Time-of-day radiotherapy alters radiation pneumonitis risk but not survival in lung cancer patients with interstitial lung disease

Background: Lung cancer patients with comorbid interstitial lung disease (ILD) are highly susceptible to radiation pneumonitis (RP) after thoracic radiotherapy (RT). Circadian biology suggests that RT time-of-day (ToD) may influence normal-tissue injury, but evidence in ILD remains limited. Objectives: To evaluate the association of RT ToD with RP risk and survival outcomes. Design: Retrospective single-centre cohort study. Methods: We retrospectively analysed 424 patients with lung cancer and pre-existing ILD treated with thoracic RT. Patients were classified as morning (06:00–11:59), afternoon (12:00–17:59), or night (18:00–02:00) according to predominant treatment timing. Cox models assessed associations of ToD with RP, overall survival (OS), and progression‑free survival (PFS). Results: RP incidence differed by ToD: afternoon 58.3%, morning 44.1%, night 40.3% ( p = 0.023), with afternoon RT showing the earliest and highest cumulative incidence. Using morning as reference, afternoon RT remained associated with higher RP risk in multivariable analysis (hazard ratio (HR) 1.42, 95% confidence interval (CI), 1.02–1.98; p = 0.036). Night RT showed no excess risk in univariable analysis, but was associated with increased RP risk after full adjustment (HR 1.62, 95% CI, 1.02–2.58; p = 0.043). In subgroup analyses using afternoon RT as reference, lower RP risk with morning and night RT was most evident in younger patients, men, and patients with NSCLC; in NSCLC, morning (HR = 0.64, 95% CI, 0.45–0.92) and night (HR = 0.46, 95% CI, 0.26–0.81) were associated with lower RP risk. RT ToD was not independently associated with OS or PFS, whereas RP was associated with worse survival. Conclusion: In patients with lung cancer and comorbid ILD, afternoon RT is associated with increased RP risk without an independent detriment to OS or PFS. Preferential morning scheduling, combined with careful dosimetric optimization, may help mitigate RP risk and warrants prospective validation.