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World J Gastroenterol. Dec 21, 2021; 27(47): 8123-8137
Published online Dec 21, 2021. doi: 10.3748/wjg.v27.i47.8123
Immunotherapies for well-differentiated grade 3 gastroenteropancreatic neuroendocrine tumors: A new category in the World Health Organization classification
Jun-Xi Xu, De-Hao Wu, Li-Wei Ying, Han-Guang Hu
Jun-Xi Xu, Han-Guang Hu, Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
De-Hao Wu, Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
Li-Wei Ying, Department of Orthopedic, Taizhou Hospital, Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
Author contributions: Xu JX designed the review, drafted the manuscript, sorted and analyzed the data, and prepared the table; Wu DH and Ying LW assisted in editing the table and contributed to clinical data collection; Hu HG coordinated the design of the outline and critically revised the paper; all authors have read and approved the final manuscript.
Conflict-of-interest statement: The authors have no conflict of interests to report.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Han-Guang Hu, PhD, Academic Fellow, Associate Chief Physician, Doctor, Professor, Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China. huhanguang@zju.edu.cn
Received: September 8, 2021
Peer-review started: September 8, 2021
First decision: October 16, 2021
Revised: October 28, 2021
Accepted: November 30, 2021
Article in press: November 30, 2021
Published online: December 21, 2021
Processing time: 99 Days and 21.4 Hours
Abstract

According to the 2019 World Health Organization (WHO) classification, well-differentiated grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are a new category of cancer of the digestive system. G3 GEP-NET research and treatment are not as robust as those of lower grade (G1/2) NETs and poorly differentiated neuroendocrine carcinomas (NECs). Previously, the management of high-grade NETs was mainly based on NEC therapies, as high-grade NETs were classified as NECs under the previous WHO classification. Despite this, G3 GEP-NETs are significantly less responsive to platinum-based chemotherapy regimens than NECs, due to their distinct molecular pathogenesis and course of pathological grade transition. Patients with advanced G3 GEP-NETs, who have progressed or are intolerant to chemotherapy regimens such as capecitabine plus temozolomide, have limited treatment choices. Immunotherapy has helped patients with a variety of cancers attain long-term survival through the use of immune checkpoint inhibitors. Immunotherapies, either alone or in combination with other therapies, do not have a clear function in the treatment of G3 GEP-NETs. Currently, the majority of immunotherapy studies, both prospective and retrospective, do not reliably differentiate G3 GEP-NETs from NECs. By contrast, a significant number of studies include non-GEP neuroendocrine neoplasms (NENs). Therefore, there is an urgent need to summarize and evaluate these data to provide more effective therapeutic approaches for patients with this rare tumor. The purpose of this mini-review was to screen and summarize information on G3 GEP-NETs from all studies on NENs immunotherapy.

Keywords: Gastrointestinal tract; Pancreas; Immune checkpoint inhibitors; Immunotherapy; Neuroendocrine tumors; Cytotoxic T-lymphocyte-associated protein 4 antigen

Core Tip: Several evaluations have been published on immunotherapy for neuroendocrine neoplasms. However, this is the first review to specifically focus on the efficacy of different immunotherapy strategies such as immune checkpoint inhibitor (ICI) monotherapy, dual ICI therapy, anti-angiogenesis plus ICI, and chemotherapy combined with ICI for the treatment of advanced well-differentiated high-grade gastroenteropancreatic neuroendocrine tumors.