Brain metastasis originated from gastric cancer: its clinicopathological characteristics and survival outcome

doi:10.21203/rs.3.rs-2467108/v1

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Brain metastasis originated from gastric cancer: its clinicopathological characteristics and survival outcome

https://doi.org/10.21203/rs.3.rs-2467108/v1

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Objective

The frequency and prognostic factors of brain metastasis(BM) originated from gastric cancer(GC) remain unclear. The purpose of this study was to clarify the current knowledge of BM and determine its risk factors and survival outcome.

Methods

A total of 9,278 stage IV GC patients were retrospectively identified from the Surveillance, Epidemiology, and End Results(SEER) database. Clinicopathological features and survival outcomes between patients with and without BM were compared, and significant prognostic factors were determined.

Results

The frequency of BM in stage IV patients was 2.2%(203/9,278), and 52.7%(107/203) of BM patients presented synchronous extracranial metastases at the time of diagnosis. Younger age(< 65 years old) and proximal GC were significantly associated with BM. The patients with BM had a shorter median cancer-specific survival(CSS)(3.0 months [95% CI: 2.21–3.79] vs 7.0 months [95% CI:6.73–7.27], P < 0.001) and overall survival(OS)(3.0 months [95%CI:2.27–3.73] vs 6.0 months [95%CI:5.77–6.23], P < 0.001) than those without BM. For patients with BM, the presence of synchronous extracranial metastases was significantly associated with shorter median CSS(3.0 months [95%CI: 2.30–3.70] vs 4.0 months [95%CI: 2.69–5.31], P = 0.031). However, there was no correlation between the number of extracranial metastatic organs and survival outcomes. Poorly differentiated/undifferentiated adenocarcinoma(HR:1.876, 95%CI:1.231–2.858, P = 0.003) and the presence of extracranial metastasis(HR:1.420, 95%CI:1.003–2.010, P = 0.048) were independent predictive factors for poor survival of patients with BM.

Conclusions

Brain metastasis originated from GC was not common, but survival outcome was extremely poor. For early detection of brain metastasis, it is necessary to pay more attention to patients with risk factors.

Gastric cancer

stage IV

brain metastasis

survival

prognostic factor

Despite an overall declining trend in incidence over the past decades, gastric cancer remains a common cause of cancer-related deaths for both male and female according to the recent Global Cancer Statistics.^{1, 2} As a major threat to human health, surgical resection and adequate lymphadenectomy is the only potentially curative treatment method for resectable gastric cancer. Unfortunately, a considerable proportion of gastric cancer patients were unresectable at the time of diagnosis due to synchronous distant metastasis. In terms of metastatic site, peritoneal, hepatic, pulmonary and bone involvement were more common in stage IV gastric cancer patients. In contrast, brain metastasis from gastric cancer was extremely rare, and its frequency was estimated to be ranged from 0.5–0.7%.^3–5 With improved survival and increased use of radiological assessment such as magnetic resonance imaging (MRI), however, brain metastasis was more frequently detected at the time of diagnosis over the last two decades.⁶

In general, the survival outcome of patients with brain metastasis from the gastrointestinal tract was worse than that of those brain metastasis from other malignant tumors. Since brain metastasis from gastric cancer was usually a terminal event in the clinical course of the disease, therapeutic response to palliative chemotherapy and radiotherapy was very poor for these patients. It has been reported that patients with brain metastasis had an extremely poor prognosis, and the median overall survival was just 1.3–10.0 months, even if aggressive multidisciplinary treatment was performed.^{5, 7–9}

Understanding survival outcome and prognostic factors of gastric cancer patients with brain metastasis are helpful to guide individualized treatment. To date, there have been a few case reports and literature focusing on the frequency, clinicopathologic features and prognostic outcome of brain metastasis from gastric cancer.^{5, 8, 10} However, the majority of these studies only described a small case series of patients and conflicting results still exist. In the present study, we retrospectively reviewed the clinicopathological and survival data of stage IV gastric cancer patients from the Surveillance, Epidemiology, and End Results(SEER) database in order to clarify the current knowledge about brain metastasis from gastric cancer and determine its risk factors and survival outcome.

Patients selection

The current analysis was restricted to patients who were histopathologically confirmed with primary gastric adenocarcinoma with synchronous distant metastasis at presentation (stage IV). For this purpose, we searched the Surveillance, Epidemiology, and End Results (SEER) 18 Registries Research database (1973–2016) and retrospectively identified 9,893 stage IV gastric adenocarcinoma patients from January 2004 to December 2015. Those with missing or unknown data on brain metastasis status (n = 538) and follow-up information (n = 77) were excluded. Ultimately, a total of 9,278 consecutive gastric adenocarcinoma patients were eligible for this analysis.

The protocol of this study was approved by the Ethics Committee of Tianjin First Central Hospital, and all procedures was conducted in line with the Declaration of Helsinki. The SEER was is a public database which did not include personal identifying information, and informed consent was not required for this analysis..

Data collection and follow-up

The SEER database was accessed via the free public website at www.seer.cancer.gov, and relevant data were extracted using the SEER*Stat software (version 8.3.6). Investigators received permission from the SEER program to access the original data. Demographic, clinicopathologic and survival data, including patient age, sex, race, year of diagnosis, tumor location, pathological T category (pT stage), pathological N category (pN stage), pathological TNM stage, tumor size, differentiation type, histological classification, metastatic site (liver, brain, lung and bone), follow-up duration, and vital status, were collected and analyzed. All patients were divided into < 65 years old and ≥ 65 years old groups. Tumor location included gastric antrum and pylorus, gastric body, gastric cardia and fundus, and overlapping lesion of the stomach. Differentiation degree of gastric adenocarcinoma was categorized as well-differentiated type, moderately differentiated type, poorly differentiated type and undifferentiated type. The pathological stage of gastric cancer patients was determined according to the 7th edition of the TNM classification of the American Joint Commission on Cancer (AJCC).

In the current study cohort, the median follow-up period was 6 months (range, 1–83 months). The primary end-point event of this study was cancer-specific survival (CSS), which was defined as the time interval between disease diagnosis and death owing to gastric cancer-related causes. The observations of patients who died of other causes or were alive at the end of follow-up were treated as censored events. The second end-point event was overall survival (OS), which defined as the time interval from the date of diagnosis to the date of death owing to any causes.

Statistical analysis

Categorical variables were reported as absolute numbers and percentages in a descriptive table, and they were summarized by frequency distributions and compared by Pearson’s chi-square test or Fisher’s exact test as appropriate. Continuous variables were expressed as median with range or mean with standard deviation (SD), and they were compared using an unpaired student’s t-test or Mann-Whitney test. The Logistic regression model was fit to evaluate the risk factors for brain metastasis in stage IV gastric cancer. Survival curves were plotted using the Kaplan-Meier method, and the log-rank test was used to compare the survival differences between the study groups. The prognostic significance of clinicopathologic factors was assessed by the univariate Cox regression analysis, and the variables with a significant level of less than 0.10 were included in the subsequent multivariate analysis. A Cox proportional hazard model with a backward stepwise selection procedure, in which all potential covariates were adjusted, was used to determine independent prognostic factors for stage IV patients. Results for significant prognostic factors were presented as hazard ratio (HR) and its 95% confidence intervals (CIs). All statistical analyses were carried out using the statistical package for Windows SPSS 21.0 version (IBM Inc, New York, USA), and statistical significance was accepted at a P-value < 0.05.

Patients characteristics of study cohort

In the present study, a total of 9,278 stage IV patients were included, and 2.2% (203/9,278) of patients had synchronous brain metastasis. In addition, the frequency of liver metastasis, lung metastasis and bone metastasis in stage IV gastric cancer patients were 42.7%, 15.2% and 13.6%, respectively. Of 203 patients with brain metastasis, 70.4% (143/203) were males and 29.6% (60/203) were females, and the proportion of patients aged 65 or younger was 56.7% (115/203). At the time of diagnosis, 52.7% (107/203) of gastric cancer patients with brain metastasis had synchronous extracranial metastases. Among these patients, 48 patients had extracranial metastasis to one organ, 43 patients had extracranial metastases to two organs and 16 had three or more metastatic organs.

The comparisons of clinicopathological characteristics of patients with and without brain metastasis were presented in Table 1. The incidence of brain metastasis was significantly higher in younger patients (< 65 years old, 56.7% vs 48.2%, P = 0.017), white race (84.7% vs 73.8%, P = 0.002), well-differentiated or moderately differentiated adenocarcinoma (33.8% vs 22.7%, P < 0.001), and tumors located at gastric cardia or fundus (24.1% vs 18.7%, P = 0.012). Interestingly, patients with brain metastasis had a lower frequency of pT4 stage tumors than those without brain metastasis (10.8% vs 20.0%, P < 0.001). In addition, gastric cancer patients with brain metastasis usually had a higher risk of synchronous extracranial metastases to lung (30.5% vs 14.8%, P < 0.001) and bone (31.5% vs 13.2%, P < 0.001), but a lower incidence of synchronous extracranial metastases to the liver in comparison to those without brain metastasis (35.5% vs 42.8%, P < 0.001). There were no distribution differences between patients with and without brain metastasis in terms of sex, histological type, tumor size and lymph node metastasis.

Table 1

Clinicopathological characteristics of gastric cancer patients with and without brain metastasis
Characteristics	Patients(%)	Brain metastasis
Characteristics	Patients(%)	Yes (n = 203)	No (n = 9075)	P value
Age (year)				0.017
< 65	4490(48.4%)	115(56.7%)	4375(48.2%)
≥ 65	4788(51.6%)	88(43.3%)	4700(51.8%)
Sex				0.080
Male	5996(64.6%)	143(70.4%)	5853(64.5%)
Female	3282(35.4%)	60(29.6%)	3222(35.5%)
Race				0.002
White	6865(74.0%)	172(84.7%)	6693(79.0%)
Black	1185(12.8%)	17(8.4%)	1168(8.4%)
Other	1228(13.2%)	14(6.9%)	1214(12.6%)
Tumor location				< 0.001
Gastric antrum/Pylorus	1441(15.5%)	11(5.4%)	1430(15.8%)
Gastric body	909(9.8%)	9(4.4%)	900(9.9%)
Gastric cardia/fundus	3550(38.3%)	126(62.1%)	3423(37.7%)
Overlapping	810(8.7%)	9(4.4%)	801(8.8%)
Stomach, NOS	2569(27.7%)	48(23.6%)	2521(27.8%)
Differentiation type				0.012
WD/MD	1743(18.8%)	49(24.1%)	1694(18.7%)
PD/UD	6204(66.9%)	116(57.1%)	6088(67.1%)
Unknown	1331(14.3%)	38(18.7%)	1293(14.2%)
Histological type				0.112
Adenocarcinoma, NOS	6578(70.9%)	156(76.8%)	6422(70.8%)
MUC	147(1.6%)	1(0.5%)	146(1.6%)
SRC	2553(27.5%)	46(22.7%)	2507(27.6%)
pT stage				< 0.001
T1	1697(18.3%)	31(15.3%)	1666(18.4%)
T2	438(4.7%)	6(3.0%)	432(4.8%)
T3	1339(14.4%)	27(13.3%)	1312(14.5%)
T4	1835(19.8%)	22(10.8%)	1813(20.0%)
Tx	3969(42.8%)	117(57.6%)	3852(42.4%)
pN stage				0.843
N0	155(1.7%)	2(59.4%)	153(1.7%)
N1	365(3.9%)	14(27.8%)	351(3.9%)
N2	197(2.1%)	1(12.8%)	196(2.1%)
N3	300(3.2%)	3(12.8%)	297(3.2%)
Nx	8261(89.0%)	183(3.9%)	8078(89.0%)
Tumor size (cm)				0.102
≤ 5cm	2086(22.5%)	48(23.6%)	2038(22.5%)
> 5cm	1722(18.6%)	26(12.8%)	1696(18.7%)
Unknown	5470(59.0%)	129(63.5%)	5341(58.9%)
Mean ± SD	5.68 ± 5.33 cm	5.14 ± 2.53 cm	5.69 ± 5.37 cm	0.393
Bone metastasis				< 0.001
No	7965(85.8%)	131(64.5%)	7834(86.3%)
Yes	1259(13.6%)	64(31.5%)	1195(13.2%)
Unknown	54(0.6%)	8(3.9%)	46(0.5%)
Liver metastasis				< 0.001
No	5218(56.2%)	119(58.6%)	5099(56.2%)
Yes	3958(42.7%)	72(35.5%)	3886(42.8%)
Unknown	102(1.1%)	12(5.9%)	90(1.0%)
Lung metastasis				< 0.001
No	7688(82.9%)	124(61.1%)	7564(83.3%)
Yes	1406(15.2%)	62(30.5%)	1344(14.8%)
Unknown	184(2.0%)	17(8.4%)	167(1.8%)
NOS: no otherwise specified; WD: well-differentiated; MD: moderately differentiated; PD: poorly differentiated; UD: undifferentiated; MUC: mucinous adenocarcinoma; SRC: signet-ring cell carcinoma; SD: standard deviation.

We further performed the univariate and multivariate logistic regression analysis to determine the risk factors for gastric cancer from brain metastasis. According to the results of univariate analysis, patient age < 65 (P < 0.05), race (P < 0.05), tumor location (P < 0.001), and differentiation type (P < 0.05) were significantly associated with the presence of brain metastasis. After adjusting for potential covariates, younger age (< 65 years old, OR:1.431, 95% CI: 1.079–1.894, P = 0.013) and tumors located at gastric cardia and/or fundus (OR:4.783, 95% CI: 2.575–8.886, P < 0.001) were identified as risk factors for brain metastasis (Table 2).

Table 2

Univariate and multivariate analysis of risk factors for brain metastasis in gastric cancer patients
Factor	Univariate analysis		Multivariate analysis
Factor	OR (95% CI)	P value	OR (95% CI)	P value
Age (year)		0.018		0.013
≥ 65	Reference		Reference
< 65	1.404 (1.060–1.859)		1.431 (1.079–1.894)
Sex		0.081		0.907
Male	Reference		Reference
Female	0.762 (0.562–1.034)		0.981 (0.714–1.349)
Race
White	Reference		Reference
Black	0.566 (0.343–0.936)	0.026	0.712 (0.427–1.187)	0.192
Other	0.449 (0.259–0.776)	0.004	0.577 (0.331–1.005)	0.052
Tumor location
Gastric antrum/Pylorus	Reference		Reference
Gastric body	1.300 (0.537–3.149)	0.561	1.289 (0.532–3.124)	0.574
Gastric cardia/fundus	4.785 (2.576–8.889)	< 0.001	4.783 (2.575–8.886)	< 0.001
Overlapping	1.461 (0.603–3.540)	0.401	1.433 (0.591–3.474)	0.426
Stomach, NOS	2.475 (1.281–4.781)	0.007	2.449 (1.268–4.732)	0.008
Differentiation type
WD/MD	Reference		Reference
PD/UD	0.659 (0.470–0.924)	0.016	0.769 (0.544–1.087)	0.137
Unknown	1.016 (0.661–1.562)	0.942	1.137 (0.735–1.758)	0.564
Histological type
Adenocarcinoma, NOS	Reference		Reference
MUC	0.282 (0.039–2.028)	0.209	0.364 (0.050–1.087)	0.317
SRC	0.755 (0.542–1.053)	0.098	1.137 (0.735–1.758)	0.452
pT stage
T1	Reference
T2	0.746 (0.309–1.801)	0.515	-
T3	1.106 (0.657–1.862)	0.705	-
T4	0.652 (0.376–1.131)	0.128	-
Tx	1.632 (1.094–2.435)	0.016	-
pN stage
N0	Reference
N+	1.632 (0.375–7.103)	0.514	-
Nx	1.733 (0.426–7.046)	0.442	-
Tumor size (cm)
≤ 5cm	Reference		Reference
> 5cm	0.651 (0.402–1.054)	0.081	0.747 (0.459–1.216)	0.241
Unknown	1.025 (0.773–1.434)	0.883	1.138 (0.809–1.601)	0.457
NOS: no otherwise specified; WD: well-differentiated; MD: moderately differentiated; PD: poorly differentiated; UD: undifferentiated; MUC: mucinous adenocarcinoma; SRC: signet-ring cell carcinoma.

Survival outcome and prognostic factors of gastric cancer patients with brain metastasis

Complete follow-up data were available for 7,978 gastric cancer patients. In the current cohort, 1-year, 2-year and 3-year CSS rate of stage IV patients was 29.8%, 12.6% and 6.8%, respectively; while 1-year, 2-year and 3-year OS rate was 27.1%, 10.6% and 5.2%, respectively. Figure 1A showed the survival curves of gastric cancer patients with and without brain metastasis. The presence of brain metastasis was significantly associated with shorter median CSS (3.0 months, 95% CI: 2.21–3.79 months vs 7.0 months vs 95% CI: 6.73–7.27 months), and 1-year CSS rate of stage IV patients with and without brain metastasis was 19.7% and 30.0%, respectively (P < 0.001). Similarly, the median OS for patients with brain metastasis was 3.0 months (95% CI: 2.27–3.73 months), which was significantly shorter than those without brain metastasis (median OS: 6.0 months, 95% CI: 5.77–6.23 months). The 1-year OS rate of two patient groups was 18.6% and 25.0%, respectively(P < 0.001)(Fig. 1B).

For patients with brain metastasis, the median CSS for those with and without synchronous extracranial metastases was 3.0 months (95% CI: 2.30–3.70 months) and 4.0 months (95% CI: 2.69–5.31 months), respectively. The patients with synchronous extracranial metastases had a shorter 1-year CSS rate than those without extracranial metastases(14.5% vs 26.6%, P = 0.031)(Fig. 2A). However, the survival difference for OS between two patient groups did not reach a statistical significance (median OS: 3.0 months, 95% CI: 2.27–3.73 months vs 4.0 months, 95% CI: 3.27–4.73 months; 1-year OS rate: 14.6% vs 23.6%, P = 0.215)(Fig. 2B).

We next evaluate the association between the number of synchronous extracranial metastases and survival outcome of gastric cancer patients with brain metastasis. The results demonstrated that the median CSS for patients with extracranial metastasis to one organ was 3.0 months (95% CI: 2.19–3.81 months) compared to 3.0 months (95% CI: 2.05–3.95 months) for those with two or more metastatic organs. The number of synchronous extracranial metastases had no negative impact on the survival outcome of patients with brain metastasis (1-year CSS rate: 8.3% vs 16.8%, P = 0.143). A similar finding was observed in the comparison of OS between patients with one organ and two or more metastatic organs (1-year OS rate: 11.6% vs 14.9%, P = 0.556)(Fig. 3).

The results of univariate and multivariate analysis for prognostic factors in gastric cancer patients with brain metastasis were listed in Table 3. We found that poorly differentiated/undifferentiated adenocarcinoma (HR:1.876, 95% CI: 1.231–2.858, P = 0.003) and the presence of extracranial metastasis to other organs (HR:1.420, 95% CI: 1.003–2.010, P = 0.048) were independently associated with worse survival outcome.

Table 3

Univariate and multivariate analysis of prognostic factors for gastric cancer patients with brain metastasis (CSS)
Factor	Univariate analysis		Multivariate analysis
Factor	HR (95% CI)	P value	HR (95% CI)	P value
Age (year)		0.205
< 65	Reference		-
≥ 65	1.251 (0.885–1.768)		-
Sex		0.179
Male	Reference		-
Female	1.289 (0.890–1.866)		-
Race
White	Reference
Black	1.228 (0.672–2.245)	0.505	-
Other	1.008 (0.555–1.830)	0.980	-
Tumor location
Gastric antrum/Pylorus/body	Reference
Gastric cardia/fundus	0.682 (0.393–1.184)	0.174	-
Overlapping/Stomach, NOS	1.033 (0.564–1.895)	0.915	-
Differentiation type
WD/MD	Reference		Reference
PD/UD	1.817 (1.195–2.763)	0.005	1.876 (1.231–2.858)	0.003
Unknown	1.553 (0.912–2.642)	0.105	1.514 (0.889–2.576)	0.127
Histological type
Adenocarcinoma, NOS	Reference		-
MUC/SRC	1.393 (0.926–2.096)	0.111	-
pT stage
T1-T2	Reference
T3-T4	1.009 (0.604–1.687)	0.972	-
Tx	1.324 (0.852–2.058)	0.213	-
Tumor size (cm)
≤ 5cm	Reference
> 5cm	1.040 (0.574–1.884)	0.897	-
Unknown	1.161 (0.769–1.753)	0.476	-
Extracranial metastasis (bone, liver or lung)
No	Reference		Reference
Yes	1.364 (0.967–1.922)	0.077	1.420 (1.003–2.010)	0.047
NOS: no otherwise specified; WD: well-differentiated; MD: moderately differentiated; PD: poorly differentiated; UD: undifferentiated; MUC: mucinous adenocarcinoma; SRC: signet-ring cell carcinoma.

Using a large patient cohort from the SEER database, the current analysis revealed several important findings concerning brain metastasis from gastric cancer. First, younger age and gastric cardia/ fundus adenocarcinoma were significantly associated with the presence of brain metastasis. Second, patients with brain metastasis had a shorter CSS and OS than other stage IV gastric cancer patients. Third, extracranial metastasis to other organs and poorly differentiated/undifferentiated adenocarcinoma were independent prognostic factors for gastric cancer patients with brain metastasis. However, the number of extracranial metastatic organs were not associated with worse survival.

In general, metastatic tumors of the brain mainly originated from lung cancer, breast cancer and renal cell carcinoma.⁶ In contrast, the frequency of brain metastasis from esophageal and gastrointestinal cancer, especially for gastric cancer, was extremely rare.^{4, 11} In the present study, the incidence of brain metastasis from gastric cancer was only 2.2% in stage IV patients, which was much lower than that of hepatic, pulmonary and bone metastasis. By analyzing clinicopathological characteristics, an important finding was that young patients with gastric cardia/fundus adenocarcinoma had a higher incidence of brain metastasis. These results were supported by the previous report.¹² It has been demonstrated that brain metastasis was more frequent in proximal gastric cancer and gastroesophageal junction adenocarcinoma (especially for Siewert type I). Harada et al retrospectively analyzed the clinicopathological characteristics of 2,348 upper gastrointestinal cancer patients, and the results showed that the incidence of brain metastasis from gastroesophageal junction adenocarcinoma (Siewert I and II type) was 4.8% compared to 0% from gastric adenocarcinoma.¹² Proximal gastric cancer usually had more aggressive biological features and advanced tumor stage than distal cancer.^{13, 14} From an anatomical standpoint, the gastroesophageal junction, the posterior wall of the gastric fundus and the portions of the lesser and greater curvature of the proximal stomach were not covered by the visceral peritoneum,¹⁵ which increased the possibility of cancer cells exfoliation and occult distant dissemination. What’s more, it is thought that the presence of pulmonary metastasis, which made systematic dissemination of cancer cells possible, may confer an increased risk of brain metastasis.^{16, 17} In the present study, 30.5% of patients with brain metastasis presented with synchronous pulmonary metastasis compared with 14.8% of those without brain metastasis. Also, 31.5% of patients with brain metastasis were associated with synchronous bone metastasis compared to 14.8% of those without brain metastasis. In clinical practice, it is necessary to pay more attention to patients with these characteristics as early detection of brain metastasis may provide them with potential benefits from aggressive interventions.

Due to the presence of the blood-brain barrier, most of circulating cells and molecules was not easy to cross it. To date, it is still unclear how cancer cells resulted in the breakdown of the blood–brain barrier and further migrate to brain tissue. Some research reported that tumor-derived exosomes and heparinase secreted by cancer cells may play an important role in the development of brain metastasis.^{18, 19} On the other hand, recent studies have reported that malignant tumors with positive expression of the human epidermal growth factor receptor 2 (HER2) had a higher propensity to spread to the central nervous system.^{20, 21} However, Harada et al showed that HER2 status was not associated with brain metastasis originated from gastric cancer.¹² The exact molecular mechanism of brain metastasis, especially from gastric cancer, needs to be further understood and explored.

Brain metastasis from gastric cancer occurred predominantly at the end-stage of the clinical course of the disease. In this analysis, our data indicated that both median CSS and OS for patients with brain metastasis was significantly shorter than those without brain metastasis. These findings were consistent with previous reports on brain metastasis originated from colorectal cancer.^{22, 23} The presence of brain metastasis had a significant influence on survival outcome in stage IV patients.

Determining prognostic factors for gastric cancer patients with brain metastasis is helpful to predict survival outcome and guide treatment strategy. Several studies have revealed that extracranial metastasis to liver, lung or bone was significantly associated with worse survival in patients with brain metastasis.^{12, 23, 24} According to the reports of Harada et al, the median OS for patients with and without extracranial metastasis was 3.84 and 14.4 months in upper gastrointestinal cancer, respectively.¹² Similarly, Kraszkiewicz et al reported that patients with other metastatic sites had a shorter median OS than those without metastases to other organs (2.6 months vs. 12.7 months, P = 0.018).²⁵ In our study, the presence of synchronous extracranial metastases was identified as an independent prognostic factor for gastric cancer patients with brain metastasis. Of these patients, 52.7% presented synchronous extracranial metastases, which further resulted in a worse survival.

Although histological differentiation was not correlated with brain metastasis from gastric adenocarcinoma, it independently affected the survival outcome of patients with brain metastasis. It has been well established that poorly differentiated and undifferentiated adenocarcinoma are independent prognostic factors for advanced gastric cancer patients.²⁶ The current research further highlighted its prognostic significance for those with brain metastasis. Additionally, we found that the survival outcome of patients with extracranial metastasis to one organ was not significantly different from that of those with two or more metastatic organs. There was no relationship between the number of extracranial metastatic organs and survival outcome of patients with brain metastasis.

Individualized treatment selection was crucial to relieve neurological symptoms caused by brain metastasis and improve the survival outcome of patients. According to the treatment guidelines for brain metastasis,²⁷ the alternative method included conventional surgery, whole-brain radiotherapy, stereotactic radiosurgery and systematic chemotherapy. Despite various therapeutic modalities, there is no consensus on the optimum management for patients with brain metastasis from malignant tumors.²⁸ In terms of therapeutic effect, no sufficient evidence supported any available approach could significantly improve the quality of life and survival rate of patients with brain metastasis. However, aggressive multidisciplinary intervention might be valuable for patients with brain metastasis if performance status was appropriate.^{25, 29} With the advancement in individual treatment modalities, we expected that median survival of patients with brain metastasis could be further improved.

Several limitations of this study require further discussion. Firstly, the current study shares the limitations of any retrospective analysis, and the potential selection bias could not be neglected. Secondly, since relevant data on adjuvant chemoradiotherapy were unavailable in the public SEER database, we could not evaluate the impact of treatment strategy on the prognosis of patients with brain metastasis. Thirdly, several important clinicopathologic variables such as the Karnofsky performance status, recursive partitioning analysis (RPA) class and the number of brain metastatic lesions were not included in this analysis. Despite a few limitations, this study still represented the largest population-based analysis on this topic to date.

In conclusion, our results demonstrated that brain metastasis originated from gastric cancer was not common, but survival outcome was extremely poor. Synchronous extracranial metastasis and poorly differentiated/undifferentiated adenocarcinoma were independent prognostic factors for patients with brain metastasis. In addition, the younger patients (< 65 years old) with gastric cardia/fundus adenocarcinoma had a higher risk of brain metastasis than other patients. For early detection of brain metastasis, it is necessary to pay more attention to gastric cancer patients with these clinical characteristics.

Acknowledgments None.

Authors’ Contributions ZBC contributed to study design, data analysis, data interpretation and drafted this manuscript; WJC and MZC performed data analysis and interpretation; WWQ contributed to manuscript editing; MKW and YT conceived this project and reviewed this manuscript. All authors have read and approved the final version of this manuscript.

Funding This work was supported by the Tianjin Health Science and Technology Project (NO.ZC20213).

Availability of data and materials The supportive data of this manuscript are available from the public SEER database (https:// seer. cancer. gov/. ).

Ethics approval and consent to participate The protocol of this study was approved by the Ethics Committee of Tianjin First Central Hospital, and all procedures was conducted in line with the Declaration of Helsinki. The SEER was is a public database which did not include personal identifying information, and informed consent was not required for this analysis..

Consent for publication Not applicable.

Competing interests The authors declare that they have no conflict of interest.

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No competing interests reported.

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Brain metastasis originated from gastric cancer: its clinicopathological characteristics and survival outcome

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Introduction

Materials And Methods

Patients selection

Data collection and follow-up

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Results

Patients characteristics of study cohort

Survival outcome and prognostic factors of gastric cancer patients with brain metastasis

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