bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-effectiveness evaluation of abiraterone in the treatment of patients with castration-resistant prostate cancer who previously received docetaxel.
Authors: Chopra Akhil , Gluck Stefan , Montero Alberto J. , Avancha Kiran Kumar Venkata Raja , Lopes Gilberto 
Published: March 2020

e15107 Background: Treatment with abiraterone improves overall survival (OS), time to prostate-specific antigen progression and radiologic progression-free survival when added to prednisone and best supportive care in patients with advanced castrate-resistant prostate cancer (CRPC) who previously received docetaxel. Little is known about its cost-effectiveness in the United States. Methods: In order to raise awareness of pharmacoeconomics concepts and inform policy-makers in the US, this study aimed to assess the cost-effectiveness of abiraterone in the treatment of advanced CRPC patients, from a payer perspective. We created a decision-analytical model using clinical data from the pivotal phase III trial: COU-AA-301. Health utilities were derived from the available literature. Costs for drug acquisition, physician visits and laboratory tests were obtained from the Center for Medicare Services Drug Payment Table and Physician Fee Schedule and are represented in 2011 US dollars. Life-years saved (LY), Quality-adjusted life years (QALY) and Incremental Cost Effectiveness Ratio (ICER) were calculated using updated survival data presented at the 2011 ASCO meeting. Other main scenarios used the original median survival data published in the New England Journal of Medicine article and adjusted median OS to represent an overall survival hazard ratio of .66. Sensitivity analyses were performed using the confidence intervals for median OS in the pivotal study as well as by halving or doubling all other model inputs. No discounting was used due to the short time-horizon. Results: Abiraterone added 0.38 LY and 0.30 QALY with an incremental cost of $39,320 and therefore a cost of $102,600/LY and an ICER of $129,000/QALY. The main drivers of the model were drug acquisition cost, median OS, and health utility values. The results of the model were robust in different scenarios and sensitivity analyses. Conclusions: Using commonly accepted willingness-to-pay thresholds, such as those suggested by the World Health Organization, treatment of patients with advanced CRPC patients with abiraterone is likely to be cost-effective in the US.
Secondary rectal malignancy risk reduction with IMRT and rectal balloon placement during radiation therapy.
Authors: Ng John , Burri Ryan J. , Horowitz David Paul , Cesaretti Jamie A. , Kao Johnny , Thompson Dawn , Stephens Talitha , Chao K. S. Clifford , Brenner David J. , Shuryak Igor 
Published: March 2020

e15162 Background: The risk of secondary rectal malignancies (SRMs) is a significant concern following radiation therapy for prostate cancer patients. Modern prostate radiotherapy techniques include the use of intensity modulated radiation therapy (IMRT) and rectal balloons to decrease treatment related toxicity. These technologies may also lower the likelihood of radiation-induced SRMs. In this study, a novel biologically-based carcinogenesis model was used to quantify and to compare the predicted risks of SRMs in men treated with or without a rectal balloon in place using either standard 3-D conformal radiotherapy (3D-CRT) or IMRT radiotherapy. Methods: Treatment plans were developed for ten clinically localized prostate cancer patients using CT scans obtained both with and without a rectal balloon in place. Target and normal structures were contoured, and dose-volume histograms (DVHs) for these organs were determined with a planned 3D-CRT dose of 75.6 Gy or with a planned IMRT dose of 81 Gy. A biologically-based mathematical model of spontaneous and radiation-induced carcinogenesis was used to determine the excess absolute risk of SRMs for each plan. These risks were then compared to one another and to the baseline population. Results: Treatment with IMRT and a rectal balloon in place resulted in a significantly lower mean rectal wall dose in all patients compared with treatment with 3D-CRT without a rectal balloon. The average mean rectal wall dose with IMRT and a rectal balloon in place was 31.0 Gy versus 40.1 Gy with 3D-CRT without the rectal balloon (p < 0.001). A significantly higher risk of SRMs was predicted for patients treated with 3-D CRT without rectal balloons when compared with patients treated with IMRT with balloons in place (p < 0.001, relative risk 1.30; 95% confidence interval 1.16-1.44). Conclusions: For prostate cancer patients treated with definitive radiotherapy, the use of IMRT and rectal balloons during radiation, when compared to treatment with 3-D conformal radiotherapy, is associated with a significant reduction in the predicted risk of secondary rectal malignancies.
Assessment of abiraterone (ABI) tumor cell activity via in vitro models of androgen (A)-responsive prostate cancer.
Authors: Hickson Ian , Marien Ann , Derks Maarten , Janssen Marc 
Published: March 2020

e15166 Background: Inhibition of CYP17 by abiraterone acetate (AA) blocks A biosynthesis, reduces A levels and results in inhibition of A-dependent tumor growth. AA has been shown to improve survival in patients with metastatic castrate-resistant prostate cancer (HR = 0.74) (Scher, ASCO 2011). AA is converted to ABI in vivo. This study investigates whether direct effects of ABI on tumor cells (ie, blockade of intratumoral A synthesis) may contribute to the clinical efficacy of AA using in vitro models. Methods: LNCaP cells (human prostate cancer cell line [HPCCL]) were grown in 2D and 3D cultures, and ABI activity was assessed by reduction of androgen receptor (AR) output in gene expression profiling (Affymetrix microarray), reporter assay, and by immunoblot for A-responsive signals. Using ABI-sensitive LNCaP cells, responses were further characterized in the presence or absence of ligand (dihydrotestosterone [DHT]) and with A-targeting agents TOK-001 and MDV3100. Results: ABI exposure resulted in dose-dependent modulation of A-dependent gene expression in Affymetrix microarray analysis of 2D and 3D cultures. Similar results were seen in an analysis of AR-dependent protein and in an AR-driven reporter assay in 2D LNCaP or VCaP (another HPCCL) cell culture. In LNCaP, AR output was inhibited by low concentrations of ABI (IC50 100-300 nM), comparable to TOK-001 (IC50 30-100 nM) and less potent than MDV3100 (IC50 10-30 nM). Growth inhibition (MTT assay) occurred at concentrations 10-fold higher for all compounds. For ABI and TOK-001, inhibition of AR output was reduced by DHT (30- to 100-fold increase in IC50); with MDV3100, the shift in IC50 was less (10-fold) with agonism of AR output at low nM concentrations. Conclusions: ABI has an inhibitory effect on AR output in LNCaP cells. Partially overcoming this inhibition through addition of DHT implies that CYP17 inhibition and the subsequent A reduction play a role in the intratumoral activity of AA. However, persistent inhibition of AR output in the presence of DHT implies additional anti-A effects of AA in prostate tumor cells. This model may provide a useful tool for the study of AR-targeted therapies, combinations of agents, and resistance to agents targeting A.
VT-464: A novel, selective inhibitor of P450c17(CYP17)-17,20 lyase for castration-refractory prostate cancer (CRPC).
Authors: Eisner Joel Robert , Abbott David H , Bird Ian M , Rafferty Stephen W , Moore William R , Schotzinger Robert J 
Published: March 2020

e15167 Background: CYP17 is a single protein with two distinct enzyme activities, 17 α-hydroxylase (hydroxylase) and 17,20-lyase (lyase). Reduction of extra-gonadal androgen production through CYP17 inhibition is a validated CRPC treatment paradigm. While treatment with the recently-approved CYP17 inhibitor, abiraterone acetate (AA), increases overall survival in post-docetaxel CRPC patients (de Bono et al, N Engl J Med 2011; 364:1995-2005), it is also associated with cortisol (F) suppression and increased steroid concentrations up-stream of CYP17 hydroxylase. The clinical candidate VT-464 is an oral, non-steroidal, lyase-selective CYP17 inhibitor. The study objectives were to compare VT-464 to abiraterone in regards to in vitro selectivity and to compare VT-464 to AA in regards to in vivo primate endocrine response. Methods: Human CYP17 hydroxylase and lyase IC50 values were determined for VT-464 and abiraterone in vitro. Plasma progesterone (P), F, and testosterone (T) responses were measured 0-24 hours after single subcutaneous doses of AA (12.5 mg/kg), VT-464 (6.25 and 12.5 mg/kg), or vehicle in adult, castrate, male rhesus monkeys. Results: Human lyase and hydroxylase IC50 values were 69nM and 670nM for VT-464 and 15nM and 2.5nM for abiraterone, respectively. AA and both dose levels of VT-464 produced a similar overall reduction in plasma T, compared to vehicle (p ≤ 0.009). AA treatment resulted in an elevated plasma P (peak increase >9,000%; p ≤ 0.05), compared to both VT-464 treatments and vehicle. F was not affected by either VT-464 dose, whereas AA resulted in F suppression (p ≤ 0.005) compared to vehicle. Conclusions: VT-464 was 10-fold more selective for human CYP17 lyase vs. hydroxylase inhibition. This selectivity was associated with androgen suppression, but not increases of up-stream steroids or F suppression in male monkeys. In contrast, abiraterone was 6-fold more selective for hydroxylase vs. lyase inhibition resulting in associations with increased up-stream steroids and F suppression in AA-treated male monkeys, consistent with clinical observations in CRPC. VT-464 may thus provide a more lyase-selective alternative to AA for extra-gonadal androgen suppression in CRPC.
Validity and utility of the University of Texas M. D. Anderson Symptom Inventory (MDASI) among prostate cancer patients: Data from E2Z02: Symptom Outcomes and Practice Patterns (SOAPP).
Authors: Patrick-Miller Linda J. , Zhao Fengmin , Cleeland Charles S. , Wagner Lynne I. , Fisch Michael , Mendoza Tito R. 
Published: March 2020

e15173 Background: Optimal treatment outcomes for patients (pts) with prostate cancer are dependent upon rigorous symptom assessment. The MDSAI, a patient-reported outcome measure of symptoms (sxs) and their impact validated in a sample of patients of diverse cancer types has the potential to inform symptom experience and guide treatment specific to prostate cancer pts. Methods: SOAPP, an Eastern Cooperative Oncology Group (ECOG) study, was conducted at academic and community medical oncology clinics and included pts with prostate cancer of all stages and phases of care. At baseline and 4 weeks, pts completed a measure of symptom severity and functional interference (MDASI). Symptom experiences and psychometric properties of the MDASI in prostate cancer pts (n = 320) were analyzed. Results: The 5 most prevalent moderate/severe sxs reported at baseline were fatigue (34%), disturbed sleep (25%), drowsiness (18%), pain (17%), and dry mouth (15%); moderate/severe nausea (5%) and vomiting (2%) were the least prevalent. At baseline ECOG performance status (PS) was ≥2 in 9% of pts. Pain, sadness, and difficulty remembering things occurred in 17%, 14%, and 13% respectively, and among pts whose PS worsened, severity of these sxs had the highest change scores at follow-up. Internal consistency and test-retest reliability of the MDASI were good, with Cronbach coefficient alphas ≥0.84 and intra-class correlations ≥0.78 for all subscales. Significantly higher scores and moderately large effects for the MDASI severity scale were reported by pts with poorer PS (2.2 vs 1.0, ES=.83) and tumor progression (2.4 vs 1.2, ES=.73) p<.05. Results were similar for the interference scale, demonstrating MDASI known-group validity. Pts whose quality of life declined showed significantly greater increase in severity (1.1 vs .14, p<.01) and interference (1.9 vs .28, p<.004) from baseline to follow-up than pts whose quality of life was unchanged, demonstrating MDASI sensitivity to change. Conclusions: The MDASI is a valid, reliable, and sensitive symptom assessment method for descriptive and clinical studies, and patient care in medical oncology outpatients with prostate cancer.
Detecting circulating tumor cells (CTCs) in patients with high-risk, localized prostate cancer using the CellSearch platform.
Authors: Pal Sumanta Kumar , Lau Clayton , He Miaoling , Twardowski Przemyslaw , Wilson Timothy G. , Kawachi Mark H. , Torres Alejandra , Carmichael Courtney , Yen Yun , Kortylewski Marcin , Jones Jeremy 
Published: March 2020

e15178 Background: Enumeration of circulating tumor cells (CTCs) using the CellSearch platform has prognostic value in patients with metastatic castration resistant prostate cancer. However, the prognostic value of CTC enumeration in high-risk, localized prostate cancer (HRLPC) remains undefined. Methods: Patients with HRLPC (defined by ≥1 of the following criteria: ≥ cT3a disease, Gleason score 8-10, or PSA > 20 ng/mL) who have chosen prostatectomy for their definitive management were prospectively identified. Patients were consented to receive 4 sequential 30 mL blood draws, each collected in 3 separate 10 mL EDTA tubes. The first 2 blood draws were conducted 2 weeks prior and immediately prior to surgery, while the second 2 blood draws were conducted 4-6 weeks and 3 months following surgery. Within 4 hrs of blood collection, the white blood cell (WBC) fraction was pooled and Ficoll purified. The WBC fraction was transferred to a CellSave tube, and CTCs were enumerated using the CellSearch system. Expression of CD133 and E-cadherin was characterized using the CellSearch system in patients with detectable CTCs. Results: Within 3 monthsof study initiation in Nov 2011, 19 of a planned 37 patients have been accrued. Median age in the cohort was 65 (range, 51-74), and the number of patients with Gleason score 8-10, ≥ cT3a disease, or PSA > 20 ng/mL was 16, 4, and 2, respectively. The majority of patients (17/19, or 89%) had only one high-risk feature. Mean baseline PSA for the cohort was 11.4 (range, 3.4-37). CTCs were detectable in 67% of patients prior to surgery, 27% of patients at 1 month following surgery and 67% of patients at 3 months following surgery. Amongst those patients with detectable CTCs, the median count was 3 (range, 1-7). Further, in these patients, CD133 and E-cadherin were detected in 44% and 46% of specimens assessed, respectively. Full details of these analyses will be provided at the time of the meeting. Conclusions: Using a modified methodology, CTC enumeration using the CellSearch platform is feasible in patients with HRLPC. Interestingly, markers of epithelial-mesenchymal transition and stem cell lineage are detectable in a proportion of patients with localized disease.
Efficacy of abiraterone acetate in the treatment of castration-resistant prostate cancer: Early results from the German compassionate-use program.
Authors: Ohlmann Carsten Henning , Stöckle Michael , Pfister David A. , Heidenreich Axel , Merseburger Axel S. , Kuczyk Markus , Manka Lukas , Hammerer Peter , Albers Peter , Arsov Christian , Retz Margitta , Gschwend Jürgen E. , Feyerabend Susan , Stenzl Arnulf , Banek Severine , Marin Jan , Gleissner Jochen , Wirth Manfred , Zastrow Stefan , Heck Matthias 
Published: March 2020

e15195 Background: Abiraterone acetate (AA) plus prednisone (P) has demonstrated an improved survival of patients with castration-resistant prostate cancer (CRPC) compared to placebo plus P in a large phase III trial. In Germany, patients were able to receive AA within a compassionate-use program (CUP). Here, we report the first results of the program. Methods: Patients were eligible for the CUP if they progressed on or after at least one cytotoxic chemotherapy regimens. For CUP entry, patients were considered to have disease progression if they had radiographic evidence of disease progression in soft tissue or bone with or without PSA-progression and ongoing androgen deprivation. Patients received AA 1000mg daily plus prednisone 5mg BID until progression of disease or unacceptable toxicity. Results: Between 02-05/2011, 398 patients were registered for the CUP in Germany. Data from 191/350 (47.9%) of the patients treated at 10 different sites were available for evaluation of efficacy. Median age was 70.72yrs (52.35-87.61) and patients received a median of 1 (1-4) chemotherapy lines prior to CUP entry. Median PSA at baseline was 220.5 ng/ml (0.47-4245); 168 (88%) of patients presented with bone metastasis. With regard to efficacy, 64/191 (33.5%) of the patients showed an unconfirmed PSA-response ≥50%. At a median follow-up of 5.3 months, 51/191 (26.7%) patients had died, resulting in a median PSA-progression free and overall survival of 8.3 and 10.61 months, respectively. In a subset of patients (71/191, 37.2%) data regarding objective response was available with 25/71 (35.2%) achieving an objective response. Data from 114 pts. revealed fatigue (20.3%), hot flushes (15.8%), edema (10.6%), elevated liver enzymes (8.0%) and asthenia (7.9%) being the most frequent toxicities (any grade). Conclusions: Treatment of CRPC patients with AA outside controlled clinical trials leads to considerable PSA- and objective response rates with a favourable toxicity profile, comparable to the results from COU-AA-301 registration trial. Due to the short median follow-up, conclusions regarding PSA-progression free and overall survival may not be drawn.
Risk of skeletal-related events (SREs) in patients with prostate cancer (PC) and newly diagnosed metastases to bone.
Authors: Glass Andrew , Lamerato Lois , Edelsberg John , Richert-Boe Kathryn E. , Taneja Charu , Wolff Greg G. , Czapski Natalie , Chung Karen , Richhariya Akshara , Oster Gerry 
Published: March 2020

e15197 Background: Bone is a common site of metastatic involvement in patients (pts) with PC. Bony metastases (mets) are often associated with SREs (spinal cord compression [SCC], pathologic fracture [PF], surgery to bone [SB], radiotherapy to bone [RT]). Skeletal complications cause significant morbidity and mortality. Current estimates of SRE risk come principally from randomized clinical trials. Information from routine clinical practice is limited. Methods: Using the tumor registry and electronic data stores at a large U.S. Midwest healthcare system that serves approximately 800,000 persons, we retrospectively identified all pts aged ≥18 yrs with primary PC and newly diagnosed bone mets between 1/1/95 and 12/31/09. Electronic medical records were reviewed by trained abstractors for evidence of SREs between date of bone mets diagnosis and death, loss to follow-up, or end of study for evidence of first SRE. Cumulative incidence of SREs was estimated in the presence of competing risk of death. Results: We identified a total of 420 men with primary PC and newly diagnosed bone mets; 42 pts had evidence of SREs at initial diagnosis of bone mets and were excluded from the analyses. Among the remaining 378 pts, mean (SD) age was 72.7 yrs (9.8 yrs); 38% were Caucasian and 58% were African-American. Median duration of follow-up after diagnosis of bone mets was 17.1 months (mos). At 12 mos, cumulative incidence of SREs was 31.6% (SCC, 6.1%; PF, 15.0%; SCC and/or PF, 19.1%; SB, 3.9%; RT, 24.4%) (Table). Corresponding figures at 24 mos were 45.3% (SCC, 12.5%; PF, 22.2%; SCC and/or PF, 30.2%; SB, 6.2%; RT, 34.9%). Relatively few pts (14.6%) received intravenous bisphosphonates prior to SRE. Conclusions: Pts with PC in routine clinical practice are at high risk of SREs following initial diagnosis of bone mets. [Table: see text]
Initial experience with sipuleucel-T (sip-T) in the immediate post-approval setting: The University of Washington (UW) experience.
Authors: Dean James P. , Yu Evan Y. , Beauchene Suzanne , Hall Suzanne P , Higano Celestia S. 
Published: March 2020

e15206 Background: UW has participated in clinical trials of sip-T for over 15 years. After sip-T administration in the 3 phase III trials, patients (pts) did not receive additional therapy until objective progression. However, the course of treatment after administration of sip-T outside the setting of a clinical trial is not defined. In order to better understand our own practices in response to this new clinical scenario, we evaluated our institutional experience with commercial sip-T after FDA approval. Methods: Charts of all pts treated with sip-T at UW with at least 3 mos follow-up were retrospectively reviewed. Pt characteristics and treatments administered during the first 3 mos after sip-T infusion were collected. The institutional review board approved this study. Results: Between June 2010 and Nov 2011, 36 pts with mCRPC were treated with commercial sip-T by 3 different MDs. There were 31 Caucasian, 3 African American, and 2 Asian pts. At diagnosis, Gleason score (# pts) was 3+3 (2), 3+4 (5), 4+3 (7), 4+4 (4), 4+5 (16), 5+5 (2); initial therapy was watchful waiting (1), ADT with brachytherapy [BT] (1), BT with XRT (4), ADT/XRT (6), radical prostatectomy [RP] (9), ADT/RP (1). At the time of sip-T therapy, median age 67.8 yrs (44.2 to 84.5), median PSA 56.0, LDH 179.5, alk phos 77, Hgb 12.7, CTC 2. 3 pts had prior chemotherapy for metastatic disease. 34, 2, and 1 pts received 3, 2, and 1 sip-T infusion(s) respectively. Within the first 3 mos after the last sip-T dose, 29 pts had no significant symptoms and received no additional therapy other than ADT +/- ongoing zoledronic acid or denosumab (27), ketoconazole (1), or nilutamide (1); 7 developed pain and received docetaxel [D] (1), XRT and D (3), XRT (1), nilutatmide/D (1), or cabozantinib (1). 6 pts died a median of 10 months after sip-T; none had received chemotherapy before sip-T therapy. Conclusions: The majority of UW pts (80%) received no additional therapy in the first 3 mos after sip-T while 20% developed pain and were treated with docetaxel or other systemic therapy. What treatments should be given and at what interval after sip-T remains unclear. It is likely that new agents will impact the treatment paradigm after sip-T.