This study analyzed the data of 24140 patients with stage IV GC from the SEER database and made two critical findings. First, survival analysis showed that patients who underwent surgery at the primary tumor site had an advantage in OS/CSS compared with patients who did not undergo surgery. Surgery was a protective factor affecting patients' CSS. Second, through the re-grouping of patients who underwent surgery at the primary tumor site, we preliminarily identified and described the factors related to the benefits of surgery at the primary tumor site.
Our conclusions are consistent with a previous study that evaluated patients in the SEER database who were diagnosed with stage IV GC between 2010 and 2015 7. However, unlike our study, this study did not include the T stage and N stage, which are closely related to prognosis, because the SEER database lacks stage information in the eighth edition of AJCC. Our study chose to include larger sample size, eligible patients between 2004 and 2015, and reclassified TNM stages according to AJCC 8th, making our results more convincing.
At present, the primary treatment for stage IV GC is systematic. Surgeries are often performed in emergencies such as bleeding, perforation, or obstruction 12. Moreover, the surgery of the primary tumor can also reduce the tumor burden, reverse the tumor-induced immunosuppression, and eliminate the source of further metastasis 13. Many studies have shown that resection of the primary tumor can prolong the survival time of patients with stage IV GC. A retrospective study of 288 patients in Turkey showed that surgery at the primary tumor site in patients with stage IV GC might improve survival regardless of the occurrence of life-threatening tumor-related complications (12vs.7.8 months, p < 0.001) 6. Another study, based on the GIRGC database, focused on factors that affect the risk of survival and recurrence. The results show that patients with stage IV GC can benefit from radical gastrectomy after chemotherapy. Further analysis showed that the only independent prognostic factor affecting OS was the presence of more than one type of metastasis (HR4.41,95%CI1.72 ~ 11.3, p = 0.002) 14.
However, an open, randomized phase 3 trial (REGATTA) denied the benefits of surgery at the primary tumor site (16.6vs.14.3 months, P = 0.70) 9. Although this study represents the highest level of such research at present, there are still some limitations. First, the study focused only on the prognosis of patients, such as post-chemotherapy surgery, which hindered the broad clinical application of the results. Secondly, the chemotherapy regimen used in this study was S-1 plus cisplatin. A phase III study showed that SOX (S-1 plus oxaliplatin) chemotherapy regimen for patients with stage IV GC was safer than S1 plus cisplatin 15. Not only that, we found that in this study, the chemotherapy cycle of patients in the surgical group was shorter than that in the chemotherapy group alone, which may have an impact on survival outcomes.
The differences in the results of the above different studies also reveal that not all patients who undergo surgery for primary tumors can benefit from the surgery, which also shows that there are still limitations in the choice of patients undergoing surgery. Therefore, we propose a new selection process to determine the benefit factors associated with surgery to primary tumor site: First, Patients with stage IV GC who meet the criteria were included. PSM was used to eliminate the selection bias according to the baseline characteristics. Second, According to the median CSS time (7 months) of the non-surgery group, the patients in the surgery group were subdivided into benefit group (survival time more than 7 months) and non-benefit group (survival time less than 7 months). Third, A multivariate logistic regression model was established according to the pre-surgery baseline characteristics of beneficial and non-beneficial groups. The model determined the related factors of surgical benefit.
The results showed that the patients with T stage T4b and histological grade GIII/GIV could not benefit from the surgery. When the tumor is in the T4b stage, it shows that the tumor has invaded the adjacent structures and organs, which means that a broader range of surgery and more surgery-related complications occur. Similarly, higher-grade tumors usually lead to the rapid development of the disease. They are less sensitive to radiotherapy and chemotherapy, and surgery can bring limited survival benefits to such patients, which can explain our results to some extent. Our analysis shows that receiving chemotherapy is more beneficial to patients from surgery. Therefore, active surgery should be recommended for lower T-stage patients, lower histological grade, and chemotherapy. However, the SEER database does not provide information on the sequence of chemotherapy and surgery. In the real world, most clinicians will choose pre-surgery chemotherapy to reduce the size of the tumor and eliminate micro-metastasis to improve the effectiveness of surgical treatment 16,17. This result also confirms our view that only specific patients will benefit from the surgery. The potential benefits will vary depending on the characteristics and treatment of the primary tumor.
There are limitations to this study. First of all, the SEER database lacks the number of metastatic sites and surgical data. It has been proved that the number of distant metastases has a significant impact on the prognosis 14. It is a limitation of the database itself. Secondly, the SEER database lacks information on targeted therapy and immunotherapy. We cannot answer whether resection of the primary tumor will bring more survival benefits before or after targeted therapy and immunotherapy. Finally, despite the use of the retrospective study of PSM, there may still be research biases. And this is only a preliminary study, and the results need to be verified by future prospective trials. Finally, despite the use of PSM to reduce selective bias, this retrospective study may still be biased. And this is only a preliminary study, and the results need to be verified by future prospective trials.
Generally, surgery at the primary tumor site can bring survival benefits to patients with stage Ⅳ GC. In addition, we propose a new selection process to screen patients with stage IV GC who can benefit from surgery. The analysis results showed that patients with T stage T4b and histological grade GIII/GIV could not benefit from the operation, and such patients should consider comprehensive treatment. Patients who receive chemotherapy can benefit from surgery, and such patients should be recommended to undergo surgery actively.