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A Case of Immunotherapy-Induced Colitis Complicated by Perforation and Treated with Infliximab Postoperatively

A Case of Immunotherapy-Induced Colitis Complicated by Perforation and Treated with Infliximab... Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 9069354, 6 pages https://doi.org/10.1155/2019/9069354 Case Report A Case of Immunotherapy-Induced Colitis Complicated by Perforation and Treated with Infliximab Postoperatively 1 1 1 1 Lukas Delasos , Aakash Desai, Nerea Lopetegui Lia, Nikhila Kethireddy, and Carolyn Ray Department of Medicine, University of Connecticut, Farmington, CT, USA Department of Medical Oncology, Smilow Cancer Hospital at St. Francis, Hartford, CT, USA Correspondence should be addressed to Lukas Delasos; delasos@uchc.edu Received 2 April 2019; Accepted 9 July 2019; Published 22 July 2019 Academic Editor: Jose I. Mayordomo Copyright © 2019 Lukas Delasos et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The advent of checkpoint inhibitor therapy in medical oncology has led to an increase in hospitalizations for immune-related adverse effects. Severe colitis has been reported in approximately 5% of patients treated with cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitors, such as ipilimumab. Standard management for those with severe colitis includes administration of systemic corticosteroids with the reservation of antitumor necrosis factor (anti-TNF) therapy, such as infliximab, if there has been no improvement. Rarely, immunotherapy-induced colitis can become life-threatening and result in bowel perforation requiring surgical intervention. Yet, there are no specific recommendations for medical management following colectomy in these situations. In cases of severe colitis from Crohn’s disease, postoperative treatment with infliximab has been found to be safe when administered shortly after intestinal resection. However, there remains limited data to support administration of infliximab following bowel perforation due to immunotherapy-induced colitis. Our case illustrates management of a severe adverse reaction to checkpoint inhibitor therapy and the need to further evaluate the role of infliximab postoperatively in patients who develop colitis complicated by bowel perforation. 1. Introduction attention directed towards the treatment of melanoma with immunotherapy based on promising outcomes observed in clinical trials. Ipilimumab, a fully human monoclonal anti- Favorable objective response rates and progression free sur- body (IgG1) that blocks CTLA-4, has not only shown vival have made the use of immune checkpoint inhibitors more widespread throughout the past decade for the treat- improved survivability when combined with other therapeu- tic agents, including vaccines, but also as monotherapy for ment of both solid and hematological malignancies. Most patients with metastatic melanoma [2, 3]. Additionally, notable are monoclonal antibodies directed against cytotoxic patients with advanced treatment-refractory melanoma on T-lymphocyte-associated antigen-4 (CTLA-4), programmed maintenance nivolumab, a PD-1 immune checkpoint inhibi- cell death 1 (PD-1) receptor, and programmed cell death ligands (i.e., PD-L1 and PD-L2) [1]. By blocking the interac- tor, have demonstrated similar objective response rates and long-term safety as compared to matching patient popula- tion between CTLA-4 with B7 costimulatory molecules tions with different solid tumor types [4]. (CD80/86) or PD-1 with PD-L1/PD-L2, the normally associ- With the advent of checkpoint inhibitor therapy in ated T cell-suppressive response is prevented thus allowing medical oncology, there has been an increase in the num- for T cell-mediated destruction of tumor cells [1]. Identifying these mechanisms of T cell regulatory function has led to the ber of patients hospitalized with immune-related adverse effects. Retrospective analysis of immune-related adverse largely adopted idea that the immune system can overcome events leading to emergency department visits has demon- the inhibitory effects of cancer cells with therapy directed strated multiple organs affected, including gastrointestinal, against these signals. In fact, there has been widespread 2 Case Reports in Oncological Medicine with the development of large volume hematochezia accom- pulmonary, cardiac, dermatologic, hepatic, pancreatic, and renal involvement [5]. Of these adverse effects, gastrointesti- panied by severe right upper quadrant abdominal pain. nal toxicities have remained amongst the highest reported The patient immediately returned to the hospital at the with complaints of diarrhea being most frequent [6]. The direction of his oncologist. Stool studies were repeated and frequency of colitis in medical literature, for example, has again found to be negative. Computed tomography (CT) ranged from 8% to 27% with the incidence of diarrhea being imaging of the abdomen and pelvis revealed moderate as high as 54% in patients treated with CTLA-4 inhibitors [6]. circumferential thickening of the large bowel wall suggestive Those receiving a combination of CTLA-4 inhibitors and of pancolitis (Figures 1(a) and 1(b)). More importantly, there was evidence of pneumoperitoneum with a moderate amount PD-1 inhibitors are at even greater risk for colitis as well as developing more severe symptoms (i.e., grade 3/4 colitis) of free air in the upper abdomen and a focal disruption noted [7]. Standard management for those with severe colitis in the anterior wall of the mid transverse colon which was felt includes administration of systemic corticosteroids with the to be the site of perforation (Figure 1(c)). Of note, the patient reservation of antitumor necrosis factor (anti-TNF) biotech- was also found to have had a significant response to immuno- nical drugs, such as infliximab, if there has been no improve- therapy with a decrease in size of his liver metastases by up to ment [8]. Rarely, colitis can result in bowel perforation 70%. An emergent laparotomy was performed with extended requiring surgical intervention as described by Marthey right hemicolectomy and end ileostomy after perforations et al. in which 13% of patients who developed anti-CTLA-4 were identified along the cecum and transverse colon. enterocolitis underwent colectomy for perforation [9]. Inter- Postoperatively, he continued on intravenous steroids. However, on the first postoperative day, the patient had a estingly, fatal immune checkpoint inhibitor toxicities are most commonly due to colitis (70%) with anti-CTLA-4 large bloody bowel movement without evidence of blood in inhibitors as compared to pneumonitis (35%) and hepatitis the ileostomy. His hematochezia continued into the second (25%) with anti-PD-1/PD-L1 inhibitors [10]. Here, we postoperative day. This raised concern for an increased risk describe a case of severe immunotherapy-induced colitis of recurrent perforation given the patient’s poor response to standard therapy and severe pancolitis evident on his pre- complicated by bowel perforation requiring emergent colect- omy and subsequent treatment with infliximab after failed surgical CT scan. After a thorough discussion with both the steroid therapy. surgical and gastroenterology teams, it was determined that the benefit of treating his ongoing colitis with infliximab out- weighed the risks of adverse effects associated with this med- 2. Case Presentation ication while in the postoperative state. He was administered A 72-year-old male was found to have advanced melanoma one dose of infliximab 5 mg/kg intravenously with continued metastatic to the liver and lung. Results from his biopsy were corticosteroid therapy. Over the next several days, the negative for BRAF mutation. Thus, the patient was eligible patient’s symptoms improved without further episodes of rec- for first-line immunotherapy and began treatment with ipili- tal bleeding. Endoscopic evaluation was deferred by gastroen- terology while the patient was hospitalized given evidence of mumab and nivolumab. The patient began his first cycle of therapy with a single clinical improvement and the high risk of iatrogenic bowel dose of ipilimumab, 290 mg, and nivolumab, 97 mg. Two perforation. Shortly afterward, he was started on a clear liquid weeks later, prior to any additional immunotherapy, he devel- diet and gradually advanced to a low fiber diet with adequate oped hematochezia. Given concerns for grade 3 drug-induced function of his ileostomy. The patient’s condition continued to improve, and he was eventually discharged to a rehabili- colitis, he was hospitalized and started on intravenous meth- ylprednisolone 80 mg daily in addition to maintenance intra- tation facility with instructions to complete a slow taper of venous fluids. Stool studies were negative for Clostridium oral prednisone. Due to the severity of his immune check- difficile toxin, Salmonella, Shigella, Shiga toxins 1 and 2,Cam- point inhibitor toxicities, the patient was no longer a candi- pylobacter, Escherichia coli O157:H7, ova, and parasites. date for further immunotherapy. His performance status remained too poor to initiate second-line therapy, and surgi- Endoscopic evaluation and intervention were deferred given the improvement of his symptoms while on steroids. The cal restoration of intestinal continuity was never performed. patient was then transitioned to oral prednisone starting at 40 mg with a plan to taper over the next several weeks. 3. Discussion Following his discharge, it was felt that he would be unable to tolerate continuation of CTLA-4 inhibitor immu- Immunotherapy-induced diarrhea and colitis remain the notherapy with ipilimumab due to the increased risk of most frequent, serious, and potentially life-threatening recurrent colitis. He was planned to resume PD-1 inhibitor adverse reactions to checkpoint inhibitor therapy. Grades of immunotherapy with nivolumab every three weeks. However, diarrhea and colitis are thoroughly described within the prior to initiating monotherapy with nivolumab, he suddenly Common Terminology Criteria for Adverse Events (CTCAE developed four episodes of diarrhea with associated nausea v. 5.0). Anti-CTLA-4 agents have demonstrated a higher risk and abdominal pain classified as a grade 2 toxicity. He was of inducing grade 3 or 4 diarrhea and colitis with rates up to administered a one-time dose of intravenous methylpredniso- 8.7% when used alone and as high as 13% when used in com- lone 100 mg as an outpatient and instructed to increase his bination with anti-PD-1 agents [7]. However, anti-PD-1 home dose of prednisone to 80 mg while holding the next agents such as nivolumab have been associated with a signif- cycle of nivolumab. Despite this, his symptoms progressed icantly lower incidence of both all-grade (2.9%) and grade 3 Case Reports in Oncological Medicine 3 (a) (b) Site of perforation (c) Figure 1 or 4 (1.8%) diarrhea and colitis when used as monotherapy based on the CTCAE grading system as noted above [7]. Khoja et al. described patterns and incidence of (Figure 2) [6, 12, 13]. For patients with grade 1 toxicities, immune-related adverse events based on cancer type and immunotherapy may be temporarily held and resumed if immunotherapy class in their large meta-analysis review. symptoms do not progress [6]. Toxicities of grade 2 or higher Within their findings, they describe a higher incidence of severity require diagnostic workup including bloodwork grade 3/4 adverse events when comparing anti-CTLA-4 (complete blood count (CBC), comprehensive metabolic inhibitors to anti-PD-1 inhibitors (31% versus 10%) [11]. panel (CMP), thyroid-stimulating hormone (TSH), erythro- cyte sedimentation rate (ESR), C-reactive protein (CRP), Specifically, anti-CTLA-4 inhibitors have been identified as more frequent offenders for all-grade colitis, hypophysitis, and cytomegalovirus PCR); stool studies (cultures, Clostrid- and dermatitis whereas anti-PD-1 inhibitors were more com- ium difficile toxin, ova and parasites, lactoferrin, and calpro- monly associated in cases of pneumonitis, hypothyroidism, tectin); and consideration for both computed tomography arthralgia, and vitiligo [11]. In addition, they found that cases imaging as well as endoscopic evaluation by gastroenterology of melanoma treated with anti-PD-1 monoclonal antibodies [6, 13]. If grade 2 symptoms persist, providers should were associated with a higher frequency of gastrointestinal consider administering corticosteroid therapy. Higher grade and dermatological adverse effects as compared to other toxicities usually require treatment with systemic corticoste- tumor types, namely non-small cell lung cancer and renal cell roids at an initial dose of 1-2 mg/kg/day of prednisone or carcinoma [11]. equivalent steroid, discontinuation of CTLA-4 inhibitors, Regarding management, the National Comprehensive and holding of PD-1 inhibitors until symptoms resolve Cancer Network (NCCN), American Society of Clinical to a grade 1 or less [6, 13]. Anti-TNF agents (i.e., inflixi- Oncology (ASCO), and Society for Immunotherapy of Can- mab, vedolizumab, and adalimumab) are usually reserved cer (SITC) all recommend treating gastrointestinal toxicities for cases refractory to management with corticosteroids. 4 Case Reports in Oncological Medicine Symptom management: hydration, Consider holding immunotherapy but may CTCAE grade 1 toxicities loperamide, diphenoxylate/atropine continue if symptoms are well controlled Start systemic Labs: CBC, CMP, Consider CT Stool: cultures, corticosteroids: Consider resuming CTCAE grade 2 TSH, ESR, CRP, imaging and/or C. diff toxin, O&P, 1 mg/kg/day immunotherapy if toxicities lactoferrin, endoscopic CMV prednisone or symptoms resolve calprotectin evaluation equivalent steroid Grade 3: Consideration for Grade 3: consider Complete Consider inpatient discontinue CTLA-4 biologic therapy resuming PD-1 CTCAE grade 3 and diagnostic workup care with systemic inhibitor therapy (i.e., infliximab) if inhibitors if grade 4 toxicities as outlined above corticosteroids: 1–2 Grade 4: refractory to symptoms resolve for grade 2 toxicity mg/kg/day discontinue further steroids to ≤ CTCAE grade 1 immunotherapy Figure 2: Recommended workflow for gastrointestinal toxicities. Abbreviations: CBC: complete blood count; CMP: complete metabolic panel; TSH: thyroid-stimulating hormone; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; C. diff: Clostridium difficile; O&P: ova and parasites; CT: computed tomography; CTLA-4: cytotoxic T-lymphocyte antigen-4; PD-1: programmed death-1. with the severity of diarrhea, are likely to require the use The use of biologic agents to treat refractory cases of immunotherapy-induced colitis has proven to be effective of biologic agents for remission [18]. This evidence argues at achieving remission. One prospective study showed rapid for the necessity of early endoscopic evaluation and the clinical improvement in four out of five patients treated with practice of a top-down approach in the management of one dose of infliximab after failing standard therapy [14]. immunotherapy-induced colitis. Retrospective analyses demonstrate statistically significant The association between CTLA-4 checkpoint inhibition improvement in time to symptom resolution as well as and immune-mediated diseases has been described outside shorter duration of steroid therapy in patients treated with of the spectrum of oncology and immunotherapy. Heterozy- infliximab and corticosteroids as opposed to those treated gous mutations in the CTLA-4 protein-encoding gene, with corticosteroids alone [15]. In cases refractory to inflix- CTLA4, causes hyperactivation of effector T cells in addition imab, NCCN guidelines recommend consideration of vedo- to loss of circulating B cells with an increase and accumula- lizumab which has shown favorable outcomes and a good tion of CD21 B cells in nonlymphoid organs [8]. Zeissig safety profile with significant clinical (86%), endoscopic et al. identified in patients affected by early-onset Crohn’s (54%), and histological (29%) remission rates [16]. Because disease a novel missense mutation in CTLA4 resulting in of these promising findings, there is now a motion towards abnormal protein folding and structural stability that subse- earlier treatment with biotechnical agents based on endo- quently leads to severe systemic autoimmunity [19]. In scopic evaluation. Endoscopically visible ulcerations may addition to inflammatory bowel diseases, other immune- be a surrogate marker for steroid-refractory disease as sug- mediated inflammatory diseases such as rheumatoid arthri- tis, ankylosing spondylitis, and psoriasis are known to share gested by Wang and colleagues [17]. Usual histological features of acute colitis secondary to anti-CTLA-4 monoclo- a common pathological pathway involving an inappropriate nal antibodies include neutrophilic infiltration of the lamina release of inflammatory cytokines, particularly tumor necro- propria and crypt abscess formation [9]. Patients with sis factor (TNF) [20]. Important to note, Coutzac and col- more severe endoscopic findings such as numerous ulcera- leagues analyzed TNF-alpha concentrations within colonic tions and/or pancolitis, while not necessarily correlating biopsies collected prior to steroid treatment in cases of Case Reports in Oncological Medicine 5 for management of immune-mediated toxicities. Therefore, immunotherapy-induced colitis and found significantly higher values of TNF-alpha within the mucosa of the biopsies it is necessary to further evaluate the role of infliximab collected from anti-CTLA-4-induced colitis than anti-PD-1- and other biotechnical agents within this subset group of induced colitis [21]. TNF helps regulate multiple immune patients who undergo emergent surgical intervention for cell functions such as proliferation, differentiation, and apo- immunotherapy-induced colitis and who are at high risk ptosis and is produced by various cell types including macro- for further complications related to the severity of their phages, NK cells, and T lymphocytes [20]. The dominant role toxicity. Furthermore, given the compelling results from played by TNF in immune-mediated inflammatory diseases small studies done to date and the more pervasive use of explains why biologic agents targeted against TNF have been immunotherapy in the field of oncology, it is feasible to so effective in the management of these disorders [22]. For design larger and more controlled studies that assess toxic- ities and clinical outcomes in patients who initially receive example, adalimumab, which was first approved for the treat- ment of rheumatoid arthritis, has proven efficacious in a wide immunomodulator therapy versus systemic steroids for the range of other autoimmune disorders attributable to the treatment of immune-mediated adverse effects. shared pathogenesis of these diseases [23]. Inhibition of CTLA-4 by target-specific monoclonal antibodies such as Conflicts of Interest tremilimumab, ticilimumab, and ipilimumab are believed to result in acquired autoimmune disease via these biological The authors declare that there is no conflict of interest mechanisms. Similarities between the pathophysiology of regarding the publication of this paper. both inherited and acquired inflammatory bowel disease help explain why anti-TNF agents are effective in treating immunotherapy-induced colitis. However, caution must be References taken when considering these agents given their potential [1] I. Mellman, G. Coukos, and G. Dranoff, “Cancer immunother- safety concerns including infections, immunogenicity, lym- apy comes of age,” Nature, vol. 480, no. 7378, pp. 480–489, phomas, cardiac failure, and hepatotoxicity observed with long-term therapy [24]. [2] “Improved survival with ipilimumab in patients with metasta- Although there is adequate data supporting the use of tic melanoma,” The New England Journal of Medicine, vol. 363, anti-TNF agents in a wide variety of autoimmune disorders, no. 13, pp. 1290–1290, 2010. there is little evidence on their efficacy and safety following [3] L. H. Camacho, “CTLA-4 blockade with ipilimumab: biology, surgical intervention for severe immunotherapy-induced safety, efficacy, and future considerations,” Cancer Medicine, colitis. 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Thein et al., “Adverse effects of recurrence in patients with Crohn’s disease who had under- immune checkpoint therapy in cancer patients visiting the gone intestinal resection for their disease when treated with emergency department of a comprehensive cancer center,” infliximab (52.6% recurrence rate) as compared to those Annals of Emergency Medicine, vol. 73, no. 1, pp. 79–87, 2019. without infliximab therapy (94.7% recurrence rate) [25]. This [6] J. R. Brahmer, C. Lacchetti, B. J. Schneider et al., “Management of immune-related adverse events in patients treated with study included 19 patients treated with intravenous inflixi- immune checkpoint inhibitor therapy: American Society of mab 5 mg/kg immediately after surgery and on postoperative Clinical Oncology clinical practice guideline,” Journal of Clin- weeks 2, 4, and 6, which was then followed by continued ical Oncology, vol. 36, no. 17, pp. 1714–1768, 2018. therapy every 8 weeks for the next 2 years [25]. An additional [7] R. 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Mussini et al., “Cancer immuno- there were no observable adverse events related to therapy therapy with anti-CTLA-4 monoclonal antibodies induces an within this study. inflammatory bowel disease,” Journal of Crohns and Colitis, Our case represents a severe adverse reaction to check- vol. 10, no. 4, pp. 395–401, 2016. point inhibitor therapy in which severe colitis refractory to [10] D. Y. Wang, J.-E. Salem, J. V. Cohen et al., “Fatal toxic effects standard therapy with systemic corticosteroids was compli- associated with immune checkpoint inhibitors,” JAMA Oncol- cated by bowel perforation. We also illustrate the efficacy of ogy, vol. 4, no. 12, pp. 1721–1728, 2018. postsurgical treatment with infliximab in a patient with pan- [11] L. Khoja, D. Day, T. Wei-Wu Chen, L. L. Siu, and A. R. colitis at high risk for recurrent perforation. As the field of Hansen, “Tumour- and class-specific patterns of immune- immunotherapy continues to evolve, so will the guidelines related adverse events of immune checkpoint inhibitors: a 6 Case Reports in Oncological Medicine systematic review,” Annals of Oncology, vol. 28, no. 10, pp. 2377–2385, 2017. [12] I. Puzanov, A. Diab, K. Abdallah et al., “Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) toxicity management working group,” Journal for Immunotherapy of Cancer, vol. 5, no. 1, p. 95, 2017. [13] J. A. Thompson, B. J. Schneider, J. Brahmer et al., “Manage- ment of immunotherapy-related toxicities (immune check- point inhibitor-related toxicities) version 2.2018,” NCCN, 2018, August 2018, https://www.nccn.org/professionals/ physician_gls/pdf/immunotherapy.pdf. [14] R. L. Johnston, J. Lutzky, A. Chodhry, and J. S. 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Rozeman, S. van Wilpe et al., “Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management,” ESMO Open, vol. 3, no. 1, 2018. [19] S. Zeissig, B.-S. Petersen, M. Tomczak et al., “Early-onset Crohn’s disease and autoimmunity associated with a variant in CTLA-4,” Gut, vol. 64, no. 12, pp. 1889–1897, 2015. [20] C. Blandizzi, P. Gionchetti, A. Armuzzi et al., “The role of tumour necrosis factor in the pathogenesis of immune- mediated diseases,” International Journal of Immunopathology and Pharmacology, vol. 27, Supplement 1, pp. 1–10, 2014. [21] C. Coutzac, J. Adam, E. Soularue et al., “Colon immune-related adverse events: anti-CTLA-4 and anti-PD-1 blockade induce distinct immunopathological entities,” Journal of Crohn’s and Colitis, vol. 11, no. 10, pp. 1238–1246, 2017. [22] A. Armuzzi, P. Lionetti, C. Blandizzi et al., “Anti-TNF agents as therapeutic choice in immune-mediated inflammatory diseases: focus on adalimumab,” International Journal of Immunopathology and Pharmacology, vol. 27, pp. 11–32, 2014. [23] G. Lapadula, A. Marchesoni, A. Armuzzi et al., “Adalimumab in the treatment of immune-mediated diseases,” International Journal of Immunopathology and Pharmacology, vol. 27, pp. 33–48, 2014. [24] R. Caviglia, I. Boškoski, and M. Cicala, “Long-term treatment with infliximab in inflammatory bowel disease: safety and tol- erability issues,” Expert Opinion on Drug Safety, vol. 7, no. 5, pp. 617–632, 2008. [25] K. Fukushima, A. Sugita, K. Futami et al., “Postoperative ther- apy with infliximab for Crohn’s disease: a 2-year prospective randomized multicenter study in Japan,” Surgery Today, vol. 48, no. 6, pp. 584–590, 2018. 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A Case of Immunotherapy-Induced Colitis Complicated by Perforation and Treated with Infliximab Postoperatively

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Abstract

Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 9069354, 6 pages https://doi.org/10.1155/2019/9069354 Case Report A Case of Immunotherapy-Induced Colitis Complicated by Perforation and Treated with Infliximab Postoperatively 1 1 1 1 Lukas Delasos , Aakash Desai, Nerea Lopetegui Lia, Nikhila Kethireddy, and Carolyn Ray Department of Medicine, University of Connecticut, Farmington, CT, USA Department of Medical Oncology, Smilow Cancer Hospital at St. Francis, Hartford, CT, USA Correspondence should be addressed to Lukas Delasos; delasos@uchc.edu Received 2 April 2019; Accepted 9 July 2019; Published 22 July 2019 Academic Editor: Jose I. Mayordomo Copyright © 2019 Lukas Delasos et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The advent of checkpoint inhibitor therapy in medical oncology has led to an increase in hospitalizations for immune-related adverse effects. Severe colitis has been reported in approximately 5% of patients treated with cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitors, such as ipilimumab. Standard management for those with severe colitis includes administration of systemic corticosteroids with the reservation of antitumor necrosis factor (anti-TNF) therapy, such as infliximab, if there has been no improvement. Rarely, immunotherapy-induced colitis can become life-threatening and result in bowel perforation requiring surgical intervention. Yet, there are no specific recommendations for medical management following colectomy in these situations. In cases of severe colitis from Crohn’s disease, postoperative treatment with infliximab has been found to be safe when administered shortly after intestinal resection. However, there remains limited data to support administration of infliximab following bowel perforation due to immunotherapy-induced colitis. Our case illustrates management of a severe adverse reaction to checkpoint inhibitor therapy and the need to further evaluate the role of infliximab postoperatively in patients who develop colitis complicated by bowel perforation. 1. Introduction attention directed towards the treatment of melanoma with immunotherapy based on promising outcomes observed in clinical trials. Ipilimumab, a fully human monoclonal anti- Favorable objective response rates and progression free sur- body (IgG1) that blocks CTLA-4, has not only shown vival have made the use of immune checkpoint inhibitors more widespread throughout the past decade for the treat- improved survivability when combined with other therapeu- tic agents, including vaccines, but also as monotherapy for ment of both solid and hematological malignancies. Most patients with metastatic melanoma [2, 3]. Additionally, notable are monoclonal antibodies directed against cytotoxic patients with advanced treatment-refractory melanoma on T-lymphocyte-associated antigen-4 (CTLA-4), programmed maintenance nivolumab, a PD-1 immune checkpoint inhibi- cell death 1 (PD-1) receptor, and programmed cell death ligands (i.e., PD-L1 and PD-L2) [1]. By blocking the interac- tor, have demonstrated similar objective response rates and long-term safety as compared to matching patient popula- tion between CTLA-4 with B7 costimulatory molecules tions with different solid tumor types [4]. (CD80/86) or PD-1 with PD-L1/PD-L2, the normally associ- With the advent of checkpoint inhibitor therapy in ated T cell-suppressive response is prevented thus allowing medical oncology, there has been an increase in the num- for T cell-mediated destruction of tumor cells [1]. Identifying these mechanisms of T cell regulatory function has led to the ber of patients hospitalized with immune-related adverse effects. Retrospective analysis of immune-related adverse largely adopted idea that the immune system can overcome events leading to emergency department visits has demon- the inhibitory effects of cancer cells with therapy directed strated multiple organs affected, including gastrointestinal, against these signals. In fact, there has been widespread 2 Case Reports in Oncological Medicine with the development of large volume hematochezia accom- pulmonary, cardiac, dermatologic, hepatic, pancreatic, and renal involvement [5]. Of these adverse effects, gastrointesti- panied by severe right upper quadrant abdominal pain. nal toxicities have remained amongst the highest reported The patient immediately returned to the hospital at the with complaints of diarrhea being most frequent [6]. The direction of his oncologist. Stool studies were repeated and frequency of colitis in medical literature, for example, has again found to be negative. Computed tomography (CT) ranged from 8% to 27% with the incidence of diarrhea being imaging of the abdomen and pelvis revealed moderate as high as 54% in patients treated with CTLA-4 inhibitors [6]. circumferential thickening of the large bowel wall suggestive Those receiving a combination of CTLA-4 inhibitors and of pancolitis (Figures 1(a) and 1(b)). More importantly, there was evidence of pneumoperitoneum with a moderate amount PD-1 inhibitors are at even greater risk for colitis as well as developing more severe symptoms (i.e., grade 3/4 colitis) of free air in the upper abdomen and a focal disruption noted [7]. Standard management for those with severe colitis in the anterior wall of the mid transverse colon which was felt includes administration of systemic corticosteroids with the to be the site of perforation (Figure 1(c)). Of note, the patient reservation of antitumor necrosis factor (anti-TNF) biotech- was also found to have had a significant response to immuno- nical drugs, such as infliximab, if there has been no improve- therapy with a decrease in size of his liver metastases by up to ment [8]. Rarely, colitis can result in bowel perforation 70%. An emergent laparotomy was performed with extended requiring surgical intervention as described by Marthey right hemicolectomy and end ileostomy after perforations et al. in which 13% of patients who developed anti-CTLA-4 were identified along the cecum and transverse colon. enterocolitis underwent colectomy for perforation [9]. Inter- Postoperatively, he continued on intravenous steroids. However, on the first postoperative day, the patient had a estingly, fatal immune checkpoint inhibitor toxicities are most commonly due to colitis (70%) with anti-CTLA-4 large bloody bowel movement without evidence of blood in inhibitors as compared to pneumonitis (35%) and hepatitis the ileostomy. His hematochezia continued into the second (25%) with anti-PD-1/PD-L1 inhibitors [10]. Here, we postoperative day. This raised concern for an increased risk describe a case of severe immunotherapy-induced colitis of recurrent perforation given the patient’s poor response to standard therapy and severe pancolitis evident on his pre- complicated by bowel perforation requiring emergent colect- omy and subsequent treatment with infliximab after failed surgical CT scan. After a thorough discussion with both the steroid therapy. surgical and gastroenterology teams, it was determined that the benefit of treating his ongoing colitis with infliximab out- weighed the risks of adverse effects associated with this med- 2. Case Presentation ication while in the postoperative state. He was administered A 72-year-old male was found to have advanced melanoma one dose of infliximab 5 mg/kg intravenously with continued metastatic to the liver and lung. Results from his biopsy were corticosteroid therapy. Over the next several days, the negative for BRAF mutation. Thus, the patient was eligible patient’s symptoms improved without further episodes of rec- for first-line immunotherapy and began treatment with ipili- tal bleeding. Endoscopic evaluation was deferred by gastroen- terology while the patient was hospitalized given evidence of mumab and nivolumab. The patient began his first cycle of therapy with a single clinical improvement and the high risk of iatrogenic bowel dose of ipilimumab, 290 mg, and nivolumab, 97 mg. Two perforation. Shortly afterward, he was started on a clear liquid weeks later, prior to any additional immunotherapy, he devel- diet and gradually advanced to a low fiber diet with adequate oped hematochezia. Given concerns for grade 3 drug-induced function of his ileostomy. The patient’s condition continued to improve, and he was eventually discharged to a rehabili- colitis, he was hospitalized and started on intravenous meth- ylprednisolone 80 mg daily in addition to maintenance intra- tation facility with instructions to complete a slow taper of venous fluids. Stool studies were negative for Clostridium oral prednisone. Due to the severity of his immune check- difficile toxin, Salmonella, Shigella, Shiga toxins 1 and 2,Cam- point inhibitor toxicities, the patient was no longer a candi- pylobacter, Escherichia coli O157:H7, ova, and parasites. date for further immunotherapy. His performance status remained too poor to initiate second-line therapy, and surgi- Endoscopic evaluation and intervention were deferred given the improvement of his symptoms while on steroids. The cal restoration of intestinal continuity was never performed. patient was then transitioned to oral prednisone starting at 40 mg with a plan to taper over the next several weeks. 3. Discussion Following his discharge, it was felt that he would be unable to tolerate continuation of CTLA-4 inhibitor immu- Immunotherapy-induced diarrhea and colitis remain the notherapy with ipilimumab due to the increased risk of most frequent, serious, and potentially life-threatening recurrent colitis. He was planned to resume PD-1 inhibitor adverse reactions to checkpoint inhibitor therapy. Grades of immunotherapy with nivolumab every three weeks. However, diarrhea and colitis are thoroughly described within the prior to initiating monotherapy with nivolumab, he suddenly Common Terminology Criteria for Adverse Events (CTCAE developed four episodes of diarrhea with associated nausea v. 5.0). Anti-CTLA-4 agents have demonstrated a higher risk and abdominal pain classified as a grade 2 toxicity. He was of inducing grade 3 or 4 diarrhea and colitis with rates up to administered a one-time dose of intravenous methylpredniso- 8.7% when used alone and as high as 13% when used in com- lone 100 mg as an outpatient and instructed to increase his bination with anti-PD-1 agents [7]. However, anti-PD-1 home dose of prednisone to 80 mg while holding the next agents such as nivolumab have been associated with a signif- cycle of nivolumab. Despite this, his symptoms progressed icantly lower incidence of both all-grade (2.9%) and grade 3 Case Reports in Oncological Medicine 3 (a) (b) Site of perforation (c) Figure 1 or 4 (1.8%) diarrhea and colitis when used as monotherapy based on the CTCAE grading system as noted above [7]. Khoja et al. described patterns and incidence of (Figure 2) [6, 12, 13]. For patients with grade 1 toxicities, immune-related adverse events based on cancer type and immunotherapy may be temporarily held and resumed if immunotherapy class in their large meta-analysis review. symptoms do not progress [6]. Toxicities of grade 2 or higher Within their findings, they describe a higher incidence of severity require diagnostic workup including bloodwork grade 3/4 adverse events when comparing anti-CTLA-4 (complete blood count (CBC), comprehensive metabolic inhibitors to anti-PD-1 inhibitors (31% versus 10%) [11]. panel (CMP), thyroid-stimulating hormone (TSH), erythro- cyte sedimentation rate (ESR), C-reactive protein (CRP), Specifically, anti-CTLA-4 inhibitors have been identified as more frequent offenders for all-grade colitis, hypophysitis, and cytomegalovirus PCR); stool studies (cultures, Clostrid- and dermatitis whereas anti-PD-1 inhibitors were more com- ium difficile toxin, ova and parasites, lactoferrin, and calpro- monly associated in cases of pneumonitis, hypothyroidism, tectin); and consideration for both computed tomography arthralgia, and vitiligo [11]. In addition, they found that cases imaging as well as endoscopic evaluation by gastroenterology of melanoma treated with anti-PD-1 monoclonal antibodies [6, 13]. If grade 2 symptoms persist, providers should were associated with a higher frequency of gastrointestinal consider administering corticosteroid therapy. Higher grade and dermatological adverse effects as compared to other toxicities usually require treatment with systemic corticoste- tumor types, namely non-small cell lung cancer and renal cell roids at an initial dose of 1-2 mg/kg/day of prednisone or carcinoma [11]. equivalent steroid, discontinuation of CTLA-4 inhibitors, Regarding management, the National Comprehensive and holding of PD-1 inhibitors until symptoms resolve Cancer Network (NCCN), American Society of Clinical to a grade 1 or less [6, 13]. Anti-TNF agents (i.e., inflixi- Oncology (ASCO), and Society for Immunotherapy of Can- mab, vedolizumab, and adalimumab) are usually reserved cer (SITC) all recommend treating gastrointestinal toxicities for cases refractory to management with corticosteroids. 4 Case Reports in Oncological Medicine Symptom management: hydration, Consider holding immunotherapy but may CTCAE grade 1 toxicities loperamide, diphenoxylate/atropine continue if symptoms are well controlled Start systemic Labs: CBC, CMP, Consider CT Stool: cultures, corticosteroids: Consider resuming CTCAE grade 2 TSH, ESR, CRP, imaging and/or C. diff toxin, O&P, 1 mg/kg/day immunotherapy if toxicities lactoferrin, endoscopic CMV prednisone or symptoms resolve calprotectin evaluation equivalent steroid Grade 3: Consideration for Grade 3: consider Complete Consider inpatient discontinue CTLA-4 biologic therapy resuming PD-1 CTCAE grade 3 and diagnostic workup care with systemic inhibitor therapy (i.e., infliximab) if inhibitors if grade 4 toxicities as outlined above corticosteroids: 1–2 Grade 4: refractory to symptoms resolve for grade 2 toxicity mg/kg/day discontinue further steroids to ≤ CTCAE grade 1 immunotherapy Figure 2: Recommended workflow for gastrointestinal toxicities. Abbreviations: CBC: complete blood count; CMP: complete metabolic panel; TSH: thyroid-stimulating hormone; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; C. diff: Clostridium difficile; O&P: ova and parasites; CT: computed tomography; CTLA-4: cytotoxic T-lymphocyte antigen-4; PD-1: programmed death-1. with the severity of diarrhea, are likely to require the use The use of biologic agents to treat refractory cases of immunotherapy-induced colitis has proven to be effective of biologic agents for remission [18]. This evidence argues at achieving remission. One prospective study showed rapid for the necessity of early endoscopic evaluation and the clinical improvement in four out of five patients treated with practice of a top-down approach in the management of one dose of infliximab after failing standard therapy [14]. immunotherapy-induced colitis. Retrospective analyses demonstrate statistically significant The association between CTLA-4 checkpoint inhibition improvement in time to symptom resolution as well as and immune-mediated diseases has been described outside shorter duration of steroid therapy in patients treated with of the spectrum of oncology and immunotherapy. Heterozy- infliximab and corticosteroids as opposed to those treated gous mutations in the CTLA-4 protein-encoding gene, with corticosteroids alone [15]. In cases refractory to inflix- CTLA4, causes hyperactivation of effector T cells in addition imab, NCCN guidelines recommend consideration of vedo- to loss of circulating B cells with an increase and accumula- lizumab which has shown favorable outcomes and a good tion of CD21 B cells in nonlymphoid organs [8]. Zeissig safety profile with significant clinical (86%), endoscopic et al. identified in patients affected by early-onset Crohn’s (54%), and histological (29%) remission rates [16]. Because disease a novel missense mutation in CTLA4 resulting in of these promising findings, there is now a motion towards abnormal protein folding and structural stability that subse- earlier treatment with biotechnical agents based on endo- quently leads to severe systemic autoimmunity [19]. In scopic evaluation. Endoscopically visible ulcerations may addition to inflammatory bowel diseases, other immune- be a surrogate marker for steroid-refractory disease as sug- mediated inflammatory diseases such as rheumatoid arthri- tis, ankylosing spondylitis, and psoriasis are known to share gested by Wang and colleagues [17]. Usual histological features of acute colitis secondary to anti-CTLA-4 monoclo- a common pathological pathway involving an inappropriate nal antibodies include neutrophilic infiltration of the lamina release of inflammatory cytokines, particularly tumor necro- propria and crypt abscess formation [9]. Patients with sis factor (TNF) [20]. Important to note, Coutzac and col- more severe endoscopic findings such as numerous ulcera- leagues analyzed TNF-alpha concentrations within colonic tions and/or pancolitis, while not necessarily correlating biopsies collected prior to steroid treatment in cases of Case Reports in Oncological Medicine 5 for management of immune-mediated toxicities. Therefore, immunotherapy-induced colitis and found significantly higher values of TNF-alpha within the mucosa of the biopsies it is necessary to further evaluate the role of infliximab collected from anti-CTLA-4-induced colitis than anti-PD-1- and other biotechnical agents within this subset group of induced colitis [21]. TNF helps regulate multiple immune patients who undergo emergent surgical intervention for cell functions such as proliferation, differentiation, and apo- immunotherapy-induced colitis and who are at high risk ptosis and is produced by various cell types including macro- for further complications related to the severity of their phages, NK cells, and T lymphocytes [20]. The dominant role toxicity. Furthermore, given the compelling results from played by TNF in immune-mediated inflammatory diseases small studies done to date and the more pervasive use of explains why biologic agents targeted against TNF have been immunotherapy in the field of oncology, it is feasible to so effective in the management of these disorders [22]. For design larger and more controlled studies that assess toxic- ities and clinical outcomes in patients who initially receive example, adalimumab, which was first approved for the treat- ment of rheumatoid arthritis, has proven efficacious in a wide immunomodulator therapy versus systemic steroids for the range of other autoimmune disorders attributable to the treatment of immune-mediated adverse effects. shared pathogenesis of these diseases [23]. Inhibition of CTLA-4 by target-specific monoclonal antibodies such as Conflicts of Interest tremilimumab, ticilimumab, and ipilimumab are believed to result in acquired autoimmune disease via these biological The authors declare that there is no conflict of interest mechanisms. Similarities between the pathophysiology of regarding the publication of this paper. both inherited and acquired inflammatory bowel disease help explain why anti-TNF agents are effective in treating immunotherapy-induced colitis. 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