bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of a 6-month moderate-intensity exercise program on metabolic parameters and bone mineral density in men on androgen deprivation therapy for prostate cancer.
Authors: Alibhai Shabbir M.H. , Durbano Sara , O'Neill Meagan , Santa Mina Daniel , Ritvo Paul , Sabiston Catherine , Krahn Murray Dale , Tomlinson George A. , Matthew Andrew , Warde Padraig Richard , Timilshina Narhari , Segal Roanne , Culos-Reed S. Nicole 
Published: February 2018

237 Background: Androgen deprivation therapy (ADT) is commonly used to treat prostate cancer (PC) but is associated with significant side effects including metabolic abnormalities and bone loss. Although multiple trials have demonstrated that exercise is associated with improvements in multiple side effects of ADT, its effects on metabolic and skeletal outcomes is unclear. We conducted a phase II randomized controlled trial (RCT) comparing three different exercise delivery models. The present analysis examined prespecified endpoints of change in metabolic parameters and bone mineral density. Methods: Men with stage TxNxMx PC starting or continuing ADT for at least 6 months were enrolled and randomized equally to personal training (n = 18), supervised group training (n = 14), or home-based training (n = 16). Participants in all intervention arms underwent moderate to vigorous physical activity with a target of 150 minutes per week for 6 months. Fasting blood work and dual x-ray absorptiometry (DXA) were done at baseline and 6 months (blood work) and 12 months (DXA). Paired t-tests and ANCOVA were used to analyze findings. Results: 48 participants (mean age 69.9 years) were enrolled. The primary analysis demonstrated no significant difference between arms on most quality of life and fitness outcomes so groups were combined for the present analysis. Exercise was not associated with statistically significant changes in hemoglobin, total cholesterol, low density lipoprotein, high density lipoprotein, triglycerides, or fasting blood glucose (p = 0.075 to 0.87). Similarly, exercise was not associated with changes in bone mineral density at lumbar spine, total hip, or femoral neck sites on DXA (p = 0.44 to 0.71). Mean weight change was +0.8 kg. There was no difference between exercise arms on any outcome. Conclusions: Although our study is limited by a small sample size, our results suggest that 6 months of moderate intensity exercise is not associated with improvements in either metabolic or skeletal outcomes in men on ADT. More intensive behavioural interventions and/or pharmacological interventions will be required to reverse the deleterious effects of ADT. Clinical trial information: NCT02046837.
Prevalence of overweight and prediabetes in men receiving systemic therapies for metastatic prostate cancer.
Authors: Finstad Warner , Galiauskas Raimundas , Cook James , Murphy Kate , O'Connor Derbrenn , O Sullivan Eoin , Markey Geraldine , Murphy Conleth G. 
Published: February 2018

289 Background: Patients with metastatic prostate cancer receive several therapies which may be associated with a tendency to overweight and impaired glucose tolerance. These include androgen deprivation therapy and long term steroid therapy. We set out to assess the prevalence of overweight and diabetes/prediabetes in a cohort of patients attending an oncology day ward for a variety of systemic therapies. Methods: We performed a retrospective review of the medical records of men attending an oncology day ward for prostate cancer treatment. As part of their usual care, these men had regular height and weight checks and also had periodic hemoglobin A1C (HbA1C) measurements performed. The prevalence of prediabetes and diabetes in this patient population was assessed from the HbA1C results using the American Diabetes Association 2016 definitions. Information on patient steroid use (and type), and treatment type were also recorded. Results: Among 34 men with metastatic prostate cancer, the mean age was 74 (range 57-88). Therapies received included androgen deprivation therapy in all cases, with chemotherapy or novel androgen receptor pathway inhibitors such as abiraterone and enzalutamide. Only 12% had a pre-existing diagnosis of diabetes mellitus (all type 2). The majority (79%) are overweight or obese. 59% have pre-diabetes as per the American Diabetes Association 2016 Guidelines, while a further 24% meet criteria for diabetes. Only 18% have HbA1c in the normal range. 56% are on continuous long term steroid therapy, usually as part of their prostate cancer therapy. A further 23% receive intermittent steroids. Only 21% had received no steroids in the 6 months prior to first HbA1C check. 18% had castrate-sensitive disease and 82% had castrate resistant disease. Even among patients with castrate sensitive disease, 2/3 had abnormal HbA1c values. Conclusions: Overweight and prediabetes are very prevalent in men receiving systemic therapies for metastatic prostate cancer. A large percentage of men are on long-term steroid therapy which may be contributing to their risk of these conditions. Intervention is required for this group of patients to reduce the impact of therapy on cardiovascular and overall health.
Real-world study of enzalutamide and abiraterone acetate (with prednisone) tolerability (REAAcT): Results.
Authors: Shore Neal D. , Saltzstein Daniel R. , Sieber Paul R. , Mehlhaff Bryan , Gervasi Lawrence , Phillips Jennifer , Wong Yu-Ning , Pei Huiling , McGowan Tracy 
Published: February 2018

296 Background: Enzalutamide (E) and abiraterone acetate with prednisone (AAP) are approved for treatment (tx) of metastatic castration resistant prostate cancer (mCRPC). Concerns of differences in CNS manifestations and tolerability between E and AAP have been reported. REAAcT evaluated tolerability in patients (pts) newly starting E and AAP for mCRPC. Methods: This was a multicenter, Phase IV, non-randomized, prospective real-world study (NCT02663193). The tx (E or AAP) determined by the treating physician was prescribed per USPI. PROs (EORTC QLQ 30, FACIT-Fatigue, FACT-Cog) and tests of 4 cognitive domains (Cogstate) were assessed at baseline (BL) and after 2 months (M2) tx and analyzed for evaluable pts who completed BL and M2 assessments with no major protocol deviations. Descriptive statistics were provided. BL Cogstate scores were used to estimate the rate of cognitive impairment defined as ≥2SD from age-matched normative means of healthy males on ≥2 tests. Reliable change index (RCI) was calculated. Pts were noted to have clinically meaningful cognitive change with a performance decline of |RCI|≥2 on ≥2 tests. Results: Of 100 pts treated, 92 pts were evaluable (E = 46 and AAP = 46). Median age was 75 years. At BL, characteristics and median scores were similar between arms, with mild cognitive impairment in ~20% of pts. Drug discontinuations due to AEs were similar (1 vs. 2 pts), but more dose reductions due to AEs occurred on E vs. AAP (16% vs. 6%). Overall, more AEs were reported on E vs. AAP (52% vs. 36%), but Grade 3/4 AEs (4% E vs. 6% AAP) were similar. Unique neuropsychiatric AEs on E included amnesia, cognitive disorders, memory impairment, and confusional state; on AAP: cerebrovascular accident, presyncope, and spinal cord compression. Regarding fatigue, more AEs were noted on E than AAP (26% vs. 8%) and showed greater worsening in E than AAP (median change -4 vs. 0) by FACIT-Fatigue. This change within E group was statistically significant (mean, 95% CI -4 (-6.61, -1.39)). Four pts on E and 1 pt on AAP had clinically meaningful cognitive decline. Conclusions: While baseline values were similar between arms, after 2 months of tx, differences of fatigue and neurocognition were noted more often with E than AAP. Clinical trial information: NCT02663193.
Consensus statement on circulating biomarkers for advanced prostate cancer.
Authors: Sumanasuriya Semini , Omlin Aurelius Gabriel , Armstrong Andrew J. , Attard Gerhardt , Chi Kim N. , Bevan Charlotte L , Waugh David J. , Ijzerman Maarten J , De Laere Bram , Lolkema Martijn P. , Lorente David , Luo Jun , Mehra Niven , Olmos David , Scher Howard I. , Soule Howard R. , Stoecklein Nikolas H. , Terstappen Leon W M M , De Bono Johann S. 
Published: February 2018

299 Background: The need for validated circulating biomarkers is well recognised in advanced prostate cancer (PCa). Circulating biomarkers evaluating plasma cell-free nucleic acids and circulating tumour cells are being investigated for their clinical utility. There has been a lack of consensus with regards to analyses, reporting and clinical effectiveness of these biomarkers. A consensus meeting was held to address these issues. Methods: A multi-disciplinary panel comprising 18 international prostate cancer experts (including surgeons, medical and radiation oncologists) were consulted prior to the consensus meeting. Four key areas relating to the field of circulating biomarkers were deemed important for discussion: 1) The current utility of circulating biomarkers in 2017; 2) The clinical needs for circulating biomarkers in PCa; 3) The most pressing blood-based molecular assays required; and 4) The steps necessary for developing circulating biomarkers. Using a modified Delphi process, 50 consensus questions were pre-defined for the panel to answer by voting anonymously but publicly at the consensus meeting. Results: A consensus was declared (i.e. ≥ 75% of panellists who did not vote ‘unqualified’ or ‘abstain’ chose the same opinion) in 12/50 (24%) questions. A further 8/50 (16%) of replies were close to reaching consensus (≥ 60% of panellists choosing the same answer). The panel agreed that there is a very high and urgent unmet need for predictive biomarkers, with consensus that DNA repair biomarkers in particular are needed urgently. Metastatic PCa was identified as having the highest clinical need for development of biomarkers to measure response and as surrogate endpoints. Panellists unanimously voted that reproducibility validation studies are of paramount importance. The consensus panel also predicted that cfDNA will impact practice by 2020. Conclusions: This expert consensus identified the need for clinical trials of validated circulating biomarkers to develop predictive, response and surrogacy assays. These could have major clinical and healthcare economic implications, minimizing over-treatment and allowing the delivery of more precise patient care.
Real world patterns of treatment sequencing in Canada for metastatic castrate-resistant prostate cancer.
Authors: Hotte Sebastien J. , Finelli Antonio , Malone Shawn , Shayegan Bobby , So Alan I. , Canil Christina M. , Hew Huong , Park-Wyllie Laura , Saad Fred , Chi Kim N. 
Published: February 2018

320 Background: The Canadian GU Research Consortium (GURC) was recently established to bring advanced prostate cancer centres together to collaborate on research, education, and adoption of best practices. As an initial step to inform the work of the GURC, an electronic questionnaire was designed to assess management of advanced prostate cancer care in Canada and how prostate cancer treatments are sequenced in a real-world setting. Methods: A 59-item online questionnaire was developed by a multidisciplinary scientific committee to measure physician practices, patterns of care, treatment sequencing, and management of mCRPC. After pre-testing, the online questionnaire was sent to 93 urologists, uro-oncologists, medical oncologists, radiation oncologists, and general practitioner oncologists who are actively involved in the treatment of prostate cancer. Results: A total of 49 (53%) respondents completed the questionnaire between April 17, 2017 to May 17, 2017. Based on physician reports, the most frequently used treatment for first-line mCRPC was AR-targeted therapy (94%, n = 46 physicians) such as abiraterone acetate plus prednisone and enzalutamide. Among those 46 physicians, AR-targeted therapy was usually followed by docetaxel second-line therapy (57%, 31 physicians). The most common line 1 to line 3 treatment sequence for mCRPC was: AR-targeted therapy--Docetaxel--AR-targeted therapy (35%, 17 physicians), followed by AR-targeted therapy--Docetaxel--Radium 223 (14%, n = 7), Provincial differences were observed in the line 1 to line 3 treatment sequences, which aligned to variation in provincial policies for access to the treatments. In patients previously treated with docetaxel in the hormone sensitive setting, the most frequently used treatment for first-line mCRPC was AR-targeted therapy (76%, 37 physicians). Conclusions: AR targeted therapy followed by docetaxel is the predominant pattern of practice for management of mCRPC, with variability beyond these lines of therapy. Prospective ongoing work through the GURC in research, education and best practices will aim to understand these practice patterns.
Sequencing radium 223 (RA223) for metastatic castration-resistant prostate cancer (mCRPC) patients (pts) in the daily practice: Preliminary results from a retrospective study in Italian centers.
Authors: Caffo Orazio , Frantellizzi Viviana , Galli Luca , Monari Fabio , Facchini Gaetano , Baldari Sergio , Tucci Marcello , Alongi Filippo , Bortolus Roberto , Agostini Stefania , Biasco Elisa , Fanti Stefano , Rossetti Sabrina , Pignata Salvatore , Zichi Clizia , Salgarello Matteo , Borsatti Eugenio , Cortesi Enrico , Sbrana Andrea , De Vincentis Giuseppe 
Published: February 2018

322 Background: The potential advantage of the sequential use of the active drugs (ADs) able to prolong overall survival (OS) in mCRPC (abiraterone, cabazitaxel, docetaxel, enzalutamide, RA223) could be limited by the development of common mechanisms of resistance. According to its unique targeted alpha-radiation mechanism of action, it could be postulated that RA223 does not induce and is not affected by cross-resistance with other agents and consequently its incorporation in therapeutic sequences may improve clinical outcomes. The present study is aimed to describe the clinical outcomes of pts who received RA223 and at least two other ADs for mCRPC. Methods: We collected data of pts who received sequentially 3 or more ADs of which one was RA223. For each pt we recorded the clinical outcome of all treatments received for mCRPC. We also compared the cumulative survival from the start of the first line to that of a contemporary series of 405 mCRPC pts without visceral mets sequentially treated with 3 or 4 ADs not comprising RA223. Results: A consecutive series of 119 mCRPC pts was collected: the median age was 72 yrs. Six pts received all 5 available ADs, 53 pts 4 ADs, and the remaining pts 3 ADs. Most of the pts received RA223 as the 3rd or 4th line of treatment (62 and 42, respectively), and the remaining were treated in less or more advanced lines (10 and 5 pts respectively). Overall the full 6-cycle treatment was completed in 61 pts (51.3%) and in 61.3% and 38.1% of pts when Ra223 was administered as 3rd and 4th treatment line respectively (p = 0.02). Partial response and stable disease as best objective response to RA223 was achieved in 11.3% and 24.5% of pts respectively, while a PSA reduction of ≥ 50% was observed in 7.2% of pts. Median OS from the start of the first line was 48 mos. In pts treated with 3 or 4 ADs that included Ra223, the median OS was significantly longer compared to that of pts whose treatment sequence did not include RA223 (48.4 vs 39.2 mos, p = 0.03). Conclusions: Despite the limitations of its retrospective nature, this preliminary data suggests that treatment sequencing of ADs that includes RA223 offers a survival advantage in mCRPC.
HSD3B1 genotype and abiraterone (Abi) metabolites in patients (pts) with prostate cancer (PCa).
Authors: Emamekhoo Hamid , Alyamani Mohammad , Park Sunho , Taylor Jennifer , Almassi Nima , Upadhyay Sunil , Tyler Allison Janine , Berk Mike , Hwang Tae Hyun , Grivas Petros , Rini Brian I. , Garcia Jorge A. , Auchus Richard J. , Sharifi Nima 
Published: February 2018

325 Background: Abi, a potent inhibitor of 17α-hydroxylase/17,20-lyase (CYP17A1), is an oral treatment option for metastatic PCa in castration-resistant and -sensitive settings. Abi is converted to ∆4, 3-keto-abi (D4A) by 3β-hydroxysteroid dehydrogenase (3βHSD). D4A is further metabolized to multiple downstream steroidal metabolites including 3-keto-5α-Abi (5αA), which is an androgen receptor (AR) agonist and might affect response and/or resistance to Abi. The common HSD3B1(1245C) germline variant encodes for a 3βHSD missense that increases enzyme activity that allows tumors to utilize extragonadal androgens and is a predictive biomarker of resistance to ADT and sensitivity to CYP17A1 inhibition. However, the more active 3βHSD protein might increase 5αA synthesis, possibly limiting the clinical benefit of Abi. Methods: Blood was collected from CRPC pts on Abi and drug metabolites (MA) were extracted from serum, and analyzed by mass spectrometry. To correct for pharmacokinetics (PK) of time from last dose to blood draw in this cohort, data were normalized to the 8-hour time point of a separate PK study of Abi MAs and grouped by HSD3B1 genotype. HSD3B1 genotype was determined using germline DNA. Results: Abi MAs were evaluated in the sera of 30 CRPC pts on Abi. Abi, D4A, 5αA, were detectable in the sera of all pts. There were 8, 19, and 3 pts with homozygous wild-type, heterozygous, and homozygous variant HSD3B1 genotypes. HSD3B1 variant allele inheritance was associated with a statistically significant increase in 5αA concentrations, with highest concentration of 5αA MAs observed in homozygous variant HSD3B1 pts (Table). Conclusions: Germline HSD3B1 variant genotype is associated with higher 5αA metabolites with possible implications for AR stimulation and adverse clinical outcomes on Abi. [Table: see text]
Enzalutamide: Do treatment modifications allow drug continuation without losing disease control?
Authors: Massalha Emma Samah , Zvirinska Lenka 
Published: February 2018

326 Background: Enzalutamide improves progression free and overall survival in men with metastatic prostate cancer (Beer T, et al. 2014; Cabot R, et al. 2012). Grade 3 adverse events occur in up to 48% (Beer T, et al. 2014; Cabot R, et al. 2012). and lead to treatment discontinuation in up to 8% (Beer T, et al. 2014; Cabot R, et al. 2012). The purpose of this retrospective analysis is to determine whether treatment modification (TM) with dose reduction (DR), treatment break (TB) or both, still allow control of prostate cancer in men who may have otherwise stopped treatment due to intolerable side effects. Methods: All patients in North Wales, UK, who commenced enzalutamide for metastatic prostate cancer in 2016 were eligible. Data was collected and recorded from electronic notes and prescriptions. Results: 66 men aged 61 to 92 (median 77) commenced treatment with enzalutamide in 2016. 17% performance status (PS) 0, 51% PS 2, 3% PS 3. Treatment has been discontinued in 80%. Adverse events (AEs) led to discontinuation in 25% cases including 2 deaths. The most common AE was fatigue in 37%. 11 patients (17%) had TM due to AEs. Mean treatment duration was 9.6 months (range 1 to 19.2 months), without TM 8.9 months, with TM, 12.8 months. Men with PS 2 were more likely to require TM or discontinuation (D) due to AEs (29% each) compared to PS 1 (24% TM, 21% D) or PS 0 (1% TM, 27% D). TBs lasted between 2 weeks and 7 months. PSA rose during that time but quality of life improved and PSA responded once treatment was recommenced. After a TB, enzalutamide was continued for 2 to 11 months (median 5.9 months). DR did not adversely affected PSA in 6 of 7 cases and improved quality of life in 2 cases. Patients continued enzalutamide 2-12 months (median 5.9 months) after dose reduction, including 4 still on treatment. Conclusions: This shows that both treatment breaks and dose reductions can improve quality of life whilst not adversely affecting outcome. However, the numbers are small and this needs to be confirmed in a prospective study. Those with lower PS are more likely to require modification.
Atezolizumab (atezo) vs. chemotherapy (chemo) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC): Immune biomarkers, tumor mutational burden (TMB), and clinical outcomes from the phase III IMvigor211 study.
Authors: Powles Thomas , Loriot Yohann , Ravaud Alain , Vogelzang Nicholas J. , Duran Ignacio , Retz Margitta , De Giorgi Ugo , Oudard Stephane , Bamias Aristotelis , Koeppen Hartmut , Leng Ning , Kadel Edward E. , Hegde Priti S. , Cui Na , Shen Xiaodong , Derleth Christina Louise , Green Marjorie C. , Banchereau Romain , Mariathasan Sanjeev , Van Der Heijden Michiel Simon 
Published: February 2018

409 Background: IMvigor211 is a global study of atezo vs chemo in platinum-treated mUC. The study did not meet its primary endpoint of overall survival (OS) in programmed death-ligand 1 (PD-L1)–selected patients (pts),1 but exploratory analyses showed improved OS for atezo in the intent-to-treat (ITT) population. Here we compare clinical outcomes in ITT and prespecified PD-L1 subgroups with those in subgroups defined by immune transcriptional gene expression (tGE) signatures and TMB. Methods: Pts with ≤ 2 prior lines of therapy for mUC who progressed during or following platinum treatment were randomized 1:1 to atezo or chemo (vinflunine, paclitaxel or docetaxel, per physician). The primary endpoint was OS, hierarchically compared between treatment arms in PD-L1–selected and ITT pts. Planned exploratory biomarker analyses included tGE (RNA-seq) and TMB (FoundationOne). Results: The ITT population included 931 pts (atezo arm, 467; chemo arm, 464), and biomarker-evaluable subgroups were representative of the ITT population. PD-L1 expression positively correlated with tGE (R = 0.61) but not TMB (R = 0.13). OS and hazard ratios (HRs) are listed in the Table. Conclusions: In this randomized Phase III study, we show that high PD-L1 and high tGE are associated with improved outcomes with both chemo and atezo. In contrast, higher TMB predicted OS in favor of atezo; however, clinical benefit with atezo was also seen in the ITT population. Clinical trial information: NCT02302807. [Table: see text]