Management of Diarrhea in Patients Receiving Liposomal Irinotecan-Based Regimens: Mechanisms, Clinical Impact, and Evidence-Based Strategies

Liposomal irinotecan (nal-IRI) has emerged as a cornerstone in the treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC), particularly in combination with 5-fluorouracil and leucovorin (5-FU/LV) following progression on gemcitabine-based therapy. Despite its demonstrated survival benefit, gastrointestinal toxicity—most notably diarrhea—remains a clinically significant adverse event that can compromise dose intensity, treatment adherence, and patient quality of life. Diarrhea associated with irinotecan-containing regimens is mechanistically complex, encompassing both acute cholinergic and delayed secretory components mediated by mucosal injury and enterohepatic recirculation of the active metabolite SN-38. The liposomal formulation alters the pharmacokinetic profile of the drug, prolonging systemic exposure while maintaining toxicity risks. This review provides a comprehensive and updated overview of the pathophysiology, incidence, and clinical implications of diarrhea in nal-IRI–based regimens. Evidence-based management strategies are discussed, including pharmacologic interventions, supportive care, dose modifications, and patient education. Emerging therapeutic approaches—including microbiome modulation and pharmacogenomic-guided therapy—are also explored. A multidisciplinary and proactive management approach is essential to optimize outcomes and minimize toxicity.