To evaluate the clinical impact of the dose to structures not routinely constrained in the radiation treatment (RT) of stage III NSCLC, such as the left anterior descending artery (LAD) and the estimated dose to the immune cells (EDIC).

The dataset of all consecutive patients affected by stage III NSCLC and treated with definitive RT between 2012 and 2022 at our Institution were retrieved in this IRB approved retrospective study. The LAD was manually contoured following published guidelines. EDIC was calculated according to the model by Jin. Overall Survival (OS) was the primary endpoint of the study. Kaplan-Meier and Cox logistic regression statistics were used. Receiver operating characteristic curves evaluated cutoff DVH values.

108 patients were analyzed with a median follow-up of 52 months (95% CI 27.5–76.5). Median RT dose was 60 Gy (54–69.3 Gy). Median OS was 29 months (95% CI 10.2–47.8). On multivariate analysis, when evaluating the EDIC as a continuous variable, EDIC (HR 1.4, 95% CI 1.08–1.8, P = 0.009) and mean heart dose (MHD) < 10 Gy (HR 1.8, 95% CI 1.0-3.2, P = 0.03) were significantly associated with OS. When the EDIC was evaluated as a categorical variable, EDIC ≥ 5 Gy (HR 2.2, 95% CI 1.2–4.1, P = 0.008), MHD < 10 (HR 1.9, 95% CI 1.1–3.2, P = 0.01) and LAD V15 < 47.5% (HR 0.5, 95% CI 0.2–0.9, P = 0.02) were significantly associated with OS. PTV was the only parameter significantly associated with EDIC > 5 Gy (HR 16,6 95% CI 4.5–61.3, P < 0.001), with a cutoff value of 457.1 cc.

The relevant impact of the EDIC on the outcome of stage III NSCLC patients treated with RT is confirmed. The EDIC threshold of 5 Gy here reported merits prospective validation. Our results also reinforced the importance of LAD contouring and optimization in the clinical practice of RT for stage III NSCLC patients.