| Background: Colorectal cancer is one of the most common digestive tract malignant tumors globally,and it ranks third in incidence and second in mortality worldwide.It is also one of the most common malignant tumors in China,seriously threatening the health of the residents.Rectal cancer,due to its special anatomy,has characteristics such as great obstacles for surgery,high local recurrence rate and distant metastasis rate,and its treatment has always been the focus and hot spot of domestic and international research.According to the National Comprehensive Cancer Network(NCCN)guideline,surgery after neoadjuvant therapy is the standard treatment for locally advanced rectal cancer(LARC),which can increase the radical surgery rate and local control rate,reduce the postoperative recurrence risk,and prolong the survival.However,the efficacy of neoadjuvant therapy in LARC patients varies greatly,with only about 20% of patients achieving pathologic complete response(p CR).And patients who are not sensitive to neoadjuvant therapy may progress during the treatment or miss the surgical opportunity.Therefore,exploring the impact of different tumor responses on long-term survival after neoadjuvant therapy for LARC is of great significance for standardizing the personalized treatment of LARC.Tumor regression grade(TRG)is a commonly used standard for evaluating pathological response to neoadjuvant therapy based on pathological morphology.TRG is generally divided into 3-5 grades based on the proportion of residual tumor cells and fibrotic tissue in the tumor area after neoadjuvant therapy.Currently,TRG is used as the main alternative endpoint for neoadjuvant therapy of LARC in multiple clinical studies.However,different TRG standards are used in different clinical studies.And although some studies have compared the accuracy of different TRG standards for predicting prognosis,no definite conclusion has been reached.This results in limited comparability of results between studies,and the relationship between TRG and prognosis after LARC neoadjuvant therapy lacks powerful evidence.Meanwhile,there is a lack of reliable predictive indicator for evaluating the long-term survival outcomes of LARC after neoadjuvant therapy in clinical practice.Therefore,the aim of this study is to explore the relationship between different TRGs,p CR,and long-term survival by reconstructing individual patient data(IPD)of long-term survival after LARC neoadjuvant therapy,identify the benefit population of neoadjuvant therapy for LARC patients,provide important evidence for individualized treatment for LARC,and guide clinical treatment strategies.Methods: Systematically search literatures about the relationship between TRG and survival outcomes of LARC patients receiving neoadjuvant therapy from the Pub Med database,Ovid database,Embase database,and Cochrane Library up to September 2020,and screen the references of relevant literatures and reviews.Based on the TRG criteria in the studies,we reclassified eight groups based on different levels of tumor regression.Survival data including survival rate,events,and corresponding number at risk were obtained from the Kaplan-Meier curves provided by the included studies using the Engauge Digitizer software.Then,IPD was constructed from the survival data using R software.Subsequently,the combined Kaplan-Meier curves for each TRG group were plotted and the disease-free survival(DFS)and overall survival(OS)at different time periods were obtained,and the hazard ratios(HRs)based on reconstructed IPD were analyzed to assess the long-term survival benefit of each TRG group by Cox proportional hazard models.To validate the reliability of the reconstructed IPD analysis results,the published HRs and 95% confidence intervals(CIs)from the included studies were combined using Stata software.The primary endpoint of this study is to evaluate the prognosis of different TRG groups after neoadjuvant therapy for LARC,and the secondary endpoint is to evaluate the relationship between p CR and survival outcomes after neoadjuvant therapy for LARC.All relevant studies were included in the overall analysis,and subgroup analyses were performed based on follow-up time(5 years),study type,and neoadjuvant therapy regimen.Results: This study included a total of 12 eligible articles and 5931 LARC patients.The TRG after neoadjuvant therapy was divided into eight groups: p CR group,np CR group(non-p CR group),Near p CR group,Good regression group,Moderate regression group,Major regression group,Poor regression group,and Minor regression group.The combined Kaplan-Meier curve results showed that the p CR group had a significant long-term survival advantage,with a 10-year OS(80.5% vs.48.3%)and a 5-year DFS(90.1% vs.69.8%) significantly higher than the npCR group.The Cox prognostic analysis results based on reconstructed IPD showed that the OS(HR=0.240,95%CI=0.177–0.325,p<0.001)and DFS(HR=0.260,95%CI=0.195–0.347,p<0.001)of the p CR group were significantly better than those of the np CR group.Moreover,there was a significant correlation between better TRG groups and better survival prognosis of patients after neoadjuvant therapy of LARC.In addition,the HR results obtained by combining the HR values directly published in the articles were similar to the HR results based on IPD data,demonstrating the accuracy and reliability of the IPD analysis results of this study.Subgroup analyses based on 5-year follow-up time,study type and neoadjuvant therapy regimen also indicated similar conclusions.Conclusion: Our results systematically outline the relationship between different TRGs and long-term prognosis after neoadjuvant therapy in LARC patients.The results indicate a significant correlation between better tumor regression and better survival outcomes in the np CR group,and that LARC patients who achieve p CR after neoadjuvant therapy have longer OS and DFS than those in the np CR group,indicating that p CR can serve as an alternative indicator of long-term prognosis after neoadjuvant therapy in LARC. |
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