Timing of immune checkpoint inhibitor infusion predicts survival in advanced esophageal squamous cell carcinoma: A retrospective cohort study.

Background: Esophageal squamous cell carcinoma (ESCC) is a highly lethal malignancy for which immune checkpoint inhibitors (ICIs) have improved outcomes, yet significant inter-patient variability in response persists. Emerging evidence suggests that circadian rhythms modulate anti-tumor immunity, but the impact of ICI infusion timing on ESCC prognosis remains unexplored. Objective: To determine whether the timing of ICI infusion impacts survival outcomes in patients with advanced ESCC and to identify an optimal infusion time window. Design: A single-center, retrospective cohort study. Methods: We included 339 patients with advanced ESCC who received ICI therapy at Zhejiang Cancer Hospital between June 2018 and September 2022. Infusion timing was examined using two metrics: (i) first infusion time, and (ii) average infusion time across the first three cycles. Restricted cubic spline models were applied to explore dose-response relationships with infusion time as a continuous variable. Patients were categorized as early (before 14:00) or late (at or after 14:00) for each metric. Survival outcomes were analyzed using univariate and multivariate Cox proportional hazards models and Kaplan-Meier methods. Sensitivity analyses included an alternative 13:30 cutoff and a subgroup analysis of patients receiving ICI monotherapy. The study was conducted in compliance with the STROBE guidelines. Results: In the primary analysis of first infusion time, each one-hour delay was associated with increased risks of disease progression (HR=1.049, 95% CI: 1.003-1.097, P=0.036) and mortality (HR=1.062, 95% CI: 1.014-1.112, P=0.010). Kaplan-Meier analysis showed significantly better median PFS (6.2 vs. 5.3 months, P=0.010) and OS (13.3 vs. 12.4 months, P=0.026) in the Early-first versus Late-first group. In the secondary analysis of average infusion time during the first three cycles, each one-hour delay increased progression risk (HR=1.073, 95% CI: 1.001-1.151, P=0.027) and mortality risk (HR=1.092, 95% CI: 1.017-1.172, P=0.015), with Kaplan-Meier analysis showing a trend toward improved median PFS (6.2 vs. 5.6 months, P=0.098) and OS (13.4 vs. 12.1 months, P=0.057) in the Early-3M versus Late-3M group. Restricted cubic spline analysis revealed a nearly linear dose-response relationship (nonlinearity P>0.05). Conclusion: The timing of ICIs infusions may be an independent prognostic factor for survival in advanced ESCC. Administration before 14:00 was associated with improved PFS and OS.