Immunotherapy in the neoadjuvant chemoradiotherapy for locally advanced rectal cancer / 中华放射肿瘤学杂志

Long-course concurrent chemoradiotherapy (CCRT) or short-course radiotherapy (SCRT) prior to surgery and postoperative chemotherapy is one of the main standard therapies for patients with locally advanced rectal cancer (LARC). On this basis, total neoadjuvant therapy (TNT) has been shown to improve disease-free survival, distant metastasis-free survival and complete response rates, whereas the 3-year distant recurrence rate is still above 20% and pathological complete response (pCR) is less than 30%. Long-term survival and adverse reactions remain to be improved. Currently, significant achivement has been obtained in immunotherapy. Application of immunotherapy in the treatment of rectal cancer remains to be urgently validated. In recent years, immunotherapy combined with preoperative chemoradiotherapy has been adopted for LARC in clinical trials. Besides, immunotherapy alone, especially programmed death-1 (PD-1) / programmed death ligand-1 (PD-L1) inhibitor, has also been utilized to treat colon rectal cancer. Relevant research progress was reviewed in this article.

Research progress on neoadjuvant chemoradiotherapy combined with immunotherapy in locally advanced rectal cancer / 中华放射肿瘤学杂志

For locally advanced (T 3-4/N +M 0) rectal cancer (LARC), neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) is the standard treatment, which have been demonstrated to decrease the local recurrence rate and increase the tumor response grade. However, the distant metastasis remains an unresolved issue. Radiotherapy and immunotherapy can supplement each other and the combination of the two treatments has a good theoretical basis. Recently, multiple clinical trials are ongoing in terms of the combination of nCRT and immunotherapy in LARC. These trials have achieved promising short-term efficacy in both microsatellite instability-high (MSI-H) and microsatellite stable (MSS) rectal cancers, which could further improve the rate of tumor response and rate of pathological complete response, increase the possibility of organ preservation and "watch and wait" approach. Large-scale clinical trials need to be performed in the future to demonstrate these findings and to improve long-term prognosis.

[Efficacy and safety of total neoadjuvant therapy versus neoadjuvant chemoradiotherapy in the treatment of locally advanced rectal cancer: a meta-analysis].

Objective: To systematically evaluate the efficacy and safety of total neoadjuvant therapy (TNT) in the comprehensive treatment of locally advanced rectal cancer. Methods: Literatures were screened from PubMed, Embase, Web of Science, Cochrane Library, CBM, Wanfang Data, VIP and CNKI from the inception date to May 2021 to collect the randomized controlled clinical trials (RCTs) of TNT followed by total mesorectal excision (TME) versus neoadjuvant chemotherapy (nCRT) followed by TME in the treatment of locally advanced rectal cancer. The data of overall survival, disease-free survival, R0 radical resection rate, pathological complete response (pCR) rate, T downstaging rate, the incidence of adverse events ≥ grade III, including neutropenia, nausea and vomiting, diarrhea, radiation dermatitis and nervous system toxicity, and the morbidity of complications within postoperative 30 days of the two groups were extracted from the included literatures. Review Manager 5.3 software was utilized for statistical meta-analysis. Results: Nine RCTs were finally enrolled including 2430 patients. Meta-analysis results showed that compared with nCRT group, patients in TNT group had longer overall survival (HR=0.80, 95%CI: 0.65-0.97, P=0.03) and higher pCR rate (RR=1.73, 95%CI: 1.44-2.08, P<0.01) with significant differences. Besides, there were no significant differences between two groups in disease-free survival (HR=0.86, 95%CI:0.71-1.05, P=0.14), R0 radical resection rate (RR=1.02, 95%CI: 0.99-1.06, P=0.17) and T downstaging rate (RR=1.04, 95%CI: 0.89-1.22, P=0.58) between two groups. In terms of treatment safety, the incidence of adverse events ≥ grade III (RR=1.09, 95%CI: 0.70-1.70, P=0.70) and morbidity of complications within postoperative 30 days (RR=1.07, 95%CI: 0.97-1.18, P=0.19) did not significantly differ between two groups. Conclusions: In the treatment of locally advanced rectal cancer, TNT may bring more survival benefits than nCRT and does not increase the incidence of adverse events and postoperative complications. Therefore, TNT could be used as a recommended treatment for patients with locally advanced rectal cancer.

Efficacy and safety of total neoadjuvant therapy versus neoadjuvant chemoradiotherapy in the treatment of locally advanced rectal cancer: a meta-analysis / 中华胃肠外科杂志

Objective: To systematically evaluate the efficacy and safety of total neoadjuvant therapy (TNT) in the comprehensive treatment of locally advanced rectal cancer. Methods: Literatures were screened from PubMed, Embase, Web of Science, Cochrane Library, CBM, Wanfang Data, VIP and CNKI from the inception date to May 2021 to collect the randomized controlled clinical trials (RCTs) of TNT followed by total mesorectal excision (TME) versus neoadjuvant chemotherapy (nCRT) followed by TME in the treatment of locally advanced rectal cancer. The data of overall survival, disease-free survival, R0 radical resection rate, pathological complete response (pCR) rate, T downstaging rate, the incidence of adverse events ≥ grade III, including neutropenia, nausea and vomiting, diarrhea, radiation dermatitis and nervous system toxicity, and the morbidity of complications within postoperative 30 days of the two groups were extracted from the included literatures. Review Manager 5.3 software was utilized for statistical meta-analysis. Results: Nine RCTs were finally enrolled including 2430 patients. Meta-analysis results showed that compared with nCRT group, patients in TNT group had longer overall survival (HR=0.80, 95%CI: 0.65-0.97, P=0.03) and higher pCR rate (RR=1.73, 95%CI: 1.44-2.08, P<0.01) with significant differences. Besides, there were no significant differences between two groups in disease-free survival (HR=0.86, 95%CI:0.71-1.05, P=0.14), R0 radical resection rate (RR=1.02, 95%CI: 0.99-1.06, P=0.17) and T downstaging rate (RR=1.04, 95%CI: 0.89-1.22, P=0.58) between two groups. In terms of treatment safety, the incidence of adverse events ≥ grade III (RR=1.09, 95%CI: 0.70-1.70, P=0.70) and morbidity of complications within postoperative 30 days (RR=1.07, 95%CI: 0.97-1.18, P=0.19) did not significantly differ between two groups. Conclusions: In the treatment of locally advanced rectal cancer, TNT may bring more survival benefits than nCRT and does not increase the incidence of adverse events and postoperative complications. Therefore, TNT could be used as a recommended treatment for patients with locally advanced rectal cancer.

[Short-term outcome of programmed cell death protein1 (PD-1) antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced middle-low rectal cancer with high risk factors].

Objective: Total neoadjuvant chemoradiotherapy is one of the standard treatments for locally advanced rectal cancer. This study aims to investigate the safety and feasibility of programmed cell death protein 1 (PD-1) antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced middle-low rectal cancer with high-risk factors. Methods: A descriptive cohort study was conducted. Clinicopathological data of 24 patients with locally advanced middle-low rectal cancer with high-risk factors receiving PD-1 antibody combined with neoadjuvant chemoradiotherapy in Gastrointestinal Cancer Center, Unit III, Peking University Cancer Hospital between January 2019 and April 2021 were retrospectively analyzed. Inclusion criteria: (1) rectal adenocarcinoma confirmed by pathology; patient age of ≥ 18 years and ≤ 80 years; (2) the distance from low margin of tumor to anal verge ≤ 10 cm under sigmoidoscopy; (3) ECOG performance status score 0-1; (4) clinical stage T3c, T3d, T4a or T4b, or extramural venous invasion (EMVI) (+) or mrN2 (+) or mesorectal fasciae (MRF) (+) based on MRI; (5) no evidence of distant metastases; (6) no prior pelvic radiation therapy, no prior chemotherapy or surgery for rectal cancer; (7) no systemic infection requiring antibiotic treatment and no immune system disease. Exclusion criteria: (1) anticipated unresectable tumor after neoadjuvant treatment; (2) patients with a history of a prior malignancy within the past 5 years, or with a history of any arterial thrombotic event within the past 6 months; (3) patients received other types of antitumor or experimental therapy; (4) women who were pregnant or breast-feeding; (5) patients with any other concurrent medical or psychiatric condition or disease; (6) patients received immunotherapy (PD-1 antibody). The neoadjuvant therapy consisted of three stages: PD-1 antibody (sintilimab 200 mg, IV, Q3W) combined with CapeOx regimen for three cycles; long-course intensity modulated radiation therapy (IMRT) with gross tumor volume (GTV) 50.6 Gy/CTV 41.8 Gy/22f; CapeOx regimen for two cycles after radiotherapy. After oncological evaluation following the end of the third stage of treatment, surgery or watch and wait would be carried out. Surgical safety, histopathological changes and short-term oncological outcome were analyzed. Results: There were 15 males and 9 females with a median age of 65 (47-78) years. Median distance from the lower margin of the tumor to the anal verge was 4 (3-7) cm. The median maximal diameter of the tumor was 5.1 (2.1-7.5) cm. Twenty patients were cT3, 4 were cT4, 8 were cN1, 5 were cN2a, 11 were cN2b. Ten cases were MRF (+) and 10 were EMVI (+). All the patients were mismatch repair proficient (pMMR). During the neoadjuvant treatment period, 6 patients (25.0%) developed grade 1-2 treatment-related adverse events, including 3 immune-related adverse events. As of April 30, 2021, 20 patients (83.3%, 20/24) had received surgical resection, including 19 R0 resections and 16 sphincter-preservation operations. Morbidity of postoperative complication was 25.0% (5/20), including 2 cases of Clavien-Dindo grade II (1 of anastomotic bleeding and 1 of pseudomembranous enteritis), 3 cases of grade I anastomotic stenosis. Pathological complete response (pCR) rate was 30.0% (6/20) and major pathological response rate was 20.0% (4/20). None of Ras/Raf mutants had pCR or cCR (0/5), while 6 of 17 Ras/Raf wild-type patients had pCR and 3 had cCR, which was significantly higher than that of Ras/Raf mutants (P<0.01). Nine of 16 patients with Ras/Raf wild-type and differentiated adenocarcinoma had pCR or cCR. Among other 4 patients without surgery, 3 patients preferred watch and wait strategy because their tumors were assessed as clinical complete response (cCR), while another one patient refused surgery as the tumor remained stable. After a median follow-up of 11 (6-24) months, only 1 patient with signet ring cell carcinoma had recurrence. Conclusions: PD-1 antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced rectal cancer has quite good safety and histopathological regression results. Combination of histology and genetic testing is helpful to screen potential beneficiaries.

[Predictive value of combination of MRI tumor regression grade and apparent diffusion coefficient for pathological complete remission after neoadjuvant treatment of locally advanced rectal cancer].

Objective: Pelvic high-resolution magnetic resonance imaging (MRI) has now become a standard method for evaluating the efficacy of neoadjuvant treatment for locally advanced rectal cancer (LARC). However, this traditional morphological qualitative assessment method based on T2-weighted imaging (T2WI) is not effective in predicting pathological complete remission (pCR). The purpose of this study is to investigate whether combining the magnetic resonance tumor regression grade (mrTRG) with apparent diffusion coefficient (ADC) can improve diagnostic value for pCR after preoperative neoadjuvant chemoradiotherapy (nCRT) of LARC. Methods: This was a diagnostic study. Clinicopathological data of 134 LARC patients who received nCRT and radical surgery in the First Affiliated Hospital of Kunming Medical University from January 2017 to December 2019 were retrospectively analyzed. All the patients underwent MRI which included T2WI and DWI sequences before and 8 weeks after nCRT. Two radiologists independently drew ROIs on T2WI and DWI to estimate mrTRG stage and calculate the mean ADC value. Receiver operating characteristics (ROC) method was applied to evaluate the predict value of mrTRG combined with mean ADC value for pCR. Results: Of 134 LARC patients, 85 were male and 49 were female with median age of 58 (28-82) years. After nCRT, MRI suggested 21 patients (15.7%) had clinical complete remission (cCR), e.g. mrTRG stage 1-2. Postoperative pathology revealed 31 (23.1%) patients had pCR. The evaluations of mrTRG and ADC value by the two readers were highly consistent, and the intra-group correlation coefficients were 0.83 (95% CI: 0.703-0.881) and 0.96 (95% CI: 0.989-0.996), respectively. There was a negative correlation between mrTRG and pCR (r(s)=-0.505, P<0.01), and a positive correlation between mean ADC value and pCR (r(s)=0.693, P<0.01). The ROC curve showed that mrTRG alone had a medium predictive value for pCR, with an area under the curve (AUC) of 0.832 (95% CI: 0.743-0.921); the mean ADC value had a higher predictive value for pCR, with AUC of 0.906 (95% CI: 0.869-0.962). The predictive value of the combined model of mrTRG and ADC value for pCR was significantly better than that of mrTRG alone (P=0.015), and the AUC was 0.908 (95% CI: 0.849-0.968). Conclusion: Both mrTRG and mean ADC value can be non-invasive methods to predict the efficacy of nCRT for LARC. Combining the mean ADC value with mrTRG can result in better pCR prediction.

Short-term outcome of programmed cell death protein1 (PD-1) antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced middle-low rectal cancer with high risk factors / 中华胃肠外科杂志

Objective: Total neoadjuvant chemoradiotherapy is one of the standard treatments for locally advanced rectal cancer. This study aims to investigate the safety and feasibility of programmed cell death protein 1 (PD-1) antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced middle-low rectal cancer with high-risk factors. Methods: A descriptive cohort study was conducted. Clinicopathological data of 24 patients with locally advanced middle-low rectal cancer with high-risk factors receiving PD-1 antibody combined with neoadjuvant chemoradiotherapy in Gastrointestinal Cancer Center, Unit III, Peking University Cancer Hospital between January 2019 and April 2021 were retrospectively analyzed. Inclusion criteria: (1) rectal adenocarcinoma confirmed by pathology; patient age of ≥ 18 years and ≤ 80 years; (2) the distance from low margin of tumor to anal verge ≤ 10 cm under sigmoidoscopy; (3) ECOG performance status score 0-1; (4) clinical stage T3c, T3d, T4a or T4b, or extramural venous invasion (EMVI) (+) or mrN2 (+) or mesorectal fasciae (MRF) (+) based on MRI; (5) no evidence of distant metastases; (6) no prior pelvic radiation therapy, no prior chemotherapy or surgery for rectal cancer; (7) no systemic infection requiring antibiotic treatment and no immune system disease. Exclusion criteria: (1) anticipated unresectable tumor after neoadjuvant treatment; (2) patients with a history of a prior malignancy within the past 5 years, or with a history of any arterial thrombotic event within the past 6 months; (3) patients received other types of antitumor or experimental therapy; (4) women who were pregnant or breast-feeding; (5) patients with any other concurrent medical or psychiatric condition or disease; (6) patients received immunotherapy (PD-1 antibody). The neoadjuvant therapy consisted of three stages: PD-1 antibody (sintilimab 200 mg, IV, Q3W) combined with CapeOx regimen for three cycles; long-course intensity modulated radiation therapy (IMRT) with gross tumor volume (GTV) 50.6 Gy/CTV 41.8 Gy/22f; CapeOx regimen for two cycles after radiotherapy. After oncological evaluation following the end of the third stage of treatment, surgery or watch and wait would be carried out. Surgical safety, histopathological changes and short-term oncological outcome were analyzed. Results: There were 15 males and 9 females with a median age of 65 (47-78) years. Median distance from the lower margin of the tumor to the anal verge was 4 (3-7) cm. The median maximal diameter of the tumor was 5.1 (2.1-7.5) cm. Twenty patients were cT3, 4 were cT4, 8 were cN1, 5 were cN2a, 11 were cN2b. Ten cases were MRF (+) and 10 were EMVI (+). All the patients were mismatch repair proficient (pMMR). During the neoadjuvant treatment period, 6 patients (25.0%) developed grade 1-2 treatment-related adverse events, including 3 immune-related adverse events. As of April 30, 2021, 20 patients (83.3%, 20/24) had received surgical resection, including 19 R0 resections and 16 sphincter-preservation operations. Morbidity of postoperative complication was 25.0% (5/20), including 2 cases of Clavien-Dindo grade II (1 of anastomotic bleeding and 1 of pseudomembranous enteritis), 3 cases of grade I anastomotic stenosis. Pathological complete response (pCR) rate was 30.0% (6/20) and major pathological response rate was 20.0% (4/20). None of Ras/Raf mutants had pCR or cCR (0/5), while 6 of 17 Ras/Raf wild-type patients had pCR and 3 had cCR, which was significantly higher than that of Ras/Raf mutants (P<0.01). Nine of 16 patients with Ras/Raf wild-type and differentiated adenocarcinoma had pCR or cCR. Among other 4 patients without surgery, 3 patients preferred watch and wait strategy because their tumors were assessed as clinical complete response (cCR), while another one patient refused surgery as the tumor remained stable. After a median follow-up of 11 (6-24) months, only 1 patient with signet ring cell carcinoma had recurrence. Conclusions: PD-1 antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced rectal cancer has quite good safety and histopathological regression results. Combination of histology and genetic testing is helpful to screen potential beneficiaries.

Predictive value of combination of MRI tumor regression grade and apparent diffusion coefficient for pathological complete remission after neoadjuvant treatment of locally advanced rectal cancer / 中华胃肠外科杂志

Objective: Pelvic high-resolution magnetic resonance imaging (MRI) has now become a standard method for evaluating the efficacy of neoadjuvant treatment for locally advanced rectal cancer (LARC). However, this traditional morphological qualitative assessment method based on T2-weighted imaging (T2WI) is not effective in predicting pathological complete remission (pCR). The purpose of this study is to investigate whether combining the magnetic resonance tumor regression grade (mrTRG) with apparent diffusion coefficient (ADC) can improve diagnostic value for pCR after preoperative neoadjuvant chemoradiotherapy (nCRT) of LARC. Methods: This was a diagnostic study. Clinicopathological data of 134 LARC patients who received nCRT and radical surgery in the First Affiliated Hospital of Kunming Medical University from January 2017 to December 2019 were retrospectively analyzed. All the patients underwent MRI which included T2WI and DWI sequences before and 8 weeks after nCRT. Two radiologists independently drew ROIs on T2WI and DWI to estimate mrTRG stage and calculate the mean ADC value. Receiver operating characteristics (ROC) method was applied to evaluate the predict value of mrTRG combined with mean ADC value for pCR. Results: Of 134 LARC patients, 85 were male and 49 were female with median age of 58 (28-82) years. After nCRT, MRI suggested 21 patients (15.7%) had clinical complete remission (cCR), e.g. mrTRG stage 1-2. Postoperative pathology revealed 31 (23.1%) patients had pCR. The evaluations of mrTRG and ADC value by the two readers were highly consistent, and the intra-group correlation coefficients were 0.83 (95% CI: 0.703-0.881) and 0.96 (95% CI: 0.989-0.996), respectively. There was a negative correlation between mrTRG and pCR (r(s)=-0.505, P<0.01), and a positive correlation between mean ADC value and pCR (r(s)=0.693, P<0.01). The ROC curve showed that mrTRG alone had a medium predictive value for pCR, with an area under the curve (AUC) of 0.832 (95% CI: 0.743-0.921); the mean ADC value had a higher predictive value for pCR, with AUC of 0.906 (95% CI: 0.869-0.962). The predictive value of the combined model of mrTRG and ADC value for pCR was significantly better than that of mrTRG alone (P=0.015), and the AUC was 0.908 (95% CI: 0.849-0.968). Conclusion: Both mrTRG and mean ADC value can be non-invasive methods to predict the efficacy of nCRT for LARC. Combining the mean ADC value with mrTRG can result in better pCR prediction.

[Role of radiotherapy in watch and wait strategy after neoadjuvant trerapy for rectal cancer].

For locally advanced (T3-4/N+M0) rectal cancer (LARC), radiation-based neoadjuvant therapy followed by total mesorectal excision (TME) is the standard treatment. For those who achieved clinical complete response (cCR), a non-operative management called "watch and wait" (W&W) strategery can preserve organ function and improve the life quality. For W&W strategy, radiotherapy is still the core part of neoadjuvant therapy. To increase the tumor response grade and cCR rate is the goal of optimized neoadjuvant regimens. In this review, we summarized the role of radiotherapy in the W&W strategy and discussed the advances of optimized radiation-based neoadjuvant therapy to achieve higher cCR rate, including new radiosensitizing agents, induction and consolidation chemotherapy, combination with immunotherapy, and prolonged interval time. All of the above efforts aim to improve patient survival and quality of life.

[Comparison of long-term efficacy between watch and wait strategy and total mesorectal excision in locally advanced rectal cancer patients with clinical complete response after neoadjuvant therapy].

Objective: To compare long-term efficacy between watch and wait (W&W) strategy and total mesorectal excision (TME) in patients who were diagnosed with locally advanced rectal cancer (LARC) and attained clinical complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT). Methods: A retrospective cohort study was carried out. A total of 238 patients with stage II-III LARC exhibiting cCR after nCRT in Sun Yat-sen University Cancer Center from September 16, 2010 to January 9, 2018 were enrolled. Patients who were diagnosed with other malignant tumor within 5 years, did not receive regular follow-up in our center for more than 1 year and had no complete examination items after nCRT were excluded. Of 238 patients, 151 were male and 87 were female with a median age of 57 (27-83) years old. According to TNM stage, 61 cases were cII, 177 cases were cIII. Concurrent chemoradiotherapy (CCRT) was performed in 20 patients. CCRT plus induction/consolidated chemotherapy was performed in 218 patients. Intensity-modulated radiotherapy (IMRT) was applied to radiotherapy. The median radiation dose was 50 Gy/25 Fr for both the primary tumor and clinical target volumes, and the total dose was 45.0 to 50.6 Gy for 227 patients. In 27 patients, single-agent fluorouracil or capecitabine was used as concurrent chemotherapy. But in the other 211 patients, a combined regimen of oxaliplatin and fluorouracil or capecitabine was used. After nCRT, 59 and 179 patients received W&W (W&W group) and TME 6-12 weeks later (TME group), respectively. After the ending of treatment, patient was interviewed one time every 3 months and after 3 years, one time every six months. Overall survival (OS) rate, distant-metastasis-free survival (DMFS) rate, and local-recurrence-free survival (LRFS) rate were compared between two groups. The salvage treatment and sphincter preservation rate were analyzed. The survival curve was drawn with Kaplan-Meier method and evaluated by log-rank method. Results: In the cases treated with TME, the median interval from nCRT to surgery was 59 days. The postoperative pCR rate was 63.1%(113/179). The median follow-up time of the whole cohort was 41.8 (12.0-99.0) months. The 3-year and 5-year OS rates were 98.4% and 96.5%; the 3-year and 5-year LRFS rates were 96.5% and 96.5%; the 3- and 5-year DMFS rates were 91.0% and 87.9%, respectively. The 3-year OS rates in the W&W group and the TME group were 100% and 97.9%; the 5-year OS rates in W&W group and the TME group were 90.6% and 97.9% (P=0.339); The 3-year local recurrence rate (LRR) in the W&W group was 12.9% (7 cases recurred within 2 years), which was significanthy higher then that in the TME group (0.6%, P=0.003). Salvage surgery was successful in 5/6 cases. After salvage surgery, LRFS rate was not significantly different between the two groups (P=0.137). The 3-year DMFS rate in the W&W group and the TME group were 88.4% and 81.1%, whose difference was not significant (P=0.593). Recurrence with simultaneous metastasis was seen in 3/7 cases of the W&W group. The sphincter was preserved in 89.8% (53/59) of patients in the W&W group, which was significantly higher than 73.7% (132/179) in the TME group (P<0.001). When distance of tumor from the anal verge was ≤ 5 cm, the sphincter preservation rate (SPR) in the W&W group was 88.0% (44/50), which was significantly higher than the 54.4% (56/103) in the TME group (P<0.001). Conclusions: W&W is safe and feasible for patients with LARC and cCR after nCRT. The results should be verified by further clinical trials.

[Comparison of short-term efficacy and perioperative safety between neoadjuvant therapy and total neoadjuvant therapy in patients with locally advanced rectal cancer].

Objective: To compare the short-term efficacy and perioperative safety of neoadjuvant chemoradiotherapy (nCRT) with total neoadjuvant treatment (TNT) in patients with locally advanced rectal cancer (LARC). Methods: A retrospective cohort analysis was carried out. Inclusion criteria: (1) rectal adenocarcinoma confirmed by pathology with a distance from tumor inferior border to anal verge within 12 cm; (2) clinical stage cT3-4N0 or cT1-4N1-2 diagnosed by magnetic resonance imaging (MRI) or endorectal ultrasonography; (3) a single rectal tumor confirmed by colonoscopy; (4) patients suitable for chemoradiotherapy; (5) no previous history of other tumors. Exclusion criteria: (1)patients with previous rectal cancer surgery and local recurrence; (2) those who did not complete nCRT course; (3) those with distant metastases; (4) those with defective clinicopathological data. According to the above criteria, a total of 134 LARC patients at the Department of General Surgery of Beijing Chaoyang Hospital from January 2016 to January 2019 were enrolled, including 82 males and 52 females, with a male-female ratio of 1.58∶1.00 and mean age of (59.6±11.2) (26-81) years. Based on neoadjuvant regimen, patients were divided into nCRT group (n=55) and TNT group (n=79). There were no statistically significant differences in baseline data, such as age, sex, distance from tumor to anal verge, Eastern Cooperative Oncology Group (ECOG) performance status and clinical TNM stage, between the two groups (all P>0.05). All the patients received pelvic intensity-modulated radiotherapy (IMRT) with a total dose of 50.4 Gy in 28 fractions. Patients in nCRT group received oral capecitabine chemotherapy during radiotherapy and underwent surgery 6-8 weeks after chemoradiation. Patients in TNT group received one cycle of induction CapeOX (oxaliplatin and capecitabine) and concurrent chemoradiotherapy, then underwent a radical surgery two weeks after completion of consolidation chemotherapy. The efficacy of neoadjuvant therapy, adverse events of chemoradiotherapy and perioperative safety were compared between the two groups. Results: Patients of two groups completed the course of neoadjuvant therapy. There were no statistically significant differences between nCRT group and TNT group in the incidence of adverse events in neutropenia [7.3% (4/55) vs. 10.1% (8/79)], anemia [3.6% (2/55) vs. 3.8% (3/79)], thrombocytopenia [5.5% (3/55) vs. 7.6% (6/79)], gastrointestinal dysfunction [3.6% (2/55) vs. 6.3% (5/79)] and radiation enteritis [9.1% (5/55) vs. 8.9% (7/79)] (all P>0.05). One hundred and thirty patients completed TME surgery, including 54 patients in nCRT group and 76 patients in the TNT group. Compared with the nCRT group, the proportion of abdominoperineal resection (APR) was higher in the TNT group [31.6% (25/76) vs. 13.0% (7/54), χ(2)=9.382, P=0.009]. No statistically significant differences in morbidity of postoperative complication, operation time, intraoperative blood loss and postoperative hospital stay between the two groups were found (all P>0.05). The distal and circumferential margins were negative in all the patients. Seventeen patients in the TNT group 22.4% (17/76) got pathologic complete response (pCR), which was significantly higher than 7.4% (4/54) in nCRT group (χ(2)=5.217, P=0.022). There were no statistically significant differences in ypTNM classification, perineural invasion and venous invasion between the two groups (all P>0.05). Conclusion: The pCR of TNT is higher than that of nCRT without increasing the incidence of toxicity and complications of radiotherapy and chemotherapy for patients with locally advanced rectal cancer.

[The significance of lymph node yield in rectal cancer after neoadjuvant chemotherapy].

Neoadjuvant therapy has become an indispensable part of the treatment in locally advanced mild-low rectal cancer. Neoadjuvant therapy can cause the regression of the tumor body as well as drainage lymph nodes, which may influence the size, number, and metastatic status of the lymph nodes. In clinical practice, the total number of lymph nodes detected in rectal cancer treated with neoadjuvant therapy were significantly decreased, making it difficult to meet the standard of the NCCN guideline that at least 12 regional lymph nodes should be harvested. The optimal detection of yielded lymph nodes in rectal cancer is essential for accurate staging, response assessment, and adjuvant treatment decision. The lymph node diameter is significantly reduced after neoadjuvant therapy in locally advanced rectal cancer. In general, the number of detected lymph nodes is significantly reduced without additional pathological examination. The detected lymph nodes would increase by deliberate pathological examination, improvement of the detection method, or using a lymph node tracer. However, whether the number of detected lymph nodes is still needed to meet the requirements of the NCCN guideline, and the relationship between the number of detected lymph nodes and the prognosis are still controversial. At present, the number of negative lymph nodes, LNR, LODDS, etc. can be also used to predict prognosis in addition to ypN staging. For patients with ypN0 and ypN+ stage, different evaluation methods can be selected. For patients with ypN0, the number of detected lymph nodes still has important clinical significance for the prognosis and treatment decision. This article will introduce the related issues, and provide more evidence-based diagnosis and treatment practice.

[Rational evaluation of the complete response after neoadjuvant therapy in locally advanced mid-low rectal cancer: the pros and cons of "watch and wait" strategy].

Neoadjuvant chemoradiotherapy plus total mesorectal excision (TME) is the standard care for locally advanced middle-low rectal cancer. Some patients could benefit from neoadjuvant chemoradiotherapy to achieve clinical complete response (cCR). Therefore, in recent years, for patients with cCR after neoadjuvant therapy, the "watch and wait" strategy has been widely recommended by their doctors to let them enter "waiting period" without surgery, so that the quality of life is improved. However, the "watch and wait" strategy also has many practical problems that have not been resolved. Firstly, the diagnostic criteria for cCR and pathologic complete response (pCR) are not uniform and different significantly. Secondly, some cCR patients have found tumor regrowth and subsequently underwent salvage surgery during the "watch and wait" period. Thirdly, there is no clinical consensus on the adjuvant therapy for patients during the "watch and wait" period. Fourthly, the role of surgery in patients with cCR is controversial. Finally, we need to accumulate more clinical evidence to confirm whether the "watch and wait" strategy can be selected immediately after achieving cCR for rectal cancer. At the same time, we should find novel molecular markers that can predict the efficacy of chemoradiotherapy. Only rational choice of "watch and wait" strategy will allow more patients with rectal cancer to benefit from chemoradiotherapy.

[Transition of treatment strategy for locally advanced rectal cancer towards "watch and wait"].

Therapeutic goal for locally advance rectal cancer (LARC) patients includes long-term survival and function preservation of pelvic organs. During the recent two decades, treatment strategy for LARC is gradually shifing to minimally invasive surgery, even avoiding a major surgery. "Watch and wait (W&W)" strategy is effective in dramatically decreasing surgical trauma and significantly improving preservation of defecation, urination and sexual function. Total neoadjuvant therapy (TNT) shifts all or part of adjuvant chemotherapy to the neoadjuvant phase and has showed obvious advantage in tumor shrinkage and complete clinical response (cCR) achievement. This article will summarize the transition of treatment strategy of LARC towards W&W from standard treatment. After more than ten years of development, both NCCN and ESMO guidelines recommend stratified neoadjuvant treatment considerations based on distinct risk classifications and especially suggest TNT for LARC patients with advanced diseases, which affirms the value of TNT in tumor shrinkage. Although accumulating data show that pelvic control and organ preservation using W&W strategy after cCR is equal or non-inferior to standard surgery, impact on long-term survival still needs prospective randomized controlled study; no consensus has been achieved for the detail of the W&W strategy. Thus W&W strategy is suggested to applied in hospitals specialized in the treatment of rectal cancer within the framework of multiple disciplinary treatment. In view of special medical conditions of our country, we still need to accumulate more experience and data of W&W strategy for rectal cancer patients with appeals for sphincter preservation and actively participate in international researches.

[Controversies and progress in adjuvant chemotherapy for patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy].

Colorectal cancer is one of the most common malignant tumors worldwide. Surgical resection is the most important and decisive method in the treatment of rectal cancer. Total mesorectal excision (TME) has greatly reduced the local recurrence rate of middle and low rectal cancer. However, local recurrence and distant metastasis remain the leading cause of death in patients with rectal cancer. 5-fluorouracil (5-FU)-based neoadjuvant chemoradiotherapy has been widely accepted in locally advanced rectal cancer and was recommended by various clinical practice guidelines as the standard treatment option. Tumors often achieve satisfactory reduced stage after neoadjuvant radiotherapy, and some patients even achieve pathological complete regression, which brings much controversies to the choice of adjuvant chemotherapy. This article intends to introduce evidence-based evidences for adjuvant chemotherapy for rectal cancer, impact of current neoadjuvant models on choice of adjuvant chemotherapy strategies, controversies and considerations for adjuvant chemotherapy in the context of neoadjuvant radiotherapy.

[Analysis on efficacy and safety of total neoadjuvant therapy in patients with locally advanced rectal cancer with high risk factors].

Objective: To evaluate the safety and preliminary efficacy of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer (LARC) with high risk factors. Methods: Data of 101 patients who were diagnosed with stage II-III rectal cancer with high risk factors and received TNT between March 2015 and January 2018 at West China Hospital of Sichuan University were analyzed retrospectively. Inclusion criteria: (1) patients were diagnosed with stage II-III rectal cancer by high-resolution MRI combined with CT and endorectal ultrasound; (2) at least one high risk factor: cT4a, cT4b, cN2, EMVI+, CRM+ and lateral lymph node+; (3) distance from tumor to anal verge was within 15 cm; (4) Eastern Collaborative Oncology Group (ECOG) performance status score was 0-1; bone marrow function, liver function and kidney function were suitable for chemoradiotherapy; (5) patients were treated with TNT strategy; (6) the follow-up data and postoperative pathological data were complete. Patients with previous rectal cancer surgery (except prophylactic colostomy), pelvic radiotherapy, and systemic chemotherapy, those with distant metastases, those without neoadjuvant radiotherapy, those receiving less than 4 cycles of neoadjuvant chemotherapy were excluded. The regimen of TNT: 3 cycles of induction CAPOX (oxaliplatin plus capecitabine) were followed by pelvic radiotherapy and concurrent CAPOX, then 3 cycles of consolidation CAPOX were delivered after radiotherapy. Total mesorectal resection (TME) or watch-and-wait strategy was selected according to the therapeutic effect and patients' wishes. Short-term efficacy, including tumor regression grade (TRG), pathological complete response (pCR), clinical complete response (cCR), postoperative complications within 30 days of surgery, and adverse events (AE) to radiotherapy and chemotherapy (measured using CTCAE 4.0) was analyzed. Results: The 101 patients included 68 males (67.3%) and 33 females (32.7%) with a median age of 54 years. The proportion of patients with cT4a, cT4b, cN2 and enlarged lateral lymph node was 13.9%, 29.7%, 56.4% and 43.6%, respectively. The mean cycle of neoadjuvant chemotherapy was 6.0±1.3. Seventy-five patients (74.3%) received at least 6 cycles of neoadjuvant chemotherapy and 100 (99.0%) completed radiotherapy. The mean cycle of induction and consolidation chemotherapy was 2.0±0.9 and 2.8±1.0 respectively. Most common grade 3 AE was leucopenia (n=13, 12.9%) and thrombocytopenia (n=7, 6.9%). Grade 3 diarrhea and radiation dermatitis were observed in 5 cases (5.0%) respectively. Grade 3 anemia and rectal pain were observed in 4 cases (4.0%) respectively. And rectal mucositis was observed in 2 cases (2.0%). Most of the AE was observed during concurrent chemoradiotherapy. No grade 4 or higher AE was observed. After TNT, 32 patients (31.7%) achieved pCR or cCR, and 62 patients (60.4%) achieved partial response (PR). Only 2 patients (2.0%) developed distant metastasis after chemoradiotherapy, while the other patients did not show disease progression. Seven patients (6.9%) with cCR refused surgery and selected watch-and-wait, while 7 patients without cCR still refused surgery. The other 87 patients (86.1%) underwent TME successfully. The mean interval from the completion of chemoradiotherapy to surgery was (20.1±8.5) weeks. The R0 resection rate was 97.7% (85/87).The morbidity of surgical complication was 16.1% (14/87), including pelvic infection or abscess in 6 cases (6.9%), anastomotic leakage in 3 (3.4%), hemorrhage in 2 (2.3%), and gastrointestinal dysfunction in 3 (3.4%). Pathological findings revealed that 24 cases (27.6%) had TRG 0, 20 (23.0%) had TRG 1, 30 (34.5%) TRG 2, and 13 (14.9%) TRG 3. Conclusion: TNT is safe and has good short-term efficacy for locally advanced rectal cancer patients with high risk factors.

The significance of lymph node yield in rectal cancer after neoadjuvant chemotherapy / 中华胃肠外科杂志

Neoadjuvant therapy has become an indispensable part of the treatment in locally advanced mild-low rectal cancer. Neoadjuvant therapy can cause the regression of the tumor body as well as drainage lymph nodes, which may influence the size, number, and metastatic status of the lymph nodes. In clinical practice, the total number of lymph nodes detected in rectal cancer treated with neoadjuvant therapy were significantly decreased, making it difficult to meet the standard of the NCCN guideline that at least 12 regional lymph nodes should be harvested. The optimal detection of yielded lymph nodes in rectal cancer is essential for accurate staging, response assessment, and adjuvant treatment decision. The lymph node diameter is significantly reduced after neoadjuvant therapy in locally advanced rectal cancer. In general, the number of detected lymph nodes is significantly reduced without additional pathological examination. The detected lymph nodes would increase by deliberate pathological examination, improvement of the detection method, or using a lymph node tracer. However, whether the number of detected lymph nodes is still needed to meet the requirements of the NCCN guideline, and the relationship between the number of detected lymph nodes and the prognosis are still controversial. At present, the number of negative lymph nodes, LNR, LODDS, etc. can be also used to predict prognosis in addition to ypN staging. For patients with ypN0 and ypN+ stage, different evaluation methods can be selected. For patients with ypN0, the number of detected lymph nodes still has important clinical significance for the prognosis and treatment decision. This article will introduce the related issues, and provide more evidence-based diagnosis and treatment practice.

Controversies and progress in adjuvant chemotherapy for patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy / 中华胃肠外科杂志

Colorectal cancer is one of the most common malignant tumors worldwide. Surgical resection is the most important and decisive method in the treatment of rectal cancer. Total mesorectal excision (TME) has greatly reduced the local recurrence rate of middle and low rectal cancer. However, local recurrence and distant metastasis remain the leading cause of death in patients with rectal cancer. 5-fluorouracil (5-FU)-based neoadjuvant chemoradiotherapy has been widely accepted in locally advanced rectal cancer and was recommended by various clinical practice guidelines as the standard treatment option. Tumors often achieve satisfactory reduced stage after neoadjuvant radiotherapy, and some patients even achieve pathological complete regression, which brings much controversies to the choice of adjuvant chemotherapy. This article intends to introduce evidence-based evidences for adjuvant chemotherapy for rectal cancer, impact of current neoadjuvant models on choice of adjuvant chemotherapy strategies, controversies and considerations for adjuvant chemotherapy in the context of neoadjuvant radiotherapy.

Transition of treatment strategy for locally advanced rectal cancer towards "watch and wait" / 中华胃肠外科杂志

Therapeutic goal for locally advance rectal cancer (LARC) patients includes long-term survival and function preservation of pelvic organs. During the recent two decades, treatment strategy for LARC is gradually shifing to minimally invasive surgery, even avoiding a major surgery. "Watch and wait (W&W)" strategy is effective in dramatically decreasing surgical trauma and significantly improving preservation of defecation, urination and sexual function. Total neoadjuvant therapy (TNT) shifts all or part of adjuvant chemotherapy to the neoadjuvant phase and has showed obvious advantage in tumor shrinkage and complete clinical response (cCR) achievement. This article will summarize the transition of treatment strategy of LARC towards W&W from standard treatment. After more than ten years of development, both NCCN and ESMO guidelines recommend stratified neoadjuvant treatment considerations based on distinct risk classifications and especially suggest TNT for LARC patients with advanced diseases, which affirms the value of TNT in tumor shrinkage. Although accumulating data show that pelvic control and organ preservation using W&W strategy after cCR is equal or non-inferior to standard surgery, impact on long-term survival still needs prospective randomized controlled study; no consensus has been achieved for the detail of the W&W strategy. Thus W&W strategy is suggested to applied in hospitals specialized in the treatment of rectal cancer within the framework of multiple disciplinary treatment. In view of special medical conditions of our country, we still need to accumulate more experience and data of W&W strategy for rectal cancer patients with appeals for sphincter preservation and actively participate in international researches.

Rational evaluation of the complete response after neoadjuvant therapy in locally advanced mid-low rectal cancer: the pros and cons of "watch and wait" strategy / 中华胃肠外科杂志

Neoadjuvant chemoradiotherapy plus total mesorectal excision (TME) is the standard care for locally advanced middle-low rectal cancer. Some patients could benefit from neoadjuvant chemoradiotherapy to achieve clinical complete response (cCR). Therefore, in recent years, for patients with cCR after neoadjuvant therapy, the "watch and wait" strategy has been widely recommended by their doctors to let them enter "waiting period" without surgery, so that the quality of life is improved. However, the "watch and wait" strategy also has many practical problems that have not been resolved. Firstly, the diagnostic criteria for cCR and pathologic complete response (pCR) are not uniform and different significantly. Secondly, some cCR patients have found tumor regrowth and subsequently underwent salvage surgery during the "watch and wait" period. Thirdly, there is no clinical consensus on the adjuvant therapy for patients during the "watch and wait" period. Fourthly, the role of surgery in patients with cCR is controversial. Finally, we need to accumulate more clinical evidence to confirm whether the "watch and wait" strategy can be selected immediately after achieving cCR for rectal cancer. At the same time, we should find novel molecular markers that can predict the efficacy of chemoradiotherapy. Only rational choice of "watch and wait" strategy will allow more patients with rectal cancer to benefit from chemoradiotherapy.