bluuebunny/crossref_metadata_2025_split huggingface dataset:
Can MRI accurately define tumor boundaries to guide focal salvage after radiotherapy?
Authors: Iupati D. , Haider M. A. , Chung P. W. , Bayley A. , Catton C. , Milosevic M. , Bristow R. G. , Morton G. , Warde P. R. , Menard C. 
Published: February 2017

124 Background: We evaluated the role of MRI (plus/minus biopsy) in delineating tumour boundaries for focal salvage therapy of prostate cancer recurrence after external beam radiotherapy. Methods: Patients with biochemical failure after radiotherapy were enrolled in a prospective clinical trial mapping sites of local recurrence. An integrated diagnostic MRI and interventional mapping biopsy procedure was performed under sedation in a 1.5T scanner. Patients were imaged with a pelvic coil and an endorectal coil attached to a stereotactic transperineal template assembly. Multiparametric MRI images were acquired, followed by targeted radial biopsy of suspicious regions and random sextant sampling of the normal-appearing peripheral zone. Histology maps were generated by delineation and registration of biopsy cores onto diagnostic images using point-based rigid image registration. Two independent blinded observers reviewed images offline and delineated tumours boundaries which were compared against overlaid histology maps. Coverage was considered accurate if all pathologically proven tumour sites were encompassed within delineated boundaries. Results: Of the 18 patients analysed to date, the majority (83%) were found to have local recurrence. Patients with <6 informative cores were excluded, leaving 15 patients for analysis. Observers performed comparably, whereby mean MRI sensitivity, specificity, PPV and NPV for detecting tumor was 0.76, 0.7, 0.7, and 0.75. The MRI tumour boundary was accurate in 5/15 patients, and improved to 8/15 patients with addition of a 5-mm expansion margin. Targeted radial biopsies improved accuracy to 14/15 patients, by excluding false positive regions (n=2), increasing tumor volumes (n=2) or both (n=2). Random sampling biopsy was only relevant in 1 patient by detecting tumor not identified by MRI and targeted biopsy. Conclusions: MRI alone is not sufficiently accurate to define boundaries for tumor-targeted salvage even with addition of an uncertainty margin. Targeted biopsy improved both detection and delineation accuracy for recurrent tumor regions, and changed salvage therapy planning in 40% of patients. No significant financial relationships to disclose.
Phase II study of tasquinimod in chemotherapy-naive patients with metastatic castrate-resistant prostate cancer (CRPC): Safety and efficacy analysis including subgroups.
Authors: Armstrong A. J. , Haggman M. , Stadler W. M. , Gingrich J. R. , Assikis V. J. , Nordle O. , Forsberg G. , Carducci M. A. , Pili R. 
Published: February 2017

126 Background: Tasquinimod (TASQ) is an oral quinoline-3-carboxamide derivative that binds to S100A9 and displays anti-angiogenic and anti-tumor activity in prostate cancer (PC) models. In a randomized blinded phase II study, 206 (136 TASQ, 70 placebo [P]) men with metastatic castrate resistant (CRPC) were assigned to TASQ/P once-daily at an initial dose level of 0.25 mg/day escalating to 1.0 mg/day over 4 weeks. The primary endpoint to demonstrate an improvement in PCWG2 criteria-defined progression at 6 months was met and presented at ASCO 2010. This abstract provides an update on safety and efficacy including CRPC subgroups. Methods: Subgroups of patients based on baseline criteria were investigated for safety using NCI CTC v 3.0 criteria, PK and efficacy. Results: 201 (134 TASQ, 67 P) pts with a median age of 72.6 years received treatment and were evaluable for efficacy and safety. The updated analysis based on 5 additional PFS events confirmed an improved PFS of 7.6 vs. 3.3 months for pts on TASQ vs. P. Most progression events in both arms were radiological, but more pts progressed on bone scan in the P group. Radiographic PFS was 8.8 vs 4.4 months. Significant PFS improvements were observed in the PCWG2 risk groups with bone metastatic and visceral disease. TASQ treatment led to a transient increase in inflammatory lab markers such as CRP and fibrinogen, as well as asymptomatic increases in amylase/lipase. CRP increase was associated with adverse events (AEs) such as muscle and joint pain, while increased amylase was associated with a lower risk for gastrointestinal AEs. TASQ treatment was associated with anaemia, but did not affect CV risk factors such as hypertension or QTc prolongation, and the rate of composite cardiac events was acceptably low. Clearance of TASQ is decreased with age (1.4 % per year) and patients over 80 often required dose reduction due to increased exposure and toxicities. Conclusions: TASQ improved PFS in men with metastatic CRPC. Side effects are manageable and seem to correlate with laboratory markers. Individualized dosing based on tolerability is recommended and a phase III placebo-controlled study is being initiated. [Table: see text]
Role of detection of metastatic disease as a leading cause of screening failure in an ongoing phase III trial of zibotentan versus placebo in patients with nonmetastatic castration-resistant prostate cancer (CRPC).
Authors: Yu E. Y. , Nathan F. E. , Higano C. S. 
Published: February 2017

135 Background: Many patients with biochemical relapse after definitive therapy for prostate cancer receive androgen deprivation therapy. Although most patients experience a decline in PSA, PSA eventually rises despite a castrate level of testosterone. Many of these patients have non-metastatic disease and do not develop metastases for a median of 30 mos (Smith MR. JCO, 2005). However, there is no standard therapy for asymptomatic patients with non-metastatic CRPC. ENTHUSE M0 (Study 15) is an ongoing global phase III study comparing zibotentan 10 mg (an oral specific endothelin A receptor antagonist) vs placebo in non-metastatic CRPC patients. Co-primary endpoints are overall survival and progression-free survival; secondary endpoints are safety, PSA, quality of life, and time to symptomatic progression. Eligible patients are screened for metastases by bone and CT/MRI scan and other parameters. An unexpectedly high number of patients failed screening, prompting this analysis. Methods: All patients who were screened were included in the analysis. Reasons for exclusion were recorded. Results: As of June 3, 2010, 1,756 patients completed screening. Of these patients, 960 (55%) were randomized and 796 (45%) failed screening. The leading causes of screen failures are listed in the table. Exclusion rates by investigator specialty and country will be reported. Conclusions: As 30% of patients had metastatic disease on screening and were excluded, these data suggest that the frequency of asymptomatic metastases is high in men thought to have non-metastatic CRPC. These findings stress the value of periodic staging studies in men progressing from hormone sensitive to non-metastatic CRPC as metastatic CRPC patients may benefit from standard treatments or research treatments on other protocols. [Table: see text] [Table: see text]
Phase II study of AT-101 to abrogate Bcl-2-mediated resistance to androgen-deprivation therapy (ADT) in patients (pts) with newly diagnosed androgen-dependent metastatic prostate cancer (ADMPC).
Authors: Stein M. N. , Khan I. , Hussain M. , Liu G. , Wilding G. , Posadas E. M. , Stadler W. M. , Jeyamohan C. , Eddy S. , DiPaola R. S. ,   Prostate Cancer Clinical Trials Consortium
Published: February 2017

137 Background: Preclinical studies demonstrate that Bcl-2 is over-expressed in most pts with prostate cancer, causes drug resistance to ADT, and that modulation of Bcl-2 improves sensitivity of tumor cells. We are conducting a phase II study for men with ADMPC to test the hypothesis that AT-101, a small molecule Bcl-2 inhibitor, improves clinical results of pts initiating ADT for metastatic prostate cancer. Building on results from SWOG 9346 (Hussain JCO 2006) demonstrating that PSA nadir after 7 mo of ADT predicts survival, we are using a novel phase II trial design, in which the primary endpoint is the percentage of patients with PSA ≤ 0.2 ng/ml at 7 mo of ADT plus AT-101. Methods: Pts had ADMPC, PSA > 5.0 ng/ml within 12 wks prior to registration and no prior ADT for metastatic disease. ADT with LHRH agonist and bicalutamide started 6 wks prior to initiation of oral AT-101, 20 mg/day for 21 days of 28 day cycle. Pts received up to 8 cycles of ADT and AT-101. A total of 55 pts were enrolled (to obtain 48 evaluable pts) to in a two stage design with null hypothesis 48% versus alternative 68% with PSA ≤ 0.2 at 7 mo. With α = 0.1 and β = 0.9, > 27 pts meeting this endpoint are required to recommend further study. Results: 55 pts were enrolled, median age 61.5 y; Gleason score (GS) 6 (5%),GS 7 (30%), GS 8 (24%), and GS 9 (41%). 3 pts had visceral mets and the remaining pts had bone or nodal metastasis. 42 pts have discontinued (9 toxicity, 9 progression, 1 withdrew) or completed (n = 23) 7 mo of treatment. In intention to treat analysis, 11 of 42 pts (26%) met the primary endpoint 10, of 42 (23%) pts had PSA > 0.2 and < 4.0 ng/ml after 7 mo. Grade 1/2 toxicities (%) included fatigue (36/9), nausea (20/9), vomiting (13/7), anorexia (15/2), AST/ALT (25/5), hypercalcemia (9/0), constipation (13/3), dry skin (9/0), anemia (18/0), sensory neuropathy (7/7), vomiting (12/7), hyperglycemia (7/4). Grade 3 toxicities were sensory neuropathy 2 pts, GI obstruction 1 pt, syncope 1 pt. Conclusions: Although final study results are pending the analysis of pts currently on therapy, 26% of pts achieved an undetectable PSA at 7 mo in a population with aggressive disease (66% GS ≥ 8). No significant financial relationships to disclose.
Safety and efficacy of ketoconazole (K) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Contemporary experience and prognostic indicators.
Authors: Keizman D. , Huang P. , Carducci M. A. , Denmeade S. R. , Eisenberger M. A. 
Published: February 2017

145 Background: Intracrine conversion of adrenal androgens to testosterone play an important role in CRPC progression. Treatments (tx) that block adrenal steroid synthesis have shown significant clinical benefits in mCRPC. Aims: To evaluate contemporary data on safety and efficacy associated with K in mCRPC. Methods: All/unselected mCRPC pts progressing on GnRH-a and antiandrogens (AA) treated with K were retrospectively analyzed. Pts were maintained on gonadal suppression, discontinued AA, and received and K 200-400 mg t.i.d. until disease progression or dose-limiting toxicity (DLT). Initial 600mg/d dose was escalated to 1,200mg/d if a PSA decrease was not seen at 3 months (mos) or if a response/subsequent progression to 600/mg/d was observed (optional). Follow up included hematological/chemical profile q 3 mos, scans upon clinical (physical exam/symptoms) or at biochemical progression (PSA increase ≥ 25% and ≥2ng/mL from nadir). A multivariate cox regression model was used to identify variables significantly associated with disease progression. Results: From 1999-2010 (mean follow up 40 mos, range 5-129), 114 m-CRPR pts were treated with K 200mg (n=82, 72%) or 400mg (n=32, 28%) tid. Most common grade 3/4 tox events (n=23) were fatigue, abdominal discomfort, nausea, and dizziness. 9 pts (8%) had DLT (fatigue n=7, hepatotoxicity/thrombocytopenia n=1). 55/114 (48%) had ≥ 50% PSA decline. Overall median time to progression (TTP) was 8 mos (range 1-129). 14 pts remain progression free > 7 mos (range 7-129). Significant prognostic factors (table) were response to prior AA (≥6 vs <6 mos), pre-tx PSADT (≥3 vs <3 mos) and extent of disease (limited-axial skeleton and/or nodal vs extensive- appendicular skeleton and/or visceral). Conclusions: K is effective and safe in m-CRPC. Prior response to AA, PSADT ≥ 3mos and limited metastatic disease is associated with TTP and further supports a therapeutic role for suppressing adrenal androgens in m-CRPC. [Table: see text] No significant financial relationships to disclose.
How does neoadjuvant bicalutamide 150 mg monotherapy compare to lutenising hormone-releasing hormone agonist (LHRHa) therapy in localized prostate cancer treated with radical radiotherapy? A case-matched comparison of PSA kinetics and biochemical outcome.
Authors: McGivern U. , Mitchell D. M. , O'Hare J. , Corey G. , O'Sullivan J. M. 
Published: February 2017

146 Background: In patients treated with neoadjuvant lutenising hormone-releasing hormone agonist (LHRHa) therapy prior to radical prostate radiotherapy the PSA nadir in the first week of radiotherapy has been correlated with subsequent biochemical failure free survival (BFFS). Bicalutamide monotherapy (BC) is increasingly being used as a neoadjuvant therapy in place of LHRHa. We wished to compare the initial PSA response to neoadjuvant BC or LHRHa in this setting as well as examining subsequent biochemical failure rates. Methods: We retrospectively reviewed the case notes of consecutive men with prostate cancer treated with BC monotherapy prior to radical prostate radiotherapy from April 2004 to December 2008 and case-matched them to men treated with neoadjuvant LHRHa. PSA levels and kinetics prior to radiotherapy and subsequent BFFS were analysed. Results: Eighty nine men treated with BC with a median follow-up of 42 months were case matched to 89 men treated with LHRHa. There were no significant differences in age, initial PSA, Gleason, or T stage. The median nadir PSA on day 1 of radiotherapy was 2.2ng/mL (0.1-11.2) for BC patients and 0.9ng/mL (0.1-11.2) for LHRHa patients (p=0.0007). There were no significant differences in PSA velocity or doubling time during the neoadjuvant period. A PSA of <1.0ng/mL on day 1 of radiotherapy was seen in 29 (32%) and 47 (52%) of BC and LHRHa patients respectively. Biochemical failure was seen in 10 (11.2%) and 2 (2.2%) of BC and LHRHa patients respectively. PSA kinetics did not predict for subsequent BFFS at this duration of FU for men receiving neoadjuvant BC. Conclusions: In this case-matched study, neoadjuvant BC therapy does not provide the same level of pre-radiotherapy PSA suppression when compared to neoadjuvant LHRHa. Higher biochemical failure rates are seen in patients treated with BC than LHRHa however this may be a result of prolonged castration. No significant financial relationships to disclose.
Tolerability and efficacy of anti-androgen manipulation versus taxotere and anti-androgen manipulation in patients with hormone-naive, high-risk/metastatic prostate cancer: A phase II, open-labeled, randomized study.
Authors: Pedley I. D. , Frew J. A. , Wilson J. M. , Abdul Razak A. R. , Azzabi A. , McMenemin R. , Stockley J. , Soomro N. , Durkan G. , Leung H. 
Published: February 2017

147 Background: Anti-androgen manipulation (AA) is considered the standard initial therapy for high-risk/metastatic prostate cancer. The role of chemotherapy and anti-androgen manipulation (TAA) is still undefined in this group. GenTax is a phase II trial investigating clinical outcome and gene profiling in prostate cancer before and after AA or TAA. Here we present the clinical outcome data. Methods: Patients with T3/4 disease, PSA ≥ 50 ng/ml or Gleason score ≥ 8, or metastatic disease were enrolled. Patients were randomised at histological diagnosis to AA or TAA (goserelin 3.6 mgs q28 ± taxotere 75 mg/m2 q21 for 6 cycles). TRUS biopsies were taken at randomisation and 22 weeks after treatment initiation. Clinical assessment including KPS, QOL using QLQ-C30, bloods/PSA were measured 3 weekly until 22 weeks then 3 monthly. Data was analysed for PFS, OS, toxicities and QOL. Results: 30 patients were recruited with 15 patients in each arm from 10/13/2005 to 12/02/2009. The median age was 62.2 yrs (range 48.9-75.1). All patients had a KPS of ≥ 90%. 12 (40%) and 18 (60%) of patients had stage 3 and 4 disease respectively. At randomization 10 patients had bone and 4 had visceral metastases. 29 had a Gleason score of ≥ 7. There were no statistical differences for age, KPS, disease stage or Gleason score between the two arms. Treatment was well tolerated in both groups with no G3-4 toxicity in the AA arm. In the TAA arm, 4 patients had dose delays or reductions; with one G3 incidence of neutropenia. G3-4 non-hematological toxicities were infrequent; fatigue and one episode of anaphylaxis occurring in separate patients. Median PFS and OS between the two treatments have not been reached at median follow up of 25 months. The 2-year PFS rate was not significantly different, (50% vs 60% p = 0.788) between the AA and TAA groups. There were no significant differences in QOL measures. Conclusions: Combination therapy of taxotere and anti-androgen manipulation is safe and well tolerated. The gene profiling results may provide important information in selecting patients who will benefit from more aggressive initial therapy. [Table: see text]
Using Gleason pattern 5 to refine risk stratification for prostate cancer patients treated with dose-escalated radiotherapy and androgen-deprivation therapy.
Authors: Sabolch A. , Feng F. Y. , Daignault-Newton S. , Halverson S. , Blas K. , Phelps L. , Olson K. B. , Sandler H. M. , Hamstra D. A. 
Published: February 2017

15 Background: The division of Gleason score (GS) into three categories (2-6, 7, 8-10), may not fully utilize its prognostic power as shown by recent reports demonstrating that the presence of Gleason Pattern 5 (GP5) is a strong adverse prognostic factor. Therefore, we analyzed clinical outcomes for patients treated with dose-escalated radiation therapy (RT) based upon the presence or absence of GP5 within the biopsy specimens. Methods: Clinical outcomes were analyzed for 718 men treated for localized prostate cancer with definitive external beam RT to at least 75 Gy. We assessed the impact of GP5 as well as pre-treatment and treatment related factors on freedom from biochemical failure (FFBF), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS). Results: Median follow-up was 64 months. At biopsy, 89% of patients had no GP5 while 11% had GP5. There was no difference in age, co-morbid illness, clinical T-stage, PSA, or the use or duration of androgen deprivation therapy (ADT) between GS8 without GP5 and GS8-10 with GP5. The presence of GP5 predicted lower FFM (p<0.002 [HR: 3.4{1.7-7.1}]), CSS (p<0.0001 [HR: 12.9 {5.4-31}]), and OS (p<0.0001 [HR: 3.6 {2.0-6.5}]) when compared to GS8 (without GP5). Ten-year FFM, CSS, and OS were 89%, 98%, and 57% for those with Gleason 8 prostate cancer without GP5 as compared to 61%, 55%, and 31% for those with GP5. In addition, both FFM and CSS were strongly influenced by ADT use concurrent with RT. On multivariate analysis GP5 was the strongest prognostic factor for all clinical end-points. Conclusions: The presence of GP5 predicts for worse clinical behavior, which therefore needs to be accounted for by risk stratification schemes. Further intensification of local and/or systemic therapy may be appropriate for such patients. No significant financial relationships to disclose.
A phase I/II randomized study of panobinostat and bicalutamide in castration-resistant prostate cancer (CRPC) patients progressing on second-line hormone therapy.
Authors: Ferrari A. C. , Stein M. N. , Alumkal J. J. , Gomez-Pinillos A. , Catamero D. D. , Mayer T. M. , Collins F. , Beer T. M. , DiPaola R. S. ,   The Prostate Cancer Clinical Trials Consortium
Published: February 2017

156 Background: Aberrant expression and function of the androgen receptor (AR) is determinant of CRPC progression. We previously demonstrated that the histone-deacetylase inhibitor panobinostat (PAN) decreased AR levels and reversed resistance of androgen-independent AI-LNCaP and Rv1 cells to the antiandrogen bicalutamide (Bic). We designed a ph-I/II study to determine whether PAN would restore the sensitivity to Bic in CRPC patients (pts). We report the ph-I results evaluating safety and maximum tolerated dose (MTD) of Bic combined with oral, intermittent PAN. Methods: Men with CRPC and limited bone metastasis, ECOG PS 0-2, PSA>2 ng/ml (or <2 + new metastases), adequate organ function and QTc<450 ms progressing on at least two prior hormones including antiandrogens were assigned each to one of 3 cohorts (C) for treatment with Bic 50 mg PO daily with oral PAN at 3 dose levels: C1, 20 mg tri-wkly (60 mg/wk) 2 of 3 wks; C2: 30 mg tri-wkly (90mg/wk) 2 of 3 wks, 40 mg PO tri-wkly (120mg/wk) 3 of 3 wks. Cycles (Cy) repeated every 21 days. Minimum treatment was 3 wks. Treatment could continue if clinical benefit. DLT were: grade (G) 3-4 febrile neutropenia >5 days and/or hospitalization; G3 thrombocytopenia with bleeding; QTcF>500 ms any G4 except nausea, vomiting, or diarrhea. Results: Nine men, median (m) 65 yrs were treated in cohorts of three. mPSA at entry 9.26 ng/mL (IQR:8.24), mCy number, 6 (IQR: 5). MTD was not reached. All experienced some grade of toxicity attributable to PAN. Toxicity: no G4, only G3 was thrombocytopenia without bleeding in 3 pts (1 in C1, 2 in C3) that resolved spontaneously and controlled by dose reduction; G2: thrombocytopenia in 3, fatigue 2, high cholesterol 2, hypothyroidism 2; G1 thrombocytopenia in 2, fatigue 3, dyspepsia 3, anorexia 2. PSA decline ≥50% was achieved in 2 pts, stable PSA in 3 pts. Ph-II recommended PAN doses: Arm A: 40 mg tri-wkly (120 mg/wk) 2 of 3 wks; Arm B: 20 mg tri-wkly (60 mg/wk) 2 of 3wks with Bic 50 mg/daily. Conclusions: Oral, intermittent PAN in combination with daily Bic is well tolerated in CRPC pts progressing on second line hormones and shows promising PSA responses suggesting anti-AR activity. Ph-II is ongoing. [Table: see text]
Elderly patients with metastatic castrate-resistant prostate cancer (mCRPC): Safety and efficacy of docetaxel retreatment.
Authors: Gernone A. , Pagliarulo A. , Calderoni G. , Pagliarulo V. 
Published: February 2017

161 Background: Comorbidities are considered a therapeutically limiting problem in elderly patients (pts) with mCRPC. We analysed correlations between comorbidity, toxicity and efficacy of docetaxel re-treatment in pts ≥ 70 years with mCRPC. Methods: Pts were evaluated according to comprehensive geriatric assessment (CGA). From 2003 to 2010, 70 pts ≥ 70 years with mCRPC received 3-wk first line docetaxel therapy followed by retreatment on biochemical disease progression. Each patient was assessed according the Cumulative Illness Score Rating-Geriatrics (CISR-G) manual. The score was 0-4. The median age was 77 (70-84), ECOG PS 0-2, median baseline PSA 180 ng/ml (15-1200). The more frequent comorbidities were hypertension, diabetes, arrhythmias, chronic obstructive pulmonary disease. The endpoints were: PSA response proportion to first-second-third line chemotherapy, median survival in responding patients and toxicity. Results: All pts received a standard 3-wk regimen, dose was reduced by 25% for pts score 4. The incidence of adverse events was relatively low and no pts died on therapy. There were no episodes of neutropenic fever. Pts with score 1-2 were 70% (49 pts); pts with score 3 were 20% (14); pts with score 4 were 10% (7). 70 pts (score 0-4) received first line docetaxel chemotherapy with a median no of cycles 14 (6-18), a median survival of 18 months (mos), PSA response 70%. Of these pts 26 (score 0-3) were re-treated with the same regimen with no of cycles 12 (8-18), a median survival of 14 mos, PSA response 45%, duration of first chemotherapy holiday 5 mos (median). Of these pts, 4 (score 0-3) received third line treatment with no of cycles 10 (6-14), a median survival of 10 mos, PSA response 22%, duration of second chemotherapy holiday 4 mos (median). Of these pts only 1 (score 1) received third re-treatment with 8 cycles, PSA response 20%, third chemotherapy holiday 4 mos. 80% of symptomatic pts reported an improvement in symptoms control with docetaxel chemotherapy. Conclusions: Re-treatment with docetaxel is safe in mCRPC elderly pts despite the association of important comorbidities. Median survival in responding pts was approximately 40 mos from the first to the third line. No significant financial relationships to disclose.