| Chapter ?Application value of adjuvant chemotherapy for locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy and radical resectionBackground:Neoadjuvant chemoradiotherapy(NCRT)followed by total mesorectal excision(TME)and adjuvant chemotherapy(AC)has now become the preferred care for locally advanced rectal cancer(LARC).The National Comprehensive Cancer Network(NCCN)guidelines recommend adjuvant chemotherapy for all rectal cancer patients after neoadjuvant chemoradiotherapy regardless of postoperative pathological stage,while The European Society for Medical Oncology(ESMO)guidelines suggest:Although the level of evidence is much lower than that of colon cancer,it is reasonable to accept AC for those high-risk ypTNM ? and ypTNM ? patients.At present,the current clinical guidelines provide discordant suggestions for the management for rectal cancer patients after NCRT.And the application value of AC for locally advanced rectal cancer patients receiving neoadjuvant therapy is still controversial,which has brought some confusion to clinicians.Aim:To evaluate the benefit of AC and try to explore potential clinical factors for the selection of patients who might benefit from AC.Methods:We retrospectively recruited 369 LARC patients who underwent NCRT+TME surgery.Patients were classified into 2 groups depending on whether receiving adjuvant chemotherapy or not(the AC group and the nAC group).Propensity-score matching was used to balance the differences about distribution of clinical features between the the AC and the nAC group.Kaplan-Meier analysis,log-rank tests,were used to assess Overall survival(OS)and disease-free survival(DFS).Results:After propensity-score matching,110 patients are in the AC group and other 110 patients are in the nAC group for subsequent analysis.No significant difference was found in the OS(P=0.106)or DFS(P=0.635)rates between AC and nAC groups.Further subgroup analysis showed that patients with ypTNM 0-? stage couldn't benefit from AC both in OS and DFS(all P>0.05).In the ypTNM ? subgroup,AC group showed higher 5-year rates of OS than nAC group(70.6%vs 46.3%,P=0.033),while no DFS advantage was found compared with nAC group(P=0.083).Moreover,ypTNM ? patients with poor response of primary tumor and lymph node would benefit in improving OS from the receiving adjuvant chemotherapy(all P<0.05).And patients with ypN2 stage would have improvements in both OS and DFS with AC(all P<0.05).Those ypTNM ? patients with ypT3-4 stage could benefit from AC in OS(P=0.017)but not DFS(P=0.055).ypTNM ? stage patients within 5-10 cm of the anal verge could benefit from AC in 5-year OS(P=0.013),but no DFS(P=0.060).Conclusion:No OS and DFS benefit of adjuvant chemotherapy was observed in patients with ypTNM 0-? substage.ypTNM ? rectal cancer patients can benefit from AC,especially those patients with poor response of primary tumor and lymph node,ypN2 stage,ypT3-4stage and the tumor location>5cm should be recommended to receive more intensive adjuvant chemotherapy.Chapter ?Clinicopathological and prognostic features of young onset patients with locally advanced rectal cancer received neoadjuvant chemoradiotherapyBackground:The clinical characteristics of colorectal cancer in China are early-onset age and more common rectal cancer especially those middle-low rectal cancer.Early onset colorectal cancer(eoCRC)is also known as young onset colorectal cancer(YCRC).The upper age of eoCRC onset has not been unified,usually between 30 and 50 years old.Most studies defined eoCRC as colorectal cancer patients under 40 years old.Early onset colorectal cancers most commonly occur in the rectum,with a high degree of malignancy and poor prognosis.Recently,the incidence of eoCRC has been increasing.Patients with young onset cancer(YRC)are more likely to receive neoadjuvant chemoradiotherapy and adjuvant chemotherapy,and their prognosis and disease recurrence characteristics may be different from those later onset patients.At present,there are very few clinical studies on early-onset rectal cancer after neoadjuvant therapy.Therefore,more attention should be paid to this part of patients and more reasonable diagnosis,treatment and follow-up plans should be made for them.Objective:To explore the clinicopathological and prognostic features of early/young onset patients with middle-low rectal cancer who received neoadjuvant chemoradiotherapy(NCRT).Methods:After NCRT,a total of 441 patients with primary middle-low rectal cancer treated with radical surgery from January 2004 to December 2016 were included.According to the age of disease onset,the patients were divided into the early onset group(age?40)and the later onset group(age>40),and the clinicopathological characteristics and survival were analyzed.Results:In the early onset group,68.6%of patients received radical surgery within 7 weeks after NCRT,which was higher than that in the later onset group(52.8%,P=0.047).The early onset group had more patients with ypTNM III stage(51.0%vs 34.1%,P=0.027)and more patients with ypN+stage(51.0%vs 34.1%,P=0.047),compared with the later onset group.The incidence of disease progression in the early onset group was higher compared with that in the later onset group(39.2%vs 25.1%,P=0.049),and the incidence of distant metastasis was also higher than that in the later onset group(35.3%vs 21.5%,P=0.047).Most cases of disease progression occurred in the first 3 years after surgery for the early onset group,especially in the second year after surgery,the incidence of disease progression in the early onset group was higher than that in later onset group(55.0%vs 26.5%,P=0.025).The 3-year and 5-year disease-free survival(DFS)rates for the two groups were 63.7%vs 81.0%and 58.2%vs 74.3%(P=0.016),respectively;The 3-year and 5-year overall survival(OS)rates for the two groups were 85.4%vs 93.6%,69.2%vs 84.1%(P=0.033),respectively.In the multivariate analysis,response of primary tumor(HR=4.804,95%CI:1.360?16.973)and total number of examined lymph nodes(TLN)(HR=4.336,95%CI:1.739?10.809)in the early onset group were independent prognostic factors related to DFS.The TLN(HR=3.295,95%CI:1.076?10.091)was an independent prognostic factor related to OS.In the later onset group,response of primary tumor(HR=2.626,95%CI:1.354?5.091),ypTNM stage(ypTNM ?:HR=5.837,95%CI:2.968?11.479)and tumor location distance from the anal verge(HR=0.500,95%CI:0.308?0.812)were independent prognostic factors related to DFS.Lymphovascular invasion(HR=0.500,95%CI:0.308?0.812)and ypTNM stage(ypTNM ?:HR=16.322,95%CI:5.049?52.771)were independent prognostic factors related to OS.Conclusion:Young onset rectal cancer patients after neoadjuvant chemoradiotherapy were associated with shorter operation time interval,advanced pathological stage and poorer prognosis.Enough attention should be paid to more intensive adjuvant treatment and more intensive post-treatment surveillance for early onset rectal cancer with NCRT.Chapter ?miRNA signatures associated with predicting response to neoadjuvant chemoradiation in locally advanced rectal cancer patientsBackground:Preoperative chemoradiotherapy combined with radical resection is the preferred treatment for locally advanced rectal cancer.However,the response of patients to chemoradiotherapy is highly divergent,and not all patients could benefit from neoadjuvant chemoradiotherapy(NCRT).To date,there is no effective method to predict patients' response to NCRT.MicroRNAs(miRNAs)are small non-coding RNAs that could regulate pathogenesis of many cancers,such as rectal cancer.miRNAs could be used as promising predictive biomarkers in patients with NCRT.Objective:To discern some miRNAs signatures that could be used to predict responses to NCRT in rectal cancer patients with preoperative chemoradiotherapy.Methods:Two data sets,GSE68204 and GSE29298,met the inclusion criteria after screening of miRNA expression data from GEO database,with a total of 75 tumor tissue samples.Response to preoperative chemoradiotherapy was determined according to the Mandard TRG scale.TRG1-2 were grouped as the NCRT-sensitive group(Response,R group)and those with TRG3-5 as the NCRT-resistant group(Non-response,NR group).Robustrankaggreg(RRA)method was used to perform the integration analysis of the two datasets to obtain integrated differentially expressed miRNAs.Logistic regression analysis was performed to establish a prediction model based on miRNA signatures to predict neoadjuvant chemoradiation response in locally advanced rectal cancer.Results:According to the P value<0.05,|log2FC|>0.5 standard,6 different miRNAs were identified by RRA method.After comparison with the miRBase database,hsa-miR-1202,hsa-miR-210 and hsa-miR-96 were finally included to establishment of a prediction model for neoadjuvant chemoradiation resistance in locally advanced rectal cancer.In the development group,the AUC of predicting NCRT-resistance was 0.774,the sensitivity was 0.792,and the specificity was 0.724,while in the validation group,the AUC of predicting NCRT-resistance was 0.892,the sensitivity was 0.800,the specificity was 0.833,the positive predictive value was 0.800,the negative predictive value was 0.833,and the predictive accuracy was 0.818.Conclusion:The prediction model based on 3-miRNAs for NCRT-resistance could potentially predict neoadjuvant chemoradiation response in rectal cancer patients,but it is essential to conduct clinical studies and basic experiments to furtherly assess and verify the prediction model,in order to providing personalized neoadjuvant therapies. |
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