bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical characteristics and outcomes of patients with prostate cancer and parenchymal brain metastases (PBM).
Authors: Bambury Richard Martin , Hatzoglou Vaios , Curtis Kristen Rebecca , Patel Gita V , Scher Howard I. , Young Robert J. , Morris Michael J.
Published: February 2017

187

Background: Parenchymal brain metastases' (PBM's) are rare in prostate cancer (PCa), but the introduction of novel therapies that prolong life for metastatic disease has raised the possibility that the distribution of disease may be changing as patients live longer. In an effort to establish the clinical characteristics and outcomes of PBM as a comparator for future studies, we reviewed all cases at our institution over a 13 year period. Methods: Patients (pts) diagnosed with PBM at Memorial Sloan-Kettering Cancer Center between 2000 and 2010 were retrospectively identified by billing codes for prostate cancer, brain metastases, and no additional primary cancers. Additional cases since 2010 were manually collected prospectively. Direct extension of osseous skull metastases or leptomeningeal disease were not considered PBM. Demographic, clinical, and pathologic characteristics were recorded. Results: 5,474 pts with metastatic PCa and no other primary malignancy were identified of whom 21 had PBM. An additional four PBM cases were prospectively identified, for a total of 25 pts. Twenty two pts (88%) had prostate adenocarcinoma (adeno), of which 14 had Gleason 8 or more disease, 20 had castration resistant disease, and nine had prostate-specific antigen (PSA) less than 5ng/mL. The other three (12%) had atypical histologies (osteosarcoma, small cell carcinoma, and high grade neuroendocrine carcinoma). Median time from diagnosis of PCa to diagnosis of PBM was 3.7 years (range 0 to 19.8) and from discovery of metastatic PCa to PBM was 2.3 years (range 0 to 10). At the time of PBM diagnosis all pts had 1 or more additional site of disease - bone metastases in 20 (80%), lung in 13 (52%), liver in nine (36%). Treatments included whole brain RT in 10 (45%), surgery +/- RT in 8 (36%) and stereotactic RT in 2 (9%). Median overall survival from diagnosis of PBM was 4.3 months (0.7-18.1) in adeno pts compared with 0.7 months (0.7-1.0) in atypical histology pts. Only four pts (16%) survived 12 or more months. Conclusions: In this contemporary cohort, PBM cases were often associated with PCa of atypical histology, high Gleason grade, frequent visceral disease, and low PSA production. Survival was poor after diagnosis of PBM despite treatment. These data can be used as a comparator to track whether treatment with novel PCa therapies is altering the incidence and characteristics of CNS involvement.
The role of FSH in castration-induced adipogenesis and cardiovascular diseases: Highlighting differences between orchiectomy, GNRH agonists, and antagonists.
Authors: Pinthus Jehonathan H. , Hopmans Sarah , Werstuck Geoff , Duivenvoorden Wilhelmina CM
Published: February 2017

191

Background: Androgen deprivation therapy (ADT) is associated with weight gain and development of the metabolic syndrome (MS). Different modes of ADT can achieve castration but with different affects on serum FSH levels. Inspired by the observation that adiposity accompanies the incremental increase in serum follicle stimulating hormone (FSH) levels in menopause, we hypothesized that gonadotrophin-releasing hormone (GnRH) antagonists which maximally inhibit FSH levels will associate with reduced adiposity and MS development compared to GNRH analogues and orchiectomy. Methods: In-vitro models of adipocyte differentiations were used to investigate FSH effects on lipid accumulation and expression of the rate limiting enzyme in this process-FAS. In-vivo models for adipogenesis and MS (LDL receptor KO mice) were used to investigate and compare the effects of orchiectomy (n=12), sham surgery (control, n=12), sham surgery plus GNRH antagonist (Degarelix, n=12) and sham surgery plus GNRH agonist (Enanton, n=12). Mice were also manipulated by two nutritional conditions (normal/high fat diet). Longitudinal weight gain (four month), visceral fat accumulation (CT measurements), fasting blood glucose, two hours glucose tolerance tests, serum triglycerides, FSH, LH, and testosterone levels were studied along with number and characteristics of aortic atherosclerotic plaques. Results: The lowest and highest serum FSH levels were recorded in mice treated with degarelix versus orchiectomy and significantly lower levels of FSH and LH in mice treated with degarelix versus enanthon were recorded. Mice treated with enantone gained significantly more weight and visceral fat compared to mice treated with degarelix. Significant lower levels of serum triglycerides and better response to glucose loading were recorded in mice treated with degarelix. Data on atherosclerotic plaques is currently processed and will be discussed, but preliminary analysis reveal lower plauque size in mice treated with degarelix. Conclusions: Usage of GNRH antagonists as ADT attenuates weight gain and development of the MS in preclinical models.
Urinary obstruction following stereotactic body radiation therapy (SBRT) for clinically localized prostate cancer.
Authors: Arscott W. Tristram , Chen Leonard , Wilson Nathan , Bhagat Aditi , Kim Joy S. , Yung Thomas M. , Lei Siyuan , Collins Brian Timothy , Suy Simeng , Dritschilo Anatoly , Lynch John H. , Collins Sean P.
Published: February 2017

196

Background: Obstructive urinary symptoms are common following prostate cancer treatment with radiation therapy. Given the higher dose of radiation per fraction using stereotactic body radiation therapy (SBRT) there is concern that post-SBRT obstructive urinary symptoms would be more severe. This study sought to evaluate obstructive urinary symptoms and urinary retention requiring catheterization following SBRT for prostate cancer. Methods: Patients treated with SBRT monotherapy for localized prostate cancer from August 2007 to July 2011 at Georgetown University Hospital with a minimum of two years of follow-up were included in this study. Treatment was delivered using the CyberKnife with doses of 35 Gy to 36.25 Gy in five fractions. Urinary retention was recorded and scored using the CTCAE v.4. Patient-reported urinary symptoms were assessed using the International Prostate Symptom Score (IPSS) before treatment and at months 1, 3, 6, 9, and 12 and every six months thereafter. Results: Two hundred sixty nine patients at a median age of 69 received SBRT with a median follow-up of three years. Prior to treatment, 32.1% of patients utilized alpha-antagonists and 17.8% were dissatisfied with their urinary function. The two-year actuarial incidence rates of acute and late urinary retention greater than or equal to grade 2 were 39.5% and 41.4%. Alpha-antagonist utilization rose at one month (57.9%) and 18 months (48.0%) post-treatment. However, grade 3 urinary retention was low with four men (1.5%) requiring catheterization and/or transurethral resection of the prostate. A mean baseline IPSS obstructive symptom score of 3.6 significantly increased to 5.0 at one month (p < 0.0001), however returned to baseline at three months (p = 0.74). Late IPSS increases were common, but transient. The IPSS obstructive symptom score returned to baseline in 79.6% of patients by six months and 92.6% by two years. Dissatisfaction with urinary function declined to 14% by two years post treatment (p < 0.05). Conclusions: Treatment of prostate cancer with SBRT resulted in an acute increase in obstructive urinary symptoms, which peaked at one month post-treatment. However, the risk of acute urinary retention requiring catheterization was low. Obstructive urinary symptoms returned to baseline in the majority of patients by six months and in more than 90% by two years.
Results of subset analyses on overall survival (OS) from study CA184-043: Ipilimumab (Ipi) versus placebo (Pbo) in post-docetaxel metastatic castration-resistant prostate cancer (mCRPC).
Authors: Drake Charles G. , Kwon Eugene D. , Fizazi Karim , Bossi Alberto , van den Eertwegh Alfons JM , Logothetis Christopher , Scher Howard I. , Beer Tomasz M. , McHenry Brent , Liu David , Gerritsen Winald R.
Published: February 2017

2

Background: The CA184-043 phase 3 study did not reach statistical significance for its primary endpoint of OS (HR=0.85, p=0.053). However, antitumor activity was observed in other efficacy endpoints, including progression-free survival. Prespecified subset analyses were performed to understand if any prognostic features may identify mCRPC patients (pts) more likely to benefit from Ipi treatment. Methods: 799 pts were randomized to receive a single dose of radiotherapy (RT) followed by either Ipi (N=399) or Pbo (N=400). Prespecified subset analyses based on Kaplan-Meier/Cox methodology were performed using known prognostic factors for OS in mCRPC. Results: Prespecified subset analyses suggested that Ipi may be more active in pts with favorable prognostic factors, including no visceral disease, alkaline phosphatase <1.5 ULN, and hemoglobin ≥11 g/dL (Table). The safety profile in this study was consistent with previous reports of Ipi. Conclusions: Based on these subset analyses, Ipi added to RT appears to have greater activity than RT alone in pts with a favorable prognostic profile. These results support continued investigation of Ipi in the ongoing CA184-095 study in chemotherapy-naive mCRPC pts. Clinical trial information: NCT00861614. [Table: see text]
Is there an anti-androgen withdrawal effect with enzalutamide?
Authors: Rodriguez-Vida Alejo , Bianchini Diletta , Hughes Simon , Lorente David , Crawley Danielle , Van Hemelrijck Mieke , Voskoboynik Mark , Chau Noan Minh , Rudman Sarah Maria , Powles Thomas , Payne Heather , De Bono Johann Sebastian , Chowdhury Simon
Published: February 2017

200

Background: The second generation anti-androgen enzalutamide has demonstrated improved survival in patients with metastatic castration-resistant prostate cancer (CRPC) progressing after docetaxel. While an anti-androgen withdrawal effect has been reported for bicalutamide, flutamide, and other non-steroidal and steroidal anti-androgens, there is no published evidence of any withdrawal effect with enzalutamide. Methods: We retrospectively identified 30 consecutive patients with advanced prostate cancer who were treated with enzalutamide post-docetaxel at three London hospitals. All patients were withdrawn from enzalutamide due to clinical (73%), PSA (87%) and/or radiological progression (47%). Post-discontinuation prostate-specific antigen (PSA) results were available for all patients and were determined two-weekly for at least six weeks until starting further anti-cancer treatment. PSA withdrawal response was defined as a 50% decline in PSA from baseline, with a confirmed decrease after 3 weeks or more. Clinical tumor and patient characteristics were evaluated in relation to the withdrawal effects using multivariate logistic regression analyses. Results: Median age was 71 (range 54 to 87). The median follow-up was 5.4 months (range: 0.5 to 16.0 months). At enzalutamide initiation, ECOG performance status was 0 and 1 in 10% and 69% of patients, respectively. The most common metastatic sites were bone (87%), lymph nodes (68%), liver (17%), and lung (6%). Most patients (70%) had been on abiraterone previously and 11 patients (37%) had also received prior cabazitaxel. The median treatment duration with enzalutamide was 3.7 months. Only one patient (3%) had a confirmed PSA response of 50% or more after enzalutamide discontinuation and two patients (7%) had a confirmed PSA response between 30% and 50%. None of the clinical variables assessed in relation to withdrawal effects were found to be statistically significantly associated. Conclusions: This preliminary case series represents the first clinical evidence that enzalutamide may have an anti-androgen withdrawal effect in a minority of patients. These results warrant further prospective and controlled validation of a potential enzalutamide withdrawal effect and its clinical relevance in prostate cancer management.
The expression levels of microRNAs that have the androgen receptor in localized prostate cancer as a target.
Authors: Leite Katia Ramos Moreira , Florez Manuel Garcia , Reis Sabrina Thalita , Viana Nayara , Katz Betina S. , Dip Nelson , Silva Iran Amorin , Pontes Jr Jose , Srougi Miguel
Published: February 2017

206

Background: Prostate cancer (PC) depends on the androgen activity being the androgen blockage the main treatment in the setting of metastatic disease. Mechanisms of resistance in metastatic tumors are not completely known. MicroRNAs (miRNA) are small non-coding molecules that have as canonical mechanism the negative control of gene expression promoting messenger RNA (mRNA) degradation or impairing protein translation. The role of miRNAs that have as target the AR are still unknown. Our objective is to study the expression profile of miRNAs that have AR as target in localized prostate cancer. Methods: The expression levels of miRNAs that have as target AR (miR9, 34a, 34c, 185, 130a, 299, 421, 371, 541) were studied using qRT-PCR in the surgical specimens of 83 patients that underwent radical prostatectomy to treat localized prostate cancer. The expression levels of miRNAs were correlated to Gleason score (GS), pre-operatory PSA, pathological stage and biochemical recurrence (PSA>0.2 ng/mL) in a mean follow up of 45.9 months. The mean age was 62.9, mean GS was 7.2, mean PSA was 7.93 ng/mL, and 42 (50.6%) patients were staged pT2. Twenty-four (28.9%) patients presented biochemical recurrence. Specimens of six patients submitted to open surgery to treat benign prostate hyperplasia (BPH) composed the control group. Results: The mean expression of AR was 1.63, being overexpressed in 59% of the cases. The mean expression levels of the nine studied miRNAs was miR9=3.06, miR34a=0.76, miR34c=1.14, miR185=1.65, miR130a=1.9, miR299=6.23, miR421=2.84, miR371=1.41, and miR541=0.93. The univariate analysis showed that pT2 tumors have higher expression of miR371(p=0.009). Conclusions: In localized PC the higher expression of miR371 is related with organ-confined disease. This miRNA could be important in the control of AR and the comprehension of its role in PC might bring alternatives to treat metastatic disease. Funded by FAPESP – 2012/50163-0.
Clinical outcomes of patients (pts) age 60 or younger treated with docetaxel (DOC) for castration-resistant prostate cancer (CRPC): Results of an Italian multicenter retrospective study (CYCLOP study).
Authors: Veccia Antonello , Ortega Cinzia , di Lorenzo Giuseppe , La Russa Francesca , Burgio Salvatore Luca , Facchini Gaetano , Messina Caterina , Sacco Cosimo , Spizzo Gilbert , Aieta Michele , Lodde Michele , Mansueto Giovanni , Zucali Paolo A. , D'Angelo Alessandro , Iacovelli Roberto , Massari Francesco , Morelli Franco , Procopio Giuseppe , Ruatta Fiorella , Caffo Orazio ,   CYCLOP Study Group
Published: February 2017

214

Background: Since prostate cancer is usually diagnosed in patients (pts) over age 60, castration-resistant prostate cancer (CRPC) is rarely observed in pts age 60 or younger. Despite the clinical outcomes of these pts are not clearly defined, there is a common feeling of a worse prognosis for pts with CRPC age 60 or younger. The present study is aimed to assess the clinical outcomes of this specific population. Methods: In this multicentric retrospective study, after Ethical Committee approval, we have reviewed the clinical records of all pts younger than 60 with CRPC from participating institutions, treated with docetaxel (DOC), both in clinical trials and in clinical practice. We recorded the pre- and post-DOC clinical history, the DOC treatment details and outcomes. Results: To date we have collected a consecutive series of 128 pts from 24 Italian hospitals. The median age was 57 (range 41 to 60). The median baseline prostate-specific antigen (PSA) was 85 ng/ml (range 1 to 3,020); 87% of the pts had bone metastases while 47%, 10%, and 13% showed nodal, liver and lung metastases, respectively. All but 12 pts received DOC with a 3 week standard schedule, the remaining being treated with a weekly schedule. A PSA reduction greater than 50% was observed in 61% of the pts; among the 86 pts with measurable disease who underwent a radiological re-evaluation at the treatment end, four and 13 pts achieved complete and partial response, respectively (response rate 20%). The main grade 3-4 toxicities were anemia (five pts), neutropenia (18 pts), febrile neutropenia (one pt), fatigue (five pts), peripheral neuropathy (three pts). The median progression-free survival (PFS) and overall survival (OS) were 7 months and 21 months, while the 1 year PFS and OS rates were 17.6% and 74.9%, respectively. Conclusions: Our data seems to not confirm that younger pts with CRPC have a worse prognosis compared to the older pts since their survival outcomes and response rate are similar to those observed in general population of pts wiht CRPC.
A safety study of trebananib (AMG 386) and abiraterone in metastatic castration-resistant prostate cancer.
Authors: Ojemuyiwa Michelle A. , Karzai Fatima H. , Shah Avani Atul , Theoret Marc Robert , Harold Nancy , Chun Guinevere , Couvillon Anna , Apolo Andrea Borghese , Price Douglas K. , Madan Ravi Amrit , Figg William Douglas , Gulley James L. , Dahut William L.
Published: February 2017

218

Background: Trebananib is an angiopoietin1/2 antagonist peptibody. Androgens stimulate expression of VEGF via activation of hypoxia inducible factor-a (HIFa). Androgen deprivation therapy (ADT) is associated with lower HIF1a gene expression in prostate cancer tissue. Dual targeting of the androgen and angiogenic axis represents a potential synergistic anti-angiogenic therapeutic approach in metastatic castration resistant prostate cancer (mCRPC). In this preliminary safety study we hypothesize that trebananib in combination with abiraterone will have a favorable tolerability and efficacy profile. Methods: Patients with mCRPC were treated with abiraterone 1000mg daily and prednisone 5 mg twice daily. Trebananib was administered intravenously every week, in escalating doses from 15mg/kg to 30mg/kg on days 1, 8, 15, and 22 every 28-days. Results: A total of 9 patients were enrolled. Three of nine patients had prior chemotherapy. The median age was 63.8 (63-71yrs). No dose limiting toxicities were observed. The most common grade ≥ 2 toxicities included limb edema (3/9), hyperglycemia (1/9), gastrointestinal (2/9), fatigue (2/9), hypertension (1/9), confusion (1/9), weight gain (1/9) and insomnia (2/9). 5/9 of patients had an overall PSA decline of >30%. 8/9 patients were evaluable for response. Prior chemotherapy patients were on study for 1 and 3 months. No prior chemotherapy patients were treated for 1, 6, 9, 10, 10, and 17 months. Conclusions: Trebananib in combination with abiraterone is well tolerated and displayed an acceptable safety profile in patients with mCRPC. Based on this safety data a randomized phase II study randomizing chemotherapy-naïve mCRPC patients to either abiraterone/prednisone plus AMG 386 at 30mg/kg or abiraterone/prednisone is currently accruing at the NCI. Clinical trial information: NCIT01553188.
Clinical and biologic factors for immune response to sipuleucel-T (SipT) for metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Hepgur Mehmet Faith , Dorff Tanya B. , Brining Lucy , Cai Jie , Pinski Jacek K. , Reed Mary , Luther Michael , Chan Betty , Quinn David I.
Published: February 2017

219

Background: SipT prolongs overall survival of men with asymptomatic or minimally symptomatic mCRPC. Recently, it has been demonstrated that SipT immune parameters correlate with survival. We prospectively collected biological and inflammatory markers as part of an audit to identify possible predictors of immune response in patients (pts) receiving SipT. Methods: Circulating tumor cells (CTC), PSA, prostatic acid phosphatase (PAP), albumin (Alb), hemoglobin (Hb), serum alkaline phosphatase (SAP), LDH, C-reactive protein (CRP) and β2-microglobulin (β2m) were evaluated in reference lab before SipT. Product parameters CD54, CD54 upregulation (UPREG) and total nucleated cells (TNC) were measured by Dendreon. These datasets were analyzed using Spearman coefficients for continuous variables and the Kruskal-Wallis test for categorical variables. Results: 92 pts who received SipT were included. Median age was 69 (48-90). 43% had Gleason 8-9. 42% had ECOG Performance Status (PS) 0, 44% PS 1, and 13% PS 2. 26% had received prior chemotherapy and 18% had used opioids. 84% had bone mets, 42% had lymphadenopathy, 12% had visceral mets. Of clinical factors only PS was inversely correlated with UPREG (p=0.014) and TNC (p= 0.023). Biomarkers which significantly correlated with SipT immune parameters are shown in the Table. Age, location of mets, prior chemotherapy or opioid use did not impact the immune response to SipT Conclusions: Better product parameters correlated with good ECOG PS, lower PSA and SAP, and higher Hgb and Alb, suggesting that SipT induces a greater immune response in men with lower disease burden. The correlation of increased CD54 count with lower CRP, a surrogate for IL-6 activity, warrants investigation. [Table: see text]
Impact of number of lines of therapy following docetaxel (D) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Sonpavde Guru , Bhor Menaka , Hennessy Daniel , Bhowmik Debajyoti , Shen Liji , Schnadig Ian D.
Published: February 2017

223

Background: The impact of number of lines of therapy on outcomes following docetaxel (D) in metastatic castration-resistant prostate cancer (mCRPC) is unclear. We examined outcomes with cabazitaxel (C) and/or abiraterone acetate (A), following D during a period when all three therapies were available. We previously reported that most patients received only two of these three therapies. Among patients who received all three, DCA was administered more commonly and exhibited better overall survival (OS) than DAC after controlling for prognostic factors. Here, we report the impact of number of lines of therapy following D. Methods: A retrospective analysis of the U.S. Oncology network electronic health records (EHR) was conducted of post-D patients with mCRPC who received C and/or A from April 2011 to May 2012. Median OS was analyzed by Kaplan-Meier method. Cox proportional hazard models were used to evaluate impact on OS of number of therapies administered, age, Prostate Cancer Working Group (PCWG2) subtype, Charlson comorbidity index, prostate-specific antigen (PSA), alkaline phosphatase, hemoglobin, narcotic use, and treatment duration. Results: Multivariate analysis showed significantly lower mortality in the three-drug group compared to the two-drug group (HR 0.209 95% CI: 0.092-0.476, p<0.05). 113 patients received three drugs (DCA=77, DAC=36) and 237 received two drugs (DA=183, DC=54). The three-drug cohort was significantly younger than the two-drug group (median age 69 vs. 73). Other significant covariates (p<0.05) for mortality were narcotic use (HR 2.010 [1.240-3.259]), PSA (HR 1.014 [1.001-1.027] and alkaline phosphatase (HR 1.001 [1.000-1.001]. Conclusions: In men with mCRPC receiving C and/or A post-D, patients receiving all three therapies were younger and exhibited significantly better OS after controlling for clinical factors. In those receiving only two therapies, there appeared to be no difference in outcomes for second-line C versus A. Given the favorable impact of receiving all three therapies, more frequent administration of DCA in the three-drug group and better OS for DCA compared to DAC, we hypothesize that DCA may be a more optimal sequence. These results are exploratory and prospective validation is necessary.
Effects of testosterone deficiency or manipulation on prostate cancer.
Authors: Yassin Aksam , Yassin Dany-Jan , Hammerer Peter
Published: February 2017

229

Background: There is controversy over whether testosterone replacement therapy is a risk factor for prostate cancer. Herein, we evaluate whether testosterone deficiency (TD), testosterone replacement therapy (TRT) or 5-alpha reductase inhibitor (5-ARI) therapy affect the risk of prostate cancer. Methods: Data were collected from 224 male patients who had an indication for prostate biopsy: Prostate specific antigen (PSA) greater than 4, PSA-Velocity >=0.75 in a year, hypogonadism with PSA >=1.5, positive digital rectal exam (DRE) and/or positive Transrectal Ultrasonography (TRUS) finding. Each patient was then subjected to a TRUS-guided 10 core prostate biopsy. Results: 25% (3 out of 12) of the patients on TRT were found to have prostate cancer via biopsy and 32.1% (68 out of 212) of patients who did not receive TRT were found to have prostate cancer; insignificant with p = 0.757. Seventeen our of 76 (22.4%) of the patients on 5-ARI treatment were found to have prostate cancer and 36.5% (54 out of 148) of the patients who did not receive 5-ARI were found to have prostate cancer; significant with p = 0.03. There was no significant statistical difference in Gleason grades among patients who were on TRT, no TRT, on 5-ARI and no 5-ARI. Conclusions: Our data suggest that TRT is not associated with increased risk of prevalence or Gleason grade of prostate cancer. 5-ARI therapy is associated with lower prevalence of prostate cancer but with no relationship to Gleason grade.
Triweekly docetaxel versus biweekly docetaxel as a treatment for advanced castration resistant prostate cancer: Quality of life analysis.
Authors: Kellokumpu-Lehtinen Pirkko-Liisa Irmeli , Harmenberg Ulrika , Hervonen Petteri , Joensuu Timo K. , McDermott Raymond S. , Ginman Claes , Luukkaa Marjaana , Nyandoto Paul , Hemminki Akseli , Nilsson Sten , McCaffrey John , Asola Raija , Turpeenniemi Hujanen Taina , Laestadius Fredrik , Tasmuth Tiina , Sandberg Katinka , Keane Maccon M. , Lehtinen Ilari , Luukkaala Tiina , Joensuu Heikki ,   The Prosty Study Group
Published: February 2017

23

Background: Bi-weekly docetaxel (T) with prednisone improved progression free survival and overall survival when compared with the standard tri-weekly T as first-line treatment for advanced castration resistant prostate cancer (CRPC) (Lancet Oncol. 2013;14:117-124). We report here the quality of life (QoL) results of this prospective randomized trial. Methods: Three hundred and forty-six patients were randomly allocated centrally to receive intravenous therapy T of either 75 mg/m² d1 q3 wks (the triweekly arm) or 50 mg/m² d1 and d 14, q4 wks (the biweekly arm) (identifier NCT00255606). Prednisone (10 mg/d) was administered orally in both groups. The baseline patients characteristics were well balanced between the groups with respect to the performance status, mean age (69, range 45 to 87 vs. 68, range 46 to 85), and median serum prostate-specific antigen (PSA) content (109 µg/L, range 11 to 1,230 vs. 116 µg/L, range 12 to 1,870). Quality of life (QoL), the frequency and severity of symptoms including pain were assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) version 4.0 questionnaire. Results: The baseline (QoL) of both treatment groups was compared to QoL after six months of the treatment within each treatment group and between groups. Changes in fatigue, symptoms of pain and nausea, and the overall performance status did not differ between the groups. There were statistically significant differences in overall quality of life values (p=0.010) and discomforting pain values (p=0.028) favoring the bi-weekly treatment arm. Conclusions: Bi-weekly T is better tolerated than the tri-weekly standard T. Following the results from the clinical outcome and the QoL outcome in the PROSTY trial we would recommend the use of bi-weekly docetaxel as first line treatment of CRPC Clinical trial information: NCT00255606.
The natural history of bone metastases in castrate-resistant prostate cancer.
Authors: Pell Robert James , Harland Stephen John
Published: February 2017

239

Background: Previous authorities have commented on the lack of data regarding overall prevalence of Skeletal-Related Events (SREs) in Castrate Resistant Prostate Cancer (CRPC) in patients who have not received therapy for SRE prevention. We describe a cohort of 129 patients followed to death. Methods: 129 patients treated with palliative chemotherapy for CRPC at University College Hospital London between 01/01/2006 and 31/12/2010 had retrospective collection of data concerning date of prostate cancer diagnosis, date of CRPC, date of death, date of bone metastasis development, radiotherapy treatment, pathological fracture, bone surgery, and spinal cord compression up until 01/06/2013. Results: Median age at castrate resistant prostate cancer development was 70 years. Overall median time from prostate cancer diagnosis to establishment of castrate-resistant state was 33 months (range 5-223). Median time from castrate-resistant state to death was 23 months (0-99). Only 9/129 patients failed to develop bone metastases. A total of 162 palliative radiotherapy treatments were given to 74 patients. Only 10 radiotherapy treatments occurred prior to the development of castrate-resistant disease, the remaining 152 all occurred after castrate-resistance occurred. Symptomatic pathological fracture occurred 28 times in 22 (17%) patients. One or more surgical interventions for bone disease were carried out in 23 (18%) patients. 27 (21%) patients were treated for spinal cord compression. In total, 352 skeletal-related events occurred in 89 patients. Conclusions: Important skeletal-related events occurred in 69% of patients with mCRPC. It is possible that incomplete follow-up in clinical trials of agents such as bisphosphonates considerably under estimate the effect of the investigational agent. The frequency of pathological long bone fracture suggests current measures to detect prefracture and intervene are inadequate. [Table: see text]
A multicenter phase I study of cabazitaxel (Cbz), mitoxantrone (Mito), and prednisone (Pred) (CAMP) for chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Aggarwal Rahul Raj , Weinberg Vivian K. , Ryan Charles J. , Harzstark Andrea , Bryce Alan H. , Derleth Christina Louise , Lowe Kimberly , Small Eric Jay
Published: February 2017

243

Background: Cbz/pred extends survival in mCRPC patients (pts) following docetaxel and first-line studies comparing Cbz to docetaxel are ongoing. Mito/pred also has anti-tumor activity in mCRPC and a non-overlapping mechanism of action and toxicity profile with Cbz. A multicenter phase I trial was initiated through the DOD PCCTC to establish the maximally tolerated dose (MTD) of the combination of Cbz, Mito, and Pred. Methods: Chemotherapy (chemo)-naive pts with mCRPC were enrolled in an accelerated titration design. The primary objective was to determine the MTD of CAMP; secondary objectives included assessing PSA and objective response rates and duration of response. Starting dose of Cbz was 25 mg/m2 (the currently approved single-agent dose) and Mito 4 mg/m2, administered on day 1 of a 21-day cycle. Mito was escalated by 2 mg/m2 per dose level. Pred 5 mg BID and pegfilgrastim were administered with each cycle. Results: 9 pts were enrolled (dose level I, N = 1; dose level II, N = 1; dose level III, N = 3; dose level IV N = 4). The median age was 67 (range 55-81) and the median baseline PSA was 82.3 (range 20.4-791.2). There were 2 DLTs observed at dose level IV (Cbz 25 mg/m2 + mito 10 mg/m2), both grade 4 sepsis. The most common grade 3 adverse events were hematologic (neutropenia, n = 5; febrile neutropenia, n = 2, thrombocytopenia, n = 2). 6 of 9 pts remain on study (range 2.2 - 10.5+ months). Maximal PSA declines from baseline > 50% have been observed in 4/7 (57%) evaluable pts to date. 2 of 4 pts with measurable disease have experienced partial responses and a third has had a minor response after 4 cycles of chemo. The median progression-free survival and duration of response have not been reached. Conclusions: The approved single-agent dosage of Mito (12 mg/m2) could not be safely reached in combination with Cbz 25 mg/m2. Pre-planned evaluation of an alternate dosing strategy combining Mito with Cbz 20 mg/m2, which has demonstrated activity in mCRPC and potentially less hematologic toxicity, is underway. Preliminary efficacy data are encouraging but additional follow-up and further study of the treatment combination is required. Clinical trial information: NCT01594918.
Increase in bone scan index during abiraterone treatment in relation to reduced survival in mCRPC patients.
Authors: Reza Mariana , Bjartell Anders , Ohlsson Mattias , Edenbrandt Lars , Tragardh Elin
Published: February 2017

244

Background: Abiraterone acetate (AA) is one of several new treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC). It has showed to prolong survival in patients who had disease progression after chemotherapy. An objective biomarker that is associated with improvement in survival would be of value in the management of patients under AA treatment, for example in decisions to continue or change treatment. Bone Scan Index (BSI) is a measurement that reflects the tumor burden in bone as a percent of the total skeletal mass. The purpose of this study was to evaluate BSI as a response biomarker in mCRPC patients on treatment with AA. Methods: We retrospectively studied a consecutive series of 28 mCRPC patients who received AA following disease progression after chemotherapy. All patients had undergone whole-body bone scan before and during AA treatment. Baseline and follow-up BSI data was obtained using the automated quantification software EXINI Bonebsi(EXINI Diagnostics AB, Sweden). Data on prostate-specific antigen (PSA) and survival were collected from the medical records. Cox proportional-hazards regression models and Kaplan-Meier estimates of the survival function were used to investigate the association between changes in BSI and PSA from baseline to follow-up and survival. Discrimination between prognostic variables was assessed using the concordance index (C-index). Results: Patients with an increase in BSI of at least 0.2 (n=15) had a worse one-year survival (36%) than those with improvement or stable disease (BSI change <0.2) (96%) (p< 0.006). Both follow-up BSI and the BSI change from baseline to follow-up showed higher C-index (0.80) than the corresponding PSA values (0.73 and 0.75). Conclusions: Increase in BSI is significantly associated with reduced survival in mCRPC patients under AA treatment following disease progression after chemotherapy. Calculation of BSI could be a valuable tool for treatment response evaluation as a complement to the traditional methods. [Table: see text]
Prospective phase I/II trial of dose-painting prostate brachytherapy guided by cancer-specific ultrasound-based tissue-type imaging (TTI).
Authors: Ennis Ronald D. , Trichter Frieda , Saigal Kunal , Quinn Stuart A. , Feleppa Ernest J.
Published: February 2017

246

Background: Standard treatments treat the entire prostate gland uniformly, while focal treatments target only the dominant tumor. We propose an alternative approach wherein tumor areas are treated with an escalated dose of radiation while the remainder of the prostate with dose de-escalation. Tissue-type images (TTIs), which identify intraprostatic tumors via ultrasound spectral analysis, were used to identify tumors. Methods: 14 low risk patients were enrolled. TTIs and standard B-mode ultrasound images were generated and fused intraoperatively. Based on TTIs, plans were developed to deliver 200% prescription dose to the tumors and 100% to the prostate. Doses above 100% to non-tumor regions were minimized and standard normal tissue constraints were respected. Results: 12 patients were successfully treated. Technical problems occurred in the first patient and another received a standard implant due to discordance of TTIs with MRI and biopsy findings. One patient passed away soon after the procedure of unrelated cause. A total of 28 tumors were identified in these 12 patients (median 2 tumors/patient, range 1-4). Mean tumor volume was 0.72cc (range 0.03cc -4.07cc). Tumor dose was significantly higher in TTI-based plans, with mean tumor V200%: TTI vs. standard 97% vs. 48%, p<0.05. Modest dose reduction of the whole prostate was also achieved. Median follow-up was 25.7 months (range 21.3-48 months). A low incidence of grade 2 toxicities and no grade 3-4 toxicities were seen (Table). Two patients experienced a biochemical failure per the nadir+2 definition, both failures are attributable to PSA bounce (PSA down to 1.0 and 0.59 at 42 and 30 mos., respectively). Post-treatment biopsies have been performed on 5/11 patients (4 refused), with 2 patients with pending biopsies. 4/5 available biopsies are negative, with 1 patient having a small focus of residual cancer. Conclusions: Dose-painting prostate brachytherapy is technically feasible. This tumor-directed approach, more rational than uniform whole gland treatments, offers the promise of excellent cancer control, low toxicity and low risk of re-treatment. Clinical trial information: NCT01227642. [Table: see text]
The difference in implantation quality between loose seed and variable spacing strand seeds in the field of prostate brachytherapy.
Authors: Grégoire Pigné , Grégoire Pigné , Ronan Tanguy , Julien Ribouton , Ruffion Alain , Chapet Olivier
Published: February 2017

252

Background: Concordance between intraoperative and postoperative dosimetry is a well-known marker of implant quality in prostate brachytherapy. The aim of the study was to evaluate if the use of variable distance strand seeds allows an improvement in the quality of the post implantation dosimetry. Methods: Before December 2010, an iodine 125 loose-seed technique was used for prostate brachytherapy. Since this date, patients have been treated with new variable distance strand seeds (ProLink; Bard). Post implant dosimetry was compared to intraoperative dosimetry in 30 patients treated with loose seeds and 29 patients treated with strand seeds. The prescribed dose was 145Gy. Variations of dosimetric parameters were used to set the two techniques against one another: prostate V100 and D90 and rectum V145 and V160. Results: There was a significant difference between intraoperative and postoperative V100 and D90 for all 59 patients: V100 preop-postop: mean 6,65% +/- SD 4,5; D90 preop-postop: 18,73Gy +/- SD 15 (p<0,0001). This dosimetric difference between pre and post-operative dosimetry is more important using loose seeds brachytherapy: V100 preop-postop: 9,5% +/- SD 4,1 vs 3,7% +/- SD 2,7 for loose seeds and strand seeds respectively (p<0,0001), and D90 preop-postop: 27,9Gy +/-SD 13,6 vs 9,2Gy +/- SD 9,7 for loose seeds and strand seeds respectively (p<0,0001). For V145 rectum and V160 rectum, dosimetric difference wasn't significant: V145 rectum preop-postop: -0,9% +/- SD 1,4 with stranded seeds vs. -1,6% +/- SD 2,1 with loose seeds (p=0,14) and V160 rectum pre-postop: -0,5% +/- SD 0,8 with strand seeds vs. -0,5% +/- SD 0,8 with loose seeds (p=0,16). Conclusions: Stranded seeds implantation increases the quality of implantation by reducing the dosimetric difference (V100 and D90) between intra and post-operative dosimetry to a maximum of 6% and 7% vs. more than 20% with loose seed implantation. Moreover, this technique doesn’t seem to modify the risk of rectal toxicity. This achievement in implantation and dosimetric quality might lead to a gain in clinical results.
Safety and clinical outcome of a cohort of patients (pts) with castration resistant prostate cancer (CRPC) treated with abiraterone acetate (AA) in a named patient program (NPP): Updated results of a retrospective study from an Italian cooperative group.
Authors: Caffo Orazio , Fratino Lucia , Lo Re Giovanni , Basso Umberto , D'Angelo Alessandro , Donini Maddalena , Santini Daniele , Procopio Giuseppe , Massari Francesco , Gasparro Donatello , Verderame Francesco , Sacco Cosimo , Messina Caterina , Iacovelli Roberto , Zustovich Fable , Vicario Giovanni , Fraccon Anna Paola , Conteduca Vincenza , Maines Francesca , De Giorgi Ugo
Published: February 2017

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Background: Abiraterone acetate (AA) provided a survival advantage compared to placebo in patients (pts) with castration resistant prostate cancer (CRPC) who had received docetaxel (de Bono JS et al, NEJM 2011). The present retrospective study is aimed to assess safety and clinical outcome in an unselected CRPC population which received AA in a named patient program (NPP). Methods: We retrospectively reviewed the clinical records of all pts treated with AA for CRPC by NPP in our institutions. All pts have been previously treated with a docetaxel-based first-line chemotherapy and received the standard AA dose of 1,000 mg daily plus prednisone 10 mg daily. For each pt we recorded the pre- and post-AA clinical history, the AA treatment details toxicities and clinical outcomes. Results: To date we have collected a consecutive series of 245 pts from 18 Italian hospitals. The median age was 73 (range 45 to 91). The median baseline prostate-specific antigen (PSA) level was 100 ng/ml (range 0.33->100.000); 79% of the pts had bone metastases, while nodal, lung and liver metastases were observed in 52%, 9%, and 7% of the pts, respectively. The median duration of AA treatment was 5 months (range, 1 to 26). Grade 3 to 4 toxicities were anemia (11 pts), fatigue (nine pts), bone pain (four pts), constipation (two pts), thrombocytopenia (two pts), nausea (one pt), diarrhea (one pt), dyspnea (one pt), edema (one pt), hypertension (one pt), hyperbilirubinemia (one pt), and hypokaliemia (one pt). A PSA reduction of more than 50% was observed in 50.9% of the pts. The median progression-free survival (PFS) and overall survival (OS) were 6 months and 15 months, respectively; the 1 year PFS and OS rates were 24.3% and 56.9%, respectively. Conclusions: Our results have confirmed the safety and efficacy of AA in an unselected population of pts with pre-treated CRPC outside clinical trials and provided further support concerning the good safety profile of the drug.
Characteristics and outcome of octogenarian versus young patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) treated with ketoconazole.
Authors: Sinibaldi Victoria J. , Dadon-Nachum Michal , Gottfried Maya , Maimon Natalie , Dovrish Zamir , Peer Avivit , Neumann Avivit , Sella Avishay , Kovel Svetlana , Carducci Michael Anthony , Eisenberger Mario A. , Kejzman Daniel
Published: February 2017

256

Background: Standard treatment options for patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) include docetaxel based chemotherapy, abiraterone, and radium 223. Octogenarian pts (age 80 and older) are often considered to be unfit for chemotherapy. However, recommendations for their management is limited by the paucity of clinical trials data in this population. In countries where abiraterone in the pre-chemotherapy setting has not been approved yet, or for pts who can’t afford it, the CYP 17 inhibitor ketoconazole is used as an alternative advanced hormonal tx. We aimed to study baseline characteristics and outcome of octogenarian versus young (age 60 or younger) pts with mCRPC treated with ketoconazole. Methods: We performed an international multicenter retrospective study of pts with mCRPC, who were treated with ketoconazole at four centers across two different countries. We compared baseline characteristics and outcome of octogenarian versus young pts. The effect of very old age on prostate-specific antigen (PSA) response, progression free survival (PFS), and overall survival (OS), was tested with adjustment of other known confounding risk factors using a chi-square test and partial likelihood test from Cox model. Results: Between 2004 and 2013, 35 octogenarians (median age 83) and 33 young pts with (median age 57) mCRPC were treated with ketoconazole. The groups were balanced regarding the following baseline clinicopathologic characteristics: extent of disease (limited-axial skeleton and/or nodal versus extensive-appendicular skeleton and/or visceral), combined gleason score, pre-treatment risk category (Keizman, Oncologist 2012; based on pre-tx neutrophil to lymphocyte ratio/prostate-specific antigen doubling time, and prior response to ADT), pain intensity, ECOG performance status, alkaline phosphatase level, hemoglobin level, PSA level. In octogenarian versus young pts, PSA response (greater than or equal to 50% decline from baseline) was 40% versus 61% (OR 3.5, p=0.04), median PFS 7 versus 8 months (HR 0.91, p=0.44), and median OS 31 versus 36 months (HR 0.66, p=0.31). Conclusions: In very old vs young mCRPC patients treated with ketoconazole, PSA response was lower. Baseline clinicopathologic characteristics, PFS, and OS were not significantly different between the groups.
Efficacy of new agents on advanced castration-refractory prostate cancer with RAPID progression.
Authors: Wu Shenhong
Published: February 2017

257

Background: Five new agents with diverse mechanisms of action have been shown to improve overall survival for patients with advanced castration-refractory prostate cancer (CRPC). Because of a heterogeneity in cancer growth and proliferation, it is not clear whether these agents are effective in patients with rapid progressive disease. Therefore, we conducted a systematic review and meta-analysis of published randomized controlled clinical trials (RCTs) to assess the effect of these new agents on three month progression and mortality. Methods: Databases from PUBMED, the Web of Science, and abstracts presented at the American Society of Clinical Oncology (ASCO) conferences until June, 2013 were searched to identify relevant studies. Early progression was defined as progressive disease or death at three months after the initiation of clinical trial. Eligible studies included prospective RCTs in which a new agent was compared to a control in metastatic CRPC patients. Summary incidences of three month progression or mortality, relative risk (RR), and 95% confidence interval (CI) were calculated based on the heterogeneity of included studies. Results: A total of 5,895 patients (new agents: 3,623, control: 2,272) with CRPC from seven RCTs were included for analysis. The new therapy significantly reduced the risk of mortality in the overall patient population (HR=0.69, 95% CI: 0.64-0.74) without significant variation among different agents (P=0.82). The new therapy also reduced the risk of three month mortality (RR=0.76, 95% CI: 0.60-0.97, P=0.027). However, significant risk reduction was only seen for enzalutamide (RR=0.54, 95% CI: 0.31-0.94; P=0.03). In addition, the new therapy reduced the risk of three month progression (RR=0.61, 95% CI: 0.46-0.81, P=0.001). The risk varied among these agents (P<0.001), with significant risk reduction seen for enzalutamide (RR=0.47, 95% CI: 0.21-0.54), abiraterone (RR=0.57, 95%CI: 0.35-0.97), and cabazitaxel (RR=0.80, 95% CI: 0.72-0.89), but not for Sipuleucel-T (RR=1.10, 95% CI: 0.21-5.76). Conclusions: The new agents may have a differential impact on the outcome of CRPC with rapid progression.