The Effect Of Neoadjuvant Rectal Score And Biopsy-Adapted Immunoscore In Different Neoadjuvant Chemoradiotherapy Strategies For Rectal Cancer

Part I:Prognostic Role,Time-Varying Failure Hazard and Adjuvant Chemotherapy Decision-Making of Neoadjuvant Rectal(NAR)Scores in the STELLAR Randomized Phase 3 TrialPurpose:To examine the prognostic role of the neoadjuvant rectal(NAR)score in disease-free survival(DFS)in the STELLAR phase Ⅲ trial(NCT02533271)and assess the time-varying failure hazard.Methods:The study included patients from the STELLAR trial who underwent total mesorectal excision and had calculable NAR scores.Chi-square tests were used to analyse the distribution of demographic information,treatment information,and NAR scores,while Kaplan-Meier and Cox regression analyses were used to assess DFS and evaluate hazard variations with smoothed hazard plots,respectively.Results:Of 461 patients,231 received total neoadjuvant therapy(TNT),and 229 received concurrent chemoradiotherapy(CRT).With a median follow-up of 37 months,3-year DFS rates by low,intermediate,and high NAR score were 86.2%,71.8%,and 53.1%,respectively(P<0.001).NAR scores were significant prognostic factors for DFS in both treatment groups(P<0.001).Multivariate analysis showed NAR scores as independent prognostic factors for DFS[intermediate vs.low,hazard ratio(HR)=2.55,95%confidence interval(CI):1.37-4.75,P<0.003;high vs.low,HR=4.68,95%CI:2.51-8.72,P<0.001].The hazard rate of failure for NAR score groups initially increased and then decreased,with second-year peaks of 5.0%,11.6%,and 21.5%for low,intermediate,and high NAR scores,respectively.After the fourth year,the high NAR score still had a higher failure hazard(12.5%),while the intermediate and low NAR scores had a lower failure hazard(<3%).In the TNT group,patients with R0 resection and low or intermediate NAR scores who received adjuvant chemotherapy had significantly higher 3-year DFS rates compared to those who did not(97.8%vs 43.2%for low NAR score,78.0%vs 50.6%for intermediate NAR score;P<0.001,P=0.002).However,among patients with high NAR scores,there was no significant difference in the 3-year DFS rates between those who received adjuvant chemotherapy and those who did not(54.2%vs 53.3%;P=0.214).Conclusion:The NAR score was strongly prognostic for DFS in the STELLAR trial,independent of TNT or CRT treatment strategies.The NAR score provides valuable guidance for personalized follow-up strategies and with potential implications for subsequent decisions regarding adjuvant chemotherapy in rectal cancer patients.Warrant further investigation with NAR scores used as endpoints.PART Ⅱ:Prognostic Values of a Modified Diagnostic Biopsy-Adapted Immunoscore Based on Double Immunohistochemical Staining in Patients with Locally Advanced Rectal CancerObjective:The aim of this study was to evaluate the prognostic value of the modified diagnostic biopsy-adapted immunoscore(mISb)based on double immunohistochemical staining for patients with locally advanced rectal cancer(LARC).Methods:In this sub-study of a prospective trial(NCT02533271),181 LARC patients undergoing neoadjuvant chemoradiotherapy were included,with 151 patients(83.4%)receiving surgery and 30 patients(16.6%)managed with a watch-and-wait(W&W)strategy.CD8+and CD3+T cell densities in tumor biopsy specimens were quantified using double immunohistochemical staining,and mISb was constructed by combining CD8+T cell densities and the CD8/CD3 ratio.Spearman correlation analysis was performed for correlations.Kaplan-Meier survival analysis,univariate and multivariate Cox regression models were used to assess the prognostic value of mISb for disease-free survival(DFS),and the role of mISb in the W&W strategy was further investigated.Results:CD8+T cell density was strongly correlated with CD3+T cell density(R=0.86,P<0.001)and moderately correlated with the CD8/CD3 ratio(R=0.45).The number of patients with low,intermediate,and high mISb were 35(23.2%),84(55.6%),and 32(21.2%),respectively.The 3-year DFS for the entire cohort was 69.9%,with 59.0%,69.5%,and 80.1%for low,intermediate,and high mISb groups,respectively(P=0.01).Multivariate analysis in surgically treated patients showed mISb,resection margin status,and neoadjuvant rectal score(or ypTNM)as independent prognostic factors for DFS.In the W&W cohort,6 patients(37.5%)in the mISb≤50%group experienced local or distant metastasis,while only 1 patient(7.1%)in the mISb>50%group had local recurrence.Conclusion:The mISb,as a potential prognostic assessment tool,demonstrated considerable value in in evaluating the prognosis of LARC patients.Future research is warranted to further explore the clinical application of mISb in rectal cancer prognostic assessment,particularly in the context of W&W.