bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cabazitaxel plus cisplatin coadministration and drug-interaction study in patients with advanced solid tumors.
Authors: Mita Alain C. , Sundaram Shankar , Sarantopoulos John , Mita Monica M. , Lane Alex R. , Moseley Jennifer L. , Mahalingam Devalingam , Tan Benjamin R. , Dedieu Jean-Francois , Stash Diane , Zhi Xin , Mazuir Florent , Lockhart Albert C. 
Published: March 2020

e15116 Background: Cabazitaxel (Cbz) is a novel taxane with in vivo efficacy in taxane-sensitive and -resistant tumors. Therapeutic synergism of Cbz/cisplatin (Cis) has been shown in tumor-bearing mice. Since Cbz is primarily metabolized by CYP3A, drug interactions may occur with modulators of CYP3A. Methods: The primary objective of part 1 of this phase I study (NCT00925743) was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz/Cis. Secondary objectives included safety, pharmacokinetics (PK) and efficacy. The objective of part 2 was to assess efficacy at the MTD. The effect of the antiemetic aprepitant (a moderate CYP3A inhibitor) on the PK of Cbz was also examined. Eligible patients (pts) had ECOG PS ≤ 1 and confirmed metastatic or unresectable solid tumors for which Cis therapy was considered appropriate. A 3 + 3 dose escalation at a starting dose (level 0) of 20/75 mg/m2 (Cbz/Cis), administered IV Q3W, was used. The MTD was the highest dose at which 0/3 or ≤ 1/6 pts experienced a DLT in Cycle 1. Results: Pts (n = 25; 10 in part 1; 15 in part 2) with a median age of 56 yrs were enrolled. The most frequent primary tumors were lung (n = 4), prostate, ovary and pancreas (each n = 2). Of 6 evaluable pts, 2 had a DLT at dose level 0 (Grade 3 acute renal failure; febrile neutropenia). The MTD was 15/75 mg/m2 as no DLTs were observed; 18 pts were treated at the MTD and 60 cycles were administered (median = 3; range 1–8). The most frequent non-hematologic treatment-related adverse events (all grades/grade 3–4) were nausea (78%/22%), vomiting (72%/11%), fatigue (61%/17%), anorexia (67%/11%) and diarrhea (44%/0%). Incidence of grade 3–4 neutropenia was 78%; 1 pt had febrile neutropenia. The combined PK profile of Cbz/Cis did not appear to differ vs those of the single agents. The ratio of Cbz clearance with vs without aprepitant co-administration was 0.81 (90% CI 0.36–1.85). Stable disease was seen in 11 pts; 1 pt (prostate carcinoma) had an unconfirmed partial response. Conclusions: The MTD of Cbz/Cis was 15/75 mg/m2. The combination had a manageable safety profile consistent with a platinum/taxane combination. No PK interactions between Cis and Cbz were seen; aprepitant did not appear to alter the PK of Cbz.
Racial differences in prostate cancer incidence and mortality.
Authors: Bjurlin Marc , Guinan Patrick , Christensen Kevin , Rubenstein Marvin 
Published: March 2020

e15119 Background: Prostate cancer is the second leading cause of male cancer deaths in the U.S. There are significant racial differences in prostate cancer incidence and mortality. Methods: The SEER Database for 2008 was analysed for designated areas: Connecticut, Detroit, and Hawaii, assuming that these areas are surrogates for whites, blacks, and Asians, respectively. Results: Incidence and mortality (see Table). Conclusions: Assuming that the geographic SEER areas (Conn, Det, Ha) are surrogates for whites, blacks, and Oriental populations, we conclude that the incidence and mortality rates for blacks are higher than those for whites and Orientals. [Table: see text]
Impact of salvage therapy with APC8015F on the overall survival (OS) benefit achieved with sipuleucel-T in three phase III studies of metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Gomella Leonard G. , Nabhan Chadi , DeVries Todd , Whitmore James Boyd , Frohlich Mark Walter , George Daniel J. 
Published: March 2020

e15120 Background: Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic or minimally symptomatic mCRPC. Three phase III sipuleucel-T trials (D9901, D9902A and D9902B [IMPACT]) allowed control patients (pts) to receive salvage treatment with an autologous product derived from previously frozen cells (APC8015F). We previously reported that salvage therapy with APC8015F demonstrated no deleterious effect and may have improved outcomes in control pts, potentially reducing the observed survival benefit seen with sipuleucel-T. Thus, we performed an exploratory analysis of pooled data from phase III studies to estimate the impact of APC8015F treatment on the OS benefit conferred by sipuleucel-T. Methods: We analyzed the effect of salvage APC8015F therapy on OS, and used a rank-preserving structural failure time (RPSFT) model to estimate control arm OS if treatment with APC8015F had not occurred. This allows estimation of the effect of sipuleucel-T treatment on OS, adjusting for salvage effect. Results: Median OS from randomization in the three pooled trials was 25.4 months with sipuleucel-T (n=488) and 21.5 months with control (n=249). Of the control arm pts, 165 (66.3%) subsequently received APC8015F. Median OS from randomization in the control population was 23.6 months for pts receiving APC8015F and 12.7 months for those who did not. Using the RPSFT model, and assuming APC8015F was as effective as sipuleucel-T, the estimate of median OS for control pts was 17.3 months, representing an 8.1 month median increase in OS with sipuleucel-T. Results from extensions of the RPSFT model, where APC8015F is assumed to have less treatment effect than sipuleucel-T, will be presented. Conclusions: These analyses estimated a median OS benefit for sipuleucel-T between 3.9 and 8.1 months, assuming that APC8015F had either no efficacy or comparable efficacy to sipuleucel-T, respectively. The results suggest a possible greater treatment effect of sipuleucel-T than was reported in the three phase III studies. Future studies should account for potential crossover treatment bias as this may diminish estimates of OS benefit.
Venous thromboembolism in prostate cancer patients treated with robot-assisted radical prostatectomy and pelvic lymph nodes dissection.
Authors: Hamdan Shadi E. , Kozyreva Olga N. , Tuerk Ingolf , Gupta Shachi 
Published: March 2020

e15123 Background: Cancer and cancer treatment increases the risk of venous thromboembolism (VTE). Pelvic lymph nodes dissection (PLND) during radical prostatectomy increases the risk of VTE. Robot-assisted radical prostatectomy (RARP) is becoming increasingly popular, yet VTE data are not well reported. The aim of the study is to assess the rate of VTE in prostate cancer patients who underwent RARP with and without PLND. Methods: The records of 768 patients who underwent RARP by a single surgeon from 2008-2011 were reviewed for postoperative venous thromboembolism. Patient demographics, Gleason score, clinical stage, PSA, surgical approach and other operative variables were collected by prospective prostate cancer database. Information obtained from patient visit 6-8 weeks after the surgery was included in the database. VTE diagnosis was retrieved from inpatient and outpatient medical records. Fisher's exact test was used to determine the association between RARP with PLND and the occurrence of postoperative VTE. Results: Of the 768 patients who underwent RARP (mean age was 59.8 years, range: 40-77 years), 419 (54%) underwent PLND. Compared to patients who underwent RARP alone, patients who underwent RARP with PLND had higher PSA (mean PSA 7.3 vs. 5.3 p=0.0002), rate of Gleason score ≥ 7 (82% vs. 13% p=<0.0001) and more advanced tumor stage pT3 (39% vs. 12% p=<0.0001). Venous thromboembolism occurred in 5 of 419 (1.2%) patients who underwent RARP with PLND, and in 1 of 349 (0.28%) patients who underwent RARP (p=0.22). The lymph node metastasis rate was 7%. Conclusions: The incidence of VTE in prostate cancer patients treated with RARP is low. PLNDis not associated with a significantly increased risk of venous thromboembolism as compared to RARP alone.
Correlation of circulating tumor cells (CTCs) and clinical biomarker endpoints in metastatic prostate cancer patients.
Authors: Amato Robert J. , Melnikova Vladislava O. , Zhang Yujian , Liu Wen , Wang Yuan , Shah Parth K. , Jensen Brett T , Torres Karen E. , Davis Darren W. 
Published: March 2020

e15124 Background: Circulating tumor cells (CTCs) are found in human blood when cancers undergo metastatic dissemination, and CTCs have been reported as a surrogate marker for tumor response and linked to shorter survival in metastatic prostate cancer patients. This study assessed the use of CTCs as a continuous factor for clinical monitoring of prostate cancers patient in real time and evaluated the association between baseline CTC number, various clinical characteristics, and survival. Methods: CTCs were enumerated using the CellSearch FDA cleared CTC kit in 206 patients with metastatic prostate cancer. Variables including metastatic site, PSA, Gleason score, level of testosterone and androgen treatment were tested for association with CTC number. The probability of patient survival over time was estimated by the Kaplan-Meier method. Results: Baseline CTC numbers were strongly associated with survival (p<0.0001), with overall survival being significantly poorer in patients with ≥5 CTCs. Significantly higher CTC numbers were observed in patients with bone metastasis (mean=41.1 CTCs) compared to those with lymph node metastasis (mean=2.5 CTC, p=0.026). Analysis of the association between CTC counts and PSA level revealed a weak positive correlation between CTC number and PSA (Correlation coefficient r=0.269, Significance level p<0.001). CTC number further correlated with the Gleason score (p=0.009) and lower testosterone levels (p<0.0001). Patients with no androgen depletion had significantly lower numbers of CTCs (median=3.94) compared to those with androgen depletion (median=406, p<0.001). Conclusions: Baseline CTCs are predictive of patient survival and are significantly correlated with clinical characteristics in prostate cancer patients.Our study confirms previous findings that support the use of CTC levels as a prognostic biomarker for prostate cancer patients.
Effects of 6 months of abiraterone acetate (AA) on muscle and adipose mass in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Brondfield Samuel Craig , Weinberg Vivian K. , Koepfgen Kathryn M. , Molina Arturo , Ryan Charles J. , Small Eric Jay , Harzstark Andrea Lynne 
Published: March 2020

e15137 Background: AA, an inhibitor of androgen biosynthesis, has been shown to prolong overall survival in patients with mCRPC who have previously been treated with chemotherapy. ADT has been shown to result in muscle wasting in prostate cancer patients. The effects of AA on progression of muscle and fat wasting have not been characterized. We evaluated whether 6 months of AA therapy altered total skeletal muscle mass or adipose mass. Methods: 10 sequential patients who responded to AA therapy for at least 6 months and had available computed tomography (CT) scans were retrospectively selected from the phase I-II COU-AA-002 study. CT image analysis was used to quantify change from baseline in total skeletal muscle and adipose tissue after 6 months of AA treatment. Skeletal muscle and adipose tissue cross-sectional area were calculated at the L3 level using Slice-O-Matic software V4.3. Previously published regression models were used to estimate fat-free mass, fat mass and skeletal muscle mass. Paired t-tests were performed to determine the change in measurements. Results: At baseline, 7 of 10 patients were overweight or obese (body mass index [BMI] > 25 kg/m2), and none were underweight. Advanced muscle wasting (sarcopenia, previously defined as the ratio of skeletal muscle cross-sectional area at L3 level to height < 52.4 cm2/m2) was present at baseline and 6 months in 9 of 10 pts. Over 6 months of AA treatment, patients lost an average of 1.9 kg ± 3.6 kg (p = 0.13). Mean changes (kg) (±standard deviation) in total skeletal muscle mass (-0.80 ± 1.71, p = 0.18) and total non-adipose mass (-1.44 ± 3.09, p = 0.17) were not significant. A significant decrease in total adipose mass (-0.61 ± 0.84, p = 0.048) was observed. Conclusions: Sarcopenia is prevalent in patients with mCRPC. AA was not related to significantly worsening sarcopenia or overall weight loss during the first 6 months of treatment; however, this may reflect a relatively short duration of therapy and/or small sample size. A significant loss of adipose tissue was observed, which is unexpected given the known effects of ADT, which increases adipose mass. Evaluation of additional AA treated patients is ongoing.
Progression of castrate-resistant (CR) disease in nonmetastatic (M0) prostate cancer (PC) patients: A retrospective cohort study using data from the Henry Ford Health System (HFHS).
Authors: Beebe-Dimmer Jennifer , Cetin Karynsa , Yee Cecilia , Lamerato Lois , Stryker Scott , Liede Alexander , Schwartz Kendra L. , Shahinian Vahakn B. 
Published: March 2020

e15147 Background: Androgen deprivation therapy (ADT) is the cornerstone treatment of advanced PC, but is frequently used in the M0 setting. After a variable period of hormone-sensitivity, most patients develop CR disease (rising prostate-specific antigen [PSA] despite ongoing ADT). These men are at increased risk of developing bone metastases (BMT), particularly in those with higher serum PSA and shorter PSA doubling time (DT). The epidemiology and natural history of M0 CRPC has not been well-studied in a population-based setting. Methods: A retrospective cohort study was conducted using HFHS administrative data and included 691 men diagnosed with M0 PC between 1996 and 2005, who received ADT, with serial PSA measurements to determine CR. Patient records through 12/31/2008 were reviewed for outcomes of interest. CRPC was defined as 2 consecutive PSA rises, with “high risk” defined as PSA ≥8 ng/mL or PSA DT ≤10 months (mos) after the development of CRPC (Smith MR et al. Lancet 379:39-46, 2012). The risk of BMT was estimated for the entire cohort and for the CRPC and high-risk CRPC subsets. Results: Of the 691 patients included in the cohort (median age: 73 years, 48% African American), 98% received only GnRH agonists and 2% had orchiectomy. Median follow-up for the entire cohort after ADT initiation was 49 mos (IQR=45). 101 patients (15%) met criteria for CRPC during follow-up, with a median of 18 mos on active ADT prior to CRPC development (IQR=14). Of CRPC patients, 85% met criteria for high-risk (of those, 16% had PSA ≥8 ng/mL, 12% had PSA DT ≤10 mos, and 72% had both). Among all patients, 12% (n=82) developed BMT during follow-up, with 42% (n=36) of the high-risk CRPC subset developing BMT. Median time from high-risk CRPC to BMT was 9 mos (IQR=17). Conclusions: The HFHS resource allowed for our investigation of PSA characteristics corresponding to disease progression in a racially diverse patient population. A substantial proportion of M0 PC patients on ADT will eventually develop CR disease. Once a patient has CRPC, the risk of BMT is relatively high.
Therapeutic options in metastatic castration-resistant prostate cancer (mCRPC): A cost-effectiveness analysis.
Authors: Zhong Lixian , Srinivas Sandy , Pon Vickie , Nguyen Nicole , Frear Meghan , Kwan Sherry , Gong Cynthia , Malmstrom Robert , Loucks Aimee , Wilson Leslie 
Published: March 2020

e15154 Background: Initial therapy for metastatic prostate cancer is androgen deprivation therapy. Uniformly progression of disease occurs despite castration. Docetaxel is then the standard of care. Abiraterone (Abi) and cabazitaxel (Cab) are approved for mCRPC post docetaxel with improvements in survival We seek to evaluate the cost-effectiveness of Abi and Cab compared to mitoxantrone (Mit) and prednisone for mCRPC. Methods: A decision tree model was constructed comparing four treatments for mCRPC patients over an 18 month period: 1) Abi, 2) Cab, 3) Mit, and 4) prednisone only. Chance nodes included baseline pain as a severity indicator, grade III & IV adverse events (AE) (neutropenia and cardiac ) and survival at 18mos. Survival rates and probabilities were from published data. Cost of drug regimens were based on 2010 US dollars and average wholesale price (AWP). Model cost inputs included drug-costs, administration costs, management of AE’s, radiation for pain, and costs associated with death. Health utilities for baseline pain, bone pain, neutropenia, cardiac events, and radiation were obtained from published data. Sensitivity analyses were conducted focused on baseline severity and costs of drug. Results: Base case estimates suggest that Cab and Abi are most effective. The incremental cost effectiveness ratio (ICER) for Mit vs. placebo is $110K/QALY, Abi vs. Mit is $76K/QALY and for Cab vs. Abi, the ICER is $925K/QALY. Model-sensitive parameters include Abi AWP and cost of Mit side effect management; Abi becomes less cost-effective as its AWP increases, or if the cost of Mit side effect management decreases. When baseline severity increases, Mit becomes cost-effective over placebo and Abi remains cost-effective over Mit. Cab remains not cost-effective at tolerable thresholds. Conclusions: Compared to Cab, Mit, and placebo, Abi is the most cost-effective option in docetaxel-refractory mCRPC patients due to its ability to prolong survival and maintain a willingness-to-pay threshold (WTP) of $100K. Despite higher survival with Cab, it is not cost-effective because of costs associated with treatment of neutropenia. In situations where illness is more severe, Abi remains the cost-effective choice.
Histone deacetylase inhibitor (HDACi) LBH589 interference with androgen receptor expression transcriptional activity in prostate cancer cells.
Authors: Thelen Paul , Ringert Rolf-Hermann , Strauß Arne 
Published: March 2020

e15156 Background: Development of incurable castration resistant prostate cancer (CRPC) is intrinsically tied to androgen receptor (AR) deregulation. Our previous research demonstrated that the estrogen receptor-β regulates AR transcriptional activity when relieved from epigenetic repression by HDACi treatments. Here we investigated the HDACi LBH589 established clinically in cancer treatments for its therapeutic function in CRPC. Methods: LBH589 (obtained from Novartis, Switzerland) was used (1 through 100µM) to treat representative CRPC-cell models i.e. LNCaP with an AR mutation and VCaP featuring AR overexpression. We investigated tumor cell proliferation with a BrdU-test and investigated AR including AR splice variants, PSA, PCA3,TMPRSS2-ERG, IGF-axis genes and ERβ expression by real-time RT-PCR, ELISA and Western blots. Results: LBH589 treatment even at low concentrations of 1µM reduced excessively AR expression in LNCaP and diminished even overexpressed AR to moderate levels in VCaP. Accordingly, tumor cell proliferation and the expression of androgen regulated genes PSA, PCA-3 and TMPRSS2-ERG (in VCaP) decreased. Furthermore, the expression of IGF-1 receptor and IGF-1 was reduced. Whereas, the expression of pro-apoptotic, anti-proliferative IGFBP-3 and the expression of tumor suppressor ERβ were increased, even at highest LBH589 concentrations. Conclusions: The main target in CRPC therapy is the AR equipped with resurgent activity by gain of function and overexpression. HDACi treatments with LBH 589 while restoring ERβ expression directly intervenes with this AR surge resulting in reduced tumor cell proliferation and tumor cells adopt a less malignant phenotype. Such measures in the core of CRPC deregulations alone or in combination with further anti-androgen treatments might reduce the potential of escape mechanisms of CRPC-tumors in future therapy approaches.
Antitumor effects of zoledronic acid in combination with histone deacetylase inhibitor valproic acid.
Authors: Strauß Arne , Loertzer Hagen , Ringert Rolf-Hermann , Thelen Paul 
Published: March 2020

e15158 Background: The established utilisation of bisphosphonates is the treatment of metastatic bone disease derived from several tumor types including prostate (PCa) and breast cancer. However, recently preclinical as well as clinical evidence support anti-tumor activities of these drugs in their own right. To probe into the molecular basis of such observations we treated PCa bone metastasis derived cell lines (VCaP, PC-3) and breast cancer cells (MCF-7) with zoledronic acid (ZA) and ZA in combination with valproic acid (VPA). HDAC-Inhibitor VPA according to our previous findings rectifies aberrant androgen receptor signalling and thus, implies an anti-androgen element in these treatments. Methods: PCa cells (VCaP, PC-3) and breast cancer cells (MCF-7) were treated with ZA (Zometa, Novartis) at 0, 5, 25 or 100µM or same ZA concentrations in combination with VPA (5mM). Tumor cell viability and proliferation were analysed by AlamarBlue- and BrdU-tests. Gene expression and PSA secretion was quantitated by real time RT-PCR and was further assessed with ELISA-kits, respectively. Results: In all cell types ZA has no impact on tumor cell viability or proliferation of its own exceeding the effects of VPA alone. Likewise, PSA secretion in VCaP cells is not further diminished in the combined ZA/VPA treatments. However, among a marked impact on cancer relevant gene expression protective elements such as vitamin D- and β-estrogen-receptor are up-regulated by ZA alone and in excess by the combined treatment. Other genes associated with protective features such as IGFBP-3, SOCS-3 and Se-BP-3 are up-regulated only by the ZA/VPA combination. Conclusions: We present molecular evidence for anti-tumor effects of zoledronic acid. Our data suggest the necessity of a concomitant anti-androgen treatment for maximal benefit. The genes addressed by such treatments are more associated with cancer prevention than immediate androgen signalling targets. Therefore, the main anti-tumor potential of ZA may emerge from an early onset of combined therapies to prevent bone metastases.
Testosterone levels as a prognostic factor for survival in patients with castrate-restistant prostate cancer (CRPC).
Authors: Gomez de Liaño Alfonso , Maroto José Pablo , Martin Lorente Cristina , Cillan Elena , Macias Ismael , Stradella Agostina , Sullivan Ivana , Murata Paola , Arqueros Cristina , Anguera Georgia , Condori Dhiossett , Barnadas Agust 
Published: March 2020

e15159 Background: To analyze the prognostic value for survival of the absolute levels of serum testosterone in patients under the definition of CRPC (PSA and/or clinical progression with a testosterone level below 50 ng/dL). Methods: 49 patients were included in 4 non-hormonal first line phase II-III trials in our institution since August 2006 until Jan 2012 for metastatic CRPC. Inclusion criteria of those trials uniformly required castrate levels of testosterone. Survival was calculated since the date of entrance in the trial. Results: Median age was 71 years (53-89). 9/49 (18%) of the patients had visceral metastases. Median PSA was 66.7 U/L (0.1-936). Median testosterone level was 11.54 ng/dL (range 0.2-49.9). All patients had metastatic prostate cancer, previous treatment consisted of at least 2 hormonal maneuvers (adding or stopping antiandrogen for a wash-up period of 42 days for bicalutamide). All patients received at least one line of chemotherapy for CRPC as part of the trial or after the completion of the trial. Median survival was 21.85 months. For 26 patients with a serum testosterone level below the median value, median survival was 17 months and 35.45 months for those patients with a testosterone level over 11.51 ng/dL (p value 0.036). Conclusions: Testosterone serum levels even under castration level (below 50 ng/dL) were a prognostic factor for survival in patients with metastatic prostate cancer considered castration resistant.