Incidence Of Prostate Cancer-specific Mortality Research Articles

Association between health-care system and prostate cancer mortality for African American men with localized and metastatic prostate cancer.

27 Background: African American (AA) men with prostate cancer (PC) present with more advanced disease and have worse survival than comparable non-Hispanic White (White) men. Recent studies suggest that receiving care within an equal access setting may attenuate these disparities. We hypothesize that AA men receiving care within the Veterans Health Administration (VHA) will have improved outcomes compared to AA men receiving care in the general population as assessed by the Surveillance, Epidemiology, and End Results (SEER) database. Methods: We identified AA men diagnosed with PC between 2004 and 2015 in the VHA and SEER. For comparisons of covariate distributions across subgroups, we used the chi-squared test with continuity correction. We analyzed the cumulative incidence (with 95% confidence intervals (CIs)) of PC specific mortality (PCSM) in the VHA and SEER. Additionally, multivariable Cox proportional hazards models controlling for demographic information were performed. Results: The cohort included 85,409 AA men (VHA: 27,415, SEER: 57,994). Median follow-up was 4.79 years in the VHA and 5.16 years in SEER. In the VHA, AA men were more likely to present with localized disease (VHA 94.7% vs SEER 86.4%, p < 0.001) and less likely to have metastatic disease (3.2% vs 4.3%, p < 0.001). The 5-year cumulative incidence of PCSM was lower for patients in the VHA (VHA: 3.8% [CI: 3.5-4.1%] vs. SEER: 5.0% [CI: 4.8-5.2%], p < 0.001). The PCSM difference was largest in men with metastatic disease. In metastatic patients, cumulative incidence of PCSM at five years was significantly lower in the VHA (VHA 52.5% [CI: 48.0-56.5%] vs. SEER 64.8% [CI: 62.3-67.1%], p < 0.001). In contrast, AA men with localized disease had similar PCSM in the VHA and SEER (VHA 2.4% [CI: 2.2-2.6%] vs. SEER 2.6% [CI: 2.4-2.7%], p = 0.09 at five years). On multivariable analysis, VHA system was associated with lower PCSM [Hazard Ratio (HR): 0.91, p < 0.001]. There was a significant interaction between VHA system and distant metastases at diagnosis [p < 0.001] indicating larger differences in PCSM by healthcare system in metastatic patients as compared to localized patients. VHA system was associated with reduced PCSM in metastatic patients [HR 0.84, p < 0.001] but not in localized patients [HR 0.96, p = 0.13]. Conclusions: AA men in the VHA had a significantly lower incidence of PCSM than those in the SEER database, especially for those who presented with distant metastases at diagnosis. Future work should examine how cost and access to care affect disparities in outcomes for AA men.

Dose Escalation for Prostate Adenocarcinoma: A Long-Term Update on the Outcomes of a Phase 3, Single Institution Randomized Clinical Trial

To determine the long-term outcomes for prostate adenocarcinoma when escalating radiation dose from 70Gy to 78Gy. Between 1993 and 1998, 301 patients with biopsy-proven clinical stage T1b-T3 prostate adenocarcinoma, any prostate-specific antigen level, and any Gleason score were randomized to 70Gy in 35 fractions versus 78Gy in 39 fractions of photon radiation therapy using a 4-field box technique without hormone deprivation therapy. The primary outcome was powered to detect a 15% difference in biochemical or clinical failure. Secondary outcomes included survival, prostate cancer mortality, biochemical failure, local failure, nodal failure, distant failure, and secondary malignancy rates. With a median follow-up of 14.3years, the cumulative incidence of 15-year biochemical or clinical failure was 18.9% versus 12.0% in the 70Gy versus 78Gy arms, respectively (subhazard ratio [sHR], 0.61; 95% confidence interval [CI], 0.38-0.98; Fine-Gray P=.042). The 15-year cumulative incidence of distant metastasis was 3.4% versus 1.1%, respectively (sHR, 0.33; 95% CI, 0.13-0.82; Fine-Gray P=.018). The 15-year cumulative incidence of prostate cancer-specific mortality was 6.2% versus 3.2%, respectively, (sHR, 0.52; 95% CI, 0.27-0.98; Fine-Gray P=.045). There were no differences in overall survival (HR, 1.10; 95% CI, 0.84-1.45; log rank P=.469) or other-cause survival (sHR, 1.33; 95% CI, 0.99-1.79; Fine-Gray P=.061). Salvage therapy was more common in the 70Gy arm, at 38.7% versus 21.9% in the 78Gy arm (P=.002). There was a 2.3% secondary solid malignancy rate (1 bladder, 6 rectal) within the radiation treatment field, which was not significantly different between treatment arms. Dose escalation by 8Gy (78Gy vs 70Gy) provided a sustained improvement in biochemical and clinical failure, which translated into lower salvage rates and improved prostate cancer-specific mortality, but not overall survival. Long-term follow-up demonstrated a low incidence of potential solid tumor secondary malignancies.

Which patients with localized prostate cancer account for the greatest proportion of prostate cancer deaths?

130 Background: We sought to determine which groups of patients, stratified by risk group and age, account for the greatest absolute number of deaths due to prostate cancer. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 437,150 men diagnosed with prostate cancer from 2004 to 2014. Men were excluded if they had N1 or M1 disease, risk group could not be determined, or if prostate cancer was not their first malignancy. Men were categorized as having low (Gleason ≤6, prostate-specific antigen [PSA] < 10 ng/mL, and cT1-T2a), intermediate (Gleason 7, PSA 10-20 ng/mL, or cT2b-T2c), or high risk disease (Gleason 8-10, PSA > 20 ng/mL, or cT3-T4). We calculated the cumulative incidence of prostate cancer-specific mortality (PCSM). Results: Median follow-up was 4.8 years. The overall incidences of diagnosis of low, intermediate, and high risk disease were 29.7% (n = 129,925), 48.0% (n = 209,643), and 22.3% (n = 97,582), respectively. 5-year PCSM for men with low, intermediate, and high risk disease was 0.5%, 1.4%, and 9.4%, respectively, and the 10-year PCSM was 1.6%, 4.0%, and 16.8%. Within 10 years of diagnosis, 6.5% (n = 905) of patients who died of prostate cancer were low risk, 27.4% (n = 3,834) were intermediate risk, and 66.2% (n = 9,278) were high risk. In particular, patients age 70 or older accounted for 49.9% of all high risk prostate cancer diagnoses, but 65.3% of deaths due to high risk prostate cancer. Conclusions: While high risk disease accounted for only 22.3% of the diagnoses, it accounted for 66.2% of the prostate cancer deaths within 10 years of diagnosis. Therefore, high risk patients account for the vast majority of prostate cancer deaths and should remain the focus of the majority of our research efforts. In addition, older patients with high risk disease die of prostate cancer at a disproportionately high rate, which runs counter to the notion that the disease is less of a threat to survival in older men.

Impact of percent positive biopsy cores on cancer-specific mortality for patients with high-risk prostate cancer.

78 Background: A high percent positive biopsy cores (PBC), typically dichotomized at ≥50%, is prognostic of worse cancer-specific outcomes for patients with low- and intermediate-risk prostate cancer. The prognostic value of ≥50% PBC for patients with high-risk disease is poorly understood. We examined the association between ≥50% PBC and prostate cancer-specific mortality (PCSM) for patients with high-risk prostate cancer. Methods: We identified 7,569 men from the Surveillance, Epidemiology, and End Results program who were diagnosed with high-risk prostate cancer (Gleason 8-10, prostate-specific antigen > 20 ng/mL, or cT3-T4 stage without evidence of nodal or metastatic disease) in 2010 or 2011 and had 6-24 cores sampled at biopsy. Multivariable Fine and Gray competing risks regression was utilized to examine the association between ≥50% PBC and PCSM, with adjustments for sociodemographic and clinicopathologic factors. Results: Median follow-up was 3.8 years (interquartile range 3.3-4.3 years). 56.2% of patients (4,253) had ≥50% PBC. The 4-year unadjusted cumulative incidences of PCSM were 2.0% (95% confidence interval [CI] 1.5-2.6%) and 5.6% (95% CI 4.9-6.4%) for patients with < 50% and ≥50% PBC, respectively. On multivariable analysis, the presence of ≥50% PBC was associated with a significantly higher risk of PCSM (adjusted hazard ratio [AHR] 1.95, 95% CI 1.43-2.66, P< 0.001). On subgroup analysis, ≥50% PBC was associated with a significantly higher risk of PCSM only for cT1-T2 disease (AHR 2.21, 95% CI 1.59-3.07, P< 0.001) but not cT3-T4 disease (AHR 0.77, 95% CI 0.33-1.81, P= 0.547), with a significant interaction ( Pinteraction= 0.012). Conclusions: In this large, contemporary cohort of patients with high-risk prostate cancer, ≥50% PBC was independently associated with a two-fold increased risk of PCSM for patients with cT1-T2, but not cT3-T4, tumors. Percent PBC should be used to routinely risk stratify men with high-risk disease and identify patients who may benefit from intensification of therapy, such as adding docetaxel or abiraterone to radiotherapy with androgen deprivation therapy, to optimize cancer-specific outcomes.

Extremely Dose Escalated Radiation Therapy Improves Cancer-Specific Survival Compared With Radical Prostatectomy or Conventionally Dose-Escalated Radiation Therapy in Gleason Score 9-10 Prostate Adenocarcinoma: A Multi-institutional Analysis of 1403 Patie

Purpose/Objective(s): To compare the outcomes of a modern cohort of patients with Gleason Score (GS) 9-10 prostate adenocarcinoma (PCa) following treatment with external beam radiotherapy (EBRT), extremely dose-escalated radiotherapy (exemplified by EBRT with a brachytherapy boost [EBRT+BT]), and radical prostatectomy (RP). Materials/Methods: One thousand four hundred three patients with biopsy GS 9-10 PCa who received definitive treatment between 2000 and 2013 were included (506 treated with EBRT, 392 with EBRT+BT, and 505 with RP). Distant metastasis-free survival (DMFS) and prostate cancer-specific mortality (PCSM) were compared across the three cohorts with four cause-specific Cox regression models: (a) unadjusted, (b) covariate-adjusted for age, ln(iPSA), cT stage, and GS, (c) propensity score adjusted for the same covariates, and (d) in a doubly robust analysis (i.e., propensity score and covariate adjusted). Four analogous Fine and Gray competing risk models were developed to compare cumulative PCSM incidence. Results: The median follow-up period was 5.1 years (5.1, 6.4, and 4.3 years in the EBRT, EBRT + BT, and RP cohorts, respectively). The median doses among EBRT and EBRT+BT patients were isoeffective to 81 Gy and 96 Gy in 1.8 Gy fractions, respectively. Over 90% of patients treated with EBRT or EBRT+BT received ADT (median durations of 23 months and 12 months, respectively). Nearly 40% of RP patients received postoperative RT; 78% of postoperative RT was delivered in the salvage setting. PCSM was significantly lower among EBRT+BT patients than among either EBRT or RP patients in all cause-specific hazard models and Fine and Gray competing risk models, including unadjusted models (P<0.05 in unadjusted models and P<0.01 in all other models). PCSM was not significantly different between EBRT and RP patients in any model. DMFS was also significantly higher among patients treated with EBRT+BT in all cause-specific hazard models. In all adjusted models, DMFS was significantly superior among EBRT patients than RP patients (P<0.05). Five- and 10-year cumulative incidences of PCSM were 3% and 12% with EBRT+BT, 10% and 20% with EBRT, and 9% and 19% with RP, respectively (P<0.001). Overall survival was not significantly different between cohorts. Conclusion: In this multi-institutional consortium comprising over 1400 patients with GS 9-10 PCa, extremely dose-escalated radiotherapy offered improved systemic control and reduced PCSM when compared with either EBRT or RP in multiple models. Notably, this was achieved despite a significantly shorter median duration of ADT than in the EBRT cohort. This is hypothesis generating and suggests that improved local control via dose-escalation may have systemic control and survival implications even for patients with very high risk disease.

External Beam Radiation Therapy With a Brachytherapy Boost Versus Radical Prostatectomy in Gleason Pattern 5 Prostate Cancer: A Population-Based Cohort Study

Patients with prostate cancer (PCa) containing Gleason pattern (GP) 5 disease experience a greater and earlier incidence of prostate cancer-specific mortality (PCSM) than general PCa patients. This affords the statistical power to compare PCSM outcomes among different treatment modalities even when restricting the analysis to patients treated in the modern era. The purpose of the present study was to compare the survival outcomes among patients with GP 5 PCa on needle core biopsy or transurethral resection of the prostate who underwent extremely dose-escalated radiation therapy (RT; exemplified by external beam RT with a brachytherapy boost [EBRT+BT]) versus radical prostatectomy (RP) in the modern era. A total of 7669 men with a diagnosis of GP 5 PCa from 2004 to 2013 who had undergone EBRT+BT or RP were identified using the Surveillance, Epidemiology, and End Results database. After propensity score matching to balance the patient characteristics, PCSM was compared between modalities using a multivariate Fine and Gray competing risk model that accounted for other-cause mortality, with adjustment for age, race, GP, and clinical T stage. Patients treated with RP were younger and had a lower burden of GP 5, lower T stage, and lower other-cause mortality than patients who underwent EBRT+BT. After propensity score matching, no difference was found in PCSM between the RP and EBRT+BT groups (adjusted hazard ratio 1.018; P=.910). The cumulative 5-year PCSM incidence rates were 5.6% and 6.1% for patients undergoing RP and EBRT+BT, respectively. Patients with primary GP 5 experienced significantly greater PCSM than those with secondary GP 5, regardless of the treatment modality. For patients with GP 5 PCa found on needle core biopsy or transurethral resection of the prostate, RP and EBRT+BT offer equivalent PCSM in a competing risk model after propensity score matching to balance the differences in patient characteristics.

Abstract PR04: Ethnic heterogeneity and prostate cancer mortality in Hispanic/Latino men

Abstract Purpose: Few studies have focused on the rapidly growing and extremely diverse Hispanic/Latino population in regards to prostate cancer outcomes. Our study explores whether heterogeneity between Hispanic/Latino men of diverse ancestry potentially contributes to unexplored disparities in five-year prostate cancer-specific mortality and all-cause mortality. Patients and Methods: From the Surveillance, Epidemiology, and End Results program (SEER), we designed a population-based cohort of men diagnosed with local-regional prostate cancer (n= 432,356) from 2000-2012. Five-year cumulative incidence of prostate cancer-specific mortality was obtained using competing risks analysis and all-cause mortality was determined by using one minus the Kaplan-Meier survival estimate of overall survival. This was examined for different racial and/or ethnic groups: Non-Hispanic White (n= 313,514), Non-Hispanic Black (n= 62,346), Hispanic/Latino (n= 36,407), and Asian American/Pacific Islander (n= 20,089). We also measured prostate cancer-specific and all-cause mortalities in Hispanic/Latino subgroups: Mexican (n= 7,273), Puerto Rican (n= 1,174), South or Central American (n= 2,666), Cuban (n= 747), and Dominican (n= 292). Results: In all racial/ethnic groups, five-year cumulative incidence rates were highest for Non-Hispanic Black men at 15.96% (95% CI: 15.6 - 16.3) and were lowest in Hispanic/Latino men at 13.08% (95% CI: 12.6 - 13.5) and Asian American/Pacific Islander men at 13.33% (95% CI: 12.7 - 13.9). Within ethnic subgroups, Puerto Rican men at 22.06% (95% CI: 19.4 - 25.1) and Cuban men 20.91% (95% CI: 17.8 - 24.5) showed significantly higher five-year all-cause mortality than all other groups. Mexican men showed the third highest rate of all groups with 16.47% (95% CI: 15.4 - 17.6). For five-year prostate cancer-specific mortality, both Non-Hispanic Black and Hispanic/Latino men showed similar rates that were higher than other racial/ethnic groups with 3.39% (95% CI: 3.22 - 3.57) and 3.29% (95% CI: 3.07 - 3.52), respectively. For ethnic subgroups, Puerto Rican men at 5.26% (95% CI: 3.88 - 6.92) and Mexican men at 4.77% (95% CI: 4.19 - 5.40) showed significantly higher five-year prostate cancer-specific mortality than all other groups. Cuban and Dominican men showed high rates of both five-year all-cause and prostate cancer-specific mortality, but without significance. Conclusions: Our findings indicate previously unknown disparities in five-year prostate cancer-specific mortality in Mexican and Puerto Rican men. We also note the increased all-cause mortality within Puerto Rican men diagnosed with prostate cancer, of which may be influenced by comorbid disease. These findings should be further explored and considered in screening and management guidelines. Citation Format: Felix M. Chinea, Vivek N. Patel, Deukwoo Kwon, Chris J. Lopez, Narottam Lamichhane, Sanoj Punnen, Erin Kobetz, Matthew C. Abramowitz, Alan Pollack. Ethnic heterogeneity and prostate cancer mortality in Hispanic/Latino men. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr PR04.

Brachytherapy improves outcomes in young men (≤60 years) with prostate cancer: A SEER analysis

PurposeThe aim of the study was to compare prostate cancer–specific mortality (PCSM) in young men with clinically localized prostate cancer treated by either external beam radiation (EBRT) alone or brachytherapy with or without external beam radiation. Methods and MaterialsUtilizing the Surveillance, Epidemiology and End Results database, 15,505 patients ≤60 years of age diagnosed with prostate cancer between 2004 and 2009 and treated with radiation therapy alone were identified. Incidence of PCSM was determined for both groups and compared using competing risk models. ResultsThe overall 8-year PCSM for the study population was 1.9% (95% confidence interval [CI]: 1.6–2.2). For patients treated with EBRT or brachytherapy with or without external beam, the 8-year PCSM was found to be 2.8% (CI: 2.2–3.4) and 1.2% (CI: 0.9–1.6), respectively (p < 0.001). Univariable analysis demonstrated that brachytherapy was associated with lower PCSM risk (hazard ratio = 0.40; CI: 0.30–0.54; p < 0.001). High Gleason risk category, black race, higher Tumor (T) stage, and higher grade were all associated with greater mortality risk (p < 0.01). On multivariable analysis, brachytherapy continued to be associated with a significantly lower mortality risk (hazard ratio = 0.65; CI: 0.47–0.89; p = 0.008). Subgroup analyses found that among those with Gleason score ≥8, younger patients had increased risk of PCSM (p = 0.001). ConclusionsIn men ≤60 years of age with prostate cancer, radiation therapy continues to offer excellent outcomes. After adjusting for relevant variables, the use of brachytherapy was associated with reduced PCSM compared to treatment with EBRT alone.

Risk of prostate cancer diagnosis and mortality in men with a benign initial transrectal ultrasound-guided biopsy set: a population-based study

The risk of missing prostate cancer in the transrectal ultrasound-guided systematic biopsies of the prostate in men with suspected prostate cancer is a key problem in urological oncology. Repeat biopsy or MRI-guided biopsies have been suggested to increase sensitivity for diagnosis of prostate cancer, but the risk of disease-specific mortality in men who present with raised prostate-specific antigen (PSA) concentration and a benign initial biopsy result remains unknown. We investigated the risk of overall and prostate cancer-specific mortality in men with a benign initial biopsy set. Data were extracted from the Danish Prostate Cancer Registry-a population-based registry including all men undergoing histopathological assessment of prostate tissue. All men who were referred for transrectal ultrasound-guided biopsy for assessment of suspected prostate cancer between Jan 1, 1995, and Dec 31, 2011, in Denmark were eligible for inclusion. Follow-up data were obtained on April 28, 2015. The primary endpoint was the cumulative incidence of prostate cancer-specific mortality, analysed in a competing risk setting, with death from other causes as the competing event. Between Jan 1, 1995, and Dec 31, 2011, 64 430 men were referred for transrectal ultrasound-guided biopsy, of whom 63 454 were eligible for inclusion. Median follow-up was 5·9 years (IQR 3·8-8·5) and the total follow-up time, from the enrolment of the first patient on Jan 1, 1995, until the extraction of causes of death on April 28, 2015, was 20 years. 10 407 (30%) of 35 159 men with malignant initial biopsy sets died from prostate cancer, compared with 541 (2%) of 27 181 men with benign initial biopsy sets. Estimated overall 20-year mortality was 76·1% (95% CI 73·0-79·2). In all men referred for transrectal ultrasound-guided biopsy, the cumulative incidence of prostate cancer-specific mortality after 20 years was 25·6% (24·7-26·5) versus 50·5% (47·5-53·5) for mortality from other causes. In men with benign initial biopsy sets, the cumulative incidence of prostate cancer-specific mortality was 5·2% (3·9-6·5) versus 59·9% (55·2-64·6) for mortality from other causes. In men with PSA concentrations 10 μg/L or lower and benign initial biopsy sets (2779 men), the cumulative incidence of prostate cancer-specific mortality was 0·7% (0·2-1·3). Cumulative incidence of prostate cancer specific mortality in men with benign initial biopsy sets was 3·6% (95% CI 0·1-7·2) for men with a PSA higher than 10 ng/mL but 20 ng/mL or less (855 men) and 17·6% (12·7-22·4) and for men with a PSA higher than 20 ng/mL (454 men). The first systematic transrectal ultrasound-guided biopsy set holds important prognostic information. The 20-year risk of prostate cancer-specific mortality in men with benign initial results is low. Our findings question whether men with low PSA concentration and a benign initial biopsy set should undergo further diagnostic assessment in view of the high risk of mortality from other causes. Capital Region of Denmark's Fund for Health Research, Danish Cancer Society, Danish Association for Cancer Research, and Krista and Viggo Petersen's Foundation.

Radical prostatectomy in Denmark: Survival analysis and temporal trends in clinicopathological parameters with up to 20 years of follow-up

ObjectivesTo describe mortality, cause of death, and temporal trends in clinicopathological parameters with up to 20 years of follow-up in a nationwide cohort of prostate cancer (PCa) patients who underwent radical prostatectomy (RP). Materials and methodsA total of 6857 patients with PCa treated with RP at six different hospitals in Denmark between 1995 and 2011. Data were extracted from the nationwide DaPCa database. Histopathology reports from the RP specimens were manually reviewed. Date and cause of death were obtained from national registries and cross-checked in patient files.The cumulative incidence of PCa specific mortality (PCSM) was analysed with the Aalen-Johansen method for competing risks with non-PCa death as a competing event. Risk of PCSM was analysed in a multivariate Cox regression model using age, preoperative PSA level, surgical margin status, RP Gleason score (GS), pathological T-category, and N-category as explanatory variables. ResultsThe median follow-up was 6.4 years. Significant temporal changes in clinicopathological parameters were observed. During the study period, median age at surgery increased from 61.4 to 64.8 years and median preoperative PSA declined from 12.0 to 8.0 ng/ml. The proportion of men with pT2 PCa increased from 65% to 75% whereas the proportion of pT3 cancers decreased from 28% to 25%. The percentage of men with positive surgical margins decreased from 37% to 20%. During follow-up, 644 patients died, whereof 189 (29.3%) died from PCa. The cumulative incidence of PCSM and other-cause mortality after 15 years was 10.3% (95% CI 8.0–12.7) and 18.2% (95% CI 15.4–20.9), respectively. In a multivariate analysis, RP GS (P ≤ 0.001) and pT-category (P ≤ 0.001) were significantly associated with the risk of PCSM. Compared with GS ≤6, both GS +4 (HR 1.47), GS 4 + 3 (HR 2.32), GS 8 (HR 4.8) and GS 9 or 10 (HR 5.26) significantly increased the risk of PCa death. T3a PCa and T3b/T4 was also a significant predictor of PCSM with an increased risk of PCa death compared with pT2 of 2.24 and 4.5, respectively. ConclusionsIn a complete national cohort of men treated with RP during a 17-year period, we described the incidence of mortality after RP and predictors of PCSM. We demonstrated that RP GS and pT-category are the most significant predictors of PCa mortality. We found that an increasing proportion of men undergo RP for low-risk PCa suggesting that early detection of PCa is indeed undergoing in Denmark despite national recommendations. The Danish national results seem to concur with findings from international single- and multi-institutional reports.

Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): an open-label, randomised, phase 3 factorial trial

We investigated whether 18 months of androgen suppression plus radiotherapy, with or without 18 months of zoledronic acid, is more effective than 6 months of neoadjuvant androgen suppression plus radiotherapy with or without zoledronic acid. We did an open-label, randomised, 2 × 2 factorial trial in men with locally advanced prostate cancer (either T2a N0 M0 prostatic adenocarcinomas with prostate-specific antigen [PSA] ≥10 μg/L and a Gleason score of ≥7, or T2b-4 N0 M0 tumours regardless of PSA and Gleason score). We randomly allocated patients by computer-generated minimisation--stratified by centre, baseline PSA, tumour stage, Gleason score, and use of a brachytherapy boost--to one of four groups in a 1:1:1:1 ratio. Patients in the control group were treated with neoadjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly) for 6 months (short-term) and radiotherapy alone (designated STAS); this procedure was either followed by another 12 months of androgen suppression with leuprorelin (intermediate-term; ITAS) or accompanied by 18 months of zoledronic acid (4 mg every 3 months for 18 months, intravenously; STAS plus zoledronic acid) or by both (ITAS plus zoledronic acid). The primary endpoint was prostate cancer-specific mortality. This analysis represents the first, preplanned assessment of oncological endpoints, 5 years after treatment. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00193856. Between Oct 20, 2003, and Aug 15, 2007, 1071 men were randomly assigned to STAS (n=268), STAS plus zoledronic acid (n=268), ITAS (n=268), and ITAS plus zoledronic acid (n=267). Median follow-up was 7·4 years (IQR 6·5-8·4). Cumulative incidences of prostate cancer-specific mortality were 4·1% (95% CI 2·2-7·0) in the STAS group, 7·8% (4·9-11·5) in the STAS plus zoledronic acid group, 7·4% (4·6-11·0) in the ITAS group, and 4·3% (2·3-7·3) in the ITAS plus zoledronic acid group. Cumulative incidence of all-cause mortality was 17·0% (13·0-22·1), 18·9% (14·6-24·2), 19·4% (15·0-24·7), and 13·9% (10·3-18·8), respectively. Neither prostate cancer-specific mortality nor all-cause mortality differed between control and experimental groups. Cumulative incidence of PSA progression was 34·2% (28·6-39·9) in the STAS group, 39·6% (33·6-45·5) in the STAS plus zoledronic acid group, 29·2% (23·8-34·8) in the ITAS group, and 26·0% (20·8-31·4) in the ITAS plus zoledronic acid group. Compared with STAS, no difference was noted in PSA progression with ITAS or STAS plus zoledronic acid; however, ITAS plus zoledronic acid reduced PSA progression (sub-hazard ratio [SHR] 0·71, 95% CI 0·53-0·95; p=0·021). Cumulative incidence of local progression was 4·1% (2·2-7·0) in the STAS group, 6·1% (3·7-9·5) in the STAS plus zoledronic acid group, 1·5% (0·5-3·7) in the ITAS group, and 3·4% (1·7-6·1) in the ITAS plus zoledronic acid group; no differences were noted between groups. Cumulative incidences of bone progression were 7·5% (4·8-11·1), 14·6% (10·6-19·2), 8·4% (5·5-12·2), and 7·6% (4·8-11·2), respectively. Compared with STAS, STAS plus zoledronic acid increased the risk of bone progression (SHR 1·90, 95% CI 1·14-3·17; p=0·012), but no differences were noted with the other two groups. Cumulative incidence of distant progression was 14·7% (10·7-19·2) in the STAS group, 17·3% (13·0-22·1) in the STAS plus zoledronic acid group, 14·2% (10·3-18·7) in the ITAS group, and 11·1% (7·6-15·2) in the ITAS plus zoledronic acid group; no differences were recorded between groups. Cumulative incidence of secondary therapeutic intervention was 25·6% (20·5-30·9), 28·9% (23·5-34·5), 20·7% (16·1-25·9), and 15·3% (11·3-20·0), respectively. Compared with STAS, ITAS plus zoledronic acid reduced the need for secondary therapeutic intervention (SHR 0·67, 95% CI 0·48-0·95; p=0·024); no differences were noted with the other two groups. An interaction between trial factors was recorded for Gleason score; therefore, we did pairwise comparisons between all groups. Post-hoc analyses suggested that the reductions in PSA progression and decreased need for secondary therapeutic intervention with ITAS plus zoledronic acid were restricted to tumours with a Gleason score of 8-10, and that ITAS was better than STAS in tumours with a Gleason score of 7 or lower. Long-term morbidity and quality-of-life scores were not affected adversely by 18 months of androgen suppression or zoledronic acid. Compared with STAS, ITAS plus zoledronic acid was more effective for treatment of prostate cancers with a Gleason score of 8-10, and ITAS alone was effective for tumours with a Gleason score of 7 or lower. Nevertheless, these findings are based on secondary endpoint data and post-hoc analyses and must be regarded cautiously. Long- term follow-up is necessary, as is external validation of the interaction between zoledronic acid and Gleason score. STAS plus zoledronic acid can be ruled out as a potential therapeutic option. National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, Abbott Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, University of Newcastle (Australia), Calvary Health Care (Calvary Mater Newcastle Radiation Oncology Fund), Hunter Medical Research Institute, Maitland Cancer Appeal, Cancer Standards Institute New Zealand.

Causes of Mortality After Dose-Escalated Radiation Therapy and Androgen Deprivation for High-Risk Prostate Cancer

Men with high-risk prostate cancer have other competing causes of mortality; however, current risk stratification schema do not account for comorbidities. We aim to identify the causes of death and factors predictive for mortality in this population. A total of 660 patients with high-risk prostate cancer were treated with definitive high-dose external beam radiation therapy (≥ 74 Gy) and androgen deprivation (AD) between 1996 and 2009 at a single institution. Cox proportional hazards regression analysis was conducted to determine factors predictive of survival. The median radiation dose was 78 Gy, median duration of AD was 6 months, and median follow-up was 74 months. The 10-year overall survival (OS) was 60.6%. Prostate cancer was the leading single cause of death, with 10-year mortality of 14.1% (95% CI 10.7-17.6), compared with other cancers (8.4%, 95% CI 5.7-11.1), cardiovascular disease (7.3%, 95% CI 4.7-9.9), and all other causes (10.4%, 95% CI 7.2-13.6). On multivariate analysis, older age (HR 1.55, P=.002) and Charlson comorbidity index score (CS) ≥ 1 (HR 2.20, P<.0001) were significant factors predictive of OS, whereas Gleason score, T stage, prostate-specific antigen, duration of AD, radiation dose, smoking history, and body mass index were not. Men younger than 70 years of age with CS = 0 were more likely to die of prostate cancer than any other cause, whereas older men or those with CS ≥ 1 more commonly suffered non-prostate cancer death. The cumulative incidences of prostate cancer-specific mortality were similar regardless of age or comorbidities (P=.60). Men with high-risk prostate cancer are more likely to die of causes other than prostate cancer, except for the subgroup of men younger than 70 years of age without comorbidities. Only older age and presence of comorbidities significantly predicted for OS, whereas prostate cancer- and treatment-related factors did not.

RETRACTED: High-Dose Conformal Radiotherapy Reduces Prostate Cancer–Specific Mortality: Results of a Meta-analysis

To determine in a meta-analysis whether prostate cancer-specific mortality (PCSM), biochemical or clinical failure (BCF), and overall mortality (OM) in men with localized prostate cancer treated with conformal high-dose radiotherapy (HDRT) are better than those in men treated with conventional-dose radiotherapy (CDRT). The MEDLINE, Embase, CANCERLIT, and Cochrane Library databases, as well as the proceedings of annual meetings, were systematically searched to identify randomized, controlled studies comparing conformal HDRT with CDRT for localized prostate cancer. Five randomized, controlled trials (2508 patients) that met the study criteria were identified. Pooled results from these randomized, controlled trials showed a significant reduction in the incidence of PCSM and BCF rates at 5 years in patients treated with HDRT (p = 0.04 and p < 0.0001, respectively), with an absolute risk reduction (ARR) of PCSM and BCF at 5 years of 1.7% and 12.6%, respectively. Two trials evaluated PCSM with 10 years of follow up. The pooled results from these trials showed a statistical benefit for HDRT in terms of PCSM (p = 0.03). In the subgroup analysis, trials that used androgen deprivation therapy (ADT) showed an ARR for BCF of 12.9% (number needed to treat = 7.7, p < 0.00001), whereas trials without ADT had an ARR of 13.6% (number needed to treat = 7, p < 0.00001). There was no difference in the OM rate at 5 and 10 years (p = 0.99 and p = 0.11, respectively) between the groups receiving HDRT and CDRT. This meta-analysis is the first study to show that HDRT is superior to CDRT in preventing disease progression and prostate cancer-specific death in trials that used conformational technique to increase the total dose. Despite the limitations of our study in evaluating the role of ADT and HDRT, our data show no benefit for HDRT arms in terms of BCF in trials with or without ADT.

Mutations of BRAF and KRAS2 in the development of Barrett's adenocarcinoma

To describe mortality, cause of death, and temporal trends in clinicopathological parameters with up to 20 years of follow-up in a nationwide cohort of prostate cancer (PCa) patients who underwent radical prostatectomy (RP).A total of 6857 patients with PCa treated with RP at six different hospitals in Denmark between 1995 and 2011. Data were extracted from the nationwide DaPCa database. Histopathology reports from the RP specimens were manually reviewed. Date and cause of death were obtained from national registries and cross-checked in patient files.The cumulative incidence of PCa specific mortality (PCSM) was analysed with the Aalen-Johansen method for competing risks with non-PCa death as a competing event. Risk of PCSM was analysed in a multivariate Cox regression model using age, preoperative PSA level, surgical margin status, RP Gleason score (GS), pathological T-category, and N-category as explanatory variables.The median follow-up was 6.4 years. Significant temporal changes in clinicopathological parameters were observed. During the study period, median age at surgery increased from 61.4 to 64.8 years and median preoperative PSA declined from 12.0 to 8.0 ng/ml. The proportion of men with pT2 PCa increased from 65% to 75% whereas the proportion of pT3 cancers decreased from 28% to 25%. The percentage of men with positive surgical margins decreased from 37% to 20%. During follow-up, 644 patients died, whereof 189 (29.3%) died from PCa. The cumulative incidence of PCSM and other-cause mortality after 15 years was 10.3% (95% CI 8.0–12.7) and 18.2% (95% CI 15.4–20.9), respectively. In a multivariate analysis, RP GS (P ≤ 0.001) and pT-category (P ≤ 0.001) were significantly associated with the risk of PCSM. Compared with GS ≤6, both GS +4 (HR 1.47), GS 4 + 3 (HR 2.32), GS 8 (HR 4.8) and GS 9 or 10 (HR 5.26) significantly increased the risk of PCa death. T3a PCa and T3b/T4 was also a significant predictor of PCSM with an increased risk of PCa death compared with pT2 of 2.24 and 4.5, respectively.In a complete national cohort of men treated with RP during a 17-year period, we described the incidence of mortality after RP and predictors of PCSM. We demonstrated that RP GS and pT-category are the most significant predictors of PCa mortality. We found that an increasing proportion of men undergo RP for low-risk PCa suggesting that early detection of PCa is indeed undergoing in Denmark despite national recommendations. The Danish national results seem to concur with findings from international single- and multi-institutional reports.