bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quality-adjusted survival comparison between androgen deprivation with radiation therapy versus radiation therapy alone for locally advanced prostate cancer: Decision analysis from RTOG 85-31 trial.
Authors: Jeong Chang Wook , Ahn Soyeon , Lee Minjung , Ku Ja Hyeon , Kwak Cheol 
Published: February 2017

265 Background: Radiation Therapy Oncology Group (RTOG) trial 85-31 has shown that addition of androgen deprivation therapy to radiation therapy (RT+ADT) for patients with locally advanced prostate cancer benefits local control and progression-free survival compared to RT alone. However, the survival gain may be diluted with increased toxicity of hormone manipulation. There is a need to develop new decision analysis methods to incorporate survival time and quality of life (QoL) adjusting for various health states and persistent complications. Methods: We previously developed “quality-adjusted survival analysis using duration” (QASAD) and “quality-adjusted survival analysis using probability” (QASAP) to estimate quality-adjusted survival time. The QASAD uses the median duration in each state to weight the utilities, while the QASAP uses the proportional probability of being in each state for weighting. The survival and complication rates of RTOG 85-31 were reconstructed based on published Kaplan-Meier survival curves, and the utility values for states were obtained from the literature. Probabilistic sensitivity analysis was applied using Monte Carlo simulation with 1000 simulated samples. Results: QASAD and QASAP showed that the quality-adjusted life year (QALY) values in RT+ADT were generally higher than those in RT. In probabilistic sensitivity analysis, QASAD resulted in 4.93 (95% bootstrapped confidence interval [CI] = 4.12 to 5.71) for RT and 5.60 (95% CI = 4.30 to 6.48) for RT+ADT. QASAP resulted in 4.85 (95% CI = 4.16 to 5.39) for RT and 4.96 (95% CI = 3.73 to 5.78) for RT+ADT. Conclusions: The decision analyses showed that RT+ADT provided slightly better quality-adjusted survival outcome after treatment than RT alone. The QASAD and QASAP methods may help the decision of optimal treatment balancing between survival gain and unfavorable quality of life. [Table: see text]
Phase Ib trial of docetaxel, prednisone, and pazopanib, in men with metastatic castration resistant prostate cancer (mCRPC).
Authors: George Daniel J. , Halabi Susan , Healy Patrick , Gemberling Sarah , Winters Carolyn , Mundy Kelly , Harrison Michael Roger , Szmulewitz Russell Zelig , Armstrong Andrew J. 
Published: February 2017

275 Background: Docetaxel prednisone (DP) is a standard of care for men with metastatic castrate resistant prostate cancer (mCRPC) with median progression-free survival (PFS) of 4-6 months and overall survival (OS) of 19 months, supporting a need for further treatment options. Pazopanib (PAZO) is a multi-targeted kinase inhibitor of VEGF receptors approved for treatment of kidney cancer and sarcoma. We performed a two center, Phase Ib study of DP + PAZO to evaluate the safety and early efficacy in mCRPC. Methods: This is a 2 site phase 1 DOD Prostate Cancer Clinical Trials Consortium trial of DP + PAZO once daily with ongoing ADT in men with mCRPC. The primary endpoint was safety; secondary endpoints included evaluation of a maximum tolerated dose (MTD) through a dose escalation and expansion design, pharmacokinetic assessments, PSA and radiographic responses, and toxicity. Results: Twenty-five men were treated over 6 dose levels using a 3+3 design. Pegfilgrastim (Neu) was added to the regimen after myelosuppression limited dose escalation. With Neu, our target MTD of D 75 mg/m2; P 10 mg QD and PAZO 800 mg QD was reached. Eleven additional patients were accrued at this dose level for a total of 36 patients. 17 patients had received prior Abi and/or Enza. The most common AEs were alopecia (86%), fatigue (69%), diarrhea (58%), and nausea (53%), and the most common Grade 3-5 SAEs were neutropenia (33%) and leukopenia (19%). Three deaths attributed to study treatment occurred: one from pneumonitis, one from respiratory failure, and one from intracranial hemorrhage. The proportion of 30%, 50% and 90 % PSA declines were 69%, 58% and 25%, respectively. The objective response rate was 31% (11/36). Median PFS was 18.6 months (95% CI: 6.5, 27.7) and OS was 22.2 months (95% CI: 14.7, -). Predicted median OS using the Halabi nomogram was 20.9 months (95% CI: 19.2, 23.0) with 23%, 34% and 43% of patients in low, intermediate and high risk groups, respectively. Conclusions: DP + PAZO (with Neu) were tolerable at full doses and demonstrated a surprisingly long PFS and high objective response rate in a relatively poor risk group of mCRPC patients. These data support further randomized studies of DP + Pazo in Abi/Enza refractory patients. Clinical trial information: NCT01385228.
[18F]NaF PET/CT imaging biomarkers of progression-free survival in metastatic prostate cancer.
Authors: Harmon Stephanie , Perk Tim , Eickhoff Jens C. , Staab Mary Jane , Choyke Peter L. , Dahut William L. , Apolo Andrea B. , Humm John , Larson Steven M. , Morris Michael J. , Perlman Scott , Liu Glenn , Jeraj Robert 
Published: February 2017

277 Background: 18F-Sodium Fluoride (NaF) PET/CT has been shown to be superior to 99mTc-MDP SPECT in detection of bone metastases and shows great promise to reliably measure functional changes in bone. This study assesses the relationship of Progression Free Survival (PFS) with NaF PET/CT measures in patients with metastatic Castration-Resistant Prostate Cancer (CRPC). Methods: 55 CRPC patients had NaF PET/CT scans performed at baseline, which was repeated at week 9 if receiving taxane-based therapy (N = 16) or week 12 if receiving androgen-signaling pathway (AR) inhibitors (N = 39). Bone lesions were identified using a novel technique allowing for extraction and tracking of PET metrics from individual lesions at every timepoint. Cox proportional hazard regression analyses were conducted to evaluate associations between imaging metrics and PFS. Results: Median PFS was 8.3 months (range 1.0-30.3+). The strongest predictor of PFS in univariate analysis was total functional burden (SUVtotal) (P < 0.0001) during treatment for all patients. Predictors of PFS differed between both treatment cohorts of patients (Table 1), including number of lesions, fraction of skeletal involvement, and average lesion activity (SUVmean). Maximum PSA benefit (percent decrease) during the first 12 weeks of therapy was highly predictive of PFS in the AR-directed cohort of patients (HR = 1.012 , P = 0.0005), as was change in the number of lesions (HR = 1.01, P = 0.03). Conclusions: There is indication thattotal functional burden of disease during treatment with taxane or AR-directed therapy is a strong predictor of PFS. In addition, change in number of lesions was predictive of treatment efficacy. This supports ongoing development of NaF PET/CT based imaging biomarkers in mCRPC. Clinical trial information: NCT01516866. [Table: see text]
Outcomes and patient-related reported urinary toxicity of low dose rate brachytherapy for localized prostate cancer.
Authors: Meeks Marshall , Michalski Jeff M. , Markovina Stephanie Subasic , DeWees Todd A. 
Published: February 2017

29 Background: Brachytherapy (BT) is a common treatment modality for localized prostate cancer (LPCa). Here we report our institutional outcomes and patient-reported genitourinary (GU) toxicity following BT for LPCa. Methods: Medical records of patients with LPCa treated with low dose rate (LDR) BT at our institution from 1997-2011 were reviewed. BT prescriptions were 145 Gray (Gy) and 109Gy for mono- and combined iodine 125 (125I) therapy, and 125Gy and 100Gy for mono- and combined palladium 103 (103Pd) therapy. Biochemical failure was defined by the Phoenix definition. Kaplan Meier curves were used to compare biochemical relapse-free survival (bRFS), metastasis-free survival (MFS), and overall survival (OS). Patient-reported GU toxicity was evaluated by the American Urological Association Symptom Score (AUAS), and results binned into three time intervals, 1, 6, and 12 months post-BT. Repeated measures analysis determined a trend in AUAS score over time. Effect of age as a continuous variable, prostate specific antigen, Gleason score, clinical T stage, combined external beam radiotherapy + BT and use of neoadjuvant androgen deprivation therapy (nADT) on AUAS score was determined. Results: Of 459 patients identified, 400 received BT monotherapy and 8% received nADT. Median follow-up was 5.8 years. Nine-year bRFS, MFS, and OS were 92.8%, 97.9%, and 79.7%. Pretreatment AUAS scores were available for 252 patients. For 69 patients with all four values, median baseline AUAS scores rose from 6 to 14 at one month following BT (p < 0.0001). AUAS scores did not change from one-month to 6 months post-BT (p = 0.99), but decreased to a median of 8 (p < 0.0001) by 12 months post-BT. In the 69 patients with all values, no factors were found significant for change in AUAS scores. For 252 patients with pre-treatment AUAS and at least one additional value (assuming values missing at random), analysis revealed older age and use of nADT were associated with higher AUAS scores at all time points. Conclusions: LDRBT for LPCa offers excellent bRFS, MFS, and OS. AUAS scores rose in the first 6 months following BT but returned to pre-treatment baseline by 12 months post-BT. Older age and nADT use may be associated with higher AUAS scores.
A drug-drug interaction (DDI) study to assess the effect of oral galeterone on the pharmacokinetics (PK) of oral midazolam.
Authors: Ferrante Karen J. , Jacoby Douglas B , Sonnichsen Daryl 
Published: February 2017

316 Background: Galeterone (gal) is a semisynthetic steroid that targets androgen receptor (AR) signaling via increased AR protein degradation, inhibition of CYP17 activity, and inhibition of androgen binding to AR. Gal is a novel potential treatment for prostate cancer. In vitro, gal competitively inhibits CYP3A4 (IC50 = 5.5 μM; midazolam as substrate). This clinical study evaluated whether multiple daily doses of gal alter the single-dose PK of midazolam, a sensitive probe substrate for functional CYP3A4 intestinal and hepatic activity. Methods: In an open-label, fixed sequence, DDI study, 18 healthy male volunteers received midazolam 2 mg Day 1 and Day 5 and gal 2550 mg Days 2-5. Midazolam plasma PK was determined on Days 1 and 5. The effect of gal on the natural log-transformed Cmax, AUC0-inf, and AUC0-t of midazolam was assessed with a linear mixed-effects model; point estimates for geometric means, geometric mean ratios with 90% confidence intervals were determined. Safety was also monitored. Results: The Tmax of midazolam was not altered by gal coadministration. The < 2-fold increases in midazolam Cmax and AUCs were statistically significant. For Cmax, the point estimate of the geometric least squares (LS) mean ratio between the 2 treatments was 1.25 (90% CI: 1.05, 1.48). Higher ratios were observed for the AUC ratios, with LS mean ratio for AUC0-t of 1.57 (90% CI: 1.43, 1.73) and for AUC0-inf of 1.58 (90% CI: 1.42, 1.75). The mean midazolam t1/2 was approximately 76% higher with gal coadministration. Multiple doses of gal were well tolerated with no apparent effect on the safety of midazolam. Conclusions: Per FDA guidance, < 2-fold increases in midazolam Cmax and AUCs observed with gal coadministration support its classification as a weak inhibitor of CYP3A4. Given the similar or higher in vitro IC50’s for CYP2C8 and CYP2C19, respectively, a comparable or lesser degree of enzyme inhibition is expected for gal 2550 mg daily. Based on these results, concurrent CYP3A4, CYP2C8, and CYP2C19 substrates are not contraindicated in patients taking gal; caution is advised in patients receiving or initiating sensitive CYP3A4, CYP2C8, and CYP2C19 substrates, especially those with a narrow therapeutic range.
Application of abiraterone acetate (AA) in chemo-naïve metastatic castration-resistant prostate cancer (mCRPC) patients who did not fulfil the patient inclusion criteria in the COU-AA-302 study.
Authors: Poon Darren M. C. , Kuen Chan , Lee S.H. , Chan T.W. , Sze Chun-Kin , Lee Ka Chai , Lam Daisy , Ting Chan Fong 
Published: February 2017

317 Background: Visceral metastases or poor performance status (ECOG 2 or above) were the major exclusion criteria in the COU-AA-302 study, and hence the efficacy of abiraterone acetate (AA) in chemo-naïve mCRPC patients with these characteristics remain undetermined. Our study compares the clinical efficacy of AA in chemo-naïve mCRPC patients with or without the aforementioned characteristics. Methods: The clinical records of chemo-naïve mCRPC patients from all 6 public oncology centers in Hong Kong between August 2011 and December 2014 were reviewed. Patients with visceral disease who were medically unfit for, or who declined, chemotherapy, were allowed for AA in the study period. The median overall survival (OS), progression-free survival (PFS), patient and disease characteristics were compared between groups which satisfied, and did not satisfy, the inclusion criteria of COU-AA-302 study. Results: Fifty-eight consecutive chemo-naïve mCRPC patients had received AA in the review period, of which 29 fulfilled the inclusion criteria for the COU-AA-302 study (Group Eligible). All the remaining patients (Group Ineligible) had ECOG 2 or above, including 3 who had non-nodal visceral metastases. Group Ineligible had higher baseline PSA, haemoglobin and alkaline phosphatase level than Group Eligible, but otherwise there was no significant difference in the baseline characteristics between the groups for age, Gleason score, and co-morbidities. Group Ineligible had significantly shorter OS than Group Eligible (7.7 vs 25.0 months, p = 0.0095) and also a shorter PFS that did not reach statistical significance (5.3 vs 9.8 months, p = 0.2936). The duration of use of AA, and frequency of employment of post-AA treatment were comparable between the groups. Conclusions: Our study demonstrated a poor efficacy of AA in chemo-naïve patients who did not fulfil the inclusion criteria for COU-AA-302 study, by virtue of poor performance status or presence of visceral metastases. The impact of AA in this group of patients warrants further examination in clinical trials before its routine clinical use in this subgroup.
Changing characteristics of patients treated with sipuleucel-T (sip-T) over time: Real-world experience from the PROCEED registry.
Authors: Armstrong Andrew J. , Higano Celestia S. , Sartor A. Oliver , Vogelzang Nicholas J. , Berry William R. , Penson David F. , Kassabian Vahan , Nordquist Luke T. , Chang Nancy N. , LIll Jennifer Susan , Cooperberg Matthew R. 
Published: February 2017

320 Background: Sip-T is an autologous cellular immunotherapy approved by the FDA for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. PROCEED (NCT01306890) is a phase 4 registry evaluating men receiving sip-T therapy in the US. Patient characteristics and treatment trends were assessed from 2011 to 2013, when several agents with an overall survival benefit became commercially available. Methods: For patients enrolled from 2011 to 2013, baseline patient and disease characteristics at the first sip-T infusion, trends in prior therapy, and pre–sip-T baseline prostate-specific antigen (PSA) levels were examined year over year. Results: From 2011 to 2013, 1902 patients were enrolled and received ≥ 1 sip-T infusion: 2011, n = 145; 2012, n = 967; 2013, n = 790. During this time period, enrollment of African American men nearly doubled from 6.9% to 13.4%, and central venous catheter use to facilitate sip-T infusion decreased (from 53.8% to 44.1%). Median baseline lactate dehydrogenase (LDH) levels and the number of lymph node metastases also decreased as well as median baseline PSA values (17.8 ng/mL to 11.9 ng/mL [P = 0.002]). Prior use of first-generation anti-androgens (from 73.1% to 60.5%), ketoconazole (17.2% vs. 6.3%), and estrogen (4.8% vs. 1.6%) decreased along with prior docetaxel use (19.3% vs. 7.5%). In contrast, prior investigational use of abiraterone acetate (from 3.4% to 8.9%) and enzalutamide (1.4% vs. 3.2%) increased over time. Conclusions: Over the duration of PROCEED, the decrease in baseline PSA, lower LDH, fewer nodal metastases, and decline in prior docetaxel use suggest that sip-T is being used earlier in the course of metastatic castration-resistant disease. Moreover, second-line hormonal therapy use with agents that do not improve overall survival appears to be substituted by therapies that do. This decrease in second-line hormonal therapies during PROCEED could suggest a real-world preference for earlier sip-T use. Clinical trial information: NCT01306890.
Simulation in oncologic care: Advancing evidence-based decisions in the management of metastatic castration resistant prostate cancer.
Authors: Herrmann Tara , Warters Martin , Blevins Douglas 
Published: February 2017

322 Background: A considerable proportion of prostate cancer cases among men progress to mCRPC. As a result, appropriate treatment selection and sequencing is crucial to maximizing patient outcomes. A study was conducted to determine if simulation-based educational interventions to address underlying clinical practice gaps could improve clinical decisions of oncologists in the management of mCRPC. Methods: A cohort of US-practicing oncologists who participated in online simulation-based education was evaluated. The intervention consisted of two cases presented in a platform that allowed learners to assess the patient and choose from an extensive database of diagnostic and treatment possibilities matching the scope and depth of actual practice. Clinical decisions made by participants were analyzed using a decision engine, and instantaneous clinical guidance employing current evidence-based and expert faculty recommendations was provided at each decision point. Participant decisions before and after clinical guidance were compared using a 2-tailed paired T-test to provide p-values for assessing the impact of simulation-based education on the clinical decisions made by participants between 2/25/2014 and 9/12/2014. Results: The assessment sample consisted of 107 oncologists who made clinical decisions within the simulation. As a result of clinical guidance, significant improvements were observed in: a) Selection of an evidence-based regimen that included mCRPC targeted therapy (17%, p = 0.027) and treatment for bone metastases (26%, p < 0.0001), in an individual with a 6-year history of prostate cancer whose disease presented with bone metastasis; and b) Starting a bone resorption inhibitor (25%, p < 0.001) and switching mCRPC therapies (28%, p < 0.001) in a patient whose PSA levels were rising despite treatment. Conclusions: This study showed improvements in clinical decisions of oncologists in selecting evidence-based therapeutic regimens for patients with mCRPC. This study demonstrates that online, simulation-based instruction can result in an increase in appropriate clinical decisions, and may play a role in improving the quality of care and patient outcomes.
Long-term outcomes and predictive factors in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) showing abiraterone withdrawal syndrome (AWS) after docetaxel (DOC) treatment.
Authors: Caffo Orazio , Maines Francesca , Trentin Chiara , Veccia Antonello , Galligioni Enzo 
Published: February 2017

324 Background: AWS has been rarely described as a possible PSA reduction, with or without radiological responses, observed after abiraterone acetate (AA) suspension due to disease progression. According to this possibility, all pts progressing under AA were usually monitored for at least 4 wks to evaluate if they developed AWS; if PSA decreased, the subsequent treatment was delayed until the occurrence of biochemical and/or radiological progression. The present study is aimed to assess long-term outcomes and predictive factors in DOC pre-treated mCRPC pts experiencing AWS. Methods: We evaluated a consecutive series of 73 pre-treated mCRPC pts, who received AA in our Hospital after DOC failure: all pts were treated with AA 1,000 mg po + prednisone 10 mg po daily; the treatment continued until progression disease (PD) which required to be confirmed by imaging. For each pt we have recorded the pre and post-AA clinical history, the treatment details and outcomes. All pts stopped AA due to progressive disease and AWS was defined by PSA reduction ≥ 25%, compared to the AA-end values, observed in the first month after AA stop. A logistic regression analysis was performed in order to assess the ability of a series of 18 selected clinical factors to predict AWS. Results: AWS was observed in 7 pts (9.5%) with a median duration of 17 wks (range 9-33). Two pts undergoing the 3-monthly radiographic restaging showed an objective response. A significant difference in terms of post-AA median OS was observed between AWS- and AWS+ pts (3.6 vs 27.9 mos; p = 0.02); this differences was confirmed by 1-month landmark analysis (4.6 vs 27.9 mos; p = 0.03). Among the factors, only the absence of pain at AA therapy baseline was able to predict the AWS: 100% of AWS+ pts were asymptomatic, compared to 64.6% of AWS- pts (p = 0.04). Conclusions: Despite AWS remains an unpredictable and rare phenomenon, it could represent a chance to delay the start of subsequent therapeutic line after AA failure. Moreover, our results seem to suggest that the occurrence of AWS may have a positive impact on the OS of mCRPC pts.
Activity of new agents (NAs) as third-line treatment in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) after a long-term disease control (LTDC) with abiraterone acetate (AA) or enzalutamide (ENZ) post docetaxel (DOC): Preliminary results from a multicenter Italian study.
Authors: Veccia Antonello , De Giorgi Ugo , Facchini Gaetano , Fratino Lucia , Gasparro Donatello , Alesini Daniele , Basso Umberto , Tucci Marcello , Ortega Cinzia , Scagliarini Sarah , Verderame Francesco , Lo Re Giovanni , Procopio Giuseppe , Sabbatini Roberto , Campadelli Enrico , Zucali Paolo Andrea , Morelli Franco , Sartori Donata , Conteduca Vincenza , Caffo Orazio 
Published: February 2017

325 Background: Although the expected median progression free survival (mPFS) with AA and ENZ in DOC-pretreated pts is 6-8 mos, a quote of pts may experience a LTDC without progression of disease (PD) for more than 12 mos. Since the androgen receptor machinery remains the ultimate target of NAs in mCRPC post-DOC, some mechanisms of resistance could be common to all NAs. This may be crucial in planning their sequential use, mainly when a LTDC is observed in hormone NAs-based (HNAs) second line. The present study was aimed to assess the activity of NAs in pts who previously showed a LTDC with HNAs administered after DOC. Methods: We collected data of pts who received sequentially two NAs after DOC in 38 Italian hospitals. For each pt we recorded the clinical outcome of all treatments received after DOC. For the study purpose, LTDC was defined as the absence of PD ≥ 12 mos in pts treated with second-line AA or ENZ. Results: A consecutive series of 291 mCRPC pts, median age 71 yrs (46-91), with bone (88%), nodal (53%) or visceral (18%) mets, was collected. All pts received NAs as second line after DOC: in particular 160 (55%) received AA and 32 (11%) ENZ, with 41 pts (21%) showing a LTDC (36 AA – 5 ENZ). Among LTDC pts, third line treatment was cabazitaxel (CABA) in 25 cases and one hormonal NA in the remaining (2 AA - 14 ENZ). The clinical outcomes of the third line therapy are detailed in the table. Conclusions: From this preliminary data, it appears that third line CABA could be slightly more active in pts achieving a LTDC with HNAs in second line LTDC, despite the clinical outcomes were not significantly different compared to HNAs. Analyses on larger patients populations are needed to confirm these findings. [Table: see text]