|
1
|
Pizuorno Machado A, Shatila M, Liu C, Lu Y, Altan M, Glitza Oliva IC, Zhao D, Zhang HC, Thomas A, Wang Y. Characteristics, treatment, and outcome of patients with bowel perforation after immune checkpoint inhibitor exposure. J Cancer Res Clin Oncol 2023; 149:5989-5998. [PMID: 36611109 DOI: 10.1007/s00432-022-04569-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 12/31/2022] [Indexed: 01/09/2023]
Abstract
PURPOSE Exposure to immune checkpoint inhibitors (ICIs) can predispose to immune-related adverse events (irAEs) involving the gastrointestinal tract. The association between ICIs and bowel perforation has not been well studied. We aimed to describe the clinical course, complications, treatment, and outcomes of patients experiencing bowel perforation during or after ICI treatment. METHODS This retrospective, single-center study included adult cancer patients with bowel perforation that occurred between the first dose of ICI treatment and up to 1 year thereafter between 1/1/2010 and 4/30/2021. Patients' clinical course, imaging, treatment, and outcomes related to bowel perforation were collected and analyzed. RESULTS Of the 13,991 patients who received ICIs during the study period, 90 (0.6%) met the inclusion criteria. A majority were male (54.4%), the most common cancer type was melanoma (23.3%), and most patients had received PD-1/L1 inhibitor treatment (58.8%). Onset of perforation occurred after a median of four ICI treatment cycles. The most common symptom was abdominal pain (95.5%). The colon was the most common location for the perforation (37.7%). Evidence of diverticulitis, enterocolitis, or appendicitis was seen in 32 (35.6%) patients, and 6 (6.6%) patients had luminal cancer involvement at the time of perforation. The overall hospitalization rate related to perforation was 95.5%, with mortality of 15.5% during the same admission. Antibiotics were given in 95% of our sample; 37.8% of patients also required surgical/interventional radiology intervention. Forty-six patients (51.1%) had perforation-related complications (e.g., sepsis, fistula, abscess), which were associated with a higher mortality rate (30%). CONCLUSION Our findings suggest a low incidence of bowel perforation after ICI treatment (0.6%), with 40% of patients having coexisting bowel inflammation as a potential contributing factor. Patients with bowel perforation had an aggressive disease course and high rates of hospitalization, complications, and mortality. Early recognition and prompt intervention is critical to improve patient outcomes. Future studies are warranted to further investigate the cause, predictive markers, and optimal treatment for this patient population.
Collapse
Affiliation(s)
- Antonio Pizuorno Machado
- Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Malek Shatila
- Department of Gastroenterology, Hepatology and Nutrition, Unit 1466, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Cynthia Liu
- Department of Internal Medicine, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Yang Lu
- Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Mehmet Altan
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Isabella C Glitza Oliva
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Dan Zhao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Hao Chi Zhang
- Department of Gastroenterology, Hepatology and Nutrition, Unit 1466, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Anusha Thomas
- Department of Gastroenterology, Hepatology and Nutrition, Unit 1466, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology and Nutrition, Unit 1466, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
| |
Collapse
|
|
2
|
Cheng Y, Ling F, Li J, Chen Y, Xu M, Li S, Zhu L. An updated review of gastrointestinal toxicity induced by PD-1 inhibitors: from mechanisms to management. Front Immunol 2023; 14:1190850. [PMID: 37404814 PMCID: PMC10315615 DOI: 10.3389/fimmu.2023.1190850] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 06/05/2023] [Indexed: 07/06/2023] Open
Abstract
PD-1 inhibitors, as one of commonly used immune checkpoint inhibitors, enable T-cell activation and prevent immune escape by blocking the PD-1/PD-L1 signaling pathway. They have transformed the treatment landscape for cancer in recent years, due to the advantages of significantly prolonging patients' survival and improving their life quality. However, the ensuing unpredictable immune-related adverse effects (irAEs) plague clinicians, such as colitis and even potentially fatal events like intestinal perforation and obstruction. Therefore, understanding the clinical manifestations and grading criteria, underlying mechanisms, available diverse therapies, accessible biomarkers, and basis for risk stratification is of great importance for the management. Current evidence suggests that irAEs may be a marker of clinical benefit to immunotherapy in patients, so whether to discontinue PD-1 inhibitors after the onset of irAEs and rechallenge after remission of irAEs requires further evaluation of potential risk-reward ratios as well as more data from large-scale prospective studies to fully validate. At the end, the rare gastrointestinal toxicity events caused by PD-1 inhibitors are also sorted out. This review provides a summary of available data on the gastrointestinal toxicity profile caused by PD-1 inhibitors, with the aim of raising clinicians' awareness in daily practice, so that patients can safely benefit from therapy.
Collapse
|
|
3
|
Mohammad AW, Kusnik A, Mostafa MR, Tan J, Strapko A. Checkpoint Inhibitor Colitis With Superimposed Clostridioides difficile Infection. Cureus 2023; 15:e37006. [PMID: 37139037 PMCID: PMC10150835 DOI: 10.7759/cureus.37006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/01/2023] [Indexed: 04/03/2023] Open
Abstract
Immune checkpoint inhibitors (ICI) are commonly used for various malignancies. A particular checkpoint inhibitor is the anti-PD-1 antibody pembrolizumab. Immune-mediated diarrhea and colitis (IMDC) is the most frequently observed immune-related adverse event (irAE) involving the gastrointestinal system. Although immune-mediated colitis precipitated by pembrolizumab is rarely life-threatening, it often necessitates a detailed diagnostic workup, including stool studies, imaging, and colonoscopy, to establish an accurate diagnosis. The coexistence of IMDC and Clostridioides difficile infection is not well understood, but patients undergoing pembrolizumab treatment have comparable risk factors to those who develop C. difficile infection. We report a case of a 76-year-old female with nonmetastatic non-small cell lung cancer who was diagnosed with IMDC responsive to steroid treatment but later developed worsening diarrhea leading to a diagnosis of checkpoint inhibitor colitis with superimposed C. difficile infection.
Collapse
|
|
4
|
Yong J, Gröger S, von Bremen J, Meyle J, Ruf S. PD-L1, a Potential Immunomodulator Linking Immunology and Orthodontically Induced Inflammatory Root Resorption (OIIRR): Friend or Foe? Int J Mol Sci 2022; 23:ijms231911405. [PMID: 36232704 PMCID: PMC9570182 DOI: 10.3390/ijms231911405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/19/2022] [Accepted: 09/23/2022] [Indexed: 11/16/2022] Open
Abstract
Orthodontically induced inflammatory root resorption (OIIRR) is considered an undesired and inevitable complication induced by orthodontic forces. This inflammatory mechanism is regulated by immune cells that precede orthodontic tooth movement (OTM) and can influence the severity of OIIRR. The process of OIIRR is based on an immune response. On some occasions, the immune system attacks the dentition by inflammatory processes during orthodontic treatment. Studies on the involvement of the PD-1/PD-L1 immune checkpoint have demonstrated its role in evading immune responses, aiming to identify possible novel therapeutic approaches for periodontitis. In the field of orthodontics, the important question arises of whether PD-L1 has a role in the development of OIIRR to amplify the amount of resorption. We hypothesize that blocking of the PD-L1 immune checkpoint could be a suitable procedure to reduce the process of OIIRR during orthodontic tooth movement. This review attempts to shed light on the regulation of immune mechanisms and inflammatory responses that could influence the pathogenesis of OIIRR and to acquire knowledge about the role of PD-L1 in the immunomodulation involved in OIIRR. Possible clinical outcomes will be discussed in relation to PD-L1 expression and immunologic changes throughout the resorption process.
Collapse
Affiliation(s)
- Jiawen Yong
- Department of Orthodontics, Faculty of Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany
- Department of Periodontology, Faculty of Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310003, China
- Correspondence: or ; Tel.: +49-641-99-46131
| | - Sabine Gröger
- Department of Orthodontics, Faculty of Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany
| | - Julia von Bremen
- Department of Orthodontics, Faculty of Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany
| | - Joerg Meyle
- Department of Periodontology, Faculty of Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany
| | - Sabine Ruf
- Department of Orthodontics, Faculty of Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany
| |
Collapse
|
|
5
|
Steiger S, Marcucci V, Desai V, Zheng M, Parker G. Refractory Fulminant Colitis Requiring Surgical Intervention in a Patient With Ulcerative Colitis on Atezolizumab Therapy for Small Cell Lung Cancer: An Atypical Case. Cureus 2022; 14:e25437. [PMID: 35774647 PMCID: PMC9239293 DOI: 10.7759/cureus.25437] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/28/2022] [Indexed: 12/15/2022] Open
Abstract
Atezolizumab is a programmed death-ligand 1 (PD-L1) targeted antibody that prevents the binding of PD-L1 to specific T-cell receptors, thereby increasing anticancer immunity. It has been regarded as a useful first-line treatment in patients with small-cell lung cancer with a more tolerable side effect profile than chemotherapeutic agents. However, few studies focusing on the severity of adverse effects from immune checkpoint inhibitors (ICPI) have been previously reported, particularly acute fulminant colitis requiring surgical invention. We report a case of fulminant colitis refractory to high dose corticosteroid treatment in a patient with known ulcerative colitis (UC) undergoing treatment for small-cell lung cancer (SCLC) with atezolizumab. The upregulation of PD-L1 expression in patients with ulcerative colitis may play a significant role in an imbalanced T-helper cell response creating a pro-inflammatory state. The use of ICPIs to treat SCLC has been reported to increase the risk of developing inflammatory colitis. Atezolizumab use in a patient with known inflammatory bowel disease (IBD) may predispose this population to a higher risk of developing severe inflammatory colitis. We present an unusual complication associated with medical intervention in an immunocompromised patient without an established pathophysiology. The suspicion of using ICPIs in patients with IBD as a potential cause for the development of fulminant colitis is relevant and essential in the diagnostic workup for this patient population complaining of significant gastrointestinal symptoms.
Collapse
|
|
6
|
Bhaumik S, Mickael ME, Moran M, Spell M, Basu R. RORγt Promotes Foxp3 Expression by Antagonizing the Effector Program in Colonic Regulatory T Cells. THE JOURNAL OF IMMUNOLOGY 2021; 207:2027-2038. [PMID: 34518282 DOI: 10.4049/jimmunol.2100175] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 08/04/2021] [Indexed: 02/02/2023]
Abstract
RORγt is the master transcription factor for the Th17 cells. Paradoxically, in the intestine, RORγt is coexpressed in peripherally induced regulatory T cells (pTregs) together with Foxp3, the master transcription factor for Tregs. Unexpectedly, by an unknown mechanism, colonic RORγt+ Tregs show an enhanced suppressor function and prevent intestinal inflammation more efficiently than RORγt-nonexpressing pTregs. Although studies have elucidated the function of RORγt in Th17 cells, how RORγt regulates pTreg function is not understood. In our attempt to understand the role of RORγt in controlling Treg function, we discovered a RORγt-driven pathway that modulates the regulatory (suppressor) function of colonic Tregs. We found that RORγt plays an essential role in maintaining Foxp3 expression. RORγt-deficient Tregs failed to sustain Foxp3 expression with concomitant upregulation of T-bet and IFN-γ expressions. During colitis induced by adoptive transfer of CD45RBhi cells in Rag1 -/- mice, RORγt-deficient colonic Tregs transitioned to a Th1-like effector phenotype and lost their suppressor function, leading to severe colitis with significant mortality. Accordingly, Foxp3-expressing, RORγt-deficient Tregs showed impaired therapeutic efficacy in ameliorating colitis that is not due to their reduced survival. Moreover, using the Treg-specific RORγt and T-bet double-deficient gene knockout mouse, we demonstrate that deletion of T-bet from RORγt-deficient Tregs restored Foxp3 expression and suppression function as well as prevented onset of severe colitis. Mechanistically, our study suggests that RORγt-mediated repression of T-bet is critical to regulating the immunosuppressive function of colonic Tregs during the inflammatory condition.
Collapse
Affiliation(s)
- Suniti Bhaumik
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL
| | | | - Monica Moran
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL; and
| | - Marion Spell
- Center for AIDS Research, University of Alabama at Birmingham, Birmingham, AL
| | - Rajatava Basu
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL;
| |
Collapse
|
|
7
|
Affiliation(s)
- Barnabas Yik
- Santa Clara Valley Medical Center, San Jose, CA, USA.
| | - Nimeesh Shah
- Santa Clara Valley Medical Center, San Jose, CA, USA.,Stanford University Hospital, Stanford, CA, 94305, USA
| |
Collapse
|
|
8
|
Cho HJ, Kim WR, Kim JH, Kim DH, Kim DJ, Kang H. Colonic Perforation After Treatment With Nivolumab in Esophageal Cancer: A Case Report. Ann Coloproctol 2021; 37:S39-S43. [PMID: 34167190 PMCID: PMC8359691 DOI: 10.3393/ac.2020.00213.0030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/31/2020] [Accepted: 06/04/2020] [Indexed: 02/08/2023] Open
Abstract
With the advent of checkpoint inhibitors, it has opened up opportunities for numerous cancer patients. However, as is the case with every treatment, complications need to be weighed. Gastrointestinal adverse effects, such as diarrhea and colitis are well-known complications for checkpoint inhibitors. In severe cases, colitis-induced colonic perforation may occur with an estimation of 1.0% to 1.5% in anti-CTLA-4 antibodies. However, only a handful of cases of such devastating complications have been reported in anti-PD-1 antibodies such as pembrolizumab and nivolumab. We here report a case of intestinal perforation in a patient treated with nivolumab.
Collapse
Affiliation(s)
- Hye Jung Cho
- Department of Surgery, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Woo Ram Kim
- Department of Surgery, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Joo-Hang Kim
- Department of Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Duk Hwan Kim
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Dae Jung Kim
- Department of Radiology, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Haeyoun Kang
- Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| |
Collapse
|
|
9
|
Patil PA, Zhang X. Pathologic Manifestations of Gastrointestinal and Hepatobiliary Injury in Immune Checkpoint Inhibitor Therapy. Arch Pathol Lab Med 2021; 145:571-582. [PMID: 32338534 DOI: 10.5858/arpa.2020-0070-ra] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/24/2020] [Indexed: 02/05/2023]
Abstract
CONTEXT.— Immune checkpoint inhibitors (CPIs), including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors and the programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors, are being increasingly used for treating many advanced malignancies. However, CPI therapy is also associated with gastrointestinal and hepatobiliary adverse effects. OBJECTIVES.— To review the adverse effects of CPI therapy on the gastrointestinal tract and hepatobiliary system. To describe histopathologic patterns and discuss differential diagnostic considerations in the diagnosis of CPI injuries. DATA SOURCES.— Published peer-reviewed literature in the English language and personal experience in the diagnosis of CPI injuries. CONCLUSIONS.— The pathologic manifestations of CPI therapy-induced gastrointestinal and hepatobiliary injury are broad. The patterns of esophageal CPI injury include lymphocytic inflammation and ulcerative esophagitis, while those of gastric injury include chronic active gastritis, lymphocytic gastritis, focal enhancing gastritis, and periglandular inflammation. The duodenal injury may present as duodenitis with villous blunting and granulomas. We also noticed active colitis, microscopic colitis, chronic active colitis, increased apoptosis, ischemic colitis, and nonspecific inflammatory reactive changes in colonic injuries. The reported histologic features of hepatobiliary injuries are panlobular hepatitis, centrilobular necrosis, portal inflammation with bile duct injury, steatosis, nodular regenerative hyperplasia, and secondary sclerosing cholangitis. In summary, we discuss the pathologic features and differential diagnosis of CPI therapy-induced gastrointestinal and hepatobiliary injury. Recognition of CPI injury is important to determine the proper management that often includes cessation of CPI therapy, and administration of steroids or other immunosuppressive agents, based on severity of injury.
Collapse
Affiliation(s)
- Pallavi A Patil
- From the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Xuchen Zhang
- From the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| |
Collapse
|
|
10
|
Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of severe gastrointestinal and hepatic toxicities from checkpoint inhibitors. Support Care Cancer 2020; 28:6129-6143. [PMID: 32856210 DOI: 10.1007/s00520-020-05707-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 08/20/2020] [Indexed: 02/06/2023]
Abstract
Immune-related adverse events (IrAEs) affecting the gastrointestinal (GI) tract and liver are among the most frequent and most severe inflammatory toxicities from contemporary immunotherapy. Inflammation of the colon and or small intestines (entero)colitis is the single most common GI IrAE and is an important cause of delay of discontinuation of immunotherapy. The severity of these GI IrAEs can range from manageable with symptomatic treatment alone to life-threatening complications, including perforation and liver failure. The frequency and severity of GI IrAEs is dependent on the specific immunotherapy given, with cytotoxic T lymphocyte antigen (CTLA)-4 blockade more likely to induce severe GI IrAEs than blockade of either programmed cell death protein 1 (PD-1) or PD-1 ligand (PD-L1), and combination therapy showing the highest rate of GI IrAEs, particularly in the liver. To date, we have minimal prospective data on the appropriate diagnosis and management of GI IrAEs, and recommendations are based largely on retrospective data and expert opinion. Although clinical diagnoses of GI IrAEs are common, biopsy is the gold standard for diagnosis of both immunotherapy-induced enterocolitis and hepatitis and can play an important role in excluding competing, though less common, diagnoses and ensuring optimal management. GI IrAEs typically respond to high-dose corticosteroids, though a significant fraction of patients requires secondary immune suppression. For colitis, both TNF-α blockade with infliximab and integrin inhibition with vedolizumab have proved highly effective in corticosteroid-refractory cases. Detailed guidelines have been published for the management of low-grade GI IrAEs. In the setting of more severe toxicities, involvement of a GI specialist is generally recommended. The purpose of this review is to survey the available literature and provide management recommendations focused on the GI specialist.
Collapse
|
|
11
|
Dougan M. Gastrointestinal and Hepatic Complications of Immunotherapy: Current Management and Future Perspectives. Curr Gastroenterol Rep 2020; 22:15. [PMID: 32185493 DOI: 10.1007/s11894-020-0752-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
PURPOSE OF REVIEW Checkpoint inhibitor (CPI) immunotherapy has transformed the treatment of multiple cancers over the past decade, leading to durable remissions, but also to severe inflammatory toxicities. These toxicities, termed immune-related adverse events (irAEs), can affect any organ system in the body, but commonly induce inflammation in barrier organs. Gastrointestinal (GI) and hepatic irAEs are among the most frequent and most severe from contemporary immunotherapies, with inflammation in the colon and or small intestines (entero)colitis as the single most common GI irAE. The aim of this review is to describe the evidence supporting our current understanding of CPI enterocolitis and hepatitis, as well as the management of these entities. RECENT FINDINGS Although most patients who develop enterocolitis recover without long-term GI sequelae, enterocolitis is still an important reason for treatment discontinuation, which, in patients with metastatic cancer, can be a life-threatening outcome. At present, we have almost no prospective, randomized data regarding the management of CPI enterocolitis, and current management algorithms are based on expert opinion and small retrospective studies with a high likelihood of bias. Retrospective studies have defined colonic ulceration as a predictor of colitis responsiveness to corticosteroids, and have defined microscopic colitis as a subtype of CPI enterocolitis with a distinct treatment response. Corticosteroids appear to be effective for 60-70% of patients with CPI enterocolitis, with about a third of patients requiring escalation to a biologic agent such as infliximab or vedolizumab. Yet proper sequencing of these treatments to minimize risk and maximize treatment benefit has not been established, and we do not know how treatment of colitis influences cancer outcomes. CPI enterocolitis and hepatitis are important causes of treatment interruption and discontinue, and significant morbidity in patients undergoing immunotherapy. As guidelines for diagnosis and management rely heavily on expert opinion, we have an urgent need for randomized and prospective trials that use both colitis and cancer outcomes to determine optimal management strategies.
Collapse
Affiliation(s)
- Michael Dougan
- Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
12
|
Immune Checkpoint Inhibitor-Induced Colitis Successfully Followed up by Ultrasonography. ACTA ACUST UNITED AC 2020. [DOI: 10.1007/s42399-019-00211-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
|
|
13
|
Ibraheim H, Perucha E, Powell N. Pathology of immune-mediated tissue lesions following treatment with immune checkpoint inhibitors. Rheumatology (Oxford) 2019; 58:vii17-vii28. [PMID: 31816081 PMCID: PMC6900915 DOI: 10.1093/rheumatology/kez465] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 09/05/2019] [Indexed: 01/03/2023] Open
Abstract
Immune check point inhibitor (CPI) therapy has revolutionized treatment paradigms for several cancers, but at the cost of triggering a diverse spectrum of immune-mediated injury to non-cancer tissues. The complex biology of these toxicities remains incompletely understood, partly because tissue acquisition from affected areas can be challenging to retrieve, thus hindering development of targeted therapy. Here, we review the literature describing pathology of immune-mediated tissue lesions including gastrointestinal, skin, rheumatic, pulmonary, cardiac, renal and hepatic lesions and highlight key immunological insights.
Collapse
Affiliation(s)
- Hajir Ibraheim
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, UK
- Gastroenterology Unit, Royal Marsden Hospital, London, UK
| | - Esperanza Perucha
- Centre for Inflammation Biology and Cancer Immunology, Centre for Rheumatic Diseases, King’s College London
| | - Nick Powell
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, UK
- Gastroenterology Unit, Royal Marsden Hospital, London, UK
| |
Collapse
|
|
14
|
Beck TN, Kudinov AE, Dulaimi E, Boumber Y. Case report: reinitiating pembrolizumab treatment after small bowel perforation. BMC Cancer 2019; 19:379. [PMID: 31018834 PMCID: PMC6482547 DOI: 10.1186/s12885-019-5577-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 04/03/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have emerged as paradigm shifting treatment options for a number of cancers. Six antibodies targeting the immune checkpoint proteins programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1) or cytotoxic T-lymphocyte associated protein 4 (CTLA4) have been approved. In some cases, response rates have been impressive, but not uniformly so and not consistently; similarly, toxicity to this class of therapeutic is often unpredictable and can be life threatening. Predicting treatment response and toxicity are two main obstacles to truly individualize treatment with ICIs. One of the most severe and life-threatening adverse events is colitis induced colonic perforation, estimated to occur in 1.0 to 1.5% of patients treated with ICIs. An important question to address is, under what circumstances is it appropriate to reinitiate ICI treatment post-bowel perforation? CASE PRESENTATION The patient is a 62-year-old woman, who presented with stage IV lung cancer. Immunohistochemical staining indicated that 80% of the patient's tumor cells expressed PD-L1. The patient was started on a three-week cycle of pembrolizumab. Subsequent reducing in tumor burden was observed within ten weeks. Initially, pembrolizumab was tolerated fairly well, with the exception of immunotherapy related hypothyroidism. However, the patient experienced a second, more serious immune-related adverse event (irAE), in the form of enteritis, which led to small bowel perforation and necessitated exploratory laparotomy. The concerning part of the small bowel was resected, and a primary anastomosis was created. Based on the pathological and surgical findings, the patient was diagnosed with pembrolizumab-associated small bowel perforation. The patient recovered well from surgery and, considering the patient's remarkable response to treatment, a collective decision was made to reinitiate pembrolizumab on post-operative day twenty-eight. The patient is continuing her immunotherapy with ongoing partial response and is able to continue her full-time job. CONCLUSIONS This case report highlights the challenges of identifying patients likely to respond to ICIs and those that are likely to experience irAEs and it discusses the impressive work that has been done to start to address these challenges. Lastly, the topic of reinitiating pembrolizumab treatment even after colonic perforation is discussed.
Collapse
Affiliation(s)
- Tim N Beck
- Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA, 19129, USA. .,Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA. .,Department of General Surgery, Cleveland Clinic, Cleveland, OH, 44195, USA.
| | - Alexander E Kudinov
- Department of Internal Medicine, University of New Mexico, Albuquerque, NM, 87131, USA
| | - Essel Dulaimi
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Yanis Boumber
- Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA. .,Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA. .,Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.
| |
Collapse
|
|
15
|
Zhou C, Klionsky Y, Treasure ME, Bruno DS. Pembrolizumab-Induced Immune-Mediated Colitis in a Patient with Concurrent Clostridium Difficile Infection. Case Rep Oncol 2019; 12:164-170. [PMID: 31043955 PMCID: PMC6477466 DOI: 10.1159/000497155] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 01/22/2019] [Indexed: 12/11/2022] Open
Abstract
Pembrolizumab is a programmed death receptor-1 (PD-1) inhibitor that has been approved for treatment of a wide variety of malignancies. Immune-mediated colitis is a known but uncommon adverse effect of pembrolizumab. Symptoms of immune-mediated colitis can be similar to those of many other gastrointestinal illnesses, including Clostridium difficile infection (CDI). If not recognized and treated in a timely fashion, immune-mediated colitis can lead to significant morbidity in cancer patients. We report the case of a 56-year-old woman on pembrolizumab for metastatic non-small cell lung cancer (NSCLC) who presented with severe colitis symptoms and initially tested positive for CDI. Her colitis symptoms worsened despite appropriate treatment for CDI but later improved rapidly after systemic corticosteroid was started for suspected immune-mediated colitis. To our knowledge, this is the first reported case of concurrent pembrolizumab-induced colitis and CDI. Immune-mediated colitis should be considered in the differential diagnoses in patients on pembrolizumab or other immune checkpoint inhibitors who present with colitis symptoms, even when a concurrent infectious etiology is suspected.
Collapse
Affiliation(s)
- Cheng Zhou
- Department of Medicine-Pediatrics, MetroHealth Medical Center, Cleveland, Ohio, USA
| | - Yael Klionsky
- Department of Internal Medicine, MetroHealth Medical Center, Cleveland, Ohio, USA
| | - Michelle E Treasure
- Department of Internal Medicine, Hematology and Oncology Division, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Debora S Bruno
- Department of Internal Medicine, Hematology and Oncology Division, University Hospitals - Seidman Cancer Center, Cleveland, Ohio, USA
| |
Collapse
|
|
16
|
Ahmed M. Checkpoint inhibitors: What gastroenterologists need to know. World J Gastroenterol 2018; 24:5433-5438. [PMID: 30622372 PMCID: PMC6319137 DOI: 10.3748/wjg.v24.i48.5433] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 11/07/2018] [Accepted: 11/16/2018] [Indexed: 02/06/2023] Open
Abstract
Checkpoint inhibitors are increasingly being used in clinical practice. They can cause various gastrointestinal, hepatic and pancreatic side effects. As these side effects can be serious, appropriate management is essential. The different checkpoint inhibitors with their mechanisms of action and indications, as well as evaluation and management of gastrointestinal, hepatic and pancreatic side effects, are discussed in this article.
Collapse
Affiliation(s)
- Monjur Ahmed
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA 19107, United States
| |
Collapse
|