Clinical and dosimetric risk factors for radiation pneumonitis after proton therapy in lung cancer patients: a retrospective study

Introduction

Recent global cancer statistics indicate that lung cancer remains the most prevalent cancer and the leading cause of cancer-related mortality worldwide, accounting for approximately 2.5 million new cases and 1.8 million deaths annually (1). Radiotherapy has demonstrated improved survival outcomes in lung cancer patients and is widely employed across all disease stages (2). While conventional lung cancer treatment commonly utilizes photon-based external beam radiotherapy, proton radiotherapy demonstrates superior dose conformability and target coverage, minimizing radiation exposure to adjacent normal tissues. These dosimetric benefits suggest a potential reduction in treatment-related toxicities, including radiation pneumonitis (RP) (3,4). Despite technological advancements in radiation delivery, RP continues to be a significant dose-limiting toxicity in thoracic radiotherapy. The incidence of RP following thoracic irradiation has been reported to be as high as 30% (5), with even higher rates observed in patients receiving concurrent immunotherapy (6-8). Given the increasing clinical utilization of proton therapy and the critical need to mitigate RP risk, our center conducted a retrospective analysis to identify patient-specific and dosimetric factors associated with the development of RP in lung cancer patients treated with proton radiotherapy. RP represents the primary dose-limiting complication of thoracic radiation therapy. Grade ≥2 RP requires clinical intervention, can significantly prolong hospitalization, adversely impact clinical outcomes and quality of life, and, in severe cases, may result in mortality. Therefore, identifying high-risk factors for RP is essential for effective prevention and management. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-776/rc).

Methods

Patient selection

This retrospective cohort study included patients with lung cancer who received proton therapy at the Ion Medicine Center of the First Affiliated Hospital of University of Science and Technology of China (USTC) from March 2022 to January 2025. The inclusion criteria were as follows: histologically confirmed primary lung cancer; eligibility for and completion of proton radiotherapy; provision of informed consent by the patient or legal guardian; Eastern Cooperative Oncology Group (ECOG) score of 0 or 1; and availability of complete clinical and dosimetric data. Patients were excluded if they experienced radiotherapy interruptions exceeding one week, were pregnant or breastfeeding, had severe psychiatric disorders, or had follow-up periods less than 1-month post-radiotherapy completion. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The First Affiliated Hospital of USTC (No. 2025-RE-155) and informed consent was obtained from all individual participants.

Clinical and dosimetric data collection

Comprehensive clinical characteristics and dosimetric data were collected from medical records and radiotherapy planning systems. Clinical data included sex, age, ECOG score, smoking history, underlying pulmonary disease, diabetes mellitus, history of lung surgery, tumor clinical stage, tumor size and location, combination therapy status (immunotherapy, chemotherapy and targeted therapy), prior thoracic radiotherapy status, total prescribed radiation dose, serum albumin, and hemoglobin levels.

Dosimetric parameters included V5, V10, V20, V30, V40, V50, V60, and mean lung dose (MLD) for both ipsilateral and total lung, as well as cardiac V20, cardiac mean dose, and clinical target volume (CTV).

Radiotherapy protocol

All patients underwent simulation in the supine position using a computed tomography (CT) scanner with 3-mm slice thickness. Four-dimensional CT (4DCT) imaging of the thorax was acquired to evaluate respiratory motion and facilitate motion-managed treatment planning. Treatment was delivered using the Varian ProBeam multicompartment proton therapy system. Treatment planning was performed with the Eclipse system.

Target delineation was performed by junior or mid-level radiation oncologists and reviewed and approved by senior radiation oncologists. The gross tumor volume (GTV) encompassed the primary lesion and clinically involved lymph nodes, while CTV included the potential microscopic extension surrounding the primary tumor. The prescribed radiation doses ranged from 40 to 80 Gy [relative biological effectiveness (RBE)], administered in fractionated doses of 2 to 11 Gy (RBE), depending on the clinical context. Patient chest CT images were reviewed before, during, and after radiotherapy, with follow-up imaging performed at regular intervals to monitor treatment response and potential radiation-related toxicities.

Diagnostic criteria and grading of RP

The diagnosis and grading of RP were determined by a radiologist and a radiation oncologist. The grading criteria followed the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, published by the National Cancer Institute (9). The grading is as follows: grade 1, asymptomatic with radiographic findings only; grade 2, mild symptoms not interfering with activities of daily living; grade 3, significant symptoms interfering with activities of daily living or requiring supplemental oxygen therapy; grade 4, life-threatening respiratory compromise requiring continuous ventilatory support; and grade 5, death.

Patient evaluation for RP occurrence involved reviewing medical records and chest CT. The primary study endpoint was the diagnosis of symptomatic RP, defined as the occurrence of grade 2 or higher RP following proton therapy completion.

Statistical analysis

Statistical analysis was performed using SPSS software (version 26.0). The Chi-squared (χ²) test is used to examine the associations between different categorical variables, whereas the t-test is used to compare the mean differences between two groups of continuous variables. Categorical data were presented as percentages (%) and analyzed using the Chi-squared (χ²) test. Continuous data were expressed as mean ± standard deviation and analyzed using the t-test.

Univariate and multivariable logistic regression analyses were conducted to identify risk factors associated with the occurrence of grade ≥2 RP. Independent risk factors identified through multivariable analysis were incorporated into receiver operating characteristic (ROC) curve analysis to determine the critical values for predicting the occurrence of grade ≥2 RP. A two-sided P-value of less than 0.05 was considered statistically significant.

Results

Incidence of RP

A total of 65 patients were included according to the study design. Among these patients, 18 were excluded, as they did not meet the study criteria. Ultimately, 47 patients were included in this analysis (Figure 1). There were 30 males and 17 females, with a median age of 67 years (range: 42–88 years). Clinical staging at diagnosis included 10 patients in stage I, 2 in stage II, 13 in stage III, and 22 in stage IV. The median follow-up time was 12.0 months, with a 100% follow-up rate.

Figure 1 Flow diagram of patient selection. RP, radiation pneumonitis.

The overall incidence of grade ≥2 RP was 10.6% (5 out of 47 patients). Specifically, 5 patients (10.6%) developed grade 2 RP, with no cases of grade 3 or higher RP observed. Regarding the timing of RP development, two patients developed RP within 1 to 3 months post-radiotherapy, while the remaining three patients developed RP more than 3 months after the completion of radiotherapy. Chest CT imaging revealed RP characterized by patchy, homogeneous, and flocculent opacities localized within the irradiation field. These opacities were accompanied by thickening of vascular and bronchial structures and exhibited indistinct margins adjacent to normal lung parenchyma. The involved regions appeared denser than ground-glass opacities and demonstrated solid features with clear demarcation from surrounding normal tissues (10) (Figure 2).

Figure 2 Radiographic evolution of radiation-induced lung injury following radiotherapy for right upper lobe lung cancer. (A) Baseline pre-radiotherapy CT image demonstrating the primary right upper lobe lung cancer, indicated by red arrow. (B) Axial CT image acquired three months post-radiotherapy, revealing extensive consolidation surrounding the treated tumor (blue arrow). Note the presence of linear, non-anatomic consolidation margins (white arrow), air bronchograms within the consolidated regions (red arrow), and associated pleural thickening/adhesions. (C) CT image illustrating consolidation along the interlobar fissure of the right upper lobe and the dorsal segment of the right lower lobe within the radiation field. Some consolidations display a stellate morphology. Multiple patchy ground-glass opacities are also observed peripherally (white arrow), suggestive of radiation pneumonitis. CT, computed tomography.

Univariate analysis of clinical data

A univariate analysis was performed to evaluate clinical factors potentially associated with the development of symptomatic RP in lung cancer patients receiving proton radiotherapy. We performed Chi-squared tests to examine the associations between categorical variables and the occurrence of RP. The variables analyzed included sex, age, ECOG performance status, smoking history, pre-existing pulmonary diseases, diabetes mellitus, prior lung surgery, tumor clinical stage, tumor size and tumor location, administration of combined therapy, receipt of secondary radiotherapy, total prescribed radiotherapy dose, serum albumin level, and hemoglobin level. No statistically significant associations were found between these factors and the incidence of grade ≥2 RP (all P>0.05). Detailed results are provided in Table 1.

Univariate analysis of dosimetric data

The univariate analysis of dosimetric factors associated with the development of symptomatic RP in lung cancer patients undergoing proton radiotherapy identified several significant correlations. We also conducted t-tests to evaluate the relationships between continuous variables and RP occurrence. The analysis revealed that dosimetric parameters of the ipsilateral lung, including V5, V10, V20, V30, V40, V50, V60, and MLD, showed significant associations with the development of grade ≥2 RP. Moreover, the total lung V40, V50, and V60 demonstrated significant correlations with grade ≥2 RP occurrence. All of these parameters exhibited statistically significant differences (P<0.05). Detailed results are presented in Table 2.

Multivariable analysis of dosimetric factors

A multivariable logistic regression analysis was conducted to evaluate the association between dosimetric parameters and the incidence of RP. The analysis identified several significant dosimetric parameters for the development of grade ≥2 RP in lung cancer patients receiving proton radiotherapy. For the ipsilateral lung, significant factors included V10, V20, V30, V40, V50, V60, and MLD. For the total lung, V40, V50, and V60 were identified as significant factors. Those dosimetric parameters demonstrated an increased adjusted odds ratio (AOR) greater than 1, with corresponding P values less than 0.05, indicating a higher risk of grade ≥2 RP. Detailed results are presented in Table 3.

ROC curve analysis of dosimetric risk factors

ROC curve analysis was performed to assess the predictive performance of dosimetric parameters identified as independent risk factors for grade ≥2 RP. The analysis revealed high area under the curve (AUC) values for the ipsilateral lung parameters V10 (0.824), V20 (0.869), V30 (0.876), V40 (0.921), V50 (0.962), V60 (0.921), and MLD (0.886), as well as the total lung parameters V40 (0.824), V50 (0.883), and V60 (0.888). These results indicate strong predictive capability for the occurrence of grade ≥2 RP.

We identified specific dose thresholds associated with a high risk of developing grade ≥2 RP. For the ipsilateral lung: V10 >28.45%, V20 >15.55%, V30 >12.7%, V40 >10.3%, V50 >8.05%, V60 >2.35%, MLD >868.85 cGy (RBE). For the total lung: V40 >4.7%, V50 >3.55%, V60 >1.15%. These thresholds may serve as clinically relevant guidance for identifying patients at high risk of developing grade ≥2 RP. Detailed results are presented in Table 4.

Discussion

In this study, we assessed both clinical and dosimetric factors in lung cancer patients undergoing proton therapy and found that independent risk factors for grade ≥2 RP includedV10, V20, V30, V40, V50, V60, and MLD of the ipsilateral lung, as well as V40, V50, and V60 of the total lung (AOR >1, P<0.05).

Previous studies have reported that the incidence of symptomatic RP in lung cancer patients treated with thoracic radiotherapy ranges from 10% to 40% (11-13). Proton radiotherapy has been associated with a lower risk of RP in literature (14,15). He et al. (16) reported that among early-stage non-small cell lung cancer patients treated with proton radiotherapy, the incidence of grade ≥2 RP was 8.7%. In a retrospective analysis, among 669 patients with non-small cell lung cancer who received proton therapy, the incidence of grade ≥2 RP was 11.5% (17). A multi-institutional study of 965 lung cancer patients treated with proton beam therapy found 250 patients (25.9%) experienced grade ≥2 pulmonary toxicity (14). In our cohort, 5 of 47 patients (10.6%) developed grade ≥2 RP. The incidence of grade ≥2 RP varies widely due to patient heterogeneity and differences in radiotherapy protocols. Our findings of a relatively low incidence of symptomatic pneumonitis following proton therapy, with no grade 3 or higher RP cases, align with literature reports (18).

Multiple studies have identified clinical factors potentially influencing RP occurrence, including advanced age, tumor location in the lower lung lobes, high total radiation dose, use of immune checkpoint inhibitors, impaired lung function, lower baseline platelet count, and elevated levels of interleukins and transforming growth factor β (TGF-β). These factors demonstrate strong associations with RP incidence (5,14,19-21). In our study, we evaluated a range of clinical factors; however, none of these factors were significantly associated with the incidence of grade ≥2 RP in our cohort. This finding contrasts with previous studies and may require further investigation, particularly with larger sample sizes and extended follow-up periods, to better assess their predictive value.

Notably, pulmonary function tests and related cytokine examinations were not conducted in this study. Future research should incorporate comprehensive pulmonary function evaluations before treatment, as well as regular monitoring of cytokine levels before and after proton therapy, to better understand their impact on RP incidence. Additionally, 74.4% of our patients were over the age of 60 years. Previous studies have indicated that elderly patients with multiple comorbidities may benefit more from proton therapy due to its reduced toxicity profile (3). Therefore, proton therapy may represent a more effective treatment option for older patients with multiple comorbidities.

Among factors predicting RP, lung dose remains the most crucial determinant (22). Our univariate analysis indicated that the ipsilateral lung V5 and V10 were significantly associated with the occurrence of grade ≥2 RP (P<0.05). However, the ipsilateral lung V5 was not retained as an independent risk factor in the subsequent multivariable analysis. Previous research has highlighted the relevance of low-dose lung exposures, such as V5 and V10, in the development of RP (5,11,23-25). For instance, Tang et al. (23) reported that an ipsilateral lung V5 ≥55.65% was associated with an increased risk of developing RP. Another study demonstrated lung V5 remained a significant predictor of grade ≥2 PR even after adjusting for MLD in multivariable analysis (24). A comprehensive review of 80 studies also identified V5 as a consistent risk factor for RP (5). Boonyawan et al. (26) analyzed 199 lung cancer patients undergoing postoperative radiotherapy with concurrent chemotherapy and found a significant association between lung V10 and RP development. Three additional studies also demonstrated the predictive value of lung V10 in RP development (11,24,25). In our study, the V5 and V10 doses for the ipsilateral lung were relatively low, consistent with findings by He et al. (16), who demonstrated that proton therapy is more effective than photon therapy in minimizing low-dose exposure to adjacent normal lung tissue.

In contrast to previous studies, the present multifactorial analysis revealed that high-dose regions, specifically ipsilateral lung V40, V50, and V60, as well as total lung V40, V50, and V60, were independent risk factors for the development of grade ≥2 RP. Harris et al. (27) reported that, compared to photon therapy, proton therapy allows for the use of higher dose-volume thresholds (V35, V40, V50) with potentially lower pulmonary toxicity. This finding is consistent with our findings and suggests that incorporating these newly high-dose dosimetric criteria may improve risk stratification and treatment outcomes in patients receiving proton therapy. Currently, standardized criteria for low-dose lung volumes remain undefined, highlighting the need for further research to establish optimal dosimetric parameters for minimizing RP risk. Importantly, due to the distinct physical properties and dose distribution between photon and proton therapy, dose factors effective in photon therapy may not be directly applicable to proton therapy. Therefore, clinical practice should consider the integration of both high- and low-dose volume constraints when planning proton therapy in order to more effectively mitigate RP risk.

The MLD is also a significant factor in the development of RP (5,24,25,28). Research has demonstrated that higher ipsilateral lung mean doses significantly increase the likelihood of pulmonary toxicity in lung cancer patients receiving proton therapy (P=0.003) (14). The risk of grade ≥2 RP may increase in patients with an ipsilateral lung mean dose ≥11.86 Gy (23). Kenndoff et al. (29) reported that the probability of developing grade ≥2 RP was significantly increased for MLD values greater than 9.2 Gy. In our study, the cut-off MLD value of 868.85 cGy (RBE) for symptomatic RP was consistent with previous reports (29). In clinical radiotherapy for lung cancer, V20 is commonly used to evaluate treatment regimens. Multiple studies have established an association between V20 and RP occurrence (5,24,25,28,30). O’Reilly et al. (31) identified a correlation between V20 and RP in both photon (P=0.01) and proton therapy (P=0.04). Both univariate and multivariable analyses in our study confirmed V20 as a predictor of RP (P=0.006 and 0.02, respectively), consistent with previous studies (32). Additionally, several studies have demonstrated V30’s utility in predicting RP occurrence (33). In univariate analysis, V30 was positively associated with the risk of grade ≥2 RP (24). Doshita et al. (34) found that the occurrence of grade 2 RP correlated with lung V30 >20%. When V30 <18%, the risk of RP was shown to be extremely low, while when V30 ≥18%, the risk of RP can reach 24% (7). Our study identified a critical value of 12.7% for symptomatic RP in ipsilateral lung V30, which is lower than previously reported values.

However, the development of RP is influenced by a combination of clinical and dosimetric factors. Clinical practice necessitates integrating these various factors to provide personalized predictions of a patient’s risk for RP. Given the sensitivity of Bragg peaks to respiratory motion, anatomical structures, and density variations, treating mobile lung cancers may result in tumor underdosing and unintended irradiation of adjacent normal tissue. As a result, motion analysis and management using 4DCT become particularly critical in proton therapy compared to photon therapy. In this study, proton therapy was delivered based on 4DCT under strict motion management and quality assurance protocols to minimize uncertainties in the proton range within the lung.

Nevertheless, several limitations must be acknowledged. First, as a retrospective study conducted at a single institution, the findings may be influenced by selection bias and other inherent limitations. Second, the relatively small sample size and short follow-up period may limit the generalizability of our findings.

Conclusions

In summary, high values of V10, V20, V30, V40, V50, V60, and MLD in the ipsilateral lung, along with elevated V40, V50, and V60 in the total lung, were identified as independent risk factors for grade ≥2 RP in lung cancer patients receiving proton radiotherapy. These findings underscore the importance of rigorously constraining relevant dosimetric parameters during treatment planning to minimize the risk of RP. Future research should focus on large-sample, prospective, multicenter studies to further validate these findings and establish more definitive clinical guidelines.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-776/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-776/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-776/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-776/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The First Affiliated Hospital of USTC (No. 2025-RE-155) and informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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