Abstract
Background
Although acute exacerbation (AE) after treatment for lung cancer (LC) is a poor prognostic factor in patients with interstitial lung disease associated with lung cancer (ILD‐LC), the risk of AE according to cancer treatment type remains unclear. Therefore, in the present study, we aimed to investigate the association between AE and treatment received for LC in patients with ILD‐LC.
Methods
We conducted a retrospective study of patients with ILD‐LC who had undergone treatment for LC between January 2018 and December 2022. The primary study outcome was the incidence of AE within 12 months of treatment for LC according to treatment type. The association between AE and all‐cause mortality was evaluated as a secondary outcome.
Results
Among a total of 137 patients, 23 (16.8%) developed AE within 12 months of treatment for LC. The incidence of AE according to treatment type was 4.3% for surgery, 16.2% for radiotherapy, 15.6% for chemotherapy, and 54.5% for concurrent chemoradiation therapy (CCRT). Patients who received CCRT were more likely to develop AE, even after adjustment for covariables (hazard ratio [HR], 15.39; 95% confidence interval [CI]: 4.00–59.19; p < 0.001). In addition, AE within 12 months of treatment for LC was associated with an increased risk of all‐cause mortality (HR, 2.82; 95% CI: 1.13–7.04; p = 0.026).
Conclusion
Among treatment options for patients with ILD‐LC, CCRT was associated with an increased risk for AE. In addition, patients with AE had a higher mortality rate than patients without AE.
Keywords: complications, interstitial lung disease, lung cancer, prognosis, risk factors
This single‐center, retrospective study investigated the association between acute exacerbation and treatment received for lung cancer in patients with interstitial lung disease and lung cancer. Among a total of 137 patients, 23 (16.8%) developed acute exacerbation within 12 months of treatment for lung cancer. After adjustment for covariables, only concurrent chemoradiation therapy was associated with an increased risk for acute exacerbation.
INTRODUCTION
Patients with interstitial lung disease (ILD), particularly idiopathic pulmonary fibrosis (IPF), are at increased risk of developing lung cancer (LC). 1 , 2 Patients with ILD associated with LC (ILD‐LC) have been found to have a worse prognosis than those with LC alone. 3 , 4 The treatment of ILD‐LC is challenging and requires multidisciplinary evaluation as standard treatments for LC are not always appropriate due to toxicity or insufficient respiratory reserve. 5 All treatments for LC can influence the risk of acute exacerbation (AE). 6 , 7 In patients treated with surgery, ventilator‐associated lung injury induced by decreased lung compliance due to ILD may contribute to postoperative AE, particularly with single‐lung ventilation of the nonoperative lung. 8 Further, AE is frequent in patients with pre‐existing ILD who receive chemotherapy including immunotherapy. 9 , 10 In patients treated with radiotherapy, ILD is reportedly associated with an increased risk of pulmonary toxicity. 11 As the development of AE after treatment can be fatal, the selection of optimal treatment strategies for patients with ILD‐LC must ensure a balance between efficacy and safety considerations. 12 However, previous studies have often evaluated the incidence of AE after a specific therapy, such as surgery or chemotherapy. 11 , 13 In addition, the majority of these studies included a small proportion of patients with ILD. 14 , 15 The risk of AE in patients with ILD‐LC according to cancer treatment type remains unclear. We therefore investigated the incidence of AE according to the type of treatment for LC and further evaluated the effect of AE on prognosis in patients with ILD‐LC.
METHODS
Study design
This was a retrospective study comprising patients with ILD‐LC who had undergone treatment for LC at Asan Medical Center between January 2018 and December 2022. The present study included patients who were diagnosed with LC during the study period and had ILD at or before the diagnosis of LC. Patients that did not receive treatment for LC during the study period were excluded. The primary study outcome was the incidence of AE within 12 months according to the type of treatment for LC. AE was defined as acute worsening of dyspnea of less than 1 month duration with new bilateral ground‐glass opacities and/or consolidation not fully explained by cardiac failure or fluid overload. 16 The study authors reviewed all cases of AE. The association between AE and all‐cause mortality was evaluated as a secondary outcome. The present study was approved by Asan Medical Center Institutional Review Board (no. 2022‐0777). The present study was conducted in full accordance with the Guidelines for Good Clinical Practice and the 1964 Declaration of Helsinki.
Data collection
ILD profiles and the following baseline characteristics were recorded at the time of LC diagnosis through electronic medical records: age, sex, body mass index (BMI), smoking history, pulmonary function tests, and laboratory data. ILD profiles included the type of ILD, chest CT findings, histological analyses for usual interstitial pneumonia (UIP), and treatments for ILD at the time of LC diagnosis. The type of ILD was divided into IPF, unclassifiable ILD, and others. The diagnosis of IPF was made according to the ATS/ERS/JRS/ALAT Clinical Practice Guideline. 17 Other types of ILD included hypersensitivity pneumonitis, nonspecific interstitial pneumonia, smoking‐related ILD, and connective tissue disease‐related ILD. Pirfenidone and nintedanib were classified as antifibrotics for the treatment of ILD. Factors related to LC, such as LC and initial treatment, were also recorded. LC was diagnosed according to histological evaluation and confirmed by two pathologists at our institutions. Initial cancer treatments were divided into surgery, radiotherapy, chemotherapy, and concurrent chemoradiation therapy (CCRT). Patients that received adjuvant chemotherapy after lobectomy for LC were recorded as having undergone both surgery and chemotherapy as treatments for LC.
Statistical analysis
Categorical variables are presented as numbers with percentages. Continuous variables are presented as the median with the interquartile range (IQR). Chi‐squared or Fisher's exact tests were used to compare categorical variables between the two groups. Student's t‐test or the Mann–Whitney U test were used to compare continuous variables with a normal or non‐normal distribution, respectively, between groups. The Kaplan–Meier method was used to perform a time‐to‐event analysis for AE and mortality. The Kaplan–Meier curve of AE within 12 months was right‐censored at 12 months. Univariable and multivariable Cox proportional hazards regression models were used to identify factors associated with acute exacerbation within 12 months and all‐cause mortality. A final model was constructed using a stepwise method with backward selection. We selected covariables with p‐values less than 0.10 in the univariable analysis after correction for collinearity. Results are presented as the hazard ratio (HR) with the 95% confidence interval (CI). The proportional hazard assumption was assessed by inspection of Schoenfeld residuals. Two‐sided p‐values less than 0.05 were considered statistically significant. All analyses were performed using SPSS version 26.0 (IBM Corporation) software.
RESULTS
During the study period, 168 patients were assessed for inclusion (Figure 1). Six patients that did not have biopsy‐proven LC and 25 patients who did not receive treatment for LC were excluded. Accordingly, a total of 137 patients were included in the final study analysis.
FIGURE 1.
Flow chart for patient inclusion. ILD, interstitial lung disease; LC, lung cancer.
Baseline patient characteristics
Baseline patient characteristics at the time of LC diagnosis are summarized in Table 1. The median age and BMI were 70.0 (65.0–74.0) years and 24.7 (22.6–26.5) kg/m2, respectively. Patients included in the study were predominantly male (93.4%) and ever‐smokers (92.0%). Baseline pulmonary function tests demonstrated a median predicted forced vital capacity (FVC), predicted forced expiratory volume in 1 s (FEV1), and FEV1/FVC ratio of 78.0% (68.0%–89.0%), 81.0% (71.0%–91.0%), and 73.0 (69.0–78.0), respectively. The median diffusing capacity for carbon monoxide (DLCO) was 58.5% (48.0%–67.8%). ILD types among included patients consisted of IPF (n = 77, 56.2%), unclassifiable ILD (n = 35, 25.5%), and others (n = 25, 18.2%). A total of 45 patients (32.8%) had radiological UIP on chest CT and 25 patients (18.2%) had histologically‐confirmed UIP. Of the 97 patients who were tested for Krebs von den Lungen‐6 (KL‐6), 24 (24.7%) had a serum KL‐6 level ≥ 1000 U/mL. Approximately 50% of patients received antifibrotics as treatment of ILD.
TABLE 1.
Baseline characteristics of patients with interstitial lung disease and lung cancer at lung cancer diagnosis.
| Characteristic | Total (n = 137) |
|---|---|
| Age, years | 70.0 (65.0–74.0) |
| Gender | |
| Male | 128 (93.4) |
| BMI, kg/m2 | 24.7 (22.6–26.5) |
| Ever‐smoker | 126 (92.0) |
| Pulmonary function test | |
| FVC (predicted), % (n = 136) | 78.0 (68.0–89.0) |
| FEV1 (predicted), % (n = 136) | 81.0 (71.0–91.0) |
| FEV1/FVC (n = 136) | 73.0 (69.0–78.0) |
| DLCO (predicted), % (n = 124) | 58.5 (48.0–67.8) |
| Type of ILD | |
| Idiopathic pulmonary fibrosis | 77 (56.2) |
| Unclassifiable | 35 (25.5) |
| Others a | 25 (18.2) |
| Chest CT findings | |
| UIP | 45 (32.8) |
| Possible UIP | 45 (32.8) |
| Inconsistent with UIP | 47 (34.3) |
| Histological pattern of definite UIP | 25 (18.2) |
| Laboratory data | |
| KL‐6 ≥ 1000 U/mL (n = 97) | 24 (24.7) |
| Treatment of ILD | |
| Antifibrotic agent | 69 (50.4) |
| Corticosteroid | 12 (8.8) |
| Immunosuppressant | 4 (2.9) |
Note: Data are reported as median (interquartile range) for continuous variables and number (percentage) for categorical variables.
Abbreviations: BMI, body mass index; CT, computed tomography; DLCO, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; ILD, interstitial lung disease; KL‐6, Krebs von den Lungen‐6; TLC, total lung capacity; UIP, usual interstitial pneumonia.
Other types of ILD include hypersensitivity pneumonitis, nonspecific interstitial pneumonia, smoking‐related interstitial lung disease, organizing pneumonia, and connective tissue disease‐related interstitial lung disease.
Lung cancer profiles
A total of 117 (85.4%) patients had non‐small cell lung cancer (NSCLC) and 20 patients (14.6%) had small cell lung cancer (SCLC, Table 2). The most common histological type of NSCLC was adenocarcinoma (53.8%), followed by squamous cell carcinoma (42.7%) and others (3.4%). Among patients with NSCLC, 35.9% patients had stage I disease. Among patients with SCLC, 12 (60.0%) patients had limited stage disease. A total of 19 patients received more than two initial treatments for LC. In the present study, 46.7% of patients received chemotherapy. The proportions of patients treated with surgery, radiotherapy, and CCRT were 34.3%, 27.0%, and 8.0%, respectively.
TABLE 2.
Lung cancer characteristics in patients with ILD‐LC.
| Characteristic | Total (n = 137) |
|---|---|
| Type of lung cancer, % | |
| NSCLC | 117 (85.4) |
| SCLC | 20 (14.6) |
| Type of NSCLC (n = 117), % | |
| Adenocarcinoma | 63 (53.8) |
| Squamous cell carcinoma | 50 (42.7) |
| Others | 4 (3.4) |
| Stage of NSCLC (n = 117), % | |
| I | 42 (35.9) |
| II | 13 (11.1) |
| III | 32 (27.4) |
| IV | 30 (25.6) |
| Stage of SCLC (n = 20), % | |
| Limited | 12 (60.0) |
| Extensive | 8 (40.0) |
| Initial treatment for lung cancer a , % | |
| Surgery | 47 (34.3) |
| Radiotherapy | 37 (27.0) |
| Chemotherapy | 64 (46.7) |
| Concurrent chemoradiation therapy | 11 (8.0) |
Abbreviations: ILD, interstitial lung disease; LC, lung cancer; NSCLC, non‐small cell lung cancer; SCLC, small cell lung cancer.
Nineteen patients received more than two treatments: 11 patients were treated with chemotherapy after surgery, three patients received radiotherapy and chemotherapy followed by surgery, four patients received both radiotherapy and chemotherapy, and one patient received concurrent chemoradiation therapy after surgery.
Incidence of AE
Among included patients, 23 (16.8%) developed AE within 12 months of treatment for LC. The median time to the occurrence of AE following treatment for LC was 6.9 (3.9–12.0) months. A comparison of baseline characteristics and LC profile according to the occurrence of AE within 12 months is presented in Table S1. The incidence of AE within 12 months according to cancer treatment type was 4.3% for surgery, 16.2% for radiotherapy, 15.6% for chemotherapy, and 54.5% for CCRT, respectively (Figure 2). The median time to the occurrence of AE after surgery, radiotherapy, chemotherapy, and CCRT was 12.0 (6.4–12.0), 8.6 (3.9–12.0), 7.1 (4.4–11.9), and 3.7 (2.3–6.2) months, respectively. Univariate and multivariate analyzes were conducted to identify risk factors for AE within 12 months of treatment for LC (Table 3). Cox proportional hazard models for AE within 12 months of treatment for LC that included FVC, DLCO, KL‐6 ≥ 1000 U/mL, SCLC, surgery, and CCRT as covariables demonstrated that serum KL‐6 ≥ 1000 U/mL (HR, 2.86; 95% CI: 1.01–8.08; p = 0.048) and CCRT (HR, 15.39; 95% CI: 4.00–59.19; p < 0.001) were associated with an increased risk of AE within 12 months of treatment for LC.
FIGURE 2.
Cumulative incidence of acute exacerbation within 12 months of treatment for LC according to treatment type. (a) Surgery, (b) chemotherapy, (c) radiotherapy, and (d) concurrent chemoradiation therapy. OP, operation; CTx, chemotherapy; RT, radiotherapy; CCRT, concurrent chemoradiation therapy.
TABLE 3.
Cox proportional hazards model of factors associated with acute exacerbation within 12 months of treatment for LC.
| Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|
| Variable | HR | 95% CI | p‐value | HR | 95% CI | p‐value |
| Age | 0.96 | 0.90–1.02 | 0.159 | |||
| Female | 1.09 | 0.26–4.66 | 0.905 | |||
| BMI | 0.94 | 0.81–1.08 | 0.369 | |||
| Never‐smoker | 1.46 | 0.43–4.92 | 0.540 | |||
| Pulmonary function test | ||||||
| FVC (predicted), % | 0.97 | 0.95–0.99 | 0.021 | |||
| FEV1 (predicted), % | 0.98 | 0.95–1.00 | 0.060 | |||
| DLCO (predicted), % | 0.98 | 0.96–1.00 | 0.064 | 0.97 | 0.94–1.00 | 0.066 |
| IPF (vs. non‐IPF ILD) | 0.89 | 0.38–2.06 | 0.783 | |||
| KL‐6 ≥ 1000 U/mL | 2.55 | 1.02–6.37 | 0.045 | 2.86 | 1.01–8.08 | 0.048 |
| ILD treatment | ||||||
| Antifibrotics | 1.44 | 0.63–3.34 | 0.390 | |||
| Corticosteroid | 0.78 | 0.18–3.35 | 0.742 | |||
| Immunosuppressants | 2.60 | 0.61–11.10 | 0.197 | |||
| SCLC (vs. NSCLC) | 2.47 | 1.01–6.01 | 0.047 | |||
| Initial treatment for lung cancer | ||||||
| Surgery | 0.14 | 0.03–0.60 | 0.008 | |||
| Chemotherapy | 0.82 | 0.36–1.88 | 0.641 | |||
| Radiotherapy | 0.94 | 0.37–2.39 | 0.899 | |||
| CCRT | 5.87 | 2.28–15.14 | < 0.001 | 15.39 | 4.0–59.19 | < 0.001 |
Abbreviations: BMI, body mass index; CCRT, concurrent chemoradiation therapy; CI, confidence interval; DLCO, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; HR, hazard ratio; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; KL‐6, Krebs von den Lungen‐6; NSCLC, non‐small cell lung cancer; LC, lung cancer; SCLC, small cell lung cancer; TLC, total lung capacity.
Effect of AE on prognosis
Regarding survival outcomes, we performed a survival analysis of all patients with ILD‐LC according to the presence of AE within 12 months of treatment for LC (Figure 3). Overall survival was significantly higher in patients without AE (median 27.0 months; 95% CI: 20.6–33) than in those with AE (median 10.5 months; 95% CI: 0.3–20.7, p = 0.001). In addition, multivariate analysis after adjustment for FVC, DLCO, antifibrotics, surgery, and chemotherapy demonstrated that AE within 12 months of treatment for LC (HR, 2.82; 95% CI: 1.13–7.04; p = 0.026) was independently associated with all‐cause mortality (Table 4).
FIGURE 3.
Comparison of survival curves between patients with acute exacerbation and without acute exacerbation within 12 months of lung cancer (LC) treatment. AE, acute exacerbation.
TABLE 4.
Cox proportional hazards model of factors associated with all‐cause mortality.
| Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|
| Variable | HR | 95% CI | p‐value | HR | 95% CI | p‐value |
| Age | 1.000 | 0.961–1.042 | 0.987 | |||
| Female | 0.041 | 0.001–2.780 | 0.138 | |||
| BMI | 0.921 | 0.832–1.019 | 0.112 | |||
| Never‐smoker | 0.466 | 0.143–1.521 | 0.206 | |||
| Pulmonary function test | ||||||
| FVC (predicted), % | 0.983 | 0.967–1.000 | 0.050 | |||
| FEV1 (predicted), % | 0.980 | 0.961–1.001 | 0.056 | |||
| DLCO (predicted), % | 0.987 | 0.972–1.002 | 0.095 | |||
| IPF (vs. non‐IPF ILD) | 0.845 | 0.469–1.523 | 0.575 | |||
| KL‐6 ≥ 1000 U/mL | 2.338 | 1.119–4.883 | 0.024 | |||
| ILD treatment | ||||||
| Antifibrotics | 0.591 | 0.326–1.070 | 0.082 | |||
| Corticosteroid | 1.088 | 0.458–2.584 | 0.848 | |||
| Immunosuppressants | 0.045 | 0.000–12.519 | 0.280 | |||
| SCLC | 1.580 | 0.758–3.294 | 0.222 | |||
| Initial treatment of lung cancer | ||||||
| Surgery | 0.181 | 0.076–0.431 | <0.001 | 0.358 | 0.131–0.981 | 0.046 |
| Chemotherapy | 3.332 | 1.767–6.284 | <0.001 | 2.487 | 1.092–5.665 | 0.030 |
| Radiotherapy | 0.932 | 0.488–1.779 | 0.831 | |||
| CCRT | 0.201 | 0.028–1.465 | 0.113 | |||
| Acute exacerbation at 12 m | 2.290 | 1.199–4.372 | 0.012 | 2.820 | 1.130–7.036 | 0.026 |
Abbreviations: BMI, body mass index; CCRT, concurrent chemoradiation therapy; CI, confidence interval; DLCO, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; HR, hazard ratio; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; KL‐6, Krebs von den Lungen‐6; SCLC, small cell lung cancer; TLC, total lung capacity.
DISCUSSION
This single center, retrospective study analyzed the incidence of AE within 12 months of treatment for LC among patients with ILD according to cancer therapy type. In the present study, AE occurred more frequently in patients who received CCRT, followed by radiotherapy, chemotherapy, and operation, respectively. After adjusting for the effect of covariates, only CCRT among cancer therapeutic options was significantly associated with a higher rate of AE within 12 months of treatment for LC. Furthermore, AE within 12 months of treatment for LC was significantly associated with increased mortality among patients with ILD‐LC. Accordingly, the risks and benefits of individual therapeutic modalities for LC must be considered before determining treatment plans for LC in patients with ILD.
Previous studies have reported the risks associated with individual cancer treatment options among patients with ILD. In patients treated with surgery for LC, the reported incidence of postoperative morbidity, including AE, ranges from 9.3% to 26%. 18 , 19 , 20 As the risk of AE differs according to surgical technique, intraoperative duration ≥4 h and surgical extent greater than lobectomy affected the incidence of AE. 21 Further, the reported incidence of AE following cytotoxic chemotherapy (5%–20%) varies widely in previous studies. 22 For example, in a retrospective study of 122 LC patients who received first‐line chemotherapy, patients with SCLC (63%) had a higher rate of AE than those with NSCLC (31%). 23 Most previous studies of radiotherapy in patients with ILD‐LC have focused on the risk of radiation pneumonitis. Patients with ILD‐LC are at increased risk of radiation pneumonitis, with reported rates ranging from 19% to 32%. 11 , 24 , 25 In the present study, the median incidence of AE (16.8%) was similar to that of previous studies. 12 However, patients who underwent surgery in our study (4.3%) had a lower incidence of AE compared to other studies. 21 The postoperative risk of AE is evaluated in all patients prior to surgery at our institution. Thus, patients at high risk of AE may be excluded from surgery. In addition, approximately 50% patients received antifibrotics following a diagnosis of LC in the present study. As previous studies have reported that perioperative antifibrotic treatment reduces the occurrence of AE following cancer surgery in patients with IPF, the low incidence of postoperative AE in the present study may be attributable to the use of antifibrotics. 26
Unlike other cancer treatments, studies evaluating the incidence of AE after CCRT are scarce. In a retrospective study of 37 ILD‐LC patients treated with CCRT, 17 (46%) developed AE within the first year. 27 Currently, CCRT is not recommended for patients with ILD‐LC due to the high risk of AE based on limited data. 28 , 29 As with previous studies, the results of the present study demonstrate that CCRT is associated with a higher rate of AE within the first year. In multivariate analysis adjusting for covariates, CCRT was significantly associated with an increased risk of AE. However, the pathophysiology underlying this increased rate of AE remains poorly understood. 27 Mechanistically, radiation‐induced lung injury is mediated by DNA damage and molecular dysregulation that triggers loss of barrier function and promotes inflammation. 30 , 31 In addition, most chemotherapeutic drugs target DNA replication and repair to specifically inhibit the proliferation or growth of cancer cells. 32 We hypothesized that the synergistic effect of chemoradiation on the induction of DNA damage may contribute to impaired repair and accelerated lung injury leading to the occurrence of AE. Further studies are required to elucidate the mechanisms underlying the pathogenesis of AE following chemoradiation therapy which may lead to improvements in the prognosis of patients with ILD‐LC.
A significant association between serum KL‐6 ≥ 1000 U/mL and AE within 12 months of treatment for LC was observed in the present study. KL‐6 is a high‐molecular‐weight mucin‐like glycoprotein found on bronchiolar epithelial cells and type II pneumocytes in alveoli. 33 KL‐6 is highly expressed on proliferating and regenerating type II pneumocytes. A serum KL‐6 level greater than 1000 U/mL in patients with ILD is known to be associated with a worse prognosis. 34 In previous studies, elevated serum KL‐6 levels have been reported in patients with ILD‐LC. 35 Furthermore, KL‐6 levels are reportedly higher in patients that develop AE compared to those with stable ILD. 36 The findings of these previous studies indicate KL‐6 may have utility as a prognostic marker of AE in patients with ILD‐LC.
The development of AE has been previously reported to have a significant impact on overall survival in patients with ILD. 37 AE of IPF is generally associated with a mortality of up to 50%. 38 In addition, the incidence of post‐exacerbation mortality is reportedly up to 30% greater than in other fibrosing ILDs. 39 , 40 Similarly, patients with ILD‐LC who experienced AE had worse outcomes after adjusting for confounders. Although antifibrotics may delay the development of AE, there is currently no approved treatment for preventing AE after LC treatment in patients with ILD‐LC. 26 , 41 Accordingly, a personalized approach to patients with ILD‐LC should be used when considering the risk of AE.
The results of the present study should be interpreted considering its limitations. First, it was a retrospective study performed at a single center. The retrospective nature of the present study may have introduced selection bias into the study analysis. Second, an evaluation of postoperative complication before surgery in our institution may have resulted in the selection bias and affected the incidence of AE. Third, as the patients included in this study were only representative of a single nation, it is difficult to extrapolate our findings to other ethnic populations. In addition, we could not conduct further evaluation of the risk analysis of AE according to the type of chemotherapeutic drugs or the cause of death or the association between the type of ILD and AE because of the relatively small sample size. Finally, the diagnosis or classification of ILD in our patients may be inaccurate because the pathologic examination of ILD was not performed in all patients. Despite these limitations, the results of the present study demonstrate the incidence of AE in patients with ILD‐C according to cancer treatment type. Further large‐scale studies are required to confirm these results.
In conclusion, the results of the present study demonstrate that CCRT is associated with an increased risk of AE in patients with ILD‐LC. Furthermore, patients who had AE within 12 months of treatment for LC had a worse prognosis compared to patients who did not. Accordingly, a personalized approach to patients with ILD‐LC should be used when considering the risks and benefits of treatment options for LC.
AUTHOR CONTRIBUTIONS
Dong‐gon Hyun: Conceptualization (lead); data curation (lead); formal analysis (lead); investigation (lead); methodology (lead); writing–review and editing (lead). Soo Jin Han: Data curation (equal); formal analysis (equal); writing–review and editing (equal). Wonjun Ji: Data curation (equal); formal analysis (equal); writing–review and editing (equal). Chang‐Min Choi: Data curation (equal); formal analysis (equal); writing–review and editing (equal). Jae Cheol Lee: Conceptualization (equal); data curation (equal); formal analysis (equal); writing–review and editing (equal). Ho Cheol Kim: Conceptualization (lead); data curation(equal); formal analysis (equal); funding acquisition (lead); investigation (lead); writing–review and editing (lead).
CONFLICT OF INTEREST STATEMENT
The authors declare that they have no competing interests.
CONSENT TO PARTICIPATE
The requirement for informed consent was waived due to the retrospective nature of this study.
Supporting information
Data S1. Supporting Information.
ACKNOWLEDGMENTS
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education (2021R1A4A5032806). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Hyun D, Han SJ, Ji W, Choi C‐M, Lee JC, Kim HC. Clinical characteristics and prognostic impact of acute exacerbations in patients with interstitial lung disease and lung cancer: A single‐center, retrospective cohort study. Thorac Cancer. 2023;14(33):3323–3330. 10.1111/1759-7714.15124
DATA AVAILABILITY STATEMENT
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
REFERENCES
- 1. Hubbard R, Venn A, Lewis S, Britton J. Lung cancer and cryptogenic fibrosing alveolitis. A population‐based cohort study. Am J Respir Crit Care Med. 2000;161:5–8. [DOI] [PubMed] [Google Scholar]
- 2. Kreuter M, Ehlers‐Tenenbaum S, Schaaf M, Oltmanns U, Palmowski K, Hoffmann H, et al. Treatment and outcome of lung cancer in idiopathic interstitial pneumonias. Sarcoidosis Vasc Diffuse Lung Dis. 2015;31:266–274. [PubMed] [Google Scholar]
- 3. Alomaish H, Ung Y, Wang S, Tyrrell PN, Zahra SA, Oikonomou A. Survival analysis in lung cancer patients with interstitial lung disease. PLoS One. 2021;16:e0255375. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Lee T, Park JY, Lee HY, Cho YJ, Yoon HI, Lee JH, et al. Lung cancer in patients with idiopathic pulmonary fibrosis: clinical characteristics and impact on survival. Respir Med. 2014;108:1549–1555. [DOI] [PubMed] [Google Scholar]
- 5. Fisher DA, Murphy MC, Montesi SB, Hariri LP, Hallowell RW, Keane FK, et al. Diagnosis and treatment of lung cancer in the setting of interstitial lung disease. Radiol Clin North Am. 2022;60:993–1002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Sato T, Teramukai S, Kondo H, Watanabe A, Ebina M, Kishi K, et al. Impact and predictors of acute exacerbation of interstitial lung diseases after pulmonary resection for lung cancer. J Thorac Cardiovasc Surg. 2014;147:1604. [DOI] [PubMed] [Google Scholar]
- 7. Wang Y, Miao L, Hu Y, Zhou Y. The efficacy and safety of first‐line chemotherapy in patients with non‐small cell lung cancer and interstitial lung disease: a systematic review and meta‐analysis. Front Oncol. 2020;10:1636. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Patel NM, Kulkarni T, Dilling D, Scholand MB. Preoperative evaluation of patients with interstitial lung disease. Chest. 2019;156:826–833. [DOI] [PubMed] [Google Scholar]
- 9. Zhang M, Fan Y, Nie L, Wang G, Sun K, Cheng Y. Clinical outcomes of immune checkpoint inhibitor therapy in patients with advanced non‐small cell lung cancer and preexisting interstitial lung diseases: a systematic review and meta‐analysis. Chest. 2022;161:1675–1686. [DOI] [PubMed] [Google Scholar]
- 10. Long K, Suresh K. Pulmonary toxicity of systemic lung cancer therapy. Respirology. 2020;25(Suppl 2):72–79. [DOI] [PubMed] [Google Scholar]
- 11. Glick D, Lyen S, Kandel S, Shapera S, Le LW, Lindsay P, et al. Impact of pretreatment interstitial lung disease on radiation pneumonitis and survival in patients treated with lung stereotactic body radiation therapy (SBRT). Clin Lung Cancer. 2018;19:e219–e226. [DOI] [PubMed] [Google Scholar]
- 12. Frank AJ, Dagogo‐Jack I, Dobre IA, Tait S, Schumacher L, Fintelmann FJ, et al. Management of Lung Cancer in the patient with interstitial lung disease. Oncologist. 2023;28:12–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Tasaka Y, Honda T, Nishiyama N, Tsutsui T, Saito H, Watabe H, et al. Non‐inferior clinical outcomes of immune checkpoint inhibitors in non‐small cell lung cancer patients with interstitial lung disease. Lung Cancer. 2021;155:120–126. [DOI] [PubMed] [Google Scholar]
- 14. Tsurugai Y, Takeda A, Sanuki N, Enomoto T, Kaneko T, Hara Y, et al. Stereotactic body radiotherapy for lung cancer patients with idiopathic interstitial pneumonias. Radiother Oncol. 2017;125:310–316. [DOI] [PubMed] [Google Scholar]
- 15. Shibaki R, Murakami S, Matsumoto Y, Yoshida T, Goto Y, Kanda S, et al. Association of immune‐related pneumonitis with the presence of preexisting interstitial lung disease in patients with non‐small lung cancer receiving anti‐programmed cell death 1 antibody. Cancer Immunol Immunother. 2020;69:15–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Collard HR, Ryerson CJ, Corte TJ, Jenkins G, Kondoh Y, Lederer DJ, et al. Acute exacerbation of idiopathic pulmonary fibrosis. An international working group report. Am J Respir Crit Care Med. 2016;194:265–275. [DOI] [PubMed] [Google Scholar]
- 17. Raghu G, Remy‐Jardin M, Richeldi L, Thomson CC, Inoue Y, Johkoh T, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2022;205:e18–e47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Kawasaki H, Nagai K, Yoshida J, Nishimura M, Nishiwaki Y. Postoperative morbidity, mortality, and survival in lung cancer associated with idiopathic pulmonary fibrosis. J Surg Oncol. 2002;81:33–37. [DOI] [PubMed] [Google Scholar]
- 19. Okamoto T, Gotoh M, Masuya D, Nakashima T, Liu D, Kameyama K, et al. Clinical analysis of interstitial pneumonia after surgery for lung cancer. Jpn J Thorac Cardiovasc Surg. 2004;52:323–329. [DOI] [PubMed] [Google Scholar]
- 20. Iwata T, Yoshida S, Fujiwara T, Wada H, Nakajima T, Suzuki H, et al. Effect of perioperative Pirfenidone treatment in lung cancer patients with idiopathic pulmonary fibrosis. Ann Thorac Surg. 2016;102:1905–1910. [DOI] [PubMed] [Google Scholar]
- 21. Naccache JM, Gibiot Q, Monnet I, Antoine M, Wislez M, Chouaid C, et al. Lung cancer and interstitial lung disease: a literature review. J Thorac Dis. 2018;10:3829–3844. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Ikeda S, Kato T, Kenmotsu H, Sekine A, Baba T, Ogura T. Current treatment strategies for non‐small‐cell lung cancer with comorbid interstitial pneumonia. Cancers (Basel). 2021;13:13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Kenmotsu H, Naito T, Kimura M, Ono A, Shukuya T, Nakamura Y, et al. The risk of cytotoxic chemotherapy‐related exacerbation of interstitial lung disease with lung cancer. J Thorac Oncol. 2011;6:1242–1246. [DOI] [PubMed] [Google Scholar]
- 24. Bahig H, Filion E, Vu T, Chalaoui J, Lambert L, Roberge D, et al. Severe radiation pneumonitis after lung stereotactic ablative radiation therapy in patients with interstitial lung disease. Pract Radiat Oncol. 2016;6:367–374. [DOI] [PubMed] [Google Scholar]
- 25. Yamaguchi S, Ohguri T, Ide S, Aoki T, Imada H, Yahara K, et al. Stereotactic body radiotherapy for lung tumors in patients with subclinical interstitial lung disease: the potential risk of extensive radiation pneumonitis. Lung Cancer. 2013;82:260–265. [DOI] [PubMed] [Google Scholar]
- 26. Petnak T, Lertjitbanjong P, Thongprayoon C, Moua T. Impact of Antifibrotic therapy on mortality and acute exacerbation in idiopathic pulmonary fibrosis: a systematic review and meta‐analysis. Chest. 2021;160:1751–1763. [DOI] [PubMed] [Google Scholar]
- 27. Kobayashi H, Naito T, Omae K, Omori S, Nakashima K, Wakuda K, et al. Impact of interstitial lung disease classification on the development of acute exacerbation of interstitial lung disease and prognosis in patients with stage III non‐small‐cell lung cancer and interstitial lung disease treated with Chemoradiotherapy. J Cancer. 2018;9:2054–2060. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Kewalramani N, Machahua C, Poletti V, Cadranel J, Wells AU, Funke‐Chambour M. Lung cancer in patients with fibrosing interstitial lung diseases: an overview of current knowledge and challenges. ERJ Open Res. 2022;8:02022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Ogura T, Takigawa N, Tomii K, Kishi K, Inoue Y, Ichihara E, et al. Summary of the Japanese respiratory society statement for the treatment of lung cancer with comorbid interstitial pneumonia. Respir Investig. 2019;57:512–533. [DOI] [PubMed] [Google Scholar]
- 30. Rubin P, Johnston CJ, Williams JP, McDonald S, Finkelstein JN. A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys. 1995;33:99–109. [DOI] [PubMed] [Google Scholar]
- 31. Hallahan D, Kuchibhotla J, Wyble C. Cell adhesion molecules mediate radiation‐induced leukocyte adhesion to the vascular endothelium. Cancer Res. 1996;56:5150–5155. [PubMed] [Google Scholar]
- 32. Li L, Mok H, Jhaveri P, Bonnen MD, Sikora AG, Eissa NT, et al. Anticancer therapy and lung injury: molecular mechanisms. Expert Rev Anticancer Ther. 2018;18:1041–1057. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Ohshimo S, Yokoyama A, Hattori N, Ishikawa N, Hirasawa Y, Kohno N. KL‐6, a human MUC1 mucin, promotes proliferation and survival of lung fibroblasts. Biochem Biophys Res Commun. 2005;338:1845–1852. [DOI] [PubMed] [Google Scholar]
- 34. Satoh H, Kurishima K, Ishikawa H, Ohtsuka M. Increased levels of KL‐6 and subsequent mortality in patients with interstitial lung diseases. J Intern Med. 2006;260:429–434. [DOI] [PubMed] [Google Scholar]
- 35. Miyazaki K, Kurishima K, Kagohashi K, Kawaguchi M, Ishikawa H, Satoh H, et al. Serum KL‐6 levels in lung cancer patients with or without interstitial lung disease. J Clin Lab Anal. 2010;24:295–299. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Zhang T, Shen P, Duan C, Gao L. KL‐6 as an immunological biomarker predicts the severity, progression, acute exacerbation, and poor outcomes of interstitial lung disease: a systematic review and meta‐analysis. Front Immunol. 2021;12:745233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Kolb M, Bondue B, Pesci A, Miyazaki Y, Song JW, Bhatt NY, et al. Acute exacerbations of progressive‐fibrosing interstitial lung diseases. Eur Respir Rev. 2018;27:180071. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Kondoh Y, Cottin V, Brown KK. Recent lessons learned in the management of acute exacerbation of idiopathic pulmonary fibrosis. Eur Respir Rev. 2017;26:170050. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Park IN, Kim DS, Shim TS, Lim CM, Lee SD, Koh Y, et al. Acute exacerbation of interstitial pneumonia other than idiopathic pulmonary fibrosis. Chest. 2007;132:214–220. [DOI] [PubMed] [Google Scholar]
- 40. Miyashita K, Kono M. Prognosis after acute exacerbation in patients with interstitial lung disease other than idiopathic pulmonary fibrosis. Clin Respir J. 2021;15:336–344. [DOI] [PubMed] [Google Scholar]
- 41. Richeldi L, Cottin V, du Bois RM, Selman M, Kimura T, Bailes Z, et al. Nintedanib in patients with idiopathic pulmonary fibrosis: combined evidence from the TOMORROW and INPULSIS(®) trials. Respir Med. 2016;113:74–79. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1. Supporting Information.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.