bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reproducibility of pretreatment lymphocyte-to-monocyte ratio (LMR) in rectal cancer.
Authors: Gawiński Cieszymierz , Winiarek Mariola , Rybski Sebastian , Temnyk Maciej , Kokoszyńska Katarzyna , Wyrwicz Lucjan 
Published: January 2019

715 Background: Lymphocyte-to-monocyte ratio (LMR) is a strong prognostic factor in many cancers. Recently, in Polish-2 study it was demonstrated to have a predictive value for hypofractionated neoadjuvant radiotherapy in rectal cancer (WCGIC 2017). LMR > 2.6 was associated with significant improvement of overall survival after short-course radiotherapy (5x5 Gy) and consolidating chemotherapy when compared to chemoradiotherapy (HR 0.36). To our knowledge this is the first observation on use of a predictive biomarker for hypofractionated radiotherapy. In this study we assessed the intra-patient variability of pre-treatment LMR in order to evaluate its reproducibility. Methods: Patients with rectal cancer treated in Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland between January 2013 and August 2017 were identified. In order to test reproducibility of the biomarker, only the patients with minimum two peripheral blood morphology tests within 5 weeks prior to any anti-cancer therapy were selected. Other inclusion criteria were locally advanced rectal cancer with no distant metastasis; no prior radiotherapy or chemotherapy. Patients with LMR > 2.6 were identified as “LMR high”. Results: After pre-screening of 719 rectal cancer patients, 50 patients met the inclusion criteria. LMRs calculated at two time-points were correlated with the coefficient of 0.588 (p < 0.05). 40% of assessments were “LMR high”. In 18% of patients the second test has not confirmed initial assignment to LMR class (95% CI 8.6%-31.4%). If LMR at the first time-point was in the range of 2.2-3.0 (+/- 0.4 from cut off), the chance for misclassification rose to 40% (95% CI 12.2%-73.8%), while outside of this range it dropped to 7.5% (95% CI 1.6%-20.4%). Conclusions: In our study LMR demonstrated significant intra-patient variability, espetially in patients with LMR outside of the indicated range (2.2-3.0). Further translational research is needed to identify the exact biological context of this biomarker in order to identify the molecular subtype of rectal cancer responding to hypofractionated radiotherapy.
SAPPHIRE: A randomized phase II study of mFOLFOX6 + panitumumab versus 5-FU/LV + panitumumab after 6 cycles of frontline mFOLFOX6 + panitumumab in patients with colorectal cancer.
Authors: Nakamura Masato , Munemoto Yoshinori , Takahashi Masazumi , Kotaka Masahito , Kuroda Hiroaki , Kato Takeshi , Minagawa Noritaka , Noura Shingo , Fukunaga Mutsumi , Kuramochi Hidekazu , Touyama Tetsuo , Takahashi Takao , Akagi Yoshito , Satake Hironaga , Kurosawa Shuichi , Miura Tomoko , Mishima Hideyuki , Sakamoto Junichi , Oba Koji , Nagata Naoki 
Published: January 2019

729 Background: FOLFOX therapy, an infusion of 5-fluorouracil (5-FU) with leucovorin in combination with oxaliplatin (OXA), is a common first-line chemotherapy regimen for unresectable, advanced or recurrent colorectal carcinoma (CRC). However, long-term administration of OXA is associated with peripheral neuropathy (PN); decreasing treatment length of OXA may be beneficial without reducing its efficacy. Methods: Chemotherapy-naïve pts aged ≥20 yrs with RAS wild-type advanced/recurrent CRC were enrolled to receive 6 cycles of panitumumab (Pmab) + mFOLFOX6 once every 2 wks. Pts who completed 6 cycles of Pmab + mFOLFOX6 and confirmed no progressive disease were subsequently randomized 1:1 to continue to receive Pmab + mFOLFOX6 (arm 1) or Pmab + 5-FU/LV (arm 2). The primary endpoint was progression-free survival (PFS) rate at 9 mos after randomization. The threshold PFS rate was defined as 30%, and the expected rate was set at 50%, with a 90% power and a 1-sided alpha value of 0.10. In the primary analysis, a binomial test was conducted separately for each arm. This study was designed as a phase II randomized screening comparison study which does not use direct comparison for the primary analysis. Results: Of 164 enrolled pts who received initial Pmab + mFOLFOX6 treatment, 56 were randomized to arm 1 and 57 to arm 2. PFS rates at 9 mos after randomization were significantly higher than the defined threshold at 44.6% (80% CI, 36.4–53.2) in arm 1 and 47.4% (39.1–55.8) in arm 2. Median PFS after randomization was 9.1 (8.6–11.2) and 9.3 (6.0–13.0) mos, respectively. Grade ≥2 PNs occurred in 6 (10.7%) and 1 (1.8%) pts in arms 1 and 2, respectively. Serious AEs occurred in 14 (25.0%) pts in arm 1 and in 9 (16.7%) pts in arm 2. Conclusions: The results of this trial suggest that Pmab + 5-FU/LV after 6 fixed-cycles of Pmab + mFOLFOX6 may be a treatment option in pts with RAS wild type chemotherapy-naïve advanced/recurrent CRC. Pts treated with Pmab + 5-FU/LV had a lower occurrence of grade ≥2 PNs compared with Pmab + mFOLFOX6. Clinical trial information: NCT02337946.
Impact of primary tumor sidedness on erlotinib efficacy in patients with metastatic colorectal cancer treated with bevacizumab maintenance: Results from the DREAM phase III trial.
Authors: Chibaudel Benoist , Andre Thierry , Samson Benoit , Garcia-Larnicol Marie-Line , Dauba Jérôme , Lledo Gerard , Dupuis Olivier Jean Marie , Rinaldi Yves , Mabro May , Aucoin Nathalie , Viret Frédéric , Tubiana-Mathieu Nicole , Khalil Ahmed , Baba Hamed Ghaouti Nabil , Scheithauer Werner , Carola Elisabeth , Vernerey Dewi , Louvet Christophe , De Gramont Aimery , Tournigand Christophe ,   GERCOR
Published: January 2019

737 Background: Primary tumor sidedness (PTS) could be a predictive maker for treatment efficacy of EGFR inhibitors monoclonal antibodies in patients with wild-type (WT) RAS metastatic colorectal cancer (MCRC), cetuximab having limited efficacy in patients with WT-RAS right-sided tumors. DREAM study demonstrated that adding erlotinib, an oral EGFR tyrosine kinase inhibitor (TKI) to bevacizumab during maintenance therapy improved clinical outcomes (RR, PFS, OS) in patients with MCRC, whatever KRAS status. The aim of this post-hoc analysis is to evaluate the clinical outcomes according to KRAS mutational status and PTS when adding erlotinib to bevacizumab maintenance therapy. Methods: PTS was retrospectively collected in patients from the DREAM phase III trial treated with bevacizumab with or without erlotinib as maintenance therapy for MCRC who have been controlled by induction therapy. The limit for the definition of PTS was splenic flexure, and rectal tumors were considered as left-sided tumors. The primary endpoint was overall survival (OS). Results: Among 452 patients who received maintenance therapy, PTS ascertainment was 84.7% (n = 383) with 265 (71.0%) patients having left-sided primary tumor and 108 (28.9%) having right-sided primary tumors (3 patients had both and tumor location was unknown in 7 patients). Median OS and treatment effect are presented in table 1. Conclusions: The greatest OS benefit of adding erlotinib to bevacizumab maintenance therapy was observed in patients with WT-KRAS and right-sided MCRC, suggesting a clinical impact of the different mechanism of action between EGFR TKI and monoclonal antibodies. Clinical trial information: NCT00265824. [Table: see text]
Influence of timing of surgery on perioperative morbidity after neoadjuvant therapy for locally advanced rectal cancer.
Authors: Roxburgh Campbell SD , Strombom Paul , Lynn Patricio B , Paty Philip , Guillem Jose G. , Nash Garrett Michael , Smith Jesse Joshua , Wei Iris H , Garcia-Aguilar Julio , Weiser Martin R. 
Published: January 2019

754 Background: Timing of surgery following completion of neoadjuvant therapy (NT) for locally advanced rectal cancer (LARC) has important implications for treatment response. However, it was recently reported in the GRECCAR 6 trial that delayed surgery beyond 8 weeks from completion of NT is associated with increased complications. Within a cohort of LARC patients treated with NT (CRT alone, Total NT (TNT) and chemotherapy alone) we examine perioperative complications based on time from NT to surgery. Methods: Patients with Stage II/III LARC ≤15cm from the anal verge who received NT from 06/01/09 – 03/01/15 were identified and preoperative morbidity collected on those undergoing rectal resection. Patients were grouped according to time of surgery from completion of NT (5-8 weeks – early surgery / 8-12 weeks – late surgery). Results: 798 patients were identified and 547 underwent rectal resection within 12 weeks of completing NT (440 LAR and 107 APR). Surgery was performed 5-8 following NT in 252 pts and 8-12 weeks following NT in 246 pts. 204 patients (41%) had a post-op complication: 53 (10%) Grade 3-5 complication and 83 (17%) SSI. There were no statistically significant differences in rates of all complications (44% vs 38%), grade 3-5 complications (9% vs 11%), SSI (17% vs 17%), and LOS (median 6 days vs 6 days) between the early and late surgery groups. Similar results were obtained when evaluating the subgroups by type of NT (CRT alone, chemo alone or TNT), surgical approach (open vs minimally invasive and sphincter preservation vs colostomy), post-treatment TNM stage and year of treatment (all NS). In addition, we did not observe differences in rates of downstaging responses: T downstaging (63% vs 64%), N downstaging (61% vs 54%), > 95% regression (34% vs 34%) or pCR rates (18% vs 18%) between the early and later surgery groups. Conclusions: In patients undergoing radical surgery for LARC post NT, we do not observe an effect of timing of surgery on surgical complications. Although timing of surgery is reported to influence response rates, we did not reproduce these findings, likely as a consequence of the high rate of deferral of surgery/ non-operative management in this cohort.
The impact of pre-operative chemotherapy in patients with peritoneal lavage cytology positive or localized peritoneum metastasis for gastric cancer: A multicenter retrospective study.
Authors: Makuuchi Rie , Yamaguchi Toshifumi , Takashima Atsuo , Nagashima Kengo , Yamada Tatsuya , Kinoshita Takahiro , Hata Hiroaki , Kawachi Yasuyuki , Kawabata Ryohei , Tsuji Toshikatsu , Hirabayashi Naoki , Sakamoto Takeshi , Inada Takao , Ishiyama Koshiro , Fukagawa Takeo , Boku Narikazu , Katai Hitoshi 
Published: January 2019

95 Background: Peritoneal lavage cytology of positive and localized peritoneum metastasis of gastric cancer (GC) are defined as CY1 and P1 in the 14th edition of the Japanese Classification of GC. Patients (pts) with CY1 and/or P1 have poor prognosis after removing all macroscopically visible disease by standard gastrectomy followed by S1. The aim of this study was to investigate the efficacy of pre-operative chemotherapy (Pre-Cx) in patients with CY1 and/or P1. Methods: We retrospectively reviewed the GC pts who were diagnosed to have CY1 and/or P1 at 34 institutions participating in the Stomach Cancer Group of Japan Clinical Oncology Group between 2007 and 2012. Inclusion criteria were: no distant metastasis other than CY1 or P1, no prior treatment for GC. The subjects were divided to two groups according to treatment strategy with/without Pre-Cx before surgery. In the Pre-Cx group, status of CY and P was diagnosed by laparoscopy before and after Pre-Cx, and indication of surgical resection was decided by each physician. Results: A total of 824 pts were collected from 34 institutions. Of the 713 eligible pts, 150 pts received Pre-Cx (Pre-Cx group) and 563 pts underwent surgery followed by Cx (Post-Cx group). Proportions of P0CY1/P1CY0/P1CY1 were 69/12/19% and 69/17/14% in the Pre- and Post-Cx. Cx regimen for Pre-Cx were S1 plus cisplatin/ docetaxel and cisplatin plus S1/others (n=90/37/23). In the Pre-Cx, 57 (38%) pts who achieved P0CY0 after Pre-Cx showed better survival than the remaining 92 pts (overall survival (OS), 31.0 vs. 19.9 months (M), HR=1.99, 95% CI 1.32-2.93, p=0.001). OS was 24.8 and 24.0 M in the Pre- and Post-Cx (HR 1.07; 95% CI 0.87-1.32, p=0.502). In multivariate analysis, P1CY1, over 65 years old and clinical N3 lymph node metastasis were identified as the independent prognostic factor for OS (p<0.05). Conclusions: Although Pre-Cx showed favorable survival in case of achieving P0 and CY0, Pre-Cx did not show a survival benefit for GC pts with CY1 and /or P1.
CheckMate 648: A randomized phase 3 study of nivolumab plus ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin in patients with unresectable advanced, recurrent, or metastatic previously untreated esophageal squamous cell carcinoma.
Authors: Ajani Jaffer A. , Kato Ken , Doki Yuichiro , Chau Ian , Xynos Ioannis , Balogh Agnes , Kitagawa Yuko 
Published: January 2019

TPS193 Background: Esophageal cancer (EC) is the sixth most common cause of cancer-related death worldwide, with a 5-y survival rate of 5%–8% in pts with metastatic disease. First–line platinum-based doublet chemotherapy (CTX) provides a modest survival benefit in pts with metastatic squamous cell EC (mESCC), with a median OS of 7.6 months. Over 40% of pts with EC have PD-L1+ tumors, which are associated with worse OS outcomes. Nivolumab (NIVO), an anti–PD-1 mAb, demonstrated efficacy and a manageable safety profile in pts with ESCC. In the phase 2 ATTRACTION-1 trial, NIVO 3 mg/kg produced an ORR of 17% and median OS of 10.8 months in heavily pretreated pts with ESCC (Kudo T et al Lancet Oncol 2017). NIVO + ipilimumab (IPI) yielded enhanced responses with a manageable safety profile in multiple tumor types. Similarly, NIVO + platinum-based CTX resulted in encouraging clinical activity and an acceptable safety profile in pts with metastatic gastric cancer and SCC NSCLC. This randomized phase 3 study will evaluate the efficacy and safety of NIVO + IPI or NIVO + fluorouracil (5-FU)/cisplatin (Cis) vs 5-FU/Cis as first-line treatment (Tx) in pts with advanced (adv) or mESCC (CheckMate 648; NCT03143153). Methods: 939 pts aged ≥ 18 y with histologically confirmed unresectable advanced, recurrent or mESCC, not amenable to curative approaches, and no prior systemic therapy for advanced/metastatic disease, with adequate organ function and ECOG PS 0 or 1 will be randomized 1:1:1 to NIVO + IPI, NIVO + 5-FU/Cis or 5-FU/Cis. Pts with autoimmune diseases, serious or uncontrolled medical disorders; active infections or positive for HIV, AIDS, or hepatitis B/C, indicating acute or chronic infection and/or detectable virus; and previous Tx with other therapy targeting T-cell co-stimulation or immune checkpoint pathways are excluded. Primary endpoints are OS and PFS by central assessment in pts with a PD-L1+ tumor (defined as PD-L1 expression on ≥ 1% of tumor cells). Secondary endpoints include ORR, PFS, and OS in all pts, as well as ORR in pts with PD-L1+ tumors. Clinical trial information: NCT03143153.
Phase II study of copanlisib (BAY 80-6946) in combination with gemcitabine and cisplatin in advanced cholangiocarcinoma.
Authors: Mehta Rutika Jitesh , Kim Dae Won , Soares Heloisa P. , Kim Jongphil , Kim Richard D. 
Published: January 2019

TPS525 Background: The current standard of treatment for cholangiocarcinoma (CCA) is gemcitabine and cisplatin that favored both overall survival (OS) and progression free survival (PFS) when compared to gemcitabine alone. The survival however remains less than than 1 year. Predominant activation of PI3K/AKT signaling pathway is seen in cell line and human tumors of CCA promoting tumorigenesis and increased resistance to radiation and chemotherapy. Inhibition of this pathway sensitizes CCA cells to therapies. Copanlisib is a selective and reversible pan-class I PI3K inhibitor. In preclinical studies, copanlisib demonstrated anti-tumor activity in PIK3CA mutated cells particularly in BC. In a Phase I study, 4 treatment naïve patients with CCA showed response, including 1 complete response. The maximum tolerated dose of copanlisib was determined to be 0.8 mg/kg in this study. We hypothesize that the addition of copanlisib to gemcitabine + cisplatin will enhance the efficacy of the current standard regimen in advanced CCA. Tumor tissue will be collected on every patient for PTEN immunohistochemical staining and NGS analysis using a 26-genes panel. Methods: This is a single institution phase II single arm two-stage design trial using copanlisib in combination with gemcitabine and cisplatin in patients with advanced CCA. Eligible patients include those diagnosed with advanced, unresectable CCA that are treatment naïve or should have received adjuvant treatment more than 6 months prior to initiating the trial. Patients will be treated with Cisplatin (25 mg/m2) plus Gemcitabine (1000 mg/m2) and Copanlisib (60 mg) on days 1 and 8 on a 21 days cycle. Primary objective of the study is PFS at 6 months with secondary objectives being response rate, median PFS, OS, safety and tolerability. Accrual began on June 28, 2016, with planned enrollment for 25 patients. 14 eligible patients will be enrolled in the first stage. If 8 or more patients (≥57%) are alive and progression free at 6 months, an additional 11 patients will be enrolled in the second stage. 11 patients have been enrolled until now. After 3 cycles, response and progression will be evaluated using RECIST v1.1. Clinical trial information: NCT02631590.
ACELARATE: A phase III, open label, multicentre randomised clinical study comparing Acelarin (NUC-1031) with gemcitabine in patients with metastatic pancreatic carcinoma.
Authors: Palmer Daniel H. , Ross Paul J. , Silcocks Paul , Greenhalf William , Faluyi Olusola Olusesan , Ma Yuk Ting , Wadsley Jonathan , Rawcliffe Charlotte Louise , Valle Juan W. , Neoptolemos John P. 
Published: January 2019

TPS537 Background: Single agent gemcitabine still remains an appropriate choice for patients with metastatic pancreatic adenocarcinoma who are not suitable for combination therapy. Known resistance factors, such as low hENT1 and dCK, and CDA overexpression limit gemcitabine’s efficacy. NUC-1031 (Acelarin), is designed to overcome this resistance and deliver significantly higher intracellular levels of the active agent, dFdCTP, than gemcitabine. In Phase I studies Acelarin has shown activity in a range of metastatic cancers, including pancreatic, biliary and ovarian cancers. This Phase III study is designed to show superiority of Acelarin over gemcitabine in patients unsuitable for combination chemotherapy. Methods: To date, 85 patients have been randomised in this multicentre, Phase III study comparing Acelarin with gemcitabine first-line in patients with metastatic pancreatic adenocarcinoma. Patients must have a Performance Status of 0-2 and be unsuitable for combination chemotherapy. To detect a hazard ratio of 0.705 between the two arms, 270 events must be obtained from 328 patients, assuming a median survival of 6 months in the control arm. Currently, pts are being recruited at 27 centres. Patients receive either 825mg/m2 Acelarin or 1000mg/m2 gemcitabine on Day 1, 8 and 15 of a 28-day cycle until disease progression. The primary outcome measure is Overall Survival. Secondary outcome measures include Progression Free Survival, Response Rate, Disease Control Rate and Toxicity. Translational research will explore the use of biomarkers for predictive benefit of Acelarin over gemcitabine. Clinical trial information: ISRCTN16765355.
An open-label, phase II study of intravenous anetumab ravtansine, an anti-mesothelin antibody drug conjugate, in pretreated mesothelin-expressing advanced pancreatic cancer.
Authors: Chokshi Saurin , Hochster Howard S. 
Published: January 2019

TPS540 Background: Advanced pancreatic cancer remains one of the deadliest malignancies with median OS of 11 months with the most aggressive therapy regimen. Hence, a need exists for more effective, durable, and targeted therapies. Mesothelin is a membrane associated antigen overexpressed in most pancreatic adenocarcinomas. The biological function of mesothelin remains unknown but it is an internalizing antigen. Given its limited expression in normal tissue and high expression in malignant cells, mesothelin is an excellent target for antibody directed cytotoxic drug delivery. Anetumab ravtansine (AR) is an ADC consisting of a fully human IgG1 antibody directed at mesothelin and conjugated to tubulin-binding toxophore, DM4 (maytansine derivative). Preclinical efforts have shown antiproliferative activity in mesothelin positive cancer cell lines and 75% tumor regression in pancreatic xenograft models (Golfier S, et al. Mol Cancer Ther 13(6):1537-48, 2014). Methods: This is a multicenter, non-randomized, Phase II study evaluating the efficacy of AR in pretreated mesothelin-expressing advanced pancreatic cancer. The study utilizes minimax, Simon 2-stage design testing 5% null hypothesis versus 21% alternative. If no response among the first 20, trial will terminate early. If at least one response among the first 20, trial will accrue additional 10 patients for maximum of 30. Four or more responses out of 30 will reject the null hypothesis. Significance level (alpha) is 0.1 and power is 90%. Probability of stopping early is 36% if the response rate is 5% or lower. Patients will receive AR infusion at 6.5 mg/kg on Day 1 of 21-day cycle. Primary objective: response rate per RECIST 1.1. Secondary objectives: time to progression; toxicity. Eligibility: measurable disease per RECIST 1.1; no more than two prior chemotherapy regimens; 30% of cells with 2+/3+ mesothelin staining per IHC; no history of keratitis or corneal disease. Correlative studies: serum soluble mesothelin levels and apoptotic factors (CK18, caspase-cleaved fragments) at baseline and throughout the study to predict treatment response/outcome. Enrollment is on-going. Clinical trial information: NCT03023722.