Timing of immune checkpoint inhibitor infusion predicts survival in advanced esophageal squamous cell carcinoma: A retrospective cohort study
Wenjing Wang, Chengyuan Fan, Li Shen, Ruijie Ni, Lisha Ye, Weimin Mao, Wei Hong, Xiaoling XuBackground
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.