bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized phase II study of bicalutamide (BIC) followed by placebo or gamma secretase inhibitor RO4929097 (RO492) in men with rising PSA.
Authors: Stein Mark N. , DiPaola Robert S. , Mayer Tina M. , Jeyamohan Chandrika , Metzger Dorinda , Anand Monica , Ivy S. Percy ,   Prostate Cancer Clinical Trials Consortium
Published: February 2017

219 Background: Notch signaling is a key determinant of cell fate. RO492 is a selective γ-secretase inhibitor blocking cleavage of Notch. We hypothesize that anti-androgen therapy will lead to an enriched population of basal prostate cancer stem cells. Targeting Notch following anti-androgen treatment will lead to delay in re-growth of mature luminal PC cells. We are using a novel double blind, placebo controlled randomized discontinuation design to treat men with rising PSA. A non-castrating anti-androgen (BIC) was used to induce initial tumor regression Methods: Pts with rising PSA after primary therapy for PC, and no radiographic evidence of disease were enrolled in this ongoing study. All pts received BIC 50mg/day for 16 weeks (induction phase). Pts achieving a >50% (modified from 80% decrease after the first 8 pts) decrease in PSA were randomized to placebo or RO492 20mg orally 3 days on/ 4 days off per week (randomization phase). Primary endpoint is PSA progression (increase in PSA by 50% over nadir with minimum PSA rise of 2ng/mL) during randomization phase. Pts meeting primary endpoint could receive 12 months of RO492 and BIC (combination phase). Serum is collected for evaluation of soluble markers of gamma secretase inhibition. 29 pts/arm in randomization phase gives 90% power to detect a decrease in1 yr PFS from 80% to 45% with 5% alpha. Results: We report on the first 16 patients that have enrolled. Median pretreatment PSA was 6.3ng/ml (0.35 to 34). 9 of 16 pts on the induction phase came off study due to PSA progression, although 5 of 9 pts would have been randomized using the 50% PSA response criteria. 6 pts have been randomized to RO492 or placebo (1 pt not yet randomized) and 2 pts have proceeded to combination phase. Median PSA decrease during induction phase in 6 pts who went on to randomization was 86% (69–97). Overall decline in PSA in induction phase was 67% (7.3-99%). Placebo/RO492 has been well tolerated with 1 pt experiencing g1 fatigue, and 1 pt experiencing g1 nausea in the combination phase. 8/16 pts had g1 breast tenderness with BIC. Conclusions: In this ongoing randomized phase II trial, BIC decreased PSA by >50% in 12/16 pts. Placebo/RO492 is well tolerated. Enrollment continues with analysis of plasma correlates to be compared to clinical results.
Effect of a therapeutic sphingosine 1-phosphate antibody on intratumoral hypoxia and standard chemotherapy in a preclinical model of prostate cancer.
Authors: Cuvillier Olivier , Ader Isabelle , Bouquerel Pierre , Sabbadini Roger Allen , Malavaud Bernard 
Published: February 2017

223 Background: Hypoxia promotes vascularization, metastasis and resistance to treatments. The activation of HIF-1α is identified as the master mechanism of adaptation to hypoxia. We recently identified the sphingosine kinase 1/sphingosine 1- phosphate (SphK1/S1P) pathway as a new modulator of HIF-1α activity under hypoxia in multiple cancer cell models (Ader et al, Cancer Res, 2008). S1P elicits proliferation, survival, or angiogenesis, and is believed to exert most of its actions as a ligand for a family of specific GPCRs to elicit paracrine or autocrine signaling. We have suggested that inhibiting SphK1/S1P signaling, which is upregulated under hypoxia, may normalize the microenvironment and increase sensitivity to chemotherapy, in the broader concept of «normalization of tumor vessels» as tumor oxygenation is known to enhance response to chemotherapy (Ader et al., Cancer Res, 2009). Methods: Quantitation of hypoxia and angiogenesis, and treatment efficacy using an orthotopic (o.t) xenograft model of fluorescent HRPC cells. Results: We provide in vitro evidence that inhibiting the S1P exogenous signaling, through pharmacological inhibition of its receptors or by taking advantage of a monoclonal antibody neutralizing S1P, blocks HIF-1α accumulation and its activity in prostate cancer cells under hypoxia. Second, using an o.t model of prostate cancer, we show that an anti-S1P antibody inhibits intratumoral hypoxia, modifies vessel architecture and improves tumor perfusion within 5 days of treatment. Third, we demonstrate that an anti-S1P strategy sensitizes to docetaxel, the ’gold standard’ treatment for HRPC. A 5-day anti-S1P antibody pretreatment markedly sensitizes to docetaxel in an o.t. PC-3/GFP model established in nude mice. The combination anti-S1P antibody together with docetaxel was not only accompanied by a smaller primary tumor volume compared to docetaxel alone, but also significantly reduced the occurrence and number of metastases. Conclusions: These data establish the proof-of-concept that blocking the exogenous action of S1P reduces intratumoral hypoxia and sensitizes to chemotherapy in prostate cancer animal model.
An age-corrected matched-pair study of erectile function in patients treated with adaptive intensity modulated radiation therapy (IMRT) versus high-dose-rate brachytherapy (HDR) in prostate cancer.
Authors: Warner Jillian Nicole , Marina Ovidiu , Grills Inga S. , Shah Chirag , Wallace Michelle , Marvin Kimberly , Ye Hong , Gustafson Gary S. , Brabbins Donald , Kestin Larry Llyn , Ghilezan Michel , Martinez Alvaro 
Published: February 2017

225 Background: Increasing age is a likely contributor to erectile dysfunction (ED) after radiotherapy for prostate cancer. A matched-pair (MP) analysis, with age as a criterion, was used to investigate ED after IMRT and HDR monotherapy for prostate cancer. Methods: 430 patients with low (63%) or intermediate risk (37%) prostate cancer with full or partial erectile function were treated between 4/00 and 9/10 with IMRT (n=215) or brachytherapy (n=215). Patients with follow up (FU) <1y were excluded. IMRT dose was 70.2–82.8 Gy (median 75.6) in 1.8 Gy/fx. HDR was given as 9.5 Gy x 4 (median), 13.5 Gy x 2 or 12 Gy x 2. MP, univariate, and multivariate analyses examined ED using CTCAEv4. Match criteria were age (±5y), Gleason (6,7), T stage (T1, T2), and PSA (<4, 4–10, >10). BF was by modified Phoenix criteria (nadir+5 for 2y, nadir+2 after). Results: Median FU was 3.4y (range 1–7.1) for IMRT and 3.1y (range 1–10.9) for HDR. There was no difference in PSA (4.8 vs. 4.6, p=0.4), T stage (88% vs. 88% T1, p=1.0) and Gleason score (63% vs. 63% 6, p=1.0) between IMRT and HDR. Despite age matching, IMRT patients were older (median 65 vs. 62 y, p=0.05). Pre-treatment potency grade 0, 1, and 2 were found in 70%, 14% and 15% of IMRT and 69%, 20% and 11% of HDR patients. 5y OS, CSS, and BF were 100%, 100% and 2.4% for IMRT, and 99% (p=0.35), 100% (p=1.0), and 10.6% (p=0.001) for HDR. On subset analysis of pre-treatment grade 0 patients, univariate analysis showed HDR (p<0.001), increasing Gleason (p=0.05) and increasing FU time (p<0.001) correlated with post-treatment ED, while age (p=0.32), PSA (p=0.46) and T stage (p=0.76) did not. On multivariate analysis, increasing FU time correlated with ED (p<0.001), while treatment type (p=0.10) and Gleason (p=0.49) did not. Conclusions: Both IMRT and HDR yield comparable low (25%) rates of 1+ ED for patients with no ED at baseline. Increasing age does not appear to significantly impact ED for both IMRT and HDR. [Table: see text]
Palliative transurethral resection in men with castration-resistant prostate cancer (CRPC): Minimally invasive procedure with minimal morbidity?
Authors: Piper Charlotte , Epplen Robin , van Erps Thomas , Pfister David J. K. P. , Porres Daniel , Heidenreich Axel 
Published: February 2017

233 Background: About 20 to 30% of men with CRPC with a prostate in situ will develop subvesical obstruction due to locally progressing prostate cancer with time. Treatment options include palliative TURP, urinary diversion by transurethral or suprapubic catheters. There are only few reports critically evaluating the outcome of palliative TURP and the development of associated symptoms of locally progressing CRPC. Methods: We retrospectively reviewed all patients who underwent palliative TURP for locally advanced CRPC with regard to the functional and oncological outcome. In addition, we analysed the frequency of complications associated with locally advanced (LA) CRPC. Patient with incidental prostate cancer were excluded from the analysis. Results: Between 2004–2010 a total of 83 patients were identified. The mean age of the patients was 76 (60–91) years. Mean PSA at time of TURP was 78 (1–253) ng/ml. Initial therapy included androgen deprivation monotherapy in 67.8%, radiation therapy in 28.6% and active surveillance in 3.4%.The mean size of the prostate was 40 (15–130) ml, the mean resected prostate weight was 18.6 (2–56) g. The mean Gleason score was 8.3 (6–10). The indication for palliative TURP was subvesical obstruction with a postvoid residual urine > 100ml in 68.8 %, recurrent gross hematuria in 13.2% and acute urinary retention in 18.1%. 19 (2.9%) pts demonstrated uni- or bilateral upper urinary tract obstruction necessitating drainage by endoluminal stenting or percutaneous nephrostomy. The mean catheterization time was 3.4 (2–6) days; postoperative complications developed in 15 (18.1%) pts and included: urinary retention in 2 pts, intravesical blood clots in 3 pts, permanent suprapubic catheter in 3 pts, stress urinary incontinence in 2 pts and re-do TURP in 3 pts. Perioperative mortality was 0% and after a mean follow-up of 3.6 years, 27 (32.5%) pts had died due to prostate cancer. Conclusions: Palliative TURP in men with LA-CRPC is fairly safe, but side effects are higher compared to conventional TURP. Due to a high frequency of involvement, the upper urinary tract has to be screened prior to palliative TURP.
Multi-institutional outcomes following LDR brachytherapy in patients with higher-risk prostate cancer.
Authors: Conroy Ruth , Hoskin Peter , Bottomley David , Mandall Paula , Swindell Ric , Wylie James 
Published: February 2017

238 Background: We report the outcomes for a cohort of men with higher risk prostate adenocarcinoma treated with LDR brachytherapy in a multi-institutional UK practice. Methods: 217 men treated between 2003-2007 with Iodine-125 brachytherapy at Christie, Leeds and Mount Vernon were identified from a multi-institutional database. Higher risk was defined as patients with ≥ 2 D’Amico intermediate risk factors (PSA 10-20, GS 7 or clinical T2c) or ≥1 high risk factor (PSA > 20, GS ≥ 8). Kaplan-Meier methods were used to estimate biochemical relapse free survival (BRFS) defined using both Phoenix and ASTRO definitions. A univariate analysis was performed to assess the significance of Gleason score, PSA, T-stage, pre- or post-implant dosimetry, and additional hormones on BRFS. Results: The median age was 65yrs (43–79yrs) with a median PSA follow up of 62months (14–102months). Median pre-implant doses (ranges) were: V150 59.6(43.7–89.8), V200 20.1(11.6–36). 75 patients had post-implant dosimetry, median dose (range) was: D90 132.8Gy (75-192Gy). No patients had external beam radiotherapy. 67 patients had additional hormone treatment, median duration 7 months (3 – 22 months). The 3 and 5 year BRFS as defined by Phoenix were 85.4% and 74.4% and as defined by ASTRO were 76.6% and 69.8%. On univariate analysis there were no statistically significant predictors of inferior outcome. Conclusions: Single modality LDR brachytherapy is a well established treatment for low risk prostate adenocarcinoma reporting excellent long term BRFS. Some authors have advocated the addition of external beam radiotherapy when treating higher risk disease. These results show that good BRFS can be obtained with LDR brachytherapy alone and no additional benefit has been shown by the addition of adjuvant hormone therapy. These results appear comparable with other treatment modalities available to these patients.
Primary androgen deprivation (PAD) followed by active surveillance for newly diagnosed prostate cancer (PC).
Authors: Scholz Mark Creamer , Groom Meg , Kaddis Andrew , Lam Richard Y. , Jennrich Robert 
Published: February 2017

244 Background: Men undergoing local therapy (LT) with radiation or surgery incur substantial risk of permanent sexual, urinary and rectal toxicity. Active surveillance is only recommended for men with Low-Risk PC who have < 34% biopsy cores positive. Studies of PAD as an alternative to LT are sparse. Methods: Retrospective analysis of 102 men with localized PC administered 12 months of an LHRH agonist and antiandrogen (PAD) followed by immediate biopsy (BX1). Outcome assessed: The incidence of implementing further treatment with either LT or androgen deprivation (AD) if there was subsequent progression on active surveillance (PAS) or if BX1 was positive. Post PAD monitoring included quarterly PSA testing, follow-up biopsy and imaging with color doppler ultrasound and endorectal MRI. Participants were screened for heart disease and osteoporosis and monitored for changes in body weight, BP, liver enzymes, anemia, blood sugar and cholesterol. All received empiric bisphosphonates and 5-alpha reductase inhibitors and were instructed to eat a low fat diet and perform resistance exercise. Results: Patient characteristics: D’Amico risk category (DRC) Low: n=22; Intermediate: n=30; High: n= 50. Baseline factors assessed as potential predictors of PAS: Age, PSA, PSA velocity, PSA nadir, Gleason, % core biopsies, stage, prostate volume, DRC. Baseline medians for the 102 men: Age 67.3, PSA 7.8, Gleason 3+4, Cores > 50%, stage T1c, prostate volume 45cc. 55 men had PAS and required LT and/or AD over a median of 7.3 years follow up. Type of treatment administered after PAS by DRC: Low: AD 1, LT 3. Intermediate: AD 5, LT 10. High: AD 15, LT 21. Two men developed clinical progression. There were no PC deaths. Four men died of other causes: lung CA, melanoma, emphysema and MI. Only DRC (p<0.01) and PSA nadir (p<0.04) predicted PAS (3 men had PSA nadir > 0.1 and all were positive at BX1). Conclusions: PAD frequently induces durable remissions in men with Low and Intermediate risk PC despite a high prevalence of > 50% core biopsies positive at baseline in this population. 38% of the 55 men with PAD elected additional AD rather than undergoing LT suggesting that for some men enduring the toxicity profile of AD was preferable to the perceived risks of LT.
Tolerability of and biochemical control of permanent Pd-103 brachytherapy followed by external beam radiotherapy for localized prostate adenocarcinoma.
Authors: Richter Samuel M. , Aridgides Paul D. , Shapiro Oleg , Aronowitz Jesse N. , Bogart Jeffrey 
Published: February 2017

245 Background: The optimal sequencing of brachytherapy and external radiotherapy (EBRT) for patients receiving combined therapy for localized prostate cancer has not been established, and in this series we report our experience of patients treated with brachytherapy followed by EBRT. Methods: Retrospective review of patients treated with combined Pd-103 brachytherapy and EBRT with minimum of 2 years of follow-up. Variables assessed included T stage, Gleason score, pre-treatment PSA, use of androgen suppression (ADT), EBRT dose and brachytherapy dose. Biochemical failure was defined as a PSA rise of ≥ 2 ng/mL above nadir. Results: 87 patients received Pd-103 brachytherapy (median 80 Gy) followed by EBRT (median 45 Gy). Median age was 65 years (49–80). By risk groupings (Zelefsky) 26.4% of patients were low risk, 47.1% were intermediate risk, and 26.4% were high risk. Most low risk patients had either perineural invasion or ≥ 50% involved biopsy cores. Neoadjuvant and concurrent ADT was given in 21% of patients. With a median follow-up of 56 months (range 24 to 113), there were 4 failures (all in the intermediate or high risk group), with an overall 5-year biochemical failure free survival (BFFS) of 91.8%. 2 patients had documented distant failures, while none of the presumed local failures had a positive biopsy. There was no statistical difference in BFFS based on risk group, T stage, Gleason score, initial PSA, or ADT use. The median PSA nadir was 0.1 and occurred at a median of 30 months from brachytherapy. A nadir of ≤ 0.5 was seen in 87% of patients and was associated with improved 5-year BFFS (100% vs 22%, p<.0001). The median time to PSA nadir for patients < 60 years was 34.5 months compared to 26.5 months in patients ≥ 60 (p=.036). Overall, treatment was well-tolerated with no cases of late Grade ≥ 2 rectal or urinary toxicity reported. Conclusions: Excellent long-term disease control and low morbidity was observed for patients with localized prostate adenocarcinoma treated with interstitial brachytherapy followed by EBRT. Future prospective research assessing the relative therapeutic ratio of alternate sequencing approaches would appear warranted.
Awareness, concern, and communication between physicians and patients on bone health in nonmetastatic prostate cancer.
Authors: Moul Judd W. , Ferenz Krag S , Mautner Beatrice Delhey 
Published: February 2017

246 Background: Little is known about physicians’ (MDs) and prostate cancer (PC) patients’ (pts) levels of awareness or concern about bone health or how/when MDs discuss bone health with at-risk pts. An online survey was conducted to explore these issues and evaluate knowledge levels and attitudes about cancer treatment-induced bone loss (CTIBL). Methods: A total of 4,403 oncologists and 4,961 urologists randomly selected from the American Medical Association master physician list, 533 oncologists from the Harris Physician Panel, and 3,400 pts from Harris’ Chronic Illness Panel were invited to participate in the survey. Surveys lasted on average 10 minutes; MD and pt surveys were weighted to be representative of the populations of interest. Descriptive statistical analyses were used. Results: Of those invited, 113 urologists and 63 oncologists completed the survey. The 186 PC pts who answered the survey (median age, 74 yrs; median time since PC diagnosis, 88 mos.) included 96 pts with nonmetastatic disease. Current or prior ADT was reported by 96% of pts. Of these pts, 48% were aware of CTIBL, 23% of whom were concerned about it and 55% of whom had discussed it with their MD. As many as 46% of pts obtained information on bone health exclusively from their healthcare team, rather than seeking information from other sources. Both oncologists and urologists (98% and 90%) considered CTIBL to be a serious issue for their patients, however, more oncologists than urologists perceived that their pts were concerned about CTIBL (71% vs 36%). More oncologists than urologists expressed concern about fractures due to CTIBL (58% vs 46%), and indicated that treatment-induced fractures would require additional intervention (91% vs 76%), treatment interruption (61% vs 43%), or change in treatment (55% vs 42%). Conclusions: Bone health is considered a serious issue for patients with nonmetastatic PC treated with ADT by both oncologists and urologists. However, there remains a gap in physician-patient communication regarding CTIBL and its clinical consequences. As primary sources of information for pts, MDs should proactively educate pts on CTIBL, its consequences, appropriate monitoring, and treatment options.
Overcoming docetaxel resistance in advanced castration-resistant prostate cancer (CRPC): A phase I/II trial of the combination of temsirolimus and docetaxel.
Authors: Duran Ignacio , Montagut Clara , Calvo Emiliano , Galtes Susana , Navarrete Alicia , Rodriguez-Pascual Jesus , Hidalgo Manuel , Rodriguez-Moreno Juan Francisco , Cubillo Antonio , Garcia Antonia , Sanchez Lorena , Barbas Coral , Viqueira Andrea , Bellmunt Joaquim 
Published: February 2017

250 Background: Mechanisms of resistance to docetaxel (D) are not fully understood. Preclinical work showed that administration of temsirolimus (T) between courses of D delays the growth of PTEN deficient tumors in xenografts. (Wu et al. Cancer Res 2005) The current study aims to determine the recommended phase II dose (RPTD), toxicity, pharmacokinetics (PK) and preliminary activity of D in combination with T in CRPC patients (pts). Methods: Pts aged ≥ 18 with advanced solid tumors refractory to standard therapy, ECOG ≤2, adequate bone marrow and renal function were eligible. D was given once q. 3 weeks along with T on days 2, 9 &16. The protocol was later amended and day 9 of T omitted due to excessive myelotoxicity. A 3+3 rule dose escalation was used with the next dose levels (DL) planned: DL1: D 50mg/m2, T 15 mg; DL2: D 65mg/m2, T 15 mg; DL3: D 75mg/m2, T 15 mg; DL4: D 75mg/m2, T 25 mg. An expanded cohort for pts with CRPC who have progressed to D will enroll pts once the RPTD has been defined. Results: To date 13 pts have been enrolled, median age = 65 (range 35–76), 9 male and 8 ECOG 0, Forty-seven cycles (median: 2; range: 1–9) were administered. The most frequent related adverse events (AEs) of all grades expressed as % of cycles were: leucopenia (80.8%), hyperglycemia (70.2%), anemia (68.1%) and hypercholesterolemia (65.9%). The most common Grade 3–4 AEs as % of cycles were: leucopenia (27.6%), neutropenia (29.7%), and hypophosphatemia (23%). Two pts in DL2 experienced dose limiting toxicities (DLT) consisting of intolerable grade 2 mucositis and febrile neutropenia respectively. DL1 was expanded and 3 additional pts treated with no DLTs. No drug-drug PK interactions were observed. Among 13 pts evaluable for response, 6 (2 pancreas, 2 CRPC, 1 rectal and 1 sarcoma) achieved stable disease. One pt with CRPC who had previously progressed on docetaxel received 9 cycles of treatment with sustained clinical benefit. The expanded cohort for CRPC patients is opened and recruiting. Conclusions: T and D can be safely combined at reduced doses of both agents with no PK interaction. Preliminary antitumor activity has been observed in CRPC patients. Data on the expanded cohort will be presented.