bluuebunny/crossref_metadata_2025_split huggingface dataset:
A deep learning algorithm to predict coexisting metastatic disease using intraprostatic [F18]DCFPYL PSMA image alone in veterans with prostate cancer.
Authors: Nickols Nicholas George , Anand Aseem , Sjöstrand Karl , Jafari Lida , Ceccoli John , Lin Tess , Richter Jens , Rettig Matthew 
Published: February 2020

25 Background: [F18]DCFPyL (PyL) is a PSMA targeted imaging agent for prostate cancer. Independent of manual feature selection, a deep learning algorithm might offer additional insight into the disease biology. We explored the performance of a deep learning algorithm on PyL images of the primary tumor to predict co-existing distant metastases. Methods: 74 veterans with high risk primary prostate cancer tumors were imaged with both PyL PSMA PET/CT and conventional imaging (bone scan and CT or MRI of the abdomen/pelvis). 26% were confirmed with metastatic disease (M1) by conventional imaging. The PyL images of the primary tumor were analyzed with EXINI’s PyL-AI algorithm. Location of the prostate was defined on low dose CT via automatic segmentation using a deep convolutional network. The segmentations were used to map the PyL PET image of the prostate. The image based PyL-AI model was made up of a Conv3D layer of 4 kernels, a Conv3D layer of 8 kernels, a dense layer of 64 nodes followed by a final dense layer with 2 nodes. The model training was performed on the images using 5-fold cross validation with non-overlapping validation sets. The test predictions were compared with ground truth (M1); the area under ROC curve (AUC) was computed to determine the performance of the model in predicting the presence of distant metastases. A logistical regression model from baseline clinicopathologic features of the primary tumor (baseline PSA, biopsy gleason score, percent cores positive, T stage) was created as a comparator. Results: The logistical regression model using clinicopathologic features had an AUC of 0.71, while the PyL-AI model based on intra-prostatic PyL Images alone had an AUC of 0.81 for prediction of metastatic disease as defined by conventional imaging. Adding clinical parameters in the image based PyL-AI model incrementally increased the AUC to 0.82. Conclusions: The image based PyL-AI deep learning model demonstrates a higher predictive accuracy over the logistic model using classical clinicopathologic features. The study is hypothesis generating observation that needs prospective validation in an independent data set.
Five-year results from a phase I/II study of moderately hypofractionated intensity-modulated radiation therapy (IMRT) for localized prostate cancer including simultaneously integrated boost and pelvic lymph node (LN) coverage.
Authors: Ricco Anthony , Mukhopadhyay Nitai , Holdford Diane , Skinner Vicki , Saraiya Siddharth , Moghanaki Drew , Anscher Mitchell Steven , Chang Michael G. , Deng Xiaoyan 
Published: February 2020

299 Background: This study reports the 5 year toxicity and efficacy data of a phase I/II trial of moderately hypofractionated intensity modulated radiation therapy (IMRT) for localized prostate cancer utilizing a simultaneous integrated boost and pelvic lymph node (LN) coverage. Methods: Men with localized prostate cancer were prospectively enrolled and received IMRT to the prostate +/- seminal vesicles (SVs) +/- LNs based on National Comprehensive Cancer Network (NCCN) guidelines. Low-risk (LR) patients received 69.6 Gy in 29 fractions to the prostate alone; intermediate-risk (IR) and high-risk (HR) patients received 72Gy to the prostate, 54Gy to the SVs, and 50.4Gy to LNs (if risk of LN involvement > 15% by the Roach formula) all in 30 fractions. IR and HR patients received androgen deprivation therapy. Results: Fifty-five patients were enrolled and 49 patients evaluable with a median follow up of 60 months. There were 11 (20%) LR, 23 (41.8%) IR, and 21 (38.2%) HR patients. Twenty-five patients (51%) received prostate and LN treatment. At 5 years, the cumulative incidence of late grade 2+ gastrointestinal (GI) and genitourinary (GU) toxicity was 22.6% and 38.2% respectively. Prevalence rates of late grade 2 GI toxicity at 1, 3, and 5 years was 5.8%, 3.9%, and 5.8% respectively. Late grade 2+ GI toxicities that did not resolve by 60 months included 3 out of 52 patients (5.8%). Prevalence rates of late grade 2 GU toxicity at 1, 3, and 5 years rates were 15.4%, 7.7%, and 13.5% respectively. There were 3 patients (5.8%) who experienced grade 3 GU toxicity and no grade 3 GI toxicities. The biochemical relapse free survival at 5 years for the cohort was 88.3%. There were no local, regional, or distant failures, with all patients still alive at last follow up. Conclusions: Moderate hypofractionation of localized prostate cancer utilizing a simultaneous integrated boost and LN coverage produces excellent biochemical control and acceptable acute/late toxicity. This phase I/II trial adds to maturing data with 5 year outcomes which justify its use for cost and patient convenience factors. Clinical trial information: NCT01117935.
18-year prostate cancer-specific mortality after prostatectomy, brachytherapy, external beam radiation therapy, hormonal therapy, or monitoring for localized prostate cancer.
Authors: Herlemann Annika , Cowan Janet E. , Washington Samuel L. , Wong Anthony C. , Broering Jenny M. , Carroll Peter R. , Cooperberg Matthew R. 
Published: February 2020

300 Background: The optimal treatment of localized prostate cancer (PCa) remains controversial. We compared long-term survival among men who underwent radical prostatectomy (RP), brachytherapy (BT), external beam radiation therapy (EBRT), primary androgen deprivation therapy (PADT), or monitoring (AS/WW) for localized PCa. Methods: Within the CaPSURE registry, we analyzed 12,062 men with localized PCa. PCa risk was assessed using the Stephenson preoperative nomogram and the Cancer of the Prostate Risk Assessment (CAPRA) score. Multivariable analyses were performed to compare prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) by primary treatment, adjusting for age and case-mix. An inverse probability weighted regression adjustment was used to reflect propensity for treatment assignment and any imbalances in censoring. Results: 6,357 men (53%) underwent RP, 1,351 (11%) BT, 1,716 (14%) EBRT, 1,605 (13%) PADT, and 1,033 (9%) AS/WW. During the 18-year follow-up period, 514 men died from PCa. Adjusting for clinical CAPRA score, the hazard ratios for PCSM relative to RP were 1.46 (95% CI, 1.00-2.12, p=0.050) for BT, 1.81 (95% CI, 1.43-2.30, p<0.001) for EBRT, 2.77 (95% CI, 2.18-3.51, p<0.001) for PADT, and 1.81 (95% CI, 1.23-2.66, p=0.003) for AS/WW. The greatest difference in PCSM between treatment modalities was observed for high-risk patients. Adjusting for age, comorbidity, and clinical CAPRA score, the hazard ratios for ACM were 1.46 (95% CI, 1.28-1.67) for BT, 1.38 (95% CI, 1.24-1.54) for EBRT, 1.89 (95% CI, 1.67-2.13) for PADT, and 1.60 (95% CI, 1.39-1.84) for AS/WW compared to RP (all p<0.001). Additional analyses using 100-Stephenson score or Fine-Gray competing risks analysis demonstrated similar results. Conclusions: In a large, prospective cohort of men with localized PCa, after adjustment for age and comorbidity, risk of PCSM and ACM was lowest after RP. Mortality was significantly higher after EBRT and AS/WW, and highest after PADT. RP should be offered as part of the management paradigm for high-risk disease, AS/WW should be preferred for most low-risk PCa.
Adverse event profiles of apalutamide, enzalutamide, and darolutamide in SPARTAN, PROSPER, and ARAMIS: How confident are we about which drug is safest?
Authors: Drago Joshua Z. , Kantoff Philip W. , Stopsack Konrad H. 
Published: February 2020

318 Background: Apalutamide, enzalutamide, and darolutamide were approved for non-metastatic castration-resistant prostate cancer (nmCRPC) based on three randomized placebo-controlled trials that showed similar efficacy. Adverse event (AE) profiles have been invoked to differentiate the drugs but have only been informally compared. Methods: We accounted for baseline characteristics, AE collection and reporting, and statistical uncertainty when comparing AE risks in the drug and placebo arms of SPARTAN (NCT01946204), PROSPER (NCT02003924), and ARAMIS (NCT02200614). Results: Patients in SPARTAN, PROSPER, and ARAMIS had a similar median age (74 years in all studies), median PSA doubling time (3.7-4.7 months) and ECOG performance status (68-80% with ECOG 0). AEs were gathered consistently using CTCAE 4.0 or 4.03. However, PROSPER and ARAMIS reported AEs occurring in ≥5% of patients; SPARTAN reported AEs occurring in ≥15%. Trials also reported 5 to 14 ‘AEs of interest.’ Of 34 AE types reported overall, only 10 were reported in all three trials. Absolute risks of adverse events in the placebo arms differed considerably. Compared to the placebo arm of SPARTAN, AEs were on average 44% less common in the placebo arm of PROSPER (95% CI, 28-56%) and 54% less common in the placebo arm of ARAMIS (95% CI, 41-64%), a difference not explained by length of follow-up. With lower event numbers, relative risk estimates were less precise with wider confidence intervals. For example, comparing treatment vs. placebo arms, the relative risk for fatigue, the most common AE, was 1.45 (95% CI, 1.16-1.80) in SPARTAN, 2.37 (95% CI, 1.86-3.04) in PROSPER, and 1.39 (95% CI, 1.01-1.91) in ARAMIS. Across all AE types, compared to SPARTAN, relative risks from PROSPER were 23% less precise and relative risks from ARAMIS were 30% less precise. Conclusions: While conducted in similar patient populations, these trials had remarkable differences in AE reporting and in absolute AE risks between placebo arms. Rather than indicating better safety, low absolute adverse event numbers decrease confidence in AE profiles. Published data are insufficient to differentiate the AE profiles of these agents in nmCRPC.
Clinical outcomes and patient (pt) profiles in REASSURE: An observational study of radium-223 (Ra-223) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Higano Celestia S. , Saad Fred , Sartor A. Oliver , Miller Kurt , Conti Peter , George Daniel J. , Sternberg Cora N. , Shore Neal D. , Sade Juan Pablo , Bellmunt Joaquim , Smith Matthew Raymond , Logothetis Christopher , Verholen Frank , Kalinovsky Jan , Bayh Inga , TOMBAL Bertrand F. 
Published: February 2020

32 Background: Ra-223 is a targeted alpha therapy that showed a survival advantage and favorable safety profile in the phase 3 ALSYMPCA trial in pts with mCRPC. REASSURE (NCT02141438) is evaluating the long-term safety of Ra-223 in routine clinical practice in pts with mCRPC over a 7-year follow-up period. Methods: In this global, prospective, single-arm, observational study, the second prespecified interim analysis (data cut-off March 2019) evaluated safety and clinical outcomes of Ra-223 in pts with mCRPC. Primary outcome measures were incidence of second primary malignancies (SPM), bone marrow suppression and short- and long-term safety in pts who had ≥1 Ra-223 dose. Secondary outcomes included overall survival (OS). Results: For 1465 pts in the safety analysis, median follow up was 11.5 months. Median PSA (n=1053), ALP (n=1048), and LDH (n=555) levels at baseline were 59 ng/mL, 135 U/L, and 269 U/L, respectively. 81% of pts had bone metastases only at baseline; 19% of pts had other metastatic sites, mostly in the lymph nodes. 19% of pts had <6 metastatic sites, 47% had 6–20 sites, 20% had >20 lesions but not a superscan, and 6% had a superscan. 45%, 38%, 37%, 9%, and 8% of pts received prior abiraterone, docetaxel, enzalutamide, cabazitaxel, or sipuleucel-T as prior therapies, respectively. Median number of Ra-223 doses received was 6; 67% of pts had ≥5 doses. SPM occurred in 1% of pts. The most common treatment-emergent drug-related adverse event (AE) of any grade was diarrhea (11%). 10% of pts had a bone-associated event, 5% had fractures, and 15% had a hematological AE. Median OS was 15.6 months (95% CI 14.6–16.5). Conclusions: In REASSURE, there was a low incidence of SPM, bone fractures, and bone marrow suppression after Ra-223 treatment, with no new AEs identified. This study confirms that in routine clinical practice, Ra-223 AE rates were low, and pts generally received ≥5 doses. Clinical trial information: NCT02141438. [Table: see text]
A systematic review and network meta-analysis of FDA approved treatment options in men with nonmetastatic, castration-resistant prostate cancer (M0CRPC).
Authors: Riaz Irbaz Bin , Asghar Noureen , Lang Daenielle K. , Yao Yuan , Riaz Anum , Almutairi Abdulaali , Wang Zhen , Abraham Ivo , Murad M. Hassan , Kohli Manish 
Published: February 2020

335 Background: Network meta-analysis can provide useful evidence for relative efficacy and toxicity of different treatment options in absence of head-to-head trials. Previously, we reported no difference in efficacy between Apalutamide (APA) and Enzalutamide (ENZA). In this analysis, we provide updated indirect comparisons of all FDA approved agents (APA,ENZA, Darolutamide(DARO) for the treatment of M0CRPC with rapid PSA doubling time. Methods: MEDLINE, EMBASE and Cochrane Library were searched to identify relevant clinical trials. Hazard ratios (HR) and 95% confidence interval (CI) for Metastasis Free Survival (MFS), Overall Survival (OS) and data on grade 3 or higher AEs were abstracted. Bayesian network meta-analysis was conducted using WinBUGS 1.4.3 software (MRC Biostatistics Unit, Cambridge, UK) to perform an indirect comparisons. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: Three RCTs (SPARTAN, PROSPER and ARAMIS) compared APA, ENZA and DARO respectively in combination with ADT to ADT alone. A total of 4117 patients were included in efficacy analysis (2694 received novel hormonal agents and 1423 received ADT and placebo). There were no statistically significant differences in MFS (HR 0.97, 95% CrI 0.74 - 1.30) between APA and ENZA; however, both APA 0.69 (95% CI 0.52 -0.92) and ENZA 0.71 (95% CrI 0.53, 0.92) significantly improved MFS as compared to DARO. There were no statistically significant differences in OS between these drugs. DARO had fewer grade 3 or higher adverse events of fatigue (HR 0.09, 95% CrI 0.01 – 0.51) compared to ENZA. However other common adverse events such as hypertension, falls, coronary artery disease/myocardial infarction and diarrhea were not significantly different between treatment groups. There was low risk of bias amongst included studies. Conclusions: APNA and ENZA provide significant improved in MFS as compared to DARO in patients with M0CRPC. The drugs have similar toxicity profile except that DARO was associated with lower incidence of fatigue compared to ENZA. Cost effective analysis of these drugs will be reported separately.
Loss of SNAI2 in prostate cancer and effect on patient response to androgen deprivation therapy.
Authors: Corcoran Niall , Cmero Marek , Kurganovs Natalie , McCoy Patrick , Costello Anthony , Ryan Andrew , Parente Phillip , Hovens Christopher 
Published: February 2020

338 Background: Androgen receptor (AR) signalling is important in prostate cancer progression, and therapies that specifically target this pathway are the mainstay of treatment for advanced disease. Treatment however is non-curative, and resistance develops inevitably with time. Although the mechanisms that drive castration resistant disease have been intensively analysed, how tumours survive and persist during the initial pathway inhibition is unclear. Methods: To track this process in detail we performed a Phase II neo-adjuvant study of a novel combination of AR targeting therapies (degarelix & abiraterone & bicalutamide) for 6 months prior to prostatectomy in men with high risk, localised disease. To determine what was driving tumour persistence in poorly responding patients, we comprehensively characterised pre- and post-treatment samples using both whole genome and RNA-sequencing, validating pertinent findings by qRT-PCR, IHC and FISH. Results: Despite universal ‘biochemical responses’, objective responses to treatment as measured by residual tumours volumes were highly variable. This state which we term ‘castration-persistence’, is molecularly distinct from ‘castration-resistance’, and is characterised by global transcriptional reprogramming leading to a transitional EMT state. Whole genome sequencing confirms tumour persistence is not associated with the emergence of a ‘driver’ lesion, rather treatment response is associated with regression of a ‘treatment sensitive’ subclonal population, defined by deletion of the EMT master regulator SNAI2. The extent of treatment response observed was determined by the prevalence of cells with loss of SNAI2 in pre-treatment biopsies. Conclusions: Cell plasticity with transition to a mesenchymal phenotype defines prostate cancer cell survival to acute AR signalling inhibition. Tumour response is determined by the proportion of cells present harbouring defects in this program.
Ability of the combined clinical cell-cycle risk score to identify patients that benefit from multi versus single modality therapy in NCCN intermediate and high-risk prostate cancer.
Authors: Tward Jonathan David , Schlomm Thorsten , Bardot Stephen , Freedland Stephen J. , Lenz Lauren , Cohen Todd , Stone Steven , Bishoff Jay 
Published: February 2020

346 Background: Prolaris combines RNA expression analysis of cell cycle progression genes with clinicopathologic information to create a combined clinical cell-cycle risk score (CCR). We evaluated the ability of CCR to predict metastasis (mets) in men for whom guidelines indicate that multimodality therapy (MTx) should be considered. Methods: A commercial cohort (N=15669) of National Comprehensive Cancer Network unfavorable intermediate-risk (UFI) and high-risk (HR) men revealed a distribution of 70.5% and 29.5% respectively. A CCR threshold of 2.112 was selected so that 29.5% of these men were above the threshold. MTx was defined as combined use of androgen deprivation therapy with radiation (RT) or surgery, or with adjuvant RT. Associations were evaluated in a 718-person retrospective, multi-institutional database of Prolaris-tested UFI and HR men. Kaplan-Meier (KM) analyses and Cox regressions were used to estimate the effects of prognostic covariates. Results: Median follow-up was 5.13 years. CCR predicted mets in the full cohort (HR =3.8 [2.7,5.2], p<10−15) and after accounting for CAPRA (HR=4.3 [2.7,7.0], p< 10−7). CCR also was a significant predictor of mets in patients who received STx, as a continuous predictor (HR=4.0 [2.6,6.1], p<10−9) and when dichotomized at the threshold (HR=15.9 [5.4,46.5], p< 10−9). The KM probability of mets by 10 years for those below and above the threshold was 4.3% and 20.4% respectively. MTx reduced patients’ risk of mets (HR=0.46 [0.22,0.97], p=0.04), and treatment benefit can be evaluated as a function of CCR score (Table). Conclusions: The CCR score prognosticates a clinically meaningful different risk of metastasis for those receiving MTx versus STx. Approximately 27% and 73% of people with HR or UFI risk cancer have CCR scores below the risk threshold and may consider STx after considering the difference in risk of mets.[Table: see text]
A tale of lineage plasticity: Intense neoadjuvant testosterone lowering therapy in localized prostate cancer (PCa) harboring high-risk genomic signatures.
Authors: Karzai Fatima , Madan Ravi Amrit , Sowalsky Adam G. , Bilusic Marijo , Chun Guinevere , Cordes Lisa M. , Wilkinson Scott C. , Terrigino Nicholas , Harmon Stephanie , Pinto Peter A. , Choyke Peter L. , Turkbey Baris , Gulley James L. , Dahut William L. 
Published: February 2020

368 Background: PCa is driven by androgen receptor (AR) signaling and neoadjuvant therapy with AR inhibitors offer an opportunity to improve cure rates in high-risk PCa particularly with utilization of multiparametric MRI (mpMRI). A loss of AR-regulated lineage characteristics and genomic loss of tumor suppressors RB1 and TP53 or mutations in DNA damage repair (DDR) genes can represent aggressive prostate variants. We conducted a feasibility study using mpMRI to evaluate tumor responses and resistance in newly diagnosed, high-risk PCa (NCT02430480). Methods: Pts were treated with androgen deprivation therapy (ADT) + enzalutamide (enza) 160 mg daily for 6 months (mos). Pts underwent 2 mpMRIs: baseline and post 6 mos treatment (trt). Post-trt mpMRI was followed by radical prostatectomy (RP). Primary endpoint: feasibility of mpMRI for localization and detection of PCa before and after ADT + enza. Results: 39 pts were enrolled on-study with 36 pts completing 6 mos trt and undergoing RP. Of 39 pts, 3 had disease progression. Conclusions: Neoadjuvant intense testosterone lowering therapy shows activity in PCa but a subset of pts not respond to AR-targeted therapies through lineage plasticity enabled by characteristic loss of RB1 and TP53 or due to genetic alterations. Identification of this high-risk patient population, along with development of treatment options, needs further investigation. Clinical trial information: NCT02430480. [Table: see text]
The SEMITEP trial: De-escalating chemotherapy in low-volume metastatic seminoma based on early FDG-PET.
Authors: Loriot Yohann , Texier Matthieu , Culine Stephane , Flechon Aude , Nguyen Thierry , Gravis Gwenaelle , Geoffrois Lionnel , Chevreau Christine , Gross-Goupil Marine , Barthelemy Philippe , Bompas Emmanuelle , Mahammedi Hakim , Laguerre Brigitte , Abadie Lacourtoisie Sophie , Helissey Carole , Ladoire Sylvain , Massard Christophe , Grimaldi Serena , Fizazi Karim 
Published: February 2020

387 Background: A negative FDG-positron emission tomography/computerized tomography (PET) predicts the absence of viable seminoma cells after chemotherapy in men with metastatic seminoma. In this study, we assessed whether patients (pts) with low-volume metastatic seminoma can be treated with 2 cycles of etoposide-cisplatin (EP) followed by only one cycle of carboplatin (CARBO) on the basis of a negative interim PET, thereby limiting the burden of toxicity. Methods: In this non-randomised, multiple-center, phase 2 trial (NCT01887340), we enrolled pts with low-volume metastatic seminoma (with good prognosis according to IGCCCG and the Medical Research Council classifications). All pts with baseline PET-positive received EP for two cycles. After completion of first two cycles, pts underwent a second PET to assess response. Patients with a persistent positive PET (based on local review) proceeded directly to two additional EP cycles (for a total of 4); those who achieved a PET-negative received only one cycle of CARBO (AUC=7). The primary outcome was the proportion of pts who were PET-negative on interim PET and received de-escalating chemotherapy. Secondary endpoints include progression-free survival (PFS) and overall survival (OS). Results: Between June 2013 and July 2017, 102 pts were enrolled in the study. Three pts were deemed ineligible or not evaluable and thus 99 patients received treatment. After 2 first EP cycles, PET was available in 94 pts. Interim PET was negative in 68 pts (72%) and positive in 26 pts (28%). Overall, 63 pts (67.0%; 95% CI 57.5-76.5) were PET-negative and proceeded to one single cycle of CARBO. Overall, 24 (25.5%, 95% CI 17.1-34.9) patients had a PET positive after 2 EP and received 2 additional cycles of EP. After a median follow-up of 34.4 months, only 8 patients relapsed (2 in EP group and 6 in CARBO group). 2-year PFS rates were respectively 93.7% (95% CI 84.9-97.5) in the CARBO group and 92.9% (95% CI 77.4-98.0) in the EP group. Only one patient died during the 2 first cycles. Conclusions: De-escalating treatment based on a negative PET after 2 cycles of chemotherapy appears to be safe and feasible in the majority of patients with low-volume metastatic seminoma. Clinical trial information: NCT01887340.