bluuebunny/crossref_metadata_2025 huggingface dataset:
Early response assessment and bone flare phenomenon on 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) in patients (pts) with metastatic castration-resistant prostate cancer (CRPC) treated with abiraterone acetate.
Authors: Burgio Salvatore Luca , Matteucci Federica , Menna Cecilia , Caroli Paola , Moretti Andrea , Bianchi Emanuela , Rossi Lorena , Kopf Barbara , Masini Carla , Fabbri Francesca , Amadori Dino , De Giorgi Ugo
Published: February 2017

134

Background: In this prospective study, in patients with CRPC previously treated with docetaxel, we evaluated prostate specific antigen (PSA) and FCH-PET/CT for early response assessment to abiraterone acetate, and assessed frequency of early FCH-PET/CT discordant with PSA and clinical response. Methods: Twenty nine metastatic CRPC pts progressing after docetaxel chemotherapy received abiraterone acetate 1,000 mg daily with prednisone 5 mg twice daily in continuous 28-day cycles. Patients were evaluated monthly for serological PSA response and safety. FCH-PET/CT was repeated after 4-6 weeks and a CT scan was done after 3 months of abiraterone acetate. FCH-PET/CT bone flare was defined as the combination, after 3 months of therapy, of an interpreting radiologist’s report indicating progressive disease (PD) in context of a ≥50% decline in PSA, no PD at 3-month CT scan, with FCH-PET/CT improvement or stability 2-3 months later. Results: Three of 29 patients treated with abiraterone acetate did not perform the follow-up FCH-PET/CT due to rapidly PD with a decline in performance status. Of the remaining 26 patients, 4 are still undergoing early response evaluation. Twenty two pts, median age was 71 yrs (range, 57-86 yrs) were evaluable for this analysis. A ≥50% PSA decline was observed in 15/22 (68%) evaluable pts. Undetectable PSA levels (≤0.1 ng/mL) occurred in one case. Early FCH PET/CT response assessment was as follows: complete response (n=2, 9%), partial response (n=7, 32%), stable disease (n=3, 14%), PD (n=10, 45%), but in 4 of 10 pts with PD a bone flare phenomenon on FCH PET/CT was observed. PSA decline ≥50% and FCH PET/CT response correlated in 19 of 22 pts (86%). Conclusions: Discordant findings between serologic PSA response and increases in early FCH-PET/CT bone lesion intensity are reported here for the first time in CRPC. Further investigation is needed to clarify the confounding effect of FCH-PET/CT bone flare on patient management and interpretation of results.
Efficacy of cabazitaxel and its relationship with predictors of poor response to second hormonal therapies (2d HT) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Oudard Stephane , Mercier Florence , Flechon Aude , Guillot Aline , Le Moulec Sylvestre , Gravis Gwenaelle , Beuzeboc Philippe , Massard Christophe , Fizazi Karim , De La Motte Rouge Thibault , Elaidi Reza-Thierry , Angelergues Antoine
Published: February 2017

137

Background: Potential predictors of low response to 2d HT including new agents have been recently identified: high Gleason score, rapid progression with first androgen deprivation therapy (ADT), chemotherapy lines >1 and low baseline testosterone (T) levels. We evaluated the influence of these factors on the efficacy of cabazitaxel (C), a new taxane developed to overcome docetaxel (D) resistance. Methods: Records of 84 consecutive mCRPC pts (median 67 yrs) treated with C for disease progression on D or after D were retrospectively collected in 8 French centers. Baseline characteristics, disease history, PSA response, overall survival (OS) and radiological or clinical progression-free survival (PFS) were collected. Results: At C initiation, 84% of pts were ECOG 0-1, 59% had pain and 24% received ≥2 prior chemotherapy lines. Metastases were located in bone (93%), lymph nodes (49%) and visceral/soft tissues (9%). Gleason score was 8-10 in 47%, median time to progression with first ADT was 20 months and median T was 0.1 ng/ml. Median number of C cycles received was 6 (range 2-14). Efficacy of C was not influenced by Gleason score, response duration to first ADT, prior number of chemo lines, or baseline T (table). Main grade ≥ 3 toxicities were neutropenia (32%), anaemia (17%), thrombocytopenia (8%), diarrhoea (6%), and febrile neutropenia (5%). There was no grade ≥3 peripheral neuropathy and no toxic death. Conclusions: This retrospective study suggests that C is effective and shows an acceptable safety profile. Efficacy was not influenced by predictors of poor response to 2d HT (high Gleason, short response to first ADT, Number of chemo lines, low T levels). If these results are confirmed in further investigations, cabazitaxel could be proposed whatever the baseline characteristics of mCRPC pts. [Table: see text]
Hypofractionated radiotherapy (66Gy at 3Gy per fraction) for favorable-risk prostate cancer: Long-term outcomes.
Authors: Patel Nita , Faria Sergio , Cury Fabio L. , David Marc , Duclos Marie , Shenouda George , Souhami Luis
Published: February 2017

141

Background: Hypofractionated radiotherapy (HypoRT) is increasingly being used to treat prostate cancer to take advantage of its likely low α/β ratio. There is limited experience in delivering a high biologically equivalent dose with HypoRT. We report long-term outcomes from patients treated with high-dose HypoRT. Methods: Patients with low and intermediate risk prostate cancer were treated using 3-dimensional conformal radiotherapy at a dose of 66Gy in 22 daily fractions of 3Gy without hormonal therapy. A uniform 7mm margin was created around the prostate for the planning target volume (PTV) and treatment was prescribed to the isocentre. Treatment was delivered using daily ultrasound image guided radiotherapy (IGRT). The CTCv3.0 was used to prospectively score toxicity. Biochemical failure was defined using the Phoenix criteria of nadir+2ng/ml. Results: A total of 129 patients were treated between November 2002 and December 2005. With a median follow-up of 90 months, the 5- and 8-year actuarial biochemical control rate was 97% and 92% respectively. The 5- and 8-year actuarial overall survival was 92% and 88% respectively. Only one patient died from prostate cancer at 92 months after treatment resulting in an 8-year actuarial cancer specific survival of 98%. Radiotherapy was well tolerated with 57% of patients experiencing no acute gastrointestinal (GI) or genitourinary (GU) toxicity. For late toxicity, the worst grade ≥2 rate for GI and GU toxicity was 27% and 33% respectively, but at the last follow-up the rate of grade ≥2 was only 1.5% for both GI and GU toxicity (Table). Conclusions: High dose HypoRT delivering 66 Gy in 22 fractions at 3Gy per fraction is a safe, effective and convenient modality of delivering radiotherapy to patients with favorable risk prostate cancer with excellent biochemical control rates and acceptable rates of acute and late GI and GU toxicity. [Table: see text]
A phase Ib trial of mushroom powder in biochemically recurrent, hormone-naive prostate cancer.
Authors: Twardowski Przemyslaw , Frankel Paul Henry , Pal Sumanta Kumar , Synold Timothy W. , Ruel Christopher , Junqueira Maribel , Nguyen Tina , Palomares Melanie R. , Tryon Pamela Renee , Chen Shiuan
Published: February 2017

142

Background: Biochemically recurrent prostate cancer (PC) is a common presentation of relapse after primary local therapies. Strategies to delay disease progression and defer initiation of androgen deprivation therapy and associated side effects are needed. White button mushroom (WBM, Agaricus bisporus) extract suppresses prostate cancer tumor growth in animals, and prior human experience indicates favorable toxicity profile. Methods: Patients (pts) with rising PSA of ≥0.2 ng/mL after prostatectomy (RP) and/or radiation (RT) and no radiographic evidence of metastases were treated with WBM powder tablets at 4, 6, 8, 10, 12 and 14 grams po daily. Dose escalation was conducted in cohorts of 6 and continued as long as no more than 1 patient per cohort experienced dose limiting toxicity (DLT). Therapy continued until PSA increased by ≥100% and by ≥1 ng/mL, or clinically detectable metastases or unacceptable toxicity occurred. Primary objective was feasibility and toxicity, secondary objective was the effect of WBM on serum PSA and androgen levels. Results: Thirty six pts were treated. Median age was 68 (53-80).Thirty three pts (92%) had prior RP and all underwent previous RT. Median PSA was 1.9 (0.2-22.2). Mean compliance was 98.6 %. No DLT’s were encountered. The most common side effect was grade 1 abdominal bloating (39%); one patient experienced asymptomatic grade 3 hyponatremia. Overall PSA response rate was 11% (95% CI: 4%-27%). Two pts receiving 8 and 14 gm/day demonstrated a PSA complete response (CR), defined as a decline in PSA to undetectable levels that continues for 26 and 7 months respectively. Two pts, receiving 8 and 14 gm/day, experienced confirmed PSA partial responses (PR), defined as a ≥50% PSA decline on treatment. After 3 months of therapy 36% of pts (13/36) demonstrated some PSA decrease below baseline. No association between PSA response and serum testosterone, DHT or DHEA levels was observed. Median duration on therapy is 10.2 months (0.9 – 35.3). Ten pts remain on therapy. Conclusions: Therapy with WBM was well tolerated. Our data suggest that WBM intake results in durable decreases in PSA level in some patients with biochemically recurrent PC. Further studies to clarify mechanism of action are warranted. Clinical trial information: NCT00779168.
Quality-of-life outcomes for prostate cancer treatment in Australia.
Authors: Millar Jeremy L. , Evans Susan M. , Frydenberg Mark , Murphy Declan G. , Bolton Damien M. , Giles Graham G. , Davis Ian D.
Published: February 2017

143

Background: We aimed to use a population based quality registry established in Australia, to review patient-reported health-related QOL after the diagnosis of Prostate Cancer (PCa). Methods: Prospective registry of men with PCa from statutory notifications to the canonical population-based cancer registry in Victoria. An "opt-off" mechanism used. Coverage expanded from 30%-80% of State population over time. Demographics and disease features, management, and outcomes from medical record; men phoned at 12 and 24 months (m), interviewed with script including SF12 and items from standard form (UCLA PCI) for specific QOL outcomes. Urinary, rectal, and sexual function bother (UB, RB, and SB) scores where analysed by univariate and multivariable modelling for relationship of these with presentation or management factors, adjusting for risk. Results: Men from 8/2008 - 2/2011; 1.9% of eligible opted out. Followed 1172 to 12 & 24 m. Median diagnosis age 65 yr; median PSA 6.8 ng/mL; 97.3% clinically localised with 47.7% having NCCN intermediate risk. 520 had treatment with Radical Prostatectomy (RP) (89 also with external beam-EBRT), 171 had EBRT (with or without HDR brachy), and 211 seed implant (SI). 226 had no treatment (NT) in the first 12 m. 52.5% managed in public hospitals, rest private. Univariate analysis: UB associated with management type, and hospital type, and RB and SB associated with these factors, as well as age and disease stage. On multivariate regression SB at 12 m was associated with increasing age (p=0.002) and radical treatment types (RP and EBRT/HDR, p<0.001 and 0.003 respectively)—except SI—compared to NT; RB was associated with SI (0.02) and EBRT/HDR (0.007) and treatment in a public hospital (0.006); and UB was associated with public hospital (<0.001). All associations at 12 m remained significant at 24 m. SF12 physical score had a positive association with RP vs NT (0.014), hospital type (0.001) and younger age. SF12 mental health also showed associations. Conclusions: A large scale registry in Australia assessing patient-reported quality of life outcomes after prostate cancer treatment shows patterns similar to that seen in North American reports.
Outcomes in elderly patients with metastatic castration-resistant prostate cancer (mCRPC) treated with the androgen receptor inhibitor enzalutamide: Results from the phase III AFFIRM trial.
Authors: Sternberg Cora N. , De Bono Johann Sebastian , Chi Kim N. , Fizazi Karim , Mulders Peter , Hirmand Mohammad , Forer David , Scher Howard I.
Published: February 2017

16

Background: Enzalutamide (ENZA) inhibits multiple steps in the androgen receptor signaling pathway (Tran et al, Science. 2009;324:787). The phase III AFFIRM trial demonstrated that ENZA increased median overall survival (OS) by 4.8 months with a 37% reduction in the risk of death (P <0.001, HR 0.63) vs placebo (PBO) in post-docetaxel mCRPC patients (pts) (Scher et al, NEJM 2012; 367:1187). In a post-hoc analysis, the effect of ENZA on outcomes in elderly (≥ 75 yrs) vs younger (< 75 yrs) pts in the AFFIRM trial was assessed. Methods: The AFFIRM trial was a Phase III multinational, randomized, double-blind study in post-docetaxel mCRPC pts. Randomization was 2:1 to ENZA 160 mg/day or PBO, stratified by baseline ECOG performance status and mean pain score. Statistics are presented by age group (≥75, yrs <75 yrs) for efficacy outcomes of OS, radiographic progression-free survival (rPFS), and time to prostate-specific antigen (PSA) progression. Top line safety results are also presented for both age groups. Results: Elderly pts comprised 25% (199/800) of ENZA pts and 26% (104/399) of PBO pts. Improved outcomes with ENZA treatment were observed in both elderly and younger pts, with similar safety profiles in each age group. Conclusions: ENZA significantly improved outcomes in both elderly (≥ 75yrs) and younger pts (< 75yrs). Safety and tolerability findings were comparable between the two age groups. Clinical trial information: NCT00974311. [Table: see text]
Use of biopsy detail to identify subgroup risk in high-risk patients with prostate cancer.
Authors: Townsend Natasha C. , Buyyounouski Mark K. , Ruth Karen J. , Kutikov Alexander , Viterbo Rosalia , Sobczak Mark , White Terry , Horwitz Eric M.
Published: February 2017

169

Background: High Risk (HR) prostate cancer (CaP) patients (pts) are a heterogeneous group. A recursive partitioning analysis (RPA) was performed to determine if tissue involvement could identify patients at risk for biochemical failure (BF). Methods: Between 1992-2009, 608 HR CaP pts with complete prostate biopsy detail data (% overall tissue involvement (%TI), GP45 (weighted average of %TI for Gleason Pattern 4 or 5), Gleason Score (GS)) underwent RT with/out ADT. Primary endpoint was freedom from biochemical failure (FFBF). RPA based on time to BF was used to determine cutpoints for each prognostic variable. Multivariable (MVA) RPAs were used to assess interactions of significant variables (p<0.05) from univariate analysis (UVA). Results: Median follow up for PSA measurement was 45 months (3-193 mo). UVA RPA revealed significant cutpoints for FFBF for Tstage (higher risk of BF(HRBF) for T2c,T3b,T3c,T4,Tx vs lower risk of BF(LRBF) for T1,T2a,T2b,T3a, (p<0.001)); GS(HRBF 3+4/5, 4+5 vs LRBF 2-6, 2+3/4, 5+3/4/5 (p=0.011); iPSA (LRBF ≤37 vs HRBF >37 ng/ml (p<0.001)); dose (HRBF ≤74.9 vs LRBF >74.9 Gy); RT type(LRBF IMRT vs HRBF 3D-CRT, p=0.032), %TI (LRBF ≤53% vs HRBF >53% (p<0.001)); GP45 (LRBF ≤33% vs HRBF >33%(p<0.001)). Overall, FFBF at 5 yr was 79.2% (95%CI 75.0-82.8). For MVA RPA, splits are same as UVA unless noted. MVA RPA excluding GP45 and %TI showed 5 groups (5 yr FFBF 45.9%, 66.8%, 74.2%, 84.2% and 89.5%; N 16, 195, 69, 20 and 308, respectively). Tstage, iPSA, GS and RT type had significant interactions, with highest risk group including PSA >44ng/ml, low Tstage and 3D-CRT, and lowest risk group including PSA ≤44 ng/ml, lower risk Tstage, and lower risk GS. Including %TI in the RPA, significant interactions were between %TI (2 splits), iPSA and GS (5 yr FFBF 50.0%, 62.5%, 71.9%, 80.4% and 92.7%; N 80, 24, 65, 233, and 206, respectively). Highest risk group included pts with %TI >53%; lowest risk included pts with %TI <17%, iPSA <40 ng/mL, and GS lower risk. Using GP45 instead of %TI, 3 groups were found: high GP45; low GP45 and iPSA ≥40; low GP45 and iPSA<40 ng/ml, (5 yr FFBF 58.9%, 67.7% and 85.5%; N 103, 63 and 442, respectively). Conclusions: Pts with > 53% TI, > 33% GP45 and iPSA > 40 ng/ml are at highest risk of failure, and should be considered for most aggressive treatment.
Effect of enzalutamide on health-related quality of life (HRQoL) in men with metastatic castration-resistant prostate cancer (mCRPC) following docetaxel-based therapy: Results from the AFFIRM study.
Authors: Miller Kurt , Scher Howard I. , Fizazi Karim , Basch Ethan M. , Sternberg Cora N. , Hirmand Mohammad , Cella David , Ivanescu Cristina , Phung De , Spalding James Robert , Bui Cat N. , Holmstrom Stefan , De Bono Johann Sebastian
Published: February 2017

17

Background: In the AFFIRM trial, enzalutamide (ENZ), an oral androgen receptor inhibitor, was superior to placebo (PBO) in overall survival (HR=0.63 [0.53, 0.75], p<0.001) [Scher et al. NEJM 2012;367:1187]. This analysis focuses on impact of ENZ on HRQoL. Methods: Men with mCRPC previously treated with docetaxel were randomized (2:1) to receive ENZ (160mg/day) or PBO. HRQoL was assessed at baseline (BL), weeks 13, 17, 21, 25 and every subsequent 12 weeks using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. Patients with BL and ≥1 post-BL evaluable forms were included in this analysis. Change from BL in FACT-P scores over 25 weeks of treatment was analyzed using linear mixed models. HRQoL improvement/deterioration was defined as a 10-point or higher increase/decrease during the study compared to BL on the FACT-P total score. Results: The HRQoL analysis included 938 patients. Changes from BL in FACT-P total score and domains over 25 weeks of treatment were significantly smaller (less decline) with ENZ than PBO (Table). A greater percentage of patients on ENZ reported HRQoL improvement compared to PBO (42.2% vs 14.5%; p<0.001). Median time to first HRQoL deterioration was 9.0 months for ENZ and 3.7 months for PBO (p<0.001). Overall, 46.8% of patients on ENZ and 59.3% on PBO experienced HRQoL deterioration at some point while on treatment (p=0.001). Conclusions: Compared to PBO, therapy with ENZ yields significantly better HRQoL across all domains and delays deterioration. The extent of the HRQoL advantage, along with the previously established overall survival gain of ENZ over PBO, suggest that ENZ confers a significant and meaningful clinical benefit to men with mCRPC. [Table: see text]
Long-term outcomes of active surveillance for prostate cancer: 10 years later.
Authors: Buethe David D. , Russell Christopher , Yue Binglin , Lin Hui-Yi , Pow-Sang Julio M.
Published: February 2017

170

Background: Prostate cancer (CaP) has exhibited a downward stage migration during the PSA era. Approximately 70% of those newly diagnosed with CaP, harbor tumors of low-risk. Such tumors often prove to be of low-volume and of clinical insignificance at time of radical prostatectomy (RP), suggesting over treatment and excessive exposure to the morbidity associated with definitive management. Over the last decade, active surveillance (AS) strategies have become a more accepted practice when addressing low-risk tumors. We present the long-term oncologic outcomes of patients placed on AS. Methods: An IRB approved retrospective chart review identified 114 patients placed on AS for their CaP between November of 1997 and November of 2000. Of those, 96 patients meet study inclusion criteria mandating a Gleason sum of < 7, tumor presence in < 4 sextets, and involvement of <50% of any single biopsy core. Eligible patients were surveyed by serum PSA , digital rectal exam, and surveillance transrectal ultrasound (TRUS)-guided biopsies at physician determined intervals. Results: At diagnosis, the mean age was 70.3 (SD±5.3) years with a mean PSA value of 8.2 (SD±8.2) ng/dL. Surveillance patterns approached acquisition of a PSA at a mean of 9 months and a TRUS-guided biopsy of the prostate every 1.5 years. The median total number of PSA’s and biopsies obtained while on surveillance were 6.0 (SD±5.72) and 3.5(SD±2.02), respectively. At a median follow-up of 134.8 months (95%CI: 114.5, 148.7), 52 (54%) of patients had been reclassified or demonstrated disease progression. The median progression-free and overall survival for the cohort were 68.7 (95%CI: 53.2, 97.3) months and 156.9 (95%CI: 139.9, 161.5) months, respectively. Only one prostate cancer specific mortality was identified. Conclusions: AS presents a reasonable management strategy option for low-risk prostate cancer in appropriately selected patients. However, treatment at time of disease progression did not improve survival. A significant percentage of men on AS are exposed to progression of their disease if alive beyond 10 years from their diagnosis.
Pathologic findings in additional prostatic and periprostatic tissue removed during radical prostatectomy.
Authors: Chen Henry , Kahnoski Richard J. , Lane Brian R.
Published: February 2017

172

Background: Additional prostatic and periprostatic tissue (PPT) can be removed during radical prostatectomy (RP) when there is concern for incomplete removal of the entire prostate gland or residual extraprostatic extension of cancer. The presence of cancer in PPT during RP is largely unknown. We analyzed the rate of positive PPT findings during RP in a community-based health system to determine the yield of PPT resection to inform future clinical practice. Methods: Retrospective review of pathology reports from 976patients undergoing RP between 1998-2011 was performed. Demographic and pathologic data were collected in an IRB-approved database. Results: Of 976 RP, 267 patients (27%) had PPT excised (median: 1, range: 1-4). Median PSA was 5.0 (IQR: 3.9-7), clinical stage was T1c in 69%, and biopsy Gleason score was 6 or lower in 39%, 7 in 52% and 8 or higher in 9%. Pathologic stage was pT2 in 85%, T3 in 13%, and LN positive in 2.6%. Among 177 bladder neck biopsies, 31% contained benign prostate and 3.4% (n=6) had adenocarcinoma. Of 37 urethral biopsies, 46% contained benign prostate and 16% (n=6) had adenocarcinoma. Of 21 prostatic apical excisions, 86% contained benign prostate and 14% (n=3) contained adenocarcinoma. Of 35 excisions of suspected residual (or fragmented) prostate (posterior-lateral, median, base, capsule, pedicle), 94% contained prostate and 0% contained adenocarcinoma. No prostate tissue or cancer was present in 15 samples labeled as “periprostatic fat” and 9 “neurovascular bundle”. Conclusions: Complete excision of adenocarcinoma during RP remains the primary surgical objective. Clinical suspicion of incomplete excision of benign or cancer-containing prostate tissue may lead to removal of additional PPT samples. In this single-center study, prostate tissue was present in 45% of such samples overall, supporting this practice. However, cancer is rarely present in such samples (5.6% of cases with PPT removed, 1.5% of RP overall), with apical/urethral regions appearing to be at highest risk (~15% of samples).
Effect of PEDF on the in vivo antitumor activities of low-dose chemotherapy in CRPC.
Authors: Nelius Thomas , Cobos Everardo , Hirsch Jennifer , Filleur Stephanie
Published: February 2017

173

Background: The development of metronomic/low dose administration of conventional chemotherapeutic drugs has shown great promise in the treatment of castration-refractory prostate cancer (CPRC). Pigment Epithelium-Derived Factor (PEDF) is a natural angio-inhibitor which is down-regulated in prostate cancer. We have previously demonstrated that the over-expression of PEDF in human CRPC PC3 cells decreased tumor growth in vivo. In the present study, we further validated PEDF anti-tumor properties in the highly metastatic CRPC LNCaP-derivative CL1 cells. We also hypothesized that PEDF may enhance the cytotoxicity effects of low dose docetaxel (DTX) and cyclophosphamide (CTX) chemotherapies in vivo. Methods: PC3 and CL1 cell lines were genetically modified to stably express the fluorescent DsRed Express protein with PEDF. Resulting cells were characterized in vitro for PEDF expression by western blot and, for proliferation by growth curves and clone formation in matrigel. PEDF anti-tumor effects were assessed on established s.c. xenografts in mice treated with DTX (5mg/kg ip every 4 days, 1mg/kg ip daily for 10 days, 0.5mg/kg every other day), CTX (10-20mg/kg in the drinking water) or placebo. Survival studies were performed by injecting CL1-PEDF or -control cells into the left lobe of the dorsal prostate of anesthetized mice. Results: We showed that PEDF expression inhibits the proliferation and induces the differentiation of CPRC cells in vitro, and decreases by 85% and 70% the development of s.c. PC3 and CL1 tumors, respectively. In the survival study, PEDF expression prolongs significantly (P=0.01; 95% confidence interval) the median survival of CL1 tumor-bearing mice (53±0.001 days versus 57±1). Furthermore, we demonstrated that PEDF enhances the cytotoxicity effects of low dose chemotherapy on established s.c. tumors (best Doc dose: 1mg/kg for PC3 and 5mg/kg for CL1; best CTX dose: 10mg/kg for PC3 and CL1) and prolongs significantly the survival of tumor-bearing mice undergoing low dose chemotherapy. Conclusions: These data reinforce the significance of PEDF as a potent target for the treatment of CRPC. It also emphasizes PEDF as a promising new agent to enhance the anti-tumor efficacy of low dose chemotherapies.
Circulating tumor cells (CTCs) in biochemical recurrence (BR) of prostate cancer: Final results.
Authors: Aragon-Ching Jeanny B. , Simmens Samuel J. , Andrawis Ramez , Hendricks Frederick , Frazier Harold , Phillips Michael , Jarrett Thomas , Patierno Steven R. , Siegel Robert S.
Published: February 2017

179

Background: CTCs have known prognostic implications in metastatic prostate cancer. We presented initial data on the role of CTCs in BR of prostate cancer (Aragon-Ching et. al., ASCO GU 2011). The primary aim of this study was to determine whether there is a correlation between the number of CTCs with prostate specific antigen (PSA) levels and PSA doubling time (PSADT) in men with BR. Methods: BR was defined as patients who have undergone primary treatment with prostatectomy or radiation or both, with a rise to ≥ 0.2 from a prior undetectable level for prior prostatectomy or > 2 mg/dl rise for post-nadir radiotherapy. 36 patients (pts) were enrolled from May 2010 to May 2012. CTCs were evaluated in 7.5 mL of peripheral blood using the CTC CellSearch test. Results: The median age for 36 pts was 69.5 (range: 51 – 91) with a median PSA of 1.65 ng/mL (range 0.2 – 65.8) and testosterone levels of 315 ng/dL (range: 31 – 727). Gleason scores ranged from 5 to 9 (median=7). Prostatectomy was the primary treatment in 25 pts, radiotherapy in 9 pts, Cyberknife in 1 pt and combined radiohormones in 1 pt. PSADT varied between 0.35 to 55 months, with a median of 7.43 mos. The incidence of positive CTCs was 8.3% (3 out of 36 pts) of whom 2 had biopsy-proven bony lesions upon presenting with equivocal scans. The 3 pts who had measurable CTCs had PSADT of 2.27, 4.99 and 3.08 months, respectively. Conclusions: Obtaining CTCs in unselected patients presenting with biochemical recurrence have low yield. However, obtaining a positive CTC raises the suspicion of presence of metastatic disease and may have utility for longitudinal follow-ups of patients with BR. Supported by IRG-08-091-01 from ACS to GWU Cancer Institute.
15-year survival after radical prostatectomy (RP): Which prognostic factors are available for patient counseling?
Authors: Fossa Sophie D. , Waehre Haakon , Cvancarova Milada , Danielsen Haavard E
Published: February 2017

181

Background: Studies on 15-year Post-RP survival including data on PSA relapse (PSA-Rel) are rare. We established the 15-year post-RP prostate cancer specific mortality (PCSM), to explore the time to PSA-Rel and PCSM thereafter, and to identify clinically available prognostic factors. Methods: In men prostatectomized from 1987-2004 slightly modified D`Amico risk groups were identified (T1: No palpable tumor ;”T2 unilateral”/”T2 bilateral” according to tumor palpability in one or both lobes). PSA –Rel was defined as PSA ≥4 µg/l before 2000, and thereafter as PSA >0.2 µg/l. Delay of RP was defined as RP performance 3-12 months after diagnosis. Competing risk modeling was performed with a significance level of <0.05. Results: After a median observation time of 12 years (range: 0-22), of 309 men (median age:62 years [range:40-74]) 40 have died from prostate cancer ( PCa) and 68 due to other causes (15-year PCSM: 15% [95%CI: 10-19%). No difference of PCSM was found between the low (N: 12) and the intermediate group (N: 121), the “conventional” high risk group ( N: 121) displaying a 24% PCSM rate (95% CI:16-32%) with particularly poor prognosis for men who presented with two high risk factors ( N. 32 ; PCSM: 33% [95% CI:20-46%]). The median time to PSA relapse (N: 152) was 5 years (range: 0-17), the median overall survival time after PSA- Rel being 7 years (range: 0-17). PCSM continued to increase after 10 years. Delay of RP had no impact on PCSM. Conclusions: After a median observation time of 12 years approximately 1 of 7 men with localized PCa, most of them diagnosed before the PSA- era, have died of prostate cancer. The “conventional” high-risk group is prognostically heterogeneous: Men with two high risk criteria have a particularly poor prognosis. PSA-Rel 10 years after RP is no rare event followed by survival times of >10 years. Delay of RP for up to one year had no impact on PCSM.
Evolving patterns of metastatic disease in castration-resistant prostate cancer (CRPC) reported in clinical trials from 1990 to 2011.
Authors: Oh William K. , Doctor Stephanie , Godbold James H. , Galsky Matt D. , Tsao Che-Kai
Published: February 2017

195

Background: Bone remains the most common site of metastasis in CRPC. With new therapies extending survival in metastatic CRPC (mCRPC), we hypothesized that the incidence of non-osseous metastases is increasing over time. In this study, we evaluated the pattern of metastatic disease in mCRPC as reported in baseline characteristics of prospective clinical trials over 2 decades. Methods: We identified all therapeutic studies in patients with mCRPC in Pubmed and ASCO abstracts from 1990-2011. Inclusion criteria included phase 2 or 3 clinical trials in mCRPC with available baseline demographic data and no exclusion of specific site of metastatic disease (except brain). ASCO abstracts were limited to presentations in which data were available online. For each study, demographic data and study-reported sites of non-osseous metastatic disease were recorded (lymph node, visceral, soft tissue, liver). For each type of metastasis, weighted least squares linear regression models were used to evaluate temporal trends. Results: We identified a total of 290 eligible studies (270 phase II and 20 phase III) involving 19,110 patients. Of these, 127 studies reported data on non-osseous metastases and prior chemotherapy. There was a significant trend over time (p=0.001) of increasing proportions of patients with non-osseous metastasis in both chemotherapy- naïve and treated groups (1.4% per year increase). Increased lymph node, visceral, and soft tissue metastases were seen over the study period. However, the proportion of patients with liver metastasis remained relatively stable. Conclusions: In this study, we noted an increasing trend of non-osseous metastatic disease in patients with mCRPC over 20 years. This included lymph node, visceral and soft tissue metastatic disease, and this trend was observed in both chemotherapy-naïve and treated patients. Longer survival and new therapies may be changing the clinical presentation of patients with mCRPC.
Evaluation of a genomic-based prognostic test for metastasis in high-risk post-prostatectomy patients: Does it impact physician decision making?
Authors: Badani Ketan K. , Thompson Darby J. S. , Mitra Anirban Pradip , Ghadessi Mercedeh , Buerki Christine , Davicioni Elai , Wood Penelope J.
Published: February 2017

196

Background: Currently, identification of individual patients who are truly at risk of developing lethal prostate cancer after radical prostatectomy (RP) is based on clinical nomograms. A prospectively validated genomic classifier (Decipher) has been shown to more accurately predict metastatic disease post RP than established clinical predictors and can identify patients with adverse pathology who may be cured by RP alone and may therefore not require additional treatment. Methods: An IRB-approved study assessed the impact of a genomic classifier (GC) test in 240 pathologically high-risk post RP case reviews. Twenty (20) urologic oncologists from 18 institutions reviewed 12 cases presented in a randomized, de-identified fashion via a secure online platform to provide treatment recommendations pre- and post- patient GC test results. Possible recommendations included referral to radiation oncologist and/or initiation of adjuvant hormones, close observation, or other. The primary endpoint was any change in treatment recommendation after unblinding of GC test results. Confidence in treatment recommendations was assessed using a 5-point Likert scale. Results: Following unblinding of GC test results, treatment recommendations changed in 43% (95% CI: 37-49) of all cases. Specifically, among cases with a pre-GC recommendation involving treatment, 31% (95% CI: 23-41) of respondents changed their recommendation to observation post-GC.Respondents considered the GC result to have influenced their recommendation in 63% (95% CI: 56-68) of cases. The addition of information provided by the GC result increased decision making confidence in 39% (95% CI: 30-49) of cases where a change of treatment recommendation was made. Following unblinding, physicians reported that the GC result was clinically relevant in 84% (95% CI: 79-84) of cases. Conclusions: GC appears to influence treatment recommendations and decision making confidence for high-risk prostatectomy patients. This study suggests that clinical implementation of GC may potentially impact treatment recommendations.
Effect of the ERα agonist GTx-758 on bone turnover markers in men with advanced prostate cancer.
Authors: Yu Evan Y. , Keane Thomas E. , Tutrone Ronald , Belkoff Laurence , 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

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Background: Men with advanced prostate cancer are being treated with androgen deprivation therapy (ADT) for longer periods of time. The use of ADT can be limited by estrogen deficiency side effects, including a loss of bone and a higher incidence of fractures. GTx-758 is an ERα agonist that lowers serum free testosterone greater than an LHRH agonist. Herein we compare the effects of GTx-758 and leuprolide on markers of bone turnover, C-terminal telopeptides and bone specific alkaline phosphatase, 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 and analyzed by a reference laboratory. C-terminal telopeptides (pg/ml) and bone specific alkaline phosphatase (U/L) were measured as indicators of bone turnover. All p values describe the comparison of the GTx-758 treatment groups to the leuprolide treated men at day 120. Results: Men receiving the 1000 mg and 2000 mg doses of GTx-758 had lower C-terminal telopeptide levels with a mean percentage change of -56.9 ± 12.5 and -54.8 ± 23.1, respectively, as compared with an increase of 46.0 ± 48.9 percentage in the men receiving the leuprolide (p<0.001). Similarly, bone specific alkaline phosphatase levels were lower in men treated with GTx-758, with mean percentage changes of-28.5 ± 11.7 and -19.8 ± 14.7, respectively, compared with an increase of 8.1 ± 24.3 percent in the leuprolide treated group (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 on the study reached the 120 day treatment dates (71 evaluable). Conclusions: Patients receiving GTx-758 experienced a significant decrease in markers of bone turnover indicating potential improvement and not a loss of bone on ADT. Since changes in bone mineral density are a major side effect that can negatively affect the quality of life in men on ADT, the improvements in bone turnover observed in men treated with GTx-758 could be significant. A Phase II clinical trial utilizing lower doses of GTx-758 (G200712) is currently being performed. Clinical trial information: NCT01326312.
A novel method for decreasing rectal toxicity during prostate radiotherapy by prostate-rectum separation: An evaluation of irradiation dose parameters and acute side effects.
Authors: Mathers Michael J. , Klotz Theodor , Lazar Yvonne , Eckl Thomas , Hermani Horst , Gagel Bernd
Published: February 2017

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Background: Prostate cancers (PCA) frequently arise in the peripheral posterior zone of the gland and therefore adjacent to the rectum. Treatment can include brachytherapy and/or radiotherapy (RT); however, rectal toxicity can complicate therapy. A dilemma therefore arises in the balance between radiation dose and rectal adverse effects. Methods: Starting February 2012, until now 37 patients were included in this investigation. Under ultrasound guidance, a synthetic hydrogel (SpaceOAR) was injected between the prostate and the rectum, thus moving the rectum away from the high radiation dose volume, allowing dose escalation. The procedure was carried out in general anaesthesia and required approx. 10 min. The prescribed dose for the prostate was 80.0 Gy in 40 fractions. In 20 patients also the pelvic lymph nodes were irradiated with 50.4 Gy. IMRT planning was realized with and without hydrogel. During the treatment and 3 months after treatment acute toxicity was documented by the use of common toxicity criteria version 3.0. Results: So far median follow up time post hydrogel injection for all patients is 6 months. No acute toxicity for the hydrogel-application was observed. In the middle plane of the gland, the space between rectal wall and prostate could be increased by an average of 1.34cm. The mean V70 with hydrogel was 1.6% (range 0-8%) and without hydrogel 17.3% (range 8- 42%) resulting in a mean reduction of V70 of 90,9%. Until now 24 patients finished RT. 14 of these patients showed gastrointestinal toxicity (GIT) grade 1. No grade 2. GIT was observed. 13 patients reached the first follow up 3 months after RT. Only 2 of these patients showed GIT grade 1. No GIT grade 2 was described. Conclusions: Injected liquid to solid inert substance for prostate-rectum separation appears to be safe. Reducing rectal irradiation doses has the potential to lower rates of rectal toxicity and therefore improving QOL in men receiving RT for prostate cancer. More research is needed before conclusions can be reached as to the technology’s potential place in therapy.
Potential cost-effectiveness of a diagnostic that identifies localized versus metastatic prostate cancer in men with biochemical recurrence after radical prostatectomy.
Authors: Bensink Mark Eliot , Berry Kristin , Musa Zahra , Bodnar Carolyn , Barocas Daniel Ari , Lin Daniel W. , Ramsey Scott David
Published: February 2017

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Background: Asymptomatic men with low but detectable PSA elevation following radical prostatectomy, often receive costly, burdensome, and potentially damaging salvage radiation therapy with uncertain benefit. A new prostate cancer specific functional imaging technology capable of identifying residual localized disease vs. small volume metastatic disease, to more accurately guide therapy decisions, could be of benefit. As a guide to diagnostic development efforts, the objective of this study was to assess the potential cost-effectiveness of using a novel diagnostic in this way. Methods: A Markov model was built to reflect the life-time natural history of prostate cancer recurrence. The model was used to estimate the incremental impact on costs (US healthcare system perspective) and quality adjusted life years (QALYs) of two alternative strategies: 1) using the new diagnostic to guide therapy vs. 2) usual care - using a combination of CT, MRI and bone scan to guide therapy. Costs were based on estimates from the literature, Medicare reimbursement and expert opinion. Prostate cancer progression, survival, and utilities plus the background risk of all-cause mortality, were obtained from the literature. Base-case diagnostic sensitivity, specificity, and cost were 75%, 90%, and $2,500. Results: The new diagnostic strategy provided an average per patient gain of 1.83 (95% UI: 1.41 - 2.5) QALYs and added cost of $15,600 (95% UI: -$7,000 - 48,800) with an incremental cost-effectiveness ratio of $8,500/QALY (95% UI: -$4,100 - 22,900). Results were most influenced by utility parameters and test performance characteristics however; the new diagnostic provided clinical benefits over a wide range of specificity and sensitivity. Conclusions: This analysis suggests that a diagnostic technology capable of identifying whether men with biochemical recurrence after radical prostatectomy have localized vs. metastatic disease would be cost-effective by reducing the costs and quality-of-life burden associated with non-beneficial radiation therapy. These results support additional investment in the development and validation of such a diagnostic.
The use of electromagnetic transponder beacons to reduce planning target volume (PTV) margins in post-prostatectomy patients undergoing adjuvant or salvage radiation therapy.
Authors: Kathpal Madeera , Ninneman Stephanie , Huang Raywin Rufus , Wendt Stacie , Malmer Cynthia , Brand Timothy , Halligan John B. , Brooks Joseph P. , Brown Michael , Tinnel Brent , Macdonald Dusten
Published: February 2017

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Background: We determined necessary PTV margins when beacons are used to localize the prostatic fossa in post-prostatectomy patients. We hypothesized beacon localization would allow for decreased PTV margins and increased normal tissue sparing. Methods: 10 patients requiring post-prostatectomy radiation were treated on this IRB-approved prospective study. Each patient had 3 beacons placed in the prostatic fossa. Daily radiation was localized by beacons and a cone-beam CT (CBCT) taken for analysis. By measuring differences between the treated clinical target volume (CTV) and relevant anatomy on 5 equally-spaced axial CT slices we calculated necessary PTV margins for each fraction. We then auto-fused each CBCT scan with the treatment planning scan, recorded the shifts incurred, and repeated our measurements, representing a hypothetical CBCT - localized treatment. We report a PTV margin for each technique that would cover the CTV during 90% of all 304 fractions analyzed. We also used intra-fraction motion data to produce a worst-case estimate of required PTV bladder margins. Results: The average shifts from the beacon to CBCT- localized isocenter were 2.9, 3.2, 1.0 mm and 0.58 degrees in the vertical, longitudinal, lateral, and rotational planes, respectively. Necessary PTV margins for beacon and CBCT localization are listed in the Table. Conclusions: Beacon localization “attaches” the CTV to the bladder, allowing a decrease in PTV margin or the amount of posterior bladder included in the CTV. This could lead to decreased rates of bladder toxicity. Clinical trial information: NCT01624623. [Table: see text]
Metabolite assay and histology on exactly the same tissue.
Authors: Troyer Dean A. , Shuster Jeffrey R. , Baxter Sarah , Su Mingming , Lance Ray
Published: February 2017

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Background: Metabolites are emerging biomarkers of cancer described as a link between genotype and phenotype. In previous studies we used molecular preservation by extraction and fixation (mPREF) on a metabolomics platform to screen for candidate metabolites using 18 gauge core needle biopsies of prostate tissues obtained ex vivo. Methods: Single core needle biopsies are immediately placed in 80% aqueous alcohol and transferred to formalin after 12-24 hours. The alcohol is retained, dried down and the residue reconstituted with 95 µL of acetonitrile plus 95 µL of water. Histology is performed on exactly the same tissue. Results: Using metabolomics, 83 metabolites showed differences between cancer containing vs. non-cancer containing biopsies. For nine of these differential metabolites, quantitative LC-MS assays have been developed using the same 18 gauge needle biopsy protocol. Thirty mPREF samples including tumor/non-tumor were analyzed using the developed method and the concentration ranges obtained. These analytes were selected in part because they could all be assayed on a single LC/MS run. Results comparing no tumor/tumor normalized to surface area of the biopsy core were as follows (see Table). Histology and immunohistochemistry (IHC) were satisfactory, and as the biopsy cores were moved to formalin, the work flow fits well with existing histopathology processing and microtomy methods. Conclusions: Our results confirm the original discovery trends and indicate that metabolites can be quantitated in single core biopsies fixed in aqueous methanol. From our experience and the literature, the performance of DNA/RNA extraction methods, in-situ hybridization, and proteomic analysis should differ very little from the use of formalin as primary fixative. The ability to quantitate any constituent of intact tissue is significant since most available methods such as IHC are subject to many variables and are difficult to quantitate. [Table: see text]
The risk of debilitating falls in Manitobans living with prostate cancer (pc).
Authors: Gingerich Joel Roger , Lambert Pascal , Doupe Malcolm , Daeninck Paul Joseph , Pitz Marshall W. , Czaykowski Piotr , Bertram-Farough Alison
Published: February 2017

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Background: Falls and fall-related injuries are important patient safety problems. Some studies suggest that pc patients have higher fall rates, however the severity of these falls is unknown. We sought to measure if pc patients are at increased risk of a debilitating fall requiring hospitalization. Methods: This is a retrospective population-based study utilizing the Manitoba Cancer Registry and Manitoba Health administrative databases. Our cohort consists of all community-dwelling patients living in Manitoba Canada who were diagnosed with pc between 2004 and 2008. These individuals were matched by age, sex, and time of diagnosis with up to three cancer-free controls. Debilitating falls were defined as falls/fractures requiring hospitalization and were identified using ICD-9 and -10 billing codes. A competing risk model was used to compare debilitating falls between the pc and cancer-free cohorts and expressed as sub-hazard ratios. Follow-up ended December 31, 2009. Results: 2,903 pc patients were identified along with 8,686 matched controls. The mean age was 69.3 and 68.8 respectively. The median follow-up was 3.05 years. Debilitating falls were identified in 109 patients (3.8%) with pc and 345 (4%) matched controls. The cumulative incidence of debilitating falls for those with pc vs cancer-free controls were: 1.08% vs. 1.13% at 1-year and 5.25% vs. 5.96% at five years of follow-up (SHR = 0.95, 95% CI = 0.77 – 1.18, p = 0.65). On univariate analysis, patients with stage IV pc were at higher risk of falls compared to matched controls. This difference was not significant on multivariate analysis though (SHR = 1.19, 95% CI = 0.74 – 1.89, p = 0.48). On multivariate analysis, patients with a Gleason score of ≤6 experienced a reduced risk of debilitating falls compared to matched controls (SHR = 0.44, 95% CI = 0.27 – 0.72, p = 0.001), whereas patients with other Gleason scores did not. The analysis was similar when patients with fractures were excluded. Conclusions: In this large population-based study, the 1- and 5-year cumulative incidence of debilitating falls did not differ significantly for patients with vs without pc. In fact, compared to matched controls, low grade pc patients were less likely to experience a debilitating fall.