bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiplexed protein and gene profiling of circulating tumor cells (CTCs) in metastatic castration-resistant prostate cancer (mCRPC) using automated immunofluorescence and fluorescence in situ hybridization.
Authors: Nagy Dea , Tucker Eric , Rajkovich Samatha , French Steven , Garsha Karl , Yun Steve , Smith Katherine , Sallam Karim , Liabotis Elias , Otter Michael , Marrinucci Dena , Dittamore Ryan
Published: February 2017

158

Background: Clinically, CTCs are used primarily in longitudinal monitoring of metastatic disease progression. However, the analysis of specific CTC biomarkers has the potential to optimize patient management by identifying those likely to respond to specific targeted agents. Often, mCRPC is driven by dysregulation of the androgen receptor (AR) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) oncogenic pathways such that blockade of one pathway stimulates the other. These functional deficits in the AR and PI3K/AKT pathways are associated with fusion of the TMPRSS2 and ERG genes and with loss of PTEN protein, respectively. Therefore, we sought to characterize CTCs for the simultaneous presence of both these biomarkers using immunofluorescence (IF) and fluorescence in situ hybridization (FISH). Methods: Nucleated peripheral blood cells from mCRPC patients were attached to slides and examined using CTC technology (Epic Sciences). Cytokeratin-positive/CD45-negative cells with an intact nucleus and a malignancy-consistent morphology were identified as CTCs, and their exact positions on the slides were recorded. The slides were then subjected to multiplex Quantum Dot IF and FISH procedures with anti-AR, -ERG, and -PTEN antibodies and 5’ERG, 3’ERG, PTEN, and Cen10 probes, respectively, on an automated slide-staining platform (Ventana Medical Systems, Inc.). The IF and FISH signals were visualized by spectral imaging (Ventana). Results: The automated IF/FISH staining procedure facilitated multiplex characterization of individual CTCs from patient samples for the protein biomarker targets AR, ERG, and PTEN and the genomic biomarker targets 5’ERG, 3’ERG, PTEN, and Cen10. Conclusions: This method for high-sensitivity, multiplex molecular characterization of critical CTC biomarkers in mCRPC patients might aid oncologists in identifying and stratifying those patients likely to respond to combination therapy with targeted PI3K/AKT inhibitors and anti-androgens/Cyp17 inhibitors. Patient trials examining the clinical utility of this assay in mCRPC are currently underway.
Castration resistance and risk of bone metastases among men with nonmetastatic prostate cancer on androgen-deprivation therapy: A population-based cohort study from the Henry Ford Health System (HFHS) in Detroit, Michigan.
Authors: Beebe-Dimmer Jennifer , Cetin Karynsa , Yee Cecilia , Stryker Scott , Lamerato Lois , Schwartz Kendra L. , Shahinian Vahakn B.
Published: February 2017

163

Background: Androgen deprivation therapy (ADT) is the cornerstone treatment of metastatic prostate cancer (PC), but is frequently used in the non-metastatic (M0) setting. After a variable period of hormone sensitivity, most patients develop castration-resistant prostate cancer (CRPC). These men are at increased risk of developing bone metastases (BM), particularly in those with higher serum PSA and shorter PSA doubling time (DT). The epidemiology and natural history of M0 CRPC has not been well studied in a population-based setting. Methods: Using HFHS patient records, a retrospective cohort study was conducted among 723 men diagnosed with M0 PC between 1996 and 2005 (with follow-up [f/u] for outcomes through 12/31/2008), who received ADT, including 613 men with serial PSA measurements for CRPC determination. CRPC was defined as 2 consecutive PSA rises, with “high-risk” defined as PSA ≥ 8 ng/mL or PSA DT ≤ 10 months (mos) after the development of CRPC. The risk of subsequent BM was estimated for the overall cohort and for the CRPC and non-CRPC subsets. Results: The median age among patients in the study was 73 years, 48% were African American, and median f/u time after ADT initiation was 58 mos. 15% (n=93) met criteria for CRPC during f/u (with a median of 23 mos between ADT initiation and establishment of CRPC), with the majority considered being at high risk (n=81). Among the entire cohort, 74 men (10%) developed BM during f/u. The rate of BM was 4 times higher among CRPC patients compared to non-CRPC patients (p<0.001), with a median of 6 mos between CRPC and subsequent BM. No racial difference was observed with either the incidence of CRPC or BM. Conclusions: The HFHS resource allowed for investigation of disease progression in a racially diverse population. A substantial proportion of M0 PC patients on ADT will eventually develop CRPC and once castration-resistant, risk of BM is high.
Stereotactic body radiation therapy (SBRT) following procedures for benign prostatic hyperplasia (BPH): A report on early toxicity.
Authors: Gurka Marie Kate , Horne Zachary D. , Chen Leonard , Lei Sue , Krishnan Pranay , Kowalczyk Keith , Suy Simeng , Dritschilo Anatoly , Lynch John H. , Collins Sean P.
Published: February 2017

165

Background: When treating patients with prostate cancer, hypofractionation with SBRT takes advantage of radiobiologically favorable factors as compared to conventional fractionation. However, this may increase the risk of urinary toxicity, especially in patients with prior procedures for BPH. Herein, we report early urinary toxicity following SBRT in patients with a history of procedures for BPH. Methods: Thirty three patients treated with SBRT for localized prostate cancer from February 2009 to October 2011 at Georgetown University Hospital with history of a prior procedure for BPH were included in this retrospective analysis. Treatment was delivered using the CyberKnife with doses of 35 Gy-36.25 Gy in 5 fractions. Toxicities were scored using the CTCAE v.3. Cystoscopy findings were retrospectively reviewed. Patient-reported urinary symptoms were assessed using the American Urological Association Symptom Score (AUA). Results: The median age was 70 years (range, 64 - 84). The median follow-up time was 18.7 months (range 9.2 – 38.9). Grade 2 or 3 urinary toxicity occurred in 9 patients and there were no grade 4 or 5 toxicities. Hematuria occurred in 12 patients. The median time to onset of hematuria from SBRT was 6 months (range 1 – 30). Grade 1 hematuria occurred in 7 patients, grade 2 in 4 patients and 1 patient experienced grade 3. Cystoscopy was performed in 9 of these patients at a median time of 9 months (range 3-27). Eight had hyperemia or evidence of bleeding from the prostatic urethra and 5 of these patients also had evidence of bleeding from the bladder neck/wall. All patients except one, who died from other causes, are still being followed and hematuria has resolved in 9 of the 12 patients. The median baseline AUA symptom score of 7 increased to 11 at 1 month, however decreased to a median score of 6 at 3 months. The median AUA symptom score increased to 9 at 1 year. Conclusions: A history of prior transurethral resection of prostate may predispose patients to increased urinary toxicity and hematuria following prostate SBRT. Stricter urethra/bladder neck dosimetric criteria or alternative fractionation regimens may be required to decrease urinary toxicity in these patients.
PSA doubling time of ≤6 months as the optimal cutoff for predicting clinically relevant outcomes for men receiving salvage radiation therapy post radical prostatectomy.
Authors: Jackson William C. , Johnson Skyler B. , Foster Benjamin , Foster Corey , Song Yeohan , Li Darren , Sandler Howard Mark , Palapattu Ganesh S. , Hamstra Daniel A. , Feng Felix Yi-Chung
Published: February 2017

167

Background: Short PSA doubling time (PSADT) after biochemical recurrence (BR) post radical prostatectomy (RP) is known to predict worse outcomes following salvage external beam radiation therapy (SRT). The ideal PSADT cut-off, however, in this context remains uncertain. In this study, we sought to identify the best PSADT cut-off for predicting clinical outcomes following SRT for BR after RP. Methods: 575 patients who received SRT at a single institution for BR after RP were retrospectively reviewed in an IRB approved analysis. The impact of PSADT on biochemical failure (BF), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall survival (OS) was assessed using Kaplan-Meier and Cox Proportional Hazards models. Results: Median follow up was 56.7 months post SRT. PSADTs could be calculated for 277 patients. PSADT strongly predicted BF, DM, PCSM, and OS on univariate analysis regardless of cut-off point. There was no statistical difference in BF, DM, PCSM, or OS between patients with PSADT <3 (n=40) and 3-6 months (n=61) or between 6-10 (n=62) and >10 months (n=114). A difference existed in BF (p<0.01 HR: 2.2 [95%CI: 1.4-3.5]) and DM (p=0.02 HR: 2.2 [95%CI: 1.2-4.3]) between PSADT of 3-6 and 6-10 months. PSADT ≤6 had the largest positive predictive value (PPV) for BF (70%), DM (36%), and PCSM (13%) at 5 years. There was no difference in negative predictive value between a PSADT >10 vs. >6 months for BF, DM, PCSM, and OS with 5 year rates of (60% vs. 60%, 86% vs. 86%, 99% vs. 98%, and 95 vs. 94% respectively). On multivariate analysis PSADT ≤6 was a strong predictor of BF (p<0.01 HR: 2.1 [95%CI: 1.5-3.0]), DM (p=0.01 HR: 2.0 [95%CI: 1.2-3.4]), and PCSM (p=0.04 HR: 2.3 [95%CI: 1.1-5.2]), with a trend towards predicting OS (p=0.12 HR: 1.5 [95%CI: 0.9-2.6]). Conclusions: A PSADT ≤6 months was the best predictor of outcomes in our data set, particularly for DM and PCSM. Currently, the most common predictive nomogram for SRT uses PSADT <10 months as the cut-off point for BF. These results suggest that using a PSADT of ≤6 months may improve the ability to predict clinically significant outcomes and hence identify men who may benefit from additional therapy.
Long-term tolerance of neoadjuvant docetaxel/estramustine chemotherapy in patients with high-risk localized prostate cancer treated at IGR in the GETUG 12 phase III trial.
Authors: Bosset Pierre-Olivier , Albiges Laurence , Laplanche Agnes , Massard Christophe , Loriot Yohann , Di Palma Mario , Fizazi Karim
Published: February 2017

168

Background: The GETUG 12 phase III trial tested the adjunction of docetaxel-estramustine to standard treatment in 413 patients with high-risk prostate cancer (Eur J Cancer 2012, 48: 209-17). Patients in both arms received androgen deprivation therapy (ADT) for 3 years plus local treatment (radiotherapy: 87%, median dose: 74 Gy). Pts in the chemotherapy arm also received 4 cycles of docetaxel 70mg/m2 /3weeks + estramustine 10 mg/kg/d d1-5, repeated every 3 weeks. Immediate tolerance was acceptable with only 2% of febrile neutropenia and no toxic deaths. As the long-term impact of chemotherapy in this setting is unknown, long-term side effect assessment was undertaken in pts from GETUG 12 who were treated at the Institut Gustave Roussy (n=81). Methods: After pts had completed the planned 3 years of ADT, they were followed-up every 6 months. Data on weight, sexual function, serum testosterone, and cardiac complications were obtained prospectively, in parallel with efficacy data. Pts requiring salvage therapy for cancer progression were censored in this analysis. Results: The median follow-up is 71.6 months (range: 36- 108 months). The main long-term side effects are listed in the table below. 4 (4.9%) and 1(1.2%) cardiovascular events occurred in the ADT and the ADT + chemotherapy arm, respectively. Conclusions: Docetaxel-estramustine chemotherapy had no adverse long-term impact on serum testosterone, weight, and sexual function in patients with high-risk localized prostate cancer treated with ADT and radiotherapy. [Table: see text]
Variations in treatment modality use for the definitive management of prostate cancer in the United States.
Authors: Ciezki Jay P. , Reddy Chandana A. , Ulchaker James , Angermeier Kenneth , Stephans Kevin L. , Tendulkar Rahul D. , Stephenson Andrew J. , Chehade Nabil , Altman Andrew , Klein Eric A.
Published: February 2017

174

Background: No prospective, randomized comparative efficacy trial exists to guide treatment of definitively managed prostate cancer patients. Despite this, treatment selection varies nationally and we attempt to assess these patterns of use. Methods: The SEER database was queried to identify cases of prostate cancer diagnosed between 1998-2008. The modalities identified were brachytherapy (brachy), combination of brachytherapy and external beam radiation (CombRT), external beam radiotherapy (EBRT), radical prostatectomy and external beam radiotherapy (RP+RT), and radical prostatectomy (RP). The number of cases by year, patient age and SEER region was computed. Results: There were 361,135 men in this analysis: 12.4% brachy, 6.8% CombRT, 27.5% EBRT, 3.1% RP+RT, and 50.3% RP. As expected, treatment modality varied by age with younger men more likely to receive RP and older man more likely to receive EBRT or brachy. There was some variation in choice of treatment modality over time: 6.6% for brachy; 4.2% for CombRT; 1.9% for EBRT; 2.0% for RP+RT; and 7.8% for RP. The variation in treatment modality by region was surprisingly wide (table): 14.4% for brachy; 25.5% for CombRT; 28.5% for EBRT; 3.8% for RP+RT; and 26.8% for RP. Conclusions: Choice of prostate cancer treatment modality varies by age, year of treatment, and most notably geographical region. Surprisingly the changes in reimbursement rates over the study period seem to have had minimal impact on choice of treatment modality. The regional variation implies that affiliations among healthcare providers significantly impact treatment. [Table: see text]
Heterogeneity of treatment effects (HTE) in stage IV prostate cancer (S4PC).
Authors: Mitikiri Nirupama Devi , Reese Emily S , Hussain Arif , Onukwugha Ebere , Pritchard Daryl , Dubois Robert W. , Mullins C. Daniel
Published: February 2017

180

Background: HTE occurs when individual patient factors modify a treatment’s effect on health outcomes in a non-random and predictable manner. HTE results in specific subgroups of patients in the same study having different responses to the same treatment due to interactions between their individual factors and the treatment. Methods: A systematic literature review was conducted of articles published between 1946 and 2011. Inclusion criteria required that articles examine the impact of HTE factors on survival outcomes (OS, TTP, PFS) or QOL among S4PC patients, in the context of a specific treatment. The quality of evidence was graded as good, fair or poor, per AHRQ guidelines. Results: The search identified 2,659 articles of which 92 met study inclusion criteria. Most articles (46%) were post-hoc analyses of randomized clinical trials. PC treatments included chemotherapy, radiation, hormonal therapy (74%) and bone-modifying agents. HTE in S4PC was identified for both biologic and non-biologic factors. Factors related to clinical signs/symptoms, laboratory tests and disease severity have been extensively studied in the literature (Table). Age and race seldom showed any correlation with PC outcomes. Conclusions: Current evidence reveals diverse factors contributing to HTE in S4PC. Ultimately, such knowledge can help oncologists prescribe more personalized medicine, help patients make more informed treatment choices, and inform policy making and treatment coverage decisions. [Table: see text]
Genetic instability after radiotherapy in prostate cancer: TMRSS2-ERG fusion in salvage radical prostatectomies.
Authors: Pfister David J. K. P. , Lindemann Katarina , Porres Daniel , Piper Charlotte , Knuchel Ruth , Heidenreich Axel
Published: February 2017

182

Background: TMRSS2-ERG fusion is the most frequent genetic abberation in prostate cancer. Till now its expression is not associated with a poorer prognosis. In cell line models the fusion can be induced by exogenic factors as hormonal treatment or radiotherapy. Additionally its expression leads to different sensitivities to radiotherapy in different cell line models. We analyzed TMPRSS2-ERG fusion for the first time in patients with salvage radical prostatectomy and correlated it to radical prostatectomy specimen without prior treatment. Methods: 38 radical prostatectomy specimen of patients formaly treated with radiotherapy and recurrent disease and 38 primary RPEs were analyzed for ERG expression (15 external RT, ERT, 18 LDR, 5 HDR). ERG expression was detected by a highly sensitive monoclonal antibody as described recently. Results: Median PSA preoperatively was 3.6 (0.1-27) ng/ml. More patients had locally advanced dieseasae in the final pathologic specimen (17:21). In 18 (47,4%) patients (8 (44,4%) in LDR, 3 (60%) in HDR, 7(46,7%) in ERT) an ERG expression was detected. There is no difference in the ERG expression compared to an independend cohort of radical prostatectomy specimen (47,4% versus 47,4%). Conclusions: We are the first to analyze ERG expression in salvage radical prostatectomies. In this cohort there is no difference in the ERG expression rate after applied radiotherapy. The risk of inducing a gene fusion by external influence as seen in cell cultures cannot be transferred to daily practice.
Wait time intervals for patients with prostate cancer in a multidisciplinary rapid diagnostic unit compared to a community-based referral pattern.
Authors: Sethukavalan Perakaa , Zhang Liying , Jethava Vibhuti , Stevens Christiaan , Flax Stan , Buckley Roger , Bondy Sue , Loblaw D. Andrew
Published: February 2017

183

Background: Wait times in cancer diagnosis and treatment are important measures of how quickly patients are getting access to care. Prolonged wait times may affect a cancer patient’s treatment outcome, prognosis and quality of life. A previous study conducted in 2003 found the median wait time from suspicion of prostate cancer to radiotherapy (RT) was 247 days. The purpose of this study was to capture wait time intervals for patients referred to and treated with radical RT at the Odette Cancer Centre, comparing patients diagnosed in a rapid diagnostic unit (RDU) versus the usual community referral process. Methods: Patients were screened during RT planning for their newly diagnosed, biopsy-confirmed prostate adenocarcinoma. A semi-structured interview and chart abstraction was conducted in order to obtain the best estimation of key wait time milestones in the care pathway. Results: A total of 87 patients participated in the study: 44 RDU patients and 43 community patients. The median overall wait time interval from suspicion of prostate cancer to RT was 138 days for the RDU cohort and 183 days for the community cohort (p=0.046). There were statistically significant differences between the two cohorts, favouring the RDU cohort, for other key intervals, namely, suspicion to decision-to-treat (DTT; p=0.012), urologist to diagnosis (p=0.0094), diagnosis to DTT (p=0.018), and diagnosis to treatment (p=0.016). Among all patients, 25% perceived a delay in treatment and among those patients, 64% identified a systematic reason for the delay. There was no significant difference on the cause of delay between the RDU and community cohorts (p=0.86). Conclusions: Wait time intervals from suspicion to treatment are significantly shorter for prostate cancer patients in 2011-2 than in 2003 when diagnosed and referred in the community setting. A prostate-specific RDU further reduced wait time intervals supporting more multidisciplinary RDUs for common diseases. However, even in the RDU system, a minority of patients met provincial consensus-based wait time standards. Further work needs to be done to identify why delays are occurring and develop new processes to minimize delays.
Photoselective vaporization of the prostate compared to transurethral resection of the prostate in patients who develop prostatic obstruction following brachytherapy.
Authors: Abelson Benjamin , Reddy Chandana A. , Ciezki Jay P. , Angermeier Kenneth , Ulchaker James , Klein Eric A. , Wood Hadley
Published: February 2017

187

Background: Patients who undergo brachytherapy are at risk of developing prostatic obstruction, and a subset of these patients requires prostate reduction surgery. These patients pose a challenge to urologists who seek to determine the appropriate form of intervention given the reduced healing capacity of irradiated tissue. Given our observation that certain patients suffer recalcitrant prostatic obstruction following photoselective vaporization of the prostate (PVP), we evaluated outcomes after TURP compared to PVP for patients who experienced bladder outlet obstruction after brachytherapy. Methods: Cleveland Clinic’s prostate cancer database includes 3,600 patients who have undergone prostate brachytherapy since 1996. We cross-referenced these patients with the EMR to identify patients who required prostate reduction surgery following brachytherapy. We reviewed operative notes for these patients to identify the type of intervention completed, and we used the EMR to identify post-PVP/TURP complications requiring intervention. Clinical and demographic characteristics were obtained from the prospective database. Results: Sixty of the 3,600 patients developed urinary retention requiring prostate reduction surgery. The average age of these patients was 69 and the average prostate size was 52 grams. Forty patients underwent TURP and 20 patients were treated with PVP. Of the TURP patients, 19/40 (47.5%) required subsequent TURP, dilation, incision or permanent diversion, including 9 patients (22.5%) who required at least 2 further procedures. Of the PVP-treated patients, 10/20 (50%) required subsequent instrumentation including 4 (20%) who underwent at least 2 procedures. Conclusions: Half of the patients who require prostate reduction surgery for urinary retention following brachytherapy may require further procedures regardless of whether TURP or PVP is performed. Neither procedure confers less morbidity. [Table: see text]
Novel methodology for cost evaluation of anticancer drugs in castrate-resistant prostate cancer.
Authors: Guirgis Helmy M.
Published: February 2017

200

Background: There is a need for a screening methodology to evaluate cost effectiveness of anticancer drugs. High costs raise concerns on approval, affordability and utilization. Objectives: Develop simplified methodology to screen and score cost versus value survival of docetaxel, cabazitaxel, abiraterone and sipuleucel-T in castrate- resistant prostate cancer (CRPC) Methods: Estimated costs in US $ of the entire course of an evaluated drug were added to downstream ancillary costs. The total was divided by the reported median survival gain over control in days. A reference value scale between 0- 100% was constructed with 0% assigned to cost/overall survival (OS) > $750, life threatening/ fatal adverse events (AEs) and worsened quality of life (QoL). A plan was designed to correct for AEs and QoL. Results were expressed as cost/OS and value and corrected scores. Results: Abiraterone at $5,000 per month x 6 months demonstrated cost/OS of $256 with 66% value and 61% corrected scores. Abiraterone x 9-12 months raised cost/OS and decreased scores. Generic docetaxel x 8 cycles demonstrated $63 cost/OS and 92% value score. Ancillary treatment increased cost/OS to $136 and decreased score to 82%. Cost/OS of cabazitaxel x 6 cycles ranged from $477- $596 with 21-36% scores. Corrections for AEs and QoL reduced scores to 6-21%. Sipuleucel-T demonstrated relatively higher cost/OS and lower scores. Conclusions: Preliminary findings would support utilization of docetaxel and abiraterone more than cabazitaxel and sipuleucel-T. The proposed methodology of cost versus value-survival could facilitate cost evaluation and budgetary planning of anticancer drugs.
Stability of white blood cell counts following standard radiation approaches for high-risk adenocarcinoma of the prostate: Implications for combination therapy.
Authors: Finkelstein Steven E. , Myslicki Francisco A. , Salenius Sharon , Mantz Constantine , Shore Neal , Fernandez Eduardo , DeVries Todd , Sims Robert Brownell
Published: February 2017

201

Background: Traditional wisdom has suggested that under some circumstances radiation therapy may be immunosuppressive, thus obviating effective combination approaches with immunotherapy. Our purpose was to test whether standard radiation therapy for high-risk prostate cancer are immune modulating, thereby prohibiting potential combination with cellular based immunotherapies such as sipuleucel-T. Methods: Retrospective analysis of complete blood count with differential (CBC) data was performed on 26 patients with high-risk adenocarcinoma of the prostate undergoing external beam radiation therapy between January 2008 and November 2010. CBC data were collected prior to radiation therapy and at up to 4 time points thereafter, and compared to normal ranges from an outside reference lab (WBC 3,800-10,700/μL; ALC 910-4,280/μL). Results: The median age was 73 (range 62-86), and 16 patients were on concurrent androgen deprivation therapy. Patients received intensity modulated, dose-escalated external beam radiotherapy. Baseline and subsequent median white blood counts (WBC) and absolute lymphocyte counts (ALC) remained within the normal ranges. In the clinically relevant time frame of <3 months following radiation therapy where sipuleucel-T could be considered, the WBC and ALC were 5,350 and 970, respectively. The median WBC and ALC then gradually increased to 5,800 and 1,250, respectively, at 6-12 months post radiation therapy. Conclusions: These data suggest that in the setting of external beam radiation approaches for high-risk adenocarcinoma of the prostate, no significant changes in either WBC or ALC were observed. The hematologic status in these patients remained stable, suggesting that combination radiation / cellular based immunotherapy approaches are feasible. Further analysis is warranted to test the potential of novel immunotherapeutic agents with radiation therapy. [Table: see text]
Health services utilization differences between patients with metastatic (M1) and nonmetastatic (M0) prostate cancer (PCa).
Authors: Yong Candice , Onukwugha Ebere , Mullins C. Daniel , Seal Brian S. , Hussain Arif
Published: February 2017

203

Background: Metastatic (M1) disease is diagnosed in up to 5% of PCa patients, but there is limited information about the differences in health services utilization between stage IV M1 and stage IV M0 patients in the one year leading up to and following diagnosis. Methods: We analyzed patients aged 66 or older from the linked Surveillance, Epidemiology, and End Results & Medicare (SEER-Medicare) database. Patients with incident stage IV PCa diagnosed between 2005 and 2007 were identified and followed until one year post-diagnosis. Health services utilization measures included skilled nursing facility (SNF) stay, hospice stay, hospitalization, use of walking aid, wheelchair, and oxygen. We calculated the proportion of M1 and M0 patients utilizing each health service in the year before and after diagnosis. Results: Application of inclusion criteria resulted in 3,379 patients, of which 671 (19.9%) had M0 and 2,708 (80.1%) had M1 disease. The mean (median) age of the sample was 78 (77) years. The increase in the percentage of patients with SNF stay from the year prior to diagnosis to the year post-diagnosis was much larger in the M1 population (M0: 2.1% to 8.7%; M1: 5.2% to 23.6%). The proportion of M1 patients with hospice stay increased from 0.1% in the year prior to diagnosis to 21.1% in the year post-diagnosis, compared to an increase from 0% to 5.1% in the M0 population. Compared to M0 patients, M1 patients also exhibited greater increases in oxygen use (M0: 5.3% to 6.6%; M1: 6.5% to 12.6%), walking aid use (M0: 3.4% to 4.3%; M1: 3.5% to 10.6%), and wheelchair use (M0: 1.8% to 4.5%; M1: 4.1% to 11.4%) in the year following diagnosis. However, the increase in hospitalization in the year following diagnosis was lower in the M1 population (M0: 17.9% to 76.9%; M1: 24.4% to 66.6%). Conclusions: Among stage IV PCa patients, health services utilization is generally higher for M1 patients than M0 patients in the one year following diagnosis. However, hospitalization is lower among M1 patients compared to M0 patients in the one year following diagnosis. The finding that more than 20% of M1 patients had SNF and hospice stays in the one year following diagnosis suggests that M1 PCa is associated with substantial disease burden.
Effect of dutasteride on tumor proliferation during the regrowth phase of intermittent androgen ablation therapy in men with advanced prostate cancer.
Authors: Shevrin Daniel H. , MacVicar Gary R. , Kuzel Timothy , Stadler Walter Michael , Jovanovic Borko , Kaul Karen , Wang Zhou
Published: February 2017

21

Background: We have previously shown in an animal model of IAAT that blocking testosterone (T) to DHT by a 5α-reductase inhibitor (5ARI) has a more significant effect on tumor growth in a "regressed" prostate, ie previously treated with AAT, than in an "intact" prostate. It was also observed that 5ARI significantly inhibited tumor proliferation, but only early in the regrowth phase. A randomized phase II trial was done in which dut or placebo was given during the regrowth phase and a prostate biopsy was done to measure tumor proliferation. Methods: Eligible patients (pts) had metastatic, castrate-sensitive prostate cancer and had an intact prostate (no previous surgery or XRT). Treatment consisted of AAT for 8 months. Responding pts were randomized to receive dut (0.5 mg daily) or placebo during the regrowth phase. When serum T normalized, pts underwent a research biopsy of the prostate and then were resumed on AAT. Responding pts were then crossed-over to receive dut or placebo during the second regrowth phase. When T normalized, a second research biopsy was done and the pts resumed AAT. PSA levels were measured monthly to determine PSA doubling time (PSADT). Tumor proliferation was measured by Ki-67 index. Statistical analysis was by students t-test. Results: 21 pts were enrolled onto the study. 16 pts were randomized to dut vs placebo and 11 pts underwent prostate biopsies. Dut resulted in significant inhibition of tumor proliferation as measured by Ki-67 index compared to placebo (3.65 ± 1.7 vs 8.5 ± 2.3, p=0.001). PSADT during the regrowth phase was similar between the 2 groups. Dut was well tolerated without significant toxicities. Conclusions: The clincial observation of an early inhibitory effect of 5ARI on tumor proliferation during regrowth of a regressed (treated) prostate is novel and was similar to that observed in our animal xenograft model of IAAT. This suggests that using a 5ARI during the regrowth phase of IAAT and using T normalization as the trigger for resumption of AAT may result in improved efficacy of this treatment. This study was supported in part by NIH Grant P50 CA90386 (Prostate SPORE). Clinical trial information: NCT00668642.
Effect of simultaneous blockade of androgen and estrogen receptors on prostate cancer: In vivo study.
Authors: Nunez-Nateras Rafael , Ferrigni Erin N. , Gades Naomi M. , Castle Erik P.
Published: February 2017

214

Background: In our preliminary in vitro studies, we have demonstrated evidence of enhanced apoptosis and inhibition of cellular proliferation in both hormone sensitive and castrate resistant prostate cancer (PCa) cell lines using a combination of an antiandrogen (Bicalutamide) and a selective estrogen receptor modulator (Raloxifene). The aim of this study was to study the effect of the administration of these two drugs in in vivo models of castrate resistant PCa. Methods: In vivo model consisted on NCr Nude: Mice bearing s.c. human prostate (PC3 cell line) xenografts. Based on the treatment received, mice were divided into 5 groups as follows: Group 1: No drugs (control); Group 2: Bicalutamide 50mg; Group 3: Raloxifene 60 mg; Group 4: Combined administration of Bicalutamide 50 mg and Raloxifene 60 mg; Group 5 Combined administration of Bicalutamide 150 mg and Raloxifene 120 mg. A total of 10 mice where included in each group. All drugs dosages were converted to their equivalent in the mice. Drugs were administered by gavage technique to the mice once per day for a total of 14 days. Results: As expected, Bicalutamide administered alone causes minimal inhibition without reaching statistical significance (Group 2: 0.34 g Vs Group 1: 0.40 g; p=0.073). Although Raloxifene causes some marked growth inhibition, its effect is not statistically significant (Group 3: 0.31 Vs Group 1: 0.40 g; p=0.062). Bicalutamide and Raloxifene, when administered in combination, induced prominent growth inhibition in PC3 tumors when compared to the control group (Group 4: 0.26 g Vs Group 1: 0.40 g; p=0.038). Growth inhibition is significantly more evident when the drugs dosages are increased (Group 5: 0.17 g Vs Group 1: 0.40 g; p=0.024). Conclusions: The simultaneous administration of Bicalutamide and Raloxifene appears to have a synergistic effect on tumor growth inhibition in PC3 xenografts. The pathway(s) responsible for this observation may be independent of the androgen receptor as PC3 cells are AR negative and still affected by the combination over the drugs administered alone. Research is warranted to identify these potential pathways.
Prognostic value of serum androgens, by ultrasensitive assay, in metastatic castration-resistant prostate cancer (mCRPC): Phase III trial data.
Authors: Ryan Charles J. , Molina Arturo , Li Jinhui , Kheoh Thian San , Small Eric Jay , Haqq Christopher M. , Grant Russell P , De Bono Johann Sebastian , Scher Howard I.
Published: February 2017

22

Background: Serum testosterone (T) and precursors, dehydroepiandrosterone sulfate (DHEAS) and androstenedione (A4), may be prognostic of overall survival (OS) by identifying patients (pts) with varying dependency on androgen. To test this hypothesis, we investigated the relationship between the distribution of serum androgen concentrations measured by ultrasensitive mass spectrometric assays with OS, in pts with mCRPC treated in COU-AA-301, a randomized phase III study of abiraterone acetate (AA)(1000mg) plus prednisone (P) vs P. Methods: Pts were stratified by ECOG PS (0-1 vs 2), pain (present vs absent), prior chemotherapy regimens (1 vs 2), and type of progression (PSA only vs radiographic). Eligibility required baseline T ≤50 ng/dL. In a post hoc exploratory analysis, the effect of baseline serum androgen levels (T, DHEAS, A4) on OS (95% CI, months), stratified by quartiles of each androgen was determined. T, DHEAS, and A4 serum levels were measured using novel liquid-liquid extraction 1D or 2D-LC/tandem mass spectrometry ((LC)-LC-MS/MS) assays. Univariate and multivariate analyses using the Cox proportional hazards regression model were performed. Results: Baseline T levels were available from 97% of pts (93% with baseline T ≤15 ng/dL). Median OS increased in a step-wise fashion per T quartile, regardless of treatment (p<0.0001) (Table). Similar results were observed for DHEAS and A4. A positive association was observed in the multivariate analysis adjusted for treatment, other androgens, and lab parameters (LDH, HGB, ALKP, PSA; all p<0.0001). In AA and P-treated pts, respectively, the hazard ratio for OS (95% CI) comparing pts with baseline T above and below baseline median was 0.64 (0.53-0.77; p<0.0001) and 0.51 (0.39-0.67; p=0.0004). Conclusions: Baseline serum androgen concentrations as measured by an ultrasensitive mass spectrometric assay may be prognostic of OS in mCRPC pts and bear consideration as a stratification variable in phase III studies. Clinical trial information: NCT00638690. [Table: see text]
Cell-free DNA as a prognostic marker for response to taxan-based chemotherapy in patients with prostate cancer (CaP).
Authors: Kienel Alexandra , Porres Daniel , Piper Charlotte , van Erps Thomas , Heidenreich Axel , Pfister David J. K. P.
Published: February 2017

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Background: PSA is of limited value for predicting response to chemotherapy in castration resistant CaP patients. Nevertheless there is no better biological marker to control therapy response. cfDNA showed significant results in prostae cancer diagnostics and predicting recurrence after radical prostatectomy. We analyzed for the first time the role of cfDNA in castration resistant CaP predicting response to chemotherapy. Methods: We analyzed cfDNA isolated from an EDTA blood sample from 58 patients taken before initiating a first or second-line taxan based chemotherapy. 54 (93,1%), 8 (13,8%) and 3 (5.1%) of the patients had bone, lymph node or parenchymatous metastases respectively. Patients were selected according to PSA response after at least 3 cycles of chemotherapy to 30% (A), 50% (B) and 80% (C) decrease under chemotherapy. The concentration of cfDNA at the beginning of the therapy was correlated to PSA resonse at the end of the treatment. Results: Mean PSA and cfDNA concentration at therapy initiation was 391 (0,1-2663)ng/ml and 32,5 (8,93-136,63)ng/ml. In group A there was a trend of higher cfDNA concentration in the patients not achieving a PSA decrease of at least 30% (24,6ng/ml versus 35.5ng/ml) not reaching statistical significance (p=0,078). Conclusions: Patients with PSA decrease of less than 30% and PSA progression under chemotherapy have the poorest outcome. cfDNA is easy to investigate and is probably of importance to distinguish patients profiting from chemotherapy in a palliative setting. These data should be validated in a larger patient cohort.
Paradoxical significance of endorectal MRI (erMRI) response to neoadjuvant chemotherapy in patients with high-risk localized prostate cancer (HRLPC).
Authors: Galsky Matt D. , Xie Wanling , Nakabayashi Mari , Ross Robert W. , Fennessy Fiona M. , Tempany Clare M. , Choueiri Toni K. , Khine Krystal , Kantoff Philip W. , Taplin Mary-Ellen , Oh William K.
Published: February 2017

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Background: Intermediate endpoints are desirable to expedite the integration of perioperative systemic therapy in HRLPC. erMRI response has been utilized as an endpoint in neoadjuvant trials but has not been correlated with clinical outcomes. Methods: Data were pooled from two trials exploring neoadjuvant chemotherapy in HRLPC. Trial 1 explored docetaxel for 6 months and Trial 2 explored docetaxel plus bevacizumab for 4.5 months, both prior to radical prostatectomy (RP). erMRI was done at baseline and end of chemotherapy. erMRI response was categorized as PR (>50% decline in largest lesion), MR (25%-50% decline), or no response. PSA response was defined as >50% decline in PSA compared to baseline. Multivariable Cox regression was undertaken to evaluate the association between clinical parameters and biochemical recurrence (BCR). Results: Trial 1 enrolled 19 patients and Trial 2 enrolled 41 patients. Among the 60 evaluable patients in the combined analysis, 20 (33%) achieved a PSA response, 16 (27%) achieved an erMRI PR, and 24 (40%) achieved an erMRI MR. Median follow-up was 4.2 years and 33 of 53 evaluable (62%) patients developed BCR. Median time to BCR from RP was 26.2 months (95% CI 12.5-53.2 mos). The multivariable model is shown in the Table. Conclusions: Response by erMRI does not correlate with decreased likelihood of BCR in patients with HRLPC treated with neoadjuvant docetaxel and may be associated with inferior outcomes. While speculative, this unexpected result could potentially be explained by a higher likelihood of erMRI response in more highly proliferative tumors. These data do not support the use of erMRI response as an endpoint in neoadjuvant chemotherapy trials. [Table: see text]
Phase II trial of acai juice product in biochemically recurrent prostate cancer.
Authors: Kessler Elizabeth Riley , Su Lih-Jen , Yang Xiaoping , Lu Xian , Morales Diana , Anduha Mary , Chronister Nicole , Wacker Michael , Flaig Thomas W. , Glode L. Michael , Lam Elaine Tat
Published: February 2017

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Background: There are conflicting data as to the benefit of treating patients with biochemically recurrent prostate cancer (PCa). Plant derivatives, called “nutraceuticals” such as grape seed extract or milk thistle, have been studied as therapies for PCa based on their purported anti-inflammatory and anti-oxidant properties and low toxicities. Acai is a fruit rich in bioflavinoids shown to induce apoptosis in preclinical studies of PCa, leukemia and esophageal cancer. Anecdotal experience of two patients with falling prostate specific antigen (PSA) values while consuming acai juice prompted us to evaluate its efficacy in a clinical trial. Methods: This was a phase II Simon two-stage open-label single-arm single-institution study of the efficacy of Acai Juice Product in asymptomatic PCa patients with a rising PSA. Eligibility included lack of current hormone therapy, hormone sensitivity, and a PSA doubling time of >4 weeks. Patients consumed 2 oz of Acai Juice Product twice daily for 30 weeks, with a primary endpoint of PSA response. Secondary endpoints included PSA doubling time, PSA velocity, and duration of PSA response. Progression was defined as a rise of 25% from baseline PSA with absolute rise of 2ng/dL. Results: 21 patients were enrolled in the first stage of the trial. Median baseline PSA was 2.74 (range 0.38-36.88). Eighteen patients have completed therapy with 1 PSA response. In the one responder, the patient entered with a doubling time of 4 months and a PSA of 12.57, which was 2.15 at 36 weeks suggesting a prolonged and continued response. PSA either decreased or doubling time prolonged from baseline in 18 patients. PSA velocity was a negative rate of change per month in 4 patients. Conclusions: Acai juice did not produce enough PSA responses in this patient population to proceed beyond the first stage of this trial. However, PSA doubling time did slow in 85.7% of patients, and the one observed PSA response was sustained over at least 36 weeks at the time of data cutoff. Thus, we will analyze potential cellular signals through an M30 Apotosense ELISA assay and Human Cytokine 10-plex panel on patient samples with data available for presentation at the meeting. Clinical trial information: NCT01521949.
Utilization of local salvage therapy after primary radiotherapy for prostate cancer.
Authors: Tran Henry , Kwok Jaime , Pickles Tom , Tyldesley Scott , Black Peter C.
Published: February 2017

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Background: Early biochemical detection and subsequent slow progression of recurrent prostate cancer after primary radiotherapy permit the delivery of potentially curative local salvage therapy (LST). Several LST options are available, including cryotherapy, brachytherapy (BT), and radical prostatectomy (RP). We studied the rates at which patients are offered, and receive LST after failure of primary radiotherapy. Methods: Patients with localized prostate cancer who received primary radiotherapy with curative intent between 1999-2000 were identified in the British Columbia radiotherapy database. Data on clinicopathologic features, primary therapy, PSA kinetics, and salvage therapy were collected retrospectively. We excluded patients with T4 tumors, PSA >40, or age >72 years at time of primary therapy. Biochemical recurrence (BCR) was defined by the Phoenix criteria. Patients were also deemed radiation failures if salvage therapy was started without meeting criteria for BCR. Results: Out of 1785 patients treated with radiation, 1067 met the inclusion criteria. Of these, 257 experienced BCR. Five patients received LST (3 RP, 2 BT). LST was considered in 11 other patients, but 2 were not referred for urologic opinion, and 9 declined intervention. 60 patients were considered ineligible for LST: 43 due to suspected metastasis and 17 due to other comorbidities. LST was unlikely to be offered to 80 patients due to age >75 at time of BCR. 59 additional patients appeared to be eligible for LST but there was no evidence that it was considered in the medical record. ADT was started within 12 months of BCR in 118 patients, and after at least one year of observation in another 66. Conclusions: Few patients were considered for LST in the study period, and only 5 received it. This review of practice patterns reveals a lack of uniform monitoring and treatment strategies in this challenging patient population, and indicates a need for more collaboration between all treating physicians, as well as with tertiary care centers.
Experimental therapy of PC-3 and DU-145 human androgen-independent prostate cancers with targeted cytotoxic analog of somatostatin AN-162.
Authors: Rick Ferenc , Abi-Chaker Andrew , Szalontay Luca , Block Norman L. , Halmos Gabor , Schally Andrew V.
Published: February 2017

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Background: Management of castration-resistant prostate cancer (CRPC) is challenging because of limitations in efficacy of current therapies. Somatostatin receptors are expressed in human CRPC. Here we tested targeted somatostatin AN-162 analog consisting of doxorubicin (DOX) conjugated to octapeptide RC-121, acting as a carrier, in human androgen-independent prostate cancer cell lines in vitro and in vivo. Methods: Expression of mRNA for the five subtypes of the somatostatin receptor in PC-3 and DU-145 human prostate cancer cell lines was evaluated by RT-PCR. Somatostatin receptor binding was measured with radioligand assays. The effect of AN-162 and DOX on the viability of PC-3 and DU-145 cells was assessed by MTS assay. Nude mice bearing PC-3 and DU-145 tumors were randomized to 5 groups (control, AN-162, DOX, somatostatin analog RC-160 as a control, and DOX + RC-160). Treatment consisted i.v. injections of AN-162, DOX, RC-160, DOX + RC-160, or vehicle once a week for 4 weeks. Tumor volume was measured every week; the study lasted 28 days. The doses of AN-162 were equivalent to 1.45 mg/kg DOX (2.5 μmol/kg). Results: The PC-3 and DU-145 cell lines were positive for the five subtypes of the somatostatin receptor. AN-162 and DOX (0.10–10 µM) inhibited the proliferation of PC-3 and DU-145 prostate cancer cells in a dose-dependent manner. AN-162 exerted a stronger inhibition of proliferation than DOX alone, but in vitro the difference was not significant. In vivo, AN-162 significantly inhibited growth of both tumor models’ compared with the controls and the groups given equimolar doses of doxorubicin, RC-160, or doxorubicin unconjugated to RC-160. Conclusions: Our work demonstrates potent inhibitory effects of AN-162 on somatostatin receptor positive androgen-independent prostate cancers, which were greater than any of the components of AN-162. The mechanisms of action of targeted cytotoxic analog of somatostatin AN-162 in CRPC should be explored. Our findings suggest the possible use of AN-162 in patients with CRPC.