Abstract
Background/Aim: In lung cancer (LC) patients, pre-existing interstitial lung disease (ILD) is a risk of chemotherapy-associated acute exacerbation of ILD (AE-ILD). AE-ILD shows a diverse clinical course varying from fatal respiratory failure to asymptomatic event, and the prognostic impact is still unclear. Materials and Methods: We retrospectively evaluated the association between the prognosis and AE-ILD in 86 LC patients with pre-existing ILD who were treated with cytotoxic chemotherapy, especially focusing on histological types of LC. Results: Thirty (34.9%) patients had AE-ILD, that was significantly associated with a poor prognosis in LC patients with ILD. When analyzed by histological types, a significant association of AE-ILD with shorter survival was observed only in the small cell LC (SCLC) group, but not in the non-small cell LC group. Conclusion: The development of AE-ILD by cytotoxic chemotherapy is associated with poor prognosis in LC patients with ILD, especially in patients with SCLC.
Lung cancer (LC) is the most common cause of cancer-related death worldwide. Some studies have shown that smoking, chronic obstructive pulmonary disease, and interstitial lung disease (ILD) are the risk factors of LC (1-4). Especially in patients with ILD, the incidence of LC has been reported to be 4.4-16.7% (4). In general, advanced LC patients with ILD are treated with cytotoxic chemotherapy based on several phase II trials, elucidating the efficacy and safety of cytotoxic chemotherapy in this population (5-7). However, pre-existing ILD is related to poorer prognosis in patients with LC (8). This is possibly because LC in patients with ILD is associated with higher resistance against systemic chemotherapy and a higher incidence rate of drug-induced interstitial lung disease (D-ILD) (8-11).
Several clinical studies have shown that pre-existing ILD is a risk factor for D-ILD (9, 12, 13). D-ILD in LC patients with ILD, which is generally recognized as a chemotherapy-associated acute exacerbation of ILD (AE-ILD), is developed in as high as 13.3-30.6% of the patients (9-11). It should be noted that chemotherapy-associated AE-ILD shows a diverse clinical course varying from fatal respiratory failure to asymptomatic event. Chemotherapy cannot be resumed in most of the patients who have developed symptomatic and corticosteroid-treated AE-ILD. These data let us speculate that AE-ILD would be associated with poor prognosis in LC patients with ILD. However, no significant association has been reported between the prognosis and AE-ILD in LC patients with ILD (10, 11).
The aim of this study was to assess the prognostic impact of AE-ILD caused by cytotoxic chemotherapy in LC patients with ILD. First, we evaluated the association between prognosis and AE-ILD in LC patients with ILD. Second, as a sub-group analysis, we separately analyzed the survival rate in the small cell LC (SCLC) and non-small cell LC (NSCLC) groups.
Materials and Methods
Subjects. We retrospectively reviewed the medical records of 98 advanced LC patients who had pre-existing ILD and were subsequently treated with cytotoxic chemotherapy at the Hiroshima University Hospital between October 2003 and December 2018. To evaluate the association between prognosis and cytotoxic chemotherapy-associated AE-ILD, 12 of 98 patients were excluded, 8 of 12 patients received radical thoracic radiation therapy, and 2 of 12 patients had AE-ILD caused by immune checkpoint inhibitors. The other two patients had AE-ILD which was not related to cytotoxic chemotherapy before the diagnosis of LC. As a result, 86 patients were included in this study.
Baseline characteristics of patients.
The baseline clinical characteristics within one month before administration of the first-line chemotherapy were obtained. We defined advanced LC as a case of stage III/stage IV/postoperative recurrence, who could not be treated with curative surgical procedure, by using the 8th edition of the TNM classification of LC (14). This study was approved by the Ethics Committee of Hiroshima University Hospital (M326), and all participants provided written informed consent.
Definition of pre-existing ILD and chemotherapy-associated AE-ILD. The diagnostic criteria for ILD were the existence of bilateral reticulation, and consolidation or ground-glass attenuation on pre-treatment computed tomography (CT), which was performed within one month before first-line chemotherapy administration. Chemotherapy-associated AE-ILD was diagnosed using the following criteria, which were modified from those having idiopathic pulmonary fibrosis (IPF) to practically adapt to the situation of cancer chemotherapy (7, 15-17):
Acute worsening or development of dyspnea within one month
CT showing new ground-glass abnormality bilaterally and/or consolidation
No indication of apparent heart failure, pulmonary invasion of LC, or pulmonary infection; no improvement with antibiotic treatment, and negative sputum and/or blood cultures
Development of AE-ILD within one month after the last chemotherapy
Statistical analysis. The data are expressed as the mean±standard deviation (SD). The results of the two groups were compared with the Mann-Whitney U-test or Pearson's chi-squared test. The survival rate and time from AE-ILD onset to death were evaluated using the Kaplan–Meier approach and the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazard models to assess the association between the various factors and the prognosis of LC patients with ILD. All p-values of <0.05 were considered significant. All data analyses were performed using JMP statistical software version 14.1.0 (SAS Institute Inc., Cary, NC, USA).
Results
Patient characteristics. The baseline characteristics of the total study population are shown in Table I. The mean age was 71.1±8.2 years, and the majority of the patients were male. Histologically, the data of 30 patients with SCLC (34.9%) and 56 patients with NSCLC (65.1%) were obtained. Regarding pre-existing ILD, 81 patients (94.2%) had idiopathic ILD and another five patients had secondary ILD (2, rheumatoid arthritis; 1, systemic sclerosis; 1, mixed connective tissue disease; and 1, asbestos inhalation). Four patients received immunosuppressive treatment before and during cancer treatment. Although there were nine defects in the data of forced vital capacity (FVC), the mean FVC was 86.4±19.2% among 77 patients.
Of the 86 patients with ILD, 30 patients (34.9%) had cytotoxic chemotherapy-associated AE-ILD. There were no significant differences in the baseline characteristics between patients with AE-ILD and those without. Only FVC in patients with AE-ILD tended to be lower than in those without (Table I). The frequency and severity of AE-ILD according to each drug and line are summarized in Table II. None of the patients with NSCLC were treated with tyrosine kinase inhibitors. The events were commonly severe at ≥grade 3 regardless of the drugs selected. Of the 30 patients with AE-ILD, 28 were treated with corticosteroids and no additional immunosuppressants were used. The other two cases were improved by the withdrawal of chemotherapy.
Association between AE-ILD and prognosis. In LC patients with ILD, Kaplan–Meier curve analysis revealed that the survival rate in patients with AE-ILD was significantly lower than that in those without [Figure 1; median survival time (MST), 258 vs. 394 days; p=0.012]. In the univariate Cox proportional analysis, the development of AE-ILD was significantly associated with poor prognosis [hazard ratio (HR), 1.912; 95% confidence interval (CI) 1.135-3.206, p=0.015]. The multivariate analysis also demonstrated that AE-ILD was a significant and independent prognostic factor in LC patients with ILD adjusted for performance status (PS) (HR=2.074; 95%CI=1.224-3.508; p=0.007) (Table III). Additionally, in patients with FVC data (n=77), AE-ILD was also found to be a significant prognostic factor after adjustment of PS and FVC (HR=1.947; 95%CI=1.097-3.429; p=0.023) (data not shown).
Cytotoxic chemotherapy regimens and lines considered causing AE-ILD.
Comparison of small cell carcinoma and non-small cell carcinoma. We separately analyzed the association of AE-ILD with the prognosis in the SCLC and NSCLC groups. In Kaplan–Meier curve analysis, the significant association of AE-ILD with poor prognosis was observed only in the SCLC group, but not in the NSCLC group (Figure 2; p=0.005 and p=0.242, respectively). Cox proportional analysis based on histological types demonstrated that AE-ILD was a significant and independent prognostic factor only in the SCLC group (HR=3.709; 95%CI=1.403-10.376; p=0.009), but not in the NSCLC group (Table III). We next performed a comparison of patients with AE-ILD between the SCLC and NSCLC groups. There was no significant difference in the baseline characteristics, overall survival, time from AE-ILD onset to death, AE-ILD grade, and chemotherapy resumption after the onset of AE-ILD (Table IV). On the other hand, although not significant, the survival rate in SCLC patients without AE-ILD tended to be higher than those in NSCLC patients without AE-ILD (Figure 3; MST, 674 vs. 305 days; p=0.081).
Kaplan–Meier analysis of the survival rate in patients with or without acute exacerbation of interstitial lung disease (AE-ILD). In lung cancer patients with ILD, the survival rate in patients with AE-ILD was significantly lower than that in patients without ILD (median survival time, 258 vs. 394 days, p=0.012).
The association between acute exacerbation of interstitial lung disease (AE-ILD) and prognosis based on the histological types. The significant association between AE-ILD and poor prognosis was observed only in the small cell lung cancer (SCLC) group (median survival time, 270 vs. 674 days, p=0.005), but not in the non-small cell lung cancer (NSCLC) group (median survival time, 233 vs. 305 days, p=0.242).
The association between histological types and prognosis in patients without acute exacerbation of interstitial lung disease (AE-ILD). The survival rate in small cell lung cancer (SCLC) patients without AE-ILD tended to be higher than that in non-small cell lung cancer (NSCLC) patients without AE-ILD (median survival time, 674 vs. 305 days, p=0.081).
Discussion
This study first verified that the development of AE-ILD was independently associated with poor prognosis in LC patients with ILD. In addition, the analysis based on histological types showed that AE-ILD might be more strongly associated with poor prognosis in SCLC patients than in NSCLC patients. This study has shown that AE-ILD is a problematic complication in LC patients having ILD in the clinical practice.
To the best of our knowledge, this is the first report to show that AE-ILD is statistically an independent poor prognostic factor in LC patients with ILD. In LC patients, pre-existing ILD is recognized as a risk of D-ILD with an incidence rate of 13.3-30.6% (9-11). Furthermore, the mortality rate related to AE-ILD is high at 29.2-70.0%, when LC patients with ILD are treated with cytotoxic chemotherapy (9, 18, 19). Consistent with previous studies, this study also showed that 30 (34.6%) of 86 LC patients with ILD had cytotoxic chemotherapy-associated AE-ILD, and 11 (36.7%) of the 30 patients died from respiratory failure within one month. Additionally, chemotherapy could be resumed in only seven (23.3%) of 30 patients with AE-ILD, which was much higher than a previous study where only one of 24 patient with AE-ILD could resume the treatment (9). These data suggest that AE-ILD might result in poorer prognosis in LC patients with ILD because of high mortality and difficulty in treatment resumption.
The sub-group analysis based on histological types revealed that a significant association of AE-ILD with poor prognosis was observed only in the SCLC group but not in the NSCLC group. Additionally, between patients with AE-ILD who had SCLC and NSCLC, there was no significant difference in the overall survival and the time from AE-ILD onset to death. In contrast, if AE-ILD was not developed during the treatment of cytotoxic chemotherapy, SCLC patients tended to have a better prognosis than NSCLC patients in this study. SCLC generally has a poor prognosis characterized by rapid progression of the tumor with extensive metastasis (20, 21), but SCLC also has a significant survival benefit from cytotoxic chemotherapy because of high sensitivity to the treatment (22-25). Additionally, previous studies have shown that pre-existing ILD is significantly associated with cancer resistance to cytotoxic chemotherapy in patients with metastatic NSCLC, but not in patients with SCLC (8, 26). These data suggest that the significant association of AE-ILD with poor prognosis in SCLC patients with ILD may be related to the high efficacy of cytotoxic chemotherapy leading to prolongation of life when AE-ILD has not developed.
Cox proportional hazard models to assess the association between various factors and the prognosis of lung cancer patients with ILD.
Comparison between the AE-ILD developed patients with SCLC and NSCLC.
Contrary to this study, two previous studies could not show the independent association of AE-ILD and poor prognosis in LC patients with ILD. Enomoto et al. enrolled 85 LC patients with ILD including 20 patients with SCLC (23.5%) and Minegishi, et al. enrolled 83 LC patients with ILD including 22 patients with SCLC (26.5%) (10, 11). This study enrolled 86 LC patients with ILD including 30 patients with SCLC (34.9%), which were higher than the patients of the previous studies. As mentioned above, SCLC patients, but not NSCLC patients, with AE-ILD had significantly shorter survival than those without AE-ILD. Although there are also several differences in the baseline characteristics, these data suggest that the discrepancy of the results between this study and the previous two studies might be caused by the higher prevalence rate of SCLC in this study. Further investigations are needed to elucidate the predictive value of AE-ILD based on histology types in LC patients with ILD.
There are several limitations to this study. First, it was a small retrospective study performed at a single institution in Japan. A prospective multicenter study is expected to exclude the possible bias and verify our findings. Second, administration of different types of chemotherapy regimens may have affected the incidence and prognosis of AE-ILD. Lastly, this study showed that AE-ILD was significantly associated with a poor prognosis in LC patients with ILD. However, we cannot sufficiently prevent and predict the development of AE-ILD. The J-SONIC study is currently underway to examine the suppressive effects of cytotoxic chemotherapy associated AE-ILD by adding nintedanib to weekly nab-paclitaxel combined with carboplatin in NSCLC patients with IPF (27). If the suppressive effect of AE-ILD by adding nintedanib is observed, it should be confirmed in SCLC patients with ILD.
Conclusion
The development of AE-ILD caused by cytotoxic chemotherapy is associated with poor prognosis in LC patients with ILD, especially in patients with SCLC. The preventive intervention for AE-ILD is needed to prolong the prognosis of LC patients with ILD.
Footnotes
Authors' Contributions
SN designed the study, performed the data analysis and interpretation, and wrote the manuscript. KY designed the study, interpreted the data, and edited the manuscript. SS, YH, TM, SM, TN, HI, KF, HH, and NH interpreted the data and helped to draft the manuscript. All Authors enrolled patients and collected data. All Authors also read and approved the final manuscript.
Conflicts of Interest
The Authors declare that they have no conflict of interest regarding this study.
- Received August 22, 2019.
- Revision received September 5, 2019.
- Accepted September 9, 2019.
- Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
