Thymus Composition Predicts Pneumonitis Risk in Lung Cancer Therapy

Background Durvalumab consolidation after concurrent chemoradiotherapy (cCRT) is the standard-of-care for unresectable stage III non–small cell lung cancer (NSCLC) without actionable driver mutations. However, pneumonitis remains a dose-limiting toxicity that often precludes or interrupts immunotherapy. Conventional predictors based on lung dosimetry alone exhibit limited individual-level discrimination. We investigated whether the thymus, long considered vestigial in adults, influences post-treatment immune recovery and susceptibility to inflammatory toxicity.

We analyzed patients with locally advanced NSCLC treated with cCRT in the RTOG 0617 trial (n = 490) and with standard-of-care cCRT followed by consolidation durvalumab at Memorial Sloan Kettering Cancer Center (MSKCC, n = 230). Percent thymic tissue (pTT), a novel imaging parameter that quantifies the proportion of residual functional thymic tissue on pre-treatment CT scans, was derived using an autosegmentation and Gaussian mixture modeling framework. Logistic regression with restricted cubic splines assessed associations between pTT, mean radiation dose to the thymic region (MDTR), and volume of the lungs receiving ≥20 Gy (lung V20) with high-grade (≥ 3) pneumonitis.

Across both cohorts, pTT was inversely associated with severe pneumonitis independent of lung V20. Grade 3+ pneumonitis incidence in low-vs high-pTT groups was 7.3% vs 2.9% (p = 0.038) in the RTOG 0617 cohort and 13.9% vs. 5.2% (p = 0.042) in the MSKCC cohort. The combination of low pTT and high lung V20 was associated with the highest rates of severe pneumonitis with 11.5% in RTOG 0617 and 20.8% in MSKCC (compared with 3.3% and 1.9% for high pTT/low lung V20), identifying a subgroup at particularly high risk. MDTR showed a weaker, non-linear relationship with pneumonitis risk, increasing at moderate doses and declining at the highest radiation exposures.

This study established pTT, a quantitative marker of residual functional thymus in adults, as a novel, independent predictor of severe pneumonitis following cCRT with or without consolidation immunotherapy. Incorporating pTT into multimodal risk-stratification frameworks could improve patient selection, personalize radiation planning, and enhance safe delivery of curative-intent cCRT and immunotherapy in locally advanced NSCLC. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study was supported in part by the National Cancer Institute Cancer Center Core Grant (P30 CA008748),National Institutes of Health (NIH)/National Cancer Institute (NCI), L30 CA284553 (PI: Chaunzwa), and the Radiological Society of North America (RSNA) #RR2311 (PI: Chaunzwa). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of Memorial Sloan Kettering Cancer Center gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes This study was supported in part by the National Cancer Institute Cancer Center Core Grant (P30 CA008748), National Institutes of Health (NIH)/National Cancer Institute (NCI), L30 CA284553 (PI: Chaunzwa), and the Radiological Society of North America (RSNA) #RR2311 (PI: Chaunzwa). Data Availability The study was conducted using an MSKCC institutional cohort of radiotherapy patients obtained with IRB approval, and a publicly available dataset, available on TCIA: https://www.cancerimagingarchive.net/collection/nsclc-cetuximab/