Compare clinical efficacy and safety of neoadjuvant therapy and neoadjuvant chemoradiotherapy for locally advanced rectal cancer: Meta-analysis

BACKGROUND To compare the efficacy and safety of total neoadjuvant therapy(TNT)and neoadjuvant chemoradiotherapy(nCRT)in the treatment of middle and low locally advanced rectal cancer.Our study will systematically collect and integrate studies to evaluate the ability of these two treatments to improve tumor shrinkage rates,surgical resection rates,tumor-free survival,and severe adverse events.AIM To provide clinicians and patients with more reliable treatment options to optimize treatment outcomes and quality of life for patients with locally advanced rectal cancer by comparing the advantages and disadvantages of the two treatment options.METHODS A full search of all clinical studies on the effectiveness and safety of TNT and nCRT for treating locally advanced rectal cancer identified in Chinese(CNKI,Wanfang,China Biomedical Literature Database)and English(PubMed,Embase)databases was performed.Two system assessors independently screened the studies according to the inclusion and exclusion criteria.Quality evaluation and RESULTS Finally,14 studies were included,six of which were randomized controlled studies.A total of 3797 patients were included,including 1865 in the TNT group and 1932 in the nCRT group.The two sets of baseline data were comparable.The results of the meta-analysis showed that the pCR rate[odds ratio(OR)=1.57,95%confidence interval(CI):1.30-1.90,P<0.00001],T stage degradation rate(OR=2.16,95%CI:1.63-2.57,P<0.00001),and R0 resection rate(OR=1.42,95%CI:1.09-1.85,P=0.009)were significantly greater in the nCRT group than in the nCRT group.There was no significant difference in the incidence of grade 3/4 acute toxicity or perioperative complications between the two groups.The 5-year OS[hazard ratio(HR)=0.84,95%CI:0.69-1.02,P=0.08]and DFS(HR=0.94,95%CI:0.03-1.39,P=0.74)of the TNT group were similar to those of the nCRT group.CONCLUSION TNT has greater clinical efficacy and safety than nCRT in the treatment of locally advanced rectal cancer.

Local excision for middle-low rectal cancer after neoadjuvant chemoradiation:A retrospective study from a single tertiary center

BACKGROUND Rectal cancer has become one of the leading malignancies threatening people’s health.For locally advanced rectal cancer(LARC),the comprehensive strategy combining neoadjuvant chemoradiotherapy(NCRT),total mesorectal excision(TME),and adjuvant chemotherapy has emerged as a standard treatment regimen,leading to favorable local control and long-term survival.However,in recent years,an increasing attention has been paid on the exploration of organ preservation strategies,aiming to enhance quality of life while maintaining optimal oncological treatment outcomes.Local excision(LE),compared with low anterior resection(LAR)or abdominal-perineal resection(APR)was introduced dating back to 1970’s.LE has historically been linked to a heightened risk of recurrence compared to TME,potentially due to occult lymph node metastasis and intraluminal recurrence.Recent evidence has demonstrated that LE might be an alternative approach,instead of LAR or APR,in cases with favorable tumor regression after NCRT with potentially better quality of life.Therefore,a retrospective analysis of clinicopathological data from mid-low LARC patients who underwent LE after NCRT was conducted,aiming to evaluate the treatment's efficacy,safety,and oncologic prognosis.AIM To explore the safety,efficacy,and long-term prognosis of LE in patients with mid-low rectal cancer who had a good response to NCRT.METHODS Patients with LE between 2012 to 2021 were retrospectively collected from the rectal cancer database from Gastro-intestinal Ward III in Peking University Cancer Hospital.The clinicopathological features,postoperative complications,and long-term prognosis of these patients were analyzed.The Kaplan-Meier method was used to create cancer-specific survival curve,and the log-rank test was used to compare the differences regarding outcomes.RESULTS A total of 33 patients were included in this study.The median interval between NCRT and surgery was 25.4(range:8.7-164.4)weeks.The median operation time was 57(20.0-137.0)minutes.The initial clinical T staging(cT):9(27.3%)patients were cT2,19(57.6%)patients were cT3,and 5(15.2%)patients were cT4;The initial N staging(cN):8 patients(24.2%)were cN negative,25 patients(75.8%)were cN positive;The initial M stage(cM):2 patients(6.1%)had distant metastasis(ycM1),31(93.9%)patients had no distant metastasis(cM0).The pathological results:18(54.5%)patients were pathological T0 stage(ypT0),6(18.2%)patients were ypT1,7(21.2%)patients were ypT2,and 2(6.1%)patients were ypT3.For 9 cT2 patients,5(5/9,55.6%)had a postoperative pathological result of ypT0.For 19 cT3 patients,11(57.9%)patients were ypT0,and 2(40%)were ypT0 in 5 cT4 patients.The most common complication was chronic perineal pain(71.4%,5/7),followed by bleeding(43%,3/7),stenosis(14.3%,1/7),and fecal incontinence(14.3%,1/7).The median follow-up time was 42.0(4.0-93.5)months.For 31 patients with cM0,the 5-year disease-free survival(DFS)rate,5-year local recurrence-free survival(LRFS)rate,and 5-year overall survival(OS)rate were 88.4%,96.7%,and 92.9%,respectively.There were significant differences between the ycT groups concerning either DFS(P=0.042)or OS(P=0.002)in the Kaplan-Meier analysis.The LRFS curve of ycT≤T1 patients was better than that of ycT≥T2 patients,and the P value was very close to 0.05(P=0.070).The DFS curve of patients with ypT≤T1 was better than that of patients with ypT≥T2,but the P value was not statistically significant(P=0.560).There was a significant difference between the ypT groups concerning OS(P=0.014)in the Kaplan-Meier analysis.The LRFS curve of ypT≤T1 patients was better than that of ypT≥T2 patients,and the P value was very close to 0.05(P=0.070).Two patients with initial cM1 were alive at the last follow-up.CONCLUSION LE for rectal cancer with significant tumor regression after NCRT can obtain better safety,efficiency,and oncological outcome.Minimally invasive or nonsurgical treatment with patient participation in decision-making can be performed for highly selected patients.Further investigation from multiple centers will bring better understanding of potential advantages regarding local resection.

Neoadjuvant intermediate-course versus long-course chemoradiotherapy in T3-4/N0+rectal cancer:Istanbul R-02 phase II randomized study

Radiation therapy(RT)is typically applied using one of two standard approaches for preoperative treatment of resectable locally advanced rectal cancer(LARC):short-course RT(SC-RT)alone or long-course RT(LC-RT)with concurrent fluorouracil(5-FU)chemotherapy.The Phase II single-arm KROG 11-02 study using intermediate-course(IC)(33 Gy(Gray)/10 fr(fraction)with concurrent capecitabine)preoperative chemoradiotherapy(CRT)demonstrated a pathologically complete response rate and a sphincter-sparing rate that were close to those of LC-CRT.The current trial aim to compare the pathological/oncological outcomes,toxicity,and quality of life results of LC-CRT and IC-CRT in cases of LARC.The prescribed dose was 33 Gy/10 fr for the IC-CRT group and 50.4 Gy/28 fr for the LC-CRT group.Concurrent chronomodulated capecitabine(Brunch regimen)1650 mg/m2/daily chemotherapy treatment was applied in both groups.The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Colorectal Cancer Module(EORTC QLQ-CR29)was administered at baseline and at three and six months after CRT.A total of 60 patients with LARC randomized to receive IC-CRT(n=30)or LC-CRT(n=30)were included in this phase II randomized trial.No significant difference was noted between groups in terms of pathological outcomes,including pathological response rates(ypT0N0-complete response:23.3%vs.16.7%,respectively,and ypT0-2N0-downstaging:50%for each;p=0.809)and Dworak score-based pathological tumor regression grade(Grade 4-complete response:23.3 vs.16.7%,p=0.839).The 5-year overall survival(73.3 vs.86.7%,p=0.173)rate was also similar.The acute radiation dermatitis(p<0.001)and any hematological toxicity(p=0.004)rates were significantly higher in the LC-CRT group,while no significant difference was noted between treatment groups in terms of baseline,third month,and sixth month EORTC QLQ-CR29 scores.

Effect of postoperative adjuvant chemotherapyon the prognosis of patients with ypT0-3N0 rectalcancer undergoing neoadjuvant chemoradiotherapy

Objective The aim of this study was to investigate the effect of adjuvant chemotherapy (AC) on theprognosis of patients with ypT0-3N0 rectal cancer undergoing neoadjuvant chemoradiotherapy.Methods The study participants were 110 patients with locally advanced rectal cancer. Thirty-fourpatients did not receive postoperative AC treatment, and the other 76 patients received postoperative ACtreatment. The differences in the 5-year overall survival (OS) and disease-free survival (DFS) between thetwo groups were compared.Results Age was an important determinant of the patients’ decision to undergo postoperative treatment.Patients who did not receive AC treatment were significantly older than those who received AC treatment(P < 0.05). The tumor location (distance above anal margin) in the AC group was significantly larger thanthat in the non-AC group (P < 0.05). Moreover, there was no significant difference in the 5-year DFS andOS between the two groups. Postoperative AC did not significantly improve the prognosis of patients withrectal cancer. Age, tumor differentiation, and the number of resected lymph nodes were independent factorsaffecting the OS of patients (P < 0.05). Older patients, patients with lower degree of tumor differentiation,and patients with <12 resected lymph nodes showed worse prognosis (P < 0.05).Conclusion Patients with rectal cancer whose ypT0-3N0 stage is reduced after neoadjuvantchemoradiotherapy, especially those without adverse prognostic factors, do not need AC after surgery.

Postoperative chemoradiotherapy with capecitabine and oxaliplatin vs.capecitabine for pathological stage N2 rectal cancer

Objective:Several studies have been conducted on the effects and toxicity of adding oxaliplatin to fluorouracilbased or capecitabine-based chemoradiotherapy(CRT)regimens as significantly increasing the toxic response without benefit to survival.In this study,we further explored the role of these two postoperative CRT regimens in patients with pathological stage N2 rectal cancer.Methods:This study was a subgroup analysis of a randomized clinical trial.A total of 180 patients with pathological stage N2 rectal cancer were eligible,85 received capecitabine with radiotherapy(RT),and 95 received capecitabine and oxaliplatin with RT.Patients in both groups received adjuvant chemotherapy[capecitabine and oxaliplatin(XELOX);or fluorouracil,leucovorin,and oxaliplatin(FOLFOX)]after CRT.Results:At a median follow-up of 59.2[interquartile range(IQR),34.0−96.8]months,the three-year diseasefree survival(DFS)was 53.3%and 64.9%in the control group and the experimental group,respectively[hazard ratio(HR),0.63;95%confidence interval(95%CI),0.41−0.98;P=0.04].There was no significant difference between the groups in overall survival(OS)(HR,0.62;95%CI,0.37−1.05;P=0.07),the incidence of locoregional recurrence(HR,0.62;95%CI,0.24−1.64;P=0.33),the incidence of distant metastasis(HR,0.67;95%CI,0.42−1.06;P=0.09)and grade 3−4 acute toxicities(P=0.78).For patients with survival longer than 3 years,the conditional overall survival(COS)was significantly better in the experimental group(HR,0.39;95%CI,0.16−0.96;P=0.03).Conclusions:Our results indicated that adding oxaliplatin to capecitabine-based postoperative CRT is safe and effective in patients with pathological stage N2 rectal cancer.

Clinical parameters predicting pathologic complete response following neoadjuvant chemoradiotherapy for rectal cancer

Introduction:Preoperative chemoradiotherapy(CRT),followed by total mesorectal excision,has become the standard of care for patients with clinical stages II and III rectal cancer.Patients with pathologic complete response(pCR) to preoperative CRT have been reported to have better outcomes than those without pCR.However,the factors that predict the response to neoadjuvant CRT have not been well defined.In this study,we aimed to investigate the impact of clinical parameters on the development of pCR after neoadjuvant chemoradiation for rectal cancer.Methods:A total of 323 consecutive patients from a single institution who had clinical stage II or III rectal cancer and underwent a long-course neoadjuvant CRT,followed by curative surgery,between 2005 and 2013 were included.Patients were divided into two groups according to their responses to neoadjuvant therapy:the pCR and non-pCR groups.The clinical parameters were analyzed by univariate and multivariate analyses,with pCR as the dependent variable.Results:Of the 323 patients,75(23.2%) achieved pCR.The two groups were comparable in terms of age,sex,body mass index,tumor stage,tumor location,tumor differentiation,radiation dose,and chemotherapy regimen.On multivariate analysis,a pretreatment carcinoembryonic antigen(CEA) level of <5 ng/mL[odds ratio(OR) = 2.170,95%confidence interval(CI) = 1.195-3.939,P = 0.011]and an interval of >7 weeks between the completion of chemoradiation and surgical resection(OR = 2.588,95%CI = 1.484-4.512,P = 0.001) were significantly associated with an increased rate of pCR.Conclusions:The pretreatment CEA level and neoadjuvant chemoradiotherapy-surgery interval were independent clinical predictors for achieving pCR.These results may help clinicians predict the prognosis of patients and develop adaptive treatment strategies.

Long-term outcomes in patients with ypT0 rectal cancer after neoadjuvant chemoradiotherapy and curative resection

Objective： For patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy（NCRT）, significant pathological response of the primary tumor has been proposed to identify candidates for organ preservation. However, this does not address metastatic lymph nodes in the mesorectum. The aim of this study was to assess the incidence of lymph node metastases in ypT0 patients treated with NCRT and curative resection and to explore risk factors associated with survival.Methods： This was a retrospective study of patients with ypT0 rectal cancer after NCRT and curative resection at a tertiary care center in China from 2005 to 2014.Results： A total of 60（18.6%） patients who underwent surgery after NCRT and achieved ypT0 were enrolled in this study; one patient was excluded owing to lack of follow-up. Of these 59 patients, lymph node metastases were found in the mesorectum（ypT0N＋） in eight（13.6%） patients. After a median follow-up of 52 months, 5-year recurrence-free survival（82.7% vs. 62.5%, P=0.014） and overall survival（OS）（90.9% vs. 70.0%, P=0.032） were much higher in ypN0 than yp N＋ patients. Multivariate analyses showed that ypN＋ status（P=0.009） and perioperative blood transfusion（BT）（P=0.001） were significantly independent risk factors associated with recurrence; however, no factor was correlated with 5-year OS.Conclusions： Patients with ypT0N0 rectal cancer can achieve excellent long-term outcomes; however, positive lymph nodes or tumor deposits can still be found in 13.6% of ypT0 patients. Nodal positivity in the mesorectum and perioperative BT are independent risk factors for recurrence.

Neoadjuvant chemoradiotherapy for locally advanced rectal cancer:The debate continues

Rectal carcinoma represents the 30% of all colorectal cancers, with about 40000 new cases/years. In the past two decades, the management of rectal cancer has made important progress, highlighting the main role of a multimodality strategy approach, combining surgery, radiation therapy and chemotherapy. Nowadays, surgery remains the primary treatment and neoadjuvant chemoradiotherapy, based on fluoropyrimidine(5-FU) continuous infusion, is considered the standard in locally advanced rectal carcinoma. The aim is to reduce the incidence of local recurrence and to perform a conservative surgery. To improve these purposes different drugs combination have been tested in the neo-adjuvant setting. At American Society of Clinical Oncology 2014 an important abstract was presented focusing on the role of adding oxaliplatin to concomitant treatment, in patients with locally advanced rectal carcinoma. Rodel et al reported on the CAO/ARO/AIO-04 randomized phase Ⅲ trial that compared standard treatment with 5-FU and radiation therapy, to oxaliplatin plus 5-FU inassociation with radiation therapy. The addition of oxaliplatin to the neo-adjuvant treatment has been shown to improve disease-free survival from 71.2% to 75.9%(P = 0.03). This editorial was planned to clarify the optimal treatment in patients with locally advanced rectal cancer, considering the results from CAO/ARO/AIO-04 study.

Selective lateral lymph node dissection after neoadjuvant chemoradiotherapy in rectal cancer

BACKGROUND Lateral lymph node metastasis is one of the leading causes of local recurrence in patients with advanced mid or low rectal cancer.Neoadjuvant chemoradiotherapy(NCRT)can effectively reduce the postoperative recurrence rate;thus,NCRT with total mesorectal excision(TME)is the most widely accepted standard of care for rectal cancer.The addition of lateral lymph node dissection(LLND)after NCRT remains a controversial topic.AIM To investigate the surgical outcomes of TME plus LLND,and the possible risk factors for lateral lymph node metastasis after NCRT.METHODS This retrospective study reviewed 89 consecutive patients with clinical stage II-III mid or low rectal cancer who underwent TME and LLND from June 2016 to October 2018.In the NCRT group,TME plus LLND was performed in patients with short axis(SA)of the lateral lymph node greater than 5 mm.In the non-NCRT group,TME plus LLND was performed in patients with SA of the lateral lymph node greater than 10 mm.Data regarding patient demographics,clinical workup,surgical procedure,complications,and outcomes were collected.Multivariate logistic regression analysis was performed to evaluate the possible risk factors for lateral lymph node metastasis in NCRT patients.RESULTS LLN metastasis was pathologically confirmed in 35 patients(39.3%):26(41.3%)in the NCRT group and 9(34.6%)in the non-NCRT group.The most common site of metastasis was around the obturator nerve(21/35)followed by the internal iliac artery region(12/35).In the NCRT patients,46%of patients with SA of LLN greater than 7 mm were positive.The postoperative 30-d mortality rate was 0%.Two(2.2%)patients suffered from lateral local recurrence in the 2-year follow up.Multivariate analysis showed that cT4 stage(odds ratio[OR]=5.124,95%confidence interval[CI]:1.419-18.508;P=0.013),poor differentiation type(OR=4.014,95%CI:1.038-15.520;P=0.044),and SA≥7 mm(OR=7.539,95%CI:1.487-38.214;P=0.015)were statistically significant risk factors associated with LLN metastasis.CONCLUSION NCRT is not sufficient as a stand-alone therapy to eradicate LLN metastasis in lower rectal cancer patients and surgeons should consider performing selective LLND in patients with greater LLN SA diameter,poorer histological differentiation,or advanced T stage.Selective LLND for NCRT patients can have a favorable oncological outcome.

Risk factors for local recurrence following neoadjuvant chemoradiotherapy for rectal cancers

Local recurrence(LR)has an adverse impact on rectal cancer treatment.Neoadjuvant chemoradiotherapy(nCRT)is increasingly administered to patients with progressive cancers to improve the prognosis.However,LR still remains a problem and its pattern can alter.Correspondingly,new risk factors have emerged in the context of nCRT in addition to the traditional risk factors in patients receiving non-neoadjuvant therapies.These risk factors are decisive when reviewing treatment options.This review aims to elucidate the distinctive risk factors related to LR of rectal cancers in patients receiving nCRT and to clarify their clinical significance.A search was conducted on PubMed to identify original studies investigating patients with rectal cancer receiving nCRT.Outcomes of interest,especially potential risk factors for LR in patients with nCRT,were then analyzed.The clinical importance of these risk factors is discussed.Remnant cancer cells,lymph-nodes and tumor response were found to be major risk factors.Remnant cancer cells decide the status of resection margins.Local excision following nCRT is promising in ypT0-1N0M0 cases.Dissection of lateral lymph nodes should be considered in advanced lowlying cancers.Although better tumor response resulted in a relatively lower recurrence rate,the evidence available is insufficient to justify a non-operative approach in clinical complete responders to nCRT.LR cannot be totally avoided by current multidisciplinary approaches.The related risk factors resulting from nCRT should be considered when making decisions regarding treatment selection.

Predictive factors for early distant metastasis after neoadjuvant chemoradiotherapy in locally advanced rectal cancer

BACKGROUND Distant relapse is the leading cause of cancer-related death in locally advanced rectal cancer.Neoadjuvant chemoradiation(NACRT)followed by surgery inevitably delays delivery of systemic treatment.Some patients show early distant metastasis before systemic treatment.AIM To identify the most effective treatments.We investigated prognostic factors for distant metastasis,especially early distant metastasis,using the standard treatment paradigm to identify the most effective treatments according to recurrence risk.METHODS From January 2015 through December 2019,rectal cancer patients who underwent NACRT for having clinical T 3-4 or clinical N 1-2 disease according to the 8th American Joint Committee on Cancer staging system were included.Radiotherapy was delivered to the whole pelvis with concomitant chemotherapy.Patients received surgery 6-8 wk after completion of NACRT.Adjuvant chemotherapy was administered at the physician’s discretion.RESULTS A total of 127 patients received NACRT.Ninety-three patients(73.2%)underwent surgery.The R0 resection rate was 89.2%in all patients.Pathologic tumor and node downstaging rates were 41.9%and 76.3%.Half the patients(n=69)received adjuvant chemotherapy after surgery.The 3-year distant metastasis-free survival(DMFS)and overall survival(OS)rates were 81.7%and 83.5%.On univariate analyses,poorly differentiated tumors,>5 cm,involvement of mesorectal fascia(MRF),or presence of extramural involvement(EMVI)were associated with worse DMFS and OS.Five patients showed distant metastasis at their first evaluation after NACRT.Patients with early distant metastasis were more likely to have poorly differentiated tumor(P=0.025),tumors with involved MRF(P=0.002),and EMVI(P=0.012)than those who did not.CONCLUSION EMVI,the involvement of MRF,and poor histologic grade were associated with early distant metastasis.In order to control distant metastasis and improve treatment outcome,selective use of neoadjuvant treatment according to individualized risk factors is necessary.Future studies are required to determine effective treatment strategies for patients at high risk for distant metastasis.

Delaying surgery after neoadjuvant chemoradiotherapy improves prognosis of rectal cancer

AIM To investigate the prognostic effect of a delayed interval between neoadjuvant chemoradiotherapy(CRT) and surgery in locally advanced rectal cancer.METHODS We evaluated 87 patients with locally advanced mid-or distal rectal cancer undergoing total mesorectal excision following an interval period after neoadjuvant CRT at ?i?li Hamidiye Etfal Training and Research Hospital,Istanbul between January 2009 and January 2014.Patients were divided into two groups according to the intervalbefore surgery: < 8 wk(group Ⅰ) and ≥ 8 wk(group Ⅱ).Data related to patients,cancer characteristics and pathological examination were collected and analyzed.RESULTS When the distribution of timing between group Ⅰ(n = 45) and group Ⅱ(n = 42) was viewed,comparison of interval periods(median ± SD) of groups showed a significant difference of as 5 ± 1.28 wk in group Ⅰ and 10.1 ± 2.2 wk in group Ⅱ(P < 0.001).The median follow-up period for all patients was 34.5(9.9-81) mo.group Ⅱ had significantly higher rates of pathological complete response(p CR) than group Ⅰ had(19% vs 8.9%,P = 0.002).Rate of tumor regression grade(TRG) poor response was 44.4% in group Ⅰ and 9.5% in group Ⅱ(P < 0.002).A poor pathological response was associated with worse disease-free survival(P = 0.009).The interval time did not show any association with local recurrence(P = 0.79).CONCLUSION Delaying the neoadjuvant CRT-surgery interval may provide nodal down-staging,improve p CR rate,and decrease the rate of TRG poor response.

Lymph node regression grading of locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy

Neoadjuvant chemoradiotherapy(nCRT)and total rectal mesenteric excision are the main standards of treatment for locally advanced rectal cancer(LARC).Lymph node regression grade(LRG)is an indicator of prognosis and response to preoperative nCRT based on postsurgical metastatic lymph node pathology.Common histopathological findings in metastatic lymph nodes after nCRT include necrosis,hemorrhage,nodular fibrosis,foamy histiocytes,cystic cell reactions,areas of hyalinosis,residual cancer cells,and pools of mucin.A number of LRG systems designed to classify the amount of lymph node regression after nCRT is mainly concerned with the relationship between residual cancer cells and regressive fibrosis and with estimating the number of lymph nodes existing with residual cancer cells.LRG offers significant prognostic information,and in most cases,LRG after nCRT correlates with patient outcomes.In this review,we describe the systematic classification of LRG after nCRT,patient prognosis,the correlation with tumor regression grade,and the typical histopathological findings of lymph nodes.This work may serve as a reference to help predict the clinical complete response and determine lymph node regression in patients based on preservation strategies,allowing for the formulation of more accurate treatment strategies for LARC patients,which has important clinical significance and scientific value.

Predictive value of a serum tumor biomarkers scoring system for clinical stage Ⅱ/Ⅲ rectal cancer with neoadjuvant chemoradiotherapy

BACKGROUND Multiple classes of molecular biomarkers have been studied as potential predictors for rectal cancer(RC)response.Carcinoembryonic antigen(CEA)is the most widely used blood-based marker of RC and has proven to be an effective predictive marker.Cancer antigen 19-9(CA19-9)is another tumor biomarker used for RC diagnosis and postoperative monitoring,as well as monitoring of the therapeutic effect.Using a panel of tumor markers for RC outcome prediction is a practical approach.AIM To assess the predictive effect of pre-neoadjuvant chemoradiotherapy(NCRT)CEA and CA19-9 levels on the prognosis of stage II/III RC patients.METHODS CEA and CA19-9 levels were evaluated 1 wk before NCRT.According to the receiver operating characteristic curve analysis,the optimal cut-off point of CEA and CA19-9 levels for the prognosis were 3.55 and 19.01,respectively.The novel serum tumor biomarker(NSTB)scores were as follows:score 0:Pre-NCRT CEA<3.55 and CA19-9<19.01;score 2:Pre-NCRT CEA>3.55 and CA19-9>19.01;score 1:Other situations.Pathological information was recorded according to histopathological reports after the operation.RESULTS In the univariate analysis,pre-NCRT CEA<3.55[P=0.025 for overall survival(OS),P=0.019 for disease-free survival(DFS)],pre-NCRT CA19-9<19.01(P=0.014 for OS,P=0.009 for DFS),a lower NSTB score(0-1 vs 2,P=0.009 for OS,P=0.005 for DFS)could predict a better prognosis.However,in the multivariate analysis,only a lower NSTB score(0-1 vs 2;for OS,HR=0.485,95%CI:0.251-0.940,P=0.032;for DFS,HR=0.453,95%CI:0.234-0.877,P=0.019)and higher pathological grade,node and metastasis stage(0-I vs II-III;for OS,HR=0.363,95%CI:0.158-0.837,P=0.017;for DFS,HR=0.342,95%CI:0.149-0.786,P=0.012)were independent predictive factors.CONCLUSION The combination of post-NCRT CEA and CA19-9 was a predictive factor for clinical stage II/III RC patients receiving NCRT,and the combined index had a stronger predictive effect.

Consolidation chemotherapy with capecitabine after neoadjuvant chemoradiotherapy in high-risk patients with locally advanced rectal cancer:Propensity score study

BACKGROUND The effects of consolidation chemotherapy(CC) in neoadjuvant therapy in locally advanced rectal cancer(LARC) have been explored. However, the optimal neoadjuvant chemoradiotherapy(NCRT) and surgery interval, regimen, and cycles of chemotherapy remains unclear.AIM To evaluate the effects of one to two cycles of CC with capecitabine on high-risk patients with LARC without extending NCRT and surgery interval.METHODS We retrospectively evaluated high-risk patients with LARC, who were defined as having at least one of the following factors by magnetic resonance imaging: depth of invasion beyond the muscularis propria of more than 5 mm(c T3c-c T3d), T4, meso-rectal fascia or extramural vascular invasion positive, and treatment date between January 2015 and July 2019 in our center. Patients were divided into the CC and non-CC group according to whether they received CC(capecitabine 1000 mg/m^(2) twice daily from days 1 to 14 every 21 d) after NCRT. Propensity score matching(PSM) and inverse probability of treatment weight(IPTW) were used to balance the differences between the two groups. The main outcome was the complete response(CR) rate.RESULTS A total of 265 patients were enrolled: 136 patients in the CC group and 129 patients in the non-CC group. The median interval was 70 d(range, 37-168). The CR rate was 24.3% and 16.3%(P = 0.107) in the CC and non-CC groups’ original samples, respectively. After PSM and IPTW, the CR rate in the CC group was higher than that in non-CC group(27.6% vs 16.2%, P = 0.045;25.9% vs 16.3%, P = 0.045). The median follow-up was 39.8 mo(range, 2.9-74.8), and there were no differences in 3-year non-regrowth disease-free survival nor overall survival in the original samples(73.2% vs 71.9%, P = 0.913;92.3% vs 86.7%, P = 0.294), PSM(73.2% vs 73.5%, P = 0.865;92.5% vs 89.3%, P = 0.612), and IPTW(73.8% vs 72.1%, P = 0.913;92.4% vs 87.4%, P = 0.294). There was also no difference in grade 2 or higher acute toxicity during neoadjuvant therapy in the two groups(49.3% vs 53.5%, P = 0.492).CONCLUSION One to two cycles of CC with capecitabine after NCRT was safe and increased the CR rate in highrisk LARC but failed to improve the long-term outcomes.

Predictive value of indirect bilirubin before neoadjuvant chemoradiotherapy in evaluating prognosis of local advanced rectal cancer patients

BACKGROUND Many biomarkers have predictive value for overall survival(OS)and disease-free survival(DFS)in tumor patients.However,the role of indirect bilirubin(IBIL)in local advanced rectal cancer(LARC)patients treated with neoadjuvant chemoradiotherapy(nCRT)has not been studied.AIM To explore the predictive value of IBIL before nCRT(pre-IBIL)for the OS and DFS of LARC patients treated with nCRT.METHODS A total of 324 LARC patients undergoing nCRT with total mesorectal excision(TME)were enrolled.Preoperative clinical features and postoperative pathological characteristics were collected.Cox regression analysis was performed,and a Cox-based nomogram was developed to predict OS and DFS.We also assessed the predictive performance of the nomogram with calibration plots and receiver operating characteristic(ROC)curves.RESULTS Among 324 patients,the median pre-IBIL was 6.2μmol/L(interquartile range:4.6μmol/L-8.4μmol/L).In the Cox multivariate regression analysis,we found that pre-IBIL,smoking history,tumor regression grade(TRG),vascular invasion,and carbohydrate antigen 19-9 before nCRT(pre-CA19-9)were predictors of OS.Additionally,pre-IBIL,body mass index(BMI),nCRT with surgery interval,TRG,and vascular invasion were predictors of DFS.Predictive nomograms were developed to predict 5-year OS and 5-year DFS with area under the ROC curve values of 0.7518 and 0.7355,respectively.Good statistical performance on internal validation was shown by calibration plots and ROC curves.CONCLUSION This study demonstrated that pre-IBIL was an independent prognostic factor for OS and DFS in LARC patients treated with nCRT followed by TME.Nomograms incorporating pre-IBIL,BMI,smoking history,nCRT with surgery interval,TRG,vascular invasion,and pre-CA19-9 could be helpful to predict OS and DFS.

CEA levels predict tumor response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer

Objective The aim of this study was to evaluate the impact of serum carcinoembryonic antigen(CEA)in the prediction of pathological complete response(pCR)in locally advanced rectal cancer(LARC)patients treated with neoadjuvant chemoradiotherapy(nCRT).Methods A total of 925 LARC patients who underwent nCRT followed by TME between March 2006 and February 2018 were enrolled at Fudan University Shanghai Cancer Center.Using logistic regression models,we investigated the associations between serum CEA levels and pathological complete remission(pCR).Further stratified analyses were performed according to different CEA thresholds.Results We found that pre-nCRT CEA and post-nCRT CEA were negatively correlated with pCR(P<0.001).Stratified analyses revealed that when the CEA cutoff value was set to 5 ng/mL,10.6%of patients with post-nCRT CEA levels>5 ng/mL achieved pCR.Meanwhile,when the CEA cutoff value was set to 10 ng/mL,only 6.8%of the patients with post-nCRT CEA levels>10 ng/mL achieved pCR.Conclusion In summary,pre and post-nCRT CEA levels≤5 ng/mL were favorable predictors of pCR in LACR patients,and the“watch and wait”strategy is not recommended for patients with post-nCRT CEA levels>10 ng/mL.

Neoadjuvant vs adjuvant pelvic radiotherapy for locally advanced rectal cancer: Which is superior?

The treatment of locally advanced rectal cancer including timing and dosage of radiotherapy, degree of sphincter preservation with neoadjuvant radiotherapy, and short and long term effects of radiotherapy are controversial topics. The MEDLINE, Cochrane Library databases, and meeting proceedings from the American Society of Clinical Oncology, were searched for reports of randomized controlled trials and meta-analyses comparing neoadjuvant and adjuvant radiotherapy with surgery to surgery alone for rectal cancer. Neoadjuvant radiotherapy shows superior results in terms of local control compared to adjuvant radiotherapy. Neither adjuvant or neoadjuvant radiotherapy impacts overall survival. Short course versus long course neoadjuvant radiotherapy remains controversial. There is insufficient data to conclude that neoadjuvant therapy improves rates of sphincter preserving surgery. Radiation significantly impacts anorectal and sexual function and includes both acute and long term toxicity. Data demonstrate that neoadjuvant radiation causes less toxicity compared to adjuvant radiotherapy, and specifically short course neoadjuvant radiation results in less toxicity than long course neoadjuvant radiation. Neoadjuvant radiotherapy is the preferred modality for administering radiation in locally advanced rectal cancer. There are significant side effects from radiation, including anorectal and sexual dysfunction, which may be less with short course neoadjuvant radiation.

Down-staging depth score to predict outcomes in locally advanced rectal cancer achieving ypl stage after neoadjuvant chemo-radiotherapy versus de novo stage pl cohort:A propensity score-matched analysis

Objective：Prognosis of patients with locally advanced rectal cancer（LARC）but achieving yp T1–2N0 stage after neoadjuvant concurrent chemo-radiotherapy（CRT）has been shown to be favorable.This study aims to determine whether the long-term outcome of yp T1–2N0 cases can be comparable to that of p T1–2N0 cohort that received definitive surgery for early disease.Method：From January 2008 to December 2013,449 consecutive patients with rectal cancer were treated and their outcome maintained in a database.Patients with LARC underwent total mesorectal excision（TME）surgery at4–8 weeks after completion of CRT,and those achieving stage yp I were identified as a group.As a comparison,stage p I group pertains to patients whose initially limited disease was not upstaged after TME surgery alone.After propensity score matching（PSM）,comparisons of local regional control（LC）,distant metastasis-free survival（DMFS）,disease-free survival（DFS）and overall survival（OS）were performed using Kaplan-Meier analysis and log-rank test between yp I and p I groups.Down-staging depth score（DDS）,a novel method of evaluating CRT response,was used for subset analysis.Results：Of the 449 patients,168 matched cases were generated for analysis.Five-year LC,DMFS,DFS and OS for stage p I vs.yp I groups were 96.7%vs.96.4%（P=0.796）,92.7%vs.73.6%（P=0.025）,91.2%vs.73.6%（P=0.080）and 93.1%vs.72.3%（P=0.040）,respectively.In the DDS-favorable subset of the yp I group,LC,DMFS,DFS and OS resulted in no significant differences in comparison with the p I group（P=0.384,0.368,0.277 and0.458,respectively）.Conclusions：LC was comparable in both groups;however,distant metastasis developed more frequently in down-staged LARC than de novo early stage cases,reflecting the need to improve the efficacy of systemic treatment despite excellent pathologic response.DDS can be an indicator to identify a subset of the yp I group whose longterm oncologic outcomes are as good as those of stage p I cohort.

Neoadjuvant hyperfractionated accelerated radiotherapy plus concomitant 5-fluorouracil infusion in locally advanced rectal cancer: A phase Ⅱ study

AIM To evaluate the efficacy and tolerability of neoadjuvant hyperfractionated accelerated radiotherapy(HART)and concurrent chemotherapy in patients with locally advanced infraperitoneal rectal cancer. METHODS A total of 30 patients with histopathologically confirmed T2-3/N0+ infraperitoneal adenocarcinoma of rectum cancer patients received preoperative 42 Gy/1.5 Gy/18 days/bid radiotherapy and continuous infusion of 5-fluorouracil(325 mg/m^2). All patients were operated 4-8 wk after neoadjuvant concomitant therapy. RESULTS In the early phase of treatment, 6 patients had grade Ⅲ-Ⅳ gastrointestinal toxicity, 2 patients had grade Ⅲ-Ⅳ hematologic toxicity, and 1 patient had grade Ⅴ toxicity due to postoperative sepsis during chemotherapy. Only 1 patient had radiotherapy-related late side effects, i.e., grade Ⅳ tenesmus. Complete pathological response was achieved in 6 patients(21%), while near-complete pathological response was obtained in 9(31%). After a median follow-up period of 60 mo, the local tumor control rate was 96.6%. In 13 patients, distant metastasis occurred. Disease-free survival rates at 2 and 5 years were 63.3% and 53%, and corresponding overall survival rates were 70% and 53.1%, respectively.CONCLUSION Although it has excellent local control and complete pathological response rates, neoadjuvant HART concurrent chemotherapy appears to not be a feasible treatment regimen in locally advanced rectal cancer, having high perioperative complication and intolerable side effects. Effects of reduced 5-fluorouracil dose or omission of chemotherapy with the aim of reducing toxicity may be examined in further studies.