bluuebunny/crossref_metadata_2025_split huggingface dataset:
Upfront docetaxel with androgen deprivation therapy in the elderly patient with metastatic hormone-naïve prostate cancer: Single institution experience.
Authors: Rayner Lindsay Jennifer Andrew , Challapalli Amarnath , Blackmore Eve , Rea Katherine , Wells Natasha , White Paul , Hilman Serena , Masson Susan , Huckett Rebecca , Garadi Krishna , Kirk Hannah , Kabala Julian , Oikonomopoulou Viktoria , Bahl Amit 
Published: February 2018

328 Background: Following CHAARTED & STAMPEDE, upfront Docetaxel chemotherapy became standard of care for metastatic hormone-naïve prostate cancer (mHNPC). We sought to evaluate our experience in the elderly group of patients (>70 yrs) compared with the non-elderly cohort. Methods: A retrospective analysis was undertaken of 38 patients commenced on upfront docetaxel chemotherapy, from Jan 16 - Jan 17. Patients were stratified as low (LR) and high risk (HR), as per the LATITUDE study. Progression was defined as per PCWG-3 criteria. The progression free survival (PFS) was calculated as time from start of treatment to date of progression and analysed by Kaplan-Meier estimates and log-rank test. Rates of febrile neutropenia (FN) were also evaluated. Results: The median age was 69 (range: 53-80) yrs, with 50% (19/38) HR patients. The median PFS was 11.5m for progressors (P; 42%) and not reached for non-progressors (NP; 58%), (p<0.0001). Granulocyte colony stimulating factor (G-CSF) was used in 13/38 (34%) patients; these did not experience FN. The overall rate of FN was 20% where G-CSF was not used. Overall 31/38 (81.6%) completed 6 cycles of chemotherapy, with 26% requiring dose reductions (Table). Overall, of the 9/16 (56.3%) patients who progressed within 6m of completing docetaxel, 3 had Cabazitaxel as the next treatment (P: 2/3 (66.7%), median PFS 6.2m) and 6 had novel androgen receptor targeted therapy (P: 5/6 (83.3%), median PFS 3.3m). Conclusions: Upfront docetaxel is reasonably well tolerated in the elderly with comparable median PFS to younger patients. Use of GCSF significantly minimizes the risk of FN in this group and should be considered as standard of care. In patients who progress within 6m of completing docetaxel, we feel optimal sequencing to be Cabazitaxel followed by subsequent therapies.[Table: see text]
The survival outcome, prostate-specific antigen (PSA) response and risk of fatigue of enzalutamide as first- and later-line treatment options in patients with metastatic castration-resistant prostate cancer (mCRPC): The real-world experience.
Authors: Poon Darren M.C. , Wong Kenneth C.W. , Chan T.W. , Law Kitty , Chan Kuen , Lee Ka Chai , Lee Conrad , Ting Chan Fong ,   Hong Kong Society of Uro-Oncology
Published: February 2018

330 Background: The real-world data regarding the efficacy and toxicity, particularly fatigue, of Enzalutmide (Enza) as first and later line treatment options in mCRPC patients is currently lacking. We aimed to evaluate the survival outcome, PSA response and rate of fatigue of Enza in clinical practice outside trial setting. Methods: The clinical records of mCRPC patients treated with Enza from all 7 public oncology centers in Hong Kong between August 2015 and October 2017 were reviewed. The treatment efficacy and its determinants, and toxicities were determined. Results: A total of 117 mCRPC patients were treated with Enza, of whom 29.1%, 48.7%, 19.3% had Enza as their first (chemo-naïve), 2nd (post-docetaxel or abiraterone) and 3rd or above (had at least 2 of the prior followings: docetaxel, abiraterone, cabazitaxel or radium-223) line treatment options. Visceral metastases were present in 20.6/29.8/50% patients with 1st/ 2nd / 3rd or above line Enza. The median overall survival (OS) and progression-free survival (PFS) were not reached (1yr OS rate: 82%)/15.8/7.4 and 7.1/3.9/2.2 months for 1st/2nd/3rd or above lines Enza, respectively (p = 0.0002). PSA responses ( > 50% decline of PSA from baseline with Enza) were achieved in 73.5/35.1 (post-docetaxel: 53.8%/post-abiraterone: 29.5%)/19.2% patients with 1st/2nd/3rd or above lines Enza (p < 0.001). The presence of PSA response was associated with both favorable OS (HR 0.19; p < 0.0001) and PFS (HR 0.29; p < 0.001) in the multivariate analysis of whole cohort. Grade 1-2 and 3-4 fatigue was present in 44.1/59.6/57.7% and 5.9/7.0/19.2% patients with 1st/2nd/3rd or above line Enza, respectively (p = 0.023). The use of 3rd or above lines of Enza is significantly associated with grade 2 or above fatigue in multivariate analysis of whole cohort (HR = 8.05; p = 0.01). Conclusions: In real-world clinical setting, more frequent PSA response, longer OS and PFS was found in chemo-naïve patients with Enza. Patients with later lines of Enza had higher risk of fatigue.
Use of low-dose, weekly carboplatin in men with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: O'Leary-Kelly Meghan , Gao Dexiang , Weisdack Sarah , Lam Elaine Tat , Bernard Brandon David , Flaig Thomas W. , Kessler Elizabeth Riley 
Published: February 2018

331 Background: Medical treatment options for advanced prostate cancer have evolved rapidly in recent years, with multiple new agents available. Our group had previously reported the use of weekly carboplatin for mCRPC in the pre-docetaxel era. The efficacy and toxicities of low-dose, weekly carboplatin were evaluated in a more contemporary patient cohort. Methods: We performed a retrospective review of patients with mCRPC treated with carboplatin from 2006-17 at a single health system. Carboplatin (AUC 2) was given weekly for 4 weeks of a 6-week cycle in combination with 1mg daily dexamethasone. Results: Sixty-four carboplatin-treated patients were identified, with a mean baseline prostate-specific antigen (PSA) of 568.55 ng/mL (range 0.02-4322). The median number of treatment cycles was 3 (range 1-10). The therapy was generally well tolerated and a dose-reduction was required for only 4 patients. Previous therapy included: docetaxel 95.3%, cabazitaxel 21.9%, abiraterone 53.1%, and enzalutamide 29.7%. A PSA decline of 30% occurred in 20 of 64 patients (31%). The response rate varied based on prior therapy. The most common adverse events were fatigue (80%), anemia (64%), and neuropathy (48%). There were 20 patients with Grade 3 adverse events. The most common was thrombocytopenia (n = 9), and 1 grade 4 thrombocytopenia. No other grade 4 toxicities were noted. Conclusions: New treatment options are needed for mCRPC after progression on currently approved agents. Platinum therapy may have increased activity in specific genomic subtypes of prostate cancer. These results compare favorably with the TROPC study of cabazitaxel (39% PSA response) in spite of the heavy pretreatment of our population. This retrospective report shows that carboplatin has activity and little toxicity in an unselected cohort of mCRPC.
Prediction of outcome in bone metastatic, castration-resistant prostate-cancer-patients under enzalutamide by combining biomarkers.
Authors: Schlack Katrin , Schrader Andres Jan , Krabbe Laura-Maria , Kannen Karoline , Semjonow Axel , Boegemann Martin 
Published: February 2018

334 Background: Under early Enzalutamide (Enza) treatment of bone mCRPC (bmCRPC), prostate-specific antigen (PSA) might be misleading, since a PSA-flare may occur. Bouncing of alkaline phosphatase (APB) was shown as a promising surrogate for survival outcome. Low lactate dehydrogenase (LDH) usually predicts better outcome. The purpose of this study was to evaluate the prognostic ability of APB, LDH, PSA and information of the pooled markers after initiation of Enza. Methods: 89 bmCRPC-patients were analyzed. PSA, LDH and AP were monitored at 2, 4, 8, 12 and 20 weeks. APB was defined as an increase of AP after initiation of Enza with a subsequent, significant decline below baseline during the first 8 weeks of therapy. APB vs. no Bounce as well as LDH and PSA increase vs. decline were analyzed using Kaplan-Meier analyses (KMA) and uni- and multivariate (UV/MV) cox-regression models. Results: In KMA declining PSA and LDH as well as APB were associated with longer median PFS with 7 (95% confidence interval: 4.2-9.8) vs. 3 months (2.3-3.7) for PSA, 6 (4.1-8) vs. 2 (1.2-2.8) for LDH and 8 (0-16.3) vs. 3 (1.9-4.1) for APB. Analysis of OS showed similar results with 17 (11.7-22.3) vs. 12 months (7.0-17.1) for PSA, 17 (13.2-20.8) vs. 7 (5,8-8.2) for LDH and 19 (7.9-30.1) vs. 12 (7.7-16.3) for APB. In UV APB (Hazard Ratio (HR): 0.52 (0.3-1.0); p = 0.02), PSA-decline ≥50% (HR: 0.49 (0.3-0.7); p < 0.01) and LDH-normalization (LDHnorm) (HR: 0.39 (0.2-0.6); p < 0.01) were significantly associated with longer PFS. Considering OS LDHnorm was a significant prognosticator for longer survival (HR: 0.39 (0.2-0.6); p < 0.01). In MV only LDHnorm showed a trend towards better OS (HR: 0.49 (0.2.-1.1); p = 0.09). Combining those markers and separating a group with APB, LDHnorm and PSA-decline and a group with PSA-decline alone KMA showed better PFS (11 (0.2-21.8) vs. 4 (0-8.6)) and OS (20 (17.7-22.3) vs. 8 (0.3-15.7)) in favor of the group with 3 beneficial markers. In UV the presence of all 3 markers was significantly associated with longer PFS (HR: 0.23 (0.1-0.7); p < 0.01) and OS (HR: 0.26 (0.1-0.8); p = 0.02). Conclusions: APB and LDHnorm may add to identifying bmCRPC-patients with favorable prognosis during early Enza-therapy.
Relationship between neutrophil lymphocyte ratio (NLR) and MDSC concentration in localized and metastatic castration resistant prostate cancer (mCRPC) patients.
Authors: Basu Arnab , Kollengode Kanthi Athreya , Rafatnia Ali , Manoli Hugh , Danenberg Genevieve , Chakravartty Eesha , Epstein Alan L. , Pinski Jacek K. 
Published: February 2018

338 Background: Human Myeloid Derived Suppressor Cells (MDSCs) have gained recognition as a significant population of cells that arise in cancer patients to mediate immune tolerance. MDSCs have been validated as a prognostic factor in several tumor types. The Neutrophil-Lymphocyte Ratio (NLR) is an easily obtained marker of inflammation that has also been validated as a prognostic marker in tumors including prostate cancer. We measured and compared MDSC concentrations and NLR in a cohort of patients with prostate cancer and also examined thier relationship with PSA Progression, a validated marker of overall survival. Methods: Blood was collected from patients with localized prostate cancer (n = 14) and mCRPC (n = 44) at 0 and 6 months. The percent CD33+ HLA-DRlow HIF1a+, CD33+ HLADRlow C/EBPb+, CD11b+ HLA-DRlow HIF1a+, and CD11b+ HLA-DRlow C/EBPb+cells as a fraction of PBMC were determined and reported. NLRs were obtained within 4 weeks of MDSC measurements. Patients were followed for a period of 2 years; PSA-Progression (PSA-P) was defined as a PSA doubling time of < 3 months in association with an increase of at least > 5ng/mL from PSA nadir Results: Higher Gleason scores were statistically associated with a NLR of greater than 2 (r = 0.07, p = 0.02, 95% CI [0.01-0.14]). Increasing MDSC% did not correlate with increasing Gleason scores (r = 0.13, p = 0.31) or predict PSA-P at 6 months (p = 0.16). MDSC% in patients with mCRPC (4.25%, 95% CI[3.34-5.17]) were significantly higher than localized prostate cancer (1.7%, 95% CI[1.02-2.37]) . There was a highly statistically significant relationship between the percentage of MDSC in PBMC with the neutrophil lymphocyte ratio (r = 0.68, p = 0.001, 95% CI [0.31-1.05]). Conclusions: MDSC concentrations in metastatic prostate cancer patients are significantly higher than those with localized disease and are associated with an increased neutrophil lymphocyte ratio. Although a trend was detected towards MDSC% predicting PSA-P, in this limited sample it was not statistically significant.
CYP11A1 inhibition as a therapeutic approach for the treatment of castration resistant prostate cancer.
Authors: Oksala Riikka , Karimaa Mari , Simola Outi , Ramela Meri , Riikonen Reetta , Vehmaan-Kreula Pirjo , Rummakko Petteri , Wohlfahrt Gerd , Kallio Pekka , Mustonen Mika VJ 
Published: February 2018

340 Background: Castration-resistant prostate cancer (CRPC) is a major cause of cancer mortality worldwide. The mechanisms behind the development of resistance are complex and not fully understood; altered androgen synthesis, androgen receptor (AR) overexpression or gene amplification, and mutations have been indentified. However, tumor growth may still be responsive to therapies that can further suppress de novo intratumoral steroid synthesis upstream of CYP17A1. ODM-208 is an oral, non-steroidal and selective inhibitor of CYP11A1 enzyme that suppresses the synthesis of all steroid hormones and their precursors. Methods: The inhibition of CYP11A1 was measured in vitro by the formation of radiolabelled isocapronic acid in a human adrenal cortex cell line (H295R), and further analysing pregnenolone (Preg) and testosterone (T) formation by ELISA. The tumor growth inhibition of ODM-208 alone or in combination with prednisone (Pred) was studied in VCaP CRPC xenograft where also concentrations of main steroid hormones progesterone (P), corticosterone (CORT) and T in tumors and adrenals were analysed. In addition, plasma ACTH and LH levels were measured at the end of the xenograft study. In dogs an ACTH stimulation test was done. Toxicity studies were conducted in rats and dogs. Results: ODM-208 potently inhibits CYP11A1 and synthesis of Preg and T with nM concentrations in vitro. In the VCaP CRPC xenograft ODM-208 alone and in combination with Pred significantly inhibited tumor growth. Concentrations of T, P and CORT were significantly decreased in the adrenals, indicating strong CYP11A1 inhibition. Also, significantly decreased steroid levels in tumors was observedhe Pred combination increased plasma ACTH levels less than ODM-208 alone, whereas no difference was seen in the LH. In dogs ACTH-stimulated cortisol production was significantly inhibited after single oral dose of ODM-208. In toxicological studies ODM-208 showed expected reversible findings in target tissues, mainly related to the pharmacology. Conclusions: ODM-208 shows promising antitumor activity in preclinical CRPC models with favorable toxicological profile. Thus, ODM-208 might have potential for treating the patients with CRPC.
Treatments for metastatic hormone-sensitive prostate cancer: A systematic review.
Authors: Firwana Belal , Sonbol Mohamad Bassam , Mahmoud Fade A. , Arnaoutakis Konstantinos 
Published: February 2018

346 Background: Over the past few years, the treatment of metastatic hormone sensitive prostate cancer (mHSPC) was revolutionized with the addition of docetaxel (DOC) or abiraterone (ABI) to the previous standard of care androgen deprivation treatment (ADT). Here, we sought to compare the effectiveness of docetaxel and abiraterone directly against ADT and indirectly to each other. Methods: We included randomized controlled trials (RCT) evaluating the efficacy of treatments in adults with newly diagnosed mHSPC. First-line treatments with DOC and ABI were considered. Efficacy outcome measures are overall survival (OS) and failure-free survival as (FFS) as defined by individual trial. If FFS was not reported, biochemical progression-free survival was considered FFS due to its specificity. The overall effect was pooled using the DerSimonian random effects model. Testing for subgroup difference was conducted using meta-regression method. Results: A total of five RCTs were included; three RCTs compared DOC+ADT versus ADT involving 2,992 participants, and two RCT compared ABI+ADT versus ADT involving 2,201 participants. The addition of DOC to ADT showed a significant improvement in OS compared to ADT monotherapy (HR 0.77, 95% CI 0.66 to 0.89) as well did the addition of ABI to ADT (HR 0.62, 95% CI 0.53 to 0.71). p-value for subgroup interaction was <0.05, suggesting a significant difference between pooled DOC and ABI effects, favoring the addition of ABI vs. DOC to ADT. Similar effects were found in significantly improving FFS when adding DOC (HR 0.64, 95% CI 0.58 to 0.70) or ABI (HR 0.30, 95% CI 0.27 to 0.34) to ADT compared to ADT monotherapy. p-value for interaction subgroup interaction was again significant <0.05 favoring the addition of ABI vs. DOC to ADT. Conclusions: The addition of either DOC or ABI to ADT showed significant improvement in OS and FFS when compared to ADT monotherapy in patients with mHSPC. Test for interaction suggests better outcome of ABI in comparison against DOC. Discussion with patients is encouraged to choose the appropriate treatment considering the adverse event profile for each. Further head-to-head comparison is needed to determine the effect.
The docetaxel-abiraterone acetate sequence compared to the abiraterone acetate-docetaxel sequence in metastatic castration-resistant prostate cancer patients with a response to previous castration superior to 12 months.
Authors: Desle Maxime , Derminne Alexandre , Lejeune Sarah , Seront Emmanuel 
Published: February 2018

353 Background: With the approval of the multiple new life-prolonging treatments for men with metastatic castration-resistant prostate cancer (mCRPC), the optimal sequencing of chemotherapy and androgen-receptor (AR) targeting agents remains unclear. Although response duration to castration could influence decision choice for second hormonal therapies, we do not know whether chemotherapy efficacy could be similar to AR targeting agents such as abiraterone acetate (AA). Methods: A retrospective analysis of mCRPC patients treated at Jolimont Hospital is reported. Patients included were castration-resistant PC with a response to castration superior to 12 months. They were treated with sequential docetaxel and AA, in either order. The combined progression-free survival (combined PFS: PFS1 + PFS2) of AA followed by docetaxel is compared to the reverse sequence (docetaxel followed by AA). Baseline characteristics are reported prior to the start of the first agent in the sequence. Results: Forty-two patients who started treatment for mCRPC between January 2013 and February 2017 were identified: 22 were in the docetaxel-AA sequence (Group A) and 20 were in the AA-docetaxel sequence (Group B). The median duration of response to castration was 16 months in Group A and 18 months in Group B. Proportion of Gleason > 8 was higher in group A (60% vs 50%). Visceral or lymph node disease was more important in group A (35% vs 16%). Median pre-treatment PSA was similar in the two groups (27 and 30). In the group A, PFS1 was 9 months and PFS2 was 8 months, resulting in a combined PFS of 17 months (range 5 to 47months). In the group B, PFS1 was 8 months and PFS2 was 7 months, resulting in a combined PFS of 15 months (range 4 to 45 months). Conclusions: We do not observe differences in clinical outcomes based on alternative sequencing of AA and docetaxel in men with mCRPC with a previous response duration to castration longer than 12 months.
Abiraterone or docetaxel in men with metastatic castration-sensitive prostate cancer: A pooled analysis of castration resistance-free survival and toxicity.
Authors: Helou Joelle , Catton Charles N , Bauman Glenn , Fazelzad Rouhi , Raphael Jacques 
Published: February 2018

354 Background: Recent meta-analyses suggested an improvement in overall survival (OS) with the addition of Abiraterone (A) vs Docetaxel (D) to androgen deprivation therapy (ADT) in the treatment of men with metastatic castration-sensitive prostate cancer. However, none have reported castration resistance-free survival (CFS) and toxicity data; two clinically relevant outcomes for physicians and patients. Methods: We conducted a systematic review and meta-analysis to assess CFS and toxicity of adding A or D to ADT in men with castration-sensitive prostate cancer. The electronic databases Ovid MEDLINE, Cochrane Central Register of Controlled Trials and EMBASE, were searched for randomized controlled trials. Pooled hazard ratios (HR) for CFS, and pooled risk ratios (RR) for grade 3 or higher toxicity were analyzed using the Mantel-Haenszel method and generic inverse variance. To account for between-studies heterogeneity, random-effect models were used to compute pooled estimates. Subgroup analyses compared patients on A and D in terms of CFS. Results: Five studies were included. The addition of A or D to ADT decreased the risk of development of castration-resistance by 53% (5 studies, 4,462 participants, HR = 0.47, 95% CI 0.33-0.67). In a subgroup analysis, the addition of A seemed to be better than D for the outcome CFS (5 studies, HR = 0.31, 95% CI 0.27-0.34 versus HR = 0.62, 95% CI 0.56-0.69, test for subgroup difference, p< 0.001). Different profiles of toxicity were seen with A and D. While A increased the risk of hypokalemia (3,107 participants, HR = 6.63, 95% CI 3.5-12.5) and cardiac toxicity (3,107 participants, HR = 2.4, 95% CI 1.7-3.3), D increased the risk of neutropenia (2,151 participants, HR = 13, 95% CI 8.9-18.8) and neuropathy (2,151 participants, HR = 2.25, 95% CI 1.18-4.3). Conclusions: The addition of A and D to ADT increases CFS in men with castration-sensitive prostate cancer, with a longer CFS noted for A compared to D. Considering CFS and OS, A may be preferred to D as initial therapy. Toxicity profiles differed between A and D. Quality of life and cost differences between A and D are other important factors and were not considered in this analysis.
Association of single nucleotide polymorphisms (SNPs) in CYP17A1 and SLCO2B1 genes and clinical outcome in metastatic castration-resistant prostate cancer patients treated with abiraterone acetate: results of the ABIGENE prospective study.
Authors: Borchiellini Delphine , Mahammedi Hakim , Viotti Julien , Gravis Gwenaelle , Roubaud Guilhem , Beuzeboc Philippe , Largillier Remy , Linassier Claude , Khalil Ahmed , Kaphan Regis , Joly Florence , Eymard Jean-Christophe , Falkowski Sabrina , Bompas Emmanuelle , Zanetta Sylvie , Schiappa Renaud , Maurin Maeva , Etienne-Grimaldi Marie-Christine , Milano Gerard A. , Ferrero Jean-Marc 
Published: February 2018

358 Background: Abiraterone acetate (AA), a CYP17A1 inhibitor, has been approved in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Germline polymorphisms in genes involved in androgen biosynthesis or transport may influence response and survival in this setting. Methods: ABIGENE is a multicentric prospective non-randomized pharmacogenetic study (NCT01858441). The primary objective was to investigate the association between 13 SNPs in genes related to AA pharmacology (CYP17A1, SLCO2B1 and SLCO2B3) and radiographic progression-free survival (rPFS), according to PCWG2 criteria, in pts with mCRPC treated with first-line AA + prednisone. The main secondary objectives were to evaluate the impact of these SNPs on radiographic and PSA response, overall survival (OS) and toxicity. SNPs were detected in blood samples before starting AA and analyzed by pyrosequencing or PCR-RFLP methods. Kaplan-Meyer’s curves with log-rank tests and cox regression models were used to identify relationships between SNPs and survival. Chi2 tests and student t-tests were used to identify association with response rate and toxicity. Results: 147 pts in 17 french centers were included between 2013 and 2017. Here are presented the results for the first 109 pts. The median follow-up was 28.7 months. Overall response rate (ORR) was 17%, and 74% pts had stable disease as the best response. Median rPFS was 10.9 months (95% CI 9.2-15.3). One SNP (rs10883782) in CYP17A1 was associated with rPFS on AA therapy (Table). Two other SNPs in CYP17A1 (rs4919683) and SLCO2B1 (rs1077858) were significantly associated with radiographic response. Data on PSA response, OS and toxicity will be presented at the meeting. Conclusions: This is the first prospective dedicated study to show an association between SNPs related to androgen metabolism and clinical outcome in mCRPC treated with AA. Clinical trial information: NCT01858441. [Table: see text]