Impact of cancer-directed surgery for gastric cancer patients with lung metastasis: a prognosis analysis
Highlight box
Key findings
• Cancer-directed surgery (CDS) may improve the prognosis of patients with lung metastatic gastric cancer (LMGC).
What is known and what is new?
• Surgery may be an effective treatment for patients with metastatic gastric cancer.
• For LMGC, especially for male patients with well-differentiated tumors, who received chemotherapy or radiotherapy, CDS should be seriously considered, since this would bring significant survival benefits.
What is the implication, and what should change now?
• Our research can provide reference for the treatment of LMGC patients.
Introduction
The fifth-highest prevalence of all malignancies and the fourth-leading cause of cancer-directed mortality globally is gastric cancer (GC) (1,2). Helicobacter pylori infection, genetics, poor diet, and environmental pollutants are the key risk factors for GC. These variables work in tandem with endogenous factors to exacerbate the course of GC (3,4). As a highly invasive malignancy with heterogeneity, GC patients experiment economic and mental burden.
Due to obscure clinical symptoms, approximately 40% of patients lose the opportunity to receive radical gastrectomy due to advanced disease during diagnosis (5). The prognosis for metastatic GC remains dismal, with a 5-year survival rate of <10% (6). Furthermore, merely 0.50–16.00% of GC patients with distant metastases present with lung metastases (LMs), making this a relatively uncommon finding (7,8). Present recommendations state that the standard treatment for patients with LM is systemic chemotherapy. However, the prognosis remains unsatisfactory for LMGC, with a median overall survival (OS) of four months, and a 5-year OS of approximately 2–4% (9). Thus, effective and novel therapeutic strategies are urgently needed.
It has been shown that LM resection works well for certain patients with colorectal or renal cancer (10,11). This surgery is called cancer-directed surgery (CDS). However, the outcomes of CDS for LMGC remain controversial. Therefore, in order to provide more evidence on the effectiveness of CDS for LMGC, a comprehensive analysis was performed using the Surveillance, Epidemiology, and End Results (SEER) database. In addition, in order to balance the baseline characteristics between CDS subjects and their non-CDS groups, the propensity score matching (PSM) method was used. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-976/rc).
Methods
Data source and patient selection
The dataset used for the present study was retrieved using the SEER*Stat program from the SEER database (https://seer.cancer.gov/). The age, gender, race, marital status, tumor stage, histological kinds, and treatment techniques were among the variables available in the SEER database, and these included data on 28% of the US population. A total of 130,826 subjects with GC diagnoses between 2000 and 2020 were obtained from this database for the present study. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.
The precise requirements for inclusion were as follows (Figure 1): (I) excluding cases without metastasis and cases with liver, brain, and bone metastases, merely 1,170 LMGC patients were enrolled, these patients are all primary GC patients with LM, and then consider whether to receive CDS treatment; (II) patients in the CDS group should undergo resection of the primary tumor and all visible tumors. The remaining patients were included in the non-CDS group. Prior to this, the 125 excluded cases of “Not underwent CDS for other factors” mainly included preoperative patient death, other contraindications not undergoing surgery, recommended surgery but patient refusal, and unknown whether surgery was ultimately performed.
Variables and endpoints
The age, gender, race, marital status, tumor grade, radiation history, T stage, N stage, chemotherapy history, and OS were obtained. Age was classified as <60 or ≥60 years old. Race was classified as black, white, and others (Asian or Pacific Islander, American Indian/Alaska Native, and unknown). Marital status was classified as married or single/unknown. The tumor grades were categorized as well, moderately, poorly differentiated, or undifferentiated. The T stages were categorized as T1–T2, T3–T4, and others. The N stages were categorized as N−, N+, and others. Patients who underwent “beam radiation”, “radiation, NOS method, or source not specified” and “radioactive implants” were considered as having a radiation history.
Statistical analysis
The PSM method was used to balance the baseline characteristics. The patients were matched in a 3:1 ratio by PSM analysis, with a caliper value of 0.02. Categorical variables were compared using chi-squared test. The Kaplan-Meier method with log-rank test was used to compare the OS in each group after PSM. The Cox proportional hazards model was established to identify the independent prognostic factors associated to OS. Variables with a P value of <0.05 in univariate model were included in the multivariate model. The significance of all variables was presented in a forest plot. A P value of <0.05 was considered statistically significant.
Results
Limitations
The limitations of the present study should not be neglected. Although the SEER database provided detailed and accurate clinical information, the specific criteria for resection of LMs (size, quantity, location), the latest treatment plans, programmed death-ligand 1 (PD-L1)/combined positive score (CPS) status, Her2 status and post-operative complications were not included. In addition, some factors, such as the serum level of important tumor markers and the immunotherapy/targeted therapy history, were not included in the present analysis. Thus, patients with unavailable information have affected the present results to some extent.
Study cohort selection and PSM
A total of 1,045 LMGC patients were identified from the SEER database (Figure 1). The demographic and tumor features of patients with LMGC before and after matching are described in detail in Table 1. Before PSM, 75 (7.18%) LMGC patients underwent CDS, while 970 (92.82%) patients did not undergo CDS. The marital status (P=0.02), tumor grade (P=0.001), T stage (P<0.001), N stage (P<0.001), and radiation history (P<0.001) all had statistical differences, which may have caused significant bias. In performing PSM, the investigators attempted to preserve the data as much as possible (3:1 matching). After PSM, there were 63 (27.63%) patients in the CDS group and 165 (72.37%) patients in the non-CDS group, and all parameters were balanced (Table 1).
Table 1
| Variable | Before PSM | After PSM | |||||
|---|---|---|---|---|---|---|---|
| Non-CDS (n=970) | CDS (n=75) | P | Non-CDS (n=165) | CDS (n=63) | P | ||
| Age (years) | 0.38 | 0.80 | |||||
| <60 | 300 (30.90) | 19 (25.33) | 40 (24.20) | 17 (27.00) | |||
| ≥60 | 670 (69.10) | 56 (74.67) | 125 (75.80) | 46 (73.00) | |||
| Gender | 0.71 | 0.55 | |||||
| Male | 606 (62.50) | 49 (65.30) | 116 (70.30) | 41 (65.10) | |||
| Female | 364 (37.50) | 26 (34.70) | 49 (29.70) | 22 (34.90) | |||
| Race | 0.63 | 0.97 | |||||
| Black | 738 (76.10) | 57 (76.00) | 123 (74.50) | 48 (76.20) | |||
| White | 91 (9.40) | 5 (6.70) | 14 (8.50) | 5 (7.90) | |||
| Other | 141 (14.50) | 13 (17.30) | 28 (17.00) | 10 (15.90) | |||
| Marital status | 0.02 | >0.99 | |||||
| Married | 521 (53.70) | 51 (68.00) | 104 (63.00) | 39 (61.90) | |||
| Single/unknown | 449 (46.30) | 24 (32.00) | 61 (37.00) | 24 (38.10) | |||
| Grade | 0.001 | 0.43 | |||||
| Grade I/II | 143 (14.70) | 10 (13.30) | 19 (11.50) | 10 (15.90) | |||
| Grade III/IV | 360 (37.10) | 44 (58.70) | 77 (46.70) | 32 (50.80) | |||
| Unknown | 467 (48.10) | 21 (28.00) | 69 (41.80) | 21 (33.30) | |||
| T | <0.001 | 0.11 | |||||
| T1–T2 | 186 (19.20) | 21 (28.00) | 40 (24.20) | 15 (23.80) | |||
| T3–T4 | 84 (8.70) | 19 (25.30) | 17 (10.30) | 13 (20.60) | |||
| Other | 700 (72.20) | 35 (46.70) | 108 (65.50) | 35 (55.60) | |||
| N | <0.001 | 0.58 | |||||
| N− | 210 (21.60) | 10 (13.30) | 23 (13.90) | 10 (15.90) | |||
| N+ | 189 (19.50) | 32 (42.70) | 43 (26.10) | 20 (31.70) | |||
| Other | 571 (58.90) | 33 (44.00) | 99 (60.00) | 33 (52.40) | |||
| Radiation | <0.001 | >0.99 | |||||
| No/unknown | 827 (85.30) | 50 (66.70) | 116 (70.30) | 44 (69.80) | |||
| Yes | 143 (14.70) | 25 (33.30) | 49 (29.70) | 19 (30.20) | |||
| Chemotherapy | <0.001 | 0.62 | |||||
| No/unknown | 430 (44.30) | 25 (33.30) | 68 (41.20) | 23 (36.50) | |||
| Yes | 540 (55.70) | 50 (66.70) | 97 (58.80) | 40 (63.50) | |||
Data are presented as n (%). CDS, cancer-directed surgery; N, node; PSM, propensity score matching; T, tumor.
Survival outcomes after PSM
The median OS was significantly longer in the CDS group, when compared to the non-CDS group (nine months vs. four months, P=0.02; Figure 2A). After adjusting for gender, the conclusion became stable (Figure 2B). The present findings revealed that CDS significantly improved the survival of patients with poorly differentiated tumors, and that the benefits were more obvious in patients with well and moderately differentiated tumors (Figure 2C). In addition, the prognosis of patients who received chemotherapy or radiation combined with surgery was better, when compared to patients who did not receive surgery (Figure 2D,2E).
The univariate analysis results revealed that gender, tumor differentiation grade, radiation, chemotherapy, and CDS were associated to OS in LMGC patients. A forest plot was established after including the aforementioned five variables to the multivariate Cox model (Figure 3). It was identified that receiving chemotherapy or CDS was an independent protective prognostic factor [hazard ratio (HR) =0.26, 95% confidence interval (CI): 0.19–0.36, P<0.001; HR =0.61, 95% CI: 0.44–0.85, P=0.003] for worse OS. Furthermore, gender, tumor differentiation grade, and radiation were identified as non-independent prognostic factors (Figure 3 and Table 2).
Table 2
| Variable | Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|---|
| HR | 95% CI | P | HR | 95% CI | P | ||
| Age (years) | |||||||
| <60 | 1.00 | ||||||
| ≥60 | 1.21 | 0.87–1.68 | 0.25 | ||||
| Gender | |||||||
| Male | 1.00 | 1.00 | |||||
| Female | 1.41 | 1.05–1.90 | 0.02 | 0.84 | 0.60–1.17 | 0.30 | |
| Race | |||||||
| White | 1.00 | ||||||
| Black | 1.06 | 0.63–1.79 | 0.82 | ||||
| Other | 1.67 | 1.15–2.42 | 0.007 | ||||
| Marital status | |||||||
| Married | 1.00 | ||||||
| Single/unknown | 1.22 | 0.92–1.63 | 0.17 | ||||
| Grade | |||||||
| Grade I/II | 1.00 | 1.00 | |||||
| Grade III/IV | 2.35 | 1.50–3.68 | <0.001 | 1.72 | 1.07–2.76 | 0.02 | |
| Unknown | 1.35 | 0.84–2.16 | 0.22 | 1.35 | 0.78–2.01 | 0.35 | |
| T | |||||||
| T1–T2 | 1.00 | ||||||
| T3–T4 | 1.05 | 0.67–1.65 | 0.83 | ||||
| Other | 0.66 | 0.47–0.91 | 0.01 | ||||
| N | |||||||
| N− | 1.00 | ||||||
| N+ | 0.80 | 0.52–1.23 | 0.32 | ||||
| Other | 0.50 | 0.33–0.74 | <0.001 | ||||
| Radiation | |||||||
| No/unknown | 1.00 | 1.00 | |||||
| Yes | 0.60 | 0.44–0.83 | <0.001 | 0.80 | 0.57–1.12 | 0.19 | |
| Chemotherapy | |||||||
| No/unknown | 1.00 | 1.00 | |||||
| Yes | 0.27 | 0.20–0.36 | <0.001 | 0.29 | 0.21–0.40 | <0.001 | |
| Surgery | |||||||
| Non-CDS | 1.00 | 1.00 | |||||
| CDS | 0.68 | 0.48–0.93 | 0.02 | 0.62 | 0.45–0.86 | 0.004 | |
CDS, cancer-directed surgery; CI, confidence interval; HR, hazard ratio; N, node; T, tumor.
Discussion
The effectiveness of CDS in LMGC patients remains unclear. The data obtained from the SEER database was employed for the present study. It was found that CDS presented with survival benefits for patients with LMGC. This benefit may be attributed to the following factors: (I) the tumor burden was reduced by surgery, and the equal dose of chemotherapy regimens was able to damage more tumor cells in LMGC patients; (II) the likelihood of tumor-related acute complications, such as bleeding, obstruction and perforation, was reduced by the surgical resection. The multivariable Cox regression analysis results revealed that CDS and chemotherapy were the independent factors that influenced the prognosis of LMGC. This effect was more obvious in patients with well-differentiated tumors.
LMGC is usually considered as a poor surgical candidate. However, multiple studies have reported that active local treatment (including surgery) can improve OS (12,13). In the present study, the treatment of CDS was analyzed with the OS of LMGC patients and the subgroups of patients who would most likely benefit from the CDS treatment. PSM was performed to minimize the bias caused by the baseline characteristics.
Recently, several studies have reported the benefits of CDS in metastatic head and neck cancer (14,15), metastatic breast cancer (16), and metastatic pancreatic cancer (17,18). For metastatic GC, Sun et al. concluded that CDS can prolong the survival of stage IV GC patients (19). Nevertheless, a number of clinical parameters should be taken into account before making a decision. The present study was the first to determine the impact of CDS in LMGC. Although the present study was retrospective in nature, the conclusions can help surgeons make treatment strategies in clinical practice.
In the subgroup analysis, it was found that regardless of the gender, LMGC patients in the CDS group had a longer OS. For the degree of tumor differentiation, patients with well-differentiated tumors (grade I/II) had better OS, and benefitted more from CDS. For the treatment for metastatic and unresectable GC, the systemic chemotherapy was effective (20). For patients with metastatic GC, who received fluoropyrimidine combined with platinum, the median OS was approximately one year (21). The present study revealed that chemotherapy was an independent protective factor. Furthermore, the benefit of radiotherapy was entirely context dependent (22,23). For metastatic GC, radiotherapy frequently continues to be an effective symptom management technique (24). The present study revealed that LMGC patients who underwent radiotherapy had better survival outcomes, when compared to non-radiotherapy patients. Thus, it can be speculated that by relieving local symptoms, radiotherapy can improve the quality of life of patients, and ultimately prolong their survival. Furthermore, CDS in combination with radiotherapy would bring greater benefits to LMGC patients.
However, the latest IKF-575/RENAISSANCE trial suggests limited benefit for upfront surgery following system therapy in all GC patients with limited metastatic, which seems contradict with our study. Thus, we carefully compared the differences between these two studies. As to the IKF-575/RENAISSANCE trial, only patients with oligometastatic GC were enrolled, and negative results for surgery in GC with oligo LM were observed. However, we did not limit the number of metastatic lesions in our study, therefore, the basic characteristics of the enrolled patients were different. Based on the findings of our study, we still suggest that CDS would bring benefits to LMGC patients. Of course, prospective, large-scale, multicenter studies are needed in the future to further confirm the reliability of the results obtained.
The present study had several intrinsic limitations, even though the study demonstrated the survival advantage of CDS in LMGC. First, the selection bias and unmeasured factors could not be removed from the retrospective analysis, even with the PSM approach. Second, the detailed chemotherapy schemes and radiotherapy information were not recorded in the SEER database. These factors may have affected the patient’s prognosis, and influenced the present analysis. Third, in recent years, immunotherapy has been incorporated into standard treatment for metastatic GC (25). However, the SEER database lacked the information on both immunotherapy and targeted therapy. Fourth, the SEER database lacked a number of crucial factors, and these were classified as “Unknown”. Thus, the interpretation of data remains limited. Furthermore, multicenter, randomized controlled clinical trials are needed for further verification.
Conclusions
In conclusion, there is a lack of high-quality comparative studies that evaluate CDS treatment for LMGC patients. The present retrospective cohort study indicated that for LMGC, especially for male patients with well-differentiated tumors, who received chemotherapy or radiotherapy, CDS should be seriously considered, since this would bring significant survival benefits.
Acknowledgments
None.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-976/rc
Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-976/prf
Funding: This work was supported in part by grants from
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-976/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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