bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of local treatment in patients with prostate cancer with clinically pelvic lymph node-positive disease at initial diagnosis.
Authors: Abdollah Firas , Seisen Thomas , Vetterlein Malte , Karabon Patrick , Jindal Tarun , Sood Akshay , Nocera Luigi , Nguyen Paul L. , Choueiri Toni K. , Trinh Quoc-Dien , Menon Mani 
Published: March 2017

164 Background: There is limited evidence supporting the use of local treatment (LT) for prostate cancer (PCa) patients with clinically pelvic lymph node-positive (cN1) disease. Against this backdrop, we sought to examine the efficacy of any form of LT+/-androgen deprivation therapy (ADT) in treating these individuals. Methods: Within the National Cancer Data Base (2004-2012), we identified 2,967 individuals who received LT+/-ADT vs. ADT alone for cN1 PCa. Only radical prostatectomy (RP) and radiation therapy (RT) were considered as definitive LT. Instrumental variable analyses (IVA) were performed using a two-stage residual inclusion approach to compare overall mortality-free survival between patients who were treated with LT+/-ADT vs. ADT alone. The same methodology was used to further compare overall mortality-free survival between patients who were treated with RP+/-ADT vs. RT+/-ADT. Results: Overall, 1,987 (67.0%) and 980 (33.0%) patients received LT+/-ADT and ADT alone, respectively. In the LT+/-ADT group, 751 (37.8%) and 1,236 (62.2%) patients received RP+/-ADT and RT+/-ADT, respectively. In IVA, LT+/-ADT was associated with a significant overall mortality-free survival benefit (HR = 0.31; 95% CI = [0.13-0.74]; P= 0.007), when compared to ADT alone. At 5-year, overall mortality-free survival was 78.8% (95% CI: 74.1%-83.9%) vs. 49.2% (95% CI: 33.9%-71.4%) in the LT+/-ADT vs. ADT alone groups. When comparing RP+/-ADT vs. RT+/-ADT, IVA showed no significant difference in survival between the two treatment modalities (HR = 0.54; 95% CI = [0.19-1.52]; P= 0.24). Conclusions: Our study shows a significant overall mortality-free survival benefit for cN1 PCa patients who were treated with LT+/-ADT as compared to their counterparts treated with ADT alone. Conversely, no significant survival difference was observed between patients treated with RP+/-ADT vs. RT+/-ADT.
Cabozantinib plus androgen deprivation therapy in patients with androgen-dependent metastatic prostate cancer.
Authors: Corn Paul Gettys , Zurita Amado J. , Subudhi Sumit Kumar , Tu Shi-Ming , Aparicio Ana , Araujo John C. , Kim Jeri , Wang Jennifer , Efstathiou Eleni , Pagliaro Lance C. , Logothetis Christopher 
Published: March 2017

169 Background: Cabozantinib (Cabo), a tyrosine kinase inhibitor of c-Met and VEGFR2, modulates the tumor microenvironment in a therapeutically favorable manner. We combined Cabo with androgen deprivation therapy (ADT) in patients (pts) with androgen-dependent metastatic prostate cancer (PCa) (NCT01630590). Methods: Pts received Cabo (starting dose 60 mg PO daily) and ADT with a GnRH analogue. Pts could receive up to 3 months of ADT prior to initiating Cabo. Bone scan (BS) and CT scans were performed every 12 weeks (wks). Efficacy endpoints included response in markers, BS and RECIST, and time to castrate-resistant progression defined by radiographic progression, clinical progression, or receipt of additional anti-cancer therapy. Results: From 01/27/2014 to 01/12/2016, 62 pts were enrolled: 94% (58/62) with bone metastasis, 56% (35/62) with measurable disease, 15% (9/62) with visceral involvement and 26% (16/62) with prior treatment of their primary tumor. 79% (49/62) of pts have high volume disease defined by > 4 bone lesions and/or involvement of viscera. Median time from start of ADT to start of Cabo was 3.4 wks. Improvements in BS were observed in 81% (44/54) of evaluable pts including complete responses (CR) in 15% (8/54). In evaluable pts with measurable disease, best response was stable disease in 9% (3/33), PR in 61% (20/33) and CR in 30% (10/33). Reductions in PSA > 90%, bone specific alkaline phosphatase > 50% and urine N-telopeptides > 50% occurred in 83% (50/60), 87% (34/39), 86% (19/22) of evaluable pts, respectively. With a median follow up of 21.4 months (mo), median PFS is 15.6 mo. Median duration of Cabo treatment is 13 mo. Most common toxicities are Grade 3 hypertension (16%), pulmonary embolus (6%), diarrhea (4%), fatigue (3%), nausea (3%), and deep venous thrombosis (3%) with no Grade 4 events. Cabo dose reductions to 40 and 20 mg occurred in 68% and 18% of pts, respectively, with discontinuations due to toxicity in 10% of pts. Conclusions: Cabo plus ADT has potent clinical activity in pts with high volume androgen-dependent PCa including improvements BS and reduction in markers of bone stromal function. Studies are underway to identify biomarkers predictive of best response. Clinical trial information: NCT01630590.
A prospective international randomized phase II study evaluating the food effect on the pharmacokinetics (PK) and pharmacodynamics (PD) of abiraterone acetate (AA) in men with castration-resistant prostate cancer (CRPC).
Authors: Szmulewitz Russell Zelig , Ibraheem Abiola Falilat , Peer Cody J. , Figg William Douglas , Carthon Bradley Curtis , Kozloff Mark , Harvey Donald , Fishkin Paul A. S. , Yong Wei Peng , Chiong Edmund , Nabhan Chadi , O'Donnell Peter H. , Stadler Walter Michael , Ratain Mark J. 
Published: March 2017

176 Background: AA is a standard of care for the treatment of metastatic CRPC, with an approximate retail cost of $8000/month. Despite a large food effect (~17-fold increase in CMax with a high-fat meal), AA was administered under fasting conditions in its pivotal trials. There are no randomized continuous dosing studies examining prandial state dosing on AA PK/PD. We sought to test the hypothesis that LOW (250mg w/food) would have similar PK/PD and safety to standard (STD, 1000mg fasting) in patients with progressive CRPC. Methods: Patients (n = 72) with progressive CRPC from seven institutions in the US and Singapore were randomized to treatment with STD or LOW (with low-fat breakfast). Both arms received prednisone 5mg twice daily. PSA was assessed monthly, and testosterone, DHEA/DHEAS were assessed every 12 weeks along with standard disease burden assessments. PK samples were collected at day 1, 8 and months 2, 3, 4. Log change in PSA response rate from baseline to week 12 was examined as the primary endpoint, with a non-inferiority design based on a non-inferiority margin of 15%. This margin corresponds to a 0.51 standard deviation (SD) difference in the mean log changes between the groups. Results: Accrual was completed with n = 36 on STD and n = 36 on LOW. Median (range) age was 74 (52-89) and baseline PSA was 39.2(range 0.6-1789). Mean log-change in PSA at 12 weeks was nominally greater in the LOW arm (-1.59 vs. -1.19). The 95% confidence for the difference (STD-LOW) ranged from -0.40 to 1.19, with lower limit corresponding to -0.24SD. Thus, non-inferiority of LOW was established. Median time to PSA progression was ~14 month in both arms (p = 0.53). Preliminary analysis of PK showed no difference in CMaxbeyond the first cycle with lower PK variability in the LOW arm. Conclusions: Low-dose (250mg/day) abiraterone acetate with a low-fat breakfast is non-inferior to standard dosing in a fasted state with respect to PSA and PK metrics. Although PSA response and progression are not clinically validated surrogates, given the pharmacoeconomic implications, these data warrant consideration by prescribers and payors. Clinical trial information: NCT01543776.
Racial disparities in prostate cancer outcome among prostate-specific antigen screening eligible populations in the United States.
Authors: Mahal Brandon Arvin Virgil , Chen Yu-Wei , Muralidhar Vinayak , Mahal Amandeep R. , Choueiri Toni K. , Hoffman Karen E. , Hu Jim C. , Sweeney Christopher , Beard Clair , Martin Neil E. , Feng Felix Yi-Chung , Kim Simon P. , Yu James B. , Trinh Quoc-Dien , Nguyen Paul L. 
Published: March 2017

18 Background: In 2012, the United States Preventive Services Task Force (USPSTF) recommended against Prostate-Specific Antigen (PSA) screening, despite evidence that Black men are at a higher risk of prostate cancer-specific mortality (PCSM). We evaluated whether Black men of potentially screening-eligible age (55-69) are at a disproportionally high risk of poor outcomes. Methods: The SEER database was used to study 390,259 men diagnosed with prostate cancer in the United States between 2004-2011. Multivariable logistic regression modeled the association between Black race and stage of presentation, while Fine-Gray competing risks regression modeled the association between Black race and PCSM, both as a function of screening eligibility (age 55-69 vs not). Results: Black men were more likely to present with metastatic disease (adjusted odds ratio [AOR] 1.65; 1.58-1.72; P< 0.001) and were at a higher risk of PCSM (adjusted hazard ratio [AHR] 1.36; 1.27-1.46; P< 0.001) compared to Non-Black men. There were significant interactions between race and PSA-screening eligibility such that Black patients experienced more disproportionate rates of metastatic disease (AOR 1.76; 1.65-1.87 vs. 1.55; 1.47-1.65; Pinteraction< 0.001) and PCSM (AHR 1.53; 1.37-1.70 vs. 1.25; 1.14-1.37; Pinteraction= 0.01) in the potentially PSA-screening eligible group than in the group not eligible for screening. Conclusions: Racial disparities in prostate cancer outcome among Black men in are significantly worse in PSA-screening eligible populations. These results raise the possibility that Black men could be disproportionately impacted by recommendations to end PSA screening in the United States and suggest that Black race should inform clinical decisions on PSA screening.
Therapeutic targeting of tumor-associated macrophages through microscale engineering of the prostate cancer microenvironment.
Authors: Kosoff David , Yu Jiaquan , Schehr Jennifer L , Beebe David J. , Lang Joshua Michael 
Published: March 2017

184 Background: The tumor microenvironment (TME) plays integral roles in prostate cancer progression and is a high value therapeutic target. The development of effective TME-targeted therapies is limited by current technologies which are insufficient to replicate or analyze this complex environment. To address these challenges, we have developed a microfluidic cell culture platform known as STACKS, which permits co-culture of up to 6 patient-derived cell populations as well as compartmentalized, multiplexed analysis of gene expression, cell signaling, and matrix remodeling. We have focused on investigation of tumor-associated macrophages (TAMs), which have been implicated in prostate cancer growth, metastasis, survival, and therapeutic resistance. Methods: Using blood and prostate tissue obtained through biomarker studies at the University of Wisconsin, we isolated patient-derived cell populations for culture and analysis within the STACKS device. Monocytes obtained from peripheral blood were differentiated into tumor inhibitory (M1) and tumor promoting (M2) macrophages in the device. RNA, protein, and secretory factor expression were analyzed following manipulations of culture surface, cytokine exposure, and multi-cell culture with tumor and stromal cell populations. Results: We report that physical properties of the TME, such as topography and hydrophilicity, impact expression of tumor-promoting genes within macrophages. We also characterized macrophage expression of pro- and antitumor genes, including CCL18, CXCL10, CXCL11, IL-10, IL-12b, VEGF, and identified expression profiles that are dependent on tumor and stromal cell populations in co-culture and diverge from classical M1/M2 characterization. Conclusions: The STACKS platform is capable of advanced modeling and analysis of the prostate cancer TME. Investigation of patient-derived monocytes within STACKS has identified physical properties of the TME that affect tumor-related functions of macrophages and has also demonstrated that an M1/M2 classification spectrum may not be sufficient for characterizing TAMs. These findings represent new therapeutic targets for prostate cancer treatment.
A drug-drug interaction study on the combination of cabazitaxel with enzalutamide in patients with metastatic castration-resistant prostate cancer.
Authors: Belderbos Bodine P.S. , Bins Sander , van Leeuwen Roelof W.F. , De Hoop Esther Oomen , van der Meer Nelly , de Bruijn Peter , Hamberg Paul , Overkleeft Esther N.M. , van der Deure Wendy M. , Lolkema Martijn P. , De Wit Ronald , Mathijssen Ron H.J. 
Published: March 2017

188 Background: Cabazitaxel and enzalutamide are effective single agent treatment options for metastatic castration resistant prostate cancer (mCRPC). Preclinical studies suggest enhanced efficacy of the combination of a taxane with enzalutamide. Recently, Morris et al. (CCR 2016) reported on an interaction study between docetaxel and enzalutamide: docetaxel mean exposure decreased by 12% during a short period of co-treatment with enzalutamide, probably due to enzyme (CYP3A4) induction. Since cabazitaxel is a CYP3A4 substrate, we investigated the influence of enzalutamide on cabazitaxel pharmacokinetics (PK) and toxicity during 3 chemotherapy cycles. Methods: We performed a cross-over study in 14 evaluable mCRPC patients who were treated with i.v. cabazitaxel Q3W (25 mg/m2). PK-sampling (over 24h) was conducted on day 1 of each cycle during 3 consecutive cabazitaxel cycles. From day 8 (±1) of the first cycle until day 8 (±1) of the third cycle, enzalutamide (160 mg/day) was administered concomitantly. Primary endpoint was the difference in geometric mean area under the curve (AUC0-24h) between the first and third cycle. Secondary endpoints included safety parameters and PSA response. Results: The AUC was 22% (95%CI 9-34%) lower during the third cycle (181 ng*h/mL, 95%CI 150-219 ng*h/mL) than during the first cycle (234 ng*h/mL, 95%CI 209-261 ng*h/mL; p = 0.005). No relevant adverse events occurred due to the drug combination. Nine patients (64%) received the full dose of cabazitaxel during the 3 study cycles. No enzalutamide dose reductions took place, and the combination was well tolerated. PSA response ( ≥ 50% decrease of baseline PSA ) was observed in 10 patients (71%). Conclusions: Cabazitaxel exposure is both statistically and clinically significantly reduced by concomitant enzalutamide use. Since the PROSELICA study (De Bono et al, ASCO 2016) may lead to an adapted standard cabazitaxel dose of 20 mg/m2, the clinical relevance of this interaction may be extensive, since it is likely to result in suboptimal exposures. We stimulate clinical studies with this combination, but these should include monitoring of the PK of cabazitaxel, and appropriate dose adaptations. Clinical trial information: NTR5164.
The association of androgen deprivation therapy and anxiety among 78,000 patients with localized prostate cancer patients.
Authors: Dinh Kathryn T , Reznor Gally , Muralidhar Vinayak , Martin Neil E. , Orio Peter F. , Trinh Quoc-Dien , Nguyen Paul L. 
Published: March 2017

19 Background: Androgen deprivation therapy (ADT) has been associated with cognitive and psychological effects, including depression. ADT may also cause an increased incidence of anxiety; however, most studies have not considered anxiety as an individual outcome. We aimed to determine if receipt of any ADT or longer duration of ADT for prostate cancer is associated with increasing risk of being diagnosed with anxiety. Methods: We identified 78,552 men over 65 with stage I-III prostate cancer using the Surveillance, Epidemiology, and End Results-Medicare linked database from 1992-2006, excluding patients with psychiatric diagnoses within the prior year. Our primary analysis was the association of pharmacologic ADT with the diagnosis of anxiety using Cox-proportional hazard regression with propensity matching. Drug-data for treatment of anxiety was not available. Our secondary analysis was the association of ADT duration with a diagnosis of anxiety. Results: Overall, 43% (33,882) of patients who received ADT and had higher 3-year cumulative incidence of anxiety (4.1% vs. 3.5%) than patients without ADT (p < 0.001). Adjusted cox-analyses with propensity matching demonstrated patients with ADT had a 17% increased risk of anxiety (adjusted hazard ratio [AHR] = 1.17, 95% CI = [1.088-1.263]) compared to patients without ADT (p < 0.0001). The risk of anxiety increased with duration of ADT, from 4.5% with ≤ 6 months, 5.8% with 7-11 months, to 15.7% with ≥ 12 months (p-trend = 0.0123). Conclusions: Pharmacologic ADT is associated with an increased risk of anxiety in this large study of elderly men with localized prostate cancer. This risk increased with longer duration of ADT. Anxiety should be consider among the possible psychiatric effects of ADT and should be discussed along with depression prior to initiating ADT.
Clinical versus radiographic progression and overall survival for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) from COU-AA-302.
Authors: Ryan Charles J. , Kheoh Thian , Scher Howard I. , De Porre Peter , Yu Margaret K. , Morris Michael J. 
Published: March 2017

193 Background: COU-AA-302 evaluated abiraterone acetate plus prednisone (AA) vs prednisone (P) in chemotherapy-naïve mCRPC pts, with overall survival (OS) and radiographic progression-free survival (rPFS) as co-primary end points. Per study criteria, pts with radiographic progression (RAD) only were allowed to continue treatment, while those with unequivocal clinical progression (UCP) only were not, and were censored for rPFS. We evaluated the clinical significance of survival outcomes for pts with UCP only vs RAD only from the prospective COU-AA-302 trial. Methods: UCP was defined per protocol as ≥ 1 of the following: initiation of chronic opiates, ECOG performance status (PS) decline to ≥ 3, or initiation of chemotherapy, palliative radiation therapy, or surgery. OS was evaluated for each type of progression using Cox proportional hazard models. Results: 500 (92%) pts in the AA arm and 540 (100%) in the P arm discontinued study treatment. Of the 736 pts who discontinued treatment for a protocol-defined reason, 280 (38%) discontinued for UCP only, 332 (45%) for RAD only, and 124 (17%) for both UCP and RAD. Clinical events cited as the reason for discontinuation for UCP (AA vs P arm) included pain requiring opiates (22% vs 25%), ECOG PS ≥ 3 (4% vs 5%), and initiation of chemotherapy (50% vs 53%), radiation therapy (36% vs 27%) and surgery (3% vs 5%). UCP only pts had shorter median OS compared with RAD only pts (Table). Conclusions: UCP is a criterion used as an indicator for a censored event, yet appears to confer inferior survival relative to RAD. The high frequency of UCP implies that it may be an important determinant of clinical outcome. The events that drive UCP should be defined as part of the development of more informative interim trial end points, in line with the PCWG3-proposed “no longer clinically benefitting” outcome measure, which captures pts with UCP. Clinical trial information: NCT00887198. [Table: see text]
Outcomes for men under 65 with high-risk prostate cancer with Medicaid versus private insurance.
Authors: Mahal Amandeep R. , Mahal Brandon Arvin Virgil , Nguyen Paul L. , Yu James B. 
Published: March 2017

198 Background: Increased Medicaid coverage, due to the Affordable Care Act, has been hypothesized to reduce racial disparities. We therefore examined the association between private insurance vs. Medicaid, race, and outcomes for the treatment of high-risk prostate cancer (CaP) among men < 65 years old. Methods: The Surveillance, Epidemiology, and End Results Program identified 116,853 men < 65 diagnosed with CaP from 2007-2011. Multivariable logistic regression modeled the association between insurance status (IS) and stage at presentation. Among men with high-risk CaP, the associations between IS and receipt of definitive therapy (DT) and prostate cancer-specific mortality (PCSM) were determined using multivariable logistic and Fine and Gray competing-risks regression models, respectively. Results: Compared to privately insured men, those with Medicaid were more likely to present with metastatic disease (Mets) (adjusted odds ratio (AOR) 5.79; 95% confidence interval (CI) 5.25-6.40; P < 0.001). Among men with high-risk disease, men with Medicaid were less likely to receive DT (AOR 0.55; 95% CI 0.51-0.60; P < 0.001) and had increased PCSM (adjusted hazard ratio (AHR) 1.8; 95% CI 1.27-2.54; P = 0.001). There were significant interactions (INT) between race and Medicaid for the outcomes of PCSM (PINT= 0.05) and Mets (PINT= 0.003). Specifically, gaps in PCSM and Mets were observed among privately insured men, with increased PCSM (AHR 1.51; 95% CI 1.18-1.94; P = 0.001) and Mets (AOR 1.33; 95% CI 1.20-1.48; P < 0.001), while there were no observed disparities among men with Medicaid with regards to PCSM (AHR 0.72; 95% CI 0.34-1.52; P = 0.387) and Mets (AOR 1.03 95% CI 0.86-1.24; P = 0.730). Conclusions: Among men with CaP, African American men are more likely to present with Mets, less likely to receive DT, and have increased PCSM compared to non-black men. These disparities are observed in heterogeneous privately insured cohorts. However, among men with Medicaid, outcomes were equally worse. Furthermore, there was a significant INT between race and IS, indicating more-than-additive effects. Our study suggests that while increased access to Medicaid could act to reduce disparities seen in CaP, outcomes need to be improved overall.
Taste and prostate cancer: Preliminary data on a novel patient-reported outcomes.
Authors: Chow Lydia D. , Cotogno Patrick , Ernst Emma M. , Manogue Charlotte , Ledet Elisa M. , Sartor Oliver 
Published: March 2017

201 Background: Taste alterations are a common yet frequently under-assessed problem in cancer patients. Health-related quality-of-life (HRQOL) instruments for prostate cancer (PCa) patients (pts) do not assess taste despite these hypothetically being related to both appetite and weight loss. Herein we begin to assess taste using a novel instrument evaluating taste alterations with a focus on PCa. Methods: 61 PCa pts treated at Tulane Cancer Center were enrolled in this prospective study. An 18-item questionnaire assessed appetite, taste, smell, and diet. 127 questionnaires were completed (mean 2.1 responses/pt). In a subset of questionnaires, we compared self-reported taste, appetite, and weight loss over a 6-month period. In another subset, we compared taste and appetite to treatments with abiraterone, docetaxel, or enzalutamide. Non-parametric testing was performed. Results: Of the 61 participants with PCa, 18.0% reported poor taste, 17.1% reported poor appetite, and 6.6% reported nausea while eating. When asked to assess to what extent this was a perceived problem, 16.4% rated taste, 13.1% rated nausea, and 16.4% rated appetite as a “moderate” or “big” problem. Men with poor or very poor taste (1 or 2 on a 5 point Likert scale) had a significant association with poor appetite (OR = 7.9, P = 0.0002). There was no direct relationship observed between taste and weight loss. The population with poor appetite was more likely (OR = 21.25, P < 0.0001) to have had ≥ 5% weight loss as compared to those without a poor appetite. Those reporting at least some nausea were also (OR = 8.645, P = 0.0007) more likely to have ≥ 5% weight loss. In the treatment subset, pts on docetaxel at time of survey were 15.17 fold more likely to have poor taste as compared to those on abiraterone (p = 0.0145). Conclusions: We observed that perceived problems with taste were associated with loss of appetite which in turn was associated with weight loss. Weight loss is a known adverse prognostic factor in pts with advanced PCa. Further studies are warranted on this important patient-centric assessment.