Risk Of Prostate Cancer-specific Mortality Research Articles

Very High-Risk Localized Prostate Cancer: Outcomes Following Definitive Radiation

Existing definitions of high-risk prostate cancer consist of men who experience significant heterogeneity in outcomes. As such, criteria that identify a subpopulation of National Comprehensive Cancer Network (NCCN) high-risk prostate cancer patients who are at very high risk (VHR) for poor survival outcomes following prostatectomy were recently developed at our institution and include the presence of any of the following disease characteristics: multipleNCCN high-risk factors, primary Gleason pattern 5 disease and/or ≥5 biopsy cores with Gleason sums of 8 to 10. Whether these criteria also apply to men undergoing definitive radiation is unclear, as is the optimal treatment regimen in these patients. All men consecutively treated with definitive radiation by a single provider from 1993 to 2006 and who fulfilled criteria for NCCN high-risk disease were identified (n=288), including 99 patients (34%) with VHR disease. Multivariate-adjusted competing risk regression models were constructed to assess associations between the VHR definition and biochemical failure (BF), distant metastasis (DM), and prostate cancer-specific mortality (PCSM). Multivariate-adjusted Cox regression analysis assessed the association of the VHR definition with overall mortality (OM). Cumulative incidences of failure endpoints were compared between VHR men and other NCCN high-risk men. Men with VHR disease compared to other NCCN high-risk men experienced a higher 10-year incidence of BF (54.0% vs 35.4%, respectively, P<.001), DM (34.9% vs 13.4%, respectively, P<.001), PCSM (18.5% vs 5.9%, respectively, P<.001), and OM (36.4% vs 27.0%, respectively, P=.04). VHR men with a detectable prostate-specific antigen (PSA) concentration at the end of radiation (EOR) remained at high risk of 10-year PCSM compared to VHR men with an undetectable EOR PSA (31.0% vs 13.7%, respectively, P=.05). NCCN high-risk prostate cancer patients who meet VHR criteria experience distinctly worse outcomes following definitive radiation and long-term androgen deprivation therapy, particularly if an EOR PSA is detectable. Optimal use of local therapies for VHR patients should be explored further, as should novel agents.

Validation of the Combination Gleason Score as an Independent Favorable Prognostic Factor in GS 7-10 Prostate Cancer Treated With Dose-Escalated Radiation Therapy

The combination Gleason Score (ComboGS) at time of biopsy is a recently proposed prognostic marker defined as the presence of at least 1 biopsy core of lower Gleason Score (GS) in men who have a highest GS ≥7 prostate cancer. In single-institution reports, the presence of ComboGS decreased the risk of pathologic upgrading at time of prostatectomy and decreased the risk of prostate cancer-specific mortality (PCSM) following external beam radiation therapy (EBRT); however, these findings have not been validated. Herein, we evaluated if the presence of ComboGS was prognostic for improved outcome in an independent cohort of men receiving EBRT for prostate cancer. At a single institution from 1988 to 2012, 788 consecutive men with prostate cancer received dose-escalated EBRT (minimum 75 Gy). Endpoints analyzed included PCSM, overall survival (OS), freedom from distant metastases (FFDM) and freedom from biochemical failure (FFBF, with failure defined as a rise in prostate-specific antigen [PSA] of 2 ng/mL or more above nadir). Statistical analysis was performed using Kaplan-Meier and Stepwise Cox proportional hazards models. In the 532 men with a GS of 7-10, the median follow-up was 89 (interquartile range [IQR]:57-128) months. Of these men, 259 (49%) had a ComboGS, while 272 (51%) did not. Men with ComboGS had similar age, T stage, Cancer of the Prostate Risk Assessment (CAPRA) score, and rate of androgen deprivation therapy (ADT) use (P>.05). Men with comboGS had higher baseline GS (7, 57% vs 67%; 8, 15% vs 17%; 9, 20% vs 9.5%; 10, 8% vs 7%, P=.005), and slightly lower PSA (14.2 vs 16.3, P=.02). On univariate analysis, men with ComboGS had improved 10-year FFBF (75.2% vs 54.9%, HR: 0.59, 95% CI: 0.42-0.82), FFDM (95.7% vs 84.3%, HR: 0.26, 95% CI: 0.15-0.47), PCSM (93.7% vs 88.1%, HR: 0.42, 95% CI: 0.22-0.81), and OS (82.4% vs 67.7%, HR: 0.45, 95% CI: 0.31-0.64). In men with intermediate-risk disease, the presence of comboGS decreased 10-year distant metastasis (DM) rates from 7.2% (±2.3) to 0.8% (±0.8) (HR: 0.17, 95% CI: 0.53-0.57), while in high-risk men, 10-year DM rates decreased from 21.9% (±4.1) to 9.1% (±3.5) (HR: 0.32, 95% CI: 0.17-0.63). On multivariate analysis, ComboGS was associated with decreased BF (HR: 0.59, 95% CI: 0.40-0.86, P=.007), DM (HR: 0.20, 95% CI: 0.09-0.43, P=.0001), PCSM (HR: 0.37, 95% CI: 0.16-0.85, P=.02), and OS (HR: 0.32, 95% CI: 0.20-0.52, P<.0001) after correction for age, GS, PSA, T stage, Charlson Co-Morbidity Index, percent cores positive, and ADT use. The addition of ComboGS increased the prognostic power of CAPRA score as measured by the concordance index for BF (0.709 vs 0.693), DM (0.833 vs 0.801), and PCSM (0.827 vs 0.811). ComboGS is an independent favorable prognostic factor for all clinical endpoints that is readily available but not routinely utilized. ComboGS increases the prognostic power of the CAPRA score and may identify men in whom therapy may be de-escalated

Short-course androgen deprivation therapy and the risk of death from high-risk prostate cancer in men undergoing external beam radiation therapy and brachytherapy.

We estimated the risks of prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) in men with high-risk prostate cancer (PC) undergoing external beam radiation therapy and brachytherapy with short-course androgen deprivation therapy (ADT) (median 4 months) as compared with men with more favorable-risk PC undergoing standard of care as per the National Comprehensive Cancer Network guidelines. The prospective study cohort comprised 6595 consecutively treated men with T1-4 N0M0 PC whose treatment included brachytherapy between October 16, 1997, and May 28, 2013. Fine and Gray competing risk regression and Cox regression analyses were used to assess the risks of PCSM and ACM in men with high, unfavorable intermediate, and favorable intermediate risk as compared with low-risk PC. After median followup of 7.76 years, 820 men died (12.43%): 72 of PC (8.78%). Men with favorable intermediate-risk PC did not have significantly increased PCSM risk as compared with men with low-risk PC (adjusted hazard ratio [AHR], 1.26; 95% confidence interval [CI] 0.56, 2.88; p-Value 0.58), whereas men with high-risk PC (AHR, 3.74; 95% CI 1.12, 12.53; p-Value 0.032) and unfavorable intermediate-risk PC (AHR, 3.10; 95% CI 1.43, 6.72; p-Value 0.004) did. Based on 10-year adjusted point estimates of PCSM and ACM for men with high-risk PC being 6.01% (95% CI 3.79%, 8.94%) and 21.30% (95% CI 17.45%, 25.42%), respectively, PCSM comprised 28% of ACM. In the setting of external beam radiation therapy and brachytherapy, men with high-risk PC have low absolute adjusted estimates of PCSM (~6%) during the first decade after treatment despite receiving only short-course ADT. Whether long-term ADT can lower PCSM and improve survival in these men requires additional study.

Abstract 4603: Male pattern baldness in relation to prostate cancer-specific mortality: A prospective analysis in the NHANES I Epidemiologic Followup Study (NHEFS)

Abstract Background: Androgenic action underlies prostate gland development and prostate cancer progression. However, the role of such in prostate carcinogenesis remains unclear. Results from studies that have quantitated pre-diagnostic, circulating androgens at a single time-point in relation to prostate cancer are inconsistent, possibly due to the failure to capture cumulative or relevant age-specific hormone exposure. Therefore, we used male pattern baldness as a proxy of long-term androgen exposure, and investigated the association between dermatologist-assessed male pattern baldness and prostate cancer-specific mortality in the NHANES-I Epidemiologic Followup Study (NHEFS). Methods: We included 4,316 men from NHEFS, who were 25-74 years, received dermatologic exams, and had no prior cancer diagnosis at baseline. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) were estimated using Cox proportional hazards regression with age as the time-metric and baseline hazard stratified by age at baseline. A hybrid model was used to account for stratification and clustering of the survey design, while adjusting for variables used to calculate sample weights. Results: During follow-up (median = 21 years), 3,284 deaths occurred, 107 of which had the underlying cause of prostate cancer. Any degree of baldness was associated with a 56% increased risk of prostate cancer-specific mortality (HR = 1.56; 95%CI = 1.02, 2.37) and, specifically, moderate balding was associated with an 83% increased risk of the outcome (HR = 1.83; 95%CI = 1.15, 2.92), each compared with no balding. Conversely, male pattern baldness was not statistically significantly associated with all-cause mortality. Conclusion: Our analysis suggests that male pattern baldness is associated with an increased risk of fatal prostate cancer, and supports the hypothesis of overlapping pathophysiological mechanisms. Impact: If the association between male pattern baldness and fatal prostate cancer is substantiated in future studies, male pattern baldness may contribute to predictive algorithms of prostate cancer risk, helping guide individuals as to whether they should opt to undergo cancer screening. Citation Format: Cindy Ke Zhou, Paul H. Levine, Sean D. Cleary, Heather J. Hoffman, Barry I. Graubard, Michael B. Cook. Male pattern baldness in relation to prostate cancer-specific mortality: A prospective analysis in the NHANES I Epidemiologic Followup Study (NHEFS). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4603. doi:10.1158/1538-7445.AM2015-4603

Abstract 880: Obesity predicts prostate cancer-specific mortality after radical prostatectomy: Results from the SEARCH database

Abstract INTRODUCTION: At the population level among otherwise “healthy” men, obesity is associated with prostate cancer mortality. However, few studies analyzed the associations between obesity and long-term progression after surgery, such as castration-resistant prostate cancer (CRPC) and prostate cancer-specific mortality (PCSM). We examined the effect of obesity at the time of radical prostatectomy (RP) on long-term prostate cancer-specific outcomes among men treated at Veterans Affairs Hospitals in the USA. METHODS: We combined data from patients undergoing RP at six Veterans Affairs Medical Centers (West Los Angeles, San Diego, and Palo Alto, CA; Augusta, GA; and Durham and Asheville, NC) into the SEARCH database. Our exposure, body mass index (BMI) was abstracted from the medical records at the time of but prior to RP and categorized as normal weight (&amp;lt;25 kg/m2), overweight (25-29.9kg/m2), and obese (≥30kg/m2). Crude and adjusted Cox models accounting for known risk cofactors were used to examine the associations between BMI and PCSM (primary outcome), biochemical recurrence (BCR) and CRPC. Hazard ratios for the risk of CRPC and PCSM were analyzed using competing-risks regression analysis accounting for non-PC death as a competing risk. RESULTS: Overall, 839 (23%) men had normal weight, 1,675 (45%) were overweight, and 1,184 (32%) were obese. A higher BMI was associated with younger age at surgery (p&amp;lt;0.001), lower PSA (median 6.9 vs. 6.3 vs. 6.1; p&amp;lt;0.001), and a shorter follow-up (p = 0.009). After adjusting for clinical and pathological features, both overweight (HR 2.85, p = 0.039) and obesity (HR 3.38, p = 0.017) were significantly associated with PCSM relative to normal weight. Obesity (vs. normal weight) was also associated with a higher risk of BCR (HR = 1.20, p = 0.026) and CRPC (HR = 2.12, p = 0.026), even after adjusting for clinical and pathological characteristics. Overweight was not associated with BCR (HR = 1.01, p = 0.948) or CRPC (HR = 1.44, p = 0.274) on multivariable analysis. CONCLUSIONS: Our study supports the hypothesis that obese men undergoing RP are at increased risk of worse long-term prostate cancer outcomes including PCSM. Our findings are consistent with a growing body of literature documenting that obesity in general is associated with more aggressive prostate cancer. Citation Format: Adriana C. Vidal, Lauren E. Howard, Matthew R Cooperberg, Christopher J. Kane, William J. Aronson, Martha K. Terris, Christopher L. Amling, Stephen J Freedland. Obesity predicts prostate cancer-specific mortality after radical prostatectomy: Results from the SEARCH database. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 880. doi:10.1158/1538-7445.AM2015-880

Conditional cancer-specific mortality in T4, N1, or M1 prostate cancer: implications for long-term prognosis.

BackgroundThe risk of prostate cancer-specific mortality (PCSM) following a diagnosis of prostate cancer may improve after patients have survived a number of years after diagnosis. We sought to determine long-term conditional PCSM for patients with stage T4, N1, or M1 prostate cancer.MethodsWe identified 66,817 patients diagnosed with stage IV (T4N0M0, N1M0, or M1) prostate cancer between 1973 and 2011 using the Surveillance, Epidemiology, and End Results (SEER) database. Conditional five-year PCSM was evaluated for each group of patients at 5, 10, and 15 years of survival according to the Fine & Gray model for competing risks after adjusting for tumor grade, age, income level, and marital status. Race-stratified analyses were also performed.Results There were 13,345 patients with T4 disease, 12,450 patients with N1 disease, and 41,022 patients with M1 disease. Median follow-up among survivors in the three groups was 123 months (range: 0–382 months), 61 months (range: 0–410 months), and 30 months (range: 0–370 months), respectively. Conditional PCSM improved in all three groups over time. Among patients with T4 disease, 5-year PCSM improved from 13.9 % at diagnosis to 11.2, 8.1, and 6.5 % conditioned on 5, 10, or 15 years of survival, respectively (p < 0.001 in all cases). In patients with N1 disease, 5-year PCSM increased within the first five years and decreased thereafter, from 18.9 % at diagnosis to 21.4 % (p < 0.001), 17.6 % (p = 0.055), and 13.8 % (p < 0.001), respectively. In patients with metastatic disease, 5-year PCSM improved from 57.2 % at diagnosis to 41.1, 28.8, and 20.8 %, respectively (p < 0.001). White race was associated with a greater increase in conditional survival compared to non-white race among those with T4 or N1 disease.ConclusionsWhile patients with T4, N1, or M1 prostate cancer are never “cured,” their odds of cancer-specific survival increase substantially after they have survived for 5 or more years. Physicians who take care of patients with prostate cancer can use this data to guide follow-up decisions and to counsel newly diagnosed patients and survivors regarding their long-term prognosis.

Definition and Validation of “Favorable High-Risk Prostate Cancer”: Implications for Personalizing Treatment of Radiation-Managed Patients

To define and validate a classification of favorable high-risk prostate cancer that could be used to personalize therapy, given that consensus guidelines recommend similar treatments for all radiation-managed patients with high-risk disease. We studied 3618 patients with cT1-T3aN0M0 high-risk or unfavorable intermediate-risk prostate adenocarcinoma treated with radiation at a single institution between 1997 and 2013. Favorable high-risk was defined as T1c disease with either Gleason 4 + 4 = 8 and prostate-specific antigen <10 ng/mL or Gleason 6 and prostate-specific antigen >20 ng/mL. Competing risks regression was used to determine differences in the risk of prostate cancer-specific mortality (PCSM) after controlling for baseline factors and treatment. Our results were validated in a cohort of 13,275 patients using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Patients with favorable high-risk disease had significantly better PCSM than other men with high-risk disease (adjusted hazard ratio [AHR] 0.42, 95% confidence interval [CI] 0.18-0.996, P=.049) and similar PCSM as men with unfavorable intermediate-risk disease (AHR 1.17, 95% CI 0.50-2.75, P=.710). We observed very similar results within the SEER-Medicare cohort (favorable high-risk vs other high-risk: AHR 0.21, 95% CI 0.11-0.41, P<.001; favorable high-risk vs unfavorable intermediate-risk: AHR 0.67, 95% CI 0.33-1.36, P=.268). Patients with favorable high-risk prostate cancer have significantly better PCSM than other patients with high-risk disease and similar PCSM as those with unfavorable intermediate-risk disease, who are typically treated with shorter-course androgen deprivation therapy. This new classification system may allow for personalization of treatment within high-risk disease, such as consideration of shorter-course androgen deprivation therapy for favorable high-risk disease.

The effect of smoking on prostate cancer survival: a cohort analysis in Barcelona.

The aim of this study was to analyse the effect of smoking on prostate cancer-specific mortality and all-cause mortality. A retrospective cohort study was conducted with 1109 patients with prostate cancer diagnosed from 1992 to 2008, identified through the Hospital del Mar Cancer Registry (Barcelona, Spain). Information on smoking habits was retrieved from clinical records and patients were classified into three categories: never smoker, exsmoker and current smoker. Patients were followed up until December 2011. Survival curves were plotted using Kaplan-Meier methods. Cox models were used to estimate hazard ratios and 95% confidence intervals. Median age at diagnosis was 70.6 years and 16.7% of patients had stage IV tumours. During the follow-up period, 466 deaths occurred, 36.1% of them being specifically due to prostate cancer. The median follow-up time of the censored patients was 5.8 years. There was a significant difference in disease-specific survival between never smokers, exsmokers and current smokers (P=0.0001). Current smokers presented a worse 5-year survival rate (82.9%) compared with exsmokers (88.9%) and never smokers (89.6%). In the multivariate analysis, after adjusting for age, disease stage, Gleason score and prostate-specific antigen, the hazard ratio for smokers was 1.80 (95% confidence interval: 1.04-3.13) compared with never smokers. In the exsmokers group the risk for prostate cancer-specific mortality was very similar to that of never smokers. However, the statistical difference disappeared when we stratified by stage (I-III and IV). In conclusion, smoking was identified as an independent and negative prognostic factor for prostate cancer-specific and all-cause mortality. These findings suggest that smoking-cessation programmes could be beneficial for prostate cancer patients.

Fat intake after prostate cancer diagnosis and mortality in the Physicians' Health Study.

Diet after prostate cancer diagnosis may impact disease progression. We hypothesized that consuming saturated fat after prostate cancer diagnosis would increase risk of mortality, and consuming vegetable fat after diagnosis would lower the risk of mortality. This was a prospective study among 926 men with non-metastatic prostate cancer in the Physicians' Health Study who completed a food frequency questionnaire a median of 5years after diagnosis and were followed for a median of 10years after the questionnaire. We examined post-diagnostic saturated, monounsaturated, polyunsaturated, and trans fat, as well as animal and vegetable fat, intake in relation to all-cause and prostate cancer-specific mortality. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariate Cox proportional hazards regression. We observed 333 deaths (56 prostate cancer deaths) during follow-up. Men who obtained 5% more of their daily calories from saturated fat and 5% less of their daily calories from carbohydrate after diagnosis had a 1.8-fold increased risk of all-cause mortality (HR 1.81; 95% CI 1.20, 2.74; p value 0.005) and a 2.8-fold increased risk of prostate cancer-specific mortality (HR 2.78; 95% CI 1.01, 7.64; p value 0.05). Men who obtained 10% more of their daily calories from vegetable fats and 10% less of their daily calories from carbohydrates had a 33% lower risk of all-cause mortality (HR 0.67; 95% CI 0.47, 0.96; p value 0.03). Among men with non-metastatic prostate cancer, saturated fat intake may increase risk of death and vegetable fat intake may lower risk of death.

Dairy intake after prostate cancer diagnosis in relation to disease-specific and total mortality.

Information regarding postdiagnostic dairy intake and prostate cancer survival is limited. We evaluated intake of total, high-fat and low-fat dairy after prostate cancer diagnosis in relation to disease-specific and total mortality. We included 926 men from the Physicians' Health Study diagnosed with non-metastatic prostate cancer between 1982 and 2000 who completed a diet questionnaire a median of 5 years after diagnosis and were followed thereafter for a median of 10 years to assess mortality. Cox proportional hazards regression was used to estimate associations between dairy intake and prostate cancer specific and all-cause mortality. During 8,903 person-years of follow-up, 333 men died, 56 due to prostate cancer. Men consuming ≥3 servings/day of total dairy products had a 76% higher risk of total mortality and a 141% higher risk of prostate cancer-specific mortality compared to men who consumed less than 1 dairy product/day (hazard ratio (HR) = 1.76, 95% confidence interval (CI): 1.21, 2.55, ptrend < 0.001 for total mortality; HR = 2.41, 95% CI: 0.96, 6.02, ptrend = 0.04 for prostate cancer-specific mortality). The association between high-fat dairy and mortality risk appeared to be stronger than that of low-fat dairy, but the difference between them was not statistically significant (p for difference = 0.57 for prostate cancer-specific mortality and 0.56 for total mortality). Among men without metastases when diagnosed, higher intake of dairy foods after prostate cancer diagnosis may be associated with increased prostate cancer-specific and all-cause mortality.

Duration of Androgen Deprivation Therapy Influences Outcomes for Patients Receiving Radiation Therapy Following Radical Prostatectomy

BackgroundLimited data exist to guide the use of androgen deprivation therapy (ADT) for men treated with radiation therapy (RT) after radical prostatectomy (RP). The optimal duration of ADT in this setting is unknown. ObjectiveTo determine if the duration of ADT influences clinical outcomes for men receiving post-RP RT. Design, setting, and participantsA total of 680 men who received adjuvant radiation therapy (n=105) or salvage radiation therapy (n=575) between 1986 and 2010 at a single tertiary care institution were reviewed retrospectively. Median follow-up post-RT was 57.8 mo. InterventionRT was delivered using three-dimensional conformal or intensity-modulated RT in 1.8-Gy fractions. For patients treated with ADT, >80% were treated with a gonadotropin-releasing hormone agonist with or without a nonsteroidal antiandrogen. Outcome measurements and statistical analysisBiochemical failure (BF), distant metastasis (DM), prostate cancer–specific mortality (PCSM), and overall mortality were assessed using Kaplan-Meier analysis and propensity score analysis. Results and limitationsOverall, 144 patients (21%) received ADT with post-RP RT, most of whom had high-risk disease features such as Gleason score 8–10, seminal vesicle invasion, or pre-RT prostate-specific antigen >1 ng/ml. Median ADT duration was 12 mo (interquartile range: 6.0–23.7). Patients who received <12 mo of ADT had an association with increased BF (hazard ratio [HR]: 2.27; p=0.003) and DM (HR: 2.48; p=0.03) compared with patients receiving ≥12 mo of ADT. The 5-yr rates of DM were 6.0% and 23% for ≥12 and <12 mo of ADT, respectively. On propensity score analysis controlling for pretreatment and treatment-related factors, each month of ADT was associated with a decreased risk for BF (HR: 0.95; p=0.0004), DM (HR: 0.88; p=0.0004), and PCSM (HR: 0.90; p=0.037). These findings are limited by the retrospective nature of our analysis. ConclusionsFor men with high-risk disease features receiving ADT with post-RP RT, the duration of ADT is associated with clinical outcomes. Our findings suggest that for these men an extended course of ADT ≥12 mo may be preferable. Validation of our findings is needed. Patient summaryWe evaluated outcomes for men with high-risk disease features treated with androgen deprivation therapy (ADT) and radiotherapy after radical prostatectomy. Longer durations of ADT resulted in improved patient outcomes.

Differential post-prostatectomy cancer-specific survival of occult T3 vs. clinical T3 prostate cancer: Implications for managing patients upstaged on prostate magnetic resonance imaging

Purpose/objectiveLong-term androgen deprivation therapy (ADT) was proven in randomized trials to be superior to short-term ADT for radiation-managed patients who have clinical T3 (cT3) disease, but it is unknown whether patients with T3 disease seen only on magnetic resonance imaging require similarly aggressive treatment. We attempted to study this issue by analogy by comparing the long-term post-prostatectomy survival of patients with cT3 disease versus cT1/T2 disease upstaged to pathologic T3 disease. MethodsThe Surveillance, Epidemiology, and End Results (SEER) database was used to identify 60,165 men diagnosed with prostate adenocarcinoma between 1995 and 2002 who underwent prostatectomy. Prostate cancer–specific mortality (PCSM) was evaluated by stage after adjusting for grade, marital status, race, sex, year of diagnosis, and age. ResultsThe median follow-up was 10.5 years. Patients with cT1/T2 but pathologic T3a disease had significantly better 10-year PCSM than men with cT3 disease had (3.0% vs. 9.9%, adjusted hazard ratio [AHR] = 0.420, P<0.001), but they had worse PCSM than men with pathologic T2 disease had (3.0% vs. 0.91%, AHR = 2.53, P<0.001). Of patients with occult T3a disease, those with low-grade/intermediate-grade disease (Gleason score 7 or less) had a slightly higher 10-year PCSM when compared with those with pathologic T2 disease (1.34% vs. 0.91%, AHR = 1.69, P<0.001). Patients with cT1/T2 and pathologic T3b disease had similar PCSM as men presenting with cT3 disease (11.0% vs. 9.86%, AHR = 1.14 [0.862, 1.52], P = 0.353). ConclusionsPatients with occult T3a disease had less than half the risk of PCSM as those with cT3 disease, and a subset of those men had similar risk as patients with pathologic T2 disease. Therefore, it is possible that radiation-managed patients with low-grade/intermediate-grade T3a disease by magnetic resonance imaging only might not require long-term ADT. However, patients with occult T3b or high-grade occult T3a disease have similar PCSM as that of those presenting with cT3 disease, so they should be treated as aggressively, including long-course ADT when managed by radiation.

Androgen deprivation therapy and the risk of death from prostate cancer among men with favorable or unfavorable intermediate-risk disease.

Radiotherapy (RT), short-course androgen deprivation therapy (ADT), and brachytherapy in various combinations are treatment options for patients with intermediate-risk prostate cancer (PC), but the question of which combination if any is necessary to minimize PC-specific mortality (PCSM) risk in patients with favorable or unfavorable intermediate-risk PC is unknown. The authors assessed PCSM risk after commonly used treatments. The cohort consisted of 2510 men with favorable (1902 men; 75.78%) or unfavorable (608 men; 24.22%) intermediate-risk PC who were treated from 1997 to 2013. Treatment included brachytherapy with or without neoadjuvant ADT among men with favorable disease and brachytherapy with neoadjuvant RT or ADT among men with unfavorable disease. Fine and Gray's competing-risks regression model was used to assess whether ADT among men with favorable disease or RT or ADT among men with unfavorable disease decreased PCSM risk after adjusting for treatment propensity score, year of brachytherapy, and PC prognostic factors. After a median follow-up of 7.78 years, 366 deaths (14.58%) were observed, 29 of which (7.92%) were from PC. There was a significant reduction in PCSM risk in men with unfavorable disease who were treated with ADT versus RT (adjusted hazard ratio, 0.34; 95% confidence interval, 0.13-0.91 [P = .03]), but no significant difference in PCSM risk in men with favorable disease who received ADT and brachytherapy versus brachytherapy (adjusted hazard ratio, 0.67; 95% confidence interval, 0.18-2.57 [P =.56]). Neoadjuvant ADT does not appear to reduce PCSM risk in men undergoing brachytherapy for favorable intermediate-risk PC and should not be considered a standard; however, it appears superior to neoadjuvant RT in men with unfavorable intermediate-risk PC undergoing brachytherapy, making neoadjuvant ADT and brachytherapy a preferred option in these men.

5α-Reductase Inhibitors and the Risk of Cancer-Related Mortality in Men With Prostate Cancer.

5α-Reductase inhibitors (5-ARIs) are widely used in the treatment of benign prostatic hyperplasia. However, randomized clinical trials have raised concerns that their use may be associated with an increased risk of high-grade prostate cancer tumors that would ultimately lead to worse prostate cancer outcomes. To date, few observational studies have addressed this important safety concern. To determine whether the use of 5-ARIs before prostate cancer diagnosis is associated with an increased risk of cancer-specific and all-cause mortality in men with a new diagnosis of prostate cancer in the real-world setting. A retrospective cohort study was conducted in a cohort of 13,892 men with a new diagnosis of prostate cancer between January 1, 1999, and December 31, 2009, who were followed up until October 1, 2012. Patients were individually linked across 4 databases from the United Kingdom: National Cancer Data Repository, Clinical Practice Research Datalink, Hospital Episodes Statistics database, and Office for National Statistics database. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% CIs of prostate cancer-specific and all-cause mortality associated with prediagnostic use of 5-ARIs. For each outcome, 2 models were constructed, one adjusted for predefined covariates (conventional model) and another adjusted for high-dimensional propensity score (HD-PS) deciles. During a mean (SD) of 4.5 (3.1) years, 5001 deaths occurred, including 2429 from prostate cancer (crude incidence rate of 3.86 per 100 person-years [95% CI, 3.71-4.02]). In the conventional model, use of 5-ARIs before prostate cancer diagnosis was not associated with an increased risk of prostate cancer-specific mortality (crude incidence rates, 3.76 [95% CI, 3.04-4.59] [use] vs 3.87 [95% CI, 3.71-4.03] [nonuse] per 100 person-years; adjusted hazard ratio [aHR], 0.86 [95% CI, 0.69-1.06]) and all-cause mortality (crude incidence rates, 8.42 [95% CI, 7.32-9.64] [use] vs 7.93 [95% CI, 7.71-8.16] [nonuse] per 100 person-years; aHR, 0.87; 95% CI, 0.75-1.00). Similar results were observed with the HD-PS adjusted model (prostate cancer-specific mortality: aHR, 0.90 [95% CI, 0.73-1.13]; and all-cause mortality: aHR, 0.92 [95% CI, 0.80-1.07]). The use of 5-ARIs was not associated with an increased risk of prostate cancer-specific and all-cause mortality in men with a new diagnosis of prostate cancer. While these results provide reassurance, additional studies are needed to replicate these findings.

PD46-04 TREATMENT AND SURVIVAL IN MEN UNDER AGE 55 YEARS DIAGNOSED WITH GLEASON 8-10 PROSTATE CANCER: IMPLICATIONS OF PSA SCREENING

You have accessJournal of UrologyProstate Cancer: Detection and Screening V1 Apr 2015PD46-04 TREATMENT AND SURVIVAL IN MEN UNDER AGE 55 YEARS DIAGNOSED WITH GLEASON 8-10 PROSTATE CANCER: IMPLICATIONS OF PSA SCREENING Brian Winters, Sarah Holt, Daniel Lin, Michael Porter, Heather Cheng, and Jonathan Wright Brian WintersBrian Winters More articles by this author , Sarah HoltSarah Holt More articles by this author , Daniel LinDaniel Lin More articles by this author , Michael PorterMichael Porter More articles by this author , Heather ChengHeather Cheng More articles by this author , and Jonathan WrightJonathan Wright More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2735AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The USPTF recommended against PSA screening in 2012. Following that, the AUA released guidelines in 2013 recommending against routine screening for men ages 40-54 years. A subset of these young men will harbor aggressive prostate cancer (PCa) and are at high risk of PCa-specific mortality (PCSM). Failure to screen these men may lead to delay in diagnosis and loss of opportunity for curative treatment. Using a population-based registry, we examined the PCa treatment and survival experience of young men (age < 55 years) in the years leading up to these USPTF recommendations. METHODS The Surveillance, Epidemiologic, and End Results (SEER) database was queried for all patients diagnosed with PCa between 2004 and 2011 who underwent definitive locoregional therapy with either radical prostatectomy (RP) or radiation (external beam and/or brachytherapy (RT)). Cox-proportional hazards for risk of PCSM was performed adjusting for clinical factors (age, race, PSA, stage), and type of treatment (RP or RT). RESULTS 26,156 patients with Gleason 8-10 PCa treated with either RP or RT were identified with 2,256 (9%) men <55 years old. The majority of men were Caucasian (75%) and had a PSA >4 ng/ml (90%, 91%, and 92% of men aged < 55, 55-64, and 65-74 years, respectively). RP was performed in 69%, 62%, and 36% of men aged < 55, 55-64, and 65-74 years, respectively. PCSM was observed in 6% overall. Compared to men < 55 years old treated with RP, those aged ≥ 55 years old had a 50% increased risk of PCSM (HR 1.54, 95% CI 1.04-2.27) on multivariate analysis. Young men treated with RT had a more than 3 fold increased risk of PCSM compared to young men treated with RP (HR 3.38, 95% CI 2.22-5.15). In men ≥ 55 years old, there was an increased risk of PCSM with RT (compared to RP) but less pronounced than in younger men (HR 2.36, 95% 1.47-3.80). CONCLUSIONS In this cohort, the majority of men < 55 years of age with Gleason 8-10 PCa had a PSA > 4.0. As these men are at the highest risk for PCSM, failure to screen younger men may result in a missed opportunity for treatment with curative intent. The finding that younger men treated with XRT had worse PCSM compared to those treated with RP requires further evaluation. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e957 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Brian Winters More articles by this author Sarah Holt More articles by this author Daniel Lin More articles by this author Michael Porter More articles by this author Heather Cheng More articles by this author Jonathan Wright More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

PD47-03 EXPRESSION OF CYTOPLASMIC ERβ1 AND NUCLEAR ERβ2 IS ASSOCIATED WITH POOR OUTCOMES FOLLOWING RADICAL PROSTATECTOMY FOR LOCALIZED PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Localized VII1 Apr 2015PD47-03 EXPRESSION OF CYTOPLASMIC ERβ1 AND NUCLEAR ERβ2 IS ASSOCIATED WITH POOR OUTCOMES FOLLOWING RADICAL PROSTATECTOMY FOR LOCALIZED PROSTATE CANCER George R. Schade, Sarah K. Holt, Xiaotun Zhang, Jonathan L. Wright, Shan Shan Zhao, Suzanne Kolb, Hung-Ming Lam, Linda Levin, Yuet-Kin Leung, Shuk-Mei Ho, and Janet Stanford George R. SchadeGeorge R. Schade More articles by this author , Sarah K. HoltSarah K. Holt More articles by this author , Xiaotun ZhangXiaotun Zhang More articles by this author , Jonathan L. WrightJonathan L. Wright More articles by this author , Shan Shan ZhaoShan Shan Zhao More articles by this author , Suzanne KolbSuzanne Kolb More articles by this author , Hung-Ming LamHung-Ming Lam More articles by this author , Linda LevinLinda Levin More articles by this author , Yuet-Kin LeungYuet-Kin Leung More articles by this author , Shuk-Mei HoShuk-Mei Ho More articles by this author , and Janet StanfordJanet Stanford More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2747AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Data regarding the expression of estrogen receptors (ER) and prostate cancer (PCa) outcomes are limited. We evaluated the relationship of expression profiles of ERβ; isoforms and the membrane bound estrogen receptor GPR30 with patient factors and outcomes following radical prostatectomy (RP). METHODS Tissue microarrays constructed from 566 men who underwent RP for localized PCa were analyzed with immunohistochemistry targeting ERβ1, ERβ2, ERβ5 and GPR30. An experienced, blinded pathologist scored receptor distributions and staining intensities. Demographic and clinical data were evaluated with descriptive statistics. Correlations between PCa ERβ; isoform and GPR30 expression and clinicopathologic data were analyzed with χ2 tests. Cox proportional hazards models were used to examine associations between each ER's staining pattern and time to recurrence and prostate cancer-specific mortality (PCSM). Receptor sub-type staining patterns found to have a significant association with recurrence or PCSM were further analyzed using the Kaplan-Meier method. Significance was set at α <0.05, two-tailed test. RESULTS PCa cells had unique staining patterns with ERβ1 demonstrating predominantly nuclear localization, while ERβ2, ERβ5 and GPR30 were predominantly cytoplasmic. Median follow-up among was 10.5 years. After controlling for patient factors, increasing cytoplasmic ERβ1 (cERβ1) (HR 1.53, 95% CI 1.01-2.32, p=0.047) and nuclear ERβ2 (nERβ2) (HR 1.55, 95% CI 1.01-2.38, p=0.043) staining were associated with significantly worse 5-year recurrence-free survival (RFS). Increasing cERβ1 (HR 4.67, 95% CI 1.80 – 12.11, p=0.002) and nERβ2 (HR 2.49, 95% CI 1.08 – 5.80, p=0.033) expression were also associated with significantly increased risk of PCSM. Patients with cERβ1 and nERβ2 co-staining had significantly worse 15-year PCSM vs. patients expressing only cERβ1, only nERβ2, or neither (16.4% vs. 4.3% vs. 0.0% vs 2.0 %, respectively p=0.001) (Figure). CONCLUSIONS Increased cERβ1 and nERβ2 expression are associated with worse PCa-specific outcomes following RP. These findings suggest that evaluating tumor ERβ1 and ERβ2 staining patterns following RP may provide prognostic information © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e962 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information George R. Schade More articles by this author Sarah K. Holt More articles by this author Xiaotun Zhang More articles by this author Jonathan L. Wright More articles by this author Shan Shan Zhao More articles by this author Suzanne Kolb More articles by this author Hung-Ming Lam More articles by this author Linda Levin More articles by this author Yuet-Kin Leung More articles by this author Shuk-Mei Ho More articles by this author Janet Stanford More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

PD47-04 PATHOLOGICAL FEATURES OF THE INDEX AND NON-INDEX LESIONS IN RADICAL PROSTATECTOMY SPECIMENS: IMPLICATIONS FOR FOCAL THERAPY.

INTRODUCTION AND OBJECTIVES: Data regarding the expression of estrogen receptors (ER) and prostate cancer (PCa) outcomes are limited. We evaluated the relationship of expression profiles of ERb; isoforms and the membrane bound estrogen receptor GPR30 with patient factors and outcomes following radical prostatectomy (RP). METHODS: Tissue microarrays constructed from 566 men who underwent RP for localized PCa were analyzed with immunohistochemistry targeting ERb1, ERb2, ERb5 and GPR30. An experienced, blinded pathologist scored receptor distributions and staining intensities. Demographic and clinical data were evaluated with descriptive statistics. Correlations between PCa ERb; isoform and GPR30 expression and clinicopathologic data were analyzed with c2 tests. Cox proportional hazards models were used to examine associations between each ER’s staining pattern and time to recurrence and prostate cancer-specific mortality (PCSM). Receptor sub-type staining patterns found to have a significant association with recurrence or PCSM were further analyzed using the Kaplan-Meier method. Significance was set at a <0.05, two-tailed test. RESULTS: PCa cells had unique staining patterns with ERb1 demonstrating predominantly nuclear localization, while ERb2, ERb5 and GPR30 were predominantly cytoplasmic. Median follow-up among was 10.5 years. After controlling for patient factors, increasing cytoplasmic ERb1 (cERb1) (HR 1.53, 95% CI 1.01-2.32, p1⁄40.047) and nuclear ERb2 (nERb2) (HR 1.55, 95% CI 1.01-2.38, p1⁄40.043) staining were associated with significantly worse 5-year recurrence-free survival (RFS). Increasing cERb1 (HR 4.67, 95% CI 1.80 e 12.11, p1⁄40.002) and nERb2 (HR 2.49, 95% CI 1.08 e 5.80, p1⁄40.033) expression were also associated with significantly increased risk of PCSM. Patients with cERb1 and nERb2 co-staining had significantly worse 15-year PCSM vs. patients expressing only cERb1, only nERb2, or neither (16.4% vs. 4.3% vs. 0.0% vs 2.0 %, respectively p1⁄40.001) (Figure). CONCLUSIONS: Increased cERb1 and nERb2 expression are associated with worse PCa-specific outcomes following RP. These findings suggest that evaluating tumor ERb1 and ERb2 staining patterns following RP may provide prognostic information Source of Funding: R01-CA056678, R01-CA092579, R03CA137799, and P50-CA097186

Age, Comorbidity, and the Risk of Prostate Cancer-Specific Mortality in Men With Biopsy Gleason Score 4+3: Implications on Patient Selection for Multiparametric MRI

BackgroundSome men with biopsy Gleason score (GS) 7 prostate cancer (PC) harbor occult GS 8 to 10 PC and might be undertreated with short-term androgen deprivation therapy (ADT) and radiation therapy (RT). With advancing age associated with occult high-grade PC, we evaluated PC-specific mortality (PCSM) risk after RT and short-term ADT for older men with GS 4+3 PC and men of any age with GS 8 to 10 PC. Patients and MethodsThe study cohort comprised 206 men with unfavorable-risk PC treated with RT or RT and 6 months of ADT on a randomized trial between 1995 and 2001. Competing risks regression was used to compare PCSM risk for men with GS 8 to 10 PC to men with GS ≤ 3+4, GS 4+3 and age ≤ 73 years (median age), and GS 4+3 and age > 73 years, adjusting for PC risk factors, comorbidity, and treatment. ResultsAfter a median follow-up of 14.3 years, 135 men died (65.53%), 24 (17.78%) of PC. Men age > 73 years with GS 4+3 PC did not have significantly lower PCSM risk compared with men with GS 8 to 10 (adjusted hazard ratio [AHR], 1.08; 95% confidence interval [CI], 0.29-4.06; P = .91); whereas unhealthy men (AHR, 0.20; 95% CI, 0.04-0.93; P = .04) and men age ≤ 73 years with GS 4+3 (AHR, 0.09; 95% CI, 0.01-1.03; P = .05) fared better. ConclusionMen age > 73 years with biopsy GS 4+3 did not have a significant difference in PCSM risk than men with GS 8 to 10, supporting further study of multiparametric magnetic resonance imaging in such men with no or minimal comorbidity before determining ADT duration.

Short-course hormonal therapy and the risk of death from prostate cancer in men with intermediate-risk prostate cancer undergoing high-dose radiation therapy.

27 Background: We assessed the risk of prostate cancer-specific mortality (PCSM) in men with unfavorable and favorable intermediate-risk prostate cancer (PC) who received dose-escalated radiotherapy (RT) with or without short-course androgen deprivation therapy (ADT). Methods: The cohort consisted of 2,668 men with intermediate-risk PC (71.3% favorable, 28.7% unfavorable) who were treated with dose-escalated RT with or without ADT (median 4 mos.) from 1997 - 2013. Fine and Gray's competing risks regression was used to assess whether ADT decreased PCSM-risk in an adjusted multivariable model (Table). An interaction term was included to assess for potential differences in the impact of ADT on PCSM risk in men with favorable versus unfavorable intermediate-risk PC. Results: After a median follow-up of 7.84 years, there were 393 deaths (14.73%), of which 33 were from PC (8.40%). There was significant reduction in PCSM-risk in men with unfavorable intermediate-risk PC who received ADT (AHR 0.39, 95% CI 0.16 to 0.92, P=0.033), but no significant difference in PCSM-risk in men with favorable intermediate-risk PC who received ADT (AHR 0.68, 95% CI 0.19 to 2.49, P=0.561). Conclusions: While ADT reduced PCSM-risk in men with unfavorable intermediate-risk PC, there was no significant improvement in men with favorable intermediate-risk PC, suggesting that for these patients ADT in addition to dose-escalated RT may not be required to minimize PCSM-risk. [Table: see text]

Are men with favorable intermediate-risk prostate cancer candidates for active surveillance?

82 Background: Active surveillance (AS) is considered appropriate for patients with low-risk prostate cancer (PC) and a life expectancy of at least 10 years. However, with grade migration following the 2005 International Society of Urologic Pathology consensus conference, AS may also be an initial option for men with favorable intermediate-risk PC. We estimated and compared the risk of PC-specific mortality (PCSM) following high dose radiation therapy and androgen deprivation therapy as appropriate amongst men with low, favorable intermediate, unfavorable intermediate, and high-risk PC. Methods: The study consisted of 6,595 consecutively treated men (median age: 68 years) with localized or locally advanced PC at the Chicago PC Center between 1997 and 2013. Fine and Gray competing risks regression analyses (table) were used to assess the risk of PCSM in men with favorable intermediate, unfavorable intermediate or high-risk compared to low-risk PC, adjusting for age at and year of treatment. Results: After median follow-up of 7.76 years, 820 men died: 72 of PC. While men with favorable intermediate-risk did not have significantly increased risk of PCSM as compared to low-risk PC (adjusted hazard ratio (HR) 1.28, 0.63-2.62 95% confidence interval (CI), p-value 0.49), men with high (adjusted HR 9.91, 5.48-17.94 95% CI, p-value &lt;0.0001) or unfavorable intermediate-risk PC (adjusted HR 3.17, 1.60-6.30, p-value 0.001) did. Eight-year point estimates of PCSM were low: 0.68% [0.32-1.31% 95% CI] and 0.44% [0.25-0.75% 95% CI] for men with favorable intermediate and low-risk PC, respectively. Conclusions: Men with low and favorable intermediate-risk PC have similar and low estimates of PCSM during the first decade following standard management. These results provide evidence to support AS as an initial approach for men with favorable intermediate-risk PC. [Table: see text]