bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized controlled phase II study of the prophylactic effect of urea-based cream on the hand-foot skin reaction associated with sorafenib in advanced hepatocellular carcinoma.
Authors: Ren Zhenggang , Zhu Kangshun , Kang Haiyan , Lu Minqiang , Qu Zengqiang , Lu Ligong , Song Tianqiang , Zhou Weiping , Wang Hui , Yang Weizhu , Wang Xuan , Yang Yongping , Shi Lehua , Bai Yuxian , Ye Sheng-Long 
Published: March 2020

4008 Background: Sorafenib (SOR) has become the standard treatment for advanced hepatocellular carcinoma (HCC). Hand-foot skin reaction (HFSR) is one of the most common adverse events associated with SOR and its occurrence can impact patient quality of life and lead to dose modification or interruption, both of which may negatively impact clinical outcomes. This randomized controlled trial is the first large prospective study to investigate the prophylactic effect of urea-based creams on HFSR associated with SOR. Methods: Patients with advanced HCC treated with SOR were randomly assigned 1:1 to receive prophylactic urea-based cream (Arm A) or best supportive care (BSC) following development of HFSR (Arm B). SOR was administered 800 mg daily. Urea-based cream was given twice daily for up to 12 weeks starting on Day 1. BSC was at the physician’s discretion and excluded urea-based creams. The primary endpoint was the incidence of all-grade HFSR in the first12 weeks. Results: Eight hundred sixty eight patients were enrolled; 439 patients in Arm A and 432 patients in Arm B. There was no difference of baseline characteristics between two arms. Over the 12 week period of study, the incidence of all-grade HFSR was significantly lower in Arm A compared to Arm B; n=246 (56.0%) patients in Arm A versus n=318 (73.6%) patients in Arm B, p<0.0001. The incidence of grade ≥2 HFSR tended to be lower in Arm A compared to Arm B, but did not reach statistical significance; n=96 (21.9%) patients Arm A versus n=126 (29.2%) patients in Arm B, p=0.1638. The median time to the first HFSR event was 2.5 fold longer in Arm A compared to Arm B; 84 days (95% CI 45-93 days) in Arm A and 34 days (95% CI 29-43 days) in Arm B (p<0.001). Conclusions: This is the first large prospective, randomized control trial examining the prophylactic use of urea-based creams for treatment of HFSR associated with a multikinase inhibitor. Compared to BSC, prophylactic topical use of a urea-based cream appears to be effective in preventing and/or delaying the incidence of HFSR associated with SOR treatment in patients with advanced HCC.
Profiling of activated receptor tyrosine kinases in advanced gastric cancers identifies patients with poor prognosis.
Authors: Kim Phillip Sangwook , Lee Jeeyun , Kim Sung , Liu Xinjun , Park Joon Oh , Lee Tani Ann T. , Kim Kyoung-Mee , Kuller Anne , Singh Sharat , Kang Won Ki 
Published: March 2020

4011 Background: Metastatic gastric cancer (GCA) remains a therapeutic challenge due to its poor prognosis. Trastuzumab is the only known targeted therapy that has demonstrated a survival benefit in a small subset of metastatic GCAs. Addition of molecular diagnostics for predicting prognosis and therapeutic outcomes can significantly enhance the clinical management of GCAs. Herein, we identify activated receptor tyrosine kinases (RTKs) in distinct GCA subsets that correlate with disease-free survival post-curative GCA surgery. Methods: Fresh frozen GCA tissues from 434 stage I to IV GCA patients were profiled for HER1, HER2, HER3, p95HER2, c-MET and IGF1R RTKs using the multiplexed Collaborative Enzyme Enhanced Reactive (CEER) immunoassay. CEER is a highly sensitive and specific proximity assay that relies on the formation of a triple antibody complex surrounding the target protein. Results: p95HER2, a known trastuzumab resistance mechanism, was identified for the first time in 79% of IHC/FISH-based HER2(+) GCAs. Full-length HER2 expression was heterogeneous with ~20% of HER2(-) GCAs still expressing the HER2 protein. 232/434 GCAs expressed at least one activated RTK analyzed in our study. Of these 232 patients, 121 patients that presented with stage II or III disease at the time of surgery; demonstrated a worse progression-free survival as compared to those where none of the analyzed RTKs were activated (32.6 months vs 76.5 months, p=0.0318). HER axis members were the most commonly activated RTKs with 64% of such GCAs. Approximately 71% of activated cMET tumors demonstrated a co-activation with a HER axis member with a preference for HER1 in ~61% of cMET-activated GCAs. Patients with p-MET(+):p-HER1(+) GCAs had a worse prognosis as compared to those with p-MET(+):p-HER1(-) GCAs (46.2 months vs 82.8 months, p=0.0184). Conclusions: CEER-based RTK characterization revealed concomitantly activated signaling pathways in GCAs which could predict disease recurrence. Comprehensive molecular profiles of GCA tumors can allow for the implementation of these companion biomarkers in GCA therapeutic clinical trials.
Actionable targets in pancreatic cancer detected by immunohistochemistry (IHC), microarray (MA) fluorescent in situ hybridization (FISH), and mutational analysis.
Authors: Von Hoff Daniel D. , Ramanathan Ramesh K. , Evans Douglas B. , Demeure Michael J. , Maney Todd , Wright Brian , Gatalica Zoran , McGinniss Matthew Jerome 
Published: March 2020

4013 Background: A great need exists for new therapeutic approaches for patients with pancreatic cancer. Methods: The study cohort included 1029 patients analyzedfor a.) up to 29 different immunohistochemical biomarkers – (e.g., COX-2, MGMT, PGP, RRM1, TOPOI, TOPOII, SPARC etc.)b.); in up to 450 patients’ specimens a whole genome expression analysis was performed using HumanHT-12 v4 beadChips ( Illumina Inc.,San Diego, CA) c.) in up to 695 patients FISH for c-Myc, EGFR, HER2 and TOPO2A gene copy amplifications; and d.) in up to 783 patients sequencing for KRAS, EGFR, PI3CA and BRAF, was performed. Results: IHC identified actionable targets included; 74% high COX-2; 57% negative ERCC1; 8% negative MGMT; 22% negative MRP1; 47% negative PGP; 77% low RRM1, 44% high SPARC; 30% high TOPO2A; 61% high TOPOI and 73% negative TS. Other biologically important findings by IHC for possible new therapeutics included 27% negative PTEN; and 20% high PDGFR. Microarray results presented multiple overexpressed targets for consideration including 36% of specimens with overexpressed adenosine deaminase; 28% asparagine synthase; 17% BCL2; 20% survivin; 23% carboxylesterase; 67% DNMT1; 40% thymidine phosphatase; 49% EPHA2 (and others in the src family of kinases); 57% FOLR2; 41% HDAC1; 62% HiF1α; 23% IL2RA (CD25); 46% NFkB1; 48% OGFR; 32% RARA; 26% VEGFR; and 43% vitamin D receptor. FISH yielded 2% amplified EGFR and 10% amplified Her2neu. Sequencing noted 73% mutated KRAS and 3% mutated PIK3CA. Conclusions: Examining actionable targets in patients’ pancreatic cancers (a)reiterates the commonality and importance of KRAS mutations in this disease (needs renewed targeting effort) (b)suggests that TOPO2 inhibitors (particularly if transport into tumor can be improved) should be examined in this disease (c)suggests other pathways to target including DNA repair, epigenetic, Src and inflammation (d) suggests protein turnover, amino acid targets and folate receptor2 as fresh areas to explore against the disease. Supported in part by a Stand Up To Cancer Dream Team Award.
Dual blockade of epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) signaling in metastatic pancreatic cancer: Phase I/randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG-0727).
Authors: Philip Philip Agop , Goldman Bryan H. , Ramanathan Ramesh K. , Lenz Heinz-Josef , Lowy Andrew M. , Whitehead Robert P. , Iqbal Syma , Gaur Rakesh , Benedetti Jacqueline K. , Blanke C. D. 
Published: March 2020

4019 Background: Targeting a single pathway in pancreatic adenocarcinoma (PAC) is unlikely to impact its natural history. EGFR targeting with erlotinib added to gemcitabine (G) marginally improved the outcome of patients with advanced disease. We tested the hypothesis that if the EGFR and IGF-1R pathways are simultaneously blocked then progression free survival (PFS) would be significantly improved by abrogating reciprocal signaling that leads to resistance to either drug. Methods: This was a phase I/randomized phase II (RP2) study testing the anti-IGF-1R monoclonal antibody cixutumumab combined with erlotinib and G in patients with metastatic PAC. The control arm was erlotinib plus G. The primary endpoint of the RP2 portion of the study was PFS. Eligibility included patients with untreated metastatic disease, performance status 0/1, fasting blood glucose less than institutional upper limit of normal, and willingness to provide tissue and blood specimens for correlative studies. Results: In phase I portion (n=10) safety of cixutumumab 6 mg/kg IV/wk, erlotinib 100 mg/day orally and G 1000 mg/m2 IV D 1, 8, and 15 of a 28-day cycle was established. In the RP2 portion (n=124) 114 eligible patients (median age 63) were included. On the cixutumumab arm, 59% of patients were female vs. 40% on control arm. Median PFS and overall survival were 3.7 and 6.7 months, respectively, in both arms of the study. Major grade 3 and 4 toxicities were (cixutumumab/control) elevation of transaminases (12%/6%), fatigue (16%/12%), gastrointestinal (35%/28%), neutropenia (21%/10%), and thrombocytopenia (16%/7%). Grade 3/4 hyperglycemia was seen in 16% of patients on cixutumumab. Grade 3 or 4 kin toxicity was similar in both arms of the study (< 5%). Five treatment-related deaths were reported: 2 cardiac on each arm, 1 pulmonary on cixutumumab. Conclusions: IGF-1R inhibitor cixutumumab did not improve the progression free or overall survival of patients with metastatic PAC treated with erlotinib and G in a molecularly unselected population.
Observations of hepatocellular carcinoma (HCC) management patterns from the global HCC bridge study: First characterization of the full study population.
Authors: Park Joong-Won , Sherman Morris , Colombo Massimo , Roberts Lewis R. , Schwartz Myron E. , Degos Francoise , Chen Pei-Jer , Chen Minshan , Kudo Masatoshi , Johnson Philip James , Huang Baisong , Orsini Lucinda S. 
Published: March 2020

4033 Background: HCC is a major health problem across the world. The global HCC BRIDGE study is the first global, large-scale, observational study to document the real-world experience of HCC patients from diagnosis to death. Methods: This longitudinal cohort study (started March 2009) includes HCC patients newly diagnosed between January 2005 and June 2011 and treated at major medical centers, with data collected retrospectively and prospectively as recorded in patient charts. Full patient enrollment is expected at the end of January 2012. Results: At the time of the first interim analysis (July 2011), 12,442 treated HCC patients were enrolled at 42 sites in Asia (n=8909, 72% [China: n=6295, 71%; Japan: n=295, 3%]), Europe (n=2040, 16%) and North America 1493 (n=1493, 12%). Mean age was 57 years; 82% were male. The predominant risk factor was HBV in Asia (76%) and HCV in Europe (48%), North America (45%) and Japan (69%). Most patients were diagnosed without surveillance (Asia, 82%; Europe, 73%; North America, 69%; Japan, 64%). In Asia, Europe and North America, the predominant BCLC stage at diagnosis was C (48%, 46%, 46%) followed by A (34%, 28%, 26%). First recorded treatments in Asia, Europe and North America were resection (31%, 15%, 21%), transplantation (1%, 3%, 1%), TACE (49%, 30%, 36%), other locoregional therapy (12%, 35%, 23%) and systemic therapy (3%, 10%, 8%). Treatments ever used (2005–2011) in Asia, Europe and North America were resection (33%, 17%, 24%), transplantation (2%, 6%, 12%), TACE (57%, 35%, 48%), other locoregional therapy (20%, 42%, 37%) and systemic therapy (9%, 20%, 21%). These results will be updated with data from the full study population (approx. 19,000 patients), and preliminary survival data will be presented. Conclusions: As the largest study of its type, in 19,000 patients worldwide, the HCC BRIDGE study provides valuable insights into global HCC disease characteristics and patient management. Based on prior analyses, differences in risk factors among regions confirm well-known trends, while other observed differences (e.g., treatment variations) may be related to country- and site-specific practices and patient characteristics.
Antitumor activity of nab-paclitaxel and gemcitabine in resectable pancreatic cancer.
Authors: Alvarez-Gallego Rafael , Cubillo Antonio , Rodriguez-Pascual Jesus , Quijano Yolanda , De Vicente Emilio , García Lina , López-Ríos Fernando , Plaza Carlos , García-García Elena , Morelli María Pia , Hidalgo Manuel 
Published: March 2020

4040 Background: Nab-paclitaxel in combination with gemcitabine has shown interesting clinical activity in patients with advanced pancreatic cancer (PDA) likely related to its ability to eliminate pancreas cancer stroma. In this study we explore clinical and pathological effects of the combination in patients with operable PDA. Methods: Patients with resectable o borderline resectable pancreatic cancer were treated with gemcitabine(1000mg/m2 days 1, 8 and 15) and nab-paclitaxel(125mg/m2 days 1, 8 and 15) for two cycles prior to surgery. Response was assessed by FDG-PET, CA199 levels and elastography, an EUS-based non invasive assessment of tumor stroma. Results: 16 patients were included into the study. 2 patients (12.5%) showed a progression disease (both with hepatic metastases) and were not operated. Median value for PET SUVmax decreased from 7,1 pre-treatment to 4,6 post-treatment(p=0.004), including 7(50%) of patients with a partial metabolic response and the mean CA199 decreased from 2654 to 52(p=0.02) with 43% patients having a more that 75 % decrement in tumor marker. The elastography ratio value diminished from 36 pre-treatment to 18 post-treatment(p=0.003) and correlated with improvement in SUVmax(p=0.04) and CA199 response(p=0,07). Grade 3-4 toxicities were neutropenia in 18% (none febrile neutropenia), thrombocytopenia in 12.5 and 6.2% transaminase elevation. So far 9 patients have been operated and in 8(89%) a complete resection (R0) was achieved. 1 patient had a complete pathological response and 4 patients had near complete responses with only a few(< 5%) residual tumor. In-depth analysis of stromal composition after treatment showed, compared to a series of 10 cases untreated and treated with conventional chemoradiation, decreased myofibroblast content, increase vessel density and distorted collagen fibers. Conclusions: Neoadjuvant treatment with gemcitabine plus nab-paclitaxel is feasible and results in significant clinical activity. Non-invasive elastography appears and attractive method to monitor tumor response. The rate of pathological responses and R0 resections in substantial for this setting. Biological studies of resected specimens show unique effects in tumor stroma.
Multicenter retrospective analysis of systemic chemotherapy for advanced poorly differentiated neuroendocrine carcinoma of the digestive system.
Authors: Machida Nozomu , Yamaguchi Tomohiro , Kasuga Akiyoshi , Takahashi Hideaki , Sudo Kentaro , Nishina Tomohiro , Tobimatsu Kazutoshi , Ishido Kenji , Furuse Junji , Boku Narikazu 
Published: March 2020

4046 Background: No standard regimen is yet established for advanced poorly differentiated neuroendocrine carcinoma (PDNEC) although regimens for small-cell lung carcinoma are usually adopted such as irinotecan + cisplatin (IP) or etoposide + cisplatin (EP). Our aim was to respectively investigate outcomes for advanced PDNEC of the digestive system according to patient characteristics and regimens. Methods: Data was collected from patient medical records at 23 hospitals in Japan. The selection criteria were as follows: 1) histologically proven PDNEC, small cell carcinoma, mixed endocrine-exocrine carcinoma with a PDNEC component, or histologically proven neuroendocrine tumor with rapidly progressive clinical course; 2) primary tumor arising from the gastrointestinal tract (GI) or the hepato-biliary-pancreatic system (HBP); and 3) inoperable or recurrent disease treated with systemic chemotherapy (Cx) between April 2000 and March 2011. Results: This study included 258 patients (males/females, 182/76) with median age of 62.5 years. Primary sites were esophagus/stomach/small bowel/colorectum/hepato-biliary system/pancreas in 85/70/6/31/31/35 patients (pts). According to the primary sites, the median overall survival period (mOS) was 13.4/13.3/29.7/7.6/7.9/8.5 months, and that of GI/HBP was 13.0/7.9 months, respectively. Most common regimen was IP (160 pts, 62%), followed by EP (46 pts, 18%). For IP/EP patients, response rates (RR) were 50%/27%, the median progression free survival periods (mPFS) were 5.2/4.0 months. Second line Cx was performed for 88 pts (55%)/28 pts (61%) and mOS from first line Cx were 13.0/7.3 months in IP/EP groups. Multivariate analysis demonstrated that a primary site of HBP (HR=1.96, p=0.003) and performance status of 2 and more (HR=2.32, p=0.01) were independent unfavorable prognostic factors of PDNEC patients treated with systemic Cx, while the hazard ratio comparing IP with EP was 0.79 (p=0.305). Conclusions: PDNEC of HBP had poorer prognosis than GI. IP was the most common treatment regimen and seemed to show better treatment outcomes than EP.
A randomized phase III multi-institutional study of TNFerade biologic with 5-FU and radiotherapy for locally advanced pancreatic cancer: Final results
Authors: Wild Aaron Tyler , Laheru Dan , Wang Hao , Chang Kenneth J. , Taylor Gretchen Elizabeth , Donehower Ross C. , Pawlik Timothy M , Ziegler Mark A. , Cai Hongyan , Savage Dionne T , Davis Yolanda M. , Klapman Jason , Reid Tony , Shah Raj J. , Wolfgang Christopher Lee , Rosemurgy Alexander , Herman Joseph M. 
Published: March 2020

4055 Background: TNFerade biologic (TNF) is a novel means of selective delivery of TNF-α to tumor cells by gene transfer through intratumoral (IT) injection. TNF is a replication deficient adenovirus vector containing TNF-α cDNA ligated downstream from a radiation-inducible Egr-1 promoter, allowing spatiotemporal constraint of TNF-α production to the radiation field. Herein we report the final results of a multi-center, randomized, open-label, controlled phase III trial of TNF with chemoradiotherapy for locally advanced pancreatic ductal adenocarcinoma (PDA). Methods: Pts with locally advanced PDA were randomized 1:2 to standard of care (SOC; 5-FU/RT followed by GEM) versus TNF + SOC. RT dose was 50.4 Gy in 28 fractions. Concurrent 5-FU (200 mg/m2/day IV) started on day 1 of RT each wk. TNF was injected IT ~4 hrs prior to RT weekly by percutaneous (PTA) or endoscopic (EUS) approach. 4 wks after RT, GEM (1000 mg/m2 IV) was given until progression or toxicity. Results: Of 277 pts, 187 were randomized to TNF and 90 to SOC. Demographic/baseline characteristics were similar between arms (all NS), as was GEM received (67 vs. 68%; 7.0 vs. 7.6 total wks). Median f/up was 9.1 mos (range, 0.1-50.5). Median OS for TNF by ITT analysis was 10.1 mos (95% CI, 9.1-11.7) vs. 10.0 mos (95% CI, 7.6-11.2) for SOC (p=0.6). TNF delivery method did not affect OS (9.4 mos for PTA vs. 11.5 for EUS; p=0.7). Baseline CA19-9 > 1000 was found to impart independent risk to TNF pts (HR=1.7; p=0.02). Subgroup analysis (SGA) of 86 pts with T1-T3 disease showed an OS benefit for TNF compared to SOC (10.9 vs. 9.0 mos, respectively; p=0.04). TNF resulted in more grade 1-2 fever/chills (p<0.001) as well as grade 3 (p<0.001) and 4 (p=0.05) toxicities (commonly lymphopenia, hypo/hyperkalemia, abd/chest pain) than SOC. Use of PTA vs. EUS did not affect grade 3/4 toxicity rates. Conclusions: TNF + SOC did not prolong OS for locally advanced PDA. SGA reveals a possible OS benefit for early stage (T1-T3) tumors and CA19-9 < 1000. PTA and EUS injection achieved similar rates of efficacy and toxicity. Grade 1-2 toxicity typical of systemic exposure to TNF-α (pyrexia/hypotension/chills) was common, but grade 3-4 was minimal.
Correlation between overall survival and other endpoints in clinical trials of second-line chemotherapy for patients with advanced gastric cancer.
Authors: Shitara Kohei , Matsuo Keitaro , Muro Kei , Ohtsu Atsushi 
Published: March 2020

4067 Background: The correlation between progression-free survival (PFS) or time to progression (TTP) and overall survival (OS) has been evaluated in patients with advanced gastric cancer (AGC) who received first-line chemotherapy (Shitara, K et al. Invest New Drug 2011; Shitara K and Burzykowski T, et al, ASCO 2011). However, no corresponding analysis had been done in patients who underwent second-line chemotherapy for AGC. Methods: We evaluated the potential of PFS, TTP, response rate (RR), or disease control rate (DCR) to act as surrogates for OS in phase II and III trials of second-line chemotherapy for AGC by comprehensive literature-based analysis. Correlations between each endpoint and OS were evaluated by Spearman rank correlation coefficient (ρ). Subgroup analyses by trial region or type of failure to previous chemotherapy were also conducted. Results: Fifty-six trials, including four randomized studies, were selected for analysis and covered a total of 61 treatment arms and 3,038 patients; 34 studies were conducted in Asia, 20 studies in Non-Asian countries, and two studies in both regions. Median PFS were similar in Asian and Non-Asian trials (3.0 vs. 3.3 months). In contrast, median OS tended to be longer in Asian vs. Non-Asian trials (8.0 vs. 6.0 months; p<0.01). Median PFS/TTP and OS showed a moderate correlation with ρ of 0.51 (95% CI, 0.31-0.73). Correlation tended to be higher in PFS (ρ = 0.62) than TTP (ρ = 0.29) and higher in non-Asian trials (ρ = 0.73) than Asian trials (ρ = 0.32). Correlation between PFS/TTP and OS among the trials in which eligibility required failure to previous fluorouracil and cisplatin also showed low correlation (ρ = 0.48). The RR and DCR also did not show high correlation with OS (ρ = 0.30 for RR; 95% CI 0.04-0.56; ρ = 0.53 for DCR; 95% CI 0.31-0.75). The hazard ratio (HR) of PFS and OS in each arms of the four randomized studies showed a low correlation with ρ of 0.10. Conclusions: Our results indicate that PFS/TTP, RR, and DCR did not correlate sufficiently with OS to be used as surrogate endpoints in patients with AGC who underwent second-line chemotherapy. Further research is needed based on individual patient data from ongoing randomized trials.