Differential neurotoxicity patterns across neuroendocrine tumor grades: A real-world analysis of 12,847 patients.

640 Background: Neuroendocrine tumors (NETs) exhibit substantial heterogeneity across WHO grades, yet treatment-related neurotoxicity is poorly characterized. We hypothesized that higher-grade NETs have increased neurotoxicity risk, which may inform monitoring and early intervention. Methods: Retrospective analysis of 12,847 NET patients (Grade 1: 5,234; Grade 2: 6,018; Grade 3: 1,595) treated systemically in the TriNetX Global Health Research Network (2015–2024). NET cases were identified using ICD-10 codes for malignant carcinoid/neuroendocrine tumors (C7A.xx by primary site, C7B.xx for metastatic, and C25.x for pancreatic NETs). Grade (G1: Ki-67 ≤2%; G2: 3–20%; G3: >20%) was obtained from structured pathology and tumor registry fields mapped within TriNetX; free-text clinical notes were not accessed. Neurotoxicity was classified as mild–moderate (Grade 1–2) or severe (Grade 3–4). Primary endpoints were incidence and severity by grade; secondary endpoints included hospitalization and long-term sequelae. Propensity score matching adjusted for age, sex, comorbidities, prior treatments, and tumor burden. Cox models assessed time-to-event outcomes. Results: Neurotoxicity incidence increased with tumor grade: 18.2% (Grade 1), 31.7% (Grade 2), 47.9% (Grade 3). Adjusted OR for Grade 3 vs Grade 1: 3.84 (95% CI 3.42–4.31, p