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Immune checkpoint inhibitor–related luminal GI adverse events

Published:September 14, 2019DOI:https://doi.org/10.1016/j.gie.2019.09.009
      The early promising results of the use of immune checkpoint inhibitors in the treatment of selected malignancies has ushered a new era in cancer research and the development of treatment options. With the increasing use of this class of medications, a wide array of adverse events is becoming evident, many of which will be encountered by the gastroenterologist. The second most common adverse event associated with immune checkpoint inhibitors involves the GI tract and includes diarrhea and colitis. These are experienced by up to 50% of patients on these agents. The severity of these events varies greatly and may range from mild to fatal. Therefore, it is important that the gastroenterologist is aware of the spectrum of potential GI adverse events. For this review, we conducted an extensive literature search and compiled all relevant information pertaining to the luminal GI tract. The presentation, approach to the patient with luminal GI adverse reactions, risk stratification, management, challenging populations, endoscopic considerations and findings, and histologic findings are discussed in this review.

      Graphical abstract

      Abbreviations:

      CTCAE (Common Terminology Criteria for Adverse Events), CTLA (cytotoxic T lymphocyte-associated antigen), IBD (inflammatory bowel disease), ICI (immune checkpoint inhibitor), irAE (immunotherapy-related adverse event), NCCN (National Comprehensive Cancer Network), PD (programmed cell death), PD-L (programmed cell death ligand)
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      References

        • Thompson J.A.
        • Schneider B.J.
        • Brahmer J.
        • et al.
        Management of immunotherapy-related toxicities, version 1.2019.
        J Natl Compr Cancer Netw. 2019; 17: 255-289
        • Bertrand A.
        • Kostine M.
        • Barnetche T.
        • et al.
        Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis.
        BMC Med. 2015; 13: 211
        • Ascierto P.A.
        • Vecchio M.D.
        • Robert C.
        Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial.
        Lancet Oncol. 2017; 18: 611-622
        • Wang P.F.
        • Chen Y.
        • Song S.Y.
        Immune-related adverse events associated with anti-PD-1/PD-L1 treatment for malignancies: a meta-analysis.
        Front Pharmacol. 2017; 8: 730-741
        • Wang D.Y.
        • Salem J.E.
        • Cohen J.V.
        Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis.
        JAMA Oncol. 2018; 4: 1721-1728
        • Wolchok J.D.
        • Chiarion-Sileni V.
        • Gonzalez R.
        Overall survival with combined nivolumab and ipilimumab in advanced melanoma.
        N Engl J Med. 2017; 377: 1345-1356
        • Hellmann M.D.
        • Rizvi N.A.
        • Goldman J.W.
        Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study.
        Lancet Oncol. 2017; 18: 31-41
        • Velasco G.D.
        • Je Y.
        • Bossé D.
        Comprehensive meta-analysis of key immune-related adverse events from CTLA-4 and PD-1/PD-L1 inhibitors in cancer patients.
        Cancer Immunol Res. 2017; 5: 312-318
        • Weber J.S.
        • Yang J.C.
        • Atkins M.B.
        • et al.
        Toxicities of immunotherapy for the practitioner.
        J Clin Oncol. 2015; 33: 2092-2099
        • Teulings H.E.
        • Limpens J.
        • Jansen S.N.
        Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis.
        J Clin Oncol. 2015; 33: 773-781
        • 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. 2018; 6: 37-49
        • Kostine M.
        • Rouxel L.
        • Barnetche T.
        • et al.
        Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study.
        Ann Rheum Dis. 2018; 77: 393-398
        • Wang Y.
        • Abu-Sbeih H.
        • Mao E.
        • et al.
        Endoscopic and histologic features of immune checkpoint inhibitor-related colitis.
        Inflamm Bowel Dis. 2018; 24: 1695-1705
        • Weber J.S.
        • Kahler K.C.
        • Hauschild A.
        Management of immune-related adverse events and kinetics of response with ipilimumab.
        J Clin Oncol. 2012; 30: 2691-2697
        • Schadendorf D.
        • Wolchok J.D.
        • Hodi F.S.
        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. 2017; 35: 3807-3814
        • Haanen J.
        • Carbonnel F.
        • Robert C.
        • et al.
        Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2017; 28: iv119-iv142
        • Spain L.
        • Diem S.
        • Larkin J.
        Management of toxicities of immune checkpoint inhibitors.
        Cancer Treat Rev. 2016; 44: 51-60
        • Geukes Foppen M.H.
        • Rozeman E.A.
        • van Wilpe S.
        • et al.
        Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management.
        ESMO Open. 2018; 3e000278
        • Som A.
        • Mandaliya R.
        • Alsaadi D.
        • et al.
        Immune checkpoint inhibitor-induced colitis: a comprehensive review.
        World J Clin Cases. 2019; 7: 405-418
        • Yamauchi R.
        • Araki T.
        • Mitsuyama K.
        • et al.
        The characteristics of nivolumab-induced colitis: an evaluation of three cases and a literature review.
        BMC Gastroenterol. 2018; 18: 135
        • Marin-Acevedo J.A.
        • Chirila R.M.
        • Dronca R.S.
        Immune checkpoint inhibitor toxicities.
        Mayo Clin Proc. 2019; 94: 1321-1329
        • Gupta A.
        • De Felice K.M.
        • Loftus Jr., E.V.
        • et al.
        Systematic review: colitis associated with anti-CTLA-4 therapy.
        Aliment Pharmacol Ther. 2015; 42: 406-417
        • Grover S.
        • Rahma O.E.
        • Hashemi N.
        • et al.
        Gastrointestinal and hepatic toxicities of checkpoint inhibitors: algorithms for management.
        Am Soc Clin Oncol Educ Book. 2018; 38: 13-19
        • Wang D.Y.
        • Ye F.
        • Zhao S.
        Incidence of immune checkpoint inhibitor-related colitis in solid tumor patients: a systematic review and meta-analysis.
        Oncoimmunology. 2017; 6e1344805
        • Abu-Sbeih H.
        • Ali F.S.
        • Luo W.
        • et al.
        Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor-induced colitis.
        J Immunother Cancer. 2018; 6: 95
        • Abu-Sbeih H.
        • Ali F.S.
        • Alsaadi D.
        • et al.
        Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor-induced colitis: a multi-center study.
        J Immunother Cancer. 2018; 6: 142
        • Nishida T.
        • Iijima H.
        • Adachi S.
        Immune checkpoint inhibitor-induced diarrhea/colitis: Endoscopic and pathologic findings.
        World J Gastrointest Pathophysiol. 2019; 10: 17-28
        • Kim K.W.
        • Ramaiya N.H.
        • Krajewski K.M.
        • et al.
        Ipilimumab-associated colitis: CT findings.
        AJR Am J Roentgenol. 2013; 200: W468-W474
        • Barina A.R.
        • Bashir M.R.
        • Howard B.A.
        • et al.
        Isolated recto-sigmoid colitis: a new imaging pattern of ipilimumab-associated colitis.
        Abdom Radiol (NY). 2016; 41: 207-214
        • Weber J.S.
        • Kudchadkar R.R.
        • Yu B.
        • et al.
        Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma.
        J Clin Oncol. 2013; 31: 4311-4318
        • Zitvogel L.
        • Ma Y.
        The microbiome in cancer immunotherapy: diagnostic tools and therapeutic strategies.
        Science. 2018; 359: 1366-1370
        • Gopalakrishnan V.
        • Spencer C.N.
        Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.
        Science. 2018; 359: 97-103
        • Dubin K.
        • Callahan M.K.
        • Ren B.
        • et al.
        Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis.
        Nat Commun. 2016; 7: 10391
        • Derosa L.
        • Hellmann M.D.
        • Spaziano M.
        • et al.
        Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer.
        Ann Oncol. 2018; 29: 1437-1444
        • Wang Y.
        • Wiesnoski D.H.
        • Helmink B.A.
        • et al.
        Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis.
        Nat Med. 2018; 24: 1804-1808
        • Wang Y.
        • Wiesnoski D.H.
        • Helmink B.A.
        • et al.
        Author correction. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis.
        Nat Med. 2019; 25: 188
        • Weber J.
        • Thompson J.A.
        • Hamid O.
        • et al.
        A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma.
        Clin Cancer Res. 2009; 15: 5591-5598
        • Downey S.G.
        • Klapper J.A.
        • Smith F.O.
        • et al.
        Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade.
        Clin Cancer Res. 2007; 13: 6681-6688
        • Weber J.S.
        • Hodi F.S.
        • Wolchok J.D.
        Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma.
        J Clin Oncol. 2017; 35: 785-792
        • Arbour K.C.
        • Mezquita L.
        • Long N.
        • et al.
        impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer.
        J Clin Oncol. 2018; 36: 2872-2878
        • Johnson D.H.
        • Zobniw C.M.
        • Trinh V.A.
        • et al.
        Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis.
        J Immunother Cancer. 2018; 6: 103
        • Bergqvist V.
        • Hertervig E.
        • Gedeon P.
        • et al.
        Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis.
        Cancer Immunol Immunother. 2017; 66: 581-592
        • Mir R.
        • Shaw H.M.
        • Nathan P.D.
        Mycophenolate mofetil alongside high-dose corticosteroids: optimizing the management of combination immune checkpoint inhibitor-induced colitis.
        Melanoma Res. 2019; 29: 102-106
        • Stucci S.
        • Palmirotta R.
        • Passarelli A.
        • et al.
        Immune-related adverse events during anticancer immunotherapy: pathogenesis and management.
        Oncol Lett. 2017; 14: 5671-5680
        • Dalakas M.C.
        Neurological complications of immune checkpoint inhibitors: what happens when you 'take the brakes off' the immune system.
        Ther Adv Neurol Disord. 2018; 11: 1-9
        • Reddy H.G.
        • Schneider B.J.
        • Tai A.W.
        Immune checkpoint inhibitor-associated colitis and hepatitis.
        Clin Transl Gastroenterol. 2018; 9: 180
        • Stroud C.R.
        • Hegde A.
        • Cherry C.
        • et al.
        Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade.
        J Oncol Pharm Pract. 2019; 25: 551-557
        • Buchman A.L.
        Side effects of corticosteroid therapy.
        J Clin Gastroenterol. 2001; 33: 289-294
        • Liu D.
        • Ahmet A.
        • Ward L.
        • et al.
        A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy.
        Allergy Asthma Clin Immunol. 2013; 9: 30
        • James S.F.
        • Chahine E.B.
        • Sucher A.J.
        • et al.
        Shingrix: the new adjuvanted recombinant herpes zoster vaccine.
        Ann Pharmacother. 2018; 52: 673-680
        • Vaughn B.P.
        • Doherty G.A.
        • Gautam S.
        • et al.
        Screening for tuberculosis and hepatitis B prior to the initiation of anti-tumor necrosis therapy.
        Inflamm Bowel Dis. 2012; 18: 1057-1063
        • van der Have M.
        • Oldenburg B.
        • Fidder H.H.
        • et al.
        Optimizing screening for tuberculosis and hepatitis B prior to starting tumor necrosis factor-alpha inhibitors in Crohn's disease.
        Dig Dis Sci. 2014; 59: 554-563
        • Rampton D.S.
        Preventing TB in patients with Crohn's disease needing infliximab or other anti-TNF therapy.
        Gut. 2005; 54: 1360-1362
        • Abdel-Wahab N.
        • Shah M.
        • Lopez-Olivo M.A.
        Use of immune checkpoint inhibitors in the treatment of patients with cancer and preexisting autoimmune disease: a systematic review.
        Ann Intern Med. 2018; 168: 121-130
        • Donia M.
        • Pedersen M.
        • Svane I.M.
        Cancer immunotherapy in patients with preexisting autoimmune disorders.
        Semin Immunopathol. 2017; 39: 333-337
        • Johnson D.B.
        • Sullivan R.J.
        • Ott P.A.
        Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders.
        JAMA Oncol. 2016; 2: 234-240
        • Pollack M.H.
        • Betof A.
        • Dearden H.
        Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma.
        Ann Oncol. 2018; 29: 250-255
        • Carbonnel F.
        • Soularue E.
        • Coutzac C.
        • et al.
        Inflammatory bowel disease and cancer response due to anti-CTLA-4: is it in the flora?.
        Seminars in immunopathology. 2017; 39: 327-331
        • Kähler K.C.
        • Eigentler T.K.
        • Gesierich A.
        • et al.
        Ipilimumab in metastatic melanoma patients with pre-existing autoimmune disorders.
        Cancer Immunol Immunother. 2018; 67: 825-834
        • Chae Y.K.
        • Galvez C.
        • Anker J.F.
        • et al.
        Cancer immunotherapy in a neglected population: the current use and future of T-cell-mediated checkpoint inhibitors in organ transplant patients.
        Cancer Treat Rev. 2018; 63: 116-121
        • Tio M.
        • Rai R.
        • Ezeoke O.M.
        • et al.
        Anti-PD-1/PD-L1 immunotherapy in patients with solid organ transplant, HIV or hepatitis B/C infection.
        Eur J Cancer. 2018; 104: 137-144
        • Kuo J.C.
        • Lilly L.B.
        • Hogg D.
        Immune checkpoint inhibitor therapy in a liver transplant recipient with a rare subtype of melanoma: a case report and literature review.
        Melanoma Res. 2018; 28: 61-64
        • Kittai A.S.
        • Oldham H.
        • Cetnar J.
        Immune checkpoint inhibitors in organ transplant patients.
        J Immunother. 2017; 40: 277-281
        • Jain A.
        • Lipson E.J.
        • Sharfman W.H.
        Colonic ulcerations may predict steroid-refractory course in patients with ipilimumab-mediated enterocolitis.
        World J Gastroenterol. 2017; 23: 2023-2028
        • Gonzalez R.S.
        • Salaria S.N.
        • Bohannon C.D.
        • et al.
        PD-1 inhibitor gastroenterocolitis: case series and appraisal of 'immunomodulatory gastroenterocolitis'.
        Histopathology. 2017; 70: 558-567
        • Cramer P.
        • Bresalier R.S.
        Gastrointestinal and hepatic complications of immune checkpoint inhibitors.
        Curr Gastroenterol Rep. 2017; 19: 3
        • Boike J.
        • Dejulio T.
        Severe esophagitis and gastritis from nivolumab therapy.
        ACG Case Rep J. 2017; 4: e57
        • Onuki T.
        • Morita E.
        • Sakamoto N.
        • et al.
        Severe upper gastrointestinal disorders in pembrolizumab-treated non-small cell lung cancer patient.
        Respirol Case Rep. 2018; 6e00334
        • Kobayashi M.
        • Yamaguchi O.
        • Nagata K.
        • et al.
        Acute hemorrhagic gastritis after nivolumab treatment.
        Gastrointest Endosc. 2017; 86: 915-916
        • Smith S.C.L.
        • Zardo D.
        • Cannatelli R.
        • et al.
        Endoscopic findings of checkpoint inhibitor-induced ileitis with use of the latest advanced endoscopic optical diagnosis: near-focus narrow-band imaging.
        VideoGIE. 2019; 4: 133-135
        • Karamchandani D.M.
        • Chetty R.
        Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists' perspective.
        J Clin Pathol. 2018; 71: 665-671