Short Communication

Evaluation of appendectomy as a potential risk factor for immune checkpoint inhibitor-associated enterocolitis

Harvard Medical School, Boston, MA 02115, USA

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Donald F Chute

Department of Vascular Surgery, UMass Memorial Medical Center, Worcester, MA 01605, USA

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Ayo S Falade

Department of Medicine, Mass General Brigham Salem Hospital, Salem, MA 01970, USA

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Crystal M North

Harvard Medical School, Boston, MA 02115, USA

Division of Pulmonology/Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA

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Kerry L Reynolds

Harvard Medical School, Boston, MA 02115, USA

Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA

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Michael L Dougan

*Author for correspondence: Tel.: +1 617 726 3527;

E-mail Address: mldougan@partners.org

https://orcid.org/0000-0001-9266-2009

Harvard Medical School, Boston, MA 02115, USA

Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA

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Published Online:9 Jun 2023https://doi.org/10.2217/imt-2022-0245

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Abstract

Aims: The relationship between appendectomy and immune checkpoint inhibitor (ICI) enterocolitis was explored. Methods: Patients who began ICIs between July 2010 and September 2020 (n = 10,907) were included. The exposure group included patients with evidence of appendectomy prior to ICIs in operative notes (n = 380). The control group included patients with evidence of normal appendix in radiologic reports (n = 3602). ICI enterocolitis was defined as histopathologic evidence of colitis or enteritis attributed to ICIs. The association between appendectomy and ICI enterocolitis was characterized by multivariate logistic regression. Results: 248 patients (6.2%) developed ICI enterocolitis. The odds of ICI enterocolitis were similar among those with prior appendectomy and those without appendectomy (adjusted odds ratio: 0.82; 95% CI: 0.49–1.36; p = 0.449). Conclusion: No association was found between prior appendectomy and ICI enterocolitis.

Plain language summary

Immune checkpoint inhibitors (ICIs) are a form of cancer treatment that ‘unleash the brakes’ on the body's immune system. One common and sometimes serious side effect of this type of drug is gut inflammation. Studies have shown that appendectomy, or surgical removal of the appendix, lowers the risk of inflammatory bowel disease, which is another cause of gut inflammation. This research assessed whether appendectomy reduces the risk of gut inflammation caused by ICIs. Patients on ICIs for cancer with and without prior appendectomy were identified. The rates of gut inflammation caused by ICIs between these two groups were compared and the rates of this side effect were similar. This suggests that appendectomy does not reduce the risk of gut inflammation caused by ICIs.

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References

1. Bagchi S, Yuan R, Engleman EG. Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Annu. Rev. Pathol. Mech. Dis. 16(1), 223–249 (2021). • An informative recent review of immune checkpoint inhibitors (ICIs) in the treatment of cancer.
CASGoogle Scholar
2. Baumeister SH, Freeman GJ, Dranoff G, Sharpe AH. Coinhibitory pathways in immunotherapy for cancer. Annu. Rev. Immunol. 34(1), 539–573 (2016).
Medline CASGoogle Scholar
3. Ramos-Casals M, Brahmer JR, Callahan MK et al. Immune-related adverse events of checkpoint inhibitors. Nat. Rev. Dis. Primer 6(1), 38 (2020). www.nature.com/articles/s41572-020-0160-6 • An excellent review of immune-related adverse events (irAEs).
MedlineGoogle Scholar
4. Pauken KE, Dougan M, Rose NR, Lichtman AH, Sharpe AH. Adverse events following cancer immunotherapy: obstacles and opportunities. Trends Immunol. 40(6), 511–523 (2019).
Medline CASGoogle Scholar
5. Xu C, Chen Y-P, Du X-J et al. Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis. BMJ 363, k4226 (2018). • This meta-analysis includes 36 different phase II and III randomized trials and provides general rates of irAEs with different ICI antibodies.
MedlineGoogle Scholar
6. Wang DY, Salem J-E, Cohen JV et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 4(12), 1721 (2018). • This meta-analysis retrospectively investigates fatal effects caused by ICIs and identifies colitis as the most common fatal adverse effect with certain regimens.
MedlineGoogle Scholar
7. Larkin J, Chiarion-Sileni V, Gonzalez R et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373(1), 23–34 (2015).
Medline CASGoogle Scholar
8. Khoja L, Day D, Wei-Wu Chen T, Siu LL, Hansen AR. Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review. Ann. Oncol. 28(10), 2377–2385 (2017).
Medline CASGoogle Scholar
9. Xing P, Zhang F, Wang G et al. Incidence rates of immune-related adverse events and their correlation with response in advanced solid tumours treated with NIVO or NIVO + IPI: a systematic review and meta-analysis. J. Immunother. Cancer 7(1), 341 (2019). • This meta-analysis provides detailed incidence rates of different types of irAEs in patients treated with PD-1 and PD-1/CTLA-4 combination therapy.
MedlineGoogle Scholar
10. Beck KE, Blansfield JA, Tran KQ et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte–associated antigen 4. J. Clin. Oncol. 24(15), 2283–2289 (2006).
Medline CASGoogle Scholar
11. Thompson JA, Schneider BJ, Brahmer J et al. Management of Immunotherapy-Related Toxicities, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology. J. Natl Compr. Canc. Netw. 17(3), 255–289 (2019).
Medline CASGoogle Scholar
12. Schadendorf D, Wolchok JD, Hodi FS et al. Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 35(34), 3807–3814 (2017).
Medline CASGoogle Scholar
13. Wang DY, Ye F, Zhao S, Johnson DB. Incidence of immune checkpoint inhibitor-related colitis in solid tumor patients: a systematic review and meta-analysis. OncoImmunology 6(10), e1344805 (2017). • This meta-analysis summarizes rates of all-grade and severe colitis and severe diarrhea with different ICI regimens and identifies that rates are highest with CTLA-4 regimens compared with PD-1/PD-L1 inhibitors.
MedlineGoogle Scholar
14. Hodi FS, O'Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363(8), 711–723 (2010).
Medline CASGoogle Scholar
15. Gupta A, De Felice KM, Loftus EV, Khanna S. Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment. Pharmacol. Ther. 42(4), 406–417 (2015).
Medline CASGoogle Scholar
16. Som A, Mandaliya R, Alsaadi D et al. Immune checkpoint inhibitor-induced colitis: a comprehensive review. World J. Clin. Cases 7(4), 405–418 (2019).
MedlineGoogle Scholar
17. Tang L, Wang J, Lin N et al. Immune checkpoint inhibitor-associated colitis: from mechanism to management. Front. Immunol. 12, 800879 (2021).
Medline CASGoogle Scholar
18. Wang Y, Abu-Sbeih H, Mao E et al. Immune-checkpoint inhibitor-induced diarrhea and colitis in patients with advanced malignancies: retrospective review at MD Anderson. J. Immunother. Cancer 6(1), 37 (2018). • This is a single-center study that retrospectively characterized a large cohort of patients with ICI colitis and identified Caucasian ethnicity, melanoma, stage 3 cancer and ipilimumab as predictors of more severe colitis.
MedlineGoogle Scholar
19. Grover S, Dougan M, Tyan K et al. Vitamin D intake is associated with decreased risk of immune checkpoint inhibitor-induced colitis. Cancer 126(16), 3758–3767 (2020).
Medline CASGoogle Scholar
20. Marthey L, Mateus C, Mussini C et al. Cancer immunotherapy with anti-CTLA-4 monoclonal antibodies induces an inflammatory bowel disease. J. Crohns Colitis 10(4), 395–401 (2016).
Medline CASGoogle Scholar
21. Chaput N, Lepage P, Coutzac C et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann. Oncol. 28(6), 1368–1379 (2017).
Medline CASGoogle Scholar
22. Dubin K, Callahan MK, Ren B et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat. Commun. 7(1), 10391 (2016).
Medline CASGoogle Scholar
23. Lozano AX, Chaudhuri AA, Nene A et al. T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma. Nat. Med. 28(2), 353–362 (2022).
Medline CASGoogle Scholar
24. Hayase E, Jenq RR. Role of the intestinal microbiome and microbial-derived metabolites in immune checkpoint blockade immunotherapy of cancer. Genome Med. 13(1), 107 (2021).
MedlineGoogle Scholar
25. Luoma AM, Suo S, Williams HL et al. Molecular pathways of colon inflammation induced by cancer immunotherapy. Cell 182(3), 655–671.e22 (2020). • An interesting study that sought to identify the cellular and molecular pathogenesis of ICI-induced enterocolitis by conducting single-cell analysis and T-cell receptor sequencing of involved immune populations.
Medline CASGoogle Scholar
26. Sasson SC, Slevin SM, Cheung VTF et al. Interferon-gamma-producing CD8+ tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis. Gastroenterology 161(4), 1229–1244.e9 (2021).
Medline CASGoogle Scholar
27. Feuerstein JD, Moss AC, Farraye FA. Ulcerative colitis. Mayo Clin. Proc. 94(7), 1357–1373 (2019).
MedlineGoogle Scholar
28. Andersson RE, Olaison G, Tysk C, Ekbom A. Appendectomy and protection against ulcerative colitis. N. Engl. J. Med. 344(11), 808–814 (2001).
Medline CASGoogle Scholar
29. Harries AD, Baird A, Rhodes J. Non-smoking: a feature of ulcerative colitis. BMJ 284(6317), 706–706 (1982).
Medline CASGoogle Scholar
30. Frisch M, Pedersen BV, Andersson RE. Appendicitis, mesenteric lymphadenitis, and subsequent risk of ulcerative colitis: cohort studies in Sweden and Denmark. BMJ 338(mar09 2), b716–b716 (2009).
MedlineGoogle Scholar
31. Suazo-Zepeda E, Bokern M, Vinke PC, Hiltermann TJN, de Bock GH, Sidorenkov G. Risk factors for adverse events induced by immune checkpoint inhibitors in patients with non-small-cell lung cancer: a systematic review and meta-analysis. Cancer Immunol. Immunother. 70(11), 3069–3080 (2021).
Medline CASGoogle Scholar
32. Sahami S, Kooij IA, Meijer SL, Van den Brink GR, Buskens CJ, te Velde AA. The link between the appendix and ulcerative colitis: clinical relevance and potential immunological mechanisms. Am. J. Gastroenterol. 111(2), 163–169 (2016).
Medline CASGoogle Scholar
33. Mizoguchi A, Mizoguchi E, Chiba C, Bhan AK. Role of appendix in the development of inflammatory bowel disease in TCR-alpha mutant mice. J. Exp. Med. 184(2), 707–715 (1996).
Medline CASGoogle Scholar
34. Cai S, Fan Y, Zhang B et al. Appendectomy is associated with alteration of human gut bacterial and fungal communities. Front. Microbiol. 12, 724980 (2021).
MedlineGoogle Scholar
35. Abu-Sbeih H, Faleck DM, Ricciuti B et al. Immune checkpoint inhibitor therapy in patients with preexisting inflammatory bowel disease. J. Clin. Oncol. 38(6), 576–583 (2020).
Medline CASGoogle Scholar
36. Hone Lopez S, Kats-Ugurlu G, Renken RJ et al. Immune checkpoint inhibitor treatment induces colitis with heavy infiltration of CD8 + T cells and an infiltration pattern that resembles ulcerative colitis. Virchows Arch. 479(6), 1119–1129 (2021).
MedlineGoogle Scholar
37. Addiss DG, Shaffer N, Fowler BS, Tauxe RV. The epidemiology of appendicitis and appendectomy in the United States. Am. J. Epidemiol. 132(5), 910–925 (1990).
Medline CASGoogle Scholar
38. Dougan M, Wang Y, Rubio-Tapia A, Lim JK. AGA Clinical Practice Update on diagnosis and management of immune checkpoint inhibitor colitis and hepatitis: expert review. Gastroenterology 160(4), 1384–1393 (2021).
Medline CASGoogle Scholar

Vol. 15, No. 12

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History

Received 27 September 2022

Accepted 23 May 2023

Published online 9 June 2023

Published in print August 2023

Information

Keywords

Author contributions

N Krasnow, D Chute, K Reynolds and M Dougan were involved in conceptualization and data curation. N Krasnow, C North and M Dougan were involved in data analysis. N Krasnow, D Chute, A Falade, C North, K Reynolds and M Dougan were involved in the interpretation of data. N Krasnow, D Chute, A Falade, C North, K Reynolds and M Dougan were involved in writing and revising the manuscript. M Dougan was responsible for the supervision of this project.

Financial & competing interests disclosure

M Dougan is supported by R01CA177684, R01AI169188-01, National Institutes of Health Mentored Clinical Scientist Development Award 1K08DK114563–01, the Fariborz Maseeh Award for Innovative Medical Education and The Peter and Ann Lambertus Family Foundation. M Dougan has received research funding Eli Lilly; he has received consulting fees from Genentech, ORIC Pharmaceuticals, Partner Therapeutics, SQZ Biotech, AzurRx, Eli Lilly, Mallinckrodt Pharmaceuticals, Aditum, Foghorn Therapeutics, Palleon, Sorriso Pharmaceuticals, Generate Biomedicines, Asher Bio, Neoleukin Therapeutics and Moderna; and he is a member of the Scientific Advisory Board for Veravas and Cerberus Therapeutics. K Reynolds has received consulting fees from Teladoc and Medscape. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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