bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sensitivity analyses for progression-free survival (PFS) and radiographic PFS (rPFS) from the phase II STRIVE trial comparing enzalutamide (ENZA) with bicalutamide (BIC) in men with castration-resistant prostate cancer (CRPC).
Authors: Penson David F. , Armstrong Andrew J. , Concepcion Raoul S. , Wu Kenneth , Wang Fong , Krivoshik Andrew P. , Phung De , Higano Celestia S. 
Published: February 2017

169 Background: STRIVE was arandomized, double-blind, phase 2 trial comparing ENZA vs BIC in nonmetastatic (M0) or metastatic (M1) CRPC. In this study, ENZA significantly reduced the risk of prostate cancer progression or death compared with BIC in patients with M0 or M1 CRPC. Methods: 396 men with M0 (n = 139) or M1 (n = 257) CRPC were randomized to ENZA 160 mg/day or BIC 50 mg/day. The primary endpoint of PFS was defined as the time from randomization to radiographic progression, PSA progression, or death from any cause, whichever occurred first. rPFS was defined as the time from randomization to death or the first objective evidence of radiographic disease progression in soft-tissue disease per RECIST v1.1 or in bone per PCWG2 guidelines. Sensitivity analyses were prespecified to assess the impact of alternative definitions for PFS in all patients and were performed post hoc for the key secondary endpoint of rPFS in patients with M1 disease only (table). Results: Consistent with the primary analyses of PFS and rPFS, the results from all sensitivity analyses favored ENZA over BIC (table). Conclusions: PFS and rPFS sensitivity analyses in STRIVE demonstrated a consistent and robust treatment benefit with ENZA compared with BIC by any variation of the original definition of PFS. Clinical trial information: NCT01664923. [Table: see text]
The RADICAL-PC trial.
Authors: Pinthus Jehonathan H , Klotz Laurence , Lukka Himanshu , Duivenvoorden Wilhelmina CM , Pettit Shirley , Pohl Kayla , Siemens D. Robert , Fradet Vincent , Mourtzakis Marina , Kavsac Peter , Devereaux PJ , Leong Darryl 
Published: February 2017

178 Background: Cardiovascular disease (CVD) occurs frequently in men with prostate cancer (PC), but the reasons are unclear. Specifically, the role of androgen deprivation therapy (ADT) in promoting CVD remains uncertain. There is a lack of evidence to inform preventive strategies against CVD in this high risk group. It is unknown if the evidence to support CVD preventive strategies in the general population can be validly extrapolated to men with PC. Methods: RADICAL-PC combines two prospective studies, one of which is embedded in the other. The Role of Androgen Deprivation Therapy in Cardiovascular Disease – A Longitudinal Prostate Cancer Study (RADICAL PC1) is a prospective cohort study of men within one year of their first diagnosis of PC, or who are within one month of commencing ADT for the first time. Its goal is to identify factors associated with the development of CVD among men with PC, with a particular focus on ADT. The Randomized Intervention for Cardiovascular and Lifestyle Risk Factors in Prostate Cancer Patients (RADICAL PC2) is a randomized, controlled trial embedded in RADICAL PC1. RADICAL PC2 will test a systematic approach to modifying CV and lifestyle risk factors. The intervention group will receive: 1) Standardized advice on healthy diet and exercise; 2) Low-dose antiplatelet agent; 3) Low- to moderate-dose statin; and 4) ACE-I for baseline systolic blood pressure ≥ 130mmHg. Results: The study has been recently funded by Movember clinical trial program of Prostate Cancer Canada, and is launched across Canada. The primary outcome is the occurrence of the composite of cardiovascular death, myocardial infarction, stroke, heart failure, or arterial revascularization. For RADICAL-PC1, 6000 participants will have 90% power to detect a hazard ratio 0.86 for a given exposure. For RADICAL-PC2, 4116 participants randomized, with 434 primary outcome events will have 85% power to detect a hazard ratio of 0.75 in the intervention group. Conclusions: RADICAL PC will be one of the largest prospective studies of CVD – the main competing risk – in men with PC. It will clarify the determinants of CVD in these men, the role of ADT in CVD, and will simultaneously test an intervention to lower the CVD risk in this high-risk population.
Androgen-deprivation therapy plus docetaxel-based chemotherapy in metastatic hormone-sensitive prostate cancer. A meta-analysis of randomized clinical trials.
Authors: Ramos-Esquivel Allan , Baptista Joao M. , Corrales-Rodriguez Luis , GonzÃƒÂ°lez Ileana , Juarez Villegal Melissa , Zeledon Zenen , FernÃƒÂ°ndez Cristina 
Published: February 2017

188 Background: Androgen-deprivation therapy (ADT) is the standard of treatment for patients with newly diagnosed metastatic prostatic cancer. Nevertheless, recent trials have suggested a role for chemotherapy in these patients. We performed a systematic review and meta-analysis to assess the efficacy and safety of docetaxel-based chemotherapy in combination with ADT for patients with hormone-sensitive metastatic prostate cancer. Methods: Randomized clinical trials (RCT) were identified after systematic searching of electronic databases (MEDLINE, OVID and The Cochrane Central Register of Controlled Trials), as well as ASCO conference proceedings from 2010 to 2015. We included only RCT comparing ADT versus the combination of ADT plus docetaxel-based chemotherapy in patients with newly diagnosed metastatic prostate cancer. A random-effect model was used to determine the pooled hazard ratio (HR) for the efficacy outcomes: overall survival (OS) and clinical progression-free survival (PFS), according to the inverse-variance method. Heterogeneity was measured using the Q and I2statistics. Results: Three RCT (n = 2 262), were included in our meta-analysis (E3805, GETUG-AFU 15 and the M1 subgroup from STAMPEDE Trial). Docetaxel-based chemotherapy plus ADT was associated with improved OS (HR: 0.74; 95% CI: 0.60-0.90; p = 0.003). The heterogeneity of these trials was moderate (Tau2: 0.02; I2: 51%; p = 0.13). Clinical PFS was also significantly better in patients receiving docetaxel-based chemotherapy (HR: 0.67; 95% CI 0.55-0.82; p = 0.0001), with moderate between-study heterogeneity detected (Tau2: 0.01; I2: 42%; p = 0.19). Different subset of patients in these trials can explain the aforementioned heterogeneity. Regarding adverse drug reactions grade 3 or higher, neutropenia was reported in a range from 36% in the GETUG-AFU 15 Trial to 12% in the STAMPEDE trial and febrile neutropenia was reported from 6.1% in the E3805 Trial to 12% in the STAMPEDE Trial. Conclusions: The addition of docetaxel-based chemotherapy to ADT improves OS and clinical PFS. New trials are needed to determine which patients benefit the most from this intervention.
Stereotactic body radiation therapy for low-, intermediate- and high-risk prostate cancer: Disease control and quality of life at 9 years.
Authors: Katz Alan J. , Kang Josephine 
Published: February 2017

20 Background: Stereotactic body radiation therapy (SBRT) takes advantage of the prostate’s low α/β ratio to deliver a large radiation dose in a few fractions. This prospective study expands upon prior studies to further evaluate SBRT efficacy and QOL for a large patient population that includes low-, intermediate- and high-risk patients with prostate cancer. Methods: 515 patients with organ-confined prostate cancer (471 T1c and 44 T2a, all N0M0) received robotic SBRT. The median age was 69 years and the median PSA was 6.48 ng/ml. By NCCN criteria, 324 patients were low-risk, 139 were intermediate-risk, and 52 were high-risk. Androgen deprivation therapy was administered to 70 patients for up to one year. 158 patients with Gleason scores < 4+3 received 35 Gy delivered in 5 daily fractions. The remaining patients, from all risk groups, received a total dose of 36.25 Gy in 5 daily fractions. The proximal seminal vesicles were treated except in low-risk cases. Biochemical failure was assessed using the Phoenix criterion and QOL was assessed with EPIC scoring. Results: At a median follow-up of 84 months, 74 patients died (72 from unrelated causes). The median PSA at 78 months was 0.11 ng/ml. The actuarial 9 year freedom from biochemical failure was 95%, 89%, and 66% for the low-, intermediate- and high-risk groups (p = 0.01). For patients with Gleason scores < 4+3, there was no difference in terms of median nadir or biochemical control between doses of 35 and 36.25 Gy. Late RTOG toxicity was mild with 4% grade 2 rectal, 9.5% grade 2 urinary, and 1.9% grade 3 urinary. Late grade 2-3 urinary toxicity was 6.9% for 35 Gy vs. 13.2% for 36.25 Gy (p = 0.01). Mean EPIC urinary and bowel QOL declined at 1 month post-treatment and returned to baseline by 2 years where it remains. EPIC sexual QOL declined by 29% at 78 months. Conclusions: SBRT alone produces excellent biochemical control rates at up to 9 years with mild toxicity and minimal impact on quality of life. These long-term results appear superior to standard IMRT with lower cost and are strikingly similar to HDR therapy. These results also strongly suggest that 35 Gy is as effective as 36.25 Gy for patients with Gleason < 4+3, with less urinary toxicity.
Comorbidity and the risk of all-cause and prostate cancer–specific mortality in men with unfavorable risk prostate cancer undergoing high dose radiation therapy alone.
Authors: Huynh Mai Anh , Chen Ming-Hui , Wu Jing , Braccioforte Michelle H. , Moran Brian Joseph , D'Amico Anthony V. 
Published: February 2017

207 Background: An association between shortened survival and 6 months of androgen deprivation therapy (ADT) use has been observed in men with moderate to severe comorbidity undergoing external beam radiation therapy (RT) for unfavorable-risk prostate cancer (PC). Whether these men would benefit from treatment with high dose RT alone remains unknown and was explored. Methods: Between October 1997 and May 2013, 7533 men with T1-3NxM0 PC were treated with brachytherapy with or without neoadjuvant RT at the Chicago Prostate Cancer Center. We used competing risks and Cox regression multivariable analyses to evaluate whether the risk of PC-specific and all-cause mortality (PCSM, ACM) were increased in men with unfavorable-intermediate or high risk as compared to favorable-intermediate or low risk PC undergoing brachytherapy adjusting for number of comorbidities (diabetes mellitus, myocardial infarction, congestive heart failure), age at and year of brachytherapy, use of supplemental RT, and an RT treatment propensity score. Results: Of 7533 men treated with curative intent 5737 (76.2%), 1470 (19.5%) and 326 (4.3%) had no, 1, or 2 or more comorbidities respectively. After a median follow up of 7.7 years 958 men died, 81 (8.5%) and 877 (91.5%) of PC and other causes respectively. In the no comorbidity subgroup the risk of PCSM (Adjusted hazard ratio (AHR): 2.39; [95% Confidence interval (CI): 1.32 to 4.31]; p = 0.004) and ACM (AHR: 1.25; [95% CI:1.05 to 1.50]; p= 0.013) were significantly increased in men with unfavorable-intermediate or high-risk PC as compared to favorable-intermediate or low risk PC; however, this was not the case in men with 1 or at least 2 comorbidities as shown in the table. Conclusions: Withholding ADT in men with unfavorable-intermediate or high-risk PC and at least 1 significant comorbidity did not appear to increase the risk of PCSM or shorten survival. [Table: see text]
Analysis of Surveillance, Epidemiology, and End Results Program (SEER) PSA coding error using primary data.
Authors: Schultheiss Timothy E. , Hall Matthew David , Farino Ginamarie , Wong Jeffrey Y.C. 
Published: February 2017

21 Background: SEER did not report PSA values for the 2014 submission because of inaccurate coding. This inaccuracy was a result of a confusing data entry guideline where PSA is coded in a 3-digit field with an implied decimal between digits 2 and 3. Our study uses original registry data to assess the magnitude and implications of these coding errors. Methods: The National Oncology Data Alliance is a database of more than 150 Commission-on-Cancer compliant tumor registries that use proprietary cancer registry software sold by Elekta AB (Stockholm, Sweden) and contains the same data sent to state tumor registries and SEER. De-identified data from all newly diagnosed prostate cancer cases from 2005-2013 were extracted (n = 89,379). PSA data were acquired from both the Collaborative Staging (CS) Site Specific Factor 1 (SSF1) for prostate cancer and from de-identified text fields. SSF1 contained the error prone datum that was transferred to SEER. The PSA data contained in the text fields, which are used to record lab results, etc. verbatim, were taken to be definitive. PSA values from both SSF1 and text fields were complete in 63,051 patients. AJCC Stage was determined using the clinical T stage field and the SSF fields that code for Gleason score. We calculated the error rates and their directions for PSA stratification into three levels (0 to < 10, 10 to < 20, and ≥ 20) and for the AJCC stage. Results: The measured error rate in PSA values in SSF1 caused by erroneous decimal placement was 9.0%. The resulting error rate in PSA stratification was 7.5%, with the SSF1 PSA value giving a higher PSA category in 4.8% of cases and lower in 2.7%. The consequent error rate in AJCC staging was 2.8% overall, with the PSA error resulting in a higher stage group in 1.9% and lower in 0.9%. Conclusions: Many factors can contribute to the overall error rate in PSA values in SEER data, but we are addressing only the errors associated with the implied decimal. The consequences of this error are modest despite a 9% error rate. However, SSF1 for prostate cancer is not the only confusing SSF introduced by the CS system. The current cancer registry database design is derived from outdated technology and needs restructuring to be a more effective surveillance and research tool.
Sequential administration of new agents (NAs) after docetaxel (DOC) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts): Impact of disease control (DC) duration in second line on the subsequent line outcomes.
Authors: Maines Francesca , De Giorgi Ugo , Facchini Gaetano , Fratino Lucia , Gasparro Donatello , Alesini Daniele , Basso Umberto , Tucci Marcello , Ortega Cinzia , Scagliarini Sarah , Verderame Francesco , Barni Sandro , D'Angelo Alessandro , Vicario Giovanni , Donini Maddalena , Carrozza Francesco , Sava Teodoro , Sirotova Zuzana , Santini Daniele , Caffo Orazio 
Published: February 2017

210 Background: Abiraterone acetate (AA), cabazitaxel (CABA), and enzalutamide (ENZ) are NAs which demonstrated their efficacy in mCRPC pts who have previously treated with DOC. Unfortunately all pts develop a resistance to these drugs and eventually show a progression of disease. Since the androgen receptor machinery remains the ultimate target of NAs in mCRPC post-DOC, some mechanisms of resistance could be common to all NAs. To date, NAs are sequentially administered in the hope of obtaining a cumulative survival benefit. To date it is unknown if the DC duration influence the outcomes of the subsequent treatments. The present study was aimed to retrospectively assess this issue in a large series of mCRPC pts. Methods: We recorded the clinical outcomes of all treatments received after DOC. For the study purpose, we categorized the pts according to the duration of DC (absence of progression) during NA-based second line: DC ≤ 3 mos (primary resistance – PRe); DC from 3.1 to 11.9 mos (intermediate sensitivity – IS); DC ≥ 12 mos (long term disease control – LTDC). Results: A consecutive series of 291 mCRPC pts, median age 71 yrs (46-91), with bone (88%), nodal (53%) or visceral (18%) mets, was collected. All pts received a NA-based as second line after DOC: 160 (55%) received AA, 99 (33%) CABA and 32 (11%) ENZ. PRe was observed in 56 pts (23 AA – 25 CABA – 8 ENZ), IS in 178 (101 AA – 58 CABA – 19 ENZ), LTDC in 57 (36 AA – 16 CABA – 5 ENZ). The third-line clinical outcomes are detailed in the table. Conclusions: From this data, it appears that DC duration may be a prognostic factor, as a probable result of pts/disease selection. In fact, pts progressing more than 12 mos from the start of NA-based second line appear to have more probabilities to live longer, compared to pts progressing earlier, when they receive another NA-based third line therapy. [Table: see text]
Impact of single agent daily prednisone on survival and toxicities in post-docetaxel men with metastatic castration-resistant prostate cancer (mCRPC): An analysis of 2 phase III trials.
Authors: Sonpavde Guru , Pond Gregory Russell , Templeton Arnoud J. , Kwon Eugene D. , De Bono Johann S. 
Published: February 2017

213 Background: Daily oral prednisone (P) has been employed for the therapy of mCRPC, alone or in combination regimens. Despite palliative benefits and PSA responses, the overall clinical impact of P is unknown and it may foster resistance mechanisms. We performed a pooled analysis of control arms of randomized trials which either did or did not administer single agent P to evaluate its impact on overall survival (OS) and toxicities. Methods: Individual patient data from control arms ofrandomized trials of post-docetaxel men receiving placebo or P + placebo were eligible for analysis. Patient demographics, survival, and toxicity data were collected. The impact of P on OS and toxicities was investigated in Cox regression models adjusted for known clinical and laboratory prognostic factors. Statistical significance was defined as a p-value < 0.05 and all tests were two-sided. Results: The control arms of 2 randomized phase III trials were available totaling 794 men: the COU-AA-301 trial (n = 394) administered P plus placebo and the CA184-043 trial (n = 400) administered placebo alone. P plus placebo was not significantly associated with OS compared to placebo alone in a multivariable analysis (HR = 0.89 [95% CI 0.72-1.10], p = 0.27). Other factors associated with poor OS were Eastern Cooperative Oncology group (ECOG)-performance status (PS) ≥ 1, Gleason Score ≥ 8, liver metastasis, high PSA, hypoalbuminemia, and elevated LDH.In contrast, CTCAE grade ≥ 3 therapy-related toxicities were significantly increased with P plus placebo compared to placebo alone (HR = 1.48 (1.03-2.13), p = 0.034) in a multivariable analysis. Other baseline factors significantly associated with a higher risk of grade ≥ 3 toxicities were ECOG-PS ≥ 1, hypoalbuminemia and elevated LDH. Conclusions: P plus placebo compared with placebo alone for post-docetaxel men with mCRPC was not associated with extension of OS, but was associated with higher grade ≥ 3 toxicities. With the exception of the use of P in combination with abiraterone, P alone or in combination regimens should be questioned given its unclear palliative benefits and association with increased toxicities.
Trends in utilization of novel oral therapeutic agents for men with metastatic castrate-resistant prostate cancer within the United States Veteran’s Affairs Health System.
Authors: Henry Elizabeth , Silva Abigail , Tarlov Elizabeth , Gaynor Ellen R. 
Published: February 2017

220 Background: Therapeutic options for men with metastatic castrate resistant prostate cancer (mCRPC) have expanded significantly over the past 5 years with several new agents demonstrating improved survival, including two oral agents. Abiraterone acetate (AA), a CYP-17 androgen synthesis inhibitor, obtained initial FDA approval in 2011 for post-docetaxel (D) use, and gained expanded approval in 2012 for pre-D use. Enzalutamide (ENZ), an androgen receptor signaling inhibitor, also gained FDA approval in 2012 (post-D) and indication was expanded in 2014 (pre-D). Due to the relatively recent approvals of these agents, there is limited data on rates of uptake and prescribing patterns for patients (pts) with mCRPC. Methods: For this observational study, Veterans Affairs (VA) healthcare system data (including hospitalizations, outpatient visits, and pharmacy) were used to identify male veterans who received treatment for mCRPC between fiscal years 2008 and 2014. Descriptive statistics were used to classify treatment patterns. Results: During the time period, 75,199 pts with prostate cancer were medically or surgically castrated. Of those, 43,805 were treated with anti-androgens and 7,890 went on to receive advanced lines of therapy associated with mCRPC. The median age at the time of mCRPC treatment was 73y. Between 2008-2010 (pre-AA) and 2011-2014 (post-AA), the proportion of mCRPC pts treated with ketoconazole or D dropped from 95% to 59% (p < 0.0001). Conversely, the proportion of pts who received AA or ENZ increased from 19% to 68% (p < 0.0001). Among the 3,763 pts treated with AA or ENZ between 2011 and 2014, the proportion treated with first-line D decreased, while the proportion treated with first-line AA increased (p < 0.00001). Conclusions: The FDA approval of AA and ENZ has had a significant impact on treatment patterns for men with mCRPC within VA, with decreased use of ketoconazole and delayed use of chemotherapy. Further information regarding patient and disease characteristics is needed. The rapid uptake of these novel agents has significant implications for disease-related outcomes as well as anticipated pharmacy costs within the VA.
The expression profiles of miRNAs in the progression of prostate cancer from high-grade prostatic intraepithelial neoplasia to metastatic diseases.
Authors: Eminaga Okyaz , Fries Jochen , Woetzel Fabian , Neiss Susanne , Warnecke-Eberz Ute , Heitmann Michaela , Heidenreich Axel 
Published: February 2017

221 Background: The epigenetic regulation by miRNA plays an important role in tumor progression of prostate cancer (PCa). Methods: The expression data of 1054 miRNAs from TCGA were applied to identify relevant miRNAs associated with tumor progression (i.e. miR-210, miR-375, miR-378, miR-345, miR-143 miR-183 and miR-98). miRNA were isolated by miRNeasy FFPE kit (Qiagen, Hilden, Germany) from paraffin-embedded tissues of prostate specimens with PCa, HGPIN and normal tissues. Early-stage PCa was defined as PCa with pT2 tumor stage, Gleason score < = 7a (3+4) and PSA level < 10 ng/ml. PCa with pT3/4 or Gleason > 7a was defined as advanced PCa. PCa with pN1 were considered as metastatic diseases. Additionally, 3 cases with castration-resistant prostate cancer (CRPC) were considered. Quantitative miRNA expression data were acquired and analyzed using a real-time TaqMan-based PCR. ANOVA analyses were performed to evaluate the expression of miRNAs between HGPIN, Normal and PCa tissues. The small nuclear U6 RNA was used as an endogenous control Results: ANOVA analysis revealed a significant variation in expression of all miRNAs among groups. The expression level of miR-183 and miR-375 increased with the tumor progression. miR-143, miR-375-3p were inversely correlated with the tumor progression. miR-210 and miR-183 were significantly overexpressed in metastatic diseases compared to non-metastatic diseases (FDR < 0.01), whereas the expression level of miR-378-3p was lower in metastatic diseases than in organ-confined PCa. The expression of miR-98 was lower in PCa compared to normal tissues. In silico analysis, the down-regulation of miR-98 and miR-345-5p seems to activate the HIF-1 signaling pathway initiating the up-regulation of miR-210 that interact with genes related to cell cycle, RNA transcription, homologous recombination and non-homologous end-joining. Conclusions: Our data reveal epigenetic regulations of miRNA, which are associated with transition from normal tissues to HGIPN, from HGPIN to early-stage PCa, and early-stage PCa to advanced PCa. Advanced PCa represents the first stage of metastatic diseases.