bluuebunny/crossref_metadata_2025 huggingface dataset:
Multicenter phase II study of neoadjuvant chemotherapy with S-1 and oxaliplatin for locally advanced gastric cancer (Neo G-SOX PII).
Authors: Kondo Masato , Satake Hironaga , Mizumoto Motoko , Miki Akira , Watanabe Takanori , Tanaka Norimitsu , Hirata Kenro , Tanioka Hiroaki , Okita Yoshihiro , Kyogoku Takahisa , Tatsumi Mitsutoshi , Matoba Koreatsu , Adachi Shinichi , Kaihara Satoshi , Yasui Hisateru , Tsuji Akihito
Published: February 2020

399

Background: Prognosis for locally advanced gastric cancer (LAGC), such as clinical T4 disease, bulky nodal metastases, type 4 and large type 3 gastric cancer, was not satisfactory even by D2 gastrectomy followed by adjuvant chemotherapy. Neoadjuvant chemotherapy is another promising approach, therefore, we have conducted a phase II study to evaluate the efficacy and safety of the neoadjuvant chemotherapy of S-1 and oxaliplatin (G-SOX) followed by gastrectomy with D2/3 lymph node dissection for LAGC, and the primary endpoint of curative resection rate was met [Miki A, ESMO 2019]. We show longer follow-up data from this study. Methods: Patients with adenocarcinoma of the stomach; clinical T4; clinically resectable gastric cancer of type 4 or large type 3; bulky nodal involvement around major branched arteries to the stomach were enrolled. Patients receive two cycles of neoadjuvant chemotherapy with S-1 (80 mg/m2, p.o., days 1-14 followed by 1 week rest) and oxaliplatin (130 mg/m2 at day 1), followed by D2 or higher surgery with no residual disease. Patients with pathological R0/1 resection received S-1 (80 mg/m2, p.o., days 1-28 followed by 2 week rest) for 1 year as adjuvant chemotherapy. Primary endpoint was curative resection rate. Results: Between August 2015 and March 2017, forty-one patients were in enrolled. Of the patients, 39 patients (95%) completed the two courses of neoadjuvant chemotherapy of G-SOX, 37 (90%) received gastrectomy, and 36 (87.8%) received curative resection (R0/1). Grade 3 or higher toxicities during neoadjuvant chemotherapy of G-SOX were neutropenia (7%), fatigue (7%), diarrhea (5%) and thrombocytopenia (2%). No treatment related deaths were observed. Surgical complications including postoperative complications were observed in 13 patients (35%). Pathological response rate after neoadjuvant G-SOX was 40%. With a median follow-up period of 33.8 months, 3year-relapse free survival and 3year-ovearll survival was 54.3% and 73.1%, respectively. Conclusions: An update analysis confirmed that neoadjuvant chemotherapy of G-SOX is a feasible and might be one of the promising strategies for patients with LAGC. Clinical trial information: UMIN000018661.
Surgery for stage IV gastric cancer: An Italian perspective.
Authors: Bencivenga Maria , Ministrini Silvia , Solaini Leonardo , Marino Elisabetta , d’Ignazio Alessia , Mura Gianni , Sofia Silvia , Sofia Silvia , Cipollari Chiara , Marrelli Daniele , Degiuli Maurizio , Donini Annibale , Roviello Franco , Morgagni Paolo , De Manzoni Giovanni , Tiberio Guido
Published: February 2020

403

Background: Surgical approach to gastric cancer with hepatic metastases is becoming more and more accepted but few information exist concerning the surgical management of gastric cancer with extra-hepatic metastases. With this retrospective study we evaluated if the prognosis is influenced by different metastatic sites and we looked for the presence of prognostic factors. Methods: We analysed 282 patients with gastric cancer and synchronous metastases treated at our Institutions from 2010 to January 2017. We investigated survival performances after surgery according to the site of metastases: peritoneal, haematogenous, hepatic, distant lymph nodes and more than one site. Furthermore, we investigated how survival was influenced by patient-, gastric cancer-, metastases- and treatment-related prognostic factors. Results: Median overall survival was 10.9 months. We found no survival differences according to the site of metastases: median survival was 11.2, 11.6, 9.8, 21.4, 7.0 months for peritoneal, hepatic, lymph-nodal, haematogenous and more than1 site of metastases, respectively (p = 0.797). In all subgroups we observed an interesting number of long-term survivors (peritoneal 14.3% ≥36 months, 7.6% ≥60 months; hepatic 13.0% ≥36 months, 2.2% ≥60 months; lymph nodes 12.5% ≥36 months, 3.1% ≥60 months; > 1 site 18.7% ≥36 months, 1.6% ≥60 months). At multivariate analysis the factors that influenced survival were: number of resected lymph-nodes (p = 0.013), extension of lymphadenectomy (p < 0.001), pN (p = 0.003), curativity (p = 0.032) and histology (p = 0.028). Conclusions: We showed that no differences in overall survival according to site of metastases exist and we suggest that patients in whom a curative resection is possible, should be treated by resection of both gastric cancer and metastases.
Significance of intratumoral tertiary lymphoid structure (TLS) as predictictive factors of nivolumab therapy after conversion surgery for unresectable gastric cancer: A retrospective study.
Authors: Tanaka Hiroaki , Mori Takuya , Kimura Kenjiro , Muguruma Kazuya , Hirakawa Kosei , Ohira Masaichi
Published: February 2020

412

Background: Conversion surgery for unresectable advanced gastric cancer has been increasing with the development of chemotherapy. Adjuvant chemotherapy regimens after conversion surgery have not been standardized. The main mechanism of nivolumab is augmentation of antitumor immune response of tumor infiltrating cytotoxic T cells (CTL) to cancer cells, and it has recently been reported that nivolumab therapy before and after chemotherapy is effective in other carcinomas. We previously reported that tertiary lymphoid architecture (TLS) correlates with tumor-infiltrating T cells and is associated with a better prognosis in untreated patients. The purpose of this study was to investigate the relationship between the presence of TLS in the primary tumor and prognosis in patients with gastric cancer who underwent conversion therapy. Methods: We evaluated 52 patients with advanced gastric cancer including 17 patients underwent conversion surgery and 35 patients underwent palliative surgery without prior chemotherapy in our department from 2009 to 2017. The local immune environment and presence of TLS was evaluated by immunohistochemical staining. Results: Intratumoral TLS occurred in 20% of patients with advanced cancer who did not receive chemotherapy before surgery and in 52% of patients who received conversion surgery. And the prognosis of patients with the presence of TLS was better than no TLS. Intratumoral CD8 T-cell infiltration was slightly associated presence of TLS. We had a case in which nivolumab was highly effective and converted to conversion surgery, and a case in which nivolumab was highly effective in patients with recurrence after conversion surgery. TLS was observed in the vicinity of the tumor in these patients. Conclusions: The prognosis was good in the case in which intratumoral TLS was present after conversion surgery. These results suggest that the adjuvant nivolumab therapy may improve the outcome of patients underwent conversion surgery for advanced gastric cancer. These results suggest that peri-tumor TLS is a predictor of nivolumab efficacy in adjuvant therapy after conversion surgery.
Outcomes of appendiceal adenocarcinomas compared to right and left-sided colorectal adenocarcinomas: An analysis from the National Cancer Database (NCDB).
Authors: Nair Kanika Gupta , Wei Wei , Cruise Michael , Tullio Katherine , Estfan Bassam N.
Published: February 2020

42

Background: Appendiceal carcinomas (AC) account for 1-2% of colorectal cancers (CRC) and are generally treated like other CRC. However, there is limited data to guide treatment. While AC originate on the right side of the colon, it is unclear if they behave like as right-sided CRC (R-CRC). We seek to learn how AC differ from right versus left-sided CRC (L-CRC). Methods: We identified histologically confirmed cases of appendiceal and colorectal adenocarcinomas with information about stage and overall survival (OS) diagnosed between 2004 and 2016 from the National Cancer Database. Kaplan-Meier method and log-rank test were used to estimate and compare OS. Results: 833,939 patients met our inclusion criteria: 15,138 (1.8%) AC, 447,551 (53.7%) L-CRC, 308,794 (37.0%) R-CRC, and 62,456 (7.5%) transverse CRC (T-CRC). Median age at diagnosis of all patients was 68 years (range:18-90); AC was lowest at 61 years for stage I-III disease and 58 years for stage IV disease. Stage IV AC was more common in females 3628/5739 (63.22%). AC had the best OS among site groups in stage I-III. Median OS for stage I-III AC was 128.8 months (95% CI: 117.9-139.0), with 5-year OS rate of 0.69 (95% CI: 0.67-0.70); L-CRC median OS was 111.6 months (95% CI: 110.9-112.4), with 5-year OS rate of 0.681 (95% CI: 0.680-0.683); R-CRC median OS was 88.5 months (95% CI: 87.8-89.1), with 5-year OS rate of 0.613 (95% CI: 0.611-0.615); and T-CRC median OS was 86.2 months (95% CI: 84.7-87.6), with 5-year OS rate of 0.608 (95% CI: 0.604-0.613) (p <0.0001) (Table). Similar difference was observed in stage IV patients (Table). Conclusions: Patients with AC had significantly better OS for stages I-III and stage IV compared to patients with L-CRC, R-CRC, and T-CRC, though outcomes were more similar to L-CRC. The difference is more evidence for patients with stage IV disease. T-CRC had similar OS to R-CRC, as anticipated.

[Table: see text]
Efficacy of pembrolizumab (pembro) monotherapy versus chemotherapy for PD-L1–positive (CPS ≥10) advanced G/GEJ cancer in the phase II KEYNOTE-059 (cohort 1) and phase III KEYNOTE-061 and KEYNOTE-062 studies.
Authors: Wainberg Zev A. , Fuchs Charles S. , Tabernero Josep , Shitara Kohei , Muro Kei , Van Cutsem Eric , Bang Yung-Jue , Chung Hyun Cheol , Yamaguchi Kensei , Varga Eniko , Chen Jen-Shi , Hochhauser Daniel , Thuss-Patience Peter C. , Al-Batran Salah-Eddin , Garrido Marcelo , Kher Uma , Shih Chie-Schin , Shah Sukrut , Bhagia Pooja , Chao Joseph
Published: February 2020

427

Background: Pts with advanced gastric/gastroesophageal junction (G/GEJ) cancer received pembro monotherapy (200 mg Q3W) 3L+ in cohort 1 of KEYNOTE-059 (NCT02335411), 2L in KEYNOTE-061 (NCT02370498), or 1L in KEYNOTE-062 (NCT02494583). We present efficacy data for patients with PD-L1 combined positive score (CPS) ≥10 tumors in these trials. Methods: In study 059, 46 pts in cohort 1 with PD-L1 CPS ≥10 received pembro. In study 061, 108 pts with PD-L1 CPS ≥10 received pembro (n=53) or chemotherapy (chemo; n=55). In study 062, 182 pts with CPS ≥10 received pembro (n=92) or placebo + chemo (n=90). Efficacy end points included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR). Results: Median follow-up in study 059 was 5.6 mo. Median OS with pembro was 7.9 mo (95% CI, 5.8-11.1), and 12-mo OS was 32.6%. PFS at 6 mo was 17.4%, ORR was 17.4%, and median DOR was 20.9 mo (2.8+ to 34.9+). In study 061, after a median follow-up of 8.8 mo, pembro prolonged OS vs chemo (median 10.4 vs 8.0 mo; HR, 0.64; 95% CI, 0.41-1.02); 12-mo OS was 45.3% for pembro and 23.6% for chemo. Median PFS was 2.7 mo for pembro and 3.4 mo for chemo (HR, 0.86; 95% CI, 0.56-1.33). ORR was 24.5% vs 9.1%, and median DOR was NR (4.1-26.0+) and 6.9 mo (2.6-6.9) for pembro vs chemo. In study 062, median follow-up was 17.4 mo for pembro and 10.8 mo for chemo. Pembro prolonged OS vs chemo (median 17.4 vs 10.8 mo; HR, 0.69; 95% CI, 0.49-0.97); 12-mo OS was 56.5% vs 46.7%. Median PFS was 2.9 mo vs 6.1 mo (HR, 1.09, 95% CI, 0.79-1.49). ORR was 25.0% vs 37.8%, and median DOR was 19.3 mo (1.4+ to 33.6+) vs 6.8 mo (1.5+ to 30.4+) for pembro vs chemo, respectively. Conclusions: Collectively, these data indicate that 1L, 2L, and 3L+ pembro monotherapy showed clinically meaningful efficacy in CPS ≥10, with a more durable response than chemotherapy. Clinical trial information: NCT02335411, NCT02370498, and NCT02494583.

[Table: see text]
Survival impact on regorafenib (REG) and trifluridine/tipiracil hydrochloride (FTD/TPI) for patients with metastatic colorectal cancer: Single institutional experience.
Authors: Chida Keigo , Kotani Daisuke , Sawada Kentaro , Nakamura Yoshiaki , Kawazoe Akihito , Kuboki Yasutoshi , Shitara Kohei , Kojima Takashi , Taniguchi Hiroya , Yoshino Takayuki
Published: February 2020

43

Background: Regorafenib (REG) and trifluridine/tipiracil hydrochloride (FTD/TPI) demonstrated overall survival (OS) benefit in patients (pts) with metastatic colorectal cancer (mCRC) in the CORRECT and RECOURSE phase III trials. In Japan, REG and FTD/TPI have been approved in 2013 and 2014, respectively. However, little is known about survival impact on these agents in the real-world setting. Therefore, the aim of this retrospective study was to evaluate the effects of REG and FTD/TPI in pts with mCRC. Methods: We collected medical records from consecutive 1142 pts who had been initiated with first-line chemotherapy for mCRC from 2008 to 2016 at National Cancer Center Hospital East. The survival outcomes were compared between pts from 2008 to 2011 (cohort A) and those from 2012 to 2016 (cohort B). This study excluded pts who have not been refractory or intolerant to standard chemotherapy including fluoropyrimidine, oxaliplatin, irinotecan, and anti-EGFR antibody if KRAS exon 2/ RAS wild-type tumors. Results: A total of 590 pts were analyzed (cohort A; N = 236 and cohort B; N = 354). More patients received at least one of REG or FTD/TPI in cohort B (16.1% vs. 59.9%, p < 0.001). The time from initiation to end of standard chemotherapy was comparable between the two cohort (20.0 vs. 17.5 months, p = 0.266). With a median follow-up period of 34.9 months, salvage-line OS (sOS) after standard chemotherapy was significantly longer in cohort B (4.8 vs. 6.6 months, p = 0.001), while there was only a favorable trend in cohort B in terms of OS from start of first-line treatment (27.3 vs. 28.5 months, p = 0.516). In cohort B, pts who sequentially received both of REG and FTD/TPI showed longest sOS (median, both of REG and FTD/TPI; 11.3 months, either REG or FTD/TPI; 7.0 months, neither REG nor FTD/TPI; 3.1 months). Conclusions: Our study showed that REG and FTD/TPI led to prolongation of sOS in the real-world setting, indicating the importance of strategies which make all active agents available to pts with mCRC.
Pembrolizumab (pembro) in microsatellite instability-high (MSI-H) advanced gastric/gastroesophageal junction (G/GEJ) cancer by line of therapy.
Authors: Chao Joseph , Fuchs Charles S. , Shitara Kohei , Tabernero Josep , Muro Kei , Van Cutsem Eric , Bang Yung-Jue , De Vita Ferdinando , Landers Greg A. , Yen Chia-Jui , Chau Ian , Elme Anneli , Lee Jeeyun , Ozguroglu Mustafa , Catenacci Daniel V.T. , Li Xiaodong , Shih Chie-Schin , Shah Sukrut , Bhagia Pooja , Wainberg Zev A.
Published: February 2020

430

Background: Pembro has demonstrated promising antitumor activity in patients (pts) with advanced G/GEJ cancer with PD-L1 CPS ≥1 and CPS ≥10 irrespective of MSI-H status. Here, we examine the antitumor activity of pembro monotherapy vs chemo in pts with MSI-H, advanced G/GEJ cancer in KEYNOTE (KN)-059 (NCT02335411), KN061 (NCT02370498), and KN062 (NCT02494583). Methods: Eligible pts with advanced G/GEJ cancer with ≥2 prior therapies (KN059 cohort 1; 3L+), 1 prior therapy (KN061; 2L), or no prior therapy (KN062; 1L) were enrolled. In KN059 cohort 1, pts received pembro only. In KN061 pts were randomized to pembro or paclitaxel (chemo), and in KN062 to pembro, pembro + cisplatin+5-FU/cape (chemo), or chemo. Pts received pembro 200 mg Q3W for up to 2 y. MSI-H status was determined centrally by PCR. Endpoints included OS, PFS, ORR, and safety. Data cutoff dates were Aug 8, 2018 (KN059), Oct 26, 2017 (KN061), and Mar 26, 2019 (KN062). Results: At data cutoff, 259 pts (n = 7 [3%] MSI-H) had enrolled in KN059 cohort 1 (3L+), 592 (27 [5%] MSI-H]) in KN061 (2L), and 763 (50 [7%] MSI-H] in KN062 (1L). Median follow-up was 5.6 mo, 7.9 mo, and 11.3 mo, respectively. For the overall study populations, median OS was 5.5 mo for pembro (3L+), 6.7 mo vs 8.3 mo for pembro vs chemo (2L), and 10.6 mo vs 11.0 mo for pembro vs chemo (1L). Median PFS was 2.0 mo (3L+), 1.5 vs 4.1 mo (2L), and 2.0 vs 6.4 mo (1L). ORR was 11.6% (3L+), 11.1% vs 12.5% (2L), and 14.8% vs 37.2% (1L), with median DOR of 16.1 mo, 18.0 vs 5.5 mo, and 13.7 vs 6.8 mo. In pts with MSI-H tumors, OS and PFS were prolonged with pembro vs chemo, with higher ORR (Table). Conclusions: As with PD-L1 expressers, MSI-H status is a predictive biomarker for pembro monotherapy in advanced G/GEJ cancer irrespective of line of therapy. Clinical trial information: (KN)-059 (NCT02335411), KN061 (NCT02370498), and KN062 (NCT02494583). Merck & Co., Inc., Kenilworth, NJ, USA.[Table: see text]
Gastric Cancer Registry: A comprehensive patient-reported resource for multidisciplinary and translational genomic approaches to gastric cancer.
Authors: Almeda Alison Figueroa , Hooker Anna , Lee Hojoon , Mills Meredith , Van Hummelen Paul , Ford James M. , Ji Hanlee
Published: February 2020

432

Background: Gastric cancer (GC) is the fifth leading cancer diagnosis and third frequent cause of cancer death globally. GC results from a cascade of molecular and genetic changes owing to environmental and genetic factors. While there are known risks to GC, more is to be learned about its development so to establish effective screens for early stages of cancer. Methods: The Gastric Cancer Registry (GCR) was built to investigate GC and discover informative genomic biomarkers. The GCR comprises medical, family, and social history and genomics data from patients with GC, a family history of GC, and/or a known mutation in the gene CDH1. Samples of saliva and gastric tumors are collected when available. The GCR allows us to leverage several genome sequencing datasets to construct a complete molecular landscape of GC. Early analysis of GC tissue includes whole exome sequencing (WES) to identify mutations, whole genome sequencing (WGS) for copy number variation, and RNA sequencing (RNAseq) for expression profiling. Results are used to inform of clonal neoantigens, microbiome, and immune cell populations. Saliva will be analyzed with linked reads sequencing to unearth germline mutations not picked up in standard clinical gene panels. Results: Datasets from 455 patients and samples from 159 patients have been collected. In a pilot study, we pinpointed specific mutations using WES and revealed extensive changes in genome copy number involving clinically actionable genes through WGS. Most tumors had a high degree of genomic instability and exhibited candidate markers for treatment decisions and response. Additionally, we found that RNAseq revealed tumor subgroups through gene expression signatures. Conclusions: The GCR is an informative resource enabling the identification of biomarkers for GC. With the GCR we are integrating expertise in translational cancer genomics with molecular biology, statistics, and bioinformatics to build a platform for discovery and the development of tools that will ultimately improve the detection, treatment, and prevention of GC.
MT-5111: A novel HER2 targeting engineered toxin body in clinical development.
Authors: Waltzman Roger J. , Sarkar Asis , Williams Eric T , Iberg Aimee T. , Higgins Jack T. , Willert Erin K.
Published: February 2020

433

Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered Shiga-like Toxin A subunit genetically fused to antibody-like binding domains. MT-5111 is a de-immunized ETB targeting HER2 for solid tumors. MT-5111 works through a novel mechanism of direct cell-kill, via enzymatic ribosome inactivation, and may not be subject to resistance mechanisms that exist for TKI, ADC, or antibody modalities. MT-5111 binds an epitope on HER2 distinct from trastuzumab or pertuzumab, that may provide for combination potential with other HER2 targeting agents. MT-5111 is a 55 kilodalton protein and may have improved tumor penetration capability in solid tumor settings. Methods: HER2 expression and activity of MT-5111 was assessed in vitro by flow cytometry and cell viability assays. Serum exposure and tolerability of MT-5111 was measured in non-human primate (NHP) studies. Results: MT-5111 effectively kills 8/9 cell lines (2 gastric) with moderate to high HER2 surface expression, as well as two additional gastric cell lines with lower HER2 expression. No cytotoxicity is observed on multiple HER2- cell lines. As a protein, MT-5111 is not a substrate of drug efflux transporters that limit efficacy of ADCs. MT-5111 demonstrates effective cell-killing in vitro against cell lines expressing HER2 but resistant to trastuzumab (HCC1954) or T-DM1 (JIMT-1 and gastric SNU-216), highlighting the benefit of a novel mechanism of action to treat resistant disease. MT-5111 binds human and NHP HER2 protein. Based on serum exposure of MT-5111 in NHPs used to model pharmacokinetics, planned MT-5111 dosing in humans is above the IC50 required for HER2-specific cellular cytotoxicity in vitro. MT-5111 has a short half-life that, while allowing for efficient tumor cell targeting, minimizes serum exposure to avoid systemic effects over time. Conclusions: A Phase 1, first in human, open-label dose escalation and expansion study of MT-5111 (NCT04029922) in subjects with HER2+ solid tumors whose disease has progressed after treatment with other approved therapies is open for enrollment. MT-5111 represents a novel HER2 targeted therapy for patients with HER2+ cancers with potential to overcome mechanisms of tumor resistance to existing therapies.
A novel gene signature for predicting response to chemoradiotherapy in esophageal adenocarcinoma.
Authors: Ghatak Souvik , Omstead Ashten N. , Jobe Blair A , Kreft Rachael , Gorbunova Anastasia , Salvitti Madison , Kelly Ronan Joseph , Zaidi Ali Hussainy , Goel Ajay
Published: February 2020

445

Background: While neoadjuvant chemoradiotherapy (CRT) has emerged as an important treatment modality in patients with locally advanced esophageal adenocarcinoma (EAC), ~60%-70% of patients do not respond to such treatments; but are exposed to their toxicity nonetheless. This highlights the clinical need for the development of biomarkers that can robustly predict response to CRT and spare others from the toxicity and expense associated with these treatments. Herein, we systematically identified a biomarker signature that predicts response to CRT in EAC patients. Methods: Using a clinical-trial driven cohort of 25 EAC patients treated with 5- fluorouracil plus carboplatin and concurrent radiation therapy, we performed whole-exome sequencing (WES) in paired biopsy specimens obtained at baseline and 3-6 weeks post-treatment. In addition, we also analyzed the predictive potential of a panel of immune-related genes (TIM3, LAG3, IDO1 and CXCL9) in these matched tissues. Results: In our cohort, based upon RECIST criteria, 14 EAC patients were categorized as non-responders, while 11 were deemed as responders to CRT. Among responders, the most frequently mutated genes were NOTCH1, NOTCH2, NOTCH3, and MLL2; and the overall tumor mutation burden (TMB) was significantly reduced for these genes in post-treatment specimens (P<0.001). In contrast, in non-responders, NFE2L2, KEAP1, FAT1, FAT2, FAT3 and PIK3CA, harbored frequent mutations. Similarly, all four immune-related genes were significantly up-regulated in post-treatment specimens (p<0.05-0.001). Interestingly, the progression-free survival was significantly greater in patients with lower TMB (64.1%, p=0.04) and increased immunogenic scoring (62.7%, p=0.01). We finally constructed a risk-stratification model that comprised of mutational scores from 10 most frequently mutated genes, together with 4 immune-related genes, which achieved an AUC of 0.83 in predicting response to CRT in EAC patients. Conclusions: Using a systematic biomarker discovery approach, we have developed a novel biomarker signature that robustly predicts response to CRT in EAC patients and has a significant potential for personalized management of EAC patients.
Clinicopathological features of multifocal gastric carcinoma: A retrospective study.
Authors: Zou Xi , Zhang Runfeng , Lei Qi , Zhou Aiping , Du Chun-Xia
Published: February 2020

453

Background: The occurrence of multifocal gastric carcinoma (MGC) is growing in China, while relevant study remains limited. This study aimed to collect more information of MGC for further research. Methods: Patients with MGC treated at China National Cancer Center from January 2010 to December 2017 were enrolled in this retrospective study. A 6-month interval was used to separate synchronous and metachronous foci. Results: 103 patients were included. 88 (85.4%) were males. 96 (93.2%) patients had two foci and 7 (6.8%) had three or more foci, contributing a total of 216 tumor foci. 185 (85.6%) foci were adenocarcinoma, 18 (8.3%) were intraepithelial neoplasia, 2 (0.9%) were lymphoepithelioma-like carcinoma and 1 (0.5%) was small cell carcinoma. Intestinal, diffuse, and mixed type accounted for 49.7%, 14.6% and 11.4% respectively, with 24.3% unknown.In 96 patients with 2 foci, 56 (58.3%) patients had synchronous diseases, and 40 (41.7%) had metachronous diseases. The median age at the diagnosis of first tumor was 62 (55-71) years. The median diagnosis interval of metachronous tumor foci was 41.4 (23.5-88.3) months. The locations and sizes of foci are shown in Table. In synchronous cases, 6 foci of accessory tumor were less than 1cm including one being 0.4 cm. In metachronous cases, 4 foci of second tumor were less than 1 cm. 51 (49.5%) patients were current smokers or ex-smokers, and 44 (42.7%) were regular alcohol consumers. 26 (25.2%) patients had a first-relative family history, including 14 (13.6%) having a family history of gastrointestinal carcinoma. Conclusions: The second gastric tumor should be thoroughly detected to avoid missed diagnosis, since the accessory tumor might be rather small. Further genetic research is warranted to explore the potential pathogenesis of MGC.

[Table: see text]
Prognostic implications of tumor sidedness in colorectal cancer patients in South Dakota, 2006-2015.
Authors: Bleeker Jonathan Scott , Atiq Muslim , Nelson Morgan , Dosch Kay
Published: February 2020

46

Background: Tumor “sidedness” is emerging as an important prognostic and predictive factor in patients with metastatic colorectal cancer (CRC), with right sided colon cancer (RC) associated with poorer overall survival (OS) than left sided colon cancer (LC). This distinction has been noted in clinical trials and large databases, where American Indian (AI) populations are generally underrepresented. This project aims to investigate the prognostic implications of CRC sidedness in the state of South Dakota, focusing on the AI population. Methods: Data from patients diagnosed with CRC in the South Dakota cancer registry from January 1, 2006 to December 31, 2015 were analyzed for demographic and presenting features as well as survival outcomes. A total of 3,637 cases were included in the analysis, of which 191 (5%) were AI. Tumors arising from the cecum, ascending colon, hepatic flexure and transverse colon were considered RC while those arising from the splenic flexure, descending colon, sigmoid colon and rectum were considered LC. Results: In all patients, 47.1% of cases were RC; Caucasians (C) were significantly more likely to have RC, as 47.7% of cases in Caucasians were RC, whereas in the AI population, 35.6% cases were RC (p=0.005). Patients with RC were more likely to be female and older and less likely to present with metastatic disease than LC. Tumor sidedness was not associated with OS when analyzing all patients regardless of stage or in patients with non-metastatic disease. In patients with metastatic disease, RC was associated with inferior OS compared to LC [Median OS (mo): 9.9 v. 23.6, p<0.001]. When analyzed by race, RC was associated with inferior OS in C [Median OS (mo): 9.6 v. 23.6, p=0.002] but not in AI [Median OS (mo): 10.2 v. 10.4, p=0.082]. Conclusions: Although limited by small sample size, this analysis is hypothesis generating, as AI patients with CRC were more likely to have LC than Caucasians and the well described prognostic implications of RC were not noted in the AI population. Larger population studies and further investigation as to potential explanations for this finding are recommended.
A United States Rectal Cancer Consortium study of inferior mesenteric artery versus superior rectal artery ligation: How high do we need to go?
Authors: Turgeon Michael K. , Gamboa Adriana C. , Lee Rachel M. , Maniko Jeffrey , Maguire Lillias , Mohammed Maryam , Holder-Murray Jennifer , Abdel-Misih Sherif , Kimbrough Charles , Wiseman Jason T. , Edwards-Hollingsworth Kamren , Hawkins Alexander , Bauer Philip , Silviera Matthew , Maithel Shishir K. , Balch Glen C.
Published: February 2020

47

Background: The optimal level of pedicle ligation during proctectomy for rectal cancer, either at the origin of the inferior mesenteric artery (IMA) or the superior rectal artery (SRA), is still debated. Reasons for IMA ligation include facilitating a tension-free anastomosis and improved clearance of regional lymph nodes. Our aim was to determine if SRA ligation portends inferior outcomes. Methods: The US Rectal Cancer Consortium database (2007-2017) was reviewed for pts with primary, non-metastatic rectal adenocarcinoma who underwent treatment with low anterior resection or abdominoperineal resection. Primary outcomes were anastomotic leak rate and lymph node (LN) harvest. Secondary outcomes were locoregional recurrence-free survival (LRFS), recurrence-free survival (RFS), and overall survival (OS). Results: Of 877 pts, median age was 59 years (IQR52-67) and 62% were male (n = 541). 86% received an IMA ligation (n = 755) while 14% SRA (n = 122). 12% were pathologic stage 0 (n = 101), 33% stage I (n = 281), 24% stage II (n = 206), and 31% stage III (n = 269). Median follow-up was 34 mos. SRA ligation was more common in stage III disease (43vs30%, p = 0.005) while IMA ligation was more often performed with a minimally invasive approach (70vs42%, p < 0.001). SRA ligation was associated with a nearly identical anastomotic leak rate compared to IMA (9vs8%, p = 1.0). Similarly, the median number of LNs removed was the same between both ligation groups (15vs15, p = 0.38). On multivariable analysis accounting for an open approach, advanced pathologic stage, and positive resection margin status, SRA ligation was not associated with increased anastomotic leak rate or reduced LRFS, RFS, or OS (all p > 0.1). Conclusions: If a tension-free anastomosis is feasible, SRA ligation is not associated with either a worse technical outcome or inferior lymph node harvest. Furthermore, all cancer survival metrics are similar between SRA and IMA ligation. Given that either approach is safe and feasible from both a technical and oncologic standpoint, this study questions the routine practice of IMA ligation.
Ramucirumab (RAM) or merestinib (MER) or placebo (PL) plus gemcitabine (GEM) and cisplatin (CIS) as first-line treatment for advanced or metastatic biliary tract cancer (BTC): A randomized, double-blind, phase II study.
Authors: Valle Juan W. , Bai Li-Yuan , Orlova Rashida , Van Cutsem Eric , Adeva Alfonso Jorge , Chen Li-Tzong , Obermannova Radka , Ettrich Thomas Jens , Chen Jen-Shi , Wasan Harpreet Singh , Denlinger Crystal S. , Vogel Arndt , He Aiwu Ruth , Bousmans Nathalie , Girvan Allicia C , Zhang Wei , Walgren Richard A. , Carlesi Roberto , Oh Do-Youn
Published: February 2020

477

Background: We assessed RAM or MER plus standard of care GEM+CIS as first-line treatment for BTC. Methods: Patients (pts) with BTC, ECOG PS 0/1, and measurable disease were randomized 2:1:2:1 to oral MER 80 mg QD, oral PL QD, IV RAM 8 mg/kg days 1 and 8 Q3W or IV PL days 1 and 8 Q3W. Pts also received up to 8 cycles IV GEM 1000 mg/m2 + CIS 25 mg/m2 days 1 and 8 Q3W. RAM, MER, or PL could continue until disease progression. Primary endpoint: progression-free survival (PFS). Secondary endpoints: overall survival (OS), objective response rate (ORR), and safety. PFS and hazard ratios (HRs) were compared using stratified log-rank tests and Cox regression models, respectively. NCT02711553. Results: 309 pts were randomized to RAM (106), MER (102), or pooled PL (101). More pts in the RAM (54.7%) and MER (49.0%) groups had baseline ECOG PS 1 vs PL (38.6%). Efficacy endpoints are in Table. Fewer pts received post-discontinuation systemic therapy in the RAM group (RAM 37.5%, MER 50.0%, PL 52.0%). The most common grade ≥3 treatment-emergent adverse events were: RAM vs PL: neutropenia (49.0% vs 33.0%), thrombocytopenia (34.6% vs 17.0%), and anemia (26.9% vs 19.0%); MER vs PL: neutropenia (47.1% vs 33.0%), thrombocytopenia (18.6% vs 17.0%), and alanine aminotransferase increased (10.8% vs 5.0%). Conclusions: PFS, OS, and ORR were not improved with the addition of RAM or MER to GEM+CIS. Treatment was well tolerated, with safety profiles consistent with known profiles for RAM, MER, and GEM+CIS. Translational studies are ongoing. Clinical trial information: NCT02711553 . [Table: see text]
Immune checkpoint blockade (ICB) response evaluation with MRI/MR elastography (MRE) in surgical and nonsurgical patients with HCC.
Authors: Qayyum Aliya , Avritscher Rony , Aslam Rizwan , Ma Jingfei , Pagel Mark David , Sun Jia , Abugabal Yehia I. , Hassan Manal , Amin Hesham M. , Rashid Asif , Lee Sunyoung S. , Wolff Robert A. , Yao James C. , Ehman Richard , Duda Dan G. , Kaseb Ahmed Omar
Published: February 2020

480

Background: Currently, there is a lack of imaging biomarkers of immunotherapy outcome in hepatocellular carcinoma (HCC). The study aim was to determine if HCC enhancement on MRI and stiffness change measured by magnetic resonance elastography (MRE) can predict immunotherapy response. Methods: This was a prospective, Institutional Review Board approved study of 38 patients with HCC treated with immune checkpoint blockade (ICB) therapy. All patients had liver MRI/MRE and HCC biopsy at baseline, and MRI/MRE with biopsy or resection after 6 weeks therapy. HCC stiffness (kPa) was measured on MRE elastograms (liver stiffness maps). HCC enhancement and change in stiffness were compared with treatment response to ICB in 1) non-surgical patients (pembrolizumab), and 2) surgical patients (nivolumab +/- ipilimumab). For non-surgical patients, treatment response was defined as overall survival >1 year. For surgical patients, treatment response was defined as <50% viable tumor at time of resection. Analysis was performed using descriptive statistics and Spearman correlation; p-value <0.05 was considered statistically significant. Results: Twenty-five patients were evaluable. Median age was 67 years (32, 78). Etiology of liver disease was NASH (n=8), HCV (n=8), HBV (n=2) and unknown (n=7). Treatment response occurred in 11/25 (44%) patients. Median HCC size and change in size were 4.7 cm (1.2, 14.0) and –0.32 cm, respectively. Median baseline HCC stiffness and change in stiffness were 5 kPa (2.2, 12.4) and –0.1 kPa (–2.2, 1.5), respectively. Median change in HCC size for responders and non-responders was –1.2 cm (–4.8, 0.4) and 0 cm (–1.5, 1.1), respectively (p = 0.02). Treatment response was associated with absence of portal venous phase capsular enhancement and increase in HCC stiffness, (p<0.001). Conclusions: Capsular enhancement and MRE stiffness change may be useful biomarkers of immune cell activated response to ICB therapy.
Clinical predictors of progression of a hepatic lesion from Li-RADS (LR) 3 to LR5 among patients (pts) at risk of hepatocellular carcinoma (HCC).
Authors: Hannan Lindsay Marie , Harris William Proctor , Ojeda Patricia I. , Park James O. , Mieloszyk Rebecca , Bhargava Puneet , Johnson Guy E.
Published: February 2020

481

Background: We sought to identify predictors of progression of LR3 lesions (i.e. indeterminate for HCC) to LR5 lesions (i.e. definitely HCC) on follow-up imaging among cirrhotic pts. Methods: Imaging reports with LR assignments were identified among pts seen at the University of Washington, 2013-2017. Cirrhotic pts with a LR3 lesion and follow-up scan within 1 year (yr) of LR3 lesion date were included (n = 313). Clinical features were abstracted from chart review. Survival analyses employing interval censoring were performed. Variables as potentially predictive of LR3 progression were identified in univariate analyses, with backwards elimination done (p < 0.05) to obtain the final multivariate model. Results: 20.4% of LR3 lesions progressed to LR5 within 1 yr; 73% were still LR3, 8% progressed to LR4. The population was predominantly male (61%), Caucasian (71%), older than 55 (63%). The most common cirrhotic etiologies were HCV (46.7%), alcohol (32.6%), and NASH (12.8%), not mutually exclusive. AFP at the time of LR3 scan was low if available (39% with AFP <5, 16% 5-10, 28% unknown). 22.7% had impaired liver function (ALBI grade 3); 19.5% lacked data to calculate ALBI grade. CT scan was the most common exam (56%). Multiple LR3 lesions were seen on 51% of scans. Most LR3 lesions were right sided (75%), < 1 cm (51%); 7% of lesions were > 2cm. Men (HR 2.0, p = 0.02), earlier scan yr (HR 0.47 per yr, p < 0.0001), older age (HR 1.42 per 15 yr, p = 0.047), lesion size (HR 1.21 for 2cm+, global p = 0.02) appeared as independent predictors of LR3 to LR5 progression based on the final model. Of 16 variables examined, men were more likely to have chronic HCV, history of alcohol use and less likely to have autoimmune hepatitis. No other differences were seen. In an a priori analysis, risk of male sex (HR 1.99, p = 0.03) persisted despite control for HCV, alcohol, age, race, scan yr, lesion size, and number of lesions. Conclusions: Identification of clinical factors associated with LR3 progression may allow for risk modeling tools that may assist in determining imaging frequency and timing of intervention. The increased risk among men vs women is not explained by clinical or radiographic features listed above.
Potential use of lenvatinib for patients with unresectable hepatocellular carcinoma beyond progression of sorafenib treatment: A real-world evidence and in vitro assessment with protein phosphorylation array.
Authors: Sato Yasushi , Tomonari Tetsu , Tanaka Hironori , Tanaka Takahiro , Hirao Akihiro , Okamoto Koichi , Miyamoto Hiroshi , Muguruma Naoki , Kagiwada Harumi , Kitazawa Masashi , Fukui Kazuhiko , Horimoto Katsuhisa , Takayama Tetsuji
Published: February 2020

485

Background: No information is available on the efficacy and safety of lenvatinib (LEN) as a second/third-line treatment for unresectable hepatocellular carcinoma (HCC) after sorafenib (SOR) therapy. We evaluated the characteristics and the therapeutic efficacy and safety of LEN as a second- and third-line treatment as well as first- treatment for unresectable HCC patients in clinical settings. Moreover, to rationalize these clinical findings in vitro, we assessed the anti-tumor activity of LEN on SOR-resistant cell line and performed a comprehensive phosphorylated protein array analysis associated with 377 signal transduction pathways using SOR-resistant and parental HCC cells. Methods: We retrospectively enrolled 51 unresectable HCC patients. Radiologic responses in 41 patients were evaluated by modified RECIST. Active signal transduction pathways in the cells were identified by protein array analysis, including 1205 proteins. Results: The evaluated patients comprised 25 TKI-naive (first- line), 7 intolerant to SOR (second-line), and 9 patients resistant to regorafenib (third-line). The ORRs were 64% in first-line, 42.8% in second-line, and 22.2% in third-line groups (first-line vs. third-line p< 0.05). The OS in the first-line was significantly longer than that in third-line group ( p< 0.05). Patients with better liver functional reserve (Child score, ALBI grade) exhibited higher ORR and longer OS. LEN was well-tolerated in the second/third-line treatment. The IC50 value of LEN against PLC/PRF5-R2 (30 μM) was significantly higher than that against PLC/PRF5 (6.4 μM). LEN significantly inhibited more signal transduction pathways related to FRS2, a crucial FGFR downstream molecule, in PLC/PRF5 than in PLC/PRF5-R2 cells. Conclusions: Our study indicates that LEN was active and safe in the second/third-line treatment for unresectable HCC. LEN seems more effective for HCC patients with better hepatic reserve function, or before TKI-resistance is acquired because of the partial cross-resistance to SOR.
Randomized, open-label, perioperative phase II study evaluating nivolumab alone or nivolumab plus ipilimumab in patients with resectable HCC.
Authors: Kaseb Ahmed Omar , Duda Dan G. , Tran Cao Hop Sanderson , Abugabal Yehia I. , Vence Luis M. , Rashid Asif , Pestana Roberto , Blando Jorge M. , Singh Shalini , Vauthey Jean-Nicolas , Hassan Manal , Amin Hesham M. , Qayyum Aliya , Chun Yun Shin , Tzeng Ching-Wei David , Sakamuri Divya , Wolff Robert A. , Yao James C. , Allison James Patrick , Sharma Padmanee
Published: February 2020

486

Background: In HCC, surgical resection is associated with high recurrence rates, and no effective neoadjuvant or adjuvant therapies currently exist. Immunotherapy using anti-PD-1 antibodies has shown promised but limited increase in survival in advanced disease. To maximize the benefit, we are studying the efficacy and safety of anti–PD-1 (nivolumab) and anti–CTLA-4 (ipilimumab) antibodies against HCC for resectable HCC. Methods: This is a randomized phase II trial of nivolumab (Arm A) or nivolumab + ipilimumab (Arm B) as pre-operative treatment for patients with HCC who are eligible for surgical resection. Pts are given nivolumab 240 mg every 2 weeks (wks) for a total of 6 wks. Pt in Arm B are treated concurrently with ipilimumab 1 mg/kg every 6 wks. Surgical resection occurs within 4 wks after last cycle of therapy. Pts continue adjuvant immunotherapy for up to 2 years after resection. The primary objective is the safety/tolerability of nivolumab +/- ipilimumab. Secondary objectives include overall response rate, complete response rate and time to progression. Exploratory objectives include evaluating the pre- and post-treatment immunological changes in tumor tissues and peripheral blood. Results: Twenty-six patients were enrolled at the time of this interim analysis, of which 20 have evaluable data. Most pts (55%) were between 60-70yo and male (75%). Four pts were HCV-positive, 6 had HBV and 10 had no hepatitis. 20 patients proceeded with resection as planned, surgery was aborted for 5 patients (1 for frozen abdomen and 2 development of contralateral liver nodule). Three are still receiving preoperative therapy. Pathologic complete response (pCR) was observed in 5/20 evaluable patients – 2 in Arm A and 3 Arm B (25% pCR rate). Five patients in Arm B and 1 in Arm A experienced grade 3 or higher toxicity prior to surgery. No grade 4 or higher toxicity were observed. Conclusions: We report a pCR rate of 25% for resectable HCC after preoperative immunotherapy in a randomized phase II pilot trial. Treatment was safe and surgical resection was not delayed. The study is ongoing. These promising results may contribute to a paradigm shift in the perioperative treatment of resectable HCC. Clinical trial information: NCT03510871.
Economic burden and patterns of care in patients with advanced hepatocellular carcinoma.
Authors: Aly Abdalla , Malangone-Monaco Elisabetta , Noxon Virginia , Henriques Caroline , Benavente Fernando , Kim Amy K.
Published: February 2020

487

Background: Hepatocellular carcinoma (HCC) is often diagnosed in advanced stages. While sorafenib has been the standard of care for advanced HCC, treatment guidelines are not clearly defined. We studied real world systemic lines of therapy (LOT) and economic burden in HCC patients. Methods: The MarketScan database was used to identify patients newly diagnosed with HCC (ICD-9 155.0, ICD-10 C22.0, C22.8) from 2011-2018 and continuously enrolled for ≥6 months prior and ≥1 month post HCC diagnosis. Patients with prior liver transplantation or metastasis, or other primary cancers, pregnancy, or clinical trial participation at any time were excluded. Systemic LOT were identified and ended due to discontinuation, switch, or end of follow up. Transarterial procedures (chemoembolization [TACE], radioembolization [TARE]) were also reported. Results: A total of 1,558 patients (mean age, 62; 78% male; median follow up, 8.8 months) were studied. The first LOT was mostly sorafenib (78%). The median time from HCC diagnosis to start of sorafenib was 43 days. The median duration of therapy on sorafenib was 60 days, with patients ending sorafenib use due to discontinuation (40%) or switching (6%). Only 16% of patients received second LOT, of which 10% were PD-1 inhibitors. Use of TACE and TARE over the follow up period was 15% and 12%, respectively. TACE was more prevalent prior to first LOT (11%) compared to during first LOT (4%) and between first and second LOT (6%). This trend was also observed for TARE (7%, 3%, and 4%, respectively). Patients incurred a mean all-cause total cost of $181,036 and $17,235 per-patient per-month (PPPM), of which $9494 were HCC-specific (Table). Conclusions: Most patients received sorafenib as first line in advanced HCC, but only for 2 months. Only 16% of patients receive second line therapy. HCC patients have a high economic burden and there is a need for more effective and safe treatments. [Table: see text]
Primary liver angiosarcoma and factors associated with improved outcomes: An analysis of the National Cancer Database.
Authors: Jain Prantesh , Cioffi Gino , Patil Nirav , Opneja Aman , Alahmadi Asrar , Bajor David Lawrence , Saltzman Joel N. , Getty Patrick J. , Ammori John Brian , Bhatt Aashish D. , Mansur David B. , Lee Richard T. , Mangla Ankit
Published: February 2020

498

Background: Primary liver angiosarcoma (LAS) is a rare and aggressive tumor of the liver. In this analysis of the national cancer database (NCDB) we sought the risk of mortality and factors associated with survival amongst patient diagnosed with LAS. Methods: Patients diagnosed with hepatocellular carcinoma (HCC) or LAS from 2004 – 2014 were identified in the NCDB. The Kaplan-Meier method with the log-rank test was used to calculate survival for HCC and LAS patients. Additional analyses were performed on the cohort with LAS to assess the impact of surgery, chemotherapy, radiation therapy (RT) and facility type on overall survival (OS). Multivariable analyses using cox proportional methods, adjusted for age, sex, Charlson/Deyo score, race, ethnicity, insurance status, facility location and type, surgery status, and chemotherapy status were performed to obtain adjusted hazard ratio (aHR). Results: Total of 118,066 patients with HCC and 346 patients with LAS were identified in the database. Median survival for HCC patients was 11.9 months (95% CI: 11.7-12.2) and 2.0 months for LAS patients (95% CI: 1.8 – 2.4). Risk of mortality was higher for patients with LAS compared to those with HCC (aHR (95% CI): 2.23 (1.97 - 2.53), p < .0001). Among the LAS patients, those who received surgery had a median survival of 8.6 months (95% CI: 5.6 - 17.3), and 1.8 months for those who did not (95% CI: 1.48 - 1.94). Risk of mortality was lower in patients who received surgery compared to those who did not (aHR (95% CI): 0.23 (0.15 - 0.37), p < .0001). Patients treated at and academic center had a higher median survival (3.3 months, 95% CI: 2.2 - 4.1) then those treated at a non-academic center (1.5 months, 95% CI: 1.2 - 1.8). Though, there was no significant difference in OS (aHR (95% CI): 0.48 (0.21 - 1.10), p = 0.082). A very small number of patients received chemotherapy or RT to conduct a meaningful analysis. Conclusions: Patients diagnosed with primary LAS have a worse OS compared to those with HCC. Amongst patients with primary LAS, surgical resection is associated with best survival outcomes. Treatment at an academic center is associated with better median survival, although OS did not reach statistical significance in our analysis.