bluuebunny/crossref_metadata_2025 huggingface dataset:
Total mesorectal excision compared to local excision in locally advanced rectal cancer achieving complete pathological response with neoadjuvant therapy: A National Cancer Database Analysis.
Authors: Abdalla Ahmed , Malapati Sindhu Janarthanam , Singh Sunny R K , Szpunar Susan , Hadid Tarik H. , Kafri Zyad , Aref Amr
Published: May 2020

4107

Background: Total mesorectal excision (TME) is the standard surgical intervention for patients with locally advanced rectal cancer (LARC) regardless of response to neoadjuvant therapy. In this study, we perform a comprehensive review of the National Cancer Database (NCDP) to compare the clinical and surgical outcomes of TME to local excision (LE) in patients with LARC. Methods: NCDP was systematically researched to abstract all patients with stage II and III rectal adenocarcinoma between the years 2004 and 2015. We subsequently excluded all the patients who did not achieve complete pathological response (pT0) after neoadjuvant therapy. The patients were then divided into two groups; those who underwent TME and those who underwent LE. Data were analyzed using SPSS v. 26.0, SAS v. 9.4. Results: A total of 4,705 were included in the study; 4,589 in the TME group and 116 in the LE group. Baseline characteristics were similar between the groups except for age. A total of 81(1.8%) of patients in the TME group and 8(6.9%) of patients in the LE group did not receive radiation (p=0.006) and 19(0.4%) of patients the TME group and 4(3.4%) of patients in the LE group did not receive chemotherapy. There was no difference in median overall survival between TME and LE groups. The median length of hospital stay was remarkably shorter in the LE group compared to the TME group (1 day vs 6 days, p<0.0001). The rate of 30-day and 90-day postoperative mortality were similar between the two groups (p-value=0.334 and 0.06, respectively). In the LE group, 4 (3.4%) of patients were readmitted within 30 days of the resection compared to 374 (8.5%) in the TME group but was not a statistically significant difference (p=0.059). Conclusions: In this study, TME and LE had similar overall survival and time to 25% mortality in patients with LARC who achieved complete pathological response after neoadjuvant therapy. Also, LE had a shorter hospital stay compared to the TME group. This study is limited by its retrospective nature, however these interesting observations warrant further investigation in randomized clinical trials. [Table: see text]
Does neoadjuvant FOLFOX chemotherapy improve the oncological prognosis of high-risk stage II and III colon cancers ? Three years’ follow-up results of the Prodige 22 phase II randomized multicenter trial.
Authors: Karoui Medhi , Gallois Claire , Piessen Guillaume , Legoux Jean-Louis , Barbier Emilie , De Chaisemartin Cecile , Lecaille Cedric , Bouché Olivier , Ammarguellat Hanifa , Brunetti Francesco , Prudhomme Michel , Regimbeau Jean-Marc , Glehen Olivier , Lièvre Astrid , Portier Guillaume , Hartwig Johannes , Goujon Gael , Romain Benoît , Lepage Come , Taieb Julien
Published: May 2020

4110

Background: Neoadjuvant chemotherapy in a perioperative setting has proven valuable in locally advanced resectable colon cancer (CC) in terms of toxicity, postoperative morbidity and downstaging, but its effect on oncological outcomes remains uncertain. Methods: Prodige 22 was a randomized multicenter phase II trial in patients with resectable high-risk T3, T4 and/or N2 CC on baseline CT-scan. Patients were randomized to receive either 6 months of adjuvant FOLFOX after colectomy (control) or perioperative FOLFOX for 4 cycles before surgery and 8 cycles after (FOLFOX peri-op). In RAS wild-type (wt) patients a third arm testing perioperative FOLFOX-cetuximab was added. Primary endpoint was the Tumor Regression Grade. Secondary endpoints were 3-years overall (OS), disease-free survival (DFS) and time to recurrence (TTR). Results: 120 patients were enrolled. At interim analysis, the FOLFOX-cetuximab arm was stopped for futility. The remaining 104 patients (control, n = 52; FOLFOX peri-op n = 52) represented our intention-to-treat population. In the FOLFOX peri-op group, 96% received the schedule 4 cycles prior to surgery and all but one underwent adjuvant FOLFOX for a total of 12 cycles. In the control arm, 38 patients received adjuvant FOLFOX (1 postoperative death and 13 low-risk stage II patients). Median follow-up was 54.3 months [48.5-57.2]. Nineteen deaths and 26 disease recurrences were observed leading to a 3 years-OS of 90.3% in both arms (p = 0.7) and to a 3-years DFS of 76.8% and 69.2% in the peri-op and control arm respectively (p = 0.6). A trend to a better TTR in the peri-op arm was observed with a 3-years TTR of 82% as compared to 72% in the control arm (p = 0.3). No benefit from adding Cetuximab was observed in the 16 RAS-wt treated patients. Conclusions: In this pilot randomized study, perioperative FOLFOX chemotherapy has no detrimental effect on long term oncological outcomes and may be an option for some patients with locally advanced CC. A pooled analysis of randomized trials testing peri-operative strategies in this setting is warranted. Clinical trial information: NCT01675999 .
Pembrolizumab (pembro) versus standard of care chemotherapy (chemo) in patients with advanced gastric or gastroesophageal junction adenocarcinoma: Asian subgroup analysis of KEYNOTE-062.
Authors: Satake Hironaga , Lee Keun Wook , Chung Hyun Cheol , Lee Jeeyun , Yamaguchi Kensei , Chen Jen-Shi , Yoshikawa Takaki , Amagai Kenji , Yeh Kun-Huei , Goto Masahiro , Chao Yee , Lam Ka-On , Han Shi Rong , Shiratori Shinichi , Shah Sukrut , Shitara Kohei
Published: May 2020

4523

Background: First-line treatment with pembro or pembro + chemo vs chemo alone was evaluated in patients with PD-L1 combined positive score (CPS) ≥1, HER2-negative advanced gastric cancer in the randomized, active-controlled, phase 3 KEYNOTE-062 study (NCT02494583). We present results from the Asian subpopulation receiving pembro monotherapy or chemo. Methods: Eligible patients were randomly assigned 1:1:1 to pembro 200 mg, pembro + chemo (cisplatin + 5-FU or capecitabine), or placebo + chemo every 3 weeks for ≤35 cycles (~2 years). Randomization was stratified by region, disease status, and fluoropyrimidine treatment. Primary end points for this analysis were overall survival (OS) in patients with CPS ≥1 and patients with CPS ≥10; progression-free survival (PFS) and objective response rate (ORR) were exploratory end points. Data cutoff was March 26, 2019. Results: Globally, 256 patients received pembro monotherapy and 250 received chemo. Pembro was noninferior to chemo for OS in CPS ≥1 per prespecified margins (median OS, 10.6 vs 11.1 months, respectively; HR [99.2% CI], 0.91 [0.69-1.18]). In the Asian population 62 patients received pembro and 61 received chemo; 26 and 22 had CPS ≥10 (Table). Compared with the global population, Asian patients had a higher proportion of ECOG performance status 0, more diagnoses of stomach cancer, and a greater proportion with 0-2 metastatic sites. Median OS was longer with pembro than chemo using both CPS cutoffs (HR [95% CI]: CPS ≥1, 0.54 [0.35-0.82]; CPS ≥10, 0.43 [0.21-0.89]); 12- and 24-month OS rates were higher for pembro using both CPS cutoffs (12-month OS: CPS ≥1, 69% vs 54%; CPS ≥10, 81% vs 68%; 24-month OS: CPS ≥1, 45% vs 23%; CPS ≥10, 54% vs 27%). The HR (95% CI) for PFS was 1.11 (0.76-1.64) for CPS ≥1 and 0.71 (0.36-1.39) for CPS ≥10. Conclusions: In Asian patients with advanced gastric cancer, OS favored pembro in patients with CPS ≥1 and CPS ≥10. Clinical trial information: NCT02494583 . [Table: see text]
A phase Ib study of nivolumab plus trastuzumab with S-1/capecitabine plus oxaliplatin for HER2-positive advanced gastric cancer (Ni-HIGH study): Safety evaluation.
Authors: Takahari Daisuke , Shoji Hirokazu , Minashi Keiko , Hara Hiroki , Chin Keisho , Ooki Akira , Ogura Mariko , Nakayama Izuma , Kato Ken , Iwasa Satoru , Hirano Hidekazu , Amanuma Yusuke , Ishizuka Naoki , Boku Narikazu , Yamaguchi Kensei
Published: May 2020

4525

Background: Addition of an anti-PD-1 antibody to trastuzumab (Tmab) reportedly enhances ADCC activity of Tmab, leading to an additive antitumor effect. We investigated the safety and tolerability of nivolumab (Nivo) plus Tmab combined with S-1 or capecitabine (Cape) and oxaliplatin (Ox) for pts with HER2-positive (+) advanced gastric cancer (AGC). Here, we report the safety evaluation results. Methods: This open-label, phase 1b study was conducted at four centers in Japan. The study consisted of safety (n = 12) and expansion (n = 24–30) parts. Chemotherapy-naïve pts aged ≥ 20 years with histopathologically confirmed HER2+ AGC and measurable lesions were eligible. In the safety evaluation, pts were assigned to cohort 1 or 2 in sequence. Pts received Nivo (360 mg, day 1), Tmab (course 1: 8 mg/kg; course 2–: 6 mg/kg, day 1), Ox (130 mg/m2, day 1) and either S-1 (40 mg/m2 bid, days 1–14; cohort 1) or Cape (1000 mg/m2 bid, days 1–14; cohort 2) every 3 weeks until disease progression or unacceptable toxicity. The primary purpose of the safety evaluation was to determine the toxicity and tolerability of this combination therapy. An independent data and safety monitoring committee assessed the tolerability of the study treatments before starting the second treatment course. A preliminary evaluation of tumor response on the cut-off date (December 16, 2019) was also performed. Results: From November 2018 to August 2019, 12 pts with HER2+ AGC were enrolled in the safety part (six pts each in cohorts 1 and 2). During the 1st course, all 12 pts experienced at least one adverse event (AE). The most common AEs were peripheral sensory neuropathy (PSN) (n = 4) and leukocytopenia (n = 3) in cohort 1 and PSN (n = 5) and anorexia (n = 4) in cohort 2. AEs of grade ≥ 3 were observed in only one pt in cohort 1 (grade 3 neutropenia). No pt suspended or discontinued study treatments due to AEs. One pt in cohort 1 reduced dose of S-1 due to grade 2 erythema and continued the subsequent courses with the dose. After a median follow-up of 6.1 (range, 3.1–13.3) months, one pt from cohort 1 achieved a complete response, eight pts (four in each cohort) achieved a partial response, and three pts (one in cohort 1 and two in cohort 2) showed stable disease. No progressive disease was observed. Conclusions: Both Nivo plus Tmab and either S-1 or Cape plus Ox are tolerable in pts with HER2+ AGC. Both cohorts 1 and 2 have progressed to the expansion part of the study. Clinical trial information: 000034222 .
Assessment of FcgRIIIA single nucleotide polymorphisms (SNPs) on the efficacy of IgG1 monoclonal antibodies (mAbs) in PANGEA study patients (pts) with advanced gastroesophageal adenocarcinoma (aGEA).
Authors: Serritella Anthony , Peterson Bryan , Zhou Katherine I. , Arndt Nicole , Del Gaudio Daniela , Arndt Kelly , Das Soma , Klempner Samuel J , Liu Ping , Catenacci Daniel V.T.
Published: May 2020

4526

Background: Targeted therapies (Ttx) have had limited efficacy in aGEA. The phase IIa PANGEA trial assessed the outcomes of pts treated with IgG1 mAbs targeting receptor tyrosine kinases (RTKs) or PD-1 based on predefined molecular groups. The fragment C (Fc) portion of mAbs binds to IgG receptors (FcgR) of immunologic effector cells such as natural killer (NK) cells, leading to antibody-dependent cell-mediated cytotoxicity (ADCC). The FcgR subclass, FcgRIIIA, has genetic variants with different Fc binding affinities. A single nucleotide polymorphism (SNP) in FcgRIIIA substitutes phenylalanine (F) with valine (V) at amino acid position 158, enhancing FcgR’s affinity for the IgG1 Fc domain. Pts with V/V or V/F FcgRIIIA allotypes have enhanced NK cell binding affinity compared to the homozygous F/F allotype. We evaluated the association of FcgRIIIA SNPs on Ttx outcomes amongst PANGEA pts and another cohort of aGEA pts treated with IgG1 mAbs. Methods: Whole-blood samples were identified from aGEA pts (N = 104), including 70/80 available PANGEA pts, who were treated with an IgG1 mAb (trastuzumab 24, anti-EGFR 21, anti-PD1 30, ramucirumab 48) in at least 1 Ttx line. After lymphocyte DNA extraction, FcgRIIIA genotyping was performed. The Cox proportional hazard model and log-rank tests, adjusted for pt age, were used to assess for an association of genotype with overall survival (OS). Results: Of 104 genotyped pts, the F/F, F/V & V/V genotypes were observed at a frequency of 32%, 51% and 17% respectively. There was no significant difference in median OS (mOS) between the F/F, F/V or V/V or comparing F/F vs V/F+V/V overall, nor in the PANGEA-only cohort. A trend of increased mOS was seen in 20 non-PANGEA pts harboring F/V or V/V compared to 14 F/F pts (mOS 43.4 vs 23.1 months, HR 0.41 [0.15-1.14] p = 0.09). However, 3-year OS rates trended higher in V/F+V/V pts (22%, 16/71) compared to F/F pts (7%, 2/33) (p = 0.09). At 3 years, 50% of V/V+V/F non-PANGEA pts were alive versus 13% of F/F pts (p = 0.04), while 13% of V/V+V/F PANGEA pts were alive versus 0% of F/F pts (p = 0.32). Conclusions: Amongst pts receiving IgG1 mAbs, the high affinity V FcgRIIIA SNP enriched for a subgroup of ‘extreme responders’ alive 3 years from diagnosis. Multivariate analyses accounting for baseline characteristics in a larger number of pts are ongoing to further elucidate the role of FcgRIIIA SNPs as predictive biomarkers. These findings may have implications on IgG1 mAb ADCC optimization.
X versus XELOX versus PF in definitive concurrent chemoradiotherapy (DCRT) for local advanced squamous esophageal cancer (ESCC): Update from a multicenter, open-label, randomized III trial, CRTCOESC trial.
Authors: Jia Ruinuo , Shan Tanyou , Wan Lixin , Zheng Anping , Hui Shuang , Xu Zhiqiao , Wang Feng , Zheng Guobao , Lu Ping , Zhang Guifang , Zheng Yingjuan , Cui Yanhui , Luo Xiaoyong , Zhang Weiguo , Li Wanying , Li Ruonan , Zhou Fuyou , Gao Shegan
Published: May 2020

4531

Background: PF (5-fluorouracil plus cisplatin) is the standard regimen for local advanced ESCC with DCRT. CRTCOESC aims to evaluate the effect and safety of X (capecitabine) regimen versus XELOX (capecitabine plus oxaliplatin) and PF in Chinese local advanced ESCC with DCRT by randomized, open-label, multicenter designed. Methods: Patients with ESCC (T2-4N0-2M0) were randomized to 3 groups as X (capecitabine 625mg/m2, bid d1-5, 6 weeks), XELOX (oxaliplatin: 65mg/m2, d1, 8, 22, 29; capecitabine: 625mg/m2, bid d1-5; 6 weeks), or PF (cisplatin: 75mg/m2 d1, 29, 5-Fu: 750mg/m2 CIV24h d1-4, d29-32), Intensity Modulated Radiation Therapy (IMRT) was delivered by 50Gy/2Gy currently. In addition, quadratic randomize were done within all groups to decide whether 2 cycles chemotherapy adding or not after DCRT. 2-year OS and Grade 3-5 AEs were the primary endpoints, 2-year PFS and short-term efficacy (STE) as rates of CR and ORR (CR+PR+SD) (confirmed by gastroscopy biopsy at 16 weeks) were the secondary endpoints. Results: 244 pts successfully were accrued from 13 centers during 2014.10-2020.1. 209 pts were finished DCRT and 193 were evaluated STE at 16 weeks. 192 and 147 pts were followed up for 1- and 2- years respectively. There were no differences between 3 groups on patients’ baseline characters including age, gender, ECGO score, clinical stage, pathology grade and smoking. In X, XELOX and PF groups, the 2-year OS were 63.8% (30/46), 61.5% (32/52) and 62.5% (30/49) ( P = 0.973), the median OS were 39.7 (6.567), 40 (5.195) and 34 (5.736) (months, P = 0.703); the incidences of AEs (grade 3-5) were 26.5% (18/68), 33.8% (25/74) and 49.3% (33/67) ( P = 0.0193); the 2-year PFS were 54.3% (25/46), 53.8% (28/52) and 51% (25/49) ( P = 0.939), the median PFS were 29.06 (6.124), 17.4 (8.745) and 24.833 (6.777) (months, P = 0.811); the CR rate were 43.8% (28/64), 41.4% (29/70), and 42.4% (25/59) ( P = 0.964), and the ORR were 85.6%, 88.6%, and 96.6% ( P = 0.119), respectively. There were no differences on OS, PFS and rates of CR and ORR between 3 groups but the incidence of AEs in X group was the lowest significantly. Subgroup analysis results shown adding 2 cycles chemotherapy after CRT had both OS and PFS advantages but lacked statistically significance. Conclusions: Compared with PF, DCRT with X or XELOX shown lower incidence of AEs and similar OS, PFS and STE. X regimen carried out the lowest AEs incidence. Adding 2 cycles chemotherapy after DCRT seemly had advantages on OS and PFS. Clinical trial information: NCT02025036 .
Final results of a phase II trial of first-line FOLFIRINOX for advanced gastroesophageal cancers.
Authors: Jin Ramon , Park Haeseong , Wang-Gillam Andrea , Suresh Rama , Rigden Caron E. , Amin Manik A. , Tan Benjamin R. , Pedersen Katrina , Lim Kian-Huat , Trikalinos Nikolaos , Acharya Abhi , Copsey Megan , Navo Katie , Morton Ashley , Gao Feng , Lockhart A. Craig
Published: May 2020

4532

Background: Standard first-line regimens for patients with metastatic gastroesophageal adenocarcinomas have moderate clinical benefit with objective response rates (ORR) of approximately 40-50%. FOLFIRINOX has been shown to be an effective and well-tolerated first line therapy in other GI cancers. In this open-label, single-arm phase II study of patients with advanced gastroesophageal adenocarcinomas, we sought to evaluate the safety and clinical activity of FOLFIRINOX. Methods: The primary endpoint was ORR, and secondary endpoints included safety profile, progression free survival (PFS), overall survival (OS), time to progression (TTP), clinical benefit rate (CBR), and duration of response. Estimated sample size included 41 patients with HER2 negative disease with 90% power to detect an ORR≥60% with alpha of 0.10. No enrollment goal was planned for HER2 positive patients, but they were allowed participation to receive study treatment in combination with trastuzumab. Treatment consisted of 400mg/m2 5-FU bolus, 400 mg/m2 leucovorin, 2400 mg/m2 5-FU infusion over 46 hours, 180 mg/m2 irinotecan, and 85 mg/m2 oxaliplatin. Trastuzumab was administered intravenously as a 6 mg/kg loading dose then given 4 mg/kg every 14 days for HER2 positive patients. This trial is registered with ClinicalTrials.gov, NCT01928290. Results: From November 2013 to May 2019, 67 patients were enrolled, of which 26 (39%) had HER2 positive disease. Median follow-up was 16.1 months. ORR was 61% (25/41) for HER2 negative and 85% (22/26) for HER2 positive groups. Overall, one patient (2%) had a complete response, 36 patients (69%) had partial responses, and 13 patients (19%) had stable disease for >6 months; therefore, CBR was 96%. Median PFS was 11.9 months, median OS was 17.4 months. 41 patients (83.7%) had dose modification or treatment delay with the most common toxicities being neutropenia, diarrhea, peripheral sensory neuropathy, and nausea with no unexpected toxicities. Conclusions: FOLFIRINOX is a highly effective three-drug regimen for first-line treatment of advanced gastroesophageal cancer with expected, tolerable toxicities. Clinical trial information: NCT01928290 .
Personalized neoantigen/cancer testis antigen nanovaccine (PVAC) mobilize specific therapeutic immunity for high-risk resected gastric cancer.
Authors: Liu Qin , Qian Hanqing , Shao Jie , Xu Qiuping , Sha Huizi , Yang Yang , Wang Weifeng , Yu Lixia , Liu Baorui , Wei Jia
Published: May 2020

4535

Background: 35% of stage IIIB/C Gastric cancer patients will recurrent after D2 gastrectomy within one year. Mutation-derived epitopes (neoantigens) has been demonstrated to induce tumor cell specific immune responses controlling the tumor growth. Nanovaccine can increase antigen presentation efficiency and elicit potent antitumor T cell responses with robust therapeutic efficacy. We hypothesized that vaccination with neoantigens/cancer testis (CT) antigens could expand pre-existing and induce antigen-specific T-cells populations, favouring of tumor control enhancement. Here, we report the first-in-human application of this concept in gastric cancer. Methods: Patient-specific mutation-containing neoantigens were selected on the basis of tumour-specific mutations whole-exome sequencing (WES) and RNA sequencing. Cancer testis antigens were obtained according to immunohistochemical staining and HLA-binding affinity prediction. PVAC is an amphiphiles nanovaccine loaded with multiple personalized neoantigens/cancer testis antigens designed to induce antigen specific T cells and associated antitumor responses. PVAC will be administrated to stage IIIB/IIIC gastric carcinoma after six cycles of adjuvant chemotherapy (S-1/Oxaliplatin or S-1/docetaxel). Each patient received PVAC by subcutaneous injection on Days 1, 4, 8, 15, 22, 43, 64, 85, 169, administrated with the adjuvant montanide ISA 51 VG. Safety, immunogenicity and clinical efficacy will be evaluated. Results: 25 stage IIIB or IIIC gastric cancer patients were enrolled in this study. Mean age was 54.3 years old (range: 34-70), and ECOG performance scores were 0 or 1. Repeated dosing has been well tolerated with mild local discomfort and no DLTs. Three patients were observed grade 2 local skin reactions in the injection sites. No SAEs related to PVAC have been observed. Among median follow up time of 12.6 months (range: 8.5-25.0 months), only two patients had local recurrence at 24.0 months and 10.5 months after surgery, respectivelt. The rest 23 patients remain disease free on study. Neoantigen specific T cell responses have been detected by IFN-γ Elispot from PBMCs. Conclusions: PVAC is a multiple neoantigen/CT antigens nanovaccine that personalizes tumor specific antigens and the individual patient’s capacity to respond. Addition of PVAC may prolong progression-free survival (PFS) after the standard of care chemotherapy. Clinical trial information: ChiCTR1800017319 .
Translational analysis of esophageal adenocarcinoma (EAC) patients treated with oxaliplatin and capecitabine (Xelox) +/- the dual ErbB inhibitor AZD8931 in the DEBIOC study.
Authors: Lavery Anita , Stevenson Leanne , McManus Damian , Logan Gemma E. , Walker Steven M. , Jellema Gera L. , Van Schaeybroeck Sandra , Virdee Pradeep Singh , Elhussein Leena , Turbitt Julie , Colinson Diane , Miedzybrodzka Zofia , Petty Russell D. , Harkin Paul D. , Kennedy Richard D. , Eatock Martin McKinlay , Middleton Mark R. , Thomas Anne L. , Turkington Richard C.
Published: May 2020

4539

Background: The Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC) trial reported an acceptable safety profile for neoadjuvant Xelox +/- AZD8931 but limited efficacy. We utilized EAC patient samples from DEBIOC to evaluate the impact of neoadjuvant Xelox +/-AZD8931 on biological pathways using a unique software driven solution. Methods: 24 pre-treatment FFPE EAC biopsies and 17 matched surgical resection specimens were transcriptionally profiled using the Almac Diagnostics Xcel Array. Gene expression data was analyzed using the Almac claraT total mRNA report V3.0.0, reporting on 92 gene expression signatures and 7337 single genes associated with 10 key biologies. Paired Wilcoxon tests (5% significance level) were used to evaluate changes in claraT scores pre- and post-treatment. EGFR and Her2 expression were assessed by IHC and FISH. Results: 15 patients received Xelox+AZD8931 and 9 Xelox alone. Hierarchical clustering of biopsies identified 4 major clusters: Inflammation active, Genomic Instability active, EGFR & MAPK active, and EMT & Angiogenesis active. Comparison of signature scores pre- and post- neoadjuvant treatment demonstrated a significant reduction in scores relating to DNA damage repair (DDR) deficiency (Almac DNA Damage assay, p< 0.0001; BRCAness Profile, p= 0.0025; HRD Gene Signature, p< 0.0001; BRCA1ness Signature, p= 0.0004) and a significant increase in angiogenesis signatures (Almac Angiogenesis Assay, p= 0.0002; Angio Predictive G model, p= 0.0228; Angiogenesis Signature A, p= 0.0034) and EMT signatures (EMT Signature, p= 0.0031, EMT Enrichment Score, p= 0.0013, Pan-Can EMT Signature B, p= 0.0001). Comparing pre- and post-treatment signature scores in patients treated with Xelox +/-AZD8931 revealed a significant reduction in EGFR Sensitivity Signature ( p= 0.0088), ERBB2-specific Gene Expression Signature ( p= 0.0127) and Hallmark PI3K-AKT-MTOR Signaling ( p= 0.0195) in those treated with Xelox + AZD8931 in keeping with the mechanism of action of AZD8931. Downregulation of AKT signaling was confirmed in AZD8931 treated and resistant cell lines. Conclusions: We report the use of a novel software tool to apply 92 gene expression signatures to EAC biopsy and resection specimens from the DEBIOC trial to provide insight into mechanisms of action. Neoadjuvant treatment was associated with a reduction in DDR deficiency and an increase in angiogenesis and EMT signatures whilst a reduction in EGFR, Her2 and AKT pathways was noted with AZD8931 treatment.
Interim safety analysis of the DANTE trial: Perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esophagogastric adenocarcinoma—A randomized, open-label phase II trial of the German Gastric Group at the AIO and SAKK.
Authors: Homann Nils , Lorenzen Sylvie , Schenk Michael , Thuss-Patience Peter C. , Goekkurt Eray , Hofheinz Ralf Dieter , Kretzschmar Albrecht , Bolling Claus , Angermeier Stefan , Wicki Andreas , Siebenhuener Alexander Rheinhard , Lindig Udo , Pink Daniel , Ettrich Thomas Jens , Schmalenberg Harald , Waberer Lisa , Talbot Jonathan , Pauligk Claudia , Goetze Thorsten Oliver , Al-Batran Salah-Eddin
Published: May 2020

4549

Background: The DANTE study evaluates atezolizumab in the perioperative treatment of locally advanced, potentially resectable gastric or GEJ adenocarcinoma in combination with perioperative FLOT. Here, we report the protocol-defined interim safety analysis. Methods: DANTE is a multinational, prospective, multicenter, randomized, investigator-initiated, open label phase II trial. Patients (pts) with locally advanced, potentially resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N-positive) without distant metastases are enrolled. Pts are randomized 1:1 to 4 pre-operative 2-week cycles of FLOT followed by surgery and 4 additional cycles of FLOT plus atezolizumab at 840 mg every 2 weeks, followed by a total of 8 additional cycles of atezolizumab at 1200 mg every 3 weeks as monotherapy (arm A) or FLOT alone (arm B). Primary endpoint is time to disease progression or relapse after surgery (PFS/DFS). Results: Recruitment started in Sep 2018; by Feb 2020, a total of 175 pts have been randomized. This analysis is based on the first 40 pts (20 pts in each arm). The pts had a median age of 62 y and 75% of pts had an ECOG PS of 0 in both arms. The cohort was well balanced in terms of tumor location and clinical stage. 5% of the 40 patients (overall 7.4% of 175 pts enrolled) showed microsatellite instability. 90% of pts enrolled completed all pre-operative cycles in each arm. Total number of adverse events with relation to study treatment was 154 in arm A and 148 in arm B. Total number of serious adverse events (SAE; related or not) was 16 in Arm A and 14 in arm B. 20% of pts in each arm had an SAE due to perioperative morbidity. No surgical mortality was observed. 18 and 19 pts proceeded to operation in arms A and B, respectively. Premature treatment discontinuation occurred in 2 pts in each arm: disease progression (1) and deterioration of general health condition (1) in arm A; and pts’ wish (1) and death (1) in arm B. Median hospitalization time was 15 days in arm A and 16 days in arm B. Conclusions: Perioperative atezolizumab plus FLOT is feasible and safe. The study continues recruitment. Clinical trial information: NCT03421288 .
A population-based study on gender differences in tumor and treatment characteristics and survival of curable gastroesophageal cancer.
Authors: Kalff Marianne C. , Dijksterhuis Willemieke P.M. , Verhoeven Rob H.A. , Wagner Anna Dorothea , Lemmens Valery E.P.P. , Van Laarhoven Hanneke W.M. , Gisbertz Suzanne S. , van Berge Henegouwen Mark I.
Published: May 2020

4550

Background: Although curative treatment options for gastroesophageal cancer are identical for men and women, outcomes may vary. This study examined differences in tumor and treatment characteristics and survival between men and women with potentially curable gastroesophageal cancer. Methods: Nationwide data was acquired from the Netherlands Cancer Registry. Patients with a potentially curable gastroesophageal carcinoma (cT1-T4a or cTx, any cN, cM0 or cMx) diagnosed between 2006 and 2017 were selected. Patient stratification was performed for tumor location and histology. The primary endpoint, relative survival, was compared between men and women with esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC) and gastric adenocarcinoma (GAC), adjusted for the normal life expectancy for men and women separately. Results: In total, 13,391 patients with an EAC (79.1% men), 5,103 patients with an ESCC (54.7% men), and 8,149 patients with a GAC (60.1% men) were included. Women with gastroesophageal cancer were older than men. Lower cT-stages were observed in women with EAC and ESCC (both p < 0.001) and lower cN-stages were observed in women in all groups, although clinical T- and N-stage were more frequently graded as cTx and cNx in women. In women, EAC tumors were less frequently located in the distal esophagus (70.4% vs. 58.6%, p < 0.001), ESCC tumors had a more proximal tumor location (p < 0.001), and GAC tumors were more frequently located at the antrum (32.3% vs. 37.2%, p < 0.001). For EAC and GAC, but not for ESCC, men were more frequently allocated to a potentially curative treatment; endoscopic resection, surgical resection or definitive chemoradiotherapy (EAC: 74.6% vs. 60.1%, p < 0.001; GAC: 69.0% vs. 65.4%, p 0.001; ESCC: p 0.117). An inferior 5-year relative survival was observed in women with EAC (34.3% vs. 30.1%, p < 0.001) and GAC (36.1% vs. 33.2%, p 0.016). In women with ESCC a superior 5-year relative survival was observed (24.4% vs 28.5%, p 0.001). Conclusions: Remarkable differences in 5-year relative survival were observed between men and women with gastroesophageal cancer, in addition to important differences in tumor stage, tumor location and treatment. Strikingly, men with esophageal and gastric adenocarcinoma were more frequently allocated to a potentially curative treatment compared to women. These findings illustrate the need for further exploration and consideration of gender differences in gastroesophageal cancer treatment.
Diagnostic accuracy of CT-staging of advanced gastric cancer following neoadjuvant chemotherapy.
Authors: Jang Jong Keon , Lee Jong Seok , Ryu Min-hee , Yook Jeong Hwan , Park Young-Kyu , Kim Young Woo , Kim Jin Young , Rha Sun Young , Chung Ik-Joo , Kim In-Ho , Oh Sang Cheul , Yoo Chang Hak , Choi Jin-Hyuk , Zang Dae Young , Kim Gyunji , Lee YeonJu , Noh Sung Hoon , Kang Yoon-Koo
Published: May 2020

4551

Background: Neoadjuvant or perioperative chemotherapy has been accepted as a standard treatment globally in patients (pts) with locally advanced gastric cancer (LAGC). In PRODIGY phase III study (n = 530), we have demonstrated that neoadjuvant chemotherapy with DOS regimen (docetaxel, oxaliplatin, S-1) led to significant tumor downstaging and improved PFS in Korean LAGC pts (Kang, et al. ESMO 2019). Although CT has been performed to re-stage the tumor after neoadjuvant chemotherapy, there has been a relative paucity of diagnostic accuracy data. This study is to evaluate the diagnostic performance of restaging of LAGC after neoadjuvant chemotherapy using CT in PRODIGY study population. Methods: Of 266 pts, who had been diagnosed LAGC of T2-4 or N+ stage as assessed with CT and randomized to neoadjuvant chemotherapy arm (CSC) in PRODIGY study, 214 pts underwent gastrectomy were included in this analysis. The post-chemotherapy T- and N- stage was determined based on CT scan taken just prior to surgery and compared with the pathologic stage (AJCC 7th edition). Two experienced radiologists independently evaluated depth of primary tumor and reached consensus if any discrepancy between two readers. Diameter of short axis of the largest regional lymph node was measured to predict metastatic lymph node. Result of histopathologic T- and N-staging using surgical specimen was used as reference standard. Results: The study cohort consisted of pathologic T0 (n = 22), T1(n = 39), T2(n = 31), T3(n = 79), and T4(n = 43). The overall diagnostic accuracy of CT was 45%. For each T-stage, accuracy of T0,T1,T2,T3, and T4 was 0%, 26%, 29%, 55% and 79%, respectively. Rate of over- and under- staging was 47% and 8%, respectively. Accuracy for prediction of downstaging to early gastric cancer (T0-T1) was 83%. Interobserver agreement of T-staging was moderate (k = 0.41). There were 98 patients of N+ and 116 patients of N- at histopathology. Area under the curve of receiver operating characteristics to differentiate lymph node metastasis was 0.63. Sensitivity and specificity of size criteria of the largest lymph node (cut off value: > 6mm, > 7mm, and > 8mm) to predict pathologic N+ were 90% and 17%, 78% and 34%, and 68% and 51%, respectively. Conclusions: Re-staging using CT after neoadjuvant chemotherapy showed suboptimal accuracy and over-staged residual tumor. However, it predicted downstaging of gastric cancer with high accuracy.
Molecular correlates of PD-L1 expression in patients (pts) with gastroesophageal (GE) cancers.
Authors: Wang Jingyuan , Xiu Joanne , Shields Anthony Frank , Grothey Axel , Weinberg Benjamin Adam , Marshall John , Lou Emil , Khushman Moh'd M. , Sohal Davendra , Hall Michael J. , Battaglin Francesca , Arai Hiroyuki , Soni Shivani , Zhang Wu , Korn Wolfgang Michael , Lenz Heinz-Josef
Published: May 2020

4558

Background: The increased PD-L1 expression evaluated by combined positive score (CPS) is associated with improved efficacy of immunotherapy in GE cancers. The impact of tumor molecular alterations on PD-L1 expression is still not well-studied. We aimed to characterize specific molecular features of tumors with different CPS levels in GE cancers. Methods: 2,707 GE tumors [1,662 gastric/GE junction adenocarcinoma (GA), 856 esophageal adenocarcinoma (EA), 75 esophageal squamous (ES) and 114 GE unspecified] collected between 2000.8 and 2019.7 were analyzed using NextGen DNA sequencing (NGS), immunohistochemistry (IHC) and fragment analysis (FA) (Caris Life Sciences, Phoenix, AZ). Tumor mutation burden (TMB) was calculated based on somatic nonsynonymous missense mutations. dMMR/MSI status was evaluated by a combination of IHC, FA and NGS. PD-L1 expression measured by IHC (22c3) was evaluated by CPS scores. Molecular alterations were compared in three groups (CPS ≥ 10, H; CPS = 1~9, M; CPS = 0, L) using Fisher-Exact or Chi-square and adjusted for multiple comparison by Benjamini-Hochberg. Significance was determined by adjusted (adj) p < .05. Results: Overall, CPS-H, M, and L were seen in 18% (n = 494), 28% (n = 765) and 53% (n = 1,448) of GE tumors respectively. CPS-H was the most prevalent in ES (43%) followed by GA (19%) and lowest in EA (14%). Overall, TMB was similar between CPS-L and M, but was significantly increased in H (average TMB = 8.4 vs. 8.6 vs. 11 mt/MB, adj p < .0001); the effect was seen in EA and GA, but not in ES. An overall significant association between MSI/dMMR status and PD-L1 expression levels was seen (2%, 3.2% and 12% in CPS-L, M and H, adj p < .05) in GE tumors; the significance was seen in GA, but not in EA or ES. Amplifications of PD-L1 (H: 1.5%, M: 0.1% and L: 0) and PD-L2 (H: 1.1%, M: 0.1%, L: 0) were the highest in CPS-H, while ASPSCR1 (H: 0, M: 0, L: 1%) and TNFRSF14 (H: 0, M: 0.4, L: 2%) were the lowest (adj p < .01). Genes involved in epigenetic modification (top 5: ARID1A, ASXL1, BCL9, BCOR, CREBBP), MAPK ( KRAS, MAP2K1) and mismatch repair ( MLH1, MSH6) had the highest mutation rates in CPS-H, compared to M and L ( p < .0001). In contrast, CDH1 had higher mutation rates in CPS-L (12%), compared to M and H (5% and 5%) ( p < .0001). Conclusions: This is the largest study to investigate the distinct molecular landscape of pts with different PD-L1 expression levels in GE cancers. Our data may provide novel insights for pt selection (e.g. pts with gene mutations involved in epigenetic modification) and the development of rational combination immunotherapy (e.g. drugs targeting MAPK pathway).
Health-related quality-of-life assessment in accordance with reconstruction procedures for distal gastrectomy for stage I gastric cancer using data from JCOG0912.
Authors: Fujiya Keiichi , Ando Masahiko , Mizusawa Junki , Katai Hitoshi , Yamada Takanobu , Ito Seiji , Fukagawa Takeo , Bando Etsuro , Misawa Kazunari , Tanizawa Yutaka , Morita Shinji , Katayama Hiroshi , Yoshikawa Takaki , Terashima Masanori , Sasako Mitsuru ,   Stomach Cancer Study Group, Japan Clinical Oncology Group
Published: May 2020

4562

Background: There are three major reconstruction methods after gastrectomy for distal gastric cancer; Billroth-I (B-I), Roux-en-Y (RY) and pylorus-preserving gastrectomy (PPG). These procedures can affect postoperative health-related quality-of-life (HRQoL), but the method is often selected due to physician’s preference or each institutional policy without solid evidence. We aimed to explore differences in HRQoL after each reconstruction procedure selected in JCOG0912, a phase III noninferiority trial comparing open and laparoscopic distal gastrectomies for stage I gastric cancer. Methods: Among 33 institutions participated in JCOG0912, 4 major cancer centers were selected for HRQoL assessment. HRQoL was assessed using the EORTC QLQ-C30 and STO22 before (baseline) and at 1, 3, 12, and 36 months after surgery as preplanned exploratory analysis. Results: Excluding 2 patients who didn’t answer the questionnaire, 590 patients were analyzed in this study. For reconstruction, B-I was performed for 222 patients (37.7%), RY for 178 (30.2%) and PPG for 189 (32.1%). Proportion of the opted reconstruction procedures was not different in open and laparoscopic gastrectomies. Global health status (GHS) scores of QLQ-C30 were not different among 3 groups at any time point. In comparison of B-I and RY, B-I was better than RY in constipation, while RY was better than B-I in diarrhea and reflux symptoms. In comparison of B-I and PPG, B-I was better than PPG in constipation and reflux symptoms, while PPG was better than B-I in diarrhea. When comparing RY and PPG, RY was better than PPG in constipation and reflux symptoms, while PPG was better than RY in taste (table). Conclusions: GHS scores were similar regardless of the reconstruction procedure, however postoperative symptoms including reflux, constipation, and diarrhea were various according to reconstruction methods. [Table: see text]
Final results of a phase III randomized trial of comparison of three paclitaxel-based regimens concurrent with radiotherapy for patients with local advanced esophageal squamous cell carcinoma.
Authors: Ai Dashan , Ye Jinjun , Chen Yun , Liu Qi , Zheng Xiangpeng , Li Yunhai , Wei Shihong , Li Jiancheng , Lin Qin , Luo Hui , Cao Jianzhong , Zhou Jialiang , Huang Guang , Fan Min , Wu Kailiang , Yang Huanjun , Zhu Zhengfei , Zhao Weixin , Li Ling , Zhao Kuaile
Published: May 2020

4564

Background: Paclitaxel (PTX) is effective in concurrent chemoradiation (CCR) against esophageal squamous cell carcinoma (ESCC). Which regimen, among cisplatin (DDP) (TP), carboplatin (CBP) (TC) or 5-Fu (TF) in combination with PTX concurrent with radiotherapy, provides best prognosis with minimum adverse events (AEs) is still unknown. Methods: The study compared two pairs of regimens: TF vs. TP and TF vs. TC concurrent with radiotherapy. Patients with histologically confirmed ESCC (clinical stage II, III or IVa) 20 were randomized into the three groups. Patients in TP group were treated with 2 cycles of CCR followed by 2 cycles of consolidation chemotherapy with TP (DDP 25 mg/m2/d, d1-3, PTX 175 mg/m2, d1, q28d). Patients in TF group were treated with 6 cycles of TF (5-Fu 300 mg/m2, civ 96h, PTX 50 mg/m2, d1, qw) in CCR followed by 2 cycles of TF (5-FU 1800 mg/m2, civ 72h, PTX 175 mg/m2, d1, q28d) in consolidation chemotherapy. Patients in TC group were treated with 6 cycles of TC (CBP AUC = 2, d1, PTX 50 mg/m2, d1, qw) in CCR followed by 2 cycles of TC (CBP AUC = 5, d1, PTX 175 mg/m2 d1, q28d) in consolidation chemotherapy. The radiotherapy dose in all groups was 61.2 Gy delivered in 34 fractions. The primary endpoint was overall survival (OS) and the secondary endpoints were progression-free survival (PFS) and adverse events. Results: Between July 2015 and January 2018, 321 ESCC patients in 11 centers were enrolled. Median follow-up of patients who survived was 36.3 months (IQR 27.9–45.2). The 3-yr OS was 58.2% in TF group and 59.5% in both TP and TC group. (TF vs. TP, HR 0.935, 95% CI 0.627-1.417; TF vs. TC, HR 0.881, 95% CI 0.578-1.342; P = 0.839). No significant differences were found in 3-yr PFS between TF, TP and TC groups [48.3% vs. 45.5%(TP) or 48.3% (TC). P = 0.820]. TP group had a significant higher incidence of acute Grade 3/4 neutropenia [60.7% vs. 16.8%(TF) or 32.7%(TC)], thrombocytopenia [13.1% vs. 2.8%(TF) or 4.7%(TC)], anemia [5.6% vs. 1.9%(TF) or 3.7% (TC)], fatigue [10.3% vs. 1.9%(TF) or 0.9%(TC)] and vomiting [5.6% vs. 0%(TF) or 0.9%(TC))]than other two groups ( P< 0.05). TF group had a significant higher incidence of Grade 3/4/5 esophagitis [11.2% vs. 0.9%(TP) or 4.7%(TC))]and pneumonitis [4.6% vs. 0%(TP) or 1.9% (TC)]than other two groups ( P< 0.05). Conclusions: No statistical differences were found in OS and PFS among TF, TP and TC groups. TC might be an option used in CCR in ESCC patients with mild of side effects compared with other two groups, although it did not significantly prolong OS. Clinical trial information: NCT02459457 .
Second primary malignancies in patients with clinical T1bN0 esophageal squamous cell carcinoma after definitive therapies: Supplementary analysis of the JCOG trial, JCOG0502.
Authors: Mitani Seiichiro , Kato Ken , Daiko Hiroyuki , Nozaki Isao , Kojima Takashi , Yano Masahiko , Nakagawa Satoru , Ueno Masaki , Watanabe Masaya , Tsunoda Shigeru , Abe Tetsuya , Kadowaki Shigenori , Kadota Tomohiro , Fukuda Haruhiko , Machida Ryunosuke , Kitagawa Yuko
Published: May 2020

4565

Background: Esophageal squamous cell carcinoma (ESCC) is associated with synchronous or metachronous cancer at other primary sites. Previous studies have suggested that patients (pts) with ESCC are still at a high risk of second primary malignancies after definitive therapies. In particular, early-stage ESCCs result in good prognosis, which is associated with a higher risk of second primary malignancies. Methods: The JCOG0502 was a phase III trial, which included a randomized and a non-randomized part and compared esophagectomy with definitive chemoradiotherapy in clinical T1bN0 ESCC. We additionally reviewed data of all pts enrolled in the JCOG0502 for second primary malignancies. Lugol-voiding lesions (LVLs) were assessed in the noncancerous esophageal mucosa before the treatments. Results: Among 379 enrolled pts, 213 pts received esophagectomy and the remaining received chemoradiotherapy. Patient characteristics of overall cohort were as follows: male, 85%; median age, 63 (range, 41–75) years; upper- /middle- /lower thoracic esophagus, 11/63/27%; alcohol consumption history, 79%; smoking history, 66%; prevalence of no LVLs/several LVLs/many LVLs/unknown, 45/36/8/11%. With a median follow-up of 7.1 years, a total of 118 second malignancies were observed in 99 pts (26%). Cumulative incidences of second malignancies after 3, 5, 10 years were 9, 15, 36%, respectively. Most common primary tumor sites were head and neck (35%), followed by stomach (20%) and lung (14%). In multivariable analyses, several LVLs [hazard ratio (HR): 2.24, 95% confidential interval (CI): 1.32–3.81, vs. no LVLs] and many LVLs (HR: 2.88, 95% CI: 1.27–6.52, vs. no LVLs) were significantly associated with the development of second malignancies. Regarding the three most common types of cancers, 62 out of the 77 cancers (81%) were diagnosed in clinical stage 0–I. Seventeen pts died due to second primary malignancies. There were 4 and 3 deaths from head and neck and lung cancer, respectively. Whereas, mortality caused by stomach cancer was not observed. Conclusions: In the JCOG0502, the incidence of second malignancies was high, indicating that careful follow-up is required for ESCC pts even after treatment completion. The presence of LVLs in esophagus was identified as an independent predictive factor for second primary malignancies, which may be useful for surveillance strategies. Clinical trial information: UMIN000000551 .
Peripheral blood immune correlates associated with TGF-β inhibition (galunisertib) and stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC).
Authors: Wattenberg Max Miller , Reiss Kim Anna , Giannone Michael , Damjanov Nevena , Prechtel Dunphy Elizabeth , DiCicco Lisa , Garcia-Marcano Luis , Karasic Thomas Benjamin , Furth Emma , Wojcieszynski Andrzej , Vonderheide Robert H. , Ben-Josef Edgar , Beatty Gregory Lawrence
Published: May 2020

4575

Background: TGF-β is a pleiotropic cytokine with immunosuppressive activity. In mouse models, blockade of TGF-β signaling enhances the activity of radiation and invokes T cell dependent anti-tumor immunity. We previously reported preliminary safety and efficacy results from a pilot study combining galunisertib (LY2157299), an oral TGF-β inhibitor, with SBRT for the treatment of patients with advanced HCC. Here, we investigate immunological mechanisms and potential biomarkers associated with therapeutic activity. Methods: Patients with advanced HCC who had progressed on or refused sorafenib were treated with galunisertib (150 mg PO BID) on days 1-14 of each 28-day cycle. SBRT (18 Gy) was delivered in a single dose between days 15-28 of cycle 1. Blood was collected at baseline, following two weeks of galunisertib and following SBRT for high-dimensional analysis using a 37-marker CyTOF panel. Patients were dichotomized based on best response as either progressor (PD) or non-progressor (PR+SD). The frequency of immune subsets was compared between groups. Results: Fifteen patients were enrolled and treated. One patient was not evaluable. The most common adverse event was grade 1 or 2 fatigue in 53% of patients. The only possibly-related grade 3 event was achalasia in one patient which coincided with disease progression. Two patients achieved a PR and six patients had SD (DCR 57%) with a median progression-free survival of 3.7 months and a median overall survival of 9.0 months. For most patients, regardless of outcome, galunisertib treatment was associated with a decrease in activated Ki67+ Treg cells. However, pre-treatment immune composition within the blood of progressors and non-progressors was distinct. At baseline, progressors had an increased frequency of naive-like CD8+ T cells, whereas non-progressors had an increased frequency of non-classical monocytes. After combination therapy, only non-progressors showed a significant increase in CD8+PD1+TIGIT+ T cells. Conclusions: Galunisertib combined with SBRT was well-tolerated with modest efficacy. Immune profiling of the blood revealed distinct pre- and post-treatment signatures that differentiated patients with progression versus non-progression. These findings show that the combination of anti-TGF-β therapy with radiation can mediate disease control and identify potential correlates of efficacy. Clinical trial information: NCT02906397 .