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

## TL;DR

Surgery improves survival in metastatic GEP-NENs compared to systemic therapy alone, across different tumor grades and locations.

## Contribution

This study provides national evidence that surgical cytoreduction offers a survival benefit over systemic therapy in metastatic GEP-NENs.

## Key findings

- Cytoreductive surgery alone was associated with a median survival of 140.9 months, significantly higher than systemic therapy alone (51.6 months).
- The survival benefit of surgery was consistent across histologic grades and primary tumor sites, including midgut and pancreatic NENs.
- Systemic chemotherapy was associated with increased mortality in multivariable analysis.

## Abstract

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.

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.

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).

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.