Study cohort
The study cohort consisted of 355 patients with clinical N0 NSCLC with solid tumor component diameters > 5 cm on chest CT. A total of 132 (37.2%) patients were assigned to the VATS group and 223 (62.8%) patients were assigned to the thoracotomy group. There were more women (27.3% in the VATS group vs 12.1% in the thoracotomy group; P < 0.001) and never-smokers (32.6% in the VATS group vs 12.1% in the thoracotomy group; P < 0.001) in the VATS group. The median clinical tumor size was 57 mm (interquartile range [IQR], 54–65) in the VATS group and 61 mm (IQR, 55–75) in thoracotomy group (P < 0.001). The most common histology was adenocarcinoma (66.7%) in the VATS group but squamous cell carcinoma (48.4%) in the thoracotomy group (P < 0.001).
After propensity score matching, 204 patients were available for analysis. The median clinical tumor size was 67 mm (IQR, 60–72) in the VATS group and 67 mm (IQR, 61–72) in the thoracotomy group (P = 0.871). The VATS and thoracotomy groups were well balanced for demographic and clinical characteristics (Table 1).
Table 1
Variables
|
Unmatched cohort
|
Propensity score-matched cohort
|
Thoracotomy
(n = 223)
|
VATS
(n = 132)
|
P-value
|
Thoracotomy (n = 102)
|
VATS
(n = 102)
|
P-value
|
Age
|
68 (61.0–73.0)
|
66 (59.8–71.0)
|
0.139
|
67 (61.0–72.0)
|
67 (60.0–72.0)
|
0.871
|
Sex
|
|
|
|
|
|
|
Female
|
27 (12.1%)
|
36 (27.3%)
|
< 0.001
|
17 (16.7%)
|
18 (17.6%)
|
> 0.999
|
Male
|
196 (87.9%)
|
96 (72.7%)
|
85 (83.3%)
|
84 (82.4%)
|
Smoking
|
|
|
|
|
|
|
Never
|
27 (12.1%)
|
43 (32.6%)
|
< 0.001
|
19 (18.6%)
|
25 (24.5%)
|
0.829
|
Former
|
102 (45.7%)
|
55 (41.7%)
|
44 (43.1%)
|
47 (46.1%)
|
Current
|
94 (42.1%)
|
34 (25.8%)
|
39 (38.2%)
|
30 (29.4%)
|
FEV1 (%)
|
|
|
|
|
|
|
≥80%
|
51 (22.9%)
|
20 (15.2%)
|
0.079
|
81 (79.4%)
|
84 (82.4%)
|
0.701
|
<80%
|
172 (77.1%)
|
112 (84.9%)
|
|
21 (20.6%)
|
18 (17.6%)
|
|
DLCO (%)
|
|
|
|
|
|
|
≥80%
|
26 (11.7%)
|
8 (6.1%)
|
0.083
|
91 (89.2%)
|
94 (92.2%)
|
0.607
|
<80%
|
197 (88.3%)
|
124 (93.9%)
|
11 (10.8%)
|
8 (7.8%)
|
CCI
|
|
|
|
|
|
|
0
|
146 (65.5%)
|
88 (66.7%)
|
0.627
|
66 (64.7%)
|
64 (62.7%)
|
0.809
|
1
|
49 (22.0%)
|
31 (23.5%)
|
26 (25.5%)
|
27 (26.5%)
|
2
|
18 (8.1%)
|
6 (4.5%)
|
5 (4.9%)
|
5 (4.9%)
|
≥ 3
|
10 (4.5%)
|
7 (5.3%)
|
5 (4.9%)
|
6 (5.9%)
|
Tumor size
|
61 (55.0–75.0)
|
57(54.0–65.0)
|
< 0.001
|
59 (54.3–68.5)
|
59 (54.0–67.0)
|
0.777
|
Location
|
|
|
|
|
|
|
RUL
|
53 (23.8%)
|
29 (22.0%)
|
0.060
|
20 (19.6%)
|
22 (21.6%)
|
0.106
|
RML
|
2 (0.9%)
|
7 (5.3%)
|
2 (2%)
|
7 (6.9%)
|
RLL
|
54 (24.2%)
|
40 (30.3%)
|
25 (24.5%)
|
32 (31.4%)
|
LUL
|
56 (25.1%)
|
26 (19.7%)
|
26 (25.5%)
|
20 (19.6%)
|
LLL
|
58 (26.0%)
|
30 (22.7%)
|
29 (28.4%)
|
21 (20.6%)
|
Histology
|
|
|
|
|
|
|
ADC
|
90 (40.4%)
|
88 (66.7%)
|
< 0.001
|
62 (60.8%)
|
63 (61.8%)
|
> 0.999
|
SCC
|
108 (48.4%)
|
30 (22.7%)
|
28 (27.5%)
|
26 (25.5%)
|
Others
|
25 (11.21%)
|
14 (10.61%)
|
12 (11.8%)
|
13 (12.7%)
|
Data are presented as number (%), or median (interquartile range). FEV1 forced expiratory volume at 1 s, DLCO diffusing capacity for carbon monoxide, CCI Charlson comorbidity index, ADC adenocarcinoma, SCC squamous cell carcinoma, VATS video-assisted thoracic surgery. |
Perioperative outcomes
There were 10 conversions to thoracotomy from VATS: six were due to diffuse tight pleural adhesion, and four were due to anthracofibrotic lymph node around the pulmonary artery.
In the unmatched cohort, the median pathologic tumor size was 55 mm (IQR, 45–64.5) in the VATS group and 60 mm (IQR, 52.5–74) in thoracotomy group (P < 0.001). The VATS group had a shorter hospital stay than the thoracotomy group (6 days [5–8 days] vs 8 days [6–11 days]; P < 0.001). The 30-day morbidity and mortality did not show any significant differences between the two groups. In the propensity score-matched cohort, the median pathologic tumor size was 56 mm (IQR, 48–65) in the VATS group and 55.5 mm (IQR, 50–65) in the thoracotomy group (P = 0.348). The VATS group had a shorter hospital stay than the thoracotomy group (6 days [5–8 days] vs 7 days [6–10 days]; P < 0.001), whereas there were no differences in the 30-day morbidity and mortality (Table 2). The detailed information regarding complications within 30 days is shown in Table 3. In the unmatched cohort, the VATS group showed a lower incidence of pneumonia (0.8% vs 5.8%; P = 0.018) and arrhythmia (9.1% vs 17.9%; P = 0.023) than the thoracotomy group. Conversely, in the propensity score-matched cohort, the incidence of pneumonia was not significantly different (4.9% vs 0%; P = 0.064) between the two groups, but the incidence of arrhythmia was still significantly lower in the VATS group than in the thoracotomy group (8.1% vs 21.6%; P = 0.005).
Table 2
Variables
|
Unmatched cohort
|
Propensity score-matched cohort
|
Thoracotomy (n = 223)
|
VATS
(n = 132)
|
P-value
|
Thoracotomy
(n = 102)
|
VATS
(n = 102)
|
P-value
|
Harvested LN number
|
22 (16.0–30.0)
|
16 (12.0–22.0)
|
< 0.001
|
22.5 (17.0–29.8)
|
16 (11.0–22.8)
|
< 0.001
|
Bronchial margin
|
|
|
|
|
|
|
R0
|
222 (99.6%)
|
132 (100%)
|
> 0.999
|
111 (100%)
|
111 (100%)
|
> 0.999
|
R1
|
1 (0.4%)
|
0 (0.0%)
|
0 (0%)
|
0 (0%)
|
Hospital length of stay
|
8 (6.0–11.0)
|
6 (5.0–8.0)
|
< 0.001
|
7 (6.0–10.0)
|
6 (5.0–8.0)
|
< 0.001
|
30-day morbidity
|
94 (42.2%)
|
42 (31.8%)
|
0.053
|
41 (40.2%)
|
32 (31.4%)
|
0.188
|
30-day mortality
|
2 (0.9%)
|
0 (0.0%)
|
0.147
|
1 (1%)
|
0 (0%)
|
> 0.999
|
Pathologic tumor size
|
60 (52.5–74)
|
55 (45–64.5)
|
< 0.001
|
55.5 (50–65)
|
56 (48–65)
|
0.348
|
Pathologic N stage
|
|
|
|
|
|
|
pN0
|
169 (75.8%)
|
106 (80.3%)
|
0.147
|
72 (70.6%)
|
86 (84.3%)
|
0.143
|
pN1
|
29 (13.0%)
|
9 (6.8%)
|
18 (17.6%)
|
5 (4.9%)
|
pN2
|
25 (11.2%)
|
16 (12.1%)
|
12 (11.8%)
|
11 (10.8%)
|
Visceral pleural invasion
|
38 (17.0%)
|
28 (21.2%)
|
0.404
|
25 (24.5%)
|
23 (22.5%)
|
0.864
|
Adjuvant treatment
|
|
|
|
|
|
|
No adjuvant treatment
|
93 (41.7%)
|
65 (49.2%)
|
0.204
|
43 (42.2%)
|
53 (52%)
|
0.262
|
Chemotherapy
|
110 (49.3%)
|
62 (47%)
|
52 (51%)
|
46 (45.1%)
|
Radiotherapy
|
7 (3.1%)
|
1 (0.7%)
|
1 (1%)
|
1 (1%)
|
Chemoradiotherapy
|
13 (5.8%)
|
4 (3%)
|
6 (5.9%)
|
2 (2%)
|
Data are presented as number (%) or median (interquartile range). |
Table 3 Complications within 30 days
Complications
|
Unmatched cohort
|
|
Propensity score-matched cohort
|
Thoracotomy (n = 223)
|
VATS (n = 132)
|
P-value
|
|
Thoracotomy (n = 102)
|
VATS (n = 102)
|
P-value
|
|
Number of patients
|
94 (42.2%)
|
42 (31.8%)
|
0.053
|
|
41 (40.2%)
|
32 (31.4%)
|
0.188
|
Number of events
|
119 (53.4%)
|
48 (36.4%)
|
|
|
92 (90.2%)
|
61 (59.8%)
|
|
Pulmonary
|
41 (18.4%)
|
23 (17.4%)
|
0.820
|
|
16 (15.7%)
|
20 (19.6%)
|
0.585
|
Pneumonia/empyema
|
13 (5.8%)
|
1 (0.8%)
|
0.018
|
|
5 (4.9%)
|
0 (0%)
|
0.063
|
ARDS
|
7 (3.1%)
|
4 (3%)
|
>0.999
|
|
2 (2%)
|
4 (3.9%)
|
0.687
|
Prolonged air leak/pneumothorax
|
16 (7.2%)
|
16 (12.1%)
|
0.116
|
|
8 (7.8%)
|
15 (14.7%)
|
0.167
|
Secretion retention/atelectasis
|
4 (1.8%)
|
0 (0%)
|
0.301
|
|
1 (1%)
|
0 (0%)
|
>0.999
|
Others*
|
1 (0.4%)
|
2 (1.5%)
|
0.558
|
|
0 (0%)
|
1 (1%)
|
>0.999
|
Cardiac
|
41 (18.4%)
|
12 (9.1%)
|
0.018
|
|
21 (20.6%)
|
6 (5.9%)
|
0.003
|
Arrhythmia
|
40 (17.9%)
|
12 (9.1%)
|
0.023
|
|
20 (19.6%)
|
6 (5.9%)
|
0.004
|
MI
|
1 (0.4%)
|
0 (0%)
|
>0.999
|
|
1 (1%)
|
0 (0%)
|
>0.999
|
CVA
|
6 (2.7%)
|
1 (0.8%)
|
0.265
|
|
3 (2.9%)
|
1 (1%)
|
0.625
|
Bleeding
|
1 (0.4%)
|
2 (1.5%)
|
0.558
|
|
0 (0%)
|
1 (1%)
|
>0.999
|
Wound dehiscence
|
4 (1.8%)
|
1 (0.8%)
|
0.655
|
|
3 (2.9%)
|
1 (1%)
|
0.625
|
Others**
|
26 (11.7%)
|
9 (6.8%)
|
0.139
|
|
12 (11.8%)
|
6 (5.9%)
|
0.180
|
Data are presented as number (%)
ARDS acute respiratory distress syndrome, MI myocardial infarction
*Other pulmonary complications include pleural effusion and acute exacerbation of chronic obstructive pulmonary disease.
**Other complications include delirium, chylothorax, ileus, vocal cord palsy, and urinary tract infection.
Survival outcomes
The median follow-up period of the entire cohort was 80 months. At the completion of the study, 134 patients died, and 130 patients had recurrence during the follow-up. In the VATS group, 33 patients died, and 44 patients had recurrence, while, in the thoracotomy group, 101 patients died, and 86 patients had recurrence. The 5-year OS rates were 75.5% in the VATS group and 56.1% in the thoracotomy group. The log-rank test showed that the VATS group had significantly superior OS compared with the thoracotomy group (P < 0.001). In contrast, the 5-year RFS rates was not significantly different between the groups (59.8% in the VATS group vs. 50.6% in the thoracotomy group, P = 0.160) (Fig. 1a).
After propensity score matching, the 5-year OS rates were 71.5% in the VATS group and 64.4% in the thoracotomy group. The 5-year RFS rates were 60.1% in the VATS group and 51.5% in the thoracotomy group. There were no significant differences in the OS and RFS between the VATS and thoracotomy groups (OS, P = 0.390; RFS, P = 0.210) (Fig. 1b). Additional survival analysis was performed in the subgroups of the matched cohort. In the subgroups stratified by pathologic lymph node metastasis, there were no statistically significant differences in OS between the VATS and thoracotomy groups (Supplementary Fig. 2a). Similarly, no significant survival differences were observed in subgroups stratified by tumor histology (Supplementary Fig. 2b).
In the multivariate Cox proportional hazard model analysis for OS, surgical approach (VATS vs. thoracotomy) was not an independent risk factor for survival (hazard ratio, 0.76; 95% confidence interval, 0.51–1.15; P = 0.195) after adjusting for sex, age, Charlson comorbidity index, pathologic tumor size, pathologic lymph node metastasis, tumor histology, and adjuvant therapy (Table 4).
Table 4 Multivariable Cox proportional hazard model for OS in unmatched cohort
Variable
|
Univariable analysis
|
Multivariable analysis
|
Hazard ratio
|
95% CI
|
P-value
|
Hazard ratio
|
95% CI
|
P-value
|
VATS (vs. thoracotomy)
|
0.56
|
0.38
|
0.82
|
0.003
|
0.81
|
0.54
|
1.23
|
0.331
|
Sex, male (vs. female)
|
2.23
|
1.28
|
3.88
|
0.005
|
1.65
|
0.93
|
2.95
|
0.087
|
Age (per year)
|
1.05
|
1.03
|
1.08
|
<0.001
|
1.04
|
1.02
|
1.07
|
<0.001
|
CCI ≥2 (vs. CCI<2)
|
2.10
|
1.34
|
3.30
|
0.001
|
1.72
|
1.09
|
2.74
|
0.021
|
FEV1≥ 80% (vs. < 80%)
|
1.02
|
0.66
|
1.56
|
0.935
|
|
|
|
|
DLCO≥ 80% (vs. < 80%)
|
0.77
|
0.45
|
1.32
|
0.349
|
|
|
|
|
Pathologic tumor size
|
1.02
|
1.01
|
1.03
|
<0.001
|
1.02
|
1.01
|
1.03
|
<0.001
|
Pathologic N+ (vs. pN0)
|
1.90
|
1.32
|
2.75
|
0.001
|
2.33
|
1.60
|
3.40
|
<0.001
|
Histology (ref = ADC)
|
|
|
|
0.009
|
|
|
|
|
SCC
|
1.65
|
1.16
|
2.36
|
|
1.13
|
0.77
|
1.65
|
0.542
|
Others
|
0.87
|
0.46
|
1.66
|
|
0.86
|
0.44
|
1.65
|
0.643
|
Adjuvant treatment
|
0.65
|
0.47
|
0.92
|
0.013
|
0.69
|
0.47
|
1.03
|
0.071
|
Statistically significant variates (P < 0.1) in the univariable analysis were used as covariates for multivariable analysis
VATS video-assisted thoracic surgery, CCI Charlson comorbidity index, FEV1 forced expiratory volume at 1 s, DLCO diffusing capacity for carbon monoxide, ADC adenocarcinoma, SCC squamous cell carcinoma
Recurrence patterns
Of the 130 patients with recurrence, locoregional recurrence occurred in 22 patients, distant recurrence occurred in 86 patients, and ipsilateral pleural recurrence occurred in 24 patients (Supplementary Table 2). The cumulative incidence rate (CIR) of locoregional recurrence at 5 years was 6.4% in the VATS group and 9.1% in the thoracotomy group (Gray’s test, P = 0.260). The CIR of distant metastasis was similar between the two groups (26.6% vs 32.3%; P = 0.429). No differences were observed in the CIR of locoregional recurrence and distant metastasis after propensity matching (P = 0.679 and P = 0.364, respectively) (Fig. 2). The VATS group did not show an increased risk of ipsilateral pleural recurrence in the unmatched cohort (10.1% in the VATS group vs. 7.7% in the thoracotomy group, P = 0.737) and matched cohort (12.0% in the VATS group vs. 7.9% in the thoracotomy group, 0.582).