Abstract
BACKGROUND: While immune-chemotherapy represents the first-line standard for advanced esophageal squamous cell carcinoma (ESCC), fluorouracil-platinum (FP) and taxane-platinum (TP) regimens remain the fundamental cytotoxic backbones. Despite their widespread clinical application, robust comparative data on their relative efficacy and safety in real-world populations are lacking, creating an evidence gap that hampers optimal backbone selection. OBJECTIVES: This study aimed to compare the effectiveness and safety of first-line FP versus TP chemotherapy in patients with advanced ESCC using large-scale, multicenter real-world data. DESIGN: This was a large-scale, multicenter, retrospective cohort study employing a propensity score-matched design to compare two treatment cohorts: patients receiving FP chemotherapy versus those receiving TP chemotherapy for unresectable advanced ESCC. Data spanned from January 2013 to December 2023, ensuring a contemporary and representative treatment population. METHODS: Data were extracted from a national cancer database. Patients with unresectable ESCC receiving first-line FP or TP chemotherapy were included. Propensity score matching (PSM) in a 1:1 ratio was used to balance the baseline characteristics. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), duration of response (DOR), overall survival (OS), and safety. RESULTS: After PSM, 3440 matched pairs were generated (N = 6880 total). The median follow-up was 6.3 years. The TP regimen demonstrated superior short-term efficacy compared to FP: median PFS was 5.2 versus 4.4 months (hazard ratio (HR), 0.91; 95% confidence interval (CI), 0.86-0.96; p = 0.0004); ORR was 22.2% versus 19.5% (p = 0.026); and among responders, median DOR was 10.8 versus 4.4 months (HR, 0.77; 95% CI, 0.64-0.94; p = 0.009). However, no significant difference was observed in OS (median OS: 15.9 vs 16.1 months; HR, 1.00; 95% CI, 0.94-1.06; p = 0.901). Toxicity profiles were distinctly regimen-specific, with FP associated with higher rates of hand-foot syndrome and gastrointestinal events, whereas TP was linked to higher incidences of neuropathy and alopecia. CONCLUSION: In this large-scale real-world analysis, first-line TP chemotherapy provided significantly better disease control and response durability compared to FP in advanced ESCC, albeit without an OS benefit. The distinct toxicity profiles of each regimen offer additional considerations for individualized treatment selection. These findings offer critical evidence to guide backbone selection in contemporary treatment algorithms.