bluuebunny/crossref_metadata_2025_split huggingface dataset:
REGARD: A phase III, randomized, double-blinded trial of ramucirumab and best supportive care (BSC) versus placebo and BSC in the treatment of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing combination therapy.
Authors: Fuchs Charles S. , Tomasek Jiri , Cho Jae Yong , Dumitru Filip , Passalacqua Rodolfo , Goswami Chanchal , Safran Howard , dos Santos Lucas Vieira , Aprile Giuseppe , Ferry David R. , Melichar Bohuslav , Tehfe Mustapha , Topuzov Eldar , Tabernero Josep , Zalcberg John Raymond , Chau Ian , Koshiji Minori , Hsu Yanzhi , Schwartz Jonathan D. , Ajani Jaffer A. 
Published: February 2017

LBA5 Background: VEGF and VEGF receptor-2 mediated signaling and angiogenesis may contribute to gastric cancer pathogenesis. Ramucirumab (RAM; IMC-1121B) is a fully human IgG1 monoclonal antibody targeting VEGF-receptor 2. We conducted a placebo-controlled, double-blind, phase III international trial to evaluate the safety and efficacy of RAM in pts with metastatic gastric or GEJ adenocarcinoma progressing on first-line platinum- and/or fluoropyrimidine containing combination therapy. Methods: Pts were randomized 2:1 to receive RAM (8 mg/kg IV) plus BSC or placebo (PL) plus BSC every 2 weeks (wks) until disease progression, unacceptable toxicity, or death. Eligible patients had disease progression within 4 months (m) after 1st-line therapy for metastatic disease or within 6 m after adjuvant therapy. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), 12-wk PFS rate, overall response rate (ORR) and safety. Results: From 10/09 to 01/12, 355 pts were randomized (RAM: 238; PL: 117). Baseline characteristics were well balanced between arms. The Hazard Ratio (HR) for OS was 0.776 (95% CI, 0.603-0.998; p = 0.0473). Median OS was 5.2 m for RAM and 3.8 m for PL. The HR for PFS was 0.483 (95% CI, 0.376-0.620; p < 0.0001). Median PFS was 2.1 m for RAM and 1.3 m for PL. 12-wk PFS was 40% for RAM and 16% for PL. ORR was 3.4% for RAM and 2.6% for PL. Disease control rate was 49% for RAM and 23% for PL (p < 0.0001). Use of anti-cancer therapy post-study: 32% RAM; 39% PL. The most frequent of grade ≥ 3 adverse events (AEs) were: hypertension (7.2% RAM; 2.6% PL), anemia (6.4% RAM; 7.8% PL), abdominal pain (5.1% RAM; 2.6% PL), ascites (4.2% RAM; 4.3% PL), fatigue (4.2% RAM; 3.5% PL), decreased appetite (3.4% RAM; 3.5% PL) and hyponatremia (3.4% RAM; 0.9% PL). Conclusions: Ramucirumab conferred a statistically significant benefit in OS and PFS compared to PL in metastatic gastric or GEJ adenocarcinoma following progression on 1st-line therapy with an acceptable safety profile. Clinical trial information: NCT00917384.
A phase II randomized clinical trial of samarium-153 EDTMP (Sm-153) with or without PSA-TRICOM vaccine in metastatic castration-resistant prostate cancer (mCRPC) after docetaxel.
Authors: Heery Christopher Ryan , Madan Ravi Amrit , Bilusic Marijo , Kim Joseph W. , Singh Nishith K. , Rauckhorst Myrna , Steinberg Seth M. , Dahut William L. , Chen Clara , DiPaola Robert S. , Stein Mark N. , Panicali Dennis , Hodge James W. , Schlom Jeffrey , Gulley James L. 
Published: February 2017

102 Background: A prior randomized, placebo-controlled, multi-center phase 2 trial of PSA-TRICOM demonstrated survival benefit. Sm-153 is a radiopharmaceutical that targets osteoblastic lesions. Preclinical data indicated that Sm-153 could alter tumor phenotype, causing upregulation of Fas, MHC Class I, and tumor-associated antigens, making tumor cells more amenable to immune-mediated killing. This trial was intended to examine the safety and efficacy of the Sm-153 with PSA-TRICOM vs. Sm-153 alone. Methods: This phase 2 multi-center trial was designed to randomize 68 pts to Sm-153 with or without PSA-TRICOM. Eligibility included mCRPC, bone metastases, no visceral disease, prior docetaxel, ECOG ≤2, and normal organ function. Sm-153 was given at 1mCi/kg IV on day 8 and then every 12 weeks. PSA-TRICOM was given on days 1, 15, 29, then every 4 weeks. The 1° endpoint was comparison of progression-free survival at 4 months (mo) utilizing PCCWG, but not PSA criteria. A Fisher’s exact test, assuming a one-tailed alpha = 0.10, was used to compare these fractions. 2° endpoints were OS, ORR, PSA changes, immunologic, and toxicity. Results: 44 pts were enrolled, 5 were not evaluable for the 1° endpoint due to withdrawal prior to 4 mos (4 on Arm A, 1 on Arm B). PFS and PSA findings are provided below. Hematologic toxicities were most common, and were well matched. Conclusions: This final analysis suggests the combination of PSA-TRICOM and Sm-153 has a similar toxicity profile to Sm-153 alone. Despite early closure of this trial due to poor accrual, which may be related to recent approval of multiple agents for mCRPC, this analysis appears to demonstrate improvement in PFS with the combination. This may indicate synergy between PSA-TRICOM and bone-seeking radiopharmaceuticals. Based on the data presented here, we are exploring the potential to combine PSA-TRICOM with alpharadin (radium-223), a next generation bone-seeking radiopharmaceutical. Clinical trial information: NCT00450619. [Table: see text]
Effect of GTx-758, an ERα agonist, on serum-free testosterone and serum PSA in men with advanced prostate cancer.
Authors: Yu Evan Y. , Gittelman Marc , Keane Thomas E. , Tutrone Ronald , Belkoff Laurence , Given Robert , Bass Joel , Chu Franklin , Gambla Mike , Gaylis Franklin , Bailen James , Getzenberg Robert H. , Coss Christopher , Hancock Michael L. , Dalton James T. , Steiner Mitchell S. 
Published: February 2017

104 Background: Androgen deprivation therapy (ADT) improves disease-free survival in men with advanced prostate cancer, but patients develop castrate resistant prostate cancer (CRPC); one of the causes of which is ineffective castration. Total serum testosterone (T) does not accurately predict prostatic levels of T. Further reduction of androgens in men with CRPC can result in improvement of survival. Herein we compare the effects GTx-758 an oral, selective estrogen receptor alpha (ERα) agonist versus leuprolide on total and free (unbound) serum T levels in men with advanced prostate cancer. Methods: In Phase II studies, men with advanced prostate cancer (n=164) received 1000 mg or 2000 mg GTx-758 daily or Lupron Depot (4 month), while men with CRPC (n=9) received 2000 mg GTx-758 daily. Serum concentrations of total T, free T, SHBG and PSA were determined at baseline and during treatment. Results: In ADT naïve advanced prostate cancer patients, 28 days of 1000 mg or 2000 mg daily GTx-758 or Lupron therapy castrated (T<50ng/dL) 50, 31 and 100% of patients, reducing mean serum total T in castrated patients to 23±14, 19±9 and 14±7 ng/dL, respectively. However, treatment with 1000 mg or 2000 mg GTx-758 daily reduced mean free T levels to a greater extent (0.9±0.7 and 0.7±0.7 pg/mL, respectively) than Lupron (1.7±1.1 pg/mL). Changes in PSA at 28 days were more closely associated with the observed changes in free T, with reductions of 74, 72 and 56% for 1000 mg, 2000 mg doses of GTx-758 and Lupron, respectively. In CRPC patients, 2000 mg GTx-758 daily did not further reduce serum total T levels, but did result in free T reductions and PSA decreases from baseline following 15 days of therapy in all of the men maintained on ADT with LHRH agonists alone. Conclusions: Although GTx-758 and LHRH based ADT both reduce total serum T and PSA levels in ADT naïve advanced prostate cancer patients, free T was rapidly reduced to a greater degree in the GTx-758 treated patients. In men with CRPC, GTx-758 therapy resulted in significant reductions in free T and resultant PSA declines. The ability of GTx-758 to reduce free T provides a unique mechanism to treat men with advanced prostate cancer and CRPC. Clinical trial information: NCT01326312.
Updated analysis of radium-223 dichloride (Ra-223) impact on skeletal-related events (SRE) in patients with castration-resistant prostate cancer (CRPC) and bone metastases from the phase III randomized trial (ALSYMPCA).
Authors: Vogelzang Nicholas J. , Parker Chris , Nilsson Sten , Coleman Robert Edward , O'Bryan-Tear C. Gillies , Shan Minghua , Sartor A. Oliver 
Published: February 2017

11 Background: Ra-223 is a first-in-class alpha-pharmaceutical targeting bone metastases (mets) with high-energy, short-range (< 100 μm) alpha-particles. In the phase 3, double-blind, randomized, multinational ALSYMPCA study, Ra-223 significantly improved OS in CRPC patients (pts) with bone mets by a median increase of 3.6 months compared with placebo (median OS: 14.9 vs 11.3 mo; P < 0.001; HR = 0.69; 95% CI: 0.58-0.83). An updated analysis of the SRE secondary endpoint is presented. Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving best standard of care (BSoC); and either previously received docetaxel, or did not because they were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra‑223 (50 kBq/kg IV) q4wk or matching placebo and stratified by prior docetaxel use, baseline alkaline phosphatase level, and current bisphosphonate use. Results: 921 pts were randomized (Ra-223, n = 614; placebo, n = 307); 40% had >20 mets. Ra-223 significantly delayed time to first SRE versus placebo by a median increase of 5.8 months (median time to SRE: 15.6 vs 9.8 mo; P < 0.001; HR = 0.66; 95% CI: 0.52-0.83). Ra-223 also reduced the risk of time to first event for all 4 SRE components versus placebo. Conclusions: Ra-223 significantly delayed time to first SRE with a reduction in risk observed for all 4 SRE components. Despite the longer time at risk, Ra-223 patients had an approximately 50% reduction in risk for SCC. Ra-223 is an effective therapy with a highly favorable safety profile and may provide a new standard of care for treatment of CRPC pts with bone mets. Clinical trial information: NCT00699751. [Table: see text]
Comparison of PSA slope and nadir between hypofractionated SBRT and conventionally fractionated EBRT.
Authors: Anwar Mekhail , Weinberg Vivian K. , Chang Albert , Hsu I-Chow Joe , Roach Mack , Gottschalk Alexander 
Published: February 2017

112 Background: Patients with early stage prostate cancer have a challenge in selecting from a variety of curative radiotherapy options, including external beam radiotherapy (EBRT) and hypofractionated stereotactic body radiotherapy (SBRT). Rapid post-treatment PSA decline and low PSA nadir have been associated with improved clinical outcomes. The purpose of this study was to compare the PSA measurements over time between conventionally fractionated EBRT and SBRT in newly diagnosed localized prostate cancer. Methods: 104 patients with low to low-intermediate risk prostate cancer (GS 3+3, PSA < 20 or 3+4, PSA < 15) treated with standard fractionated EBRT (> 70.2 Gy, < 76 Gy) without hormones to the prostate only were identified from a prospectively collected cohort of patients treated at the University of California, San Francisco (1997-2012). Patients were excluded if they failed therapy by the Phoenix definition. All included patients had at least 1 year of follow up and 3 serial PSAs. 35 patients that were treated with SBRT to the prostate to 38 Gy in 4 daily fractions also met the same criteria. Of these, 47 and 19 patients treated with EBRT and SBRT, respectively, had a yearly increase in PSA follow-up over 3 years. PSA nadir and rate of change in PSA over time (e.g. slope) were calculated from the completion of RT to 1, 2 and 3 years post RT. Results: The median PSA nadir and slope for patients treated with EBRT was 0.80, 0.50, 0.40 ng and ‑0.07, ‑0.02, ‑0.01 ng/ml/month, respectively, for durations of 1, 2 and 3 years post RT. Similarly, for SBRT, the median PSA nadir and slope were 0.73, 0.50, 0.24 ng and ‑0.09, ‑0.06, ‑0.05 ng/ml/month. The PSA slope for SBRT was greater than EBRT (p = 0.001) at 2 and 3 years following RT, although similar during the first year. These results were consistent when limited to patients with more complete PSA follow-up each year, with PSA nadir significantly lower 3 years after treatment with SBRT compared with EBRT (p = 0.03). Conclusions: Patients treated with SBRT experienced a more rapid decline in PSA 2 and 3 years following completion of RT than with EBRT, and for those with continuous long term followup, a lower PSA nadir, consistent with delivery of a higher bioequivalent dose.
Disparities in prostate cancer treatment associated with population density of the county of residence.
Authors: Cary Clint , Odisho Anobel , Cooperberg Matthew R. 
Published: February 2017

117 Background: We sought to assess disparities in primary treatment of prostate cancer by examining the effect of population density of the county of residence on treatment for clinically localized prostate cancer and quantify variation in primary treatment attributable to county and SEER site. Methods: Participants included 138,226 men with clinically localized prostate cancer who underwent surgery, radiation, or conservative therapy in the Surveillance, Epidemiology, and End Result (SEER) database diagnosed in 2005 through 2008. Mixed effects hierarchical logit models were used to examine the effect of population density of the county of residence on treatment while accounting for the random effects of counties nested within SEER sites. In order to quantify the effect of county and SEER site on individual treatment, the percent of total variance in treatment attributable to county of residence and SEER site was estimated with residual intraclass correlation coefficients. Results: Men in metropolitan counties had 23% higher odds of being treated compared with men in rural counties, controlling for number of urologists per county as well as patient clinical and sociodemographic characteristics. Age, race/ethnicity, PSA at diagnosis, and tumor characteristics were also significant predictors of treatment in the multivariable model. The percent of variation in treatment attributable to the county of residence was consistently higher than that attributable to SEER site. 3% (95% CI: 1.2%-6.2%) of the total variation in treatment was attributable to SEER site, while 6% (95% CI: 4.3%-9.0%) of variation was attributable to county of residence, controlling for clinical and sociodemographic characteristics. This variation at the county and SEER site increased to 4% and 10%, respectively, when specific type of treatment (surgery or radiation) was assessed. Conclusions: Variation in treatment for localized prostate cancer exists for men living in different population dense counties of the country. These findings highlight the need for comparative effectiveness research and health policy initiatives to advance prostate cancer research and reduce disparities in current clinical practice.
Influence of ischemia on tissue androgens in eugonadal and androgen-deprived men treated with prostatectomy.
Authors: Montgomery Robert B. , Risk Michael Christopher , Lin Daniel W. , Matsumoto Alvin M. , Marck Brett , Wright Jonathan L. , Nelson Peter , Mostaghel Elahe A. 
Published: February 2017

118 Background: Optimizing tissue androgen suppression may provide a higher rate of complete pathologic response in patients with localized prostate cancer (PCa). The ability to accurately assess tissue androgens may be influenced by ischemic time and catabolism after devascularization. This study was performed to determine if ischemia influences tissue androgen in eugonadal men and in men treated with various types of neoadjuvant androgen deprivation (ADT). Methods: Eugonadal men (n=12) or men treated with neoadjuvant ADT using LHRH agonist and Casodex or LHRH agonist with Dutasteride, Casodex or all three with Ketoconazole (n=34) underwent prostatectomy for localized PCa. Tissue was acquired by needle biopsy at the time of ligation of the vascular pedicles, at prostate removal and at 30 minutes after prostate removal. Prostate tissue was flash-frozen and tissue dihydrotestosterone (DHT) and testosterone (T) were determined by LC/MS/MS. Change in tissue androgens from clamp was assessed at each time point. Trends in androgen levels were assessed by ANOVA for eugonadal men and within each treatment group Results: Average time from clamp to removal was 23 minutes (± 8) and from removal to subsequent biopsy 32 minutes (± 2). There was no evidence for a significant change in T or DHT over the time intervals tested (one way ANOVA p>0.05 for all measures) except in patients treated with LHRH agonist and Casodex alone. In this group of patients, T declined by 34%by the time of prostate removal, and by 83% at 30 minutes after removal when compared to levels at clamp (one way ANOVA p=0.017, test for linear trend =0.007). In all other treatment groups, both T and DHT were stable for 60 minutes. Conclusions: Assessment of DHT levels in prostate tissue at prostatectomy is not compromised by ischemia. Tissue sampling from 30-60 minutes after vascular clamping yields a stable measure of tissue DHT in the majority of patients. In the absence of SRD5A blockade, testosterone sampling in castrate men is sensitive to ischemia, and delayed sampling underestimates tissue androgen levels due to ischemia-related metabolism. These results lend important insight into clinical trial design and translational endpoints.
Retrospective registry evaluating the PSA flare phenomenon with cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Angelergues Antoine , Mercier Florence , Flechon Aude , Guillot Aline , Le Moulec Sylvestre , Gravis Gwenaelle , Beuzeboc Philippe , Massard Christophe , Fizazi Karim , De La Motte Rouge Thibault , Elaidi Reza-Thierry , Oudard Stephane 
Published: February 2017

122 Background: PSA initial flare followed by a decrease is documented in up to 18% of mCRPC patients (pts) treated with docetaxel (D). There is no standard definition of this phenomenon, and its significance in terms of treatment efficacy and prognosis remains unclear. We evaluated the PSA flare incidence and characteristics with cabazitaxel (C), a new taxane developed to overcome D resistance, and its impact on outcome. Methods: A retrospective review of 84 consecutive pts (median 67 yrs) treated with C for mCRPC progressing during or after D was conducted in 8 French centers. Baseline characteristics, disease history, PSA values before and during C, overall survival (OS) and radiological or clinical progression-free survival (PFS) were collected. Results: At C initiation, most pts (84%) were ECOG 0-1, 59.5% had pain and 23.8% received ≥2 chemotherapy lines. Metastases were located in bone (92.9%), lymph nodes (48.8%) and visceral/soft tissues (9.5%). Median number of C cycles was 6 (range 2-14). Median OS and PFS from first C cycle were 16.4 and 6.7 months, respectively. Flare incidence, PFS and OS varied with the definition used (table). Definition [3] seems to us the most clinically relevant, and showed a close estimate of PFS compared to pts with immediate PSA decrease from baseline. We recommend to use this definition in clinical practice. Conclusions: PSA flare occurred in 16% pts treated with C and was associated with as good outcome as immediate responders. C should not be withdrawn prematurely in case of isolated initial PSA rise. This finding supports the PCWG 2 recommendation that early rise (prior to 12 weeks) with cytotoxics should be ignored in determining PSA response. [Table: see text]
From trial to practice: The Princess Margaret Hospital (PMH) experience with docetaxel and prednisone for men with metastatic castration resistant prostate cancer (mCRPC).
Authors: Templeton Arnoud , Wang Lisa , Vera-Badillo Francisco , Attalla Mirna , De Gouveia Paulo , Leibowitz-Amit Raya , Knox Jennifer J. , Moore Malcolm J. , Sridhar Srikala S. , Joshua Anthony Michael , Tannock Ian 
Published: February 2017

125 Background: Docetaxel (75mg/m2every 3 weeks [q3w]) plus prednisone (5mg bid) is standard first-line chemotherapy for men with mCRPC since FDA approval in 2004. It is unclear how results from trials translate to daily practice. Our hypothesis was that patients (pts) treated in trials would have better outcome and less toxicity. Methods: We reviewed all pts with mCRPC treated with docetaxel at PMH until the end of 2011. Primary outcomes were overall survival (OS) and PSA response rate (confirmed decline ≥ 50%). Secondary outcomes were reasons for discontinuation, febrile neutropenia and predictive factors for the primary outcomes. Data were analyzed using the Kaplan-Meier method and Cox regression for OS. Results: 438 men were treated between 2001 and 2011. At start of treatment median age was 71 (range 44 – 90) years, 80 (18%) had visceral metastasis, and the median number of docetaxel cycles was 6 (range 1 – 15). Outcomes are shown in the table. Reasons for treatment discontinuation were progressive disease (38%), completion of treatment (27%), toxicity (22%), death within 30 days of last administration (5%), and other reasons (8%). In multivariate analysis better performance status (p < 0.0001), and more recent treatment (p < 0.0001) were baseline factors associated with longer OS for pts receiving primary treatment with docetaxel q3w. Conclusions: In less selected pts with CRPC treated with docetaxel/prednisone PSA response rates are similar, OS shorter and toxicity more frequent as compared to men treated in the pivotal or in other trials. Supported by a research grant from CIHR. [Table: see text]
Feasibility of continuing docetaxel-based therapy in patients with metastatic castrate-resistant prostate cancer (mCRPC) that experience hypersensitivity reactions (HSR).
Authors: Couvillon Anna , Beatson Melony A. , Harold Nancy , Karzai Fatima H. , Madan Ravi Amrit , Gulley James L. , Dahut William L. 
Published: February 2017

132 Background: Patients that receive docetaxel are observed closely for HSRs. Severe HSRs have been reported in patients premedicated with corticosteroids. The rate of allergic reactions reported in the TAX 327 trial (n=332) was 8% (any grade) and 1% (grade 3/4). In TAX 327 treatment was stopped after a total of 10 cycles of docetaxel. A recent trial conducted at the NCI has included patients treated with docetaxel-based therapy until radiographic progression with no cap on total dose or cycle number. Most patients have had significantly more than 10 cycles (median greater than 16 with a range of 1 to 48; however, some cycles did not include docetaxel). Given the increased incidence of HSR to docetaxel on our protocols, we developed guidelines for the clinical management of HSRs to docetaxel. Methods: We reviewed the literature on taxane HSRs and developed a 4-step clinical management guideline for the prevention and treatment of HSRs to docetaxel. Our guidelines utilize increasing amounts of H1/H2 antihistamines, corticosteroids, slower infusion rates of docetaxel, and/or decreasing concentrations of docetaxel. Results: From August 2009 to present, 63 mCRPC patients have been treated with docetaxel-based therapy. Twenty-three patients (37%) have experienced a HSR to docetaxel. HSRs initially occurred at cycle 1 (17%), cycle 2 (48%), cycle 3 (17%), cycle 4 (n=2), cycle 14 (n=1), cycle 16 (n=1). All patients were re-challenged with docetaxel using our 4-step clinical management guideline approach. Ten patients continued docetaxel without further HSRs. The remaining 13 patients continued to experience HSRs but were able to safely complete each infusion of docetaxel. No patients required discontinuation of therapy. Of the 23 patients with HSRs, 21 received more than 10 cycles of therapy with a median of 17 and a range of 1 to 38. Conclusions: Patients with mCRPC disease that is taxane sensitive and who experience HSR to docetaxel can continue to receive docetaxel safely. Most of these patients demonstrated a continued PSA, clinical, and radiographic response to therapy.