Survival Benefit Of Postoperative Chemotherapy In Stage Ⅱ-Ⅲ Gastric Signet Ring Cell Carcinoma Patients

Objective: Gastric cancer is the fifth most commonly diagnosed cancer and ranks fourth in terms of mortality.In 2020,there were more than 1 million new gastric cancer cases,of which about 769000 died of gastric cancer.The incidence of gastric adenocarcinoma has decreased,but the incidence of gastric signet ring cell carcinoma(SRCC)is still very high.So far,there are many controversial studies on gastric SRCC chemotherapy.Clinical question 23 ’is it recommended to choose adjuvant chemotherapy according to the pathological stage or histological type of gastric cancer?’ was mentioned in the fifth edition of the Japanese Gastric Cancer Association(JGCA)guidelines for gastric cancer.Only relevant question arised in the guidelines,and no treatment recommendations based on histological types was mentioned.Given the differences in the current results of gastric SRCC adjuvant chemotherapy,we conducted a retrospective analysis based on two independent data sets to determine whether adjuvant chemotherapy in stage Ⅱ and Ⅲ gastric SRCC can improve the survival rate compared with the simple operation group,and to explore whether histological types are influencing factors of adjuvant chemotherapy for gastric cancer.Methods: This study proceeds in two datasets,the one is the Surveillance,Epidemiology,and End Results(SEER)database for evaluation and monitoring,including patients diagnosed with malignant gastric tumors from 1988 to 2015.The other database is the China Medical University Surgical Oncology(CMU-SO)database,which includes patients with malignant gastric tumors diagnosed from January 2000 to September 2016.Through data preprocessing and strict inclusion and exclusion criteria,gastric cancer cases with pathological stage Ⅱ-Ⅲ were extracted from the two databases as the research dataset.17827 patients with stage Ⅱ-Ⅲ gastric cancer were included in the SEER dataset(group A),including 3902 patients with gastric SRCC,and 1912 patients with stage Ⅱ-Ⅲ gastric cancer included in the CMU-SO dataset(group B),including 223 patients with gastric SRCC.The endpoints of the study were overall survival(OS)and cancer-specific survival(CSS).Description of pathological features:Chi-square test and independent-sample t-test/Mann-Whitney U test was utilized to compare the distribution of clinicopathological factors between the chemotherapy group and non-chemotherapy group.The Spearman rank correlation method analyzed the annual trend of postoperative adjuvant chemotherapy rate.Survival analysis: the Kaplan-Meier survival curve was drawn based on OS and CSS,and a log-rank method tested the P-value.The Cox proportional hazard model was used to analyze the variables determined by univariate analysis to be significantly related to survival,and the risk ratio(HR)and 95% confidence interval(95%CI)were calculated.In addition,we used two propensity score analysis methods,including Propensity Score Matching(PSM),and Inverse Probability Of Treatment Weight(IPTW),with a cut-off value of0.01,0.99 of stable weight to adjust the influence of confounding factors.The KaplanMeier method drew the OS and CSS curves of PSM and IPTW patients.Using Cox proportional hazard model,the HR of 95% CI after PSM was calculated based on OS and CSS.Simultaneously,interaction and subgroup analyzes were performed to evaluate the heterogeneity of chemotherapy effect in patients after PSM.Results:(1)Survival benefit of postoperative chemotherapy in stage Ⅱ-Ⅲ gastric SRCC patients based on the SEER datasetThe COX multivariate analysis of gastric SRCC in the SEER dataset showed that adjuvant chemotherapy significantly reduced the overall mortality risk in patients with gastric SRCC(P<0.001,HR=0.76,95%CI= 0.69-0.83)and cancer-specific mortality risk(P< 0.001,HR=0.80,95%CI=0.72-0.87).The difference was statistically significant with the log-rank test P<0.0001 of OS in the 1:1 PSM dataset and the logrank test P<0.0001 of OS in the IPTW analysis.In the 1:1 PSM dataset,the log-rank test P=0.014 of CSS,and in the IPTW analysis,the log-rank test P<0.0001 of CSS.In addition to the treatment of gastric SRCC patients received in 1988 to 2005,1720 patients with confirmed gastric SRCC were reserved in 2006-2015.The multifactor Cox results were: adjuvant chemotherapy had more significant OS benefits(P<0.001,HR = 0.62,95% CI = 0.54-0.72)and CSS benefits(P <0.001,HR = 0.65,95%Ci = 0.56-0.76).Among them,for patients with stage Ⅱ gastric SRCC,adjuvant chemotherapy significantly reduced overall mortality risk(P <0.001,HR = 0.46,95%Ci = 0.34-0.63)and cancer-specific mortality risk(P <0.001,HR = 0.50,95% CI = 0.36-0.70).For patients with stage Ⅲ gastric SRCC,adjuvant chemotherapy also significantly reduced overall mortality risk(P <0.001,HR = 0.68,95% Ci = 0.57-0.80)and cancer-specific mortality risk(P <0.001,HR = 0.70,95% Ci = 0.59-0.83).In the subgroup analysis of PSM,the protective effect of adjuvant chemotherapy on the prognosis of gastric SRCC patients had no significant heterogeneity except the year of chemotherapy.(2)Survival benefit of postoperative chemotherapy in stage Ⅱ-Ⅲ gastric SRCC patients based on the CMU-SO datasetThe benefits of adjuvant chemotherapy for patients with gastric SRCC were not obvious.Among the patients in stage Ⅱ gastric SRCC,the chemotherapy and the surgical group’s survival rate was not different.However,in patients with stage Ⅲ gastric SRCC,we found the adjuvant chemotherapy for 3-year,5-year OS / CSS rate higher than the surgical group,although there was no significant statistical significance of Log-Rank Test P-value.Analysis of the chemotherapy regimen showed that the 5-year OS rate of two-drug regimen was significantly higher than that of single-drug regimen in patients with gastric SRCC in stage Ⅲ,and log-rank test P = 0.0055.Similar results have been suggested in CSS-based analysis,and log-rank test P = 0.02.(3)Analyze the impact of histological type on adjuvant chemotherapyIn the interaction analysis of the impact of histological type on the effects of adjuvant chemotherapy,P intertion > 0.05,and there is no statistical significance.That is,the histological type is not a decisive factor affecting the effect of gastric cancer.Conclusion: For patients with stage Ⅲ gastric SRCC,the adjuvant chemotherapy can significantly extend the live time.Double drug combined chemotherapy solutions may have more significant survival benefits.For patients with stage Ⅱ gastric SRCC,adjuvant chemotherapy effects still have no dispute,and different database results have differences and may be derived from the installment bias caused by racial differences and the number of lymph nodes examined,and more clinical trials still need further study.