Incidence
Among the 95191 patients with lung cancer, 10765 patients developed brain metastasis, with a rate of 11.31%. Patients were stratified by the primary site of tumor, median household income, residence type, age, histological type, race, gender and extracranial metastatic sites to bone or liver, the number and proportion of patients with brain metastasis from lung cancer were provided in Table 1. We found the rate of brain metastasis is highest when the primary site of tumor is main bronchus, up to 14.60%. In addition, younger patients were more likely to develop brain metastasis, the metastatic rate among patients aged 18-41 years and 41-60 years were 16.22% and 17.65%, respectively. SCLC and adenocarcinoma had higher rates of brain metastasis (16.62% and 13.37%, respectively) compared with other histological types. The incidence of brain metastasis among Asian population was 14.83%, which was higher than that in other ethnic groups. In addition, when patients had extracranial metastasis to bone and liver, the incidence of brain metastasis was as high as 28.65%.
Table 1. Incidence proportion and median overall survival of lung cancer patients with brain metastasis
Variables
|
Patients, No
|
Incidence
Proportion of Brain Metastasis, %
|
Median Overall Survival Among Patients with Brain Metastasis,
month (IQR)
|
With Lung
Cancer (n=95191)
|
With Brain Metastasis (n=10765)
|
Primary site
Upper lobe
Middle lobe
Lower lobe
Overlapping
Main bronchus
|
55082
5072
29861
1046
4130
|
6368
520
3144
130
603
|
11.56
10.25
10.53
12.43
14.60
|
6.22 (2-12)
5.43 (2-10)
6.16 (2-12)
5.61 (1-9)
4.59 (1-9)
|
Median household income
<$35000
$35000-$54999
$55000-$74999
$75000+
|
313
20882
43759
30237
|
34
2391
4742
3598
|
10.86
11.45
10.84
11.90
|
NA
5.17 (2-11)
5.55 (2-11)
7.13 (2-13)
|
Residence
Urban
Rural
|
83715
11476
|
9410
1355
|
11.24
11.81
|
6.03 (2-12)
6.51 (2-11)
|
Age
18-40
41-60
61-80
>80
|
592
18751
61352
14496
|
96
3310
6474
885
|
16.22
17.65
10.55
6.11
|
15.08 (3-19)
8.52 (2-15)
5.42 (1-11)
2.86 (1-6)
|
Histological type
Squamous cell carcinomas
Adenocarcinoma
Adenosquamous carcinoma
Neuroendocrine carcinoma
Small cell lung carcinoma
|
25071
52783
1196
3514
12627
|
1282
7056
108
221
2098
|
5.11
13.37
9.03
6.29
16.62
|
3.68 (1-7)
6.72 (2-13)
6.46 (2-13)
6.44 (1-11)
6.02 (1-10)
|
Race
White
Black
Asian
American Indian
|
76211
10647
7816
517
|
8210
1345
1159
51
|
10.77
12.63
14.83
9.86
|
5.65 (2-11)
5.93 (2-11)
9.39 (2-16)
6.77 (2-12)
|
Gender
Female
Male
|
47301
47890
|
5342
5423
|
11.29
11.32
|
6.73 (2-13)
5.40 (1-10)
|
Extracranial metastatic sites
to bone and liver
None
Liver
Bone
Liver and Bone
|
74709
11015
4601
4866
|
5963
2536
872
1394
|
7.98
23.02
18.95
28.65
|
7.48 (2-14)
5.37 (2-11)
3.51 (1-7)
3.81 (1-8)
|
In the multivariable logistic regression model for the incidence analysis of brain metastasis, the primary site: main bronchus (vs upper lobe; odds ratio [OR], 1.12; 95%CI, 1.01-1.23; P =0.024), the residence type: rural (vs urban; OR, 1.10; 95%CI, 1.02-1.18; P = 0.008), the histological type: adenocarcinoma (vs squamous cell carcinomas; OR, 2.41; 95%CI, 2.27-2.57; P<0.001), adenosquamous carcinoma (vs squamous cell carcinomas; OR, 1.62; 95%CI, 1.31-1.99; P<0.001) and small cell lung carcinoma (vs squamous cell carcinomas; OR, 2.48; 95%CI, 2.29-2.68; P<0.001), the race: Black (vs White; OR, 1.13; 95%CI, 1.06-1.21; P<0.001) and Asian (vs White; OR, 1.29; 95%CI, 1.20-1.39; P<0.001), and extracranial metastasis to liver (vs no extracranial metastasis to liver and bone; OR, 3.03; 95%CI, 2.87-3.19; P<0.001), extracranial metastasis to bone (vs no extracranial metastasis to liver and bone; OR, 2.46; 95%CI, 2.26-2.67; P<0.001) and extracranial metastasis to liver and bone (vs no extracranial metastasis to liver and bone; OR, 3.92; 95%CI, 3.66-4.21; P<0.001) were significantly more likely to have brain metastasis at diagnosis. When the primary site of lung cancer was the middle lobe (vs upper lobe; OR, 0.88; 95%CI, 0.80-0.97; P=0.009) and lower lobe (vs upper lobe; OR, 0.94; OR, 0.90-0.99; P=0.013), the risk of developing brain metastasis is significantly reduced. Furthermore, patients aged 61-80 (vs aged 18-40; OR, 0.62; 95%CI, 0.50-0.79; P<0.001) and older than 80 (vs aged 18-40; OR, 0.36; 95%CI, 0.28-0.46; P<0.001) were also associated with significantly lower odds of having brain metastasis. The median household income and gender were not associated with a risk of brain metastasis. The forest plot makes these results more intuitive (Figure 1).
Survival
In this study, 7221 deaths (83.43%) were observed among 8,655 lung cancer patients with brain metastasis, the cumulative overall survival curve showed the median OS among patients with brain metastasis was 6.05 months. Patients were stratified by the primary site of tumor, median household income, residence type, age, histological type, race, gender and extracranial metastatic sites to bone or liver, the median OS of patients with brain metastasis in each subgroup was shown in Table 1. The cumulative overall survival curves were plotted through Kaplan-Meier method and the influence of each factor on prognosis of patients with brain metastasis was identified by Log-Rank test. The results indicated that the primary site, median household income, age, histological type, race, gender and extracranial metastatic sites to bone or liver were all independent prognostic factors of brain metastasis among lung cancer patients (Figure 2).
In the multivariable Cox regression model for the analysis of all-cause mortality of brain metastasis patients among lung cancer, main bronchus (vs upper lobe; hazard ratio [HR], 1.18; 95%CI, 1.07-1.31; P=0.001), age 41-60 years (vs age 18-40 years; HR, 1.45; 95%CI, 1.10-1.91; P=0.009), age 61-80 years (vs age 18-40 years; HR,1.91; 95%CI, 1.45-2.51; P<0.001) and age older than 80 years (vs aged 18-40 years; HR, 3.24; 95%CI, 2.44-4.29; P<0.001), male (vs female; HR, 1.13; 95%CI, 1.08-1.18, P<0.001) and extracranial metastasis to liver (vs no extracranial metastasis to liver and bone; HR, 1.34; 95%CI, 1.26-1.42; P<0.001), extracranial metastasis to bone (vs no extracranial metastasis to liver and bone; HR, 1.80; 95%CI, 1.65-1.96; P<0.001) and extracranial metastasis to liver and bone (vs no extracranial metastasis to liver and bone; HR, 1.75; 95%CI, 1.63-1.87; P<0.001) were significantly associated with a higher all-cause mortality. In addition,$55000-$74999 (vs$35000-$54999; HR, 0.90; 95%CI, 0.84-0.97; P=0.004) and$75000+ (vs$35000-$54999; HR, 0.80; 95%CI, 0.75-0.86; P<0.001), adenocarcinoma (vs squamous cell carcinomas; HR, 0.66; 95%CI, 0.61-0.71; P<0.001), adenosquamous carcinoma (vs squamous cell carcinomas; HR, 0.78; 95%CI, 0.61-0.98; P<0.001), neuroendocrine carcinoma (vs squamous cell carcinomas; HR, 0.69; 95%CI, 0.58-0.82; P<0.001) and small cell lung carcinoma (vs squamous cell carcinomas; HR, 0.80; 95%CI, 0.74-0.88; P<0.001) and Asian (vs White; HR, 0.77; 95%CI, 0.71-0.83; P<0.001) were associated with a lower all-cause mortality. The results were showed in Table 2.
Table 2 Multivariable Cox regression for all-cause mortality and cancer–specific mortality among patients with brain metastasis
Variables
|
Patients with brain metastasis (n=8255)
|
All-Cause Mortality
|
Cancer-Specific Mortality
|
Hazard Ratio (95CI%)
|
P-value
|
Hazard Ratio (95CI%)
|
P-value
|
Primary site
Upper lobe
Middle lobe
Lower lobe
Overlapping
Main bronchus
|
5123
418
2544
98
472
|
Reference
1.10 (0.99-1.23)
0.98 (0.93-1.03)
1.12 (0.90-1.39)
1.18 (1.07-1.31)
|
NA
0.078
0.490
0.316
0.001
|
Reference
1.03(0.92-1.16)
0.96(0.91-1.01)
1.02(0.81-1.28)
1.14(1.02-1.26)
|
NA
0.620
0.110
0.880
0.022
|
Median household income
$35000-$54999
$55000-$74999
$75000+
|
1328
3811
3516
|
Reference
0.90(0.84-0.97)
0.80(0.75-0.86)
|
NA
0.004
<0.001
|
0.93(0.87-1.00)
0.85(0.79-0.91)
|
NA
0.056
<0.001
|
Age
18-40
41-60
61-80
>80
|
80
2649
5181
745
|
Reference
1.45(1.10-1.91)
1.91(1.45-2.51)
3.24(2.44-4.29)
|
NA
0.009
<0.001
<0.001
|
1.41(1.11-1.79)
1.67(1.32-2.11)
2.40(1.87-3.08)
|
NA
0.005
<0.001
<0.001
|
Histological type
Squamous cell carcinomas
Adenocarcinoma
Adenosquamous carcinoma
Neuroendocrine carcinoma
Small cell lung carcinoma
|
970
5770
88
179
1648
|
Reference
0.66(0.61-0.71)
0.78(0.61-0.98)
0.69(0.58-0.82)
0.80(0.74-0.88)
|
NA
<0.001
0.033
<0.001
<0.001
|
0.74(0.68-0.80)
0.91(0.74-1.12)
0.75(0.62-0.90)
0.90(0.82-0.98)
|
NA
<0.001
0.350
0.002
0.019
|
Race
White
Black
Asian
American Indian
|
6209
1292
1112
42
|
Reference
0.98(0.91-1.05)
0.77(0.71-0.83)
1.08(0.78-1.50)
|
NA
0.512
<0.001
0.626
|
NA
0.93(0.87-1.00)
0.83(0.77-0.89)
1.00(0.74-1.36)
|
NA
0.040
<0.001
0.990
|
Gender
Female
Male
|
4352
4303
|
Reference
1.13(1.08-1.18)
|
NA
<0.001
|
NA
1.11(1.06-1.16)
|
NA
<0.001
|
Extracranial metastatic sites
to bone and liver
None
Liver
Bone
Liver and Bone
|
4766
2085
708
1096
|
Reference
1.34(1.26-1.42)
1.80(1.65-1.96)
1.75(1.63-1.87)
|
NA
<0.001
<0.001
<0.001
|
NA
1.30(1.23-1.38)
1.60(1.47-1.75)
1.59(1.48-1.71)
|
NA
<0.001
<0.001
<0.001
|
In the Fine and Gray’s competing risk regression model for the analysis of cancer-specific mortality of brain metastasis patients among lung cancer, $55000-$74999 (vs$35000-$54999; HR, 0.93; 95%CI, 0.87-1.00; P=0.056) and adenosquamous carcinoma (vs squamous cell carcinomas; HR, 0.91; 95%CI, 0.74-1.12; P=0.350) were not significantly associated with a lower cancer-specific mortality. The results were also showed in Table 2. Based on the results of Fine and Gray’s competing risk regression, we developed a novel visual nomogram to predict the cancer-specific survival of lung cancer patients with brain metastasis, showed in Figure 3. A patient’s cancer-specific survival probability can be easily estimated by calculating the scores for each variable. Through internal validation by Heagerty’s concordance index, the established nomogram showed a good discriminative ability, the C-index was 0.61.