bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of hypofractionated high-dose intensity-modulated radiotherapy schedules for prostate cancer: Results from the phase III randomized CHHiP trial (CRUK/06/016).
Authors: Dearnaley David P. , Syndikus Isabel , Mossop Helen , Birtle Alison J. , Bloomfield DJ , Cruickshank Clare , Graham John , Hassan Shama , Khoo Vincent , Logue John P. , Mayles Helen , Money-Kyrle Julian , Naismith Olivia Frances , Panades Miguel , Patterson Helen , Scrase Christopher D , Staffurth John , Tremlett Jean , Griffin Clare , Hall Emma 
Published: February 2017

2 Background: We aimed to explore the dose response relationship for two 3 Gray (Gy) hypofractionated radiotherapy (hRT) schedules for localised prostate cancer (PCa). Methods: hRT schedules of 60Gy/20 fractions (f) and 57Gy/19f were compared with conventional RT (cRT) 74Gy/37f; iso-effective for alpha-beta ratios of 2.5Gy and 1.5Gy respectively. The trial was powered to demonstrate non-inferiority between each hRT schedule and cRT, with 3,213 patients (pt) needed to rule out 5% inferiority (80% power, 1-sided alpha 5%) assuming 70% event-free rate in cRT, corresponding to a critical hazard ratio (HR) of 1.21. The trial was not formally powered to directly compare the two hRT schedules. Pt with N0 T1b-T3a localised PCa were randomized (1:1:1 ratio). The primary endpoint was PCa progression (freedom from biochemical failure by Phoenix consensus guidelines or PCa recurrence). Acute toxicity was assessed up to 18 weeks post treatment and late side effects to 5 years (yr) by RTOG, LENT-SOM and patient reported outcomes (PROs). Results: 3,216 pts were randomized between 2002 and 2011; 1,065 (74Gy), 1,074 (60Gy), 1,077 (57Gy). Baseline characteristics were well balanced across groups: median age 69 yr; NCCN risk group 15% low, 73% intermediate, 12% high. With median follow up 5.2yr, 5yr progression-free rate (95% CI) was 74Gy: 88.3% (86.0%, 90.2%); 60Gy: 90.6% (88.5%, 92.3%), 57Gy: 85.9 (83.4, 88.0); HR60/74: 0.83, 90% CI (0.68, 1.03), HR57/74: 1.20, 90% CI (0.99, 1.45). Significantly more events were observed with 57Gy compared to 60Gy; HR57/60: 1.44, 90% CI (1.18, 1.75), log-rank p=0.003. No significant difference in acute RTOG bladder or bowel toxicity was observed between hRT schedules. Late toxicity profile was favorable; with grade 2+ RTOG bladder (60Gy: 16/960 (1.7%); 57Gy: 11/962 (1.1%), p=0.34) and bowel (60Gy: 28/960 (2.9%); 57Gy: 17/962 (1.8%), p=0.10) toxicity at 2yr. Analysis of LENT-SOM and PROs supported these results. Conclusions: With 5 yr follow-up treatment with a 3Gy schedule of 60Gy/20f shows improved treatment efficacy compared to 57Gy/19f and is non-inferior to 74Gy/37f with a similar low level of acute and late normal tissue damage. Clinical trial information: ISRCTN97182923.
Novel agents’ sequencing following first-line docetaxel in mCRPC patients: CAPRO study.
Authors: Puente Javier , Gonzalez del Alba Aranzazu , Sala Nuria , Méndez-Vidal María José , Pinto Alvaro , Rodriguez Sanchez Angel , Cuevas Sanz Jose Miguel , Guma Josep , Borrega Pablo , Molins Carmen , García Domínguez Rocío , Basterrechea Laura , López Jiménez Antonio , Gonzalez-Billalabeitia Enrique , Crespo Guillermo , Domenech Montserrat , Cabrera Suárez Miguel Ángel , Luque Raquel , Ruiz Pedro , Vazquez-Estevez Sergio 
Published: February 2017

229 Background: Novel agents, such as abiraterone (A), cabazitaxel (CZ), and enzalutamide are currently available for the treatment of docetaxel (D)-treated metastatic castration resistant prostate cancer (mCRPC). The sequencing approach following D progression is still unknown. We now explore which factors are driving sequencing decisions in routine clinical practice in Spain. Methods: A prospective multicenter national observational descriptive study collecting data of 2nd line (L) treatments in mCRPC patients to analyze responses and progression to 1stL D. Results: 149 patients have been recruited from July 2013 to January 2015. Median age was 72 (48-89). Median D cycles was 6 (1-24), and median dose: 75 mg/m2 (30-75). 24 patients (16%) required dose reduction. The reasons for D ending were treatment completion (40%, n = 60), toxicity (15.3%, n = 23), progression (radiological, biochemical, clinical; 42%, n = 63), or others (2.7%, n = 4). 67% (n = 100) of the patients received A, 25% (n = 44) CZ, and 8% (n = 5) other treatments as 2ndL. From those who completed or progressed to D (n = 123), 2ndL initiation was mainly determined by two progression criteria (2C; biological and radiological), followed by one progression criteria (1C). This was independent of the 2ndL treatment chosen, and it was observed in similar ratios in both A (2C: 50%, n = 39; 1C: 37.2%, n = 29) and CZ (2C: 62.5%, n = 25; 1C: 27.5%, n = 11). Nevertheless, A was predominantly given when patients progressed after D ending, whereas CZ was mostly given when progressing during D (Table 1). Conclusions: A is the 2ndL treatment of choice in routine clinical practice in Spain, independent of the type and time of progression. CZ is preferentially used in patients progressing during D treatment. [Table: see text]
Pre-clinical rationale for combination PI3K and BRD4 inhibition in advanced prostate cancer.
Authors: Toren Paul , Zoubeidi Amina , Allman Jared 
Published: February 2017

234 Background: The PI3K/Akt pathway is frequently activated in aggressive and resistant prostate cancer. Here we detail our pre-clinical evaluation of AZD8186, a novel β and δ selective PI3K small molecule inhibitor. Further, we investigate how increased transcription of the myc oncogene may represent a mechanism of resistance to monotherapy PI3K/Akt inhibition. Therefore, we further evaluated co-targeting strategies against both the PI3K/Akt pathway and the epigenetic reader protein BRD4. Methods: Human prostate cancer cell lines LNCaP and 22RV1 were tested for sensitivity to AZD8186 in vitro. Caspase-3 activity and flow cytometry were used to assess apoptosis. Western blotting and RT-qPCR were used to measure AR and myc pathway genes and protein expression. Castrate resistant LNCaP xenografts were treated with 10mg/kg and 25mg/kg doses of AZD8186 given orally 4 days on, 3 off. Results: In vitro results demonstrated sensitivity to AZD8186 with decreases in cell proliferation and increases in apoptosis. In vivo results demonstrated a dose-dependent decrease in tumor growth velocity with AZD8186 with on-target decreases in pAkt was observed in xenograft tumour samples. Further, increases in myc protein and mRNA levels were seen in xenograft samples treated with AZD8186 compared to control. Downstream increases in EGFR and IGF-IR mRNA transcripts induced by AZD8186 were also seen in vitro and in vivo. Increases in myc, EGFR and IGF-IR was also seen in cells and tumours treated with an Akt inhibitor. Addition of the BDR4 inhibitor JQ1 decreased the increase of myc induced by AZD8186 and also partially abrogated the increases in EGFR, IGFR. Greater suppression of PSA expression was seen with the combination of AZD8186 and JQ1 compared to AZD8186 and enzalutamide. Similar results were seen in the 22RV1 cell line. Conclusions: Inhibition of PI3K with AZD8186 inhibits growth of PTEN-negative LNCaP cells. However, feedback activation of myc and AR pathways occurs. We demonstrate BRD4 inhibition using JQ1 which co-targets both myc and AR feedback pathways as a rationale combination strategy with PI3K inhibition. This strategy warrants further investigation in prostate cancers with an activated PI3K/Akt pathway.
Bipolar androgen therapy (BAT) in men with hormone sensitive (HS) prostate cancer (PC).
Authors: Schweizer Michael Thomas , Wang Hao , Luber Brandon , Nadal Rosa Maria , Spitz Avery N. , Rosen David Marc , Cao Haiyi , Antonarakis Emmanuel S. , Eisenberger Mario A. , Carducci Michael Anthony , Paller Channing Judith , Denmeade Samuel R. 
Published: February 2017

236 Background: We documented a paradoxical anti-tumor effect when castration-resistant prostate cancer patients were treated with intermittent, high-dose testosterone (i.e. BAT) [PMID: 25568070]. Since the adaptive increase in androgen receptor expression that follows chronic androgen deprivation therapy (ADT) may underlie this effect, we tested whether men with HS PC would also respond to BAT if given following a 6-month ADT lead-in. Methods: Men with asymptomatic HS PC and low metastatic burden (N = 20) (no visceral disease, ≤ 10 bone metastases, no lymph nodes > 5 cm short axis diameter) or non-metastatic biochemically recurrent disease (N = 13) were enrolled. Following 6-months of ADT, those with a PSA < 4 ng/ml went on to receive 2 cycles of BAT. A cycle of BAT was defined as intramuscular testosterone (T) cypionate or enanthate 400 mg on Days (D) 1, 29 and 57 followed by ADT alone D 85-169. ADT was continued throughout the study to allow for rapid cycling from near castrate to supraphysiologic range T following T injections. The primary endpoint was the percent of patients with a PSA < 4 ng/ml after 2 cycles of BAT, with the study designed to reject a null rate of 40% at a one-sided alpha = 0.1. Secondary endpoints included quality of life (QOL) as measured by the SF-36, FACT-P, IIEF and IPSS surveys. Results: Twenty-nine of 33 patients received BAT following the ADT lead-in (1 withdrew consent, 3 had PSA > 4 ng/ml). The primary endpoint was met, with 17/29 men (59%, lower bound 90% confidence interval = 45%) having a PSA < 4 ng/ml after 2 cycles of BAT. Ten patients receiving BAT had RECIST evaluable disease, and 8 (80%) objective responses were observed (4 complete; 4 partial). Three patients progressed per RECIST criteria and 3 had unconfirmed progression on bone scan. Men treated with 6-months of ADT had improved QOL after the first cycle of BAT. The median improvement in SF-36, FACT-P, and IIEF total scores were 3.2 (range, -20 to 48; P = 0.21), 3.5 (range, -30 to 50; P = 0.04), and 10 (range, -4 to 59; P < 0.001) points, respectively. There was no change in total IPSS score (median change 0 [range, -9 to 8; P = 0.87]). Conclusions: BAT demonstrated preliminary efficacy in men with HS PC following 6-months of ADT. BAT may improve QOL in men that have received ADT. Clinical trial information: NCT01750398.
Association of androgen receptor V9 (ARV9) mRNA expression in metastatic tissue with early resistance to pre-chemotherapy abiraterone acetate/prednisone (AA/P).
Authors: Kohli Manish , Hillman David W. , Carlson Rachel , Wang Liguo , Li Ying , Tan Winston , Ho Thai Huu , Sicotte Hugues , Wang Liewei , Costello Brian Addis , Pitot Henry C. , Quevedo Fernando , Dronca Roxana Stefania , Moynihan Timothy Jerome , Atwell Thomas D , Eiken Patrick W , McMenomy Brendan P , Bryce Alan Haruo , Wu Kevin , Dehm Scott 
Published: February 2017

237 Background: AA/P is an approved treatment for mCRPC but there are no known predictive markers of response or resistance. We conducted a prospective trial to evaluate if Androgen Receptor (AR) & AR-variant (ARV) expression in tissue metastases can predict resistance to AA/P. Methods: mCRPC stage patients (pts) initiating pre-chemo AA/P underwent metastatic site biopsies prior to (pre-AA/P) and after 12 weeks of treatment. Composite progression at 12 weeks, (primary endpoint) was evaluated with PSA, RECIST, bone scan and symptoms (per PCWG2). mRNA expressions of pre-AA/P ARFL, ARV3, ARV7, ARV9, ARV23, ARV45, four cell cycle division genes, Chromogranin-A (CHGA) together with PSA/testosterone levels, Gleason Score (GS) at initial diagnosis; high versus low volume disease; time from starting hormone therapy to mCRPC stage and serum CHGA levels were evaluated using a logistic regression model for predicting resistance at 12 weeks of therapy. A final multivariate model fitted only those factors thought to be clinically relevant or with an entry threshold of p ≤ 0.3 in univariate analysis. Results: Between 6/2013 & 3/2015, 82 pts were enrolled of which 52 had complete mRNA expression & disease assessment data at the12-week time point for analysis. Median age of the cohort was 72.5 yrs (IQR: 68.5-78); median pre-AA/P PSA was 18 ng/ml (IQR: 8.1- 46.6); GS distribution at initial diagnosis for GS 2-6; 7; 8-10 was 11; 14; 27 respectively. Progression was observed in 21/52 pts after 12 weeks. At the univariate level elevated pre-AA/P expression of ARV3 (p = 0.08), ARV7 (p = 0.26), ARV9 (p = 0.04), and cell division cycle gene CDC45 (p = 0.19) along with GS at diagnosis (p = 0.29) met the threshold for inclusion into multivariate analysis. Elevated expression of pre-therapy ARV9 in metastases alone was associated with progression at 12 weeks (OR: 3.9; CI 1.07 – 14.16; C-Index: 0.63). The 12-week biopsy of pts with progression had increased ARV9 mRNA expression compared to pts responding at 12 weeks (p = 0.14). Conclusions: Increased ARV9 mRNA expression in metastases is associated with early resistance to AA/P. This observation will need further validation in comparable datasets. Clinical trial information: NCT #0195364.
Pilot study of clinical targeted next generation sequencing for prostate cancer: Consequences for treatment and genetic counseling.
Authors: Cheng Heather H. , Klemfuss Nola , Montgomery Robert B. , Higano Celestia S. , Schweizer Michael Thomas , Mostaghel Elahe A. , Yu Evan Y. , Nelson Peter , Pritchard Colin C. 
Published: February 2017

251 Background: Targeted next generation sequencing (NGS) panels for identification of actionable mutations are increasingly used in oncology for therapeutic decision-making, but have yet to be widely used for prostate cancer.To determine the utility of applying a targeted next generation sequencing to prostate cancer management, we conducted a pilot study using the clinical molecular diagnostic assay, UW-OncoPlex, on primary and metastatic tumors from patients with prostate cancer. Methods: Patients receiving treatment for prostate cancer by a medical oncologist were eligible. After providing informed consent, tumor DNA was extracted from formalin-fixed, paraffin-embedded (FFPE)primary tumors and/or metastatic biopsies. Extracted DNA was analyzed using UW-OncoPlex, a targeted NGS panel designed to assess genomic alterations in 234 cancer-associated genes (PMID: 24189654). Results were discussed at a monthly multidisciplinary precision tumor board prior to communicating results to patients. Results: Forty patients consented to the study and 31 (78%) had reportable results. Findings included frequently observed prostate cancer genomic aberrations, including: TMPRSS2-ERG fusions and copy-number alterations of PTEN, TP53, FOXA1, AR, and SPOP. We also observed potentially actionable alterations in BRAF, MAP2K1 (MEK1), PIK3R1, MET, FGFR1, and FGFR3, which inform future treatment and clinical trial considerations. Notably, 8/31 (25%) patients had suspected high penetrance germline mutations, including in BRCA2 (N = 3), TP53 (N = 2), ATM (N = 1), and CHEK2 (N = 2). These 8 individuals were referred to medical genetics and 7 of 8 mutations were confirmed to be germline. One patient was found to have a hypermutated phenotype associated with bi-allelic MSH6 mutation and microsatellite instability. Conclusions: Targeted NGS panel testing may be useful in informing future treatment approaches and clinical trial selection for patients with prostate cancer. In addition, we observed a high proportion of cases with suspected high-penetrance germline mutations and immediate actionability through referral to medical genetics.
Understanding prostate cancer survivorship relative to co-habitation.
Authors: Mitteldorf Darryl 
Published: February 2017

253 Background: Studies suggest that married men diagnosed with prostate cancer survive longer than single men. None of the published research shows why this might be the case. Nothing is known about how treatment choice satisfaction and aspects of the psycho-social experience might differ between single and married men. Our aim was to understand if there are any differences in key indicators which might influence survivorship between single and married or partnered men. Methods: 1,762 men diagnosed with prostate cancer completed a lengthy online survey during a one month in 2014. The men were randomly selected from a national Prostate Cancer support group network. We investigated compliance and satisfaction in their treatment choices, activities of life satisfaction, spirituality and overall life sentiment. We included questions relating to the length of time between diagnosis and the survey and the size and location of the respondents community. We stratified each question by whether or not a person lived alone or was married or partnered or lived in some other communal situation. Results: There were no significant differences in diagnosis years by living status. A higher proportion of people with prostate cancer who live alone get more than 3 days per week strenuous exercise than those who live in communal situations. 20.26% of men who live alone exercised seven days, while only 14.24% of the married/partnered group exercised as much We used the CORR procedure in SAS to determine if a correlation existed between answers to specific questions and whether or not a person lived alone. Very few response patterns were correlated with being alone. No question in the survey was able to produce a correlation greater than 0.31. A feeling of loneliness was most correlated with being alone (r = 0.302). Trouble urinating (r = 0.24134) and trouble moving one’s bowels (r = 0.16904) were also mildly correlated with being single. Conclusions: Our study shows that being married, partnered or single is irrelevant to prostate cancer survivorship. Our results suggest that we have to look for reasons unrelated to personal relationships and household composition to understand why married men diagnosed with prostate cancer hold a longevity advantage over single men.
Mapping prostate cancer (CaP) recurrence after prostatectomy with c-11 choline PET/CT and 3T pelvic MRI in the contemporary era.
Authors: Sobol Ilya , Haloi Rimki , Park Sean Sunghun , Viers Boyd , Davis Brian , Mynderse Lance A , Boorjian Stephen A. , Thompson Robert Houston , Tollefson Matthew K. , Gettman Matthew , Quevedo Fernando , Froemming Adam , Lowe Val J. , Frank Igor , Karnes R. Jeffrey , Kwon Eugene D. 
Published: February 2017

255 Background: The purpose of this study was to identify site-specific recurrence patterns for patients (pts) with biochemical recurrence (BCR) after prostatectomy (RP) using C-11 Choline PET/CT (C11Ch) and 3T pelvic MRI with endorectal coil (pMRI). Methods: Between 2008 and 2006, 2,466 men underwent C11Ch and pMRI for BCR after RP. From this cohort, we identified 261 pts who received no adjuvant or salvage therapy (androgen deprivation or radiation). Suspected radiographic relapse was confirmed by biopsy (46%) or progression/response to treatment in concordance with subsequent rise/decline in PSA (54%). Results: Of the 261 men evaluated, 202 (75%) had positive pMRI, C11Ch or both. Seventy nine (39%), 105 (52%) and 18 (9%) pts had high, intermediate, and low risk CaP, respectively at RP. Median PSA at the time of positive scan was 2.3 ng/mL, with a median time from BCR to radiographic disease identification of 15 months. Of these 202 men, 67 (33%) harbored prostate fossa recurrence only, 44 (22%) had a combination of local and metastatic disease and 91 (45%) had metastatic disease without local recurrence. Forty (20%) pts had pelvic nodal recurrence only and 18 (9%) had perirectal nodal involvement. Median PSA for pts with local only recurrence, distant metastases only, and local + distant disease was 2.3, 2.7 and 2.2 ng/mL, respectively, with a median interval from BCR to positive scan of 16.7, 7.9 and 11 months. Imaging revealed that 33% to 66% of our cohort would have all sites of disease treated by salvage RT depending on the extent of the treatment field Conclusions: C11Ch and pMRI were used to identify recurrence patterns in pts with BCR after RP only. At median PSA of 2.3 ng/ml, our study demonstrates a low rate of local-only recurrence, higher than anticipated frequency of metastatic recurrence with peak frequency within the pelvic lymph nodes, and substantial perirectal recurrences. Despite the high rates of distant recurrences, 2/3 of our cohort had their disease limited to the pelvis and could be potential candidates for local therapies, including salvage radiation.
Is salvage focal cryotherapy curative treatment for patients with localized recurrent prostate cancer?
Authors: Katz Aaron , Kosinski Kaitlin E. , Berg Courtney 
Published: February 2017

26 Background: The salvage therapy options for patients with recurrent unilateral prostate cancer after primary radiation, or cryotherapy, are limited. Salvage focal cryotherapy is becoming a more popular treatment option as it has shown success in its disease-free survival rates. Salvage focal cryotherapy enables patients to delay or negate the use of hormone therapy, which has many unfavorable adverse effects. The aim of this study is to report on the curative success of salvage focal cryotherapy in patients with recurrent unilateral prostate cancer. Methods: We identified patients who underwent salvage focal cryotherapy at Winthrop University Hospital between February 2011 and August 2015. Age at the time of treatment, follow-up time, nadir PSA levels, and follow-up treatments were assessed. Results: From 2011 to 2015, 88 patients underwent salvage focal cryoablation. Of these patients, 14 (15.9%) required another therapy treatment after salvage focal cryoablation. Hormone therapy was a necessary treatment for 9 patients. Only 6 patients (6.8%) went on to hormone therapy due to an MRI finding of a local, nodal, or distant relapses. Three (3.4%) patients went on to hormone therapy due to a rise in PSA. Conclusions: Focal salvage therapy is associated with very low risk of clinical and radiographic progression of cancer. In our patients with radiation recurrent cancer, we were able to prevent or delay the use of hormone therapy in the majority of these men. [Table: see text]
A randomized trial of abiraterone acetate (AA) administered with 1 of 4 glucocorticoid (GC) regimens in metastatic castration-resistant prostate cancer (mCRPC) patients (pts).
Authors: Attard Gerhardt , Merseburger Axel S. , Sternberg Cora N. , Cerbone Linda , Recine Federica , Jones Robert J. , Feyerabend Susan , Berruti Alfredo , Joniau Steven , Schatteman Peter , Geczi Lajos , Tenke Peter , Werbrouck Patrick , Lefresne Florence , Nave Shelby Florence , Lahaye Marjolein , Pick Corinna , Tombal Bertrand F. 
Published: February 2017

261 Background: AA is approved for mCRPC, coadministered with prednisone (P) (5 mg BID) to prevent adverse events (AEs) associated with mineralocorticoid excess (ME). Lower GC doses had not previously been formally evaluated in combination with AA. Methods: This was an open-label, multicenter, phase 2 trial (NCT01867710) of asymptomatic chemotherapy-naïve mCRPC pts randomized 1:1:1:1 to AA (1000 mg QD) plus P 5 mg BID or P 5 mg QD or P 2.5 mg BID or dexamethasone (DEX) 0.5 mg QD. Pts who had previously received GC or ketoconazole were excluded. The primary end point was no ME (% of pts experiencing neither hypokalemia nor hypertension during the first 24 weeks of treatment).Secondary end points included additional safety, as well as response rate in the first 24 weeks, defined as a decline in prostate-specific antigen (PSA) ≥ 50% confirmed after 4 weeks. Results: 164 pts were randomized; 133 (81.6%) completed 24 weeks’ treatment. Median age: 70 years. Table 1 shows the rates of ME, hypertension, hypokalemia and PSA response. Changes in HbA1c values were minimal and observed in 16 (10.7%) pts. Conclusions: These data suggest that P 5 mg BID, which is approved in combination with AA, and DEX 0.5 mg QD, are effective in preventing ME-associated AEs, and that P 2.5 mg BID and P 5 mg QD can be safely used with appropriate monitoring. The suggestion of a higher PSA response rate with DEX 0.5 mg QD arm warrants further validation. Clinical trial information: NCT01867710. [Table: see text]