Pretreatment PSA Research Articles

National trends in the management of patients with positive surgical margins at the time of radical prostatectomy.

111 Background: The optimal management approach for patients with positive surgical margins (PSM) at radical prostatectomy (RP) has not been definitively assessed. To better understand contemporary patterns of care, we sought to examine time trends and determinants of adjuvant therapy in a large national sample of men with prostate cancer (PCa) treated with RP. Methods: We queried the National Cancer Database (NCDB) to identify men with clinically-localized PCa diagnosed from 2010 to 2014 who had PSM at RP performed as initial primary definitive treatment. We used descriptive statistics to examine subsequent management strategies, assessed as no adjuvant therapy as part of the initial planned course of management, receipt of adjuvant radiation therapy (RT), and receipt of adjuvant RT in combination with androgen deprivation therapy (ADT). Binary logistic regression models were constructed to identify patient, tumor, and facility features associated with receipt of adjuvant therapy. Results: During the study period, we identified 44,523 patients with PSM. Of those, 5,179 (11.6%) men received any adjuvant RT (+/- ADT), while only 1,380 (3%) received adjuvant RT with ADT. Use of adjuvant RT did not change over the study period ( p= 0.61). On multivariable analysis men of uninsured status (p = 0.003), Medicaid insurance (p = 0.001), and patients treated in non-academic facilities (p < 0.001) were more likely to receive adjuvant RT. In addition, use of adjuvant RT was associated with higher pre-treatment PSA (p < 0.001), pathologic stage (p < 0.001) and Gleason grade group (p < 0.001), decreasing distance from the treatment center (p < 0.001), and shorter duration between diagnosis and RP (p < 0.001). Receipt of adjuvant ADT with RT was associated with clinical and pathologic features; however, not with sociodemographic factors. Conclusions: The majority of patients experiencing PSM at RP did not receive adjuvant RT, and rates of adjuvant therapy have remained stable over time. In addition to adverse clinical and pathologic features, sociodemographic and facility factors were significantly associated with receipt of adjuvant RT; however, the addition of ADT appears largely driven by disease characteristics.

The docetaxel-abiraterone acetate sequence compared to the abiraterone acetate-docetaxel sequence in metastatic castration-resistant prostate cancer patients with a response to previous castration superior to 12 months.

353 Background: With the approval of the multiple new life-prolonging treatments for men with metastatic castration-resistant prostate cancer (mCRPC), the optimal sequencing of chemotherapy and androgen-receptor (AR) targeting agents remains unclear. Although response duration to castration could influence decision choice for second hormonal therapies, we do not know whether chemotherapy efficacy could be similar to AR targeting agents such as abiraterone acetate (AA). Methods: A retrospective analysis of mCRPC patients treated at Jolimont Hospital is reported. Patients included were castration-resistant PC with a response to castration superior to 12 months. They were treated with sequential docetaxel and AA, in either order. The combined progression-free survival (combined PFS: PFS1 + PFS2) of AA followed by docetaxel is compared to the reverse sequence (docetaxel followed by AA). Baseline characteristics are reported prior to the start of the first agent in the sequence. Results: Forty-two patients who started treatment for mCRPC between January 2013 and February 2017 were identified: 22 were in the docetaxel-AA sequence (Group A) and 20 were in the AA-docetaxel sequence (Group B). The median duration of response to castration was 16 months in Group A and 18 months in Group B. Proportion of Gleason > 8 was higher in group A (60% vs 50%). Visceral or lymph node disease was more important in group A (35% vs 16%). Median pre-treatment PSA was similar in the two groups (27 and 30). In the group A, PFS1 was 9 months and PFS2 was 8 months, resulting in a combined PFS of 17 months (range 5 to 47months). In the group B, PFS1 was 8 months and PFS2 was 7 months, resulting in a combined PFS of 15 months (range 4 to 45 months). Conclusions: We do not observe differences in clinical outcomes based on alternative sequencing of AA and docetaxel in men with mCRPC with a previous response duration to castration longer than 12 months.

Definitive radiation therapy and survival in clinically node-positive prostate cancer.

168 Background: The survival benefit of combined radiation therapy (RT) and androgen deprivation therapy (ADT) compared to ADT alone for clinically lymph node-positive prostate cancer remains controversial. Methods: We identified clinically node-positive, non-metastatic prostate cancer patients diagnosed between 2000-2015 and treated with ADT (n = 450) or ADT/RT (n = 198) from a national Veterans Affairs database. We compared prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) between treatment groups using multivariable Cox regression, controlling for potential confounders. All tests of statistical significance were two sided. Results: Compared to ADT alone, ADT/RT was associated with improved ACM (hazard ratio [HR]: 0.56, 95% CI 0.41-0.76, p < 0.001) and PCSM overall (HR 0.65, 95% CI 0.43-0.97, p = 0.03). We noted a significant interaction between ADT/RT and pre-treatment PSA for PCSM (p for interaction = 0.005) and ACM (p for interaction < 0.001). ADT/RT was associated with improved PCSM among patients with PSA less than (HR 0.43, 95% CI 0.24-0.78, p = 0.004) but not greater than the median of 26 ng/mL (HR 1.01, 95% CI 0.60-1.71, p = 0.96). ADT/RT was also associated with improved ACM among patients with PSA less than (HR 0.38, 95% CI 0.25-0.57, p < 0.001) but not greater than the median (HR 0.91, 95% CI 0.60-1.38, p = 0.66). Conclusions: Definitive treatment with ADT/RT is associated with improved ACM and PCSM among patients with clinically node-positive prostate cancer. The survival benefit of ADT/RT is only apparent among patients with lower baseline PSA. Patients with clinically node-positive disease appear to be a heterogeneous cohort, with a subset that may achieve long-term survival with combined radiation and androgen deprivation therapy.

104 Low PSA Level In Men Diagnosed With Prostate Cancer Predicts Testosterone Deficiency (TD)

PSA secretion is a testosterone (T) dependent process. There is published data suggesting that low serum total T level is an independent predictor of higher stage, higher grade prostate cancer. However, the link between men diagnosed with prostate cancer with low PSA values and T deficiency (TD) has not been explored before. All men diagnosed with prostate cancer since 2000 that had a record of pre-treatment early morning total T level measurement were included in the analysis. We analyzed demographic, clinical and pathological data. Patients were stratified according to pre-treatment PSA levels: 0-2; 2.1-4; >4 ng/ml. TD was defined as total T < 300 ng/dL. We evaluated the relationship between these PSA groups and TD. Age, diabetes, and hyperlipidemia were also included in both univariate and multivariable analyses. Mean age of 349 men was 64±8 years. The distribution by PSA group was: 5% (0-2), 16% (2.1-4), and 79% (>4). The mean T level across the entire cohort was 358±192 ng/dl. Overall, 38% had a T level < 300 ng/dl; 63% > 300 ng/dl. 9% had diabetes, 10% had hyperlipidemia. The mean T level by PSA group was: 265±168 (0-2); 328±210 (2.1-4); and 371±189 (>4), p=0.03. The percentage of men with TD by PSA group was: 53% (0-2); 49% (2.1-4); and 35% (>4), p=0.05. The percentage of men with extremely low T levels (<200) by PSA group was: 35% (0-2); 22% (2.1-4); and 13% (>4), p=0.01. Age, diabetes, and hyperlipidemia were not related to T level grouping on univariate analyses (p=0.35 to p=0.81). On multivariable analysis, PSA 0-2 compared to PSA >4: OR=2.1, 95% CI: 0.82-5.36, p=0.12; PSA 2.1-4 compared to PSA >4: OR=1.9, 95% CI: 1.02-3.34, p=0.04. PSA 0-2 compared to PSA >4 was not significant due to low sample size.

Monitoring of Circulating Tumor Cells in Patients With High-Risk Nonmetastatic Prostate Cancer Treated With Radiation Therapy and Hormones: Preliminary Data of an Observational Prospective Phase 2 Study

Circulating tumor cells (CTCs) are a cellular source repeatedly obtainable by blood sampling that could serve as a surrogate marker for treatment efficacy. The presence of CTCs is an established marker for prognosis in men with castration-resistant prostate cancer. In contrast, the value of CTCs detection in men with localized high-risk prostate cancer is unknown. The purpose of this study is to evaluate the proportion of patients with high-risk prostate cancer (HRPCa) that presents CTCs in peripheral blood (PB) before and after androgen deprivation therapy (ADT) and radiation therapy (RT) in order to establish its prognostic value. We present preliminary data of CTCs monitoring detection. Hypothesis: The detection of CTCs is a potential surrogate marker for treatment efficacy in HRPCa. Prospective analysis of biological material obtained from PB samples in 65 patients with HRPCa treatment naïve between 2014 and 2016. Blood samples were analyzed to detect CTCs using an immunomagnetic method based on the CellSearch system in 4 periods of time: 1) Before starting any treatment; 2) following neoadjuvant ADT and prior to RT; 3) at the end of RT; 4) 6-12 months following the end of RT in those patients with 0 CTCs in the first determination and positive CTCs in the following determinations. A cut off of 0 vs ≥ 1CTCs/7.5ml blood was defined as a threshold for negative versus positive CTCs status. We also analyzed whether CTCs presence was associated with clinic-pathological features using the chi-square or Fisher exact test. The median age was 71 years and median PSA was 12.6 ng/ml. Twenty-eight patients had Gleason score ≥ 8 and 48 patients had clinical stage T3. CTCs were detected in 5/66 patients (7.5%) at diagnosis (baseline), in 8/62 (12.9%) following neoadjuvant ADT and in 11/59 (18.6%) at the end of RT with a median CTC count/7.5ml of 1 (range:1-136). Only 1 patient presented positive CTCs detection 6-13 months after RT. Positive CTCs status (at any period) did not correlate with patient age, pre-treatment PSA, T stage, N stage or Gleason score. The preliminary data obtained from this observational feasibility study showed an infrequent detection of CTCs in patients with HRPCa with no correlation to known clinical prognostic factors. The positive cases for CTCs after ADT and RT (mostly with very low levels and not maintained over time) are probably due to a passive mechanism associated with the destruction of the tumor. A more acute assessment method to detect CTCs together with larger cohorts with extended follow-up are needed to validate this finding.

Ductal Adenocarcinoma of the Prostate Gland Treated With Radical Prostatectomy or Radiation Therapy: A Single Institutional Retrospective Review With Long-Term Follow-Up

Ductal adenocarcinoma is a rare variant of prostate cancer considered to be more aggressive than pure acinar adenocarcinoma which often presents at advanced clinical stages in elderly men with urinary symptoms. To better elucidate the behavior of this subtype, we investigated the clinical outcomes of patients who were managed with curative intent. We retrospectively evaluated 31 patients with histologically-confirmed, non-metastatic ductal adenocarcinoma of the prostate who were treated with radical prostatectomy (RP) or radiation therapy (RT) at our institution from 2002-2014. Pathology was required to demonstrate ductal adenocarcinoma in either a pure form or intermixed with acinar elements. Median follow-up was 64.9 months (range: 20.5-174.5 months). 29% of patients presented with significant urinary symptoms including 5 with gross painless hematuria. Median age was 66 (range: 53-80 years) and median pre-treatment PSA was 6.7 (range: 2.3-15.2). Palpable nodularity consistent with cT2 disease was noted in 15 patients; another 15 exhibited clinical T1c exams. Of the cohort, 25 patients underwent RP and 6 patients underwent RT (including 3 patients who received androgen deprivation therapy for at least 6 months). Overall, 15 patients developed biochemical and/or clinical progression and 2 patients died (both from metastatic disease). The RP group accounted for all but one incidences of progression and both deaths. The 5-year/10-year progression-free probability (PFP), prostate-cancer-specific survival (PCSS), and overall survival (OS) rates were 56%/49%, 100%/86%, and 100%/86%. In the RP group, surgical pathology revealed pure ductal type in 7 (28%) patients and mixed ductal/acinar type in 18 (72%) patients. Twelve (48%) patients had pathological tumor classification of pT3a or higher, 11 patients (44%) had post-surgical Gleason score of 8 or higher, and 10 patients (40%) had positive margins. No statistically significant differences were observed between pure type and mixed type in terms of PFS, PCSS, or OS. There was a trend towards pure ductal type presenting in older patients (p=0.07), but no other significant demographic or pathologic differences were found. In the RT group, a high proportion (66%) of patients exhibited pure type, likely secondary to the limitations of biopsy sampling. Notably, the two patients who underwent RP and died from metastatic disease had pure type, pT3b, Gleason 9-10, positive margins, and perineural invasion. In one of the largest single-institution retrospective series of the modern era investigating ductal adenocarcinoma of the prostate treated with curative intent, our data suggest a favorable prognosis comparable to that of pure acinar adenocarcinoma. Although the degree of ductal involvement (pure versus mixed) on pathology was not predictive of outcomes, it may be associated with differences in patient characteristics, especially age.

Hypoxia Gene Expression Signature Independently Predicts Prognosis for Prostate Cancer Patients

Approximately 160,000 cases of prostate cancer are diagnosed annually in the United States. Prostate cancer is the third leading cause of cancer death in American men. Hypoxia is associated with radiotherapy resistance and a poor prognosis in prostate cancer. There is evidence that only the most hypoxic tumors benefit from hypoxia-targeted treatment, but there is no clinically validated method identifying hypoxic prostate cancers. We aimed to derive and validate a gene expression signature reflecting hypoxia in prostate cancer. RNA sequencing was performed to identify genes induced by 1% hypoxia for 24 hours in four prostate cancer cell lines, including PNT2-C2, PC-3, LNCaP, and DU145. In vitro hypoxia gene analysis was then combined with in vivo analysis of gene co-expression network from TCGA cohort to generate a hypoxia gene expression signature. The signature was locked and independently validated in seven retrospective cohorts of low- to high-risk patients with localized disease. A 28-gene signature was derived. Twenty-one signature genes were regulated by hypoxia in vitro. In seven independent patient cohorts, the hypoxia signature score was positively correlated with pathological Gleason score and tumor stage, but not pre-treatment PSA level. Patients stratified as high hypoxia were associated with significantly poorer biochemical-relapse free survival. The hypoxia signature remained an independent predictor in a multivariate analysis after adjusting for Gleason score, tumor stage, and pre-treatment PSA. The signature also predicted benefit from hypoxia-modifying therapy with carbogen and nicotinamide in bladder cancer patients (n = 113, HR 0·54, 95% CI 0·32-0·91, P = 0·021). A 28-gene hypoxia signature has a strong and independent prognostic value for prostate cancer patients.

Long-Term Results of a Phase 3 Randomized Prospective Trial of Erectile Tissue Sparing IMRT for Men With Clinically Localized Prostate Cancer

To prospectively determine if a novel technique to limit the doses delivered to the penile bulb (PB) and corporal bodies (CB) with IMRT preserves erectile function to a greater degree compared to standard IMRT in men with low to intermediate risk prostate cancer. From 2003-2012, 116 patients with low to intermediate risk, clinical T1a-T2c prostate adenocarcinoma were enrolled to a single-institution, prospective, phase III randomized trial. All patients received definitive IMRT to 74-80 Gy in 37-40 fractions. Patients were assigned to receive standard IMRT (s-IMRT) or erectile tissue sparing IMRT (ETS-IMRT), which placed additional planning constraints that limited the D90 to the PB and CB to ≤15 Gy and ≤7 Gy, respectively. Patients were blinded to the treatment arm. Erectile potency was defined as the ability to attain and maintain penile erection sufficient for satisfactory sexual performance >50% of the time and was assessed using the simplified International Index of Erectile Function (IIEF-5) and PDE5 inhibitor medication records. Comparison of potency preservation outcomes was conducted at various time points in an intention-to-treat analysis using two-sample, two-sided chi-square tests. Biochemical failure and late toxicities were compared using Kaplan-Meier survival analysis and the log-rank test. Sixty-two patients received ETS-IMRT and 54 received s-IMRT. Treatment arms were balanced with respect to age (median 62 years [range 42-77]), race, smoking status, BMI, baseline AUA score, hypertension, diabetes, and hypercholesterolemia. The majority of patients presented with Gleason 6 disease (ETS-IMRT 79%, s-IMRT 93%, P = 0.06), T1c stage (ETS-IMRT 73%, s-IMRT 82%, P = 0.32), and pre-treatment PSA <10 (ETS-IMRT 94%, s-IMRT 93%, P = 0.99). Prior to treatment, all patients in both arms reported erectile potency. 4 patients (6%) on the ETS-IMRT arm and 1 patient (2%) on the s-IMRT arm reported PDE5 inhibitor use prior to treatment (P = 1.00). D90 to the PB ≤ 15 Gy was met in 88% of ETS-IMRT patients and 75% of s-IMRT patients. D90 to the CB ≤ 7 Gy was met in 71% of ETS-IMRT patients and 43% of s-IMRT patients. With a median follow-up time of 6.1 years, 85 patients were eligible for potency preservation analysis. At 19-30 months after treatment, erectile potency was seen in 52% of patients in the ETS-IMRT arm and 51% of patients in the s-IMRT arm (P = 0.95). PDE5 inhibitors were initiated in 52% of ETS-IMRT patients and 44% of s-IMRT patients (P = 0.49). Among all patients enrolled, there was no difference in freedom from biochemical failure between those treated with ETS-IMRT and s-IMRT (91.8% vs 90.7%, P = 0.77) with a median follow-up of 7.4 years. There were no differences in acute or late GI or GU toxicity. Erectile tissue sparing IMRT that limits dose to the PB and CB is safe and feasible, although there was no significant difference in potency preservation at 6 years.

The prostate clinical outlook (PCO) classifier for predicting biochemical recurrences in patients treated by stereotactic body radiation therapy.

e16552 Background: Although prostate cancer risk classifiers have been developed for predicting surgical and radiation therapy outcomes, a classifier suitable for predicting biochemical recurrence (BCR) in patients undergoing stereotactic body radiation therapy (SBRT) remains to be defined. SBRT is delivered in large fractions of highly conformal radiation therapy and such treatments are believed to be radiobiologically more effective in treating prostate cancers. The aim of this study is to develop a new classifier specifically for informing patients electing to undergo prostate cancer treatment with SBRT. Methods: We have studied outcomes of 809 patients treated with SBRT between August 2007 and November 2016 at MedStar-Georgetown University Hospital. A Cox regression to BCR was performed and the Prostate Clinical Outlook (PCO) score was calculated at diagnosis based on age at diagnosis, clinical-radiological staging, pre-treatment PSA and Gleason score. Accuracy of the PCO classifier was assessed with concordance (c)-indexes. The results were also compared to classifications by D’Amico and National Comprehensive Cancer Network (NCCN) recurrence risk groups. Results: PCO total scores range from zero to 156 points. The PCO classifier splits patients into 3 risk-groups with the following 5-year BCR-free survival: for low-risk 98%; for intermediate-risk 95%; for high-risk 86%. Our classifier outperforms D’Amico and NCCN for all of the evaluated end-points, with concordance indices of 74 % versus 64 % and 66%, respectively. Conclusions: The PCO classifier is a potential tool for employing readily available parameters to stratify prostate cancer patients and to predict probabilities of BCR after SBRT.

The IMPACT of 68GA-PSMA-PET in definitive radiotherapy planning for prostate cancer patients.

79 Background: The implementation of 68Ga-PSMA-PET-imaging for staging and the impact on stage adaption during treatment radiotherapy (RT) planning is not well studied yet. The present work is to evaluate the integration of 68Ga-PSMA-PET into standard RT planning and to determine the influence on staging and on changes in the initially planned treatment concept for definitive RT in prostate cancer patients. Methods: A total of 66 prostate cancer patients with PSMA-PET delivered before treatment were retrospectively analyzed. All patients had bone scintigraphy and magnetic resonance imaging (MRI) of abdomen (52 patients; 79%) or thoraco-abdominal computed tomography (CT) (14 patients; 21%). After PSMA-imaging, all information was reviewed and re-classification was performed with the additional information taken into account. Thereafter, patients were evaluated with the information obtained by PSMA-PET imaging led to a change in staging and subsequently resulted in a change of the RT concept and treatment fields. Results: Median age of patients was 66 years (range 46 – 84 years). Median pretreatment PSA level was 25.2 ng/mL (range 4.4 – 130.8 ng/mL). The initial stage was changed in 27 patients (41%); 8 patients (12%) under-staged, 11 patients (17%) over-staged and 8 patents (12%) had distant metastasis. RT fields changed in 9 patients (14%) and RT cancelled because of distant metastasis detected with PSMA-PET in 6 patients (9%). The mean pretreatment PSA values were significantly higher in over-staged patients or patient with distant metastasis compared to under-staged patients (55.0±38.8 ng/mL vs. 28.1±19.1 ng/mL; p = 0.02). Also upstaging was observed more frequently in patients with ≥ T3a disease compared to patients with &lt; T3 disease (15 patients [56%] vs. 4 patients [15%]; p = 0.04). However, Gleason score and primary tumor SUV had no significant impact on stage change and particularly on RT decision and treatment plan changes. Conclusions: The performance of a PSMA-PET frequently leads to changes in the stage, altering the RT treatment regimen especially in patients with extensive stage disease and higher pretreatment PSA values.

Difference in risk factors associated with biochemical recurrence after salvage RT compared to post-prostatectomy patients with negative margins.

39 Background: Previous research has also shown that higher pathologic stage, higher Gleason score (GS) and positive margins are associated with increased rates of disease recurrence after prostatectomy and may be indicators for early intervention with adjuvant or salvage radiotherapy (SRT). Conversely, a negative surgical margin is a negative prognostic factor for the success of SRT. We sought to investigate the relative significance of prognostic factors in patients grouped by margin status and differences in their response to treatment. Methods: 227 patients were treated with SRT at our institution between Jan 2005 and Dec 2013. Patients with positive lymph nodes at surgery, those treated with adjuvant radiation and patients with metastases prior to SRT were excluded, leaving 196 for analysis. Biochemical recurrence (BCR) was defined as post-SRT PSA nadir + 0.2 ng/mL. Median follow-up was 48 mo. Covariates evaluated were factors found to be significant in previous studies on SRT (pre-SRT PSA, pathologic stage, GS) as well as treatment to the pelvis vs fossa. Patients were grouped by margins and evaluated using Kaplan-Meier and multivariate Cox regression. Results: In univariate analysis of patients with positive margins significant factors for increased rates of recurrence were pre-SRT PSA (p = 0.016), GS (p &lt; 0.001), and pathologic stage (p &lt; 0.001). Treatment to the pelvis was not significant. Conversely, in patients with negative margins, pre-SRT PSA and GS no longer significantly affected BCR and pathologic stage only approached significance (p = 0.061). In these patients treatment to the pelvis was significantly associated with decreased BCR (p = 0.005). On multivariate analysis these trends in significance were maintained. Conclusions: In post-prostatectomy patients with negative margins treatment to the pelvis is associated with improved bPFS, while traditional factors associated with recurrence such as pathologic stage, GS and pre-treatment PSA were not significant. Patients with negative margins and PSA recurrence after prostatectomy should be considered for treatment to the pelvic nodes, even in the absence of nodal involvement on imaging.

Prostate cancer-specific death in brachytherapy treated high-risk patients stratified by pre-treatment PSA.

PurposeTo evaluate prostate-cancer specific mortality (PCSM) in a cohort of high-risk patients treated with a permanent prostate brachytherapy approach, stratified by pre-treatment PSA.Material and methods448 high-risk patients (NCCN criteria) underwent permanent prostate brachytherapy. High risk patients were stratified by pre-treatment PSA (≤ 10.0, 10.1-20, and > 20 ng/ml). Biochemical failure (BF), prostate cancer-specific mortality (PCSM), distant failure (DM), and overall mortality (OM) were assessed as a function of prognostic group. Multiple clinical, treatment, and dosimetric parameters were evaluated for impact on outcome.ResultsThe 10-year OM, BF, and PCSM for the entire cohort were 28.5%, 13.3%, and 4.9%, respectively. At 10 years, PCSM was 2.5%, 10.7%, and 4.5% in the PSA ≤ 10, 10.1-20, and > 20 ng/ml groups, respectively. No statistically significant differences in BF or overall survival (OS) were noted when stratified by pre-treatment PSA. DF was the most common in the 10.1-20 ng/ml cohort (8.6% at 10 years). In multivariate analysis, PCSM was most closely related to percent positive biopsies (p = 0.001) and tobacco (p = 0.042).ConclusionsHigh-risk prostate cancer treated with permanent prostate brachytherapy and supplemental external beam radiotherapy resulted in excellent long-term biochemical control and PCSM. Overall, PCSM was low in all cohorts but highest in the intermediate PSA group (10.1-20 ng/ml).

Prognostic Value of Twist-1, E-cadherin and EZH2 in Prostate Cancer: An Immunohistochemical Study.

There is an urgent need to identify molecular biomarkers rather than clinical markers to distinguish aggressive prostate cancer from the indolent majority for proper treatment and accurate prediction of prognosis. We aimed to investigate the immunohistochemical expression of epithelial-mesenchymal transition (EMT)-related molecules (Twist-1 and E-cadherin) and the stem cell marker EZH2 in prostate cancer and to assess their ability to identify the high-risk patients, in a trial to explore their prognostic implications. Immunohistochemical expression of Twist-1, E-cadherin and EZH2 in 50 specimens of prostate cancer and 20 cases of benign prostatic hyperplasia were studied. The relationship between their expression and the clinicopathological variables, biochemical recurrence, and biochemical progression-free survival were investigated. Our results revealed that high Twist-1, as well as high EZH2 expression, was strongly associated with higher pre-treatment PSA level, Gleason score ≥7, advanced tumor stage, lymph node involvement, distant metastasis and biochemical progression. Aberrant E-cadherin expression was significantly associated with higher pre-treatment PSA level, Gleason score ≥7, advanced tumor stage, lymph node involvement, and distant metastasis. A significant positive correlation between Twist-1 and EZH2 expression was found (p < 0.001), while E-cadherin expression showed a negative correlation with both markers (p < 0.001). A significant association was found between high Twist-1, high EZH2& aberrant E-cadherin expression, and shorter biochemical progression-free survival. The high Twist-1 expression, aberrant E-cadherin and high EZH2 expression in primary prostate cancer are considered as adverse prognostic markers of an aggressive tumor with high metastatic potential. Assessment of their expression level would contribute to the accurate prediction of biochemical progression.

Modeling Biochemical Relapse-Free Survival in Intraoperative Planned Low-Dose-Rate Prostate Brachytherapy: A Multicenter Cohort Analysis

To develop a model of biochemical relapse free survival (bRFS) outcomes in prostate cancer patients treated with intraoperatively planned low dose rate prostate brachytherapy using an automated delivery system (IO-LDRB). A total of 3286 patients with low or low-tier intermediate risk prostate cancer were treated with single modality IO-LDRB at 3 centers between December 1997 and August 2015. Data from 2 centers was used to develop a model for bRFS and data from the third center was used for external validation. Data was analyzed using R version 3.1.3, and is presented as medians (range; P value) unless otherwise indicated. After censuring for missing data, 2730 patients were analyzed: 1780 in the training and 950 in the comparison cohort. Median follow-ups were 52.9 (0.0-136.0) and 36.0 (0.0-114; <0.001) months, respectively. Ages were 64 (42-84) and 65 (44-80; <0.001) years. Pre-treatment PSAs were 5.6 (0.03-16.6) and 5.5 (0.2-18.5; 0.3) ng/mL. A total of 1,298 (73%) and 713 (75%; 0.7) were T1; the remainder were T2. A total of 1,380 (78%) and 651 (68.5; <0.001) patients had Gleason 6; 375 (21%) and 651 (30.5%; <0.001) had Gleason 7 disease. 307 (17.3%) and 7 (1%) received hormones for medians of 3.0 (0.5-32.1) and 4.5 (3-8; 0.1) months respectively. Median implant D90s were 190.6 (135.5-237.0) and 161.3 (97.0-273.0; <0.001) Gray. For the training cohort, median gland volume was 34.8 (10.9 – 66.9) cc. In the training cohort there were 85 (4.8%) biochemical failures as defined by the Phoenix definition. Median time to failure was 49.4 (6.3-132.3) months. In the validation cohort 26 (2.7%; <0.001) patients failed in a median of 48.1 (11.6 – 99.6; 1.0) months. Somer’s D was 0.44 after internal validation. Factors predicting bRFS were pre-treatment PSA, Gleason sum, stage, gland volume, D90 and hormone use. Predicted 5 and 10-year survival for patients with 34.8cc glands, PSA 5.6, T1 and Gleason 6 disease, treated to D90 = 190.6 and without hormones were 96% and 87%, respectively. Model prediction of survival estimates in the external validation cohort converged with Kaplan-Meier estimates confirming model validity. IO-LDRB is an effective treatment option for patients with low and low-tier intermediate risk prostate cancer. Despite low relapse rates, probability of relapse is predictable based on tumor and treatment characteristics. We present a comprehensive model for predicting bRFS in these patients.

PSA nadir as a predictive factor for biochemical disease-free survival and overall survival following whole-gland salvage HIFU following radiotherapy failure

Background:Treatment options for radio-recurrent prostate cancer are either androgen-deprivation therapy or salvage prostatectomy. Whole-gland high-intensity focussed ultrasound (HIFU) might have a role in this setting.Methods:An independent HIFU registry collated consecutive cases of HIFU. Between 2005 and 2012, we identified 50 men who underwent whole-gland HIFU following histological confirmation of localised disease following prior external beam radiotherapy (2005–2012). No upper threshold was applied for risk category, PSA or Gleason grade either at presentation or at the time of failure. Progression was defined as a composite with biochemical failure (Phoenix criteria (PSA>nadir+2 ng ml−1)), start of systemic therapies or metastases.Results:Median age (interquartile range (IQR)), pretreatment PSA (IQR) and Gleason score (range) were 68 years (64–72), 5.9 ng ml−1 (2.2–11.3) and 7 (6–9), respectively. Median follow-up was 64 months (49–84). In all, 24/50 (48%) avoided androgen-deprivation therapies. Also, a total of 28/50 (56%) achieved a PSA nadir <0.5 ng ml−1, 15/50 (30%) had a nadir ⩾0.5 ng ml−1 and 7/50 (14%) did not nadir (PSA non-responders). Actuarial 1, 3 and 5-year progression-free survival (PFS) was 72, 40 and 31%, respectively. Actuarial 1, 3 and 5-year overall survival (OS) was 100, 94 and 87%, respectively. When comparing patients with PSA nadir <0.5 ng ml−1, nadir ⩾0.5 and non-responders, a statistically significant difference in PFS was seen (P<0.0001). Three-year PFS in each group was 57, 20 and 0%, respectively. Five-year OS was 96, 100 and 38%, respectively. Early in the learning curve, between 2005 and 2007, 3/50 (6%) developed a fistula. Intervention for bladder outlet obstruction was needed in 27/50 (54%). Patient-reported outcome measure questionnaires showed incontinence (any pad-use) as 8/26 (31%).Conclusions:In our series of high-risk patients, in whom 30–50% may have micro-metastases, disease control rates were promising in PSA responders, however, with significant morbidity. Additionally, post-HIFU PSA nadir appears to be an important predictor for both progression and survival. Further research on focal salvage ablation in order to reduce toxicity while retaining disease control rates is required.

Abstract 4339: Prognostic significance of copy number alteration burden in unfavorable intermediate-risk prostate cancers harboring intraductal carcinoma and cribriform architecture

Abstract Aim: Men with intermediate-risk prostate cancer represent a heterogeneous group of patients with varying prognoses. Intraductal carcinoma (IDC), cribriform architecture (CA), and high copy number alteration burden are novel pathological and genomic indices that predict aggressive disease and inferior clinical outcomes in patients with localised prostate cancer. We aimed to test the independent prognostic effect of these indices in a cohort of intermediate-risk prostate cancers. Experimental methods: We defined a set of clinical and genomic indices to test for their prognostic significance in a cohort of individuals with NCCN-defined intermediate-risk prostate cancer, who were treated with radical prostatectomy (RadP) or radiotherapy (RT) (N = 173, RadP; N = 358, RT). Clinical indices include primary T-category, pre-treatment PSA level, Gleason's score and pattern, and presence of IDC and/or CA. Pathological features were reviewed centrally by two expert pathologists. Copy number alteration burden was assessed in 215 tumours of the cohort using SNP array profiling (Affymetrix Oncoscan), and reported as percent genome aberration (PGA). Our primary endpoint was to test if a model incorporating IDC/CA and PGA stratifies patients with intermediate-risk disease for risk of biochemical relapse after primary treatment. Results: Biochemical relapse was associated with PGA on univariable and multivariable analysis for the sub-cohort of 215 patients (HR of High vs Low PGA defined by median = 1.61, 95% CI = 1.04-2.49, Wald's p = 0.033). Based on modelling of the clinical indices, presence of IDC/CA was associated with biochemical relapse-free rate (bRFR) on univariable and multivariable analyses (HR = 1.90, 95% CI = 1.34-2.69, p = 0.00034), along with PSA level. Risk stratification considering both IDC/CA and PGA indicated an additive prognostic effect of IDC/CA to PGA for early biochemical relapse, with 18-month bRFR of 83% in High PGA, present IDC/CA vs 94% in Low PGA, absent IDC/CA subgroups (HR = 2.55, 95% CI = 1.49-4.39, p = 0.00069). A comparison of risk stratification models revealed that inclusion of PGA to IDC/CA yielded the strongest model for predicting 18-month bRFR in patients with intermediate-risk prostate cancer following treatment (area under the curve, AUC = 0.580, 95% CI = 0.456-0.675 [T-category, PSA, and IDC/CA] vs 0.649, 95% CI = 0.476-0.776 [T-category, PSA, IDC/CA, and PGA]). Conclusions: We herein demonstrate for the first time a novel risk stratification model integrating pathological (IDC/CA) and genomic (PGA) indices to identify patients with unfavourable intermediate-risk prostate cancer, who may benefit from intensification to conventional definitive treatment. Citation Format: Melvin Lee Kiang Chua, Jure Murgic, Melania Pintilie, Emilie Lalonde, Charlotte Kweldam, Winnie Lo, Alejandro Berlin, Alan Dal Pra, Michele Orain, Valerie Picard, Helene Hovington, Alain Begeron, Yves Fradet, Bernard Tetu, Julie Livingstone, Alice Meng, Jun Yan Zhang, Gaetano Zafarana, Neil Fleshner, Mike Fraser, Paul Boutros, Robert Bristow, Theodorus van der Kwast. Prognostic significance of copy number alteration burden in unfavorable intermediate-risk prostate cancers harboring intraductal carcinoma and cribriform architecture. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4339.

SU-F-R-25: Automatic Identification of Suspicious Recurrent/residual Disease Regions After Prostatectomy

Purpose: To automatically identify and outline suspicious regions of recurrent or residual disease in the prostate bed using Dynamic Contrast Enhanced-MRI (DCE-MRI) in patients after prostatectomy. Methods: Twenty-two patients presenting for salvage radiotherapy and with identified Gross Tumor Volume (GTV) in the prostate bed were retrospectively analyzed. The MRI data consisted of Axial T2weighted-MRI (T2w) of the pelvis: resolution 1.25×1.25×2.5 mm; Field of View (FOV): 320×320 mm; slice thickness=2.5mm; 72 slices; and Dynamic Contrast Enhanced MRI (DCE-MRI)–12 series of T1w with identical spatial resolution to T2w and at 30–34s temporal resolution. Unsupervised pattern recognition was used to decompose the 4D DCE data as the product W.H of weights W of k patterns H. A well-perfused pattern Hwp was identified and the weight map Wwp associated to Hwp was used to delineate suspicious volumes. Threshold of Wwp set at mean(Wwp)+S*std(Wwp), S=1,1.5,2 and 2.5 defined four volumes labeled as DCE1.0 to DCE2.5. These volumes were displayed on T2w and, along with GTV, were correlated with the highest pre-treatment PSA values, and with pharmacokinetic analysis constants. Results: GTV was significantly correlated with DCE2.0(ρ= 0.60, p<0.003), and DCE 2.5 (ρ=0.58, p=0.004)). Significant correlation was found between highest pre-treatment PSA and GTV(ρ=0.42, p<0.049), DCE2.0(ρ= 0.52, p<0.012), and DCE 2.5 (ρ=0.67, p<<0.01)). Kruskal-Wallis analysis showed that Ktrans median value was statistically different between non-specific prostate bed tissue NSPBT and both GTV (p<<0.001) and DCE2.5 (p<<0.001), but while median Ve was statistically different between DCE2.5 and NSPBT (p=0.002), it was not statistically different between GTV and NSPBT (p=0.054), suggesting that automatic volumes capture more accurately the area of malignancy. Conclusion: Software developed for identification and visualization of suspicions regions in DCE-MRI from post-prostatectomy patients has been validated by PSA and pharmacokinetic constants analysis showing that it generates clinically relevant volumes.

Hypofractionated Volumetric Modulated Arc Radiotherapy with simultaneous Elective Nodal Irradiation is feasible in prostate cancer patients: A single institution experience

PurposeTo assess feasibility, toxicity and biochemical relapse-free survival (b-RFS) for a group of organ confined (OC) Saudi prostate cancer patients treated by hypo-fractionated Volumetric Modulated Arc Radiation Therapy (VMAT) Simultaneous Integrated Boost (SIB) Elective Nodal Irradiation (ENI) whole pelvic radiotherapy (WPRT). Patients and methodsBetween March 2009 and January 2014, 29 OC prostate cancer patients; median age 64years, PS 0–1 were treated in King Faisal Specialist Hospital – Riyadh, Kingdom of Saudi Arabia using VMAT–SIB–ENI–WPRT, to a total dose of 70Gy in 28 fractions. Twenty Four patients (83%) were treated with neo-adjuvant; concurrent androgen deprivation therapy (ADT). Median follow-up (FU) was 42months (range: 18–72months). ResultsThe 3-year actuarial b-RFS for low/intermediate and high risk groups were 100%, and 48%, respectively (p=0.09) with a median FU period of 34months (range: 14–53months). Gleason Score (p=0.02), and pretreatment PSA (p=0.01) were predictive for biochemical failure on univariate analysis; with no observed prostate cancer-related deaths. Grade 2 acute/late GI and GU toxicities were 28%/0% and 17%/10% respectively with no reported grade 3/4 toxicities. Four (50%) out of the 8 patients with baseline partial potency, retained sexual function on long term follow-up. ConclusionsHypo-fractionation dose escalation VMAT–SIB–ENI–WPRT using 2 arcs is a feasible technique for intermediate/high risk OC prostate cancer patients, with acceptable rates of acute/late toxicities, much favorable planning target volume (PTV) coverage, and shorter overall treatment time. Prospective randomized controlled trials are encouraged to confirm its equivalence to other fractionation schemes.

PD03-06 RADICAL PROSTATECTOMY FOLLOWING ACTIVE SURVEILLANCE IS ASSOCIATED WITH INCREASED RATES OF UNFAVOURABLE PATHOLOGY

You have accessJournal of UrologyProstate Cancer: Localized: Active Surveillance I1 Apr 2016PD03-06 RADICAL PROSTATECTOMY FOLLOWING ACTIVE SURVEILLANCE IS ASSOCIATED WITH INCREASED RATES OF UNFAVOURABLE PATHOLOGY Richard Savdie, Robert Bell, Jonathan Anning, Alan So, Martin Gleave, Peter Black, and Larry Goldenberg Richard SavdieRichard Savdie More articles by this author , Robert BellRobert Bell More articles by this author , Jonathan AnningJonathan Anning More articles by this author , Alan SoAlan So More articles by this author , Martin GleaveMartin Gleave More articles by this author , Peter BlackPeter Black More articles by this author , and Larry GoldenbergLarry Goldenberg More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2094AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Our centre has offered AS to men with very low to low-tier intermediate risk PCa based on patient and physician accepted balance of competing risks. We aimed to analyse the rates of unfavourable pathology in those undergoing radical prostatectomy (RP) following AS and compare these with a contemporary immediate RP group. METHODS Patients were stratified into very low risk (Epstein), low and intermediate NCCN risk groups. Rates of unfavourable pathology (predominant Gleason pattern 4 or ≥pT3 disease) and PSA failure following radical prostatectomy were analysed. A 2:1 propensity score matched analysis was performed using age, pre-treatment PSA, biopsy Gleason score and clinical T stage with a cohort of immediate RP patients from the same time period. RESULTS 651 men had AS (including 144 Intermediate Risk) with a median follow-up of 4.5 years (range 0.6-19.1). 203 patients had radical prostatectomy after AS (AS+RP) with an overall rate of unfavourable pathology of 34.9%. 195 AS+RP were matched to 390 immediate RP (IRP) with excellent correlation between covariates. The median time to surgery was 1.59 years for the AS+RP group vs 0.3 years for the IRP group ( p<0.001). There were slightly higher rates of EPE in AS+RP vs IRP group but this was not statistically significant (20% v 17%, p=0.5). Predominant Gleason pattern 4 was seen in significantly more men who had delayed RP compared to their matched counterparts (24.6% vs 12%, p<0.001). There was no difference in unfavourable pathology in the very low risk AS+RP vs IRP group (p=0.17). Despite differences in unfavourable pathology, there was no difference in the PSA failure free survival between the two groups at 3 years (Log Rank, p=0.47). CONCLUSIONS Active surveillance carries an increased risk of unfavourable pathology at the time of delayed RP in low and intermediate but not very low risk groups. Early data suggests that PSA recurrence rates are similar following RP despite delay in treatment. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e58 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Richard Savdie More articles by this author Robert Bell More articles by this author Jonathan Anning More articles by this author Alan So More articles by this author Martin Gleave More articles by this author Peter Black More articles by this author Larry Goldenberg More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

V4-03 CONCOMITANT URETHRAL SLING AT THE TIME OF ROBOTIC PROSTATECTOMY USING AN IN SITU VASCULARIZED ROTATIONAL PERITONEAL FLAP

You have accessJournal of UrologyRobotics – Prostate/Novel Imaging1 Apr 2016V4-03 CONCOMITANT URETHRAL SLING AT THE TIME OF ROBOTIC PROSTATECTOMY USING AN IN SITU VASCULARIZED ROTATIONAL PERITONEAL FLAP Tom Feng, Lauren Wood, and Soroush Ramin Tom FengTom Feng More articles by this author , Lauren WoodLauren Wood More articles by this author , and Soroush RaminSoroush Ramin More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1807AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Post prostatectomy stress urinary incontinence is common. Many men ultimately require surgical intervention for correction of their incontinence. Our objective was to describe our initial experience with a novel technique performed at the time of robotic prostatectomy to improve postoperative continence. METHODS The technique consists of a suburethral hammock using a vascularized flap of peritoneum. During the dissection of the seminal vesicles through the posterior cul de sac, a 4 cm flap of peritoneum is raised off the posterior bladder. Upon completion of the prostatectomy and bilateral pelvic lymphadenectomy, the flap is placed onto the prostatic fossa with the peritoneal surface facing the anastomosis. The posterior urethral stitch is placed through the cut edge of the peritoneal flap and then on to the posterior bladder neck. Three such sutures are placed at 5, 6 and 7 o'clock bringing together urethra, edge of peritoneal flap, and bladder neck. The remainder of the urethrovesical anastomosis is then performed. An absorbable suture is placed along each lateral aspect of the peritoneal flap at the level of the anastomosis and secured to the periosteum of the pubic bone directly anterior to the anastomosis, thereby lifting the urethrovesical anastomosis and placing it to its normal anatomic position and angle. RESULTS 113 men with complete 2 year follow-up after robotic assisted laparoscopic prostatectomy with concomitant sling were identified. Mean age was 63 and pretreatment PSA was 9.15 ng/mL. The majority of men had clinical T1c disease with Gleason grades 6 and 7. At one month postoperatively, pad usage per day was reported as 0 pads in 36% of men, 1 pad in 21%, 2 pads in 11%, and 3 or more pads in 32%. Pad use decreased over time with less than 6% of patients reporting using more than 1 pad per day at 24 months follow-up (Figure 1). No clinical urine leaks, urinary retention, bladder neck contractures, or significant voiding complaints were noted. CONCLUSIONS Our experience with this novel technique using a well vascularized peritoneal flap at time of vesicourethral anastomosis is a safe and effective method that appears to improve early return of continence in men undergoing robotic prostatectomy. Further research is needed to recommend its universal use. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e517 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Tom Feng More articles by this author Lauren Wood More articles by this author Soroush Ramin More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...