Factors associated with preserved pulmonary function in non-smallcell lung cancer patients after video-assisted thoracic surgery

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1 European Journal of Cardio-Thoracic Surgery 49 (2016) doi: /ejcts/ezv325 Advance Access publication 15 September 2015 ORIGINAL ARTICLE Cite this article as: Kim SJ, Ahn S, Lee YJ, Park JS, Cho Y-J, Cho S et al. Factors associated with preserved pulmonary function in non-small-cell lung cancer patients after video-assisted thoracic surgery. Eur J Cardiothorac Surg 2016;49: Factors associated with preserved pulmonary function in non-smallcell lung cancer patients after video-assisted thoracic surgery Se Joong Kim a, Soyeon Ahn b, Yeon Joo Lee a, Jong Sun Park a, Young-Jae Cho a, Sukki Cho c, Ho Il Yoon a, Kwhanmien Kim c, Jae Ho Lee a, Sanghoon Jheon c and Choon-Taek Lee a, * a Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea b Division of Statistics, Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seongnam, South Korea c Department of Thoracic and Cardiovascular Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea * Corresponding author: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Gumi-Ro, Bundang-gu, Seongnam-si, Gyeonggi-do , Republic of Korea. Tel: ; fax: ; ctlee@snu.ac.kr (C.-T. Lee). Received 14 April 2015; received in revised form 18 June 2015; accepted 30 June 2015 Abstract OBJECTIVES: Some non-small-cell lung cancer patients have preserved pulmonary function after surgery. Compared with open thoracotomy, video-assisted thoracic surgery (VATS) is widely performed and preserves pulmonary function. Patients with non-small-cell lung cancer have an extremely poor prognosis without surgery. Clinicians should therefore decide which patients can safely tolerate lung resection. This study aimed to identify factors associated with preserving pulmonary function after VATS in non-small-cell lung cancer patients. METHODS: Three hundred and fifty-one patients with non-small-cell lung cancer underwent VATS and preoperative and 12-month postoperative pulmonary function tests. Patients with and patients without preserved forced expiratory volume in 1 s (FEV 1 ) and diffusing capacity of carbon monoxide were compared. RESULTS: The FEV 1 was preserved after VATS in 142 (40.5%) patients. In multivariable analysis, this group was significantly associated with VATS sublobar resection (P < 0.001) and resection at the right upper lobe or right middle lobe (vs right lower lobe, P = 0.048; vs left upper lobe, P = 0.003; vs left lower lobe, P = 0.015). Diffusing capacity of carbon monoxide was preserved in 129 (36.8%) patients. Multivariable analysis showed that VATS sublobar resection (P <.001), lower baseline diffusing capacity of carbon monoxide (P < 0.001) and right upper lobe or right middle lobe resection (vs right lower lobe, P = ; vs left upper lobe, P = 0.029, vs left lower lobe, P = 0.014) were significantly associated with preserved diffusing capacity of carbon monoxide. CONCLUSIONS: For preserving pulmonary function after non-small-cell lung cancer surgery, VATS sublobar resection was superior to VATS lobectomy, and surgery on the right upper lobe or right middle lobe was superior to that at other sites. Keywords: Lobectomy (lung) Lung cancer surgery Lung segmentectomy/wedge resection Pulmonary function Thoracoscopy/videoassisted thoracoscopic surgery INTRODUCTION The World Health Organization estimates that the worldwide lung cancer mortality will continue to rise, largely because of the increase in global cigarette smoking [1], which is the most important reversible risk factor for lung cancer. Cigarette smoking also causes other pulmonary diseases such as chronic obstructive pulmonary disease and interstitial lung disease [2]. Thus, patients with lung cancer are likely to have other pulmonary diseases simultaneously. These comorbid diseases can cause postoperative complications and limit tolerability to radical lung resection in lung cancer patients [3]. One study showed that approximately 37% of patients with resectable lung cancer could not be surgical candidates because of other pulmonary diseases [4]. To predict postoperative complications and intolerabilities, the pulmonary function test (PFT) has been widely used since the 1950s [5]. High-risk patients with marginal pulmonary function could experience many complications such as respiratory failure or death after lobectomy, which has been the gold standard therapy for patients with non-small-cell lung cancer (NSCLC) [6]. To reduce postoperative complications, sublobar resection which includes segmentectomy and wedge resection may be an alternative therapy in high-risk patients. In recent years, sublobar resection has been increasingly performed, although no definitive The Author Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

2 S.J. Kim et al. / European Journal of Cardio-Thoracic Surgery 1085 conclusions have been reached regarding the preservation of pulmonary function [7]. VATS is a more beneficial surgical method than open thoracotomy [8]. The National Comprehensive Cancer Network guidelines also recommend VATS for resectable NSCLC [9]. VATS minimizes chest wall destruction, and results in less postoperative pain, fewer adhesions and faster recovery. With respect to pulmonary function, VATS lobectomy outperforms open thoracotomy [10]. Because VATS decreases postoperative complications, high-risk patients with marginal pulmonary function can undergo surgery [5]. However, which patients will safely maintain pulmonary function after VATS remains unknown. Because NSCLC patients have an extremely poor prognosis without surgery, clinicians should decide who could safely tolerate lung resection. In this study, we evaluated the factors associated with preserved pulmonary function after 12 months in NSCLC patients who underwent VATS lobectomy or VATS sublobar resection. MATERIALS AND METHODS Patients We previously compared pulmonary function change between VATS lobectomy and VATS sublobar resection in patients with NSCLC [11]. The current study was a subgroup analysis of previous study. A registry and management protocol were started in August 2003 for patients with NSCLC who underwent surgery at Seoul National University Bundang Hospital (Seongnam, South Korea). From August 2003 to December 2012, 1799 patients were enrolled in the registry. Among them, 900 patients underwent VATS lobectomy or VATS sublobar resection. We excluded patients who had missing PFT data at 12 months. We further excluded patients who had simultaneous resection of more than two lobes, pleurodesis due to pleural effusion or pneumothorax, irregular inhaler use (in patients with chronic obstructive pulmonary disease or asthma), interstitial lung disease or atelectasis on chest computerized tomography (CT) imaging, and sustained smoking after VATS. Three hundred and fifty-one patients were ultimately enrolled in this study (Fig. 1). Video-assisted thoracic surgery VATS was performed through three ports. Two incisions were used for a 10-mm thoracoscopic port and a 5-mm surgical instrument port. Rib cutting or rib spreading was not used. We chose the surgical approach (e.g. VATS lobectomy or VATS sublobar resection such as wedge resection and segmentectomy) while considering the NSCLC stage, tumour size, tumour location, patient age and pulmonary function through a multidisciplinary tumour board conference. Except for patients with pleural adhesions, we planned VATS for all patients with early-stage lung cancer. However, we sometimes had to convert to thoracotomy if unexpected bleeding occurred or if an anthracotic calcified lymph node was tightly adhered to the pulmonary artery. There is no consensus concerning which patients should undergo lobectomy and which patients should undergo sublobar resection. We performed sublobar resection on patients with a ground-glass opacity measuring <2 cm and a maximum standardized uptake value of <2 in positron emission tomography computed tomography. We dissected all N 1 and N 2 Figure 1: Study enrolment flow chart. CT: computed tomography; ILD: interstitial lung disease; NSCLC: non-small-cell lung cancer; PFT: pulmonary function test; VATS: video-assisted thoracic surgery. nodes during the VATS lobectomy. For patients with ground-glass opacities, we only sampled N 1 and N 2 nodes during the VATS sublobar resection. The resection margin was more than twice the tumour size, based on the frozen section pathological examination in VATS sublobar resection. The Institutional Review Board of Seoul National University Bundang Hospital approved this study (B-1401/ ). Data collection Clinicodemographic data such as age, sex, body mass index, smoking history and pathological stage were collected, based on the International Association for the Study of Lung Cancer (7th edition), histology, tumour size and tumour location. The PFTs were performed by spirometry (V62J; Sensor Medics Corp., Yorba Linda, CA, USA) in accordance with the American Thoracic Society recommendations [12]. The parameters of the PFT included forced expiratory volume in 1 s (FEV 1 ) and diffusion capacity of carbon monoxide (DLCO), which are the most useful predictors of postoperative morbidity and mortality [13]. Based on the PFT values, patients with a FEV 1 /forced vital capacity ratio <70 and FEV 1 <80% were diagnosed as having moderate to severe chronic obstructive pulmonary disease. The standardized differences in pulmonary function were calculated as follows: (preoperative values postoperative values)/standard deviation of the preoperative values. We divided the patients into two groups: the preserved group and the deteriorated group. In the preserved group, the PFT values improved after VATS or the standardized differences were within 0.2 because it is traditionally regarded as clinically not significant. The deteriorated group is worsened below 0.2 standardized differences after VATS. Statistical analysis Data are summarized as the mean (standard deviation, interquartile range) or as number (%). Intergroup differences were compared by THORACIC

3 1086 S.J. Kim et al. / European Journal of Cardio-Thoracic Surgery the χ 2 test, based on the surgical location: right side [i.e. right upper lobe (RUL), right middle lobe (RML) and right lower lobe (RLL)] versus left side [i.e. left upper lobe (LUL) and left lower lobe (LLL)]; and upper lobe (i.e. RUL, RML, and LUL) versus lower lobe (i.e. RLL and LLL). We compared the most preserved group with the worst preserved group, based on the surgical method (i.e. VATS lobectomy or VATS sublobar resection), surgical location and DLCO above 100% or not in the FEV 1 group and in the DLCO group. Clinically meaningful variables were considered in the univariable analysis. Statistically meaningful variables were further selected for the multivariable analysis. To fit a reliable model, the skewdistributed variables were checked by using histogram analysis. The possibility of collinearity was assessed by Pearson correlation and linearity was assessed by restricted cubic spline curves across all continuous variables. Multivariable analysis was performed by binary logistic regression to determine the odds ratio (OR) and 95% confidence interval (CI). We also evaluated goodness of fit of the multivariable model using the Hosmer Lemeshow test and performed a bootstrap resampling technique to assess the stability of the variables. The variables showed acceptable linearity, appropriate goodness-of-fit and good stability between variables. All s were two-sided with P < 0.05 regarded as significant. The statistical tests were performed using SPSS version 21.0 software (IBM, Inc., Armonk, NY, USA) and STATA version 14.0 software (STATA, Inc., College Station, TX, USA). RESULTS Overall patient characteristics Table 1 shows the baseline characteristics of the 351 patients. The mean age was 63.3 years and the sex ratio was well balanced. A VATS lobectomy was performed in 267 (76.1%) patients. Five patients showed unexpected pleural metastasis and were classified as having pathological stage IV lung cancer. One patient initially had stage IV lung cancer and underwent VATS sublobar resection for palliative purposes. In the VATS sublobar resection group, most patients underwent wedge resection. Their lung cancer was stage IA with small pure or mixed ground-glass opacity nodules in the peripheral region; we therefore believed that wide wedge resection was sufficient for treatment. In patients undergoing segmentectomy, only one segment was resected. No patient in the VATS sublobar resection group had lymph node metastasis, except for 1 patient who had stage IV cancer. Three patients in the VATS sublobar resection group died. However, after lung cancer surgery, 2 of these 3 patients had another malignancy: breast cancer and small-cell lung cancer. Their cause of death was not the primary lung cancer but the secondary malignancy. Another patient who initially had stage IV lung cancer underwent VATS sublobar resection with a palliative goal. After VATS, the PFT values of all patients had significantly decreased at 12 months (Table 2). Preservation of forced expiratory volume in 1 s after video-assisted thoracic surgery Of the 351 patients, 142 (40.5%) patients showed preserved FEV 1 after VATS. In univariable analysis, preserved FEV 1 was associated with an older age, a greater likelihood of undergoing VATS Table 1: Baseline characteristics of the enrolled patients Parameters Patient (n = 351) Age (years), mean (SD, IQR) 63.3 (10.3, 57 71) Women, n (%) 172 (49.0) VATS lobectomy, n (%) 267 (76.1) Smoking status, n (%) Current smoker 61 (17.4) Former smoker 94 (26.8) Never smoker 196 (55.8) Smoking amount in every smokers (pack-years), 32.0 (23.8, 0 25) mean (SD, IQR) Moderate to severe COPD, n (%) 25 (7.1) Lung cancer histology, n (%) Adenocarcinoma 307 (87.5) Squamous cell carcinoma 36 (10.3) Others 8 (2.3) Body mass index (kg/m 2 ), mean (SD, IQR) 23.9 (2.9, ) Emphysema in CT, n (%) 63 (17.9) Non-small-cell lung cancer stage, n (%) IA 212 (60.4) IB 82 (23.4) IIA 25 (7.1) IIB 6 (1.7) IIIA 20 (5.7) IIIB 0 (0) IV 6 (1.7) RUL or RML 113 (32.2) RLL 82 (23.3) LUL 95 (27.1) LLL 61 (17.4) COPD: chronic obstructive pulmonary disease; CT: computed tomography; IQR: interquartile range; LLL: left lower lobe; LUL: left upper lobe; RLL: right lower lobe; RML: right middle lobe; RUL: right upper lobe; SD: standard deviation; VATS: video-assisted thoracic surgery. sublobar resection, lower baseline FEV 1 and surgical location. If the surgical location was divided into right side and left side, the FEV 1 was preserved more significantly on the right side than on the left side. However, the surgical location did not show a significant difference if the surgical location was divided into upper lobe and lower lobe (Table 3). After adjusting for confounding factors, older age, VATS sublobar resection and the surgical location of RUL or RML were independently associated with preserved FEV 1 after VATS in multivariable analysis (Table 4). Preservation of diffusion capacity of carbon monoxide after video-assisted thoracic surgery One hundred and twenty-nine (36.8%) patients showed preserved DLCO after VATS. In univariable analysis, the group with preserved DLCO had greater likelihood of undergoing VATS sublobar resection and the surgical location of RUL or RML as well as a lower baseline DLCO in comparison with the group with deteriorated DLCO. If the surgical location was divided into upper lobe and lower lobe, VATS in the upper lobe showed significantly more preservation of the DLCO, compared with the lower lobe. However, if the surgical location was divided into right side and left side, VATS did not show a significant difference (Table 3). In multivariable analysis, VATS sublobar resection, lower baseline

4 S.J. Kim et al. / European Journal of Cardio-Thoracic Surgery 1087 Table 2: Change in pulmonary function at 12 months after video-assisted thoracic surgery Parameters Preoperative mean value Postoperative mean value Mean % of change FVC (SD) (l) 3.39 (0.80) 3.19 (0.79) 5.71 (10.04) <0.001 FVC (SD) (%) (14.9) 98.4 (16.3) 5.19 (10.52) <0.001 FEV 1 (SD) (l) 2.45 (0.61) 2.25 (0.59) 7.85 (10.07) <0.001 FEV 1 (SD) (%) (19.2) 98.2 (19.4) 6.86 (10.31) <0.001 FEV 1 /FVC (SD) (%) 72.4 (9.1) 70.9 (10.0) 1.95 (8.38) <0.001 DLCO (SD) (ml/mmhg/min) 18.9 (4.7) 17.2 (4.4) 7.52 (16.40) <0.001 DLCO (SD) (%) (19.7) 96.3 (18.5) 6.97 (14.83) <0.001 DLCO: diffusion capacity of carbon monoxide; FEV 1 : forced expiratory volume in 1 s; FVC: forced vital capacity; SD: standard deviation. DLCO and surgical location of the RUL or RML were independently associated with the preservation of DLCO after VATS (Table 5). Preservation of both forced expiratory volume in 1 s and diffusion capacity of carbon monoxide after video-assisted thoracic surgery Sixty-eight (19.4%) patients had preservation of the FEV 1 and DLCO values after VATS. This preservation was associated with VATS sublobar resection, lower baseline DLCO and surgical location, based on univariable analysis. VATS showed significant preservation of both FEV 1 and DLCO when performed on the right side or upper lobe than on the left side or lower lobe (Table 3). In multivariable analysis, VATS sublobar resection, lower baseline DLCO and surgical location of RUL or RML were independently associated with the preservation of both FEV 1 and DLCO (Table 6). If a patient with a DLCO below 100% underwent VATS sublobar resection in the RUL or RML, then FEV 1 and DLCO were both more significantly preserved, compared with patients with a DLCO above 100% who underwent VATS lobectomy of the LLL (OR, 1.89; 95% CI, ; P < 0.001). DISCUSSION Guidelines for the preoperative evaluation of NSCLC patients were produced by the British Thoracic Society and Society of Cardiothoracic Surgeons of Great Britain and Ireland Working Party in 2001 [14], and by the American College of Chest Physicians in 2003 [15]. Their recommendations are similar and include the following: individuals with an FEV 1 2l or 80% of the predicted normal are suitable for pneumonectomy, and individuals with an FEV l are suitable for lobectomy. If an individual is with FEV 1 or a DLCO <80% of the predicted normal, the predicted postoperative lung function should be estimated. However, these guidelines did not take into consideration the surgical method (i.e. VATS or open thoracotomy), surgical extension (i.e. lobectomy vs sublobar resection) or location of the resected lobe. Among these factors, pulmonary function after VATS is superior to open thoracotomy [16]. Thus, our study enrolled only patients who had undergone VATS. It remains controversial whether sublobar resection could be considered an appropriate therapy for NSCLC patients. In 1995, the Lung Cancer Study Group found that, compared with lobectomy, sublobar resection did not improve morbidity, mortality and pulmonary function [17]. After this study, sublobar resection has been regarded as a compromise therapy. However, there have been significant advances in minimally invasive surgical techniques. Recent studies demonstrate that sublobar resection results in a similar prognosis to lobectomy in patients with early-stage NSCLC [18], and sublobar resection has a more favourable pulmonary function [19]. These studies did not use VATS. However, our results also support these recent studies. Both FEV 1 and DLCO were more preserved after VATS sublobar resection than after VATS lobectomy. The FEV 1 was more preserved after resection in the right lung (i.e. RUL, RML or RLL). The FEV 1 has traditionally represented the key test in the functional work-up of surgical candidates. A reduced FEV 1 is associated with increased respiratory morbidity and mortality [20]. After lung resection, the remaining lobe of greater part of the ipsilateral lung and lesser part of the contralateral lung expand and somewhat compensate for the resected lobe [21]. The right lung consists of three lobes. The RUL and RML are relatively small lobes, compared with the other lobes. However, the left lung consists of two relatively large lobes. If one of the two lobes is resected, the remaining lobe seems not to compensate appropriately. Therefore, we believe that the FEV 1 could be compensated by the remaining lobes after resection of one of the right side lobes. The DLCO was more preserved after resection of the upper lung (i.e. RUL, RML or LUL). The DLCO has been associated with long-term survival and quality of life [22]. Guidelines recommend measuring the DLCO, regardless of FEV 1 values [14, 15]. The DLCO implies the available capillary surface area for gas diffusion across the alveoli. Thus, the DLCO value depends on a normal alveolar surface area, which is larger in the lower lobes than in the upper lobes. Therefore, we believe the DLCO can be more greatly preserved after upper lobe resection. The preservation of DLCO was also associated with lower baseline DLCO values. It is well known that the degree of functional loss appears to be less in patients with a poor baseline pulmonary function [23]. This is the first noteworthy study that compared the characteristics between pulmonary function preservation and deterioration after VATS in NSCLC patients. Previous studies evaluated only the degree of decrease in pulmonary function after surgery [7, 19, 21]. The present study has several limitations. Firstly, we could not evaluate the patients aerobic capacity by the exercise pulmonary test. The peak oxygen consumption is the most important parameter for predicting postoperative complications [24]. However, the exercise pulmonary test is not easy to perform and may be impossible to perform in a large population. Secondly, because of the THORACIC

5 Table 3: Factors associated with the preservation of pulmonary function after video-assisted thoracic surgery, based on univariable analysis Parameters FEV 1 after VATS DLCO after VATS FEV 1 and DLCO after VATS Preserved group 142 (40.5) Deteriorated group 209 (59.5) Preserved group 129 (36.8) Deteriorated group 222 (63.2) Preserved group 68 (19.4) Deteriorated group 283 (80.6) Age (years), mean (SD, IQR) 65.0 (10.0, 59 72) 62.1 (10.3, ) (10.0, 57 72) 63.2 (10.4, ) (10.6, ) 63.0 (10.2, 57 70) 0.21 Women, n (%) 71 (50.0) 101 (48.3) (46.5) 112 (50.5) (50.0) 138 (48.8) 0.86 Smoking amount (pack-year), 12.8 (20.0, 0 20) 15.0 (24.0, 0 25) (20.6, 0 25) 13.7 (23.5, ) (20.1, ) 14.4 (23.0, 0 25) 0.73 mean (SD, IQR) Moderate to severe COPD, n (%) 13 (9.2) 12 (5.7) (7.8) 15 (6.8) (8.8) 19 (6.7) 0.60 Lung cancer histology, n (%) Adenocarcinoma 120 (84.5) 187 (89.5) (88.4) 193 (86.9) (86.8) 248 (87.6) Squamous cell CA 16 (11.3) 20 (9.6) 13 (10.1) 23 (10.4) 7 (10.3) 29 (10.3) Others 6 (4.2) 2 (0.9) 2 (1.5) 6 (2.7) 2 (2.9) 6 (2.1) Body mass index (kg/m 2 ), mean 23.8 (3.0, ) 23.9 (2.9, ) (3.1, ) 23.9 (2.8, ) (3.0, ) 24.0 (2.9, ) 0.10 (SD, IQR) VATS sublobar resection, n (%) 52 (36.6) 32 (15.3) < (37.2) 36 (16.2) < (42.6) 55 (19.4) <0.001 Emphysema in CT 29 (20.4) 34 (16.3) (19.4) 38 (17.1) (23.5) 47 (16.6) 0.18 Baseline FEV 1 (%) (SD, IQR) (20.6, ) (18.0, ) (20.6, ) (18.4, ) (22.4, ) (18.4, ) 0.91 Baseline DLCO (%) (SD, IQR) (20.1, ) (19.4, ) (18.2, ) (19.0, ) < (19.8, ) (19.4, ) Lung cancer stage, n (%) IA or IB 118 (83.1) 176 (84.2) (84.5) 185 (83.3) (82.3) 238 (84.1) 0.77 IIA or IIB 15 (10.6) 16 (7.7) 13 (10.1) 18 (8.1) 8 (11.8) 23 (8.1) IIIA or IIIB 5 (3.5) 15 (7.2) 5 (3.9) 15 (6.8) 3 (4.4) 17 (6.0) IV 4 (2.8) 2 (0.9) 2 (1.5) 4 (1.8) 1 (1.5) 5 (1.8) RUL or RML 61 (43.0) 53 (25.4) (42.6) 59 (26.6) (51.5) 79 (27.9) RLL 30 (21.1) 51 (24.4) 24 (18.6) 57 (25.7) 13 (19.1) 68 (24.0) LUL 32 (22.5) 63 (30.1) 32 (24.8) 63 (28.4) 13 (19.1) 82 (29.0) LLL 19 (13.4) 42 (20.1) 18 (14.0) 43 (19.3) 7 (10.3) 54 (19.1) Right lung 91 (64.1) 104 (49.8) (61.2) 116 (52.3) (70.6) 147 (51.9) Left lung 51 (35.9) 105 (50.2) 50 (38.8) 106 (47.7) 20 (29.4) 136 (48.1) Upper lung 93 (65.5) 116 (55.5) (67.4) 122 (55.0) (70.5) 161 (56.9) Lower lung 49 (34.5) 93 (44.5) 42 (32.6) 100 (45.0) 20 (29.4) 122 (43.1) 1088 S.J. Kim et al. / European Journal of Cardio-Thoracic Surgery CA: carcinoma; COPD: chronic obstructive pulmonary disease; CT: computed tomography; DLCO: diffusion capacity of carbon monoxide; FEV 1 : forced expiratory volume in 1 s; FVC: forced vital capacity; ICR: interquartile range; LLL: left lower lobe; LUL: left upper lobe; RLL: right lower lobe; RML: right middle lobe; RUL: right upper lobe; SD: standard deviation; VATS: video-assisted thoracic surgery.

6 S.J. Kim et al. / European Journal of Cardio-Thoracic Surgery 1089 Table 4: Factors associated with the FEV 1 preserved group (n = 142, 40.5%) after video-assisted thoracic surgery, based on multivariable analysis Table 6: Factors associated with preservation of both FEV 1 and DLCO (n = 68, 19.4%) after VATS, based on multivariable analysis Parameter Adjusted odds ratio 95% Confidence interval Parameter Adjusted odds ratio 95% confidence interval Age (years) VATS sublobar <0.001 resection Baseline FEV 1 (%) Surgical location RUL or RML versus RLL LUL LLL FEV 1 : forced expiratory volume in 1 s; LLL: left lower lobe; LUL: left upper lobe; RLL: right lower lobe; RML: right middle lobe; RUL: right upper lobe; VATS: video-assisted thoracic surgery. Table 5: Factors associated with the DLCO preserved group (n = 129, 36.8%) after VATS, based on multivariable analysis Parameter Adjusted odds ratio 95% Confidence interval VATS sublobar <0.001 resection Baseline DLCO (%) <0.001 Surgical location RUL or RML versus RLL LUL LLL DLCO: diffusion capacity of carbon monoxide; LLL: left lower lobe; LUL: left upper lobe; RLL: right lower lobe; RML: right middle lobe; RUL: right upper lobe; VATS: video-assisted thoracic surgery. strict inclusion criteria, a relatively large number of patients were excluded. In particular, many patients were excluded because they had missing 12-month follow-up PFT data. Some of these patients had died or were in too poor condition to perform PFT because they were undergoing chemotherapy or radiotherapy. Therefore, compared with the enrolled patients, they had a poorer clinical condition. However, the baseline PFT values were not different between the enrolled patients and patients excluded because of missing PFTs. Thirdly, many of our enrolled patients were non-smokers and sustained good pulmonary function, even postoperatively. Many of our patients had early lung cancer that presented as a ground-glass opacity, which is not closely associated with smoking [25]. In Korea, the smoking rate among women is low (5.8%, 2013 OECD health data). Considering the lung cancer incidence rates in women, our study had a relatively large number of women, possibly because it included a large number of non-smokers. Thus, our findings may not reflect the situation of patients with high-risk marginal pulmonary function. In conclusion, VATS sublobar resection and the surgical location in the RUL or RML are associated with FEV 1 and DLCO preservation, VATS sublobar resection Baseline DLCO (%) Surgical location RUL or RML versus RLL LUL LLL DLCO: diffusion capacity of carbon monoxide; FEV 1 : forced expiratory volume in 1 s; LLL: left lower lobe; LUL: left upper lobe; RLL: right lower lobe; RML: right middle lobe; RUL: right upper lobe; VATS: video-assisted thoracic surgery. especially in patients with low baseline DLCO values. However, VATS lobectomy and surgical location in the LLL are more likely to deteriorate the FEV 1 and DLCO. Because NSCLC is a fatal disease without surgery, clinicians should consider these factors when determining surgery in high-risk patients with marginal pulmonary function. More large-scale, multicentre studies are warranted to verify these findings. ACKNOWLEDGEMENTS The authors thank the Medical Research Collaborating Center at Seoul National University Bundang Hospital (Seongnam, South Korea) for performing the statistical analyses. Conflict of interest: none declared. REFERENCES [1] Liu W, Pan YL, Gao CX, Shang Z, Ning LJ, Liu X. Breathing exercises improve post-operative pulmonary function and quality of life in patients with lung cancer: a meta-analysis. Exp Ther Med 2013;5: [2] Galvin JR, Franks TJ. Smoking-related lung disease. J Thorac Imaging 2009; 24: [3] Poonyagariyagorn H, Mazzone PJ. Lung cancer: preoperative pulmonary evaluation of the lung resection candidate. Semin Respir Crit Care Med 2008;29: [4] Baser S, Shannon VR, Eapen GA, Jimenez CA, Onn A, Keus L et al. Pulmonary dysfunction as a major cause of inoperability among patients with non-small-cell lung cancer. Clin Lung Cancer 2006;7: [5] Wang JS. Pulmonary function tests in preoperative pulmonary evaluation. Respir Med 2004;98: [6] Taylor MD, LaPar DJ, Isbell JM, Kozower BD, Lau CL, Jones DR. Marginal pulmonary function should not preclude lobectomy in selected patients with non-small cell lung cancer. J Thorac Cardiovasc Surg 2014;147: ; discussion [7] Deng B, Cassivi SD, de Andrade M, Nichols FC, Trastek VF, Wang Y et al. Clinical outcomes and changes in lung function after segmentectomy versus lobectomy for lung cancer cases. J Thorac Cardiovasc Surg 2014;148: e3 [8] Atkins BZ, Harpole DH Jr, Mangum JH, Toloza EM, D Amico TA, Burfeind WR Jr. Pulmonary segmentectomy by thoracotomy or thoracoscopy: reduced hospital length of stay with a minimally-invasive approach. Ann Thorac Surg 2007;84: ; discussion THORACIC

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