bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase II study with window-design to evaluate anti-tumor activity of the survivin antisense oligonucleotide (ASO) ly2181308 in combination with docetaxel for first-line treatment of castrate-resistant prostate cancer (CRPC).
Authors: Wiechno Pawel J. , Chlosta Piotr , Pikiel Joanna , Somer Bradley G. , Mellado Begoña , Duran Martinez Ignacio , Castellano Daniel E. , Wedel Steffen , Cervera Grau Jose Manuel , Callies Sophie , Andre Valerie , Brown Jacqueline , Hurt Karla , Lahn Michael M. F. , Stöckle Michael , Reuter Christoph , Heinrich Bernhard 
Published: March 2020

5019 Background: In prostate cancer, expression of survivin, a protein that inhibits apoptosis, is associated with resistance to taxanes and poor outcome. LY2181308 reduces survivin expression and consequently is expected to improve activity of taxanes, such as docetaxel. A randomized phase II study was conducted to assess the activity of the combination. Methods: Adult patients (pts) with CRPC, ECOG performance status <2, and no bone or CNSmetastases were randomized 1:2 to standard docetaxel/prednisone every 21 days (Arm A) or standard therapy combined with LY2181308 given as a 3-hr IV infusion (Arm B). Analysis was planned and performed after 130 pts progressed or died. This assessment provided a 70% chance of detecting a difference in progression-free survival (PFS) at the 10% significance level. Initially, LY2181308 was given as a loading dose (3 consecutive days) and then as a weekly 3-hr IV maintenance dose. Arm B also included a window treatment with LY2181308 monotherapy equivalent to a 21-day cycle of docetaxel before starting combined treatment. The primary endpoint was PFS. Results: This study enrolled 154 pts. The median PFS for Arm B was 8.64 (90% CI, 7.39–10.45) months vs. 9.00 (90% CI, 7.00–10.09) months in Arm A, showing no statistical difference (log rank p=0.755). The median overall survival (OS) for Arm B was 27.04 (90% CI, 19.94–33.41) months vs. 29.04 (90% CI, 20.11–39.26) months for Arm A (log-rank p= 0.838). The PSA responses (>50% reduction in PSA) were similar: 56.9% for Arm A and 56.1% in Arm B (p=0.856). Most pts had no pain or mild pain at baseline and during the active period. Pts treated in Arm B had a higher frequency of serious and nonserious adverse events (AEs) than those in Arm A. The observed AE and pharmacokinetic (PK) profiles were consistent with the known safety and PK profiles of LY2181308 and docetaxel. Conclusions: The addition of LY2181308 to a standard docetaxel/prednisone regimen showed no improvement in PFS, PSA response, and OS in first line CRPC pts. The safety profile of docetaxel and LY2181308 is predictable and consistent with the known safety profiles. Clinical trial information: NCT00642018.
The genomic relationship among matched prostate cancer foci.
Authors: VanderWeele David James , Brown Christopher D. , Grossman Robert L. , Taxy Jerome B. , Stadler Walter Michael , White Kevin P. 
Published: March 2020

5028 Background: Cancer management is influenced by how one views progression and how one calculates the risk of metastases and death. For prostate cancer, this is based largely on histologic appearance, or Gleason score. Cancers with a Gleason score of 6 exhibit indolent behavior and are often considered low risk. Despite recommendations supporting active surveillance for Gleason 6 prostate cancer, the vast majority of American patients receive aggressive local therapy, in part based on a presumption that low grade cancer progresses to high grade, lethal disease. Methods: To assess the genomic relationship between low and high grade disease, laser capture microdissection was used to isolate concurrent cancer foci from prostates with multifocal disease, and somatic mutations were identified using exome sequencing. The relationship between a Gleason 6 focus and a concurrent Gleason 8 or higher focus was determined for four subjects, and a lymph node metastasis was examined for two of those subjects. Results: We obtained an average of 41-fold median coverage of the exome, with an average high confidence mutation rate of 0.8/Mb. Seventy of 79 (0.886) high confidence somatic mutations in low grade disease were private to the low grade foci. For the cases for which a metastatic focus was available, 15 of 80 (0.188) high confidence somatic mutations in the high grade focus were private. Seven of the 80 (0.088) were shared with low grade foci, and 65 (0.813) were shared with metastatic foci. Conclusions: The pattern of shared versus private mutations is consistent with early divergence between Gleason 6 and Gleason 8 or 9 disease, and late divergence between Gleason 8 disease and lymph node metastases. These data support a model of parallel evolution of lower and higher Gleason score disease, rather than progression from Gleason 6 to higher Gleason scores.
The ELDORADO study: A phase II randomised study of concurrent weekly docetaxel, IMRT, and ltadt in patients with high-risk prostate cancer.
Authors: Wilke Derek , Wood Lori , Walker Heather , Bell David , Rendon Ricardo A. , Hollenhorst Helmut , Rutledge Robert , Bowes David , Robar James , Drucker Arik Marc , Cwajna Slawa , Bailly Greg , Ago Tetteh 
Published: March 2020

5048 Background: Treatment intensification is warranted for ‘high risk’ prostate cancer. Docetaxel (DO) and radiotherapy (IMRT) may cause dose-limiting GI or GU toxicity. Treating the whole pelvis last (WP-L) versus the whole pelvic lymphatics first (WP-F) could reduce the number of dose delays or omissions of DO. Methods: We performed a double-blind, randomized trial, in patients with ‘high risk’ non-metastatic prostate cancer who had any one of the following: 1) ≥ T2c TNM category, 2) Gleason score ≥ 8, or PSA > 20 and < 50 µg/L, OR have a greater than 50% risk of recurrence after radical prostatectomy (RP), as predicted by the Kattan nomogram, with no evidence of metastatic disease. Patients receive long-term androgen deprivation therapy (LTADT), and after 4 months of neoadjuvant ADT, receive IMRT and concurrent DO 20 mg/m2 x 8 weekly infusions. Patients were randomized to receive WP-F followed by a boost to the prostate/prostate bed, or to have WP-L. The primary outcome was to compare the number of DO dose reductions, delays or omissions due to GI or GU toxicity, between arms. Target sample size was 86 patients (pts). Results: 98 pts were registered, 88 were randomized, 2 withdrew consent, leaving 42 pts randomized to WP-F, and 44 pts to WP-L. The trial was closed to accrual Feb 2, 2012. Twenty-five pts had previous RP (29%). Seven pts (16.6%) allocated to WP-F had chemotherapy dose reductions/delays versus 3 pts (6.8%) allocated to WP-L , which was not statistically significant (p=0.19). Overall 80.2% of pts received all 8 weekly doses of DO and IMRT (WP-F vs. WP-L: 78.6% vs.81.8%, p=0.9). Actuarial overall survival at 4 years is 96 % (WP-F vs. WP-L: 94% vs.97%, p=0.6). Biochemical relapse-free survival at 4 years is 96.7% (WP-F vs. WP-L: 98% vs.97%, p=0.92). Two patients have needed surgical intervention for Grade > 3 GU toxicity. Cumulative treatment-related grade 3 or 4 GI or GU toxicity was 36%. When patients were last seen, only 2/84 (2.3%) patients had ongoing grade 3 GI or GU toxicity at a median follow up of 2.7 years Conclusions: Concurrent use of DO and IMRT is feasible with reasonable toxicity. Sequence inversion does not enhance chemotherapy delivery. Clinical trial information: NCT00452556.
A phase I/II study of cabazitaxel (Cbz) combined with abiraterone acetate (AA) and prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) whose disease has progressed after docetaxel (D) chemotherapy: Preliminary results.
Authors: Massard Christophe , Pezaro Carmel , Bobilev Dmitri , Omlin Aurelius Gabriel , Bianchini Diletta , Lorente Estelles David , Albiges Laurence , Loriot Yohann , Varga Andrea , Nguyen Thi Xuan Quyen , Fizazi Karim , De Bono Johann Sebastian 
Published: March 2020

5049^ Background: Both Cbz and AA have demonstrated significantly improved survival in randomized Ph 3 studies in pts with mCRPC and progressive disease after D treatment. Cbz and AA have established non-overlapping adverse event (AE) profiles. A Ph 1/2 study was initiated to investigate the combination of Cbz + AA for the treatment of mCRPC (NCT01511536). Methods: Pts with progressive mCRPC after D were enrolled. The primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz + AA (Ph 1), and the PSA response rate (RR) with this combination (Ph 2). Secondary endpoints included AEs, pharmacokinetics (PK) and efficacy. All pts received oral AA 1000 mg QD and P 5 mg BID. In Ph 1, pts received 1 of 2 dose levels (DL) of Cbz (20 and 25 mg/m2 IV Q3W) according to a 3+3 design. A 2-cycle DLT observation period was used. Here, we report results of Ph 1. Results: Ten pts were enrolled in Ph 1; 9 were evaluable: 3 at DL1 and 6 at DL2 completed 2 cycles without DLTs (total number of cycles = 46). In general, AEs were Grade (Gr) 1/2; the most frequent all-Gr AEs by pt cycle were asthenia (39%), diarrhea (37%; Gr 3 in 1 pt), back pain (26%), nausea (20%), constipation (20%), anemia (17%), decreased appetite (17%) and fatigue (15%; Gr 3 in 2 pts). In the safety population, 0/3 pts at DL1 and 2/7 pts at DL2 experienced Gr 3–4 neutropenia. The MTD was established at the full approved doses of both drugs (Cbz 25 mg/m2/AA 1000 mg). In 6 pts evaluable for PK (DL1 and DL2), median Cbz clearance (coefficient of variation %) was similar at cycle 1 (Cbz alone: 28.9 L/h/m2 [11%]) and cycle 2 (Cbz + AA coadministration: 28.6 L/h/m2 [42%]). In 9 evaluable pts, 55% PSA RR was observed. Conclusions: In this Ph 1 study, Cbz in combination with AA appeared to have a manageable safety profile. Gr 3–4 neutropenia was observed in 2 of 10 patients. Daily AA treatment did not affect Cbz clearance; Cbz exposure was comparable to previous studies of Cbz + P treatment. The Ph 2 portion is ongoing at the established MTD. Detailed safety, PK and preliminary efficacy data (Ph 1) will be presented. Clinical trial information: NCT01511536.
Clinicopathologic features and clinical outcomes associated with Gleason upgrading from biopsy to radical prostatectomy.
Authors: Yoo Sun Mi , Werner Lillian , Nakabayashi Mari , Sweeney Christopher , Hirsch Michelle S. , Kantoff Philip W. , Pomerantz Mark M 
Published: March 2020

5056 Background: Gleason score stratifies patients into prognostic categories and is critical in guiding treatment. Previous series indicate that ~25% of patients with low-grade (Gleason ≤6) disease on biopsy are upgraded to higher grade disease upon radical prostatectomy (RP). We sought to characterize the clinical and pathologic variables associated with upgrading and investigate its clinical implications. Methods: 1,469 prostate cancer patients underwent prostate biopsy and RP, were seen at Dana-Farber Cancer Institute/Brigham and Women’s Hospital (DFCI/BWH), and had tissue specimens reviewed by DFCI/BWH genitourinary pathologists between 1999-2011. Associations between Gleason upgrading and clinical and pathologic variables were assessed using Wilcoxon’s non-parametric test and Fisher’s exact tests. Log rank test was used to assess association between upgrading and time to biochemical recurrence (BCR). Results: Of 1,469 patients, 958 (65%) had biopsy Gleason 6 and 511 (35%) had biopsy Gleason 7. Among individuals with biopsy Gleason 6, 336 (35%) were upgraded to Gleason ≥7 upon RP (275 3+4 and 49 4+3) while 622 (65%) remained Gleason 6 at RP. Variables associated with increased risk of upgrading: greater PSA at diagnosis (p=1x10-4); age >58 (OR=1.62, p < 1x10-4); >1/3 positive biopsy cores (OR=2.1 for 33-50% compared to ≤33%, p < 1x10-4). In this study the number of cores biopsied was not associated with upgrading. Gleason upgrading was also associated with extraprostatic tissue involvement (OR=1.69, p=0.005). Patients upgraded from biopsy Gleason ≤6 to Gleason 7 on RP had a longer time to BCR than those with Gleason 7 on both biopsy and RP, but a shorter time to BCR than those who remained Gleason 6 on RP (adjusted hazard ratio 0.69, 95% CI 0.49-0.98, p=0.03). Conclusions: Gleason upgrading from low-grade to higher grade disease is associated with a higher PSA at diagnosis, older age at diagnosis, and a greater number of positive biopsy cores. Clinically, prostate cancers upgraded from Gleason ≤6 to Gleason 7 appear to behave differently than those who are not upgraded. These results could have implications in determining ideal candidates for active surveillance.
Novel predictive markers of PSA response to abiraterone acetate in men with metastatic castration-resistant-prostate-cancer (mCRPC).
Authors: Leibowitz-Amit Raya , Templeton Arnoud J. , Atenafu Eshetu G. , Vera-Badillo Francisco Emilio , Chllamma Muralidharan , Solow Henry L. , Knox Jennifer J. , Tannock Ian , Sridhar Srikala S. , Joshua Anthony Michael 
Published: March 2020

5058 Background: Abiraterone acetate (AA) prolongs survival in men with mCRPC pre- and post- chemotherapy. To date, clinical predictive biomarkers of response remain poorly characterized. The aim of this retrospective study was to identify and analyze predictors of response to AA in men with mCRPC. Methods: All men receiving AA at the Princess Margaret Cancer Centre between November 2009 and December 2012 were reviewed. PSA response rate (RR) was defined according to PCWG2 criteria and assessed 12 weeks after AA start. Potential predictive factors were analyzed using uni- and multivariable logistic regression models. Results: In total, 70 patients were evaluable for response: 34 men were chemotherapy naive and had a PSA RR of 44% (95% CI 27-62%); 36 men had prior chemotherapy and had a PSA RR of 33% (95% CI 17-50%). In univariable analysis, pre-treatment lactate dehydrogenase (LDH) level >220 U/L (ULN) and a neutrophil-to-lymphocyte ratio (NLR) >5 were both significantly associated with a lack of PSA response. On multivariable analysis, NLR>5 remained significantly associated with lack of a PSA response (Table 1A). Men were then stratified into three groups according to these two variables. These groups were significantly associated with RRs (Table 1B). PSA RR was not found to be associated with the Gleason score, initial stage, time from initial diagnosis to mCRPC or to AA initiation, prior ketoconazole or docetaxel treatment, pre-treatment alkaline phosphate or PSA doubling time. Conclusions: A pretreatment NLR>5 and an LDH>ULN were both strongly associated with a lack of PSA response to AA. These factors may be key in stratifying men into different response groups to AA. [Table: see text]
Factors impacting decision by African American and underserved populations to choose active surveillance in early-stage prostate cancer.
Authors: Gillespie Theresa Wicklin , Petros John , Goodman Michael , Lipscomb Joseph , Britan Laura , Rowell Jessica Lauren , Herrel Lindsey Allison , Echt Katharina V 
Published: March 2020

5067 Background: African-American (AA) men have the highest rates of prostate cancer (PCa) incidence and mortality in the U.S. Screening for PCa with prostate specific antigen (PSA) has allowed detection of early stage disease, but side effects of radical prostatectomy and radiation raise concerns about unfavorable risk:benefit ratios of PSA screening and subsequent therapy. Active surveillance (AS) is an option for early-stage PCa (ESPC), but only 10% of men eligible for AS choose this approach. The 2011 NIH State-of-the-Science Conference promoted the need to enhance decision-making (DM) about AS. In 2012, the U.S. Preventive Services Task Force recommended against PSA screening, while encouraging patient DM. Our study examined DM needs by men (N=204; 68% AA; screening PSA within normal limits) and their significant others (SO) (N=181; 65% AA) regarding AS and other ESPC options. Methods: This multi-center, mixed methods study (N=402; 51% rural) included 5 sites nationwide. Subjects completed quantitative questionnaires prior to focus groups (FG); 54 FG were held, with separate groups for men and SO. Results: After adjusting for education, comorbidities, insurance, age, health literacy, distance to treatment center, willingness to travel, income and numeracy score, AA men were significantly more likely to be influenced by convenience (OR: 2.84, 95% CI: 1.42-5.65) compared to Caucasians. Rural residence, however, did not affect DM. In qualitative analysis, numerous themes were identified relevant to choice of AS: physician treatment discussions being limited to their own specialty; confusion due to conflicting sources of information; convenience; worry about untreated cancer remaining and treatment toxicities; and lack of awareness of AS as an option. SO tended to value cure over avoiding side effects. Conclusions: While the impact of new PCa screening guidelines is uncertain, for AS to become a viable treatment option, providers will need to discuss along with other therapeutic alternatives. SO are influential in DM and may be less enthusiastic about AS than men. For AA men, AS may be a particularly attractive option given the relative influence of convenience in DM.
Risk of missing advanced stage or high grade tumors during active surveillance (AS) even in favorable-risk prostate cancer (PC).
Authors: Kim Jeri , Ward John Francis , Pettaway Curtis A. , Wang Xuemei , Kuban Deborah A. , Frank Steven J. , Lee Andrew , Pisters Louis L. , Matin Surena F. , Shah Jay Bakul , Karam Jose A. , Chapin Brian Francis , Papadopoulos John N. , Achim Mary F. , Hoffman Karen Elizabeth , Pugh Thomas J. , Choi Seungtaek , Logothetis Christopher , Troncoso Patricia , Davis John W. 
Published: March 2020

5069 Background: Owing to tumor heterogeneity, no standard selection criteria exist among prospective AS cohorts. Generally, men with low-stage, -volume, and -grade PC and low prostate-specific antigen (PSA) are eligible. In our prospective single-institution AS trial, men with early-stage PC were stratified: Gr I (favorable risk), II (pt’s choice), or III [competing comorbidities prevent local therapy (Tx)]. We report our experience with Gr I. Methods: Eligibility for Gr I: Gleason score (GS) ≤6, 1 positive (pos) core (<3 mm), and PSA <4 ng/mL or GS 7 (3+4), 1 pos core (<2 mm), and PSA <4 ng/mL. Monitoring q6mo included PSA, testosterone, and digital rectal exam. All pts had repeat biopsy (re-BX) at 1 y and then on predetermined BX scheme. Later, re-BX was required within 6 mo of study entry per an 11-core BX scheme (also used during AS). Definitive Tx was offered to pts who met reclassification based on clinical, BX (upgrading, ↑ in pos core BX, and/or ↑ tumor length), and/or radiographic progression. Imaging studies [bone/CT scans, endorectal MRI (eMRI)] were at physician’s discretion. Results: From 2/2006 to 2/2012, 585 pts enrolled; 191 met Gr I criteria (41 before, 150 after re-BX requirement). Median age was 64 y (range, 36–83); 82% were white, 8% African-American, 8% Hispanic, 2% Asian; 4% had cT1a/cT1b, 84% cT1c, and 12% cT2 disease. Most (189/191) had GS 6 [1 had GS 5, and 1, GS 7 (3+4)]. Median PSA was 3.3 (range, 0.2–10). With median follow-up of 36.2 mo (95% CI: 30.6–41.7), 32/191 (17%) were reclassified [20/41 (49%) before and 12/150 (8%) after re-BX requirement]. Of 32 reclassified, 17 were due to GS: 11 to GS 7 (3+4), 4 to GS 7 (4+3), and 2 to GS 8 (4+4). Ten of the 32 reclassified chose Tx [4 radical prostatectomy (RP); 4 radiation; 2 cryotherapy]. RP showed a pT2N0 GS9 (4+5) apical tumor in 1 at 5 y, a pT3aN0 GS7 (4+3) tumor in 1 at 3 y, a pT2N0 GS7 (4+3) tumor in 1 at 1 y, and a T2N0 GS 7 (3+4) tumor in 1 at 2 y. Conclusions: Restrictive selection criteria and re-BX at study entry improve clinical risk classification; however, other improvements, including imaging and markers of disease progression could enhance pt selection for AS.
Final results of a phase II study of neoadjuvant metformin in prostatic carcinoma.
Authors: Joshua Anthony Michael , Zannella Vanessa E. , Downes Michelle R , Bowes Barbara , Koritzinsky Marianne , Sweet Joan , Trachtenberg John , Jewett Michael A. S. , Finelli Antonio , Fleshner Neil Eric , Pollak Michael N. 
Published: March 2020

5070 Background: Metformin is an inhibitor of the complex 1 in the respiratory chain, and is widely used in diabetes due to its effect on reducing insulin resistance. It has also been recently described to have effects via AMPK on inhibiting the mTOR kinase. Significant preclinical and epidemiological studies suggest its role in chemoprevention. These actions provide significant rationale to evaluate its utility in prostate cancer. Methods: Men were required to have histologically confirmed prostate cancer involving at least 20% of at least 1 unfragmented biopsy core. Exclusion criteria included patients who were found to be on treatment with any drug used for the treatment of any form of diabetes, or patients that began treatment for any form of diabetes during the course of the study. Pts were treated with up to 500mg tid of metformin. The primary objectives were to demonstrate safety and tolerability of neoadjuvant metformin administration in men with prostate cancer and to document changes in phospho-AKT signalling indices. Results: 24 patients were enrolled with 21 patients evaluable; median age was 64 yrs (range, 45-70 yrs). Baseline characteristics included median PSA 6 ng/mL (range, 3.22-36.11ng/mL). Median duration of drug treatment was 41 days (range 18-81). No grade 3 adverse events were reported during treatment or radical prostatectomy that were related to metformin. Significant pre-and post changes were noted in serum IGF1 (p=0.02), fasting glucose (p=0.03), BMI (p<0.01) and waist/hip ratio (p<0.01). There was a trend for a PSA reduction (p=0.08). There were no correlations between any metabolic, morphometric or cancer-related serum indices. On a per patient analyses, metformin reduced a computerised relative ki67 proliferation index by an average of 29% (absolute difference of 1.4%) compared to the baseline biopsy (p=0.006). P-4eBP1 staining was also reduced as assessed by H-score (p<0.01) consistent with the ability of metformin to inhibit mTOR. Conclusions: Neoadjuvant metformin is well tolerated prior to radical prostatectomy and shows promising effects on proliferation and signaling indices. Further research is needed to define the clinical utility of metformin in prostate cancer. Clinical trial information: NCT00881725.