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      A meta-analysis with systematic review: Efficacy and safety of immune checkpoint inhibitors in patients with advanced gastric cancer

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          Abstract

          Background

          While the efficacy of immune checkpoint inhibitors (ICIs) is increasingly recognized in advanced gastric cancer (aGC), overall survival (OS) has not been consistently improved across the different randomized controlled trials (RCTs). This meta-analysis aimed to quantify the efficacy and safety of ICI and explore potential predictive tumor tissue biomarkers in aGC.

          Methods

          A random-effect pairwise meta-analysis was used to evaluate the primary outcome of OS. Sensitivity analysis was performed to investigate the effects of ICIs on PD-L1 status, TMB, MSI-H, and the Asian patient population. We extracted the OS Kaplan–Meier curves from the included trials to compare the effect of PD-L1 status on response to ICIs using DigitizeIt 2.5 and Guyot’s algorithm.

          Results

          A pairwise meta-analysis of seven RCTs included in this study showed that ICIs were more effective than the comparator in improving OS (pooled HR: 0.84). We demonstrated that PD-1 ICIs were additive when combined with the comparator arm (pooled HR: 0.79). A sensitivity analysis showed that PD-1 ICIs were associated with better OS outcomes in the Asian patient population as monotherapy (pooled HR: 0.66) or in combination with chemotherapy (pooled HR: 0.83). We demonstrated that tumors with PD-L1 ≥1 ( P = 0.02) and PD-L1 ≥10 ( P = 0.006) derived OS benefit from ICI monotherapy. Equally, MSI-H ( P <0.00001) and TMB-high ( P <0.0001) tumors derived favorable survival benefits from ICIs.

          Conclusions and relevance

          The results of this meta-analysis suggest that ICIs result in improved OS outcomes in aGC. The benefits varied with different ethnicities, class of ICI, PD-L1 expression, MSI status, and TMB

          Systematic Review Registration

          https://www.crd.york.ac.uk/prospero, identifier (CRD42019137829).

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          Most cited references43

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          Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

          This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
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              Estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012 are now available in the GLOBOCAN series of the International Agency for Research on Cancer. We review the sources and methods used in compiling the national cancer incidence and mortality estimates, and briefly describe the key results by cancer site and in 20 large "areas" of the world. Overall, there were 14.1 million new cases and 8.2 million deaths in 2012. The most commonly diagnosed cancers were lung (1.82 million), breast (1.67 million), and colorectal (1.36 million); the most common causes of cancer death were lung cancer (1.6 million deaths), liver cancer (745,000 deaths), and stomach cancer (723,000 deaths). © 2014 UICC.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                31 October 2022
                2022
                : 12
                : 908026
                Affiliations
                [1] 1 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital , Hong Kong, Hong Kong SAR, China
                [2] 2 School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong, Hong Kong SAR, China
                [3] 3 Department of Gastrointestinal Oncology, National Cancer Center Hospital East , Kashiwa, Japan
                [4] 4 Department of Medicine, Johannes-Gutenberg University Clinic , Mainz, Germany
                [5] 5 Department of Oncology and General Medicine, IMSUT Hospital, Institute of Medical Science, The University of Tokyo , Tokyo, Japan
                [6] 6 Department of Biostatistics and Bioinformatics, Duke University of Medicine , Durham, NC, United States
                Author notes

                Edited by: Zhongwu Li, Peking University, China

                Reviewed by: Michio Nakamura, Sapporo City General Hospital, Japan; Saori Mishima, National Cancer Center Hospital East, Japan; Xi Zou, Jiangsu Provincial Hospital of Traditional Chinese Medicine, China

                *Correspondence: Ka On Lam, lamkaon@ 123456hku.hk

                This article was submitted to Gastrointestinal Cancers: Gastric and Esophageal Cancers, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2022.908026
                9660259
                36387109
                b486f499-ccdc-4896-ba64-d8009f129f42
                Copyright © 2022 El Helali, Tao, Wong, Chan, Mok, Wu, Shitara, Mohler, Boku, Pang and Lam

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 March 2022
                : 26 September 2022
                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 44, Pages: 12, Words: 5382
                Categories
                Oncology
                Systematic Review

                Oncology & Radiotherapy
                advanced gastric adenocarcinoma,immune checkpoint inhibition (ici),pd-l1,tumor mutational burden (tmb),microsatellite instability (msi)

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