bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of trastuzumab deruxtecan and nivolumab as third- or later-line treatment for HER2-positive advanced gastric cancer: A single-institution retrospective study.
Authors: Shimozaki Keitaro , Nakayama Izuma , Takahari Daisuke , Nagashima Kengo , Yoshino Koichiro , Fukuda Koshiro , Fukuoka Shota , Osumi Hiroki , Ogura Mariko , Wakatsuki Takeru , Ooki Akira , Shinozaki Eiji , Chin Keisho , Yamaguchi Kensei
Published: January 2024

265

Background: Despite the difficulty of directly comparing trastuzumab deruxtecan (T-DXd) and nivolumab as third- or later-line treatment for HER2-positive advanced gastric cancer (AGC) in randomized trials, discussions regarding optimal treatment strategies are desired. Methods: This single-institution retrospective study aimed to describe the real-world efficacy and safety of T-DXd and nivolumab as third- or later-line treatment for patients with HER2-positive AGC treated between March 2016 and May 2022. Results: Overall, 58 patients (median age, 64 years; 69% male) were eligible (T-DXd group, n = 20; nivolumab group, n = 38). Most had HER2 3+ (72%) and presented with metastatic disease at diagnosis (66%). Response rates in the 41 patients with measurable lesions were 50% and 15% in the T-DXd and nivolumab groups, respectively. The T-DXd and nivolumab groups had a median progression-free survival of 4.8 months (95% confidence interval [CI], 3.3–7.0) and 2.3 months (95% CI, 1.5–3.5), median overall survival of 10.8 months (95% CI, 6.9–23.8) and 11.7 months (95% CI, 7.6–17.1), and grade 3 or greater adverse event rates of 50% and 2%, respectively. Overall, 64% received subsequent treatment. Among 23 patients who received both regimens, the T-DXd–nivolumab and nivolumab–T-DXd groups had a median overall survival of 14.0 months (95% CI, 5.0–not reached) and 19.3 months (95% CI, 9.5–25.1), respectively. Conclusions: T-DXd and nivolumab had distinctive efficacy and toxicity profiles as third- or later-line treatment for HER2-positive AGC. Considering the distinct features of each regimen might help clinicians personalize the optimal treatment approaches for patients with HER2-positive AGC.
A scoring system for selecting nivolumab or irinotecan in the later-line chemotherapy for advanced gastric cancer: A Japanese multicenter retrospective study.
Authors: Amanuma Yusuke , Suzuki Takeshi , Kawakami Takeshi , Aoki Masahiko , Yamamoto Yoshiyuki , Shimozaki Keitaro , Satake Hironaga , Nojima Masanori , Boku Narikazu , Takahari Daisuke
Published: January 2024

266

Background: Although Nivolumab (NIVO) or Irinotecan (IRI) monotherapy is one of the later-line chemotherapies for the advanced gastric cancer (AGC) patients, there are no prospective data of their comparison, and no indicators for selection of them. Methods: Clinical data of AGC patients treated with NIVO or IRI as later-line were collected from 7 institutions between September 2015 and September 2018. Efficacy of the two treatment groups was compared in the entire cohort and in the propensity score matching cohort. Factors which affect the prognosis were explored by multivariate analyses and the scoring system was developed using Cox regression. Results: In the analysis of entire cohort (317 patients), the median OS was 4.8 months (95% CI: 3.6–5.8) in the NIVO group and 5.9 months (95% CI: 4.9–7.2) in the IRI group, and those were 4.8 months (95% CI: 3.6–5.7) and 6.0 months (95% CI: 4.5–7.2) in the analysis of the propensity score matching cohort (248 patients), respectively. There were no differences in OS. We developed a risk score involving 1-Neutrophil to Lymphocyte Ratio (NLR), 2-age, 3-ECOG performance status, 4-peritoneal metastasis, 5-gastrectomy, and 6-liver metastasis to assess potential effect modification. Based on the result, IRI was favored in the higher-risk group (≥4 points, with double weight to 2, 3, and 4) for both OS/PFS. In contrast, NIVO was better OS/PFS in the lower-risk group (<1 point). Conclusions: According to the real-world data from multicenter in Japan, NIVO and IRI generally showed equivalent outcomes. The scoring system we explored may be useful for selecting appropriate later-line chemotherapy, either NIVO or IRI.
Comprehensive molecular characteristics of clinical responses to PD-1 inhibitors plus anti-angiogenic agents (PA) in metastatic HER2-negative gastric adenocarcinoma.
Authors: Wang Jingyuan , Liu Yutong , Liu Tianshu
Published: January 2024

279

Background: Anti-angiogensis agents were reported to enhance the efficacy of PD-1 inhibitor by inhibiting the infiltration of suppressive immune cell populations. Clinical studies indicated the synergistic anti-tumor effect of the combination of PD-1 inhibitors and anti-angiogenesis agents (PA). We aim to assess the efficacy of PA versus chemo-PA regiment in mGC, as well as the potential predictive biomarkers. Methods: A total of 55 GC tumors were analyzed using the next-generation sequencing (NGS), immunohistochemistry (IHC), and the tumor immune microenvironment (TIME) by multiplex immunofluorescence (mIHC). Clinical outcomes [Disease Control Rate (DCR), Progression-free survival (PFS) and overall survival (OS)] were compared between patients receiving PA treatment (n=32) and chemo-PA (n=23) treatment. Exploratory biomarker analyses were conducted for the prediction for the efficacy of PA/chemo-PA treatment. Results: Patients receiving PA regiment had comparable DCR (69% vs 50%, P =0.25) and PFS (median PFS: 6.53 vs 4.73 months, HR=0.70, 95%CI: 0.27-1.78, P =0.52), compared with those treated with combination of chemo-PA regiment as second or later-line treatment in mGC. Patients with HMCN1 wild-type showed significant improvements in DCR (77% vs 0%, P =0.023) and PFS (median PFS: 6.53 vs 1.17 months, P =0.0017), versus those with HMCN1 mutations in PA treatment cohort. HMCN1 mutations are associated with lower infiltration of endothelial cells and lower score of VEGF ligand-receptor interaction, according to the EPIC and pathway enrichment analysis ( P < 0.05). In addition, analysis of TIME by mIHC revealed that the fraction of CD68+ tumor-associated macrophages in the tumor center was higher in responders than non-responders before treatment (median: 17.59% vs 2.45%, P=0.016). Conclusions: PA regiment and chemo-PA regiment had similar efficacy in second or later line treatment of mGC. HMCN1 mutations maybe a predictive marker for PA regiment in HER2-negative mGC, which should be further validated in a large cohort.
Clinical outcomes of conversion surgery following immune checkpoint inhibitors and chemotherapy in stage IV gastric cancer with peritoneal metastasis.
Authors: Liang Huayuan , Li Fengping , Zhang Huimin , Xie Qing , Zhong Rou , Huang Kaihua , Yan Xiao , Li Zhiwei , Huang Zhicheng , Hu Yanfeng , Yu Jiang , Liu Hao , Li Guoxin , Zhao Liying
Published: January 2024

281

Background: Although anti-PD-1 antibody in combination with chemotherapy and/or targeted therapy has shown promising antitumor activity in advanced gastric adenocarcinoma (GC), the evidence of conversion therapy for initially GC with peritoneal metastasis is limited. This study aimed to clarify the clinical outcomes of conversion therapy for such patients. Methods: In this retrospective single institution cohort study, we analyzed 83 GC patients with peritoneal metastasis who received first-line anti-PD-1 antibody and chemotherapy and/or target therapy (trastuzumab) between November 2019 and June 2023. In patients who respond well to treatment, when preoperative imaging studies, multidisciplinary team discussions, and staged laparoscopy indicated the absence of peritoneal metastasis and the possibility of R0 resection, patients were offered conversion surgery. In this study, palliative surgery was not included. Patients were divided into two groups: conversion therapy group and palliative therapy group. Results: All patients underwent staging laparoscopy at their initial visit and underwent at least 2 treatment cycle, with a median follow-up time of 20.3 (16-24.6) months. Of the 83 patients, 32 patients presented a clinical response and underwent re-laparoscopy. Negative peritoneal metastasis and peritoneal cytology were confirmed in 25 patients who proceeded to undergo the conversion surgery. Compared with palliative therapy group, surgery group had a significantly better median progression-free survival (PFS) (20.3 vs 5.1 months; p < 0.001) and a prolonged median overall survival (OS) (33.4 vs 11.7 months; p < 0.001). In the surgery group, 24 (96%) of 25 patients were performed laparoscopic gastrectomy radical laparoscopic gastrectomy with more than D2 lymph node dissection (only one patient underwent open gastrectomy), 19 (76%) patients achieved R0 resection, 2 (8%) patients achieved pathologic complete response (pCR) and 4 (16%) patients reached tumor regression grade (TRG) 0-1. It was observed that patients with PCI score ≤ 2 experienced a longer median OS in comparison to those with PCI scores > 2 ( unreached vs 28.5 months, P < 0.031). And multivariate analysis associated with PFS among surgery cases identified signet ring cell carcinoma as an independent adverse prognostic factor (HR 4.66; 95% CI 1.19–18.22; p = 0.027). No serious treatment-related adverse events resulted in termination of treatment or death. Conclusions: Conversion surgery following first-line anti-PD-1 antibody in combination with chemotherapy and/or targeted therapy represented a promising treatment strategy for GC patients with peritoneal metastasis. When immunochemotherapy is effective, active second-look staging laparoscopy should be performed to clarify the possibility of conversion surgery.
Health-related quality of life (HRQOL) with pembrolizumab (pembro) plus trastuzumab (tras) and chemotherapy (chemo) in first-line HER2-positive (HER2+) advanced gastric cancer: KEYNOTE-811 trial results.
Authors: Janjigian Yelena Y. , Kawazoe Akihito , Xu Jianming , Lonardi Sara , Metges Jean-Philippe , Wyrwicz Lucjan S. , Shen Lin , Ostapenko Yuriy , Bilici Mehmet , Lowery Maeve Aine , Valderrama Adriana , Guan Yanfen , Li Kan , Shih Chie-Schin , Rha Sun Young
Published: January 2024

286

Background: In the phase 3 KEYNOTE-811 study (NCT03615326), first-line (1L) pembro with tras + chemo (pembro arm) yielded superior PFS and improved ORR with durable responses versus placebo (pbo) with tras + chemo (pbo arm) in pts with HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, notably in pts with PD-L1 combined positive score (CPS) ≥1. Key prespecified exploratory HRQOL outcomes supporting these data are presented. Methods: Pts with untreated histologically or cytologically confirmed advanced HER2+ G/GEJ adenocarcinoma, measurable disease per RECIST v1.1 by investigator, and ECOG PS of 0 or 1 were randomly assigned 1:1 to receive pembro 200 mg or pbo IV every 3 weeks (Q3W) with tras + chemo (cisplatin + 5-fluorouracil or capecitabine + oxaliplatin). HRQOL was evaluated in pts who received ≥1 dose of study treatment and completed ≥1 pt-reported outcome (PRO) assessment. End points were least squares mean (LSM) change from baseline, time to deterioration (TTD), and overall improvement/stability rate in prespecified subscales of EORTC QLQ-C30, QLQ-STO22, EuroQol EQ-5D-5L. LSM changes from baseline were analyzed at wk 24 when prespecified completion and compliance rates of ~60% and 80%, respectively, were met, based on review of blinded data. Results: In the PRO analyses, 685 pts were evaluable (345 pembro with tras + chemo; 340 pbo with tras + chemo). Median time from randomization to data cutoff (May 25, 2022) was 28.4 mo (range, 9.3-42.6). Completion rates were >92% at baseline and >55% at wk 24 for all assessments in both arms. Similar changes in PRO scores from baseline to wk 24 were observed for the pembro versus pbo arms (Table). Similar percentages of pts in each arm had improved or stable scores for the EORTC QLQ-C30 GHS/QOL and physical functioning scales and EORTC QLQ-STO22 subscales. TTD was similar between arms for all prespecified subscales. Conclusions: The addition of pembro to tras + chemo did not negatively affect HRQOL during treatment. Combined with safety and efficacy data, these results support the use of pembro with tras + chemo for first-line treatment of pts with HER2+ advanced gastric cancer. Clinical trial information: NCT03615326 . [Table: see text]
Design, synthesis, and evaluation of (1E,4E,6E)-1,7-diphenyl hepta-1,4,6-trien-3-one analogues-inspired o-methoxy phenyl group as potential anti–gastric cancer agents.
Authors: Khushafah Fatehi Rashad Abdulwahab
Published: January 2024

292

Background: Gastric cancer (GC) is a major global malignancy causing significant mortality. Most diagnoses occur at advanced stages. Current treatments involve surgery, chemotherapy, and targeted therapies. Targeted drugs face resistance and side effects. Curcumin, derived from Curcuma longa, shows promise against GC. Improved analogs addressing bioavailability have been developed. Some curcumin-based compounds with o-methoxy phenyl groups exhibit enhanced anticancer activity. We designed and synthesized (1E,4E,6E)-1,7-diphenyl hepta-1,4,6-trien-3-one analogs inspired by o-methoxy phenyl for anti-gastric cancer evaluation in vitro and in vivo. Methods: We designed and synthesized a series of analogs named (1E,4E,6E)-1,7-diphenyl hepta-1,4,6-trien-3-one analogues inspired by the o-methoxy phenyl group based on association theory. Anti-tumor activity was evaluated in vitro using gastric cancer cell lines BGC-823 and SGC-7901. Compound 2 was selected as a prime candidate based on its potency. Results: Compound 2 demonstrated potent anti-tumor effects in vitro by suppressing growth, migration, and invasion of SGC-7901 and BGC-823 cells. Impressively, it prompted cell cycle arrest at the G2/M phase and initiated apoptosis through Bax activation and caspase 3 inhibition. Moreover, in vivo trials on xenograft model nude mice validated the compound's substantial anti-gastric cancer potential while maintaining a favorable safety profile. Conclusions: A group of curcumin analogs exhibiting strong anti-gastric cancer activity was developed. The active compound 2 is capable of inhibiting the growth, colony formation, migration, and invasion of gastric cancer cells. It also arrests the cell cycle at the G2/M phase and stimulates the expression of apoptosis-related proteins, showcasing a powerful anti-gastric cancer effect in vitro. Furthermore, it demonstrates significant anti-gastric cancer activity in vivo while maintaining a favorable safety profile. Our research underscores the potential of (1E, 4E, 6E)-1,7-diphenylheptyl-1,4,6-trien-3-one analogs with o-methoxyphenyl in combatting tumors and highlights their promise as a secure anti-tumor candidate drug.
Surgical decision making in locally advanced esophageal adenocarcinoma.
Authors: Sanderfer Van Christian , Holland Alexis , Donahue Erin E. , Shea Reilly , Schwarzen Ella , Mullis Nicholas , Bellavia Sophia , Kadakia Kunal C. , Salo Jonathan C.
Published: January 2024

299

Background: Trimodality therapy consisting of chemoradiation followed by surgery (CRT+S) is considered optimal therapy for locally advanced adenocarcinoma (ACA) of the esophagus, yet the morbidity of surgery is substantial. We used CT-derived body composition and age to categorize patients into perioperative surgical mortality risk groups. Among patients with locally advanced esophageal ACA who were treated with CRT, the benefit of surgery (CRT+S) was examined in low-risk and high-risk patients. Methods: The association of perioperative mortality with age and skeletal muscle gauge (SMG) was estimated using a group of 290 patients undergoing esophagectomy of various histologies between 2010 and 2022. CT scans were analyzed to calculate SMG as the product of skeletal muscle area and skeletal muscle density. Logistic regression models were used to evaluate the association of age and SMG with 90-day surgical mortality. Patients were classified based on their predicted probability of 90 day mortality into low and high risk groups, where high risk was defined as the highest-risk 25% of patients. This model was then applied to the study cohort of patients with ACA. Log-rank tests were used to compare overall survival by treatment (CRT vs CRT+S) in the high risk and low risk groups. Results: Of 316 patients with locally advanced ACA treated with CRT, 254 underwent surgery (CRT+S). 90-day post operative mortality in the CRT+S group was 5.1%. 74 patients were categorized as high-risk and 242 as low-risk. Among low-risk patients, 213 (88.0%) were treated with surgery (CRT+S) and had a significantly longer overall survival compared to CRT (p<0.0001), with median survival of 40.6mo (95% CI 32.3, 55.5) in the CRT+S group and 17.3mo (95% CI 13.3, 36.4) in the CRT group. Among 74 high risk patients, 41 (55.4%) were treated with surgery. We did not find a difference in overall survival between the surgical group (CRT+S) and the group treated with CRT alone (p=0.34). The median survival was 27.4mo (95% CI 15.8, 32.9) in the CRT group compared to 23.0mo (95% CI 14.7, 54.4) in the CRT+S group. Conclusions: Our retrospective study demonstrated that for low-risk patients with adenocarcinoma of the esophagus, there is a survival benefit to the addition of surgery. Conversely, we failed to detect a survival benefit to the addition of surgery in the highest-risk quartile of patients. Measurement of body composition may help identify a high-risk subset of patients with locally advanced adenocarcinoma of the esophagus who may benefit from forgoing surgery after chemoradiation.
Body composition and postoperative outcomes after minimally invasive esophagectomy.
Authors: Sanderfer Van Christian , Holland Alexis , Donahue Erin E. , Shea Reilly , Schwarzen Ella , Kadakia Kunal C. , Salo Jonathan C.
Published: January 2024

300

Background: Esophagectomy is a complex operation associated with significant morbidity for even fit, healthy patients. Prior studies have utilized hand grip strength or muscle mass to predict postoperative esophagectomy outcomes. This study however, used skeletal muscle gauge (SMG), a CT-derived body composition measure, along with age, to classify patients into groups to summarize perioperative surgical mortality after minimally invasive esophagectomy. Methods: A total of 396 patients undergoing minimally invasive esophagectomy between 2010 and 2022 were identified. Preoperative CT scans at the L3 vertebral level were analyzed to calculate skeletal muscle gauge (SMG) as the product of skeletal muscle area and skeletal muscle density. Patient demographics, histology, treatment, and outcomes including anastomotic leak, pneumonia, prolonged ventilation, discharge destination, 30-day readmission, and 90-day mortality were collected. Patients were grouped into quartiles of SMG and by age (≥75 and <75 years). 90-day postoperative mortality for the high risk group in the bottom SMG quartile (Q1) was compared to the low-risk group in the top 3 quartiles (Q234). Results: Mean age was 62.8 years (SD 10.4). Patients were 84.4% male with 87.4% White, 10.6% Black, 1.8% Hispanic, and 0.3% Asian. Histologically, 86.4% of patients had adenocarcinoma while 11.4% had squamous cell carcinoma. Anastomotic leak occurred in 8.1%, pneumonia in 16.7%, ventilation greater than 48 hours in 20.7%, and discharge to home in 82.1% of patients. 30-day readmission occurred in 16.4% and 90-day mortality in 6.1% of patients. 8 patients did not have CT scans available. Analysis of 90-day mortality as a function of age >75 and SMG risk group showed 33.3% mortality among patients >75 in Q1 for SMG, 9.6% for patients <75 in Q1 for SMG, 5.6% for patients >75 in Q234 for SMG, and 2.2% in 264 patients <75 in Q234 for SMG for subjects who had available scan data (n = 388). Conclusions: As expected, patients with older age and lower SMG have higher mortality after esophagectomy compared to younger patients with higher SMG. Patients who are >75 years old and in the bottom SMG quartile represent a small group (27/388 = 7% of the total) which are identified as a high-risk group with a mortality of 33.3%. This study identifies a small subset of patients whose risk of surgery may outweigh the benefit, particularly in patients already treated with chemoradiation. Preoperative body composition, as measured by SMG, in combination with age can be used to predict postoperative mortality after minimally invasive esophagectomy and guide treatment decisions. [Table: see text]
Clinical outcomes of primary esophagectomy and secondary esophagectomy after endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma: A propensity-score matched analysis.
Authors: Kim Minjee , Kim Tae Jun , Lee Hyuk , Min Byung-Hoon , Lee Jun Haeng , Rhee Poong-Lyul , Kim Jae J. , Min Yang Won
Published: January 2024

307

Background: Currently it is unknown whether secondary esophagectomy after endoscopic submucosal dissection (ESD) is comparable to primary esophagectomy considering outcomes in patients with T1 esophageal cancer. We compared short- and long- term clinical outcomes between the two groups. Methods: Primary surgery (esophagectomy) was performed in 191 patients between 2003 and 2014, and 62 patients underwent secondary surgery (esophagectomy) after ESD for T1 esophageal cancer between 2007 and 2019. Propensity matching was performed for age, sex, Charlson Comorbidity Index (CCI), location, pathology, degree of differentiation, tumor size, and invasion depth. Lymph node metastasis (LNM), overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS) and postoperative complications were compared between groups. Results: Sixty-eight patients were included after propensity score matching, LNM, OS, DSS, and RFS were comparable between the two groups. Comparing primary and secondary surgery, the respective LNM rates were 23.5% and 26.5%, 6-year OS 78.0% and 89.7%, P= 0.15; DSS were 80.4% and 96.8%, P= .057; and RFS 80.8% and 89.7%, P= .069. Multivariate analyses revealed no statistically significant differences between among LNM, OS, and RFS rates. Comparing the adverse events between the two groups, more early complications were observed in the primary surgery group than in secondary surgery group (50% vs. 20.6%, P = .021). Conclusions: Secondary surgery did not increase the risk of LNM. The long-term outcomes were comparable. Therefore, attempts to perform upfront ESD for superficial esophageal squamous cell cancers are justified.
The efficacy and safety of conversion therapy after initial systemic chemotherapy in advanced esophageal cancer with distant metastases: A multicenter retrospective observational study.
Authors: Tsuji Takayuki , Matsuda Satoru , Sato Yuta , Tanaka Koji , Tsuruta Yusuke , Watanabe Masaya , Hamai Yoichi , Nasu Motomi , Saze Zenichiro , Nakashima Yuichiro , Nomura Motoo , Yamamoto Shun , Booka Eisuke , Ishiyama Koshiro , Bamba Takeo , Sakanaka Katsuyuki , Tsushima Takahiro , TAKEUCHI HIROYA , Kato Ken , Kawakubo Hirofumi
Published: January 2024

310

Background: Systemic chemotherapy, with or without radiation, has been the standard treatment for esophageal squamous cell carcinoma (ESCC) with distant metastasis. The increased efficacy of multimodality treatment allows for the consideration of conversion therapy with curative intent for initially unresectable ESCC after initial treatment. In the present study, we examined the safety and effectiveness of conversion therapy for ESCC. Methods: Conversion therapy was defined as surgery or chemoradiation therapy (CRT) aiming at cure after initial treatment for tumors that were initially unresectable due to distant metastasis. The patients who underwent conversion therapy for ESCC between 2011 and 2021 at participating institutions were retrospectively reviewed. Patient backgrounds, treatment outcomes, and overall survival (OS) were evaluated. Results: From 22 institutions, 149 patients were enrolled. As defined, all patients received systemic chemotherapy as an initial treatment. The distant metastatic sites in para-aortic lymph nodes/extra regional mediastinal lymph nodes/lung/liver/bone/others were 81(54%)/19 (13%)/14 (9%)/11 (7%)/4 (3%)/20 (14%), respectively. After the initial treatment, 116 patients underwent surgery and 33 patients received CRT as conversion therapy. Of 116 patients who underwent conversion surgery, the incidence rate of postoperative pneumonia/leakage/recurrent laryngeal nerve palsy was 16%/7%/6%, respectively. R0 resection was obtained in 87%. Regarding the non-hematological toxicities during conversion CRT (CTCAE grade 3 or higher), decreased appetite/dysphagia/esophagitis was 21%/15%/9%, respectively. No grade 4 or higher hematologic toxicities were observed. The 3-year OS (3y-OS) rate for all patients was 41.9%; no significant differences were found between surgery and CRT groups (43.3% vs 37.0%, p = 0.112). Pathological responders showed a significantly longer OS than non-responders (3y-OS, 56.4% vs 36.1%, p = 0.010). The distribution or number of distant metastases were not identified as prognostic factors. Conclusions: This study showed that conversion therapy for ESCC patients with distant metastasis could be conducted safely and have a favorable prognosis. Since its survival benefit would depend on the pathological response, it is important to develop an indicator to predict pathological response before surgery and carefully select appropriate candidates of conversion therapy in ESCC.
Neutrophil-to-lymphocyte ratio to predict metachronous cancer after curative resection of early gastric cancer.
Authors: Kim Sunsuk , Joo Moon Kyung , Park Jong-Jae , Kwon Chan Mi , Kim Jun Hee , Kang Ji Min , Kang Min Hyung , Lee Si Eun , Kim Won Shik , Kim Seung Han , Lee Beom Jae , Chun Hoon Jai
Published: January 2024

313

Background: We investigate the predictive value of inflammatory markers for occurrence of metachronous cancers among patients who underwent endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) and are judged as curative resection (CR). Methods: We enrolled patients who were diagnosed as EGC and underwent ESD during 2006 and 2020. We retrospective collected data of inflammatory indexes such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and erythrocyte sediment ratio (ESR). Results: A total of 1,011 patients underwent ESD for EGC, achieved CR and were followed up more than 12 months. Among them, 86 patients had metachronous cancers (85/1011, 8.4%) during 53.4 months of follow-up. Compared with patients without metachronous cancers, those with metachronous cancers were significantly older (66.9 vs. 63.8 years, P=0.004) and had higher NLR (2.1 vs. 1.8, P=0.002), however, other inflammatory indexes such as PLR and ESR were not significantly different between two groups. Kaplan-Meier analysis showed that patients with NLR ≥ 2.0 had significantly higher possibility of metachronous cancer compared with patients with NLR < 2.0 ( P=0.049 by log rank test). After adjusting age, atrophy and Helicobacter pylori status, NLR was the only significant risk factor for metachronous cancer (odds ratio: 1.33, 95% confidence interval: 1.007-1.665, P=0.011). Conclusions: NLR may have a predictive value for occurrence of metachronous cancer after CR of EGC by ESD. Further thorough investigation is necessary to validate this outcome.
Adjuvant chemoradiotherapy (CRT) plus pembrolizumab for locally advanced esophageal squamous cell carcinoma (ESCC) with high risk of recurrence after neoadjuvant CRT plus surgery: A single-arm phase II study.
Authors: Guo Jhe-Cyuan , Huang Ta-Chen , Kuo Hung-Yang , Lin Chia-Chi , Hsu Feng-Ming , Cheng Jason C. , Huang Yen-Lin , Hsieh Min-Shu , Huang Pei-Ming , Lee Jang-Ming , Wu Shu-Ling , Hsu Chih-Hung
Published: January 2024

320

Background: Adjuvant anti-PD-1 therapy with nivolumab has shown efficacy in reducing recurrence rates in patients with locoregional esophageal cancer including squamous cell carcinoma who achieved R0 resection but harboring pathologic residual disease following neoadjuvant CRT. However, the efficacy of adjuvant anti-PD-1 therapy in improving outcomes for patients at higher risk of recurrence, especially those with involved or close resection margin (≤1 mm), remains unclear. Methods: We conducted a phase II trial of adjuvant cisplatin (30mg/m2 IV every week for 2 cycles)-based CRT (180-200cGy per fraction for 10-13 fractions) followed by pembrolizumab (200mg IV every 3 weeks for 18 cycles) in patients with locally advanced ESCC who had high-risk recurrence features in esophagectomy tumor tissues, including involved or close margin (≤1 mm), extranodal extension (ENE) of involved lymph node, and ypN2-3, following neoadjuvant CRT (ClinicalTrials.gov Identiﬁer: NCT03322267). Primary endpoint was 1-year relapse-free survival (RFS) rate in comparison with a historical control of 32%.1 Secondary endpoints included RFS, overall survival (OS), and toxicity. Results: Between Nov 2018 and Dec 2022, we enrolled a total of 25 patients with high risk recurrence features, including margin ≤1 mm (18 patients), ENE of involved lymph node (9), and ypN2-3 (9). Majority of patients were male (88%) and current smokers (84%). The median follow-up duration was 16.5 months (95% CI 10.6-27.1). One-year RFS rate was 63.3% (95% CI 44.5-79.8). Median RFS and OS were 15.3 months (95% CI 10.2-20.4) and 38.3 months (95% CI 10.2-66.3), respectively. Any grade treatment emergent adverse events (TEAEs) occurred in 56% and 75% of patients during cisplatin-based CRT and pembrolizumab treatment, respectively. Grade 3 TEAEs were infrequent, including leukopenia (4%), pancreatitis (4%), infection (8%), and colitis (4%). There was no grade 4 TRAE. Conclusions: Adjuvant cisplatin-based CRT followed by 1-year treatment of pembrolizumab was well-tolerated, and was associated with an improved 1-year RFS rate in patients with pathologic residual disease and high risk for recurrence following trimodality therapy for locally advanced ESCC. 1. Guo JC et al: J Thorac Oncol 2015;10:1481-9. Clinical trial information: NCT03322267 .
Tislelizumab combined with POFI (irinotecan, paclitaxel, oxaliplatin and 5-FU/levoleucovorin) as first-line treatment of advanced gastric/gastroesophageal junction adenocarcinoma (AGC): Preliminary results of a single-arm, open-label phase I/II trial (SYLT-023).
Authors: Lin Rongbo , Zaisheng Ye , Changhua Zhuo , Wei Shenghong - , Li Zhixiong , Zhao Shen , Su Liyu
Published: January 2024

331

Background: Tislelizumab is a humanised IgG4 monoclonal antibody with high affinity and binding specificity for PD-1. Combined with fluoropyrimidine + platinum (XELOX or FP), it is approved in China as first-line treatment of advanced gastric cancer (AGC). Both irinotecan and paclitaxel have also shown antitumor activity in advanced gastric/gastroesophageal junction adenocarcinoma. In this phase I/II study, we explore the safety, tolerability, and efficacy of tislelizumab + irinotecan, paclitaxel, oxaliplatin and 5-FU (POFI) as first-line treatment of HER-2 negative, pMMR AGC. Methods: In a phase I dose finding study using a standard 3+3 design, subjects received four escalating dose levels (dl) of irinotecan/paclitaxel (mg/m2): 135/45 (dl #1), 150/45 (dl #2), 135/67.5 (dl #3), and 135/90 (dl #4) in combination with tislelizumab 200 mg plus oxaliplatin 85 mg/m2, levoleucovorin 200 mg/m2, and 5-FU 2400 mg/m2 for 46 hours every 2 weeks. Primary endpoints were safety, tolerability, and recommended phase 2 dose (RP2D). Results: Fifteen subjects with treatment naïve AGC were enrolled (3 each in dl #1, dl #2, and dl #3 and 6 in dl #4). The median age was 65 years (range 36-72); 80% were male. Two subjects (13.3%) were diagnosed with gastroesophageal junction cancer, 9 (60%) had poorly differentiated disease, and 5 (33.3%) had liver metastasis. PD-L1 CPS scores were: 5 (n=5); 1 (n=1); and 0 (n=9). All subjects were evaluated for dose-limiting toxicity (DLT). One DLT (grade 4 neutropenia) occurred within 28 days in dl #4. No maximum tolerated dose was reached; the RP2D was dl #4. All subjects had ≥1 treatment-related adverse event (TRAE) and 10 (66.7%) had ≥1 grade 3-4 TRAE per NCI CTC-AE 5.0. The most frequent grade 3-4 TRAEs were neutropenia (n=8; 53.3%), anemia (n=2; 13.3%), and increased glutamyl transpeptidase (n=2 pts; 13.3%). Confirmed objective response rate in 13 subjects with measurable disease was 100% (1 complete response [CR], 12 partial responses [PR]) per RECIST 1.1. Of the 2 subjects with non-measurable disease, one was a CR and the other was non-CR/non-PD. Survival data are immature. Conclusions: Tislelizumab+POFI was well tolerated and showed preliminary antitumor activity. A phase II study at the RP2D is ongoing. Clinical trial information: NCT05319639 .
Impact of adding nivolumab to first-line chemotherapy in patients with advanced gastric cancer.
Authors: Utsumi Mai , Yukami Hiroki , Okemoto Dai , Kadono Toru , Yamaguchi Toshifumi , Goto Masahiro , Nishikawa Hiroki
Published: January 2024

334

Background: Nivolumab plus chemotherapy (Nivo-Chemo) is the standard treatment for advanced gastric cancer based on the results of CheckMate 649 trial and ATTRACTION-4 trial. However, real-world data on the efficacy of Nivo-Chemo are limited. This study aimed to assess the efficacy of Nivo-Chemo in the clinical practice setting by comparing it to chemotherapy alone. Methods: We retrospectively reviewed the medical records of patients with advanced gastric cancer who received palliative chemotherapy in our hospital between 2017 and 2023. The inclusion criteria were as follows: age ≥ 20 years; histologically confirmed advanced unresectable or recurrent gastric/gastro-esophageal junction adenocarcinoma; HER2 negative or unknown; and no prior treatment. Patients were divided into two groups based on their first-line treatment: the Nivo-Chemo group and chemotherapy alone (Chemo) group. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) were assessed. Results: Of 78 patients, 52 patients were in the Chemo group and 26 patients were in the Nivo-Chemo group. Median age were 69 years (range 30–83) and 67 years (range 39–76) in the Chemo group and Nivo-Chemo group. Eastern Cooperative Oncology Group performance status (ECOG PS) was 0/1/2 in 18/27/7 patients (35%/52%/13%) in the Chemo group and in 17/8/1 patients (65%/31%/4%) in the Nivo-Chemo group. Histological type (Intestinal type/diffuse type) was 19/33 (37%/63%) in the Chemo group and 8/18 (31%/69%) in the Nivo-Chemo group. Combined positive score (CPS) was assessed in 21 patients in the Nivo-Chemo group. The CPS <1/1-5/>5 was in 3/10/8 (12%/38%/31%). In the Chemo group, 28 patients (54%) received anti-PD-1 monotherapy after progression of first-line chemotherapy. The median PFS was 5.7 months in the Chemo group and 6.0 months in the Nivo-Chemo group (HR 0.88, 95% CI 0.50-1.55, p = 0.66). The median OS was 15.0 months in the Chemo group and 18.6 months in the Nivo-Chemo group (HR 0.76, 95% CI 0.37-1.53, p = 0.44). The ORR was 50% in the Chemo group and 54% in the Nivo-Chemo group, while the DCR was 63% and 69%, respectively. Conclusions: In clinical practice, the addition of nivolumab to chemotherapy tended to provide a survival benefit compared to chemotherapy alone.
Anlotinib combined with penpulimab and nab-paclitaxel as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, open-label phase II clinical trial.
Authors: Chang Zhiwei , Liu Xiao-Lei , Yu Dan-Dan , Han Hui-Qiong , He Jian , Wang Rui-Rui , Qin Yan-ru
Published: January 2024

340

Background: Recently, PD-1 blockades combined with dual chemotherapy in first-line setting exhibited encouraging efficacy for patients with ESCC. However, the safety profile of conventional dual chemotherapy remained unsatisfactory. Therefore, PD-1 blockades combined with anti-angiogenic tyrosine kinase inhibitors (TKIs) and single chemotherapy regimen might be a promising strategy. Anlotinib, a novel multitarget TKI primarily targeting VEGFR1-3, demonstrated promising therapeutic activity as first-line combination therapy or second-line monotherapy for patients with ESCC in China clinically. Therefore, this study was designed to explore the efficacy and safety of anlotinib combined with penpulimab (PD-1 blockade) and nab-paclitaxel as first-line therapy in advanced ESCC. Methods: Patients with previously untreated metastatic or locally advanced ESCC were recruited and treated with anlotinib (12mg, po, d1~14, q3w) and penpulimab (200mg, iv, d1, q3w) plus nab-paclitaxel (220mg/m2, iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 using CT scans every two cycles. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 30. Primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and OS. Results: From Jul 2022 to Aug 2023, a total of 23 patients were enrolled, 19 patients who had received first tumor response were included in this analysis. The best overall response indicated that there were 14 PR (73.7%), 2 SD (10.5%) and 3 NE (15.8%). Therefore, the preliminary ORR was 73.7% (95%CI: 48.8%-90.9%), DCR was 84.2% (95%CI: 60.4%-96.6%). Median PFS of the 19 patients was not yet reached. Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-emergent adverse events among the 23 patients with the incidence >20% were leukopenia (30%) and anemia (30%). Common grade ≥3 treatment-emergent adverse events were leukopenia (9%), glutamic-pyruvic transaminase was elevated (4%), glutamic oxaloacetic transaminase increased (4%), hypertension (4%) and diarrhea (4%). Conclusions: The combination of anlotinib plus penpulimab and nab-paclitaxel as first-line therapy for advanced ESCC demonstrated promising efficacy and manageable safety profile. The conclusions needed to be confirmed in subsequent trials.
Advantages of robotic surgery for advanced gastric cancer in short-term outcomes: A single-center retrospective study using propensity score matching.
Authors: Komatsu Masaru , Yura Masahiro , Yoshida Mitsumasa , Habu Takumi , Nagata Hiromi , Kinoshita Takahiro
Published: January 2024

343

Background: The advantages of robotic gastrectomy (RG) for gastric cancer are being demonstrated. However, there are few reports that have focused on advanced gastric cancer and examined the advantages of RG for laparoscopic gastrectomy (LG). We conducted the following study to clarify the advantages of RG for advanced gastric cancer. Methods: This single-center retrospective study reviewed the clinical data of 1531 patients who underwent either RG or LG from 2014 to 2023. 473 patients were with clinically diagnoses as having advanced gastric cancer. They were divided into the RG group (n = 143) and the LG group (n = 330). Propensity score matching was employed to adjust the background of the two groups, as covariates of age, gender, BMI, surgical method (distal gastrectomy/total gastrectomy), stage (early cancer/advanced cancer), and presence or absence of preoperative chemotherapy. Then, the treatment results were compared and examined. Results: 130 patients in each group were extracted by propensity score matching. There were no significant differences in age, gender, and ECOG-PS between the two groups. Compared to the LG group, the RG group had more cases with deeper invasion depth ≥T3 (93.1 vs 84.6%, P = 0.04), more D2 dissection (96.9 vs 88.5%, P = 0.01), and longer operative time (339.5 vs 294.5min, P <0.01). The number of retrieved lymph nodes was larger (49.5 vs. 44, P <0.01) in the RG group. Importantly, in the RG group, there were fewer complications with Clavien-Dindo (CD) classification ≥Grade II (11.5 vs 21.5%, P = 0.04) and CD classification ≥Grade III (0.8% vs 6.9%, P = 0.01). Postoperative hospital stay was shorter (8 vs 9 days, P = 0.01) in the RG group. Conclusions: RG for advanced gastric cancer has the potential to reduce complications compared to LG. Long-term survival outcomes should be investigated.
Use of novel cancer staging model to analyze healthcare costs of commercially insured patients with colorectal cancer.
Authors: Smith Rebecca , Cao Xiting , Cuyun Carter Gebra , Pope Andreyah , Fayyaz Ifrah , Ellenberg Phil , Miller-Wilson Lesley-Ann , Limburg Paul J. , Pyenson Bruce
Published: January 2024

35

Background: Earlier colorectal cancer diagnosis can improve patient outcomes, but the payer cost impact of earlier stage at cancer diagnosis is not well understood because stage information is not directly available in administrative claims data. This data gap impairs researchers’ ability to fully evaluate the financial impact of earlier neoplasia detection resulting from colorectal cancer screening. In prior work, we used SEER-Medicare data to develop machine learning algorithms to assign AJCC stages to colon (CC) and rectal (RC) cancer patients using treatment flags derived from claims data. These algorithms were 83% (CC) and 69% (RC) accurate at assigning incident cancer patients to their SEER-recorded AJCC stage. This new work applied those validated algorithms to commercial claims data to study the healthcare costs by stage of patients identified with incident CC or RC. Methods: Newly diagnosed CC and RC patients were identified in Milliman’s 2019-2020 Consolidated Health Cost Guidelines Sources Data for commercially insured patients. Patients were assigned a cancer stage using a claims-based predictive multinomial logistic regression model (R Statistical Software - v4.1.2 R Core Team 2021; nnet package - Venables and Ripley 2002). Allowed medical and pharmacy costs were summarized by month, starting from each patient’s initial claim with a cancer diagnosis through the end of the patient’s enrollment or through September 2022. Patients with each cancer type were then grouped by stage, and mean cumulative costs at 12-, 24-, and 36-months were calculated. Results: CC patients with stage 4 disease incur costs over 4x greater than those with stages 2B or lower and 1.7x greater than patients with stages 2B/3 during the first year after diagnosis. Cost differentials by stage are smaller among patients with RC. RC patients with stage 4 disease incur costs 2.2x greater than those with stages 2B or lower and 1.3x greater than patients with stages 2B/3 over the first year after diagnosis. For both CC and RC, substantial differences in cost persist over a 3-year period post-diagnosis. Conclusions: We applied a novel cancer staging model to commercial claims to estimate patients’ healthcare costs by stage at diagnosis. CC and RC patients’ costs increase substantially as their stages at diagnosis increase. In addition to improving patient outcomes, diagnosis of CC and RC at earlier stages among commercial patients could reduce treatment costs. [Table: see text]
Updated pooled analyses of first-line anti-PD1/PD-L1 inhibitors plus chemotherapy in advanced esophageal squamous cell carcinoma.
Authors: Vilbert Maysa , Priantti Jonathan N , Madeira Thiago , Moraes Francisco Cezar A , Tojjari Alireza , Sahin Ibrahim Halil , Cavalcante Ludimila , Saeed Anwaar
Published: January 2024

366

Background: Advanced and metastatic esophageal squamous cell carcinoma (ESCC) patients have limited treatment options and poor prognosis. Recently, several studies demonstrated the clinical benefit of combining immune checkpoint inhibitors (ICI) and chemotherapy (CT), leading to its approval in the first-line setting. Since then, efforts have been made to identify the patients who may benefit the most or not from the combination of ICI plus CT. Methods: We searched PubMed, Scopus, and the Cochrane Library for randomized clinical trials investigating first-line ICI plus chemotherapy (CT) for advanced or metastatic ESCC patients. Outcomes of interest included: overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and OS according to gender, PD-L1 expression (<1% / ≥1%), and PD-L1 CPS (<10 / ≥10). We used I2 statistics to assess heterogeneity, and the fixed-effect model was used to pool studies. Results: Eight studies were included with 4,702 patients. Of them, most had an ECOG 0 or 1, and were younger than 65 years (62%), male (77%), and Asian (78%). Metastatic disease was diagnosed in 75% of patients. ICI plus CT was administered to 58%, and 43% received CT +/- placebo. Median follow-up ranged from 7.1 to 22.6 months. ICI plus CT significantly improved all efficacy outcomes compared to CT alone: decreasing the risk of death by 32% (HR for OS: 0.68; 95%CI 0.63-0.74; p<0.00001); reducing the risk of progression or death by 38% (HR for PFS: 0.62; 95%CI 0.58-0.67; p<0.00001); and increasing the objective response rate (risk difference: 0.17; 95%CI 0.14-0.20; p<0.00001). A survival benefit was seen across all subgroup analyses, but it was significantly higher in patients with PD-L1 ≥1% compared to those with PD-L1 <1% (reduction in the risk of death of 38% versus 23% respectively, p=0.03). OS was not significantly different between males versus females, or PD-L1 CPS≥10 versus CPS<10. Conclusions: Our large systematic review and meta-analysis support the efficacy and survival benefit of ICI plus CT as first-line therapy for all ESCC patients, regardless of gender or PD-L1 expression.
The implication of failure patterns after neoadjuvant chemoradiotherapy with small involved-field in esophageal squamous cell carcinoma.
Authors: Shin Hyunju , Oh Dongryul , Noh Jae Myoung , Yang Kyungmi
Published: January 2024

376

Background: In this study, we aimed to analyze failure patterns, the clinical and biological prognostic factors for treatment outcomes, and evaluate the feasibility of involved-field irradiation (IFI) in patients with esophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant chemoradiotherapy (CCRT). Methods: We retrospectively reviewed the medical records of 511 patients diagnosed with ESCC and underwent neoadjuvant CCRT and radical esophagectomy between January 2016 and February 2022 at Samsung Medical Center. For IFI, the clinical target volume (CTV) was defined as the primary gross tumor volume (GTV) plus a 2.0-3.0 cm longitudinal margin and a 0.5-1.0 cm circumferential margin, as well as the GTV of lymph nodes (LN) plus a 0.5-1.0 cm margin. For elective nodal irradiation (ENI), the CTV encompassed supraclavicular, mediastinal, or abdominal LN regions based on the primary tumor location. IFI was applied in most cases (98%). The failure patterns, loco-regional control (LRC), and survival outcome were analyzed. Regional lymph nodes (LNs) were defined and classified according to the AJCC 8th edition. Non-regional LNs were defined as metastatic LNs in neck, thorax, abdominal area except regional LNs. Results: With a median follow-up of 44.4 months, 213 (41.7%) patients experienced recurrence. The first recurrent sites were locoregional (LR) in 98 patients (19.2%), non-regional LN in 81 (15.9%), and distant organs in 152 (29.7%). Among the 98 patients with LR recurrence, RT in-field failure occurred in 53 (10.4%) patients, in & out-field failure in 18 (3.5%), and out-field failure in 27 (5.3%). In 27 cases of out-field failure only, LR recurrent lesion could be included in the target volume in 7 (1.4%) cases if ENIs were applied. Among the 27 patients, 10 received salvage treatment and 2 did not experience further recurrence. The analysis for the detailed LN recurrence showed that the upper mediastinal and supraclavicular LNs were the most frequent area, regardless of the primary tumor location and other clinical factors. Among 213 recurrent cases, 54 (10.5%) recurred in upper paratracheal LN and 40 (7.8%) in supraclavicular LN. The 5-year LRC rates, disease-control rates, and overall survival (OS) rates were 77.5%, 53%, and 54.3%, respectively. Multivariate analysis revealed that gender, age, cStage, ypStage, and resection margin status were independent prognostic factors for OS. Conclusions: Neoadjuvant CCRT using IFI with a small margin showed favorable treatment outcomes and out-field recurrence that the traditional ENI field could cover accounted for a small portion; thus, it might be feasible in the neoadjuvant setting. However, we need to consider that the upper mediastinal and supraclavicular areas were the most frequent recurrence sites.