Rethinking stage IVB gallbladder cancer: Decoupling N2M0 from M1 via de-escalation, chemotherapy, and risk stratification.

INTRODUCTION

In the AJCC 8th edition, N2M0 and M1 gallbladder cancer (GBC) are classified into Stage IVB, leading clinicians to treat them identically. This study separates N2M0 from M1 disease, re-evaluating chemotherapy, surgical quality, and establishing a clinical risk stratification system (CRSS).

MATERIALS AND

METHODS

Stage IVB GBC patients (2000-2022) were identified from the SEER database. A 1:3 propensity score matching (PSM) balanced N2M0 and M1 baseline characteristics. Overall survival was compared, optimal lymph node ratio (LNR) was identified, and the prediction model internally verified using 1000 bootstrap resamples.

RESULTS

From 7270 initial IVB patients, PSM matched 125 N2M0 and 343 M1 patients. N2M0 patients demonstrated superior median overall survival versus M1 patients (17 vs. 9 months, P = 0.001). However, this survival advantage depended entirely on adjuvant chemotherapy. Untreated N2M0 patients had a worse prognosis than treated M1 patients (P = 0.002). For N2M0 patients, extended multi-organ resection offered no survival benefit over standard radical cholecystectomy (HR = 0.724, P = 0.225). A lower LNR (<0.875) predicted longer survival. We developed a three-tier CRSS separating median survival: 22 months (Tier 1: Low LNR + Chemotherapy), 12 months (Tier 2: High LNR or No Chemotherapy), and 9 months (Tier 3: M1 Systemic Disease). The nomogram C-index was 0.676.

CONCLUSIONS

N2M0 GBC is biologically different from M1 disease, and should not be grouped together in future staging. For N2M0 patients, the best strategy is to focus on thorough lymph node dissection and mandatory adjuvant chemotherapy, not extended organ resection.