OBJECTIVE: To evaluate the prognostic impact of primary surgery on patients with HPV-independent, advanced or metastatic endocervical adenocarcinoma (EAC) who typically exhibit poor survival outcomes and resistance to conventional therapies such as chemoradiotherapy. METHODS: A bi-institutional retrospective study was conducted at Samsung Medical Center and Taiwan National University Hospital. Between 2001 and 2023, 92 patients with HPV-independent advanced or metastatic EAC were included. Patients were divided into two groups: 54 (58.7%) underwent primary surgery and 38 (41.3%) received non-surgical treatments, including definitive radiotherapy or palliative chemotherapy. Kaplan-Meier analysis was used to compare progression-free survival (PFS) and overall survival (OS) between groups. Multivariate analysis was performed to identify independent prognostic factors. RESULTS: The surgery group demonstrated significantly improved outcomes, with a median PFS of 19.2 months, compared with 10.0 months in the non-surgery group (P <
0.001). Median OS was not reached in the surgery group, whereas it was 24.1 months in the non-surgery group (P = 0.002). Multivariate analysis showed that non-surgical treatment was an independent predictor of poor PFS (hazard ratio [HR] 2.25
95% confidence interval [CI] 1.18-4.29
P = 0.013) and OS (HR 3.25
95% CI 1.37-7.73
P = 0.008). Additionally, the recurrence rate was significantly lower in the surgery group (55.6%) than in the non-surgery group (84.2%
P = 0.006). CONCLUSION: Primary surgery significantly improves survival outcomes in patients with HPV-independent advanced or metastatic EAC. These findings suggest that surgery should be considered as part of a multimodal treatment strategy for this aggressive subtype, highlighting the need for individualized therapeutic approaches beyond standard chemoradiotherapy protocols.