bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II study on stereotactic hypofractionated once-weekly radiation therapy (SHORT) for localized prostate cancer.
Authors: Mallick Indranil , Arunsingh Moses , Prasath Sriram , Arun B , Roy Paromita , Dabkara Deepak , Gupta Sujoy 
Published: March 2017

130 Background: The low α/β ratio of prostate cancer (PrCa) is well established. However, stereotactic hypofractionated radiotherapy (SRT) has been investigated primarily in highly selected patient populations with low-intermediate risk disease. We performed a clinical trial of SRT delivered in once-weekly fractions on an unselected cohort of patients with non-metastatic PrCa. Methods: In this Phase I/II study 30 patients with non-metastatic PrCa (multiparametric MRI cT1-4N0, M0, Gleason 6-10, PSA < = 60 ng/ml) were treated with SRT to a prescription dose of 35Gy in 5 fractions delivered once a week (overall treatment time 29 days). Elective nodal RT at 25Gy/5Fr was delivered in patients high-risk by NCCN criteria, and androgen deprivation therapy given to intermediate and high-risk patients. SRT was planned using volumetric intensity modulated arc therapy (VMAT) or Helical Tomotherapy (HT) with pre-defined dose-criteria. The primary endpoint was acute toxicity NCI CTC v4, and secondary endpoints were biochemical control and late toxicity. Results: Thirty patients completed treatment per-protocol. Stage T3, Gleason 8-10, and PSA > 10 was seen in 18 (60%), 7 (23%) and 24 (80%) respectively. Overall 20 (66.7%) were high-risk. Median of Mean PTV dose was 36Gy, and normal tissue constraints could be met in all patients (Table). Acute urinary toxicities (Gr 0: 1; Gr 1: 27; Gr 2: 1; Gr 3-4: 0) and acute rectal toxicities (Gr 0: 20; Gr 1: 10; Gr 2: 0; Gr 3-4: 0) were very modest. The mean IPSS scores at baseline, end of treatment and 3 months after treatment were 8.8, 14.7, and 9.9. With a median follow up of 23.7 months, the 2 year biochemical control was 96%. Late grade 2 rectal bleeding developed in 1 patient. Conclusions: Carefully planned stereotactic VMAT/HT based once-weekly SRT to a predominantly high-risk non-metastatic PrCa cohort was very well tolerated and found to be safe for clinical use. Preliminary biochemical control and late toxicity profiles are encouraging. Clinical trial information: CTRI/2016/02/006671. [Table: see text]
Impact of proximity to NCI- and NCCN-designated cancer centers on outcomes for patients with prostate cancer undergoing radical prostatectomy.
Authors: Ghaffary Cameron , Dafashy Tamer , Kosarek Christopher David , Duan Zhigang , Chapin Brian F. , Chamie Karim , Kim Simon P. , Fang Justin Edwin , Kerr Preston , Hoffman Karen E. , Giordano Sharon Hermes , Orihuela Eduardo , Williams Stephen Bentley 
Published: March 2017

14 Background: National Cancer Institute (NCI) and National Comprehensive Cancer Network (NCCN)-designated cancer centers (CCs) offer patients state-of-the-art treatment. We sought to identify whether proximity to NCI/NCCN CCs was associated with survival outcomes for prostate cancer patients who undergo radical prostatectomy (RP). Methods: A total of 12,478 total patients diagnosed with clinical stage T1 or T2 prostate cancer between 2004–2011 using linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data were included. Multivariable regression analyses were used to quantify overall survival and use of secondary therapies for RP patients according to proximity to NCI/NCCN CCs. Cox proportional hazards models were used to quantify the association between survival outcomes and access to NCI/NCCN CCs. Results: Patients with proximity to ≥ 2 NCI centers and those diagnosed in 2011 enjoyed a statistically significant overall survival advantage when compared to no access to an NCI center (Hazard Ratio (HR) 0.72; 95% confidence interval (CI) 0.57–0.92, p < 0.01). Proximity to an NCCN CC, when compared with men who did not have access, was associated with improved overall survival (HR 0.76; 95% CI 0.61–0.95, p = 0.015). There was no significant difference in use of secondary therapies according to NCI or NCCN access. Conclusions: Patients who undergo RP with access to an NCI/NCCN CCs experienced improved overall survival with no significant difference in utilization of secondary therapies. Given the need for improved health quality measures in cancer care, these findings may support health policy implementation and regionalization of care to these centers.
Association of changes in circulating cell-free plasma DNA (cfDNA) and circulating tumor cells (CTC) during treatment with clinical outcome from olaparib in castration-resistant prostate cancer (CRPC): Exploratory analyses from the TOPARP-A trial.
Authors: Mateo Joaquin , Mossop Helen , Goodall Jane , Lorente David , Porta Nuria , Carreira Suzanne , Miranda Susana , Zafeiriou Zafeiris , Ralph Christy , Jain Suneil , Jones Robert J. , Hussain Syed A. , Elliott Tony , Protheroe Andrew , Ebbs Berni , Leonard Lorna , Bianchini Diletta , Flohr Penelope , Hall Emma , De Bono Johann S. 
Published: March 2017

141 Background: Response biomarkers are needed to optimize treatment switch decisions in CRPC patients. CTC and cfDNA may have clinical utility as response biomarkers; we studied them during olaparib treatment in a phase II trial in CRCP (Mateo et al NEJM 2015). Methods: CTC were enumerated using CellSearch (Jannsen Diagnostics) and cfDNA was extracted with the QIASymphony circulating DNA kit (Qiagen) from blood samples taken at baseline, 4- and 8-weeks (wk) of therapy. Radiological progression-free survival (rPFS) was defined as time from starting treatment to progression by RECIST 1.1, bone scan (PCWG2) or death. Overall survival (OS) was defined as time from starting treatment to death. CTC changes were categorized based on conversion from ≥ 5 to < 5 CTC/7.5ml blood and on ≥ 30% decline (Lorente et al Eur Urol 2016). cfDNA changes were evaluated as percentage change from baseline (continuous and binary). The prognostic value of CTC and cfDNA changes were assessed by Landmark analysis and Cox models with time-varying covariates; p-value < 0.01 were considered significant to account for multiple tests. Results: Overall, 13/47 (28%) and 16/42 (38%) evaluable patients had a CTC conversion at 4- and 8-wk respectively. A CTC conversion after 4-wk of olaparib associated with longer rPFS (median 8.9 vs 2.7 months [m], p = 0.001); a similar association was found at 8-wk. A 30% CTC decline at 4-wk also associated with longer rPFS (median 4.4 vs 2.6 m, p = 0.004). CTC conversion as a time-varying covariate associated with longer OS (HR 0.26, 95%CI 0.14-0.50, p < 0.001). Median baseline cfDNA was 31.6 ng/ml (IQR 19.4-57.1); 46 and 42 patients were evaluable for cfDNA changes at 4- and 8-wk. Percentage changes in cfDNA at 4- and 8- wk associated with rPFS (HR 1.01 and 1.005; p = 0.005 and 0.002 respectively) but association with OS was not significant. cfDNA declines ≥ 50% at 8- wk associated with longer rPFS (median 8.9 vs 2.7 m, p = 0.007) and OS (17.0 vs 10.1 m, p = 0.004). Conclusions: Decreases in CTC counts and cfDNA concentration associate with improved outcome from olaparib (rPFS, OS) in the TOPARP-A trial. Clinical trial information: NCT01682772.
Seizure rates in enzalutamide (ENZ)-treated men with metastatic castration-resistant prostate cancer (mCRPC) at increased risk of seizure: UPWARD study.
Authors: Slovin Susan F. , Clark William , Carles Joan , Krivoshik Andrew , Wook Park Jung , Wang Fong , George Daniel 
Published: March 2017

147 Background: ENZ is an androgen receptor inhibitor that improved survival in studies of men with mCRPC. Seizure is a risk of ENZ treatment, and patients (pts) with seizure risk factors were excluded in prior studies. In the TRUVEN report (data on file), pts with mCRPC and potential seizure risk factors, but no ENZ exposure, had a seizure rate of 2.8/100 pt-years. The UPWARD study assessed the seizure risk in ENZ-treated pts with mCRPC who had potential seizure risk factors. Methods: This was a global, multicenter, single-arm, open-label safety study. Enrolled pts had ≥ 1 baseline potential seizure risk factor, including medications lowering seizure threshold, stroke, or prior seizure history. Evaluable pts had ≥ 3 months (ms) of treatment with ENZ or ≥ 1 confirmed seizure in a 4-m treatment period. Exclusion criteria included seizure within the past 12 ms and receipt of anti-epileptic medication. Pts received ENZ (160 mg/day). The primary end point was the proportion of evaluable pts with ≥ 1 confirmed seizure during the 4-m treatment period. Results: A total of423 pts received ENZ; 366 were evaluable. Baseline seizure risk factors were medications lowering seizure threshold (n = 242), brain injury (n = 112), and cerebrovascular accident/transient ischemic attack history (n = 94). Four (1.1%) evaluable pts had ≥ 1 confirmed seizure within 4 ms of ENZ initiation. Four (1.1%) pts had a first seizure after 4 ms. The rate of confirmed seizure was 2.6/100 pt-years. 357 pts (84.4%) experienced ≥ 1 treatment-emergent adverse event (TEAE); 141 (33.3%) had ≥ 1 serious TEAE and 29 (6.9%) had ≥ 1 drug-related serious AE. 38 (9.0%) deaths were reported during treatment/within 30 days of discontinuation; four deaths were considered possibly drug related (cerebral hemorrhage, mCRPC progression, sudden cardiac death, and general deterioration). Conclusions: The incidence of confirmed seizures in the UPWARD study is similar to pts with mCRPC and similar risk factors but no ENZ exposure in the TRUVEN report. ENZ was generally well tolerated, and TEAE data are consistent with its known safety profile. These results suggest that ENZ did not increase the risk of seizures in the UPWARD study. Clinical trial information: NCT01977651.
Circulating tumor (ct)-DNA alterations in metastatic castration-resistant prostate cancer (mCRPC): Association with outcomes and evolution with therapy.
Authors: Sonpavde Guru , Nagy Rebecca J , Sartor A. Oliver , Pond Gregory Russell , Gourdin Theodore Stewart , Nandagopal Lakshminarayanan , Ledet Elisa M. , Agarwal Neeraj , Carroll Emma , Naik Gurudatta , Wang Jue , Bilen Mehmet Asim , Grivas Petros , Lanman Richard B. , Talasaz AmirAli , Lilly Michael B. 
Published: March 2017

149 Background: Cell-free ctDNA may be prognostic and evolve following therapy. We report ctDNA profiling of patients (pts) with mCRPC and their association with clinical outcomes and evolution with therapy. Methods: Pts with mCRPC that underwent baseline ctDNA analysis for potentially actionable alterations using Guardant360 before new systemic therapy were identified. Data were requested for clinical factors, current and prior therapy, TTF (time to failure) and survival. A 70-gene cfDNA next generation sequencing panel from a CLIA-licensed, CAP-accredited laboratory (Guardant Health, Inc.) offers complete exon sequencing for 29 genes, critical exons in 39 genes and amplifications (16 genes), fusions (6 genes) and indels (3 genes) harvested from 10 mL of peripheral blood. Alterations were reported and association of alterations with outcomes and prior therapy was examined. Results: Of 514 with confirmed mCRPC, 482 (94%) had ≥ 1 ctDNA alteration. The median age was 70 years (range 39-91). The most common recurrent somatic mutations were in TP53 (36% of patients), AR (22%), APC (10%), NF1 (9%), EGFR, CTNNB1 and ARID1A (6% each) and BRCA1, BRCA2 and PIK3CA (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%) and BRAF (18%). Clinical outcomes were available for 163 pts, of whom 46 (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations was associated with shorter TTF (HR: 1.05, p = 0.026). AR alterations had a trend for shorter TTF (HR: 1.42, p = 0.053) and survival (HR: 2.51, p = 0.09). Pts who received prior therapy had new alterations in AR (56% vs. 37%, p = 0.028) compared to untreated pts. Serial ctDNA profiling of 64 pts revealed the evolution of alterations in AR, BRCA1 and BRCA2 following therapy. Conclusions: ctDNA was frequently detected in patients with mCRPC, and alterations appear similar to tumor tissue alterations. A higher number of overall gene alterations and AR alterations appeared associated with poor clinical outcomes and new AR and BRCA alterations appeared following therapy. These data suggest that developing salvage agents targeting AR alterations and PARP inhibitors hold promise.
Radium-223 (Ra-223) in asymptomatic metastatic castration-resistant prostate cancer (mCRPC) patients treated in an international early access program (iEAP).
Authors: Heidenreich Axel , Gillessen Silke , Heinrich Daniel , Keizman Daniel , O'Sullivan Joe M. , Carles Joan , Wirth Manfred , Miller Kurt , Huang Liping , Seger Monica , Nilsson Sten , Saad Fred 
Published: March 2017

158 Background: Ra-223, a targeted alpha therapy, is currently used to treat mCRPC patients (pts). To investigate Ra-223 when used early in the disease course, we analyzed safety and efficacy in mCRPC pts with no symptoms at baseline treated in an iEAP. Methods: This was a prospective, single-arm phase 3b study of mCRPC pts (malignant lymphadenopathy not exceeding 6 cm was allowed, visceral disease was excluded). Pts received Ra-223, 55 kBq/kg IV, every 4 weeks for up to 6 cycles. Co-primary endpoints were safety and overall survival (OS). Post hoc analyses were performed according to asymptomatic or symptomatic disease status at baseline. Asymptomatic was defined as no pain and no opioid use at baseline. Results: 708 pts received ≥1 Ra-223 injection: 548 (77%) were defined as symptomatic and 135 (19%) were defined as asymptomatic. Asymptomatic pts had more favorable baseline characteristics than symptomatic pts (table). Fewer asymptomatic pts had received prior abiraterone (34 pts, 25% vs 190, 35%), enzalutamide (5 pts, 4% vs 43, 8%) and prior docetaxel (70 pts, 52% vs 339, 62%). More asymptomatic pts received 6 cycles of Ra-223 (96, 71% vs 300, 55%). Adverse events (AEs) were reported for fewer pts with asymptomatic vs symptomatic disease: any grade, 61% vs 79%; grade 3/4, 29% vs 40% and serious AEs, 22% vs 38%. OS was longer in asymptomatic pts and ALP normalization was more common (table). Conclusions: Asymptomatic pts were more likely to have a better prognosis and to complete all 6 cycles of Ra-223. Ongoing first-line combination studies (ERA-223: NCT02043678 and PEACE-3: NCT02194842) may show whether Ra-223 administered early in the disease course will lead to better outcomes. Clinical trial information: NCT01618370. [Table: see text]
The acute toxicity results of the GETUG-AFU 22 study: A multicenter randomized phase II trial comparing the efficacy of a short hormone therapy in combination with radiotherapy to radiotherapy alone as a salvage treatment for patients with detectable PSA after radical prostatectomy.
Authors: Guerif Stephane Gilles , Latorzeff Igor , Roca Lise , Allouache Djelila , Supiot Stephane , Lagneau Edouard , Richaud Pierre , Elisabeth Deniaud-Alexandre , Ronchin Philippe , Ahmed Benyoucef , Cartier Lysian , Hamidou Hadji , Hasbini Ali , Crehange Gilles , Pommier Pascal , De Laroche Guy , Habibian Muriel , Gross Emmanuel , Fourneret Philippe , Salomon Laurent 
Published: March 2017

16 Background: Radical prostatectomy (RP) is recommended as a standard treatment for localized prostate cancer. However no recommendations exist for pts with detectable PSA after RP. Methods: Pts with localized prostate cancer, treated by RP (R0 or R1), with a PSA level post-RP ≥ 0.2 ng/mL and ≤ 2 ng/mL at randomization and N0 M0 on imaging were included. Pts were randomized (1:1) to radiotherapy (RT) alone (RT arm) or 6 months degarelix hormone therapy (HT) with RT (RT+HT arm). RT consisted of pelvic irradiation (46 Gy in 23 Fr) with a boost on the prostate bed (66 Gy in 33 Fr). The primary endpoint is the event-free survival (EFS). Secondary endpoints are: 5-yr EFS and metastases-free survival, 5 and 10-yr OS, acute and late toxicity (CTCAE V4.0), and QOL. With 122 patients, the probability of selecting the most effective arm is over 80% for a 20% reduction in the HR = 0.80. Results: From Dec-2012 to Sept-2015, 125 pts were included (RT arm: 64 pts; RT+HT arm: 61). Median follow up is 14.7 months (6.2; 33.5). The baseline characteristics are well-balanced: median age was 66 yrs (50-77), all men having an ECOG ≤ 1 (ECOG 0 in 92%), a median Gleason score of 7 (3-9), a median PSA of 0.3 ng/mL (0.09-1.82) post-RP and 0.6 ng/mL (0.12-3.65) at randomization. All pts received 33 Fr of RT. In the RT+HT arm 98.4% of pts received the 6 months of HT planned. All pts were eligible for safety analysis. No grade 4 toxicity or toxic death was reported. Grade 3 acute toxicity, occurring within 6 months of RT, were reported for 11/125 pts (9%): 3/64 pts (5%) in the RT arm and 8/61 pts (13%) in RT+HT arm (NS). Regarding grade 3 toxicities, the following occurred only in the RT+HT arm: erectile dysfunction (3 pts) and urinary incontinence (2 pts); in contrast, dysuria/pollakiuria (2 pts) occurred only in the RT arm. In the RT+HT arm, grade 2 toxicities included hot flushes (8 pts) and decreased libido (7 pts). Conclusions: In terms of acute toxicities the RT+HT arm is well tolerated with the observed toxicities usually expected with concomitant HT. The primary endpoint analysis is expected for 2018. Clinical trial information: NCT01994239.
Survival trends in patients diagnosed with metastatic prostate cancer: A nationwide analysis.
Authors: Thomas Helgstrand John , Klemann Nina , Toft Birgitte Grønkaer , Vainer Ben , Brasso Klaus , Brooks James D. , Iversen Peter , Røder Martin Andreas 
Published: March 2017

171 Background: The risk of prostate cancer (PCa)-death in men diagnosed with metastatic (M+) PCa is high. During the past decade, new life-prolonging therapies have been approved for the treatment of advanced PCa. Even though demonstrated in randomized clinical trials, the impact of these advancements on mortality of men with newly diagnosed M+ PCa has not been described in a nation-wide setting. Methods: In the Danish Prostate Cancer Registry (DaPCaR), all men diagnosed with M+ PCa in Denmark from 1995 to 2011 were identified. Patients were grouped according to the year of diagnosis; 1995-2000, 2001-2005 and 2006-2011. In a competing risk setting, the 5-year cumulative incidences of PCa, other-cause, and overall death were calculated. Multivariate cause-specific Cox analysis was performed. Results: A total of 1,892 (1995-2000), 2,329 (2001-2005), and 2,653 (2006-2011) men were included (total: 6,874). Patient characteristics at diagnosis showed essential differences as median age and median PSA decreased by 1.0 year (74.1 to 73.1) and 134 ng/mL (276 to 142), respectively, in the period studied. The 5-year PCa-specific mortality decreased by 17.0% from 72.8% (1995-2000) (95%CI: 70.8% – 74.8%) to 55.8% (2006-2011) (95%CI: 53.9% – 57.7%), p < 0.0001. The 5-year other-cause mortality increased by 5.7% from 11.4% (95%CI: 9.9% – 12.8%) to 17.1% (95%CI: 15.6 – 18.6), p < 0.0001. The risk of PCa-death decreased for patients diagnosed in 2000-2005; HR: 0.69 (95%CI 0.61-0.79) and for patients diagnosed in 2006-2011; HR: 0.53 (95%CI 0.47-0.61) compared to patients diagnosed in 1995-2000, when adjusting for age, PSA, and Gleason score (GS) in the statistical analysis. Conclusions: A significant reduction in 5-year PCa-specific mortality was observed in a nationwide cohort of patients diagnosed with M+ PCa since 1995. Changes in age and PSA at diagnosis suggest that lead-time introduced by increased PSA use may have affected the results. However, in multivariate analysis, a significant reduction in hazard of almost 50% was observed when adjusting for age, PSA, and GS. Only minor changes in other cause mortality were found, which suggests that the improvement to a large extend can be credited to improved management of men with advanced PCa.
Independent validation of effect of HSD3B1 genotype on response to androgen deprivation therapy (ADT) in hormone-sensitive prostate cancer (HSPC).
Authors: Hahn Andrew W. , Gill David Michael , Poole Austin , Farnham James M. , Cannon-Albright Lisa A , Agarwal Neeraj 
Published: March 2017

172 Background: A germline inherited polymorphic variant (1245A→C) in the HSD3B1 gene was recently reported to correlate with shorter duration of response to ADT in men with HSPC (Hearn JW, Lancet Oncology, 2016). HSD3B1 gene encodes the enzyme 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), which catalyzes adrenal androgen precursors into dihydrotestosterone, the most potent androgen. Presence of one or more variant alleles was associated with shorter response to ADT compared to those with no variant alleles of this gene. Objective of this study was to validate these results in an independent cohort. Methods: Clinical data and samples were from a prospectively maintained prostate cancer registry at the University of Utah (Salt Lake City, UT). Genotyping was performed as described by Hearn at al. Primary endpoint was progression-free survival on ADT, i.e time to onset of castration resistance. We performed pre-specified multivariate analyses to assess the independent predictive value of HSD3B1 genotype on PFS on ADT (Table). Results: 102 men with new mHSPC met eligibility and included in the analysis. The allelic frequency of the HSD3B1 (1245C) variant in our cohort was 31%, i.e. similar to that reported by Hearn et al. In multivariate analysis, those men in the homozygous variant group had significantly shorter PFS in comparison to those in the homozygous wild type group; no significant difference in PFS was observed in those men in the heterozygous group compared to those in the homozygous wild type group (Table). Conclusions: HSD3B1(1245C) predicted inferior response to ADT in our independent cohort of men with mHSPC. We also confirm that this polymorphism is quite common in this population. [Table: see text]
Evidence of linkage in MSH6-associated region exclusive to high-risk African-American families with prostate cancer.
Authors: Ledet Elisa M. , Sartor Oliver , Walter Rayford , Bailey-Wilson Joan , Mandal Diptasri 
Published: March 2017

180 Background: The significance of germline variants and their implications for prostate cancer (PCa) patients has gained prominence. Mismatch repair (MMR) genes such as MSH6 and MSH2, along with DNA repair genes, may be more important in PCa than previously appreciated. In the present study, we compared linkage results between African American (AA) and Caucasian (CA) PCa families with multiple affected family members. Methods: Study subjects were from 15 large, high-risk, clinically homogenous AA families and 4 CA families from Southern Louisiana. All families had at least ≥ 3 members with family member diagnosed with PCa. Genotyping for linkage analyses was done using Illumina Infinium II SNP HumanLinkage-12 panel. 6,068 SNPs were released for linkage analyses. Parametric linkage analyses were performed using Merlin software, version 1.1.2. An HLOD score > 1.86 was considered suggestive of linkage. Results: A total of 129 individuals from 15 AA families were genotyped including 45 affected men, 44 unaffected men, and 40 women. The average age at diagnosis was 61; 8 of 15 families had more than 4 affected individuals. 50 CA individuals from similar families were genotyped including 12 affected men, 26 presently unaffected men, and 12 women. For CA families, the average age of onset was 66, with at least 5 affected individuals in each family. In AAs, we identified a peak of suggestive linkage at chromosome 2p16 (HLOD = 1.97). Similarly, in CA families, the strongest linkage signal was observed on chromosome 2q14.1 with an HLOD score of 1.94. At the2 q14 linkage region, there was no linkage in AA PCa families (HLOD = 0.0004). Similarly, on 2p16, there was no linkage in the CA cohort (HLOD = 0). Conclusions: The MSH6 gene is located in 2p16 region. MMR gene mutations have been shown to have evidence of microsatellite instability in PCa as well as hereditary nonpolyposis colorectal cancer. MSH6 gene may represent a genetic variant contributing to risk of PCa in high risk AA families. This potentially has therapeutic implications for use of PD1 inhibitors in this population.