We enrolled patients who underwent pulmonary resection for primary NSCLC at the Asan Medical Center, Seoul, Korea, between January 2004 and December 2018. Patients who underwent wedge resection or surgery for diagnostic intent were excluded from the study. In addition, patients who received neoadjuvant therapy, which is thought to have different risks related to surgery, were excluded. Patients with any other concurrent malignancy were also excluded when analyzing the long-term survival outcomes. The pathological staging of NSCLC was based on the recommendations by the 8th edition American Joint Committee on Cancer in a retrospective manner.6 Tumor histology was categorized according to the World Health Organization classification.7 Lobectomy with systematic lymph node dissection was adopted as a standard procedure for primary lung cancer; however, segmentectomy was performed in some old patients and those with borderline lung function and early-stage adenocarcinoma. Surgical resection was performed in patients with clinical stage I–IIIA, including N2 node metastasis. All patients were followed up either until death or the last follow-up date of the study (March 1, 2021).

Follow-up information of all the patients was obtained from the notes of the clinical follow-up, which was conducted every 3–6 months during the first 2 years after surgery and every 6–12 months thereafter. Chest computed tomography scans were performed at the time of clinical visits or at any time when disease recurrence was suspected. Treatment modalities and chemotherapeutic regimens in cases with relapse were determined at the discretion of the attending physician.

The residual pulmonary function was estimated as follows: it is assumed that the lungs in a normal individual have a total of 19 segments (right upper lobe: 3, right middle lobe: 2, right lower lobe: 5, left upper lobe: 3, lingula: 2, lower left lobe: 4 segments), each contributing equally to ventilation that is 1/19 (nineteenth part).8 Thus, the predicted postoperative forced expiratory volume in 1 second (ppoFEV1) and diffusing capacity of carbon monoxide (DLCO) were calculated as follows: preoperative FEV1 or DLCO × (19 segments – the number of segments to be removed during the surgery) ÷ 19. Cardiopulmonary complications fundamentally complied with the terminology of the ESTS and Society of Thoracic Surgeons, which included the following: prolonged air leak (lasting more than 7 days), airway stenosis, atelectasis, pneumonia, acute respiratory distress syndrome, bronchopleural fistula, pulmonary embolism, pulmonary edema, respiratory failure requiring reintubation, empyema, recurrent laryngeal nerve palsy, phrenic nerve palsy, chylothorax, postoperative bleeding, atrial arrhythmia, myocardial infarction, stroke, and acute renal failure.49 Extended resection was defined as follows: 1) chest wall resection, 2) Pancoast tumors, 3) resection of the atrium, superior vena cava, aorta, diaphragm, or vertebra, 4) bronchial sleeve resection, 5) pleuropneumonectomy, 6) sleeve pneumonectomies, or 7) intrapericardial pneumonectomy. Mortality was defined as death within 30 days after surgery or death occurring at any time during the same hospital stay. The overall survival (OS) was calculated as the time interval between the date of surgery and the date of death, which was determined by reviewing the patient records from the Korean National Security Death Index Database. Aggregate Eurolung1 (morbidity) and Eurolung2 (mortality) scoring systems were developed by assigning proportional weightages of the predictors estimates, which are listed in the Eurolung model,4 assigned a value of 1 to the smallest coefficient. Thus, the Eurolung1 score was calculated as a sum of the points based on the following variables: 1 point for age > 70 years and ppoFEV1 < 70%; 1.5 points for male sex and extended resection; and 2 points for open surgery (as opposed to minimally invasive surgery) (Table 1). For the Eurolung2 system, age > 70 years and ppoFEV1 < 70% were assigned 1 point; male sex, open surgery (as opposed to minimally invasive surgery), and body mass index (BMI) < 18.5 kg/m² were assigned 2.5 points; and pneumonectomy was assigned 3 points (Table 1).

Continuous variables are presented as means and standard deviations, and categorical variables are presented as frequencies and percentages. The normality of individual distributions of the parameters was assessed using the Shapiro–Wilk test. Student’s t-test or the Wilcoxon rank-sum test was used for the comparison of continuous variables between the two groups, and the χ² test or Fisher’s exact test was used for categorical variables between the two groups. The area under the receiver operating characteristic curve (AUC) is presented as a statistical indicator for quantifying the discrimination ability of the scoring system. The Hosmer–Lemeshow test for the goodness-of-fit was used for calibration of the logistic regression model.

To determine the long-term prognostic ability of the Eurolung2 scoring system, we conducted a survival analysis of patients who underwent complete resection for stage I, II, and III NSCLC. The Kaplan-Meier method was used to analyse OS, and their differences were assessed using the log-rank test. For multiple comparisons of the survival curves (≥ 3 curves), Bonferroni correction was applied to calculate the P values in the log-rank test. A Cox proportional-hazards model was used for the univariate and multivariate analyses to identify the prognostic ability of the Eurolung2 scoring system.

All statistical calculations were performed with R, version 4.0.2 (The R Foundation for Statistical Computing, Vienna, Austria), using the Survival, ggplot2, GGally, survminer, and rms packages. P < 0.05 was considered significant.

This retrospective study was approved by the Asan Medical Center Ethics Committee/Review Board, and this center waived the need for informed consent (approval No. 2021-0544).

The median follow-up period was 53.6 ± 35.9 months. The clinicopathological characteristics of the patients are summarized in Table 2. A total of 7,278 patients were enrolled in this study. There were 1,531 (21.0%) patients aged > 70 years and 159 (2.2%) patients with BMI < 18.5 kg/m². In addition, 3,659 patients had ppoFEV1 < 70%. Lobectomy was performed in 5,957 patients (81.8%), and video-assisted thoracoscopic surgery was performed in 4,646 patients (63.8%). In terms of the pathological stage, there were 3,999 (54.9%), 1,554 (21.4%), 1,560 (21.4%), and 159 (2.2%) patients with stage I, II, III, and IV disease, respectively.

Regarding cardiopulmonary complications, 687 (9.4%) patients had a cardiopulmonary event regardless of event grade, the details of which are summarized in Supplementary Table 1. Fifty-three (0.7%) patients died within 30 days after surgery or at any time during the same hospital stay. The rate of cardiopulmonary complications gradually increased with the increase in the Eurolung1 risk score (P < 0.001) (Fig. 1A). A similar trend was observed in the mortality rate (P < 0.001) (Fig. 1B). The AUC was 0.623 and 0.815 for the Eurolung1 and Eurolung2 scores, respectively (Fig. 2). The Hosmer–Lemeshow tests of the two models were not significant (P = 0.442 for the Eurolung1 and 0.390 for the Eurolung2 scoring system).

According to the Kaplan-Meier estimates, survival curves stratified by the Eurolung2 scoring system showed a stepwise deterioration of OS with the increase in risk scores (Fig. 3A). When the risk scores were grouped into four categories, each group had a significantly different prognosis (Fig. 3B). Subgroup analyses were performed for four categories of the Eurolung2 scoring system in patients with stage I, II, and III NSCLC (Fig. 4). Although the difference in survival between the patients with scores 3–5 and 5.5–6.5 was not significant in stages II and III, the Eurolung2 risk scoring system still showed a favorable discrimination ability in all the stages.

In accordance with the Cox proportional hazard analysis, the Eurolung2 scoring system, classified into four categories, was found to be a significant prognostic factor for OS even after adjusting for confounders such as tumor histology and pathological stage in patients who underwent complete resection (P < 0.001) (Table 3). In addition, the higher the risk score, the higher was the hazard ratio, indicating a gradual deterioration in the prognosis with an increase in the risk score (Table 3).