bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of a genomic-clinical classifier model for predicting clinical recurrence of patients with localized prostate cancer in a high-risk population.
Authors: Jenkins Robert B. , Bergstralh Eric J , Davicioni Elai , Karnes R. Jeffrey , Ballman Karla V. , Fink Stephanie , Black Peter C. , Ghadessi Mercedeh , Triche Timothy J. , Klee George G , Kollmeyer Thomas M. , Vergara Ismael A , Crisan Anamaria , Erho Nicholas , Sierocinski Thomas , Buerki Christine , Carlson Rachel , Grill Diane E , Zimmermann Benedikt , Haddad Zaid
Published: February 2017

175

Background: The efficient delivery of adjuvant and salvage therapy after radical prostatectomy in patients with prostate cancer is hampered by a lack of biomarkers to assess the risk of clinically significant recurrence and progression.

Methods: Mayo Clinic Radical Prostatectomy Registry (RP) patient specimens were selected from a case-control cohort with 14 years median follow-up for training and initial validation of an expression biomarker genomic classifier (GC). An independent, blinded case-cohort study of high-risk RP subjects was used to validate GC, comparing the performance of GC to a multivariate logistic regression clinical model (CM) and GC combined with clinical variables (genomic-clinical classifier, GCC) for predicting clinical recurrence (defined as positive bone or CT scan within 5 years after biochemical recurrence). The concordance index (c-index) and Cox model were used to evaluate discrimination and estimate the risk of clinical recurrence.

Results: In the training subset (n=359), both GC and GCC had a c-index of 0.90 whereas CM had a c-index of 0.76. In the internal validation set (n=186), GC and GCC had a c-index of 0.76 and 0.75, while CM had a c-index of 0.69. In an independent high-risk study (n=219), GC and GCC had a c-index of 0.77 and 0.76, while CM had a c-index of 0.68. In subset analysis of Gleason score 7 patients within the high-risk group, GC and GCC showed improved discrimination with c-index of 0.78 and 0.76, respectively compared to 0.70 for CM. In the high-risk group, the risk of recurrence by GC model score quartiles at 5 years after RP was estimated at 1%, 5%, 5% and 18%.

Conclusions: The GC model shows improved performance over CM in the prediction of clinical recurrence in a high-risk cohort and in subset analysis of Gleason score 7 patients. The addition of clinical variables to the GC model did not significantly contribute to classifier performance in patients with high-risk features. We are further testing the performance of the GC and GCC models and their usefulness in guiding decision-making (e.g., for the adjuvant therapy setting) in additional studies of prostate cancer clinical risk groups.
Comparison of PSA, FDG-PET, and Prostate Cancer Working Group 2 (PCWG2) criteria to interpret apparent progression on first post-treatment bone scan.
Authors: Autio Karen A. , Fox Josef J. , Haupt Eric Conrad , Schöder Heiko , Scher Howard I. , Larson Steven M. , Morris Michael J.
Published: February 2017

20

Background: The risk of prematurely discontinuing effective therapy in patients with metastatic castrate resistant prostate cancer (mCRPC) because of apparent initial progression on bone scan has repercussions for drug development and clinical practice. We evaluated three methods to distinguish disease progression (POD) from non-progressive bone disease or flare response.

Methods: The dataset was comprised of men with mCRPC enrolled in contemporary clinical trials using AR-directed or targeted therapy. To be included, a worsened bone scan (increased size, intensity, or number of lesions) at the time of initial follow-up at 8-12 wks (FU1), a concurrently performed FDG-PET and PSA, and a second follow-up bone scan (FU2) > 6 wks after FU1 were required. Pts were evaluated by three methods: 1) PSA-guided approach: POD was defined as a PSA increase >25% from baseline at FU1; for non-progressors, a special category was created for flare response defined as a PSA decline >50% and a FU2 bone scan documenting stability/improvement; 2) FDG-PET approach: POD was defined as a new bone lesion or increase in SUV >10% at FU1; 3) Bone scan only approach: POD was defined by PCWG2 requiring 2 new bone scan lesions at FU1 and 2 additional lesions at FU2.

Results: 66 pts registered to trials conducted between 2007-2011 were examined; 38/66 (57.6%) pts had a worsened bone scan at FU1, 23 of whom had a FU2 bone scan and were considered evaluable for this analysis.

Conclusions: Over half of mCRPC pts have a worsening bone scan during the first three months of therapy. PCWG2 controls for flare without use of PSA, confirms radiographic POD, and maintains pts on study longer than use of early post-treatment PSA changes. FDG-PET at first assessment appears to identify an identical percentage of progressors as PCWG2 did at the second assessment. PCWG2 is undergoing prospective validation in phase III trials; the use of FDG PET as an early response biomarker is currently under investigation.

[Table: see text]
Relationship of opioid analgesic (OA) use at 3 months and overall survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Halabi Susan , Kelly William Kevin , Kaplan Ellen B , Small Eric Jay
Published: February 2017

200

Background: Baseline pain has been shown to be a significant predictor of overall survival (OS) in mCRPC pts. The objectives of this analysis were to identify predictors of OA use at 3-months after initiating frontline chemotherapy, and to determine if OA use at 3-months predicts overall OS in mCRPC pts.

Methods: Data from CALGB 90401, a phase III trial of 1,050 mCRPC pts randomized with equal probability to receive docetaxel, prednisone with either bevacizumab or placebo was analyzed. OA use was collected at baseline and at 3-month follow-up. OA use was classified as: pts not on OA at baseline and at 3-months (OA1); OA at baseline but not on at 3-months (OA2); No OA at baseline but on OA at 3-months (OA3); and OA at both time points (OA4). The logistic regression method was utilized to identify predictors of OA use at 3-months. Furthermore, the proportional hazards model was used to assess the prognostic significance of OA use in predicting OS adjusting for stratification factors.

Results: 836 pts had complete OA data. The overall distribution of pts with the associated median survival times is presented in the table. There was a linear trend between OA use and overall survival (log-rank p-value<0.0001). The multivariable hazard ratio (HR) for death was 1.34 (95% CI=1.12-1.61) comparing OA4 vs. OA1. In multivariable logistic regression model, statistically significant predictors of OA at 3-months were OA use at baseline, hemoglobin, and alkaline phosphatase.

Conclusions: The strongest predictor of OA use at 3-months was use at baseline. In addition, this analysis shows that OA use after initiating chemotherapy is a statistically significant predictor of overall survival in mCRPC pts. These results require prospective validation.

[Table: see text]
Identification of prostate cancer-expressed microRNAs associated with clinical recurrence (cR) and prostate cancer-specific survival (PCSS) following radical prostatectomy (RP).
Authors: Klein Eric A. , Kiefer Mike , Crager Michael , Magi-Galluzzi Cristina , Falzarano Sara Moscovita , Pelham Robert J. , Millward Carl , Cherbavaz Diana B. , Baker Joffre , Shak Steven , Lee Mark
Published: February 2017

21

Background: We previously identified messenger RNAs (mRNAs) whose expression can distinguish aggressive from indolent prostate cancer. Representing multiple key genomic pathways, these mRNAs are significantly associated with cR and PCSS after RP, providing prognostic information beyond PSA, cT stage and Gleason Score. We evaluated microRNA expression in the same specimens for association with cR and PCSS.

Methods: All cT1/cT2 prostate cancer pts treated with RP at Cleveland Clinic from 1987-2004 were identified (n~2,600), of which 127 pts w/ cR and 374 pts w/o cR after RP were randomly selected using cohort sampling. RNA was purified from 2 macrodissected FPE tumor specimens per pt. Expression of 76 test and 5 reference microRNAs was quantified by RT-PCR. Cox regression and control of the false discovery rate (FDR) was used to assess reference-normalized microRNA and mRNA expression for association with cR and PCSS.

Results: 106 pts with cR and 310 without cR had sufficient RNA and successful microRNA assays. Analysis of primary Gleason pattern tumor tissue for each pt identified 21 microRNAs associated with cR and 13 microRNAs associated with PCSS, with FDR at 10%; 8 microRNAs were associated with both endpoints. Similar analysis of highest Gleason pattern tumor tissue for each pt identified 22 microRNAs associated with cR (17 overlapping with those for the primary Gleason pattern) and 7 microRNAs associated with PCSS, with FDR at 10%; 4 were associated with both endpoints. miR-1, miR-21, miR-93, and miR-106b were associated with both cR and PCSS in primary and highest Gleason pattern specimens. The 76 microRNAs in this study tended to have weaker association with cR and PCSS than the 732 mRNAs. In multivariate analyses, mRNAs and microRNAs provided prognostic information beyond PSA, cT stage, and biopsy Gleason score. MicroRNAs co-express more frequently with each other than with mRNAs, which may indicate distinct biological regulation.

Conclusions: Expression of some microRNAs assayed in FPE prostate tumor tissue was associated with cR and PCSS after RP in this study, and may retain prognostic value in the face of tumor heterogeneity.
Modafinil for fatigue associated with docetaxel-based chemotherapy: A randomized controlled trial.
Authors: Hovey Elizabeth J. , De Souza Paul L. , Marx Gavin M. , Parente Phillip , Rapke Tal , Hill Andrew , Bonaventura Antonino , Michele Antonio , Craft Paul Stanley , Abdi Ehtesham A. , Lloyd Andrew R.
Published: February 2017

211

Background: Chemotherapy-induced fatigue is a common complaint for patients with cancer. We investigated whether modafinil, a psychostimulant, could reduce fatigue in patients on chemotherapy.

Methods: A multicenter, randomized, double-blind, placebo-controlled, parallel group study was conducted in patients with metastatic prostate or breast cancer suffering significant chemotherapy-related fatigue whilst undergoing docetaxel-based chemotherapy. Patients were enrolled at the start of their 3rdor subsequent cycles of docetaxel which was continued for up to four further cycles (defined here as ‘treatment periods’). Patients were randomized 2:1 to receive modafinil 200mg daily or placebo for 15 days during each treatment period. Fatigue was evaluated by the MD Anderson Symptom Inventory (MDASI). The primary endpoint was MDASI area under the curve (AUC) during the first 7 days of study medication for the first two treatment periods (possible range 0-70). Other validated tools were used to record disturbances in sleep, mood and functional status.

Results: Eighty-three patients (65 with prostate cancer) were randomized and received at least one dose of study medication. The number of grade 3 or 4 adverse events (AEs) was 16/55 (29.1%) in the modafinil group and 5/28 (17.9%) in the placebo group. The toxicity profile was largely consistent with docetaxel-based chemotherapy and with previously reported AEs associated with modafinil use in the community; 11 AEs were possibly related to docetaxel; 1 to modafinil and 9 to neither treatment.

Conclusions: Managing chemotherapy-related fatigue remains a major challenge. Despite not reaching the primary endpoint, there was a consistent trend towards improvement of chemotherapy-related fatigue in the modafinil arm. Further studies are needed to better understand the clinical implications of these findings. Funding sanofi-aventis; Study ID NCT00917748 .

[Table: see text]
Role of lymphotoxin-a and interleukin-17A in human prostate cancer.
Authors: Burbridge Sophie , Goldstein Robert Michael , Cahill Declan , Chowdhury Simon , Maher John
Published: February 2017

212

Background: Infiltrating immune cells have been implicated in prostate carcinogenesis. Murine studies suggest that B-cell-derived lymphotoxin (LT)a may be a key effector in the evolution to castrate-resistant prostate cancer (CRPC) (Ammirante et al, Nature 2011). Lymphotoxin a has also been implicated in the progression of murine fibrosarcoma, where it complements interleukin (IL)-17A, to synergistically enhance NFkB signaling. This interaction may also apply to human prostate cancer since IL-17-producing Th17 cells are abundant in these tumors. However, the role of LTα in human as distinct from murine prostate cancer remains unclear. Clinical validation is vital since murine models poorly recapitulate the behavior of prostate cancer in man.

Methods: Serum levels of LTα and IL-17A were measured by ELISA in patients with benign (n=22) and malignant prostate disease (n=87). Samples were from 29 early prostate cancer patients (amenable to radical therapy), 28 with androgen-sensitive (AS) disease and 30 with CRPC. Data were not normally distributed and thus were analyzed by Mann-Whitney U test.

Results: Serum LTαand IL-17A were significantly elevated in patients with both CRPC and early stage prostate cancer, compared to those with benign disease. LTαwas significantly raised in CRPC compared to AS disease. IL-17A was significantly higher in the early stage disease compared to AS prostate cancer.

Conclusions: Based upon these data, we hypothesize that B-cell derived LTα synergises with Th17 derived IL-17A from the earliest stage of primary tumor development. In support of this, blockade of LTα in prostate cancer-prone (TRAMP) mice delays primary tumor onset and inhibits metastasis. Furthermore, NSAIDs protect more strongly against lifetime risk of prostate cancer in those individuals with an LTα over-producer polymorphism. Prostate cancer preferentially metastasizes to local lymph nodes and bone – sites at which mature B-cells are plentiful. Consequently, tumor-trophic effects of LTα would become increasingly efficient with disease progression. Our data are incompatible with and thus refute the clinical relevance of a role for androgen ablation in promoting LTα-driven CRPC.
Patient-reported toxicity after treatment for prostate cancer (PC).
Authors: Hill-Kayser Christine E. , Vachani Carolyn , Hampshire Margaret K. , DiLullo Gloria A , Metz James M.
Published: February 2017

221

Background: PC patients may be at risk for significant late effects after treatment, the impact of which may difficult to evaluate in the clinical setting. This Internet based study evaluates patient perceptions of toxicity after treatment for PC.

Methods: Patient-reported data was gathered via a convenience sample frame from PC survivors voluntarily utilizing a publically available, free, Internet-based tool for creation of survivorship care plans. Available at www.livestrongcareplan.com, the tool allows survivors to enter data regarding diagnosis, demographics, and treatments, and provides customized guidelines for future care. During use of the tool, PC survivors are queried regarding late effects associated with specific treatments, and asked to answer “yes,” “no,” or “I don’t know.” They are also asked to score urinary and sexual symptoms using adapted scales.

Results: Of 4378 survivors using this tool from 4/10-7/11, 203 (5%) had a diagnosis of PC. Median diagnosis age was 59 and median current age 63. 47% reported having undergone radical prostatectomy (RP) and 53% radiation (RT). RT was delivered via x-ray (80%), brachytherapy (15%), protons (3%), and combinations (3%). Hormonal treatment was delivered to 50%. Erectile dysfunction was reported by 65% of PC survivors using this tool, 80% of those having undergone RP, and 52% of those RT. Of men reporting ED, 97% reported that they could have an erection prior to PC treatment. Survivors treated with RP most commonly reported urinary incontinence (42%) and dry ejaculation (27%). Survivors treated with RT reported urinary incontinence (14%) and chronic diarrhea (10%). Most (75%) survivors reported they would share the care plan with their healthcare team; of 25% who reported that they would not, the most common reason was “I did not think they would care.”

Conclusions: Survivors using this tool anonymously and voluntarily report significant toxicity after PC treatment, including ED and urinary incontinence. Not all survivors appear comfortable discussing these issues with healthcare providers. This tool offers a unique way for survivors to report their experiences; the data reported here may be of significant impact in future study of quality of life, patient counseling and survivor care.
Effect of Wnt signaling protein (Wisp2/CCN5) on angiogenesis and invasion in prostate cancer.
Authors: Hashimoto Yasunobu
Published: February 2017

227

Background: The Wnt-Induced Signaling Protein-2 (Wisp-2 /CCN5) is a secreted protein implicated in modification of extracellular matrix, invasion, and angiogenesis. The regulation of Wisp-2 and its function in CaP is poorly explored although it is highly expressed in advanced CaP cells. We discovered recently that a pro-inflammatory chemokine, Interleukin-8 (IL-8) strongly modulates Wisp2 expression in CaP cells. Since IL-8 is a major effecter of inflammatory pathway, we investigated the physiological consequence of Wisp-2 modulation in CaP cells. We hypothesised that Wisp-2 is a down-stream effector of IL-8 induced angiogenesis and invasion.

Methods: Quantitative PCR (qPCR) was used to determine the expression of Wisp-2 mRNA and other mRNA in prostate epithelial and cancer cells. Wisp-2 mediated-VEGF secretion was determined by ELISA and endothelial tube formation assay using human vascular endothelial cells (HUVEC). Invasive activity and their attributes were determined using gelatin-zymography for matrix metalloproteinases (MMPs), and Matrigel invasion assay.

Results: Wisp2 RNA was strongly expressed in two highly metastatic CaP cell lines, DU145 and PC-3 and moderately in less invasive LAPC4 and LNCaP cells. Constitutive autocrine expression or external addition of IL-8 increased Wisp-2 mRNA by ≥15.2 times in LNCaP, and 7.4 times in LAPC4 cells. Depleting Wisp-2 by RNA interference caused 82% reduction of Wisp2 in DU145, and 75% in PC-3. Depletion of Wisp2 did not affect cell proliferation in DU145 and PC3 but it reduced expression of VEGF mRNA by 64% in DU145 and 43% in PC3. Secreted VEGF protein in cultures of DU145 and PC-3 cells showed a decrease of 62% in DU145 and 30% in PC3. Condition medium of Wisp-2 depleted DU145 cell cultures showed 20% decrease in proliferation and vessel formation activity in HUVEC cells. Further, Wisp-2 depletion in DU145 cells resulted in significant decrease in chemoinvasion activity (28%) and secretion of MMP-9 (25%).

Conclusions: These results show that Wisp2 is down stream effector of IL-8 and is an important modulator, affecting extracellular matrix to stimulate angiogenesis and invasiveness in CaP cells. Suppression of Wisp-2 in CaP may reduce their metastatic potential.
Transperineal sector biopsies: Their role in prostate cancer active surveillance.
Authors: Vyas Lona
Published: February 2017

228

Background: Many men with low risk prostate cancer on transrectal biopsy appear suitable for active surveillance (AS). Under staging and grading at diagnosis can result in delayed treatment and risk of poorer oncological outcomes. In most AS series about 30% men have active treatment at a median of two years for presumed disease progression/choice but this may represent disease mischaracterised at initial biopsy. So it is essential to accurately stratify patients before surveillance. We have routinely offered transperineal sector prostate biopsies (TPSB), using 24-32 cores, to all patients considering AS.

Methods: 350 patients with apparent low to intermediate risk prostate cancer after transrectal prostate biopsy (TRUS Bx) underwent transperineal sector biopsies.

Results: Median age 64 yrs (38–84). Median PSA 7.2 ug/l (0.14–58). 190 had Gleason 3+3, 115 had Gleason 3+4 and 45 >3+4 disease. 145 (41%) patients elected for definitive treatment, in 112 because there was an upgrade or higher disease volume compared with the original TRUS Bx. 33 patients chose definitive treatment rather than continued AS. 205 (59%) patients entered our AS programme, in 25 follow up data is incomplete leaving 180 for analysis. 61 have had repeat TPSB within our protocol and at a median follow up at 2 years in 56/61 (92%) the Gleason score and volume of disease was unchanged. Only 5/180, 2.8% have had treatment for disease progression and additionally 4/180 (2.2%) have chosen active intervention over continued surveillance, despite no evidence of progression.

Conclusions: TRUS biopsies under-estimate Gleason grade or cancer volume compared with TPSB. In our cohort of AS patients only 2.8%, at a median follow up of two years, have transferred to definitive treatment for disease progression. TPSB provides the best method to exclude higher risk disease from AS programmes.
Use of the slope of the DVH curve for predicting late rectal toxicity in IMRT for patients with localized prostate cancer.
Authors: Crehange Gilles , Walker Paul M , Gauthier Mélanie , Mirjolet-Didelot Céline , Petitfils Aurelie , Martin Etienne , Chamois Jérôme , Khoury Cedric , Maingon Philippe
Published: February 2017

230

Background: Dose volume specific endpoints (DVSE) have been demonstrated to be reliable and reproducible for predicting late toxicity with conformal 3D-RT. New highly sophisticated delivery techniques such as IGRT or IMRT or combined IG-IMRT can spare rectum more efficiently while substantially increasing the delivered dose to the prostate. The purpose of this study is to investigate whether the slope of the DVH curve could predict late rectal toxicity more accurately than DVSE in prostate cancer (PCa) patients.

Methods: Charts from164 men with complete DVH data who had a localized PCa were treated with exclusive IG-IMRT. The rectum was defined as a cylindrical structure around the outer rectal wall and contoured from the ischial tuberosities to the rectosigmoid junction. A set of DVSE were registered (V75, V70, V60). Four distinct DVH groupings were defined for each DVSE: [0–5%], ]5–10%], ]10–15%] and ]15–20%]. In parallel, we decided to calculate the slope of the DVH curves encompassing the 3 DVSE: 60Gy, 70Gy and 75Gy. The median dose prescribed to the prostate was 78Gy (min. 74Gy – max. 78Gy). Late toxicity was retrospectively scored according to the CTC v.3.0 morbidity grading scales. Univariate analysis using a logistic regression was performed to determine the relationship between DVSE, the slope 60-75Gy and the appearance of any late rectal toxicity (grade ≥ 1).

Results: With a median follow-up of 38.3 months [5.25 – 87.3], the rates of grade (G) 1, G2 gastrointestinal toxicity were 20.4%, 2.4%. No grade 3 or 4 occurred. For the rectum, the average Dmean, D98, V75, V70 and V60 were 39.9 Gy [25.7–61.1], 8.9Gy [1.0–38.8], 1.1Gy [0.0–33.3], 6.0 Gy [0.0–44.0] and 19.0 Gy [1.0–70.0]. DVH groupings for V75, V70 and V60 were not predictive of any G≥1 late rectal toxicity (p= 0.836, p= 0.580 and p= 0.152, respectively). The slope 60-75Gy was significantly correlated with late rectal toxicity ≥ G1 (OR= 0.55, [CI95%: 0.33–0.92], p= 0.024).

Conclusions: DVSE could be irrelevant with IG-IMRT, thus jeopardizing the clinical benefit of dose escalation. The slope of the curve predicts more accurately late toxicity when attempting to optimize dose distribution.
Survey on management of metastatic hormone-refractory prostate cancer upon progression during or following first-line chemotherapy in five European countries.
Authors: Auziere Sebastien , Flinois Alain , Obi-Tabot Eliot , Rose Mathieu , Parnaby Adam
Published: February 2017

232

Background: In Europe, docetaxel is the standard first-line (1L) chemotherapy for patients with metastatic hormone-refractory prostate cancer (mHRPC). Upon progression, either during or after 1L chemotherapy, treatment options are limited. This study evaluated how patients who progressed during or after 1L docetaxel between October 2009 and June 2010 were managed.

Methods: A representative sample of 349 physicians (oncologists, urologists) who managed patients with mHRPC selected from Germany, France, United Kingdom, Spain and Italy were surveyed. Information on the treatments used at the time of progression (during or within the first 6 months following 1L treatment with docetaxel was provided.

Results: Information on a total of 2,870 mHRPC patients was provided of which 2,670 (94 %) had received docetaxel in 1L. 1,389 (52%) patients progressed during 1L docetaxel or within 6 months following treatment; of these, 615 (44 %) received as 2L chemotherapy the agents listed in the table.

Conclusions: In this study, mitoxantrone was the most commonly used chemotherapy agent for 2L treatment of patients with mHRPC who progressed during treatment or within the first 6 months following the end of 1L. Docetaxel rechallenge was uncommon for patients experiencing progression early, during or after the end of 1L.

[Table: see text]
Physical activity and prostate cancer risk reduction: Does race matter?
Authors: Singh Abhay A , Antonelli Jodi A , Jones Lee , Gerber Leah , Calloway Elizabeth Ellen , Shuler Kathleen , Hoyo Cathrine , Grant Delores , Freedland Stephen J. , Banez Lionel Lloyds
Published: February 2017

235

Background: We previously reported that physical activity may reduce prostate cancer (CaP) risk among men undergoing prostate biopsy. However, whether the potential benefit of exercise against cancer differs by race is unclear. We therefore sought to further characterize the link between physical activity and CaP risk as a function of race.

Methods: Men undergoing prostate biopsy at the Durham VA Hospital were asked to complete a survey assessment of current exercise habits including frequency of differing intensities (mild, moderate and strenuous) as well as the average duration. Total current exercise was calculated by multiplying the frequency of sessions within each intensity by their average duration, weighted by the estimated metabolic equivalent (MET) and then summed across all intensities expressed as average total MET hrs/wk. Specifically, exercise intensities were as follows: mild (3 METs, e.g. easy walking), moderate (5 METs, e.g. tennis), and strenuous (9 METs, e.g. running). Quantified exercise was compared between race groups using rank sum test. Associations between exercise and CaP risk was determined using crude and adjusted logistic regression stratified by race.

Results: A total of 308 men had complete data for analysis. Of these men, 53% were white and 47% were black. There was no significant difference in the amount of physical activity between race groups (p= 0.11). Increased amount of exercise was associated with decreased CaP risk for white men in both crude (OR= 0.89; 95% CI=0.81–0.98; p=0.02) and adjusted (OR=0.90; 95% CI=0.82−0.99; p=0.04) regression models that controlled for age, BMI, DRE, previous biopsy, and family history of CaP. We found no association between exercise and CaP risk among black men in both crude (p=0.79) and adjusted regression models (p=0.87).

Conclusions: Increased physical activity was associated with CaP risk reduction among white men but not among black men. Further investigations to validate this potential source of CaP race disparity and to identify exercise-specific parameters that influence CaP risk reduction (ex. age-specific or cumulative exercise) are required. Investigating the race-specific mechanisms through which exercise modifies CaP risk is also warranted.
Circulating tumor cells (CTCs) as a predictor of metastatic disease in patients with biochemical recurrence (BR) of prostate cancer with equivocal scan results.
Authors: Aragon-Ching Jeanny B. , Simmens Samuel J. , Patierno Steven R. , Siegel Robert S.
Published: February 2017

239

Background: Staging for BR is challenging since the yield of computed tomography (CT) and bone scans are low, especially in patients with low prostate specific antigens (PSA) levels. We examined the utility of circulating tumor cells (CTCs) to predict metastatic disease in a cohort of patients who presented with BR (Aragon-Ching, et. al. ASCO GU 2011;abstr 60).

Methods: 33 pts enrolled from May 2010 to September 2011 with BR, defined as patients (pts) who have undergone primary treatment with PSA rise to >/= 0.2 from a prior undetectable level for prior prostatectomy or > 2 mg/dl rise from post-nadir radiotherapy, were included. PSA doubling time (PSADT), scan results, Gleason scores, age, testosterone levels were all obtained. CTCs were evaluated in 7.5 mL of peripheral blood using the CTC CellSearch test. BR patients with equivocal CT and/or bone scan results who were biopsiable and consentable underwent bone biopsy to confirm metastatic disease.

Results: The median age for 33 patients was 71 y/o (range: 51 – 91), median PSA of 1.7 ng/mL (range 0.2 – 65.8), testosterone levels of 315.5 ng/dL (range: 31 – 727), Gleason score of 7, hemoglobin of 13.78 g/dL, BMI of 27.72 and alkaline phosphatase of 68 IU/L. Prostatectomy was the primary treatment in 23 pts, radiotherapy in 9 pts and Cyberknife in 1 pt. Median PSADT varied between 0.35 to 55.2 months. Only a small number of patients had either biopsy confirmed metastatic disease (n=2) or detectable CTC (n=3). Both of the 2 patients with metastatic disease had detectable CTC (sensitivity = 1.00, 95% CI: .34, 1.00). For the patients without signs or confirmation of metastatic disease, 30/31 had no detectable CTC (specificity = .97, 95% CI: .84, .99).

Conclusions: While most pts with BR have negative blood CTCs, patients with detectable CTCs and equivocal findings on scans should raise suspicion and prompt a search for metastatic disease, given increasing available treatment options for metastatic prostate cancer. However, the limited number of patients may preclude reliable statistical evaluation of CTCs in this population. Supported by IRG-08-091-01 from ACS to GWU Cancer Institute.
A combination herbal supplement for biochemically recurrent prostate cancer.
Authors: Dorff Tanya B. , Hawes Debra , Tsao-Wei Denice D. , Quinn David I. , Goldkorn Amir , Lieskovsky Gary , Vogelzang Nicholas J. , Groshen Susan G. , Pinski Jacek K.
Published: February 2017

24

Background: After curative local therapy, thousands of men will have rising PSA as an early indicator of recurrent prostate cancer. For them, no standard of care exists, and concern over serious side effects of androgen deprivation (ADT) makes delaying ADT common. We tested Prostate Health Cocktail (PHC), which contains vitamins D & E, saw palmetto, lycopene, green tea and soy extracts, in this population, to see whether it could induce PSA declines.

Methods: Eligible men had rising PSA with doubling time (DT) 3-36 months, with no evidence of metastases on CT and bone scans. After IRB approval, 28 men were treated with PHC 3 capsules PO daily for 4 week cycles. PSA was repeated after the first cycle, then every 2 cycles with imaging only as clinically indicated; the primary endpoint was PSA decline. PSA progression was defined as 25% increase and absolute increase of 5 ng/mL or return to baseline. Circulating tumor cells (CTCs) were measured at baseline and after 3 cycles using parylene membrane filters.

Results: The median age was 67 (range 54-84) and baseline PSA was 2.9 ng/mL (1.1-53.2); the median number of cycles was 6 (1-13). Stable PSA was the best response for 23/28 men (83%) and 8/27 men (29.6%) had a PSA decline (1.1%-29.4% maximum decrease). 47% stopped therapy for progression with median time to progression=9.2 months. There was no association between Gleason score or baseline PSA, vitamin D or selenium level and PSA decline. CTCs were detected in 5 of the first 23 subjects. The median PSA for these men was 2.77 ng/mL (range 1.63-16.8). There was no significant change in testosterone or DHT during treatment. Median PSA DT at baseline was 7.8 months (range 3-36). One patient had grade 3 transaminitis in the setting of alcohol consumption, otherwise toxicities were limited to grade 1 or 2 hypercalcemia(1), hyperkalemia(2), hyperglycemia(4), flatulence(4), other GI(5), and rash(1).

Conclusions: PHC demonstrated activity in men with biochemically recurrent prostate cancer, resulting in PSA declines in nearly a third of cases, and was not associated with changes in serum androgens or significant toxicities. For the first time, we are reporting that circulating tumor cells can be detected in men with biochemical recurrence using filter technology.
Ipilimumab (IPI) in metastatic castrate-resistant prostate cancer (mCRPC): Results from an open-label, multicenter phase I/II study.
Authors: Slovin Susan F. , Hamid Omid , Tejwani Sheela , Higano Celestia S. , Harzstark Andrea , Alumkal Joshi J. , Scher Howard I. , Chin Kevin M. , Gagnier Paul , McHenry M. Brent , Beer Tomasz M.
Published: February 2017

25

Background: IPI is a fully human, anti-CTLA-4 monoclonal antibody capable of enhancing anti-tumor immunity. Preclinically, radiotherapy (XRT) and CTLA-4 blockade have synergistic anti-tumor activity. This phase 1/2 study in patients (pts) with mCRPC was designed to assess: safety of IPI at various doses, feasibility of combining IPI with XRT, and activity.

Methods: mCRPC pts with or without prior chemotherapy were enrolled. In the dose-escalation phase, 33 pts (³6 pts per cohort) received IPI q3 weeks x 4 doses at 3, 5, or 10 mg/kg, or with XRT at 3 or 10 mg/kg. Single dose XRT (8 Gy/lesion, up to 3 lesions per pt) was given 24 to 48 h before the first IPI dose. The 10 mg/kg ± XRT cohorts were expanded to 50; 34 received IPI + XRT (Table). Based on clinical benefit, pts received additional doses of IPI. Endpoints were safety, and activity as assessed by serum prostate-specific antigen (PSA) and RECIST criteria. PSA was monitored monthly, with scans q3 months (mos).

Results: There were no dose-limiting toxicities; 10 mg/kg ± XRT cohorts were, therefore, expanded for phase 2 evaluation. Treatment-related adverse events (AEs) and immune-related AEs (irAEs) were common across all cohorts with or without XRT. Common (≥ 15%) treatment-related AEs of any grade in the 10 mg/kg ± XRT group were fatigue (50%), diarrhea (54%), nausea (24%), colitis (22%), decreased appetite (22%), vomiting (18%), rash (32%) and pruritus (20%). Most common grade 3/4 irAEs were colitis (16%), diarrhea (8%) and hepatitis (10%). irAEs were generally responsive to immunosuppressives. Of 50 PSA-evaluable pts in the 10 mg/kg ± XRT group, 8 had PSA response (Table) lasting between 3 and 13+ mos. Of the 28 tumor-evaluable pts receiving 10 mg/kg ± XRT, 1 had complete response and 6 had stable disease.

Conclusions: In pts with mCRPC, IPI 10 mg/kg alone or in combination with XRT showed clinical antitumor activity with disease control in some patients, and a generally manageable safety profile. The combination (IPI 10 mg/kg ± XRT) and monotherapy (IPI 10 mg/kg) are being explored in randomized phase 3 trials.

[Table: see text]
First results of a phase II trial to assess the efficacy of efavirenz in patients with metastatic androgen-independent prostate cancer.
Authors: Houede Nadine , Pulido Marina , Mourey Loic , Joly Florence , Ferrero Jean Marc , Bellera Carine , Priou Franck , Lalet Caroline , Laroche Audrey , Canal-Raffin Mireille , Piazza Pier Vi
Published: February 2017

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Background: This Phase II trial assessed the efficacy of efavirenz, a non-nucleoside reverse transcriptase inhibitor in patients with asymptomatic HRPC [hormone refractory prostate cancer] who progressed, before docetaxel based chemotherapy. Preclinical studies showed that efavirenz, via Line-1 inhibition, could block proliferation and induced re-differentiation of prostate cancer cell line. We then investigated if efavirenz treatment can delay biological and clinical progression.

Methods: The primary objective was to assess the efficacy of efavirenz in patients, with no clinical symptom related to disease progression. Each patient received efavirenz 600 mg/day until objective biological progression or study discontinuation. It was possible to increase the dose (up to 1200 mg daily) in case of PSA progression at 3 months. Efficacy was measured in terms of 3-month non-progression. Based on a 2-stage Simon’s design, a total of 16 non-progressions out of 54 eligible patients were required to claim efficacy.

Results: 61 patients were enrolled in the study with 53 eligible for the primary endpoint. At baseline, median age was 71 years and median PSA level was 49.6 ng/mL. A total of 15/53 (28%) non-progressions were observed at 3 months. As patients are still being followed, overall survival, PSA progression free survival and symptomatic progression free survival at one year will be presented. Sixty patients were assessable for toxicity. Of these, 9 (15%) experienced at least one grade III/IV toxicity i.e. neuropsychiatric adverse events already reported in efavirenz-treated HIV patients. With regard to pharmacokinetics (PK), preliminary data indicates variability in the 3-month efavirenz concentration. Ongoing preliminary analyses suggest a better response in patients with elevated (>3000ng/ml) plasmatic concentration.

Conclusions: Current analyses do not allow to claim efficacy of Efavirenz at the 600 mg dose. The ongoing analysis of the relationship between plasmatic concentration of efavirenz and treatment efficacy could confirm that higher doses of efavirenz may constitute an efficient treatment. A phase I dose escalation study is currently being performed.
Use of radiographic progression to predict overall survival in men with castration-refractory prostate cancer.
Authors: Kamoi Kazumi , Okihara Koji , Takaha Natsuki , Iwata Tsuyoshi , Kawauchi Akihiro , Miki Tsuneharu
Published: February 2017

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Background: The purpose of this study was to analyze prognostic factors to predict overall survival in patients with castration-refractory prostate cancer (CRPC).

Methods: A total of 68 patients with CRPC treated by secondary hormonal therapy (dexamethasone) and/or chemotherapy including docetaxel were analyzed. Primary endpoint was survival after PSA relapse. PSA relapse was defined as 3 consecutive PSA increase and serum PSA more than 4 ng/ml. Factors analyzed to predict survival were initial PSA value, initial clinical stage, pathological tumor grade (WHO grade), time to PSA relapse, nadir PSA value, time to nadir PSA, age at PSA relapse, PSA value at relapse, radiographic progression revealed by bone scan or CT scan, and bone pain. Univariate and multivariate analysis were performed using Cox regression hazard model.

Results: Univariate analysis revealed nadir PSA value, time to nadir PSA, PSA value at relapse, radiographic progression revealed by bone scan or CT scan, and bone pain were significant predictors (p<0.05). Multivariate analysis revealed only radiographic progression was the independent predictor for survival after PSA relapse (p=0.039). Median survival time was 63.5 and 23.5 months in patients with (n=39) and without (n=29) radiographic progression, respectively (log-rank p=0.0002). Median survival time in 39 patients with radiographic progression in bone (n=31), lymph nodes (n=6), visceral lesion (n=3), and local lesion (n=4) were 23.5, 5, 2, and 12.5 months, respectively.

Conclusions: For patients with PSA relapse after hormonal therapy, the finding of radiographic progression was the only independent factor to predict overall survival.
A QTc study of cabazitaxel in patients with advanced solid tumors.
Authors: Wade James Lloyd , Dakhil Shaker R. , Baron Ari David , Rottey Sylvie , Millard Frederick E. , Daugaard Gedske , Machiels Jean-Pascal H. , Conkright William A. , Sharma Sunil , Soetekouw Patricia M.M.B. , Yachnin Jeffrey , Sengeløv Lisa , van Veldhuizen Peter , Agarwala Sanjiv S , Nguyen TX Quyen , Chadjaa Mustapha , Maison-Blanche Pierre
Published: February 2017

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Background: Cabazitaxel (Cbz) improves overall survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel failure, compared with mitoxantrone (HR 0.70; 95% CI 0.59–0.83; P < 0.0001). Following Cbz approval for the treatment of mCRPC, this study was undertaken to evaluate any effect of Cbz on the QTc interval.

Methods: This prospective, multinational, open-label study ( NCT01087021 ) enrolled pts with advanced solid tumors (without other therapeutic options). Cbz 25 mg/m² IV was administered on Day 1 Q3W. QTc and other ECG intervals were assessed on Day 1 of Cycle 1. Triplicate ECGs were obtained from 12-lead Holter recordings and concomitant serial blood samples were collected for pharmacokinetic (PK) analysis. The primary endpoint was change from baseline in the corrected QTc interval (according to the Fridericia formula QTcF).

Results: A total of 96 pts were enrolled; 32 pts under the original protocol (6-h Holter) and 64 pts following protocol amendment 1, which extended ECG and PK monitoring (24-h Holter). Median age was 63 yrs (69.8% male), 30.5% and 57.9% of pts were ECOG PS 0 and 1 respectively; 33 pts (34.4%) had prostate cancer. Screening ECG was abnormal but not clinically significant in 39.6% of pts. The majority (n = 65) of pts received ≥ 3 treatment cycles; safety and ECG parameters were evaluated in 95 and 94 pts, respectively. In the 24-h Holter group (n = 63), the maximum least squares (LS) mean change from baseline in QTcF was 4.8 msec (90% CI 2.1–7.5), returning to baseline by 24 h. Similar results were observed in the overall population (n = 94). At Cmax, Cbz concentration had no effect on QTcF change from baseline; the mean (CV%) Cmax (n = 91) and AUC (n = 92) were 276 ng/ml (63%) and 1245 ng.h/ml (82%). The LS mean change from baseline in heart rate increased up to 24 h but remained < 10 beats per minute. The most common Grade 3/4 AEs were neutropenia (27.4%), febrile neutropenia (12.6%), fatigue (12.6%) and dehydration (5.3%). No Grade 3/4 cardiac AEs were reported. Of the 6 deaths reported, 1 (infection) was study drug related.

Conclusions: Cbz had no significant effect on QTc interval in pts with advanced tumors. The Cbz safety profile is consistent with previous findings and with other taxane-based therapies.
Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: First results from STAMPEDE (MRC PR08, CRUK/06/019), a randomized controlled trial.
Authors: James Nicholas David , Sydes Matthew Robert , Mason Malcolm David , Clarke Noel W , Anderson John , Dearnaley David Paul , Dwyer John , Jovic Gordana , Ritchie Alastair SW , Russell J. Martin , Sanders Karen , Thalmann George , Bertelli Gianfilippo , Birtle Alison J , O'Sullivan Joe M. , Protheroe Andrew , Sheehan Denise , Srihari Narayanan , Parmar Mahesh ,   STAMPEDE Investigators
Published: February 2017

26

Background: Long-term hormone therapy (HT) alone is standard of care for men with metastatic or high-risk non-metastatic prostate cancer (PCa). STAMPEDE investigates whether early use of additional therapies improves overall survival. It is an international randomised controlled trial ( NCT00268476 ) using novel multi-arm, multi-stage methods to assess adding 1 or 2 of three agents (docetaxel, zoledronic acid (ZA), celecoxib) in 5 research arms in men with PCa starting long-term HT for the first time.

Methods: HT was given as per standard care. Celecoxib was planned as 400mg bid until the sooner of 1 year or disease (including PSA) progression. The trial has 3 intermediate activity stages (I-III) where the outcome measure (OM) is failure-free survival (FFS) and 1 final efficacy stage (IV) with overall survival as primary OM. At the end of each stage, research arms are compared pairwise to the control arm. Accrual of further patients is discontinued early for any research arm either showing (a) safety concerns or (b) insufficient evidence of activity (lack-of-benefit) where the treatment effect on FFS is compared against a pre-defined stopping guideline. The interim activity “hurdle” becomes increasingly stringent stage-by-stage.

Results: From Oct-2008 to Feb-2011, 2114 patients were consented and randomised, including 875 in this comparison. With 205 control FFS events, there was evidence of insufficient activity for HT+celecoxib over HT-alone: HR 0.98 (95%CI 0.90-1.06). The Independent Data Monitoring Committee recommended stopping accrual to this arm; stopping celecoxib was also recommended for patients currently on treatment. (Accrual was also stopped to HT+celecoxib+ZA but data are not disclosed.) There was no evidence of differences in toxicity: 25% and 23% of patients reporting grade ≥3 toxicities or adverse events with or without celecoxib. Control arm FFS was 51% at 2 years, in line with expectations.

Conclusions: Celecoxib shows no evidence of activity in this setting. Accrual continues seamlessly to the other research arms. Follow-up of all arms is ongoing. Support: MRC, Cancer Research UK, Novartis, Sanofi-Aventis, Pfizer.
Flexible trial design in practice: Dropping and adding arms in STAMPEDE (MRC PR08, CRUK/06/019)—A multiarm, multistage randomized controlled trial.
Authors: Sydes Matthew Robert , James Nicholas David , Mason Malcolm David , Clarke Noel W , Amos Claire , Anderson John , De Bono Johann Sebastian , Dearnaley David Paul , Dwyer John , Jovic Gordana , Ritchie Alastair SW , Russell J. Martin , Sanders Karen , Thalmann George , Parmar Mahesh ,   STAMPEDE Investigators
Published: February 2017

27

Background: STAMPEDE ( NCT00268476 ) is a multi-centre, RCT using novel multi‐arm, multi‐stage (MAMS) methods. We describe the methodological and practical issues arising with early stopping of recruitment to some arms following an intermediate analysis and the issues in adding new research arms during the trial.

Methods: The trial recruits men with locally advanced or metastatic prostate cancer starting standard long-term hormone therapy. There are 5 research and 1 control arm assessed over 3 intermediate activity stages I-III [outcome measure: failure-free survival (FFS)] and a final efficacy stage IV [outcome measure: overall survival]. At the end of each stage, research arms are formally compared to the control arm. Accrual of further patients is discontinued early for research arms not showing sufficient evidence of activity or with adverse safety considerations; accrual continues to the other arms; this interim hurdle is increasingly stringent at each stage. The addition of new research arm(s) can be actively considered when sufficiently interesting agents emerge. New research arms are compared only to contemporaneously-recruited control arm pts using the same intermediate guidelines in a time-delayed manner.

Results: (1) After the second intermediate activity analysis (Mar-2011), the IDMC recommended and the Trial Steering Committee ratified discontinuation of recruitment to two research arms for lack-of-sufficient activity. Nearly 100 recruiting centres in UK and Switzerland had to promptly implement changes. Detailed advanced preparation meant that activation was swift and recruitment continued seamlessly into Activity Stage III. (2) An application to add a new research arm, abiraterone, has been agreed by funders, industry partner and ethics committee; regulatory approval awaited. Details on methodological and practical issues and implementation of these changes will be presented.

Conclusions: The STAMPEDE experiences shows that recruitment to MAMS trials is achievable and that mid-flow changes to trial design are practicable and encouraged.