Interstitial Lung Disease and Partial Resection Are Poor Prognostic Factors for pStage IA NSCLC: a Retrospective Study


 Introduction: The prognostic factors in patients who underwent pulmonary resection with early stage non-small cell lung cancer (NSCLC) have not been elucidated.Materials and methods: Clinical data of 540 patients with pathological stage IA NSCLC were analyzed. Patient factors such as sex, age, comorbidities, carcinoembryonic antigen (CEA), smoking history, and operative aspects such as operative approach and operative procedures were collected and analyzed.Results: There were significant prognostic differences according to the interstitial lung disease (p<0.0001), CEA (p = 0.007), and partial resection (p = 0.002) in the relapse-free survival (RFS). There were significant prognostic differences according to the interstitial lung disease (p = 0.0015), CEA (p < 0.0001), and smoking history (p = 0.0003) in the overall survival (OS). Interstitial lung disease (hazard ratio [HR]: 7.725, p = 0.003), CEA (HR: 1.923, p = 0.045), and operative procedure (HR: 2.086, p = 0.025) were risk factors for RFS in a multivariate analysis. Smoking history (HR: 2.539, p = 0.002) and CEA (HR: 2.464, p = 0.002) were risk factors for OS in a multivariate analysis.Conclusion: Interstitial lung disease, CEA, and operative procedure were risk factors for RFS, while smoking history and CEA were risk factors for OS.


Introduction
Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for more than 80% of all cases [1]. Although the standard treatment for early stage NSCLC is lobectomy combined with systematic lymph node dissection, sublobar resection for early stage NSCLC leads toward a more favorable prognosis than lobectomy [2,3].
Video-assisted thoracic surgery (VATS) for patients with NSCLC has been widely adopted, and various studies have reported the advantages of this approach [4][5][6][7]. These reports revealed that VATS is associated with minimal pain, shorter hospital stay, less reduction in the in ammatory immune response, and maintenance of postoperative respiratory function when compared with thoracotomy. However, the relationship between the prognosis and operative approaches such as VATS in NSCLC patients who underwent pulmonary resection has not been elucidated.
In the present study, we retrospectively evaluated the prognostic factors in pathological stage IA NCSLC patients who underwent pulmonary resection.

Operative factors
The operative approach was divided into four categories: complete VATS (C-VATS, surgery performed only to provide a monitoring view), hybrid VATS (H-VATS, surgery combined with direct vision without rib spreading), robot-assisted thoracic surgery (RATS), and open thoracotomy. The operative procedure was strati ed into three categories: partial resection, segmentectomy, and lobectomy.

Postoperative complications
Postoperative complications were categorized into ve grades according to the Clavien-Dindo classi cation system [15]. The Clavien-Dindo classi cation was established in 1992. It is a simple and feasible grading system for all types of postoperative complications [16]. In 2004, it was modi ed to allow grading of life-threatening complications and long-term disability caused by a complication [17].
This revised version has de ned ve grades of severity with subgrades (grades I, II, IIIa, IIIb, IVa, IVb, and V), and the su x "d" (for "disability") is used to denote any postoperative impairment. This modi ed version of the Clavien-Dindo classi cation has been widely used in clinical practice.

Statistical analyses
We used Pearson's chi-square test of independence to compare the frequencies of the variables.
Cumulative survival was calculated by the Kaplan-Meier method and survival curves were compared using the Logrank test. Risk factors associated with postoperative complications were analyzed using logistic regression analysis. All statistical analyzes were performed on both sides and the statistical signi cance was set to p < 0.05. Statistical analysis was performed using JMP software program version 13.2 (SAS Institute Inc., Cary, NC, USA).
This study was conducted in accordance with the principles of the Declaration of Helsinki. The institutional review committee of Kanazawa Medical University approved the protocol (approval number: I392), and all patients gave written informed consent

Patient characteristics
The clinicopathological characteristics of the 540 NSCLC patients with pathological stage IA are listed in Table 1. Among these, 310 were men and the median age was 70.6 years. The median Brinkman index was 400. Altogether, 310 patients had comorbidities including 7 with interstitial lung disease, 107 with malignant disease, and 35 with angina pectoris. The median CEA was 3.0 ng/mL. The median %VC was 100.7% and the median FEV 1 % was 73.9%. The pulmonary lobes resected for NSCLC included the right upper lobe in 169 patients, right middle lobe in 33, right lower lobe in 118, left upper lobe in 130, and left lower lobe in 94 patients.

Univariate and multivariate analysis
Page 7/17 The relationship between clinicopathological patient characteristics or operative factors and RFS was analyzed (

Discussion
In the present study, we analyzed the prognostic factors for inpatients who underwent pulmonary resection for pathological stage IA NSCLC. This study demonstrated that interstitial lung disease, CEA, and partial resection were signi cant prognostic factors for RFS, whereas CEA and smoking history were signi cant prognostic factors for OS. Although survival was similar for patients treated with limited resection to that of patients receiving lobectomy in some reports [19][20], partial resection was reported as the risk factor for locoregional recurrence in other reports [8, [21][22][23]. Because these reports showed a trend toward a higher locoregional recurrence rate in patients who underwent wedge resection compared with segmentectomy [8, [21][22][23], segmentectomy should be the more suitable surgical procedure in patients being considered for sublobar resection.
We previously reported that the presence of CPFE was a statistically signi cant predictor of recurrence for patients with clinical stage I NSCLC [12]. Furthermore, lung cancer patients with idiopathic pulmonary brosis (IPF) showed a statistically signi cant worse mortality rate compared to lung cancer patients without IPF [24]. IPF is the most frequent and severe type of idiopathic interstitial pneumonia and has a median survival of approximately 3 years after diagnosis [25]. In the treatment of lung cancer patients with IPF, physicians are reluctant to treat lung cancer because of the poor prognosis [26]. GAP (gender [G], age [A], and two lung physiology variables [P]) staging system has been used to predict the mortality and the timing of lung transplantation in IPF patients [27]. Although bene cial treatment modalities were not found at GAP stage II/III, active therapies such as surgery for lung cancer patients with IPF in GAP stage I are recommended in the previous study [28]. Therefore, the bene t of surgery for NSCLC patients with interstitial lung disease should be carefully evaluated by using the GAP staging system.
Reportedly, VATS is associated with minimal pain, less reduction in the in ammatory immune response, and maintenance of postoperative respiratory function when compared with thoracotomy. Therefore, VATS is considered as a less invasive procedure [4][5][6][7]. However, the relationship between prognosis and operative approaches such as VATS or RATS in NSCLC patients who have undergone pulmonary resection has not been elucidated. Our previous study revealed that operative invasiveness does not affect the prognosis of patients with NSCLC [29]. Because VATS and RATS were not prognostic factors in the present study, the operative approach therefore does not in uence the prognosis of NSCLC patients.
The present study has several limitations. First, the study was retrospective in nature and potentially involved unobserved cofounding and selection biases. Second, the present study was performed at a single institution, and the study population was relatively small.

Conclusions
Our ndings described the prognostic factors in pathological stage IA NCSLC patients who underwent pulmonary resection. This study revealed that interstitial lung disease, CEA, and operative procedure were risk factors for RFS while smoking history and CEA were risk factors for OS. These results thereby postulate that segmentectomy is a more suitable surgical procedure for patients who are being considered for sublobar resection. Furthermore, the bene t of surgery for NSCLC patients with interstitial lung disease should be carefully evaluated.

Declarations
Ethics approval and consent to participate The present study was conducted in accordance with the amended Declaration of Helsinki. The Institutional Review Boards of Kanazawa Medical University approved the protocol (approval number: I392), and written informed consent was obtained from all of the patients. Relapse-free survival for non-small cell lung cancer patients with pathological stage IA (a) Coexistence of interstitial lung disease group was signi cantly worse than the absent of interstitial lung disease group. (b) Positive of carcinoembryonic antigen group was signi cantly worse than negative of carcinoembryonic antigen group. (c) Partial resection group was signi cantly worse than segmentectomy or lobectomy group.