bluuebunny/crossref_metadata_2025_split huggingface dataset:
Surgeon and hospital variation in adjuvant chemotherapy delivery to patients with stage III colon cancer.
Authors: Xu Zhaomin , Justiniano Carla Francesca , Becerra Adan Z , Aquina Christopher Thomas , Boscoe Francis P. , Schymura Maria J. , Temple Larissa K. F. , Fleming Fergal J. 
Published: September 2018

3596 Background: It is well established that age and comorbidities have significant impact on adjuvant chemotherapy delivery to stage III colon cancer patients. This study examines differences in the hospital and surgeon-specific probabilities of adjuvant therapy delivery to stage III colon cancer patients by comorbidity burden and age. Methods: Patients who underwent surgery for stage III colon cancer from 2004-2013 were included from the New York State Cancer Registry and the Statewide Planning and Research Cooperative System. Comorbidity burden was defined with the Charlson Comorbidity Index (CCI). Multilevel logistic regressions characterized variation in adjuvant chemotherapy delivery among individual hospitals and surgeons by CCI and age. Results: 11575 patients met inclusion criteria, of which 59% received adjuvant therapy. Younger age, lower CCI, and high volume surgeons/hospitals were associated with delivery of adjuvant therapy (p < 0.01). Median time to chemotherapy was 43 days among CCI = 0 vs 48 among CCI≥2. The risk adjusted hospital and surgeon-specific probabilities of adjuvant delivery decreased with increasing CCI and age. The proportion of variation attributable to surgeons, vs hospitals, increased with CCI and age. Hospital variation between the highest and lowest hospitals increased from a 6-fold difference among CCI = 0 to an 11 fold difference among CCI≥2. Surgeon variation increased from a 14-fold difference among CCI = 0 to a 40 fold difference among CCI≥2. Conclusions: Variation in adjuvant chemotherapy delivery to stage III colon cancer patients increased with higher comorbidity burden and age. While a larger proportion of variation is attributable to surgeons among patients with the highest CCI and the most elderly, the vast majority of the variation is related to hospital factors. Even taking into account that some patients may be unfit for adjuvant therapy, this variation in treatment is alarmingly high. [Table: see text]
Microbiota as a new indicator of colorectal cancer (CRC) heterogeneity.
Authors: Sobhani Iradj , Ghozelane Amine , Bergsten Emma Bergsten , Kennedy Sean 
Published: September 2018

3615 Background: Location and somatic gene signature of CRCs may impact prognosis and therapy response. The aim was to characterize colon Microbiota in CRC patients regarding location, gene markers and outcome. Methods: Patients (N = 173) signed consent for whole metagenome (shot gun sequencing on Illumina HiSeq2500) analysis of stool DNA: 72 CRC (53 sporadic-S, 19 Lynch-L), 87 asymptomatic subjects (normal colonoscopy), 14 first degree healthy relatives from Lynch families. "MOCAT" pipeline was used, library sorted (Phred quality score ¡20 Alientrimmer v0.4.0) after exclusion of < 35 nt, human genes or phage sequences. Quality sequences were aligned (REFMG.V13) and most abundant genes constructed (MBMA program v0.1). The Shaman program (shaman.c3bi.pasteur.fr) was used. The number of bacteria was estimated (REFMG program). The linear model (GLM) was implemented in the DESeq2 R kit. Dfferences between Control (N = 87) and CRCs (N = 69), between L (N = 19) and S CRCs(N = 50), and between LCRC (N = 19) and Healthy Lynch relatives were obtained after interaction of age, BMI and gender was considered (GLM model). The P < 0.1 value was retained after correction (Benjamini and Hochberg). The specific taxonomic composition of the control and CRC groups was subjected to random analysis ( Caret's R package) with two optimization parameters (precision and kappa) in the model. Results: There was no difference for gender, age (p = 0.08) and BMI (p = 0.187) in the L and S CRCs. Significant differences were observed between Normal and CRCs, C-CRC and L-CRC, L-CRC and first degree relatives based on the common component (similarity of sequences): 13 species differentiated Normal and CCRs, two were more prevalent in L-CRCs. The panels of bacteria linked with location, MSI, Ras mutations, methylation phenotypes and survival were identified. No significant link was observed with TNM Staging: I (N = 17, 2L and 15S), II (N = 12, 5L and 7S), III (N = 20, 10L, 10S), IV (N = 22.1L, 21S). DFS might be dysbiosis dependent. Conclusions: CRC dysbiosis is location-dependent. Several bacteria are associated with Ras mutation, MSI, and methylation status. They may directly or through therapies impact the prognosis. Microbiota signature should be taken in consideration in trials.
KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer.
Authors: Fuchs Charles S. , Doi Toshihiko , Jang Raymond Woo-Jun , Muro Kei , Satoh Taroh , Machado Manuela , Sun Weijing , Jalal Shadia Ibrahim , Shah Manish A. , Metges Jean-Philippe , Garrido Marcelo , Golan Talia , Mandala Mario , Wainberg Zev A. , Catenacci Daniel V.T. , Bang Yung-Jue , Wang Jiangdian , Koshiji Minori , Dalal Rita P. , Yoon Harry H. 
Published: September 2018

4003 Background: Pembro has shown promising antitumor activity and manageable safety in a phase 1 study of pts with previously treated advanced gastric cancer. We conducted a global, multicohort, phase 2 study of pembro in pts with advanced gastric or gastroesophageal junction (G/GEJ) cancer (KEYNOTE-059;NCT02335411). Methods: Cohort 1 enrolled 259 pts, aged ≥18 y with measurable recurrent or metastatic G/GEJ adenocarcinoma who had progressed on ≥2 prior chemotherapy regimens and had ECOG PS 0-1. Pts received pembro 200 mg Q3W up to 2 y or up to 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). Primary end points: ORR (RECIST 1.1, by central review), safety, and tolerability. Results: Of 259 pts in cohort 1, 76.4% were men; median age was 62.0 y. 51.7% and 48.3% received pembro as 3rd-line (3L) and 4L+ therapy, respectively. 57.1% had PD-L1+ tumors. At data cutoff (Oct 19, 2016), median duration of follow-up was 5.4 mo (range, 0.5 to 18.7). Overall ORR (CR + PR) was 11.2% (95% CI, 7.6-15.7); 1.9% of pts (95% CI, 0.6-4.4) had CR, 9.3% had PR (95% CI, 6.0-13.5), 17% (95% CI, 12.6-22.1) had SD, and 55.6% (95% CI, 49.3-61.7) had PD. Median DOR was 8.1 mo (range, 1.4+ to 15.1+). ORR was 14.9% (95% CI, 9.4-22.1) in 3L pts and 7.2% (95% CI, 3.3-13.2) in 4L+. In PD-L1+ pts, ORR was 15.5% (95% CI, 10.1-22.4) with 2.0% (95% CI, 0.4-5.8) CR and 13.5% (95% CI, 8.5-20.1) PR; in PD-L1– pts, ORR was 5.5% (95% CI, 2.0-11.6), with 1.8% (95% CI, 0.2-6.5) CR and 3.7% (95% CI, 1.0-9.1) PR. In 3L pts with PD-L1+ tumors, ORR was 21.3% (95% CI, 12.7-32.3), with 4.0% (95% CI, 0.8-11.2) CR; in 3L pts with PD-L1– tumors, ORR was 6.9% (95% CI, 1.9-16.7), with 3.4% (95% CI, 0.4-11.9) CR. Grade 3-5 treatment-related AEs (TRAEs) occurred in 43 pts (16.6%). TRAEs led to discontinuation in 2 pts (abnormal LFT, bile duct stenosis) and were fatal in 2 pts (acute kidney injury, pleural effusion). Conclusions: Pembro showed encouraging efficacy and manageable safety after ≥2 prior lines of therapy in pts with advanced G/GEJ cancer in this large phase 2 trial. Survival and additional biomarker data, including MSI status, will be presented. Clinical trial information: NCT02335411.
Results of the randomized phase II portion of NRG Oncology/RTOG 0848 evaluating the addition of erlotinib to adjuvant gemcitabine for patients with resected pancreatic head adenocarcinoma.
Authors: Safran Howard , Winter Kathryn A , Abrams Ross A. , Regine William , Goodman Karyn A. , Berger Adam C. , Gillin Michael , Philip Philip Agop , Lowy Andrew M. , Wu Abraham Jing-Ching , DiPetrillo Thomas A. , Corn Benjamin W. , Seaward Samantha A. , Haddock Michael G. , Song Suisui , Jiang Yixing , Fisher Barbara Jean , Katz Alan W. , Mehta Sharmila P. , Crane Christopher H 
Published: September 2018

4007 Background: NRG/RTOG 0848 is a 2-step study designed to determine whether erlotinib (E) added to gemcitabine (G) (randomized Ph II) &/or adjuvant radiation with concurrent 5-FU or capecitabine following 6 months of systemic chemotherapy (Ph III), improve survival in patients (pts) with resected pancreatic head adenocarcinoma. The erlotinib results are reported here. Methods: Eligible pts include those with resected pancreatic head adenocarcinoma, pathologic stage T1-T3, N0-1, M0; PS 0-1, & CA19-9 ≤ 180 IU/L. Pts in Arms 1 & 2 received G 1 gm/m2 weekly for 3 weeks in a 28-day cycle for 6 cycles. Pts in Arm 2 also received E 100 mg/day. The primary hypothesis for the E portion was that G+E would increase overall survival (OS) compared to G alone. With a 1-sided alpha of 0.15, 200 OS events provide 80%/90% power to detect a signal for an increase in median OS from 22 to 28.8/30.6 months (mos). OS was estimated by the Kaplan-Meier method & arms compared using the log rank test. The Cox proportional hazards model was used to analyze treatment effect. Results: 336 pts were randomized from 11/17/2009 to 2/28/2014, with 163 pts evaluable for G and 159 for G+E. Median age was 63 years (39-86). Most pts had pathologic T3 disease (78%) & CA19-9 ≤ 90 (93%). There are 32 pts (20%) with grade 4 adverse events (AEs) & 2 pts (1%) with grade 5 AEs on G and 27 (17%) & 3 (2%) on G+E arm, respectively. There are fewer grade ≥ 3 GI AEs on the G arm (22%) as compared to the G+E arm (28%), and 110 (69.2%) & 93 (59.6%) pts received at least 85% of planned G dose for the G & G+E arms, respectively. 58% of E pts received at least 85% of planned E dose. The median follow-up for alive pts is 42.5 mos (min-max: < 1-75). With 203 deaths, median & 3-yr OS (95% CI) are 29.9 mos (21.7-33.4) & 39% (30, 45) for G and 28.1 mos (20.7-30.9) & 39% (31, 47) for G+E; log-rank p = 0.62. The hazard ratio (95% CI) comparing OS of G+E to G is 1.04 (0.79- 1.38). Conclusions: The addition of adjuvant E to G did not provide a signal for increased OS in pts with resected pancreatic head cancer compared to G alone. Accrual to the trial is continuing to answer the Ph III radiation question. Clinical trial information: NCT01013649.
A randomized phase II pilot study prospectively evaluating treatment for patients based on ERCC1 for advanced/ metastatic esophageal, gastric, or gastroesophageal junction cancer: SWOG S1201.
Authors: Iqbal Syma , McDonough Shannon , Lenz Heinz-Josef , Ilson David H. , Burtness Barbara , Nangia Chaitali Singh , Barzi Afsaneh , Schneider Charles , Liu Jijun , Dotan Efrat , Guthrie Katherine A , Hochster Howard S. 
Published: September 2018

4009 Background: Platinum based treatment (tx) is standard in HER2 negative patients (pts) with advanced esophagogastric cancer (AEGC). Retrospective data suggest intratumoral ERCC1 levels may determine platinum sensitivity. A randomized phase II study was performed in pts with AEGC to explore whether the efficacy of a platinum 5-FU/LV/Oxaliplatin (FOLFOX) vs. non-platinum containing regimen irinotecan/taxotere (IT) differed according to ERCC1 levels. Methods: 203 untreated pts with AEGC, Her2 -, Zubrod PS 0-1, were randomized to FOLFOX vs. IT, stratified by intratumoral ERCC1 low (<1.7) vs. high (≥1.7). Objectives were to assess PFS and OS in all pts treated with FOLFOX compared with IT, and in those pts with low and high ERCC1 levels and to assess for interactive effects between ERCC1 expression and tx arm. Results: 86% of pts had ERCC1 values <1.7. Thus, evaluation of ERCC1 pts in the high subgroup was not feasible. Tx groups were well matched by age, sex, race, ERCC1 level, and site. A series of K-M plots were used to explore whether tx arm differences in PFS varied based on ERCC1 levels; little evidence of such was noted. Grade ≥ 3 anemia, dehydration, diarrhea and fatigue were greater in pts with IT. Grade ≥ 3 neuropathy and decreased neutrophils were greater in pts with FOLFOX. Conclusions: In all pts, FOLFOX had a statistically superior PFS and RR, when compared with IT. In pts with ERCC1 <1.7 receiving FOLFOX, PFS and RR was statistically superior, with no difference in OS. There was no significant evidence of differential treatment effect on PFS across ERCC1 levels. Clinical trial information: NCT01498289. [Table: see text]
Cisplatin/5-FU (CF) +/- panitumumab (P) for patients (pts) with non-resectable, advanced, or metastatic esophageal squamous cell cancer (ESCC): An open-label, randomized AIO/TTD/BDGO/EORTC phase III trial (POWER).
Authors: Moehler Markus H. , Thuss-Patience Peter C. , Brenner Baruch , Longo Federico , Meiler Johannes , Ettrich Thomas Jens , Hofheinz Ralf , Al-Batran Salah-Eddin , Vogel Arndt , Mueller Lothar , Lutz Manfred P. , Borchert Kersten , Greil Richard , Alsina Maria , Karatas Aysun , Van Cutsem Eric , Keller Ralph , Larcher-Senn Julian , Lorenzen Sylvie ,   AIO/BDGO/TTD/EORTC
Published: September 2018

4011 Background: Most ESCC pts have advanced disease at time of diagnosis. Chemotherapy (CTX) is used to improve quality of life (QoL) and overall survival (OS), but still with limited impact. Prior studies suggested increased efficacy of EGFR antibodies (AB) combined with CF (Lorenzen, Ann Oncol 2009). Methods: This open-label, randomized (1:1), multicenter, multinational phase III included pts with non-resectable, advanced or metastatic ESCC (RECIST1.1), not radiochemotherapy (RCTX) eligible and ECOG 0-1. Previous CTX in metastatic setting, concurrent RCTX and exposure to EGFR-AB were excluded. Pts received CF (C 100 mg/m² d1 + F 1000 mg/m²/d, d1-4) or CFP (9 mg/kg d1) q3 weeks until disease progression. Due to more Gr3-4 SAEs in the first 60 Pts with CFP, C was reduced to 80mg/m²d1 Tumor assessment was performed q9 weeks. Primary objective was OS: superiority of CFP (9 months [mo]) over CF (6 mo) with 300 pts (90% power). Results: Between 6.2012-5.2015, 146/155 pts were randomized. After interim analysis for futility, the trial was stopped. 60(83%) of CFP and 55(79%) of CF pts had any AE, mostly diarrhea, hypokalemia, hypomagnesaemia, rash, and hand-foot syndrome. Main Gr≥3 AEs were low neutrophils 21/ 24% and anemia 13/16 % for CFP vs CF, respectively. Gr 3-4 skin reactions and rash were higher in CFP (10%) vs CF (0%). Overall, 51/72 (71%) of CFP and 36/70 (51%) of CF had SAE. Main SAE were dysphagia, acute kidney injury, diarrhea, fevers and febrile neutropenia in 6/6%, 7/4%, 7/3%, 3/6% and 6/1% for CFP vs CF, respectively. For all CFP vs CF pts, median OS was 9.4 vs. 10.2 mo (hazard ratio (HR) 1.17, 95%CI 0.79-1.75; P=0.43). For 56 pts treated with cisplatin 100mg/m²d1, OS was 9.4 vs. 12.9 mo (HR 1.83, 95 % CI 0.98-3.42; P=0.06). After C was reduced (80mg/m²), OS (85 pts) favored CFP vs CF, with 9.8 vs. 8.3 mo (HR 0.84, 95%CI 0.49-1.43; P=0.51). Median PFS for all CFP vs CF pts, was 5.3 vs. 5.8 mo. (HR 1.21, 95%CI 0.85-1.73; P=0.29) respectively. Conclusions: Addition of Panitumumab to CF provided no additional benefit to chemotherapy alone as first-line treatment of ESCC. Biomarker program is going on for further analyses. Clinical trial information: NCT1627379.
A phase II trial of gemcitabine (G), cisplatin (C), and nab-paclitaxel (N) in advanced biliary tract cancers (aBTCs).
Authors: Shroff Rachna T. , Borad Mitesh J. , Xiao Lianchun , Kaseb Ahmed Omar , Varadhachary Gauri R. , Wolff Robert A. , Raghav Kanwal Pratap Singh , Iwasaki Michiko , Masci Peter , Ramanathan Ramesh K. , Ahn Daniel H. , Bekaii-Saab Tanios S. , Javle Milind M. 
Published: September 2018

4018 Background: BTCs are often diagnosed at an advanced stage and have a poor prognosis. The standard therapy for aBTCs is the combination of GC. However, the median overall survival (mOS) is dismal at 11.7 months (mos) with a median progression free survival (mPFS) of 8 mos. Methods: A single arm, phase II study was conducted at MD Anderson and Mayo Clinic Arizona. Patients (pts) with aBTC were treated at initial dose level of G/C/N (in mg/m2) at 1000/25/125 (n = 27) which was reduced to lower doses due to grade 3/4 hematological (heme) toxicity (tox) - G/C/N: 800/25/100 (n = 33). Cycles were q21 days with restaging q3 cycles until progression. PFS was the primary endpoint (endpt). Using a Bayesian hypothesis test-based design, we assumed mPFS of 8 mos under the null hypothesis (H0), 10 mos under the alternative (H1). Secondary endpts included mOS, RECIST v1.1 response rate (RR), safety and CA19-9 response. Results: 60 pts were enrolled with data on 51 available as of the time of this abstract (age: median 60 yrs [range 31-77], ECOG PS 0/1 (17/34), M/F (30/21), intrahepatic cholangiocarcinoma/extrahepatic/gallbladder (32/8/11). Median follow-up was 11.5 mos and median number of treatment (trmt) cycles = 5. Pts at initial dose level had significant grade 3/4 heme tox: neutropenia, febrile neutropenia, anemia, and thrombocytopenia leading to trmt discontinuation in 6/27 pts. After dose reduction to G/C/N (in mg/m2) at 800/25/100, trmt was better tolerated with only 4 pts experiencing grade 4 heme tox. Non-heme tox were grade 3 in 10 pts: nausea/vomiting, diarrhea, thromboembolic event/CVA, hypokalemia, constipation, cystitis, LFT elevations. In the initial 51 pts, mPFS = 11.4 mos (95% CI: 6.1, not reached) and mOS not reached (estimated > 20 mos, 1-year survival rate 66.7%; 95%CI: 65.9-92.2%). 34 pts evaluable for response: disease control rate (PR+CR+SD)-82.3% and RR-32.3%. 3 unresectable cases were operated post trmt with 1 pathologic CR. Conclusions: The combination of GCN was well tolerated at adjusted doses and demonstrates encouraging preliminary efficacy having met its mPFS endpt and a 1-year survival rate higher than historical control. These results merit evaluating GC +/-N in a randomized controlled study. Clinical trial information: NCT02392637.
Clinical impact of microsatellite instability in patients with stage II and III gastric cancer: Results from the CLASSIC trial.
Authors: Choi Yoon Young , Kim Hyunki , Yang Han-Kwang , Kim Woo Ho , Kim Young Woo , Kook Myeong-Cherl , Park Young-Kyu , Kim Hyung-Ho , Lee Hye-Seung , Lee Kyung Hee , Gu Mi Jin , Choi Seung Ho , Hong Soon Won , Kim Jong Won , Noh Sung Hoon , Cheong Jae-Ho 
Published: September 2018

4022 Background: The clinical implications of microsatellite instability (MSI) in gastric cancer are unclear. We investigated the usefulness of MSI status as a predictor of prognosis and responsiveness to adjuvant chemotherapy in patients with stage II and III gastric cancer. Methods: Tumor specimens and clinical information were collected from patients enrolled in the CLASSIC trial, a randomized controlled study of capecitabine plus oxaliplatin-based adjuvant chemotherapy. Five mononucleotide markers were used to assess tumor MSI status. Results: Of 592 specimens, 36 (6.1%) were MSI-high (MSI-H), whereas others were MSI-low or microsatellite-stable (MSS). Among 286 patients not treated with adjuvant therapy, those with MSI-H tumors had a better 5-year disease-free survival rate than did those with MSI-low/MSS tumors (hazard ratio adjusted by age, sex, tumor grade, disease stage, tumor location: 0.244 [95% confidence interval, 0.069–0.867]; p = 0.0292). Among 306 patients who received adjuvant chemotherapy, MSI-H status did not correlate with better disease-free survival (adjusted hazard ratio: 0.561 [95% confidence interval, 0.190–1.654]; p = 0.2946). Benefits from adjuvant chemotherapy differed by MSI status; although adjuvant chemotherapy improved disease-free survival among patients with MSI-low/MSS (adjusted hazard ratio: 0.634 [95% confidence interval, 0.485–0.828]; p = 0.0008), no benefit was observed in the MSI-H group (adjusted hazard ratio: 1.877 [95% confidence interval, 0.284–12.390]; p = 0.5130). Conclusions: Among patients with stage II and III gastric cancer, a MSI-H status correlated with a favorable prognosis, and adjuvant chemotherapy benefited those with MSI-L/MSS tumors but not those with MSI-H tumors.
PD-L1 expression and response to neo-adjuvant chemotherapy in esophageal adenocarcinoma.
Authors: Parkes Eileen E. , Blayney Jaine K. , McCarron Eamon , Douglas Rosalie V. , Stevenson Leanne , McManus Damian , McQuaid Stephen , Arthur Ken , James Jacqueline , Salto-Tellez Manuel , Noble Fergus , Underwood Timothy J , O'Neill Robert , Fitzgerald Rebecca C. , Kennedy Richard D. , Turkington Richard C. 
Published: September 2018

4023 Background: Programmed Death-1 Receptor (PD-1) and its ligand (PD-L1) downregulate T cell activation and suppress tumor killing. This study investigated the role of PD-L1 and tumor infiltrating lymphocytes (TILs) in response to neo-adjuvant therapy and prognosis in esophageal adenocarcinoma (EAC). Methods: Transcriptional profiling of 273 formalin fixed paraffin embedded pre-treatment endoscopic EAC biopsies was carried out using the Almac Diagnostics Xcel array and the expression levels of PD-L1 probesets corresponding to protein encoding extracted. Response was assessed by tumor regression grade (TRG; score ≤ 2 = response). Immunohistochemistry (IHC) for PD-L1 and CD8 was performed in matched resection specimens from 135 patients. All EAC patients were treated with cisplatin-based neo-adjuvant chemotherapy followed by surgical resection between 2003 and 2014 at four UK centers as part of the OCCAMS consortium. Associations between expression, protein levels and TRG were assessed by Kruskal-Wallis, Mann-Whitney Unpaired, Spearman rank correlation or chi-squared tests. Survival analysis was performed using Cox Proportional Hazards regression. Results: High PD-L1 gene expression in the pre-chemotherapy biopsies was associated with pathological response (TRG ≤ 2; p = 0.02) following neo-adjuvant chemotherapy. PD-L1 ( > 5%) was expressed in the tumor or stromal cells in 4% and 15% of resection specimens respectively. PD-L1 gene and IHC expression ( > 5%) were closely associated between the biopsies and both the tumor (p = 0.032) and stroma (p = 0.019) of the matched resection specimens. Patients with PD-L1 IHC positivity in tumor cells demonstrated improved relapse-free survival (HR 0.314; 95% CI 0.099-0.997; p = 0.049) and positive stromal PD-L1 IHC staining correlated with pathological response (p = 0.05). Biopsy gene expression of PD-L1 and CD8 was closely associated (p = 0.024) and the presence of CD8+ TILs in the microenvironment strongly correlated with tumor (p < 0.001) and stromal (p < 0.001) PD-L1 positivity. Conclusions: High PD-L1 expression in the pre-treatment biopsies in EAC is predictive of response to neo-adjuvant chemotherapy and may aid selection of conventional and immune-targeted agents.