Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, Ulsan University College of Medicine, Seoul, Korea
Copyright © 2025 by the Korean Cancer Association
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Ethical Statement
This study was approved by the Institutional Review Board of Asan Medical Center, and this center waived the need for informed consent (approval no. 2023-1514, approval date: 28 November 2023).
Author Contributions
Conceived and designed the analysis: Kim IH, Yun JK.
Collected the data: Kim IH, Lee GD.
Contributed data or analysis tools: Kim IH, Lee GD, Choi S, Yun JK.
Performed the analysis: Kim IH, Kim YH, Yun JK.
Wrote the paper: Kim IH, Kim HR, Yun JK.
Writing-review & editing: Kim IH, Lee GD, Choi S, Kim HR, Kim YH, Kim DK, Park SI, Yun JK.
Conflict of Interest
Conflict of interest relevant to this article was not reported.
Values are presented as mean±standard deviation or number (%). DLCO, diffusing capacity to carbon monoxide; FEV1, forced expiratory volume in 1 second; IASLC, International Association for the Study of Lung Cancer; LN, lymph node; NSCLC, non–small cell lung cancer; R, resection; R0, complete resection; R1/2, incomplete resection; R(un), uncertain resection; VATS, video-assisted thoracic surgery.
Adenoca, adenocarcinoma; CI, confidence interval; DLCO, diffusing capacity to carbon monoxide; FEV1, forced expiratory volume in 1 second; HR, hazard ratio; IASLC, International Association for the Study of Lung Cancer; LN, lymph node; pN2, pathologic N2; R0, complete resection; R1/2, incomplete resection; R(un), uncertain resection; Sqcc, squamous cell carcinoma; VATS, video-assisted thoracic surgery.
Variable |
Overall |
Locoregional |
Distant |
Mixed |
||||
---|---|---|---|---|---|---|---|---|
HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | |
Highest LN positivitya) | 1.17 (0.93-1.48) | 0.177 | 0.61 (0.32-1.18) | 0.142 | 1.44 (1.08-1.92) | 0.013 | 0.95 (0.56-1.60) | 0.842 |
N2 subclassification | ||||||||
N2a2 vs. N2a1 | 1.48 (1.14-1.92) | 0.004 | 1.24 (0.67-2.32) | 0.498 | 1.45 (1.03-2.05) | 0.034 | 1.77 (1.04-3.03) | 0.036 |
N2b vs. N2a1 | 1.79 (1.34-2.40) | < 0.001 | 1.99 (0.97-4.06) | 0.059 | 1.85 (1.28-2.69) | 0.001 | 1.52 (0.80-2.88) | 0.204 |
CI, confidence interval; HR, hazard ratio; LN, lymph node; Mixed, locoregional and distant recurrence; R0, complete resection; R(un), uncertain resection.
a) Adjustment by age, sex, histology (adenocarcinoma, squamous cell carcinoma, and others), pathological stage (IIIA, and IIB), N2 subtype (N2a1, N2a2, and N2b), and adjuvant therapy.
Variable | Total (n=1,373) | IASLC classification |
p-value | ||
---|---|---|---|---|---|
R0 (n=576) | R(un) (n=286) | R1/2 (n=511) | |||
Age (yr) | 61.7±10.0 | 61.7±10.1 | 62.4±9.9 | 61.4±10.0 | 0.398 |
Sex | |||||
Male | 862 (62.8) | 368 (63.9) | 173 (60.5) | 321 (62.8) | 0.623 |
Female | 511 (37.2) | 208 (36.1) | 113 (39.5) | 190 (37.2) | |
Smoking history | 806 (58.7) | 346 (60.1) | 159 (55.6) | 301 (58.9) | 0.451 |
No. of comorbidities | |||||
0-1 | 1,088 (79.2) | 458 (79.5) | 219 (76.6) | 411 (80.4) | 0.594 |
2 | 204 (14.9) | 84 (14.6) | 51 (17.8) | 69 (13.5) | |
≥ 3 | 81 (5.9) | 34 (5.9) | 16 (5.6) | 31 (6.1) | |
Pulmonary function test | |||||
FEV1 (%) | 87.6±15.4 | 88.1±15.5 | 87.3±16.3 | 87.3±14.9 | 0.650 |
FEV1 < 60% | 46 (3.4) | 21 (3.6) | 9 (3.1) | 16 (3.1) | 0.875 |
DLCO (%) | 85.1±18.0 | 85.0±17.8 | 86.5±17.9 | 84.5±18.2 | 0.322 |
DLCO < 60% | 76 (5.8) | 32 (5.8) | 15 (5.6) | 29 (6.0) | 0.975 |
Invasive mediastinal staging | |||||
Endobronchial ultrasound | 297 (21.6) | 115 (20.0) | 67 (23.4) | 115 (22.5) | 0.424 |
Mediastinoscopy | 71 (5.2) | 27 (4.7) | 15 (5.2) | 29 (5.7) | 0.762 |
Clinical N category | |||||
cN0 | 661 (48.1) | 322 (55.9) | 155 (54.2) | 184 (36.0) | < 0.001 |
cN1 | 234 (17.0) | 96 (16.7) | 28 (9.8) | 110 (21.5) | |
cN2 | 478 (34.8) | 158 (27.4) | 103 (36.0) | 217 (42.5) | |
Location | |||||
Right | 803 (58.5) | 364 (63.2) | 142 (49.7) | 297 (58.1) | 0.001 |
Left | 570 (41.5) | 212 (36.8) | 144 (50.3) | 214 (41.9) | |
Surgical approach | |||||
VATS | 700 (51.0) | 327 (56.8) | 161 (56.3) | 212 (41.5) | < 0.001 |
Open thoracotomy | 599 (43.6) | 233 (40.5) | 113 (39.5) | 253 (49.5) | |
Thoracotomy conversion | 74 (5.4) | 16 (2.8) | 12 (4.2) | 46 (9.0) | |
Histologic subtype | |||||
Adenocarcinoma | 966 (70.4) | 398 (69.1) | 209 (73.1) | 359 (70.3) | 0.659 |
Squamous cell carcinoma | 313 (22.8) | 141 (24.5) | 58 (20.3) | 114 (22.3) | |
Others | 94 (6.8) | 37 (6.4) | 19 (6.6) | 38 (7.4) | |
Histologic grade | |||||
Grade I | 33 (2.4) | 13 (2.3) | 11 (3.8) | 9 (1.8) | 0.033 |
Grade II | 839 (61.1) | 376 (65.3) | 167 (58.4) | 296 (57.9) | |
Grade III | 404 (29.4) | 148 (25.7) | 93 (32.5) | 163 (31.9) | |
Cannot be assessed | 97 (7.1) | 39 (6.8) | 15 (5.2) | 43 (8.4) | |
Pathological tumor size (mm) | 38.7±19.5 | 37.9±19.4 | 37.6±19.4 | 40.3±19.7 | 0.073 |
Surgical extent | |||||
Lobectomy | 1,142 (83.2) | 499 (86.6) | 245 (85.7) | 398 (77.9) | < 0.001 |
Bilobectomy | 97 (7.1) | 41 (7.1) | 8 (2.8) | 48 (9.4) | |
Pneumonectomy | 70 (5.1) | 20 (3.5) | 13 (4.5) | 37 (7.2) | |
Sleeve lobectomy | 34 (2.5) | 8 (1.4) | 11 (3.8) | 15 (2.9) | |
Segmentectomy | 30 (2.2) | 8 (1.4) | 9 (3.1) | 13 (2.5) | |
Visceral pleural invasion | 520 (37.9) | 193 (33.5) | 105 (36.7) | 222 (43.4) | 0.003 |
Lymphovascular invasion | 966 (70.4) | 375 (65.1) | 199 (69.6) | 392 (76.7) | < 0.001 |
The number of harvested LNs | 28.9±11.3 | 29.5±10.7 | 26.6±11.3 | 29.3±11.8 | 0.001 |
Pathological T factor | |||||
pT1 | 336 (24.5) | 160 (27.8) | 83 (29.0) | 93 (18.2) | < 0.001 |
pT2 | 656 (47.8) | 282 (49.0) | 141 (49.3) | 233 (45.6) | |
pT3 | 244 (17.8) | 85 (14.8) | 40 (14.0) | 119 (23.3) | |
pT4 | 137 (10.0) | 49 (8.5) | 22 (7.7) | 66 (12.9) | |
N2 subclassification | |||||
N2a1 | 279 (20.3) | 183 (31.8) | 52 (18.2) | 44 (8.6) | < 0.001 |
N2a2 | 548 (39.9) | 299 (51.9) | 66 (23.1) | 183 (35.8) | |
N2b | 546 (39.8) | 94 (16.3) | 168 (58.7) | 284 (55.6) | |
Pathological stage | |||||
IIIA | 992 (72.3) | 442 (76.7) | 224 (78.3) | 326 (63.8) | < 0.001 |
IIIB | 381 (27.7) | 134 (23.3) | 62 (21.7) | 185 (36.2) | |
Adjuvant therapy | 1,198 (87.3) | 498 (86.5) | 242 (84.6) | 458 (89.6) | 0.095 |
Chemoradiation therapy | 709 (51.6) | 284 (49.3) | 148 (51.7) | 277 (54.2) | 0.272 |
Chemotherapy only | 303 (22.1) | 137 (23.8) | 59 (20.6) | 107 (20.9) | 0.425 |
Radiotherapy only | 186 (13.5) | 77 (13.4) | 35 (12.2) | 74 (14.5) | 0.665 |
None | 175 (12.7) | 78 (13.5) | 44 (15.4) | 53 (10.4) | 0.095 |
Variable | Univariate |
Multivariate |
||
---|---|---|---|---|
HR (95% CI) | p-value | HR (95% CI) | p-value | |
Age | 1.00 (1.00-1.01) | 0.413 | ||
Sex (male vs. female) | 0.87 (0.75-1.01) | 0.066 | ||
Smoking history | 0.92 (0.80-1.07) | 0.297 | ||
No. of comorbidities | ||||
2 vs. 0-1 | 1.21 (0.98-1.48) | 0.072 | ||
≥ 3 vs. 0-1 | 1.03 (0.73-1.45) | 0.857 | ||
FEV1 < 60% | 0.78 (0.49-1.24) | 0.288 | ||
DLCO < 60% | 1.25 (0.89-1.75) | 0.190 | ||
Clinical N category | ||||
cN1 vs. cN0 | 1.41 (1.15-1.72) | 0.001 | ||
cN2 vs. cN0 | 1.36 (1.15-1.60) | < 0.001 | ||
Location (right vs. left) | 1.01 (0.87-1.17) | 0.939 | ||
Surgical approach | ||||
Thoracotomy vs. VATS | 1.24 (1.06-1.44) | 0.006 | ||
Conversion vs. VATS | 1.31 (0.95-1.80) | 0.103 | ||
Histology | ||||
Sqcc vs. adenoca | 0.69 (0.57-0.83) | < 0.001 | 0.67 (0.55-0.82) | < 0.001 |
Others vs. adenoca | 1.26 (0.94-1.69) | 0.117 | 1.19 (0.88-1.60) | 0.259 |
Histologic grade | ||||
Grade II vs. Grade I | 0.91 (0.59-1.39) | 0.652 | ||
Grade III vs. Grade I | 1.00 (0.64-1.55) | 0.998 | ||
Cannot be assessed vs. Grade I | 1.40 (0.86-2.29) | 0.174 | ||
Pathological tumor size (mm) | 1.01 (1.00-1.01) | < 0.001 | ||
Surgical extent | ||||
Segmentectomy vs. lobectomy | 0.89 (0.49-1.62) | 0.702 | ||
Bilobectomy vs. lobectomy | 1.16 (0.87-1.55) | 0.310 | ||
Pneumonectomy vs. lobectomy | 1.50 (1.12-2.01) | 0.007 | ||
Sleeve lobectomy vs. lobectomy | 1.34 (0.85-2.12) | 0.205 | ||
Visceral pleural invasion | 1.41 (1.22-1.64) | < 0.001 | ||
Lymphovascular invasion | 1.21 (1.03-1.43) | 0.021 | ||
No. of harvested LNs | 1.01 (1.00-1.01) | 0.112 | ||
Subdivided N2 descriptor | ||||
pN2a2 vs. pN2a1 | 1.42 (1.14-1.78) | 0.002 | 1.38 (1.10-1.73) | 0.006 |
pN2b vs. pN2a1 | 2.11 (1.70-2.62) | < 0.001 | 1.76 (1.39-2.23) | < 0.001 |
Pathological stage | ||||
IIIB vs. IIIA | 1.46 (1.24-1.71) | < 0.001 | 1.32 (1.12-1.56) | 0.001 |
Resection status (IASLC) | ||||
R(un) vs. R0 | 1.42 (1.16-1.73) | 0.001 | 1.18 (0.96-1.46) | 0.123 |
R1/2 vs. R0 | 1.88 (1.59-2.22) | < 0.001 | 1.58 (1.31-1.90) | < 0.001 |
Adjuvant therapy | 0.53 (0.43-0.66) | < 0.001 | 0.45 (0.36-0.57) | < 0.001 |
Variable | Total |
N2a1 |
N2a2 |
N2b |
||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
R0 (n=576) | R(un) (n=286) | p-value | R0 (n=183) | R(un) (n=52) | p-value | R0 (n=299) | R(un) (n=66) | p-value | R0 (n=94) | R(un) (n=168) | p-value | |
Overall | 248 (43.1) | 156 (54.5) | 0.002 | 64 (35.0) | 24 (46.2) | 0.191 | 138 (46.2) | 33 (50.0) | 0.667 | 46 (48.9) | 99 (58.9) | 0.152 |
Locoregional | 46 (8.0) | 18 (6.3) | 0.451 | 14 (7.7) | 4 (7.7) | > 0.99 | 24 (8.0) | 2 (3.0) | 0.244 | 8 (8.5) | 12 (7.1) | 0.875 |
Distant | 137 (23.8) | 112 (39.2) | < 0.001 | 33 (18.0) | 17 (32.7) | 0.037 | 74 (24.7) | 25 (37.9) | 0.044 | 30 (31.9) | 70 (41.7) | 0.154 |
Mixed | 65 (11.3) | 26 (9.1) | 0.385 | 17 (9.3) | 3 (5.8) | 0.602 | 40 (13.4) | 6 (9.1) | 0.456 | 8 (8.5) | 17 (10.1) | 0.837 |
Variable | Overall |
Locoregional |
Distant |
Mixed |
||||
---|---|---|---|---|---|---|---|---|
HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | |
Highest LN positivity |
1.17 (0.93-1.48) | 0.177 | 0.61 (0.32-1.18) | 0.142 | 1.44 (1.08-1.92) | 0.013 | 0.95 (0.56-1.60) | 0.842 |
N2 subclassification | ||||||||
N2a2 vs. N2a1 | 1.48 (1.14-1.92) | 0.004 | 1.24 (0.67-2.32) | 0.498 | 1.45 (1.03-2.05) | 0.034 | 1.77 (1.04-3.03) | 0.036 |
N2b vs. N2a1 | 1.79 (1.34-2.40) | < 0.001 | 1.99 (0.97-4.06) | 0.059 | 1.85 (1.28-2.69) | 0.001 | 1.52 (0.80-2.88) | 0.204 |
Values are presented as mean±standard deviation or number (%). DLCO, diffusing capacity to carbon monoxide; FEV1, forced expiratory volume in 1 second; IASLC, International Association for the Study of Lung Cancer; LN, lymph node; NSCLC, non–small cell lung cancer; R, resection; R0, complete resection; R1/2, incomplete resection; R(un), uncertain resection; VATS, video-assisted thoracic surgery.
Adenoca, adenocarcinoma; CI, confidence interval; DLCO, diffusing capacity to carbon monoxide; FEV1, forced expiratory volume in 1 second; HR, hazard ratio; IASLC, International Association for the Study of Lung Cancer; LN, lymph node; pN2, pathologic N2; R0, complete resection; R1/2, incomplete resection; R(un), uncertain resection; Sqcc, squamous cell carcinoma; VATS, video-assisted thoracic surgery.
Values are presented as number (%). Mixed, both locoregional and distant recurrence; R0, complete resection; R(un), uncertain resection.
CI, confidence interval; HR, hazard ratio; LN, lymph node; Mixed, locoregional and distant recurrence; R0, complete resection; R(un), uncertain resection. Adjustment by age, sex, histology (adenocarcinoma, squamous cell carcinoma, and others), pathological stage (IIIA, and IIB), N2 subtype (N2a1, N2a2, and N2b), and adjuvant therapy.