Thymic radiation is associated with worse outcomes in patients with NSCLC

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BACKGROUND: Emerging evidence indicates the functional importance of the thymus in adult health and may influence oncologic outcomes, yet current radiotherapy (RT) practice does not consider the thymus as an organ of interest. Because RT may incidentally expose the thymus to radiation, we hypothesized that thymic radiation dose is negatively associated with major clinical outcomes. PATIENTS AND METHODS: This multicohort analysis included 1,107 patients with non-small cell lung cancer (NSCLC), including the phase III RTOG-0617 trial (n=460) and two independent real-world cohorts of patients treated with chemoradiotherapy alone (n=422; HARVARD-CRT) or in combination with consolidation immunotherapy (n=225; HARVARD-DURVA). We quantified thymic function using a deep-learning system that assessed thymic radiographic characteristics as a proxy for thymic function. Mean Thymic Dose (MTD) was used to measure thymic radiation exposure. RESULTS: Incidental thymic irradiation was associated with increased risk of distant metastases after confounding adjustments. Concretely, a 1Gy increase in MTD was associated with an increased distant metastasis risk of 1.57-4.21% (RTOG-0617: adjusted hazard-ratio [aHR]=1.29; P=0.0028; HARVARD-CRT: aHR=1.33; P=0.011; HARVARD-DURVA: aHR=1.95; P=0.007). In Thymic-Health-stratified analysis, patients with preserved Thymic Health prior to radiotherapy appeared to be at particularly greater risk, whereas no significant associations emerged in patients with impaired Thymic Health. One-year follow-up imaging demonstrated dose-dependent declines in thymic health and lower circulating lymphocyte counts, consistent with a possible biological link between thymic irradiation and immune competence loss. An exploratory feasibility study suggested that re-optimizing RT planning for thymic sparing can be achieved without compromising tumor coverage or cardiopulmonary constraints. CONCLUSIONS: Thymic radiation exposure was independently associated with higher risks of metastasis and death in NSCLC patients, especially in those with preserved thymic function. These findings raise awareness towards considering the thymus as an organ of interest in radiotherapy and suggest that thymus-sparing strategies may help preserve immune health and improve patient outcomes.

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