Comparative Effectiveness of Cytoreductive Surgery and Systemic Therapy in Stage IV Gastroenteropancreatic Neuroendocrine Neoplasms

The definitive contribution of surgical cytoreduction in stage IV gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) remains unclear, as corroborating data come largely from retrospective reviews that infrequently compare surgery with current systemic regimens. Drawing on a nationwide oncology registry, we compared overall survival (OS) with cytoreductive surgery versus systemic therapy alone. Eligible adults had a diagnosis of stage IV, well-differentiated GEP-NEN documented in the National Cancer Database between 2004 and 2020. Patients were grouped by demographic, tumor, and institutional attributes. The three therapeutic strategies evaluated were cytoreductive surgery (CRS) as the sole modality, CRS in conjunction with systemic chemotherapy, and systemic chemotherapy without surgery. Overall survival (OS) was examined via Kaplan-Meier (KM) estimation and multivariable Cox proportional hazards regression. The analytic set included 3,183 individuals with stage IV GEP-NENs. Nearly 70% (69.8%) were managed with CRS alone, a small fraction (6.7%) received both CRS and systemic chemotherapy, and the remaining 23.4% underwent systemic therapy exclusively. Median overall survival (OS) diverged substantially across these strategies: patients receiving CRS alone reached a median of 140.9 months, those receiving both modalities had a median of 96.2 months, and those receiving systemic therapy alone had a median of 51.6 months (P < 0.001). The advantage conferred by CRS within each histologic grade category, evident in G1–G2 tumors (140.9 vs. 96.2 vs. 53.6 months; P < 0.001), was also observed in G3 well-differentiated tumors (39.8 vs. 13.1 vs. 9.6 months; P < 0.001). These benefits extended across the range of primary organ sites. For midgut primaries, median OS measured 157.6, 99.2, and 87.5 months, respectively (P < 0.001); for pancreatic primaries, the figures were 117.5 months, not reached, and 50.8 months (P < 0.001). In a multivariable framework, advancing age, lower socioeconomic standing, higher comorbidity indices, colorectal primary location, positive resection margins, and increasing tumor grade independently predicted worse survival. A surgery delay beyond 35 days from diagnosis was associated with more favorable survival outcomes. CRS emerged as an independent predictor of longer OS (HR = 0.80; 95% CI: 0.67-0.94). Receipt of systemic chemotherapy, by contrast, was independently tracked with elevated mortality risk (HR = 1.71, 95% CI: 1.36-2.17). Surgical cytoreduction in metastatic GEP-NENs corresponded to a clinically meaningful survival gain over management with systemic therapy alone. This observation was reproduced within every histologic grade and primary site examined. These results lend weight to the practice of offering CRS to carefully chosen patients and highlight the pressing requirement for prospective study designs to confirm these findings.