We systematically evaluated risk factors for radiation pneumonitis (RP) in patients receiving combined thoracic volumetric modulated arc therapy (VMAT) and immune checkpoint inhibitors (ICIs), aiming to identify clinically safe radiation dose thresholds in the modern immunotherapy era. Patients treated with thoracic VMAT and ICIs between August 2020 and June 2025 were retrospectively analyzed. To ensure dosimetric consistency, all lung volumes were recontoured by a single radiation oncologist according to the Radiation Therapy Oncology Group (RTOG) 1106 protocol. Clinical and dosimetric variables—including mean lung dose (MLD) and lung volumes receiving ≥ 5 Gy (V5) through≥ 40 Gy (V40)—were evaluated using univariate and multivariate logistic regression analyses. Optimal dose thresholds were determined using receiver operating characteristic (ROC) curve analysis and the Youden index. Of 93 patients, the overall incidence of RP was 60.2%, with grade 3 events occurring in 14.1% of patients. A history of chronic obstructive pulmonary disease (COPD) was the only significant clinical risk factor, associated with a 75.6% incidence of RP (p = 0.004). Multivariate analysis identified MLD, V5, V20, V30, and V40 as independent predictors of RP (all p < 0.05). Integrating COPD history with dosimetric parameters significantly improved predictive accuracy (AUC > 0.7) compared with single-variable models. Based on the Youden index, recommended safety thresholds were MLD < 10.7 Gy, V5 < 35.0%, V20 < 21.8%, V30 < 6.7%, and V40 < 4.6%. Combined VMAT-ICI therapy shows high RP incidence, requiring stricter dosimetric constraints and risk stratification incorporating COPD history with optimized dose-volume parameters for safety. 

Yao Zou, Wanrui Lv, Dong Peng, Na Wang, Juan Luo, Rong Li. Risk Factors for Radiation Pneumonitis in Patients Receiving Thoracic VMAT and Immune Checkpoint Inhibitors. Frontiers in Medical Science Research (2026), Vol. 8, Issue 4: 8-17. https://doi.org/10.25236/FMSR.2026.080402.

[1] KäSMANN L, EZE C, TAUGNER J, et al. Chemoradioimmunotherapy of inoperable stage III non-small cell lung cancer: immunological rationale and current clinical trials establishing a novel multimodal strategy [J]. Radiation oncology (London, England), 2020, 15(1): 167.

[2] KHORASANCHI A, LI M, ZHAO S, et al. Impact of immune-related and non-immune related hospital admissions on survival of patients with non-small cell lung cancer receiving first-line immunotherapy [J]. Lung Cancer, 2025, 210: 108832.

[3] SUGAI M, AMINO Y, FUJISHIMA S, et al. Impact of immune-related adverse event severity on overall survival in patients with advanced NSCLC receiving immune checkpoint inhibitors therapy, with a focus on combination regimens [J]. Lung Cancer, 2025, 204: 108555.

[4] SHAVERDIAN N, LISBERG A E, BORNAZYAN K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial [J]. The Lancet Oncology, 2017, 18(7): 895-903.

[5] ANTONIA S J, VILLEGAS A, DANIEL D, et al. Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer [J]. N Engl J Med, 2017, 377(20): 1919-29.

[6] WANG Y, ZHANG T, HUANG Y, et al. Real-World Safety and Efficacy of Consolidation Durvalumab After Chemoradiation Therapy for Stage III Non-small Cell Lung Cancer: A Systematic Review and Meta-analysis [J]. International journal of radiation oncology, biology, physics, 2022, 112(5): 1154-64.

[7] SATO M, ODAGIRI K, TABUCHI Y, et al. Patterns and Incidence of Pneumonitis and Initial Treatment Outcomes with Durvalumab Consolidation Therapy after Radical Chemoradiotherapy for Stage III Non-Small Cell Lung Cancer [J]. Cancers (Basel), 2024, 16(6).

[8] WANG S, LIAO Z, WEI X, et al. Analysis of clinical and dosimetric factors associated with treatment-related pneumonitis (TRP) in patients with non-small-cell lung cancer (NSCLC) treated with concurrent chemotherapy and three-dimensional conformal radiotherapy (3D-CRT) [J]. International journal of radiation oncology, biology, physics, 2006, 66(5): 1399-407.

[9] LIU Y, WANG W, SHIUE K, et al. Risk factors for symptomatic radiation pneumonitis after stereotactic body radiation therapy (SBRT) in patients with non-small cell lung cancer [J]. Radiother Oncol, 2021, 156: 231-8.

[10] MARKS L B, BENTZEN S M, DEASY J O, et al. Radiation dose-volume effects in the lung [J]. International journal of radiation oncology, biology, physics, 2010, 76(3 Suppl): S70-6.

[11] OTTO K. Volumetric modulated arc therapy: IMRT in a single gantry arc [J]. Med Phys, 2008, 35(1): 310-7.

[12] WANG K, YANG F, FENG C, et al. Dose-Volume Constraints Parameters for Lung Tissue in Thoracic Radiotherapy Following Immune Checkpoint Inhibitor Treatment [J]. Journal of inflammation research, 2024, 17: 7141-54.

[13] BI J, MENG R, YANG D, et al. Dosimetric predictors of radiation pneumonitis in patients with prior immunotherapy exposure: A multi-institutional analysis [J]. Radiother Oncol, 2024, 190: 110040.

[14] INOUE H, ONO A, KAWABATA T, et al. Clinical and radiation dose-volume factors related to pneumonitis after treatment with radiation and durvalumab in locally advanced non-small cell lung cancer [J]. Invest New Drugs, 2020, 38(5): 1612-7.

[15] ZOU Y, CHEN Y, ZHOU X, et al. Combining immune checkpoint inhibitors with thoracic radiotherapy enhances outcomes in advanced non-small-cell lung cancer: a real-world study [J]. Frontiers in oncology, 2025, 15: 1611528.

[16] SHAVERDIAN N, BEATTIE J, THOR M, et al. Safety of thoracic radiotherapy in patients with prior immune-related adverse events from immune checkpoint inhibitors [J]. Annals of oncology : official journal of the European Society for Medical Oncology, 2020, 31(12): 1719-24.

[17] SAITO G, OYA Y, TANIGUCHI Y, et al. Real-world survey of pneumonitis and its impact on durvalumab consolidation therapy in patients with non-small cell lung cancer who received chemoradiotherapy after durvalumab approval (HOPE-005/CRIMSON) [J]. Lung Cancer, 2021, 161: 86-93.

[18] TANG Y, YU H, GUO S, et al. Risk factors for pneumonitis after the combination treatment of immune checkpoint inhibitors and thoracic radiotherapy [J]. BMC Pulm Med, 2025, 25(1): 404.

[19] ANTONIA S J, VILLEGAS A, DANIEL D, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC [J]. The New England journal of medicine, 2018, 379(24): 2342-50.

[20] SAOWAPA S, POLPICHAI N, SILADECH P, et al. Pneumonitis Incidence in Patients With Metastatic Non-small Cell Lung Cancer on Immunotherapy: A Systematic Review and Meta-Analysis [J]. Cureus, 2024, 16(7): e63615.

[21] SHAVERDIAN N, LISBERG A E, BORNAZYAN K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial [J]. The Lancet Oncology, 2017, 18(7): 895-903.

[22] BARNES P J. Inflammatory mechanisms in patients with chronic obstructive pulmonary disease [J]. J Allergy Clin Immunol, 2016, 138(1): 16-27.

[23] POSTOW M A, SIDLOW R, HELLMANN M D. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade [J]. The New England journal of medicine, 2018, 378(2): 158-68.

[24] LU X, WANG J, ZHANG T, et al. Comprehensive Pneumonitis Profile of Thoracic Radiotherapy Followed by Immune Checkpoint Inhibitor and Risk Factors for Radiation Recall Pneumonitis in Lung Cancer [J]. Front Immunol, 2022, 13: 918787.

[25] PU D, LIU Q, ZHANG S, et al. Real-world incidence and risk factors of pneumonitis in chemoradiation plus immune checkpoint inhibitors compared with chemoradiation alone in lung cancer: a retrospective cohort study [J]. Transl Lung Cancer Res, 2024, 13(1): 139-51.

[26] LV X, WU Y, LI Q, et al. Treatment-related pneumonitis after thoracic radiotherapy/chemoradiotherapy combined with anti-PD-1 monoclonal antibodies in advanced esophageal squamous cell carcinoma [J]. Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft [et al], 2024, 200(10): 857-66.

[27] RUAN Y, HAN J, CAO W, et al. Risk factor of pneumonitis resulting from thoracic chemoradiotherapy combined with immunotherapy in lung cancer: A meta-analysis and systematic review [J]. iScience, 2025, 28(11): 113761.

[28] HWANG W L, PIKE L R G, ROYCE T J, et al. Safety of combining radiotherapy with immune-checkpoint inhibition [J]. Nature reviews Clinical oncology, 2018, 15(8): 477-94.

[29] ZHOU Y, YAN T, ZHOU X, et al. Acute severe radiation pneumonitis among non-small cell lung cancer (NSCLC) patients with moderate pulmonary dysfunction receiving definitive concurrent chemoradiotherapy: Impact of pre-treatment pulmonary function parameters [J]. Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft [et al], 2020, 196(6): 505-14.

[30] NATIONAL COMPREHENSIVE CANCER NETWORK. NCCN Clinical Practice Guidelines in Oncology: Non-small cell lung cancer (Version 3.2026).