The impact of coexisting lung diseases on outcomes in patients with pathological Stage I non-small-cell lung cancer

The impact of coexisting lung diseases on outcomes in patients with pathological Stage I... Abstract OBJECTIVES Cigarette smoking is a well-known cause of interstitial lung disease (ILD), pulmonary emphysema and lung cancer. Coexisting pulmonary disease can affect prognosis in patients with lung cancer. The aim of this study was to determine the influence of pulmonary disease on outcomes in patients with a smoking history who had undergone surgery for pathological Stage I non-small-cell lung cancer. METHODS Medical records of 257 patients with a smoking history who underwent surgery for pathological Stage I non-small-cell lung cancer between June 2009 and December 2014 were reviewed. Coexisting ILDs were evaluated using high-resolution computed tomography. The degree of pulmonary emphysema was determined using image analysis software according to the Goddard classification. The impact of clinicopathological factors on outcome was evaluated. RESULTS Among the 257 patients, ILDs were detected via high-resolution computed tomography in 60 (23.3%) patients; of these, usual interstitial pneumonia (UIP) patterns and non-UIP patterns were seen in 25 (9.7%) and 35 (13.6%) patients, respectively. The degree of pulmonary emphysema was classified as none, mild and moderate and included 50 (19.5%), 162 (63.0%) and 45 (17.5%) patients, respectively. The 5-year overall survival, cancer-specific survival and relapse-free survival were 80.7%, 88.0% and 74.9%, respectively, during a median follow-up period of 50.5 months. In multivariate analysis, the presence of a UIP pattern was shown to be an independent risk factor for poor outcome. CONCLUSIONS The presence of a UIP-pattern ILD on high-resolution computed tomography images was shown to be a risk factor for poor outcome in patients with a smoking history who had undergone surgery for pathological Stage I non-small-cell lung cancer. Non-small-cell lung cancer, Interstitial lung disease, Pulmonary emphysema, Outcomes INTRODUCTION Small, node-negative, non-small-cell lung cancers (NSCLCs) have been increasingly detected using computed tomography (CT). In these cases, complete surgical resection is expected to result in a favourable outcome [1]. However, some patients have poor oncological outcomes, and several prognostic factors have been identified, such as visceral pleural invasion (VPI) and lymphovascular invasion. In addition, some patients have a poor outcome due to comorbid pulmonary disease [2, 3]. Coexisting pulmonary disease may also affect the treatment strategy for NSCLC. For example, a limited resection and modified lymph node dissection might be selected as the surgical procedure, and the choice of chemotherapeutic agents for recurrent disease after surgery may be limited. Interstitial lung diseases (ILDs) and pulmonary emphysema are major pulmonary diseases observed in patients with lung cancer. ILDs are associated with an increased risk of lung cancer [4, 5]. Idiopathic pulmonary fibrosis (IPF), a progressive ILD of unknown aetiology, is a life-threatening disease with few treatment options. The median survival of patients with IPF was reported to be 2–4 years [6, 7]. In addition to chronic progression, ILDs are characterized by acute exacerbations, which can occur in the postoperative setting, that substantially increase the risk of mortality [8]. Recently, a nation-wide investigation in Japan revealed a low rate of post-surgical survival in patients with lung cancer at each tumour, node and metastasis (TNM) stage and coexisting ILD. Eventually, half of these patients died due to lung cancer [9]. In addition, limited resection, including wedge resection and segmentectomy, was shown to increase mortality due to cancer in pathological Stage IA (sixth TNM) patients [9]. Based on these results, it appears that the risk of unfavourable outcome due to cancer is higher in patients with lung cancer and coexisting ILDs. Cigarette smoking causes chronic obstructive pulmonary disease (COPD) including pulmonary emphysema and lung cancer [10, 11]. Patients with lung cancer and pulmonary emphysema, as diagnosed using CT, have lower survival when compared with patients without emphysema [12, 13]. Interestingly, COPD itself, as defined by pulmonary function testing [14], does not impact mortality in smokers with NSCLC [2]. A recent meta-analysis revealed that the presence of CT-defined pulmonary emphysema has more influence on cancer outcome than spirometry-defined COPD [15]. Hence, a detailed assessment of pulmonary emphysema on pre-operative CT may help determine prognosis in patients with NSCLC. In this study, we retrospectively reviewed the clinical data of patients with a smoking history who had undergone surgery for pathological Stage I NSCLC to determine the impact of coexisting pulmonary diseases on prognostic outcome. PATIENTS AND METHODS Study population In our institute, we routinely obtained written informed consent from every patient before surgery to allow the use of clinical data in future analyses. This retrospective study protocol was approved by our institutional review board (approved ID: YUMC 28-4). Medical records and chest high-resolution computed tomography (HRCT) images of patients with a history of smoking who underwent surgical treatment for pathological Stage I NSCLC from January 2009 to December 2014, when HRCT data were available at our hospital, were retrospectively reviewed. TNM classification stages were rearranged according to the eighth edition of the TNM classification [16]. Histological type was determined according to the classification of the World Health Organization (WHO) [17]. Patients who had been treated for malignant diseases within the previous 5 years, patients who had received preoperative chemotherapy or radiotherapy and those with a history of pulmonary resection were excluded from the analysis. Patients with positive or unclear tumour margin were excluded from the study, leaving 257 patients in the final analysis (Fig. 1). Figure 1: View largeDownload slide Patient selection diagram. NSCLC: non-small-cell lung cancer. Figure 1: View largeDownload slide Patient selection diagram. NSCLC: non-small-cell lung cancer. Assessment of interstitial lung diseases using high-resolution computed tomography Chest CT scans were performed using a 64-row detector CT scanner (Aquilion 64, Toshiba Medical Systems, Japan) within 1 month of surgery. Scans were performed on patients in the supine position during full inspiration without intravenous contrast materials. Coexistence of radiological ILD [usual interstitial pneumonia (UIP) versus non-UIP pattern] was evaluated by 2 radiologists with more than 10 years of experience in chest CT interpretation, in accordance with the ATS/ERS/Japanese Respiratory Society/Latin American Thoracic Association Statement [7]. Decisions regarding ILD features were determined by consensus. Emphysema quantification and scoring HRCT images for 3D CT were reconstructed with 2-mm-thick slices. Using image analysis software (Synapse Vincent ver. 4.4, Fujifilm Medical, Tokyo, Japan), the degree of emphysema was semiautomatically quantified and scored. Briefly, 3D-reconstructed bilateral lung parenchyma was divided into 3 segments using horizontal lines at the top of the aortic arch, the carina and the diaphragm. In each segment, the percentage of low-attenuation area (LAA) was calculated by the software and scored according to the Goddard classification [18] as follows: (i) 0–5%; (ii) 6–25%; (iii) 26–50%; (iv) 51–75% and (v) >76%. The low-attenuation threshold was −950 HU [19]. The degree of emphysema was determined based on the sum of all 6 segments as follows: 0, none; 1–7, mild; 8–15, moderate and 16–24, severe. Spirometry For all patients, the forced expiratory volume in 1 s (FEV1), the vital capacity and the forced vital capacity were measured preoperatively by spirometry. Airflow limitation severity in COPD (FEV1/forced vital capacity <0.7) was classified based on the global initiative for chronic obstructive lung disease (GOLD) 2017 recommendations: GOLD 1, mild (FEV1 ≥80% predicted); GOLD 2, moderate (FEV1 ≥50% and <80% predicted); GOLD 3, severe (FEV1 ≥30% and <50% predicted) and GOLD 4, very severe (FEV1 <30% predicted) [20]. Patient follow-up and data collection All patients were followed up postoperatively by routine physical examination and imaging studies including chest or systemic CT scan with or without enhancement every 6–12 months for the first 2 years and then plain CT annually. Overall survival (OS) time was defined as the time from operation to death or last follow-up. Cancer-specific survival (CSS) time was defined as the time from operation to death due to lung cancer or last follow-up. Relapse-free survival (RFS) time was defined as the time from operation to proven detection of recurrence or metastases. Local relapse was defined as recurrent diseases at the primary site or in lymphatic drainage areas either hilar or mediastinal within the ipsilateral thoracic cavity [21]. Statistical analyses Cohen’s kappa coefficient was used to determine interobserver agreement. The impact of clinicopathological factors on OS, CSS and RFS was evaluated using the Kaplan–Meier analyses and log-rank tests with 95% confidence intervals. The Cox proportional hazards models were also employed to evaluate factors predictive of survival. All tests of significance were 2-sided, and P-values <0.05 were considered statistically significant. All statistical analyses were conducted using the SPSS statistics software (version 24; IBM SPSS, Chicago, IL, USA). RESULTS Patient characteristics Patient characteristics are summarized in Table 1. Most of the patients were men, and one-third of the patients were current smokers. Open thoracotomy was performed in 74 patients and video-assisted thoracic surgery in 183 patients. Limited resection was generally selected for patients with compromised cardiopulmonary reserve. Wide-wedge resection and segmentectomy were performed in 27 (10.5%) patients. Among these patients, 4 patients underwent wide-wedge resection for subcentimetre tumours, and 11 patients underwent segmentectomy for tumours that were believed to be non-invasive. Ultimately, 15 (5.8%) patients underwent intended limited resection and 39 (15.2%) underwent palliative limited resection. Table 1: Clinicopathological characteristics Characteristics  n (%)  Total cases  257  Age (years), mean (SD)  69.4 (9.1)   ≥75  82 (31.9)  Gender     Male  223 (86.8)  Smoking status     Current  72 (28.0)   Former  185 (72.0)  Pathological T     T1mi  6 (2.3)   T1a  25 (9.7)   T1b  59 (23.0)   T1c  66 (25.7)   T2a  101 (39.3)  ILDs on HRCT image     UIP pattern  25 (9.7)   Non-UIP pattern  35 (13.6)   None  197 (76.7)  Degree of emphysema     None  50 (19.5)   Mild  162 (63.0)   Moderate  45 (17.5)  %VC     <80  25 (9.7)  FEV1.0%     <70  98 (38.1)   GOLD 1  44 (17.1)   GOLD 2  44 (17.1)   GOLD 3  9 (3.5)   GOLD 4  1 (0.4)  Operation     Wide wedge  27 (10.5)   Segmentectomy  27 (10.5)   Lobectomy  202 (78.6)   Pneumonectomy  1 (0.4)  Pathological stage     IA1  31 (12.1)   IA2  59 (23.0)   IA3  66 (25.7)   IB  101 (39.3)  VPI     PL0  192 (74.7)   PL1  50 (19.5)   PL2  11 (4.3)   PL3  4 (1.5)  Lymphatic invasion     Ly0  214 (83.3)   Ly1  43 (16.7)  Vascular invasion     V0  188 (73.2)   V1  69 (26.8)  Characteristics  n (%)  Total cases  257  Age (years), mean (SD)  69.4 (9.1)   ≥75  82 (31.9)  Gender     Male  223 (86.8)  Smoking status     Current  72 (28.0)   Former  185 (72.0)  Pathological T     T1mi  6 (2.3)   T1a  25 (9.7)   T1b  59 (23.0)   T1c  66 (25.7)   T2a  101 (39.3)  ILDs on HRCT image     UIP pattern  25 (9.7)   Non-UIP pattern  35 (13.6)   None  197 (76.7)  Degree of emphysema     None  50 (19.5)   Mild  162 (63.0)   Moderate  45 (17.5)  %VC     <80  25 (9.7)  FEV1.0%     <70  98 (38.1)   GOLD 1  44 (17.1)   GOLD 2  44 (17.1)   GOLD 3  9 (3.5)   GOLD 4  1 (0.4)  Operation     Wide wedge  27 (10.5)   Segmentectomy  27 (10.5)   Lobectomy  202 (78.6)   Pneumonectomy  1 (0.4)  Pathological stage     IA1  31 (12.1)   IA2  59 (23.0)   IA3  66 (25.7)   IB  101 (39.3)  VPI     PL0  192 (74.7)   PL1  50 (19.5)   PL2  11 (4.3)   PL3  4 (1.5)  Lymphatic invasion     Ly0  214 (83.3)   Ly1  43 (16.7)  Vascular invasion     V0  188 (73.2)   V1  69 (26.8)  FEV1.0: forced expiratory volume in 1 s; GOLD: global initiation for chronic obstructive lung disease; HRCT: high-resolution computed tomography; ILD: interstitial lung disease; Ly: lymphatic invasion; SD: standard deviation; UIP: usual interstitial pneumonia; V: vascular invasion; VC: vital capacity; VPI: visceral pleural invasion. Table 1: Clinicopathological characteristics Characteristics  n (%)  Total cases  257  Age (years), mean (SD)  69.4 (9.1)   ≥75  82 (31.9)  Gender     Male  223 (86.8)  Smoking status     Current  72 (28.0)   Former  185 (72.0)  Pathological T     T1mi  6 (2.3)   T1a  25 (9.7)   T1b  59 (23.0)   T1c  66 (25.7)   T2a  101 (39.3)  ILDs on HRCT image     UIP pattern  25 (9.7)   Non-UIP pattern  35 (13.6)   None  197 (76.7)  Degree of emphysema     None  50 (19.5)   Mild  162 (63.0)   Moderate  45 (17.5)  %VC     <80  25 (9.7)  FEV1.0%     <70  98 (38.1)   GOLD 1  44 (17.1)   GOLD 2  44 (17.1)   GOLD 3  9 (3.5)   GOLD 4  1 (0.4)  Operation     Wide wedge  27 (10.5)   Segmentectomy  27 (10.5)   Lobectomy  202 (78.6)   Pneumonectomy  1 (0.4)  Pathological stage     IA1  31 (12.1)   IA2  59 (23.0)   IA3  66 (25.7)   IB  101 (39.3)  VPI     PL0  192 (74.7)   PL1  50 (19.5)   PL2  11 (4.3)   PL3  4 (1.5)  Lymphatic invasion     Ly0  214 (83.3)   Ly1  43 (16.7)  Vascular invasion     V0  188 (73.2)   V1  69 (26.8)  Characteristics  n (%)  Total cases  257  Age (years), mean (SD)  69.4 (9.1)   ≥75  82 (31.9)  Gender     Male  223 (86.8)  Smoking status     Current  72 (28.0)   Former  185 (72.0)  Pathological T     T1mi  6 (2.3)   T1a  25 (9.7)   T1b  59 (23.0)   T1c  66 (25.7)   T2a  101 (39.3)  ILDs on HRCT image     UIP pattern  25 (9.7)   Non-UIP pattern  35 (13.6)   None  197 (76.7)  Degree of emphysema     None  50 (19.5)   Mild  162 (63.0)   Moderate  45 (17.5)  %VC     <80  25 (9.7)  FEV1.0%     <70  98 (38.1)   GOLD 1  44 (17.1)   GOLD 2  44 (17.1)   GOLD 3  9 (3.5)   GOLD 4  1 (0.4)  Operation     Wide wedge  27 (10.5)   Segmentectomy  27 (10.5)   Lobectomy  202 (78.6)   Pneumonectomy  1 (0.4)  Pathological stage     IA1  31 (12.1)   IA2  59 (23.0)   IA3  66 (25.7)   IB  101 (39.3)  VPI     PL0  192 (74.7)   PL1  50 (19.5)   PL2  11 (4.3)   PL3  4 (1.5)  Lymphatic invasion     Ly0  214 (83.3)   Ly1  43 (16.7)  Vascular invasion     V0  188 (73.2)   V1  69 (26.8)  FEV1.0: forced expiratory volume in 1 s; GOLD: global initiation for chronic obstructive lung disease; HRCT: high-resolution computed tomography; ILD: interstitial lung disease; Ly: lymphatic invasion; SD: standard deviation; UIP: usual interstitial pneumonia; V: vascular invasion; VC: vital capacity; VPI: visceral pleural invasion. Coexisting pulmonary diseases Among the 257 study patients, coexisting ILDs were observed in 60 (23.3%) patients, including UIP pattern in 25 (9.7%) and non-UIP pattern in 35 (13.6%). There was substantial interobserver agreement (κ = 0.7). The degree of emphysema, which was determined based on the HRCT image, was mild in 162 (63.0%) patients and moderate in 45 (17.5%) patients. Fifty (19.5%) patients were diagnosed with no pulmonary emphysema, and no patient was diagnosed with severe emphysema. Restrictive ventilatory impairment (%vital capacity < 80) was detected in 25 (9.7%) patients. Obstructive ventilatory impairment (FEV1/forced vital capacity < 0.7) was detected in 98 (38.1%) patients, including GOLD 1 in 44 (17.1%), GOLD 2 in 44 (17.1%), GOLD 3 in 9 (3.5%) and GOLD 4 in 1 (0.4%). Outcome The 5-year OS, CSS and RFS were 80.7%, 88.0% and 74.9%, respectively [median follow-up period: 50.5 (3–105) months]. Because the survival curves of patients with UIP-pattern ILD on high-resolution computed tomograph were distinctly worse when compared with those with non-UIP-pattern ILD and those without ILD (Fig. 2), the following analyses were performed as a UIP pattern on high-resolution computed tomograph versus all others. The results of the univariate analysis for survival are summarized in Table 2. In the multivariate analysis, older age, the presence of a UIP pattern on high-resolution computed tomograph and restrictive ventilatory impairment were determined as independent risk factors for poor OS. In addition to these 3 factors, positive VPI and pathological Stage IB were determined as independent risk factors for poor CSS and RFS, respectively (Table 3). Notably, pulmonary emphysema determined based on either HRCT or spirometry was not observed to be an independent risk factor for poor outcome (Fig. 3). Table 2: Univariate analysis Variables  5-Year OS (%)  P-value  5-Year CSS (%)  P-value  5-Year RFS (%)  P-value  Total cases  80.7  88.0  74.9  Age (years)     <75  87.5  <0.001  91.1  0.016  78.9  0.007   ≥75  66.1  80.9  66.4  Gender     Female  92.0  0.058  92.0  0.285  88.8  0.070   Male  79.0  87.4  72.7  UIP pattern on HRCT image     Yes  22.0  <0.001  34.1  <0.001  30.2  <0.001   No  87.2  92.8  79.6  Degree of emphysema     Moderate  66.0  0.005  75.9  0.015  65.8  0.075   Mild and none  83.9  90.5  76.9  %VC     <80  51.4  <0.001  74.0  0.002  39.1  <0.001   ≥80  83.6  89.2  78.5  FEV1.0%     <70  75.0  0.205  84.7  0.517  67.1  0.076   ≥70  84.1  90.1  80.1  Severity of COPD     GOLD 2 or more  74.8  0.318  67.9  0.308  83.4  0.533   Others  82.5  76.9  89.4  Tumour location     Upper or middle lobe  85.4  0.036  91.3  0.137  78.9  0.057   Lower lobe  72.5  81.3  67.4  Operation     Wide wedge  65.6  0.046  80.1  0.207  69.4  0.552   Anatomical  82.9  89.0  75.5  Histology     Adenocarcinoma  85.7  0.011  91.8  0.022  77.0  0.140   Non-adenocarcinoma  73.3  82.2  71.5  pStage     IA  84.9  0.024  93.4  0.001  80.2  0.017   IB  74.4  79.8  66.6  VPI     Negative  83.6  0.014  92.7  <0.001  77.9  0.012   Positive  72.4  74.9  65.7  Lymphatic invasion     Negative  79.8  0.807  87.7  0.860  75.0  0.737   Positive  85.2  89.4  73.4  Vascular invasion               Negative  81.6  0.284  90.2  0.040  75.9  0.352   Positive  78.5    82.4    71.9    Variables  5-Year OS (%)  P-value  5-Year CSS (%)  P-value  5-Year RFS (%)  P-value  Total cases  80.7  88.0  74.9  Age (years)     <75  87.5  <0.001  91.1  0.016  78.9  0.007   ≥75  66.1  80.9  66.4  Gender     Female  92.0  0.058  92.0  0.285  88.8  0.070   Male  79.0  87.4  72.7  UIP pattern on HRCT image     Yes  22.0  <0.001  34.1  <0.001  30.2  <0.001   No  87.2  92.8  79.6  Degree of emphysema     Moderate  66.0  0.005  75.9  0.015  65.8  0.075   Mild and none  83.9  90.5  76.9  %VC     <80  51.4  <0.001  74.0  0.002  39.1  <0.001   ≥80  83.6  89.2  78.5  FEV1.0%     <70  75.0  0.205  84.7  0.517  67.1  0.076   ≥70  84.1  90.1  80.1  Severity of COPD     GOLD 2 or more  74.8  0.318  67.9  0.308  83.4  0.533   Others  82.5  76.9  89.4  Tumour location     Upper or middle lobe  85.4  0.036  91.3  0.137  78.9  0.057   Lower lobe  72.5  81.3  67.4  Operation     Wide wedge  65.6  0.046  80.1  0.207  69.4  0.552   Anatomical  82.9  89.0  75.5  Histology     Adenocarcinoma  85.7  0.011  91.8  0.022  77.0  0.140   Non-adenocarcinoma  73.3  82.2  71.5  pStage     IA  84.9  0.024  93.4  0.001  80.2  0.017   IB  74.4  79.8  66.6  VPI     Negative  83.6  0.014  92.7  <0.001  77.9  0.012   Positive  72.4  74.9  65.7  Lymphatic invasion     Negative  79.8  0.807  87.7  0.860  75.0  0.737   Positive  85.2  89.4  73.4  Vascular invasion               Negative  81.6  0.284  90.2  0.040  75.9  0.352   Positive  78.5    82.4    71.9    COPD: chronic obstructive lung disease; CSS: cancer-specific survival; FEV1.0: forced expiratory volume in 1 s; GOLD: global initiation for chronic obstructive lung disease; HRCT: high-resolution computed tomography; OS: overall survival; RFS: relapse-free survival; UIP: usual interstitial pneumonia; VC: vital capacity; VPI: visceral pleural invasion. Table 2: Univariate analysis Variables  5-Year OS (%)  P-value  5-Year CSS (%)  P-value  5-Year RFS (%)  P-value  Total cases  80.7  88.0  74.9  Age (years)     <75  87.5  <0.001  91.1  0.016  78.9  0.007   ≥75  66.1  80.9  66.4  Gender     Female  92.0  0.058  92.0  0.285  88.8  0.070   Male  79.0  87.4  72.7  UIP pattern on HRCT image     Yes  22.0  <0.001  34.1  <0.001  30.2  <0.001   No  87.2  92.8  79.6  Degree of emphysema     Moderate  66.0  0.005  75.9  0.015  65.8  0.075   Mild and none  83.9  90.5  76.9  %VC     <80  51.4  <0.001  74.0  0.002  39.1  <0.001   ≥80  83.6  89.2  78.5  FEV1.0%     <70  75.0  0.205  84.7  0.517  67.1  0.076   ≥70  84.1  90.1  80.1  Severity of COPD     GOLD 2 or more  74.8  0.318  67.9  0.308  83.4  0.533   Others  82.5  76.9  89.4  Tumour location     Upper or middle lobe  85.4  0.036  91.3  0.137  78.9  0.057   Lower lobe  72.5  81.3  67.4  Operation     Wide wedge  65.6  0.046  80.1  0.207  69.4  0.552   Anatomical  82.9  89.0  75.5  Histology     Adenocarcinoma  85.7  0.011  91.8  0.022  77.0  0.140   Non-adenocarcinoma  73.3  82.2  71.5  pStage     IA  84.9  0.024  93.4  0.001  80.2  0.017   IB  74.4  79.8  66.6  VPI     Negative  83.6  0.014  92.7  <0.001  77.9  0.012   Positive  72.4  74.9  65.7  Lymphatic invasion     Negative  79.8  0.807  87.7  0.860  75.0  0.737   Positive  85.2  89.4  73.4  Vascular invasion               Negative  81.6  0.284  90.2  0.040  75.9  0.352   Positive  78.5    82.4    71.9    Variables  5-Year OS (%)  P-value  5-Year CSS (%)  P-value  5-Year RFS (%)  P-value  Total cases  80.7  88.0  74.9  Age (years)     <75  87.5  <0.001  91.1  0.016  78.9  0.007   ≥75  66.1  80.9  66.4  Gender     Female  92.0  0.058  92.0  0.285  88.8  0.070   Male  79.0  87.4  72.7  UIP pattern on HRCT image     Yes  22.0  <0.001  34.1  <0.001  30.2  <0.001   No  87.2  92.8  79.6  Degree of emphysema     Moderate  66.0  0.005  75.9  0.015  65.8  0.075   Mild and none  83.9  90.5  76.9  %VC     <80  51.4  <0.001  74.0  0.002  39.1  <0.001   ≥80  83.6  89.2  78.5  FEV1.0%     <70  75.0  0.205  84.7  0.517  67.1  0.076   ≥70  84.1  90.1  80.1  Severity of COPD     GOLD 2 or more  74.8  0.318  67.9  0.308  83.4  0.533   Others  82.5  76.9  89.4  Tumour location     Upper or middle lobe  85.4  0.036  91.3  0.137  78.9  0.057   Lower lobe  72.5  81.3  67.4  Operation     Wide wedge  65.6  0.046  80.1  0.207  69.4  0.552   Anatomical  82.9  89.0  75.5  Histology     Adenocarcinoma  85.7  0.011  91.8  0.022  77.0  0.140   Non-adenocarcinoma  73.3  82.2  71.5  pStage     IA  84.9  0.024  93.4  0.001  80.2  0.017   IB  74.4  79.8  66.6  VPI     Negative  83.6  0.014  92.7  <0.001  77.9  0.012   Positive  72.4  74.9  65.7  Lymphatic invasion     Negative  79.8  0.807  87.7  0.860  75.0  0.737   Positive  85.2  89.4  73.4  Vascular invasion               Negative  81.6  0.284  90.2  0.040  75.9  0.352   Positive  78.5    82.4    71.9    COPD: chronic obstructive lung disease; CSS: cancer-specific survival; FEV1.0: forced expiratory volume in 1 s; GOLD: global initiation for chronic obstructive lung disease; HRCT: high-resolution computed tomography; OS: overall survival; RFS: relapse-free survival; UIP: usual interstitial pneumonia; VC: vital capacity; VPI: visceral pleural invasion. Table 3: Multivariate analysis Risk factor  OS   CSS   RFS   HR (95% CI)  P-value  HR (95% CI)  P-value  HR (95% CI)  P-value  Age (+1 year)  1.08 (1.04–1.13)  <0.001  1.07 (1.02–1.13)  0.010  1.04 (1.00–1.07)  0.024  UIP pattern on HRCT image  6.33 (3.26–12.3)  <0.001  7.30 (3.10–16.9)  <0.001  4.39 (2.37–8.13)  <0.001  %VC <80  4.08 (2.04–8.20)  <0.001  2.81 (1.06–7.46)  0.038  3.95 (2.12–7.35)  <0.001  Positive VPI      4.02 (1.82–8.85)  0.001      pStage IB          2.02 (1.21–3.38)  0.007  Risk factor  OS   CSS   RFS   HR (95% CI)  P-value  HR (95% CI)  P-value  HR (95% CI)  P-value  Age (+1 year)  1.08 (1.04–1.13)  <0.001  1.07 (1.02–1.13)  0.010  1.04 (1.00–1.07)  0.024  UIP pattern on HRCT image  6.33 (3.26–12.3)  <0.001  7.30 (3.10–16.9)  <0.001  4.39 (2.37–8.13)  <0.001  %VC <80  4.08 (2.04–8.20)  <0.001  2.81 (1.06–7.46)  0.038  3.95 (2.12–7.35)  <0.001  Positive VPI      4.02 (1.82–8.85)  0.001      pStage IB          2.02 (1.21–3.38)  0.007  CI: confidence interval; CSS: cancer-specific survival; HR: hazard ratio; HRCT: high-resolution computed tomography; OS: overall survival; RFS: relapse-free survival; UIP: usual interstitial pneumonia; VC: vital capacity; VPI: visceral pleural invasion. Table 3: Multivariate analysis Risk factor  OS   CSS   RFS   HR (95% CI)  P-value  HR (95% CI)  P-value  HR (95% CI)  P-value  Age (+1 year)  1.08 (1.04–1.13)  <0.001  1.07 (1.02–1.13)  0.010  1.04 (1.00–1.07)  0.024  UIP pattern on HRCT image  6.33 (3.26–12.3)  <0.001  7.30 (3.10–16.9)  <0.001  4.39 (2.37–8.13)  <0.001  %VC <80  4.08 (2.04–8.20)  <0.001  2.81 (1.06–7.46)  0.038  3.95 (2.12–7.35)  <0.001  Positive VPI      4.02 (1.82–8.85)  0.001      pStage IB          2.02 (1.21–3.38)  0.007  Risk factor  OS   CSS   RFS   HR (95% CI)  P-value  HR (95% CI)  P-value  HR (95% CI)  P-value  Age (+1 year)  1.08 (1.04–1.13)  <0.001  1.07 (1.02–1.13)  0.010  1.04 (1.00–1.07)  0.024  UIP pattern on HRCT image  6.33 (3.26–12.3)  <0.001  7.30 (3.10–16.9)  <0.001  4.39 (2.37–8.13)  <0.001  %VC <80  4.08 (2.04–8.20)  <0.001  2.81 (1.06–7.46)  0.038  3.95 (2.12–7.35)  <0.001  Positive VPI      4.02 (1.82–8.85)  0.001      pStage IB          2.02 (1.21–3.38)  0.007  CI: confidence interval; CSS: cancer-specific survival; HR: hazard ratio; HRCT: high-resolution computed tomography; OS: overall survival; RFS: relapse-free survival; UIP: usual interstitial pneumonia; VC: vital capacity; VPI: visceral pleural invasion. Figure 2: View largeDownload slide The Kaplan–Meier estimates for overall (A), cancer-specific (B) and relapse-free (C) survival based on the presence of interstitial lung diseases on high-resolution computed tomographs in patients with smoking history who underwent surgery for pStage I non-small-cell lung cancer. UIP: usual interstitial pneumonia. Figure 2: View largeDownload slide The Kaplan–Meier estimates for overall (A), cancer-specific (B) and relapse-free (C) survival based on the presence of interstitial lung diseases on high-resolution computed tomographs in patients with smoking history who underwent surgery for pStage I non-small-cell lung cancer. UIP: usual interstitial pneumonia. Figure 3: View largeDownload slide The Kaplan–Meier estimates for overall (A), cancer-specific (B) and relapse-free (C) survival based on the degree of emphysema in patients with smoking history who underwent surgery for pStage I non-small-cell lung cancer. Figure 3: View largeDownload slide The Kaplan–Meier estimates for overall (A), cancer-specific (B) and relapse-free (C) survival based on the degree of emphysema in patients with smoking history who underwent surgery for pStage I non-small-cell lung cancer. Tumour recurrence was observed in 46 (17.9%) patients. Of those, local recurrence alone was observed in 17 patients, distant recurrence alone was observed in 20 patients and both local and distant recurrences were observed in 2 patients. Seven patients had unknown recurrence sites due to missing data. Among the 25 patients with a UIP pattern on high-resolution computed tomograph, 12 (48.0%) patients had a recurrence during the follow-up period. Local recurrence alone was observed in 6 patients, and distant recurrence alone was observed in 4 patients. Two patients had unknown recurrence sites due to missing data. Among the patients with local recurrence, lobectomy was performed in 5 patients and wide-wedge resection was performed in 1. Acute exacerbation of IPF occurred in 2 (3.3% of patients with ILDs on high-resolution computed tomograph) patients who had a UIP pattern on high-resolution computed tomograph and had undergone lobectomy at 2 and 3 months after surgery. The risk scores for acute exacerbation [22] were 14 and 13, respectively. Both patients chose to pursue limited medical care and eventually died. DISCUSSION In this study, we found that the presence of a UIP pattern on high-resolution computed tomograph and restrictive ventilatory impairment were independent risk factors for poor outcome in patients with a smoking history who had undergone surgery for pathological Stage I NSCLC. Pulmonary emphysema was associated with poor outcome in the univariate analysis; however, this comorbidity was not shown to be a risk factor in the multivariate analysis. Patients with both lung cancer and ILD are known to have unfavourable outcomes [23, 24]. A multicentre investigation [9] showed 5-year survivals of 59% and 42% for pTNM (sixth edition of the TNM classification stages) IA and IB patients, respectively. Among these patients, cancer-related death was the main cause of mortality, even in patients with Stage IA disease [9]. Hata et al. [25] reported that in patients with lung cancer and concomitant ILD, the incidence of VPI and malignant pleurisy detected at the time of thoracotomy was significantly higher than in patients without ILD. They concluded that these characteristics contribute to unfavourable outcome after surgery. Similarly, we found that VPI was frequently observed in patients with a UIP-pattern ILD on high-resolution computed tomograph (data not shown) and was a risk factor for poor CSS. The possibility that ILDs promote tumour invasiveness should be pursued in the future studies. The degree of pulmonary emphysema can be accurately assessed by quantification of LAA using CT. Haruna et al. [26] reported that a quantitative evaluation of emphysematous changes based on LAA calculation using CT could predict respiratory mortality in patients with pulmonary emphysema. In this study, we used a quantitative evaluation of LAA to determine the degree of pulmonary emphysema. We found that pulmonary emphysema was related to poor outcome but was not an independent risk factor in the multivariate analysis. These results suggest that the degree of pulmonary emphysema may have prognostic influence, but the presence of a UIP-pattern ILD is more predictive of poor outcome. It should be noted that some previous reports [2, 12, 13] investigating the prognostic importance of pulmonary emphysema did not include ILDs in the analysis. In fact, when we excluded ILDs in our analysis, moderate pulmonary emphysema became an independent risk factor for poor OS and CSS (data not shown). We should also note that in this study, as many as 40% of patients had COPD. As Johannessen et al. [27] pointed out, the risk of mortality based on the degree of pulmonary emphysema would be assessed in a cohort where most patients have mild or no COPD, such as a community-based study. The incidence of tumour recurrence has been reported [28] to be approximately 20% in Stage I NSCLC after curative resection. Considering the fact that half of the patients with Stage I lung cancer and ILD died due to lung cancer [9], the recurrence rate in those patients was higher than that of the general cohort. Similarly, we found that the recurrence rate in patients with a UIP-pattern ILD was as high as 48.0%. In our study, limited resection including wide-wedge resection was not always selected for patients with a UIP-pattern ILD who subsequently developed recurrence, suggesting that it may be difficult to perform curative resection in patients who have potentially curative lung cancer and a UIP pattern on high-resolution computed tomograph. Limitations A major limitation of this study is that it was a single institution, retrospective analysis based on a small-sized cohort. In addition, treatment strategies were different depending on the patient. For example, chemotherapeutic agents were not used in patients with ILD to avoid ILD progression [29], and this may worsen cancer-related prognosis. Although we included only patients with pathological Stage I NSCLC to reduce potential bias due to the use of adjuvant chemotherapy, the difference in treatment strategies, including surgical strategies, may substantially influence outcome. The optimal surgical procedure for resectable NSCLC in patients with ILD has not yet been established and will likely depend on tumour stage and ILD subtype. Recently, Tsutani et al. [30] reported the feasibility of sublobar resection for clinical Stage I NSCLC with ILD, with regard to short- and long-term outcomes, when compared with lobar resection. This issue should be pursued in future prospective studies. We should also note that a ‘UIP pattern’ on high-resolution computed tomograph does not always equate to a pathological UIP-pattern IPF. Although a pathological diagnosis of ILD would be important for prognostic purposes, it could not be obtained in all the patients, because the surgical specimens were not always within the ILD region. CONCLUSION In conclusion, the presence of a UIP-pattern ILD on high-resolution computed tomograph was shown to be an independent risk factor for poor outcome in patients with a smoking history who underwent surgery for pathological Stage I NSCLC. 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The impact of coexisting lung diseases on outcomes in patients with pathological Stage I non-small-cell lung cancer

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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1569-9293
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1569-9285
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10.1093/icvts/ivx441
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Abstract

Abstract OBJECTIVES Cigarette smoking is a well-known cause of interstitial lung disease (ILD), pulmonary emphysema and lung cancer. Coexisting pulmonary disease can affect prognosis in patients with lung cancer. The aim of this study was to determine the influence of pulmonary disease on outcomes in patients with a smoking history who had undergone surgery for pathological Stage I non-small-cell lung cancer. METHODS Medical records of 257 patients with a smoking history who underwent surgery for pathological Stage I non-small-cell lung cancer between June 2009 and December 2014 were reviewed. Coexisting ILDs were evaluated using high-resolution computed tomography. The degree of pulmonary emphysema was determined using image analysis software according to the Goddard classification. The impact of clinicopathological factors on outcome was evaluated. RESULTS Among the 257 patients, ILDs were detected via high-resolution computed tomography in 60 (23.3%) patients; of these, usual interstitial pneumonia (UIP) patterns and non-UIP patterns were seen in 25 (9.7%) and 35 (13.6%) patients, respectively. The degree of pulmonary emphysema was classified as none, mild and moderate and included 50 (19.5%), 162 (63.0%) and 45 (17.5%) patients, respectively. The 5-year overall survival, cancer-specific survival and relapse-free survival were 80.7%, 88.0% and 74.9%, respectively, during a median follow-up period of 50.5 months. In multivariate analysis, the presence of a UIP pattern was shown to be an independent risk factor for poor outcome. CONCLUSIONS The presence of a UIP-pattern ILD on high-resolution computed tomography images was shown to be a risk factor for poor outcome in patients with a smoking history who had undergone surgery for pathological Stage I non-small-cell lung cancer. Non-small-cell lung cancer, Interstitial lung disease, Pulmonary emphysema, Outcomes INTRODUCTION Small, node-negative, non-small-cell lung cancers (NSCLCs) have been increasingly detected using computed tomography (CT). In these cases, complete surgical resection is expected to result in a favourable outcome [1]. However, some patients have poor oncological outcomes, and several prognostic factors have been identified, such as visceral pleural invasion (VPI) and lymphovascular invasion. In addition, some patients have a poor outcome due to comorbid pulmonary disease [2, 3]. Coexisting pulmonary disease may also affect the treatment strategy for NSCLC. For example, a limited resection and modified lymph node dissection might be selected as the surgical procedure, and the choice of chemotherapeutic agents for recurrent disease after surgery may be limited. Interstitial lung diseases (ILDs) and pulmonary emphysema are major pulmonary diseases observed in patients with lung cancer. ILDs are associated with an increased risk of lung cancer [4, 5]. Idiopathic pulmonary fibrosis (IPF), a progressive ILD of unknown aetiology, is a life-threatening disease with few treatment options. The median survival of patients with IPF was reported to be 2–4 years [6, 7]. In addition to chronic progression, ILDs are characterized by acute exacerbations, which can occur in the postoperative setting, that substantially increase the risk of mortality [8]. Recently, a nation-wide investigation in Japan revealed a low rate of post-surgical survival in patients with lung cancer at each tumour, node and metastasis (TNM) stage and coexisting ILD. Eventually, half of these patients died due to lung cancer [9]. In addition, limited resection, including wedge resection and segmentectomy, was shown to increase mortality due to cancer in pathological Stage IA (sixth TNM) patients [9]. Based on these results, it appears that the risk of unfavourable outcome due to cancer is higher in patients with lung cancer and coexisting ILDs. Cigarette smoking causes chronic obstructive pulmonary disease (COPD) including pulmonary emphysema and lung cancer [10, 11]. Patients with lung cancer and pulmonary emphysema, as diagnosed using CT, have lower survival when compared with patients without emphysema [12, 13]. Interestingly, COPD itself, as defined by pulmonary function testing [14], does not impact mortality in smokers with NSCLC [2]. A recent meta-analysis revealed that the presence of CT-defined pulmonary emphysema has more influence on cancer outcome than spirometry-defined COPD [15]. Hence, a detailed assessment of pulmonary emphysema on pre-operative CT may help determine prognosis in patients with NSCLC. In this study, we retrospectively reviewed the clinical data of patients with a smoking history who had undergone surgery for pathological Stage I NSCLC to determine the impact of coexisting pulmonary diseases on prognostic outcome. PATIENTS AND METHODS Study population In our institute, we routinely obtained written informed consent from every patient before surgery to allow the use of clinical data in future analyses. This retrospective study protocol was approved by our institutional review board (approved ID: YUMC 28-4). Medical records and chest high-resolution computed tomography (HRCT) images of patients with a history of smoking who underwent surgical treatment for pathological Stage I NSCLC from January 2009 to December 2014, when HRCT data were available at our hospital, were retrospectively reviewed. TNM classification stages were rearranged according to the eighth edition of the TNM classification [16]. Histological type was determined according to the classification of the World Health Organization (WHO) [17]. Patients who had been treated for malignant diseases within the previous 5 years, patients who had received preoperative chemotherapy or radiotherapy and those with a history of pulmonary resection were excluded from the analysis. Patients with positive or unclear tumour margin were excluded from the study, leaving 257 patients in the final analysis (Fig. 1). Figure 1: View largeDownload slide Patient selection diagram. NSCLC: non-small-cell lung cancer. Figure 1: View largeDownload slide Patient selection diagram. NSCLC: non-small-cell lung cancer. Assessment of interstitial lung diseases using high-resolution computed tomography Chest CT scans were performed using a 64-row detector CT scanner (Aquilion 64, Toshiba Medical Systems, Japan) within 1 month of surgery. Scans were performed on patients in the supine position during full inspiration without intravenous contrast materials. Coexistence of radiological ILD [usual interstitial pneumonia (UIP) versus non-UIP pattern] was evaluated by 2 radiologists with more than 10 years of experience in chest CT interpretation, in accordance with the ATS/ERS/Japanese Respiratory Society/Latin American Thoracic Association Statement [7]. Decisions regarding ILD features were determined by consensus. Emphysema quantification and scoring HRCT images for 3D CT were reconstructed with 2-mm-thick slices. Using image analysis software (Synapse Vincent ver. 4.4, Fujifilm Medical, Tokyo, Japan), the degree of emphysema was semiautomatically quantified and scored. Briefly, 3D-reconstructed bilateral lung parenchyma was divided into 3 segments using horizontal lines at the top of the aortic arch, the carina and the diaphragm. In each segment, the percentage of low-attenuation area (LAA) was calculated by the software and scored according to the Goddard classification [18] as follows: (i) 0–5%; (ii) 6–25%; (iii) 26–50%; (iv) 51–75% and (v) >76%. The low-attenuation threshold was −950 HU [19]. The degree of emphysema was determined based on the sum of all 6 segments as follows: 0, none; 1–7, mild; 8–15, moderate and 16–24, severe. Spirometry For all patients, the forced expiratory volume in 1 s (FEV1), the vital capacity and the forced vital capacity were measured preoperatively by spirometry. Airflow limitation severity in COPD (FEV1/forced vital capacity <0.7) was classified based on the global initiative for chronic obstructive lung disease (GOLD) 2017 recommendations: GOLD 1, mild (FEV1 ≥80% predicted); GOLD 2, moderate (FEV1 ≥50% and <80% predicted); GOLD 3, severe (FEV1 ≥30% and <50% predicted) and GOLD 4, very severe (FEV1 <30% predicted) [20]. Patient follow-up and data collection All patients were followed up postoperatively by routine physical examination and imaging studies including chest or systemic CT scan with or without enhancement every 6–12 months for the first 2 years and then plain CT annually. Overall survival (OS) time was defined as the time from operation to death or last follow-up. Cancer-specific survival (CSS) time was defined as the time from operation to death due to lung cancer or last follow-up. Relapse-free survival (RFS) time was defined as the time from operation to proven detection of recurrence or metastases. Local relapse was defined as recurrent diseases at the primary site or in lymphatic drainage areas either hilar or mediastinal within the ipsilateral thoracic cavity [21]. Statistical analyses Cohen’s kappa coefficient was used to determine interobserver agreement. The impact of clinicopathological factors on OS, CSS and RFS was evaluated using the Kaplan–Meier analyses and log-rank tests with 95% confidence intervals. The Cox proportional hazards models were also employed to evaluate factors predictive of survival. All tests of significance were 2-sided, and P-values <0.05 were considered statistically significant. All statistical analyses were conducted using the SPSS statistics software (version 24; IBM SPSS, Chicago, IL, USA). RESULTS Patient characteristics Patient characteristics are summarized in Table 1. Most of the patients were men, and one-third of the patients were current smokers. Open thoracotomy was performed in 74 patients and video-assisted thoracic surgery in 183 patients. Limited resection was generally selected for patients with compromised cardiopulmonary reserve. Wide-wedge resection and segmentectomy were performed in 27 (10.5%) patients. Among these patients, 4 patients underwent wide-wedge resection for subcentimetre tumours, and 11 patients underwent segmentectomy for tumours that were believed to be non-invasive. Ultimately, 15 (5.8%) patients underwent intended limited resection and 39 (15.2%) underwent palliative limited resection. Table 1: Clinicopathological characteristics Characteristics  n (%)  Total cases  257  Age (years), mean (SD)  69.4 (9.1)   ≥75  82 (31.9)  Gender     Male  223 (86.8)  Smoking status     Current  72 (28.0)   Former  185 (72.0)  Pathological T     T1mi  6 (2.3)   T1a  25 (9.7)   T1b  59 (23.0)   T1c  66 (25.7)   T2a  101 (39.3)  ILDs on HRCT image     UIP pattern  25 (9.7)   Non-UIP pattern  35 (13.6)   None  197 (76.7)  Degree of emphysema     None  50 (19.5)   Mild  162 (63.0)   Moderate  45 (17.5)  %VC     <80  25 (9.7)  FEV1.0%     <70  98 (38.1)   GOLD 1  44 (17.1)   GOLD 2  44 (17.1)   GOLD 3  9 (3.5)   GOLD 4  1 (0.4)  Operation     Wide wedge  27 (10.5)   Segmentectomy  27 (10.5)   Lobectomy  202 (78.6)   Pneumonectomy  1 (0.4)  Pathological stage     IA1  31 (12.1)   IA2  59 (23.0)   IA3  66 (25.7)   IB  101 (39.3)  VPI     PL0  192 (74.7)   PL1  50 (19.5)   PL2  11 (4.3)   PL3  4 (1.5)  Lymphatic invasion     Ly0  214 (83.3)   Ly1  43 (16.7)  Vascular invasion     V0  188 (73.2)   V1  69 (26.8)  Characteristics  n (%)  Total cases  257  Age (years), mean (SD)  69.4 (9.1)   ≥75  82 (31.9)  Gender     Male  223 (86.8)  Smoking status     Current  72 (28.0)   Former  185 (72.0)  Pathological T     T1mi  6 (2.3)   T1a  25 (9.7)   T1b  59 (23.0)   T1c  66 (25.7)   T2a  101 (39.3)  ILDs on HRCT image     UIP pattern  25 (9.7)   Non-UIP pattern  35 (13.6)   None  197 (76.7)  Degree of emphysema     None  50 (19.5)   Mild  162 (63.0)   Moderate  45 (17.5)  %VC     <80  25 (9.7)  FEV1.0%     <70  98 (38.1)   GOLD 1  44 (17.1)   GOLD 2  44 (17.1)   GOLD 3  9 (3.5)   GOLD 4  1 (0.4)  Operation     Wide wedge  27 (10.5)   Segmentectomy  27 (10.5)   Lobectomy  202 (78.6)   Pneumonectomy  1 (0.4)  Pathological stage     IA1  31 (12.1)   IA2  59 (23.0)   IA3  66 (25.7)   IB  101 (39.3)  VPI     PL0  192 (74.7)   PL1  50 (19.5)   PL2  11 (4.3)   PL3  4 (1.5)  Lymphatic invasion     Ly0  214 (83.3)   Ly1  43 (16.7)  Vascular invasion     V0  188 (73.2)   V1  69 (26.8)  FEV1.0: forced expiratory volume in 1 s; GOLD: global initiation for chronic obstructive lung disease; HRCT: high-resolution computed tomography; ILD: interstitial lung disease; Ly: lymphatic invasion; SD: standard deviation; UIP: usual interstitial pneumonia; V: vascular invasion; VC: vital capacity; VPI: visceral pleural invasion. Table 1: Clinicopathological characteristics Characteristics  n (%)  Total cases  257  Age (years), mean (SD)  69.4 (9.1)   ≥75  82 (31.9)  Gender     Male  223 (86.8)  Smoking status     Current  72 (28.0)   Former  185 (72.0)  Pathological T     T1mi  6 (2.3)   T1a  25 (9.7)   T1b  59 (23.0)   T1c  66 (25.7)   T2a  101 (39.3)  ILDs on HRCT image     UIP pattern  25 (9.7)   Non-UIP pattern  35 (13.6)   None  197 (76.7)  Degree of emphysema     None  50 (19.5)   Mild  162 (63.0)   Moderate  45 (17.5)  %VC     <80  25 (9.7)  FEV1.0%     <70  98 (38.1)   GOLD 1  44 (17.1)   GOLD 2  44 (17.1)   GOLD 3  9 (3.5)   GOLD 4  1 (0.4)  Operation     Wide wedge  27 (10.5)   Segmentectomy  27 (10.5)   Lobectomy  202 (78.6)   Pneumonectomy  1 (0.4)  Pathological stage     IA1  31 (12.1)   IA2  59 (23.0)   IA3  66 (25.7)   IB  101 (39.3)  VPI     PL0  192 (74.7)   PL1  50 (19.5)   PL2  11 (4.3)   PL3  4 (1.5)  Lymphatic invasion     Ly0  214 (83.3)   Ly1  43 (16.7)  Vascular invasion     V0  188 (73.2)   V1  69 (26.8)  Characteristics  n (%)  Total cases  257  Age (years), mean (SD)  69.4 (9.1)   ≥75  82 (31.9)  Gender     Male  223 (86.8)  Smoking status     Current  72 (28.0)   Former  185 (72.0)  Pathological T     T1mi  6 (2.3)   T1a  25 (9.7)   T1b  59 (23.0)   T1c  66 (25.7)   T2a  101 (39.3)  ILDs on HRCT image     UIP pattern  25 (9.7)   Non-UIP pattern  35 (13.6)   None  197 (76.7)  Degree of emphysema     None  50 (19.5)   Mild  162 (63.0)   Moderate  45 (17.5)  %VC     <80  25 (9.7)  FEV1.0%     <70  98 (38.1)   GOLD 1  44 (17.1)   GOLD 2  44 (17.1)   GOLD 3  9 (3.5)   GOLD 4  1 (0.4)  Operation     Wide wedge  27 (10.5)   Segmentectomy  27 (10.5)   Lobectomy  202 (78.6)   Pneumonectomy  1 (0.4)  Pathological stage     IA1  31 (12.1)   IA2  59 (23.0)   IA3  66 (25.7)   IB  101 (39.3)  VPI     PL0  192 (74.7)   PL1  50 (19.5)   PL2  11 (4.3)   PL3  4 (1.5)  Lymphatic invasion     Ly0  214 (83.3)   Ly1  43 (16.7)  Vascular invasion     V0  188 (73.2)   V1  69 (26.8)  FEV1.0: forced expiratory volume in 1 s; GOLD: global initiation for chronic obstructive lung disease; HRCT: high-resolution computed tomography; ILD: interstitial lung disease; Ly: lymphatic invasion; SD: standard deviation; UIP: usual interstitial pneumonia; V: vascular invasion; VC: vital capacity; VPI: visceral pleural invasion. Coexisting pulmonary diseases Among the 257 study patients, coexisting ILDs were observed in 60 (23.3%) patients, including UIP pattern in 25 (9.7%) and non-UIP pattern in 35 (13.6%). There was substantial interobserver agreement (κ = 0.7). The degree of emphysema, which was determined based on the HRCT image, was mild in 162 (63.0%) patients and moderate in 45 (17.5%) patients. Fifty (19.5%) patients were diagnosed with no pulmonary emphysema, and no patient was diagnosed with severe emphysema. Restrictive ventilatory impairment (%vital capacity < 80) was detected in 25 (9.7%) patients. Obstructive ventilatory impairment (FEV1/forced vital capacity < 0.7) was detected in 98 (38.1%) patients, including GOLD 1 in 44 (17.1%), GOLD 2 in 44 (17.1%), GOLD 3 in 9 (3.5%) and GOLD 4 in 1 (0.4%). Outcome The 5-year OS, CSS and RFS were 80.7%, 88.0% and 74.9%, respectively [median follow-up period: 50.5 (3–105) months]. Because the survival curves of patients with UIP-pattern ILD on high-resolution computed tomograph were distinctly worse when compared with those with non-UIP-pattern ILD and those without ILD (Fig. 2), the following analyses were performed as a UIP pattern on high-resolution computed tomograph versus all others. The results of the univariate analysis for survival are summarized in Table 2. In the multivariate analysis, older age, the presence of a UIP pattern on high-resolution computed tomograph and restrictive ventilatory impairment were determined as independent risk factors for poor OS. In addition to these 3 factors, positive VPI and pathological Stage IB were determined as independent risk factors for poor CSS and RFS, respectively (Table 3). Notably, pulmonary emphysema determined based on either HRCT or spirometry was not observed to be an independent risk factor for poor outcome (Fig. 3). Table 2: Univariate analysis Variables  5-Year OS (%)  P-value  5-Year CSS (%)  P-value  5-Year RFS (%)  P-value  Total cases  80.7  88.0  74.9  Age (years)     <75  87.5  <0.001  91.1  0.016  78.9  0.007   ≥75  66.1  80.9  66.4  Gender     Female  92.0  0.058  92.0  0.285  88.8  0.070   Male  79.0  87.4  72.7  UIP pattern on HRCT image     Yes  22.0  <0.001  34.1  <0.001  30.2  <0.001   No  87.2  92.8  79.6  Degree of emphysema     Moderate  66.0  0.005  75.9  0.015  65.8  0.075   Mild and none  83.9  90.5  76.9  %VC     <80  51.4  <0.001  74.0  0.002  39.1  <0.001   ≥80  83.6  89.2  78.5  FEV1.0%     <70  75.0  0.205  84.7  0.517  67.1  0.076   ≥70  84.1  90.1  80.1  Severity of COPD     GOLD 2 or more  74.8  0.318  67.9  0.308  83.4  0.533   Others  82.5  76.9  89.4  Tumour location     Upper or middle lobe  85.4  0.036  91.3  0.137  78.9  0.057   Lower lobe  72.5  81.3  67.4  Operation     Wide wedge  65.6  0.046  80.1  0.207  69.4  0.552   Anatomical  82.9  89.0  75.5  Histology     Adenocarcinoma  85.7  0.011  91.8  0.022  77.0  0.140   Non-adenocarcinoma  73.3  82.2  71.5  pStage     IA  84.9  0.024  93.4  0.001  80.2  0.017   IB  74.4  79.8  66.6  VPI     Negative  83.6  0.014  92.7  <0.001  77.9  0.012   Positive  72.4  74.9  65.7  Lymphatic invasion     Negative  79.8  0.807  87.7  0.860  75.0  0.737   Positive  85.2  89.4  73.4  Vascular invasion               Negative  81.6  0.284  90.2  0.040  75.9  0.352   Positive  78.5    82.4    71.9    Variables  5-Year OS (%)  P-value  5-Year CSS (%)  P-value  5-Year RFS (%)  P-value  Total cases  80.7  88.0  74.9  Age (years)     <75  87.5  <0.001  91.1  0.016  78.9  0.007   ≥75  66.1  80.9  66.4  Gender     Female  92.0  0.058  92.0  0.285  88.8  0.070   Male  79.0  87.4  72.7  UIP pattern on HRCT image     Yes  22.0  <0.001  34.1  <0.001  30.2  <0.001   No  87.2  92.8  79.6  Degree of emphysema     Moderate  66.0  0.005  75.9  0.015  65.8  0.075   Mild and none  83.9  90.5  76.9  %VC     <80  51.4  <0.001  74.0  0.002  39.1  <0.001   ≥80  83.6  89.2  78.5  FEV1.0%     <70  75.0  0.205  84.7  0.517  67.1  0.076   ≥70  84.1  90.1  80.1  Severity of COPD     GOLD 2 or more  74.8  0.318  67.9  0.308  83.4  0.533   Others  82.5  76.9  89.4  Tumour location     Upper or middle lobe  85.4  0.036  91.3  0.137  78.9  0.057   Lower lobe  72.5  81.3  67.4  Operation     Wide wedge  65.6  0.046  80.1  0.207  69.4  0.552   Anatomical  82.9  89.0  75.5  Histology     Adenocarcinoma  85.7  0.011  91.8  0.022  77.0  0.140   Non-adenocarcinoma  73.3  82.2  71.5  pStage     IA  84.9  0.024  93.4  0.001  80.2  0.017   IB  74.4  79.8  66.6  VPI     Negative  83.6  0.014  92.7  <0.001  77.9  0.012   Positive  72.4  74.9  65.7  Lymphatic invasion     Negative  79.8  0.807  87.7  0.860  75.0  0.737   Positive  85.2  89.4  73.4  Vascular invasion               Negative  81.6  0.284  90.2  0.040  75.9  0.352   Positive  78.5    82.4    71.9    COPD: chronic obstructive lung disease; CSS: cancer-specific survival; FEV1.0: forced expiratory volume in 1 s; GOLD: global initiation for chronic obstructive lung disease; HRCT: high-resolution computed tomography; OS: overall survival; RFS: relapse-free survival; UIP: usual interstitial pneumonia; VC: vital capacity; VPI: visceral pleural invasion. Table 2: Univariate analysis Variables  5-Year OS (%)  P-value  5-Year CSS (%)  P-value  5-Year RFS (%)  P-value  Total cases  80.7  88.0  74.9  Age (years)     <75  87.5  <0.001  91.1  0.016  78.9  0.007   ≥75  66.1  80.9  66.4  Gender     Female  92.0  0.058  92.0  0.285  88.8  0.070   Male  79.0  87.4  72.7  UIP pattern on HRCT image     Yes  22.0  <0.001  34.1  <0.001  30.2  <0.001   No  87.2  92.8  79.6  Degree of emphysema     Moderate  66.0  0.005  75.9  0.015  65.8  0.075   Mild and none  83.9  90.5  76.9  %VC     <80  51.4  <0.001  74.0  0.002  39.1  <0.001   ≥80  83.6  89.2  78.5  FEV1.0%     <70  75.0  0.205  84.7  0.517  67.1  0.076   ≥70  84.1  90.1  80.1  Severity of COPD     GOLD 2 or more  74.8  0.318  67.9  0.308  83.4  0.533   Others  82.5  76.9  89.4  Tumour location     Upper or middle lobe  85.4  0.036  91.3  0.137  78.9  0.057   Lower lobe  72.5  81.3  67.4  Operation     Wide wedge  65.6  0.046  80.1  0.207  69.4  0.552   Anatomical  82.9  89.0  75.5  Histology     Adenocarcinoma  85.7  0.011  91.8  0.022  77.0  0.140   Non-adenocarcinoma  73.3  82.2  71.5  pStage     IA  84.9  0.024  93.4  0.001  80.2  0.017   IB  74.4  79.8  66.6  VPI     Negative  83.6  0.014  92.7  <0.001  77.9  0.012   Positive  72.4  74.9  65.7  Lymphatic invasion     Negative  79.8  0.807  87.7  0.860  75.0  0.737   Positive  85.2  89.4  73.4  Vascular invasion               Negative  81.6  0.284  90.2  0.040  75.9  0.352   Positive  78.5    82.4    71.9    Variables  5-Year OS (%)  P-value  5-Year CSS (%)  P-value  5-Year RFS (%)  P-value  Total cases  80.7  88.0  74.9  Age (years)     <75  87.5  <0.001  91.1  0.016  78.9  0.007   ≥75  66.1  80.9  66.4  Gender     Female  92.0  0.058  92.0  0.285  88.8  0.070   Male  79.0  87.4  72.7  UIP pattern on HRCT image     Yes  22.0  <0.001  34.1  <0.001  30.2  <0.001   No  87.2  92.8  79.6  Degree of emphysema     Moderate  66.0  0.005  75.9  0.015  65.8  0.075   Mild and none  83.9  90.5  76.9  %VC     <80  51.4  <0.001  74.0  0.002  39.1  <0.001   ≥80  83.6  89.2  78.5  FEV1.0%     <70  75.0  0.205  84.7  0.517  67.1  0.076   ≥70  84.1  90.1  80.1  Severity of COPD     GOLD 2 or more  74.8  0.318  67.9  0.308  83.4  0.533   Others  82.5  76.9  89.4  Tumour location     Upper or middle lobe  85.4  0.036  91.3  0.137  78.9  0.057   Lower lobe  72.5  81.3  67.4  Operation     Wide wedge  65.6  0.046  80.1  0.207  69.4  0.552   Anatomical  82.9  89.0  75.5  Histology     Adenocarcinoma  85.7  0.011  91.8  0.022  77.0  0.140   Non-adenocarcinoma  73.3  82.2  71.5  pStage     IA  84.9  0.024  93.4  0.001  80.2  0.017   IB  74.4  79.8  66.6  VPI     Negative  83.6  0.014  92.7  <0.001  77.9  0.012   Positive  72.4  74.9  65.7  Lymphatic invasion     Negative  79.8  0.807  87.7  0.860  75.0  0.737   Positive  85.2  89.4  73.4  Vascular invasion               Negative  81.6  0.284  90.2  0.040  75.9  0.352   Positive  78.5    82.4    71.9    COPD: chronic obstructive lung disease; CSS: cancer-specific survival; FEV1.0: forced expiratory volume in 1 s; GOLD: global initiation for chronic obstructive lung disease; HRCT: high-resolution computed tomography; OS: overall survival; RFS: relapse-free survival; UIP: usual interstitial pneumonia; VC: vital capacity; VPI: visceral pleural invasion. Table 3: Multivariate analysis Risk factor  OS   CSS   RFS   HR (95% CI)  P-value  HR (95% CI)  P-value  HR (95% CI)  P-value  Age (+1 year)  1.08 (1.04–1.13)  <0.001  1.07 (1.02–1.13)  0.010  1.04 (1.00–1.07)  0.024  UIP pattern on HRCT image  6.33 (3.26–12.3)  <0.001  7.30 (3.10–16.9)  <0.001  4.39 (2.37–8.13)  <0.001  %VC <80  4.08 (2.04–8.20)  <0.001  2.81 (1.06–7.46)  0.038  3.95 (2.12–7.35)  <0.001  Positive VPI      4.02 (1.82–8.85)  0.001      pStage IB          2.02 (1.21–3.38)  0.007  Risk factor  OS   CSS   RFS   HR (95% CI)  P-value  HR (95% CI)  P-value  HR (95% CI)  P-value  Age (+1 year)  1.08 (1.04–1.13)  <0.001  1.07 (1.02–1.13)  0.010  1.04 (1.00–1.07)  0.024  UIP pattern on HRCT image  6.33 (3.26–12.3)  <0.001  7.30 (3.10–16.9)  <0.001  4.39 (2.37–8.13)  <0.001  %VC <80  4.08 (2.04–8.20)  <0.001  2.81 (1.06–7.46)  0.038  3.95 (2.12–7.35)  <0.001  Positive VPI      4.02 (1.82–8.85)  0.001      pStage IB          2.02 (1.21–3.38)  0.007  CI: confidence interval; CSS: cancer-specific survival; HR: hazard ratio; HRCT: high-resolution computed tomography; OS: overall survival; RFS: relapse-free survival; UIP: usual interstitial pneumonia; VC: vital capacity; VPI: visceral pleural invasion. Table 3: Multivariate analysis Risk factor  OS   CSS   RFS   HR (95% CI)  P-value  HR (95% CI)  P-value  HR (95% CI)  P-value  Age (+1 year)  1.08 (1.04–1.13)  <0.001  1.07 (1.02–1.13)  0.010  1.04 (1.00–1.07)  0.024  UIP pattern on HRCT image  6.33 (3.26–12.3)  <0.001  7.30 (3.10–16.9)  <0.001  4.39 (2.37–8.13)  <0.001  %VC <80  4.08 (2.04–8.20)  <0.001  2.81 (1.06–7.46)  0.038  3.95 (2.12–7.35)  <0.001  Positive VPI      4.02 (1.82–8.85)  0.001      pStage IB          2.02 (1.21–3.38)  0.007  Risk factor  OS   CSS   RFS   HR (95% CI)  P-value  HR (95% CI)  P-value  HR (95% CI)  P-value  Age (+1 year)  1.08 (1.04–1.13)  <0.001  1.07 (1.02–1.13)  0.010  1.04 (1.00–1.07)  0.024  UIP pattern on HRCT image  6.33 (3.26–12.3)  <0.001  7.30 (3.10–16.9)  <0.001  4.39 (2.37–8.13)  <0.001  %VC <80  4.08 (2.04–8.20)  <0.001  2.81 (1.06–7.46)  0.038  3.95 (2.12–7.35)  <0.001  Positive VPI      4.02 (1.82–8.85)  0.001      pStage IB          2.02 (1.21–3.38)  0.007  CI: confidence interval; CSS: cancer-specific survival; HR: hazard ratio; HRCT: high-resolution computed tomography; OS: overall survival; RFS: relapse-free survival; UIP: usual interstitial pneumonia; VC: vital capacity; VPI: visceral pleural invasion. Figure 2: View largeDownload slide The Kaplan–Meier estimates for overall (A), cancer-specific (B) and relapse-free (C) survival based on the presence of interstitial lung diseases on high-resolution computed tomographs in patients with smoking history who underwent surgery for pStage I non-small-cell lung cancer. UIP: usual interstitial pneumonia. Figure 2: View largeDownload slide The Kaplan–Meier estimates for overall (A), cancer-specific (B) and relapse-free (C) survival based on the presence of interstitial lung diseases on high-resolution computed tomographs in patients with smoking history who underwent surgery for pStage I non-small-cell lung cancer. UIP: usual interstitial pneumonia. Figure 3: View largeDownload slide The Kaplan–Meier estimates for overall (A), cancer-specific (B) and relapse-free (C) survival based on the degree of emphysema in patients with smoking history who underwent surgery for pStage I non-small-cell lung cancer. Figure 3: View largeDownload slide The Kaplan–Meier estimates for overall (A), cancer-specific (B) and relapse-free (C) survival based on the degree of emphysema in patients with smoking history who underwent surgery for pStage I non-small-cell lung cancer. Tumour recurrence was observed in 46 (17.9%) patients. Of those, local recurrence alone was observed in 17 patients, distant recurrence alone was observed in 20 patients and both local and distant recurrences were observed in 2 patients. Seven patients had unknown recurrence sites due to missing data. Among the 25 patients with a UIP pattern on high-resolution computed tomograph, 12 (48.0%) patients had a recurrence during the follow-up period. Local recurrence alone was observed in 6 patients, and distant recurrence alone was observed in 4 patients. Two patients had unknown recurrence sites due to missing data. Among the patients with local recurrence, lobectomy was performed in 5 patients and wide-wedge resection was performed in 1. Acute exacerbation of IPF occurred in 2 (3.3% of patients with ILDs on high-resolution computed tomograph) patients who had a UIP pattern on high-resolution computed tomograph and had undergone lobectomy at 2 and 3 months after surgery. The risk scores for acute exacerbation [22] were 14 and 13, respectively. Both patients chose to pursue limited medical care and eventually died. DISCUSSION In this study, we found that the presence of a UIP pattern on high-resolution computed tomograph and restrictive ventilatory impairment were independent risk factors for poor outcome in patients with a smoking history who had undergone surgery for pathological Stage I NSCLC. Pulmonary emphysema was associated with poor outcome in the univariate analysis; however, this comorbidity was not shown to be a risk factor in the multivariate analysis. Patients with both lung cancer and ILD are known to have unfavourable outcomes [23, 24]. A multicentre investigation [9] showed 5-year survivals of 59% and 42% for pTNM (sixth edition of the TNM classification stages) IA and IB patients, respectively. Among these patients, cancer-related death was the main cause of mortality, even in patients with Stage IA disease [9]. Hata et al. [25] reported that in patients with lung cancer and concomitant ILD, the incidence of VPI and malignant pleurisy detected at the time of thoracotomy was significantly higher than in patients without ILD. They concluded that these characteristics contribute to unfavourable outcome after surgery. Similarly, we found that VPI was frequently observed in patients with a UIP-pattern ILD on high-resolution computed tomograph (data not shown) and was a risk factor for poor CSS. The possibility that ILDs promote tumour invasiveness should be pursued in the future studies. The degree of pulmonary emphysema can be accurately assessed by quantification of LAA using CT. Haruna et al. [26] reported that a quantitative evaluation of emphysematous changes based on LAA calculation using CT could predict respiratory mortality in patients with pulmonary emphysema. In this study, we used a quantitative evaluation of LAA to determine the degree of pulmonary emphysema. We found that pulmonary emphysema was related to poor outcome but was not an independent risk factor in the multivariate analysis. These results suggest that the degree of pulmonary emphysema may have prognostic influence, but the presence of a UIP-pattern ILD is more predictive of poor outcome. It should be noted that some previous reports [2, 12, 13] investigating the prognostic importance of pulmonary emphysema did not include ILDs in the analysis. In fact, when we excluded ILDs in our analysis, moderate pulmonary emphysema became an independent risk factor for poor OS and CSS (data not shown). We should also note that in this study, as many as 40% of patients had COPD. As Johannessen et al. [27] pointed out, the risk of mortality based on the degree of pulmonary emphysema would be assessed in a cohort where most patients have mild or no COPD, such as a community-based study. The incidence of tumour recurrence has been reported [28] to be approximately 20% in Stage I NSCLC after curative resection. Considering the fact that half of the patients with Stage I lung cancer and ILD died due to lung cancer [9], the recurrence rate in those patients was higher than that of the general cohort. Similarly, we found that the recurrence rate in patients with a UIP-pattern ILD was as high as 48.0%. In our study, limited resection including wide-wedge resection was not always selected for patients with a UIP-pattern ILD who subsequently developed recurrence, suggesting that it may be difficult to perform curative resection in patients who have potentially curative lung cancer and a UIP pattern on high-resolution computed tomograph. Limitations A major limitation of this study is that it was a single institution, retrospective analysis based on a small-sized cohort. In addition, treatment strategies were different depending on the patient. For example, chemotherapeutic agents were not used in patients with ILD to avoid ILD progression [29], and this may worsen cancer-related prognosis. Although we included only patients with pathological Stage I NSCLC to reduce potential bias due to the use of adjuvant chemotherapy, the difference in treatment strategies, including surgical strategies, may substantially influence outcome. The optimal surgical procedure for resectable NSCLC in patients with ILD has not yet been established and will likely depend on tumour stage and ILD subtype. Recently, Tsutani et al. [30] reported the feasibility of sublobar resection for clinical Stage I NSCLC with ILD, with regard to short- and long-term outcomes, when compared with lobar resection. This issue should be pursued in future prospective studies. We should also note that a ‘UIP pattern’ on high-resolution computed tomograph does not always equate to a pathological UIP-pattern IPF. Although a pathological diagnosis of ILD would be important for prognostic purposes, it could not be obtained in all the patients, because the surgical specimens were not always within the ILD region. CONCLUSION In conclusion, the presence of a UIP-pattern ILD on high-resolution computed tomograph was shown to be an independent risk factor for poor outcome in patients with a smoking history who underwent surgery for pathological Stage I NSCLC. 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Journal

Interactive CardioVascular and Thoracic SurgeryOxford University Press

Published: Jan 31, 2018

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