Comparisons of Non-Oral Immune-Related Adverse Events Among Patients With Cancer With Different Oral Toxicity Profiles

Abstract

Objectives: Immune-related adverse events (irAEs) are common. Oral irAEs tend to cluster in patients who experience concurrent toxicities. We aimed to characterize the frequency and trajectory of non-oral irAEs in patients who developed oral irAEs, assess their relationship with non-oral irAEs, and compare those characteristics with patients without oral irAEs.

Methods: A retrospective chart review was conducted to identify patients who started ICIT between December 11, 2011, and September 15, 2019 (n = 4683) in the Mass General Brigham Registered Patient Data Registry. Demographic information, cancer diagnosis, ICIT regimen, treatment duration, and time and number of infusions to irAE onset were recorded. Non-oral irAEs were categorized into 13 groups. Patients with melanoma, pulmonary cancer, or head and neck cancer who had oral irAEs were then matched with those without oral irAEs to compare the prevalence of concomitant non-oral irAEs.

Results: Three hundred and fourteen patients with oral irAEs with a mean age of 65.9 ± 12.6 years (43.3% females) were included. Patients with multiple oral irAEs were more likely to have non-oral irAEs (OR: 2.7, 95% CI, 1.3-3.5), including cutaneous (OR: 1.7, 95% CI, 1.1-3.0), rheumatological (OR: 2.2, 95% CI, 1.1-4.2), thyroid (OR: 2.4, 95% CI, 1.2-4.9), and neurological irAEs (OR: 2.5, 95% CI, 1.0-6.3). Compared to matched patients with non-oral irAEs, patients with oral irAEs were more likely to have cutaneous (OR: 1.7, 95% CI, 1.0-2.8) and thyroid (OR: 2.86, 95% CI, 1.1-7.5) irAEs. The development of oral and non-oral irAEs is often coincidental.

Conclusion: Patients who have non-oral irAEs should be monitored for development of oral irAEs for prompt management.

Keywords: dysgeusia; head and neck cancer; immune checkpoint inhibitor therapy; immune-related adverse events; lung neoplasms; melanoma; oral mucositis; xerostomia.

Figure 1.

This is a step-by-step illustration of the inclusion of patients with oral irAEs and matched patients without oral irAEs. Of 1565 patients who had oral conditions after ICIT, 314 patients were considered presenting with oral irAEs and 1248 patients without (3 patients were excluded due to conflicting descriptions). In 314 patients with oral irAEs, patients with a single oral irAE were compared with those with multiple oral irAEs. In addition, 153 patients with oral irAEs were matched (1:1 ratio) with patients without oral irAEs for further analysis. Abbreviations: CT: chemotherapy; EMR: electronic medical records; HNRT: head and neck radiation therapy; ICIT: immune checkpoint inhibitor therapy; irAEs: immune-related adverse events.

Figure 2.

Comparison of the trajectory of the oral and non-oral irAEs in the patients who had oral irAEs. (A) Timeline illustrating the number of oral and non-oral immune-related adverse events on a biweekly basis. The histogram shows the distribution of the onset timeline of both oral and non-oral irAEs in the 314 patients who had oral irAEs. We focus on the 3 major non-oral irAEs that affect the skin, the gastrointestinal tract, and the lung. The temporal distribution of non-oral irAE was similar to that of oral irAEs. (B) Boxplots show the median, interquartile range, and outlines of the time to the onset of oral and major non-oral irAEs. There is no statistically significant difference among the symptom onset time of the oral and non-oral irAEs (P = .205, Kruskal Wallis test). Abbreviations: ICIT: immune checkpoint inhibitor therapy; irAEs: immune-related adverse events.

Figure 3.

Number of ICIT infusions when patients started to have the onset of oral and non-oral irAEs. The histogram shows a similar distribution of the total number of ICIT infusions by the onset of oral and major non-oral irAEs. Abbreviations: ICIT: immune checkpoint inhibitor therapy; irAEs: immune-related adverse events.

Figure 4.

Association of oral irAEs and non-oral irAEs in patients with melanoma or lung cancer: Patients with melanoma (n = 44) and lung cancer (n = 76) with oral irAEs were matched with the same number of patients without oral irAEs as previously described. The risk of having a non-oral irAE associated with oral irAEs was assessed by the odds ratios (dot) with 95% confidence intervals (bar). Patients without oral irAEs were considered as the reference. Oral irAEs were associated with cutaneous irAEs in patients with melanoma and were associated with rheumatological irAEs in patients with lung cancer. Abbreviations: irAEs: immune-related adverse events.