Abstract
Background/Aim: Radiotherapy of lung cancer can lead to pneumonitis. This study aimed to identify risk factors and create a prognostic tool. Patients and Methods: Sixteen factors were evaluated in 169 patients irradiated for lung cancer including age, sex, lung function, primary tumor/nodal stage, histology, tumor location, surgery, systemic treatment, radiation volume, total dose, mean dose to ipsilateral lung, history of another malignancy, pack years, chronic inflammatory disease, and cardiovascular disease. Results: Forty-one patients experienced pneumonitis. Significant associations were found for total doses >56 Gy (p=0.023), mean lung doses >20 Gy (p=0.002) or >13 Gy (p<0.001), and chronic inflammatory disease (p=0.034). Considering mean lung dose and chronic inflammatory disease, scores were 2, 3, 4, or 5 points. Pneumonitis rates were 0% (0/35), 24% (14/58), 32% (21/66), and 60% (6/10) (p=0.001), respectively. Conclusion: Based on significant risk factors, a prognostic tool was developed that can help estimate the risk of pneumonitis and contribute to personalized follow up of patients.
Among all kinds of solid malignancies, lung cancer is one of the most frequently occurring types and responsible for many of the cancer-related deaths (1). Many patients with locally advanced tumors receive radiotherapy, either alone or in combination with systemic therapies (chemotherapy and/or immunotherapy) as definitive or adjuvant treatment (2, 3). A subacute side effect of radiotherapy for lung cancer is pneumonitis, which can be quite severe and is associated with a mortality rate of 2% (2). Therefore, it is very important to identify and treat patients who experience radiation pneumonitis as early as possible. Risk factors and a prognostic tool may help identify these patients. Associations between radiation pneumonitis and parameters such as radiation dose, chronic inflammatory disease, systemic treatment, significant cardiovascular disease, number of pack years have already been reported (4–7). The corresponding studies include our own work, which forms the background of the present study (8). However, in the previous study, we only described the characteristics that were common in patients who developed pneumonitis during or following radiotherapy of lung cancer (8). A direct comparison of the distribution of these characteristics in patients developing pneumonitis and those patients who did not experience this complication was not performed. Therefore, the present study was conducted to compare the potential risk factors for radiation pneumonitis in both groups and aimed to create a prognostic tool based on factors achieving significance.
Patients and Methods
A total of 169 patients with lung cancer who received irradiation to the primary tumor with or without loco-regional lymph nodes at our institution between 2016 and 2019 were included in this retrospective study. The study was approved by the responsible ethics committee (University of Lübeck, reference number 21-087). The endpoint was the development of symptomatic pneumonitis during or after radiation treatment. Sixty-five patients (38%) had concurrent distant metastases at the time of irradiation. Radiation treatment was performed with volumetric modulated arc therapy (VMAT) using conventional fractionation with doses per fraction of 2 Gy.
Sixteen potential risk factors for pneumonitis were analyzed (Table I) including age at start of irradiation (≤66 vs. ≥67 years, median=66 years), sex (female vs. male), lung function represented by the forced expiratory volume in 1 second (≤1.69 vs. 1.69 l, median=1.69 l), primary tumor stage (T1-2 vs. T3-4), nodal stage (N0-1 vs. N2-3), histology [non-small cell lung cancer (NSCLC) vs. small-cell lung cancer (SCLC)], main tumor location (upper lobe vs. lower or middle lobe vs. central or main bronchus), upfront surgery (no vs. yes), systemic treatment before, during and/or following radiotherapy (no vs. yes), treatment volume of irradiation (primary tumor alone vs. primary tumor plus lymph nodes), total radiation dose (≤56 vs. >56 Gy, median=56 Gy), mean radiation dose to ipsilateral lung (≤13 vs. 13.1-20.0 vs. >20 Gy), history of another malignancy (no vs. yes), number of pack years (<40 vs. ≥40), history of chronic inflammatory disease including bronchial asthma, neurodermatitis, rheumatoid arthritis, and psoriasis arthritis (no vs. yes), and history of significant cardiovascular disease (no vs. yes). According to QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic), mean lung doses of 13 Gy and 20 Gy are associated with rates of symptomatic pneumonitis of 10% and 20%, respectively (9).
Distribution of the investigated potential risk factors for radiation pneumonitis.
Median follow up after radiotherapy was 53 weeks (range=3-243 weeks). Statistical analyses regarding associations between potential risk factors and pneumonitis were performed with the Chi-square test or the Fisher’s exact test (in case of less than five patients in one group). Factors significantly associated with the occurrence of pneumonitis were used to develop a prognostic tool to estimate the risk of this subacute toxicity.
Results
Forty-one patients (24%) experienced pneumonitis after a median of 12 weeks following irradiation. Symptoms included dyspnea in 35 patients, cough in 32 patients, and fever in 10 patients. Significant associations with the occurrence of pneumonitis were found for total radiation doses >56 Gy (compared to ≤56 Gy, p=0.023), mean lung doses >20 Gy (compared to ≤20 Gy, p=0.002), mean lung doses >13 Gy (compared to ≤13 Gy, p<0.001), and history of chronic inflammatory disease (compared to no such history, p=0.034). The results regarding all investigated factors are summarized in Table II. Since total radiation dose and mean lung dose were considered confounding variables and the mean lung dose was considered more important, mean lung dose and history of chronic inflammatory disease were used to create the prognostic tool.
Associations between potential risk factors and occurrence of radiation pneumonitis.
The following scoring points were assigned for mean lung doses: ≤13 Gy=1 point, 13.1-20.0 Gy=2 points, >20 Gy=3 points. Patients with a history of chronic inflammatory disease received 2 points, and patients without such history received 1 point. Thus, sum scores for individual patients were 2, 3, 4, or 5 points. The corresponding rates of pneumonitis were 0% (0/35), 24% (14/58), 32% (21/66), and 60% (6/10), respectively (p=0.001, goodness of fit test). When combining patients with 3 and 4 points to one group, the pneumonitis rate was 28% (35/124).
Discussion
Pneumonitis is considered a serious complication of radiotherapy for lung cancer, which can be life threatening or even fatal (2). Thus, it is crucial to identify affected patients as soon as possible in order to allow initiation of treatment before it becomes difficult to control the situation. Therefore, we aimed to develop an easy-to-use prognostic tool allowing for an a priori estimate of the risk for radiation pneumonitis. Initially, 16 potential risk factors were evaluated for associations with the occurrence of pneumonitis.
These factors included characteristics that were found to be common in patients experiencing radiation pneumonitis in our previous study (8). These characteristics included mean radiation dose to the ipsilateral lung, systemic treatment, significant cardiovascular disease, number of pack years, age, chronic inflammatory disease, and history of a previous malignancy. In the present comparative study, the occurrence of radiation pneumonitis was significantly associated with total radiation dose, radiation dose to the ipsilateral lung, and history of chronic inflammatory disease. These results were in accordance with the findings of several previous studies (10–14). A positive correlation between radiation pneumonitis and the (total and mean) radiation doses can be expected, since a higher dose implies increased toxicity and damage of lung tissue with a stronger inflammatory response as a consequence (8, 10). A chronic inflammatory disease likely indicates a patient’s tendency to inflammation-like reactions such as radiation pneumonitis (13, 14). For similar reasons, correlations between radiation pneumonitis and a history of significant cardiovascular diseases or a greater number of pack years might have been expected. In the present study, certain trends were observed regarding these two characteristics, although statistical significance was not achieved. This may be due to the retrospective study design, which might have led to inaccuracies. For example, the number of pack years was calculated based on the patient’s memory, and the history of significant cardiovascular disease on the patient’s memory in addition to information from the patient files. In contrast to the present study, the meta-analysis of Palma et al. showed a significant correlation between radiation pneumonitis and systemic treatment (15). In this meta-analysis, only eight types of systemic therapy were used in a cohort of 836 patients, whereas systemic therapies were considerably more heterogeneous in the present study (35 different regimens, 139 patients). Thus, the lack of the present study to show a significant association between systemic treatment and pneumonitis may be explained by the smaller number of patients and the high number of different regimens when compared to the meta-analysis of Palma et al. (15).
Based on two significant risk factors, namely mean radiation dose to the ipsilateral lung and history of chronic inflammatory disease, an easy-to-use prognostic tool was created. The pneumonitis rates were 0% (2 points), 24% (3 points), 32% (4 points) and 60% (5 points), respectively. Patients with 3 and 4 points can be combined to one group with a pneumonitis rate of 28%. Since the risk of pneumonitis in patients of the 2-points group was 0%, regular follow-up visits (first visit after 6-8 weeks following radiotherapy, second visit after 1 year) appear sufficient. Patients of the other groups will need closer follow up visits. This is particular important for patients of the 5-points group, since more than every second patient will develop radiation pneumonitis. When following these recommendations, the limitations of this study, in particular its retrospective design, need to be considered.
In conclusion, a prognostic tool was developed based on two significant risk factors. This new easy-to-use instrument can help estimate the risk of pneumonitis and contribute to personalized follow up programs of patients irradiated for lung cancer.
Footnotes
Authors’ Contributions
E.G., E.M.W., S.B. and D.R. designed this study. E.G. provided the data that were analyzed by D.R. Interpretation of the data was performed by all Authors. E.G. and D.R. drafted the manuscript, which was reviewed finally approved by all Authors.
Conflicts of Interest
On behalf of all Authors, the corresponding Author states that there are no conflicts of interest related to this study.
Funding
As part of the project NorDigHealth, this study was funded by the European Regional Development Fund through the Interreg Deutschland-Danmark program.
- Received January 31, 2022.
- Revision received February 10, 2022.
- Accepted February 11, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
