Does Surgical Resection Improve the Survival of Patients with Gastric Cancer Liver Metastases? A Population-Based, Propensity Score–Adjusted Analysis

doi:10.21203/rs.3.rs-3111105/v1

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Research Article

Does Surgical Resection Improve the Survival of Patients with Gastric Cancer Liver Metastases? A Population-Based, Propensity Score–Adjusted Analysis

https://doi.org/10.21203/rs.3.rs-3111105/v1

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Purpose

The use of surgery in the management of patients with gastric cancer liver metastases (GCLM) has been debatable. We aimed to assess whether surgical resection is associated with improved patient survival.

Methods

Patients with GCLM were identified in the Surveillance, Epidemiology, and End Results database between 2010 and 2015. Adult gastric cancer patients (aged ≥ 18 years) with liver metastases living longer than one month were eligible for this analysis. The overlap weighting method based on lasso regression with penalty factors (OW_pLasso) was applied to reduce the selection bias. The survival times of patients who underwent surgery and those who did not were compared using OW_pLasso adjusted Kaplan-Meier curves and Cox proportional hazards models.

Results

A total of 3694 patients with GCLM were identified. Of those, 354 (9.58%) patients underwent cancer-directed surgery (CDS). After OW_pLasso adjustment, the median overall survival was 12 months [95% confidence interval (CI) 11–16] in the CDS group and 6 months [95% CI 5–6] in the Non-CDS group. In Cox regression analysis, primary cancer resection was associated with a significantly better overall survival [hazard ratio (HR) 0.562, 95% confidence interval (CI) 0.482–0.656]. The benefit of surgical resection persisted in patients with worse conditions (large size and high-grade tumors, advanced T stages, and limited lymph node metastases).

Conclusions

In this population-based cohort analysis of patients with gastric cancer and liver metastases, surgical resection was linked to a better overall survival. As a result, surgery has the potential to be an option for treating patients with liver metastases.

Gastric cancer liver metastases

Survival

Overlap weighting

Cancer-directed surgery

SEER

Gastric cancer (GC) is one of the most frequent malignancies, and it is the third leading cause of cancer death globally, accounting for an estimated 26,500 new cancer cases and almost 11,130 deaths in 2023 (https://cancerstatisticscenter.cancer.org/#!/cancer-site/Stomach). Over one-third of patients have signs of distant metastases at the time of initial diagnosis because of the early GC's modest symptoms. About 3.5–14% of GC patients have metastases in the liver, which is one of the more typical locations (Cheon et al., 2008; Elias et al., 1998; Imamura et al., 2001; Makino et al., 2010; Okano et al., 2002; Saiura et al., 2002; Shirabe et al., 2003). Gastric cancer with liver metastases (GCLM) is associated with more aggressive tumor behaviors, leading to a dismal prognosis (Bang et al., 2010; Koizumi et al., 2008; Yamada et al., 2015). Systemic chemotherapy is currently considered the standard treatment for patients with GCLM (Ajani et al., 2022). However, the prognosis of patients with GCLM undergoing chemotherapy treatment remains poor, with a 5-year survival rate of less than 10% (Boku et al., 2009; Van Cutsem et al., 2006; Yagi, Seshimo, & Kameoka, 2000).

The value of surgical intervention for GCLM patients is still debatable. According to National Comprehensive Cancer Network (NCCN) recommendations, stage IV patients with tumor-related symptoms such bleeding, perforation, or obstruction should undergo surgical resections in a palliative setting (Ajani et al., 2022). However, the Japanese Gastric Cancer Association (JGCA) guidelines suggest that gastrectomy can be considered an option in patients with metastases without severe symptoms (jp, 2020). Although no randomized controlled trials have been published to examine the potential beneficial effect of surgery on survival outcomes in patients with GCLM, several retrospective studies and meta-analyses have reported significant survival benefits from surgical resection in stage IV cancers (Al-Batran et al., 2017; Ambiru et al., 2001; Baba et al., 1992; S. Chen et al., 2012; Dittmar et al., 2012; Gavriilidis, Roberts, de’Angelis, & Sutcliffe, 2019; Kanda et al., 2012; Kerkar, Kemp, & Avital, 2010; C. Li et al., 2010; W. Li et al., 2019; Liao et al., 2017; Montagnani et al., 2018; Saito et al., 1996; Saiura et al., 2002; Shirabe et al., 2003; Tiberio et al., 2009; K. Yoshida, Yamaguchi, Okumura, Tanahashi, & Kodera, 2016; M. Yoshida et al., 2004; Zurleni, Gjoni, Altomare, & Rausei, 2018).

The objective of the present study was to explore the effect of surgery on the long-term survival of patients with GCLM. We performed a population-based study using data from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2015. The propensity score weighting method based on overlap weights was applied to reduce potential selection bias brought on by measured patient characteristics.

Data source

The SEER data from 18 population-based cancer registries covering about 28% of the US population was used to identify patients with gastric cancer (www.seer.cancer.gov). This study was restricted to cases with liver metastases from January 2010 to December 2015, as the database did not provide related information until 2010.

Study population

We collected data using the SEER*Stat software (Version 8.4.0.). Gastric cancer was identified by the International Classification of Diseases for Oncology (ICD-O-3) codes C16.0-C16.9. Inclusion criteria were as follows: (1) Metastases in the liver; (2) Age ≥ 18 years; (3) Gastric cancer was the first diagnosed malignancy. SEER lacks information on metachronous metastasis. All of our analysis was based on synchronous liver metastasis. Patients with no evidence of a primary tumor, diagnosed with autopsy or death certificate, had a survival time < 1 month, lacked race information, and tumors identified as diffuse carcinoma or linitis plastic were excluded from the analysis. Additionally, we excluded patients who: were unknown if surgery was performed, surgery was contraindicated due to other conditions, and died before recommended surgery. The remaining patients were categorized into the CDS group (cancer-directed surgery performed) and the Non-CDS group (cancer-directed surgery not performed). A total of 3,694 gastric cancer patients with GCLM were included in the final cohort (Fig. 1).

Covariates and endpoints

Age was categorized into 18–39, 40–64, 65–79, and 80 and older based on the previous studies. Race was classified as white, black and others. Sites were categorized as: cardia (C16.0), body (C16.1-2, C16.5-6), lower (C16.3-4), overlapping lesion (C16.8), and not-specified (C16.9). Grade was categorized into the following groups; well/moderately differentiated (Grade I-II), poorly differentiated/undifferentiated (Grade III-IV), and unknown. Histological types were defined by the following ICD-O-3 codes: 8140 for adenocarcinoma, 8490 for signet ring cell carcinoma, and the remaining for others. Staging was classified by the 7th edition of the American Joint Committee on Cancer (AJCC) TNM staging system. T staging included T1, T2, T3, T4, and unknown. N staging included N0, N1, N2, N3, and unknown. Tumor size was categorized into four groups (< 2cm, 2-5cm, ≥5cm, and unknown). Marital status was classified as married, unmarried/separated (including divorced and widowed), and unknown. The primary endpoint in this study was overall survival (OS), which was defined as the time interval from diagnosis to death due to any cause, or until the last follow-up time point.

Statistical analysis

Demographic characteristics and clinical variables were compared between the two groups using the chi-square test for categorical variables and the Student t test for continuous variables.

To reduce the bias of patient selection, we applied the propensity score (PS) weighting method using overlap weights to balance the distribution of covariates between the CDS and Non-CDS groups. The traditional inverse propensity score weighting (IPW) method suffers from extreme weights when the PS distributions lack overlap between the treatment groups. Overlap weighting (OW) is a method that eliminates extreme weights by estimating the treatment effect in the target population with the most overlap in observed characteristics between treatment and control arms (Fan Li, 2018; F. Li, Thomas, & Li, 2019).

Specifically, we first estimated the propensity score using a multivariate lasso regression model with the CDS group as the dependent variable. All of the baseline variables were included in the PS model. Furthermore, factors would not be penalized if they were identified as significant confounders for survival (p < 0.1 in both univariate and multivariate cox regressions). This propensity score weighting method is hereinafter referred to as “OW_pLasso”. The individuals’ weights were achieved by assigning a weight of 1-PS to patients in the treatment arm and a weight of PS to patients in the control arm. The weighted standardized difference was calculated for all predictors to assess the balance of patient characteristics in the study cohort after applying the OW_pLasso adjustment.

The derived weights were then applied to the analyses of overall survival. The Kaplan–Meier method with log-rank test was applied to compare differences in survival time between the CDS and Non-CDS groups. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox regression analysis. We conducted these tests before and after weighting. In addition, subgroup analyses were performed for Cox regression stratified by all covariates (not including subgroups with unknown data).

All statistical analysis was conducted using R software version 4.1.2. A p-value less than 0.05 (two-sided) was considered statistically significant.

Patient Characteristics

A total of 3,694 patients with GCLM were eligible for the first step estimation of the propensity score. The primary PS model included all study variables as they all achieved p < 0.2 in chi-square tests and log-rank tests. Of these patients, 354 (9.58%) received CDS (CDS group) and 3,340 (90.4%) did not (Non-CDS group) (Fig. 1). Comparison of baseline characteristics between patients with and without CDS before and after weighting are presented in Table 1. Before propensity score weighting, patients who underwent CDS were more often with large tumor sizes, lower site tumors, a lower ratio of adenocarcinoma cancers, poorly differentiated tumors, advanced T and N stages, and less likely to receive chemotherapy and radiation than patients who did not undergo CDS. There were no significant differences in these characteristics between the two groups after OW_pLasso adjustment (Table 1). The effect of OW_pLasso adjustment on standardized differences of baseline characteristics is depicted in Fig. S1. A standardized difference of less than 0.1 indicates a good balance of covariates between the two groups. OW_pLasso adjusted standardized differences were all less than 0.1 and around the zero line.

Table 1

Comparison of patient characteristics between CDS and Non-CDS groups before and after propensity score weighting.
Variables	Unweighted, n (%)				OW_pLasso Weighted, %
	Overall	CDS	Non-CDS	P value	CDS	Non-CDS	P value
	(N = 3694)	(N = 354)	(N = 3340)
Age, years
Median [IQR]	65.0 [18.0, 85.0]	65.0 [18.0, 85.0]	65.0 [21.0, 85.0]	0.311	64.0 [56.0, 74.0]	64.0 [56.0, 74.0]	0.945
Age Group				0.165			1.000
18–39	135 (3.7%)	19 (5.4%)	116 (3.5%)		4.2%	4.2%
40–64	1678 (45.4%)	155 (43.8%)	1523 (45.6%)		45.9%	45.9%
65–79	1386 (37.5%)	140 (39.5%)	1246 (37.3%)		38.7%	38.7%
≥ 80	495 (13.4%)	40 (11.3%)	455 (13.6%)		11.1%	11.1%
Sex				0.001			1.000
Male	2602 (70.4%)	222 (62.7%)	2380 (71.3%)		65.8%	65.8%
Female	1092 (29.6%)	132 (37.3%)	960 (28.7%)		34.2%	34.2%
Race				< 0.001			1.000
White	2631 (71.2%)	211 (59.6%)	2420 (72.5%)		64.5%	64.5%
Black	595 (16.1%)	82 (23.2%)	513 (15.4%)		21.5%	21.5%
Others	468 (12.7%)	61 (17.2%)	407 (12.2%)		13.9%	13.9%
Marital Status				0.045			1.000
Married	2130 (57.7%)	222 (62.7%)	1908 (57.1%)		61.7%	61.7%
Unmarried/Separated	1400 (37.9%)	113 (31.9%)	1287 (38.5%)		32.5%	32.5%
Unknown	164 (4.4%)	19 (5.4%)	145 (4.3%)		5.8%	5.8%
Tumor Size				< 0.001			1.000
< 2cm	84 (2.3%)	19 (5.4%)	65 (1.9%)		4.9%	4.9%
2-5cm	612 (16.6%)	76 (21.5%)	536 (16.0%)		21.0%	21.0%
≥ 5cm	1000 (27.1%)	207 (58.5%)	793 (23.7%)		49.7%	49.7%
Unknown	1998 (54.1%)	52 (14.7%)	1946 (58.3%)		24.5%	24.5%
Primary Site				< 0.001			1.000
Cardia	1539 (41.7%)	61 (17.2%)	1478 (44.3%)		25.2%	25.2%
Body	832 (22.5%)	104 (29.4%)	728 (21.8%)		28.7%	29.0%
Lower	507 (13.7%)	113 (31.9%)	394 (11.8%)		22.4%	22.4%
Overlapping lesion	231 (6.3%)	26 (7.3%)	205 (6.1%)		7.3%	7.1%
Not specified	585 (15.8%)	50 (14.1%)	535 (16.0%)		16.4%	16.4%
Histologic Type				< 0.001			1.000
Adenocarcinoma	2404 (65.1%)	143 (40.4%)	2261 (67.7%)		47.6%	47.6%
Signet ring-cell carcinoma	226 (6.1%)	17 (4.8%)	209 (6.3%)		5.1%	5.1%
Others	1064 (28.8%)	194 (54.8%)	870 (26.0%)		47.3%	47.3%
Grade				< 0.001			1.000
I-II	1010 (27.3%)	120 (33.9%)	890 (26.6%)		31.1%	31.1%
III-IV	1809 (49.0%)	182 (51.4%)	1627 (48.7%)		49.5%	49.5%
Unknown	875 (23.7%)	52 (14.7%)	823 (24.6%)		19.4%	19.4%
Chemotherapy				0.002			1.000
Yes	2434 (65.9%)	207 (58.5%)	2227 (66.7%)		65.6%	65.6%
No/Unknown	1260 (34.1%)	147 (41.5%)	1113 (33.3%)		34.4%	34.4%
Radiation				0.027			1.000
Yes	653 (17.7%)	47 (13.3%)	606 (18.1%)		17.2%	17.2%
No/Unknown	3041 (82.3%)	307 (86.7%)	2734 (81.9%)		82.8%	82.8%
T Stage				< 0.001			1.000
T1	708 (19.2%)	29 (8.2%)	679 (20.3%)		12.5%	12.5%
T2	131 (3.5%)	21 (5.9%)	110 (3.3%)		7.2%	7.2%
T3	485 (13.1%)	128 (36.2%)	357 (10.7%)		30.6%	30.6%
T4	665 (18.0%)	145 (41.0%)	520 (15.6%)		35.1%	35.1%
Unknown	1705 (46.2%)	31 (8.8%)	1674 (50.1%)		14.7%	14.7%
N Stage				< 0.001			1.000
N0	1327 (35.9%)	125 (35.3%)	1202 (36.0%)		42.4%	42.4%
N1	1400 (37.9%)	89 (25.1%)	1311 (39.3%)		32.6%	32.6%
N2	183 (5.0%)	56 (15.8%)	127 (3.8%)		11.1%	11.1%
N3	162 (4.4%)	76 (21.5%)	86 (2.6%)		10.1%	10.1%
Unknown	622 (16.8%)	8 (2.3%)	614 (18.4%)		3.8%	3.8%
CDS cancer-directed surgery, OW_pLasso overlap weighting method based on lasso regression with penalty factors, IQR interquartile range.

Overall Survival

Unweighted median OS was 12 months (95% CI 11–16) in the CDS group and 6 months (95% CI 5–6) in the Non-CDS group. After OW_pLasso adjustment, these values were 13 months (95% CI 11–17) and 7 months (95% CI 6–7), respectively. In univariate Cox proportional hazards regression analysis, CDS was significantly associated with survival benefit before and after OW_pLasso adjustment (HR 0.480 [95% CI 0.424–0.545] vs. HR 0.562 [95% CI 0.482–0.656]) (Fig. 2).

Subgroup analyses

Forest plots of HRs for OS across subgroups were generated to illustrate subgroup analyses (Fig. 3). Overall survival benefit from CDS was consistent across most subgroups except for subgroups with younger ages (18–39 years), signet ring-cell carcinoma cancers and advanced N stages (N2, N3) (Fig. 3). Detailed estimated HRs and median OS for each subgroup are presented in Table S1 and Table S2. CDS prolonged the survival time of patients with large and high-grade tumors, advanced T stages, or limited lymph node metastases with extended OS ≥ 10 months (Table S2).

In this population-based study, we were able to confirm the beneficial effects of CDS on survival among patients with GCLM after adjustment for patient characteristics using the propensity score methods. This finding suggests that surgical resection may prolong survival in patients with GCLM, even in those with poor conditions such as large and high-grade tumors, advanced T stages and limited lymph node metastases.

Currently, treatment options for stage IV gastric cancer include chemotherapy, radiotherapy, palliative surgery, immunotherapy, and targeted therapy. Nevertheless, hepatic metastases from GC are rarely considered eligible for surgery because of multiple intrahepatic nodules and extra-hepatic metastases (L. Chen et al., 2013; Romano et al., 2012; Takemura et al., 2012). Probably due in part to a lack of prospective randomized trials in patients with GCLMs, no conclusions have been drawn regarding the value of surgical resection for such patients. In practical guidelines of the United States and Europe, surgery is indicated for stage IV patients who have symptoms or complications (Ajani et al., 2022; Smyth et al., 2016). However, a recent version of the Chinese Society of Clinical Oncology (CSCO) Clinical guidelines for diagnosing and treating of gastric cancer recommend sequential systemic chemotherapy and surgery for patients with single liver metastasis (Wang et al., 2021). And the guidelines in Japan suggest asymptomatic patients with metastatic gastric cancer may be considered candidates for gastrectomy (jp, 2020). Thus, the value of surgical intervention on survival for patients with advanced GC has been a matter of debate.

The major finding of the present study in line with previous studies suggesting survival benefits from the use of surgical resection in patients with metastatic GC (Al-Batran et al., 2017; Ambiru et al., 2001; Baba et al., 1992; S. Chen et al., 2012; Dittmar et al., 2012; Gavriilidis et al., 2019; Kanda et al., 2012; Kerkar et al., 2010; C. Li et al., 2010; W. Li et al., 2019; Liao et al., 2017; Montagnani et al., 2018; Saito et al., 1996; Saiura et al., 2002; Shirabe et al., 2003; Sun et al., 2013; Tiberio et al., 2009; K. Yoshida et al., 2016; M. Yoshida et al., 2004; Zurleni et al., 2018). A retrospective study showed survival benefits through sequential chemotherapy and surgery among selective patients with GCLM (W. Li et al., 2019). Saito et al suggested surgical resection for GC patients with metachronous hepatic metastases even with various incurable factors (Saito et al., 1996). In a meta-analysis included 14 studies, Sun et al. performed a meta-analysis to investigate whether palliative gastrectomy was suitable for patients with incurable advanced gastric cancer. The results showed that surgical intervention significantly improved survival of patients with liver metastases, with a HR of 0.41 (95%CI 0.30–0.55) (Sun et al., 2013), which was similar to our results (unweighted HR 0.480, 95% CI 0.424–0.545). Despite the encouraging evidence reviewed above, the REGATTA study found no survival benefit of palliative surgery followed by chemotherapy in metastatic gastric cancer patients when compared to chemotherapy alone (median OS: 14.3 vs. 16.6 months) (Fujitani et al., 2016). Most patients enrolled in this trial were accompanied by peritoneal metastases (approximately 75%), which possibly affected the results of the study.

Our study showed no evidence of improvement in overall survival in patients with extensive lymph node metastasis, and multiple lesions. These metastasis patterns have been associated with extremely poor prognosis (Baba et al., 1992; C. Li et al., 2010). Strict selection of patients with no lymphatic invasion for surgery had been suggested by Shirabe et al. and Saiura et al (Saiura et al., 2002; Shirabe et al., 2003). However, results in this study indicated a positive effect of surgery on survival in patients with lymph nodes number less than 3. In a clinical phase 2 trial with the surgical management adopted gastrectomy with D2 lymphadenectomy, a significant survival benefit from surgical resection was observed in patients with limited metastatic gastric or gastroesophageal junction cancer (median OS: 31.3 vs. 15.9 months) (Al-Batran et al., 2017). The existing evidence indicates that surgical resection including extended lymph node dissection should be considered for GC patients with multiple lymph node metastases. Survival benefits failed to persist in patients with younger ages after OW_pLasso adjustment in our results. This might due to limited sample size of CDS-treated patients in this subgroup. In fact, previous studies have identified younger age as prognostic factor for improved survival (Dittmar et al., 2012; Hartgrink et al., 2002; Park et al., 2009).

We acknowledge that there were some limitations within the study. First, some factors that have been demonstrated previously to be associated with the prognosis of gastric cancer are not available in the SEER database, including information about peritoneal metastases, comorbidities, chemotherapeutic regimen and cycle, and patient’s performance status and clinical response. These factors might play an essential role in the choice of treatment and prognosis of the patients with GCLM. Second, it was an observational study and we were unable to establish a causal link between surgery and survival outcomes of patients with GCLM. Nonetheless, applying overlap weighting, which is a causal inference method, allow us to emulate a target trial in observational data (Thomas, Li, & Pencina, 2020). Third, information on metachronous metastases to liver cannot be ascertained in the SEER database. Therefore, we could not evaluate the effect of surgery on such patients. Nevertheless, it has been reported that hepatectomy might be associated with prognostic benefit in patients with metachronous metastases to liver (Ambiru et al., 2001; Kerkar et al., 2010; Tiberio et al., 2009). Our results offered preliminary evidence on survival advantages associated with surgery. However, because some key data points are missing from the SEER database, further study is warranted to determine who may benefit from resection of liver metastases in patients with gastric cancer. Despite of these limitations, to our knowledge, this is the first population-based study to perform effectiveness assessment of the association between surgery and the prognosis of GCLM with a registry-based database. The SEER registry mirrors the real-world outcomes for patients with metastatic gastric cancer, and is considered to be more generalizable. In addition, previous studies lacked the evaluation of the effect of surgery on long-term survival in patients with GCLM. The maximum follow-up time was 93 months in our study, enabling us to demonstrate the long-term survival benefits from surgery in a large number of patients.

In this population-based study, we validated that surgical resection significantly improved the survival of gastric cancer patients with liver metastases, regardless of the coexistence of some severe conditions such as high-grade tumors, advanced T stages, and limited lymph node metastases. However, further large-scale prospective studies are needed to further evaluate the role of surgical resection in treating patients with GCLM.

Address all correspondence and requests for reprints to:

Xiawei Li, M.D., Department of surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. 310000, China. E-mail: [email protected]

Funding

None.

Competing Interests

The authors declare no conflict of interest.

Ethics Approval

Since SEER is an open database and all the data extracted from SEER is publicly available and identifiable and therefore does not require patient informed consent. Written informed consent has also been waived.

Data Availability

The data presented in this study are openly available in the SEER Registries database (https://seer.cancer.gov/registries/).

Author contributions

All authors contributed to the study conception and design. Data analysis and manuscript writing were performed by Zheping Yuan. Study supervision and manuscript editing was performed by Xiawei Li and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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No competing interests reported.

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Does Surgical Resection Improve the Survival of Patients with Gastric Cancer Liver Metastases? A Population-Based, Propensity Score–Adjusted Analysis

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