Thymus Composition Predicts Pneumonitis Risk in Lung Cancer Therapy

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.