Circulating-blood dose is associated with severe lymphopenia in thoracic radiotherapy, but added simulation complexity provides no detectable incremental information.

Abstract Purpose: To compare scalar circulating blood dose summaries, assess whether associations with grade 3 or higher lymphopenia and overall survival persisted after planning target volume (PTV) adjustment, and distinguish scalar from exploratory dynamic blood dose analyses. Methods and Materials: The assembled dataset included 133 patients from 2 retrospective thoracic radiation cohorts; 121 entered the dosimetric main analysis and 116 passed a post hoc dosimetric gate. Six scalar exposures were compared: an ICE3 (Immune Circulation radiation Exposure Estimator Engine) 10 compartment mean-dose metric, corrected effective dose to immune cells (EDIC), body remainder dose, a hematological dose (HEDOS) derived organ-mean approximation, mean lung dose, and mean heart dose. Logistic base models included baseline absolute lymphocyte count, concurrent chemotherapy, and cohort; PTV was then added. Overall survival used cohort-stratified Cox models on an endpoint-specific common set. Benjamini Hochberg correction was applied within prespecified 6exposure families and, separately, across 3 selected post hoc bootstrap contrasts. Results: The lymphopenia analysis included 94 patients and 69 events. After PTV adjustment, the HEDOS derived approximation remained nominally associated (odds ratio, 2.54; 95% confidence interval, 1.18-5.45; P=.017; q=.102), but no exposure survived false-discovery-rate control. The survival set contained 92 patients and 42 deaths; no PTV adjusted scalar exposure was associated with survival (all q>=.531). In post hoc analyses, the standardized association of mean heart dose with overall survival was more positive than that of ICE3 (difference in log hazard ratios, 0.44; 95% CI, 0.13 0.94; multiplicity-adjusted q=.024). The corresponding contrast with the HEDOS derived approximation did not meet the adjusted significance threshold (q=.053). These coefficient contrasts do not establish superior predictive performance or causality. Exported ICE3 kinetic summaries had no false-discovery-rate-significant residual associations. A 13 case HEDOS bDVH audit showed little change under one continuous versus 10 second gap perturbation. Conclusions: PTV adjustment attenuated scalar blood-dose associations with severe lymphopenia, and no scalar exposure retained a multiplicity-robust survival association. The selected mean heart dose coefficient contrast is hypothesis generating and does not establish superior prediction. The primary cohort comparison evaluated a HEDOS derived organ-mean approximation rather than the full dynamic HEDOS framework; therefore, these findings should not be interpreted as evidence against the potential value of particle level blood dose distributions or time-dependent blood-flow modeling.