bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors for reclassification at repeat biopsy in active surveillance cohort for low-risk prostate cancer: From an interim analysis of PRIAS-JAPAN.
Authors: Sugimoto Mikio , Kakehi Yoshiyuki , Hirama Hiromi , Naito Seiji , Yamaguchi Akito , Koga Hirofumi , Shinohara Nobuo , Maruyama Satoru , Arai Yoichi , Mitsuzuka Koji , Egawa Shin , Sasaki Hiroshi , Homma Yukio , Fukuhara Hiroshi ,   PRIAS-JAPAN study group
Published: March 2017

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Background: The Prostate Cancer Research International: Active Surveillance (PRIAS) study is a large international prospective observational AS study that commenced in 2006. Japan has participated in the study (PRIAS-JAPAN) since 2010, and recruitment remains ongoing. The objective of this study is to define clinical and pathological factors predicting reclassification at the time of 1-year repeat biopsy (re-Bx) based on a Japanese cohort forming part of the PRIAS study. Methods: The inclusion criteria for the PRIAS study are as follows: clinical stage T1c/T2, PSA ≤ 10 ng/ml, PSA density (PSAD) < 0.2 ng/ml per milliliter, one or two positive biopsy cores, and Gleason score (GS) ≤ 6 at initial diagnostic biopsy. Baseline clinical characteristics and prostate-specific antigen doubling time (PSADT) at the time of re-Bx were analyzed via multivariate logistic regression with respect to reclassification on the 1-year re-Bx. Results: A total of 711 patients were enrolled in PRIAS-JAPAN by September 2016. Of these, 409 underwent re-Bx at 1-year. The re-Bx acceptance rate was 83.3%. A total of 122 (29.8%) was reclassified whereas 150 (36.7%) had no cancer. Older age, a higher PSAD, a higher positive core rate, and a shorter PSADT were significant predictors of reclassification. Among them, the positive core rate was the strongest predictor for pathological reclassification at 1-year after starting AS. The AS remaining rates at 1, 2, 3, 4 and 5 years were 93.9%, 70.6%, 65.7%, 60.0% and 49.5% respectively Conclusions: An interim analysis of a Japanese AS cohort participating in PRIAS revealed that the positive core rate was strongly associated with reclassification at the 1-year re-Bx. Clinical trial information: UMIN000002874. [Table: see text]
Factors affecting the risk of erroneous interpretation of online surgeon rating websites among the general population.
Authors: Weight Christopher J. , Watson Brett , Labine Lucas , Albersheim-Carter Jacob , Konety Badrinath R.
Published: March 2017

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Background: Several websites present estimated individual surgeon complication rates for surgeons in both the United States and Great Britain. Though some researchers have raised questions as to the validity and appropriateness of these publicly displayed outcome measures, there remains very little research into how the general public may interpret these data to make health care decisions. Methods: We invited attendees of the 2016 Minnesota State Fair who met entry criteria, (adults > 18 years old, English speakers who were able to use a tablet computer) to complete our survey. Demographic data was presented along with various screen shots from online surgeon rating websites. Patients were then asked to interpret these graphics and report complication rates. Some graphics displayed complications rates for one surgeon alone, while others compared multiple surgeons side-by-side. Results: 392 participants completed the survey from a broad geographic distribution from the upper Midwest (179 unique zip codes). Median age was 49 (Interquartile range 28-61), the female:male ratio was 3:2, 57% had completed a college or graduate degree and 85% were Caucasian vs. 15% ethnic minorities. The majority of participants (76%) were able to correctly estimate complication rates when a single surgeon and his or her complication rates were shown, but when respondents were asked to compare/rank multiple surgeons, respondents overestimated complication rates by 5-7 fold, on average, for the lower ranking surgeons and only 15% of respondents could correctly identify the complication rate of the lowest performing surgeon. College graduates and those with a graduate degree were more likely to correctly estimate complication rates compared to participants with less education (odds ratio 1.98 95% CI 1.04-3.75, p = 0.035). Conclusions: Online surgeon rating websites that compare and rank surgeons may lead the general public to drastically overestimate the risk of postoperative complications. These errors in estimating complication rates appear to be reduced amongst those who are college educated and when viewing single surgeon outcomes in the absence of a comparison.
Development of a screening tool to assess prostate cancer health literacy.
Authors: Kotwal Ashwin A. , Master Viraj A. , Jani Ashesh B. , Fraser Gertrude , Wolf Andrew M , Wang Daniel Shin-Ping , Duncan Howard , Ewur Kwesi , Taber Angela Marie , Kilbridge Kerry L.
Published: March 2017

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Background: Poor comprehension of prostate cancer (PCa) related terms can create barriers to informed discussions on screening, treatment, and measuring outcomes, and contribute to disparities in African American (AA) men. We developed a screening tool to assess for low PCa-related health literacy. Methods: We assessed PCa-related literacy in a sample of 189 AA men, age >40 years from diverse socioeconomic status (SES) using a 27-item scale derived comprehension of commonly used terms for urinary, bowel and sexual function. Using item-response models we examined differential item functioning by education. We developed rapid screening tools based on understanding of 1 or 2 words to predict overall comprehension. Receiver operating characteristic curves assessed the sensitivity and specificity for individuals understanding less than a pre-specified threshold of 70% on the overall scale, defined as “low literacy.” Results are being tested in an independent sample of 110 AA men. Results: The 27-item scale had good internal reliability (Cronbach alpha = 0.93). 47% of the sample met criteria for low literacy. Lower education groups had relatively poor comprehension of sexual function terms compared to higher education groups. 1-item scales using comprehension of the term “rectal urgency” had a sensitivity of 95% for identifying low literacy, “erection” had a specificity of 98%, and “vaginal intercourse” had a sensitivity of 91% and specificity of 81%. Combining “vaginal intercourse” and “rectal urgency” yielded a 2-item scale with strong characteristics (sensitivity 88%, specificity 89%), as did combining “vaginal intercourse” and “erection” (sensitivity 94%, specificity 81%). Conclusions: Rapid screening tools assessing PCa-related literacy performed well in a community sample of AA men with varied SES. Providers can use these tools to identify those at risk of poor comprehension to tailor outcome measurement and shared decision making. [Table: see text]
Is there a protective role of testosterone against high-grade prostate cancer? Incidence and severity of prostate cancer in 553 patients undergoing prostate biopsy in a prospective data register.
Authors: Yassin Aksam , Salman Mahmoud
Published: March 2017

128

Background: Major concern regarding testosterone therapy (TRT) in middle-aged and elderly men is still prostate safety or cancer Methods: 553 prostate biopsies (2008-2013) were performed at our institute. 22 patients refused biopsy. We investigated incidence and severity of PCa in three groups: hypogonadal (T ≤ 350 ng/dl) men receiving TRT, hypogonadal untreated, and eugonadal men. All groups underwent similar screening intensity of at least once per year. Biopsies were performed when indicated according to EAU guidelines. Results: In 42 hypogonadal men receiving TRT, 7 (16.7%) had a positive biopsy. Of these, 5 had a Gleason score ≤ 6 (71.4%) and 2 subjects a Gleason score > 6 (28.6%). Predominant Gleason score was 3 in all 7 men (100%). Tumor grade was II in 6 (85.7%) and II-III in 1 (14.3%) men. 162 untreated hypogonadal men, 84 (51.9%) had a positive biopsy. Of these, 34 had a Gleason score ≤ 6 (40.5%) and 50 a Gleason score > 6 (59.5%). Predominant Gleason score was 3 in 65 (77.4%), 4 in 17 (20.2%) and 5 in 2 (2.4%) men. Tumor grade was II in 35 (41.7%), II-III in 10 (11.9%), III in 34 (40.5%) and IV in 5 (6.0%) men. In 349 eugonadal men, 132 (37.8%) had a positive biopsy. Of these, 56 had a Gleason score ≤ 6 (42.4%) and 76 a Gleason score > 6 (57.6%). Predominant Gleason score was 3 in 109 (82.6%), 4 in 22 (16.7%) and 5 in 1 (0.1%) men. Tumor grade was II in 59 (44.7%), II-III in 6 (4.5%), III in 63 (47.7%) and IV in 4 (3.0%) men. Conclusions: The incidence of positive prostate biopsies was lowest in hypogonadal men receiving TRT. The severity of PCa – in terms of Staging and Grading - was significantly lower in hypogonadal patients receiving TRT. TRT may protect against high-grade PCa. Protective role of TRT against PCa must be discussed and considered in larger studies.
A combination of both testosterone and white blood count as predictive factors of overall survival in localized prostate cancer.
Authors: Taussky Daniel , Soulieres Denis , Azoulay Laurent , Yin Hui , Bahig Houda , Bahary Jean-Paul , Delouya Guila
Published: March 2017

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Background: Low testosterone is generally associated with a higher overall mortality rate. We previously published that an increase in neutrophils is associated with lower overall survival in a large population of patients with localized prostate cancer. In this study, we tested a combination of both testosterone and neutrophils to predict for overall survival in a prospective cohort of patients treated with radiotherapy for localized prostate cancer. Methods: 414 patients from our institutional database were enrolled prospectively in phase 2 or 3 studies. To be included in this present analysis, patients had to have a baseline testosterone and complete blood count before enrollment in their respective study. Thirty-three patients were excluded for missing data for a total of 381 (92%) patients were included for analysis. Multivariate cox proportional hazards models were used to analyze the influence of white blood count (WBC = neutrophils + lymphocytes) and testosterone level on biochemical recurrence (Phoenix definition) and overall survival (OS). A cutoff level for testosterone of 10.4 nmol/l ( = 300ng/dL) was used as an indicator of hypogonadism and a WBC cutoff of 6.2 (109/L) representing the median value of this study population. Results were adjusted for cancer characteristics, comorbidities and androgen deprivation therapy. Results: Median age (range) was 71 (52-82) years. The median follow-up for biochemical recurrence and OS analysis were 72 and 78 months, respectively. WBC and testosterone were not predictive of biochemical recurrence, but CAPRA score 6-10 vs. ≤ 2 was (HR 5.39, 95% CI 1.19-24.45). WBC ≥ 6.2 alone was not associated with OS (HR 0.66, 95% CI 0.30-1.46), but when combined with a testosterone > 10.3 nmol/l, it was associated with a HR of 2.96 (95%CI 1.45-6.06) when compared to a WBC < 6.2, P-interaction = 0.01. Conclusions: A combination of high WBC and normal testosterone levels seem to be associated with increased mortality in patients with localized prostate cancer. Validation in larger samples is needed and could help to identify patients with increased risk of mortality within the first 6-7 years post treatment.
Phase I/II study on stereotactic hypofractionated once-weekly radiation therapy (SHORT) for localized prostate cancer.
Authors: Mallick Indranil , Arunsingh Moses , Prasath Sriram , Arun B , Roy Paromita , Dabkara Deepak , Gupta Sujoy
Published: March 2017

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

14

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

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

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

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

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

16

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

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

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

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Background: The significance of germline variants and their implications for prostate cancer (PCa) patients has gained prominence. Mismatch repair (MMR) genes such as MSH6 and MSH2, along with DNA repair genes, may be more important in PCa than previously appreciated. In the present study, we compared linkage results between African American (AA) and Caucasian (CA) PCa families with multiple affected family members. Methods: Study subjects were from 15 large, high-risk, clinically homogenous AA families and 4 CA families from Southern Louisiana. All families had at least ≥ 3 members with family member diagnosed with PCa. Genotyping for linkage analyses was done using Illumina Infinium II SNP HumanLinkage-12 panel. 6,068 SNPs were released for linkage analyses. Parametric linkage analyses were performed using Merlin software, version 1.1.2. An HLOD score > 1.86 was considered suggestive of linkage. Results: A total of 129 individuals from 15 AA families were genotyped including 45 affected men, 44 unaffected men, and 40 women. The average age at diagnosis was 61; 8 of 15 families had more than 4 affected individuals. 50 CA individuals from similar families were genotyped including 12 affected men, 26 presently unaffected men, and 12 women. For CA families, the average age of onset was 66, with at least 5 affected individuals in each family. In AAs, we identified a peak of suggestive linkage at chromosome 2p16 (HLOD = 1.97). Similarly, in CA families, the strongest linkage signal was observed on chromosome 2q14.1 with an HLOD score of 1.94. At the2 q14 linkage region, there was no linkage in AA PCa families (HLOD = 0.0004). Similarly, on 2p16, there was no linkage in the CA cohort (HLOD = 0). Conclusions: The MSH6 gene is located in 2p16 region. MMR gene mutations have been shown to have evidence of microsatellite instability in PCa as well as hereditary nonpolyposis colorectal cancer. MSH6 gene may represent a genetic variant contributing to risk of PCa in high risk AA families. This potentially has therapeutic implications for use of PD1 inhibitors in this population.
Long-term follow-up from STAMP, a phase II trial, evaluating sipuleucel-T and concurrent (CON) vs sequential (SEQ) abiraterone acetate + prednisone in metastatic castration-resistant prostate cancer patients (pts).
Authors: Small Eric Jay , Lance Raymond S. , Redfern Charles H. , Millard Frederick E. , Gardner Thomas A. , Dawson Nancy Ann , Fong Lawrence , Karsh Lawrence Ivan , Corman John M. , Nordquist Luke T. , Murdock Myron I , Curti Brendan D. , Chang Nancy N. , Shore Neal D.
Published: March 2017

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Background: The optimal sequence and combination of life-extending anticancer therapies in mCRPC pts remains unknown. Sipuleucel-T (sip-T), an autologous cellular immunotherapy approved for the therapy of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC) pts, was evaluated in combination with abiraterone acetate and prednisone (abi) in the phase II STAMP trial (NCT01487863), with pts randomly assigned to receive CON sip-T + abi or SEQ sip-T followed by abi. The combination was well-tolerated and did not alter the immune response parameters that correlate with overall survival (OS) (Small Clin Can Res 2015). Here, we present long-term follow-up of clinical outcomes, including OS. Methods: mCRPC pts were randomized 1:1 to CON or SEQ therapy with sip-T and abi. Abi began 1 day after (CON) or at wk 10 (SEQ) after the first sip-T infusion and continued for 26 wk of therapy, after which continued abi therapy was permitted. Long-term clinical outcomes included OS, disease-specific death (DSS), progressive disease (PD), time to first anticancer intervention (tACI), and safety. Results: 69 pts were enrolled (35 CON; 34 SEQ). Median OS was 34.0 mo (95% CI, 24.4-not estimable [NE]; 30.0 mo CON; 34.2 mo SEQ; p = 0.921), and median time to DSS was not reached (CON vs SEQ; p = 0.733). Median time to PD was 17.3 mo (95% CI, 9.7–NE; 17.7 mo CON vs 13.9 mo SEQ; p = 0.914; consistent with higher rates of abi discontinuation due to PD in SEQ [26.5% vs 14.3% in CON]). tACI was similar between arms at 15.4 mo (95% CI, 11.0–19.9). No new safety signals were observed with the combination, and no discernable difference in clinical outcomes was observed with CON or SEQ treatments. Conclusions: Long-term follow-up data confirm that sip-T + CON or SEQ abi is well-tolerated, with no new safety signals. No clear differences were observed in clinical outcomes between arms, although the study was not powered to detect these differences. Future and more appropriately powered studies on the effect of sip-T + continuous abi for responding pts may provide further insights on the benefit of combination therapy. Clinical trial information: NCT01487863.
Adjuvant androgen deprivation (ADT) versus mitoxantrone plus prednisone (MP) plus ADT in high-risk prostate cancer (PCa) patients following radical prostatectomy: A phase III intergroup trial (SWOG S9921) NCT00004124.
Authors: Glode L. Michael , Tangen Catherine M. , Hussain Maha , Swanson Gregory P. , Wood David Peter , Sakr Wael , Dawson Nancy Ann , Haas Naomi B. , Flaig Thomas W. , Dorff Tanya B. , Lin Daniel W. , Crawford E. David , Quinn David I. , Vogelzang Nicholas J. , Thompson Ian Murchie
Published: March 2017

2

Background: High risk localized Pca patients are more likely to relapse and suffer morbidity/mortality from metastatic disease after prostatectomy. Adjuvant ADT can reduce this risk. We hypothesized that MP in addition to two years of ADT could further reduce mortality from PCa. Methods: Participants with clinically localized (T1-T3, N0, M0) PCa received radical prostatectomy. Eligibility required ≥ 1 high risk criteria defined as Gleason sum ≥8; pT3b or pT4 or N1; Gleason 7 with positive margin; any one of these preoperative findings: PSA>15ng/ml, biopsy Gleason >7, biopsy Gleason >6 with PSA>10. ADT arm consisted of bicalutamide and goserelin for 2 years. ADT+MP arm received ADT plus 6 cycles of M 12mg/m2+ P 5mg BID. Primary endpoint was survival (OS). Median OS was anticipated to be 10 years in ADT arm requiring 680 patients/arm to detect a hazard ratio of 1.30 with 92% power and one-sided α=0.05. Results: S9921 enrolled patients from 10/99 to 1/07 when the DSMC recommended stopping due to increased incidence of leukemia in the ADT+MP arm. Of 983 patients randomized, 22 ineligible. 481 eligible on ADT and 480 on ADT+MP. Patients were stratified by stage (≤pT2, ≥pT3, N0 or N+), Gleason score, and intent to receive adjuvant radiation (RT) (Y/N). Median age was 60 years, 84% were white, presurgical PSA was 7.6 ng/ml, 16% had positive nodes, 26% intended to receive RT, 63% had positive margins. 11 ADT and 20 ADT+ MP received no protocol treatment. Median follow-up is 11.2 years. Conclusions: Survival was greater than anticipated in both arms. MP increases the risk of leukemia. There is no evidence that MP improves PCa specific survival when added to 2 years of adjuvant ADT. Clinical trial information: NCT00004124. [Table: see text]
Preclinical discovery and validation of high-dose androgen drug synergies for the treatment of prostate cancer.
Authors: Nyquist Michael D. , Corella Alexandra N , Coleman Ilsa , Gao Shuai , Tharakan Robin , Riggan Luke , Cai Changmeng , Nelson Peter , Mostaghel Elahe A.
Published: March 2017

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Background: Recent clinical studies have taken advantage of the dichotomous ability of androgen receptor signaling to elicit growth-suppressive and differentiating effects by giving hyper-physiological levels of testosterone. This approach has demonstrated safety, improved quality of life, and met primary endpoints for efficacy in clinical trials; however, novel strategies to enhance and optimize the anti-tumor efficacy of this approach are needed. Methods: We performed high-throughput drug screening in PCa cell lines to identify agents showing synergy with high-dose androgen treatment. Results: The Survivin inhibitor YM155, demonstrated a potent synergy with high-dose androgen. YM155 IC50 values shifted from 24 nM without R1881 to 3.85 nM with 160 pM R1881.Using qRT-PCT and ChIP-qPCR we establish the mechanism of this synergy was due to the direct upregulation of YM155 transporter SLC35F2 by androgen receptor transcriptional activity. Knockdown and overexpression of SLC35F2 dramatically modulated sensitivity to YM155. In two xenograft models SLC35F2 and tumor DHT levels are highly correlated and castration-induced decreases in tumor androgens cause an identical decline in levels of SLC35F2. In CRPC metastases SLC35F2 expression significantly correlated with AR activity score (r = 0.62, p < 0.001). However, ~1/3 of tumors examined had transcripts for AR and SLC35F2, 1/3 AR+ but SLC35F2 negative, and 1/3 are negative for both. Conclusions: We describe a novel synergy between YM155 and high-dose androgen therapy mediated by the direct upregulation of YM155 transporter SLC35F2 by androgen receptor and implicate SLC35F2 expression as a potential biomarker for YM155 sensitivity. Whether ligand independent AR variants (AR-Vs) can constitutively mediate SLC35F2 expression is unknown, but if so would also provide a means of stratifying identifying men likely to respond to YM155.This study demonstrates a novel paradigm for precision medicine in the pharmacologic induction of drug sensitivity in a tissue restricted manner. Hormonal induction of carrier-mediated drug transport is a completely novel and unexplored concept that is poised to exploit androgen-based treatment strategies.
Long-term efficacy and safety of enzalutamide (ENZ) monotherapy in hormone-naïve prostate cancer (HNPC): 3-year, open-label, follow-up results.
Authors: Tombal Bertrand F. , Borre Michael , Rathenborg Per , Werbrouck Patrick , Van Poppel Hendrik , Heidenreich Axel , Iversen Peter , Braeckman Johan , Heracek Jiri , Baron Benoit , Krivoshik Andrew , Hirmand Mohammad , Smith Matthew Raymond
Published: March 2017

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Background: A phase 2 study of the androgen receptor inhibitor ENZ as monotherapy in patients with HNPC [NCT01302041] showed a high prostate-specific antigen (PSA) response rate, regardless of baseline metastases, and favorable tolerability. In a 1- and 2-year follow-up, ENZ maintained long-term reductions from baseline in PSA, with minimal impact on total-body bone mineral density (BMD). Herein, results from a pre-specified 3-year follow-up are reported. Methods: A total of67 patients with HNPC and non-castrate testosterone ( ≥ 230 ng/dL) received ENZ 160 mg/day until disease progression or unacceptable toxicity. The primary end point of PSA response ( ≥ 80% decline from baseline) was analyzed at week 25 and 1, 2, and 3 years. Other end points were best overall tumor response, BMD, body composition, quality of life, and safety. Results: At the 3-year visit, 42 (62.7%) patients remained on the study medication. Of those, 38 (90.5%; 95% confidence interval 77.4%, 97.3%) maintained a PSA response. Of the 26 patients with metastases at baseline, 17 (65.4%) had a complete or partial response as best overall response at 3 years. In patients who completed the 3-year visit, minimal changes from baseline were observed in total-body BMD or in BMD of the femoral neck, trochanter, spine L1–L4, or forearm (median and mean changes ranged from –3.6% to 1.3% and –2.7% to –0.1%, respectively). The EORTC QLQ-C30 global health status results showed a small decrease at 3 years versus baseline (–3.96 points), consistent with the 2-year results. At 3 years, measurements for total body fat increased (median, 14.7%; mean, 16.5%) and total body lean decreased (median, –6.3%; mean, –6.5%) from baseline. Physical functioning, fatigue, and dyspnea worsened ( > 10 points) at 3 years, similar to results at 2 years. The most frequently reported adverse events ( > 10%) were gynecomastia, fatigue, hot flush, nipple pain, hypertension, diarrhea, nausea, pain in extremity, back pain, and constipation. Conclusions: In patients with HNPC treated with ENZ for 3 years, the efficacy of ENZ as monotherapy was maintained. Overall, BMD, global health status, and safety results were similar to those at 2 years. Clinical trial information: NCT01302041.
Real-world treatment with abiraterone acetate in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC).
Authors: Boegemann Martin , Hatzinger Martin , Hercher Dirko , Matus Geoffrey , Everaert Els Grieta , Dopchie Catherine , Sheehan Denise , Birtle Alison J. , Garcia Alvarez Laura , Zou Lu , Kluska Martin , Antoni Laurent , Pissart Geneviève , Lukac Martin , Dearden Lindsay
Published: March 2017

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Background: In the COU-AA-302 trial, abiraterone acetate plus prednisone (AAP) resulted in extension of radiographic progression-free survival (rPFS) and overall survival in chemotherapy-naïve mCRPC patients compared to prednisone alone. However, limited data on AAP treatment and outcomes is available in the real-world in this setting. The aim of this study is to describe the duration of AAP treatment in routine clinical practice in mCRPC patients prior to chemotherapy. Methods: The study was designed as a retrospective chart review of mCRPC patients identified through oncology and urology practice in Belgium, France, Germany and the UK. This first analysis reports baseline patient characteristics at AAP initiation for the first 224 patients. Treatment duration, PFS and rPFS were estimated using Kaplan-Meier curves. Potential factors associated with treatment duration were explored using the log-rank test. Results: Data from 224 mCRPC patients treated with AAP (Belgium: 67; Germany: 150; UK: 7; none from France) across 19 centres was considered in this initial analysis. At baseline, the median age was 75.5 years (interquartile range [IQR]: 69.0-82.0) and the median PSA level was 50.0 ng/mL (IQR: 21.0-121.0). Patients with visceral metastases (9.8%) and ECOG 2-3 (9.4%) were included in this study, in contrast to those included in the COU-AA-302 study. Median duration of AAP treatment was 11.6 months (95% confidence interval [CI]: 10.2-12.8), whilst median PFS and rPFS were 11.9 months (95% CI: 10.8-13.3) and 16.5 months (95% CI: 13.5-20.0), respectively. Reasons for discontinuing AAP involved PSA progression (52.2%), radiographic progression (38.9%), symptomatic progression (27.8%), non-toxic death (19.4%) and toxicity (2.2%). Treatment duration was significantly longer in mCRPC patients with either baseline ECOG status 0, lower PSA, alkaline phosphatase, aspartate aminotransferase, or lactate dehydrogenase levels (p < 0.05). Conclusions: The results of this study suggest similar treatment duration and rPFS for mCRPC patients in this real-life cohort with poorer clinical features compared to those observed in the COU-AA-302 trial population.