Risk factors for radiation pneumonitis following adjuvant radiotherapy for breast cancer: a retrospective cohort study

Abstract

Objective:

To delineate the risk factors associated with radiation pneumonitis (RP) in breast cancer patients receiving adjuvant radiotherapy, thereby informing strategies for dosimetric optimization and risk mitigation.

Methods:

A retrospective analysis was performed on 811 female patients who underwent postoperative radiotherapy for breast cancer to investigate the potential risk factors associated with RP. Specifically, univariate analysis was employed to identify factors associated with RP, followed by multivariate logistic regression modeling to determine independent risk factors. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performance of identified risk factors, with diagnostic accuracy quantified by the area under the curve (AUC).

Results:

Univariate analysis demonstrated that the tumor stage, chest wall + supraclavicular + internal mammary lymph node irradiation (CSI), the number of chemotherapy cycles, the ipsilateral lung V₅, V₁₀, V₂₀, and mean lung dose (MLD) were all significantly associated with RP (all P < 0.05). Multivariate analysis identified MLD (odds ratio [OR] = 11.136, 95% confidence interval [CI]: 5.494 ∼22.571; P < 0.001), the number of chemotherapy cycles (OR = 2.739, 95% CI: 1.597 ∼ 4.696; P < 0.001) and CSI (OR =5.654, 95% CI: 1.768 ∼ 18.080; P = 0.003) as risk factors for RP. With a diagnostic threshold of MLD = 12.70 Gy, the predictive sensitivity and specificity for RP were 0.898 and 0.965, respectively. Setting the number of chemotherapy cycles at 7 as the threshold yielded a sensitivity of 0.898 and specificity of 0.587 for RP prediction. For CSI, the predictive sensitivity and specificity were 0.878 and 0.810, respectively.

Conclusions:

The MLD, the number of chemotherapy cycles and CSI were confirmed as risk factors for RP. Bootstrap internal validation confirmed the robustness of these findings. Stringent dosimetric constraints to minimize MLD are imperative, particularly in patients with extended chemotherapy histories (≥ 7 cycles) undergoing CSI.

1 Introduction

Breast cancer is one of the leading threats to women’s health globally, an estimated 670,000 deaths worldwide were attributed to breast cancer in 2022 (1, 2). Multimodal therapy for breast cancer typically encompasses surgical resection, radiotherapy, chemotherapy, and endocrine therapy. Radiation therapy plays a pivotal role in breast cancer management, with approximately 70% of breast cancer patients receiving radiotherapy as part of their treatment regimen (3–5).

Despite therapeutic advances, incidental irradiation of adjacent normal tissues remains inevitable, predisposing patients to radiation-induced injury. Radiation pneumonitis (RP) typically manifests within 1 to 6 months post-treatment completion, representing an unavoidable complication in thoracic tumor radiotherapy (6, 7). The clinical grading criteria for RP are fundamentally anchored in the impact on patients’ pulmonary function, which demonstrates a positive correlation with the volume of lung tissue injury (8). The Common Terminology Criteria for Adverse Events (CTCAE) 5.0 developed by the National Cancer Institute (NCI) classifies the severity of RP as follows: Grade 1 (mild) is characterized by asymptomatic or mild symptoms that are detected exclusively through clinical examination or imaging, and no treatment intervention is required.​ Grade 2 (moderate) refers to moderate symptoms that necessitate local or non-invasive treatment such as oxygen therapy.​ Grade 3 (severe) is defined by severe symptoms and may require oxygen therapy or bronchodilator administration.​ Grade 4 (life-threatening) denotes a critical condition that poses an immediate threat to life, requiring urgent interventions such as mechanical ventilation or endotracheal intubation.​ Grade 5 (death) is classified when the demise of the patient is directly attributable to the adverse event (9).

Investigation of RP specifically in the breast cancer population has been limited by its relatively low incidence, predominantly mild (Grade 1–2) presentation, and challenges in long-term follow-up. However, with prolonged survival outcomes in breast cancer, mitigation of treatment-related toxicity is paramount for preserving long-term quality of life. Consequently, while ensuring radiotherapy plans meet clinical endpoints, dosimetrically targeted optimization thereof is indispensable for mitigating both the incidence and severity of RP.

Prior studies have demonstrated that potential relevant factors for RP include the number of chemotherapy cycles, chemotherapy regimen, history of lung disease, age, chest wall + supraclavicular + internal mammary lymph node irradiation (CSI), surgical approach, chemo-radiotherapy interval, tumor stage, and dose parameters of the ipsilateral lung (10–16). A case report published in the New England Journal of Medicine highlighted that V₂₀ and mean lung dose (MLD) of the ipsilateral lung may serve as key metrics for RP, and advocated for the assessment of cumulative effects in low-dose regions (V₅ and V₁₀) in clinical practice (10). A multicenter study published in JAMA Oncology demonstrated that MLD and V₂₀ of the ipsilateral lung are associated with acute skin toxicity, thereby indirectly supporting their potential role as predictors of pulmonary toxicity (12). The IMPORT HIGH trial, published in Lancet Oncology, demonstrated that restricting lung high-dose regions (V₂₀ < 25%) reduces the risk of RP. In subgroup analysis, patients with (V₅ ≥ 45.9%) and (V₁₀ ≥ 29.4%) had a significantly higher incidence of RP (HR = 1.8), 95% CI: 1.1 ~ 3.0), indicating that low-dose region parameters should be integrated into assessment (13).

This study aims to comprehensively identify factors associated with RP in a cohort of breast cancer patients receiving postoperative radiotherapy. We performed univariate analysis on parameters including chemotherapy cycle number, CSI, chemotherapy regimens, age, surgical method, chemotherapy-radiotherapy interval time, tumor stage, V₅, V₁₀, V₂₀ and MLD of the ipsilateral lung, and the volume of planning target volume (PTV) to identify factors associated with RP in breast cancer patients receiving postoperative radiotherapy. Furthermore, multivariate logistic regression analysis will be performed to identify independent risk factors for RP and evaluate the predictive value of each factor.

2 Materials and methods

2.1 Patients selection

A total of 1,027 female breast cancer patients who received radiotherapy at our department between July 2021 and December 2024 were retrospectively enrolled. Following rigorous screening, patients were excluded if they met any of the following criteria: PTV involving breast prostheses; bilateral breast cancer; concurrent severe cardiovascular or pulmonary diseases (e.g., congenital heart disease, coronary artery disease, cardiomyopathy, chronic obstructive pulmonary disease, asthma, pulmonary tuberculosis, pulmonary fibrosis, etc.); follow-up period < 6 months or loss to follow-up; history of smoking; concurrent autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, etc.) or acquired immunodeficiency syndrome (AIDS).

The CONSORT flow diagram of this study presented in Figure 1.

Figure 1

A total of 811 patients were ultimately enrolled in this study. The baseline characteristics of patients with breast cancer in this study were summarized in Table 1.

2.2 CT scanning

Patients were immobilized in the supine position using a head-neck-thorax thermoplastic mold. CT scans were performed on the Somatom Confidence CT scanner (Siemens, Germany), with the scanning range extending from the mandible to the inferior border of the liver and a slice thickness of 3 mm.

2.3 Contouring

Gross target volume (GTV) and organ at risk (OAR) were defined according to International Commission on Radiation Units & Measurement Report 50 and 83 (18, 19). The GTV was expanded by a margin based on the breast cancer setup errors previously documented in our department (20), and designated as the PTV. Namely, GTV was expanded by 5 mm isotropically to form CTV, which was further expanded by 5 mm isotropically to generate PTV. OARs, including both lungs, heart, contralateral breast, ipsilateral humeral head, spinal cord and thyroid gland, were delineated.

2.4 Treatment planning, verification and delivery

Plans were created for all patients using the Eclipse treatment planning system (Varian Medical Systems, Version 15.6, USA). The dose objectives for PTV and dose constraints for OARs were summarized in Table 2.

For patients underwent MRM, the prescribed dose was 50 Gy in 25 fractions to the PTV. Patients after BCS received 50 Gy in 25 fractions to the PTV followed by a sequential boost of 10 Gy in 5 fractions to the tumor bed. All plans were reviewed and approved by senior medical physicists and radiation oncologists. Furthermore, prior to the first fraction of radiotherapy, all treatment plans underwent gamma passing rate verification using the SNC Patient gamma analysis software (SUN NUCLEAR Corporation) on the ArcCheck 3-dimensional verification system, performed by qualified medical physicists. With the gamma passing rate evaluated under 3 mm/3% criteria, the passing rates ranged from 98.4% to 100%; under 2 mm/2% criteria, the rates ranged from 96.0% to 100%, all results meeting the recommendations of American Association of Physicists in Medicine (AAPM) Task Group 218 (TG-218) Report (21). All plans were deemed clinically acceptable for treatment. All patients received radiotherapy on a Varian Halcyon v2.0 linear accelerator, and cone-beam computed tomography (CBCT) image guidance was performed before each fraction.

2.5 Radiation pneumonitis diagnosis, grading, follow-up, image interpretation and differential diagnosis

RP was diagnosed and graded in strict adherence to the CTCAE V5.0. All enrolled patients followed a standardized follow-up regimen uniformly. Clinical symptom assessment was performed at one month (30 days ∼ 32 days) after the completion of radiotherapy, and routine chest computed tomography (CT) surveillance was scheduled at the 3^rd month (90 days ∼ 92 days) and 6^th month (180 days ∼ 182 days) post-treatment; no additional imaging examinations were conducted for any participant.

All chest CT images were independently interpreted and graded by one senior radiologist and one senior radiation oncologist under double-blinded conditions. In the event of interpretive discrepancies, a third senior specialist was consulted for joint review to reach a unanimous conclusion.

Rigorous differential diagnostic procedures were implemented to distinguish RP from other pulmonary disorders. Pulmonary infection was ruled out based on the presence of fever and elevated inflammatory biomarkers. Pulmonary lymphangitis and other interstitial lung abnormalities were differentiated according to imaging manifestations, medical history and clinical course. A definitive diagnosis of RP was established only when patients fully met the diagnostic criteria of CTCAE V5.0.

2.6 Statistical methods

Data analysis was performed using IBM SPSS Statistics 27 software. For univariate analysis, the t-test or the Mann-Whitney U test was used for continuous variables, while the chi-square test was applied to categorical data. Multivariate analysis was performed using binary logistic regression to identify independent risk factors for RP. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the predictive utility of these factors, with the area under the curve (AUC) quantified to assess diagnostic accuracy. A P-value < 0.05 was considered statistically significant.

3 Results

According to the CTCAE 5.0 criteria for RP, among 811 enrolled patients, 36 (4.44%) exhibited grade 1 RP, 13 (1.60%) had grade 2 RP, and no grade 3 or higher toxicity was documented. The cumulative incidence of RP at 1 month, 3 months, and 6 months after radiotherapy was 0.99% (8/811), 4.69% (38/811), and 6.04% (49/811), respectively. The majority of RP cases (38/49) occurred within 3 months after radiotherapy.

Univariate analysis of categorical variables (surgical approach, tumor stage, chemotherapy regimens, chemotherapy-radiotherapy interval time, CSI) demonstrated that RP in breast cancer patients was not significantly associated with surgical approach (P = 0.057), chemotherapy regimens (P = 0.350) and chemotherapy-radiotherapy interval time (P = 0.533), but was significantly correlated with tumor stage (P = 0.010) and CSI (P < 0.001), as detailed in Table 3.

Univariate analysis of continuous variables demonstrated that RP was not significantly associated with age and the volume of PTV (all P > 0.05). Conversely, the number of chemotherapy cycle, the ipsilateral lung V₅, V₁₀, V₂₀ and MLD were all significantly correlated with RP (all P < 0.05). Details are presented in Table 4.

Considering that ipsilateral lung V₅, V₁₀, V₂₀ and MLD are inherently highly correlated. We performed collinearity diagnosis via Variance Inflation Factor (VIF) before multivariate modeling. The results showed that VIF values of V₁₀ and V₂₀ were greater than 10, indicating severe collinearity. In order to avoid distortion of model regression caused by severe collinearity, we first excluded the dosimetric parameters with VIF > 10 (V₁₀, V₂₀), and then retained the MLD with the lowest VIF (4.819) among the remaining indicators. The results of multicollinearity diagnostics for dosimetric parameters are summarized in Table 5.

Finally, MLD, tumor stage, CSI and the number of chemotherapy cycles were incorporated into the subsequent multivariate analysis. Given the evidence that CSI is a causal factor for increased MLD, and the two variables share the same causal pathway, we established separate models and discuss mediating effects. The detailed results are summarized in Table 6.

It can be seen from Table 6 that multivariate logistic regression analysis without adjusting for MLD revealed that CSI was associated with a 22.560-fold increased risk of RP. After adjusting for MLD, the direct effect of CSI on RP remained significant but was greatly attenuated (OR = 5.654, 95%CI: 1.768∼18.080, P = 0.003).

Additional multivariate analysis including both CSI and MLD are presented in Table 7. The results confirmed that MLD was the strongest predictor of RP (OR = 11.136, 95%CI: 5.494∼22.571, P < 0.001), while CSI and chemotherapy cycles remained independent predictors.

ROC analysis was conducted to evaluate MLD and the number of chemotherapy cycles. Results demonstrated that for the number of chemotherapy cycles, the area under the curve (AUC) for RP was 0.811, with a 95% confidence interval (95% CI) of 0.754 to 0.867. When a cutoff value of 7 was applied to the number of chemotherapy cycles, the predictive sensitivity and specificity for RP were 0.898 and 0.587, respectively. Specifically, 196 patients (24.17%) received 7 cycles, 148 patients (18.25%) received 8 cycles, and 15 patients (1.85%) received 9 cycles. For MLD, the AUC for RP was 0.964, with a 95% CI of 0.937 to 0.992. Using a cutoff value of 12.70 Gy to MLD, the predictive sensitivity and specificity for RP were 0.898 and 0.965, respectively. The ROC curves are presented in Figure 2.

Figure 2

To evaluate the robustness and generalizability of the multivariate prediction model, we performed internal validation using the bootstrap method with 1000 resamples. As shown in Table 8, the bootstrap-corrected AUC of MLD and chemotherapy cycles were close to the original AUC with a Brier score were 0.025 for MLD and 0.052 for cycles.

The calibration curves of the prediction models are in Figure 3.

Figure 3

For CSI, since CSI is a binary variable and thus has only one valid cut-off point, we used a contingency table to analyze the association of CSI with the outcome. As shown in Table 9, patients receiving CSI had a significantly higher risk of RP compared to those not receiving CSI (OR = 28.761, 95%CI: 12.020∼68.817, P < 0.001). Additionally, the sensitivity and specificity were 0.878 and 0.810, respectively. And the AUC was 0.839.

4 Discussions

RP remains a significant dose-limiting toxicity in thoracic radiotherapy, with incidence and severity modulated by both treatment-related and patient-specific factors. At present, in accordance with clinical guidelines and related research for the diagnosis and management of radiation-associated pneumonitis, definitive diagnosis necessitates immediate suspension of radiotherapy and initiation of targeted therapeutic interventions (22, 23). The overall therapeutic principle involves administering glucocorticoid therapy with sufficient dosage, adequate course, and individualized regimen. The use of glucocorticoids should follow a gradual tapering principle to prevent rebound of RP. Additionally, in the event of pulmonary infection, empirical antimicrobial therapy with antibiotics should be initiated promptly. In addition to glucocorticoid and antibiotic therapies, adjunctive treatments such as antitussive and expectorant medications, oxygen therapy, or nebulization should be administered based on the patient’s clinical symptoms.

Consistent with previous reports (24–26), our findings underscore the critical role of lung dosimetry, demonstrating that MLD is the most robust independent predictor of RP in breast cancer radiotherapy (AUC=0.964). This reinforces the clinical imperative to rigorously minimize MLD during plan optimization. In the study, the cut-off value of MLD was 12.70 Gy, which was lower than the 13 ∼ 20 Gy dose constraint proposed in the QUANTEC guidelines (27). The primary reason for this discrepancy is that the QUANTEC guideline was derived from three-dimensional conformal radiotherapy (3D-CRT) and designed to limit the risk of grade ≥2 symptomatic RP to below 10% ∼ 20%. In contrast, this study was based on intensity-modulated radiotherapy (IMRT), and all RP cases observed in the cohort were grade 1 or 2.

The association between CSI and elevated RP risk (OR = 5.654) is particularly salient, as irradiation of the internal mammary chain inevitably increases the volume of ipsilateral lung receiving low- to moderate-dose exposure, thereby augmenting the effective lung dose. The mediation analysis demonstrated that the majority of the effect of CSI on RP was mediated through elevated MLD, which is consistent with previous studies. Therefore, dose optimization strategies aimed at reducing MLD should be the primary approach to decrease the risk of RP in patients receiving CSI irradiation. The independent predictive value of chemotherapy cycles further highlights the synergistic toxicity of cytotoxic agents and radiation, potentially through subclinical lung injury that sensitizes parenchyma to radiation-induced inflammation. The identified threshold of >7 cycles provides a practical clinical benchmark for heightened vigilance and more stringent dosimetric constraints in this subgroup.

Mitigation of RP risk may be achieved through advanced radiotherapy techniques. Respiratory motion management, such as deep inspiration breath-hold (DIBH), has been demonstrated to significantly reduce cardiac and pulmonary doses, thereby lowering RP probability (28, 29). Furthermore, the dosimetric advantages inherent to proton therapy, characterized by a steep Bragg peak and absence of exit dose, confer substantial normal tissue sparing. Comparative studies of proton versus photon plans have shown marked reductions in lung V₂₀ and MLD, even in complex clinical scenarios such as bilateral breast cancer or comprehensive nodal irradiation (30, 31). These modalities represent promising strategies for further reducing RP incidence in high-risk populations identified by the present study.

Nevertheless, this study has several limitations. First, 73.5% of RP cases were asymptomatic CTCAE Grade 1 subclinical lesions. Although we adopted standardized follow-up, double-blind image review and strict differential diagnosis to reduce surveillance and ascertainment bias, subjective interpretation of imaging findings may still exist. Secondly, the number of clinically meaningful symptomatic RP (Grade ≥ 2) was only 13 cases, with insufficient sample size for grade-stratified analysis. Therefore, we combined all RP grades for statistical analysis in this study. And then, the incidence of RP in patients without CSI was extremely low, resulting in sparse cells in the contingency table and a relatively wide 95% confidence interval of the OR value for CSI. Fourth, this study did not explore the potential interaction effects among the three identified risk factors due to the relatively small sample size of the high-risk subgroup with all three characteristics. Finally, our study excluded patients with a history of smoking, pre-existing cardiopulmonary diseases, and autoimmune disorders. It also limits the external validity of our results.

In addition, it is more noteworthy that the exceptionally high discriminative performance of MLD reported in this study must be interpreted strictly within the specific context of its generation. First, the rigorous institutional planning dose constraints may have inadvertently enriched a patient subset with a highly prominent threshold effect, thereby leading to the exaggerated manifestation of the model’s predictive performance in this cohort. Second, the inherent limitations of a single-center retrospective design, coupled with potential unmeasured confounding factors, preclude the direct generalization of this threshold and the associated AUC value to other clinical centers with divergent treatment protocols and greater population heterogeneity. Finally, from a biological standpoint, RP is a complex multifactorial pathological process. The near-perfect predictive accuracy achieved by a single dosimetric parameter further indicates that the observed association may be amplified by the specific case composition of our study sample. Therefore, we conservatively assert that while MLD represents an extremely potent risk stratification tool, its utility as a standalone predictive model urgently requires rigorous external validation in prospective cohorts employing different dose constraint strategies and encompassing more diverse patient populations.

In the next phase, the study will continue to enroll more breast cancer patients receiving radiotherapy to continue to investigate the problem of RP and to address the study limitations mentioned earlier. More importantly, we also plan to incorporate multiple factors closely associated with lung toxicity and treatment intensity, including molecular subtype, HER2 status, anti-HER2 targeted therapy, endocrine therapy, DIBH, radiotherapy techniques and tumor laterality to improve the generalizability of the model.

5 Conclusions

RP is one of the most prevalent complications in thoracic malignancy radiotherapy, imposing constraints on radiation dosage and compromising treatment efficacy while deteriorating patient quality of life. Notably, RP manifests with low incidence (typically <5%) and mild symptomatology in breast cancer radiotherapy, thus the relevant research into breast cancer-specific RP remain scarce. In this study, 49 out of 811 patients developed RP (grade 1: 36, grade 2: 13), representing a 6.04% incidence rate. Multivariate analysis revealed that the number of chemotherapy cycles, MLD and CSI were risk factors for RP. It is therefore recommended that clinicians strictly constrain the MLD, particularly in patients with a history of more than 7 chemotherapy cycles who are also receiving chest wall + supraclavicular + internal mammary lymph node irradiation.

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