bluuebunny/crossref_metadata_2025_split huggingface dataset:
Addition of docetaxel to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Long-term survival, quality-adjusted survival, and cost-effectiveness analysis.
Authors: James Nicholas , Woods Beth , Sideris Eleftherios , Spears Melissa Ruth , Dearnaley David P. , Mason Malcolm , Clarke Noel , Parmar Mahesh K B , Sydes Matthew Robert , Sculpher Mark ,   STAMPEDE Investigators
Published: February 2018

162 Background: Results from large randomised controlled trials have shown that adding docetaxel to standard of care (SOC) in men initiating hormone therapy for prostate cancer prolongs survival for those with metastatic disease and prolongs time to treatment failure for those without metastatic disease. We report on the impact of docetaxel on health related quality of life (HRQoL), resource use and cost-effectiveness for men treated in the STAMPEDE trial. Methods: Health outcomes and costs in the UK NHS were modelled using EuroQol (EQ-5D)and resource use data collected within the STAMPEDE trial (STAMPEDE enrolled men advanced prostate cancer starting first line hormone therapy. SOC was hormone therapy for ≥2 years and radiotherapy in some patients. Docetaxel (75 mg/m2) was administered alongside SOC for six 3-weekly cycles with prednisolone 10 mg daily. Lifetime predictions of costs, changes in predicted survival duration, quality adjusted life years (QALYs), and incremental cost effectiveness ratios (ICERs) were calculated. Results: Compared to patients allocated SOC, docetaxel was estimated to extend predicted survival by an average of 0.89 years for M1 patients and 0.78 years for M0 patients. Docetaxel was estimated to extend discounted QALYs by 0.51 years in M1 patients and 0.39 years in M0 patients. QALY gains in M0 patients were driven by the beneficial effect of delayed and reduced relapse. Docetaxel was cost-effective both in M1 patients (ICER = £5,514/QALY vs. SOC) and M0 patients (higher QALYs, lower costs vs. SOC). The probabilistic sensitivity analysis indicated a very high probability ( > 99%) that docetaxel is cost-effective in both M0 and M1 patients. Docetaxel remained cost effective in M0 patients even when no survival advantage was assumed due to reductions and delays in relapse. Conclusions: Docetaxel improves overall HRQoL, delays time to, and reduces the need for, subsequent therapy, and is cost-effective, amongst patients with both non-metastatic and metastatic disease. Clinicians should consider whether the evidence is now sufficiently compelling to support docetaxel use in non-metastatic patients. Clinical trial information: ISRCTN78818544.
Comparative assessment of abiraterone or enzalutamide activity in the PROREPAIR-B study.
Authors: Lozano Rebeca , Romero-Laorden Nuria , del Pozo Angela , Medina Ana , Mendez Maria Jose , Morales Barrera Rafael , Gonzalez del Alba Aranzazu Aranzazu , Rodriguez-Vida Alejo , Hernandez Amaia , Silla-Castro Juan Carlos , Vazquez Sergio , Gonzalez Belen , Pinto Alvaro , Perez Gracia Jose Luis , Querol Rosa , Cañadilla Vanessa , Domenech Montserrat , Pritchard Colin , Castro Elena , Olmos David 
Published: February 2018

164 Background: Germline mutations in DNA repair genes have been associated with poor prostate cancer outcomes in retrospectives studies. Such defects have been identified in 12% of mCRPC patients. Several studies are ongoing to assess the benefit of these patients from platinum-based chemotherapy and PARP inhibitors, but no conclusive data are available with regards to currently approved therapies for mCRPC, as Abiraterone or Enzalutamide. Methods: PROREPAIR-B (NCT03075735) is a prospective multicentre observational cohort study. Patients diagnosed with mCRPC, with unknown mutational status at study entry and who were going to start a first-line treatment for mCRPC were eligible. For this sub-analysis patients who received Abiraterone or Enzalutamide as first androgen receptor targeted therapy (ART) were selected. The endpoints of this sub-analysis included to assess the impact of BRCA1, BRCA2, ATM, PALB2 and other germline mutations in DNA repair genes on cause-specific survival (CSS), progression-free survival (PFS), time to PSA progression (bPFS) and response to the first ART received as 1st or 2nd line therapy. Results: 337 patients were eligible for this analysis. CSS from mCRPC was not significantly different between gDDR carriers and non-carriers. However, CSS from mCRPC in BRCA2 carriers was significantly shorter than in non-carriers (23.3 Vs 34.6 months, p = 0.02). CSS from first ART, PFS and response-rates were not significantly different between both groups. However, the bPFS was significantly shorter in patients harbouring gDDR mutations (7.3 Vs 3.8 months, p = 0.04), especially in BRCA2 carriers (7.3 Vs 3.0 months, p = 0.03). Conclusions: This is the first study to prospectively follow-up DNA repair germline mutations to determine the outcome on standard treatment for mCRPC. The results suggest that different gDDR defects may have different impact on mCRPC outcomes. Clinical trial information: NCT03075735.
Incidence and severity of prostate cancer (PCa) in 792 hypogonadal men with and without long-term testosterone therapy (TTh): Results from a controlled registry study.
Authors: Haider Ahmad , Haider Karim Sultan 
Published: February 2018

167 Background: There is no evidence that TTh in hypogonadal men increases PCa incidence or severity. A US-Scandinavian group recently found that men receiving TTh had lower risk of aggressive PCa (Loeb S et al., J Clin Oncol 2017; 35:1430-6). Methods: 412 men with testosterone ≤350 ng/dL and symptoms received testosterone undecanoate 1000 mg every 3 months for up to 12 years. 380 hypogonadal men (57-74) opted against TTh. Median follow-up: 9 years. Total observation time covered approximately 6,400 patient-years. Prostate volume (PV) and PSA were measured and digital rectal examination/transrectal ultrasound performed before treatment/observation initiation and then every 3-6 months (T-group) or once or twice per year (CTRL). Biopsies were performed when indicated according to EAU guidelines. Results: In the T-group, 11 men (2.7%) were diagnosed with PCa. In CTRL, 34 (8.9%) were diagnosed with PCa. The incidence per 10,000 years was 33 in the T-group and 108 in CTRL. The mean baseline age of PCa patients was 65.2 years in the T-group and 64.3 in CTRL. All PCa diagnoses in the T-group were made within the first 18 months of treatment initiation. In CTRL, PCa was diagnosed at any time during the observation time. In the T-group, radical prostatectomy was performed in all men. All but 1 patient had a Gleason score (GS) ≤6, and all but 1 a predominant GS of 3. Tumor grade was G2 in all 11 (100%), tumor stage T2a in 7 (64%), T2b in 3 (27%), and T2c in 1 (9%) patient(s). In CTRL, radical prostatectomy was performed in all but 6 patients. GS was > 6 in all 34 patients. 7 men had a GS of 7, 17 a GS of 8, and 10 a GS of 9. 2 men had a predominant Gleason score of 3, 22 had 4, and 10 had 5. Tumor grade was G2 in 6 (17.6%) and G3 in 28 (82.4%) patients, tumor stage T2c in 1 (0.3%), T3a in 3 (8.8%), T3b in 13 (38.2%) and T3c in 17 (50%) patients. In CTRL, biochemical recurrence occurred in 8 (23.5%) patients. These patients received androgen deprivation therapy (ADT). 10 (29.4%) patients died of whom 5 were on ADT. In the T-group, there were no biochemical recurrences or deaths during the observation time. Conclusions: In hypogonadal men, TTh may decrease PCa incidence compared to CTRL. PCa was less severe in the T-group.
Glypican-1 as a novel immunotherapeutic target in prostate cancer.
Authors: Zaslavsky Alexander , Adams Mackenzie , Wissmueller Sandra , Campbell Douglas , Klingemann Hans , Walsh Brad , Palapattu Ganesh S. 
Published: February 2018

174 Background: New effective therapies for men with prostate cancer are desperately needed. Recently, cancer immunotherapy has emerged as an important new treatment strategy for prostate cancer and for castrate resistant prostate cancer (CRPC). Multiple studies have identified the heparan sulfate proteoglycan-1 Glypican 1 (GPC-1) as being overexpressed in different cancers, and also as being a possible marker of poor prognosis in several solid tumor cancers. GPC-1 has been recently identified as a potential marker for prostate cancer. The MIL-38 monoclonal antibody detects GPC-1 and an IgG1 chimeric version of this antibody has been developed for preclinical studies. Here we sought to examine MIL-38 binding to a panel of prostate cancer cell lines and examine its feasibility as a novel immunotherapeutic agent targeting GPC-1 in prostate cancer Methods: Expression of GPC-1 in CRPC cell lines was examined by Flow cytometry and Western Blotting using MIL-38 as the detector antibody. The competency of GPC-1 as an immunotherapeutic target was assessed via chimeric MIL-38 induced Antibody Dependent Cell Cytotoxicity (ADCC) using high affinity Natural Killer cells (haNKs) in vitro . Results: Flow cytometry and Western blot assessments of normal prostatic epithelial cells (i.e. RWPE-1) and cells from prostate cancer cell lines (i.e. PC-3, 22RV1, DU-145, VCaP, LNCaP, CWR-R1, and LAPC-4) revealed that only cancer cells expressed GPC-1. Enzalutamide resistant cell lines demonstrated higher expression of GPC-1 than their respective parental line. ADCC assays demonstrated enhanced haNK – prostate cancer cell cytotoxicity in the presence of chimeric MIL-38 anti-GPC-1 antibody, while the IgG1 isotype control had no effect. Conclusions: GPC-1 protein was expressed by most prostate cancer cell lines, including enhanced expression by enzalutamide resistant cells. Preliminary in vitro ADCC assay results revealed the potential utility of GPC-1 as an immunotherapeutic target in prostate cancer.
Extended radical prostatectomy following neoadjuvant chemohormononal therapy (low dose estrmustine + LHRH agonist/antagonist) contributes to good cancer control for patients with high risk localized prostate cancer.
Authors: Enokida Hideki , Yoshino Hirofumi , Nakagawa Masayuki 
Published: February 2018

185 Background: Patients with high-risk prostate cancer (PCa) according to D’Amico risk categories are prone to a pathological diagnosis of positive margins or lymph node invasion and biochemical recurrence, despite having undergone radical prostatectomy (RP). Therefore, it is controversial whether RP should be done for high risk PC patients. Methods: 87 high-risk PCa patients prospectively underwent ‘extended’ RP following neoadjuvant chemohormonal therapy (NAC); primarily 6 months of estramustine phosphate 280 mg bid, along with a LH-RH agonist/antagonist. Our surgical technique was developed to reduce the rates of positive surgical margins. The goal is to approach the muscle layer of the rectum by dissecting the mesorectal fascia and continuing the dissection through the mesorectum until the muscle layer of the rectum is exposed. The procedure was safely performed as a result of good recognition of the structure between the perineal body and the rectal surface. We also performed extended lymphadenectomy if the patients meet two or more of D’Amico risk categories Results: More than 1 year had elapsed after surgery in 69 of the 87 patients with the median follow-up period of 36.2 months. Among those 69 patients, 18 (26.1%) experienced PSA failure. Kaplan-Meier analyses revealed that significant poorer PSA progression-free survival were observed in patients with higher positive biopsy core ratio, lymph node metastasis, and higher pathological stage (pT3a/b). Multivariate Cox-regression analysis revealed that higher pathological stage (pT3a/b) was the only independent valuable for predicting PSA progression failure. These 18 cases received salvage androgen deprivation therapy followed-by external beam radiotherapy and showed no progression after the salvage therapies (median follow-up period, 34.6 months after PSA progression). Conclusions: NAC concordant with extended RP is feasible and contributes to negative surgical margins that might provide good cancer control for patients with high-risk PCa.
Efficacy of ferumoxytol as a lymphatic contrast agent in prostate cancer.
Authors: Dattoli Michael J. , Bravo Stephen M , Kaplon Daniel , Hayes Matt , Osorio Alexandria , Dycus Patricia M , Bostwick David G. , Kaminski Joseph 
Published: February 2018

186 Background: Ferumoxytol (Feraheme) is a ferromagnetic nanoparticle with lymphotrophic biokinetics, delivered to lymph nodes by normal macrophages. MRI suppresses normal lymph nodes containing Feraheme. Objective is to validate safety and efficacy in finding lymph node positivity in prostate cancer (PCa). Methods: Nonrandomized prospective evaluation of 178 consecutive PCa patients (pts) at high risk for lymph node spread enrolled 2/13-3/15. All received IV Feraheme. 177 received 6/mg/kg over 20 min. One pt received 3 mg/kg infusion. T2 MEDIC and T2* sequence imaging of abdomen and pelvis, given 24 hours later. Images reviewed by 2 board certified radiologists with same interpretations, blinded to clinical and histo-path info (pre-MRI TNM stage/PSA/Gleason). Nodes were deemed abnormal if they did not suppress after Feraheme infusion (group 1, 94 patients). Nodes were deemed suspicious if suppressed and met usual size criteria with high signal intensity on DWI and decreased ADC map values and morphologic features (group 2, 84 pts). 83 group 1 pts had CT biopsies (77 pelvis, 6 retroperitoneum);11 pts had open PLND. 382 lymph nodes sampled. 76 group 2 patients had CT biopsies (73 pelvis, 3 retroperitoneum); 9 pts had open PLND. 340 lymph nodes sampled. Rad-path correlation was performed. Nodes were stained; reviewed by a single pathologist with no knowledge of MRI findings. Histo-path results for each node were cataloged for later MRI comparison. Results: 90 group 1 pts (96%) proved metastatic PCa; 4 pts (4%) were normal. 68 group 1 pts (77%) had malignant lymph nodes not meeting usual imaging criteria. 39 group 2 pts (47%) showed metastatic PCa; 46 pts (53%) were normal. One group 2 pt had an allergic reaction with hives; infusion ceased at 3mg/kg; pt treated to full resolution with 50 mg IV Benadryl. Conclusions: Feraheme can evaluate lymphatic dissemination of metastatic disease in PCa patients, with a lower limit of resolution of focal lymph node metastases of 2-3 mm. Better resolution gives implications for therapeutic radiation planning of newly diagnosed or recurrent/metastatic PCa. Toxicity was very acceptable at 6mg/kg. Feraheme may play a significant role as a lymphatic contrast agent in the early dissemination of lymphatic metastatic disease.
Local ablative radiotherapy: A means to revert low volume castration-resistant prostate cancer into a hormone-sensitive status?
Authors: HÃ¶lscher Tobias , Lohaus Fabian , Zoephel Klaus , Wirth Manfred , Baumann Michael , Troost Esther 
Published: February 2018

188 Background: (Stereotactic) Ablative radiotherapy (aRT) in patients with oligometastatic prostate cancer is safe, achieves high local control rates and its clinical benefit is currently being addressed in clinical trials. However, the selection of patients benefitting most from aRT remains unclear. Moreover, the highly specific and sensitive multimodality functional imaging modality, 68Ga-PSMA-PET-CT/-MR, is widely available. Therefore, we retrospectively evaluated the efficacy of PSMA-PET guided local aRT in low volume oligometastatic castration resistant prostate cancer (CRPC) patients. Methods: Fifteen patients with metachronous oligometastatic CRPC as diagnosed on PSMA-PET were treated with local aRT. Nine patients were treated with a conventionally fractionated regime (25 x 2 Gy) and six with stereotactic hypofractionated RT (3 x 10 Gy), while in all androgen deprivation was continued. The time to PSA-progression, i.e. PSA-nadir + 2 ng/ml (PSA+2) was estimated with the Kaplan-Meier method and compared to an individually estimated time to PSA+2 according to the individually calculated pre-RT PSA doubling time (PSA-DT). Results: At staging PSMA-PET, the median PSA was 3.4 ng/ml (range 1.3 -14.5) and the median PSA-DT was 3.2 months (range 0.6 - 15.3). In four patients no PSA-response after aRT was observed. The responding eleven patients (73%) had a mean decrease in PSA-level of 80% from baseline. The mean time to PSA-nadir was 10.7 months (range 4.5 - 11.5). The mean time to PSA+2 or last follow-up was 15.6 months [95%CI: 9.7 - 21.4] compared to 3.3 months [95%CI: 1.5 - 5.1] estimated PSA-DT without local aRT (p < 0.001). Conclusions: A relevant subset of patients with 68Ga PSMA-PET-detected oligometastatic low volume CRPC had a meaningful PSA-response with aRT. They were reverted into an earlier stage of their disease again. A prospective clinical trial on this clinically highly relevant question is being prepared.
Niclosamide in combination with abiraterone and prednisone in men with castration-resistant prostate cancer (CRPC): initial results from a phase Ib/II trial.
Authors: Pan Chong-xian , Lara Primo , Evans Christopher P. , Parikh Mamta , Dall'era Marc , Liu Chengfei , Robles Daniel , Gao Allen 
Published: February 2018

192 Background: Prostate cancer is driven by androgen receptor (AR) signaling. The variant AR-V7 lacks the ligand binding domain, constitutively activates the AR pathway, and confers resistance to Abiraterone (Abi) and enzalutamide (Enza). We discovered that the anti-helminthic drug niclosamide targets AR-V7 and sensitizes resistant CRPC to Enza and Abi. We hypothesize that niclosamide/PDMX1001 potentiates the efficacy of Abi against CRPC. Here we report the initial results of this ongoing investigator-initiated phase Ib/II trial. Methods: Eligible patients (pts) have progressive CRPC with serum testosterone < 50 ng/dl. No prior Abi was allowed. In the Phase Ib cohort, pts received Abi 1000 mg PO qd, prednisone 5 mg PO bid, with intrapatient dose-escalation of niclosamide/PDMX1001 from 400 mg PO bid to 1600 mg PO tid. Trough niclosamide/PDMX1001 levels were measured. The Phase II cohort will enroll 27 patients with detectable AR-V7 in the peripheral blood. Co-primary endpoints include toxicity and response as determined by the Prostate Cancer Working Group 2 criteria. Results: Of 6 pts (age 74-83) in the Phase Ib cohort, five pts tolerated a niclosamide/PDMX1001 dose of 1,600 mg po tid without dose limiting toxicity; per protocol, this is the recommended Phase II dose. Niclosamide/PDMX1001 trough level was 0.305 and 0.496 µM in the two pts analyzed thus far, higher than the target level of 0.1µM required for anti-cancer activity. Of 6 pts, two pts achieved complete PSA response ( < 0.01 ng/ml), compared to historical control 0/30 pts treated with Abi alone; two with partial PSA response (≥50% decrease). Of the remaining two pts, one was prematurely taken off from the study after one cycle because of rising PSA, and the other had PSA decrease of 17.1%, but biopsy of the only enlarged lymph node showed all necrotic tissue. The only toxicity was Grade 1 nausea and diarrhea. The Phase II cohort will now enroll. Molecular correlative studies will be presented. Conclusions: The combination of niclosamide/PDMX1001, Abi and prednisone is well tolerated with promising safety and efficacy data. Targeted serum trough levels of niclosamide are clinically achievable. Clinical trial information: NCT02807805.
Visceral metastases on abiraterone vs. placebo: A post-hoc analysis of mode of radiographic progression in COU-AA-302.
Authors: Teply Benjamin A. , Qiu Fang , Antonarakis Emmanuel S. , Carducci Michael Anthony , Denmeade Samuel R. 
Published: February 2018

194 Background: Abiraterone prolongs survival in patients with prostate cancer due to its potent inhibition of androgen synthesis. We previously observed increased rates of visceral metastatic disease at the time of progression on abiraterone compared to baseline, a poor prognostic feature associated with non-AR dependent prostate cancer. We hypothesized that the rate of development of visceral disease was increased with abiraterone compared to other treatments without potent androgen signaling inhibition. In order to test this, we examined time to visceral disease among patients treated with abiraterone vs placebo on the COU-AA-302 trial. Methods: We performed a post-hoc analysis of radiographic progression data for the phase 3 study of abiraterone vs placebo, via a data sharing agreement through the Yale Open Data Access Project. Data were censored at end of study treatment. The distribution of cumulative incidence for visceral metastases was calculated by the Kaplan-Meier method and compared with log-rank testing. Multivariable cox regression analysis was performed to assess for independent association of study treatment (abiraterone vs placebo) with the development of visceral metastases. Results: Median follow-up was 12.5mo, and 84 of 1088 patients developed visceral metastases. Univariate log-rank testing showed no difference in time to visceral metastasis between groups (p = 0.97). 1- and 3-yr cumulative incidence of visceral metastases were estimated at 6.4% and 15.6% for abiraterone and 4.6% and 17.0% for placebo, respectively. Study treatment was not a significant predictor for the development of visceral metastasis (HR 0.76; 95% CI 0.47-1.21) after adjustment for baseline metastatic disease burden (soft tissue and bone) and LDH. Conclusions: Abiraterone was not associated with increased visceral metastases at progression compared to placebo. These data give more confidence to oncologists that abiraterone is not driving prostate cancer to an aggressive phenotype characterized by visceral metastases - a finding that is particularly important as abiraterone is increasingly used in early disease states.
Indirect treatment comparison (ITC) of abiraterone acetate (AA) plus prednisone (P) and docetaxel (DOC) on patient-reported outcomes (PROs) in metastatic castration-naïve prostate cancer (mCNPC).
Authors: Feyerabend Susan , Saad Fred , Li Tracy , Ito Tetsuro , Diels Joris , Van Sanden Suzy , De Porre Peter , Abogunrin Seye , Koufopoulou Maria , Fizazi Karim 
Published: February 2018

200 Background: AA + P added to androgen deprivation therapy (ADT) improved overall survival among newly diagnosed mCNPC patients (pts) with high-risk disease (HRD) vs placebos (PBOs) + ADT in the phase 3 LATITUDE study. Although ADT with or without chemotherapy is recommended in clinical guidelines as the mainstay of management for mCNPC, adding DOC to ADT does not consistently improve health-related quality of life (HRQoL). We performed an ITC to understand the relative impact of AA + P vs DOC on PROs in mCNPC pts. Methods: PROs were assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Brief Pain Inventory (BPI). Mean change from baseline (BL) was based on differences in FACT-P and BPI scores between active vs control arms in LATITUDE (intention-to-treat [ITT] population) and CHAARTED (available data included mCNPC pts with high-volume disease [HVD] and low-volume disease [LVD]). Higher FACT-P score indicates better outcome/function; lower BPI score indicates better outcome/less pain. The probability of AA + P being better than DOC at 3, 6, 9, and 12 mos after treatment was based on fixed-effects Bayesian network meta-analysis. Results: Benefits in PROs with AA + P vs DOC were observed from 3 mos and sustained at least 1 year after treatment. Bayesian probability of AA + P being the better treatment for PROs ranged from 92.3% to 100%. Conclusions: Results from a Bayesian ITC suggest that AA + P was superior to DOC in improving PROs for at least 1 year after initiating treatment in men with mCNPC. In the absence of head-to-head trials, these analyses can provide useful insights on the relative impact of treatment options on HRQoL in mCNPC pts. Clinical trial information: NCT01715285. [Table: see text]