Abstract
Background/Aim: Pneumonitis is a serious radiotherapy complication. This study, which is a prerequisite for a prospective trial, aimed to identify the prevalence of pneumonitis and risk factors in elderly patients with lung cancer. Patients and Methods: Ninety-eight lung cancer patients aged ≥65 years were included. Seventeen factors were investigated regarding grade ≥2 pneumonitis at 24 weeks following radiotherapy. Results: The prevalence of grade ≥2 pneumonitis at 24 weeks was 27.3%. On univariate analysis, a significant association was observed for mean (ipsilateral) lung dose (MLD; ≤13.0 vs. 13.1-20.0 vs. >20.0 Gy; 0% vs. 24.9% vs. 48.7%). Results were significant also for ≤13.0 vs. >13.0 Gy (0% vs. 37.1%) or ≤20.0 vs. >20.0 Gy (13.4% vs. 48.7%). MLD achieved significance on multivariate analysis. Conclusion: Elderly patients receiving MLDs >13.0 Gy, particularly >20.0 Gy, have a high risk of grade ≥2 pneumonitis. These results are important for designing a prospective trial.
Lung cancer is a common cancer type worldwide and responsible for a significant number of cancer-associated deaths (1). Many lung cancer patients receive radiotherapy of the primary tumor plus/minus regional lymph nodes, often combined with chemotherapy or immunotherapy. One subacute complication of thoracic irradiation is pneumonitis, which can significantly impair the patient’s quality of life and even lead to death (2). Since pneumonitis may occur only weeks or even months after completion of the radiotherapy course, it may not be related to the previous treatment and mistaken for pneumonia or severe bronchitis (3, 4). This can be quite dangerous for the patients, because they do not receive the required corticosteroids but antibiotics instead, and pneumonitis may become more severe or even fatal (2). Therefore, it is crucial to diagnose and treat radiation pneumonitis as early as possible. This may be facilitated by a mobile application (app) that can be used by the patients at home to specify and rate their symptoms (4, 5). Based on the information given by the patients, a scoring system can be created to diagnose pneumonitis and discriminate it from other lung diseases. Symptoms of pneumonitis generally include cough, shortness of breath, and fever. In a previous prospective trial that investigated patients of any age, scoring points between 0 and 3 were assigned to each of the three symptoms (4, 5). Thus, total scores for individual patients ranged between 0 and 9 points. In the previous study, the optimal cut-off score for identification of pneumonitis was 5 points. In addition, an increase by 3 or more points from baseline was a significant indicator of pneumonitis.
Since the previous trial was performed in lung cancer patients of any age, it is not clear whether its results hold true for elderly patients, an age group that is constantly growing (6). Moreover, several studies have shown that elderly patients with lung cancer have a higher risk of radiation pneumonitis than younger patients (7-13). Therefore, it may be questioned whether a cut-off score of 5 points and an increase by 3 points are optimal parameters for identification of pneumonitis in elderly patients. Therefore, an additional prospective trial is planned in elderly patients with lung cancer. This retrospective study is a prerequisite for that trial. Its goals include determination of the prevalence of pneumonitis in elderly lung cancer patients at 24 weeks after local or loco-regional irradiation and identification of risk factors. This information is mandatory for designing the planned prospective trial.
Patients and Methods
The data of 98 elderly lung cancer patients aged ≥65 years treated with radiotherapy alone or chemoradiation between 2016 and 2019 were retrospectively analyzed for associations with grade ≥2 pneumonitis. The study was approved by the ethics committee of the University of Lübeck, Germany (file number 2024-147). Its major goal was the identification of the prevalence of grade ≥2 pneumonitis at 24 weeks following radiotherapy. In addition, 17 potential risk factors were evaluated for potential associations with grade ≥2 pneumonitis (Table I). These factors included age (<80 vs. ≥80 years), sex (female vs. male), main tumor localization (central or main bronchus vs. lower or middle lobe vs. upper lobe), upfront resection (no vs. yes), forced expiratory volume in one second (≤1.69 vs. >1.69 l), history of chronic inflammatory disease (no vs. yes), history of chronic obstructive pulmonary disease (no vs. yes), history of significant cardiovascular disease (no vs. yes), smoking history (<40 vs. ≥40 pack years), systemic treatment prior to and/or during radiotherapy (no vs. yes), histology (non-small-cell vs. small-cell lung cancer), primary tumor stage (T1 or T2 vs. T3 or T4), nodal stage (N0 or N1 vs. N2 or N3), history of another malignancy (no vs. yes), total radiation dose (≤56 vs. >56 Gy), treatment volume (primary tumor plus lymph nodes vs. primary tumor alone), and mean (ipsilateral) lung dose (MLD; ≤13.0 vs. 13.1-20.0 vs. >20.0 Gy). The cut-off values for the MLD were selected in accordance with the data from the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) (14). According to these analyses, MLDs of 13 Gy and 20 Gy are associated with a risk of symptomatic pneumonitis of 10% and 20%, respectively. In the present study, chronic inflammatory diseases included bronchial asthma (three patients), rheumatoid arthritis (three patients), and Hashimoto’s thyroiditis (one patient). Significant cardiovascular diseases included coronary heart disease (21 patients), cardiomyopathy (six patients), and history of cerebral apoplexy or transient ischemic attack (five patients). Other malignancies were head-and-neck cancer (seven patients), bladder cancer (four patients), prostate cancer (three patients), breast cancer (two patients), melanoma (two patients), colon cancer (two patients), and other tumors (four patients).
Associations between patient characteristics and prevalence of pneumonitis.
Radiotherapy was performed with volumetric modulated arc therapy using conventional fractionation with doses per fraction of 2.0 Gy. The median total dose was 56.0 Gy (range=36.0-66.0 Gy). Seven patients (7.1%) were treated with adjuvant radiotherapy or chemoradiation and 91 patients (92.9%) with definitive treatment. Forty-eight patients (49.0%) received systemic treatment prior to radiotherapy. Regimens mainly included cisplatin/etoposide or carboplatin/etoposide for small-cell lung cancer, cisplatin/pemetrexed or paclitaxel alone for adenocarcinoma, and cisplatin/vinorelbine, carboplatin/paclitaxel or vinorelbine alone for squamous-cell carcinoma. Forty-five patients (45.9%) received systemic treatment given concurrently with radiotherapy using the same or similar regimens.
The median period of follow up after radiotherapy was 51 weeks (range=1.5-237 weeks). Univariate analyses regarding the prevalence of grade ≥2 pneumonitis at 24 weeks were performed using the Kaplan–Meier method and the log-rank test. For the multivariate analysis, a stepwise regression of all variables with ≤5 missing values was performed to identify the final parsimonious model. Significance levels of 0.20 and 0.25, respectively, were required for a variable to be included in the model and to stay in the model. For the statistical analyses, the software SAS 9.4 was used (SAS Institute Inc, Cary, NC, USA). p-Values <0.05 were considered significant.
Results
Twenty-five patients (25.5%) developed grade ≥2 pneumonitis after a median of 9.5 weeks (range=0-27 weeks) following irradiation. In 24 of these patients, pneumonitis occurred within 24 weeks after radiotherapy, in two patients even during the radiotherapy course. According to the Kaplan-Meier analysis, the prevalence of grade ≥2 pneumonitis at 24 weeks was 27.3%. A significant association was found between grade ≥2 pneumonitis and the mean dose to the ipsilateral lung. The prevalence was 0.0% for ≤13.0 Gy, 24.9% for 13.1-20.0 Gy, and 48.7% for >20.0 Gy, respectively (p<0.001; Table I and Figure 1). Significant differences were also found when comparing MLDs ≤13.0 vs. >13.0 Gy (0.0% vs. 37.1%, p=0.001; Figure 2) or ≤20.0 vs. >20.0 Gy (13.4% vs. 48.7%, p<0.001; Figure 3). Since prevalence was 0.0% for MLDs ≤13.0 Gy, the comparison of ≤20.0 vs. >20.0 Gy was used for the parsimonious model (multivariate analysis). In addition to the MLD, history of another malignancy (no vs. yes) and systemic treatment prior to and/or during radiotherapy (no vs. yes) qualified for staying in the parsimonious model. However, only the MLD achieved significance (Table II).
Kaplan–Meier curves for occurrence of grade ≥2 pneumonitis (failure probability) comparing mean doses to the ipsilateral lung of ≤13.0 Gy vs. 13.1-20.0 Gy vs. >20.0 Gy. The p-value was calculated with the log-rank test.
Kaplan–Meier curves for occurrence of grade ≥2 pneumonitis (failure probability) comparing mean doses to the ipsilateral lung of ≤13.0 Gy vs. >13.0 Gy. The p-value was calculated with the log-rank test.
Kaplan–Meier curves for occurrence of grade ≥2 pneumonitis (failure probability) comparing mean doses to the ipsilateral lung of ≤20.0 Gy vs. >20.0 Gy. The p-value was calculated with the log-rank test.
Multivariate analysis (parsimonious model after stepwise regression).
Discussion
Patients with lung cancer receiving radiotherapy or chemoradiation may experience symptomatic pneumonitis, which can be serious or even fatal (2). Therefore, early diagnosis and treatment are important. In a previous prospective trial, foundations for the design of an app to be used by the patients at home have been laid (4, 5). A scoring system with scoring points ranging between 0 and 9 points was developed and tested, and the optimal cut-off score (5 points) for identification of pneumonitis was defined. In addition, an increase by at least 3 points was significantly associated with the development of pneumonitis (4).
Several studies found that elderly patients are more likely to experience symptomatic pneumonitis during or following radiotherapy for lung cancer than younger patients (7-13). In two studies of Schild et al., patients aged ≥70 years had a higher prevalence of grade ≥4 pneumonitis than patients younger than 70 years (7, 8). In an international meta-analysis of individual patient data, older age was significantly associated with symptomatic pneumonitis on univariate analysis and showed a corresponding trend on multivariate analysis (9). The highest rate of pneumonitis was found in patients who were older than 65 years and received additional chemotherapy with carboplatin and paclitaxel. In the study of Kharofa and Gore that included 256 patients receiving definitive radiotherapy or chemoradiation for non-small-cell or small-cell lung cancer, age ≥70 years was significantly associated with grade ≥2 pneumonitis in both univariate and multivariate analyses (10). The study of Zhou et al. analyzed the data of 153 patients with locally advanced non-small-cell lung cancer (11). Patients experiencing grade ≥2 pneumonitis were almost significantly older than patients with no or grade 1 pneumonitis (65.70±9.58 years vs. 62.19±8.89 years, p=0.050). In 2020, Zhang et al. presented a cohort of 749 patients with unresectable non-small-cell lung cancer receiving radiotherapy alone or combined with concurrent or sequential chemotherapy (12). Patients were stratified according to age. Two groups were formed considering the optimal cut-off, namely <65 years and ≥65 years. The prevalence of overall, symptomatic and severe pneumonitis was similar in both age groups. The prevalence of fatal pneumonitis was significantly higher in elderly patients (4.5% vs. 1.7%, p=0.039). The cut-off value of the study of Zhang et al. was also used as criterion for inclusion in our present study (12). In a report of exploratory analyses of outcomes of a randomized trial that investigated consolidation durvalumab in patients with unresectable stage III non-small-lung cancer by age (post-hoc age threshold of 70 years), grade ≥2 pneumonitis occurred more often in patients aged ≥70 years (22.8% vs. 11.7%) (13).
Considering the higher risk of symptomatic pneumonitis in elderly patients reported by most studies, it was considered reasonable to develop an additional scoring system for identification of pneumonitis particularly for this age group. The scoring system, which will be tested in a prospective trial, is the prerequisite for an app that can be used by the patients at home. This app will allow the patients to specify their potentially pneumonitis-related symptoms. Afterwards, it will indicate whether pneumonitis is possible or likely and whether any action (e.g., consulting a pulmonologist or visiting the outpatient clinic of a hospital) is required. For calculation of the required sample size of the prospective trial, the prevalence of grade ≥2 pneumonitis in elderly patients with lung cancer is required. Moreover, for definition of the inclusion criteria, independent risk factors of pneumonitis are helpful.
The present study aimed to define both, prevalence and risk factors of grade ≥2 pneumonitis in patients aged ≥65 years. The prevalence at 24 weeks following radiotherapy was 27.3%, and the median dose to the ipsilateral lung was identified as independent risk factor. MLDs of ≤13.0 Gy, 13.1-20.0 Gy and >20.0 Gy were associated with grade ≥2 pneumonitis rates of 0.0%, 24.9% and 48.7%, respectively. Patients receiving >13 Gy had a prevalence of 37.1%. Since the prevalence of grade ≥2 pneumonitis was 0.0% in patients receiving ≤13.0 Gy, a MLD of >13.0 Gy will be used as criterion for inclusion in the planned prospective trial. The prevalence of grade ≥2 pneumonitis in our present study was in the range of 7.2-49.5% found in previous studies for patients of any age (9-11, 13, 15-23). Three larger studies including 82, 156 and 267 elderly lung cancer patients, respectively, reported the prevalence of grade ≥2 pneumonitis for this age group (12, 13, 19). In these studies, the prevalence ranged between 16.1% and 28.0%. Thus, the prevalence of our present study was in this range. Since the previous studies did not report the prevalence in elderly patients with risk factors, it is difficult to compare our patients receiving >13 Gy to the other cohorts.
The MLD was previously identified as risk factor of symptomatic pneumonitis in patients of any age (3, 11, 15-24). In contrast to our study, these studies did not report the prevalence of grade ≥2 pneumonitis in elderly patients receiving higher mean doses to the ipsilateral lung. Despite the novelty and relevant findings of our study, one has to be aware of its limitations, particularly the retrospective design bearing the risk of hidden selection biases. However, the main study goals, determination of the prevalence of grade ≥2 pneumonitis and identification of at least one independent risk factor, were achieved. These results will be considered when designing a subsequent prospective trial.
In conclusion, the prevalence of grade ≥2 pneumonitis and the predictive value of the mean dose to the ipsilateral lung were identified. Elderly patients receiving >13.0 Gy, particularly >20.0 Gy, have a high risk of grade ≥2 pneumonitis. These results are important for the proper design of a prospective trial that will be initiated soon.
Footnotes
Authors’ Contributions
All Authors have contributed to the design of the study. D.R. collected the data that were analyzed by a professional statistician. D.R. drafted the article, which was reviewed and approved by all Authors.
Conflicts of Interest
The Authors indicate that there are no conflicts of interest related to this study.
- Received February 14, 2024.
- Revision received March 1, 2024.
- Accepted March 4, 2024.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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