Retrospective Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 7, 2021; 27(41): 7190-7206
Published online Nov 7, 2021. doi: 10.3748/wjg.v27.i41.7190
Clinical characteristics of gastrointestinal immune-related adverse events of immune checkpoint inhibitors and their association with survival
Kentaro Yamada, Tsunaki Sawada, Masanao Nakamura, Takeshi Yamamura, Keiko Maeda, Eri Ishikawa, Tadashi Iida, Yasuyuki Mizutani, Naomi Kakushima, Takuya Ishikawa, Kazuhiro Furukawa, Eizaburo Ohno, Takashi Honda, Hiroki Kawashima, Masatoshi Ishigami, Satoshi Furune, Tetsunari Hase, Kenji Yokota, Osamu Maeda, Naozumi Hashimoto, Masashi Akiyama, Yuichi Ando, Mitsuhiro Fujishiro
Kentaro Yamada, Masanao Nakamura, Takeshi Yamamura, Eri Ishikawa, Tadashi Iida, Yasuyuki Mizutani, Naomi Kakushima, Takuya Ishikawa, Kazuhiro Furukawa, Eizaburo Ohno, Takashi Honda, Masatoshi Ishigami, Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya City 4668560, Aichi, Japan
Tsunaki Sawada, Keiko Maeda, Hiroki Kawashima, Department of Endoscopy, Nagoya University Hospital, Nagoya City 4668560, Aichi, Japan
Satoshi Furune, Osamu Maeda, Yuichi Ando, Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya City 4668560, Aichi, Japan
Tetsunari Hase, Naozumi Hashimoto, Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya City 4668560, Aichi, Japan
Kenji Yokota, Masashi Akiyama, Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya City 4668560, Aichi, Japan
Mitsuhiro Fujishiro, Department of Gastroenterology and Hepatology, Graduate School of Medicine, The University of Tokyo, Tokyo 1138655, Japan
Author contributions: Yamada K and Sawada T contributed to the conception and design of the study; Yamada K, Sawada T, Yamamura T, and Nakamura M contributed to the analysis and interpretation of the data; Yamada K drafted the article; Ishikawa E, Maeda K, Kakushima N, Furukawa K, Honda T, Iida T, Mizutani Y, Ishikawa T, Ohno E, Kawashima H, Ishigami M, Furune S, Hase T, Yokota K, Maeda O, Hashimoto N, Akiyama M, and Ando Y critically revised the article for important intellectual content; Yamamura T performed the statistical analysis; Fujishiro M approved the final version of the article to be published; All authors have read and approved the final manuscript.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of Nagoya University Hospital (No. 2018-0438, 15006).
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymous clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: Hase T received personal fees from AstraZeneca, Chugai Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., and Bristol-Myers Squibb Co. and grants from AstraZeneca and Chugai Pharmaceutical Co. Ltd., outside the submitted work. Hashimoto N received a grant from Boehringer Ingelheim, outside the submitted work. Ando Y received grants from Mochida Pharmaceutical Co. Ltd.; grants and personal fees from Chugai Pharmaceutical Co. Ltd., Kyowa Kirin Co. Ltd., Nippon Kayaku Co. Ltd., Yakult Honsha Co. Ltd., Ono Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., Daiichi Sankyo Company Ltd., Eisai Co. Ltd.; and personal fees from Eli Lilly Japan K.K., Novartis Pharma K.K., Bayer Holding Ltd., Bristol-Myers Squibb, Sawai Pharmaceutical Co. Ltd., Tsumura & Co., Otsuka Holdings Co. Ltd., Roche Diagnostics K.K., AstraZeneca K.K., and MSD K.K, outside the submitted work. We declare that there are no conflict of interest.
Data sharing statement: No additional data are available.
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: Tsunaki Sawada, PhD, Assistant Professor, Department of Endoscopy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya City 4668560, Aichi, Japan. t.sawada@med.nagoya-u.ac.jp
Received: July 4, 2021
Peer-review started: July 4, 2021
First decision: July 14, 2021
Revised: July 27, 2021
Accepted: August 31, 2021
Article in press: August 31, 2021
Published online: November 7, 2021
Processing time: 124 Days and 22 Hours
Abstract
BACKGROUND

Despite the popularity of immune checkpoint inhibitors (ICIs) in the treatment of advanced cancer, patients often develop gastrointestinal (GI) and non-GI immune-related adverse events (irAEs). The clinical characteristics and survival outcomes of GI-irAEs have not been fully elucidated in previous reports. This necessitates the evaluation of the impact of GI-irAEs on patients receiving ICI treatment.

AIM

To evaluate the clinical characteristics of GI-irAEs and their impact on survival in patients treated with ICIs.

METHODS

In this single-center, retrospective, observational study, we reviewed the records of 661 patients who received ICIs for various cancers at Nagoya University Hospital from September 2014 to August 2020. We analyzed the clinical characteristics of patients who received ICI treatment. We also evaluated the correlation between GI-irAE development and prognosis in non-small cell lung cancer (LC) and malignant melanoma (MM). Kaplan-Meier analysis was used to compare the median overall survival (OS). Multivariate Cox proportional hazards models were used to identify prognostic factors. A P value < 0.05 was considered statistically significant.

RESULTS

GI-irAEs occurred in 34 of 605 patients (5.6%) treated with an anti-programmed cell death-1/programmed death-ligand 1 (anti-PD-1/PD-L1) antibody alone and in nine of 56 patients (16.1%) treated with an anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody alone or a combination of anti-PD-1 and anti-CTLA-4 antibodies. The cumulative incidence and median daily diarrhea frequency were significantly higher in patients receiving anti-CTLA-4 antibodies (P < 0.05). In 130 patients with MM, OS was significantly prolonged in the group that continued ICI treatment despite the development of GI-irAEs compared to the group that did not experience GI-irAEs (P = 0.035). In contrast, in 209 patients with non-small cell LC, there was no significant difference in OS between the groups. The multivariate analyses showed that a performance status of 2-3 (hazard ratio: 2.406; 95% confidence interval: 1.125–5.147; P = 0.024) was an independent predictive factor for OS in patients with MM.

CONCLUSION

Patients receiving anti-CTLA-4 antibodies develop GI-irAEs more frequently and with higher severity than those receiving anti-PD-1/PD-L1 antibodies. Continuing ICI treatment in patients with MM with GI-irAEs have better OS.

Keywords: Colitis; Cytotoxic T-lymphocyte antigen 4; Diarrhea; Drug-related side effects and adverse reactions; Immune checkpoint inhibitors; Prognosis

Core Tip: We compared the clinical characteristics of gastrointestinal immune-related adverse events (GI-irAEs) in patients receiving anti-programmed cell death-1/programmed death-ligand 1 (anti-PD-1/PD-L1), anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), or a combination of anti-PD-1 and anti-CTLA-4 antibodies. We also examined the correlation between GI-irAE development and the prognosis of patients with non-small cell lung cancer (LC) and malignant melanoma (MM). GI-irAEs occurred more frequently and with higher severity in patients receiving anti-CTLA-4 antibodies than in those receiving anti-PD-1/PD-L1 antibodies. Patients with MM, but not non-small cell LC, who continued immune checkpoint inhibitor treatment after developing GI-irAEs had better overall survival.