bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of the optimal patients for trifluridine/tipiracil (FTD/TPI) treatment in mCRC: A Spanish real-world analysis.
Authors: Fernandez Montes Ana Fernandez , Vazquez Rivera Francisca , Martinez Lago Nieves , Covela Rúa Marta , Castiñeiras Antia Cousillas , Gonzalez Villarroel Paula , De la camara Juan , Méndez Méndez Carlos , Salgado Fernandez Mercedes , Candamio Folgar Sonia , Reboredo Lopez Margarita , Carmona Campos Marta , Gallardo Martin Elena , Jorge Fernandez Monica , Pellon Augusto Maria Luz , Garcia Gomez Jesus ,   Galician Research Collaborative Group
Published: February 2020

146

Background: FTD/TPI has demonstrated significantly overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC) refractory to standard therapies. Nevertheless, data regarding the pt profile that benefits most from this FTD/TPI is scarce. Some reports have shown optimal benefit for pts with low tumor burden indolent disease, ECOG PS 0-1, and no liver metastasis. Methods: We conducted a retrospective, multicenter, observational study of pts treated with FTD/TPI at eight hospitals from the Galician Research Group on Digestive Tumours (GITuD). Data were analyzed for a correlation between prognostic characteristics (good prognostic characteristics (GPC) vs. poor prognostic characteristics (PPC)), clinicopathological characteristics and survival. The GPC group was composed of pts who have one or two metastatic sites and time from diagnosis of 1st metastases to treatment ≥ 18 months. Results: Between January 1, 2017 and August 20, 2018, 160 pts were included in the study, of which 85 pts (53.1%) were classified as PPC and 75 pts (46.9%), as GPC. Pts with PPC were associated with younger age (60.5 vs. 63.7 years, p=0.034), higher presence of liver metastases (83.5% vs. 60%, p=0.001) and lower incidence of primary tumor resection (34.1% vs. 17.3%, p=0.019), without differences in ECOG PS, RAS mutation, tumor stage at diagnosis, lung metastases and sidedness. In the whole population of pts median OS and PFS were 7.63 months and 2.75 months, respectively. However, in the GPC and PPC groups mPFS were 2.64 vs. 2.33 months, respectively (p=0.311). Also, median OS was 8.23 months for GPC and 6.75 months for PPC, respectively. Interestingly,the mOS reached 10.5 months in those patients in the GPC group without liver metastasis. OS according ECOG PS 0/1/2 were 10.9 vs. 7.8 vs. 4.4 months, respectively (p=0.004) in the GPC group of pts. Conclusions: We have identified a subgroup of pts who most benefit from FTD/TPI, characterized by ECOG PS 0, low tumor burden, indolent disease and no liver metastasis.
Phase Ib study to test the safety and activity of pembrolizumab (anti-PD-1) and trebananib (angiopoietin-2 inhibitor [Ang-2]) in patients with advanced solid tumors: Updated analysis of the colorectal cancer (CRC) cohort.
Authors: Rahma Osama E. , Cleary James M. , Ng Kimmie , Schlechter Benjamin L. , Eno Jessica , Maloney Anna , Giobbie-Hurder Anita , McDermott David F. , Hodi F. Stephen
Published: February 2020

155

Background: Ang-2 is produced by endothelial cells, predominantly in tissues undergoing vascular remodeling. Current studies suggest that Ang-2 partially suppresses T cell activation by increasing PD-L1 expression and decreasing activation of monocytes. We demonstrated that high pre-treatment serum Ang-2 is associated with reduced overall survival in patients treated with PD-1 blockade. We therefore hypothesized that the combination of Ang-2 and PD-1 blockade may be effective for treatment of patients with advanced cancer. Methods: We initiated a phase 1b trial of the combination of pembrolizumab and trebananib, an Ang-1/2 neutralizing peptibody in advanced solid tumors. Treatment consisted of an induction phase of pembrolizumab 200 mg every 3 weeks and trebananib weekly (with an initial run-in dose escalation of 15-30 mg/kg) for 12 weeks followed by pembrolizumab alone for 2 years. Here we present the updated data in the fully enrolled CRC expansion cohort. Results: The study enrolled 18 microsatellite stable (MSS) CRC patients. There were no DLTs in the dose escalation phase, and 30mg/kg was deemed to be the MTD. This summary is based on 15 CRC patients treated with 30 mg/kg trebananib plus pembrolizumab. The most common treatment-related adverse events (AEs) were abdominal distension, diarrhea, limb edema, transaminitis, and proteinuria, each reported in 40% of the patients. As of September 2019 (median follow up of 10 months), 13 patients were off treatment and two were continuing. Eleven patients were off treatment due to disease progression and 2 due to unacceptable toxicities (grade 4 pneumonitis and grade 3 transaminitis). The response rate was 7% (1 partial response for 23.8+ months) and the disease control rate was 27%, with 4 stable disease for a median of 10 months (4-18 months). Median time to progression and overall survival were 2.8 months (90% CI: 1.5 to 8.1 months) and 9.0 months (90% CI: 2.6 months to ∞), respectively. Conclusions: The combination of pembrolizumab and trebananib is well tolerated and demonstrated promising activity in patients with heavily treated MSS CRC. Clinical trial information: NCT03239145.
Regorafenib with TAS-102 (REGOTAS) in metastatic colorectal cancer patients who progressed after at least two standard therapies: Efficacy and safety results of a multicenter phase I study (REMETY).
Authors: Moehler Markus H. , Stein Alexander , Trojan Jorg , Marquardt Jens Uwe , Quidde Julia , Waidmann Oliver , Weinmann Arndt , Woerns Marcus , Schroeder Helge , Maenz Martin , Karatas Aysun , Foerster Friedrich
Published: February 2020

158

Background: The multi-kinase inhibitor regorafenib (REGO) and oral fluoropyrimidine TAS-102 (TAS) show efficacies as single agents in treatment of refractory metastatic CRC patients (pts). We conducted a conventional 3+3 dose finding to determine a recommended phase II dose (RP2D) of its combination REGOTAS and efficacy in 3-4.-line. Methods: Eligible patients with ECOG 0-1, measurable mCRC, not amenable to surgery had at least 3rd-line treatments. Prior fluoropyrimidine-based and anti-VEGF (R) combinations were mandatory, and anti-EGFR for RAS WT tumors. TAS was given on days 1-5 and 8-12 (28-days cycle); REGO on days 2-22 (dose levels see table below). The following major AE categories were used to define DLTs if they occurred during the first 2 treatment cycles: any grade ≥3 non-hematologic toxicity (except vomiting, nausea, non-significant lab abnormalities), grade ≥3 hematological toxicities, grade ≥3 bleeding. Tumor response was assessed Q8W as per RECIST1.1. EudraCT 2016-001968-11; NCT03305913. Results: All observed toxicities were consistent with safety profile of individual IMPs. 6 pts were enrolled into each DL1 and DL2 (n=12 in total). One DLT was observed in 1/6 pts in DL1; 2 DLTs in 2/6 pts in DL2. All DLTs were only grade 3 hypertension was well manageable, causality was attributed to REGO. No DLT resulted in treatment discontinuation. Results indicate a RP2D of 25mg/m² TAS-102 BID + 120mg REGO daily. No remissions were observed. Overall disease control rate (DCR) after 8 weeks was promising with 58.3% (DCR of 33.3% for DL1 and 83.3% in DL2) and remarkably better as historical data with 41/44% for REGO/TAS102 alone, respectively (Lancet 2013/NEJM 2015). Conclusions: Toxicities of REGOTAS were consistent with safety profiles of REGO and TAS alone. No additional DLTs were attributed to REGOTAS. Thus, the risk-benefit assessment of REGOTAS was positive. DCR was clinically quite meaningful. Mature PFS and OS will be presented at the meeting. Clinical trial information: NCT03305913.

[Table: see text]
Impact of antibiotic exposure on the efficacy of immune checkpoint blockade in MSI-H metastatic CRC.
Authors: Serpas Victoria , Rogers Jane Elizabeth , Xiao Lianchun , Mola-Rudd Kerri , Dasari Arvind , Kee Bryan K. , Overman Michael J. , Johnson Benny
Published: February 2020

161

Background: Immunotherapy has improved outcomes for many patients (pts) with advanced cancers found to be microsatellite instability high (MSI-H). However, not all MSI-H pts exhibit the same efficacy from immunotherapy. Previous studies have suggested that concomitant antibiotic use while receiving immunotherapy may result in poorer outcomes. We aimed to evaluate what factors impacted immune checkpoint blockade (ICB) response in pts with MSI-H metastatic colorectal cancer (mCRC) treated at a large academic referral center. Methods: We completed a single-site, retrospective review of 45 pts with MSI-H mCRC that received ICB. Data was collected including patient demographics, tumor and mutational data, ICB agent, length of treatment, and antibiotic use. Both single and multi-course antibiotic use was included from 2 weeks prior until 6 weeks following ICB treatment. Fisher’s exact test was used to evaluate the association of response and covariables. Log rank test was used to compare progression free survival (PFS) between subgroups. Results: A majority of pts were male (n = 25, 56%) and Caucasian (n = 30, 66%) with right sided tumors (n = 26, 62%). Combination Nivolumab and Ipilimumab was used in 7 (16%) with single agent Nivolumab in 10 (22%) and single agent pembrolizumab in 28 (62%). Of the pts in this cohort, 28 (62%) received antibiotics with 11 (39%) receiving a single round of antibiotics and 17 (61%) receiving multiple courses. Those that did not receive antibiotics had a greater response (partial or complete) at first scan while on ICB therapy (75% vs 32%, p = 0.01). No significant difference was noted between class of antibiotic, age, sex, or tumor sidedness. The median 12 month PFS (12-PFS) was also higher in the group that did not require antibiotics but was not statistically significant (82% vs 72%, p = 0.298). Conclusions: This study shows that MSI-H mCRC pts that received antibiotics while on ICB had impaired response rate and a trend towards lower PFS. This suggests alteration of the gut microbiome may impact ICB response warranting a larger, prospective study.
Skeletal muscle index (SMI) status and survival in patients undergoing surgery for colorectal cancer (CRC): A longitudinal study.
Authors: Abbass Tanvir , Dolan Ross , McSorley Stephen Thomas , Horgan Paul G. , McMillan Donald C.
Published: February 2020

175

Background: There is now good evidence that low skeletal muscle index (SMI) using established thresholds is associated with poor survival in patients undergoing surgery for CRC. However, to date few studies have carried out longitudinal analyses. Such studies also inform, the determinants of SMI status. Methods: From prospectively maintained database, pre-operative and 1 year follow up CT scans were analysed at L3 level for SMI (n=794).The relationship between SMI status before and after surgery (both high (n=366)/high then low (n=52)/low then high (n=108) and both low (n=268), clinicopathological parameters and overall survival was analysed. Results: The majority of patients were > 65 years of age (75%), male (56%), ASA<3 (67%), had TNM stage <3 (65%) and were not systemically inflamed (mGPS = 0 in 73%, and NLR <3 in 53%). Patients with low SMI at any time point (before surgery, after surgery, or both) had significantly poorer survival (p<0.001), were more likely to be over 65 years (p<0.001), and with mGPS>0 (p<0.001) than those who had high SMI at both time points. In those patients who were high then low SMI, they had poor survival (p<0.001) and were more likely >65 years old (p<0.001) compared with high high SMI. There was no difference in survival between those with low high SMI compared with low low SMI status (p=0.296). Conclusions: In this longitudinal study, low SMI status was associated with older age, increased systemic inflammatory response and poorer survival whether prior to or following surgery for CRC. Interestingly, surgery did not affect preoperative SMI status in the majority of patients, suggesting that host responses perhaps have a greater effect than the presence of the tumour itself. Reference: Martin L, Birdsell L, Macdonald N, et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol. 2013;31: 1539-1547.
Immune modulation after Toca 511 and Toca FC treatment of colorectal cancer patients.
Authors: Falchook Gerald Steven , Rodon Ahnert Jordi , Venkat Shree , Donahue Arthur , Horner Peder , Thomassen Amber , Accomando William , Rodriguez-Aguirre Maria , Bentley Cornelia , Hogan Daniel , Ostertag Derek , Yavrom Sharon , Kheoh Thian , Jolly Douglas J. , Gruber Harry E. , Shorr Jolene , Merchan Jaime R.
Published: February 2020

186

Background: Toca 511 (vocimagene amiretrorepvec) is a cancer-selective, retroviral replicating vector encoding yeast cytosine deaminase that converts 5-fluorocytosine (5-FC) into 5-fluorouracil in the tumor microenvironment (TME). In animal models, Toca 511 and 5-FC kill dividing cancer and nearby immunosuppressive cells, leading to antitumor immune activity. A Phase 1 study of Toca 511 & Toca FC (extended-release 5-FC) in patients with recurrent high grade glioma revealed results consistent with this proposed mechanism. A Phase 3 trial is ongoing. Methods: Toca 6 (NCT02576665) is a Phase 1b, single-arm, multicenter study designed to investigate immunological changes after Toca 511 & Toca FC treatment in patients with advanced solid tumors, including colorectal cancer (CRC). Patients received intravenous (IV) Toca 511 for 3 days, and underwent biopsy of metastatic tumor before and ~ 4 weeks after starting oral Toca FC. Toca FC was repeated every 4-6 weeks. Peripheral blood mononuclear cells and tumor biopsies were evaluated for treatment related immune responses. Results: 17 CRC patients with a median 5 lines of prior chemotherapy were enrolled. At last data cut-off, 9 patients were alive and the median overall survival was 9.4 months. A patient receiving concomitant panitumumab had a partial response. IV Toca 511 led to viral expression in tumor, which decreased post-Toca FC while maintaining a reservoir of virus in the remaining tumor. T cells shifted from naïve to effector phenotypes, CD4 memory T cells expanded, and/or B cells increased after Toca FC treatment in 36% of patients. Marked changes in tumor infiltrating cells (CD11b myeloid cells, Tregs, exhausted T cells and CD8 T cells) occurred after Toca FC treatment. Treatment has been generally well tolerated. We also plan to report insights gained from RNA analysis of TME and update on clinical finding. Conclusions: Clinical data suggest a signal of activity in these heavily pretreated CRC patients warranting further exploration. IV Toca 511 administration showed viral infection of CRC metastatic tumor. Toca 511 & Toca FC may be associated with T cell mediated immune activity in peripheral blood and metastatic tumor, consistent with pre-clinical data in multiple tumor types. Clinical trial information: NCT02576665.
Allele frequencies of two dihydropyrimidine dehydrogenase (DPYD) risk variants, c.1905+1G>A (*2A) and c.2846A>T (D949V), in a direct-to-consumer genetic database.
Authors: Kosinski Cindy , Wen Jingran , Nhan Hoang , Chubb Alison , Wu Shirley ,   23andMe Health Team
Published: February 2020

2

Background: Pharmacogenetic (PGt) testing holds great potential for supporting clinical decision making and optimizing medication outcomes for cancer patients. Genetic variants in the DPYD gene are associated with reduced dihydropyrimidine dehydrogenase enzyme activity, and can cause severe fluoropyrimidine-related toxicity. However, the clinical uptake of PGt testing has been slow. Recent FDA authorization for a direct-to-consumer (DTC) PGt test will improve access to PGt testing. This study assessed the frequency of two DPYD variants, c.1905+1G > A (*2A) and c.2846A > T (D949V), in a generally unselected group of genotyped individuals who have used DTC genetic testing (23andMe, Inc. Sunnyvale, CA). Methods: Study participants were genotyped using Illumina genotyping arrays that included the DPYD c.1905+1G > A and c.2846A > T variants. Eligible subjects were 23andMe U.S. customers who were at least 18 years of age and consented to participate in research. IRB approval was obtained from Ethical & Independent Review Services. Results: Out of approximately 6.4 million eligible participants included in this analysis, the overall allele frequencies of DPYD c.1905+1G > A and c.2846A > T were 0.42% and 0.47%, respectively. People of Ashkenazi Jewish, South Asian, and European descent had the highest frequencies (0.56%, 0.56%, and 0.47%, respectively) for the DPYD c.1905+1G > A variant, and people of European and Hispanic/Latino descent had the highest frequencies (0.55% and 0.43%, respectively) for the DPYD c.2846A > T variant. Conclusions: This is the first description of an unselected cohort of individuals with DPYD c.1905+1G > A and c.2846A > T variants identified through DTC genetic testing. Preemptive DTC PGt testing can help disseminate potentially clinically useful information to a large number of consumers.
A unique ex vivo tumor model: 3D cocultured system with cancer and stromal cells including blood microvessels.
Authors: Takahashi Yuki , Tsukamoto Kei , Morimura Rii , Nada Isana , Shimizu Yuki , Katayama Ryohei , Shinozaki Eiji , Nagayama Satoshi , Matsusaki Michiya , Kitano Shiro , Yamaguchi Kensei , Fujita Naoya
Published: February 2020

211

Background: Importance of interaction between cancer and stromal cells has been widely recognized in tumor progression and tolerance against treatment. Although 2D culture and spheroid consisting only cancer cells still remains the preferred platform for most laboratory preclinical studies while these provide only limited information about tumor microenvironment. In order to mimic the patient tumor tissue, ex vivo model which recaptures the tumor microenvironment is required. Methods: Layered 3D stromal tissues comprising microvascular network were produced by culturing fibroblasts and endothelial cells coated with the extra-cellular matrix (ECM) and natural polysaccharide, namely collagen and heparin. The layered 3D stromal tissues and co-cultured tumor were morphologically evaluated by HE stain, immunohistochemistry and immunofluorescence (IF). Their gene expression and secretome profile were characterized by RNA-sequencing and bio-plex suspension array technologies. Furthermore, drug sensitivity assay were conducted using popular colorectal cancer cell lines, and patient-derived cell lines (PDCs) established in the laboratory of JFCR. Remaining cancer cells post drug treatment were quantified by IF and imaging analysis. Results: The 3D stromal tissues including CD31 positive luminal structure were multi-layered (approximately 20 layers), and the tendency that dense microvascular network was formed nearby cancer cells was observed. In comparison with 2D culture or 3D mono-cultured spheroid model, decreased drug sensitivities were represented in the layered 3D co-cultured model. Omics profiles difference among models suggest that our 3D model has some similarity to in vivo tumor. Conclusions: We developed the layered 3D stromal tissue culture system including blood micro-vessels. Drug sensitivity in the co-cultured tumors may reflect the response of cancer cells in in vivo. Our unique 3D ex vivo model appear to be a valuable tool for drug evaluation, and thus testing approved and/or developing compounds with patient-derived cells would enable better prediction their efficacy.
Post hoc safety and effectiveness analysis of aflibercept + FOLFIRI for patients with metastatic colorectal cancer (mCRC) previously treated with antiepidermal growth factor receptor (EGFR) therapy in OZONE.
Authors: Cartwright Thomas H. , Fakih Marwan , Garcia-Alfonso Pilar , Linke Zdenĕk , Ruíz Casado Ana , Polo Marques Eduardo , Picard Pascaline , Celanovic Marina , Singh Arvind Rup , Salinardi Taylor , Chau Ian
Published: February 2020

212

Background: Anti-EGFR therapies are frequently given as first-line therapy for patients with mCRC, while anti-angiogenic therapies may be suitable at any line. Despite improving outcomes for patients with mCRC, there is still an unmet need regarding the optimal treatment sequence. In this post hoc analysis, the safety and effectiveness of aflibercept + FOLFIRI was evaluated for patients with mCRC based on their prior anti-EGFR therapy use. Methods: OZONE is a prospective, multicenter, observational, non-comparative study evaluating patients receiving aflibercept + FOLFIRI in the clinical setting, for 24 months from aflibercept initiation or until death. Patients were retrospectively assessed according to prior use of anti-EGFR therapy (defined as patients who received cetuximab and/or panitumumab as previous anti-cancer therapy). Overall survival (OS) and progression-free survival (PFS) were analyzed by hazard ratios (HR) and 95% confidence intervals (CI); overall response rate (ORR) was analyzed by odds ratios (OR) and 95% CI. Results: Among the overall treated population (N = 766), 19.2% (n = 147) received prior anti-EGFR therapy. Prior anti-EGFR therapy had no significant impact on the median OS (11.47 vs 12.58 months; HR [95% CI] 1.112 [0.889–1.390]), median PFS (5.29 vs 6.24 months; HR [95% CI] 1.022 [0.830–1.260]), or ORR (14.96% vs 18.75%; OR [95% CI] 0.597 [0.332–1.071]) of patients vs those who did not receive prior anti-EGFR therapy. Rates of grade ≥ 3 treatment-emergent adverse events (TEAEs) were similar between patients who did vs did not receive prior anti-EGFR therapy (70.7% vs 67.7%). The most frequently reported grade ≥ 3 TEAEs for patients who did vs did not receive prior anti-EGFR therapy were neutropenia (12.2% vs 15.0%), hypertension (8.8% vs 10.3%), and diarrhea (10.2% vs 9.4%). Conclusions: This post hoc analysis of the OZONE study did not reveal major differences in safety and effectiveness according to prior anti-EGFR therapy. Clinical trial information: ENCEPP/SDPP/4836.
Effect of phenotype on outcome in synchronously resected primary colorectal cancer and matched liver metastases.
Authors: Pennel Kathryn AF , Steele Colin William , Quinn Jean A. , Roseweir Antonia K. , Jackstadt Rene , Nixon Colin , Cortes-Lavaud Xabier , Roxburgh Campbell SD , Van Wyk Hester Catharina , McMillan Donald C. , Horgan Paul G. , Sansom Owen , Edwards Joanne
Published: February 2020

221

Background: 5-year survival of patients with resectable colorectal liver metastases is 25-40%. Mechanisms of disease progression are heterogenous and do not follow a clearly defined pathway from genotype to phenotype. In stage I-III colorectal cancer (CRC), patients with high tumor stroma exhibit poor prognosis, while those with high immune cell infiltrate do well following resection. We hypothesise that stromally-dense phenotypes lead to T cell exclusion, myeloid cell accumulation and aggressive metastatic progression. Here, we examine relationships between histological tumor phenotype, cellular infiltrate and outcomes in metastatic CRC. Methods: A unique cohort of synchronously resected primary CRC and matched liver metastases (n = 46) were assessed for immune cell infiltration (CD3, CD4, CD8, CD68, CD66b), inflammatory signalling (CXCR2, PDL-1, MMP9) and hypoxia (CAIX) using immunohistochemistry. Tumors were phenotypically subtyped using immune infiltrate (Klintrup-Makinen Grade (KM)), stromal invasion (tumor-stroma percentage (TSP)) and proliferation (Ki67). Results: Phenotypic subtype of primary tumors was predictive of metastatic subtype (rho = 0.522, p = 0.003). Immune phenotypes were associated with good prognosis and stromal phenotypes with poor prognosis (p = 0.004). Infiltration of macrophages and granulocytes associated with poor outcomes (p = 0.018) and increased CXCR2 expression (p = 0.03) at both sites. Increased CXCR2+ cells and macrophages at both sites associated with stromal phenotype (p = 0.02), tumour budding (p = 0.002), low KM grade (p = 0.05) and poor prognosis (p = 0.002). Macrophage and MMP9 levels increased in metastases compared to primary tumour, but no changes were seen in lymphocyte infiltration, CXCR2 and CD66b. Conclusions: Density of immune cell infiltrate, in the primary and metastatic niche, conferred good prognosis. In contrast, stromal, myeloid rich tumors convey poor prognosis. This clinically relevant and histologically efficient process permits segregation of disease and supports further study of relationships in the tumour microenvironment of CRC in the context of chemotherapy to better target therapeutics to individual patients.
The pretreatment lymphocyte-to-monocyte ratio (LMR) to predict treatment efficacy and prognosis in metastatic colorectal cancer treated with the combination of TAS-102 and bevacizumab (TAS-CC3 Study).
Authors: Matsuda Akihisa , Yoshida Yoichiro , Kamiyama Hirohiko , Kosugi Chihiro , Yoshida Hiroshi , Ishibashi Keiichiro , Ihara Keisuke , Takahashi Makoto , Kuramochi Hidekazu , Fukazawa Atsuko , Sonoda Hiromichi , Yoshimatsu Kazuhiko , Yamaguchi Satoru , Ishida Hideyuki , Hasegawa Suguru , Yamada Takeshi , Sakamoto Kazuhiro , Koda Keiji ,   TAS-CC3 Study Group
Published: February 2020

224

Background: The combination regimen of TAS-102 and bevacizumab as salvage-line therapy for metastatic colorectal cancer (mCRC) was established based on its high clinical effectiveness (C-TASK FORCE). Recently, our current phase II TAS-CC3 study demonstrated comparable median progression-free survival (PFS: 4.5m) and overall survival (OS: 9.2m) with exclusive inclusion of 3rd line therapy patients. However, practical predictors for its efficacy are lacking. This study evaluated inflammation-based scores as potential predictors for this combination therapy. Methods: This is a post hoc analysis of investigator-initiated, open-label, single-arm, multicentered phase II study (TAS-CC3) in Japan with 32 mCRC patients treated with the combination therapy. We investigated the predictive and prognostic values of pretreatment blood inflammation-based scores, including neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), and lymphocyte-monocyte ratios (LMR), on disease-control (DC), PFS and OS. These were divided into two groups (high and low) using cut-off of each median values. This study was registered at the University Hospital Medical Information Network, as UMIN#000022438. Results: ROC curve analyses of 3 inflammation-based scores versus DC showed a best predictive performance in LMR, followed by NLR and PLR (AUC: 0.89, 0.85, and 0.68, respectively). The high LMR group had a significantly higher DC rate than the low group (87.5 vs. 43.8%, P= 0.023). Two patients showing partial responses were in the high group. The high LMR group showed significantly longer survivals compared with the low group (4.9 vs. 2.3m, respectively for median PFS, P= 0.014) (20.5 vs. 5.1m, respectively for median OS, P< 0.001). The values of LMR were significantly correlated with PFS and OS (r = 0.56: P< 0.001 and 0.62: P< 0.001, respectively). Conclusions: Pretreatment LMR is a valid predictive and prognostic biomarker for mCRC patients with TAS-102 and bevacizumab treatment and might be clinically useful for selecting patients of the responder. Clinical trial information: 000022438.
Racial variation in molecular profile of advanced gastrointestinal cancers.
Authors: Macherla Shravanti , Nandimandalam Sujitha , Jayananda Sriraksha , Appah Ebenezer Ofori , Bulumulle Anushi , Baig Sameer , Patel Anokhi , Polsani Shanker , Muzaffar Mahvish
Published: February 2020

236

Background: Heterogeneity in the tumor molecular profile based on race is poorly understood. We sought to review the utilization of next generation sequencing (NGS) in patients with advanced gastrointestinal (GI) malignancies treated at a rural academic center and analyze inter racial variations in the molecular tumor profile. Methods: We conducted a retrospective review of patients with advanced GI malignancies that underwent NGS between 2015 to 2018 at East Carolina University.104 patients met eligibility criteria but 8 patients were excluded due to insufficient tissue sampling. Patients with colorectal, gastric, pancreatic, biliary, small intestinal and esophageal cancers were included. Targeted NGS using Caris Life Sciences¨ platform was performed to obtain molecular analysis. We conducted descriptive univariate analysis, cox regression and Kaplan-Meier survival curve analysis. Results: Median age at diagnosis was 64yrs and 64% of patients were black. The study cohort had 41% (n=39) with colon cancer, 18%(17) gastric cancer, 30% (29) pancreatic cancer, 6%(6) biliary cancer, 4%(4) small intestinal cancer and 1%(1) esophageal cancer. 60% (55) had de novo Stage IV disease. Median overall survival (OS) was 25 months (mo), 30 mo in blacks and 32 mo in whites (p value =0.46). Microsatellite stability was seen in 94% (87) and instability in 3% (3). Overall cohort had mutations (mut) in KRAS (50%), TP53 (64%), BRAF (4%), and ERBB amplification (3%). On the cox regression model APC mutation was associated with worse outcome. Black patients had more alterations in KRAS, TP53 (both not significant), and APC (p=0.02). Conclusions: In our analysis we observed inter racial variations in molecular profile of advanced GI malignancies. Black patients had increased rates of APC, KRAS and TP 53 mut. Further studies are required to analyze the impact of these molecular variations on outcomes. Results.

[Table: see text]
Exploratory analysis of trifluridine/tipiracil in late-stage metastatic colorectal cancer (mCRC): Prognostic factors.
Authors: Karthaus Meinolf , Hoell B , Zaun G , Guyot M , Schuler Martin H. , Kasper Stefan
Published: February 2020

24

Background: Trifluridine/Tipiracil (FTD/TPI) is effective in pts with refractory mCRC. Enrollment into in the RECOURSE trial was allowed only for pts with ECOG < 1 pts, while real world pts may have a lower ECOG. In addition, predictive markers for the efficacy of FTD/TPI at late stage are open. This exploratory analysis assessed outcome of mCRC pts (including ECOG PS ≥ 2) upon FTD/TPI treatment by prognostic factors in the real world setting. Methods: This cohort included mCRC pts who were treated with FTD/TPI from 01/2016 until 08/2019 at two large volume CRC centers in Germany. Pts were classified with good prognosis characteristics (GPC) according to Tabernero et al. (abstract 677, ASCO-GI 2019) defined by 1 or 2 metastatic sites and time since diagnosis of first metastases ≥ 18 mo. Pts of this group without liver metastases had the best prognostic characteristics. Pts with poor prognostic characteristics (PPC) were characterized by ≥ 3 metastases sites and time since diagnosis of first metastases ≤ 18 mo. Results: A total of 44 mCRC pts were included in this analysis (mean age 62.5 yrs; 22 males and 22 females). Within the GPC population (n=28; median age 67 yrs; KRAS wt n= 21; KRAS mt n= 7; ECOG 0-1 n= 23; ECOG ≥ 2n=7) 6 pts were alive up to 08/2019 and 4 were lost to FU. Four pts of the GPC were without liver metastases. Within the PPC group (n=16; median age 59 yrs; KRAS wt n= 6; KRAS mt n= 10; ECOG 0-1 n= 15; ECOG ≥ 2 n=1) 2 pts were alive and 2 were lost to FU. The mPFS and mOS of the GPC group (n=18) were 2,15 mo (range 0,62-10,13) and 4,63 mo (range 0,95-14,39), respectively. The mPFS and mOS of the PPC group (n=12) were 1,31 mo (range 0,76-9,72) and 4,72 mo (range 0,76-16,61), respectively. Pts with an ECOG ≥ 2 had a mOS of 2,76 mo (range 0,95-6,92), and a mPFS 1,67 mo (range 0,53-1,77). Conclusions: GPC and PPC group pts treated with FTD/TPI differed with respect to mPFS, but these pts had a comparable mOS in the real world setting. PFS and OS were lower when compared to the Tabernero analysis of the RECOURSE trial, which may reflect the real world setting. Inclusion of pts with an ECOG of ≥ 2 was feasible but showed poor survival data in the third line. Nevertheless, all pts with mCRC benefited from FTD/TPI treatment.
Systematic review of gastrointestinal cancer studies of concordance with expert opinion for a clinical decision support system (CDSS).
Authors: Arriaga Yull Edwin , Draulis Karlis , Hekmat Rezzan , Wang Suwei , Felix Winnie , Dankwa-Mullan Irene , Rhee Kyu , Jackson Gretchen
Published: February 2020

250

Background: Watson for Oncology (WfO), a cognitive CDSS, provides therapeutic options to cancer-treating physicians. We reviewed the concordance of WfO therapeutic options in gastrointestinal cancers with experts’ treatment decisions. Methods: Systematic review to identify WfO concordance studies in gastrointestinal cancers, published from June 2015 to June 2019. Concordance was defined as agreement between WfO “Recommended” and “For Consideration” treatment options and decisions made by experts. Mean concordance rates were calculated as an average, weighted by the number of patients in each study. Results: 2,407 patients were identified (Table). Overall treatment decision concordance was 67.2% (SD 25.7%). Concordance for rectal, colon, hepatocellular, and gastric cancers were 90.5% (SD 9.4%), 80.9% (SD 24.3%), 58.5%, and 47.5% (SD 33.9%), respectively. Concordance with WfO were significantly higher for rectal versus colon cancer ( p = .001), rectal versus gastric cancer ( p < .0001) and for colon versus gastric cancer ( p <.0001). Conclusions: Concordance between WfO and treatment decisions by experts for rectal and colon cancers were high. Concordance for HCC and gastric cancer were the lowest. A higher discordance in gastric cancer is likely related to disease-specific and management differences compared to United States practice. Variable concordance between expert clinical decisions and CDSS suggestions and can be minimized by localization efforts.

[Table: see text]
A randomized controlled phase III multicenter study on dose escalation in definitive chemoradiation for patients with locally advanced esophageal cancer: ARTDECO study.
Authors: Hulshof Maarten C.C.M. , Geijsen Debby , Rozema Tom , Oppedijk Vera , Buijsen Jeroen , Neelis Karen J. , Nuyttens Joost , Van Der Sangen Maurice , Jeene Paul , Reinders Janny , van Berge Henegouwen Mark I. , van Hooft Jeanin E. , Van Laarhoven Hanneke W.M. , Gaast Ate Van Der
Published: February 2020

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Background: To analyze the effect of radiation dose escalation to the primary tumor on local control, locoregional control, survival and toxicity in definitive chemoradiation for esophageal cancer. Methods: Patients with clinical stage T2-4, N0-3, M0 carcinoma of the esophagus were randomized between a standard dose of 50.4 Gy/1.8 Gy/5,5 weeks to the tumor and regional lymph nodes (SD) versus the same dose combined with an integrated boost of 0,4 Gy per fraction (total 61,6 Gy) to the primary tumor (HD). Chemotherapy consisted of 6 weekly concurrent carboplatin (AUC 2) and paclitaxel (50 mg/m2) in both arms. The primary endpoint was local progression free survival (LPFS) and 260 patients were needed to detect a difference of 15% (power: 80%). Secondary endpoints were locoregional progression free survival (LRPFS), overall survival (OS) and toxicity. Patients were stratified for histological subtype. Results: Between September 2012 and June 2018, 260 patients were included. Reasons for inoperability were proximal localization and patient preference (44%), comorbidity (30%), unresectable lymph nodes (11%), T4 (5%), local recurrence 2% and combinations (7%). 61% of the patients had a squamous cell carcinoma (SCC) and 39% had an adenocarcinoma (AC). 94% completed radiation treatment and 85% had at least 5 courses chemotherapy. Median follow up time was 45 months. 3-year LPFS was 70% in the SD arm versus 76% in the HD arm (ns). LPFS for SCC and AC was 74% versus 81% and 62% versus 65% for SD and HD, resp. (ns). 3-year LRPFS was 53% and 63% for the SD and HD arm resp. (p = 0.08). 1 year any progression free survival was 60% for SCC and 50% for AC, without a significant difference between SD and HD (p = 0,5). 3-year OS was 41% versus 40% for SD and HD resp. Overall grade 4 and 5 CTC toxicity was 12% and 4% in the SD arm versus 14% and 10% in the HD arm, resp. Conclusions: In definitive chemoradiation for esophageal cancer, radiation dose escalation up to 61,6 Gy to the primary tumor did not result in a significant increase in local control over 50,4 Gy. Numerical improvement of locoregional control after HD was observed with an increase in toxicity and without improving OS. Clinical trial information: NL38343.018.11.
Usefulness of laparoscopic narrow-band imaging for the evaluation of therapeutic effects on peritoneal metastasis in gastric cancer.
Authors: Kikuchi Hirotoshi , Soneda Wataru , Kawata Sanshiro , Hirotsu Amane , Matsumoto Tomohiro , Hiramatsu Yoshihiro , Kamiya Kinji , Morita Yoshifumi , Sakaguchi Takanori , TAKEUCHI HIROYA
Published: February 2020

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Background: As recent advances in chemotherapy improved prognosis of gastric cancer (GC) patients with peritoneal metastasis (PM), accurate diagnosis of PM has become more important. However, the sensitivity of conventional imaging modalities such as CT or PET is not satisfactory. Staging laparoscopy (SL) is often used to diagnose PM in advanced GC patients, but accurate detection of PM can be difficult. In this study, we evaluate the usefulness of laparoscopic narrow-band imaging (NBI) versus conventional laparoscopic white-light imaging (WLI) for the diagnosis of PM and for the evaluation of therapeutic effect of chemotherapy. Methods: We excised 54 white nodules from the parietal peritoneum of 40 GC patients. Among them, 9 patients received chemotherapy for advanced or recurrent GC before SL, and 31 did not receive chemotherapy except for adjuvant chemotherapy with S-1. The WLI and NBI findings were compared with the pathological findings. Results: Intranodular vessels were evaluated by WLI and NBI for dilatation, tortuousness, heterogeneity, and brown spots. Detection of any one abnormal finding on NBI plus clear demarcation of the peritoneal nodules on WLI more properly diagnosed 42 peritoneal nodules of 31 patients who did not receive chemotherapy (sensitivity, 100%; specificity, 88.9%; accuracy, 95.2%). In contrast, diagnosis ability was poor for 12 peritoneal nodules of 9 patients who received chemotherapy before SL (sensitivity, 66.7%; specificity, 33.3%; accuracy, 58.3%). Conclusions: Laparoscopic NBI is a useful tool for the diagnosis of PM in advanced GC before chemotherapy, and disappearance of dilated vessels on laparoscopic NBI could be useful to evaluate the therapeutic effect.
The impact of single-hetero UGT1A1 on clinical outcomes of irinotecan monotherapy in gastric cancer after fluoropyrimidine, platinum, and taxanes: Multicenter retrospective study.
Authors: Ito Ken , Komatsu Yoshito , Yuki Satoshi , Nakano Shintaro , Nakatsumi Hiroshi , Kawamoto Yasuyuki , Muranaka Tetsuhito , Sawada Kentaro , Ando Takayuki , Kajiura Shinya , Miyagishima Takuto , Harada Kazuaki , Kobayashi Yoshimitsu , Hatanaka Kazuteru , Ishiguro Atsushi , Honda Takuya , Dazai Masayoshi , Sasaki Takahide , Sakamoto Naoya
Published: February 2020

296

Background: Japanese gastric cancer treatment guidelines (5th edition) recommend irinotecan (IRI) after fluoropyrimidine, platinum and taxanes as a third line chemotherapy. We previously reported that patients with UGT1A1 single heterozygous (SH) had significantly high frequency of severe hematological adverse events (AEs) compared to patients with UGT1A1 wild type (WT) in IRI monotherapy for advanced gastric cancer (AGC). However, it remains unclear that UGT1A1 SH affect efficacy and safety of IRI after fluoropyrimidine, platinum and taxanes compared to WT as a salvage line. Methods: We retrospectively analyzed the clinical data of patients who received IRI monotherapy after fluoropyrimidine, platinum and taxanes in the multi-institutional retrospective study. From January 2010 to December 2017, 69 eligible patients were registered from 8 centers in Japan. Results: Forty one patients with UGT1A1 WT and 28 patients with UGT1A1 SH were included in this study. In WT/SH patients, performance status 0/1/≥2 was 12/25/4 and 5/17/6, treatment line 3rd/4th or later was 33/8 and 26/2, HER2 status positive/negative was 12/29 and 5/23, respectively. In WT/SH patients, rate of initial dose reduction was 22 and 28% (P = 0.363), median relative dose intensity (RDI) was 82% and 80% (P = 0.309). Of 88 patients who have measurable lesions, the overall response rate (ORR) was 5.7% and 4.2% (P = 1.000), disease control rate (DCR) was 54% and 38% (P = 0.289). Median progression free survival was 3.2 and 2.1 months (HR 0.607, P = 0.058) and median overall survival from initial day of IRI monotherapy was 10.0 and 7.0 months (HR 0.618 P = 0.086). In WT/SH patients, severe hematological AEs (≥G3) were observed more frequently in patients with UGT1A1 SH (WT: 43% and SH: 68%, P = 0.050), although frequency of severe non-hematological AEs (≥G3) were not significantly different in both groups (13% and 25%, P = 0.211). Conclusions: Compared to UGT1A1 WT, UGT1A1 SH status may be associated with poor efficacy and be a risk factor of higher frequency of severe hematological AEs.
Conversion gastrectomy for stage IV unresectable gastric cancer: A retrospective cohort study.
Authors: Sagawa Tamotsu , Sato Yasushi , Hamaguchi Kyoko , Hirakawa Masahiro , Nagashima Hiroyuki , Waga Eriko , Fujikawa Koshi , Takahashi Yasuo
Published: February 2020

298

Background: Stage IV Gastric cancer (GC) is a heterogeneous biological condition with a mixture of distant metastases, including hematologic, lymph nodal and/or peritoneal. In the recent classification introduced by Yoshida et al with the proposal to identify objective principles for conversion surgery, stage IV GC patients were subdivided into 4 new categories. In this study, we retrospectively investigated the efficacy of conversion gastrectomy for stage IV GC patients, with particular focus on the Yoshida’s classification. Methods: A retrospective, single center cohort study was performed in patients who had undergone conversion gastrectomy between 2005 and 2018. Data were extracted from Hokkaido Cancer Center database including all metastatic gastric cancer patients submitted to surgery. Only stage IV unresectable tumors/metastases which became resectable after chemotherapy were included in this analysis. Results: Forty-two resected stage IV GC patients were included in this analysis. Median overall survival (OS) was 40.0 months and 1-, 3- and 5-year survivals were 92.9, 70.7 and 57.7%, respectively. Univariate analysis among the patients with conversion gastrectomy identified macroscopic type, clinical response to 1st line therapy, pathological tumor depth, pathological nodal stage, R0 resection as significant prognostic factors. The MSTs of the patients with conversion gastrectomy for each category were 50.1 months for category 1, 46.6 months for category 2, 22.7 months for category 3 and 17.2 months for category 4. Conclusions: Unresectable stage IV GC patients could benefit from radical surgery after chemotherapy and achieve long survivals. Adequate selection of stage IV GC patients for conversion therapy may be an important role.
Perioperative FLOT in resectable gastric cancer: Italian real-world data from the RealFLOT study.
Authors: Giommoni Elisa , De Vita Ferdinando , Pecora Irene , Iachetta Francesco , Strippoli Antonia , Satolli Maria Antonietta , Spallanzani Andrea , Puzzoni Marco , Stragliotto Silvia , Sisani Michele , Formica Vincenzo , Giovanardi Filippo , Pozzo Carmelo , Prisciandaro Michele , Di Donato Samantha , Petrillo Angelica , Catanese Silvia , Tirino Giuseppe , Lavacchi Daniele , Antonuzzo Lorenzo ,   On behalf of GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica)
Published: February 2020

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Background: Perioperative treatments have significantly improved survival in patients with resectable gastric cancer, increasing 5-year overall survival from 23% with surgery alone to 45% with FLOT (fluorouracil, oxaliplatin, docetaxel). Pathological regression is a prognostic marker of better survival. Methods: In this observational, retro- and prospective study we collected data from patients with resectable gastric or gastro-oesophageal junction (GEJ) adenocarcinoma treated, as clinical practice, with perioperative FLOT. All patients had clinical T2 or higher and/or nodal involvement, according to FLOT4-AIO trial. Results: A total of 206 patients received perioperative chemotherapy with FLOT at 15 Italian centres, between September 2016 and September 2019. Overall, 186 (90.3%) patients completed the preoperative phase, 190 (92%) underwent surgery, and 142 (68.9%) started the postoperative phase. Among patients who started the postoperative phase, 105 (51.0%) received FLOT, while 37 (18%) received less intensive regimens (e.g. FOLFOX or De Gramont), depending on performance status after surgery or toxicity in the preoperative phase. Pathological complete response (pCR) was obtained in 7.3% of cases. In the preoperative phase, grade (G) 3-4 hematological and gastrointestinal adverse events (AEs) were reported in 42 (20.4%) and 13 (6.3%) patients, respectively. Conclusions: These real data confirmed the feasibility of perioperative FLOT in a less-selected population, representative of the clinical practice. The pCR rate was lower than in the FLOT4-AIO trial. The survival outcomes, potential predictive or prognostic factors and comprehensive safety data will be included in the final analysis.

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Baseline features predicting receipt of chemotherapy in metastatic esophageal cancer: A National Cancer Database analysis of 12,370 patients.
Authors: Manguso Nicholas , Kim Sungjin , Hendifar Andrew Eugene , Klempner Samuel J. , Chao Joseph , Guan Michelle , Placencio-Hickok Veronica , Kim Haesoo , Liu Jar-Yee , Burch Miguel , Gangi Alexandra , Atkins Katelyn Mae , Kamrava Mitchell , Gong Jun
Published: February 2020

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Background: We investigated predictors for chemotherapy (CTX) and prognostic variables in a large metastatic esophageal cancer (mEC) patient data set. Methods: We interrogated the National Cancer Database between 2004-2015 and included patients (pts) with M1 disease who had known CTX status (received or did not receive CTX). Univariable and multivariable analyses were performed, and a logistic regression model was used to estimate the effect of CTX with adjustment for potential confounders. Results: We included 12,370 mEC patients with available CTX status for multivariable analyses. Predictors for CTX treatment included year of diagnosis 2010-2014 (odds ratio (OR) 1.29, 95% confidence interval (CI) 1.17-1.43), median income > $46,000 (OR 1.49, 1.27-1.75), and node-positivity (OR 1.35, 1.20-1.52; all p < 0.05), while female gender (OR 0.86, 0.76-0.98), black race (OR 0.76, 0.67-0.93), uninsured (OR 0.41, 0.33-0.52), and Charlson Comorbidity Index (CCI) ≥2 (OR 0.61, 0.50-0.74) predicted for lower odds of receiving CTX (all p < 0.05). Median OS for pts receiving CTX was 9.53 mos (9.33-9.72) vs. 2.43 mos (2.27-2.60) with no CTX (p < 0.001). Modeling the effect of CTX to OS using a time-dependent coefficient showed that CTX was associated with improved OS up to 10 months, after which there is no significant effect on OS. Independent predictors of OS included treatment at an academic center (hazard ratio (HR) 0.91, 0.87-0.94), CCI ≥2 (HR 1.16, 1.07-1.26), and uninsured status (HR 1.20, 1.09-1.31). Conclusions: We identified several predictors for receipt of CTX and OS in pts with mEC. The benefit of CTX on OS is time-dependent and favors early initiation. Focused outreach in lower income and underinsured patients is critical as receipt of CTX is associated with improved OS.