Background
Immune checkpoint inhibitors (ICIs) are revolutionary agents that are increasingly used to treat a variety of malignancies.1–3 These agents typically target inhibitory regulators of T cells, including CTLA-4, PD-1, and PD-L1. Blockade of these immune checkpoints leads to enhanced immune response against neoplastic cells.4,5 This has resulted in improved survival for multiple cancers.1–3
ICI use is associated with increased nonspecific immune response, which can result in toxic effects referred to as immune-related adverse events (irAEs). Commonly affected organs and organ systems include the gastrointestinal tract, skin, liver, lungs, and endocrine system.6–9 Gastrointestinal irAEs frequently present with lower gastrointestinal manifestations, such as diarrhea and colitis, and tend to be more common with CTLA-4 blockade than with PD-1 or PD-L1 blockade.10–12 In patients given CTLA-4 inhibitors, reported incidence rates for grade 3/4 diarrhea and colitis were 18% and 5%, respectively,13,14 with average times to symptom onset ranging from 6 to 9 weeks.14,15
Upper gastrointestinal tract irAEs are less common than lower gastrointestinal irAEs, and the clinical manifestations of upper gastrointestinal toxicity are less well described in the literature.16–23 Beck et al21 reported mucosal injury limited to the stomach and duodenum in 5% of patients treated with ICIs. Additionally, Tang et al18 found that upper gastrointestinal irAEs were more commonly associated with anti–PD-1/PD-L1 agents than with anti–CTLA-4 agents, with gastric involvement more common than duodenal involvement according to endoscopy and histology. Similar to other upper gastrointestinal irAEs, these episodes of esophagitis were associated with use of anti–PD-1 agents.16,17,24,25 Onset of upper gastrointestinal irAEs in these cases is later than that of lower gastrointestinal irAEs, with Boike and Dejulio16 and Onuki et al17 describing onset of symptoms 6 months after initiation of treatment with anti–PD-1 agents. Other than these few cases, there has been little published literature describing the endoscopic and histologic features of ICI-related esophagitis, treatment response, or clinical outcomes.
There is a gap in knowledge regarding the typical characteristics of ICI-related esophagitis and the appropriate treatments for this condition. In this retrospective study, we aimed to characterize esophagitis associated with the use of ICIs and describe its clinical, endoscopic, and histologic features. Additionally, we sought to determine the severity, disease course, treatment response, and outcomes of esophagitis.
Methods
Study Design
This retrospective analysis included consecutive patients at The University of Texas MD Anderson Cancer Center (MDACC) receiving ICI-based therapy from June 2011 to January 2020 who underwent upper endoscopies revealing esophagitis. Patients with preexisting gastroesophageal reflux disease (GERD), eosinophilic esophagitis, esophageal cancer, or known esophageal infections (eg, Candida, cytomegalovirus, herpes simplex virus) or who underwent esophagogastric surgery or head, neck, or chest irradiation were excluded. In the included patients, esophagitis was determined to be caused by ICIs based on endoscopic appearance and the exclusion of other causes of esophagitis.
This study was approved by the Institutional Review Board of MDACC (PA18-0472). Consent was waived for this study and a waiver of consent was granted.
Patient Characteristics
The following information was obtained via review of the patients’ medical records: demographic variables (eg, age, sex, race), smoking status, medical comorbidities (eg, hypertension, hyperlipidemia, diabetes mellitus), cancer type and stage according to the 7th edition of the AJCC Cancer Staging Manual, type and duration of ICI-based therapy, chemotherapy and nonsteroidal anti-inflammatory drug (NSAID) use within 3 months of ICI use, and other reported irAEs.
Clinical Characteristics of Esophagitis
The following esophagitis-related information was collected from the patients’ medical records: presenting symptoms, indications for esophagogastroduodenoscopy (EGD), grade of esophagitis using the CTCAE, severity of esophagitis (Los Angeles Classification System grade), anatomic location and pattern of esophagitis, time from ICI treatment initiation to onset of toxicity, and histologic diagnosis.
The patients’ EGD reports and pathologic images and reports were reviewed. The distribution of esophageal inflammation was divided into the upper, middle, and distal thirds of the esophagus, and the gastroesophageal junction. The pattern of esophagitis was described as patchy or diffuse based on the assessment of 2 endoscopists. The histologic findings were categorized as acute inflammation (neutrophilic or eosinophilic infiltration, fibrinous exudates, or ulcerations) or chronic inflammation (histiocytic, plasma cell, or lymphocytic infiltration; fibrosis; or architecture distortion) assessed by 2 gastrointestinal pathologists. Patients with features of both acute and chronic inflammation were included in the chronic inflammation category.
Medical records were also reviewed for treatment with proton pump inhibitors (PPIs), sucralfate, histamine 2 receptor (H2) blockers, and steroids. Immunosuppressant use for esophagitis and for other gastrointestinal toxic effects was also recorded. Hospitalization, length of hospital stay, complications related to esophagitis, recurrence of esophagitis, and data from follow-up endoscopy were also gathered. The date of last follow-up visit or date of death for each patient was also collected.
Statistical Analysis
Categorical variables were summarized using frequencies and percentages. Continuous variables were summarized using means and standard deviations or medians and interquartile ranges (IQRs). A chi-square test was used to analyze associations between categorical variables. The Mann-Whitney U test was used to compare differences between continuous variables. P values <.05 were considered significant.
Results
Patient Characteristics
Of 657 patients who received ICI-based therapy and underwent EGD at MDACC during the study period, 21 (3%) had esophagitis deemed to be associated with ICI use and not attributable to any other obvious etiology. The patient selection diagram is shown in Figure 1. We observed that in this small cohort, 1 patient (5%) received anti–CTLA-4 monotherapy, 15 (71%) received anti–PD-1/PD-L1 monotherapy, and 5 (24%) received a combination of these. Four patients (19%) received chemotherapy known to rarely cause esophagitis concurrently with ICI therapy, namely pemetrexed, docetaxel, or cytarabine.26–28 Only 1 patient (5%) took NSAIDs within 3 months before the onset of esophagitis.
Selection flowchart of the study patients.
Abbreviations: CMV, cytomegalovirus; EGD, esophagogastroduodenoscopy; GERD, gastroesophageal reflux disease; HSV, herpes simplex virus; ICI, immune checkpoint inhibitor.
Citation: Journal of the National Comprehensive Cancer Network 19, 8; 10.6004/jnccn.2020.7675
Selection flowchart of the study patients.
Abbreviations: CMV, cytomegalovirus; EGD, esophagogastroduodenoscopy; GERD, gastroesophageal reflux disease; HSV, herpes simplex virus; ICI, immune checkpoint inhibitor.
Citation: Journal of the National Comprehensive Cancer Network 19, 8; 10.6004/jnccn.2020.7675
Selection flowchart of the study patients.
Abbreviations: CMV, cytomegalovirus; EGD, esophagogastroduodenoscopy; GERD, gastroesophageal reflux disease; HSV, herpes simplex virus; ICI, immune checkpoint inhibitor.
Citation: Journal of the National Comprehensive Cancer Network 19, 8; 10.6004/jnccn.2020.7675
Patient characteristics are listed in Table 1. Mean patient age at the time of ICI initiation was 64 years. Most patients were White (62%) and male (62%). Approximately one-half of the patients (52%) had a history of smoking, and 43% had comorbidities, including hypertension (29%), hyperlipidemia (29%), type 2 diabetes mellitus (24%), and hypothyroidism (24%). The most common malignancy was non–small cell lung cancer (n=6; 29%) followed by cancer of the gastrointestinal tract (n=4; 19%) and melanoma (n=4; 19%). The most common ICI-related toxic effect outside of the upper gastrointestinal system was colitis (24%).
Patient Characteristics
Clinical Characteristics and Treatment of Esophagitis
Patients underwent EGD primarily for evaluation of nausea and vomiting (33%), dysphagia (19%), or hematemesis (19%). The median time from ICI initiation to onset of endoscopic evidence of esophagitis was 4 months (interquartile range [IQR], 2–9 months), with a median of 3 ICI infusions (IQR, 1.5–5.5). The median duration of esophagitis symptoms was 30 days (IQR, 9–43 days). Most patients (n=17; 81%) had mild esophagitis (CTCAE grade 1–2) (Table 2).
Clinical Information Related to Treatment With ICIs and Esophagitis (N=21)
Additional endoscopic and histologic findings are summarized in Table 3. Esophagitis severity varied widely from mild inflammation to severe inflammation with ulceration based on endoscopy (Figure 2). On EGD, only 3 patients (14%) had isolated esophageal involvement; 18 (86%) had concurrent involvement of the stomach, duodenum, or both. A total of 11 patients (52%) had inflammation of multiple segments of the esophagus, whereas the others had isolated involvement of the middle one-third of the esophagus (n=7; 33%), distal third of the esophagus (n=2; 10%), or gastroesophageal junction (n=1; 5%). Only 10 patients (48%) underwent esophageal biopsies; 5 demonstrated acute inflammation, whereas the other 5 demonstrated chronic inflammation. Of the 11 patients who did not undergo biopsy, one had a prior EGD that showed a normal esophagus and 10 had no prior EGDs.
Endoscopic and Pathologic Findings
Endoscopic and histologic features of ICI-related esophagitis. (A) Multiple large circumferential ulcers in the middle third of the esophagus. (B) Inflammation in the GEJ. (C) Nonbleeding erosions in the lower third of the esophagus. (D) Hematoxylin-eosin–stained section (original magnification ×20) of esophageal mucosa showing chronic active esophagitis, with increased numbers of neutrophils in the squamous epithelium and lamina propria. Granulation tissue, clusters of lymphocytes, and plasma cells are shown in the lamina propria (arrows). (E) Hematoxylin-eosin–stained section (original magnification ×20) of esophageal mucosa showing esophageal ulceration with underlying chronic active inflammation (arrows).
Abbreviations: GEJ, gastroesophageal junction; ICI, immune checkpoint inhibitor.
Citation: Journal of the National Comprehensive Cancer Network 19, 8; 10.6004/jnccn.2020.7675
Endoscopic and histologic features of ICI-related esophagitis. (A) Multiple large circumferential ulcers in the middle third of the esophagus. (B) Inflammation in the GEJ. (C) Nonbleeding erosions in the lower third of the esophagus. (D) Hematoxylin-eosin–stained section (original magnification ×20) of esophageal mucosa showing chronic active esophagitis, with increased numbers of neutrophils in the squamous epithelium and lamina propria. Granulation tissue, clusters of lymphocytes, and plasma cells are shown in the lamina propria (arrows). (E) Hematoxylin-eosin–stained section (original magnification ×20) of esophageal mucosa showing esophageal ulceration with underlying chronic active inflammation (arrows).
Abbreviations: GEJ, gastroesophageal junction; ICI, immune checkpoint inhibitor.
Citation: Journal of the National Comprehensive Cancer Network 19, 8; 10.6004/jnccn.2020.7675
Endoscopic and histologic features of ICI-related esophagitis. (A) Multiple large circumferential ulcers in the middle third of the esophagus. (B) Inflammation in the GEJ. (C) Nonbleeding erosions in the lower third of the esophagus. (D) Hematoxylin-eosin–stained section (original magnification ×20) of esophageal mucosa showing chronic active esophagitis, with increased numbers of neutrophils in the squamous epithelium and lamina propria. Granulation tissue, clusters of lymphocytes, and plasma cells are shown in the lamina propria (arrows). (E) Hematoxylin-eosin–stained section (original magnification ×20) of esophageal mucosa showing esophageal ulceration with underlying chronic active inflammation (arrows).
Abbreviations: GEJ, gastroesophageal junction; ICI, immune checkpoint inhibitor.
Citation: Journal of the National Comprehensive Cancer Network 19, 8; 10.6004/jnccn.2020.7675
The treatments and outcomes of esophagitis are listed in Table 4. A total of 10 patients (48%) required hospitalization for upper gastrointestinal symptoms. Patients most commonly received PPI treatment (n=14; 67%); only 4 (19%) received steroids (3 received prednisone and 1 received oral budesonide) for a median duration of 50 days (IQR, 35–134 days). Infliximab and vedolizumab were administered for concurrent lower gastrointestinal toxic effect. Of 17 symptomatic patients, 15 experienced symptom resolution after the initial course of treatment with PPIs, steroids, sucralfate, H2 blockers, or a combination of these. Two had recurrent symptoms after initially receiving treatment with PPIs: 1 after 12 days and the other after 182 days. Afterward, one of these patients received treatment with steroids, and the other received a PPI, resulting in complete resolution of their symptoms. The remaining 2 patients died due to other causes and never experienced symptom resolution. Of the 5 patients who had a repeat EGD, 4 had resolution of esophagitis.
Treatment and Outcomes of Esophagitis
Serious complications caused by esophagitis were rare; 3 patients (14%) had bleeding upon EGD and 1 (5%) required total parenteral nutrition support. ICI-based therapy was stopped permanently for 15 patients because of all irAEs. Esophagitis was the principal toxic effect leading to discontinuation of ICI-based therapy in only 2 patients. A total of 8 patients (38%) died during the study period (median follow-up, 15 months [IQR, 4 months to 4.2 years]); all were attributed to the patients’ malignancies.
Patient Characteristics According to Esophagitis Risk Factors
We compared the clinical characteristics of patients with risk factors for esophagitis other than ICI use and those without other risk factors. We defined these risk factors as NSAID use within 3 months prior to esophagitis onset, any chemotherapy administered within 3 months prior to esophagitis onset, and chemotherapy given concurrently with ICIs. We found no statistically significant differences in the features of inflammation (P=.92), esophagitis distribution (P=.36), duration from initiation of ICI use to onset of esophagitis (P=.34), or duration of hospitalization (P=.71) or symptoms (P=.77) between these 2 groups (Table 5).
Characteristics of Esophagitis in Patients Without Versus With Other Risk Factors for Esophagitis
Discussion
Gastrointestinal toxicity is one of the most common types of toxicity, occurring in up to 35% of patients treated with ICIs.29–31 Although gastrointestinal irAEs can affect any segment of the gastrointestinal tract, they tend to be most common in the colon. Most trials in patients with gastrointestinal toxic effects of ICIs have mainly focused on colitis.11,32,33 Tang et al18 reported on the largest case series of upper gastrointestinal irAEs in 2019, which included 60 patients. ICI-related esophagitis in particular is exceptionally rare, with only 4 cases reported in the literature.16,17,34,35 Our report represents the largest case series of esophagitis attributed to the use of ICIs.
The spectrum of ICI-related esophagitis clinical presentations is wide, and endoscopic features range from mild inflammation to severe ulceration.16,18,34 Most of our patients had low-grade esophagitis symptoms, with 81% experiencing peak CTCAE grades of 1 or 2. Most of the patients had symptom resolution with simple, low-cost treatment, with only 2 having recurrent symptoms. These treatments included PPIs, H2 blockers, and sucralfate. Only 4 patients received steroids in the context of concurrent colitis, and none of these 4 received other immunosuppressants, such as infliximab and vedolizumab. Overall, esophagitis tended to be mild, and symptoms resolved quickly without the need for aggressive immunosuppression. Systemic steroids seemed to work well for severe cases. However, drawing strong conclusions on the utility of steroids for management of ICI-related esophagitis in this cohort is difficult given multiple confounding factors. The role of immunosuppression in treating ICI-related esophagitis will require larger prospective studies.
The reported upper gastrointestinal symptoms of ICI-related esophagitis were nonspecific. We excluded patients with a history of conditions that cause esophagitis, such as GERD, eosinophilic esophagitis, and known or suspected pill esophagitis. In addition, we examined characteristics such as distribution and histologic patterns to help distinguish different types of esophagitis. For example, pill esophagitis often occurs in the middle one-third of the esophagus, tends to be focal, and can present with neutrophilic inflammation.36 Reflux and eosinophilic esophagitis tend to have different endoscopic distributions, and although both can present with eosinophilia, it can vary in degree and location.36,37 In our cohort, 33% of the patients had esophagitis isolated to the middle one-third of the esophagus, and 52% had a diffuse distribution. The histopathology of the esophageal biopsy specimens in our study demonstrated features of both acute and chronic inflammation similar to those seen in ICI-related colitis.9 These findings are consistent with those of a recent study by Patil and Zhang38 that showed ICI-related esophagitis was characterized by ulcerations and lymphocytic inflammation. Given the lack of pathognomonic features of ICI-related esophagitis, a definitive diagnosis of ICI-related esophagitis could not be made based on histologic evaluation alone. ICI-related esophagitis remains a diagnosis of exclusion.
In our small cohort, we observed that anti–PD-1/PD-L1 therapies were more commonly associated with esophagitis than were anti–CTLA-4 therapies, which is consistent with previous reports. A meta-analysis by Khoja et al32 of 48 trials of ICI-based monotherapy demonstrated that colitis was strongly associated with anti–CTLA-4 therapy (odds ratio, 8.7; 95% CI, 5.8–12.9). Although data on upper gastrointestinal toxicity are limited, the case series by Tang et al18 showed an association between treatment with PD-1/PD-L1 inhibitors and upper gastrointestinal toxicity. Case reports by Boike and Dejulio16 and Onuki et al17 also demonstrated upper gastrointestinal toxicity associated with treatment with the PD-1 inhibitors nivolumab and pembrolizumab, respectively. In addition, use of anti–CTLA-4 regimens has been associated with more severe toxicity than has use of anti–PD-1/PD-L1 regimens.31,39,40 Researchers hypothesized that the specific toxic effects associated with each class of ICI are related to variable expression of the targets in different tissues.32,41 However, the distribution of CTLA-4 and PD-1/PD-L1 expression along the gastrointestinal tract has not been well described.
The median time from initiation of ICI use to onset of esophagitis in our study was approximately 4 months, which is similar to the time of onset described by other authors.18 This is a longer time to onset than is generally observed for other irAEs. For example, lower gastrointestinal irAEs such as colitis tend to have an onset of 6 to 8 weeks,42 in contrast with upper gastrointestinal irAEs, which tend to have an onset of 4 to 9 months.16–18,43 However, retrospective analyses have shown that colitis associated with PD-1/PD-L1 blockade has a later onset than does colitis associated with CTLA-4 blockade.39 Delayed onset of upper gastrointestinal toxic effects may be explained by their association with anti–PD-1/PD-L1 therapy. Confirming this requires further evaluation.
In our cohort, 77% of the patients received PPIs or H2 blockers, and their symptoms resolved in a median of 30 days. In our median follow-up period of 15 months, we did not observe any long-term sequelae, such as esophageal stricture and Barrett esophagus. However, given the low percentage of repeat EGDs (24%) and the short duration between serial EGDs (median, 59 days), our data are likely insufficient to describe long-term consequences of ICI-related esophagitis. A longer follow-up period with close surveillance would be needed to detect long-term complications of ICI-related esophagitis.
Patients with varying clinical grades of esophagitis, namely CTCAE grades 1 through 4, had similar endoscopic findings. Therefore, it appeared that clinical grade does not correlate with endoscopic features of severity. However, this finding could be limited by our small sample size. Likewise, we also speculate that endoscopic features of esophagitis cannot be used as prognostic factors to determine the need for aggressive therapy based on our data. A larger-scale study would be needed to determine high-risk endoscopic features of esophagitis and its prognostic value. Because the prevalence of ICI-related esophagitis is low, we recommend initial empirical therapy with PPIs in the absence of alarming symptoms. If symptoms persist, endoscopy could be pursued along with additional therapies, such as steroids. Although evidence supporting this proposed management of ICI-related esophagitis is lacking, it is routinely used for esophagitis of other etiologies with reasonable success.
Despite the many strengths of our study, its limitations are important to acknowledge. First, data collection was relatively limited because of the retrospective, single-center study nature, which may have resulted in some selection and confounding biases. Second, some patients may have had mild symptoms that did not trigger endoscopy and were excluded from the study. Third, given a lack of current guidelines for treatment of ICI-related esophagitis, patients underwent treatment according to the treating physician’s discretion, leading to variation in treatment. Fourth, the study lacked randomization, a control population, and biomarker assessment. Fifth, the lack of pathognomonic histologic and clinical features of ICI-related esophagitis makes it a diagnosis of exclusion. For example, cases that occurred in the context of underlying GERD or eosinophilic esophagitis could have been excluded. Inversely, lack of recognition of confounding conditions may have caused inclusion of cases that should have been excluded. Sixth, although this is the largest study of its kind, the small sample restricted advanced statistical analyses and comparisons. Despite these limitations, our study generated interesting hypotheses and can inform the sparse literature on this important topic.
Conclusions
The rate of ICI-related esophagitis in patients with upper gastrointestinal symptoms undergoing EGD is as low as 3%. It presents similarly to esophagitis of other etiologies and remains a diagnosis of exclusion. Esophageal toxic effects frequently present in conjunction with other gastrointestinal toxic effects that are more severe, but alone rarely lead to termination of ICI use. Most patients have mild symptoms, and their esophagitis can be effectively managed with nonimmunosuppressive treatments. The benefit of use of steroids is unclear. A larger prospective study with longer follow-up would help further characterize this condition longitudinally and determine optimal management.
Acknowledgments
The datasets used and analyzed in the present study are available from the corresponding author upon reasonable request. Editing of this paper was provided by Scientific Publications, Research Medical Library at The University of Texas MD Anderson Cancer Center.
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