bluuebunny/crossref_metadata_2025 huggingface dataset:
Results of a phase II trial of neoadjuvant abiraterone + prednisone+ enzalutamide + leuprolide (APEL) versus enzalutamide + leuprolide (EL) for patients with high-risk localized prostate cancer (PC) undergoing radical prostatectomy (RP).
Authors: McKay Rana R. , Xie Wanling , Lis Rosina , Ye Huihui , Zhang Zhenwei , Trinh Quoc-Dien , Chang Steven Lee , Harshman Lauren Christine , Ross Ashley , Pienta Kenneth J. , Lin Daniel W. , Ellis William J , Montgomery Robert B. , Chang Peter , Wagner Andrew , Bubley Glenn , Kibel Adam S. , Taplin Mary-Ellen
Published: February 2018

79

Background: Patients with high-risk PC have an increased risk of recurrence and mortality despite therapy. Abiraterone, a CYP17 inhibitor, and enzalutamide, a next generation anti-androgen, have demonstrated improved overall survival in metastatic PC. In this multicenter randomized phase II trial, we evaluate the impact of second generation hormone therapy on RP pathologic outcomes. Methods: Eligible patients had biopsy Gleason score ≥4+3=7, PSA >20 ng/mL or cT3 disease (by prostate MRI). Lymph node were require to be <20 mm. Patients were randomized 2:1 to APE:EL for 6 cycles (24 weeks) followed by RP. All RPs underwent central pathology review. The primary endpoint was the rate of pathologic complete response (pCR) or minimum residual disease (MRD, tumor ≤5 mm). Secondary endpoints include PSA response, surgical staging at RP, positive margin rate, and safety. Results: 75 patients were enrolled at four sites: DFCI/BWH (n=55), BIDMC (n=11), UW (n=5), JHU (n=4). Median age was 62 years. Most patients had NCCN high-risk disease [n=66, 88%; cT3 n=21 (28%), Gleason 8-10 n=59 (79%), PSA >20 ng/mL n=17 (23%)]. All patients completed 6 cycles followed by RP. Median PSA nadir was 0.03 and 0.02 ng/mL and time to nadir was 3.7 and 4.6 months in the APEL and EL arms, respectively. The combined pCR or MRD rate was 30% (n=15/50) in the APEL arm and 16% (n=4/25) in the EL arm. The response difference was 14% (80% CI -3%-30%, p=0.263). 15 patients (14 in APEL; 1 in EL) had grade 3 adverse events (AEs). The most common grade 3 AEs were hypertension (n=7) and ALT increase (n=5). No grade 4-5 AEs occurred. Conclusions: Neoadjuvant hormone therapy plus RP in men with high-risk PC resulted in favorable pathologic responses (≤5 mm residual tumor) in 16-30% with a trend towards improved pathologic outcomes with APEL and acceptable safety profile. Follow-up is necessary to evaluate the impact of therapy on recurrence rates. Clinical trial information: NCT02268175. [Table: see text]
Pilot study of moderately-hypofractionated intensity-modulated radiation therapy over 3 weeks for localized prostate cancer.
Authors: Nakamura Kiyonao , Inokuchi Haruo , Ikeda Itaru , Kamba Tomomi , Inoue Takahiro , Yamasaki Toshinari , Kobayashi Takashi , Ogawa Osamu , Mizowaki Takashi
Published: February 2018

8

Background: The purpose of this trial was to prospectively evaluate the short-term outcomes of moderately hypofractionated intensity-modulated radiation therapy (MH-IMRT) for localized prostate cancer. Methods: In November 2013, we started a pilot study of MH-IMRT for prostate cancer. Eligible patients were 50 to 80 years old and had D’Amico’s low- or intermediate-risk disease. Fifty-four Gy in 15 fractions (3.6 Gy per fraction), in which the equivalent total dose in 2-Gy fractions to prostate cancer was estimated about 78 Gy, were delivered over 3 weeks using image-guided IMRT based on daily cone beam CT without intraprostatic fiducial markers. Neoadjuvant androgen deprivation therapy was given 4 to 8 months before the start of IMRT. The primary endpoint was incidence rates of acute toxicities, and the secondary endpoints were incidence rates of late toxicities at 2 years and biochemical relapse free survival (BRFS) at 2 years. Acute toxicities were evaluated based on the Common Terminology Criteria for Adverse Events version 4.0 criteria. Late toxicities were evaluated based on RTOG/EORTC Late Radiation Morbidity Scoring Schema. Biochemical relapse was defined according to the Phoenix definition (absolute nadir + 2 ng/ml). The planned sample size was 25 patients. Results: Twenty-five patients were enrolled in this trial. Twenty-four patients were treated with MH-IMRT, and 1 patient was treated with conventionally fractionated IMRT because his small intestine was close to the target. The median age in the cohort was 71 years old, and median follow-up period was 31 months (range 24-42). Four patients (17%) had low- and 20 (83%) had intermediate-risk disease. No grade ≥3 acute toxicity was observed and the incidence rates of grade 2 acute genitourinary and gastrointestinal toxicities were 21% and 4%, respectively. So far no grade ≥2 late toxicity has been observed and the 2-year BRFS is 95.8%. Transient PSA elevation over 0.4 ng/ml was observed in 11 patients (46%) and in 5 patients (21%) PSA rose ≥1.0 ng/ml above nadir. Conclusions: Sort-term outcome of MH-IMRT delivering 54 Gy in 15 fractions over 3 weeks for prostate cancer was comparable to that of conventionally fractionated IMRT. Clinical trial information: UMIN000012057.
The impact of prostate cancer (PC) margin extent (ME) at radical prostatectomy (RP) on biochemical relapse-free survival (bRFS).
Authors: Seyedin Steven Neema , Mott Sarah L , Snow Anthony N , Russo James Kyle , Watkins John
Published: February 2018

83

Background: Surgical margin involvement (M+) by PC at RP is associated with suboptimal bRFS; however, the interaction of M+ with coincident high-risk clinicopathologic and treatment factors obscures accurate estimation of recurrence risk. The objective of this study is to determine whether ME permits risk stratification. Methods: Retrospective analysis of clinicopathologic factor association with bRFS. Eligible patients underwent RP alone for clinically localized PC. Patients with metastatic disease, PSA > 30 at diagnosis, pathologic involvement of seminal vesicles or lymph nodes at RP, insufficient follow-up, or receipt of pre-RP or adjuvant therapy were excluded. Slides from RP specimens with close or positive margins were re-reviewed by study pathologists blinded to outcome. Results: From 2002-2010, 667 patients were eligible for analysis. The median age was 61 yrs (range, 43-76), and all had cT1-2 disease (83% T1c), with median PSA 5.6 (0.9-28.0; 85% ≤10). Robot-assisted RP was employed in 141 cases (21%). Two hundred ten patients (31%) had M+, with single maximal ME 3mm (0.1-23), and cumulative ME 4mm (0.1-34). At median follow-up of 102 months (13-184), 149 patients (22%) had recurrence, with estimated 8-year bRFS rates of 85%/56% for M-/+ patients (p < 0.01). Multivariable analysis identified PSA, Gleason score (GS), extraprostatic extension, and M+ as associated with bRFS. Specific to patients with involved margins, the combination of ME and GS permitted recurrence risk stratification, with a low-risk subset identified (GS≤6 and ME < 3mm; Table). Conclusions: The current investigation suggests that GS6 patients with maximal or cumulative ME < 3mm appear to have favorable early 8-year bRFS following RP. GS6 patients with wider ME and GS ≥7 with any extent M+ appear to have suboptimal bRFS. RP pathology reports should include ME details, in order to more precisely estimate risk of subsequent disease recurrence. [Table: see text]
Long-term outcomes of stereotactic body radiotherapy for low- and intermediate-risk prostate adenocarcinoma: A multi-institutional consortium study.
Authors: Kishan Amar Upadhyaya , Katz Alan J. , Mantz Constantine , Chu Fang-I , Appelbaum Limor , Loblaw Andrew , Cheung Patrick , Kaplan Irving D. , Fuller Donald B. , Pham Huong T. , Meier Robert , Buyyounouski Mark K. , Shaverdian Narek , Dang Audrey , Yuan Ye , Bagshaw Hilary , Prionas Nicolas , Kupelian Patrick , Steinberg Michael L. , King Christopher R.
Published: February 2018

84

Background: While a growing body of evidence supports the use of stereotactic body radiotherapy (SBRT) for the treatment of low- and intermediate-risk prostate adenocarcinoma (PCa), some trepidation exists regarding its long-term efficacy and safety. Methods: Men with low- and intermediate-risk PCa, as defined per the National Comprehensive Cancer Network guidelines, who were enrolled on various institutional phase II trials of SBRT between 2000-2012 were included in a multi-institutional consortium. Biochemical relapse (BCR) was defined as PSA > “nadir +2” or initiation of androgen deprivation therapy (ADT). Toxicity data were scored according to the CTCAE v 3.0 or Radiation Therapy Oncology Group scoring systems. Results: A total of 1644 men were eligible for analysis, with a median followup of 7.2 years. 297 patients (18.1%) had at least 9 years of followup. Fractionation schemes ranged from 33.50-40 Gy in 4-5 fractions. 892 patients had low-risk disease and 752 had intermediate-risk disease. 59 patients (3.6%) received short-term ADT. 100 patients (6.0%) experienced BCR, and 7 (0.4%) experienced distant metastases. No patients died of PCa. By Kaplan-Meier analysis, 5- and 10-year BCR-free survival rates were 98% and 94% in the low-risk group and 96% and 90% in the intermediate-risk group (p < 0.05 by log-rank test). 5- and 10-year overall survival rates were 93% and 86% in the low-risk group and 95% and 91% in the intermediate-risk group (p > 0.05 by log-rank test). Five patients (0.3%) experienced grade 3 acute genitourinary (GU) toxicities, including urinary retention, hematuria, and frequency. 30 (2%) experienced grade 3 late GU toxicity, including urinary strictures, hematuria, and retention. One late grade 4 GU toxicity (hemorrhagic urethritis) and one late grade 4 gastrointestinal toxicity (fistula-in-ano) were seen. Conclusions: To the best of our knowledge, this is the largest analysis of long-term outcomes following SBRT for PCa. The results indicate that SBRT has an efficacy and toxicity profile that compares favorably to more widespread forms of treatment, such as conventionally-fractionated external beam radiotherapy and brachytherapy.
Derivation of dose/volume constraints for the anorectum from clinician-reported outcomes (CRO) in the CHHiP trial of radiotherapy (RT) fractionation.
Authors: Wilkins Anna , Naismith Olivia Frances , Brand Douglas , Fernandez Katie , Hall Emma , Dearnaley David P. , Gulliford Sarah
Published: February 2018

87

Background: CHHiP (ISRCTN97182923, CRUK/06/016) randomised 3216 men with localised prostate cancer (1:1:1) to 3 RT fractionation schedules: 74Gy/37 fractions (f) over 7.4 weeks, 60Gy/20f/4 weeks and 57Gy/19f/3.8 weeks. Literature-based dose constraints were applied with adjustment for the hypofractionated arms. For standard fractionation the constraints (absolute dose) included V30Gy≤80%, V40Gy≤70%, V50Gy≤60%, V60Gy≤50%, V70Gy≤15%. This study aimed to derive anorectal dose constraints based on prospectively collected CRO. Methods: A case-control study design was used, 4 bowel symptoms were independently evaluated. Cases were patients experiencing a moderate or worse grade symptom 1 to 5 years post RT, who had not had the symptom pre-RT. Controls did not experience the symptom between 1 and 5 years post RT. The anorectum was re-contoured from the anal verge to the recto-sigmoid junction using VODCA software. Dose/volume parameters were extracted and hypofractionated dose schedules were converted to 2Gy equivalent schedules using an α/β ratio of 3Gy. Bootstrapped ROC analysis (1000 replicates, balanced outcomes) was used to derive dose constraints using both the Youden index and “Closest top Left” (CtL). Only AUC with a lower limit of the 95% confidence interval >0.5 were considered statistically significant. Any constraint derived in <99% of bootstraps was excluded. Results: Statistically significant dose constraints were derived for rectal bleeding, increased bowel frequency, faecal incontinence and rectal pain (table). Conclusions: Dose constraints differed between symptoms, indicating potentially different pathogenesis of each radiation-induced side effect. Derived dose constraints were tighter than those used in CHHiP; use of these may reduce anorectal symptoms post RT. Comparable data derived from the hypofractionated cohorts will be presented. [Table: see text]
Contribution of microRNA-200b-3p to radiation therapy resistance in 22RV1 prostate cancer cells.
Authors: Thoms John , Aoki Satoko , Pena Castillo Lourdes
Published: February 2018

89

Background: Radiation therapy (RT) is a standard treatment option for men with localized prostate cancer. Despite having well-established treatment regimens, such men still fail RT at a rate of up to 30-50%. RT resistant phenotype is a key component leading to treatment failure. MicroRNAs (miRNAs) can influence the response to RT, and the abundance or lack of certain miRNAs can induce a RT resistant phenotype through alteration of survival pathways. We show that altered expression of miR-200b-3p plays an important role in contributing to RT resistance. Methods: RT resistant subline from the parental 22RV1 prostate cancer cell line was generated by exposure to fractionated RT – 22RV1-RT. The global expression level of miRNAs and mRNA was determined, using the Affymetrix GeneChip®: miRNA 4.0 and Human Gene 2.0 ST Arrays. Parental and 22RV1-RT cells were transfected with miR-200b-3p mimics or negative control. The influence of miR-200b-3p on cellular proliferation, morphology, migration, clonogenic survival and response to RT was determined by standard assays. Results: MiR-200b-3p was the only miRNA that was statistically differentially expressed between the two cell lines. There were 39 differentially expressed genes. Of the 65 genes predicted to be regulated by miR-200b-3p as identified from miRTarBase, only Fibronectin 1 (FN1) was in common. FN1 was up-regulated in 22RV1- RT cells. MiR-200b-3p mimics; in comparison to negative control mimics, suppressed cell proliferation in both cell lines. Both cell lines with negative control mimics have fibroblastic-type morphology and display a stretched shape following RT. While, cells transfected with miR-200b-3p mimics demonstrated a round morphology and formed clusters following RT. Over-expression of miR-200b-3p mimics inhibited cell migration synergically with RT and demonstrated a lower degree of clonogenic survival following RT in 22RV1-RT cells compared to negative control mimics. Surprisingly, miR-200b-3p mimics reversed the observed RT resistance and the sensitivity to RT was to the same degree as the parental 22RV1 cells. Conclusions: Together, these data suggest that miR-200b-3p independently contributes to RT resistance in 22RV1 prostate cancer cells.
Microrna-198: A novel tumor suppressor in prostate cancer.
Authors: Ray Jessica , Hoey Christianne , Huang Xiaoyong , Boutros Paul Christopher , Liu Stanley K.
Published: February 2018

92

Background: microRNAs (miRNAs) are small non-coding RNA molecules which act as repressors of gene function, and have been identified as playing substantial roles in cancer as both tumor suppressors and oncogenes. miR-198 has been reported to be down-regulated in several cancers, with low expression associated with worse overall survival. In addition, miR-198 has demonstrated tumor suppressor effects by altering several hallmarks of cancer. Despite compelling evidence in other cancers, miR-198's role in prostate cancer aggression has not yet been evaluated. Methods: Experiments were conducted by overexpressing miR-198 in three prostate cancer cell lines: DU145, LNCaP and 22RV1. To examine miR-198's effect on hallmarks of cancer in vitro, we used standard protocols to assay proliferation, colony formation, cell cycle profile, migration, and invasive potential. Gene array, qPCR, western blotting, and siRNA knockdown experiments were used to establish miR-198 downstream targets. Results: Overexpression of the candidate tumor suppressor miR-198 diminished proliferation in all prostate cancer cell lines and significantly impaired colony formation in soft agar. Subsequently, miR-198 expression was also demonstrated to reduce growth and tumor formation in vivo using LNCaP xenografts. Gene arrays and in silico target prediction identified several candidate targets, none of which have been previously linked to miR-198. MIB1, an E3 ubiquitin ligase, was the only target we have since identified to be reduced with miR-198 overexpression at both the RNA and protein levels. Knockdown of MIB1 recapitulated miR-198's effects on proliferation and colony formation, and further experiments are underway to demonstrate a direct binding relationship. An additional gene array with MIB1 siRNA will be performed to highlight pathways through which MIB1/miR-198 suppress tumorigenesis. Conclusions: Our evidence supports miR-198 as an important tumor suppressor in prostate cancer, with elevated expression impairing proliferation, colony formation, and in vivo tumor formation. This investigation into miR-198 highlights a potential role as a prostate cancer biomarker, or as a potential target of therapeutics to restore miRNA activity.
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.
Impact of cabazitaxel on metastatic bone health in patients with castration resistant prostate cancer previously treated with docetaxel: CaBone Study.
Authors: Santini Daniele , Morelli Franco , Bertoldo Francesco , Facchini Gaetano , Rizzi Daniele , Gatti Davide , Maiello Evaristo
Published: February 2018

TPS405

Background: The most significant morbidity of prostate cancer (PC) is bone metastasis (BM). More than 90% of patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) have radiologic evidence of BM, which are a major cause of death, disability, decreased QoL, and increased treatment cost. Unlike deaths from many other types of cancer, deaths from PC are often due to bone disease and its complications. In vitro data demonstrate a role for taxanes in the regulation of osteoclast formation and function, with a decreased resorption activity. ÊSTAMPEDE study has shown a strong clinical benefit, in term of OS, PFS and skeletal related events (SREs) delay compared with ADT alone, in metastatic hormone-sensitive pts treated with docetaxel (DOC) and ADT. TROPIC Study has shown that cabazitaxel (CBZ) prolongs OS regardless of DOC response in responder, resistant and refractory pts. Some data are available on pain progression, pain response and ECOG PS deterioration but in a unselected ITT population with a low prevalence of only BM disease at baseline, 25% of men had visceral metastasis. No data are available on effects of CBZ on BM and his direct impact on quality of life, bone turnover markers and time to the first SRE events. The aim of CaBone phase II study is to investigate, specifically, the effects on bone disease, bone turnover and on the bone related quality of life of CBZ in mCRPC pts with skeletal involvement without visceral disease. Methods: CaBone is a single arm, prospective, open label, multi center, phase II - GOIM - cooperative study of CBZ 25 mg/m2 q21 plus daily PDN (10 mg) in mCRPC pts with bone mets without visceral disease progressed during or after DOC treatment. Primary endpoint is Bone PFS according to PCWG2 while the Secondary are related on Evaluation of bone disease: Time to SRE, Time to Bone Pain Progression, Bone Pain Response, Time to opiate use for cancer-related pain, Time to deterioration in ECOG PS, Evaluation of Quality of Life and Functional status, Safety and centralized bone turnover markers: ALP, Bone ALP , LDHÊ, Serum CTx, iPTH, 1.25 (OH)2ÊD3. 107 subjects will be enrolled in CaBone study. CaBone is partially supported by Sanofi Genzyme. Clinical trial information: 2016-001253-41.
Randomized phase III study of gemcitabine and cisplatin (GC) versus dose dense methotrexate, vinblastine, doxorubicin and cisplatin (DD-MVAC) in the perioperative setting for patients with locally advanced transitional cell cancer of the bladder: The French GETUG/AFU V05 VESPER trial.
Authors: Pfister Christian , Gravis Gwenaelle , Pignot Geraldine , Flechon Aude , Soulie Michel , Chevreau Christine , Guy Laurent , Laguerre Brigitte , Mottet Nicolas , Joly Florence , Henry-Amar Michel , Radvanyi Francois , Allory Yves , Culine Stephane
Published: February 2018

TPS530

Background: Radical cystectomy remains the gold standard treatment for invasive non metastatic transitional cell cancer of the bladder. Perioperative chemotherapy (adjuvant ou neoadjuvant) has been developed to increase overall survival. However, the chemotherapy administration time and optimal chemotherapy regimen are not yet determined. As DD-MVAC has been shown to be associated with higher response rates in bladder metastatic disease, also a better efficacy can be suspected in the perioperative setting. Methods: We designed a randomized phase III study to compare the efficacy of GC and DD-MVAC in term of progression-free survival in patients for whom chemotherapy has been decided, before or after radical cystectomy (disease defined by a T2, T3 or T4a N0 M0 stadification for patients receiving neoadjuvant chemotherapy or pT3 or pT4 or pN+ and M0 for patients receiving adjuvant chemotherapy). Secondary endpoints include overall survival, side effects, response rate in the neoadjuvant setting. Main exclusion criteria were histological variants (pure adenocarcinoma or pure epidermoid carcinoma or pure or mixed small-cell neuro-endocrine carcinoma) and ventricular ejection fraction under 50%. The total number of patients projected was 500 based on the median progression-free survival rate of 50% at 3 years observed in patients treated with GC (standard arm A) in the perioperative setting. An absolute improvement of 10% (HR = 0.74) was expected with DD-MVAC (experimental arm B) with a = 0.05 and b = 0.20. In October 2017, 460 patients have been included. An interim analysis is planned after the occurrence of 174 events. With an estimated uniform accrual rate of 140 patients per year for 3.5 years and exponential survival, the final analysis is expected to occur 8 years after the start of the trial. Concomitant ancillary study has also started, focusing on the identification of subgroups for muscle invasive bladder tumors sensitivity to neoadjuvant chemotherapy, as suggested by the recent MDA classification. Clinical trial information: NCT 018 12369.