bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of whole pelvic nodal radiotherapy compared with prostate bed only radiotherapy after radical prostatectomy for prostate cancer.
Authors: Caubet Matthieu , Pasquier David , Bertaut Aurelie , Grobois Simon , De Bari Berardino , Kleinclauss Francois , Thiery Vuillemin Antoine , Martin Etienne , Quivrin Magali , Cormier Luc , Crehange Gilles 
Published: February 2018

93 Background: In international guidelines, target volumes for postoperative radiotherapy (PORT) after radical prostatectomy concern the bed of the prostate and seminal vesicles. The benefit of whole pelvic nodal radiotherapy (WPRT) in the case of PORT remains uncertain. Methods: We reviewed the charts of all patients diagnosed with high-risk prostate cancer after radical prostatectomy who were selected for PORT and treated with adjuvant radiotherapy (n = 242, 43.1%) or early salvage RT (n = 320, 56.9%) between 2002 and 2011. 111 patients (19.8%) who underwent WPRT were compared with 441 patients (80.2%) who had prostate bed radiotherapy only (PBRT). We examined associations between patient, tumor, and treatment characteristics and biochemical progression-free survival (bPFS), disease-free survival (DFS) and overall survival (OS) with uni- and multivariate analyses using Cox models. Acute and late toxicities were also compared between the two groups. Results: We found a significantly lower rate of acute G2+ gastrointestinal (GI) toxicity with PBRT than with WPRT with neither difference in acute G3+ nor on late GI toxicity. Regarding genitoruinary (GU) toxicity, we found no difference in acute G2+ or G3+ toxicity but rates of late G3+ GU toxicity were significantly lower in PBRT (1.55%) than in WPRT patients (p = 0.035). With a median follow-up of 65.2 months [95% CI: 62.8 - 67.9], a deleterious effect of WPRT was observed on OS (HR = 3.27 [95% CI: 1.44 - 7.45], p = 0.009). We found no impact of WPRT on bPFS (HR = 0.79 [95% CI: 0.49 - 1.25], p = 0.31) or DFS (HR = 0.97 [95% CI: 0.63 - 1.49], p = 0.88). Only a positive surgical margin was an independent prognostic factor for better bPFS. Age≥63 years and WPRT (HR = 2.86 [95% CI: 1.20-6.80], p = 0.018) were independent prognostic factors for worse OS. Conclusions: After radical prostatectomy, we found no difference on bPFS or DFS but lower rates of OS with WPRT compared to PBRT. PBRT must remain the standard of care. The results of RTOG NRG Oncology 0534 should shed light on this unresolved issue.
Assessment of Ki67 in relation to radiotherapy (RT) fractionation and prognosis in the CHHiP (CRUK/06/016) trial.
Authors: Wilkins Anna , Gusterson Barry , Szijgyarto Zsolt , Haviland Joanne , Griffin Clare , Stuttle Christine , Daley Frances , Corbishley Catherine M , Dearnaley David P. , Hall Emma , Somaiah Navita 
Published: February 2018

98 Background: A uniform fractionation schedule is used to deliver external beam RT for localised prostate tumours Individualising fractionation according to tumour biology may improve outcomes. In addition recurrence rates after RT vary considerably and better prognostic markers are needed to guide treatment choices. This study aims to identify if the cell proliferation marker Ki67 predicts response to RT fractionation in CHHiP, a randomised trial of 3 RT fractionation schedules. It also aims to identify if Ki67 predicts prognosis. Methods: A matched case:control study design was used, patients with biochemical or clinical failure > 2 years after RT (BCR) were matched to patients without recurrence according to established prognostic factors (Gleason score, PSA, Tumour-stage) and fractionation schedule. Immunohistochemical (IHC) staining of diagnostic biopsy sections was carried out using the MIB1 Ki67 antibody. Two independent investigators scored Ki67 using the unweighted global method (1) to derive a mean and maximum percentage of cells staining positive (mean Ki67 and maximum Ki67 respectively). Conditional logistic regression models were fitted with interaction terms between the biomarker and the fractionation schedules to determine whether Ki67 predicted BCR according to fractionation. Secondly models were fitted using the entire case:control study sample to estimate the prognostic value of Ki67 on risk of BCR. Results: Ki67 results were available for 173 matched pairs. The interaction terms between Ki67 and the fractionation schedules were not significant. However mean and maximum Ki67 were significant prognostic markers for BCR in a model adjusted for established prognostic factors. Conditioning on matching variables and age, the odds of BCR is estimated to increase by 9% per 1 point increase in mean Ki67 (OR = 1.09, 95%CI:1.04–1.15, p = 0.001). Conclusions: Ki67 did not predict BCR according to fractionation schedule in CHHiP, however it did predict prognosis independently of established prognostic factors. Additional IHC biomarkers are under evaluation.
SAKK 08/15-promet: Multicenter, randomized phase II trial of salvage radiotherapy +/- metformin for patients with prostate cancer after prostatectomy.
Authors: Dal Pra Alan , Ghadjar Pirus , Supiot Stephane , Omlin Aurelius Gabriel , Hayoz Stefanie , Zwahlen Daniel Rudolf , Pollak Michael N. , Gillessen Silke , Aebersold Daniel M. 
Published: February 2018

TPS157 Background: Salvage radiotherapy (SRT) is as a potentially curative treatment for prostate cancer (CaP) patients presenting biochemical relapse after radical prostatectomy (RP). Metformin is a well-known antidiabetic drug that has demonstrated anti-cancer and radio-sensitizing effects. We aim to study whether metformin combined with SRT will improve cancer control by prolonging time to progression (TTP). Methods: This is a multicenter, randomized (1:1) phase II trial of SRT (70Gy/35fr to the prostate bed) with or without metformin (850mg BID for 52 wks) (NCT02945813). Metformin 850mg q.d. is started 4 wks prior to SRT. Stratification variables include Gleason score, PSA at randomization, surgical margin status and ADT use (allowed if PSA > 0.5, R0, post-RP PSA-DT < 6 mos or pT3b). Major eligibility criteria include: histologically proven CaP adenocarcinoma pT2a-3b, pN0 or cN0, M0; RP > 12 wks before registration; PSA progression after RP defined as 2 consecutive rises with final PSA > 0.1 ng/mL or 3 consecutive rises; and PSA ≤ 2 ng/mL within 14 days prior to registration. A sample size of 170 patients (85 per arm) is planned based on the primary endpoint TTP. Using a type I error of 5% and a power of 80%, 62 events are needed to show superiority of the treatment arm under the alternative hypothesis that the hazard ratio (HR) is 0.65 (TTP at 18 mos of 80% in the control arm vs. 86.5% in the treatment arm). All efficacy endpoints will be analyzed based on the full analysis population. The treatment effect will be assessed using Cox regression with the treatment arm as independent variable and the stratification factors as strata. Correlative studies including prostate tissue, blood (metabolic parameters), saliva and feces (microbiota) will be performed. Conclusion: Centers in Switzerland, Germany and France (GETUG) will recruit patients for this study. If positive, these results could help elucidate the role of metformin in CaP and determine the design of a subsequent phase III trial. Clinical trial information: NCT02945813.
Phase I study of stereotactic body radiotherapy following radical prostatectomy.
Authors: Ballas Leslie , Aron Monish , Jhimlee Shamim , Shuryak Igor , Dorff Tanya B. , Yang Dongyun , Brenner David J. , Groshen Susan G. 
Published: February 2018

TPS158 Background: Although multiple Phase I/II studies demonstrate safety and low rates of toxicity following stereotactic body radiotherapy (SBRT) to the intact prostate, there are limited data on hypofractionation and SBRT after prostatectomy. This Phase I study was performed to evaluate acute toxicity associated with dose escalation from 3.6 Gy per fraction to 7.1 Gy per fraction to the prostate bed in the post-prostatectomy treatment of prostate cancer. We hypothesize that the toxicity of escalating the dose per fraction to the prostate fossa in the post-operative setting will be well tolerated; and we expect toxicity to be comparable to normal fractionation schedules. Methods: This study (NCT02446366) was designed to look at acute toxicity, defined as toxicity that occurred within the first 10 weeks of RT, of different dose fractionation schemes in the post-prostatectomy setting. The doses chosen for dose escalation on this study are based on an equivalent biological effective dose to a previously published hypofractionated post-prostatectomy study that showed no increase in acute bowel or bladder toxicity. The dose levels are as follows: Level 1 -3.6 Gy x 15 fractions; Level 2- 4.7 Gy x 10 fractions; Level 3 - 7.1 Gy x 5 fractions. Eligibility for participation on the trial was for patients who had pT3N0 disease regardless of margin status in the post-prostatectomy setting, pT2N0 patients with positive margin or with a negative surgical margin and a rising post-operative PSA. Patients could be on concurrent ADT and enroll on this study. Dose was escalated according to a 6+6 schema. For purposes of deciding whether to escalate to a new dose level, expand a dose level or de-escalate from a dose level, we used toxicities and adverse events that occur during the 1st 10 weeks after completion of radiotherapy. Six patients were enrolled on each new dose level with a total of 12 patients required at the maximum tolerated dose. Dose-limiting toxicity (DLT) was defined as grade 3 or worse fatigue, gastrointestinal (GI) or genitourinary (GU) toxicity by Common Terminology Criteria of Adverse Events (version 4.03). Dose levels 1 and 2 have been completed without any DLT. Dose level 3 has enrolled 9/12 patients without any DLT. Clinical trial information: NCT02446366.
What fixes PSA screening guidelines gone wrong?
Authors: Talcott James Austin , Bezuhly Maureen , Osborne Michael P. 
Published: February 2018

TPS159 Background: Guidelines provide guidance but patient (PT) factors alter recommendations. We studied PT factors that alter the correct recommendation (CR) and physician (MD) advice in real-time cancer screening discussions in a 2x2 cluster-randomized trial of MD educational supports. Methods: We enrolled an age-(30-89 years) and sex-stratified sample of 18 patients (PTs) who underwent a physical examination at 2 urban hospitals by each of 12 primary care MDs. We assigned screening guideline formatting (color-coding [CC]) and academic detailing (AD) to MDs randomly. Immediate post-encounter surveys recorded PT and MD recall of screening discussions. Because PSA screening, the focus here, is controversial, we defined correct recommendations (CR) only when against screening, for men too old ( > 75 yrs) or too young (African American [AA] < 40 or non-AA < 50). For other men, either recommendation was considered correct. MD-reported serious comorbidity or PT choice against screening were also valid reasons against. Results: Of the first 174 participants, 92 were male. They were diverse (69% white) and highly educated (87% attended, 61% graduated college). Using age and race alone, 49% should not be screened, but increased to 65% by adding comorbidity (1%) and PT choice (15%). By these criteria, MDs advised correctly in 91% of encounters. In univariate analysis, CC (p = 0.08) but not AD, PT education, shared decision making and age tended to increase CR. Conclusions: In a highly educated, diverse patient population, including comorbidity and PT choice increased CR against screening to 16% more men. An educational support (CC) tended to increase CR. General guidelines can produce incorrect recommendations. Simple supports may improve them. Clinical trial information: NCT02430948.
c15-162: Phase IB trial of radium 223 and niraparib in patients with castrate resistant prostate cancer (NiraRad).
Authors: Godwin James Luke , Hoffman-Censits Jean H. , Den Robert Benjamin , Knudsen Karen E. , Schiewer Matthew Joseph , Leiby Benjamin E. , Southwell Traci , Hubert Christine , Patnaik Akash , Sonpavde Guru , Sartor A. Oliver , Yang Eddy Shih-Hsin , Kelly William Kevin ,   The Prostate Cancer Clinical Trials Consortium
Published: February 2018

TPS385 Background: PARP1 is a key regulator of the transition to lethal castrate resistant prostate cancer (CRPC); niraparib is a potent and selective PARP-1 and PARP-2 inhibitor that has shown single agent clinical activity in CRPC. Radium-223 is an alpha particle emitter that causes DNA double strand breaks and is FDA approved for use in CRPC. The addition of a PARP inhibitor (niraparib) may further enhance the clinical benefit of Radium-223 through inhibition of DNA repair and modifications in the bone microenvironment. We hypothesize that targeting the PARP1/androgen receptor (AR) axis in combination with radiopharmaceutical therapy will be safe and may improve clinical outcomes for men with advanced CRPC. Furthermore, combining clinical and pathologic features with correlative studies on tumor tissue, blood, and circulating tumor cells (CTCs) may help us develop biomarkers for future use in the treatment of CRPC. Methods: This is aphase IB dose finding study of patients with metastatic CRPC using a time-to-event continual reassessment (TITE-CRM) design to identify the maximum tolerated dose (MTD) of niraparib (100, 200, or 300 mg QD) in combination with standard doses of Radium-223 in patients with and without prior chemotherapy. Niraparib dosing will continue after 6 cycles of radium-223 until disease progression or intolerable adverse events. Correlative studies include the assessment of tumor biopsy tissues using DNA and RNA next-generation sequencing to assay for the presence of DNA repair aberrations in genes; targeted gene expression profiling of serial RNA (baseline and after cycles 1 and 3) performed on whole blood using the Nanostring PanCancer panel; and evaluation of pre- and post-therapy bone marrow biopsies in a subcohort to characterize the effects of the combined therapy on the bone microenvironment. Additional correlative studies that will be performed on CTC include: assay for nuclear AR expression; immunostaining for the presence of persistent g-H2AX foci, (markers of unrepaired DNA double strand breaks); NFkB activity assayed by immunostaining for p-p65). Enrollment to Dose Level 1 began in October 2017. Clinical trial information: NCT03076203.
Intergroup study EORTC-1333-GUCG: A randomized multicenter phase III trial comparing enzalutamide vs. a combination of Ra223 and enzalutamide in asymptomatic or mildly symptomatic castration resistant prostate cancer (CRPC) patients metastatic to bone (PEACE III).
Authors: Tombal Bertrand F. , Loriot Yohann , Saad Fred , McDermott Raymond S. , Marreaud Sandrine , Collette Laurence , Gillessen Silke 
Published: February 2018

TPS390 Background: α-emitting radiopharmaceutical Ra-223 reduces the risk of death by 30% vs placebo in phase 3 ALSYMPCA (Parker et al. NEJM 2013). Ra-223’s favourable safety profile and lack of significant toxicity support combining it with other agents. The ALSYMPCA trial was developed to add Ra-223 on the contemporary standard of care that did not include last generation AR pathway inhibitors enzalutamide, one of the modern reference treatments for asymptomatic or moderately symptomatic metastatic CRPC (Gillessen et al. Eur Urol. 2017). In addition Ra-223 is registered in symptomatic prostate cancer (PCa), a very late stage of modern patient disease. There is thus a good rationale to combine Ra-223 to modern AR pathway inhibitors and to initiate the treatment in asymptomatic or moderately symptomatic patients. Methods: The EORTC 1333-GUCG study will run in 51 sites (21 activated) across 7 European countries, 4 sites in US and 12 sites in Canada. The study is an intergroup initiative between EORTC (Coordinating Group), UNICANCER; Cancer Trials Ireland (Ireland), ACCRU (The United States), and CUOG (Canada). A total of 560 patients will be randomized in a 1:1 ratio to receive enzalutamide 160 mg q.d. p.o. or enzalutamide at the same dose and Ra223 at 55 kBq/kg i.v. monthly for 6 months. Patients will be stratified by country, pain (BPI 0-1 vs BPI 2-3), prior docetaxel use (no vs yes) and use of bone targeting agents (no vs yes). The main inclusion criteria require asymptomatic or mildly symptomatic (defined as no opioids and BPI-SF question 3 < 4), metastatic to bone with ≥ 2 bone metastases with or without additional lymph node metastases. Visceral metastases are not allowed. The primary endpoint is radiological progression-free survival (rPFS1), according to PCWG3. Secondary endpoints include: overall survival, PCa specific survival, 1st symptomatic skeletal event (SSE), time to initiation of next systemic anti-neoplastic therapy, time to pain progression, health-related quality of life (EQ-5D-5L and BPI). Clinical trial information: NCT02194842.
Influence of cardiovascular (CV) comorbidities on the selection of hormone deprivation therapy (HDT) in the treatment of metastatic prostate cancer (mPCa).
Authors: Lehmann Jan , Flesch Markus , Vosgerau Sebastian , Gedamke Michael 
Published: February 2018

TPS392 Background: HDT with LHRH agonists (LHRH) or LHRH-antagonists (degarelix, D) is the standard of care in advanced mPCa. A correlation between leuprolide/goserelin and an increased risk of CV events as compared to D has been shown in a pooled analysis of 6 RCTs in 2013, therefore we aimed to evaluate potential changes in selection of HDTs in Germany. Methods: To evaluate changes in selection of HDT, we compared data from a retrospective (2013 - 2014) and prospective (FPFV in 09/2014) study on CV disease and selection of ADT that were collected from the same pool of study sites. In the ProComD, a two-arm, prospective non-interventional study (NIS), potential comorbidity dependent differences in the selection of D vs LHRH treatment were investigated. Preceding the ProComD we conducted the retrospective randomised analysis to determine baseline CV disease frequencies in ADT treated patients. Results: In the retrospective part, frequencies of CV-disease were skewed towards LHRH compared to D (59.8 vs. 49.0 %). In the prospective ProComD data on patients with a minimum follow-up period of one year (visit 5, n = 238, D = 149, LHRH = 89) up to two years (visit 7, n = 84, D = 51, LHRH = 33) were documented. Baseline criteria were generally similar except for disease T-stage (p = 0.0038). The average age of patients was 74.4 years. Stage distribution: D vs. LHRH, pT2 26.8/28.1 %, pT3 23.5/38.2 %, pT4 5.4/1.1 %, unkown. 44.3/32.6 %, cNX 51.0/44.9 %, cN0 32.2/42.7 %, cN+ 16.8/12.4 %, cMX 26.8/23.3 %, cM0 34.9/47.2 %, cM1 38.2/29.2 %. Comorbidities were reported in 184 patients (77.3 %). Most frequent comorb. were vascular and metabolic diseases (hypertension and diabetes mellitus; (n = 139/57; 75.5/31.0 %) followed by cardiac diseases (n = 74; 40.2 %). More patients with peripheral arterial disease (PAD) (17.9 vs 3.0 %) and cardiac diseases (41.9 vs 37.3 %) received D as compared to LHRH. Conclusions: Our results indicate that selection of ADT seems to have shifted following new data on CV-risk differences between leuprolide/goserelin and degarelix. Patients with cardiac and PAD comorbidities have received more often degarelix treatment as compared to LHRH treatment.
Randomized, multicentre phase II trial of the sequencing of radium-223 and docetaxel plus prednisone in symptomatic bone-only metastatic castration-resistant prostate cancer (mCRPC).
Authors: Conteduca Vincenza , Severi Stefano , Gori Stefania , Galli Luca , Aieta Michele , Facchini Gaetano , Masini Cristina , Gasparro Donatello , Fratino Lucia , Baier Susanne , Scarpi Emanuela , Testoni Sara , Sirna Valeria , Valmorri Linda , Vertogen Bernadette , Paganelli Giovanni , De Giorgi Ugo 
Published: February 2018

TPS396 Background: Currently, the challenge is to reach a consensus on the best way to sequence different therapies for mCRPC patients (pts) in terms of efficacy and tolerability. Radium223 is a novel survival-prolonging targeted-α-therapy, but timing of its use in the treatment sequence of mCRPC remains an unanswered question, given the wide availability of therapeutic options Methods: This is a prospective, multicenter, randomized phase II study in symptomatic bone-only mCRPC pts who progressed after any androgen deprivation therapy, abiraterone and/or enzalutamide. Pts will be randomized 1:1 to receive radium223 initially followed by docetaxel+prednisone at the time of progression, or docetaxel+prednisone initially followed by radium223 at progression. In both treatment arms, the second step will be optional according to clinical evolution of disease (clinical deterioration and/or development of visceral metastases); however, each patient that will not enter in the second step will be still evaluable for the objectives of the study. No stratification factor will be used for randomization. Primary endpoint is to determine the better tolerated sequencing between radium223 and docetaxel in terms of health-related quality of life after completing the sequence and separately after each treatment. Based on primary endpoint, considering a type I error 0.1, type II error 0.2, proportion of responder pts in the standard arm 0.1 and in the experimental arm of 0.4, and assuming 10% loss to follow-up, a total of 70pts (35 for each arm) will be enrolled in the study. The study duration will be 36months; 15months of accrual, and 1 year of follow-up on the last participant enrolled. Secondary endpoints are to compare overall/progression-free/total progression free survival in pts treated with sequential therapy between radium223 and docetaxel. Additional secondary objective is to identify predictive factors for radium223 therapy, including potential circulating biomarkers through the plasma collection from all enrolled pts at different timepoints and the early prognostic role of functional imaging, such as PET with choline and/or PSMA. Clinical trial information: NCT03230734.
An observational study profiling biospecimens from 10,000 metastatic prostate cancer (mPCa) patients to screen for molecular alterations.
Authors: Kim Won , Kwiatkowski Kat , Brown Justin , Rhodes Dan R , Tomlins Scott A , Feng Felix Y , Small Eric Jay 
Published: February 2018

TPS402 Background: Despite recent success in development and use of targeted agents in patients with solid tumors, there is a paucity of such therapies approved for use in prostate cancer. This observational study provides next-generation sequencing (NGS) to men with mPCa to evaluate the proportion of patients available for targeted therapy clinical trials in mPCa and to assess the feasibility of using a large-scale NGS screening program to match patients for eligibility criteria in clinical trials. Methods: Using a virtual clinical trial model to maximize patient access and enrollment, this study is providing next-generation sequencing (NGS) to 10,000 men with mPCa. Patients with histologically-documented mPCa and surplus formalin-fixed paraffin-embedded tumor tissue are eligible for enrollment. Leftover archival tissue is submitted for NGS to Strata Oncology, a clinical laboratory improvement amendments (CLIA)-certified lab. The StrataNGS assay sequences DNA and RNA, and simultaneously detects a range of actionable genomic alterations including gene mutations, small insertions and deletions, copy number changes, and gene fusions in 87 cancer-related genes. Microsatellite instability status is determined via the number of length variant alleles observed in NGS sequencing data at several microsatellite loci. Test reports presented to the clinician include all positive and negative variants detected, and information about potential matching therapeutic protocols. Clinical trial information: NCT03061305.