Radiation-Induced Lymphopenia is a Causal Mediator of Survival after Chemoradiotherapy for Esophagus Cancer

Purpose : Radiation-induced lymphopenia (RIL) is common during chemoradiotherapy. Severe lymphopenia is associated with reduced survival. Proton beam therapy (PBT), with its substantially more compact dose distributions, spares circulating lymphocytes and immuno-organs at risk to a greater extent than does photon therapy. Recent studies comparing PBT to photon radiotherapy, specifically intensity-modulated radiation therapy (IMRT), for esophageal cancer (EC) showed that the incidence of grade 4 RIL (G4RIL) is significantly reduced among patients receiving PBT for esophageal cancer. However, whether the extent of this reduction has a direct causative link with improved survival is unknown. This study applies causal mediation analysis to answer this question. Methods and Materials : We retrospectively assessed 734 patients treated with concurrent chemoradiotherapy for biopsy-proven EC from 2004 through 2017. To address the potential for bias in the choice of radiation modality, propensity score analysis was used to evaluate and reduce imbalances between the PBT and IMRT cohorts. Causal mediation analysis was applied to decompose the total effect of radiation modality on overall survival (OS) into indirect (mediated through G4RIL) and direct effects. Results : We found that PBT was associated with significantly lower incidence of G4RIL and prolonged OS compared with IMRT (odds ratio [OR]= 0.41, 95% confidence interval [CI] 0.28 to 0.60, P<0.001). In the propensity-matched cohort of 506 patients (253 PBT, 253 IMRT), G4RIL risk reduction with PBT vs. IMRT translated into a 5% reduction in the relative rate of death (P=0.032). Mediation of G4RIL explained ∼14.5% of the difference in OS. Conclusions : G4RIL was found to mediate survival; however, statistically significant direct effect of PBT on survival was not observed. In other words, the survival benefit from protons over photons in this EC cohort was lost in the absence of G4RIL risk reduction.