bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of supportive measures to improve outcome and decrease toxicity in docetaxel-based antiangiogenesis combinations.
Authors: Karzai Fatima H. , Adesunloye Bamidele , Ning Yangmin M. , Madan Ravi Amrit , Gulley James L. , Apolo Andrea Borghese , Beatson Melony A. , Couvillon Anna , Harold Nancy , Parnes Howard L. , Arlen Philip M. , Wright John Joseph , Chen Clara , Dawson Nancy Ann , Figg William Douglas , Dahut William L. 
Published: February 2017

128 Background: We have recently completed accrual of 63 patients (pts) to our study combining lenalidomide (L), with bevacizumab (B), docetaxel (D), and prednisone (P) (ART-P). Due to the lack of improved survival and the increased toxicity of anti-angiogenic docetaxel combinations in the MAINSAIL and CALGB 90410 trials we attempted to contrast and compare our studies with the failed phase III trials. Methods: Among the first 52 pts on the ART-P, 3 received L 15 mg daily, 3 had 20 mg daily, and the rest had 25 mg daily for 14 days of every 21−day cycle (C). We later enrolled 11 more pts at L 15 mg. All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily throughout each C. Pegfilgrastim was given on day 2. Patients on CALGB 90410 received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and on MAINSAIL received D 75 mg/m2, L 25 mg daily for 14 days of every 21−day cycle with daily P. Patients on CALGB 90410 and MAINSAIL did not receive enoxaparin or pegfilgrastim prophylactically. Results: Median number of Cs in ART-P was 16 (3−38). PFS was 22 months and median OS has not been reached. Pts with measurable disease had 1 CR and 25 PR (86.7% RR). Two patients (3%) had deep vein thromboses. Of 1,219 cycles given, 14 cycles were complicated by febrile neutropenia (FN) (1.1%). There were no treatment related deaths. In comparison, median number of Cs in MAINSAIL L+DP arm was 6, with a PFS of 45 weeks and an OS of 77 weeks. Thirty-four pts (6.5%) developed pulmonary emboli and there were 2 deaths due to toxicity in the experimental arm. Nearly 12% of Cs were complicated by FN. In the experimental arm of CALGB 90410 trial, median OS was 22.6 months with median PFS of 9.9 months. Median number of Cs was 8, and 19 pts developed thromboses/emboli (3.6%). In addition, 7% of patients developed FN and treatment related deaths were reported at 4%. Conclusions: The use of supportive care allows the ART-P combination to be given for more cycles than were given in MAINSAIL and CALGB 90401 potentiating a longer PFS, RR and possibly OS with an improved toxicity profile. This data demonstrates the potential importance of supportive measures and is hypothesis generating for future combination studies. Clinical trial information: NCT00942578.
Analysis of putative resistance mechanisms in recent treatments targeting the androgen receptor in castration-resistant prostate cancer (CRPC).
Authors: Thelen Paul , Walleck Eiko , Bremmer Felix , Trojan Lutz , Strauß Arne 
Published: February 2017

130 Background: Recent breakthrough therapies targeting androgen receptor signalling in CRPC involve multifunctional androgen receptor (AR) blockade and exhaustive androgen deprivation. Nevertheless, limitations to an enduring effectiveness of new drugs are anticipated in resistance mechanisms occurring under such treatments. Here we specify the origin of CYP17A1 up-regulation under abiraterone acetate treatment in CRPC cell models. Methods: CRPC cell models VCaP and LNCaP as well as AR-negative PC-3- and non-neoplastic epithelial BPH-1-cells were treated with various concentrations of abiraterone hydrolyzed from abiraterone acetate (AA, Janssen-Cilag, Germany). Functional analyses by RNA interference were done with AR- and CYP17A1-siRNA. Expression of androgen regulated genes and CYP17A1, AKR1C3 was quantitated by real time PCR. Protein analyses were performed by western blots and PSA secretion was assessed by ELISA kits. Results: AA treatments (5 to 25 µM) of AR positive CRPC cell models led to decreased expression of androgen regulated genes such as PSA. In these cells diminished expression of androgen regulated genes was accompanied by an up-regulation of CYP17A1 expression (>2-fold at 25µM AA) within short treatments of 24 hours. No such effects became evident in AR-negative PC-3 cells. AR directed siRNA (siAR) used in VCaP cells significantly reduced mRNA expression and AR protein abundance. Such interference with AR signalling in the absence of AA also caused an (up to 8-fold) up-regulation of CYP17A1 expression. Conclusions: In AR-positive cells AA treatments cause a down-regulation of androgen regulated genes in spite of an elevated expression of CYP17A1, the very target enzyme for this drug. CYP17A1 up-regulation already occurs within 24 hour treatments of AA and does not require adaptation events over several cell cycles. CYP17A1 is also up-regulated in the absence of AA when AR signalling is physically eliminated by siAR. These results reveal an immediate counter-regulation of CYP17A1 expression whenever AR-signalling is inhibited adequately but not a persisting adaptation yielding drug resistance.
Long-term immune responses elicited by a DNA vaccine encoding prostatic acid phosphatase (PAP) in patients with nonmetastatic castrate-resistant prostate cancer.
Authors: McNeel Douglas G. , Becker Jordan T. , Eickhoff Jens C. , Johnson Laura E. , Liu Glenn , Olson Brian M. 
Published: February 2017

135 Background: We have previously reported a phase I/II trial with a DNA vaccine encoding PAP in patients with stage M0 CaP. Vaccination was found to be safe and immunologically active. Th1-biased PAP-specific immune responses were associated with increases in PSA doubling time (DT). In the current trial, we sought to evaluate the immunological efficacy of immunizations performed over a 1-2-year period of time, with the goal of identifying a preferred schedule. Methods: Patients (pts) were randomized to a schedule of 6 immunizations at 2-wk intervals followed by quarterly booster immunizations, or a schedule determined by frequent immune monitoring. Immune monitoring was by IFNγ and granzyme B ELISPOT and antigen-specific T-cell proliferation. Pts continued immunization until evidence of radiographic progression, toxicity, two years, or 24 total immunizations, whichever occurred first. Results: 17 pts were enrolled, of whom 11 completed at least 1 year on treatment, and 4 completed 2 years. 3 pts remain on study. 1 pt experienced a grade 3 allergic reaction (angioedema) after 11 immunizations; no other events > grade 2 were observed. 6/16 evaluable pts developed durable immune responses, defined as statistically significant PAP-specific T-cell responses by at least two separate measures that were at least 3-fold the baseline response and detectable at >1 post-treatment time point. 2 pts in the immune-monitoring arm developed immune responses after 6 immunizations that were detectable at each quarterly time point up to 2 years. 5/15 evaluable pts were observed to have a >3-fold increase in PSA DT; the 2 with the greatest increase in PSA DT developed PAP-specific IFNγ-secreting T cells detectable at multiple time points after immunization. Conclusions: Repetitive immunization with this vaccine appears safe and immunologically active. Presence of durable Th1-biased antigen-specific immune responses is a mechanistically rational biomarker, and may be associated with favorable increases in PSA DT observed in 2 separate trials. Impact of vaccination on time to radiographic disease progression awaits results from an ongoing randomized clinical trial. Clinical trial information: NCT00849121.
Value of NADiA ProsVue on the CAPRA-S nomogram for predicting postprostatectomy clinical recurrence.
Authors: Moul Judd W. , Lilja Hans , Lance Raymond , Vessella Robert , McDermed Jonathan E. , Sarno Mark J. , Adams Thomas H. 
Published: February 2017

139 Background: The post-radical prostatectomy (RP) CAPRA-S nomogram stratifies men into low, intermediate and high risk groups for biochemical recurrence (BCR) and proved accurate for predicting 3 and 5 year BCR rates in a large study cohort. NADiA ProsVue is a prognostic test that identifies men at reduced risk of clinically recurrent prostate cancer when used with traditional risk factors. We assessed ProsVue, a prognostic test for identifying post-RP clinical recurrence, in an independent population of men classified into low, intermediate and high CAPRA-S risk groups. Methods: The 304 men in the ProsVue 510(k) study were categorized into low (scores 0-2), intermediate (3-5) and high (≥6) CAPRA-S risk groups. Men were categorized as “at reduced risk” or “not at reduced risk” using a 2.0 pg/mL/month ProsVue cutpoint. Clinical recurrence was defined by positive biopsy or imaging results or death due to prostate cancer. Clinical progression-free survival (cPFS) was determined between subgroups using univariate Cox regression and Kaplan-Meier survival analyses and Wilcoxon and log-rank p values were reported. Results: Recurrence occurred in 8/156 (5.1%), 20/93 (21.5%) and 32/55 (58.2%) of men in the low, intermediate, and high CAPRA-S risk groups, respectively (P<0.0001). After 3, 5, 8 and 15 year followup, men in all CAPRA-S risk groups with ProsVue results ≤2.0 had significantly longer cPFS compared to men with results >2.0. The differences are marked as early as 3 years post-RP in the intermediate and high risk groups. Conclusions: ProsVue added significant prognostic value for identifying risk of clinical recurrence within low, intermediate and high CAPRA-S risk groups. ProsVue is the strongest independent predictor of clinical recurrence of prostate cancer post-RP. [Table: see text]
Overtreatment of prostate cancer in Florida.
Authors: Gilbert Scott Michael , Henriksen Carl 
Published: February 2017

140 Background: Although most evidence suggests that older men with localized prostate cancer do not benefit from treatment, many men with relatively limited (<10 years) life expectancy continue to seek and receive treatment. Given mounting concerns regarding overtreatment, we sought to better understand geographic differences in the potential overtreatment of prostate cancer. Methods: We used the Florida Cancer Data System (FCDS) to identify treated and untreated cases of prostate cancer between 2004-2007. The FCDS is a large statewide cancer registry that collects clinical, demographic and treatment information for incident cancers. We defined potential overtreatment according to risk of disease (Gleason <=7, stage T2 and less) and age ( >75 years). We used Geographic Information Systems (GIS) to map differences in overtreatment across Health Service Areas (HSAs) in Florida. We then examined the relationship between the number of urologists and radiation oncologists reported in the Area Resource File and potential overtreatment using linear regression models. All analyses were performed using standard statistical software (SAS and ArcGIS). Results: Among men older than 75 years (n=10,411), 9.2% received surgery, 38.7% received external radiation therapy, 15% received brachytherapy and 10.5% received primary androgen deprivation therapy; only 26.6% of patients were managed expectantly. Overtreatment varied significantly across Florida. Among some HSA clusters in Central and Panhandle Florida, overtreatment was estimated in less than 21.6 % of cases. Much higher rates of overtreatment (36-52% of cases) was observed among other HSAs, particularly in South Florida. Although the number of urologists (per 100,000 male population) was not associated with an increased propensity for overtreatment in regression models, the concentration of radiation oncologists was associated with an increase of 0.64 cases of overtreatment (per 100,000 men) for each additional radiation oncologist (p<0.0001). Conclusions: Treatment among older men with low- and intermediate-risk localized prostate cancer is more common than expectant management. The propensity for overtreatment varies considerably according to geographic and healthcare market factors.
Dose-escalated adaptive image-guided radiotherapy versus high-dose-rate brachytherapy monotherapy for low-risk prostate cancer.
Authors: Marina Ovidiu , Krauss Daniel J. , Brabbins Donald , Wallace Michelle , Martinez Alvaro A , Ye Hong , Gustafson Gary S. 
Published: February 2017

145 Background: Both IGRT and HDR are used for definitive treatment of low-risk prostate. No comparative study of these contemporary modalities exists. Methods: Charts for patients with low-risk prostate cancer by NCCN criteria treated 1999-2012 were reviewed. For IGRT, the clinical target volume (CTV) included the prostate and proximal seminal vesicles. A CT-based, off-line adaptive treatment plan was made with a patient-specific confidence-limited planning target volume (cl-PTV) based on the planning plus four additional daily CT scans. Overall survival (OS) was calculated by the Kaplan-Meier method (log-rank test), with Cox regression for uni- and multi-variate analysis. Cumulative incidence (Gray’s test), with competing risks analysis (Fine and Gray) were used for biochemical control (BC) and freedom from local recurrence (FFLR). Results: There were 598 IGRT and 399 HDR patients (see Table), with a median follow-up of 6.1 and 3.6 years, respectively (p<0.001). The median prescribed IGRT dose was 75.6 Gy (range 73.8-79.2). HDR doses were 24 Gy (n=126) or 27 Gy (n=151) in 2 fractions, or 36 Gy (n=3) or 38 Gy (n=335) in 4 fractions. Five- and 10-year BC was 99% and 94% for IGRT and 98% and 95% for HDR (p=0.77); FFLR was 100% and 99% for both (p=0.89); and OS was 95% and 75% for IGRT and 97% and 85% for HDR (p=0.04). On multivariate analysis, predictors (p<0.10) for OS were age (p<0.001) and PNI (p=0.04); for LR, PPC (p=0.01); and for BC, a trend for PSA (p=0.08). Treatment type was not a predictor of OS, BC or FFLR (p>0.5). Conclusions: Both dose- escalated IGRT and HDR monotherapy yield similarly excellent outcomes for low-risk prostate cancer. Our experience supports the continued use of brachytherapy as monotherapy in low-risk prostate cancer. [Table: see text]
Immune response with sipuleucel-T in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Phase II ProACT study.
Authors: Gardner Thomas A. , Petrylak Daniel Peter , Corman John M. , Hall Simon , Weinstein Ralph , Keyser Robert , Sims Robert Brownell , Sanders Amanda , Sheikh Nadeem A. , Higano Celestia S. 
Published: February 2017

148 Background: Sipuleucel-T is an autologous cellular immunotherapy for asymptomatic or minimally symptomatic mCRPC. Sipuleucel-T prepared using 10μg/mL PA2024 (PAP-GM-CSF antigen) stimulates immune responses and prolongs overall survival (OS). ProACT is an ongoing phase 2 study to evaluate immune responses and OS of sipuleucel-T when manufactured using 3 different concentrations of PA2024. Here we report data from the FDA-approved concentration, 10μg/mL PA2024 (n=40). Methods: Pts with asymptomatic or minimally symptomatic mCRPC (n=120) received sipuleucel-T manufactured using 2, 5 or 10μg/mL PA2024 for a total of 3 infusions with 2-wk intervals. Peripheral immune responses were evaluated 2, 4 and 6 mo after 1st infusion by serum ELISA (n=40), and B cell activation phenotype was characterized during the manufacture of the product by flow cytometry (n=19). Results: During product manufacture both mature and memory B cells were activated; the percentage of B cells that had a mature phenotype (defined as CD20+ IgD+ CD27+ CD86+) was increased only after culture of each successive treatment. Activated memory B cells (defined as CD20+ IgD- CD27+ CD86+) were also increased after culture of each successive treatment and in pre-culture cells at the 3rd treatment. At mo 2, median serum anti-PA2024 and anti-PAP titers (IgG and IgM combined) were 128 and 32-fold higher vs baseline respectively, compared to median serum anti-GM-CSF titers, which were 16-fold higher vs baseline. Median serum anti-PA2024 titers (IgG and IgM combined) were significantly higher than those for anti-GM-CSF (p<0.001) at all timepoints and correlated with anti-PAP titers (r=0.840). PA2024 and PAP responder frequencies (IgG and IgM titers combined >12,800) were 79% and 47% of pts, respectively. Anti-tetanus titers were predominantly IgG and did not differ between timepoints. Conclusions: These data indicate that sipuleucel-T induces an activated memory phenotype, evident after each culture in vivo after the first two treatments. Sipuleucel-T also appears to generate robust, long lasting anti-PA2024 and anti-PAP responses. Analyses comparing the 3 dosing cohorts will be reported in future publications. Clinical trial information: NCT00715078.
Does the diagnosing urologist influence choice of initial active treatment versus observation in older men with favorable prostate cancer?
Authors: Hoffman Karen Elizabeth , Niu Jiangong , Shen Yu , Jiang Jing , Shah Jay Bakul , Smith Grace L. , Davis John W. , Kim Jeri , Volk Robert , Kuban Deborah A. , Giordano Sharon Hermes , Smith Benjamin D. 
Published: February 2017

15 Background: Upfront treatment of older men with favorable prostate cancer yields substantial morbidity but does not improve survival. Deferring treatment in favor of observation promises to reduce morbidity without compromising survival, yet few patients select observation. Prior literature focuses on patient factors contributing to active treatment but the influence of the patient’s urologist on treatment choice remains uncertain. Methods: We identified men age 66 and older with favorable prostate cancer (cT1c or cT2; Gleason 6) diagnosed from 2004-2007 in the SEER-Medicare and Texas Cancer Registry-Medicare databases whose catchments include 34% of the United States (US). Diagnosing urologist, practice setting and cancer-directed treatment within 12 month of diagnosis (prostatectomy, radiotherapy, cryotherapy or androgen deprivation) were determined from claims data. Physician characteristics were obtained from the AMA Master File. Fixed effect and random effect hierarchical multivariate models evaluated physician variation and factors associated with observation. Results: 17,468 patients received care from 2,613 urologists. 64% of patients had T1c cancer. 85% received active treatment and 15% had observation. Even among men 80 and older, 67% received active treatment. The diagnosing urologist accounted for 10% of the variance in choice of active treatment versus observation. After adjusting for patient factors, urologists practicing in an office setting (vs. hospital; p<0.001) and not trained in the US (vs. US-trained; p=0.006) were less likely to manage patients with observation. With adjustment for case mix, only 3.5% of urologists demonstrated a higher than average likelihood of managing their patients with observation; 34% of men diagnosed by these urologists were observed. Conclusions: The vast majority of older men, even those over 80, received active treatment for favorable prostate cancer. The diagnosing urologist contributed to variation in the choice of treatment versus observation. Less than 5% of urologists demonstrated higher than average use of observation suggesting widespread bias against observation during the study era.
Phase II trial of combination therapy with intravenous carboplatin (C) and oral everolimus (EVE) and prednisone (P) in docetaxel-pretreated (DP) metastatic castrate-resistant prostate cancer (mCRPC): A Prostate Cancer Clinical Trial Consortium study.
Authors: Veeraputhiran Muthu Kumaran , Shevrin Daniel H. , Heilbrun Lance K. , Smith Daryn , Li Jing , Dickow Brenda , Heath Elisabeth I. , Vaishampayan Ulka N. 
Published: February 2017

156 Background: Platinum based therapies have demonstrated efficacy in DP mCRPC. EVE demonstrated preclinical efficacy in chemotherapy resistant prostate cancer models. Clinical synergy was noted between C and EVE, hence a phase II trial of the combination was conducted. Methods: Primary endpoint was time to progression (TTP). Progression was defined per RECIST criteria for measurable disease (MD), or skeletal event, or > 2 new areas of bone metastases. DP mCRPC patients with adequate renal and liver function, and performance status of 0 or 1 were eligible. Intravenous C at target AUC of 5 on day 1, and oral EVE 5mg once daily and P 5mg twice daily were administered in 21 day cycles. PSA was assessed every 21 days and radiologic response was assessed every 3 cycles. Secondary endpoints included overall survival (OS), correlation of TTP and PSA response, with markers such as phopho mTOR, pAKT, p70S6 and circulating tumor cells (CTC). Results: 26 patients (pts) enrolled, including 8 African Americans, and accrual is complete. Median age was 69 years (range 54-86). Median pretherapy PSA was 190 ng/ml (range 13 - 2174). 18 pts (69%) had bone pain. Gleason score was > 8 in 18 pts. 19 pts had measurable disease of which 15 had MD progression, 18 had bone scan progression, and 2 had PSA-only progression. 124 cycles have been administered; median 3 cycles (range 1 - 16). The predominant grade 3 or 4 toxicities were thrombocytopenia in 8 pts, pulmonary embolism in 2 and neutropenia in 3. No treatment related deaths occurred. Of 26 pts who are response evaluable, 4 (15%) had a > 30% PSA decline and 1 had a >90% PSA decline. Of 19 pts with MD, 8 had stable disease and no objective responses were observed. The median TTP and OS were 2.5 months (90% CI: 1.8 - 4.3), and 12.5 months (90% CI: 6.7 - 16.1), respectively. Correlative studies including pharmacokinetic and pharmacodynamic evaluations are ongoing, and will be reported. Conclusions: The combination was tolerable but revealed modest clinical efficacy. Biomarker evaluation may help identify a subset likely to benefit from mTOR inhibition strategy in mCRPC. Clinical trial information: NCT01051570.