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Published on: April 22, 2019
Thymic radiation is associated with worse outcomes in patients with NSCLC
V Prudente1, S Bernatz2, S Pai1
1Artificial Intelligence in Medicine (AIM) Program, Mass General Brigham, Harvard Medical School, Boston, USA; Department of Radiology and Nuclear Medicine, CARIM & GROW, Maastricht University, Maastricht, The Netherlands; Department of Radiation Oncology, Mass General Brigham Cancer Institute, Harvard Medical School, Boston, USA.
Background:
Emerging evidence indicates the functional importance of the thymus in adult health and may influence oncological 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 1107 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 1-Gy 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 (TH)-stratified analysis, patients with preserved TH before RT appeared to be at particularly greater risk, whereas no associations emerged in patients with impaired TH. One-year follow-up imaging demonstrated dose-dependent declines in TH and lower circulating lymphocyte counts, consistent with a possible biological link between thymic irradiation and loss of immune competence. An exploratory feasibility study suggested that reoptimizing 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 patients with NSCLC, especially in those with preserved thymic function. These findings raise awareness toward considering the thymus as an organ of interest in RT and suggest that thymus-sparing strategies may help preserve immune health and improve patient outcomes.