Implications of recent neoadjuvant clinical trials on the future practice of radiotherapy in locally advanced rectal cancer

Over the last two decades, the standard treatment for locally advanced rectal cancer(LARC) has been neoadjuvant chemoradiotherapy plus total mesorectal excision followed by adjuvant chemotherapy. Total neoadjuvant treatment(TNT) and immunotherapy are two major issues in the treatment of LARC. In the two latest phase Ⅲ randomized controlled trials(RAPIDO and PRODIGE23), the TNT approach achieved higher rates of pathologic complete response and distant metastasis-free survival than conventional chemoradiotherapy. Phase I/II clinical trials have reported promising response rates to neoadjuvant(chemo)-radiotherapy combined with immunotherapy. Accordingly, the treatment paradigm for LARC is shifting toward methods that increase the oncologic outcomes and organ preservation rate. However, despite the progress of these combined modality treatment strategies for LARC, the radiotherapy details in clinical trials have not changed significantly. To guide future radiotherapy for LARC with clinical and radiobiological evidence, this study reviewed recent neoadjuvant clinical trials evaluating TNT and immunotherapy from a radiation oncologist’s perspective.

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.

Neoadjuvant radiotherapy for rectal cancer management

Thirty per cent of all colorectal tumours develop in the rectum.The location of the rectum within the bony pelvis and its proximity to vital structures presents significant therapeutic challenges when considering neoadjuvant options and surgical interventions.Most patients with early rectal cancer can be adequately managed by surgery alone.However,a significant proportion of patients with rectal cancer present with locally advanced disease and will potentially benefit from down staging prior to surgery.Neoadjuvant therapy involves a variety of options including radiotherapy,chemotherapy used alone or in combination.Neoadjuvant radiotherapy in rectal cancer has been shown to be effective in reducing tumour burden in advance of curative surgery.The gold standard surgical rectal cancer management aims to achieve surgical removal of the tumour and all draining lymph nodes,within an intact mesorectal package,in order to minimise local recurrence.It is critically important that all rectal cancer cases are discussed at a multidisciplinary meeting represented by all relevant specialties.Pre-operative staging including CT thorax,abdomen,pelvis to assess for distal disease and magnetic resonance imaging to assess local involvement is essential.Staging radiology and MDT discussion are integral in identifying patients who require neoadjuvant radiotherapy.While Neoadjuvant radiotherapy is potentially beneficial it may also result in morbidity and thus should be reserved for those patients who are at a high risk of local failure,which includes patients with nodal involvement,extramural venous invasion and threatened circumferential margin.The aim of this review is to discuss the role of neoadjuvant radiotherapy in the management of rectal cancer.

How reliable is current imaging in restaging rectal cancer after neoadjuvant therapy?

In patients with advanced rectal cancer,neoadjuvant chemo radiotherapy provides tumor downstaging and downsizing and complete pathological response in up to 30%of cases.After proctectomy complete pathological response is associated with low rates of local recurrence and excellent long term survival.Several authors claim a less invasive surgery or a non operative policy in patients with partial or clinical complete response respectively,however to identify patients with true complete pathological response before surgical resection remains a challenge.Current imaging techniques have been reported to be highly accurate in the primary staging of rectal cancer,however neoadjuvant therapy course produces deep modifications on cancer tissue and on surrounding structures such as overgrowth fibrosis,deep stroma alteration,wall thickness,muscle disarrangement,tumor necrosis,calcification,and inflammatory infiltration.As a result,the same imaging techniques,when used for restaging,are far less accurate.Local tumor extent may be overestimated or underestimated.The diagnostic accuracy of clinical examination,rectal ultrasound,computed tomography,magnetic resonance imaging,and positron emission tomography using 18F-fluoro-2’-deoxy-Dglucose ranges between 25%and 75%being less than 60%in most studies,both for rectal wall invasion and for lymph nodes involvement.In particular the ability to predict complete pathological response,in order to tailor the surgical approach,remains low.Due to the radio-induced tissue modifications,combined with imaging technical aspects,low rate accuracy is achieved,making modern imaging techniques still unreliable in restaging rectal cancer after chemo-radiotherapy.

Prediction of pathological nodal stage of locally advanced rectal cancer by collective features of multiple lymph nodes in magnetic resonance images before and after neoadjuvant chemoradiotherapy

Objective:To predict pathological nodal stage of locally advanced rectal cancer by a radiomic method that uses collective features of multiple lymph nodes(LNs)in magnetic resonance images before and after neoadjuvant chemoradiotherapy(NCRT).Methods:A total of 215 patients were included in this study and chronologically divided into the discovery cohort(n=143)and validation cohort(n=72).In total,2,931 pre-NCRT LNs and 1,520 post-NCRT LNs were delineated from all visible rectal LNs in magnetic resonance images.Geometric,first-order and texture features were extracted from each LN before and after NCRT.Collective features are defined as the maximum,minimum,mean,median value and standard deviation of each feature from all delineated LNs of each participant.LN-model is constructed from collective LN features by logistic regression model with L1 regularization to predict pathological nodal stage(ypN0 or ypN+).Tumor-model is constructed from tumor features for comparison by using DeLong test.Results:The LN-model selects 7 features from 412 LN features,and the tumor-model selects 7 features from 82 tumor features.The area under the receiver operating characteristic curve(AUC)of LN-model in the discovery cohort is 0.818[95%confidence interval(95%CI):0.745-0.878],significantly(Z=2.09,P=0.037)larger than 0.685(95%CI:0.602-0.760)of the tumor-model.The AUC of LN-model in validation cohort is 0.812(95%CI:0.703-0.895),significantly(Z=3.106,P=0.002)larger than 0.517(95%CI:0.396-0.636)of the tumor-model.Conclusions:The usage of collective features from all visible rectal LNs performs better than the usage of tumor features for the prediction of pathological nodal stage of locally advanced rectal cancer.

Role of radiation therapy in neoadjuvant era in patients with locally advanced rectal cancer

Surgery remains the primary determinant of cure in patients with localized rectal cancer, and total mesorectal excision is now widely accepted as standard of care. The widespread implementation of neoadjuvant shortcourse radiotherapy (RT) or long-course chemoradiotherapy (CRT) has reduced local recurrence rates from 25% to 40% to less than 10%; Preoperative RT in resectable rectal cancer has a number of potential advantages, most importantly reducing local recurrence, and down-staging effect. In this article making a comprehensive literature review searching the reliable medical data bases of PubMed and Cochrane we present all available information on the role of radiation therapy alone or in combination with chemotherapy in preoperative setting of rectal cancer. Data reported show that in locally advanced rectal cancer the addition of radiation therapy or CRT pre surgically has significantly improved sphincter prevention surgery. Moreover, the addition of chemotherapy to radiation therapy in preoperative setting has significantly improved pathologic complete response rate and loco-regional control rate without improvement in sphincter preserving surgery. Finally, the results of recently published randomized trials have shown a significant improvement of prevs postoperative CRT on local control; however, there was no effect on overall survival.

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.

Impact of interval between neoadjuvant chemoradiotherapy and surgery in rectal cancer patients

BACKGROUND Epidemiologically,in China,locally advanced rectal cancer is a more common form of rectal cancer.Preoperative neoadjuvant concurrent chemoradiotherapy can effectively reduce the size of locally invasive tumors and improve disease-free survival(DFS)and pathologic response after surgery.At present,this modality has become the standard protocol for the treatment of locally advanced rectal cancer in many centers,but the optimal time for surgery after neoadjuvant therapy is still controversial.AIM To investigate the impact of time interval between neoadjuvant therapy and surgery on DFS and pathologic response in patients with locally advanced rectal cancer.METHODS A total of 231 patients who were classified as having clinical stage II or III advanced rectal cancer and underwent neoadjuvant chemoradiation followed by surgery at the National Cancer Center/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College from November 2014 to August 2017 were involved in this retrospective cohort study.The patients were divided into two groups based on the different time intervals between neoadjuvant therapy and surgery:139(60.2%)patients were in group A(≤9 wk),and 92(39.2%)patients were in group B(>9 wk).DFS and pathologic response were analyzed as the primary endpoints.The secondary endpoints were postoperative complications and sphincter preservation.RESULTS For the 231 patients included,surgery was performed at≤9 wk in 139(60.2%)patients and at>9 wk in 92(39.8%).The patients’clinical characteristics,surgical results,and tumor outcomes were analyzed through univariate analysis combined with multivariate regression analysis.The overall pathologic complete response(pCR)rate was 27.2%(n=25)in the longer time interval group(>9 wk)and 10.8%(n=15)in the shorter time interval group(≤9 wk,P=0.001).The postoperative complications did not differ between the groups(group A,5%vs group B,5.4%;P=0.894).Surgical procedures for sphincter preservation were performed in 113(48.9%)patients,which were not significantly different between the groups(group A,52.5%vs group B,43.5%;P=0.179).The pCR rate was an independent factor affected by time interval(P=0.009;odds ratio[OR]=2.668;95%CI:1.276-5.578).Kaplan-Meier analysis and Cox regression analysis showed that the longer time interval(>9 wk)was a significant independent prognostic factor for DFS(P=0.032;OR=2.295;95%CI:1.074-4.905),but the time interval was not an independent prognostic factor for overall survival(P>0.05).CONCLUSION A longer time interval to surgery after neoadjuvant therapy may improve the pCR rate and DFS but has little impact on postoperative complications and sphincter preservation.

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 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.

Nomograms and risk score models for predicting survival in rectal cancer patients with neoadjuvant therapy

BACKGROUND Colorectal cancer is a common digestive cancer worldwide.As a comprehensive treatment for locally advanced rectal cancer(LARC),neoadjuvant therapy(NT)has been increasingly used as the standard treatment for clinical stage II/III rectal cancer.However,few patients achieve a complete pathological response,and most patients require surgical resection and adjuvant therapy.Therefore,identifying risk factors and developing accurate models to predict the prognosis of LARC patients are of great clinical significance.AIM To establish effective prognostic nomograms and risk score prediction models to predict overall survival(OS)and disease-free survival(DFS)for LARC treated with NT.METHODS Nomograms and risk factor score prediction models were based on patients who received NT at the Cancer Hospital from 2015 to 2017.The least absolute shrinkage and selection operator regression model were utilized to screen for prognostic risk factors,which were validated by the Cox regression method.Assessment of the performance of the two prediction models was conducted using receiver operating characteristic curves,and that of the two nomograms was conducted by calculating the concordance index(C-index)and calibration curves.The results were validated in a cohort of 65 patients from 2015 to 2017.RESULTS Seven features were significantly associated with OS and were included in the OS prediction nomogram and prediction model:Vascular_tumors_bolt,cancer nodules,yN,body mass index,matchmouth distance from the edge,nerve aggression and postoperative carcinoembryonic antigen.The nomogram showed good predictive value for OS,with a C-index of 0.91(95%CI:0.85,0.97)and good calibration.In the validation cohort,the C-index was 0.69(95%CI:0.53,0.84).The risk factor prediction model showed good predictive value.The areas under the curve for 3-and 5-year survival were 0.811 and 0.782.The nomogram for predicting DFS included ypTNM and nerve aggression and showed good calibration and a C-index of 0.77(95%CI:0.69,0.85).In the validation cohort,the C-index was 0.71(95%CI:0.61,0.81).The prediction model for DFS also had good predictive value,with an AUC for 3-year survival of 0.784 and an AUC for 5-year survival of 0.754.CONCLUSION We established accurate nomograms and prediction models for predicting OS and DFS in patients with LARC after undergoing NT.

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.

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.

Neoadjuvant radiotherapy dose escalation for locally advanced rectal cancers in the new era of radiotherapy:A review of literature

BACKGROUND The standard treatment of locally advanced rectal cancers(LARC)consists on neoadjuvant chemoradiotherapy followed by total mesorectal excision.Different data in literature showed a benefit on tumor downstaging and pathological complete response(pCR)rate using radiotherapy dose escalation,however there is shortage of studies regarding dose escalation using the innovative techniques for LARC(T3-4 or N1-2).AIM To analyze the role of neoadjuvant radiotherapy dose escalation for LARC using innovative radiotherapy techniques.METHODS In December 2020,we conducted a comprehensive literature search of the following electronic databases:PubMed,Web of Science,Scopus and Cochrane library.The limit period of research included articles published from January 2009 to December 2020.Screening by title and abstract was carried out to identify only studies using radiation doses equivalent dose 2 Gy fraction(EQD2)≥54 Gy and Volumetric Modulated Arc Therapy(VMAT),intensity-modulated radiotherapy or image-guided radiotherapy(IGRT)techniques.The authors’searches generated a total of 2287 results and,according to PRISMA Group(2009)screening process,21 publications fulfil selection criteria and were included for the review.RESULTS The main radiotherapy technique used consisted in VMAT and IGRT modality.The mainly dose prescription was 55 Gy to high risk volume and 45 Gy as prophylactic volume in 25 fractions given with simultaneous integrated boosts technique(42.85%).The mean pCR was 28.2%with no correlation between dose prescribed and response rates(P value≥0.5).The R0 margins and sphincter preservation rates were 98.88%and 76.03%,respectively.After a mean follow-up of 35 months local control was 92.29%.G3 or higher toxicity was 11.06%with no correlation between dose prescription and toxicities.Patients receiving EQD2 dose>58.9 Gy and BED>70.7 Gy had higher surgical complications rates compared to other group(P value=0.047).CONCLUSION Dose escalation neoadjuvant radiotherapy using innovative techniques is safe for LARC achieving higher rates of pCR.EQD2 doses>58.9 Gy is associated with higher rate of surgical complications.

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.

Efficacy of neoadjuvant chemotherapy for initially resectable colorectal liver metastases:A retrospective cohort study

BACKGROUND The liver is the most common metastatic site of colorectal cancer.Hepatectomy is the mainstay of treatment for patients with colorectal liver metastases(CRLMs).However,there are cases of early recurrence after upfront hepatectomy alone.In selected high-risk patients,neoadjuvant chemotherapy(NAC)may improve longterm survival.AIM To determine the efficacy of NAC for initially resectable CRLMs.METHODS Among 644 patients who underwent their first hepatectomy for CRLMs at our institution,297 resectable cases were stratified into an upfront hepatectomy group(238 patients)and a NAC group(59 patients).Poor prognostic factors for upfront hepatectomy were identified using multivariate logistic regression analysis.Propensity score matching was used to compare clinical outcomes between the upfront hepatectomy and NAC groups,according to the number of poor prognostic factors.Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test.RESULTS Preoperative carcinoembryonic antigen levels(≥10 ng/mL)(P=0.003),primary histological type(other than well/moderately differentiated)(P=0.04),and primary lymph node metastases(≥1)(P=0.04)were identified as independent poor prognostic factors for overall survival(OS)in the upfront hepatectomy group.High-risk status was defined as the presence of two or more risk factors.After propensity score matching,50 patients were matched in each group.Among high-risk patients,the 5-year OS rate was significantly higher in the NAC group(13 patients)than in the upfront hepatectomy group(18 patients)(100%vs 34%;P=0.02).CONCLUSION NAC may improve the prognosis of high-risk patients with resectable CRLMs who have two or more risk factors.

Impact factors of lymph node retrieval on survival in locally advanced rectal cancer with neoadjuvant therapy

BACKGROUND Conventional clinical guidelines recommend that at least 12 lymph nodes shouldbe removed during radical rectal cancer surgery to achieve accurate staging.Thecurrent application of neoadjuvant therapy has changed the number of lymphnode dissection.AIM To investigate factors affecting the number of lymph nodes dissected afterneoadjuvant chemoradiotherapy in locally advanced rectal cancer and to evaluatethe relationship of the total number of retrieved lymph nodes(TLN)with diseasefreesurvival(DFS)and overall survival(OS).METHODS A total of 231 patients with locally advanced rectal cancer from 2015 to 2017 wereincluded in this study.According to the American Joint Committee on Cancer(AJCC)/Union for International Cancer Control(UICC)tumor-node-metastasis(TNM)classification system and the NCCN guidelines for rectal cancer,thepatients were divided into two groups:group A(TLN≥12,n=177)and group B(TLN<12,n=54).Factors influencing lymph node retrieval were analyzed byunivariate and binary logistic regression analysis.DFS and OS were evaluated byKaplan-Meier curves and Cox regression models.RESULTS The median number of lymph nodes dissected was 18(range,12-45)in group A and 8(range,2-11)in group B.The lymph node ratio(number of positive lymphnodes/total number of lymph nodes)(P=0.039)and the interval betweenneoadjuvant therapy and radical surgery(P=0.002)were independent factors ofthe TLN.However,TLN was not associated with sex,age,ASA score,clinical T orN stage,pathological T stage,tumor response grade(Dworak),downstaging,pathological complete response,radiotherapy dose,preoperative concurrentchemotherapy regimen,tumor distance from anal verge,multivisceral resection,preoperative carcinoembryonic antigen level,perineural invasion,intravasculartumor embolus or degree of differentiation.The pathological T stage(P<0.001)and TLN(P<0.001)were independent factors of DFS,and pathological T stage(P=0.011)and perineural invasion(P=0.002)were independent factors of OS.Inaddition,the risk of distant recurrence was greater for TLN<12(P=0.009).CONCLUSION A shorter interval to surgery after neoadjuvant chemoradiotherapy for rectalcancer under indications may cause increased number of lymph nodes harvested.Tumor shrinkage and more extensive lymph node retrieval may lead to a morefavorable prognosis.

Prognostic impact of at least 12 lymph nodes after neoadjuvant therapy in rectal cancer: A meta-analysis

BACKGROUND The number of dissected lymph nodes(LNs)in rectal cancer after neoadjuvant therapy has a controversial effect on the prognosis.AIM To investigate the prognostic impact of the number of LN dissected in rectal cancer patients after neoadjuvant therapy.METHODS We performed a systematic review and searched Pub Med,Embase(Ovid),MEDLINE(Ovid),Web of Science,and Cochrane Library from January 1,2000 until January 1,2020.Two reviewers examined all the publications independently and extracted the relevant data.Articles were eligible for inclusion if they compared the number of LNs in rectal cancer specimens resected after neoadjuvant treatment(LNs≥12 vs LNs<12).The primary endpoints were the overall survival(OS)and disease-free survival(DFS).RESULTS Nine articles were included in the meta-analyses.Statistical analysis revealed a statistically significant difference in OS[hazard ratio(HR)=0.76,95%confidence interval(CI):0.66-0.88,I2=12.2%,P=0.336],DFS(HR=0.76,95%CI:0.63-0.92,I2=68.4%,P=0.013),and distant recurrence(DR)(HR=0.63,95%CI:0.48-0.93,I2=30.5%,P=0.237)between the LNs≥12 and LNs<12 groups,but local recurrence(HR=0.67,95%CI:0.38-1.16,I2=0%,P=0.348)showed no statistical difference.Moreover,subgroup analysis of LN negative patients revealed a statistically significant difference in DFS(HR=0.67,95%CI:0.52-0.88,I2=0%,P=0.565)between the LNs≥12 and LNs<12 groups.CONCLUSION Although neoadjuvant therapy reduces LN production in rectal cancer,our data indicate that dissecting at least 12 LNs after neoadjuvant therapy may improve the patients’OS,DFS,and DR.

Trends with neoadjuvant radiotherapy and clinical staging for those with rectal malignancies

AIM To see how patterns of care changed over time,and how institution type effected these decisions.METHODS A retrospective analysis was performed using the National Cancer Database,looking at all patients that were diagnosed with rectal cancer from 1998 to 2011. We tested differences in rates of treatment and stage migration using χ~2 tests and logistic regression models. RESULTS A review of ninety thousand five hundred and ninety four subjects underwent multimodality therapy for cancer of the rectum. Staging and response to treatment varied greatly between centers. Forty-six percent of the time staging was missing in academic practices,vs fiftyfour percent of the time in community centers(P < 0.001). As a result,twenty-percent were down-staged and eight percent up-staged in academia,whereas only fifteen percent were down-staged and 8% up-staged in community practices(P < 0.001). Forty-two percent of individuals underwent radiation before surgery in 1998.Within two years this increased to fifty-three percent. This increased to eighty-six percent by 2011(P < 0.001). Institution specific treatment varied greatly. Fifty-one percent received therapy before surgery in academic centers in 1998. Thirty-nine percent followed this pattern in the same year in the community(P < 0.001). By 2011,ninety-one percent received radiation before their procedure in academic centers,vs eighty-four percent in the community(P < 0.001). Rates of adoption were better in academia,although an increase was seen in both center types. CONCLUSION From the study dates of 1998 to 2011,preoperative treatment with radiation has been on the rise. There is certainly an increased rate of use of radiation in academia,however,this trend is also seen in the community. Practice patterns have evolved over time,although rates of assigning clinical stage are grossly underreported prior to initiation of preoperative therapy.

Impact of Neoadjuvant Therapy on Body Composition and Prognosis in Rectal Cancer Patients

Objectives The aim of this study was to assess the impact of neoadjuvant chemo-radiotherapy (nCRT) on body composition in patients who subsequently underwent curative surgery for low rectal cancer. Methods Thirty-eight consecutive patients who underwent nCRT and subsequent laparoscopic proctectomy for locally advanced low rectal cancer have been studied. In all patients body composition was measured by computed tomography before and after nCRT. Pathology response on CRT, postoperative short-term outcome, overall and disease-free long-term survival were assessed. Results Twelve patients (31.5%) had skeletal muscle loss 2% after nCRT. No correlation was found between changes in body composition and postoperative complications. Skeletal muscle loss after nCRT significantly correlated with a shorter 5-year disease-free survival. Conclusion Preliminary data suggests that skeletal muscle loss after nCRT negatively impacted on disease-free survival in patients with locally advanced rectal cancer.