Risk Factors for Pneumonitis Induced by Combined Radiotherapy and Immunotherapy: A Multicenter Prospective Study

The combination of radiotherapy (RT) and immune checkpoint inhibitors (ICIs) has become an important therapeutic approach for lung cancer. However, pneumonitis remains a major treatment-related toxicity of this therapeutic approach, and the risk factors for pneumonitis associated with combined RT and ICIs under different treatment sequences have not been clearly defined.

Patients with lung cancer who received thoracic RT were prospectively enrolled from 3 centers. Pneumonitis was assessed according to CTCAE version 4.0 by a multidisciplinary team. Cox proportional hazards models were used to identify factors associated with pneumonitis.

During a median follow-up of 28.2 months, 133 of 380 (35.0%) patients developed symptomatic pneumonitis (grade ≥2). Treatment with ICIs was associated with an increased risk of symptomatic pneumonitis (hazard ratio [HR], 1.69; 95% CI, 1.20-2.39; P=.003). Among 170 patients treated with ICIs, 89 received ICIs before RT (ICI-first group) and 81 received ICIs after RT (RT-first group). In the ICI-first group, 42 (47.2%) patients developed symptomatic pneumonitis, and an interval of <21 days between ICI administration and RT and a higher percentage of lung volume receiving ≥20 Gy (V20) were associated with an increased risk of pneumonitis. In the RT-first group, 32 (39.5%) patients developed symptomatic pneumonitis, with older age and higher V20 identified as risk factors.

Administration of ICIs before RT significantly increases the risk of pneumonitis in patients receiving thoracic RT. The dosimetric factor V20 consistently emerged as a key determinant of pneumonitis risk in both the ICI-first and RT-first groups. These findings aid in preventing the occurrence of pneumonitis induced by combined RT and ICIs, thereby improving patients' quality of life and survival outcomes.