*P value for chi-square test or Fisher’s exact test.
†P value for McNemar’s test or general McNemar’s test.
‡The 6th Edition of the AJCC Cancer Staging Manual.
§Isotope, implant or the combination.
The median follow-up was 25 months. Cancer-specific survival (HR=0.863, 95%CI: 0.771 to 0.965, P=0.010) and OS (HR=0.875, 95%CI: 0.793 to 0.967, P=0.008) were significantly superior with left-sided pneumonectomy compared with right-sided pneumonectomy with the 5-year OS rate of 36.4% (95%CI: 33.4% to 39.6%) and 40.2% (95%CI: 37.5% to 43.1%) for patients received right-sided and left-sided pneumonectomy respectively (eFigure 2). After multivariable adjustment, differences were also significant between left-sided and right-sided pneumonectomy both in cancer-specific survival (HR=0.836, 95%CI :0.746 to 0.937, P=0.002) and OS (HR=0.841, 95%CI: 0.760 to 0.929, P<0.001) (Table 2).
Table 2
Prognostic Factors for Overall and Cancer-specific Survival in All Stage I-IIIA NSCLC Patients with Pneumonectomy in Original Data Set
Variable
|
Overall Survival
|
Cancer-specific Survival
|
Unadjusted
|
Adjusted
|
Unadjusted
|
Adjusted
|
HR (95% CI)
|
P
|
HR (95% CI)
|
P
|
HR (95% CI)
|
P
|
HR (95% CI)
|
P
|
Age
|
|
|
|
|
|
|
|
|
Up to 40 years
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
41 to 69 years
|
1.944(1.073-3.520)
|
0.028
|
2.104(1.158-3.825)
|
0.015
|
1.694(0.908-3.159)
|
0.098
|
1.918(1.024-3.591)
|
0.042
|
70+ years
|
3.143(1.728-5.717)
|
<0.001
|
3.333(1.824-6.090)
|
<0.001
|
2.421(1.290-4.542)
|
0.006
|
2.726(1.446-5.140)
|
0.002
|
Gender
|
|
|
|
|
|
|
|
|
Male
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
Female
|
0.817(0.734-0.910)
|
<0.001
|
0.809(0.723-0.905)
|
<0.001
|
0.895(0.794-1.009)
|
0.070
|
0.861(0.759-0.975)
|
0.019
|
Race/ethnicity
|
|
|
|
|
|
|
|
|
Caucasian
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
African-American
|
0.909(0.756-1.093)
|
0.310
|
0.967(0.802-1.166)
|
0.726
|
0.921(0.748-1.133)
|
0.437
|
0.952(0.771-1.176)
|
0.652
|
Asian
|
0.977(0.755-1.265)
|
0.861
|
0.918(0.707-1.192)
|
0.523
|
1.050(0.791-1.395)
|
0.735
|
0.956(0.718-1.274)
|
0.763
|
Other/Unknown
|
0.561(0.325-0.968)
|
0.038
|
0.597(0.345-1.035)
|
0.066
|
0.454(0.226-0.910)
|
0.026
|
0.480(0.238-0.966)
|
0.039
|
Year of diagnosis
|
|
|
|
|
|
|
|
|
2004 - 2007
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
2008 - 2011
|
0.811(0.726-0.905)
|
<0.001
|
0.817(0.731-0.914)
|
<0.001
|
0.771(0.681-0.872)
|
<0.001
|
0.773(0.682-0.877)
|
<0.001
|
2012 - 2014
|
0.779(0.658-0.922)
|
0.004
|
0.880(0.741-1.044)
|
0.143
|
0.709(0.585-0.859)
|
<0.001
|
0.785(0.646-0.954)
|
0.015
|
Tumor stage‡
|
|
|
|
|
|
|
|
|
Stage I
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
Stage II
|
1.147(1.014-1.298)
|
0.029
|
0.861(0.622-1.193)
|
0.369
|
1.355(1.171-1.568)
|
<0.001
|
1.070(0.750-1.526)
|
0.706
|
Stage IIIA
|
1.455(1.283-1.649)
|
<0.001
|
0.744(0.423-1.308)
|
0.304
|
1.824(1.576-2.111)
|
<0.001
|
0.960(0.520-1.771)
|
0.897
|
Clinical T stage
|
|
|
|
|
|
|
|
|
T1
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
T2
|
1.210(1.026-1.427)
|
0.023
|
1.267(1.070-1.499)
|
0.006
|
1.443(1.179-1.767)
|
<0.001
|
1.484(1.207-1.824)
|
<0.001
|
T3
|
1.347(1.113-1.632)
|
0.002
|
1.723(1.293-2.296)
|
<0.001
|
1.749(1.393-2.196)
|
<0.001
|
2.002(1.45-2.766)
|
<0.001
|
TX
|
1.359(0.558-3.309)
|
0.499
|
1.256(0.511-3.090)
|
0.619
|
1.264(0.401-3.984)
|
0.688
|
0.946(0.297-3.008)
|
0.925
|
Clinical N stage
|
|
|
|
|
|
|
|
|
N0
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
N1
|
1.175(1.046-1.320)
|
0.006
|
1.593(1.152-2.202)
|
0.005
|
1.308(1.143-1.497)
|
<0.001
|
1.454(1.024-2.063)
|
0.036
|
N2
|
1.484(1.307-1.684)
|
<0.001
|
2.370(1.399-4.016)
|
0.001
|
1.780(1.542-2.054)
|
<0.001
|
2.165(1.225-3.826)
|
0.007
|
Original site
|
|
|
|
|
|
|
|
|
Lung lobe
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
Main bronchus
|
0.889(0.745-1.062)
|
0.195
|
0.894(0.746-1.072)
|
0.227
|
0.915(0.749-1.117)
|
0.381
|
0.931(0.759-1.141)
|
0.492
|
Overlapping lesion of lung
|
0.888(0.738-1.069)
|
0.209
|
0.852(0.706-1.027)
|
0.094
|
0.958(0.782-1.175)
|
0.684
|
0.909(0.739-1.118)
|
0.367
|
NOS
|
1.507(1.148-1.979)
|
0.003
|
1.508(1.146-1.986)
|
0.003
|
1.467(1.074-2.006)
|
0.016
|
1.440(1.051-1.974)
|
0.023
|
Histology
|
|
|
|
|
|
|
|
|
Adenocarcinoma
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
Squamous cell carcinoma
|
1.041(0.929-1.165)
|
0.485
|
0.979(0.868-1.104)
|
0.737
|
0.914(0.805-1.037)
|
0.164
|
0.863(0.754-0.988)
|
0.032
|
Large cell carcinoma
|
1.474(1.155-1.882)
|
0.002
|
1.373(1.072-1.758)
|
0.012
|
1.593(1.231-2.061)
|
<0.001
|
1.469(1.131-1.907)
|
0.004
|
Other
|
1.348(1.045-1.738)
|
0.021
|
1.337(1.034-1.729)
|
0.026
|
1.329(1.004-1.759)
|
0.046
|
1.302(0.981-1.727)
|
0.067
|
NSCLC NOS
|
1.011(0.830-1.232)
|
0.912
|
0.977(0.799-1.195)
|
0.824
|
0.989(0.794-1.233)
|
0.928
|
0.918(0.733-1.149)
|
0.456
|
Lymph node dissection
|
|
|
|
|
|
|
|
|
1 to 3 removed
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
4 or more removed
|
0.846(0.685-1.045)
|
0.120
|
0.845(0.682-1.047)
|
0.125
|
0.942(0.732-1.212)
|
0.642
|
0.916(0.709-1.184)
|
0.506
|
None/Unknown
|
0.964(0.737-1.260)
|
0.788
|
0.989(0.754-1.297)
|
0.936
|
1.128(0.827-1.539)
|
0.448
|
1.153(0.842-1.578)
|
0.374
|
Radiotherapy
|
|
|
|
|
|
|
|
|
None/Unknown
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
Other§
|
1.714(0.992-2.961)
|
0.053
|
2.278(1.310-3.962)
|
0.003
|
1.884(1.040-3.415)
|
0.037
|
2.256(1.236-4.118)
|
0.008
|
Beam radiation
|
1.162(1.033-1.306)
|
0.012
|
1.238(1.083-1.416)
|
0.002
|
1.280(1.124-1.457)
|
<0.001
|
1.217(1.050-1.411)
|
0.009
|
Chemotherapy
|
|
|
|
|
|
|
|
|
Yes
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
No/Unknown
|
1.479(1.340-1.633)
|
<0.001
|
1.741(1.555-1.950)
|
<0.001
|
1.255(1.123-1.404)
|
<0.001
|
1.577(1.388-1.791)
|
<0.001
|
Cancer side
|
|
|
|
|
|
|
|
|
Right-sided
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
Left-sided
|
0.875(0.0.793-0.967)
|
0.008
|
0.841(0.760-0.929)
|
<0.001
|
0.863(0.771-0.965)
|
0.010
|
0.836(0.746-0.937)
|
0.002
|
Abbreviations: AJCC, American Joint Committee on Cancer; Sdiff, standardized difference.
‡The 6th Edition of the AJCC Cancer Staging Manual.
§Isotope, implant or the combination.
Patients who had T2 or T3 (P<0.001), had N1(P=0.036) or N2 (P=0.007), were large cell carcinoma (P=0.004), were diagnosed before 2008 (P<0.001), were diagnosed older than 40 (P<0.042), were male (P<0.019), did not receive chemotherapy (P<0.001), received beam radiotherapy (P=0.009) or other radiotherapy (P=0.008) were associated with significant poorer cancer-specific survival in multivariate analysis (Table 2).
After propensity score matching, the propensity score for NSCLC patients who received right-sided and left-sided pneumonia were both 0.566±0.073 respectively (P=0.833) (eFigure3). After matching procedure, 2,050 patients were included for further analysis with 1,025 patients in both group (Table 1). Cancer-specific survival (HR=0.847, 95%CI: 0.745 to 0.963, P=0.011) and OS (HR=0.858, 95%CI: 0.768 to 0.959, P=0.007) were significantly longer with left-side compared with opposite side (Figure 1).
Adjuvant therapy
We further analyzed the impact of adjuvant therapy on survival. Among left-sided pneumonectomy patients, patients received adjuvant therapy (N=860) significantly prolonged cancer-specific survival (65 versus 44 months, HR=1.319, 95%CI: 1.134 to 1.534, P<0.001) and OS (47 versus 28 months, HR=1.489, 95%CI: 1.305 to 1.701, P<0.001) than patients received pneumonectomy alone (N=673) (eFigure 4). Among right-sided pneumonectomy patients, patients received adjuvant therapy (N=582) significantly prolonged OS (36 versus 25 months, HR=1.335, 95%CI: 1.152 to 1.548, P<0.001) but did not improve cancer-specific survival (46 versus 46 months, HR=1.056, 95%CI: 0.893 to 1.249, P=0.522) compared with patients received pneumonectomy alone (N=568) (eFigure 5). After matching procedure, cancer-specific survival (67 versus 51 months, HR=1.314, 95%CI: 1.093 to 1.579, P=0.004) and OS (46 versus 30 months, HR=1.458, 95%CI: 1.239 to 1.715, P<0.001) were also significantly longer for patients received adjuvant therapy (N=581) compared with patients received left-sided pneumonectomy alone (N=444) (Figure 2). Patients received right-sided pneumonectomy and adjuvant therapy (N=525) were not associated with superior cancer-specific survival (46 versus 42 months, HR=1.112, 95%CI: 0.933 to 1.325, P=0.236) compared with patients received pneumonectomy alone (N=500) although adjuvant therapy could improve OS (36 versus 25 months, HR=1.362, 95%CI: 1.165 to 1.592, P<0.001) (Figure 3).
Subgroup analysis showed that adjuvant therapy could significantly improve cancer-specific survival and OS for stage II and stage IIIA patients with pneumonectomy in both side (P<0.05). Adjuvant therapy was not associated with prolonged cancer-specific survival (P=0.687) and OS (P=0.177) for stage I patients with right-sided pneumonectomy. Although adjuvant therapy could increase OS for stage I patents with pneumonectomy in left lung (P=0.014) but no differences of cancer-specific survival were observed(P=0.273).
Subgroup analysis showed that adjuvant chemotherapy could significantly improve cancer-specific survival and OS for all pneumonectomy patients. But radiotherapy was associated with worse OS and cancer-specific survival for patients with right-sided pneumonectomy. The median OS for right-sided pneumonectomy patients received chemotherapy alone, radiotherapy alone, chemoradiotheapy and no adjuvant therapy were 54 months, 12 months, 28 months, and 25 months, respectively (P<0.001) with the median cancer-specific survival of 68 months, 13 months, 32 months, and 46 months respectively (P<0.001). Radiotherapy did not significantly improve OS and cancer-specific survival for left-sided pneumonectomy patients either. The median OS for left-sided pneumonectomy patients received chemotherapy alone, radiotherapy alone, chemoradiotheapy and no adjuvant therapy were 59 months, 33 months, 36 months, and 28 months, respectively (P<0.001) with the median cancer-specific survival of 94 months, 44 months, 44 months, and 44 months respectively (P<0.001).
OS was favorable for left-sided pneumonectomy across clinical subgroups including stage II or IIIA, squamous cell carcinoma, received chemoradiotherapy or radiotherapy (Figure 4).