Prediction of pathological complete response and prognosis in locally advanced rectal cancer

BACKGROUND Colorectal cancer is currently the third most common malignant tumor and the second leading cause of cancer-related death worldwide.Neoadjuvant chemoradiotherapy(nCRT)is standard for locally advanced rectal cancer(LARC).Except for pathological examination after resection,it is not known exactly whether LARC patients have achieved pathological complete response(pCR)before surgery.To date,there are no clear clinical indicators that can predict the efficacy of nCRT and patient outcomes.AIM To investigate the indicators that can predict pCR and long-term outcomes following nCRT in patients with LARC.METHODS Clinical data of 128 LARC patients admitted to our hospital between September 2013 and November 2022 were retrospectively analyzed.Patients were categorized into pCR and non-pCR groups.Univariate analysis(using the χ^(2) test or Fisher’s exact test)and logistic multivariate regression analysis were used to study clinical predictors affecting pCR.The 5-year disease-free survival(DFS)and overall survival(OS)rates were calculated using Kaplan-Meier analysis,and differences in survival curves were assessed with the log-rank test.RESULTS Univariate analysis showed that pretreatment carcinoembryonic antigen(CEA)level,lymphocyte-monocyte ratio(LMR),time interval between neoadjuvant therapy completion and total mesorectal excision,and tumor size were correlated with pCR.Multivariate results showed that CEA≤5 ng/mL(P=0.039),LMR>2.73(P=0.023),and time interval>10 wk(P=0.039)were independent predictors for pCR.Survival analysis demonstrated that patients in the pCR group had significantly higher 5-year DFS rates(94.7%vs 59.7%,P=0.002)and 5-year OS rates(95.8%vs 80.1%,P=0.019)compared to the non-pCR group.Tumor deposits(TDs)were significantly correlated with shorter DFS(P=0.002)and OS(P<0.001).CONCLUSION Pretreatment CEA,LMR,and time interval contribute to predicting nCRT efficacy in LARC patients.Achieving pCR demonstrates longer DFS and OS.TDs correlate with poor prognosis.

Minimally invasive pelvic exenteration for primary or recurrent locally advanced rectal cancer:A glimpse into the future

Surgeons have grappled with the treatment of recurrent and T4b locally advanced rectal cancer(LARC)for many years.Their main objectives are to increase the overall survival and quality of life of the patients and to mitigate postoperative complications.Currently,pelvic exenteration(PE)with or without neoadjuvant treatment is a curative treatment when negative resection margins are achieved.The traditional open approach has been favored by many surgeons.However,the technological advancements in minimally invasive surgery have radically changed the surgical options.Recent studies have demonstrated promising results in postoperative complications and oncological outcomes after robotic or laparoscopic PE.A recent retrospective study entitled“Feasibility and safety of minimally invasive multivisceral resection for T4b rectal cancer:A 9-year review”was published in the World Journal of Gastrointestinal Surgery.As we read this article with great interest,we decided to delve into the latest data regarding the benefits and risks of minimally invasive PE for LARC.Currently,the small number of suitable patients,limited surgeon experience,and steep learning curve are hindering the establishment of minimally invasive PE.

Hsa-miR-483-5p/mRNA network that regulates chemotherapy resistance in locally advanced rectal cancer identified through plasma exosome transcriptomics

BACKGROUND Chemoresistance is the primary contributor to distant metastasis in the context of neoadjuvant chemoradiotherapy(nCRT)for rectal cancer.However,the underlying mechanisms remain elusive.AIM To detect the differential expression profiles of plasma exosomal microRNAs(miRNAs)in poor and good responders and explore the potential mechanisms of chemoresistance.METHODS In this study,the profiles of plasma exosomal miRNAs were compared in two dimensions according to treatment responses(poor/good responders)and treatment courses(pre/post-nCRT)using RNA sequencing.RESULTS Exosome hsa-miR-483-5p was up-regulated in good responders post-nCRT.Bioinformatics analysis revealed that the target genes of hsa-miR-483-5p were mainly enriched in tumor-specific pathways,such as the MAPK signaling pathway,EGFR tyrosine kinase inhibitor resistance,Toll-like receptor signaling pathway,VEGF signaling pathway,and mTOR signaling pathway.Further analysis indicated that MAPK3,RAX2,and RNF165 were associated with inferior recurrence-free survival in patients with rectal cancer,and the profiles of MAPK3,TSPYL5,and ZNF-417 were correlated with tumor stage.In addition,the expression profiles of MAPK3,RNF165,and ZNF417 were negatively correlated with inhibitory concentration 50 values.Accordingly,an hsa-miR-483-5p/MAPK3/RNF 165/ZNF417 network was constructed.CONCLUSION This study provides insights into the mechanism of chemoresistance in terms of exosomal miRNAs.However,further research is required within the framework of our established miRNA-mRNA network.

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.

Locally advanced rectal cancer:The importance of a multidisciplinary approach

Rectal cancer accounts for a relevant part of colorectal cancer cases,with a mortality of 4-10/100000 per year.The development of locoregional recurrences and the occurrence of distant metastases both influences the prognosis of these patients.In the last two decades,new multimodality strategies have improved the prognosis of locally advanced rectal cancer with a significant reduction of local relapse and an increase in terms of overall survival.Radical surgery still remains the principal curative treatment and the introduction of total mesorectal excision has significantly achieved a reduction in terms of local recurrence rates.The employment of neoadjuvant treatment,delivered before surgery,also achieved an improved local control and an increasedsphincter preservation rate in low-lying tumors,with an acceptable acute and late toxicity.This review describes the multidisciplinary management of rectal cancer,focusing on the effectiveness of neoadjuvant chemoradiotherapy and of post-operative adjuvant chemotherapy both in the standard combined modality treatment programs and in the ongoing research to improve these regimens.

Whole lesion histogram analysis of apparent diffusion coefficient predicts therapy response in locally advanced rectal cancer

BACKGROUND Whole-tumor apparent diffusion coefficient(ADC)histogram analysis is relevant to predicting the neoadjuvant chemoradiation therapy(nCRT)response in patients with locally advanced rectal cancer(LARC).AIM To evaluate the performance of ADC histogram-derived parameters for predicting the outcomes of patients with LARC.METHODS This is a single-center,retrospective study,which included 48 patients with LARC.All patients underwent a pre-treatment magnetic resonance imaging(MRI)scan for primary tumor staging and a second restaging MRI for response evaluation.The sample was distributed as follows:18 responder patients(R)and 30 non-responders(non-R).Eight parameters derived from the whole-lesion histogram analysis(ADCmean,skewness,kurtosis,and ADC10^(th),25^(th),50^(th),75^(th),90^(th) percentiles),as well as the ADCmean from the hot spot region of interest(ROI),were calculated for each patient before and after treatment.Then all data were compared between R and non-R using the Mann-Whitney U test.Two measures of diagnostic accuracy were applied:the receiver operating characteristic curve and the diagnostic odds ratio(DOR).We also reported intra-and interobserver variability by calculating the intraclass correlation coefficient(ICC).RESULTS Post-nCRT kurtosis,as well as post-nCRT skewness,were significantly lower in R than in non-R(both P<0.001,respectively).We also found that,after treatment,R had a larger loss of both kurtosis and skewness than non-R(Δ%kurtosis and Δ skewness,P<0.001).Other parameters that demonstrated changes between groups were post-nCRT ADC10^(th),Δ%ADC10^(th),Δ%ADCmean,and ROIΔ%ADCmean.However,the best diagnostic performance was achieved byΔ%kurtosis at a threshold of 11.85%(Area under the receiver operating characteristic curve[AUC]=0.991,DOR=376),followed by post-nCRT kurtosis=0.78×10^(-3)mm^(2)/s(AUC=0.985,DOR=375.3),Δskewness=0.16(AUC=0.885,DOR=192.2)and post-nCRT skewness=1.59×10^(-3)mm^(2)/s(AUC=0.815,DOR=168.6).Finally,intraclass correlation coefficient analysis showed excellent intraobserver and interobserver agreement,ensuring the implementation of histogram analysis into routine clinical practice.CONCLUSION Whole-tumor ADC histogram parameters,particularly kurtosis and skewness,are relevant biomarkers for predicting the nCRT response in LARC.Both parameters appear to be more reliable than ADCmean from one-slice ROI.

Bevacizumab in the pre-operative treatment of locally advanced rectal cancer: A systematic review

Despite advances in the management of patients with locally advanced, non-metastatic rectal adenocarcinoma (LARC), prognosis remains largely unsatisfactory due to a high rate of distant relapse. In fact, currently available neoadjuvant protocols, represented by fluoropyrimidine-based chemo-radiotherapy (CT-RT) or short-course RT, together with improved surgical techniques, have largely reduced the risk of local relapse, with limited impact on distant recurrence. Available results of phase III trials with additional cytotoxic agents combined with standard CT-RT are disappointing, as no significant reduction in the risk of recurrence has been demonstrated. In order to improve the control of micrometastatic disease, integrating targeted agents into neoadjuvant treatment protocols thus offers a rational approach. In particular, the antiangiogenic agent bevacizumab has demonstrated synergistic activity with both CT and RT in pre-clinical and clinical models, and thus may represent a suitable companion in the neoadjuvant treatment of LARC. Preliminary results of phase&#x02005;I-II clinical studies are promising and suggest potential clinical parameters and molecular predictive biomarkers useful for patient selection: treatment personalization is indeed the key in order to maximize the benefit while reducing the risk of more complex neoadjuvant treatment schedules.

High-dose-rate intraluminal brachytherapy during preoperative chemoradiation for locally advanced rectal cancers

AIM:To determine the feasibility and safety of high dose rate intraluminal brachytherapy(HDR-ILBT) boost during preoperative chemoradiation for rectal cancer.METHODS:Between 2008 and 2009,thirty-six patients with locally advanced rectal cancer(≥ T3 or N+),were treated initially with concurrent capecitabine(825 mg/m2 oral twice daily) and pelvic external beam radiotherapy(EBRT)(45 Gy in 25 fractions),then were randomized to group A;HDR-ILBT group(n = 17) to receive 5.5-7 Gy×2 to gross tumor volume(GTV) and group B;EBRT group(n = 19) to receive 5.4 Gy×3 fractions to GTV with EBRT.All patients underwent total mesorectal excision.RESULTS:Grade 3 acute toxicities were registered in 12 patients(70.6%) in group A and in 8(42.1%) in group B.Complete pathologic response of T stage(ypT0) in group A was registered in 10 patients(58.8%) and in group B,3 patients(15.8%) had ypT0(P < 0.0001).Sphincter preservation was reported in 6/9 patients(66.7%) in group A and in 5/10 patients(50%) in group B(P < 0.01).Overall radiological response was 68.15% and 66.04% in Group A and B,respectively.During a median follow up of 18 mo,late grade 1 and 2 sequelae were registered in 3 patients(17.6%) and 4 patients(21.1%) in the groups A and B,respectively.CONCLUSION:HDR-ILBT was found to be effective dose escalation technique in preoperative chemoradiation for rectal cancers,with higher response rates,downstaging and with manageable acute toxicities.

Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure

BACKGROUND For locally advanced rectal cancer(LARC),standard therapy[consisting of neoadjuvant chemoradiotherapy(CRT),surgery,and adjuvant chemotherapy(ChT)]achieves excellent local control.Unfortunately,survival is still poor due to distant metastases,which remains the leading cause of death among these patients.In recent years,the concept of total neoadjuvant treatment(TNT)has been developed,whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.AIM To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.METHODS In a retrospective study,we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT.High-risk for failure was defined according to the presence of at least one of the following factors:T4 stage;N2 stage;positive mesorectal fascia;extramural vascular invasion;positive lateral lymph node.TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid,fluorouracil and oxaliplatin,CRT with capecitabine,and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid,fluorouracil and oxaliplatin prior to surgery.The primary endpoint was pathological complete response(pCR).In total,72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.RESULTS Compared to standard therapy,TNT showed a higher proportion of pCR(23%vs 7%;P=0.01),a lower neoadjuvant rectal score(median:8.43 vs 14.98;P<0.05),higher T-and N-downstaging(70%and 94%vs 51%and 86%),equivalent R0 resection(95%vs 93%),shorter time to stoma closure(mean:20 vs 33 wk;P<0.05),higher compliance during systemic ChT(completed all cycles 87%vs 76%;P<0.05),lower proportion of acute toxicity grade≥3 during ChT(3%vs 14%,P<0.05),and equivalent acute toxicity and compliance during CRT and in the postoperative period.The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetricmodulated arc radiotherapy than with 3D conformal radiotherapy(32%vs 9%;P<0.05).CONCLUSION Compared to standard therapy,TNT provides better outcome for LARC patients with high-risk factors for failure,in terms of pCR and neoadjuvant rectal score.

Predictive significance of cancer related-inflammatory markers in locally advanced rectal cancer

BACKGROUND Locally advanced rectal cancer is treated using neoadjuvant chemoradiation(nCRT),followed by total mesorectal excision(TME).Tumor regression and pathological post-treatment stage are prognostic for oncological outcomes.There is a significant correlation between markers representing cancer-related inflammation,including high neutrophil-to-lymphocyte ratio(NLR),monocyteto-lymphocyte ratio(MLR),and platelet-to-lymphocyte(MLR)and unfavorable oncological outcomes.However,the predictive role of these markers on the effect of chemoradiation is unknown.AIM To evaluate the predictive roles of NLR,MLR,and PLR in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiation.METHODS Patients(n=111)with locally advanced rectal cancer who underwent nCRT followed by TME at the Minimally Invasive Surgery Unit,Siriraj Hospital between 2012 and 2018 were retrospectively analyzed.The associations between post-treatment pathological stages,neoadjuvant rectal(NAR)score and the pretreatment ratios of markers of inflammation(NLR,MLR,and PLR)were analyzed.RESULTS Clinical stages determined using computed tomography,magnetic resonance imaging,or both were T4(n=16),T3(n=94),and T2(n=1).The NAR scores were categorized as high(score>16)in 23.4%,intermediate(score 8-16)in 41.4%,and low(score<8)in 35.2%.The mean values of the NLR,PLR,and MLR correlated with pathological tumor staging(ypT)and the NAR score.The values of NLR,PLR and MLR were higher in patients with advanced pathological stage and high NAR scores,but not statistically significant.CONCLUSION In patients with locally advanced rectal cancer,pretreatment NLR,MLR and PLR are higher in those with advanced pathological stage but the differences are not significantly different.

Contemporary management of locally advanced rectal cancer:Resolving issues, controversies and shifting paradigms

Advancements in rectal cancer treatment have resulted in improvement only in locoregional control and have failed to address distant relapse, which is the predominant mode of treatment failure in rectal cancer. As the efficacy of conventional chemoradiotherapy（CRT） followed by total mesorectal excision（TME） reaches a plateau, the need for alternative strategies in locally advanced rectal cancer（LARC） has grown in relevance. Several novel strategies have been conceptualized to address this issue, including： 1） neoadjuvant induction and consolidation chemotherapy before CRT; 2） neoadjuvant chemotherapy alone to avoid the sequelae of radiation; and 3） nonoperative management for patients who achieved pathological or clinical complete response after CRT. This article explores the issues, recent advances and paradigm shifts in the management of LARC and emphasizes the need for a personalized treatment plan for each patient based on tumor stage, location, gene expression and quality of life.

New standard in locally advanced rectal cancer

In the following review we intend to ascertain the optimal neoadjuvant therapy inpatients with locally advanced rectal cancer. In 2004, a study revealed thatchemoradiotherapy (CRT) resulted in better local control when performedpreoperatively rather than postoperatively, thus neoadjuvant treatment wasestablished as a standard treatment. Subsequently, the Polish study and the Trans-Tasman Radiation Oncology Group showed no statistically significant differencebetween concomitant CRT over 5 wk vs short-course radiotherapy (RT).Therefore, both were established as standard neoadjuvant treatments. Later, theStockholm III study demonstrated that short-course RT had a higher completepathological response than long-course RT. It also showed that a delay betweenRT and surgery presented fewer complications. This opened a window of time toprovide an early and effective systemic treatment to prevent distant metastases.Studies show that short-course RT plus oxaliplatin-based chemotherapy couldachieve this. When comparing this total neoadjuvant treatment (TNT) vsconcomitant CRT, the former showed greater complete pathological response andlower acute toxicity. Studies presented during 2020 have also shown the benefitsof TNT in terms of complete pathological response, as well as disease andmetastasis-free survival. Our review suggests that probably TNT should be thenew standard treatment for these patients. However, we will have to wait for thefull text publications of these studies to confirm this statement.

Retrospective research of neoadjuvant therapy on tumordownstaging,post-operative complications,and prognosis in locally advanced rectal cancer

BACKGROUND Neoadjuvant therapy(NAT)is becoming increasingly important in locally advanced rectal cancer.Hence,such research has become a problem.AIM To evaluate the downstaging effect of NAT,its impact on postoperative complications and its prognosis with different medical regimens.METHODS Seventy-seven cases from Shanghai Ruijin Hospital affiliated with Shanghai Jiaotong University School of Medicine were retrospectively collected and divided into the neoadjuvant radiochemotherapy(NRCT)group and the neoadjuvant chemotherapy(NCT)group.The differences between the two groups in tumor regression,postoperative complications,rectal function,disease-free survival,and overall survival were compared using theχ2 test and Kaplan-Meier analysis.RESULTS Baseline data showed no statistical differences between the two groups,whereas the NRCT group had a higher rate of T4(30/55 vs 5/22,P<0.05)than the NCT groups.Twelve cases were evaluated as complete responders,and 15 cases were evaluated as tumor regression grade 0.Except for the reduction rate of T stage(NRCT 37/55 vs NCT 9/22,P<0.05),there was no difference in effectiveness between the two groups.Preoperative radiation was not a risk factor for poor reaction or anastomotic leakage.No significant difference in postoperative complications and disease-free survival between the two groups was observed,although the NRCT group might have better long-term overall survival.CONCLUSION NAT can cause tumor downstaging preoperatively or even complete remission of the primary tumor.Radiochemotherapy could lead to better T downstaging and promising overall survival without more complications.

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.

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 oxaliplatin and capecitabine combined with bevacizumab plus radiotherapy for locally advanced rectal cancer: results of a single-institute phase II study

Background:Neoadjuvant chemoradiotherapy followed by surgery is recommended as the standard of care for locally advanced rectal cancer,reducing local recurrence but not distant metastasis.Intensified systemic therapy is warranted to reduce the risk of distant metastasis.The present study aimed to evaluate the safety and efficacy of neo-adjuvant oxaliplatin and capecitabine(XELOX)combined with bevacizumab plus radiotherapy for locally advanced rectal cancer.Methods:Patients with stages II to III rectal cancer received one cycle of induction chemotherapy and concurrent chemoradiotherapy with XELOX plus bevacizumab.Surgery was performed 6-8 weeks after completion of radiotherapy,and postoperative chemotherapy with three cycles of XELOX and two cycles of capecitabine were given.The primary endpoints were pathologic complete response(pCR)rate and safety,and the secondary endpoints were 3-year overall survival and progression-free survival.Results:Forty-five patients were enrolled between February 2013 and April 2015.All completed the neoadjuvant therapy.Seven patients(15.6%)refused subsequent surgical therapy for personal reasons,and the other 38 patients received radical resection,with a sphincter preservation rate of 84.2%and a pCR rate of 39.5%.Toxicity was acceptable,with grades 3-4 hematological toxicity and diarrhea observed in six and two patients,respectively.Incidence of anastomotic leak that required surgical intervention was 13.3%.After a median follow-up period of 37 months,five patients developed disease progression and two died of cancer.The 3-year overall survival rate and 3-year progres-sion-free survival rate were 95.3%and 88.6%,respectively.Conclusions:The addition of bevacizumab to neoadjuvant chemoradiotherapy resulted in a satisfying pCR rate and 3-year survival,but also may increase the risk of anastomotic leak,thus this regimen is not suitable to be considered for regular recommendation for locally advanced rectal cancer.

Impact of neoadjuvant chemoradiotherapy on the local recurrence and distant metastasis pattern of locally advanced rectal cancer: a propensity score-matched analysis

Background:Previous studies have demonstrated different predominant sites of distant metastasis between patients with and without neoadjuvant chemoradiotherapy(NCRT).This study aimed to explore whether NCRT could influence the metastasis pattern of rectal cancer through a propensity score-matched analysis.Methods:In total,1296 patients with NCRT or post-operative chemoradiotherapy(PCRT)were enrolled in this study between January 2008 and December 2015.Propensity score matching was used to correct for differences in baseline characteristics between the two groups.After propensity score matching,the metastasis pattern,including metastasis sites and timing,was compared and analyzed.Results:After propensity score matching,there were 408 patients in the PCRT group and 245 patients in the NCRT group.NCRT significantly reduced local recurrence(4.1%vs.10.3%,P=0.004),but not distant metastases(28.2%vs.27.9%,P=0.924)compared with PCRT.In both the NCRT and PCRT groups,the most common metastasis site was the lung,followed by the liver.The NCRT group developed local recurrence and distant metastases later than the PCRT group(median time:29.2[18.8,52.0]months vs.18.7[13.3,30.0]months,Z=–2.342,P=0.019;and 21.2[12.2,33.8]vs.16.4[9.3,27.9]months,Z=–1.765,P=0.035,respectively).The distant metastases occurred mainly in the 2nd year after surgery in both the PCRT group(39/114,34.2%)and NCRT group(21/69,30.4%).However,20.3%(14/69)of the distant metastases appeared in the 3rd year in the NCRT group,while this number was only 13.2%(15/114)in the PCRT group.Conclusions:The predominant site of distant metastases was the lung,followed by the liver,for both the NCRT group and PCRT group.NCRT did not influence the predominant site of distant metastases,but the NCRT group developed local recurrence and distant metastases later than the PCRT group.The follow-up strategy for patients with NCRT should be adjusted and a longer intensive follow-up is needed.

Nomogram for predicting pathological complete response and tumor downstaging in patients with locally advanced rectal cancer on the basis of a randomized clinical trial

Background:Preoperative fluoropyrimidine with radiotherapy was regarded as the standard of care for locally advanced rectal cancer(LARC).The model for predicting pCR in LARC patients was based on standard treatment only.This study aimed to establish a nomogramwith pretherapeutic parameters and different neoadjuvant regimens for predicting pathologic complete response(pCR)and tumor downstaging or good response(ypT0-2N0M0)after receiving neoadjuvant treatment in patients with LARC based on a randomized clinical trial.Methods:Between January 2011 and February 2015,309 patients with rectal cancer were enrolled from a prospective randomized study(NCT01211210).All pretreatment clinical parameters were collected to build a nomogram for predicting pCR and tumor downstaging.The model was subjected to bootstrap internal validation.The predictive performance of the model was assessed with concordance index(C-index)and calibration plots.Results:Of the 309 patients,53(17.2%)achieved pCR and 132(42.7%)patients were classified as tumor downstaging with ypT0-2N0M0.Based on the logistic-regression analysis and clinical consideration,tumor length(P=0.005),tumor circumferential extent(P=0.036),distance from the anal verge(P=0.019),and neoadjuvant treatment regimen(P<0.001)showed independent association with pCR following neoadjuvant treatment.The tumor length(P=0.015),tumor circumferential extent(P=0.001),distance from the anal verge(P=0.032),clinical T category(P=0.012),and neoadjuvant treatment regimen(P=0.001)were significantly associated with good tumor downstaging(ypT0-2N0M0).Nomograms were developed to predict the probability of pCR and tumor downstaging with a C-index of 0.802(95%confidential interval[CI],0.736-0.867)and 0.730(95%CI,0.672-0.784).Internal validation revealed good performance of the calibration plots.Conclusions:The nomogramprovided individual prediction responses to different preoperative treatment for patients with rectal cancer.This model might help physicians in selecting an optimized treatment,but warrants further external validation.

Laparoscopic lateral lymph node dissection in two fascial spaces for locally advanced lower rectal cancer

BACKGROUND The procedure for lateral lymph node(LLN)dissection(LLND)is complicated and can result in complications.We developed a technique for laparoscopic LLND based on two fascial spaces to simplify the procedure.AIM To clarify the anatomical basis of laparoscopic LLND in two fascial spaces and to evaluate its efficacy and safety in treating locally advanced low rectal cancer(LALRC).METHODS Cadaveric dissection was performed on 24 pelvises,and the fascial composition related to LLND was observed and described.Three dimensional-laparoscopic total mesorectal excision with LLND was performed in 20 patients with LALRC,and their clinical data were analyzed.RESULTS The cadaver study showed that the fascia propria of the rectum,urogenital fascia,vesicohypogastric fascia and parietal fascia lie side by side in a medial-lateral direction constituting the dissection plane for curative rectal cancer surgery,and the last three fasciae formed two spaces(Latzko's pararectal space and paravesical space)which were the surgical area for LLND.Laparoscopic LLND in two fascial spaces was performed successfully in all 20 patients.The median operating time,blood loss and postoperative hospitalization were 178(152-243)min,55(25-150)mL and 10(7-20)d,respectively.The median number of harvested LLNs was 8.6(6-12),and pathologically positive LLN metastasis was confirmed in 7(35.0%)cases.Postoperative complications included lower limb pain in 1 case and lymph leakage in 1 case.CONCLUSION Our preliminary surgical experience suggests that laparoscopic LLND based on fascial spaces is a feasible,effective and safe procedure for treating LALRC.

Neoadjuvant treatment of rectal cancer: Where we are and where we are going

Locally advanced rectal cancer requires a multidisciplinary approach based on total neoadjuvant treatment with radiotherapy(RT)and chemotherapy(ChT),followed by deferred surgery.Currently,alternatives to the standard total neoadjuvant therapy(TNT)are being explored,such as new ChT regimens or the introduction of immunotherapy.With standard TNT,up to a third of patients may achieve a complete pathological response(CPR),potentially avoiding surgery.However,as of now,we lack predictive markers of response that would allow us to define criteria for a conservative organ strategy.The presence of muta-tions,genes,or new imaging tests is helping to define these criteria.An example of this is the diffusion coefficient in the diffusion-weighted sequence of magnetic resonance imaging and the integration of this imaging technique into RT treatment.This allows for the monitoring of the evolution of this coefficient over successive RT sessions,helping to determine which patients will achieve CPR or those who may require intensification of neoadjuvant therapy.