bluuebunny/crossref_metadata_2025 huggingface dataset:
MRI-based prostate specific antigen density predicts Gleason score upgrade in an active surveillance cohort.
Authors: Washington Samuel L. , Baskin Avi Lefridge , Ameli Niloufar , Nguyen Hao Gia , Westphalen Antonio C. , Shinohara Katsuto , Carroll Peter
Published: March 2019

107

Background: Elevated prostate specific antigen density (PSAD) based on transrectal ultrasound (TRUS) measurements has been shown to be strongly associated with clinically significant disease and to predict progression on active surveillance for men with low stage/grade disease. We hypothesize that elevated MRI PSAD is similarly associated with increased risk of progression on subsequent biopsy. Methods: Patients with Gleason grade 3+3 on diagnostic transrectal ultrasound-guided biopsy who were managed with active surveillance and underwent at least one additional biopsy were included. Patients who underwent MRI greater than 6 months after diagnosis were excluded. Summary statistics were generated for demographic and clinical characteristics. MRI PSAD was calculated using prostate volume on MRI and PSA temporally closest to the MRI. Multivariable logistics regression models were used to evaluate the association between MRI PSAD and predictors of upgrade on serial biopsy. Results: 166 patients were included in the study. Of these patients, 74 of them were upgraded to Gleason grade ≥7 on follow up biopsy. TRUS volume was noted be strongly correlated with MRI prostate volume (Pearson’s r=0.82, p<0.01). MRI PSAD 0.15-0.225 ng/ccl and ≥0.0225 ng/cc were significantly associated with upgrade to Gleason grade 7 compared to MRI PSAD <0.075 ng/ml/ml after controlling for age and time since diagnosis. MRI PSAD less than 0.15 was not associated with upgrade on follow up biopsy (in any patient, if so, state that no one with a PSAD < 0.15 upgraded). Conclusions: MRI PSAD is significantly associated with Gleason upgrading on follow up biopsy for men initially diagnosed with Gleason grade 3+3 disease. This finding is important because surveillance MRI is increasingly being used to monitor men on active surveillance.
MRI targeted biopsy dramatically increases detection of clinically significant prostate cancer while reducing the risk of indolent cancer detection.
Authors: Ahdoot Michael , Lebastchi Amir H , Gharam Sandeep , Gomella Patrick H , Dibianco John , Bloom Jonathan , Hale Graham , Gold Samuel A , Turkbey Baris , Pinto Peter A. , Sanford Thomas , Choyke Peter L. , Parnes Howard L.
Published: March 2019

108

Background: MRI fusion prostate biopsy has been shown to improve detection of clinically significant prostate cancer, however the degree of this benefit is poorly characterized in large clinical trials. Methods: 1750 MRI targeted plus sextant biopsies were performed in 1742 male patients from 2007 to 2017. Patient demographics, PSA, prostate volume, primary and secondary Gleason scores, Johns Hopkins Grade Groups, number of MRI targeted lesions, number of cores obtained, and biopsy yield were recorded. Results: The patient population consisted of men averaging 62.9-year-old (36-86) with a mean PSA 9.6ng/mL, and prostate volume of 59.2 ml. A total of 804 cancers were detected on sextant biopsy and 839 were detected on MRI targeted biopsy. Relative to targeted biopsy, sextant biopsy detected only significantly more Gleason 6 disease (14% vs 21.5%, p < 0.0001) than targeted biopsy. Targeted biopsy detected more Gleason 7 (21% vs 16.6%, p = 0.0009) and Gleason 8-10 (13.4% vs 9.4%). Additionally, Gleason 7 sub-stratification demonstrated substantially more Gleason 4+3 detection in targeted group vs sextant biopsy (4% vs 0.5%, p < 0.0001). When stratified by Grade Group targeted biopsy detected 76% more Grade Group 3-5 cancers (p < 0.0001) and 17.7% less Gleason Group 1-2 cancers (p < 0.0001). Only 1.7% of Grade Group 3-5 cancers were detected on sextant biopsy alone, where as 15.7% of Grade Group 3-5 cancers were detected on targeted biopsy alone. Conclusions: MRI targeted biopsy significantly increases the likelihood of detecting clinically significant cancer and decreases the risk of indolent cancer detection. These finding strongly support the use of MRI targeted biopsy when possible.
Optimizing the use of androgen deprivation therapy in men with localized intermediate-risk prostate cancer in the era of modern dose-escalated radiation therapy.
Authors: Patel Sagar Anil , Nguyen Kevin H. , Lee Alan K. , Demanes David Jeffrey , Chang Albert
Published: March 2019

109

Background: While level one evidence has shown an overall survival (OS) advantage with the addition of androgen deprivation therapy (ADT) to radiotherapy (RT) for intermediate risk prostate cancer (PCa), the benefit in the era of modern dose escalation is controversial, especially given the heterogeneity within this risk group. We assessed the impact of adding ADT to high dose RT on OS for intermediate risk PCa stratified by number of intermediate risk factors (IRF). Methods: We identified 114,339 men with intermediate risk PCa (Gleason 7, clinical stage T1-2, PSA < 20 ng/mL) using the National Cancer Database. Men were stratified into the following subgroups based on the number of IRFs (Gleason 7, cT2b-c, PSA > 10-20 ng/mL): A) Gleason 3+4 and no other IRF, B) Gleason 4+3 and no other IRF, C) two IRFs, and D) three IRFs. The addition of ADT to dose-escalated external beam RT (DE-EBRT, ≥ 75.6 Gy), brachytherapy (BT), or combination EBRT+BT on OS was assessed within each subgroup using Kaplan-Meier and log-rank tests in propensity score-matched cohorts in all men and subsequently only in those with Charlson-Deyo comorbidity index (CDI) of zero. Results: There was no OS benefit with the addition of ADT to DE-EBRT, BT, or EBRT+BT in groups A, B, and C, even after limiting the cohort to men with CDI = 0. However, in group D, the addition of ADT to DE-EBRT was associated with a trend for OS improvement in patients with CDI = 0 only (8-year OS with and without ADT 68.3% and 62.4%, respectively, log-rank P= .07). Conversely, there was a trend for OS decrement with the addition of ADT to DE-EBRT in men with CDI ≥ 1 (8-year OS with and without ADT 61.8% and 67.5%, respectively, log-rank P= .06). There was no OS benefit of ADT in group D treated with BT or EBRT+BT, regardless of comorbidity status. Conclusions: The OS benefit of ADT in men with intermediate risk PCa may be limited to those with 3 IRFs and minimal comorbidities treated with DE-EBRT. If prospectively validated, extreme dose escalation achieved with BT (alone or in combination with EBRT) may obviate the addition of ADT in all men with intermediate risk disease, especially in an era of advanced molecular imaging.
Incidence and pathological features of metachronous bladder cancer in prostate cancer patients treated with brachytherapy or radical prostatectomy in a single institution.
Authors: Obayashi Kotaro
Published: March 2019

111

Background: Although previous studies have reported that the incidence of metachronous bladder cancer (MBC) is not significantly different after brachytherapy (BT) compared to radical prostatectomy (RP), few studies have reported differences in the pathological features (PF) of MBC between them. This study was conducted to clarify differences in the incidence and PF of MBC between BT and RP in our hospital. Methods: We reviewed 504 patients treated with BT and 471 referred patients treated with RP from 2006 to 2017 in our hospital. We checked the incidence of MBC in all patients and examined the PF including the tumor number, location within the bladder, histology, and time from BT or RP to the occurrence. The chi-square test and Mann-Whitney U test were performed to analyze the differences between the two groups. Results: After a median follow-up time of 66 months, a total of 8 cases of BC occurred in the BT group (1.6 %) and 5 in the RP group (1.1 %). The median time from initial treatment to the occurrence of MBC was 56 months (12-121) in BT and 71 months (4-126) in RP (p = 0.622). Average tumor number was not significantly different (BT:1.38, RP: 2.2, p = 0.265). The incidence of MBC in each location within the bladder for BT vs. RP was 4 vs 0 in the right wall, 3 vs 0 in the left wall, 0 vs 3 in the posterior wall, 0 vs 2 in the dome, and 1 vs 0 in the trigone. The incidence in the lateral wall was significantly higher in BT than in RP (p = 0.00466). There were 3 muscle-invasive cases in BT and 1 case in RP (p = 1.00). High-grade urothelial cancer occurred more in BT 8 than in RP 1 (p = 0.00699). Conclusions: The risk of MBC after BT appeared to be equivalent to patients after RP. MBC after BT occurred more in the lateral wall with worse PF compared to those after RP.
Overall survival outcomes with the use of adjuvant chemotherapy, radiation therapy and hormone therapy in high-risk, very-high-risk and node-positive prostate cancer post radical prostatectomy: A NCDB analysis.
Authors: Basnet Alina , Formica Margaret K , Ramadas Poornima , Benjamin Sam
Published: March 2019

118

Background: Phase III trials have not consistently demonstrated overall survival (OS) advantage of adjuvant radiation therapy (ART) in prostate cancer (PC) with high risk/very high risk features after radical prostatectomy (RP). Adjuvant hormone therapy (AHT) in PC after RP improved OS in patients with positive lymph nodes (pLNs). We report an observational study on the impact of AHT to ART in NCCN defined high-risk/very high risk (Group 1), and adjuvant chemotherapy (ACT) to AHT in pLNs (group 2) post RP on OS. Methods: We conducted a retrospective study of PC patients (group 1 and group 2) who underwent RP and/or pelvic lymph node dissection. OS was calculated using Kaplan Meier analysis. Group 1 compared ART+AHT vs ART and Group 2 AHT+ ACT vs AHT within 16 weeks of RP. Multivariate analysis was performed with Cox proportional hazard regression model to adjust for different variables. Results: Out of 1,390,357 PC patients reported in NCDB (2004-2015) 182,653 and 11,972 met our inclusion criteria for Group 1 and Group 2 respectively. 3.37% of Group 1 received ART and/or AHT. 19.81% of Group 2 received AHT and/or ACT. Patients who received ART + AHT were more likely to be older, Non-Hispanic white, more likely to have pT4, and have higher prostate specific antigen (PSA) and Gleason scores (GS). Patients who received AHT+ACT were more likely to be younger, with private insurance, and lower Charlson-Deyo Score (CDCC) score. Five and seven year OS with adjusted hazard ratio (aHR) among Group 1 and Group 2 are depicted in table. Conclusions: No statistically significant difference in OS was seen among respective treatment groups. Limitations that exist with this registry based study include lack of randomization, differences in surgical and radiation techniques, duration and choices of ACT and AHT.[Table: see text]
Conservative management of low-risk prostate cancer among young versus older men in the United States: Trends and outcomes from a novel national database.
Authors: Mahal Amandeep R , Butler Santino , Franco Idalid Ivy , Pike Luke Roy George , Zhao Shuang , Sanford Nina Niu , Dess Robert Timothy , Feng Felix Y , D'Amico Anthony Victor , Spratt Daniel Eidelberg , Yu James B. , Nguyen Paul L. , Rebbeck Timothy , Mahal Brandon Arvin Virgil
Published: March 2019

12

Background: The optimal management for men age ≤55 with low-risk prostate cancer (PCa) is debated given quality of life implications with definitive treatment versus potential missed opportunity for cure with conservative management. We sought to define rates of conservative management for low-risk PCa and associated short-term outcomes in young versus older men in the United States (U.S.). Methods: The Surveillance, Epidemiology, and End Results (SEER) Prostate with Active Surveillance/Watchful Waiting (AS/WW) Database identified 50,302 men diagnosed with low-risk PCa from 2010-2015. AS/WW rates in the U.S. were stratified by age (≤55 versus ≥56). Prostate cancer-specific mortality (PCSM)and overall mortality were defined by initial management type (AS/WW versus definitive treatment [referent]) and age. This non-public data was released by the SEER custom data group. Results: AS/WW utilization increased from 8.61% in 2010 to 34.56% in 2015 among men age ≤55 (Ptrend< 0.001) and from 15.99% to 43.81% among men age ≥56 (Ptrend< 0.001). Among patients with ≤2 positive biopsy cores, AS/WW rates increased from 12.90% to 48.78% for men age ≤55 and from 21.85% to 58.01% for men age ≥56. Among patients with ≥3 positive biopsy cores, AS/WW rates increased from 3.89% to 22.45% for men age ≤55 and from 10.05% to 28.49% for men age ≥56 (all Ptrend< 0.001). Five-year PCSM rates were below 0.30% across age and initial management type subgroups. Conclusions: AS/WW rates quadrupled for patients age ≤55 from 2010-2015, with favorable short-term outcomes. These findings demonstrate the short-term safety and increasing acceptance of AS/WW for both younger and older patients. However, there are still higher absolute rates of AS/WW in older patients (P < 0.001), suggesting some national ambivalence toward AS/WW in younger patients.
Racial differences in long-term prostate cancer specific mortality following conservative management for low-risk prostate cancer: A population-based study.
Authors: Lu-Yao Grace L. , Nikita Nikita , Keith Scott W , Banks Joshua , Handley Nathan , Rebbeck Timothy , Cullen Jennifer , Domingo-Domenech Josep , Kelly William Kevin
Published: March 2019

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Background: It is uncertain whether the same criteria for active surveillance can be applied universally across races. This population-based study was undertaken to quantify racial differences in long-term risk of prostate cancer-specific mortality (PCSM) among patients with low-risk prostate cancer (PCa) receiving conservative management. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients who had low-risk PCa (T1-T2a & Gleason 6 & PSA ≤ 10 ng/mL & N0 & M0) diagnosed in 2004 – 2015 and did not receive radical prostatectomy or radiation therapy within one year of diagnosis. Kaplan-Meier analysis was used to calculate PCSM. The Clopper-Pearson method was used to calculate associated 95% confidence intervals. Hazard ratio of PCSM among those with a high PSA (PSA 4-10) compared to those with a low PSA (PSA < 4) was calculated using Cox proportional hazards models adjusted for covariates (including age, race, marital status, insurance status, U.S. region, year of diagnosis, and AJCC clinical tumor stage). Results: Among 33,740 patients with low-risk PCa, long-term PCSM varied with race and PSA levels at diagnosis. For instance, 10-year PCSM was 2.62% (95% CI: 1.15%-5.05%) among African Americans with PSA 4-10 and 0.98% (95% CI:0.16%-3.12%) among Caucasian patients with PSA < 4. There was no significant statistical interaction between race and PSA level on PCSM (p = 0.81). After adjusting for potential confounders, men with PSA 4-10 experienced 2-fold higher PCSM relative to those with PSA < 4 (HR = 1.96, p = 0.011) and African Americans men experienced a 43% higher PCSM compared to Caucasians (HR = 1.43, p = 0.03). Conclusions: Among men diagnosed with low-risk PCa, long-term PCSM varies by race and PSA at diagnosis. More refined risk stratification may improve PCa management among low-risk PCa patients. [Table: see text]
The validation of the 2014 International Society of Urological Pathology (ISUP) grading system for patients with high-risk prostate cancer: A single-center retrospective study.
Authors: Liu Jiandong
Published: March 2019

128

Background: Since the new 2014 grading system was recommended by the International Society of Urological Pathology (ISUP), it has been validated in patients with localized prostate cancer (PCa) and has shown excellent prognostic value. However, its predictive power in high-risk PCa remained unclear. Methods: Overall, 420 patients with high-risk PCa who underwent radical prostatectomy (RP) were included. Biochemical recurrence-free survival (BRFS) was set as the endpoint. Results: Biochemical recurrence occurred in 84/420 (20.0%) patients at the end of follow-up. Compared to the three-tier grouping system, the five-tier grouping system could more effectively distinguish the BRFS of patients with higher predictive accuracy (C-index: 0.599 vs 0.646). The BRFS of patients with grade group (GG) 1 and GG 2 was similar (p = 0.593). Also, the prognosis between those in the GG 2 and GG 3 could be clearly distinguished (p = 0.001). Whereas the discrimination capacity between patients with GG 3 and GG 4 was limited (p = 0.681). The high proportion of tertiary Gleason pattern 5 (TGP5) among patients with GG 3 might be an important confounder leading to the overlap of survival between GG 4 and GG 3. Conclusions: This study is the first one to validate the new 2014 ISUP grading system in patients with high-risk PCa who underwent RP. The 2014 system could effectively separate patients into five groups with high predictive accuracy. Notably, the existence of TGP5 needs to be routinely reported in clinical practice, which could help to support the predictive ability of the new grading system.
Management of low-risk prostate cancer in a population-based cohort of Australian men between 2008 and 2016.
Authors: Ong Wee Loon , Foroudi Farshad , Evans Susan M. , Millar Jeremy Laurence
Published: March 2019

13

Background: The aim of this study is to evaluate the practice pattern of management of NCCN low-risk prostate cancer (LRPC) in a population-based cohort of Australian men. Methods: This is prospective cohort of men captured in Prostate Cancer Outcomes Registry Victoria (PCOR-Vic), who were diagnosed with LRPC between Aug 2008 and Dec 2016. Conservative management was defined as no active treatment (surgery, radiotherapy, or other local therapy) within 12-month of LRPC diagnosis. Chi-squared test for trend was used to evaluate change in practice over time. Multivariate logistics regressions were used to patient-, tumour- and institutional factors influencing the likelihood of conservative management for LRPC. Results: A total of 3238 men with LRPC were identified in the PCOR-Vic database. The median age was 62.6 (range:37-94). The median PSA level was 5.1ng/mL (range: 0.01-9.96). Overall, 1934 (60%) had conservative management, of which 1668 (86%) were documented as being on active surveillance. Of the 1304 (40%) men who active treatment within 12-month of diagnosis, 977 (30%) had surgeries, 289 (9%) had radiotherapy, and 38 (1%) had other local treatment. Overall, there is increasing trend in conservative management for LRPC from 52% in 2009 to 73% in 2016 (P<0.001). In multivariate analyses, age, PSA, clinical stage, institutions and year of diagnosis were all independently associated with conservative management. Men diagnosed in private and regional centres were 26% (95%CI=0.63-0.88, P=0.001) and 40% (95% CI=0.51-0.72, P<0.001) less likely to have conservative management for LRPC. Conclusions: This is the largest Australian series on management of LRPC to date. We observe increasing use of conservative management for LRPC over time, however, there is large institutional variations in care with men diagnosed in private and regional centres more likely to have active local management for LRPC.
Reduced risk of prostate cancer in a cohort of Lithuanian diabetes mellitus patients.
Authors: Patasius Ausvydas , Kincius Marius , Linkeviciute-Ulinskiene Donata , Zabuliene Lina , Smailyte Giedre
Published: March 2019

130

Background: An inverse association has been shown between diabetes and prostate cancer risk. The aim of this study was to determine whether type 2 diabetes mellitus (T2DM) and metformin is associated with prostate cancer risk. Methods: A retrospective cohort design was used to examine the relationship between diabetes and prostate cancer risk. The cohort was composed of male patients identified with diagnosis of T2DM in the National Health Insurance Fund database during 2000–2016. Cancer cases were identified by record linkage with the Lithuanian Cancer Registry which is a nationwide population-based cancer registry that contains personal and demographic information, as well as information on diagnosis of all people diagnosed with cancer in Lithuania since 1978. We calculated standardized incidence ratios (SIRs) for prostate cancers as a ratio of observed number of cancer case in people with diabetes diagnosis to the expected number of cancer cases in the underlying general population. Results: Overall, 68,449 males were diagnosed with diabetes in Lithuania between 2000 and 2016 were included in final cohort. 2,754 prostate cancers were observed versus 3,111.26 expected within a period of observation entailing an SIR of 0.89 (95% CI: 0.85–0.92). Significantly lower risk of prostate cancer was found in diabetic patients in all age groups, there were no differences in prostate cancer risk by time since diabetes diagnosis. Significantly lower risk of prostate cancer also was found in both metformin users and never-users groups, with higher risk reduction in metformin users (SIR 0.71, 95% CI: 0.68–0.75) than in T2DM patients never-users (SIR 0.88, 95% CI: 0.80–0.96). Conclusions: In the large population-based study we found significantly decreased risk of prostate cancer among men with T2DM. Our study suggests that metformin use in patients with T2DM may be associated with reduced risk of developing prostate cancer.
Genomic findings in adenocarcinoma of the urinary bladder.
Authors: Shapiro Oleg , Kotula Leszek , Byler Timothy , Jacob Joseph , Alexander Brian Michael , Gay Laurie M. , Millis Sherri Z. , Elvin Julia Andrea , Chung Jon , Vergilio Jo-Anne , Ramkissoon Shakti , Severson Eric Allan , Killian Jonathan Keith , Ali Siraj Mahamed , Schrock Alexa Betzig , Miller Vincent A. , de La Roza Gustavo , Ross Jeffrey S. , Bratslavsky Gennady , Liu Nick
Published: March 2019

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Background: Prostatic ductal carcinoma (PDC) is an uncommon centrally located prostate with a characteristic tubulopapillary histology. PDC shares some biomarker features with the more common prostatic acinar carcinoma (PAC) including PSA expression. Methods: In this comparative comprehensive genomic profiling (CGP) study, FFPE samples from 61 clinically advanced PDC and 4,132 PAC were profiled for all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: The age, frequency of genomic alterations (GA) per tumor and TP53 GA of PDA and PAC were similar (Table). TMPRSS2:ERG fusions and AR GA were more often identified in PAC than PDC whereas PTEN GA were more common in PDC than PAC. Targetable GA were identified at similar frequencies in both groups focused on BRCA2 (PARP inhibitors), BRAF (BRAF/MEK inhibitors) and PIK3CA (MTOR inhibitors). ATM GA (PARP inhibitors) were more common in PAC than PDC. CDK12 GA potentially associated with immunotherapy (IO) benefit were similar in PDA and PAC as were the frequencies of MSI-High status, median TMB and high TMB levels. Conclusions: The pathologic features of PDC and PAC have been classically maintained as representative of 2 different tumor types with potentially contrasting histogenesis. In the current CGP-based study, PDA and PAC did not display significant differences in genomic signatures. CGP may reveal biomarkers that could direct patients to targeted (PARP, MTOR and BRAF/MEK inhibitors) or immunotherapies ( CDK12 GA, MSI-High or high TMB status) in both PDA and PAC. [Table: see text]
Prostate cancer in young men: Our experience.
Authors: Barreira Joao Vasco , Falcão Gil , Parmanande Anuraj , Spencer Ana Sofia , Simão Diana , Winckler Patricia , Luz Ricardo
Published: March 2019

133

Background: Prostate cancer (PCa) diagnosis is not uncommon in younger men. The three recognized risk factors for PCa are increasing age, african-american race and a family history (FH). Data about PCa treatment outcomes are controversial, younger men may have more aggressive disease and worse prognosis. On the other hand, more recent studies suggest higher rates of indolent PCa with more favorable outcomes in young men after radical prostatectomy (RP). We aimed to compare younger (G1, ≤ 55 yo) vs. older adults (G2, > 56 yo) who underwent RP for PCa between 2010-2016 in terms of FH, race and tumor aggressiveness. Secondly, to determine if the PCa in G1 is more aggressive when there is a PCa familiar background. Methods: Between 2010-2016, 419 men underwent RP for clinically localized PCa at Central Lisbon Hospitals, of which 49 were aged ≤55 years at the time of RP. Clinical characteristics such as race, FH, PSA level, clinical stage, and biopsy Gleason score (BGS) were recorded before RP. Pathological parameters (pathological stage, GS and PSA) were collected after surgery. Results: In G1, 31% had PCa FH vs. 10% in G2 (p < 0.001). Before RP, the average PSA in G1 was 7.47 vs. 8.08 in G2 (p = 0.371). In BGS, 44,3% had Gleason (G) 6, 37,4% G7, 6.9% G≥8, not significantly different between both groups (p = 0.651). Albeit, G1 had more aggressive tumors after RP: 27% G6, 45% G7 e 29% G≥8 vs. 37%, 53% e 11% respectively in G2 (p = 0.002). The pathological stage (pT) was not significantly different between groups (p = 0.243). Biochemical recurrence (BCR) was higher in G1 20% vs. 9% (p = 0.010). In a multivariate logistic regression model, the G1 had more BCR (p = 0.047) and higher PCa FH incidence (p = 0.002). When comparing african vs. caucasian men, the first group had more aggressive tumor histology (p = 0.021). Conclusions: Our study demonstrated that the youngest had superior pathological grades with higher BCR rates. Also, we found a strong relationship between G1 and FH of PCa. Data regarding pathological findings after RP in young men are still controversial. Recent studies confirm that pathological PCa characteristics in young men are not more aggressive than in older men. The present intends to add to the scientific debate around the impact of patients’ age in PCa aggressiveness and prognosis.
Experience of a single Brazilian center on PSMA-PET in biochemical recurrence in patients with prostate cancer.
Authors: Lages Paulo Sergio , Prado Junior Luciano , Prado Leonardo , Lages Luciana
Published: March 2019

134

Background: Biochemical recurrence in prostate cancer is a common event, and we have data showing that PSMA-PET may guide therapy when it happens. Objectives: Verify the sensibility of PSMA-PET on biochemically recurrent prostate cancer and correlate it with PSA level and Gleason score. Methods: From October 2015 to August 2018, 547 PSMA-PET (68Ga-PSMA) was performed to evaluate prostate cancer individuals. 276 patients had already been treated from prostate cancer and were in biochemical recurrence. From these patients, 122 had information regarding Gleason Score. Results: From the 276 patients, we found 216 positive exams (78.3%). What we can see, and according to the present data we already have, is that the positivity rises with increasing PSA level. Conclusions: PSMA-PET is a useful strategy for planning treatment in patients with biochemical recurrent prostate cancer. The sensibility varies according to PSA level and Gleason Score. An interest thing observed is that the sensibility for Gleason 3+4 is similar to Gleason 3+3 and the sensibility for Gleason 4+3 is similar to 4+4, showing that the Gleason 7 disease has different behaviors, as previous shown in other trials. This dataset reinforces the importance of incorporating PSMA-PET in clinical practice.[Table: see text][Table: see text][Table: see text]
The effect of urologic oncology fellowship training on type and yield of prostate biopsy.
Authors: DeWitt-Foy Molly Elmer , El-Shafei Ahmed , Coronado Wendy Melissa , Abouassaly Robert
Published: March 2019

135

Background: Prostate biopsy is a commonly performed procedure done in the evaluation of elevated prostate specific antigen (PSA), abnormal digital rectal exam (DRE), or for patients with a known prostate cancer diagnosis on active surveillance. The diagnostic yield of prostate biopsy is related to patient factors including age and race, but may also be correlated with provider factors, including clinical experience and training. We aim to determine the relationship between urologic oncology fellowship training (UOFT) and years of training with diagnostic yield of prostate biopsy. Methods: A retrospective review was conducted of patients who underwent prostate biopsy across the Cleveland Clinic between 2000 and 2018. Biopsies done by urologists with and without UOFT were detailed via descriptive statistics and with appropriate (chi square, Student t) tests. Logistic regression was performed, adjusting for last PSA, age, race, and type of biopsy. Results: A total of 11,255 biopsies performed by 129 urologists had complete information for review. The average patient age at biopsy was 65 years. The mean number of years in practice was 16 with a range from < 1 to 46 (SD 11.26). Of 129 urologists 16 (12.4%) had completed a urology oncology fellowship. Those with UOFT were more likely to use MRI guidance for biopsy (7.73% v 2.89%). Overall, 35.5% of all biopsies were positive for prostate cancer, with a significantly higher rate of positive biopsy for urologists with UOFT (40.7% v 32.43%, OR 1.4, p < 0.0001). Having completed greater than 5 years of clinical practice was correlated with greater odds of positive biopsy (OR 1.170, p < 0.0001), but significance of this association was lost when adjusting for oncology fellowship. UOFT remained a significant predictor of diagnostic yield even when adjusting for most recent PSA, age and race of patient, provider years in practice, and type of biopsy (MRI v transrectal ultrasound). Conclusions: Urologic oncology fellowship training is associated with a higher diagnostic yield on prostate biopsy, and a higher uptake of MRI guided biopsy. Higher rate of positivity on biopsy may be attributable to more nuanced patient selection for biopsy or to biopsy technique.
Updated analysis of progression-free survival with first subsequent therapy (PFS2) and safety in the SPARTAN study of apalutamide (APA) in patients (pts) with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Small Eric Jay , Saad Fred , Chowdhury Simon , Oudard Stephane , Hadaschik Boris A. , Graff Julie Nicole , Olmos David , Mainwaring Paul N. , Lee Ji Youl , Uemura Hiroji , Lopez-Gitlitz Angela , Espina Byron M. , Shu Youyi , Rackoff Wayne R. , Rooney Oliver Brendan , Londhe Anil , Cheng Shinta , Smith Matthew Raymond
Published: March 2019

144

Background: In the phase 3 SPARTAN study, compared with placebo (PBO), APA, a next-generation androgen receptor inhibitor, decreased the risk of distant metastasis or death by 72% (hazard ratio [HR], 0.28; p < 0.0001) in men with high-risk nmCRPC. After 1 year of additional follow-up, PFS2 and safety were reevaluated to ensure maintenance of benefit against potential harm. Methods: Pts with nmCRPC and prostate-specific antigen doubling time of ≤ 10 mos were randomized 2:1 to APA (240 mg QD) + androgen deprivation therapy (ADT) or PBO + ADT. All pts who developed distant metastasis, determined by blinded independent central review, were eligible to receive subsequent therapy including open-label treatment with abiraterone acetate + prednisone, provided by the sponsor. The exploratory PFS2 end point (time from randomization to disease progression on subsequent anticancer therapy or death) was evaluated, as was incidence of treatment-emergent adverse events (TEAEs). Results: Median treatment duration with APA was 25.7 mos; with PBO, 11.5 mos (original analysis, mos: APA, 19.2; PBO, 11.2). Pts randomized to APA continued to show significant benefit in PFS2 (HR, 0.5; 95% CI, 0.39-0.63; p < 0.0001) vs PBO (APA median time to PFS2 not reached vs PBO 39.3 mos). At a median follow-up of 32 mos, 51.3% of pts receiving APA, 8% of the 75 pts who crossed over from PBO to APA, and 99.7% of remaining PBO pts had discontinued study treatment. Rates of discontinuations due to progressive disease and AEs were 27.3% and 12.7%, respectively, in the APA group and 73.4% and 8.4% in the PBO group. There was no substantial change in the incidence of TEAEs in the APA group at the 1-year update. With regard to drug specific TEAEs, there were no grade 4 or 5 events; grade 3 TEAEs consisted of rash, 5.2%; falls, 2.4%; fractures, 3.1%; hypothyroidism, 0%; and seizures, 0%. Conclusions: APA was previously shown to result in an improvement in metastasis-free survival and symptomatic progression. With a median APA treatment duration of 25.7 mos, APA continues to show significant benefit in PFS2, and its safety profile remains unchanged. Clinical trial information: NCT01946204.
Keynote-365 cohort a: Pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Yu Evan Y. , Massard Christophe , Retz Margitta , Tafreshi Ali , Carles Galceran Joan , Hammerer Peter , Fong Peter C.C. , Shore Neal D. , Joshua Anthony , Linch Mark David , Gurney Howard , Romano Emanuela , Augustin Marinela , Piulats Josep M. , Wu Haiyan , Schloss Charles , Poehlein Christian Heinrich , De Bono Johann S.
Published: March 2019

145

Background: Activity with pembro or olaparib has been observed in mCRPC pts who progressed on 2nd-generation hormonal therapy (HT) and chemotherapy. From KEYNOTE-365 (NCT02861573), a phase 1b/2 umbrella study testing combinations in mCRPC, we report early results from cohort A combining pembro + olaparib. Methods: Pts with mCRPC were eligible if they progressed within 6 months prior to screening determined by either PSA progression or radiologic progression in bone or soft tissue. Pts were docetaxel-pretreated for mCRPC, may have received 1 other chemotherapy, and had ≤2 2nd-generation HT. Pts received pembro 200 mg IV Q3W + olaparib 400 mg orally twice daily. Primary end points: safety and PSA response rate (confirmed PSA decline ≥50%). Key secondary end points: ORR RECIST v1.1 (investigator review), disease control rate (DCR: CR+PR+SD ≥6 mo), time to PSA progression, composite response rate (ORR RECIST v1.1, confirmed PSA response, or confirmed decrease in circulating tumor cell count from ≥5 to <5 cells/7.5 mL blood), rPFS, and OS. Results: Median follow-up was 11 mo. 41 initiated treatment (median age 69 years; PD-L1+ 27%; visceral disease 42%; RECIST-measurable 68%; homologous recombination repair mutation [HRR] 0%). See efficacy in table below. Treatment-related AEs occurred in 39 (95%) pts. Most frequent (≥30%) were anemia (37%), fatigue (34%), and nausea (34%). Grade 3-5 treatment-related AEs were in 21 (51%) pts. There were 2 deaths; only 1 was treatment-related (cause unknown). Conclusions: Combination of pembro + olaparib has activity in pts previously treated with docetaxel and ≤2 2nd-generation HT for mCRPC and who are HRR wild type. Observed safety profile for the combination is consistent with individual profiles of pembro and olaparib. Clinical trial information: NCT02861573. [Table: see text]
Late administration of luteinizing hormone-releasing hormone (LHRH) agonists and the impact on testosterone suppression in the real-world management of prostate cancer.
Authors: Twardowski Przemyslaw , Sartor A. Oliver , McLane John A. , Boldt-Houle Debbie , Atkinson Stuart , Tagawa Scott T.
Published: March 2019

149

Background: LHRH agonists are standard for androgen deprivation therapy (ADT) for advanced prostate cancer (PCa). Increasing evidence suggests maintaining very low testosterone (T) levels is desirable and correlate with disease-specific survival. However, T levels may rise above castrate level between administrations, especially if the next dose is delayed. A previous publication showed that subcutaneously-administered leuprolide acetate (LA) provided a longer duration of action than intramuscularly-administered LA past the dosing interval. This study evaluated the timeliness of LHRH agonist administrations and subsequent rate of T breakthroughs in PCa patients. Methods: A retrospective review of electronic medical records from 1/1/07-6/30/16 of 85,030 LHRH agonist administrations for PCa treatment was conducted to evaluate the percentage of late subsequent administrations and T tests with T > 50 ng/dL. A late administration was defined as occurring on or after day 33 (1 mo formulation), 98 (3 mo), 129 (4 mo), or 195 (6 mo). Descriptive statistics were used. Results: 26.9% of all subsequent LHRH agonist administrations were late: 14.4% were ≤ 1 week late, 3.1% were between 1 and 2 weeks late, and 9.4% were > 2 weeks late. 21% of T tests demonstrated T > 50 ng/dL when administrations were late, in contrast to only 4% of measured T levels exceeded 50 ng/dL when LHRH agonists were administered early or on time. Conclusions: Across LHRH agonists, greater than a quarter of subsequent administrations were defined as late. Among late administrations, about half were > 1 week late, and more than a third were > 2 weeks late. Late administrations were correlated with inadequate castration over 20% of the time. Considering the clinical benefits of maintaining effective T suppression during ADT, clinicians should administer treatments within approved dosing instructions, include routine monitoring of T levels, and consider prescribing treatments with proven prolonged effect through the dosing period to achieve T suppression to castrate levels.
Prospective head-to-head comparison of 18F-fluciclovine and 68Ga-PSMA-11 PET/CT for localization of prostate cancer biochemical recurrence after primary prostatectomy.
Authors: Calais Jeremie , Ceci Francesco , Nguyen Kathleen , Gartmann Jeannine , Eiber Matthias , Reiter Robert Evan , Kishan Amar Upadhyaya , Jadvar Hossein , Fendler Wolfgang P , Czernin Johannes
Published: March 2019

15

Background: 18F-Fluciclovine PET/CT (FACBC) is standard-of-care in US for localization of prostate cancer (PCa) biochemical recurrence (BCR) after definitive therapy. 68Ga-PSMA-11 PET/CT (PSMA) detects PCa BCR even at low prostate-specific antigen (PSA) levels (<2.0 ng/mL). We conducted a single-center prospective head-to-head comparison of these 2 PET/CT imaging tracers for localizing PCa BCR after radical prostatectomy (RP) in patients with PSA < 2.0 ng/ml. Methods: Patients with PCa BCR after RP and PSA levels ranging from ≥0.2 to ≤2.0 ng/mL without any prior salvage therapy were eligible. All patients underwent FACBC and PSMA scans within ≤15 days. Images analysis was performed a) by on-site clinical reading and b) by 3 blinded international expert readers for each modality. Detection rates on per-patient and per-region based analysis served as primary study endpoints. Based on literature data we hypothesized a detection rate difference of 22% in favor of PSMA. A power analysis determined a sample size of 50 patients. Results: The 50 patients were enrolled from March to September 2018. Median PSA level was 0.50 ng/ml. Median time interval between the 2 scans was 6 days. We present here the preliminary results from the non-blinded clinical reads. Detection rate on a per-patient basis was 69% for PSMA and 34% for FACBC. Concordant findings were observed in 30/49 patients (61%): 16/49 (32%) with both positive scans and 14/49 (29%) with both negative scans. Discordant findings were observed in 19/49 patients (39%): 18/49 (37%) had a positive PSMA but a negative FACBC scan while 1/49 (2%) had a positive FACBC with a negative PSMA (local recurrence). Detection rates were consistently lower for FACBC than for PSMA for all regions: Prostate bed (12% vs 20%), pelvic nodes (14% vs 37%), extra-pelvic nodes (2% vs 8%), skeleton (2% vs 8%) and visceral organs (2% vs 6%). Conclusions: This preliminary analysis from the non-blinded on-site clinical reads demonstrates prospectively that PSMA detection rates is more than double the FACBC detection rate in patients with PCa BCR after RP and with PSA ≤2.0 ng/ml. Clinical trial information: NCT03515577.
Efficacy of docetaxel and androgen receptor axis-targeted agents in castration-resistant prostate cancer patients with intraductal carcinoma of the prostate.
Authors: Yamamoto Akiyuki , Kato Masashi , Tsuzuki Toyonori , Gotoh Momokazu
Published: March 2019

150

Background: This study aimed to investigate the efficacy of docetaxel and androgen receptor axis-targeted (ARAT) agents in castration-resistant prostate cancer (CRPC) patients with intraductal carcinoma of the prostate (IDC-P). Methods: We retrospectively identified 311 CRPC patients from June 2002 to February 2016. All patients were initially administered with androgen deprivation therapy (ADT), followed by docetaxel or ARAT (abiraterone or enzalutamide) after progressing to CRPC. The primary outcome of interest was overall survival (OS) from the time of CRPC diagnosis and progression-free survival (PFS) from the time of administration of docetaxel or ARAT. Results: IDC-P was found in 180 of 311 patients. The median OS was 33.4 and 64.0 months with and without IDC-P, respectively (hazards ratio [HR], 2.14; P < 0.001). For the first treatment for CRPC, docetaxel was administered to 71 and 50 patients with and without IDC-P, respectively, with a median OS of 30.4 and 64.0 months, respectively (HR, 2.62; P < 0.001). ARAT was administered to 109 and 81 patients with and without IDC-P, respectively, with a median OS of 45.0 and 69.9 months, respectively (HR, 1.84; P = 0.017). Regarding patients with IDC-P, the OS in patients who were administered with ARAT was longer than that in those administered with docetaxel (HR, 0.58; P = 0.008). The median PFS was 7.5 and 12.1 months with and without IDC-P, respectively (HR, 1.36; P = 0.03). Multivariate analysis showed that the prognostic factors for OS were the presence of IDC-P (HR, 1.91; P < 0.001), and administration of ARAT (HR, 0.66; P = 0.02). Conclusions: The presence of IDC-P is an independent prognostic factor for OS and PFS in CRPC patients. ARAT may prolong OS in CRPC patients with IDC-P.
Quality of life differences for LHRH-antagonist versus LHRH-agonist in special patient groups with cardiovascular comorbidities and higher tumor burden in patients with hormone-sensitive prostate cancer (hsPCa).
Authors: Lehmann Jan , Flesch Markus , Gedamke Michael
Published: March 2019

153

Background: ADT with LHRH-agonists or LHRH-antagonists (degarelix, D) is the standard of care in advanced hsPCa. An analysis of ProComD from 2018 showed that D was more frequently used in patients with cardiac and peripheral arterial disease. Methods: In the ProComD, a two-arm, prospective non-interventional study, potential differences in comorbidity and other parameters such as baseline PSA and metastatic status on patient reported outcome between D and LHRH-agonists treatment were investigated. Results: Data on patients with a minimum follow-up period of one year (n = 285, D = 179, LHRH-agonist = 106) up to three years (n = 62, D = 40, LHRH-agonist = 22) were documented. Baseline criteria were generally similar except for disease T-stage (p = 0.0238), metastatic status (p = 0.0419) and PSA (p = 0.0041). The average age of patients was 74.1 years. Stage distribution: D vs LHRH-agonists, pT2 25.7/24.5%, pT3 24.1/34.9%, pT4 6.1/2.8%, unknown. 44.1/37.7%, cNX 49.7/44.3%, cN0 32.4/42.5%, cN+ 17.9/12.3%, cMX 27.4/25.5%, cM0 34.1/49.1%, cM1 38.6/25.5%. Global health status (EORTC) did not change over 12 months neither for D nor for LHRH-agonists. Differences in subscales between D and LHRH-agonists were observed for role functioning, cognitive functioning and, while QoL was unchanged under D, LHRH-agonists sig. reduced QoL (p = 0.073, p = 0.0368). Pain (marginal sig.) p = 0.0621) as well as analgesics (17.3% vs 1.1% at 3 months vs baseline) were reduced by D. Since baseline PSA differed sig., we specifically evaluated the subgroup of patients with a PSA > 50 ng/ml, where Global Health Status was found to be different between D and LHRH-agonists already at month 6 and at month 12 (p = 0.0331, p = 0.0232), favoring D. Conclusions: Our results indicate that Degarelix, with a different mode of action, is used in a different patient group (CVD and higher tumor stage as well as metastatic patients) compared to LHRH-agonists treatment. EORTC Global Health is similar to LHRH-agonists, but differences occur in subscales (role and cognitive functioning) as well as in subgroups (PSA > 50 ng/ml) in favour of the LHRH-antagonist. Clinical trial information: NCT02234089.
The effect of VERU-111, a novel oral inhibitor of α and β tubulin, on tumor growth in the human castration-resistant, AR-variant prostate cancer (PCa) model 22Rv1.
Authors: Markowski Mark Christopher , Getzenberg Robert H. , Steiner Mitchell S. , Azad Nilofer Saba , Eisenberger Mario A. , Antonarakis Emmanuel S.
Published: March 2019

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Background: VERU-111 is a novel, oral α and β tubulin inhibitor that blocks tubulin polymerization and is not a substrate for multi-drug resistance. In xenograft mouse models of taxane responsive and resistant cancers, VERU-111 results in tumor inhibition at ≤20 mg/kg orally dosed infrequently as 1/week. VERU-111 and docetaxel were tested in the human PCa model, 22Rv1, which expresses androgen receptor splice variants, including AR-V7, and is resistant to abiraterone and enzalutamide. Methods: Human 22Rv1 cells were implanted into SCID mice. When tumors reached 150-200 mm , the animals were randomized into 4 groups (n = 10 per group): PO vehicle; PO VERU-111 5 or 20 mg/kg; or IP docetaxel 10 mg/kg 3X per week. Animal weights and tumor volumes were measured 2X week and at study end. Animals were removed from study when the tumor volume exceeded 2000 mm or upon treatment for 28 days. Results: VERU-111 (PO 5 and 20 mg/kg) 3X/week significantly reduced tumors by 31% (p = 0.049) and 49% (p = 0.010), respectively, compared to vehicle. Administration of 10 mg/kg docetaxel IP had a nonsignificant reduction in tumor size. With respect to toxicity, mice treated with oral VERU-111 either significantly gained (5 mg/kg) or maintained their weight (20 mg/kg), whereas the docetaxel treated mice lost weight (p = 0.013). There was a significantly greater weight in mice treated with VERU-111 versus docetaxel (p = 0.014). Conclusions: VERU-111, a next generation, orally α and β tubulin inhibitor, has significant anti-tumor activity against PCa and other tumors. In the human PCa model 22Rv1, VERU-111 had a statistically significant reduction in tumor growth and was well tolerated. In contrast, IP docetaxel did not significantly reduce tumor growth and had greater toxicity. A phase 1/2 trial evaluating VERU-111 in men with metastatic castration and novel androgen blocking agent (abiraterone or enzalutamide) resistant prostate cancer is in progress. [Table: see text]