bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of genetic variations in genes implicated in the axis with outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with cetuximab plus chemotherapy.
Authors: Miyamoto Yuji , Stintzing Sebastian , Heinemann Volker , Zhang Wu , Cao Shu , Okazaki Satoshi , Berger Martin D. , Suenaga Mitsukuni , Schirripa Marta , Soni Shivani , Matsusaka Satoshi , Ning Yan , Yang Dongyun , Gopez Roel , Melendez Elizabeth , Hanna Diana L. , Barzi Afsaneh , Baba Hideo , Lenz Heinz-Josef 
Published: September 2018

3585 Background: Accumulating evidence suggests that right- and left-sided CRCs have different prognoses and different sensitivities to EGFR inhibitors in several phase3 trials. These differences might be related to different embryological origins, which are reflected in different molecular profiles of tumors. LEFTY, Nodal and ACVR2B, which are TGF-betasuperfamily, are key regulators of left-right axis during embryogenesis; these expressions control sidedness. Our aim was to evaluate whether SNPs in these genes are associated with clinical outcomes in mCRC pts enrolled in the FIRE3 trial. Methods: Genomic DNA was obtained from mCRC pts receiving cetuximab plus FOLFIRI as first-line treatment and analyzed by using PCR-based direct sequencing. Four functional SNPs in 4 genes ( LEFTY1, LEFTY2, Nodal, and ACVR2B) were tested in 305 pts in FIRE3 trial cetuximab cohort (NCT00433927). Main characteristics were the following: male/female = 207/98; median age = 64; RAS-wildtype/mutant = 195/95; median PFS = 9.6 months; median OS = 26.5 months, median follow-up time = 41.8 months. Results: In patients with left sided tumor ( N= 237), LEFTY2 rs3007716 G/G variants ( N= 14) showed shorter PFS than any A variants ( N= 222) in univariate (8.0 months (M) vs. 10.3 M, HR = 2.24, 95%CI = 1.27-3.94, P < 0.01) and multivariate analyses (HR = 2.12, 95%CI = 1.20-3.75, P < 0.01). Nodal rs1904589 T/T ( N= 36) showed longer OS than any C variants ( N= 196) in univariate analysis (50.1 m vs. 29.8 M, HR = 0.61, 95% = 0.37-1.01, P = 0.048) and multivariate analyses (HR = 0.59, 95%CI = 0.35-0.99, P = 0.046). In patients with right sided tumors ( N= 58), ACVR2B rs2268753 C/C ( N= 12) showed shorter PFS than any T variants ( N= 43) in univariate analysis (3.7 m vs. 7.7 M, HR = 1.93, 95% = 0.99-3.77, P = 0.038) and multivariate analysis (HR = 2.24, 95%CI = 1.12-4.51, P = 0.023). Conclusions: Our study showed for the first time that genetic variations in sidedness related genes are associated with PFS and OS in patients receiving cetuximab based chemotherapy, which may dependent on location.
Association of T-cell infiltration assessed in pretherapeutic biopsies (PTB) of patients with locally advanced rectal adenocarcinoma (LARC) with tumor response and relapse after chemoradiotherapy (CRT) and rectal surgery.
Authors: Van Den Eynde Marc , El Sissy Carine , Kirilovsky Amos , Marliot Florence , Haicheur Nacilla , Dragean Cristina Anca , Danse Etienne , Denis Marie-Armelle , Kartheuser Alex , Remue Christophe , Leonard Daniel , Bachman Radu , Baldin Pamela , Decuyper Astrid , Humblet Yves , Scalliet Pierre , Jouret-Mourin Anne , Galon Jerome , Pages Franck 
Published: September 2018

3599 Background: Pre-operative CRT followed by total mesorectal excision (TME) is nowadays the standard of care for patient with LARC (cT3-T4N0 or cTxN+). Currently, pathologic complete response occurs in +/- 15% after CRT. Colorectal cancer T-cell infiltration is a strong prognostic factor for survival after primary tumor resection. Our aim was to determine whether T-cell infiltration in PTB could be predictive of tumor response and relapse after CRT + TME. Methods: Between 1999 and 2012, patients with LARC who underwent CRT + TME and with available clinical follow-up and PTB (with sufficient tumor cells density) were identified at the Cliniques universitaires St-Luc. The density of CD3 (T cells) and CD8 (cytotoxic) was quantified on immunostained PTB slides and analyzed with a dedicated image analysis software on whole-slide imaging. Comparisons were made using the Wilcoxon-Mann-Whitney test. Cumulative disease-free survival (DFS) was performed using the Kaplan-Meier estimator and compared by log-rank tests. Cox regression we used for uni- and multi-variate analysis. P value of less than 0.05 was considered statistically significant. Results: 154 patients (sex ratio M/F 1.8; mean age 65 years-old; upper (20%), mid (29%) and low rectum (51%), synchronous metastases (11%)) were analyzed. High CD3 and CD8 PTB densities were significantly associated with a higher pathological response (Dworak 3-4) and lower ypTNM stage after CRT +TME (p < 0,05). Higher CD3 and CD8 PTB densities were associated with higher patient DFS (CD3: HR = 2,30 (CI95%:1,15-4,59) p = 0,02; CD8: HR = 1,95 (CI95%: 1,01-3,75) p = 0,04). These results were confirmed in uni and multivariate analysis. CD3 and CD8 PTB densities added to pathological response (ypTNM/Dworak) but also clinical response (ycTNM) after CRT + TME increases significantly the accuracy prediction of tumor relapse. Conclusions: Pretherapeutic T-cell infiltration of LARC is predictive of tumor response and relapse after CRT +TME. This biomarker could be helpful for patient treatment decision. It must be validated in larger patient cohorts.
A randomized phase II trial of consolidation chemotherapy after preoperative chemoradiation (preop CRT) versus CRT alone for locally advanced rectal cancer (LARC).
Authors: Kim Sun Young , Kim Tae Won , Hong Yong Sang , Kim Jeong Eun , Lee Keun Wook , Kim Ji-Won , Hwang In Gyu , Kim Beom Gyu , Ahn Joong Bae , Oh Ho-Suk , Zang Dae Young , Joo Jungnam , Kim Dae Yong , Oh Jae Hwan , Baek Ji Yeon 
Published: September 2018

3606 Background: In LARC, preop CRT followed by total mesorectal excision (TME) is a standard of care. Recently consolidation chemotherapy after CRT was shown to be safe and to improve pathologic complete response (pCR) rate in LARC. We aimed to evaluate downstaging (DS) rate (the proportion of ypT0-2N0M0) of CRT followed by consolidation chemotherapy (capecitabine and oxaliplatin: CapOx) compared to that of CRT alone. Methods: Patients (pts) with adenocarcinoma of rectum(≤ 12cm from anal verge), ECOG PS 0 or 1, and cT3-4NxM0 were enrolled. CRT (50-50.4Gy/25-28fx) with Cap (825mg/m2/day for 5 days per week throughout CRT) followed by TME was planned in Arm A (control arm). In Arm B, 2 cycles of CapOx was given a week after completion of CRT before TME (Cap 850mg/m2/day from day 1 to day 14; Ox 100mg/m2on day 1; q 3w). 110 pts (55 per arm) were needed to show improvement of DS rate in per-protocol population (PP set) from 30% to 50% in arm B with one-sided α = 0.15, 1- β = 0.85, and follow-up loss in 5%. Results: From 9/2014 Sep to 2/2016, 110 (56 in arm A; 54 in arm B) were enrolled; 108 (55 in arm A; 53 in arm B) were randomized and started study treatment. Median age was 56 years; male/ECOG PS 1/cT4 was 76%/70%/18%. 100 pts (54 in arm A; 46 in arm B) completed CRT ± CapOx and surgery (R0 or R1 resection), while 8 (1 in arm A, 7 in arm B) dropped out mainly due to consent withdrawal. 2 of each arm underwent non-TME; that leaves 96 (52 in arm A and 44 in arm B) in PP set. Relative dose intensity of CapOx was 96% (Cap) and 95% (Ox). The main treatment outcome is described in table. The mean interval days between completion of CRT and surgery was significantly longer in arm B (52.9 vs 61.3, p < 0.0001). Conclusions: 2 cycles of CapOx after completion of CRT was feasible and safe, and it showed improvement in DS rate, even with high dropout rates (13%). Clinical trial information: NCT01952951. [Table: see text]
Pathologic complete response rate after neoadjuvant chemoradiation in patients with locally advanced rectal cancer affects survival in patients with prolonged radiation-surgery interval.
Authors: Motz Benjamin Mitchell , Lorimer Patrick Daniel , Boselli Danielle , Perry I'sis N , Hill Joshua S. , Salo Jonathan C. 
Published: September 2018

3608 Background: The current standard of care in locally advanced rectal cancer is neoadjuvant chemoradiation and R0 resection. An optimal radiation-surgery interval (RSI) has not been established. A small institutional dataset showed RSI > 49 days improved pathologic complete response (pCR) rates and disease free survival. However, in a national dataset, RSI greater than 60 days was associated with increased rates of positive margins and impaired overall survival. Because pCR is associated with improved survival, we used a national database to evaluate the relationship between RSI, pCR and survival after neoadjuvant therapy for rectal cancer. Methods: The NCDB was queried for cases 2004-2013 of AJCC stage II or III rectal adenocarcinoma that underwent neoadjuvant radiation followed by radical resection. We excluded patients with missing and outlier RSI. pCR was defined as ypT0N0M0. Chi-square, univariate, multivariable Cox model, and Cochran-Armitage time trend analyses were performed. Results: 23475 patients were identified. 7901 (33.7%) had RSI ≥60 days. pCR occurred in 1766 (11.3%) of the < 60 group and 1174 (14.9%) of the ≥60 group (p < 0.001). RSI ≥60 days has increased over time, from 22.1% in 2004 to 45.4% in 2013 (p < 0.001), as have pCR rates, from 8.4% in 2004 to 14.2% in 2013 (p < 0.001). Multivariable Cox model of the total cohort showed that RSI ≥60 days (HR = 1.11, 95% CI = 1.04-1.19) and residual disease (HR = 2.04, 95% CI = 1.78-2.34) were associated with increased mortality. Subgroup analysis of patients with pCR showed RSI ≥60 days was not associated with worse survival (HR = 1.07, 95% CI = 0.82-1.41). However, analysis of patients with residual disease showed RSI ≥60 days was associated with worse survival (HR = 1.13, 95% CI = 1.06-1.21). Conclusions: In a large national database, RSI ≥60 days worsens survival in patients who have residual disease after neoadjuvant therapy for locally advanced rectal cancer, while there is no difference in those with pCR. Emphasis should be placed on identifying patients who are unlikely to have pCR and to prioritize resection in these patients within 60 days of completion of chemoradiation.
Impact of adjuvant treatment in elderly patients with locally advanced rectal cancer: A population-based retrospective study.
Authors: Liu Shiru Lucy , O'Brien Pierre , Zhao Yizhou , Hopman Wilma M , Lamond Nathan William Dana , Ramjeesingh Ravi 
Published: September 2018

3613 Background: Little is known about the benefit and use of adjuvant chemotherapy (ADJ) in the elderly population (age ≥ 65) with locally advanced rectal cancer (LARC). We undertook a provincial review of LARC patients to evaluate the potential benefits, including survival and time to relapse (TTR), of ADJ in elderly patients. Methods: We performed a retrospective analysis of 286 LARC patients (stage 2 and 3) diagnosed between January 2010 and December 2013 from Nova Scotia, Canada, who underwent curative-intent surgery. Baseline patient, tumor and treatment characteristics were collected. Survival and TTR analysis were performed using Kaplan-Meier and Cox-regression statistics. Results: 152 patients were age ≥65, and 92 age ≥70. Median follow-up was 46 months. 178 patients (62%) received neoadjuvant chemo-radiation (NEOADJ). While 109 patients (81%) age < 65 received ADJ, only 68 patients (45%) age ≥ 65 received ADJ. Kaplan-Meier analysis revealed a significant survival and TTR advantage for ADJ irrespective of age (table). In cox-regression multivariate analysis, ECOG status, T stage, and ADJ were significant predictors of survival (p < 0.04), while age was not. Similarly, N stage, NEOADJ, and ADJ were significant predictors of TTR (p < 0.007). Poor ECOG status was the most common cause of ADJ omission. There was a significantly higher amount of grade≥ 1 chemotherapy-related toxicity experienced by patients age ≥ 65 treated with ADJ compared to no ADJ (77% vs 32%, p < 0.0001), which consisted mostly of diarrhea and mucositis. Toxicity was the main reason for non-completion of ADJ in the elderly. Conclusions: Elderly patients with LARC have significantly improved overall survival with ADJ, but the use of ADJ is lower than in patients age < 65. However, elderly patients experience more chemotherapy-related toxicities, leading to higher rates of early treatment discontinuation. [Table: see text]
Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial.
Authors: Al-Batran Salah-Eddin , Homann Nils , Schmalenberg Harald , Kopp Hans-Georg , Haag Georg Martin , Luley Kim Barbara , Schmiegel Wolff H. , Folprecht Gunnar , Probst Stephan , Prasnikar Nicole , Thuss-Patience Peter C. , Fischbach Wolfgang , Trojan Jorg , Koenigsmann Michael , Pauligk Claudia , Goetze Thorsten Oliver , Jaeger Elke , Meiler Johannes , Schuler Martin H. , Hofheinz Ralf 
Published: September 2018

4004 Background: The MAGIC trial established perioperative (periop) epirubicin, cisplatin, and 5-FU (ECF) as a standard treatment for patients (pts) with operable esophagogastric cancer, but survival continues to remain poor. FLOT4 (NCT01216644) is a multicenter, randomized, investigator-initiated, phase 3 trial. It compares the docetaxel-based triplet FLOT with the anthracycline-based triplet ECF/ECX as a periop treatment for pts with resectable gastric or GEJ adenocarcinoma. Methods: Eligible pts of stage ≥cT2 and/or cN+ were randomized to either 3 preoperative and 3 post-operative 3-week cycles of ECF/ECX (epirubicin 50 mg/m2, cisplatin 60 mg/m², both d1, and 5-FU 200 mg/m² as continuous infusion or capecitabine 1250 mg/m2 orally d1-21) or 4 pre-operative and 4 post-operative 2-week cycles of FLOT (docetaxel 50 mg/m2, oxaliplatin 85 mg/m², leucovorin 200 mg/m², and 5-FU 2600 mg/m² as 24-hour infusion, all d1). The primary endpoint was overall survival (OS; 80% power; HR of 0.76; 2-sided log-rank test at 5% type I error). Results: Between Aug 2010 and Feb 2015, 716 pts (360 ECF/ECX; 356 FLOT) were randomly allocated. Baseline characteristics were similar between arms (overall, male 74%; median age 62; cT3/T4 81%; cN+ 80%; GEJ 56%). 91% and 37% of pts with ECF/ECX and 90% and 50% with FLOT completed planned pre-operative and post-operative cycles, respectively. Median follow-up was 43 mon. 369 pts died (203 ECF/ECX; 166 FLOT). FLOT improved OS (mOS, 35 mon with ECX/ECF vs. 50 mon with FLOT; HR 0.77 [0.63 - 0.94]; p = 0.012). 3y OS rate was 48% with ECF/ECX and 57% with FLOT. FLOT also improved PFS (mPFS, 18 mon with ECX/ECF vs. 30 mon with FLOT; HR 0.75 [0.62 - 0.91]; p = 0.004). Periop complications were 50% with ECF/ECX and 51% with FLOT. 30- and 90-day mortality was 3% and 8% with ECF/ECX and 2% and 5% with FLOT. There was more G3/4 nausea and vomiting with ECF/ECX and more G3/4 neutropenia with FLOT. Conclusion: Periop FLOT improved outcome in patients with resectable gastric and GEJ cancer compared to periop ECF/ECX. Clinical trial information: NCT01216644.
KEYNOTE-059 cohort 2: Safety and efficacy of pembrolizumab (pembro) plus 5-fluorouracil (5-FU) and cisplatin for first-line (1L) treatment of advanced gastric cancer.
Authors: Bang Yung-Jue , Muro Kei , Fuchs Charles S. , Golan Talia , Geva Ravit , Hara Hiroki , Jalal Shadia Ibrahim , Borg Christophe , Doi Toshihiko , Wainberg Zev A. , Wang Jiangdian , Koshiji Minori , Dalal Rita P. , Chung Hyun Cheol 
Published: September 2018

4012 Background: Preliminary analyses from the global, multicohort, phase 2 KEYNOTE-059 (NCT02335411) study suggested that safety of pembro + 5-FU + cisplatin is manageable as 1L therapy in pts with advanced gastric or gastroesophageal junction (G/GEJ) cancer (cohort 2). We present efficacy and updated safety data from KEYNOTE-059 cohort 2. Methods: Cohort 2 enrolled pts ≥18 y with HER2 – recurrent or metastatic G/GEJ adenocarcinoma, measurable disease, no prior therapy for metastatic/advanced disease, and ECOG PS 0-1. Pts received pembro 200 mg on day 1 of each 21-day cycle + cisplatin 80 mg/m2 for 6 cycles + 5-FU 800 mg/m2 (or capecitabine 1000 mg/m2 in Japan) Q3W for up to 2 y or until disease progression, investigator/pt decision to withdrawal, or unacceptable toxicity. PD-L1+pts had expression in ≥1% tumor or stromal cells using IHC (22C3 antibody). End points were safety and tolerability (primary), ORR (RECIST v1.1, by central review), DOR, PFS, and OS (secondary). Results: Of 25 enrolled pts, 64% were men, 68% were Asian, and 64% had PD-L1+ tumors. Median age was 64 y. At data cutoff (Oct 19, 2016), median duration of follow-up was 12.2 mo (range, 1.8 to 19.6) and 84% of pts had discontinued treatment, mainly owing to clinical or radiologic disease progression (64%). ORR (CR + PR) was 60% (95% CI, 38.7-78.9) in all pts. Overall, 32% of pts had SD (95% CI, 14.9-53.5), 4% had PD (95% CI, 0.1-20.4), and 4% were not evaluable (95% CI, 0.1-20.4). ORR was 68.8% (95% CI, 41.3-89.0) in PD-L1+ pts and 37.5% (95% CI, 8.5-75.5) in PD-L1– pts. Median DOR (range) was 4.6 mo (2.6 to 14.4+) in all pts, 4.6 mo (3.2 to 14.4+) in PD-L1+ pts, and 5.4 mo (2.8 to 8.3+) in PD-L1–pts. Median PFS was 6.6 mo (95% CI, 5.9-10.6); median OS was 13.8 mo (95% CI, 7.3-not estimable). Grade 3-4 treatment-related adverse events (TRAEs) occurred in 76% of pts. TRAEs led to discontinuation in 3 pts (grade 3 stomatitis, grade 2 hypoacusis, and grade 1 creatinine increase). No TRAEs were fatal. Conclusions: Pembro + 5-FU + cisplatin showed manageable safety and encouraging antitumor activity as 1L therapy for pts with advanced G/GEJ cancer. Further exploration of pembro + 5-FU + cisplatin in this setting is warranted. Clinical trial information: NCT02335411.
Assessment of conditional survival probability in resected esophageal adenocarcinoma.
Authors: Graham Donna M. , Bannon Finian , Lloyd Megan , Noble Fergus , Walker Rob , Griffiths Ewen , Bedford Matthew , Whiting John , Nutzinger Barbara , Grehan Nicola , O'Neill Robert , Skipworth Richard , Mercer Stuart , Saunders John , Parsons Simon L. , Kennedy Richard D. , Fitzgerald Rebecca C. , Underwood Timothy J , Turkington Richard C. ,   On Behalf of the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium
Published: September 2018

4030 Background: Prognostication for cancer patients is based upon factors determined at baseline and becomes less relevant over time. Conditional survival (CS) estimates future prognosis based upon survival to a specific time point after treatment. We analyzed CS for patients in the United Kingdom (UK) undergoing surgery and neoadjuvant chemotherapy (NAC) for gastro-esophageal junction (GEJ) or esophageal adenocarcinoma (EAC). Methods: 1409 patients with GEJ/EAC treated with NAC and surgical resection at 7 centers across the UK from 2002-2014 were identified. Clinicopathological and survival data was collected as part of the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) consortium. A multivariable Cox survival model was used to analyze the association of factors such as node positivity (N+), lymphovascular invasion (LVI+), tumor differentiation, circumferential resection margin involvement (CRM+) and pathological response by tumor regression grade (TRG ≤2) with risk of relapse (RR) or death from time of surgery. Results: Of 1409 patients, 726 (51.5%) were aged <65 years, and 1195 (84.8%) were male. Hazard ratios (HR) for RR conditional on recurrence-free (RF) years to date are detailed below. N+ was the most robust predictor of relapse and mortality over time. LVI+ and moderate to poor differentiation influenced relapse in the first 2 years whereas CRM+ and TRG≤2 had their greatest effect in the year following surgery. Age, sex, and year of surgery had no association with RR or mortality. Similar patterns were observed for risk of death. Conclusions: CS provides a more dynamic estimate of future RR and survival among patients who have accrued survival time, especially in patients with high-risk features. CRM+ and LVI+ govern early survival events but as time from surgery increases these factors become less relevant. [Table: see text]
Patterns of care and treatment outcomes of patients with stage I esophageal cancer: A National Cancer Database analysis.
Authors: Moreno Amy Catherine , Zhang Ning , Lin Steven H. , Giordano Sharon Hermes 
Published: September 2018

4035 Background: The aim of this study was to examine current patterns of care and associated outcomes for patients with stage I esophageal cancer (EC) treated in the United States. Methods: The National Cancer Data Base (NCDB) was queried for patients diagnosed with clinical stage T1-2N0 EC from 2004-2012. Patients were categorized into four treatment groups: observation without definitive therapy (Obs), chemoradiotherapy (CRT), local excision (LE), and esophagectomy (Eso). Patient, tumor, and treatment parameters were compared between groups. Kaplan-Meier 5-year overall survival (OS) estimates, postoperative 30- and 90-day mortality comparisons, and multivariate Cox proportional hazards modeling are reported. Results: A total of 5,460 patients met the criteria. Of these, 21% were observed, 14% underwent CRT, 23% LE, and 42% Eso. Median age and follow up were 67 years and 28 months, respectively. Eso was the primary treatment for patients of age ≤ 80 while 48% of patients age > 80 were observed. Age, race, comorbidity score, tumor location within the esophagus, type of medical insurance, median income, type of facility (academic vs. non-academic), and distance from treating facility were significant factors for predicting receipt of local therapy over observation. Postoperative 30-day mortality between the LE and Eso groups was 0.5% and 2.9%, respectively ( P< .001), which increased to 1.4% and 5.5% at 90 days ( P< .001). Five-year OS was 21% for Obs, 26% CRT, 64% LE, and 63% Eso ( P < .001). Multivariate analyses demonstrated improved OS with any form of local definitive therapy: CRT ( HR: 0.54, 95% CI [0.48 - 0.61], P< .001), LE ( HR: 0.24, [0.20 - 0.27], P< .001), Eso (HR: 0.31, [0.28 - 0.35], P< .001). Age, comorbidity score, facility type, distance, median income quartile, and insurance status were also independently associated with OS. Conclusions: Management of stage I EC is influenced by several demographic and socioeconomic factors. Clinical observation yields suboptimal outcomes compared to any local therapy, and a surgical approach should be considered over CRT whenever feasible.