Combined pulmonary fibrosis and emphysema and idiopathic pulmonary fibrosis in non-small cell lung cancer: impact on survival and acute exacerbation

The study was conducted retrospectively in two tertiary hospitals in South Korea. We evaluated all chest computed tomography (CT) scans of patients with a diagnosis of IPF and lung cancer that were obtained in the Severance Hospital and Seoul National University Bundang Hospital between November 2003 and February 2018. The inclusion criteria were as follows: (1) fulfilment of diagnostic criteria of IPF and CPFE, (2) availability of CT scan images at the time of diagnosis in the institutional radiology database; and (3) availability of clinical data from medical records. In total, 435 patients were considered after applying the inclusion criteria. Among these, patients were excluded if they (1) were diagnosed with small cell lung cancer (n = 59); (2) had non-confirmed pathology (n = 17); (3) had incomplete data available (n = 76); or (4) were lost to follow-up (n = 20). Finally, 283 patients were included in the analysis.

Clinical and laboratory data were collected retrospectively from medical records. Data on age, smoking history, pulmonary function test results, underlying diseases, height and weight at the time of the diagnosis, gender–age–physiology (GAP) index score [18], Eastern Cooperative Oncology Group performance status (ECOG) [19], histological type of NSCLC, and clinical and/or pathologic staging of NSCLC were collected for all patients. Information on the treatment modality used for NSCLC; date of treatment; AE after surgery, chemotherapy, or radiotherapy (including the date AE was confirmed); and mortality data (including mortality due to AE) was also collected for all patients. According to smoking status, patients were categorized into two groups (never-smoker vs. ever-smoker [a person who had smoked at least 100 cigarettes and cigars during the course of their life]). The GAP score was calculated based on gender (0–1 points), age (0–2 points), forced vital capacity (FVC) (0–2 points), and diffusing capacity of carbon monoxide (DLco) (0–3 points), and was classified into stages I (0–3 points), II (4–5 points), or III (6–8 points), as previously described [18]. Early NSCLC was defined as stage I or II, while advanced NSCLC was defined as stage III or IV according to the eighth edition lung cancer stage classification [20]. The primary outcome was the development of AE and overall survival. Overall survival was estimated from the date of diagnosis of NSCLC and IPF/CPFE until death. Death registration data were provided by the Ministry of Security and Public Administration of Korea.

IPF was diagnosed using the criteria for the usual interstitial pneumonia (UIP) pattern as described in an official ATS/ERS/JRS/ALAT statement [21], as follows: subpleural, basal, predominantly reticular abnormality or honeycombing, with or without traction bronchiectasis, and the absence of an inconsistent UIP pattern. Diagnosis was confirmed at each hospital by a multi-disciplinary team consisting of specialists in pulmonary medicine, radiology, and pathology.

CPFE was defined according to Cottin et al.’s and Ryerson et al.’s definitions, namely the presence of classic features of centrilobular and/or paraseptal emphysemas (≥ 10%) in the upper lobes and pulmonary fibrosis (mainly IPF/UIP) in the lower lobes radiographically [7, 13]. Classification of CPFE and IPF was based on radiologic findings on chest CT scans. All CT scans of the included patients were reviewed by two radiologist and four pulmonologists, independently.

AE was defined according to the International Working Group Report by Collard et al. [22]: previous or concurrent diagnosis of IPF, acute worsening or development of dyspnea, typically < 1 month in duration, and CT scan with new bilateral ground-glass opacity and/or consolidation, with the deterioration not fully explained by cardiac failure or fluid overload. In the present study, acute exacerbation of IPF or CPFE within 1 month after treatment (chemotherapy, surgery, or radiotherapy) was defined as AE, in order to evaluate the effect of CPFE on the treatment of NSCLC.

Baseline characteristics of CPFE-NSCLC and IPF-NSCLC patients were compared using an unpaired t-test for continuous variables or χ2 test for categorical variables and are presented as mean ± standard deviation and numbers (percentage). Multiple logistic regression models were used to estimate odds ratios (ORs) for AE. Survival times were estimated using the Kaplan–Meier method and compared with the log-rank test. Multivariate Cox proportional hazards models were performed to investigate the relationships between clinical parameters and mortality. Variables that overlapped (e.g., age, gender, FVC, and DL_CO in the GAP index) were excluded in the multivariate Cox proportional hazards models. An adjusted P-value < 0.05 was considered statistically significant. All statistical analyses were performed with SPSS version 23.0 (SPSS Inc., Chicago, IL, USA).

This research protocol was approved by the Institutional Review Board of Severance Hospital, South Korea (IRB No. 4–2018-0770). The study design was approved by the appropriate ethics review boards. The requirement to obtain informed patient consent was waived.

Baseline characteristics of the study subjects are provided in Table 1. Men constituted 95.1% of the study cohort. The mean age for the patients overall was 70.3 years (range, 46–89 years); the mean ages of CPFE and IPF patients were 70.4 years (range, 46–89 years) and 70.1 years (range, 51–87 years), respectively. Compared with IPF patients, CPFE patients had a heavier smoking history, lower DLco (78.0% vs. 64.8%, P <  0.001), and lower forced expiratory volume in 1 s (FEV₁)/FVC ratio (75.1% vs. 71.2%, P = 0.001). Body mass index (BMI), FVC, NSCLC histology, FVC predicted %, FEV₁ predicted %, NSCLC stage, ECOG status, treatment modality, and GAP score did not differ significantly between IPF and CPFE patients.

Of the NSCLC patients overall, 71.7% died during the follow-up period; 71.6% died in the CPFE group and 72.0% in the IPF group. The respective follow-up periods were 18.6 months and 24.1 months (P = 0.975). CPFE patients had an increased tendency to develop AE, although this was not statistically significant in the univariate analysis (12.5% vs. 21.3%, P = 0.098). The time elapsed between diagnosis of CPFE or IPF and NSCLC was analyzed but did not differ significantly between the two groups (16.1 months vs. 16.4 months, P = 0.937).

Additional file 1: Table S1 shows the incidences of AE after treatment according to the treatment modality. Nine patients had undergone surgery and adjuvant chemotherapy, 22 patients had undergone concurrent chemoradiation therapy, and four patients had undergone surgery, followed by concurrent chemoradiation therapy. All AE were calculated separately after the respective treatments. NSCLC patients with CPFE tended to have more AE after surgery (IPF 8.6% vs. CPFE 21.6%, P = 0.073). Although the incidence of AE was higher in the CPFE group (13.1% vs. 21.3%, P = 0.098), no statistically significant difference was found.

Table 2 shows the relationship between CPFE and AE in the logistic regression model. GAP stage, smoking status, NSCLC histology, NSCLC stage, and CPFE were included in the regression model. In the analysis, due to the small number of patients in the GAP stage III group (n = 14), this group was combined with the GAP stage II group. CPFE (OR: 2.26, 95% CI: 1.09–4.69, P = 0.029) and GAP stage > II (OR: 2.20; 95% CI: 1.05–4.64; P = 0.037) showed a significant correlation with AE. NSCLC histology, smoking history (ever-smoker), and NSCLC stage > III did not show significant correlations with AE.

There was no significant difference in survival rates between the IPF and CPFE groups (P = 0.972), according to analysis of the Kaplan–Meier survival curves (Fig. 1).

The relationships between all-cause mortality and clinical parameters, including CPFE, were evaluated using Cox proportional hazards analysis (Table 3). Univariate analysis showed that advanced stage NSCLC, higher GAP index score (P <  0.001), AE (P <  0.001), lower FVC predicted, lower FEV1 predicted, lower DLco predicted, higher FEV1/FVC, %, and histological type other than adenocarcinoma or squamous cell carcinoma were significantly correlated with all-cause mortality. BMI, smoking history, time elapsed between diagnosis of IPF or CPFE and diagnosis of NSCLC, and CPFE did not correlate with all-cause mortality.

Multivariate Cox proportional hazards analyses were performed to compare the contributions of these indices (Table 4). Stepwise Cox proportional hazards analysis demonstrated that higher ECOG status (HR: 1.30; 95% CI: 1.16–1.55; P = 0.003), advanced stage NSCLC (HR: 3.15; 95% CI: 2.21–4.49; P <  0.001), and higher GAP score (HR: 1.31; 95% CI: 1.16–1.48; P <  0.001) were risk factors for all-cause mortality. CPFE (HR: 0.89; 95% CI: 0.66–1.21; P = 0.466) was not a significant risk factor for all-cause mortality in multivariate analysis.