EDRIC-associated immune injury correlates with one-third of the survival detriment of elective nodal irradiation in esophageal squamous cell carcinoma

Background and purpose The survival benefit of elective nodal irradiation (ENI) over involved-field irradiation (IFI) in ESCC remains unclear, suggesting uncharacterized systemic costs. Radiation-induced lymphopenia (RIL) is increasingly recognized as an adverse prognostic factor that may undermine antitumor immunity. We investigated whether ENI increases EDRIC, a validated dosimetric biomarker of RIL, and whether EDRIC mediates ENI’s survival disadvantage via immune injury. Methods This retrospective cohort study analyzed 279 ESCC patients treated with definitive concurrent chemoradiotherapy (2011- 2015). EDRIC was computed using a validated model incorporating mean lung, heart, and body doses and fraction number. Inverse probability weighting balanced 14 baseline covariates. Causal mediation analysis within the counterfactual framework quantified the proportion of the total effect of radiotherapy field strategy on OS mediated by EDRIC. Results ENI significantly elevated EDRIC compared with IFI (8.17 vs. 7.42 Gy; P = 0.01). High EDRIC (>7.8 Gy) independently predicted worse OS (HR = 1.746; P<0.001), PFS, and LRFFS. The IFI- low EDRIC subgroup achieved the best 10- year OS (28.3%), significantly superior to both IFI- high EDRIC (12.0%; P = 0.004) and ENI- H group (13.5%; P = 0.024). ENI increased mortality risk by 52% (total effect Rte=1.52; P = 0.016). Causal mediation analysis revealed that EDRIC mediated 33% of this effect (indirect effect Rtnie=1.13; 95% CI: 1.02-1.29; P = 0.015). Conclusion Elevated EDRIC was statistically associated with one-third of ENI’s excess mortality risk. Applying the exploratory 7.8 Gy median cutoff, low-EDRIC IFI was associated with superior long-term survival, suggesting a potential immunoprotective strategy that warrants further validation. These findings support optimizing radiotherapy field design to preserve host immunity in future combination regimens.