bluuebunny/crossref_metadata_2025_split huggingface dataset:
A genomic classifier to identify men with adverse pathology post radical prostatectomy who benefit from adjuvant radiation therapy.
Authors: Den Robert Benjamin , Yousefi Kasra , Trabulsi Edouard John , Abdollah Firas , Choeurng Voleak , Feng Felix Yi-Chung , Dicker Adam , Lallas Costas D. , Gomella Leonard G. , Davicioni Elai , Karnes R. Jeffrey 
Published: February 2017

168 Background: The optimal timing of postoperative radiotherapy following radical prostatectomy (post-RP RT) is unclear. We hypothesized that a genomic classifier (GC) would provide prognostic and predictive insight into the development of clinical metastases in men receiving post-RP RT and inform decision-making. Methods: GC scores were calculated from 188 patients with pT3 or margin positive PCa, who received post-RP RT at Thomas Jefferson University and Mayo Clinic, between 1990 and 2009. The primary endpoint was clinical metastasis. Prognostic accuracy of the models were tested using c-index and decision curve analysis. Cox regression tested the relationship between GC and metastasis. Results: The cumulative incidence of metastasis at 5 years post-RT was 0%, 9%, and 29% for low, average, and high GC scores, respectively (p=0.002). In multivariable analysis, GC and pre-RP PSA were independent predictors of metastasis (both p<0.01). Within the low GC score (<0.4), there were no differences in the cumulative incidence of metastasis comparing those who received adjuvant or salvage RT (p=0.79). However, for patients with higher GC scores (≥0.4) cumulative incidence of metastasis at 5-year was 6% vs. 23% for patients treated with adjuvant vs. salvage RT (p<0.01). Conclusions: In patients treated with post-RP RT, GC is prognostic for the development of clinical metastasis beyond routine clinical/pathologic features. Though preliminary, patients with low GC are best treated with salvage radiation, while those with high GC benefit from adjuvant therapy. These findings provide the first rationale selection of timing of post-RP RT.
Quantitative bone scan lesion area as an early surrogate outcome measure indicative of overall survival in metastatic castration-resistant prostate cancer.
Authors: Brown Matthew S. , Kim Hyun J. , Chu Gregory H. , Allen-Auerbach Martin , Fischer Cheryce , Levine Benjamin , Gupta Pawan , Schiepers Christiaan , Goldin Jonathan 
Published: February 2017

179 Background: Bone Scan Lesion Area (BSLA) is a biomarker that can be computed semi-automatically from whole-body scintigraphic imaging as a measure of overall bone tumor burden. Initial development and validation, including correlation with outcomes, was performed in trial cohorts from a single drug treatment with controls in subjects with metastatic castrate-resistant prostate cancer (CRPC). A 30% increase/decrease in BSLA was defined as progression/response on bone scan. We hypothesize that, when applied to an independent treatment trial cohort with a different mechanism of drug action, baseline BSLA and Week 12 change post-treatment are predictive of a subject's overall survival. Methods: From an anonymized imaging research database a cohort of 198 CRPC subjects was identified who enrolled in a treatment trial (127 treated, 71 placebo). This cohort was independent of those used for biomarker development and initial validation, and involved a different mechanism of drug action. Subjects underwent standard of care whole-body bone scintigraphy with 99mTc-Methyl diphosphonate (99mTc-MDP). BSLA was calculated at baseline and response at Week 12. Multivariate Cox regression was used to test whether (1) baseline BSLA, and (2) early changes in BSLA (12 weeks post treatment) were predictive of overall survival. Results: BSLA < 2000 mm2 at baseline was a prognostic factor (HR=0.6; p=0.003) and predictive of longer survival (HR=0.4; p<0.001). Subjects without PD by BSLA at Week 12 had significantly longer survival than subjects with PD: median 170 days vs. 186 days in the placebo group and 260 days vs. 392 days in the treatment group. The overall survival rates between non-PD and PD subjects were statistically different (HR=0.64, p=0.007). Conclusions: BSLA is calculated semi-automatically from bone scans and provides a quantitative and objective treatment response assessment. Baseline BSLA and early changes post treatment were found to be predictive of overall survival in patients with metastatic castration-resistant prostate cancer. BSLA has now been demonstrated to be an early surrogate outcome for overall survival in different drug treatments.
Real-world use of epic for clinical practice (EPIC-CP) to assess patient-reported prostate cancer quality of life in the clinical setting.
Authors: Chang Peter , Carneiro Arie , Dovirak Ostap , Taylor Kimberly , Crociani Catrina , Sanda Martin G. , Percy Andrew , McAnally Kyle , Wagner Andrew A 
Published: February 2017

18 Background: Prostate cancer practitioners tend to underestimate patients’ treatment-related side effects. We developed the Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) to facilitate patient-reported health-related quality of life (HRQOL) assessment at the point-of-care (Chang P et al, J Urol Sep 2011). We sought to demonstrate the feasibility of EPIC-CP use in routine clinical care, and to compare longitudinal patient-reported and practitioner-reported prostate cancer outcomes. Methods: We reviewed practitioner- and patient-reported HRQOL outcomes in 482 patients who underwent radical prostatectomy at our institution from 2010 to 2014. All EPIC-CP questionnaires were administered and interpreted without research personnel. Practitioner-reported outcomes were assessed using chart review. We used the paired t-test and Wilcoxon signed-rank test to compare pre- and post-treatment EPIC-CP domain scores, and Fisher’s exact test to compare patient-reported and practitioner-reported outcomes. We considered p-values < 0.05 statistically significant. Results: 708 total EPIC-CP questionnaires were completed. Mean urinary incontinence domain scores increased (worsened) significantly from baseline (0.6±0.2) to 3 (3.1±2.3) and 6 months (2.2±2.1) post-treatment, but were not statistically changed from baseline at 12 months (1.6±1.7). Patient-reported incontinence pad-free rates using EPIC-CP at 3, 6, and 12 months were 47%, 76%, and 78%, respectively, which were consistent with practitioner-reported rates. Mean sexual domain scores were significantly worse at 12 months (5.9±3.3) compared to baseline (2.4±2.8). Practitioners significantly overestimated the rate of functional erections compared to patients’ EPIC-CP-reported rates at 3 months (18% vs 12%, p < 0.05) and 12 months (45% vs 23%, p < 0.05). Bowel and vitality/hormonal scores were unchanged, and urinary irritation/obstruction scores improved after surgery. Conclusions: EPIC-CP is feasible to use in the routine clinical care of prostate cancer patients, and can help practitioners more accurately assess patients’ post-treatment symptom severity.
External beam radiation therapy (EBRT) use and safety with radium-223 dichloride (Ra-223) in patients (pts) with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases (mets) from the ALSYMPCA trial.
Authors: Finkelstein Steven E. , Michalski Jeff M. , O'Sullivan Joe M. , Parker Chris , Garcia-Vargas Jose E. , Sartor A. Oliver 
Published: February 2017

182 Background: In ALSYMPCA, Ra-223, a first-in-class α-emitter, improved overall survival and delayed time to first symptomatic skeletal event vs placebo (pbo). This post hoc analysis evaluated safety and efficacy of Ra-223 plus EBRT. Methods: Pts had symptomatic (recent EBRT for bone pain or any regular analgesic use) CRPC with ≥ 2 bone and no visceral mets; best standard of care; and prior docetaxel (pD) or were unfit for or declined docetaxel (no pD). Pts were stratified by pD use (yes/no), baseline total alkaline phosphatase level (tALP; < 220 U/L or ≥ 220 U/L), and current bisphosphonate (bp) use (yes/no) and randomized 2:1 to 6 Ra-223 injections (50 kBq/kg IV q 4 wk) or pbo. EBRT for bone pain was permitted within 12 weeks prior to randomization and during study. Baseline pain by prior EBRT, time to first on-study EBRT use for bone pain, and adverse events (AEs) by concomitant EBRT (cEBRT) were analyzed. Results: Pts with no prior EBRT had less pain at baseline; a WHO pain score ≤ 1 (no opioid use) was present in 46% (355/724) of pts with no prior EBRT vs 36% (53/147) of pts with prior EBRT. Ra-223 vs pbo significantly reduced EBRT use in the overall population (HR = 0.67, P = 0.001) and in pts with ≤ 20 bone mets (HR = 0.49, P < 0.001), current bp use (HR = 0.47, P = 0.004), tALP < 220 U/L (HR = 0.66, P = 0.008), and no pD (HR = 0.65, P = 0.038). At 6 months, the percentage of Ra-223 pts requiring EBRT was similar for prior and no prior EBRT subgroups (24% vs 20%), increasing at 12 months (38% vs 29%). cEBRT did not affect Ra-223 safety, and myelosuppression was low (Table). Conclusions: cEBRT did not adversely affect Ra-223 hematologic safety. Ra-223 significantly reduced risk of EBRT use. In Ra-223 pts, prior EBRT did not appear to affect later EBRT use. Clinical trial information: NCT00699751. [Table: see text]
Association of changes in measurable disease by RECIST with survival in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Sonpavde Guru , Pond Gregory Russell , Templeton Arnoud J. , Petrylak Daniel Peter , Tombal Bertrand F. , Rosenthal Mark , Tannock Ian 
Published: February 2017

186 Background: In men with mCRPC receiving chemotherapy, measurable disease response by World Health Organization criteria has been demonstrated to be prognostic for overall survival (OS). We aimed to explore the association of changes in measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) with OS. Methods: Data from the control arm (n=612) of the phase III VENICE trial receiving docetaxel plus prednisone combined with placebo were available. Data on baseline clinical and laboratory variables were obtained in addition to outcome measures: best RECIST 1.0 response, PSA response and OS. Cox proportional hazards regression was used to evaluate the prognostic ability of RECIST-defined changes for OS using a 90-day landmark analysis. Results: 363 of 612 patients (59.3%) had measurable lesions, of whom 296 were evaluable for landmark analysis. 28 (9.5%) had progressive disease (PD) prior to day 90, while 58 (19.6%) had unconfirmed partial response (PR), i.e. declines ≥30% of the sum of diameters of target lesions. Median OS beyond day 90 for men with PR, stable disease (SD), and PD was 28.3, 23.3, 11.4 months, respectively (P < 0.001). In a multivariable analysis adjusting for pain, PCWG-2 subtype, type of progression (PSA vs. other), Gleason Score (≤ 7 vs. > 7), PSA, derived neutrophil-lymphocyte ratio, ECOG performance status and alkaline phosphatase, the hazard ratio (HR) for OS for patients with PR was 0.64 (95% CI 0.42 – 0.99, P = 0.045) compared to those without PR, and 1.78 (95% CI 1.07 – 2.95, P = 0.026) for those with PD compared to those without PD. PD remained significant (HR = 1.85, 95% CI 1.10 – 3.12, P = 0.020) after adjusting for PSA changes, but PR (P = 0.14) did not. Conclusions: In men with mCRPC receiving first-line docetaxel-based chemotherapy PR and PD by RECIST 1.0 within 90 days were associated with longer or shorter OS, respectively. Given the more frequent detection of measurable disease with current imaging, the accrual of patients with measurable tumors in phase II trials to assess RECIST changes may provide an objective signal of efficacy of new drugs.
Everolimus plus bicalutamide for castration resistant prostate cancer (CRPC): Bench to bedside and back.
Authors: Chow Helen , Ghosh Paramita , D'Abronzo, Leandro S , de Vere White Ralph , Dall'Era Marc , Evans Christopher P. , Yap Stanley A , Lara Primo , Pan Chong-Xian 
Published: February 2017

189 Background: We previously reported that the mammalian target of rapamycin (mTOR) pathway was upregulated in CRPC, and that simultaneous blockade of both androgen receptor (AR) and mTOR pathways synergized in killing CRPC cells. Methods: Eligible patients (pts) must have progressive CRPC with serum testosterone <50 ng/dl. No prior bicalutamide (except to prevent flare) or everolimus was allowed. Treatment regimen included daily bicalutamide 50 mg and everolimus 10 mg orally. Primary endpoint was prostate specific antigen (PSA) response (defined as ≥30% reduction). Sample size of 23 pts would have the power of 0.8 and alpha error of 0.05 (one-sided) if the combination had a PSA response rate of 50% vs. a historical rate of 25% with bicalutamide alone. Molecular correlative studies including serum ERBB3 levels were performed by ELISA. LNCaP and C4-2 cells, modeling bicalutamide-sensitivity and resistance, respectively, were transfected with ErbB3 or an empty vector and subjected to western blotting. Results: Of 24 pts enrolled, the mean number of treatment cycles was 7.9 (1.0-23.0). Eighteen pts had a PSA response (75%, 95% CI: 0.53-0.90). Median overall survival was 28 months (95% CI 14.1-42.7). Fourteen pts (54%, 95% CI 0.37, 0.78) developed Grade 3 (13 pts) or Grade 4 (1 pt with sepsis) adverse events attributed to study treatment. Pts with partial response showed a greater decline in ErbB3 (P=0.037) compared to those with stable disease or disease progression. Consistent with these findings, everolimus induced a decline in ErbB3 in hormone-sensitive LNCaP cells but failed to affect ErbB3 in CRPC C4-2 cells, which expressed 8-fold higher levels of ErbB3. Increased expression of ErbB3 in LNCaP cells resulted in resistance to everolimus, whereas bicalutamide initially prevented this effect. Prolonged exposure to bicalutamide also resulted in an increase in ErbB3 which correlated with increased growth rates and cell invasion. Conclusions: The combination of bicalutamide and everolimus has very encouraging efficacy in men with bicalutamide-naïve CRPC, but with substantial everolimus-related toxicity. ERBB3 may contribute to resistance and deserves further study. Clinical trial information: NCT00814788.
Adjuvant radiotherapy versus wait-and-see strategy for pathologic T3 or margin-positive prostate cancer: A meta-analysis.
Authors: Shaikh Mohammad Parvez , Harkenrider Matthew M. , Wu Meng-Jia 
Published: February 2017

19 Background: Optimal management after radical prostatectomy (RP) remains controversial in patients with pathologic T3 or margin-positive prostate cancer with the options being early adjuvant radiotherapy (ART) versus wait-and-see (WS). Methods: A comprehensive Medline search to identify randomized controlled trial (RCT) of ART vs WS was done. Synthesized results from the included studies show Metastasis-Free Survival (MFS) and overall survival (OS) rates at 10 years as well as Grade 2 or greater GI and GU toxicities in the studies. Results were based on the random-effect (RE) model if there was evidence of between-trial heterogeneity, otherwise the fixed-effect (FE) model was used. Results: A total of 3 RCTs (ARO9602/AUO AP09/95, EORTC22911, SWOG8794) were identified with 1,737 patients (ART: n=864, WS: n=873). 10-year estimates of MFS and OS rates were reported for SWOG and EORTC studies, and estimated for ARO 96-02/AUO AP09/95 study from their Kaplan-Meier curves (Table). Pooled 10-year MFS data showed a significant improvement with ART vs WS (OR= 0.77; 95% CI 0.62–0.96, p=0.02, FE). However, pooled 10-year OS was not significantly different (OR= 0.98; 95% CI 0.64–1.49, p=0.91, RE). Grade 2 or greater GI toxicity was reported by all three studies and was significantly higher in ART (2.5%) compared with WS (1.1%), p=0.04. Grade 2 or greater GU toxicity was reported by ARO9602 and EORTC studies and was significantly higher in ART (17.1%) compared with WS (10.3%), p=0.0004. Conclusions: 10-year MFS is significantly improved with ART compared with WS. No benefit in 10-year OS was found. Grade 2 or greater GI and GU toxicities where greater in ART compared with WS. [Table: see text]
3-year safety follow-up of radium-223 dichloride (Ra-223) in patients (Pts) with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases (Mets) from ALSYMPCA.
Authors: Parker Chris , Vogelzang Nicholas J. , Sartor A. Oliver , Coleman Robert E. , Fang Fang , Skjorestad Irene , Nilsson Sten 
Published: February 2017

195 Background: In ALSYMPCA, the first-in-class α-emitter Ra-223 had a highly favorable safety profile and was well tolerated. Safety monitoring of Ra-223 is essential for a complete safety profile. Here are final safety data including long-term follow-up safety 3 years after last pt’s first injection (inj). Methods: Pts received 6 inj and entered designated follow-up from 4 wks after their last inj to 3 years after first inj. Pts were to be evaluated during tx period and 9 follow-up visits. All adverse events (AEs) were collected until 12 wks after last inj; thereafter, only AEs deemed tx-related were collected. Additional long-term safety data were assessed by specific diseases including acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia, and new primary cancer in bone or other organs. Results: Safety population (pts receiving ≥ 1 inj) included 901 pts (Ra-223, n = 600; placebo [pbo], n = 301); 572 pts (Ra-223, n = 405; pbo, n = 167) entered follow-up. 60 pts (Ra-223, n = 49; pbo, n = 11) completed all follow-up visits. Overall, 564 (94%) Ra-223 and 292 (97%) pbo pts had ≥ 1 tx-emergent AE (Table). During long-term follow-up, there were no reports of AML, MDS, or new primary bone cancer. New primary cancers in other organs were reported: 2 Ra-223 (1 bladder, 1 lymph node mets), 3 pbo (2 skin, 1 adenocarcinoma rectum and sigmoideum), and 2 pbo cross-over pts (1 skin, 1 meningioma). Aplastic anemia was reported in 1 Ra-223 pt. Conclusions: Ra-223 remained safe and well tolerated 3 years after the last pt’s first inj. No major safety issues were identified during the ALSYMPCA 3-year long-term follow-up. Clinical trial information: NCT00699751. [Table: see text]
Androgen deprivation with or without radiation therapy for clinically node-positive prostate cancer.
Authors: Efstathiou Jason Alexander , Lin Chun Chieh , Gray Phillip John , Jemal Ahmedin 
Published: February 2017

198 Background: Clinically lymph node positive (cN+) prostate cancer (PCa) is an often fatal disease. Its optimal management remains largely undefined given a lack of prospective, randomized data to inform practice. We sought to describe modern practice patterns in the management of cN+ PCa and assess the effect of adding radiation therapy (RT) to androgen deprivation therapy (ADT) on survival using the National Cancer Data Base. Methods: Patients with cN+ PCa with no distant metastases diagnosed between 2004-2011 were included. Five-year overall survival for patients diagnosed between 2004-2006 and treated with ADT alone or ADT+RT were compared. Propensity score (PS) matching was used to balance baseline characteristics and Cox multivariate regression analysis was used to estimate hazard ratios (HRs) for all-cause mortality. Results: 3,540 patients were included. 32.2% were treated with ADT alone and 51.4% received ADT+RT. Patients aged <65, those with private insurance, lower comorbidity scores, higher Gleason scores, and lower PSA values were significantly more likely to receive ADT+RT (p<.05). After PS matching, 318 patients remained in each group. Compared to ADT alone, ADT+RT was associated with a 50% decreased risk of five-year mortality (HR: 0.497, 95% CI: 0.37-0.67, p<.001). Conclusions: Using data recorded in a large national database, we have identified a significant survival benefit for patients with cN+ PCa treated with ADT+RT. These data, if appropriately validated, suggest that a significant proportion of such patients at high risk for prostate cancer death may be undertreated warranting a re-evaluation of current practice guidelines.
Prognostic significance of the PSA nadir after salvage radiotherapy following radical prostatectomy in prostate cancer.
Authors: Wiegel Thomas , Bartkowiak Detlef , Bottke Dirk , Siegmann Alessandra , Budach Volker , Hinkelbein Wolfgang 
Published: February 2017

207 Background: Salvage radiotherapy (SRT) is a curative approach in recurrent prostate cancer after radical prostatectomy. The outcome depends on various parameters. We report the long term results of SRT with special respect to the course of PSA after SRT. Methods: Between 1997 and 2007, 307 patients received SRT with 66.6 (N=240) or 70.2 Gy (N=67) using CT-based 3D planning. The median pre-SRT PSA was 0.297 ng/ml. Post-SRT progression was defined as either PSA rising >0.2 ng/ml above nadir, or hormone treatment, or clinical recurrence. Data were analyzed with the Kaplan-Meier method (Logrank-test) and with multivariate Cox regression. Results: Patients were followed up for median 7.2 (max. 14.4) years. Recurrence occurred in median 9.4 months post-RP. In 112 patients, SRT was administered before their PSA reached 0.2 ng/ml, 195 men were above that threshold. After SRT, 222 patients achieved a PSA nadir <0.1 ng/ml, 85 retained higher values. SRT given at a PSA <0.2 ng/ml correlated with achieving a post-SRT nadir <0.1 ng/ml (p<0.0001) and with improved freedom from progression (p=0.0133). Men with a post-SRT nadir <0.1 ng/ml (undetectable range) had significantly less recurrences (p<0.0001) and a better overall survival (p=0.0248). In multivariate analysis of pre-SRT parameters, pT≥3, Gleason Score ≥7, a post-RP PSA nadir ≥0.1 ng/ml and pre-SRT PSA ≥0.2 ng/ml increased the risk of progression. If failing the post-SRT nadir <0.1 ng/ml was included in the model, then this was the strongest risk factor (hazard ratio 7.93). Conclusions: Our data suggest early salvage RT at a PSA level below 0.2 ng/ml to be a favorable treatment option for post-RP PSA recurrence. It increases the chances of achieving a post-SRT PSA-nadir <0.1 ng/ml, which is associated with an improved outcome in terms of PSA progression and overall survival.