survival. Practice patterns suggest that some providers believe dose escalation through brachytherapy boost may obviate the need for ADT in some high-risk patients, but this hypothesis requires further testing.

Feasibility of brachytherapy as monotherapy for high-volume, low-risk prostate cancer.

BACKGROUND: We sought to determine whether patients with high-volume, low-risk prostate cancer are suitable candidates for ultrasound-guided brachytherapy, monotherapy alone, without supplemental external beam radiation. MATERIALS AND METHODS: The study cohort comprised 200 consecutive patients who received ultrasound.guided monotherapy from November 02, 1998 to March 26, 2010. Real.time intraoperative treatment planning was performed for all patients. 145. Gy with I125 was prescribed to the prostate with no margin. The primary endpoint was time to prostate-specific antigen. (PSA) failure using the phoenix definition. Cox multivariable regression analysis was used to determine the factors significantly associated with time to PSA failure. RESULTS: Median follow-up was 59 months (range 1.2-146.8 months). The median PSA was 5.0 ng/ml. For the overall cohort, both 5- and 8-year PSA failure-free survival was 92.3% (95% confidence interval [95% CI]: 86.5-95.7%). Low-risk patients per the NCCN criteria had 5- and 8-year PSA failure-free survival of 93.6%. On cox multivariable analysis, only baseline PSA (adjusted hazard ratio: 1.29 [95% CI: 1.02-1.65], P = 0.036) was associated with outcome. Among patients with Conclusions: Our analysis indicates that patients with a high number of cores positive for cancer can be adequately treated with modern brachytherapy as monotherapy and be spared the additional morbidity and cost of supplemental external beam radiation or androgen deprivation therapy.

Occult High-risk Disease in Clinically Low-risk Prostate Cancer with ≥50% Positive Biopsy Cores: Should National Guidelines Stop Calling Them Low Risk?

OBJECTIVE: To identify contemporary, clinically low-risk patients with ≥50% cores positive and compare the risk of upgrading at prostatectomy with other low- or intermediate-risk patients. MATERIALS AND METHODS: We studied 14,902 patients with prostate cancer in the Surveillance, Epidemiology, and End Results database in 2010-2011 treated with prostatectomy. Patients were categorized by National Comprehensive Cancer Network clinical risk groups, separating low-risk patients by percent positive biopsy cores (PBC). We measured incidence of pathologic high-risk disease, defined as pT3a-T4 or Gleason 8-10, and multivariable logistic regression was used to determine if patients with clinical low-risk disease and ≥50% PBC were similar to other low- or intermediate-risk patients. This analysis was repeated with favorable and unfavorable intermediate risk. RESULTS: At prostatectomy, 9.2% of clinically low-risk patients with <50% PBC, 18.6% of clinically low-risk patients with ≥50% PBC, and 27.6% of clinically intermediate-risk patients had occult, high-risk disease (P <.001). On multivariable logistic regression, low-risk patients with ≥50% PBC were more likely than low-risk patients with <50% PBC to have pathologic high-risk disease (adjusted odds ratio [AOR] 2.28, 95% confidence interval 1.90-2.73, P <.001), had similar risk to favorable intermediate patients overall (AOR 1.09, 0.91-1.31, P = .33), and had higher risk than favorable intermediate patients aged over 60 years (AOR 1.28, 1.00-1.64, P = .04). Low-risk patients with ≥50% PBC had a mean tumor size similar to unfavorable intermediate-risk patients (21.3 vs 21.0 mm, P = .82). CONCLUSION: Nearly 1 in 5 clinically low-risk prostate cancer patients with ≥50% PBC harbor occult pT3a-T4 or Gleason 8-10, suggesting that national guidelines should not classify low-risk patients with ≥50% cores positive as "low risk," and patients should be made aware of this excess risk if considering active surveillance.

Trends in disparate treatment of African American men with localized prostate cancer across National Comprehensive Cancer Network risk groups.

OBJECTIVE: To determine whether African Americans (AAs) with intermediate- to high-risk prostate cancer (PCa) receive similar treatment as white patients and whether any observed disparities are narrowing with time. METHODS: We used Surveillance, Epidemiology, and End Results to identify 128,189 men with localized intermediate- to high-risk PCa (prostate-specific antigen ≥10 ng/mL, Gleason score ≥7, or T stage ≥T2b) diagnosed from 2004 to 2010. We used multivariate logistic regression analyses to determine the impact of race on the receipt of definitive treatment. RESULTS: AA men were significantly less likely to receive curative-intent treatment than white men (adjusted odds ratio [AOR], 0.82; 95% confidence interval [CI], 0.79-0.86; P <.001). There was no evidence of this disparity narrowing over time (Pinteraction 2010 vs 2004 = .490). Disparities in the receipt of treatment between AA and white men were significantly larger in high-risk (AOR, 0.60; 95% CI, 0.56-0.64; P <.001) than in intermediate-risk disease (AOR, 0.92; 95% CI, 0.88-0.97; P = .04; Pinteraction <.001). After adjusting for treatment, demographics, and prognostic factors, AA men had a higher risk of prostate cancer-specific mortality (adjusted hazard ratio, 1.12; 95% CI, 1.01-1.25; P = .03). CONCLUSION: AA men with intermediate- to high-risk PCa are less likely to be treated with curative intent than white men. This disparity is worse in high-risk disease and is not improving over time. Factors underlying this treatment disparity should be urgently studied as it is a potentially correctable contributor to excess PCa mortality among AA patients.

Placement of empty catheters for an HDR-emulating LDR prostate brachytherapy technique: comparison to standard intraoperative planning.

PURPOSE: We sought to determine whether placing empty catheters within the prostate and then inverse planning iodine-125 seed locations within those catheters (High Dose Rate-Emulating Low Dose Rate Prostate Brachytherapy [HELP] technique) would improve concordance between planned and achieved dosimetry compared with a standard intraoperative technique. METHODS AND MATERIALS: We examined 30 consecutive low dose rate prostate cases performed by standard intraoperative technique of planning followed by needle placement/seed deposition and compared them to 30 consecutive low dose rate prostate cases performed by the HELP technique. The primary endpoint was concordance between planned percentage of the clinical target volume that receives at least 100% of the prescribed dose/dose that covers 90% of the volume of the clinical target volume (V100/D90) and the actual V100/D90 achieved at Postoperative Day 1. RESULTS: The HELP technique had superior concordance between the planned target dosimetry and what was actually achieved at Day 1 and Day 30. Specifically, target D90 at Day 1 was on average 33.7 Gy less than planned for the standard intraoperative technique but was only 10.5 Gy less than planned for the HELP technique (p < 0.001). Day 30 values were 16.6 Gy less vs. 2.2 Gy more than planned, respectively (p = 0.028). Day 1 target V100 was 6.3% less than planned with standard vs. 2.8% less for HELP (p < 0.001). There was no significant difference between the urethral and rectal concordance (all p > 0.05). CONCLUSIONS: Placing empty needles first and optimizing the plan to the known positions of the needles resulted in improved concordance between the planned and the achieved dosimetry to the target, possibly because of elimination of errors in needle placement.

Medical oncology consultation and minimization of overtreatment in men with low-risk prostate cancer.

PURPOSE: Specialist bias, in which specialists recommend the therapy that they are capable of delivering, is thought to influence the treatment of patients with localized prostate cancer and to contribute to overtreatment of men with limited life expectancy. Consequently, rates of active surveillance, the preferred management modality per the National Comprehensive Cancer Network (NCCN) for patients with low- and very low-risk disease and a life expectancy of less than 10 and less than 20 years, respectively, are low. We sought to determine whether consultation with a medical oncologist is associated with increased rates of active surveillance in men with low-risk prostate cancer. METHODS: We identified 188 patients with low-risk prostate cancer undergoing active surveillance at one of three referral centers in Boston, MA in 2009. Multivariable logistic regression was used to determine whether consultation with a medical oncologist was associated with selection of active surveillance. The data were reanalyzed for patients with low- and very low-risk disease and a life expectancy of less than 10 and less than 20 years, respectively. RESULTS: Consultation with a medical oncologist was associated with increased rates of active surveillance (37% v 21%, P = .01), an association that remained significant on multivariable logistic regression (odds ratio [OR] = 2.70; 95% CI, 1.27 to 5.75; P = .01). When applied to patients with limited life expectancy, this finding remained significant (OR = 4.74; 95% CI, 1.17 to 19.25; P = .03). CONCLUSION: Consultation with a medical oncologist is associated with increased rates of active surveillance, adherence to NCCN guidelines, and minimization of overtreatment in men with early prostate cancer and limited life expectancy.