Role of fecal elastase in the context of diarrhea related to immune checkpoint inhibitors

Background: Immune checkpoint inhibitors (ICIs) have restructured cancer therapy but often cause gastrointestinal adverse events, especially diarrhea. Although fecal elastase assesses pancreatic function, its utility in ICI-induced diarrhea is unclear. This study explores whether low fecal elastase reflects true pancreatic insufficiency or stool dilution. Methods: We retrospectively reviewed ICI-treated patients with diarrhea who underwent fecal elastase testing between 2016 and 2024 at two academic centers (The University of Texas MD Anderson Cancer Center, and the Cleveland Clinic), analyzing clinical, diagnostic, and treatment data. Results: Among 388 patients (median age 65.2 years [interquartile range 56.1–72.5 years]), 213 (54.9%) were male and 280 (72.2%) were White. Alcohol use was reported in 174 (44.8%) of patients. Stage III-IV cancer was present in 244 (62.9%), and 223 (57.5%) received programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1). Diarrhea was the most common symptom (198 patients, 51.0%). Fecal elastase was normal in 220 (56.7%) and low in 168 (43.3%) of the patients. The low elastase group had significantly higher calprotectin (356.0 vs. 124.9 mcg/g; P <0.001), indicating greater gastrointestinal inflammation. Active inflammation on colonoscopy/flexible sigmoidoscopy was observed in 86/148 (58.1%) patients with low elastase and 77/116 (66.4%) patients with normal elastase ( P =0.170). Histologic inflammation was observed in 84/123 (68.3%) and 90/126 (71.4%), respectively ( P =0.590). Pancreatic enzyme replacement therapy use was higher in the low elastase group (33/168 [19.6%] vs. 3/220 [1.4%]; P <0.001). Diarrhea remission rates were similar between the low and normal elastase groups (125/168 [74.4%] vs. 152/220 [69.1%]; P =0.251). Baseline pancreatic abnormalities were rare and unrelated to elastase levels. Conclusions: In ICI-related diarrhea, low fecal elastase levels often accompany inflammatory findings and elevated biomarkers, yet outcomes are similar to those with normal levels. This suggests low elastase is likely dilutional. If pancreatic disease is suspected, fecal fat testing can be considered for further confirmation of pancreatic insufficiency before initiation of pancreatic enzyme replacement therapy.