Abstract
Background
Radiation pneumonitis (RP) is a common but severe complication in lung cancer patients undergoing thoracic radiotherapy, significantly impacting patient survival and quality of life. Currently, standardized clinical protocols for predicting, preventing, and managing RP remain insufficiently applied, and the clinical effectiveness of consensus-driven management guidelines in reducing RP remains unclear. This study aimed to clarify whether implementing the Chinese expert consensus on RP could effectively decrease the incidence and severity of RP, and identify independent clinical risk factors.
Methods
This retrospective comparative study included 616 lung cancer patients who underwent thoracic radiation therapy at Shanghai Pulmonary Hospital between August 2020 and January 2022. Patients were divided into two groups based on treatment periods relative to the implementation of consensus recommendations in August 2021: the pre-consensus group (treated from August 2020 to July 2021) and the post-consensus group (treated from August to January 2022). The consensus-driven interventions included three key strategies: strict limitation of planning target volume (PTV) margins, individualized lung dose constraints, and standardized steroid treatment protocols. RP incidence and severity were assessed over a 12-month follow-up according to the Common Terminology Criteria for Adverse Events (CTCAE, v5.0). Multivariate logistic regression was conducted to identify predictors for severe RP (SRP, grade ≥3).
Results
The clinical characteristics were comparable between the pre- and post-consensus groups. After implementing consensus recommendations, the overall incidence of RP decreased significantly (67.3% vs. 55.2%, P=0.003), and grade ≥3 RP markedly reduced (9.9% vs. 3.4%, P=0.005). Multivariate logistic regression analysis identified independent predictors for grade ≥3 RP: pre-existing interstitial lung disease (ILD), forced expiratory volume in 1 second (FEV1), diffusing capacity for carbon monoxide (DLCO), lymphocyte baseline counts, limited PTV margin, standardized steroids use, radiotherapy dose and V20.
Conclusions
Risk factor prevention and standardized treatment could decrease the occurrence of SRP. Clinicians should implement the recommendations in the RP management consensus in clinical practice. Special attention should be given to patients with identifiable risk factors such as pre-existing ILD, compromised lung function, high radiotherapy dose and low lymphocyte baseline counts, to improve patient prognosis and treatment safety.
Keywords: Radiation pneumonitis (RP), radiotherapy, standardized steroids, diffusing capacity for carbon monoxide (DLCO)
Highlight box.
Key findings
• Implementation of consensus recommendations significantly reduced radiation pneumonitis (RP) incidence (67.3% vs. 55.2%, P=0.003).
• Multivariate analysis identified interstitial lung disease (ILD), forced expiratory volume in 1 second (FEV1), diffusing capacity for carbon monoxide (DLCO), lymphocyte baseline counts, standardized steroids use, limited planning target volume (PTV) margin, radiotherapy dose and V20 as independent predictors of grade ≥3 RP.
What is known, and what is new?
• RP remains a life-threatening complication of thoracic radiotherapy.
• Our study demonstrates that consensus-based approaches can reduce the occurrence of RP, supporting their broader clinical adoption.
What is the implication, and what should change now?
• Clinical adoption of the Chinese expert consensus (individualized lung constraints, strict PTV margins, steroid standardization) is warranted.
• High-risk patients (ILD, impaired lung function, higher radiotherapy dose or low pre-radiotherapy lymphocytes) require prioritized implementation. Multicenter validation is recommended.
Introduction
Radiation pneumonitis (RP) is a common and potentially life-threatening complication among lung cancer patients receiving thoracic radiotherapy. It significantly impacts treatment outcomes, patient survival, and quality of life. According to clinical data, symptomatic RP (grade ≥2) occurs in up to 40% of patients within six months after completing radiotherapy (1). Severe radiation pneumonitis (SRP), defined as grade 3–5 RP under the Common Terminology Criteria for Adverse Events (CTCAE), may lead to respiratory failure and secondary infections, which may contribute to treatment-related mortality (2). Retrospective studies from Japan and France have reported a 21% mortality rate in lung cancer patients with grade ≥3 RP, primarily due to respiratory failure, resulting from extensive lung tissue damage (3,4). Moreover, secondary lung infections are common in SRP patients; a Chinese study reported that 44.5% of non-small cell lung cancer (NSCLC) patients with SRP (777 of 1,746 patients) developed secondary lung infections, and 22.4% of patients with SRP succumbed to infections (5). As such, minimizing both the incidence and severity of RP is crucial not only for improving patient prognosis and tolerability of cancer therapy but also for enabling uninterrupted oncologic treatment.
Presently, optimizing dosimetric parameters is one of the important research directions for reducing the risk of RP. International guidelines, including those from the National Comprehensive Cancer Network (NCCN) (6), recommend strict control of the percentage of lung volume receiving ≥20 Gy (V20) and mean lung dose (MLD), with tighter constraints advised for high-risk subgroups such as the elderly or those with pre-existing interstitial lung disease (ILD). In conventional fractionation regimens, keeping V20 below 30–35% and MLD below 20–23 Gy has been associated with a reduction in RP incidence to approximately 20% (6). Emerging evidence supports further refinement through ipsilateral lung constraints (e.g., ipsilateral V20 <40% and ipsilateral MLD <18 Gy for conventional radiotherapy), which have shown strong correlations with SRP development (7). Nonetheless, these strategies, while valuable, often fall short in real-world application due to a lack of individualized adaptation and comprehensive implementation.
Corticosteroid therapy remains the cornerstone of RP management. While effective for symptom control, significant uncertainties persist regarding optimal treatment protocols, including initiation timing, dosing, and tapering strategies. Current guidelines recommend initiating corticosteroids for grade ≥2 RP (symptomatic cases), whereas grade 1 disease (radiographic changes without symptoms) generally requires only monitoring. Notably, Voruganti Maddali et al. proposed oral prednisone 60 mg/day with gastroprotection as a standard initial regimen for uncomplicated RP, although the ideal dosing strategy remains controversial (8). While inhaled corticosteroids have been explored for mild cases, robust evidence supporting their efficacy in preventing disease progression is lacking (9). Furthermore, debate continues regarding whether to initiate treatment upon radiographic detection or await clinical symptom onset (e.g., dyspnea). Collectively, these knowledge gaps highlight the urgent need for evidence-based, standardized treatment algorithms.
To address these clinical gaps, Chinese experts discussed the consensus on the diagnosis and treatment of RP in Shanghai Pulmonary Hospital in August 2021. This consensus delineated critical risk factors for RP, including irradiated lung volume and pre-existing ILD and so on, while providing a detailed management protocol for its treatment. In alignment with these recommendations, our institution adopted standardized interventions, including stringent planning target volume (PTV) margin restrictions, individualized lung dose constraints, and a CTCAE grade-stratified corticosteroid regimen. However, the real-world efficacy of these consensus-driven strategies in mitigating RP incidence and severity has yet to be systematically evaluated.
To address this knowledge gap, we conducted a retrospective comparative study to assess whether the implementation of the Chinese expert consensus significantly reduces the incidence and severity of RP in lung cancer patients undergoing thoracic radiotherapy. By analyzing clinical outcomes before and after the consensus adoption at Shanghai Pulmonary Hospital, this study offers timely, evidence-based insights into the impact of standardized RP management. Our findings aim to not only validate the current consensus recommendations but also optimize clinical practices for RP prevention and treatment, ultimately enhancing patient safety and therapeutic outcomes in thoracic oncology. We present this article in accordance with the TRIPOD reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-151/rc).
Methods
Patients
We conducted a single-center, retrospective analysis of patients with NSCLC or small cell lung cancer (SCLC) who received radiotherapy at the Shanghai Pulmonary Hospital between August 2020 and January 2022. Patients with primary lung cancer received standard treatments, including radiotherapy, according to the NCCN guidelines. To be eligible for inclusion in this study, the patients had to meet the following inclusion criteria: (I) have lung cancer confirmed by histological or cytological examination; (II) be aged 18 years or older; (III) have stage I–IV lung cancer according to the American Joint Committee on Cancer (seventh edition); and (IV) have received thoracic intensity-modulated radiation therapy (IMRT) with radiation regimens of 50–66 Gy delivered in 25–33 fractions, with or without other therapies, such as surgery, targeted therapy, chemotherapy, and immunotherapy. Patients were excluded from the study if they met any of the following exclusion criteria: had metastatic lung cancer; had not completed the radiotherapy course; had a severe underlying lung disease before radiotherapy; had drug-related pneumonitis; and/or had received therapy of long-term steroids, or anti-inflammatory drugs. The RP grade was evaluated over a 12-month follow-up according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Ethics Board of the Shanghai Pulmonary Hospital (No. K25-572). The requirement of individual consent for this retrospective analysis was waived.
Treatment methods
All patients received conventional radiotherapy. The gross tumor volume (GTV) images included the primary tumor and metastatic lymph nodes, as delineated based on findings from diagnostic computed tomography (CT) and by fluorodeoxyglucose positron emission tomography (FDG-PET) scans. For the patients receiving conventional radiotherapy, the clinical target volume (CTV) was defined as the GTV plus a margin of 6–8 mm according to the pathological tumor type (squamous: 6 mm, adenocarcinoma: 8 mm; the CTV should be adjusted according to the structure of the organ at risk). The PTV was defined as the CTV plus a margin of 5 mm, depending on set-up errors and interfractional uncertainty. The prescription dose was normalized to cover 100% of the composite GTV, 99% of the ITV, and 95% of the PTV, respectively. Dosimetric constraints for MLD, lung V20 and V5, and critical organs at risk (spinal cord, esophagus, and heart) were applied in strict accordance with the recommendations outlined in the NCCN guidelines (6). All lung dose-volume parameters were calculated using the total lung minus GTV definition (i.e., lung-GTV).
Following the discussion and establishment of the RP consensus in August 2021, clinicians implemented standardized treatment protocols of radiotherapy and RP that emphasized three key aspects derived from the consensus recommendations: (I) limiting the irradiated PTV for the following patients: those aged ≥70 years; those who had a history of gemcitabine or taxane-based chemotherapy; and those with poor lung function [e.g., forced expiratory volume in 1 second (FEV1) or diffusing capacity for carbon monoxide (DLCO) <50%, and accompanying ILD] (10). The intermediate CTV was omitted and applied a direct 5 mm expansion from the GTV to form the PTV, effectively using a slightly larger treatment margin around the gross tumor volume. To support this reduced margin, daily cone-beam computed tomography (CBCT)-based image-guided radiotherapy (IGRT) was adopted for all such patients to ensure accurate positioning. The plan robustness and normal lung sparing were prioritized over conformity in these patients; (II) limiting the individualized lung dose for the above-mentioned patients: to reduce lung dose in these high-risk individuals, we placed higher priority weights on ipsilateral lung V20 and MLD during inverse optimization; and (III) administering standardized steroid therapy: oral prednisone was administered at a dose of 0.5–1 mg/kg/d for patients with grade 2 RP with obvious symptoms. If the patient’s condition improved or stabilized after 2–4 weeks, the dose was gradually reduced by 5–10 mg every week or every 2 weeks for 4–12 weeks. For patients with grade ≥3 RP, an intravenous injection of dexamethasone or methylprednisolone (the equivalent dose of methylprednisolone was 1–4 mg/kg/d) was administered, and the dose was decreased after the symptoms improved or stabilized (usually in 1–2 weeks). The guidelines recommended that the original dose be subtracted by one-third to one-quarter every 3 days until the minimum dose was reached. Upon stabilization or improvement to grade 2 or lower RP, the intravenous glucocorticoids were switched to oral glucocorticoids, and the oral dose was gradually reduced.
The incidence and grading of RP were assessed, and the standardized application of glucocorticoids and symptomatic treatments were administered according to their respective grades.
Statistical analysis
According to the type of data, categorical data was detected by chi-square test or fisher accurate test, and the continuous data was analyzed by t-test. Univariate and multivariate logistic regression analyses were used to select clinical variables with P<0.05 for model construction. The optimal cut-off values of parameters and predictive performance was evaluated with the receiver operator characteristic (ROC). All statistical analyses were carried out using IBM SPSS 27.0 (IBM Corp., Armonk, NY USA) and R software (version 4.5.0). A two-sided P value <0.05 was considered statistically significant.
Results
Between August 2020 and January 2022, a total of 840 patients with lung cancer received thoracic IMRT at the Shanghai Pulmonary Hospital. After discussing the RP consensus in August 2021, we standardized the radiotherapy schedule and the treatment of RP. These standardizations included more precisely limiting the irradiated PTV-GTV margin, more rigorously individualizing the lung dose limitation, and further standardizing the administration of glucocorticoids. Notably, before August 2021, some patients had already received these normative measures under the guidance of experienced clinicians. The patients were consciously intervened in accordance with three key aspects outlined above after August 2021 from three aspects.
We collected the patients’ basic clinical information and tracked the occurrence of RP over a 12-month follow-up period. Of the initial cohort, 75 patients were excluded due to a lack of RP-related information, 33 patients were excluded because they did not receive the prescribed radiation dose according to the NCCN guidelines, 86 patients were excluded due to missing basic clinical or follow-up data and 30 patients who withdrew consent (none experienced early SRP). Ultimately, 616 patients were included in the study, of whom 413 patients were in the pre-intervention group from August 2020 to July 2021, and 203 patients were in the post-intervention group from August 2021 to January 2022 (Figure 1). The basic clinical information of the patients, including their general characteristics and treatment patterns, is presented in Table 1. The background demographics of the patients were similar in both the pre- and post-intervention groups.
Figure 1.
Flowchart of study enrollment.
Table 1. Clinical characteristics of all patients.
| Characteristics | Pre-intervention (n=413) | Post-intervention (n=203) | P value |
|---|---|---|---|
| Age (years) | 0.20 | ||
| <70 | 332 (80.4) | 154 (75.9) | |
| ≥70 | 81 (19.6) | 49 (24.1) | |
| Gender | 0.40 | ||
| Male | 343 (83.1) | 163 (80.3) | |
| Female | 70 (16.9) | 40 (19.7) | |
| Smoking | 0.08 | ||
| Yes | 187 (45.3) | 107 (52.7) | |
| No | 226 (54.7) | 96 (47.3) | |
| ECOG PS | 0.90 | ||
| 0 | 90 (21.8) | 45 (22.2) | |
| 1 | 299 (72.4) | 148 (72.9) | |
| 2 | 24 (5.8) | 10 (4.9) | |
| ILD | 0.36 | ||
| Yes | 16 (3.9) | 5 (2.5) | |
| No | 397 (96.1) | 198 (97.5) | |
| COPD | 0.94 | ||
| Yes | 23 (5.6) | 11 (5.4) | |
| No | 390 (94.4) | 192 (94.6) | |
| Emphysema | 0.13 | ||
| Yes | 97 (23.5) | 59 (29.1) | |
| No | 316 (76.5) | 144 (70.9) | |
| Pathology | 0.83 | ||
| NSCLC | 325 (78.7) | 157 (77.3) | |
| SCLC | 87 (21.1) | 45 (22.2) | |
| Mixed | 1 (0.2) | 1 (0.5) | |
| Stage | 0.07 | ||
| Stage I–III NSCLC | 259 (62.7) | 121 (59.6) | |
| Stage IV NSCLC | 77 (18.6) | 43 (21.2) | |
| Limited-stage SCLC | 43 (10.4) | 31 (15.3) | |
| Extensive-stage SCLC | 34 (8.2) | 8 (3.9) | |
| FEV1 (%) | 82.53±19.98 | 83.23±21.15 | 0.72 |
| DLCO (%) | 89.68±21.29 | 89.51±24.33 | 0.94 |
| Lymphocyte baseline (×109/L)† | 1.66±0.61 | 1.69±0.61 | 0.50 |
| Lymphocyte after irradiation (×109/L) | 0.88±0.45 | 0.91±0.43 | 0.35 |
| Therapeutic scheme | 0.22 | ||
| CCRT | 66 (16.0) | 38 (18.7) | |
| SCRT | 317 (76.8) | 149 (73.4) | |
| Radiotherapy alone | 16 (3.9) | 13 (6.4) | |
| Radiotherapy and others | 14 (3.4) | 3 (1.5) | |
| Surgery | 0.10 | ||
| No | 309 (74.8) | 164 (80.8) | |
| Yes | 104 (25.2) | 39 (19.2) | |
| Immunotherapy | 0.25 | ||
| No | 328 (79.4) | 153 (75.4) | |
| Yes | 85 (20.6) | 50 (24.6) | |
| Targeted therapy | 0.77 | ||
| No | 399 (96.6) | 197 (97.0) | |
| Yes | 14 (3.4) | 6 (3.0) | |
| Chemotherapy regimen | 0.18 | ||
| GEM | 49 (11.9) | 16 (7.9) | |
| TAX | 124 (30.0) | 76 (37.4) | |
| Other | 210 (50.8) | 95 (46.8) | |
| None | 30 (7.3) | 16 (7.9) | |
| Standardized steroids use | N=278 | N=112 | <0.001 |
| No | 89 (32.0) | 0 (0.0) | |
| Yes | 189 (68.0) | 112 (100.0) | |
| Irradiated PTV | <0.001 | ||
| Conventional PTV margin | 273 (66.1) | 98 (48.3) | |
| Limited PTV margin | 140 (33.9) | 105 (51.7) | |
| Radiotherapy dose | 0.24 | ||
| <54 Gy | 113 (27.4) | 43 (21.2) | |
| 54–60 Gy | 173 (41.9) | 90 (44.3) | |
| ≥60 Gy | 127 (30.8) | 70 (34.5) | |
| Total V5 | 37.38±8.82 | 36.90±10.19 | 0.57 |
| Total V20 | 20.91±5.10 | 19.97±5.55 | 0.04 |
| Total V30 | 14.88±4.30 | 13.73±4.21 | 0.002 |
| Total MLD | 10.89±2.61 | 10.26±2.75 | 0.006 |
| Contralateral V5 | 19.95±9.28 | 18.71±10.64 | 0.14 |
| Contralateral V20 | 5.39±5.83 | 4.90±5.64 | 0.32 |
| Contralateral V30 | 2.55±2.95 | 2.48±3.51 | 0.81 |
| Contralateral MLD | 4.28±2.23 | 3.94±2.56 | 0.09 |
| Ipsilateral V5 | 58.61±13.64 | 57.17±14.51 | 0.23 |
| Ipsilateral V20 | 39.64±11.39 | 37.38±11.01 | 0.02 |
| Ipsilateral V30 | 30.36±9.89 | 27.08±9.20 | <0.001 |
| Ipsilateral MLD | 19.44±6.36 | 17.59±5.24 | <0.001 |
Data are presented as mean ± standard deviation or number (percentage). †, two patients lacked of the data of lymphocyte baseline. CCRT, concurrent chemoradiation therapy; COPD, chronic obstructive pulmonary disease; DLCO, diffusing capacity for carbon monoxide; ECOG PS, Eastern Cooperative Oncology Group performance status; FEV1, forced expiratory volume in 1 second; GEM, gemcitabine; ILD, interstitial lung disease; MLD, mean lung dose; NSCLC, non-small cell lung cancer; PTV, planning target volume; SCLC, small cell lung cancer; SCRT, sequential chemoradiation therapy; TAX, paclitaxel; V5, percentage of lung volume receiving ≥5 Gy; V20, percentage of lung volume receiving ≥20 Gy; V30, percentage of lung volume receiving ≥30 Gy.
We examined the occurrence of RP in these patients. The median time of occurrence of RP from the onset of radiotherapy was 110 days. The occurrence of different grades of RP was detailed in Table 2. The implementation of the consensus guidelines led to significant reductions in RP incidence. The overall RP rate decreased from 67.3% to 55.2% (P=0.003), with particularly notable reductions in symptomatic RP (grade ≥2: 40.2% to 28.6%; P=0.005) and severe RP (grade ≥3: 9.9% to 3.4%; P=0.005). Two fatal RP events occurred (one in each group).
Table 2. Incidence of different grades of RP in different periods.
| Radiation pneumonitis | Pre-intervention (n=413), n (%) | Post-intervention (n=203), n (%) |
|---|---|---|
| None | 135 (32.7) | 91 (44.8) |
| Grade 1 | 112 (27.1) | 54 (26.6) |
| Grade 2 | 125 (30.3) | 51 (25.1) |
| Grade 3 | 39 (9.4) | 6 (33.0) |
| Grade 4 | 1 (0.2) | 0 (0.0) |
| Grade 5 | 1 (0.2) | 1 (0.5) |
P=0.009. RP, radiation pneumonitis.
The results of the univariate and multivariate analyses examining the association between the baseline factors and grade ≥3 RP are displayed in Table 3. The univariate analysis showed that ILD, FEV1, DLCO, lymphocyte baseline, lymphocyte after irradiation, standardized steroids use, radiotherapy dose, limited PTV margin, the total V20, the ipsilateral V5, the ipsilateral V20, the ipsilateral V30, and the ipsilateral MLD were significantly correlated with grade ≥3 RP (P<0.05). The multivariate analysis revealed that ILD [odds ratio (OR) =6.144, 95% confidence interval (CI): 1.219–30.955, P=0.03], FEV1 (OR =0.970, 95% CI: 0.942–1.000, P=0.047), DLCO (OR =0.953, 95% CI: 0.917–0.990, P=0.01), lymphocyte baseline (OR =0.180, 95% CI: 0.033–0.969, P=0.046), standardized steroids use (OR =0.015, 95% CI: 0.003–0.064, P<0.001), radiotherapy dose (OR =6.458, 95% CI: 1.761–23.687, P=0.005), limited PTV margin (OR =0.170, 95% CI: 0.034–0.837, P=0.03), and the total V20 (OR =4.046, 95% CI: 1.035–15.814, P=0.044) were significantly associated with SRP. The patients with ILD were more likely to develop grade ≥3 RP. The cut-off values for the FEV1 and DLCO were 84.7% and 87.0%, respectively. The patients with better lung functions (FEV1 >84.7% and DLCO >87.0%) and higher lymphocyte baseline (>1.97×109/L) who were treated by clinicians with standardized steroids had a lower risk of developing grade ≥3 RP.
Table 3. Univariate and multivariate analyses of the association between the baseline factors and grade ≥3 RP.
| Variables | Univariable analysis | Multivariable analysis | |||||
|---|---|---|---|---|---|---|---|
| OR | 95% CI | P | OR | 95% CI | P | ||
| Age ≥70 years | 1.432 | 0.734–2.793 | 0.29 | ||||
| Gender | 1.569 | 0.650–3.788 | 0.32 | ||||
| Smoking | 0.766 | 0.422–1.392 | 0.38 | ||||
| ECOG PS | |||||||
| 0 | Reference | ||||||
| 1 | 2.055 | 0.851–4.965 | 0.11 | ||||
| 2 | 2.081 | 0.493–8.784 | 0.32 | ||||
| ILD | 13.325 | 5.325–3.346 | <0.001 | 6.144 | 1.219–30.955 | 0.03 | |
| COPD | 0.728 | 0.169–3.136 | 0.67 | ||||
| Emphysema | 1.529 | 0.814–2.869 | 0.19 | ||||
| Surgery | 0.747 | 0.353–1.583 | 0.45 | ||||
| Pathology | |||||||
| NSCLC | Reference | ||||||
| SCLC | 0.831 | 0.392–1.763 | 0.63 | ||||
| Mixed | 0.000 | 0.000–NA | >0.99 | ||||
| Stage | |||||||
| Stage I–III NSCLC | Reference | ||||||
| Stage IV NSCLC | 1.061 | 0.502–2.239 | 0.88 | ||||
| LS-SCLC | 1.219 | 0.514–2.890 | 0.65 | ||||
| ES-SCLC | 0.285 | 0.038–2.142 | 0.22 | ||||
| FEV1 | 0.976 | 0.961–0.992 | 0.004 | 0.970 | 0.942–1.000 | 0.047 | |
| DLCO | 0.979 | 0.962–0.996 | 0.02 | 0.953 | 0.917–0.990 | 0.01 | |
| Treatment | |||||||
| Radiotherapy alone | Reference | ||||||
| CCRT | 1.414 | 0.159–12.606 | 0.76 | ||||
| SCRT | 2.629 | 0.348–19.835 | 0.35 | ||||
| Radiotherapy and other | 3.733 | 0.312–44.626 | 0.30 | ||||
| Chemotherapy regimen | |||||||
| None | Reference | ||||||
| GEM | 2.012 | 0.504–8.034 | 0.32 | ||||
| TAX | 1.505 | 0.426–5.316 | 0.53 | ||||
| Other | 0.899 | 0.254–3.181 | 0.87 | ||||
| Immunotherapy | 1.206 | 0.609–2.388 | 0.59 | ||||
| Targeted therapy | 0.615 | 0.081–4.694 | 0.64 | ||||
| Lymphocyte baseline >1.97×109/L | 0.355 | 0.148–0.851 | 0.02 | 0.180 | 0.033–0.969 | 0.046 | |
| Lymphocyte after irradiation >0.89×109/L | 0.424 | 0.212–0.849 | 0.02 | 0.680 | 0.184–2.522 | 0.56 | |
| Standardized steroids use | 0.030 | 0.014–0.062 | <0.001 | 0.015 | 0.003–0.064 | <0.001 | |
| Radiotherapy dose ≥60 Gy | 1.900 | 1.048–3.445 | 0.03 | 6.458 | 1.761–23.687 | 0.005 | |
| Limited PTV margin | 0.237 | 0.104–0.537 | <0.001 | 0.170 | 0.034–0.837 | 0.03 | |
| Total V5 ≥35% | 1.883 | 0.959–3.697 | 0.07 | ||||
| Total V20 ≥23% | 3.114 | 1.693–5.728 | <0.001 | 4.046 | 1.035-15.814 | 0.044 | |
| Total V30 ≥16% | 0.783 | 0.423–1.447 | 0.43 | ||||
| Total MLD ≥13 Gy | 0.895 | 0.389–2.057 | 0.79 | ||||
| Contralateral V5 ≥26% | 1.486 | 0.792–2.788 | 0.22 | ||||
| Contralateral V20 ≥4% | 1.059 | 0.587–1.911 | 0.85 | ||||
| Contralateral V30 ≥2% | 1.065 | 0.586–1.937 | 0.84 | ||||
| Contralateral MLD ≥2 Gy | 1.662 | 0.641–4.309 | 0.30 | ||||
| Ipsilateral V5 ≥52% | 2.553 | 1.172–5.563 | 0.02 | 2.055 | 0.277–15.251 | 0.42 | |
| Ipsilateral V20 ≥36% | 2.530 | 1.236–5.179 | 0.01 | 1.349 | 0.156–11.686 | 0.79 | |
| Ipsilateral V30 ≥25% | 2.634 | 1.209–5.739 | 0.01 | 1.081 | 0.157–7.426 | 0.94 | |
| Ipsilateral MLD ≥18 Gy | 2.289 | 1.186–4.418 | 0.01 | 0.401 | 0.060–2.687 | 0.35 | |
CCRT, concurrent chemoradiation therapy; CI, confidence interval; COPD, chronic obstructive pulmonary disease; DLCO, diffusing capacity for carbon monoxide; ECOG PS, Eastern Cooperative Oncology Group performance status; ES, extensive-stage; FEV1, forced expiratory volume in 1 second; GEM, gemcitabine; ILD, interstitial lung disease; LS, limited-stage; MLD, mean lung dose; NA, not available; NSCLC, non-small cell lung cancer; OR, odds ratio; PTV, planning tumor volume; RP, radiation pneumonitis; SCRT, sequential chemoradiation therapy; SCLC, small cell lung cancer; TAX, paclitaxel; V5, percentage of lung volume receiving ≥5 Gy; V20, percentage of lung volume receiving ≥20 Gy; V30, percentage of lung volume receiving ≥30 Gy.
Table 4 lists the important risk factors for seven patients with SRP in the post-intervention group. Among all the variables, at least two variables changed in terms of their being risk factors for the development of SRP. Four of the seven patients had pre-existing lung diseases, including chronic obstructive pulmonary disease (COPD), ILD, and emphysema. The patient who died from grade 5 RP had ILD. All the patients with SRP had reduced lung diffusion functions, with DLCO values below 87.0% (which was the cut-off value for DLCO). The lymphocyte counts before radiotherapy of all the patients were under 1.97×109/L. One patient aged ≥70 years had a limited PTV margin at the targeted delineation. All the patients were treated with standardized steroids and demonstrated tolerance to the treatment. Of the 616 patients, 10 treated with steroids developed fungal infections, and five experienced pneumocystis carinii pneumonia (PCP).
Table 4. The risk factors for seven patients with SRP in the post-intervention group.
| ID | RP | Age, years | Lung disease | FEV1 (%) | DLCO (%) | Lymphocyte baseline (×109/L) | Limited PTV margin | Radiotherapy dose (cGy) | Total V20 (%) | Standardized steroids use | Predicted risk rate of RP (%) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 516 | 5 | 68 | ILD | 92.2 | 64.6 | 1.5 | No | 5,000 | 12.95 | Yes | 8.2 |
| 527 | 3 | 76 | No | 93.4 | 65.2 | 1.73 | Yes | 6,000 | 23.34 | Yes | 4.9 |
| 551 | 3 | 60 | No | 60.0 | 68.3 | 1.7 | No | 6,000 | 30.39 | Yes | 42.2 |
| 565 | 3 | 63 | Emphysema | 57.8 | 55.6 | 1.35 | No | 5,000 | 23.62 | Yes | 21.5 |
| 581 | 3 | 65 | No | 82.3 | 72.5 | 0.92 | No | 6,000 | 20.62 | Yes | 6.5 |
| 633 | 3 | 69 | COPD | 43.4 | 79.6 | 1.65 | No | 6,000 | 23.53 | Yes | 42.2 |
| 697 | 3 | 54 | Emphysema | 84.6 | 66.5 | 1.44 | Yes | 5,400 | 14.20 | Yes | 0.3 |
COPD, chronic obstructive pulmonary disease; DLCO, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 second; ILD, interstitial lung disease; PTV, planning tumor volume; RP, radiation pneumonitis; SRP, severe radiation pneumonitis; V20, percentage of lung volume receiving ≥20 Gy.
The ROC curve, which reflects the predictive capacity of the significant variables (P<0.05) in the multivariate logistic regression analysis for SRP, is shown in Figure 2. The area under the curve (AUC) value was 0.946 (95% CI: 0.902–0.991), indicating strong predictive ability of above variables for SRP. The nomogram in Figure 2 shows the evaluated risk of SRP for every patient, including the seven SRP cases (for further details, see Table 4).
Figure 2.
The ROC and nomogram of all patients. *, P<0.05; **, P<0.01; ***, P<0.001. AUC, area under the curve; CI, confidence interval; DLCO, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 second; ILD, interstitial lung disease; PTV, planning target volume; ROC, receiver operating characteristic; V20, percentage of lung volume receiving ≥20 Gy.
Discussion
Data on the occurrence of RP was collected and analyzed from 616 patients receiving thoracic IMRT at the Shanghai Pulmonary Hospital between August 2020 and January 2022. Our findings demonstrated a significant reduction in the incidence of high-grade RP following the implementation of standardized treatment protocols based on the RP consensus established in August 2021. The incidence of grade ≥3 RP decreased from 9.9% to 3.4%, and the incidence of symptomatic grade ≥2 RP decreased from 40.2% to 28.6%. These results indicated that individualized and precise radiotherapy regimens and standardized steroid therapy in reducing the occurrence and severity of RP. The results of the multivariate logistic regression analysis showed that ILD, FEV1, DLCO, lymphocyte baseline, standardized steroids use, radiotherapy dose, limited PTV margin, and the total V20 were associated with SRP. The ROC curve (AUC: 0.946, 95% CI: 0.902–0.9291) had good fitting ability. The nomogram evaluated the risk of SRP for every patient.
The standard delineation of the PTV in lung cancer radiation therapy involved an appropriate expansion of the GTV according to established radiotherapy guidelines (11). Reports 62 and 83 of the International Commission on Radiation Units and Measurements (ICUR) define the target volumes for three-dimensional conformal radiotherapy and IMRT. The PTV margin can be decreased through techniques such as immobilization, motion management, and image-guided radiotherapy (IGRT), allowing for flexibility in PTV delineation across different clinical centers. In our study, multivariate logistic regression analysis indicated that limiting the irradiated PTV-GTV margin was a protective factor for high-grade RP (OR =0.170, 95% CI: 0.034–0.837). This finding was consistent with the results of Jiang et al., who used machine-learning models to evaluate the prediction of symptomatic RP by analyzing dosimetric factors and radiomics features, and found that identified radiomics features related to the PTV-GTV margin were better able to predict RP after the PTV field was narrowed (12). Many studies have confirmed that controlling the scope of the PTV-GTV margin in patients receiving radical radiotherapy helps to limit the dose to surrounding normal tissue and to ensure good therapeutic outcomes (12-14). Therefore, during target delineation, the PTV-GTV margin should be reasonably reduced while adhering to the radiotherapy consensus recommendations. It may be affected by the composite effects of other treatment parameters. The range of the target delineation is a valuable indicator in the analysis of RP; therefore, exploring a reasonable and appropriate range for the target delineation is a task of paramount importance in this field.
In this study, we found poor lung function and underlying lung disease had an obvious influence on SRP. Consistent with our findings, previous studies have demonstrated that reduced pulmonary function markedly increases the risk of RP (15-19). A systematic review of multifactorial risk assessments for radiation-induced lung toxicity concluded that a low FEV1 before RT was associated with a higher risk of RP (15). Another study demonstrated that patients with poor pulmonary function (including low FEV1 and DLCO, and high fractional exhaled nitric oxide) undergoing concurrent chemoradiation therapy (CCRT) are also at greater risk of RP (17). Similarly, patients treated with carbon-ion radiation therapy (CIRT) for treat stage-I NSCLC and had a FEV1 <0.9 L were found to have an increased risk of grade 2 RP (18), and those receiving durvalumab following chemoradiotherapy (CRT) for stage-III NSCLC with a pre-treatment DLCO <60% had a higher risk of RP (P=0.04) (19). Anyway, poor pulmonary function increased the risk of RP for patients regardless of stage or radiotherapy mode. Therefore, we recommend that all patients undergo pre-radiotherapy pulmonary function tests (PFTs). Particular caution should be exercised during target volume delineation in patients with FEV1% <84.7% or DLCO% <87.0%. Underlying lung diseases also affected the risk of SRP for patients receiving irradiation. Numerous studies have shown that ILD is strongly correlated with RP (20-22). For example, a retrospective study of stage-I NSCLC patients treated with stereotactic body radiation therapy (SBRT) confirmed that pre-existing ILD was a significant risk factor for symptomatic RP and SRP and worse 3-year overall survival (20). A similar outcome was also observed in palliative RT patients (21). Moreover, subclinical ILD tended to be significant for the occurrence of Grade 5 RP and more extensive ILD (bilateral fibrosis in multiple lobes) was recognized in patients with Grade 5 RP (22). In light of these findings, efforts should be made to protect the normal lung tissue of patients with baseline lung diseases during radiotherapy to reduce the occurrence of SRP.
In this study, we implemented stricter lung dose constraints to the high-risk individuals in the post-intervention group, specifically limiting dosimetric parameters such as V20 and MLD, with the aim of reducing the incidence of SRP. Our multivariate analysis demonstrated that both the total V20 and the overall RT dose were independently and significantly associated with SRP (P<0.05), consistent with previous findings (23-26). For instance, in a retrospective study of SRP in patients receiving concurrent CRT for NSCLC, Tsujino et al. concluded that the V5 and V20 were independent and significant risk factors in the occurrence of SRP (25). McFarlane et al. discovered MLD and V20 were statistically significant predictors for SRP (27). The observed decline in SRP incidence in our post-intervention group highlights the clinical benefit of implementing stricter dose-volume limits, particularly in high-risk populations. These results reinforce the importance of individualized treatment planning and careful dose optimization to protect normal lung tissue while maintaining tumor control. Therefore, incorporating stringent RT dose and V20 constraints into routine practice represents a practical and effective approach to minimizing pulmonary toxicity in thoracic radiotherapy.
At present, there is no specific therapy for RP other than symptomatic and steroid treatments. Based on our clinical treatment experience at the Shanghai Pulmonary Hospital and previous clinical trials, we implemented standardized steroid protocols for the treatment of RP, as recommended in the discussion of the Chinese consensus on RP (28). We found a reduction in the incidence of high-grade RP after standardized steroid therapy (P=0.005), indicating the effectiveness of this treatment scheme. However, seven patients still suffered from SRP, and some RP patients had worse treatment effects due to tolerance/resistance. Numerous studies are being conducted on the development of innovative pharmacotherapeutic agents for the management of RP, including pentoxifylline, chitosan microspheres, and gene-modified mesenchymal stem cells, to improve therapeutic outcomes (29-31). Azithromycin, in particular, has been reported to reduce the incidence of RP in animal studies, which provides a rationale for its use in clinical settings (32). To further investigate its potential, a prospective randomized controlled study on the use of azithromycin for low-grade RP is currently being conducted at the Shanghai Pulmonary Hospital. Additionally, in our study, five patients developed PCP and five patients developed other fungal infections after receiving a long-term and high initial dose of steroids. This is likely due to the immunosuppressive effects of steroid, which can predispose patients to fungal infections (33). Therefore, clinicians should be alert to fungal infections when using high-dose steroid therapy in patients with RP, normalize the steroid use in symptomatic RP patients, and search for other alternative treatments.
Our study had some limitations. First, as we employed a retrospective design, bias might have been introduced. Second, further narrowing the PTV volume under the existing standard should be considered to reduce the occurrence of adverse responses. Third, this study only followed up with patients for up to 1 year after radiotherapy to observe RP. Data on their long-term survival status were not reported in this article but will be published in another study. Finally, replacement treatments should be explored for patients with steroid resistance.
Conclusions
Our study showed that preventive measures for risk factors and standardized treatment measures significantly reduced the morbidity associated with grade ≥3 RP, which is vital in the comprehensive curative management of lung cancer patients receiving radiotherapy. This reduction was likely due to changes in prescriptions related to steroid treatment and improvements in target delineation and lung dose limitation. We hope this approach can be adopted by other radiotherapy centers. We plan to further improve the cycles of RP by implementing early interventions for RP and managing the complications associated with high-dose steroid therapy.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Ethics Board of the Shanghai Pulmonary Hospital (No. K25-572). The requirement of individual consent for this retrospective analysis was waived.
Footnotes
Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-151/rc
Funding: The study was supported by the Start-Up Fund for Talent Introduction of Shanghai Pulmonary Hospital (No. 20180101), the 2023 Development Fund of Discipline-Department of Radiotherapy (Shanghai Pulmonary Hospital), the foundation of National Natural Science Foundation of China (No. 82473560), the Technical Standards Project of the Science and Technology Commission of Shanghai Municipality (No. 21DZ2201900), and the Bethune Young and Middle-aged Physicians Oncology Research Fund (No. YDTR-008).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-151/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-151/dss
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