Background
Brain is a common metastasis site in lung cancer patients. However, homogeneous and heterogeneous risk/prognostic factors of brain metastasis for lung cancer patients have not been comprehensively elucidated. This study aimed to explore the brain metastasis risk and prognostic factors in lung cancer patients using the Surveillance, Epidemiology, and End Results (SEER) database.
Methods
Lung cancer data were downloaded from SEER database to investigate risk factors for developing brain metastasis using logistic regression analysis. Univariate and multivariate Cox analyses were used to identify potential prognostic factors. Kaplan–Meier analysis was conducted to evaluate the survival. Propensity score matching was conducted to eliminate baseline differences between two groups.
Results
A total of 10 818 (14.1%) patients with brain metastasis were diagnosed among 76 483 lung cancer patients. For non–small-cell lung carcinoma (NSCLC), distant liver/bone/lymph node metastases, higher T, N stages were risk factors. Black race, bone metastases and distant lymph node metastases and T4 were brain metastasis risk factors for SCLC patients. Cox analysis suggested that older age, male, primary lesion at main bronchus, liver/ bone/distant lymph node metastases, T2-4, N1-3, no surgery/chemotherapy/radiotherapy were associated with worse prognosis of NSCLC-brain metastasis patients. Age older than 80, liver/bone metastases, without radiotherapy and chemotherapy were associated with worse prognosis of SCLC-brain metastasis patients. Surgery of primary site could prolong the overall survival (OS) of NSCLC patients with brain metastasis, but not SCLC.
Conclusion
In this study, we analyzed the homogeneous and heterogeneous risk/prognostic factors of brain metastasis in lung cancer patients. What is more, our results showed that surgery of primary site was associated with longer OS of NSCLC patients with brain metastasis.
Keywords: brain metastasis, lung cancer, risk factors, prognosis, surgery
Introduction
It is estimated that about 236 740 new cases of lung cancer will be diagnosed in the USA in 2022, with 130 180 cases of deaths. Lung cancer is the second most common cancer in both men and women, less than breast cancer (in female) or prostate cancer (in male), and is the leading cause of death of cancer patients, with low 5-year survival rate (Siegel et al., 2022). Metastasis is a characteristic of cancer and is responsible for the greatest number of cancer-related deaths (Fares et al., 2020). Brain is a common metastasis site of lung cancer. About 20% of cancer patients will develop brain metastases (Achrol et al., 2019), and brain metastases from lung cancer account for about 45% of total brain metastases (Schouten et al., 2002; Lowery and Yu, 2017). What is more, it is reported that about 10% of small-cell lung cancer (SCLC) patients have brain metastases at the time of initial diagnosis (Castrucci and Knisely, 2008).
Despite the rapid development of multiple therapies, such as targeted therapy and immunotherapy, the prognosis of patients with advanced lung cancer remains poor (Achrol et al., 2019). The median survival time of brain metastasis patients was about 6–10 months (Steeg et al., 2011; Bacha et al., 2018; Zhu et al., 2022). A study focusing on non–small-cell lung carcinoma (NSCLC) suggested that the median overall survival (OS) after NSCLC diagnosis was 13.33 months and the median OS after brain metastasis was 10.6 months (Bacha et al., 2018). Focusing on the high-risk population that is susceptible to brain metastasis and identifying potential brain metastasis before clinical symptoms could provide patients with the chance of receiving treatment timely and benefit the prognosis (Sanchez de Cos et al., 2009). Therefore, it is very important to identify risk and prognostic factors, evaluate individual metastatic risk, and make diagnosis accurately, so as to improve the therapy.
Clinical characteristics including age, race, sex, Gleason score, smoking, histological type, T stage, N stage, insurance status, and marital status were found to correlate with survival of lung cancer patients with brain metastasis (Reddy et al., 2020; Shen et al., 2021; Sung et al., 2021). The number and total volume of brain metastasis are also key factors that influence patient survival (Aoyama et al., 2006; Sanchez de Cos et al., 2009; Yamamoto et al., 2013). Several nomograms predicting the brain metastasis of lung cancer patients based on clinical characteristics were proposed (Li et al., 2021; Zuo et al., 2021). However, few studies focused on the comparison of risk and prognostic value of different clinical factors. The purpose of our study was to investigate the risk factors for brain metastasis and prognostic factors for lung cancer patients with brain metastasis based on large data from the Surveillance, Epidemiology, and End Results (SEER) database. We further investigated homogeneous and heterogeneous risk and prognostic factors.
Methods
Population
In this population-based study, lung cancer data were downloaded from the SEER database. SEER*Stat version 8.4.0 (https://seer.cancer.gov/seerstat/) was used to get the patient information (Doll et al., 2018). Lung cancer patients diagnosed with brain metastasis between 2010 and 2017 were included in this study. Patient information was excluded when it is not the first primary site or follow-up information is incomplete. The inclusion and exclusion process is shown in Fig. 1. A total of 76 483 patients diagnosed with lung cancer between 2010 and 2017 were used to investigate brain metastasis risk factors, and then prognostic factors were explored for 10 813 lung cancer patients with brain metastasis. Subgroup analysis was based on the pathology of lung cancer patients. Patient information with survival time was used to investigate the prognostic role of surgery for NSCLC patients with brain metastasis.
Fig. 1.
Flowchart of the process of data selection. BM, brain metastasis.
Statistical analysis
This study included the following variables: age (<50, 50–59, 60–69, 70–79, ≥80); sex (male and female); race [white, black, other (American Indian/AK Native, Asian/Pacific Islander), unknown]; pathology (adenocarcinoma, non–small-cell carcinoma, small-cell carcinoma, large-cell carcinoma, squamous-cell carcinoma, other); site of primary tumor (left main bronchus, left upper lobe, left lower lobe, right main bronchus, right upper lobe, right middle lobe, right lower lobe, other); T stage (T1, T2, T3, T4, other); N stage (N0, N1, N2, N3, other); liver metastasis status (Yes, No, unknown); bone metastasis (Yes, No, unknown); brain metastasis (Yes, No, unknown); surgical treatment (Yes, No, unknown); radiotherapy (Yes, No, unknown); and chemotherapy (Yes, No, unknown). Univariate and multivariate logistic regression were used to identify the risk factors for brain metastasis. Kaplan–Meier method was conducted to investigate OS outcomes. Univariate and multivariate Cox regression analyses were used to identify potential prognostic factors. Propensity score matching (PSM) (ratio 1:1, caliper: 0.2 SD of propensity score) was conducted to eliminate baseline differences between the two groups using the ‘Matching’ R package (Huber et al., 2017; Zhao et al., 2021). P < 0.05 was considered to be statistically significant. All statistical analyses were conducted within R software (version 4.1.0).
Results
Patient characteristics
A total of 76 483 lung cancer patients were initially identified between 2010 and 2017. Of these patients, 10 818 (14.1%) patients were diagnosed with brain metastasis, and most patients were without brain metastasis (85.9%, N = 65 665). 13 960 (18.3%) patients were more than 80 years. A total of 39 642 (51.8%) patients were male. A total of 39.1% were diagnosed with lung adenocarcinoma (N = 29 878). Over half of the patients were white (76.7%, N = 155 877). As for the lesion site, the right upper lobe is the most common, about 28.6% (N = 21 842). Most patients were without bone metastases (N = 60 706, 79.4%), liver metastases (N = 66 410, 86.8%), or distant lymph node metastases (N = 17 880, 23.4%). 14.9 % of patients (N = 11 363) were T1 and 27.6% (N = 21 129) were N0. More details about patient clinical characteristics are shown in Table 1.
Table 1.
Clinical characteristics of lung cancer patients
| Brain metastases | ||||
|---|---|---|---|---|
| Overall | No | Yes | P | |
| n | 76 483 | 65 665 | 10 818 | |
| Age (%) | <0.001 | |||
| <50 | 3040 (4.0) | 2397 (3.7) | 643 (5.9) | |
| 50–59 | 12 290 (16.1) | 9781 (14.9) | 2509 (23.2) | |
| 60–69 | 23 822 (31.1) | 20 008 (30.5) | 3814 (35.3) | |
| 70–79 | 23 371 (30.6) | 20 611 (31.4) | 2760 (25.5) | |
| ≥80 | 13 960 (18.3) | 12 868 (19.6) | 1092 (10.1) | |
| Race (%) | <0.001 | |||
| Black | 6948 (9.1) | 5902 (9.0) | 1046 (9.7) | |
| White | 60 578 (79.2) | 52 284 (79.6) | 8294 (76.7) | |
| Other | 8802 (11.5) | 7340 (11.2) | 1462 (13.5) | |
| Unknown | 155 (0.2) | 139 (0.2) | 16 (0.1) | |
| Sex (%) | ||||
| Female | 36 841 (48.2) | 31 698 (48.3) | 5143 (47.5) | 0.162 |
| Male | 39 642 (51.8) | 33 967 (51.7) | 5675 (52.5) | |
| Pathology (%) | <0.001 | |||
| Squamous-cell carcinoma | 14 957 (19.6) | 14 058 (21.4) | 899 (8.3) | |
| Adenocarcinoma | 29 878 (39.1) | 24 393 (37.1) | 5485 (50.7) | |
| Non–small-cell carcinoma | 4894 (6.4) | 3976 (6.1) | 918 (8.5) | |
| Small-cell carcinoma | 9544 (12.5) | 7834 (11.9) | 1710 (15.8) | |
| Large-cell carcinoma | 1009 (1.3) | 819 (1.2) | 190 (1.8) | |
| Other | 16 201 (21.2) | 14 585 (22.2) | 1616 (14.9) | |
| Location (%) | <0.001 | |||
| Left lower | 8995 (11.8) | 7763 (11.8) | 1232 (11.4) | |
| Left upper | 17 139 (22.4) | 14 747 (22.5) | 2392 (22.1) | |
| Left main bronchus | 1366 (1.8) | 1163 (1.8) | 203 (1.9) | |
| Right lower | 11 402 (14.9) | 9993 (15.2) | 1409 (13.0) | |
| Right middle | 3530 (4.6) | 3094 (4.7) | 436 (4.0) | |
| Right upper | 21 842 (28.6) | 18 850 (28.7) | 2992 (27.7) | |
| Right main bronchus | 1841 (2.4) | 1539 (2.3) | 302 (2.8) | |
| Other | 10 368 (13.6) | 8516 (13.0) | 1852 (17.1) | |
| Bone metastasis (%) | <0.001 | |||
| No | 60 706 (79.4) | 53 994 (82.2) | 6712 (62.0) | |
| Yes | 15 094 (19.7) | 11 275 (17.2) | 3819 (35.3) | |
| Unknown | 683 (0.9) | 396 (0.6) | 287 (2.7) | |
| Liver metastasis (%) | <0.001 | |||
| No | 66 410 (86.8) | 58 173 (88.6) | 8237 (76.1) | |
| Yes | 9274 (12.1) | 7091 (10.8) | 2183 (20.2) | |
| Unknown | 799 (1.0) | 401 (0.6) | 398 (3.7) | |
| Distant lymph node metastasis (%) | <0.001 | |||
| NO | 17 880 (23.4) | 15 616 (23.8) | 2264 (20.9) | |
| Yes | 1730 (2.3) | 1267 (1.9) | 463 (4.3) | |
| Unknown | 56 873 (74.4) | 48 782 (74.3) | 8091 (74.8) | |
| T (%) | <0.001 | |||
| T1 | 11 363 (14.9) | 10 550 (16.1) | 813 (7.5) | |
| T2 | 15 451 (20.2) | 13 525 (20.6) | 1926 (17.8) | |
| T3 | 11 117 (14.5) | 9386 (14.3) | 1731 (16.0) | |
| T4 | 12 184 (15.9) | 9910 (15.1) | 2274 (21.0) | |
| Other | 26 368 (34.5) | 22 294 (34.0) | 4074 (37.7) | |
| N (%) | <0.001 | |||
| N0 | 21 129 (27.6) | 19 590 (29.8) | 1539 (14.2) | |
| N1 | 4930 (6.4) | 4246 (6.5) | 684 (6.3) | |
| N2 | 19 457 (25.4) | 15 985 (24.3) | 3472 (32.1) | |
| N3 | 8164 (10.7) | 6439 (9.8) | 1725 (15.9) | |
| Other | 22 803 (29.8) | 19 405 (29.6) | 3398 (31.4) | |
Risk factors for developing brain metastases
The univariate and multivariate logistic regression analyses were conducted to investigate the risk factors associated with brain metastases. Results showed that age, race, pathology, primary lesion site, bone metastases, liver metastases, distant lymph node metastases, T stage, N stage were all associated with the development of brain metastasis. The association between sex and brain metastasis was not significant. The multivariate logistic regression revealed that patients older than 60 were less likely to develop brain metastasis. Other races, non–squamous-cell carcinoma, bone metastases, liver metastases, distant lymph node metastases, higher T stage, and higher N stage were risk factors of brain metastasis. As for the primary site, compared with the left upper lobe, patients whose tumor were present in right middle lobe and right lower lobe had a lower risk of developing brain metastasis. The logistic regression analysis results are shown in Table 2.
Table 2.
The logistic regression analysis results
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| OR (95% CI) | P value | OR (95% CI) | P value | |
| Age | ||||
| <50 | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| 50–59 | 0.96 (0.87–1.05) | 0.368 | 1 (0.9–1.11) | 0.971 |
| 60–69 | 0.71 (0.65–0.78) | <0.001 | 0.8 (0.72–0.88) | <0.001 |
| 70–79 | 0.5 (0.45–0.55) | <0.001 | 0.6 (0.54–0.66) | <0.001 |
| ≥80 | 0.32 (0.28–0.35) | <0.001 | 0.38 (0.34–0.43) | <0.001 |
| Race | ||||
| White | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Black | 1.12 (1.04–1.2) | 0.002 | 1 (0.93–1.08) | 0.902 |
| Other | 1.26 (1.18–1.33) | <0.001 | 1.17 (1.09–1.24) | <0.001 |
| Unknown | 0.73 (0.43–1.22) | 0.225 | 0.82 (0.48–1.39) | 0.461 |
| Sex | ||||
| Female | 1 (Reference) | 1 (Reference) | ||
| Male | 1.03 (0.99–1.07) | 0.158 | ||
| Pathology | ||||
| Squamous-cell carcinoma | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Adenocarcinoma | 3.52 (3.27–3.78) | <0.001 | 3.03 (2.81–3.27) | <0.001 |
| Non–small-cell carcinoma | 3.61 (3.27–3.98) | <0.001 | 3.04 (2.75–3.37) | <0.001 |
| Small-cell carcinoma | 3.41 (3.13–3.72) | <0.001 | 2.3 (2.1–2.51) | <0.001 |
| Large-cell carcinoma | 3.63 (3.06–4.31) | <0.001 | 2.92 (2.44–3.48) | <0.001 |
| Other | 1.73 (1.59–1.89) | <0.001 | 1.82 (1.67–1.99) | <0.001 |
| Location | ||||
| Left upper | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Left lower | 0.98 (0.91–1.05) | 0.563 | 1.02 (0.94–1.1) | 0.684 |
| left main bronchus | 1.08 (0.92–1.26) | 0.354 | 0.88 (0.75–1.04) | 0.126 |
| Right upper | 0.98 (0.92–1.04) | 0.464 | 0.95 (0.89–1.01) | 0.098 |
| Right middle | 0.87 (0.78–0.97) | 0.012 | 0.84 (0.75–0.95) | 0.003 |
| Right lower | 0.87 (0.81–0.93) | <0.001 | 0.9 (0.84–0.97) | 0.005 |
| Right main bronchus | 1.21 (1.06–1.38) | 0.004 | 0.95 (0.83–1.09) | 0.505 |
| Other | 1.34 (1.25–1.43) | <0.001 | 0.95 (0.88–1.02) | 0.126 |
| Bone metastases | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 2.72 (2.61–2.85) | <0.001 | 1.79 (1.71–1.88) | <0.001 |
| Unknown | 5.83 (5–6.8) | <0.001 | 2.54 (2.12–3.05) | <0.001 |
| Liver metastases | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 2.17 (2.06–2.29) | <0.001 | 1.4 (1.31–1.48) | <0.001 |
| Unknown | 7.01 (6.09–8.07) | <0.001 | 3.76 (3.19–4.44) | <0.001 |
| Distant lymph node metastases | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 2.52 (2.25–2.83) | <0.001 | 1.7 (1.51–1.92) | <0.001 |
| Unknown | 1.14 (1.09–1.2) | <0.001 | 1.54 (1.37–1.72) | <0.001 |
| T | ||||
| T1 | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| T2 | 1.85 (1.7–2.01) | <0.001 | 1.58 (1.44–1.73) | <0.001 |
| T3 | 2.39 (2.19–2.61) | <0.001 | 1.73 (1.58–1.9) | <0.001 |
| T4 | 2.98 (2.74–3.24) | <0.001 | 1.92 (1.76–2.11) | <0.001 |
| Other | 2.37 (2.19–2.57) | <0.001 | 1.93 (1.74–2.15) | <0.001 |
| N | ||||
| N0 | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| N1 | 2.05 (1.86–2.26) | <0.001 | 1.65 (1.49–1.82) | <0.001 |
| N2 | 2.76 (2.59–2.95) | <0.001 | 1.88 (1.75–2.01) | <0.001 |
| N3 | 3.41 (3.17–3.67) | <0.001 | 1.98 (1.83–2.15) | <0.001 |
| Other | 2.23 (2.09–2.37) | <0.001 | 1.97 (1.76–2.2) | <0.001 |
CI, confidence interval; HR, hazard ratio; OR, odds ratio.
Considering that there are significant differences in tissue behavior between SCLC and NSCLC, we divided the patients in the cohort into two groups according to the pathological type: NSCLC group and SCLC group, and carried out logistic regression in two subgroups. The results showed that there were significant differences between NSCLC and SCLC in the factors related to brain metastasis. In NSCLC, the results of univariate logistic regression suggested that age, race, location of primary lesion, presence of bone metastasis, liver metastasis, distant lymph node metastasis, T stage and N stage were related to the occurrence of brain metastasis. While in multivariate analysis, lesion in middle and lower lobe of the right lung were related to the lower risk of brain metastasis. The risk of synchronous brain metastasis is increased in patients with other races, synchronous distant metastasis (liver, bone, distant lymph node metastasis), higher T stage, and higher N stage. More details are shown in Table 3.
Table 3.
The logistic regression analysis results of brain metastasis in non–small-cell lung cancer patients
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| OR (95% CI) | P | OR (95%CI) | P | |
| Age | ||||
| <50 | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| 50–59 | 0.94 (0.85–1.04) | 0.229 | 0.98 (0.88–1.09) | 0.704 |
| 60–69 | 0.67 (0.61–0.74) | <0.001 | 0.74 (0.67–0.82) | <0.001 |
| 70–79 | 0.48 (0.43–0.53) | <0.001 | 0.54 (0.49–0.6) | <0.001 |
| ≥80 | 0.3 (0.27–0.33) | <0.001 | 0.34 (0.3–0.38) | <0.001 |
| Race | ||||
| White | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Black | 1.12 (1.04–1.2) | 0.004 | 0.99 (0.91–1.07) | 0.755 |
| Other | 1.3 (1.22–1.39) | <0.001 | 1.23 (1.15–1.31) | <0.001 |
| Unknown | 0.64 (0.35–1.15) | 0.136 | 0.76 (0.41–1.39) | 0.368 |
| Sex | ||||
| Female | 1 (Reference) | 1 (Reference) | ||
| Male | 1.01 (0.97–1.06) | 0.530 | ||
| Location | ||||
| Left upper | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Left lower | 0.98 (0.9–1.06) | 0.602 | 1.01 (0.93–1.1) | 0.813 |
| left main bronchus | 1.1 (0.91–1.32) | 0.319 | 0.83 (0.69–1.01) | 0.063 |
| Right upper | 0.98 (0.92–1.04) | 0.530 | 0.99 (0.92–1.05) | 0.656 |
| Right middle | 0.87 (0.77–0.98) | 0.017 | 0.86 (0.76–0.98) | 0.019 |
| Right lower | 0.88 (0.81–0.95) | 0.001 | 0.9 (0.83–0.98) | 0.010 |
| Right main bronchus | 1.26 (1.08–1.47) | 0.003 | 0.92 (0.78–1.08) | 0.304 |
| Other | 1.41 (1.32–1.52) | <0.001 | 1.01 (0.93–1.1) | 0.775 |
| Bone metastases | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 3.03 (2.89–3.18) | <0.001 | 2.08 (1.97–2.19) | <0.001 |
| Unknown | 6.68 (5.63–7.93) | <0.001 | 2.75 (2.24–3.37) | <0.001 |
| Liver metastases | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 2.66 (2.51–2.83) | <0.001 | 1.62 (1.51–1.73) | <0.001 |
| Unknown | 7.92 (6.79–9.24) | <0.001 | 4.03 (3.36–4.82) | <0.001 |
| Distant lymph node metastases | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 2.66 (2.34–3.02) | <0.001 | 1.75 (1.53–2) | <0.001 |
| Unknown | 1.14 (1.08–1.2) | <0.001 | 1.53 (1.36–1.73) | <0.001 |
| T | ||||
| T1 | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| T2 | 1.92 (1.75–2.1) | <0.001 | 1.53 (1.39–1.68) | <0.001 |
| T3 | 2.53 (2.3–2.78) | <0.001 | 1.62 (1.47–1.8) | <0.001 |
| T4 | 3.19 (2.91–3.5) | <0.001 | 1.85 (1.67–2.04) | <0.001 |
| Other | 2.49 (2.29–2.71) | <0.001 | 1.94 (1.72–2.17) | <0.001 |
| N | ||||
| N0 | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| N1 | 2.08 (1.87–2.3) | <0.001 | 1.64 (1.47–1.82) | <0.001 |
| N2 | 2.97 (2.77–3.17) | <0.001 | 2.05 (1.9–2.2) | <0.001 |
| N3 | 3.77 (3.48–4.09) | <0.001 | 2.23 (2.05–2.43) | <0.001 |
| Other | 2.29 (2.14–2.45) | <0.001 | 1.96 (1.73–2.21) | <0.001 |
CI, confidence interval; HR, hazard ratio; OR, odds ratio.
In the SCLC group, we got different results. First of all, in the univariate logistic regression, the site of the primary lesion and N stage were not related to the occurrence of brain metastasis. In multivariate logistic regression, compared with patients younger than 50 years old, patients older than 70 years old have a lower risk of synchronous brain metastasis. Compared with white race, black race patients with SCLC have a higher risk of brain metastasis. There was no significant correlation between sex and brain metastasis. Patients with bone metastasis and distant lymph node metastasis were associated with a higher risk of brain metastasis, but not synchronous liver metastasis. It is worth noting that compared with T1, only T4 has significant correlation with the risk of synchronous brain metastasis, while T2 and T3 have no difference compared with T1. See Table 4 for more details of logistic regression analysis.
Table 4.
The logistic regression analysis results of brain metastasis in small-cell lung cancer patients
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| OR (95% CI) | P | OR (95% CI) | P | |
| Age | ||||
| <50 | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| 50–59 | 1.08 (0.79–1.46) | 0.634 | 1.11 (0.82–1.51) | 0.493 |
| 60–69 | 0.97 (0.72–1.3) | 0.843 | 0.99 (0.73–1.33) | 0.930 |
| 70–79 | 0.69 (0.51–0.93) | 0.016 | 0.71 (0.53–0.97) | 0.031 |
| ≥80 | 0.54 (0.39–0.76) | <0.001 | 0.57 (0.41–0.8) | 0.001 |
| Race | ||||
| White | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Black | 1.27 (1.05–1.54) | 0.015 | 1.24 (1.02–1.51) | 0.032 |
| Other | 1.09 (0.9–1.32) | 0.385 | 1.11 (0.92–1.35) | 0.281 |
| Unknown | 1.34 (0.44–4.09) | 0.604 | 1.31 (0.43–4.02) | 0.636 |
| Sex | ||||
| Female | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Male | 1.14 (1.02–1.26) | 0.017 | 1.08 (0.97–1.21) | 0.141 |
| Location | ||||
| Left upper | 1 (Reference) | 1 (Reference) | ||
| Left lower | 1.01 (0.83–1.24) | 0.892 | ||
| left main bronchus | 0.82 (0.61–1.1) | 0.186 | ||
| Right upper | 1 (0.86–1.17) | 0.981 | ||
| Right middle | 0.9 (0.67–1.2) | 0.481 | ||
| Right lower | 0.87 (0.71–1.05) | 0.146 | ||
| Right main bronchus | 0.88 (0.68–1.14) | 0.341 | ||
| Other | 0.94 (0.8–1.11) | 0.480 | ||
| Bone metastases | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 1.42 (1.27–1.6) | <0.001 | 1.4 (1.23–1.58) | <0.001 |
| Unknown | 2.86 (2–4.08) | <0.001 | 2.11 (1.41–3.14) | <0.001 |
| Liver metastases | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 1.01 (0.9–1.13) | 0.847 | 0.89 (0.79–1.01) | 0.063 |
| Unknown | 3.27 (2.31–4.65) | <0.001 | 2.36 (1.6–3.49) | <0.001 |
| Distant lymph node metastases | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 1.81 (1.39–2.36) | <0.001 | 1.7 (1.3–2.23) | <0.001 |
| Unknown | 1.15 (1.01–1.32) | 0.038 | 1.19 (0.98–1.44) | 0.076 |
| T | ||||
| T1 | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| T2 | 1.21 (0.95–1.53) | 0.125 | 1.16 (0.91–1.47) | 0.231 |
| T3 | 1.33 (1.04–1.69) | 0.023 | 1.27 (0.99–1.62) | 0.057 |
| T4 | 1.46 (1.16–1.83) | 0.001 | 1.33 (1.06–1.68) | 0.014 |
| Other | 1.34 (1.08–1.67) | 0.008 | 1.32 (1.03–1.7) | 0.029 |
| N | ||||
| N0 | 1 (Reference) | 1 (Reference) | ||
| N1 | 1.18 (0.9–1.54) | 0.223 | ||
| N2 | 1.12 (0.92–1.35) | 0.250 | ||
| N3 | 1.21 (0.98–1.49) | 0.083 | ||
| Other | 1.18 (0.97–1.43) | 0.099 | ||
CI, confidence interval; HR, hazard ratio; OR, odds ratio.
Prognostic factors for lung cancer patients with brain metastasis
A total of 10 813 lung cancer patients with brain metastasis and follow-up information between 2010 and 2017 were included to conduct Cox regression analysis and investigate potential prognostic factors. Treatment information was also collected, including surgery, radiotherapy and chemotherapy. Two hundred sixty-one patients (2.4%) received surgical treatment of primary lesions, 7861 patients (72.7%) received radiotherapy, and 6036 patients (55.8%) received chemotherapy. SEER database also provides the type of radiotherapy, as shown in Supplementary Table 1 and 2, Supplemental Digital Content 1, http://links.lww.com/EJCP/A378. The vast majority of patients (71.9%) received beam radiation treatment, and a few patients also received radioactive implant or radioisotope treatment. The median survival of lung cancer patients with brain metastasis was 5 months. The 1-year, 3-year, and 5-year survival rates for brain metastasis patients were 25.27%, 8.19%, and 4.51%, respectively. The univariate Cox regression analysis suggested that older age, male, liver metastases, bone metastases, distant lymph node metastases, higher T or N stage, no surgery, no radiotherapy, no chemotherapy were risk factors of brain metastasis patient prognosis. Multivariable Cox regression analysis showed that older age, male, white race, SCC, liver metastases, bone metastases, distant lymph node metastases, T2-4, N1-3, no surgery, no chemotherapy were associated with worse prognosis. Compared with SCC, brain metastasis patients whose pathology was adenocarcinoma had a better prognosis. Brain metastasis patients with tumors that originated in the left upper lobe of lung had longer survival time than those in the right main bronchus. Cox analysis results are shown in Table 5.
Table 5.
Univariate and multivariate Cox regression analysis results. P < 0.05 was considered statistically significant
| Univariate Cox regression | Multivariate Cox regression | |||
|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | |
| Age | ||||
| <50 | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| 50–59 | 1.42 (1.30–1.56) | <0.001 | 1.38 (1.26–1.52) | <0.001 |
| 60–69 | 1.66 (1.51–1.81) | <0.001 | 1.55 (1.42–1.70) | <0.001 |
| 70–79 | 2.12 (1.93–2.32) | <0.001 | 1.81 (1.65–1.99) | <0.001 |
| ≥80 | 3.16 (2.84–3.50) | <0.001 | 2.31 (2.07–2.57) | <0.001 |
| Sex | ||||
| Female | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Male | 1.22 (1.18–1.27) | <0.001 | 1.18 (1.14–1.23) | <0.001 |
| Race | ||||
| Wihte | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Black | 0.95 (0.89–1.01) | 0.114 | 0.92 (0.86–0.99) | 0.018 |
| Other | 0.73 (0.69–0.78) | <0.001 | 0.73 (0.69–0.77) | <0.001 |
| Unknown | 0.76 (0.44–1.30) | 0.312 | 0.94 (0.54–1.62) | 0.817 |
| Pathology | ||||
| Squamous-cell carcinoma | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Adenocarcinoma | 0.61 (0.57–0.66) | <0.001 | 0.71 (0.66–0.76) | <0.001 |
| Non–small-cell carcinoma | 0.88 (0.80–0.96) | 0.005 | 0.88 (0.80–0.97) | 0.011 |
| Small-cell carcinoma | 0.81 (0.75–0.88) | <0.001 | 0.94 (0.86–1.02) | 0.132 |
| Large-cell carcinoma | 0.82 (0.70–0.96) | 0.014 | 1.03 (0.88–1.21) | 0.736 |
| Other | 0.98 (0.90–1.07) | 0.686 | 0.85 (0.78–0.92) | <0.001 |
| Primary lesion site | ||||
| Left upper | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Left lower | 1.02 (0.95–1.09) | 0.682 | 1.01 (0.94–1.09) | 0.768 |
| Left main bronchus | 1.22 (1.06–1.42) | 0.007 | 1.16 (1.00–1.34) | 0.055 |
| Right upper | 1.03 (0.98–1.09) | 0.236 | 1.02 (0.96–1.07) | 0.589 |
| Right middle | 0.99 (0.89–1.10) | 0.860 | 0.95 (0.85–1.05) | 0.316 |
| Right lower | 1.05 (0.98–1.13) | 0.154 | 1.04 (0.97–1.11) | 0.273 |
| Right main bronchus | 1.27 (1.13–1.44) | <0.001 | 1.14 (1.01–1.29) | 0.040 |
| Other | 1.26 (1.18–1.34) | <0.001 | 1.07 (1.00–1.14) | 0.053 |
| Bone metastases | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 1.17 (1.12–1.22) | <0.001 | 1.23 (1.18–1.29) | <0.001 |
| Unknown | 1.38 (1.22–1.55) | <0.001 | 1.00 (0.86–1.18) | 0.973 |
| Liver metastases | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 1.51 (1.44–1.58) | <0.001 | 1.47 (1.40–1.55) | <0.001 |
| Unknown | 1.29 (1.16–1.43) | <0.001 | 0.94 (0.82–1.08) | 0.369 |
| Distant lymph node metastases | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 1.18 (1.06–1.31) | 0.002 | 1.16 (1.04–1.30) | 0.006 |
| Unknown | 1.24 (1.18–1.30) | <0.001 | 1.08 (0.97–1.20) | 0.144 |
| T | ||||
| T1 | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| T2 | 1.17 (1.07–1.27) | <0.001 | 1.16 (1.07–1.27) | <0.001 |
| T3 | 1.34 (1.23–1.46) | <0.001 | 1.30 (1.19–1.42) | <0.001 |
| T4 | 1.38 (1.27–1.50) | <0.001 | 1.32 (1.22–1.44) | <0.001 |
| Other | 1.17 (1.08–1.27) | <0.001 | 1.09 (0.99–1.20) | 0.096 |
| N | ||||
| N0 | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| N1 | 1.05 (0.96–1.15) | 0.301 | 1.12 (1.02–1.23) | 0.015 |
| N2 | 1.15 (1.08–1.22) | <0.001 | 1.24 (1.17–1.32) | <0.001 |
| N3 | 1.17 (1.10–1.26) | <0.001 | 1.31 (1.22–1.41) | <0.001 |
| Other | 1.01 (0.95–1.08) | 0.762 | 1.08 (0.98–1.20) | 0.126 |
| Surgery | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 0.43 (0.38–0.50) | <0.001 | 0.53 (0.46–0.61) | <0.001 |
| Unknown | 1.59 (0.99–2.56) | 0.056 | 1.07 (0.66–1.74) | 0.788 |
| Radiotherapy | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 0.39 (0.32–0.46) | <0.001 | 0.99 (0.82–1.19) | 0.896 |
| None/unknown | 0.73 (0.61–0.87) | <0.001 | 1.15 (0.96–1.38) | 0.137 |
| Chemotherapy | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 0.35 (0.34–0.37) | <0.001 | 0.38 (0.36–0.39) | <0.001 |
CI, confidence interval; HR, hazard ratio.
Supplementary Table 1, Supplemental Digital Content 1, http://links.lww.com/EJCP/A378. The type of radiotherapy that lung cancer-brain metastasis patients received.
Since our previous analysis results suggest that there is significant heterogeneity between SCLC group and NSCLC group, here we conducted subgroup analysis again, and compared the prognostic factors of patients with brain metastasis in SCLC and NSCLC groups through univariate and multivariate cox analysis. In NSCLC group, the prognosis of patients with brain metastasis was worse with older age, and the prognosis of female patients was better than that of male patients. Compared with white race, patients of black race and other races have better prognosis. As for the primary lesion, compared with the left upper lobe, the prognosis of patients with primary lesions in the left and right main bronchi was worse. Based on the existence of brain metastasis, synchronous liver metastasis, bone metastasis, distant lymph node metastasis, and higher T and N staging led to poor prognosis. Surgical treatment, radiotherapy and chemotherapy of primary lesions could prolong the survival of patients (Table 6).
Table 6.
Univariate and multivariate Cox regression analysis results of non–small-cell lung carcinoma-brain metastasis patients
| Univariate cox | Multivariate cox | |||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Age | ||||
| <50 | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| 50–59 | 1.43 (1.29–1.58) | <0.001 | 1.4 (1.27–1.55) | <0.001 |
| 60–69 | 1.7 (1.54–1.87) | <0.001 | 1.6 (1.45–1.77) | <0.001 |
| 70–79 | 2.13 (1.93–2.35) | <0.001 | 1.82 (1.64–2.01) | <0.001 |
| ≥80 | 3.14 (2.81–3.5) | <0.001 | 2.32 (2.07–2.6) | <0.001 |
| Sex | ||||
| Female | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Male | 1.25 (1.2–1.3) | <0.001 | 1.2 (1.15–1.26) | <0.001 |
| Race | ||||
| White | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Black | 0.97 (0.9–1.04) | 0.361 | 0.92 (0.86–0.99) | 0.035 |
| Other | 0.73 (0.69–0.78) | <0.001 | 0.7 (0.66–0.74) | <0.001 |
| Unknown | 0.9 (0.48–1.67) | 0.728 | 1.15 (0.62–2.14) | 0.661 |
| Location | ||||
| Left upper | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Left lower | 1.02 (0.94–1.1) | 0.677 | 1.01 (0.94–1.1) | 0.714 |
| left main bronchus | 1.35 (1.13–1.61) | 0.001 | 1.31 (1.09–1.56) | 0.003 |
| Right upper | 1.06 (0.99–1.12) | 0.074 | 1.03 (0.97–1.09) | 0.381 |
| Right middle | 0.98 (0.88–1.11) | 0.785 | 0.94 (0.84–1.06) | 0.298 |
| Right lower | 1.05 (0.98–1.13) | 0.173 | 1.05 (0.98–1.13) | 0.181 |
| Right main bronchus | 1.32 (1.14–1.52) | <0.001 | 1.21 (1.05–1.4) | 0.010 |
| Other | 1.29 (1.21–1.39) | <0.001 | 1.11 (1.03–1.19) | 0.006 |
| Bone metastases | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 1.16 (1.11–1.22) | <0.001 | 1.22 (1.17–1.28) | <0.001 |
| Unknown | 1.38 (1.2–1.57) | <0.001 | 1.04 (0.87–1.24) | 0.648 |
| Liver metastases | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 1.49 (1.41–1.57) | <0.001 | 1.48 (1.4–1.57) | <0.001 |
| Unknown | 1.3 (1.16–1.45) | <0.001 | 0.93 (0.8–1.08) | 0.350 |
| Distant lymph node metastases | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 1.16 (1.03–1.3) | 0.017 | 1.15 (1.02–1.3) | 0.020 |
| Unknown | 1.24 (1.18–1.31) | <0.001 | 1.21 (1.08–1.35) | 0.001 |
| T | ||||
| T1 | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| T2 | 1.19 (1.09–1.3) | <0.001 | 1.19 (1.08–1.3) | <0.001 |
| T3 | 1.39 (1.26–1.52) | <0.001 | 1.34 (1.22–1.48) | <0.001 |
| T4 | 1.42 (1.3–1.56) | <0.001 | 1.37 (1.25–1.51) | <0.001 |
| Other | 1.21 (1.11–1.32) | <0.001 | 1.17 (1.05–1.3) | 0.004 |
| N | ||||
| N0 | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| N1 | 1.07 (0.97–1.19) | 0.165 | 1.18 (1.06–1.3) | 0.002 |
| N2 | 1.14 (1.07–1.22) | <0.001 | 1.24 (1.16–1.33) | <0.001 |
| N3 | 1.16 (1.08–1.25) | <0.001 | 1.32 (1.22–1.43) | <0.001 |
| Other | 1.01 (0.94–1.08) | 0.851 | 1.12 (1–1.25) | 0.045 |
| Surgery | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 0.44 (0.38–0.51) | <0.001 | 0.51 (0.44–0.59) | <0.001 |
| Unknown | 1.62 (0.92–2.85) | 0.097 | 1.22 (0.69–2.16) | 0.500 |
| Radiotherapy | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 0.4 (0.33–0.49) | <0.001 | 0.77 (0.63–0.93) | 0.008 |
| None/unknown | 0.76 (0.63–0.93) | 0.006 | 1.08 (0.89–1.32) | 0.419 |
| Chemotherapy | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 0.35 (0.33–0.36) | <0.001 | 0.35 (0.34–0.37) | <0.001 |
CI, confidence interval.
In SCLC, gender and the site of the primary lesion did not affect the survival of patients with brain metastasis (Table 7). Patients older than 80 years old, with liver metastasis and bone metastasis had a worse prognosis, while patients of other race groups had a better prognosis. It should be noted that the T and N stages of the primary lesion and the metastatic status of distant lymph node were not related to the survival time of SCLC patients with brain metastasis. Primary lesion surgery cannot prolong the survival time of patients, while radiotherapy and chemotherapy were associated with a better prognosis for patients. This is different from the cox analysis results of NSCLC patients with brain metastasis, suggesting that there is heterogeneity between SCLC and NSCLC.
Table 7.
Univariate and multivariate Cox regression analysis results of small-cell lung cancer-brain metastasis patients
| Univariate cox regression | Multivariate cox regression | |||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Age | ||||
| <50 | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| 50–59 | 1.16 (0.88–1.53) | 0.303 | 1.03 (0.78–1.37) | 0.812 |
| 60–69 | 1.2 (0.91–1.57) | 0.198 | 1.03 (0.78–1.36) | 0.825 |
| 70–79 | 1.73 (1.31–2.28) | <0.001 | 1.29 (0.98–1.71) | 0.074 |
| ≥80 | 2.94 (2.16–4.01) | <0.001 | 1.61 (1.17–2.21) | 0.004 |
| Sex | ||||
| Female | 1 (Reference) | 1 (Reference) | ||
| Male | 1.08 (0.98–1.19) | 0.111 | ||
| Race | ||||
| White | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Black | 0.85 (0.71–1.01) | 0.063 | 0.87 (0.73–1.04) | 0.115 |
| Other | 0.83 (0.7–0.99) | 0.037 | 0.78 (0.65–0.93) | 0.006 |
| Unknown | 0.45 (0.14–1.39) | 0.163 | 0.7 (0.22–2.21) | 0.549 |
| Location | ||||
| Left upper | 1 (Reference) | 1 (Reference) | ||
| Left lower | 1.03 (0.86–1.23) | 0.779 | ||
| left main bronchus | 0.88 (0.67–1.16) | 0.374 | ||
| Right upper | 0.89 (0.78–1.03) | 0.125 | ||
| Right middle | 1.04 (0.79–1.37) | 0.758 | ||
| Right lower | 1.07 (0.89–1.28) | 0.479 | ||
| Right main bronchus | 1.05 (0.83–1.33) | 0.693 | ||
| Other | 1.03 (0.89–1.2) | 0.701 | ||
| Bone metastases | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 1.3 (1.17–1.45) | <0.001 | 1.13 (1–1.27) | 0.042 |
| Unknown | 1.4 (1.05–1.86) | 0.022 | 1.02 (0.7–1.5) | 0.909 |
| Liver metastases | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 1.59 (1.43–1.77) | <0.001 | 1.59 (1.42–1.79) | <0.001 |
| Unknown | 1.23 (0.94–1.62) | 0.136 | 0.93 (0.65–1.34) | 0.699 |
| Distant lymph node metastases | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 1.25 (0.98–1.59) | 0.070 | 1.03 (0.81–1.32) | 0.796 |
| Unknown | 1.19 (1.05–1.35) | 0.008 | 1.14 (1–1.29) | 0.053 |
| T | ||||
| T1 | 1 (Reference) | 1 (Reference) | ||
| T2 | 0.99 (0.79–1.24) | 0.941 | ||
| T3 | 1.04 (0.83–1.31) | 0.713 | ||
| T4 | 1.1 (0.89–1.36) | 0.370 | ||
| Other | 0.91 (0.74–1.11) | 0.360 | ||
| N | ||||
| N0 | 1 (Reference) | 1 (Reference) | ||
| N1 | 0.86 (0.67–1.1) | 0.228 | ||
| N2 | 1.15 (0.96–1.37) | 0.128 | ||
| N3 | 1.21 (1–1.47) | 0.056 | ||
| Other | 1 (0.83–1.2) | 0.978 | ||
| Surgery | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 0.39 (0.21–0.74) | 0.003 | 0.54 (0.29–1.01) | 0.054 |
| Unknown | 1.51 (0.63–3.64) | 0.356 | 0.93 (0.37–2.34) | 0.880 |
| Radiotherapy | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 0.23 (0.14–0.39) | <0.001 | 0.58 (0.34–0.99) | 0.047 |
| None/unknown | 0.44 (0.26–0.75) | 0.003 | 0.86 (0.5–1.47) | 0.571 |
| Chemotherapy | ||||
| No | 1 (Reference) | 1 (Reference) | 1 (Reference) | 1 (Reference) |
| Yes | 0.26 (0.23–0.29) | <0.001 | 0.29 (0.26–0.33) | <0.001 |
CI, confidence interval; HR, hazard ratio.
Effects of surgery on survival of non–small-cell lung carcinoma patients with brain metastasis
Since the cox results showed that surgery on primary tumor was associated with longer survival of NSCLC-brain metastasis patients, we then explored whether it still benefited patients after adjusting for other clinical factors. Among 10 813 patients with survival time, 10 795 patients were confirmed with or without surgery, and 9090 patients were NSCLC. Therefore, these patients were included in Kaplan–Meier survival analysis to explore the significance of surgery for primary lesion. In order to explore whether there were confounding bias, we analyzed the differences in clinical information between surgery and non-surgery groups. Results showed that all clinical characteristics, except sex, race, and distant lymph node metastases were unevenly distributed between two groups. Therefore, 1:1 PSM (caliper: 0.2 SD of propensity score) was then conducted using the ‘Matching’ package in R software. All the clinical factors including age, race, sex, location, bone metastasis, liver metastasis, Distant lymph node metastasis, T, N, radiotherapy, chemotherapy were included to calculate propensity score. Clinical characteristics between surgery and non-surgery groups are shown in Table 8. After PSM, 498 patients were selected and the baseline differences between two groups were balanced.
Table 8.
The clinical characters of surgery and non-surgery groups, before Propensity score matching and after Propensity score matching
| Before PSM | After PSM | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Overall | Surgery – No | Surgery – Yes | P | Overall | Surgery – No | Surgery – Yes | P | ||
| 9090 | 8841 | 249 | 498 | 249 | 249 | ||||
| Age | <0.001 | Age | 0.62 | ||||||
| <50 | 583 (6.4) | 553 (6.3) | 30 (12.0) | <50 | 54 (10.8) | 24 (9.6) | 30 (12.0) | ||
| 50–59 | 2101 (23.1) | 2031 (23.0) | 70 (28.1) | 50–59 | 147 (29.5) | 77 (30.9) | 70 (28.1) | ||
| 60–69 | 3141 (34.6) | 3041 (34.4) | 100 (40.2) | 60–69 | 199 (40.0) | 99 (39.8) | 100 (40.2) | ||
| 70–79 | 2316 (25.5) | 2274 (25.7) | 42 (16.9) | 70–79 | 79 (15.9) | 37 (14.9) | 42 (16.9) | ||
| ≥80 | 949 (10.4) | 942 (10.7) | 7 (2.8) | ≥80 | 19 (3.8) | 12 (4.8) | 7 (2.8) | ||
| Sex | 0.058 | Sex | 1 | ||||||
| Female | 4336 (47.7) | 4202 (47.5) | 134 (53.8) | Female | 267 (53.6) | 133 (53.4) | 134 (53.8) | ||
| Male | 4754 (52.3) | 4639 (52.5) | 115 (46.2) | Male | 231 (46.4) | 116 (46.6) | 115 (46.2) | ||
| Race | 0.087 | Race | 0.704 | ||||||
| White | 904 (9.9) | 881 (10.0) | 23 (9.2) | White | 42 (8.4) | 19 (7.6) | 23 (9.2) | ||
| Black | 6859 (75.5) | 6656 (75.3) | 203 (81.5) | Black | 406 (81.5) | 203 (81.5) | 203 (81.5) | ||
| Other | 1315 (14.5) | 1292 (14.6) | 23 (9.2) | Other | 50 (10.0) | 27 (10.8) | 23 (9.2) | ||
| Unknown | 12 (0.1) | 12 (0.1) | 0 (0.0) | Unknown | |||||
| Location | 0.008 | Location | 0.808 | ||||||
| Left upper | 2022 (22.2) | 1955 (22.1) | 67 (26.9) | Left upper | 134 (26.9) | 67 (26.9) | 67 (26.9) | ||
| Left lower | 1057 (11.6) | 1028 (11.6) | 29 (11.6) | Left lower | 58 (11.6) | 29 (11.6) | 29 (11.6) | ||
| left main bronchus | 140 (1.5) | 138 (1.6) | 2 (0.8) | Left main bronchus | 2 (0.4) | 0 (0.0) | 2 (0.8) | ||
| Right upper | 2564 (28.2) | 2491 (28.2) | 73 (29.3) | Right upper | 151 (30.3) | 78 (31.3) | 73 (29.3) | ||
| Right middle | 371 (4.1) | 358 (4.0) | 13 (5.2) | Right middle | 28 (5.6) | 15 (6.0) | 13 (5.2) | ||
| Right lower | 1220 (13.4) | 1178 (13.3) | 42 (16.9) | Right lower | 75 (15.1) | 33 (13.3) | 42 (16.9) | ||
| Right main bronchus | 216 (2.4) | 213 (2.4) | 3 (1.2) | Right main bronchus | 6 (1.2) | 3 (1.2) | 3 (1.2) | ||
| Other | 1500 (16.5) | 1480 (16.7) | 20 (8.0) | Other | 44 (8.8) | 24 (9.6) | 20 (8.0) | ||
| Bone metastases | <0.001 | Bone metastases | 0.801 | ||||||
| No | 5557 (61.1) | 5347 (60.5) | 210 (84.3) | No | 425 (85.3) | 215 (86.3) | 210 (84.3) | ||
| Yes | 3303 (36.3) | 3268 (37.0) | 35 (14.1) | Yes | 66 (13.3) | 31 (12.4) | 35 (14.1) | ||
| Unknown | 230 (2.5) | 226 (2.6) | 4 (1.6) | Unknown | 7 (1.4) | 3 (1.2) | 4 (1.6) | ||
| Liver metastases | <0.001 | Liver metastases | 0.721 | ||||||
| No | 7112 (78.2) | 6880 (77.8) | 232 (93.2) | No | 464 (93.2) | 232 (93.2) | 232 (93.2) | ||
| Yes | 1642 (18.1) | 1630 (18.4) | 12 (4.8) | Yes | 26 (5.2) | 14 (5.6) | 12 (4.8) | ||
| Unknown | 336 (3.7) | 331 (3.7) | 5 (2.0) | Unknown | 8 (1.6) | 3 (1.2) | 5 (2.0) | ||
| Distant lymph node metastases | 0.215 | Distant lymph node metastases | 0.886 | ||||||
| No | 1944 (21.4) | 1893 (21.4) | 51 (20.5) | No | 99 (19.9) | 48 (19.3) | 51 (20.5) | ||
| Yes | 370 (4.1) | 365 (4.1) | 5 (2.0) | Yes | 9 (1.8) | 4 (1.6) | 5 (2.0) | ||
| Unknown | 6776 (74.5) | 6583 (74.5) | 193 (77.5) | Unknown | 390 (78.3) | 197 (79.1) | 193 (77.5) | ||
| T | <0.001 | T | 0.883 | ||||||
| T1 | 700 (7.7) | 668 (7.6) | 32 (12.9) | T1 | 67 (13.5) | 35 (14.1) | 32 (12.9) | ||
| T2 | 1655 (18.2) | 1585 (17.9) | 70 (28.1) | T2 | 131 (26.3) | 61 (24.5) | 70 (28.1) | ||
| T3 | 1490 (16.4) | 1446 (16.4) | 44 (17.7) | T3 | 93 (18.7) | 49 (19.7) | 44 (17.7) | ||
| T4 | 1838 (20.2) | 1802 (20.4) | 36 (14.5) | T4 | 75 (15.1) | 39 (15.7) | 36 (14.5) | ||
| Other | 3407 (37.5) | 3340 (37.8) | 67 (26.9) | Other | 132 (26.5) | 65 (26.1) | 67 (26.9) | ||
| N | <0.001 | N | 0.896 | ||||||
| N0 | 1376 (15.1) | 1283 (14.5) | 93 (37.3) | N0 | 189 (38.0) | 96 (38.6) | 93 (37.3) | ||
| N1 | 575 (6.3) | 546 (6.2) | 29 (11.6) | N1 | 60 (12.0) | 31 (12.4) | 29 (11.6) | ||
| N2 | 2827 (31.1) | 2771 (31.3) | 56 (22.5) | N2 | 116 (23.3) | 60 (24.1) | 56 (22.5) | ||
| N3 | 1429 (15.7) | 1419 (16.1) | 10 (4.0) | N3 | 17 (3.4) | 7 (2.8) | 10 (4.0) | ||
| Other | 2883 (31.7) | 2822 (31.9) | 61 (24.5) | Other | 116 (23.3) | 55 (22.1) | 61 (24.5) | ||
| Radiotherapy | 0.006 | Radiotherapy | 0.179 | ||||||
| No | 109 (1.2) | 109 (1.2) | 0 (0.0) | No | 80 (16.1) | 34 (13.7) | 46 (18.5) | ||
| Yes | 6663 (73.3) | 6460 (73.1) | 203 (81.5) | Yes | 418 (83.9) | 215 (86.3) | 203 (81.5) | ||
| None/unknown | 2318 (25.5) | 2272 (25.7) | 46 (18.5) | ||||||
| Chemotherapy | <0.001 | Chemotherapy | 0.499 | ||||||
| No | 4281 (47.1) | 4199 (47.5) | 82 (32.9) | No | 156 (31.3) | 74 (29.7) | 82 (32.9) | ||
| Yes | 4809 (52.9) | 4642 (52.5) | 167 (67.1) | Yes | 342 (68.7) | 175 (70.3) | 167 (67.1) | ||
PSM, Propensity score matching.
Kaplan–Meier survival analysis suggested that for NSCLC patients with brain metastasis, surgical treatment of the primary lesion could prolong patients’ survival. A similar result was obtained after removing the influence of other clinical factors (Fig. 2). NSCLC patients with brain metastasis who received surgery for primary lesion had longer median survival time than those who did not have surgery (16.0 months vs. 4.0 months P < 0.001 and 16.0 months vs. 8.0 months P < 0.001 after PSM). This result suggests that surgery on primary site could bring survival benefits to NSCLC-brain metastasis patients. Further clinical trials are required to explore its therapeutic value and side effects in the future.
Fig. 2.
Result of Kaplan–Meier analysis. (a) Kaplan–Meier analysis including 9090 patients. (b) After PSM, a similar result was obtained. PSM, Propensity score matching.
Considering that the T and N stage of tumor, liver metastasis and bone metastasis status all affected the survival time of patients with brain metastasis, we divided the patients cohort after PSM into T1-2 or T3-4 groups, N0-1 or N2-3 groups, with or without liver metastasis groups, with or without bone metastasis groups, and further explored the impact of primary lesion surgery on the prognosis in subgroups. The results showed that for NSCLC-brain metastasis patients with different T and N groups, the resection of the primary lesion could prolong the survival time of patients (Fig. 3).
Fig. 3.
Kaplan–Meier analysis of the effect of primary lesion surgery in T1-2 patients (a), T3-4 patients (b), N0-1 patients (c), and N2-3 patients (d).
The metastasis of other organs affected the prognosis of patients. For NSCLC-brain metastasis patients with no liver metastasis or bone metastasis, surgical treatment of the primary focus could significantly prolong the survival of patients. However, for patients with liver metastasis and bone metastasis, there was no significant difference in survival time between surgery and non-surgery groups (Fig. 4). These results suggested that for NSCLC patients with brain metastasis, if there is no other organ metastasis, the operation of the primary focus can benefit the patient’s survival, while if there is other organ metastasis, the surgical treatment is meaningless.
Fig. 4.
Kaplan–Meier analysis of the effect of primary lesion surgery in patients without liver metastasis (a), with liver metastasis (b), without bone metastasis (c), and with bone metastasis (d).
Discussion
Our results showed that brain metastases occurred in 14.1% of patients with lung cancer. Adenocarcinoma is the most common pathological type of lung cancer (Yang et al., 2018). Our logistic regression analysis and cox analysis results showed that SCLC and NSCLC were quite different. Furthermore, by combining the results, we found several homogeneous and heterogeneous factors, which have never been discussed in detail in previous studies. The homogeneous brain metastasis risk and prognostic factors in NSCLC were distant metastases (including liver/bone/distant lymph node), T/N stage and were bone metastases in SCLC. Our results showed that both older NSCLC and SCLC patients had a lower risk of brain metastases, but worse survival. A similar result was also obtained in a previous study (Barnholtz-Sloan et al., 2004; Reddy et al., 2020). As for the pathology, patients with lung adenocarcinoma have a higher risk of developing brain metastasis. However, among patients with brain metastasis, adenocarcinoma patients have longer survival time. A similar result was achieved when investigating the role of race. NSCLC patients with other races were at higher risk for developing brain metastasis, but had a better prognosis among patients with brain metastasis. Previous research exploring the risk factor for brain metastasis from esophageal cancer revealed that other races (American Indian/Alaska Native race) were positively associated with the occurrence of brain metastases (Cheng et al., 2021). These results showed that race may influence tumor metastasis. Interestingly, the T and N stages of the primary lesion and the distant lymph node status were not related to the survival time of SCLC patients with brain metastasis, but were closely associated with the prognosis of NSCLC, which indicated the heterogeneity between SCLC and NSCLC.
Few articles focused on the site of primary lesion. In our study, primary site is associated with the risk of developing brain metastasis. NSCLC patients whose tumor was present at right middle/lower lobe had a lower risk of developing brain metastasis than at left upper lobe. However, for NSCLC-brain metastasis patients, primary lesion at main bronchus was associated with worse survival. For SCLC, primary lesion site was not related to brain metastasis risk or survival time. Further studies are required to reveal the molecular mechanism of this result.
Surgery, chemotherapy, and radiotherapy are common therapies for cancers. Providing individualized treatment for different patients so as to maximize the personal survival benefits is a research direction (Kang et al., 2020). Previous studies have suggested that surgery could improve the prognosis of IV cancer patients with distant metastases. Mastectomy is associated with better OS among patients with stage IV breast cancer, compared with those who do not undergo surgery (Bilani et al., 2021). For patients with metastatic adrenocortical carcinoma, primary lesion surgery improved OS and cancer-specific survival (Tsilimigras et al., 2021). What is more, the surgical resection of primary gastrointestinal neuroendocrine tumor was correlated with a survival benefit among individuals with unresected metastases (Wang et al., 2017). However, the role of surgical resection of primary lesion has not been discussed among lung cancer patients with brain metastasis. Our results suggested that primary lesion surgery cannot prolong the survival time of SCLC-brain metastasis patients, but could improve the survival of NSCLC-brain metastasis patients with different T and N stages. Radiotherapy and chemotherapy were associated with a better prognosis for patients. We also performed a subgroup analysis of NSCLC-brain metastasis patients to investigate the role of primary lesion surgery. The results suggested that surgery could improve the prognosis of patients with brain metastasis only. However, for NSCLC-brain metastasis patients with liver and bone metastases, there was no significant difference in survival between the surgical and non-surgical groups. Further multicenter prospective studies are still required to validate these outcomes.
This study has some limitations. The accuracy of identifying brain metastasis depends on brain imaging type (including CT and MRI) (Lamba et al., 2021). However, SEER does not provide information relating to the imaging examination for brain metastasis diagnosis. What is more, not all the brain metastasis status of lung cancer patients in SEER database is sure. Therefore the incidence of brain metastasis may be inaccurate. For many patients, the status of surgery, lymph node metastasis, T stage, N stage, radiotherapy, and chemotherapy were unknown, which reduced the number of patients included in the study cohort. In addition, we do not have specific treatment information such as chemotherapy protocol and radiation planning technique, which may influence the prognosis of brain metastasis patients.
Conclusion
In this study, we found that the incidence of brain metastasis in lung cancer patients was about 14.1%, and the median survival of lung cancer patients with brain metastasis was 5 months. Our study also suggested several homogeneous and heterogeneous risk/prognostic factors associated with brain metastasis, which need to be paid more attention in clinical practice. Using PSM approach, we found that surgery on primary lesion could improve survival in NSCLC patients with brain metastasis, but not SCLC patients with brain metastasis. These results are helpful for clinicians to conduct clinical evaluations and make individualized therapeutic strategies.
Acknowledgements
Y.H.: research design, data collection, interpretation and analysis, article drafting. GL: Research design, critical article revision.
The data used in this study are available from publicly available SEER database. SEER*Stat version 8.4.0 (https://seer.cancer.gov/seerstat/) was used to get data.
SEER database is publicly accessible worldwide. The authors signed the SEER database agreement and got the license to access SEER data.
Conflicts of interest
There are no conflicts of interest.
Supplementary Material
Footnotes
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.eurjcancerprev.com).
References
- Achrol AS, Rennert RC, Anders C, Soffietti R, Ahluwalia MS, Nayak L, et al. (2019). Brain metastases. Nat Rev Dis Primers 5:5. [DOI] [PubMed] [Google Scholar]
- Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, et al. (2006). Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295:2483–2491. [DOI] [PubMed] [Google Scholar]
- Bacha S, Cherif H, Rabaa D, Habibech S, Cheikhrouhou S, Racil H, et al. (2018). Brain metastases of non-small cell lung cancer: prognostic factors and management. Tunis Med 96:165–171. [PubMed] [Google Scholar]
- Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. (2004). Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the metropolitan detroit cancer surveillance system. J Clin Oncol 22:2865–2872. [DOI] [PubMed] [Google Scholar]
- Bilani N, Elson L, Liang H, Elimimian EB, Nahleh Z. (2021). Effect of surgery at primary and metastatic sites in patients with stage IV breast cancer. Clin Breast Cancer 21:170–180. [DOI] [PubMed] [Google Scholar]
- Castrucci WA, Knisely JP. (2008). An update on the treatment of CNS metastases in small cell lung cancer. Cancer J 14:138–146. [DOI] [PubMed] [Google Scholar]
- Cheng S, Yang L, Dai X, Wang J, Han X. (2021). The risk and prognostic factors for brain metastases in esophageal cancer patients: an analysis of the SEER database. BMC Cancer 21:1057. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Doll KM, Rademaker A, Sosa JA. (2018). Practical guide to surgical data sets: surveillance, epidemiology, and end results (SEER) database. JAMA Surg 153:588–589. [DOI] [PubMed] [Google Scholar]
- Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y. (2020). Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct Target Ther 5:28. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Huber S, Dietrich JF, Nagengast B, Moeller K. (2017). Using propensity score matching to construct experimental stimuli. Behav Res Methods 49:1107–1119. [DOI] [PubMed] [Google Scholar]
- Kang Y, Jin Y, Li Q, Yuan X. (2020). Advances in lung cancer driver genes associated with brain metastasis. Front Oncol 10:606300. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lamba N, Wen PY, Aizer AA. (2021). Epidemiology of brain metastases and leptomeningeal disease. Neuro Oncol 23:1447–1456. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li N, Chu Y, Song Q. (2021). Brain metastasis in patients with small cell lung cancer. Int J Gen Med 14:10131–10139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lowery FJ, Yu D. (2017). Brain metastasis: unique challenges and open opportunities. Biochim Biophys Acta Rev Cancer 1867:49–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reddy SP, Dowell JE, Pan E. (2020). Predictors of prognosis of synchronous brain metastases in small-cell lung cancer patients. Clin Exp Metastasis 37:531–539. [DOI] [PubMed] [Google Scholar]
- Sanchez de Cos J, Sojo Gonzalez MA, Montero MV, Perez Calvo MC, Vicente MJ, Valle MH. (2009). Non-small cell lung cancer and silent brain metastasis. Survival and prognostic factors. Lung Cancer 63:140–145. [DOI] [PubMed] [Google Scholar]
- Schouten LJ, Rutten J, Huveneers HA, Twijnstra A. (2002). Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 94:2698–2705. [DOI] [PubMed] [Google Scholar]
- Shen H, Deng G, Chen Q, Qian J. (2021). The incidence, risk factors and predictive nomograms for early death of lung cancer with synchronous brain metastasis: a retrospective study in the SEER database. BMC Cancer 21:825. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Siegel RL, Miller KD, Fuchs HE, Jemal A. (2022). Cancer statistics, 2022. CA Cancer J Clin 72:7–33. [DOI] [PubMed] [Google Scholar]
- Steeg PS, Camphausen KA, Smith QR. (2011). Brain metastases as preventive and therapeutic targets. Nat Rev Cancer 11:352–363. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249. [DOI] [PubMed] [Google Scholar]
- Tsilimigras DI, Hyer JM, Paredes AZ, Ejaz A, Cloyd JM, Beane JD, et al. (2021). Resection of primary gastrointestinal neuroendocrine tumor among patients with non-resected metastases is associated with improved survival: a SEER-medicare analysis. J Gastrointest Surg 25:2368–2376. [DOI] [PubMed] [Google Scholar]
- Wang S, Gao WC, Chen SS, Bai L, Luo L, Zheng XG, et al. (2017). Primary site surgery for metastatic adrenocortical carcinoma improves survival outcomes: an analysis of a population-based database. Onco Targets Ther 10:5311–5315. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yamamoto M, Kawabe T, Sato Y, Higuchi Y, Nariai T, Barfod BE, et al. (2013). A case-matched study of stereotactic radiosurgery for patients with multiple brain metastases: comparing treatment results for 1-4 vs >/= 5 tumors: clinical article. J Neurosurg 118:1258–1268. [DOI] [PubMed] [Google Scholar]
- Yang J, Zhang Y, Sun X, Gusdon AM, Song N, Chen L, et al. (2018). The prognostic value of multiorgan metastases in patients with non-small cell lung cancer and its variants: a SEER-based study. J Cancer Res Clin Oncol 144:1835–1842. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhao QY, Luo JC, Su Y, Zhang YJ, Tu GW, Luo Z. (2021). Propensity score matching with R: conventional methods and new features. Ann Transl Med 9:812. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhu Y, Cui Y, Zheng X, Zhao Y, Sun G. (2022). Small-cell lung cancer brain metastasis: From molecular mechanisms to diagnosis and treatment. Biochim Biophys Acta Mol Basis Dis 1868:166557. [DOI] [PubMed] [Google Scholar]
- Zuo C, Liu G, Bai Y, Tian J, Chen H. (2021). The construction and validation of the model for predicting the incidence and prognosis of brain metastasis in lung cancer patients. Transl Cancer Res 10:22–37. [DOI] [PMC free article] [PubMed] [Google Scholar]