Patient characteristics
Between January 2005 and October 2019, a total of 1330 patients with lung cancer underwent surgical resection at our institution. Of these, 192 patients (14.4%) met the inclusion criteria. A total of 62 patients had at least 1 exclusion criterion (Supplementary Fig. 1).
A total of 130 patients with COPD who underwent surgical resection of lung cancer and who received perioperative rehabilitation were enrolled in this study. The patients were divided into 3 subgroups according to their perioperative management: the LAMA/LABA group (n = 64), the LAMA group (n = 23), and the No-BD group (rehabilitation only; n = 43). The main patient characteristics are summarized in Table 1. Patients who received LAMA/LABA therapy were significantly older than patients in the LAMA group (p = 0.045) and those in the No-BD group (p = 0.014). There was no significant difference between patients in the LAMA/LABA group and the other groups with regard to sex, smoking status or pack-years of smoking.
Table 1
| Patients with COPD (n = 130) |
| LABA/LAMA | LAMA | p value* | No-BD | p value** |
n = 64 | n = 23 | n = 43 |
Age | 73.4 ± 6.7 | 70.6 ± 6.5 | 0.045 | 70.5 ± 6.2 | 0.014 |
Sex | | | | | |
Male | 50 (78.1) | 19 (82.6) | 0.644 | 39 (90.7) | 0.088 |
Female | 14 (21.9) | 4 (17.4) | | 4 (9.3) | - |
Smoking status | | | | | |
Current smoker | 25 (39.0) | 11 (47.8) | 0.466 | 18 (41.9) | 0.772 |
Ex-smoker | 39 (61.0) | 12 (52.2) | | 25 (58.1) | |
Tobacco, pack-years | 53.2 ± 27.3 | 60.6 ± 29.4 | 0.86 | 63.8 ± 40.2 | 0.976 |
Pulmonary function | | | | | |
FEV1 (mL) | 1787.5 ± 558.8 | 1429.5 ± 412.5 | 0.003 | 2168.8 ± 535.2 | 0.999 |
FEV1/FVC (%) | 58.3 ± 9.6 | 53. 4 ± 11.4 | 0.027 | 61.4 ± 10.2 | 0.947 |
FEV1 %pred (%) | 85.3 ± 22.6 | 64.3 ± 12.4 | < 0.001 | 94.6 ± 2.9 | 0.991 |
Severity of AFL | | | | | |
Mild | 32 (50.0) | 1 (4.4) | < 0.001 | 36 (83.7) | 0.002 |
Moderate to Severe | 32 (50.0) | 22 (95.6) | | 7 (16.3) | |
Surgical procedure | | | | | |
Pneumonectomy | 1 (1.6) | 0 | 0.367 | 0 | 0.844 |
Lobectomy | 56 (87.5) | 23 (100.0) | | 40 (93.0) | |
Segmentectomy | 2 (3.1) | 0 | | 1 (2.3) | |
Partial resection | 5 (7.8) | 0 | | 2 (4.7) | |
Histology | | | | | |
Adenocarcinoma | 31 (48.4) | 6 (26.1) | 0.172 | 26 (60.5) | 0.412 |
Squamous cell carcinoma | 28 (43.8) | 14 (60.9) | | 15 (34.9) | |
Other | 5 (7.8) | 3 (13.0) | | 2 (4.6) | |
Pathologic staging | | | | | |
I | 50 (78.1) | 11 (47.8) | 0.063 | 33 (76.7) | 0.706 |
II | 8 (12.5) | 9 (39.0) | | 3 (7.0) | |
III | 6 (9.4) | 3 (13.0) | | 7 (16.3) | |
Recurrence (present) | 7 (10.9) | 11 (47.8) | < 0.001 | 15 (34.9) | 0.008 |
Data are presented as n (%) or as mean ± SD; *Significance of LAMA/LABA vs LAMA; **Significance of LAMA/LABA vs No-BD; COPD: chronic obstructive pulmonary disease; LAMA: long-acting muscarinic antagonists; LABA: long-acting β2 –agonists; BD: bronchodilator; FEV1: forced expiratory volume in 1 second; FEV1%pred: percentage of predicted forced expiratory volume in 1 second; FVC: forced vital capacity; AFL: airflow limitation; |
Pulmonary function at the initial visit was significantly worse in the LAMA group than in the LAMA/LABA group, as measured by FEV1, FEV1/FVC, and the percentage of predicted FEV1 (FEV1% pred) (p < 0.05 for all). The LAMA group had a higher proportion of patients with moderate to severe AFL than the LAMA/LABA group (p < 0.001), while the No-BD group included a higher proportion of patients with mild AFL (p = 0.002).
Perioperative inhaled therapy
The components of perioperative inhaled therapy are provided in Supplementary Table 1. In the LAMA/LABA group, patients received a LAMA plus a LABA (n = 11) or a combined LAMA/LABA agent (n = 53). All patients in the LAMA group received inhaled tiotropium bromide hydrate. The average duration of preoperative inhalation therapy in the LAMA/LABA group and the LAMA group was 27.7 days and 24.5 days, respectively. The postoperative inhalation period was 396.6 days and 827.2 days, respectively.
Improvement in lung function with preoperative inhaled LAMA/LABA therapy
We reassessed lung function 1 or 2 days before surgery. The values for FEV1 and FEV1 %pred were significantly improved in the LAMA/LABA group (both p < 0.001; Fig. 1A, B). In the LAMA/LABA group, the treatment response tended to correlate with the severity of AFL. The patients with severe AFL showed an excellent response compared with patients with mild or moderate AFL (both p < 0.05; Fig. 1C). We also compared the improvement in lung function between the LAMA/LABA group and the LAMA group. The increases in FEV1 and FEV1 %pred were significantly higher for LAMA/LABA therapy than for LAMA therapy (ΔFEV1, 223.1 mL vs 130.0 mL; ΔFEV1 %pred, 10.8% vs 6.8%; both p < 0.05; Fig. 2A, B). The proportion of excellent treatment response was also higher in the LAMA/LABA group (ΔFEV1 > 200 mL, 59.4% vs 17.4%; ΔFEV1 > 300 mL, 34.4% vs 4.4%; both p < 0.05; Fig. 2C)
Postoperative morbidity and mortality
Patient characteristics are given in Table 1. There was no significant difference between patients in the LAMA/LABA group and the other groups with regard to the type of surgical procedure performed. Most patients underwent lobectomy (LAMA/LABA, 87.5%; LAMA, 100%; No-BD, 93.9%). Postoperative complications and mortality are summarized in Table 2. Postoperative complications were more frequent in the LAMA group than in the LAMA/LABA group (p = 0.007). The proportion of patients who required home oxygen therapy was higher in the LAMA group than in the LAMA/LABA group (p = 0.008). Prolonged air leakage was more frequent in the No-BD group than in the LAMA/LABA group (p = 0.012). The incidence of all postoperative complications was lower in the LAMA/LABA group than in the other groups. Only the LAMA/LABA group had no mortality at 90 days.
Table 2
Postoperative complications and mortality
| Patients with COPD (n = 130) |
| LABA/LAMA | LAMA | p value* | No-BD | p value** |
n = 64 | n = 23 | n = 43 |
Complications | | | | | |
Any | 14 (21.9) | 12 (52.2) | 0.007 | 16 (37.2) | 0.083 |
Pneumonia | 7 (11.0) | 6 (26.1) | 0.081 | 7 (16.3) | 0.422 |
Prolonged air leakage | 6 (9.4) | 5 (21.7) | 0.126 | 11 (25.6) | 0.012 |
Atrial fibrillation | 4 (6.3) | 2 (8.7) | 0.776 | 4 (10.5) | 0.557 |
Introduction of HOT | 3 (4.7) | 3 (13.0) | 0.008 | 0 | 0.176 |
30-day mortality | 0 | 0 | - | 0 | - |
90-day mortality | 0 | 1 (4.4) | 0.093 | 1 (2.3) | 0.246 |
Data are presented as n (%) COPD: chronic obstructive pulmonary disease; LAMA: long-acting muscarinic antagonists; LABA: long-acting β2 –agonists; BD: bronchodilator; HOT: home oxygen therapy |
*Significance of LAMA/LABA vs LAMA **Significance of LAMA/LABA vs No-BD |
Survival analysis of all patients
Patient characteristics are presented in Table 1. There was no significant difference between patients in the LAMA/LABA group and the other groups in regard to tumor histology, pathologic staging. Although a comparable proportion of patients received adjuvant chemotherapy or treatment for recurrence in all groups (data not shown), the recurrence rate was significantly lower in the LAMA/LABA group compared with both the LAMA group (p < 0.001) and the No-BD group (p = 0.008).
Five patients (7.8%) in the LAMA/LABA group, 14 patients (60.8%) in the LAMA group, and 20 patients (46.5%) in the No-BD group died during the study period. The causes of death for these 39 patients are given in Supplementary Table 2. Lung-cancer related death was the most frequent cause in all groups. No patients in the LAMA/LABA group died of pneumonia. The cumulative OS at 5 years was 79.8% in the LAMA/LABA group, 53.2% in the LAMA group, and 51.7% in the No-BD group (Fig. 3A). The DFS at 5 years was 70.8%, 39.2%, and 39.9%, respectively (Fig. 3B). The patients in the LAMA/LABA group had significantly longer OS and DFS than patients in the LAMA group (p = 0.021; p = 0.017), and longer DFS than patients in the No-BD group (p = 0.044).
Survival analysis of patients with moderate to severe AFL
We assessed the effects of perioperative inhaled LAMA/LABA therapy on the prognosis of patients with moderate to severe AFL. A total of 51 patients with moderate to severe AFL were included in the study. Of these, 32 were in the LAMA/LABA group, 12 were in the LAMA group, and 7 were in the No-BD group. Patient characteristics are given in Table 3. There was no significant difference between patients in the LAMA/LABA group and the other groups in regard to age, sex, smoking status, severity of AFL, surgical procedure, pathologic staging, or treatment for recurrence. A comparable proportion of patients received adjuvant chemotherapy in all groups. As seen in the analysis of COPD patients of all severities, the recurrence rate was significantly lower in the LAMA/LABA group compared with the LAMA group (p = 0.006) and the No-BD group (p = 0.008; Table 3).
Table 3
Characteristics of patients with moderate to severe airflow limitation
| Patients with moderate to severe AFL (n = 61) |
| LABA/LAMA | LAMA | p value* | No-BD | p value** |
n = 32 | n = 22 | n = 7 |
Age | 72. 2 ± 6.7 | 70.8 ± 6.6 | 0.236 | 69.9 ± 5.6 | 0.203 |
Sex | | | 0.804 | | 0.929 |
Male | 27 (84.4) | 18 (81.8) | | 6 (85.7) | |
Female | 5 (15.6) | 4 (18.2) | - | 1 (14.3) | - |
Smoking status | | | 0.412 | | 0.262 |
Current smoker | 11 (34.4) | 10 (45.5) | | 4 (57.1) | |
Ex-smoker | 21 (65.6) | 12 (54.5) | | 3 (42.9) | - |
Severity of AFL | | | 0.344 | | 0.399 |
Moderate | 29 (90.6) | 18 (81.8) | | 7 (100) | |
Severe | 3 (9.4) | 4 (18.2) | | 0 | |
Surgical procedure | | | 0.098 | | 0.887 |
Lobectomy | 26 (81.3) | 22 (100) | | 6 (85.7) | |
Segmentectomy | 1 (3.1) | 0 | | 0 | |
Partial resection | 5 (15.6) | 0 | | 1 (14.3) | |
Pathologic staging | | | 0.063 | | 0.228 |
I | 16 (81.3) | 11 (50.0) | | 4 (57.1) | |
II | 2 (6.2) | 8 (36.4) | | 0 | |
III | 4 (12.5) | 3 (13.6) | | 3 (42.9) | |
Adjuvant chemotherapy | 4 (12.5) | 5 (22.7) | 0.322 | 2 (28.6) | 0.286 |
Recurrence (present) | 4 (12.5) | 10 (45.5) | 0.006 | 4 (57.1) | 0.008 |
Treatment for recurrence | | | | | |
Anticancer drug | 2 | 6 | | 3 | |
Molecular targeted drug | 0 | 1 | | 1 | |
ICI | 0 | 0 | | 0 | |
None | 2 | 2 | | 0 | |
Data are presented as n (%) or as mean ± SD; COPD: chronic obstructive pulmonary disease; LAMA: long-acting muscarinic antagonists; LABA: long-acting β2 –agonists; BD: bronchodilator; AFL: airflow limitation; ICI: Immune checkpoint inhibitor |
The OS in the LAMA/LABA, LAMA, and No-BD groups at 5 years was 82.7%, 55.8%, and 28.6%, respectively (Fig. 4A). The DFS at 5 years was 75.3%, 41.1%, and 14.3% (Fig. 4B). The patients in the LAMA/LABA group had significantly longer OS and DFS compared with the LAMA group (p = 0.043; p = 0.026) and with the No-BD group (p = 0.002; p < 0.001).
Univariate and multivariate analyses of beneficial factors for long-term mortality
On univariate analysis, a low pathologic stage and perioperative LAMA/LABA therapy were beneficial factors for long-term mortality. On multivariate analysis, perioperative LAMA/LABA therapy remained a beneficial factor (Table 4A). Only perioperative LAMA/LABA therapy was identified as a beneficial factor for recurrence on both univariate and multivariate analyses (Table 4B).
Table 4. Univariate and multivariate analysis of favorable factors for postoperative prognosis in patients with moderate to severe AFL
A. Analysis of favorable factors for overall survival
Clinicopathologic variable
|
Univariate analysis
|
Multivariate analysis
|
RR
|
95%CI
|
p value
|
RR
|
95%CI
|
p value
|
Sex (male)
|
1.24
|
0.35–3.38
|
0.703
|
-
|
-
|
-
|
Age (< 75 y)
|
0.88.
|
0.44–3.50
|
0.797
|
-
|
-
|
-
|
Histology:
|
|
|
0.083
|
-
|
-
|
-
|
Squamous cell carcinoma
|
1.00
|
reference
|
|
-
|
-
|
-
|
Adenocarcinoma
|
0.46
|
0.17–1.13
|
0.094
|
-
|
-
|
-
|
Other
|
0.17
|
0.01–1.08
|
0.051
|
-
|
-
|
-
|
Lymph node metastasis (absent)
|
0.61
|
0.25–1.55
|
0.289
|
-
|
-
|
-
|
Pathologic stage:
|
|
|
0.027
|
|
|
0.154
|
I
|
1.00
|
reference
|
|
1.00
|
reference
|
|
II
|
2.96
|
0.11–0.94
|
0.052
|
2.25
|
0.65–7.36
|
0.190
|
III
|
3.65
|
0.08–0.77
|
0.024
|
2.58
|
0.80–8.07
|
0.107
|
Bronchodilator
|
|
|
0.011
|
|
|
0.062
|
LAMA/LABA
|
1.00
|
reference
|
|
1.00
|
reference
|
|
LAMA
|
3.26
|
0.99–14.1
|
0.049
|
2.43
|
0.66–11.2
|
0.186
|
No-BD
|
7.54
|
1.97-35.4
|
0.003
|
5.59
|
1.31-21.5
|
0.019
|
COPD: chronic obstructive pulmonary disease; LAMA: long-acting muscarinic antagonists; LABA: long-acting β2 –agonists; BD: bronchodilator; RR: relative risk ; CI: confidence interval
|
B. Analysis of favorable factors for disease-free survival
Clinicopathologic variable
|
Univariate analysis
|
Multivariate analysis
|
RR
|
95%CI
|
p value
|
RR
|
95%CI
|
p value
|
Sex (male)
|
1.18
|
0.44–4.07
|
0.757
|
-
|
-
|
-
|
Age (< 75 y)
|
0.58
|
0.19–1.45
|
0.265
|
-
|
-
|
-
|
Histology:
|
|
|
0.038
|
|
|
0.362
|
Squamous cell carcinoma
|
1.00
|
reference
|
|
1.00
|
reference
|
|
Adenocarcinoma
|
0.42
|
0.17–0.96
|
0.039
|
0.56
|
0.18–1.73
|
0.311
|
Other
|
0.16
|
0.08–0.90
|
0.035
|
0.22
|
0.01–1.56
|
0.142
|
Lymph node metastasis (absent)
|
0.48
|
0.22–1.12
|
0.091
|
-
|
-
|
-
|
Pathologic stage
|
|
|
0.007
|
|
|
0.065
|
I
|
1.00
|
reference
|
|
1.00
|
reference
|
|
II
|
3.21
|
1.17–8.16
|
0.024
|
1.48
|
0.41–5.55
|
0.541
|
III
|
4.13
|
1.47–10.9
|
0.008
|
2.01
|
0.55–6.77
|
0.278
|
Bronchodilator
|
|
|
0.003
|
|
|
0.025
|
LAMA/LABA
|
1.00
|
reference
|
|
1.00
|
reference
|
|
LAMA
|
3.14
|
1.16–9.91
|
0.023
|
2.47
|
0.78–8.45
|
0.120
|
No-BD
|
7.29
|
2.17–25.5
|
0.001
|
6.04
|
1.63–23.6
|
0.007
|
COPD: chronic obstructive pulmonary disease; LAMA: long-acting muscarinic antagonists; LABA: long-acting β2 –agonists; BD: bronchodilator; RR: relative risk; CI: confidence interval
|