bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection and genomic interrogation of circulating tumor cells (CTCs) and circulating tumor stem cells (CTSCs) from men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Friedlander Terence W. , Ngo Vy , Doty Shaun , Zhao Qiang , Dong Huang , Ryan Charles J. , Chen Wen-Tien , Paris Pamela
Published: February 2017

144

Background: Isolation, enumeration, and genomic profiling of CRPC CTCs offers the potential to discover genetic changes that occur in advanced disease. The Vitatex VitaCap platform captures CTCs based on their ability to invade collagenous matrices (CAM), allows for CTC and CTSC capture independent of EpCAM status, and yields viable cells suitable for comprehensive genomic analysis. In this study we sought to compare CTC yields between the VitaCap and the Veridex CellSearch platforms, to determine the utility of prostate-specific membrane antigen (PSMA) as a mCRPC CTC biomarker, to identify CTSCs and CTC clusters, and to explore the feasibility of CTC epigenomic analysis. Methods: CTCs were isolated and enumerated simultaneously using the CellSearch and VitaCap platforms in 23 men. CAM isolated CTCs and CTSCs were defined as EpCAM+PSMA+ and CD44+DPPA5+ respectively, and were enumerated immunocytochemically (ICC) and by flow cytometry. CTC clusters were enumerated by ICC. The Illumina HumanMethylation27 BeadChip was used to determine whole genome methylation status for CAM isolated cells. Results: 35 samples were collected for CAM analysis. A median of 27 (range 0-800) and 23 (range 2-390) CAM+ CTCs/ml were detected by ICC and flow respectively. In a subset of 20 samples, a median of 7 CTCs/ml (range 0-85) were detected by the CellSearch platform. CTCs were detectable by either CAM or CellSearch in >95% of samples. CAM isolated CTC clusters were observed in 23% of samples with a median 7 clusters/ml (range 1-200). CTSCs were detected in 70% and 97% of samples by ICC and flow respectively, with a median of 9 CTSCs/ml (range 1-264) by flow. The CTC methylation profile highly resembled mCRPC with hypermethylation occurring more frequently in pathways associated with apoptosis (p<0.006), angiogenesis (p<0.007), and VEGF signaling (p<0.003). Conclusions: CAM and CellSearch platforms yield comparable CTC counts. CTSCs and CTC clusters are detectable using the CAM platform, and the CTC methylome closely resembles that of mCRPC. Correlation with clinical data may yield further insight into the functional significance of these findings.
P10-1 open-label, multicenter study of sipuleucel-T in metastatic castrate-resistant prostate cancer (mCRPC) patients (pts) previously treated with sipuleucel-T: Evaluation of antigen-presenting cell (APC) activation.
Authors: Beer Tomasz M. , Glode L. Michael , Lance Raymond , Greengold Richard , Sims Robert Brownell , Wang Yang , Sheikh Nadeem A. , Corman John M.
Published: February 2017

147

Background: Sipuleucel-T is an autologous cellular immunotherapy that has demonstrated an improvement in survival among men with asymptomatic or minimally symptomatic mCRPC. P10-1 (NCT01338012) is an open-label, multicenter study of sipuleucel-T in men with mCRPC previously treated with sipuleucel-T in the androgen-dependent setting on the PROTECT trial (a prospective, randomized, controlled Phase III study of sipuleucel-T in men with prostate-specific antigen recurrence following radical prostatectomy; NCT00779402). This preliminary analysis of P10-1 evaluates the pattern of APC activation in pts re-treated with sipuleucel-T after progression to mCRPC. Methods: Eligible pts include those previously treated with at least one infusion of sipuleucel-T on PROTECT and who progressed to the mCRPC state. Pts receive up to three additional infusions of sipuleucel-T. APC activation is assessed by CD54 upregulation expressed as the ratio of the average number of CD54 molecules on post-culture vs. pre-culture cells. Results: As of September 14, 2012, 7 pts have been enrolled and have received an infusion of sipuleucel-T. The median interval between the last infusion in PROTECT and the first infusion in P10-1 was 8.6 years. The Table shows a higher fold change in CD54 expression in the first P10-1 treatment compared with the initial infusion in PROTECT. Conclusions: This is the first report of pts re-treated with sipuleucel-T after prior treatment in an earlier disease setting. These preliminary data are consistent with the presence of an immunological memory response to the immunizing antigen several years following initial treatment. Clinical trial information: NCT01338012. [Table: see text]
Location of local recurrence after MRI-guided partial prostate brachytherapy targeting only the peripheral zone: Implications for focal therapy.
Authors: Kovtun Konstantin , Penzkofer Tobias , Agrawal Neha , Kapur Tina , Fedorov Andriy , Cormack Robert A. , D'Amico Anthony Victor , Tempany Clare M. , Nguyen Paul Linh
Published: February 2017

149

Background: Prostate cancer local recurrences usually occur at the same site as the dominant primary tumor in patients treated with radiation therapy to the whole gland. We characterized location of local recurrences in patients who were treated with MRI Guided Partial Brachytherapy in which only the peripheral zone was targeted. Methods: We retrospectively reviewed ten patients with initial cT1c, Gleason score 3+4 or less prostate cancer who developed biopsy proven local recurrences and had available imaging after MRI Guided Partial Brachytherapy targeting the peripheral zone from 1998 to 2006. All 10 patients had 1.5T endorectal coil MRI at diagnosis, performed primarily for staging and not for tumor localization, while at recurrence 8 had 3T endorectal coil MRI and 2 had 1.5T endorectal coil MRI. Scans consisted of at least T1 and T2 sequences. Two radiologists (C.T. and T.P.) blinded to clinical data reviewed diagnosis MRI scans together and quantified likelihood of tumor on a 1 to 5 scale in each section of an eight part prostate in both pre-treatment and recurrence scans. Local recurrence was judged to be in the same location as the baseline tumor if at least 50% of the tumor location overlapped. Results: Only 3 of 10 patients had local recurrences at the same location as the baseline tumor with a mean overlap of 64%. 7 of 10 patients had local recurrences at a different location with a mean overlap of 5%. 5 of 10 patients had recurrences in the central zone of the prostate which did not definitively show tumor on review of the initial 1.5T staging scan. Conclusions: After MRI-guided brachytherapy targeting only the peripheral zone in men initially staged with 1.5T MRI, 50% of the local recurrences occurred at the non-targeted central zone, raising the possibility that focal therapy directed only at the dominant tumor will result in increased out-of-field recurrences. Whether the superior ability of modern 3T multiparametric MRI to detect and precisely localize occult prostate cancer foci will reduce this risk is the subject of current study.
Gleason pattern 5 as a pathologic predictor of recurrence, development of metastasis, and prostate cancer-specific death for patients receiving salvage radiation therapy following radical prostatectomy.
Authors: Jackson William C. , Johnson Skyler B. , Foster Corey , Li Darren , Foster Benjamin , Song Yeohan , Sandler Howard Mark , Palapattu Ganesh S. , Kunju Priya , Mehra Rohit , Hamstra Daniel A. , Feng Felix Yi-Chung
Published: February 2017

151

Background: The presence of primary, secondary, and tertiary Gleason pattern 5 (GP5) in prostate cancer has been shown to predict outcomes and improve risk stratification following radical prostatectomy (RP) and external beam radiation therapy (EBRT). However, the predictive value of GP5 has not been assessed in salvage EBRT (SRT) for a rising PSA after RP. We sought to assess the prognostic capability of the presence of GP5 in this setting. Methods: 575 patients who received SRT at a single institution for biochemical recurrence after RP were retrospectively reviewed in an IRB approved analysis. We assessed the impact of GP5 on biochemical failure (BF), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall survival (OS) using Kaplan-Meier and Cox Proportional Hazards models. Results: Median follow up was 56.7 months post SRT. On pathologic evaluation, 563 patients had a documented Gleason score (GS). 60 patients (10.7%) had primary, secondary, or tertiary GP5. GP5 was the strongest pathologic predictor of DM (p<0.01 HR: 1.9 [95%CI: 1.3-2.9]) and PCSM (p<0.01 HR: 4.0 [95%CI: 2.1-7.7]) on univariate analysis. The presence of GP5 was a better predictor of BF, DM, PCSM, and OS than stratification by GS8-10. Patients with GP5 had clinically worse outcomes than GS8 patients without GP5. There was no difference in outcome between primary, secondary, and tertiary GP5. On multivariate analysis, GP5 was the strongest pathologic predictor of BF (p<0.01 HR: 2.7 [95%CI: 1.6-4.5]), DM (p<0.01 HR: 11.2 [95%CI: 3.9-32.2]), and PCSM (p<0.01 HR: 6.0 [95%CI: 1.8-19.6]). Conclusions: In SRT, where pathologic factors including extra-capsular extension, seminal vesicle invasion, and margin status are known, the presence of GP5 is the strongest pathologic predictor of BF, DM, and PCSM. Traditional GS risk stratification fails to fully utilize the prognostic capabilities of individual GP’s for SRT patients following RP. Intensification of treatment regimens, such as early use of androgen deprivation therapy or adjuvant radiation, may be appropriate for patients with GP5 in this setting.
Results of a phase II study of sunitinib (SU) maintenance after response to docetaxel in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Eigl Bernhard J. , Eliasziw Misha , North Scott A. , Trudeau Marc G. , Winquist Eric , Chi Kim N. , Ruether Joseph D.
Published: February 2017

153

Background: Docetaxel (D) remains the standard first cytotoxic therapy in mCRPC. Given its mechanism of action, acceptable toxicity profile and simple administration, SU had potential as maintenance therapy for mCRPC. In this multicenter study, we evaluated the tolerability and efficacy of SU monotherapy in patients (pts) with mCRPC who have responded to D. Methods: Pts withmCRPC and responding/stable disease at the time of D completion were enrolled in this multicentre trial. Pts received 50mg of SU daily on 4/2 week on/off cycles. The primary endpoint was progression-free survival (PFS), defined on the basis of RECIST criteria and worsening disease-related symptoms requiring further therapy. Because the effect of SU on PSA is not well known, PSA progression alone was not considered disease progression. PFS of 180 days was considered to be a clinically meaningful threshold for recommending further study of SU. PSA response was a secondary endpoint. The threshold for PSA-progression (PSA-P) was defined as a 25% increase in PSA over baseline. Results: Twenty-three pts were enrolled and treated. Mean age was 66.5 years (48-78). ECOG scores of 0, 1, and 2 were reported for 9, 13 and 1 pts respectively. Mean number of prior cycles of D was 8.6 (4-12). A total of 92 cycles of SU were administered; a mean of 4 per pt (1-11). Mean follow-up was 5.4 months (0.6-15). A total of 479 adverse events (AE) were recorded, of which 88% were Grade 1-2 and 12% were Grade 3-4. The AE were of a type and severity expected for SU. Three Grade 4s occurred, consisting of hepatitis, myelosuppression, and pneumonia. Median PFS was 133 days (95% CI: 48-154). Most pts had immediate PSA increases without evidence of disease progression, with the mean increases in PSA over baseline being 197%, 342%, and 1437% in Cycles 1, 2, and 3, respectively (p<0.05). Conclusions: Although SU was well tolerated as maintenance therapy with predictable side-effects, median PFS was lower than the predefined threshold of 180 days. PSA values were not informative as significant increases were observed as early as Cycle 2. This agent is not considered worthy of further investigation in this setting of maintenance therapy. Clinical trial information: NCT00550810.
Sensitivity of PTEN-deficient prostate carcinoma cells to ionizing radiation through inhibition of treatment-induced CXCL8 signaling.
Authors: Armstrong Chris , Coulter Jonathan , Maxwell Pamela , Berlingeri Silvia , O'Sullivan Joe M. , Prise Kevin , Waugh David J.
Published: February 2017

154

Background: We recently demonstrated that loss of PTEN in CaP cell lines increases expression of the pro-inflammatory chemokine CXCL8. Increased expression and signalling of this chemokine is detectable in PIN-foci and increases with disease progression. Our objective was to determine how induction of CXCL8 signalling affects the sensitivity of PTEN-deficient CaP cells to radiotherapy, a major treatment modality used in locally-confined CaP. Methods: Established cell-based models of CaP with differential expression of PTEN were subjected to ionizing radiation (IR) under normal or hypoxic culture conditions. Changes in chemokine expression in CaP cells were analyzed by real-time PCR, immunoblotting, and ELISA. siRNA- or shRNA-directed strategies were used to repress PTEN expression and/or attenuate autocrine CXCL8 signalling by down-regulating CXCR1 and CXCR2 gene expression.The effects of modulating chemokine signaling on cell viability following exposure to clinically-relevant doses of IR were assessed by colony formation assays, cell proliferation analysis, and analysis of apoptosis and/or cellular senescence. Results: Exposure to IR (3 Gy) in normoxic and hypoxic cells increased gene expression of CXCL8 and its receptors CXCR1 and CXCR2, a response potentiated in PTEN depleted cells. Loss of PTEN had different effects on the sensitivity of CaP cell lines; shRNA-mediated loss of PTEN conferred increased radioresistance in DU145 cells but increased the sensitivity of 22Rv1 cells to IR. However, despite these variable responses, siRNA-mediated repression of CXCR1/2 expression increased the sensitivity of all PTEN-depleted cell-based models to IR, under both normal and hypoxic conditions. Interestingly, inhibition of CXCL8 signalling reinforced IR-induced senescence in PTEN-depleted 22Rv1 cells (Tp53 WT) but increased apoptosis in PTEN-depleted DU145 cells (Tp53 mutant). Conclusions: Targeting IR-induced autocrine CXCL8 signalling is a novel therapeutic strategy to enhance the sensitivity of PTEN-deficient CaP cells to IR, taking on added significance in cells harbouring mutations or loss of Tp53 expression.
Is there a predictive value for measurement of tumor percentage and the number of tumor foci after prostatectomy?
Authors: Hinkelammert Reemt , Eminaga Okyaz , Semjonow Axel
Published: February 2017

159

Background: The prognostic relevance of tumor volume (TV), tumor percentage (TP) and number of tumor foci (NF) as predictors of biochemical recurrence (BCR) in prostate cancer (PCA) following radical prostatectomy (RPE) is controversial. Methods: The cohort consisted of 758 referred subjects who underwent RPE between 2000 and 2005 at the University of Muenster. The mean time of follow up was 62 months. TV, TP and NF were estimated visually with the assistance of a pathologic mapping grid for embedded RPE specimens. In addition, TV and TP were assessed in a categorized fashion by using medians as cut points. Subgroup analyses for high (i.e. any of the following: > pT2, Gleason score ≥ 8, PSA > 20 ng/ml) and low risk (not high risk) patients were performed. Univariate and multivariate Cox propotional hazard analyses for BCR were performed. Results: TV, TP, and NF were strongly related to tumour stage, Gleason score, surgical margin status (SM) and preoperative prostate specific antigen (PSA). In univariate analysis all pathologic parameters including TV, TP, and NF were predictive for BCR. In multivariate analysis only TP, tumour stage, Gleason score, and PSA level were independent predictors. In subgroup analysis, TP was an independent predictor for BCR in the high risk group, but not in the low risk group. Conclusions: TP, but not TV or NF was found to be an independent predictor for BCR in patients after RPE. TP seems to be more relevant in high risk patients.
Effectiveness of abiraterone as salvage therapy in patients with docetaxel- and castration-resistant prostate cancer (mDCPC) that progressed during second-line chemotherapy with carboplatin plus weekly docetaxel (DC).
Authors: Reuter Christoph W. , Morgan Michael A. , Fenner Martin , Grünwald Viktor , Ganser Arnold
Published: February 2017

162

Background: Our recent data have shown that carboplatin AUC5 on d1 plus docetaxel at a dose of 35 mg/m2 iv on d1, 8, 15 every 4 weeks (q4w) is an effective salvage therapy in mDRPC. Patients (pts) who have progressive disease during DC treatment survive only ~7 months and many are symptomatic. We have demonstrated that high free testosterone (FT) serum levels during DC treatment have a negative prognostic value for PSA response and overall survival in these pts. In this study the impact of abiraterone treatment and other subsequent salvage regimens after DC failure was analyzed. Methods: DC failure was defined as disease progression during DC treatment according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Since February 2005, 74 consecutive DRPC pts were treated with at least 2 cycles DC until disease progression. At the time of the current analysis 67 pts have progressed and 41 pts received one or more subsequent therapies (1-3). Results: Overall survival (OS) of all 67 pts who have progressed during DC treatment was 7.1 months (CI 95% 1.8, 12.3). 41 pts received subsequent salvage therapies including mitoxantrone-prednisone-etoposide (MPE) (n=10), cabazitaxel (n=10), docetaxel-oxaliplatin (n=8), abiraterone (n=15) and doxorubicin-ketokonazol (n=5). OS of these 41 pts was 14.6 months (CI 95% 11.0, 18.3).In pts receiving abiraterone as salvage treatment, OS after DC was 21.8 months (CI 95% 7.2, 36.5) versus 11.9 months (CI 95% 9.0, 14.8) in pts receiving other regimens (HR 0.302, CI 95% 0.11, 0.8; p=0.016). Responses of prostate-specific antigen (PSAR; ≥30% and ≥50%) were only observed in pts receiving abiraterone (8/15, 53.3% and 4/15, 26.7%, respectively). Conclusions: Our data demonstrate for the first time that testosterone is an important prognostic factor for PSA response and OS in mDRPC patients receiving DC chemotherapy and that targeting testosterone after DC failure prolongs post-DC survival.
Serum insulin-like growth factor-1 levels in response to dasatinib-based regimens in bone-metastatic prostate cancer.
Authors: Dayyani Farshid , Varkaris Andreas , Araujo John C. , Song Jian H. , Trudel Geralyn C. , Logothetis Christopher , Gallick Gary E.
Published: February 2017

166

Background: Dasatinib, an inhibitor of Src-family kinases, combined with docetaxel in men with castrate-resistant prostate cancer (CRPC), affects bone turnover markers. Only a subset of men benefit from this therapy, and predictive markers are lacking. We hypothesized a role for insulin-like growth factor-1 (IGF-1) as a predictive marker, since IGF-1 is important in both prostate cancer (PCa) progression and bone development. Hence, we determined the association of IGF-1 expression to treatment response, and whether this expression resulted from tumor cells, the microenvironment, or their interactions. Methods: We first measured serum IGF-1 levels in men with CRPC treated with dasatinib plus docetaxel. To investigate the source of IGF-1, we utilized different mouse models harboring human PCa cells, and used species-specific IGF-1 ELISA kits (mouse vs. human). Results: In men with CRPC, an increase in IGF-1 levels after one cycle of treatment is associated with a higher response rate and longer duration of treatment with docetaxel and dasatinib. Xenograft experiments with subcutaneous, and intratibial injection of PCa cells and treatment of mice with dasatinib-based combinations suggest that direct interaction of PCa cells with bone microenvironment is necessary for IGF-1 induction, is entirely host-derived, and occurs only in mice that respond to dasatinib-based therapy. Conclusions: Our results support a role for serum IGF-1 as a potential biomarker for dasatinib-based combination treatments in CRPC. Inoculation of human PCa cells into murine hosts was essential in determining that IGF-1 results from the bone microenvironment. Further studies are warranted to validate these findings in a larger cohort of patients in a prospective manner.
Serum IGF-1 levels in men with advanced prostate cancer treated with the ERα agonist, GTx-758.
Authors: Yu Evan Y. , Gittelman Marc , Keane Thomas E. , Tutrone Ronald , Belkoff Laurence , Given Robert , Bass Joel , Chu Franklin , Gambla Mike , Gaylis Franklin , Bailen James , Getzenberg Robert H. , Coss Christopher , Hancock Michael L. , Dalton James T. , Steiner Mitchell S.
Published: February 2017

171

Background: The insulin pathway and, in particular, insulin-like growth factor-1 (IGF-1), has been implicated in the development of prostate cancer, and serum IGF-1 levels have been associated with advanced disease. GTx-758, an ERα agonist that is being evaluated for the treatment of advanced prostate cancer, reduces serum total testosterone (T) and free T and increases SHBG. Herein, we compare the effects of GTx-758 and leuprolide on serum IGF-1 levels in men with advanced prostate cancer treated with ADT. Methods: In a Phase II study (G200705), men with advanced prostate cancer (n=159) received 1000 mg or 2000 mg of GTx-758 daily or leuprolide. Serum samples were collected from all of the men in the study and serum IGF-1 levels (ng/ml) were analyzed by a reference laboratory. All p values describe the comparison of GTx-758 treatment groups to the leuprolide treated men. Results: Through day 90, in men receiving the 1000 mg and 2000 mg doses of GTx-758 , serum IGF-1 levels were decreased by more than 70 ng/ml (greater than 50%), while levels stayed constant or increased slightly in men on leuprolide (p<0.001). As a result of an increased risk of venous thromboembolic events (VTEs) at these higher doses of GTx-758, the trial was stopped prior to its completion, and not all of the men in the study reached the 90 day treatment date (92 men reached that date). Conclusions: In men with advanced prostate cancer, the ERα agonist, GTx-758, can decrease the active form of testosterone, serum free T, to significantly lower levels than leuprolide. Patients receiving GTx-758 experienced a significant decrease in serum IGF-1. Since changes in insulin metabolism are involved in regulating prostate cancer as well as bone and systemic metabolism, the observed decreases in IGF-1 could be significant. A Phase II clinical trial utilizing lower doses of GTx-758 (G200712) is currently ongoing to determine if similar effects can be observed with a lower rate of VTEs. Clinical trial information: NCT01326312.
Impact of body mass index on clinicopathologic outcome and biochemical recurrence after radical prostatectomy in 1,257 Japanese patients with prostate cancer.
Authors: Narita Shintaro , Mitsuzuka Koji , Yoneyama Takahiro , Kawamura Sadafumi , Arai Yoichi , Ohyama Chikara , Tochigi Tatsuo , Yamaguchi Takuhiro , Habuchi Tomonori
Published: February 2017

176

Background: To determine the impact of body mass index (BMI) on the clinicopathological characteristics and biochemical recurrence of prostate cancer (PCa) after radical prostatectomy (RP) in Japanese men. Methods: The medical records of 1,257 men with PCa treated by radical prostatectomy without neoadjuvant therapy at four medical centers between 2001 and 2009 were retrospectively reviewed. Patients were categorized into four groups using the WHO BMI classification and recommended BMI quartiles. Associations of the various BMI categories with clinicopathological characteristics and biochemical recurrences were statistically evaluated. Biochemical recurrence was defined as a prostate specific antigen (PSA) level of >0.2 ng/ml. Results: Of the 1,257 patients, 230 (18.1%) experienced biochemical recurrence during the median follow-up period of 49 months. The median BMI was 23.8 kg/m2, and 1.4% patients were underweight, 65.4% were of normal weight, 30.9% were overweight, and 2.4% were obese (WHO classification). Preoperative PSA levels and PSA density (PSAD) were significantly higher in the underweight group than in the other groups. Pathological characteristics did not differ significantly among BMI categories. As per the WHO classification and quartile categories, biochemical recurrence rate was comparable among the BMI groups. After adjusting for other pre- and perioperative covariables, multivariate Cox proportional hazards analysis revealed that a high BMI did not have an independent impact on biochemical recurrence-free survival. Conclusions: Underweight Japanese PCa patients who underwent radical prostatectomy had higher preoperative PSA levels and PSAD. However, high BMI was not associated with increased biochemical recurrence rate.
Prostate cancer (PC) follow-up and treatment by race in an equal access health system: A pilot study.
Authors: Mitikiri Nirupama Devi , Nallu Anitha , Mullins C. Daniel , Onukwugha Ebere , Hussain Arif
Published: February 2017

177

Background: There are known racial disparities in the incidence and outcomes of PC as well as in receipt of treatment. Although some studies in the Veterans Affairs Health System (VA) suggest that utilization and outcomes are as good, if not better, for African Americans (AA) as for Whites (WH), race appears to have mixed impact on stage-specific PC survival in the VA population. This pilot study aims to identify racial disparities in PC care in an equal access health system such as the VA. Methods: A retrospective cohort study was conducted of 109 consecutive patients with newly diagnosed PC in the year 2010 at the Baltimore VA Medical Center (BVAMC). Baseline characteristics (age, prostate specific antigen (PSA) at diagnosis, Gleason score (GS), stage, race) were extracted from the electronic medical records. Patterns of treatment and follow-up care, including specialist (urologist, medical oncologist, radiation oncologist) visits, time to first treatment, and primary treatment in the first year of diagnosis were examined. Results: Of 109 patients, 32 (30%) were WH, 69 (63%) AA and 8 (7%) other racial groups. AA and WH had similar median age (62, 64), GS (7, 7) and PSA (8.06, 7.46) at diagnosis. More AA were diagnosed with stage IV PC compared to WH (13% vs. 3%). Median time to first follow-up specialist visit since diagnosis was 15 (0-140) and 19.5 (2-169) days for AA and WH, respectively. Median time to initial treatment was 99.5 (1-306) and 146 (6-345) days for AA and WH, respectively. For localized PC, 30% AA received prostatectomy (RP) and 70% external beam radiation therapy (EBRT); in WH it was 19% and 76%, respectively. Conclusions: In an equal access health system such as the BVAMC, there did not appear to be racial differences in PC follow-up with specialists and time to initial treatment. AA had more advanced disease at diagnosis. Interestingly, although both AA and WH received EBRT more often than RP for localized PC, AA underwent RP more frequently than WH. It will be of interest to determine whether these patterns hold for other years and in other equal access health systems.
11C-choline PET/CT in selection of patients for salvage cryoablation in recurrent prostate cancer.
Authors: Breeuwsma Anthonius J. , Rybalov Maxim , Leliveld Anna Maria , Dierckx Rudi A. , Pruim Jan , de Jong Igle J.
Published: February 2017

188

Background: 11C-choline PET/CT has proven to be a sensitive technique for re-staging after radiation therapy (RT). The aim of this study was to analyze the clinical impact of 11C-choline-PET/CT in the selection of patients with biochemical recurrence (BCR) after RT for salvage cryoablation of the prostate. Methods: This prospective study was conducted between November 2006 and February 2012 on patients considered as candidates for salvage cryoablation. 74 patients, mean age 69.2 years, median – 70.3 years (range 49-79), who were being followed up after RT for histological proven prostate cancer (according to ASTRO-Phoenix) were included. Until 2009 we used PET/CT fusion, but from 2009 all patients were examined with an integrated PET/CT system. After receiving 400 MBq 11C-choline intravenously, a whole body scan was made. As reference we used biopsy-proven histology from site of suspicion, confirmative imaging modalities (bonescan, CT) or clinical follow-up. PSA doubling time and velocity was calculated. Results: According to the PET/CT results, 40 (54%) patients had a local recurrence, 20 (27%) had regional/distant metastases and 14 (19%) had a negative scan. The positive PET findings were proved by histology from prostate biopsies and/or pelvic lymph node dissections in 63% of cases. Considering PET/CT results: 50/74 (68%) patients received cryoablation, for 24/74 (32%) treatment was changed (active surveillance or androgen deprivation therapy). Conclusions: 11C-choline-PET/CT could be useful for the selection of patients with BCR after RT for salvage cryoablation of the prostate. 11C-choline-PET/CT was decisive and led to therapy change in 32% of cases. [Table: see text]
Which data for cabazitaxel (Cbz) from the real world? The safety experience from the Italian centres participating in the Expanded Access Programme (EAP).
Authors: Bracarda Sergio , Marchetti Paolo , Gasparro Donatello , Gernone Angela , Boccardo Francesco , Messina Caterina , Gianni Luca , Bortolus Roberto , Fratino Lucia , Fornarini Giuseppe , Carteni Giacomo , Tucci Marcello , Mazzanti Roberto , Scotto Tiziana , Martoni Andrea , Basso Umberto , Procopio Giuseppe , Morelli Franco , Mattioli Rodolfo , Di Lorenzo Giuseppe
Published: February 2017

189

Background: A significant percentage of metastatic castration-resistant prostate cancer (mCRPC) patients (pts) progressing during or after a docetaxel (D) based therapy are candidates for additional effective treatments. Taxanes remain the mainstay of treatment for a wide range of tumours including mCRPC. Cabazitaxel, a next generation of taxane, was approved based on results from the TROPIC study (NCT00417079). Cbz plus prednisone (P) was associated with a higher overall survival than mitoxantrone (MTX) (15.1 vs 12.7 mo, HR=0.70; P<0.0001). Moreover CbzP was associated with clinical benefits, better PFS, maintenance of ECOG PS, improved tumour and PSA response, longer time to tumour and PSA progression while pain control was similar to MTX. These clear benefits supported a global EAP. Methods: Here we report, the preliminary safety analysis of 165 pts entered in the study from 25 Italian centres between Jan and Nov 2011. Pts received Cbz 25 mg/m2(intravenous every 3 weeks) plus P 10 mg (oral daily). Results: Median age was 70 years (21.8% of the cases were ≥75 years); pts with PS 0-1=98.2%; median number of previous D cycles was 8; 30.8% received 450 ÷ 675 mg, 14.7% received 675 ÷ 900 mg and 28.2% received ≥ 900 mg of D. Median time from last D dose to first CbzP dose was 5 months including any other eventual chemotherapy treatment. 49.1% of the pts entered in this EAP because refractory to D (PD during or within 3 months since the last D administration), overall 72 % of pts had 2 or more met sites. At the time of this analysis approximately 50% of pts received 4 cycles. A total of 68 pts discontinued CbzP due to PD (38.2%), AEs related and not related (38.2)%, Investigator’s decision (2.9%) or other reasons (20.6%). The most common G 3/4 AEs were neutropenia (35.2%), leukopenia (17.6%), anaemia (5.5%) febrile neutropenia (4.2%); main non-haematological AEs were asthenia (4.8%) and fatigue (4.2%). Conclusions: This large analysis confirms a manageable safety profile of cabazitaxel in routine clinical practice. The safety profile showed in EAP study suggests cabazitaxel a safe and effective treatment option in mCRPC pts progressing during or after a docetaxel based therapy. Clinical trial information: NCT01254279.
Dependence of intrafraction prostate motion within the pelvis on fraction duration during whole pelvic intensity modulated arctherapy (IMAT) versus dynamic IMRT.
Authors: Lescut Nicolas , Martin Etienne , Maingon Philippe , Quivrin Magali , Mirjolet Celine , Naudy Suzanne , Petitfils Aurelie , Crehange Gilles
Published: February 2017

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Background: To compare the 3-dimensional intra-fraction variations of prostate position within the pelvis with whole-pelvic fixed-field intensity-modulated radiation therapy (IMRT) vs. intensity-modulated arc therapy (IMAT) in high-risk prostate cancer. Methods: Fifteen PCa patients underwent whole pelvic radiotherapy using either dynamic IMRT with a sliding window technique (n= 8) or IMAT (n= 7). All the patients had a kV cone-beam computed tomography (CBCT) before and immediately after each fraction of IMRT or IMAT. Intra-fraction motions of the prostate were determined using a 2-step procedure performed on each pre- and post-treatment imaging: 1) planning CT and CBCT were matched on bony structures after automatic semi-rigid fusion alongside the 3 axis (x, y, z), 2) planning CT and CBCT were matched on the prostate with respect to intra-prostatic markers: xsoft, ysoft, zsoft. The position of the prostate within the pelvis for each pre- and post-treatment study points was defined as xpros= (xbone – xsoft), ypros= (ybone – ysoft) and zpros= (zbone – zsoft). Rectum and bladder were outlined on each CBCT with the aim to assess changes in rectal or vesical repletion during each fraction. Organ distension was assessed by measuring the average rectal cross-sectional area (rCSA; defined as the rectal volume divided by length), and the area of the bladder when evaluated 2.5cm above the prostate base (A-blad) on pre- and post-treatment CBCT. Results: Two hundred and ninety four CBCT were reviewed for this analysis. The average fraction duration was shorter with IMAT than with IMRT (4’49’’, vs. 11’00’’, p< 0.001). During fractions of IMRT the prostate showed statistically significant shifts in the longitudinal (p= 0,049) and lateral (p=0,013) axis while it was not statistically significant during fractions of IMAT. Intra-fraction rCSA increased neither during IMAT nor IMRT whereas A-blad increased only during fractions of IMRT but with no correlation with prostate displacements. Conclusions: The prostate moves within the pelvis during an IMRT course which could lead to a greater daily geographic miss when compared to the IMAT technique.
A phase II study of linsitinib (OSI-906) in patients with asymptomatic or mildly symptomatic (non-opioid requiring) metastatic castrate resistant prostate cancer (CRPC).
Authors: Garcia Jorge A. , Elson Paul , Cooney Matthew M. , Tyler Allison Janine , Rezash Victoria , Borden Ernest C. , Dreicer Robert
Published: February 2017

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Background: Novel agents capable of blocking AR ligand independent pathways responsible for the development of CRPC are needed. IGF-1R and its ligands (IGF-1/IGF-2) play a key role in regulating growth, resistance to apoptosis, and invasion in PCa. IGF-1R is overexpressed in PCa and mediates resistance to ADT. OSI-906 is a small molecule potent dual inhibitor of IGF-1R and insulin receptor TK activity. To determine the activity of OSI-906 in men with CRPC a Simon two-staged phase II study was conducted. Methods: Men with asymptomatic or mildly symptomatic Met CRPC were eligible. ECOG 0-1, adequate organ function, and no prior chemotherapy for CRPC were required. Pts received OSI-906 at 150mg orally twice daily on a 28-day cycle. Endpoints included PSA response at 12 wks, safety, RECIST-defined response, time to PSA progression, and OS. Correlative studies explored the impact of OSI-906 on AR signaling (androstenedione, DHEA, DHEA-sulfate, p-IGF-1R, p-IR), markers of PD (TGF-b1, IL-6, TNF-a, MCP-1), and CTC and CECs. Results: To date 18 pts have enrolled and completed 12 wks of therapy. Median age 68 (55-78); Median pre-treatment PSA was 55.23 (range 2.46-277.60); 41% of pts had bone-only disease, 29% soft-tissue only and 29% had both. Although transient PSA declines were noted, 17/18 pts discontinued therapy sec PSA progression. RECIST-defined SD was observed in 8 pts. Pts received a median of 3 cycles of therapy (range 2-6+). Most common G1/2 AEs included AST/ALT changes observed in 41 and 18% of patients respectively, fatigue (59%); prolong QT interval (35%) and nausea/vomiting (35%). No significant change in the number of CTC and CEC counts was observed. An association between pre-treatment PSA and pre-treatment CTC was observed (Spearman r=0.49, p=.04). No correlation between CTC changes and PSA progression was observed .Evaluation of other molecular markers of PD is underway. Conclusions: Treatment with OSI-906 is safe. No PSA responses or changes in CTC/CECs were noted. Markers of PD might help elucidate potential mechanisms of escape to this alternative pathway in CRPC. OSI-906 plus an AA might provide synergistic activity in this setting. Clinical trial information: NCT01533246.
Long-term responders to enzalutamide (ENZA) during the phase III AFFIRM trial: Baseline characteristics and efficacy outcomes.
Authors: Fleming Mark T. , Scher Howard I. , Fizazi Karim , Taplin Mary-Ellen , Forer David , Hirmand Mohammad , De Bono Johann Sebastian
Published: February 2017

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Background: ENZA, an oral androgen receptor inhibitor, was shown to significantly increase overall survival by 4.8 mo (P <0.001, HR 0.63) vs placebo (PBO) in AFFIRM, a phase III trial in patients (pts) with castration resistant prostate cancer (CRPC) post- docetaxel. Here we report the baseline characteristics and efficacy outcomes of long-term responders (LTR, ≥12 months on ENZA) in the AFFIRM trial. Methods: Pts were randomized 2:1 to ENZA 160 mg/day or PBO. The primary endpoint was overall survival (OS). The study was stopped at the pre-specified interim analysis (520 events). Pts in the ENZA group were allowed to continue on ENZA post unblinding. The LTR group was defined by Aug 2012 data cut-off. Efficacy data are from interim analysis data cut-off from Sep 2011. Results: 35% (276/800) of the ENZA group were on therapy for ≥ 12 months; 22% (174/800) for > 18 months. Comparing the LTR subgroup to the all ENZA group, the LTR subgroup had been living with prostate cancer longer (7.9 vs 5.9 yrs) and had lower disease burden at baseline (Table). Pts in the LTR subgroup had improved efficacy outcomes compared to all ENZA group. Of note, 50% PSA response was 87% in LTR subgroup vs 54% in the all ENZA group. Results are preliminary, updated results will be presented. Conclusions: 35% of pts in AFFIRM received ENZA for ≥12 months. Compared to the all ENZA group, LTR pts had less disease burden at baseline and had improved efficacy outcomes. Clinical trial information: NCT00974311. [Table: see text]
Current status and outcomes of salvage radiotherapy for patients with PSA recurrence after prostatectomy: A JROSG surveillance study.
Authors: Mizowaki Takashi , Aoki Manabu , Nakamura Katsumasa , Yorozu Atsunori , Kokubo Masaki , Karasawa Katsuyuki , Kozuka Takuyo , Nakajima Nobuaki , Sasai Keisuke , Akimoto Tetsuo
Published: February 2017

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Background: Salvage radiotherapy (S-RT) for patients with prostate cancer who developed PSA failure after radical prostatectomy is widely applied. However, current status of this approach in Japan has not been surveyed so far. The aim of this study was to reveal the present conditions and outcomes of S-RT for Japanese patients with biochemically recurrent prostate cancer. Methods: Clinical data of the S-RT was gathered by sending a questionnaire to participating facilities to the Japanese Radiation Oncology Study Group (JROSG). The S-RT was defined as external-beam radiotherapy delivered to the prostate bed to patients with prostate cancer who eventually developed PSA failure, although their PSA value had once reached <0.2 ng/ml after prostatectomy. In addition, the interval between prostatectomy and the S-RT should essentially be six months or longer. PSA failure-free survival (PFFS) and clinical failure-free survival (CFFS) was calculated by the Kaplan-Meier estimation. Results: 371 cases were registered from 38 facilities. Among them, hormonal therapy was combined with S-RT in 151 patients. In 3 cases, chemotherapy was combined before or after the S-RT. The rests of the cases were treated by S-RT alone. However, prognostic information was insufficient in 28 cases, and PSA nadir was >0.2 ng/ml in 3 cases. Therefore, outcome studies were conducted in the remaining 186 cases. The median age was 67 years old. The nadir value of the PSA after prostatectomy and the PSA value at the initiation of S-RT were 0.0135 ng/ml and 0.292 ng/ml, respectively. The median period between prostatectomy and the S-RT was 18.6 months. Median follow-up period was 58 months. The 5-year PFFS and CFFS were 50.1% (95%CI: 42.8 – 57.9) and 90.1% (95%CI: 86.4 – 95.7), respectively. PFFS was significantly superior in patients with PSA values <= 0.3 ng/ml at the initiation of S-RT than those of PSA values > 0.3. (57.5% vs. 40.5%, p = 0.027) Conclusions: In Japan, hormonal therapy was combined with S-RT in about 40% of the cases. The 5-year PFFS and CFFS rates of cases treated by S-RT alone were 50.1% and 90.1%, respectively. A PSA value of 0.3 was significant cut-off point for predicting PFFS.
High-dose-rate brachytherapy combined with external beam radiotherapy for localized prostate cancer: Correlation between clinical and dosimetric parameters and the incidence of rectal bleeding.
Authors: Kariya Shinji , Yamasaki Ichiro , Ashida Shingo , Tamura Kenji , Shuin Taro , Nishioka Akihito , Ogawa Yashuhiro
Published: February 2017

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Background: Several investigators have advocated that the alpha/beta ratio for prostate cancer is atypically low, and that hypofractionated radiotherapy or high-dose-rate brachytherapy (HDR-BT) regimens using appropriate radiation doses are expected to improve the local control rate for localized prostate cancer. However, the increase in the total biological effective dose (BED) may cause increased severity and incidence of normal tissue complications. The purpose of this study was to investigate what clinical and dosimetric factors affected the incidence of rectal bleeding after HDR-BT combined with external beam radiotherapy (EBRT). Methods: A total of 143 patients with localized prostate cancer underwent HDR-BT combined with EBRT. The fractionation schema for HDR-BT and EBRT was prospectively changed: 9 Gy x 2 + 2 Gy x 20 (BED1.5 = 219 Gy, BED3 = 139 Gy) in 57 patients (Group 1); and 9 Gy x 2 + 3 Gy x 13 (BED1.5 = 243 Gy, BED3= 150 Gy) in 86 patients (Group 2). Median follow-up was 59 (range, 36 – 94) months. The toxicities were graded based on the National Cancer Institute-Common Terminology Criteria for Adverse Events v3.0. Results: Sixteen (11.2 %) and one patients developed Grade 2 and 3 rectal bleedings, respectively. There were no significant differences between Group 1 and Group 2 in the incidence of Grade 2 and 3 rectal bleedings (12.3% and 11.6%, respectively). Grade 2 and 3 rectal bleedings occurred much more in the patients receiving the antiplatelet therapy (AT) (19.4%) than those without a history of AT (9.8%) and in the patients with diabetes mellitus (DM) (37.5%) than those without DM (10.4%). However, neither AT nor DM were risk factors in univariate analysis. Regarding dosimetric factors, V75 > 2cc, V90 > 0.2cc, D2 > 7 Gy, and D1 > 7.4 Gy were statistically-significant risk factors. In multivariate analysis, DM was the only statistically-significant risk factor. Conclusions: BED escalation could be performed without severe rectal bleeding in HDR-BT combined with EBRT. V75 > 2cc, V90 > 0.2cc, D2 > 7 Gy, D1 > 7.4 Gy, and DM were risk factors for the incidence of rectal bleeding in HDR-BT combined with EBRT. Clinical trial information: 18-9.
Salvage brachytherapy for prostate bed recurrence following radical prostatectomy.
Authors: Smith Kristin , Ciezki Jay P. , Stephans Kevin L. , Reddy Chandana A. , Klein Eric A.
Published: February 2017

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Background: Approximately 10% of patients who undergo a radical prostatectomy (RP) for localized prostate cancer subsequently experience a local recurrence. A small percentage of these patients present with prostate bed nodules (PBN). We present here, a case series of 12 patients treated with low dose rate brachytherapy (BT) for a PBN post RP. Methods: All 12 patients had biopsy confirmed cases of recurrent adenocarcinoma in the prostatic bed. At the time of PBN diagnosis, 2 patients had received EBRT, 2 patients had received ADT, and 1 patient had undergone HIFU. Patients were confirmed to have a negative CT and bone scan prior to salvage BT. All patients received salvage BT with I-125 prescribed to 144 Gray. Results: The median interval between RP and BT was 8 years (range 0.5- 17.9), median PSA prior to BT was 4.53 ng/ml (range 0.55-15.2), and the median age was 69 (range 59-86). Forty-two percent of patients had a PBN Gleason score of 8, 33% had a score of 7, and a score was not reported for 25% of patients due to prior EBRT or ADT use. The median follow up for this series is 26.5 months (range 1-69). At the time of this analysis, 10 patients were evaluable for biochemical failure (bF) (nadir+2) and distant metastases (DM). The one and two year rates of bF were 0% and 52%. There was no association between pre-BT PSA and bF, nor between pre-BT Gleason score and bF. Two patients subsequently developed DM at 17 months and 55 months after BT. The pelvic lymph nodes were the site of DM for both patients. The median PSA velocity post BT was -0.120 ng/ml/yr (range -1.404- 9.096). Five patients had a negative PSA velocity at last follow-up, while 4 had an increasing PSA velocity. Velocity could not be defined for 3 patients (insufficient PSA n=2, ADT n=1). To date, no gastrointestinal or urinary toxicities have been noted. Conclusions: Brachytherapy as a salvage treatment for a PBN appears to be well tolerated. The rates of bF and DM following salvage BT are comparable to those of salvage EBRT for this patient population. Intermediate-term biochemical control was attained in a sub-set of patients with declining PSA at last follow-up.