Neoadjuvant Chemotherapy Versus Chemoradiotherapy for Locally Advanced Rectal Cancer: A Multicenter Propensity Score-Matched Study.

Locally advanced rectal adenocarcinoma: Treatment sequences, intensification, and rectal organ preservation.

Locally Advanced Rectal Cancer: What Does the Local Treatment Response Tell Us About the Global Picture?

The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Rectal Cancer.

The treatment of rectal cancer has evolved substantially over the past two decades. In the past, rectal cancer was frequently treated with surgery alone, which resulted in high rates of local failure, with significant patient morbidity and mortality. Sentinel trials in the 1980s to early 1990s demonstrated that adjuvant chemoradiotherapy resulted in lower rates of local failure and superior survival versus resection alone [1, 2]. This observation led to the adoption of adjuvant chemoradiotherapy as standard treatment for patients with stage II–III disease. Subsequently, proponents of total mesorectal excision (TME) reported that local regional failure rates were 10% with this approach, bringing the role of radiation therapy into question. However, a large, randomized Dutch trial comparing neoadjuvant radiation therapy alone followed by TME with TME alone showed that despite the superior surgical technique, radiation therapy resulted in a significantly lower rate of local failure. The 2-year local failure rate was 2.4% for patients undergoing preoperative radiation therapy and TME versus 8.2% for patients undergoing TME only (p .001) [3]. The sequencing of radiation therapy relative to surgery has been controversial for several decades. Advocates of preoperative therapy argued that this approach had many benefits, including higher rates of sphincter preservation and better radiation tolerance. In Germany, a large randomized trial (CAO/ARO/AIO-94) comparing preoperative with postoperative chemoradiotherapy confirmed that a preoperative approach resulted in superior treatment compliance, less acute and late toxicity, and a significantly higher rate of local regional control, again simply by altering the sequence of chemoradiotherapy in relationship to surgery [4]. This has led to a new standard of care in the U.S. and Europe in the treatment of stage II–III and selected stage IV rectal cancer patients. The primary disadvantage of preoperative chemoradiotherapy is the potential to irradiate patients with stage I (T1-2 N0) disease. When treated with TME alone, these patients have low rates of local recurrence and any benefit of radiation therapy is limited. Therefore, meticulous pretreatment staging with endoscopic ultrasound (EUS) and/or magnetic resonance imaging (MRI) is important. Despite this, there is still the potential to “upstage” patients who have early-stage disease. This is exemplified in the adjuvant arm of the German rectal trial where 18% of patients staged to have stage II or greater disease by EUS preoperatively were found to have pathologic stage I disease [4]. The integration of thin-section MRI into the pretherapy evaluation of rectal cancer patients likely represents a further refinement in staging accuracy and may potentially spare stage I patients from neoadjuvant therapy. In the hands of experienced endoscopists and radiologists, preoperative EUS and MRI appear to strongly correlate with pathologic stage. As discussed by Drs. Glynne-Jones and Harrison [5], contemporary randomized trials have demonstrated that neoadjuvant chemoradiotherapy produces superior tumor downstaging, pathologic complete response rates, and local control relative to preoperative radiation therapy alone. Therefore, it is logical to assume that, in patients with lowlying rectal cancers, sphincter preservation through downstaging may be achieved in some patients with neoadjuvant therapy, particularly with the knowledge that “historically” large distal margins may not be necessary to obtain durable

PurposeColorectal cancer is the second leading cause of cancer death worldwide. Standard treatments for locally advanced rectal cancer include neoadjuvant chemoradiotherapy and total mesorectal excision (TME), which are associated with significant morbidity. After neoadjuvant therapy, one-third of patients achieve a pathological complete response (pCR) and are eligible for a watch-and-wait approach without TME. The purpose of this study was to determine the potential predictors of pCR before surgery.MethodsThe demographic, clinical, and endoscopic data of 119 patients with primary locally advanced rectal cancer without distant metastasis who underwent restaging endoscopy and TME 6–8 weeks after the end of neoadjuvant therapy were collected. The absence of tumor cells in the histological examination of the TME specimen after neoadjuvant therapy was considered pCR. Binary logistic regression and receiver operating characteristic curves were utilized for analysis.ResultsAccording to the multivariate logistic regression analysis, flattening of marginal tumor swelling (p value < 0.001, odds ratio = 100.605) emerged as an independent predictor of pCR in rectal cancer patients. Additionally, receiver operating characteristic curve analysis revealed that lower preoperative carcinoembryonic antigen and erythrocyte sedimentation rate levels predict pCR, with cutoffs of 2.15 ng/ml and 19.0 mm/h, respectively.ConclusionCarcinoembryonic antigen and erythrocyte sedimentation rate, along with the presence of flattening of marginal tumor swelling, can predict pCR after neoadjuvant chemoradiotherapy in patients with primary rectal cancer. These factors offer a potential method for selecting candidates for conservative treatment based on endoscopic and laboratory findings.

Local excision of rectal cancer afterchemoradiation: feasibility depends on the primary stage

Objective To investigate the feasibility of non-operative management (NOM) by comparing the therapeutic effects between NOM and total mesorectal excision (TME) for rectal cancer patients with clinical complete response (cCR) after neo-adjuvant chemoradiotherapy. Methods A total of 135 patients with stage Ⅱ/Ⅲ rectal cancer who obtained cCR after neo-adjuvant chemoradiotherapy in Sun Yat-sen University Cancer Center from 2006 to 2016 were recruited and assigned into the NOM (n=43) and standard operative management (SOM) groups (n=92). The local recurrence rate, accumulative local control (LC) rate after salvage therapy, disease-free survival (DFS), overall survival (OS) and sphincter preservation rate were statistically compared between two groups. Kaplan-Meier analysis and log-rank test were utilized to calculate the LC, OS and DFS.Chi-square test was performed to calculate the sphincter preservation rate. Results The mean follow-up duration was 39 months (range: 10-127 months). Of 135 patients, the local recurrence rate and distant metastasis rate were 3.7% and 11.1%, and the 3-year DFS and OS were 90.5% and 97.0%.In the NOM and SOM groups, the 3-year DFS were 87% and 93%, and the 5-year DFS were 73% and 87%(P=0.089). The 3-year OS were 98% and 99%, and the 5-year OS were 98% and 97%(P=0.578). In the NOM group, the local recurrence rate was 12%(n=5), 80% of patients received salvage treatment and the accumulative LC rate was calculated as 98%.In the SOM group, the local recurrence rate was 0, which was significantly lower than that in the NOM group (P=0.010). In the NOM group, the sphincter preservation rate was 93%, significantly higher compared with 70% in the SOM group (P=0.030). Conclusions It is feasible for rectal cancer patients with cCR to receive NOM following neo-adjuvant chemoradiotherapy. Partial locally recurrent patients can be healed by timely salvage therapy, thereby averting TME and relevant complications and enhancing the quality of life of rectal cancer patients. Key words: Rectal neoplasm; Neo-adjuvant chemoradiotherapy; Clinical complete response; Follow-up observation

Purpose. The efficacy of laparoscopic total mesorectal excision (TME) in locally advanced rectal cancer has not been demonstrated. The aim of the study is to evaluate the outcome of rectal cancer patients undergoing neoadjuvant chemoradiotherapy followed by laparoscopic TME in our hospital. Methods. Between January 2006 and December 2013, 90 locally advanced rectal cancer patients that underwent neoadjuvant chemoradiotherapy followed by laparoscopic TME were enrolled. The clinicopathological and surgical data of these patients were collected and retrospectively analyzed. Results. Of the 90 patients, 71.1% were men. The mean age of all patients was 59.2 years. The average distance of tumor location from the anal verge was 5.2 cm. The average interval between neoadjuvant chemoradiotherapy completion and surgery was 59 days. Only one patient required conversion (1.11%) to open surgery. Among 90 patients, 80% of the patients underwent sphincter-preserving operation. The 30-day mortality rate was 0%, and the mean hospital stay was 7.2 days. Three patients (3.3%) presented with anastomotic leakage. Local recurrence occurred in three patients (3.3%), whereas distant metastases occurred in 10 patients (11.1%). The 5-year overall survival rate was 75%, and the 5-year disease-free survival rate was 68%. Conclusions. Laparoscopic surgery after neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer is feasible and appropriate. It can provide good short-term clinical and oncological outcomes.

Updates and Debate issues form the surgical treatment of middle or low rectal cancer The main goals for the surgical treatment of rectal cancer were the complete removal of the rectal cancer with surrounding lymphatic draining area, which subsequently result in decreasing the rate of local recurrence as well as prolong patient survival. If the tumor located at the near the anal canal, concerning issues will be whether anal sphincter can be preserved or not and furthermore autonomic pelvic nervous system could be saved or not. Multidisciplinary approach for rectal cancer has been more popular and treatment strategy rapidly changing based on more accurate preoperative local staging finding and minimal invasive surgical techniques become popular too. One of the advance technology is the development of transanal local excision techniques such Transanal endoscopic microsurgery technique such as TEM(transendoscopic microsurgery), TEO(transendoscopic operation) and TAMIS (transanal minimal invasive surgery). Those techniques make us be able to excise early rectal cancer with full thickness as well as unfragmented state, also can be approached to the upper rectum, which can not approach with previous conventional transanal approach method. Local excision for early T1 rectal cancer has been regards as good treatment option because patient can avoid complication related to the radial proctotectomy such as anastomoitc leakage, postoperative sexual and voiding dysfunction and dysregulated bowel movements. Neoadjuvant chemoradiation therapy has been recommended for patient with cT3N0 or cT3 N+ rectal cancer because some clinical trials showed us preoperative chemoradiation therapy showed better local control rate and less toxicities than postoperative chemoradiation treatment. Recent clinical trial both retrospective and prospective showed us a promising results about local excision after neoadjuvant chemoradiation selectively in patients with low rectal cancer. Neoadjuvant chemoradiation therapy for cT2N0 followed by local excision reported excellent oncologic outcomes quite comparable to the radical surgery group. In addition to that, there has been some reports which showed clinical complete remission after neoadjuvant chemoradiation therapy could be wait and see. A couple of observational studies showed wait and see can be possible option of treatment in selective patients. Radial surgery for middle and low rectal cancer still remains a cornerstone of surgical treatment Ultralow anterior resection with or without intersphincteric resection became a more standard surgical method for low rectal cancer. Oncologic and functional outcomes has been reported as safe even functional outcomes study was rare. Furthermore, Abdominoperineal resection has been famous for high intraoperative tumor perforation and positive circumferential resection margin, those factors have been contributed to the high rate of local recurrence and poor survival rate compared with sphincter saving procedures for rectal cancer. Recently, there have been great efforts for reducing theses problem and total levator excision or extended abdominoperineal resection concepts emerged. Surgeons who advocated this concept recommended perineal dissection under the Jack-knife position. Surgical management for low rectal cancer should be directed for radically and preserving function based on multimodality approach. We need more high level of evidence based on prospective clinical trials for tailored treatment of rectal cancer patients

Objective To evaluate the efficacy and safety of neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer (LARC) before surgery. Methods A total of 291 LARC patients who received preoperative chemoradiotherapy and surgery with or without postoperative adjuvant chemotherapy from March 2003 to May 2012 were included in the study. The radiotherapy delivered was two-dimensional conformal radiotherapy (2DRT) and three-dimensional conformal radiotherapy (3 DRT) , and the total dose ranged from 45 to 50 Gy in 23-25 fractions. All the patients received preoperative chemotherapy including FOLFOX6, XELOX, and Xeloda for 2- 4 cycles. Surgery following the principle of total mesorectal excision was performed 3-8 weeks after radiotherapy. Postoperative adjuvant chemotherapy was delivered to 134 patients. The overall survival (OS) , disease-free survival (DFS , relapse-free survival(RFS) , and distant metastasis-free survival (DMFS) were determined using the Kaplan-Meier method, and survival difference analysis and univariate prognostic analysis were performed using the log-rank test. Multivariate prognostic analysis was performed using the Cox proportional hazard model. Results All the patients completed the preoperative neoadjuvant chemoradiotherapy and surgery. The rate of radical resection(R0) was 98.9%, and the sphincter preservation rate was 53.6%. The downstaging rates in tumor (T)stage, node (N) stage, and clinical stage were 73.1%, 83.6%, and 79.4%, respectively. Pathologic complete response rate was 26.8%. Grade 3 adverse hematologic reactions, grade 3 diarrhea, and grade 3radiodermatitis were observed in 7.9%, 7.2% and 2.7% of total patients, respectively. Postoperative perineal pain and delayed wound healing were reported in 12.3% and 8.2% of total patients, respectively. The follow-up rate was 94.5% and the 5-year sample size was 95 patients. The 5-year OS, DFS, RFS, and DMFS were 76.6%, 72.1%, 88.8%, and 79.7%, respectively. The 5-year local recurrence rate and distant metastasis rate were 7.5% and 15.8%, respectively. Multivariate analysis revealed that the postoperative pathological staging was a prognostic influencing factor. Conclusions Preoperative neoadjuvant chemoradiotherapy increases the R0 and sphincter preservation rates, and results in significant tumor downstaging. Treatment-related adverse reactions are moderate and perioperative complications are not increased. The local recurrence rate is low and long-term survival rate is increased. Clinical application of preoperative neoadjuvant chemoradiotherapy as a standard treatment regimen for LARC is highly recommended. Key words: Rectal neoplasms, locally advanced/neoadjuvant chemoradiotherapy; Rectal neoplasms, locally advanced/surgery; Prognosis

Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis

TPS3647 Background: In the treatment of patients with locally advanced very low rectal cancer, neoadjuvant chemoradiotherapy followed by total mesorectal excision (TME) is considered a standard therapeutic approach. Short-course hypofractionated radiotherapy, in combination with subsequent chemotherapy, has been shown to be comparable to long-term chemoradiotherapy in terms of neoadjuvant therapy effects in rectal cancer. Additionally, it has been observed that hypofractionated radiotherapy, when combined with programmed death L-1 (PD-L1) blockade, can enhance the immune response. This study aims to investigate efficacy and safety of organ preservation in patients with locally advanced very low rectal cancer by utilizing total neoadjuvant therapy involving split-course hypofraction radiotherapy in conjunction with CAPOX and Envafolimab (a humanized single-domain anti-PD-L1 antibody fused to an Fc fragment). Methods: TheTRACE-LE trail is an open-label, single-arm, multicenter, phase II trial. The target sample is 72 participants. Key eligibility criteria include individuals aged 18-75, confirmed rectal adenocarcinoma, cT3-4N0/cT1-4N1-2 with lower margin ≤ 2cm from anorectal ring's upper edge (MRI) and ECOG performance status of 0-2. The treatment protocol include preoperative split-course hypofractionated radiotherapy (5×7Gy), in conjunction with 6 cycles of CAPOX chemotherapy and Enverolimab (300 mg subcutaneous injections) administered in a 3-week treatment cycle. The primary outcome measure is organ preservation, specifically the rectum intact, owing to no radical total mesorectal excision (TME), no locoregional regrowth unless amenable to limited, curative (R0) salvage surgery by local excision (LE) and no permanent stoma (including a never reversed protective stoma, or a stoma owing to toxicities and/or poor functional outcomes). The secondary outcome measures encompass ypT0-1 rate, pathological complete response (pCR) rate, acute and late toxicity as per NCICTCAE V.5.0, local recurrence rate, local regional recurrence rate, disease-free survival, quality of life, and anorectal function. Clinical trial information: NCT05970900 .

Objective To evaluate the efficacy and safety of adding neoadjuvant chemotherapy following neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer. Methods A total of 80 patients confirmed with locally advanced rectal cancer were enrolled during January 2012 and December 2015 in Guizhou Medical University Affiliated Cancer Hospital and were randomized with the method of lottery into the experimental group and the control group. In the experimental group, 40 patients received 4 cycles of FOLFOX4 after chemoradiotherapy and then had total mesorectal excision (TME). Another 4 cycles of FOLFOX4 were administered after surgery. In the control group, 40 patients had TME surgery 6-8 weeks after chemoradiotherapy and received 8 cycles of FOLFOX4 as adjuvant chemotherapy. Pelvic radiotherapy dose was 50 Gy in 25 fractions, 5 days per week for 5 weeks. 5-Fu continuous infusion was administered throughout radiotherapy. The pCR rate, downstaging rate, R0 resection rate, local recurrence rate, distant metastasis rate, survival rate, incidence of toxicities, surgical complications and completion of treatment were observed. Results The pCR rate was 20.0% in the experimental group and 5.0% in the control group (χ2=4.114, P 0.05). No statistically significant difference was observed in R0 resection rate, 3-year local recurrence rate, 3-year distant metastasis rate and 3-year survival rate between the two groups (P>0.05). Patients in the experimental group had higher completion rate of 8 cycles of systemic chemotherapy (87.1% vs. 61.5%, χ2=4.985, P<0.05). No statistically significant difference was observed in acute toxicities and postoperative complications. Conclusions Adding systemic chemotherapy after neoadjuvant chemoradiotherapy for locally advanced rectal cancer has significantly higher pCR rate and lower toxicities and side events compared with chemoradiotherapy alone. Longer follow-up and larger scale of clinical research are needed. Trial registration Chinese clinical trial registry, ChiCTR-IPR-17010454. Key words: Locally advanced rectal Cancer; Chemoradiotherapy; Neoadjuvant chemotherapy; Rate of pathologic complete response; Overall survival

Objective to evaluate the safety and efficacy of neoadjuvant radiotherapy and neoadjuvant chemoradiotherapy combined with total mesorectal excision (TME) in the treatment for locally advanced rectal cancer. Methods Database including PubMed, ovid, Cochrane library, Chinese biomedical literature database ( CBM ), CNKI and Wanfang were retrieved from 2002 to 2017 on neoadjuvant therapy combined with TME surgery for locally advanced rectal cancer.The quality of the literatures that met the inclusion criteria were evaluated. Revman 5.0 software was used to examine the heterogeneity and meta-analysis was performed. Results A total of 4 randomized controlled trials involving 2272 rectal cancer patients were included in the study. There were 1133 patients in the neoadjuvant chemoradiotherapy group and 1139 patients in the neoadjuvant radiotherapy group. Compared with the neoadjuvant chemoradiotherapy y group, the complete pathological remission rate was lower in neoadjuvant radiotherapy group (OR=0.32, 95 % CI: 0.22-0.44, P<0.05 ), with higher 5-years local recurrence rate (OR=2.13, 95 % CI: 1.62-2.79, P<0.05 ), however with less serious adverse reactions (OR=0.38, 95 % CI: 0.17-0.82, P=0.01), with statistically significant difference. However, there was no significant difference of anus-preserving rate, postoperative complication rate, 5-years disease-free survival rate and overall survival rate. Conclusion Neoadjuvant chemoradiotherapy is generally superior to neoadjuvant radiotherapy alone in the treatment for advanced rectal cancer, but it is still necessary to choose a suitable neoadjuvant treatment plan according to the patient’s tolerance in clinical application. Key words: Rectal Neoplasms; Mesentery; Radiotherapy, Adjuvant; Chemotherapy, Adjuvant; Meta-Analysis

The use of robotic surgery and neoadjuvant chemoradiation therapy (CRT) for rectal cancer is increasing steadily worldwide. However, there are insufficient data on long-term outcomes of robotic surgery in this clinical setting. The aim of this study was to compare the 5-year oncological outcomes of laparoscopic vs. robotic total mesorectal excision for mid-low rectal cancer after neoadjuvant CRT. One hundred thirty-eight patients who underwent robotic (n=74) or laparoscopic (n=64) resections between January 2006 and December 2010 for mid and low rectal cancer after neoadjuvant CRT were identified from a prospective database. The long-term oncological outcomes of these patients were analyzed using prospective follow-up data. The median follow-up period was 56.1±16.6months (range 11-101). The 5-year overall survival (OS) rate of the laparoscopic and robotic groups was 93.3 and 90.0%, respectively, (p=0424). The 5-year disease-free survival (DFS) rate was 76.0% (laparoscopic) vs. 76.8% (robotic) (p=0.834). In a subgroup analysis according to the yp-stage (complete pathologic response, yp-stage I, yp-stage II, or yp-stage III), the between-group oncological outcomes were not significantly different. The local recurrence rate was 6.3% (laparoscopic, n=4) vs. 2.7% (robotic, n=2) (p=0.308). The systemic recurrence rate was 15.6% (laparoscopic, n=10) vs. 18.9% (robotic, n=14) (p=0.644). All recurrences occurred within less than 36months in both groups. The median period of recurrence was 14.2months. Robotic surgery for rectal cancer after neoadjuvant CRT can be performed safely, with long-term oncological outcomes comparable to those obtained with laparoscopic surgery. More large-scale studies and long-term follow-up data are needed.