bluuebunny/crossref_metadata_2025_split huggingface dataset:
Denosumab or zoledronic acid (ZA) therapy on pain interference and cancer-specific quality of life (CSQoL) in patients with castrate-resistant prostate cancer (CRPC) and bone metastases (BM).
Authors: Patrick Donald , Cleeland Charles S. , Fallowfield Lesley , Smith Matthew Raymond , Klotz Laurence , Oudard Stephane , Marx Gavin M. , Wei Rachel , Ohrling Katarina , Qian Yi 
Published: February 2017

12 Background: Patients with castration-resistant prostate cancer (CRPC) and bone metastases (BM) may experience debilitating pain that impacts daily functioning and diminishes the quality of life. Previous results from a phase III trial demonstrated superiority of denosumab to ZA in delaying or preventing skeletal-related events (pathological fracture, radiation or surgery to the bone, spinal cord compression) in CRPC patients with BM. In this ad-hoc analysis, we present the results of denosumab or ZA therapy on pain interference (PI) and cancer specific quality of life (CSQoL), focusing on the subgroup of CRPC patients with no/mild pain at baseline. Methods: Men with CRPC and BM (no prior IV bisphosphonate use) were randomized to receive either SC denosumab 120 mg+IV placebo or SC placebo+IV ZA 4mg (adjusted for creatinine clearance) every four weeks. Patients were instructed to take calcium and vitamin D supplements. The Brief Pain Inventory–Short Form (BPI-SF) was used to assess PI. The pre-specified clinically meaningful time of a greater than or equal to two point increase from baseline in PI score (overall, physical, and emotional subdomains) was determined for CRPC patients receiving denosumab or ZA therapy. Patients also completed the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at baseline and each monthly visit to determine CSQoL scores. Declining FACT-G scores points to worsening CSQoL, where a greater than or equal to five point decrease is clinically meaningful. Results: Of the 1,901 patients enrolled (n=950, denosumab; n=951, ZA), 1,045 (55%) had no/mild pain at baseline. Compared with ZA, denosumab therapy delayed the time to a greater than or equal to two point increase from baseline in PI for the overall score (HR=0.83 [0.71, 0.98]; P=0.023), physical (HR=0.87 [0.75, 1.02]; P=0.077) and emotional (HR=0.83 [0.71, 0.97]; P=0.020) subdomains. Over a period of 18 months, more ZA-treated patients than denosumab-treated patients experienced a greater than or equal to five point decrease in FACT-G total scores (average relative difference=6.8%, range -9.4 to 14.6%) or worsening of CSQoL. Conclusions: Denosumab therapy significantly delayed the time to worsening of pain interference and maintained a higher overall CSQoL (FACT-G) compared to ZA in CRPC patients with BM. Clinical trial information: NCT00321620.
Evaluation of the Oncotype DX genomic prostate score for risk stratification in prostate cancer patients considered candidiates for active surveilance.
Authors: Kartha Ganesh K , Nyame Yaw , Klein Eric A. 
Published: February 2017

122 Background: With evidence showing over treatment, more patients are choosing active surveillance (AS) for intermediate or lower risk prostate cancer (CaP). Genomic profiling is offered to risk stratify patients to aid in management decision−making. This study reports risk discrepancies between National Comprehensive Cancer Network (NCCN) criteria and OncotypeDx Genomic Prostate Score (GPS) and how this influences decision−making in our CaP population. Methods: An inception cohort study was carried out on 56 patients with NCCN very low to intermediate risk CaP who were candidates for AS and underwent GPS testing on prostate biopsy specimens performed within 6mo of entry. GPS provided a score corresponding to a GPS-based risk stratification. Study endpoints: 1) distribution of GPS risk groups within each NCCN risk category; 2) frequency of change to lower or higher risk based on GPS; 3) effect of GPS on physician recommendations and patient choice on disease management. Results: 52/56 patients had sufficient carcinoma on biopsy for a GPS analysis. GPS reassigned risk in 23% (12/52) of patients, with 10 going from NCCN low risk to GPS very low risk and 2 assigned to a higher GPS risk profile (Table). AS was recommended in 19 patients with GPS very low risk group and 8 patients in the GPS-defined low risk group. Physicians recommended treatment to 7 patients with GPS intermediate risk. Patient choice was congruent with physician recommendation in all cases. No patients chose AS when assigned to a higher risk category. All 10 patients reassigned to a lower risk category chose AS. Conclusions: In this CaP cohort, assessment by GPS changed risk stratification in 23% of patients. Moving to a different risk category changed physician recommendation and patient choice in the corresponding direction (to surveillance or therapy) in all cases. More study and larger sample size are needed to fully assess the effect of GPS on clinical decision making. [Table: see text]
The sequential use of abiraterone and enzalutamide in metastatic castrate resistant prostate cancer patients: Experience from seven U.K. centers.
Authors: Stevenson Robert , Fackrell David Gareth , Ford Daniel , Glaholm John , El-Modir Ahmed , Porfiri Emilio , Zarkar Anjali M , Tanguay Jacob , Rackley Thomas , James Nicholas David 
Published: February 2017

125 Background: Phase III studies have demonstrated survival benefits from abiraterone (Abi), and enzalutamide (Enz) following disease progression in metastatic castrate resistant prostate cancer (mCRPC). Abi is now available for treatment of mCRPC in the UK in patients previously treated with docetaxel. Enz has recently become available, via the UK cancer drugs fund (CDF), for progressive disease post docetaxel, prior to exposure to Abi. There has been no randomised trial on sequential usage of Enz post-Abi. We therefore, report the experience of hospitals in Coventry, Cardiff, and five centers in Birmingham. Methods: We searched the pharmacy database for patients who have received Enz as part of an early access scheme, and identified 79 patients who started treatment between the August 2012 and April 2013. A detailed notes review was carried out of these patients. Results: Median age was 74 (range of 55 to 87). All patients had received hormone androgen deprivation therapy and taxane chemotherapy (docetaxel and/or cabazitaxel) 75 patients had received previous Abi, 62 of these patients receiving Abi as the last treatment prior to Enz. The mean time to progression (TTP) for Abi in these 62 patients was 37.44 weeks (range 4 to 104). At the time of submission 55 patients had stopped Enz due to prostate-specific antigen progression with a mean TTP of 15.87 weeks and 28 patients had died. Conclusions: The AFFIRM study demonstrated TTP of 36 weeks in patients post-docetaxel. In this audit of patients receiving Enz post-Abi the TTP was only 15.87 weeks, suggesting possible reduced efficacy in patients receiving Enz post-Abi and docetaxel. Trials are underway comparing Abi alone or in combination with Enz which may improve efficacy.
Molecular characterization of circulating tumor cells (CTCs) of patients with neuroendocrine prostate cancer (NEPC).
Authors: Beltran Himisha , Louw Jessica , Kossai Myriam , Krupa Rachel , Marrinucci Dena , Mosquera Juan Miguel , Nanus David M. , Tagawa Scott T. , Dittamore Ryan , Rubin Mark A. 
Published: February 2017

177 Background: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that commonly arises in later stages of castration resistant prostate cancer (CRPC), especially with visceral metastases in the setting of a low prostate-specific antigen (PSA). The genes AURKA and MYCNare frequently amplified. There are no reliable serum markers to identify patients that are transforming to NEPC and incidence of circulating tumor cells (CTCs) in these patients is unknown. Detection of NEPC has clinical implications as these patients are often treated with platinum chemotherapy rather than with androgen receptor (AR) targeted therapies. Methods: Ten men with metastatic NEPC underwent metastatic tumor biopsy and blood collection for CTC analysis utilizing the Epic Sciences platform. Clinical characteristics, pathologic and molecular features including exome sequencing of metastatic tumors, serum PSA and neuroendocrine (NE) markers, CTC count by CellSearch were obtained on all patients. AURKA and MYCNamplification were assessed by FISH in both tumors and Epic CTCs. Results: Sites of metastases included liver (6 out of 10), bone (9 out of 10), lymph nodes (8 out of 10), pleura (1 out of 10), and lungs (2 out of 10). Serum PSA, CellSearch CTCs, and serum NE markers were variable including 4 out of 10 patients with PSA less than 1 ng/ml (range 0.02-9.39) and 3 out of 5 evaluated patients with CTC count of zero (range 0 to 94). Four out of 7 evaluated tumors displayed amplification of AURKA and MYCN. Epic CTCs demonstrated frequent clusters, dim/low cytokeratin suggesting epithelial plasticity, and low AR expression. Patients were subsequently treated with platinum (4 out of 10), AURKAinhibitor (4 out of 10), or hormonal therapy (2 out of 10). Conclusions: PSA, serum NE markers, and CTC count by CellSearch may not be reliable in identifying patients with CRPC that have NE features. Epithelial plasticity potentially arising from epithelial-mesenchymal transition may explain lack of detection using conventional CTC assays. The Epic Sciences CTC platform is capable of detecting CTCs from patients with NEPC and CTCs are molecularly similar to metastatic biopsies. Epic CTCs may be useful in the earlier detection of NEPC and inform patient selection for therapy.
Enzalutamide after failure of docetaxel and abiraterone in metastatic castrate resistant prostate cancer (mCRPC): Results from an expanded access program.
Authors: Thomson David , Charnley Natalie , Parikh Omi 
Published: February 2017

188 Background: Abiraterone or enzalutamide are licensed for use post-docetaxel in metastatic castrate resistant prostate cancer (mCRPC). Both target the androgen receptor signalling pathway. There is little information describing their sequential use. Methods: Patients with mCRPC who had failed treatment with docetaxel and abiraterone received enzalutamide as part of an expanded access program. Patients were reviewed four weekly and post-treatment PSA used to determine efficacy. Results: Twenty three patients, median age 76 (range, 65 to 82), performance status of 1 (15/23) or 2 (8/23) with mCRPC (22/23 bone and 4/23 visceral disease) were enrolled. All had received prior docetaxel and abiraterone as well as cabazitaxel (35%), dexamethasone (30%), and stillboestrol (52%). Median biochemical progression free survival (bPFS) was 11.9 weeks. Nine (39%) patients showed sensitivity to enzalutamide, defined as a greater than 50% reduction in PSA. There was a correlation between PSA response to abiraterone and enzalutamide (R=0.45, p=0.03). In 10 out of 23 and 13 out of 23 patients who were sensitive and insensitive to abiraterone, 60% and 23% had a great than 50% reduction in PSA, respectively. There was a trend to improved bPFS in those sensitive to abiraterone (15.7 vs. 11.4 weeks, p=0.40) and in those who showed any PSA response to abiraterone (15.9 vs. 5.3 weeks, p=0.06). Conclusions: Enzalutamide has activity following failure of docetaxel and abiraterone in mCRPC. The effectiveness is more pronounced in those who have responded to abiraterone.
Biochemical response to enzalutamide therapy in patients with mCRPC following docetaxel and abiraterone treatment.
Authors: Roeder M. Andreas , Thomsen Frederik Birkebæk , Brasso Klaus , Rathenborg Per , Borre Michael , Iversen Peter 
Published: February 2017

202 Background: Enzalutamide improve overall survival (OS) in patients with metastatic castrate resistant prostate cancer (mCRPC) patients following docetaxel treatment. Optimal sequencing and possible cross-resistance for novel mCRPC therapeutics is less understood. In this study we report biochemical response and OS after enzalutamide treatment in post-chemo mCRPC patients following progression on post-chemo abiraterone treatment. Methods: Twenty-four post-chemotherapy and post-abiraterone mCRPC patients with progressive disease received enzalutamide 160 mg/daily in a Danish compassionate-use program sponsored by Astellas Pharma A/S. Best PSA and alkaline phosphatase response was recorded. Fischer’s exact test, Mann-Whitney U test and linear regression model was used to test for differences in PSA response. OS was calculated from initiation of enzalutamide treatment. Results: Minimum follow-up was three months. The best median PSA response was -22% (-76% to 76%). Forty-six percent of patients had a greater than 30% decrease in PSA. The PSA response to enzalutamide did not correlate to the number of prior cancer treatments (p = 0.57), time from diagnosis to CRPC (p = 0.11), or prior response to docetaxel (p = 0.67). However, eight patients treated with second line cabazitaxel had an inferior PSA response to enzalutamide (p = 0.03), and there was a trend for the PSA response to abiraterone to correlate with the PSA response to the succeeding enzalutamide (B = 0.22, p = 0.05). The best median alkaline phosphatase response was 0.1% (-67% to 126%). Median OS was 4.8 months. Conclusions: Patients with post-chemotherapy, post-abiraterone mCRPC treated with enzalutamide showed less marked biochemical response to therapy compared to the results from the AFFIRM study where post-chemo abiraterone was not used. Whether this is an effect of cross-resistance or a result of the natural history of the disease needs further elaboration.
Phase I trial of the investigational aurora A kinase (AAK) inhibitor MLN8237 (alisertib) in combination with docetaxel (DTX) in patients (pts) with advanced solid tumors, including castration-resistant prostate cancer (CRPC).
Authors: Sarantopoulos John , Hahn Noah M. , Higano Celestia S. , Leonard E. Jane , Zhang Bin , Zhou Xiaofei , Dansky Ullmann Claudio , Graff Julie Nicole 
Published: February 2017

217 Background: Overexpression of AAK, a key regulator of mitosis, is seen in various solid tumors, including prostate cancer. This open-label, Phase 1 trial investigated the safety/tolerability of MLN8237, an oral selective AAK inhibitor, combined with DTX in pts with advanced solid tumors, including CRPC. Methods: Previously treated pts aged ≥18 y who were candidates for DTX received 21-day cycles of MLN8237 10–50 mg BID on days 1–7, escalated in 3+3 dosing cohorts, plus DTX 60 or 75 mg/m2 on day 1. To manage toxicity, a 5-day MLN8237 regimen was later evaluated with DTX 60 or 75 mg/m2+ G-CSF support. Primary endpoints were safety/tolerability and recommended phase II dose/schedule (RP2D). Pharmacokinetics (PK) and antitumor activity (RECIST 1.1/PSA) were also assessed. Results: 35 pts (median age 63 y [25–87]; 71% male; 17 CRPC) recruited into 8 cohorts received a median of 3 (1–33) cycles; 15 pts (11 CRPC) had ≥6 cycles. 14 DLTs were seen in 11 pts (5 CRPC) in Cycle 1: G4 neutropenia >7 days (n=3), G3/4 febrile neutropenia (FN; n=7), G3 stomatitis (n=3), and G3 urinary tract infection (n=1). The RP2D was MLN8237 20 mg BID on Days 1–7 + DTX 75 mg/m2 in 21-day cycles without G-CSF. Common G≥3 drug-related AEs included neutropenia (86%), leukopenia (31%), FN (23%) and stomatitis (14%). 20 (57%) pts reported SAEs, most commonly FN (n=8). 2 pts withdrew due to AEs, inc. 1 death (G3 FN; G3 mucositis); 4 pts continue on study. On-study deaths (n=2; disease progression) were not considered drug-related. Steady-state MLN8237 exposure (AUCss) increased approximately dose-proportionally over 10–30 mg BID when combined with DTX (n=16). Analysis of the effect of MLN8237 on DTX PK at RP2D is ongoing. Among 11 evaluable CRPC pts, 6 had PR (4 had PSA50) and 6 had SD (4 with PSA50). 2 other pts (bladder cancer and angiosarcoma) also had PR. Conclusions: The RP2D was MLN8237 20 mg BID on days 1–7 + DTX 75 mg/m2 on day 1. Despite myelosuppression, the combination of MLN8237 and DTX had a generally manageable toxicity profile in pts with advanced solid tumors. Further clinical study of this combination, particularly in CRPC pts, is warranted. Clinical trial information: NCT01094288.
Quality improvement opportunities in prostatectomy care in a regional hospital-based urologic quality collaborative.
Authors: Gore John L. , Porter Michael P , Corman John M. , Sutherland Douglas Edward , Schmidt Zeila , Flum David R ,   SCOAP-CERTAIN Collaborative
Published: February 2017

234 Background: Prostate cancer care is susceptible to regional variation in treatment and outcomes. Recent national recommendations have highlighted the harms of prostate cancer treatment including urinary incontinence and impotence. We prospectively evaluated radical prostatectomy (RP) outcomes at participating Washington-state hospitals to identify quality improvement opportunities in RP care. Methods: A local clinician advisory group developed a chart abstraction tool that captures potential quality concerns in RP care. The abstraction tool was implemented at nine regional hospitals with data consolidated for review quarterly. The research team and clinician advisory group were blinded to hospital identities in feedback reports. Data were analyzed as aggregate rates and hospital-specific rates without risk adjustment using descriptive statistics. Results: We identified 461 patients undergoing RP at nine area hospitals from 2011 to 2013. The majority (74%) were robot-assisted minimally invasive RPs, Participating hospitals report as many as 97% or as few as 12% robot-assisted procedures. 26.3% of cases were pathologic non-organ-confined prostate cancer (pT3 or higher); pathologic stage was not further classified beyond "T2" or "T3" in 31% of RPs. Surgical margins were positive in 18% of cases overall; hospital-specific positive margin rates ranged from 12 to 25% among organ-confined cases and 0 to 75% among stage pT3 or higher prostate cancer. Length of stay exceeded three days post-prostatectomy in more than 10% of cases at 4 hospitals including one hospital where 36% of cases had prolonged lengths of stay. Conclusions: We identified several quality improvement opportunities that may improve health outcomes among men undergoing RP for prostate cancer. Positive margin rates were excessive at some hospitals and may represent uncertainty in the surgical approach to higher risk cases. Variation in lengths of stay may represent provider variability in post-prostatectomy clinical care algorithms. Survey of provider practices may inform development of quality improvement initiatives such as clinical pathways that may address the variations in RP care identified.
Enzalutamide in men with prostate cancer resistant to docetaxel and abiraterone.
Authors: Scholz Mark Creamer , Lam Richard Y. , Turner Jeffrey S. , Chau Khang N. , Becker Lauren K. , Felarca Clifford U. 
Published: February 2017

247 Background: Since FDA approval in 2011, abiraterone (Zytiga) has supplanted docetaxel as preferred first-line treatment for metastatic castrate-resistant prostate cancer. In August 2012 enzalutamide (Xtandi) was FDA-approved for the treatment of castrate-resistant prostate cancer after docetaxel (Taxotere). We performed a retrospective chart review at a large medical oncology clinic specializing in prostate cancer to determine the PSA response rates of enzalutamide administered to men who had previously progressed on both abiraterone and docetaxel. This report includes some patients who participated in the Astellas/Medivation-sponsored Early Access Program; however, it represents the author’s independent clinical experience. Methods: Enzalutamide was administered at a dose of 160 mg daily. Patients were subsequently followed with monthly physical examination, PSA and routine blood tests. No hepatotoxicity or seizures occurred. Men were considered evaluable for PSA response if they received enzalutamide for twelve weeks. A PSA decline of 30% from baseline after 12 weeks was defined as a response. A PSA increase of 30% from baseline within 12 weeks was defined as disease progression. Men with neither a 30% increase nor a 30% decline were classified as having stable disease. Results: 66 men were treated and 63 were evaluable for PSA response. Median age was 67. Median baseline PSA was 68.5. All participants had disease that had progressed on abiraterone. 55 men received previous docetaxel. 38 had received previous Provenge. Two men stopped before 12 weeks because of intolerable fatigue. One man died of progressive disease before 12 weeks. After a median follow up of 12.5 weeks, 18(29%) men met criteria for PSA response. 13(21%) men had stable disease and 32(51%) men had PSA progression. Conclusions: Enzalutamide has activity in a heavily pretreated population of men resistant to abiraterone and docetaxel.
Premature termination of genitourinary cancer clinical trials.
Authors: Stensland Kristian D. , McBride Russell , Wisnivesky Juan P. , Latif Asma , Hendricks Ryan , Roper Nitin , Boffetta Paolo , Hall Simon J , Oh William K. , Galsky Matt D. 
Published: February 2017

288 Background: The GU oncology literature is inundated with clinical trials that terminated prematurely, particularly in bladder cancer. Such trials require substantial resource expenditure and entail the time, trust, and commitment of patients, yet contribute minimally to the scientific knowledgebase and divert resources from answering critical questions. We sought to determine the scope of this problem within the clinical trials enterprise. Methods: ClinicalTrials.gov was queried to identify all phase II-III interventional adult cancer clinical trials registered between 9/11/05 and 11/11/11. Prematurely terminated trials were “stopped early” as defined by the registry. Kaplan-Meier methods and Cox regression were used to determine risk of premature trial termination. Results: We identified 7,776 trials, including 491 prostate (PCa), 142 kidney, 75 bladder, and 34 testis cancer trials. The risk of premature termination due to any cause for all cancers was 25% (95% CI 19-31%) and the risk due to poor accrual was 10% (95% CI 9-12%). Poor accrual was the most common reason for premature termination (Table). Risk was not significantly different for kidney, bladder or testis cancers compared to other cancer types with the exception of PCa (HR 1.35 [1.03-1.78]). Industry-funded trials were more likely to terminate prematurely (HR 2.26 [1.83-2.80]). Trials with sites outside of the USA (HR 0.63 [0.54-0.74]) or both within and outside of the USA (HR 0.68 [0.54-0.74]) were less likely to terminate prematurely as were trials with multiple sites (HR 0.56 [0.48-0.64]). Conclusions: In this large cohort of clinical trials, ~1 in 4 trials terminated prematurely (1 in 10 due to poor accrual). GU cancer trials were at similar risk of termination compared to other cancer clinical trials with the exception of PCa. Novel approaches are needed to improve the efficiency of the clinical cancer research enterprise. [Table: see text]