Surgical cytoreduction versus systemic therapy in patients with metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NENS): a national cancer database analysis (NCDB)

Background: The optimal role of surgical cytoreduction in metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) remains uncertain, as supporting evidence is largely retrospective and rarely compares surgery with contemporary systemic therapy. Using a national cancer registry, we evaluated overall survival (OS) associated with cytoreductive surgery compared with systemic therapy alone. Methods: Adult patients with stage IV well-differentiated GEP-NENs were identified in the National Cancer Database (2004-2020). Demographic, tumor, and facility variables stratified patients. Treatment groups included cytoreductive surgery (CRS) alone, CRS plus systemic chemotherapy, and systemic therapy alone. Overall survival (OS) was compared using Kaplan-Meier (KM) analysis and multivariable Cox proportional hazards models. Results: Among 3,183 patients with stage IV GEP-NENs, 69.8% underwent cytoreductive surgery (CRS) alone, 6.7% received CRS plus systemic chemotherapy, and 23.4% received systemic therapy alone. Median overall survival (OS) differed significantly by treatment: CRS alone, 140.9 months; CRS plus chemotherapy, 96.2 months; and systemic therapy alone, 51.6 months (p < 0.001). The survival advantage of CRS persisted across histologic grades, including both G1-G2 tumors (140.9 vs. 96.2 vs. 53.6 months, p < 0.001) and G3 well-differentiated tumors (39.8 vs. 13.1 vs. 9.6 months, p < 0.001). Survival benefits were also observed across primary tumor sites. In midgut NENs, median OS was 157.6 vs. 99.2 vs. 87.5 months (p < 0.001), and in pancreatic NENs, 117.5 months vs. not reached vs. 50.8 months (p < 0.001). On multivariable analysis, older age, lower SES, higher comorbidity burden, colon or rectal primaries, positive margins, and higher tumor grade were associated with worse survival. Longer time from diagnosis to surgery (>35 days) was associated with improved survival. CRS remained independently associated with improved OS (HR 0.80, 95% CI 0.67-0.94), while receipt of systemic chemotherapy was associated with increased mortality (HR 1.71, 95% CI 1.36-2.17). Conclusion: Surgical cytoreduction was associated with significantly improved survival compared with systemic therapy alone in metastatic GEP-NENs, with consistent benefits across histologic grades and primary tumor sites. These findings support considering CRS in appropriately selected patients and underscore the need for prospective validation.