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Wang S, Wang H. Treatment of immune checkpoint inhibitor-related colitis: a narrative review. Transl Cancer Res 2024; 13:7002-7014. [PMID: 39816545 PMCID: PMC11729759 DOI: 10.21037/tcr-24-2150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 12/17/2024] [Indexed: 01/18/2025]
Abstract
Background and Objective Cancer is one of the most difficult diseases facing modern medicine, and increasing amounts of research and clinical treatments are being applied to the treatment of cancer. Immunotherapy, particularly immune checkpoint inhibitor (ICI) therapy, has revolutionized the treatment and overall survival of patients with several different types of cancer. Approximately one-third of patients treated with ICIs may experience immune-related adverse events (irAEs). Immune checkpoint inhibitor-associated colitis (ICIC) is the most common irAE with an incidence of approximately 8-10%, ICIC usually presents as watery or bloody diarrhea, and if the symptoms are severe, ICI treatment must be interrupted or even terminated. This review summarizes the epidemiology, pathogenesis, clinical characteristics, and therapies of ICIC, focusing on the use of biologics, in order to propose treatment options in different situations to control immune checkpoint inhibitor-related colitis as soon as possible. Methods To find relevant articles for this narrative review paper, a combination of keywords such as immune checkpoint inhibitor-related colitis, corticosteroids, biologics were searched for in PubMed databases. Key Content and Findings The pathogenesis of ICIC is complex and primarily involves antitumor effects and indirect damage to colonic tissues, as well as the activation of specific proinflammatory pathways. Corticosteroids (CSs) are the first line of treatment for ICIC, but steroid-refractory or steroid-resistant cases often occur. Patients with irAE colitis respond favorably to biologics, and patients with CS-resistant/refractory enterocolitis can benefit from the early use of biologics. Conclusions Biologics are currently recommended for the treatment of ICIC but are usually used as a supplement after the failure of first-line CS therapy. Patients with irAE colitis respond favorably to biologics, and patients with CS-resistant/refractory enterocolitis can benefit from the early use of biologics. Biologics (alone or in combination with CS) should be considered as an early therapy option for high-risk patients rather than just an escalation after a failure to respond to CS.
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Affiliation(s)
- Shiyang Wang
- Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Hanping Wang
- Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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Hirata Y, Tanaka Y, Yokota H, Ohno H, Nishida K, Shimizu H, Mizuta N, Nakazawa K, Koshiba R, Kakimoto K, Miyazaki T, Nakamura S, Nishikawa H. Gut microbiota shifts from onset to remission in immune checkpoint inhibitor-induced enterocolitis: a case report. Gut Pathog 2024; 16:33. [PMID: 38965595 PMCID: PMC11225377 DOI: 10.1186/s13099-024-00630-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 06/28/2024] [Indexed: 07/06/2024] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) are crucial in cancer treatment; however, they carry the risk of immune-related adverse events (irAEs), such as enteritis. CASE PRESENTATION This study investigated the role of the gut microbiota during the onset and remission of irAE enteritis in a patient with stage IV melanoma undergoing anti-PD-1 and anti-CTLA-4 therapy. Following commencement of ICI treatment, the patient developed severe diarrhea and was diagnosed with grade 3 irAE enteritis. Steroid and probiotic treatments provided swift symptom relief and remission, as confirmed by reduced fecal calprotectin levels and gastrointestinal imaging. Microbiota diversity analysis conducted via 16S rRNA gene sequencing identified a decrease in Streptococcus prevalence with improvement in enteritis symptoms. Conversely, genera Fusobacterium, Faecalibacterium, Bacteroides, Prevotella, and Bifidobacterium showed increased representation after remission. These genera are associated with anti-inflammatory properties and fibrous substrate degradation, aiding gut health. Immunological assessment demonstrated fluctuations in cytokine expression and the modulation of costimulatory molecules, aligning with therapeutic interventions and microbiota alterations. CONCLUSIONS Our findings indicate a significant correlation between gut microbiota and immune responses in irAE enteritis. This underscores the potential utility of microbiome profiling in predicting irAE occurrence and in providing treatment strategies, thereby promoting a more comprehensive approach to managing the adverse effects of ICIs.
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Affiliation(s)
- Yuki Hirata
- Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan.
| | | | | | | | - Koji Nishida
- Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan
| | - Hikaru Shimizu
- Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan
| | - Noboru Mizuta
- Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan
| | - Kei Nakazawa
- Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan
| | - Ryoji Koshiba
- Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan
| | - Kazuki Kakimoto
- Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan
| | - Takako Miyazaki
- Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan
| | - Shiro Nakamura
- Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan
| | - Hiroki Nishikawa
- Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan
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Wang J, Guo Z, Shen M, Xie Q, Xiang H. Potential application mechanism of traditional Chinese medicine in treating immune checkpoint inhibitor-induced colitis. Front Immunol 2024; 15:1366489. [PMID: 38660314 PMCID: PMC11039877 DOI: 10.3389/fimmu.2024.1366489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 03/08/2024] [Indexed: 04/26/2024] Open
Abstract
Cancer ranks among the foremost causes of mortality worldwide, posing a significant threat to human lives. The advent of tumor immunotherapy has substantially transformed the therapeutic landscape for numerous advanced malignancies, notably non-small cell lung cancer and melanoma. However, as immune checkpoint inhibitors (ICIs) are increasingly applied in clinical settings, a spectrum of undesired reactions, termed immune-related adverse events (irAEs), has emerged. These adverse reactions are associated with immunotherapy and can result in varying degrees of harm to the human body. Among these reactions, Immune checkpoint inhibitor-induced colitis (ICIIC) stands out as one of the most prevalent clinical adverse events. In contemporary times, traditional Chinese medicine (TCM) has demonstrated remarkable efficacy in addressing various maladies. Consequently, investigating the potential application and mechanisms of Chinese medicine in countering immune checkpoint inhibitor-induced colitis assumes significant importance in the treatment of this condition.
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Affiliation(s)
- Jing Wang
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, China
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Ziyue Guo
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, China
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Mengyi Shen
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Shangdong First Medical University & Shangdong Academy of Medical Sciences, Jinan, China
| | - Qi Xie
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
| | - Hongjie Xiang
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
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Riveiro-Barciela M, Carballal S, Díaz-González Á, Mañosa M, Gallego-Plazas J, Cubiella J, Jiménez-Fonseca P, Varela M, Menchén L, Sangro B, Fernández-Montes A, Mesonero F, Rodríguez-Gandía MÁ, Rivera F, Londoño MC. Management of liver and gastrointestinal toxicity induced by immune checkpoint inhibitors: Position statement of the AEEH-AEG-SEPD-SEOM-GETECCU. GASTROENTEROLOGIA Y HEPATOLOGIA 2024; 47:401-432. [PMID: 38228461 DOI: 10.1016/j.gastrohep.2023.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 09/28/2023] [Accepted: 10/19/2023] [Indexed: 01/18/2024]
Abstract
The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2% to 40%, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.
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Affiliation(s)
- Mar Riveiro-Barciela
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Universitat Autònoma de Barcelona (UAB), Department of Medicine, Spain.
| | - Sabela Carballal
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Gastroenterology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Universitat de Barcelona, Spain
| | - Álvaro Díaz-González
- Gastroenterology Department, Grupo de Investigación Clínica y Traslacional en Enfermedades Digestivas, Instituto de Investigación Valdecilla (IDIVAL), Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Míriam Mañosa
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | | | - Joaquín Cubiella
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Gastroenterology Department, Hospital Universitario de Ourense, Grupo de Investigación en Oncología Digestiva-Ourense, Spain
| | - Paula Jiménez-Fonseca
- Medical Oncology Department, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
| | - María Varela
- Gastroenterology Department, Hospital Universitario Central de Asturias, IUOPA, ISPA, FINBA, University of Oviedo, Oviedo, Spain
| | - Luis Menchén
- Servicio de Aparato Digestivo - CEIMI, Instituto de Investigación Sanitaria Gregorio, Marañón, Spain; Departamento de Medicina, Universidad Complutense, Madrid, Spain
| | - Bruno Sangro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Cancer Center Clinica Universidad de Navarra, Pamplona-Madrid, Spain
| | - Ana Fernández-Montes
- Medical Oncology Department, Complexo Hospitalario Universitario de Ourense, Ourense, Spain
| | - Francisco Mesonero
- Gastroenterology and Hepatology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain; Universidad de Alcalá de Henares, Spain
| | - Miguel Ángel Rodríguez-Gandía
- Gastroenterology and Hepatology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRyCIS), Madrid, Spain
| | - Fernando Rivera
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
| | - María-Carlota Londoño
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Universitat de Barcelona, Spain; Liver Unit, Hospital Clínic Barcelona, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Spain
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Velikova T, Krastev B, Gulinac M, Zashev M, Graklanov V, Peruhova M. New strategies in the diagnosis and treatment of immune-checkpoint inhibitor-mediated colitis. World J Clin Cases 2024; 12:1050-1062. [PMID: 38464930 PMCID: PMC10921308 DOI: 10.12998/wjcc.v12.i6.1050] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/20/2023] [Accepted: 01/19/2024] [Indexed: 02/20/2024] Open
Abstract
Immune-checkpoint inhibitor-mediated colitis (IMC) is an increasingly recognized adverse event in cancer immunotherapy, particularly associated with immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies. As this revolutionary immunotherapy gains prominence in cancer treatment, understanding, diagnosing, and effectively managing IMC becomes paramount. IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications. However, a precise picture of IMC pathophysiology is currently unavailable. Therefore, we aimed to summarize the existing data while acknowledging the need for further research. This comprehensive review explores the mechanisms underlying ICIs, gastrointestinal adverse effects, and, in particular, IMC's incidence, prevalence, and features. Our review also emphasizes the importance of recognizing IMC's distinct clinical and histopathological features to differentiate it from other forms of colitis. Furthermore, this paper highlights the urgent need for evolving diagnostic methods, therapeutic strategies, and a multidisciplinary approach to effectively manage IMC.
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Affiliation(s)
- Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Boris Krastev
- Medical Center Nadezhda, Medical Center Nadezhda, Sofia 1407, Bulgaria
| | - Milena Gulinac
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
- General and Clinical Pathology, Medical University of Plovdiv, Plovdiv 4002, Bulgaria
| | - Miroslav Zashev
- Department of General Surgery, University Hospital “Heart and Brain”, Burgas 8000, Bulgaria
| | - Vasko Graklanov
- First Department of Internal Diseases, Medical University of Plovdiv, Plovdiv 4000, Bulgaria
- Department of Hematology, University Hospital “St. George”, Plovdiv 4000, Bulgaria
| | - Milena Peruhova
- Division of Gastroenterology, University Hospital “Heart and Brain”, Burgas 1000, Bulgaria
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Riveiro-Barciela M, Carballal S, Díaz-González Á, Mañosa M, Gallgo-Plazas J, Cubiella J, Jiménez-Fonseca P, Varela M, Menchén L, Sangro B, Fernández-Montes A, Mesonero F, Rodríguez-Gandía MÁ, Rivera F, Londoño MC. Management of liver and gastrointestinal toxicity induced by immune checkpoint inhibitors: Position statement of the AEEH-AEG-SEPD-SEOM-GETECCU. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2024; 116:83-113. [PMID: 38226597 DOI: 10.17235/reed.2024.10250/2024] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2024]
Abstract
The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2 % to 40 %, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.
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Affiliation(s)
| | | | | | - Miriam Mañosa
- Gastroenterology, Hospital Universitari Germans Trias i Pujol
| | | | | | | | - María Varela
- Gastroenterology, Hospital Universitario Central de Asturias
| | - Luis Menchén
- Digestive Diseases, Instituto de Investigación Sanitaria Gregorio Marañón
| | | | | | | | | | - Fernando Rivera
- Hospital Universitario Marqués de Valdecilla, Medical Oncology
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Ding M, Zhang X, Wang J, Gao F, Zheng X, Yuan J, Qi X. Treatment and outcomes of immune checkpoint inhibitors-associated colitis/diarrhea: A systematic review and meta-analysis. Dig Liver Dis 2023; 55:1621-1631. [PMID: 36894390 DOI: 10.1016/j.dld.2023.02.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/15/2023] [Accepted: 02/20/2023] [Indexed: 03/11/2023]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have improved the outcomes of cancer patients. However, ICIs often lead to colitis/diarrhea. This study aimed to assess the treatment of ICIs-associated colitis/diarrhea and outcomes. METHODS PubMed, EMBASE, and Cochrane Library databases were searched for eligible studies which investigated the treatment and outcomes of colitis/diarrhea developing in patients who received ICIs. The pooled incidences of any-grade colitis/diarrhea, low-grade colitis, high-grade colitis, low-grade diarrhea, and high-grade diarrhea as well as the pooled rates of response to treatment, mortality, and ICIs permanent discontinuation and restarts in patients with ICIs-associated colitis/diarrhea were estimated using a random-effects model. RESULTS Among the 11,492 papers initially identified, 27 studies were included. The pooled incidences of any-grade colitis/diarrhea, low-grade colitis, high-grade colitis, low-grade diarrhea, and high-grade diarrhea were 17%, 3%, 17%, 13%, and 15%, respectively. The pooled rates of overall response, response to corticosteroid therapy, and response to biological agents were 88%, 50%, and 96%, respectively. The pooled short-term mortality in patients with ICIs-associated colitis/diarrhea was 2%. The pooled incidences of ICIs permanent discontinuation and restarts were 43% and 33%, respectively. CONCLUSION ICIs-associated colitis/diarrhea is common, but rarely lethal. Half of them are responsive to corticosteroid therapy. There is a fairly high rate of response to biological agents in steroid-refractory colitis/diarrhea patients.
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Affiliation(s)
- Min Ding
- Meta-Analysis Interest Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China; Postgraduate College, China Medical University, Shenyang, China
| | - Xianxian Zhang
- Meta-Analysis Interest Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China; Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Jing Wang
- Meta-Analysis Interest Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China; Department of Gastroenterology, The 960th Hospital of the PLA, Jinan, China
| | - Fangbo Gao
- Meta-Analysis Interest Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China; Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Xiaojie Zheng
- Meta-Analysis Interest Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China; Postgraduate College, China Medical University, Shenyang, China
| | - Jinqiu Yuan
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Xingshun Qi
- Meta-Analysis Interest Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China; Postgraduate College, China Medical University, Shenyang, China; Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
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Liu H, Luo SX, Jie J, Peng L, Wang S, Song L. Immune checkpoint inhibitors related respiratory disorders in patients with lung cancer: A meta-analysis of randomized controlled trials. Front Immunol 2023; 14:1115305. [PMID: 36926326 PMCID: PMC10011157 DOI: 10.3389/fimmu.2023.1115305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Accepted: 02/14/2023] [Indexed: 03/08/2023] Open
Abstract
Background In recent years, immune checkpoint inhibitors (ICIs) had extremely rapid growth in anti-cancer and improved outcomes of many malignancies, specifically lung cancer. However, the incidence of ICIs-related adverse events also raised. Using this meta-analysis, ICIs-related respiratory disorders were investigated in lung cancer patients. Methods Using Cochrane Library, Embase, and PubMed databases, we performed an integrated search for randomized controlled trials (RCTs) to compare respiratory disorders among different regimens. The data was prepared with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline, and the quality of included studies was evaluated based on the Cochrane manual. Results In total, 22 RCTs were involved in this meta-analysis. Compared with ICIs, chemotherapy reduced the risk of interstitial lung disease (p = 0.03; SMD: 2.81; 95% CI: 1.08, 7.27), pleural effusion (p = 0.002; SMD: 2.12; 95% CI: 1.32, 3.42), and pneumonitis (p < 0.00001; SMD: 9.23; 95% CI: 4.57, 18.64). ICIs plus chemotherapy could provide a higher probability for patients to suffer pneumonitis than chemotherapy (p = 0.01; SMD: 1.96; 95% CI: 1.17, 3.28). In addition, single ICI brought a lower likelihood for patients suffering pneumonitis than double ICIs (p = 0.004; SMD: 2.17; 95% CI: 1.27, 3.69). Conclusion ICIs-based treatment, such as ICIs alone, ICIs plus chemotherapy and double ICIs, can raise the incidences of some respiratory disorders in patients with lung cancer. It suggests that ICIs should be conducted based on a comprehensive consideration to prevent ICIs-related respiratory disorders. To a certain degree, this study might be provided to the clinician as a reference for ICIs practice. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022378901, identifier (CRD42022378901).
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Affiliation(s)
- Han Liu
- Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Sean X Luo
- Department of Vascular Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Jing Jie
- Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Liping Peng
- Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Shuai Wang
- Department of Vascular Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Lei Song
- Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
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Nakai M, Kai Y, Suzuki K, Matsuda M, Kikukawa S, Masuda H, Soga M, Ueda T, Yoshimura A, Takano M, Hontsu S, Uno K, Muro S. A case of perforated immune-related colitis complicated by cytomegalovirus infection during treatment of immune-related adverse effect in lung cancer immunotherapy. Respir Med Case Rep 2022; 41:101794. [PMID: 36583058 PMCID: PMC9792950 DOI: 10.1016/j.rmcr.2022.101794] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 12/10/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
Although immune checkpoint inhibitors (ICIs) can be used for lung cancer treatment, the activated immune response may cause immune-related adverse effects (irAEs). We present here a case of cytomegalovirus (CMV) enterocolitis during steroid therapy for an irAE. A 70-year-old man diagnosed with small-cell lung carcinoma (limited disease) received radiotherapy plus two chemotherapy cycles of cisplatin and etoposide. The tumor exhibited complete response but recurred after 3 years. After treatment with two cycles of carboplatin, etoposide, and atezolizumab, an inhibitors of programmed cell death receptor-1, he was switched to atezolizumab every 3 weeks for maintenance therapy. Diarrhea occurred after nine atezolizumab doses. With a strong suspicion of ICI-induced colitis, we administered methylprednisolone 500 mg for 3 days, followed by oral prednisolone 40 mg/day. Total colonoscopy during the treatment revealed mucosal inflammation of the total colon, suggesting immune-related colitis. Biopsies from the ulceration revealed crypt abscess with highly infiltrative plasma cells and lymphocytes. Furthermore, immunohistochemical staining showed positivity for CMV. With no improvement in watery diarrhea, the prednisolone dose was increased to 80 mg/day on the 11th day, and ganciclovir was additionally administered twice daily on the 26th day. On the 28th day, the patient had abdominal pain, and abdominal computed tomography revealed free air, resulting in the diagnosis of colon perforation. He underwent subtotal colectomy followed by ileostomy as emergency surgery. A colon specimen revealed colitis with CMV infection. We describe colon perforation in a patient with CMV enterocolitis complicated by refractory immune-related colitis.
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Affiliation(s)
- Masahiro Nakai
- Department of Respiratory Medicine, Minami-Nara General Medical Center, 8-1 Fukugami, Oyodo-cho, Yoshino-gun, Nara, 638-8551, Japan
| | - Yoshiro Kai
- Department of Respiratory Medicine, Minami-Nara General Medical Center, 8-1 Fukugami, Oyodo-cho, Yoshino-gun, Nara, 638-8551, Japan,Corresponding author. Department of Respiratory Medicine, Minami-Nara General Medical Center, 8-1 Fukugami, Oyodo-cho, Yoshino-gun, Nara, 638-8551, Japan.
| | - Kentaro Suzuki
- Department of Respiratory Medicine, Minami-Nara General Medical Center, 8-1 Fukugami, Oyodo-cho, Yoshino-gun, Nara, 638-8551, Japan
| | - Masayuki Matsuda
- Department of Respiratory Medicine, Minami-Nara General Medical Center, 8-1 Fukugami, Oyodo-cho, Yoshino-gun, Nara, 638-8551, Japan
| | - Shoma Kikukawa
- Department of Gastroenterology, Minami-Nara General Medical Center, 8-1 Fukugami, Oyodo-cho, Yoshino-gun, Nara, 638-8551, Japan
| | - Hiroyuki Masuda
- Department of Gastroenterology, Minami-Nara General Medical Center, 8-1 Fukugami, Oyodo-cho, Yoshino-gun, Nara, 638-8551, Japan
| | - Masahiro Soga
- Department of Surgery, Minami-Nara General Medical Center, 8-1 Fukugami, Oyodo-cho, Yoshino-gun, Nara, 638-8551, Japan
| | - Takeshi Ueda
- Department of Surgery, Minami-Nara General Medical Center, 8-1 Fukugami, Oyodo-cho, Yoshino-gun, Nara, 638-8551, Japan
| | - Atsushi Yoshimura
- Department of Surgery, Minami-Nara General Medical Center, 8-1 Fukugami, Oyodo-cho, Yoshino-gun, Nara, 638-8551, Japan
| | - Masato Takano
- Department of Diagnostic Pathology, Minami-Nara General Medical Center, 8-1 Fukugami, Oyodo-cho, Yoshino-gun, Nara, 638-8551, Japan
| | - Shigeto Hontsu
- Department of Respiratory Medicine, Nara Medical University, 840 Shijo-cho, Kashihara City, Nara, 634-8522, Japan
| | - Kenji Uno
- Department of Infectious Diseases, Minami-Nara General Medical Center, 8-1 Fukugami, Oyodo-cho, Yoshino-gun, Nara, 638-8551, Japan
| | - Shigeo Muro
- Department of Respiratory Medicine, Nara Medical University, 840 Shijo-cho, Kashihara City, Nara, 634-8522, Japan
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10
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Weingarden AR, Gubatan J, Singh S, Balabanis TC, Patel A, Sharma A, Habtezion A. Immune checkpoint inhibitor-mediated colitis is associated with cancer overall survival. World J Gastroenterol 2022; 28:5750-5763. [PMID: 36338892 PMCID: PMC9627421 DOI: 10.3748/wjg.v28.i39.5750] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 09/24/2022] [Accepted: 10/10/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event following immune checkpoint inhibitor (ICI) therapy for cancer. IMC has been associated with improved overall survival (OS) and progression-free survival (PFS), but data are limited to a single site and predominantly for melanoma patients.
AIM To determine the association of IMC with OS and PFS and identify clinical predictors of IMC.
METHODS We performed a retrospective case-control study including 64 ICI users who developed IMC matched according to age, sex, ICI class, and malignancy to a cohort of ICI users without IMC, from May 2011 to May 2020. Using univariate and multivariate logistic regression, we determined association of presence of IMC on OS, PFS, and clinical predictors of IMC. Kaplan-Meier curves were generated to compare OS and PFS between ICI users with and without IMC.
RESULTS IMC was significantly associated with a higher OS (mean 24.3 mo vs 17.7 mo, P = 0.05) but not PFS (mean 13.7 mo vs 11.9 mo, P = 0.524). IMC was significantly associated with OS greater than 12 mo [Odds ratio (OR) 2.81, 95% confidence interval (CI) 1.17-6.77]. Vitamin D supplementation was significantly associated with increased risk of IMC (OR 2.48, 95%CI 1.01-6.07).
CONCLUSION IMC was significantly associated with OS greater than 12 mo. In contrast to prior work, we found that vitamin D use may be a risk factor for IMC.
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Affiliation(s)
- Alexa R Weingarden
- Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - John Gubatan
- Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Sundeep Singh
- Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Tatiana Clorice Balabanis
- Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Akshar Patel
- Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Arpita Sharma
- Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Aida Habtezion
- Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, United States
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11
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Pharmacological Treatments Available for Immune-Checkpoint-Inhibitor-Induced Colitis. Biomedicines 2022; 10:biomedicines10061334. [PMID: 35740355 PMCID: PMC9219666 DOI: 10.3390/biomedicines10061334] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/02/2022] [Accepted: 06/02/2022] [Indexed: 12/13/2022] Open
Abstract
Immune checkpoint inhibitor treatment has shown revolutionary therapeutic effects in various carcinomas. However, immune-related adverse events (irAE) following this treatment can sometimes lead to treatment discontinuation. One such frequently encountered adverse event is immune-related colitis (irAE colitis). Corticosteroids (CS) are the first-line treatment for irAE colitis, but we often encounter CS-refractory or -resistant cases. The application of multiple biologics has been proposed as a therapy to be administered after CS treatment; however, the efficacy and safety of biologics for patients with irAE colitis who do not respond to CS have not been established. This review summarizes the treatment regimens available for irAE colitis, focusing on the mechanism of action of corticosteroids, infliximab, vedolizumab, and other drugs.
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12
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Kanji S, Morin S, Agtarap K, Purkayastha D, Thabet P, Bosse D, Wang X, Lunny C, Hutton B. Adverse Events Associated with Immune Checkpoint Inhibitors: Overview of Systematic Reviews. Drugs 2022; 82:793-809. [PMID: 35416592 DOI: 10.1007/s40265-022-01707-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/16/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Recognition and management of adverse events (AEs) associated with immune checkpoint inhibitor (ICI) use by cancer patients requires expertise from multiple disciplines. Greater awareness of potential AEs may result in earlier recognition, appropriate management, and better patient outcomes. OBJECTIVE The primary objective of this overview of systematic reviews was to synthesize and consolidate systematic review evidence describing the incidence proportion and severity of AEs associated with various ICI therapies across different cancers. METHODS A systematic literature search of four databases was conducted to identify systematic reviews that describe the incidence proportion and severity of AEs related to ICI therapy in cancer patients. A systematic review was eligible if it included adults with cancer; on ICI alone or in combination with another ICI, chemotherapy, or targeted therapy; severity (graded according to the Common Terminology Criteria for Adverse Events) and incidence proportion of AEs and whether it reported its eligibility criteria. AEs of interest were identified through an iterative ranking exercise by key stakeholders and knowledge users. Extraction of PICOTTS elements and quality indicators (AMSTAR-2) were used to manage overlap of primary studies across systematic reviews at the outcome level. Cancer subtypes were mapped to drug class and AE severity. RESULTS Overall, 129 systematic reviews met the inclusion criteria for data mapping. Systematic reviews reported incidence proportions for more than 76 AEs, of which 34 were identified as AEs of interest. After overlap assessment, 65 systematic reviews were chosen for data extraction. The three AEs with the highest median incidence were fatigue (18.3%, interquartile range [IQR] 15.0-28.0%), diarrhea (15.3%, IQR 9.7-29.2%) and rash (14.4%, IQR 10.3-19.2%). The three AEs (high-grade) with the highest median incidence were diarrhea (1.5%, IQR 1.2-6.0%), colitis (1.3%, IQR 0.6-6.1%) and neutropenia (1.2%, IQR 0.4-3.3%). Incidence proportions of high-grade AEs were often considerably lower than all-grade AEs and combination therapy (ICI combinations or combinations of ICI with chemotherapy or targeted therapy) was responsible for some of the highest incidence proportions regardless of AE. Rare AEs and certain cancer subtypes were not well reported. CONCLUSIONS Early recognition of AEs associated with ICIs requires expertise from diverse specialists, not just oncologists. Greater awareness of potential AEs may result in earlier recognition, appropriate management, and better patient outcomes. PROSPERO REGISTRATION CRD42021231593.
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Affiliation(s)
- Salmaan Kanji
- The Ottawa Hospital, 501 Smyth Rd, Ottawa, ON, K1H 8L6, Canada. .,Ottawa Hospital Research Institute, Ottawa, ON, Canada.
| | | | | | | | | | - Dominick Bosse
- The Ottawa Hospital, 501 Smyth Rd, Ottawa, ON, K1H 8L6, Canada
| | - Xiang Wang
- The Ottawa Hospital, 501 Smyth Rd, Ottawa, ON, K1H 8L6, Canada
| | - Carole Lunny
- St. Michaels Hospital, Unity Health Toronto, Toronto, ON, Canada.,University of British Columbia, Vancouver, BC, Canada
| | - Brian Hutton
- Ottawa Hospital Research Institute, Ottawa, ON, Canada
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13
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Moschen AR, Sammy Y, Marjenberg Z, Heptinstall AB, Pooley N, Marczewska AM. The Underestimated and Overlooked Burden of Diarrhea and Constipation in Cancer Patients. Curr Oncol Rep 2022; 24:861-874. [PMID: 35325401 DOI: 10.1007/s11912-022-01267-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2022] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW This review aims to summarize and discuss the diverse causes of two major gastrointestinal dysfunction symptoms, diarrhea and constipation, in cancer patients. We also discuss short- and long-term clinical, economic, and humanistic consequences, including the impact on cancer treatment regimens and patient quality of life, highlighting the limitations of the literature. RECENT FINDINGS Diarrhea and constipation as a result of cancer and its treatment can risk the success of anti-cancer therapies by requiring treatment delay or withdrawal, and imposes a substantial humanistic burden in patients with cancer. Despite its importance and frequency, gastrointestinal side effects may be overlooked due to the focus on cancer treatment, and the impact on patients may be underestimated. Additionally, the burden reported may not fully reflect current cancer management, particularly the true impact of economic consequences. A full understanding of the burden of diarrhea and constipation in patients with cancer is required, including broad evaluation of clinical considerations, the patient experience, and an updated assessment of economic burden. This would improve caregivers' appreciation of the impact of gastrointestinal dysfunction and aid the prioritization of future research efforts.
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14
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Farha N, Alkhayyat M, Lindsey A, Mansoor E, Saleh MA. Immune checkpoint inhibitor induced colitis: A nationwide population-based study. Clin Res Hepatol Gastroenterol 2022; 46:101778. [PMID: 34332139 DOI: 10.1016/j.clinre.2021.101778] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 07/01/2021] [Accepted: 07/07/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND ICIs are used in the management of several malignancies. However, they can result in immune-related adverse events, such as colitis. The aim of this study is to obtain an epidemiological survey of patients who develop immune checkpoint inhibitor (ICI)-induced colitis and identify underlying risk factors. METHODS A cohort study was performed using Explorys, a US-based population database. Our cohort included all patients in a five-year interval on an ICI. We further identified those who developed colitis after initiating an ICI. Demographic data and possible risk factors were assessed. Odds ratios were calculated and multivariable statistical analysis was performed. RESULTS 3.6% of patients developed ICI-induced colitis. Women [OR: 1.2; 95% CI 1.224-1.231, p <0.001], Caucasians [OR: 2.3; 2.284 - 2.299], individuals older than 65 years [OR: 1.3; 1.319 - 1.326], obese patients [OR: 3.3; 3.273 - 3.302], and those with a history of alcohol abuse [OR: 2.5; 2.485 - 2.523] were more likely to develop colitis. Patients who received Nivolumab [OR: 2.8; 2.563 - 3.022], Ipilimumab [OR: 4.9; 3.937 - 6.061], Pembrolizumab [OR 2.7; 2.463 - 2.868], and Atezolizumab [OR 2.9; 2.430 - 3.388] had an increased odds of developing colitis. The majority of cases were diagnosed in the first 6 months of therapy. CONCLUSIONS This is the largest study to describe the epidemiology of ICI-induced colitis and it is the first to identify underlying risk factors. Ipilimumab poses the greatest risk for ICI-induced colitis. The risk of colitis should be discussed with all patients prior to initiating an ICI, as it may be a factor in choosing among ICIs.
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Affiliation(s)
- Natalie Farha
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Motasem Alkhayyat
- Department of Gastroenterology, Hepatology & Nutrition, Cleveland Clinic Foundation, Cleveland, OH, USA.
| | - Adrian Lindsey
- Division of Gastroenterology and Liver Disease, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA
| | - Emad Mansoor
- Division of Gastroenterology and Liver Disease, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA
| | - Mohannad Abou Saleh
- Department of Gastroenterology, Hepatology & Nutrition, Cleveland Clinic Foundation, Cleveland, OH, USA
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15
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Yan YD, Cui JJ, Fu J, Su YJ, Chen XY, Gu ZC, Lin HW. A Network Comparison on Safety Profiling of Immune Checkpoint Inhibitors in Advanced Lung Cancer. Front Immunol 2021; 12:760737. [PMID: 34925331 PMCID: PMC8677695 DOI: 10.3389/fimmu.2021.760737] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 11/16/2021] [Indexed: 12/26/2022] Open
Abstract
Background Immune checkpoint inhibitors (ICIs) have become one of the standard treatment options for advanced lung cancer. However, adverse events (AEs), particularly immune–related AEs (irAEs), caused by these drugs have aroused public attention. The current network meta-analysis (NMA) aimed to compare the risk of AEs across different ICI–based regimens in patients with advanced lung cancer. Methods We systematically searched the PubMed, EMBASE, and Cochrane Library databases (from inception to 19 April 2021) for relevant randomized controlled trials (RCTs) that compared two or more treatments, with at least one ICI administered to patients with advanced lung cancer. The primary outcomes were treatment–related AEs and irAEs, including grade 1–5 and grade 3–5. The secondary outcomes were grade 1–5 and grade 3–5 irAEs in specific organs. Both pairwise and network meta-analyses were conducted for chemotherapy, ICI monotherapy, ICI monotherapy + chemotherapy, dual ICIs therapy, and dual ICIs + chemotherapy for all safety outcomes. Node–splitting analyses were performed to test inconsistencies in network. Sensitivity analyses were adopted by restricting phase III RCTs and studies that enrolled patients with non–small cell lung cancer. Results Overall, 38 RCTs involving 22,178 patients with advanced lung cancer were enrolled. Both pooled incidence and NMA indicated that treatments containing chemotherapy increased the risk of treatment–related AEs when compared with ICI-based regimens without chemotherapy. As for grade 1–5 irAEs, dual ICIs + chemotherapy was associated with the highest risk of irAEs (probability in ranking first: 50.5%), followed by dual-ICI therapy (probability in ranking second: 47.2%), ICI monotherapy (probability in ranking third: 80.0%), ICI monotherapy + chemotherapy (probability in ranking fourth: 98.0%), and finally chemotherapy (probability in ranking fifth: 100.0%). In grade 3–5 irAEs, subtle differences were observed; when ranked from least safe to safest, the trend was dual ICIs therapy (60.4%), dual ICIs + chemotherapy (42.5%), ICI monotherapy (76.3%), ICI monotherapy + chemotherapy (95.0%), and chemotherapy (100.0%). Furthermore, detailed comparisons between ICI–based options provided irAE profiles based on specific organ/system and severity. Conclusions In consideration of overall immune–related safety profiles, ICI monotherapy + chemotherapy might be a better choice among ICI–based treatments for advanced lung cancer. The safety profiles of ICI–based treatments are various by specific irAEs and their severity. Systematic Review Registration https://www.crd.york.ac.uk/prospero, identifier CRD42021268650
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Affiliation(s)
- Yi-Dan Yan
- Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiu-Jie Cui
- Department of Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Fu
- Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying-Jie Su
- Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Yu Chen
- Department of Pharmacy, The People's Hospital of Guangxi Zhuang Autonomous Region (Guangxi Academy of Medical Sciences), Nanning, China
| | - Zhi-Chun Gu
- Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hou-Wen Lin
- Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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16
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Tang L, Wang J, Lin N, Zhou Y, He W, Liu J, Ma X. Immune Checkpoint Inhibitor-Associated Colitis: From Mechanism to Management. Front Immunol 2021; 12:800879. [PMID: 34992611 PMCID: PMC8724248 DOI: 10.3389/fimmu.2021.800879] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 11/29/2021] [Indexed: 02/05/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs), as one of the innovative types of immunotherapies, including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors, have obtained unprecedented benefit in multiple malignancies. However, the immune response activation in the body organs could arise immune-related adverse events (irAEs). Checkpoint inhibitor colitis (CIC) is the most widely reported irAEs. However, some obscure problems, such as the mechanism concerning gut microbiota, the confusing differential diagnosis with inflammatory bowel disease (IBD), the optimal steroid schedule, the reintroduction of ICIs, and the controversial prognosis features, influence the deep understanding and precise diagnosis and management of CIC. Herein, we based on these problems and comprehensively summarized the relevant studies of CIC in patients with NSCLC, further discussing the future research direction of this specific pattern of irAEs.
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Affiliation(s)
- Liansha Tang
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jialing Wang
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Nan Lin
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yuwen Zhou
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Wenbo He
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jiyan Liu
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xuelei Ma
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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17
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Yanai S, Toya Y, Sugai T, Matsumoto T. Gastrointestinal Adverse Events Induced by Immune-Checkpoint Inhibitors. Digestion 2021; 102:965-973. [PMID: 34515105 DOI: 10.1159/000518543] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 07/17/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND As immune-checkpoint inhibitors (ICI) are becoming standard therapies for malignant tumors, increasing attention has been paid to their associated immune-related adverse events (irAEs). The gastrointestinal tract is the major site of irAEs, and it has recently become evident that the large bowel is the most frequently affected region. The aim of this narrative review was to clarify the endoscopic and histopathologic findings of and treatments for ICI-induced colitis. SUMMARY Endoscopic findings of ICI-induced colitis include a reddish, edematous mucosa with increased mucous exudate, loss of normal vascularity, and a granular mucosa with or without mucosal breaks. Histopathologic findings of ICI-induced colitis are expansion of the lamina propria, intraepithelial infiltration of neutrophils, crypt architectural distortion, neutrophilic crypt abscess, and prominent apoptosis. The clinical, endoscopic, and histopathologic severity of ICI-induced colitis is diverse, but colonoscopy together with biopsy is necessary for diagnosis. While a certain proportion of patients with ICI-induced colitis have an intractable clinical course, management guidelines are based on retrospective analyses. Prospective studies are needed to assess the efficacy of various medications, including immunosuppressive regimens. Key Messages: Colonoscopy with biopsy is the gold standard for the diagnosis of ICI-induced colitis. Endoscopists should be aware of the clinical features and pathophysiology of ICI-induced colitis for prompt diagnosis and treatment planning.
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Affiliation(s)
- Shunichi Yanai
- Division of Gastroenterology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
| | - Yosuke Toya
- Division of Gastroenterology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
| | - Tamotsu Sugai
- Department of Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
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18
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Weingarden AR, Rubin SJS, Gubatan J. Immune checkpoint inhibitor-mediated colitis in gastrointestinal malignancies and inflammatory bowel disease. World J Gastrointest Oncol 2021; 13:772-798. [PMID: 34457186 PMCID: PMC8371513 DOI: 10.4251/wjgo.v13.i8.772] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/09/2021] [Accepted: 07/09/2021] [Indexed: 02/06/2023] Open
Abstract
Immune checkpoint inhibitors (ICI) have markedly changed the landscape of cancer therapy. By re-invigorating the immune system against tumors, ICI provide novel therapeutic options for a broad variety of malignancies, including many gastrointestinal (GI) cancers. However, these therapies can also induce autoimmune-like side effects in healthy tissue across the body. One of the most common of these side effects is ICI-mediated colitis and diarrhea (IMC). Here, we review the incidence and risk of IMC in ICI therapy, with a focus on what is known regarding IMC in patients with GI malignancies. We also discuss data available on the use of ICI and risk of IMC in patients with pre-existing inflammatory bowel disease, as these patients may have increased risk of IMC due to their underlying intestinal pathology.
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Affiliation(s)
- Alexa R Weingarden
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Redwood City, CA 94063, United States
| | - Samuel J S Rubin
- Stanford University School of Medicine, Stanford University, Redwood City, CA 94063, United States
| | - John Gubatan
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Redwood City, CA 94063, United States
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