Background
Immune checkpoint inhibitors (ICIs) are immunotherapeutic agents that inhibit checkpoint ligands and receptors that serve as downregulators of the adaptive and innate immune system, stimulating an immune response against cancer cells. Since their development, such as inhibitors of CTLA-4, PD-1, and PD-L1, ICIs have been found to be effective treatment options for various solid tumors, including melanoma; lung, genitourinary, colorectal, and head and neck malignancies; and leukemias.1–5
Although ICIs have changed the landscape of cancer therapy, their enhancement of nonspecific immune responses can lead to immune-related adverse events (irAEs) of any organ system. These irAEs are observed in the skin, gastrointestinal tract, liver, lungs, and other systems.4,5–8 irAEs occur at any time during ICI treatment, range from mild symptoms to severe life-threatening or fatal events, and may require management using immunomodulatory agents and discontinuation of ICI therapy.5,6,9
Gastrointestinal irAEs frequently involve the colon, liver, and stomach and present with nausea, vomiting, diarrhea, rectal bleeding, or abdominal pain.9–14 Rare gastrointestinal irAEs have been reported, such as esophagitis, pancreatitis, and cholecystitis.15–17 Furthermore, investigators have described adverse events in the oral cavity, including xerostomia, dysgeusia, lichenoid reactions, mucositis, and stomatitis.18–28
The clinical presentation of ICI-mediated mucositis (IMM) can range from mild to severe, with onset ranging from several weeks to months after treatment initiation.18–23 The literature contains several reports of severe mucositis induced by pembrolizumab, an anti–PD-1 agent,24–27 with symptom onset occurring up to 1 year after initiation and mucositis lasting several months after discontinuation. Physical and endoscopic findings showed mucosal erythema, edema, and ulceration with odynophagia and dysphagia symptoms, resulting in limited food intake, weight loss, and hospitalization. Successful management was accomplished via discontinuation of ICI and immunosuppression using steroids.
The pathogenesis of irAEs has yet to be fully elucidated, and their occurrence can impact quality of life and the ICI therapy course and lead to morbidity and mortality. Given the limited data on IMM, we evaluated the clinical characteristics, disease course, treatment, and outcome of IMM in patients at a tertiary cancer center.
Methods
Study Design and Population
This was a retrospective, descriptive, single-center study of adult patients at The University of Texas MD Anderson Cancer Center who received ICI therapy and experienced oral mucositis from January 2009 through September 2019. Inclusion criteria included age ≥18 years, a diagnosis of oral mucositis and/or stomatitis based on ICD-9 and ICD-10 codes, and therapy using CTLA-4 or PD-1/L1 inhibitors alone or combined with other agents. Patients who received a combination of ICI and non-ICI chemotherapy were included. The event time window for mucositis/stomatitis was from administration of the first ICI dose to 6 months after the last ICI dose. Exclusion criteria included (1) radiation therapy to the head, neck, or chest within 3 months of mucositis/stomatitis onset; (2) stem cell or bone marrow transplantation with gastrointestinal graft-versus-host disease; (3) confirmed upper gastrointestinal viral, fungal, or bacterial infection; (4) cancer in the oral cavity; and (5) mucositis resulting from other non-ICI cancer treatment. In patients in whom the etiology of mucositis was ambiguous, attribution to ICI therapy was made based on typical timing of disease onset from initiation of ICI therapy.
Clinical Data
Patient demographics, medical and oncologic history, cancer treatment regimens, and irAEs were collected. Demographics included age, sex, and ethnicity. Comorbidities evaluated included hypertension, coronary artery disease, congestive heart failure, atrial fibrillation, cerebral vascular disease, diabetes mellitus, chronic obstructive pulmonary disease, asthma, HIV infection, and thyroid disease. Information collected regarding presumed risk factors for mucositis included smoking history, use of nonsteroidal anti-inflammatory agents, other concurrent chemotherapy using ICIs, and premucositis use of immunosuppressants. Oncologic data analyzed included cancer type and stage, cancer treatment agents (ICI and non-ICI chemotherapy), and irAEs. ICIs administered included ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, and tremelimumab. ICI regimens were categorized as single-agent or combined regimens. The duration of each ICI regimen before onset of mucositis was recorded. Information regarding mucositis and other irAEs within the same study window and their medical treatments was also documented.
Mucositis Data
Mucositis events were screened for time of onset, duration, severity, treatment, complications, recurrence, and need to hold or discontinue the ICI regimen. Mucositis severity was graded based on version 5 of the NCI’s CTCAE.28 Signs of mucositis identified in history and physical examination were recorded as ulcers/aphthae or nonulcer inflammation. Symptoms included oral pain, odynophagia, dysphagia, nausea or vomiting, and bleeding. Treatment of mucositis was categorized as nonimmunosuppressive (proton pump inhibitors [PPIs], H2 blockers, sucralfate, or topical anesthetics) or immunosuppressive, including topical agents (eg, liquid dexamethasone, fluocinonide ointment) and systemic agents (intravenous methylprednisolone, oral dexamethasone, and oral prednisone). Duration of systemic steroid use was defined as the time from initiation to either cessation of treatment or return to the baseline maintenance dose. Clinical outcomes included requirement of hospitalization, duration of hospital stay, requirement of additional nutrition support, clinical resolution and recurrence of mucositis, and overall survival (OS) after mucositis onset.
Statistical Analysis
Statistical analysis was performed using RStudio version 1.0.136 (R Foundation for Statistical Computing) and SPSS Statistics, version 24.0 (IBM Corp). 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 determine associations between categorical variables. The Mann-Whitney U test was used to compare differences between continuous variables. Differences in OS durations between groups were analyzed using the Kaplan-Meier method and a log-rank test. P values up to .05 were considered significant.
Results
Baseline Characteristics
Of the 10,275 patients who received ICI therapy during the study period, 652 (6.3%) developed mucositis, 500 of whom were excluded (supplemental eFigure 1, available with this article at JNCCN.org); 152 patients were included in the final analysis. Mean age at ICI initiation was 60 years, 51% were men, and 72% were White (Table 1). Concurrent chemotherapy in addition to ICIs (57%) and history of smoking (47%) were the most prevalent baseline risk factors, and the most common malignancies were melanoma (28%), lung (10%), head and neck (8%), and hematologic (16%). Most patients (73%) had stage IV disease.
Baseline Clinical Characteristics
Mucositis-Related Characteristics
Among different ICI regimens, 119 patients (78%) received PD-1/L1 monotherapy and 33 (22%) received CTLA-4–based therapy. In the latter group, 16 received monotherapy and 17 received combination therapy (Table 2). Clinically, patients presented most commonly with odynophagia and/or oral pain (89%) followed by nausea or vomiting (20%). Most patients (91%) had mild disease, with a peak CTCAE grade of 1 or 2. Median time of mucositis onset after ICI initiation was 91 days (IQR, 27–174 days), with a shorter duration in the anti–CTLA-4 versus the anti–PD-1/L1 group (73 vs 96 days, respectively; P=.077). Nearly all patients (97%) presented with oral ulcers or aphthae (Figure 1), with a median duration of symptoms of 48 days (IQR, 19–99 days). Although most patients received supportive therapy, 36 (24%) needed immunosuppressants (systemic or topical steroids), with a median duration of 51 days (IQR, 26–81 days). Of these patients, 22 received systemic steroids alone, 7 received topical steroids alone, and the remaining 7 received a combination. No patient received biologic therapy for mucositis.
Oral mucositis.
(Courtesy of Andrea M. Perdue and John A. Thompson at the University of Washington, Seattle, Washington).
Citation: Journal of the National Comprehensive Cancer Network 19, 12; 10.6004/jnccn.2020.7697
Clinical Characteristics of Mucositis by Type of ICI Therapy
Overall, 88% of patients had clinical improvement or resolution of mucositis: 92% in the anti–PD-1/L1 group versus 76% in the anti–CTLA-4 group (P=.029). Seventeen patients (11%) were hospitalized for a median stay of 10 days (IQR, 6–20 days). Of those hospitalized, 4 (24%) had central line placement due to mucositis and 1 (6%) had line-related bloodstream infection. Six patients (4%) had mucositis compromising nutrition, necessitating support via tube feeding (2 using nasogastric feeding, 4 using percutaneous endoscopic gastrostomy tube) or total parenteral nutrition. Thirty-four percent of patients had recurrence of mucositis, leading to 1.3% of patients requiring rehospitalization. Among all patients, 64% had irAEs in addition to mucositis, with a higher incidence in patients given CTLA-4–based regimens than in those with anti–PD-1/L1–based regimens (82% vs 60%; P=.032). Of these irAEs, 25% involved the gastrointestinal system, including gastritis and enterocolitis. ICI therapy was interrupted in 77% of patients because of irAEs. The all-cause mortality rate at the end of the study period was 50% (Table 2).
Immunosuppressive therapy was associated with a longer duration of mucositis-related symptoms compared with nonimmunosuppressive therapy (84 vs 34 days; P=.002) (Table 3). The other parameters were comparable in these 2 groups. In the immunosuppressive therapy group, patients who received topical therapy generally had milder symptoms compared with those who received systemic therapy, and all patients had resolution of their symptoms (P > .05; supplemental eTable 1).
Clinical Characteristics and Outcomes of Mucositis by Immunosuppressive and Nonimmunosuppressive Treatment
We found that patients receiving anti–CTLA-4 therapy were more likely to have mucositis and other irAEs than were those receiving anti–PD-1/L1 therapy (P=.032; supplemental eTable 2). Basic risk factors at the time of mucositis diagnosis did not affect the severity or outcomes of mucositis.
Recurrence of Mucositis
Among 134 patients who achieved symptom improvement/resolution, 52 (39%) had recurrence of mucositis (Table 4). Recurrence was associated with the presence of coexisting irAEs (P=.038) and the requirement of immunosuppression for the initial mucositis event (P=.006). Median duration of symptoms was longer in patients with recurrence versus without (56 vs 36 days; P=.058). Univariate logistic regression analysis showed that the following factors were significantly associated with mucositis recurrence: dysphagia symptoms (odds ratio [OR], 3.222; P=.047), longer duration of symptoms (OR, 1.003; P=.051), and immunosuppressant use for the initial mucositis event (OR, 3.317; P=.004) (Table 5).
Clinical Characteristics of Patients With Responses or Resolution of Initial Mucositis Episodes
Univariate Logistic Regression Analysis for Recurrence of Mucositis
Overall Survival
Patients in whom ICI therapy was continued or resumed after interruption had significantly favorable OS (P=.037; Figure 2). We observed a complete separation in the OS curves for patients with and without recurrent mucositis, although the difference was not significant (supplemental eFigure 2A). In addition, OS was not associated with immunosuppressant use or the presence of other irAEs along with mucositis (P > .05) (supplemental eFigure 2B, C).
Overall survival based on ICI treatment status.
Abbreviation: ICI, immune checkpoint inhibitor.
Citation: Journal of the National Comprehensive Cancer Network 19, 12; 10.6004/jnccn.2020.7697
Discussion
ICI therapy can have a dramatic positive impact on OS in patients with advanced cancers.1–4 However, decreased immune regulation can involve a breakdown of tolerance to self-antigens, leading to the development of irAEs.5 Oral mucositis has not been well studied given the variations in its diagnosis, determination of causality, and mild presentation when compared with other irAEs.25 This study is the first focused analysis with the largest sample size to characterize the clinical presentations, response to therapy, and outcomes of ICI-related oral mucositis.
Our study showed that the median time to onset of mucositis was 3 months after ICI initiation, similar to ICI colitis.29 Patients receiving anti–CTLA-4–based therapy had earlier onset of mucositis, lower mucositis treatment response rates, and more irAEs than did those receiving anti–PD-1/L1 therapy, although the peak CTCAE grade of symptoms was comparable. irAEs of greater toxicity are more frequently related to anti–CTLA-4 therapy,30–33 possibly because of the different mechanisms of action of these agents. Although PD-1/L1 inhibition restores immune function and decreases the regulation of specific T cells inactivated due to high levels of antigen exposure, CTLA-4 inhibition leads to the activation and proliferation of a large number of effector T cells and decreases their regulation regardless of T-cell specificity, potentially leading to greater autoreactivity.34 Both mechanisms can lead to severe irAEs.
In our sample, most patients with mucositis had mild symptoms (CTCAE grade 1 or 2). Although 11% of patients did not receive treatment, the remainder needed supportive care (65%) or immunosuppressive therapy (24%). Management of mucositis was highly variable due to a lack of available guidelines. Most management strategies are extrapolated from guidelines for mucositis secondary to irradiation or treatment using other antineoplastic agents,35,36 although the pathophysiology differs starkly. Notably, regardless of the use of immunosuppressive therapy in patients with long symptom durations, we found negligible improvement in their clinical outcomes (eg, hospitalization, length of hospital stay, mucositis response rate) and a dramatically higher recurrence rate. These findings question the benefit of corticosteroids in the management and outcomes of mucositis and highlight potential complications.37 However, disease severity, timing of immunosuppressive therapy initiation, treatment duration, and concomitant medications and comorbidities can also confound the outcomes.
In our cohort, mucositis improved with supportive care in most patients. Sucralfate, an agent that creates a protective mucosal barrier, had mixed outcomes in mucositis treatment,38 although a few trials have shown improvement of radiation- and 5-FU–induced oral mucositis.39,40 Small case series have shown improvement of radiation-induced mucositis using PPIs, although they seem to be helpful only in patients with severe reflux symptoms.41 Although authors have cautioned against the use of PPIs without clear indication,42 largely due to the risk of hypersensitivity and cutaneous reactions,43–46 our findings illustrate the benefit of their use as first-line therapy for mild mucositis.
Topical immunosuppressive agents can serve as alternatives to systemic corticosteroids given their highly favorable adverse effect profiles. In our cohort, we observed that patients who received topical steroid therapy alone had lower mucositis grades, complete symptom improvement, fewer hospitalizations, and shorter hospital stays than did those undergoing systemic immunosuppression. In previous case studies, the use of topical corticosteroids in the management of inflammatory mucositis in patients with graft-versus-host disease was promising.47–49 Bertelli et al49 described a patient with severe oral mucositis limiting nutritional intake whose condition was completely resolved using systemic methylprednisolone followed by oral viscous budesonide. Our findings suggest that topical immunosuppressants can be beneficial in the management of IMM, which should be further explored.
Our findings illustrate the critical need for a standardized approach to managing IMM. Topical agents should be considered before systemic therapy. Elad et al50 reported the efficacy of topical immunomodulators (azathioprine, benzydamine, and tetracyclines) in managing IMM refractory to topical corticosteroids. In addition, high-risk patients who would benefit from maintenance therapy to prevent recurrence of IMM should be identified. If patients are refractory to steroid treatment, then biologics may be considered as a potential salvage option. For instance, Horisberger et al51 reported success in treating refractory mucositis and esophageal stenosis using anti–PD-1 therapy and tocilizumab, an IL-6 blocker. Other studies have shown promising outcomes in patients with immune-mediated colitis treated using infliximab or vedolizumab as adjunct or salvage therapy, with 70% to 85% clinical improvement, and a much lower recurrence rate with vedolizumab maintenance therapy among patients at high risk for recurrence of immune-mediated colitis.52–55 Unfortunately, evidence regarding the efficacy of biologic therapy for upper gastrointestinal toxicities is limited.
In addition to medical options, oral microbial derangements were recently found to be associated with recurrent aphthous stomatitis and ulceration.56–58 Wang et al59 showed that the reconstitution of the gut microbiome via fecal microbiota transplantation in patients with immune-mediated colitis led to the resolution of inflammation and the upregulation of colonic regulatory T lymphocytes. We speculated that oral microbiome modification may provide a similar benefit to mucositis and could be explored further as a novel therapeutic avenue.
As shown previously, irAEs are generally associated with improved OS, progression-free survival, and ICI efficacy in patients with advanced cancer.11,60–65 Severe forms of irAEs—higher CTCAE grade, more organ involvement, and irAE-related complications—have been associated with longer OS.17,37,65 An irAE may recur despite resolution of the initial event and ICI discontinuation, as reported previously.51,66–68 A severe, refractory irAE prompts cessation of ICI therapy for the underlying malignancy in view of poor quality of life, which is likely reflective of the long-lasting systemic effect of ICIs and lingering toxicities that may be associated with favorable oncologic outcomes. This is supported by previous studies of other irAEs16,17 and suggested by the superior OS in patients with ICI continuation in this study. An OS benefit was not manifested in our patients with recurrent mucositis, perhaps because of the small sample size and other confounders. Overall, these findings raise the question of how to optimize ICI treatment duration while effectively managing irAEs.
Our study has some limitations. First, data collection and analysis were limited by the retrospective, single-center design and small sample size. Second, the true incidence and severity of mucositis may have been underrepresented with mild or subclinical cases. The CTCAE grading system, although standardized, relies purely on self-reported documentation, with wide variation. Third, diagnosis, monitoring, and management of mucositis were performed at the discretion of the provider and bore no standardized management approach. Patients who received treatment for coexisting irAEs may have confounded outcomes of mucositis. Finally, we did not perform landmark analysis given neglectable immortal time and did not conduct subgroup OS analysis for different types of malignancy because of the small sample size. However, despite these limitations, we present new, important data that generate hypotheses in a clinically relevant setting and that support further investigation of this topic.
Conclusions
IMM is an underrecognized irAE in patients receiving ICI therapy, and is often mild and effectively managed using supportive medications. Rarely, patients with severe IMM require hospitalization, immunosuppression, nutrition support, and disruption of ICI treatment. Our findings showed that up to 39% of patients may experience recurrence, which is associated with longer duration of symptoms and immunosuppressive therapy for the initial episode, and that ICI interruption due to irAEs shortens OS. Further studies are warranted to identify risk factors associated with refractory mucositis, clarify the role and logistics of immunosuppressive therapy, and develop standardized diagnostic and management strategies to optimize the clinical benefit of ICI therapy in patients with mucositis.
Acknowledgments
Editing of this article was provided by Scientific Publications, Research Medical Library at The University of Texas MD Anderson Cancer Center. Ethics approval for this study was granted by the Institutional Review Board of The University of Texas MD Anderson Cancer Center (PA18-0472). Patient consent was waived for this study. The datasets used and analyzed in this study are available from the corresponding author upon reasonable request.
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